1
Chapter 1
INTRODUCTION
Background
The synthesis of heterocycles is of great importance in pharmaceutical and medicinal
chemistry. The ever-increasing demand for novel biologically-active compounds and the
laborious process of lead discovery and optimization have resulted in the continuous search for
simple and efficient methods for generating libraries for biological screening. 1,2,3-Triazoles
have not been isolated in any naturally occurring compounds,1 however the 1,2,3-triazole moiety
has been utilized in many applications ranging from industrial to pharmaceutical uses. The
applications of 1,2,3-triazoles are widespread, making 1,2,3-triazole derivatives a highly studied
class of molecules.
Triazoles belong to a class of compounds called azoles. An azole contains a fivemembered aromatic ring with at least one nitrogen atom and another heteroatom such as a
nitrogen, sulfur, or oxygen. A 1,2,3-traizole structure contains three adjacent nitrogen atoms with
three available substitution sites found at positions 1, 4 and 5 (Figure 2).
Substitution
Positions
H
N
2
N
1
5
N
3
4
Figure 2. Structure of an unsubstituted 1H-1,2,3-triazole.
2
Although the nitrogen at the N1 position is shown with a proton, this atom does not
remain stationary. At both equilibrium and room temperature, the 1,2,3-triazole contains both 1H
and 2H tautomers in dilute solutions. In more concentrated solutions and at lower temperatures,
the 1H structure predominates.2-6 The tautomerizism at room temperature can be seen in the 1H
NMR spectrum of dimethyl 1H-1,2,3-triazole-4,5-dicarboxylate (Figure 3). The observed peak
for the N-H (A) is not a single sharp peak, but rather a broad peak 15.6 to 16.8 ppm due to the
averaging of the triazole tautomer signals. The two different methyl esters (B) appear to be
identical since an equilibrium between the 1H and 2H tautomers is established so rapidly, that at
SpinWorks 2.3:
room temperature, only a single signal appears in the NMR.7 It should be noted that if the proton
is substituted with a larger group (i.e. phenyl), the larger group remains stationary and no
tautomerization occurs.
A
H
N
B
H3CO2C
A
B
H3CO2C
N
N H
N
B
N
H3CO2C
A
B
N
H3CO2C
x 256.000
16.4
PPM
16.0
15.0
16.0
14.0
B
15.6
13.0
12.0
11.0
10.0
9.0
8.0
7.0
6.0
file: C:\DocumentsandSettings\Cat Roush\My Documents\Under GradClass\CHEM189&198\Paper PublicationData\Dr KNMRspectraanddata\1H_diester inDMSO\1\fid expt:
freq.
<zg30>
of 0ppm: 300.142603MHz
transmitter freq.: 300.144690MHz
processedsize: 32768complexpoints
timedomainsize: 65536points
LB: 0.000 GB: 0.0000
width: 6172.84Hz=20.566213ppm=0.094190Hz/pt
number of scans: 16
5.0
4.0
3.0
2.0
1.0
0.0
Figure 3. 1H NMR Spectrum of dimethyl 1H-1,2,3-triazole-4,5-dicarboxylate in d6-DMSO.
-1.0
3
The development of 1,2,3-triazoles for drug discovery and industrial use has been shown
to be very versatile. The uses for triazoles have been found in various areas and are continuously
growing. The applications of these triazoles are increasingly found in all aspects of drug
discovery, ranging from cutting edge research through combinatorial chemistry and targettemplated in situ chemistry, to proteomics and DNA research using bioconjugation reactions. 8
These triazole products are more than just passive linkers; they readily associate with biological
targets, through hydrogen bonding and dipole interactions.8 Derivatives of 1,2,3-triazole have
been found to have anti-HIV,9 anti-allergenic,10 antimicrobial, cytostatic, virostatic, antiinflamatory11 and anti-bacterial12 activities. Triazoles are also being studied for the treatment of
obesity13 and osteoarthritis.14 The increased interest in the 1,2,3-triazole is due to it being nontoxic, benign and stable. Triazoles are particularly interesting for medicinal use because they are
more likely to be water soluble than normal aromatic compounds, and are stable in biological
systems.15
On the industrial side, 1,2,3-triazoles are found in hydraulic fluids, agrochemicals
(fungicides), and photochemical products.16,
17
They have also been used as herbicides, light
stabilizers, fluorescent whiteners, optical brightening agents, pigments and corrosion retardants. 11,
18-20
This allows for the applications of 1,2,3-triazoles to grow exponentially due to their
reliability, tolerance to a wide variety of functional groups, regiospecificity and the readily
available starting materials. Through this, 1,2,3-triazoles are very attractive to use and apply in
many fields.
4
1,3-Dipolar Cycloaddition
Most of the classic reactions for the synthesis of heterocyclic are accomplished by
cyclization, since cycloaddition reactions provide routes to heterocycles with well-defined
substitution patterns.21 This can vary in complexity from a one-step synthesis using a single
reaction component, to a multicomponent procedure with a large number of steps.20 The synthesis
of the 1,2,3-triazole ring structure is typically accomplished by a 1,3-dipolar cycloaddition using
an alkyne and an azide (Scheme 1).
R2
N
1
C
C
R
N
N
1
R
N
1
C R
N
R2
N
C
R1
Scheme 1. Alkyne and azide react to produce a 1,2,3-traizole.
The approach of 1,3-dipolar cycloadditions constitutes a powerful tool in the synthesis of
five-membered heterocyclic rings. This technique does not restrict what compounds may be
synthesized. The Woodward-Hoffmann theories of orbital symmetry conservation, as well as
frontier orbital theory have provided a basis for the understanding of these mechanisms and for
interpreting the effect of substituents on the rates and selectivities of cycloadditions. 21,
22
1,3-
Dipolar cycloadditions are an excellent method for constructing five membered rings with a wide
variety of 1,3-dipoles commercially available today.
5
The concept of 1,3-dipolar cycloaddition originated when Rolf Huisgen published a
review article in 1955.23 Huisgen discussed the resonance structures of CH2N2 which explained
the valence bond description of 1,3-dipolar cycloaddition (Scheme 2). His breakthrough
consisted of the realization that the description of diazoalkanes can be applied to a series of other
structures (i.e. alkynes and azides) in which carbon, nitrogen, and oxygen are affected in the
resonance structure that may hold a charge.
HC
N
H2C
N
H2C N
N
N
N
Scheme 2. Resonance structures of CH2N2.
The 1,3-dipolar cycloaddition, also known as the Huisgen cycloaddition, is a classic
approach in organic chemistry consisting of the reaction of a dipolarophile with a 1,3-dipolar
compound that allows for the production of various five-membered heterocycles.24 Most of
dipolarophiles are alkenes, alkynes and molecules possessing related heteroatom functional
groups (such as carbonyls and nitriles). A 1,3-dipole is a three-atom conjugated system with four
π-electrons delocalized over the three atoms. The name 1,3-dipole was coined because it is
impossible to write electron-paired resonance structures for these species without incorporating
charges.25 1,3-dipolar compounds contain one or more heteroatoms and can be described as
6
having at least one resonance structure that represents a charged dipole. It is important to note
that 1,3-dipolar species contain a heteroatom as the central atom. This allows the 1,3-dipolar
species to be formally sp- or sp2-hybridized depending on whether or not there is a double bond
orthogonal to the delocalized π-system. The 1,3-dipoles can be divided into two different types:
1) the allyl anion type such as nitrones, azomethine ylides which contains a nitrogen atom in the
middle of the dipole, carbonyl ylides, or carbonyl imines, which contains an oxygen atom in the
middle of the dipole and 2) the linear propargyl/allenyl anion type such as nitrile oxides,
nitrilimines, nitrile ylides, diazoalkanes, or azides. These two types of 1,3-dipole are shown
below in Table 1.
7
Table 1. 1,3-Dipoles useful in cycloaddition reactions.25
X
Y
Y
Z
X
Linear Propargyl/Allyl Type
N
N
Allyl Anion Type
N
N
azides
N
N
C
HC
HC
HC
N
N
O
diazo
C
N
C
compounds
HC
Z
N
nitrones
azomethine imides
O
N
nitrile oxides
C
nitrile imides
C
nitrile sulfides
C
C
azomethine ylides
N
N
N
O
C
carbonyl ylides
S
C
nitrile ylides
S
C
thiocarbonyl ylides
8
The substrates shown in Table 1 are examples of compounds that may be used in a 1,3dipolar cycloaddition reaction. These particular substrates are known as 1,3-dipoles.
Dipolarophiles are alkenes, alkynes or molecules that possess a heteroatom functional group. The
two π-electrons supplied by the dipolarophile and the four electrons of the dipolar compound
participate in a concerted, pericyclic shift. The addition is stereoconservative (suprafacial), and
the reaction is therefore a [2s+4s] cycloaddition, more commonly known as a 1,3-dipolar
cycloaddition (Scheme 3).26,
27
The regioselectivity of the reaction depends on electronic and
steric effects. Meaning, if there are functional groups on each of the substrates that are large, it is
possible to obtain a single isomer. If not, then isomers will be formed and no regioselectivity will
be observed.
R2
R1
C
C
1
R
2 pi
N
R1
N
R2
N
N
N
C
C
N
R1
N
4 pi
1
C R
N
R2
N
C
R1
2s + 4s cycloaddition
Scheme 3. Example of a 1,3-dipolar cycloaddition reaction.
These five-membered heterocyclic rings are not limited to carbon, nitrogen, and oxygencontaining compounds, but also allow for phosphorus and sulfur to be included in the ring. There
are various 1,3-dipoles (Table 1) that may be used to construct different 1,2,3-triazoles. The
result is an ever-growing number of heterocyclic compounds that may be constructed using this
ingeniously simple technique.
9
The 1,3-dipolar cyloaddition can be accomplished using an alkyne and an azide to
produce a wide variety of 1,2,3-triazoles with great ease. This simple method allows for 1,2,3triazoles to be synthesized with only two components, although the approach does potentially
lead to regioisomeric products. Sharpless and coworkers introduced the term “click chemistry”
for this approach, which denotes the development of a set of powerful, highly reliable, and
selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries
through heteroatom links. Click chemistry does not replace existing methods for drug discovery,
but rather, it complements and extends them. It works well in conjunction with structure-based
design and combinatorial chemistry techniques, and, through the choice of appropriate building
blocks, can provide derivatives or mimics of ‘traditional’ pharmacophores, drugs and natural
products.28, 29
The benefits of 1,3-dipolar cycloaddition allows for many new compounds to be
synthesized quickly and efficiently. An increase in demand for fast and effective reactions makes
the 1,3-dipolar cycloaddition reaction indispensible. Even though this technique is used
frequently for many applications today, 1,2,3-triazoles were synthesized quite differently in the
past. Many of the old synthesis techniques required harsh conditions, high temperatures, high
pressures and long reaction times. Synthesizing 1,2,3-triazoles was a multi-step process which
required purification for every step. The discovery of simpler and more straightforward
techniques in synthesizing 1,2,3-triazoles would lead to the creation for the concept of 1,3-dipolar
cycloaddition reactions.
10
Brief History for the Discovery and Optimization of the 1,2,3-Triazole
The history of the 1,2,3-triazoles began with several isolated events that did not suggest
to the chemists at the time that these compounds would produce any significant contribution to
organic chemistry. In 1860, Zinin30 was investigating two isomeric compounds that were isolated
from the nitration of diphenyldiazene-1-oxide and were identified as nitroazoxybenzene and
isonitrosazoxybenzene (Scheme 4). When both isomers were reduced with ammonium sulfide,
Zinin
stated
that
isonitroazoxybenzene
produced
six
equivilants
of
sulfur
while
nitroazoxybenzene only produced four equivalants. Since Zinin was using the older atomic
weight (O = 8), it was not possible for him to determine a molecular formula of
isonitroazoxybenzene that would have enabled him to make a successful identification of the
nature of his compound. Later, in 1899, it was shown that Zinin’s reduction product was actually
2-phenylbenzotriazole-1-oxide, a derivative of the 1,2,3-triazole.
O
N
N
HNO3
N
H2SO4
diphenyldiazene-1-oxide
O
O
N
N
N
O
N
+
N
O
nitroazoxybenzene
OH
isonitrosazoxybenzene
(NH4)2S
O
N
N
N
2-phenylbenzotriazole-1-oxide
Scheme 4. The nitration of diphenyldiazene-1-oxide.30
11
Prior to 1888, all reactions that produced a 1,2,3-triazole were derivatives of
benzotriazole. The discovery of simple, monocylic 1,2,3-triazoles is credited to Han von
Pechmann. In 1888, von Pechmann synthesized a monocyclic triazole and correctly formulated
the 1,2,3-triazole ring. He was able to do this for both 1H-1,2,3-triazole and substituted triazole
derivatives.31,
32
During von Pechmann’s investigations of “osotetrazones” - derivatives of
osazones - he was able to determine the actual structure of a 1,2,3-triazole. He did this by heating
a compound derived from dimethylglyoxal (C16H16N4) with nitric acid to obtain a colorless oil
(C10H11N8). Another reaction using dimethylphenylosazone, derived from phenylhydrazine and a
sugar, upon long heating with acid produced C6H5NH2 as the side product. From these studies,
von Pechmann proposed that the products formed contained a common unsaturated ring, C2H2N3,
as shown in Figure 4. The compounds that von Pechmann investigated were called
“osotriazoles”, a designation which is still retained for certain 2-substituted triazole derivatives.33
Examples of reactions formulated by von Pechman are shown below in Scheme 5.
H
N
N
N
HC
CH
V
Figure 4. von Pechmann's proposed unsaturated triazole ring.
12
H
N
N
N
N
H
H3C
(CH3CO)2O
C
N
C
C
C
CH3
H3C
CH3
H3C
CH3
C
N
C
C
(CH3CO)2O
N
+
N
4,5-dimethyl-2-phenyl-2H-1,2,3-triazole
Biacetyl di(phenylhydrazone)
HO
NH2
N
N
N
C
N
H
H3C
aniline
+
H2O
N
CH3
(2E,3E)-3-(2-phenylhydrazono)butan-2-one oxime
4,5-dimethyl-2-phenyl-2H-1,2,3-triazole
Scheme 5. Example reactions by which von Pechamnn made 1,2,3-triazoles.33
Von Pechmann was very perceptive and realized that the compounds he was isolating
were actually derivatives of a compound having the formula C2H3N3. Once he realized this, he set
out to prepare the parent compound via a degradation reaction.33 Starting with 2-phenyl-1,2,3triazole-4-carboxylic acid (obtained by the oxidation of the 4-methyl derivative31) he first
oxidized this compound with potassium permanganate, converting the methyl group on the
triazole to a carboxylic acid. This intermediate was next nitrated in the para position of the
phenyl group. The 1,2,3-triazole-4-carboxylic acid was obtained by first reducing the nitro group
to an amino group by utilizing a mixture of tin (II) chloride and hydrochloric acid. This aminated
phenyl compound was removed by oxidative cleavage followed by a decarboxylation which led
to the desired unsubstituted triazole (Scheme 6).
