Rh-catalyzed one-pot reductive alkylation of malononitrile under transfer hydrogenation conditions

Article abstract of DOI:10.1080/00397911.2010.481741

Efficient synthesis of monosubstituted malononitriles was achieved by one-pot reductive alkylation of malononitrile with carbonyl compounds via [Cp*RhCl₂]₂-catalyzed transfer hydrogenation reaction.

Full text of DOI:10.1080/00397911.2010.481741

Synthetic Communications1, 41: 1218–1226, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.481741
Rh-CATALYZED ONE-POT REDUCTIVE ALKYLATION
OF MALONONITRILE UNDER TRANSFER
HYDROGENATION CONDITIONS
Jiashou Wu and Huajiang Jiang
School of Pharmaceutical and Chemical Engineering, Taizhou University,
Taizhou, China
GRAPHICAL ABSTRACT
Abstract Efficient synthesis of monosubstituted malononitriles was achieved by one-pot
reductive alkylation of malononitrile with carbonyl compounds via [CpꢀRhCl2]2-catalyzed
transfer hydrogenation reaction.
Keywords Monosubstituted malononitrile; reductive alkylation; rhodium; transfer
hydrogenation
The formation of carbon–carbon bonds is one of the most important reactions for
the construction of useful organic molecules in organic synthesis.[1] Synthesis of
monosubstituted malononitriles via carbon–carbon bond formation has been a dif-
ficult synthetic problem in organic chemistry.[2] Alkylation of malononitrile with
alkyl halides is the most direct way to monosubstituted malononitriles, but this
method has shortcomings such as using excess of malononitrile to avoid overalkyla-
tion and poor yield with secondary alkyl halide even after long reaction times.[2b,c]
A
more selective route to monosubstituted malononitrile is the reduction of alkylide-
nedinitrile, which is prepared by the Knoevenagel condensation of malononitrile
with a ketone or aldehyde.[3] Although a one-pot, two-step synthesis of monosubsti-
tuted malononitrile without the isolation of alkylidenedinitrile has been reported,[4]
from a synthetic point of view, the development of a one-step method to monosub-
stituted malononitrile is more attractive.[5] Recently, organocatalytic tandem
Knoevenagel=hydrogenation reactions to monosubstituted malononitriles have been
developed, but the method still suffers from drawbacks such as producing pyridine
by-product,[5a–d] using excess aldehyde for generation of reducing agent with
o-phenylenediamine, and limited substrate scope.[5e,f] Dunham et al. reported a
Received July 9, 2009.
Address correspondence to Jiashou Wu, School of Pharmaceutical and Chemical Engineering,
Taizhou University, Taizhou, China. E-mail: jsw79@tzc.edu.cn
1218

