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UNIVERSITY OF SURREY LIBRARY
Unis
MICROWAVE ASSISTED ORGANIC SYNTHESIS
A thesis subm itted in part fulfilment o f the degi ee o f doctor o f philosophy to the
University o f Suirey
By
BIMBISARDESAI (BSc, MSc)
Chemistry
U niversity o f Siuxey
Guildford, Smxey
GU2 7XH
D ECEM BER 2002
ProQuest Number: 10130396
All rights reserved
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ABSTRACT
The area o f chemical reseai'ch and synthesis increasingly recognises the need for
im proved teclmologies and methods, w hich involves chemical processes w ith less
energy consumption, tim e savings, reduction and/or m inim isation o f waste, simple
processes and an overall clean production. M icrowave heating has been exploited in
a variety o f disciplines for m any useful applications and organic synthesis is an area,
w hich has benefited significantly over the past decade.
The present study investigates organic reactions accelerated under microwave
in adiations. In particulai", the study involves use o f recyclable Polym er an d Inorganic
Solid Supported Reagents for application in transfer hydrogenation. Reductions o f
electron deficient alkenes have been studied using polym er and inorganic solid
suppoifed formates. M icrowave irradiations have been used to study transfer
hydrogenations in presence o f W ilkinson’s catalyst [RliCl(PPli3)3]. The application o f
the P olym er Supported R eagents {PSR) has been investigated for studying transfer
hydrogenation
in
A-benzyl
deprotections.
M icrowave
assisted
synthesis
of
foiinam ides from prim ary and secondary amines have been studied using supported
formates. M icrowave in-adiations have also been applied in studying heterocycle
synthesis by cycloaddition o f nitrones w ith Pt (II) and Pd(II) bound organonitriles.
The study broadly demonsfrates a m eans o f simplifying reaction procedures and
purification along w ith reduction in waste o f reagents and release o f toxic residues.
M ore im portantly, use o f m icrowave irradiations has been used to substantially
im prove the reaction yields and reduce reaction times, lower energy consum ption and
solvent volumes. The use o f this m ethodology significantly benefits in the
developm ent o f ''Green C hem istiy” and autom ated systems for chemical synthesis in
m any indushral sectors.
Bim bisar Desai
D ecem ber 2002
CONTENTS
Abstract
ii
List o f contents
iii
Acknowledgements
vi
Publications
vii
List o f abbreviations
viii
Chapter 1 INTRO DUCTIO N AND LITERATURE SURVEY
1.0
Introduction
01
1.1
N on-Classical or Exti'eme Tecliniques
01
1.2
Introduction to M icrowaves
03
1.3
M icrowave Effect
06
1.4
The Apparatus
08
1.5
M icrowave assisted Organic Synthesis using Solvents or under
W et Conditions
10
Organic Synthesis under D ry or Solvent Free Conditions
23
1.8
Chapter 2 AIM S AND OBJECTIVES
2.0
Outline
33
2.1
Hydrogenation
33
2.2
Catalytic Transfer Hydrogenation (CTH)
33
2.3
Aims and Objectives
35
Chapter 3 DEVELO PM ENT OF SUPPORTED REAGENTS
3.0
hitroduction to Supported Reagent C hem ishy
37
3.1
Types o f Supported Reagents
37
3.2
Development o f N ovel Supported Reagents as H ydrogen D onors
41
Chapter 4 SUPPORTED REAGENTS FO R HYDRO GENATION OF
ALKENES AND SYNTHESIS OF FORM AM IDES
4.0
Outline
51
4.1
Hydrogen Donors for Reduction or Transfer Hydrogenations
51
4.2
Heterogeneous or H om ogeneous Catalysts for Transfer H ydrogenation
56
4.3
M icrowave assisted Hydrogenation o f Electron-Deficient A lkenes using
Polym er Supported Hydrogen D onor (Aminometliylpolystyrene)
61
Tliennal and M icrowave assisted Hydrogenation o f E lectron-D eficient
Alkenes using a Polym er Supported Hydrogen Donor
(Amberlite® IRA 938 (anionic))
65
A ttem pted M icrowave assisted A-Debenzylation using Am berlite
Supported Form ate Leading to A-Form ylation
74
Formarnide Synthesis using A mberlite Supported Form ate
as Form ylating Agent
76
4.7
A lum ina Supported Form ate for Hydrogenation o f A lkenes
83
4.8
Form amide Synthesis using Ahm iina Supported Form ate as
Form ylating A gent
90
Attem pted M icrowave assisted Hydr ogenation o f A lkenes using
PEG Derivatised Hydrogen D onor
97
4.4
4.5
4.6
4.9
Chapter 5 REDUCTION OF KETONES, OXIDATIO NO F ALCOH OLS
AND CYCLOADDITONS ON M ETAL BOUND ORGANONITRILES
5.0
Reduction o f Ketones
98
5.1
Attem pted M icrowave assisted Reduction o f Ketones
100
5.2
Supported Reagents on Clay
103
5.3
Attem pted M icrowave assisted O xidation o f alcohol using P d(0 A c)2
and M olecular Oxygen
105
Pd(II) H ydrotalcite for Oxidation o f Alcohol under M icrowave
Conditions
106
5.5
Cycloadditions under M icrow ave Conditions - Backgrormd
108
5.6
Cycloaddition o f N itrones to Platinum Bound Organonitriles
112
5.4
6.0
Conclusions and Future W ork
124
Chapter 6 EXPERIM ENTAL
127
REFERENCES
159
A CIiNO W LED G EM ENTS
I w ould like to express m y gratitude to m y supeiwisors Dr. Tim othy N. Dairies and Dr.
Gabriele W agner firstly for giving m e an opportunity to w ork w ith them and also for
giving an invaluable guidance and support. I am thankful to Prof. P. G. Saimnes and
Prof. R. C. T. Slade (HOD) for their support and co-operation. I am thankflil to
Personal Chemistry for fimding this project and for the provision o f the Smithcreator®
and Labwell AB for the provision o f m icrow ell 10. I also extend m y thanks to
Jolmson Matthey, U K for the loan o f catalysts.
I express m y appreciation to the technical staff at the Chemistry departm ent for their
assistance and support in m y work.
M y special thanlcs to m y parents who have been m y eternal inspiration and courage. I
deeply thank m y U ncle (Fuaji), A unty (Bafoi) and cousins at R eading for their love,
caring and guidance. I also acloiowledge m y friends and colleagues for making m y
experience at SuiTey a wonderhil one.
Publications
1. Thermal and microwave-assisted hydrogenation o f electron-deficient alkenes using a
polym er supported hydrogen donor, B im bisar Desai and Tim othy N. Dairies,
Tetrahedron L e tt, 2001, 42, 5963.
2. Alum ina-supported fo rm a te fo r the hydrogenation o f alkenes, T im othy N. Danks and
Bimbisar-Desai, Green Chemistiy, 2002, 4, 179.
3. Cycloaddition o f N itrones to Free and Co-ordinated Cinnamonitrile: Effect o f M etal
Co-ordination and M icrowave Irradiation on the Selectivity o f the Reaction, Bimbisar
Desai, Tim othy N. Danks and Gabriele W agner, 2002, submitted.
V II
L ist o f Abbreviations
MW
M icrowave
NMR
N uclear m agnetic resonance
ppm
parts per m illion
s
singlet
t
triplet
m
multiplet
br
broad
TLC
T hin layer chrom atography
IR
hiEared
M. P.
M elting point
D CM
Dichloroniethane
M eOH
M ethanol
DMF
Dimethyl formamide
DM SO
Dimethyl sulphoxide
MeCN
A cetonitrile
PhCN
Benzonitrile
THF
T etralrydro finan
Eton
Ethanol
Pr'OH
Isoproparrol
Pr"OH
n-Propanol
PEG
Polyethylene glycol
TM EDA
Tetr-arnethyl ethylene diam ine
PCC
Pyridiniurn chlorochroniate
PTSA
jrara-T oluene sulphonic acid
dppp
1,3-diphenyl phosphirio propane
BINAP
Binaphthyl
M S3A
M olecular sieves
NM F
N - methylformam ide
NM M
N - methylm orpholine
DuPHOS
2,5 -Dialkylphospholano benzene
MOM
M ethoxymethyl
BOM
B enzyloxyniethyl
Bn
Benzyl
Vlll
Chapter 1
Introduction and Literature Survey
INDEX
C HAPTER 1
INTRO DUCTIO N AND LITERATURE SURVEY
1.0 INTRO DUCTIO N
01
1.1 N on-Classical or Extrem e Techniques
01
1.1.1 H igh Pressure
01
1.1.2 Supercritical fluids
02
1.1.3 Ultrasound
02
1.2 Introduction to M icrowaves
03
1.2.1 M icrowaves - D efinition
03
1.2.2 M icrowave H eating
04
1.2.3 H eating by Dielectric Polarisation
04
1.2.4 H eating by Conduction Losses
05
1.3 M icrowave E ffect
06
1.3.1 Tbeiinal Effects
06
1.3.2 Specific Effects
07
1.3.3 Solvent Effects
07
1.4 The Apparatus
08
1.4.1 M ultim ode Reactor
08
1.4.2 M onom ode Reactor
09
1.5 Organic Synthesis using Solvents or under W et Conditions
10
1.5.1 Pericyclic reactions
10
1.5.2 Cycloadditions
11
1.5.3 Cyclisations
12
1.5.4 Aromatic and Nucleophilic Substitution Reactions
13
1.5.5 Condensations
15
1.5.6 Alkylations
16
1.5.7 Acylations
18
1.5.8 A lkene Fimctionalisation
18
1.5.9 Estérification and ^ra«5-esterification
18
1.6.0 ReaiTangements and Isomérisations
19
1.6.1 Organometallic Reactions
19
1.6.2 Oxidations
20
1.6.3 Reductions
21
1.6.4 Miscellaneous
22
1.7 Organic Synthesis under Dry or Solvent Free Conditions
23
1.7.1 Protection and Deprotections
23
1.7.2 Diels-A lder Cycloaddition
24
1.7.3 Nucleophilic and Aromatic Substitutions
25
1.7.4 Alkylations and Acylations
25
1.7.5 Condensations
27
1.7.6 ReaiTangements
27
1.7.7 Oxidations
28
1.7.8 Reductions
29
1.7.9 M iscellaneous
29
1.8.0
M icrowave assisted organic synthesis using polym er supported reagents
30
Chapter 1
1.0 INTRO DUCTIO N
111 a standard laboratory practice, synthetic reactions are still earned out in glassware and
heating processes requiring oil baths, heating mantles, and hotplates. However, the past
few decades have significantly contributed to the advancem ent o f practical organic
chemistry w ith introduction o f novel synthetic strategies, m ethods' and analytical
teclmiques.^ Research activities focussed on the application o f innovative techniques for
chemical transfonnations at a fimdamental and applied level have gained priority. These
teclmiques aim to achieve chemical synthesis w hich are efficient, selective, time saving
and involve easier processing conditions.
This chapter discusses a b rie f outlook o f significant teclmiques o f a non-conventional
natm e exploited in chemical synthesis. Following w hich is a discussion on the definition
and the elem entary concepts o f one such teclmique, m icrowaves, the use o f w hich is
im portant in organic synthesis.
1.1 Non-Classical or Extrem e Techniques
Recent activities in chemical process developm ent and m anagem ent have stimulated the
exploitation o f different methods, hi particular, non-classical or extreme teclmiques like
high pressm e, supercritical fluids, ulfiasoimd, microwaves and pulse-plasm a discharges
have cm cially contributed in the developm ent o f chemical synthesis w ith lower energy
consumption, cleaner and m ore selective chemical transfonnations (see Figure 1.1). The
m ost advantageous features involving these teclmiques m ay be highlighted as under.
Reactants
High Pressure/temperature
Supercritical Fluids
Ionic liquid
-------------------------------------*Pulse-plasma discharge
Ultrasound
Microwaves
Microreactors
^
,
Products
Figure 1.1 Chemical transformation under non-classical or extreme conditions
1.1.1
High Pressure
The advantages o f high pressm e application have been know n fiom the pioneering
studies on an effective com se o f the D iel-Alder reaction
in synthesis o f important
heterocyclic systems. The rates and equilibriimr o f m any chemical reactions is
1
Chapter 1
influenced by pressure. The application o f high pressure offers the possibility o f
carrying reactions imder m ild conditions usually preventing adverse side effects,
reducing reaction times and giving enhanced yields. H igh pressure, apart h orn the rateconstant also influences the regio- and stereoselectivity o f organic reactions w ith good
y i e l d s . I n some cases, it also allows compounds to be obtained that are usually
therm odynam ically less favoured at norm al pressure. H igh pressure conditions also
enliance solubilities.^^ Generally, high pressure conditions in chemical transformations
leads to a more effective conhol over chemical synthesis, product selectivity, and
chemical reactivity. However, high pressm e conditions usually involve the use o f
specific equipments like autoclaves and m any safety aspects have to be imdertaken
during the experiments w hich are not always possible to implement.
1.1.2 Supercritical Fluids
Supercritical fluids (SCF) form an im portant ar'ca o f fimdamental research with
applications leading to new separation teclmologies like extraction o f highly polluting
organic contaminants from waste w a t e r s , m i l d e r reaction conditions and improved
transport phenomena, high turnover numbers in heterogeneous catalytic systems'*'^ and
im proved solubilities.'*'’ Studies on the application o f SCF in organic synthesis have
been carried on the D iels-A lder reaction,'*® cycloaddition reaction'*’^ and on a
heterogeneously
catalysed
gas-phase
reaction,
viz.
Fischer-Tropsch
synthesis'*®
exhibiting a faster heat transport, m ore efficient mass transfer, in situ extraction o f high
m olecular weight products from the pores o f the catalyst and a high olefin selectivity in
the supercritical phase'**’"-’ Use o f supercritical fluids is not always favourable because,
only certain liqrrids can reach their supercritical point and also the substrate solubility is
specific w ith certain fluids.
1.1.3 Ultrasound
“Sonochernistry” along w ith its broad spread applications defines the application o f
ultrasoimd - the energies generated by acoustic activation to accelerate chemical
transformations. M ost studies take place in the frequency range o f 20-100 kHz and
reqirire the presence o f a liquid to transm it its power. Ulfrasound has been exploited in
chemical synthesis offering a unique m ethod o f activating and accelerating chemical
reactions w ith enlianced rates^'“ and product yields in solid phase organic reactions.
Chapter 1
Applications in organic fine synthesis are numerous, especially in reactions via free
radicals and polymerisation^'’, inducing degradation o f p o ly m ers/'’ This teclmique is
particularly beneficial in the synthesis o f organom etallic intermediates^'' and for
im proving m ost types o f catalysis including phase transfer,^® solid supported types^^
and enzymes/® hr addition, it has foimd effective application in enliancing the catalytic
activity o f metal p a rtic le s/'’’’ A nother very im portant dom ain lies in the use o f
ultrasound for the destruction o f organic m aterial and toxic pollutants in indusfrial
wastewater, w hich resist to other treatments/^ Ultrasound is sensitive only for selected
organic tiansfbrm ations and its application in m any other reaction schemes does not
show any useful effects.
1,2 Introduction to M icrowaves
A m ongst these synthetic teclmiques o f a non-conventional nature,^"'’ m icrowaves,
com m only employed in the domestic heating o f food stuffs, have been recognised by
scientists as potentially useful in various other disciplines.’’'^ hrterestingly, there has also
been a considerable expansion in the use o f microw ave activation for organic synthesis,'^
following some m dim entary illustrations''' o f organic reactions accelerated in domestic
ovens.
This chapter discusses the definition o f microwaves, principles o f m icrow ave heating,
m icrowave effect, the m icrowave reactors/apparatuses and solvents.
1.2.1 M icrowaves - Definition
y-ray
W avelength (m)
X-ray UV
Visible
3x1 O '* 3x10 " 3x10 '^ 3x10 **
Infrared M icrowaves
3x1 Q-'"’
3x10-’
Radiowaves
3x10»
Figure 1.2 Electromagnetic spectrum.
Microwaves are electromagnetic radiations w ith wavelengths ranging from 1cm to Im ,
coiTCSponding to fr equencies betw een 30 GHz to 300 M Hz.'^ The m icrowave region o f
the electrom agnetic specfrum (see Figure 1.2) includes some w avelengths in the 1-25
cm range w hich have been extensively employed for RAD AR and telecoimnmiications.
In order to avoid any disruption in these activities, the international convention
3
Chapter 1
allocated in the following frequencies for indusfrial, domestic and scientific microwave
heating and drying: 915 ± 25 M Hz, 2450 ± 13 MHz, 5800 ± 75 M Hz, 2215 ± 125
MHz.'® The equipm ent operating at a frequency o f 2450 M H z corresponding to a
wavelength o f 12.2 cm is m ost comm only used for heating applications.
1.2.2 M icrowave Heating
M ost organic reactions have heen heated using conventional heat transfer equipment
like oil haths, sand baths and heating jackets. The energy transfer in these teclmiques is
rather slow w ith a poor heat transfer prim aiily achieved by conduction or by convection
involving successive heat transm ission tluough layers from the surface to the cenfr'e.
This m ay develop a tem perature gi'adient w ithin the sam ple giving a major
inconvenience o f local overheating and possible decomposition o f the product, reagent
and the substrate. The release o f heat is instantaneous, so that therm al phenom ena o f
conduction, convection and radiation play only a secondary role in temperature
equilibrium.
1.2.3 H eating by Dielectric Polarisation
= D ip o la r m olecule
Figure 1.3 Dipolar rotation under the influence of electromagnetic radiation
H eating by m icrowave energy clearly differs from the classical way, and the dissipation
o f microw ave energy into heat energy is m ainly achieved b y dipole rotation or ionic
conduction '®’'® (see Figure 1.3). A dipolar m olecule w hen subjected to an elecfric field
rotates to align itself w ith the incident field. A t the m olecular level, polarisation by
dipole aligrmient occurs at these higher m icrowave fr equencies and forms the basis o f
dielectric heating. Energy dissipation is ohseiwed w hen the m olecule attempts to realign
w ith any changes in the incident field and this continuous, reorientation provides an
agitation in the molecule generating heat.
Chapter 1
Current /
5y /
Ixsin 5
Electi'ic field, E
A
B
Figure 1.4 (A) Phase displacement when energy is converted to heat. (B) The relationship
between e’ and e” .
The ability o f a m aterial to convert electromagnetic energy into heat energy at a given
fi-equency and tem perature is calculated using the equation o f the loss angle tanô,
e” / 6’ = T a n §
[Eqn. 1.2.1]
w here 5 is the dissipation factor. Dielectric loss, e ” , measures the efficiency w ith which
heat is generated from electromagnetic radiation and the dielectiic constant, C ,
describes the ability o f the molecule to be polarised. In the gaseous state the molecules
are disposed far apart and their alignment w ith the applied field is therefore rapid.
However, in liquids, due to presence o f other molecules the ability to align w ith the
applied field varies w ith the different frequencies and w ith the viscosity o f the liquid.
H eating by interfacial polarisation, also loiown as the M ax w ell-W agner effect, occurs
w hen the conducting particles are in contact w ith a non-conducting m edium, i.e. in
heterogeneous conditions, and the dieleehic loss relates to the build up o f charges
between the interfaces. In general, compounds w ith high dieleehic constants tend to
heat readily while those w ith no net dipole m om ent and highly ordered crystalline
materials are poorly absorbing.
1.2.4 H eating by Conduction Losses
= Free ions
Figure 1.5 Energy dissipation by ionic conduction
Chapter 1
U nder the second m ajor influence o f electiic field, energy dissipation by ionic conduction
occurs by the migi'ation o f dissolved ions w ith the incident oscillating electric field (see
Figure 1.5). A solution containing flee ions in the sample w ill m ove tln'ough the solution
mider the influence o f the applied field. This will result in the dissipation o f energy due to
an increased collision rate converting kinetic energy into heat energy. H eat generation is
due to frictional losses, depending on the size, charge and the conductivity o f the ions and
their interaction w ith the solvent.
1.3 M icrowave Effect
M icrowave activation as a non-classical energy soruce has been grow ing as a propitious
technology in organic chem ishy. M any publications'’’^^ describe im portant accelerations
over a w ide range o f organic reactions associated w ith large reductions in reaction times,
enliancements in conversions and, sometimes, in selectivity, proving quite advantageous
in the eco-friendly approach. Num erous reports, based on inaccurate comparisons with
classical conditions, do not allow for m aking conclusions concerning the microwave
effects and thus discussion on the nature o f the effects o f microw aves on organic
reactions follows a significant level o f conhoversy."*’’^ That the acceleration o f reactions
by m icrowave inadiation resulting fi'oin m aterial-wave interactions leads to both thermal
effects and specific effects, possibly explains the microwave effect.
1.3.1 Therm al Effects
The interaction o f electrom agnetic field and dipolar m olecules results in dipolar
polarisation, giving rise to thermal effects (dielectric heating). These effects originate in
the process o f energy dissipation into heat due to the agitation and intermolecular- fiictiorr
o f molecules. Essentially, dipolar changes arise from changes in m olecular orientations in
response to the alterations o f the incident electric field. Energy dissipation in the core o f
the materials arising fiom therm al effects gives a m uch m ore even distribrrtion in
tem perature whereas under classical conditiorrs, the tem perature distributiorr and
equilibration by conduction and corrvection is compar'atively less regirlar. In cases o f
variety o f m ineral oxides or metallic species,^^ possessing fi'ee conduction elechons, the
phenom ena o f charge space polarisation’"' rmder the influerrce o f m icrow ave fi-equency
range (u = 2450 M Hz), conhibutes to heating.
Chapter 1
1.3.2 Specific Effects
These m ainly originate by (a) non-pm-ely tliem ial effects and (b) therm al effect involving
the developm ent o f “/zot spots”.
The non-pm ely therm al effect (not from dielectiic heating) m ay be understood to have
several origins. A rationale to these effects m ay be given by considering the AiThenius
k = A exp(-A G ^/R T).............. [Eqn. 1.3.1]
A n increase in the pre-exponential factor ri is an indicative o f the probability o f
m olecular impacts. Typically, in a reaction, the collision efficiency o f polar molecules
can be effectively explained by their mutual orientation, depending on the vibration
fr-equency o f the atoms at the reaction interface. The influence o f m icrow ave field at the
reaction interface provides a plausible explanation to this effect.
Considering the equation,
AG''= AH^ - TAS''............[Eqn. 1.3.2]
hr a reaction controlled rmder m icrowave conditions; the m agnitude o f the term -TAS^
therein m ay be expected to increase being a m ore ordered system due to dipolar
polarisation as compared to classical heating. As an event, decrease in the activation
energy AG*^, contributes to the obseiwed non-pinely therm al effect. Sometimes, the
developm ent o f localised microscopic high tem peratrue points,^’’^® hot spots, generated
by dielectric relaxation on a m olecular scale m ay be able to explain the origin o f
m icrowave activation.^^’^*^
1.3.3 Solvent Effects
In case o f liquid substi'ates or solvents, only polar' molecules absorb m icrowaves and non­
polar molecules are not influenced by microw ave dielectric loss. In this context, higher
boiling point values o f solvents could be achieved w hen subm itted to microwave
m adiations as compared to conventional heating. The relaxation tim e ( t) o f molecules
depends on tem perature and tends to decrease as the ternperatiu'e is increased. Both the
dielectric constant (e’) and the dielectric loss factor (e” ) are dependent on r. In effect, the
7
Chapter 1
ability o f a solvent to dissipate microwave energy into heat energy will be dependent also
on the temperature apart from the incident microwave frequency. The heating rates o f
solvents with high relaxation times will increase during microwave dielectric heating
most probably due to the limited formation o f ‘boiling nuclei’, described as a
Superheating effect and may result in the boiling points o f the solvents to rise by up to
26°C above their conventional values.^^'^^ This phenomenon is believed to be responsible
for many rate accelerations involved in solution phase reactions under microwave
conditions at atmospheric pressure.^^ Typically, under microwave irradiations, materials
with high dielectric constants tend to heat readily while those with no net dipole moment
and highly ordered crystalline materials absorb poorly. In context, polar solvents such as
water, dichloromethane, acetone, ethyl acetate, methanol, dimethyl formamide, dimethyl
sulphoxide etc. are heated readily whereas non-polar solvents such as hexane, toluene,
carbon tetrachloride etc. do not heat. Ionic liquids also account for dipolar aprotic
solvents bearing excellent dielectric properties. These have low vapour pressure and can
absorb microwave irradiation quite efficiently, besides, they dissolve much appreciably in
a wide range of organic solvents. Hence they are also much suited to microwave assisted
organic synthesis. 34-35
1.4 T he A pparatus
There are basically two main types o f microwave apparatuses useful in the study of
laboratory scale organic synthesis. These may be classified as 1) multimode reactors and
2) monomode reactors.
1.4.1
M ultim ode R eactor
M AGNETRON
-,v,
Figure 1.6 Multimode reactor (Domestic microwave oven) and heterogeneous microwave
distribution in the multimode reactor cavity.
Chapter 1
Most o f the introductory attempts to study laboratory scale organic synthesis under
microwave conditions involved the use o f the domestic microwave ovens which is a
multimode reactor (see Figure 1.6). Clearly, these are not quite useful in chemistry as
they present several drawbacks. The distribution o f the electric field inside the cavity is
heterogeneous, resulting from multiple reflections on the walls. The temperature cannot
be measured accurately. In most cases, the power is not tuneable and the sample is
subjected to maximum power levels for varying periods o f time. Consequently, the
reproducibility of the experiments is poor especially when dealing with small amounts of
products.
They are not compatible with corrosive and inflammable compounds and
reaction conditions involving high pressure.
1.4.2 M onom ode R eactor
Cap
with
Rubber
Septum
\
V
/
Magnetron
Wave Guide
Cavity
Pyrex glass
Reaction tu b es
Figure 1.7 Reaction tubes and schematic for monomode reactor
Labwell AB Monomode reactor
Smith Creator® (Personal chemistry)
Figure 1.8 Monomode reactors
Chapter 1
The di'awbacks in using domestic ovens for laboratory scale organic synthesis led to the
developm ent o f m onom ode reactor (see Figures 1.7 & 1.8). hr this case, the
electromagnetic radiations are focussed onto the sample cavity through an accurately
dim ensioned wave-guide. This ensures a hom ogeneous dishibution o f the elechic field.
Also, there is a m uch more control on the pow er setting and a reproducible energy can be
delivered. Some o f these applicators are also equipped to m easure tem perature and
pressure developing in the reaction m ixtine. Typically, reactions using these applicators
are done in a Pyrex® glass tube (see Figure 1.4.2) w ith a screw cap equipped w ith a
pressm e release septum to allow rem oval o f any excess pressm e developed in the
reaction tube during hnadiation. Overall, m onom ode applicators are suitable in studying
sm all sample volumes o f synthetic chemistry.
1.5 M icrowave assisted Organic Synthesis nsing Solvents or under W et Conditions
M icrowave technology has heen very com m only exploited for domestic pmposes.
However, the application o f the rapid heating featm-e o f microw aves is not limited to the
kitchen and it has been recognised considerably in a variety o f disciplines and for many
other useful pm poses. These include sample preparation for analysis,^'^ waste treatment,*
polym er
technology,^
drug
release/targeting, ^^
ceramics,^ ^
alkane
and
acid
decomposition,’'^’^^®’^^® digestion teclmiques’®’’^’’® etc. A pplication o f this teclmique to
inorganic and solid state synthesis has also shown significant advantages.
A mongst m any interesting applications o f m icrowave teclmology, organic synthesis is
an area w hich has developed rapidly. Several recent reviews**" have illustrated the
advances w ith m any different organic reactions and hansfonnations accom plished under
m icrowave conditions. This section attempts to give a b rie f oveiwiew o f some very
im portant reaction schemes achieved under m icrowave conditions.
1.5.1 Pericyclic Reactions
The very first highlights o f m icrowave assisted organic synthesis appeared in two
im portant contributions fiom Gedye, Smith and Westaway*’®and Giguere, M ajetich and
co-workers*”" The potential o f microwaves for accelerating organic reactions was
illustrated by dramatic reduction in reaction times in D iel-Alders, Claisen and ene
reactions (see Schemes 1-2).
10
Chapter 1
CO,M e
M eO.C
1
2
SC H E M E 1
Reagents and conditions: i) neat, dimethyl fumarate,/>-xylene; ii) MW, 10 minutes.
Ov
SC H EM E 2
Reagents and conditions: i) neat, NMF; ii) MW, 90 seconds.
1.5.2
Cycloadditions
M icrowaves have found applieation in stereoselective cycloaddition approaches to the
synthesis o f the taxoid skeleton by intram olecular Diels-Alder reaction in 30-40% yield^^“
(see Scheme 3).
M OM O'
M OMO
SC H E M E 3
Reagents and conditions: i) PhMe; ii) MW.
Ar
R = Me
SC H EM E 4
Reagents and conditions: i) neat, MW.
H
Chapter 1
Examples for microw ave induced 1,3-dipolar cycloaddition using nitrones showing 7080% yield o f the cycloaddition product have heen reported^^'^ (see Scheme 4).
1.5.3
Cyclisation Reactions
The application o f m icrowave technology has heen demonstrated to [3,3]-sigmatropic
reaiTangement involved in Fischer cyclisations.^®'^ (see Scheme 5)
NH
Ph
10
SC H E M E 5
Reagents and conditions: i)
MW.
M icrowaves have also heen used to im prove som e other types o f cyclisation reactions
like H antsch-1,4-dihydropyridine synthesis^®'' (see Scheme 6) w hich provided reduced
reaction times and im proved yields.
CO,Me
MeO,C.
M e'
Me
13
SC H E M E
6
Reagents and conditions: i) CH3COCH2C02Me; N H 4 O H / EtOH; ii) MW
HN
•CO,Et
C O ,Et
SC H EM E 7
Reagents and conditions: i) CO(NH2)2; NaOEt; EtOH; ii) MW.
Chapter 1
® .CO;Bn
OBn
+
'^ Y ^ p h
Ph
18
SC H E M E
8
Reagents and conditions: i) CH3CN, MW, 15 minutes.
Scheme 7 describes a cyclisation reaction to synthesise harbituric acid in high yields
under m icrowave conditions.^®® M icrowave assisted cyclisation has been achieved w ith
dramatic reduction in reaction times and im provem ent in yields as compared to the
conventional reflux conditions.®®® (see Scheme 8).
RNHj
+
19
20
^
R
R=
21
SC H E M E 9
Reagents and conditions: i) MW.
PyiToles have also been synthesised in 75-90% yields under m icrow ave inadiation using
amines and 1, 4-dicarhonyl compoimds®®^ (see Scheme 9).
1.5.4
Arom atic and Nucleophilic Substitution Reactions
M icrowave assisted Friedel-Crafts geim ylation o f benzene and toluene w ith enhanced
reaction yields have been reported®^“ (see Scheme 10).
H
GeCl,
,
o ,c ,
23
22
24
SC H E M E 10
Reagents and conditions: i) AICI3; MW.
13
Chapter 1
U nder m icrowave conditions, aromatic nucleophilic substitution o f aniline using 2,4diniti'ochlorobenzene using tetraethylene glycol as solvent has been achieved in up to
85% yields.^^^
NO
S
0 %N
NO;
27
26
SC H E M E 11
Reagents and conditions: i) tetiaethylene glycol, MW.
Another example o f aromatic nucleophilic substitution reports l,3,5-tiichloro-2,4,6triazine substitution using sodhun phenoxides under m icrowave conditions in 85-90%
yields.^^^ (see Scheme 12)
OAr
Cl
Ai— O-
Na+
+
^
1
------------------------ Y|
28
Y
ArO
29
OAr
30
SC H E M E 12
Reagents and conditions: i) MW
Some interesting halogénations o f carbohydrates have also been reported using
microwave conditions showing 25-95% yields^^*^ (see Scheme 13 and 14).
pH
^
H0„. \
X.
i
yO
OMe
"
R' and R" = H, Bn
^2 “ Cl, Hr, OH
SC H E M E 13
Reagents and conditions: i) PPha; KCl or KBr; CCI4 or (CCbBr);; ii) MW
14
Chapter 1
.R"
O
Bn
O
OMe
Bn
Bn
OMe
Bn
34
33
R' and R" = H, Bn
X | and Xg = Cl, Br, OR' or OR"
SCHEME 14
R eagents an d conditions: i) PP ha; K C l o r K B r; C C I 4 o r (C C l 2 B r) 2 ; ii) M W
1.5.5 Condensations
Microwave conditions have shown appreciably high yields in different types o f
condensation reactions including the Knoevenagel and A ldol reactions'*® (see Scheme 1517).
OHO
R"^
NO^
35
+
R'
36
R' = H, 4-OH, 1-Napthyl
R" = H
SCHEME 15
R eagents and conditions: i) NH4OAC; ii) M W
co,n
RCHO
R=Ph
SCHEME 16
R eagents an d conditions: i) NH4OAC; ii) M W
GO,H
SCHEME 17
R eagents an d conditions: i) K O A c , M W .
NO.
Chapter 1
Some interesting illustration on m icrowave assisted W ittig olefmations have also been
reported w ith high yields, (see Scheme
and
)
CN
45
S C H E M E 18
R eagents and conditions: i) P h a P - C H C N , P h M e ; ii) M W
EtO,C,
46
47
S C H E M E 19
Reagents and conditions: i) P h 2 P = C H C 0 2 E t; ii) M W .
1.5.6
Alkylations
C-Alkylation reaction o f M ichael type additions have heen reported under microwave
conditions w ith quantitative yields"^^® (see Scheme 20).
0
R'"
0
0
R""
48
^
'R"
"R"
49
O"
R = Me, Ph
R" = Me, OEt
R" = Me
R"" = H
R
50
S C H E M E 20
Reagents and conditions: i) EUCI 3 .6 H 2 O ; ii) M W .
M ichael type N-alkylations have also heen quite favourably achieved under microwave
conditions w ith alm ost quantitative yields in m any cases'*^'’ (see Scheme 21)
16
C h a p te r 1
O
R '"
^
R""
+
R"
51
R'"
V
Tl""
52
53
R'-R'" = Me, R"" = H
S C H E M E 21
R eagents and conditions: i) H ^O ; ii) M W .
Examples on m icrowave assisted 0-alkylatioii like éthérification/^'^ (see Scheme 22)
W illiam son’s reactioi/^’’(see Scheme 23) have been reported.
R
OH
-------------------^
54
R
"
R = Ph
O
R
55
S C H E M E 22
R eagents and conditions: i) R C H 2 B 1" ii) M W .
OH
OMe
56
57
S C H E M E 23
Reagents an d conditions: i) M e S 0 4 , N a O H , te tra e th y le n e g ly c o l; ii) M W .
Reports also describe m icrowave assisted thio-alkylation w ith very high yields"^^*^ (see
Scheme 24).
^ ^
HS
58
S C H E M E 24
Reagents an d conditions: i) B n B r, N a H , D M F ; ii) M W .
17
Chapter 1
1.5.7 Acylations
Synthesis o f phtlialiniides by N -acylation mider microwave conditions has been reported
in alm ost quantitative yields'^^ (see Scheme 25).
Ç1
CK
\|
+
Q,H
II
cr
I
Y
b
CO,H
\
o
Cl
62
S C H E M E 25
R eagents an d conditions: i) D M F , N M M ; ii) M W .
1.5.8 A lkene Functionalisation
The utility o f m icrowave inadiation has been demonshated'*'^ to achieve the BaylisH ilm an reaction. This synthetically nsefril reaction, rather slow conventionally could be
accelerated imder m icrowave conditions. Typically, the reaction could be achieved in 10
minutes under microw ave conditions as opposed to 10 days at room tem perature (see
Scheme 26).
,C O ,M e
63
64
S C H E M E 26
Reagents and conditions: i) C H sC H ^ C H C O z M e , D A B C O ; ii) M W
1.5.9 Estérification and tm ns-esterification
M icrowave inadiations have also been exploited in achieving estérification and
transestérification reactions. Transestérification o f sugars have been studied and
microw ave conditions have favoured m ixtures o f monoesters and diesters"*^ (see Scheme
27 ).
18
C h a p te r 1
“
h
o
]
OMe
“
ii
^^°°R C O O
R-Ph
“
OMe
S C H E M E 27
Reagents and conditions: i) PhCOzMe, K2CO3, TEA, DMF; ii) MW
1.6.0
R earrangem ent and Isom érisations
Scheme 28 illustrates the application o f m icrowave irradiation in rearrangem ent o f
benzodiazepine-diones/'^^ Isomérisation o f safrole and errgenol has been reported in
alm ost quantitative yields under microwave eonditions'^*''’ (Scheme 29).
H
H
,0
N -f
:
■N
6
Cl
67
68
S C H E M E 28
Reagents and conditions: i) P O C h -p y iid in e ; ii) MW
69
S C H E M E 29
Reagents and conditions: i) KOH, ROH; ii) MW.
1.6.1 Organom etallic Reactions
Reports describe organom etallic reactions achieved under m icrow ave conditions. Stille
coupling has been studied in presence o f PdC l2(PPh3)2 catalyst w ith 49-96% yields."^’“
(see Scheme 30). Another example reports H eck virrylation accelerated by m icrowave
irradiation'*^'’ (see Scheme 31).
19
C h a p te r 1
R""
R"
+
73
72
R'-R" = H, R'" = OMe, R"" = H
X = I, Br
S C H E M E 30
R eagents and conditions: i) P d C l 2 (P P h 3 ) 2 , L iC l, D M F ; ii) M W
HO
:k
•
74
%
75
X = OTf, Br
76
R' = H, R" & R'" = CH2CH3
S C H E M E 31
R eagents an d conditions: i) P d (O A c ),, E tsN ; ii) d p p p , T IO A c , D M S O , M W .
1.6.2
Oxidations
M icrowave accelerated oxidations have also been reported. Oxidations o f prim ary and
secondary alcohols have been docimiented w ith high yields'*^’
R'
R'
OH
R"
"
77
R"
78
R' = C^,,,C„H3,
R" = H
S C H E M E 32
R eagents an d conditions: i) P C C , D C M ; ii) M W .
