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Chemical Technology: Microwave Assisted Continuous-flow OrganicSynthesis (MACOS) and its use in Azide Chemistry

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Chemical Technology: Microwave Assisted Continuous-flow Organic
Synthesis (MACOS) and its use in Azide Chemistry
Mario Orestano
A thesis submitted to the Faculty of Graduate Studies in
partial fulfillment of the requirements
for the degree of
Master of Science
Graduate Program in Chemistry
York University
Toronto, Ontario
August 2010
???
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Chemical Technology: Microwave Assisted Continuous-flow
Organic Synthesis (MACOS) and its use in Azide Chemistry
By Mario Orestano
A thesis submitted to the Faculty of Graduate Studies of York
University in partial fulfillment of the requirements for
the degree of
MASTER OF SCIENCE
© 2010
Permission has been granted to: a) YORK UNIVERSITY LIBRARIES
to lend or sell copies of this dissertation in paper, microform or
electronic formats, and b) LIBRARY AND ARCHIVES CANADA to
reproduce, lend, distribute, or sell copies of this dissertation
anywhere in the world in microform, paper or electronic formats
arid to authorize or procure the reproduction, loan, distribution or
sale of copies of this dissertation anywhere in the world in micro-
form, paper or electronic formats.
The author reserves other publication rights, and neither the
dissertation nor extensive extracts from it may be printed or
otherwise reproduced without the author's written permission.
ABSTRACT
Azides offer a rich diversity of chemistry, and their use is becoming prevalent
especially in the pharmaceutical industry. Unfortunately their use is limited because
azides are highly unstable and extremely toxic.
The growing use of azide
functionality stresses the importance of having a safe, and scalable method which
azides can be readily accessed. Recent technological advances have introduced two
new tools to chemistry, those being microwave and microfiuidic flow technology.
Each of the new technologies offers its own unique advantages and in an attempt to
harness the individual benefits of both technologies into one unit a new technology
has been developed; Microwave Assisted Continuous-flow Organic Synthesis
(MACOS). Using MACOS a safe and scalable method was developed to synthesize
organic azides and use them in both Schmidt and triazole chemistry. Three lactam
products have been achieved in good yield, including one example in gram quantities.
Further, the foundation has been set for reaction optimization of poly azide use with
the isolation of a bis-triazole compound.
IV
DEDICATION
There is not one thing more important in my life than my family. This thesis is
dedicated to my parents Angelo and Maria for all their love and support through out
my education. I would also like to thank Diana, who has taught me more than she
knows. Lastly, I would like to thank my nonni, it was them who made me the person
I am today—they taught me what education cannot.
V
ACKNOWLEDGEMENTS
I would like to thank: my supervisor Prof. Organ for all his support in the lab, my
collaborators at the University of Kansas-CMLD unit in particular Prof. Aube. Dr.
Hunter for all his spectroscopy help, my committee members, and finally all my
colleagues for their advice, laughter, and support.
VI
Table of Contents
List of Tables
VIII
List of Figures
IX
List of Schemes
X
List of Abbreviations
Chapter 1
XI
1
1 .0 Introduction
1.1 Microwaves
2
2
1.2 Dielectric Heating of Microwaves
1.3 Microwaves and Chemistry
1 .4 Microfluidic Flow Technology
4
6
8
1.4.1 Microreactors
10
1.5 Microwave Assisted Continuous-flow Organic Synthesis (MACOS)
12
1.6Azides
14
1.7 Schmidt Chemistry
1.8 Triazole Chemistry
1.9 Plan of Study
16
18
19
Chapter II
22
2.1 Azide Stability
23
2.2 Intramolecular Schmidt Reaction on six-member rings
2.3 Intramolecular Schmidt Reaction on a seven-member ring
2.4 Intramolecular Schmidt Reaction on five-member rings
24
32
36
2.5 Acyclic Variation
38
Chapter III
41
3.0 Bis-Azide Extension
42
3.1 Optimization of Triazole Chemistry
3.2 Synthesis ofregioselective triazoles
3.3 MACOS-Batch efficacy comparison
42
44
46
Chapter IV
49
4.1 Experimental
4.2 Appendices
51
61
4.3 References
71
2.0 Results and Discussion
2.6 Scale-Out
4.0 Conclusion
23
39
50
List of Tables
Table 1: Heating rates using a 2-D coupled electromagnetic-thermal model
14
Table 2: Optimization of formation of azide 3 using MACOS
24
Table 3: Multistep flow for the formation of lactam 4 using MACOS
26
Table 4: Multistep flow using MACOS for the formation of lactam 7
28
Table 5: MACOS optimization for formation of lactam 13
31
Table 6: Reaction optimization for compound 36
33
Table 7: Multistep flow using MACOS for compound 18
34
Table 8: Multistep flow using MACOS for formation of lactam 21
36
Table 9: Multistep flow using MACOS for pyrrolidine formation
38
Table 10: Multistep flow using MACOS to form non-regioselective bis-triazole.... 43
Table 11: Selectivity determination in different solvents using a batch microwave 44
Table 12: Regioselective triazole formation using MACOS
46
VIII
List of Figures
Figure 1: Electromagnetic spectrum
3
Figure 2: An example of a microreactor
10
Figure 3: Schematic and actual representation of a microfluidic setup
10
Figure 4: Comparison of a schematic diagram and the actual setup of MACOS
13
Figure 5: Microreactor containing two tubes housed in a microwave chamber
21
Figure 6: The transition state ofbond breaking in the intramolecular-Schmidt
reaction
29
Figure 7: Phenyl ring stabilizing through space the sigma orbitals of the migrating
Bond
:
.'
.'29
Figure 8: Charring and rupturing of the microreactor during lactam 21 formation.. 37
Figure 9: Melted 1700 µ?? (I.D.) borosilicate tubes with a thin Cu-film on the inner
all
Figure 10: A screen shot displaying the temperature range of an alumina oxide
tube
43
47
Figure 11: 1H-NMR spectrum comparison of a reaction done in batch vs MACOS 48
IX
List of Schemes
Scheme 1: Description of the mesomeric structures of the azide functional group ..15
Scheme 2: Generic Schmidt reaction
16
Scheme 3: Generalized reaction sequence of the intramolecular Schmidt reaction.. 17
Scheme 4: Triazole formation done in the absence of a copper source
18
Scheme 5: Catalytic cycle for the regioselective synthesis of 1 ,4-triazoles
18
Scheme 6: An example of a regioselective bis-triazole reaction
20
Scheme 7: An example of an intramolecular Schmidt reaction
20
Scheme 8: Azide formation under extended microwave irradiation
23
Scheme 9: Attempted trapping of aziridine intermediate
24
Scheme 10: Formation of lactam 10 using MACOS
30
Scheme 11: Unoptimized batch conditions for formation ofbicyclic lactam 13
30
Scheme 12: Multistep flow using MACOS for lactam 13
32
Scheme 13: Synthesis of starting material and desire lactam 18
33
Scheme 14: General transformations to reach desired product 24
38
Scheme 15: An example of a scale out reaction producing 1.1 g of compound 4 in
71% yield
40
X
List of Abbrevations
MACOS: Microwave Assisted Continuous-flow Organic Synthesis
ISM: Industrial Scientific Medical
PEEK: Polyether Ether Ketone
LA: Lewis Acid
I.D.: Internal Diameter
TFA: Trifluoroacetic acid
1H-NMR: Proton Nuclear Magnetic Resonance
DMF: 7V,7V-Dimethylformamide
DMSO: Dimethyl Sulfoxide
MeCN: Acetonitrile
DCM: Dichloromethane
IPA: Isopropyl alcohol
nBuLi: iV-Butyllithium
Et: Ethyl
Me: Methyl
r.t.: Room Temperature
LR.: Infrared
Chapter I
?
1.0 Introduction
The field of chemistry has been primarily directed by the development of new
chemical transformations and chemical reagents. Despite these novel discoveries the
tools used for chemical synthesis have changed very little since their inception
(flasks, beakers, heating mantle, oil bath, etc...)· Recently, there is a gaining interest
in developing new technologies to serve as tools to conduct chemical synthesis. It is
envisioned, that the development of new technologies can create unique reaction
conditions to overcome limitations facing current techniques, such as rapid chemical
optimization, scale up, and the safe implementation of highly exothermic reactions.
Presently, the two most prominent technologies being developed are microwave and
microfluidic flow technology.
1.1 Microwaves
Microwaves are electromagnetic waves consisting of wavelengths of 1 cm to
1 m, with frequencies of 30 GHz to 300 MHz, and are situated between radio and
infrared electromagnetic waves in the electromagnetic spectrum. The energy that
microwaves possess can be determined qualitatively by its position in the
electromagnetic spectrum (see Figure 1) relative to other sources of radiation or
quantitatively by using the relationship, given in equation I.1 '
2
Wavelength (m«)
400
!450 500
600
550
700
Violet] Blue Green Yellow Orange !Red
•s
CB
e
e
co
O
9>
S
I
'> ¿1
?
t-
C-I—G T—»7G?
IO"'- 10,-io W
10
..
?*
io*
?—t<?·4
io-*
T
KT
Wavelength (meters)
1 nm
1 um
1 cm
Long Radio
Waves
<
t—?—G-t—G-1—!
1
102
10"
10b
1km
Figure 1. A diagram of the electromagnetic spectrum, including wavelengths.
