Synthesis of 2,5,6-Trisubstituted Benzimidazoles by Heck and Subsequent 6π-Electrocyclization-Dehydrogenation Reactions of 2,4,5-Tribromo-N-methylimidazole and 2-Aryl-4,5-dibromo-N-methylimidazoles

Abstract

2,5,6-Trisubstituted benzimidazoles were prepared by Heck reactions of 2,4,5-tribromo-N-methylimidazole and 2-aryl-4,5-dibromo-N-methyl-imidazoles and subsequent 6π-electro­cyclization-dehydrogenation reactions.

Key words

catalysis - palladium - Heck reaction - electrocyclization - benzimidazole

References and Notes

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• 12 De Meijere and coworkers reported twofold Heck reactions of 1,2-dibromocycloalk-1-enes and related substrates and subsequent 6π-electrocyclization: Voigt K. von Zezschwitz P. Rosauer K. Lansky A. Adams A. Reiser O. de Meijere A. Eur. J. Org. Chem.  1998,  1521 ; and references cited therein. For examples from our group, see ref. 8c-e

13

General Procedure for the Synthesis of 4a-h and 8a-d
In a pressure tube (glass bomb) a suspension of Pd(OAc)₂ (12 mg, 0.05 mmol, 5 mol%) and TCHP (28.04 mg, 0.10 mmol, 10 mol%) in DMF (5 mL) was purged with Ar and stirred at 20 ˚C to give a yellowish or brownish clear solution. To the stirred solution were added 2 or 7 (1.0 mmol), Et₃N (1.1 mL, 8.0 mmol) and the alkene (2.5 equiv per bromine atom of the substrate). The reaction mixture was stirred at 100 ˚C for 24 h. The solution was cooled to 20 ˚C, poured into a mixture of H₂O and CH₂Cl₂ (25 mL each), and the organic and the aqueous layer were separated. The latter was extracted with CH₂Cl₂ (3 × 25 mL). The combined organic layers were washed with H₂O (3 × 20 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by chromatography (flash silica gel, heptanes-EtOAc).

14

(2 E ,2′ E ,2′′ E )-Trimethyl 3,3′,3′′-(1-Methyl-1 H -imidazole-2,4,5-triyl)triacrylate (4f)
Starting with 2 (318 mg, 1.0 mmol), 4f was isolated as a yellow highly viscous oil (254 mg, 76%). ^¹H NMR (250 MHz, CDCl₃): δ = 3.70 (s, 3 H, NCH₃), 3.72, 3.75, 3.76 (s, 3 H, OCH₃), 6.20 (d, 1 H, J = 16.2 Hz, CH), 6.74 (d, 1 H, J = 15.4 Hz, CH), 6.91 (d, 1 H, J = 15.3 Hz, CH), 7.41 (d, 1 H, J = 15.3 Hz, CH), 7.53 (d, 1 H, J = 16.2 Hz, CH), 7.57 (d, 1 H, J = 15.4 Hz, CH). ^¹³C NMR (75 MHz, CDCl₃): δ = 31.7 (NCH₃), 51.7 (OCH₃), 52.0 (2 OCH₃), 120.0, 121.0, 124.1, 127.4, 128.4 (CH), 130.7 (C), 133.1 (CH), 140.3, 146.1 (C), 166.5, 166.6, 167.4 (CO). IR (KBr): 3041, 2991, 2948, 2847 (w), 1708, 1695, 1622 (s), 1519 (w), 1431, 1411, 1306 (m), 1279, 1261, 1193, 1165 (s), 1065, 1034, 1014, 984 (m), 959 (s), 931, 879, 869, 811, 748, 713, 700, 665, 611 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 334(74) [M]⁺, 303(41), 276(13), 275(82), 244(16), 243(100), 231(27), 216(12), 215(18), 199(17), 185(28), 184(10), 171(25), 157(44), 156(21). HRMS (EI, 70 eV): m/z calcd for C₁₆H₁₈O₆N₂ [M]⁺: 334.11594; found: 334.11621.

