Copper-catalyzed aerobic oxidative amidation of terminal alkynes: Efficient synthesis of ynamides

Article abstract of DOI:10.1021/ja077406x

A copper-catalyzed method for the preparation of ynamides has been identified that proceeds via aerobic oxidative coupling of terminal alkynes with various nitrogen nucleophiles, including cyclic carbamates, amides and ureas, and N-alkyl-arylsulfonamides and indoles. Copyright

Full text of DOI:10.1021/ja077406x

Published on Web 01/01/2008
Copper-Catalyzed Aerobic Oxidative Amidation of Terminal Alkynes: Efficient
Synthesis of Ynamides
Tetsuya Hamada, Xuan Ye, and Shannon S. Stahl*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue, Madison, Wisconsin 53706
Received September 25, 2007; E-mail: stahl@chem.wisc.edu
Scheme 1. Copper-Catalyzed Pathways for Ynamide Synthesis
Metal-catalyzed cross-coupling reactions are among the most
powerful methods available for the formation of carbon-carbon
and carbon-heteroatom bonds.1,2 Oxidative-coupling reactions,
particularly methods that enable direct functionalization of C-H
bonds, have been the focus of significant recent interest.3 Unfor-
tunately, such methods often require stoichiometric oxidants that
reduce their appeal relative to classical cross-coupling reactions.
Our interest in aerobic oxidation reactions4 prompted us to consider
Cu-catalyzed oxidative coupling reactions that could employ
molecular oxygen as the stoichiometric oxidant, and we describe
here a new Cu-catalyzed method for the synthesis of ynamides via
direct amidation of the C-H bond of terminal alkynes (eq 1). The
reactions exhibit quite a broad scope with respect to the alkyne
and nitrogen nucleophile, and O2 may be used as the stoichiometric
oxidant. The utility of ynamides as synthons in organic chemistry
has expanded significantly in recent years,5,6 and ynamide prepara-
tion via oxidative coupling represents an efficient alternative to
known two-step methods, such as involving alkyne halogenation
followed by C-N cross-coupling (Scheme 1).7,8
Table 1. Selected Screening Results for Copper-Mediated
Oxidative Coupling of Phenylacetylene and 2-Oxazolidinone
% yieldb
3a (4/5)
entry
reaction conditions (equiv of reagents)a
solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
CuCl2 (2), Cs2CO3 (2), 1 equiv 2ac
CuCl2 (2), Cs2CO3 (2)c
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
26 (42/17)
53 (24/4)
70 (28/-)
89 (4/-)
trace (19/-)
90 (4/-)
46 (2/-)
60 (2/-)
64 (2/-)
85 (2/-)
43 (26/-)
68 (17/-)
65 (7/-)
48 (3/-)
53 (2/-)
65 (3/-)
89 (2/-)
69 (16/4)
CuCl2 (2), Cs2CO3 (2)d
CuCl2 (2), Cs2CO3 (2)
CuCl2 (0.2), Cs2CO3 (2)
CuCl2 (0.2), NaHCO3 (2)
CuCl2 (0.2), NaHCO3 (2)
Two important precedents provided a basis for our investigation
of the alkyne amidation reactions: (1) the Glaser-Hay oxidative
dimerization of alkynes (eq 2)9 and (2) the oxidative coupling of
arylboronic acids and nitrogen nucleophiles, first reported by Chan
and Lam (eq 3).10,11 These results suggested that, under appropriate
CuCl2 (0.2), NaHCO3 (2), pyridine (0.4)
CuCl2 (0.2), NaHCO3 (2), pyridine (0.8)
CuCl2 (0.2), NaHCO3 (2), pyridine (2)
CuCl2 (0.2), NaHCO3 (2), phene (0.2)
CuCl2 (0.2), NaHCO3 (2), bpye (0.2)
CuCl2 (0.2), NaHCO3 (2), DMEDe (0.2)
CuCl2 (0.2), NaHCO3 (2), 2-ACHe (0.2)
CuCl2 (0.2), NaHCO3 (2), DMAPe (2)
CuCl2 (0.2), NaHCO3 (2), CF3pye (2)
CuCl2 (0.2), Na2CO3 (2), pyridine (2)
CuCl2 (0.2), Na2CO3 (2), pyridine (2),
1 equiv 2a
19
20
21
CuBr2 (0.2), Na2CO3 (2), pyridine (2)
Cu(OAc)2 (0.2), Na2CO3 (2), pyridine (2)
Cu(TFA)2e (0.2), Na2CO3 (2), pyridine (2)
toluene
toluene
toluene
81 (2/-)
88 (3/-)
73 (3/-)
conditions, aerobic oxidative cross-coupling of alkynes and nitrogen
nucleophiles might be possible. Hints of such reactivity are evident
in the literature,12,13 but several recent examples of metal-catalyzed
oxidative amination of alkynes yield carboxamides rather than
ynamides.14 The present results represent the first catalytic synthesis
of ynamides directly from alkynes.