E= hv
(1)
E= Energy
h= Planck's Constant
v= frequency
Microwaves are used in a variety of applications including cooking (domestic
microwave ovens), telecommunications, and industrial processing where heat is
necessary.^"43 The wide use ofmicrowaves created specified bands (according to use)
to avoid interference for scientific research and development; The ISM band
(Industrial, Scientific, and Medical band) has set microwave frequencies of 915 MHz
and 2.45 GHz and laboratory scale microwaves dedicated to chemical synthesis
operate at 2.45 GHz.[2,5]
3
1.2 Dielectric Heating of Microwaves
The energy supplied by microwaves is too low to cleave chemical bonds and
therefore it cannot promote chemical reactions by direct absorption of
electromagnetic irradiation.2 For chemical synthesis it is the efficient heating
capabilities of microwaves that have attracted their use in laboratories. Microwaves
heat by a method called dielectric heating and it comes in two forms, ionic and
dipolar polarization.
In the absence of microwaves, molecules in solution can undertake any
orientation and maintain a random distribution of collisions. Under microwave
irradiation, the applied electric field causes molecules with a significant dipole to
undergo a torque that attempts to align the molecule parallel to the electric field. As
the electric field oscillates it does so faster (ca. 10"12 s) than what the molecules can
perfectly align themselves parallel to the electric component of the electromagnetic
wave.1 For this reason there is a slight lag between the orientation of the molecules in
solution and the electric component of the microwave. This causes the molecules to
rotate in solution resulting in molecular friction. Molecular friction is the cause of
heating in dipolar polarization.2 Ionic polarization behaves in a similar manner, with
the exception that ions oscillate under microwave irradiation and the increased
frequency of collisions between the ions and the matrix is what causes the heating
effect. In general ionic polarization heating is more efficient than dipolar polarization
heating.2 The principle of dielectric heating of microwaves can be described
4
quantitatively by the loss tangent (tan d) factor. The value of tan d is related by
equation 2.
(2)
E" = dielectric loss
F = dielectric constant
tan d = Loss tan factor
E" describes the efficiency of material to convert microwave irradiation into heat and
E' is related to how well molecules align themselves in an electric field. The larger
the loss tan d value, the more efficient the material will be at generating heat. Tan d
values > 0.5 are high efficiency, tan d values 0.1-0.5 are medium, and tan d values <
0.1 are low and considered to be microwave transparent.4 Many common organic
solvents fall under low tan d values including benzene, toluene, dichloromethane, and
acetone. Although these solvents are microwave transparent this does not exclude
their use in microwave applications. The addition of highly polar reagents or
catalysts can facilitate microwave absorption; further the addition of high tan d value
solvents as an additive can be introduced to allow an acceptable amount of
microwave heating.
5
1.3 Microwaves and Chemistry
Microwave chemistry began in the late 1980' s using domestic microwave
ovens as the source of microwave radiation. Unfortunately domestic microwaves
were ill suited to conduct chemistry as they lacked stirring, pressure control,
homogeneity of the microwave field, and had poor reproducibility. Further, the lack
of safety features often resulted in violent explosions creating an unsafe working
environment for scientists. In the mid-1990's dedicated laboratory-scale microwaves
were introduced offering the components necessary to conduct chemistry in a safe
and reproducible manner. Since its inception, microwave chemistry has grown in
popularity and in 2007 alone there were over 1100 published manuscripts where
microwaves were used to perform organic synthesis.2 The advantages that is offered
in using microwave synthesis is reduced reaction times, higher yields, and increased
purity.2
The advantages offered in microwave synthesis were thought to originate by
the microwave itself and was termed "non-thermal microwave effects".[2'6] The theory
of "non-thermal microwave effects" arose from altered product distributions and
yields when microwave reactions were run in comparison to an oil bath as the heat
source.6 These differences were later explained by showing inaccurate temperature
controls on the microwave unit. When accurate fiber optic probes were used to get a
temperature reading by directly immersing them in the reaction, the temperature
recorded by the microwaves IR sensor was found to be significantly higher. When the
new temperatures were replicated in an oil bath there was no difference in selectivity,
6
conversion, or yield.6 Today, scientists agree that "non-thermal microwave effects"
do not exist and the enhanced reaction profiles observed in microwave synthesis stem
from the enhanced thermal and kinetic profiles resulting from the efficient heating by
microwave irradiation.2
Application of the Arrhenius equation can offer an
explanation to the rate enhancements ofmicrowave chemistry (see equation 3).
k = Ae
(3)
k= rate constant, Ea= Activation Energy
A= Arrhenius Constant, R= Gas Constant
T= Temperature
For example, applying equation 3 it can be calculated that a reaction that would take
68 days to achieve 90 % conversion at 27 °C would reach the same result in 1.61
seconds at 227 °C.4 In addition to thermally induced rate enhancements, the ability to
superheat solutions at above atmospheric pressure to achieve high temperatures
quickly and rapid air-jet cooling allows for a narrower reaction temperature band.
This eliminates wall effects caused by inverted temperature gradients allowing for
minimal product distributions, resulting in increased purity.[2'4]
7
1.4 Microfluidic Flow Technology
The development of new chemical technologies is growing and in the last
decade microfluidic flow technology has emerged as a powerful tool in chemistry.
Microfluidic flow technology is best described as the continuous processing of
chemical reactions in well defined channels.
The channels are housed in a
microreactor, and the interior diameter of the channels typically range from 10 µp? to
several millimeters. Chemistry performed in microfluidic channels is associated with
many benefits such as, the efficient mixing of reactions, rapid optimization, ease of
scale up, and the safe use ofhigh energy reactions and molecules.[ "
In batch reactors mixing is controlled by stirring either by a stir bar or an
impeller.8 It was found that the majority of mixing occurs only near the source of
stirring, and the farther away from the stirrer little to no mixing occurs. These poorly
mixed spots can be a source of lower selectivity, diminished yield, and increase
chemical waste.8 However, in microfluidics the small cross sectional area of the
reaction channels makes mixing by diffusion possible (In situations where laminar
flow do not dominate). This leads to complete mixing of reagents in seconds leading
to better control over reaction conditions and as a result higher purity, yield,
selectivity and less waste.8 Moreover, the optimization of chemical reactions in flow
is economical, since smaller volumes of solution are used to find optimal
conditions.[79] The ability to develop 'smart systems' that have built in analytics that
monitor in real time can control reaction parameters until optimal reaction
performance is observed. This facilitates automation, and to conduct chemical
8
transformations unassisted.17"91 Particularly attractive for industry is the ease of scale
up to produce more desired product without the safety concerns presented by batch
reactors. In microfluidics a reaction optimized to produce milligram quantities can be
used to make gram or even kilogram quantities by simply flowing for a longer period
of time or running several reactions in parallel, a technique termed numbering up or
scaling out.10 The simplicity of making more material has attracted industry as it
removes the financial risk from failure as chemistry translates from research lab to
pilot plant and finally manufacturing.7 In fact the concept of numbering up for large
scale manufacturing is in use, Merck produces vitamin H using 5 mini-reactors with
a continuous recovery of material greater than 92 %.
The increased heat transfer in microfluidic flow chemistry makes it a useful
tool for highly exothermic reactions. Since the reactants are brought together in
smaller volumes than what is found in batch type reactors the reaction can be rapidly
cooled and controlled.8 This offers access to safely conduct chemical reactions with
large exotherms. Further, microfluidic flow chemistry offers access to the use of
high-energy intermediates that are unstable and possibly toxic. The use of azides is
limited due to the dangers they pose, but microfluidic flow offers a method of
reacting azides in a safe and controllable manner. More specifically, the use of small
reaction volumes and the continuous movement of material coupled with enhanced
rates of reactions ensures that a large concentration of azide will not accumulate.
9
1.4.1 Microreactors
Microreactors are composed of a network of capillaries that range in internal
volumes from µ? to several litres, they are constructed of many different types of
materials such as glass, silicon, ceramics, metals, and range in different geometries
and structure.[9'12] Each material used in microreactor technology offers its own
unique advantage, and there is no universally applied material for all microreactors.
Glass, is a popular choice for microreactors because it is inexpensive, easily
functionalized, inert, and allows for visible inspection of reactions.[9,13] Silicon has
similar advantages to glass, as oxidized silicon is also chemically inert, but it also
displays enhanced thermal transfer rates. For this reason silicon is an excellent choice
for constructing microreactors that contain reactions with large exotherms. Stainless
steel is often used in large scale batch reactors and microreactors constructed for
larger scale purposes have also been produced out of stainless steel. These
microreactors are of interest to pilot plants and fine chemical applications. There are
many types of geometries and structures used in microreactor construction,
particularly because the construction of microreactors is easy and their specifications
are customized to suite the reaction needs (Figure 2 & 3).
10
ELiCT RODES
•S3LICON
<&*
GELCHANNELS
PHOTODETECTORS
VMlRE 6ON DS
HEATERS
TEMPERATUBE
DETECTORS
FLUIDIC CHANNELS
A!R VENTS
Figure 2. An example of a microreactor used in microfluidic flow chemistry.
14
Monitoring Unit
Pressure]
Temperature
----—·
control
Reagenti
Reagent?
¦tei Micro
<x>M
Product
reactor
Thermobath
Figure 3. A) Left, a schematic of a microfluidic flow chemistry setup. B) Right, a picture of a
customized glass reactor.15
The movement of material through the microreactor is also another critical
consideration and two main methods exist, hydrodynamic pumping and
electrokinetically-driven systems.13 The simplest, and by far the most used is
hydrodynamic pumping. A range of pumping sources exist and range in complexity
from simple screw-driven syringe pumps to fully computerized pumps such as
Syrris™ flow pumps. Syrris™ pumps offer high precision, the ability to work 24
hours, remote control, and continuous flow capabilities.16 Electrokinetically-driven
11
systems is an emerging field, and involves the continuous movement of fluid through
a microreactor based on differences in electric potential. Electrodes are placed on the
flow unit and voltage levels are varied to control flow rate, mixing, and chemical
separation.13 The process can be computer-controlled, offers the advantages of inline
purification, and the elimination of an external pumping system. Unfortunately, the
use of electrokinetically-driven microreactors is limited to small volumes on the order
ofnL.13
1.5 Microwave Assisted Continuous-flow Organic Synthesis (MACOS)
MACOS combines the efficient heating of microwaves with the advantages of
flow technology. The MACOS setup is simple and consists of a microreactor
consisting of a stainless steel mixing chamber with PEEK™ fittings to adjoin small
diameter borosilicate tubes. The tube resides in the microwave chamber of a modified
Biotage Initiator™ and can be irradiated from 1-400 W of power (Figure 4). The
pumping system consists of a dual port Harvard™ screw-driven syringe pump that
allows for flow rates from µ?/p?? to L/hours.