13
HC
C
H3C
N
alkaline
KMnO4
N
N
HC
N
C N
C
HO
HNO3
HC
N
HO
O
H
C
HEAT
N
- CO2
HC
N
C
H
C
alkaline
KMnO4
NH
C
N
O
N
SnCl2
HCl
HC
HO
NO2
N
N
O
HO
NH
C
N
C
C
N
NH2
N
N
O
Scheme 6. Von Pechmann synthesis of 1H-1,2,3-triazole.31, 33
J. A. Bladin34 later showed that the same ring system was present in the benzotriazole
compounds. He managed to remove the benzene ring of 5-methylbenzotriazole by oxidation,
resulting in a 1,2,3-triaozle-carboxylic acid. This compound was then decarboxylated to give the
unsubstituted triazole (Scheme 7), identical to the one obtained by von Pechmann.
H
N
H
N
N
N
H3C
N
H
N
N
HEAT at 200oC
alkaline
KMnO4
C
O
C
C
N
HC
C
N
CH
O
OH HO
Scheme 7. Bladin synthesis of 1H-1,2,3-triazole.34
After von Pechmann’s work, a large number of publications covering the 1,2,3-triazole
appeared. These reactions ranged in complexity in how the 1,2,3-triazole was obtained. Much of
14
the work involved extensions of Hofmann’s diazotization synthesis of fused-ring 1,2,3-triazoles
and von Pechmann’s osazone synthesis. Among the important investigations were those of
Dimroth and Fester,35 who discovered that the combination of hydrogen azide or phenyl azide
reacting with acetylene formed 1H-1,2,3-triazole and 1-phenyl-1,2,3-triazole, respectively,
resulting in the first Click Chemistry reactions.
The Dimroth and Fester35 method required acetylene to be dissolved in acetone, hydrogen
azide, and absolute alcohol. The mixture would react in a sealed tube at 100oC for 70 hours
(Scheme 8). Later, it was found that the combination of phenyl azide with acetylene under similar
conditions proceeded more easily, requiring only 40 hours of heating time.
H
N
N
HC
CH
acetylene
+
HN3
hydrogen azide
CH
N
CH
1H-1,2,3-triazole
Scheme 8. Acetylene and hydrogen azide producing 1H-1,2,3-traizole.35
Other methods used to obtain the 1H-1,2,3-triazole required the use of compounds
already containing a triazole ring. This was accomplished by reduction,36,
37
oxidation,37 or
heating33, 38-40 a substituted triazole to form the 1H-1,2,3-traizole. More elaborate methods were
designed to synthesize a 1H-substituted-1,2,3-triazole as well as the 1,4- and 1,5- disubstituted
triazoles.41 These methods utilized various alkenes, alkynes, azides, salts and high-pressured
reactions. Many of these reactions were accomplished through the use of metal catalysts 39, 42 such
15
as palladium and manganese. Synthesizing regioselective triazoles was also accomplished by
using an alkali salt,41 by employing the Grignard43 reaction, or by utilizing alkoxides44-47 to
selectively produce either 1,4- or 1,5- disubstituted triazole.37
Since Dimroth and Fester35 in 1910, highly considered methods were devised to
synthesize various 1,2,3-triazoles. Many of the reactions employed utilized harsh conditions and
carcinogenic solvents. The approach to synthesizing 1,2,3-triazoles using an alkyne and azide was
not frequently used until the late 1950’s. The reaction of acetylene and hydrogen azide performed
by Dimroth and Fester is an early example of a 1,3-diploar cycloaddition reaction (Scheme 8).
The concept of the 1,3-dipolar cylcoaddition, often referred to as a “Huisgen Cycloaddition”
reaction, was truly developed and expended by Rolf Huisgen. This method popularized the idea
of creating five-membered heterocyclic rings in a more direct route. After his publication in
1955,23 research in Huisgen group immediately boomed, leading to two review articles published
in 1963.48,
49
These articles illustrated various reactions using the 1,3-dipolar cycloaddition
principle. Since then, research in the synthesis of 1,2,3-triazole derivatives has increased
exponentially. The ease of synthesizing a triazole made it easier to research possible applications
for the 1,2,3-triaozle derivatives. The disadvantage to this approach was that using an
unsymmetric alkyne would lead to different regioisomeric products (Scheme 9). Since there was
not a universal method that would guarantee regioselectivity from these reactions, the problem of
how to favor the formation of the 1,4- versus the 1,5-disubstituted products became a focus of
much research.
16
1
N
O
+
N N N
N
N
5
4
+
O
1
N
N 5
O
N
4
1,4-isomer
1,5-isomer
Scheme 9. Example of regioisomeric products when using asymmetric alkyne.
In 2002, Meldal and co-workers found a way to synthesize 1,4-disubstituted-1,2,3triazoles selectively using a copper-(I)-catalyzed reaction.50 This method was typically done with
an alkyl azide and an alkyne under either ambient or heated conditions. Through this approach,
the synthesis of a regioselective triazole could be accomplished in high yield. Even though these
reactions could be performed using copper (I) such as copper iodide or copper bromide, 50,
51
Meldal found that using a mixture of copper (II) (i.e. copper(II)sulfate) and a reducing agent (i.e.
sodium ascorbate) to produce copper (I) in situ worked infinitely better.50 Although this method
produced a triazole from an alkyne and an azide, it was no longer formally a 1,3-dipolar
cycloaddition reaction. This type of reaction was better classified as a Copper-(I) catalyzed
Azide-Alkyne Cycloaddition (CuAAC),52 since the copper (I) readily coordinates with the alkyne
in the presence of a mild base (i.e. K2CO3) in aqueous solution (Scheme 10), in an approach
which resembles a Sonogashira reaction.50, 53
17
N
R2
N
N
R'
R1
C
C
H
CuLx
H
'
R
CuLx
H+
5
N
N
N
H
H+
1
R2
R'
R1
C
C
C
C
CuLx
CuLx
R2
N
4
2
N
C
R1
R2
R2
N
N
N N
N
CuLx
3
R'
C
N N
C
CuLx
Scheme 10. Copper-(I) catalyzed Azide-Alkyne Cycloaddition (CuAAC) mechanism.
The blue in denoted for the alkyl azide and the red is denoted for the
alkyne.50, 53
The very success in the selective formation of the 1,4-isomer using CuAAC highlights
the need for selective access to the complementary regioisomer, the 1,5-disubstituted-1,2,3triazole. Although 1,5-disubstituted triazoles were successfully formed by Kleinfeller in 1931,43
as well as L’Abbe in 1969,56 using bromomagnesium acetylides and organic azides, it lacked the
scope and the convenience of the CuAAC process.52 The very successful CuAAC was excellent
for synthesizing the 1,4-regioisomer, but did not product the complementary 1,5-disubstituted
triazole. To achieve this, Sharpless and coworkers utilized several different ruthenium complexes
18
to produce either the 1,4- or the 1,5- disubstituted triazole selectively in “perfect” 100% yield,
suggesting complete regiochemical control (Scheme 11).52
N3
Ru
+
Ru(OAc)2(PPh3)2
CpRuCl(PPh3)2
Cp*RuCl|PPh3)2
Cp*RuCl|NBD)
N
N N
N
N
N
+
1a
1b
85%
100%
100%
100%
15%
-------
Scheme 11. Ruthenium-Catalyzed Cycloaddition of Benzyl Azide to
Phenylacetylene. 52
There have been many creative methods devised to synthesize 1,2,3-triazoles ranging
from complex, step-by-step processes of structural transformation, to the simple cycloaddition of
an azide and an alkyne. Since von Pechmann’s discovery of them in 1888, there has been a rapid
growth and interest in synthesizing triazoles which stems from the desire to create compounds for
use in antifungal drugs, plant protection, anti-allergenics, obesity treatment and osteoarthritis
drugs. The catalytic processes discussed seem to offer an unprecedented level of selectivity,
reliability, and scope for these synthetic endeavors. However, the success observed using a metal
catalyst reduces the “greenness” of these reactions. Prolonged exposure to these metallic salts
(either copper or ruthenium) can cause memory loss, increased allergic reactions, high blood
pressure, depression, irritability, poor concentration, aggressive behavior, sleep disabilities,
fatigue, speech disorders, high blood pressure, autoimmune diseases, and chronic fatigue are just
19
some of the many conditions resulting from exposure to toxins.57 In addition, these reactions
often employ organic solvents and metallic salts that are highly toxic and harmful to the aquatic
environment. With these concerns came a growing interest in reducing or eliminating the use and
generation of substances hazardous to human health and the environment. The field of Green
Chemistry was created to encourage the design, development, and implementation of chemical
products and processes to reduce or eliminate the use and generation of hazardous substances.
Improving research and development productivity has been one of the biggest problems in
designing more environmentally friendly processes. The bottleneck for conventional
combinatorial synthesis was the optimization of reaction conditions to afford the desired products
in suitable yields and purities. Since many reaction sequences require at least one or more heating
steps for extended time periods, these optimizations are often difficult and time-consuming.
Microwave-assisted heating has been shown to reduce the need for solvents and catalysts, making
the reaction “greener” and more environmentally friendly.
20
Brief History for the Discovery and Optimization of Microwave Chemistry
The development of the microwave was stimulated by World War II when a magnetron
was designed to generate a fixed frequency of microwaves for Radio Detection and Ranging
(RADAR) devices.58,
59
In 1946, an engineer by the name of Dr. Percy Spencer came across
something interesting when studying the magnetron. He noticed that the microwave energy was
able to cook food when a candy bar in his pocket melted during one of his magnetron
experiments. Further studies showed that microwaves could increase the internal temperature of
foods much more quickly than a conventional oven.60 This drove companies to invest in the idea
of a commercial microwave for household use in 1954.
Investigation into industrial applications for microwave energy also began in the 1950’s,
and has led to applications including the removal of sulfur and other pollutants by the irradiation
of coal,60 rubber vulcanization,60 product drying,60,
solvent and compound extraction.65,
66
61
moisture and fat analysis,62-64 along with
As improvements and simplifications increased, the
purchase cost for the microwave decreased, allowing it to become an affordable, common
household item. Investigation into modifying and applying the domestic microwave oven for
scientific research was not examined until the late 1980’s. In 1988, there were two papers
published on microwave-assisted reactions,67, 68 and since then, many chemists have discovered
the benefits of using microwave energy to drive synthetic reactions. In 2010, more than 16,000
papers regarding microwave-assisted chemistry were published.
Many reactions were performed using a household microwave until problems arose.
These household microwave ovens were not designed for rigors of laboratory use since there
were no built-in safety controls. Acids and solvents quickly corroded the interior of the
microwave, and the ability to regulate temperature and pressure had not yet been developed. In
21
addition, the cavity of the microwave was not designed to withstand explosions that occurred
when vessels failed during runaway reactions.60,
69
These problems encouraged companies to
manufacture a multi-mode microwave oven that addressed all of these issues. These laboratory
grade microwaves worked well for large-scale applications, but had some fundamental limitations
in performing small-scale synthesis. Recently, single-mode technology which provides more
uniform and concentrated microwave power has become widely available.60
The use of the microwave oven in synthetic chemistry has increased because of its
efficiency, the option for solvent-free reaction conditions, reduced reaction times, enhanced
yields, and selectivity. Several of these advantages lend themselves to an eco-friendly approach,
termed Green Chemistry.70-72 Green Chemistry has twelve basic principles that act as guidelines
for what are environmentally friendly reactions. Among the twelve principle of Green Chemistry,
the best principles to facilitate the design of sustainable processes for the chemical industry 73 are
shown by performing reactions that are solvent-free, metal-free, and that reduce waste.
Microwave-assisted synthesis has now been using in many types of reactions, in
particular cycloaddition reactions, which are widely used reactions in organic synthesis. 74,
75
Cycloaddition reactions typically require the use of elevated temperatures and long reaction
times, however, the shorter reaction times associated with microwave-assisted reactions makes it
a very attractive application. The shorter reaction times lower the possibility for the
polymerization and the decomposition of reagents and products which often plague the thermal
cyclizations.74,
76
Several methods have been devised using the microwave to assist in the
synthetic process for cycloaddition reactions. These reactions have been performed under a
variety of conditions including 1) in sealed vessel under pressure,67, 68 2) with refluxing,77, 78 3)
22
under neat or solvent-free,71, 72, 79 4) using mineral supports,80-82 5) without supports,83-85 and 6)
heat captors to assist in rapid heating of a reaction.86
From the examples listed above, the versatility microwave-driven syntheses can be easily
seen. Microwave-assisted reactions often simplify the process needed to synthesize compounds
compared to conventional methods. The rapid heating of the microwave avoids the excessive
heating associated with classic heating. In fact, the microwave-assisted approach facilitates 1,3dipolar cycloadditions that are typically difficult, and sometimes impossible, to achieve with the
classical approach.87 Successful 1,3-dipolar cycloaddition reactions have been accomplished with
various 1,3-dipoles such as azomethine ylides,87 nitrones,88 azomethine imines and azides89 (see
Table 1). Synthesizing 1,2,3-triazoles using 1,3-dipolar cycloaddition by microwave irradiation
opens up the possibility for the synthesis of various triazoles that once seemed difficult. Many
triazoles that have been synthesized classically have also been successfully accomplished using
microwave irradiation, producing excellent results compared to classic synthesis. For example,
triazoles have been synthesized to contain sulfur,90 phosphorus,91 boron,92 or a metal93
incorporated in the compound at either the N1, C4 and C5 positions.
The interest of using the 1,3-dipolar cycloaddtion in the microwave came about at the
turn of the 21st century. The first 1,2,3-triazole was successfully synthesized using a household
microwave oven in 2001, a year before Meldal published his work on selective synthesis of 1,4disubstituted-1,2,3-triazoles. Tao and co-workers successfully synthesized several 1,2,3-triazoles
without a metal catalyst using a domestic microwave oven.94 The reaction simply required an
azide, an α-keto phosphorus ylide and recyclable silica gel (as a support) in an open vessel which
was irradiated for 4-10 minutes at 400 Watts with moderate to excellent yields (Scheme 12).
