Baker’s Yeast-Mediated Regioselective Reduction of 2,4-Dinitroacylanilines: Synthesis of 2-Substituted 6-Nitrobenzimidazoles

Abstract

Several 2,4-dinitro-N-acylanilines were regioselectively reduced at the C-2 position by baker’s yeast in slightly basic media (pH = 7.5) to afford 2-amino-4-nitroacylanilines, which were then cyclized under acidic conditions to the corresponding 2-substituted-6-nitrobenzimidazoles. The benzimidazoles thus obtained can be employed as precursors for bioactive derivatives.

Key words

regioselective - reduction - baker’s yeast - dinitroacyl­anilines - nitrobenzimidazoles

References

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18

Representative Reduction of Substituted 2,4-Dinitro- N -acylanilines with Baker’s Yeast.
In a typical experiment, the substrate 2,4-dinitroacylaniline 1e (0.5 mmol) was dissolved in 5 mL of acetone-EtOH 1:1 v/v and the resulting solution was added to a prehydrated (30 min) suspension of 10 g dried yeast (Saf-instant) in 100 mL of 0.5 M phosphate buffer (pH = 7.5) and containing 10 g of sucrose at 30 °C. The mixture was stirred on an orbital shaker (150 rpm) and the pH was kept constant by adding portions of 0.5 M NaOH. The stirring was continued until all the substrate was consumed or remained unchanged as judged by TLC. The mixture was then saturated with NaCl, diluted with 100 mL of EtOAc and combined with 20 g of celite. After vigorous stirring, the cells were removed by vacuum filtration over a bed of celite, the two phases of the filtrate were separated and the aqueous layer extracted with EtOAc (3 × 100 mL); the filter cake was rinsed with EtOAc (3 × 100 mL) and the combined organic extracts were dried over anhyd Na₂SO₄ and concentrated in vacuo. The resulting oil was purified by column chromatography on silica gel. Elution with CH₂Cl₂-MeOH (95:5) yielded 2-amino-4-nitroacylaniline 2e:
¹H NMR (300 MHz, CDCl₃-d ₆-DMSO): δ = 9.14 (1 H, s, NH), 7.73 (1 H, d, J = 9.0 Hz, ArH⁶), 7.65 (1 H, d, J = 2.7 Hz, ArH³), 7.47 (1 H, dd, J _5-6 = 8.8 Hz, J _5-3 = 2.8 Hz, ArH⁵), 5.05 (2 H, s, NH₂), 2.44 (2 H, t, CH₂, C-1), 2.44 (2 H, sext, CH₂, C-3), 1.69 (2 H, q, CH₂, C-2), 0.95 (2 H, t, CH₃, C-4). ¹³C NMR (75 MHz, CDCl₃-d ₆-DMSO): δ = 172.00, 144.17, 140.11, 129.78, 123.03, 111.83, 110.171, 35.92, 27.14, 21.75, 13.33. IR (KBr): ν_max = 3452 (Ar-NH₂), 3374, 3255
(-NH), 2916, 2847 (CH₂, CH₃), 1653 (C=O), 1347
(Ar-NO₂), 876, 739 (NH₂, Ar) cm^-1. MS (EI): m/z (%) = 237 (40) [M⁺], 180 (12), 177 (29), 153 (100), 107 (12), 85 (25), 57 (35). Yield: 214 mg (90%); mp 123-125 °C.
A typical example for the cyclization of 2-amino-4-nitro-acylanilines into substituted nitrobenzimidazoles is as follows: 2,4-dinitroacylaniline 2e (118.5 mg, 0.5 mmol) was dissolved in 5 mL of glacial acetic acid and then this solution was carried out at 60 °C for 6 h. After completion, the solution was concentrated in a rotary evaporator to remove the HOAc and the residue was recrystallized from MeOH-H₂O to afford 2-butyl-6-nitrobenzimidazole (3e):
¹H NMR (300 MHz, CDCl₃-d ₆-DMSO): δ = 12.14 (1 H, s, NH¹), 8.50 (1 H, d, J _7-5 = 2.0 Hz, ArH⁷), 8.19 (1 H, dd, J _5-4 = 8.8 Hz, J _5-7 = 2.0 Hz, ArH⁵), 7.60 (1 H, d, J _4-5 = 8.8 Hz, ArH⁴), 3.00 (2 H, t, CH₂, C-1), 1.89 (2 H, q, CH₂, C-2), 1.46 (2 H, sext, CH₂, C-3), 0.96 (3 H, t, CH₃, C-4). ¹³C NMR (75 MHz, CDCl₃-d ₆-DMSO): δ = 159.59, 142.50. 114.44, 118.48, 143.57, 111.56, 138.41, 29.95, 29.21, 22.42, 13.69. IR (KBr): ν = 3430 (NH), 3000-2800 (NH), 2980, 2939 (CH₂, CH₃), 1625 (Ar), 1592, 1472, 1452 and 1418 (C=N and C=C), 1514 and 1341 (Ar-NO₂), 825, 734 (Ar) cm^-1. MS (EI): m/z (%) = 219 (6) [M⁺], 218 (1), 204 (5), 190 (24), 177 (100), 158 (7), 144 (12), 131 (32). Yield: 98.5 mg (90%); mp 134-135 °C (Lit.¹⁹ 139-141 °C).