A new and effective method for providing optically active monosubstituted malononitriles: Selective reduction of α,β-unsaturated dinitriles catalyzed by copper hydride complexes

Article abstract of DOI:10.1016/j.tetasy.2005.11.013

A copper hydride complex, which was generated in situ from CuOt-Bu, BINAP, and PhSiH₃, was found to be a highly effective catalyst for the reduction of the CC of α,β-unsaturated dinitriles. In addition to CuOt-Bu, some air and moisture stable C

Full text of DOI:10.1016/j.tetasy.2005.11.013

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 4010–4014
A new and effective method for providing optically
active monosubstituted malononitriles: selective reduction of
a,b-unsaturated dinitriles catalyzed by copper hydride complexes
Yunlai Ren, Xianlun Xu,* Kunpeng Sun and Jian Xu
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences and Graduate School of the Chinese Academy of Sciences, 342 Tianshui Road, Lanzhou 730000, China
Received 20 September 2005; revised 6 November 2005; accepted 10 November 2005
Abstract—A copper hydride complex, which was generated in situ from CuOt-Bu, BINAP, and PhSiH3, was found to be a highly
effective catalyst for the reduction of the C@C of a,b-unsaturated dinitriles. In addition to CuOt-Bu, some air and moisture stable
Cu salts were also effective as catalyst precursors in this reduction. Herein, we have developed an effective method for providing
optically active monosubstituted malononitriles.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
R1
CN
R1
R2
CN
R3
CuH
R
2
R
3
The selective reduction of the C@C units conjugated
with electron-withdrawing groups is an important multi-
step transformation in synthetic organic chemistry.1
Amongst these types of reactions, selective reduction
of a C@C conjugated with a cyano group has long
been a difficult synthetic problem, because it often pro-
ceeds with concomitant decyanation, reduction of the
nitrile moiety, hydrodimerization, and polymerization.2
Recently, some excellent reducing reagents such as
1,4-dihydropyridine ester,3 2-phenylbenzimidazoline,1,4
indium metal,5 2-phenylbenzothiazoline,6 and indium
hydride,7,8 have been found. However, the number of
examples of the catalytic reduction of the C@C of a,b-
unsaturated dinitriles is still scant. To the best of our
knowledge, there is only one example of an asymmetric
reduction of the carbon–carbon double bond of a,b-
unsaturated dinitriles.9 In this example, a chiral dia-
mine–ruthenium complex was used as catalyst with the
obtained enantioselectivities being unsatisfactory.
Scheme 1. Paquetteꢀs method for the reduction of C@C bonds
conjugated with a cyano group.
have been also found to be effective reducing reagents
in the reduction of C@C bonds conjugated with a cyano
group (Scheme 1). However, the use of copper hydride
complexes was not in a catalytic amount.24 Inspired by
these results, we attempted to use a catalytic amount
of copper hydride complexes to finish this reaction,
and were pleased to find that the copper hydride com-
plexes displayed high catalytic activity in the reduction
of a,b-unsaturated dinitriles. In order to optimize the
procedure for asymmetric reduction of the carbon–car-
bon double bonds of a,b-unsaturated dinitriles, we first
used ( )-BINAP as the ligand for the catalyst. Then, by
applying the optimized procedure, we investigated the
asymmetric reduction of the carbon–carbon double
bonds of a,b-unsaturated dinitriles (Scheme 2).
Recently, copper hydride complexes have been found to
be highly effective catalysts for the conjugate reduction
of a,b-unsaturated carbonyl complexes10–20 and nitro-
alkenes.21–23 In addition, copper hydride complexes
2. Results and discussion
In order to search for an optimized procedure for the
asymmetric reduction of the carbon–carbon double
bonds of a,b-unsaturated dinitriles, we first used
*
Corresponding author. Tel.: +86 931 4968537; fax: +86 931
8274069; e-mail: xlxu@ns.lzb.ac.cn
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.11.013

Y. Ren et al. / Tetrahedron: Asymmetry 16 (2005) 4010–4014
4011
PPh2
PPh2
R1
R2
CN
CN
R1
R2
CN
CN
5% Cu salt, 5% (S)-BINAP
*
1.2 eq. PhSiH3, 4 mL THF
(S)-BINAP
Scheme 2. Our method for the reduction of C@C conjugated with cyano group.
