Copper-catalyzed asymmetric reduction of 3,3-diarylacrylonitriles

Article abstract of DOI:10.1021/ol0712071

Equation Presented CuH-catalyzed enantioselective conjugate reduction of 3,3-diaryl-substituted acrylonitriles is described. A range of 3-aryl-3-pyridylacryionitriles were reduced with high levels of enantioselectivity under optimal conditions employing a

Full text of DOI:10.1021/ol0712071

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2749-2751
Copper-Catalyzed Asymmetric Reduction
of 3,3-Diarylacrylonitriles
Daehyung Lee, Youngmin Yang, and Jaesook Yun*
Department of Chemistry and Institute of Basic Science, Sungkyunkwan UniVersity,
Suwon 440-746, Korea
jaesook@skku.edu
Received May 22, 2007
ABSTRACT
CuH-catalyzed enantioselective conjugate reduction of 3,3-diaryl-substituted acrylonitriles is described. A range of 3-aryl-3-pyridylacrylonitriles
were reduced with high levels of enantioselectivity under optimal conditions employing a copper/Josiphos complex in the presence of
polymethylhydrosiloxane (PMHS).
The 3,3-diarylpropylamine moiety is an important structural
motif in many biologically active compounds and pharma-
ceutical agents (Scheme 1).1 In view of the fact that the
methods of such building blocks is of great importance. A
convenient route to 3,3-diarylpropylamines would be the
enantioselective reduction of diaryl-substituted alkenyl sub-
strates. However, â,â-diaryl-substituted alkenyl substrates
have received little attention as the starting materials among
a number of alkenyl substrates with various substitution
patterns in asymmetric reductions.3 This is presumably
because low enantioselectivity is generally expected from
the small steric difference between two aryl substituents and
because steric congestion of the aryl groups influences
activity of the catalysts. Only a few reports4 appeared in the
field of Rh- and Ru-catalyzed asymmetric hydrogenation that
required an additional coordinating functionality to the metal
of catalysts such as carbonyl,4a alcohol,4b and pyridyl4c for
catalyst reactivity and enantioselectivity.
Scheme 1
marketing of single enantiomers is becoming more popular,2
the development of efficient enantioselective preparation
Copper hydride (Cu-H) ligated by nonracemic ligands has
been shown to be a powerful reagent for effecting asym-
(1) (a) Moe, S. T.; Smith, D. L.; DelMar, E. G.; Shimizu, S. M.;
Wagenen, B. C. V.; Balandrin, M. F.; Chien, Y.; Raszkiewicz, J. L.; Artman,
L. D.; White, H. S.; Mueller, A. L. Bioorg. Med. Chem. Lett. 2000, 10,
2411. (b) Almansa, C.; Go´mez, L. A.; Cavalcanti, F. L.; de Arriba, A. F.;
Rodr´ıguez, R.; Carceller, E.; Garc´ıa-Rafanell, J.; Forn, J. J. Med. Chem.
1996, 39, 2197. (c) Cumming, J. G.; Cooper, A. E.; Grime, K.; Logan, C.
J.; McLaughlin, S.; Oldfield, J.; Shaw, J. S.; Tucker, H.; Winter, J.;
Whittaker, D. Bioorg. Med. Chem. Lett. 2005, 15, 5012. (d) Lee, J.; Kang,
S.-U.; Lim, J.-O.; Choi, H.-K.; Jin, M.; Toth, A.; Pearce, L. V.; Tran, R.;
Wang, Y.; Szabo, T.; Blumberg, P. M. Bioorg. Med. Chem. 2004, 12, 371.
(2) Tomaszewski, J.; Rumore, M. M. Drug DeV. Ind. Pharm. 1994, 20,
119.
(3) (a) Cui, X.; Burgess, K. Chem. ReV. 2005, 105, 3272. (b) Ohkuma,
T.; Kitamura, M.; Itoh, K. In Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; Wiley-VCH: New York, 2000; Chapter 1.