a Standard conditions: 0.1 mmol 1a, 0.5 mmol 2a, 1 atm O2, 1 mL of
solvent, 70 °C. 4 h; phenylacetylene added dropwise to the reaction mixture
over 4 h. b 3a: isolated yields; 4 and 5: GC yields. c Alkyne added in a
single aliquot. d Alkyne added to the solution over 1 h. e Abbreviations:
phen ) phenanthroline; bpy ) 2,2′-bipyridine; DMED ) N,N′-dimethyl-
ethylenediamine; 2-ACH ) 2-Ac-cyclohexanone; DMAP ) 4-N,N-dim-
ethylaminopyridine; CF3py ) 4-trifluoromethylpyridine; TFA ) trifluoro-
acetate.
We initiated our studies by examining the reaction of pheny-
lacetylene (1a) with 2-oxazolidinone (2a) in the presence of
stoichiometric copper salts under 1 atm of O2. In our initial
screening of Cu sources, Brønsted bases and solvents, optimal
results were observed with 2 equiv of CuCl2 and Cs2CO3 in
dimethylsulfoxide (DMSO) (Table 1, entries 1-4).15a When the
substrates were combined in a 1:1 ratio, we observed the formation
of 3a together with the homocoupled dimer 4 and alkynyl chloride
5 (entry 1).16 The yield of 3a was enhanced, and side products
were reduced by increasing the quantity of nitrogen nucleophile to
5 equiv (entries 2-4) and by adding the alkyne to the reaction
mixture over a period of 4 h (entry 4). When the copper loading
was reduced to 20 mol %, good yields of 3a were obtained by
replacing Cs2CO3 with NaHCO3 as the base (entries 5 and 6).
Further screening of the catalytic reaction conditions revealed that
toluene was also a suitable solvent if nitrogen donor ligands were
included in the reaction mixture (entries 7-21). Optimal conditions
featured 20 mol % CuCl2 and 2 equiv of Na2CO3 and pyridine
(entry 17). A useful yield of 3a (69%) was also obtained under
catalytic conditions with a 1a:2a ratio of 1:1. As expected, a higher
yield of diyne byproduct 4 is formed under these conditions (16%);
however, this result is significant for the synthesis of ynamides
with nitrogen nucleophiles that are not commercially available.17
Chelating ligands that have been used in other Cu-catalyzed C-N
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J. AM. CHEM. SOC. 2008, 130, 833-835
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C O M M U N I C A T I O N S
Table 3. Cu-Catalyzed Oxidative Amidation of Alkynesa
Table 2. Cu-Catalyzed Oxidative Coupling of Phenylacetylene
with Nitrogen Nucleophilesa
a Reaction conditions: 0.1 mmol 1a, 0.5 mmol R1R2NH, 0.2 mmol
Na2CO3, 0.02 mmol CuCl2, 0.2 mmol pyridine, toluene (1.0 mL), 1 atm
O2, 70 °C, 1a added to the reaction over a 4-h period. b Isolated yields.
coupling reactions (entries 11-14)2d-f and pyridine derivatives
(entries 15 and 16) led to inferior results. Among the Cu sources
tested, both CuCl2 and Cu(OAc)2 were effective and performed
better than CuBr2 and Cu(O2CCF3)2.
The oxidative coupling of phenylacetylene with various nitrogen
nucleophiles was examined with 2 equiv of CuCl2 in DMSO and
20 mol % CuCl2 in toluene. The results under catalytic conditions
were consistently better than those obtained under stoichiometric
conditions15b and led to moderate-to-excellent isolated yields of the
alkynamide products (Table 2). Cyclic carbamate, amide, and urea
nucleophiles gave the desired ynamides in high yield (entries 1, 3,
and 4). For reasons that are not yet clear, pyrrolidinone is an
ineffective nucleophile under these conditions (entry 2); however,
a 55% yield of the desired product could be obtained with
stoichiometric CuCl2 in DMSO.15b Acyclic nucleophiles, including
N,O-dimethylcarbamate, acetanilide, and N,N′-dimethylurea, showed
almost no reactivity under either set of conditions. 4-Substituted-
N-alkyl benzenesulfonamides afforded ynamides in moderate-to-
high yields (entries 5-9), and indoles with substituents at the 2-
or 3-position were also viable substrates (entries 10-12).
