Unprecedented reaction between ethyl α-cyanocinnamate and o-phenylenediamine: Development of an efficient method for the transfer hydrogenation of electronically depleted olefins

Article abstract of DOI:10.1055/s-2007-991087

A reaction between ethyl α-cyanocinnamate and o-phenylenediamine under thermal conditions yielded 2-cyano-3-phenyl-propionic acid ethyl ester, 2-phenyl benzimidazole, and ethyl cyanoacetate. The mechanistic revelations led to the development of a simple and efficient transfer-hydrogenation process from the in situ generated benzimidazolines to activated olefins under solventless and catalyst-free conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-991087

LETTER
2809
Unprecedented Reaction between Ethyl a-Cyanocinnamate and o-Phenylene-
diamine: Development of an Efficient Method for the Transfer Hydrogenation
of Electronically Depleted Olefins
Transfer
Hydr
a
o
t
f
Elec
t
i
ronica
l
s
ly
D
eplete
h
dOlefins Kumar, Kamal K. Kapoor*
Department of Chemistry, University of Jammu, Jammu 180 006, India
Fax +91(191)2431365; E-mail: k2kapoor@yahoo.com
Received 1 June 2007
byproduct from the reaction mixture. In this regard, devel-
opment of biomimetic reducing agent generated in situ, in
which the byproducts can easily be separated by simple
filtration, is of considerable significance.
Abstract: A reaction between ethyl a-cyanocinnamate and o-phen-
ylenediamine under thermal conditions yielded 2-cyano-3-phenyl-
propionic acid ethyl ester, 2-phenyl benzimidazole, and ethyl
cyanoacetate. The mechanistic revelations led to the development
of a simple and efficient transfer-hydrogenation process from the in
situ generated benzimidazolines to activated olefins under solvent-
less and catalyst-free conditions.
Herein, we disclose a highly efficient and metal-free
transfer-hydrogenation process from in situ generated
benzimidazolines to activated olefins under solvent-free
and catalyst-free conditions.
Key words: organocatalytic reaction, hydrogen transfer, electroni-
cally depleted olefins, benzimidazoline, metal-free reduction
In an attempted synthesis of substituted benzodiazepines11
on heating ethyl a-cyanocinnamate (1a), with o-phen-
ylenediamine (2) in equimolar quantities at 100 °C, the
starting material 1a was found to vanish completely with
the appearance of three new components (TLC: EtOAc–
PE eluent, 1:9). The most polar compound was isolated by
precipitation from EtOAc–PE (7:3) and the remaining
compounds were purified by column chromatography
(EtOAc–PE, 1:20). Spectroscopic analysis showed that
none of these products corresponded to the desired prod-
ucts, which were characterized as 2-cyano-3-phenyl-pro-
pionic acid ethyl ester (3a), 2-phenylbenzimidazole (4a),
and ethyl cyanoacetate (ECA; 5a) in the respective yields
of 88%, 90%, and 65%. Recovery of half of the amount of
o-phenylenediamine used prompted us to use 0.5 equiva-
lent and, in agreement with our expectations, the reaction
proceeded smoothly to produce 3a, 4a, and 5a with 95%,
92%, and 60% yield, respectively (Scheme 1, Table 1, en-
try 1).13 To check the scope of this unusual transforma-
tion, a range of Knoevenagel condensation products 1 was
subjected to analogous reaction conditions and similar ob-
servations were noticed (Table 1). For substrates 1 with
melting points higher than 100 °C (Table 1; entries 5, 7, 9,
and 13), the reactions were carried out at higher tempera-
ture (140 °C).
Reduction of double-bond-containing compounds such as
carbonyl, imines, and olefins is crucial in the industrial
production of chemicals as well as for living organisms.
These powerful transformations often use organometallic
catalysts and hydrogen gas.1
Recently, hydrogen transfer from water to alkenes and
metal-free catalytic hydrogenation of olefins have been an
emerging area in the field of green catalysis.2 Although
less explored, it is well established that heterocyclic com-
pounds having a hydrogen-donating ability such as
dihydrobenzazoles3 or 1,4-dihydropyridines4 are useful as
biomimetic reducing agents. There are reports5 of organo-
catalytic biomimetic chemoselective reduction of double
bonds in electronically deficient olefins using 1,4-dihy-
dropyridine derivatives such as 3,5-bis(ethoxycarbonyl)-
1,4-dihydro-2,6-dimethylpyridine (Hantzsch ester) as the
reducing agent. These esters are known to reduce ketones6
and aldehydes7 to their respective alcohols in the presence
of Lewis acids, and some studies have shown promise for
asymmetric reductions,8 reductive aminations,9 and the
photoinduced reduction of a,b-epoxyketones.10 The main
drawback of these reactions is removal of the pyridine
EWG1
NH2
N
EWG1
EWG2
1 (1.0 equiv)
EWG1
EWG2
100 °C
R
+
+
+
oil bath
N
H
R
EWG2
NH2
R
2 (0.5 equiv)
3
4
5
Scheme 1
SYNLETT 2007, No. 18, pp 2809–2814
x
x
.x
x
.2
0
0
7
Advanced online publication: 12.10.2007
DOI: 10.1055/s-2007-991087; Art ID: D16907ST
© Georg Thieme Verlag Stuttgart · New York