23
Ar
N
Ar-N3 + R-CO-CH=PPH3
MW , 4-10 min.
silica gel
C R
N
N
C
H
60-90%
Scheme 12. Formation of a derivative of 1,2,3-triazole using an azide and an ylide.94
Interestingly enough, the α-keto phosphorus ylides used may be seen as having internal
stereocontrol for the formation of triazoles, since all of the triazoles produced were the 1,5disubstituted regioisomer. This was an interesting finding because it illustrated two important
synthetic features. The first, formation of 1,2,3-triazole in a microwave oven and the second,
regioselective synthesis. This could very well have been the first green triazole synthesis
employing a microwave and exhibiting regioselectivity. The significance of the work from both
Meldal and Tao shows that microwave-assited heating could reduce heating times of classical
cycloaddition reactions from hours to a matter of minutes with similar or often better results.
Later, in 2004, Van der Eycken and co-workers were able to synthesize various 1,2,3triazole derivatives using copper (I) catalysis in the microwave oven. 95 This synthetic approach
formed only the 1,4-disubstituted triazole isomer and reduced the reaction time tremendously
compared to the previous CuAAC approach utilizing conventional methods. The copper (I)
catalyzed reaction for this kind of transformation has placed it in a class of its own and has
enabled many novel applications.96 Similarly to Meldal’s approach, Van der Eycken had to use a
mixture of copper (II) and a reducing agent to produce copper (I) in situ for the reaction to
proceed successfully with no trace of the 1,5-regioisomer. In that same year, Van der Eycken97
24
was able to synthesize 1,2,3-triazole derivatives using terminal acetylenes and glycosyl β-azides
in the presence of copper (I), which resulted in moderate to high yields of 30-90%. Ruthenium
catalysis, which was used to selectively synthesize the 1,5-regioisomer in classical synthesis, has
not yet been shown to be successful in microwave reactions.
25
Statement of Problem
The primary goal of this research was to synthesize various 1,2,3-triazoles using a
domestic microwave oven and without the use of organic solvent, catalysts or extended
heating. This will serve to emphasize the significance of green chemistry. The synthetic
method chosen provided a fast and efficient technique to obtain the desired triazoles and
afforded a good alternative to the classical synthesis without the use of toxic and
environmentally unsafe reagents.
26
Chapter 2
RESULTS AND DISCUSSION – BACKGROUND ANALYSIS
The purpose of this work was to design a synthetic method that could be used to
synthesize a wide variety of simple and complex 1,2,3-triazoles under the greenest conditions
possible. Synthesis of these triazoles was done by microwave heating a mixture of an alkyne and
an azide utilizing minimal to no solvent (Scheme 13). In designing methods for the formation of
1,2,3-triazoles, two main principles have been used as guidelines: 1) preventing waste is better
than cleaning it up, and 2) less toxic alternatives should be used wherever possible. To adhere to
these principles, the study was focused on reactions that can be run in the absence of solvents
(thereby eliminating the major source of waste in any reaction) and without added catalyst, since
many catalysts are toxic, metal-based compounds. These reactions were also designed to be
performed in an inexpensive, domestic-style microwave oven to avoid the high costs of the
laboratory-grade microwave.
R
R N3
+
2
R
R3
mw
N
N
R2
N
R3
Scheme 13. 1,3-Dipolar cyclization forming a 1,2,3-triazole, where R, R2 and R3 are
carbon based substitutents.
27
Typically, triazole-forming cycloaddition reactions have been attempted under a wide
variety of conditions, with varying degrees of success. Triazoles have be synthesized using
thermally driven cyclizations. However these reactions are generally slow and require high
temperatures, often utilizing steel bomb reactors.98-101 Triazole formation has also been
successfully accomplished using metal-based catalysis in reactions which exhibit both high yields
and regioselectivity.50, 52, 95 The disadvantage to this approach is that these reactions often employ
organic solvent, such as dimethyl sulfoxide (DMSO), and that the metallic salts utilized as
catalysts are highly toxic and harmful to the aquatic environment. Therefore a “greener”, more
eco-friendly, procedure would be desirable. The utilization of microwave-assisted synthesis
reactions offers several advantages over standard heating methods. Not only are microwaveassisted reactions faster than their classical counterparts, they are generally cleaner, require less
energy to run, and allow for easy heating of small-scale reaction mixtures. The use of standard
laboratory glassware and a domestic microwave oven keeps the costs associated with these
experiments much lower than procedures that utilize laboratory grade microwave ovens and
specialty glassware.
The reactions performed in this study demonstrate that various 1,2,3-triazoles could be
generated without the use of conventional heating or the use of expensive mono-mode microwave
ovens. The reactions in this study were performed primarily in a domestic-model microwave oven
using standard glassware to show that microwave assisted organic synthesis can be accomplished
without specialized materials, illustrating that this method was capable of producing several
1,2,3-triazoles with equal or better results compared to those in literature. In this study, benzyl
azide was used extensively to create several 1,2,3-triazoles. However, it was also of interest to
observe if this method may be applied to other azides, rather than just benzyl azide. The goal of
using different azides would be to illustrate the diversity and versatility of this developed
28
technique. The production of different azides was accomplished by using known and accepted
literature methods, these azides were ethyl 2-azidoacetate, 2-(2-Azidoethoxy)ethanol and 1,4bis(azidomethyl)benzene (Figure 5). Some 1,2,3-triazoles synthesized in this study were not
found in the literature, and required more advanced spectral analysis (i.e. Nuclear Overhauser
Effect, nOe) to determine the regioisomer isolated. The goal of the study presented here was to
illustrate how the synthesis of pharmaceutically useful triazole moieties could be accomplished
easily and in moderate to high yields without use of expensive laboratory equipment.
O
N3
N3
O
benzyl azide
N3
ethyl 2-azidoacetate
O
HO
N3
2-(2-Azidoethoxy)ethanol
N3
1,4-bis(azidomethyl)benzene
Figure 5. Various azides used in this study.
Initial microwave explorations were performed by setting the microwave at 30% power
and heating for 3 minutes. The starting materials were all placed in an Erlenmeyer flask and
loosely covered (Figure 6). This design was incorporated for all reactions to allow for some
venting, because heat and pressure can build up during the reaction. This design allowed for the
excess heat and pressure to be released safely.
29
Figure 6. Glassware used for the optimized reactions.
Optimization of each reaction was conducted to determine the proper power setting and
reaction time needed in order to achieve optimal results. Variations in the power settings and
times for each reaction may have been due to the fact that the power levels on a domestic
microwave oven are not controlled and do not indicate an actual change in power output. Rather,
a setting of 30% power indicates that the microwave will be on at full power but only irradiating
the sample 30% of the time. The remaining 70% of the time, the sample is rotating on the
carousel absorbing the remaining microwaves that may be reflecting inside the microwave cavity.
Thus, microwaves of wattages under identical power level settings will have significant
differences in power output.
It was also noted that the amount of power which needed to be applied to the mixture
varied with the subsituents on the alkyne. From classical synthetic methods, it was observed that
the ease of the azide cyclization is governed by the polarization of the acetylene. It was found that
when the electron density of the alkyne was reduced, (i.e. when the alkyne carried strong electron
withdrawing groups), the reaction reached completion faster with the least amount of power
30
output from the microwave. The opposite was true when the alkyne had substituents that were
electron donating – rich alkyne required the most power output and took longer to reach
completion.
Some of the results obtained for the single ring systems were the preliminary reactions
explored during undergraduate work. The results showed a variation of yields that were obtained
depending on the chosen starting materials. This preliminary data provided the background
needed for the graduate study. Preliminary studies illustrated that a 1,3-dipolar cycloadition
reaction with a domestic microwave oven. The data obtained here were necessary to provide
comparisons for the reactivity differences between the single and double ring systems.
31
Single 1,2,3-Triazoles
1,3-Dipolar cycloaddition reactions were originally believed to work only if the alkyne
contained two electron withdrawing substituents. However, this theory was quickly proven to be
incorrect as preliminary studies showed that any alkyne could undergo this cyclization in a
domestic microwave to some degree. The biggest disadvantage to working with alkynes that were
more electron rich was the increased reaction times and applied power necessary to drive the
reactions. This discovery broadened the scope of the possible triazoles that may be synthesized
with relative ease. The collected results from this study of 1,3-dipolar cycloaddition reactions of a
variety of alkynes and with azides are shown in Table 2.
Table 2. 1,3-Dipolar cycloaddition reactions between an alkyne and azide to produce simple 1,2,3-triazoles.
Entry
Azide
Alkyne
Reaction Conditions
Products
Yield
CH2Ph
1
N3CH2Ph
H C
C CO2H
N
N
30% power/5 min
99%
H
N
H
PhH2C
N
2
N3CH2Ph
Ph C
C Ph
80% power/15 min
Ph
80%
N
N
Ph
CH2Ph
H3CO2C
3
N
30% power/30 sec
N3CH2Ph
H3CO2C C
N
C CO2CH3
98%
N
H3CO2C
CH2CO2CH2CH3
H3CO2C
4
N3CH2CO2CH2CH3
H3CO2C C
C CO2CH3
30% power/10 sec
N
H3CO2C
N
H3CO2C
5
TMSN3
H3CO2C C
C CO2CH3
87%
N
H
N
30% power/6 min
N
H3CO2C
61%
N
32
33
Using symmetric alkynes (i.e. alkynes containing the same functional groups on each end
of the molecule) made it easy to determine the success of the reaction because there were no
concerns about isomer formation. An interesting result of early inestigations suggested that
microwave heating could not only drive the desired cyclization reaction, but could also provide
unexpected results. The reaction between benzyl azide and propiolic aicd (entry 1, Table 2) was
expected to result in the acid-substitution triazole. Instead it produced unsubstituted 1-benzyl1,2,3-triazole. The change in functional group from the carboxylic acid would result from a
decarboxylation, which is commonly thermally driven. The loss of carbon dioxide from βcarboxylic acid shown in Scheme 14.
O
H3C
H
O
O
heat
OH
H3C
O
OH
O
O
+
H3C
β-keto acid
tautomerization
CH2
enol
O
C
O
H3C
CH3
keto
Scheme 14. Decarboxylation of a β-carboxylic acid.
Typically, the decarboxylation of simple carboxylic acids are considered difficult and are
rarely encountered.102 However, it was of interest to see that under this greener approach to 1,3dipolar cyclization which is done without solvents, buffering solutions or protecting groups, an
unexpected decarboxylation did occur. Reported triazole cyclizations using carboxylated alkynes
show no evidence of a decarboxylation reaction accompanying the triazole formation.1 It is
believed that this decarboxylation is thermally driven, as the method employed did not include
34
any attempt to control the heat of the cyclization reaction. The 1H NMR spectrum of this
decarboxylated product is shown in Figure 7 below.
SpinWorks 2.3:
B
Ph
A
H 2C
N
N
H
N
B
C
A
H
C
PPM
D
D
7.6
7.4
7.2
7.0
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transmitter freq.: 300.144690 MHz
time domain size: 65536 points
width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 16
6.8
6.6
6.4
6.2
6.0
5.8
5.6
5.4
5.2
freq. of 0 ppm: 300.142604 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
Figure 7. The 1H NMR of 1-benzyl-1,2,3-triazole.
From the 1H NMR, it was observed that the carboxylic acid was not present in the
expected downfield range of about 11.4 ppm. The -CH2- peak from benzyl azide was shifted from
4.4 ppm in the starting material to 5.6 ppm in the product. Chemical shifts for this product were
compared to literature spectral data and results were comparable.12 The decarboxylation was
believed to take place after the triazole formation, since if propiolic acid decarboxylated prior to
cyclization it would produce acetylene, boiling point -83.3oC, which would have vaporized before
it could react with benzyl azide since no effort was taken to seal the reaction vessel. Thus, it is
believed that the carboxylic acid acted as an auxiliary group, activating the alkyne to react
quickly under these simple conditions, before detaching to leave the unactivated triazole product.
35
In this way, it could be possible to produce triazoles which appear to originate from electron-rich
terminal alkynes.
Another interesting point to highlight was the result from the use of electron-rich alkynes
in this 1,3-dipolar cyclization reaction. Diphenylacetylene has been reported to be sluggish or
unreactive towards triazole formation in the absence of an outside catalyst.52 However, using this
method, diphenylacetylene reacted smoothly with benzyl azide to provide 4,5-diphenyltriazole in
high yields under simple heating by a domestic microwave oven, giving comparable results to
literature data (entry 2, Table 2). This reaction required a microwave heating power of 80% and
irradiation of the mixture of benzyl azide and diphenyl acetylene for 15 minutes in order to obtain
the desired product (Figure 8). Typically, reactions utilizing more electron-rich alkynes required
more intense heating, causing a greater loss of compounds (possibly due to evaporation). This
lead to slightly lower yields for these products as the heating times become longer.
SpinWorks 2.3:
B
Ph
B, C & D
A
CH2
N
N
N
Ph
C
Ph
D
PPM
7.8
7.6
7.4
7.2
7.0
6.8
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transmitter freq.: 300.144690 MHz
time domain size: 65536 points
width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 16
6.6
6.4
6.2
6.0
5.8
A
5.6
freq. of 0 ppm: 300.142607 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
Figure 8. The 1H NMR of 1-benzyl-4,5-diphenyl-1,2,3-triazole in CDCl3.
5.4
5.2
5.0
4.8
36
Figure 8 shows the 1H NMR of 1-benzyl-4,5-diphenyl-1,2,3-triazole produced by this
reaction. The product was analyzed by 1H NMR immediately after the reaction completed without
further purification. The -CH2- peak (A) for the starting material was no longer present at 4.31
ppm and had shifted to 5.40 ppm. The aromatic region for this triazole was integrated and was
found to integrate to 15 protons as expected.
D
D
D
D
SpinWorks 2.3:
D
D
E
B-E
E
E
x 1.000
144.0
140.0
136.0
132.0
C
C
N
E
E
N
N
A
B
B
B
B
E
B
B
CDCl3
128.0
A
PPM
135.0
125.0
115.0
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transmitter freq.: 75.478523 MHz
time domain size: 65536 points
width: 17985.61 Hz = 238.287803 ppm = 0.274439 Hz/pt
number of scans: 1024
105.0
95.0
85.0
75.0
65.0
55.0
freq. of 0 ppm: 75.470919 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
Figure 9. The 13C NMR of 1-benzyl-4,5-diphenyl-1,2,3-triazole in CDCl3.