OH
79
80
S C H E M E 33
R eagents and conditions: i) M n O a, d ie th y l e th e r; ii) M W
20
(see Scheme 32, 33).
Chapter 1
1.6.3 Reductions
M icrowave assisted reductions have also been studied to a considerable extent. Studies
have demonstrated a rapid transfer hydrogenation'’^®in an unm odified oven in essentially
quantitative yields (see Scheme 34). hi another example, selective hydiogenolysis o f Obenzyl groups in jS-lactams and reduction o f im satiuated ester groups have been reported
(see Scheme 35).
K
BnO.
,Ph
81
^
SCHEME 34
R eagents an d conditions: i) HCO2NH4, R a n e y n ic k e l, e th y le n e g ly c o l; ii) M W .
.COjMe
^COgMe
HO
BnO
A Al­
o
es
SCHEME 35
R eagents an d conditions: i) H C O 2 N H 4 , 10% P d /C , e th y le n e g ly c o l; ii) M W .
Reports also describe the m icrowave assisted reduction o f (^-substituted cinnamic acid
using difonnic salt o f TM EDA in presence o f W ilkinson’s catalyst (see Scheme 36).'*^'^
O
Pli
O
'O H
^
Pli
y
OH
R = Me, Ph
85
SCHEME 36
Reagents and conditions: i) d ifo n n ic a c id s a lt o f T M E D A , W ilk in s o n ’s c a ta ly s t, D M S O ; ii) M W .
M icrowave irradiation has been reported to favour Leuckait reductive amination^” and
also in im ine reduction
(see Scheme 37, 38).
21
Chapter 1
O
HN
_ _ . i ......
R"^
"
R', R" = CgH^, 4-MeOCgH^
87
H
.
R"
SCHEME 37
R eagents an d conditions: i) HCONH2, HCO2H; ii) MW
CO^Me
CO,Me
SCHEME 38
R eagents an d conditions: i) 10% Pd/C, HCO2NH4; ii) MW.
1.6.4 M iscellaneous
M icrowave
irradiations
have
demonstrated
other
interesting
applications
like
decarboxylation,^'^ (see Scheme 39) multicom ponent reactions (see Scheme 40).^"^
OH o
92
91
SCHEME 39
Reagents an d conditions: i) M W .
O
93
A
94
HN.
95
R, R' = Et, Me, CjH[q
SCHEME 40
Reagents and conditions: i) M W .
Reports describe microwave assisted formation o f azo compounds.^^“ (see Scheme 41)
The Willgerodt-ICindler reaction for synthesis o f thioamides has been dem onstrated under
m icrowave conditions'^’’ (see Scheme 42).
22
Chapter 1
ArN O ,
---------------------------------------Ar-N=N-Ar
ii
97
98
S C H E M E 41
R eagents and conditions: i) B i-K O H , M e O H ; ii) M W .
s
99
100
S C H E M E 42
R eagents and conditions: i) Sg, m o ip lio lin e ; ii) M W .
1.7 Organic Synthesis nnder Dry or Solvent Free Conditions
There have also been notable developments in microwave assisted organic synthesis
involving solvent-less procedines^®’
and also w ith processes involving the use o f
supported reagents or catalysts w hich are o f m ineral or polym er origin.^^®’'^’‘^’^ A t times in
a chemical synthesis, recovery o f the organic solvent during product pm ification m ay
involve loss o f products; however, avoiding the use o f organic solvents prom ises cleaner
chemistry, simple work-up procedures and m ore significantly reduces m m ecessary waste
o f reagents. U se o f reagents and catalysts im m obilised on solid supports not only
simplifies purification processes but also prevents release o f reaction residues into the
enviromnent. A brief o v e m e w o f the very im portant contributions and developm ents in
solvent h e e procedures and use o f polym er and inorganic solid supported reagents under
microwave conditions follows.
1.7.1 Protection and Deprotection
U nder solvent fi'ee conditions, m icrowave inadiations have found significant utility in
achieving protection/deprotection procedures.
Aldehydes and ketones have been
protected as acetals and dioxolanes using orthofonnates, 1,2-ethanediol or 2,2-dimethyl1,3-dioxolane in presence o f /(-toluene sulphonic acid or ICSF clay (see Scheme 4 3 ) . ^
23
Chapter 1
R'x
°
„ A
R""^
,O H
. R"
„
9
+
101
X
p
+
H ,0
103
102
R' =H, R" =Ph
,R"
S C H E M E 43
Reagents and conditions: i) PTSA; ii) MW.
Selective deprotectioii/cleavage o f N -teit-butoxycarbonyl group (Nboc) can be achieved
readily in presence o f a Lewis acid as aluininhun chloride ‘doped’ alm nina on microwave
irradiation (see Scheme 44).^'^'^
?■'
,N
^
i
R '\
^
C (C H ,),
u
NH
R ,/
o
104
R' = H, R" = Ph
105
S C H E M E 44
Reagents and conditions: i) AICI3/AI2O3; ii) MW
1.7.2
D iels-Alder Cycloaddition
The D iels-alder eycloaddition reactions has been extended, under solvent free conditions,
to poorly reactive dienophiles and considerably good yields o f desired products have
been isolated under microwave conditions (see Scheme 45).^^“'*
.C O ,E t
N,
?
107
N
Ph
Ph
106
108
S C H E M E 45
Reagents and conditions: i) MW.
M icrowave assisted 1, 3-dipolar activity o f hydrazonyl chlorides and oxim e chlorides
over alum ina w ith different alkenes and alkynes has been reported (see Scheme 46).^^
24
Chapter 1
CO^Me
Cl
A r"
N
.O H
+
-CO ,M e
no
109
Ar
111
R = Ph; Ar = Ph, p-ClC^H^
S C H E M E 46
Reagents and conditions: i) AI2O3, MW.
1.7.3
Nucleophilic and Arom atic Substitutions
Reports^^** describe m icrowave assisted aromatic nucleopliilic substitutions over an
alum ina support (see Scheme 47).
R'
o
+
HO'
O
HO
113
114
S C H E M E 47
Reagents and conditions: i) MW.
M icrowave assisted aromatic halogénations o f quinones over alm nina have also been
repoited^^'^ (see Scheme 48).
R', R" = H, Me
S C H E M E 48
Reagents and conditions: i) B12, AI2O3; ii) MW.
1.7.4
Alkylations and Acylations
M ichael type C-alkylations mrder microw ave conditions over alum ina have been
reported^^“ (see Scheme 49). Reports also describe M ichael type N-alkylation^^'^ and O25
Chapter 1
glycosidation^^'^ in the presence o f alm nina (see Scheme 50 and 51). Thio-alkylation^^'’
has also been achieved in solvent free conditions imder m icrow ave conditions (see
Scheme 52). M icrowave assisted N-acylation^’®has been reported to favom in presence
o f silica (see Scheme 53).
ff
Ph
^
0
Ph
+
MeNO,
2
118
117
Ph
Ph
119
S C H E M E 49
Reagents and conditions: i) AI2O3, MW.
OH
,
N
•N
/NH
N
121
120
I
-CN
122
S C H E M E 50
Reagents and conditions: i) AI2O3, MW.
OH
OH
pH
HO—
"
R = H , R " = Me
S C H E M E 51
Reagents and conditions: i) glycosidase, AI2O3; ii) MW.
i
/O E t
126
°
N —N
O
127
128
S C H E M E 52
Reagents and conditions: i) K2CO3; ii) MW.
26
Chapter 1
.
N
A
V " "
130
R'
"N
R' = p-NO^CgH^, MeOCgH^
129
R'
R" = p-NO,CgH,
131
SCHEME 53
Reagents and conditions: i) Si02; ii) MW.
1.7.5
Condensations
K noevenagel condensation has been achieved using alum ina supported KF imder
m icrowave conditions'*^ (see Scheme 54).
Ar
H
132
^
133
134
SCHEME 54
Reagents and conditions: i) ICF-AI2O3; ii) MW.
M icrowave inadiation has also been utilised to achieve H orner olefination using CsF
supported on alumina.^*'’ (see Scheme 55)
O
O R
EtO— P
^
P— OEt
E tc/
II
^CHO
I
^
OEt
V
II
I
OEt
,3 5
SCHEME 55
Reagents and conditions: i) CS2O3, CSF-AI2O3; ii) MW.
1.7.6
Rearrangements
Reports describe Beckmaim reaiTangement^^“ (see Scheme 56) in the presence o f KIO
Clay imder microw ave conditions. The Fries rearrangement^^'' (see Scheme 57) has also
been achieved using AlCb-ZnCla over silica.
27
Chapter 1
.O H
N
R""
R""
R"
ii
'N '
H
.R"
139
138
R '- Av, Cycloallcyl
R - Me, Ph, Cycloallcyl
SCHEME 56
R eagents an d conditions: i) K IO C la y ; ii) M W .
R = Me, OMe, 1-Naphthyl
SCHEME 57
R eagents and conditions: i) A lC ls-Z n C la , S iO ;; ii) M W .
1.7.7 Oxidations
M icrowave assisted oxidation o f arenes using potassium peiinanganate in presence o f
alm nina has been reported''®* (see Scheme 58). U se o f sodimn periodate in presence o f
silica favom s oxidation o f sulfides®®'' (see Scheme 59). In presence o f bentonite,
microwaves assist the oxidation o f allylic methyl groups in presence o f SeOz catalyst in
up to 85% yields.®®" (see Scheme 60).
142
SCHEME 58
Reagents and conditions: i) K M 11 O 4 , A I 2 O 3 ; ii) M W .
R"^
145
R"
144
R'-^M'^R"
O
146
R' = P h C H „R " = Pli
SCHEME 59
Reagents and conditions: i) 1.7 e q u iv . N a lO ^ , M W ; ii) 3 e q u iv . N alO ^ , M W .
28
Chapter 1
R = (CH2)20H, (CH2)20Ac
S C H E M E 60
Reagents and conditions: i) SeOz, Bu'OaH, SiOa; ii) MW.
1.7.8
Reductions
M icrowave assisted reduction o f aldehydes and ketones using alm nina supported sodium
borohydride have been reported*^'® (see Scheme 61). Reductive am ination has also been
achieved imder m icrowave condition using sodium borohydride supported on KIO clay*"'’’
(see Scheme 62).
Q
OH
.
149
R-
150
R = H, R' = Me
S C H E M E 61
Reagents and conditions: i) NaBH^-AhOg; ii) MW.
O
. A „"R"
„
R,^
HN
+
A'"
H.N-R'"
R '^
151
152
R"
153
R' = Ph, R" = H, R'" = H
S C H E M E 62
Reagents and conditions: i) KIO clay, NaBH^-KlO clay; ii) MW.
1.7.9 M iscellaneous
M icrowave irradiations have favoured multicom ponent synthesis o f pyrrole in presence
o f silica®^“ (see Scheme 63). M icrow ave assisted synthesis o f nihiles from aldehydes
using sulphuric acid in presence o f silica has been^ reported^^’’ (see Scheme 64).
Thiocarbonyls have heen converted to caihonyls in presence o f clay under microwave
conditions w ith high yields*’^'^ (see Scheme 65).
29
Chapter 1
NOz
Y
156
R' = Ph
R" = H
R'" = H, Me, Ph
R"" = PhCH,
154
R""
157
SCHEME 63
Reagents and conditions: i) SiO z; ii) M W .
R"^
R'
H
158
= N
159
R' = Ph
SCHEME 64
Reagents an d conditions: i) N H z O H .H C l, N aH S O ^ .S iO z; ii) M W .
, A „ R'
„
R, '^
R '^
R"
161
160
SCHEME 65
R eagents an d conditions: i) F e N O s o r N H 4N O 3, c la y ; ii) M W .
1.8.0 M icrowave assisted Organic Synthesis using Polymer Supported Reagents
The growing demand for diverse libraries o f compounds in ding discovery and medicinal
chemistry has significantly attracted m icrowave iiTadiation teclmique. The application o f
m icrowave heating and combinatorial chem istry serves as a convenient tool for a rapid
parallel synthesis o f combinatorial libraries. In context, the application o f polym er
assisted solution phase synthesis utilising reagents and catalysts im m obilised on polym er
backbone has grown to be very advantageous. The pioneering application o f the
Memfield®^“ polym er support is responsible for the fast growing interest and
developm ent in insoluble matrices in organic synthesis. Polym er-supported reagents,
catalysts^^'^ and scavengers''^^ have found significant utility in high-speed microwave
assisted organic synthesis. The use o f polym er supported reagents is particularly
advantageous because often these reagents could be used in excess to drive the reaction to
completion and in the purification stage, can be easily rem oved b y filtration. Some recent
applications follow.
30
Chapter 1
A polym er supported Lawesson type tliionating agent serves for a rapid conversion o f
amides to thioamides under m icrowave conditions'^^® (see Scheme 66). A noticeahle
reduction in the reaction times has heen ohserved and a range o f secondary and tertiary
amides have been converted to conesponding thioamides in high yields and pmity.
V
'NH
Ü
U
M W 200C,^ 15 min
R ' ^ N R ' R " — --------—
Toluene, Ionic Liq.
162
y -L .
R
NR'R"
163
R = P h , Ph(CHz)2
R' - R" = Me
SCHEME 66
Reports describe an interesting one-pot tlu'ce component W ittig reaction^^^ achieved
under m icrowave conditions using polym er supported triphenyl phosphine The desired
olefins have heen prepared in a few minutes (see Scheme 67).
0
MW, 150C, 5 min
^R"
R ""
"H
'
164
^
^
R"
MeOH, KjCOj
166
165
R' = Ph, Et
R" = COjMe
SCHEME 67
0
0
0
O
+
R " '^ H
O
+
H ,N
( J —SO^^Yb
3 '"
NH
168
169
+
R"-
NH
R'
O — SOjH
167
R"
'N
u '^ 0
_
( 2 ) — NMCj ÔH
170
R = M e,R ' = O E t,R "= P h
SCHEME 68
Polym er supported reagents have heen interestingly utilised as catalysts and scavengers
in achieving a clean and efficient organic synthesis. A n example o f a paiallel synthesis o f
dihydropyiimidones tlirough a Bignelli reaction®^® (see Scheme 68) describes a polym er
bound lanthanide (III) (Yh(III)-resin) to catalyse the solution phase condensation. Finally,
31
Chapter 1
during the purification stage, a strongly basic quartem aiy ainnionium functionalised resin
and a sulphonic acid functionalised resin used sei^ve to scavenge excess urea and by­
products derived from side condensations.
32
Chapter 2
Aims and Objectives
INDEX
C HAPTER 2
AIM S AND OBJECTIVES
2.0 Outline
33
2.1 H ydrogenation
33
2.2 Catalytic Transfer Hydrogenation (CTH)
33
2.3 Aims and Objectives
35
Chapter 2
2.0 Outline
There is a vast an ay o f synthetic m ethods and reagents available to synthetic organic
chemists. N ew and unfam iliar m ethods continue to he developed, hi synthetic organic
chemistry, out o f the numerous organic reactions, hydrogenation is one o f the m ost useful
and wide-scoped reaction.
2.1 Hydrogeuation
Laboratory scale catalytic hydiogenation'''^ plays an important role in the area o f chemical
research and the synthesis o f organic intemiediates. In m ost research laboratories
hydrogenation, reduction or hydiogenolysis is comm only achieved in a comm ercially
available apparatus using pure hydrogen gas. M any functional groups can be readily
reduced and quite often in high chemo-, regio- and stereoselectivity. H owever, use o f this
method o f hydrogenation has a few disadvantages.
♦> Hydrogenation using pure hydiogen gas could only he achieved in specifically
designed apparatus or hydrogenators and hydrogen is dispensed from cylinders fitted
w ith appropriate valve system.
♦> A ir and hydrogen mixture in the hydrogenators ai'e a serious hazard if flames or
sparks are produced nearby. Therefore, air in the hydrogenator has to he completely
rem oved either by lowering the pressure in the system and refilling w ith hydrogen or
flushing the system for several minutes w ith hydrogen gas. In doing so, a large
volum e o f hydrogen is wasted.
❖ Hydrogen
gas
has
low
solubility in
organic
solvents
and
therefore
most
hydrogenation processes have to he perform ed under high pressures (40 psi to 1000
psi or more).
2.2 Catalytic Transfer Hydrogenation (CTH)
A potentially desirable alternative to the use o f gaseous hydrogen is catalytic transfer
hydrogenation (CTH), has heen used in overcom ing the limitations o f using hydrogen gas
where m ostly the transformations can he achieved under m ilder conditions, h i this case,
simple organic/inorganic molecules, such as cyclohexane,*^^ cyclohexadiene,*^*^ formic
acid,*^’ amm onium formate,^* hydrazine^^ and phosphinic acid^° are used as in situ sources
o f hydrogen in presence o f metal catalysts such as, palladium on carbon, Raney nickel,
33
Chapter 2
Platinum. Hydrogen transfer occurs betw een a donor compoimd (D), and an acceptor
com pound (A) (see Scheme 69). As a result, the unsaturated groups in A m ay he reduced
and/or susceptible honds m ay be cleaved by hydiogenolysis.
H yD + A
C ataly st
-----------------------A H y + D
SCHEME 69
Studies’ * reveal that formate salts serve as better hydrogen donors than formic acid.
Ammonium formate has heen the m ost convenient and efficient hydrogen source in
studying catalytic transfer hydrogenation.” The utility o f amm onium form ate as an in situ
hydrogen donor has also heen reported in diverse hansform ations.’^ hiterestingly,
catalytic transfer hydrogenation has been conducted rapidly and in alm ost quantitative
yields inside an urunodifred m icrowave oven.'*^ Reduction and hydrogeriolysis has been
achieved using armnoniurn formate as the hydrogen donor in presence o f Pd/C (10%)
catalyst under m icrowave conditions (see Schemes 34 and 35, Chapter 1). hr general,
ammonium formate in presence o f suitable catalysts has been applied to reduce a variety
o f im portant functional groups and has the advantage o f being stable, readily available and
relatively inexpensive. And its use is ideally advocated in several catalytic transfer
hydrogenations, however, this does not account for m any o f its disadvantages
❖ A lthough efficient, the use o f armnoniurn formate does not deter a m ajor potential
hazard o f its sublim ation at higher temperatures, resulting in blocking o f the reaction
apparatus.
❖ Ammonium formate m ost rmdesirahly dissociates at high temperatures.
heat
H CO yN H /
H CO ,H
+
NH,
*t* It is also responsible for undue developm ent o f high pressures in the reaction systems.
34
Chapter 2
2.3 Aims and Objectives
This project broadly studies the application o f microwaves for achieving organic
reactions. In particular it seeks to introduce m ethods for experim ental simplicity and
im proving the efficiency o f the organic transformation. The aims and objectives in this
project can be highlighted as under.
>
Developm ent o f novel transfer hydrogenation sources
In view o f the limitations o f using the conventional hydr ogen donors, this project aims to
develop novel hydrogen donors serving as transfer hydrogenation sources which are able
to overcome the problem s o f sublimation, amm onia release and excess pressure.
>
Study of model reactions
The developm ent o f novel hydrogen donors w ill be based on m odel studies. Initially
m odel reactions will he studied on simple systems which w ill investigate the scope and
feasibility o f developing novel hydrogen donors and provide a suggestive pathway.
>
Novel transfer hydrogenation sources as supported reagents
The developm ent o f novel hydrogen donors w ill be investigated on different solid
m ahices or supports. The m ain solid supports o f interest are (a) Insoluble cross-linked
polystyiene polymers; (b) soluble polyethylene glycol (PEG); (c) inorganic solid like
ahunina (basic).
>
Organic synthesis using polym er and inorganic solid supported reagents under
m icrowave conditions and therm al comparisons
The polym er supported reagents w ill be employed in transfer hydrogenations using
suitable catalysts like W ilkinson’s catalyst (RlrCl(PPh3)3). The potential o f these novel
polym er supported reagents as hydrogen donors w ill be investigated. M ore importantly,
microwave assisted transfer hydiogenation involving reduction o f electron-deficient
alkenes, W debenzylation w ill be studied using polym er supported reagents. The reactions
w ill be studied while optimising the microw ave energy for m ost favourable reaction
conditions and reaction yields. T hennal comparisons w ill he done to evaluate the effect o f
microwaves on organic transformations.
35
Chapter 2
>
Synthesis of form amides using supported reagents under microwave conditions.
The applications o f the novel polym er and inorganic solid supported reagents will be
investigated in the synthesis o f foiinamides. U nder m icrowave conditions, the supported
reagents will be studied as fom iylating agents for prim ary and secondary amines. Thermal
comparisons w ill be done to study the influence o f microw aves on N -fonnylation
reactions.
>
M icrowave assisted reduction o f ketones using polym er supported formates
The polym er supported foim ate w ill be investigated as a transfer hydrogenation source for
studying reduction o f carbonyl function in ketones. Reductions w ill be studied under
m icrow ave conditions in the presence o f hom ogeneous rathenium catalysts.
>
Therm al and microwave assisted oxidation using clay supported Pd catalysts
The study w ill involve the im m obilisation o f a Pd Catalyst on hydrotalcite clays. Such
insoluble catalysts w ill be investigated for applications in oxidation reactions. In
particular, therm al and m icrowave assisted oxidation o f alcohols w ill be investigated.
>
Therm al and microwave assisted cy d o addition o f nitrones and metal coordinated
cinnam onitrile
The study involves developm ent o f novel cinnamonitrile complexes coordinated with
Pt(II) and Pd(II) m etal centres. M icrowave assisted [2+3] cycloadditions reactions o f
nitrones and these complexes w ill be studied. The investigations on selectivity o f
cycloaddition reactions o f metal bound cinnam onihile complexes and nitrones under
microwave conditions w ill be o f particular interest. Thermal com parisons o f cycloaddition
reactiorrs w ill be done using free and metal coordinated cirmamorritrile arrd nihones to
study the irrfluence o f m icrowaves on such reactiorrs.
36
Chapter 3
Development of Supported Reagents
CHAPTER 3
DEVELO PM ENT OF SUPPORTED REAGENTS
3.0 Introduction to Supported R eagent Chemistry
37
3.1 Types o f Supported Reagents
37
3.1.1 Polym er (organic) Supports
37
3.1.2 Inorganic Supports
39
3.2 Developm ent o f Novel Supported Reagents as Hydrogen Donors
41
3.2.1 M odel Studies and Development o f Aminomethylpolystyi'cne
Supported Hydrogen Donor
42
3.2.2 Development o f Supported hydiogen D onor using Ion-exchange Resin
(Amberlite® IRA 938 (anionic))
44
3.2.3 M odel Studies and Approaches to the Development o f H ydrogen Donor
Supported on a Soluble Polym er Support (Polyethylene glycol 8000)
47
3.2.4 Development o f a Hydrogen Donor Supported on Basic A lum ina
50
Chapter 3
3.0
Introduction to Supported Reagent Chemistry
The area o f supported reagent chem istry developed as early as 1924^"^ reporting the use o f
chemical reagents on porous earners to achieve some “highly selective and m ild chemical
operations.” Begimiing w ith the pioneering w ork by Menifield,*^^®’’^ polym er supports
have also become a subject o f increasing interest as insoluble matrices in organic
synthesis. W ith growing need for preparing compoimd libraries in phaiinaceutical and
agrochemical research laboratories, the industry seeks for im proved autom ation o f
synthetic processes. The developm ent o f new synthetic m ethods using polym eric supports
is regarded as a key for successfully generating this libraiies.^^ hr view o f these changes,
the utilisation o f polym er supported reagents^^'^'^^^and catalysts^^^ have been developing.
3.1 Types o f Supported Reagents
Supported reagents have conveniently been classified based on the use o f
(A) Organic Supports &
(B) hiorganie Supports.
3.1.1 Polym er (O rganic) Supports
-CH -CH ,-
171
SO,H
f
^
Base
Polymer
Reactive
Site
f
.)— N t
OH
R'
Strongly basic ion-exchange resin
Strongly acidic ion-exchange resin
Figure 3.1 Polymer supports and functionalised reactive sites
Organic
Supports
are
invariably
polym eric
and
generally
are
fimctionalised
polystyrene/divinyl benzene copolymers. Polym eric supports ranging from simple ionexchange resins to elegantly designed ones incorporating a linker w hich joins the base
37
Chapter 3
polym er to a fimctionalised reactive site are used (see Figure 3.1).
Chemical
functionalities are attached to the polym eric supports by either physical adsorption or by
chemical bonding. Chemical attaclnnent is usually achieved by covalent bonding. The
highly attractive ion-exchange resins, w idely employed in autom ation are prepared by the
fom ier m ethod o f attachment. Cross linked poly (styiene-co-divinylbenzene) resins (1%
to 2% cross-linking) are w idely used as fimctionalised polym ers because they are stable,
possess' high loading capacity (>lm m ol/g) and have good sw elling characteristics to
prom ote reaction support preparation. In addition, they are compatible w ith a variety o f
non-protic solvents. Typically, m ost o f the fimctional groups on the polym er supported
system are w ithin a polym er bead o f diam eter o f about 100 fim. M ost o f the reactants in
the solution enter the beads and react in the gel phase. It is also noted that the swelling
properties in the polym eric bead reduces m arkedly as the percentage o f cross linking
increases from 1% to 2% or more. Therefore, the choice o f reaction solvent is cracial in
such polym er-supported reactions. Often obseiwed is the size selectivity displayed by the
polym er supported reactant. The diffusion o f the soluble substrate into the polym eric bead
is rate determining and at times selectivity’’ arises because a m ore bulky group diffiises
more slowly into the reactive sites. The accessibility o f reactive sites in the polymeric
supports can be im proved by using m acroporous or rnacroreticular polym ers.’®Typically,
such rnacroreticular beads have a rigid porous sfrrrcture and norm ally they do not swell in
most organic solvents. For example, the cormnercially available m acroporous polym er
supports like certain anion exchange resins (Figiue 3.1) are ideally sirited for making
anions available for reactions in non-aqueous solvents.’^^
The use o f polym er supported irmnobilised reagents and catalysts has various advantages
over conventional solution-phase chemistry.
»
Supported species can be easily separated fiom the reaction m ixtures, by filfration and
washing.
•
B y using excess o f reagents, the reaction could be forced to com pletion without
having to face the w ork-up problems.
•
The supported reagent or catalyst can often be readily regenerated and reused in
fiuther reactions.
•
The supported species can be easily adapted to continuous flow processes and hence
they stand w ider possibility o f use in autom ated synthesis.
•
The use o f supported species as compared to the low m olecular w eight unsupported
analogues greatly reduces the toxicity and odom- in the chemical operation.
38
Chapter 3
•
Supported species also introduce chemical differences such as prolonged activity or
altered selectivity in supported form compared to its soluble analogue.
Nevertheless, functionalised polym ers also associate a few drawbacks w ith their use,
particularly in comparison w ith their soluble analogues.
•
M any o f these polym er supports ar e relatively expensive.
•
The polym eric supports often display pronounced size selectivity and therefore results
in limited diffusion o f the soluble subshate into the polym eric beads.
•
There is a difficulty in str uctural analysis o f the supported reagerrts.
•
The polym er bound inrpurities ofteir fourrd irr the supported species carmot be
separated.
3.1.2 Inorganic Supports
Inorganic Supports for developirrg supported reagerrts are rrrmrerous and include silica,’^'’
alurnina,^^'^ zeolites,^^^ celite,’^® carbon,’^^ morrtrnorillonite,^^^ acid treated clay’^® and
alumino s i l i c a t e s . T h e r e is specific emphasis in supported reagents obtained by
deliberate irrtroduction o f a reagerrt irrto or onto an inert, generally porous, inorganic
support in liquid phase orgarric reactiorrs. hr laboratory arrd rnarrufacturirrg scale syrrthesis,
reagents irmnobilised on porous solids are utilised in heterogerreous organic reactions arrd
offer numerous poterrtial advarrtages.
•
The iirorganic solid supports offer good dispersiorr o f active (reagerrt) sites leadirrg to a
sigrrifrcant im provem ent irr reactivity.
•
The characteristics o f surface adsorptiorr carr lead to useful improvernerrts in reaction
selectivity.
•
M ost inorgarric solid supports have good thermal arrd nrecharrical stabilities.
However, use o f such irrorgarric solid supported reagerrts also does involve some
disadvarrtages.
•
Ofterr observed in the use o f supported reagerrts is that orgarric molecules get trapped
in the pores o f the support.
•
There is a difficulty in ensuring a good m ixing o f a solid-liquid or solid-liquid-gas
mixture.
•
Solid supports, specifically o f the rnicroporous type, are not suitable for chemistry
involving large molecules.
39
Chapter 3
There are a few im portant factors involved in detem iining the best support for a particular
application. These include(a) Surface Area.
(b) Pore Size.
(c) Acidity-Basicity.
Generally, the larger the surface area o f the support, the better suited for applications as a
support. Surface areas for comm on supports range from ca. 100 m^ g'^ for some aluminas
and crude clays to close to 1,000 n f g'^ for some activated carbons.
The average pore diameter, pore size distribution, total porosity and perm eability are all
relevant to optimise the diffusion control o f the reaction, hr cases, o f rnicroporous zeolites,
the pore shnctm'es are regular w hereas siuTaces like silica, aluminas have a wide range o f
pores.
The application o f supports in catalysis interestingly deals w ith the im portance o f acidity
and basicity. Montirrorillonites irr the acid h eated forms (KIO, KSF, etc.),’^®Zeolites w ith
excharrgeable
versioirs have been broadly studied.^^''
Chapter 3
3.2 Developm ent o f N ovel Supported Reagents as Hydrogen Donors
One o f the m ajor interests in this project is the developm ent o f novel supported reagents
for applications in transfer hydrogenation. The supported reagents w ould be used as
hydrogen donors and are envisaged to overcom e the limitations o f using conventional
hydrogen donors.
Two broad categories o f supports have been studied for the developm ent o f supported
transfer hydrogenation sornces/hydiogen donors (see Scheme 70).
S u p p o rted H y d ro g en D on ors
Polymers
Minerals
-Insoluble
-Soluble
SC H E M E 70
The developm ent o f a supported transfer hydrogenation sources has been further elassified
as insoluble polym er backbones w hich includes (a) aminomethyl polystyrene and
(b) basic ion-exchange resin (anionic) (Amberlite® IRA 938 / Amberlite® IRA 400).
Also studied are the soluble polym er backbones involving (c) soluble di-A-ethyl
polyethylene glycol supports.
U nder the supports o f m ineral origin, the studies have concentrated on the use o f basic
alumina.
41
Chapter 3
3.2.1 M odel studies and Developm ent o f A m inom ethylpolystyrene Supported Hydrogen
Donor
Initially, the developm ent o f a supported hydrogen donor has been studied using
aminomethyl polystyrene. Amino-fuiictioiialised polystyrenes provide indispensable
platform s for solid phase mediated organic transformations e.g. in peptide synthesis, D NA
and combinatorial synthesis a p p lic a tio n s .T y p ic a lly , these are solid supports o f
polystyrene beads crosslinlced w ith 1 or 2% divinyl benzene fimctionalised w ith
aminomethyl groups. These are synthesised by reaction o f chlorom ethyl resins w ith an
excess o f ammonia^
or w ith potassium phthalim ide to give phthalirnidornethyl resins,
w hich by hydrolysis yields the arnine.^^^ And also by direct arnidornethylation using A(hydroxymethyl)phthalirnide or A-(chloromethyl phthalimide) using an acid catalyst as
HF, C F 3 S O 3 H or SnCl4.®^‘^'‘^ hr the present study, aminomethyl polystyrene resin w ith an
amine loading value o f 0.6 nnnoFg o f resin was utilised w ith good sw elling properties.
C T '^ (Xts,
172
SC H E M E 71
Reagents and conditions: i) HCOOH; ii) stin in g , room temperatur e.
Developm ent o f a hydrogen donor on aminomethyl polystyr ene w as m odelled by studying
a reaction on a benzylam ine 172 m oiety (see Scheme 71). Typically, benzylarnine 172 on
treatm ent w ith formic acid 173 on stin in g at room ternperatine generated its formate salt
174 by a proton donor-acceptor mechanism betw een the amine and the acid subshate.
Accordingly, reaction on the benzylic amine m oiety o f resin 175 w as done by treatm ent o f
the resin suspended in dichlorornethane (DCM) and allowing the resin to swell. The resin
suspension was then w ashed w ith 173 (20% solution in DCM ). The w ashed resin was
separated as the formate salt 176 and used as a hydr ogen donor in transfer hydrogenations
after drying (see Scheme 72).
^
^
175
^
Hco,
176
SC H E M E 72
Reagents and conditions: i) HCOOH in dichlorornethane (20%); ii) stin in g , room temperature.
42
Chapter 3
The loading value o f the fom iate was detenuined as 0.6 nuiiol/g resin by using
potentiom etric titrations.
43
Chapter 3
3.2.2 Developm ent o f a Supported
(Amberlite® IR A 938 (anionic))
H ydrogen
Donor
using
Ion-exchange
Resin
Ion-exchange resins have been coinnionly used for rem oval o f ionie impurities in many
industrial and chemical p r o c e s s e s . T h e s e resins are well suited for such applications
because o f their high stability, ready regenerability and negligible tem perature effects.
Both natural (zeolite) and synthetic ion exchange materials exist in the m arkets today. A
vast m ajority o f these materials applied in the industrial processes^^®’^ are organic resins o f
synthetic origin. The synthetic resins available are broadly o f two types: (a) cation
exchange resins and (b) anion exchange resins.
M ost o f the ion-exchange resins aie m anufactm ed by suspension polym erisation process
using styi'ene 177 and divinyl benzene (DVB) 178. The styrene and DVB are introduced
in a chemical reactor w ith equal amounts o f water. Additionally, a suifactant is also
introduced to keep the entire reaction mixture dispersed. The reaction m ixtm e is agitated
to fonn large globules o f the m aterial and w ith more vigorous agitation the globules break
up into sm all droplets to reach a size o f about 1 nun. The polym erisation is then initiated
by introducing benzoyl peroxide, to form polystyrene/DVB beads. The physical shength
o f the macroreticular beads is rendered by the cross-linking divinyl benzene, making the
resin w ater insoluble.
h i the present study, emphasis has been laid on the use o f a strong anion exchange resin
for the developm ent o f a supported hydrogen donor. Such anion exchange resins are
coim nercially available and are prepared by starting w ith Polystyi'ene-DVB beads and
activating them in a two step process (see Scheme 73).
44
Chapter 3
Ç H -C H ,
CH=CH,
Ç H -C H -Ç H -C H -
■
ÇH-CH - CH-CH^ — '
+
177
CH=CH,
CH-CH,
171
178
IH -C H j-C H -C H - C H -C H j-Ç H -C H j— -
H -C H ,- Ç H -C H - ÇH-CH,— CH-CH
---■CH-CH,-NR,
--C H -C H
NR
179
180
SC H E M E 73
Reagents and conditions: i) polymerisation; ii) chlorométhylation; iii) amination.
Strongly basic anion exchange resins derive their functionality from quarteiiiary
amm onium exchange sites. Often these strong basic anionic exchange resins have tliree
methyl groups (R = Me) and exist in the chloride and hydr oxide form. (N^^Rs C l and ISTRs
OH ) Strongly basic exchangers have highly ionised fimctional group (OH') and m ay
readily exchange.
C
^cf
181
/ HCO,(
) = Polystyi-ene/DVB
18%
Amberlite
HCO,- form
Amberlite
C1‘ form
SC H E M E 74
Reagents and conditions: i) HCOOH (98%).
The developm ent o f a hydiogen donor used a comm ercially available strongly basic
anionic exchange resin (Amberlite® IRA 938 (C f form)) 181. A packing o f Amberlite
resin 181 was prepared in a coluimi and w ashed several times w ith 98% formic acid 173
until complete elution o f chloride and subsequently washed w ith w ater (see Scheme 74).
The strongly basic quarferiiary amrnonimn frmction in the chloride form readily
exchanges w ith the formate (HCO2") delivered by the forrnie acid. The resin was
dismantled from the colum n and dried under vacuum for 24 hours, to give the formate
45
Chapter 3
fonn 182. The dried resin is now ready for application in transfer hydrogenations. The
loading value o f the formate was determined to be 2.5 mm ol/g resin using potentiom etric
tihations.
Chapter 3
3.2.3 M odel Studies and Approaches to the Developm ent o f a H ydrogen Donor
Supported on a Soluble Polym er Support (Polyethylene glycol 8000).
Polyethylene glycols (PEG) are amongst the m ost studied soluble polym ers for organic
synthesis.®^'*’ The wide application o f PEG is attributed to its broad range o f solubility in
solvents like dimethyl foimam ide (DMF), DCM , toluene, acetonitrile, w ater and
methanol. Again, it could be precipitated from solvents such as diethyl ether, isopropanol
and cold ethanol. Also, PEGs in particular w ith hydroxyl groups at either ends o f the
chain lends itself generously to introduce organic moieties tluough simple reactions. PEGs
are formed from the polym erisation o f ethylene oxide. Typically, tlrrough anionic
polym erisation o f ethylene oxide a polyether staicture possessing either hydroxyl gi'oups
at both ends, or a m ethoxy gi'oup at one end and a hydroxyl group at the other can be
prepared. PEGs o f m olecular w eights 2000 to 20000 are crystalline w ith loading
capacities o f 0.1 to 1 nnnol/g.
hiitially, a m odel study was perfoim ed on small ‘P E G ’ using the low er chain length o f
tetraethylene glycol 183. A quartem ary aim nonim n function was introduced onto the
pendant hydioxyl groups tluough a simple W illiamson ether synthesis using a suitable
alkylating agent like 2-diethyl aminoethyl chloride hydrochloride salt 184 (2 m ol equiv.)
and a deprotonating base like potassim n carbonate (2 m ol equiv.) (see Scheme 75) in
m ethanol at 50 “C for 12 hours.
HCl N
N HCl
188
SC H EM E 75
Reagents and conditions: i) K2CO3, 2-diethylaminoethylchloride hydrochloride 184, MeOH;
ii) 50°C, 12 hours.
