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Microwave assisted Diels-Alder reaction: Synthesis of substituted furan, pyridine and benzene

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MICROWAVE ASSISTED DIELS -ALDER REACTION:
SYNTHESIS OF SUBSTITUTED FURAN, PYRIDINE AND BENZENE
BY
EMMANUEL OKON OBOT
A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENT
FOR THE DEGREE MASTER OF SCIENCE/ CHEMISTRY
MORGAN STATE UNIVERSITY
%
NOVEMBER 2003
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UMI Number: 1420573
Copyright 2004 by
Obot, Emmanuel Okon
All rights reserved.
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MICROWAVE ASSISTED DIELS-ALDER REACTION: SYNTHESIS OF
SUBSTITUTED FURAN, PYRIDINE AND BENZENE
BY
Emmanue! Okon Obot
has been approved
November 2003
THESIS COMMITTEE APPROVAL:
. Advisor
.^ u s e f H g : P h .V
I
Santosh Mandat, Ph.D
-/Ail
■■
Emanuel Waddell, Ph:D.
Richard Wiffams, Ph.D.
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ABSTRACT
yicrowave Assisted Dieis - Aider Reaction: Synthesis Of Substituted Furan,
Pyridine And Benzene
By
Obot, Emmanuel Okon
yicrowave assisted synthesis is affecting the field of organic chemistry
greatly. Reactions under the microwaves tend to go faster. The reactions are
fast and high yielding, and do not need of supporting solvents. Microwave
assisted reactions are increasing exponentially and it being used in industn/, and
academic labs,
in this instance, there is a focus on the Diels-Alder (DA)
reactions under microwaves as this reaction is a thermal reaction and is a good
candidate for study under microwaves.
This work presents microwave assisted DA reactions of the dienes, 2,5dimethylfuran and 2,4,5-trimethyloxazoie, 2-trimethylsi!yioxy1,3-cyclohexadienes
and
2-buty!-1,3-cyclohexadienes with acetylenic and oiefinic dienophiies.
Microwave assisted reactions were run from 2 to 20 minutes. The DA reactions
of the dienes with acetylenic dienophile resulted in the formation of the
cycloadduct as an intermediate that proceeded via the retro DA reaction to give
substituted furan, pyridine and substituted benzene in good yields 60-90%. The
compounds were identified by GC-MS and compared to authentic samples.
The reactions of the oiefinic dienophiies as N-methylmaleimide, maleic
anhydride with the furans gave the adducts in good yields, that lost water to give
substituted benzene, while the reaction with 2,4,5-trimethyloxazole gave
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Ill
substituted pyridines upon dehydration. Less reactive dienophiies as
benzoquinone, 2 -cyclohexenone, p-nitrostyrene, and dibenzoylethyiene were
unreactive under the microwave conditions and the reactions were futile.
1,3-cyclohexadienes were synthesized by the addition of alkyl lithium to Rcarvone and 2 ~cyciohexenone and dehydration under mild conditions with
dehydrated copper sulfate with azeotropic removal using Dean Stark trap,
yixtyres of two isomeric compounds were obtained for each dienes synthesized.
yicrowave assisted DA reactions of 1,3-cyclohexadienes with acetylenic
dienophile resulted in the formation of substituted benzene, upon cycloaddition
and loss of ethylene.
2-Trfmethylsilytoxy-1,3“Cyclohexadiene gave diethyl-4-
hydroxyphthalate upon reaction with diethylacebylenedicarboxylate (DEAD) under
microwave irradiation, followed by acid hydrolysis. Reactive oiefinic dienophiies
as N-methylmaleimide and maleic anhydride resulted in the formation of the
adduct containing the silyl enol ether. Acid hydrolysis gave the corresponding
bicyclic ketone. Less reactive oiefinic dienophiies were sluggish, with negligible
or no product formation.
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ACKNOWLEDGEMENTS
! wish to express my sincere gratitude to Dr. Yousef
Hijji, for his
refentlessfy tireless effort in terms of his devoted time, material, mora! and
exceptional intellectual support, patience, and tolerance. Dr. Santosh IVIandal for
always being there to answer inteilectuai, technical questions. To Mr. Solomon
Taddese, thanks for the marvelous job in repairing any broken down equipment.
To my daughter, Miss Ekaette E. Obot, and to my wife, Mrs. Marcella R. Obot,
thanks for always helping in typing this Thesis. Also thanks to Ms. Ayesha
Muhammad and Ms. Rena Santos for your assistance with computer problems.!
wish to thank the entire faculty and staff of the Chemistry Department and
Morgan State University at large for creating the proper environment for me to
achieve my goal.
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List of Figures
Page
Figure 1: Microwave radiation.......... ...............................................1
Figure 2: Diagram of conventional h e a tin g ........................................2
Figure 3: Diagram of microwave h e a tin g .................................... ...
3
Figure 4: Reaction coordinates....,
5
List of Schemes
Scheme 1: Anthracene Diels - Aider reaction with Fumarate.................. ....6
Scheme li: Furan Diels - Alder reaction with Diethyl acetylene
dicarboxylate (DEAD)
.1
......................
Scheme III: Diels - Aider reaction of Furan with oiefinic dienophiies
Scheme IV: Diels
-
Alder reaction mechanism
........................................
.7
.........8
Scheme V; Diels - Alder reaction of Oxazoles and
possible transformations
.........
11
Scheme VI: Examples of biologically active compounds that can
be obtained from fu ra n ................ • ......
Scheme VII: Structure of dienes and dienophiies for this study.
13
....... 16
Scheme Vlil: The mechanism of Diels - Alder reaction of
2,5-dimethy!furan with acetylenic dienophiies...................... 19
Scheme IX: Synthesis of 1,3-dienes from enone.................................2 7
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V
I
List of Tables
Page
TaWe 1: Reaction of 2,5 -■ dimethyffuran with acetylenic dienophiies...... 18
Table 2: Diels - Alder Reaction of 2,5 - dimethyl furan with oiefinic
dienophiies under microwave irradiation
......
22
Table 3: The reactions of 2,4,5 - trimethyioxazole with acetylenic
Table 4: The reactions of 2,4,5- trimethyioxazole with oiefinic
d ie n o p liiie s...............................................
.............25
Table 5: Synthesis of 1,3- dienes, from alky! lithium, ketones, and copper
sulfate catalyzed dehydration
Table
6
......
.28
; Diels-Alder reaction of substituted 1,3 dienes with + Acetylene Under
Microwave C o n d itio n s.....................................................30
Table 7: Diels - Alder reaction of substituted 1,3 - dienes with oiefinic
dienophiies under microwave conditions.......................
....30
Table 8: The reaction of 2-trimethylsily!oxy - 1,3 - diene with acetylenic
Dienophiies................
.32
Table 9: Diels - Alder reaction of 2 - trimethylsilyloxy - 1,3 - cyclohexadiene
with oiefinic dienophiies....
......
..........3 4
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TABLE OF CONTENTS
PAGE
1. Title of Thesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... ... . .. i
.......................................
2. Abstract
..ii-iii
3. Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . ........................
iv
4. List of Figures and s c h e m e s ........................................................ v
5. List of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi
6.
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
A. Microwaves: What are microwaves
I.
Conventional Heating
II.
How does Microwave heat a substance? ........
III.
How do microwaves increase reaction rates?...........4
........ .....2
...3
B. Microwave application in organic synthesis...........................5
C. Diels-Alder Reaction.....
D. Furans....
...8
.............
E. Synthesis of the 1,3-dienses.
11
....... .............................13
7. RESULTS AND DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . ...... 16
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8
I,
Diels - Alder Reactions under microwave conditions..........17
II.
Oxazoles ..................................................................2 3
Hi.
1,3-Cyciohexadiene ....................................................2 6
. EXPERIMENTAL . . . . . . . . . . . . . . . . . . . . . . .
. . ............... . . .. ....35
General Methods and Materials
A. Synthesis of 1, 3-Dienes ..................................................3 6
B. Diels-Alder reaction of 2,5- dimethylfuran
under yicrowave ............................................................3 9
C. Diels-Alder Reaction of 2, 4, 5-trimethloxazofe with acetylene
dienophiies...
