Facile Synthesis of 5-Carboxamide-oxazolines via a Passerini 3CC-Staudinger-aza-Wittig Sequence

Abstract

5-Carboxamide-oxazolines were synthesized via a Passerini 3CC-Staudinger-aza-Wittig sequence in moderate to good yields, starting from easily accessible chloroacetaldehyde, isocyanides, and various acids.

oxazoline - Passerini reaction - aza-Wittig reaction - Staudinger reaction - iminophosphorane

References and Notes

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<A NAME="RW16511ST-18">18</A>

Preparation of Chlorides 1 via Passerini Reaction To a solution of chloroacetaldehyde (40% soln in H₂O, 0.50 mL, 3 mmol) in MeOH (15 mL) was added sequentially acid (3 mmol) and isocyanide (3 mmol) at r.t. After the reaction was complete at ambient temperature (monitoring by TLC), the solvent was removed under reduced pressure, and the residue was recrystallized from Et₂O-PE to obtain the chloride 1.
Spectral Data for Compound 1a
White crystals; mp 141-142 ˚C. IR (KBr): 3310, 3087, 2983, 1732, 1670, 1561, 1263, 1123, 711 cm^-¹. ^¹H NMR (600 MHz, CDCl₃): δ = 8.10 (d, J = 7.8 Hz, 2 H, ArH), 7.67-7.51 (m, 3 H, ArH), 6.11 (s, 1 H, NH), 5.58 (t, J = 3.6 Hz, 1 H, COCH), 4.15-3.95 (m, 2 H, ClCH₂), 1.39 (s, 9 H, 3 CH₃) ppm. MS: m/z (%) = 283 (1) [M⁺], 211 (5), 122 (9), 105 (100), 77 (21). Anal. Calcd for C₁₄H₁₈ClNO₃: C, 59.26; H, 6.39; N, 4.94. Found: C, 59.34; H, 6.58; N, 4.82.

<A NAME="RW16511ST-19">19</A>

5-Carboxamide-oxazolines 4 A mixture of chloride 1 (1 mmol) and NaN₃ (0.13 g, 2 mmol) was stirred for 2 h at 100 ˚C in anhyd DMF (10 mL). After the completion of the reaction (monitoring by TLC), the reaction mixture was filtered, the residue was concentrated in vacuo, and toluene (10 mL) was added. Then Ph₃P (0.26 g, 1 mmol) in toluene (5 mL) was added dropwise at r.t. The reaction mixture was stirred for 2 h at r.t. and then for additional hours (Table  [²] ) at refluxing temperature. The solvent was removed off under reduced pressure, and the residue was purified by silica gel chromatography (hexanes-EtOAc = 3:1) to afford 5-carboxamide-oxazolines 4 in moderate to good yields.
Spectral Data for Compounds 4a
White crystals; mp 106-107 ˚C. IR (KBr): 3290, 3091, 2968, 1725, 1672, 1649, 1543, 1263, 717, 694 cm^-¹. ^¹H NMR (600 MHz, CDCl₃): δ = 7.97 (d, J = 7.8 Hz, 2 H, ArH), 7.56-7.45 (m, 3 H, ArH), 6.17 (s, 1 H, NH), 4.95-4.91 (m, 1 H, COCH), 4.42-4.14 (m, 2 H, NCH₂), 1.34 (s, 9 H, 3 CH₃) ppm. ^¹³C NMR (150 MHz, CDCl₃): δ = 169.6, 162.4, 131.6, 128.5, 128.00, 127.9, 126.9, 59.5, 51.1, 28.5 ppm. MS: m/z (%) = 246 (2) [M⁺], 146 (23), 105 (100), 77 (34). Anal. Calcd for C₁₄H₁₈N₂O₂: C, 68.27; H, 7.37; N, 11.37. Found: C, 67.92; H, 7.54; N, 11.65.