Isocyanide-based multicomponent reactions: Synthesis of alkyl-2-(1-(alkylcarbamoyl)-2,2-dicyanoethyl)benzoate and isochromeno[3,4-b] pyrrole derivatives

Article abstract of DOI:10.1021/jo201908f

A novel four-component reaction between 2-formylbenzoic acids, malononitrile, isocyanides, and alcohols has been developed for a highly efficient preparation of alkyl-2-(1-(alkylcarbamoyl)-2,2-dicyanoethyl)benzoate derivatives. This high atom economy reac

Full text of DOI:10.1021/jo201908f

Note
pubs.acs.org/joc
Isocyanide-Based Multicomponent Reactions: Synthesis of Alkyl-2-(1-
(alkylcarbamoyl)-2,2-dicyanoethyl)benzoate and Isochromeno[3,4-
b]pyrrole Derivatives
Ebrahim Soleimani* and Mohsen Zainali
Department of Chemistry, Razi University, Kermanshah 67149-67346, Iran
S
* Supporting Information
ABSTRACT: A novel four-component reaction between 2-formylbenzoic acids, malononitrile, isocyanides, and alcohols has
been developed for a highly efficient preparation of alkyl-2-(1-(alkylcarbamoyl)-2,2-dicyanoethyl)benzoate derivatives. This high
atom economy reaction led to the construction of two carbon−carbon bonds, one amide, and one ester group in a single
synthetic step. Furthermore, a three-component reaction between 2-formylbenzoic acids, malononitrile, and isocyanides in
dichloromethane for the preparation of isochromeno[3,4-b]pyrroles has been reported.
Scheme 1. Synthesis of 3,3-Dicyano-N-alkyl-2-
ulticomponent reactions (MCRs) provide unmatched
Mopportunities for the expeditious increase of complexity
and diversity in synthetic outcomes. The strategy offers
significant advantages over classical stepwise approaches,
allowing the formation of several bonds and the construction
of complex molecular architectures from simple precursors in a
single synthetic operation without the need for isolation of
intermediates.1 The ability of isocyanide to undergo facile α-
addition with a nucleophile and an electrophile under mild
conditions made it a popular reactant for the development of
novel MCRs.2 As a result of this orthogonal reactivity, MCRs
that involve isocyanides are considered as powerful tools in
modern organic synthesis as well as in the fields of
combinatorial chemistry and drug discovery.3 Therefore, the
design of novel isocyanide-based multicomponent reactions
(IMCRs) can be considered as 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.2,4,5 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 ketone and an isocyanide.6 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 compounds.
arylpropanamides7
Herein, we aimed to modify the reaction to make it more
convenient and efficient. Since 2-formylbenzoic acid 5 contains
both an aldehyde functional group and a carboxylic acid group,
it could be used instead of aldehyde and acetic acid in the above
reaction. Theoretically, using this substrate could allow us to
confirm the role of alcohol in the reaction mechanism.
Therefore, we examined the reaction between 2-formylbenzoic
acid 5, malononitrile 2, isocyanide 3, and alcohol 6 at room
temperature. Gratifyingly, this reaction worked well, leading to
the expected product 7 (Scheme 2). In this reaction, the
Recently, we described the synthesis of 3,3-dicyano-N-alkyl-
2-arylpropanamides 4 by a new isocyanide-based multi-
component reaction of aldehydes 1, malononitrile 2, iso-
cyanides 3, and acetic acid in ethanol.7 In accord with our
suggested mechanism, we believe that the reaction could be
considered as a special case of the Ugi multicomponent
reaction (Scheme 1).
Received: September 16, 2011
Published: November 3, 2011
© 2011 American Chemical Society
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Note
NaOH, Et3N, NaOH, and tBuOK, were not as efficient for this
transformation. For instance, when the reaction was performed
in the presence of 10 mol % of Na2CO3 at room temperature
for 5 h, the desired product 7a was obtained in 86% yield
(Table 1, entry 1). Notably, even in the absence of Na2CO3 or
other additive, 7a was still produced in 51% yield after 12 h at
room temperature. Next, we studied the model reaction
catalyzed by Na2CO3 (10 mol %) at different temperatures.
