One-pot regioselective synthesis of 2,9-disubstituted imidazo[1,2-a] benzimidazoles from 2-aminobenzimidazole and α-tosyloxy ketones

Article abstract of DOI:10.3184/030823407X244850

One-pot regioselective synthesis in high yields of 2,9-disubstituted imidazo[1,2-a]benzimidazoles from 2-aminobenzimidazole and α-tosyloxy ketones is described.

Full text of DOI:10.3184/030823407X244850

JOURNAL OF CHEMICAL RESEARCH 2007
SEPTEMBER, 519–520
RESEARCH PAPER 519
One-pot regioselective synthesis of 2,9-disubstituted imidazo[1,2-a]
benzimidazoles from 2-aminobenzimidazole and a-tosyloxy ketones
Ashok Kumar, Sunil Kumar, Devinder Kumar* and Rakesh K. Gupta
Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar-125001, Haryana, India
One-pot regioselective synthesis in high yields of 2,9-disubstituted imidazo[1,2-a]benzimidazoles from 2-amino-
benzimidazole and a-tosyloxy ketones is described.
Keywords: fused imidazoles, benzimidazoles, 2-aminobenzimidazole, a-tosyloxy ketones
Imidazo[1,2-a]benzimidazoles are versatile compounds
useful as analgesics,1 anxiolytics and anticonvulsants,2 and as
corticotropin-releasingfactor1receptorangonists3.Thedihydro
and tetrahydro imidazo[1,2-a]benzimidazoles derivatives have
been shown to exhibit antihypertensive,4 antihistamine5 and
antiproliferative activity6. The synthesis of imidazo[1,2-a]benz
imidazoles has been reported utilising thermal rearrangement of
3-(o-aminophenyl)-2-imino-4-phenyl-4-thiazoline,7 gas phase
pyrolysis of 1-(2-azidophenyl)imidazole8 and condensation of
2-amino-benzimidazole and α-bromoketones1 or hydrazonoyl
bromides9 involving a number of steps.
a-Tosyloxy ketones are versatile intermediate for the
synthesis of a variety of heterocycles.10 [Hydoxy(tosyloxy)
iodo]benzene (HTIB, Koser’s reagent) and poly[4-(hydroxy
(tosyloxy)iodo)]styrene are key reagents for the synthesis of
a-tosyloxy ketones from enolisable ketones.11-13 The value
of a-tosyloxy ketones lies in replacing a-halo ketones, which
are highly lachrymatory. Herein, we report the regioselective
synthesis of 2,9-disubstituted imidazo[1,2-a]benzimidazol
es by the reaction of 2-aminobenzimidazole with different
a-tosyloxy ketones in high yields.
CH2COAr
N
N
ArCOCH2OTs
NH2
N
EtOH, reflux, 6-8 hr
N
H
N
Ar
2
1
2a: Ar = C6H5
2b: Ar = C6H4CH3 (-p)
2c: Ar = C6H4OCH3 (-p)
2d: Ar = C6H4OCH3 (-o)
2e: Ar = C6H4Cl (-p)
2f: Ar = C6H4Br (-p)
2g: Ar = C6H4F (-p)
2h: Ar = 2-thienyl
N
N
CH2COAr
N
Ar
3
Scheme 1
appeared at 1685±5 cm-1 (see experimental). The isomeric
compound 3 was ruled out on the basis of NMR (1H and 13C)
study. The structure assignment of 2 finds further support
from comparison with the published NMR (1H and 13C) data
of 9-methylimidazo[1,2-a]benzimidazole.14 These authors
also synthesised the 1-methylimidazo[1,2-a]benzimidazole
in addition to the 9-methyl compound and the structure
comparison was based on rigorous NMR (1H and 13C) analysis
which clearly established the structure as 2 instead of 3.14 The
mass spectral fragmentation of 2 proceeds with elimination of
the aroyl moiety at position 9 to generate the stable fragment
ion as base peak.
The mechanism involves the nucleophilic attack of NH
of 1 on methylene of a-tosyloxy ketones to generate 4 by
displacement of tosylate group that may cyclise to give 5 after
dehydration. The recent study of the tautomerism of imidazo
[1,2-a]benzimidazoles showed that the tautomeric proton is on
N-9. Ab initio calculations confirm the greater stability of 9H-
over 1H-imidazo[1,2-a]benzimidazole.12 The reaction of 5
Results and discussion
We investigated the reaction of 2-aminobenzimidazole (1)
with a-tosyloxy ketones and found the formation of 2,9-
disubstituted imidazo[1,2-a]benzimidazoles (2) regioselectively
in ethanol under reflux (Scheme 1). The isomeric compound
3 could not be detected even in traces. Further, there was
no product formation on stirring 1 and a-tosyloxy ketones
at room temperature. However, with one equivalent each of
1 and a-tosyloxy ketone in refluxing ethanol, some amount
of 1 was left unreacted along with formation of 2. The
reaction could be optimised by taking two equivalents of the
a-tosyloxy ketone.
