Highly enantioselective conjugate reduction of β,β-disubstituted α,β-unsaturated nitriles

Article abstract of DOI:10.1002/anie.200600184

(Chemical Equation Presented) Easy access: The highly enantioselective conjugate reduction of α,β-unsaturated nitriles is achieved by employing bench-top stable copper(II) acetate and josiphos (L) as the ligand in the presence of polymethylhydrosiloxane (

Full text of DOI:10.1002/anie.200600184

Angewandte
Chemie
Reduction
highly enantioselective conjugation reduction of a,b-unsatu-
rated nitriles employing a Cu(OAc)2/josiphos catalyst.
Recently, we described the first use of air-stable CuII
precursors Cu(OAc)2 and Cu(OAc)2·H2O for the reproduci-
ble generation of copper(i) hydride in copper-catalyzed
reduction methodology.[6b,11] In contrast to previous reports
of reductions catalyzed by copper hydride by others,[12] an
inhibitory effect by the CN functional group on the activity of
copper(i) hydride was not observed under our reduction
conditions,[6b,13] in which a chelating bisphosphine ligand was
used in combination with the copper precursors. On the basis
of these results, we started to investigate asymmetric reduc-
AHCTREUNG
DOI: 10.1002/anie.200600184
G
ACHTREUNG
Highly Enantioselective Conjugate Reduction of
b,b-Disubstituted a,b-Unsaturated Nitriles**
Daehyung Lee, Daesung Kim, and Jaesook Yun*
Optically active nitrile compounds with a b-stereocenter are
versatile synthetic intermediates for a number of biologically
active compounds.[1] The nitrile group is a very useful
synthetic group that can be transformed into other useful
functionalities, such as amine, aldehyde, and carboxylic acid
groups; furthermore, the isolation of nitrile-containing natu-
ral products continues to increase.[2] Despite recent advances
in metal-catalyzed conjugate reductions, the development of
asymmetric reductions of conjugated nitriles still remains
challenging because of their intrinsic low reactivity[3] and the
linearity of the CN group. The two asymmetric examples that
we are aware of are the Co-catalyzed conjugate reduction of
a,b-unsaturated nitriles[4] and the Rh-catalyzed hydrogena-
tion of a,b-unsaturated nitriles.[5] However, the enantioselec-
tivities achieved by these catalyst systems were significantly
lower than those for analogous esters and amides, presumably
because of the steric and coordinating environment exerted
by the linear nitrile group (Scheme 1).
tions of b-substituted cinnamonitrile (1a) using CuACHTRE(UNG OAc)2 as
the catalytic precursor and a chiral bisphosphine ligand in the
presence of polymethylhydrosiloxane (PMHS; Table 1). In
Table 1: Asymmetric conjugate reduction of 1a.[a]
Entry Substrate Ligand
t [h]
>24[d] RT
T [8C] Yield [%][b] ee [%][c]
1
(E)-1a
(E)-1a
(Z)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(Z)-1a
(Z)-1a
(S)-BINAP
25
92
65
92
90
81
80
91
87
65 (S)
65 (R)
2 (S)
97 (S)
65 (R)
96 (R)
95 (R)
99 (S)
89 (S)
2
3
(R)-p-tol-BINAP
(R)-p-tol-BINAP
11
11
5
RT
RT
0
4
A
5
A
24
0
6
C
4.5
0
7[e]
8[f]
9
E
A
12.5 RT
4.5
4.5 RT
0
[a] Reaction conditions: CuACHTRE(UNG OAc)2 (3 mol%), ligand (3 mol%), PMHS
(4 equiv), and tBuOH (4 equiv) were used unless otherwise noted.
[b] Yield of the isolated product. [c] Determined by chiral HPLC.
[d] Incomplete conversion. [e] Catalyst=1.5 mol%. [f] Ligand=(R,S)-
josiphos.
Scheme 1. Comparison of the coordinating environments of
a,b-unsaturated esters, amides, and nitriles.
initial experiments, C2-symmetric binaphthyl-based bisphos-
phine ligands, such as (1,1ꢀ-binaphthalene)-2,2ꢀ-diylbis(diphe-
nylphosphine)((S)-BINAP) and (R)-p-tol-BINAP, were
Copper hydride ligated by non-racemic ligands has been
used for effecting the asymmetric hydrosilylation of aromatic
ketones,[6] imines,[7] enones,[8] a,b-unsaturated esters,[9] and
nitroalkenes[10] in the presence of excess hydrosilane. How-
ever, an enantioselective asymmetric conjugate reduction
method of a,b-unsaturated nitriles catalyzed by copper
hydride has not been reported yet. Herein, we report a
investigated. The catalyst system prepared from CuACHTREUNG(OAc)2/
BINAP was not effective for the reduction of (E)-1a, as it lost
its catalytic activity before the completion of the reaction
(Table 1, entry 1). Although the reaction progressed smoothly
to completion in 11 h with (R)-p-tol-BINAP, the saturated
nitrile 2a was produced with only moderate enantiomeric
excess (65% ee; Table 1, entry 2). This level of enantioselec-
tivity is considerably lower than that achieved for the
reduction of analogous esters and enones with copper(i)
hydride and the same ligand.[8a,9a] Moreover, when we applied
this system to (Z)-1a, an almost racemic mixture of product
(2% ee) was obtained (Table 1, entry 3).
[*] D. Lee, D. Kim, Prof. J. Yun
Department of Chemistry and Institute of Basic Science
Sungkyunkwan University
Suwon 440-746 (Korea)
Fax: (+82)31-290-7075
E-mail: jaesook@skku.edu
[**] This work was supported by a Korea Research Foundation grant
funded by the Korean Government (R08-2004-000-10429-0). The LC
and GC equipment was supported by the Faculty Research Fund
2005, Sungkyunkwan University. Prof. C. Song and E. Kwon at SKKU
