Synthesis of 1-Methylbenzimidazoles from Carbonitriles

Abstract

The NaH-mediated N-methylbenzimidazole formation starting from carbonitriles and N-methyl-1,2-phenylenediamine is reported to be a procedure compatible with acid-labile acetal protective groups within the starting materials. Products were further converted in Suzuki, Sonogashira, Heck and Buchwald-Hartwig reactions.

benzimidazoles - heterocycles - carbonitriles - cross-coupling

References and Notes

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11

2-Cyclohexyl-1-methyl-1 H -benzimidazole (3a)
Diamine 1 (244 mg, 2.00 mmol), NaH (80.0 mg, 60% dispersion in mineral oil, 2.00 mmol), and abs. toluene (1.0 mL) were successively added to nitrile 2a (218 mg, 2.00 mmol). The mixture was stirred for 3 h at 120 ˚C in a tightly closed reaction vial, then completely transferred on top of a column (SiO₂), and chromatographed (hexane-EtOAc, 1:1; R _f  = 0.32) to give the title compound 3a (384 mg, 1.79 mmol, 90%) as a light brown solid, mp 102 ˚C (lit.^¹³a 104 ˚C). ^¹H NMR (500 MHz, CDCl₃): δ = 1.30-1.48 (m,
3 H), 1.74-2.03 (m, 7 H), 2.84 (tt, J = 3.5, 11.6 Hz, 1 H), 3.74 (s, 3 H), 7.20-7.31 (m, 3 H), 7.72-7.77 (m, 1 H) ppm. ^¹³C{^¹H} NMR (125 MHz, CDCl₃): δ = 25.82 (CH₂), 26.32 (2 CH₂), 29.52 (CH₃), 31.46 (2 CH₂), 36.33 (CH), 108.80 (CH), 119.27 (CH), 121.66 (CH), 121.87 (CH), 135.64 (C), 142.55 (C), 159.00 (C) ppm. IR (ATR): ν =  3173 (w), 3052 (w), 2929 (s), 2851 (m), 1730 (m), 1615 (m), 1506 (m), 1441 (s), 1278 (m), 1239 (m), 842 (m), 736 (s) cm^-¹. MS (EI, 70 eV): m/z (%) = 214 (14) [M⁺], 159 (100). HRMS (CI, isobutane): m/z calcd for C₁₄H₁₉N₂: 215.1548; found: 215.1548 [M + H⁺]. Anal. Calcd for C₁₄H₁₈N₂ (214.31): C, 78.46; H, 8.47; N, 13.07. Found: C, 78.40; H, 8.55; N, 13.05.

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23

1-Methyl-2-phenyl-1 H -benzimidazole (3h)
Diamine 1 (6.1 g, 50 mmol), NaH (2.0 g, 60% dispersion in mineral oil, 50 mmol) and abs. mesitylene (10 mL) were successively added to nitrile 2h (5.2 g, 50 mmol). The mixture was heated to reflux for 16 h (inner temp ca. 170 ˚C, oil bath 210 ˚C). After cooling to ambient temperature, the mixture was filtered through SiO₂ (1 cm), the residue washed with CH₂Cl₂ (5 mL), and the combined filtrates evaporated. The residue was chromatographed (SiO₂, hexane-EtOAc, 1:1; R _f  = 0.34) to give the title compound 3a (6.2 g, 30 mmol, 60%) as a light yellow solid, mp 91 ˚C (lit.^¹8b 92-93 ˚C). ^¹³C{^¹H} NMR (125 MHz, CDCl₃): δ = 31.57 (CH₃), 109.54 (CH), 119.76 (CH), 122.33 (CH), 122.67 (CH), 128.58 (2 CH), 129.35 (2 CH), 129.63 (CH), 130.16 (C), 136.51 (C), 142.91 (C), 153.70 (C) ppm. All other data were in accordance with the literature.^¹8b

cataCXium FSulf = dicyclohexyl{2-sulfo-9-[3-(4-sulfo-phenyl)propyl]-9-fluorenyl}phosphonium hydrogensulfate; for use in Suzuki reactions, see:

