Isocyanide-based multicomponent reactions: Synthesis of 3,3-dicyano-N-alkyl-2-arylpropanamide derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.06.013

A new isocyanide-based multicomponent reaction between an aromatic aldehyde, malononitrile, an isocyanide, and acetic acid efficiently provides 3,3-dicyano-N-alkyl-2-arylpropanamide derivatives in excellent yields in ethanol at 70 °C. This reaction led to

Full text of DOI:10.1016/j.tetlet.2011.06.013

Tetrahedron Letters 52 (2011) 4186–4188
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Isocyanide-based multicomponent reactions: synthesis
of 3,3-dicyano-N-alkyl-2-arylpropanamide derivatives
Ebrahim Soleimani a, , Mohsen Zainali a, Saadi Samadi b
⇑
a Department of Chemistry, Razi University, Kermanshah 67149-67346, Iran
b Department of Chemistry, Shahid Beheshti University, Tehran 19396-4716, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A new isocyanide-based multicomponent reaction between an aromatic aldehyde, malononitrile, an iso-
cyanide, and acetic acid efficiently provides 3,3-dicyano-N-alkyl-2-arylpropanamide derivatives in excel-
lent yields in ethanol at 70 °C. This reaction led to the construction of two carbon–carbon bonds and one
amide group in a single synthetic step.
Received 1 April 2011
Revised 15 May 2011
Accepted 3 June 2011
Available online 13 June 2011
Ó 2011 Published by Elsevier Ltd.
Keywords:
Isocyanide
3,3-Dicyano-N-alkyl-2-arylpropanamide
Multi-component reactions
Malononitrile
Multicomponent reactions (MCRs) are very efficient synthetic
methods. They offer significant advantages over classical stepwise
approaches allowing the formation of several bonds and the con-
struction of complex molecular architectures from simple precur-
sors in a single synthetic operation without the need for isolation
of intermediates.1 MCRs that involve isocyanides are powerful
tools in the modern drug discovery process and allow rapid, auto-
mated, and high-throughput generation of organic compounds.2
The pharmaceutical industry has focused more and more on diver-
sity-oriented and biased combinatorial libraries.3 Furthermore, the
discovery of novel isocyanide-based multicomponent reactions
(IMCRs) can be considered an interesting research topic that also
satisfies the practical interest of applied science.4 As a result, the
number of new IMCRs reported in recent years has grown rapidly.4
The most versatile of all IMCRs so far is the Ugi four-component
condensation (U-4CC) of an acid, an amine, an aldehyde, or a ke-
tone and an isocyanide.5 The U-4CC is applicable to a broad range
of starting materials including bifunctional examples and plays an
important role in the isocyanide-based synthesis of organic com-
pounds. However, to our knowledge, the U-4CC using malononitri-
le instead of amine components has not been described.
(Scheme 1). In this reaction, the role of the carboxylic acid is not
only to trap the nitrilium intermediate, but also to activate the al-
kene and aldehyde toward nucleophilic attack.
For optimization of this reaction, we investigated the effect of
solvent, amount of acetic acid, and temperature on the yield and
selectivity between the formation of product 4 and intermediate
5. The reaction of malononitrile, benzaldehyde, and acetic acid
with cyclohexyl isocyanide was selected as a model reaction and
various solvents were screened under different reaction conditions
(Table 1). When the reaction was carried using the aprotic solvents
benzene, toluene, acetonitrile, and dichloromethane, the dominant
product was intermediate 5 (Table 1, entries 1–4). However, when
the reaction was carried out using protic solvents such as water,
methanol and ethanol, the major product was 4a (Table 1, entries
5–11). Ethanol proved to be the best solvent (Table 1, entry 7).
Next, we studied the model reaction in ethanol at different tem-
peratures (Table 1, entries 9–11). The reaction rate increased as the
temperature was raised. At 70 °C, the maximum yield (97%) was
obtained in a reaction time of 12 h (Table 1, entry 7).
The model reaction in ethanol at 70 °C was also studied using
different amounts of acetic acid. The best results were obtained
with 100 mol % of acetic acid. Acetic acid is an important compo-
nent of the reaction acting as both reagent and catalyst. Further
work indicated that the best results were obtained when the reac-
tion was carried out at 70 °C for 12 h in ethanol using 100 mol % of
acetic acid (Table 1, entry 7).
Due to above-mentioned reasons, and as a part of our ongoing
research on isocyanide-based MCRs,6 we report herein the synthe-
sis of 3,3-dicyano-N-alkyl-2-arylpropanamide derivatives 4 via a
three-component condensation reaction of aldehydes 1, malono-
nitrile (2), isocyanides 3, and acetic acid in ethanol at 70 °C
With optimized conditions established, we next attempted to
extend the process to three different isocyanides: cyclohexyl
isocyanide, tert-butyl isocyanide, and 1,1,3,3-tetramethylbutyl
⇑
Corresponding author. Fax: +98 831 4274559.
E-mail address: e_soleimanirazi@yahoo.com (E. Soleimani).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.06.013