However, a further increase in the reaction temperature had an
adverse effect.
Scheme 2
alcohol is not only playing the role of a solvent, but also taking
part in the reaction as a reagent.
With the optimized conditions established above, we decided
to probe the generality of this multicomponent reaction. A
variety of starting materials including two formylbenzoic acids
(5) such as 2-formylbenzoic acid and 5,6-dimethoxy-2-
formylbenzoic acid, two isocyanides such as 1,1,3,3-tetrabutyl
isocyanide and tert-butyl isocyanide, and four different alcohols
such as methanol, ethanol, propanol, and iso-propanol were
tested in this new condensation. Results in Table 1 clearly show
that all reactions proceeded smoothly to afford the expected
alkyl-2-(1-(alkylcarbamoyl)-2,2-dicyanoethyl)benzoates in
good yields. The structure of the products were deduced
We chose the reaction of 2-formylbenzoic acid 5,
malononitrile 2, tert-butyl isocyanide 3, and methanol 6 as a
model system for the optimization study. First, several basic
and acidic catalysts were examined to set up a standard reaction
condition. The experimental results showed that the reaction
proceeds promisingly under basic conditions. Then, various
basic catalysts such as Na2CO3, K2CO3, Et3N, NaOH, and
tBuOK were examined in the reaction. The results indicated
that although K2CO3 was found to be effective for this reaction
system, the best result was obtained when Na2CO3 was utilized
as the base. In contrast to Na2CO3, the other bases, such as
1
from their IR, mass, H NMR, and 13C NMR spectra (see the
Experimental Section).
a
Table 1. Synthesis of Alkyl-2-(1-(alkylcarbamoyl)-2,2-dicyanoethyl)benzoate Derivatives
b
entry
R1
R2
R3
product
yield (%)
1
2
H
H
H
H
H
H
tert-butyl
tert-butyl
tert-butyl
Me
Et
7a
7b
7c
7d
7e
7f
86
85
86
90
87
84
90
93
87
90
3
n-pr
Me
Et
4
1,1,3,3-tetramethylbutyl
1,1,3,3-tetramethylbutyl
1,1,3,3-tetramethylbutyl
1,1,3,3-tetramethylbutyl
1,1,3,3-tetramethylbutyl
1,1,3,3-tetramethylbutyl
1,1,3,3-tetramethylbutyl
5
6
n-pr
Me
Et
7
OCH3
OCH3
OCH3
H
7g
7h
7i
8
9
n-pr
iso-pr
10
7j
a
Reaction conditions: 2-formylbenzoic acid 5 (1 mmol), malononitrile 2 (1 mmol), alcohol 6 (2 mL), and Na2CO3 (0.1 mmol) were stirred at 70
b
°C. After 20 min, isocyanide 3 (1 mmol) was added, and the mixture was stirred for 5 h at room temperature. Isolated yield.
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Note
During our investigation, we tried to change the solvent
system to utilize alcohol in an equivalent amount. For this aim,
we have examined the reaction of alcohols 6 with 2-
formylbenzoic acid 5, malononitrile 2, and isocyanides 3 in
dichloromethane at room temperature in the presence of
Na2CO3. To our surprise, we found that alcohol was not
involved in the reaction, and consequently, the expected
product alkyl-2-(1-(alkylcarbamoyl)-2,2-dicyanoethyl)-
benzoates 7 was not obtained. Isolation and characterization
of the resulted product showed that under this condition, the
different isocyanides, such as cyclohexyl isocyanide, tert-butyl
isocyanide, and 1,1,3,3-tetramethylbutyl isocyanide, and ethyl
isocyanoacetate. It is worth mentioning here that during the
optimization of this new reaction, it was found that in contrast
to Na2CO3, triethylamine (Et3N) as a basic reagent showed
promising results. Therefore, it was decided to employ this
reagent for the synthesis of isochromeno[3,4-b]pyrrole
derivatives 8. The results are summarized in Table 2. We
found that all reactions proceeded smoothly to afford the
expected isochromeno[3,4-b]pyrroles 8 in good yields. The
1
structure of the products were deduced from their IR, mass, H
NMR, and 13C NMR spectra (see the Experimental Section).
