A novel isocyanide-based three-component synthesis of benzimidazo[1,2-a][1, 4]diazepinones

Article abstract of DOI:10.1016/j.tetlet.2011.01.073

3-(2-Formyl-1H-benzimidazol-1-yl)propanoic acid, as a bifunctional formyl acid was prepared in four steps. This compound underwent a one-pot reaction with amines and alkyl isocyanides via the Ugi 4-center-3-component condensation. A series of novel benzimidazole-fused 1,4-diazepine-5-ones were obtained via this method in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2011.01.073

Tetrahedron Letters 52 (2011) 1228–1232
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Tetrahedron Letters
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A novel isocyanide-based three-component synthesis
of benzimidazo[1,2-a][1,4]diazepinones
⇑
Mehdi Ghandi , Nahid Zarezadeh, Abuzar Taheri
School of Chemistry, College of Science, University of Tehran, PO Box 14155 6455, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
3-(2-Formyl-1H-benzimidazol-1-yl)propanoic acid, as a bifunctional formyl acid was prepared in four
Received 20 November 2010
Revised 20 December 2010
Accepted 14 January 2011
Available online 25 January 2011
steps. This compound underwent a one-pot reaction with amines and alkyl isocyanides via the Ugi 4-cen-
ter-3-component condensation.
A series of novel benzimidazole-fused 1,4-diazepine-5-ones were
obtained via this method in moderate to excellent yields.
Ó 2011 Elsevier Ltd. All rights reserved.
During the past decade, significant interest has been focused on
multicomponent reactions (MCRs)1 in general and isocyanide-
based multicomponent reactions (IMCRs)2 in particular. As a result
of diversity oriented methodology,3 IMCRs such as the Ugi four-
component reaction (U-4CR) is an important tool in combinatorial
chemistry.4 Utilization of bifunctional reagents, in which the par-
ticipating functional groups of two components of the U-4CR are
present in one structure, is another strategy to increase scaffold
diversity. The synthesis of various lactams using bifunctional
keto-acids or formyl acids, amines, and isocyanides as starting
materials in the Ugi three-component reaction (U-3CR) has been
reported.5
azole rings fused to a [1,4]benzodiazepine framework are available
in the literature,21 we decided to synthesize a new series of fused
benzimidazole-1,4-diazepin-5-ones.
Initially, 2-(2-formyl-1H-benzimidazol-1-yl)propionic acid (4)
was synthesized according to the procedure presented in Scheme
1. 2-(Diethoxymethyl)-1H-benzimidazole (1) was prepared using
the previously reported method.22 The spectral data of 1 were sim-
ilar to those of an authentic sample. Subsequent treatment of 1
with methyl acrylate in the presence of K2CO3 in refluxing CH3CN
for 5 h afforded methyl 2-[2-(diethoxymethyl)-1H-benzimidazol-
1-yl]propanoate (2) in 95% yield.23 Transformation of 2 into 2-
[2-(diethoxymethyl)-1H-benzimidazol-1-yl]propanoic acid (3)
was then carried out in a mixture of methanolic NaOH at rt for
4 h in 92% yield.24 Reaction of 3 with HCl in THF/H2O under reflux
for 24 h finally afforded the desired bifunctional compound 4 in
90% yield.25 The structures of compounds 2, 3, and 4 were con-
firmed from analytical and spectral data.
Ugi 4-center three-component reactions employing 4, various
amines 5a–f and isocyanides proceeded in methanol at 40 °C to
yield the novel benzimidazo[1,2-a][1,4]diazepinones 6a–k in mod-
erate to excellent yields (Scheme 2, Table 1).26 Typically, full con-
version of the reactants was achieved within 4–10 h, depending
on the structure of the initial amines and isocyanides. The struc-
tures of compounds 6a–k were confirmed from analytical and
spectral data.
