Synthesis of 2,4,5-Trisubstituted Oxazoles with Complementary Regioselectivity from α-Oxoketene Dithioacetals and β-(Methylthio)-β-(het)aryl-2-propenones

Abstract

An efficient protocol for the synthesis of 2,5-substituted 4-acyloxazoles and the related 2,4-substituted 5-acyloxazoles with complementary regioselectivity from the corresponding α-oxoketene dithioacetals or β-(het)aryl/(methylthio)enone precursors has been reported. In the first protocol, the α-oxoketene dithioacetals or β-(methylthio)enones were converted to the corresponding α-bromo-β-(methylthio)enones followed by copper catalyzed inter/intramolecular annulation of these intermediates with various primary amides affording 2-(het)aryl/alkyl-4-(het)aroyl-5-(methylthio)/(het)aryloxazoles via concomitant formation of the C4-N and C5-O bond via enamide intermediates. In the second approach, the starting α-oxoketene dithioacetals or β-(methylthio)-β-(het)arylenones were subjected to base induced conjugate addition-elimination with various primary amides to furnish β-aroylenamides, which, on subsequent iodine catalyzed intramolecular oxidative C-H functionalization/C-O bond formation, afforded the corresponding regioisomeric 2-(het)aryl/alkyl-4-(methylthio)/(het)aryl-5-(het)aroyloxazoles in excellent yields. The methodology has also been extended for the synthesis of regioisomeric 4- or 5-aminooxazoles and 4- or 5-( n-butyl)oxazoles from the corresponding 4- or 5-(methylthio)oxazoles.

Single-Pot Preparation of 4-Amino-2-(het)aryl-5-Substituted Thiazoles Employing Functionalized Dithioesters as Thiocarbonyl Precursors

“…Since the past few years, we have been exploring newly designed organosulfur intermediates − which are readily obtained by the condensation of the appropriate active methylene derivatives with functionalized dithioesters in the presence of base, followed by alkylation of the generated enethiolate intermediates. By utilizing these precursors, we have developed new synthetic routes for a variety of (het)­aryl/alkylsubstituted, sulfur containing, as well as sulfur-free five membered heterocycles, , such as pyrazoles, isoxazoles, oxazoles, imidazoles, thiophenes, thiazoles, and the corresponding benzo/heterofused analogues, i.e., indoles, , benzothiophenes, ,, and benzofurans . These methods provide alternate way for regiospecific introduction of (het)­aryl groups in various heterocycles from built-in precursors by utilizing (het)­aryl/alkyldithioesters, instead of transition metal catalyzed coupling reactions .…”

Lewis acid-mediated transformations of 5-acyl-N-fluoroalkyl-1,2,3-triazoles to cyclopentenones, indenones, or oxazoles

“…There is no general synthetic approach leading to these structures and each type of product requires a specic methodology. Despite the availability of numerous synthetic methods for the preparation of mono-or di-substituted oxazoles, 7 access to tri-substituted 4-carbonyl oxazoles is not well explored and relies mainly on the intramolecular Cu-catalyzed cyclization of (thio)enamides 8 or bromo(thio) enones, 9 or on a protocol starting from 2-azido enones 10 or alkynyl ketones. 11 2-N-substituted indenones can be accessed from ynamides, 12 2-alkynylbenzoyl cyanides, 13 or 2-hydroxy-substituted internal alkynes.…”

Regiodivergent Synthesis of 4‐ and 5‐Sulfenyl Oxazoles from Alkynyl Thioethers

“…Ideally, the same starting materials would be used to selectively access different regioisomers. Only one such regiodivergent synthesis exists, where Ila and co‐workers employed oxidative additions to α‐oxoketene dithioacetals, but with a narrow substrate scope (Scheme 1c) [15] . Our interest in alkynyl thioether chemistry led us to investigate whether these substrates could be used as the basis for a regiodivergent synthesis of sulfenylated heterocycles.…”