Identification of Reactive Intermediates for the Decarbonylative Reaction of 1-Alkylprolines

Abstract

1-Alkylprolines undergo decarbonylative reactions with oxalyl chloride and subsequent Mannich reactions with nonactivated C–H nucleophiles to give 2-substituted pyrrolidines as Mannich adducts. We showed that 1-alkyl-1-pyrrolinium compounds are the reactive intermediates formed by the decarbonylative reactions of 1-alkylprolines. Our results also confirmed that an azomethine ylide, although unreactive toward the Mannich reaction and not involved in the decarbonylative Mannich reaction, can be generated by deprotonation of the corresponding 1-alkyl-1-pyrrolinium compound under mild conditions.

Key words

pyrrolidines - pyrrolinium compounds - azomethine ylides - Mannich reaction - electrophilic aromatic substitution

• References and Notes

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1-(Benzyl-d ₇)proline (1a-d ₇) was prepared from benzyl-d ₇ bromide and proline by the same procedure as the unlabeled compound; see:
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• 12 The deuterated Mannich adducts were prepared from 1-(benzyl-d ₇)proline (1a-d ₇) and a carbon nucleophile (pyrrole, indole, or acetophenone, 9a–c) by the same procedure as for the unlabeled compounds, previously reported by our group.
• 13 2-[1-(Benzyl-d ₇)pyrrolidin-2-yl]-1-phenylethanone (2aa-d ₇) Prepared from 1-(benzyl-d ₇)proline (1a-d ₇) and acetophenone (9a) by the procedure previously reported. The product was purified by flash column chromatography [silica gel, hexane–EtOAc (8.5:1.5)] to give an oil; yield: 0.1349 g (0.471 mmol, 42%); R_f = 0.14 (hexane–EtOAc, 8:2); ¹H NMR (400 MHz, CDCl₃): δ = 7.94–7.92 (m, 2 H), 7.55 (t, J = 7.3 Hz, 1 H), 7.45 (t, J = 7.6 Hz, 2 H), 3.33 (dd, J = 3.6, 15.9 Hz, 1 H), 3.16–3.09 (m, 1 H), 3.02 (dd, J = 8.9, 15.8 Hz, 1 H), 2.99–2.93 (m, 1 H), 2.25 (dd, J = 9.0, 17.4 Hz, 1 H), 2.20–2.11 (m, 1 H), 1.80–1.69 (m, 2 H), 1.58–1.50 (m, 1 H); ¹³C NMR (100 MHz, CDCl₃): δ = 199.6, 139.0, 137.2, 132.9 (CH), 128.5 (CH), 128.4 (t, J _C–D = 96 Hz), 128.0 (CH), 127.7 (t, J _C–D = 96 Hz), 126.4 (t, J _C–D = 96 Hz), 60.5 (CH), 58.1 (quint, J _C–D = 80 Hz), 53.9 (CH₂), 44.1 (CH₂), 31.3 (CH₂), 22.3 (CH₂); MS (EI): m/z (%) = 97 (52), 168 (100), 188 (42), 286 (6) [M+]; HRMS (EI, magnetic sector): m/z [M+] calcd for C₁₉H₁₄D₇NO: 286.2063; found: 286.2060
• 14 3-[(1-Benzyl-d ₇)pyrrolidin-2-yl]-1H-indole (2ab-d ₇) Prepared from 1-(benzyl-d ₇)proline (1a-d ₇) and indole (9b) by the procedure previously reported. The product was purified by flash column chromatography [silica gel, hexane–EtOAc (7.75:2.25)] to give an oil; yield: 0.0888 g (0.313 mmol, 63%); R_f = 0.15 (hexane–EtOAc, 7:3); ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (br s, 1 H, NH), 7.92 (d, J = 7.9 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.24–7.15 (m, 3 H), 3.71 (t, J = 8.3 Hz, 1 H), 3.15–3.11 (m, 1 H), 2.30–2.20 (m, 2 H), 2.12–1.92 (m, 2 H), 1.89–1.80 (m, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ = 139.7, 136.8, 128.4 (t, J _C–D = 95 Hz), 127.5 (t, J _C–D = 95 Hz), 126.7, 126.0 (t, J _C–D = 95 Hz), 122.0 (CH), 121.9 (CH), 120.1 (CH), 119.1 (CH), 118.1, 111.1 (CH), 62.2 (CH), 57.4, 53.4 (CH₂), 33.0 (CH₂), 22.2 (CH₂); MS (EI): m/z (%) = 98 (21), 157 (27), 283 (100) [M+]; HRMS (EI, magnetic sector): m/z calcd for C₁₉H₁₃D₇N₂: 283.2066; found: 283.2066
• 15 2-[(1-Benzyl-d ₇)pyrrolidin-2-yl]-1H-pyrrole (2ac-d ₇) Prepared from 1-(benzyl-d ₇)proline (1a-d ₇) and pyrrole (9c) by the procedure previously reported. The product was purified by flash column chromatography [silica gel, CH₂Cl₂–Et₂O (9:1)] to an oil; yield: 0.0581 g (0.2490 mmol, 50%), R_f = 0.13 (hexane–EtOAc, 9:1); ¹H NMR (500 MHz, CDCl₃): δ = 8.62 (br s, 1 H, NH), 6.77 (s, 1 H), 6.17–6.16 (m, 1 H), 6.13 (s, 1 H), 3.58 (t, J = 7.7 Hz, 1 H), 3.06 (t, J = 8.3 Hz, 1 H), 2.24 (dd, J = 8.6, 17.3 Hz, 1 H), 2.17–2.11 (m, 1 H), 1.89–1.77 (m, 3 H); ¹³C NMR (125 MHz, CDCl₃): δ = 138.9, 133.0, 128.3 (t, J _C–D = 95 Hz), 127.6 (t, J _C–D = 95 Hz), 126.3 (t, J _C–D = 95 Hz), 117.0 (CH), 107.9 (CH), 106.5 (CH), 62.5 (CH), 57.3 (quint, J _C–D = 81 Hz), 52.9 (CH₂), 33.1 (CH₂), 22.2 (CH₂); MS (EI): m/z (%) = 98 (77), 107 (54), 149 (86), 167 (38), 233 (100) [M+]; HRMS (EI, magnetic sector): m/z [M+] calcd for C₁₅H₁₁D₇N₂: 233.1909; found: 233.1909