Highly efficient conjugate reduction of α,β-unsaturated nitriles catalyzed by copper/xanthene-type bisphosphine complexes

Article abstract of DOI:10.1039/b418586b

α,β-Unsaturated nitriles are chemoselectively reduced to the corresponding saturated nitriles in high yields using a copper-DPEphos or Xantphos complex as catalyst in the presence of polymethylhydrosiloxane (PMHS) as the stoichiometric reducing agent and t-butanol as additive. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b418586b

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Highly efficient conjugate reduction of a,b-unsaturated nitriles
catalyzed by copper/xanthene-type bisphosphine complexes{
Daesung Kim, Bu-Mahn Park and Jaesook Yun*
Received (in Cambridge, UK) 10th December 2004, Accepted 20th January 2005
First published as an Advance Article on the web 7th February 2005
DOI: 10.1039/b418586b
In our initial investigations on the reduction of
(E)-cinnamonitrile (3a) with PMHS, we employed the
Cu(OAc)2?H2O/BINAP catalyst system, which was quite effective
for the reduction of aromatic ketones. However, the reaction
showed no appreciable conversion even after long reaction times.
We screened a series of commercially available bisphosphine
ligands and organosilanes with no success. We then turned our
attention to the use of additives to promote reaction rates since
many hydrosilylation reactions were reported to be accelerated by
alcohol additives.9 Addition of 4 equiv of t-BuOH to the reaction
mixture led to an increased rate of reduction10 and 3a was quite
efficiently reduced to its saturated analogue in high yield (Table 1,
entry 5). Other achiral bisphosphine ligands were investigated and
the results are summarized in Table 1. While bisphosphine ligands
that have flexible backbones such as dppb, dppp are either inactive
or moderately active (entries 3 and 4), bisphosphines based on
rigid aromatic backbones proved quite efficient (entries 5–7). In
particular, Xantphos (1)11 was quite effective for the reduction of
3a yielding the saturated counterpart 4a in high yield (entries 7 and
8). DPEphos11 showed comparable reactivity, but the isolated
yield of 4a was lower for this substrate.
a,b-Unsaturated nitriles are chemoselectively reduced to the
corresponding saturated nitriles in high yields using a copper-
DPEphos or Xantphos complex as catalyst in the presence
of polymethylhydrosiloxane (PMHS) as the stoichiometric
reducing agent and t-butanol as additive.
a,b-Unsaturated nitriles are versatile synthetic intermediates in
organic synthesis1 and the selective reduction of conjugated nitriles
to their saturated counterparts has long been a synthetic interest.
While various reduction methods of a,b-unsaturated nitriles have
been developed by using a stoichiometric amount of metal2 and
metal hydrides,3 only a few metal-catalyzed conjugate reductions
were reported with a relatively nonreactive source of hydride
entities such as silanes.4 These reducing systems, however, have
limitations, as the reduction is very slow, low-yielding, and often
b,b-disubstituted-a,b-unsaturated nitriles cannot be reduced at all.
Despite recent advances of Cu–H catalyzed hydrosilylation
methodologies,5 an efficient conjugate reduction method of
a,b-unsaturated nitriles catalyzed by Cu–H has not been reported.
It was observed that unsaturated nitriles reacted more slowly than
other related unsaturated functionalities in various metal-catalyzed
reductions4,6 and the linearity of the CN group prevented the
formation of a stable enolate analogue.4b The CN functionality
was also reported to inhibit the catalytic activity of Cu–H in other
copper-catalyzed reductions.5c,7
As shown in Table 2, a range of a,b-unsaturated nitriles
prepared from the corresponding aldehydes or ketones were
chemoselectively reduced smoothly at room temperature in high
yields by a Cu(OAc)2/Xantphos catalyst or Cu(OAc)2/DPEphos
catalyst, in the presence of PMHS and t-BuOH.12 A wide range of
aromatic and aliphatic substrates were reduced to the saturated
nitrile products in good yields. Functional groups such as MeO,
Cl, F, CN were tolerated (entries 2–4 and 9). A heterocyclic
substrate, 3-(2-furanyl)-2-propenenitrile (3e), was also effectively
Recently, we have shown that Cu–H for the asymmetric
reduction of ketones could be generated from the combination of
catalytic amounts of copper(II) acetate or copper(II) acetate
monohydrate and (S)-BINAP in the presence of Ph2SiH2 or
PhSiH3.8 We, therefore, decided to investigate the conjugate
reduction of a,b-unsaturated nitriles with our catalytic system and
report here that a complex of copper(II) acetate and Xantphos (1)
or DPEphos (2) is quite effective for catalyzing the conjugate
reduction of a,b-unsaturated nitriles in the presence of PMHS at
ambient temperature.