Based on the
13
C NMR, it was observed that the alkyne carbons were absent from the
spectrum, as shown in Figure 9. If alkyne carbons were still in the crude mixture, they would be
found at around 90 ppm. In addition, the -CH2- carbon of the benzyl azide starting material would
typically be found at 60 ppm. The -CH2- in the product triazole was observed upfield from this
37
position, around 52 ppm. The chemical shifts of the aromatic carbons were compared to literature
and were found to agreed well.52 Thus, through these findings, it was concluded that 1-benzyl4,5-diphenyl-1,2,3-triazole was successfully synthesized in 80% yield.
Also included in the preliminary studies was an exploration of the affects of azide
substitutions on the cyclization reaction. In these reactions, azides that were either electron
withdrawing or donating were used to study the effects on the reaction to the production of
triazoles. Several attempts were made to create new azides that could be used to synthesized
novel triazoles, since the reactions performed utilizing benzyl azide (an electron donating 1,3dipole) had worked so successfully. Only a few of these azides produced triazole products in
good yields. The two azides that were successful in producting triazoles under neat conditions
were ethyl 2-azidoacetate and trimethylsilyl azide. In the reactions with dimethyl
acetylenedicarboxylate, all of the azides tested gave moderate to high yields with their
corresponding triazoles (61-98%).
The reaction of benzyl azide with dimethyl acetylenedicarboxylate (entry 3, Table 2)
was successful, producing virtually quantitative yields of the desired product. Analysis of the
crude product by 1H NMR in CDCl3 and showed the methyl esters (C & D) as two peaks, each
integrating to 3H (Figure 10). When the product was analyzed in d6-DMSO, an unexpected
outcome arose. In d6-DMSO, both of the methyl ester signals appeared as one peak at about 3.84
ppm, suggesting a triazole that was symmetric (Figures 11).
38
SpinWorks 2.3:
B
A
Ph
H2C
C
H3CO2C
N
N
N
H3CO2C
D
C
D
4.0
3.8
A
B
PPM
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
5.8
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transmitter freq.: 300.144690 MHz
time domain size: 65536 points
width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 16
5.6
5.4
5.2
5.0
4.8
4.6
4.4
4.2
freq. of 0 ppm: 300.142603 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
Figure 10. The 1H NMR of dimethyl-1-benzyl-1,2,3-triazole-4,5-carboxylate in CDCl3.
SpinWorks 2.3:
B
A
Ph
H2C
C
H3CO2C
N
N
D
H3CO2C
C, D
A
B
PPM
N
7.2
7.0
6.8
6.6
6.4
6.2
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transmitter freq.: 300.144690 MHz
time domain size: 65536 points
width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 16
6.0
5.8
5.6
5.4
5.2
5.0
4.8
4.6
4.4
4.2
4.0
freq. of 0 ppm: 300.142597 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
Figure 11. The 1H NMR of dimethyl-1-benzyl-1,2,3-triazole-4,5-carboxylate in d6-DMSO.
3.8
39
It is believed that the overlapping signals in d6-DMSO are fortuitous (Figure 11), and do
not reflect the actual structure of the molecule. It is not likely the benzyl group would be able to
shift from the 1-N nitrogen to the 2-N nitrogen position (as a proton would be capable of doing),
since a benzyl group is much larger and is held by a stronger bond. It is more likely that the
benzyl group resides on the 1-N position. The -CH2- group (A) was found to be a singlet since
there were no neighboring hydrogens, and in both solvent systems the -CH2- was found around
5.80 ppm.
The reaction of dimethyl acetylenedicarboxylate with ethyl 2-azidoacetate (entry 4,
Table 2) was also attempted with great success. The crude product was analyzed by 1H NMR and
the spectrum showed that product was very clean without any need for further purification. The
1
H NMR spectrum for this product is shown in Figure 12 below.
SpinWorks 2.3:
O
B
A
C
O
O
N
N
O
E
N
E
O
D
O
D
C
A
B
PPM
5.2
4.8
4.4
TMS
4.0
3.6
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transmitter freq.: 300.144690 MHz
time domain size: 65536 points
width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 16
3.2
2.8
2.4
2.0
1.6
1.2
0.8
0.4
-0.0
freq. of 0 ppm: 300.142597 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
Figure 12. The 1H NMR of dimethyl-1-(2-ethoxy-2-oxoethyl)-1,2,3-triazole-4,5-carboxylate in
CDCl3.
40
From Figure 12, the 1H NMR spectrum looks rather simple, but tells a lot about the
product synthesized. The CH3 (A) and CH2 (B) protons from the ethyl group were found at 1.30
ppm and 4.26, respectively. Since these protons did not shift much from their location in the
starting material, then NMR did not immediately suggest that the product was formed. The
methyl ester peaks, D and E, were found as two peaks each integrating to 3H and found 3.99
ppm, not far from the original 3.85 ppm in the starting material. The biggest change upon
formation of the product triazole occurred with the -CH2- peak (C). The starting material, ethyl 2azidoacetate, showed a -CH2- peak at 3.97 ppm, while the product 1H NMR shows this peak
shifted further downfield to 5.45 ppm. Through these findings, it was concluded that dimethyl-1(2-ethoxy-2-oxoethyl)-1,2,3-triazole-4,5-carboxylate was successfully synthesized in 87% yield.
Another interesting reaction was observed in the reaction of trimethylsilane azide (TMSN3) and dimethyl acetylenedicarboxylate. In the reaction of TMS-N3 with dimethyl
acetylenedicarboxylate, the analysis of the crude product mixture immediately after heating
indicated that no TMS group was present. The 1-H triazole (entry 5, Table 2) was successfully
isolated in 61% yield. Typically, the removal of a trimethyl silyl (TMS) group would be
accomplished by nucleophilic displacement with fluoride or oxygen nucleophiles (i.e. water),
however neither of these should have been present in the reaction system. To confirm the initial
analysis, the crude product was dissolved in diethyl ether and washed with sodium bicarbonate to
help purify the product further. The 1H NMR spectrum from the initial analysis and the extracted
product were the The 1H NMR showed the N-H (A) as a very broad peak at 16.28 ppm, as shown
in Figure 13.
41
A
A
B
H3CO2C
H
N
x 256.000
16.4
16.0
B
15.6
B
N
H3CO2C
N
TMS
PPM
16.0
15.0
14.0
13.0
12.0
11.0
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
-1.0
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freq.
<zg30>
of 0ppm: 300.142603MHz
transmitter freq.: 300.144690MHz
processedsize: 32768complexpoints
timedomainsize: 65536points
LB: 0.000 GB: 0.0000
width: 6172.84Hz=20.566213ppm=0.094190Hz/pt
number of scans: 16
Figure 13. The 1H NMR of dimethyl-1H-1,2,3-triazole-4,5-carboxylate, with an insert showing
he N-H peak region from 15.6 – 16.6 ppm.
The observed peaks for the -CH3- groups (B) of the two methyl esters were seen at 3.95
ppm (Figure 13). The observed peak for the N-H was a broad peak due to the averaging signals
of the two triazole tautomers. This broad peak illustrated that the rate of proton exchange from
N1 to N2 is extremely fast (Figure 14). The δ-values for the methyl esters in 1-H-1,2,3-triaozle4,5-dicarboxylate were identical (B) because of the fast equilibrium between the 1-H and 2-H
tautomers.7
H
N
N 1
O
O
O
N
O
O
1-H tautomer
N
H
N2
N
O
O
O
2-H tautomer
Figure 14. Dimethyl-1H-1,2,3-triazole-4,5-carboxylate.
42
Had the TMS group remained intact and localized on the 1-H position, the 1H NMR
analysis would have shown a single sharp peak integrating to nine protons. These methyl groups
would have been quite shielded and would have been observed near 0 ppm. Since this was not
observed, it was postulated that the loss of the TMS group occurred during an intermediate step in
the process of forming the 1,2,3-triazole. The reaction was believed to proceed via a 1,3-dipolar
cyclization as shown in Scheme 15.
H2
C
CO2CH3
C
Si(CH3)3
(H3C)2Si
H
N
C
CO2CH3
H
N
N
N
C
CO2CH3
N
N
N
N
CO2CH3
Si
+
N
C
CH2
CO2CH3
H3C
CH3
CO2CH3
dimethylmethylenesilane
Intermediate Step
Scheme 15. Purposed mechanistic pathway affording dimethyl-1H-1,2,3-triazole-4,5-carboxylate.
Typically, TMS deprotection reactions require the presence of a nucleophile to drive the
TMS group off of the nitrogen. However, the reaction condition employed was neat and did not
include an available nucleophile source. Thus, the suggested mechanism, shown in Scheme 15,
proposes that a proton from one of the nearby methyl groups on the silicon atom was donated to
the nitrogen during an elimination reaction. The resulting side product would then be
dimethylmethylene silane, a low-boiling point compound which would have vaporized during
heating. This would explain why none of it was recovered or observed in the 1H NMR of the
crude or purified product.
43
Chapter 3
RESULTS AND DISCUSSION – CURRENT WORK
Isomers of Simple 1,2,3-Triazoles
Preliminary studies into the formation of substituted 1,2,3-triazoles using a domestic
microwave oven showed that the approach could provide products in high yields and with some
interesting and unexpected results. These results provided a basis for the present study which
focused on several new aspects to this reaction method. These new aspects include the possibility
of regioisomer formation and the ability to form multiple triazole rings from a difuntionalized
substrate. It was of interest to synthesize more complex 1,2,3-triazoles to observe the versatility
of this method and compare results for reactions that have been successfully completed and
published in the literature.
When using an unsymmetrically substituted alkyne, there are actually 2 possible
regioisomers which can be produced in the dipolar 1,3-addition reaction (Scheme 16). The
method employed in this study does not attempt to control the regiospecificity of the sysnthesis of
1,2,3-triazoles. Many 1,2,3-triazoles published today, which afford regioselectivity, have utilized
metal-based complexes to synthesize a single desired isomer.50,
96
However, if metal-based
complexes are not used and no attempt to control the reaction is undertaken, the result should be a
mix of both 4- and 5-substituted isomers. It is important to note that even though the product
should theoretically produce a 1:1 ratio of each isomer, there is always the possibility that one
isomer will predominate due to steric hinderence. The overall yields of the several nonregiospecific reactions for the synthesis of substituted 1,2,3-triazoles are summarized in Table 3.
44
1
N
O
+ N N N
N
N
5
+
4 O
1,4-isomer
Scheme 16. Example of regioisomeric products when using asymmetric alkyne.
1
N 5
N
N
O
4
1,5-isomer
Table 3. 1,3-Dipolar cycloaddition reactions between an alkyne and azide to produce non-regiospecific 1,2,3-triazoles.
Entry
Azide
Alkyne
Reaction Conditions
Products
CH2Ph
H
1
N3CH2Ph
H C
C Ph
N
N
N
H
24.2 %
+
2
N3CH2Ph
HO2C C
C Ph
N
N
N
H
32 %
+
3
N3CH2Ph
Ph C
C CO2CH2CH3
N
54.1%
1 : 2.9
68.7%
1.1 : 1
N
N
+
N
H3CH2CO2C
1 : 2.3
CH2Ph
H3CH2CO2C
N
30% power/6 min
46%
14 %
CH2Ph
Ph
2.5 : 1
N
+
N
Ph
46%
CH2Ph
Ph
N
30% power/6 min
1:1
24.1 %
CH2Ph
H
48.3%
N
+
N
Ph
Ratio
CH2Ph
Ph
N
80% power/9 min
Yield
N
Ph
14 %
+
32 %
CH2Ph
H
CH2Ph
N
N
4
N3CH2Ph
C
C H
+
N
N
N
+
H
H C
C CH2OH
N
30% power/6 min
N
HOH2C
+
O
HOH2C
N
H
N
N
N
36.1 %
40.1 %
OH
O
N3CH2CH2OCH2CH2OH
N
H
14.0 %
5
N
N
N
50% power/9 min
+
OH
32.6 %
45
46
One of the first molecules to be studied arose from the reactions of phenylacetylene and
phenylpropiolic acid with benzyl azide (entries 1 & 2, Table 3). An interesting observation
occurred from the analysis of the products from these reactions. Even though these reactions
involve the use of two different alkyne starting materials, both reactions resulted in the formation
of the same product – a mixture of 1-benzyl-4-phenyl-1,2,3-triazole and 1-benzyl-5-phenyl-1,2,3triazole. The reaction of phenylproiolic acid and benzyl azide was accompanied by complete
decarboxylation in the resulting triazole products. The 1H NMR spectra are shown in Figures 15
and 16.
SpinWorks 2.3:
C
Ph
A
H
B
CH2
N
N
C
C
Ph
N
B
A
C
PPM
7.6
7.4
7.2
7.0
file: C:\Documents and Settings\Cathleen Roush\My Documents\Research\BOOK 3\2006\071106_CR190A\1\fid expt: <zg30>
transmitter freq.: 300.144690 MHz
time domain size: 65536 points
width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 128
6.8
6.6
6.4
6.2
freq. of 0 ppm: 300.142605 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
Figure 15. The 1H NMR of 1-benzyl-4-phenyl-1,2,3-triazole in CDCl3.
6.0
5.8
5.6
47
SpinWorks 2.3:
C
Ph
B
H2C
C
Ph
N
C
N
N
H
A
B
A
PPM
7.6
7.4
7.2
7.0
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transmitter freq.: 300.144690 MHz
time domain size: 65536 points
width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 128
6.8
6.6
6.4
6.2
6.0
5.8
5.6
freq. of 0 ppm: 300.142603 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
Figure 16. The 1H NMR of 1-benzyl-5-phenyl-1,2,3-triazole in CDCl3.
Previous studies had shown that propiolic acid reacted under these conditions to form a
decarboxylated triazole product, the reaction of phenylpropiolic acid was observed for any
similarities to the previous reactions. Analysis of the crude reaction product showed that the
carboxylic acid was no longer present. Additional studies in which the phenylpropiolic acid was
heated by itself in the microwave showed that no decarboxylation occurred in the absence of the
triazole ring formation. It was therefore concluded that this reaction occured by first undergoing
the 1,3-dipolar cyclization reaction, with the decarboxylation occurring afterwards. This was
further supported by the observation that both the phenylacetylene (entry 1, Table 3) and
phenylpropiolic acid (entry 2, Table 3) each react with benzyl azide to give the same triazoles
with the same overall isolated yield. However, the more polar phenylpropiolic acid produced the
4-subsituted product in a 2.5:1 ratio over the 5-substituted product while the phenylacetylene
cyclization produced a 1:1 ratio of these same isomers. Thus, the carboxylic acid group must have
48
stayed on long enough to exert a large influence on the regioselectivity of the dipolar
cycloaddition reaction before decarboxylation take
place.
