Synthesis of Polysubstituted Pyrrolidines from Cyclic Sulfate Esters and Enamines

Abstract

The bis-lithium dianions of N-ethyl and N-aryl enamines of methyl acetoacetate react with cyclic sulfate esters of vic-diols to give tri- and tetrasubstituted pyrrolidine derivatives. The N-ethyl enamine of pentane-2,4-dione can also be converted to the corresponding pyrrolidine.

Key words

carbanions - cyclic sulfates - enamines - heterocycles - pyrrolidines

References

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11

General Procedure: The enamine (5.6 mmol) in THF (5 mL) was added slowly to freshly prepared LDA (11.6 mmol) in THF (20 mL) at 0 °C under nitrogen. The mixture was warmed to 30-35 °C for 30 min, cooled to 0 °C and treated slowly with a solution of the cyclic sulfate ester (5.8 mmol) in THF (5 mL), stirred at r.t. overnight, and finally heated to reflux for 5 h. The THF was evaporated and the residue partitioned between Et₂O and H₂O. The aq phase was extracted with Et₂O, the combined organic phases were washed with brine, dried (MgSO₄) and chromatographed using cyclohexane/Et₂O mixtures.
Compound 14: Yellow oil (0.60 g, 56%). ¹H NMR (CDCl₃): δ = 4.43 (1 H, s, =CH), 3.55 (3 H, s, OCH₃), 3.58 (1 H, m, 5-H), 3.07 (4 H, m, 3-H₂ + NCH₂), 2.04 (1 H, m, 4-H_α), 1.46 (1 H, m, 4-H_β), 1.11 (3 H, d, J = 6.2 Hz, 5-CH₃), 1.04 (3 H, t, J = 7.2 Hz, CH₂CH ₃). ¹³C NMR (CDCl₃): δ = 169.7 (2-C), 164.6 (C=O), 76.7 (=CH), 58.0 (5-C), 49.7 (OCH₃), 38.3 (NCH₂), 30.9 (3-C), 29.3 (4-C), 19.4 (5-CH₃), 11.4 (CH₂ CH₃). IR (liquid film): ν_max = 2965, 2872, 1686, 1592, 1458, 1418, 1379, 1357, 1307, 1277, 1244, 1214, 1149, 1055, 956, 784 cm^-1. HRMS (ES): [M + H]⁺ found 184.1340. C₁₀H₁₈NO₂ requires 184.1337.
Compound 15: Orange oil (0.20 g, 24%). ¹H NMR (CDCl₃): δ = 7.33 (2 H, t, J = 7.8 Hz, 3′-,5′-H), 7.22 (1 H, t, J = 6.9 Hz, 4′-H), 7.05 (2 H, d, J = 7.9 Hz, 2′-,6′-H), 4.45 (1 H, s, =CH), 3.95 (1 H, m, 5-H), 3.49 (3 H, s, OCH₃), 3.33 and 3.08 (2 H, 2 ¥ m, 3-H₂), 2.24 and 1.62 (2 H, 2 ¥ m, 4-H₂), 1.01 (3 H, d, J = 5.7 Hz, 5-CH₃). ¹³C NMR (CDCl₃): δ = 169.7 (2-C), 165.8 (C=O), 139.8 (1′-C), 129.5 and 127.2 (2′-,3′-,5′-,6′-C), 127.0 (4′-C), 80.1 (=CH), 60.7 (5-C), 49.9 (OCH₃), 31.1 (3-C), 30.0 (4-C), 19.7 (5-CH₃). IR (liquid film): ν_max = 2969, 2944, 1688, 1607, 1579, 1495, 1454, 1434, 1398, 1309, 1284, 1210, 1186, 1135, 1050, 974, 797, 764, 698 cm^-1. HRMS (ES): [M + H]⁺ found 232.1339. C₁₄H₁₈NO₂ requires 232.1337.
Compound 16: Yellow oil (0.43 g, 38%). ¹H NMR (CDCl₃): δ = 4.41 (1 H, s, =CH), 3.55 (1 H, m, 5-H), 3.54 (3 H, s, OCH₃), 3.18 (3 H, m, NCH₂ + 3-H_α), 2.55 (1 H, m, 3-H_β), 2.27 (1 H, m, 4-H), 1.05 (3 H, t, J = 7.2 Hz, CH₂CH ₃), 0.94 (3 H, d, J = 6.7 Hz) and 0.90 (3 H, d, J = 6.9 Hz, 4, 5-CH₃). ¹³C NMR (CDCl₃): δ = 169.7 (2-C), 163.7 (C=O), 76.5 (=CH), 60.8 (5-C), 49.6 (OCH₃), 38.5 (NCH₂), 33.1 (4-C), 26.7 (3-C), 14.0 and 13.3 (4-,5-CH₃), 11.4 (CH₂ CH₃). IR (liquid film): ν_max = 2970, 2877, 1687, 1593, 1466, 1423, 1380, 1355, 1301, 1239, 1189, 1144, 1117, 1057, 952, 784 cm^-1. HRMS (ES): [M + H]⁺ found 198.1494. C₁₁H₂₀NO₂ requires 198.1494.
Compound 17: Orange oil (0.82 g, 55%). ¹H NMR (CDCl₃): δ = 7.29 (2 H, t, J = 7.4 Hz, 3′-5′-H), 7.16 (1 H, t, J = 7.3 Hz, 4′-H), 7.06 (2 H, d, J = 8.4 Hz, 2′-6′-H), 4.47 (1 H, t, J = 1.2 Hz, =CH), 3.89 (1 H, quintet, J = 6.7 Hz, 5-H), 3.47 (3 H, s, OCH₃), 3.40 (1 H, ddd, J = 17.3, 7.8, 1.2 Hz, 3-H _α ), 2.78 (1 H, ddd, J = 17.3, 7.9, 1.2 Hz, 3-H _β ), 2.46 (1 H, m, 4-H), 0.96 (3 H, d, J = 7.2 Hz, 4-,5-CH₃) and 0.86 (3 H, d, J = 6.7 Hz, 4-,5-CH₃). ¹³C NMR (CDCl₃): δ = 169.6 (2-C), 164.4 (C=O), 139.8 (1′-C), 129.3 and 127.0 (2′-,3′-,5′-,6′-C), 126.7 (4′-C), 80.1 (=CH), 63.4 (5-C), 49.7 (OCH₃), 38.5 (4-C), 33.3 (3-C), 14.2 and 13.7 (4-,5-CH₃). IR (liquid film): ν_max = 2966, 2876, 1682, 1574, 1494, 1454, 1402, 1366, 1297, 1223, 1183, 1131, 1097, 1052, 955, 915, 797, 760, 699 cm^-1. HRMS (ES): [M + H]⁺ found 246.1495. C₁₅H₂₀NO₂ requires 246.1494.
Compound 18: Yellow-orange rods (0.36 g, 38%), mp 106-107 °C. ¹H NMR (CDCl₃): δ = 7.47 (2 H, d, J = 8.1 Hz, N-C₆H₄) and 7.44 (2 H, d, J = 6.7 Hz, N-C₆H₄), 7.28 (3 H, m, C₆H₅) and 7.10 (2 H, d, J = 8.1 Hz, C₆H₅), 4.57 (1 H, s, =CH), 3.89 (1 H, quintet, J = 6.7 Hz, 5-H), 3.47 (3 H, s, OCH₃), 3.41 (1 H, dd, J = 17.4, 7.9 Hz, 3-H_α), 2.77 (1 H, dd, J = 17.4, 8.1 Hz, 3-H_β), 2.44 (1 H, q, J = 7.2 Hz, 4-H), 0.94 (3 H, d, J = 7.1 Hz, 4-,5-CH₃) and 0.87 (3 H, d, J = 6.6 Hz, 4-,5-CH₃). ¹³C NMR (CDCl₃): δ = 169.6 (2-C), 164.3 (C=O), 140.0, 139.5, 139.0, 128.6, 128.0, 127.3, 127.2, 126.8 (Ar-C₁₂), 80.5 (=CH), 63.5 (5-C), 49.8 (OCH₃), 38.5 (4-C), 33.4 (3-C), 14.2 and 13.8 (4-,5-CH₃). IR (nujol mull): ν_max 1679, 1612, 1581, 1513, 1270, 1186, 1140, 1109, 1092, 1086, 825, 808, 768, 726, 702, 576 cm^-1. HRMS (ES): [M + H]⁺ found 322.1804. C₂₁H₂₄NO₂ requires 322.1807.

