Enantioselective Bronsted acid catalyzed transfer hydrogenation: Organocatalytic reduction of imines

Article abstract of DOI:10.1021/ol0515964

(Chemical Equation Presented) The first enantioselective Bronsted acid catalyzed reduction of imines has been developed. This new organocatalytic transfer hydrogenation of ketimines with Hantzsch dihydropyridine as the hydrogen source offers a mild method

Full text of DOI:10.1021/ol0515964

ORGANIC
LETTERS
2
005
Vol. 7, No. 17
781-3783
Enantioselective Brønsted Acid
Catalyzed Transfer Hydrogenation:
Organocatalytic Reduction of Imines
3
Magnus Rueping,* Erli Sugiono, Cengiz Azap, Thomas Theissmann, and
Michael Bolte
Degussa Endowed Professorship, Institute of Chemistry and Chemical Biology,
Johann-Wolfgang Goethe UniVersity Frankfurt am Main, Marie-Curie-Str. 11,
D-60439 Frankfurt, Germany
m.rueping@chemie.uni-frankfurt.de
Received July 7, 2005
ABSTRACT
The first enantioselective Brønsted acid catalyzed reduction of imines has been developed. This new organocatalytic transfer hydrogenation
of ketimines with Hantzsch dihydropyridine as the hydrogen source offers a mild method to various chiral amines with high enantioselectivity.
The stereochemistry of the chiral amines can be rationalized by a stereochemical model derived from an X-ray crystal structure of a chiral
BINOL phosphate catalyst.
5
6
7
8
The enantioselective reduction of imines to obtain chiral
amines still represents a challenging topic. Although many
highly enantioselective hydrogenations of ketones and alk-
enes are known, only less effective reductions of imines are
available. Current methods include transition metal catalyzed
thiourea, diol, amidinium, and phosphate catalysts have
been reported. These reactions, similar to several enzymatic
processes, proceed through hydrogen bonding activation.
(
1) For reviews, see: (a) Blaser, H. U.; Malan, C.; Pugin, B.; Spindler,
1
2
high-pressure hydrogenations, hydrosilylations, or transfer
F.; Steiner, H.; Studer, M. AdV. Synth. Catal. 2003, 345, 103. (b) Tang,
3
hydrogenations, using a variety of chiral Pd, Ti, Rh, Ru,
W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(
2) Recent reviews, see: (a) Riant, O.; Mostefai, N.; Courmarcel, J.
and Ir-complexes (eq 1).
Synthesis 2004, 2943. (b) Carpentier, J. F.; Bette, V. Curr. Org. Chem.
002, 6, 913. Organocatalytic hydrosilylation: Malkov, A. V.; Mariani,
A.; MacDougall, K. N.; Ko e` ovsk y´ , P. Org. Lett. 2004, 6, 2253.
2
(
3) Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003, 42, 5472.
(4) For reviews on chiral Brønsted acid catalysis, see: (a) Schreiner, P.
R. Chem. Soc. ReV. 2003, 32, 289. (b) Pihko P. M. Angew. Chem., Int. Ed.
004, 43, 2062.
5) (a) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int.
Ed 2000, 39, 1279. (b) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
2
(
1
1
1
1
4
24, 10012. (c) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
24, 12964. (d) Okino T.; Hoashi Y.; Takemoto Y. J. Am. Chem. Soc. 2003,
25, 12672. (e) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004,
26, 10558. (f) Yoon T. P.; Jacobsen E. N. Angew. Chem., Int. Ed. 2005,
4, 466. (g) Berkessel, A.; Cleemann, F.; Mukherjee S.; M u¨ ller, T. N.;
Lex. J. Angew. Chem., Int. Ed. 2005, 44, 807.
6) (a) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature
4
(
Recently, chiral Brønsted acids have become an important
alternative to metal catalysts, and examples of highly
enantioselective nonmetallic transformations, based on chiral
2
2
003, 424, 146. (b) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc.
003, 125, 12094. (c) Thadani, A. N.; Stankovic, A. R.; Rawal, V. H. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5839.
1
0.1021/ol0515964 CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/26/2005