(4) (a) Boulton, L. T.; Lennon, I. C.; McCague, R. Org. Biomol. Chem.
2003, 1, 1094. (b) Bissel, P.; Sablong, R.; Lepoittevin, J.-P. Tetrahedron:
Asymmetry 1995, 6, 835. (c) Wabnitz, T. C.; Rizzo, S.; Go¨tte, C.; Buschauer,
A.; Benincori, T.; Reiser, O. Tetrahedron Lett. 2006, 47, 3733.
10.1021/ol0712071 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/08/2007

metric reductions of aryl ketones,5 imines,6 enones,7 R,â-
unsaturated esters,8 nitroalkenes,9 and R,â-unsaturated ni-
triles.10 We envisioned that an asymmetric conjugate reduction
of 3,3-diaryl-substituted acrylonitriles via copper hydride
catalysis would be an unique and attractive route to 3,3-
diarylpropionitriles and thus to 3,3-diarylpropylamines. Since
the nitrile group prefers end-on coordination to a metal, most
asymmetric hydrogenation catalysts are not generally com-
petent. One report has been recently made on the enantio-
selective reduction of 3-aryl-3-pyridyl-R,â-unsaturated ni-
triles catalyzed by Ru-phosphine complexes.4c However,
only substrates with a suitable secondary coordinating atom
were reactive under high hydrogen pressure. In this reprot,
we describe a copper-catalyzed enantioselective conjugate
reduction of 3,3-diarylacrylonitriles that efficiently occurs
with high levels of enantioselectivity. The substrate scope
of this reaction includes 3,3-diaryl-substituted unsaturated
substrates having no secondary coordinating functional
groups and this is, to the best of our knowledge, the first
example of the enantioselective reduction of such com-
pounds.
Figure 1. Structures of pheniramines and arpromidine.
product 2a of very high ee (96% ee; Table 1, entry 1).
Reductions with Mandyphos ((R)-(S)-4; entry 5) and Wal-
phos-type ligand ((R)-(S)-5; entry 6) were very slow,
Table 1. Asymmetric Conjugate Reduction of (E)-1a with
We prepared (E)-3-phenyl-3-(pyridin-2-yl)acrylonitrile
(1a) as the starting material. The aryl(pyridyl)propionitriles
resulting from this type of substrate constitute a characteristic
feature of H1 antihistaminic agents, pheniramines,11 and the
potent histamine H2 agonist, arpromidine and its analogues
(Figure 1).12 In initial studies on the reduction of (E)-1a with
3 mol % of Cu(OAc)2 in the presence of excess PMHS, we
screened various chiral ligands (Table 1). To our delight,
with Josiphos-type ligands (3a-d),13 the reaction proceeded
Various Ligands
temp
(°C)
concn
(M)
time
(h)
yield
(%)
ee
entry
ligand
(%)a
1
2
3
4
5
6
7
8b
9
3a (Josiphos)
0
0
0
0
0
0
0
rt
0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
17
12
24
24
60
60
24
4
90
70
70
78
66
87
70
86
91
96
86
65
53
18
94
37
92
95
3b
3c
3d
4
5
6
3a
3a
17
a Determined by chiral HPLC. b rt ) ∼ 22 °C.
although the latter ligand gave good enantioselectivity. The
C2-symmetric (R)-Ph-MeOBiphep ligand (6; entry 7) showed
poor enantioselectivity. We chose Josiphos as the chiral
ligand for further investigation. Increasing reaction temper-
ature to room temperature resulted in a small drop in ee (entry
8) with an increase of reaction rate, and conducting the
reduction of 1a at a higher substrate concentration had no
significant effect on the enantioselectivity (entry 9).
