J. Am. Chem. Soc. 2001, 123, 7727-7729
7727
industrial laboratories. While the importance of such reactions
cannot be overstated, the necessity to use high temperatures,
highly polar solvents, and often large amounts of copper reagents
have prevented these reactions from being employed to their full
potential. We have previously disclosed Ullmann-type methodol-
ogy for the N-arylation of imidazoles11 and for the formation of
diaryl ethers.12 Both of these used 1,10-phenanthroline/(CuOTf)2‚
benzene with various additives. This led us to examine the
efficiency of other chelating nitrogen ligands in copper-catalyzed
carbon-heteroatom bond forming processes. We show here that
the combination of air stable CuI and racemic trans-1,2-
cyclohexanediamine (1a) in the presence of K3PO4, K2CO3,
Cs2CO3, or NaOt-Bu comprises an extremely efficient and general
catalyst system for the N-amidation of aryl and heteroaryl iodides
and bromides and the N-arylation of a number of heterocycles.
Preliminary studies with this catalyst also show that it is even
capable of the amidation of unactivated aryl chlorides. Moreover,
we show for the first time to our knowledge that a Goldberg
reaction can be carried out at room temperature.
As shown in Table 1, lactams, primary amides, and formamides
derived from primary amines and acetanilide can be coupled to
a variety of aryl iodides. In general, 1 mol % of air-stable CuI in
combination with 10 mol % of inexpensive racemic trans-
cyclohexanediamine 1a is sufficient to obtain a high yield after
23 h at 110 °C in the presence of K3PO4. In some cases, the
commercial mixture of the cis and trans diastereomers of 1,2-
cyclohexanediamine could be used with comparable results (entry
2h). While the time for each reaction has not been optimized,
we have found that in some cases the reactions are nearly complete
(∼90%) after 1 h. Of particular interest are entries 2a (2° amide),13
2b (free NH2), and 2c (free NH2 in nitrogen nucleophile) in which
substrates not compatible with the Pd-catalyzed methodology are
transformed in high yield. As can be seen in entries 2d-f the
presence of strongly electron-donating substituents at the ortho
or para position has no deleterious effects. In the case of 2f, the
reaction has been carried out with 0.2 mol % CuI (S/C ) 500)
and proceeds in 98% yield. N-BOC aniline can also be arylated
in virtually quantitative yield. As shown for case 2i, the reaction
of benzamide and 3,5-dimethyliodobenzene proceeds in high yield
at room temperature using 5 mol % of CuI.
A General and Efficient Copper Catalyst for the
Amidation of Aryl Halides and the N-Arylation of
Nitrogen Heterocycles
Artis Klapars, Jon C. Antilla, Xiaohua Huang, and
Stephen L. Buchwald*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed May 18, 2001
ReVised Manuscript ReceiVed June 22, 2001
During the past few years significant advances have occurred
in the development of cross-coupling methodology; some of these
have emanated from our own labs. Of particular interest has been
the acquisition of the ability to utilize inexpensive aryl chlorides.1
This represents a partial solution to a long-standing problem in
organometallic chemistry and catalysis. By far, however, the
largest application of cross-coupling chemistry, particularly C-N
bond-forming processes, occurs in the medicinal and discovery
groups of pharmaceutical companies and in academic laboratories.
For the vast majority of these cases the scope, experimental ease,
and reliability of a method is much more important than whether
aryl chlorides can be used rather than aryl bromides or aryl
iodides. Despite significant improvements,2 the scope of cross-
coupling methodology to form aryl and heteroaryl C-N bonds
lags that of analogous C-C bond-forming processes such as
Suzuki, Stille, and Negishi coupling reactions.3 There are many
reasons for these limitations, including the sensitivity of many
functional groups to the combination of amine and base required
in C-N coupling protocols. Substrates that contain certain
functional groups have proven to be persistently problematic. Of
the functional groups that are incompatible with the Pd-catalyzed
amination methodology, the most important are probably 1° and
2° amides.4 Another problematic situation is when there is a free
OH or NH directly bound to the aromatic ring that contains the
halide or sulfonate.5 While some progress has been made in the
N-arylation of heterocycles and amination of heterocyclic halides,
the scope has been quite limited.6 Moreover, as the cost of Pd
remains at $600-700/ounce, less costly alternatives become more
desirable.7 In this paper we describe a vastly enhanced version
of the venerable Goldberg reaction, the copper-catalyzed amida-
tion of aryl and heteroaryl halides. We also describe the
application of this catalyst system to the N-arylation of a variety
of heterocycles and other nitrogenous substrates.