We have believed that the reaction mechanism is a special
case of the Ugi multicomponent reaction. Mechanistically, it is
conceivable that the reaction involves the initial formation of
the activated alkene, benzylidenemalonodinitrile14 9, through a
Knoevenagel condensation of malononitrile 2 and 2-formyl-
benzoic acid 5. Intermediate 9 undergoes nucleophilic addition
with the isocyanide followed by a nucleophilic attack on the
isocyanide by carboxylate to afford the isocoumarin ring 11.
Subsequently, ring-opening of isocoumarin ring by nucleophilic
addition of alcohol 6 afforded alkyl-2-(1-(alkylcarbamoyl)-2,2-
dicyanoethyl)benzoate derivatives 7 (Scheme 4). When the
solvent is dichloromethane, the intermediate 11 undergoes
Thorpe−Ziegler intermolecular cyclization into isochromeno-
[3,4-b]pyrrole derivates 8. To clarify the proposed mechanism,
first the activated alkene 9 was synthesized by condensation of
malononitrile 2 and 2-formylbenzoic acid 5 in the presence
Na2CO3. Next, the reaction of 9 with the isocyanide and
alcohol in the absence of Na2CO3 afforded the corresponding
alkyl-2-(1-(alkylcarbamoyl)-2,2-dicyanoethyl)benzoate deriva-
tives 7. It should be noted that the basic catalyst, Na2CO3, is
required only for the condensation of malononitrile 2 and 2-
formylbenzoic acid 5.
Scheme 3
reaction afforded isochromeno[3,4-b]pyrrole 8 instead
(Scheme 3).
Isocoumarins (isochromens)8 are an important class of
naturally occurring lactones that exhibit a wide range of
biological activities such as antimicrobial,9 antifungal,10 and
antiangiogenic11 properties and enzyme inhibition.12 In
addition, the isocoumarin ring system is a useful synthetic
intermediate for the synthesis of hetero- and carbocyclic
compounds including isocarbostyrils, isochromenes, or iso-
quinolines.13 Therefore, we focused on examining the efficiency
of this new multicomponent reaction by employing a series of
In conclusion, we have developed two new isocyanide-based
multicomponent reactions for the synthesis of a wide range of
alkyl-2-(1-(alkylcarbamoyl)-2,2-dicyanoethyl)benzoate deriva-
tives and isochromeno[3,4-b]pyrrole derivates from 2-for-
a
Table 2. Synthesis of Isochromeno[3,4-b]pyrrole Derivatives
b
entry
R2
product
yield (%)
1
2
3
4
tert-butyl
8a
8b
8c
8d
86
84
92
87
1,1,3,3-tetramethylbutyl
cyclohexyl
ethyl acetate
a
Reaction conditions: 2-formylbenzoic acid 5 (1 mmol), malononitrile 2 (1 mmol), and Et3N (0.1 mmol) in dichloromethane (2 mL) were stirred at
b
room temperature. After 20 min, isocyanide 3 (1 mmol) was added, and the mixture was stirred for 5 h at room temperature. Isolated yield.
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Note
Scheme 4. Proposed Mechanism
(CN), 1713, 1656, 1530; MS, m/z 342 (M+ + 1), 326, 286, 254, 215,
179, 143, 57, 41; 1H NMR (200 MHz, CDCl3) δH (ppm) 1.07 (3H, t,
mylbenzoic acid, malononitrile, and isocyanides in dichloro-
methane and alcohol, respectively. These high yielding
reactions have been shown to display a good functional
group tolerance, while the product isolation is very
straightforward. We hope that this approach may be of value
to others seeking novel synthetic fragments with unique
properties for medicinal chemistry programs.
