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A general route to 1,5-disubstituted 1,2,3-triazoles
with alkyl/alkyl, alkyl/aryl, aryl/aryl combinations: a
Cite this: RSC Adv., 2014, 4, 9275
metal-free, regioselective, one-pot three
Received 26th November 2013 component approach†
Accepted 21st January 2014
Santu Dey and Tanmaya Pathak*
DOI: 10.1039/c3ra47062h
www.rsc.org/advances
An experimentally simple one-pot reaction, affording 1,5-disubstituted
1H-1,2,3-triazoles in good to excellent yields by combining vinyl
sulfones, sodium azide and alkyl bromides, -tosylates, -mesylates or
aryl amines, -iodides is reported. The organic azides, generated in situ
react with vinyl sulfones in a regioselective fashion in the absence of
metal ions. Unlike many of the recently reported strategies, this
method is capable of generating alkyl/alkyl, alkyl/aryl and aryl/aryl
containing 1,5-disubstituted 1,2,3-triazoles under simple reaction
conditions.
The ever increasing demand for new chemical entities and the
laborious process of lead discovery as well as optimization have
resulted in the continuous search for simple and efficient
methods for the generation of biologically active compounds.1
The quest for such a strategy led to the discovery of copper-
catalyzed azide–alkyne cycloaddition reaction (CuAAC) afford-
ing 1,4-disubstitued 1,2,3-triazoles (1,4-DTs).1a,f,2 The reaction
found numerous applications in bioconjugation,1b,c biology,1d,g,h
medicinal chemistry1e and materials science.1i The wide ranging
uses of 1,4-DTs also triggered interest in the regioisomeric
counterpart 1,5-disubstitued 1,2,3-triazoles (1,5-DTs) which are
considered as cis-peptide bond surrogates.1d 1,5-DTs can be
synthesized using halomagnesium acetylenes-3 or trimethylsilyl
acetylenes-4 based triazolylation with limited success. The
ruthenium-catalyzed azide–alkyne cycloaddition reaction
(RuAAC), carried out at elevated temperature under inert
atmosphere is widely used; however, this strategy is susceptible
to steric demands.5 An indirect route using Pd-catalyzed aryla-
tion of 4,5-unsubstituted N-monosubstituted 1,2,3-triazole
regioselectively yielded only 1,5-DTs.6 The Sm[N(SiMe3)2]3-
catalyzed synthesis of 1,5-DTs also requires elevated tempera-
ture and an inert environment.7 The eagerness to develop a
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721
302, India. E-mail: tpathak@chem.iitkgp.ernet.in; Tel: +91 (3222)283342
† Electronic supplementary information (ESI) available: Experimental section;
1
H/13C/DEPT spectrum, HRMS data, rotation value of the compounds. See DOI:
10.1039/c3ra47062h
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general method led to the synthesis of 1,5-DTs using up to three
equivalents of pyrophoric and hygroscopic ZnEt2.8
Most azides are not commercially available and must be
synthesised when required. Additionally low molecular weight
organic azides are highly energetic and potentially explosive.9
1,4-DTs10a–d,f and 1,5-DTs10e have been synthesized from alkynes
by generating organic azides in situ. The sole report on the one-
pot synthesis of 1,5-DTs used RuAAC and in situ generated
azides from a wide variety of primary alkyl halides; however, this
method did not afford 1,5-DTs when secondary azides were
employed.10e Additionally, the potential toxicity of metal cata-
lysts11a,b also encouraged researchers to devise metal-free
routes.11,12 For example, the ligation of aromatic azides and
aromatic alkynes in the presence of a catalytic amount of tet-
raalkylammonium hydroxide did produce 1,5-DTs but alkyl
acetylenes failed to react and the reactions are to be carried out
under strictly CO2-free conditions.12e
Almost all metal-catalyzed1,10e and metal-free approaches11,12
for the synthesis of 1,5-DTs involve the use of alkynes. We
looked beyond alkynes13 because phenyl vinyl sulfoxide,
considered as an acetylene equivalent14 afforded a mono-
substituted 1,2,3-triazole.15 Since vinyl sulfones are more easily
available than sulfoxides16 from a wide variety of 1,2- diols,
olens, epoxides and aldehydes,16 we developed a metal-free
and water-based general methodology for the synthesis of 1,5-
DTs from vinyl sulfones13 and showed its applications by
synthesizing a variety of triazolylated carbohydrates.17 To widen
the scope of this strategy, we planned to develop its practical
multicomponent variant by generating the azides in situ from
the corresponding halides, tosylates or mesylates. Therefore
four different vinyl sulfones 1a–d (Fig. 1) carrying both phenyl
and alkyl groups were selected.
Our strategy is crucially dependent on easy access to vinyl
sulfones decorated with different functional groups. Vinyl
sulfones 1b and 1d were synthesized using our reported strategy
(See ESI†).17,18 Additionally, a mixture of commercially available
2,3-dibromopropanol and sodium p-toluene sulnate in DMF
under elevated temperature yielded the desired vinyl sulfone 1a
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Table 1 Synthesis of 1,5-DTs from vinyl sulfones and aryl/alkyl halides,

mesylates or tosylates by one pot three component strategy
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Fig. 1 Alky- and aryl–vinyl sulfones selected for triazole synthesis.