( )-BINAP as a ligand for the catalyst. The catalyst was
generated in situ from CuCl, NaOt-Bu, ( )-BINAP, and
PhSiH3. The desired product was obtained in very low
yield (8%) after 24 h. The low yield possibly resulted
from the concomitant product (NaCl), which could pos-
sibly inhibit catalytic activity. A similar problem was
also reported by Carreira in the catalytic conjugate
reduction of disubstituted nitroalkenes.21–23 As a result,
we used isolated CuOt-Bu to enhance the reaction yield;
a yield of 89% was obtained after 24 h (Scheme 3). It is
unfortunate, however, that CuOt-Bu is an extremely air-
and moisture-sensitive complex, which is a drawback to
the broad application of this process. These questions
prompted us to search for other air stable copper
sources to replace the air and moisture sensitive CuOt-
Bu.
Recently, it was observed by Buchwald that the addition
of some alcohols could result in the rate acceleration of
the conjugate reduction of unsaturated esters.18 As a
result, we also added some alcohols to optimize our
reaction system (Table 1, entries 5–13). When three
equivalents of t-BuOH were added to the reaction mix-
ture, a yield of 90% was obtained after 6 h (Table 1,
entry 5). Other alcohols, such as EtOH, t-AmOH, and
i-PrOH, also enhanced the reaction rate. However, with
three equivalents of MeOH, rapid gas (H2) evolution
was observed, and no reduction was observed even after
10 h.
Among the screened catalyst precursors, CuF2 and some
copper carboxylates turned out to be highly effective in
this reaction (Table 1). However, when Cu(NO3)2Æ3H2O
and Cu(SO4)2Æ5H2O were used, low yields were obtained
after 12 h (Table 1, entries 11 and 12). As reported in the
previous literature,25 an oxygen acceleration effect was
observed in hydrosilylation of ketones catalyzed by
copper fluoride–phosphine complexes. This finding
prompted us to examine exposure of our system to air
(CuF2 was used as copper source); however, it was
unfortunate that the presence of air led to significant
inhibition of the reduction.
CN
NC
CN
NC
5% CuOtBu, 5% ( )-BINAP
1.2 eq. PhSiH3, 4 mL THF
89% yield
Scheme 3.
Fortunately, some copper carboxylates and other cop-
per salts were also effective as catalyst precursors (Table
1, entries 2–13). For example, with the Cu(OAc)2 sys-
tem, the product was obtained in high yield after 24 h.
Air and moisture stable Cu(OAc)2ÆH2O was also as
effective as Cu(OAc)2 in the reaction. However, it was
not satisfactory that the above reactions required a long
reaction time.
The above optimization studies revealed that the best
results were obtained when 5 mol % of Cu(OAc)2ÆH2O,
5 mol % of ( )-BINAP and 3 equiv of t-BuOH were
used. Applying this optimized procedure [instead of
( )-BINAP, (S)-BINAP was used], we investigated the
asymmetric reduction of the carbon–carbon double
bonds of a,b-unsaturated dinitriles, and up to 93% ee
was obtained (Table 2). When both the substituted
groups of 1,1-dicyanoalkene were alkyl groups, a good
yield was obtained, although the observed ee was low
(Table 2, entry 1). When one of the two substituted
groups was a benzene derivative, most of the obtained
yields and enantioselectivities were satisfying (Table 2,
entries 2–10). In addition, the electronic properties of
the substrates had a remarkable effect on the enantiose-
lectivity of this reaction. a-Methyl-p-chlorobenzylidene-
malononitrile gave only 68% ee (Table 2, entry 4),
whereas a-methylbenzylidenemalononitrile gave 80%
ee (Table 2, entry 2).
Table 1. Catalytic reduction of C@C in a-methylbenzylidenemalono-
nitrile with copper hydride complexes generated in situ from Cu salts,
a
(
)-BINAP and PhSiH3
Entry Cu precursor
Alcohol
Time (h) Yield (%)b
1
2
3
4
5
6
7
8
CuOt-Bu
CuOAc
Cu(OAc)2
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(acac) Æ1/2H2O
—
—
—
—
t-BuOH
t-AmOH
i-PrOH
EtOH
t-BuOH
24
24
24
24
6
8
6
8
6
89
91
82
86
90
79
81
56
79
83
21
15
85
3. Conclusion
9
10
11
12
13
Cu(CF3COO)2ÆH2O t-BuOH
6
In conclusion, some copper hydride complexes were
found to be highly effective catalysts in the reduction
of the C@C of a,b-unsaturated dinitriles (high yields
were obtained after 6 h). Moreover, the asymmetric
reduction of the carbon–carbon double bonds of a,b-
unsaturated dinitriles was also investigated. Herein, it
Cu(NO3)2Æ3H2O
Cu(SO4)2Æ5H2O
CuF2
t-BuOH
t-BuOH
t-BuOH
12
12
6
a Reaction conditions and analytical procedures are shown in
Section 4.
b Isolated yield.

