Selective formation of 1,5-substituted sulfonyl triazoles using acetylides and sulfonyl azides

Article abstract of DOI:10.1021/ol200696q

The reaction of acetylides with sulfonyl azides was found to selectively form 1,5-substituted sulfonyl triazoles. This reaction thus provides access to the regioisomeric product as compared to the popular copper-catalyzed azide-alkyne cycloaddition. The reaction is efficient and selective with a variety of alkyne sources and sulfonyl azides and can incorporate an additional electrophile to yield 1,4,5-trisubstituted sulfonyl triazoles.

Full text of DOI:10.1021/ol200696q

ORGANIC
LETTERS
2011
Vol. 13, No. 12
2984–2987
Selective Formation of 1,5-Substituted
Sulfonyl Triazoles Using Acetylides and
Sulfonyl Azides
~
Maria Elena Meza-Avina, Mudita Kishor Patel, Cylivia B. Lee, Thomas J. Dietz, and
Mitchell P. Croatt*
Department of Chemistry and Biochemistry, University of North Carolina at
Greensboro, Greensboro, North Carolina 27402, United States
mpcroatt@uncg.edu
Received March 15, 2011
ABSTRACT
The reaction of acetylides with sulfonyl azides was found to selectively form 1,5-substituted sulfonyl triazoles. This reaction thus provides access
to the regioisomeric product as compared to the popular copper-catalyzed azideÀalkyne cycloaddition. The reaction is efficient and selective with
a variety of alkyne sources and sulfonyl azides and can incorporate an additional electrophile to yield 1,4,5-trisubstituted sulfonyl triazoles.
The copper-catalyzed reaction of terminal alkynes with
azides to yield 1,2,3-triazoles has deservedly received much
attention in recent years.1 This reaction regioselectively
forms 1,4-substituted triazoles using alkyl, aryl, or sulfonyl
azides.2 Although it was reported that 1,4-substituted sul-
fonyl triazoles could be converted to 2,4-substituted
triazoles using amine bases,3 there are no efficient methods
to selectively convert terminal alkynes and sulfonyl azides to
1,5-substituted triazoles.4À6 In 2004, there was an excellent
report for the reaction of alkynyl Grignard reagents with
carbon-substituted azides to yield 1,5-disubstituted triazoles
and 1,4,5-trisubstituted triazoles.7 Interestingly, no reac-
tions were reported with sulfonyl azides despite the authors’
(1) For a recent set of reviews in this area, see the themed issue: Chem.
Soc. Rev. 2010, 39, 1221À1408.
(6) For the synthesis of 1,5-substituted sulfonyl triazoles from sulfo-
nyl azides and phosphorus ylides, see: Harvey, G. R. J. Org. Chem. 1966,
31, 1587.
(2) (a) 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. (b)
Wang, F.; Fu, H.; Jiang, Y.; Zhao, Y. Adv. Synth. Catal. 2008, 350, 1830.
(3) Yamauchi, M.; Miura, T.; Murakami, M. Heterocycles 2010, 80,
177.
ꢀ
(7) (a) Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6,
1237. For seminal work, see:(b) Akimova, G. S.; Chistokletov, V. N.;
Petrov, A. A. Zh. Org. Khim. 1967, 3, 968. (c) Akimova, G. S.;
Chistokletov, V. N.; Petrov, A. A. Zh. Org. Khim. 1967, 3, 2241. (d)
Akimova, G. S.; Chistokletov, V. N.; Petrov, A. A. Zh. Org. Khim. 1968,
4, 389.
(8) For representative examples, see: (a) Raushel, J.; Fokin, V. V.
Org. Lett. 2010, 12, 4952. (b) Chuprakov, S.; Kwok, S. W.; Zhang, L.;
Lercher, L.; Fokin, V. V. J. Am. Chem. Soc. 2009, 131, 18034. (c) Yoo,
E. J.; Ahlquist, M.; Bae, I.; Sharpless, K. B.; Fokin, V. V.; Chang, S.
J. Org. Chem. 2008, 73, 5520. (d) 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.
(4) For a report of the conversion of aryl or alkyl azides to 1,5-
triazoles, see: Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.;
Zhao, H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130,
8923.
(5) For earlier reports of reactions of acetylides with sulfonyl azides
with low efficiency or no yield reported, see: (a) Boyer, J. H.; Mack,
C. H.; Goebel, N.; Morgan, L. R., Jr. J. Org. Chem. 1958, 23, 1051. (b)
Robson, E.; Tedder, J. M.; Webster, B. J. Chem. Soc. 1963, 1863. (c)
€
Huisgen, R.; Knorr, R.; Mobius, L; Szeimies, G. Chem. Ber. 1965, 98,
4014. (d) Helwig, R.; Hanack, M. Chem. Ber. 1985, 118, 1008.
r
10.1021/ol200696q
Published on Web 05/25/2011
2011 American Chemical Society