R0 –X Vinyl sulfone / product (yield, time)

in good yield (Scheme 1).19 On the other hand, the commercially
available epichlorohydrin 3 was converted to its p-methoxy-
benzyl (PMB) derivative 4 in the presence of p-methoxybenzyl BnBr
alcohol (PMB–OH) and sodium hydride in dry DMF. The C–S
bond formation with 4-chlorobenzenethiol and 1,1,3,3-tetra-
methylguanidine (TMG) at elevated temperature followed by
oxidation of the sulde 5 using magnesium bis(monoperoxy-
phthalate) hexahydrate (MMPP) in MeOH afforded sulfone 6.
Mesylation of sulfone 6 with methanesulfonyl chloride (MsCl)
yielded the desired vinyl sulfone 1c in good overall yield
(Scheme 2).
Initially, reactions of benzyl bromide, 2-bromo-2- 3b-
methanesulfonyl-5-
phenylethanol and 3b-methanesulfonyl-5-cholestene with 1b or cholestene
1d were selected because they were expected to produce 1,5-DTs
previously reported by us.13 Thus, a well-stirred solution of an
appropriate halide (2 mmol), vinyl sulfone (1 mmol) and sodium
azide (2 mmol) in dry DMF (20 ml) was heated at 100
C. Aer
usual work-up and purication 1,5-DTs 7b, 7d, 8b and 9b were
obtained in 75–80% yields (Table 1).20 The triazole was formed in
a completely regioselective manner, with no contamination by
the 1,4-regioisomer. Subsequently, vinyl sulfones 1a–d were
reacted with a wide range of organic bromides, tosylates or
BrCH2CO2Et
mesylates and sodium azide using similar reaction conditions to
afford exclusively 1,5-DTs (Table 1).20 It should be noted that the
use of one equivalent of azide required longer reaction time
resulting in decomposition of starting materials and/or products. CH3(CH2)7OTs
Therefore, two equivalents of organic azides were used to maxi-
mize the yields of the 1,5-DTs.

Scheme 1 Synthesis of vinyl sulfone 1a from 2,3-dibromo-propanol 2.

MsO(CH2)4NHBoc

For the aryl/aryl combination, aryl azides were generated in

situ from the corresponding aryl amines and sodium azide via
diazotization reactions.21 Once again, the reported13 1,5DTs 15b,
15d and 19d were prepared rst and thereaer, 1a-b and 1d
were reacted with other aryl azides in water to afford 1,5-DTs
15a/18a, 15b and 15d–17d/19d respectively (Table 2).20 It is also
possible to generate aryl azides from aryl iodides in situ using a
Cu(I) mediated strategy22 and react the former with vinyl
Scheme 2 Synthesis of 1c from epichlorohydrin 3. sulfones to obtain 1,5-DTs in high yields (Table 3). We have

9276 | RSC Adv., 2014, 4, 9275–9278 This journal is © The Royal Society of Chemistry 2014

Communication
Table 2 Synthesis of 1,5-DTs from vinyl sulfones and aryl amines by
one pot three component fashion
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Ar–NH2 Vinyl sulfone / product (yield, time)
established that the presence of Cu(I) does not in any way
inuence the outcome of reactions reported in Table 3 (see
ESI†). Therefore the strategy for the generation of aryl azides
may be selected depending on the availability of the aryl
components as well as the stability of other functional groups of
the vinyl sulfones under the reaction conditions.
Table 3 Synthesis of 1,5-DTs from vinyl sulfones and aryl iodides by
one pot three component fashion
Ar–I Vinyl sulfone / product (yield, time)
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In addition to the comparison of spectral data of some of
these products with those of the regioisomeric 1,4-DTs,13 we
also directly assigned the structures of all triazoles using the 1H
NMR data. The chemical shi values of C4 and C5 of 1,5-DTs
ranging between 122.1–133.1 ppm and 134.2–148.0 ppm,
respectively made D(dC4  dC5) values signicantly smaller (ca.
13.5 ppm) as expected.23
To summarize, an efficient three-component reaction for the
generation of 1,5-DTs in a regioselective manner has been
developed. The method avoids the isolation and handling of
potentially unstable small organic azides and provides 1,5-DTs
in the absence of any metal catalyst. Since vinyl sulfones can be
easily synthesized,16 in the context of the non-availability of a
metal-free, efficient, exible and general method,12e our expe-
dient and general strategy offers a practical route to a wide
variety of 1,5-DTs using vinyl sulfones, sodium azide and alkyl
bromides, -tosylates, -mesylates or aryl amines, -iodides. To the
best of our knowledge, this is the only method known so far,
which makes use of tosylates and mesylates, easily available
from the cheaper alcohols instead of the more expensive
halides. An unprotected nucleophilic group of 1a does not
interfere with the reaction and is amenable to further synthetic
modications. Moreover, this method unlike many reported
strategies, is capable of generating 1,5-DTs with alkyl/alkyl,
alkyl/aryl and aryl/aryl combinations.
Acknowledgements
T. Pathak thanks the Department of Science and Technology
(DST), New Delhi for nancial support. S. Dey thanks the
Council of Scientic and Industrial Research for a fellowship.
Notes and references
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