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Y. Ren et al. / Tetrahedron: Asymmetry 16 (2005) 4010–4014
Table 2. Catalytic asymmetric reduction of the C@C in a,b-unsaturated dinitriles with copper hydride complexes generated in situ from
a
Cu(OAc)2ÆH2O, (S)-BINAP and PhSiH3
Entry
Substrate
Product
Time (h)
6
Yield (%)b
87
ee (%)c
22
CN
CN
CN
CN
1
1
CN
CN
CN
CN
2
3
4
5
6
7
6
6
90
87
72
79
85
80
80d
83
68
87
76
91
2
CN
CN
CN
CN
3
CN
CN
CN
10
12
10
8
CN
Cl
Cl
4
CN
CN
CN
CN
5
6
CN
CN
CN
CN
O
O
CN
CN
CN
CN
MeO
MeO
7
CN
CN
CN
CN
8
10
10
12
65
59
47
90
90
93
8
CN
CN
CN
9
CN
MeS
MeS
MeS
9
O
O
N
CN
CN
N
CN
CN
10
MeS
10
CN
CN
CN
CN
11
12
9
65
18
83
39
11
CN
CN
12
CN
CN
12
a Reaction conditions and analytical procedures are shown in Section 4.
b Isolated yield.
c The ee was determined by HPLC analysis using a chiral OD column.
d The absolute configuration was R as determined by comparison of the specific rotation.28
is important that we have developed a new and effective
method for providing optically active monosubstituted
malononitriles from ketones and malononitrile
(Scheme 4).26 Although the obtained enantioselectivities
CN
NC
R1
CN
NC
R1
R2
Catalytic asymmetric reduction
CN
Al2O3
NC
+
O
*
R2
R2
R1
Monosubstituted malononitrile
Scheme 4.

Y. Ren et al. / Tetrahedron: Asymmetry 16 (2005) 4010–4014
4013
1
were moderate (up to 93% ee), we believe that excellent
enantioselectivities can be obtained by searching for
other chiral ligands. This search is currently underway
in our laboratory.
1,1-Dicyano-2,4-dimethylpentane 1: H NMR (DMSO-
d6): d = 3.64 (d, J = 5.2 Hz, 1H, CNCHCN), 2.18–2.25
(m, 1H), 1.61–1.67 (m, 1H), 1.31–1.39 (m, 2H), 1.19
(d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H), 0.88 (d,
J = 6.4 Hz, 3H); 13C NMR (DMSO-d6): d = 112.3,
111.8, 42.5, 33.3, 29.4, 24.9, 22.9, 21.4, 16.7.
4. Experimental
1,1-Dicyano-2-phenylpropane 2: 1H NMR (CDCl3):
d = 7.31–7.42 (m, 5H, Ph), 3.86 (d, J = 6.4 Hz, 1H,
CNCHCN), 3.42–3.45 (m, 1H, PhCH), 1.62 (d,
J = 6.8 Hz, 3H, CH3); 13C NMR (CDCl3): d = 138.1,
129.1, 128.7, 127.2, 112.0, 111.9, 40.9, 31.0, 17.6.
4.1. Reagents and materials
a,b-Unsaturated dinitriles were readily obtained in one
step standard procedures as described in previous
literatures.26 THF was freshly distilled from sodium
benzophenone ketyl under argon before use. i-PrOH,
t-BuOH, and t-AmOH (tert-amyl alcohol) were freshly
distilled from CaH2 under argon before use. CuCl was
prepared from CuCl2 and Cu.27 NaOt-Bu was pur-
chased from Aldrich and used as received. BINAP was
purchased from Alfa Aesar and used as received.
NaBH4 and other Cu(I) and Cu(II) salts were purchased
from Chinese Tianjin Chemical Reagent Co. and used as
1,1-Dicyano-2-(4-methylphenyl)propane 3: 1H NMR
(CDCl3): d = 7.14–7.34 (m, 4H, Ph), 3.86 (d,
J = 6.0 Hz, 1H, CNCHCN), 3.42–3.45 (m, 1H, PhCH),
2.38 (s, 3H, PhCH3), 1.63 (d, 3H, J = 6.8 Hz, CH3); 13
C
NMR (CDCl3): d = 138.4, 135.1, 129.7, 127.0, 112.1,
111.8, 40.5, 31.1, 20.9, 17.6.