12
Reagent Leads from
V iinge Pump
^^
^
y\
?
Stainless Steel
M
^Ps
Vl ¡xing Chamber
withMaciinec ^\
Cticiririul
Microtijht™
D
Fittings
--"^5SSH
Micro/uave
Microwave
Chamber
Char ber
?
Glass Reaction
Microwave
Capillary
D
-Q-^- Va Kre
Cahmber
\
To co lection
1S.
V
"^
J
Figure 4. A comparison of a schematic diagram (left) and the actual setup (right) of the
MACOS setup.
In MACOS the use of metal-coated capillaries offer enhanced reaction rates
because of their ability to achieve high temperatures, and simultaneously act as a
catalyst.
Microwave-metal interaction/absorption is different than non-metal
microwave interactions because metals have free electrons that are able to couple
with the electric portion of the electromagnetic wave and create eddy currents. Eddy
currents are localized electrical conduction, and they are able to generate hot spots on
the metal films. These hot spots can reach temperatures in excess of 700 0C within
minutes (see Table 1).
17
13
Metal
Temp. (0C)
Al
Cu
Fe
577
697
228
6
3
7
96.2
232.3
109.7
78
4.5
17.3
Al2O3
CuO
1012
Time (min.)
625
Rate (°C/min)
161.9
Table 1 . Heating rates using a 2-D coupled electromagnetic-thermal
model.17
Further, if the thin film is paramagnetic it will also interact with the magnetic portion
of the electromagnetic wave, although the effects of magnetic interactions are not
known for organic chemistry.17 Aside from the rapid heating of metal films, they also
possess the ability to serve as a catalyst for a given reaction. This has been
demonstrated and metal films in MACOS have been used to catalyze Heck
reactions,18 Suzuki-Miyaura coupling,19 Diels-Alder,20 indole synthesis,21
hydrosilylation of alkynes,22 benzannulation reactions,23 and propargyl amine
synthesis.24
1.6 Azides
The first synthesis of an organic azide was the synthesis of phenyl azide by
Peter Grieb in 1864, but it was not until the 1950's and 1960's did azides find wide-
spread use in organic chemistry in the form of acyl, aryl, and alkyl azides. Presently
azides are most notably used in the formation of nitrogen-containing heterocycles,
and their use in industry is increasing, including applications in pharmaceutical
14
discovery, airbags, detonators, and blowing agents.25 Azides are highly unstable
functional groups and can decompose rapidly on the smallest input of external
energy. Further, their high toxicity has caused an irrational fear of azide chemistry,
that Professor Sharpless has called "azidophobia".[25'26] Despite their inherent
instability and toxicity azides are a versatile functional group and provide a rich array
of chemistry.
Azides consist of three nitrogens covalently bonded together in a linear
fashion. They exist in four mesomeric structures (Scheme 1), and most of the
chemistry involving azides can be explained using these structures.
+ -
- +
+
R-N=N-N ¦*—»» R-N=N=N -«—»-R-N-???-«—*- R-N-N=N
R-N3 =
1
1a
1b
1c
1d
25
Scheme 1. Mesomeric structures of the azide functional group.
Using methyl azide as a model substrate azide bond angles and lengths have been
calculated. Azide bond angles were determined to be 115.2° (R-N^N2) and 172.5°
(R-N2-N3). Therefore, an almost linear moiety exists with sp2 hybridization at N1.
Bond lengths, were determined to be 1.472 À (R-N1), 1.244 À (N'-N2), 1.162 À (N2N3).25
Synthesis of organic azides is primarily done through addition, substitution,
diazo transfer, diazotization, and cleavage of triazines.25 In order to construct an
15
organic azide molecule with enough stability to perform further transformations the
general equation 4 should be followed:
(Nc+N0)
(4)
Nn
Nc = Number of Carbons
N0 = Number of Oxygens
Nn= Number ofNitrogens
Organic azide molecules in agreement with the equation are safe to work with, but
prudent handling methods should always follow
27
1.7 Schmidt Chemistry
In general the Schmidt reaction is the addition of hydrazoic acid to a carbonyl,
followed by elimination of nitrogen gas and subsequent amide formation (Scheme
2).28 The utility of this reaction has caused a rapid expansion in the scope of Schmidttype chemistry, and a diverse range of reaction conditions exist.
o
O N3
R
HN,
Rv>C
HN
N2
R
?
Scheme 2. A generic Schmidt reaction.
16
The intramolecular variation proceeds with out the use of hydrazoic acid and uses an
organic azide molecule. After the formation of the organic azide, the azide moiety
loses most of its nucleophilicity but retains some dipolar character, that can be
rationalized by reviewing its mesomeric structures (Scheme 1).
LA
Cl
N3"
G?^?^?3 Lewis Acid
vAA
Scheme 3. A generalized reaction sequence of the intramolecular Schmidt reaction.
-N,
-CP1
The intramolecular Schmidt reaction has been established as a useful synthetic tool
and has also found value in total synthesis. It has been used as the key steps in the
total synthesis of (+)-aspidospermidine, (+)-sparteine, and the denrobatid alkaloid
indolizidine
28
1.8 Triazole Chemistry
Azides can undergo 1,3-dipolar cycloadditions in the presence of alkynes and
result in a 5-member heterocycle known as a triazole. Thermally induced dipolar
cycloadditions often lead to a mixture of regioisomers (see Scheme 3) and attempts to
control the regioselectivity of triazole formation have been achieved with varying
success.
26
17
R1-= + R2-N3
?-?„?2
\ .
XR1
?'?> r2
Ri
1:1 selectivity
Scheme 4. Triazole formation done in the absence of a copper source.
It was found that when the reaction is performed in the presence of copper (I), very
high levels of regioselectivity could be achieved.26 The proposed mechanism for the
use of copper (I) as a catalyst is shown in scheme 5.
R2-N,
Cu" + Ascorbic
Acid
1 ,4 Regioselectivity
N1
CuLn
Scheme 5. Catalytic cycle for the regioselective synthesis of 1 ,4-triazoles.26
The ease of triazole chemistry in the presence of copper (I) has led to the term
"click chemistry", which is a term given to reactions that are modular, wide in scope,
offer high yields, create benign byproducts, are stereospecific, require simple reaction
18
conditions, are achieved from readily available starting materials, use no solvent or
one that is benign, and give easily isolated products.
Click-chemistry is expanding rapidly and its use in chemistry is most
prominently seen in the development of pharmaceuticals including new HIV-drugs,
inhibitors for Alzheimer's disease, acetyl Cholinesterase inhibitors, neurogeneration
agents for Huntington's Disease, and drugs for oncogene-based human cancers.
30
1.9 Plan of Study
Azides offer a rich and diverse range of chemistry; unfortunately their use is
often avoided because of their instability and high toxicity. Given the increasing
importance of azide intermediates, access to these molecules would be useful in
synthetic chemistry. MACOS as a synthetic tool minimizes the dangers associated
with azide chemistry, and offers an avenue to explore azides. There are several
advantages to the MACOS system that are inherent to its setup. For instance the
ability to keep all starting reagents separate in sealed reactor units, and only bring
them together in small reaction volumes at the time of reaction, gives greater operator
control over azide production. Moreover the continuous movement of material,
coupled with the enhanced mixing and reaction rates ensures that a large
concentration of organic azide will never accumulate, essentially consuming any
azide as it is formed.
19
To investigate the ability to use MACOS as a synthetic tool for azide
chemistry two well-developed reactions were explored the intramolecular Schmidt
reaction, and triazole cycloaddition (Scheme 6 & 7).
?~?
CI^YY'CI N3" _ Ns^^V N3
Cu(I)
Scheme 6. An example of a regioselective bis-triazole reaction
nBu4NN3
Cl
? il
/^
\J
%
™_ Ap
Scheme 7. An example of an intramolecular Schmidt reaction
Both reactions can be considered two-step processes that proceed via an organic azide
intermediate (Scheme 6 & 7). The two-step process can be translated to MACOS
using a microreactor such as that depicted in figure 5.
20
C
i
à
à
iMicrowavel
IMicrowavel
Chamber
Chamber
JtD [ L
Ao
t1 t1 1I
A B
Product
Figure 5. A microreactor containing two tubes adjoined with PEEK™
fittings residing in a microwave chamber. Starting reagents are loaded
onto entry points A, B, and C. Product collection occurs at the exit
point labeled product.
Initial starting reagents would be connected at entry points A and B (Figure 5) and as
the starting reagents flow into the microwave chamber the formation of the
intermediate azide would be completed and only exist as a "transient" species in the
connecting loop between the two tubes. The organic azide would then immediately
mix with the third reagent C and the resulting mixture would be sent back down the
microwave chamber to complete the second step of the reaction resulting in the
desired product. Upon optimization of reaction conditions, an expansion of the scope
of the methodology will be developed to produce a library of compounds. To show
the scalability of MACOS with azides an example of gram quantity production of
lactam will be pursued.
