Efficient Synthesis of Functionalized 2,5-Dihydropyrrole Derivatives by Ph₃P-Promoted Condensation between Acetylene Esters and α-Arylamino Ketones

Abstract

A new and efficient one-pot synthesis of polysubstituted 2,5-dihydropyrrole derivatives by reaction between dialkyl acetylenedicarboxylates and β-aminoketones promoted by triphenyl­phosphine, is described. The prepared 2,5-dihydropyrroles can be easily oxidized to the corresponding pyrrole derivatives by chromium trioxide.

Key words

2,5-dihydropyrroles - dialkyl acetylenedicarboxylates - β-aminoketones - triphenylphosphine - intramolecular Wittig reaction

References and Notes

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16

General procedure for the preparation of compounds 3a-h: To a magnetically stirred solution of β-aminoketone (1 mmol)­ and triphenylphosphine (0.28 g, 1 mmol) in CH₂Cl₂ (10 mL), was added dropwise a mixture of dialkyl acetylenedicar-boxylate (1 mmol) in CH₂Cl₂ (5 mL) at room temperature. The reaction mixture was stirred for 24 h, then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane-EtOAc). The solvent was removed under reduced pressure to afford the product.
3a: White powder; mp 110-112 ˚C; IR (KBr): 1740, 1699 (ester) cm^-¹; Anal. Calcd for C₂₁H₂₀BrNO₅: C, 56.52; H, 4.52; N, 3.14. Found: C, 56.51; H, 4.33; N, 3.17; MS: m/z (%) = 445 (4); ^¹H NMR (500 MHz, CDCl₃): δ = 3.70, 3.73 and 3.75 (9 H, 3 × s, 3 × OCH₃), 4.50 (1 H, dd, J = 15.7 Hz, J = 2.3 Hz, HCH), 4.72 (1 H, dd, J = 15.7 Hz, J = 6.5 Hz, HCH), 5.39 (1 H, dd, J = 6.5 Hz, J = 2.3 Hz, CH), 6.63 and 6.85 (4 H, 2 × d, J = 8.9 Hz, ArH), 7.35 and 7.55 (4 H, 2 × d, J = 8.4 Hz, ArH); ^¹³C NMR (125.8 MHz, CDCl₃): δ = 52.3, 52.9 and 56.2 (3 × OCH₃), 61.3 (CH₂), 70.3 (CH), 113.1, 115.6, 124.2, 125.3, 130.2, 131.8, 131.9, 140.1, 151.2 and 152.6 (aromatic and olefinic carbons), 163.5 and 172.1 (2 × CO ester). 3b: Viscose oil; IR (neat): 1726 (ester) cm^-¹; Anal. Calcd for C₂₃H₂₄BrNO₅: C, 58.24; H, 5.10; N, 2.95. Found: C, 58.10; H, 5.29; N, 2.78; MS: m/z (%) = 473 (11); ^¹H NMR (500 MHz, CDCl₃): δ = 1.20 (6 H, m, 2 × CH₃), 3.73 (3 H, s, OCH₃), 4.14 (4 H, m, 2 × OCH₂), 4.77 (1 H, dd, J = 15.6 Hz, J = 2.3 Hz, HCH), 4.71 (1 H, dd, J = 15.6 Hz, J = 6.5 Hz, HCH), 5.38 (1 H, dd, J = 6.5 Hz, J = 2.3 