Br?nsted acid catalysis: Organocatalytic hydrogenation of imines

Article abstract of DOI:10.1055/s-2005-872251

A new Br?nsted acid catalysed hydrogenation of imines with Hantzsch dihydropyridine as the hydrogen source has been developed. Diphenyl phosphate (DPP) and various other acids catalyse this first metal-free hydrogen transfer to give various amines under m

Full text of DOI:10.1055/s-2005-872251

LETTER
2367
Brønsted Acid Catalysis: Organocatalytic Hydrogenation of Imines
O
M
rganocatalytic
H
ydro
a
genation of
g
Imines nus Rueping,* Cengiz Azap, Erli Sugiono, Thomas Theissmann
Degussa Endowed Professorship, Institute of Organic Chemistry and Chemical Biology, Johann-Wolfgang Goethe University Frankfurtam
Main, Marie-Curie-Str. 11, 60439 Frankfurt, Germany
Fax +49(69)79829248; E-mail: M.Rueping@chemie.uni-frankfurt.de
Received 4 July 2005
In each instance the reaction was carried out with 1.4
Abstract: A new Brønsted acid catalysed hydrogenation of imines
equivalents of 2 in benzene for two hours. In the absence
with Hantzsch dihydropyridine as the hydrogen source has been
of acid no hydrogen transfer was observed. From the
catalyse this first metal-free hydrogen transfer to give various different acids tested diphenyl phosphate (DPP) appeared
developed. Diphenyl phosphate (DPP) and various other acids
amines under mild reaction conditions.
to be the best catalyst for this transformation, showing
the highest rate and best yields of the amine 4a formed
(entry 5, 6).
Key words: Hantzsch 1,4-dihydropyridine, transfer hydrogenation,
reduction, organocatalysis, Brønsted acid
Table 1 Brønsted Acid Catalysed Reduction of Imine 1a
O
O
The development of catalysts for the asymmetric hydro-
genation of imines is a topic of ongoing interest. Current
methods include transition-metal-catalysed high-pressure
PMP EtO
Et
OEt
PMP
N
HN
N
H
2
1
2
Ph
Ph
Et
hydrogenations, hydro-silylations, or transfer hydroge-
cat. 3
3
nations using ammonium formate. Additionally, metal-
1a
4a
catalysed reductions using chiral biomimetic NADH
models have been reported. Among these, Hantzsch 1,4-
dihydropyridine is a widely used model compound with
Entrya
Brønsted acid 3
CSA
3 (mol%)
Yield 4a (%)b
4
1
2
3
4
5
6
10
10
10
10
10
5
79
41
74
71
82
76
–
application in the reduction of a,b-unsaturated carbonyl
5
6
compounds, conjugated olefins and metal-catalysed
HCl
7
reductive aminations. However, to date no metal-free
TFA
transfer hydrogenation of imines has been reported.
HBF4
DPP
Recently, the use of chiral Brønsted acids as catalysts
8
became apparent. This observation encouraged us to
investigate an organocatalytic reduction of imines
mediated by catalytic amounts of proton acid under
hydrogen transfer conditions (Scheme 1). We reasoned
that activation of the imine 1 by catalytic protonation
would enable the hydrogen transfer from the dihydro-
pyridine 2 to generate the amine 4.
DPP
7
None
–
a
All reactions were performed using imine 1a (0.125 mmol) and
dihydropyridine 2 (0.175 mmol) at 65 °C in benzene using 10 mol%
of acid catalyst.
b
Isolated yield after chromatography.
O
O
R3
R2
EtO
OEt
R3
R2
N
HN
R1
Further exploration of the diphenyl phosphate catalysed
transfer hydrogenation concentrated on the solvent
employed (Table 2). We found that the reaction can be
carried out in most of the common solvents.
N
H
2
R1
cat. proton acid 3
1
4
Scheme 1 Proton acid catalysed transfer hydrogenation
Best results were obtained in non-polar solvents such as
dichloromethane, chloroform and benzene at elevated
temperatures. Performing the reaction at lower tempera-
tures (40 °C instead of 65 °C) in benzene resulted in lower
yields (entry 2). Surprisingly, in more polar media the
reaction was sluggish and yields were considerably
diminished (entries 6–9).
Hence, initial experiments focused on the examination of
various Brønsted acids for this transformation (Table 1).
From this survey, we found that several proton acids 3
(
5–10 mol%) catalyse the reduction of ketimine 1a using
Hantzsch dihydropyridine 2 as the hydrogen source.
With the reaction conditions using dichloromethane as
solvent and DPP (5 mol%) as catalyst we decided to ex-
plore the scope of this metal-free transfer hydrogenation
(Table 3).9
SYNLETT 2005, No. 15, pp 2367–2369
Advanced online publication: 29.07.2005
DOI: 10.1055/s-2005-872251; Art ID: G17905ST
1
9
.0
9
.2
0
0
5
©
Georg Thieme Verlag Stuttgart · New York