3
3JHH = 7.4 Hz), 1.27 (9H, s), 1.85 (2H, m), 4.35 (2H, t, JHH = 6.7
Hz), 4.78 (1H, d, 3JHH = 10.4 Hz), 5.12 (1H, d, 3JHH = 10.4 Hz), 6.87
(1H, brs), 7.42−7.64 (3H, m), 8.00 (1H, d, 3JHH = 7.8 Hz); 13C NMR
(75 MHz, CDCl3) δC (ppm) 10.5, 21.9, 25.4, 28.4, 47.8, 52.0, 67.8,
111.9, 112.2, 127.2, 129.0, 130.1, 131.4, 133.4, 134.7, 166.1, 168.2.
Anal. Calcd for C19H23N3O3: C, 66.84; H, 6.79; N, 12.31. Found: C,
66.88; H, 6.83; N, 12.24.
Methyl 2-(1-(2,4,4-Trimethylpentan-2-ylcarbamoyl)-2,2-
dicyanoethyl)benzoate (7d). White powder (0.33 g, yield 90%):
mp 160−163 °C; IR (KBr) (νmax/cm−1) 3336 (NH), 2964, 2894, 2250
(CN), 1701, 1656, 1562; MS, m/z 370 (M+ + 1), 339, 298, 258, 213,
EXPERIMENTAL SECTION
■
General Procedure for Synthesis of Alkyl-2-(1-(alkylcarba-
moyl)-2,2-dicyanoethyl)benzoates 7a−i. A solution of 2-formyl-
benzoic acid (0.15 g, 1 mmol), malononitrile (0.07 g, 1 mmol), alcohol
(2 mL), and Na2CO3 (0.01 g, 0.1 mmol) was stirred at 70 °C. After 20
min, isocyanide (1 mmol) was added, and the mixture was stirred for 5
h at room temperature. After completion of the reaction as indicated
by TLC, the precipitate was filtrated and washed with ether to afford
the products.
1
128, 135, 97, 58, 41; H NMR (200 MHz, CDCl3) δH (ppm) 0.77
2
(9H, s), 1.31 (3H, s), 1.34 (3H, s), 1.58 (1H, d, JHH = 15.0 Hz), 1.72
2
3
(1H, d, JHH = 15.0 Hz), 4.00 (3H, s), 4.83 (1H, d, JHH = 10.7 Hz),
5.10 (1H, d, 3JHH = 10.7 Hz), 6.98 (1H, brs), 7.40−7.64 (3H, m), 7.96
3
(1H, d, JHH = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δC (ppm) 25.2,
28.9, 29.2, 31.2, 31.4, 47.9, 51.0, 53.2, 55.9, 111.9, 112.2, 127.1, 129.0,
129.8, 131.3, 133.5, 134.4, 165.3, 168.7. Anal. Calcd for C21H27N3O3:
C, 68.27; H, 7.37; N, 11.37. Found: C, 68.22; H, 7.41; N, 11.33.
Ethyl 2-(1-(2,4,4-Trimethylpentan-2-ylcarbamoyl)-2,2-
dicyanoethyl)benzoate (7e). White powder (0.33 g, yield 87%):
mp 140−143 °C; IR (KBr) (νmax/cm−1) 3305 (NH), 2951, 2882, 2250
(CN), 1701, 1669, 1555; MS, m/z 384 (M+ + 1), 338, 312, 272, 255,
Methyl 2-(1-(tert-Butylcarbamoyl)-2,2-dicyanoethyl)-
benzoate (7a). Brown powder (0.27 g, yield 86%): mp 130−132
°C; IR (KBr) (νmax/cm−1) 3349 (NH), 2995, 2962, 2913, 2244 (CN),
2174 (CN), 1694, 1656; MS m/z 314 (M+ + 1), 282, 258, 254, 187,
115, 59, 57, 41; 1H NMR (200 MHz, CDCl3) δH (ppm) 1.27 (9H, s),
3
3
4.00 (3H, s), 4.77 (1H, d, JHH = 10.4 Hz), 5.11 (1H, d, JHH = 10.4
3
Hz), 6.81 (1H, brs), 7.42−7.65 (3H, m), 8.00 (1H, d, JHH = 7.9 Hz);
1
227, 149, 97, 58, 41; H NMR (200 MHz, CDCl3) δH (ppm) 0.77
13C NMR (75 MHz, CDCl3) δC (ppm) 25.4, 28.4, 47.9, 52.0, 53.1,
3
(9H, s), 1.31 (3H, s), 1.34 (3H, s), 1.46 (3H, t, JHH = 7.1 Hz), 1.57
111.9, 112.2, 127.3, 129.0, 129.7, 131.5, 133.6, 134.8, 166.0, 168.5.
