Highly efficient Rh(I)-catalyzed asymmetric hydrogenation of enamines using monodente spiro phosphonite ligands

Article abstract of DOI:10.1021/ja0644778

A highly enantioselective hydrogenation of nonfunctionalized enamines has been developed by using rhodium complexes of chiral spiro phosphonite ligands, providing chiral tertiary amines in excellent enantioselectivities. Copyright

Full text of DOI:10.1021/ja0644778

Published on Web 08/19/2006
Highly Efficient Rh(I)-Catalyzed Asymmetric Hydrogenation of Enamines
Using Monodente Spiro Phosphonite Ligands
Guo-Hua Hou, Jian-Hua Xie, Li-Xin Wang, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai UniVersity, Tianjin 300071, China
Received June 23, 2006; E-mail: qlzhou@nankai.edu.cn
Chiral amines are an important class of compounds in organic
and pharmaceutical synthesis, and a great effort has been made to
develop efficient synthetic methods for chiral amines. In the past
decades, the catalytic asymmetric hydrogenation of functionalized
enamines, such as R- and â-N-acylamino acrylates, and enamides
have been extensively studied, and a great number of highly
enantioselective protocols for the synthesis of enantiomer-enriched
Scheme 1
1
primary and secondary amines have been documented. However,
only a limited progress has been achieved in the direct preparation
of chiral tertiary amines, which broadly occurred in the biologically
2
active molecules and natural products, by asymmetric hydrogena-
tion of the corresponding N,N-dialkylenamines. This is not surpris-
ing because one substantial drawback in the current approaches to
asymmetric hydrogenation of enamides is the requirement of an
3
N-acyl group in the substrate. This N-acyl group is considered
indispensable for the substrate to form a chelate complex with metal
of catalyst in transition state, giving a good reactivity and
enantioselectivity. Up to now, only two groups have tackled the
challenging class of N,N-dialkylenamine substrates in the asym-
metric hydrogenation. In 1994, Buchwald et al. reported the first
example of catalytic asymmetric hydrogenation of simple enamines.
Table 1. Rh(I)-Catalyzed Asymmetric Hydrogenation of Enamine
2
a, Optimizing Reaction Conditionsa
4
5
PH
2
time
(h)
addition
(mol %)
ee
(%)b
entry
ligand
solvent
(atm)
2
By using 5 mol % chiral titanocene catalyst [(S,S,S)-(EBTHI)TiO -
binaphtho] they achieved excellent enantioselectivities (up to 98%
ee) in the hydrogenation of 1-(dialkylamino)-1-arylethenes. Few
years later, B o¨ rner and co-workers used chiral Rh(I)-diphosphine
complexes for this hydrogenation and obtained the chiral tertiary
amines in moderate enantiomeric excesses (up to 72%). These
results are very encouraging and suggested that new efficient
catalysts are necessary for the development of highly enantio-
selective hydrogenation of simple nonfunctionalized enamines to
give chiral tertiary amines in broad scope.
1
2
3
4
5
6
7
8
9
0
(S)-1a
(S)-1b
(S)-1c
(S)-1c
(S)-1c
(S)-1c
(S)-1c
(S)-1c
(S)-1c
(S)-1c
(S)-1c
(S)-1c
(S)-1c
(S)-1c
(S)-1c
(S)-1c
(S)-1c
(S)-1a
(S)-1b
(R)-4
THF
THF
THF
THF
THF
THF
Et2O
dioxane
CH2Cl2
toluene
DME
MeOH
THF
THF
THF
THF
THF
100
100
100
100
100
100
100
100
100
100
100
100
100
30
10
10
5
10
10
10
10
48
48
48
48
48
48
48
48
48
48
48
48
12
12
12
24
22
12
12
12
12
none
none
none
I2 (5)
I2 (2)
I2 (1)
I2 (2)
I2 (2)
I2 (2)
14
4
33
71
83
77
66
72
78
60
20
12
78
78
87
77
80
32
62
56
33
6
1
I2 (2)
I2 (2)
I2 (2)
11
12
Recently, we demonstrated that the chiral monodentate phos-
phoramidites and phosphonites containing a 1,1′-spirobiindane
scaffold were highly enantioselective ligands for the Rh-catalyzed
asymmetric hydrogenation of N-(R-arylethenyl)-acetamides and
1
1
1
3
4
5
I2/HOAc (2/50)
I2/HOAc (2/30)
I2/HOAc (2/20)
I2/HOAc (2/20)
I2/HOAc (2/20)
I2/HOAc (2/20)
I2/HOAc (2/20)
I2/HOAc (2/20)
I2/HOAc (2/20)
16c
7
N-acyl R- and â-dehydroamino acid derivatives. As a part of our
17
1
1
2
2
8
9
0
1
THF
THF
THF
THF
sustained efforts in this area, we herein wish to report the
asymmetric hydrogenation of N,N-dialkylenamines using chiral
spiro phosphonite ligands 1, providing chiral tertiary amines in
excellent enantiomeric excesses (up to 99.9%).