E. Soleimani et al. / Tetrahedron Letters 52 (2011) 4186–4188
NC
4187
CN
O
CHO
H
CN
CN
N
AcOH
EtOH, 70 oC
R2
R2
N C
+
+
R1
R1
4
1
2
3
Scheme 1. Synthesis of 3,3-dicyano-N-alkyl-2-arylpropanamides 4.
Table 1
Optimization of the three-component reaction
NC
CN
NC
CN
O
CHO
H
N
CN
CN
+
+
N
C
+
5
4a
Entry
Solvent
Acetic acid (mol %)
Product
Temperature (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
Benzene
Toluene
CH2Cl2
MeCN
H2O
MeOH
EtOH
EtOH
100
100
100
100
100
100
100
70
5
5
5
5
4a
4a
4a
4a
4a
4a
4a
70
70
25
70
70
70
70
70
70
50
25
70
80
50
80
50
75
97
65
35
85
70
EtOH
EtOH
EtOH
40
100
100
10
11
Table 2
The reaction mechanism can be regarded as a special case of the
Ugi four-component reaction. Mechanistically, it is conceivable
that the reaction involves the initial formation of the activated al-
kene, benzylidenemalonodinitrile7 5 through knoevenagel conden-
sation of malononitrile (2) and the aldehyde 1. Intermediate 5
undergoes nucleophilic addition with the isocyanide 3 followed
by nucleophilic attack on the isocyanide by the carboxylate to af-
ford intermediate 6. Subsequently, intermediate 6 undergoes
nucleophilic addition with ethanol to afford 3,3-dicyano-N-alkyl-
2-arylpropanamide derivatives 4 (Scheme 2). To clarify the pro-
posed mechanism, first, the activated alkene 5 was synthesized
by condensation of malononitrile (2) and aldehyde 1. Next, reac-
tion of 5 with the isocyanide and acetic acid in ethanol afforded
the corresponding 3,3-dicyano-N-alkyl-2-arylpropanamide deriva-
tives. Also, for further clarification, the reaction was studied in the
absence of acetic acid. Under these conditions, no product was ob-
tained even after 24 h.
It should be noted that the reaction between the activated alkene
(2-methylenemalononitrile) and isocyanides in methanol to afford
2-[(E)-2-methoxybut-2-enyl]malononitrile was published more
than 30 years ago.8 Recently, Mironov et al. reported the reaction be-
tween benzylidenemalonodinitrile, an isocyanide and phenol in the
presence Et3N/Py.9 Also, Shaabani et al. reported the reaction be-
tween an activated alkene (Meldrum’s acid), an aldehyde, an isocy-
anide and an amine or alcohol in dichloromethane.10
Synthesis of 3,3-dicyano-N-alkyl-2-arylpropanamide derivatives
Entry
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
H
Cy
Cy
Cy
Cy
4a
4b
4c
4d
4e
4f
97
95
98
96
97
99
91
98
4-O2N
4-CH3O
4-H3C
4-Cl
H
4-H3C
4-H3C
Cy
1,1,3,3,-Tetramethylbutyl
1,1,3,3,-Tetramethylbutyl
tert-Butyl
4g
4h
isocyanide, and various aromatic aldehydes. The results are sum-
marized in Table 2. The structures of the products were established
by spectroscopic methods. In all cases, excellent yields were ob-
tained, regardless of the nature of the substituent present on the
aldehyde (electron-donating or electron-withdrawing). This con-
firms the reliability of the synthetic method.
The structures of the products were deduced from their IR,
mass, 1H NMR, and 13C NMR spectra. The mass spectra of these
compounds displayed molecular ion peaks at appropriate m/z val-
ues. The 1H NMR spectrum of 4a consisted of a multiplet for the
cyclohexyl ring protons (d = 1.03–1.96), a multiplet for the N–CH
cyclohexyl proton (d = 3.77–3.89), two doublets for the CH–
3
In conclusion, we have developed a new and efficient approach
for the synthesis of a wide range of 3,3-dicyano-N-alkyl-2-arylpro-
panamide derivatives from aldehydes, malononitrile, isocyanides,
and acetic acid. The reaction has been shown to display good func-
tional group tolerance, is high yielding and product isolation is
very straightforward.
CH(CN)2 (d = 4.00, JHH = 7.6 Hz) and CH–CH(CN)2 (d = 4.65,
3JHH = 7.6 Hz) protons,
a doublet for the CH–NH (d = 5.39,
3JHH = 7.3 Hz) proton, and a multiplet for the aromatic protons
(d = 7.39–7.51). The 1H decoupled 13C NMR spectrum of 4a showed
15 distinct resonances, partial assignment of these resonances is
given in the experimental section.