21
Chapter II
22
2.0 Results and Discussion
2.1 Azide Stability
Azide chemical decomposition was an initial concern in testing Schmidt
chemistry under MACOS conditions; and azide stability was tested using model
substrate 3. Azide 3 was formed from chloride 2 under high temperatures using
extended microwave irradiation, and the good recovery of azide 3 signifies its thermal
stability.
O
DMSO
??^^a
nBU4NN31 hr. L J
1000C1
^^ 2
80 %
&-
Scheme 8. Azide formation under extended microwave irradiation
To further ensure the chemical stability of azide 3 it was flowed in MACOS in the
presence of neat TFA and at high power. The preferred method of chemical
decomposition for azides is through a nitrene mechanism. Nitrenes readily react with
elements of unsaturation to form aziridines. Flowing azide 3 in the presence of excess
TFA, and four equivalents of cyclohexene while using 100 W of microwave
23
O
4 equiv.
Scheme 9. Attempted trapping of aziridine intermediate. The solution was flowed at 10 µ?7p??
in excess TFA at 100 W of power.
irradiation produced no aziridine (Scheme 9) as determined by 1H-NMR
spectroscopy. Therefore, organo-azides appear to possess good stability to low pH
and high temperature conditions.
2.2 Intramolecular Schmidt Reaction on a Six-Membered Ring
To investigate formation of the intermediate azide using MACOS the initial
starting reagents were pre-mixed to avoid any poor mixing that may result due to
laminar flow.
24
AiBu4NN3^ f^V^^^Ng
Entry
1
2
3
4
5
2 (M)
0.6
0.6
1.0
2.0
3.0
Equiv. (N3:2)
% Conversion (3)a
1.3
1.5
1.0
1.0
1.0
74
80
100
100
100
Table 2. Optimiziation of azide formation in MACOS using
microreactor A (appendix A). DMF, 15 µ?,/????, under 5 atm
of air pressure.* Determined by 1H-NMR spectroscopy.
Initial reaction conditions attempted started at a modest concentration level of
compound 2 (0.6 M) but delivered only moderate success (Table 2, Entry 1).
Increasing the concentration of starting reagent 2 with a subsequent increase in azide
equivalent led to an increase in intermediate azide formation (Table 2, Entry 2).
Unfortunately the excess of azide source posed a safety concern and it was our goal to
reduce the quantity of azide. A reduction of azide to one equivalent with an overall
reaction mixture concentration of 1 M formed the desired azide 3 quantitatively, as
determined by 1H-NMR spectroscopy (Table 2, Entries 3-5). It was concluded that a
minimum of 1 M concentration was needed for azide intermediate 3 to form. There is
a practical consideration to observe in flow chemistry and that is the output ofproduct
per unit time; the higher the molarity of the initial solution the higher the output per
unit of time, and it was determined that the most practical solution to work with at
milligram scale was a 2 M solution. Above 2 M the volume of the reaction mixture
25
was low and resulted in a substantial amount of material being lost to the dead
volume of the microreactor.
With the first step elucidated, the second step of the reaction was optimized.
Using concentration and power values from the azide reaction optimization (Table 2)
excellent product formation was observed in the 1H-NMR spectra of a small sample
of reaction mixture, but poor recovery of desired lactam 4 resulted (Table 3, Entry 1).
HBu4NN3
O
TFA
JLn^
Cl
3
Entry
Ï
Solvent
Power (W)
DMF
400
DMSO
100
2
3
DMF
DMSO
5
6
7d
DMSO
Toluene
MeCN
4
4
(%) Conversion
[%Yield (4)]c
100 [30]
300
200
100 [41]
100 [41]
50
100
125
95 [52]
100 [65]
100 [71]
100 [39]
Table 3. Multistep flow for the formation of lactam 4 using MACOS
"Formation of lactam 4 in MACOS TFA introduced at 25 µ?,/p???,
pressurized to 5 atm. Microreactor B (appendix B) bEntries 2-5 under
atomspheric pressure, isolated yield. dUnder 40 p.s.i ofpressure, TFA
introduced at 50 µ?7p???. eEntry 6 microreactor C (appendix C) .
fConversion determined over both steps using 1H-NMR spectroscopy.
Chemical decomposition of product 4 was suspected at 400 W, so the power level
was sequentially reduced but no increase in yield was achieved (Table 3, Entries 2-5).
26
To investigate loss of material and to ensure accurate analysis of reaction H-NMR
spectrum, control studies in D7-DMF were conducted. Initial effluent from the
microreactor was collected and analyzed. Upon analysis of the 1H-NMR spectra of
the non-purified effluent, 100 % product was observed with no starting reagents, or
by-products and further investigation of the experimental protocol revealed that the
problem was with the aqueous work up procedure. In fact up to 74 % of the desired
lactam was being lost in the aqueous layer of the aqueous purification. This
prompted a solvent switch to solvents that were easily removed and avoided aqueous
purifications.
With the avoidance of aqueous workup the neutralization of TFA remained an
issue since the aqueous purification also served to remove remaining TFA, passing
the reaction solution through a short column of basic alumina easily solved this
problem. Subsequently, the use of toluene as the solvent and implementation of the
new workup proved advantageous as the desired lactam was isolated in 65 % yield
(Table 3, Entry 5). The yield was further increased with the use of MeCN, and
accompanied by a slight increase in power the desired lactam 4 was now recovered in
71 % isolated yield (Table 3, Entry 6).31
In an attempt to expand the substrate scope, the migrating carbon was
functionalized; and the resulting substrates were flowed in MACOS. As a starting
point initial conditions that resulted in moderate success from table 3, entry 6 were
attempted. The use of toluene gave less than optimal results, as poor solubility led to
blockages in the microreactor (Table 4, Entry 1). It was not until a solvent switch to
27
MeCN that optimal results were observed, and the desired lactam 7 was isolated in 60
% isolated yield (Table 4, Entry 4). An increase in power by 25 W and pressurization
to 40 p.s.i increased the isolated yield to 68 % (Table 4, Entry 5), although some
^S
Entry
1
2
3
4C
5d
6d
6
R
Solvent
Power (W)
CO2Et
Toluene
100
CO2Et Toluene:EtOH(2:l) 100
CO2Et
IPA
100
CO2Et
CO2Et
Ph
MeCN
MeCN
MeCN
100
125
125
7
Concentration (5, M)
% Yield (7)b
1
2
2
2
2
2
>\0
33
0
60
68
5
Table 4. Multistep flow using MACOS for the formation of lactam 7. "Entries 1-4, starting reagent 7
introduced at 10 µ?,/pp?, at atomspheric pressure using microreactor C (appendix C). isolated yields over the
both steps. «Bromide equivalent ofreagent 5 used. dstarting reagents introduced at 50 µ?7p»?, under 40 p.si. of
pressure, microreactor B (appendix B) used.
starting reagent 5, and intermediate azide 6 were present in small quantities.
Replacing the ethyl ester on the migrating carbon with a phenyl group and
implementing the same reaction conditions used in entry 5 unexpectedly gave a low
isolated yield (5 %) (Table 4, Entry 6), and most of the collected effluent consisted of
intermediate azide 6 (63 %) and starting chloride 5 (16 %).31
The decrease in isolated yield upon functionalizing the a-carbon suggests that
the reaction mechanism is being affected. Analysis of the proposed reaction
mechanism reveals that when a phenyl group is appended to the migrating carbon, an
28
increase in stabilization of the transition state can result. This can occur because as
the antiperiplanar bond (bolded in Figure 6) begins to break there is an increase in
electron density on the migrating carbon. The increase in electron density can
momentarily be stabilized by the pi-system of the phenyl group (pathways A-C,
Figure 6). The increased stabilization is sufficient enough to allow disassociation of
the Bronsted acid to occur at a faster rate than rearrangement.
CP
+
N2
Ph
X
n:
B
oh
Ph
&
N2-N
OH
N3
Ph
-X—- /—-N
OH
Figure 6. The various conformations adopted by compound 5. The various pathways
are labeled A-D The bolded bond is the migrating bond, (figure adapted from reference [32]).
29
O
Orbital alignment
1
Figure 7. A diagram of the orbitals on the phenyl ring stabilizing
the sigma orbitals of the migrating bond. Some bonds eliminated for
clarity.
Only pathway D allows for the migrating bond not to be aligned with the pi-system of
the phenyl ring, unfortunately bond migration at this position results in a twisted
amide. Twisted amides are highly unstable and readily decompose. Removing the
aromatic ring from the migrating carbon and placing it on a remote position, does not
interfere with the reaction mechanism and produced lactam 10 in 62 % isolated yield
(Scheme 1O).31
8
9
10
62%
Scheme 10. Formation of lactam 10 using MACOS. The microwave unit was set at 125 W, and the
reaction was performed under 40 p.s.i ofpressure. Microreactor C (appendix C) used.
A unique bicyclic molecule (Scheme 11, Compound 11) was investigated, and
the two-step process was first attempted not using MACOS. It was discovered that the
formation of the lactam is not as facile as other substrates in comparable conditions.
30
jì_c|
^NN^ X^^N3
n\j
DMSO, 110 °C, 25 min I \J
11
\~y
^^ 12
°
3
r.t.3748hrs.
%
12
\3^«
Scheme 11. Unoptimized batch conditions for formation ofbicyclic
lactam 23.
Given the difficulty in forming the lactam, attention was focused on the second step
of the reaction. To force the reaction to completion in MACOS high power levels
would have to be used. Using a single capillary microreactor Ti(IV) isopropoxide
was used as both the Lewis acid and as a medium for microwave absorption. It was
thought that the efficient microwave absorption properties of titanium would have
increased the reaction temperature sufficiently, while not creating the harsh
conditions of excess TFA. Unexpectedly, only trace amounts of lactam were obtained
(Table 6, Entry 1).