Next, we examined the asymmetric reductions of several
substrates by employing a catalytic amount of Cu(OAc)2 and
3a in toluene in the presence of PMHS and t-BuOH (Table
2). In general, most of the reactions proceeded to completion
within 1-4 h at room temperature to furnish diaryl products
in good ee and yields. Both (E)- and (Z)-isomers (1d, 1e,
and 1g) were reduced smoothly, affording the product in the
opposite configuration.14
smoothly to yield the desired product (entries 1-4). In
particular, the Josiphos ligand (3a) afforded the reduced
(5) (a) Lipshutz, B. H.; Noson, K.; Chrisman, W. J. Am. Chem. Soc.
2001, 123, 12917. (b) Lee, D.; Yun, J. Tetrahedron Lett. 2004, 45, 5415.
(6) Lipshutz, B. H.; Shimizu, H. Angew. Chem., Int. Ed. 2004, 43, 2228.
(7) (a) Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald, S. L. J.
Am. Chem. Soc. 2000, 122, 6797. (b) Lipshutz, B. H.; Servesko, J. M.
Angew. Chem., Int. Ed. 2003, 42, 4789.
(8) (a) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473. (b) Lipshutz, B. H.;
Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc. 2004, 126, 8352.
(9) Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 4793.
(10) Lee, D.; Kim, D.; Yun, J. Angew. Chem., Int. Ed. 2006, 45, 2785.
(11) (a) Anthes, J. C.; Gilchrest, H.; Richard, C.; Eckel, S.; Hesk, D.;
West, R. E.; Williams, S. M.; Greenfeder, S.; Billah, M.; Kreutner, W.;
Egan, R. W. Eur. J. Pharmacol. 2002, 449, 229. (b) Botteghi, C.; Chelucci,
G.; Ponte, G. D.; Marchetti, M.; Paganelli, S. J. Org. Chem. 1994, 59, 7125
and references cited therein.
(12) (a) Dove, S.; Elz, S.; Seifert, R.; Buschauer, A. Mini-ReV. Med.
Chem. 2004, 4, 941. (b) Buschauer, A. J. Med. Chem. 1989, 32, 1963. (c)
Buschauer, A.; Friese-Kimmel, A.; Baumann, G.; Schunack, W. Eur. J.
Med. Chem. 1992, 27, 321.
(13) For a review of Josiphos ligands, see: Blaser, H.-U.; Brieden, W.;
Pugin, B.; Spindler, F.; Studer, M.; Togni, A. Top. Catal. 2002, 19, 3.
2750
Org. Lett., Vol. 9, No. 14, 2007

12, Table 2), in cases where cooling the reaction increased
the selectivity. To examine further a temperature effect on
the enantioselectivity, we carried out reductions of the two
substrates 1b and 1c at higher temperatures. Increasing the
reaction temperature had a negative effect on enantioselec-
tivity in both cases, providing 1b in 84% ee at 40 °C (entry
3), and 2c in 89% ee at 40 °C (etnry 6) and in 85% ee at 60
°C (entry 7). The results show the existence of the inversion
temperature (Tinv)15 for both 1b and 1c around room
temperature.16
To see whether the 2-pyridyl group is a requisite for the
reactivity and good enantioselectivity of the reduction, we
prepared substrates 1f and 1g that possess the 3-pyridyl and
4-pyridyl group, respectively. The compounds were reduced
with high levels of enantioselectivities as well (90-96% ee;
entries 13-15), showing that the position of the N-atom of
the pyridyl substituent is not crucial to high enantioselec-
tivity. These results also indicate that an additional coordina-
tion site is not a requirement for reaction conversion in the
copper hydride catalysis. Given the similar sterics of the
phenyl and 3-/4-pyridyl substituent around the CdC bond,
this level of enantioselectivity was rather unexpected.
Encouraged by these results, we carried out the conjugate
reduction of (E)-3-phenyl-3-p-tolylacrylonitrile (1h). The
desired product was obtained in 94% ee in high yield again
(entry 16).
In summary, we have developed a copper-catalyzed
asymmetric reduction of 3,3-diarylacrylonitriles that provides
ready access to optically active 3,3-diarylpropionitriles and
thus to 3,3-diarylpropylamines. A range of 3-aryl-3-pyridyl-
acrylonitriles were reduced with high degrees of enantio-
selectivity over 90% ee under optimal conditions employing
a copper/Josiphos complex in the presence of hydrosilane.