4188
E. Soleimani et al. / Tetrahedron Letters 52 (2011) 4186–4188
O
O
H
O
O
H
NC
H
R
Me
CN
R1
N
O
Me
O
CN
+
RNH2
+
H
R1
H
R1
R1
H
CN
C
5
C
1
2
N
R2
N
R2
3
O
Me
O
EtOH
CN
R1
NC
NR
H
CN
O
O
O
R1
Me
CN
H
NHR
H
R1
Me
HN
O
HN
O
R1
R2
R2
N
N
R2
R2
4
6
This Reaction
Ugi Reaction
Scheme 2. The typical Ugi reaction mechanism and the proposed overall mechanism for this reaction.
Typical procedure for the preparation of 3,3-dicyano-N-
Acknowledgments
cyclohexyl-2-phenylpropanamide (4a)
We gratefully acknowledge financial support from the Iran Na-
tional Science Foundation (INSF) and Research Council of Razi
University.
A solution of benzalaldehyde (0.106 g, 1 mmol), malononitrile
(0.066 g, 1 mmol) and acetic acid (0.060 g, 1 mmol), in EtOH
(10 mL) was stirred at 70 °C. After 30 min, cyclohexyl isocyanide
(0.109 g, 1 mmol) was added and the mixture stirred for 12 h at
70 °C. After completion of the reaction, as indicated by TLC, H2O
(10 mL) was added and the resulting precipitate washed with
H2O to afford the product 4a as a yellow powder (0.27 g, yield
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.013.
97%); mp 185–187 °C. IR (KBr) (m
max/cmÀ1): 3279 (NH), 3084,
2928, 2850, 2250 (CN), 1644, 1563. MS, m/z (%): 282 (M++1, 50),
200 (15), 155 (20), 129 (25), 126 (20), 83 (100), 55 (50), 41 (25).
1H NMR (200 MHz, CDCl3): dH (ppm) 1.03–1.96 (10H, m, 5CH2 of
cyclohexyl), 3.77–3.89 (1H, m, CH–NH of cyclohexyl), 4.00 (1H, d,
References and notes
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3
3JHH = 7.6 Hz, –CH–CH(CN)2), 4.65 (1H, d, JHH = 7.6 Hz, –CH–
3
CH(CN)2), 5.39 (1H, d, JHH = 7.3 Hz, CH–NH), 7.39–7.51 (5H, m,
H–Ar). 13C NMR (75 MHz, CDCl3): dC (ppm) 24.6, 24.7, 25.3, 32.5,
32.7 (C-cyclohexyl), 26.9 (–CH–CH(CN)2), 49.4 (–CH–CH(CN)2),
53.0 (CH–NH), 111.5, 112.1 (2CN), 128.6, 129.7, 130.0, 132.5 (C–
Ar), 166.2 (C@O). Anal. Calcd for C17H19N3O: C, 72.57; H, 6.81; N,
14.94. Found: C, 72.50; H, 6.75; N, 14.83.
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27.
3,3-Dicyano-N-cyclohexyl-2-(4-nitrophenyl)propanamide (4b)
Yellow powder (0.31 g, yield 95%); mp 160–162 °C. IR (KBr)
(m
max/cmÀ1): 3273 (NH), 2926, 2850, 2215 (CN), 1646, 1524,
1349. MS, m/z (%): 327 (M++1, 25), 326 (M+, 5), 245 (25), 201
(25), 150 (50), 126 (30), 83 (100), 81 (65), 43 (85). 1H NMR (200
MHz, CDCl3): dH (ppm) 1.07–2.11 (10H, m, 5CH2 of cyclohexyl),
3.81–3.87 (1H, m, CH–NH of cyclohexyl), 4.11 (1H, d, 3JHH = 8.3 Hz,
–CH–CH(CN)2), 4.67 (1H, d, 3JHH = 8.3 Hz, –CH–CH(CN)2), 5.49 (H, d,
3JHH = 6.4 Hz, CH–NH), 7.67 (2H, d, 3JHH = 8.7 Hz, H–Ar), 8.35 (2H, d,
3JHH = 8.7 Hz, H–Ar). 13C NMR (75 MHz, DMSO-d6): dC (ppm) 24.7,
24.8, 25.5, 32.2, 32.5 (C-cyclohexyl), 26.6 (–CH–CH(CN)2), 48.7 (–
CH–CH(CN)2), 50.1 (CH–NH), 113.5, 113.6 (2CN), 124.3, 130.3,
142.1, 148.1 (C–Ar), 166.2 (C@O). Anal. Calcd for C17H18N4O3: C,
62.57; H, 5.56; N, 17.17. Found: C, 63.00; H, 5.52; N, 17.21.
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