Parallel synthesis of a library of benzoxazoles and benzothiazoles using ligand-accelerated copper-catalyzed cyclizations of ortho-halobenzanilides.
A general method for the formation of benzoxazoles via a copper-catalyzed cyclization of ortho-haloanilides is reported. This approach complements the more commonly used strategies for benzoxazole formation which require 2-aminophenols as substrates. The reaction involves an intramolecular C-O cross-coupling of the ortho-haloanilides and is believed to proceed via an oxidative insertion/reductive elimination pathway through a Cu(I)/Cu(III) manifold. The reaction is also applicable to the formation of benzothiazoles. A variety of ligands including 1,10-phenanthroline and N,N'-dimethylethylenediamine were shown to provide ligand acceleration/stabilization in the reaction. Optimal conditions for cyclization used a catalyst combination of CuI and 1,10-phenanthroline (10 mol %). The method was amenable to a parallel-synthesis approach, as demonstrated by the synthesis of a library of benzoxazoles and benzothiazoles substituted at various positions in the ring. Most examples utilized the cyclization of ortho-bromoanilides, but ortho-iodoanilides and ortho-chloroanilides also undergo a reaction under these conditions. The rate of reaction of the ortho-haloanilides follows the order I > Br > Cl, consistent with oxidative addition being the rate-determining step.
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6.
Ghotas
G
Evindar
Robert A
RA
Batey
D000813:Anilides / Q000737:chemistry*; D052160:Benzothiazoles / Q000138:chemical synthesis*; D001583:Benzoxazoles / Q000138:chemical synthesis*; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D003300:Copper / Q000737:chemistry*; D003500:Cyclization; D005029:Ethylenediamines / Q000737:chemistry; D008024:Ligands; D010165:Palladium / Q000737:chemistry; D010618:Phenanthrolines / Q000737:chemistry; D013696:Temperature
D000813:Anilides; D052160:Benzothiazoles; D001583:Benzoxazoles; D005029:Ethylenediamines; D008024:Ligands; D010618:Phenanthrolines; C027450:dimethylethylenediamine; D010165:Palladium; D003300:Copper; C025205:1,10-phenanthroline