ONE-POT REDUCTIVE ALKYLATION OF MALONONITRILE
1219
convenient one-step method to primary and secondary monosubstituted malononi-
triles with sodium borohydride as the only reagent.[6] However, in most cases the
reaction proceeded with a large excess of carbonyl substrates, and the competitive
carbonyl reduction was also a problem.
Recently, Deng et al. developed ruthenium-catalyzed transfer hydrogenation of
[3e–g]
In our continuous study on transition metal–catalyzed
=
activated C C bonds.
transfer hydrogenation reactions, we found that one-step reductive alkylation of
malononitrile with carbonyl compounds proceeded smoothly under [CpꢀRhCl2]2-
catalyzed transfer hydrogenation condition using HCOOH–Et3N (5:2) as the hydro-
gen source.
In preliminary studies, we tried the reaction of benzaldehyde and malononitrile
in the presence of 0.5 mol% [RuCl2(p-cymene)]2 in CH2Cl2 using HCOOH–Et3N
(5:2) as the hydrogen source. Unfortunately, no desired reductive alkylation product
was detected, and a Knoevenagel condensation product was isolated in 82% yield
after 1 h at 40 ꢁC. A better result was obtained with [CpꢀIrCl2]2, giving benzylmalo-
nonitrile in 30% yield, but still with 58% yield of benzylidenemalononitrile intermedi-
ate. To our delight, benzylmalononitrile could be obtained as the only product in
90% yield within 1 h at 40 ꢁC when [CpꢀRhCl2]2 was used. CH2Cl2 was found to
be the solvent of choice. Other solvents such as dimethylformamide (DMF), EtOH,
and CH3CN gave relatively poor yields with 85%, 29%, and 35% yields, respectively.
An attempt to run the reaction in neat formic acid–triethylamine azeotropic mixture
resulted in 69% yield. Thus, the one-step reductive alkylation of malononitrile with
benzaldehyde was best effected with [CpꢀRhCl2]2 using HCOOH–Et3N (5:2) as the
hydrogen source in CH2Cl2. With optimal reaction conditions in hand (Table 1,
Table 1. Optimization of reaction conditionsa
Entry
Metal complex
Solvent
Yield (%)b
c
1
[RuCl2(p-cymene)]2
[CpꢀIrCl2]2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
—
2d
3
30
90
85
29
35
69
[CpꢀRhCl2]2
[CpꢀRhCl2]2
[CpꢀRhCl2]2
[CpꢀRhCl2]2
[CpꢀRhCl2]2
4
5e
6f
7
EtOH
CH3CN
g
—
aReaction conditions: 0.5 mmol benzaldehyde, 0.5 mmol malononitrile, metal complex (0.5 mol%),
1.5 mL solvent, and 0.2 mL HCOOH–Et3N (5:2) at 40 ꢁC for 1 h.
bIsolated yield.
cBenzylidenemalononitrile was isolated in 82% yield.
dBenzylidenemalononitrile also isolated (58%).
eBenzylidenemalononitrile also isolated (32%).
fBenzylidenemalononitrile also isolated (62%).
gWith neat formic acid–triethylamine azeotropic mixture (0.5 mL).

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J. WU AND H. JIANG
Table 2. One-pot reductive alkylation of malononitrile with aldehydes=ketonesa
Entry
1
Aldehyde=ketone
Time
Product 2
Yield (%)b
1
90
2
3
4
5
1
83
93
78
84
1
2.5
2.5
6
2
75
7
8
9
8
7
1
70
83
80
10
1
80
(Continued )

ONE-POT REDUCTIVE ALKYLATION OF MALONONITRILE
1221
Yield (%)b
74
Table 2. Continued
Entry
11
Aldehyde=ketone
Time
0.5
Product 2
12c
2
85
13d
14
4
4
3
70
83
84
15
16
8
70
aReaction condition: 0.5 mmol aldehyde=ketone, 0.5 mmol malononitrile, [CpꢀRhCl2]2 (0.5 mol%),
1.5 mL CH2Cl2, and 0.2 mL HCOOH–Et3N (5:2) at 40 ꢁC.
bIsolated yield.
c1.2 equiv. of aldehyde was used due to evaporation.
d1.2 equiv. of ketone was used due to evaporation.
entry 3), we assessed the scope of the one-pot reductive alkylation reaction by react-
ing a range of carbonyl compounds with malononitrile, and the results are summar-
ized in Table 2. The tandem process works very well for a variety of aromatic
aldehydes (Table 2, entries 1–11). Reactions of aldehyde with electron-withdrawing
substituent proceeded successfully in good yields (Table 2, entries 1–6). Relatively
long reaction time was required when more electron-deficient substrate was used
to obtain satisfactory yield (70% and 83% yields for 1 g and 1 h respectively with
the nitro group unaffected). Aldehydes with electron-donating substituents seem
to be more reactive (Table 2, entries 9–11). The reaction of malononitrile and
4-methoxybenzaldehyde 1 k completed within 0.5 h under the present reductive alky-
lation condition to give the desired product in 74% yield (Table 2, entry 11).
Aliphatic aldehyde was also a good substrate (Table 2, entry 12). The substrate scope
was further tested with ketones. Both cyclic and acyclic aliphatic ketones reacted
smoothly (Table 2, entries 13–15). Aromatic ketone was also reactive, although with
relatively low reactivity (70% yield for 1p after 8 h; Table 2, entry 16).

