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.

Key words

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

References

• 1a Comprehensive Heterocyclic Chemistry II   Katritzky AR. Rees CW. Scriven EFV. Pergamon Press; Oxford: 1996. 
• 1b Laschat S. Liebigs Ann./Recl.  1997,  1 ; and references cited therein
• 2a Fioravanti S. Morreale A. Pellacani L. Tardella PA. Synthesis  2001,  1975 
• 2b Colantoni D. Fioravanti S. Pellacani L. Tardella PA. Org. Lett.  2004,  6:  197 
• 3 Fioravanti S. Morreale A. Pellacani L. Tardella PA. Synlett  2004,  1083 
• 4a Huisgen R. Scheer W. Huber H. J. Am. Chem. Soc.  1967,  89:  1753 
• 4b Baldwin JE. Pudussery RG. Qureshi AK. Sklarz B. J. Am. Chem. Soc.  1968,  90:  5325 
• 5 Texier-Boullet F. Foucaud A. Tetrahedron Lett.  1982,  23:  4927 
• 7a Pihuleac J. Bauer L. Synthesis  1989,  61 
• 7b Hanessian S. Johnstone S. J. Org. Chem.  1999,  64:  5896 
• 7c Fioravanti S. Marchetti F. Morreale A. Pellacani L. Tardella PA. Org. Lett.  2003,  5:  1019 
• 7d Fioravanti S. Colantoni D. Pellacani L. Tardella PA. J. Org. Chem.  2005,  70:  3296 
• 8 The formation of the unstable 2,3-dihydroisoxazole (4-isoxazoline) (IV, Figure 1), as the precursor of aziridine I shown in the Scheme 2, is not supported by any experimental evidence. For a recent example of 2,3-dihydroisoxazoles as synthons for 2-acyl aziridines see: Ishikawa T. Kudoh T. Yoshida J. Yasuhara A. Manabe S. Saito S. Org. Lett.  2002,  4:  1907 
• 9 Lopez-Calle E. Keller M. Eberbach W. Eur. J. Org. Chem.  2003,  1438 
• 10a Lown JW. Smalley RK. Dallas G. J. Chem. Soc., Chem. Commun.  1968,  1543 
• 10b Lown JW. Matsumoto K. Can. J. Chem.  1970,  48:  3399 
• 10c Person H. Luanglath K. Baudru M. Foucaud A. Bull. Soc. Chim. Fr.  1976,  1989 
• 10d Freeman JP. Chem. Rev.  1983,  83:  241 
• 11a Najera C. Sansano JM. Curr. Org. Chem.  2003,  7:  1105 
• 11b Eberbach W. Methods of Molecular Transformations, In Science of Synthesis (Houben-Weyl)   Vol. 27:  Padwa A. Georg Thieme Verlag; Stuttgart: 2004.  p.441 
• 13 We reported that stable polyfunctionalized 2-acyl aziridines were obtained using nosyloxycarbamates and a Wittig reaction led us to interesting alkenyl aziridines. See: Fioravanti S. Morreale A. Pellacani L. Tardella PA. Mol. Diversity  2003,  6:  177 
• 14a Vedejs E. Grissom JW. J. Am. Chem. Soc.  1988,  110:  3238 
• 14b Vedejs E. Monahan SD. J. Org. Chem.  1997,  62:  4763 
• 15a Jones WD, Ciske FL, Dinerstein RJ, and Diekema KA. inventors; U.S.  6004959.  ; Chem. Abstr. 1999, 132, 35524
• 15b Hanaki N, and Goto T. inventors; Jpn. Kokai Tokkyo Koho, JP  2000273333.  ; Chem. Abstr. 2000, 133, 268226
• 15c Hanaki N, and Goto T. inventors; Jpn. Kokai Tokkyo Koho, JP  2000275773.  ; Chem. Abstr. 2000, 133, 288779
• 16 Caiazzo A. Dalili S. Picard C. Sasaki M. Siu T. Yudin AK. Pure Appl. Chem.  2004,  76:  603 

6

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.

12

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.