BF3·Et2O promoted one-pot expeditious and convenient synthesis of 2-substituted benzimidazoles and 3,1,5-benzoxadiazepines

Article abstract of DOI:10.1016/j.tetlet.2004.03.117

2-Substituted benzimidazoles and 3,1,5-benzoxadiazepines have been synthesized in excellent yields in a single pot by cyclodehydration of N-acyl-1,2-phenylenediamines and N,N^′-diacyl-1,2- phenylenediamines prepared in situ from the corresponding 1,2-phenylenediamines and an acid chloride, respectively.

Full text of DOI:10.1016/j.tetlet.2004.03.117

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4185–4187
BF ÆEt O promoted one-pot expeditious and convenient synthesis
3
2
of 2-substituted benzimidazoles and 3,1,5-benzoxadiazepines
*
Vishnu K. Tandon and Manoj Kumar
Department of Chemistry, University of Lucknow, Lucknow 226007, India
Received 17 November 2003; revised 12 March 2004; accepted 19 March 2004
Abstract—2-Substituted benzimidazoles and 3,1,5-benzoxadiazepines have been synthesized in excellent yields in a single pot by
0
cyclodehydration of N-acyl-1,2-phenylenediamines and N,N -diacyl-1,2-phenylenediamines prepared in situ from the corresponding
,2-phenylenediamines and an acid chloride, respectively.
1
Ó 2004 Elsevier Ltd. All rights reserved.
The benzimidazole ring is a crucial pharmacophore in
drug discovery. Benzimidazole derivatives are an unique
and broad-spectrum class of antirhino/enteroviral
agents. Benzimidazoles exhibit significant activity
2
R
N
NH
2
N
(i) RCOCl
(ii) BF .Et
(i) 2RCOCl
(ii) BF .Et
R
O
R1
N
H
3
2
O
R1
NH2
3
2
O
R
1
N
R2
R2
1
R2
R
1
2
3
3
R1 = R2 = H
R1 = Cl, R2 = H
R1 = H, R2 = Cl
against several viruses including HIV, herpes (HSV-1),
4
5
RNA,
influenza
and human cytomegalovirus
HCMV). In recent years benzimidazoles have been
2a
(
reported to act as topoisomerase I inhibitors, selective
R1 = NO2, R2 = H
6
7
neuropeptide Y Y1 receptor antagonists, angiotensin II
8
Scheme 1.
2a
(
HT
AII) inhibitors, inhibitors of HCMV replication, 5-
9
3
antagonists in isolated guinea pig ileum, potential
antitumour agents, antimicrobial agents, smooth
muscle cell proliferation inhibitors, a treatment for
interstitial cystitis, as factor Xa inhibitors and in
diverse areas of chemistry.
Benzoxadiazepines have been found to possess marked
10
11
During the course of our studies towards the develop-
ment of new routes to the synthesis of heterocycles, we
12
13
14
employed BF
3
ÆEt
2
O as a selective reagent for cyclode-
15
0
hydration of N-acyl-1,2-phenylenediamines and N,N -
diacyl-1,2-phenylenediamines, resulting in the formation
of 2-substituted benzimidazoles and 2,4-disubstituted
benzoxadiazepines (Scheme 1).
16
biological effects as CNS stimulants, muscle relax-
18
17
ants, tranquilizers, anticonvulsants, antibacterial and
antiinflamatory agents and pesticides and insecti-
19
We envisaged that cyclodehydration of N-acyl and
0
18
cides.
N,N -diacyl derivatives 4 and 5 with BF
3
2
ÆEt O would
lead to the formation of 2-substituted benzimidazoles 2
and 2,4-disubstituted 3,1,5-benzoxadiazepines 3.
A number of synthetic methods have been developed in
recent years to uncover a variety of new reagents for the
20–26
synthesis of 2-substituted benzimidazoles.
However,
O
the yields reported in the above methods are moderate
or poor. Moreover more than one step is involved in the
synthesis of these compounds. Few methods are avail-
able in the literature for the synthesis of benzoxadiaze-
NH
2
NH
NH
R
R
R1
NH
R
R1
R2
R2
27–30
O
O
pines.
5
4
*
0
Corresponding author. Tel.: +91-522-2322283; fax: +91-522-23266-
5; e-mail: vishnutandon@yahoo.co.in
A typical reaction procedure involves the addition of
1,2-phenylenediamines 1 to the acid chloride (1 equiv) at
6
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.117

