Synthesis of Highly Substituted 3-Acylpyrroles by a Four-Component Sonogashira Alkynylation–Amine Addition–Nitroalkene Michael Addition–Cyclocondensation

Abstract

A consecutive four-component alkynylation–amine addition–nitroalkene addition–cyclocondensation one-pot reaction of acid chlorides, alkynes, amines, and nitroalkenes furnished a library of 3-acylpyrroles in modest to good yields. The sequence takes advantage of a synergism between a Brønsted acid (acetic acid) and a Lewis acid [iron(III) chloride] in the terminal addition-cyclocondensation step of the intermediately formed enaminones with nitroalkenes.

Key words

alkynylation - copper catalysis - cyclocondensation - multicomponent reaction - cascade reaction - pyrroles

Publication History

Received: 28 February 2023

Accepted after revision: 19 April 2023

Accepted Manuscript online:
19 April 2023

Article published online:
07 June 2023

• References and Notes

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• 28 Pyrroles 3; General Procedure PdCl₂(PPh₃)₂ (42 mg, 0.06 mmol, 2 mol%) and CuI (23 mg, 0.12 mmol, 4 mol%) were dissolved in 1,4-dioxane (1.2 mL, 0.4 mL/mmol) under N₂ in an oven-dried Schlenk tube equipped with a magnetic stirrer bar. Et₃N (304 mg, 0.42 mL, 3.0 mmol) and the appropriate alkyne 5 (1.0 equiv) and acid chloride 4 (1.0 equiv) were added, and the resulting mixture was stirred for 2 h (for experimental details, see Supplementary Information, Table S1). MeOH (0.1 mL) and the appropriate amine 6 (1.0 equiv) were then added, and the mixture was stirred at 70 °C for 24 h. After complete conversion (TLC), the appropriate nitroalkene (1.1 equiv), FeCl₃ (24 mg, 0.15 mmol, 5 mol%), and AcOH (0.34 mL, 6.0 mmol, 2.0 equiv) were added, and the reaction temperature was increased to 130 °C. After 24 h (TLC), the mixture was diluted with EtOAc (20 mL) and transferred into a separating funnel. H₂O (25 mL) was added, and the aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic phases were dried (Na₂SO₄) and filtered, and the product was adsorbed on Celite and purified by flash chromatography (silica gel, hexane–EtOAc).
• 29 (1-Benzyl-2,4-diphenyl-1H-pyrrol-3-yl)(2-fluorophenyl)methanone (3a) Prepared by the general procedure and purified by flash chromato­graphy [silica gel, hexane–EtOAc (10:1)] as a clear color­less oil; yield: 232 mg (0.54 mmol, 54%); R_f = 0.31 (hexane–acetone, 5:1). IR (neat): 3061 (w), 3030 (w), 2926 (w), 1634 (m), 1607 (w), 1576 (w), 1520 (w), 1479 (m), 1450 (m), 1406 (m), 1354 (w), 1296 (w), 1267 (w), 1221 (w), 1206 (w), 1188 (w), 1155 (w), 1146 (w), 1101 (w), 1074 (w), 1043 (w), 1022 (w), 997 (w), 901 (m), 833 (w), 810 (w), 752 (s), 733 (m), 696 (s), 667 (w), 648 (m), 615 (w) cm^–1. ¹H NMR (300 MHz, CD₂Cl₂): δ = 5.00 (s, 2 H), 6.67 (t, J = 9.8 Hz, 1 H), 6.87 (dt, J = 0.7 Hz, J = 7.4 Hz, 2 H), 7.03 (m, 2H), 