N-Aryl-2-nitrosoanilines
as Intermediates in the Two-Step Synthesis of Substituted
1,2-Diarylbenzimidazoles from Simple Nitroarenes

Zbigniew Wróbel; Karolina Stachowska; Krzysztof Grudzień; Andrzej Kwast

doi:10.1055/s-0030-1260764

LETTER

N-Aryl-2-nitrosoanilines as Intermediates in the Two-Step Synthesis of Substituted 1,2-Diarylbenzimidazoles from Simple Nitroarenes

Zbigniew Wróbel*^a, Karolina Stachowska^a, Krzysztof Grudzień^b, Andrzej Kwast^a
^a Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44, 01-224 Warszawa 42, POB 58, Poland
Fax: +48(22)6326681; e-Mail: wrobel@icho.edu.pl;
^b Faculty of Chemistry, University of Warsaw, ul. Pasteura 1, 02-093 Warszawa, Poland

Abstract

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Abstract

N-Aryl-2-nitrosoanilines, easily available from reaction of nitroarenes with anilide anions, undergo base-promoted condensation reaction with substituted benzyl aryl sulfones, furnishing 1,2-diaryl-1H-benzimidazoles.

Key words

heterocycles - nitroso group - carbanions - condensation - sulfones - cyclization

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References

References and Notes

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4a Grimmett MR. Product Class 4: Benzimidazoles, In Science of Synthesis Neier R. Springer; New York: 2002. p.529

4b Preston PN. Chem. Rev. 1974, 74: 279

5a Yun YK. Porco JA. Labadie J. Synlett 2002, 739

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5c Lin S.-Y. Isome Y. Stewart E. Liu J.-F. Yohannes D. Yu L. Tetrahedron Lett. 2006, 47: 2883

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7 Benzylic alcohols have been used instead of aldehydes, with MnO₂ as a double oxidant. See: Wilfred CD. Taylor RJK. Synlett 2004, 1628

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9 Hornberger KR. Badiang JG. Salovich JM. Kuntz KW. Emmitte KA. Cheung M. Tetrahedron Lett. 2008, 44: 6348

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14

Procedure A
To a solution of the nitrosoaniline 1 (0.5 mmol) and the sulfone (0.6 mmol) in a specified solvent (3 mL or 6 mL in the case of K₂CO₃ used as base) DBU (0.3 mL), Et₃N (0.3 mL), or K₂CO₃ (700 mg) was added, according to Table [¹] , and the mixture was stirred at r.t. for the time specified in Table [¹] . In the case when K₂CO₃ was used, it was then filtered off. The mixture was poured into 10% HCl aq (ca. 50 mL) and extracted with EtOAc. The extract was washed with H₂O and brine and dried with Na₂SO₄. After evaporation, the crude product mixture was subjected to column chromatography (SiO₂, hexane-EtOAc).

15

Procedure B
A solution of nitrosoaniline 1b (163 mg, 0.614 mmol) and benzyl tolyl sulfone (184 mg, 0.75 mmol) in toluene (3 mL) was vigorously stirred with 50% NaOH (1 mL) and TBAB (30 mg) at r.t. for 1.5 h. The mixture was then diluted with H₂O (100 mL) and extracted with EtOAc. The extracts were washed with H₂O three times, dried with Na₂SO₄, and evaporated. The mixture was subjected to column chromatography (SiO₂, hexane-EtOAc), and the crude 3m was recrystallized from EtOAc.