2810
S. Kumar, K. K. Kapoor
LETTER
Table 1 Unprecedented Reaction between Electronically Deficient Olefins and o-Phenylenediamine in Solventless Conditionsa
Yield (%)b
Entry
1
1
Time (min)
30
3
4
5c
N
CN
CO2Et
CN
5a
ECA,
60
95
90
93
92
92
N
H
CO2Et
1a
1b
1c
1d
3a
4a
4b
4c
4d
CN
CO2Et
CN
CO2Et
N
5a
ECA,
55
Cl
OMe
Me
2
3
4
30
30
35
86
90
87
N
H
Cl
Cl
3b
3c
3d
CN
CN
N
5a
ECA,
62
CO2Et
CO2Et
N
MeO
MeO
H
N
CN
CN
5a
ECA,
63
CO2Et
CO2Et
N
Me
Br
Me
Br
H
N
CN
CN
5a
ECA,
69
5
6
45
30
85
87
92
80
N
CO2Et
CO2Et
H
Br
1e
1f
3e
3f
4e
4f
Cl
Cl
N
5a
ECA,
73
CN
CN
N
H
CO2Et
CO2Et
Cl
OMe
OMe
OMe
MeO
MeO
CN
MeO
MeO
CN
N
5a
ECA,
65
CO2Et
CO2Et
7
45
82
82
N
H
OMe
OMe
1g
3g
4g
4h
OMe
MeO
CN
MeO
CN
5a
ECA,
66
N
8
9
40
45
88
77
87
75
CO2Et
CO2Et
N
H
1h
1i
3h
3i
OMe
OH
MeO
HO
CN
MeO
HO
CN
5a
ECA,
56
N
CO2Et
CO2Et
N
H
4i
4i
4i
4c
N
CO2Et
CO2Et
CO2Et
CO2Et
5b
10
11
12
30
35
30
90
80
92
85 DEM,
N
H
65
1j
1k
1l
3j
3k
3l
N
CN
CN
5c
MN,
60
82
CN
CN
N
H
CO2Et
CO2Et
CO2Et
CO2Et
N
5b
OMe
87 DEM,
N
62
MeO
MeO
H
Synlett 2007, No. 18, 2809–2814 © Thieme Stuttgart · New York

LETTER
Transfer Hydrogenation of Electronically Depleted Olefins
2811
Table 1 Unprecedented Reaction between Electronically Deficient Olefins and o-Phenylenediamine in Solventless Conditionsa (continued)
Yield (%)b
Entry
13
1
Time (min)
60
3
4
5c
CO2
CO2Et
H
N
5a
ECA,
70
CN
CN
N
55
65
CN
CN
EtO2C
EtO2C
N
N
H
1m
3m
4j
a The reactants 1 and 2 were mixed and heated in an oil bath at temperatures of 100 °C or 140 °C (entries 5, 7, 9, and 13).
b Yield was calculated with respect to 2 and refers to the filtration of 4 followed by column chromatography to obtain 3 and 5.
c ECA = ethyl cyanoacetate, DEM = diethylmalonate, MN = malononitrile.
The formation of various products can be rationalized To extend the scope of this conversion, a four-component
from the mechanism proposed in Scheme 2. The driving reaction using a 2:1:1 mixture of aldehyde, o-phenylene-
force for the hydrogen transfer is presumably the gain of diamine, and an active CH acid (e.g. ECA, DEM, or MN)
aromaticity in the benzimidazole nucleus.
was conceived. The o-phenylenediamine should facilitate
the in situ formation of Knoevenagel condensation prod-
uct 1 from one equivalent each of aldehyde and CH acid
followed by the cascade leading to the desired products 3
and 4. Towards this end, a mixture of benzaldehyde, o-
phenylenediamine, and ethyl cyanoacetate was heated
without solvent and the expected products 3a and 4a were
obtained in good yields. The results for a range of sub-
strates are summarized in Table 3.
To support our rationale, a 1:1:1 mixture of 1a, o-phen-
ylenediamine, and benzaldehyde was heated under sol-
vent-free conditions at 100 °C to produce the expected
dihydro product 3a and benzimidazole 4a in 92% and
90% yields, respectively, with no formation of ethyl cy-
anoacetate (Table 2, entry 1). In the latter case, the
reaction was completed faster than that without the aral-
dehyde presumably due to the faster formation of benz-
imidazoline from o-phenylenediamine and benzaldehyde. In conclusion, direct in situ organocatalyzed hydrogena-
This reaction was also extended to a variety of substrates tion of electronically deficient olefins has been carried out
and the results are shown in Table 2. Benzimidazolines under solvent- and catalyst-free conditions. This experi-
have been reported earlier to reduce the chemically mentally simple and environment friendly approach can
activated olefins in a cascade approach via amino acid be used to make 2-substituted active CH acids and 2-sub-
catalysis.12
stituted benzimidazoles in very good yields.
H2N
NH2
H
N
a
H2N
NH2
b
N
NH2
path b
2
N
C
N
3
CO2Et
CO2Et
CO2Et
path a
CN
A
1a
CN
CO2Et
5
CO2Et
5
CN
EtO2C
H
N
H
N
N
NH
+
H
NH
NH2
H
EtO2C
N
B
3a
4a
C
Scheme 2 Proposed mechanism of the reaction
Synlett 2007, No. 18, 2809–2814 © Thieme Stuttgart · New York