expertise with this electrophilic azide source.8 Additionally,
the copper-catalyzed reaction with sulfonyl azides often
forms products other than the typical triazoles.8 Due to
the significance of substituted triazoles in ligand design,
drug discovery, and biochemical applications,1 it is attrac-
tive to have a facile, regioselective, and efficient route to 1,5-
substituted sulfonyl triazoles. In this report we describe an
efficient method for the selective synthesis of 1,5-substituted
sulfonyl triazoles from terminal alkynes and sulfonyl azides.
During our initial study of the reactivity of acetylides
and sulfonyl azides, it was determined that the major
product of the reaction with 1-heptyne was 1,5-triazole 3
(Scheme 1). This was true for both sulfonyl azides 2a and
2b. The structures were determined by comparison to the
1,4-triazoles formed by reaction with CuI and 2,6-lutidine
along with X-ray crystallographic analysis of 3a (see
Supporting Information).
Supporting Information for a more detailed optimization
table). Interestingly, it was found that other counterions,
including sodium and potassium, allowed for the formation
of 1,5-triazoles; however the reactions were not as efficient,
potentially due to the poor solubility of the anions at À78 °C
(entry 1 versus 3 and 4). A very poor yield was observed with
a Grignard reagent (not shown) which likely illustrates why
the reactions described herein were not described in prior
reports.7 A final key reaction condition for the optimization
wastouseaslightexcessofthealkyne, relative to the sulfonyl
Table 2. Alkyne Screena
Scheme 1. Synthesis of 1,5-Substituted Triazoles
Although this reaction appears similar to the frequently
employed copper-catalyzed azideÀalkyne cycloaddition
(CuAAC) and complementary ruthenium-catalyzed cy-
cloaddition (RuAAC),4 there are two main differences.
First, the reaction described herein produces 1,5-substi-
tuted triazoles whereas the CuAAC yields 1,4-substituted
triazoles. Second, this reaction works efficiently with
sulfonyl azides, whereas the RuAAC has notbeen reported
with sulfonyl azides. Based on these differences, it was
decided to optimize this reaction and study its scope.
Optimization of the reaction conditions determined
that if the reaction was not kept at À78 °C, mixtures of
differentially substituted triazoles (mostly the 1,4-substituted
triazoles) were isolated (Table 1, entry 1 versus 2; see the
Table 1. Optimization for Synthesis of 1,5-Triazoles 3a
heptyne (equiv)/
ArSO2N3 (equiv)
base
time
(h)
yield
of 3b
entry
(equiv)
1
1 (1.0)/2a (1)
1 (1.0)/2a (1)
1 (1.0)/2a (1)
1 (1.0)/2a (1)
1 (1.2)/2a (1)
1 (1.2)/2b (1)
1 (1.2)/2c (1)
n-BuLi (1.2)
n-BuLi (1.2)
NaHMDS (1.2)
KHMDS (1.2)
n-BuLi (1.2)
n-BuLi (1.2)
n-BuLi (1.2)
2
64% 3a
39% 3a
23% 3a
27% 3a
90% 3a
67% 3b
79% 3c
2c
3
5
2
4
2
5
0.3
0.3
2
a Reaction conditions (unless otherwise noted): 1.2 equiv of n-BuLi
was added to a solution of the indicated alkyne (1.2 equiv) in THF at
À78 °C. After 15 min, 1 equiv of the indicated sulfonyl azide was added,
and the reaction was stirred for the time indicated at which point the
sulfonyl azide was fully consumed as judged by TLC. b Isolated yield.
c Quantitative recovery of starting alkyne and sulfonylazide as judged by
1H NMR of the crude reaction mixture. Ts = p-toluenesulfonyl; Tris =
2,4,6-triisopropylphenylsulfonyl; p-Ns = p-nitrophenylsulfonyl.
6
7d
a Reaction conditions (unless otherwise noted): The indicated base
was added to a solution of heptyne in THF at À78 °C. After 15 min, the
indicated sulfonyl azide (1 equiv) was added, and the reaction was stirred
for the time indicated. b Isolated yield. c The reaction temperature was
increased to ambient temperature after 2 h. d 2c, Ar = p-NO2-Ph.
Org. Lett., Vol. 13, No. 12, 2011
2985