Table 1 Conjugate reduction of (E)-cinnamonitrile under various
conditions
a
Entry
Ligand
Additive
Time/h
Yield/%
1b
2
(S)-BINAP
Xantphos
dppb
—
—
no rxn
no rxn
no rxn
21
1.5
,1
,1
—
—
—
70
90
83
92
96
3c
4d
5
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
dppp
(S)-BINAP
DPEphos
Xantphos
Xantphos
b
6
7
8e
a
,1
{ Electronic supplementary information (ESI) available: experimental
procedures and spectroscopic data of all products (4a–4j). See http://
www.rsc.org/suppdata/cc/b4/b418586b/
Isolated yields. No reaction occurred with Ph2SiH2 and PhSiH3
c
either. dppb 5 1,4-Bis(diphenylphosphino)butane. dppp 5 1,3-
d
e
Bis(diphenylphosphino)propane. Cu(OAc)2 was used.
*jaesook@ajou.ac.kr
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Cu/Xantphos system, leading reaction to completion in reasonable
reaction times.
Table 2 Catalytic conjugate reduction of a,b-unsaturated nitriles
Copper complexes of Xantphos or DPEphos are thermally
more stable and more efficient for the hydrosilylation of nitriles
than a Cu/BINAP complex. While the Cu/Xantphos-type ligands
system reduces b,b-disubstituted-a,b-unsaturated nitriles effec-
tively, the Cu/BINAP system results in slow conversion of the
substrate and the reaction mixture eventually turns to a black color
in hours (ca. 12 h), which is presumably resulted from
decomposition of Cu–H at room temperature.14
a
Entry Substrate 3
Ligand Time/h Yield/%
1b
3a
3b
1
,1
92
It seems that in our reducing system employing a Cu(II) salt as
the catalyst precursor, the active catalyst is Cu(I)–H, which is the
same species normally generated from copper(I) chloride, sodium
t-butoxide, and a reducing agent.15 We postulate that 1,4-addition
of the Cu–H to a,b-unsaturated nitriles takes place and the
resulting organocopper species16 reacts with t-BuOH to yield the
protonated product rapidly and a copper alkoxide. The latter then
regenerates the active catalyst Cu–H with PMHS.
2
1
1
89
3b
1
1
90
3c
3d
4
1
2
1
1
92
87
In conclusion, we have developed an efficient method for the
conjugate reduction of a,b-unsaturated nitriles based on Cu(I)–H
generated in the presence of the xanthene-based ligands 1 and 2.
The active Cu(I)–H was generated from copper(II) acetate with an
organosilane, and was thermally stable enough to carry out the
reduction at ambient temperature. The use of t-BuOH as additive
was a key to success and inexpensive polymeric hydrosilane PMHS
could be used as the stoichiometric reducing agent. An asymmetric
version of this reaction is actively under investigation in our group
with chiral bisphosphine ligands based on a xanthene or ferrocenyl
framework.
5
6
3e
3f
1
1
1
7
85
80
7
3g
3h
3i
1
2
2
3.5
87
87
84
The authors thank the Korea Science and Engineering
Foundation (KOSEF) for financial support of this research
(R08-2004-000-10429-0).
Daesung Kim, Bu-Mahn Park and Jaesook Yun*
Department of Molecular Science and Technology, Ajou University,
Suwon, Korea 443-749. E-mail: jaesook@ajou.ac.kr;
Fax: +82-31-219-1915; Tel: +82-31-219-2555
8c
10
Notes and references
9c
9
1 F. F. Fleming and B. C. Shook, J. Org. Chem., 2002, 67, 3668 and
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K. Miura and A. Hosomi, Tetrahedron Lett., 1997, 38, 8887; (c) B–H;
J. W. Grissom, D. Klingberg, S. Meyenburg and B. L. Stallman, J. Org.
Chem., 1994, 59, 7876; (d) Fe–H; J. P. Collman, R. G. Finke,
P. L. Matlock, R. Wahren, R. G. Komoto and J. I. Brauman, J. Am.
Chem. Soc., 1978, 100, 1119; (e) Cr–H; G. P. Boldrini and A. Umani-
Ronchi, Synthesis, 1976, 596.