1222
J. WU AND H. JIANG
In summary, we have developed an efficient one-pot method to synthesize
monosubstituted malononitriles via [CpꢀRhCl2]2-catalyzed transfer hydrogenation
reaction using HCOOH–Et3N (5:2) as hydrogen source. The scope and synthetic
applications of this reaction are currently under investigation.
EXPERIMENTAL
NMR spectra were recorded on Varian Mercury-Vx200. Chemical shifts in
NMR spectra are reported in parts per million from tetramethylsilane (TMS) with
solvent resonance as the internal standard (s ¼ singlet, d ¼ doublet, dd ¼ double
doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet, br ¼ broad). All melting points were
measured on a melting apparatus with a microscope and hot stage and were uncor-
rected. All reagents were purchased from commercial sources and were used without
further purification.
General Procedure for the One-Step Reductive Alkylation Reaction
To a solution of aldehyde=ketone (0.5 mmol), malononitrile (0.5 mmol), and
[CpꢀRhCl2]2 (0.5 mol%) in CH2Cl2 (1.5 mL), 0.2 mL HCOOH-Et3N azeotropic mix-
ture was added. The resulting mixture was stirred at 40 ꢁC under Ar for a certain per-
iod of time, made basic by addition of aqueous Na2CO3, and then extracted with
CH2Cl2 (3 mL) three times. The combined organic layers were dried over anhydrous
Na2SO4, concentrated in vacuo, and purified by flash chromatography to afford pure
product 2.
Characterization Data for Monosubstituted Malononitrile 2
Benzylmalononitrile (2a).[4b] White solid, column chromatography (silica
gel, petroleum ether (PE)=EtOAc ¼ 10=1, Rf ¼ 0.54), mp 87.8–88.5 ꢁC. 1H NMR
(200 MHz, CDCl3): d ¼ 7.30 ꢂ 7.43 (m, 5H), 3.91 (t, J ¼ 7.0 Hz, 1H), 3.30 (d,
J ¼ 7.0 Hz, 2H) ppm. 13C NMR (50 MHz, CDCl3): d ¼ 25.3, 36.9, 112.4, 129.1,
129.4, 129.6, 133.2 ppm.
(4-Chlorobenzyl)malononitrile (2b).[4b] White solid, column chromato-
graphy (silica gel, PE=EtOAc ¼ 5=1, Rf ¼ 0.47), mp 92.7–93.5 ꢁC. 1H NMR
(200 MHz, CDCl3): d ¼ 7.38 (dd, J ¼ 2.1, 6.4 Hz, 2H), 7.26 (dd, J ¼ 2.1, 6.4 Hz,
2H), 3.90 (t, J ¼ 6.7 Hz, 1H), 3.25 (d, J ¼ 6.7 Hz, 2H) ppm. 13C NMR (50 MHz,
CDCl3): d ¼ 25.1, 36.2, 112.2, 129.8, 130.8, 131.5, 135.3 ppm.
(4-Bromobenzyl)malononitrile (2c).[4b] White solid, column chromato-
graphy (silica gel, PE=EtOAc ¼ 5=1, Rf ¼ 0.47), mp 95.4–96.0 ꢁC. 1H NMR
(200 MHz, CDCl3): d ¼ 7.54 (d, J ¼ 8.4 Hz, 2H), 7.21 (d, J ¼ 8.4 Hz, 2H), 3.92 (t,
J ¼ 6.9 Hz, 1H), 3.48 (d, J ¼ 6.9 Hz, 2H) ppm. 13C NMR (50 MHz, CDCl3):
d ¼ 25.0, 36.2, 112.2, 123.4, 131.1, 132.0, 132.7 ppm.
(2-Chlorobenzyl)malononitrile (2d).[4b] Colorless liquid, column chromato-
graphy (silica gel, PE=EtOAc ¼ 5=1, Rf ¼ 0.46). 1H NMR (200 MHz, CDCl3):
d ¼ 7.31–7.46 (m, 4H), 4.11 (t, J ¼ 7.9 Hz, 1H), 3.46 (d, J ¼ 7.9 Hz, 2H) ppm.