7.08–7.39 (m, 15 H). ¹³C NMR (75 MHz, CD₂Cl₂): δ = 51.07 (CH₂), 115.84 (d, J = 22.4 Hz, CH), 121.43 (CH), 122.62 (C_quat), 123.74 (d, J = 3.6 Hz, CH), 126.49 (2 × CH), 126.96 (C_quat), 127.27 (2 × CH), 128.06 (CH), 128.25 (3 × CH), 128.68 (CH), 129.02 (CH), 129.10 (C_quat), 129.95 (d, J = 13.1 Hz, CH), 131.11 (CH), 131.13 (CH), 131.31 (CH), 131.26 (2 × CH), 132.70 (d, J = 8.5 Hz, CH), 135.24 (C_quat), 137.78 (C_quat), 139.70 (C_quat), 141.85 (d, J = 6.3 Hz, C_quat), 160.34 (d, J = 251.6 Hz, C_quat), 189.51 (C_quat). ¹⁹F NMR (300 MHz, CD₂Cl₂): δ = –114.1. HRMS-ESI; m/z [M + H]⁺ calcd for C₃₁H₂₂FNO: 432.1758; found: 432.1757. Anal. Calcd for C₃₀H₂₂FNO (431.51): C, 83.50; H, 5.14; N, 3.25. Found: C, 83.44; H, 5.12; N, 3.40. [1-Benzyl-2-isopropyl-4-(4-nitrophenyl)-1H-pyrrol-3-yl](3-fluorophenyl)methanone (3g) Prepared by the general procedure and isolated as a red powder; yield: 605 mg (1.37 mmol, 38%); mp 173.5–174.5 °C; R_f = 0.31 (hexane–acetone, 5:1). IR (neat): 3121 (w), 3073 (w), 3061 (w), 3032 (w), 2985 (w), 2930 (w), 2866 (w), 2828 (w), 2598 (w), 2425 (w), 2386 (w), 1983 (w), 1703 (w), 1651 (m), 1634 (w), 1585 (s), 1504 (s), 1479 (m), 1468 (w), 1435 (m), 1402 (w), 1383 (w), 1335 (s), 1325 (s), 1294 (s), 1271 (s), 1229 (m), 1186 (m), 1169 (m), 1159 (m), 1134 (m), 1107 (s), 1086 (m), 1076 (m), 1020 (w), 989 (w), 945 (m), 926 (w), 903 (w), 891 (w), 864 (m), 847 (s), 816 (m), 791 (s), 773 (m), 762 (m), 748 (s), 736 (s), 729 (s), 711 (m), 692 (s), 658 (m) cm^–1. ¹H NMR (300 MHz, CD₂Cl₂): δ = 1.20 (d, J = 7.2 Hz, 6 H), 3.18 (h, J = 7.1 Hz, 1 H), 5.23 (s, 2 H), 6.86 (s, 1 H), 7.04 (tdd, J = 0.9, 2.6, 8.3 Hz, 1 H), 7.10–7.24 (m, 5 H), 7.29–7.45 (m, 4 H), 7.50 (dt, J = 1.2 Hz, J = 7.7 Hz, 1 H), 7.92 (m, 2 H). ¹³C NMR (75 MHz, CD₂Cl₂): δ = 21.98 (2 × CH₃), 26.70 (CH), 51.64 (CH₂), 116.44 (d, J = 22.4 Hz, CH), 119.41 (d, J = 22.2 Hz, CH), 119.85 (CH), 121.18 (CH), 123.52 (C_quat), 123.77 (CH), 126.00 (d, J = 2.9 Hz, CH), 126.92 (2 × CH), 128.28 (2 × CH), 128.30 (CH), 129.36 (2 × CH), 130.16 (d, J = 7.7 Hz, CH), 137.57 (C_quat), 142.00 (d, J = 6.2 Hz, C_quat), 142.52 (C_quat), 143.69 (C_quat), 145.86 (C_quat), 162.82 (d, J = 246.5 Hz, C_quat), 194.13 (d, J = 2.3 Hz, C_quat). ¹⁹F NMR (300 MHz, CD₂Cl₂): δ = –113.6. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₇H₂₄FN₂O₃: 443.1765; found: 443.1768. Anal. Calcd for C₂₇H₂₃FN₂O₃ (442.49): C, 73.29; H, 5.24; N, 6.33. Found: C, 72.95; H, 5.33; N, 6.12. (1-Benzyl-5-methyl-2,4-diphenyl-1H-pyrrol-3-yl)(3-fluorophenyl)methanone (3n) Prepared by the general procedure and isolated as a white powder; yield: 431 mg (0.97 mmol, 33%); mp 143–144 °C; R_f = 0.33 (hexane–acetone, 5:1). IR (neat): 3067 (w), 3028 (w), 2955 (w), 2940 (w), 2913 (w), 1703 (w), 1643 (m), 1599 (w), 1584 (w), 1557 (w), 1520 (w), 1491 (w), 1474 (w), 1443 (m), 1421 (w), 1404 (w), 1375 (w), 1348 (w), 1333 (w), 