The reaction scope was also investigated with respect to the
alkyne coupling partner (Table 3). Once again, the use of catalytic
conditions in toluene typically led to higher yields than the
stoichiometric conditions in DMSO.15b The reaction is compatible
with a variety of different terminal alkynes, including alkyl-, aryl-,
and silyl-substituted alkynes. TBS-protected hydroxyalkyl ana-
logues, including propargyl alcohol derivatives, are effective. In
general, electron-rich alkynes are more effective coupling partners.
For example, triisopropylsilylacetylene reacts successfully with
a Reaction conditions: 0.1 mmol alkyne, 0.5 mmol R1R2NH, 0.2 mmol
Na2CO3, 0.02 mmol CuCl2, 0.2 mmol pyridine, toluene (1.0 mL), 1 atm
O2, 70 °C, The alkyne was added to the reaction over a 4 h period. b Isolated
yields. c Obtained with the stoichiometric CuCl2/DMSO system; see SI for
details.
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C O M M U N I C A T I O N S
Scheme 2. Mechanistic Proposal for Copper-Catalyzed Oxidative
Coupling of Terminal Alkynes and Nitrogen Nucleophiles
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R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575-7606.
(b) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379-
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1455-1475.
pyrrolidinone (entry 3), an ineffective nucleophile in the reaction
with phenylacetylene (see above); the corresponding ynamide was
obtained in high yield (95%). Electron-deficient alkynes, such as
ethylpropiolate and 4-nitrophenylacetylene, were less effective,
resulting in ynamide yields of e10% and 35%, respectively, with
oxazolidinone as the nucleophile.
(6) For selected recent applications of ynamides, see: (a) Kohnen, A. L.;
Mak, X. Y.; Lam, T. Y.; Dunetz, J. R.; Danheiser, R. L. Tetrahedron
2006, 62, 3815-3822. (b) Mart´ınez-Espero´n, M. F.; Rodr´ıguez, D.;
Castedo, L.; Saa´, C. Tetrahedron 2006, 62, 3843-3855. (c) Villeneuve,
K.; Riddell, N.; Tam, W. Tetrahedron 2006, 62, 3823-3836. (d) Marion,
F.; Coulomb, J.; Servais, A.; Courillon, C.; Fensterbank, L.; Malacria,
M. Tetrahedron 2006, 62, 3856-3871. (e) Mori, M.; Wakamatsu, H.;
Saito, N.; Sato, Y.; Narita, R.; Sato, Y.; Fujita, R. Tetrahedron 2006, 62,
3872-3881. (f) Couty, S.; Liegault, B.; Meyer, C.; Cossy, J. Tetrahedron
2006, 62, 3882-3895. (g) Zhang, Y. Tetrahedron 2006, 62, 3917-3927.
(h) Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006, 128,
4586-4587. (i) Oppenheimer, J.; Johnson, W. L.; Tracey, M. R.; Hsung,
R. P.; Yao, P.-Y.; Liu, R.; Zhao, K. Org. Lett. 2007, 9, 2361-2364. (j)
Oppilliart, S.; Mousseau, G.; Zhang, L.; Jia, G.; Thue´ry, P.; Rousseau,
B.; Cintrat J.-C. Tetrahedron 2007, 63, 8094-8098 and references therein.
(7) (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang,
J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003,
125, 2368-2369. (b) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5,
4011-4014. (c) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz. K. C.
M.; Vera, E. L. Org. Lett. 2004, 6, 1151-1154. (d) Zhang, X.; Zhang,
Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.; Peterson,
M. E.; Sagamanova, I. K.; Shen, L.; Tracey, M. R. J. Org. Chem. 2006,
71, 4170-4177. (e) Buissonneaud, D.; Cintrat, J.-C. Tetrahedron Lett.
2006, 47, 3139-3143. (f) Kohnen, A. L.; Dunetz, J. R.; Danheiser, R. L.
Org. Synth. 2007, 84, 88-101. (g) Sagamanova, I. K.; Kurtz, K. C. M.;
Hsung, R. P. Org. Synth. 2007, 84, 359-367.
(8) Other stepwise methods for ynamide syntheses are known. For leading
references, see the review articles in ref 6 and the following representative
methods that employ alkynyliodonium salts: (a) Murch, P.; Williamson,
B. L.; Stang, P. J. Synthesis 1994, 1255-1256. (b) Witulski, B.; Stengel,
T. Angew. Chem., Int. Ed. 1998, 37, 489-492. (c) Feldman, K. S.; Bruendl,
M. M.; Schildknegt, K.; Bohnstedt, A. C. J. Org. Chem. 1996, 61, 5440-
5452.
(9) (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422-424. (b) Hay, A. S.
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Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632-2657.
(10) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933-2936. (b) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.
Tetrahedron Lett. 1998, 39, 2941-2944. (c) Chan, D. M. T.; Lam, P. Y.