The structure of 2 was established through physical and
analytical data. The carbonyl stretching frequency band in 2
CH2COAr
N
ArCOCH2OTs
N
ArCOCH2OTs
NH2
1
NH
EtOH, reflux, 6-8 h
N
N
CH2COAr
CH2COAr
CH2COAr
4
6
2
9
N
N
H
ArCOCH2OTs
X
ArCOCH2OTs
1
N
3
N
N
N
Ar
Ar
5
Scheme 2
* Correspondent. E-mail: dk_ic@yahoo.com
PAPER: 07/4700

520 JOURNAL OF CHEMICAL RESEARCH 2007
109.9, 110.6, 111.0, 111.6, 120.3, 120.9, 121.1, 123.0, 123.6, 124.7,
125.1, 127.2, 128.1, 131.4, 135.2, 136.4, 139.7, 156.1, 159.7, 192.8.
Anal. Calcd. for C25H21N3O3: C, 72.98; H, 5.14; N, 10.21. Found: C,
73.14; H, 5.20; N, 10.01%.
produces 2 regioselectively instead of 3. Alternatively, 4 may
react with another molecule of a-tosyloxy ketone to afford 6
that may cyclise to give 2 after dehydration (Scheme 2).
The present approach for the synthesis of 2,9-disubstituted
imidazo[1,2-a]benzimidazoles (2) is significant because
it utilises a-tosyloxy ketones, that are easy to prepare from
enolisable ketones and HTIB/poly[4-hydroxy(tosyloxy)iodo]
styrene, instead of the lachrymatory a-bromo ketones. Further,
it is a one-pot regioselective instead of a multistep synthesis
and no chromatography is required for purification/separation
of the product.
Compound 2e (Ar = C6H4Cl-p): M.p. 238–240°C (Lit.1 240-242°C),
yield 74%. IR: 3118, 1688, 1604, 1534, 1445, 1342, 1219, 1102, 948,
850 cm-1. NMR: δH 5.78 (s, 2H, CH2), 7.24–7.30 (m, 3H), 7.34 (d,
2H, J = 8.5 Hz), 7.55 (d, 2H, J = 7.6 Hz), 7.65 (d, 1H, J = 7.6 Hz),
7.78 (dd, 2H, J = 7.7, 1.8 Hz), 7.83 (s, 1H), 8.09 (dd, 2H, J = 1.8,
6.7 Hz); δC 49.3, 102.5, 110.0, 111.2, 121.0, 123.7, 124.9, 126.4,
128.8, 129.4, 129.7, 132.6, 133.2, 135.0, 135.8, 140.9, 190.8. MS:
Calcd. for C23H15Cl2N3O: 419.0592, found 419.0599 (44); 421.0156
(30), 423.0544 (6), 282.0615 (33), 280.0640 (100), 139.0019 (15),
110.9927 (11).
Experimental
Compound 2f (Ar = C6H4Br-p): M.p. 206–207°C (Lit.1 208–209°C),
yield 75%. IR: 3121, 1679, 1595, 1528, 1448, 1336, 1224, 1107, 950,
853 cm-1. NMR: δH 5.74 (s, 2H, CH2), 7.21–7.28 (m, 3H), 7.48 (d,
2H, J = 8.5 Hz), 7.64 (d, 1H, J = 7.8 Hz), 7.72 (m, 4H), 7.81 (s, 1H),
8.01 (d, 2H, J = 8.6 Hz). MS: Calcd. for C23H15Br2N3O: 506.9582.
Found: 506.9581 (35), 508.9563 (71), 510.9553 (36), 324.0111 (99),
324.0130 (100), 184.9425 (14), 156.9491 (8).
Compound 2g (Ar = C6H4F-p): M.p. 182°C, yield 75%. IR: 3130,
1665, 1587, 1525, 1459, 1330, 1219, 1097, 976, 848 cm-1. NMR: 5.66
(s, 2H, CH2), 7.04–7.13 (m, 3H), 7.17–7.28 (m, 4H), 7.54 (d, 1H,
J = 7.3 Hz),7.58 (s, 1H), 7.69–7.78 (m, 2H), 8.10–8.14 (m, 2H);
δC 49.2, 102.0, 110.0, 111.2, 115.4, 115.6, 116.2. 116.4, 121.0, 123.6,
124.9, 126.9, 127.0, 131.0, 131.1, 135.8, 143.4, 149.8, 190.3. Anal.