2812
S. Kumar, K. K. Kapoor
LETTER
Table 2 Cascade in situ Reduction of 1 with o-Phenylenediamine and Araldehyde
H
N
EWG1
EWG2
EWG1
EWG1
NH2
NH2
+
+
R' CHO
aldehyde
+
R'
R
R
N
1
3
4
Entry
R¢
Time (min)
Yield (%)
1
3
4
CN
CO2Et
1
2
3
4
5
Ph
1a
15
20
15
15
15
3a 92
3b 90
3c 94
3d 90
3e 88
4a 90
CN
CO2Et
CN
4-ClC6H4
1b
1c
1d
1e
4b 88
4c 93
4d 85
4e 87
Cl
4-MeOC6H4
4-MeC6H4
3-BrC6H4
CO2Et
MeO
CN
CO2Et
Me
Br
CN
CO2Et
Cl
CN
CO2Et
6
2-ClC6H4
1f
10
20
3f 85
3g 85
4f 84
4g 78
MeO
MeO
MeO
CN
7
3,4,5-(MeO)3C6H2
1g
CO2Et
OMe
CN
8
9
3-MeOC6H4
3-MeO-4-HO-C6H3
Ph
1h
1i
10
30
15
3h 89
3i 76
3h 90
4h 84
4i 78
4a 92
CO2Et
CN
MeO
HO
CO2Et
CN
10
1h
CO2Et
CN
MeO
MeO
11
Ph
1g
20
3g 87
4a 88
CO2Et
MeO
OMe
CN
12
13
14
Ph
Ph
Ph
1d
1l
15
15
20
3d 91
3l 86
3e 88
4a 87
4a 90
4a 92
CO2Et
Me
CO2Et
CO2Et
CN
MeO
Br
1e
CO2Et
MeO
HO
CN
15
Ph
1i
25
3i 82
4a 86
CO2Et
Synlett 2007, No. 18, 2809–2814 © Thieme Stuttgart · New York