S. Boronic Acids in Organic Synthesis and Chemical Biology; Wiley-
VCH: New York, 2005; pp 205-240.
(11) For a related reaction involving directed functionalization of aryl C-H
bonds of 2-phenylpyridines, see: (a) Chen, X.; Hao, X.-S.; Goodhue, C.
E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790-6791. (b) Uemura, T.;
Imoto, S.; Chatani, N. Chem. Lett. 2006, 35, 842.
The reactions are not limited to the small scale described above
(i.e., 0.1 mmol). Ynamides 3a, 3f, and 10 were successfully
prepared on 1 mmol scale in yields comparable to or higher than
those on small scale (91%, 98%, and 85%, respectively), and
ynamide 3f was prepared on 10 mmol scale (85% yield).15a
The mechanism of this reaction remains to be elucidated. The
formation of alkynyl chlorides as side products in the reaction raises
the possibility that C-N bond formation could arise from Cu-
mediated cross-coupling of an alkynyl chloride and a nitrogen
nucleophile. Attempts to use alkynyl chlorides directly as substrates,
however, resulted in negligible yields of ynamide. Therefore, we
postulate a catalytic mechanism that features sequential activation
of the alkyne and nitrogen nucleophile, followed by C-N reductive
elimination and aerobic reoxidation of the catalyst (Scheme 2). This
mechanism rationalizes the beneficial effect of using excess
equivalents of the nitrogen nucleophile: formation of the mixed
CuII(alkynyl)(amidate) species C is expected to compete directly
with activation of a second equivalent of alkyne to form bis-alkynyl-
CuII species D. The latter intermediate will produce the undesired
diyne byproduct. Factors that contribute to the success (or failure)
of different nitrogen nucleophiles are presently poorly understood,
although the substrate pKa presumably plays an important role.
Nucleophiles effective in the reactions above exhibit a pKa in the
range of 15-23 (DMSO); however, not all substrates with a pKa
in this range, including pyridone (17.0) and acetanilide (21.5), are
effective. Systematic investigation of these issues will be the focus
of future studies.
(12) The oxidative coupling of phenylacetylene and dimethylamine yields N,N-
dimethyl-2-phenylethynylamine, which undergoes rapid hydrolysis to form
N,N-dimethylphenylacetamide: Peterson, L. I. Tetrahedron Lett. 1968,
9, 5357-5360.
(13) An ynamide was obtained as an unexpected byproduct in the reaction
between an alkynylcopper reagent and an iodoalkyl-substituted â-lactam.
Balsamo, A.; Macchia, B.; Macchia, F.; Rossello, A.; Domiano, P.
Tetrahedron Lett. 1985, 26, 4141-4144.
In conclusion, we have developed a copper-catalyzed method
for aerobic oxidative coupling of terminal alkynes with a variety
of nitrogen nucleophiles. The reactions provide efficient access to
ynamides and provide a benchmark for the development of new
aerobic oxidative coupling reactions.
(14) (a) Chan, W.-K.; Ho, C.-M.; Wong, M.-K.; Che, C.-M. J. Am. Chem.
Soc. 2006, 128, 14796-14797. (b) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang,
S. J. Am. Chem. Soc. 2005, 127, 16046-16047. (c) Cassidy, M. P.;
Raushel, J.; Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 3154-3157.
(15) (a) See Supporting Information for additional details. (b) A complete
presentation of screening and preparative data obtained with the CuCl2/
DMSO reaction systems (stoichiometric and catalytic) is also presented
in the Supporting Information
(16) For examples of halogenation with copper halides, see: (a) Uemura, S.;
Okazaki, H.; Okano, M.; Sawada, S.; Okada. A.; Kuwabara, K. Bull. Chem.
Soc. Jpn. 1978, 51, 1911-1912. (b) Casarini, A.; Dembech, P.; Reginato,
G.; Ricci, A.; Seconi, G. Tetrahedron Lett. 1991, 32, 2169-2170. (c)
Yan. J.; Li, J.; Cheng, D. Synlett 2007, 2442-2444.
Acknowledgment. We thank the DOE (DE-FG02-05ER1590),
Bristol-Myers Squibb, and Mitsui Chemicals, Inc. (T.H.) for
financial support of this work.
Supporting Information Available: Experimental details, ad-
ditional screening data, and characterization data for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(17) The nitrogen nucleophiles appear to be stable under the reaction conditions,
and the unreacted nucleophile may be recovered from the reaction mixture,
if desired. This point was successfully demonstrated in the 10 mmol scale
preparation of ynamide 3f (Table 2), from which 90% recovery of the
unreacted nucleophile was achieved. See Supporting Information for
details.
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JA077406X
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