pubs.acs.org/joc
and polar organic solvents. Great efforts have been made to
A Facile and Practical Copper Powder-Catalyzed,
Organic Solvent- and Ligand-Free Ullmann
Amination of Aryl Halides
minimize these problems and marked progress achieved.1
The most effective alternative should be Buchwald-Hartwig
amination,2,3 which proceeds under a milder condition in the
presence of palladium-based catalysts with phosphine li-
gands or N-heterocyclic carbenes. A blemish in this amina-
tion reaction is that these ligands are often air-sensitive,
toxic, and expensive.2,3 Consequently, the copper-based pro-
tocols of Ullmann type amination attracted the attention
again in view of its low cost and low toxicity.1
Jiao Jiao, Xi-Ru Zhang, Ning-Hui Chang, Jie Wang,
Jun-Fa Wei,* Xian-Ying Shi, and Zhan-Guo Chen
School of Chemistry and Materials Science, Shaanxi Normal
University and Key Laboratory for Macromolecular Science
of Shaanxi Province, Xi’an, 710062, P. R. China
Over the past decade, D. W. Ma’s group and others have
developed a set of efficient improvements on the aryl amina-
tion of this type, making this old reaction more practical
in organic synthesis.4,5 The most efficient ones include
using amino acids as cocatalyst and coupling partner.4a
Buchwald’s group reported a CuI-catalyzed Ullmann reac-
tion wherein aryl halides were aminated by various amines in
glycol with high efficiency even in air.4b Wolf and co-workers
reported a regioselective amination of 2-bromobenzoic acid
using Cu/CuO as catalyst in 2-ethoxyethanol at 130 °C.4c
Collectively, albeit these modifications of the Ullmann ami-
nation overcome some shortcomings of the classic reaction,
most of them still need ligands and, in particular, they cannot
get rid of expensive, harmful, and uneasily recoverable orga-
nic solvents such as DMSO, DMF, and NMP.4,6 Recently,
Wolf’s group reported a ligand-free method using 5 mol %
Cu2O as catalyst in aqueous ammonia system using NMP
(NMP/water=1:1 v/v) as cosolvent.7a Yadav et al. reported an
Ullmann amination with stoichiometric amounts of active
copper in aqueous media or under solvent-free conditions
with microwave irradiation.7b
Received October 31, 2010
A facile and practical method that the copper powder-
catalyzed Ullmann amination of aryl halides with aque-
ous methylamine under organic solvent- and ligand-free
condition at 100 °C and in air gave N-arylamines as sole
products in good to excellent yields. The presence of a
small amount of air is essential. Other aliphatic primary
amines show good to very high reactivity. Secondary
amines and aniline are not reactive. Sensitive substituents
(i.e., CHO, MeCO, CN and Cl) are tolerable in the
reaction.
Performing organic transformations on/in water has gained
increasing attention recently because water is a cheap, green,
(4) (a) Ma, D. W.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459–12467. (b) Kwong, F. Y.; Klapars, A.; Buchwald., S. L.
Org. Lett. 2002, 4, 581–584. (c) Wolf, C.; Liu, S.; Mei, X.; August, A. T.;
Casimir, M. D. J. Org. Chem. 2006, 71, 3270–3273. (d) Cai, Q.; Zhu, W.;
Zhang, H.; Zhang, Y.; Ma, D. Synthesis 2005, 496–499. (e) Son, S. U.; Park,
I. K.; Park, J.; Hyeon, T. Chem. Commun. 2004, 778–779. (f) Ma, D. W.; Cai,
Q.; Zhang, H. Org. Lett. 2003, 5, 2453–2455. (g) Ma, D.; Xia, C. Org. Lett.
2001, 3, 2583–2586. (h) Zhao, H.; Fu, H.; Qiao, R. J. Org. Chem. 2010, 75,
3311–3316. (i) Zeng, L.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Adv. Synth.
Catal. 2009, 351, 1671–1676. (j) Takahoso, H.; Ikegami, T. JP2008273883,
2008. (k) Zhang, H.; Cai, Q.; Ma, D. W. J. Org. Chem. 2005, 70, 5164–5173.
(l) Baqi, Y.; Mueller, C. E. Org. Lett. 2007, 9, 1271–1274. (m) Jiang, Q.; Jiang,
D.; Jiang, Y.; Fu, H.; Zhao, Y. Synlett 2007, 1836–1842. (n) Baqi, Y.;
Mueller, C. E. Nat. Protocols 2010, 5, 945–953. (o) Truong, V. L.; Morrow,
M. Tetrahedron Lett. 2010, 51, 758–760. (p) Kubo, T.; Katoh, C.; Yamada,
K.; Okano, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2008, 64, 11230–
11236. (q) Shen, G. D.; Lv, X.; Qian, W. X.; Bao, W. L. Tetrahedron Lett.
2008, 49, 4556–4559.
Ullmann-type aryl amination reaction has emerged as a
powerful and frequently used tool for C-N bond formation
in organic synthesis and pharmaceutical industry.1 However,
the classic Ullmann amination requires stoichiometric
amounts of copper, harsh reaction conditions, strong bases,
(1) For recent reviews: (a) Gwilherm, E.; Nicolas, B.; Mathieu, T. Chem.
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ꢀ
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Published on Web 01/24/2011
DOI: 10.1021/jo102169t
r
2011 American Chemical Society