Copper hydride catalyzed enantioselective conjugate reduction of unsaturated nitriles

Article abstract of DOI:10.1055/s-2007-966068

α,β-Unsaturated nitriles were reduced with high levels of enantioselectivity via copper hydride catalysis. In this procedure, bench-top stable copper(II) acetate and Josiphos ligand are used as the chiral catalyst and an inexpensive hydrosilane, polymethy

Full text of DOI:10.1055/s-2007-966068

PRACTICAL SYNTHETIC PROCEDURES
2233
Copper Hydride Catalyzed Enantioselective Conjugate Reduction of
Unsaturated Nitriles
Copper
Hydride
C
a
atalyzed En
e
a
ntioselect
h
ive Conjugat
y
e
Reduction
u
of
U
nsaturat
ned Nitriles g Lee, Youngmin Yang, Jaesook Yun*
Department of Chemistry and Institute of Basic Science, Sungkyunkwan University,
Suwon 440-746, Korea
Fax +82(31)2907075; E-mail: jaesook@skku.edu
PSP
Received 14 February 2007
No90
Abstract: a,b-Unsaturated nitriles were reduced with high levels of enantioselectivity via copper hydride catalysis. In this procedure,
bench-top stable copper(II) acetate and Josiphos ligand are used as the chiral catalyst and an inexpensive hydrosilane, polymethylhydrosi-
loxane (PMHS) is employed as the stoichiometric reducing agent. While the reactions are conducted at 0 °C in most cases, they also can be
conducted at room temperature at enhanced rates with no significant drop in enantiomeric excess.
Key words: asymmetric catalysis, copper hydride, hydrosilanes, reduction, a,b-unsaturated nitriles
Procedure 1
CN
Me
CN
Me
PCy2
PPh2
3 mol% Cu(OAc)2/L1
PMHS, t-BuOH, r.t., 1 h
91%
L1 =
Fe
⋅EtOH
(R)-(S)-Josiphos·EtOH
(E)-1a
2a: 97% ee
Procedure 2
CN
Me
CN
Me
Pt-Bu2
PPh2
N
2 mol% Cu(OAc)2/L2
PMHS, t-BuOH, r.t., 1 h
88%
N
*
L2 =
Fe
(R)-(S)-PPF-Pt-Bu2
(E)-3
4: 92% ee
Scheme 1
Introduction
tioselective reduction of a,b-unsaturated nitriles by
employing copper(II) acetate as the precatalyst and Josi-
Enantiomerically enriched nitrile compounds with a b- phos as the chiral ligand.4 This reaction provides b-chiral
stereocenter are valuable intermediates in organic nitriles in good yields and with excellent enantioselectiv-
synthesis1 and the nitrile group is a versatile functional ities.
group that can be transformed into other useful function-
alities. The selective reduction of conjugated nitriles to
their saturated counterparts has long been a synthetic
Scope and Limitations
problem.2 Recently, we have reported that the combina-
tion of copper(II) acetate and a chelating diphosphine is The enantioselective reduction was optimized using (E)-
effective for the catalytic conjugate reduction of a,b-un- 3-phenylbut-2-enenitrile (1a) as the starting material. The
saturated nitriles.3 The method reduces a range of a,b-un- use of Josiphos5 as the chiral ligand was essential for a
saturated nitriles including b,b-disubstituted substrates in high level of enantiomeric excess (procedure 1,
good yields and displays good functional group toler- Scheme 1). C2-Symmetric binaphthyl-based bisphosphine
ance.3 Based on these results, we have developed an enan- ligands, such as (S)-BINAP6 and (R)-p-Tol-BINAP,7 were
not effective for the reduction, yielding the desired prod-
uct 2a with only modest enantiomeric excess (65% ee).
SYNTHESIS 2007, No. 14, pp 2233–2235
Advanced online publication: 11.05.2007
DOI: 10.1055/s-2007-966068; Art ID: Z03707SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7
Other structurally related Josiphos-type ligands such as
8
9
(R)-(S)-PPF-Pt-Bu2 and (R)-(S)-Cy2PF-PCy2 were less
enantioselective than Josiphos. While the reduction could