This study was extended to include the reaction of a lower-polarity alkyne – ethyl
phenylpropiolate with benzyl azide (entry 3, Table 3). Two factors made this reaction of
potential interest – electronegativity and sterics. The ethyl phenylpropiolate contained an ester
which is a strong electron withdrawing group. In previous reactions, electron poor alkynes
produced the highest yields of triazole products. In addition, the phenyl group on the alkyne was
larger and bulkier than the ester group present on the other side of the alkyne. Hence, steric
factors should be more pronounced in the reaction, and should influence how much of each
isomer would form. With the reaction of ethyl phenylpropiolate and benzyl azide optimized, the
isomers were purified and isolated successfully in an overall yield of 46%. Unfortunately, the
higher yields expected with the electron-withdrawing group was not observed. This reaction
illustrated that electonegativity was clearly not the only factor which determined how well these
reactions would proceed. The 1H NMR spectra for both product isomers are shown in Figures 17
and 18.
49
SpinWorks 2.3:
SpinW orks 2.3:
D
E
x
A
H3C
1.000
7.70
7.60
7.50
B
H2
C
Ph
C
D
H2C
O
C
O
N
N
7.40
N
Ph
E
CH2Cl2
D
E
A
C
B
PPM
8.4
8.0
7.6
7.2
6.8
6.4
6.0
file: C :\ Do cumen ts and Settings\C athleen Roush\ My D ocu ments\Resea rc h\BOOK 2\ 0630 05_C R21 2\1\ fid
5.6
5.2
4.8
4.4
TMS
4.0
expt: <zg30 >
transmitter freq .: 300. 14469 0 MH z
3.2
2.8
2.4
2.0
1.6
1.2
0.8
0.4
-0.0
-0.4
-0.8
proce ssed size : 32 768 complex points
time d omain size: 655 36 p oints
LB:
1
0. 000
GB: 0. 0000
Figure
17.
The
H 6.4
NMR6.0of ethyl
1-benzyl-4-phenyl-1,2,3-triazole-5-carboxylate
CDCl
3. 1.2
7.6
7.2
6.8
5.6
5.2
4.8
4.4
4.0
3.6
3.2
2.8
2.4
2.0
1.6
width: 6 172. 84 Hz = 20.5 6621 3 pp m = 0. 0941 90 H z/ pt
PPM
3.6
freq. of 0 ppm: 300 .142 609 MHz
numb er of scans: 16
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transmitter freq.: 300.144690 MHz
time domain size: 65536 points
width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 16
0.8
freq. of 0 ppm: 300.142609 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
D
SpinWorks 2.3:
E
SpinW orks 2.3:
C
PhD
H2C
E
Ph
N
N
x
H3C
O C
C
A
H
B2
O
2.000
7.4
7.2
7.0
A
C
E
D
N
acetone
B
TMS
H2 O
PPM
PPM
7.6
7.2
6.8
7.2
6.8
6.4
6.4
6.0
6.0
5.6
file: C :\ Do cumen ts and Settings\C athleen Roush\ My D ocu ments\Resea rc h\BOOK 2\ 0630 05_C R21 2A\1 \fid
transmitter freq .: 300. 14469 0 MH z
5.6
5.2
e xpt: <zg3 0>
file: C:\Documents and Settings\Cathleen Roush\My Documents\Research\BOOK 2\063005_CR212A\1\fid expt: <zg30>
time d omain size: 655 36 p oints
transmitter freq.: 300.144690 MHz
width: 6 172. 84 Hz = 20.5 6621 3 pp m = 0. 0941 90 H z/ pt
time domainnumb
size:er 65536
points
of scans: 16
width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 16
1
5.2
4.8
4.8
4.4
4.4
4.0
3.6
4.0
3.6
3.2
2.8
3.2
2.4
2.8
2.0
2.4
1.6
1.2
2.0
0.8
1.6
0.4
1.2
freq. of 0 ppm: 300 .142 603 MHz
proce ssed size : 32 768 complex points
LB:
freq. of 0 ppm: 300.142603 MHz
0. 000 GB: 0. 0000
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
Figure 18. The H NMR of ethyl 1-benzyl-5-phenyl-1,2,3-triazole-4-carboxylate CDCl3.
-0.0
0.8
-0.4
0.4
0.4
-0.0
50
The assignment of each isomer was made by comparison to the findings of Cwiklicki and
Rehse.103 Cwiklicki and Rehse reported that the compound which eluted first from the column
was the 5-carboxylate, and it was followed by the 4-carboxylate. According to this literature
source, the isomer assignments were made from the 1H NMR of the benzylic -CH2- group in the
1-position of the triazole. The paper suggested that if the ester was vicinal to the benzylic group,
(i.e. in the 5-position) then there would be an anisotropic effect, causing a downfield shift of the CH2- group to about 5.94 ppm. Having the phenyl group in the vicinal position, (i.e. the ester in
the 4-position) resulted in a more upfield position for this methylene signal at about 5.35 ppm.
Experimental results from this study showed the -CH2- protons at 5.94 ppm when the ester was at
the 5-position and at 5.42 ppm when the ester was at the 4-position. Based on these assignments,
the major product in the reaction of ethyl phenylpropiolate and benzyl azide was determined to be
ethyl 1-benzyl-4-phenyl-1,2,3-triazole-5-carboxylate (32% yield). Ethyl 1-benzyl-5-phenyl-1,2,3triazole-4-carboxylate was isolated at a significantly lower yield (14%). The sterics caused by the
benzyl group apparently influenced the reaction to produce more of the 4-phenyl isomer than the
5-phenyl isomer (a ratio of about 2.3:1). The results obtained in this study reflect the conclusion
obtained by Cwiklicki and Rehse in that the 4-phenyl triazole was the major product.
Another interesting observation occurred in the reaction of 2-ethynylpyridine and benzyl
azide (entry 4, Table 3). 2-Ethynylpyridine contained a nitrogen in the aromatic ring which
caused the electronegativity of the ring to increase, and thereby also increased the
electronegativity of the alkyne. This resulted in the need for a shorter overall reaction time and
lower power settings on the microwave compared to the reaction of phenylacetylene and benzyl
azide.
51
Although a few publications were found which included the reaction of 2ethynylpyridine and benzyl azide, most of them did not provide adequate spectral data for
comparison. A group lead by Warren G. Lewis reported a triazole created using 2ethynylpyridine and benzyl azide, however the paper did not give any specific data for this
particular triazole.104 Another literature report by Gonda and Novák105 cited the spectroscopic
data for their study using bis-triphenylphosphano complexes of copper (I) carboxylates as
efficient catalysts for synthesizing 1,2,3-triazoles. According to this literature source, the reaction
utilizing 2-ethynylpyridine formed only the 4-pyridyl isomer. Using a domestic microwave, 2ethynylpyridine easily underwent reaction with benzyl azide to form a triazole without the use of
any catalyst. The method employed showed that both the 4-pyridyl and 5-pyridyl-1,2,3-triazoles
were formed. The isomers were separated by chromatography and then analyzed by 1H NMR
(Figures 19 and 20).
52
SpinWorks 2.3:
C
Ph
B
CH2
N
N
N
C
A
H
D
B
D
D
N
A
D
D
D
PPM
8.6
8.4
8.2
8.0
7.8
7.6
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transmitter freq.: 300.144690 MHz
time domain size: 65536 points
width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 32
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
freq. of 0 ppm: 300.142603 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
Figure 19. The 1H NMR of 1-benzyl-4-pyridyl-1,2,3-triazole in CDCl3.
SpinWorks 2.3:
C
Ph
B
CH2
D
D
D
N
N
N
N
D
PPM
8.4
8.2
8.0
7.8
B
H
A
C
A
D
D
D
7.6
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transmitter freq.: 300.144690 MHz
time domain size: 65536 points
width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 84
7.4
7.2
7.0
6.8
6.6
6.4
6.2
freq. of 0 ppm: 300.142603 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
Figure 20. The 1H NMR of 1-benzyl-5-pyridyl-1,2,3-triazole in CDCl3.
6.0
5.8
5.6
53
Initially, the 1H NMR spectra for each isomer were identified by using a pattern
established by previously discussed triazoles, i.e. that when the proton was in the 4-postion of the
triazole ring, the singlet observed is further downfield compared to that of the proton on the 5position in the other regioisomer. The benzyl group (-CH2Ph) also showed a typical pattern for
chemical shifts in the two isomers. The -CH2- singlet for the benzyl group of the 5-pyridyl
triazole was observed further upfield compared to the -CH2- singlet for the 4- pyridyl isomer.
Even though these comparisons suggest the correct isomer identification, it was felt that these
NMR trends were not enough to confirm the isomers’ identity. Also, Gonda’s literature only had
spectral data for the 4-isomer triazole and did not describe the 5-isomer. From this, it was felt that
spectral confirmation was needed. Nuclear Overhauser Effect (nOe) experiments were therefore
performed to confirm the initial assignments.
An nOe experiment is used to show which hydrogens interact with other neighboring
hydrogen through space, since nOe effects become smaller as the atoms being studied get are
farther apart in the 3-dimensional structure of the molecule. This effect can be seen as positive
peaks observed for protons whose area has been enhanced by the nOe interaction, while negative
peaks show no interaction. Two hydrogens appeared to be well placed for an nOe study: the
benzyl -CH2- and the single hydrogen on the triazole ring. In the 4-substituted isomer, the
hydrogens should be fairly close together, while the 5-substituted isomer then would be rather far
apart. The nOe spectra were obtained for each isomer and are shown in Figures 21 and 22 below.
54
B
TMS
A
Ph
B
CH2
N
HA
N
N
N
Figure 21. nOe spectrum for 1-benzyl-4-pyridinyl-1,2,3-triazole in CDCl3.
A
B
TMS
Ph
B
CH2
N
N
N
N
H
A
Figure 22. nOe spectrum for 1-benzyl-5-pyridinyl-1,2,3-triazole in CDCl3.
55
In these studies, the triazole ring hydrogen (A) was irradiated and the benzyl -CH2protons (B) were observed for any changes. The 4-pyridyl isomer, in which the triazole hydrogen
(A) was closer to the benzyl -CH2- protons (B), was observed to have a large positive nOe effect
(Figure 21). For the 5-pyridyl isomer, in which the triazole hydrogen (A) was further from the
benzyl -CH2- protons (B) the signal appeared to have a very small positive nOe effect (Figure 22)
suggesting that these protons were too far apart to give a large nOe effect. While both of these
nOe spectra also contain small negative peaks, these do not represent nOe effects for each proton.
These negative peaks are considered to be false positive information and are obtained when the
T1 time for the selected proton was not set properly during the set up for the nOe experiment.
Overall, the nOe studies were conclusive in reinforcing the identification for each of the isomers
isolated, i.e. that the 1-benzyl-5-pyridinyl-1,2,3-triazole was isolated with the highest isolated
yield of 40.1% and 1-benzyl-4-pyridinyl-1,2,3-triazole was isolated with the lowest yield of 14%.
The results obtained from the study of 2-ethynylpyridine and benzyl azide resulted in an
unexpected outcome where the 5-pyridyl triazole dominated in yield compared to the 4-pyridyl
isomer, since Gonda reported the use of a copper catalyst which resulted with the selective
formation of the 4-pyridyl isomer. Gonda’s reaction, however, took place using a copper catalyst
which has been known to influence the regioselectivity of these reactions. It is clear that in this
microwave driven reaction steric factors did not dominate, since the more hindered 5-pyridyl
isomer was formed in a 2.9:1 ratio over the less hindered 4-pyridyl isomer. Further studies are
needed to better understand the observed selectivity.
The final reaction studied using an unsymmetric alkyne was the reaction of propargyl
alcohol with 2-(2-azidoethoxy)ethanol. This azide was synthesized and studied because it
contained a second functional group (an alcohol) on the azide. Alcohols are important in organic
56
chemistry because they can be converted into many other types of functional groups using a
variety of reactions. Alcohol groups are versatile and may be used as building blocks for larger,
more complex molecules which may be used for a variety of applications ranging from food
flavorings and fragrances to biological applications. The reaction of 2-(2-Azidoethoxy)ethanol
and propargyl alcohol was accomplished successfully to produce 1-(2-(2-azidoethoxy)ethanol)-4hydroxymethyl-1,2,3-triazole with a yield of 36.1% and 1-(2-(2-azidoethoxy)ethanol)-5hydroxymethyl-1,2,3-triazole with a yield of 32.6% (entry 5, Table 3). The 1H NMR spectra of
both regioisomers are shown below in Figures 23 and 24.
57
SpinWorks 2.3:
C
G
SpinWorks 2.3:
B, H
F
E
A
H
A
x
D
OH
G
O
7.6
7.4
4.2
4.0
3.8
3.6
3.4
H
N
Unknown
Contaminent
N
HOH2C
C B
7.8
1.000
4.4
N
PPM
E, F
D
7.2
7.0
6.8
6.6
6.4
6.2
6.0
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transmitter freq.: 300.144690 MHz
time domain size: 65536 points
width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 16
5.8
5.6
PPM
1
5.4
5.2
freq. of 0 ppm: 300.142596 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
7.6
5.0
4.8
4.6
7.2
4.4
6.8
4.2
4.0
6.4
3.8
6.0
3.6
3.4
5.6
5.2
4.8
Figure 23. The H NMR of 1-(2-(2-azidoethoxy)ethanol)-4-hydroxymethyl-1,2,3-triazole in
CDCl3.
SpinWorks 2.3:
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transmitter freq.: 300.144690 MHz
time domain size: 65536 points
width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 16
C B
HOH2C
F
D
OH
G
O
x
freq. of 0 ppm: 300.142
processed size: 32768
LB: 0.000 GB: 0.00
E, F
B, C
E
4.0
G
H
SpinWorks 2.3:
4.4
1.000
H
4.6
N
4.4
4.2
4.0
3.8
3.6
3.4
N
A
H
A
N
D
PPM
7.4
7.2
7.0
6.8
6.6
6.4
6.2
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transmitter freq.: 300.144690 MHz
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width: 6172.84 Hz = 20.566213 ppm = 0.094190 Hz/pt
number of scans: 32
6.0
5.8
5.6
5.4
5.2
5.0
4.8
4.6
4.4
4.2
4.0
3.8
3.6
3.4
3.2
freq. of 0 ppm: 300.142599 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
Figure 24. The 1H NMR of 1-(2-(2-azidoethoxy)ethanol)-5-hydroxymethyl-1,2,3-triazole
in
PPM
7.2
6.8
6.4
6.0
5.6
5.2
CDCl3.