are acknowledged for valuable advice and assistance with the chiral
analysis.
We continued our investigation with screening of the
commercially available josiphos family of ligands 3–5, which
were found to be effective in a number of asymmetric
reactions (Scheme 2).[14] Gratifyingly, the use of josiphos
ligand 3 dramatically enhanced the enantioselectivity of the
reduction of (E)-1a, thus providing 2a in 97% ee (Table 1,
entry 4). Ligand 4 proved to be inferior to the other
Supporting information for this article is available on the WWW
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Communications
nitriles in good yields and with high enantioselectivities. The
reduction of Cl- and CH3-substituted aromatic unsaturated
nitriles provides the respective saturated nitrile products in
good yield and with high enantiomeric excess (Table 2,
entries 1–3). Bulky alkyl substituents (Et, iPr) at the b-
position of the nitrile did not affect the efficiency of the
process, thus affording reduced products 2d and 2e in 98 and
99% ee, respectively (Table 2, entries 4 and 5). The substrate
1 f with the phenyl ring substituted at the ortho position was
reduced with high enantioselectivity as well (Table 2, entry 6).
However, the level of enantioselectivity (65% ee) obtained
with a heteroaromatic pyridyl substrate 1g was significantly
lower than that of the analogous phenyl derivative (Table 2,
entry 7). It is presumed that the steric change at the
ortho position of the aromatic counterpart is the main
reason for the lower enantiomeric excess.
Currently, we presume that a bisphosphine-ligated cop-
per(i) hydride species is the active catalytic species and that
silanes[15] effect the generation of copper(i) hydride from the
CuII precursor. The active copper hydride species reacts with
a a,b-unsaturated nitrile to form a new organocopper species,
and the intermediate undergoes rapid deprotonation by
tBuOH to yield the chiral protonated product and a copper
alkoxide. The latter then regenerates the active copper
hydride catalyst with PMHS.
Scheme 2. Chiral ferrocenyl-based bisphosphines.
structurally related bisphosphine ligands in terms of reactivity
and enantioselectivity (Table 1, entry 5). Ligand 5, which
possesses tert-butyl groups instead of the cyclohexyl groups of
the original josiphos ligand 3, displayed a similar reactivity
but yielded the product 2a with a lower enantiomeric excess
(Table 1, entry 6). It is of note that ligand 3 was also highly
effective for the reduction of (Z)-1a, thus affording 2a in
91% yield and with 99% ee (Table 1, entry 8). The reduction
of the E and Z isomers resulted in the formation of opposite
enantiomers.
With an established, optimal protocol using ligand 3, the
conjugate reduction of different b-aryl-substituted a,b-unsa-
turated nitriles was examined, and the results are summarized
in Table 2. In general, the reduction of the substrates occurred
smoothly at 08C to give the corresponding chiral saturated
In summary, we have shown that a highly enantioselective
reduction of a,b-unsaturated nitriles can be conducted by
using a CuCAHTER(UNG OAc)2/josiphos complex as the catalyst under
Table 2: Enantioselective conjugate reduction of a,b-unsaturated nitri-
les.[a]
hydrosilylation conditions. This reaction provides access to
valuable b-aryl-substituted chiral nitriles in good yields and
with excellent enantioselectivities by employing a bench-top
stable catalytic precursor and a readily available, commercial
bisphosphine ligand. Studies are underway to establish the
full scope of this methodology.
Entry
Substrate
Ligand
t [h]
Yield [%][b]
92
ee [%][c]
1
(S,R)-3
23
97
2
A
23
98
94
Experimental Section
General procedure for the conjugate reduction of a,b-unsaturated
nitriles: CuACHTRE(UNG OAc)2 (2.72 mg, 0.015 mmol) and ligand (0.015 mmol)
were placed in an oven-dried Schlenk tube, and PMHS (0.12mL,
2mmol) and toluene (0.5 mL) were added under nitrogen. The
reaction mixture was stirred for 5 min at 08C and then a,b-
unsaturated nitrile (0.5 mmol) was added, followed by tBuOH
(0.19 mL, 2.0 mmol). The reaction tube was washed with toluene
(0.5 mL) and sealed, and the reaction mixture was stirred until no
starting material was detected by TLC analysis. The reaction mixture
was quenched with water and transferred into a round-bottom flask
with the aid of Et2O (10 mL), and then NaOH (2.5m, 1.2mL) was
added. The biphasic mixture was stirred vigorously for 0.5 h. The
layers were separated and the aqueous layer was extracted with Et2O
(3 ” 20 mL). The combined organic layers were washed with brine,
dried over MgSO4, and concentrated. The product was purified by
chromatography on silica gel or Kugelrohr distillation.
3
4
5
C
21
12
10
91
88
81
95 (S)
98
99
6
7
10
92
96
98
65
Received: January 17, 2006
Published online: March 20, 2006
8.5
[a] Reaction conditions: CuACHTRE(UNG OAc)2 (3 mol%), ligand (3 mol%), PMHS
(4 equiv), and tBuOH (4 equiv) in toluene at 08C. [b] Yield of the isolated
product. [c] Determined by chiral HPLC.
Keywords: asymmetric catalysis · copper · enantioselectivity ·
nitriles · reduction
.
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