Calcd. for C23H15F2N3O: C, 71.31; H, 3.90; N, 10.85. Found: C,
71.10; H, 3.96; N, 10.74%.
FTIR spectra were obtained in KBr on a Perkin Elmer Spectrum
RX1 instrument. 1H and 13C NMR spectra were recorded on
Bruker Avance II spectrometer at 400 and 100 MHz, respectively,
in CDCl3 + DMSO-d6; shifts are expressed as ppm with respect to
TMS. Elemental analysis was carried out on a Perkin Elmer 2400
instrument. HRMS were measured in EI mode on a Kratos MS-50
spectrometer.
a-Tosyloxy ketones were obtained by the reaction of enolisable
ketones either with HTIB or poly-[4-hydroxy(tosyloxy)iodo]styrene
in acetonitrile and were used without further purification.11-13
2-Aryl-9-(aroylmethyl)imidazo[1,2-a]benzimidazoles (2–2h): general
procedure
The a-tosyloxy ketone (4 mmol) was added to 2-aminobenzimidazole
(1, 266 mg, 2 mmol) in dry ethanol (20 ml) and 3–4 drops of glacial
acetic acid were added. The reaction mixture was refluxed for
6–8 h. The excess of ethanol was distilled off and the residue was
cooled to room temperature. Water was added to precipitate the
product, which was filtered off, washed with water, aqueous sodium
bicarbonate, again with water, and dried to afford 2, which was
crystallised from aqueous ethanol.
Compound 2h (Ar = 2-thienyl): M.p. 202–205°C, yield 63%.
IR: 2921, 1671, 1499, 1446, 1408, 1349, 1239, 1188, 1152, 1040,
1006, 919, 854 cm-1. NMR: δH 5.77 (s, 2H, CH2), 7.01–7.04 (m, 1H),
7.19–7.38 (m, 5H), 7.68 (d, 1H, J = 7.5 Hz),7.84 (s, 1H), 7.93 (d, 1H,
J = 4.5 Hz), 8.20 (d, 1H, J = 3.2 Hz). Anal. Calcd. for C19H13N3OS2:
C, 62.79; H, 3.61; N, 11.56. Found: C, 62.68; H, 3.68; N, 11.32%.
Compound 2a (Ar = Ph): M.p. 217–218°C (lit.1 M.p. 218°C), yield
76%. IR: 3069, 1688, 1620, 1540, 1498, 1450, 1354, 1321, 1233,
1161 cm-1. NMR: δH 5.75 (s, 2H, CH2), 7.19–7.29 (m, 4H), 7.35–
7.39 (m, 2H), 7.55–7.62 (m, 3H), 7.69 (t, 1H, J = 7.0, 7.3 Hz), 7.75
(s, 1H), 7.83 (d, 1H, J = 7.4 Hz), 8.11 (d, 1H, J = 7.4 Hz); δC 48.8,
102.2, 110.7, 120.0, 122.8, 124.1, 124.4, 126.2, 127.8, 128.0, 128.3,
128.4, 133.6, 134.0, 134.4, 135.6, 143.2, 149.4, 191.9. MS: Calcd.
for C23H17N3O: 351.1372, found 351.1361 (54); 246.1036 (100),
233.0941 (11), 105.0342 (16), 77.0390 (20).
The authors are thankful to CSIR and UGC, New Delhi
for financial support and Mr. Avtar Singh, SAIF, Panjab
University, Chandigarh for recording NMR data.
Received 14 June 2007; accepted 6 September 2007
Paper 07/4700 doi: 10.3184/030823407X244850
Compound 2b (Ar = C6H4CH3-p): M.p.168–170°C, yield 71%.
IR: 2916, 1693, 1603, 1497, 1408, 1347, 1232, 1131, 1060, 973,
811, 735 cm-1. NMR: δC 2.35 (s, 3H, CH3), 2.46 (s, 3H, CH3), 5.71
(s, 2H, CH2), 7.16–7.25 (m, 5H), 7.35 (d, 2H, J = 8.0 Hz), 7.58 (d,
1H, J = 7.5 Hz), 7.70 (d, 2H, J = 8.0 Hz), 7.72 (s, 1H), 7.98 (d, 2H,
J = 8.2 Hz); δC 21.3, 21.8, 49.2, 101.7, 110.0, 111.0, 120.6, 123.3,
124.9, 125.1, 128.4, 128.7, 129.3, 129.6, 132.0, 135.9, 136.6, 144.5,
145.2, 149.9, 191.5. MS: Calcd. for C25H21N3O: 379.1685, found
379.1679 (69); 260.1199 (100), 119.0495 (40), 91.05441 (19). Anal.