azide source (entry 5). With these optimal conditions, other
sulfonyl azide sources (2a and 2c) were examined and the
reaction was found to maintain efficiency (entries 6 and 7).
With conditions in hand for the efficient transformation
of heptyne into 1,5-triazoles, a variety of different alkynes
were studied in the reaction (Table 2). Importantly, the
reaction with phenylacetylene was also efficient with all
three of the sulfonyl azide sources (entries 1À3). It was
determined that electron-rich arenes worked better in this
reaction than electron-poor arenes (entry 4 versus 6),
although the more sterically hinderered ortho-anisole sub-
strate was not as efficient (entry 5). Although a nitro-group
was tolerated on the sulfonyl azide, the nitro-substituted aryl
acetylide did not yield any desired product and only starting
material was isolated (entry 7). The silyl-substituted acet-
ylide was low yielding for this reaction (entry 8), whereas the
tert-butyl acetylide was highly efficient (entry 9).
Table 3. Electrophile Screena
Scheme 2. Proposed Mechanism for the Reactions
a Reaction conditions (unless otherwise noted): 1.2 equiv of n-BuLi
was added to a solution of the indicated alkyne (1.2 equiv) in THF at
À78 °C. After 15 min, 1 equiv of p-toluenesulfonyl azide was added,
the reaction was stirred for 30 min, and then 2 equiv of the
indicated electrophile were added. The reactions were stirred at À78
°C. b Isolated yield. c After addition of MeI the reaction was warmed
Based on the proposed reaction mechanism (Scheme 2),
it was decided to explore the reactions of the triazole anion
(C) with other electrophiles (formation of E). Using iden-
tical conditions as described earlier, the reactions were
quenched with electrophiles other than a Brønsted acid
(Table 3). Acid chlorides (entries 1À3) were able to yield
the respective ketones with moderate efficiency. Un-
fortunately, the reactions with benzylchloroformate or a
chlorosilane were not high yielding (entries 4 and 5), but the
reaction with the iodomethane proceeded smoothly (entry
6). Unexpectedly, when the p-nitrophenylsulfonyl azide
source (2c) was used in slight excess, the free triazole was
isolated where the presumed anion (Scheme 2, C) reacted
similarly to an intermolecular electrophilic aromatic sub-
stitution and subsequently cleaved the sulfurÀnitrogen
bond (Table 3, entry 7). These reactions formally represent
highly regioselective cycloadditions between sulfonyl azides
and internal alkynes, a reaction that is otherwise difficult.
It should be noted that the 1,5-substituted sulfonyl
triazoles isomerized to the 1,4-triazoles to a moderate
amount when being purified by silica gel chromatography,
presumably via an acid-catalyzed pathway. To circumvent
this, crystallization was utilized to isolate the pure
1,5-triazoles. Surprisingly, when the crystals of some of
the 1,5-triazole products were stored in a À20 °C freezer
for extended periods (>1 week), isomerization to the
1,4-triazoles still occurred. When the same 1,5-triazoles
to ambient temperature. Ts
triisopropylphenylsulfonyl.
= p-toluenesulfonyl; Tris =2,4,6-
were stored as solutions in CDCl3 no observable isomer-
ization occurred (see Supporting Information for more
details). These data lend evidence for the isomerization
Figure 1. Adjacent triazoles in crystal structure of 3a. Carbon
atoms are colored gray, nitrogen atoms are blue, oxygen atoms
are red, and sulfur atoms are yellow.
2986
Org. Lett., Vol. 13, No. 12, 2011

taking place even in the crystalline form. The crystal
structure of 3a further supports this hypothesis since the
nitrogen atom in the 3-position is in relatively close
proximity to the sulfur atom of an adjacent molecule
(Figure 1). Other isomerization mechanisms are also
possible, including radical reactions, but these were not
explored since the isomerization did not occur to an
appreciable amount in solution.
Importantly, the reactionsdescribed hereincombinetwo
readily available starting materials, terminal alkynes and
sulfonyl azides, to efficiently and selectively assemble 1,5-
substituted sulfonyl triazoles. This reaction displays the
substituents of the triazole much closer together than
the complementary 1,4-triazoles and thus provides for
new structural opportunities. Additionally, the putative
triazole anion was trapped with various electrophiles to
regioselectively form 1,4,5-trisubstituted triazoles. Further
explorations into this reaction, including the isomerization
of 1,5-triazoles to 1,4-triazoles, are ongoing.
Acknowledgment. Funding for this project from The
University of North Carolina at Greensboro is gratefully
acknowledged. The authors thank Dr. Franklin J. Moy
(UNCG), Dr. Brandie Ehrmann (UNCG), and Dr.
Cynthia S. Day (Wake Forest University) for assisting
with the analysis of NMR, mass spectrometry, and X-ray
crystallography data, respectively.
Supporting Information Available. Experimental data
and spectroscopic characterization of all products and
crystallographic data for 3a. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 12, 2011
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