2234
D. Lee et al.
PRACTICAL SYNTHETIC PROCEDURES
be conducted either at 0 °C4 or at room temperature, the diphenylsilane or phenylsilane could be used without af-
reaction proceeded at faster rates at room temperature fecting reactivity and enantioselectivity.
with little change in enantiomeric excess (98% ee vs 97%
ee). The inexpensive polymeric hydrosilane, polymethyl-
hydrosiloxane (PMHS) was employed as the stoichiomet-
ric reducing agent for the reduction although monomeric
b,b-Disubstituted a,b-unsaturated nitriles (1a–f, 3) react-
ed to yield the corresponding saturated nitriles (2a–f, 4) in
good yield and with excellent enantioselectivity
(Table 1). Both the E- and Z-isomers of 1a and 1f were
readily reduced to form the opposite enantiomers. Nitrile
Table 1 Enantioselective Conjugate Reduction of a,b-Unsaturated Nitrilesa
Entry
Substrate
Temp (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
0
r.t.
5
1
92
91
98 (R)
97 (R)
CN
Me
(E)-1a
3d
0
4.5
91
99
NC
Me
(Z)-1a
4d
5
0
r.t.
23
2
92
88
97
96
CN
Me
(E)-1b
Cl
6
r.t.
1
92
94 (R)
CN
Me
(E)-1c
Me
7
8
0
r.t.
13
2
88
91
98
97
CN
Me
(E)-1d
9d
0
0
0
10
10
8
81
92
95
99
NC
Me
Me
(Z)-1e
10
98
CN
Me
Me
(E)-1f
11
>99
NC
Me
Me
(Z)-1f
(E)-3
12e
r.t.
1
88
92
CN
Me
N
a Reaction conditions: Cu(OAc)2 (3 mol%), (R)-(S)-Josiphos·EtOH (3 mol %), PMHS (4 equiv), t-BuOH (4 equiv) in toluene.
b Yield of isolated product.
c Determined by chiral HPLC.
d (S)-(R)-Josiphos was used as ligand.
e 2 mol% each of Cu(OAc)2 and (R)-(S)-PPF-P(t-Bu)2 ligand were used.
Synthesis 2007, No. 14, 2233–2235 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Conjugate Reduction of Unsaturated Nitriles
2235
rubber septum. PMHS (0.12 mL, 2.0 mmol) and toluene (0.5 mL)
were added via syringe and the mixture was stirred at r.t. for 15 min.
The unsaturated nitrile (E)-3 (72 mg, 0.50 mmol) was added, fol-
lowed by t-BuOH (0.19 mL, 2.0 mmol). The reaction tube was
washed with toluene (0.5 mL), sealed with a Teflon screwcap, and
stirred until the starting material was completely consumed as
judged by TLC. The mixture was quenched with H2O and trans-
ferred to a round-bottomed flask with the aid of Et2O (10 mL), and
2.5 M NaOH (1.2 mL) was added. The biphasic mixture was stirred
vigorously for 0.5 h. The layers were separated and the aqueous lay-
er was extracted with Et2O (3 × 20 mL). The combined organic lay-
ers were washed with brine, dried (MgSO4), and concentrated. The
crude product was purified by column chromatography (hexanes–
EtOAc, 1:1) to give 4 (64 mg, 88%); 92% ee; chiral HPLC (AS-H
column, i-PrOH–hexane 10:90, 0.5 mL/min); tR = 16.5 (major iso-
mer) and 18.2 min (minor isomer).
substrates (1d, 1e) that possess bulkier alkyl substituents
(Et, i-Pr) than methyl were also suitable substrates for the
reaction (entries 7–9). The substrate 3 with a 2-pyridyl
substituent at the b-position was reduced with high enan-
tioselectivity (92% ee) by employing (R)-(S)-PPF-
P(t-Bu)2 as the chiral ligand (entry 12).
In summary, the enantioselective reduction of a,b-unsat-
urated nitriles is conducted by using a copper(II) acetate/
Josiphos complex under hydrosilylation conditions. The
resulting b-chiral nitriles are valuable building blocks in
organic synthesis.
Procedures
Herein, we describe two typical procedures for the enantioselective
reduction of a,b-unsaturated nitriles depicted in Scheme 1 and
Table 1. Both procedures describe reactions conducted at room
temperature and Procedure 2 uses the ligand PPF-P(t-Bu)2 instead
of Josiphos for the reduction of (E)-3. Except for these two facts, the
procedures described here are almost the same as the one previously
reported.4
IR (neat): 3010, 2970, 2246, 1591, 1474, 1435, 1375 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.57 (d, J = 4.4 Hz, 1 H), 7.68–
7.64 (m, 1 H), 7.27–7.17 (m, 2 H), 3.31 (m, 1 H), 2.84 (dd, J = 16.7,
6.4 Hz, 1 H), 2.74 (dd, J = 16.7, 7.1 Hz, 1 H), 1.46 (d, J = 6.6 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 161.6, 149.6, 136.9, 122.4, 121.9,
119.2, 38.4, 24.4, 20.6.
Cu(OAc)2, hydrosilanes, and other commercial substrates were pur-
chased and used as received and toluene was distilled under N2 from
sodium benzophenone ketyl. NMR spectra were obtained on Varian