31
see table for
conditions
^y-N3
13
12
Entry Lewis Acid
1 Ti (IV) isopropoxide
2
3
TFA
TFA
[M]b
N
Power (W) F.R. ^L/min)c % Conversion (13)d
3
3
7
Trace
0
Trace
50
10
10
300
400
400
Table 5. MACOS optimization for formation of lactam 13. aSolvent used is DMF, and 5 atm of
backpressure applied, microreactor D (appendix D). bOveral concentration of compound 12. cFlow
rate. d Determined by 1H-NMR spectroscopy.
Reverting back to TFA as the Bronsted acid it was suspected that a similar yield
could be achieved as the reaction not using MACOS (Scheme 11) however, only
small amounts ofproduct are observed (Table 6, Entries 2-3). An additional tube was
added to the microreactor (appendix C) extending the reaction time of the problematic
step.
Cl
TFA
nBu4NN3
10 µ?/????
N,
-------------------------------------H
11
N
35 pL/min
12
13
Scheme 12. Multistep flow using MACOS. The microwave unit was set at 300 W, and
the concentration of compound 11 was 2 M. Only trace amounts ofproduct was
detected via 1H-NMR spectroscopy.
32
This should have provided the necessary time for the formation of product, but only
trace amounts were observed (Scheme 12). Further increasing the reaction time
would have made the time required to complete the experiment undesirably long, and
therefore this route was abandoned.
2.3 Intramolecular Schmidt Reaction on a seven-membered ring
With the moderate success of the intramolecular Schmidt reaction on six-
membered substrates, the reaction was attempted on seven-membered rings. The
route to the desired lactam was synthesized in batch (Scheme 13), and the successful
completion of the synthetic route prompted the transition to flow.
nBuLi
Xl
THF
r\^^c\
50C, 18 hr
14
15
72%
DMS0 .
O
Ó^^CI
?? + nBuNN3? „„??„
11O0C, on
20 mm.
16
85 %
16
O
rV^N,
^J
17
.0
O
\
J
17
overnight
\__/
18
Scheme 13. Synthesis of starting material and desired lactam 18.
33
Using a single capillary microreactor the formation of the lactam from the azide
intermediate was investigated. The intermediate azide was formed in a mono-mode
batch microwave and the solution was used without purification to simulate the
second step in continuous flow.
O
Ii
O
r\S^^ N3
U
see table for
conditions
-o>
17
18
Entry Concentration (M)a Power (W) F.R. ^L/min)b % Conversion (18)c
1
2
3
4
5
6
2
2
2
3
4
2
200
300
300
300
300
100
45
45
35
35
35
35
27
38
37
71
75
100
Table 6. Reaction optimization for compound 18. All reactions were done in DMF, and
pressurized to 5 atm. ofpressure. Interior diameter of capillary used is 1200 µp?.
Concentration of compound 18. bFlow rate determined by 1H-NMR spectroscopy.
eMicroreactor D (appendix D) used for entries 1-5, and microreactor E (appendix E)
used for entry 6.
The optimization of lactam 18 was done at the same time as the six membered ring 2.
The conditions from table 3 (with the exception of flow rate) were utilized however,
poor product formation was observed (Table 6, Entry 1). Increasing the power (Table
6, Entry 2) by 100 W increased product formation by 10 %. Decreasing the flow rate
by 10 µ??p?? (Table 6, Entry 3) gave similar product conversion to entry 2, where
increasing reaction concentration gave good product formation of the desired lactam
34
18 (Table 6, Entries 4-5). Although the amount of product observed did increase, it
was not until an additional tube was added (appendix E) to increase the reaction time
that the reaction completed (Table 6, Entry 6).
O
nBuNN3
y
Q~» -w- CjN' "^
16
Entry
1
2
3
4
5
17
Power (W)
300
400
400
400
300
(%)Yieldb
15
% Conversion (18)c
69-74
Decomposition
0
81
100
Table 7. Multistep flow using MACOS reaction optimization. aTFA introduced at 25 µ?/????. Capillaries used
were 1200 µ?? (I.D.) and concentration of compound 16 was 2 M bislated yield of 18. 'Determined by 1H-NMR
spectroscopy over both steps. dEntry 4, last two capillaries changed to 1700 µ?? (I.D.). e Entries 1-4
Microreactor C (appendix C) was used. Entry 5 microreactor F (appendix F) was used.
Unexpectedly, when the two-step sequence reaction was flowed through the
microwave chamber only 69-74 % 1H-NMR conversion (based on consumption of
compounds 16, 17) to product was achieved (Table 7, Entry 1). Substantial amounts
of compounds 16 and 17 were present. The incomplete formation of the azide
intermediate was surprising considering the success achieved with similar substrates.
Increasing the power by 100 W (Table 7, Entry 2) afforded no product, and
decomposition was suspected as charring on the interior of the borosilicate tubes was
noted. It was suspected that pressurizing the microreactor was contributing to the
decomposition, but upon conducting the reaction at atmospheric pressure no product
35
was isolated (Table 7, Entry 3). In order to create less harsh conditions and yet still
work at a high power 1700 µ?? (I.D.) borosilicate glass tubes were used. Although it
is not known why, lower reaction temperatures are achieved when using 1700 µ??
(I.D.) capillaries when compared to the 1200 µ?? (I.D.) capillaries at the same power.
That said, this proved beneficial and decent product formation was observed (Table 7,
Entry 4). Unsatisfactory results, coupled with isolation difficulties noted with DMF
prompted a solvent change to toluene along with the addition of an extra borosilicate
tube (appendix F) to increase the reaction time for the transformation of compound 17
to compound 18. With these modifications in place, no starting or intermediate
compounds were noted in the 1H-NMR spectra of the effluent collected. The
isolation of 18 in just 15 % yield (Table 7, Entry 5) was an unforeseen result, and it is
thought that the high temperatures, and extended reaction times give an opportunity
for vaporization of product and intermediate leaving less product available for
isolation.
2.4 Intramolecular Schmidt reaction on five-membered rings
In an effort to expand the substrate scope, a cyclopentanone core was
investigated. Using reaction conditions previously optimized for other substrates did
not work, as recovery of the desired lactam 21 was low (Table 8, Entry 1). Subjecting
cyclopentanone to increasingly forceful conditions by increasing power,
concentration, and using a higher microwave-absorbing solvent did not increase
yields (Table 8, Entries 2-4) and decomposition was suspected as charring of the
36
InBu4NN3 r-?
R
Cl
TFA
R
19
N3
20
Entry R Concentration (M)b Power (W) Solvent (%) Yield6
IH
2
H
3
H
4
H
2
3
3
3
125
150
200
300
MeCN
DMF
DMF
DMF
9
0
0
0
5 CO2Et
6 CO2Et
2
2
125
300
MeCN
MeCN
0
5
Table 8. Multstep flow using MACOS for formation of lactam 21. "Entries 2-4
used microreactor G (appendix G) and 5 atm ofpressure, all other entries used
microreactor B (appendix B) and 40 p.s.i. ofpressure. bconcentration of starting
reagent 19. Tsolated yield of lactam 21 over both steps.
Figure 8. Charring and rupturing of the microreactor
during formation of lactam 21.
microreactor was noted (Figure 8). In a last effort an electron withdrawing group
was attached to the migrating carbon to hopefully facilitate rearrangement but no
lactam 21 was produced, and the majority product was intermediate azide 20 (66 %)
with the rest consisting of initial chloride 19 (16 %) (Table 8, Entry 5). Subjecting
ethyl ester 19 to higher power formed the product lactam 21 in only 5 % yield with
37
the majority product being intermediate azide 20 (43 %) (Table 8, Entry 6).31 It is
obvious that at high powers (> 200 W) chemical decomposition is occurring (Figure
8). Cyclopentane decomposes into ethylene and propylene at 2600C and temperatures
of at least 7000C is being achieved in our reaction as evidenced by the melted
borosilicate glass (Figure 8).33
2.5 Acyclic Variation
To investigate an acyclic variation of the intramolecular Schmidt reaction,
model substrate 22 was chosen and reaction conditions from moderate yielding six
membered ring substrates were applied.
TFA
nBu4NN3
e
22
N3
23
?
O
24
Scheme 14. General transformations to reach desired product 24.
38
TFA
nBu4NN3
Cl
1
2
3
4
24
23
22
Entry
?
N3
R
Solvent
Me
Me
Me
Toluene
MeCN
MeCN
(CH2)CO2Et
MeCN
Power (W)
O
(%)Yielda
100
125
300
125
25
26
27
0
Table 9. Multistep flow using MACOS for pyrrolidine formation. All reactions performed
at a 2 M concentration, isolated yield of comound 24. bEntry 1 used microreactor
C (appendix C) cEntries 2-4 used microreactor B (appendix B) and introductory flow rates of
50 µ??p?? with 40 p.s.i of pressure.
Unfortunately, the acyclic variation of the intramolecular Schmidt reaction proved
less than ideal, yielding only 25 % of JV-acetylpyrrolidine (Table 9, Entry 1).
Increasing the power of the reaction and application ofbackpressure failed to increase
yield (Table 9, Entries 2-3) and analysis of the product mixture revealed that the
majority product was intermediate azide.31 Mass balance determination revealed that
on average 40 % of the total input mass was recovered indicating that significant
chemical decomposition or vapourization was occurring due to the lower boiling
point of all substrates. In an attempt to prevent vaporization an ethyl ester moiety
was appended to the distal carbon. The increased mass and polarity would have
increased the boiling point to aid recovery however the chemical reactivity changed
and no lactam product was observed (Table 9, Entry 4). The difficulty in forming
pyrrolidines with the substrates chosen caused us to abandon this route.