(S)-ShiP
a
The chiral tertiary 1,2-diarylethanamine is a very useful unit; it
Reaction conditions: 1 mol % [Rh(COD)2]BF4, 2.2 mol % ligand,
b
8
[substrate] ) 0.125 M, room temperature, 100% conversion. Determined
widely exists in natural products such as benzylisoquinolines. The
by chiral HPLC using a chiralcel OD-H column. c With 0.5 mol % catalyst,
catalytic asymmetric hydrogenation of N,N-dialkylenamines is one
8
7% conversion.
of the most straightforward accesses to the optically active tertiary
1
(
,2-diarylethanamines. In our study, the hydrogenation of (E)-1-
1-pyrrolidinyl)-1,2-diphenylethene (2a) was initially performed
under 100 atm of H in THF with the rhodium catalyst generated
in situ from 1 mol % [Rh(COD) ]BF and 2.2 mol % phosphorus
10%). Most of monophosphorus ligands illustrated in Scheme 1
also gave very low enantioselectivity (ee e 14%) except for spiro
phosphonite ligand (S)-1c, which provided chiral tertiary amine 3a
in 33% ee (Table 1, entry 3).
2
2
4
ligands. A brief screening on the chiral phosphorus ligands available
in our laboratory showed that the diphosphine ligands including
BINAP, SDP, and JosiPhos were inefficient in the reaction (ee e
It was reported that the additives might play a crucial role for
the high reactivity and enantioselectivity in the hydrogenations of
simple olefins, ketones, and imines. To improve the enantio-
9
10
11
11774
9
J. AM. CHEM. SOC. 2006, 128, 11774-11775
10.1021/ja0644778 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
selectivity in the hydrogenation of enamine 2a catalyzed by Rh/
S)-1c complex, we investigated the effect of additives. When
o-phthalimide, HOAc, or H SO were added, the catalyst was
strongly deactivated and only very low conversions were obtained.
However, a promising result was obtained when I was added. In
the presence of 5 mol % I , the enantioselectivity of reaction was
dramatically increased to 71% ee (entry 4). Adjusting the amount
of I , we found that 2 mol % I was suitable for achieving a high
enantioselectivity (83% ee) (entry 5). Different solvents were then
compared in the presence of 2 mol % I . A full conversion was
obtained in all tested solvents. In addition to THF, the solvents
including Et O, dioxane, CH Cl , and toluene also could be
employed, albeit the enantioselectivities were slightly lower (60-
8% ee). However, the reactions in MeOH and chelate solvent DME
1,2-dimethoxyethane) had very low enantioselectivities (entries 11
and 12). Although the addition of I significantly improved the
Table 2. The Asymmetric Hydrogenation of Enamines 2
Catalyzed by Rh(I)/(S)-1c Complexa
(
ee
(%)b
2
4
entry
Ar1
Ar2
product
2
1
2
3
4
5
6
7
8
9
C6H5 (2a)
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2-MeC6H4
2-ClC6H4
3-ClC6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
87
91
90
90
95
99
73
94
4-MeC6H4 (2b)
3-MeC6H4 (2c)
2-MeC6H4 (2d)
4-MeOC6H4 (2e)
3,4-(MeO)2C6H3 (2f)
4-ClC6H4 (2g)
C6H5 (2h)
2
2
2
2
C6H5 (2i)
C6H5 (2j)
93
90
80
2
2
2
1
0
3j
11
12
C H (2k)
C6H5 (2l)
6
5
4-MeC H4
4-ClC6H4
6
3k
3l
7
(
96
c
1
1
1
16
17
3
4
5
C6H5 (2m)
C6H5 (2n)
3-MeC6H4 (2o)
4-BrC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-ClC6H4
3m
3n
3o
3p
3q
97(R)
99.9
90
2
enantioselectivity of hydrogenation of enamine 2a, the reaction rate
was still too low.