16

Analytical Data for the Products 3a-m
6-Chloro-1-(4-ethoxyphenyl)-4-methoxy-2-(4-nitrophenyl)-1 H -benzimidazole (3a) Yellow crystals, mp 211-212 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 1.37 (t, J = 7.0 Hz, 3 H), 4.03 (s, 3 H), 4.10 (q, J = 7.0 Hz, 2 H), 6.74 (d, J = 1.8 Hz, 1 H), 6.92 (d, J = 1.8 Hz, 1 H), 7.09-7.13 (m, 2 H), 7.38-7.43 (m, 2 H), 7.75-7.79 (m, 2 H), 8.21-8.25 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.6, 56.3, 63.5, 103.2, 105.4, 115.8, 123.6, 127.9, 128.7, 129.2, 130.0, 131.6, 135.6, 139.2, 147.6, 149.0, 151.8, 159.0. MS (EI): m/z (%) = 423 (95) [M⁺], 422 (100), 394 (43), 376 (9), 348 (13). Anal. Calcd for C₂₂H₁₈O₄N₃Cl: C, 62.3; H, 4.3; N, 9.9. Found: C, 62.3; H, 4.3; N, 9.8.
6-Chloro-2-(5-chloro-2-nitrophenyl)-1-(4-ethoxyphenyl)-4-methoxy-1 H -benzimidazole (3b)
Yellow solid, mp 145-148 ˚C. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.33 (t, J = 7.0 Hz, 3 H), 4.00 (s, 3 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.84 (d, J = 1.8 Hz, 1 H), 6.93 (d, J = 1.8 Hz, 1 H), 6.99-7.04 (m, 2 H), 7.23-7.28 (m, 2 H), 7.83 (dd, J = 8.7, 2.3 Hz, 1 H), 7.89 (d, J = 2.3 Hz, 1 H), 8.09 (d, J = 8.7 Hz, 1 H). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.5, 56.3, 63.4, 103.02, 105.3, 115.5, 126.4, 126.5, 126.6, 128.2, 129.0, 131.3, 131.5, 132.7, 137.7, 138.2, 146.9, 147.1, 151.7, 158.7. MS (EI): m/z (%) = 459 (70), 457 (100) [M⁺], 428 (23), 409 (13), 289 (34), 261 (45). HRMS (EI): m/z calcd for C₂₂H₁₇O₄N₃ ^³5Cl₂ [M]⁺: 457.0596; found: 457.0611.
6-Chloro-2-(5-methoxy-4-methyl-2-nitrophenyl)-1-(4-ethoxyphenyl)-4-methoxy-1 H -benzimidazole (3c) Creamy powder, mp 175-176 ˚C (hexane-EtOAc). ^¹H NMR (600 MHz, DMSO-d ₆): δ = 1.32 (t, J = 7.0 Hz, 3 H), 2.23 (s, 3 H), 3.87 (s, 3 H), 4.00 (s, 3 H), 4.02 (q, J = 7.0 Hz, 2 H), 6.81 (d, J = 1.7 Hz, 1 H), 6.92 (d, J = 1.7 Hz, 1 H), 6.96-6.99 (m, 2 H), 7.20-7.24 (m, 2 H), 7.31 (s, 1 H), 7.94 (s, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 14.7, 16.1, 56.1, 56.3, 63.7, 103.5, 104.9, 113.7, 115.2, 125.7, 127.1, 127.2, 128.0, 129.5, 129.9, 131.7, 137.9, 140.7, 149.4, 151.7, 158.9, 161.2. MS (EI): m/z (%) = 467 (100) [M⁺], 438 (14), 289 (68), 178 (21). HRMS (EI): m/z calcd for C₂₄H₂₂O₅N₃ ^³5Cl [M]⁺: 467.1248; found: 467.1256.
