Efficient synthesis of 1-sulfonyl-1,2,3-triazoles

Article abstract of DOI:10.1021/ol102087r

An efficient room-temperature method for the synthesis of 1-sulfonyl-1,2,3-triazoles from in situ generated copper(I) acetylides and sulfonyl azides is described. The copper(I) thiophene-2-carboxylate (CuTC) catalyst produces the title compounds under both nonbasic anhydrous and aqueous conditions in good yields.

Full text of DOI:10.1021/ol102087r

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4952-4955
Efficient Synthesis of
1-Sulfonyl-1,2,3-triazoles
Jessica Raushel and Valery V. Fokin*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, United States
fokin@scripps.edu
Received September 2, 2010
ABSTRACT
An efficient room-temperature method for the synthesis of 1-sulfonyl-1,2,3-triazoles from in situ generated copper(I) acetylides and sulfonyl
azides is described. The copper(I) thiophene-2-carboxylate (CuTC) catalyst produces the title compounds under both nonbasic anhydrous and
aqueous conditions in good yields.
As latent diazo compounds, 1-sulfonyl-1,2,3-triazoles serve
as convenient progenitors of reactive azavinyl carbenes.1
These electron-deficient heterocycles stand out as an impor-
tant exception in the family of generally stable and unreactive
1,2,3-triazoles: the weakened N1-N2 bond in 1-sulfonyl
derivatives facilitates their ring-chain isomerism, which
leads to the formation of diazoimines and subsequent
decomposition to the transition metal stabilized carbenes.
Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC)2
could well be the most direct and practical route to 1-sulfonyl-
1,2,3-triazoles. High fidelity, efficiency, and compatibility with
a broad range of functional groups and conditions have made
it a widely utilized method for the synthesis of small molecules,
bioconjugates, and complex molecular architectures.3 However,
the outcome of the CuAAC reaction of electron-deficient azides
is affected by a wide variety of factors. Mirroring the well-
known Dimroth rearrangement,4-6 reaction medium,7 tem-
perature,8 triazole ring substituents,9,10 and ligand choice11,12
all influence the outcome of the reaction (Scheme 1).
Judicious choice of reaction conditions currently enables
isolation of either N-acyl sulfonamides 77 or 1-sulfonyl
triazoles 4. Although several recent reports have described
syntheses of 1-sulfonyl triazoles,8,12 none offer the level of
generality and simplicity required for wide adoption. In
search of a practical, simple, and robust synthesis of sulfonyl
triazoles, we examined effects of various ligands on the
outcome of the CuAAC reaction of sulfonyl azides. This
communication reports our findings.
In general, ligands that exhibit the most dramatic effect
on the course of the reaction contain nitrogen heterocycles,
(e.g., tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA)
(4) (a) Dimroth, O. Justus Liebigs Ann. Chem. 1909, 364, 183. (b) El
Ashry, E. S. H.; El Kilany, Y.; Rashed, N.; Assafir, H. AdV. Heterocycl.
Chem. 1999, 75, 79.
(5) Gilchrist, T. L.; Gymer, G. E. AdV. Heterocycl. Chem. 1974, 16,
33.
(6) L’Abbe´, G. J. Heterocycl. Chem. 1984, 21, 627.
(7) (a) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc.
2005, 127, 16046. (b) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew.
Chem., Int. Ed. 2006, 45, 3154.
(1) (a) Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.; Fokin,
V. V. J. Am. Chem. Soc. 2008, 130, 14972. (b) Chuprakov, S.; Kwok, S. W.;
Zhang, L.; Lercher, L.; Fokin, V. V. J. Am. Chem. Soc. 2009, 131, 18034.
(c) Miura, T.; Yamauchi, M.; Murakami, M. Chem. Commun. 2009, 1470.
(d) Grimster, N. P.; Zhang, L.; Fokin, V. V. J. Am. Chem. Soc. 2010, 132,
2510.
(8) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.; Sharpless,
K. B.; Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1730.
(9) Harmon, R. E.; Stanley, F., Jr.; Gupta, S. K.; Johnson, J. J. Org.
Chem. 1970, 35, 3444.
(10) Himbert, G.; Regitz, M. Liebigs Ann. Chem. 1973, 9, 1505.
(11) (a) Whiting, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45,
3157. (b) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org.
Lett. 2004, 6, 2853.
(2) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596.
(3) (a) Wu, P.; Fokin, V. V. Aldrichimica Acta 2007, 40, 7. (b) Moses,
J. E. Chem. Soc. ReV. 2007, 36, 1249. (c) For a recent collection of reviews,
see: Chem. Soc. ReV. 2010, 39(4).
(12) (a) Wang, F.; Fu, H.; Jiang, Y.; Zhao, Y. AdV. Synth. Catal. 2008,
350, 1830. (b) Cano, I.; Nicasio, M. C.; Pe´rez, P. J. Org. Biomol. Chem.
2010, 8, 536.
10.1021/ol102087r  2010 American Chemical Society
Published on Web 10/08/2010

