Efficient Synthesis of 4-Cyano 2,3-Dihydrooxazoles by Direct Amination of 2-Alkylidene 3-Oxo Nitriles

Abstract

The addition of N-protected O-sulfonyl hydroxylamine derivatives on 2-alkylidene 3-oxo nitriles gives 2,5-disubstituted 4-cyano 2,3-dihydrooxazoles (4-oxazolines) by a practical and efficient synthetic procedure under very mild conditions in high yields. Likely, the formation of N,O-heterocycles proceeds through a domino reaction involving a fast rearrangement of unstable 2-acyl 2-cyano aziridines.

Michael additions - cyclizations - domino reactions - 2-acyl aziridines - heterocycles

References

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Typical Experimental Procedure.
All compounds were synthesized with a Carousel Reaction Station from Radleys Discovery Technologies (U.K.). To the obtained 2-alkylidene 3-oxo nitriles in CH₂Cl₂, CaO and nosyloxycarbamates were added in the amounts reported in Table [1] . After completion (TLC and GC analyses), the crude reaction mixtures were filtered through plugs of silica gel using a 9:1 hexane-EtOAc mixture and the 2,5-disubstituted 4-cyano 2,3-dihydrooxazoles were obtained after solvent removal.
Selected spectral data of new compounds.
Compound 13: yellow oil. IR (CCl₄): 2223, 1714, 1630 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.94 (t, J = 7.2 Hz, 3 H), 1.28 (s, 9 H), 1.67-1.78 (m, 2 H), 5.23 (s, 2 H), 5.97 (t, J = 5.4 Hz, 1 H), 7.30-7.48 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 10.7, 23.7, 27.8, 40.9, 69.2, 91.0, 95.3, 116.4, 128.1, 128.3, 128.8, 135.1, 152.1, 157.9. GCMS: m/z (%) = 314 (2) [M⁺], 179 (11), 137 (27), 91 (100), 57 (15). HRMS (ES Q-TOF): m/z calcd for C₁₈H₂₃N₂O₃ [M + H]⁺: 315.1709; found: 315.1601.
Compound 18: yellow oil. IR (CCl₄): 2218, 1717, 1645 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.01 (d, J = 6.6 Hz, 3 H), 1.02 (d, J = 6.6 Hz, 3 H), 1.36 (t, J = 7.2 Hz, 3 H), 1.68-1.74 (m, 2 H), 1.87-1.92 (m, 1 H), 4.29 (q, J = 7.2 Hz, 2 H), 6.24 (dd, J = 6.6 Hz, 1 H), 7.40-7.53 (m, 3 H), 7.84-7.87 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.1, 22.4, 22.7, 23.4, 42.8, 63.0, 90.9, 93.7, 114.7, 125.9, 126.3, 128.6, 128.7, 131.3, 152.7, 156.3. GCMS: m/z (%) = 300(7) [M⁺], 227 (12), 171 (53), 145 (14), 105 (100), 77 (32). HRMS (ES Q-TOF): m/z calcd for C₁₇H₂₁N₂O₃ [M + H]⁺: 301.1552; found: 301.1546.

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With respect to 13, [6] the ¹H NMR spectrum of the crude mixture shows additional frequencies at δ = 1.12 (t, J = 7.2 Hz, 3 H), 1.31 (s, 9 H), 1.83-1.98 (m, 2 H), 2.90 (t, J = 6.6 Hz, 1 H), 5.08-5.20 (m, 2 H). In particular the signal at δ = 2.90 is typical of an aziridine proton.

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