Catalyst and solvent free microwave-assisted synthesis of substituted 1,2,3-triazoles

Article abstract of DOI:10.1039/c8gc01516c

We report a microwave-assisted catalyst and solvent free synthesis of 1,2,3-triazoles through the cycloaddition of trimethylsilylazide and acetylenes. Utilization of a thermally stable azide source, elimination of a metal catalyst, solvent or any additives, and a convenient isolation procedure result in an overall greener approach to access 1,2,3-triazoles on a practical scale with good to excellent yields (55-99%).

Full text of DOI:10.1039/c8gc01516c

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Catalyst and solvent free microwave-assisted
synthesis of substituted 1,2,3-triazoles†
Cite this: DOI: 10.1039/c8gc01516c
Received 16th May 2018,
Accepted 11th July 2018
a
a
b
a
Sahar Roshandel, Suresh C. Suri,* Jacob C. Marcischak, Golam Rasul and
a
G. K. Surya Prakash
*
DOI: 10.1039/c8gc01516c
rsc.li/greenchem
2
9
We report a microwave-assisted catalyst and solvent free synthesis in supramolecular chemistry,
of 1,2,3-triazoles through the cycloaddition of trimethylsilylazide science,
catalysis and materials
the pharmaceutical industry gained the most
and acetylenes. Utilization of a thermally stable azide source, elim- benefits from click chemistry to synthesize drugs and drug-
3
0–32
9
,33–35
ination of a metal catalyst, solvent or any additives, and a con- like molecules.
However, for biological applications the
venient isolation procedure result in an overall greener approach potential toxicity of even trace amounts of metal catalyst has
3
6
to access 1,2,3-triazoles on a practical scale with good to excellent always been of great concern. Moreover, the toxic and explo-
yields (55–99%).
sive nature of sodium azide, the commonly used azide source,
raises safety concerns, especially for practical scale synthesis.
Therefore, there has been increasing interest in employing
safer reagents and developing alternative metal free click reac-
NH-1,2,3-Triazoles are amongst the most desirable compounds
in biomedical research due to their diverse biological pro-
1
–5
6–9
perties
such
as
anticancer,
antifungal,
tions, such as using other non-metal additives to carry out the
1
0–12
13–17
antituberculosis,
Their ability to readily bind with a variety of receptors and
enzymes in biological systems has resulted in their extensive
application in medicinal chemistry. 1,2,3-Triazoles can be
easily accessed through 1,3-dipolar cycloaddition of an azide
with acetylene substrates first discovered by Michael in 1893,
and further studied by Huisgen as a member of the family of
and antibacterial activities (Fig. 1).
37,38
click chemistry,
alkynes
or employment of highly strained
39,40
41,42
or highly ambident electrophilic alkynes
to
accelerate the reaction rate. However, a scalable metal-free pro-
tocol that utilizes safer substrates and produces minimal
wastes for the synthesis of 1,2,3-triazoles has not yet been
achieved.
1
8
1
9
We were therefore motivated to develop an alternative green
method highly suitable for biological applications, which is
solvent-free, metal-catalyst/additive free, and atom economical
that utilizes safer reagents. Thus, trimethylsilyl azide (TMSN3),
a convenient and thermally safer replacement of sodium
2
0–22
dipolar cycloadditions.
This class of reactions was classi-
fied by Woodward and Hoffmann as thermally allowed pericyc-
2
3
lic processes. Later, Sharpless et al. categorized such chem-
istry under click reactions, the term he coined to address
“powerful, highly reliable and selective reactions for the rapid
43
azide, was selected as the azide source. Microwave irradiation
synthesis of useful new compounds and combinatorial
was preferred for heating the reaction mixtures to elevated
temperatures over the conventional heating methods as: (a)
microwave-assisted heating has been widely used for synthesis
2
4
libraries through heteroatom links”. A copper-catalyzed vari-
ation for regioselective 1,4-disubstituted cycloaddition of
azides and terminal alkynes was independently discovered by
2
5
26
Fokin, Sharpless et al. and Meldal et al. in 2002. Later, with
the discovery of ruthenium-catalyzed cycloaddition of azides
2
7,28
and alkynes,
ready access to all 1,2,3-triazole regioisomers
became possible. While click chemistry has been widely used
a
Loker Hydrocarbon Research Institute and Department of Chemistry, University of
Southern California, Los Angeles, CA, 90089-1661, USA. E-mail: gprakash@usc.edu,
sureshsuri52@gmail.com
b
Air Force Research Laboratory/Rocket Propulsion Division, Edwards Airforce Base,
CA, 93524, USA
†
Electronic supplementary information (ESI) available. CCDC 1843653. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8gc01516c
Fig. 1 Few examples of biologically active 1,2,3-triazoles.