6-Chloro-2-(4- tert -butyl-2-nitrophenyl)-1-(4-ethoxyphenyl)-4-methoxy-1 H -benzimidazole (3d) Yellow powder, mp 162-163 ˚C. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.18 (t, J = 7.1 Hz, 3 H), 1.31 (s, 9 H), 3.99 (s, 3 H), 4.03 (q, J = 7.1 Hz, 2 H), 6.81 (d, J = 1.8 Hz, 1 H), 6.91 (d, J = 1.8 Hz, 1 H), 6.99-7.03 (m, 2 H), 7.25-7.28 (m, 2 H), 7.60 (d, J = 8.1 Hz, 1 H), 7.81 (dd, J = 8.1, 1.9 Hz, 1 H), 7.98 (d, J = 1.9 Hz, 1 H). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.0, 30.5, 35.0, 56.2, 63.4, 103.0, 105.2, 115.4, 121.1, 122.0, 126.9, 128.2, 128.7, 130.3, 131.5, 132.5, 137.9, 148.1, 148.9, 151.5, 154.5, 158.6. MS (EI): m/z (%) = 479 (100) [M⁺], 450 (19), 289 (59) 260 (53). HRMS (EI): m/z calcd for C₂₆H₂₆O₄N₃ ^³5Cl [M]⁺: 479.1612; found: 479.1606.
7-[6-Chloro-4-methoxy-1-(4-ethoxyphenyl)-1 H -benzimidazol-2-yl]-8-nitroquinoline (3e) Pale yellow crystals, mp 127-130 ˚C (hexane-EtOAc). ^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.31 (t, J = 7.0 Hz, 3 H), 4.02 (q, J = 7.0 Hz, 2 H), 4.04 (s, 3 H), 6.88 (d, J = 1.7 Hz, 1 H), 6.95 (d, J = 1.7 Hz, 1 H), 7.02-7.05 (m, 2 H), 7.33-7.36 (m, 2 H), 7.52 (d, J = 8.6 Hz, 1 H), 7.80 (dd, J = 8.4, 4.1 Hz, 1 H), 8.15 (d, J = 8.6 Hz, 1 H), 8.55 (dd, J = 8.4, 1.5 Hz, 1 H), 9.09 (dd, J = 4.1, 1.5 Hz, 1 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 14.9, 56.8, 63.9, 103.6, 106.1, 116.0, 123.0, 124.7, 127.3, 127.4, 128.7, 129.2, 130.0, 130.8, 132.1, 137.0, 138.6, 138.7, 146.2, 148.1, 152.2, 154.0, 159.3. MS (EI): m/z (%) = 474 (100) [M⁺], 429 (31), 289 (59), 261 (66), 155 (25). HRMS (EI): m/z calcd for C₂₅H₁₉O₄N₄ ^³5Cl [M]⁺: 474.1095; found: 474.1089.
2-(3,4-Dichlorophenyl)-6-methoxy-1-(4-methylphenyl)-1 H -benzimidazole (3f) Yellow crystals, mp 173-177 ˚C (hexane-EtOAc). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 2.42 (s, 3 H), 3.73 (s, 3 H), 6.61 (d, J = 2.3 Hz, 1 H), 6.95 (dd, J = 8.8, 2.3 Hz, 1 H), 7.32-7.36 (m, 3 H), 7.39-7.46 (m, 2 H), 7.62 (d, J = 8.4 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.74 (d, J = 2.0 Hz, 1 H). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 20.8, 55.5, 93.3, 112.7, 120.2, 127.2, 128.5, 130.4, 130.5, 130.6, 130.7, 131.1, 131.9, 133.4, 136.7, 137.9, 138.7, 148.4, 157.0. MS (EI): m/z (%) = 384 (71), 382 (100) [M⁺], 367 (64), 159 (41). Anal. Calcd for C₂₁H₁₆ON₂Cl₂: C, 65.8; H, 4.2; N, 7.3. Found: C, 65.6; H, 4.2; N, 7.3.