.........................................................4 1
0. Diels - Aider reactions of 2- trimethylsilyloxy-1, 3- diene
{ly S O )..........................................................................4 3
E. Diets- Aider reaction of 2-Butyl-1,3-cyoiohexadiene Acetylenic
dienophiies. ..... .............. .................................... ....................... 44
F. Diels- Alder reactions of 2-Buty!-4-methyl-6-isopropyiene-1,3Cyclohexadiene with acetyienic dienophiies
......
.45
9. CONCLUSION . . . . . . . . . . . . . . . . . . . ............... . . . . . . . . . . ..........48
10. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . ................. . . . . . .......50
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iNTRODUCTiON
A. MICROWAVES: WHAT ARE MICROWAVES:
How does this conventionai microwave assist in the synthesis of organic
compounds and what is microwave? According to Brittany L. Hayes in Microwave
Synthesis, microwave is a form of eiectromagnetic energy that falls at the lower
frequency end of the electromagnetic spectrum, and at a range of 300 - 300,000
megahertz (MHz) frequency. She stated that within this region of
electromagnetic energy, only molecular rotation is affected, not the molecular
structure. The frequency range of 2450 MHz is preferred because it has the right
penetration depth to interact with laboratory scale samples. Microv/ave energy is
comprised of an electric field and a magnetic field. Though only the electric field
transfers energy to heat a substance (See figure 1). Microwaves move at the
speed of light (300,000 km/sec). The energy in microwave photons (0.037
kcal/mole) is very low relative to the typical energy required to cleave molecular
bonds (80 - 120 kcal/moie); thus, microwaves will not affect the structure of an
organic molecule, in the excitation of molecules, the effect of microwave
absorption is purely kinetic.
Figure 1; Microwave radiation
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L Conventionai Heating:
Conventionally, chemical reactions are heated by an externa! source of
heat, where the system is heated by conduction as shown in figure 2.
Heat is
driven to the substance first through the walls of the vessel in order to reach the
solvent and reactants.
Temperaiurs on the o u I sk Js surface is graaSer than ths intamal tamperature.
Figure 2: Diagram of conventional heating.
This process is inefficient and slow as it depends on the conductivity of the
materials to be penetrated. This results in temperature differences between the
solvent and the vessel, until equilibrium is reached. This can take a long time.
This also hinders control over the reactions leading to byproducts.
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IL H 0¥/ DOES A MICROWAVE HEAT A SUBSTANCE:
yicrowave heating is a very different process (See figure 3). Microwaves
couple directly with the molecules present in the reaction mixture, leading to a
rapid rise in temperature. Because the process is not dependent upon the
thermal conductivity of the vessel materials, the result is an instantaneous
localized superheating of anything that will react to either dipole rotation or ionic
conduction, the two fundamental mechanisms for transferring energy from
microwaves to the substance being heated. Dipole rotation is an interaction in
which polar molecules try to align themselves v/ith the rapidly changing electric
field of the microwave. The rotationai motion of the molecule as it tries to orient
itself with the field results in a transfer of energy.
Vessel wall
is transparent to
miciwave energy
m
m
Reactants-solvent
mixtore (absorbs
microwave energy)
.
Localized
superheaing
Figure 3: Diagram of microwave heating.
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The coupling ability of this mechanism is related to the polarity of the
molecutes and their ability to align v/ith the electric field. The second v/ay to
transfer energy is ionic conduction, which results if there are free ions or ionic
species present in the substance being heated. The electric field generates ionic
motion as the moiecuies try to orient themselves to the rapidly changing field.
111. HOW DO MICROWAVE INCREASE REACTION RATES:
In a typical reaction coordinate (See figure 4, the process begins with
reactants (A and B), which have a certain energy level (E r). In order to complete
the transformation, these reactants must colisde in the correct geometrica!
orientation to become activated to a higher - level transition state (Ejs)- The
difference between these energy levels is the activation energy (Ea) required to
reach this higher state (E ts - E r = Eg). The activation energy is the energy that
the system must absorb from its environment in order to react. Once enough
energy is absorbed, the reactants quickly react and return to a lower energy state
(Ep) of the products of the reaction (A - B).
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A---.8
A -B
Transitton
State
Activation Energy, Eg = Exg-Es
^ Heat of reaction, AH
Products
Reaction Coordinate
Figure 4: Reaction coordinates
Microwave irradiation does not affect the activation energy, but provides
the momentum to overcome this barrier and complete the reaction more quickly
than conventionai heating methods.
B. MICROWAVES APPLICATION IN ORGANIC SYNTHESIS:
Microwave synthesis represents a major breakthrough in synthetic organic
chemistry methodology.‘’"^Conventional heating is long known to be inefficient
and time consuming.
Microwave synthesis avoids heating inefficiency and
makes it possible to perform the reactions in minutes instead of hours or even
days.
The reaction can be faster v/ith improved yields, cleaner products and
creates new possibilities in chemical transform^ation.
Some of these reactions
can be performed under microwave irradiation without the need for supporting
solvent. This by itself is a break through”* in organic chemistry as the chemistry
will be greener and more eco-friendly^. It will cut significantly on the cost of
producing many products especially those used in pharmaceutical industry.
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Chemists have been conducting research in micrcwave synthesis since mid1980s and the field has been growing in popularity.^- ^There have been many
reactions investigated.
Recently the applications are in organometallic,
cycloaddition, heterocyclic synthesis, oxidations, condensation, esterification and
many other organic synthesis areas.
Old reactions are reinvestigated vdth
microwaves, and new reactions developed which have been too slow or takes
too long to be practical. These developments are reviewed in recent articles and
books.^’^
Our attention is directed at cycloaddition reactions and in particular [4+2]
cycloaddition (Diels-Alder) reaction.
Dieis-Alder cycloaddition usually requires
harsh conditions (high pressure and temperature), long reaction time and are
usually performed in sealed tubes. This makes it a good candidate for
microwaves application. It was the first reaction to be examined in conjunction
with microwave irradiation.
induced
Diels-Alder
Giguere®^’’^ showed the examples of microwave
reaction
in
1986.
Irradiating
anthracene
dimethylfumarate in a microwave gave a complete reaction in
compared to days under conventional heating.
scheme 1:
10
and
minutes
The reaction is depicted in
%
Scheme I: Anthracene DA reaction with fiimarate:
p-Xylene
Microwave 10m in87%
Conventional 72 hrs 67%
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7
yajetich and Hicks® have shov/n that the Diels-Alder reaction of furan and
diethyi acetylene dicarboxylate (DEAD) was successful in a sealed tube as
shown in scheme II:
Scheme II: Furan Dieis-Alder reaction with DEAD.
COaEt
DMF or solvent free
COaEt
Microwave 10 min 86%
Conventional 15 min 68%
De fa Hoz reported recent development in the microwave reactions of
furan and oiefinic dienophiies.® Furan and oiefinic dienophiies undergo the
cycloaddition reaction to form adducts. The adducts then undergo dehydration to
give substituted aromatic compounds under the reaction conditions in the
presence of silica supported Lewis acids catalysts, ZnCb, Et2AlCi or TiCU. The
reaction is depicted in the scheme III:
Scheme III; Diels-Alder reaction o f furan with oiefinic dienophiies
X
q
M icrowave
X
•1
dehydration
Silica.'Lewis acid
Rj
Y
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8
Our g r o u p ® ' h a s shown that Diels-Alder reactions of furans and 1,3cyclohexadienes under microwave irradiation could give substituted furans and
benzene derivatives when reacted with acetylenic dienophiies and get the
cycloadduct when reacted with oiefinic dienophiies within minutes of reaction
time.
The process involves the cycloaddition reaction followed by reto Diels-
Alder reaction.
