Published on Web 11/01/2005

Copper-Catalyzed Hydrative Amide Synthesis with Terminal Alkyne, Sulfonyl Azide, and Water
Seung Hwan Cho, Eun Jeong Yoo, Imhyuck Bae, and Sukbok Chang*
Center for Molecular Design and Synthesis (CMDS), Department of Chemistry and School of Molecular Science (BK21), Korea AdVanced Institute of Science and Technology, Daejon 305-701, Republic of Korea
Received September 24, 2005; E-mail: sbchang@kaist.ac.kr

The amide group is a key motif in chemistry and biology.1 Although traditional chemical methods for simple amide synthesis rely heavily on an interconversion strategy between carbonyl groups or their equivalent reactive compounds,2 lability of those functional groups often restricts its ubiquitous applications. Hence, the development of alternative routes has been challenging to synthetic chemists.3 As a result, the use of thio acids or thioesters as a carbonyl precursor has been actively investigated as a chemical ligation method.4 The modified Staudinger reaction of azides with phosphines has also drawn special attention to the chemoselective formation of amides.5 Separately, advances in the functionalization of multiple bonds enabled facile conversion of unsaturated hydrocarbons to the corresponding carbonyl compounds.6 Especially, the hydration of alkynes is regarded as one of the most promising reactions for this purpose, although the reactions proceed generally at high temperatures.7 In this context, catalytic carbonylation of alkynes with amines and CO of high pressure at high temperatures offers a route to the synthesis of homologated amides.8 Recently, we devised a highly efficient copper-catalyzed multicomponent reaction (MCR), in which sulfonyl azides react with a wide range of alkynes and amines to give amidines.9 Whereas electron-rich azides react with 1-alkynes mainly leading to 1,4triazoles using copper catalyst,10 the reactivity of sulfonyl azides varies significantly to result in a range of interesting amino groupcontaining compounds depending on the third coupling partners. In the course of our investigation on the mechanistic details of this MCR, we found that a trace amount of amide was generated (e5%) when aqueous cosolvent was used. This led us to delve into an optimized preparation of amides. Herein we present an interesting procedure for the amide synthesis based on the MCR employing water as one reacting species under very mild conditions (eq 1).

Table 1. Hydrative Amide Synthesis under Various Conditionsa

entry

catalyst

base

solvent

yield (%)b

1 2 3 4 5 6 7 8

CuI CuI CuI CuI CuI CuI CuI CuBrSMe2

Et3N Et3N (0.2 equiv) (i-Pr)2NEt pyridine K2CO3 Et3N Et3N

CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 THF CHCl3

<1 95 27 47 35 <1 30 67

a Phenylacetylene (0.5 mmol), p-toluenesulfonyl azide (1.2 equiv), base (1.2 equiv except entry 3), water (2.5 equiv), and catalyst (0.1 equiv) in solvent (1.0 mL). b Based on the integration of 1H NMR signals using p-anisole as an internal standard.

At the outset of our studies, we tried to optimize the reaction conditions for the selective formation of amides (Table 1).11 When the reaction of phenylacetylene (1a) with p-toluenesulfonyl azide (2a) and water was tried with CuI in the absence of an external base, no conversion was observed.12 In contrast, successful formation of N-sulfonyl amide 3a was observed in chloroform when a tertiary amine base, such as Et3N, was added. While a stoichiometric amount of triethylamine is required to achieve high efficiency (compare entries 2 and 3), the use of other bases results in significantly reduced yields (entries 4-6). Solvents other than chloroform afforded low yield (entry 7), and copper catalysts other than CuI exhibited reduced activities. The present approach for amide synthesis turned out to be quite general, and a wide range of alkynes and sulfonyl azides underwent the coupling with water by the action of copper catalyst to furnish
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the corresponding N-sulfonyl amides in high yields (Table 2). Reactions with both aromatic and aliphatic 1-alkynes were efficient and not influenced by the electronic and steric variations of the reacting substrates. A variety of labile functional groups, such as heterocyclic (entry 6), halide (entry 7), acetate (entry 8), silyloxy (entry 9), propargylic ether (entry 10), conjugated olefin (entry 11), and ester moiety (entry 12), were fully tolerated under the conditions. Intriguingly, in the case of propargylic ether (entry 10), the use of 2,6-lutidine resulted in much higher product yield than Et3N (34%). It should be mentioned that the reaction is regioselective: only terminal alkynes react, while olefin and internal triple bonds (entries 12 and 13, respectively) are intact. In addition to aryl sulfonyl azides, aliphatic variants work equally well. For instance, sulfonyl azides of phenylmethane, butane, and 2-trimethylsilylethane took part in the reaction to afford the corresponding N-sulfonyl amides in high yields (entries 14-16).13 Moreover, N-camphorsulfonyl amide 3q was obtained in good yield under the same conditions (entry 17). The present approach to amide synthesis was readily amenable to the solid-phase procedure (eq 2).14 A terminal alkyne (1r) attached onto a 2-chlorotrityl resin was readily converted to the corresponding supported N-sulfonyl amide under the similar conditions, although the reagents were used in large excess compared to solution-phase cases.15 After cleaving the resin using CF3CO2H, a derivative of hydroxy sulfonamide (3r) was isolated in 46% overall yield from three steps, indicating that each step proceeds in 77% on average.16

