A powerful Bronsted acid catalyst for the organocatalytic asymmetric transfer hydrogenation of imines

Article abstract of DOI:10.1002/anie.200503062

(Chemical Equation Presented) A little goes a long way: A 1 mol % loading of the chiral phosphoric acid catalyst 2 converts aromatic and aliphatic imines such as 1 into the corresponding amines (4) in high yields and enantioselectivities if treated with Hantzsch dihydropyridine 3.

Full text of DOI:10.1002/anie.200503062

Communications
Asymmetric Catalysis
DOI: 10.1002/anie.200503062
A Powerful Brønsted Acid Catalyst for the
Organocatalytic Asymmetric Transfer
Hydrogenation of Imines**
Sebastian Hoffmann, Abdul Majeed Seayad, and
Benjamin List*
The catalytic hydrogenation of alkenes, ketones, and imines is
arguably one of the most important transformations in
chemistry. Powerful asymmetric versions have been realized
that require metal catalysts or the use of a stoichiometric
amount of metal hydrides [Eq. (1)].[1]
Although effective and industrially relevant catalytic
asymmetric hydrogenations and transfer hydrogenations of
olefins and ketones have been developed, the corresponding
imine reductions, although potentially highly useful for the
synthesis of enantiomerically pure amines, are less
advanced.[2] Living organisms employ organic dihydropyri-
dine cofactors such as nicotinamide adenine dinucleotide
(NADH) in combination with enzyme catalysts for the
reduction of imines.[3] Chemical transition metal catalyzed
asymmetric imine reductions have also been developed,[4] and
are used, in at least one case, on an industrial scale.[5]
However, with the exception of interesting Lewis base
catalyzed asymmetric imine hydrosilylations,[6] organocata-
lytic and metal-free variants were not known. Recently, we
and MacMillan and co-workers developed an asymmetric
transfer hydrogenation of a,b-unsaturated aldehydes cata-
lyzed by a chiral ammonium salt by using Hantzsch esters as a
biomimetic hydrogen source.[7] Rueping et al.[8] very recently
reported the development of a novel and elegant approach
using Hantzsch esters as the reducing reagent for the catalytic
asymmetric reduction of imines using a chiral Brønsted acid
catalyst previously developed by Akiyama et al.[9,10] We now
report parallel and independent studies from our laboratory
[*] Dipl.-Chem. S. Hoffmann, Dr. A. M. Seayad, Prof. Dr. B. List
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
Fax: (+49)208-306-2999
E-mail: list@mpi-muelheim.mpg.de
[**] Generous support by the DFG (Priority Program 1179, Organo-
catalysis) is gratefully acknowledged. We thank Jayasree Seayad and
Sonja Mayer for catalyst preparations.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
7424
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 7424 –7427

