A metal-free, aqueous and general route to 1,5-disubstituted-1,2,3- triazoles: "Reversed regioisomeric" 1,3-dipolar cycloaddition of azides and vinyl sulfones

Article abstract of DOI:10.1055/s-0030-1260306

A metal-free, vinyl sulfone-based synthesis of 1,5-disubstituted-1,2,3- triazoles is reported for the first time. These triazoles are easily formed in a regioselective fashion by heating under reflux a mixture of a substituted vinyl sulfone and an organic

Full text of DOI:10.1055/s-0030-1260306

LETTER
2521
A Metal-Free, Aqueous and General Route to 1,5-Disubstituted-1,2,3-
triazoles: ‘Reversed Regioisomeric’ 1,3-Dipolar Cycloaddition of Azides
and Vinyl Sulfones
1
, 5-Disubstitu
a
nazoles tu Dey, Dhrubajyoti Datta, Tanmaya Pathak*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721 302, India
Fax +91(3222)282252; E-mail: tpathak@chem.iitkgp.ernet.in
Received 31 May 2011
ed with the use of olefin-based synthesis of triazoles is
that an overwhelming number of olefins generate triazo-
lines, which require an additional step of acid/base treat-
ment or oxidation to afford 1,2,3-triazoles in moderate to
Abstract: A metal-free, vinyl sulfone-based synthesis of 1,5-disub-
stituted-1,2,3-triazoles is reported for the first time. These triazoles
are easily formed in a regioselective fashion by heating under reflux
a mixture of a substituted vinyl sulfone and an organic azide ‘on wa-
ter’. This powerful and practical route has the potential to be ex- poor overall yields.6 For example, most enamines, which
ploited for the synthesis of complex 1,5-disubstituted-1,2,3-
are one of the most commonly used electron-rich olefins
for the synthesis of 1,2,3-triazoles, afforded triazolines.6,7
triazoles.
Key words: triazoles, on water, vinyl sulfone, organic azide, click
chemistry
It should be noted that the general application of acivated
olefins in 1,2,3-triazole synthesis would also crucially de-
pend on the availability of straightforward preparative
methods for these olefins from easily accessible starting
In addition to the wide-ranging applications of 1,4-disub- materials.6,7 Thus, a large number of olefin-based meth-
stituted-1,2,3-triazoles,1 the recently noted importance of ods for triazole synthesis cannot be used simply because
1,5-disubstituted-1,2,3-triazoles as cis-peptide bond modification of polyfunctionalized molecules with those
surrogates1d,2d has triggered the search2,3 for a reliable and functional groups is synthetically challenging.6,7
operationally simple avenue for accessing the latter class
Although electron-poor olefins such as vinyl sulfones are
of heterocycles. However, synthetic strategies for access-
known to produce 1,2,3-triazoles on reaction with sodium
ing 1,5-disubstituted-1,2,3-triazoles are limited in num-
azide,8 perfluoroalkyl-substituted phenyl vinyl sulfones
ber.2a,b,e,3d Synthetic approaches towards 1,5-regioisomers
reacted with sugar azides to afford a single regioisomeric
using halomagnesium acetylenes2a,e or trimethylsilyl
4-perfluoroalkyl-1,2,3-triazolle derivative.9 Since a wide
acetylenes2b have achieved only limited success. The ru-
range of functionalized vinyl sulfones,10 including vinyl
thenium-mediated strategy of ligating alkynes and organ-
sulfone-modified biomolecules1d,10c,d are easily available,
ic azides requires optimization to identify an effective
we set out to study the versatility of using vinyl sulfones
catalyst capable of efficiently combining both alkyl and
in the synthesis of disubstituted 1,2,3-triazoles. Thus, 1.5
aryl azides with any alkyne.3a–c Alternatively, the demand
equivalents of azidobenzene was reacted with the p-tolyl
for easier access to disubstituted 1,2,3-triazoles1–3 also en-
vinyl sulfone 111 (Scheme 1) in either toluene or water at
couraged research groups to devise metal-free
reflux temperature until 1 was consumed. The absence of
routes.2c,3d,4,5 For example, the ligation of aromatic azides
a sharp singlet at d = 8.2 ppm12 in the 1H NMR spectrum
and aromatic alkynes in the presence of a catalytic amount
of tetraalkylammonium hydroxide did produce 1,5-disub-
indicated that the expected 1,4-disubstituted triazole 2a
was not the product (Scheme 1). Surprisingly, the reaction
produced the 1,5-regioisomer 2b, a compound synthe-
sized from phenyl acetylene in the presence of catalytic
stituted-1,2,3-triazoles, but the method is limited because
alkyl acetylenes failed to react under these conditions.3d
Most of the metal-catalyzed1,3d and metal-free tetraalkylammonium hydroxide, with the triazolyl proton
approaches3d,4,5 for the synthesis of 1,5-disubstituted- appearing as a sharp singlet at d = 7.87 ppm.3d We pre-
1,2,3-triazoles involve the use of alkynes. Although dif- sume that, due to the polarization13 of the double bond of
ferent types of activated olefins have been used in the past vinyl sulfone A, azide B attacked the partially positively
for the synthesis of triazoles,6 there are only a few reports charged b-position to afford a cyclic intermediate C,
on the use of olefinic compounds5b,c since 1,2,3-triazoles which eliminated sulfinic acid to afford 1,5-disubstituted-
were revisited1a,e during the last decade. The under-utili- 1,2,3-triazole D regioselectively. This mechanistic expla-
zation of olefins in recent times despite their better regi- nation raised our expectations that the reaction should be
oselectivity profile over alkynes6c may be attributed to general in nature and be capable of generating a wide
various factors,3c but, one of the major problems associat- range of 1,5-disubstituted triazoles.
After several trial reactions, we decided to replace the p-
tolylsulfonyl group with much less expensive 2-mercap-
tobenzothiazole. Thus, we synthesized two simple but
SYNLETT 2011, No. 17, pp 2521–2524
Advanced online publication: 13.09.2011
x
x
.x
x
.2
0
1
1
structurally varied vinyl sulfones 6 and 10 starting from
DOI: 10.1055/s-0030-1260306; Art ID: D16611ST
© Georg Thieme Verlag Stuttgart · New York