39
2.6 Scale Out
The ability to make more material on demand is a powerful attribute of flow
chemistry and is a primary driving force for its adaptation in industry. Once primary
research on milligram scale is complete the limiting factor to make more material is
time and not scale. This concept was demonstrated with the following reaction
(Scheme 15) where 1.1 g of lactam 4 was made without a loss of yield when
compared to the small scale reaction.
O
O
11Bu4NN3
r^V^^^^CI
MeCN*
IJ
150W
4
^^ 2
50 pL/min ^^^ 3
Scheme 15. An example of a scale out reaction producing 1.1 g of compound 4
in 71% yield.
40
Chapter III
41
3.0 Bis-Azide Extension
3.1 Optimization of Triazole Chemistry
The moderate success of the intramolecular Schmidt reaction in MACOS led
us to pursue other azide chemistry, in particular the use of two azide moieties on the
same molecule. Successful completion of such a synthesis would solidify the use of
MACOS as a tool for azide synthesis, since the occurrence of two azide moieties on
the same molecule is sparingly present in the literature. To explore this concept the
synthesis of triazoles was chosen, because they are easy to form and their chemistry is
well studied.
Anaylsis of scheme 16 shows that the full reaction sequence is a two-step
process that will require a minimum of two tubes in series. In the microreactor the
crvyNci
N3~ t N3 |iy N3
O
Scheme 16. An example of a regioselective bis-triazole reaction
first tube will be clear borosilicate glass and the second will contain a thin film of
copper adhered to the inside of the tube (see Figure 5). The copper will act as the
catalyst to make triazoles regioselective for the 1,4 product. However, this presents a
potential problem because the microwave absorption capabilities of the two tubes will
42
be different. The initial challenge was to see if the two tubes could be housed in the
same microwave chamber, and a trial of the microreactor stability revealed that the
efficient microwave absorption of the copper film caused melting of the microreactor
tubes at low levels of power (not in excess of 20 W, see Figure 9). The clear
borosilicate glass tubes survived the conditions but the power levels are not high
enough to form the necessary bis-azide intermediate 26. Despite this drawback
triazole formation ensued, by removing the copper coated borosilicate glass tube and
H
I
0
Figure 9. Melted 1700 µ?? (I.D.) borosilicate tubes with a thin Cu-film on the inner wall.
replacing it with a clear borosilicate glass tube. The formation of triazoles will be in
a non- regioselective manner, and their synthesis would serve as a proof of concept
that triazoles can be formed using MACOS.
43
Cl"—t^^t'—Cl nBU4N"3 ?3^^?
25
26
Entry Power (W)
Azide Flow Rate (µ?/min)
Phenylacetylene Flow Rate (µ?/min) % Conversion (27)a
1
2
3
4
5
50
75
100
200
300
15
10
15
15
15
20
15
20
20
20
0
55
36
58
41
6b
75
5
N/A
100_
Table 10. Multistep flow using MACOS and the optimization of non-regioselective triazoles. The reaction was done
in DMSO, and 5 atm ofbackpressure applied. a Determined by 1H-NMR spectroscopy over all
steps.bPhenylacetylene was premixed in solution. c Phenylacetylene flowed in a 2 M solution ofDMSO except for
entry 2. In entry 2 neat phenylacetylene was used. All capillaries used were 1200 µ?? (I.D.).
An initial attempt using 50 W of power did not produce desired product 27
(Table 10, Entry 1), and increasing the power did not significantly increase product
formation. The amounts of product observed while increasing power levels (Table 10,
Entries 2-5) concluded that an increase in power was not the solution to increasing
product formation and optimization of other reaction parameters is necessary.
Optimizing other reaction conditions led to a decrease in flow rate, and the
introduction of neat phenylacetylene. Implementation of the new reaction conditions
produced the desired transformation to bis-triazole 27 in good conversion (Table 10,
Entry 6) as observed by 1H-NMR spectroscopy.
44
3.2 Synthesis of Regioselective Triazoles
The limiting factor in constructing regioselective triazoles was the
microreactor design. The borosilicate tubes were not durable enough to withstand the
temperatures reached and our group was investigating new materials to use in
microreactor construction. It was found that Alumina oxide (Al2O3) tubes were an
ideal choice because they were microwave transparent and offered more durability as
Al2O3 is better able to withstand higher temperatures. This prevented the rupture of
the tubes in the microwave chamber and allowed the use of a thin Cu-metal film on
the inner wall.
Regioselectivity in triazole formation is also dependent on solvent, and to
determine the best solvent to use a solvent study was performed in a batch
microwave.
Cl
^Y^CI 11Bu4NN3 N3^Nj
25
Entry
'V
26
Solvent
DMSO
Toluene:DMSO(2:l)
Toluene
MeCN
IPA
(%) Selectivity (28)a
O
50
100
70
100
Table 11. Selectivity determination in different solvents using a batch microwave, see experimental
for conditions. aDetermind by 1H-NMR spectroscopy ofthe crude reaction mixture.
45
The poor selectivity observed in DMSO or Toluene:DMSO (2:1) (Table 11, Entries
1-2) mixture ruled out their use. Toluene (Table 14, Entry 3) demonstrated excellent
selectivity but solubility issues arose after extended periods of time, and the most
practical solvents were MeCN and IPA (Table 11, Entries 4-5) as they both showed
high selectivity and good solubilizing properties.
With the appropriate solvents determined flow optimization studies began and
to ease optimization, intermediate azide 26 was preformed in a batch microwave and
the resulting mixture was used unmodified. Phenylacetylene was added directly to
the solution, and the resulting mixture was flowed using MACOS consisting of tubes
constructed out of alumina oxide with a thin film of Cu-metal on the interior of the
tube. Initial reaction conditions attempted (Table 12, Entry 1) resulted in poor
recovery of the desired bis-triazole 28, further the 1H-NMR spectra of the effluent
collected showed significant formation of other regio-isomers. The selectivity using
MeCN in MACOS was less than that observed in earlier batch solvent studies. It was
suggested that MeCN could have been assisting in the leaching of the Cu-metal
resulting in lowered selectivity's as the reaction progressed. In support of this theory
there was a gradual increase in power to maintain the appropriate temperature
indicating that less copper was present to absorb microwave irradiation. The superior
selectivity in batch experiments in the presence of IPA resulted in a solvent switch.
Unfortunately poor product formation was observed (Table 12, Entry 2), and upon
increasing temperature no product 28 or azide 26 was observed by H-NMR
spectroscopy and decomposition was suspected.
46
». i¿ ??t?
o - b
26
Entry Solvent Temperature (°C)a Flow Rate (µ?7????) % Conversion (28)b % Yield (28)c
1
2
3
MeCN
IPA
IPA
100
100
200
15
10
15
41
58
0
26
N/A
0
Table 12. Triazole formation using MACOS, compound 26 was made in the batch microwave and the
resultatnt solution used crude. The final solution was 0.5 M. Temperature determined by a FLIR-IR
camera. bDetermined by 1H-NMR spectroscopy^Isolated yield
3.3 MACOS-Batch Microwave Efficiency Comparison
To assess the efficacy of MACOS a comparison study was done between
MACOS and batch microwaves. The reaction that was chosen for the comparison
study was the synthesis of regioselective triazoles. Since MACOS uses a modified
Biotage Initiator® accurate temperatures are not known, since microwave irradiation
is controlled by power (W). To determine the temperature reached from wattage a
FLIR-IR thermal camera was setup to probe the interior of the cavity. It was found
that at a given wattage (20-30 W), there exists a gradient of temperatures from
47
a/
102.7'C
100
Analysis I ^n Position | % ObJ. Par] ? Image | P Text comment]
Label
vahjBra
Image
LIOl
LID2
ran!
30.6
33.6
79.9
Maxi
103.1
102.9
102.3
Max-Mnj
72.5
69.3
22.4
Avg
Stdev i
63.8
91.0
31.7
6.8
Result I Expression ]
80
60
40
30.7-C
100
60
60
40
Label
!_.QJLs«l.-L_J*L L_.Jͧ«__l-™_A,ífl^-J-jCa^^-J-- -°***?L-Ì
Figure 10 A display ofthe range oftemperatures reached on an alumina oxide tube that has
a thin film of Cu-metal adhered to the interior. The tube is being irradiated using 20-30 W
of microwave irradiation and the temperature data is being reordered using a FLIR-IR
camera.
80-1000C along the length of the tube (Figure 10). In MACOS there is a continuous
movement of material, this makes it difficult to reproduce in batch the gradient of
temperatures and the corresponding residence times. Therefore, it is assumed that the
reaction mixture in MACOS is only exposed to a temperature of 1000C.
The time of the reaction using MACOS was determined not based on the time
that a given plug ofreaction mixture will reside at the centre of microwave irradiation
but the total time that a plug of reaction mixture would spend in the length of the flow
tube. The reason for this assumption is because when the Cu-film is irradiated
conduction occurs increasing the temperature through out the tube, and the reaction
will initiate upon entering. The residence time was determined to be 40 minutes and
was calculated using the flow rate and the volume of the tube. When the MACOS
48
reaction conditions were applied to a batch microwave, and a comparison of the H-
NMR spectra of a sample of the reaction mixture was taken it was found that (Figure
11).
H\ Ha
Purified bis-triazole
JL
JL
MACOS
_JX_
7.0
6.5
6.0
5.5
5.0
^»jWwJJUIW» Am^w.w—w».»**
4.5
4.0
ppm
Batch MicroWttvIL
Regio-isomers _
JjLTL-W
JU
_JUWJ
Figure 11. (d6-DMSO) 300 MHz. 1H-NMR spectra comparison of bis-triazole formation
using a batch microwave and MACOS. Batch microwave has twice as much Cu-catalyst. Full
spectrum not shown.
batch microwave reactions have lower selectivity and product formation when
compared to the MACOS reaction. The enhanced chemistry in MACOS is attributed
to the geometry of the tube; by adhering copper as a film along the length of the tube
it increases the surface area of the copper, therefore increasing contact with the
49
reaction solution. The increased surface area to volume ratio using MACOS enhances
rates of heterogeneous catalysis.