Mercury 400 systems with TMS as internal standard. 13C NMR
spectra used CDCl3 as internal standard (d 77.2). IR spectra were
obtained on a Nicolet 205 FT-IR instrument. HPLC analysis was
performed on a Younglin Acme 9000 series. Low resolution MS
were recorded using a Varian 4000 GC/MS. Flash chromatography
was performed on silica gel from Merck (70–230 mesh).
MS (EI, 70 eV): m/z (%) = 146 (8) [M+], 131 (62), 106 (100), 78
(22).
Anal. Calcd for C9H10N2: C, 73.94; H, 6.89; N, 19.16. Found: C,
74.00; H, 6.91; N, 19.02.
Acknowledgment
Financial support provided by the Korea Research Foundation
(KRF-2004-205-C00114) and Sungkyunkwan University (Faculty
Research Fund 2005) is gratefully acknowledged.
Procedure 1
(R)-3-Phenylbutanenitrile (2a);10 Typical Procedure
Cu(OAc)2 (2.72 mg, 0.015 mmol) and (R)-(S)-Josiphos·EtOH (9.60
mg, 0.015 mmol) were placed in an oven-dried Schlenk tube. The
tube was evacuated and backfilled with N2 and then capped with a
rubber septum. PMHS (0.12 mL, 2.0 mmol) and toluene (0.5 mL)
were added via syringe and the mixture was stirred at r.t. for 15 min.
The unsaturated nitrile (E)-1a (72 mg, 0.50 mmol) was added, fol-
lowed by t-BuOH (0.19 mL, 2.0 mmol). The reaction tube was
washed with toluene (0.5 mL), sealed with a Teflon screwcap, and
stirred until the starting material was completely consumed as
judged by TLC. The mixture was quenched with H2O and trans-
ferred to a round-bottomed flask with the aid of Et2O (10 mL), and
2.5 M NaOH (1.2 mL) was added. The biphasic mixture was stirred
vigorously for 0.5 h. The layers were separated and the aqueous lay-
er was extracted with Et2O (3 × 20 mL). The combined organic lay-
ers were washed with brine, dried (MgSO4), and concentrated. The
crude product was purified by column chromatography (hexanes–
EtOAc, 3:1) to give 2a (66.0 mg, 91%); 97% ee, chiral HPLC (OD-
H column, i-PrOH–hexane, 5:95, 0.5 mL/min): tR = 18.0 (S-isomer)
and 20.1 min (R-isomer).
References
(1) (a) Harrowven, D. C.; Pascoe, D. D.; Demurtas, D.; Bourne,
H. O. Angew. Chem. Int. Ed. 2005, 44, 1221. (b) Banfi, L.;
Basso, A.; Gandolfo, V.; Guanti, G.; Riva, R. Tetrahedron
Lett. 2004, 45, 4221. (c) Mori, K. Tetrahedron: Asymmetry
2005, 16, 685. (d) Andrus, M. B.; Meredith, E. L.; Hicken,
E. J.; Simmons, B. L.; Glancey, R. R.; Ma, W. J. Org. Chem.
2003, 68, 8162. (e) Abate, A.; Brenna, E.; Negri, C. D.;
Fuganti, C.; Serra, S. Tetrahedron: Asymmetry 2002, 13,
899.
(2) (a) De Bellefon, C.; Fouilloux, P. Catal. Rev. 1994, 36, 459.
(b) Osborn, M. E.; Pegues, J. F.; Paquette, L. A. J. Org.
Chem. 1980, 45, 168.
(3) Kim, D.; Park, B.-M.; Yun, J. Chem. Commun. 2005, 1755.
(4) Lee, D.; Kim, D.; Yun, J. Angew. Chem. Int. Ed. 2006, 45,
2785.
(5) (R)-(S)-Josiphos (R)-(S)-PPF-PCy2 = dicyclohexyl{(R)-1-
[(S)-2-(diphenylphosphino)ferrocenyl]ethyl}phosphine. For
a review, see: Blaser, H.-U.; Brieden, W.; Pugin, B.;
Spindler, F.; Studer, M.; Togni, A. Top. Catal. 2002, 19, 3.
(6) BINAP = 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthalene.
(7) p-Tol-BINAP = 2,2¢-bis(di-4-tolylphosphino)-1,1¢-bi-
naphthalene.
IR (film): 3029, 2968, 2246, 1602, 1453, 1381 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.21 (m, 5 H), 3.15 (m, 1 H),
2.61 (dd, J = 16.7, 6.4 Hz, 1 H), 2.54 (dd, J = 16.7, 7.5 Hz, 1 H),
1.45 (d, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 143.2, 129.0, 127.5, 126.7, 118.8,
36.9, 26.8, 21.1.
(8) (R)-(S)-PPF-Pt-Bu2 = di-tert-butyl{(R)-1-[(S)-2-(diphenyl-
phosphino)ferrocenyl]ethyl}phosphine.
MS (EI, 70 eV): m/z (%) = 145 (6) [M+], 130 (2), 105 (100), 103
(9) (R)-(S)-Cy2PF-PCy2 = dicyclohexyl{(R)-1-[(S)-2-(dicyclo-
hexylphosphino)ferrocenyl]ethyl}phosphine.
(11), 79 (12).
(10) Its stereochemical assignment was made by comparison
with the optical rotation of the corresponding ester
derivative: Appella, D. H.; Moritani, Y.; Shintani, R.;
Ferreira, E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 9473.
Procedure 2
3-Pyridin-2-ylbutanenitrile (4)
Cu(OAc)2 (1.82 mg, 0.010 mmol) and (R)-(S)-PPF-P(t-Bu)2 (5.42
mg, 0.010 mmol) were placed in an oven-dried Schlenk tube. The
tube was evacuated and backfilled with N2 and then capped with a
Synthesis 2007, No. 14, 2233–2235 © Thieme Stuttgart · New York