7/31/2019 Copper-Catalyzed Hydrative Amide Synthesis

1/2

Copper-Catalyzed Hydrative Amide Synthesis with Terminal Alkyne, SulfonylAzide, 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 functionalizationof multiple bonds enabled facile conversion of unsaturated hydro-

carbons 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 multi-

component 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 1,4-

triazoles using copper catalyst,10 the reactivity of sulfonyl azides

varies significantly to result in a range of interesting amino group-

containing 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).

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 forma-

tion 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

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 regiose-

lective: 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 thecorresponding supported N-sulfonyl amide under the similar condi-

tions, 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

Table 1. Hydrative Amide Synthesis under Various Conditionsa

entry catalyst base solvent yield (%)b

1 CuI CHCl3

7/31/2019 Copper-Catalyzed Hydrative Amide Synthesis

2/2

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.

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 preparedpractically 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 chargevia 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 SupportingInformation for the comparison.

(13) Under the same conditions, treatment of methanesulfonyl azide withphenylacetylene 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) tothe reaction mixture of sulfonyl azide and water did not produce any amideproducts. 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.

JA056399E

Table 2. Copper-Catalyzed Hydrative Amide Synthesisa

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

C O M M U N I C A T I O N S

J. AM. CHEM. SOC. 9 VOL. 127, NO. 46, 2005 16047