Monosubstituted malononitriles: Efficient one-pot reductive alkylations of malononitrile with aromatic aldehydes

Article abstract of DOI:10.1055/s-2007-990945

A powerful new one-pot method has been developed for the reductive alkylation of malononitrile with aromatic aldehydes. This new procedure has vastly improved the yield and efficiency of the process, and increased the scope of the aromatic aldehydes. Inco

Full text of DOI:10.1055/s-2007-990945

PAPER
279
Monosubstituted Malononitriles: Efficient One-Pot Reductive Alkylations of
Malononitrile with Aromatic Aldehydes
Efficient
One-
a
Pot
R
educti
r
ve
A
lky
i
lations
b
of
M
alononi
a
trile Tayyari,a Dwight E. Wood,a Phillip E. Fanwick,b Robert E. Sammelson*a
a
Department of Chemistry, Ball State University, Muncie, IN 47306-0445, USA
Fax +1(765)2856505 ; E-mail: resammelson@bsu.edu
b
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
Received 13 September 2007
O
O
Abstract: A powerful new one-pot method has been developed for
the reductive alkylation of malononitrile with aromatic aldehydes.
This new procedure has vastly improved the yield and efficiency of
the process, and increased the scope of the aromatic aldehydes. In-
corporating water as the catalyst in ethanol for the condensation
step allows stoichiometric amounts of malononitrile and aldehyde
to be employed. The reduction step takes place quickly and effi-
ciently with sodium borohydride to give monosubstituted malono-
nitriles via filtration or extraction. The product from 2-
quinolinecarboxaldehyde quickly rearranges to a novel indolizine,
while alkylation of the monosubstituted derivative provides an un-
symmetrically disubstituted malononitrile that does not rearrange.
NC
R
CN
NC
R
CN
R'
R
H
R
R'
NC
CN
NaBH4
NaBH4
Scheme 1
benzaldehyde and substituted benzaldehydes with elec-
tron-withdrawing groups.6 Two independent reports have
recently shown that the Knoevenagel condensation step
between malononitrile and aromatic aldehydes can simply
occur in ethanol3c or water3d with no added catalysts. In-
deed, water can be an excellent reaction accelerant for a
variety of organic reactions7 and the green chemistry im-
plications of utilizing aqueous media for C–C bond for-
mations has been fruitful.8 Our continued work, reported
here, utilized this discovery to vastly improve the yield,
efficiency, and scope of aromatic aldehydes for the reduc-
tive alkylation.
Key words: malononitrile, aldehydes, condensation, reduction,
heterocycles
Carbon–carbon bond forming reactions are extremely im-
portant and often a difficult task in organic synthesis for
the production of complex targets from simpler building
blocks.1 Synthesis of monosubstituted malononitriles via
C–C bond formation has been a challenging problem for
organic chemists.2 The most direct route to monosubsti-
tuted malononitriles is the alkylation of malononitrile, but
this method generally produces various amounts of disub-
stituted malononitriles from overalkylation. Moreover,
unreacted malononitrile is mostly present in the product
mixture. More selective methods for the synthesis of
monosubstituted malononitriles have generally followed a
two reaction sequence. The first step is a Knoevenagel
condensation between malononitrile and an aldehyde or
ketone. The intermediate dicyanoalkene is reduced in a
second step to afford the desired monosubstituted mal-
ononitrile. Recently, there has been a good deal of re-
search on the Knoevenagel condensation3 as well as the
reduction of the electron-deficient olefins.4 Work from
this laboratory has found that sodium borohydride in iso-
propyl alcohol can produce monosubstituted malononi-
triles in good to excellent yields in a single reductive
alkylation step (Scheme 1).5
Our research began with exploring the use of water or eth-
anol for the condensation of malononitriles with benzal-
dehyde. In water at room temperature the reaction oiled
out and it was anticipated that this problem would become
even worse with our intended scope of hydrophobic alde-
hydes. In absolute ethanol the condensation reaction was
extremely sluggish. We found that the reaction was most
efficient with a mixture of water and ethanol. In most
cases we used 95% ethanol with a concentration of 1.0 M
for aldehyde and malononitrile. Table 1 shows the variety
of aldehydes employed and the times required for the con-
densation to be completed. The condensation reactions
could be stirred several days without any complication.
Dilution of the resultant mixture with additional ethanol
and cooling the reaction in an ice-water bath preceded so-
dium borohydride reduction. We have also adopted a sim-
ple aqueous filtration workup for many of the derivatives
(see experimental). This has allowed us to scale reactions
– vanillin (Table 1, entry 13) was performed on a 100
mmol scale. Another advantage of the one-pot synthesis –
particularly on larger scales – is avoiding transfers and
handling of hazardous intermediates.9
The Hantzsch (1,4-dihydropyridine) ester has recently
been utilized in the one-pot reductive benzylation of mal-
ononitrile under solvent-free mechanical milling condi-
tions to give excellent yields on a small scale for
Although product 16 contained a heterocyclic system, we
next moved our research to test the reductive alkylation
reaction with heterocyclic carboxaldehdyes (Table 2).
First, furan and thiophene were selected as examples of
five-membered heterocycles. 2-Thiophenecarboxalde-
hyde and furfural both performed very well with the latter
SYNTHESIS 2008, No. 2, pp 0279–0285
x
x
.
x
x
.2
0
0
7
Advanced online publication: 07.12.2007
DOI: 10.1055/s-2007-990945; Art ID: M06607SS
© Georg Thieme Verlag Stuttgart · New York

280
F. Tayyari et al.
PAPER
Table 1 Reductive Alkylation of Malononitrile with Aromatic Al-
dehydes
product nor could any intermediate olefin be detected be-
fore the reduction step.