4-MeOC6
95
93
H4 (2p)
4-MeOC6H4 (2q)
Acid was often utilized to accelerate the reaction rate in the Ir(I)-
catalyzed asymmetric hydrogenation of imines by preventing
deactivation of the catalyst caused by the amine products.12 It was
mentioned above that the use of acetic acid alone in this Rh(I)-
catalyzed hydrogenation of enamines strongly lowered the conver-
sion. Surprisingly, when the acetic acid was used together with 2
a
[
Rh(COD)2]BF4/(S)-1c/I2/HOAc/substrate ) 1:2.2:2:20:100, [substrate]
b
)
0.125 M, THF, rt, 10 atm H2, 12 h, 100% conversion. Determined by
HPLC using chiral columns (see Supporting Information). Determined by
X-ray diffraction analysis (see Supporting Information).
c
reaction mechanism and the extension of this novel catalytic system
to a broader rang of enamines.
2
mol % of I in the hydrogenation of enamine 2a, the reaction rate
was remarkably increased. In the presence of 20-50 mol % of
acetic acid the reaction time was shortened from 48 to 12 h without
losing enantioselectivity. A more significant improvement brought
Acknowledgment. We thank the National Natural Science
Foundation of China, and the Ministry of Education of China for
financial support.
about by the addition of I
tion could proceed under a much lower pressure of H
beneficial to high enantioselectivity. For example, employing 2 mol
and 20 mol % acetic acid as additives, the hydrogenation of
a was completed in 12 h under 10 atm of hydrogen, affording the
2
and acetic acid was that the hydrogena-
2
, which was
Supporting Information Available: Experimental procedures, the
characterizations of substrates and products, the analysis of ee values
of hydrogenation products (PDF), and the crystal data and structure
refinement for (R)-3m. This material is available free of charge via
the Internet at http://pubs.acs.org.
% I
2
2
amine 3a in 87% ee (entry 15). The comparison of ligands 1 under
the optimized conditions showed that the enantioselectivity of
catalyst was constantly enhanced as the size of R group in the
ligands 1 became larger. The ligand 1c, which contained a tert-
butyl gave the best result. Other ligands listed in Scheme 1 were
also evaluated in combination with iodine/acetic acid. Most of them
showed no enantioselectivity, with ligands 4 (56% ee) and ShiP
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(
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A variety of (E)-1-(1-pyrrolidinyl)-1,2-diarylethenes 2 can be
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2 4
(
4) For the examples of asymmetric hydrogenation of N-unprotected â-
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ee values (Table 2). The electronic nature of the aryl groups of
enamines 2 had a strong influence on the enantioselectivity of the
(
(
5) Lee, N. E.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 5985.
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1
reaction. The substrates with a Ar connecting electron-donating
groups such as Me or MeO have higher enantioselectivity (entries
2
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2
-6). However, on the Ar side, a reverse effect was observed.
2
The substrates with a Ar connecting electron-withdrawing groups
such as Cl, Br, and F on para-position gave higher enantioselectivity.
The highest enantioselectivity (99.9% ee) was achieved in the
2
hydrogenation of enamine 2n, which has a 4-F on Ar (entry 14).
(
9) (a) Ohta, T.; Ikegami, H.; Miyake, T.; Takaya, H. J. Organomet. Chem.
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The effect of N-alkyl groups of enamine substrates on the
enantioselectivity of reaction was also examined. When the
pyrrolidine moiety was changed to piperidine and morpholine the
ee values of hydrogenation products were lowered to 75% and 77%,
respectively.
In summary, a highly enantioselective hydrogenation of simple
N-unprotected enamines catalyzed by a Rh(I) complex of chiral
spiro phosphonite ligand (S)-1c has been developed, which provided
a straightforward method for the synthesis of chiral tertiary amines
with excellent ee values. Further investigation will focus on the
1
(
1
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(
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