4186
V. K. Tandon, M. Kumar / Tetrahedron Letters 45 (2004) 4185–4187
Table 1. Isolated 2-substituted benzimidazoles 2 and 3,1,5-benz-
oxadiazepines 3 from 1,2-phenylenediamines 1. All the reactions were
complete in 1–2.5 h
3. Migawa, M. T.; Girardet, J.-L.; Walker, J. A., II;
Koszalka, G. W.; Chamberlain, S. D.; Drach, J. C.;
Townsend, L. B. J. Med. Chem. 1998, 41, 1242–1251.
4. Tamm, I.; Sehgal, P. B. Adv. Virus Res. 1978, 22, 187–258.
1
2
Entry
R
R
R
Product yield
%)
5
6
. Tamm, I. Science 1957, 126, 1235–1236.
(
. (a) Wu, Z.; Jin, S.; Yang, J. M.; Xiav, H.; Sim, S. P.; Liu,
A.; Liu, L. F.; LaVoie, E. Abstracts of The American
Chemical Society, Division of Medicinal Chemistry, 222nd
ACS National Meeting, Chicago, IL Aug 26–29, 2001;
American Chemical Society: Washington, DC, 2001; 62
(b) Kim, J. S.; Gatto, B.; Yu, C.; Liu, A.; Liu, L. F.;
LaVoie, E. J. Med. Chem. 1996, 39, 992–995.
2
3
1
2
3
4
5
6
7
8
9
CH
3
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
95
97
98
97
98
94
93
92
94
92
93
94
93
95
82
88
91
93
90
92
90
83
86
85
87
92
88
92
C
6
H
5
H
4-Cl–C
6
H
4
H
4-MeO–C
6
H
4
H
4-O
2
N–C
6
H
4
H
2-C
4-C
CH
5
5
3
H
H
4
N
N
H
7. (a) Zarrinmayeh, H.; Zimmerman, D. M.; Cantrell, B. E.;
Schober, D. A.; Bruns, R. F. Bioorg. Med. Chem. Lett.
1999, 9, 647–652; (b) Zarrinmayeh, H.; Nunes, A.;
Ornstein, P.; Zimmerman, D.; Arnold, B.; Schober, D.;
Gackenheimer, S.; Bruns, R.; Hipskind, P.; Britton, T.;
Cantrell, B.; Gehlert, D. J. Med. Chem. 1998, 41, 2709–
2719.
4
H
–CH
2
–CH
2
H
2-Furyl
H
10
11
12
13
14
CH
CH
3
Cl
H
3
C
6
H
5
Cl
NO
NO
CH
3
2
2
8. Kohara, Y.; Kubo, K.; Imamiya, E.; Wada, T.; Inada, Y.;
Naka, T. J. Med. Chem. 1996, 39, 5228–5235.
6
C H
5
9
. Lopez, M. L. R.; Benhamu, B.; Morcillio, M. J.; Tejada,
I. D.; Orensanz, L.; Alfaro, M. J.; Martin, M. I. J. Med.
Chem. 1999, 42, 5020–5028.
0
°C in dry dioxane and stirring for 30 min at rt to fur-
nish the corresponding N-acyl-1,2-phenylenediamine 4.
BF ÆEt O in dry dioxane was added to crude 4 and the
1
0. Denny, W. A.; Rewcastle, G. W.; Baguley, B. C. J. Med.
Chem. 1990, 33, 814–819.
3
2
reaction mixture refluxed for 1–2.5 h at 130 °C. The
11. (a) Fonseca, T.; Gigante, B.; Gilchrist, T. L. Tetrahedron
2001, 57, 1793–1799; (b) Parikh, A. R.; Khunt, M. D.
Abstracts of The American Chemical Society, Division of
Medicinal Chemistry, 222nd ACS National Meeting,
Chicago, IL Aug 26–29, 2001; American Chemical Soci-
ety: Washington, DC, 2001; 73.
31
yields of the 2-substituted benzimidazoles were excel-
lent (92–98%) and independent of the various substitu-
ents present in the precursor (Table 1).
Employing the same procedure reported above but using
2
1
2. Elokdah, H. M.; Chai, S. Y.; Sulkowski, T. S. U.S. Patent
,763,473, June 9, 1998; Chem. Abstr. 1998, 129, 58784g.
3. Iyenger, S.; Nuhlhauser, M. A.; Thor, K. B. U.S. Patent
equiv of acid chloride, 2,4-substituted-3,1,5-benz-
5
32
oxadiazepines 3 were synthesized. The yields of 3 were
2–93% and independent of various substituents present
in the precursor (Table 1).
1
8
1
1
3,129, 1996; International PCT Patent 33,873, September
8, 1997; Chem. Abstr. 1997, 127, 293221P.
1
4. Zhao, J.; Arnaiz, D.; Griedel, B.; Sakata, B.; Dallas, J.;
Whitlow, M.; Trinh, L.; Post, J.; Liang, A.; Morrissey, M.;
Shaw, K. Bioorg. Med. Chem. Lett. 2000, 10, 963–966.
5. Stevenson, C.; Davies, R.; Jeremy, H. Chem. Res. Toxicol.
Our method for the synthesis of 2-substituted benzimid-
azoles and 2,4-disubstituted-3,1,5-benzoxadiazepines
has the following advantages over previous known
33
1
1
16. (a) Petigara, R. B.; Yale, H. L. U.S. Patent 4,134,975,
999, 12, 38–45.
methods of synthesis: (i) the precursors N-acyl and
0
N,N -diacyl-1,2-phenylenediamines need not be isolated
before cyclodehydration; (ii) the cyclodehydration and
deacylation can be accomplished in situ in one pot; (iii)
1
1
979; (b) Bristol, J. A.; Yale, H. L. U.S. Patent 4,062,852,
977.
1
1
1
2
2
2
2
7. Petigara, R. B.; Yale, H. L. U.S. Patent 3,856,801, 1974;
Chem. Abstr. 1975, 82, 31362s.
8. Singh, G.; Singh, C.; Kaur, H. Asian J. Chem. 1995, 7,
735–741. Chem. Abstr. 1996, 124, 86970e.
9. Reddy, P. S. N.; Reddy, P. P.; Padmaja, K.; Shailja, G.;
Reddy, D. S. Indian J. Chem. 1996, 35B, 1110–1112.
0. Tempest, P.; Ma, V.; Thomas, S.; Hua, Z.; Kelly, M. G.;
Hulme, C. Tetrahedron Lett. 2001, 42, 4959–4962.
1. Deluca, M. R.; Kerwin, S. M. Tetrahedron 1997, 53, 457–
BF
3
2
ÆEt O is efficient and tolerant towards a number of
substituted aromatics, unsubstituted aliphatics and het-
erocycles.
In summary, the present communication describes a
simple, efficient and convenient synthesis of 2-substi-
tuted benzimidazoles and 2,4-disubstituted 3,1,5-benz-
oxadiazepines in excellent yields using BF
cyclodehydrating and deacylating agent.
3
2
Æ Et O as the
4
64.
2. Ramsden, C. A.; Rose, H. L. J. Chem. Soc., Perkin Trans.
1997, 16, 2319–2327.
3. Lee, H. I.; Jeoung, E. H.; Lee, C. K. J. Heterocyl. Chem.
996, 33, 1711–1716.
1
1
References and notes
24. Boido, C.; Boido, V.; Novelli, F.; Paratore, S. J. Hetero-
cyl. Chem. 1998, 35, 853–858.
1
2
. Tebbe, M. J.; Spitzer, W. A.; Victor, F.; Miller, S. C.; Lee,
C. C.; Sattelberg, T. R., Sr.; McKinney, E.; Tang, C. J.
J. Med. Chem. 1997, 40, 3937–3946.
. (a) Porcari, A. R.; Devivar, R. V.; Kucera, L. S.; Drach, J.
C.; Townsend, L. B. J. Med. Chem. 1998, 41, 1252–1262;
25. Frachey, G.; Crestini, C.; Bernini, R.; Saladino, R.;
Mincione, E. Heterocycles 1994, 38, 2621–2630.
26. Zhen, S.; Huan, G. Huaxue Tongbao 1997, 10, 55–58.
27. Mazurkiewicz, R. Monatsh. Chem. 1988, 119, 1279–
1287.
(
b) Roth, M.; Morningstar, M. L.; Boyer, P. L.; Hughes,
S. H.; Buckheit, R. W., Jr.; Michejda, C. J. J. Med. Chem.
997, 40, 4199–4207.
28. Boehringer, C. Ger. 955,861, Jan 10, 1957; Chem. Abstr.
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29. Weidenhagen, R. Ber. 1936, 69(B), 2263–2272.
1