Angewandte
Chemie
on the same reaction that resulted in the development of a
significantly improved new catalyst for the highly efficient
and enantioselective transfer hydrogenation of ketimines
catalyzed by Brønsted acids.[11]
In pioneering studies, the research groups of Akiyama[10]
and Terada[11] recently introduced relatively strong chiral
phosphoric acid catalysts for asymmetric addition reactions to
aldimines as a new strategy for organic catalysis.[12,13] Inspired
by these studies, and the recent observation that imines are
reduced with Hantzsch esters in the presence of achiral Lewis
or Brønsted acid catalysts,[14] we envisioned a catalytic cycle
which is initiated by protonation of ketimine 1 from a chiral
Brønsted acid catalyst 2 [Eq. (2)]. The resulting iminium ion
pair, which may be stabilized by hydrogen bonding, is chiral
and its reaction with the Hantzsch dihydropyridine 3 could
give an enantiomerically enriched amine 4 and pyridine 5.
Table 1: Catalyst screening for the asymmetric transfer hydrogenation of
imine 1a.
Entry
R
Conversion [%] (t)
ee [%]
1
2
H
2a
2b
58 (6 h)
6
59 (17 h)
34 (17 h)
40
44
3
4
2c
2d
80 (17 h)
10 (20 h)
51
32
5
6
2e
2 f
7 (20 h)
30
With this idea in mind, we synthesized and screened a
variety of chiral phosphoric acid catalysts for the reduction of
imine 1a in the presence of Hantzsch ester 3 [Eq. (3),
Table 1].[15]
7
8
2g
2h
28 (17 h)
4 (22 h)
65
n.d.[a]
Although the commercially available phosphoric acid 2a
clearly showed turnover, the enantioselectivity was low
(entry 1). Increasing the steric bulk of the catalyst by adding
aromatic substituents at the 3,3’-positions of the binaphthol
core significantly increased the enatioselectivity but generally
reduced the turnover (entries 2–9). The highest ee value
(81%) was achieved with the new sterically congested
phosphoric acid catalyst 2i. Although the yield of 4a was
low (10% after 20 h), the only remaining material was the
starting imine 1a.
After further optimization of the reaction, which included
changing the solvent from dichloromethane to toluene,
increasing the temperature from RT to 358C, and lowering
the catalyst loading from 10 mol% to only 1 mol%, the
ee value of the product 4a could be further improved to 88%
and with an excellent yield of 96% [Table 2, entry 1]. These
conditions have been applied to several substituted aromatic
ketimines 1a–j and one aliphatic imine 1k with good to
excellent results [Eq. (4), Table 2].
9
2i
10 (20 h)
81
[a] n.d.=not determined.
groups (-NO2, -F, -CN, -OMe) are tolerated well, although
the full scope of the reaction has yet to be established.
Remarkably, even an aliphatic imine (1k) could be used to
give amine 4k with high enantioselectivity (90% ee).
A similar study by Ruepingꢀs research group using
Akiyamaꢀs phosphoric acid catalyst appeared during the
preparation of this manuscript.[8,10b] However, our reaction
times are generally shorter (42–71h versus 72 h), our temper-
ature is lower (358C versus 608C), our yields (80–98% versus
46–91%) and ee values (80–93% versus 68–84%) are higher,
and most importantly our catalyst loading is much lower
(1mol% versus 20 mol%). Moreover, we can also reduce
aliphatic ketimines highly enantioselectively while Rueping
et al. only provided aromatic examples.
Remarkably high yields were achieved in all cases, while
the ee values were generally very good (80–93%). The highest
yield was achieved with p-methyl-substituted imine 1 f, which
provided amine 4 f in 98% yield (entry 6). o-Methyl-substi-
tuted imine 1h gave the highest enantioselectivity and
furnished amine 4h with 93% ee (entry 8). Functional
Imine generation and its reduction can also be performed
in situ in the presence of molecular sieves. The ee-conserving
Angew. Chem. Int. Ed. 2005, 44, 7424 –7427
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7425