24a Fleckenstein CA. Plenio H. Green Chem.  2007,  9:  1287 

24b Fleckenstein CA. Plenio H. Chem. Eur. J.  2007,  13:  2701 

25

2-(Biphenyl-4-yl)-1-methyl-1 H -benzimidazole (4)
A mixture of bromophenyl compound 3i (91 mg, 0.32 mmol, 1.0 equiv), PhB(OH)₂ (42 mg, 0.35 mmol, 1.1 equiv), Na₂PdCl₄ (1.2 mg, 4.2 µmol, 1.3 mol%), cataCXium Fsulf (3.3 mg, 4.5 µmol, 1.5 mol%), and K₂CO₃ (131 mg, 945 µmol, 3 equiv) was placed in a Schlenk tube and twice evacuated and flushed with N₂. Degassed H₂O (0.5 mL) and BuOH (0.5 mL) were added, and the resulting mixture was stirred for 16 h at 100 ˚C. Subsequently, the organic layer was separated and the aqueous layer extracted with CH₂Cl₂ (5 mL). The combined organic layers were dried (MgSO₄), and after filtration, the solvent was evaporated and the residue chromatographed (SiO₂, hexane-EtOAc = 1:1, R _f  = 0.48) to give the title compound 4 (82 mg, 0.29 µmol, 92%) as a yellow solid, mp 164 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 3.87 (s, 3 H), 7.29-7.34 (m, 2 H), 7.35-7.40 (m, 2 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.62-7.67 (m, 2 H), 7.71-7.76 (m, 2 H), 7.81-7.87 (m, 3 H) ppm. ^¹³C{^¹H} NMR (125 MHz, CDCl₃): δ = 31.70 (CH₃), 109.57 (CH), 119.75 (CH), 122.42 (CH), 122.74 (CH), 127.08 (2 CH), 127.26 (2 CH), 127.78 (CH), 128.86 (2 CH), 128.94 (C), 129.77 (2 CH), 136.61 (C), 140.09 (C), 142.40 (C), 142.93 (C), 153.40 (C) ppm. IR (ATR): ν = 3031 (w), 2925 (w), 1463 (m), 1375 (m), 1325 (m), 1005 (m), 850 (m), 765 (m), 737 (s), 690 (s) cm^-¹. MS (EI, 70 eV): m/z (%) = 284 (98) [M⁺], 283 (100), 179 (10), 152 (10), 78 (12), 77 (29). HRMS (EI, 70 eV): m/z calcd for C₂₀H₁₆N₂: 284.1313; found: 284.1313 [M⁺].

26

cataCXium FBu = (9-butyl-9-fluorenyl)dicyclohexylphos-phonium tetrafluoroborate; for use in Sonogashira reactions, see ref. 24a

27

1-Methyl-2-[4-(phenylethynyl)phenyl]-1 H -benzimi-dazole (5) ^²8
A suspension of bromophenyl compound 3i (91 mg, 0.32 mmol, 1 equiv), phenylacetylene (38 mg, 0.38 mmol, 1.2 equiv), Na₂PdCl₄ (1.5 mg, 5.1 µmol, 1.6 mol%), cataCXium FBu (3.6 mg, 7.2 µmol, 2.3 mol%), and CuI (1.5 mg, 7.8 µmol, 2.5 mol%) in i-PrNH₂ (1.0 mL) was stirred under an inert atmosphere for 16 h at 100 ˚C. Subsequently, all volatile materials were removed in vacuo, the residue dissolved in CH₂Cl₂ (5 mL), and washed with H₂O (2 ×
3 mL). The organic layer was dried (Na₂SO₄), and after filtration, the solvent was evaporated. Chromatography of the residue (SiO₂; hexane-EtOAc, 2:1; R _f  = 0.29) gave the title compound 5 (81 mg, 0.26 mmol, 84%) as a light yellow solid, mp 152 ˚C (lit.^²8 153-155 ˚C). ^¹H NMR (500 MHz, CDCl₃): δ = 3.80 (s, 3 H), 7.26-7.37 (m, 6 H), 7.50-7.57 (m, 2 H), 7.63-7.68 (m, 2 H), 7.71-7.77 (m, 2 H), 7.79-7.86 (m, 1 H) ppm. ^¹³C{^¹H} NMR (125 MHz, CDCl₃): δ = 31.63 (CH₃), 88.71 (C), 91.27 (C), 109.58 (CH), 119.75 (CH), 122.47 (CH), 122.77 (C), 122.87 (CH), 124.62 (C), 128.31 (2 CH), 128.48 (CH), 129.20 (2 CH), 129.68 (C), 131.57
(2 CH), 131.70 (2 CH), 136.56 (C), 142.86 (C), 152.83 (C) ppm. IR (ATR): ν = 3058 (w), 2950 (w), 2216 (w), 1457 (m), 1437 (m), 1381 (m), 1329 (m), 1249 (m), 1103 (m), 1007 (m), 919 (m), 840 (s), 740 (s), 730 (s), 690 (s) cm^-¹.
MS (EI, 70 eV): m/z (%) = 308 (100) [M⁺], 307 (80), 203 (23), 176 (12), 154 (12). HRMS (EI, 70 eV): m/z calcd for C₂₂H₁₆N₂: 308.1313; found: 308.1313 [M⁺].

28 Vinodkumar R. Vaidya SD. Kumar BVS. Bhise UN. Bhirud SB. Mashelkar UC. Eur. J. Med. Chem.  2008,  43:  986 

29a Meyer FE. Ang KH. Steinig AG. de Meijere A. Synlett  1994,  191 

29b Ang KH. Bräse S. Steinig AG. Meyer FE. Llebaria A. Voigt K. de Meijere A. Tetrahedron  1996,  52:  11503 

29c de Meijere A. Meyer FE. Angew. Chem., Int. Ed. Engl.  1994,  33:  2379 ; Angew. Chem. 1994, 106, 2473

