on the subject during the past three decades. The alkylation
of amines by alcohols under harsh conditions was reported
independently by Grigg and Watanable in the early 1980s.9
In recent years, milder conditions have been achieved by
Yamaguchi and co-workers with Cp·IrCl2 as catalyst10 and
by Beller et al. using Ru3(CO)12 together with bulky
phosphines.11 Williams et al. developed an efficient [Ru-
(p-cymene)Cl2]2/phosphine catalyst system and realized the
alkylation of amines and sulfonamides with alcohols under
mild reaction conditions.12 The first step in these reactions
is the dehydrogenation of alcohols to their corresponding
aldehydes with the release of dihydrogen (Scheme 1).13
secondary amines, tertiary amines, and N-alkylated sulfona-
mides in high yields under mild conditions.16 On the other
hand, Milstein et al. developed a ruthenium-catalyzed de-
hydrogenative amide formation from alcohols and primary
amines with the libration of H2 without using a hydrogen
acceptor.17
Nitroarenes are readily available compounds and can be
reduced to amines by reducing reagents such as iron or zinc
in aq HCl.18 Using hydrogen as a reducing reagent is greener
and more economical; however, selective reduction of nitro
groups is still a challenging problem.19 The direct amination
of nitroarenes with alcohols is rare compared with the great
breakthroughs being made in the amination of amines with
alcohols.20 We envisioned a direct amination of nitroarenes
with alcohols by using a hydrogen-borrowing strategy:
alcohol is oxidized to aldehyde and releases hydrogen,
nitroarene is reduced by hydrogen, and subseqently the
reaction follows the same route as alkylation of amines.
Herein, we report a highly selectiVe ruthenium-catalyzed
direct amination of nitroarenes with alcohols (Figure 1).
Scheme 1
.
Borrowing Hydrogen Strategy in the Alkylation of
Amines with Alcohols
Subsequently, the aldehyde reacts with amines to form
imines,14 which could be reduced to secondary amines. The
latter step is known as a borrowing hydrogen methodology,
and no external molecular hydrogen is necessary.15 The metal
acts as both an alcohol oxidation catalyst and an imine
hydrogenation catalyst. The borrowing hydrogen methodol-
ogy has been used in the synthesis of primary amines,
Figure 1. Forming tertiary amines via borrowing hydrogen strategy.
To begin our study, the reaction of commercially available
and inexpensive nitrobenzene (1a) and benzyl alcohol (2a)
was chosen as a model using RuCl3 as a catalyst. When
nitrobenzene was reacted with excess benzyl alcohol in the
absence of any ligand, no desired product was formed as
(7) For a review on C-H amination, see: Collet, F.; Dodd, R.; Dauban,
P. Chem Commun 2009, 5061. For selected examples, see: (a) Jordan-Hore,
J.; Johansson, C.; Gulias, M.; Beck, E.; Gaunt, M. J. Am. Chem. Soc. 2008,
130, 16184. (b) Mei, T.; Wang, X.; Yu, J. J. Am. Chem. Soc. 2009, 131,
10806. (c) Tsang, W. C. P.; Zheng, N.; Buchwald, S. J. Am. Chem. Soc.
2005, 127, 14560. (d) Wasa, T.; Yu, J. Q. J. Am. Chem. Soc. 2008, 130,
14058. (e) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676. (f)
Shuai, Q.; Deng, G. J.; Chua, Z.; Bohle, D.; Li, C. J. AdV. Synth. Catal.
2010, 352, 632.
1
determined by GC-MS and H NMR methods (Table 1,
entry 1). Subsequently, various ligands were investigated for
this reaction under an atmosphere of argon (entries 2-8).
(16) (a) Gunanathan, C.; Milstein, D. Angew. Chem., Int. Ed. 2008, 47,
8661. (b) Yamaguchi, K.; He, J.; Oishi, T.; Mizuno, N. Chem.sEur. J.
2010, 16, 7199. (c) Zweifel, T.; Naubron, J.; Grutzmacher, H. Angew. Chem.,
Int. Ed. 2009, 48, 559. (d) Blank, B.; Michlik, S.; Kempe, R. AdV. Synth.