J. AM. CHEM. SOC. 2005, 127, 16046-16047

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Table 2. Copper-Catalyzed Hydrative Amide Synthesisa

Although it is still early to present sufficient mechanistic evidence, the reaction is thought to be initiated by the copper catalyst to form an imidate intermediate followed by tautomerization to afford the amide.18 It is also suspected that an amination of copper acetylide to an N-sulfonyl ynamide takes place prior to the addition of water to the allenamide tautomer leading to the amide product.19 Release of N2 from sulfonyl azides during the course of either process is also assumed: this drives the overall transformation. Details on the mechanistic pathways will be presented in due course. We demonstrate for the first time that amides can be prepared practically by an unconventional hydrative reaction between terminal alkynes, sulfonyl azides, and water in the presence of a copper catalyst and amine under very mild conditions. Since alkynyl and sulfonyl azido moieties are readily introduced and managed in chemical processes, the developed route to amides is highly versatile and has great potential as a synthetic tool. Acknowledgment. This research was supported by grant No. R01-2005-000-10381-0 from the Basic Research Program and CMDS. We also thank Prof. David G. Churchill for his critical reading of this manuscript.
Supporting Information Available: Experimental procedures, spectroscopic data, and copies of 1H and 13C NMR spectra for the prepared amide compounds. This material is available free of charge via the Internet at http://pubs.acs.org. References
(1) Humphrey, J. M.; Chamberlin, A. R. Chem. ReV. 1997, 97, 2243. (2) Bailey, P. D.; Collier, I. D.; Morgan, K. M. In ComprehensiVe Organic Functional Group Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon: Cambridge, 1995; Vol. 5, Chapter 6. (3) (a) Bray, B. L. Nat. ReV. 2003, 2, 587. (b) Albericio, F. Curr. Opin. Chem. Biol. 2004, 8, 211. (4) (a) Dawson, P. E.; Muir, T. W.; Clark-Lewis, I.; Kent, S. B. Science 1994, 266, 776. (b) Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams, L. J. J. Am. Chem. Soc. 2003, 125, 7754. (c) Merkx, R.; Brouwer, A. J.; Rijkers, D. T. S.; Liskamp, R. M. J. Org. Lett. 2005, 7, 1125. (5) (a) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007. (b) Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000, 2, 1939. (c) Damkaci, F.; DeShong, P. J. Am. Chem. Soc. 2003, 125, 4408. (6) (a) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368. (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079. (7) Tokunaga, M.; Wakatsuki, Y. Angew. Chem., Int. Ed. 1998, 37, 2867. (8) (a) Ali, B. E.; Tijani, J. Appl. Organomet. Chem. 2003, 17, 921. (b) Knapton, D. J.; Meyer, T. Y. Org. Lett. 2004, 6, 687. (c) Uenoyama, Y.; Fukuyama, T.; Nobuta, O.; Matsubara, H.; Ryu, I. Angew. Chem., Int. Ed. 2005, 44, 1075. (9) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038. (10) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (11) For full optimization experiments, see Supporting Information (Table S1). (12) On the basis of the kinetic observation of initial reaction rates, the reactivity of water is 2 orders of magnitude lower than that of amine. See Supporting Information for the comparison. (13) Under the same conditions, treatment of methanesulfonyl azide with phenylacetylene gave a meager 19% yield of the desired amide. (14) Walsh, D.; Wu, D.; Chang, Y.-T. Curr. Opin. Chem. Biol. 2003, 7, 353. (15) For experimental details, see Supporting Information. (16) For a recent example of solid-phase reactions using the trityl resin, see: Yadav, V.; Chu, C. K.; Rais, R. H.; Al Safarjalani, O. N.; Guarcello, V.; Naguib, F. N. M.; el Kouni, M. J. J. Med. Chem. 2004, 47, 1987. (17) Heidler, P.; Link, A. Bio. Med. Chem. 2005, 13, 585. (18) While it was observed that copper acetylide forms during the early stages of the reaction, subject of separately prepared phenylethynylcopper(I) to the reaction mixture of sulfonyl azide and water did not produce any amide products. For the preparation of copper acetylide, see: Ito, H.; Arimoto, K.; Sensui, H.; Hosomi, A. Tetrahedron Lett. 1997, 38, 3977. (19) For a recent review on ynamides, see: Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575.

a Alkyne (0.5 mmol), sulfonyl azide (1.2 equiv), Et N (1.2 equiv except 3 in entry 10), and CuI (0.1 equiv) in CHCl3 (1.0 mL). b Isolated yield. c 2,6Lutidine (1.2 equiv) was used instead of Et3N.

The reaction can be also effectively scaled up with the similar efficiency. For example, the reaction of propargylic amine derivative (1s, 10.0 mmol) gave the corresponding -amino sulfonamide (3s) in high yield even when lower amounts of copper catalyst were used (eq 3). Due to the fact that propargylic groups can be easily introduced in the chemical synthesis via N- or O-alkylation, our present protocol would be highly attractive as a viable and rapid route to the generation of amides bearing heteroatoms at the -position.

Despite the fact that N-sulfonyl amides (N-acylsulfonamides) themselves have a significant value in medicinal chemistry,17 we found that removal of the N-sulfonyl group was readily carried out in high yield with sodium in naphthalene,15 thus further applications of this protocol are feasible.

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