30

( E )-1-Methyl-2-[4-(2-phenylethenyl)phenyl]-1 H -benz-imidazole (6)
A mixture of bromophenyl compound 3i (60 mg, 0.21 mmol, 1 equiv), freshly distilled styrene (44 mg, 0.42 mmol, 2.0 equiv), Pd(OAc)₂ (5.0 mg, 21 µmol, 0.1 equiv), Ph₃P (14 mg, 51 µmol, 0.24 equiv), Et₃N (85 mg, 0.84 mmol, 4.0 equiv), and abs. DMF (3.0 mL) was stirred for 16 h at 100 ˚C under an inert atmosphere. Subsequently, all volatile materials were removed in vacuo, the residue dissolved in CH₂Cl₂ (5 mL), and washed with H₂O (2 × 3 mL). The organic layer was dried (Na₂SO₄), and after filtration, the solvent was evaporated. Chromatography of the residue (SiO₂; hexane-EtOAc, 2:1; R _f  = 0.27) gave the title compound 6 (31 mg, 0.10 mmol, 48%) as a light yellow solid, mp 150 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 3.86 (s, 3 H), 7.15 (d, J = 16.3 Hz, 1 H), 7.21 (d, J = 16.3 Hz, 1 H), 7.23-7.34 (m, 3 H), 7.33-7.41 (m, 3 H), 7.50-7.56 (m, 2 H), 7.60-7.68 (m, 2 H), 7.72-7.79 (m, 2 H), 7.80-7.87 (m, 1 H) ppm. ^¹³C{^¹H} NMR (125 MHz, CDCl₃): δ = 31.74 (CH₃), 109.56 (CH), 119.74 (CH), 122.45 (CH), 122.76 (CH), 126.63 (4 CH), 127.67 (CH), 127.97 (CH), 128.71 (2 CH), 129.01 (C), 129.68
(2 CH), 130.17 (CH), 136.62 (C), 136.90 (C), 138.68 (C), 142.91 (C), 153.40 (C) ppm. IR (ATR): ν = 3025 (w), 2953 (w), 1461 (m), 1379 (m), 1326 (m), 960 (m), 821 (s), 741 (s), 688 (s) cm^-¹. MS (EI, 70 eV): m/z (%) = 310 (100) [M⁺], 309 (75). HRMS (EI, 70 eV): m/z calcd for C₂₂H₁₈N₂: 310.1470; found: 310.1470 [M⁺].

31 Wolfe JP. Buchwald SL. J. Org. Chem.  2000,  65:  1144 

32

2-[4-(Cyclohexylamino)phenyl]-1-methyl-1 H -benzimi-dazole (7)
A suspension of Pd(OAc)₂ (3.0 mg, 11 µmol, 5.0 mol%) and rac-BINAP (7.0 mg, 11 µmol, 7.5 mol%) in abs. toluene (1.5 mL) was stirred for 5 min at 23 ˚C under an inert atmo-sphere. Bromophenyl compound 3i (60 mg, 0.21 mmol, 1 equiv), CyNH₂ (27 mg, 0.27 mmol, 1.3 equiv), and NaOt-Bu (34 mg, 0.36 mmol, 1.7 equiv) were added, and the resulting mixture was stirred for 16 h at 85 ˚C. Subsequently, it was diluted with CH₂Cl₂ (5 mL) and washed with sat. NaHCO₃ solution (5 mL). The organic layer was dried (MgSO₄), and after filtration, the solvent was evaporated. Chromatography of the residue (SiO₂; hexane-EtOAc, 1:2; R _f  = 0.44) gave the title compound 7 (42 mg, 0.14 mmol, 65%) as a light yellow solid, mp 145 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 1.13-1.29 (m, 3 H), 1.32-1.46 (m, 2 H), 1.62-1.70 (m, 1 H), 1.73-1.83 (m, 2 H), 2.01-2.13 (m, 2 H), 3.25-3.39 (m, 1 H), 3.77-3.93 (m, 4 H), 6.63-6.69 (m, 2 H), 7.23-7.28 (m, 2 H), 7.29-7.34 (m, 1 H), 7.54-7.60 (m, 2 H), 7.74-7.80 (m, 1 H) ppm. ^¹³C{^¹H} NMR (125 MHz, CDCl₃): δ = 24.89 (2 CH₂), 25.78 (CH₂), 31.74 (CH₃), 33.24 (2 CH₂), 51.40 (CH), 109.23 (CH), 112.51 (2 CH), 117.80 (C), 119.20 (CH), 121.97 (CH), 122.00 (CH), 130.65 (2 CH), 136.61 (C), 142.97 (C), 148.49 (C), 154.62 (C) ppm. IR (ATR): ν = 3335 (w), 3055 (w), 2928 (m), 2853 (m), 1608 (s), 1542 (m), 1456 (s), 1379 (m), 1323 (m), 1180 (m), 1006 (m), 888 (s), 828 (m), 814 (m), 743 (s), 731 (s) cm^-¹. MS (EI, 70 eV): m/z (%) = 305 (100) [M⁺], 304 (16), 263 (12), 262 (62), 222 (14), 131 (10). HRMS (EI, 70 eV): m/z calcd for C₂₀H₂₃N₃: 305.1892; found: 305.1892 [M⁺].