The purpose of this communication is to describe the first
enantioselective Brønsted acid-catalyzed hydrogenation of
ketimines. We found that several proton acids, such as
showing that not only steric but also electronic effects play
a role in this transformation. Further examination of the
reduction concentrated on the solvent employed (Table 2).
9
diphenyl phosphate 3, catalyze the reduction of imines 1
under hydrogen-transfer conditions with Hantzsch dihydro-
pyridine 2 as the hydrogen source (eq 2).10
Table 2. Solvent Survey of the Transfer Hydrogenation
This observation encouraged us to explore a catalytic
enantioselective variant of this process, as it would be the
first example of an enantioselective proton-acid-catalyzed
hydrogenation of imines. Initial experiments focused the
asymmetric reduction by examining various commercial
chiral proton acids. However, none of the acids tested
afforded satisfactory yields and selectivities. Therefore, we
decided to prepare chiral Brønsted acids 5a-f and tested
these catalysts in the reduction of ketimine 1a (Table 1).
entrya
yield [%]b
ee [%]c
solvent
methanol
acetonitrile
dichloromethane
chloroform
toluene
1
2
3
4
5
6
-
34
57
47
38
59
-
14
62
50
70
70
benzene
Table 1. Survey of Chiral Catalysts for the Hydrogenation
a
Reactions were performed with imine 1a and 2 (1.4 equiv) at 0.02 M
b
concentration in dichloromethane for 16 h. Yield after chromatography.
Enantiomeric excess was determined by HPLC using Chiracel OD-H or
c
AD-H columns.
From this comparison, nonpolar solvents proved to be
essential. No reaction was observed in polar protic media
such as methanol (Table 2, entry 1). However, better
selectivities were observed in chlorinated solvents (Table 2,
entry 3 and 4), and the best yields and selectivities were
obtained with catalyst 5f in benzene at 60 °C (Table 2, entry
entrya
catalyst
yield [%]b
ee [%]c
6). Lowering the temperature resulted in a lower conversion,
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
20
42
37
54
59
57
rac
38
44
40
48
62
and lowering the concentration yielded diminished enanti-
oselection. Both conversion and enantioselectivity decreased
when the reaction was performed in more concentrated
solution, indicating that the generated Hantzsch pyridine is
inhibiting the reaction rate.
Under the optimized conditions we explored the scope of
the Brønsted acid catalyzed hydrogenation of various imines
a
Reactions were performed with imine 1a and 2 (1.4 equiv) at 0.02 M
b
concentration in dichloromethane for 16 h. Yield after chromatography.
Enantiomeric excess was determined by HPLC using Chiracel OD-H or
AD-H columns.
c
(Table 3). In general, high enantioselectivities and good
yields of several N-aryl-ketimines derived from methyl-aryl
First asymmetric transfer-hydrogenations were perfomed
with imine 1a and Hantzsch dihydropyridine 2 in dichlo-
romethane catalyzed by the corresponding Brønsted acid 5a-
f. From this survey Brønsted acids 5b-f emerged as catalysts
with promising levels of enantioselection (Table 1, entry
2-6). Best selectivities were obtained with catalyst 5f
providing amine 4a with 62% ee (Table 1, entry 6) and
(
7) (a) Schuster, T.; Bauch, M.; D u¨ rner, G.; G o¨ bel, M. W. Org. Lett.
000, 2, 179. (b) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem.
Soc. 2004, 126, 3418.
8) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
004, 126, 5356. (c) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem.
2
(
2
Soc. 2004, 126, 11804. (d) Akiyama, T.; Morita H.; Itoh J.; Fuchibe, K.
Org. Lett. 2005, 7, 2583.
(
9) First presented at a DFG grant symposium in 2004.
(10) (a) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. Angew. Chem.,
Int. Ed. 2004, 43, 6660. (b) Yang, J. W.; Hechavarria Fonseca, M. T.;
Vignola, N.; List, B. Angew. Chem., Int. Ed. 2005, 44, 108. (c) Ouellet, S.
G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32.
Figure 1. Proposed mechanism for the transfer hydrogenation.
3782
Org. Lett., Vol. 7, No. 17, 2005

Mechanistically we assume that activation of ketimine 1
by protonation through Brønsted acid 5 will generate the
iminium A. Subsequent hydrogen transfer from the dihy-
dropyridine 2 yields the chiral amine 4 and pyridinium salt
B, which undergoes proton transfer to regenerate Brønsted
acid 5 (Figure 1).
Table 3. Scope of the Catalytic Enantioselective Reduction
The absolute configuration of the amines 4 can be
explained by stereochemical model derived from the X-ray
crystal structure 5c (Figure 2). In the transition state, the
Figure 2. Plausible transition structure A derived from an X-ray
crystal structure of chiral Brønsted acid 5c. Stereochemical rationale
for the transfer hydrogenation.
ketimine is activated by the Brønsted acid, thereby favoring
approach of the nucleophile from the less hindered si face,
as the re face is effectively shielded by the aryl group of the
catalyst.
In summary, we developed the first enantioselective
Brønsted acid catalyzed reduction of ketimines. The mild
reaction conditions and generally good chemoselectivity of
this metal-free transfer hydrogenation render this transforma-
tion an attractive approach to optically active amines.
a
Reactions were performed with imine 1 (0.2 mmol) and dihydropyridine
2
(1.4 equiv) at 60 °C in benzene using 20 mol % catalyst 5f at 0.05 M
concentration. Yield of 4 after chromatography. Enantiomeric excess was
determined by HPLC using Chiracel OD-H or AD-H columns. After one
recrystallization from methanol.
b
c
Acknowledgment. We are grateful to Degussa AG for
financial support.
d
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
ketones are observed. Recrystallization of amines 4a and 4j
from methanol increased the enantioselectivities up to 94%
and 98% ee, respectively.
OL0515964
Org. Lett., Vol. 7, No. 17, 2005
3783