1,1-Dicyano-2-(4-chlorophenyl)propane 4: 1H NMR
(CDCl3): d = 7.16–7.38 (m, 4H, Ph), 3.85 (d,
J = 6.4 Hz, 1H, CNCHCN), 3.41–3.46 (m, 1H, PhCH),
1.61 (d, 3H, J = 7.2 Hz, CH3); 13C NMR (CDCl3):
d = 136.5, 134.7, 129.3, 128.6, 111.7, 111.5, 40.4, 31.0,
20.8.
1
received. H NMR spectra were recorded as CDCl3 or
DMSO-d6 solutions using 400 MHz spectrometer; peak
positions are reported as d (ppm) downfield from inter-
nal Me4Si; peaks are reported as singlet (s), doublet (d),
triplet (t), quartet (q), or multiplet (m). 13C NMR were
recorded as CDCl3 solutions at 400 MHz; peak posi-
tions are reported as d (ppm). HPLC analyses were per-
formed on a Shimadzu VP liquid chromatograph
equipped with a chiral OD column. Optical rotations
were measured on a Perkin–Elmer 341 polarimeter.
1
1,1-Dicyano-2-(4-isopropylphenyl)propane 5: H NMR
(CDCl3): d = 7.17–7.22 (m, 4H, Ph), 4.19 (d, J =
6.0 Hz, 1H, CNCHCN), 2.44 (s, 3H), 1.73 (m, 1H),
1.07–1.09 (m, 1H), 0.83 (d, J = 6.4 Hz, 3H), 0.72 (d,
J = 6.4 Hz, 3H). Anal. Calcd for C14H16N2: C, 79.21;
H, 7.60; N,13.20. Found: C, 79.28; H, 7.64; N, 13.08.
4.2. Representative procedure for the catalytic reduction
of the carbon–carbon double bonds of a,b-unsaturated
dinitriles with copper hydride complexes
1,1-Dicyano-2-(2-furyl)propane 6: 1H NMR (CDCl3):
d = 6.01–7.52 (m, 3H, Ph), 4.05 (d, J = 7.2 Hz, 1H,
CNCHCN), 3.87–4.11 (m, 1H, PhCH), 1.83 (d,
J = 6.4 Hz, 3H, CH3); 13C NMR (CDCl3): d = 150.2,
138.0, 110.6, 106.2, 103.9, 39.4, 36.3, 16.6.
Copper salt (0.05 mmol) and BINAP (0.05 mmol) were
added into a flame-dried 10 ml round-bottomed flask
(RBF). Then, the mixture was stirred in THF (2 ml) at
room temperature for 30 min to give a solution. A
flame-dried 5 ml pear-bottomed flask (PBF) was cooled
under argon and charged with THF (2 ml), and then 1,1-
dicyanoalkene (1 mmol) was added at room tempera-
ture. The RBF was then charged with PhSiH3
(1.2 mmol) at room temperature to give a solution,
which was then cooled to À30 °C. The contents of the
PBF were then added to the RBF via cannula. Over
the course of the reaction, the corresponding alcohol
(3 mmol) and water (0.2 mmol) were continuously
added in 3 h. Upon completion, the reaction mixture
was quenched with H2O (5 ml) and stirred for 3 h. Puri-
fication of the mixture by column chromatography pro-
vided the desired product. The product was determined
1,1-Dicyano-2-(6-methoxynaphthyl)propane 7: 1H NMR
(CDCl3): d = 7.10–7.76 (m, 6H), 3.90 (s, 3H), 3.88 (d,
J = 2.8 Hz, 1H, CNCHCN), 3.53–3.56 (m, 1H), 1.69
(d, 3H, J = 7.2 Hz). Anal. Calcd for C16H14N2O: C,
76.78; H, 5.64; N, 11.19. Found: C, 76.65; H, 5.57; N,
11.13.