1315 (w), 1288 (w), 1271 (w), 1242 (w), 1223 (w), 1209 (w), 1198 (w), 1177 (w), 1134 (w), 1109 (w), 1072 (w), 1045 (w), 1028 (w), 1014 (w), 995 (w), 964 (w), 941 (w), 924 (w), 910 (w), 885 (w), 870 (w), 854 (m), 831 (w), 802 (w), 762 (m), 735 (m), 696 (s), 677 (w), 648 (w), 637 (w) cm^–1. ¹H NMR (300 MHz, CD₂Cl₂): δ = 2.18 (s, 3 H), 5.13 (s, 2 H), 6.90 (tdd, J = 1.00 Hz, J = 2.72 Hz, 8.46 Hz, 1 H), 6.97 (m, 2 H), 7.01–7.40 (m, 16 H). ¹³C NMR (75 MHz, CD₂Cl₂): δ = 10.97 (CH₃), 48.33 (CH₂), 116.45 (d, J = 22.2 Hz, CH), 118.50 (d, J = 21.8 Hz, CH), 121.81 (C_quat), 123.77 (C_quat), 125.78 (d, J = 2.7 Hz, CH), 126.10 (2 × CH), 126.22 (CH), 127.68 (CH), 127.91 (C_quat), 128.24 (2 × CH), 128.40 (2 × CH), 128.44 (CH), 129.21 (2 × CH), 129.52 (d, J = 8.1 Hz, CH), 130.43 (2 × CH), 131.17 (2 × CH), 131.80 (C_quat), 135.84 (C_quat), 137.45 (C_quat), 138.22 (C_quat), 142.15 (d, J = 6.3 Hz, C_quat), 160.75–164.00 (d, J = 245.3 Hz, C_quat), 192.32 (d, J = 2.2 Hz, C_quat). ¹⁹F NMR (300 MHz, CD₂Cl₂): δ = –114.8. HRMS-ESI: m/z [M + H]⁺ calcd for C₃₁H₂₅FNO: 446.1915; found: 446.1918. Anal. Calcd for C₃₁H₂₄FNO (445.54): C, 83.57; H, 5.43; N, 3.14. Found: C, 83.35; H, 5.46; N, 3.09. (3-Fluorophenyl)[1-(4-methoxyphenyl)-2,4-diphenyl-1H-pyrrol-3-yl]methanone (3m) Prepared by the general procedure and isolated as a beige powder; yield: 663 mg (1.48 mmol, 50%); mp 155–156 °C; R_f = 0.30 (hexane–acetone, 5:1). IR (neat): 3129 (w), 3071 (w), 3024 (w), 2972 (w), 2901 (w), 2884 (w), 2301 (w), 1643 (m), 1601 (w), 1585 (m), 1547 (w), 1512 (m), 1474 (m), 1435 (w), 1418 (w), 1383 (w), 1337 (w), 1275 (m), 1240 (m), 1217 (m), 1180 (w), 1169 (w), 1159 (w), 1134 (w), 1109 (w), 1078 (m), 1045 (w), 1024 (m), 1003 (w), 947 (w), 912 (w), 893 (w), 831 (m), 814 (w), 795 (m), 777 (m), 756 (s), 733 (w), 723 (w), 700 (s), 675 (m), 657 (w), 623 (w) cm^–1. ¹H NMR (600 MHz, CD₂Cl₂): δ = 3.79 (s, 3 H), 6.85 (m, 2 H), 6.99 (tdd, J = 0.9, 2.7, 8.4 Hz, 1 H), 7.06–7.19 (m, 10 H), 7.24 (m, 2 H), 7.33 (m, 2 H), 7.41 (ddd, J = 1.49, 2.45, 9.68 Hz, 1 H), 7.51 (dt, J = 1.15, 7.74 Hz, 1 H). ¹³C NMR (151 MHz, CD₂Cl₂): δ = 55.84 (CH₃), 114.52 (3 × CH), 116.57 (d, J = 22.1 Hz, CH), 119.22 (d, J = 22.2 Hz, CH), 121.84 (C_quat), 122.50 (CH), 126.05 (d, J = 3.1 Hz, CH), 126.56 (C_quat), 126.62 (2 × CH), 127.72 (3 × CH), 127.97 (2 × CH), 128.12 (3 × CH), 128.46 (3 × CH), 128.66 (3 × CH), 129.80 (d, J = 7.7 Hz, CH), 131.18 (3 × CH), 131.37 (C_quat), 132.63 (C_quat), 134.95 (C_quat), 136.86 (C_quat), 141.58 (d, J = 6.2 Hz, C_quat), 159.25 (C_quat), 162.64 (d, J = 246.5 Hz, C_quat), 193.10 (d, J = 2.1 Hz, C_quat). ¹⁹F NMR (600 MHz, CD₂Cl₂): δ = –112.4. HRMS-ESI: m/z [M + H]⁺ calcd for C₃₀H₂₃FNO₂: 448.17073; found: 448.1714. Anal. Calcd for C₃₀H₂₂FNO₂ (447.16): C, 80.52; H, 4.96; N, 3.13. Found: C, 80.39; H, 4.86; N, 3.08.
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