Communications
Brønsted acid catalysis. Further extension of this method-
ology is ongoing and will be reported shortly.
Experimental Section
General procedure for the asymmetric transfer hydrogenation
reaction: A mixture of imine 1 (0.4 mmol), Hantzsch ester 3
(142 mg, 0.56 mmol, 1.4 equiv), and phosphoric acid 2i (3 mg,
0.004 mmol) in toluene (4 mL) was stirred at 358C in an argon
atmosphere for 42–71h. The solvent was evaporated at reduced
pressure and the products were isolated by flash chromatography
(SiO2, ethyl acetate/hexane) to give pure amines 4. The ee values were
determined by using established HPLC techniques with chiral
stationary phases.
Table 2: Preliminary substrate scope of the asymmetric transfer
hydrogenation of imines.
Entry
R
t [h]
Yield [%]
ee [%]
1
a
b
c
45
96
88
2
3
4
42
42
45
87
85
95
80
84
85
Received: August 28, 2005
Revised: October 4, 2005
Published online: October 21, 2005
d
Keywords: asymmetric catalysis · chiral amines ·
.
rhomogeneous catalysis · hydrogenation · imines
5
6
7
8
e
f
42
42
45
71
96
98
84
91
80
88
89
93
[1] a) R. Noyori, Angew. Chem. 2002, 114, 2108 – 2123; Angew.
Chem. Int. Ed. 2002, 41, 2008 – 2022; b) W. S. Knowles, Angew.
Chem. 2002, 114, 2096 – 2107; Angew. Chem. Int. Ed. 2002, 41,
1998 – 2007.
[2] For reviews, see: a) V. I. Taratov, A. Börner, Synlett 2005, 203 –
211; b) T. Ohkuma, M. Kitamura, R. Noyori in Catalytic
Asymmetric Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley-VCH,
New York, 2000, chap. 1; c) T. Ohkuma, R. Noyori in Compre-
hensive Asymmetric Catalysis, Suppl. 1 (Eds.: E. N. Jacobsen, A.
Pfaltz, H. Yamamoto), Springer, New York, 2004, p. 43; d) H.
Nishiyama, K. Itoh in Catalytic Asymmetric Synthesis, 2nd ed.
(Ed.: I. Ojima), Wiley-VCH, New York, 2000, chap. 2.
g
h
9
i
45
92
80
10
11
j
71
60
88
80
92
90
[3] a) B. D. Sanwal, M. W. Zink, Arch. Biochem. Biophys. 1961, 94,
430 – 435; b) M.-R. Kula, C. Wandrey, Methods Enzymol. 1988,
136, 34 – 45.
k
[4] For examples, see: a) N. Langlois, T. P. Dang, H. B. Kagan,
Tetrahedron Lett. 1973, 4865; b) R. Becker, H. Brunner, S.
Mahboobi, W. Wiegrebe, Angew. Chem. 1985, 97, 969 – 970;
Angew. Chem. Int. Ed. Engl. 1985, 24, 995 – 996; c) X. Verdaguer,
U. E. W. Lange, M. T. Reding, S. L. Buchwald J. Am. Chem. Soc.
1996, 118, 6784; d) X. Verdaguer, U. E. W. Lange, S. L. Buch-
wald, Angew. Chem. 1998, 110, 1174 – 1178; Angew. Chem. Int.
Ed. 1998, 37, 1103 – 1107; e) Y. Nishibayshi, I. Takei, S. Uemura,
M. Hidai, Organometallics 1998, 17, 3420; f) M. C. Hansen, S. L.
Buchwald, Org. Lett. 2000, 2, 713; g) D. Xiao, X. Zhang, Angew.
Chem. 2001, 113, 3533 – 3536; Angew. Chem. Int. Ed. 2001, 40,
3425 – 3428; h) J. F. Carpentier, V. Bette, Curr. Org. Chem. 2002,
6, 913; i) Y. Chi, Y.-G. Zhou, X. Zhang J. Org. Chem. 2003, 68,
4120 – 4122; j) R. Kadyrov, T. H. Riermeier, Angew. Chem. 2003,
115, 5630 – 5632; Angew. Chem. Int. Ed. 2003, 42, 5472 – 5474;
k) B. H. Lipshutz, H. Shimizu, Angew. Chem. 2004, 116, 2278 –
2280; Angew. Chem. Int. Ed. 2004, 43, 2228 – 2230; l) O. Riant, N.
Mostefai, J. Courmarcel, Synthesis 2004, 2943 – 2958; m) K. A.
Nolin, R. W. Ahn, F. D. Toste, J. Am. Chem. Soc. 2005, ASAP.
[5] a) H.-U. Blaser, H.-P. Buser, H.-P. Jalett, B. Pugin, F. Spindler,
Synlett 1999, 867 – 868; b) H.-U. Blaser, H.-P. Buser, K. Coers, R.
Hanreich, H.-P. Jalett, E. Jelsch, B. Pugin, H. D. Schneider, F.
Spindler, A. Wegmann, Chimia 1999, 53, 275 – 280; c) H.-U.
Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer,
Adv. Synth. Catal. 2003, 345, 103 – 151.
oxidative removal of the p-methoxyphenyl (PMP) group to
give amine 6a is well established [Eq. (5); CAN = cerium(IV)
ammonium nitrate].[4i]
In summary we have developed an efficient organocata-
lytic asymmetric ketimine reduction using chiral phosphoric
acid derivative 2i in the presence of the commercially
available Hantzsch ester 3. Remarkable features of our
process include a) its high yields and enantioselectivities,
b) its scope, including both aliphatic and aromatic amines,
c) its simplicity and practicability (in situ generation and
reduction of imines), and d) the remarkably low catalyst
loading, which so far is unprecedented in asymmetric
[6] a) A. V. Malkov, A. Mariani, K. N. MacDougall, P. Kocovsky,
Org. Lett. 2004, 6, 2253 – 2256; b) F. Iwasaki, O. Omonura, K.
7426 www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 7424 –7427