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58
The two isomers were separated via flash column chromatography and a D2O shake was
used to determine the location of the alcohol groups in the 1H NMRs of both isomers. From the
D2O exchange, the disappearances of peaks for the alcohol protons for each isomer were
observed. Determining one isomer from the other cannot be achieved by locating where the
alcohol protons are. Identifying which isomer corresponded to each 1H NMR spectum was
accomplished by correlation to a synthesis published by Molteni.106 Molteni reported a triazole
that was structurally similar to the triazoles synthesized in this study, however Molteni’s triazole
contained a methoxy group on the end of the N-1 carbon chain rather than an alcohol. According
to this literature reference, the lone hydrogen in the 4- or 5-isomer was used to assist in the
determination of the absolute structure of the isomer. The proton in the 4- and 5- positions were
reported at 8.11 ppm and 7.96 ppm, respectively, suggesting that the proton located at the 4position of the triazole ring was more deshielded than that of a hydrogen in the 5-position.
Experimental results from this microwave study showed protons at 7.96 ppm and 7.61 ppm, were
therefore assigned as the 4- and 5-positions, respectively. Using the same literature reference, the
remaining protons were assigned by observing the similarities in chemical shifts between the
triazole synthesized in this study and the one reported by Molteni.
Identifying which alcohol peak was accomplished by observing where the alcohol for the
hydroxymethyl was located. From the D2O exchange, the peaks for the alcohol protons for the 4hydroxymethyl isomer were determined to be at 3.5 ppm (C) and 5.2 ppm (D). For the 5hydroxymethyl isomer, the peaks for the alcohol protons were determined to be at 4.6 ppm (C)
and 5.4 ppm (D). Proton (D) was easily distinguished in both spectra since it did not overlap with
other signals. However, the alcohol protons from (C) were not as obvious. The 1H NMR spectra
illustrating the transformations are shown below in Figures 25 and 26.
59
C
D 2O
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3.80
3.30
3.20
3.70 3.10
3.60
3.00
2.90
3.50
3.30
3.20
3.10
freq. of 0 ppm: 300.142596 MHz
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z/pt
3.40
freq. of 0 ppm: 300.142590 MHz
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Figure 25. H NMR of 1-(2-(2-azidoethoxy)ethanol)-4-hydroxymethyl-1,2,3-triazole in CDCl3
showing the D2O exchange from alcohol to a deuterated alcohol.
C
D 2O
4.90
4.80
PPM
4.60
4.70
uments\Research\BOOK 4\2008\021308_144A\1\fid expt: <zg30>
4.74 4.50 4.72
4.70
4.40
4.68
4.66
4.30
4.64
freq.
of 0C:\Documents
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and
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4.62
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4.60
4.58
4.56
4.54
4.52
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Figure 26. H NMR of 1-(2-(2-azidoethoxy)ethanol)-5-hydroxymethyl-1,2,3-triazole in CDCl3
showing the D2O exchange from alcohol to a deuterated alcohol.
4.50
4.48
60
With the observed disappearance of the alcohol peak for both isomers, identifying which
alcohol peak belonged to the appropriate alcohol on each isomer. Using Molteni literature, the 4hydroxymethyl alcohol proton was determined to be at 3.5 ppm (C), leaving the 2-ethoxyethanol
alcohol to be at 5.2 ppm (D). In the 5-hydroxymethyl isomer, the 2-ethoxyethanol was
determined to be at 5.4 ppm (D), however the 5-hydroxymethyl alcohol proton was observed
further downfield at 4.6 ppm (C) compared to the 4-isomer. With the hydroxymethyl in the 5position of the triazole, it is possibe that the alcohol can interact with the alcohol from the 2ethoxyethanol through intramolecular hydrogen bond which would result in a downfield chemical
shift. The hydroxymethyl group on the alkyne was small, so it would not have been expected to
exert a lot of steric influence for regioselectivity, as can be seen from the 1.1 : 1 ratio of isomers
produced. Interestingly, the reaction proceeded with a very high yield (68.7 %) which might be
attributed to the smaller steric hinderance in this system compared to previously discussed
triazoles.
61
Synthesis of Bis-1,2,3-Triazoles
Since the discovery and recent development of the “click” cycloaddition reaction, the
1,2,3-triazole heterocyclic motif has rapidly become one of the most popular structures in
conjugate chemistry finding applications in the preparation of hybrid compounds, surface
modification of materials and biomaterials, and molecular scaffolding.8,
50
Similarly to this
breakthrough in monocyclic triazole chemistry, the 1,4-bis(azidomethyl)benzenes counterparts
(Scheme 17) have become very popular to use in macromolecules,107 functionalized surfaces,108
multicomponent cascade reactions109 and to build libraries of various 1,2,3-triazoles rapidly and
efficiently.110 The diverse applications for bis(azidomethyl)benzene made the microwave-driven
synthesis of difunctional 1,2,3-triazoles an interesting subject for study.
N
N N
N
R
R
R
N
N
N
N N
N
N
R
R
R
N
R
N
N N
N
N
N
R
Scheme 17. Symmetrically substituted bis(1,2,3-triazoles).
Various bis-triazoles might have been synthesized from any of the previously used
alkynes in the studies already presented. However, careful consideration was taken to select an
alkyne that would produce the best results. The alkynes chosen for the production of bis-triazoles
62
were selected from successful mono-triazole cyclization reactions accomplished when using
benzyl azide. Literature sources were used as comparison for spectral data obtained in these
reactions. The bis-triazoles were synthesized using 1,4-bis(azidomethyl)benzene in the reaction
with three alkynes: dimethyl acetylenedicarboxylate, diphenylacetylene and ethyl propiolate. The
results of these studies are summarized in Table 4.
Table 4. Reactions between an alkyne and 1,4-bis(azidomethyl)benzene.
Entry
Azide
Alkyne
Reaction Conditions
Products
H3CH2CO2C
N3
H3CO2C C
1
C CO2CH3
N3
Yield
CO2CH2CH3
N
N
N
10% power/1 min
98%
N
N
N
H3CH2CO2C
Ph
N3
2
Ph
N
N
N3
Ph C
C Ph
CO2CH2CH3
N
100% power/6 min
32%
N
N
N
Ph
H3CH2CO2C
N3
3
H
N
N
H C
N3
C CO2CH2CH3
30% power/5 min
Ph
N
35%
N
N
N
H
CO2CH2CH3
63
64
It was anticipated that a reaction between an alkyne and a bis-azide would be most
successful when the alkynes used were symmetric since the formation of and purification of
isomeric product would then be avoided. The success observed in preliminary studies suggested
that symmetric alkynes, when reacted with a bis-azide, would produce similar results. The
alkynes chosen for this study were the most successful electron poor alkyne and electron rich
alkyne. In the preliminary studies, dimethyl acetylenedicarboxylate and diphenylacetylene
produced the highest yields of 98% and 80%, respectively, in the synthesis of single triazole
rings. These results are summarized in Table 2, entries 2 & 3.
A group lead by Sultan Abu-Orabi111 reported the formation of a triazole product from
the reaction between 1,4-bis(azidomethyl)benzene and dimethyl acetylenedicarboxylate,
obtaining product in 96% yield. According to this literature source, the reaction utilizing dimethyl
acetylenedicarboxylate formed the bis-1,2,3-triazole by using conventional heating methods.
Using a domestic microwave, dimethyl acetylenedicarboxylate easily underwent reaction with
1,4-bis(azidomethyl)benzene to obtain the bis-1,2,3-triazole without the use of any catalyst or
added solvent. This
microwave
reaction successfully produced tetramethyl
1,1’-(p-
phenylenedimethylene) bis[1H-1,2,3-triazole-4,5-dicarboxlate] (entry 1, Table 4) in a yield of
98%, and it was analyzed without further purification. The 1H NMR of this product is shown in
Figure 27.
65
SpinWorks 2.3:
N
N
A
C
D
N
H3CO2C
CO2CH3
B
A
N
D
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7.0
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5.0
D
B
4.0
CO2CH3
H3CO2C
N
N
C
B
TMS
acetone
3.0
2.0
1.0
0.0
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Figure 27. The 1H NMR of tetramethyl 1,1’-(p-phenylenedimethylene)bis [1H-1,2,3-triazole-4,5dicarboxlate] in CDCl3.
The reaction conditions used with 1,4-bis(azidomethyl)benzene differed from that of
benzyl azide when reacted with dimethylacetylene dicarboxylate. A preliminary study showed
that benzyl azide reacted successfully with this alkyne at 30% power for 30 seconds. Using the
same reaction conditions for 1,4-bis(azidomethyl)benzene and dimethyl acetylenedicarboxylate
proved to be difficult to control, and the reaction overheated very quickly. The solution to this
issue of overheating was to decrease the amount of applied power and to increase reaction times
so as to slowly encourage the reaction to take place, heating at 10% power for a full minute. By
applying less power the reaction was easily controlled with excellent results, providing the
desired triazole product in 98% yield.
In the 1H NMR spectrum (Figure 27), the four benzylic protons (C) and aromatic protons
(D) in the product appeared as sharp singlets with chemical shifts of 5.79 ppm and 7.25,
respectively. The methyl esters (A) and (B) appeared as two nearly overlapping singlets. The
66
methyl ester protons in the 5-position (A) were assigned to the peak observed at 3.96 ppm due to
their proximity to the N-1 nitrogen. The methyl ester protons (B) found in the 4-position were
assigned to the more upfield peak at 3.88 ppm.
Another symmetric alkyne used in these bis-triazole studies was diphenylacetylene
(entry 2, Table 4). Previous studies showed that phenylacetylene exhibited unusual reactivity
with benzyl azide under these conditions to form a diphenyl triazole, and from this, the reaction
of diphenylacetylene and 1,4-bis(azidomethyl) benzene was observed for any similarities to the
previous reaction. Had both triazole cyclization reactions proceeded at an 80% yield, the bistriazole would have been expected to form in a 64% isolated yield (80% x 80%). The initial
reaction between 1,4-bis(azidomethyl)benzene and diphenylacetylene was attempted under the
same conditions as the reaction with the mono-azide. Using the initial reaction conditions of 80%
power for 15 minutes, the mixture did not show major color changes from a yellow liquid of the
original mixture. Analysis of the crude product at this point indicated that much of the
phenylacetylene had not reacted with the 1,4-bis(azidomethyl)benzene, even after extended
heating. The reaction was attempted again, raising the irradiation power from 80% to 100%, and
heated the mixture until there was a visible color change from pale yellow to a deep, amber red (~
6 minutes). The crude mixture was purified by recrystallization utilizing a solvent mixture of
petroleum ether and methanol. The purified triazole was isolated as a dark brown solid (32%).
The 1H NMR of tetraphenyl 1,1’-(p-phenylenedimethylene)bis [4,5-diphenyl-1H-1,2,3-triazole] is
shown in Figure 28. The 1H NMR spectrum shows that no remaining starting material was
present. The single peak for the -CH2- (F) and (G) had an upfield chemical shift of 4.33 ppm to
5.35 ppm. Integrations of these peaks show that peaks for benzyl protons (F) and (G) integrate to
4 protons. The aromatic region of the spectrum contains many peaks which were found to
integrate to 24 aromatic protons.
67
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B
A
N
B
N
N
N
B
Ph
B
Ph
B
B
B
Ph
B
Ph
A
B
N
N
CHCl3
PPM
7.6
7.4
7.2
7.0
6.8
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A
6.6
6.4
6.2
6.0
5.8
5.6
5.4
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Figure 28. The 1H NMR of tetraphenyl 1,1’-(p-phenylenedimethylene)bis [4,5-diphenyl-1H1,2,3-triazole] in CDCl3.
Analysis of the crude did afford the desired bis-triazole product, however the isolated
yield dropped to 32%, compared to the reaction of diphenyl acetylene and benzyl azide which
produced 80% of the mono-triazole. This drop in yield could be due to the overall increase in
sterics for the product tetraphenyl 1,1’-(p-phenylenedimethylene) bis[4,5-diphenyl-1H-1,2,3triazole]. With this reaction, the bis-triazole now contained four appended phenyl groups causing
the space within this molecule to become crowded. This crowding might have affected the rate of
the reaction and slowed it down, making it difficult to achieve higher yield for the bis-1,2,3triazole with the current designed method.
This study was extended to include the reaction of a lower polarity alkyne (ethyl
propiolate) and 1,4-bis(azidomethyl)benzene (entry 3, Table 4). Using ethyl propiolate was of
interest in order to observe the success of a reaction when utilizing an unsymmetric alkyne. This
would increase the complexity of purification for every isomer produced in this reaction, since
68
each triazole ring formed has the potential to exist in two regioisomeric forms. The crude product
from the reaction was purified by recrystallization from petroleum ether and methanol to give a
fluffy, bright yellow solid with an isolated yield of 35%. The 1H NMR of diethyl 1,1’-(pphenylenedimethylene)bis [1H-1,2,3-triazole-4-carboxylate] is shown in Figure 29.
SpinWorks 2.3: proton
D
E
H3C
C
O
H2
C
O
H
C
A
A
N
N
N
N
N
B
N
B
C
A
A
C
H2
O
H
7.6
7.2
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5.2
4.8
4.4
4.0
3.6
3.2
TMS
E
D
CDCl3
C
PPM
Unknown
Contaminant
B
2.8
2.4
2.0
1.6
CH3
D
C
A
E
O
1.2
0.8
0.4
-0.0
freq. of 0 ppm: 300.130005 MHz
processed size: 32768 complex points
LB: 0.000 GB: 0.0000
Figure 29. The 1H NMR of diethyl 1,1’-(p-phenylenedimethylene)bis[1H-1,2,3-triazole-4carboxylate] in CDCl3.
The 1H NMR appeared very simple, but revealed a lot about the product isolated. The
unknown contaminant at 3.94 ppm could not be identified as starting material or as any known
solvent impurities. Further spectral analysis did not place this peak as part of the product
molecule, since this peak did not appear in the crude product prior to recrystallization. Thus, this
contaminant must have entered the system during purification process.
69
The product was expected to exist in isomeric forms, however the 1H NMR showed what
appeared to be a single product isomer. In great contrast to the mono-cyclization reactions
conducted with benzyl azide, the reaction of ethyl propiolate and 1,4-bis(azidomethyl)benzene
displayed complete regiospecificity under similar conditions since only one product was obtained
after purification. The success of producing a single product was highly unexpected and the
analysis of the spectrum was confirmed by comparison to literature values.111 Its possible that
complete regiospecificity was accomplished due to the influence of steric effects. The molecule
was slightly crowded with the two 1,2,3-triazoles on the para positions of the benzene ring.
