2
7,8
One-Pot Reductive Mono-N-alkylation of Aniline
Cu(PPh3)2BH4 with NH2SO3H, thiourea with Hantzsch ester,
9
amino borane derivatives with NaBH4, triazole-derived iridium-
I) carbine complexes, and [Ir(cod)2]BF4. These methods
and Nitroarene Derivatives Using Aldehydes
1
0
11
(
have some drawbacks in one way or another such as prolonged
reaction time, acidic conditions, higher reaction temperature,
excess amount of reagents, inert conditions, and toxic byprod-
ucts. Thus, it is necessary to develop an alternative method that
employs simple and mild as well as environmentally benign
conditions. In addition, there is also a growing specific interest
in developing controlled synthesis of secondary amines due to
its vast applications. Traditional methodologies for secondary
amines are often problematic because of harsh reaction condi-
tions, overalkylation, low chemical selectivity, and generally
Eunyoung Byun, Bomi Hong, Kathlia A. De Castro,
Minkyung Lim, and Hakjune Rhee*
Hanyang UniVersity, Department of Chemistry and Applied
Chemistry Ansan Sangrok-Gu Sa-3-Dong 1271,
Kyunggi-Do 426-791, Korea
12
13,14
poor yields. Recently, the use of nitrile
as alkylating agent
was published as an alternative. Herein, we report an efficient,
facile, mild, and environmentally benign one-pot reductive
mono-N-alkylation of aniline and nitroarene derivatives using
aldehydes by Pd/C catalyst in aqueous alcoholic solvents with
ammonium formate as in situ hydrogen donor.
This investigation started from our curiosity in the reductive
amination of ketone using Pd/C catalyst and formate salts.15
We wondered if this condition worked with aldehydes but to
our surprise, when we performed a test reaction using benzal-
dehyde, the reaction failed to proceed. Thus, we hypothesized
that ammonium formate is a nonparticipant in the amination
process and that it acts as an in situ hydrogen donor for
heterogeneous catalytic hydrogenation. In fact, there have been
numerous reports on the versatility of ammonium formate as
agent in catalytic hydrogen transfer reactions. Consequently,
we decided to prove this hypothesis and find appropriate
conditions for the reductive amination of aldehydes.
Initially, we checked for suitable solvent using aniline and
acetaldehyde as our test reaction as shown in Scheme 1. We
found that 2-propanol/water (10:1, v/v) would give the best yield
without dialkylation product (Table 1).
One-pot reductive mono-N-alkylation of aniline and ni-
troarene derivatives using various aldehydes by Pd/C catalyst
in aqueous 2-propanol solvent with ammonium formate as
in situ hydrogen donor is illustrated. The reaction proceeded
smoothly and selectively with excellent yield at room
temperature. Our protocol presents a facile, economical, and
environmentally benign alternative for reductive amination.
1
6
Amines and their derivatives are highly versatile building
blocks for various organic substrates and are essential precursors
to a variety of biologically active compounds. It has unique
biological properties that make it a useful target for various
1
therapeutic applications. Amines also serve other purposes in
the fields of bioorganic, industrial, and synthetic organic
chemistry.2 With this growing repertoire of applications,
developing efficient methods for the synthesis of amines draws
much attention.
SCHEME 1
Direct reductive amination of aldehydes and ketones is one
of the most attractive methods for the synthesis of amine
derivatives. This is particularly advantageous because the
carbonyl compound and the amine with the appropriate reducing
agent are treated in a one-pot fashion such that isolating the
imine intermediate is avoided. There have been many reagents
developed recently to effect reductive amination of carbonyls.
These include the following: LiClO4-zirconium borohydride
Using the same test reaction and the chosen solvent system,
we checked the optimum amount of catalyst (Pd/C) and
ammonium formate necessary to affect reductive amination
(Table 2). Various types of aldehydes were reacted with aniline
using this protocol to evaluate its general applicability.
3
4
5
6
(7) Menche, D.; Arikan, F. Synlett 2006, 6, 841.
piperazine complexes, H3PW12O40-NaBH4, NaBH(OAc)3,
(
8) Menche, D.; Bohm, S.; Li, J.; Rudolph, S.; Zander, W. Tetrahedron
Lett. 2007, 48, 365.
9) Suginome, M.; Tanaka, Y.; Hasui, T. Synlett 2006, 7, 1047.
Ph2SiH2, or PhSiH3 with catalytic Bu2SnClH-pyridine N-oxide,
(
*
(
To whom correspondence should be addressed. Fax: 82-31-407-3863.
1) Bradshaw, J. S.; Krakowisk, K. E.; Izatt, R. H. Tetrahedron 1992,
2, 4475.
2) Bhanushali, M. J.; Nandurkar, N. S.; Bhor, M. D.; Bhanage, B. M.
Tetrahedron Lett. 2007, 48, 1273.
3) Heydari, A.; Khaksar, S.; Esfandyari, M.; Tajbakhsh, M. Tetrahedron
007, 63, 3363.
4) Heydari, A.; Khaksar, S.; Akbari, J.; Esfandyari, M.; Pourayoubi,
M.; Tajbakhsh, M. Tetrahedron Lett. 2007, 48, 1135.
5) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849.
6) Kato, H.; Shibata, I.; Yasaka, Y.; Tsumoi, S.; Yasuda, M.; Baba, A.
Chem. Commun. 2006, 4189.
(10) Gnanamgari, D.; Moores, A.; Rajaseelan, E.; Crabtree, R. H.
Organometallics 2007, 26, 1226.
(11) Imao, D.; Fujihara, S.; Yamamoto, T.; Ohta, T.; Ito, Y. Tetrahedron
2005, 61, 6988.
(12) Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron 2001, 57,
7785.
(13) Sajiki, H.; Ikawa, T.; Hirota, K. Org. Lett. 2004, 6, 4977.
(14) Nacario, R.; Kotakonda, S.; Fouchard, D. M. D.; Tillekerante, L.
M. V.; Hudson, R. A. Org. Lett. 2005, 7, 471.
(15) Berdini, V.; Cesta, M. C.; Curti, R.; D’Anniballe, G.; Di Bello, N.;
Nano, G.; Nicolini, L.; Topai, A.; Allegretti, M. Tetrahedron 2002, 58,
5669.
2
(
(
2
(
(
(
(16) Ram, S.; Ehrenkaufer, R. E. Synthesis 1998, 2, 91.
1
0.1021/jo701503q CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/13/2007
J. Org. Chem. 2007, 72, 9815-9817
9815