Seven-membered heterocyclic rings are an area of considerable
interest, mainly due to their pharmacological properties.6 For
example, 1,4-diazepin-5-ones possess interesting biological prop-
erties7 that include inhibition of the lymphocyte function associ-
ated antigen-1 LFA-1, in inflammation and autoimmune
diseases,8 anticonvulsant activity,9 inhibition of reverse trans-
criptase of HIV-1,10 pharmacophores for structure–activity
relationships, and most recently,11 -turn-like mimics.7 1,4-Benzo-
c
diazepines also exhibit a broad range of therapeutic and biological
uses.12 Therefore, much attention has been paid to the replacement
of the fused benzene ring with heterocyclic rings, such as thio-
phenes,13 imidazoles,14 pyrroles,15 isoxazoles,16 pyrazines,17 and
pyrazoles.18
In medicinal chemistry,19 the privileged benzimidazole moiety
is a core structure present in a number of commercial drugs includ-
ing Prilosec, Nexium, Protonix, Atacand, Famvir, and Vermox, as
well as numerous experimental drug candidates in a wide range
of therapeutic areas.18 The synthesis of fused benzimidazole-1,4-
diazepin-2-ones as potential anticancer agents has also been
reported.20 Given that a few reports on the synthesis of benzimid-
The reaction presumably follows the same initial course as the
classical Ugi condensation with an intermediate imine being at-
tacked by the isocyanide to give a nitrilium intermediate (Scheme
3). Subsequent trapping of the nitrilium intermediate by carboxyl-
ate followed by an irreversible acyl transfer step, the Mumm
rearrangement affords the desired benzimidazole-fused 1,4-diaze-
pin-5-ones.27
With respect to the amine component, various aromatic amines,
such as substituted anilines as well as benzylamine were tolerated.
Moreover, the structure of the amine and isocyanide component
had subtle effects on the yields.
⇑
Corresponding author. Tel.: +98 21 61112250; fax: +98 21 66495291.
E-mail address: ghandi@khayam.ut.ac.ir (M. Ghandi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.073

M. Ghandi et al. / Tetrahedron Letters 52 (2011) 1228–1232
1229
O
NH2
NH2
K2CO3, CH3CN
reflux, 5 h
Na, EtOH
OCH2CH3
OCH2CH3
N
OCH2CH3
OCH2CH3
reflux, 24 h
H3CH2CO
N
H
CH2=CHCO2CH3
95%
82%
1
O
N
N
OCH2CH3
N
N
OCH2CH3
OCH2CH3
N
N
OCH2CH3
HCl, THF, H2O
reflux, 24 h
NaOH, MeOH
rt, 4 h
H
92%
90%
O
OH
OH
CH3
O
O
O
2
3
4
Scheme 1. Synthesis of formyl acid 4.
R2
MeOH
O
H
N
N
O
NH
R1
O
40°C, 4-10 h
N
N
+
R1-NH2
+
R2-NC
67-91%
N
OH
O
4
5a-f
6a-k
Scheme 2. Synthesis of benzimidazole-fused 1,4-diazepin-5-ones 6a–k.
R1
R1
R2
NH
O
N
N
HN
O
HN
H
N
N
N
N
N
R2-NC
R1-NH2
N
N
R2
H
R1
O
N
OH
O
O
O
O
O
4
6a-k
Scheme 3. Mechanism evoked for the formation of products 6a–k derivatives.
Table 1
Structures of products 6a–k obtained from 4, amines 5a–f and 1,1,3,3-tetramethylbutyl or cyclohexylisocyanides
Entry Product
R1 R2
Time (h)
Yield (%)
O
NH
O
N
N
1
7
76
N
6a
O
NH
O
N
N
2
4
87
N
6b
(continued on next page)

1230
M. Ghandi et al. / Tetrahedron Letters 52 (2011) 1228–1232
Table 1 (continued)
Entry
R1
R2
Product
Time (h)
Yield (%)
O
O
O
O
NH
O
N
N
3
4
85
N
6c
MeO
NH
O
N
N
OMe
4
5
6
8
67
79
85
N
6d
Cl
NH
N
N
Cl
7
N
O
6e
NH
O
N
N
10
N
6f
O
NH
N
N
7
8
9
7
4
4
80
91
86
N
O
6g
O
NH
O
N
N
N
6h
O
NH
O
N
N
N
6i

M. Ghandi et al. / Tetrahedron Letters 52 (2011) 1228–1232
1231
Table 1 (continued)
Entry
R1
R2
Product
Time (h)
Yield (%)
MeO
O
NH
O
N
N
10
OMe
8
74
N
6j
O
NH
O
N
N
11
10
82
N
6k
8. Wattanasin, S.; Kallen, J.; Myers, S.; Guo, Q.; Sabio, M.; Ehrhardt, C.; Albert, R.;
Hommel, U.; Weckbecker, G.; Welzenbach, K.; Weitz-Schmidt, G. Bioorg. Med.
Chem. Lett. 2005, 15, 1217–1220.