Hz, CH), 6.66 and 6.85 (4 H, 2 × d, J = 9.0 Hz, 4 H, ArH), 7.36 and 7.52 (4 H, 2 × d, J = 8.5 Hz, ArH); ^¹³C NMR (125.8 MHz, CDCl₃): δ = 23.2 and 24.2 (2 × CH₃), 55.9 (OCH₃), 61.2, 61.3 and 61.7 (3 × OCH₂), 70.4 (CH), 113.2, 115.5, 124.0, 126.2, 129.9, 130.3, 132.0, 140.1, 150.8 and 152.6 (aromatic and olefinic carbons), 162.9 and 171.7 (2 × CO ester). 3c: White powder; mp 114-116 ˚C; IR (KBr): 1735, 1709 (ester) cm^-¹; Anal. Calcd for C₂₁H₂₀ClNO₅: C, 62.77; H, 5.02; N, 3.49. Found: C, 62.91; H, 5.17; N, 3.33; MS: m/z (%) = 401 (27); ^¹H NMR (500 MHz, CDCl₃): δ = 3.51, 3.54 and 3.57 (9 H, 3 × s, 3 × OCH₃), 4.33 (1 H, dd, J = 15.6 Hz, J = 2.4 Hz, HCH), 4.53 (1 H, dd, J = 15.6 Hz, J = 6.4 Hz, HCH), 5.21 (1 H, dd, J = 6.4 Hz, J = 2.4 Hz, CH), 6.45 and 6.68 (4 H, 2 × d, J = 8.8 Hz, ArH), 7.18-7.25 (4 H, m, C₆H₄Cl); ^¹³C NMR (125.8 MHz, CDCl₃): δ = 51.8, 52.4 and 52.7 (3 × OCH₃), 60.9 (CH₂), 69.9 (CH), 112.7, 115.2, 124.8, 128.5, 129.6, 131.0, 135.5, 139.8, 150.8 and 152.2 (aromatic and olefinic carbons), 163.1 and 173.7 (2 × CO ester). 3d: Viscose oil; IR (neat): 1730, 1710 (2 × CO ester) cm^-¹; Anal. Calcd for C₂₃H₂₄ClNO₅: C, 64.26; H, 5.63; N, 3.26. Found: C, 64.20; H, 5.54; N, 3.37; MS: m/z (%) = 429 (25); ^¹H NMR (500 MHz, CDCl₃): δ = 1.01, 1.04 (6 H, 2 × t, J = 7.4 Hz, 2 × CH₃), 3.51 (4 H, m, 2 × OCH₂), 3.57 (3 H, s, OCH₃), 4.32 (1 H, dd, J = 15.6 Hz, J = 2.4 Hz, HCH), 4.53 (1 H, dd, J = 15.6 Hz, J = 6.4 Hz, HCH), 5.20 (1 H, dd, J = 6.4 Hz, J = 2.4 Hz, CH), 6.45 and 6.67 (4 H, 2 × d, J = 8.8 Hz, C₆ H ₄OCH₃), 7.18-7.26 (4 H, m, C₆H₄Cl); ^¹³C NMR (125.8 MHz, CDCl₃): δ = 14.1 and 14.2 (2 × CH₃), 55.4 (OCH₃), 60.8, 60.9 and 61.3 (3 × CH₂), 68.2 (CH), 112.8, 114.2, 115.1, 122.6, 125.3, 128.4, 129.7, 131.2, 135.3, 139.7, 150.4 and 152.1 (aromatic and olefinic carbons), 162.6 and 171.5 (2 × CO ester). 3e: Viscose oil; IR (neat): 1734, 1715 (2 × CO ester) cm^-¹; Anal. Calcd for C₂₇H₃₂ClNO₅: C, 66.73; H, 6.64; N, 2.88. Found: C, 66.91; H, 6.61; N, 2.73. MS: m/z (%) = 485 (9); ^¹H NMR (500 MHz, CDCl₃): δ = 1.19 and 1.21 (18 H, 2 × s, 6 × CH₃), 4.25 (1 H, dd, J = 15.6 Hz, J = 2.4 Hz, HCH), 4.45 (1 H, dd, J = 15.6 Hz, J = 6.4 Hz, HCH), 5.05 (1 H, dd, J = 6.4 Hz, J = 2.4 Hz, CH), 6.45 and 6.66 (4 H, 2 × d, J = 9.0 Hz, C₆ H ₄OCH₃), 7.00-7.20 (4 H, m, C₆ H ₄Cl); ^¹³C NMR (125.8 MHz, CDCl₃): δ = 27.9 and 29.8 (6 × CH₃), 55.6, 55.7 (2 × OCH₃), 60.7 (CH₂), 71.1 (CH), 81.4 and 81.8 (2 × OC), 112.9, 115.0, 124.5, 127.2, 128.6, 129.5, 131.4, 134.9, 139.9, 147.8 and 151.9 (aromatic and olefinic carbons), 161.9 and 171.8 (2 × CO ester). 