C: Dieis Aider Reaction:
The Diels-Aider reaction is well known and one of the most powerful
routes for constructing cyclohexenes and bicyciic systems.’’ ’ !t is a concerted
cycloaddition reaction of electron rich 1,3-diene and an electron deficient
dienophiie. It is a thermal reaction and can be catalyzed by Lewis acids. It has
unparalleled synthetic utility in the formation of functionalized six membered
rings. This cycioaddition reaction can provide up to 4 chira! centers in one step
making it of value in asymmetric synthesis too. The mechanism of the reaction is
as follows, scheme IV:
Schem IV: Diels-Alder reaction mechanism
The Diels-Alder reaction still remains an active research field and a crucial
key in a wide variety of natural product syntheses.’’^ For practitioners of this
natural protocol and for synthetic chemists in general, it Is probably the most
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construction process in organic syrsthesis.
The irnportance and
regio- and stereoselectivity, formation of two new carbon- carbon bonds, and
potentially, four new stereogenic centers, A useful variation involves the use of
heterodienes or dienophiies, which represents an elegant and versatile
procedure in the preparation of noncarbogenic systems.
In particular, the
process enables the synthesis of bioiogically important nitrogen and oxygencontaining heterocylces hitherto inaccessible or difficult to achieve by using
standard methodoiogy. The dienes involved in this reaction can be acyclic 1,3dienes
or
cyclic
dienes
as
1,3-cyclohexadienes,
cyclopentadienes,
or
heterocyclic dienes as furans, pyrroles, oxazoles, and thiophenes.^®
The Dieis-Alder reactions of furans are of interest to us. Where bicyclic
adducts are formed with an oxygen bridge, which tends to open and lose water to
give substituted aromatic compounds or undergo reverse Diels-Aider reaction
(retro Diels-Alder) to lose the carbon bridge generating substituted furans in
order to form the stable aromatic compounds as furans or benzenes.
This reaction has been used as a key step in the synthesis of many useful
natural products. The synthesis of substituted furans has been reviewed in the
•?!
literature.^^
The dienophiies involved in the Dieis-alder reaction can be substituted
acetylenes, as acetylene dicarboxylate, propiolate, or oiefinic dienophiies as
maleic anhydride,
maieimides, acrylates,
benzoquinone,
nitroacryiates,
2
-
cydohexenones, dibenzoylethylene, maleates, fumarates and substituted imines.
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10
A wide range cf dienophiies is utiiized in these reactions.
The presence of
electron withdrawing groups on the dienophiies enhances the reactivity by
making the dienophile more electron deficient, while the presence of electron
donating groups on the diene making it electron rich causing accelerated the
reaction.
The Diels-Aider reactions can be catalyzed by Lewis acids, as boron
trifluoride, alkylaluminum chiorides, zinc chlorides, tin chloride, silica, day, rare
metal salts as ytterbium triflate and a large hos* c Lewis a c i d s . S o m e of these
Lewis acids allowed some of the Diels-Alder reaction to proceed at a very low
temperature.
Oxazoles react as dienes in Dieis-Alder reactions. Substituted pyridines
are obtained by the loss of water from the oxa bicyclic adduct. Wong’^^ reacted
oxazoles with acetylenic dienophile as bis-trimethylsilylacetylene at 200 °C.
Diels-3,4-bistrimethylsilyi furan was obtained by DA reaction followed by retro DA
reaction with expulsion of nitrite.
adducts.
Oxazoles reaction can lead to the useful
Such intermediates possible transformation are depicted below in
scheme V:
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11
S c h e m e V: D i e l s - A l d e r reaction o f O x a zo l e s and p os s ibl e t r a n s f o r m a t i o n s
R■
" XX
R-
■H
y
OH
R
R -C N
As clearly seen from scheme V above the adduct from the DA reaction is
a versatile intermediate that can lead to substituted
hydroxypyridines.
furans,
pyridines,
This signifies the importance of this reaction and its
application in organic and natural products synthesis as alkaloids. The synthesis
is of Importance as they are useful building blocks in the
The microwave assisted Diels-Alder reaGtions of oxazoles and furans are
one of our objectives in this work, this would the first application of microwaves
assisted reaction of oxazoles in cycloaddition reactions.
P. Furans:
Furan, as one of the representative five membered heterocycles, can be
found in many naturally occurring compounds.
Polysubstituted furans play an
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12
important rote in organic chemistry not only due to their presence as key
structurai units in many natural products'^® and in important pharmaceuticals'^,
but they can also be employed in the synthetic chemistry as building blocks. For
this reason the syntheses of polysubstituted furans continue to attract the interest
of many synthetic chemists. Although a number of reviews on the synthesis of
furans have appeared in the literature, only very few of them deal with the
regioselective methods for preparing f u r a n s . 3 - S u b s t i t u t e d furans can be
synthesized by employing the Diels-Alder cycloadditon- retro Diels -Alder
reaction strategy using oxazole derivatives and dienophiies as starting materials,
bicyclic compounds couid be produced.^”^ The intermediates concerned could not
be isolated and could directly provide 3-substituted furans under thermal
conditions.
Furan rings are found in many naturally occurring moiecuies, either in fully
unsaturated forms or in reduced or partly reduced frameworks. Poiysubstituted
furans, moreover, also play a major role as key precursors in organic synthesis.
Synthetically, it has long been recognized that regioselective introduction of
carbon substituents into a furan ring is by no means trivial.
For this reason,
practical methods of procuring poiysubstituted furans usually involve acyclic
%
precursors. There are several recent reports in the literature on the synthesis of
2,3-disubstituted furans, 2,4-disubstituted furans, 3,4-disubstituted furans, 2,3,4trisubstituted furans, 2,3,5-trisubstituted furans as we!! as 2,3,4,5-tetrasubstituted
furans, which generaliy requires multi-step procedures and/or inaccessible
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13
starting materials.^' One of our objectives is to have an efficient synthesis of
multi-substituted furan.
Substituted furans are very useful intermediates for organic synthesis.
They are versatile and can be converted to a variety of other functionalized
systems as butyrolactones and butenolides, or opened to a cyclic aldehydes and
esters. Which constitute an important moiety in many active natural products as
insect antifeedants clerodane diterpenes^^, antibiotic natural
products as
paraconic acids^^ that exhibit antibiotic and anti tumor activities. Examples of
paraconic acids are shown in scheme VI.
Scheme VI: Examples of Biologically active compounds that can be obtairicd from Furans.
CO2 H
R= n-Cj3H27 Protoiichesteric acid
R ~ C}3 H27 Rocellaricacid
R= n-C,Hn Methylenoiactocin
„
^
,
Iv—'n‘“C<jjFi23 fNCpiirostsrsniic
acid
E. Synthesis 1.3-dienes:
1,3"dienes are one component in Diels-Alder reactions. Their availability
is as important as the reaction itself.
Cyclohexadiene, cyclopentadiene, and
heterocyciic dienes as furan, oxazoles, thiophenes are usually commercially
available.
Substituted 1,3-cyclohexadienes can be made from 2-cyclohexenone,
by the addition of Grignard reagent to form the tertiary alcohol, which upon
dehydration forms the substituted
1
,3-diene.^^
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14
1,3-cyclohexadienes usually are obtained from the dehydration of cyclic
allylic alcohols. The dehydration of alcohols is performed under acidic conditions
using sulfuric adds, sodium hydrogen sulfates. These procedures can provide
the dienes. The draw back for this process is the isomerization of the product or
the polymerization due to the acid sensitivity of the dienes.
Dehydration of alcohols
using
Lewis
acids
has
been
reported
Anhydrous copper{il)su!fate have been used as a mild dehydrating agent in
alcohols. The anhydrous copper sulfate was prepared by heating copper (il)
sulfate pentahydrate at 200-300 °C for 5 hours which serves as an effective
catalyst for the dehydration of secondary, tertiary, benzylic, and allelic alcohol to
the corresponding olefins. This reagent was first used to dehydrate tertiary
alcohols by heating the solid catalyst with the alcohol at 100 -160 °C for several
hours.^® The use of an acidic inorganic catalyst, including unsupported sulfates
and those supported on a solid surface, is receiving attention in current organic
chemistry and has potential for industrial applications. These supported catalysts
display a range of Bronsted vs. Lewis acid properties. (For example, the
procedure used to produce high purity a-cedene from cedrol that included the
use of a modified Dean - Stark / molecular sieve apparatus to maintain
%
anhydrous reaction conditions.^^ in the present the presence of refluxing
benzene, a broad variety of inorganic sulfates were effective dehydration
catalysts for tertiaiy alcohols. CUSO4 supported on silica^® have been applied for
dehydration of alcohols to alkenes is dominated by preparation of ethylene and
terminal
alkenes from
primary alcohois with
infrequent mention
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of the
15
dehydration of secondary alcohols. We are intending to use anhydrous copper
suifate for dehydrating the alcohols and generating the dienes using Dean- Stark
azeotrope trap that can accomplish the goal at low temperature under mild or
non-acidic conditions avoiding the destruction of the products.
