A Useful Modification of the Evans Magnesium Halide Catalyzed anti-Aldol Reaction: Application to Enolizable Aldehydes

Abstract

A practical protocol for use of the magnesium halide catalyzed anti-aldol reaction of an Evans N-acyloxazolidinone with enolizable aldehydes is reported. The yields of anti-aldol adducts for saturated or unsaturated and branched or unbranched aliphatic aldehydes are preparatively useful.

Key words

aldol reaction - aldehydes - halides - catalysis

References and Notes

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• 5b

  This decarboxylative isomerization process was first discovered during these aldol studies.

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6

General Experimental Procedure for the anti -Aldol Reaction of an N -Acyloxazolidinone with an Enolizable Aldehyde (Synthesis of 2b)
Method A: To an oven-dried reaction vessel equipped with a stir bar, oxazolidinone 1 (0.100 g, 0.429 mmol), MgCl₂ (0.042 g, 0.44 mmol), LiI (0.116 g, 0.866 mmol), EtOAc (0.85 mL), Et₃N (0.30 mL, 2.2 mmol) and TMSCl (0.22 mL, 1.7 mmol) were added sequentially. After 10 min croton-aldehyde (3b, 107 µL, 1.28 mmol) was diluted to 0.75 mL with EtOAc and added via syringe pump over 3 h. The reaction mixture was analyzed by GC (90% diastereomeric purity) and passed through a plug of silica gel using EtOAc as the eluent. After removing the solvent in vacuo, MeOH (4 mL) and p-TsOH (25 mg) were added. After 15 min desilylation was complete as judged by TLC. After concentration in vacuo the desilylated mixture was purified by MPLC (30% EtOAc-70% hexanes) to give 2b (0.086 g, 66%).
Method B: Same as method A with the following differences: oxazolidinone 1 (0.200 g, 0.858 mmol), MgCl₂ (0.084 g, 0.88 mmol), LiI (0.228 g, 1.70 mmol), EtOAc (1.7 mL), Et₃N (0.60 mL, 4.3 mmol), and TMSCl (0.44 mL, 3.4 mmol). Crotonaldehyde (3b, 36 µL, 0.42 mmol, 0.49 equiv) in EtOAc (0.21 mL) was added via syringe pump over 1 h. The desilylated mixture was purified by MPLC (30% EtOAc-70% hexanes) to give 2b (0.086 g, 66%).
2b:^{7 ¹}H NMR (500 MHz, CDCl₃): δ = 7.32-7.35 (m, 2 H, ArH), 7.23-7.29 (m, 3 H, ArH), 5.78 (ddq, J = 15.5, 6.5, 1.0 Hz, 1 H), 5.54 (ddq, J = 15.0, 7.0, 1.5 Hz, 1 H), 4.69 (dddd, J = 10.0, 7.5, 3.0, 3.0 Hz, 1 H), 4.21 (dd, J = 9.0, 7.0 Hz, 1 H), 4.16 (dd, J = 9.0, 3.0 Hz, 1 H), 3.94 (app p, J = 7.0 Hz, 1 H), 3.29 (dd, J = 13.5, 3.5 Hz, 1 H), 2.78 (dd, J = 13.5, 9.5 Hz, 1 H), 2.54 (s, 1 H, OH), 1.73 (dd, J = 6.5, 1.0 Hz, 3 H), 1.17 (d, J = 6.5 Hz, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 176.6, 153.7, 135.4, 131.7, 129.7, 129.3, 129.1, 127.5, 75.9, 66.2, 55.7, 43.5, 38.0, 17.9, 14.7. HRMS (ESI): m/z [M + Na⁺] calcd for C₁₇H₂₁O₄N: 326.1363; found: 326.1361. IR (neat): 3518, 3029, 2976, 2939, 2920, 2883, 1782, 1695, 1502, 1455, 1392, 1349, 1257, 1211, 1103, 1014, 968, 923, 800, 762, 702 cm^-¹. TLC: R _f 0.47 (30% EtOAc in hexanes); [α]^r.t. 38.5˚ (c = 0.785, CHCl₃).