V. K. Tandon, M. Kumar / Tetrahedron Letters 45 (2004) 4185–4187
4187
3
3
0. Kim, H.-O.; Huber, E. W.; Friedrich, D.; Peet, N. P.
Synthesis 1994, 1406–1408.
scopic data were obtained. Data for 2,3-bis(4-methoxy-
phenyl)-3,1,5-benzoxadiazepine (entry 4): pale yellow
1. Substituted benzimidazoles 2 reported in Table 1 are known
compounds to which the spectroscopic data was compared.
Data for entry 8: 2-n-propylbenzimidazole: mp 160–162 °C
powder, mp 124 °C; mmax (KBr/cm): 1680 (C@N), 1026
1
(C–O–C); H NMR (CDCl
3
, 200 MHz, d ppm): 3.85 (6H,
þ
s, OCH ), 6.95 (8H, m, Ph), 7.87 (4H, m, Ph); m=z M , 359
(M+1), 105, 77; C: 56.0, 114.2, 123.5, 128.3, 130.0,
3
2
9
13
(
lit. 157–159 °C); mmax (KBr/cm): 1604 (C@N), 3110 (NH);
1
H NMR(CDCl
3
CH ), 1.93 (2H, m, CH
.80–7.42 (5H, m, Ph and NH); m=z M , 161 (M+1), 160.
3
, 200MHz, d ppm): 0.80 (3H, t, J ¼ 6:5 Hz,
146.7, 164.0, 164.3; Analysis: calcd for C22 ; C,
18 2 3
H N O
2
), 2.14 (2H, t, J ¼ 6:5 Hz, CH
2
),
73.74; H, 5.02; N, 7.82; found: C, 73.92; H, 5.08; N,
7.94.
þ
6
3
2. Some of the 3,1,5-benzoxadiazepines reported in Table 1
are known compounds for which satisfactory spectro-
33. The detailed spectral data of other benzimidazoles and
benzoxadiazepines will be reported in a full paper.