ONE-POT REDUCTIVE ALKYLATION OF MALONONITRILE
1223
13C NMR (50 MHz, CDCl3): d ¼ 22.9, 35.3, 112.2, 128.0, 130.4, 130.8, 130.9, 132.2,
134.1 ppm.
(2,4-Dichlorobenzyl)malononitrile (2e).[5d] Yellowish solid, column chro-
matography (silica gel, PE=EtOAc ¼ 5=1, Rf ¼ 0.48), mp 61.1–62.8 ꢁC. 1H NMR
(200 MHz, CDCl3): d ¼ 7.47 (s, 1H), 7.32–7.34 (m, 2H), 4.07 (t, J ¼ 7.9 Hz, 1H),
3.43 (d, J ¼ 7.9 Hz, 2H) ppm. 13C NMR (50 MHz, CDCl3): d ¼ 22.8, 34.6, 112.0,
128.4, 129.4, 130.3, 132.9, 134.9, 136.2 ppm.
(3-Bromobenzyl)malononitrile (2f).[7a] White solid, column chromato-
graphy (silica gel, PE=EtOAc ¼ 5=1, Rf ¼ 0.38), mp 41.5–43.5 ꢁC. 1H NMR
(200 MHz, CDCl3): d ¼ 7.50–7.56 (m, 1H), 7.47 (s, 1H), 7.26–7.34 (m, 2H), 3.93 (t,
J ¼ 7.0 Hz, 1H), 3.26 (d, J ¼ 7.0 Hz, 2H) ppm. 13C NMR (50 MHz, CDCl3):
d ¼ 25.0, 36.4, 112.0, 123.4, 128.1, 131.1, 132.3, 132.4, 135.2 ppm.
(4-Nitrobenzyl)malononitrile (2g).[4b] White solid, column chromato-
graphy (silica gel, PE=EtOAc ¼ 2=1, Rf ¼ 0.5), mp 154.5–155.7 ꢁC. 1H NMR
(200 MHz, CDCl3): d ¼ 8.30 (d, J ¼ 8.9 Hz, 2H), 7.55 (d, J ¼ 8.9 Hz, 2H), 4.03 (t,
J ¼ 6.7 Hz, 1H), 3.42 (d, J ¼ 6.7 Hz, 2H) ppm. 13C NMR (50 MHz, CDCl3):
d ¼ 24.7, 36.3, 111.7, 124.8, 130.7, 139.8, 148.4 ppm.
(3-Nitrobenzyl)malononitrile (2h).[4b] Yellowish solid, column chromato-
graphy (silica gel, PE=EtOAc ¼ 3=1, Rf ¼ 0.49), mp 132.2–132.9 ꢁC. 1H NMR
(200 MHz, CDCl3): d ¼ 8.24–8.30 (m, 1H), 8.23 (s, 1H), 7.60–7.74 (m, 2H), 4.06 (t,
J ¼ 6.7 Hz, 1H), 3.43 (d, J ¼ 6.7 Hz, 2H) ppm. 13C NMR (50 MHz, CDCl3):
d ¼ 24.8, 36.2, 111.7, 124.2, 124.5, 130.8, 134.8, 135.6, 148.8 ppm.
(4-Methylbenzyl)malononitrile (2i).[4b] White solid, column chromato-
graphy (silica gel, PE=EtOAc ¼ 5=1, Rf ¼ 0.35), mp 78.5–80.0 ꢁC. 1H NMR
(200 MHz, CDCl3): d ¼ 7.20 (s, 4H), 3.86 (t, J ¼ 7.0 Hz, 1H), 3.23 (d, J ¼ 7.0 Hz,
2H), 2.36 (s, 3H) ppm. 13C NMR (50 MHz, CDCl3): d ¼ 21.4, 25.3, 36.6, 112.6,
129.2, 130.17, 130.19 138.9 ppm.
(3-Methylbenzyl)malononitrile (2j).[7b] Yellowish solid, column chromato-
graphy (silica gel, PE=EtOAc ¼ 5=1, Rf ¼ 0.37), mp 40.8–41.5 ꢁC. 1H NMR
(200 MHz, CDCl3): d ¼ 7.12–7.28 (m, 4H), 3.88 (t, J ¼ 7.0 Hz, 1H), 3.24 (d,
J ¼ 7.0 Hz, 2H), 2.37 (s, 3H) ppm. 13C NMR (50 MHz, CDCl3): d ¼ 21.6, 25.2,
36.9, 112.5, 126.3, 129.4, 129.8, 130.0, 133.1, 139.4 ppm. IR (KBr): 2916, 2870,
2256, 1610, 1591, 1489, 1446, 885, 777, 699 cmꢂ1. MS (EI) m=z 170 (M)þ, 171 (M
þH)þ. Anal. calcd. for C11H10N2: C, 77.62; H, 5.92; N, 16.46. Found: C, 77.50;
H, 5.95; N, 16.36.
(4-Methoxybenzyl)malononitrile (2k).[4b] White solid, column chromato-
graphy (silica gel, PE=EtOAc ¼ 5=1, Rf ¼ 0.47), mp 88.5–89.1 ꢁC. 1H NMR
(200 MHz, CDCl3): d ¼ 7.25 (dd, J ¼ 2.1, 6.5 Hz, 2H), 6.90 (dd, J ¼ 2.1, 6.4 Hz,
2H), 3.86 (t, J ¼ 7.0 Hz, 1H), 3.82 (s, 3H), 3.24 (d, J ¼ 7.0 Hz, 2H) ppm. 13C NMR
(50 MHz, CDCl3): d ¼ 25.5, 36.2, 55.6, 112.6, 114.9, 125.2, 130.6, 160.1 ppm.