2-(5-Chloro-2-nitrophenyl)-6-methoxy-1-(4-methylphenyl)-1 H -benzimidazole (3g) Yellow crystals, mp 155-158 ˚C (hexane-EtOAc). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 2.34 (s, 3 H), 3.75 (s, 3 H), 6.73 (d, J = 2.2 Hz, 1 H), 6.96 (dd, J = 8.8, 2.2 Hz, 1 H), 7.22-7.26 (m, 2 H), 7.28-7.34 (m, 2 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.80 (dd, J = 8.8, 2.3 Hz, 1 H), 7.84 (d, J = 2.3 Hz, 1 H), 8.06 (d, J = 8.8 Hz, 1 H). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 20.6, 55.6, 93.3, 112.7, 120.4, 126.4, 126.6, 127.1, 130.4, 131.0, 132.1, 132.5, 136.6, 136.9, 137.9, 138.4, 146.2, 147.2, 157.1. MS (EI): m/z (%) = 393 (38) [M⁺], 348 (9), 225 (100), 182 (20). Anal. Calcd for C₂₁H₁₆N₃O₃Cl: C, 64.0; H, 4.1; N, 10.7. Found: C, 63.8; H, 4.2; N, 10.6.
6-Methoxy-2-(5-methoxy-4-methyl-2-nitrophenyl)-1-(4-methylphenyl)-1 H -benzimidazole (3h) Yellow crystals, mp 200-201 ˚C (EtOH). ^¹H NMR (500 MHz, CDCl₃): δ = 2.26 (s, 3 H), 2.37 (s, 3 H), 3.80 (s, 3 H), 3.91 (s, 3 H), 6.73 (d, J = 2.3 Hz, 1 H), 6.99 (dd, J = 8.8, 2.3 Hz, 1 H), 7.04-7.08 (m, 3 H), 7.17 (m, 2 H), 7.76 (d, J = 8.8 Hz, 1 H), 7.80 (d, J = 0.8 Hz, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 16.1, 21.2, 55.9, 56.2, 93.8, 112.5, 113.5, 120.5, 126.0, 126.5, 127.1, 129.4, 130.2, 132.6, 136.9, 137.1, 138.5, 140.8, 148.9, 157.4, 161.2. MS (EI): m/z (%) = 403 (50) [M⁺], 361 (16), 225 (100), 182 (15). Anal. Calcd for C₂₃H₂₁N₃O₄: C, 68.5; H, 5.2; N, 10.4. Found: C, 68.4; H, 5.2; N, 10.4.
2-(4- tert -Butyl-2-nitrophenyl)-6-methoxy-1-(4-methylphenyl)-1 H -benzimidazole (3i) Yellow crystals, mp 184-188 ˚C (hexane-EtOAc). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.31 (s, 9 H), 2.34 (s, 3 H), 3.75 (s, 3 H), 6.70 (d, J = 2.3 Hz, 1 H), 6.94 (dd, J = 8.8, 2.3 Hz, 1 H), 7.24-7.33 (m, 4 H), 7.54 (d, J = 8.1 Hz, 1 H), 7.65 (d, J = 8.8 Hz, 1 H), 7.77 (dd, J = 8.1, 1.9 Hz, 1 H), 7.96 (d, J = 1.9 Hz, 1 H). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 20.7, 30.5, 35.0, 55.6, 93.4, 112.4, 120.2, 121.0, 122.5, 126.6, 130.1, 130.4, 132.3, 132.5, 136.6, 137.0, 138.2, 147.4, 149.1, 154.2, 156.8. MS (EI): m/z (%) = 415 (53) [M⁺], 370 (17), 225 (100), 182 (13). Anal. Calcd for C₂₅H₂₅N₃O₄: C, 72.3; H, 6.1; N, 10.1. Found: C, 72.1; H, 6.2; N, 9.9.