LETTER
Transfer Hydrogenation of Electronically Depleted Olefins
2813
Table 3 Four-Component Reaction Leading to Formation of 3 and 4
EWG1
EWG2
EWG1
EWG2
EWG1
EWG2
5
R
R
+
R
CHO
3
1
+
aldehyde
+
H
N
H
N
NH2
NH2
R
R
+
R
CHO
N
H
N
H
4
aldehyde
2
dihydrobenzimidazole
Entry
R
CH acid 5
Time (min) Yield (%)
EWG1
CN
EWG2
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CN
3
4
1
2
Ph
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5b
60
55
60
60
50
65
90
55
120
60
60
75
3a 75
3b 74
3c 77
3d 80
3e 72
3f 65
3g 75
3h 82
3i 66
3a 76
3a 77
3c 80
4a 80
4-ClC6H4
4-OMeC6H4
4-MeC6H4
3-BrC6H4
2-ClC6H4
CN
4b 77
4c 85
4d 83
4e 76
4f 73
4g 79
4h 77
4i 72
4a 80
4a 75
4c 79
3
CN
4
CN
5
CN
6
CN
7
3,4,5-(OMe)3C6H2
3-OMeC6H4
3-OMe-4-OH-C6H3
Ph
CN
8
CN
9
CN
10
11
12
CO2Et
CN
Ph
4-OMeC6H4
CO2Et
CO2Et
(6) (a) Tanner, D. D.; Stein, A. R. J. Org. Chem. 1988, 53,
1642. (b) Fukuzumi, S.; Mochizuki, S.; Tanaka, T. J. Am.
Chem. Soc. 1989, 111, 1497. (c) Beijer, N. A.; Vekemans, J.
A. J. M.; Buck, H. Recl. Trav. Chim. Pays-Bas 1990, 109,
434.
Acknowledgement
One of the authors, S.K. thanks CSIR, New Delhi, for financial
assistance in the form of SRF.
(7) (a) Kanomata, N.; Suzuki, M.; Yoshida, M.; Nakata, T.
Angew. Chem. Int. Ed. 1998, 37, 1410. (b) Fukuzumi, S.;
Ishikawa, M.; Tanaka, T. Tetrahedron 1986, 42, 1021.
(c) Gelbard, G.; Lin, J.; Roques, N. J. Org. Chem. 1992, 57,
1789.
References and Notes
(1) (a) Quellet, S. G.; Tuttle, J. B.; Macmillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 32. (b) Noyori, R. Angew. Chem. Int.
Ed. 2002, 41, 2008.
(8) (a) Nishiyama, K.; Baba, N.; Oda, J.; Inouye, Y. J. Chem.
Soc., Chem. Commun. 1976, 101. (b) Kanomata, N.;
Nakata, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1207.
(c) Obika, S.; Nishiyama, T.; Tatematsu, S.; Miyashita, K.;
Iwata, C.; Imanishi, T. Tetrahedron 1997, 53, 593.
(9) Itoh, T.; Nagata, A.; Kurihara, A.; Miyazaki, M.; Ohsawa, A.
Tetrahedron Lett. 2002, 43, 3105.
(10) Zhang, J.; Jin, M. Z.; Zhang, W.; Yang, L.; Liu, Z. L.
Tetrahedron Lett. 2002, 43, 9687.
(11) Ganai, B. A.; Kumar, S.; Andotra, C. S.; Kapoor, K. K.
Synth. Commun. 2006, 36, 803.
(2) (a) Campana, A. G.; Estevez, R. E.; Fuentes, N.; Robles, R.;
Cuerva, J. M.; Bunuel, E.; Cardenas, D.; Oltra, J. E. Org.
Lett. 2007, 9, 2195. (b) Yang, J. W.; Fonseca, M. T. H.;
Vignola, N.; List, B. Angew. Chem. Int. Ed. 2005, 44, 108.
(3) (a) Mashraqui, S. H.; Kellogg, R. M. Tetrahedron Lett. 1985,
26, 1453. (b) Chikashita, H.; Nishida, S.; Miyazaki, M.;
Morita, Y.; Itoh, K. Bull. Chem. Soc. Jpn. 1987, 60, 737.
(4) (a) Menche, D.; Hassfeld, J.; Li, J.; Menche, G.; Ritter, A.;
Rudolph, S. Org. Lett. 2006, 8, 741. (b) Nakamura, K.;
Fujii, M.; Ohno, A.; Oka, S. Tetrahedron Lett. 1984, 25,
3983. (c) Murakami, Y.; Kikuchi, J.-I.; Hisaeda, Y.;
Hayashida, O. Chem. Rev. 1996, 96, 721.
(12) Ramachary, D. B.; Reddy, G. B. Org. Biomol. Chem. 2006,
4, 4463.
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Oliveira, C. A. F.; Pinto, A. C.; de Alencastro, R. B. J. Org.
Chem. 2003, 68, 8815. (b) Ramachary, D. B.; Kishor, M.;
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Synlett 2007, No. 18, 2809–2814 © Thieme Stuttgart · New York

