Practical synthesis of amides from in situ generated copper(I) acetylides and sulfonyl azides

Article abstract of DOI:10.1002/anie.200503805

(Chemical Equation Presented) A direct, simple, and efficient route from terminal alkynes to amides is achieved by their copper(I)-catalyzed reaction with sulfonyl azides (see scheme). The reaction proceeds with the in situ generation of copper(I) acetylides and represents a one-step formal oxidative hydration of a triple bond.

Full text of DOI:10.1002/anie.200503805

Communications
try, and materials science. A stepwise mechanism involving
the coordination of the azide to the copper(i) acetylide
through the proximal nitrogen atom, followed by formation of
a (1,2,3-triazol-5-yl)copper species has been proposed.[1] This
mechanism is supported by computational studies, which
indicate that the activation barrier for this catalytic version of
the Huisgen cycloaddition is reduced by as much as 11 kcal
molÀ1, which corresponds to the experimentally observed rate
acceleration of seven to eight orders of magnitude.[3]
1,2,3-Triazoles are among the most stable nitrogen hetero-
cycles: they are exceedingly resistant to severe hydrolytic,
reductive, and oxidative conditions. However, 5-lithiated-
1,2,3-triazoles have been shown to spontaneously eliminate
dinitrogen at temperatures ranging from À78 to + 608C.[4]
Recently, Chang and co-workers have shown that sulfonyl
azides react with copper(i) acetylides and secondary amines to
form amidines.[5] Intrigued by their findings and interested in
its mechanistic underpinnings, we undertook a study of
reactions of sulfonyl azides with copper(i) acetylides. Herein
we report that copper(i) ions efficiently catalyze the direct
formation of N-acylsulfonamides from terminal alkynes and
sulfonyl azides in aqueous solvents (Scheme 1). The process
Synthetic Methods
DOI: 10.1002/anie.200503805
Scheme 1. Synthesis of amides from alkynes and sulfonyl azides.
Practical Synthesis of Amides from In Situ
Generated Copper(i) Acetylides and Sulfonyl
Azides**
appears to have a broad scope with respect to both
components, is experimentally simple, and furnishes pure N-
acylsulfonamide products in good yield without complicated
purification steps. Different copper(i) sources, such as CuI,
CuBr, [Cu(CH3CN)4]PF6, and CuSO4/ascorbate, could be
used for the reaction. Aqueous tert-butanol was commonly
employed as a solvent, although other aqueous systems can be
utilized. The pH value was found to have a pronounced effect
on the outcome of the reaction: highest conversions into N-
acylsulfonamides were observed under mildly basic condi-
tions, which were easily achieved by buffering the reaction
mixture with one equivalent of sodium bicarbonate. Addi-
tionally, we found that addition of only 1–2 mol% of tris[(1-
benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA)[6] strongly
accelerates the reaction, and when TBTA is bound to a resin it
greatly simplifies the purification of the products.
Michael P. Cassidy, Jessica Raushel, and
Valery V. Fokin*
Copper(i) efficiently catalyzes the “fusion” of organic azides
with terminal alkynes to produce regioselectively 1,4-disub-
stituted-1,2,3-triazoles.[1] The very broad scope, simple exper-
imental conditions, and exceptional reliability of this trans-
formation have placed it among the most reliable “stitching”
reactions[2] available today. It has resulted in applications in
organic synthesis, molecular biology, macromolecular chemis-
[*] Dr. M. P. Cassidy, J. Raushel, Prof. V. V. Fokin
Department of Chemistry
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-7562
After screening various combinations of reagents, we
arrived at a convenient procedure which performs well with
different sulfonyl azides and terminal alkynes. Thus, a
combination of 2 mol% [Cu(CH3CN)4]PF6, 2 mol%
TBTA,[7] 4 mol% sodium ascorbate (to prevent formation
of oxidation by-products), and 1 equiv sodium bicarbonate in
tert-butanol/water (2:1) as a solvent gave near quantitative
conversions in 2–8 h. N-Acylsulfonamide products were
obtained in good yields as pure materials by precipitation
and filtration.
E-mail: fokin@scripps.edu
[**] We thank the National Institutes of Health, the National Institute of
General Medical Sciences (GM28384), the Skaggs Institute for
Chemical Biology, and Pfizer, Inc. for financial support. We also
thank Prof. K. B. Sharpless, Prof. M. G. Finn, and Dr. M. Whiting for
valuable advice and stimulating discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Representative examples of this convenient amide syn-
thesis are shown in Table 1. Terminal alkynes with various
functional groups—including alcohols (entry 1), carbamates
(entry 4), ethers (entry 6), and carboxylic acids (entry 8), as
well as ethynyl estradiol, a sterically demanding tertiary
propargyl alcohol (entry 9)—participated readily in the trans-
formation. Although 4-acetamido-
benzenesulfonyl azide was com-
Table 1: Amides obtained from terminal alkynes and sulfonyl azides.
monly employed, because it is
commercially available and ame-
Entry Amide product
Procedure[a] Yield [%][b] M.p. [8C]
nable to further derivatization (see
below), other sulfonyl azides also
participate in this transformation
(entries 11 and 12). However, 4-
1
A
A
60
67
225–227
nitrobenzenesulfonyl
azide
(entry 11) resulted in markedly
lower yields.