Chapter IV
51
4.0 Conclusion
Although azides are a valuable synthetic building block their full potential has
not been reached because of the dangers they pose, and the development of a viable
tool to explore their synthetic use would be advantageous. We have demonstrated that
with the use of MACOS as a synthetic tool, azides can be reacted in a safe and
controllable manner; three lactam products were synthesized in good yield.
Moreover, the use of MACOS as a tool for bis-azide synthesis has been demonstrated
and the foundations for reaction optimization have been set. The occurrence of polyazides in literature is rare, and our safe use of these types of molecules further proves
MACOS viability as a synthetic tool for azide chemistry.
Lastly, the main driving force for flow chemistry is the ability to make more
material on demand with little risk of failure. Solidifying MACOS' existence in
academic an industrial laboratories is the proven ability to make gram quantity
product using azide starting material. Typically such a reaction on a large scale is not
preformed because of the inherent dangers, but with MACOS we were able to
produce gram quantities of lactam without any complications. Although MACOS is
in the preliminary stages of development the foundations for its use in high energy
reactions, along with the ability for it to be applied to scalable reactions has been set.
52
4.1 Experimental
General Experimental Information
All reagents and solvents were purchased from commercial vendors and were
used without purification, unless otherwise noted in the experimental procedure.
PEEK fittings for microreactor construction were purchased from Upchurch
Scientific® and borosilicate glass capillaries were purchased from Fischer Scientific
and assembled in our laboratory. Microreactor pressurization was done with
compressed air, and the collection of effluent was in a Biotage 2-5 mL sealed
microwave vial. MACOS uses a modified Biotage Initiator® unit and the pumping
system uses Harvard® 22 dual port syringe pumps. Thin layer chromatography was
performed using Whattman® 60 F254 pre-coated glass plates, and visualized using a
potassium permanganate stain or UV-light. Purification using flash chromatography
was done using Silicycle® silica gel 60 (230-400 Mesh) or a Biotage Isolera® unit
with pre-loaded silica cartages. 1H-NMR and 13C-NMR spectra were acquired using
a Bruker 300 AVANCE or Bruker 400 AVANCE spectrometers, and IR-data
acquired was recorded as cm"
Organic Azide Synthesis in Biotage Initiator™ General Procedure A
To a 0.5 mL-2.0 mL Biotage® microwave vial was placed a stir bar, starting material
and one equivalent of tetrabutylammonium azide, the mixture was dissolved in
DMSO to a final concentration of 2 M. The vial was than placed in a Biotage
Initiator™ microwave for 25 minutes at 1100C. The reaction mixture was than
53
diluted with distilled water and extracted with ethyl acetate (x3). The organic layers
were than combined and washed with a saturated brine solution (x3), and dried using
MgSO4 anhydrous. Purification was done using flash column chromatography using
silica gel.
MACOS lactamformation, General Procedure B
In a vial is mixed the appropriate starting reagent and diluted with freshly distilled
MeCN to a final concentration of 2 M. One equivalent of tetrabutylammonium azide
is added and mixed into a homogeneous solution. The resulting mixture is up taken
into an air tight syringe and loaded onto microreactor B. Neat TFA is up taken into an
air tight Hamilton® syringe and loaded onto microreactor B. The system is
pressurized with 40 p.s.i of air pressure, and microwave irradiation was set at 125 W.
Both pumps were started simultaneously and flowed at rates of 50 µ?7pp?. The
collected effluent was than concentrated and diluted three times with toluene and
filtered through basic alumina, than flushed with EtOAc.
The filtrate was
concentrated and purified via flash chromatography on silica gel (0.5 % aq. NH4OH /
2.5 % MeOH in DCM).
54
O
2-(3-Chloropropyl)cyclohexanone (Scheme 8, Compound 2) To a 50 mL round
bottomed flask a stir bar was added and flame dried under vaccum, followed by
purging with argon. 20.00 mL of freshly distilled THF was than added and set in ice
bath to O0C. 1 equivalent of nBuLi was added in one portion followed by 1.30 g of
cyclohexahydrazone. The resulting mixture was stirred for 15 minutes at 00C. 1.00
mL l-Chloro-3-iodopropane was than in one portion and stirred overnight at room
temperature. The resulting mixture was then poured into a flask containing 2.00 M
sulphuric acid, and stirred vigorously with ether for 30 minutes. The solution was
poured into a separately funnel and the organic layer collected. The aqueous layer
was extracted with ether, and the organic portions combined washed with brine, and
dried with MgSO4 anhydrous, and concentrated under vaccum. Flash column
chromatography using silica gel. (Rf= 0.3 7% EtOAc/Hex) yielded 1.21 g (75 %) of
the title compound as yellow oil. All spectral data matches those previously reported
in literature.[31,32]
O
2-(3-Chloropropyl)cycloheptanone (Scheme 13, Compound 16). To a 50 mL round
bottomed flask a stir bar was added and flame dried under vaccum, followed by
55
purging with argon. 20.00 mL of freshly distilled THF was than added and set in iceNaCl bath to -50C. 1 equivalent of nBuLi was added in one portion followed by 1.47
g of cycloheptahydrazone. The resulting mixture was stirred for 10 minutes at -5°C.
1.20 mL l-Chloro-3-iodopropane was than in one portion and stirred overnight at
room temperature. The resulting mixture was then poured into a flask containing 2 M
sulphuric acid, and stirred vigorously with ether for 45 minutes. The solution was
poured into a separatory funnel and the organic layer was collected. The aqueous
layer was extracted with ether, and the organic portions were combined, washed with
brine, and dried with MgSO4 anhydrous, and concentrated under vaccum. Flash
column chromatography using silica gel (Rf= 0.3 5% EtOAc/Hex) yielded 661.6 mg
(37 %) of the title compound as a yellow oil. All spectral data matches those
previously reported in literature.
32
3-(3-Azidopropyl)bicyclo[2.2.1]heptan-2-one (Scheme 11, Compound 12) Using
compound 11 (186.0 mg, 0.99 mmol) and following general procedure A, followed
by purification via flash chromatography on silica gel (5% EtOAc/Hex then 10 %
EtOAc/Hex) afforded 154.0 mg (80 %) of the desired compound as a yellow oil. 1HNMR (300 MHz, CDCl3) d: 1.35-1.69 (m, 11 H), 2.42 (s, 1 H), 2.55 (s, IH), 3.243.35 (m, J= 7.3 Hz, 2 H) ppm. 13C-NMR (75 MHz, CDCl3) d: 23.85, 26.32, 27.46,
56
27.84, 34.70, 39.39, 49.38, 51.13, 53.17, 219.49 ppm. IR (neat) 1355, 1741, 2094,
2877, 2954 cm"1. HRMS Caled for Ci0Hi5N3O m/z [M4Na+] 216.1113 found
216.2090.
O
2-(3-Azidopropyl)cycloheptanone (Scheme 13, Compound 17) Using general
procedure A, and purification by flash chromatography on silica gel (5% EtOAc/Hex
then 10 % EtOAc/Hex) afforded 154 mg (80 %) of the desired compound as a yellow
oil.32
CP
Hexahydro-l/y-pyrrolo[l,2-a]azepin-5(6Ä)-one (Table 3, Entry 7) Following
general procedure B, 189 mg ofthe desired lactam was isolated in 71 % isolated yield
as a yellow oil. All spectral data matches those previously reported in literature.[31,32]
57
O
Ob
(Scheme 11, Compound 13) In air a 25 mL flask is charged with a magnetic stir bar
and 127.5 mg of compound 3. 6.00 mL of TFA is added in one portion and the flask
is left to stir at room temperature for 48 hours. The reaction is than concentrated
under vacuum and diluted with distilled water and extracted with ethyl acetate (x3).
The organic layer is than washed with a sat. solution OfNaHCO3 until no more gas
liberation is observed. The organic layer is washed once with brine, and than dried
using MgSO4 anhydrous and concentrated under vaccum. Flash chromatography
using silica gel (Rf =0.1 in 20% EtOAc/Hex then EtOAc) yielded 40.6 mg (37 %) as a
yellow oil. 1H-NMR(SOO MHz, CDCl3) d: 1.35-1.89 (m, 10 H), 2.24 (s, 1 H), 2.73 (s,
1 H), 3.03 (m, 1 H), 3.13 (dd, J= 4.0 Hz, 1 H), 3.84 (m, 1 H) ppm. 13C-NMR (75
MHz, CDCl3) Ö: 21.70, 28.32,29.33, 30.17, 31.86,36.08, 42.74,43.35, 65.47,
175.05 ppm IR (neat) 1344, 1436, 1639, 2873, 2946 cm"1. HRMS Caled, for
Ci0Hi5NO m/z [M+] 165.1154 found 165.1158.
¿P
Hexahydro-lfT-pyrrolo[l,2-«]azepin-5(6fi)-one (Scheme 15, Compound 4)
Compound 2 (1.77 g, 0.01 moles) was dissolved in 5.00 mL of freshly distilled
MeCN. To this tetrabuytlammonium azide (2.89 g, 0.01 moles) was added and the
58
resulting mixture made into a homogenous solution and uptaken into an air-tight
syringe. The resulting mixture was introduced into microreactor C, at a flow rate of
50 µ?,/pp?. Neat TFA was uptaken into a 10 mL air-tight glass Hamilton syringe and
was introduced at a flow rate of 125 µ?7?p?. The microwave unit was set at 150 W
of power, and the experiment preformed at atmospheric pressure. After 4.5 hours, all
the collected effluent was concentrated under vacuum. The resulting oil was filtered
through basic alumina, and was purified on silica gel using flash column
chromatography (0.5 % aq. NH4OH / 2.5 % MeOH in DCM) to yield 1.10 g (71 %)
as a yellow oil. All spectral data matches those previously reported in literature.