NC
Ar
CN
When this new and improved reductive alkylation proce-
dure was attempted with 2-quinolinecarboxaldehyde
(Table 2, entry 6), the crude product 25 was observed but
it ‘decomposed’ upon attempted purification via recrys-
tallization or column chromatography. Fortunately when
the reaction and entire workup was carried out at 0 °C, es-
sentially pure 25 was obtained. Later, it was found that 25
rearranged on TLC and created a single fluorescent spot
with an Rf value greater than expected for the quinoline
substituted malononitrile. Nucleophilic attack of the quin-
oline nitrogen on the carbon of the nitrile followed by a
proton transfer and a tautomerization explain how indoliz-
ine 26 is created (Scheme 2). Single crystal X-ray analysis
was applied to confirm the structure of this novel rear-
ranged product.10 The importance of these aromatic het-
erocycles can be appreciated by the new methods that
have been developed for the synthesis of indolizine deriv-
atives.11 A recent report from another group shows a sim-
ilar reaction as one possible outcome from a 2-formyl-1,4-
dihydropyridine reaction.12 Monosubstituted malononi-
trile 25 could be carefully alkylated with iodomethane pri-
or to purification.2a,5 Only C-alkylation – formation of
another C–C bond – was observed and disubstituted mal-
ononitrile 27 was obtained in good yield and the structure
confirmed by single crystal X-ray analysis.10 The impor-
tance of efficient syntheses of unsymmetrically disubsti-
tuted malononitriles can be realized by the latest patents
declaring their applications for controlling various pests.13
O
1. EtOH–H2O
NC
CN
+
2. NaBH4, 0 °C
Ar
H
Entry Ar
Product Time
(h)a
Yield
(%)b
Yield
(%)c
1
2
Ph
1
2
1
98
94
92
94
96
88
94
96
97
97
80
76
84
75
98
98
92
97
62
81
85
88
76
94
91
4-MeOC6H4
4-MeC6H4
4-BrC6H4
1
3
3
3.5
2
4
4
5
4-ClC6H4
5
2
d
6
3-ClC6H4
6
4
–
d
7
2-ClC6H4
7
24
–
8
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-HOC6H4
3-HOC6H4
8
2
90
88
84
85
9
9
1.5
0.5
10
11
12
13
14
15
16
17
18
19
20
10
11
12
13
14
15
16
17
18
19
20
18
d
18
24
3
–
4-HO-3-MeOC6H3
2-(4-ClBnO)C6H4
4-Me2NC6H4
74
d
–
2.5
90
Attempts were made to further broaden the scope of our
optimized reaction to other aldehydes and ketones. Ali-
phatic aldehydes (propanal and 2,2-dimethylpropanal) did
not successfully condense in ethanol or water, and when
the reduction step took place little product was obtained.14
Although reaction with trans-cinnamaldehyde was suc-
cessful (20), trans-crotonaldehyde would not undergo no-
ticeable condensation in aqueous ethanol. Acetophenone,
an aryl ketone, also afforded the product, but it was con-
taminated with ~20% of 1-phenylethanol from direct re-
duction of the ketone and was determined to be less
satisfying than our previously reported method.5 Lastly,
we examined other activated methylene moieties. Ethyl
cyanoacetate and ethyl nitroacetate were both allowed to
react with 4-nitrobenzaldehyde (the most reactive alde-
hyde toward malononitrile) and we found that the product
was obtained in good yield from the cyano ester, but no
product was detected from the nitro ester (Scheme 3). Eth-
yl cyanoacetate was allowed to react with 4-chlorobenzal-
dehyde but no precipitate was detected for the
e
4-(2-pyridyl)C6H4
2,6-Cl2C6H3
24
4
–
86
e
2,4,6-Cl3C6H2
2-fluorenyl
24
3
–
e
–
(E)-PhCH=CH
16
53
a Time refers to the condensation step.
b Isolated yield of purified compound using extraction method work-
up.
c Isolated yield of purified compound using filtration method workup.
d No precipitate formed and extraction method workup must be used.
e Filtration method workup was not attempted.
example requiring 50% aqueous ethanol in order for the
precipitate to form in the condensation step. Both 3- and
4-pyridinecarboxaldehydes, afforded the alkylated prod-
ucts 23 and 24 in good yields (Table 2). 2-Pyridinecarbox-
aldehyde (Table 2, entry 5) did not produce any desired
NC
CN
NH2
silica gel
chromatography
NC
MeI
CN
NC
N
N
N
K2CO3
acetone
27
25
26
Scheme 2
Synthesis 2008, No. 2, 279–285 © Thieme Stuttgart · New York

PAPER
Efficient One-Pot Reductive Alkylations of Malononitrile
281
Table 2 Reductive Alkylation of Malononitrile with Heteroaromatic Aldehydes
NC
NC
O
CN
N
N
X
O
H
CN
1. NCCH2CN, EtOH–H2O
2. NaBH4, 0 °C
1. NCCH2CN, EtOH–H2O
2. NaBH4, 0 °C
X
H
X = O, S
Entry
Heteroaryl
2-thienyl
2-furyl
Product
21
Time (h)a
Yield (%)b
1
2
3
4
5
6
3
24
3
93
95
71
79
0
22
4-pyridyl
3-pyridyl
2-pyridyl
2-quinolinyl
23
24
3
–
2
25
4
91
a Time refers to the condensation step.
b Isolated yield of purified compound using extraction method workup.