9. Murthy, K. S. K.; Knaus, E. E. Drug Dev. Res. 1999, 46, 155–162.
10. Parker, K. A.; Dermatakis, A. J. Org. Chem. 1997, 62, 4164–4167.
11. Sherrill, R. G. Tetrahedron Lett. 2007, 48, 7053–7056.
12. (a) Vida, J. A. In Medicinal Chemistry Part III; Wolf, M. V., Burger, A., Eds.; Wiley:
New York, 1981; (b) Roth, H. J.; Kleemann, A. In Drug Synthesis in
Pharmaceutical Chemistry; Wiley: New York, 1988; Vol. 1,; (c) Fukinaga, M;
Ishizawa, K.; Kamei, C. Pharmacology 1998, 57, 233–241; (d) Williams, M. J.
Med. Chem. 1983, 26, 619–628.
13. Tinney, F. J.; Sanchez, J. P.; Nogas, J. A. J. Med. Chem. 1974, 17, 624–630.
14. Edenhofer, A. Helv. Chim. Acta 1975, 58, 2192–2209.
15. Fontanella, L.; Mariani, L.; Tarzia, G. Eur. J. Med. Chem. 1976, 11, 217–220.
16. Jaunin, R. Helv. Chim. Acta 1974, 57, 1934–1942.
17. Field, G. F.; Sternbach, L. H.; Walser, A. US Patent 3880840, 1975; Chem. Abstr.
1976, 85, 78175.
In conclusion, we have shown that benzimidazole-fused 1,4-
diazepin-5-ones 6a–k can be prepared efficiently by a novel
modification of the four-component Ugi reaction of bifunctional
aldehyde-acids, isonitriles, and amines. The ease of preparation
of the initial reactants, convenient synthesis, simple isolation of
products, and the overall moderate to excellent yields are the
advantages of the described transformations. These new benz-
imidazole products broaden the range of scaffolds accessible
through Ugi reactions, and several may represent interesting
pharmacophores.
Acknowledgment
18. (a) De Wald, H. A.; Nordin, I. C.; L’Italien, Y. J.; Parcell, R. F. J. Med. Chem. 1973,
16, 1346–1354; (b) De Wald, H. A.; Lobbestael, S.; Butler, D. E. J. Med. Chem.
1977, 20, 1562–1569; (c) De Wald, H. A.; Lobbestael, S.; Poschel, B. P. H. J. Med.
Chem. 1981, 24, 982–987; (d) Baraldi, P. G.; Manfredini, S.; Periotto, V.; Simoni,
D.; Guarneri, M.; Borea, P. A. J. Med. Chem. 1985, 28, 683–685.
The authors acknowledge the University of Tehran for financial
support of this research.
References and notes
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W.; Yan, B. J. Comb. Chem. 2009, 11, 1083–1093.
23. Preparation
of
methyl
3-[2-(diethoxymethyl)-1H-benzimidazol-1-
yl]propanoate (2). To a solution of 1 (3.30 g, 15 mmol) in CH3CN (30 mL)
were added methyl acrylate (2.19 g, 15.2 mmol) and K2CO3 (2.10 g, 15 mmol)
and the mixture was heated at reflux for 5 h. The resulting solid was filtered,
and the filtrate concentrated under reduced pressure to afford 4.53 g (95%) of
2. Brown oil. 1H NMR (500 MHz, CDCl3) d 1.20 (6H, t, J = 7.0 Hz, 2OCH2CH3),
2.86 (2H, t, J = 7.7 Hz, NCH2CH2CO), 3.52–3.59 (2H, m, OCH2CH3), 3.62 (3H, s,
OCH3), 3.75–3.81 (2H, m, OCH2CH3), 4.67 (2H, t, J = 7.7 Hz, NCH2CH2CO), 5.65
(1H, s, CH(OC2H5)2), 7.20 (1H, t, J = 7.3 Hz, Ar), 7.24 (1H, t, J = 7.5 Hz, Ar), 7.37
(1H, d, J = 7.8 Hz, Ar), 7.71 (1H, d, J = 7.5 Hz, Ar); 13C NMR (125 MHz, CDCl3) d
15.4 (2OCH2CH3), 34.7 (NCH2CH2CO), 40.1 (NCH2CH2CO), 52.2 (OCH3), 64.1
(2OCH2CH3), 100.0 (CH(OC2H5)2), 110.1, 120.7, 122.6, 123.7, 135.7, 142.2, 150.7
4. Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555–600.
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Ivachtchenko, A. V. J. Org. Chem. 2005, 70, 1478–1481; (b) Marcaccini, S.;
Miguel, D.; Torroba, T.; Garcia-Valverde, M. J. Org. Chem. 2003, 68, 3315–3318;
(c) Ilyn, A. P.; Loseva, M. V.; Vvedensky, V. Y.; Putsykina, E. B.; Tkachenko, S. E.;
Kravchenko, D. V.; Khvat, A. V.; Krasavin, M. Y.; Ivachtchenko, A. V. J. Org. Chem.