2
368
M. Rueping et al.
LETTER
Table 2 Solvent Effects of the Acid-Catalysed Hydrogenation
In general, differently substituted alkyl and aryl
ketimines, including a-imino esters, can be reduced in
good to excellent yields, irrespective the N-Aryl group
used.
Entrya
Solvent
Toluene
Benzene
Time (h)
Yield 4a (%)b
1
2
3
4
5
6
7
8
2
2
38
51
60
75
53
28
31
–
In summary, we have developed a new metal-free, effi-
cient, proton-acid-catalysed hydrogenation of imines
using Hantzsch dihydropyridine as reducing agent. The
operational simplicity, practicability and mild reaction
conditions render it an attractive approach to various
amines. Furthermore, the use of catalytic amounts of
diphenyl phosphate allows the extension of this procedure
to an asymmetric organocatalytic variant by employing
chiral BINOL phosphates as catalysts.
CHCl3
2
CH Cl
2
2
2
MeCN
THF
2
2
EtOAc
EtOH
MeOH
40
40
40
Acknowledgment
9
25
Financial support by Degussa AG is gratefully acknowledged.
a
All reactions were performed using imine 1a (0.125 mmol) and
dihydropyridine 2 (0.175 mmol) at 40 °C using 10 mol% DPP as
catalyst.
References
b
Isolated yield after chromatography.
(
1) For reviews: (a) Blaser, H. U.; Malan, C.; Pugin, B.;
Spindler, F.; Steiner, H.; Studer, M. Adv. Synth. Catal. 2003,
3
45, 103. (b) Tang, W.; Zhang, X. Chem. Rev. 2003, 103,
Table 3 Proton Acid-Catalysed Reduction of Various Iminesa
3029.
O
O
(2) Recent reviews: (a) Riant, O.; Mostefai, N.; Courmarcel, J.
Synthesis 2004, 2943. (b) Carpentier, J. F.; Bette, V. Curr.
Org. Chem. 2002, 6, 913. (c) For a highly enantioselective
hydrosilylation of imines see: Lipshutz, B. H.; Shimizu, H.
Angew. Chem. Int. Ed. 2004, 43, 2228. (d) Organocatalytic
hydrosilylation: Malkov, A. V.; Mariani, A.; MacDougall,
K. N.; Kočovský, P. Org. Lett. 2004, 6, 2253.
R3
EtO
OEt
R3
N
HN
R1
N
H
2
R1
R2
R2
DPP (5 mol%)
1
4
Imine 1 R1
R2
R3
Yield of 4a (%)b
(
3) Kadyrov, R.; Riermeier, T. H. Angew. Chem. Int. Ed. 2003,
2, 5472.
4
1
1
1
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
Ph
Et
Ph
70
92
75
87
67
92
70
72
67
70
66
86
76
77
(
4) Versleijen, J. P.; Sanders-Hovens, M. S.; Vanhommerig, S.
Ph
Et
PMP
Ph
A.; Vekemans, J. A.; Meijer, E. M. Tetrahedron 1993, 49,
7793.
Naph
Biph
Biph
Ph
Me
Me
Me
Bu
i-Pr
Me
Me
Me
Me
Ph
(
5) For asymmetric conjugate reductions of a,b-unsaturated
aldehydes, see: (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,
Ph
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
127, 32. (d) Adolfsson, H. Angew. Chem. Int. Ed. 2005, 44,
g
h
i
Ph
334. (e) Lui, Z.; Han, B.; Lui, Q.; Zhang, W.; Yang, L.; Lui,
Z. L.; Yu, W. Synlett 2005, 1579.
2-CH -C H
4
3
6
(
6) Garden, S. J.; Guimarães, C. R. W.; Corréa, B.; Oliveira, C.
A. F.; Pinto, A. C.; Alencastro, R. B. J. Org. Chem. 2003, 68,
4-CF -C H
4
3
6
8815.
j
2-F-C H4
(7) (a) Itoh, T.; Nagata, A.; Kurihara, A.; Miyazaki, M.;
Ohsawa, A. Tetrahedron Lett. 2002, 43, 3105. (b) Takashi,
I.; Kazuhiro, N.; Michiko, M.; Hiroyuki, I.; Ayako, K.; Akio,
O. Tetrahedron 2004, 60, 6785.
6
k
l
2,4-CH -C H
3 6 3
3-CH -C H
4
3
6
(
8) Selected examples for chiral Brønsted acids: (a) Schuster,
T.; Bauch, M.; Dürner, G.; Göbel, M. W. Org. Lett. 2000, 2,
m
n
4-MeO-C H
Me
6
4
1
79. (b) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 10012. (c) Schreiner, P. R.; Wittkopp, A. Org. Lett.
002, 4, 217. (d) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am.
1
Ph
CO Me PMP
2
2
a
All reactions were performed using imine 1 (0.3 mmol) and 2 (0.42
Chem. Soc. 2003, 125, 12672. (e) Huang, Y.; Unni, A. K.;
Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146.
mmol) at 40 °C in 2 mL CH Cl using 5 mol% diphenyl phosphate
2
2
(
DPP) for 10 h.
(
f) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003,
b
Isolated yield after column chromatography. Products were charac-
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43, 2062.
terized by comparing their data with those reported in the literature.
Synlett 2005, No. 15, 2367–2369 © Thieme Stuttgart · New York