47
Chapter 3
Figure 3.2 H NMR Spectrum of Compound 185
The quaternary amrnonimn salt functionalised tetraethylene glycol 185 was isolated in
63% yield as yellow oil. The introduction o f the quaternary amine function was confirmed
by 'H N M R analysis w hich indicated the developm ent o f a triplet at 1.02 ppm
corresponding to the methyl protons o f-N C H 2CH3 function on either side o f the chain. In
addition, there was a developm ent o f a quartet at 2.58 ppm and a triplet at 2.54 ppm
corresponding to the 12 protons o f -N C H? on either side o f the chain (see Figure 3.2).
Following the m odel studies the developm ent o f a quartem aiy amm onim n salt was
attempted on PEG 8000 186. The polym er (1 equiv.) was treated w ith 2-diethyl aminoethyl
hydrochloride 184 (2 mol equiv.) in presence o f potassim n carbonate as a base (2 mole
equiv.) using m ethanol (50 ml) as the solvent at 45-50 ®C tem peratm e for over 12 horns.
Thereafter, the polym er was isolated after reaction by reprecipitation, on pom ing into
diethyl ether. The analysis o f the isolated polym er by
N M R did not show any
developments o f the characteristic M-diethyl (-N(C2l Ï 5)2) protons and only a highly
intense broad peak at 3.46 ppm corresponding to the polyethylene protons was obseived.
The reaction was attempted using dimethyl fom iam ide (DMF) as a solvent. In this case,
the starting polym er (PEG 8000) was allowed to stir initially in a suspension o f potassium
carbonate (2 m ol equiv.) in DM F (50ml). A fter a few minutes (15-20’), the alkylating
agent (2-diethyl aminoethyl hydrochloride) (2 m ol equiv.) was introduced in the reaction
mixture and the mixture was fm fher diluted by addition o f m ore D M F (50 ml). The
mixture was set to heat while stining at 80-90 °C overnight. Thereafter, it was worked up
and the polym er was isolated by reprecipitation in diethyl ether. A nalysis o f polym er thus
obtained was only consistent w ith the star ting PEG.
48
Chapter 3
Independent attempts to study the synthesis o f quai'temaiy amine functionalised PEG
using stronger bases like sodium hydride (NaH) and potassim n teit-butoxide (KO‘B u)
were equally misuccessful. U se o f solvents like tetrahydrofuran and toluene in the reaction
mixture w ere rendered unsuccessfrd.
In m ost attempts 'H N M R analysis o f the isolated sample w as inconclusive and no
satisfactory evidence o f the amine derivatised PEG was obseiwed. A nd it was not possible
to determine w hether the introduction o f the amine was successful. The O-alkylation o f
p e g ’s
has been reported^"^ to occur sm oothly under W illiam son’s éthérification
conditions. Our model study (scheme 75) was successful suggesting that the PEG
derivatisatiori is expected to occm- in a sim ilar manner. In view o f which, the PEG isolated
after derivatisatiori was further w ashed w ith formic acid (20-40% in diethyl ether) and
dried rmder vacuum. The PEG obtained after w ashing gave a formate loading value o f 0.4
to 0.6 nnnol/g using potentiom etric titrations. W ith this obserwation, it could only be
speculated that the derivatised PEG adsorbed formic acid and also suggested a possibility
o f the presence o f the quarferiiary arnino groups. The formic acid treated derivatised PEG
187 was investigated as a transfer hydrogenation somce.
Chapter 3
3.2.4 Developm ent of a Hydrogen Donor Supported on Basic Alum ina
Am ongst a variety o f solid supports know n today, alum ina is often used as supports,
where it provides a large surface area on w hich catalysts and reagents can be highly
dispersed.
Some o f the characteristics o f alum ina influences greatly in its applications.
•
A lum ina is resistant to chemical attack by a w ide range o f chemicals even at elevated
temperatures.
•
It has a poor conductivity and is resistant to thennal shock.
•
A lum ina possesses high dielectric strength.
•
It is strong absorber to m icrowave radio frequencies.
•
M ost im portantly it is readily available and less expensive.
M ost o f the connnercially available alum ina is obtained by the calcination o f aluminium
hydroxide also know n as alum ina trihydiate or A TH (see equation 3.1 below).
2 AI2 O 3 . 3 H 2 O
^
2
AI2 O 3 (s) +
3
H 2 O (g )E q n . 3.1
For the preparation o f alum ina supported hydrogen donor, basic alum ina (broclonann
grade 1) was utilised. A clnom atography colum n was packed w ith basic alum ina 188 and
the packing was eluted five times w ith a foiniic acid 173 (20% solution in DCM). The
ahunina was rem oved and dried rmder reduced pressure for 24 hours until a free flowing
pow der was produced. The alum ina supported formic acid 189 thus obtained was ready
for fm fher application in hydrogenation reactions. The loading o f formic acid on alumina
was determined as 2 nnnol/g by potentiom etric titrations.
50
Chapter 4
Supported Reagents for Microwave assisted
Hydrogenation of Alkenes and Synthesis of
Formamides
INDEX
CHAPTER 4
SUPPORTED REAGENTS FO R H Y D RO GENATION OF ALK ENES AND
SYNTHESIS OF FORM AM IDES
4.0 OUTLINE
51
4.1 Hydrogen Donors for Rednctions or Transfer Hydrogenations
51
4.1.1 Cycloliexene
51
4.1.2 Cyclohexadiene
52
4.1.3 H ydrazine
53
4.1.4 Form ic acid and its Salts
54
4.1.5 A m monium F onnate
55
4.2 Heterogeneous or Hom ogeneous Catalysts for Transfer Hydrogenation
4.3
4.4
4.5
56
4.2.1 Outline
56
4.2.2 Heterogeneous Catalysts for Transfer Hydrogenation
56
4.2.3 Homogeneous Catalysts for Transfer H ydiogenationW ilkinson’s Catalyst
57
4.2.3.1 W ilkinson’s Catalyst-Syntliesis and Properties
57
4.2.3.2 M echanism o f Hydrogenation using W ilkinson’s
Catalyst
59
M icrowave assisted Hydrogenation o f Electron-Deficient A lkenes using
Polymer Supported Hydrogen D onor (Aminomethylpolystrene)
61
Therm al and M icrowave assisted H ydrogenation o f Electron-Deficient
Alkenes using a Polymer Supported Hydrogen Donor
(Amberlite® IR A 938 (Anionic))
65
Attem pted M icrowave assisted W -Debenzylation using Am berlite Supported
Form ate Leading to W-Formylation
74
4.6
4.7
4.8
4.9
Foi m am ide Synthesis using Am berlite Supported Formate as Form ylating
A gent
Alumina Supported Form ate for H ydrogenation of Alkenes
76
83
Foi mamide Synthesis using Alum ina Supported Formate as Form ylating
Agent
90
Attem pted M icrowave assisted Hydrogenaiton o f Alkenes using PEG
Derivatised Hydrogen D onor
97
Chapter 4
4.0 OUTLINE
“Hydrogenation” is defined as a cliemieal reaction involving the addition o f hydrogen
across a multiple bond in an organic compoimd.
O ften reductions w hich are earned out in presence o f a catalyst and a hydrogen donor are
tenned as “Catalytic Transfer Hydrogenations.” Such reactions have been broadly
applied in m any im portant conversions like acids, aldehydes and ketones to alcohols,
alkenes to alkanes, alkynes to alkenes and im ines to amines. These reactions are equally
im portant in the industrial context, w ith applications in hydrogenation o f vegetable oils to
produce margarine, hydrogenation o f fats and oils to produce w axes and other non-edible
products and even in the synthesis o f fine chemicals. Incidentally, the use o f catalytic
transfer hydrogenations has significantly grown against the use o f the m uch conventional
and older m ethods o f using hydiogen gas. M uch o f it is attributed to the experimental ease
transfer hydrogenations involve, w ith comparatively easy set up and procedures.
4.1 Hydrogen Donors for Reductions or Transfer Hydrogenations
M ost catalytic transfer hydrogenations (CTH) involve the use o f a hydrogen donor and a
suitable catalyst. M any compoiuids including cyclohexene, cyclohexadiene, hydrazine,
formic acid, ammonium formate, phosphoric acid have been used as possible in situ
hydrogen soui'ces. Hydrogen transfer using such hydrogen donors generally involves m ild
reaction conditions. Several possible hydrogen ti'ansfer reactions are envisaged including
hydrogen migration, talcing place w ithin one molecule. H ydrogen disproportionation
involving transfer taking place betw een identical donor and acceptor imits. Transferhydrogenation-dehydrogenation occum ng betw een unlike donor and acceptor units.
Initially some o f the interesting applications o f these hydrogen donors will be
suimnarised.
4.1.1 Cyclohexene
Cyclohexene 190 because o f its ready availability and high reactivity has been
conveniently used as a hydrogen source in catalytic transfer hydiogenation processes. A n
early study on the use o f cyclohexene as a hydiogen donor for reduction o f cimiamic acid
reported^*'^ that an unsubstituted cyelohexene displayed a relative ease o f dehydrogenation
51
Chapter 4
in contrast w ith cyclohexene w ith a bulky substituent. Also, substituents o f an activating
natiue like phenyl, improves its efficacy as a hydrogen donor. The application o f
cyclohexene has been repoifed^*^® as a hydiogen donor in some o f the early w ork done in
reduction o f m ore complex molecules like steroids, involving the selective reduction o f
various steroid ethers o f general type (see Scheme 76) to 6-methyl steroids.
— GAc
■GAc
=0
=G
MeO'
MeG'
191
190
SC H EM E 76
Reagents and conditions: i) 5% Pd/C, cyclohexene; ii) heat
It has also found applications in the dansfer reduction o f C=N compoiuids in presence o f
Pd/C catalyst.^'"’’ Fiuther transfer hydrogenolysis o f halides,®'^'’ benzylic^^'^ and allylic®*'®
compounds, transfer hydiogenation o f nitro compounds^®‘^ have been know n using
cyclohexene. Its applications in carbohydrate research accoiuits in synthesis o f L-glycono1,4-Lactones and is involved in the hydrogenolysis o f 0 -benzyl d e r iv a tiv e s .T h o u g h
cyclohexene offers as a suitable soiuce o f hydrogen for a niunber o f transfer
hydrogenations highlighted here, often, the tem perature available w ith cyclohexene is not
sufficient to cause reduction at an adequate rate.
4.1.2 Cyclohexadiene
A nother example is that o f Cyclohexadiene 191 w hich has also been conveniently used as
a hydrogen donor in a num ber o f transfer hydrogenations. Its m ajor applications studied
are chemoselective deprotection sti'ategies. Groups like - COOBn, -PO(OH)OBn, -0 -C B z
and -N-CBz can be readily and efficiently deprotected in presence o f B n and BOM ethers
andN -B n groups using 10% Pd/C catalyst®’ (see Scheme 77).
52
Chapter 4
BnO-^
^COOBn
COOH
192
SC H EM E 77
Reagents and conditions: i) 10% Pd/C, cyclohexadiene; ii) heat
Also studied are the chemoselective deprotection o f amines and reduction o f C-C double
bonds w hile leaving benzyl and benzyloxy methyl ethers intact*'*'® (see Scheme 78). •
'OBn
194
"
195
OBOM
OBOM
SC H E M E 78
Reagents and conditions: i) 10% Pd/C, cyclohexadiene; ii) heat
4.1.3 Hydrazine
Use o f H ydrazine 198 as a reducing agent has been well laiown w ith the W olff-Kishner
reduction.
Solutions o f hydr azine or hydrazine hydrate have been used w ith or without
bases (hydroxides) for reductions. Also, use o f hydrazine in presence o f a variety o f
catalysts has been growing for m any transfer hydrogenations. The prelim inary application
o f using hydr azine in presence o f finely divided hydrogenation catalysts like Pt, Pd and Ni
led to the decomposition o f hydrazine to liberate airmionia, nihogen and hydrogen, hi
addition, use o f bases like hydr oxides increased the generation o f hydr ogen. The use o f a
catalyst w ith hydrazine as a hydrogen donor becomes more pronoimced as this avoided
the use o f high pressure apparatuses.
Hydrazine has been broadly used for transfer
hydrogenation o f nitro compounds in presence o f suitable c a t a l y s t s . H y d r a z i n e
hydrate supported on A lum ina has been utilised for reduction o f aromatic nifio
compounds to amines in presence o f Fe(III) oxide hydroxide or Fe(III) oxides under
m icrowave conditions'^® (see Scheme 79).
53
Chapter 4
199
R' = H, 4-OCH3, 4-Cl
R" = H
SC H E M E 79
Reagents and conditions: i) H2NNH2.H2O, FeCl3.6H20; ii) MW
Interestingly, hydrazine has also been utilised in transfer hydrogenation o f sugar
derivatives.^’^ Cyclodexhin azides have been successfully converted to corresponding
amines. Hydrazines have also been reported for dehalogenations.
U sing hydrazines, the
release o f hydiogen is often proportionately increased by increasing the concenhation o f
hydroxide bases used. However, the presence o f hydroxyl ion o f the base hinders the
hydrazine dissociation and ability o f hydrogen to effect reduction is greatly reduced with
the result that it is liberated as a gas.
4.1.4 Formic Acid and its Salts
Form ic acid and form ate salts have been extensively used in the study o f transfer
hydrogenation. Forrnie acid and specially formate salts are better hydiogen donors than
other class o f compounds as alcohols and hydroaromatics. Form ic acid has been
extensively employed for transfer hydrogenation o f olefins in presence o f palladium
catalyst.^^“ Forrnie acid has also been employed for the selective transfer hydrogenation o f
a, |8- irnsaturated ketones in presence o f a modified active Ir complex catalyst.^^'^ An
effective hydrogen transfer has also been reported from a formic acid/tri ethyl amine (5:2)
azeotrope to a, /3-iuisaturated carhoxylic acids in presence o f rrrtheriiurii complex
catalysts.^®'^ In the area o f carbohydrate research, formic acid facilitates the homogeneous
hydrogenation o f two epimeric aldoses, D-glucose and D-mam iose in presence o f
ruthenium complex catalyst.^^^ Form ic acid also assists the palladium catalysed transfer
hydrogenation o f nitrates in waste and drinking w ater which w ould offer as a prom ising
method for nitrate removal.
It has been shown that salts o f formic acid are m uch better hydr ogen donors than formic
aeid.’ ' ’^° Typically, considering few o f the formate salts as HCOOM w here M = H, Na, K,
54
Chapter 4
Li, NH 4, the hydrogen donor activity w ill follow the order H CO ON H 4 > H CO OK >
H COONa > HCOOLi > HCOOH. Particularly interesting is the pronounced activity o f
annnonium formate as compared to formic acid w here size o f the cation (NH4’*') and the
nature o f the O—N ionic bond are the two imporfant contributing features.
4.1.5 Am m onium Formate
Despite the variety o f organic/inorganic hydrogen donors larown, ammonium fo rm a te 201
has been proven to be the m ost corrveriierrt and effrcierrt for catalytic transfer
hydrogenations. Over the years, m ore and more attention has been draw n irrto its use
because it is readily available, less expensive, stable and non-toxic. There has been
noticeable developm ent in the application o f arnmorriurn formate for selective redirctions
o f azide, hydrazone, nitrile, dehalogenation o f aromatic chlorocarbons, deprotection o f
orf/ro-benzyl group and m any other im portant organic transformations.^^
The stereoselective synthesis o f j8-arnino alcohols is o f corrsiderable interest in organic
synthesis as jS-arnirro alcohols constitute useful synthons to m any importarrt heterocycles.
Armnoniurn formate in THF-M eOH solvent in presence o f 10% Pd on charcoal efficiently
reduces jS-nitro alcohols to the conespondirrg /3-amino alcohols at room temperature in
high y i e l d s ^ ( s e e Scheme 80).
OH
.R
R=CH^OTHP
R = Me
SC H E M E 80
Reagents and conditions: i) HCO2NH4, 10%Pd/C, THF-MeOH; ii) stining, room temperature
Also, a, (3- unsaturated nitr'oalkenes can be readily reduced to the corresponding oxinies in
good yields using armnoniimi formate in the presence o f palladium .^”’ hr addition,
armiionimn formate has also been exploited in the reduction o f heterocyclic ring in
quinoline and isoquinoline, reduction o f carbonyl and other functional gr'oups, reduction
o f double bond in conjunction to carbonyl moiety, in regioselective reduction o f epoxides.
55
Chapter 4
chemoselective reduction o f a, /3- unsaturated sulfones and phosphonates and m any other
organic transform ations.^^
4.2
Heterogeneous and Hom ogeneous Catalysts for Transfer H ydrogenation
4.2.1 Ontline
E qually im portant is the catalyst in transfer hydrogenations. H ydrogenation catalysts are
broadly classified into two types (a) H eterogeneous Catalyst and (b) Homogeneous
Catalyst. A great m ajority o f hydrogenations are done w ith these types o f catalysts.^^^’
hr the area o f transfer hydiogenation use o f transition metal catalysts has been significant
and m any catalysts and complexes developed on Rh, Pd, Ru, Jr m etal cenhes have been
applied.
4.2.2 Heterogeneous Catalysts for Transfer Hydrogenation
Heterogeneous catalysts are solids that form a distinct phase in the gas or liquid
enviromnent. Typically, in catalytic hydrogenations, for selective reduction o f a particular
functional group in a molecule, the fimction w ould norm ally imdergo an activated
adsoiption on a catalytic site, and preferably it w ould occupy m ost o f the active sites on
the catalyst. The efficacy o f the reduction is largely affected w hen catalytic sites aie
poisoned or have been occupied by some other function. Considering an example o f the
addition o f a molecule o f hydrogen across a C-C double bond, hydrogenations perfoiined
under catalytic conditions proceed via a stepwise mechanism, w here the inteim ediates are
stabilised by interaction w ith the catalyst.^'*'’’'’ Usually, catalyst o f the gioup VIII metals,
bring along the hydr ogen and the ir-system o f the double bond (C=C) onto the active site.
In case o f heterogeneous catalysts such as Pd/C, the active site m ay be considered as a
cluster o f metal atoms. Initially, there is physisorption and then chemisorption o f the
alkene and the hydrogen onto the active surface o f the catalyst. Follow ing which, there is
a hydrogen transfer, tlnough an inteiinediate, to give an alkane (see Scheme 81).
56
Chapter 4
H-H
Catalyst surface
• BH
HA-BH
SC H E M E 81
4.2.3 Hom ogeneous Catalysts for Transfer H ydrogenation-W illdnson’s Catalyst
Homogeneous catalysts generally dissolve in the liquid enviromnent, fonning only a
single phase. Catalytic hydrogenation under homogeneous conditions w ould essentially
involve the use o f homogeneous catalysts. V ery few homogeneous catalytic systems were
reported until the seminal w ork from W ilkinson and his c o - w o r k e r s , l e a d i n g to the
developm ent o f several transition metal complexes w hich foimd applications to
hydrogenate
unsatm ated
compomids
in
homogeneous
conditions.
Tris(triphenyl
phosphine)chloro rhodium (I) (RliCl(PPli3)3) 204 was firstly reported hy W ilkinson and
his co-workers in m id 1960’s.^^ Its hydrogenating activity was further discovered
independently hy Coffey.^*^ This complex was found to he very efficient hydrogenation
catalyst and has heen extensively employed.
The W ilkinson’s catalyst foim s an integral part o f the present study and will he utilised
extensively in studying several transfer hydrogenations to be discussed in the later part o f
this chapter. In this section, emphasis has heen laid on the synthesis, some properties and
particularly the mechanism o f hydrogenation involving its use.
4.2.3.1 W ilkinson’s Catalyst- Synthesis and Some Properties
W ilkinson’s catalyst 204 is synthesised from rhodium (III) chloride trihydrate 205 hy
refluxing w ith excess triphenyl phosphine 206 in ethanol (see Scheme 82). The reaction is
done rmder nitrogen atmosphere. A fter refluxing for two hours, a red crystalline product
begins to precipitate w hich can he collected by vacuum filtration, hi case, the ethanol used
is insufficient, it leads to the developm ent o f the polym oiphic fom i o f the product which
57
Chapter 4
is orange crystalline solid only after few m inutes o f refluxing, possessing similar chemical
properties but different catalytic activity.
This orange crystalline product could be
converted to the red crystalline form by continuous refluxing. The red crystalline complex
(RliCl(PPh3)3) 212 has a m.p. o f 157"C and is soluble in chlorofoim and dichloromethane
(~ 20g 1 “'), but only slightly soluble in benzene or toluene (~ 2g 1 '^) and is considerably
less soluble in acetone and alcohols.
RhCIj +
205
4 PPli3
..
"
RhCl(PPh,)3
206
204
+
Cl^PPh]
207
SC H E M E 82
Reagents and conditions: i) ethanol ii) reflux
Solutions o f the complex in chloroform and benzene readily absorb oxygen to form an
unfavourable inactive oxygenated complex. The complex also dissociates in solution, over
long periods and m ay dimerise. The orange-pinlc dimer is only sparingly soluble in
organic solvents and giadually precipitates fi'om the solution. This dim er was predicted by
Willdnson^^’’ to be a halogen bridged sti'uctine (see Figure 4.1). The fom iation o f such
dimers could be suppressed by using an excess o f the triphenyl phosphine during the
reaction.
\/'^ P P li3
Cl
214
Figure 4.1 Halogen bridged dimer
58
Chapter 4
4 .23.2
M echanism of H ydi ogenation nsing W ilkinson’s Catalyst
-L
H ^ h — 01
^ 1— Cl
+L
"
204
208
210
L = PPh,
CzHg
213
^ -C l
L
C
H
H
211
212
SC H E M E 83
M any catalytic processes involve elem entary reactions o f organom etallic compounds. One
o f the m ost extensively studied is the homogeneous hydiogenation o f olefins by the
chlorotris(triphenyl phosphine) rhodium(I) RliCl(PPli3)3 204.^^’’'° The m ost coimnonly
accepted mechanism o f this catalytic process is due to H alpem , supported by careful
kinetic^^'^''^’^ and spectroscopic studies.^^®"’’ The predom inant catalytic cycle is shown in
Scheme 83. The cycle constitutes an oxidative addition o f hydrogen m olecule prior to the
olefin co-ordination. RliCl(PPh3)2
RliCl(PPh3)3.^^'’'‘
reacts w ith H 2 at least 10"^ times faster than
hi the dissociative pathw ay tlnough the 14e tlu'ee co-ordinate
interm ediate 208, the oxidative addition o f H 2 to the transition m etal complex is a
concerted process leading to the cis adduct 209. The adduct is a five co-ordinate dihydride
complex 216 w ith a trigonal bipyiam idal stracture. The next step is the co-ordination o f
alkene (eg; ethylene) to the complex 209, H 2RliCl(PPli3)2. Experim entally, the cis
dihydiide olefin, w hich is foimd trans to a hydride is m ore stable. Thereafter, an
intram olecular migratory olefin insertion gives the ïra/w-ethyl complex 211 w hich is the
rate determining step in the catalytic cycle, h i this stage, the olefin picks up the hydride
from the metal at its imco-ordinated caibon. The reaction thus is described as a hydrogen
migration. The ethyl complex 211 has the ethyl group trans to the hydride. In order for the
reductive elimination o f ethane to take place, these two groups have to be cis to each
other. A n isomérisation leads to the cA-ethyl hydride complex 212. Finally, the reductive
elimination o f the ethane 213 from cA-ethyl hyiide (HRliCl(PPh3)2(C2H 5)) in the
W ilkinson’s catalyst cycle is considered to be fast and regenerates the complex 208.
59
Chapter 4
In summary, a variety o f hydrogen donors and their successful application in different
transfer hydrogenations has been described. Also, the involvem ent o f catalysts o f
heterogeneous and homogeneous nature in transfer hydrogenations has been described.
However, a large m ajority o f the hydrogen soui'ces utilised are not o f a recyclable nature
and camiot be reused. M ore importantly, the m ost w idely and popularly used ammonium
formate itself has several disadvantages w hich have been highlighted in the earlier section
(see Chapter 2). This has given impetus to the development and use o f novel hydrogen
donors in the present study. The developm ent o f such novel hansfer hydrogenation
sources supported on inorganic/organic matrices has been described in the earlier section
(see Chapter 3). In continuation this chapter will emphasise the application o f these novel
hydrogen donors in studying transfer hydrogenations. The study w ill also predom inantly
involve the use o f the W ilkinson’s catalyst during the transfer hydrogenations, hi
particular, the study w ill investigate the application o f microwave conditions in achieving
transfer hydrogenations.
60
Chapter 4
4.3 M icrowave assisted Hydrogenation o f Electron-Deficient A lkenes nsing Polymer
Snpported Hydrogen Donor (Aminometliylpolystyrene)^^
Studies were earned out to investigate the potential o f the novel polym er supported
hydrogen donors. The studies involved reduction o f electron deficient alkenes like a, /3unsatiuated carbonyl compomids. This was done in presence o f the W ilkinson’s catalyst.
Particularly interesting is the idea o f studying these reactions mider the influence o f
m icrowave iiTadiations.
Initial studies w ere perfoiined utilising a hydrogen donor developed on aminomethyl
polystyrene resin 175 (see Chapter 3). The polym er supported foim ate 176, w ith a loading
value o f 0.6 mm ol/g was used as a hansfer hydrogenation source in the reduction o f
electron deficient alkenes. For a reaction done under microw ave irradiations, a solvent
w ith high dielectric properties and transparency to microwaves is preferred. Dimethyl
sulfoxide (DMSO) was chosen as a solvent, seiwing as a heat transfer agent. The reactions
were done in a Pyrex® glass tube (see Fig 1.7 in Chapter 1) w ith a screw cap top.
Microwave conditions were applied to the reaction mixture using a m onom ode microwave
reactor (M W 10 M icrow ell microw ave reactor) operating at variable pow er and time o f
inadiation.
O
Pli
Q
OH
214
»- Ph
"
^
OH
215
50%
SC H E M E 84
Reagents and conditions: i) Aminomethylpolystyi-ene supported formate 176, RhCl(PPli3)3 204,
DMSO; ii)M W
A reaction m ixtm e was prepared using
ti'OMj'-cinnamic acid 214
(0.67 mmol)
aminomethylpolystyi-ene supported fonnate 176 (0.17 mol equiv) and W ilkinson’s
catalyst 204 (0.03 m ol equiv) using a m inim um quantity o f the DM SO (see Scheme 84).
The reaction mixture was inadiated w ith microwaves at 300 W for 10 seconds. On
irradiation the mixture showed the characteristic peaks o f the (X,j9-saturated compound,
distinguished in the
N M R w ith triplets at 2.61 ppm and 2.95 ppm coiTesponding to the
desired hydrocimiamic acid 215 (on comparison w ith an authentic sample). The yield o f
61
Chapter 4
the compound was obseiwed less than 50%. Confirmation o f the fonnation o f 215 from
the above reaction was obtained by an independent synthesis. A uthentic 215 was prepared
using sodium borohydride as the reducing agent using reflux conditions in methanol. In
view o f im proving the organic transformation, the reaction was attempted by reducing the
quantity o f starting ira/i^-cimiamic acid 214 (0.3 imnol), and the quantity o f the hydrogen
donor 176 was entranced to 0.35 m ol equiv and the W ilkinson’s catalyst to 0.05 mol
equiv. using DM SO as the solvent. The mixture was irradiated w ith m icrowaves at 300 W
for 10 seconds. These changes did not help in improving the yields, retaining the
um eacted starting m aterial along w ith evidence o f the hydrocimiamic acid. A t this stage,
the amount o f the hydrogen donor 176 was increased to 0.44 m ol equiv. keeping the
amount o f the catalyst 204 consistent. This attempt did not indicate any improvements.
Equally less successful was the attempt done by increasing the quantity o f the hydrogen
donor to 0.53 m ol equiv.
Attem pts made by gradually increasing the amounts o f the W ilkinson’s catalyst 204 to
0.12 mol equivalents did not show any improvem ents in the reaction. This only made the
product piuifrcation more difficult.
Often use o f alternative solvents m ay seiwe helpful and in this case use o f a high boiling
point solvent like di-n-butyl ether did not show improvements. U se o f m ixture o f solvents
was also considered and few drops o f w ater were introduced in the reaction mixtui e which
showed no substantial im provem ents in the reaction. The reaction was also attempted by
altering the incident m icrowave pow er and tim e o f irradiation on the sample. This was
done by gradually reducing the pow er o f irradiation to 100 W and correspondingly
increasing the tim e to 20-30 seconds. M ost o f the attempts did not exhibit any noticeable
improvements.
o
Ph
g
OMe
*- Ph
OMe
ii
216
217
<50%
SC H E M E 85
Reagents and conditions: i) Aminomethylpolystyi'ene supported fonnate 176, RhCl(PPh3)3 204,
DMSO; ii) MW
62
Chapter 4
The microw ave assisted reduction o f other o,|3-unsaturated compounds like ^rani'-methyl
ciimamate 216 and fra/î.s'-ethyl chmam ate 218 were also attempted using the polym er
supported hydrogen donor 176. h i case o f ï/'an^-methyl chmamate 216 (see Scheme 85),
m ost attempts made by altering the quantities o f the hydrogen donor 176 (0.1-0.5 mol
equiv.), the catalyst 204 and the m icrowave irradiation scale indicated an incomplete
reaction. The reaction m ixtm e o f com pound 216 after inadiation show ed triplets at 2.60
ppm and 2.95 ppm w hich was consistent w ith the (X,6-satmated protons in methyl
hydiochm am ate 217 and indicated low yields (40-50%). Isolation o f com pound 217 was
not possible. The confiim ation o f the fom iation o f compoimd 217 ho rn the reaction was
obtained by an independent synthesis o f 217. A uthentic 217 was prepared using N aBH 4 as
a reducing agent in refluxing methanol.
o
o
ii
218
219
<50%
S C H E M E 86
Reagents and conditions: i) Aminoniethylpolystyi'ene supported formate 176, RliCl(PPh3)3 204,
DMSO; ii)M W
Similai'ly, the m icrowave assisted (300 W for 10 seconds) reduction o f trans-Qthyl
chmamate 218 (see Scheme 86) gave evidence o f ethyl hydrocimiamate 219 w hich was
characterised by triplets at 2.61 and 2.95 ppm o f the ce,(8-saturated m ethylene protons in
the
NM R. The inadiated reaction mixtm'e also identified the unreacted starting
material and indicated low yields (<50%) o f reduction. Confim iation o f the fonnation o f
compomid 219 fi'om the above reaction was done by an independent synthesis o f 219. An
authentic sample o f 219 was synthesised using N aBH 4 as the reducing agent. Attempts
were also m ade to study the reduction o f other compounds like an aliphatic 0,(3unsaturated crotonaldehyde 220 under m icrow ave conditions. The reaction mixture on
inadiation w ith m icrowaves was studied by
N M R indicating only traces o f the desired
hydrocrotonaldehyde 221 distinguished hy extremely less intense peaks o f the 0,(3saturated m ethylene protons obseiwed at 2.61 and 2.95 ppm on comparing w ith an
authentic
sample.
Reduction
of
1,4-diphenyl-1,3 -butadiene
222
containing
two
unsaturated olefmic system was studied using the hydrogen donor 176 and W ilkinson’s
63
Chapter 4
catalyst 204 under m icrowave iiTadiations at 300 W for 10 seconds. The m ixtuie on
inadiation identified preferential reduction at one o f the olefmic bonds w ith low intensity
triplets at 2.54 and 2.79 ppm conesponding to m ethylene protons o f 1,4-diphenyl-but-lene 223 (com parison w ith data o f an authentic sample). The reaction indicated a partial
saturation o f the compoimd w hich was very low yielding and largely identified the
unreacted starting diene.
The m icrowave assisted reductions o f the electron-deficient alkenes studied using
aminomethylpolystyi-ene supported hydrogen donor 176 were generally low yielding. It is
possible that insufficient availability o f hydrogen from the ti'ansfer hydrogenation source
176 m ay be responsible for the incom plete reduction o f 0!,jS-imsaturated alkenes studied.
Evidently, the polym er supported formate 176 had a relatively low form ate loading (0.6
mmol/g). U se o f the supported hydrogen donor 176 is lim ited fi-om 0.17 to 0.53 mol
equivalents and inti'oducing further excess o f the polym er supported reagent is not suited
w hen perfoim ing reactions in the typical reaction tubes (see Figure 1.7, Chapter 1) under
m onom ode m icrowave conditions, h i addition, the possibility o f a side reaction leading to
the formation o f a polym er supported foim am ide m ay also be held responsible in the
lower yields o f reduction. A bove all, aminomethylpolystyi-ene support is relatively
expensive.
64
Chapter 4
4.4 Therm al and M icrowave assisted Hydrogenation o f E lectron-D eficient Alkenes
using a Polymer Supported Hydrogen D onor (Amberlite® IR A 938 (anionic))
In view o f the relatively low yields o f the reductions and the relatively liigh cost o f
aminomethylpolystyi-ene, use o f a different support for fonnate was investigated.
A polym er supported fonnate has been developed using an anionic ion exchange resin
(Amberlite® IRA 938) 181. Ion exchange resins are easily available and are relatively
cheap. The Amberlite supported foi-mate 182 has been prepared (see Scheme 74, Chapter
3). The loading value o f the fonnate was detem iined as 2.5 mmol/g.
CO,H
214
S C H E M E 87
R eagents and conditions:
i) Amberlite supported foi-mate 182, RhCl(PPli3 ) 3 204, DMSO; ii) MW
hhtially, the polym er supported fonnate 182 was utilised in studying the reduction o f a,|3unsatm-ated carbonyl compomids in presence o f W ilkinson’s catalyst. A reaction mixture
o f Armi'-chmamic acid 214, A mberlite supported formate 182 (4 m ol equiv.) and
W ilkinson’s catalyst 204 (0.25 m ol equiv.) in a m inim um quantity o f DM SO (see Scheme
87) was irradiated w ith microwaves at 300 W for 10 seconds. On completion, the mixture
identified low yields o f reduction at the C-C double bond and evidence o f um eacted
starting m aterial retained in the reaction m ixtm e was obtained. In view o f im proving the
reaction, the microw ave inadiation pow er was reduced to 100 W and the time o f
irradiation was extended to 30 seconds. This resulted in the reduction o f the a,iSunsaturated fra/i^'-cimiamic acid 214 to give quantitative yields o f the desired
hydrocimiamic acid 215. This was characterised by triplets observed at 2.61 ppm and 2.95
ppm conesponding to the o^|6-saturated m ethylene protons (-CH2) appearing in the
product 215 w ith no evidence o f mireacted starting material.
In a later attempt, the reaction mixtm-es was prepared by lowering the W ilkinson’s catalyst
204 content (0.06 m ol equiv.) and it also gave quantitative yields o f reduction. On further
lowering the catalyst below 0.06 m ol equiv, the yields o f the reaction deteriorated. A
thermal control reaction was studied while maintaining the reaction m ixture scale and
65
Chapter 4
heating in an oil bath. H eating the m ixture for up to 3-4 horus at 70-80°C lowered the
yields to 80% yields.
hi comparison, reduction o f im saturated carboxylic acids like ^ra«6'-cimiamic acid and
other compounds like azlactones, a-ketocarboxylic acids have been reported in the
literature^^ to give quantitative yields o f reduction by Pd catalysed transfer hydrogenation
in alkaline aqueous medium. Synthesis o f the desired hydrocimiamic acid by this method
involves com paratively longer reaction times o f up to 12-16 hoius. Also, some other
work^^ describes selective reduction o f C-C double bonds o f o;/3-misaturated carbonyl
compounds including fran^-cimiamic acid in very high yields using hydrogen selenide
(HzSe) generated in situ. The reaction produces very high yields o f the hydrocinnamic
acid after as long as 24 hours o f reaction times and involves use o f som e rather avoidable
harm ful reagents.
216
S C H E M E 88
R eagents an d conditions:
i) Amberlite supported fonnate 182, RhCl(PPh3 ) 3 204, DMSO; ii) MW
The A mberlite supported formate 182 was ftuther employed to investigate the reduction
o f OjjS-unsatiuated carboxylic acid esters like ïran^'-methyl cimiamate 216 and trans-ethyl
cimiamate 218. A reaction mixtrue o f fra/j^-methyl cimiamate 216, A m berlite supported
fonnate 182 (4 mol equiv.) and W ilkinson’s catalyst 204 (0.06 m ol equiv.) in DM SO was
inadiated w ith microwaves at 100 W for 30 seconds (see Scheme 88). A fter inadiation
the m ixtm e indicated excellent yields (90%) o f the desired m ethyl hydro ciimamate 217.
Compound 217 was characterised in the
N M R by developm ent o f triplets characteristic
o f the saturated methylene protons obseiwed at 2.62 ppm and 2.95 ppm. Theim al
comparisons were studied by repeating the reaction on the same scale and heating in oil
bath at 70-80”C for 3-4 horns. Even after 4 horns o f reaction time, the them ial route was
not equally successful and lowered the yields o f the reduction product to 70-75%.
Synthesis o f systems like methyl hydrociimamate has been reported in the literature^”®
using other non-conventional techniques. These teclmiques report the use o f a
heterogeneous diphosphine rhodium (I) hydiogenation catalyst incorporated into an
66
Chapter 4
organic polym er utilised in a fluorous biphase solvent, showing an increase in the rate o f
reduction. Synthesis o f methyl hydrocimiamate using such systems is interesting however
the synthesis is favoured only at high pressm es. hi another case, the chemoselective
reduction o f functional groups like C=C in presence o f esters found in methyl cinnamate
have been reported'®' using tehabutylanunonium borohydride in chlorosolvents. Such
systems involve reaction tim es up to 5 horns and make the isolation o f higher yields o f the
product less tenable due to multiple steps involved.