2814
S. Kumar, K. K. Kapoor
LETTER
Ethyl 2-Cyano-3-[4-(2-cyano-2-ethoxycarbonyl-
(13) General Procedure for Transfer Hydrogenation of
Deactivated Olefins
ethyl)phenyl]propionate (3m)
Two-Component Reaction
Purified by column chromatography using EtOAc–hexane
and isolated as a liquid. IR (neat): nmax = 2986, 2251 (C½N),
1747 (O–C=O), 1518, 1446, 1028, 856, 802 cm–1. 1H NMR
(CDCl3): d = 7.24 (4 H, s, ArH), 4.21 (4 H, q, J = 7.2 Hz,
2 × OCH2CH3), 3.71 (2 H, t, J = 8.0 Hz, 2 × HCCNCO2Et),
3.20 (4 H, dABq, J = 13.6, 5.6 Hz), 1.25 (6 H, t, J = 7.2 Hz,
2 × OCH2CH3). 13C NMR (CDCl3): d = 165.3 (2 × C, O–
C=O), 134.7, 129.4 (4 × CH), 115.9 (2 × C, C½N), 62.8
(2 × CH2, OCH2CH3), 39.36, 39.34, 35.1 (2 × CH2), 13.8
(2 × CH3, OCH2CH3). LRMS: m/z calcd for C18H20N2O4:
328.1423; found: 327.10 [M – H+]. HRMS: m/z calcd for
C18H20N2O4Na: 351.1321; found: 351.1315 [M + Na+].
2-Phenyl-1H-benzoimidazole (4a)
In an open vial, ethyl a-cyanocinnamate (1a, 2.0 mmol)and
o-phenylenediamine (2, 1.0 mmol) were mixed thoroughly
and heated in an oil bath at 100 °C. The reaction mixture
liquefied and resolidified within half an hour and the
reaction was found to be complete (TLC). After cooling the
resultant semi-solid reaction mixture, a 7:3 mixture of
EtOAc and PE (15 mL) was added and the insoluble 2-
phenylbenzimidazole (4a) was filtered out (92% yield). The
filtrate was concentrated, and after column chromatography
of the residue using 5% EtOAc–PE as eluent, the reduced
product 3a and ethyl cyanoacetate (5a) were isolated in 95%
and 60% yield, respectively.
Three-Component Reaction
Mp 289 °C. IR (KBr): nmax = 3051, 1622, 1589, 1462, 1275,
In an open vial, benzaldehyde, ethyl benzylidenecyano-
acetate, and o-phenylenediamine (1:1:1, 1 mmol each) were
mixed thoroughly and then heated in an oil bath at 100 °C.
The resultant mixture liquefied and then resolidified in about
15 min with completion of the reaction (TLC). The workup
was performed as described in the two-component reaction.
Spectral Data of Selected Compounds
1003, 740, 686, 493 cm–1. 1H NMR (DMSO-d6): d = 8.09 (2
H, m), 7.68 (2 H, br s), 7.51 (3 H, m), 7.30 (3 H, m). 13
C
NMR (DMSO-d6): d = 151.7, 144.0 (C, br), 135.0 (C, br),
130.6 (C), 130.3 (CH), 129.4 (2 × CH), 126.9 (2 × CH),
122.7 (CH, br), 122.3 (CH, br), 119.3 (CH, br), 111.7 (CH,
br). ESI-MS: m/z calcd for C13H10N2: 194.084; found: 195.1
[M + H+].
Ethyl 2-Cyano-3-phenylpropionate (3a)
1,4-Di(1H-benzoimidazol-2-yl)benzene (4j)
Mp >300 °C. IR (KBr): nmax = 3058, 1620, 1583, 1498, 1430,
1274, 1122, 964, 821,747, 545, 492 cm–1. 1H NMR (DMSO-
d6): d = 8.50 (4 H, br s), 7.80 (2 H, d, J = 7.2 Hz), 7.69 (2 H,
d, J = 7.2 Hz), 7.4 (4 H, br s). 13C NMR (DMSO-d6): d =
150.9, 144.2, 135.4, 131.5, 127.3, 123.2, 122.2, 119.3,
111.8. MS: m/z calcd for C20H14N4: 310.1218; found: 311.3
[M + H+].
Purified by column chromatography using EtOAc–PE and
isolated as a liquid. IR (neat): nmax = 3043, 2957, 2251
(C≡N), 1751 (O–C=O), 1604, 1440, 1275, 1028, 860, 702
cm–1. 1H NMR (CDCl3): d = 7.31 (5 H, m, ArH), 4.25 (2 H,
q, J = 7.2 Hz, OCH2CH3), 3.74 (1 H, dd, J = 8.4, 6.0 Hz),
3.23 (2 H, dABq, J = 14.0, 5.6 Hz), 1.29 (3 H, t, J = 7.2 Hz,
OCH2CH3). 13C NMR (CDCl3): d = 165.9 (C, O–C=O),
135.1, 128.8, 128.7, 127.7, 115.9 (C, C≡N), 62.9, 39.4, 35.6,
13.8. LRMS: m/z calcd for C12H13NO2: 203.0946; found:
202.162 [M – H+].
Synlett 2007, No. 18, 2809–2814 © Thieme Stuttgart · New York

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