Preparation of azidoaryl- and azidoalkyloxazoles for click chemistry

Abstract

A series of azidoaryl- and azidoalkyl(diphenyl)oxazole scaffolds were warranted for biofilm inhibition studies. Cyclization of azidoaryl- or azidoalkyl esters of benzoin with ammonium acetate in acetic acid gives 2-azidoaryl- or 2-azidoalkyl-4,5-diphenyloxazoles. The azidoaryl esters are prepared from the corresponding azidocarboxylic acids/acid chlorides while the azidoalkyl esters are prepared from the corresponding haloalkyl esters.

Synthesis of extended oxazoles II: reaction manifold of 2-(halomethyl)-4,5-diaryloxazoles

“…The ring-closure strategy toward 2-extended oxazoles involves the fairly standard benzoin ester formation followed by generation of the heterocycle with ammonium acetate in acetic acid (Eq 3, Scheme 1). 5 Typically, the ring-closure strategy is limited by the types of substituted benzoins as well as the carboxylic acid portion of the ester which bears the soon-to-be 2-appendage at the α-position of the carbonyl. While 2-(halomethyl)oxazoles (X=Br, Cl) were first proposed as atom transfer radical polymerization (ATRP) initiators, 6 our earlier work showed their synthetic utility in preparing 2-(azidomethyl)oxazole click reactants.…”

“…While 2-(halomethyl)oxazoles (X=Br, Cl) were first proposed as atom transfer radical polymerization (ATRP) initiators, 6 our earlier work showed their synthetic utility in preparing 2-(azidomethyl)oxazole click reactants. 5 Considering the facile formation of azides from the title compounds, we now report a diverse manifold of substitution when these halogenated compounds are reacted with appropriate nucleophiles such as amines, alkoxides, thiolates, triphenylphosphine or cyanide ion thereby providing a number of interesting intermediates (Eq 4, Scheme 1). In terms of fundamental nitrogen substitution on the 2-(methylene) position of oxazoles, the simplest, most unambiguous nitrogen nucleophile, i.e.…”

Oxazoles for click chemistry II: synthesis of extended heterocyclic scaffolds

“…4 Consequently, the design and study of small-molecule, non-peptide based inhibitors of the Mfa/AgI/II interaction can involve the employment of two heterocyclic scaffolds, one being a substituted oxazole, which may be joined together via a “click” reaction. In a prior communication 5 we detailed a route to the inhibitory 4, 5-diaryl-2-azidoaryl- and 4, 5-diaryl-2-azidoalkyl oxazole scaffolds, and we now describe extensions of our methodology which enables access to a great many substituted oxazoles having diverse functionality and extended heterocyclic frameworks. Our initial route entailed the cyclization of azidoalkyl- or azidoaryl esters of benzoin with ammonium acetate in acetic acid (115°C/3h) thereby affording the corresponding 2-azidoaryl- or 2-azidoalkyl-4, 5-diphenyloxazoles.…”

“…The use of the symmetrical diaryl acyloin as a starting material was detailed in our previous communication and the use of which established the basic strategy and provided the 2-alkyl- or 2-aryl-4, 5-diphenyl substitution in the target heterocycle. 5 The scheme toward the 2-azidophenyl- and 2-azidomethyl-4-phenyl-5-alkyl-substituted oxazoles detailed herein required a somewhat different strategy and required the preparation and employment of non-symmetrical acyloins 5a-c as starting materials. Aromatic- aliphatic ketones were employed in the preparation of non-symmetrical acyloins through a two-step procedure involving oxidation-tosylation (Scheme 1).…”

Synthesis of α-Acyloxyketone Derivatives <i>via</i> the Platinum-Catalyzed Migration of Propargylic Esters

“…α-Acyloxyketone has also been used as a simple starting material for the stereoselective synthesis of a variety of different structures, including numerous 1,2-diols [4][5][6][7][8] and heterocyclic systems. [9][10][11] Based on the importance of α-acyloxyketones to chemistry, the development of a concise synthetic method for the preparation of α-acyloxyketone derivatives is important. Although a wide variety of synthetic methods have been investigated to date, 12,13) reports pertaining to the direct synthesis of α-acyloxyketone III by the oxidation of alkyne I are rare, most likely because of the difficulties associated with suppressing the over-oxidation of the product and controlling the regioselectivity of the reaction [14][15][16] (Chart 1).…”