2522
S. Dey et al.
LETTER
PhN3
Ph
X
Y
OH
O
toluene or water
BnO
OTs
reflux, 12 h
N
N
p-TolO2S
Ph
2b (75–80%)
N
3
7
1
2a X = Ph; Y = H
2b X = H; Y = Ph
2-mercaptobenzothiazole
DMF, TMG, 1 h at 90 °C
then 5 h at 90 °C
R2
N–
N+
R1
δ+
R1
R1
N
ArO2S
5
OH
ArS
H
R2
R2
OH
N
δ–
N
N
1
N
BnO
SAr
N
O2S
Ar
N
D
C
B
8 (78%)
4 (80%)
MMPP, MeOH, r.t., 6 h
OH
A
Scheme 1 Unexpected formation of 1,5-disubstituted-1,2,3-triazole
from vinyl sulfone 1
OH
ArO2S
easily accessible styrene epoxide 3 and mono-tosylated
glycerol 7, respectively (Scheme 2). In both cases, C–S
bond formation at elevated temperature followed by oxi-
dation of the sulfides 4/8 and elimination of mesylates
from sulfones 5/9 were used as a general strategy to access
the desired vinyl sulfones 6 and 10 in relatively large
quantities (Scheme 2). Vinyl sulfone 6 was selected for
further study because it was expected to produce the
known 1,5-disubstituted-1,2,3-triazoles reported earlier
and prepared through alternative routes.2a Thus, a mixture
of 6 and 1.5 equivalents of azidobenzene, 1-azido-4-meth-
oxybenzene, or 1-azido-octane in water were heated to re-
flux to afford 2b,2a 2c,2a and 2d,14 respectively, after
column purification (Scheme 3). We were unable to de-
tect any 1,4-isomer from these reactions either during pu-
rification (TLC analysis) or in the 1H NMR spectra of the
final products.
BnO
SO2Ar
9 (88%)
5 (88%)
MsCl, py, 0 °C to 4 °C
overnight
OBn
Ph
ArO2S
ArO2S
6 (82%)
10 (85%)
N
S
Ar =
Scheme 2 Synthesis of vinyl sulfones from an epoxide and a tosy-
late derivative
Ph
Since the synthesis of triazoles decorated with aromatic
rings is well-known and alkyl acetylenes do not afford
1,2,3-triazoles under metal-free conditions,3d we subject-
ed an aliphatic vinyl sulfone 10 (Scheme 4) to cycloaddi-
tion with a wide range of azides under similar reaction
conditions to those described in Scheme 3. Gratifyingly,
at reflux temperature, the mixture of 10 and 1.5 equiva-
lents of an organic azide produced 1,5-disubstituted-
1,2,3-triazoles 11a–k, exclusively . On the other hand, use
of 0.5 equivalents of an organic diazide under similar re-
action conditions generated ditriazolyl compounds 11l–n
(Scheme 4).15 As a control, a selection of azides used in
Scheme 4 were reacted with the benzyl protected propar-
gyl alcohol (HCCCH2OBn)16 under Cu(I) mediated click
conditions; all products were found to be the 1,4-regioiso-
mers of the corresponding triazoles described herein and
were different to the products listed in Scheme 4.17 Al-
though yields of the mono-triazolyl derivatives were in
the range 74–85%, no other products could be isolated.
The ditriazolyl compounds 11l–n, with yields around
65%, were also the sole products of their respective reac-
tions. Reactions of vinyl sulfones with higher amounts
(>1.5 equiv) of azides did not improve the yield nor could
the yields be improved significantly by using vinyl sul-
fone and organic azide in a ratio of 1.5:1. Compound 10
5
RN3 (1.5 equiv)
water, reflux
N
R
N
6
1
N
2b R = Ph (76%, 10 h)
2c R = 4-MeOC6H4 (78%, 10 h)
2d R = Me(CH2)7 (80%, 11 h)
Scheme 3 Synthesis of 1,5-disubstituted-1,2,3-triazoles from 2-
mercaptobenzothiazole vinyl sulfone 6
was recovered almost quantitatively even after heating to
reflux temperature in water for more than 12 hours, which
indicated that vinyl sulfone did not decompose at high
temperature.
It should be noted that the regioselectivity of formation of
2b–d and 11a–n is not clear because 1-nitroalk-1-enes
(RCH=CHNO2), which are the closest relatives of vinyl
sulfones 1, 6, or 10 reportedly react with organic azides to
afford mixtures of the regioisomeric triazoles; the relative
proportions of these compounds being dependent on the
experimental conditions.6c Therefore, the route affording
compounds 2b–d and 11a–n is regioselective in nature.
This report also highlights a reversal of the reaction pat-
tern of vinyl sulfones leading to regioisomeric triazole
formation that depends on the functional groups attached
to the substituted vinyl sulfones.9
Synlett 2011, No. 17, 2521–2524 © Thieme Stuttgart · New York