1,1-Dicyano-2-phenyl-3-methylbutane 8: 1H NMR
(CDCl3): d = 7.28–7.45 (m, 5H), 3.73 (d, J = 6.4 Hz,
1H), 3.61–3.69 (m, 1H), 2.15–2.20 (m, 1H), 0.81–0.89
(m, 6H). Anal. Calcd for C13H14N2: C, 78.75; H, 7.12;
N, 14.13. Found: C, 78.81; H, 7.14; N, 14.02.
by H NMR and 13C NMR spectra. The ee was deter-
1,1-Dicyano-2-(4-methylthiophenyl)-3-methylbutane 9:
1H NMR (CDCl3): d = 7.06–7.31 (m, 4H), 3.58 (d,
J = 6.4 Hz, 1H), 3.55–3.59 (m, 1H), 2.57 (s, 3H), 1.76–
1.83 (m, 1H), 0.83–0.86 (m, 6H). Anal. Calcd for
C14H16N2S: C, 68.81; H, 6.60; N, 11.46. Found: C,
68.72; H, 6.64; N, 11.53.
1
mined by HPLC analysis using a chiral OD column.
The absolute configuration was determined by the com-
parison with the specific rotation in the literature
report.28
The products of the reduction are simple and fami-
1
liar.1–9,28,29 As a result, only H NMR, 13C NMR spec-
1,1-Dicyano-2-(4-methylthiophenyl)-2-morpholinoethane
10: H NMR (DMSO-d6): d = 7.16–7.31 (m, 4H), 3.91
(d, J = 6.0 Hz, 1H), 3.56 (s, 3H), 3.34 (d, J = 6.4 Hz,
1
tra or elemental analysis data for the products in Table 2
are shown as follows:

4014
Y. Ren et al. / Tetrahedron: Asymmetry 16 (2005) 4010–4014
7. Ranu, B. C.; Samanta, S. Tetrahedron Lett. 2002, 43,
7405–7407.
8. Ranu, B. C.; Samanta, S. Tetrahedron 2003, 59, 7901–
7906.
1H), 2.43–2.57 (m, 4H), 1.21–1.30 (m, 4H). Anal. Calcd
for C15H17N3OS: C, 62.69; H, 5.96; N, 14.62. Found: C,
62.53; H, 5.88; N, 14.69.
9. Xue, D.; Chen, Y. C.; Cui, X.; Wang, Q. W.; Zhu, J.;
Deng, J. G. J. Org. Chem. 2005, 70, 3584–3591.
10. Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am.
Chem. Soc. 1988, 110, 291–293.
11. Mahoney, W. S.; Stryker, J. M. J. Am. Chem. Soc. 1989,
111, 8818–8823.
12. Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E.
M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473–
9474.
1-Phenyl-3-methyl-4,4-dicyano-1-butene 11: 1H NMR
(CDCl3): d = 7.34–7.40 (m, 5H), 6.58–6.68 (m, 1H),
6.07–6.11 (m, 1H), 3.74 (d, J = 5.2 Hz, 1H), 3.03–3.05
(m, 1H), 1.45 (d, J = 6.8 Hz, 3H). Anal. Calcd for
C13H12N2: C, 79.56; H, 6.16; N, 14.27. Found: C,
79.38; H, 6.19; N, 14.34.
1
Monosubstituted malononitrile 12: H NMR (CDCl3):
13. Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald,
S. L. J. Am. Chem. Soc. 2000, 122, 6797–6798.
14. Chen, J. X.; Daeuble, J. F.; Brestensky, D. M.; Stryker,
J. M. Tetrahedron 2000, 56, 2153–2166.
15. Yun, J.; Buchwald, S. L. Org. Lett. 2001, 3, 1129–1131.
16. Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 2892–2893.
d = 5.82 (s, 1H), 3.66–3.73 (m, 1H), 2.41–2.49 (m, 1H),
2.31 (d, J = 4.8 Hz, 2H), 2.13 (d, J = 9.2 Hz, 2H), 1.91
(s, 3H), 0.98 (s, 6H). Anal. Calcd for C12H16N2: C,
76.55; H, 8.57; N, 14.88. Found: C, 76.63; H, 8.61; N,
14.75.
17. Jurkauskas, V.; Sadighi, J. P.; Buchwald, S. L. Org. Lett.
2003, 5, 2417–2420.
Acknowledgements
18. Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem.
Soc. 2003, 125, 11253–11258.
19. Lipshutz, B.; Servesko, J. M.; Taft, B. R. J. Am. Chem.
Soc. 2004, 126, 8352–8353.
20. Lipshutz, B.; Servesko, J. M.; Petersen, T. B.; Papa, P. P.;
Lover, A. A. Org. Lett. 2004, 6, 1273–1275.
21. Czekelius, C.; Carreira, E. M. Angew. Chem. 2003, 115,
4941–4943.
The authors wish to thank National Nature Science
Foundation of China (No. 29933042) for financial
support.
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