Anal. Calcd for C17H19N3O3: C, 65.16; H, 6.11; N, 13.41. Found: C,
65.13; H, 6.08; N, 13.47.
2
2
(1H, d, JHH = 15.0 Hz), 1.71 (1H, d, JHH = 15.0 Hz), 4.45 (2H, q,
3JHH = 7.1 Hz), 4.82 (1H, d, 3JHH = 10.8 Hz), 5.11 (1H, d, 3JHH = 10.8
3
Hz), 7.01 (1H, brs), 7.39−7.60 (3H, m), 7.98 (1H, d, JHH = 7.4 Hz);
Ethyl 2-(1-(tert-Butylcarbamoyl)-2,2-dicyanoethyl)benzoate
(7b). White powder (0.28 g, yield 85%): mp 149−151 °C; IR (KBr)
(νmax/cm−1) 3355 (NH), 2983, 2920, 2256 (CN), 1668, 1545; MS, m/
13C NMR (75 MHz, CDCl3) δC (ppm) 14.1, 25.2, 28.9, 29.1, 31.0,
31.3, 47.9, 51.0, 55.9, 62.4, 111.9, 112.3, 127.0, 128.9, 130.1, 131.3,
133.4, 134.4, 165.4, 168.3. Anal. Calcd for C22H29N3O3: C, 68.90; H,
7.62; N, 10.96. Found: C, 68.87; H, 7.62; N, 10.91.
z 328 (M+ + 1), 282, 272, 229, 143, 115, 57, 41; H NMR (200 MHz,
1
CDCl3) δH (ppm) 1.27 (9H, s), 1.46 (3H, t, 3JHH = 7.1 Hz), 4.45 (2H,
3
3
3
Propyl 2-(1-(2,4,4-Trimethylpentan-2-ylcarbamoyl)-2,2-
dicyanoethyl)benzoate (7f). Yellow powder (0.33 g, yield 84%):
mp 116−118 °C; IR (KBr) (νmax/cm−1) 3317 (NH), 2957, 2907, 2250
(CN), 2193 (CN), 1707, 1669, 1550; MS, m/z 398 (M+ + 1), 382,
q, JHH = 7.1 Hz), 4.77 (1H, d, JHH = 10.4 Hz), 5.12 (1H, d, JHH
=
3
10.4 Hz), 6.84 (1H, brs), 7.26−7.65 (3H, m), 8.00 (1H, d, JHH = 7.8
Hz); 13C NMR (75 MHz, CDCl3) δC (ppm) 14.1, 25.3, 28.4, 47.8,
51.9, 62.3, 111.9, 112.2, 127.2, 128.9, 130.0, 131.5, 133.4, 134.7, 166.1,
168.1. Anal. Calcd for C18H21N3O3: C, 66.04; H, 6.47; N, 12.84.
Found: C, 66.14; H, 6.41; N, 12.88.