However, the sterics in the molecule was reduced when the two ester groups on each triazoles are
positioned as far away from each other as possible, i.e. in the 4-position of each triazole.
70
Other Attempted Reactions
The reaction of propiolic acid and 1,4-bis(azidomethyl) benzene was attempted in order
to explore the possibility of a double decarboxylation reaction in the formation of a bis-triazole.
Initial studies began with propiolic acid (Figure 30) and 1,4-bis(azidomethyl) benzene placed in
an 25mL Erlenmeyer flask. However, in a matter of seconds, a visible color change from clear to
a deep, amber red was observed even in the absence of any external heat source. The flask was
placed in the microwave for 30% power for 3 minutes for additional heating to ensure
completeness of the reaction. The resulting crude product showed that while some product was
formed, starting materials still remained. The reaction was attempted once more, and the flask
was irradiated at 50% power for 2 minutes. The crude product was analyzed immediately, but the
results were identical to the first experiment. The 1H NMR showed that some product had
formed, but the spectrum appeared to contain other unknown peaks that could not be identified.
Since the ability to control this reaction to form a clean product could not be accomplished over
multiple attempts, it was not pursued further.
O
H
C
C
Propiolic Acid
N3
OH
N3
1,4-bis(azidomethyl)benzene
Figure 30. Alkynes used for attempted reactions.
71
The success of this study forming various triazoles using a domestic microwave lead to
the question of how these reactions might perform in a laboratory grade microwave. Therefore,
several reactions were attempted in the MARS laboratory microwave, owned by the Department
of Chemistry at California State University, Sacramento (CSUS), which were successful using the
domestic microwave oven to optimize the comparisons. The reactions attempted utilized propiolic
acid, diphenylacetylene and dimethyl acetylenedicarboxylate, each reacting with benzyl azide. In
addition a unique reaction was attempted, that of acetylenedicarboxamide and benzyl azide. In
every case, the reactions performed produced very little product. Since the MARS microwave
system works better at larger scales and azides pose a potential explosion hazard when heated in
the microwave, the reactions could not be scaled up to properly be optimized in the MARS
microwave oven. It is also important to note that while no explosions occurred in the initial
attempts to utilize the MARS instrument with these organic azides, care was given whenever
azides were used to avoid potential hazards.
72
Chapter 4
CONCLUSIONS
Substituted 1,2,3-triazoles can be synthesized from a variety of organic azides and
alkynes via a simple cycloaddition reaction under neat conditions. The method designed for the
synthesis of 1,2,3-triazole made is possible to synthesize various types of triazoles. Through the
use of standardized glassware, the overall cost for the reactions dropped dramatically, making it
attractive to synthesize many compounds since there was no need for specialized, expensive
glassware. The reactions performed in this study illustrated several of the guiding principles of
Green Chemistry, namely that a reaction could be performed with no solvent, no catalyst, short
reactions and easy clean-ups. This study also highlighted the benefits in utilizing a microwave
oven for organic synthesis. Using a microwave oven allowed for reactions to be performed more
efficiently, affording reduced reaction times, enhanced yields, and selectivity. In the absence of a
catalyst, moderate to high yields of 1,2,3-triazoles were seen from both electron-rich and
electron-poor alkynes upon heating with an azide in a domestic microwave oven. This method
was also applied to creating larger, more complex bis-triazoles. These bis-triazoles formed were
synthesized
using
1,4-bis(azidomethyl)benzene
and
three
alkynes:
dimethyl
acetylenedicarboxylate, diphenylacetylene and ethyl propiolate, and afforded product in low to
high yields. Thus, this simple, green, microwave-assisted synthesis provides an effective
approach to the synthesis of a large variety of substituted 1,2,3-triazoles.
The development of a novel microwave enhanced synthetic protocol for the formation of
1,2,3-triazole derivatives has been accomplished. This eco-friendly, solvent-free approach using
microwave irradiation gives many possibilities for conducting rapid 1,2,3-triazole synthesis.
Triazoles have important properties and the potential to be incorporated into so many useful
73
bioactive compounds, making them of intense interest. The success of these reactions highlights
the need for future work in this area, which should include:

Performing reactions in a laboratory grade microwave for comparative results

Synthesizing 1,2,3-triazoles using various other azides (i.e. azidomethyl phenyl sulfide)
and multi-azide starting material (i.e. Polyoxyethylene bis(azide))

Synthesizing fused 1,2,3-triazole rings

Computational studies for the formation of simple and complex 1,2,3-triazoles
74
Chapter 5
EXPERIMENTAL
General Information
Abbreviations. Dimethyl sulfoxide (DMSO); Dimethyl Formamide (DMF); Deuteratated
chloroform (CDCl3); Deuterated-d6 Dimethyl sulfoxide (d6-DMSO).
Spectral. All spectra were obtained from a 300 MHz Bruker Avance AC 300 NMR spectrometer
in either CDCl3 or d6-DMSO.
Materials. Sodium azide was purchased from Matheson Coleman & Bell. Substrates purchased
from Acros Organics were benzyl chloride, ethyl bromoacetate, 2-(2-chloroethoxy)ethanol, 1,4bis(bromomethyl)benzene, ethyl propiolate, dimethylacetylene dicarboxylate, ethylphenyl
propiolate, diphenylacetylene, propiolic acid, phenyl acetylene and phenyl propiolic acd.
Substrates purchased from Aldrich Chemical Company, Inc. were azidotrimethylsilane, 2-ethynyl
pyridine and propargyl alcohol. All other reagents and solvents were of analytical grade, were
purchases from local suppliers and were used as obtained.
Overall synthesis. Synthesis for 1,2,3-triazoles were conducted in an Emerson Model 8912B
microwave oven (900 Watts). The synthesis for benzyl azide, ethyl 2-azidoacetate, 2-(2azidoethoxy)ethanol and 1,4-bis(azidomethyl)benzene were not synthesized using the microwave
oven, but by conventional methods.
75
Synthesis of the Azide Starting Materials
Benzyl azide (see Tables 2 & 3)112
A mixture of benzyl chloride (23 mL, 0.20 mol) and two equivalents of sodium azide
(25.699 g, 0.395 mols) were placed in a 125 mL Erlenmeyer flask with 45 mL of DMSO. The
flask was loosely corked and was allowed to stir overnight. The mixture was then diluted with 80
mL anhydrous diethyl ether and extracted with water (3 x 200 mL). The organic layer was dried
over sodium sulfate and concentrated by rotary evaporation. The product was isolated as a pale
yellow liquid (24.85 g, 0.187 mol, 93%).
300 MHz 1H NMR in CDCl3 (δ ppm): 4.31 (s, 2H); 7.31-7.45 (m, 5H). 75 MHz 13C NMR in
CDCl3 (δ ppm): 54.5; 128.0; 128.1; 128.6; 135.3.
Ethyl 2-azidoacetate (see Table 2)113
Ethyl bromoacetate (6.60 mL, 0.0595 mol) and sodium azide (7.79 g, 0.119 mol) were
placed in a 100 mL round-bottomed flask with 50 mL DMSO. The flask was loosely covered and
warmed at 55 oC for 2 h with stirring. The mixture was then diluted with 100 mL anhydrous
diethyl ether and extracted with water (4 x 125 mL). The combined organic layer was washed
with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary
evaporation leaving a colorless liquid (6.84 g, 0.0529 mol, 89%).
300 MHz 1H NMR in CDCl3 (δ ppm): 1.31 (t, 3H, -CH3, J = 7.13 Hz); 3.97 (s, 2H,
-
CH2-C=O); 4.27 (q, 2H, -CH2-, J = 7.20 Hz). 75 MHz 13C NMR in CDCl3 (δ ppm): 13.7; 50.0;
61.5; 168.2.
76
2-(2-Azidoethoxy)ethanol (see Table 3)114
NaN3 (4.50 g, 0.070 mol), tetrabutylammonium iodide (2.50 g, 0.060 mol), and 18-crown-6 (14
mg, 0.0530 mmol) were added to a solution of 2-(2-chloroethoxy)ethanol (5 mL, 0.045 mmol) in
2-butanone (25 mL, 0.0280 mol). The mixture was refluxed at 90 °C for 2 days with stirring. The
resulting precipitate was removed by filtration and rinsed with acetone. The combined organic
solutions were concentrated via rotary evaporation and purified by distillation, leaving a pale
yellow liquid (4.65 g, 0.035 mol, 75%). Results obtained agreed well with literature.
300 MHz 1H NMR in CDCl3 (δ ppm): 3.73-3.80 (t, 2H, -CH2-O-, J = 4.6 Hz), 3.67-3.73 (t, 2H,
N3-CH2-, J = 5.0 Hz), 3.58-3.65 (t, 2H, -O-CH2-, J = 4.5 Hz), 3.38-3.46 (t, 2H,
-CH2-OH, J =
4.9 Hz), 2.58 (s, 1H, OH). 75 MHz 13C NMR in CDCl3 (δ ppm): 54.9; 61.3; 69.7; 72.3.
1,4-bis(azidomethyl)benzene (see Table 4)115
1,4-bis(Bromomethyl)benzene (10.0 g, 0.038 mol) and sodium azide (5.0 g, 0.077 mol) were
placed in a 100 mL round-bottomed flask with 25 mL of DMF. The mixture was refluxed
overnight at 65 °C with stirring. The mixture was then diluted with 200 mL of water and
extracted with anhydrous diethyl ether (3 x 100 mL). The combined organic layers were washed
with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary
evaporation leaving a colorless liquid (6.62 g, 0.035 mol, 93%).
300 MHz 1H NMR in CDCl3 (δ ppm): 4.33 (s, 4H); 7.33 (s, 4H). 75 MHz 13C NMR in CDCl3
(δ ppm): 54.0; 128.3; 135.4.
77
Mono-1,2,3-Triazoles
1-Benzyl-1,2,3-triazole (Table 2, entry 1) 116
A mixture of propiolic acid (0.400 mL, 6.51 mmols) and benzyl azide (0.579 g, 4.34
mmols) were placed in a 25 mL Erlenmeyer flask and loosely covered with a watch glass. The
Erlenmeyer flask was placed in a microwave and irradiated at 30 % power for 5 minutes. The
flask was allowed to cool to room temperature, leaving a viscous brown oil which solidified
overnight, mp 50-52 oC (0.687 g, 0.431 mmols, 99%). Results obtained agreed well with
literature.
300 MHz 1H NMR (δ ppm): 5.57 (s, 2H); 7.23 – 7.30 (m, 2H); 7.34 – 7.41 (m, 3H); 7.47 (d, 1H,
H-triazole, J = 0.75 Hz); 7.71 (d, 1H, H-triazole, J = 0.76 Hz). 75 MHz 13C NMR in CDCl3 (δ
ppm): 53.22; 122.56; 127.23; 127.96; 128.34; 133.42; 133.90.
1-Benzyl-4,5-diphenyl-1,2,3-triazole (Table 2, entry 2)
52
A mixture of diphenylacetylene (0.852 g, 4.77 mmols) and benzyl azide (0.578 g, 4.34
mmols) were combined in a 25 mL Erlenmeyer flask and loosely covered with a watch glass. The
Erlenmeyer flask was placed in a microwave and was irradiated at 80 % power for 15 minutes.
The flask was allowed to cool to room temperature, leaving a viscous, red-brown oil which
solidified overnight. The compound was analyzed without further purification, mp 109-112oC
(1.06 g, 3.39 mmols, 80%).
300 MHz 1H NMR in CDCl3 (δ ppm): 5.40 (s, 2H); 6.99-7.05 (m, 2H); 7.11-7.17 (m, 2H); 7.227.27 (m, 5H); 7.34-7.47 (m, 4H); 7.52-7.58 (m, 2H). 75 MHz
13
C NMR in CDCl3 (δ ppm):
78
52.02; 126.68; 127.45; 127.67; 127.86; 128.10; 128.29; 128.39; 128.65; 129.11; 129.62; 130.08;
130.91; 131.58; 133.83; 135.34; 144.50.
Dimethyl-1-benzyl-1,2,3-triazole-4,5-carboxylate (Table 2, entry 3)
117
A mixture of dimethyl acetylenedicarboxylate (0.530 mL, 4.34 mmols) and benzyl azide
(0.580 g, 4.34 mmols) were combined in a 25 mL Erlenmeyer flask and loosely covered with a
stopper. The Erlenmeyer flask was placed in a microwave and was irradiated at 30 % power for
30 seconds. The flask was allowed to cool to room temperature, leaving behind a thick, red oil.
The product was analyzed without further purification (1.18 g, 0.49 mol, 98%).
300 MHz 1H NMR in CDCl3 (δ ppm): 3.86(s, 3H); 3.94 (s, 3H); 5.79 (s, 2H); 7.23-7.28 (m,
2H); 7.29-7.36 (m, 3H). 75 MHz
13
C NMR in CDCl3 (δ ppm): 52.54; 53.17; 53.79; 127.87;
128.70; 128.80; 129.67; 133.81; 140.07; 158.67; 160.29.
Dimethyl-1-((carboethoxy)methyl)-1,2,3-triazole-4,5-dicarboxylate (Table 2, entry 4)
A
mixture
of
ethyl
2-azidoacetate
(0.520
mL,
4.34
mmols)
and
118
dimethyl
acetylenedicarboxylate (0.561 g, 4.34 mmols) were combined in a 25 mL Erlenmeyer flask,
loosely covered with a watch glass, placed in a microwave, and irradiated at 30 % power for 10
seconds. The flask was allowed to cool to room temperature, leaving a visous, red-brown oil,
which solidified upon cooling. The product was then recrystallized with toluene, producing pale
yellow needle crystals, mp 124-125oC (1.00 g, 3.70 mmols, 87%).
79
300 MHz 1H NMR in CDCl3 (δ ppm): 1.29 (t, 3H, -CH3, J = 7.2 Hz); 3.97 (s, 3H, O=C-CH3);
3.99 (s, 3H, O=C-CH3); 4.26 (q, 2H, -CH2-, J = 7.1 Hz); 5.45 (s, 2H, N-CH2-). 75 MHz 13C NMR
in CDCl3 (δ ppm): 13.05; 50.64; 51.71; 52.39; 61.55; 128.91; 139.28; 157.61; 159.22; 164.48.