2006, 71, 2811–2819; (d) Ilyin, A. P.; Parchinski, V. Z.; Peregudova, J. N.;
Trifilenkov, A. S.; Poutsykina, E. B.; Tkachenko, S. E.; Kravchenko, D. V.;
Ivachtchenko, A. V. Tetrahedron Lett. 2006, 47, 2649–2653; (e) Zhang, J.;
Jacobson, A.; Rusche, J.; Herlihy, W. J. Org. Chem. 1999, 64, 1074–1076.
6. (a) Elliott, J. M.; Carlson, E. J.; Chicchi, G. G.; Dirat, O.; Dominguez, M.; Gerhard,
U.; Jelley, R.; Jones, A. B.; Kurtz, M. M.; Tsao, K. I.; Wheeldon, A. Bioorg. Med.
Chem. Lett. 2006, 16, 2929–2932; (b) Conejo-García, A.; Núñez, M.; Díaz-
Gavilán, M.; Cruz-López, O.; Gallo, M. A.; Espinosa, A.; Campos, J. M. Expert Opin.
Drug Disc. 2008, 3, 1223–1235.
(C-Ar), 171.9 (C@O); IR (KBr) m
: 1736 cmÀ1; MS (EI) m/z: 307 (M++1, 14), 262
(36), 233 (100), 173 (16), 159 (9), 131 (11), 118 (11), 87 (13), 59 (15%). Anal.
Calcd for C16H22N2O4: C, 62.73; H, 7.24; N, 9.14. Found: C, 62.53; H, 7.32; N,
9.10.
24. Preparation of 3-[2-(diethoxymethyl)-1H-benzimidazol-1-yl]propanoic acid
(3). To a stirred solution of methyl 3-[2-(diethoxymethyl)-1H-benzimidazol-
1-yl]propanoate (2) (4.6 g, 15 mmol) in MeOH (15 mL), a solution of NaOH
7. Fenster, E.; Rayabarapu, D. K.; Zhang, M.; Mukherjee, S.; Hill, D.;
Neuenswander, B.; Schoenen, F.; Hanson, P. R.; Aubé, J. J. Comb. Chem. 2008,
10, 230–234.

1232
M. Ghandi et al. / Tetrahedron Letters 52 (2011) 1228–1232
(0.72 g, 18 mmol) in H2O (7 mL) was added dropwise. The reaction mixture
146.2 (C-Ar), 172.7 (C@O), 184.9 (C@O); IR (KBr) m
: 2482–2859, 1690 cmÀ1; MS
was stirred for 4 h at rt (monitored by TLC). After evaporation of the volatiles,
the mixture was diluted with H2O (4 mL), and the pH of the reaction mixture
was adjusted to pH 3–4 with HCl. Filtration of the mixture and recrystallization
of the solid from EtOH afforded 4.05 g (92%) of 3. White solid: mp 140–142 °C;
1H NMR (500 MHz, CDCl3) d 1.29 (6H, t, J = 7.6 Hz, 2OCH2CH3), 3.01 (2H, t,
J = 7.6 Hz, NCH2CH2CO), 3.62–3.68 (2H, m, OCH2CH3), 3.85–3.91 (2H, m,
OCH2CH3), 4.81 (2H, t, J = 7.6 Hz, NCH2CH2CO), 5.87 (1H, s, CH(OC2H5)2),
7.32–7.38 (2H, m, Ar), 7.54 (1H, d, J = 7.8 Hz, Ar), 7.84 (1H, d, J = 7.7 Hz, Ar),
13.03 (1H, br s, OH); 13C NMR (125 MHz, CDCl3) d 15.5 (2OCH2CH3), 35.0
(NCH2CH2CO), 40.5 (NCH2CH2CO), 64.4 (2OCH2CH3), 99.3 (CH(OC2H5)2), 110.5,
(EI) m/z: 218 (M+, 74), 189 (20), 173 (100), 159 (20), 145 (25), 131 (48), 118
(57), 104 (19), 90 (17), 77 (24%). Anal. Calcd for C11H10N2O3: C, 60.55; H, 4.62;
N, 12.84. Found: C, 60.32; H, 4.65; N, 12.84.