Catal. 2009, 351, 2903. (e) Saidi, O.; Blacker, A.; Farah, M.; Marsden, S.;
Williams, J. M. J. Angew. Chem., Int. Ed. 2009, 48, 7375. (f) He, J.; Kim,
J.; Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2009, 48, 9888. (g)
Cui, X.; Shi, F.; Tse, M.; Go¨rdes, D.; Thurow, K.; Beller, M.; Deng, Y.
AdV. Synth. Catal. 2009, 351, 2949. (h) Shi, F.; Tse, A.; Cui, X.; Go¨rdes,
D.; Michalik, D.; Thurow, K.; Deng, Y.; Beller, M. Angew. Chem., Int.
Ed. 2009, 48, 5912. (i) Shi, F.; Tse, M.; Zhou, S.; Pohl, M.; Radnik, J.;
Hu¨bner, S.; Ja¨hnisch, K.; Bru¨cker, A.; Beller, M. J. Am. Chem. Soc. 2009,
131, 1775.
(8) Tojo, G.; Ferna´ndez, M. Oxidation of Alcohols to Aldehydes and
Ketones; Springer: New York, 2006.
(9) (a) Grigg, R.; Mitchell, T.; Sutthivaiyakit, S.; Tongpenyai, N.
J. Chem. Soc., Chem. Commun. 1981, 611. (b) Watanable, Y.; Tsuji, Y.;
Ige, H.; Ohsugi, Y.; Ohta, T. J. Org. Chem. 1984, 49, 3359.
(10) (a) Fujita, K.; Yamaguchi, R. Synlett 2005, 4, 560. (b) Fujita, K.;
Enoki, Y.; Yamaguchi, R. Tetrahedron 2008, 64, 1943. (c) Zhu, M. W.;
Fujita, K.; Yamaguchi, R. Org. Lett. 2010, 12, 1336.
(11) (a) Tillack, A.; Hollmann, D.; Michalik, D.; Beller, M. Tetrahedron
Lett. 2006, 47, 8881. (b) Hollmann, D.; Tillack, A.; Michalik, D.; Jackstell,
R.; Beller, M. Chem. Asian J. 2007, 2, 403.
(12) (a) Saidi, O.; Blacker, A.; Farah, M.; Marsden, S.; Williams, J. M. J.
Chem. Commun. 2010, 46, 1541. (b) Hamid, M.; Liana Allen, C.; Lamb,
G.; Maxwell, A.; Maytum, H.; Watson, A.; Williams, J. M. J. J. Am. Chem.
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(17) (a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317,
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(18) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New
York, 2001.
(13) This step is also known as dehydrogenation: Dobereiner, G.;
Crabtree, R. Chem. ReV 2010, 110, 681.
(19) For an excellent example of highly selective nitro hydrogenation,
see: Corma, A.; Serna, P. Science 2006, 313, 332.
(14) For imine formation from alcohols and amines, see: (a) Gnan-
aprakasam, B.; Zhang, J.; Milstein, D. Angew. Chem., Int. Ed. 2010, 49,
1468. (b) Ba¨hn, S.; Imm, S.; Mevius, K.; Neubert, L.; Tillack, A.; Williams,
J. M. J.; Beller, M. Chem.sEur. J. 2010, 16, 3590.
(20) For amination of nitroarenes with alcohols or aldehydes using
molecular hydrogen as reductant, see: (a) Yamane, Y.; Liu, X.; Hamasaki,
A.; Ishida, T.; Haruta, M.; Yokoyama, T.; Tokunaga, M. Org. Lett. 2009,
11, 5162. (b) Sreedhar, B.; Reddy, P.; Devi, D. J. Org. Chem. 2009, 74,
8806. (c) Gelman, F.; Blum, J.; Avnir, D. New. J. Chem 2003, 27, 205. For
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see: Chen, B.; Makley, D. M.; Johnston, J. M. Nature 2010, 465, 1027.
(15) For excellent recent reviews on borrowing hydrogen strategy, see:
(a) Nixon, T. D.; Whittlesey, M. K.; Williams, J. M. J. Dalton Trans. 2009,
5, 753. (b) Guillena, G.; Ramo´n, D. J.; Yus, M. Chem. ReV. 2010, 110,
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Org. Lett., Vol. 12, No. 21, 2010
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