O
CP
Ethyl 5-oxooctahydro-lÄ-pyrrolo[l,2-a]azepine-9a-carboxylate (Table 4, Entry 5)
Following general procedure B, the desired lactam was isolated in 68 % isolated
yield. All spectral data matches those previously reported in literature.1 '
59
9a-Phenylhexahydro-lÄ-pyrrolo[l,2-fl]azepin-5(6fl)-one (Table 4, Entry 6)
Following general procedure B, the desired lactam was isolated in 5 % isolated yield.
All spectral data matches those previously reported in literature.[3I'34]
2,3,ll,lla-Tetrahydro-l^-benzo[</]pyrrolo[l,2-a]azepin-5(6fl)-one (Scheme 10,
Compound 10) Following general procedure B, the desired lactam was isolated in 62
% isolated yield. All spectral data matches those previously reported in
literarure.[31'32]
Octahydropyrrolo[l,2-a]azocin-5(lÄ)-one (Table 7, Entry 5) Compound 16 (176.1
mg, 1.00 mmol) was dissolved in 0.50 mL of freshly distilled toluene and than
tetrabutylammonium azide (284.48 mg, 1.00 mmol) was added. The mixture was
made into a homogenous solution and up taken into an air tight syringe and
60
introduced into microreactor C at a flow rate of 10 µ?7?p?. Neat TFA was up taken
into a glass Hamilton® syringe and introduced into microreactor C at 25 µ?7????.
The collected effluent was concentrated and filtered through basic alumina three
times, and the resulting filtrate was than purified using flash column chromatography
on silica gel Rf= 0.5 (0.5 % aq. NH4OH / 2.5 % MeOH in DCM) to yield 24.1 mg
(15 %) of the desired lactam in a pale yellow oil. Spectral data matches that
previously reported in the literature.
Oo
Hexahydroindolizin-5(lÄ)-one (Table 8, Entry 1) Following general procedure B,
the desired lactam was isolated in 9 % isolated yield. All spectral data matches those
previously reported in literature.131'
¿P
CO2Et
Ethyl 5-oxooctahydroindolizine-8a-carboxylate (Table 8, Entry 6) Following
general procedure B, the desired lactam was isolated in 5 % isolated yield. All
spectral data matches those previously reported in literature.1 '
61
A0
JV-acetylpyyrolidine (Table 9, Entry 4) Following general procedure B, the desired
lactam was isolated in 27 % isolated yield. AU spectral data matches those previously
reported in literature.[31'
O
O
l,3-Bis((4-phenyl-l/M,2,3-triazol-l-yl)methyl)benzene (Table 12, Entry 1) In a
Biotage® microwave vial 1,3 bis(chloromethyl)benzene (132.0 mg, 0.75 mmol) was
diluted in freshly distilled MeCN to a final concentration of 0.5 M. The solution was
sonicated until homogeneous and 2 equivalents of tetrabutylammonium azide added
and dissolved. The reaction mixture was microwaved at 80 0C for one hour and the
resulting reaction mixture used without further modification. 6 equivalents of
phenylacetylene is added to the crude reaction mixture and mixed. The final reaction
mixture is up taken into an air tight syringe and loaded onto microreactor A,
containing an alumina oxide capillary coated on the interior with 6 mg of copper
metal. The microwave power was varied as necessary from 18-150 W to maintain an
internal temperature of 1 00 0C as displayed on the microwave unit. The flow rate was
set at 15 µ?7???? and the microreactor was pressurized to 5 atm. of pressure. The
62
collected effluent was concentrated and diluted with DCM, than washed once with
distilled water followed by brine. The crude product was purified by flash column
chromatography using silica gel Rf = 0.4 (30 % EtOAc/Hex then 50 % EtOAc/Hex)
77 mg (26%) of the desired bis-triazole was collected as a fine white powder. All
spectral data matches those previously reported in the literature.
63
Appendices
64
Appendix A: A schematic of the direction of flow for microreactor A
A-^
¡
Microwave
!
Chamber
Collection
Legend
One Way Valve
Mixing Chamber
65
Appendix B: A schematic of the direction of flow for microreactor B
Microwave
Chamber
Collection
Legend
One Way Valve
Mixing Chamber
66
Appendix C: A schematic of the direction of flow for microreactor C
Collection
Microwave
Chamber
Legend
One Way Valve
Mixing Chamber
67
Appendix D: A schematic of the direction of flow for microreactor D
B
A-©
¡
!
Microwave
Chamber
Collection
Legend
One Way Valve
Mixing Chamber
68
Appendix E: A schematic of the direction of flow for microreactor E
Microwave
Chamber
Collection
Legend
One Way Valve
Mixing Chamber
69
Appendix F: A schematic of the direction of flow for microreactor G
¡
!
Microwave
Chamber
Collection
Legend
One Way Valve
Mixing Chamber
70
Appendix G: A schematic of the direction of flow for microreactor H
Microwave
Chamber
Collection
Legend
One Way Valve
Mixing Chamber
71
4.3 References
1. Loupy, Andre, (ed.) Microwaves in Organic Synthesis; Wiley-VCH: Weinham, 2002
2. Kappe, O.C.; Dallinger, D.; Murphee, S. S. Practical Microwave Synthesis for Organic
Chemists; Wiley-VCH: Weinham, 2009.
3. Electromagnetic Spectrum http://www.ac.wwu.edu/~gisele/curriculum.html
(Accessed: August 12, 2010).
4. Kappe, O. C. Angew. Chem. Int. Ed. 2004, 43, 6250-6284
5. Jermolovicius, L. A.; Senise, J. T. J. Micro. Opto. 2004, 3, 97-1 12
6. Herrero, M.; Kremsner, J.; Kappe, O. C. J. Org. Chem. 2008, 73, 36-47
7. Watts, P.; Wiles, C. Eur. J. Org. Chem. 2008, 1655-1671
8. McQuade, T.D.; Bogdan, A. R.; Steinbacher, J. L.; Price, K. E.; Mason, B. P. Chem. Rev.
2007,707,2300-2318
9. Seeberger, P. H.; Blume, T. (ed) New Avenues to Efficient Chemical Synthesis: Emerging
Technologies; Springer-Verlag: Berlin, 2007
10. Taghavi-Moghadam, S.; Kleemann, ?.; Golbig, K. G. Org. Process. Dev. Res. 2001, 5,
652-658
1 1 . Microchemical Engineering in Practice, (ed) Dietrich Thomas, R. wiley-VCH: Hoboken
NJ., 2009
12.Wirth, T. (ed) Microreactors in Organic Synthesis and Catalysis; Wiley-VCH: Weinheim,
2008
13. Haswell, S. J. et al. Tetra. 2002, 4735-4757
14. Burns, M.A. et al. Science. 1998, 282, 484-487
15. Sigma Aldrich Home Page, www.sigmaaldrich.com (accessed: July 13, 2010)
16. www.svrris.com (Accessed: May 27, 2010)
17. Gupta, M.; Wong, E.; Wai, L.W. Microwaves and Metals. John Wiley: Singapore, 2007.
18. Shore, G.; Morin, S.; Mallik, D.; Organ, M.G. Chem. Eur. J. 2008, 14, 1351-1356
19. Organ, M.G.; Comer, E. J. Am. Chem. Soc. 2005, 127, 8160-8167
72
20. Shore, G.; Organ, M. G. Chem. Commun. 2008, 838-840
21. Shore, G.; Sylvie, M.; Mallik, D.; Organ, M. G. Chemistry. 2008, 4, 1351-1356
22. Shore, G; Organ, M. G. Chem. Eur. J. 2008, 14, 9641-9646
23. Shore, G.; Tsimerman, M.; Organ, M. G. Beilstein. 2009, 5, No. 35
24. Shore, G.; Yoo, W.; Li, C; Organ, M. G. Chem. Eur. J. 2010, 16, 126-133
25. Brase, S.; Gil, C; Knepper, K.; Zimmermann, V. Angew. Chem. Int. Ed. 2005, 44, 51885240
26. Sharpless, B. K.; Fokin, V. V.; Green, L. G.; Rostovtsev, V. V. Angew. Chem. Int. Ed.
2002, 41, 2596-2599
27. Dept. of Environmental Health and Safety. Stanford University. Rep# 08-203, December
2, 2008.
28. Murphy, J. ?.; Lang, S. Chem. Soc. Rev. 2006, 35, 146-156
29. KoIb, H. C; Finn, M. G.; Sharpless, B. K.; Angew. Chem. Int. Ed. 2001, 40, 2004-2021
30. Prof. Sharpless, http://www.scripps.edu/chem/sharpless/currentresearch.html (Accessed:
May 31, 2010)
3 1 . Unpublished results done in co-operation with the CMLD-unit at the University of
Kansas
32. Milligan, G. L.; Mossman, C. J.; Aube, J. J. Am. Chem. Soc. 1995, 42, 10449-10459
33. McNesby, J. R.; Gordon, A. S. J. Am. Chem. Soc. 1957, 17, 4593-4595
34. Lei, Y.; Aube, J. J. Am. Chem. Soc. 2007, 10, 2766-2767
35. Aube, J.; Grecian, S. Org. Synth. 2007, 84, 347-358
36. Wang, Z.; Zhao, Z. J. Heterocycl. Chem. 2007, /, 89-92
73
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