O
Analytical TLC was performed using Baker-Flex silica gel IB-F
plates and visualized using a UV lamp and/or stained with basic
KMnO4 [2.3 g KMnO4, 15 g K2CO3, 1.9 mL 2.5 M NaOH in 300
mL distilled (DI) H2O]. Flash chromatography was performed using
silica gel (35–70 mm, ~6 nm pore) from Acros or pre-packed silica
column (32–63 mm, 60 Å pore) from Analogix. 1H NMR spectra and
O
E
O
E
O
1. EtOH–H2O, r.t., 24 h
+
O
2. NaBH4, 0 °C, 15 min
H
Y
1
13C NMR with H decoupled spectra were recorded on a JEOL
Y
28 E = CN, Y = NO2 71%
Eclipse spectrometer at 400 MHz or 300 MHz and 100 MHz or 75
E, Y = NO2 0%
1
MHz, respectively. H chemical shifts are reported in ppm down-
field from internal tetramethylsilane and 13C chemical shifts are re-
ported in ppm relative to CDCl3 (77.00 ppm) or acetone-d6 (29.84
ppm). All chemicals were used as received without further purifica-
tion. Elemental analyses were determined at MidWest Microlab, In-
dianapolis, IN.
Scheme 3
Knoevenagel condensation and after treatment with sodi-
um borohydride, only a minor amount of C–C bond for-
mation was detected.
One-Pot Reductive Alkylation of Malononitrile with Aromatic
Aldehydes; General Procedure
In summary, a wide range of aromatic and heteroaromatic
aldehydes can be coupled together efficiently with mal-
ononitrile in a C–C bond forming reductive alkylation. In
this one-pot synthesis, aqueous ethanol is the only re-
quirement for complete condensation prior to addition of
sodium borohydride for the selective reduction. For reac-
tion workup, it is recommended that one should attempt to
follow the filtration method and only if a precipitate fails
to form would extraction with organic solvent be required.
We also have found that 2-quinolinecarboxaldehyde does
not produce an exceptionally stable product with malono-
nitrile and the product rearranges to efficiently yield a
substituted indolizine. Monosubstituted malononitriles
can be further utilized as reactants in alkylation reactions
to form unsymmetrically disubstituted malononitriles as
we have illustrated by the isolation of a stable 2-quinoline
derivative. Finally, it has been determined that ethyl cy-
anoacetate works with only very reactive aromatic alde-
hydes and that methylene acidity is not limiting reactivity
since ethyl nitroacetate does give the desired product.
Malononitrile (661 mg, 10 mmol) was dissolved in 95% EtOH (10
mL) and to this solution was added the appropriate aromatic alde-
hyde (10 mmol). The solution was stirred at r.t. until precipitation
was complete or overnight.9 Additional EtOH (20 mL) was added
and the mixture cooled to 0 °C in an ice bath. NaBH4 (169 mg, 5
mmol) was introduced to the vigorously stirred mixture and the re-
duction was complete in about 10 min.
Extraction method workup: To the reaction mixture was added DI
H2O (50 mL) and CH2Cl2 (25 mL), followed by aq 1.0 M HCl until
all hydride was quenched.15 The layers were separated and the aque-
ous layer was extracted with CH2Cl2 (2 × 25 mL). The combined or-
ganic layers were dried (Na2SO4), filtered, concentrated via
rotoevaporation and then under high vacuum, and purified via re-
crystallization or column chromatography.
Filtration method workup: The reaction mixture was poured into a
large beaker containing DI H2O (40 mL) and aq 1.0 M HCl was add-
ed until all hydride was quenched. The reaction flask was washed
with DI H2O (20 mL), combined with the quenched mixture in the
beaker and the solution/mixture was then cooled in an ice bath. Ad-
ditional cold H2O was added until precipitation was complete. If
crystallization/precipitation did not occur, then the mixture was ex-
tracted (see Extraction Method Workup above). The cold precipi-
Synthesis 2008, No. 2, 279–285 © Thieme Stuttgart · New York

282
F. Tayyari et al.
PAPER
tate was collected by vacuum filtration and washed with cold DI
H2O (20 mL).
2-Chlorobenzylmalononitrile (7)13d
The general procedure, followed to scale using malononitrile (0.660
g, 10 mmol), 2-chlorobenzaldehyde (1.405 g, 10 mmol), and
NaBH4 (0.189 g, 5 mmol), afforded an oil; yield: 1.792 g (94%).
Benzylmalononitrile (1)5
The general procedure, followed to scale using malononitrile (0.667
g, 10.09 mmol), benzaldehyde (1.071 g, 10.09 mmol), and NaBH4
(0.196 g, 5.18 mmol), afforded a solid; yield: 1.538 g (98%); mp
88–89 °C.
1H NMR (400 MHz, CDCl3): d = 7.42–7.30 (m, 5 H), 3.90 (t, J = 7.0
Hz, 1 H), 3.29 (d, J = 7.0 Hz, 2 H).
1H NMR (400 MHz, CDCl3): d = 7.46–7.32 (m, 4 H), 4.11 (t, J = 8.0
Hz, 1 H), 3.46 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 133.8, 131.7, 130.6, 130.3, 130.0,
127.6, 112.0, 34.6, 22.5.
4-Nitrobenzylmalononitrile (8)6
13C NMR (100 MHz, CDCl3): d = 132.9, 129.2, 129.1, 128.7, 112.2,
36.5, 24.8.
