Polymer-Assisted Parallel Solution Phase Synthesis of Substituted Benzimidazoles

Abstract

A small library of benzimidazoles was prepared using polymer-bound reagents and scavengers. Polymer-assisted reaction of diphenyl diamines with carboxylic acids yielded o-amido-diphenylamines in the presence of Polystyrene-Carbodiimide (PS-Carbodiimide) using 1-hydroxy-7-azabenzotriazole (HOAt) as additive. Excess HOAt was scavenged post-reaction using Polystyrene-Trisamine (PS-Trisamine) resin. Treatment of o-amido-diphenyl­amines with AcOH facilitated acid-catalyzed cyclodehydration to afford benzimidazoles in good yields and excellent purities.

combinatorial synthesis - solid-phase synthesis - polymer-supported - benzimidazole - amide coupling

References

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2

Yun, Y. K.; Porco, Jr., J. A. Synthesis of Substituted Benzimidazoles using Parallel Hydrogenation, Argonaut Technologies, Application Note APN 025.

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Representative procedure for amide coupling using PS-carbodiimide and PS-Trisamine:

8a

Method A: PS-Carbodiimide resin (2.0 equiv) was added to a dry reaction vessel. The acid (1.5 equiv) in CH₂Cl₂ (with 10% DMF added if required) was added to the dry resin and the mixture stirred at room temperature. After 5 min., amine (1.0 equiv) in CH₂Cl₂ was added and the reaction stirred at room temperature for 12 h to afford the amide product. Typical reaction solvent volumes are 10 mL/g resin.

8b

Method B: Amine (1.0 equiv) and acid (1.5 equiv) in CH₂Cl₂ (with 10% DMF added if necessary) were added to a dry reaction vessel and the mixture stirred for 10 min prior to addition of PS-Carbodiimide resin (2 equiv) with a reaction solvent volume of 10 mL/g resin. The reaction was then stirred overnight.

8c

Method C: PS-Carbodiimide (2.0 equiv), acid (1.5 equiv) and HOAt (1.7 equiv) were dissolved in CH₂Cl₂ and added to a dry reaction vessel and stirred for 5-10 min prior to addition of amine (1.0 equiv). The reaction was stirred at room temperature overnight. After the reaction, the HOAt was scavenged using PS-Trisamine resin (5 equiv) for 2 hours at room temperature prior to filtration.

8d

General Procedure for Reaction Work-up: The reaction mixture was filtered and the amide product was collected in the filtrate. The resin was further washed an additional two times with the reaction solvent (CH₂Cl₂ or CH₂Cl₂-DMF as needed for solubility). A sample from the combined fractions was generally analyzed by GC before concentration to evaluate product purity and presence (if any) of unreacted amine. Concentration afforded the amide product.

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Representative spectroscopic data for compounds 2-4, 6, and 7.2d: ¹H NMR (CDCl₃, 300 MHz): δ 9.96 (bs, 1 H, NH), 8.50 (dd, J = 8.1 Hz, 1.5 Hz, 1 H, CH), 8.43 (dd, J = 4.8 Hz, 1.8 Hz, 1 H, CH), 7.48 (d, J = 9.3 Hz, 2 H, CH), 6.93 (d, J = 9.0 Hz, 2 H, CH), 6.77 (dd, J = 8.7 Hz, 4.8 Hz, 1 H, CH), 3.82 (s, 3 H, CH₃); ¹³C NMR (CDCl₃, 75 MHz): δ 157.12, 155.45, 150.81, 135.46, 130.61, 128.30, 124.78, 114.26, 113.34, 55.48 ppm.
3d: ¹H NMR (d₆-DMSO, 300 MHz): δ 7.95 (bs, 1 H, NH), 7.49 (d, J = 9.0 Hz, 2 H, CH), 7.36 (dd, J = 4.8 Hz, 1.2 Hz, 1 H, CH), 6.90 (dd, J = 7.5 Hz, 1.2 Hz, 1 H, CH), 6.86 (d, J = 9.0 Hz, 1 H, CH), 6.58 (dd, J = 7.8 Hz, 5.4 Hz, 1 H, CH), 5.60 (bs, 2 H, NH₂), 3.71 (s, 3 H, CH₃); ¹³C NMR (d₆-DMSO, 75 MHz): δ 154.46, 144.13, 134.11, 132.20, 131.94, 121.61, 119.56, 114.89, 114.11, 55.34 ppm.
4d: ¹H NMR (CDCl₃, 300 MHz): δ 8.44 (d, J = 4.8 Hz, 1 H, CH), 8.25 (s, 1 H, CH), 8.13 (d, J = 7.8 Hz, 1 H, CH), 7.60 (d, J = 8.7 Hz, 2 H, CH), 7.30 (dd, J = 8.1 Hz, 4.8 Hz, 1 H, CH), 7.08 (d, 2 H, CH), 3.85 (s, 3 H, CH₃); ¹³C NMR (CDCl₃, 75 MHz): δ 159.30, 147.12, 144.90, 143.29, 135.71, 128.23, 128.01, 125.37, 118.71, 115.01, 55.61 ppm.
6i: ¹H NMR (CDCl₃, 300 MHz): δ 9.17 (s, 1 H, CH), 7.98 (d, J = 8.4 Hz, 2H, CH), 7.71 (dd, J = 8.7, 2.1 Hz, 2 H, CH), 7.55 (s, 1 H, CH), 7.43 (d, J = 8.7 Hz, 1 H, CH), 6.86 (d, J = 8.7 Hz, 1 H, CH), 5.41 (s, 1 H, CH), 3.23 (t, J = 6.9 Hz, 2 H, CH₂), 1.61 (tt, J = 7.5, 7.5 Hz, 2 H, CH₂), 1.43 (tq, J = 8.1, 7.2 Hz, 2 H, CH₂), 0.91 (t, J = 7.5 Hz, 3 H, CH₃) ppm.
7i: ¹H NMR (CDCl₃, 300 MHz): δ 7.97 (s, 1 H, CH), 7.82 (d, J = 8.4 Hz, 1 H, CH), 7.72 (d, J = 8.4 Hz, 2 H, CH), 7.67 (d, J = 8.7 Hz, 2 H, CH), 7.54 (d, J = 8.1 Hz, 1 H, CH), 4.27 (t, J = 7.2 Hz, 2 H, CH₂), 1.55 (tt, J = 7.5, 7.5 Hz, 2 H, CH₂), 1.05 (tq, J = 7.8, 7.2 Hz, 2 H, CH₂), 0.66 (t, J = 7.5 Hz, 3 H, CH₃); ¹³C NMR (CDCl₃, 75 MHz): δ 154.27, 141.92, 137.99, 131.89, 131.22, 129.13, 123.83, 119.17, 116.62, 44.18, 31.14, 19.14, 13.23 ppm.

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Yun, Y. K.; Vo, L.; Porco, Jr., J. A.; Labadie, J. 219^th ACS National Meeting, 2000, ORGN 1.