results were compared to the CuSO4/sodium ascorbate system
(entry 1), which generates and maintains copper in its +1
oxidation state in situ.2b
Scheme 1
.
Proposed Intermediates in the Copper(I)-Catalyzed
Reaction of Alkynes and Sulfonyl Azides
Relative to the control reaction (entry 1), tert-butyl sulfide,
benzyl phenyl sulfide, and thiophene (entries 2-4) in
conjunction with CuBr showed improved selectivity for
triazole 8 at the expense of conversion. In contrast, thiolane
(entry 5) exhibited high conversion with diminished selectiv-
ity. Addition of tert-butyl sulfide to the CuSO4/sodium
ascorbate system (entry 9) resulted in an improved ratio and
maintained high conversion. Attempts to achieve high
conversion and selectivity by screening different copper(I)
sources in the presence of tert-butyl sulfide were modestly
successful (entries 9 and 10). Finally, screening other sulfur-
containing copper(I) complexes (entries 11-13) led to the
identification of copper(I) thiophene-2-carboxylate (CuTC,
entry 13), which dramatically influenced the course of the
reaction. Conversion remained high, as seen in entries 1, 9,
and 10, yet no N-acyl sulfonamide 9 was detected by LC/
MSsresulting in exclusiVe selectiVity under heterogeneous
aqueous conditions.
Examination of a panel of solvents (see Supporting
Information) for the CuTC-catalyzed 1-sulfonyl triazole
synthesis identified water and toluene as optimal solvents,
with both leading to complete reactions in 2 h. Interestingly,
traditional CuAAC mixed cosolvent conditions (2:1 tert-butyl
alcohol:H2O) resulted in both poorer conversions and
selectivity. Acetonitrile, a strongly coordinating solvent for
copper(I), entirely suppressed product formation, while
dichloromethane and chloroform led to complete conversion
after 5 h. At lower catalyst loadings (2 mol %), complete
conversion and selectivity were achieved in 15 h, attesting
to the stability of the catalyst.
or 2,6-lutidine).8,11 However, as a “borderline soft” Lewis
acid, copper(I) also partners well with sulfur ligands, for
example, methionine in copper transport proteins and copper-
containing enzymes.13 Herein, we report that copper(I)
thiophene-2-carboxylate (Liebeskind’s reagent)14 is a con-
venient, bench-stable catalyst for the synthesis of 1-sulfonyl-
1,2,3-triazoles effective at ambient temperature both under
anhydrous conditions and as a heterogeneous suspension in
water.
Table 1. 1-Sulfonyl Triazole Synthesis: Effect of Copper(I)
Source and Sulfur Ligand
PhCCH
A variety of 1-sulfonyl triazoles were synthesized (Scheme
entry copper(I) source
ligand
consumed (%)a ratio 8:9a
2) using water as the solvent.16 Despite cooling in an ice
1
2
3
4
5
6
7
8
9
10
11
12
13
CuSO4/NaAscb
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
Cu2O
CuSO4/NaAsc
-
t-Bu2S
BnSPh
thiophene
thiolane
Bn2S
89c
40
43
37
85
44
23
13
85c
86c
17
32
95c
6:1
10:1
12:1
14:1
2:1
3:1
1:1
1:1
13:1
13:1
2:1
2:1
>100:1
Scheme 2.
Synthesis of 1-Sulfonyl-1,2,3-triazoles in Watera
Met
t-Bu2S
t-Bu2S
CuPF6·(MeCN)4 t-Bu2S
CuSCN
-
-
-
CuBr·SMe2
CuTCd
a As determined by LC/MS analysis; see Supporting Information for
details. b NaAsc ) sodium ascorbate. c TsN3 undetected by LC/MS. d CuTC
) copper(I) thiophene-2-carboxylate. Tol ) tolyl.
a 1.0 mmol scale: CuTC (10 mol %), H2O (0.2 M), alkyne (1-1.3 equiv),
azide (1 equiv), 0 °C to rt, 2-18 h.
A variety of sulfur σ-donating ligands (Table 1) were
screened under heterogeneous aqueous conditions for their
ability to effect selective formation of the 1-sulfonyl triazole
8 over N-acyl sulfonamide 9 (presumably formed via a highly
reactive N-sulfonyl ketenimine intermediate such as 6). All
water bath, an observed exotherm, most pronounced in the
presence of excess sulfonyl azide, prompted a change to
toluene as the solvent of choice.
The general procedure15 for the synthesis of 1-sulfonyl
triazoles results in good isolated yields over a range of
alkynes with tosyl azide (Table 2). Both aryl alkynes (entry
(13) Kaim, W.; Rall, J. Angew. Chem., Int. Ed. 1996, 35, 43.
(14) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748.
Org. Lett., Vol. 12, No. 21, 2010
4953