3f: Viscose oil; IR (KBr): 1733, 1711 (ester) cm^-¹; Anal. Calcd for C₂₁H₂₁NO₅: C, 68.65; H, 5.76; N, 3.81. Found: C, 68.88; H, 5.66; N, 3.94. MS: m/z (%) = 367 (23). ^¹H NMR (500 MHz, CDCl₃): δ = 3.50, 3.57 and 3.59 (9 H, 3 × s, 3 × OCH₃), 4.36 (1 H, dd, J = 15.6 Hz, J = 2.4 Hz, HCH), 4.58 (1 H, dd, J = 15.6 Hz, J = 6.4 Hz, HCH), 5.23 (1 H, dd, J = 6.4 Hz, J = 2.4 Hz, CH), 6.48 and 6.62 (4 H, 2 × d, J = 8.8 Hz, ArH), 7.23-7.55 (5 H, m, C₆H₅); ^¹³C NMR (125.8 MHz, CDCl₃): δ = 51.2, 52.4 and 52.7 (3 × OCH₃), 60.8 (CH₂), 69.9 (CH), 113.7, 115.8, 124.3, 124.9, 128.5, 129.1, 131.0, 139.8, 150.7 and 151.9 (aromatic and olefinic carbons), 163.1 and 173.7 (2 × CO ester). 3g: Viscose oil; IR (neat): 1735, 1707 (ester) cm^-¹; Anal. Calcd for C₂₁H₂₁NO₄: C, 71.78; H, 6.02; N, 3.99. Found: C, 71.70; H, 5.78; N, 3.72; MS: m/z (%) = 351 (31); ^¹H NMR (500 MHz, CDCl₃): δ = 2.33 (3 H, s, CH₃), 3.66 and 3.71 (6 H, 2 × s, 2 × OCH₃), 4.57 (1 H, dd, J = 15.8 Hz, J = 2.3 Hz, HCH), 4.76 (1 H, dd, J = 15.8 Hz, J = 6.4 Hz, HCH), 5.45 (1 H, dd, J = 6.4 Hz, J = 2.3 Hz, CH), 7.23-7.59 (9 H, m, ArH). ^¹³C NMR (125.8 MHz, CDCl₃): δ = 21.6 (CH₃), 52.2, 52.9 (2 × OCH₃), 61.0 (CH₂), 70.0 (CH), 112.2, 124.5, 127.2, 128.5, 128.6, 128.9, 129.9, 130.5, 143.5, 152.3 (aromatic and olefinic carbons), 164.3, 172.4 (2 × CO ester). 3h: Viscose oil; IR (neat): 1732, 1695 (ester) cm^-¹; Anal. Calcd for C₂₀H₁₈ClNO₄: C, 64.61; H, 4.88; N, 3.77. Found: C, 64.79; H, 4.80; N, 3.90; MS:
m/z (%) = 371 (27); ^¹H NMR (500 MHz, CDCl₃): δ = 3.69 and 3.74 (6 H, 2 × s, 2 × OCH₃), 4.55 (1 H, dd, J = 15.7 Hz, J = 2.0 Hz, HCH), 4.75 (1 H, dd, J = 15.7 Hz, J = 6.2 Hz, HCH), 5.41 (1 H, dd, J = 6.2 Hz, J = 2.0 Hz, CH), 6.61 and 7.2 (4 H, 2 × d, J = 8.9 Hz, C₆ H ₄Cl), 7.40-7.48 (5 H, m, C₆H₅); ^¹³C NMR (125.8 MHz, CDCl₃): δ = 52.2 and 53.0 (2 × OCH₃), 60.9 (CH₂), 70.0 (CH), 113.3, 115.7, 123.1, 124.4, 128.5, 128.6, 129.8, 130.0, 144.2 and 151.0 (aromatic and olefinic carbons), 163.5 and 171.7 (2 × CO ester).