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16
Results and Discussion
Scheme V II : Structures of'the dienes and dienophiies used for this study
Me
Bu
fyfesSiO^
Me
Me
Me
&u
COaEt
COoBt
CO2H
COzEt
H
CO2H
6
7
H
10
2
COaEt
XOaMe
y
/
EtOaC
NMe
0
CH2OH
H
8
.0
M
(CH2)40H
M
Mo
COPh
PhOC
o
M
M
n
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17
I. Diels-AMer reaction under microwave conditions:
Diels-AWer reactions of the dienes 2,5-difnethyl furan X, 2,4.5trimethyioxazoie 2, 2-trimethyisily!oxy-1,3-cyclohexadiene 3, and a mixture of 2butyi-1,3-cydohexadiene 4 and 2-butyl-5-isopropeny!-,3methyl-1,3cyciohexadiene 5, the dienophiies chosen were of two classes, aikynes: diethy!
acetyiene dicarboxylate, 6, ethyl propiolate 7 acetylene dicarboxylic acid 8,
propargyl alcohol 9 , 5-hexyne-1-ol 10 and olefinic dienophiies: maieic
anhydride 11., N-methylmaleimide 12, dimethvlmaieatelS . diethyifumarate 14.
p-nitrostyrene 15, dibenzoy! ethylene 16 , and benzoquinone 17 .
Furans:
The results of the microwave assisted DA reactions of 2,5-dimethylfuran i
with acetylenic dienophiies as DEAD 6, EP 7, ADCA 8 and olefinic dienophiies as
NMMA H . MA, nitrostyrene, benzoquinone, diethyifumarate, dimethyl maleate
are presented in Tables 1 and 2:
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18
Table 1; Reaction of 2,5-Dimethylfurao with Acetylenic dienophiies
Me
Me
H
MW
Me
H
Me
D ienophile
Diene
Dienophile
Microwave
Reactions Tim e
Products
ISmins
45mins
>5%
,0025!
82%
EPP
5 min.
32% and
decomposition
‘CO2H
products
The Diels-Aider reaction of diene 1 with the dienophile, DEAD 6 under
irradiation resulted in the formation of the 4+2 adduct
in addition to Ethy!-2,5-
dimethy!-3,4-furandicarboxylate , as indicated by GC-Mass analysis at early
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19
reaction time, upon continued irradiation the soie product, Elhyl-2,5-dim8thyi3,4-furandicarboxylate S is obtained in 85% yield after purification by column
chromatography on silica gel using 1:1 ether: hexane. The identity of the product
22 was determined by the GC-Mass spectrometer, M/Z= 240, the molecular
weight of the product, the mass spectrum matched that reported in NIST library
provided with the instrument. The iR spectrum showed the ester carbonyls
absorption peaks related to the ester groups. The formation of this product can
be explained by the formation of the adduct
that undergoes retro Diels-Alder
reaction by the loss of acetylene as the byproduct upon continued microwave
irradiation. The production of the gaseous acetyiene can be noticed upon
opening of the via! and the observance of increased pressure inside the vial even
after cooling. The mechanism of this reaction is presented as follows in scheme
VIII:
S ciiem e V I I I : T h e m e ch a n ism o f D ie ls - A ld e r re to -D ie ls A id e r re a c tio n o f 2 ,5 -D im e th y l fu ra n w ith
a ce tyle n ic d ie n o p h iie s
C)
\
CozEt
y
Ms
1
^ 0 0
4
Me
\ COzEt
r.n
D ie n e
n
D ie n o p h ile
adduct
2B
Me
n
p ro d u c t
This type of Diels-Alder retro Diels Alder had bedn reported decades ago, with
cyclohexadienes but occurs at elevated temperatures, it has been reported for
furans, and it required high temperature for few hours. The Diels -Alder
reactions of furan gave the adduct only when the reaction was done in sealed
tube under microwave conditions as reported by Majetichh The reaction shown
provides a very efficient synthetic pathway for tetra-substituted furan in few
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20
minutes under neat conditions. The experimental work up was very simple, as
the reaction products were taken and chromatographed on silica gel to give the
pure product in high yield. Irradiating the reaction mixture in the microwave at
tower power leads to the formation of higher amount of the adduct.
With the success of the reaction with the dienophile
6
, v/e reacted Ethyl
propiolate 7 , the less reactive dienophile as it contains one electron-withdrawing
group. The reaction proceeded slower than with
6
, the reaction took longer time
to get comparable yield 82% in 45 min. The product M was purified with
chromatography and identified by GC-MS, M"' = 168 ( molecular ion) and the
other fragmentation supported the stnjcture. The infrared spectra showed the
ester functional groups. The reaction was performed under conventional
conditions but no product was obtained when heated conventionaliy under reflux
in toluene for several hours.
For acetylene dicarboxyiic acid 8 , the reaction gave some product in
addition to dark material, as furans tend to decompose under acidic conditions at
high temperature, the yield was low, 32% of the substituted furan.
As shown in Table 1 acetylenic dienophiies tend to give substituted furan
as the final product in excellent yields especially when the dienophiies are
reactive. Other acetylenic dienophiies as diphenylacetylene and
bistrimethyfsilylacetylene were unreactive under these conditions and no product
was formed. Other inactivated acetylenic compound as 5-hexyne-1~ol 9 and
propargyl alcohol IQ were also unreactive and the reactions were futile.
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21
Olefinic dienophiies were reacted with diene 1, the results are presented
in Table 2. The reactive dienophiies as N -yethyim aleim idell and maieic
anhydride 12 were productive and afforded the adducts. Upon heating the
adducts, loss of water resulted in aromatization and the formation of substituted
aromatic compounds. A mixture of the adducts and the aromatic products are
observed. De ia Hoz® has reported the cycloaddition and dehydration from furans
and olefinic dienophiies recently under silica ge! catalyzed reaction. The results
we had and these results are comparable. The products were analyzed by GCMS.
Less reactive dienophiies as p-nitrostyrene, dibenzoyf ethylene,
benzoquinone, diethy! maieate and diethy! fumarate ¥/ere observed. No products
or traces have been detected under our conditions. Lewis acid catalysis might
be needed to effect these reactions
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22
Table 2: Diels-Alder Reactions of 2,5-dimethyi furan with olefinic dienophiies
under microwave irradiation
0
- H2O
MW
+
D ie n o p h ile
Entry
Diene
Dienophile
2,5-
Microwave
Reactions
Time
Products
%
Yield
Me
20m in .
p
23%
D lm e thylfu ra n
1
ij
ir ^ N M a
NMe
Me
NMMA 11
2
NO,
1
0
25
25mins
N/A
25rnins
N/A
15mins
Me
p
ie
6
TBN 16
3
1
DBE 17
1
<>
MA12
5
1
H” ” S
- “ (CH2) 4 0 H
2 0 m in s
26
N/A
5 m in s
N/A
iO m in s /
N/A
5-hexyn1-o! 9
6
1
H— ^ — -CHaOH
10
7
COoEt
1
____
/
/
EtOaC
13
8
1
ISmins
N/A
15
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20%
23
2. Oxazoles:
2,4,5-trimethylGxazole was used for our study, as it is commercialiy available.
This diene is chosen over the parent compound oxazoles as the reaction is
expected to lose acetonitrile opposed to hydrogen cyanide from the parent
molecule if it follows the same reaction mechanism for furans making it safer.
The substituted oxazoles might be having a lower reactivity in Diels-Alder
reaction due to steric hindrance. The Diels-Alder reaction of oxazoles 2 with
acetylenic dienophiies is shown in Table 3.