The general procedure, followed to scale using malononitrile (0.660
g, 10 mmol), 4-nitrobenzaldehyde (1.51 g, 10 mmol), and NaBH4
(0.189 g, 5 mmol), afforded a solid; yield: 1.94 g (96%); mp 151–
152 °C.
4-Methoxybenzylmalononitrile (2)5
The general procedure, followed to scale using malononitrile (0.682
g, 10.3 mmol), 4-methoxybenzaldehyde (1.388 g, 10.2 mmol), and
NaBH4 (0.193 g, 5.10 mmol), afforded a solid; yield: 1.799 g (94%);
mp 89.5–91 °C.
1H NMR (400 MHz, CDCl3): d = 7.25 (d, J = 8.8 Hz, 2 H), 6.93 (d,
J = 8.8 Hz, 2 H), 3.86 (t, J = 7.0 Hz, 1 H), 3.82 (s, 3 H), 3.24 (d,
J = 7.0 Hz, 2 H).
1H NMR (400 MHz, CDCl3): d = 8.30 (d, J = 8.8 Hz, 2 H), 7.56 (d,
J = 8.8 Hz, 2 H), 4.05 (t, J = 6.8 Hz, 1 H), 3.43 (d, J = 6.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 148.3, 139.7, 130.4, 124.4, 111.5,
36.0, 24.4.
3-Nitrobenzylmalononitrile (9)6
The general procedure, followed to scale using malononitrile (1.321
g, 20 mmol), 3-nitrobenzaldehyde (2.302 g, 15 mmol), and NaBH4
(0.378 g, 10 mmol), afforded a solid; yield: 2.69 g (88%); mp
137.5–138 °C.
1H NMR (400 MHz, CDCl3): d = 8.64 (d, J = 4.8 Hz, 1 H), 8.60 (s,
1 H), 7.72 (d, J = 7.9 Hz, 1 H), 7.37 (dd, J = 7.9, 4.8 Hz, 1 H), 4.14
(t, J = 7.0 Hz, 1 H), 3.32 (d, J = 7.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 159.9, 130.3, 124.9, 114.7, 112.2,
55.3, 36.1, 25.3.
4-Methylbenzylmalononitrile (3)5
The general procedure, followed to scale using malononitrile (0.672
g, 10.2 mmol), 4-methylbenzaldehyde (1.22 g, 10.2 mmol), and
NaBH4 (0.192 g, 5.09 mmol), afforded a solid; yield: 1.601 g (92%);
mp 78.5–80 °C.
1H NMR (400 MHz, CDCl3): d = 7.21 (s, 4 H), 3.87 (t, J = 7.0 Hz,
1 H), 3.26 (d, J = 7.0 Hz, 2 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 148.6, 135.4, 134.6, 130.5, 124.2,
124.0, 111.5, 36.0, 24.5.
2-Nitrobenzylmalononitrile (10)6
The general procedure, followed to scale using malononitrile (1.982
g, 30 mmol), 2-nitrobenzaldehyde (4.534 g, 30 mmol), and NaBH4
(0.568 g, 15 mmol), afforded a solid; 5.10 g (84%); mp 82–83 °C.
1H NMR (400 MHz, CDCl3): d = 8.17 (d, J = 8.1 Hz, 1 H), 7.75 (dd,
J = 7.7, 7.3 Hz, 1 H), 7.62 (dd, J = 8.1, 7.3 Hz, 1 H), 7.57 (d, J = 7.7
Hz, 1 H), 4.45 (t, J = 7.7 Hz, 1 H), 3.60 (d, J = 7.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 138.5, 129.9, 129.8, 128.9, 112.3,
36.1, 24.9, 21.0.
4-Bromobenzylmalononitrile (4)6
The general procedure, followed to scale using malononitrile (1.321
g, 20 mmol), 4-bromobenzaldehyde (3.700 g, 20 mmol), and
NaBH4 (0.3785 g, 10 mmol), afforded a solid; yield: 4.432 g (94%);
mp 94–94.5 °C.
1H NMR (400 MHz, CDCl3): d = 7.53 (d, J = 8.4 Hz, 2 H), 7.20 (d,
J = 8.4 Hz, 2 H), 3.94 (t, J = 6.6 Hz, 1 H), 3.23 (d, J = 6.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 148.6, 134.5, 133.4, 130.4, 128.2,
126.0, 111.9, 35.1, 23.6.
4-Hydroxybenzylmalononitrile (11)13d
13C NMR (100 MHz, CDCl3): d = 132.4, 131.8, 130.8, 123.0, 112.0,
35.8, 24.6.
The general procedure, followed to scale using malononitrile (1.982
g, 30 mmol), 4-hydroxybenzaldehyde (3.668 g, 30 mmol), and
NaBH4 (0.566 g, 15 mmol), afforded a solid; yield: 4.40 g (85%);
mp 173–175 °C.
4-Chlorobenzylmalononitrile (5)6
The general procedure, followed to scale using malononitrile (0.660
g, 10 mmol), 4-chlorobenzaldehyde (1.411 g, 10 mmol), and
NaBH4 (0.189 g, 5 mmol), afforded a solid; yield: 1.831 g (96%);
mp 90–90.5 °C.
1H NMR (300 MHz, CDCl3): d = 7.40 (d, J = 8.1 Hz, 2 H), 7.25 (d,
J = 8.1 Hz, 2 H), 3.92 (t, J = 6.7 Hz, 1 H), 3.27 (d, J = 6.7 Hz, 2 H).
1H NMR (400 MHz, CDCl3): d = 7.21 (d, J = 8.8 Hz, 2 H), 6.86 (d,
J = 8.8 Hz, 2 H), 4.92 (br s, 1 H), 3.86 (t, J = 7.0 Hz, 1 H), 3.23 (d,
J = 7.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 156.0, 130.6, 125.1, 116.1, 112.2,
36.1, 25.3.