Propyl 2-(1-(tert-Butylcarbamoyl)-2,2-dicyanoethyl)-
benzoate (7c). Brown powder (0.29 g, yield 86%): mp 100−102
°C; IR (KBr) (νmax/cm−1) 3387 (NH), 2970, 2888, 2256 (CN), 2200
1
368, 326, 310, 269, 241, 163, 156, 87, 58, 41; H NMR (200 MHz,
CDCl3) δH (ppm) 0.77 (9H, s), 1.07 (3H, t, 3JHH = 7.4 Hz), 1.31 (6H,
3
3
s), 1.55−1.87 (4H, m), 4.36 (2H, t, JHH = 6.9 Hz), 4.82 (1H, d, JHH
3
= 10.5 Hz), 5.11 (1H, d, JHH = 10.5 Hz), 7.00 (1H, brs), 7.35−7.59
(3H, m), 7.96 (1H, d, 3JHH = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δC
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Note
(ppm) 10.5, 21.9, 25.2, 28.9, 29.1, 31.0, 31.3, 47.9, 51.0, 55.8, 67.9,
111.9, 112.3, 127.1, 128.9, 130.2, 131.2, 133.4, 134.4, 165.4, 168.4.
Anal. Calcd for C23H31N3O3: C, 69.49; H, 7.86; N, 10.57. Found: C,
69.44; H, 7.87; N, 10.62.
(1H, brs), 7.35−8.27 (4H, m); 13C NMR (75 MHz, CDCl3) δC (ppm)