Table 2. 1-Sulfonyl Triazole Synthesis: Scope with Respect to
Table 3. 1-Sulfonyl Triazole Synthesis: Scope with Respect to
Alkynea
Sulfonyl Azidea
a 1.0 mmol scale unless otherwise noted; CuTC (10 mol %), toluene
(0.2 M), alkyne (1 equiv), tosyl azide (1 equiv), rt. b Isolated yield. c 5.0
mmol scale. d 1.1 equiv of alkyne. e 1.3 equiv of alkyne. f 2.4 equiv of alkyne.
g 1.2 equiv of alkyne.
a 1.0 mmol scale unless otherwise noted; CuTC (10 mol %), solvent
(0.2 M), alkyne (1 equiv), sulfonyl azide (1 equiv), rt. b Isolated yield. c 1.1
equiv of alkyne. d 5.0 mmol scale. e 10.0 mmol scale. f 1.5 equiv of alkyne.
g 0.16 mmol scale.
1) and aliphatic alkynes (entries 2-10) are competent
substrates, as well as the strongly electron-donating ethyl
ethynyl ether (entry 11). The products were isolated via
extraction into ethyl acetate and removal of residual copper
by treatment with the Cuprisorb resin.16
In addition, the general procedure can be applied to a
variety of alkyl- and arylsulfonyl azides and alkynes
(Table 3).
both in toluene and under heterogeneous aqueous condi-
tions in 2 h. The furan analogue of CuTC (CuFC, entry
4) benefits from the same intramolecular arrangement of
σ-donors as CuTC and as such performed comparably to
CuTC in toluene, despite a small decrease in selectivity
under aqueous conditions. Interestingly, the addition of
thiophene to CuOAc (entry 5) resulted in little improve-
ment in toluene compared to CuOAc alone (entry 2) and
lowered both the selectivity and conversion in an aqueous
suspension to that of thiophene and CuBr (Table 1, entry
4).
Further experiments were designed to gain insight into
the reactivity of CuTC catalyst. A comparison of three
different copper(I) carboxylates (Table 4) revealed de-
creased conversion and selectivity in aqueous suspensions
(entries 2-4). Although selectivity remained high for
CuOAc (entry 2) and CuOTf (entry 3) in toluene,
conversions were low even after 15 h, requiring days to
reach completion at room temperature. In stark contrast,
the CuTC-catalyzed reaction (entry 1) reached completion
4954
Org. Lett., Vol. 12, No. 21, 2010