13C NMR (100 MHz, CDCl3): d = 135.0, 131.2, 130.5, 129.5, 111.9,
3-Hydroxybenzylmalononitrile (12)16
35.9, 24.6.
The general procedure, followed to scale using malononitrile (1.978
g, 30 mmol), 3-hydroxybenzaldehyde (3.667 g, 30 mmol), and
NaBH4 (0.567 g, 15 mmol), afforded a solid; yield: 3.94 g (76%);
mp 49–51 °C.
1H NMR (400 MHz, acetone-d6): d = 7.22 (t, J = 7.7 Hz, 1 H), 6.94–
6.88 (m, 2 H), 6.86–6.82 (m, 1 H), 4.73 (t, J = 7.0 Hz, 1 H), 3.34 (d,
J = 7.0 Hz, 2 H).
3-Chlorobenzylmalononitrile (6)4e
The general procedure followed to scale using malononitrile (1.321
g, 20 mmol), 3-chlorobenzaldehyde (2.814 g, 20 mmol), and
NaBH4 (0.377 g, 10 mmol) afforded an oil; yield: 3.322 g (87%).
1H NMR (400 MHz, CDCl3): d = 7.39–7.18 (m, 4 H), 3.95 (t, J = 7.6
Hz, 1 H), 3.23 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, acetone-d6): d = 158.5, 136.8, 130.7, 121.2,
117.1, 116.0, 114.3, 36.4, 25.2.
13C NMR (100 MHz, CDCl3): d = 134.9, 134.7, 130.5, 129.2, 129.0,
127.3, 112.0, 35.9, 24.6.
Synthesis 2008, No. 2, 279–285 © Thieme Stuttgart · New York

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Efficient One-Pot Reductive Alkylations of Malononitrile
283
4-Hydroxy-3-methoxybenzylmalononitrile (13)4f
The general procedure, followed to scale using malononitrile (6.615
g, 100 mmol), vanillin (15.21 g, 100 mmol), and NaBH4 (1.893 g,
50 mmol), afforded a solid; yield: 14.88 g, 74%); mp 86–88 °C.
1H NMR (400 MHz, CDCl3): d = 8.69 (d, J = 4.8 Hz, 1 H), 8.03 (d,
J = 8.0 Hz, 2 H), 7.78–7.71 (m, 2 H), 7.43 (d, J = 8.0 Hz, 2 H),
7.28–7.24 (m, 1 H), 3.95 (t, J = 7.0 Hz, 1 H), 3.34 (d, J = 7.0 Hz, 2
H).
1H NMR (300 MHz, CDCl3): d = 6.93 (d, J = 8.4 Hz, 1 H), 6.85–
6.79 (m, 2 H), 5.68 (br s, 1 H), 3.91 (s, 3 H), 3.87 (t, J = 7.0 Hz, 1
H), 3.23 (d, J = 7.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 146.8, 146.1, 124.7, 122.2, 115.0,
112.3, 111.5, 56.0, 36.6, 25.3.
13C NMR (100 MHz, CDCl3): d = 156.3, 149.7, 139.8, 136.8, 133.5,
129.5, 127.6, 122.4, 120.1, 36.3, 24.7.
Anal. Calcd for C15H11N3: C, 77.23; H, 4.75; N, 18.01. Found: C,
76.88; H, 4.95; N, 17.87.
2,6-Dichlorobenzylmalononitrile (17)13d
2-(4-Chlorobenzyloxy)benzylmalononitrile (14)
2-(4-Chlorobenzyloxy)benzaldehyde
The general procedure, followed to scale using malononitrile (0.667
g, 10 mmol), 2,6-dichlorobenzaldehyde (1.76 g, 10 mmol), and
NaBH4 (0.190 g, 5.0 mmol), afforded a solid; yield: 2.08 g (92%);
mp 82–84 °C.
1H NMR (400 MHz, CDCl3): d = 7.41 (d, J = 8.4 Hz, 2 H), 7.28 (t,
J = 8.4 Hz, 1 H), 4.24 (t, J = 8.4 Hz, 1 H), 3.74 (d, J = 8.4 Hz, 2 H).
2-(4-Chlorobenzyloxy)benzaldehyde17 was prepared following
modified literature conditions for alkylation of salicylaldehyde.18
Salicylaldehyde (0.61 g, 5 mmol) and 4-chlorobenzyl chloride (0.64
g, 4 mmol) were stirred in DMF (10 mL). Na2CO3 (1.06 g, 10 mmol)
and a catalytic amount of NaI were added, and the mixture was heat-
ed to 100 °C. The heating mantel was removed after 8 h and the
mixture was allowed to cool to r.t. before the addition of Et2O (50
mL) and H2O (50 mL). The layers were separated, and the aqueous
portion was extracted with Et2O (40 mL). The combined organics
were then washed with H2O (4 × 30 mL) and brine (30 mL). The or-
ganic layer was dried (Na2SO4), filtered, and rotoevaporated to give
0.55 g (56%), after recrystallization from EtOH.
13C NMR (100 MHz, CDCl3): d = 135.9, 130.6, 129.2, 128.8, 111.6,
31.8, 20.9.
2,4,6-Trichlorobenzylmalononitrile (18)
2,4,6-Trichlorobenzaldehyde
2,4,6-Trichlorobenzaldehyde19 was prepared following a modified
directed ortho-metalation procedure.20 1,3,5-Trichlorobenzene
(1.84 g, 10.1 mmol) was dissolved in THF (40 mL) under argon.