30.3, 61.6, 69.3, 96.3, 116.9, 117.0, 120.9, 125.9, 131.0, 133.9, 135.5,
138.0, 144.4, 160.5. Anal. Calcd for C16H15N3O2: C, 68.31; H, 5.37; N,
14.94. Found: C, 68.34; H, 5.39; N, 14.91.
2-Amino-3,5-dihydro-3-(2,4,4-trimethylpentan-2-yl)-5-
oxoisochromeno[3,4-b]pyrrole-1-carbonitrile (8b). Yellow pow-
der (0.28 g, yield 84%): mp 180−183 °C; IR (KBr) (νmax/cm−1) 3374,
3317, 3248 (NH), 2193 (CN), 1720 (CO), 1606, 1555; MS, m/z
Methyl 6-(1-(2,4,4-Trimethylpentan-2-ylcarbamoyl)-2,2-di-
cyanoethyl)-2,3-dimethoxybenzoate (7g). White powder (0.39
g, yield 90%): mp 141−143 °C; IR (KBr) (νmax/cm−1) 3330 (NH),
2891, 2250 (CN), 1706, 1668, 1551; MS, m/z 430 (M+ + 1), 398, 358,
1
(%) 337 (M+), 311, 266, 244, 113, 105, 58, 41; H NMR (200 MHz,
1
318, 301, 273, 195, 136, 107, 58, 41; H NMR (200 MHz, CDCl3) δH
2
CDCl3) δH (ppm) 0.92 (9H, s), 1.99 (6H, s), 2.15 (1H, s), 4.21 (2H,
(ppm) 0.83 (9H, s), 1.36 (3H, s), 1.39 (3H, s), 1.62 (1H, d, JHH
=
3
15.0 Hz), 1.75 (1H, d, 2JHH = 15.0 Hz), 3.94 (6H, s), 4.05 (1H, d, 3JHH
= 10.5 Hz), 4.10 (3H, s), 5.81 (1H, d, 3JHH = 10.5 Hz), 6.80 (1H, brs),
brs), 7.41−7.84 (2H, m), 8.07 (1H, d, JHH = 7.5 Hz), 8.35 (1H, d,
3JHH = 8.1 Hz); 13C NMR (75 MHz, CDCl3) δC (ppm) 30.8, 31.4,
7.06 (1H, d, JHH = 8.7 Hz), 7.12 (1H, d, JHH = 8.7 Hz); 13C NMR
(50 MHz, CDCl3) δC (ppm) 24.6, 28.5, 28.6, 30.6, 30.9, 48.7, 50.6,
52.9, 55.5, 55.6, 61.1, 111.5, 112.0, 114.4, 121.8, 123.2, 128.2, 146.7,
152.9, 164.7, 168.5. Anal. Calcd for C23H31N3O5: C, 64.32; H, 7.27; N,
9.78. Found: C, 64.37; H, 7.33; N, 9.67.
3
3
31.6, 52.0, 64.7, 64.8, 100.0, 116.9, 121.0, 125.9, 131.0, 133.9, 134.1,
135.5, 144.6, 160.4. Anal. Calcd for C20H23N3O2: C, 71.19; H, 6.87; N,
12.45. Found: C, 71.23; H, 6.82; N, 12.47.
2-Amino-3-cyclohexyl-3,5-dihydro-5-oxoisochromeno[3,4-
b]pyrrole-1-carbonitrile (8c). Yellow powder (0.28 g, yield 92%):
mp 238−240 °C; IR (KBr) (νmax/cm−1) 3437, 3336, 3229 (NH), 2206
(CN), 1738 (CO), 1713, 1612, 1562; MS, m/z (%) 307 (M+), 281,
Ethyl 6-(1-(2,4,4-Trimethylpentan-2-ylcarbamoyl)-2,2-dicya-
noethyl)-2,3-dimethoxybenzoate (7h). White powder (0.41 g,
yield 93%): mp 133−135 °C; IR (KBr) (νmax/cm−1) 3331 (NH),
2289, 2250 (CN), 1700, 1663, 1552; MS, m/z 444 (M+ + 1), 412, 398,
372, 332, 315, 287, 209, 156, 107, 58, 41; 1H NMR (200 MHz,
CDCl3) δH (ppm) 0.77 (9H, s), 1.29 (3H, s), 1.33 (3H, s), 1.45 (3H,
3JHH = 7.1 Hz), 1.57 (1H, d, 2JHH = 15.0 Hz), 1.69 (1H, d, 2JHH = 15.0
1
224, 105, 83, 55, 41; H NMR (200 MHz, CDCl3) δH (ppm) 1.15−
2.08 (10H, m), 4.09−4.20 (1H, m), 6.42 (1H, s), 7.32−7.86 (3H, m),
3
8.11 (1H, d, JHH = 7.9 Hz); 13C NMR (75 MHz, CDCl3) δC (ppm)
25.1, 25.7, 30.9, 54.3, 61.5, 95.0, 116.6, 118.2, 120.0, 125.8, 131.3,
134.5, 136.2, 137.1, 146.1, 160.3. Anal. Calcd for C18H17N3O2: C,
70.34; H, 5.58; N, 13.67. Found: C, 70.33; H, 5.55; N, 13.69.
Ethyl 2-(2-Amino-1-cyano-5-oxoisochromeno[3,4-b]pyrrol-
3(5H)-yl)acetate (8d). Yellow powder (0.27 g, yield 87%): mp
219−222 °C; IR (KBr) (νmax/cm−1) 3425, 3343, 3229 (NH), 2206
(CN), 1738, 1713 (CO), 1618; MS, m/z (%) 311 (M+), 285, 266,
3
Hz), 3.88 (3H, s), 3.89 (3H, s), 4.00 (1H, d, JHH = 10.5 Hz), 4.48−
4.57 (2H, m), 4.76 (1H, d, 3JHH = 10.5 Hz), 6.75 (1H, brs), 6.99 (1H,
3
3
d, JHH = 8.7 Hz), 7.06 (1H, d, JHH = 8.7 Hz); 13C NMR (50 MHz,
CDCl3) δC (ppm) 13.8, 24.6, 28.5, 30.6, 30.9, 48.6, 50.7, 55.5, 55.6,
61.0, 62.2, 111.4, 111.9, 114.3, 121.7, 123.2, 128.6, 146.7, 152.9, 164.7,
168.0. Anal. Calcd for C24H33N3O5: C, 64.99; H, 7.50; N, 9.47. Found:
C, 64.93; H, 7.53; N, 9.46.