10b,c,d
3j
2
12
94
4 (a) E. Keinan and D. Perez, J. Org. Chem., 1987, 52, 2576; (b) E. Keinan
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E. M. Carreira, Angew. Chem. Int. Ed., 2003, 42, 4793.
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7 J.-X. Chen, J. F. Daeuble, D. M. Brestensky and J. M. Stryker,
Tetrahedron, 2000, 56, 2153.
8 D. Lee and J. Yun, Tetrahedron Lett., 2004, 45, 5415.
a
b
Isolated yield. Pure (E)-isomer was used. Cu(OAc)2 was used
c
d
instead of Cu(OAc)2?H2O. Pure (Z)-isomer was used.
reduced in 85% isolated yield (entry 5). Conjugation of the double
bond with an aromatic ring is not a requirement for reduction.
Simple aliphatic substrates, 3f derived from 2-octanone and 3g
from cyclohexanone afforded products in hours (entries 6 and 7).13
Reduction of the sterically more hindered substrates (3h–3j)
prepared from the corresponding aromatic ketones were con-
ducted more efficiently by the Cu/DPEphos system than by the
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9 (a) Use of alcohol additives in Ti-catalyzed hydrosilylation; J. Yun and
S. L. Buchwald, J. Am. Chem. Soc., 1999, 121, 5640; (b) Cu-catalyzed
hydrosilylation; G. Hughes, M. Kimura and S. L. Buchwald, J. Am.
Chem. Soc., 2003, 125, 11253; (c) Zn-catalyzed hydrosilylation; V. Bette,
A. Mortreux, C. W. Lehmann and J.-F. Carpentier, Chem. Commun.,
2003, 332.
aid of Et2O (10 mL), and then NaOH (2.5 M, 1.2 mL) 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 6 20 mL).
The combined organic layers were washed with brine, dried over
MgSO4, and concentrated. The product was purified by Kugelrohr
distillation or silica gel chromatography.
10 MeOH and i-PrOH performed less efficiently than t-BuOH, leading to
incomplete conversion and decomposition of catalyst. The amount of
t-BuOH was not fully optimized.
11 P. C. J. Kamer, P. W. N. M. Van Leeuwen and J. N. H. Reek, Acc.
Chem. Res., 2001, 34, 895.
13 Acrylonitrile was also a good substrate for the reduction and its
conversion could be followed by GC analysis (1.5 h, 100% conversion
with 2 equiv. t-BuOH). However, the nitrile substrate derived from
t-butyl methyl ketone (pinacolone) was not reduced under the reaction
conditions, probably due to its steric effect.
12 General procedure for the conjugate reduction of a,b-unsaturated
nitriles [using Cu(OAc)2?H2O and Xantphos]: Cu(OAc)2?H2O (3.0 mg,
0.015 mmol) and Xantphos (8.7 mg, 0.015 mmol) were placed in an
oven-dried Schlenk tube and toluene (0.5 mL) was added under
nitrogen. PMHS (0.12 mL, 2 mmol) was added to the reaction mixture
and the reaction was stirred for 20–30 min at room temperature.
a,b-Unsaturated nitrile substrate (0.5 mmol) was added by syringe,
followed by t-BuOH (0.18 mL, 2 mmol). The reaction tube was washed
with toluene (0.5 mL), sealed and stirred at room temperature until no
starting material was detected by TLC or GC. The reaction mixture was
quenched with water and transferred to a round-bottom flask with an
14 For the thermal instability of CuH, see ref. 5c; in this report, reactions
were conducted at low temperatures below 0 uC in order to prevent
decomposition of the Cu–H, which resulted in the gradual formation of
black particulates.
15 For the preparation of Styker’s reagent, [Ph3PCuH]6, see:
D. M. Brestensky, D. E. Huseland, C. McGettigan and J. M. Stryker,
Tetrahedron Lett., 1988, 29, 3749. The same reagent can be prepared
from the combination of copper(II) acetate, an organosilane, and PPh3;
Tetrahedron Lett., in press.
16 Trapping of the organocopper species with chlorosilane was reported.
See ref. 3b.
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Chem. Commun., 2005, 1755–1757 | 1757