Table 3: The reactions of 2,4,5-trimethyloxazole with acetylenic
Dienophiies.
Me
Ms
Me
Me.
P
+
MW
Me
Me
Entry Diene
Dienophile
Me
Y
Microwave Reaction
Time
15mins
Products
%Yieid
Me
47%
Me-
Me
Me
5m ins
Me
Me
24
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60%
24
The reaction proceeded under microwave conditions to give substituted furans as
a result of the cycloaddition to form the adduct. The adduct then underwent retro
Diels-Alder reaction and extruded acetonitrile providing diethyl 2,5-dimethy-3,4furandicarboxylate ^ from the reaction with DEAD 6. The product 22 was the
same as that obtained from 2,5-dimethyl furan 1 and 6 Reaction. GC-MS
240,
W ith
=
the same retention time. The isolated product after column
chromatography on silica gel using 1:1 etherihexane, was 47% as isolated yield.
The reaction was complete within 5 minutes. The yield is !ow due to the
sensitivity of the starting material.
Oxazole 2 reacted with ethyl propiolate 7 . The reaction took longer time
for complete conversion most probably due to the lower reactivity of the
dienophile. The yield was better 60%. The identity of the product ^
was
determined by GC-MS, M^= 168, and compared to the NIST library database
and to the products obtained from the reaction. This will add another pathway
for the synthesis of substituted furans. Oxazoie has been reported to undergo
Diels-Aider retro Diels-Aider reaction at temperature of 200 °C, in sealed tube
under conventional heating and requires many hours to give moderate yields'"^.
18-
The microwave heating seemed to provide products in minutes even with more
hindered dienophiies. This method is an excellent method for the substituted
furan even though the yields are low. The process needs further optimization to
get better yields.The Dieis-Alder reaction of oxazoles 2 with olefinic dienophiies
shown in Table 4.
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25
Table 4; The reactions of 2,4,54rfmethyloxazole with olefinic dienophiies.
Me
X
Me,
Me.
MW
Me
3
Y
Me
Entry
Diene
Dienophile
Me
1
1
P
(4.
Microwave
Reaction
Time
40min.
Me
2
2
2
6
NMMA 11
0
%Yieid
Products
2min.
Me
Q
lie
°
Me
Q
90%
13%
W
0
i
i i
MA12
It is more interesting, as the adducts formed from the addition of Nmethylmaleimide H dehydrated by the loss of water resulting in Aromatization of
the ring giving substituted pyridine 2. The products are substituted nicotinic acid
ester. The yield was 90% in addition to the adduct in 10 minutes. The reaction
seemed to proceed smoothly to form the products that were analyzed by GC-MS
after chromatography. The compounds were identified as the adduct and the
substituted pyridine based on its GC-MS data. The reaction seemed to proceed
under reflux overnight to give the product in about 50 % yield.
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26
yaleic anhydride 12 reacted with oxazoles 2 within 2 minutes to produce the
substituted pyridine 28, the loss of water v/as facile only traces of the adduct
could be obsen/ed within 1 minute.
3. 1.3-Cvciohexadienes:
The work in our lab showed that 1,3-cydohexadiene, a-terpenene reacted
with acetylenic dienophiies to give the adduct followed by retro Diels-Alder
reaction and the extrusion of ethylene resulted in the formation of diethy!
phthafate and 3-ispropyl-6-methylphtha!ate when reacted with DEAD 6
respectively.
In order to have the 1 .S-cyclohexadiene investigated, we
synthesized substituted cydohexadienes that are not available commercialiy.
Our synthetic strategy was based on the addition of alkyl lithium to enones. The
enones used were R-carvone, and 2-cyciohexenone. The addition of butyl
lithium , methyl lithium, to carvone lead to the formation of the alcohol in good
yields. Dehydration of the alcohols with sulfuric acid^° resulted in a mixture of
product in addition to polymerization. The reaction was not efficient. We turned
our attention to the use of the mild Lewis acid dehydrated copper sulfate^®’^'^. The
copper sulfate penta hydrate was dehydrated using an azeotope trap from
cydohexane. The hydrated copper suifate(blue) was refluxed in cyclohexane
and the azeotrope was removed. The color of the solid turned to while with very
light blue color to it. The dehydrated copper sulfate was filtered and dried then
stored in a desiccator. Then 1:1 mole ratio of the copper sulfate to the alcohol
were place in cyclohexane and refluxed in an a Dean-Stark setup for water
removal. After 30-40 minutes the GC-MS of the reaction mixture showed the
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27
disappearance of the alcohol and the formation of the dienes. A mixture of t\vo
dienes as usuaiiy obtained. The results are shown in Table 5. This method
seems to be superior to other dehydrating procedure using strong acids. The
work up is very simple either by the filtration of the solid copper sulfate to give the
solution of the products or addition of water to dissoive the salt, then separation
of the organic layer containing the products. The yields were high about 80%
yields for both steps, but two isomeric dienes were formed. The formation of the
isomeric dienes can be explained by the formation the tertiary aliylic carbocation.
There are two possible choices of proton loss, from either the a -carbon or the
y-carbon, resulting in the formation of both isomers. The mechanism for
formation of the dienes is shown below scheme iX;
Scheme IX ; Synthesis o f 1 , 3 -dienes from enones
iO H
R'
-B u , M e , Ph
CuSO 4
or
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28
Table 5: Synthesis of 1,3-bienes, from alky! lithium, ketones and copper sulfate
cataiyzed dehydration.
OH
o
Cum.
n -B u l
Entry
1
Ketone
R-Car^/one
R'
Alkyl
Dehydrating
Lithium
agent
n-Butyl
Copper
Lithium
sulfate
Yield
Products
n-Bu
9 '® ^
98%
5
2
3
R-Carvone
Methyl
Copper
Lithium
Sulfate
2-
n-Butyl
Copper
cyclohexenone
Lithium
Sulfate
73%
n-Bu
60% 1
4
4
Methyl
Copper
Lithium
Sulfate
Me
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60%
29
This method was used for the synthesis 1,3-cydohexadienes as mixture of
isomers, they were characterized by the GC-MS and other spectroscopic
techniques as IR. Chromatography did not accomplish their separation. The
results for the synthesis of these dienes are shown in Tabie 5.
The dienes were used as isomeric mixture for the subsequent Diels-Aider
reactions. Diels-Alder reactions of butyl-1,3-cyclohexadierses 4 isomers with
dienophile 6, resulted in the formation of the adduct that instantly lost isoprene
unit by retro Diels-Alder reaction resulting in the formation a mixture of diethyl 3butyl-phthalate ^
and diethyl 4-butyl-phtha!ate 36 in 57% yield. The products
were identified based on the molecular weight obtained by the GC-MS. Due to
the formation of other cyclohexadienes in a mixture of isomers the other isomeric
dienes were not subjected to Dieis-Alder reaction. Ethyl propiolate did not show
the formation of the products after 20 minutes of heating. The results are
presented in Tabie 6.
Further diene 4 was reacted with reactive olefinic dienophiies as N-methyl
maleiimlde 11. and maieic anhydride 12, the results are presented in Table 7.
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30
Table 6: Reaction number 5 with Acetylenic Under yicrowave
n-By
/
Entry
Diene
Dienophil
0
1
5
DEAD
6
2
5
EP7
Microwave
Reaction
Time
2Qmin.
Products
%Yie!d
57%
36
N/A
20min.
1
Table 7: Diels-Aider reaction of substituted 1,3- dienes with oiefinic dienophiies
under microwave conditions.
n- B u
Entry
Diene
n-5y
Dienophile
1
I
n
Microwave Reaction
Time
5mins
%Yieid
100%
Me
NMMA 11
2
Product
4
MA 12
38
65%
5mins
Xjr
39
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3i
The reaction proceeded smoothly to give the adducts 37 and ^
in 100 %
in 5 minutes of microwave irradiation. The adducts were isolated purified on
silica gel. GC-MS of the adducts, IR indicated the identity of the products. The
products were a mixture of isomers as the starting materia! contained two
isomers, which was reflected in the products distribution.
These kind of adduct contain the chiral center that is inherited from the chiral
carvone used. These compounds may serve as versatile intermediated in
organic synthesis, utilizing chiral induction.