12

Crystal data: C₂₁H₂₃NO₂, M_r = 321.4, monoclinic, a = 7.2995 (2), b = 15.5861 (4), c = 14.9417 (5) Å, β = 90.8073 (12), V = 1699.76 (9) Åų, Z = 4, P2₁/n, D _c = 1.26 gcm^-3, µ (MoKα) = 0.08 mm^-1, T = 120 (2) K, 3879 unique reflections, 3027 with F>4σ(F), R = 0.058, wR = 0.141. Data deposited at the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ with reference CCDC 193354.

14

Procedure for Synthesis of 19: 1.4 M MeLi (9 mL, 12.7 mmol) was slowly added to a stirring solution of the enamine (5.6 mmol) and TMEDA (1.9 mL, 12.7 mmol) in THF at 0 °C under nitrogen. The mixture was warmed to 30-35 °C and stirred for 2 h. A solution of the cyclic sulfate ester (5.8 mmol) in THF (5 mL) was slowly added at 0 °C and left to stir for 30 min DMF (15 mL) was added to dissolve the resulting precipitate and the mixture was stirred at r.t. overnight, and then heated to ca.70 °C for 5 h. Work-up as described. [11]
Compound 19: Yellow oil (0.21 g, 24%). ¹H NMR (CDCl₃): δ = 4.95 (1 H, s, =CH), 3.60 (1 H, m, 5-H), 3.12 (4 H, m, NCH₂ + 3-H₂), 2.05 (1 H, m, 4-H_α), 1.99 (3 H, s, O=C-CH₃), 1.47 (1 H, m, 4-H_β), 1.11 (3 H, d, J = 6.4 Hz, 5-CH₃), 1.07 (3 H, t, J = 7.2 Hz, CH₂CH₃). ¹³C NMR (CDCl₃): δ = 193.9 (C=O), 164.6 (2-C), 89.0 (=CH), 58.3 (5-C), 38.3 (NCH₂), 31.6 and 30.4 (3-,4-C), 29.1 (O=C-CH₃), 19.2 (5-CH₃), 11.4 (CH₂ CH₃). IR (liquid film): ν_max 2969, 2875, 1641, 1551, 1469, 1377, 1355, 1309, 1276, 1202, 1177, 1130, 957, 902, 762, 681, 656, 588 cm^-1. HRMS (ES): [M + H]⁺ found 168.1386. C₁₀H₁₈NO requires 168.1388.