ORGANIC
LETTERS
2012
Vol. 14, No. 12
3056–3059
CuI/DMPAO-Catalyzed N-Arylation of
Acyclic Secondary Amines
Yu Zhang,† Xinye Yang,† Qizheng Yao,*,† and Dawei Ma*,‡
School of Pharmacy, China Pharmaceutical University, Nanjing 21009, China, and State
Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032,
China
madw@mail.sioc.ac.cn; qz_yao@yahoo.com.cn
Received April 27, 2012
ABSTRACT
DMPAO has been found to be a powerful ligand to enable copper-catalyzed coupling of aryl halides with aliphatic acyclic secondary amines take
place under relatively mild conditions, and coupling of aryl halides with primary amines and cyclic secondary amines proceeds at low catalyst
loading.
In the past years, we have witnessed great progress in the
discovery of mild conditionsfor copper-catalyzedcoupling
reaction of aryl halides with amines.1 This progress is
highly dependent on using some bidentate ligands such
as amino acids,2 diols,3 amino alcohols,4 β-diketones,5
β-keto esters,5 2-pyridinyl β-ketones,6 and 8-hydroxyqui-
noline N-oxide.7 Although these ligands have been proven
to be powerful for accelerating copper-catalyzed coupling
of aryl halides with primary amines and cyclic secondary
amines, none of them have displayed general efficiency
for promoting copper-catalyzed N-arylation of aliphatic
acyclic secondary amines.2c,3a,7 This problem was presum-
ably due to the relative bulkiness of acyclic secondary
amines compared with primary amines and cyclic second-
ary amines and has become a major drawback of the
copper-catalyzed aryl amination in contrast to the palla-
dium-catalyzed N-arylation.8 Because aryl tertiary amines
also play an essential role in pharmaceutical and material
sciences, and the advantage of copper catalysts over
palladium catalysts for large-scale synthesis is obvious, it
is highly desirable to develop more effective copper cata-
lytic systems for N-arylation of acyclic secondary amines.9
Recently, we discovered that 2-(2,6-dimethylphenylamino)-
2-oxoacetic acid (DMPAO) is a powerful and inexpensive
ligand for copper-catalyzed aryl amination, which not only
effectively prompts N-arylation of a wide range of acyclic
secondary amines but also works well for N-arylation of
primary amines and cyclic secondary amines even at low
catalytic loadings. Herein, we disclose our results.
† China Pharmaceutical University.
‡ Shanghai Institute of Organic Chemistry.
(1) For reviews, see: (a) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41,
1450. (d) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108,
3054. (c) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48,
6954. (d) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 13.
(2) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459. (b) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453.
(c) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
(3) (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581. (b) Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007, 72,
672.
(4) Lu, Z.; Twieg, R. J.; Huang, D. Tetrahedron Lett. 2003, 44, 6289.
(5) (a) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(b) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3490. (c) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863.
(6) Wang, D.; Ding, K. Chem. Commun. 2009, 1891.
(7) Yang, K.; Qiu, Y.; Li, Z.; Wang, Z.; Jiang, S. J. Org. Chem. 2011,
76, 3151.
(8) For Pd-catalyzed N-arylation of acyclic secondary amines, see:
(a) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.;
Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101. (b) Shen, Q.; Ogata, T.;
Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 6586. (c) Fors, B. P.; Davis,
N. R.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 5766. (d)
Henderson, J. L.; Buchwald, S. L. Org. Lett. 2010, 12, 4442.
(9) For synthesis of hindered anilines via copper-catalyzed electro-
philic amination of aryl boronic esters, see: Rucker, R. P.; Whittaker,
A. M.; Dang, H.; Lalic, G. Angew. Chem., Int. Ed. 2012, 51, 3953.
r
10.1021/ol301135c
Published on Web 06/04/2012
2012 American Chemical Society