2-Alkyl-1-(2-aryl-1,1-difluoro-2-hydroxyethyl)benzimidazoles: Potential angiotensin II receptor antagonists

Article abstract of DOI:10.1016/S0040-4039(00)00148-9

2-Alkyl-1-(bromodifluoromethyl)benzimidazoles were synthesized and condensed with aromatic aldehydes to give 2-alkyl-1-(2-aryl-1,1-difluoro-2- hydroxyethyl)-benzimidazoles. A potential nonpeptide antagonist of the angiotensin II receptor with the -CF₂CH(OH)-bridge between the heterocyclic nitrogen atom and the biphenyl moiety was synthesized. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00148-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2265–2267
2-Alkyl-1-(2-aryl-1,1-difluoro-2-hydroxyethyl)benzimidazoles:
potential angiotensin II receptor antagonists
Lev M. Yagupolskii ∗ and Dmitrij V. Fedyuk
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanskaya Str, Kiev 02094, Ukraine
Received 8 January 1999; revised 14 January 2000; accepted 18 January 2000
Abstract
2-Alkyl-1-(bromodifluoromethyl)benzimidazoles were synthesized and condensed with aromatic aldehydes
to give 2-alkyl-1-(2-aryl-1,1-difluoro-2-hydroxyethyl)-benzimidazoles. A potential nonpeptide antagonist of the
angiotensin II receptor with the -CF2CH(OH)-bridge between the heterocyclic nitrogen atom and the biphenyl
moiety was synthesized. © 2000 Elsevier Science Ltd. All rights reserved.
Numerous derivatives of imidazole and benzimidazole with a biphenyl group attached to the nitrogen
atom of the heterocyclic ring through a methylene bridge have been described. Some of these compounds
exhibit the ability to block receptors of angiotensin II and to prevent thereby its hypertensive effect.1,2
The introduction of lipophilic difluoromethylene and reactive -CH(OH)-groups instead of the methylene
bridge offers considerable scope for the synthesis of new biologically active compounds.
The condensation of 2-bromodifluoromethylbenzoxazole and 5-bromodifluoromethyl-3-
phenyloxadiazole with aldehydes and tetrakis(dimethylamino) ethylene (TDAE) as the reducing
agent was reported recently.3 Similar reactions of compounds with a bromodifluoromethyl group at the
nitrogen rather than at the carbon atom have not yet been studied. Moreover, benzimidazoles with the
CF2Br group on the nitrogen atom are unknown.
In this letter we describe the synthesis of 2-alkyl-1-bromodifluoromethylbenzimidazoles and their
condensation with aromatic aldehydes.
2-Alkyl-1-bromodifluoromethylbenzimidazoles were obtained by treating sodium salts of 2-
alkylbenzimidazoles with dibromodifluoromethane in dry acetonitrile in the presence of Zn powder as
the catalyst4(Scheme 1).
The bromodifluoromethylated derivatives obtained in this way react with aromatic aldehydes in the
presence of TDAE5 (Scheme 2).
The condensation of the N-bromodifluoromethyl-2-alkylbenzimidazoles proceeds under more severe
conditions than in the case of 2-bromodifluoromethylbenzoxazole.
∗
Corresponding author. Fax: 380-(44)-573 26 43; e-mail: lev@fluor-ukr.kiev.ua (L. M. Yagupolskii)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00148-9
tetl 16428

2266
Scheme 1.
Scheme 2.
Compound (2b) was cross-coupled with arylboronic acid (3) by the reported procedure6 to afford (4),7
a potential antagonist of the angiotensin II receptor (Scheme 3).
Scheme 3.
The difluoromethylene group is not hydrolyzed on removal of the triphenylmethyl protection.
References
1. Kubo, K.; Kohara, Y.; Imamiya, E.; Sugiura, Y.; Inada, Y.; Furukawa, Y.; Nishikawa, K.; Naka, T. J. Med. Chem. 1993, 36,
2182.
2. Thomas, A. P.; Allott, C. P.; Gibson, K. H.; Major, J. S.; Masek, B. B.; Oldham, A. A.; Ratcliffe, A. H.; Roberts, D. A.;
Russell, S. T.; Thomason, D. A. J. Med. Chem. 1992, 35, 877.
3. Burkholder, C.; Dolbier Jr.,W. R.; Medebielle, M. J. Org. Chem. 1998, 63, 5385.
4. Typical procedure for the synthesis 2-alkyl-1-bromodifluoromethybenzimidazoles (1a–e). To a stirred solution of 2-
alkylbenzimidazole (20 mmol) in 50 ml of anhydrous acetonitrile, under an argon atmosphere at −15°C, was added zinc
powder (0.1 g, 1.5 mmol) and then, sodium hydride (0.53 g, 22 mmol) in portions. The mixture was stirred at −10 to −5°C
for 3 h, cooled to −15°C and dibromodifluoromethane (2.74 ml, 30 mmol) was added dropwise. The reaction mixture was
warmed to 20°C in 2 h and stirred at this temperature for a further 14 h. The solvent was evaporated under reduced pressure
and the residue was extracted with hot hexane (3×50 ml). The extract was filtered and evaporated to leave a brown oil, which
was purified by vacuum distillation or by crystallization (hexane). Compound 1a: mp 29–30°C, bp 80–82°C (0.01 mmHg),
1H NMR (300 MHz, CDCl3, TMS): δ 2.77 (s, 3H), 7.3–7.9 (m, 4H); 19F NMR (288 MHz, CDCl3, CFCl3): δ −27.76 (s,