The reactions of aryl bromides are detailed in Table 2. The
reactions are conducted under conditions similar to those in Table
1, except that K2CO3 is used as the base in some cases and often
5-10 mol % CuI is required. As can be seen, a variety of
heteroaryl bromides are excellent substrates, including both 2-
and 3-bromothiophene, the latter a substrate only moderately
Both Ullmann coupling processes8,9 and the related Goldberg
coupling reaction10 have a long history of utility in academic and
(9) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (b) Gauthier,
S.; Fre´chet, J. M. J. Synthesis 1987, 383. (c) Paine, A. J. J. Am. Chem. Soc.
1987, 109, 1496. (d) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am.
Chem. Soc. 1998, 120, 12459. (e) Goodbrand, H. B.; Hu, N.-X. J. Org. Chem.
1999, 64, 670. (f) Kalinin, A. V.; Bower, J. F.; Riebel, P.; Snieckus, V. J.
Org. Chem. 1999, 64, 2986. (g) Fagan, P. J.; Hauptman, E.; Shapiro, R.;
Casalnuovo, A. J. Am. Chem. Soc. 2000, 122, 5043. (h) Arterburn, J. B.;
Pannala, M.; Gonzalez, A. M. Tetrahedron Lett. 2001, 42, 1475. (i) Lang, F.;
Zewge, D.; Houpis, I. N.; Volante, R. P. Tetrahedron Lett. 2001, 42, 3251.
(10) (a) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691. (b) Bacon,
R. G. R.; Karim, A. J. Chem. Soc., Perkin Trans. 1 1973, 272. (c) Freeman,
H. S.; Butler, J. R.; Freedman, L. D. J. Org. Chem. 1978, 43, 4975. (d)
Yamamoto, T.; Kurata, Y. Can. J. Chem. 1983, 61, 86. (e) Dharmasena, P.
M.; Oliveira-Campos, A. M.-F.; Raposo, M. M. M.; Shannon, P. V. R. J.
Chem. Res. (S) 1994, 296. (f) Ito, A.; Saito, T.; Tanaka, K.; Yamabe, T.
Tetrahedron Lett. 1995, 36, 8809. (g) Sugahara, M.; Ukita, T. Chem. Pharm.
Bull. 1997, 45, 719. Pd-catalyzed aryl amidation: (h) Shakespeare, W. C.
Tetrahedron Lett. 1999, 40, 2035. (i) Yin, J.; Buchwald, S. L. Org. Lett. 2000,
2, 1101.
(1) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719 and references
therein.
(2) Reviews: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S.
L. Acc. Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Angew. Chem., Int. Ed.
1998, 37, 2046. (c) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125.
(3) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: Weinheim, Germany, 1998.
(4) Examples are rare and include the following: (a) Ward, Y. D.; Farina,
V. Tetrahedron Lett. 1996, 37, 6993. (b) Willoughby, C. A.; Chapman, K. T.
Tetrahedron Lett. 1996, 37, 7181. (c) Batch, A.; Dodd, R. H. J. Org. Chem.
1998, 63, 872. (d) Link, J. T.; Sorensen, B.; Liu, G.; Pei, Z.; Reilly, E. B.;
Leitza, S.; Okasinski, G. Bioorg. Med. Chem. Lett. 2001, 11, 973.
(5) Deng, B.-L.; Lepoivre, J. A.; Lemie`re, G. Eur. J. Org. Chem. 1999,
2683.
(6) (a) Mann, G.; Hartwig, J. F.; Driver, M. S.; Ferna´ndez-Rivas, C. J.
Am. Chem. Soc. 1998, 120, 827. (b) Hartwig, J. F.; Kawatsura, M.; Hauck, S.
I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575.
(c) Old, D. W.; Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403.
(7) Ni-catalyzed amination of aryl chlorides: (a) Wolfe, J. P.; Buchwald,
S. L. J. Am. Chem. Soc. 1997, 119, 6054. (b) Brenner, E.; Schneider, R.;
Fort, Y. Tetrahedron 1999, 55, 12829. (c) Lipshutz, B. H.; Ueda, H. Angew.
Chem., Int. Ed. 2000, 39, 4492.
(11) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999,
40, 2657.
(12) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 10539.
(13) Generally, N-alkylformamides react much faster than other acyclic
N-alkylamides. This accounts for the chemoselective formation of 2a.
(8) For a review, see: Lindley, J. Tetrahedron 1984, 40, 1433.
10.1021/ja016226z CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/12/2001