Ph'
''
-* ^ 2 ^ 5
218
S C H E M E 89
R eagents and conditions:
i) ikniberlite supported fonnate 182, RhCl(PPh3 ) 3 204, DMSO; ii) MW
Similarly, m icrowave inadiation o f a reaction mixtm'e prepared w ith ^ra/î^-ethyl
cimiamate 218, A mberlite supported fom iate 182 (4 mol equiv.) and W ilkinson’s catalyst
204 (0.06 m ol equiv.) in DM SO provided high yields (80%) o f the desired ethyl
hydrocimiamate 219. 'H N M R analysis o f the m ixtm e isolated as light yellow oil after
reaction showed developm ent o f a new set o f h'iplets at 2.61 ppm and 2.95 ppm
suggesting the selective reduction o f Q;/3-uiisaturatioii to have occu n ed successfully. A
thermal com parison o f the reaction studied by heating in an oil bath (75-80 °C for 3-4
horns) showed lowering in the yields (60-65%).
Reduction o f a variety o f 0!,iS-imsatm'ated esters like fran^-ethyl cimiamate and cyclic
ketones has been reported in the literature'®^^ showing a sm ooth reduction o f the C-C
double bonds w ith a com bination o f inexpensive and readily available trichlorosilane and
C0CI2. However, reductions under such m ild conditions have show n less competitive
yields. Selective reduction o f the o;/3-imsatm'ated carbonyl and ene dicarbonyl compomids
have been studied'®^'’ using relatively simple systems like ahuiiinium trichloride hydrate
and Zn in THF under amhient conditions. Such systems favour good yields o f reduction
products hut often require longer reaction times.
67
Chapter 4
/^ C H O
224
225
S C H E M E 90
Reagents and conditions:
i) Amberlite supported fomiate 182, RliCl(PPh3 ) 3 212, DMSO; ii) MW
The reduction o f 0!,iS-imsaturated carbonyl compounds like fran^-cinnamaldeliyde 224 has
also been studied under m icrowave conditions.(see Scheme 90). M icrow ave irradiation
(100 W for 30 seconds) o f a reaction mixture o f P^a/i^-cimiamaldehdye 224 with
Amberlite supported formate 182 (2 m ol equiv.) and W ilkinson’s catalyst 204 (0.06 mol
equiv.) showed only a hace o f the desired hydrociim amaldehyde 225 and largely
exhibited the um eacted starting aldehyde. Clearly, tlris observation indicated that, by
lowering the hydrogen donor content to 2 m ol equiv. significantly low ers the efficiency o f
the reduction. Reduction o f ^ran^-cimiamaldehyde 224 was attempted b y enliancing the
Amberlite supported fonnate 182 to 4 m ol equiv. On microwave irradiation (100 W for 30
seonds),
the
m ixtm e
gave
virtually
quantitative
yields
(95%)
o f the
desired
hydrociim amaldehyde 225. Theim al contiol (70 “C) o f the reaction mider identical scales
exhibited comparative lower yields even after 4 horns o f heating (70%).
Conjugate reduction o f a,/3-unsatm‘ated caibonyl compomids like fran^'-cinmiamaldehyde
by complexation w ith alm ninium tiis(2,6-diphenyl phenoxide) is reported in some recent
lite r a tu r e .H o w e v e r , this m ethod being a multistep process is less prom ising in giving
high yields o f reduction and involves a generous use o f solvents like toluene, THF, hexane
and also use o f some strong reagents like DIB AL and n-butyl lithimn.
COCK
226
S C H E M E 91
Reagents and conditions:
i) Amberlite supported formate 182, RliCl(PPh3 ) 3 204, DMSO; ii) MW
The Amberlite supported fonnate 182 has also been investigated for studying the
reductions o f ct,|8-unsatm ated ketones like benzylidene acetone 226 (see Scheme 91). A
reaction m ixture prepared using benzylidene acetone 226, the polym er supported
hydrogen donor 182 (4 m ol equiv.) and W ilkinson’s catalyst 204 (0.06 m ol equiv.) in
68
Chapter 4
m inim um quantity o f DM SO gave virtually quantitative yields o f the reduced benzyl
acetone 227 on m icrowave irradiation at 100 W for 30 seconds. The reduced product was
characterised by the developm ent o f signals corresponding to the a,jS-saturated methylene
protons at 2.78 and 2.87 ppm in the *H NM R. Theim al comparison o f the reaction earned
on the same scale for 3-4 horns showed the yields to fall to 70%.
Recent reports'°'^“ in the literatiue to reduce the C=C bond in highly activated conjugated
systems such as /3-arylenone and enone esters found in benzylidene acetone 226 have been
developed using Indium metal in aqueous ethanolic ammonium chloride used as a solvent.
This m ethod how ever new involves relatively longer reaction times (12 hours) and is
relatively low yielding (40%). Reduction o f the ce,jS-unsatm-ated ketonic systems using
N aBH 4 or NaBH 4 + C0CI2 selectively controlled by w ater or by aq. m icellar solutions
is rather simple but again involves relatively long reaction times.
228
229
S C H E M E 92
R eagents an d conditions:
i) Amberlite supported fomiate 182, RhCl(PPli3 ) 3 204, DMSO; ii) MW
Equally successful was the reduction o f o,jS-imsaturated amides like W,A^dimethyl
ciimamide 228 giving virtually quantitative yields o f reduction product, W,A^-dimethyl
hydi'ocimiamide 229. M icrowave iiTadiation o f a sample o f #,A/-dimethyl ciimamide 228,
A mberlite supported fom iate 182 (4 m ol equiv.) and W ilkinson’s catalyst 204 in DMSO
gave quantitative yields o f com pound 229 (see Scheme 92) characterised by diagnostic
triplets o f the a,/3-saturated methylene protons at 2.73 and 2.98 ppm. The peak
corresponding to the protons in -N(CH3)2 group were obseiwed overlapping at 2.93 ppm.
Thermal comparisons done by heating the reaction mixture for 3-4 hours in an oil bath at
identical scales at 70-80 °C showed reduced yields (70%).
U se o f simple systems like Lewis acid, B p3.Et20 has been reported^^^ in the literature for
the reduction o f such unsatm ated amides; however, this m ethod provides very low yields
(57%).
69
Chapter 4
230
S C H E M E 93
R eagents and conditions:
i) Amberlite supported formate 182, RhCl(PPh3 ) 3 204, DMSO; ii) MW
The reduction o f a,/S-imsatiu-ated nitriles like tran^'-cimramonitrile 230 has also been
studied under microwave conditions (see Scheme 93). M icrowave irradiation (100 W for
30 seconds) o f a reaction m ixture o f fra/^^-cimiamonihile 230, A m berlite supported
formate 182 (4 m ol equiv.) and W ilkinson’s catalyst 204 (0.06 m ol equiv.) gave virtirally
quantitative yields (95%) o f the reduced liydrocimiamonihile 231. T hennal comparisons
o f the reaction done at 70-80°C heating in an oil bath for up to 4 hours has given identical
yields (95%).
232
233
S C H E M E 94
R eagents and conditions:
i) Amberlite supported formate 182, RliCl(PPh3 ) 3 212, DMSO; ii) MW
n-Pentanoic acid (valeric acid) 233 has been synthesised in quantitative yield by reduction
o f the ct,jS-unsaturated carboxylic acid, ^ra«5-2-pentenoic acid 232 (see Scheme 94), using
4 m ol equiv. o f the A mberlite supported formate 182 and 0.06 m ol equiv. W ilkinson’s
catalyst 204 in DMSO. The thermal control reaction cariied out at 70-80 °C for 3-4 horns
showed lower yields (50%).
Ph
H bH d
Hd
222
223
S C H E M E 95
R eagents and conditions:
i) Amberlite supported formate 182, RhCl(PPli3 ) 3 204, DMSO; ii) MW
70
Chapter 4
Hydrogenation o f a sterically hindered conjugated diene like trans,
1,4-diphenyl-
1,3-butadiene 222 has been studied (see Scheme 95). M icrowave iiTadiation (100 W for
30 seconds) o f a reaction mixture w ith 1,4-diphenyl-1,3-butadiene 222, Amberlite
supported fonnate 182 (4 m ol equiv) and W ilkinson’s catalyst 204 in DM SO initially
showed selective hydrogenation o f only one C=C bond. The m ixtm e showed traces o f
trans, irani'-1,4-diphenyl-1-butene 223 and largely retained the um eacted starting diene.
Increasing the polym er supported hydrogen donor 182 to 8 m ol equiv. and the
W ilkinson’s catalyst 204 to 0.36 mol equiv., m icrowave irradiation o f the reaction mixture
preferentially hydrogenated one o f the C-C double bonds and gave 80% yield
o f the
reduction product 223. 'H N M R o f the starting material 222 shows characteristic
multiplets o f the conjugated diene across protons Ha, % and He, Hd at 7.03-6.68 ppm In
conti'ast, the product 223 isolated after iiTadiation was characterised b y a doublet observed
at 6.38 ppm coiTesponding to proton Ha o f the rem aining C-C double bond and
developm ent o f multiplets at 6.30 (Hb), 2.79 (He) and 2.54 (Hd) ppm (see schem e 95). This
observation was consistent w ith that o f an authentic sample. Thermal comparisons o f the
reaction done w ith an identical scale by heating in an oil bath at 80°C for 3-4 hours
showed poor yields (<20%) and retained the unreacted stalling material in the mixture.
AcO
HO
234
237
235
OH
251
236
A ttem pted hydrogenation o f sterically hindered or non activated steroid systems like
ergosterol 234, prognenolone acetate 235, aliphatic long chain acids like elaidic acid 236
and systems like a-pinene 237, 4-phenyl-1-butene 251 using A m berlite supported formate
were unsuccessful under m icrowave conditions.
71
Chapter 4
R eports documented in the literature^’’’ involving some deuterium labelling experiments
have provided a mechanistic rationale for selective C=C reduction o f a,iS-imsaturated
carbonyl compounds like itaconic acid derivatives using m olecular hydrogen or foimic
acid/triethylamine. Some other labelling studies reported^^’’ have also rationalised the
m echanistic details on reduction o f (x,j8-unsaturated carboxylic acids and esters using a
soluble foimate supported on TM EDA salt as a hydrogen donor in presence o f
W ilkinson’s catalyst 204. h i this case, use o f highly polar solvents like DM SO has shown
an effective reduction in comparison w ith other organic solvents.
h i this study, A mberlite supported formate 182 has been applied as a transfer
hydrogenation source for the reduction o f a,/5-misaturated electron-deficient alkenes. O iu
studies under m icrowave conditions have demonstrated that A m berlite supported fonnate
182 in presence o f W ilkinson’s catalyst 204 selectively reduces cr,/3-unsaturated olefmic
bond and affords the corresponding reduction products. M ost o f the substrates containing
an electron withdrawing substituent (R ’, see table 4.1) in conjugation w ith the a;/5unsaturated olefin have shown quantitative yields o f the reduction products. In each case a
thennal comparison for each reaction studied was imdertaken. In m ost o f the cases
studied, in comparison to the classical thennal approach, there has been a significant
im provem ent in the reaction yields activated by microwave irradiation. In particular, in
case o f compound 232 imder microwave heating, there has been a noticeable
im provem ent in the yield o f the reduction product as compared to the classical approach.
Hydrogenation o f a conjugated diene 222 has shown high yields o f selective reduetion o f
one o f the double bonds and required relatively higher quantities o f the polym er supported
donor 182 (8 mol equiv.) and the W ilkinson’s catalyst (0.36 m ol equiv.). hi case o f
substrate like ct-pinene 237, 4-phenyl-but-l-ene 251 where the olefin was not activated, no
reduction was obseived. It should also be noted that the insoluble nature o f the polym er
supported hydrogen donor has significantly contributed in simplifying the reduction
procedures. The polym er supported foim ate salt can be easily regenerated at the end o f the
reaction and could be easily rem oved fi-om the reaction mixture by filtration. Often, in the
stage o f purification by filtration, the reaction mixtures were led through a plug o f
alum ina for rem oval o f the catalyst, hi this m anner the alum ina adsorbs the catalyst fi-om
the solution. Eventually, evaporation o f the solvent leads to the isolation o f the reduced
product in a pure state. M ore importantly, the polym er supported formate could be reused
in four to five reaction/regeneration cycles before there is an appreciable decrease in the
72
Chapter 4
reaction yield.
Interestingly in most of the reductions studied, a minimal amount of
solvent was required.
/
1 . Filtration
2 . Recycling
I H C O ,-
R liC l(P P ln l/D M S O
Amounts (in mol
Substrate
R
R’
Product
Yield (%)
equiv.) of
H2 Donor
Catalyst
182
204
MW’
Thermal*’
214
Ph
CO2H
215
4
0.06
95
80
216
Ph
C O zM e
217
4
0.06
90
75
218
Ph
COzEt
219
4
0.06
80
62
224
Ph
CHO
225
4
0.06
95
70
226
Ph
COCH3
227
4
0.06
95
85
228
Ph
C 0 N (C H 3 )z
229
4
0.06
95
70
230
Ph
CN
231
4
0.06
95
95
232
Et
COzH
233
4
0.06
95
50
' A ll microwave irradiations were perform ed at 100 W fo r 30 seconds.
^ A ll thermal reactions were carried out at 70 °C fo r 3 hours in DMSO.
Table 4.1
Therm al and microwave assisted hydrogenation of electron-deficient alkenes using
Amberlite snpported formate and Wilkinson’s catalyst.
73
Chapter 4
4.5 Attem pted M icrowave assisted iV-Debenzylation
Formate Leading to A-Form ylation
using
A m berlite
Supported
Benzylic groups have been popularly employed for the protection o f amines'®^ and N, benzyl derivatives have played a central role in organic synthesis. The benzyl m oiety is
offered com m only for hetereoatom protection due to its ease o f introduction, inlierent
stability and simple procedrnes for rem oval, based on catalytic hydrogenation, catalytic
transfer hydrogenation and other reducing r e a c t io n s .A l th o u g h catalytic transfer
hydrogenation is a more efficient deprotection procedure than catalytic hydrogenation, it
has not been largely used as it m ust be earned out in high boiling solvents for relatively
long times w ith potential damage o f particulaidy sensitive organic compounds.
This section summarises the attempts made to investigate the m icrow ave assisted transfer
hydrogenation for A-benzyl deprotection studied on A-benzylated substrates, leading to Nfonnylation. The study o f 7V-debenzylation has been done using A m berlite supported
formate 182 used as a transfer hydrogenation source in presence o f 10% Pd/C catalyst
using rnonomode m icrowave iiTadiations.
hiitially, 7V-benzyl protected amine like A-benzyl-p-anisidine 240 w as synthesised using a
simple procedure, by refluxing a reaction mixture o f ^-anisidine 238 in acetonitrile for 1218 hours using potassium carbonate as the base and 1 mol equivalents o f benzyl brom ide
239 used as the benzyl protecting agent. Compound 240 was isolated as a white
crystalline solid in 40% yield on purification w ith colum n clnornatography (silica, DCM )
(see Scheme 96).
OMe
OMe
- 4
,
,
A
V
1
1
NH
NH j
238
^ P h
240
SCHEME 96
R eagents and conditions:
i) K2 CO3 , PhCHiBr 239, CH3 CN; ii) reflux, 12-18 hours.
74
Chapter 4
A reaction mixture was prepared using com pound 240, A mberlite supported fonnate 182
(2 m ol equiv.) and 10% Pd/C (0.025g) using DM SO (0.5-0.8 m l) as the solvent. On
inadiation w ith microwaves at 100 W for 30 seconds, no evidence for A -debenzylation
was obseiwed. The reaction was attempted b y doubling the amount o f polym er supported
hydrogen donor (4-5 m ol equiv.) and setting the irradiation scale to 80 W for 40 seconds.
On completion o f the reaction, a crystalline solid was isolated from the mixture.
NMR
analysis showed the presence o f a characteristic fom iam ide proton at 8.39 ppm. IR
analysis o f the solid showed presence o f a - C = 0 stretching at 1674 cm "\ This was
characteristic o f a fonnam ide carbonyl that resulted from the A -fonnylation o f the
secondary amine in com pound 240.
)Me
)Me
NH
kPh
241
240
S C H E M E 97
R eagents and conditions:
i) Amberlite supported formate 182, DMSO; ii) MW
The reaction was repeated at the same scale and maintaining the m icrow ave inadiation
scale in absence o f Pd/C catalyst (see Scheme 97). In this attempt, the isolated product
m aintained a diagnostic carbonyl stretching at 1674 c m '\ The isolated com pound (7075% yield) was confrrrned to be A-berizyl-A-forinyl-p-anisidine 241 from its melting
point, 44-46 °C, w hich was consistent w ith the literature data.'°^
This result made evident that the A mberlite supported fonnate 182 is able to formylate
amines and synthesise conesponding fonnarnides. This result led to a further investigation
on the application o f A mberlite supported fom iate 182 in the synthesis o f fonnarnides
using primar y and secondary amines.
75
Chapter 4
4.6 Form am ide Synthesis using Am berlite Snpported Formate as Form ylating Agent
Form amides are an im portant class o f intermediates in organic synthesis. They have been
w idely used in the synthesis o f phaiinaceutically im portant compounds such as
flu o ro q u in o lo n e s ,s u b s titu te d aryl i m i d a z o l e s , n i h o g e n bridged heterocycles,'
1,2-dihydroquinolines,' '
etc.
Chiral fonnarnides have
fourrd application in the
asymmetric allylation o f aldehydes.'"'® They are useful reagents in Vilsm eier formylation
r e a c t i o n s . h i addition, they have been used in the synthesis o f formamidines""® and
isocyanides.
N umerous m eth o d s'" are available for the synthesis o f fonnarnides by A -fonnylation o f
amines. A m ongst m any methods, use o f armnoniirm formate as an efficient A-formylating
agent for secondary amines and anilines has been loiow n."^ M ore recently microwave
activation has been used w ith a great deal o f sirccess in several eases o f amide synthesis
by irradiation o f arnine-carboxylic mixtures. Synthesis o f typical amides has been studied
by the pyrolysis o f the salts obtained instantaneously from rnixtrnes o f an amine and a
carboxylic acid (see Scheme 98)."^
R C O jH
+
241
R 'N H ^
^
R C O j - , + N H 3R '
242
x
243
^
RCONHR'
HjO
244
S C H E M E 98
This section discusses orrr studies m ade to synthesise formamides starting fi-om primary
and secondary amines using Annberlite supported formate 12 under m icrowave and
thermal conditions.
NH,
HN
245
H
246
S C H E M E 99
R eagents and conditions:
i) Amberlite supported formate 182, DMSO; ii) MW
76
Chapter 4
A reaction mixture was prepared using aniline 245 and polym er supported formate 182
(1.7 m ol equiv) using minim um quantity o f DM SO as the solvent. The m ixture was
irradiated w ith microwaves at 40 W for 60 seconds. A fter inadiation, the mixture had
retained the um-eacted starting material, w hich w as shown by TLC analysis (silica, 50/50
hexane/ethyl acetate) identifying distinct spots o f the starting aniline w ith Rf value 0.36
and the probable A-forinylated product, forinanilide 246 shown at Rf value 0.14. W ith this
obserwation, the reaction rnixtrrre was prepared using 5 m ol equivalents o f Amberlite
srrpported formate 182 and was irradiated w ith a stronger incident pow er o f 100 W for
about 30 seconds. The reactiorr m ixture indicated only one hom ogeneous spot on TLC
analysis and produced virtually quantitative yields o f the desired formanilide 246. The
cornpormd developed a distinguished earbonyl sftetching in the IR spectra obserwed at
1682 cm "\ conesponding to the formamide carbonyl.
f
I
.
o
Figure 4.2 E n do-exo isomerism in formanilide
Form anilide 246 isolated after m icrowave inadiation showed endo and exo isomerism
(see Figure 4.2) w hich was evident ftorn the chemical shifts o f the form am ide protons in
the conesponding ’H NMR. A large coupling constant ( J = 11.4 Hz) was obserwed for the
exo isom er (Ôh = 8.68 ppm), in w hich the NH and CH protons ar-e trans to each other. A
slightly broad peak for the endo isom er was shown at 8.37 ppm. This char-acteristic
obserwation in compound 246 was consistent w ith the literature data.'^^“ Thermal
comparisons were studied by perform ing the reaction rmder an identical scale and heating
in an oil bath. H eating the reaction mixture for 3 hours at 70 °C, show ed lowered yields
(60%).
o
I ,
247
^
248
S C H E M E 100
R eagents and conditions:
i) Amberlite supported formate 183, DMSO; ii) MW
77
Chapter 4
A^-Foiinylation was further studied by preparing a reaction m ixtm e o f benzylam ine 247
and A mberlite supported formate 182 (6-7 m ol equiv.) in DM SO. On iiTadiation w ith
microwaves at 100 W for 30 seconds (see Scheme 100), the m ixtm e identified virtually
quantitative yields o f the desired //-benzyl fom iam ide 248. D evelopm ent o f a
homogeneous spot on TLC analysis (silica, 4:1 DCM /M eOH) w ith Rf value 0.63, differed
from the starting m aterial shown at Rf value o f 0.85. A^-benzyl formamide 248 was
identified by the developm ent o f a characteristic carbonyl sbetching show n at 1667 cm"^
and a foim am ide proton signal obseiwed at 8.28 ppm in the
N M R (on comparison with
data o f an authentic sample).
249
250
S C H E M E 101
Reagents an d conditions:
i) Amberlite supported formate 182, DMSO; ii) MW
M icrowave inadiation (100 W 30 seconds) on a reaction m ixtm e o f (±)-o:-methyl
benzylamine 249 using 3-4 m ol equivalents o f the polym er supported formate 182 using
DM SO as the solvent gave quantitative yields o f the desired (±)-N-(o:-methyl- benzyl)
foim am ide 250 (see Scheme 101). Developm ent o f a singlet at 8.11 ppm in the
chai'acterised the formamide on comparison w ith the data o f an authentic sample.
Jl
NH,
Y
MeO
^
11
MeO
238
o
252
S C H E M E 102
R eagents and conditions:
i) Amberlite supported formate 182, DMSO; ii) MW
M eO
MeO
Figure 4.3 Endo-exo isomerism in /;-substituted formaniiide
78
NMR
Chapter 4
Synthesis o f 4-niethoxy formanilide 252 has also been studied using the polyiuer
supported formate 182 (4-5 m ol equiv.) w ith 4-m ethoxy-aniline 238 (see Scheme 102).
The presence o f electron donating 4-m ethoxy substituent on the aniline helps in enliancing
the nucleophilic chai'acter o f the prim ary amine. The 4-m ethoxyfoim anilide 252 is
produced in good yields (80%) on iiTadiation w ith microwaves at lOOW for BOseconds
using DM SO as the solvent. In case o f ^-substituted foim anilides like compound 252,
endo-exo isomerism (see Figure 4.2) was obseiwed which was chai'acterised by distinct N HCH peaks o f the two isomers. The exo isom er was shown as a doublet at 8.48 ppm ( / =
11.4 Hz) and the endo isom er was shown as a broad peak at 8.33 ppm. h i addition, a long
range anisotropic effect o f the caibonyl gi'oiip showed the p-substituted m ethoxy
resonances o f the exo and endo separately at 3.80 and 3.79 ppm. This w as consistent w ith
the data shown in the l i t e r a t u r e . T h e i m a l heating o f the reaction mixture with
identical scales on an oil bath for up to 4 hours at 70-75 °C produced low ered yields o f Nfom iylation product (60%).
H
ii
CHO
254
253
S C H E M E 103
Reagents and conditions: i) Amberlite supported foimate 182, DMSO; ii) MW
7/,A-Dibeiizyl formamide 254 has been synthesised by in adiatiiig a reaction mixture o f a
secondary amine like dibenzyl amine 253 w ith Amberlite supported form ate 182 (6-7 mol
equiv.) in DM SO (see Scheme 103). The reaction mixture was iiTadiated at 100 W for 30
seconds. Compound 254 was produced in very good yields (82%) and w as characterised
by the developm ent o f a carbonyl stretching in the IR spectnm i show n at 1672 cm '' and a
singlet showing at 9.42 ppm in the 'H N M R corresponding to the N -foim am ide proton.
The formamide is bridged to two benzyl moieties in compound 254 respectively and is
able to rotate freely about the N-C bond o f the foimamide. Prior to the formylation o f
compound 253, the m ethylene bridge protons o f the dibenzyl group are show n as a singlet
around 3.77 ppm in the 'H N M R spectra and on generation o f com pound 254, two
distinguished peaks are obsei-ved aioiind 4.26 ppm and 4.41 ppm characterising the two
distinct m ethylene bridge protons. T hennal comparison o f the reaction on heating in an oil
bath at 70 °C for 3-4 hours in DM SO gave nearly identical yields (80%).
79
Chapter 4
H
ÇHO
■N.
N
N
H
CHO
255
256
S C H E M E 104
Reagents and conditions: i) Amberlite supported formate 183, DMSO; ii) MW
//-Foraiylation o f a secondary diamine like piperazine 255 was studied w hile maintaining
3-4 m ol equiv o f the A mberlite supported fonnate 182 and DM SO as the solvent.
M icrowave irradiation o f the reaction mixture (100 W for 30 seconds) (see Scheme 104)
gave piperazine dicarbaldehyde 256 in fairly good yields (60%). C onfm nation o f the
formation o f 256 was obtained b y an independent synthesis. A uthentic 256 was
synthesised alternatively by refluxing the starting piperazine 255 w ith ethyl formate 257.
Compound 256 w ith nonaxially syrmnetric substituents like formyl exhibited two forms.
At room temperature, the ring protons in syn isom er exhibited a pair o f singlets at 3.39
ppm and 3.38 ppm and the a?iti isom er generated a pair o f m ultiplets shown at 3.24 and
3.43 ppm, w hich was consistent w ith the literatiue data.^^'^ Thermal com parison o f the
reaction by heating the components in an oil bath for 4 hours at 70-80 °C indicated the
yields to lower less than 50%.
N
N
H
CHO
258
259
S C H E M E 105
Reagents and conditions: i) Amberlite suppoided formate 182, DMSO; ii) MW
W-Formylation o f the secondary amine fimction in rnorpholine 258 led to the synthesis o f
4-formyl rnorpholine 259 by m icrowave inadiation at 100 W for 30 seconds (see Scheme
105). The Amberlite supported formate 182 w as utilised in a slight excess o f 5-6 mol
equivalents.
The reaction led to fairly good yields (60%) o f com pound 259. The
formation o f compound 259 was confirmed by alternative route. Authentic 259 was
synthesised by refluxing rnorpholine 258 w ith 3-4 m ol excess o f ethyl formate 258. The
80
Chapter 4
reaction was also studied therm ally (70-80 °C, 4 hours) using the polym er supported
fonnate and maintaining identical reaction scale which resulted in reduced yields (<50%).
HN
H
S C H E M E 106
Reagents and conditions: i) Amberlite supported formate 182, DMSO; ii) MW.
M icrowave assisted 77-forinylation o f 2,4-difluoroaniline 260 was studied (see Scheme
106). A reaction inixtm e was prepared using 260, 5-6 m ol equivalents o f the polymersupported formate 182 using DM SO (0.8 ml) as the solvent, h radiation o f the sample at
100 W for 30 seconds gave the desired 2,4-difluoroform anilide 262 in 67% yield afterreaction.
Cornpoimd
261
identified
the
developm ent
of a
carbonyl
stretching
conesponding to the forniamide at 1672 c in ' and also indicated, the characteristic (NHCH) peaks o f the exo-isomer ohsei-ved as a doublet at 8.54 ppm ( / = 11.4 Hz) and a
broad singlet at 8.45 ppm for the endo isomer. The compoimd w as also confirmed from
the mass spectrum indicating the M"*" ion corresponding to 261 present in the matrix.
Authentic 261 was also prepared via alternative m ethod by refluxing 2,4-difluoroaniline
260 in excess o f ethyl formate 257 for over 12 hours.
A-Forrnylation o f other prim ary amines like 2,5-di-tert-hutyl aniline 262, 2-arnino benzyl
amine 263, O-phenylene diam ine 264, 3,4-diarnino toluene 265 have been studied, hut
w ith less success. M icrow ave assisted A -formylation using the polym er supported formate
182 done on these cornpormds only indicated the urneacted starting m aterials. This m ay be
due to steric reasons or for electronic reasons. M ost o f the attempts m ade have not been
prodrrctive and rro progress irr the reactions was ohser-ved.
hr surmnary, use o f a polym er supported formate (Amberlite® IRA 938 supported
formate) has been demonstrated for applications not only as a transfer hydrogenation
source but also as a formylating agent. M icrowave assisted studies on aromatic prim ary
amines like aniline 245, henzylam ine 247, ct-methylbenzylamine 249, p-anisidine 238
81
Chapter 4
have shown very high yields o f the corresponding formamides. In case o f henzylamine
247, quantitative yields o f the conesponding fonnam ide 248 required excess o f the
polym er supported formate 182 (6-7 m ol equiv.)- Form ylation o f an aromatic secondary
amine, dibenzyl amine 253 required excess o f the polym er supported fonnate 182 (6-7
mol equiv.) and has shown quantitative yields o f the conesponding fonnam ide 254 under
microwave conditions. In each ease a thennal comparison was undeitalcen, w hich showed
that in com parison to the classical thermal approach, microwave conditions have shown
im provem ent in reaction yields and reduction o f reaction times, hr particular, substrates
238 and 245 have shown dramatic im provem ent in reaction yields under microwave
conditions. M ore significantly, use o f an insoluble polym er supported foim ylating agent
has allowed easy rem oval o f the reagent on completion o f the reaction by simple lilti ation.
Use o f such reagents has allowed sim plification o f the reaction w ith high reproducibility.
1. Filtration
2. Recycling
NCHO
NH
DMSO
Amine
Product
Substrate
Polymer
Supported
Formate
(in mol
eqniv.)
MW"
Thermal''
Yield (%)
R
R’
245
Ph
H
246
5
90
60
247
PhCHz
H
248
6-7
95
80
249
PI1 CH3 CH
H
250
3-4
95
85
238
j3-CH30C6H4
H
252
4-5
80
60
253
PhCHz
PI1 CH2
254
6-7
95
80
255
HN(CH 2 CH2 ) 2
256
3-4
60
55
258
0
(CH2 CH2 ) 2
259
5-6
60
<50
^ A ll microwave irradiations were perform ed at 100 W fo r 30 seconds.
^ A ll thermal reactions were carried out at 70-80 °C fo r 4 hours in DMSO.
Table 4.2 Thermal and microwave assisted formylation of primary and secondary amines
using polymer supported formate as formylating agent
82
Chapter 4
4.7 Alumina Supported Form ate for H ydrogenation o f Alkenes^^^
Transfer hydrogenations are often m ild and selective and are w idely utilised. These
m ethods employ a sacrificial hydrogen source such as an alcohol to deliver the reductant.
Alternatively, use o f a supported transfer hydrogen source for reduction o f alkenes has
been dem onshated earlier (see Section 4.5).
hr this section, application o f A lm nina supported formate 189 w ill be discussed as a
hydrogen donor for studying reduction o f election deficient alkenes like a,j8-unsaturated
carbonyl compounds. Development o f a hydrogen donor supported on an inert, porous
solid support as alum ina has been discussed earlier (see chapter 3). F onnic acid supported
on basic alum ina (AI2 O3 /HCOOH) 189 has been used as a transfer hydrogenation soiuce.
The formate loading was determined as 2 mmol/g.
Q
Ph
^
Q
OH
ji
214
Ph
OH
215
S C H E M E 107
Reagents and conditions: i) Alumina supported fomiate 189, DMSO; ii) MW
Initially, reduction o f an a;/?-unsaturated carboxylic acid like trans-ckm m m c 214 was
studied by preparing its reaction m ixtiue w ith A lum ina supported hydrogen donor 189 (5
mol equiv.) and W ilkinson’s catalyst 204 (0.06 mol equiv.) in DM SO.
The reaction
mixture was irradiated w ith microwaves at 100 W for 30 seconds (see Scheme 107). On
completion, the reaction mixture was filtered, and on vacuum evaporation yielded the
reduced product, hydrocinnam ic acid 215, in quantitative yields. The interesting aspect o f
the reaction here is that, use o f alm nina support aids in purification at the end o f the
reaction by acting as a scavenger o f W ilkinson’s catalyst, reducing the need for further
purification. The hydiociim amic acid 215 was characterised by developm ent o f the a,^saturated methylene protons in the
N M R spectrum, consistent w ith that o f an authentic
sample. On studying the reaction thennally, by heating on an oil bath at 70-80 °C gave
com paratively low yields (80%) and the reaction m ixtm e was observed to retain the
m neacted starting material.
83
Chapter 4
Q
Ph
^
O
OMe
jj
Ph
216
OMe
217
S C H E M E 108
Reagents and conditions: i) Alumina supported formate 189, DMSO; ii) MW
Reduction o f ct,j8-unsaturated carboxylic esters like ^rani'-methyl cinnam ate 216 and transethyl cinnamate 218 have been investigated. A reaction mixtui'e o f com pound 216 with
AI2O3/HCOOH 189 (5 m ol equiv.) and W ilkinson’s catalyst 204 (0.03 m ol equiv.) (see
Scheme 108) was irradiated w ith microwaves at 100 W for 30 seconds. A fter iiTadiation,
the reaction m ixtm e gave 88-90% yields o f the desired methyl hydrocinnam ate 217. 'H
N M R showed the characteristic ct,j8-satm ated m ethylene protons as triplets at 2.61 ppm
and 2.95 ppm w hich was consistent w ith that o f an authentic sample. Therm al comparison
o f the reaction by heating in an oil bath at 70 °C for 3-4 hours identified lowered yields
(75%).
o
Ph
—
g
OEt
Ph
OEt
ii
218
219
S C H E M E 109
Reagents and conditions: i) Alumina supported formate 189, DMSO; ii) MW.
Reduction o f trans-dà\y\ cinnamate 218 w ith 5 mol equiv. AI2O3/H COO H 189 and 0.06
mol equiv W ilkinson’s catalyst 204 in DM SO (see Scheme 109) identified 70% yields o f
ethyl hydrocimiamate 219 on completion o f the reaction. The cr,j8-saturated methylene
proton triplets observed at 2.63 ppm and 2.96 ppm were consistent w ith the data fiom an
authentic sample. Thermal comparison o f the reaction exhibited reduced yields (60%)
after about 4 hours o f heating at 70 “C.
o
Ph
^
o
H
jj
224
Ph
^
H
225
S C H E M E 110
Reagents and conditions: i) Alumina supported fonnate 189, DMSO; ii) MW
84
Chapter 4
Reduction o f ^ranj'-ciimamaldehyde 224 was studied by irradiating (100 W for 30
seconds) its reaction m ixtm e w ith 5 m ol equiv. Alumina supported hydrogen donor 189
and W ilkinson’s catalyst 204 (0.06 m ol equiv.) in DM SO, gave 60% yields o f
hydrocinnamaldehyde 225 (see Scheme 110). Attem pts to im prove the reaction yields hy
enhancing the quantities o f the hydrogen donor were mrsuccessful. On studying the
reaction under thennal conditions, the yields was low (50%) and the reaction mixture
retained the unreacted starting m aterial even after 4 hours o f heating in oil hath at 70 °C.
o
Pli
^
o
CH3
ii
pii
226
^
CH3
227
S C H E M E 111
Reagents and conditions: i) Alumina supported fonnate 269, DMSO; ii) MW
Reduction o f an a,/3-mrsaturated ketone like henzylidene ketone 226 w as done studied
using 5 m ol equiv. o f the hydrogen donor 189 and 0.06 m ol equiv. o f W ilkinson’s catalyst
204 (see Scheme 111). M icrowave irradiation o f the reaction m ixture at 100 W for 30
seconds gave virtually quantitative yields o f the hydrogenated product, benzyl acetone
227. The product was identified hy
N M R indicating the developm ent o f the diagnostic
ce,|S-saturated methylene proton hiplets shown at 2.78 ppm and 2.87 ppm. h i comparison,
the thennal reaction was done at 70°C for 4 hours in an oil hath and showed slightly lower
yields (88%).
O
Ph
O
NCCHj )^
..
P h '^ '^ - '^ '^ N C C H j ) ^
228
229
S C H E M E 112
Reagents and conditions: i) Alumina supported fonnate 189, DMSO; ii) MW
Quantitative yields o f A,iV-dimethyl hydrocimiamide 229 have heen produced hy
microw ave inadiation (100 W for 30 seconds) o f a reaction mixtm'e o f AjW dimethyl
cimiamide 228, alum ina supported formate 189 (5 m ol equiv.) w ith W illdnson’s catalyst
204 (0.06 m ol equiv) using DM SO (0.6 ml) as a solvent (see Scheme 112). The reduction
product 229 was confim ied w ith a mass spechum indicating the characteristic M”^ ion in
85
Chapter 4
the m atrix and also other spechal data w ere consistent w ith that o f an authentic sample.
The them ial reaction in comparison, delivered slightly lowered yields (70%) after 4 hours
o f heating using an oil bath at 70 °C.
Ph"
230
SC H E M E 113
Reagents and conditions: i) Alumina supported formate 189, DMSO; ii) MW
Similarly, the hydrogenation o f /raw.s-cimiamonitrile 230 yielded >95% yields o f 0,(3saturated hydrochm amonitrile 231. 4-5 mol equivalents o f the alum ina supported
hydrogen donor 189 and 0.06 mol equivalents o f the W ilkinson’s catalyst 204 was
maintained in the reaction m ixtm e. M icrowaves were made incident on the reaction
mixture at 100 W for 30 seconds using DM SO as the solvent (see Scheme 113). T hennal
comparison was studied by heating the reaction mixture in an oil bath at 70 °C, showed
identical yields after 4 hours o f heating.
232
SC H E M E 114
Reagents and conditions: i) Alumina supported formate 189, DMSO; ii) MW
M icrowave assisted reduction o f an a,/3-unsaturated acid like hnzM-2-pentenoic acid 232
was studied by preparing its reaction mixture w ith a slight excess o f the alumina
supported formate 189 (8 m ol equiv.) and the W ilkinson’s catalyst 204 (0.12 m ol equiv).
The m ixture on inadiation at 100 W for 30 seconds gave 73% yield o f trans-2-pentanoic
acid 233 (see Scheme 78). Reduction o f the olefmic system w as characterised by
developm ent o f multiplets obseiwed at 1.54-2.26 ppm (com parison w ith the
NMR
spectm m data o f an authentic sample). The reaction done thennally by heating the
components in an oil bath at 70 °C for 3-4 hom's showed lowered yields (50%).