1
224, 191, 105, 45, 29; H NMR (200 MHz, CDCl3) δH (ppm) 1.35
(3H, 3JHH = 7.1 Hz), 4.14 (1H, s), 4.30 (3H, 3JHH = 7.1 Hz), 4.72 (2H,
3
s), 7.36−7.80 (2H, m), 7.98 (1H, d, JHH = 7.8 Hz), 8.25 (1H, d, 3JHH
Propyl 6-(1-(2,4,4-Trimethylpentan-2-ylcarbamoyl)-2,2-di-
cyanoethyl)-2,3-dimethoxybenzoate (7i). White powder (0.40
g, yield 87%): mp 129−131 °C; IR (KBr) (νmax/cm−1) 3317 (NH),
2889, 2250 (CN), 1700, 1668, 1554; MS, m/z 458 (M+ + 1), 442, 426,
386, 346, 329, 301, 223, 156, 107, 58, 41; 1H NMR (200 MHz,
= 7.5 Hz); 13C NMR (75 MHz, CDCl3) δC (ppm) 14.1, 43.0, 62.9,
69.8, 95.8, 116.1, 117.5, 121.0, 126.1, 131.5, 134.1, 135.8, 136.5, 143.0,
160.4, 167.3. Anal. Calcd for C16H13N3O4: C, 61.73; H, 4.21; N, 13.50.
Found: C, 61.77; H, 4.20; N, 13.47.
3
CDCl3) δH (ppm) 0.76 (9H, s), 1.05 (3H, JHH = 7.4 Hz), 1.29 (3H,
s), 1.32 (3H, s), 1.55 (1H, d, 2JHH = 15.0 Hz), 1.69 (1H, d, 2JHH = 15.0
ASSOCIATED CONTENT
■
3
Hz), 1.73−1.92 (2H, m), 3.87 (3H, s), 3.88 (3H, s), 3.99 (1H, d, JHH
S
* Supporting Information
3
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
= 10.5 Hz), 4.29−4.50 (2H, m), 4.86 (1H, d, JHH = 10.5 Hz), 6.78
3
3
(1H, brs), 6.99 (1H, d, JHH = 8.7 Hz), 7.09 (1H, d, JHH = 8.7 Hz);
13C NMR (50 MHz, CDCl3) δC (ppm) 9.9, 21.6, 24.6, 28.5, 28.6, 30.6,
30.9, 48.6, 50.6, 55.4, 55.5, 61.0, 67.8, 111.5, 112.0, 114.3, 121.7, 123.3,
128.6, 146.6, 152.9, 164.8, 168.2. Anal. Calcd for C25H35N3O5: C,
65.62; H, 7.71; N, 9.18. Found: C, 65.65; H, 7.72; N, 9.16.
AUTHOR INFORMATION
Corresponding Author
*E-mail: E_soleimanirazi@yahoo.com; E-soleimani@razi.ac.ir.
■
Isopropyl 2-(1-(2,4,4-Trimethylpentan-2-ylcarbamoyl)-2,2-
dicyanoethyl)benzoate (7j). Yellow powder (0.36 g, yield 90%):
mp 147−149 °C; IR (KBr) (νmax/cm−1) 3318 (NH), 2953, 2909, 2251
(CN), 2192 (CN), 1711, 1666, 1551; MS, m/z 398 (M+ + 1), 382,
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the Research
Council of Razi University. We would like to thank Dr. Mostafa
Baghbanzadeh for scientific discussion during this work.
1
368, 326, 286, 269, 239, 163, 156, 87, 58, 41; H NMR (300 MHz,
DMSO-d6) δH (ppm) 0.83 (9H, s), 1.27 (3H, s), 1.33 (3H, s), 1.34
3
(6H, d, JHH = 6.4 Hz), 1.94−1.96 (2H, m), 4.99−5.12 (3H, m),
7.41−7.95 (5H, m); 13C NMR (75 MHz, DMSO-d6) δC (ppm) 22.0,
26.3, 26.5, 29.0, 29.6, 31.2, 31.6, 48.2, 50.1, 55.0, 69.4, 113.8, 114.0,
128.8, 129.1, 130.5, 131.5, 133.1, 135.9, 166.1, 167.3, 168.7. Anal.
Calcd for C23H31N3O3: C, 69.49; H, 7.86; N, 10.57. Found: C, 69.21;
H, 7.95; N, 10.50.
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