26. Representative procedure for the preparation of 3-oxo-2-phenyl-N-(1,1,3,3-
tetramethylbutyl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-
1-carboxamide (6a). A solution of 4 (0.22 g, 1.0 mmol), aniline (1.0 mmol) and
1,1,3,3-tetramethylbutyl isocyanide (1.0 mmol) in MeOH (3 mL) was stirred at
40 °C for 7 h. The progress of the reaction was monitored by TLC. On
completion, the mixture was cooled to rt, the crude solid filtered and
recrystallized from EtOH to afford 0.33 g (76%) of 6a. White solid: mp 148–
150 °C; 1H NMR (500 MHz, CDCl3) d 0.79 (9H, s, CMe3), 1.39 and 1.42 (6H, 2s,
CMe2), 1.65 (2H, AB-q, J = 15.1 Hz, CCH2C), 3.19 (1H, ddd, J = 15.0, 4.5, 1.8 Hz,
NCH2CHeqHCO), 3.40 (1H, ddd, J = 15.0, 13.2, 4.4 Hz, NCH2CHHaxCO), 4.40 (1H,
ddd, J = 13.2, 13.2, 1.8 Hz, NCHaxHCH2CO), 4.48 (1H, ddd, J = 13.2, 4.4, 4.4 Hz,
NCHHeqCH2CO), 5.78 (1H, s, NCOCHN), 6.55 (1H, br s, NH), 7.31 (1H, t,
J = 7.1 Hz, Ar), 7.36 (2H, d, J = 7.4 Hz, Ar), 7.40–7.45 (5H, m, Ar), 7.80 (1H, dd,
J = 6.3, 2.7 Hz, Ar). 13C NMR (125 MHz, CDCl3) d: 28.8 (CMe2), 29.4 (CMe2), 31.6
(CMe3), 31.8 (CMe3), 35.6 (NCH2CH2CO), 42.0 (NCH2CH2CO), 52.6 (CCH2C), 56.6
(CMe2), 66.1 (NCOCHN), 110.2 (C-Ar), 120.1 (C-Ar), 123.9 (C-Ar), 124.3 (C-Ar),
127.2 (2C-Ar), 128.0 (C-Ar), 129.8 (2C-Ar), 136.0 (C-Ar), 142.1 (C-Ar), 144.1 (C-
120.1, 123.3, 124.2, 135.3, 140.7, 150.7 (C-Ar), 175.1 (C@O); IR (KBr) m: 2362–
2778, 1696 cmÀ1; MS (EI) m/z: 293 (M++1, 8), 248 (34), 219 (100), 173 (9), 159
(7), 131 (9), 119 (16), 77 (9%). Anal. Calcd for C15H20N2O4: C, 61.63; H, 6.90; N,
9.58. Found: C, 61.43; H, 7.05; N, 9.45.
25. Preparation of 3-[2-formyl-1H-benzimidazol-1-yl]propanoic acid (4). H2O
(12 mL) and 37% HCl (10 mL) were added to a THF (45 mL) solution of the
crude 3-[2-(diethoxymethyl)-1H-benzimidazol-1-yl]propanoic acid (3) (4.38 g,
15 mmol), and the mixture was heated to reflux for 24 h. After evaporation of
the volatiles, the mixture was diluted with H2O (7 mL) and the pH of the
reaction mixture was adjusted to 3–4 with saturated K2CO3 solution. Filtration
of the mixture and recrystallization of the solid from EtOH afforded 2.95 g
(90%) of 4. White solid: mp 189–190 °C; 1H NMR (500 MHz, CDCl3) d 2.82 (2H,
t, J = 7.0 Hz, NCH2CH2CO), 4.83 (2H, t, J = 7.0 Hz, NCH2CH2CO), 7.34 (1H, t,
J = 7.5 Hz, Ar), 7.43 (1H, t, J = 7.6 Hz, Ar), 7.60 (1H, d, J = 8.2 Hz, Ar), 7.86 (1H, d,
Ar), 148.3 (C-Ar), 164.4 (C@O), 172.1 (C@O); IR (KBr) m
: 3353, 1686 cmÀ1; MS
(EI) m/z: 433 (M++1, 2), 277 (100), 249 (52), 222 (20), 157 (25), 57 (16). Anal.
Calcd for C26H32N4O2: C, 72.19; H, 7.46; N, 12.95. Found: C, 72.11; H, 7.54; N,
12.95.
J = 8.0 Hz, Ar), 10.01 (1H, s, COH); 13C NMR (125 MHz, CDCl3)
(NCH2CH2CO), 40.9 (NCH2CH2CO), 111.7, 122.4, 124.4, 127.2, 136.4, 142.9,
d
35.0
27. Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8.