Calcd. for C25H21N3O: C, 79.13; H, 5.58; N, 11.07. Found: C, 79.10;
H, 5.48; N, 11.39%.
Compound 2c (Ar = C6H4OMe-p): M.p.124–25°C, yield 72%. IR:
2942, 1683, 1602, 1493, 1450, 1308, 1236, 1169, 1027, 978, 827,
740 cm-1. NMR: δH 3.83 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 5.59 (s,
2H, CH2), 6.91 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.4 Hz), 7.10 (d,
1H, J = 7.9 Hz), 7.17–7.22 (m, 2H), 7.50 (d, 1H, J = 7.3 Hz), 7.53
(s, 1H), 7.74 (d, 2H, J = 8.7 Hz), 8.04 (d, 2H, J = 8.8 Hz); δC 49.0,
55.3, 55.6, 101.1, 110.1, 110.9, 114.1, 120.6, 123.2, 125.0, 126.5,
127.5, 127.7, 130.6, 135.9, 144.3, 149.9, 158.8, 164.2, 190.3. MS:
Calcd. for C25H21N3O3: 411.1583, found 411.1587 (73); 276.1139
(44), 135.0446 (100). Anal. Calcd. for C25H21N3O3: C, 72.98;
H, 5.14; N, 10.21. Found: C, 72.54; H, 5.23; N, 10.01%.
References
1
H. Ogura, H. Takayanagi, Y. Ymazaki, S. Yonezawa, H. Takagi,
S. Kobayashi, T. Kamioka and K. Kamoshita, J. Med. Chem., 1972, 15,
923.
2
P. George, D.D. Peretti, J. Roy, J.P. Schmitt and M. Servin, Eur Patent,
607 046, 1994; Chem. Abstr., 1994, 121, 157 646; US Patent, 5 466 706,
1995; Chem. Abstr., 1995, 123, 2 113 490.
3
4
5
X. Han, S.S. Pin, K. Burria, L.K. Fung, S. Huang, M.T. Taber, J. Zhang
and M. Dubowchik, Bioorg. Med. Chem. Lett., 2005, 15, 4029.
T. Jen, P. Bender, H. Van Hoeven, B. Dienel and B. Love, J. Med. Chem.,
1973, 16, 407.
A.A. Spasov, M.V. Chemikov, V.A. Anisimova, T.A. Kuzmenko and
M.M. Osipova, Khim-Farm. Zh., 2000, 34, 48, Chem. Abstr., 2001, 134,
216795.
6
W. Nawrocka, B. Sztuba, H. Liszkiewicz, M.W. Kowalska, J. Wietrzyk,
D. Nevozhai and A. Opolski, Polish J. Chem., 2005, 79, 709; Chem.
Abstr., 2005, 144, 36291.
7
8
R.P. Soni, Aust. J. Chem., 1981, 34, 1557.
A.J. Blake, B.A.J. Clark, H. McNab and C.C. Sommerville, J. Chem. Soc.
Perkin Trans. I, 1997, 1605.
9
A.M. Farag and K.M. Dawood, Heteroatom Chem., 1997, 8, 129.
10 K.C. Nicolaou, T. Montagnon, T. Ulven, P.S. Baran Y.L. Zhong and
F. Sarabia, J. Am. Chem. Soc., 2002, 124, 5718.
11 G.F. Koser, A.G. Relenyi, A.N. Kalos, L. Rebrovic and R.H. Wettach,
J. Org. Chem., 1982, 47, 2487.
12 O. Prakash, N. Rani and P.K. Sharma, Synlett., 1994, 221.
13 S. Abe, K. Sakuratani and H. Togo, J. Org. Chem., 2001, 66, 6174.
14 T. Mas, R.M. Claramunt, M.D.S. Maria, D. Sanz, S.H. Alarcon,
M.P. Torralba and J. Elguero, Arkivoc, 2002, v, 48.
Compound 2d (Ar = C6H4OMe-o): M.p.172–174°C, yield 63%.
IR: 2926, 1688, 1610, 1501, 1452, 1310, 1218, 1183, 1032, 981, 825,
742 cm-1. NMR: δH 4.01 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 5.63
(s, 2H, CH2), 7.01 (d, 1H, J = 7.3 Hz), 7.04–7.14 (m, 3H), 7.15–
7.31 (m, 4H), 7.53–7.58 (m, 2H), 7.94 (t, 1H, J = 7.8, 8.5 Hz), 7.99
(s, 1H), 8.21 (dd, 1H, J = 1.5, 7.7 Hz); δC 53.7, 55.4, 55.7, 106.6,
PAPER: 07/4700