The solution was cooled to –78 °C via a dry ice and acetone bath.
After the stirred solution was cooled completely (~30 min), n-BuLi
(4 mL, 10.00 mmol) was added dropwise via a syringe over 20 min.
The solution was kept at –78 °C and stirred for 30 min before DMF
(1.2 mL, 17.4 mmol) was added via a syringe. After the addition
was complete, the solution was stirred at –78 °C for 1.5 h. The re-
action was then quenched with aq 3 N HCl (40 mL) and then al-
lowed to warm to r.t. The mixture was extracted with EtOAc (60
mL). The organic layer was then washed with aq NaHCO3 (40 mL)
and brine (40 mL), dried (Na2SO4), and concentrated via rotary
evaporation to afford 1.93 g (92%) of product.
1H NMR (400 MHz, CDCl3): d = 10.50 (s, 1 H), 7.82 (dd, J = 7.7,
1.8 Hz, 1 H), 7.53–7.46 (m, 1 H), 7.34 (s, 4 H), 7.03–6.97 (m, 2 H),
5.11 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 189.4, 160.6, 135.8, 134.5, 133.9,
128.8, 128.50, 128.46, 125.0, 121.1, 112.8, 69.5.
Compound 14
The general procedure, followed to scale using malononitrile (0.143
g, 2.17 mmol), 2-(4-chlorobenzyloxy)benzaldehyde (0.530 g, 2.17
mmol), and NaBH4 (0.041 g, 1.08 mmol), afforded an oil; yield:
0.483 g (75%); mp 67–68 °C.
IR (ATR): 3061, 3035, 3014, 2914, 2876, 2256, 1603, 1590, 1496,
1454, 1246, 807, 759 cm–1.
1H NMR (400 MHz, CDCl3): d= 7.39 (d, J = 8.4 Hz, 2 H), 7.38–
7.30 (m, 3 H) 7.27 (dd, J = 7.3, 1.5 Hz, 1 H), 7.01 (td, J = 7.5, 0.9
Hz, 1 H), 6.95 (d, J = 8.0 Hz, 1 H), 5.08 (s, 2 H), 4.10 (t, J = 7.7 Hz,
1 H), 3.33 (d, J = 7.7 Hz, 2 H).
1H NMR (400 MHz, CDCl3): d = 10.44 (s, 1 H), 7.42 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 187.6, 139.3, 137.6, 129.8, 128.8.
Compound 18
The general procedure, followed to scale using malononitrile (0.473
g, 7.16 mmol), 2,4,6-trichlorobenzaldehyde (1.50 g, 7.16 mmol),
and NaBH4 (0.135 g, 3.58 mmol), afforded a solid; yield: 1.80 g
(97%); mp 91.5–92.5 °C.
13C NMR (100 MHz, CDCl3): d = 156.2, 134.6, 134.3, 131.5, 130.3,
129.1, 128.8, 121.6, 121.5, 112.5, 111.9, 69.5, 32.6, 22.6.
IR (ATR): 3086, 2906, 2259, 1724, 1580, 1547, 1436, 1376, 1214,
1138, 1075, 1016, 877, 861, 817, 672 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.84 (s, 2 H), 4.60 (t, J = 8.4 Hz,
1 H), 4.10 (d, J = 8.4 Hz, 2 H).
Anal. Calcd for C17H13ClN2O: C, 68.81; H, 4.42; N, 9.44. Found: C,
68.81; H, 4.82; N, 9.54.
4-Dimethylaminobenzylmalononitrile (15)16
The general procedure, followed to scale using malononitrile (0.660
g, 10 mmol), 4-dimethylaminobenzaldehyde (1.491 g, 10 mmol),
and NaBH4 (0.189 g, 5 mmol), afforded a solid; yield: 1.958 g
(98%); mp 59.5–61 °C.
1H NMR (400 MHz, CDCl3): d = 7.18 (d, J = 8.6 Hz, 2 H), 6.71 (d,
J = 8.6 Hz, 2 H), 3.81 (t, J = 7.0 Hz, 1 H), 3.21 (d, J = 7.0 Hz, 2 H),
2.96 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 136.4, 135.7, 128.9, 127.9, 111.4,
31.4, 20.9.
Anal. Calcd for C10H5Cl3N2: C, 46.28; H, 1.94; N, 10.79. Found: C,
46.57; H, 2.08; N, 10.52.
2-Fluorenylmethylmalononitrile (19)
The general procedure, followed to scale using malononitrile (0.138
g, 2.08 mmol), 2-fluorenecarboxaldehyde (0.405 g, 2.07 mmol),
and NaBH4 (0.037 g, 1 mmol), afforded a solid; yield: 0.3133 g
(62%); mp 163.5–164 °C.
13C NMR (75 MHz, CDCl3): d = 150.5, 129.9, 120.1, 112.6, 112.5,
40.3, 36.1, 25.4.
4-(2-Pyridyl)benzylmalononitrile (16)
IR (ATR): 3044, 2922, 2259, 1450, 1428, 1402, 1032, 1005, 954,
887, 848, 837, 800, 762, 725 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.79 (t, J = 4.8 Hz, 2 H), 7.56 (d,
J = 7.7 Hz, 1 H), 7.50 (s, 1 H), 7.41–7.37 (m, 1 H), 7.35–7.31 (m, 2
H), 3.94 (t, J = 7.0 Hz, 1 H), 3.92 (s, 2 H), 3.36 (d, J = 7.0 Hz, 2 H).