LETTER
1,5-Disubstituted-1,2,3-triazoles
2523
OBn
R
should be noted that we could not isolate, nor identify by
TLC, any intermediate corresponding to C (Scheme 1) in
the transformations listed in Scheme 3 or Scheme 4. It is
probable that the formation of cyclic intermediates such as
C and the generation of the final products 2b–d and 11a–
n is a concomitant process in the reactions reported here-
in.20
RN3
(1.5 equiv)
N
N
N
water
reflux
11a–k
10
OBn
N
N
N
X
N
N
N3-X-N3
(0.5 equiv)
Since vinyl sulfones can be easily synthesized from 1,2-
diols, olefins, epoxides, and aldehydes,9,10 in the context
of the previous lack of a metal-free, efficient, flexible, and
general methods for the synthesis of 1,5-regioisomeric tri-
azoles, our expedient and general strategy offers a practi-
cal route to simple as well as more complex 1,5-
disubstituted-1,2,3-triazoles using combinations of aryl/
alkyl vinyl sulfones and aryl/alkyl azides. This operation-
ally less complicated method is applicable to both phenyl-
and alkyl vinyl sulfones, avoids the use of high-boiling
solvents such as DMSO,3d and does not require a CO2-free
environment3d or inert atmosphere. Research is currently
in progress to study the reactions in depth by varying the
functional groups attached to the vinyl group as well as by
using different sulfones and sulfoxides. We are also ligat-
ing a wide range of polyfunctionalized molecules such as
carbohydrates and nucleosides, with different organic
molecules for the synthesis of a wide range of new chem-
ical entities with potential applications in biology and
medicine.
N
BnO
11l–n
OBn
OBn
OBn
N
N
N
N
OMe
N
N
N
N
N
11b (85%, 10 h)
11a (80%, 10 h)
11c (85%, 11 h)
OBn
OBn
N
OH
N
N
N
N
N
11e (80%, 12 h)
11d (81%, 12 h)
OBn
OBn
OBn
N
(CH2)7Me
N
N
N
N
N
N
N
N
MsHN
11f (82%, 9h )
11h (85%, 12 h)
OBn
11g (78%, 10 h)
Acknowledgment
OBn
N
OBn
T.P. thanks the Department of Science and Technology (DST), New
Delhi for financial support. S.D. and D.D. thank the Council for Sci-
entific and Industrial Research, New Delhi for fellowships. DST is
also thanked for the creation of the 400 MHz NMR facility under
the IRPHA (Intensification of Research in High Priority Areas) pro-
gram.
OMe
N
O
N
N
N
N
N
N
N
O
O
HO
OBz
HO
OBn
11i (74%, 14 h)
11j (85%, 11 h)
11k (77%, 3 h)
OBn
OBn
OBn
References and Notes
(1) For recent reviews on 1,2,3-triazoles, see: (a) Kolb, H. C.;
Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001,
40, 2004. (b) Bock, V. D.; Hiemstra, H.; Maarseveen, J. H.
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(f) Holub, J. M.; Kirshenbaum, K. Chem. Soc. Rev. 2010, 39,
1325.
N
N
N
N
N
N
N
N
N
O
N
Ts
N
N
N
N
N
N
N
N
N
OBn
OBn
OBn
11l (65%, 18 h)
11m (69%, 16 h)
11n (66%, 19 h)
(2) (a) Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett.
2004, 6, 1237. (b) Coats, S. J.; Link, J. S.; Gauthier, D.;
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Scheme 4 Synthesis of 1,5-disubstituted-1,2,3-triazoles from the
vinyl sulfone 10
Water was used as a solvent for reasons of cost, safety,
and environmental concerns, as well as because of the re-
ported observation that water-insoluble organic reactants
often proceed optimally.18,19 Since all organic reactants
used in this report are insoluble in water, the reactions
may be categorized as organic synthesis ‘on water’.18 It
Synlett 2011, No. 17, 2521–2524 © Thieme Stuttgart · New York

