A Practical Variation on the Paal-Knorr Pyrrole Synthesis

Abstract

The radical addition of α-xanthyl ketones to vinyl pivalate gives adducts that are synthetic equivalents of 1,4-ketoaldehydes; treatment with ammonia or primary amines leads to the corresponding pyrroles in high yield.

Key words

pyrroles - furans - Paal-Knorr reaction - radical additions - xanthates

References

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6

Typical experimental procedure: Xanthate 1g (1.00 g; 5.2 mmol) and vinyl pivalate (1.54 ml; 10.4 mmol) were dissolved in 1,2-dichlororethane (5.2 mL) and the resulting solution refluxed under nitrogen for 15 min. Solid lauroyl peroxide (100 mg; 5 mol%) was added, followed by an additional portion (50 mg; 2.5 mol%) after 90 min. Heating was continued until complete consumption of the starting material (TLC monitoring; further portions of lauroyl peroxide may be added if necessary). The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (eluent: petroleum ether-EtOAc, 95:5; a small layer of alumina was placed on top of the silica to remove any lauric acid present) to give 2g (1.52g; 91%) as a mixture of two diastereomers. This material was used directly in the next step. ¹H NMR (400 MHz;CDCl₃,) δ ppm: 6.62-6.59 (m, 1 H, S-CH), 4.68-4.62 (m, 2 H, OCH ₂CH₃), 2.70-2.61 (m, 1 H, CH-CH₃), 2.48-2.36 (m, 1 H, CH ₂), 2.19 (2.18) (s, 3 H, CH ₃), 1.93-1.83 (m, 1 H, CH ₂), 1.42 (t, J = 7.4 Hz, 3 H, OCH₂CH ₃), 1.20 (s, 3 H, CH ₃), 1.19 (s, 9 H, CH ₃); ¹³C NMR (CDCl₃; 100 MHz) δ ppm: 210.2 (C=S), 209.7 (C=O), 176.9(176.7) (O-C=O), 79.3 (CH-S), 70.3 (70.2) (OCH₂CH₃), 43.7 (43.3) (CH-CH₃), 39.9 (38.9) (Cq), 36.8 (36.3) (CH₂); 26.9 (3CH₃), 17.2 (CH₃), 16.7 (CH₃), 13.7 (OCH₂ CH₃); IR (film, cm^-1) 1720; 1227, 1049; MS (CI, NH₃; m/z) 219 (-t-BuCOOH); 338 (NH₄ ⁺).
To a solution of xanthate 2g (100 mg; 0.3 mmol) in dioxane (1.6 ml) were added p-toluene sulfonic acid monohydrate (30 mg; 0.3 mmol) and 1,2-diphenylethylamine (0.12 mL; 0.6 mmol). The reaction mixture was refluxed under nitrogen for 3.5 h and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether/EtOAc, 98:2) to give the pyrrole 4g′ (64 mg; 75%). ¹H NMR (CDCl₃; 400 MHz) δ ppm: 7.24-7.18 (m, 6 H, CHAr), 7.01-6.96 (m, 4 H, CHAr), 6.81 (d, J = 2.8 Hz, 1 H, NCH=), 6.00 (d, J = 3.2 Hz, 1 H, CH), 5.24-5.21 (m, 1 H, CHN), 3.53-3.48 (m, 1 H, CH ₂-Ph), 3.37-3.32 (m, 1 H, CH ₂Ph), 1.97 (s, 3 H, CH ₃), 1.85 (s, 3 H, CH ₃); ¹³C NMR (CDCl₃;100 MHz) δ ppm: 141.9 (-C=), 138.2 (-C=), 129.3, 128.6, 128.4, 127.4, 126.8, 126.6 (CHAr), 115.8 (NCH=), 114.7 (-C=), 108.9 (CH), 61.5 (CHN), 48.5 (CH₂Ph), 11.5 (CH₃), 9.7 (CH₃); IR (film, cm^-1) 3029, 2921, 2861, 1603, 1495, 1453, 1316, 1219; MS (IC, NH₃; m/z): 276(MH⁺). Calcd for C₂₀H₂₁N (%): C,87.23; H,7.69. Found (%): C,86.98; H,7.65.