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CF2Br). Compound 1b: mp 44–45°C, bp 102–103°C (0.01 mmHg), 1H NMR (CD3COCD3, TMS): δ 0.98 (t, 3H), 1.79 (spt,
2H), 2.28 (t, 2H), 7.22–7.9 (m, 4H); 19F NMR (CD3COCD3, CFCl3): δ −27.51 (s, CF2Br). Compound 1c: mp 44–45°C,
1H NMR (CDCl3, TMS): δ 4.35 (s, 2H), 7.1–7.9 (m, 9H); 19F NMR (CDCl3, CFCl3): δ −27.24 (s, CF2Br). Compound 1d:
mp 76–78°C, 1H NMR (CDCl3, TMS): δ 2.66 (s, 3H), 7.61 (s, 1H), 7.71 (s, 1H); 19F NMR (CDCl3, CFCl3): δ −28.04 (s,
CF2Br). Compound 1e: mp 93–95°C, 1H NMR (CDCl3, TMS): δ 2.80 (s, 3H), 7.4–8.2 (m, 6H); 19F NMR (CDCl3, CFCl3):
δ −26.81 (s, CF2Br).
5. Typical procedure for synthesis of 2-alkyl-1-(2-aryl-1,1-difluoro-2-hydroxyethyl)-benzimidazoles (2a–e). In a three-necked
flask equipped with a drying tube, thermometer, and an argon inlet tube were placed, under argon at −10°C a solution of
2-alkyl-1-bromodifluoromethylbenzimidazole (1a–e) (10 mmol) in 15 ml of dry DMF and the aromatic aldehyde (30 mmol).
After stirring at −10°C for 20 min, TDAE (5.1 ml, 22 mmol) was added dropwise and the stirring was continued for 1 h,
after which time the mixture was warmed to room temperature over 1 h, stirred for 28 h, heated to 40°C and stirred at this
temperature for a further 5 h. The solvent was evaporated under reduced pressure, the residue was dried in vacuum (0.01
mmHg, 40–45°C) for 3 h, cooled to room temperature, diluted with water (50 ml) and diethyl ether (30 ml) and stirred for 5
h. The organic layer was separated, the aqueous solution was extracted with ether (3×30 ml), and the combined extracts were
washed with saturated aqueous NaCl solution (2×50 ml), dried (MgSO4), and filtered. Evaporation of the solvent gave a crude
product, which was purified by crystallization (benzene:hexane 1:1). Compound 2a: mp 172–173°C, 1H NMR (CD3COCD3,
TMS): δ 2.76 (s, 3H), 5.63 (dd, 1H), 7.01 (br.s, OH), 7.2–7.8 (m, 9H); 19F NMR (CD3COCD3, CFCl3): δ −86.34 (d, JF–F=219
Hz), −90,66 (d, JF–F=219 Hz). Compound 2b: mp 186–187°C, 1H NMR (CD3COCD3, TMS): δ 0.93 (t, 3H), 1.77 (spt, 2H),
2.64 (t, 2H), 5.34 (dd, 1H), 6.94 (br.s, OH), 7.2–7.8 (m, 8H); 19F NMR (CD3COCD3, CFCl3): δ −83.73 (d, JF–F=217 Hz),
−89.67 (d, JF–F=217 Hz). Compound 2c: mp 166–167°C, 1H NMR (CD3COCD3, TMS): δ 4.02 (s, 3H), 4.31 (s, 2H), 5.34
(dd, 1H), 6.94 (br.s, OH), 7.2–7.8 (m, 13H); 19F NMR (CD3COCD3, CFCl3): δ −84.43 (d, JF–F=218 Hz), −89.66 (d, JF–F=218
Hz). Compound 2d: mp 235–237°C, 1H NMR (CD3COCD3, TMS): δ 2.46 (s, 3H), 5.63 (dd, 1H), 6.19 (br.s, OH), 7.1–7.8
(m, 6H); 19F NMR (CD3COCD3, CFCl3): δ −85.36 (d, JF–F=222 Hz), −90.38 (d, JF–F=222 Hz), −113.01 (s, 1F). Compound
1
2e: mp 229–232°C, H NMR (CDCl3, TMS): δ 2.54 (s, 3H), 5.38 (dd, 1H), 6.34 (br.s, OH), 7.0–7.8 (m, 10H); 19F NMR
(CDCl3, CFCl3): δ −86.35 (d, JF–F=231 Hz), −96.03 (d, JF–F=231 Hz).
6. Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster, B. S.; Roberts, F. E.; Yang, C.; Lieberman, D. R.; Reamer,
R. A.; Tschaen, D. M.; Verhoeven, T. R.; Reider, P. J.; Lo, Y. S.; Rossano, L. T.; Brookes, A. S.; Meloni, D.; Moore, J. R.;
Arnett, J. F. J. Org. Chem. 1994, 59, 6391.
7. Data for compound 4: mp 149–151°C, 1H NMR (CD3COCD3, TMS): δ 0.99 (t, 3H), 1.87 (spt, 2H), 2.77 (t, 2H), 5.59 (dd,
1H), 6.21 (br.s, OH), 7.2–7.9 (m, 12H), 8.19 (s, NH); 19F NMR (CD3COCD3, CFCl3): δ −84.72 (d, JF–F=218 Hz), −89.97
(d, JF–F=218 Hz).