86
Chapter 4
The application o f the alum ina supported fonnate has also been studied for hydrogenation
o f olefmic systems found in some sterically hindered systems as 1,4-diphenyl-1,3butadiene 222.
9 = He.
He
.Ph
P lf
Hb Hd Hd
222
223
S C H E M E 115
Reagents and conditions: i) Alumina supported formate 189, DMSO; ii) MW
The reduction o f 1,4-diphenyl-1,3-butadiene 222 was obseiwed to w ork successfully under
microwave conditions. This resulted in the preferential reduction o f one o f the olefmic
system foimd in the 1,4-diphenyl-1,3-butadiene. IiTadiating a reaction mixture o f 222 w ith
3-4 mol equivalents o f the hydrogen donor 189 in presence o f 0.06 m ol equivalent o f
catalyst 204 showed only m inor traces o f 1,4-diphenyl-but-1-ene 223. However, on
increasing the hydi'ogen donor quantity to 6-8 m ol equivalents and also the W ilkinson’s
catalyst to 0.3-0.35 m ol equivalents, m icrowave inadiation at 100 W for 30 seconds
resulted in very good yields (80%) o f product 223. The reduction o f one o f the olefinic
bonds was characterised by peaks observed at 6.38 ppm consistent w ith the Ha o f one o f
the C-C double bond and developm ent o f multiplets at 6.30 (Hb), 2.79 (He) and 2.54 (Hd)
ppm in the ^H NM R, consistent w ith that o f an authentic sample.
Attem pts to study the reductions o f other unsaturated compounds like chaleone 268, apinene 237, mesityl oxide 266, P-a/zj'-stilbene 267 were less successful and indicated either
very low or negligible yields o f the reduction products.
h i sununary, the study has demonstrated that formic acid m ay be supported on almnina
and used as a transfer hydrogenation som ce for the selective reduction o f a,j8-unsaturated
electron deficient alkenes using W ilkinson’s catalyst. In general, the alum ina supported
fom iate gives very high yields o f reduction w ith substrates containing an electron
withdrawing substituent (R ’, see table 4.3) in conjugation w ith the alkene. The reduction
o f an aliphatic ce,jS-unsaturated electron deficient alkene 232 required excess o f the
hydrogen donor 189 (8 m ol equiv.) and catalyst 204 (0.12 m ol equiv.) for quantitative
yields. Similarily, reduction o f a conjugated diene 222 w ith high yields, required a large
87
Chapter 4
excess o f the hydrogen donor (8 mol equiv.) and the eatalyst (0.3 m ol equiv.). More
im portantly microw ave conditions have considerably reduced the reaction times. In
comparison to the classical thermal approach, in most cases, the reaction yields have
shown an im provem ent o f 10-25% by application o f microwave conditions, hi p articulai",
there is a dramatic im provem ent in the yields o f compounds 229 and 233. More
significantly, use o f an inorganic solid like alum ina not only serves as a support for the
hydrogen donor but has also simplified the purification procedure by acting as a
scavenger for W ilkinson’s catalyst at the end o f the reaction.
1. Filtration & recycling
2. C atalyst scavenging
A l,0 ,/H C O O H
RliC l(PPh,)
D M SO
Yield (%)
Amounts (in mol
Substrate
R
R’
Product
equiv.) of
H 2 Donor
Catalyst
189
204
MW"
Thermal'’
214
Ph
COzH
215
5
0.06
95
80
216
Ph
COiM e
217
5
0.03
90
75
218
Ph
COzEt
219
5
0.06
70
60
224
Ph
CHO
225
5
0.06
60
50
226
Ph
COCH3
227
5
0.06
95
80
228
Ph
C0N(CH3)2
229
5
0.06
95
70
230
Ph
CN
231
4-5
0.06
95
90
232
Et
CO2 H
233
8
0.12
73
50
" A ll microwave irradiations were perform ed at 100 W fo r 30 seconds.
**A ll thermal reactions were carried out at 70 °C fo r 3-4 hours in DMSO.
Table 4.3 Thermal and microwave assisted hydrogenation of electron-deficient alkenes using
Amberlite supported formate and Wilkinson’s catalyst.
h i principle, Amberlite supported formate 182 and ahmiina supported formate 189 have
sei"ved as much more efficient hydrogen donors than aminomethyl polystyrene supported
hydrogen donor 176. Amberlite supported hydrogen donor 182 w ith relatively high
loading o f fonnate (2.5 mmol/g) and alum ina supported hydrogen donor 189 (formate
Chapter 4
loading o f 2 nnnol/g) give efficient reduction o f a,iS-unsaturated electron deficient
alkenes. In particular under m icrowave conditions, Amberlite supported formate 182
seiwed as a better hydrogen donor in com parison to alumina supported formate 189 and
showed sm ooth reduction o f a,jS-unsaturated carbonyl compounds like iran^-ethyl
cimiarnate 218, ^ra«5-cimiamaldehyde 224 w ith better yields, h i addition, Amberlite
supported formate 182 serwes as a better hydrogen donor in the m icrow ave assisted
reduction o f an aliphatic a,j6-unsatm ated carbonyl compound like fra«5-2-pentenoic acid
232 giving higher yields (see tables 4.1 and 4.3).
89
Chapter 4
4.8 Form am ide Synthesis using Alum ina Supported Formate as Form ylating Agent
The application o f alum ina supported fonnate as a hydrogen source in transfer
hydrogenations has been demonstrated (see Section 4.7). Studies w ere further done to
investigate the application o f alum ina supported fonnic acid in the form ylation o f piim aiy
and secondary amines.
The iV-fbnnylation o f amines like henzylamine, aniline, (±)-o!-methylbenzylamine, panisidine, 2,4-difluoroaniline and secondary amines like N, 77-dibenzyl amine, piperazine
and rnorpholine have been studied.
NH,
245
246
S C H E M E 116
Reagents and conditions: i) alumina supported fomiate 189, DMSO; ii) MW
A reaction mixture was prepared using aniline 245, ahmiina supported formate 189 (3.5-4
mol equiv.) and using DM SO as the solvent and irradiated w ith microw aves at 100 W for
30 seconds (see Scheme 80). On com pletion o f the reaction, the m ixture showed evidence
o f the forrnanilide 246 in the
NM R. This was associated w ith som e evidence o f the
unreacted starting aniline retained in the reaction mixtme. The reaction w as repeated by
enliancing the quantity o f the alum ina supported formate to 6-7 m ol equivalents. The
reaction m ixtm e was inadiated (100 W for 30 seconds) and on com pletion gave virtually
quantitative yields o f formanilide 246. The
N M R o f the isolated product did not retain
any starting material. The product 246 identified two different signals o f the -NHCH
protons shown as a broad signal at 8.37 ppm {endo isomer) and another doublet at 8.68
ppm ( J = 11.4 Hz) {exo isomer) were observed w hich was consistent w ith literature
data.^^^“ On comparing the reaction hy heating the reaction m ixture at identical scale in an
oil bath at 70 °C for 4 hours, the reaction m ixture gave lowered yields (70%).
In contrast, use o f amm onium formate as the formylating agent has been reported hr the
literature leading to quantitative yields o f cornpourrd 2 4 6 . This is, however, less
90
Chapter 4
competitive in time (10 hours) and requires reflux conditions using generous volumes o f
acetonitrile as a solvent. U se o f a non-conventional m ethod reported in literature
involving the photodecom position o f N -phenyl glycine sensitised by pyi'ene gives very
poor yields (5%) o f com pound 246.'^®“ A facile reductive A -form ylation o f aromatic nitro
compounds"*^'’ has heen reported to generate formamides like form anilide 246 using
ammonium formate. However, by this m ethod the desired form am ide is produced only
after about 12-14 hoirrs o f heating arormd 90-95 “C.
( X " ' -f- c r A
247
248
S C H E M E 117
Reagents and conditions: i) alumina supported formate 189, DMSO; ii) MW
A-Form ylation o f A-henzylarnine 247 was studied by preparing its reaction mixture w ith
alum ina supported formate 189 (4 mol equiv.) using DM SO as the solvent. The reaction
mixture was inadiated w ith microwaves at 100 W for 30 seconds (see Schenre 117). On
com pletion o f the reaction, quantitative yields o f A-henzyl fonnam ide 248 were obtained.
The reaction mixture showed a homogeneous spot on the TLC analysis (silica, 4:1
DCM /M eOH) w ith Rf value o f 0.62. The IR spectnun o f compormd 248 showed a
characteristic carbonyl stretching corTcsponding to the fonnam ide at 1667 c m '\
Reports in the l i te r a t u r e ^ d e s c r i b e the synthesis o f compound 263 in 88% yields using
arnrnorriurn formate as the fonnylating agent using reflux conditions for 6 hours in
acetonitrile. hicidentally, A -alkylation o f henzylam ine rrnder m icrow ave m adiations has
heen reported to occur in presence o f formic acid.^'^’’ The reaction has been done rrnder 5
minutes o f m icrowave inadiation using cyclopentanone as the solvent. However, the
reported yield o f com pound 248 produced in this w ay is poor (14%).
91
Chapter 4
NH.
HN
CH.
H
CH.
i
249
250
S C H E M E 118
Reagents and conditions: i) alumina supported foimate 189, DMSO; ii) MW
A lum ina supported fonnate was fm ther studied in 7V-Fonnylation o f a prim ary amine like
(±)- a-m ethylbenzylam ine 249 by irradiating its reaction m ixtiue w ith 4-5 m ol equiv o f
AI2O3/HCOOH 189 in DMSO. M icrowave irradiation at 100 W for 30 seconds gave very
good yields (80%) o f the A -fonnylation product, (±)-o;-methyl benzyl fonnam ide 250. The
reaction product was confirmed by the mass spectnun indicating the presence o f MH^
species. The 'H N M R spectrum indicated the characteristic signal o f the formamide
proton at 8.05 ppm. Thermal comparison o f the reaction showed slightly lowered yields
(80%) after heating the reaction mixtui'e for 3-4 hoius at 70“C.
Alternatively, synthesis o f 250 has been reported in the literature’'^® using ammonium
fonnate as the fonnylating agent by heating its reaction mixture for 3 hours at 180-185 °C
but in less competitive yields. Also, synthesis o f corresponding formamide from 249 has
been laiown using novel formylating agent like 2,2,2-trifiuoroethyl form ate.” '’’’ The
reagent is applied in the A -fonnylation o f amines and leads to very high yields o f the
conesponding fonnam ide. However, this reagent requires longer reaction times to
produce good yields.
Y
M eO '
M eO '^ ^
ii
251
^
252
S C H E M E 119
Reagents and conditions: i) alumina supported fonnate 189, DMSO; ii) MW
Synthesis o f 4-m ethoxyfoinianilide 251 has been achieved w ith relative ease using
alum ina supported hydiogen donor 189. M icrow ave irradiation (100 W for 30 seconds) o f
a reaction m ixture w ith 4-m ethoxyaniline 251, alum ina supported formate 189 (4 mol
92
Chapter 4
equiv.) in presence o f DM SO as the solvent provided high yields (81%) o f compound 252
(see Scheme 119). The com pound characterised two rotomers (exo and endo) in the ’H
N M R spectm m w hich was consistent w ith the literature data. Therm al comparison hy
heating the reaction mixture for 3-4 hours in an oil bath at 70 °C show ed reduced yields
(55-60%). Attem pts were also made by increasing the quantity o f the alum ina supported
hydrogen donor 189 to 6-8 m ol equiv. to study further im provem ent in the reaction and
possibly lead to the synthesis o f A,A^-diformyl substituted ^-anisidine. M ost o f the
attempts m ade w ith increased quantities o f the hydiogen donor in the reaction mixture
were rendered unsuccessful and the progiess o f the reaction was not evident further from
com pound 252.
N
i
N
H
ii
CHO
253
S C H E M E 120
Reagents and conditions: i) alumina supported formate 189, DMSO; ii) MW
Compound 254 was synthesised by irradiating a reaction m ixtm e o f 253 using almnina
supported formate 189 (6 m ol equiv). The reaction m ixture was irradiated w ith
microwaves at 100 W for 30 seconds (see Scheme 120), gave product 254 in 88-90%
yields. The MW-dibenzyl formamide 254 was characterised h y the developm ent o f a
diagnostic carbonyl stretching corresponding to the formamide shown in the IR spectrum
at 1672 cm ''. The mass speetrum confinned compound 254 indicated by the presence o f
corresponding M ’'" and MH^ ions in the matrix. Thennal comparison studied by heating the
reaction mixture w ith identical reaction scale in an oil bath for 3-4 hours at 70 °C, showed
lowering o f the yields (85%).
H
CEO
N
N
H
CEO
256
265
S C H E M E 121
Reagents and conditions: i) alumina supported fonnate 189, DMSO; ii) MW
93
Chapter 4
7V-Foniiylation o f cyclic diamine like piperazine 255 was done b y preparing its mixture
w ith AI2O3/HCOOH 189 (6-8 m ol equiv) using DM SO as the solvent. Microwave
iiTadiations at 100 W for 30 seconds (see Scheme 121) on the reaction m ixture gave 6063% yields o f 1,4-piperazine dicarbaldehyde 256. The confirm ation o f the formation o f
compound 256 was also done by an independent synthesis. Authentic 256 was synthesised
by refluxing 255 w ith excess ethyl formate 257 for over 10-12 hours. On thermal
comparison o f the reaction at an identical scale, the reaction showed less than 60% yields
after 4 hours o f heating in oil bath at 70 “C.
N
y
H
CHO
258
259
S C H E M E 122
Reagents and conditions: i) alumina supported formate 189, DMSO; ii) MW
W-Formylation o f m orpholine 257 led to the synthesis o f 4-form yl rnorpholine 258 on
microwave irradiation o f its reaction mixture prepared w ith 7-8 m ol equiv. o f alrmiina
supported formate 189 using DM SO (0.6 ml) as the solvent. M icrow ave irradiations were
done at 100 W for 30 seconds (see Scheme 122) The reaction gave 60% yields and
compourrd 259 was characterised by the 'H N M R showirrg the developm ent o f a
characteristic formamide proton singlet shown at 9.42 ppm. Compound 259 was
confirmed by comparing its spectral data w ith that o f an airthentic sample. Thermal
comparisons (70 °C for 4 horns) showed reduction in yields (<50%).
NH,
S C H E M E 123
Reagents and conditions: i) alumina supported formate 269, DMSO; ii) MW
2,4-difluoroform anilide 261 was synthesised by m icrowave irradiation o f a reaction
mixture o f 2,4-difluoroaniline 260 w ith alum ina supported formate 189 (6-7 mol equiv.)
94
Chapter 4
and DM SO as the solvent. hTadiation o f the reaction mixture at 100 W for 30 seconds
gave 70% yield o f com pound 261 on com pletion o f the reaction (see Scheme 123).
Compormd 261 was confirmed by comparing its mass spectiiun predom inantly identifying
the conesponding
and MH^ ions w hich was consistent w ith the literature data.’^^
T hennal comparison on the other hand showed lowered yields (<60%) after 3-4 hours o f
heating in an oil bath at 70 °C.
hr summary, the application o f alum ina supported formate 189 (AI2 O 3 /HCOOH) has been
studied in 77-fonnylation o f simple prim ary and secondary amines. The studies have
demonstrated that formic acid supported on fonnate can he utilised not only as a source
for hansfer hydrogenation but also seiwes as a formylating agent in the TV-formylation o f
prim ary and secondary amines. O in studies on microwave assisted form ylation o f primary
aromatic amines like aniline 245, henzylamine 247, ce-methylbenzyl amine 249 and p anisidine 238 have shown very high yields o f the corresponding formamides (see table
4.4). M icrowave assisted formylatiorr o f an arom atic secorrdary amine like diberrzyl amirre
253 shows quantitative yields o f the corresponding formamide 254. hr m ost subshates, in
comparison to the classical approach, m icrowave corrditions have show n substantial
im provem ent in the yields o f the reaction. In particular, the form ylation o f aniline 245 and
j9-anisidine 252 have shown 20-25% irrrprovernerrt in the yields. N o selectivity arrd special
effects was obserwed arrd the high yield urrder microwave corrditions is possibly due to
therirral effects. U se o f alurrrirra supported forrrrate as a form ylating agerrt is very
corrverrierrt because use o f such support is relatively cheap and easy to prepare arrd it
could be easily rem oved on corrrpletiorr o f the reactiorr by frltratiorr. In this way, the
reaction procedure is made sirrrple and easy to operate.
95
Chapter 4
1. Filtration
2. Recycling
ALO,/HCOOH
NCHO
NH
D M SO
R'
Amine
Product
Substrate
R'
Alumina
Supported
Formate
(in mol
equiv.)
MW"
Thermal'’
Yield (%)
R
R’
245
Ph
H
246
6-7
93
70
247
PhCHz
H
248
4
95
85
249
PI1CH3CH
H
250
4-5
85
80
238
P-C H 3OC6H4
H
252
4
80
55
253
PhCHz
PI1CH2
254
6
95
80
255
H N(CH 2CH2)2
256
6-8
60
55
258
0 (CH2CH2)2
259
7-8
60
<50
" A ll microwave irradiations were,perform ed a t 100 W fo r 30 seconds.
* A ll thermal reactions were carried out at 70 °C fo r 3-4 hours in DMSO.
Table 4.4 Thermal and microwave assisted formylation of primary and secondary amines
nsing alumina supported formate as formylating agent.
96
Chapter 4
4.9 Attem pted M icrowave assisted H ydrogenation using PEG D erivatised Hydrogen
Donor
Attem pts were made to study hydrogenation o f an Œ,/3-unsaturated alkene like transciimamic acid using the PEG derivatised hydrogen donor 187 (see section 3.2.3, chapter
3). A reaction mixture was prepared using Aan^-cimiamic acid 214 (0.025g, 0.16 mmol),
PEG derivatised hydrogen donor 187 (0.250 g, 0.1 mmol) and W ilkinson’s catalyst 204
(0.005 g, 0.005 mmol) using DM SO as the solvent (0.4 ml). The reaction mixture was
irradiated w ith microwaves (300 W for 10 seconds). The soluble polym er suppoid was
reprecipitated hy addition o f diethyl ether and filtered. The organic fraction was separated
and evaporated under reduced pressure. The isolated product was identified as a mixture
' ' o f reduced hydrocinnamic acid 215 and the unreacted starting material. The desired
reduced product 215 w as indicated in a low yield (<50%) hy 'H N M R analysis.
The loading capacity o f PEG (8000) lies in the range o f 1 to 0.1 mmol/g. The obtained
loading value o f fom iate adsorbed on the derivatised PEG is 0.4-0.6 mmol/g. The initial
PEG derivatisation reaction showed difficulties and it was not possible to ascertain a
complete derivatisation o f the PEG support. It has been shown that the reaction works in
principle however, the reaction conditions need to he im proved and repeated hy preparing
a fully derivatised sam ple o f PEG.
97
Chapter 5
Microwave assisted Reduction of Ketones, Oxidation
of Alcohols and Cy do additions on Metal bound
Organonitriles
CHAPTER 5
R EDUCTION OF IΠTO N ES, OXIDATIO N OF A LCOH OLS &
CYCLO ADDITION ON M ETAL BOUND ORGANONITRILES
5.0 Reduction o f Ketones
98
5.1 Attem pted M icrowave assisted Reduction o f Ketones
100
5.2 Supported Reagents on Clay - Background
103
5.2.1 Clay Supported Reagents for M icrow ave assisted
Oxidation o f A lcohols
103
5.3 Attem pted M icrowave assisted Oxidation o f Alcohol using Pd(OAc ) 2
and M olecular Oxygen
105
5.4 Pd(II) H ydrotalcite for Oxidation of Alcohol under M icrowave
C onditions
106
5.5 Cycloadditions under M icrowave Conditions - Background
108
5.6 Cycloaddition of Nitrones to Platinum bound Organonitriles
112
6.0
5.6.1 Preparation o f Platinum bound ïra/7i'-Cimaamonitrile Complex
113
5.6.2 M icrowave assisted Cycloaddition o f N itrones to Free Chm am onitrile
115
5.6.3 Cycloaddition o f C-phenyl-A-methyl Nitrone w ith Pt(II) bound
ira«5-Cimiamonitrile Complex
118
5.6.4 Preparation o f Pd bound frfl/w-Cimiamoniti'ile Complex
121
5.6.5 Cycloaddition o f C-phenyl-A-methyl N itrone w ith Pd(II) bound
^ran5-Ciimamonitrile Complex
121
Conclusions and Future W ork
124
Chapter 5
5.0 Reduction of Ketones
The results discussed in chapter 4 have demonstrated the utility o f transfer hydrogenation
and supported hydrogen donors for efficient reduction o f electron deficient alkenes in
presence o f a suitable catalyst. This m ethod is equally im portant in the study o f the
reduction o f ketones, w hich is a key transform ation in organic synthesis.
The reduction o f aldehydes and ketones usually involves use o f unlike donors and
a c c e p t o r s . F r o m an early date alcohols have been utilised as hydiogen donors.
Hydrogen transfer
reductions o f aldehydes and ketones have been r e p o r t e d ' u s i n g
low-boiling alcohols like Pr'OH, Pr"OH or EtOH. Some o f them are thennolytic
m e t h o d s r e d u c i n g ketones to conesponding alcohols at high tem peratures in absence
o f catalysts and bases. Often use o f a base is exploited for the prom otion o f reductions.
Enantioselective reduction o f ketones for synthesis o f conesponding alcohols in presence
o f suitable catalysts has been a vital organic hansfoim ation in the area o f organic
synthesis (see Scheme 124).’^^
DH,
DH^ = Hydrogen donor
269
270
SC H E M E 124
A very comm only used reagent for transfer hydrogenation o f ketones is propan-2-ol.'^^
Hydrogen donors like formic acid (generally used as an azeotrope w ith triethyl
a m i n e ) h a v e also found application. HCOzNa has been applied in selective reduction
o f carbonyl groups in aldehydes'^''“ and in ketones.'^'"’ A m m onium fonnate has been
utilised as a hydrogen donor in presence o f 10% Pd/C for the partial reduction o f aromatic
carbonyls.
O f equal importance is the catalyst'^' in the reduction o f ketones. Reduction o f
unfunctionalised ketones and enones'^^*^’® have extensively utilised catalysts based on
oxaborolidine s t r u c t u r e . O f t e n a high level o f catalyst is required (10 mole% ) and
also borane is non-com patible w ith certain functional groups, w hich som ewhat limits its
98
Chapter 5
application. Enantioselective catalysts using valions ligands like BINAP and DuPHOS
have
afforded
hydrogenation
of
functionalised
ketones
in
very
high
enantioselectivities.'^^’
The meehanism for transfer hydrogenation o f ketones using catalysts o f m ain group
e l e m e n t s i n v o l v e s a direct hydrogen hansfer w hich is similar to that o f M eeiiveinPondorf-Verley reductions. The hydrogen donor (Pr'OH) and hydrogen acceptor (ketone)
are in close proxim ity to the m etal centre (M), fonning a six m em bered cyclic hansition
state (see Figure 5.1).
\
/I
Q -“ - p
Me
Me
Figure 5.1 Six membered cyclic transition state
However, the transition metal complexes involves the formation o f a m etal hydride
130, 131
by the elimination o f acetone from the cyclic inteim ediate, w hich frufher undergoes a
hydride transfer w ith a co-ordinated ketone (see Figm e 5.2).^^^
RyCOR.
-Me..CO
H
_
273
271
272
Figure 5.2 Transfer hydrogenation by iiydridic route
128
Catalysts from metals like iridium,'^'*" rhodiiun,'^'*'’ s a m a r i u m ' h a v e also been studied
for
asyimnetric
transfer
dichlorotris(triphenyl
hydrogenation.
phosphine)
Ruthenium
m thenium
276
hydrogenation o f saturated and a,j6-unsaturated ketones.
99
has
catalysts,particularly,
been
useful
in
hansfer
Chapter 5
5.1 Attem pted M icrowave assisted Transfer Hydrogenation o f Ketones
In the present study, application o f the polym er supported hydrogen donor 182 has been
investigated for the reduction o f ketones in presence o f riithenhun catalysts. M icrowave
inadiation has been utilised for studying these reactions using the Sm ith creator® which
operates at variable tem perature and tim e o f iiTadiation.
o
OH
CH,
CH,
274
275
S C H E M E 125
Reagents and conditions: i) Amberlite supported fonnate 182, RuCl(PPli3)3 276, DCM; ii) MW
Initially studies w ere perform ed on the reduction o f ketones like acetophenone 274 by
preparing its reaction mixture using polym er supported fom iate 182 (5 m ole equiv.) and
R uCl(PPli3)3 276 (2 mg) in dichlorom ethane (1 ml) (see Scheme 125). The reaction
m ixtm e was inadiated w ith microwaves by setting tem peratm e at 120 °C for 300 seconds.
A fter irradiation, no product was obseiwed and only evidence for the um eacted starting
m aterial was obtained.
hi a later attempt, the reaction mixture was prepared w ith the same scale by degassing and
pm ging w ith N 2 and using freshly distilled dichloromethane. M icrow ave irradiations did
not show any improvem ents and only identified the um eacted starting m aterial at large,
hicreasing the quantity o f the RuCl(PPli3)3 catalyst 276 from 2 m g to 5 m g showed no
noticeable improvements in the reaction. On doubling the catalyst from 5 mg to 10 mg
and degassing the reaction mixture, iiTadiation at 120 °C for 300 seconds showed less
than 50% yields o f the desired alcohol 275 in the
NMR. This was indicated by the
development o f a characteristic doublet shown at 1.57 ppm corresponding to the (-CH3)
and a quartet shown at 4.89 ppm conesponding to the proton at the reduced carbonyl
group (-CHOH) (comparing the
N M R spectm m w ith an authentic sample).
W ith a view to improve the reaction, the reaction mixture was prepared by maintaining
the scale and using THF (1 ml) as the reaction solvent. Irradiation scale was changed by
increasing the set tem perature to 100 °C for 180 seconds. These changes did not show
100
Chapter 5
any noticeable im provem ents in the reaction and largely indicated the nm eacted stai'ting
material. This ohsei"vation was consistent even on changing the irradiation scale by
reducing the set tem perature to 80 °C and extending the time to 600 seconds.
In comparison, use o f a conventional hydrogen donor, propan-2-ol 277 (1 ml) in presence
o f R uCl2(PPh3)3 276 showed efficient reduction o f compormd 274. The reaction mixture
was completely degassed and pinged w ith N 2. hTadiation scale was set to 200 °C
tem perature for 60 seconds. This allowed virtually quantitative yields o f the desired
reduction product 275. Clearly, this study identified that rrnder m icrowave conditions,
propan-2-ol 277 used as hydrogen donor favoured the reduction o f com pound 274. More
significantly, use o f an excess o f the hydrogen donor and a preferable exclusion o f
moisture fiorn the system was crarcial in leading the reaction to completion.
Equally im portant is the activity o f the catalyst in the transfer hydrogenations. W ith a
view to im prove the reductions, use o f another catalyst w as envisaged for studying the
transfer hydrogenation o f ketones in presence o f the polym er supported hydrogen donors.
Rrr(II) complexes, particularly the [RrrCl2(arene)]2 complexes have emerged useful in
studying the asymmetric carbonyl r e d u c t i o n . O n e o f the m any w idely studied catalysts
is [RrrCl2(p-cymene)]2 catalyst 280.
The catalyst 280 was prepared by the literature procedure'"*® starting from iirthenirrm
chloride 278 (see Scheme 126).
R 11C I 3
278
+
2
I
279
>
[R uC l,(p-cyniene)],
"
280
S C H E M E 126
Reagents and conditions: i) ethanol; ii) reflux.
Compound 280 was isolated in 72% yield on refluxing for 4 horns a reaction mixture o f
278 (2 g, 7.7 imnol) with R-a- phellandrene 279 (10 m l) in ethanol (100 ml). A fter reflux,
the catalyst 280 was formed as red-brown crystalline particles settling in the bottom o f the
reaction flask after cooling and refrigerating the reaction m ixture (see Scheme 126).
The catalyst synthesised was utilised in reduction by preparing a reaction m ixtm e o f
acetophenone 274, polym er supported fonnate 182 (0.5 m ol equiv.), R u catalyst 280
101
Chapter 5
(2 mg) and dichlorom ethane (1 ml) as the solvent. The m ixtm e was iiTadiated w ith
microwaves at a set tem perature o f 90 °C for 60 seconds. On completion, the reaction
mixture identified only the um eacted starting material. The reaction was attempted by
extending the tim e o f inadiation from 60 seconds to 300 seconds. This did not show any
improvem ents in the reaction so did the increase in the amounts o f catalyst from 2 m g to
10 mg. Attem pts were also made by increasing the set tem perature values from 90-120
°C. h i m ost attempts the reaction m ixture retained the m neacted starting m aterial at large
and did not give evidence o f any progress.
The reaction was compared by using the conventional hydrogen donor like propan-2-ol in
presence o f catalyst 280. hradiation o f reaction mixtures w ith m icrowaves at 90 °C fr om
60 seconds to 300 seconds effected up to 50% reduction o f acetophenone. The reduction
o f carbonyl groups in aldehydes like benzaldehyde 281 done using catalyst 280 in
propan-2-ol was not successful and showed the um eacted starting aldehyde after
iiTadiation at tem perature 90-100 °C for 60-300 seconds.
In sunmiary, the reduction o f ketones like acetophenones using polym er supported
formate 182 as the hydrogen donor was not successful under m icrow ave conditions.
M icrowave assisted reductions studied using the conventional hydrogen donors like
propan-2-ol (70-80 m ol equiv.) did show efficient reduction. It is possible that insufficient
availability o f hydrogen from the solid ti'ansfer hydrogenation source 182 m ay be
responsible for a lower success and yields o f reduction. M ost o f the attempts using
polym er supported hydrogen donor has been lim ited to 5-6 m ol equivalents o f the
hydrogen donor in the reaction mixture. It is likely that in presence o f organic solvents
like dichloromethane, the polym er supported formate salt 182, is unable to ionise and
rem ains as an ion pair. This m ay be held responsible in failure to obseiwe hydrogenation.
In such reactions, m oisture fr-ee conditions are necessaiy in achieving the required organic
transformation. The presence o f m oistm e in the reaction m ixtm e m ay significantly reduce
the activity o f catalysts.
102
Chapter 5
5.2 Supported Reagents on Clay - Background
In chapters 3 and 4, the developm ent and applications o f novel polym er and inorganic
supported reagents have been discussed. Use o f an inorganic solid like alum ina has been
studied as a support for foiinic acid and applied in transfer hydrogenations. The synthetic
organic chem istry involving the use o f heterogeneous systems, paiticularly supported
catalysts and reagents is rather interesting and fast glowing. Inorganic solids like alumina,
silica and aluminosilicates (clays and zeolites) are some o f the m ost w idely employed
supports.
In particular, clay minerals occurring abundantly in nature have been significantly
exploited for catalytic applications. Because o f their high surface area, sorptive and ionexchange properties, the solid clays catalysts have been applied generally (a) as solid
acids, (b) as bifunctional or ‘inert supports’ and (c) as fillers to give solid catalysts w ith
required physical properties.
5.2.1 Clay Supported Reagents for M icrowave assisted Oxidation o f Alcohols
The oxidation o f alcohols is one o f the synthetically very useful transfom iations in
organic synthesis and several m ethods are k n o w n . U s e o f clay supported potassium
peiinanganate has been used for the oxidation o f alcohols to the coiTesponding carbonyl
com pounds.’'*^ The clay supported reagent is prepared by grinding the potassium
perm anganate w ith equal quantity o f rnontmorillonite as a dry solid and reaction is
performed by gentle warming and stim iig w ith the reactant in dichlorornethane. The
reaction has been observed to w ork particularly w ell w ith secondary alcohols giving up to
95% yields o f the corTesponding ketones. Allylic secondary alcohols have been observed
to react extremely sm oothly to give the ct,j3-unsaturated ketones in up to 90% yields (see
Scheme 127).
OH
282
283
S C H E M E 127
Reagents and conditions: i) ICMnO^/berrtonite, dichlorornethane; ii) 45 °C, 20 horn s
103
Chapter 5
U nlike m anganese dioxide oxidation, this m ethod does not required prior activation o f the
reagent, m aking it more advantageous.
A novel class o f m ultipiupose reagents term ed as Clayfen 284 and Claycop 285,
developed by Laszlo and co-workers have been prepared
by
the respective impregnation
o f Fe(III) and Cu(II) rritr'ates onto K 10 montrnorillonites.^'*^ Clayfen 284 has been
effectively used as for the oxidation o f secondary alcohols. The reaction is done by
simply introdrrcing Clayfen to a solution in hexane. A gentle evaporation o f the solvent
indirces the reaction and the product is isolated by simple frlhation o f the spent reagent
and evaporation o f the solvent. The reaction works w ell in oxidation o f benzylic alcohols
and gives excellent yields w ith aromatic prim ary alcohols. However, it is know n to show
a complex m ixture o f products w ith aliphatic prim ary alcohols arrd consequently poor
yields o f the correspondirrg aldehydes.
U se o f heavy metals and peracids have been comm on in oxidation but are dehirnental to
the envirornnent.''*^ hrterestirrgly, prim ary alcohols afford aldehyde under m icrowave
conditions. The oxidation is assisted using 284 under solvent-free conditions (see Scheme
128). 143
—
> 0
298
299
R = H,CH;CH,,CgH;CHO
S C H E M E 128
Reagents and conditions: i) Clayfen 284; ii) MW, 15-20 seconds
M icrowave assisted chemical oxidation o f a variety o f substrates using Claycop in the
presence o f hydrogen peroxide (sirbsfrate: claycop: H 2O2) have been accornplishedi^^c
(see Scheme 129). This method requires no pH control adjushnents and affords higher
yields o f the oxidised products relative to other processes using copper-based reagents.
i44a,b -Qgg gp a copper based stable oxidising agents like CUO2H (hydroperoxy Cu(II)
compound) requires to be neufralised by KHCO 3 to m aintain pH~5, because it
preparation involves the formation o f an acid (see Eqn 5.1).
2Cu(N03)2 + H 2O2 + 2H 2O
CUO2H + 4H NO 3
104
(Eqn 5.1)
Chapter 5
R"
298
299
R = CÆ
R" = CO^H, CN
S C H E M E 129
Reagents and conditions: i) Claycop/H202; ii) MW
5.3 Attem pted M icrowave assisted Oxidation of Alcohol using Pd(OAc ) 2 and M olecular
Oxygen
Development o f catalytic processes using aerobic conditions is im portant as they can
offset the problems o f using stoichiomeh ic amoimts o f o x i d a n t s W i t h regar d to aerobic
oxidation o f alcohols to aldehydes and ketones, palladium complexes have been
investigated, requiring the combined use o f m olecular oxygen and reoxidants.
Pd(0 A c)2 288 is a good catalyst to prom ote the oxidation o f benzyl alcohol 289 in the
presence o f base under O2 atmosphere. U se o f an organic base like pyridine has been
most effective and the reaction proceeds in quantitative yields in presence o f molecular
sieves (MS3A).^'^’ Earlier studies report the aerobic oxidation o f alcohols in toluene to the
corresponding aldehydes and ketones using a catalytic amount o f a hom ogeneous catalyst
like Pd(0 Ac)2 and pyridine 290 under an oxygen a t m o s p h e r e . T h e catalytic system
proposes that a Pd(II)-OOH species is produced in situ on reaction o f a Pd(II)-H species
w ith O2 (see Scheme 130).
Pd(0Ac)2 Py
Py = Pyridine
AcOH
Pd(II)-0
Pd(II)-OOH
Pd(II)-H
SCHEME 130
105
Chapter 5
In the present study, the oxidation o f benzyl alcohol 289 has been investigated imder
m icrowave conditions. A mixture o f benzyl alcohol 289 (0.23 im nol), P d(0 Ac)2 288
(0.0086 mm ol) and pyridine 290 (0.0067 mm ol) was prepared using toluene as the
solvent (1 ml). To this mixture, oxygen was introduced using a balloon. The m ixtine was
inadiated w ith microwaves at 40 W for 60 seconds. The reaction m ixture on w ork up
identified only the um eacted starting alcohol. Attem pts made by increasing the incident
pow er to 100 W for 20 seconds were not successful,
hr another attempt, the reaction
mixture was degassed several times and subsequently oxygen was introduced in the
m ixture before in adiation. The m ixture was irradiated w ith 100 W at 30 seconds and gave
evidences only o f the starting alcohol,
hr order to improve the reaction, the incident
pow er w as increased to 300 W for 10 seconds. However, this only resulted in catalyst
decomposition
(Pd (II) to Pd (0)) w hich was indicated by the development o f a black residue in the
reaction tube.
5.4 Pd(II) Hydrotalcite for Oxidation o f Alcohols under M icrowave Conditions
hr view o f errviromneirtal arrd ecorrornical concenrs, use o f heterogeneous catalysts with
propei-ties such as easy harrdlirrg, simple separation arrd reusability''*® is desirable. A
rratru ally o ecru ring hydrotalcite (Mgo Al2(0 H) %
gCOs. 4H 2Ü) 291 possessing layered
stm cture coirsists o f positively charged layers arrd rregatively charged coim ter ions located
in the irrterlayers has been exploited.''*^ The applicatiorr o f hydrotalcites as a solid base
catalyst in several r e a c t i o n s a n d also sorrre rrrodifred hydrotalcites used for aerobic
oxidation o f alcohols has been reported.
A Pd (II)-hydrotalcite 292 systerrr was prepared through a literature procedure'^' for
applicatiorr in oxidations. Pd (Il)-hydrotalcite (1.56 rrrrrrol g"' Pd) was prepared by rnixirrg
Pd(0 A c)2 288 (0.8 rnrrrol), pyridirre 290 (2.09 rmnol) arrd hydrotalcite (5 g) 291 in toluene
(100 ml) at 80 °C for 1 hour, followed by frlhation, washirrg arrd drying rurder reduced
pressure at roorrr temperature.
