Highly Selective Catalytic Cross-Aldol Reactions of Chloral with Aliphatic Aldehydes

Abstract

An efficient synthetic method for β-trichloromethyl-β-hydroxy aldehydes is described. Using piperidine or l-prolinamide as the catalyst, direct cross-aldol reactions of chloral with aliphatic aldehydes occur smoothly at room temperature. The cross-aldol condensation products are isolated in high yields (up to 95%), and a moderate to high enantioselectivity (up to 88% ee) is observed in the case of l-prolinamide.

Key words

β-trichloromethyl-β-hydroxy aldehydes - cross-aldol reaction - chloral - piperidine - l-prolinamide

References and Notes

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15

Compound 2: ¹H NMR (400 MHz, CDCl₃): δ = 1.08 (t, J = 7.2 Hz, 3 H, CH₂CH ₃), 1.82 (dq, J = 7.2 Hz, 2 H, CH ₂CH₃), 1.93 (dq, J = 7.2 Hz, 2 H, CH ₂CH₃), 3.03 (t, J = 7.2 Hz, 1 H, CHCH₂), 3.17 (t, J = 7.2 Hz, 1 H, CHCH₂), 4.16 (s, 1 H, CHOH), 4.29 (s, 1 H, CHOH), 4.30 (s, 1 H, CHOH), 9.75 (d, J = 2.4 Hz, 1 H, CHO), 9.94 (d, J = 2.8 Hz, 1 H, CHO). IR (film): ν = 3435, 2968, 2936, 2843, 2769, 1713, 1124, 808 cm^-1. MS (EI, 70 eV): m/z (%) = 55.22 (100), 73.05 (90), 136.69 (95), 191.82 (30), 218.90 (15) [M]⁺.

18

A Typical Procedure.
To a suspension of chloral (148 mg, 1.0 mmol) and a catalytic amount of l-prolinamide (34 mg, 0.3 mmol) in CH₂Cl₂ (8 mL) was added freshly distilled butanal (72 mg, 1.0 mmol) in one portion at 0 °C. The reaction mixture was first stirred at 0 °C for 1 h, then for additional 24 h at r.t. The reaction mixture was treated with H₂O (10 mL). Then the solution was extracted with EtOAc (3 Ž 10 mL). The combined organic layer was dried over anhyd MgSO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 6:1 (v/v) hexane-EtOAc as eluent, collecting 209 mg of product 2 in 95% yield (R _f = 0.43 for 1; R _f = 0.31 for 2). The ee was determined by chiral GC analysis with a DIKMA Chirasil-DEX CB (25 m Ž 0.25 mm) column. Temperature program: from 70 °C to 170 °C at a rate of 10 °C/min, then isotherm for 20 min at 170 °C; t _R(major) = 16.6 min; t _R(minor) = 17.2 min for anti isomer; t _R = 17.5 min, 18.3 min for syn isomer. [α]_D ²⁰ -2.9 (c 1.0, CHCl₃).

19

Compound 3: R _f = 0.21, 6:1 (v/v) hexane-EtOAc. ¹H NMR (400 MHz, CDCl₃): δ = 1.39 (d, J = 7.6 Hz, 3 H, CHCH ₃), 1.41 (d, J = 7.6 Hz, 3 H, CHCH ₃), 3.12-3.18 (m, 1 H, CHCH₃), 3.19-3.23 (m, 1 H, CHCH₃), 4.15 (br s, 1 H, CHOH), 4.23 (s, 1 H, CHOH), 4.75 (d, J = 3.2 Hz, 1 H, CHOH), 9.67 (s, 1 H, CHO), 9.95 (d, J = 2.8 Hz, 1 H, CHO). IR (film): ν = 3438, 2982, 2941, 2844, 2734, 1722, 1124, 808 cm^-1. MS (EI, 70 eV): m/z (%) = 121.92 (100), 140.79 (43), 204.47 (15) [M]⁺. [α]_D ²⁰ +4.9 (c 1.0, CHCl₃).
Compound 4: R _f = 0.36, 6:1 (v/v) hexane-EtOAc. ¹H NMR (400 MHz, CDCl₃): δ = 1.08, 1.18 [d, J = 7.2 Hz, 6 H, CH(CH ₃)₂], 1.11, 1.12 [d, J = 7.2 Hz, 6H, CH(CH ₃)₂], 2.35-2.40 [m, J = 7.2 Hz, 1 H,CH(CH₃)₂], 2.52-2.56 [m, J = 7.2 Hz, 1 H, CH(CH₃)₂], 2.87 (dd, J = 6.8, 3.2 Hz, 1 H, CHCHO), 2.98 (dd, J = 6.0, 2.4 Hz, 1 H, CHCHO), 3.04 (br s, 1 H, CHOH), 4.37 (d, J = 6.8 Hz, 1 H, CHOH), 4.82 (d, J = 7.2 Hz, 1 H, CHOH), 9.87 (d, 1 H, J = 2.8 Hz, CHO), 9.96 (q, 1 H, J = 1.2 Hz, CHO). IR (film): ν = 3437, 2953, 2935, 2852, 2734, 1713, 1126, 813 cm^-1.
Compound 5: R _f = 0.49, 6:1 (v/v) hexane-EtOAc. ¹H NMR (400 MHz, CDCl₃): δ = 0.90 (t, J = 6.4 Hz, 3 H, CH₂CH ₃), 1.32-1.45 (m, 6 H, CH ₂CH ₂CH ₂CH₃), 1.73-1.87 (m, 2 H, CHCH ₂), 4.16 (s, 1 H, CHOH), 4.56 (d, J = 2.8 Hz, 1 H, CHOH), 4.28 (s, 1 H, CHOH), 9.74 (d, J = 2.4 Hz, 1 H, CHO), 9.94 (d, J = 2.8 Hz, 1 H, CHO). IR (film): ν = 3436, 2958, 2930, 2862, 2734, 1713, 1128, 816 cm^-1. MS (EI, 70 eV): m/z (%) = 73.08 (100), 121.94 (35), 142.99 (43), 189.79 (25), 260.96 (5) [M]⁺. [α]_D ²⁰ -4.0 (c 1.0, CHCl₃).