2-trimethylsi!yioxy-1,3-cyciohexadiene 3 is commerciaily available and a
good choice for investigation of the Diels-Aider reactions. Reaction of diene 3
with the acetylenic dienophiies 6 and 7 were productive. The results are
presented in Table 8.
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32
Tabie 8: The reaction of 2-trimethy!sily!oxy-1,3-diene with acetyienic dienophiies.
X
CH2
MW
CH.2
Y
Y
Entry
Diene
Dienophiie
COjEi
yicrowave Reaction
Time
Smins
%Yieid
Products
45%
20mins
EP 7
50%
'COoEt
The cycloaddition reaction of diene 3 and DEAD 6 gave the adduct that
under went retro Diels-Aider reaction to lose ethylene and give diethyl 4trimethylsiiyloxy-phthalate 30 in 45 % yield within 5 minutes. The product was
identified by GC-MS. Treatment of the product with 10% HCl/THF mixture for 30
minutes resulted in the formation of the diethyl 4-hydroxy-phthalate 31. The
hydrolysis went smoothly in quantitative yields. Chromatography and GC-MS , !R
of the product clarified its structure.
Ethyl propiolate 7 reacted slower with diene 3. The reaction took 20
minutes to produce 50% yield of products 32 and M that was hydrolyzed with
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33
acid. This make the process of cycloaddition reactions of 1,3- cyclohexadienes
and acetyienic dienophile general in the formation of the adduct that transforms
under the reaction conditions to substituted aromatic compounds. Acetylene
dicarboxyiic acid was avoided as it might hydrolyze the silyi ether prior to the
reaction.
Further the reaction of diene 3 with olefinic dienophiies as n-methyl
maieimide 11. gave the adduct 34 in 5 minutes. The adduct was treated with acid
directly to convert the silyl end ether to the corresponding ketone. The formation
of the bicyclic ketone was accomplished through this process. The results are
shown on Tabie 9.
Maieic anhydride reacted with diene 3 under the microwave conditions
used and gave the adduct in 5 minutes. Hydrolysis of the product with acid
resulted in the formation of the keto diacid bicyclic product. These products
analyzed by GC-MS and the identity of the product confirmed. This shows how
microwaves can affect organic synthesis and revolutionize the synthetic
strategies.
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34
Table 9; Diels -A ider reaction of 2-trirfiethylsi!yloxy-1,3-cyclohexadiene with
olefinic dienophiies.
HCl/THF
MW
Entry
Diene
Dienophile
P
1
Microwave
Reaction
Time
Smins
r(
1
NMMA 11
Products
41%
\^ N M e
NMe
2
0
0
M
14%
5 min.
A
I %Y!e!d
2X>C0aH
COjH
0
MA12
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35
EXPERIMENTAL
General Methods and materials:
The chemicals used were obtained from Aldiich chemical company, used
as received. For the microwave oven used, is GE kitchen microwave 1100 W,
with a variable power, 10-100% power. For thin layer chromatography, Plastic
TLC plated obtained from, with fluorescent indicators were used. The silica gei
used for flash chromatography is 200-400 mesh.
GCyS (Gas Chromatography Mass Spectrum) was done using a Hewlett
Packard G1800A, GOD system with an electron ionization detector, it had a
special performance capillary column; HP - SMS (cross - linked 5% Ph Me
silicone). The conditions were:
initial Temperature. . . . . . . . . . ...70°C
Final Temperature
Initial Time
.................250“C
........ ....2 minutes
Rate of Heating . . . . . . . . . . . . . . 20 °C/minute
Injector Temperature . . . . . . . . ,250 °C
Detector Temperature . . . . . . . 280'C
Ss
Silica gel had the following size; BET surface area
500m^/g, pore
volume 0.75 cm % , 200 - 400, mesh Angstroms.
No stirring was done to any reaction that took place in the microwave and
ail samples were heated in the microwave without any solvent. Unless otherwise
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36
specified ai! microwave heating took place at P100 (100% power). Borosilicate
vials were used with Tefion lined caps.
IR Spectra were obtained on a Perkin Elmer IR instrument (Perkin Elmer,
1600 Series FT-IR). Liquids were run neat as thin film on sodium chlorides plate.
Solids were taken in chloroform solutions.
A. Synthesis of 1,3-Dienes
A general procedure for the synthesis of substituted 1,3-cyciohexadiene;
A.1. Synthesis of 1- Butyl-5“isopropenyl-2-methyi-2-cyclohexen-1-ol:
To 5.0 g (33mmoi) of R-Can/one in 4 0 m l of dry ether, cooled in an ice
bath for lOminutes under nitrogen was added 16.67rnL(33.3miTiol) of n-butyl
lithium 2.0M dropwise.
The mixture was stirred for additional 20 minutes. An
aliquot was taken and worked up by adding saturated sodium bicarbonate
solution. GC/MS analysis of the organic layer showed that the reaction has gone
to completion. The mixture was then transferred to a separatory funnel containing
ether and aqueous (NaHCOs). The organic layer was separated, the aqueous
Layer was extracted twice with 25 m l of ether. The organic layers were
combined and dried (Na2 S0 4 ). Filtration and solvent removal by rotor evaporator
gave 5.49g of clear liquid (66% yield) o f»1-bub/!-5-!Soprpeny!-2-methy!-2cyclohexen-1-ol. 17
Dehydration of the alcohol by copper suifate:
The alcohol ^
obtained above was dissolved in 150 m l of cyclohexane
then 6.59g of copper sulfate penta hydrate was added. The flask was equipped
with a Dean-Stark trap and a condenser. The mixture was heated to reflux and
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37
the azeotropic water was removed. The reflux was aflowed to go for
The solution was allowed to cooi to room temperature.
hours.
Copper sulfate was
filtered. The filtrate was washed with water then dried, sodium sulfate.
Concentration in vacuum provided 4.0 g (84%) of the clear liquid. GC/MS was
conducted and the results showed products formation. Column chromatography
was done using hexane and ethyi ether in a proportion of 8:2 parts respectively.
TLC and GC/MS were conducted to indicate the formation of the required
product. 2.57g (51%) yield of diene was obtained.
GC-MS m/z: 190(M^), 175, 161, 149, 113, 119, 105,91,77, 55.
A.2. Synthesis of 2-bytyI-1,3 - Cyclohexadiene:
According to the general procedure for 1,3-cydohexadienes synthesis,
I.Og (10.4 mmoi) of 2- cydohexen-1- one in 30 m l of anhydrous ether were
reacted with 6.2mL(12.4mmol) of n - Butyl lithium 2.0 M at 0 °C. The nriixture
was stirred for 30 minutes, then worked up as the general procedure. Flash
chromatography on silica gei using ether: pet. ether 2:8 V:V gave 1.25g of crude
alcohol 1-butyl-2-cyclohexene-1-ol 18.
Dehydration with 2.29g of CUSO4/
cyclohexane gave 0.80g (2 - butyl - 1, 3 - cyclohexadiene) as a clear oil 57 %
yield total yield for both steps.
%
GC-MS M /Z- 136 {M% 121, 107, 91, 79
A.3. Synthesis of 1-vinyi-1 -cyciohexene:
1.0 g (10.4 mmo!) of cydohexenone in 20 m l of anhydrous ether was
reacted with 10.4 m l of viny! magnesium bromide 1.0M. The intermediate 1-
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38
v!nyl-1-cydohexene-1-oi 19 was isoiated, without further purification, dehydration
was accomplished with 1.98g of copper suifate penta hydrate in according to the
dehydration genera! procedure in cyclohexane gave 1-vinyi-1-cyclohexe W.
The product was identified by GC-MS, and recovered in 48 % yieid.
GC-MS: m/ 2 = 108{M l, 91,79,77
A.4. Synthesis o f S^methyl-S-lsopropenyi-l ,3-cyciohexadiene:
To 1.0 g (6.6 mmo!) of R- carvone in ethanol was added 2.45 g Cerium
(II!) Chloride and 0.25 g sodium borohydride.