6-Chloro-1-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-1 H -benzimidazole (3j) Yellow solid, mp 176-178 ˚C. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.29 (d, J = 2.2 Hz, 1 H), 7.37 (dd, J = 8.4, 2.2 Hz, 1 H), 7.38 (dd, J = 8.8, 2.2 Hz, 1 H), 7.54-7.58 (m, 2 H), 7.66-7.70 (m, 3 H), 7.79 (d, J = 2.2 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 111.0, 121.5, 124.0, 128.9, 129.5, 129.9, 130.2, 130.7, 131.2, 131.5, 131.8, 133.2, 134.4, 134.8, 138.1, 141.6, 151.0. MS (EI): m/z (%) = 408 (100), 407 (89), 406 (76) [M⁺], 372 (20), 370 (20), 336 (7). Anal. Calcd for C₁₉H₁₀N₂Cl₄: C, 55.9; H, 2.5; N, 6.9. Found: C, 55.9; H, 2.7; N, 6.8.
6-Chloro-1-(4-chlorophenyl)-2-(5-chloro-2-nitrophenyl)-1 H -benzimidazole (3k) Pale yellow crystals, mp 148-149 ˚C (hexane-EtOAc). ^¹H NMR (400 MHz, CDCl₃): δ = 7.15-7.18 (m, 2 H), 7.27 (d, J = 1.9 Hz, 1 H), 7.35 (dd, J = 8.6, 1.9 Hz, 1 H), 7.40-7.43 (m, 2 H), 7.58 (dd, J = 2.3, 8.8 Hz, 1 H), 7.68 (d, J = 2.3 Hz, 1 H), 8.62 (d, J = 8.6 Hz, 1 H), 7.99 (d, J = 8.8 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 110.5, 121.5, 124.3, 126.2, 127.2, 128.1, 130.3, 130.4, 131.1, 132.9, 133.0, 135.3, 136.6, 140.1, 141.5, 146.7, 148.4. MS (EI): m/z (%) = 419 (24), 417 (25) [M⁺], 372 (27), 249 (100), 214 (22), 169 (16), 138 (18), 111 (28). HRMS (EI): m/z calcd for C₁₉H₁₀O₂N₃ ^³5Cl₃ [M]⁺: 416.9839; found: 416.9842.
6-Chloro-1-(4-chlorophenyl)-2-(2-nitrophenyl)-1 H -benzimidazole (3l) Yellow crystals, mp 274-275 ˚C (MeOH). ^¹H NMR (400 MHz, CDCl₃): δ = 7.23 (d, J = 2.0 Hz, 1 H), 7.25-7.29 (m, 2 H), 7.36 (dd, J = 8.8, 2.0 Hz, 1 H), 7.53-7.58 (m, 2 H), 7.72-7.76 (m, 2 H), 7.81 (d, J = 8.8 Hz, 1 H), 8.18-8.22 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 110.6, 121.3, 123.7, 124.6, 128.4, 130.1, 130.5, 130.8, 134.3, 135.2, 135.7, 137.7, 141.4, 148.2, 150.3. MS (EI): m/z (%) = 383 (100) [M⁺], 336 (39), 302 (15), 266 (12). HRMS (EI): m/z calcd for C₁₉H₁₁O₂N₃ ^³5Cl₂ [M]⁺: 383.0228; found: 383.0216.
6-Methoxy-1-(4-methylphenyl)-2-phenyl-1 H -benzimidazole (3m) Solid, mp 166-167 ˚C (EtOAc). ^¹H NMR (500 MHz, DMSO-d ₆): δ = 2.40 (s, 3 H), 3.72 (s, 3 H), 6.61 (d, J = 2.4 Hz, 1 H), 6.93 (dd, J = 8.8, 2.4 Hz, 1 H), 7.28-7.39 (m, 7 H), 7.47-7.50 (m, 2 H), 7.67 (d, J = 8.8 Hz, 1 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 20.7, 55.5, 93.4, 112.1, 119.9, 127.2, 128.3, 128.8, 129.1, 130.1,130.5, 133.9, 136.9, 137.8, 138.3, 150.9, 156.6. MS (EI): m/z (%) = 314 (100) [M⁺], 299 (50). Anal. Calcd for C₂₁H₁₈ON₂: C, 80.2; H, 5.8; N, 8.9. Found: C, 79.9; H, 5.7; N, 8.9.

17 Feuer H. In The Chemistry of the Nitro and Nitroso Groups Part 1: Patai S. Wiley; New York: 1969. p.278

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