113–115
(decomp)
2
Although
a detailed under-
standing of the mechanism of this
process will require additional
studies, we propose the mechanism
outlined in Scheme 2. Similar to
the copper(i)-catalyzed triazole
synthesis,[1,3] copper(i) acetylides
are first converted into the (1,2,3-
triazol-5-yl)copper species 4, which
normally undergoes proteolysis to
release the triazole product 5.
However, in the presence of a
226
(decomp)
3
4
A[c]
74
83
203–205
(decomp)
B
232–234
5
6
7
8
A
A
A
A
64
83
54
75
(decomp)[d]
strongly
electron-withdrawing
group at N-1, 4 may eliminate a
molecule of dinitrogen, thereby
producing a transient alkynamide
6. A similar transformation of 5-
lithiated-1,2,3-triazoles has been
reported before.[4] The alkynamide
6 is then protonated to give the
highly reactive ketenimine 8, which
is immediately trapped by water to
form the N-acylsulfonamide 3. An
alternative route to 8 is through a
ring-opening pathway resembling
the well-known Dimroth rear-
rangement.[10] Thus, intermediate
4 can be shunted off into this
pathway to form the diazoimine
7.[11] Although the stability of 4 is
primarily controlled by the sub-
stituent at N-1, other factors, such
as the acidity of the reaction
medium[12] and the nature of the
functional groups at C-4 and C-
5,[13] are known to influence ring-
chain isomerizations. Thus, the
strongly electronegative sulfonyl
functionality at N-1 and basic con-
ditions favor 7 which, upon release
of a molecule of dinitrogen, collap-
ses into the keteneimine 8.
204–206
(decomp)
227
(decomp)
261
(decomp)
175
(decomp)
9
A
68
195–197
(decomp)
10
11
B
A
62
27
170–171[e]
142–144[f]
12
B
69
N-acylsulfonamides are very
resistant to hydrolytic cleavage
and thus can be viewed as perma-
[a] Representative experimental procedures are described in the Experimental Section. [b] Yield of
isolated product after precipitation and filtration. [c] 2 equiv of the sulfonyl azide were used.
[d] Lit. 2398C.[8] [e] Lit. 172–1738C.[9] [f] Lit. 1498C.[8]
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Communications
mides should prove useful whenever
near-permanent, biologically benign con-
nections between structural units with
diverse functionality are required. Addi-
tional studies directed at better under-
standing the mechanism of this process
and at further exploring its utility are
currently underway and will be published
in due course.
Experimental Section
Procedure A, as exemplified for the synthesis
of N-(4-acetamidophenylsulfonyl)-2-phenyla-
cetamide (Table 1, entry 5): Phenylacetylene
(1 mmol) and 1m sodium bicarbonate solution
Scheme 2. Proposed intermediates in the copper(i)-catalyzed synthesis of N-acylsulfonamides from
alkynes and sulfonyl azides.
(1 mL), followed by 4-acetamidobenzenesul-
fonylazide (1 mmol) and 1m sodium ascorbate
nent connectors that tolerate various transformations of other
functional groups in the molecule (of course, they are also
competent hydrogen-bond donors and acceptors, and are
indeed known pharmacophores[14]). For example, acetanilides
are readily cleaved under either basic or acidic conditions and
liberate free anilines that can be further converted into other
functional groups. Furthermore, N-acylsulfonamides can be
activated by N-methylation with methyl iodide, thereby
activating the amide bond to nucleophilic cleavage.[15] Thus,
free carboxylic acids (13) and carboxamides (12) are readily
solution (0.05 mL, 0.05 mmol) were added to a solution of TBTA
(0.02 mmol) and [Cu(CH3CN)4]PF6 (0.02 mmol) in tBuOH/water
(2:1, 5 mL). The vial was loosely capped and stirred until the starting
materials had completely disappeared, as evident by LC/MS analysis.
tert-Butanol was removed in vacuo, and the remaining aqueous
solution was stirred with Cuprisorbresin and 10% NH 4OH (3 drops)
for 30 minutes, then filtered through celite, and the filtered resin
washed with MeOH. The filtrate was made slightly acidic with 1m
HCl, and the MeOH was removed in vacuo. The product was
collected by suction filtration and dried in vacuo to afford 0.25 g
(74%) of the product as an off-white solid.