The color changed within 3
minutes from milky coior to brown color then it was allowed to reflux for 20
minutes. GO - MS and TLC was indicated the completeness .of the reaction.
Showing the formation of two products with molecular weights 152 and 154
indicating the reduction of the carbonyl and reduction of both carbonyl and the
double bond. Work up with, water and extraction with ether gave a yellowish
liquid. Dehydration using copper sulfate procedure provided 0.77g (87.5) % yield
of yellowish liquid, of 3-methyl-5-isopreopenyi-1,3-cydohexadiene 21,
Mass Spec. ^ = 1 3 4 , 109, 84, 69,55.
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39
B. Diels - Aider reaction of 2,5-dimethvl furan 1 under microwave
2,5-Dimethyl furan 1 and acetylenic dienophiies
Acetylenic dienophiies: (i) Diethyiacetyiene dicarboxylate (DEAD) 6
(i!) Ethyi Propioiate (EP) 7
B.1: Reaction of 2,5-dimethylfuran 1 with Diethyiacetyiene dicarboxylate;
0.10 g (1.0 mmo!) of 1 and DEAD 6 G.18g (1.1 mmo!) were placed in a
borosilicate vial. The vial was capped with a Teflon lined cap, then placed in the
microwave oven, and irradiated for 10 minutes. The product was analyzed on the
GC-MS to show the formation diethyl-2,5-dimethy!-3,4-furandicarboxylate 22,
Flash chromatography of the product on 20 g silica gel using 1:1 ether pet. ether,
provided
2,5-d imethyi-3,4-fu rand icarboxylate.
0.24g
of
purified
22
was
recovered as coiorless oil (96% yield). Mass Spectrum: M/Z (M+) = 240, 194,
167, 166, 150, 138, 121,79.
The minor product, the adduct 23 GC-MS; 266 {M
^
), 251,240, 221, 194,
178, 166, 150, 133, 121, 96.
B.2. Reaction of 2,5-Dimethylfuran with ethyi Propiolate:
0.3g (3.1 mmol) of 1and 0.3g ethyl propioiate (3.1 mmol) and .066g Cerium
(ill) chloride were heated according to the general procedure for 30 minutes. The
mixture turned dark. The product was flash chromatographed on silica gel eluted
with ethyi acetate: petroleum ether 3:7 v:v. 0.43 g of coiorless liquid was obtained
82% Yield of ethy!-3-furancarboxylate 24.
Mass spectrum: M/Z= 168 (m+), 153, 139, 123, 95,
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40
IR neat (NaQ plates) 2,900 cm “ \ 1,700 cm
1200 cm
B.3. Reactions of 1 with 5-hexyn1-ol 9 propargyl alcohol 10, and diphenyl
acetylene :
Similar procedures were performed for the reaction of 1, with other acetylenic
dienophiies as 5-hexyne-1-o! 9, propargyl alcohol 10, diphenylacetylene, no
reaction was observed up to 20 minutes in the microwave. The decomposition of
the starting material indicated by the darkening of the reaction mixture, but
resulted with no formation of new products.
The starting materials were still
observed in the mixture when analyzed by GC- MS.
Reactions of 1 with olefinic dienophiies:
General procedure:
B.4. Reaction of 2,5-dinnethylfuran 1 with N-methyimaleimide 11:
Furan j_ 0.10 g
(1 mmo!) and 0.11 g N-methyl maieimide 1_1 (1 mmo!)
were mixed in a borosilicate vial, capped with Teflon lined cap. The mixture was
heated in the microwave for 20 minutes. A sample was taken and analyzed by
GC mass spec. The dehydrated product N-methyl-3,6-dimethy!phthalimide was
observed.
'k:
GC-MS: 189 {M
%174, 160, 146, 132, 117, 104, 91,77.
Reaction of 1 with other olefinic dienophiies as maieic anhydride 12,
diethyifumarate 13, dimethylmaleate 14 , benzoquinone 15, p-nitrostyrene 16,
1,2-dibenzoylethylene 17, according to the general procedure for up to 20
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41
minutes in the microwave were unproductive as indicated by the GC-MS analysis
of the reaction mixture.
The reactions were repeated in the presence of cerium (II!) chloride, the
reactions were futile too.
C. Diels- Alder Reactions of 2.4,5-Trimethvloxazole 2 w itli acetvienic
dienophiies:
C.1 Dieis-Alder reaction of 2,4,5-trimethyloxazole and DEAD 6:
According to the general procedure 0.10 g ( 0.9 mmol) of Trimethyioxazoie
2 and 0.15g (0.9 mmol) of diethyl acetylene dicarboxyfate 6 were irradiated in a
microwave oven for 5 minutes. The products were flash chromatographed on
silica gel eluted with petroleum ether and ethyl acetate 8:2 v: v. 0.17g of was
recovered of diethyl-3,4-furan dicarboxylate ^
78% yield.
M/Z (M+)= 240, 194,1165,166, 150, 138, 121.
IR=2983.3 cm \ 2935.9cm \ 1713.4cm \ 1593.6cm
14214cm \ 1310.2cm '
C.2 Reaction of 2,4,5-trimethyioxazoie 2 w ith ethylpropiolate 7:
O.lg (0.9 mmol) of 2, 4, 5 - rimethyioxazoie and .08g (0.9 mmol) of ethyl
propiolate 7 were placed in a borosilicate vial. The vial was capped with a Teflon
lined cap then piaced In the microwave oven and irradiated for 25 minutes GCMS results shows products formation but the reaction did not go to completion. A
fresh batch of same amount was weighed but excess ethyl propiolate and O.lg of
Cerium (ill) Chloride added and then microwave for 35 minutes. GC-MS results
indicate product formation. TLC and flash chromatograph was eluted with ethyl
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42
ether and petroleum ether 1:1 v;v,; G.07g of ethyl-3-furancarboxy!ate M , 47%
yield.
M/Z (m+)= 168
153, 139, 123, 111, 97. 67, 53.
IR=2982.6cm 7 1720.6cm \ 1369cm \ 1242.8cm ■
C.3 , Dieis-Alder reaction of Trimethyioxazoie with oiefinic dienophiies:
General procedure:
According to the general procedure .05g of Trimethyloxazole and .05g N™
methyimaieimide H were piaced in a borosilicate vial and capped with a Teflon
lined cap, then placed in the microwave oven, irradiated for 5 and 15 minutes.
Excess 2 was added and microwave for additional 20 minutes. The product was
analyzed on the GC -- MS to show the product TLC and flash chromatography
was conducted on silica gel eluted with petroleum ether and ethyl acetate 1:1, v.v
0.02g of solid yellowish color products was recovered. (42% yield). Traces of a
minor product as the oxabicyclic adduct 25, M/Z: (m+) = 222(M'"), 191, 163, 150,
137,
110,
and
the
major
product
N-methy!-2,5,6-tnmethy-pyridine-3,4-
dicarbxylimide 26, M/Z = 2 0 4 ,1 7 5 ,1 6 1 ,1 4 7 .
IR = 3350 cm "7 2981 cm
C.4
1720 cm
1445 cm
1369 cm
1242 cm
Reaction of trimethyloxazoie 2 with maieic anhydride 12:
0.16g (1.4 mmol) of 2,4,5 - trimethyloxazole 2 and 0.14g(1.45 mmol) of
maieic anhydride 12 were heated in the microwave in a borosilicate vial for 1
minute. Trace amount of product was obtained in 13% yield, as decomposition
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43
was observed. This resuited in the dehydrated product or 2,5,6-trimethy!-3,4pyridine dicraboxyfic anhydride
GC-MS; 1ST 177, 163, 147,m 91, 78.
1 .3 -D ie n e s reactions
D. Dieis-Atder reactions of 2-trimethvlsiivloxv-i .3-diene 3:
D.1; 2-trimethylsilyloxy-1,3-diene
3 + diethyl
acetylene
dicarboxylate
(DEAD) 6
0.30 g (1.8 mmol) of 3 and 0.3 (1.8 mmol) of DEAD 6 was placed in
borosilicate vial and capped with a Teflon lined cap, then heated in a microwave
for 5 minutes. TLC and flash chromatography gave 0.25g of diethyl 4trimethylsilyloxyphthalate 2
B
. (45% yield).
treatment with THE/ HOI (aqueous).