The general procedure, followed to scale using malononitrile (0.132
g, 2 mmol), 4-(2-pyridyl)benzaldehyde (0.366 g, 2 mmol), and
NaBH4 (0.037 g, 1 mmol), afforded a solid; yield: 0.460 g (98%);
mp 128–129 °C.
IR (ATR): 3090, 3060, 3015, 2922, 2256, 1587, 1565, 1467, 1434,
1019, 853, 767, 737 cm–1.
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284
F. Tayyari et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 144.2, 143.3, 142.3, 140.7, 131.2,
127.7, 127.2, 126.9, 125.7, 125.1, 120.4, 120.1, 112.3, 36.82, 36.77,
25.1.
13C NMR (100 MHz, CDCl3): d = 150.1, 150.0, 136.8, 128.7, 123.8,
111.9, 33.6, 24.5.
Anal. Calcd for C9H7N3: C, 68.78; H, 4.49; N, 26.74. Found: C,
68.58; H, 4.45; N, 26.56.
Anal. Calcd for C17H12N2: C, 83.58; H, 4.95; N, 11.47. Found: C,
83.36; H, 4.91; N, 11.40.
2-Quinolinemethylmalononitrile (25)
trans-Cinnamylmalononitrile (20)4c
The general procedure, followed to scale using malononitrile (0.336
g, 5.1 mmol), 2-quinolinecarboxaldehyde (0.80 g, 5.1 mmol), and
NaBH4 (0.094 g, 2.5 mmol), afforded a crude solid; yield: 0.949 g
(91%).
1H NMR (400 MHz, CDCl3): d = 8.19 (d, J = 8.4 Hz, 1 H), 8.06 (d,
J = 8.8 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.78–7.73 (m, 1 H),
7.60–7.55 (m, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 4.95 (t, J = 7.4 Hz, 1
H), 3.71 (d, J = 7.4 Hz, 2 H).
The general procedure, followed to scale using malononitrile (0.661
g, 10 mmol), trans-cinnamaldehyde (1.33 g, 10 mmol), and NaBH4
(0.189 g, 5 mmol), afforded a solid; yield: 0.959 g (53%); mp 65–
66.5 °C.
1H NMR (400 MHz, CDCl3): d = 7.46–7.25 (m, 5 H), 6.70 (d,
J = 15.8 Hz, 1 H), 6.17 (dt, J = 15.8, 7.7 Hz, 1 H), 3.82 (t, J = 6.6
Hz, 1 H), 2.91 (dd, J = 7.7, 6.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 137.0, 135.5, 128.6, 128.4, 126.6,
119.7, 112.2, 34.0, 23.2.
13C NMR (100 MHz, CDCl3): d = 152.3, 147.5, 137.3, 130.1, 129.0,
127.6, 127.3, 127.0, 120.6, 113.1, 38.1, 20.5.
2-Thienylmethylmalononitrile (21)13c
1-Aminopyrrolo[1,2-a]quinoline-2-carbonitrile (26)
The general procedure, followed to scale using malononitrile (0.681
g, 10.3 mmol), 2-thiophenecarboxaldehyde (1.142 g, 10.18 mmol),
and NaBH4 (0.194 g, 5.1 mmol), afforded a solid; yield: 1.0593 g
(96%); mp 46.5–47 °C.
The general procedure, followed to scale using malononitrile (0.330
g, 5 mmol), 2-quinolinecarboxaldehyde (0.786 g, 5 mmol), and
NaBH4 (0.094 g, 2.5 mmol), afforded a solid after column chroma-
tography on silica gel; yield: 0.865 g (83%); mp 148–148.5 °C.
1H NMR (400 MHz, CDCl3): d = 7.33 (d, J = 5.1 Hz, 1 H), 7.12 (d,
J = 3.3 Hz, 1 H), 7.03 (dd, J = 5.1, 3.3 Hz, 1 H), 3.94 (t, J = 6.6 Hz,
1 H), 3.54 (d, J = 6.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 133.9, 128.4, 127.7, 126.5, 111.9,
31.1, 25.5.
IR (ATR): 3352, 3308, 3235, 3135, 3051, 2212, 1625, 1643, 1559,
1524, 1474, 1430, 1402 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.77 (d, J = 8.4 Hz, 1 H), 7.57 (d,
J = 7.7 Hz, 1 H), 7.48–7.43 (m, 1 H), 7.38–7.34 (m, 1 H), 7.07 (d,
J = 9.5 Hz, 1 H), 6.87 (d, J = 9.5 Hz, 1 H), 6.50 (s, 1 H), 4.30 (br s,
2 H).
2-Furfurylmalononitrile (22)5
13C NMR (100 MHz, CDCl3): d = 141.1, 134.1, 128.4, 127.1, 126.9,
125.8, 124.9, 119.6, 118.9, 116.6, 116.3, 101.5, 83.9.
The general procedure, followed to scale using malononitrile (0.681
g, 10.3 mmol), furfural (1.142 g, 10.18 mmol), and NaBH4 (0.194
g, 5.1 mmol) in 50% aq EtOH, afforded an oil; yield: 1.0593 g
(96%).
Anal. Calcd for C13H9N3: C, 75.35; H, 4.38; N, 20.28. Found: C,
75.37; H, 4.53; N, 20.01.
1H NMR (400 MHz, CDCl3): d = 7.43 (s, 1 H), 6.41–6.36 (m, 2 H),
4.05 (t, J = 7.0 Hz, 1 H), 3.37 (d, J = 7.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 146.4, 143.2, 112.0, 110.6, 109.6,
29.1, 22.4.