Angewandte
Chemie
Mishima, T. Kanematsu, T. Maki, Y. Matsumura, Tetrahedron
Lett. 2001, 42, 2525 – 2527.
[7] a) J. W. Yang, M. T. Hechavarria Fonseca, B. List, Angew. Chem.
2004, 116, 6829 – 6832; Angew. Chem. Int. Ed. 2004, 43, 6660 –
6662; b) J. W. Yang, M. T. Hechavarria Fonseca, N. Vignola, B.
List, Angew. Chem. 2005, 117, 110 – 112; Angew. Chem. Int. Ed.
2005, 44, 108 – 110; for an independent study on the same
reaction, see: c) S. G. Ouellet, J. B. Tuttle, D. W. C. MacMillan, J.
Am. Chem. Soc. 2005, 127, 32 – 33.
[8] a) M. Rueping, E. Sugiono, C. Azap, T. Theissmann, M. Bolte,
Org. Lett. 2005, 7, 3781– 3783; this research group also reported
an effective non-asymmetric variant: b) M. Rueping, C. Azap, E.
Sugiono, T. Theissmann, Synlett 2005, asap.
[9] We made the first proposal of reducing imines with Hantzsch
esters in the presence of a chiral Brønsted acid catalyst at a DFG
proposal workshop in Bonn, Germany on December 6th 2004.
[10] Mannich reaction: a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe,
Angew. Chem. 2004, 116, 1592 – 1594; Angew. Chem. Int. Ed.
2004, 43, 1566 – 1568; imine hydrophosphonylation: b) T.
Akiyama, H. Morita, J. Itoh, K. Fuchibe, Org. Lett. 2005, 7,
2583 – 2585; see also: T. Akiyama, PCT Int. Appl.
WO 200409675, 2004.
[11] Mannich reaction: a) D. Uraguchi, M. Terada, J. Am. Chem. Soc.
2004, 126, 5356 – 5357; furan aminoalkylation: b) D. Uraguchi,
K. Sorimachi, M. Terada, J. Am. Chem. Soc. 2004, 126, 11804 –
11805; alkylation of a-diazo esters: c) D. Uraguchi, K. Sorima-
chi, M. Terada, J. Am. Chem. Soc. 2005, 127, 9360 – 9361; see
also: d) M. Terada, D. Uraguchi, K. Sorimachi, H. Shimizu, PCT
Int. Appl. WO 2005070875, 2005.
[12] For excellent reviews on Brønsted acid organocatalysis, see:
a) P. M. Pihko, Angew. Chem. 2004, 116, 2110 – 2113; Angew.
Chem. Int. Ed. 2004, 43, 2062 – 2064; b) P. Schreiner, Chem. Soc.
Rev. 2003, 32, 289 – 296; see also: J. Seayad, B. List, Org. Biomol.
Chem. 2005, 3, 719 – 724.
[13] For selected recent examples of asymmetric general Brønsted
acid organocatalysis, see: a) M. S. Sigman, P. Vachal, E. N.
Jacobsen, Angew. Chem. 2000, 112, 1336 – 1338; Angew. Chem.
Int. Ed. 2000, 39, 1279 – 1281; b) T. Okino, Y. Hoashi, Y.
Takemoto, J. Am. Chem. Soc. 2003, 125, 12672 – 12673;
c) B. M. Nugent, R. A. Yoder, J. N. Johnston, J. Am. Chem.
Soc. 2004, 126, 3418 – 3419; d) Y. Huang, A. K. Unni, A. N.
Thadani, V. H. Rawal, Nature 2003, 424, 146; e) N. T. McDougal,
S. E. Schaus, J. Am. Chem. Soc. 2003, 125, 12094 – 12095; f) T.
Schuster, M. Bauch, G. Duerner, M. W. Goebel, Org. Lett. 2000,
2, 179 – 181.
[14] T. Itoh, K. Nagata, M. Miyazaki, H. Ishikawa, A. Kurihara, A.
Ohsawa, Tetrahedron 2004, 60, 6649 – 6655.
[15] Phosphoric acids 2 were prepared according or in analogy to the
reported procedures; see references [10, 11].
Angew. Chem. Int. Ed. 2005, 44, 7424 –7427
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7427