Synthesis of 2-Aminooxazolines and Spiro-2-aminooxazolines by Using a Convenient Two-Step INCO-Mediated Reaction

Abstract

A two-step reaction sequence yielding 2-aminooxazolines under mild conditions was developed. Both electron-rich and electron-deficient styrenes as well as functionalized primary and secondary amides could be used in the reaction to afford 2-aminooxazolines in reasonable yields.

Key words

isocyanate - library generation - styrene - heterocycles - multicomponent reactions

• References


Current addresses:
• 1a Bristol-Myers Squibb Pharma Research Labs, 4570 Executive Drive, Suite 400, San Diego, CA 92121, USA.
• 1b Theravance Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
• 1c Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Dr., San Diego, CA 92121, USA.
• 2a Poos GI, Carson JR, Rosenau JD, Roszkowski AP, Kelley NM, McGowin J. J. Med. Chem. 1963; 6: 266
• 2b Harnden MR, Rasmussen R. J. Med. Chem. 1970; 13: 305
• 2c Freiter ER, Abdallah AH, Strycker SJ. J. Med. Chem. 1973; 16: 510
• 3 Hong S.-S, Bavadekar SA, Lee S.-I, Patil PN, Lalchandani SG, Feller DR, Miller DD. Bioorg. Med. Chem. Lett. 2005; 15: 4691
• 4 Wong WC, Sun W, Cui W, Chen Y, Forray C, Vaysse PJ.-J, Branchek TA, Gluchowski C. J. Med. Chem. 2000; 43: 1699
• 5 Touzeau F, Arrault A, Guillaumet G, Scalbert E, Pfeiffer B, Rettori M, Renard P, Mércour J. J. Med. Chem. 2003; 46: 1962
• 6a Hewlett NM, Tepe JJ. Org. Lett. 2011; 13: 2011
• 6b Jung SH, Kohn H. J. Am. Chem. Soc. 1985; 107: 2931
• 7 Hassner A, Lorber ME, Heathcock C. J. Org. Chem. 1967; 32: 540
• 8a Chiang C. G., Stevenson T. M., Thieu T. V., Gebreysus C., Yatsko C.; 219th National ACS Meeting Poster No. ORGN 615, March 28th, 2000.
• 8b Huang H, La DS, Cheng AC, Whittington DA, Patel VF, Chen K, Dineen TA, Epstein O, Graceffa R, Hickman D, Kiang YH, Louie S, Luo Y, Wahl RC, Wen PH, Wood S, Fremeau RT. Jr. J. Med. Chem. 2012; 55: 9156
• 9a Pitha J, Jonas J, Kovar J, Blaha K. Collect. Czech. Chem. Commun. 1961; 26: 834
• 9b Garcia Fernandez JM, Ortiz Mellet C, Pradera Adrian MA, Fuentes Mota J. J. Heterocycl. Chem. 1991; 28: 777
• 9c Cordi AA, Lacoste J.-M, Descombes J.-J, Courchay C, Vanhoutte PM, Laubie M, Verbeuren TJ. J. Med. Chem. 1995; 38: 4056
• 9d Tiecco M, Testaferri L, Marini F, Temperini A, Bagnoli L, Santi C. Synth. Commun. 1997; 27: 4131
• 10 Hassner A In Encyclopedia of Reagents for Organic Synthesis . Paquette L. John Wiley & Sons; New York: 1995: 2808
• 11a Zeng L, Kassel DB. Anal. Chem. 1998; 70: 4380
• 11b Zeng L, Wang X, Wang T, Kassel DB. Comb. Chem. High Throughput Screening 1998; 1: 101
• 11c Zeng L, Burton L, Yung K, Shushan B, Kassel DB. J. Chromatogr., A 1998; 794: 3
• 12 Hassner A, Lorber ME, Heathcock C. J. Org. Chem. 1967; 32: 540
• 13 Of the 575 reactions, 311 of the products were recovered in milligram quantities and >85% pure (by LC/MS) after HPLC purification.
• 14 Synthesis of 5-[4-(tert-butoxy)phenyl]-N,N-di-n-propyl-4,5-dihydrooxazol-2-amine (Table 1, entry 8); Typical Procedure: To a solution of iodine (38 mg, 0.15 mmol) in THF (0.3 mL) in an amber vial (wrapped in foil to exclude light), was added silver cyanate (29 mg, 0.195 mmol) and the mixture was stirred vigorously under subdued light for 30 min. 4-tert-Butoxystyrene (0.028 mL, 0.15 mmol) in THF (0.1 mL) was added and the reaction mixture was stirred vigorously for 16 h at room temperature under subdued light. The suspension was filtered through a 0.45 μm filter, under subdued light, to remove silver salts. Di-n-propylamine (0.021 mL, 0.15 mmol) and DIPEA (0.05 mL, 0.3 mmol) in THF (0.1 mL) were added to the INCO intermediate and the reaction mixture was stirred for 16 h at room temperature. Evaporation of the reaction mixture followed by HPLC purification gave the title compound as a red oil. Yield: 18 mg (40%). ¹H NMR (400 MHz, CDCl₃): δ = 7.18 (d, J = 8.6 Hz, 2 H), 6.95 (d, J = 8.5 Hz, 2 H), 5.11–5.02 (m, 1 H), 4.58 (t, J = 8.5 Hz, 1 H), 4.01 (t, J = 7.3 Hz, 1 H), 3.43–3.16 (m, 4 H), 1.80–1.64 (m, 4 H), 1.34 (s, 9 H), 0.94 (t, J = 7.4 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 162.48, 154.36, 126.92, 124.30, 78.22, 77.22, 75.47, 67.42, 50.04, 28.82, 21.44, 11.23. IR (neat): 1647, 1504, 1233, 1158, 895 cm^–1. LC/MS (ESI): t_R = 1.36 min (XIC maximum, 3 min run; m/z [M + H]⁺ found: 319.3). HRMS (ESI): m/z [MH]⁺ calcd for C₁₉H₃₁N₂O₂: 319.2386; found: 319.2393.
• 15 Prior work (see ref. 8a) had suggested that exocyclic methylidene reactants did not produce the desired 2-aminooxazolines, instead, giving the corresponding allylic iodide through simple addition/elimination.