Dimethyl-1H-1,2,3-triazole-4,5-carboxylate (Table 2, entry 5)
101
A mixture of dimethyl acetylenedicarboxylate (0.800 mL, 6.51 mmols) and
azidotrimethylsilane (0.865 g, 6.51 mmols) were combined in a 25 mL Erlenmeyer flask, loosely
covered with a stopper, placed in a microwave, and irradiated at 30 % power for 6 minutes. The
flask was allowed to cool to room temperature. The crude product was dissolved in anhydrous
diethyl ether and washed with sodium bicarbonate (1 x 25 mL) and brine (1 x 20 mL). The
organic layer was dried over sodium sulfate, filtered and concentrated by rotary evaporation to
leave a yellow solid, mp 125-128oC (0.736 g, 3.98 mmols, 61%).
300 MHz 1H NMR in d6-DMSO (δ ppm): 3.95(s, 6H); 16.28 (very broad s, 1H). 75 MHz 13C
NMR in CDCl3 (δ ppm): 51.15; 136.60; 158.37.
1-Benzyl-4-phenyl-1,2,3-triazole & 1-Benzyl-5-phenyl-1,2,3-triazole (Table 4, entry 1)
52
A mixture of phenylacetylene (0.470 mL, 4.34 mmols) and benzyl azide (1.16 g, 4.34
mmols) were placed in a 25 mL Erlenmeyer flask and loosely covered with a watch glass. The
Erlenmeyer flask was placed in a microwave and was irradiated at 80 % power for 9 minutes. The
flask was allowed to cool to room temperature, and the crude product was purified by flash
chromatography on silica gel using 100:1 dichloromethane-methanol as eluent, giving two
80
isomeric products. The 4-phenyl isomer was isolated as a pale yellow solid, mp 60-62 oC (0.244
g, 1.04 mmol, 24.2 %) and the 5-phenyl isomer was isolated as a pale yellow solid, mp 133-135
o
C (0.242 g, 1.03 mmol, 24.1%).
(4-phenyl) 300 MHz 1H NMR (δ ppm): 5.58 (s, 2H); 7.27 – 7.35 (m, 5H); 7.35 – 7.43
(m, 3H); 7.66(s, 1H, H-triazole); 7.76-7.83 (m, 2H). 75 MHz
13
C NMR in CDCl3 (δ ppm):
54.20; 119.44; 125.58; 127.94; 128.03; 128.65; 128.67; 129.04; 130.42; 134.56; 148.12.
(5-phenyl) 300 MHz 1H NMR (δ ppm): 5.53 (s, 2H); 7.04 – 7.08 (m, 2H); 7.22-7.30 (m,
5H); 7.37-7.46 (m, 3H); 7.73 (s, 1H, H-triazole). 75 MHz 13C NMR in CDCl3 (δ ppm): 51.73;
126.76; 127.03; 128.03; 128.70; 128.75; 128.84; 129.40; 133.12; 135.38; 138.05.
1-Benzyl-5-phenyl-1,2,3-triazole & 1-Benzyl-4-phenyl-1,2,3-triazole (Table 4, entry 2) 1, 52, 119
A mixture of phenyl propiolic acid (0.634 g, 4.34 mmols) and benzyl azide (1.17 g, 8.68
mmols) were combined in a 25 mL Erlenmeyer flask and loosely covered with a watch glass. The
Erlenmeyer flask was placed in a microwave and was irradiated at 30 % power for 6 minutes.
After heating, the flask was allowed to cool to room temperature, and the crude product was
purified by flash chromatography on silica gel using 1:100 methanol-dichloromethane, giving two
isomeric products. The 4-phenyl isomer was isolated as a yellow solid, mp 62-64 oC (0.323 g,
1.38 mmols, 32 %) and the 5-phenyl isomer was isolated as yellow solid mp 135-136 oC (0.141 g,
0.599 mmols, 14%).
(4-phenyl) 300 MHz 1H NMR (δ ppm): 5.57 (s, 2H); 7.27-7.34 (m, 5H); 7.34-7.42 (m,
3H); 7.65 (s, 1H, H-triazole); 7.77-7.82 (m, 2H). 75 MHz 13C NMR in CDCl3 (δ ppm): 54.20;
119.44; 125.58; 127.93; 128.03; 128.64; 128.68; 129.02; 130.45; 134.60; 148.09.
81
(5-phenyl) 300 MHz 1H NMR (δ ppm): 5.55 (s, 2H); 7.06 – 7.10 (m, 2H); 7.23-7.31 (m,
5H); 7.38 – 7.45 (m, 3H); 7.74 (s, 1H, H-triazole). 75 MHz 13C NMR in CDCl3 (δ ppm): 51.75;
126.79; 127.01; 128.02; 128.67; 128.75; 128.80; 129.35; 133.14; 135.38; 138.01.
Ethyl 1-benzyl-4-phenyl-1,2,3-triazole-5-carboxylate & Ethyl 1-benzyl-5-phenyl-1,2,3-triazole4-carboxylate (Table 4, entry 3)
103
A mixture of ethyl phenylpropiolate (0.730 mL, 4.34 mmols) and benzyl azide (1.170 g,
8.68 mmols) were placed in a 25 mL Erlenmeyer flask and loosely covered with a watch glass.
The Erlenmeyer flask was placed in a microwave and was irradiated at 30 % power for 6 minutes.
The flask was allowed to cool to room temperature, and the crude product was purified by flash
chromatography on silica gel using 1:100 methanol-dichloromethane as eluent, giving two
isomeric products. The 4-phenyl isomer was isolated as a white solid, mp 97-99 oC (0.323 g, 1.05
mmols, 32 %) and the 5-phenyl isomer was isolated as a pale yellow oil, (0.141 g, 0.459 mmols,
14%).
(4-phenyl) 300 MHz 1H NMR (δ ppm): 1.17 (t, 3H, CH3 on ethyl ester, J = 7.2 Hz);
4.42 (q, 2H, -CH2- on ethyl ester, J = 7.2 Hz); 5.94 (s, 2H, N-CH2-); 7.24 – 7.35 (m, 5H); 7.39 –
7.44 (m, 3H); 7.67 – 7.74 (m, 2H). 75 MHz 13C NMR in CDCl3 (δ ppm): 14.16; 52.20; 61.11;
125.98; 127.50; 128.39; 128.50; 128.78; 129.77; 130.07; 134.66; 137.16; 141.27; 160.90.
(5-phenyl) 300 MHz 1H NMR (δ ppm): 1.25 (t, 3H, CH3 on ethyl ester, J = 7.0 Hz);
4.29 (q, 2H, -CH2- on ethyl ester, J = 7.1 Hz); 5.43 (s, 2H, N-CH2-); 6.95 – 7.03 (m, 2H); 7.16 –
7.22 (m, 2H); 7.22 – 7.29 (m, 3); 7.39 – 7.53 (m, 3H). 75 MHz 13C NMR in CDCl3 (δ ppm):
82
13.79; 54.24; 61.85; 124.13; 127.86; 127.97; 128.37; 128.78; 128.95; 129.44; 130.31; 135.26;
150.48; 159.17.
1-Benzyl-4-pyridinyl-1,2,3-triazole & 1-Benzyl-5-pyridinyl-1,2,3-triazole (Table 4, entry 4)
105
A mixture of 2-ethynylpyridine (1.75 mL, 1.74 mmols) and benzyl azide (0.464 g, 3.48
mmols) were placed in a 25 mL Erlenmeyer flask and loosely covered with a watch glass. The
Erlenmeyer flask was placed in a microwave and was irradiated at 50 % power for 9 minutes. The
flask was allowed to cool to room temperature, and the crude product was purified by flash
chromatography on silica gel using 70:30 ethyl acetate-hexane as eluent, giving two isomeric
products. The 4-pyridyl isomer was isolated as a white solid, mp 83-84 oC (0.164 g, 0.694 mmols,
40.1 %) and the 5-pyridyl isomer was isolated as an off-white solid, mp 105-107oC (0.0571 g,
0.242 mmols, 14.0%).
(4-pyr) 300 MHz 1H NMR δ ppm): 6.16 (s, 2H); 7.20 - 7.30 (m, 6H); 7.51 - 7.56 (m,
1H); 7.70 - 7.76 (m, 1H); 8.00 (s, 1H, H-triazole); 8.67 - 8.71 (m, 1H). 75 MHz 13C NMR in
CDCl3 (δ ppm): 53.09; 122.77; 123.31; 127.83; 127.86; 128.51; 133.68; 135.60; 136.13; 137.03;
147.07; 149.53.
(5-pyr) 300 MHz 1H NMR (δ ppm): 5.89 (s, 2H); 7.20 - 7.24 (m, 1H); 7.31- 7.40 (m,
5H); 7.74 - 7.80 (m, 1H); 8.07 (s, 1H, H-triazole); 8.16 - 8.20 (m, 1H); 8.52 - 8.55 (m, 1H).
75 MHz 13C NMR in CDCl3 (δ ppm): 53.67; 119.49; 120.54; 121.20; 122.09; 127.54; 128.09;
128.41; 134.34; 136.15; 148.56; 150.26.
83
1-(2-(2-Azidoethoxy)ethanol)-4-hydroxymethyl-1,2,3-triazole & 1-(2-(2-Azidoethoxy) ethanol)5-hydroxymethyl-1,2,3-triazole (Table 4, entry 5)106
A mixture of propargyl alcohol (0.253 mL, 4.34 mmols) and 2-(2-Azidoethoxy) ethanol
(0.570 g, 4.34 mmols) were placed in a 25 mL Erlenmeyer flask and loosely covered with a watch
glass. The Erlenmeyer flask was placed in a microwave and was irradiated at 30% power for 6
minutes. The flask was allowed to cool to room temperature, and the crude product was purified
by flash chromatography on silica gel using 80:20 diethyl ether-methanol as eluent, giving two
isomeric products. The 4-hydroxymethyl isomer was isolated as a colorless thick oil (0.290 g,
1.55 mmol, 36.1%) and the 5-hydroxymethyl isomer was isolated as a colorless thick oil (0.262 g,
1.40 mmol, 32.6%).
(4-hydroxymethyl) 300 MHz 1H NMR in DMSO-d6 (δ ppm): 3.38-3.53 (m, 5H); 3.763.85 (t, 2H, J = 5.3 Hz); 4.47-4.56 (m, 4H); 5.17-5.24 (t, 1H, -OH ether, J = 5.5 Hz); 7.96 (s, 1H,
H-triazole). 75 MHz 13C NMR in DMSO-d6 (δ ppm): 49.50; 55.26; 60.32; 68.96; 72.23; 123.24;
147.97.
(5-hydroxymethyl) 300 MHz 1H NMR in DMSO-d6 (δ ppm): 3.32-3.51 (m, 4H); 3.753.86 (t, 2H, J = 5.4 Hz); 4.44-4.57 (t, 2H, J = 5.5 Hz); 6.62(s, 2H); 4.64 (s, 1H, -OH ether); 5.395.49 (t, 1H, -OH, J = 5.7); 7.61 (s, 1H, H-triazole). 75 MHz 13C NMR in DMSO-d6 (δ ppm):
47.65; 52.11; 60.24; 69.26; 72.32; 132.25; 138.15.
84
Bis-1,2,3-Triazoles
Tetramethyl 1,1’-(p-phenylenedimethylene)bis[1H-1,2,3-triazole-4,5-dicarboxlate] (Table 5,
entry 1) 111
A mixture of dimethyl acetylenedicarboxylate (0.435 mL, 3.54 mmols) and 1,4bis(azidomethyl)benzene (0.399 g, 2.13 mmols) were combined in a 25 mL Erlenmeyer flask and
loosely covered with a watch glass. The Erlenmeyer flask was placed in a microwave and was
irradiated at 10 % power for 1 minute. The flask was allowed to cool to room temperature,
leaving a viscous, yellow-brown oil which solidified overnight. The compound was analyzed
without further purification, mp 141-142 oC (0.820 g, 1.74 mmols, 98%).
300 MHz 1H NMR in CDCl3 (δ ppm): 3.88 (s, 6H, -CH3 on ester); 3.96 (s, 6H-CH3 on ester);
5.79 (s, 4H, N-CH2-); 7.25 (s, 4H, ph). 75 MHz
13
C NMR in CDCl3 (δ ppm): 52.74; 53.37;
128.72; 134.80; 140.41; 158.72; 160.40.
Tetraphenyl 1,1’-(p-phenylenedimethylene)bis[4,5-diphenyl-1H-1,2,3-triazole] (Table 5, entry 2)
A mixture of diphenylacetylene (0.775 g, 4.34 mmols) and 1,4-bis(azidomethyl) benzene
(0.815 g, 4.34 mmols) were combined in a 25 mL Erlenmeyer flask and loosely covered with a
watch glass. The Erlenmeyer flask was placed in a microwave and was irradiated at 100 % power
for 6 minutes. The flask was allowed to cool to room temperature, leaving a viscous, red oil
which solidified overnight. The product was then recrystallized with methanol-petroleum ether,
producing dark brown solid, mp 112-114 oC (0.750 g, 1.38 mmols, 32%).
85
300 MHz 1H NMR in CDCl3 (δ ppm): 5.35 (s, 4H, N-CH2-); 7.03-7.61 (m, 24H).
75 MHz 13C NMR in CDCl3 (δ ppm): 50.39; 128.33; 128.83; 128.99; 129.35; 133.44; 133.89;
145.51; 145.89.
Diethyl 1,1’-(p-phenylenedimethylene)bis[1H-1,2,3-triazole-4-carboxylate] (Table 5, entry 3)
111
A mixture of ethylpropiolate (0.530 mL, 5.21 mmols) and 1,4-bis(azidomethyl) benzene
(0.816 g, 4.34 mmols) were combined in a 25 mL Erlenmeyer flask and loosely covered with a
watch glass. The Erlenmeyer flask was placed in a microwave and was irradiated at 50 % power
for 5 minutes. After heating, the flask was allowed to cool to room temperature, and the resulting
solid was then recrystallized with methanol-petroleum ether, producing a fluffy, bright yellow
solid, mp 215-218 oC (0.492 g, 1.28 mmols, 35%).
300 MHz 1H NMR (δ ppm): 1.34-1.37 (t, 6H, -CH3 on ester, J=7.1 Hz); 4.35-4.45 (q, 4H, -CH2on ester, J=7.2 Hz); 5.59 (s, 4H, N-CH2-); 7.32 (s, 4H, ph); 8.00 (s, 2H, H-triazole). 75 MHz 13C
NMR in CDCl3 (δ ppm): 14.34; 42.37; 52.38; 61.48; 91.92; 127.36; 129.22; 165.34.
86
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