2-Methyl-2-(2-quinolinemethyl)malononitrile (27)
The crude monosubstituted malononitrile 25 was alkylated with
MeI (0.724 g, 5.1 mmol) in the presence of K2CO3 (0.705 g, 5.1
mmol) in acetone (10 mL) to afford a solid after column chromatog-
raphy on silica gel; yield: 0.949 g (86%); mp 148–148.5 °C.
4-Pyridinemethylmalononitrile (23)
IR (ATR): 3069, 3004, 2953, 2248, 1618, 1599, 1570, 1506, 1425,
1275, 1199, 1137, 816, 783, 751 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.19 (d, J = 8.4 Hz, 1 H), 8.13 (d,
J = 8.4 Hz, 1 H), 7.83 (d, J = 8.1 Hz, 1 H), 7.77–7.72 (m, 1 H),
7.59–7.55 (m, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 3.59 (s, 2 H), 1.97 (s,
3 H).
The general procedure, followed to scale using malononitrile (0.330
g, 5 mmol), 4-pyridinecarboxaldehyde (0.535 g, 5 mmol), and
NaBH4 (0.094 g, 2.5 mmol), afforded a solid; yield: 0.56 g (72%);
mp 92.5–93 °C.
IR (ATR): 3045, 2921, 2261, 1959, 1604, 1563, 1445, 1421, 1350,
1223, 1194, 1184, 994, 883, 825, 753 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.67 (d, J = 4.8 Hz, 2 H), 7.28 (d,
J = 4.8 Hz, 2 H), 4.14 (t, J = 7.0 Hz, 1 H), 3.29 (d, J = 7.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 150.6, 141.4, 124.0, 111.7, 35.4,
23.8.
13C NMR (100 MHz, CDCl3): d = 152.5, 147.7, 137.2, 130.0, 129.4,
127.5, 127.3, 127.0, 121.2, 116.2, 45.7, 30.9, 24.9.
Anal. Calcd for C14H11N3: C, 76.00; H, 5.01; N, 18.99. Found: C,
75.88; H, 5.16; N, 18.98.
Anal. Calcd for C9H7N3: C, 68.78; H, 4.49; N, 26.74. Found: C,
68.62; H, 4.55; N, 26.56.
Ethyl 2-Cyano-3-(4-nitrophenyl)propanoate (28)4g
The general procedure for the one-pot reductive alkylation of mal-
ononitrile, followed to scale using ethyl cyanoacetate (1.131 g, 10
mmol), 4-nitrobenzaldehyde (1.51 g, 10 mmol), and NaBH4 (0.189
g, 5 mmol), afforded a solid; yield: 1.76 g (71%); mp 56–58 °C.
1H NMR (400 MHz, CDCl3): d = 8.23 (d, J = 8.4 Hz, 2 H), 7.48 (d,
J = 8.4 Hz, 2 H), 4.27 (q, J = 7.1 Hz, 2 H), 3.79 (dd, J = 8.0, 5.8 Hz,
1 H), 3.39 (dd, J = 14, 5.8 Hz, 1 H), 3.33 (dd, J = 14, 8.0 Hz, 1 H),
1.30 (t, J = 7.1 Hz, 3 H).
3-Pyridinemethylmalononitrile (24)
The general procedure, followed to scale using malononitrile (0.330
g, 5 mmol), 3-pyridinecarboxaldehyde (0.535 g, 5 mmol), and
NaBH4 (0.094 g, 2.5 mmol), afforded a solid; yield: 0.62 g (79%);
mp 70–71 °C.
IR (ATR): 3038, 2997, 2881, 2618, 2552, 2248, 1595, 1575, 1479,
1446, 1424, 1024, 789 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.71–8.62 (m, 2 H), 7.72 (d,
J = 7.0 Hz, 1 H), 7.38 (dd, J = 7.0, 4.8 Hz, 1 H), 3.98 (t, J = 6.8 Hz,
1 H), 3.33 (d, J = 6.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 164.8, 147.6, 142.5, 130.2, 124.1,
115.4, 63.4, 38.8, 35.0, 13.9.
Synthesis 2008, No. 2, 279–285 © Thieme Stuttgart · New York

PAPER
Efficient One-Pot Reductive Alkylations of Malononitrile
285
(6) Zhang, Z.; Gao, J.; Xia, J.-J.; Wang, G.-W. Org. Biomol.
Chem. 2005, 3, 1617.
Acknowledgment
Acknowledgment is made to the Donors of the American Chemical
Society Petroleum Research Fund for partial support of this re-
search. This work was also supported by funds from the Lilly En-
dowment and Ball State University. The authors would like to thank
Mr. Ryan Miller, Mr. Kevin Vonderfecht, and Ms. Lauren Bailey of
this department for helpful observations and suggestions in carrying
out this research.
(7) Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492.
(8) See reference 1a and references cited therein.
(9) Extreme caution must be employed in handling
benzylidenemalononitriles (intermediates before NaBH4
reduction). The 2-chloro derivative, 2-chlorobenzal-
malononitrile (Table 1, entry 7), is known as CS, which has
been used as the active ingredient in riot control and anti-
personnel devices. See: Jones, G. R. N. Nature 1972, 235,
257.
(10) The X-ray data of 26 and 27 have been deposited at the
Cambridge Crystallographic Database Centre under CCDC
# 661126 and 661127, respectively. They can be retrieved
from the web address http://www.ccdc.cam.ac.uk/products/
csd/request/.
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Synthesis 2008, No. 2, 279–285 © Thieme Stuttgart · New York