1224
J. WU AND H. JIANG
(2-Methylpropyl)malononitrile (2l).[6] Colorless liquid, column chromato-
graphy (silica gel, PE=EtOAc ¼ 5=1, Rf ¼ 0.44). 1H NMR (200 MHz, CDCl3):
d ¼ 3.71 (t, J ¼ 7.6 Hz, 1H), 1.89–1.99 (m, 3H), 1.02 (d, J ¼ 6.2 Hz, 6H) ppm. 13C
NMR (50 MHz, CDCl3): d ¼ 21.0, 21.7, 26.2, 39.3, 112.9 ppm.
sec-Butylmalononitrile (2m).[6] Colorless liquid, column chromatography
1
(silica gel, PE=EtOAc ¼ 5=1, Rf ¼ 0.42). H NMR (200 MHz, CDCl3): d ¼ 3.67 (d,
J ¼ 6.2 Hz, 1H), 2.01–2.20 (m, 1H), 1.42–1.78 (m, 2H), 1.25 (d, J ¼ 6.7 Hz, 3H),
1.01 (t, J ¼ 7.3 Hz, 3H) ppm. 13C NMR (50 MHz, CDCl3): d ¼ 11.4, 16.8, 26.9,
29.2, 37.4, 112.0, 112.6 ppm.
(1-Ethylpropyl)malononitrile (2n).[6] Colorless liquid, column chromato-
graphy (silica gel, PE=EtOAc ¼ 5=1, Rf ¼ 0.45). 1H NMR (200 MHz, CDCl3):
d ¼ 3.79 (d, J ¼ 4.9 Hz, 1H), 1.82–1.97 (m, 1H), 1.59–1.73 (m, 4H), 1.01 (t, J ¼ 7.3 Hz,
6H) ppm. 13C NMR (50 MHz, CDCl3): d ¼ 11.1, 24.0, 26.8, 43.4, 112.5 ppm.
Cyclohexylmalononitrile (2o).[6] Colorless liquid, column chromatography
1
(silica gel, PE=EtOAc ¼ 5=1, Rf ¼ 0.52). H NMR (200 MHz, CDCl3): d ¼ 3.57 (d,
J ¼ 5.6 Hz, 1H), 1.69–2.05 (m, 6H), 1.09–1.45 (m, 5H) ppm. 13C NMR (50 MHz,
CDCl3): d ¼ 25.3, 25.5, 29.7, 30.2, 39.7, 112.2 ppm.
(1-Phenylethyl)malononitrile (2p).[6] Colorless liquid, column chromato-
graphy (silica gel, PE=EtOAc ¼ 8=1, Rf ¼ 0.43). 1H NMR (200 MHz, CDCl3):
d ¼ 7.34–7.47 (m, 5H), 3.90 (d, J ¼ 6.1 Hz, 1H), 3.43–3.58 (m, 1H), 1.71 (d,
J ¼ 7.0 Hz, 3H) ppm. 13C NMR (50 MHz, CDCl3): d ¼ 18.0, 31.4, 41.4, 112.0,
112.2, 127.5, 129.1, 129.5, 138.4 ppm.
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