In the present study, the reusable Pd (II) hydr otalcite catalytic systerrr has been applied forstudying oxidation o f alcohols. M ore importarrtly, the applicatiorr o f rrricrowave
corrditions has beerr irrvestigated for studyirrg these reactions.
106
Chapter 5
Initially, the Pd (II) hydrotalcite 292 system prepared was investigated for oxidation o f
henzyl alcohol using m olecular oxygen and toluene as the solvent. The theiinal reaction
was done using a literature p r o c e d u r e ^ a n d gave 71% yield o f henzaldehyde on heating
the reaction mixture for 2 hours at 80 °C.
The reaction was investigated under microw ave conditions by preparing a reaction
m ixture o f Pd(II) hydrotalcite 292 (0.300 g), pyridine 290 (2 mm ol) in toluene (1 ml) in a
pyiex glass reaction tube. The tube was closed w ith a cap equipped w ith a rubber septum
to allow the release o f any excess pressure building in the system. Oxygen was introduced
into the reaction tube using a balloon and then the m ixtine w as irradiated w ith
microwaves at 60 °C for 30 seconds. Benzyl alcohol 289 (0.4 mm ol) diluted w ith toluene
(1 ml) was introduced into the reaction tube. The reaction tube was further treated with
oxygen using a balloon. The reaction mixture was inadiated w ith microwaves at 60 °C
for 60 seconds. On cooling, a black residue was observed in the reaction mixture. This
m ay be obseiwed due to the Pd catalyst decomposition (Pd (II) to Pd (0)). TLC analysis
(diethyl ether, silica) indicated incom plete reaction. 'H N M R analysis o f the w orked up
reaction mixture largely identified the um eacted starting benzyl alcohol w ith only m inor
traces o f the oxidised product, henzaldehyde 281.
In another attempt, the reaetion was done by increasing the quantity o f the catalyst in the
m ixture fiom 2 m m ol to 5 mm ol and m aintaining the other reaction m ixture components.
In this case, the reaction identified a sim ilar ohseiwation, showing the degradation o f the
Pd catalyst. Pd (0) was m ade evident by the developm ent o f a grey black residue settling
in the reaction tube after inadiation.
The oxidation o f henzyl alcohol under microw ave conditions was not favoured due to the
decom position o f the Pd catalyst. Essentially, a continuous presence o f m olecular oxygen
atmosphere is vital during the reaetion. However, under microw ave conditions, an oxygen
balloon camiot he m aintained during the inadiation. This m ay be held responsible for the
degradation o f the catalyst, rendering the reaction unsuccessful. U se o f a modified
domestic m icrowave oven m ay w ell serve helpful in this case.
107
Chapter 5
5.5 Cycloadditions under M icrowave Conditions - Background
Cycloadditions reactions are extremely im portant in the ai'ea o f organic synthesis. Under
classical conditions, some o f these reactions require long reaction times, high
temperatures, and/or Lewis acid catalysts, resulting in paitial and/or total decomposition
o f sensitive compounds. This is a significant problem in the synthesis o f m any a
synthetically im portant compounds. M icrowave irradiation is an efficient methodology in
cycloaddition reaction o f compounds that are sensitive and/or have low reactivities. In
m any cases, noticeable accelerations and im provem ents in yields and reaction conditions
are observed. This m ethodology is helpful in som e cases, to introduce chemo-, regio-, or
stereoselectivity in the cycloaddition reactions.
Some o f the very prelim inary examples o f microwave induced reactions were
cycloadditions and pericyclic reactions perfoiined under pressure (see Scheme 1 & 2,
Chapter 1). The reactions showed substantial reductions in reaction times (10 minutes)
and yields (80%) under m icrowave conditions as opposed to the conventional heating
involving 4 hours o f reaction time yielding 67% o f the cycloaddition p r o d u c t . T h e
only disadvantage observed in such approaches was the im controlled rise in temperature
and pressure due to microw ave activation. This was resolved b y using appropriate higher
boiling point solvents such as dimethyl formamide, chlorohenzene, 1,2-dichlorobenzene
and 1,2,4-trichlorobenzene in modified m icrow ave o v e n s . S e v e r a l reactions have been
performed using this m ethodology, including [4+2] and [2+2] cycloadditions. These gave
significant reductions in reaction times and im provem ent in yields (see Scheme 131).
•Ar
r
Ar = p-MeOC,H5
°
S C H E M E 131
Reagents and conditions: i) Chlorohenzene, NMM; ii) MW
In m any cases o f cycloaddition reactions, Lewis acid catalysts have been used to produce
good yields. Clay catalysts have been utilised in cyclo addition reactions under solvent
fiee microw ave conditions, giving reduced reaction times w ith no changes in the
endo/exo ratios fiom those observed by classical h e a t i n g ' ( s e e Scheme 132).
108
Chapter 5
O
•NPh
o
297
300
S C H E M E 132
Reagents and conditions: i) K 10; ii) MW
U nder microw ave conditions, 1,3-dipolar cycloaddition o f aliphatic and aromatic nitriles
w ith nitrones or nitrile oxides under solvent free conditions afford synthetically important
heterocycles like oxadiazoles (see Scheme 133).'^'^^ The yields have been obseiwed to be
always higher as compared to those obtained under classical heating. The most significant
differences have been achieved w ith the less reactive nitriles. Such an observation is in
keeping w ith L ew is’s rem ark that “slower reacting systems tend to show a greater effect
under microw ave irradiation than faster reacting systems.
301
Ph
Ph^
Ph-C O ,E t
CCLEt
303
302
= N -0
304
306
N ^ -C C H j
305
S C H E M E 133
Reagents and conditions: i) neat; ii) MW
U nder m icrowave irradiation conditions, a hetero-Diels-Alder cycloaddition reaction has
been achieved in the presence o f a heat sink like giaphite in place o f any solvents.
M icrowave conditions allowed the w ork to be imdertaken at ambient pressure in an open
reactor thus avoiding the foim ation o f miwanted compounds by theiinal decomposition o f
reagents or products (see Scheme 134).'^^
109
Chapter 5
%
NMe^
307
N
CO,M e
308
CO .M e
309
S C H E M E 134
Reagents and conditions: i) Graphite; ii) MW
Studies perfom ied under reflux in xylene or dibutyl ether in some specific cycloadditions
(see Scheme 135)^^^“ have been observed to be faster under m ierow ave conditions than
when using classical heating methods. However, the influence o f any specific microwave
have not been deteiinined in these cases.
311
312
S C H E M E 135
Reagents and conditions: i) Xylene or dibutyl ether; ii) MW
The utility o f microwaves is evident in improving numerous processes or in m odifying
the obseiwed chemo-, regio- or stereoselectivity o f a reaction, h i contrast to conventional
heating, a rapid heating rate in microw ave heating is held responsible for the observed
e f f e c t s . R e a c t i o n s o f acid chlorides 313 w ith Schiff bases 314 (see Scheme 136)^''°
exhibit some differences in the selectivity o f the cycloadditions, depending signifieantly
on the order o f addition o f the reagents. Particularly, w hen the condensation is conducted
by a “norm al addition” sequence (i.e acid chloride last), only the cw-jS-lactam 316 is
formed. However in the inverse case, w hen triethylamine is introduced last, 30% cis and
70% trans jS-lactams were obtained mider identical reaction conditions, hiterestingly,
w hen the reaction w as conducted in a microwave oven using chlorohenzene, the
selectivity becomes pronounced w ith a 90:10 ratio o f trans and cis jQ-lactams formed
iiTespective o f the order o f addition.
110
Chapter 5
.0
R " '0
.
.
"^1
"V
A
314
313
315
"
',
316
R"' = C O C H 3 , Ph. R' =CH^Ar, R" = Ar
S C H E M E 136
Reagents and conditions: i) NMM; ii) chlorobenzene, MW.
Cycloaddition reactions are im portant in the multistep synthesis o f natural products
because they aid the formation o f cyclic compounds by simultaneous formation o f C-C
bonds and often w ith specific regio- and stereoselectivity.'^' W ith shorter reaction times,
microwave activation avoids the decomposition o f reagents and products and prevents the
polym erisation o f the diene and the dienopliile, which is o f significant impoifance in
m any organic synthesis including the synthesis o f natural products. Synthesis o f the
bridged sesquiterpene longifolene 319 involves a key intram olecular cycloaddition o f
com pound 317 for the construction o f the bridged system (see Scheme 137).'*'^“ Under
conventional heating, the cycloaddition afforded only 10% o f the product 318 after 24
hours reflux in toluene and decomposition predom inated at higher temperahires.
Alternatively, heating in a sealed glass vessel in a modified m icrow ave oven resulted in
the adduct in 92% yields.
CO.M e
318
317
319
R = SiMcj'Bu
S C H E M E 137
Reagents and conditions: i) Toluene; ii) MW
M icrowave irradiation has also been applied in the stereoselective synthesis o f tricyclic
taxoid skeleton by an intiam olecular D iels-A lder approach in good yields'"'^'' (see Scheme
3, chapter 1).
h i contrast to the classical cyclisation reactions, cyclo additions have becom e synthetically
m ore suitable for the constraction o f heterocyclic rings. M ore importantly, the use o f
111
Chapter 5
microwave iiTadiations has been used increasingly to achieve difficult cycloadditions and
to obtain tem perature sensitive compounds. Cycloadditions have been com m only used to
obtain /3-lactam d e r i v a t i v e s . T h e synthesis o f thienamycin side chain has been
achieved using this methodology.
1,3-Dipolar cycloadditions have been used to
produce heterocyclic five mem bered rings; m icrowave irradiations has been used to
facilitate the cyclo addition to prepare the 1,3 dipole in situ, by elimination,
thermal
o p e n i n g ' a n d thennally induced tautomérisation.'^^® The hetero-D iels-A lder reaction is
one o f the m any im portant m ethods for the synthesis o f 6-m em bered heterocycles. An
intram olecular hetero-D iels-A lder reaction o f N-alkyl-2-cyano-1 -azadienes 320 is
studied, hiterestingly, the cyclo addition reaction could be achieved under conventional
heating successfully after overnight heating at 110 °C. However, it was found that
microwave iiTadiation assisted in substantially reducing the reaction tim es to only 14
minutes for the desired reaction (see Scheme 138).'^''
NC.
320
321
S C H E M E 138
Reagents and conditions: i) MW
5.6 Cycloaddition of Nitrones to Platinnm bound Organonitriles
M any organic molecules are not sufficiently reactive in absence o f activating agents like
Lewis acid and activation o f such organic m olecules by coordination to a metal cenh e is
used for achieving r e a c t i o n s . h i this context, the activation o f nitriles towards
nucleophilic attack has been studied considerably."^^’’ A n im portant transform ation o f the
organonitriles, involves the addition o f electrophiles'^^® or nucleophiles'^^'' to the C = N
bond offering an attractive route for the creation o f novel C-C, C - N and C-O bonds. One
o f the m ain problems encountered in reactions o f nucleophilic addition is the insufficient
electrophilic activation even by very strong electron-accepting gioups R at R C N , e.g.
C I3 C C N .
These difficulties, however, can be overcome w ith the use o f metal ions,'®’’“
some times even in the low oxidation s t a t e s , a s activators tow ards the nucleophilic
attack. In particular, use o f platinum complexes has proved to be useful substrates for
this kind o f transformations. This has been demonstrated by some o f the recent
112
Chapter 5
s t u d i e s i n v o l v i n g the [2+3] cycloaddition between coordinated nitriles including
acetonitrile and benzonitrile ligands in the highly reactive P t complex and varions
nucleophilic nitrones. R e p o r t s d e s c r i b e that reaction o f N-irrethyl-C-phenyl nihone
322 and neat benzonitrile requires rather harsh conditions (10 days, 110 °C) to give the
corTespondhrg 2-m ethyl-3,5-diphenyl-A'^-l,2,4-oxadiazoline 325 in m oderate yields
(57%). hr corrhast, the Pt (II) conrplex mediated cycloadditioir w ith m nch m ilder reaction
conditions gives 88% yield (e.e. >70% ) o f 325 (see Scheme 139).
H
Me
\= n 4
ph/ \)0
pi ph
"'w sc
Pli-
H
Me
M e-^ f
o
A
V
% 23
324
\h
S C H E M E 139
Reagents and Conditions: i) 56°C, 12 hours, dichlorornethane; ii) ethane-1,2-diamine, H2O
5.6.1 Preparation o f Platinum bound P fl«s-Cinnam onitrile Complex
Earlier studies have demonstrated that the [2+3] cycloadditions o f nitrones to nretal co­
ordinated organonitriles leads to the syrrthesis o f important heterocycles viz. A'^-1,2,4oxadiazolines. Typically, the preparation o f such heterocycles is highly restricted to the
use o f irihiles bearing a strorrgly elechoir withdrawing substituent (e.g. C C I3 ). However,
this becoirres feasible under very m ild conditions with elechon-rich nitriles like M eCN or
PhCN w hen they are bound to Pt (IV) c e n t r e s . P t (II) centre has been foimd to exhibit
a slightly lesser extent o f activation, leading to a selective transform ation o f coordinated
PhCN but not M eCN .'^“ The corresponding platinum A'*-l,2,4-oxadiazoline complexes
have been obtained as air-stable compounds in high yields. The easy displacem ent o f the
new ly formed ligands from both P t (IV) and P t (II) compounds, allows an easy method
for the preparation o f heterocycles w ith substitution patterns that w ere not previously
accessible by organic methods.
The above study has dem onstrated that cycloadditions are feasible using metal bound
organonitriles. In the present case, the study has been extended by using an organonitrile
113
Chapter 5
like ?ra775-cinnamonitriIe, w ith m ore than one site for possible cycloadition. Transcinnam onitrile co-ordinated w ith platinum complex (Pt(II)) has been prepared w ith a
view to study the cycloaddition w ith nib ones.
H
/
Ph
\
3
Ph
#
H
S C H E M E 140
Reagents and conditions: i) ^7-a;w-cinnamoniti'ile (excess), 60°C, 1 week
The Pt(II)-ciimamonitrile complex 327 was prepared by heating czx/^ra7?x-PtCl2(M eCN)2
complex 326 w ith excess ^ra/^^'-cimiamonitrile 230 for a w eek at 60 °C. hi presence o f
excess o f the compound 230, a ligand exchange talces place and the acetonitrile in
complex 326 is replaced by ira/j^'-cimiamonitrile. Compound 230 has two possible co­
ordination centres viz. the nitrile and the olefin. However, the co-ordination is obseiwed to
take place on the Pt(II) metal centre with the nitrile (-C =N ). The new ly form ed complex
327 is obtained in 81% yield as light yellow solid precipitated from the reaction mixture,
by addition o f diethyl ether (excess). The organic ligands in the co-ordination sphere o f
the transition m etal are assumed to he in trans position to each other since the complex is
very unpolar and shows a similar TLC characteristic as ïra«i'-[PtC l2(PhCN)2]. A faint
spot at a lower Rf value indicates that the corresponding cA-complex is fonned in a m inor
quantity only. The co-ordination o f the nitrile end w ith the m etal centre is confiim ed by
the IR analysis showing the characteristic - C s N stretching shifted to 2276 cm'^ (as
compared to fr-ee cinnamonitrile, 2210 cnT^) under the influence o f the metal. This is
obseiwed alongside w ith the ^ra72x-HC=CH stretching from the olefin characterised at 965
c m '\ Additionally, the 'H N M R analysis gave evidence o f the unco-ordinated olefmic
protons o f the ligand maintaining a ^ranx-configuration, shown at 6.17 ppm and 7.69 ppm
(J = 16 Hz). The complex 327 consists o f two possible sites at w hich an attack fr om the
nitrones m ay be expected viz. the nitrile and the olefin.
114
Chapter 5
5.6.2 M icrowave assisted Cycloadditiou o f Nitrones to Free Cinnam onitrile
111 the present study, the influence o f m icrow ave iixadiations is investigated for the
cycloaddition o f h e e and co-ordinated cinnam onitrile w ith nitrones.
hiitially cycloaddition betw een free trans-cim iam onitrile 230 and C-phenyl-N-methyl
nitrone 322 is examined (see Scheme 141). The nitione 322 was synthesised in 35% yield
tlnough a literature procedure, by refluxing an equimolar m ixtuie o f N-methyl
hydroxylam ine hydrochloride 341 and henzaldehyde 281 in presence o f sodium carbonate
in dichlorom ethane (20 ml) and m ethanol (5 ml) mixture.
Ph
Me
^c = n4
H
230
'C©
322
Ha
Me (Hb)
He I
CN
329
Me (Hb)
M e (H b )
Me(Hb)
Me(Hb)
. 'H d
Phb
Phb
330
He
% "» '
339
Ph
S C H E M E 141
Reagents and conditions: i) MW
In the unco-ordinated state, cycloaddition o f 230 w ith 322 occins selectively across the
electron deficient olefin. The cyclo addition across the olefin m ay be view ed to generate
four possible m ajor diastereomers 329, 330 and 331, 332 o f 2-methyI-3,5-diphenyisoxazoline-4-carbonitrile and 2-m ethyl-3,5-diphenyl-5-carbonitrile respectively. And
cycloaddition across the nitrile generates 2-methyl-3-phenyl-5-[(£)-phenylvinyl]-A'*1,2,4-oxadiazole 339. hiitially, the reaction was studied imder theim al conditions by
heating an equim olar reaction m ixture o f compounds 230 and 322 at 60 °C for over two
days. The reaction did not indicate any signs o f the cycloaddition to have progiessed.
115
Chapter 5
After maintaining heat for tluee weeks, the reaction mixture developed signals which
could be interpreted as coiTesponding to two possible isomers o f cyclo addition products
across the olefin. The reaction m ixtine showed up to 30% conversion in 1:1 ratio by 'H
N M R analysis.
W ith a view to accelerate the cyclo addition o f compounds 230 and 322, the reaction was
studied under m icrowave irradiations. A reaction mixture o f P'aiii'-cimiamonitiile 230
(0.79 mm ol) and the nihone 322 (0.79 mm ol) was prepared using dichlorom ethane (1 ml)
as the solvent. The mixture was subjected to microwave inadiation (100 °C for 1800
seconds). A fter inadiation, the reaction m ixtine largely retained the m neacted starting
ciimamonitrile and the nitrone. This was associated w ith exhem ely low intense signals o f
the possible cycloaddition products. Isolation o f the cycloaddition products was not
possible due to poor yields.
In a later attempt, the reaction mixture was prepared w ithout using any solvents. In the
absence o f solvents, the radiation is directly absorbed by the reagents, so the effect o f the
microwaves is m ore marked. However, on inadiation, the reaction mixtm’e o f 227 and
335 did not show any considerable im provem ent in the reaction, exhibiting only traces o f
the probable cyclo addition products as obseiwed earlier and a large proportion o f the
uiu'eacted starting materials retained.
The reaction was further attempted by irradiating a mixtui'e o f 230 (0.79 mmol) and
excess o f nitrone 322 (3 nnnol) w ith minim al quantity o f dichlorom ethane (0.3-0.4 ml) as
the solvent. The mixture on iiTadiation (100 °C for 2 hours) gave a significant
im provem ent in the cycloaddition reaction, w hich was indicated by signals o f two
possible isomers coiTesponding to cyclo addition across the olefin. The existence o f two
isomers was obseiwed by developm ent o f two distinct signals o f the N M e (Hb) protons
showing at 2.74 ppm and 2.75 ppm. The ^H N M R gave indication 30-35% conversion to
the desired cycloaddition products. M ore significantly, in contrast w ith the theiinal
heating approach, m icrowave conditions showed a dramatic reduction in reaction times.
The obseiwed conversion was achieved in only 2 hoius o f reaction times as compared to
tlnee weeks o f thermal heating.
In the next stage, the piuification o f the ciiide cycloddition m ixtine w as essential for
assigmnent o f the two possible diastereomeric configurations. The two disastereoisom ers
116
Chapter 5
were observed to have nearly coinciding Rf values (0.45 and 0.42). Purification by
colum n chi'omatograpliy (silica, DCM /hexane 4:1) gave two fractions conesponding to
the two possible diastereoisomers, 2-methyl-3,5-diplienyl-isoxazoline-4-carbonitrile 329
and 2-m ethyl-3,5-diphenyl-isoxazoline-4-carbonitrile 330 respectively. The assigmnent o f
the protons signals o f the two obseiwed diastereoisomers can he tabulated as under (see
table 5.3).
Chemical shifts (ppm)
Protons
Diastereom er 1
D iastereom er 2
N(M e) (Hb)
2.75 (s, IH )
2.74 (s, IH )
0-C -H d
5.41, (d, J = 6.5 Hz, IH )
5.33 (d, J = 7 . 5 H z , IH)
C-Hc
3 .4 3 (d d ,y = 7 H z an d 9 .5 H z,lH )
3.56 (dd, / = 7 H z and 9 H z,lH )
N -C-Ha
3 . 9 8 ( d , / = 9 H z , IH)
3 . 9 2 ( d , / = 9 H z , IH)
7.34 (m, IH ),
7.41 (t, J = 7 . 5 H z , 2H),
7.48-7.38 (m, lOH)
Aiom aties
7.51 ( d , J = 7 H z , 2H),
7.39-7.36 (m, 5H)
Table 5.3 H assignment for the two possible diastereoisomers
IR analysis o f the two isolated diastereoisomers m aintained a characteristic nitrile (C =N )
stretching at 2245 c n f ^ w hich suggested that the cycloaddition had oceu n ed across the
Œ,/3-unsaturated olefmic bonds. Analysis o f the individual compounds by N OESY w ith a
m ixing tim e o f 1 second was consistent w ith diastereoisomers 329 rac-(3R, 4S, 5S) and
330 rac-(3S, 4S, 5S) o f 2-m ethyl-3,5-diphenyl-isoxazoline-4-carbonitrile (see Scheme
141). Compound 330 consisting o f H a proton showed a strong N O E w ith one o f the
phenyl ring which is in close proxim ity (Pha). This was in conjunction w ith He protons
showing a N O E peak w ith the proton H a indicating a cA-configuration betw een them.
The H d proton obseiwed at a higher chemical shift in compound 330 showed a NOE peak
with the proxim al phenyl ring (Phb) but not w ith proton He. On the other hand compound
329 was characterised by N O E peaks indicating that proton H e m aintained a cisconfiguration w ith the two phenyl ring (Pha & Phb). In addition, N O E ’s for the proximal
117
Chapter 5
phenyl rings Pha and Phb were observed w ith protons H a and H d respectively but no N OE
was observed betw een protons H a and H e or H d and Ho.
5.6.3 Cycloaddition
Cinnamonitrile
of
C-Plienyl-N-metliyl
Nitrone
with
Pt(II)
bonnd
trans-
Experim ents using the co-ordinated nitrile 327 were then studied. A mixture o f 327
(0.047 im nol) and the nitrone 322 (5 mole equiv.) using dichlorom ethane as the solvent
(1.8-2 ml) was prepared and irradiated w ith microwaves by setting the tem perature to 100
°C for 300 seconds (see Scheme 142). The light yellow solution after inadiation becomes
a hom ogeneous light orange solution. The mixture gave a yellow orange oily residue on
rem oval o f the solvent and was analysed by TLC analysis (DCM, silica) w hich indicated
a spot w ith Rf values 0.581 corresponding to the cycloadducts and a baseline spot
conesponding to the um eacted highly polai- n ihone 322 retained in the mixture.
H
\
Ph
___ /
DU
Ha
r
H
V
.
N
y
MeHb
\
y
■‘Kf'fr"
.K*"”"' H
S C H E M E 142
R eagents and conditions: i) d ic h lo ro m e th a n e ; ii) M W , 1 0 0 °C fo r 3 0 0 s e c o n d s.
Interestingly, the ^H N M R analysis o f the cnide m ixture indicated the cycloaddition to
have oceuned preferentially across only one o f the nitrile in the ligated complex. This
was shown by the developm ent o f a singlet at 3.00 ppm corresponding to the N CHi
protons (Hb) in the heterocycle. The chemical shift o f this peak clearly differed from the
conesponding singlet obseiwed in an um eacted nitrone observed at 3.88 ppm. Also, there
is a developm ent o f peak at 5.95 ppm conesponding to the N -C H -N (Hd) protons in the
oxadiazoline ring. The olefmic protons (He) on the heterocyclic side are observed at 7.49
ppm and 7.64 ppm, differing fiom the olefinic protons (Hd) o f the um'eacted ligand side
shown at 6.03 ppm and 7.54 ppm. It is noted that the olefmic protons He and H d
m aintained their ^rmw-configuration after irradiation, w hich is observed by retention o f
large coupling constants ( / = 16 Hz).
Compound 333 obtained in this w ay was not
118
Chapter 5
completely pure and contained a significant amount o f the unreacted starting nitrone.
N M R o f the cm de product 333 also showed the presence o f some fi'ee ciimamonitrile
w hich m ay have been released from complex 327. Some traces o f henzaldehyde were also
obseiwed w hich m ay have developed by possible hydrolysis o f the nitione due to some
moisture retained in the reaction system. These organic im pm ities can be easily rem oved
fi'om the reaction mixtui'e by washing the crude product w ith diethyl ether. The pure
product 333 is obtained as a light yellow solid, purified by colum n clnom atograpy (DCM,
silica). The highly polar um eacted nitrone 322 rem ains on the colum n and com pound 333
is eluted preferentially. IR analysis o f the com pound 333 m aintained a diagnostic C=N
stretching o f the oxadiazole ring at 1642 c m '\ characterised a free cinnam onitrile w ith a
C s N stretching at 2270 cm"' and the free olefins (trau5'-HC=CH-) at 967 c m '\ The
elemental analysis o f the com pound was consistent w ith the required composition.
Compound 333 was further confiim ed by its mass spectrum characterising 682 [M+Na]'*’,
623 [M-Cl]"" and 588 [M-2C1]' ions.
This attempt has made evident that co-ordination o f the ligand 230 w ith a strongly
electron withdrawing Pt (II) metal centre, is responsible for the observed nucleophilic
attack o f the nitrone across the nitrile. The metal co-ordination makes the nitrile a much
stronger electrophilic site even in presence to the election deficient a,|S-unsaturated
olefmic system in the same ligand. In conti ast to the metal fi'ee reaction, the cyclo addition
occurs exclusively across the C sN . M ore significantly, under the influence o f microwave
inadiation, selective m ono cycloaddition can be achieved in substantially reduced time.
In a later experiment, w ith a view to optimising the stoichiometry, the reaction mixture
was prepared using equimolai' quantities o f compound 322 and 327. h i doing so, fiuther
purification o f the final product could be avoided. The cyclo addition was effected by
irradiating the mixture w ith microwaves at 100 °C for 1200 seconds. The reaction
predom inantly gave com pound 333, precipitating out by washing the crude product w ith
diethyl ether and decanting the solvent. Com pound 333 was obtained in 35-40% yield.
The cycloaddition was also attempted by maintaining an excess (4-5 m ole equiv.) o f the
nitrone 332 in the reaction mixtiu'e w ith compoimd 327 and extending the tim e o f
microwave inadiation. U se o f an excess o f nitione w ith extended inadiation time is
aimed to study cycloaddition across the other possible sites o f attack in com pound 327 i.e.
the second C = N and/or the C=C group. Dichloromethane (2 ml) was used as a solvent.
119
Chapter 5
The reaction m ixtine was inadiated w ith microwaves at 100 °C for 7200 seconds. A fter
inadiation the light yellow solution turned in to a light orange hom ogeneous solution. The
cm de product was isolated by rem oval o f the solvent as a reddish orange oily residue.
N M R analysis o f the cm de product showed a singlet developed at 2.96 ppm
corresponding to the N M e (Hb) protons, two singlets at 5.89 ppm and 5.98 ppm
corresponding to the two possible diastereomeric N -CH-N (Ha) protons. The 'H N M R
suggested a 1:1 m ixture o f the two diasteromers in the m ixtiue. This indicated that the
cycloaddition m ay have oceuned across both the nitiile functions o f the ligated complex
327. Initially, the olefmic protons (He) w ere not evident in the 'H NM R. The um eacted
olefinic carbons (-CH=) for the two possible diastereoisomers w ere identified in
N M R at 111.2, 111.3 ppm and 144.7, 144.8 ppm. These signals conelated w ith the
corresponding broad proton signals in HM QC analysis at 7.58 ppm, 7.40 ppm and 7.55
ppm, 7.50 ppm respectively w hich w ere assigned to the olefmic protons (He). IR analysis
o f the compound 334 showed no evidence o f any h e e C = N and m aintained a C=N
stretching for the oxadiazole ring at 1639 cm "\ h i addition, the olefmic protons
maintained a h'a/î^-configuration, shown at 967 cm "\ The com pound 334 was frnther
confirmed by its mass spectrum, identifying 817 [M+Na]"^, 723 [M-2C1]^ ions. The cm de
product retained the um eacted nitrone w hich was separated and the pure bis cycloaddition
product 334 was isolated by colunm cluom atogiaphy (DCM, Silica) in 27-30% yield.
Ph
He"
P
I
\
AYVs/
Hb Me
N
C.
\ Ph
I
Ha
334
Theim al studies on cycloaddition o f the nitrone 332 (4-5 mole equiv.) w ith the complex
327 w ere done by heating the reaction m ixtm e at 45-50 °C. The m ixtm e was monitored
for progr ess by 'H N M R analysis. A fter overnight heating, a m ixtm e o f mono 333 and bis
cycloaddition 334 products is evident and the reaction mixture retained some unreacted
nitrone. This is m ade evident by the presence o f two distinguished singlets at 5.89 ppm
and 5.98 ppm o f N -CH-N (Ha) conesponding to the two diasterom ers o f the bis
120
Chapter 5
cycloaddition product 334. After heating for 4 days, the reaction m ixture predom inantly
identified the bis cyclo addition product 334.
5.6.4 Preparation o f Pd bound tra/is-C innam onitnle Complex
Studies on heterocycle synthesis on hansition metal boimd organonihile complexes was
extended
by
preparing
a
trani'-ciim amonitrile
complex
o f Pd(II).
The
Pd(II)-
ciimamonitrile complex was prepared by heating a suspension o f PdC l2 in transchm am onibile at 60 °C for two weeks. The dark PdClz 335 com pletely dissolves and
thereafter on addition o f diethyl ether, the Pd(II)-cimaamonihile com plex 336 was isolated
as orange solid after filtration and di-ying in air.
H
PdCh
335
/
-------------- ►
H
>=<
/
\
Ph
Ph
Pd
336
H
S C H E M E 143
R eagents and conditions: i) ^ ra « 5 -c m n a m o n itrile (e x c e s s ) 2 3 0 , ii) 60 °C f o r 2 w e e k s .
The co-ordination o f the Pd (II) m etal cenhe w ith the nitrile o f the ligand w as obseiwed in
the IR analysis showing the nitrile (-C =N ) stretching at 2276 c m '\ the olefinic protons in
tran^-configuration w ere shown at 965 cm"'. The
N M R analysis identified the olefmic
protons o f the ligand at 6.03 ppm and 7.66 ppm, maintaining their fran^-configuration
( J = 16 Hz), hi case o f the Pd complex, the release o f the ligand is m uch faster w hich was
made evident by the h e e ciimamonitrile obseiwed in the 'H N M R solution.
5.6.5 Cycloaddition o f C-Phenyl-A-methyl N itrone with Pd(II) bound transCinnamonitrile Complex and Displacem ent o f the Oxadiazole from the Palladium
Complex
The synthesis o f palladim n bound oxadiazoline heterocycle was studied by cycloaddition
o f C-phenyl-A-methyl nitrone 322 w ith Pd(II)-ciim amonitrile complex 336.
The
synthesis was done by heating a suspension o f Pd(II)-cimiamonitrile complex w ith Cphenyl-A-methyl nitrone (1:2 m olar ratio). Pd(II)-cinnamonitrile readily releases the
121
Chapter 5
ligand and therefore the reaction was heated in ^ra/w-cimianionitrile 230. A fter overnight
heating at 60°C a clear orange solution was fonned and the desired cycloaddition product
was precipitated w ith diethyl ether as a pale yellow pow der by filhation and dried in air.
H
\ _____
/
Ph
pj^
JZ = C
\
Ha
\ /
I
He
I
Me Hh
N/
.N
H
Ph
H
322
Hh Me
Ha
337
S C H E M E 144
Reagents and conditions: 1) tra775-cinnamoniti-ile; ii) 60°C, overnight.
Cyclo addition was observed to occin exclusively across the nitrile group on the Pd bormd
ligand. This was m ade evident in the conesponding
N M R o f the product 337 showing
the developm ent o f singlets at 2.94 ppm o f -NM e (Hb) protons and at 5.83 ppm o f N-CHN (Ha) protons. The um eacted olefinic protons (He) m aintained their fran^-configm'ation
and w ere obseiwed at 7.46 ppm and 7.68 ppm. The DR. analysis gave evidence o f the C=N stretching at 1647 cm"^ in the heterocycle, hr addition, the C HN analysis was
consistent w ith the desired product.
f
Ph
N
/
Me
Ha
™
C.
I
\
H
Ph
339
Ph
337
S C H E M E 145
Reagents and conditions: i) aq. MeNHj 338; ii) 50°C, 10 minutes.
Pd complexes facilitate an easy release o f the heterocycle produced after cycloaddition.
The displacem ent o f the 2-methyl-3-phenyl-5-[(£')-phenylvinyl]- A'*-l,2,4-oxadiazole 339
synthesised on the Pd(II) complex was done by simply adding an excess o f an aqueous
122
Chapter 5
solution o f methyl amine to a reaction m ixture o f Pd(II) heterocycle complex 337 in
chlorofonn. A fter 10 m inutes o f stirring at 50°C, the desired heterocycle 339 was isolated
as colourless oil hy rem oving the organic phase and filtering the reaction mixture through
a plug o f silica. The compoimd solidified upon standing.
Compound 339 obtained by cycloaddition across the nitrile is an isom er to compounds
329 and 330 obtained hy cyclo addition across the olefin. The diagnostic
N M R o f the
heterocycle 339 identified Hb and H a protons shown as singlets at 2.94 ppm and 5.68
ppm respectively. The um'eacted o;/3-rmsaturated m ethylene protons (He) w ere observed
as doublets at 6.71 ppm and 7.45 ppm correspondingly. IR spectrm n o f the compound
m aintained a diagnostic -C = N stretching at 1672 c n f ' and the h'au5-HC=CH shetching at
9 6 7 c m '\
Thus this study has demonstrated that m icrowave irradiation can he applied to heterocycle
synthesis on organonitriles bound on Pt(II) centres. M ore importaiitly, it has made evident
that the cycloaddition in the case o f Pt(II) bormd ligands w ith two elechophilic sites like
h'cm^-cimramoriitrile occrus selectively across the nitrile group. M icrow ave irradiations
have favoured the selective synthesis o f mono cyclo addition complex 333 and can he
easily isolated. In contrast, the conventional heating is only able to give a mixture o f
cycloaddition products. M icrowave irTadiation has also favoured the synthesis o f Pt(II)
bound heterocycles hy bis cycloaddition, complex 334. hr contrast w ith the conventional
heating involve substantially reduced reaction times and the heterocyclic complex 334
can be isolated easily. The Pt(II) bound organonitrile 327 produces a highly polar
transition state or interm ediate w ith the nitrone, thus, monocycloaddition becomes almost
exclusive under microwave conditions, hr addition, the theriiral synthesis o f Pd(II) bound
oxadiazoline 337 is possible. U se o f this methodology for heterocycle synthesis is
preferred because displacem ent o f the correspondirrg heterocycle ho rn Pd(II) metal centre
facilitates an easy release o f the heterocycle and in less time.
123
Chapter 5
6.0 Conclusions and Fnture W ork
To conclude with, the present study has broadly demonstrated the application o f
microwave irradiation in organic synthesis, hr particular, the study has provided examples
o f the advantages o f microwave heating over the classical heating approach.
The developm ent and use o f novel polym er and inorganic solid supported reagents has
been illustrated for application in some im portant organic syntheses. U se o f Novel
Polym er and Inorganic Solid Supported Formates has been successfully applied as
Transfer Hydrogenation Source and Formylating Agents in the synthesis o f
fomiamides.
In general, the m icrowave assisted reduction o f electron deficient alkenes has shown
higher yields and less reaction time as com paied to the thermal approach. This is possibly
due to them ial effects imder m icrowave conditions and no evidence o f any specific
m icrowave effect was obseiwed. Synthesis o f fonnam ides using prim ary amines has been
more successful as compared to the secondary amines. In com parison w ith the control
reactions, higher yields w ere observed under microwave conditions possibly due to
formation o f a highly polar transition state. The reproducibility o f the reaction is liigh
under microwaves and there is a significant reduction in reaction tim es and improved
yields.
Use o f insoluble supported fom iates has demonstrated a m eans o f simplifying reaction
procedures. The supported formates can be easily rem oved on com pletion o f the reaction
by simple filtration and can be utilised in fuither reaction cycles upon reloading with
formate. U se o f supported formates has reduced the hazards o f the conventional hydrogen
donors like H 2 gas, amm onium fomiate. hr particular, this has been helpful in overcoming
the disadvantages o f sublim ation and release o f toxic residue such as N H 3. Moreover, use
o f solid supported reagents (AI2O3/HCOOH) has also aided in the purification procedures
by acting as a Scavenger for W ilikinson’s catalyst.
In this study, microwave irradiation has also benefited cyclo addition reactions leading to
the synthesis o f some im portant heterocyclic systems. Synthesis o f A'^-l,2,4-oxadiazoline
heterocyclic systems on Pt(II) boim d nitrile ligands has been achieved under microwave
124
Chapter 5
iixadiations w ith substantial reduction in reaction times. Selective cycloadditions have
only been achieved by optimising the incident microwave irradiations.
In summary, use o f this methodology benefits significantly in achieving a variety o f
organic syntheses. M ore importantly, the technique provides a clean and efficient route to
heterocyclic compounds.
h i future the application o f m icrowave iixadiation w ill be investigated for studying many
other avenues o f organic synthesis.