Procedure B, as exemplified for prop-2-ynyl 3-(4-acetamidophe-
nylsulfonamido)-3-oxopropanoate (Table 1, entry 10): TBTA/[Cu]
resin (100 mg, 0.02 mmol, based upon 0.19 mmolgÀ1 loading), 1m
sodium bicarbonate solution (1 mL) and 1m sodium ascorbate
solution (0.05 mL) were added to a solution of sulfonyl azide
(1 mmol) and alkyne (1 mmol) in tBuOH/water (2:1, 5 mL). The
work-up was as described for Procedure A and afforded 0.21 g (62 %)
of the product as a white solid.
obtained from alkynes in
(Scheme 3).
a
straightforward fashion
The copper(i)-catalyzed sequence described here provides
a direct, simple, and efficient route to carboxamides from
terminal alkynes, thus representing a formal oxidative hydra-
tion of a triple bond. This latest addition to the growing list of
examples of strikingly unique reactivity of in situ generated
copper(i) acetylides is, to the best of our knowledge, the first
general method for a one-step conversion of alkynes into
amides under mild conditions.[16] This transformation of
alkynes to thermally and chemically stable N-acylsulfona-
Received: October 27, 2005
Published online: March 29, 2006
Keywords: alkynes · azides · copper · oxidation ·
.
synthetic methods
[1] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B.
Sharpless, Angew. Chem. 2002, 114, 2708; Angew.
Chem. Int. Ed. 2002, 41, 2596; b) C. W. Tornøe, C.
Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057.
[2] H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem.
2001, 113, 2056; Angew. Chem. Int. Ed. 2001, 40, 2004.
[3] F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L.
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Soc. 2005, 127, 210.
[4] a) R. Raap, Can. J. Chem. 1971, 49, 1792 – 1798; b) T. L.
Gilchrist, Adv. Heterocycl. Chem. 1987, 41, 41; c) M.
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Angew. Chem. Int. Ed. 2006, 45, 3157.
[5] I. Bae, H. Han, S. Chang, J. Am. Chem. Soc. 2005, 127,
2038.
[6] T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org.
Lett. 2004, 6, 2853.
Scheme 3. Synthesis of carboxylic derivatives from alkynes. Reagents and conditions:
a) CH3I (10 equiv), K2CO3 (2 equiv), CH3CN, RT, 81%; b) tert-butylpiperazine-1-carboxylate
(1.1 equiv), toluene, 1008C, 8 h, 97%; c) NaOH (4 equiv), MeOH, RT, 6 h, HCl workup,
60%. Boc=tert-butoxycarbonyl.
[7] TBTA can be immobilized on a tentagel resin and then
preloaded with [Cu(CH3CN)4]PF6. This resin is
convenient replacement for the free TBTA/CuSO4/
a
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Chemie
ascorbate combination, especially for an automation-assisted
parallel synthesis. Another benefit is the reduced contamination
of the products with copper ions; see Procedure B and T. R.
Chan, PhD thesis, The Scripps Research Institute, 2005 for
details.
[8] D. P. van Leeuwen, A. F. Arnold, C. G. Hartland, A. Siedsma
(PLIVA, Zagreb), Netherlands patent 298391, 1965 [Chem.
Abstr. 1966, 64, 12604c].
[9] R. Dohmori, Chem. Pharm. Bull. 1964, 12, 591.
[10] O. Dimroth, Justus Liebigs Ann. Chem. 1909, 364, 183; for
reviews see G. LꢀabbØ, Bull. Chem. Soc. Belg. 1990, 99, 281;
E. S. H. El Ashry, Y. El Kilany, N. Rashed, H. Assafir, Adv.
Heterocycl. Chem. 1999, 75, 79.
[11] N-sulfonyltriazoles are formed under neutral to slightly acidic
pH values in 20–25% yield. For example, performing the
reaction between 4-acetamidobenzenesulfonylazide and phenyl-
acetylene in tBuOH/H2O (1:1, 0.1m) in the presence of CuSO4
(2 mol%) and Na ascorbate/ascorbic acid (10 mol% each)
results in the formation of 42% of the 1-sulfonyltriazole product.
Likewise, intermediate 4 can be captured with electrophiles
other than protons. For example, 1-sulfonyl-5-allyltriazole is
isolated in 51% yield by using allyl iodide (10 equiv) in
anhydrous acetonitrile.
[12] D. J. Brown, T. Nagamatsu, Aust. J. Chem. 1977, 30, 2515.
[13] a) R. E. Harmon, F. Stanley, Jr., S. K. Gupta, J. Johnson, J. Org.
Chem. 1970, 35, 3444; b) G. Himbert, M. Regitz, Justus Liebigs
Ann. Chem. 1973, 9, 1505.
[14] Currently, there are 4 drugs on the market that contain the N-
acylsulfonamide functionality, while over 600 are currently in
different stages of development: MDDR database, Elsevier
MDL Information Systems, 2005.
[15] a) H. Nagashima, N. Ozaki, M. Washiyama, K. Itoh, Tetrahedron
Lett. 1985, 26, 657; b) B. J. Backes, J. A. Ellman, J. Am. Chem.
Soc. 1994, 116, 11171.
[16] While this manuscript was under review, the following account
describing a similar transformation of alkynes to amides was
published: S. H. Cho, E. J. Yoo, I. Bae, S. Chang, J. Am. Chem.
Soc. 2005, 127, 16046.
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