The product was hydrolyzed by
Flash chromatography gave 4-hydroxy-
diethyfphthalate 29 in 73% yield.
GC-MS: 238 (M^), 210, 193, 191, 165, 151, 137, 121, 109, 92, 63
0.2: 1,3 - Dlene (TMSO) + Ethyl Propiolate (EPP)
0.3 (I.Smmol) of 1,3 - TMSO 3 and 0.18 (0.18 mmol) of EPP 7 were
placed in borosilicate vial, capped with a Teflon lined cap and heated in a
microwave oven for ISminutes.
Then work up with HCI/ THF, the isolated
%
product was subjected to flash chromatography of the reaction mixture using 8:2
petroleum ether: ether gave 0.2g of products liquid that solidified on setting. 50%
yield. This resulted as a mixture of two products 5:95 of 3-hydroxy-ethylbenzoate
30 and 4-hydroxy ethyl benzoate 31.
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44
3-hydroxy-ethylbenzoate 30, GC- MS: m/z = 166 (H'f), 151, 138, 121, 107, 93,
81, 65, and 4-hydroxy-ethylbenzoate 31 m/z=
151, 138, 121, 10S, 93,
81, 65.
Reaction of 2-Trimethy!silyloxy1,3-dlene 3 with oiefinic dienophiie:
D.3: 2-trimethyisilyloxy1,3-diene 3 with N - Methylmaleimide (NMMA) H
0.3g
(I.Smmol) of 3 and 0.19 (I.Smmol) of NMMA were placed in
borosilicate vial and capped with a Teflon lined cap and then microwaved for 15
minutes. 6M of hydrochloric add and 20ml of tetrahydrofuran were added and
allowed to
stir for
15 minutes.
GC -
MS was
conducted
and flash
chromatography resulted in a O.GOg of the adduct 32 recovered with 41% yield.
GC-MS of ^
: 2 0 7 (M i 189, 179, 164, 151, 138, 113, 110, 94, 80, 79. 66, 55.
E. Dieis-Alder reaction o f 2 -- b u tyl-1,3 - cvcohexadiene 4 and acetyienic
dienophiies
E.1:
2 - buty! - 1,3 - Cyclohexadiene 4 + DEAD 6:
0.05(0.35mmo!) of 2 -
butyl -
1,3 -
cydohexadiene 4 and 0.06 (
0.35mmol) of DEAD were placed in a borosilicate vial and capped with a Teflon
cap and then heated in a microwave for 5, 10, 30 minutes. Excess DEAD was
added and the color turned black. GC - MS results indicate products formed, the
adduct
and the retro duels-Alder product 34, 3-butyl-diethyiphtalate,
Adduct 33: M/z= 306{M*), 281,278, 250, 233, 221,205, 177, 162, 149, 133, 106,
91, 77.
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45
GC»yS of 3»butylphthalate 34 = 278 (M% 249, 232, 217, 205, 185, 175, 158,
131, 105,91, 77=
E. 2
2 - Butyl - 1,3 - Cyclohexadiene 4_ and N - Methylmaleimide H
O.OSg (0.36mmol) of 2 ~ Butyl ~ 1,3 - cyclohexadiene and 0.04g (0.36
mmol) of NMMA 11, were placed in a borosilicate vial and capped with a Teflon
via!. It was then heated in the microwave oven for 5 minutes, according to
genera! procedure GC -- MS results obtained indicate the adduct 35 formed in
low yield.
GC-MS of 35; 247(M^), 205, 177, 136, 113, 91,79.
F.
Dieis-Alder reaction of 2 -
Butvl-4-methvl-6-isopropylene- 1.3 -
Cyclohexadiene 5 with acetyienic dienophiies
F.1
2 - Buty! -6 -is o p ro p y !e n e -1,3 - Cyclohexadiene + DEAD 6
0.15
(0.075mmol)
of
2-Butyl-4-methyl-6-isopropylene-1,3-
Cydohexadiene and 0.13g (0.075mmo!) DEAD were piaced in borosificate vial
and then capped with a Teflon lined cap and heated in microwave oven for 20
minutes according to the genera! procedure. TLC and GC - MS was conducted.
The product was flash chromatographed using petroleum ether and ethyl ether
8:2 v: v. 0.17g of products was recovered and resulted in 57% yield of diethyl- 4%
buty!-6-methyl-phtha!ate 36, GC-MS : m/z = 292, 264, 274, 219, 191, 176, 147,
120, 103, 91, and minor component the adduct 37 m/z= 360(M‘"), 314, 287, 286,
257, 240, 213, 183, 175, 157, 131,9 1,77 , 55.
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46
F.2:
2 - Butyl 4-methyl-6-isopropylene- 1,3 - Cyclohexadiene 5 + EPP 7
According to the genera! procedure, TLC and G C - MS show no reaction
and no products are obtained after 20 minutes of microwave irradiation.
2 -- Butyl 4-methyi-6-isoprop¥iene-- 1.3 ~ Cyclohexadiene + Oiefinic
dienophiies
F.3
2 - ButyI-4-fT!ethyl-6-isopropylene-1,3-Cyclohexadlene 5 + NMMA 11:
0.15g (0.075 mmol) of 5 and 0.09g (O.OSmmo!) of NMMA H was placed in
borosilicate via! and capped with a Teflon cap and then heated in a microwave
for 5 minutes. TLC and GC - MS indicates product formation. The product was
flash chromatographed on silica gel eluted with Petroleum ether and ethyi ether:
8:2 v: v 0.23g of the adduct 38 was obtained, 100% yield.
GC- MS of 38: m/z= 301,258, 191, 175,148, 119, 105, 91, 77.
F.4
2 -b u tyl- 1,3 - Cyclohexadiene + maieic anhydride
O.iSg (0.11 mmol) of 4 and .09g (0.09 mmol) of maieic anhydride 12 was
piaced in borosilicate vial and capped with a Teflon cap and then heated in a
microwave for 5 minutes. TLC and GC - MS indicates productformed. The
product was flash chromatographed on silica gel eluted with Petroleum ether and
ethy! ether: 8:2 v: v. The adduct 3 was recovered.
GC-MS: 232(M+), 204, 159, 158, 115, 92. 68.
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47
CONCLUSIONS
This work has established the feasibility of the 4-^2 cycloaddition reactions,
i.e. Diels-Alder reaction of furans, oxazoies, 1,3-cyclohexaienes with oiefinic and
acetyienic dienophiies under microwave conditions within minutes opposed to
hours and days under conventional heating.
2,5-dimethyl furan and 2,4,5-trimethy! oxazole reacted with acetyienic
dienophiies as diethyl acetylene dicarboxylate and ethyl propiolate to provide the
adducts that underwent retro Diels Alder reaction to give diethyl 2,5-furan
dicarboxylate in good yields by the loss of acetylene or acetonitrile.
The
cycloaddition with oiefinic dienophiie provides the adducts which can dehydrate
to produce aromatic compounds in the case of furan or substituted pyridine in the
case of oxazoies. The microwave heating was efficient in terms of time reduction
and enhanced yields, and the ease of reaction work up under neat reaction
conditions.
1,3-cyciohexadienes also afforded the cycloaddition products as
intermediates in the reaction of acetyienic dienophiies, which lead to substituted
benzene upon the loss of ethylene or isoprene in the retro Dieis-Alder reactions.
%
Yields were high and the time was short.
Anhydrous copper sulfate can serve as a mild efficient dehydrating agent
for tertiary alcohols.
Allylic alcohols can dehydrated to give 1,3-dienes.
The
reaction was not regiospecific as a mixture of two isomeric dienes can be
obtained. This is the first use of copper sulfate in dehydrating alcohols for the
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48
synthesis of dienes, as the method required very high temperature for
dehydration.
The process is very mild and avoids the destruction of sensitive
functionalities in the product as sulfuric acid. The dienes are stable under these
conditions.
Finally this work shows the efficiency of applying microwaves in DieisAlder reaction, to provide substituted furans, pyridines, and benzenes under neat
condition, in very short reaction time and in good yields.
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49
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