LETTER
9) General Procedure for the Acid-Catalysed Transfer
Organocatalytic Hydrogenation of Imines
2369
(
imine 1n (0.3 mmol) was transformed to amine 4n (62.6 mg,
1
Hydrogenation.
77%). H NMR (250 MHz, CDCl ): d = 3.62 (s, 3 H, OMe),
3
In a typical experiment the imine 1, diphenyl phosphate (5
mol%) and Hantzsch dihydropyridine 2 (1.4 equiv) were
suspended in CH Cl in a screw-capped vial and flushed
3.64 (s, 3 H, OMe), 4.58 (br s, 1 H, NH), 4.94 (br s, 1 H, CH),
6.42–6.48 (m, 2 H, Ar), 6.61–6.67 (m, 2 H, Ar), 7.20–7.43
1
3
(m, 5 H, Ar). C NMR (250 MHz, CDCl ): d = 52.7, 55.7,
2
2
3
with argon. The resulting mixture was allowed to stir at
0 °C for 10 h. The solvent was removed under reduced
61.6, 114.8 (2×), 114.9 (2×), 127.3 (2×), 128.3, 128.9 (2×),
4
137.8, 140.2, 152.5, 172.5. IR (KBr): 3420, 1730, 2360,
–
1
+
pressure and purification of the crude product by column
chromatography on silica gel afforded the pure amine 4.
Representative example: according to the general procedure,
1510, 1320, 1240 cm . MS-ESI: 272 [M + H] , 213 [M –
CO Me] . Anal. calcd for C H NO (271.12): C, 70.94; H,
+
2
16 17
3
6.54; N, 5.17. Found: C, 70.83; H, 6.32; N, 5.17.
Synlett 2005, No. 15, 2367–2369 © Thieme Stuttgart · New York