Some of the reduction examples showed an interesting
inverse temperature dependence of the enantioselectivity.
Current efforts are focused on exploring the scope of this
method and the temperature dependence of enantioselectivity
in more detail.
Table 2. Enantioselective Reduction of 3,3-Diarylacrylonitrilesa
sub-
entry strate
temp time yield ee
Ar
Ar′
(°C)b
(h)
(%)c (%)d
1
2
3
(E)-1b: 3,4-F2-Ph 2-Py
(E)-1b
(E)-1b
0
rt
40
18
2
1
87 84 (S)
95 91 (S)
90 84 (S)
4
5
6
7
(E)-1c: 4-Cl-Ph
(E)-1c
(E)-1c
2-Py
0
rt
40
30
2
1
91 79
89 93
92 89
(E)-1c
60 45 min 87 85
8
9
(E)-1d 4-MeO-Ph 2-Py
(Z)-1d 2-Py 4-MeO-Ph rt
rt
3
4
1
9
1
93 95
97 62
83 86
86 95
85 87
10 (E)-1e: o-tolyl
11 (Z)-1e 2-Py
12 (Z)-1e
2-Py
o-tolyl
rt
0
rt
13 (E)-1f Ph
14 (E)-1g Ph
15 (Z)-1g 4-Py
16 (E)-1h Ph
3-Py
4-Py
Ph
rt
rt
rt
rt
4
1
1
1
92 96
86 90
87 92
94 94
p-tolyl
a Reaction conditions: Cu(OAc)2 (2 mol %), (R)-(S)-Josiphos (3a) (2
mol %), PMHS (4 equiv), and t-BuOH (4 equiv) were used unless otherwise
noted. [Substrate] ) 0.5 M. b rt ) ∼22 °C. c Yield of the isolated product.
d Determined by chiral HPLC.
Intriguingly, the ee values of the nitrile substrates (1b, 1c)
bearing halogen substituents at the para and meta position
of the phenyl ring were highly sensitive to reaction temper-
ature. With these substrates, higher levels of enantioselec-
tivities were observed when the reactions were carried out
at room temperature rather than at 0 °C (entries 1-3 and
4-7). This trend is in contrast to the observed results with
(E)-1a (entries 1 and 8, Table 1) and (Z)-1e (entries 11 and
Acknowledgment. This work was supported by a Korea
Research Foundation grant funded by the Korean Govern-
ment (KRF-2004-205-C00114). LC and GC equipment was
supported by the Faculty Research Fund 2005, Sungkyun-
kwan University. We thank Solvias for supplying the ligands
used in this study.
(14) Judged by comparison of the retention time of each enantiomer on
HPLC.
(15) Tinv is the temperature at which two distinct linear regions intercept
in the Eyring graph: (a) Eyring, H. J. Chem. Phy. 1935, 3, 107. For other
recent examples of inverse temperature dependence in asymmetric catalysis,
see: (b) Fontes, M.; Verdaguer, X.; Sola`, L.; Perica`s, M. A.; Riera, A. J.
Org. Chem. 2004, 69, 2532. (c) Reboule, I.; Gil, R.; Collin, J. Tetrahedron:
Asymmetry 2005, 16, 3881. (d) Haag, D.; Runsink, J.; Scharf, H.-D.
Organometallics 1998, 17, 398. (e) Muzart, J.; He´nin, F.; Aboulhoda, S. J.
Tetrahedron: Asymmetry 1997, 8, 381.
Supporting Information Available: Experimental pro-
cedures and characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
(16) See the Supporting Information for the Eyring diagram for the
reduction of (E)-1c, although more detailed studies are needed to obtain
the exact Tinv for 1b and 1c.
OL0712071
Org. Lett., Vol. 9, No. 14, 2007
2751