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and is compatible with the process-scale preparation of yield; however, the most encouraging result (84% yield) was
4
4–46
pharmaceutical compounds,
(b) utilization of microwaves obtained only after the reaction was given enough time (6 h) to
generally reduces side reactions, improves yields, and reach an internal vessel pressure of near zero (entry 10). Fig. 2
4
5,47
enhances reproducibility,
and (c) scientific microwave reac- illustrates the temperature and pressure profiles of the reaction
tors record key reaction parameters such as microwave power, with respect to time at a constant temperature of 200 °C, as
reaction time, and internal pressure of the reaction vessel recorded using the microwave reactor. Initially, when the reac-
throughout the reaction, thus allowing for a deeper under- tion mixture is heated up to the desired temperature, an
standing of the reaction chemistry. Recently, there has been elevation in pressure is observed due to the increase in the
considerable growth in using microwaves to synthesize 1,2,3- vapour pressure of substrates. As the reaction proceeds, a
triazoles. However, to the best of our knowledge, none of the gradual decline in pressure is observed as the final product
microwave procedures are catalyst/additive and solvent (triazole) has a lower vapour pressure than that of the reactants.
4
8–57
free.
Consequently, the completion of the reaction can be visualized
Optimization was carried out by conducting a series of as the appearance of a plateau (or an internal pressure of zero)
microwave reactions using diphenylacetylene as a model sub- in the time–pressure profile (for details see the ESI†).
strate (Table 1). Initially a 1 : 1 ratio of trimethylsilyl azide and
The scope of this method was subsequently investigated by
diphenylacetylene was exposed to microwave irradiation at a conducting microwave-assisted cycloaddition reactions of
constant temperature of 200 °C for one hour to obtain different acetylenes (on a 3–5 mmol scale, for details see the
N-trimethylsilyl
4,5-diphenyl-1,2,3-triazole.
Subsequently, ESI†) with trimethylsilyl azide at 200 °C. The progress of the
exposure of the reaction mixture to air produced NH-4,5-diphe- reaction was monitored by the change in the internal pressure
nyl-1,2,3-diphenyltriazole (11), as traces of moisture readily of the vessel as discussed earlier. The efficacy of this method
hydrolyse the trimethylsilyl group to furnish the free N–H was initially tested for terminal alkynes containing aromatic
group. However, most of the starting materials remained groups (1–7). To our delight, this method afforded triazoles in
unreacted affording 11 in only 8% yield (entry 1). A higher excellent yields for both electron-rich (1,2) and electron-
amount of the triazole product was obtained with increased deficient aromatic alkynes (3). Moreover, all halogenated sub-
reaction time (entry 2–4). To our surprise, when the reaction strates were well tolerated under the reaction conditions pro-
was carried out at lower temperatures, even with a higher viding good to high yields of products (4–7).
quantity of reagents, a drastic decline in the yields was
observed, revealing the critical role of heating in this reaction treated with trimethylsilyl azide under the reaction conditions.
entries 5–7). Therefore, the optimum temperature of 200 °C Excitingly, cyclopropylacetylene also readily participated in the
Next, an alicyclic substrate (cyclopropylacetylene) was
(
was chosen for the rest of the optimization. When the amount reaction, producing the corresponding triazole (8) in an excel-
of trimethylsilyl azide was increased to 1.5 equivalents (entries lent yield (80%), and thus demonstrating the applicability of
8
and 9) promising improvement was observed in the overall this method for both aromatic and aliphatic terminal alkynes.
Next, various symmetric and asymmetric internal alkynes
(
9–16) were subjected to the reaction conditions to explore the
effect of polarity and steric hindrance on the overall yield and
time of the reactions. Since polar molecules selectively absorb
microwave irradiation while nonpolar molecules remain inert
to them, the presence of polar moieties is crucial to achieve a
more potent heating throughout the reaction. Therefore, as the
number of polar moieties increases on the substrates, a
a
Table 1 Optimization of the reaction conditions
b
Entry
TMSN
3
(equiv.)
Time (h)
Temperature (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1.5
2.5
2.5
1.5
1.5
1.5
1
2
4
8
3
3
3
2
3
6
200
200
200
200
100
100
150
200
200
200
8
10
41
53
Trace
Trace
>5
27
40
c
1
0
84 (28%)
a
Reaction conditions: All reaction vessels were sealed under inert con-
ditions of either nitrogen or argon, and were exposed to air for 30 min
b
after microwave irradiation. Isolated yield after column purification.
c
This reaction was also subjected to conventional heating (oil-bath) Fig. 2 Data acquired from the microwave reactor for the reaction of
and the corresponding triazole was obtained in only 28% yield.
diphenylacetylene and trimethylsilyl azide.