23

General procedure for the preparation of compounds 7a-c: To a magnetically stirred solution of dihydropyrrole derivative 3 (1 mmol) in CHCl₃ (10 mL), was added CrO₃ (1 mmol) at room temperature. The reaction mixture was stirred for 4 h, then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane-EtOAc). The solvent was removed under reduced pressure to afford the product.
7a: White powder; mp 123-125 ˚C; IR (KBr): 1740, 1707 (ester) cm^-¹; Anal. Calcd for C₂₁H₁₉NO₅: C, 69.03; H, 5.24; N, 3.83. Found: C, 69.31; H, 5.19; N, 3.89; MS: m/z (%) = 365 (34); ^¹H NMR (500 MHz, CDCl₃): δ = 3.76, 3.86, 3.88 (9 H, 3 × s, 3 × OCH₃), 6.98 and 7.30 (4 H, 2 × d, J = 9.0 Hz, ArH), 7.10 (1 H, s, CH of pyrrole), 7.28-7.45 (5 H, C₆H₅); ^¹³C NMR (125.8 MHz, CDCl₃): δ = 52.3, 55.9 and 56.2 (3 × OCH₃), 114.4, 121.9, 123.8, 125.0, 126.7, 127.5, 127.8, 128.1, 129.9, 132.8, 133.7 and 159.9 (aromatic and olefinic carbons), 160.9 and 167.2 (2 × CO ester). 7b: Viscose oil; IR (KBr): 1740, 1707 (ester) cm^-¹; Anal. Calcd for C₂₁H₁₉NO₄: C, 72.19; H, 5.48; N, 4.01. Found: C, 72.40; H, 5.29; N, 4.09; MS: m/z (%) = 349 (19); ^¹H NMR (500 MHz, CDCl₃): δ = 2.42, 3.73, 3.85 (9 H, 3 × s, 3 × CH₃), 6.64 and 7.10 (4 H,
2 × d, J = 8.4 Hz, C₆ H ₄CH₃), 6.99 (1 H, s, CH of pyrrole), 7.23-7.59 (5 H, m, C₆H₅); ^¹³C NMR (125.8 MHz, CDCl₃):
δ = 20.7, 52.4 and 52.8 (3 × CH₃), 121.9, 123.7, 125.1, 126.3, 126.4, 127.6, 128.1, 129.0, 130.0, 133.0, 133.6, 137.4 (aromatic and olefinic carbons), 160.9, 167.2 (2 × CO ester). 7c: Viscose oil; IR (neat): 1712, 1743 (ester) cm^-¹; Anal. Calcd for C₂₁H₁₈BrNO₅: C, 56.77; H, 4.08; N, 3.15. Found: C, 56.90; H, 4.22; N, 3.39; MS: m/z (%) = 443 (24); ^¹H NMR (500 MHz, CDCl₃): δ = 3.77, 3.83, 3.81 (9 H, 3 × s, 3 × OCH₃), 6.99 and 7.29 (4 H, 2 × d, J = 9.1 Hz, ArH), 7.15 (1 H, s, CH of pyrrole), 7.47 and 7.63 (4 H, 2 × d, J = 8.3 Hz, ArH); ^¹³C NMR (125.8 MHz, CDCl₃): δ = 52.3, 56.1 and 56.4 (3 × OCH₃), 113.1, 121.9, 123.8, 125.7, 126.7, 127.8, 130.2, 131.0, 131.7, 132.8, 133.6, 159.2 (aromatic and olefinic carbons), 160.8, 167.2 (2 × CO ester).