Observations on the Reaction of N-Alkyloxazolidines, Isocyanides and Carboxylic Acids: A Novel Three-Component Reaction Leading to N-Acyloxyethylamino Acid Amides

Abstract

N-Alkyloxazolidines, readily prepared by condensation of the parent carbonyl compounds with β-aminoalcohols, were found to undergo three-component reactions with isocyanides and carboxylic acids to give N-acyloxyethylamino acid derivatives in good yield. The reaction allows the variation of substituents at five different sites in the products through suitable choice of reagents.

Key words

amino alcohols - carboxylic acids - heterocycles - multi-component reactions - ring opening

References and Notes

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10

Oxazolidine Preparation (Method A); General Procedure. A solution of the amino alcohol (20 mmol) and aldehyde (20 mmol) in EtOH (20 mL) was stirred at r.t. for 90 min. The solvent was removed under reduced pressure; EtOH (3 × 10 mL) was added, then removed under reduced pressure repeatedly. The product was then dried under high vacuum to give the oxazolidine as a colourless oil.

11

Oxazolidine Preparation (Method B); General Procedure. A trace of iodine was added to a solution of amino alcohol (174 mmol) and aldehyde (174 mmol) in anhyd benzene (125 mL). The reaction mixture was heated under Dean-Stark water-removal conditions for 90 min. After removal of the solvent under reduced pressure the residue was distilled under reduced pressure to give the oxazolidine as a colourless oil.

12

Multicomponent Reaction; Typical Procedure. 2-Hexyl-3-methyloxazolidine (1b, 343 mg, 2 mmol), benzoic acid (244 mg, 2 mmol), p-TsOH (38 mg, 0.2 mmol) and tert-butyl isocyanide (166 mg, 2 mmol) were added to MeCN (5 mL) and refluxed under an atmosphere of nitrogen for 21 h. Excess solvent was removed under reduced pressure and the crude product was purified by column chromatography (PE-EtOAc, 4:1) to yield 2-[(tert-butylcarbamoylheptyl)methyl-amino]ethyl benzoate (5d, 599 mg, 80%) as a colourless oil. R _f 0.34 (hexanes-EtOAc, 2:1). IR: 3365 br (NH), 3026, 2948, 2926, 2856 (CH), 1724, 1674 (C=O), 1506 (NH) cm^-1. ¹H NMR (CDCl₃, 300 MHz): δ = 0.74 (3 H, t, J = 6.9 Hz, Me), 1.16 (9 H, s, t-Bu), 1.17-1.41 (6 H, m, 3 × CH₂), 1.44-1.59 (2 H, m, CH₂), 1.62-1.77 (2 H, m, CH₂), 2.23 (3 H, s, NMe), 2.77-2.87 (3 H, m, CH₂N, CHN), 4.32-4.47 (2 H, m, CH₂O), 6.62 (1 H, br s, NH), 7.40 (2 H, t, J = 7.8 Hz, m-ArH), 7.53 (1 H, t, J = 7.8 Hz, p-ArH), 8.00 (2 H, d, J = 7.8 Hz, o-ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.0, 22.5, 27.2, 27.4, 28.6, 29.5, 31.6, 38.3, 50.2, 53.7, 62.7, 68.9, 128.3, 129.5, 130.0, 133.0, 166.4, 172.2. MS (FAB): m/z (%) = 378 (18), 377 (74, M + H⁺), 375 (5), 277 (18), 276 (100), 154 (8). HRMS (FAB): m/z calcd for C₂₂H₃₇N₂O₃ [M + H]⁺: 377.28042; found: 377.28061.