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shorter reaction time can be expected. Likewise, as shown in β-silicon effect of this moiety generates a more electron rich
Table 2, a longer reaction time was required for obtaining 9, alkyne, which ultimately is unfavourable for the 1,3-dipolar
which has one polar group when compared to 12 with two cycloaddition reactions. Similarly, lower yields of 10, 14, and
polar moieties. However, it is worth noting that the presence 16 can be explained by both the steric effect and the β-silicon
of two polar moieties in 12 is not the sole reason for its effect of the trimethylsilyl moiety.
shorter reaction time. It is well understood that a more elec-
It should also be noted that the majority of the isolated tri-
tron deficient alkyne undergoes faster 1,3-dipolar cycloaddi- azoles, shown in Table 2, are observed in NMR as the 2H tauto-
tions; therefore, the effect of two highly electron-withdrawing mers. Although the 1,3 cycloaddition between the alkyne and
groups on the rate of the reaction cannot be neglected. trimethylsilyl azide initially generates the 1H tautomer, the
Likewise, when 9 and 11 are compared, the replacement of an rapid tautomerization results in the 2H isomer which is
ethyl carboxylate with a phenyl group results in a drastic reportedly the more thermodynamically stable tautomer.
1
3
increase in the reaction time as both the number of polar moi- Interestingly, in the case of 16, the C NMR spectrum showed
eties and the electronic nature of the molecule have been two different quaternary carbon peaks at 150.6 and 139.8 ppm,
1
unfavourably affected.
and the H NMR showed the presence of two trimethylsilyl
Furthermore, silylalkynes in general showed a lower reac- peaks around 0.38 ppm, revealing the lack of symmetry in the
tion rate, as observed from the pressure profile of the reaction, chemical structure of 16. This was tentatively explained as the
and also afforded an overall lower yield when compared to result of the exclusive presence of the 1H tautomer. Thus, to
those without trimethylsilyl groups. For instance cyclopropyl- gain a better understanding of the reaction, we conducted a
3
acetylene was reacted with TMSN to provide compound 8 in variable temperature NMR study. The methyl peaks gradually
an excellent yield of 80% after 4 hours whereas with cyclopro- became sharper with decreasing temperature and ultimately
pyl(trimethylsilyl)acetylene, the yield of the corresponding tri- appeared as a multiplet at −10 °C. Furthermore, even at a
azole (13) was significantly less (33%). We believe that the higher temperature of 45 °C, the two distinct trimethylsilyl
presence of the trimethylsilyl moiety not only interferes with peaks were still observed, and thus reflecting a very high
the rate of the reaction due to steric hindrance, but also the energy barrier of tautomerization for 16 from the 1H to 2H tau-
tomer (Fig. 3-left). Indeed, DFT calculations showed that even
though the 2H-tautomer (B) is more stable than A by 1.8
kcal mol− , a high activation energy of 46.3 kcal mol
1
−1
Table 2 Reaction of trimethylsilyl azide with various acetylene
substrates
prevents the tautomerization of B to A. However, the high
activation energy can be easily circumvented in acidic media
through deprotonation–reprotonation to access the more
stable tautomer (16B), as the addition of a drop of trifluoro-
a
acetic acid to a solution of 16 in CDCl resulted in the instan-
3
taneous formation of 16B at room temperature (as observed by
the appearance of only one quartenary carbon for the triazole
ring at 146 ppm).
5
8
Additionally, Goddard et al. have reported an extensive
crystal structure analysis of the 1H and 2H tautomers of the
parent 1,2,3-triazole, where they have successfully distin-
guished the crystal structure of the tautomers based on the
bond angles, as the N atom bearing the H atom shows a larger
a
Reaction conditions: All reaction vessels were sealed under inert con-
ditions of either nitrogen or argon, and were exposed to air for
3
0 minutes after microwave irradiation. All reactions were conducted
b
Fig. 3 (Left) DFT-computed relative energies of different tautomers
and the energy barrier of the transition state for 4,5-bis(trimethylsilyl)-
at 3–5 mmol scales. Reported yields are isolated yield after recrystalli-
zation (for details see the ESI). Reported yields are isolated yield after
flash column chromatography (for details see the ESI). The reported NH-1,2,3-triazole. (Right) The crystal structure of 16, showcasing the
c
d
yield is obtained from 12 mmol of phenyl acetylene.
bond angles of nitrogens.
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5
9
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1
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triazoles in this work show promising biological activities as
single molecules. For instance, compound 1 shows stronger
indoleamine 2,3-dioxygenase (IDO) inhibitory activity when
1
1
1
1
6
0
compared to the most commonly used inhibitor 1-MT, while
6
1
6
and 13 respectively show promising metalloenzyme and
6
2
viral polymerase inhibitory effects. We believe that our work
presents a green and more biologically suitable method to
synthesize such valuable compounds. Our method is not only
catalyst-free, additive-free, and solvent-free, but also provides
an atom economical, safer, and more convenient route to syn-
thesize 1,2,3-triazoles. The simple work-up and purification
procedure along with its scalability makes this method a
potent green route for synthesizing potentially pharmaceuti-
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metal contamination.
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Conflicts of interest
There are no conflicts to declare.
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