A New Three-Component Reaction Catalyzed by Silica Sulfuric Acid: Synthesis of Tetrasubstituted Pyrroles

Abstract

A novel, convenient, and efficient three-component reaction of benzoin derivatives, 1,3-dicarbonyls, and ammonium acetate in the presence of silica sulfuric acid (SSA) is described for the synthesis of 2,3,4,5-tetrasubstituted pyrroles under solvent-free conditions.

Key words

three-component reaction - silica sulfuric acid (SSA) - benzoin - 2,3,4,5-tetrasubstituted pyrroles - 1,3-dicarbonyls

• References and Notes

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• 28 Chemicals were purchased from Aldrich, Fluka, and Merck chemical companies and freshly used without purification. The products were isolated and identified by their physical and spectral data. IR spectra were recorded on FT-IR JASCO-680 using KBr disks. The ¹H NMR spectra were recorded on a Bruker instrument 400 MHz ultrashield model as CDCl₃ and DMSO-d ₆ solutions. Preparation of Silica Sulfuric Acid²¹ A 500 mL suction flask equipped with a constant-pressure dropping funnel and a gas inlet tube for conducting HCl gas over an adsorbing solution (i.e., H₂O) was used. It was charged with silica gel (60.0 g). Chlorosulfonic acid (23.3 g, 0.2 mol) was added dropwise over a period of 30 min at r.t. HCl gas evolved from the reaction vessel immediately. After the addition was completed the mixture was shaken for 30 min. A white solid (SSA) 76.0 g was obtained
• 29 General Experimental Procedure for the Synthesis of Tetrasubstituted Pyrroles A mixture of benzoin derivative (1 mmol), 1,3-dicarbonyl compound (1 mmol), NH₄OAc (2 mmol), and SSA (0.02 g) was stirred at 80 °C under solvent-free conditions. The progress of the reaction was monitored by TLC (hexane–EtOAc = 8:2). After completion of the reaction, the obtained mixture was diluted with EtOAc (10 mL) and filtered to remove the catalyst. The filtrate was washed with aq 5% NaHCO₃, dried over Na₂SO₄, and evaporated. The resulting product was purified in some cases by crystallization from H₂O–EtOH (30:70) to afford pure product
• 30 Selected Characterization Data 1-(2-Methyl-4,5-diphenyl-1H-pyrrol-3-yl)ethanone (Table 3, Entry 1) Pale yellow needles; mp 170–171 °C. IR (KBr): ν_max = 3177, 1635, 1602, 1579, 767, 698 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.72 (s, 3 H, CH₃), 2.46 (s, 3 H, CH₃), 7.10–7.36 (m, 10 H), 11.61 (s, 1 H, NH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.32, 30.96, 79.64, 122.53, 122.58, 126.53, 127.03, 127.33, 128.61, 128.76, 131.22, 132.65, 135.74, 137.57, 194.95 ppm. Anal. Calcd (%) for C₁₉H₁₇NO: C, 82.88; H, 6.22; N, 5.09. Found: C, 82.74; H, 6.19. Ethyl 2-Methyl-4,5-diphenyl-1H-pyrrole-3-carboxylate (Table 3, Entry 2) Pale yellow solid; mp 205–206 °C. IR (KBr): ν_max = 3310, 1676, 1599, 766, 697 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.93 (t, J = 6.4 Hz, 3 H, OCH₂CH₃), 2.49 (s, 3 H, CH₃), 3.91 (q, J = 6.4 Hz, 2 H, OCH₂CH₃), 7.11–7.24 (m, 10 H), 11.56 (s, 1 H, NH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.69, 14.27, 58.76, 111.91, 123.02, 126.48, 127.18, 127.33, 127.88, 128.58, 131.12, 132.71, 136.26, 137.14, 165.11 ppm. Anal. Calcd (%) for C₂₀H₁₉NO₃: C, 74.75; H, 5.96; N, 4.36; O, 14.94. Found: C, 74.50; H, 5.90. Methyl 2-Methyl-4,5-diphenyl-1H-pyrrole-3-carboxylate (Table 3, Entry 3) Pale yellow needles; mp 177–179 °C. IR (KBr): ν_max = 3340, 1681, 1598, 1522, 756, 696 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.47 (s, 3 H, CH₃), 3.45 (s, 3 H, OCH₃), 7.07–7.24 (m, 10 H), 11.58 (s, 1 H, NH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.81, 50.48, 111.57, 123.02, 126.56, 127.32, 127.57, 127.95, 128.59, 130.08, 131.08, 132.67, 136.30, 136.89, 165.53 ppm. Anal. Calcd (%) for C₁₉H₁₇NO₂: C, 78.33; H, 5.88; N, 4.81; O, 10.98. Found: C, 78.25; H, 5.82. (2-Methyl-4,5-diphenyl-1H-pyrrol-3yl)(phenyl)-methanone (Table 3, Entry 4) Yellow needles; mp 221–223 °C. IR (KBr): ν_max = 3289, 1610, 1576, 1522, 740, 696 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.24 (s, 3 H, CH₃), 6.94–7.48 (m, 15 H), 11.65 (s, 1 H, NH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 11.11, 121.49, 122.52, 126.16, 126.80, 127.31, 127.65, 128.10, 128.19, 128.70, 129.37, 130.74, 131.79, 132.73, 134.55, 136.08, 140.27, 193.27 ppm. Anal. Calcd (%) for C₂₄H₁₉NO: C, 85.43; H, 5.68; N, 4.15; O, 4.74. Found: C, 85.22; H, 5.59. 1-[4,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl]ethanone (Table 3, Entry 7) White crystals; mp 234–235 °C. IR (KBr): ν_max = 3195, 1631, 1576, 1523, 1445, 829, 798 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.82 (s, 3 H, CH₃), 3.33 (s, 3 H, CH₃), 7.08–7.40 (m, 8 H), 11.73 (s, 1 H, NH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.35, 31.10, 121.61, 122.45, 126.21, 128.80, 128.82, 131.17, 131.39, 132.14, 132.93, 136.06, 136.16, 194.50 ppm. Anal. Calcd (%) for C₁₉H₁₅Cl₂NO: C, 66.29; H, 4.39; Cl, 20.60; N, 4.07; O, 4.65. Found: C, 66.05; H, 4.25. Ethyl 4,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrole-3-carboxylate (Table 3, Entry 8) Pale yellow needles; mp 155–156 °C. IR (KBr): ν_max = 3286, 1672, 1498, 1481, 831, 732 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.09 (t, J = 7.2 Hz, 3 H, OCH₂CH₃), 2.58 (s, 3 H, CH₃), 4.09 (q, J = 7.2 Hz, 2 H, OCH₂CH₃), 6.99–7.26 (m, 8 H), 8.66 (s, 1 H, NH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 13.89, 14.04, 59.45, 112.36, 122.46, 126.50, 127.92, 128.11, 128.73, 130.38, 132.08, 132.47, 134.28, 136.15, 165.50 ppm. Anal. Calcd (%) for C₂₀H₁₇Cl₂NO₂: C, 64.18; H, 4.58; Cl, 18.95; N, 3.74; O, 8.55. Found: C, 63.96; H, 4.31. Methyl 4,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrole-3-carboxylate (Table 3, Entry 9) White crystals; mp 212–213 °C. IR (KBr): ν_max = 3330, 1685, 1524, 1499 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.33 (s, 3 H, CH₃), 3.49 (s, 3 H, OCH₃), 7.07–7.31 (m, 8 H), 11.80 (s, 1 H, NH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.79, 50.66, 111.53, 122.04, 126.63, 128.15, 128.83, 129.01, 131.13, 131.46, 131.87, 132.81, 135.38, 136.82, 165.26 ppm. Anal. Calcd (%) for C₁₉H₁₅Cl₂NO₂: C, 63.35; H, 4.20; Cl, 19.68; N, 3.89; O, 8.88. Found: C, 63.22; H, 4.38. [4,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl](phenyl)methanone (Table 3, Entry 10) Yellow solid; mp 247–249 °C. IR (KBr): ν_max = 3304, 1617, 1595, 1498, 831, 699 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.21 (s, 3 H, CH₃), 7.18–7.48 (m, 13 H), 11.85 (s, 1 H, NH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.21, 121.67, 126.42, 128.28, 128.36, 128.92, 129.31, 131.05, 131.58, 131.97, 132.36, 134.71, 135.11, 140.15, 192.98 ppm. Anal. Calcd (%) for C₂₄H₁₇Cl₂NO: C, 70.95; H, 4.22; Cl, 17.45; N, 3.45; O, 3.94. Found: C, 70.78; H, 4.37