2524
S. Dey et al.
LETTER
(3) (a) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I.
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Toward Heterocycles and Natural Products; Padwa, A.;
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(Theochem) 2007, 804, 1.
(14) (a) The 1H NMR spectral data of 2d [d = 7.67 (s, 1 H), 7.44–
7.48 (m, 3 H), 7.36–7.37 (m, 2 H) ppm] are significantly
different to those of the reported 1,4-regioisomer [d = 7.78
(d, J = 7.2 Hz, 2 H), 7.73 (s, 1 H), 7.36 (t, J = 7.2 Hz, 2 H),
7.27 (t, J = 7.2 Hz, 1 H) ppm], see: Campbell-Verduyn, L.
S.; Mirfeizi, L.; Dierckx, R. A.; Elsinga, P. H.; Feringa, B.
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(15) For the synthesis of 11k from 5-azido-5-deoxy-2,3-O-
isopropylidene-b-D-ribofuranoside, 2 equiv of NaHCO3 was
used in the reaction mixture to neutralize the acid generated
after elimination. NaHCO3 is not required for the synthesis
of 2b–d, 11a–j or 11l–n.
(16) Farran, D.; Slawin, A. M. Z.; Kirsch, P.; O’Hagan, D. J. Org.
Chem. 2009, 74, 7168.
(17) HCCCH2OBn reacts with organic azides in the presence of
Cu(I) catalysts, to generate only 1,4-disubstituted-1,2,3-
triazoles, see: (a) Collin, M. P.; Hobbie, S. N.; Bottger, E.
C.; Vasella, A. Helv. Chim. Acta 2008, 91, 1838.
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(20) General procedure for the synthesis of 1,5-disubstituted-
1,2,3-triazoles (2b–d and 11a–n): A mixture of vinyl
sulfone 6 or 10 (1 mmol), and azide (1.5 mmol for
monoazide and 0.5 mmol for diazide) in water (10 mL/mmol
of 6 or 10) was heated at reflux temperature for 3–19 h. After
completion of the reaction (monitored by TLC) the reaction
mixture was treated with sat. NaHCO3 and the product was
extracted with EtOAc (3 × 30 mL). The organic layer was
dried over anhydrous Na2SO4, filtered, and the filtrate was
evaporated to dryness under reduced pressure. The residue
was purified by silica column chromatography to afford the
corresponding 1,5-disubstituted-1,2,3-triazoles 2b–d and
11a–n.
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