15

(2 E ,2′ E )-Dibutyl 3,3′-[2-(4-Methoxyphenyl)-1-methyl-1 H -imidazole-4,5-diyl]diacrylate (8a) Starting with 7 (346 mg, 1.0 mmol), 8a was isolated as a yellow highly viscous oil (400 mg, 91%). ^¹H NMR (300 MHz, CDCl₃): δ = 0.87 (t, 3 H, J = 7.4 Hz, CH₃), 0.90 (t, 3 H, J = 7.3 Hz, CH₃), 1.31-1.41 (m, 4 H, 2 CH₂), 1.55-1.65 (m, 4 H, 2 CH₂), 3.64 (s, 3 H, NCH₃), 3.78 (s, 3 H, OCH₃), 4.12 (t, 2 H, J = 6.6 Hz, CH₂O), 4.16 (t, 2 H, J = 6.7 Hz, CH₂O), 6.20 (d, 1 H, J = 16.1 Hz, CH), 6.77 (d, 1 H, J = 15.3 Hz, CH), 6.92 (dd, 2 H, J = 2.0, 6.8 Hz, ArH), 7.48 (dd, 2 H, J = 2.1, 6.8 Hz, ArH), 7.62 (d, 1 H, J = 16.1 Hz, CH), 7.69 (d, 1 H, J = 15.3 Hz, CH). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.7 (2 CH₃), 19.2 (2 CH₂), 30.7, 30.8 (CH₂), 33.9 (NCH₃), 55.4 (OCH₃), 64.2, 64.8 (CH₂O), 114.2 (2 CH), 119.1, 119.4 (CH), 121.6 (C), 129.1 (CH), 130.0 (C), 130.7 (2 CH), 133.5 (CH), 139.7, 152.1, 160.8 (C), 166.7, 167.5 (CO). IR (KBr): 2957, 2933, 2871 (w), 1694 (s), 1622, 1612 (m), 1578, 1531 (w), 1456, 1443 (m), 1387, 1338 (w), 1278 (m), 1249, 1158 (s), 1114, 1065, 1024, 965, 835 (m), 815, 793 (w), 741 (m), 695, 638, 620, 536 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 440(30) [M]⁺, 339(25), 338(20), 284(22), 283(100), 281(12), 266(14), 265(71), 240(18), 239(96), 237(17), 41(11). HRMS (EI, 70 eV): m/z calcd for C₂₅H₃₂O₅N₂ [M]⁺: 440.23057; found: 440.22968.

16

General Procedure for the Synthesis of Benzimidazoles 5a,b,d-g, 6d-f, and 9a-d
A diphenylether solution (3 mL) of 8a-d or 4a,b,d-g was stirred at 200 ˚C for 24 h in a pressure tube. The solution was allowed to cool to 20 ˚C and Pd/C (30 mg, 10 mol%) was added. The solution was stirred at 200 ˚C for 48 h under argon atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (flash silica gel, heptanes-EtOAc).

17

Dibutyl 2-(4-Methoxyphenyl)-1-methyl-1 H -benzo[ d ]imidazole-5,6-dicarboxylate (9a)
Starting with 7 (346 mg, 1.0 mmol), 9a was prepared over two steps as a yellowish highly viscous oil (354 mg, 81%). ^¹H NMR (300 MHz, CDCl₃): δ = 0.89 (t, 6 H, J = 7.3 Hz, 2 CH₃), 1.31-1.43 (m, 4 H, 2 CH₂), 1.61-1.70 (m, 4 H, 2 CH₂), 3.79 (s, 3 H, OCH₃), 3.80 (s, 3 H, NCH₃), 4.25 (t, 4 H, J = 6.7 Hz, 2 CH₂O), 6.96 (dd, 2 H, J = 2.0, 6.9 Hz, ArH), 7.64 (dd, 2 H, J = 2.0, 6.5 Hz, ArH), 7.65 (s, 1 H, ArH), 8.05 (s, 1 H, ArH). ^¹³C NMR (62 MHz, CDCl₃): δ = 12.7 (2 CH₃), 18.1, 18.2 (CH₂), 29.5, 29.6 (CH₂), 31.1 (NCH₃), 54.4 (OCH₃), 64.3, 64.6 (CH₂O), 111.0 (CH), 113.3 (2 CH), 119.9 (CH), 120.5, 125.9, 126.1 (C), 129.9 (2 CH), 136.5, 143.0, 156.0, 160.3 (C), 167.1, 167.3 (CO). IR (KBr): 2957, 2932, 2872 (w), 1713 (s), 1609 (m), 1577, 1532 (w), 1478, 1463, 1438 (m), 1381, 1358 (w), 1327, 1306, 1271 (m), 1245, 1174 (s), 1099, 1059, 1024, 962, 943, 836, 782, 740 (m), 661, 638, 588, 549 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 438(45) [M]⁺, 310(19), 309(100), 308(12). HRMS (EI, 70 eV): m/z calcd for C₂₅H₃₀O₅N₂ [M]⁺: 438.21492; found: 438.21393.