ORGANIC
LETTERS
2011
Vol. 13, No. 20
5576–5579
Synthesis of r,r-Disubstituted Aryl
Amines by Rhodium-Catalyzed Amination
of Tertiary Allylic Trichloroacetimidates
Jeffrey S. Arnold, Gregory T. Cizio, and Hien M. Nguyen*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States
Received August 25, 2011
ABSTRACT
The rhodium-catalyzed regioselective amination of tertiary allylic trichloroacetimidates with unactivated aromatic amines is a direct and efficient
approach to the preparation of R,R-disubstituted allylic aryl amines in good yield and with excellent regioselectivity. This method is applicable to a
variety of unactivated primary and secondary amines and allows for the preparation of reverse prenylated indoles in two steps.
Amines are present in a wide range of natural products,
pharmaceutically bioactive drug candidates, materials, and
catalysts.1 Consequently, manypracticalandelegant routes
to the synthesis of amine-containing compounds have been
developed.2 In contrast, approaches for preparation of R,R-
disubstituted amines, although important synthetic targets,
are limited.3À5 Transition-metal-catalyzed amination of
allylic carbonates or acetates has been utilized to prepare
R,R-disubstituted allylic amines.6,7,9 Palladium catalysts in
combination with 1,1-dimethyl-1-propenyl acetate and al-
kyl amines selectively favor the thermodynamically formed
linear products.6 The branched products, R,R-disubstituted
amines, can be formed as the major isomer when DBU
(1 equiv) is used to suppress product isomerization. Iridium
catalysis of allylic acetates with alkyl amines also provides
R,R-disubstituted amines in high yield and regioselectivity.7
In both palladium6 and iridium7 methods, only aniline has
been reported as the aryl amine nucleophile.8 Recently, the
iron-catalyzed allylic amination reaction of 1,1-dimethyl-2-
propenyl carbonate was reported to work with para- and
meta-substituted anilines, providing the R,R-disubstituted
allylic aryl amines in good yield and with excellent levels of
regioselectivity.9 Substituents at the ortho position of ani-
line, however, did not result in the desired allylic amine
products.
(1) For review, see: Chiral Amine Synthesis; Nugent, T. C, Ed.; Wiley-
VCH: New York, 2008.
(2) Several representative examples: (a) Brown, S. P.; Goodwin,
N. C.; MacMillan, D. W. C. K. J. Am. Chem. Soc. 2003, 125, 1192.
(b) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125,
5139. (c) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004,
126, 8120. (d) Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc.
2006, 128, 2174. (e) Balskus, E. P.; Jacobsen, E. N. J. Am. Chem. Soc.
2006, 128, 6810. (f) Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc.
2006, 128, 16044. (g) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.;
Kumagai, N.; Shbasaki, M. J. Am. Chem. Soc. 2007, 129, 11342.
(h) Clayden, J.; Donnard, M.; Lefrance, J.; Minassi, A.; Tetlow, D. J.
J. Am. Chem. Soc. 2010, 132, 6624. (i) Shibasaki, M.; Kanai, M. Chem.
Rev. 2008, 108, 2853.
(3) For diastereoselective and enantioselective nucleophilic addition
of organometallic reagents to ketimines, see: (a) Spero, D. M.; Kapadia,
S. R. J. Org. Chem. 1997, 62, 5537. (b) Cogan, D. A.; Ellman, J. A. J. Am.
Chem. Soc. 1999, 121, 268. (c) Robak, M. T.; Herbage, M. A.; Ellman,
J. A. Chem. Rev. 2010, 110, 3600. (d) Bloch, R. Chem. Rev. 1998, 98,
1407. (e) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8,
1895. (f) Shintani, R.; Takeda, M.; Tsuji, T.; Hayashi, T. J. Am. Chem.
Soc. 2010, 132, 13168.
(4) (a) Shea, R. G.; Fitzner, J. N.; Fankhauser, J. E.; Spaltenstein, A.;
Carpino, P. A.; Peevey, R. M.; Pratt, D. V.; Tenge, B. J.; Hopkins, P. B.
J. Org. Chem. 1986, 51, 5243.
(5) There is only one example of palladium-catalyzed enantioselec-
tive rearrangement of 3,3-disubstituted allylic trifluoroacetimidates to
form 1,1-disubstituted allylic amines, see: (a) Fischer, D. F.; Xin, Z.-Q.;
Peters, R. Angew. Chem., Int. Ed. 2007, 46, 7704. (b) Fischer, D. F.;
Barakat, A.; Xin, Z.-Q.; Weiss, M. E.; Peters, R. Chem.;Eur. J. 2009,
15, 8722.
We recently reported a rhodium-catalyzed regioselective
amination of secondary allylic trichloroacetimidates with
(6) (a) Watson, I. D. G.; Yudin, A. K. J. Am. Chem. Soc. 2005, 127,
17156. (b) Dubovyk, I.; Watson, I. D. G.; Yudin, A. K. J. Am. Chem.
Soc. 2007, 129, 14172.
(7) Takeuchi, R.; Ue, N.; Tanabe, K.; Yamashita, K.; Shiga, N.
J. Am. Chem. Soc. 2001, 123, 9525.
(8) For recent iridium-catalyzed regio- and enantioselective reaction
of primary allylic carbonates with aryl amines to form R-substituted
allylic aryl amines, see: Shu, C.; Leitner, A.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2004, 43, 4797.
(9) Plietker, B. Angew. Chem., Int. Ed. 2006, 45, 6053.
r
10.1021/ol202313y
Published on Web 09/29/2011
2011 American Chemical Society