•
In view o f the successhil application o f polym er and inorganic solid supported
fom iates as effective hydrogen sources, their application as transfer hydrogenation
sources w ill be investigated in m icrowave assisted transfer hydrogenation o f sterically
hindered steroidal structures like ergosterol, progneiiolone acetate and substrates like
4-phenyl-but-l-ene, mesityl oxide, terpenes like a-pinene, m ainly involving the use o f
W ilkinson’s catalyst.
•
U se o f supported foixnates w ill be investigated in studying m icrowave assisted
dechlorination reactions and reduction o f aiom atic nitro compounds to amines.
•
The application o f supported formates in studying the m icrow ave assisted Nfom iylation o f amino acids like /3-alanine, L-proline will be o f interest.
•
The W ilkinson’s catalyst sequestered/scavenged on com pletion o f the reductions
(Section 4.7) w ill be applied in other transfer hydrogenations and its activity w ill be
investigated as a catalyst im m obilised on an inorganic support.
•
The study on developm ent o f a transfer hydrogenation soiu'ce supported on soluble
polyethylene glycols gave difficulties to prepare a fully derivatised PEG derivative.
This w ork needs to be repeated to prépaie a fully derivatised sam ple o f the PEG
support and applying as a transfer hydrogenation source.
•
D evelopment o f acetic acid (HOAc) supported on a quartem ary ammonium
functionalised insoluble polym er will be investigated b y ion-exchange.
The
application o f such supported reagents w ill be o f interest in m icrowave assisted
synthesis o f acetamides starting from amines.
•
Developm ent o f a novel polym er supported phosphinic acid (H3PO2) will be studied
and its application as a transfer hydrogenation souice under m icrow ave conditions
w ill be o f interest.
•
M icrowave assisted cycloadditions o f metal coordinated organonihiles and nitrones
for heterocycle synthesis w ill be studied further.
125
The study w ould involve use o f
Chapter 5
Pt(II), Pt(IV) and Pd(II) metal ceiiti'es and different dipolar reagents for synthesising
heterocycles o f different substitution patterns.
126
Chapter 6
Experimental
Chapter 6
EXPERIM ENTAL
All m icrowave assisted experimental w ork described was conducted on Labwell 10
m icrowave reactor and Smithcreator® (see Figui'es 1.8). Reaction m ixtm es were prepared
in pyrex glass tubes equipped w ith pressm e release caps and tubes w ere introduced in the
cavity o f microw ave reactors for irradiation. The Labwell 10 m icrow ave reactor operates
at variable pow er (in watts) and tim es o f inadiation (in seconds). The Smith creator
operates at variable tem peratures (in °C) and times o f irradiation (in seconds). All melting
points were recorded on the K ofler m elting point apparatus.
and ^^^Pt NM R
experiments w ere acquired on Bruker D RX 500 and B m ker A M X 300 spectrometers
using CDCI3 as the solvent unless otherwise stated. All 'H N M R chemical shifts are
quoted in ppm relative to tetram ethyl silane (TMS) used as internal reference. ^^^Pt
chemical shifts are given relative to aqueous K 2[PtCl4] = -1630 ppm. All infrared
spectrums were recorded on Perkin Elm er 2000-FTIR spectrometer. The mass spectra
were obtained on Fim iighan M AT 95XL mass spechom eter operating in E l mode.
1. M icrowave assisted hydrogenation o f tm ns-cinnamic acid using aminomethyl
polystyrene form ate and W ilkinson’s catalyst.
NH3
HCO,
RliClfPPlq),
DMSO
MW
A mixture o f tran^-ciimamic acid 214 (0.025 g, 0.168 mmol), aminomethyl polystyi'ene
supported fom iate salt 176 (0.200 g, 0.12 nmiol) and W ilkinson’s catalyst 204 (0.040 g,
0.04 mm ol) was suspended in a reaction tube using DM SO (0.4 ml) as the solvent. The
mixture was irradiated w ith microwaves at 300 W for 10 seconds. On cooling, the
mixture was diluted w ith dichlorom ethane (5 ml) and filtered under gravity. The filtrate
was dried over m agnesium sulphate (M gS04) after washing w ith sm all aliquots o f brine
( 2 x 5 ml). The w ashed organic fraction was filtered through a plug o f alum ina and
evaporated imder reduced pressure to give white crystals (0.015 g). However, this was
only a m ixture o f the reduced product and the ruu eacted starting material.
127
Chapter 6
2. Therm al and microwave assisted hydrogenation of tm ns-cinnam ic acid using
Amberlite® supported form ate and W ilkinson’s catalyst.
'N —
/ H CO,OH
OH
RhCI(PPh,),
214
DMSO
MW
215
A mixture o f ^ra/w-cimiamic acid 214 (0.025 g, 0.168 mm ol), A m berlite supported
formate 182 (0.250 g, 0.6 mm ol) and W ilkinson’s catalyst 204 (0.005 g, 0.005 mmol)
was prepared in a reaction tube using DM SO (0.5 ml) as the solvent. The reaction
mixture was inadiated w ith microwaves at 100 W for 30 seconds. On cooling the mixture
was diluted with dichlorom ethane (5 m l) and filtered under gravity. The filtrate was
washed w ith small aliquots o f brine ( 2 x 5 ml). The washed organic fraction was filtered
tlirough a plug o f alum ina and evaporated under reduced pressure to give white crystals.
(0.024 g, 95%). U nder thermal conditions m aintaining identical scales, the reaction
mixtm-e was heated at 70-80 °C for 4 hours, showed lowered yields (80%).
M.P. 47-48 °C (Lit., 48-49 °C)
2.87 (t,
6» (300 M Hz; CDCI3): 2.56 (t, / = 9 Hz, 2H, -0 % ),
9 Hz, 2H, -CH2), 7.18-7.21 (m, 5H, Ar).
in/z: 150.1 [M+], 151.1 [M+H]+.
3. Therm al and microwave assisted hydrogenation of tm «s-cinnam ic acid using alumina
supported form ate and W ilkinson’s catalyst.
AI2O3/HCOOH
OH
R hC I(P P y,
DMSO
MW
215
A mixture o f fra«5-cimiamic acid 214 (0.025 g, 0.168 mm ol), alum ina supported
hydrogen donor 189 (0.500 g, Innnol) and W ilkinson’s catalyst 204 (0.005 g, 0.005
mm ol) was prepared in a reaction tuhe using DM SO (0.5 ml) as the solvent. The reaction
mixture was iiTadiated w ith microwaves at 100 W for 30 seconds. O n cooling the mixture
was diluted w ith dichlorom ethane (5 ml) and filtered under gravity. The filtrate was
w ashed w ith small aliquots o f brine ( 2 x 5 ml) and dried over m agnesium sulphate. The
dried organic haction was evaporated under reduced pressure to give white crystals.
128
Chapter 6
(0.023 g, 95%). U nder therm al conditions m aintaining identical scales, the reaction
m ixture was heated at 70-80°C for 4 horns, showed lowered yields (80%).
M.P. 47-48 °C (Lit., 48-49 °C)
2.87
0» (300 M Hz; CDCI3): 2.56 (t, 7 = 9 Hz, 2H, -CH2),
168b
(t, 7 = 9 Hz, 2H, -CHz), 7.18-7.21 (m, 5H, Ar).
m/z: 150.1 [M+], 151.1 [M + H f.
168c
4.
M icrowave assisted hydrogenation of trans-methyl cinnam ate using aminomethyl
polystyrene supported formate and W ilkinson’s catalyst.
HCO„OMe
OMe
RliClCPPhjlj
DMSO
MW
216
217
A mixture o f trans-m ethyl cimrarnate 216 (0.05 g, 0.308 m m ol), aminomethyl
polystyrene formate salt 176 (0.200 g, 0.12 rnrnol) and W ilkinson’s catalyst 204 (0.040 g,
0.04 rnrnol) is suspended in DM SO (0.5 m l) used as a solvent. The suspension is
irradiated w ith microwaves at 300W for 10 seconds. On cooling the m ixture is diluted
w ith dichloromethane (5-10 ml) and filtered under gravity. The organic filtrate was
w ashed several times ( 2 x 5 ml) w ith brine and dried over anlrydrous m agnesium
sulphate. The dried organic fraction is filtered tlnough a plug o f alum ina and evaporated
under reduced pressure to give coloruless oil (0.024 g). However, this was only a mixture
o f the reduced product and the um eacted starting material.
5.
Therm al and microwave assisted hydrogenation of trans-methyl cinnam ate using
Amberlite® supported form ate and W ilkinson’s catalyst.
-N—
I HCO^OMe
216
OMe
RliCKPPhjlj
DMSO
MW
217
A mixture o f trans-m ethyl ciimamate 216 (0.025 g, 0.15 mm ol), A mberlite supported
formate 217 (0.250 g, 0.62 mm ol) and W ilkinson’s catalyst 204 (0.005 g, 0.04 mmol) is
suspended in DM SO (0.5 ml) used as a solvent. The suspension is inadiated with
microwaves at lOOW for 30 seconds. On cooling the m ixture is diluted w ith
129
Chapter 6
dichlorom ethane (5-10 ml) and filtered under gravity. The organic filtrate was w ashed
several times (2 x 5ml) w ith brine and dried over anlrydrous m agnesium sulphate. The
dried organic tr action is filtered tlnough a plug o f alum ina and evaporated under reduced
pressure to give coloui'less oil. (0.023 g, 90%). U nder theirnal conditions, a reaction
mixture w ith identical scales was heated at 70-80 °C for 4 hours, show ed lowering in the
yields (75%).
ÔH (300 MHz; CDCI3): 2.60 (t, J = 8 Hz, 2H, -CHz), 2.95 (t, J = 8 Hz, 2H, -CH2), 3.66 (s,
3H, -OCH3), 7.20-7.44 (m, 5H, AiH). (Lit., 7.16 (m, 5H, ArH), 3.60 (s, 3H, -OCH3), 2.87
(m, 2H, CH2), 2.53 (m, 2H, CH2))'^^m/z: 164.1 [M]+ (Lit., 164 [M]+).
6
.
Therm al and microwave assisted hydrogenation o f tr««s-methyl cinnam ate using
alumina supported form ate and W ilkinson’s catalyst.
ALO,/HCOOH
RliClfPPhjij
DMSO
MW
217
A m ixture o f ^ra«5-methyl ciimamate 216 (0.025 g, 0.15 mm ol), alum ina supported
fonnate 189 (0.500 g, 1 im nol) and W ilkinson’s catalyst 204 (0.005 g, 0.005 im nol) is
suspended in DM SO (0.5 ml) used as a solvent. The suspension is irradiated with
microwaves at 100 W for 30 seconds. On cooling the m ixture is diluted with
dichlorom ethane (5-10 ml) and filtered under gravity. The organic filtrate was washed
several times ( 2 x 5 ml) w ith brine and dried over anlrydrous m agnesium sulphate. The
dried organic fraction is filtered tlnough a plug o f alumina and evaporated under reduced
pressure to give colourless oil. (0.023 g, 90%). U nder thermal conditions, reaction was
done by maintaining the scales and heating the mixture at 70-80 °C for 3-4 hours gave
reduced yields (75%).
ÔH (300 M Hz; CDCI3): 2.60 (t, / = 8 Hz, 2H, -CH2), 2.95 (t, / = 8 Hz, 2H, -CH2), 3.66 (s,
3H, -OCH3), 7.20-7.44 (m, 5H, ArH). (L it, 7.16 (m, 5H, AiH), 3.60 (s, 3H, -OCH3), 2.87
(m, 2H, CH2), 2.53 (m, 2H, CH2)) '^®nVz: 164.1 [M]+ (Lit., 164 [M]+).
130
Chapter 6
1.
M icrowave assisted hydrogenation o f ^rrt/is-ethyl cinnam ate using aminomethyl
polystyrene form ate and W ilkinson’s catalyst
H CO,OEt
DMSO
MW
218
GEt
RhCKPPhPj
219
A m ixture o f ^ra775-ethyl ciminamte 218 (0.026 g, 0.14mniol), aminomethyl polystyi’ene
salt 176 (0.250 g) and W ilkinson’s catalyst 204 (0.040 g, 0.04 mm ol) w as prepared in a
reaction tube by suspending in DM SO (0.5 ml) used as a solvent. The reaction mixture
was inadiated w ith microwaves at 300 W for 10 seconds. On cooling the m ixture was
diluted w ith dicblorom etbane (5 ml) and filtered under gravity. The filtrate is washed
w ith several aliquots o f brine ( 2 x 5 ml) and dried over m agnesium sulphate. The dried
organic fraction is filtered through a plug o f alum ina and evaporated under reduced
pressure to give light yellow oil (0.020 g). However, this was a m ixture o f the reduced
product and the uiu’eacted starting material.
Therm al and microwave assisted hydrogenation o f trans-ethyl cinnam ate using
Amberlite® supported form ate and W ilkinson’s catalyst.
-N—
/ HCO,
GEt
GEt
mci(pph^h
218
DMSG
MW
219
A mixture o f ^ronj'-ethyl cimmamate 218 (0.026 g, 0.148 mm ol), A m berlite supported
formate 182 (0.250 g, 0.62 mm ol) and W ilkinson’s catalyst 204 (0.040 g, 0.04 mmol)
was prepared in a reaction tuhe by suspending in DM SO (0.5 ml) used as a solvent. The
reaction mixture was inadiated w ith m icrowaves at 100 W for 30 seconds. On cooling
the m ixture was diluted w ith dichlorom ethane (5 ml) and filtered under gravity. The
filtrate is w ashed w ith several aliquots o f brine ( 2 x 5 ml) and dried over m agnesium
sulphate. The dried organic h action is filtered tlnough a plug o f alum ina and evaporated
under reduced pressure to give light yellow oil. (0.021 g, 80%). U nder thermal
conditions, a reaction m ixture w ith identical scales was heated at 70-80 °C for 4 hours,
showed lowering in the yields (62%).
131
Chapter 6
Vrnax/cm'^: 3030, 2930, 1735 (-C =0) (Lit., 1735 (-C =0))
6
» (300 MHz; CDCI3 ): 1.25
(t, / = 8Hz, 3H, -CH3), 2.61 and 2.95 (t, / = 9 Hz, 2x2H, (-CHz)2 ), 4.13 (q, / = 8 Hz, 2H,
-OCH2), 7.26-7.38 (m, 5H, ArH).
9.
Therm al and microwave assisted hydrogenation o f tmHs-ethyl cinnam ate nsing
alum ina supported form ate and W ilkinson’s catalyst.
AI2O3/HCOOH
OEt
218
OEt
RhCl(PPh3)3
DMSO
MW
A mixture o f trans-ethyl cinnnam te 218 (0.025 ml, 0.14 mmol), alum ina supported
formate 189 (0.500 g, 1 mm ol) and W ilkinson’s catalyst 204 (0.040 g, 0.04 im nol) was
prepared in a reaction tube by suspending in D M SO (0.5 ml) used as a solvent. The
reaction m ixture was inadiated w ith m icrowaves at 100 W for 30 seconds. On cooling
the mixture was diluted w ith dichlorom ethane (5 ml) and filtered under gravity. The
filtrate is w ashed w ith several aliquots o f brine ( 2 x 5 ml) and dried over m agnesium
sulphate. The dried organic haction was evaporated under reduced pressure to give light
yellow oil. (0.018 g, 70%). U nder therm al conditions, a reaction mixtm-e w ith identical
scales was heated at 70-80 °C for 4 hours, showed lowering in the yields (60%).
Vrnax/cm-^: 3030, 2930, 1735 (-C =0) (Lit., 1735 (-C =0))
Sn (300 MHz; CDCI3 ): 1.25
(t, J = 8 Hz, 3H, -CH3), 2.61 and 2.95 (t, J = 9 Hz, 2x2H, (-CHz);), 4.13 (q, J = 8 Hz, 2H,
-OCH2), 7.26-7.38 (m, 5H, ArH).
10. Therm al and microwave assisted hydrogenation o f rtvms-cinnamaldehyde using
Amberlite® supported form ate and W ilkinson’s catalyst.
RliClCPPhjlj
224
DMSO
MW
225
A mixture o f fran^-ciimamaldehyde 224 (0.026 g, 0.196 nnnol), A m berlite supported
fonnate 182 (0.400 g, 1 mmol)) and W ilkinson’s catalyst (0.040 g, 0.04 mm ol) was
suspended in a reaction tube using DM SO (0.6 ml) as the solvent. The reaction mixture
132
Chapter 6
was iiTadiated w ith microwaves at 100 W for 30 seconds. On cooling, the m ixtnie was
diluted w ith dichlorom ethane (5 ml) and filtered under gi'avity. The filtrate is washed
w ith small aliquots o f brine ( 3 x 5 ml) and extracted by sm all portions ( 2 x 5 ml) o f
diethyl ether. The combined organic phase was dried over m agnesium sulphate and
filtered tlu'ough a plug o f alumina. The organic fraction thus obtained was evaporated
under reduced pressure to give yellow oil (0.024 g, 95%). H eating the reaction mixture
theim ally (70-80 °C for 4 horns) gave reduced yields (70%).
Vmax/cnT': 1677.3, 1721.9, 1626.2 (-C = 0 ) (Lit., 1724, 1603 (-0=0)).'^ ' Ôr (300 MHz;
CDCI3): 2.77 (t, J = 9 Hz, 2H, -CHj), 2.95 (t, / = 9 Hz, 2H, -CHz), 7.29-7.31 (m, 5H,
ArH), 9.81 (t, IH , -CHO).
11. Therm al and microwave assisted hydrogenation o f tm ns-cinnam aldehyde nsing
alnm ina snpported form ate and W ilkinson’s catalyst.
A L07H C 00H
RhClfPPhjlj
'
-
A m ixtrne o f tran^’-cinnamaldehyde 224 (0.026 g, 0.19 mm ol), alum ina supported
formate 189 (0.500 g) and W ilkinson’s catalyst 204 (0.040 g, 0.04 mm ol) was suspended
in a reaction tube using DM SO (0.6 ml) as the solvent. The reaction m ixture was
iiTadiated w ith microwaves at 100 W for 30 seconds. On cooling, the m ixtrne was diluted
w ith dichlorom ethane (5 ml) and filtered under gi’avity. The filtrate is w ashed w ith small
aliquots o f brine ( 3 x 5 ml) and extracted by sm all portions ( 2 x 5 ml) o f diethyl ether.
The combined organic phase was dried over magnesim n sulphate and evaporated under
reduced pressm e to give yellow oil (0.016 g, 60%). H eating the reaction mixture
therm ally (70-80 °C for 4 horns) gave reduced yields (50%).
Vmax/cnT': 1677.3, 1721.9, 1626.2 (-0 = 0 ) (L it, 1724, 1603 (-0 = 0 )).
S r (300 MHz;
ODOI3): 2.77 (t, J = 9 Hz, 2H, -OH2), 2.95 (t, / = 9 Hz, 2H, -OH2), 7.29-7.31 (m, 5H,
ArH), 9.81 (t, IH , -OHO).
133
Chapter 6
12. Therm al and microwave assisted hydrogenation o f trans-benzylidene acetone using
Amberlite® snpported form ate and W ilkinson’s catalyst.
'N —
/ HCO;-
RllCI(PPh3)3
226
DMSO
MW
227
A mixture o f fra/jj'-benzylidene acetone 226 (0.025 g, 0.17 mm ol), A mberlite supported
fonnate 182 (0.300 g, 0.7 mmol) and W ilkinson’s catalyst (0.040 g, 0.04 mmol) were
suspended in a glass tube using DM SO (0.6 ml) as the solvent. The mixture was
inadiated w ith microwaves at 100 W for 30 seconds. On cooling the m ixtrne was diluted
w ith dichlorom ethane (5 ml) and filtered under gravity. The filtrate was washed w ith
several aliquots
o f brine ( 3 x 5 ml) and extracted with diethyl ether. The combined
organic phase was dried over m agnesium sulphate and filtered tlnough a plug o f alumina.
The organic fraction thus obtained was concentrated on a rotary evaporator to give a
colourless oil. (0.023 g, 90-95%). Reaction at an identical scale under therm al conditions
(70-80 °C for 3-4 hours) gave lower yields (85%).
Vrnax/cm ': 1711.5 (-C = 0) (Lit., 1715 (-C = 0 ))
5h (300 MHz; CDCI3): 2.61 (s, 3H, -
COCH3), 2.78 (t, J = 4 Hz, 2H, -CH2), 2.87 (t, J = 4 Hz, 2H, -CHz), 7.19-7.25 (m, 5H,
ArH).
13. Thermal and microwave assisted hydrogenation of tm «s-benzylidene acetone using
alumina supported form ate and W ilkinson’s catalyst.
A LO JH CO O H
RhCI(PPh3)3
DMSO
MW
227
A mixture o f benzylidene acetone 226 (0.025 g, 0.17 mmol), ahunina supported fonnate
189 (0.500 g, 1 nrniol)) and W ilkinson’s catalyst 204 (0.040 g, 0.04 mm ol) were
suspended in a glass tube using DM SO (0.6 ml) as the solvent. The mixture was
irradiated w ith microwaves at 100 W for 30 seconds. On cooling the m ixture was diluted
w ith dichloromethane (5 ml) and filtered rmder gravity. The filtrate was w ashed w ith
several aliquots
o f brine ( 3 x 5 ml) and extracted w ith diethyl ether. The combined
organic phase was dried over magnesim n sulphate and evaporated rmder reduced pressure
134
Chapter 6
to give a colom'less oil. (0.023 g, 90-95%). T hem ial conditions w ider identical scales (7080 °C for 3-4 hours) identified reduced yields (80%).
Vrnax/cm-^: 1711.5 (-C =0) (Lit., 1715 (-C=0)).'^^ 6 » (300 MHz; CDCI3): 2.61 (s, 3H, COCH3), 2.78 (t, J = 4 Hz, 2H, -CH2), 2.87 (t, J = 4 Hz, 2H, -CH 2 ), 7.19-7.25 (m, 5H,
ArH).
14. Thermal and microwave assisted hydrogenation o f AyV-dimethylcinnamide using
Amberlite® supported form ate and W ilkinson’s catalyst.
'N —
N (C H J,
228
I
H C O j-
RhCl(PPh^),
DMSO
MW
11(CH,),
229
#,7V-Dimetliylcinnainide 228 (0.025 g, 0.13 mmol), Amberlite supported formate 182
(0.250 g, 0.62 mm ol) and W ilkinson’s catalyst 204 (0.040 g, 0.04 im nol) was suspended
in a reaction tube using DM SO (0.6 ml) as a solvent. The reaction m ixtrne was irradiated
w ith microwaves at 100 W for 30 seconds. On cooling the m ixtrne was diluted with
dicblorom etbane (5 ml) and washed w ith several small aliquots o f brine ( 3 x 5 ml). The
washed mixtrne was extracted w ith sm all aliquots o f diethyl ether ( 2 x 5 ml) and dried
over m agnesium sulphate. The dried organic fraction was filtered tlnough a plug o f
alum ina and concentrated in a rotaiy evaporator to give colow less oil. (0.023 g, 95%).
Thermal comparison (70-80 °C for 3-4 hours), w ider identical reaction scales gave
lowered yields (70%).
Vmax/cin^: 1642.2 (-C = 0), 2914.3 (-N(CH3)2) (Lit., 1655 (-C =0)).^’^“ 6 » (300 MHz;
CDCI3): 2.62 (t, J = 8Hz, 2H, -CH2), 2.93 (s, 6H, -N(CH3)2), 2.95 (t, / = 8 Hz, -CH2),
7.19-7.31 (in, 5H, ArH).
m/z: 177.1 [M ]\ 178.1 [MH]+. (Lit., 178 [MH]+, 177.1 [M]+
).
135
Chapter 6
15. Therm al and microwave assisted hydrogenation o f AyV-dimethylcinnamide using
alumina snpported form ate and W ilkinson’s catalyst.
A l^ O j/H C O O H
N(CH,
NCHO
RliCl(PPli3)3
DM SO
MW
//,A^-Dimethylcimiamide 228 (0.025 g, 0.13 mmol), alum ina supported fom iate 189
(0.500 g, 1 mm ol) and W ilkinson’s catalyst 204 (0.040 g, 0.04 m m ol) was suspended in a
reaction tube using DM SO (0.6 m l) as a solvent. The reaction m ixture was irradiated with
microwaves at 100 W for 30 seconds. On cooling the m ixtrne was diluted w ith
dichlorom ethane (5 ml) and w ashed w ith several small aliquots o f brine ( 3 x 5 ml). The
w ashed mixture was extracted w ith small aliquots o f diethyl ether ( 2 x 5 ml) and dried
over m agnesium sulphate. The dried organic fraction was evaporated under reduced
pressure to give coloruless oil (0.023 g, 95%). Reaction done at an identical scale
theim ally (70-80 °C for 3-4 hours) gave reduced yields (70%).
Vrnax/cm"': 1642.2 (-0 = 0 ), 2914.3 (-N(CH3)2) (Lit., 1655 (-0=0)).'^^" 6» (300 MHz;
CDCI3): 2.62 (t, / = 8 Hz, 2H, -0 % ), 2.93 (s, 6H, -N(CH3)2), 2.95 (t, / = 8 Hz, -CH2),
7.19-7.31 (m, 5H, ArH).
m /z : 177.1 [M]+, 178.1 [M + H ]\
(Lit., 178 [M H ]\ 177.1
[M]+)_ 173b
16. Therm al and microwave assisted hydrogenation o f /m «s-einnam onitriIe using
Amberlite® supported form ate and W ilkinson’s catalyst.
RllCl(PPh3)3
°„T
"
[j
T
^
A m ixture o f /ran^-cinnamonitrile 230 (0.025 g, 0.19 mm ol), A m berlite supported
formate 182 (0.200 g, 0.5 im nol) and W ilkinson’s catalyst 204 (0.005 g, 0.005 mmol)
was suspended in DM SO (0.6 ml). The mixture was irradiated w ith m icrowaves at 100 W
for 30 seconds. On cooling the mixture was diluted w ith dichlorom ethane (5 m l) and
washed w ith several sm all aliquots ( 3 x 5 ml) o f brine. The w ashed organic fraction was
filtered under gravity and the filtrate was diied over magnesium sulphate. The dried
136
Chapter 6
organic fraction was filtered tlnough a plug o f alum ina and evaporated under reduced
pressure to give coloruless oil. (0.024 g, 95%). U nder therm al conditions, on heating the
mixture at identical scale at 70-80 °C for 4 horns gave similar yields (90-95%).
Vrnax/cm ': 2245.5, 2216.3 (-C=N).
CH2), 2.96 (t, J =
8
6» (300 MHz; CDCI3): 2.62 (t, / = 8 Hz, 2H, -
Hz, 2H, -CH2), 7.24-7.46 (m, 5H, ArH) (Lit., 2.57 (t, J = 7.3 Hz, 2H),
2.92 ( t , J = 7 3 Hz, 2H), 7.2-7.4 (m, 5H)).^^^^^ m/z; 131.07 [ M f (Lit., 131 [M]+).
17. Therm al and microwave assisted hydrogenation o f tm ns-cinnam onitrile nsing
alumina supported form ate and W ilkinson’s catalyst.
AI2O3/HCOOH
RhcifPPh^
230
DMSO
MW
231
A mixture o f ira/jj'-cinnamonitrile 230 (0.025 g, 0.19 imnol), alum ina supported fonnate
189 (0.500 g, 1 mmol) and W ilkinson’s catalyst 204 (0.005 g, 0.005 mm ol) was
suspended in DM SO (0.6 ml). The m ixture was irradiated w ith m icrow aves at 100 W for
30 seconds. On cooling the mixture was diluted w ith dichlorom ethane (5 ml) and washed
w ith several small aliquots ( 3 x 5 ml) o f brine. The w ashed organic fraction was filtered
under gravity and the filtrate was dried over magnesium sulphate. The dried organic
filtrate was evaporated under reduced pressure to give colourless oil (0.024 g, 95%).
U nder thermal conditions, on heating the mixture at identical scale at 70-80 °C for 4
hours gave similar yields (90%).
Vrnax/cm-': 2245.5, 2216.3 (-C=N).
Sn (300 MHz; CDCI3 ): 2.62 (t, / =
8
Hz, 2H, -
CH2), 2.96 (t, / = 8 Hz, 2H, -CH2), 7.24-7.46 (m, 5H, ArH) (Lit., 2.57 (t, J = 7.3 Hz, 2H),
2.92 ( t ,y = 7.3 Hz, 2H), 1 2 -1 A (m, 5H)).^’^’^ m/z: 131.07 [ M f (Lit., 131 [M]+).
137
Chapter 6
18. Therm al and microwave assisted hydrogenation o f tm /îs-2-pentenoic acid using
Amberlite® supported form ate and W ilkinson’s catalyst.
'N —
I HCO 2
RhCl(PPli3)3
232
DM SO
MW
233
A m ixture was prepared in a reaction tube using tra7ji'-2-pentenoic acid 232 (0.024 g,
0.24 mm ol), Amberlite supported fonnate 182 (0.250 g, 0.62 mm ol) and W ilkinson’s
catalyst 204 (0.040 g, 0.04 mm ol) in DM SO (0.6 ml). The reaction m ixture was inadiated
w ith microwaves at 100 W for 30 seconds. On cooling the m ixture was diluted with
dichlorom ethane (5 ml) and filtered under gi’avity. The filtrate is w ashed w ith several
sm all aliquots ( 3 x 5 ml) o f brine and dried over magnesiimr sulphate. The dried organic
fraction is filtered tlirough a plug o f alum ina and evaporated under reduced pressui’e to
give a colourless oil. (0.023 g, 90%). Them ial conditions (80 °C for 3-4 hours) under
identical reaction scale gave reduced yields (50%).
Vmax/cnf': 3010, 2910, 1711.9 (-C = 0 ) (Lit., 1700 (-C=0)).'^^= Ôh (300 M Hz; CDCI3):
0.845 (t, J = 8 Hz, 3H, -CH3), 1.27 (111, J = 9 Hz, 2H, - % ) , 1.54 (m, / = 9 Hz, 2H, CH2), 2.26 (ill, J = 9 Hz, 2H, CH2) 11.00 (hr, s, IH).
19. Therm al and microwave assisted hydrogenation of bons-2-pentenoic acid using
alnm ina snpported formate and W ilkinson’s catalyst.
A LO JH CO O H
mCKPPlq);
232
MW
A m ixture o f Aan^'-2-penteiioic acid 232 (0.024
233
g, 0.24 mm ol), alum ina supported
formate (0.500 g, 1 mm ol) and W ilkinson’s catalyst (0.005 g, 0.005 mm ol) was
suspended in a reaction tube using DM SO (0.6 ml) as the solvent. The mixfrue was
iiTadiated w ith microwaves at 100 W for 30 seconds. On cooling the m ixture was diluted
w ith dichlorom ethane (5 ml) and filtered under gravity. The filtrate was w ashed w ith
small aliquots o f brine ( 3 x 5 ml) and extracted w ith small aliquots o f diethyl ether (2x5
ml). The combined organic fraction is dried over m agnesium sulphate and evaporated
138
Chapter 6
imder reduced pressure to give a colourless oil (0.018 g, 70%). U nder therm al conditions
(70 °C for 3-4 horns) the reaction identified lower yields (50%).
Vmax/crn': 3010, 2910, 1711.9 (-C = 0 ) (Lit., 1700 (-C=0)).'^^" 6» (300 MHz; CDCI3):
0.845 (t, J = 8 Hz, 3H, -CH 3), 1.27 (m, 7 = 9 Hz, 2H, -CH2), 1.54 (rn, 7 = 9 Hz, 2H, CH2), 2.26 (m, 7 = 9 Hz, 2H, CH2) 11.00 (hr, s, IH).
20. Therm al and microwave assisted hydrogenation o f i'm ns,i'm «s-l,4-diphenyl-l,3butadiene using Amberlite® supported form ate and W ilkinson’s catalyst.
" S '-
“
MW
223
1,4-Diphenyl-1,3-butadiene 222 (0.025 g, 0.012 nmiol), A m berlite supported
formate 182 (0.250 g, 0.62 mm ol) and W ilkinson’s catalyst 204 (0.040 g, 0.04 rmnol)
were suspended in a reaction tube using DM SO (0.6 ml) as the solvent. The reaction
mixture was irradiated w ith microwaves at 100 W for 30 seconds. On cooling the the
m ixture was diluted w ith dichlorom ethane (5-10 ml). The diluted m ixture was washed
w ith several small aliqrrots ( 3 x 5 ml) o f brine and extr acted w ith sm all aliquots o f diethyl
ether ( 2 x 5 ml). The com bined organic phase was dried over anlrydrous m agnesium
sulphate and filtered tlnough a plug o f alumina. The filtrate was evaporated under
reduced pressure to a colourless solid. (0.020 g, 80%). Thermal com parison (70-80 °C, 34 hours) on identical scales gave low er yields (<70%).
M.P. 37-38 °C (Lit., 38 °C).
(300 MHz; CDCI3): 7.17-7.31 (m, lOH, ArH), 6.44 (d,
7 = 15.9 Hz, IH , Ha), 6.25 (dt, 7 = 15.9 Hz, IH , % ), 2.81-2.76 (m, 2H, He), 2.56-2.49 (m,
2H, Hd).
21. Therm al and microwave assisted hydrogenation o f trans, /'/w /s-l,4-diphenyl-l,3butadiene using alumina supported form ate and W ilkinson’s catalyst.
Ha He
A l,0,/H C 00H
Ph"
M W
139
223
He
Chapter 6
trans, fra«5- l ,4-Diplienyl-1,3-butadiene 222 (0.025 g, 0.12 ininol), alum ina supported
formate 189 (0.500 g, 1 nunol) and W ilkinson’s catalyst 204 (0.040 g, 0.04 im nol) were
suspended in a reaction tube using DM SO (0.6 ml) as the solvent. The reaction mixture
was iiTadiated w ith m icrowaves at 100 W for 30 seconds. On cooling the the mixture was
diluted w ith dichlorom ethane (5-10 ml). The diluted mixture was w ashed w ith several
small aliquots ( 3 x 5 ml) o f brine and extracted w ith small aliquots o f diethyl ether ( 2 x 5
ml). The combined organic phase was dried over anlrydrous m agnesim n sulphate and
evaporated under reduced pressm'e to a colourless solid. (0.021 g, 85%). Theiinal
comparison (70-80 °C, 3-4 hours) on identical scales gave lower yields (<70%).
M.P. 37-38 °C (Lit., 38 °C ).‘^‘^0h (300 MHz; CDCI3); 7.17-7.31 (m, lOH, ArH), 6.44 (d,
J = 15.9 Hz, IH , Ha), 6.25 (dt, / = 15.9 Hz, IH , % ), 2.81-2.76 (m, 2H, He), 2.56-2.49 (m,
2H, Hd).
22. Synthesis o f W-benzyl-4-methoxyaniIine
OMe
PhCH,Br
K,CO,
THF
240
4-metlioxy aniline 238 (0.500 g, 4 m m ole) and anlrydrous potassimrr carbonate (1 g, 8
im nol) was suspended w ith freshly distilled acetonitrile (100 m l) in a 500 ml round
bottom flask and allowed to stir for 15-20 minutes. Benzyl brom ide 239 (0.694 g, 4
mmole) is inhoduced to the stiir ed suspension and the m ixture is set to heat w hile stirring
at 90-100 °C overnight. The mixture is then allowed to cool to room tem perature and
filtered under gravity. The filtrate is evaporated under reduced pressure to give a redbrow n oily residue w hich was purified by coliunn cluom atogiaphy to give a colourless
crystalline solid. (0.340 g, 40%)
M.P. 49-50 °C (49-51
(300 MHz; CDCI3 ): 3.72 (s, 3H, -OCH 3 ), 4.56 (s, 2H, -
CH2), 6.70-6.77 (m, 4H, ArH), 7.23-7.31 (m, 5H, ArH).'^^=
140
Chapter 6
3. Therm al and microwave assisted A'-formylation o f 7V-benzyl-4-methoxy aniline using
Amberlite® supported formate
-N—
I HCO2D M 80
240
241
A mixture o f 7V-beiizyl-4-methoxyaniline 240 (0.025 g, 0.11 mm ol), A m berlite supported
fom iate (0.250g, 0.5 mm ol) was suspended in pyi'ex glass reaction tube using DM SO
(0.4-0.5 ml) as the solvent. The mixtrne was inadiated w ith m icrowaves at 80 W for 40
seconds. On cooling the mixture was diluted w ith dichlorom ethane (5 ml) and filtered
under gi'avity. The filtrate was w ashed several times w ith sm all aliquots o f brine ( 3 x 5
ml) and the dried over anhydrous magnesium sulphate. The diied organic fraction on
evaporation under reduced pressure gave a colourless crystalline solid. (0.020 g, 7075%). U nder them ial conditions, (70-80 °C, 4 hours) the reaction indicated lower yields
(<60%).
M.P. 44-46 °C (Lit., 45 °C).^°®
1674 (-C = 0) (Lit., 1670 (-C = 0 )).’°®
24. Therm al and microwave assisted A-form ylation o f aniline using Amberlite
supported formate
NH,
^
^NHCHO
/ H CO,DMSO
245
246
Aniline 245 (0.025 g, 0.23 im nol) and A mberlite supported fonnate 182 (0.700 g, 1.75
nnnol) was suspended in a pyrex glass reaction tube using DM SO (0.6 ml) as the solvent.
The reaction mixtiu'e was inadiated w ith microwaves at 100 W for 30 seconds. On
cooling the m ixture was diluted w ith D CM (5 ml) and filtered under gi'avity. The filtrate
was w ashed several times w ith several small aliquots o f hrine ( 3 x 5 m l) and dried over
magnesium sulphate. The dried organic fr action was evaporated under reduced pressure
to give a colourless solid. (0.026 g, 90%). Them ial coniparisions by heating (70 °C for 3-
141
Chapter 6
4 hours) the reaction m ixture on an oil bath under identical scales gave reduced yields
(60%).
Vniax/cm-'; 3310, 1710 (Lit., 3300 (NH), 1700 (C =0)).