direction. Reactions of sulfonyl azides are further compli-
cated by the instability of (1,2,3-triazol-5-yl)copper species
3 (or its open chain isomer 5; the opening of the triazole
ring is, of course, not sufficient for the formation of
ketenimine 6). Therefore, when synthesis of triazole 4 is the
goal, a successful catalyst should (a) stabilize intermediate
3, thereby disfavoring its irreversible conversion to the
ketenimine 6 (a thermodynamic consideration), and/or (b)
facilitate the protiolysis step, thus favoring formation of the
desired triazole product (a kinetic consideration). We hy-
pothesize that CuTC excels at both. It stabilizes the triazolyl
intermediate 3 and its open chain isomer 5, disfavoring the
extrusion of dintrogen. If this irreversible formation of
ketenimine 6 does not occur, formation of 5-H triazole
product 4 would be favored.
Table 4. 1-Sulfonyl Triazole Synthesis: Scope with Respect to
Copper(I) Carboxylate
ratio 8:9a (PhCCH consumed (%a))
entry
CuOR
toluene
water
,
,
1
2
3
4
5
CuTC
>100:1 (98)b c
>100:1 (40)
>100:1 (17)
>100:1 (>99)
>100:1 (55)
>100:1 (95)b c
26:1 (88)b
5:1 (27)
CuOAc
CuOTf
CuFCd
CuOAce
31:1 (93)b
13:1 (32)
Notably, other copper(I) complexes, such as CuBr·SMe2
required the addition of 2,6-lutidine in order for the reaction
to proceed in toluene.18 This observation supports our
hypothesis that the carboxylate group of CuTC acts as a base
in toluene, and may do so in water, forming 2-thiophene
carboxylic acid upon the deprotonation of the alkyne.
Assuming that the acid remains coordinated to copper
throughout the catalytic cycle, the protiolysis step (3 to 4 in
Scheme 1) becomes intramolecular and therefore facile and
fast.
a As determined by LC/MS; see Supporting Information for details.
b TsN3 undetected by LC/MS. c 2 h. d CuFC ) copper(I)-furan-2-carboxylate.
e With the addition of thiophene (10 mol %).
CuAAC catalysis is complex and involves multiple
dynamic equilibria between copper acetylide species of
different coordination geometry, aggregation state, and ligand
environment.17 Controlling these equilibria is of paramount
importance for channeling the catalysis in the desired
The data presented in Table 4 indicate that the intramo-
lecular presentation of sulfur, the five-membered aromatic
heterocycle, and a carboxylate are all necessary to achieve
both selectivity and rapid conversion. Nevertheless, contribu-
tions from the varying solubility of different copper(I)
sources and ligands cannot currently be ruled out.
The disclosed method offers an efficient and broad-in-
scope means of accessing 1-sulfonyl-1,2,3-triazoles. The
procedure is experimentally simple and allows rapid access
to these important intermediates, paving the way for future
studies of their reactivity and utility as well as for probing
the mechanism of the parent CuAAC reaction. These studies
are underway and their results will be reported elsewhere.
(15) CAUTION! The reaction is exothermic, and can be accompanied
by dinitrogen release. It should not be performed in a closed vessel, and
adequate cooling should always be available. Procedure A: A scintillation
vial was charged with copper(I) thiophene-2-carboxylate (CuTC, 0.019 g,
0.1 mmol, 0.1 equiv with respect to alkyne) and water (5 mL) and cooled
in an ice-water bath. Subsequently, phenylacetylene (0.110 mL, 1.0 mmol,
1 equiv) then tosyl azide (0.155 mL, 1.0 mmol, 1 equiv) were added and
the reaction mixture allowed to warm to room temperature for 2 h. The
reaction mixture was diluted with saturated aq NH4Cl (5 mL) and extracted
into EtOAc (2 × 5 mL). The combined organics were dried (Na2SO4) and
filtered through celite. The eluent was concentrated in vacuo. To remove
copper, the concentrate was redissolved in CHCl3 and charged with
Cuprisorb resin. The mixture was stirred, filtered through celite and
concentrated in vacuo. Pulverizing the crude material in cold cyclohexane
and collection by filtration afforded 8 (0.188 g, 63% yield) as an off-white
powder. Procedure B: A 125-mL Erlenmyer flask was charged with CuTC
(0.191 g, 1.0 mmol) and dry toluene (50 mL). Subsequently, phenylacetylene
(1.10 mL, 1.02 g, 10.0 mmol) then tosyl azide (1.55 mL, 10.0 mmol) were
added, and the reaction mixture was allowed to stir for 2 h. It was then
diluted with saturated aq NH4Cl (50 mL) and extracted into EtOAc (3 ×
50 mL). The combined organics were washed with brine, dried (Na2SO4)
and concentrated in vacuo. To remove copper the concentrate was
redissolved in CHCl3 and charged with Cuprisorb resin. The mixture was
stirred, filtered through celite and concentrated in vacuo. Pulverizing the
crude material in cold cyclohexane and collection by filtration afforded 8
(2.67 g, 89% yield) as a white powder: mp 105.2-107.0 °C (lit. 107-108
°C); Rf ) 0.44 (silica gel, hexanes:EtOAc 7:3); νmax(HATR)/cm-1 3142,
Acknowledgment. The authors thank Dr. Suresh M.
Pitram, Dr. Jason E. Hein, and Mr. Sen Wai Kwok (TSRI)
for valuable advice and stimulating discussions. Financial
support from the National Institutes of Health, National
Institute of General Medical Sciences (GM087620), Eli Lilly
(JR), and the Skaggs Institute for Chemical Biology is
gratefully acknowledged.
1
1386 (SO2), 1197, 1170 (SO2), 988; H NMR (600 MHz, CDCl3) δ 8.31
(s, 1H), 8.03 (d, J ) 8.4 Hz, 2H), 7.82 (d, J ) 8.2 Hz, 2H), 7.43 (t, J ) 7.6
Hz, 2H), 7.37 (m, 3H), 2.44 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 147.3,
133.0, 130.4, 129.1, 129.0, 128.8, 128.7, 126.0, 118.9, 21.8. Anal. Calcd
for C15H13N3O2S: C, 60.18; H, 4.38; N, 14.04. Found: C, 59.84; H, 4.47;
N, 13.87.
(16) Local dealer information is available at http://www.seachem.com.
(17) Hein, J. E.; Fokin, V. V. Chem. Soc. ReV. 2010, 39, 1302.
(18) Despite attempts to exclude moisture, the formation of N-acylsul-
fonamide was always observed under these conditions.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL102087R
Org. Lett., Vol. 12, No. 21, 2010
4955