A Mannich-Cyclization Approach for the Asymmetric Synthesis of Saturated N-Heterocycles

Abstract

A concise asymmetric synthesis of disubstituted N-heterocycles is reported. Our approach utilizes an optimized Mannich reaction of functionalized aldehydes, followed by a novel dehydrative cyclization mediated by the Staab reagent (1,1′-carbonyldiimidazole, CDI). The method was applied to the synthesis of azetidines, piperidines and pyrrolidines.

Key words

stereoselective synthesis - heterocycles - cyclizations - azetidines - organocatalysis

References

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15

To a cooled (-40 °C) solution of (l)-proline (17.3 mg, 0.15 mmol) and p-anisidine (61.6 mg, 0.5 mmol) in MeCN (5 mL) was added 4-OTBS-butanal (809 mg, 4 mmol). The reaction mixture was stirred for 4 h at this temperature and then put into a freezer (-30 °C) overnight. The mixture was diluted with Et₂O (2 mL) and allowed to reach 0 °C. After the addition of NaBH₄ (500 mg), the reaction was stirred for 15 min at this temperature and allowed to reach r.t. The mixture was poured into half sat. aq NH₄Cl (50 mL). After 30 min, the aqueous layer was extracted with Et₂O (3 × 50 mL) and the combined organic layers are dried with Na₂SO₄. Removal of the solvent on a rotatory evaporator afforded the crude amino alcohol as a colorless oil. The main impurity, 4-OTBS-butanol, was removed by distillation in a Kugelrohr. The residue was purified by flash chromatography (Et₂O-pentane 1:1) on silica gel to afford 10a (218 mg, 0.426 mmol, 85%, 98% ee) as a colorless oil. R _f = 0.42 (Et₂O-pentane 1:1); HPLC [Chiracel OD (4.6 × 250 mm] n-heptane-i-PrOH 95:5, 1.0 mL/min, λ = 254 nm): major isomer: t _R = 13.3 min; minor isomer: t _R = 5.9 min. ¹H NMR (300 MHz, CDCl₃): δ = 6.78 (d, J = 8.9 Hz, 2 H), 6.62 (d, J = 8.9 Hz, 2 H), 3.80-3.55 (m, 9 H), 3.41 (m, 1 H), 2.01 (m, 1 H), 1.70-1.48 (m, 6 H), 0.91 (s, 9 H) 0.89 (s, 9 H), 0.08 (s, 6 H), 0.03 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 152.4, 141.7, 115.5 (2 C), 114.9 (2 C), 64.4, 62.7, 61.7, 58.0, 55.7, 40.1, 30.5, 29.8, 27.7, 25.9 (6 C), 18.2 (2 C), -5.5 (2 C), -5.4 (2 C). IR (CHCl₃): 3378 (m), 2932 (s), 2891 (s), 2858 (s), 1513 (s), 1468 (m), 1251 (s), 1098 (s), 1043 (m), 836 (s), 776 (s) cm^-1. MS (EI): m/z (%) = 511 (32) [M⁺], 308 (100), 176 (74). HRMS (EI): m/z calcd for C₂₇H₅₃NO₄Si₂ [M⁺]: 511.3515. Found: 511.3513. Anal. Calcd for C₂₇H₅₃NO₄Si₂: C, 63.35; H, 10.44; N, 2.74. Found: C, 62.91; H, 10.26; N, 3.17. [α]_D ²⁵ = -17.2 (c 0.98, CHCl₃).

17

5-tert-Butyldimethylsilyloxypentanal afforded the corresponding dimer in 94% ee as a 2:1 mixture in favor of the syn-diastereomer.

25

The starting materials were prepared according to ref. 15 or as described by Barbas et al. (ref. 12).

27

A solution of the corresponding amino alcohol (0.2 mmol) and 1,1′-carbonyldiimidazole (0.4 mmol) in MeCN (10 mL) was refluxed for 2 h. The solvent was evaporated in vacuo and the intermediate carbamates were heated (150 °C) in a Kugelrohr oven under high vacuum (0.05 mbar) for 2 h. The residue was purified by flash chromatography on silica gel to afford the azetidines. Products of lower molecular weight were collected in the receiving flask. Spectral data for 22d: colorless oil; R _f = 0.29 (Et₂O-pentane 1:10). ¹H NMR (400 MHz, CDCl₃): δ = 6.80 (d, J = 8.9 Hz, 2 H), 6.51 (d, J = 8.9 Hz, 2 H), 3.77 (m, 1 H), 3.75 (s, 3 H), 3.62 (dd, J = 8.0, 6.8 Hz, 1 H), 3.48 (dd, J = 6.8, 3.2 Hz, 1 H), 2.65 (m, 1 H), 1.83 (m, 2 H), 1.30 (d, J = 7.2 Hz, 3 H), 0.92 (t, J = 7.5 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 152.2, 147.4, 114.5 (2 C), 113.5 (2 C), 67.9, 58.1, 55.7, 27.5, 23.8, 14.7, 10.2. IR (capillary): 2961 (s), 2873 (m), 2834 (m), 1511 (s), 1465 (s), 1293 (m), 1240 (s), 1120 (m), 1041 (m), 819 (s) cm^-1. MS (EI): m/z (%) = 205 (100) [M⁺], 176 (58), 163 (52), 135 (45), 134 (54). HRMS (EI): m/z calcd for C₁₃H₁₉NO [M⁺]: 205.1467. Found: 205.1467. [α]_D ²⁵ -146.5 (c 1.04, CHCl₃).