/=
Ôh (300 M Hz; CDCI3): 8.72 (d,
12 Hz, IH ), 8.47 (hr, IH ), 8.37 (s, IH ), 7.08-7.56 (m, 5H).'^^ m/z: 121.05 [M ]\
122.05 [M+H]+.
25. Therm al and microwave assisted A^-formylatiou o f aniline using alumina snpported
form ate
or
NH,
/N H C H O
A LO,/HCOOH
DMSO
245
246
Aniline 245 (0.026 g, 0.238 mm ol) and alum ina supported fonnate 189 (0.700 g, 1.75
mm ol) was suspended in a pyrex glass reaction tuhe using DM SO (0.6 m l) as the solvent.
The reaction mixtrne was inadiated with microwaves at 100 W for 30 seconds. On
cooling the mixture was diluted and filtered under giavity. The filhate was washed
several times with several small aliquots o f brine ( 3 x 5 ml) and dried over m agnesium
sulphate. The dried organic fraction was evaporated under reduced pressure to give a
colourless solid. (0.027 g, 93%). Thermal comparision by heating (70 °C for 3-4 hours)
the reaction mixture on an oil hath under identical scales gave reduced yields (70%).
Vrnax/cm'^: 3310, 1710 (L it, 3300 (NH), 1700 (C =0)). ^’^Ôh (300 M Hz; CDCI3): 8.72 (d,
J = 12 Hz, IH ), 8.47 (hr, IH ), 8.37 (s, IH ), 7.08-7.56 (m, 5H).
m/z: 121.05 [M]+,
122.05 [M+H]+.
26. Therm al and microwave assisted iV-formylation of benzylam ine using Amberlite
supported formate
N H,
I HCO^-^
DMSO
248
247
B enzylam ine 247 (0.049 g, 0.45 mm ol) and A mberlite supported formate 182 (1.14 g, 2.8
mm ol) were suspended in a pyrex glass reaction tuhe using D M SO (0.8 ml). The reaction
tube was irradiated w ith microwaves at 100 W for 30 seconds. On cooling the the
142
Chapter 6
reaction m ixtrne was diluted w ith dichlorom ethane (5 ml) and filtered under gravity. The
filtrate was w ashed w ith several sm all aliquots o f brine ( 3 x 5 ml) and dried over
anlrydrous m agnesium sulphate. The dried organic fraction was concentrated on a rotary
evaporator to give a colourless solid. (0.058 g, 95%). Thermal heating (70 °C for 3-4
hours) o f the reaction m ixture at identical scale showed lower yields (80%)
M.P. 61-62 °C (Lit., 60-61 °C).
§h (300 M Hz; CDCI3): 8.27 (s, IH , -CHO), 7.43-7.16
(m, 5H, ArH), 5.83 (hr, IH , -NH), 4.48 ( d ,J =
6
Hz, 2H, -CH2).
179b
27. Therm al and microwave assisted iV-formylation of benzylam ine nsing alumina
supported formate
NH,
AI2O3/HCOOH
NHCHO
DMSO
247
248
A reaction mixture o f benzylamine 247 (0.049 g, 0.45 mm ol) and alum ina supported
formate 189 (1 g, 2 mm ol) was suspended in a reaction tube using DM SO (0.8 ml) as the
solvent. The reaction mixture was irradiated w ith microwaves at 100 W for 30 seconds.
After irradition the mixture was allowed to cool to room tem perature and diluted with
dichlorom ethane (5 ml). The diluted m ixture was filtered under gravity and w ashed with
several small aliquots o f brine ( 3 x 5 ml). The w ashed organic fraction was dried over
anlrydrous m agnesium sulphate
and evaporated
under reduced pressure to give a
colourless solid. (0.058 g, 95%) Theiinal comparison (70 °C for 3-4 horns) identified
reduced yields (85%).
M.P. 61-62 °C (Lit., 60-61 °C).
(300 MHz; CDCI3 ): 8.27 (s, IH, -CHO), 7.43-7.16
(m, 5H, ArH), 5.83 (hr, IH , -NH), 4.48 (d, J = 6 Hz, 2H, -CH2).
28. Therm al and microwave assisted A-form ylation o f (±)-o:-methylbenzylamine using
Amberlite® supported formate.
NHCHO
DMSO
249
250
143
Chapter 6
A mixture o f (±)-o;-methylbenzylamine 249 (0.047 g, 0.38 mm ol) and Amberlite
supported formate 182 (0.600 g, 1.5 mm ol) w ere suspended in a pyi'ex glass reaction tube
using DM SO (0.6 ml) as the solvent. The reaction m ixture was irradiated w ith
microwaves at 100 W for 30 seconds. After iiTadiation the mixture was allowed to cool
and diluted w ith dichlorom ethane (5 ml). The diluted fraction was w ashed w ith several
small aliquots o f hrine ( 3 x 5 ml) and dried over anhydrous m agnesim n sulpahte. The
dried fraction was evaporated under reduced pressure to give a colourless oil. (0.056 g,
95%). Thermal heating (70 °C for 4 hours) o f the reaction m ixture under identical scales
identified low er yields (85%).
M. P. 46-47 °C (Lit., 47 °C).^^° Ôh (300 MHz; C D C I 3 ): 8.12 (hr, IH , -NH), 7.85 (hr, IH , CHO), 7.35 (s, 5H, ArH), 4.270 (d, J = 6.6 Hz, IH , -CH), 1.57 (d, J = 6.8 Hz, 3H, CH3).'^° m/z: 148 [M-H]+, 150.4 [M + H ]\
29. Therm al and microwave assisted A-form ylatioii o f (±)-a-m ethylbenzylam ine using
alnm ina snpported formate.
NHj
cy
NHCHO
AI2 O 3 /H C O O H
DMSO
249
250
A mixture o f (±)-a:-methylhenzylamine 249 (0.047 g, 0.38 mm ol) and alum ina supported
fom iate 189 (0.800 g, 1.6 im nol) were suspended in a pyrex glass reaction tuhe using
DM SO (0.8 ml) as the solvent. The reaction mixture was inadiated w ith microwaves at
100 W for 30 seconds. A fter inadiation the mixtrne was allowed to cool and diluted
w ith dichlorom ethane (5 ml). The diluted fraction was washed w ith several small aliquots
o f hrine ( 3 x 5 ml) and dried over anlrydrous magnesium sulpalite. The dried fr action was
evaporated under reduced pressure to give a colourless solid (0.056 g, 85%). T h e m a l
heating (70 °C for 4 hours) o f the reaction m ixture under identical scales identified lower
yields (80%).
M. P. 46-47 °C (Lit., 47
Ôr (300 M Hz; C D C I 3 ): 8.12 (hr, IH , -NH), 7.85 (hr, IH ,-
CHO), 7.35 (s, 5H, ArH), 4.270 (m, IH , -CH), 1.57 (d, J = 6.8 Hz, 3H, -CH3).
148 [M-H]+, 150.4 [M+H]+.
144
m/z:
Chapter 6
30. Therm al and microwave assisted A'-Formylation
Amberlite® supported formate.
o f 4-m ethoxyaniline using
OMe
'N -
/ HCO,-
DMSO
NHCHO
252
A m ixture o f 4-niethoxyaiiiline 238 (0.025 g, 0.20 mm ol) and amberlite supported
formate 182 (0.400g, 1 mm ol) were suspended in reaction tube using D M SO (0.6 ml) as
the solvent. The mixtrne was irradiated w ith microwaves and on cooling was diluted
w ith dichlorom ethane (5 ml). The diluted mixtrne was washed w ith several small aliquots
o f brine ( 2 x 5 ml). The w ashed organic fraction was dried over anlrydrous m agnesium
sulphate and evaporated under reduced pressure to give a brow n solid. (0.024 g ,80%).
U nder therm al conditions, the reaction identified lower yields (60%).
M.P. 79-80 °C (Lit., 80
5h (300 MHz; CDCI3): 8.44 (d, J =
11.7 Hz, IH , -
CHO(exo)), 8.268 (d, J = 1.8 Hz, -CHO(endo)), 7.39-7.36 (m, IH , ArH), 6.97-6.94 (rn,
IH, ArH), 6.83-6.78 (m, 2H, ArH), 3.73 (d, J = 3 Hz, 3H, -OCH 3 ).
4 8
ia.b)
31. Therm al and microwave assisted A -form ylation of 4-m ethoxy aniline using alumina
supported formate
OMe
AhO/HCOOH
^
DMSO
NHCHO
238
252
A mixture o f 4-methoxy aniline 238 (0.025 g, 0.20 rnrnol) and alum ina
supported
formate 189 (0.800 g, 1.6 rmnol) were suspended in reaction trrbe using DM SO (0.6 ml)
as the solvent. The rnixtrrre was irradiated w ith microwaves and on cooling was diluted
w ith dichlorom ethane (5 ml). The diluted mixtrne was washed w ith several small aliquots
o f brine ( 2 x 5 ml). The w ashed organic fraction was dried over anlrydrous magnesium
srrlphate and evaporated under reduced pressm'e to give a brow n solid. (0.024 g, 80%).
U nder therm al conditions (70 °C for 4 horns) the reaction identified low er yields (55%).
145
Chapter 6
M.P. 79-80 °C (Lit., 80 °C
Sh (300 M Hz; CDCI3): 8.44 (d, J = 11.7 Hz, IH , -
CHO(exo)), 8.268 (d, J = 1.8 Hz, -CHO(eiido)), 7.39-7.36 (m, IH , ArH), 6.97-6.94 (m,
IH , ArH), 6.83-6.78 (m, 2H, ArH), 3.73 (d, J = 3 Hz, 3H,
32. Therm al and microwave assisted A-form ylation of dibenzylam ine using Amberlite
supported formate
Ü'
"S3
-Q
®XL
254
A,A-Dibenzylaniine 253 (0.050 g, 0.25 nnnol), Amberlite supported fom iate 182 (0.700
g, 1.7 mm ol) were suspended in a glass tube using DM SO (0.8 m l) as the solvent. The
reaction mixture was inadiated w ith m icrowaves at 100 W for 30 seconds. On cooling,
the m ixtrne was diluted w ith dichlorom ethane (5 ml) and filtered under gravity. The
filtrate was w ashed w ith several small aliquots o f brine and dried over anliydrous
m agnesium sulphate. The dried organic fraction was concentrated on a rotary evaporator
to give a colom less solid (0.055 g, 95%). R eaction done under identical scales by thermal
heating (70 °C for 3-4 hours) identified lower yields (80%)
M.P. 52-54 °C (Lit., 53-53.5 °C).
Ôh
(300 M Hz; C D C I 3 ): 9.42 (s, IH , -CHO), 7.35-
7.18 (m, lOH, ArH), 4.41 (s, 2H, -CH2), 4.26 (s, 2H, -CH2).
33. Therm al and microwave assisted A-form ylation of dibenzylam ine using alumina
supported formate.
A1,0,/HC00H
7V,A-Dibenzylamine 253 (0.050 g, 0.25mmol), alum ina supported foim ate 189 (0.650 g,
1.3 mm ol) were suspended in a glass tube using DM SO (0.8 m l) as the solvent. The
reaction mixture was hradiated w ith m icrowaves at 100 W for 30 seconds. On cooling,
the mixture was diluted w ith dichlorom ethane (5 ml) and filtered under gravity. The
filtrate was w ashed w ith several sm all aliquots o f brine and dried over anlrydrous
magnesium sulphate. The dried organic fiaction was concenhated on a rotary evaporator
146
Chapter 6
to give a colourless solid (0.054 g, 95%). Reaction done under identical scales by thermal
heating (70°C for 3-4 hours) identified lower yields (80%).
M .P. 52-54 °C (Lit., 53-53.5 °C).
6» (300 M Hz; CDCI3): 9.42 (s, IH , -CHO), 7.35-
7.18 (m, lOH, ArH), 4.41 (s, 2H, -CHz), 4.26 (s, 2H, -CH2).
’
34. Therm al and microwave assisted A-form ylation of piperazine using Amberlite
snpported form ate
/ HCO,DMSO
A reaction mixture o f piperazine 255 (0.050 g, 0.58 mm ol) and A m berlite supported
fonnate 182 (0.700
g, 1.7mmol) was prepared in a pyi’ex glass reaction tube by
suspending in DM SO (0.8 ml). The mixtiu’e was irradiated w ith microw aves at 100 W for
30 seconds. A fter irradiation, the mixture was allowed to cool and diluted
w ith
dichlorom ethane ( 2 x 5 ml). The diluted mixture was filtered under gi’avity. The filti’ate
was w ashed w ith several sm all aliquots o f brine ( 3 x 5 ml) and w ater ( 2 x 5 ml). The
washed organic fraction was dried over m agnesium sulphate (aidiydious) and evaporated
under reduced pressure to give a colourless solid (0,042 g, 60%). R eaction done under
thennal heating (70°C for 3-4 hours) identified lower yields (55%).
M.P. 127-128 °C (Lit., 127.5-128.5
Vmax/cm'': 1660.8 (-C = 0) (Lit., 1650 (-
0=0).^^^''
35. Therm al and microwave assisted A-form ylation of piperazine using alumina
supported formate
HO
N
ALOJHCOOH
H
N.
r”"
CHO
255
256
A reaction mixture o f piperazine 255 (0.025 g, 0.29 mm ol) and ahunina supported
fonnate 189 (0.800 g, 1.6 mm ol) was prepared in a pyrex glass reaction tube by
147
Chapter 6
suspending in DM SO (0.8 ml). The mixture was inadiated w ith microw aves at 100 W for
30 seconds. A fter irradiation, the mixtui'e was allowed to cool and diluted
w ith
dichlorom ethane ( 2 x 5 ml). The diluted mixture was filtered under gravity. The filhate
was w ashed w ith several small aliquots o f brine ( 3 x 5 ml) and w ater ( 2 x 5 ml). The
w ashed organic haction was dried over m agnesium sulphate (anlrydrous) and evaporated
under reduced pressure to give a coloui'less solid (0.041 g, 60%). R eaction done under
theim al heating (70 °C for 3-4 hours) identified low er yields (55%).
M.P. 127-128°C. (L it, 127.5-128.5 °C).
v„ax/cm"^: 1660.8 (-C = 0 ) (Lit., 1650 (-
C=0).'83b
36. Therm al and microwave assisted A'-formylation o f morpholine using Amberlite
supported formate
—N
/ HCOj-
"
DMSO
'L
259
A reaction mixture was prepared in a pyi'ex glass reaction tube using morpholine 258
(0.025 g, 0.28 mm ol) and A mberlite supported formate 182 (1 g, 2.5 mm ol) using DMSO
(0.8 ml). The reaction m ixtrne was irradiated w ith microwaves at 100 W for 30 seconds.
A fter inadiation, the mixture was allowed to cool and diluted w ith dichlorom ethane (5
ml). The diluted mixture was filtered under gravity. The h lh ate was w ashed subsequently
w ith several small aliquots o f brine ( 3 x 5 m l) and w ater ( 2 x 5 m l) and dried over
anhydrous m agnesium sulphate. The dried organic fraction w as concenhated on a rotary
evaporator to give an oily residue (0.020 g, 60%). Under thennal conditions (70 °C for 34 hours) the reaction showed reduced yields (<50%).
Vmax/cnf': 1651.6 (-C = 0) (Lit., 1690 (-C = 0)).
CHO), 3.51-3.40 (m, 8H, -4 CH2 ).
148
6» (300 M Hz; CDCI3): 8.26 (s, IH , -
Chapter 6
37. Therm al and microwave assisted A'-formylation o f m orpholine using alumina
supported formate
ALO,/HCOOH
DMSO
H
^ ,
Y
CHO
259
A reaction m ixture was prepared in a pyi'ex glass reaction tube using morpholine (0.025
g, 0.28 im nol) and alum ina supported formate (1.2 g, 2.4 im nol) using DM SO (0.8 ml).
The reaction mixture was inadiated w ith microwaves at 100 W for 30 seconds. A fter
inadiation, the m ixtrne was allowed to cool and diluted w ith dichlorom ethane (5 ml). The
diluted mixtrne was filtered under gi'avity. The filtrate was w ashed subsequently w ith
several sm all aliquots o f brine ( 3 x 5 ml) and w ater ( 2 x 5 ml) and dried over anhydrous
magnesium sulphate. The dried organic fraction was concentrated on a rotary evaporator
to give an oily residue (0.019 g, 60%). U nder thennal conditions (70 °C for 3-4 horns)
the reaction showed reduced yields (<50%).
Vmax/cin': 1651.6 (-C = 0) (Lit., 1690 (-C=0)).^’^ 5h (300 M Hz; CDCI3): 8.26 (s, IE , CHO), 3.51-3.40 (m, 8H, -4CH2)
(Lit., 178)
38. Therm al and microwave assisted A-form ylation
Amberlite® supported formate.
of 2,4-difIuoroaniIine using
NHCHO
DMSO
2,4-Difluoi'oaniline 261 (0.031 g, 0.24 mmol) and A mberlite supported fonnate 182
(0.600 g, 1.5 mmol) were suspended in a pyi'ex glass reaction tube equipped w ith a screw
cap top using DM SO (0.8 ml) as the solvent. The m ixture was irradiated with
microwaves at 100 W for 30 seconds. The inadiated m ixtiue was allowed to cool and
diluted w ith dichlorom ethane (5 ml). The diluted mixture was w ashed subsequently with
small aliquots o f brine ( 3 x 5 ml) and w ater ( 2 x 5 ml). The w ashed organic fraction was
dried over anliyidous magnesium sulphate and concentrated on a rotary evaporator to
149
Chapter 6
give a light brow n solid (0.022 g, 70%). T hennal com paiison o f the reaction (70 °C for 34 hours) under identical scale gave reduced yields (<60%).
Vmax/cin': 1613.1, 1667.5 (-C = 0), 1400.7, 1377.1 1273.9, 1150.3, 1092.2. 6» (300 MHz;
CDCI3): 8.54 (d, 7 = 1 1 .4 Hz, IH , -CHO), 8.45 (s, IH ), 8.29 (m, 2H), 7.36 (hr, IH , NH),
7.20
39.
(m), 6.89 (m). m/z: 157.02 [ M f , 158.02 [M+H]+ (L it, 157 [M]+).
Therm al and microwave assisted A^-formylation o f 2,4-difIuoroaniIine using alumima
supported formate.
NHCHO
NH,
AL07HC00H
DMSO
2,4-Difluoroaniline 261 (0.031 g, 0.24 mm ol) and alum ina supported formate 189 (0.800
g, 1.6 mm ol) were suspended in a pyi’ex glass reaction tube equipped w ith a screw cap
top using DM SO (0.8 ml) as the solvent. The mixture was irradiated w ith microwaves at
100 W for 30 seconds. The inadiated mixture was allowed to cool and diluted with
dichlorom ethane (5 ml). The diluted mixture was washed subsequently w ith small
aliquots o f brine ( 3 x 5 ml) and w ater ( 2 x 5 ml). The w ashed organic fraction was dried
over anhyi’dous m agnesium sulphate and concentrated on a rotary evaporator to give a
light brow n solid (0.021 g, 70%). Thermal comparison o f the reaction (70 °C for 3-4
hours) under identical scale gave reduced yields (<60%).
Vrnax/cm-': 1613.1, 1667.5 (-C = 0), 1400.7, 1377.1 1273.9, 1150.3, 1092.2. 8» (300 MHz;
CDCI3): 8.54 (d, 7 = 11.4 Hz, IH , -CHO), 8.45 (s, IH ), 8.29 (m, 2H), 7.36 (hr, IH , NH),
7.20 (m), 6.89 (m). m/z: 157.02 [ M f, 158.02[M+H]+ (Lit., 157 [M]+).
40. Attem pted microwave assisted reduction o f acetopheuoue using R uCl(PPh 3 ) 3 using
Amberlite® supported form ate as the hydrogen donor.
OH
CH,
274
' N“
/ HCOj-
RuCKPPhjlj
DCM
150
CH,
275
Chapter 6
A m ixture o f acetopheuoue 274 (0.025 ml, 0.213 mmol), A mberlite supported formate
182 (0.500 g, 1.2 mm ol) aud RuCl(PPli3)3 276 (0.002 g) w ere suspended iu a pyi'ex glass
reaction tube using DCM (1 ml) as the solvent. The reaction tube was irradiated w ith
microwaves at set tem perature o f 120 °C for 300 seconds. On completion, the mixture
was diluted w ith dicblorom etbane (5 ml) and filtered tluougb a plug o f alumina. The
filtrate was dried over anliyidous magnesim n sulphate and evaporated under reduced
pressure to give a colourless oil, identified by
N M R analysis as the um eacted starting
material.
41. Synthesis of Ru(II)-/;-cymene complex
C2H5OH
2RUCI3 +
278
[RuCblpe-CioHiOlj
279
280
In a 250 m l round bottom flask, R 11CI3 278 (2 g) was suspended in ethanol (100 ml). To
this suspension, iî-a-pbellandi'ene 279 (10 ml) was added and the mixbire was set to
reflux w hile stirring for 4 boms. Thereafter, the m ixture was allowed to cool to room
tem peratm e and refi'igerated overnight. The m ixture developed red-brow n crystalline
solid settled at the bottom o f the flask. The solid thus obtained w as separated by flirtation
and di'ied under vacuum. The filtrate was fiirtber concenti ated to h a lf the volm ne and the
solid precipitating on cooling was separated by filtration. A red-brow n crystalline solid
was collected after filtration and drying (1.7 g, 72%).
M.P. 225-230 °C (L it, 209-230 °C).
C H C H 3 ),
Ôh (300 M Hz; CDCI3): 1.26 (d, / = 7 Hz, 3H, -
2.16 (s, IH , - C H 3 ), 2.92 (m, C H C H 3 ), 5.48-5.33 (dd, J = 6 Hz, ArH).
(Lit.,140)
42. Attem pted microwave assisted reduction o f acetoplienoiie using amberlite supported
form ate and Ru(II)-p-cymene complex catalyst.
I HCO,274
[RuCl^Ort-CioH^,)]^
DCM
275
A reaction mixture was prepared in a pyrex glass reaction tube using acetopbenone 274
(0.025 ml, 0.213 mm ol) and Amberlite supported formate 182 (0.450 g, 5 mm ol) and Rup-cym ene complex 280 (0.005 g) using dicblorom etbane (1 m l) as the solvent. The
151
Chapter 6
reaction tube was irradiated w ith microwaves at set tem perature o f 90 °C for 60 seconds.
On completion, the reaction mixture was cooled to room temperatui'e and diluted with
dichlorom ethane (5 ml). The diluted mixture was filtered tlirough a plug o f alum ina and
dried over anliydrous m agnesium sulphate. The dried organic fraction was concentrated
on a rotary evaporator to give a colourless oil, largely identified as the unreacted starting
m aterial by 'H N M R analysis.
43. Attem pted microwave assisted oxidation o f benzyl alcohol using Pd(II)hydrotalcite
A m ixture Pd(II) hydrotalcite 292 (0.300 g) and pyridine 290 (0.4 m l, 2 mm ol) were
suspended in a pyi'ex glass reaction tube sealed w ith a cap equipped w ith a m bber
septum. To this m ixture toluene (1 ml) is added using a syringe and the reaction tube is
degassed and subsequently 0% is inhoduced into the tube using a balloon. The reaction
tube is iiTadiated w ith microwaves after rem oval o f the balloon at at set tem perature o f 60
°C for 30 seconds. Therafter the mixture is again subjected to oxygen using a balloon and
at this stage benzyl alcohol 289 (0.052 g, 0.4 nnnol) diluted in toluene (1 ml) is
introduced into the reaction tube using a syiinge. The m ixture is iiTadiated under
microwaves at a set tem perature o f 60 °C for 60 seconds. A fter inadiation, the reaction
mixture showed developm ent o f a black residue in the tube. The mixtur e was diluted with
diethyl ether (5 ml) and filtered under gravity. The filtrate was evaporated under reduced
pressure to give a yellow oil which identified only the unreacted starting alcohol by
N M R analysis.
44. Synthesis o f rac-(3S, 4R, 56) & rac-(3R, 4R, 56)-2-m ethyl-3,5-diphenyl-isoxazolldine4-carbonitrile by therm al and m icrowave assisted cycloaddition o f A-methyl-Cphenyl-nitrone and P ans-cinnamonitrile
M e (Hb)
M e (Hb)
TT
-N
Me
Ph,
'0 3
230
I
T
+
He""!
CN
322
?
3R, 4 5 ,5 5
329
152
ÿÇ
He "1A
^H d
CN
3 5 ,4 5 , 55
330
Ph,,
Chapter 6
A mixture o f t7-fl«5-cimiamoniti-ile 230 (0.065 g, 0.5 mm ol) and A-methyl-C-phenylnitrone 322 (0.068 g, 0.5imnol) was heated to 60 °C for three weeks. The product, 1:1
mixture o f diastereoisom ers 329 and 330, w as isolated by colum n chrom atography
(silica, DCM /hexane 4:1) and obtained as a colourless oil. (30%).
U nder m icrowave conditions, a reaction mixture o f fra/r^-cimiamonitrile 230 (0.102 g,
0.79 mm ol) and nitrone 322 (0.406 g, 3 mm ol) was suspended in dichlorom ethane (0.30.4 ml). The reaction mixture was iiTadiated w ith microwaves at 100 °C for 2 hours.
A fter iiTadiation, the reaction mixture was evaporated under reduced pressm e to give a
yellow oil. The product was a 1:1 m ixture o f the diastereoisomers 329 and 330 obtained
as a colourless oil (30%). The two diastereoisom ers w ere separated by colurmr
clnom atography (silica, D CM /hexane 4:1).
329, Vrnax/cm-': 3032 (C-H), 2964, 2245 (-C = N ). Ôr (500 M Hz; CDCI3): 2.75 (s, 3H,
N(M e)(Hb)), 3.43 (dd, J = 7 H z and 9.5 Hz, IH , He), 3.98 (d, / = 9 Hz, IH , Hd), 5.41 (d,
/ = 6.5 Hz, Hd). 7.34 (rn, IH ), 7.41 (t, J = 7.5 Hz, 2H), 7.51 (d, / = 7 Hz, 2H), 7.36-7.39
(rn, 5H, ArH (Pin)), ôc (300 MHz; CDCI3) 43.1 (NMe), 51.1 (C-CN), 77.5 (C-Ha), 80.9
(OC-Hc), 118.1 (-CN), 125.6, 127.3, 128.4, 128.9, 129.1, 134.8, 140.1 (2xPh). Accurate
mass EI-M S, nr/z: Fourrd: 264.126 [M]"^; Calcd for C 17H 16N2O: 264.125 [M]”^.
330, Vrnax/cm'^: 3065, 3034 (C-H), 2964, 2877, 2245 (-C = N ). Ôr (500 M Hz; CDCI3 ) 2.74
(s, 3H, N (M e) (Hb)), 3.92 (d, / = 9 Hz, IH , Ha), 3.56 (dd, / = 7 H z and 9 Hz, IH , Hd),
5.33 (d, J = 7.5 Hz, IH , He), 7.38-7.48 (rn, lOH, 2xPh). 6c (500M Hz; CDCI3) 43.2
(NMe), 49.3 (C-Hd), 75.1 (C-Ha), 82.9 (C-Hc) 117.9 (-C = N ), 125.8, 128.7, 129.1,129.2,
129.3, 129.4, 134.7 137.1 (2xPh). Accurate mass EI-M S, m/z: Fourrd: 264.126 [M]”^;
Calcd for C 17H 16N 2O: 264.125 [ M f .
45.
Synthesis of Pt(II)-bound
CH=CHPh} 2 ]
/m «s-cinnam onitrile
com plex
H
C.C
A"
H
/>
Ph
= <\
327
H
153
Ph
H
[tm «s-(PtCl2 {N = C-
Chapter 6
A
suspension o f cAAra«j-PtCl2(M eCN)2 326
(0.300
g,
0.86 mm ol) in trairs-
ciimamonitrile 230 (1.5 ml) was heated at 60 °C for one w eek w hereupon the yellow
finely dispersed starting complex was fiansfom ied into a crystalline yellow solid. After
addition o f diethyl ether (10 ml), the solid was filtered off, w ashed w ith diethyl ether and
dried in air. (0.360 g, 81%).
Anal. Found: C, 41.57, H, 2.45; N, 5.36; Caled for C i8H i4Cl2N 2Pt: C, 41.23; H, 2.69; N,
5.34. Vrnax/cm"': 3010 (C-H), 2276 (C ^ N ), 1610 (C=C), 965 (^ra«5-CH=CH).
ÔH (300 MHz; CDCI3): 7.69 (d, / = 16 Hz, IH , =CH-Ph), 6.17 (d, J = 16 Hz, IH , -C H CN), 7.45-7.53 (m, 5H, ArH). FAB-M S, m/z: 523 [M]+.
46. Synthesis o f transition metal oxadiazoline complex, tm ns-[PtC l 2 {N=C(CH =CH Ph) 0 -
N(Me)-clH(Pli)};I
PI.
Ph. f
/ '% p h
H bM e
Ha
L
345
A mixture o f [^ran5-(PtCl2{ N = C-CH=CHPh}2] 327 (0.025 g, 0.047 mmol) and CPhenyl-A-methyl nitrone 322 (0.031 g, 0.095 nnnol) was prepared in a pyi'cx glass
reaction tube using D CM (2ml) as the solvent. The m ixture w as iiTadiated w ith
microwaves at a set tem perature o f 100°C for 7200 seconds. On completion, the reaction
m ixture is evaporated under reduced pressuie to give a light yellow oily residue. The
yellow oil obtained is purified by colunm chiom atogiaphy (DCM, silica) and the first
fiaction was collected and concenhated on a rotary evaporator to give a light yellow oil
w hich on trituration w ith diethyl ether precipitated a light yellow solid ( 1:1 mixture o f
two diastereoisomers) obtained by decanting the ether (0.008-0.010 g, 27-30%).
Anal. Found: C, 50.21; H, 3.73; N 6.95, Calcd for C34H32Cl2N 402Pt: C, 51.39; H, 4.06;
N , 7.06. Vrnax/cm"': 3054 (C-H), 1639 (C=N), 1595 (C=C), 967.6 (/raM.s-CH=CH). 6 » (300
MHz; CDCI3): 2.96 (s, 3H, NM e), 5.89 and 5.98 (s, IH , two diasterom eric N-CH-N),
154
Chapter 6
7.67-7.37 (m, 12H), 7.58 & 7.50 (br, IH , CH=(nitrile)), 7.55 & 7.40 (br, IH ,
CH=(nitrile)). 5c (300 MHz; CDCI3): 46.2 (NMe), 91.9 (N-CH-N), 111.2 and 111.3
(CH=), 144.7 and 144.8 (CH=), 128.16, 128.18, 128.41, 128.58, 128.59, 128.96, 129.06,
129.31,129.33,130.95 (4xPh).
(500 MHz; CDCI3) -2197.7 (752Hz). FAB-MS, /wA:
817 [M+Na]^, 723 [M-2CI]'".
47. Synthesis o f transition metal oxadiazoline complex, traHs-[PtCl2 {N=C(CH =CH Ph) 0 N (M e )-c lH (P h )} { N
=C-CH=CHPh}]
Ha
» ,
.c = c
P /
A mixture o f
y
Hd
-
M eH b
/O
333
[?ra«5-(PtCl2{N = C-CH=CHPh}2] 327 (0.025 g, 0.047 mm ol) and C-
Phenyl-N-methyl nitrone 322 (0.006 g, 0.047 mmol) is prepared in a pyi'ex glass reaction
tube using dichlorom ethane (2 ml) as the solvent. The m ixtuie is iiTadiated w ith
microwaves at a set tem perature o f 100 °C for 1200 seconds. A fter inadiation, the
mixture is allowed to cool and evaporated under reduced pressure to give a light yellow
oily residue. The residue is pim fied by coluimi clnom atogiaphy (silica, DCM ) and
fractions were collected by elution w ith dichloromethane. The first fraction collected was
evaporated under reduced pressure to give a light yellow oil w hich on trituration with
diethyl ether gave yellow solid (0.012 g, 35-40%).
Anal. Found: C, 47.60, H, 3.61; N, 6.34; Calcd for C26H 23Cl2N 30Pt: C, 47.35; H, 3.52; N,
6.37. Vniax/ciiT': 3055 (=C-H), 2270 (C = N ), 1642 (C=N and C=C), 967 (iran5-CH=CH).
ÔH (300 M Hz; CDCI3): 3.00 (s, 3H, NM e), 5.95 (s, IH , N-CH-N), 6.03 (d,
16 Hz,
CH=(nitrile)), 7.54 (d, J = 16 Hz, IH , CH=(nitrile)), 7.49 (d, J = 16 Hz, IH ,
CH=(oxadiazoline)), 7.38-7.30 (m, 13H), 7.62-7.57 (m, 2H, 3xPh).
6
» (300 MHz;
CDCI3): 46.7 (NMe), 92.1 (N-CH-N), 93.7 (CH=, nitrile), 156.3 (CH=, nitrile), 111.0
(CH=, oxadiazole), 146.3 (CH=, oxadiazole), 127.8, 128.1, 128.5, 129.1, 129.3, 129.5,
155
Chapter- 6
129.9,
131.3, 132.6, 134.0 (3xPh).
(500 MHz; CDCI3): -2268 (750Hz). FAB-MS,
m/z: 682 [M4-Na]+, 623 [M-Cl]^, 588 [M-2C1]+.
48.
Synthesis of Pd(II)-bound tmHs-ciniiamonitirle complex,
tm «s-[PdC l 2 {N =C -C H =Ph} 2 ]
H
Ph
A suspension o f PdC li 335 (100 mg, 0.56 mm ol) in fra/j^-cimiamonitrile 230 (0.5 ml)
w as heated to 60 °C for two weeks until the dark PdCla was com pletely dissolved.
Diethyl ether was added, the orange solid was filtered off, w ashed w ith diethyl ether and
dried in air. (68%)
Anal. Found: C, 49.77; H, 3.09; N, 6.37; Calcd for CigHMClzNgPd: C, 49.63; H, 3.24; N,
6.43. FAB^-MS in cimiamonitrile, m/z\ 309 [M]"^. Vmax/cnf’: 3010 w (C-H),
2276 m (C =N ), 1613 m (C=C), 965 m (tra/i5-HC=CH). ôh (300 M Hz; CDCI3): 6.03 (d, J
= 16Hz, IH , =CH-CN), 7.41-7.52 (m, 5H, Ph), 7.66 (d, J = 16Hz, IH , =CH-Ph).
49.
Synthesis of transition metal oxadiazoline complex, tmHs-[PdCl2 {N=C(CH =CH Ph) 0 N ( M e ) - c l H ( P h ) } 2 ].
Ph
Hi
'
.C
C— N
He
C
/
J P d l-
\
I
../'I" !■
337
A suspension o f tran5-[PdCl2{N sC -C H =C H P h}2] 336 (50 mg, 0.16 mm ol), N-methyl-Cphenyl nitrone (47 mg, 0.35 mmol) in cimiamonitiile (0.5 ml) w as heated at 60 °C
156
Chapter 6
overnight w hereupon a clear orange solution formed. The product precipitated w ith
diethyl ether as a pale yellow pow der w hich was filtered o ff and dried in air (68%).
Anal. Found: C, 56.51; 4.66; N, 8.52; Calcd for C34H 32Cl2N 402Pd: C, 57.85; H, 4.57; N,
7.94. V rnax/cm '^ 3060 (=C-H), 1647 (C=N), 1625 (C=C), 965 (A-aMg-HC=CH). ô u (300
M Hz; CDCI3): 2.94 (s, 3H, NM e), 5.83 (s, IH , N-CH-N), 7.46 (d,
16.1 Hz, IH , CH=),
7.68 (d, / = 16.0 Hz, IH , CH=), 7.30-7.50 (m, 8H) and 7.66 (d, J = 7.4 Hz, 2H) (two Ph).
5e (300 M Hz; CDCI3): 46.7 (NMe), 92.0 (N-CH-N), 112.3 (CH=), 126.2, 128.2, 128.8,
128.9, 129.2, 131.2, 134.8 and 142.4 (two Ph), 145.5 (CH=), 163.3 (C=N). FAB-MS,
m/z: 669 [M-C1]+.
50. Synthesis of 2-metliyl-3-phenyI-5-[(JS)-2-phenyIvinyI]-2,3-dihydro-A‘’-l,2,4-oxadizole
by displacem ent o f the oxadiazoline complex from the palladium complex.
M e Hb
Ha
Ph. \
Ph
339
To a solution o f the palladium complex h'fl7î5-[PdCl2{N=C(CH=CHPli)0 -N(Me)3 f(Ph)}2] 337 (50 mg, 0.071 im nol) in CHCI3 (1 ml), an excess o f an aqueous solution
o f methyl amine 338 (0.2 ml, 40% solution) was added and the reaction mixtrue was
stirred at 50 °C for 10 minutes. The organic phase was separated o ff and filtered tluough
a plug o f silica gel. A fter evaporation o f the solvent, the product was obtained as
colourless oil w hich solidified upon standing (88%).
Vrnax/cm'^:
3062 and 3029 (=C-H), 1656 (C=N and C=C), 972 (ira«5-CH=CH). Ôh (300
MHz; CDCI3): 2.94 (s, 3H, NMe), 5.68 (s, IH , N-CH-N), 6.71 (d, J = 16.3 Hz, IH , CH=),
7.45 (d,
16.3 Hz, IH , CH=), 7.31 (t, J = 7.2 Hz, IH ), 7.37 (m, 5H), 7.43 (d, J = 7.2
Hz, 2H) and 7.50 (d, J = 7.2 Hz, 2H) (two Ph). ôc (300 M Hz; CDCI3): 47.2 (NMe), 93.9
(N-CH-N), 112.9 (CH=), 126.7, 127.8, 128.8, 129.2, 130.2, 135.1 and 140.0 (two Ph),
157
Chapter 6
141.9 (CH=), 160.4 (C=N). A ccurate mass-M S, m/z: Found: 264.126
C 17H 16N 2O: 264.125 [ M f .
158
Calcd for
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