Insertion reactions dihydrobenzofurans synthesis

A very impressive application of this chemistry is the total synthesis of (—)-ephedradine A 102.222 The key intermediate /rcarboxylic acid ester 101 was synthesized by intramolecular C-H insertion reaction. Upon treatment with a catalytic amount of Rh2(Y-DOSP)4, aryl diazo ester 100 possessing a chiral auxiliary underwent a C-H insertion reaction to give 101 in 63% yield and 86% de (Equation (83)). 

Kurosawa W, Kan T, Fukuyama T. An efficient synthesis of optically active trani -2-aryl-2,3-dihydrobenzofuran-3-carboxylic acid esters via C—H insertion reaction. Synlett 2003 1028-1030. 

The intramolecular G-H insertion of aryldiazoacetates is a very powerful strategy for synthesizing heterocyclic rings such as dihydrobenzofurans and dihydrobenzopyrans. The first effective asymmetric copper-catalyzed C-H activation reaction was reported by the group of Sulikowski in the synthesis of the anti-tumor antibiotic FR-66979 93 (Scheme 7)123 219 The G-H insertion of the aryldiazoacetate 90 formed four diastereomeric products 91a, 91b, 92a,... 

The synthesis of dihydrobenzofurans has been developed by Pena and coworkers by the formal insertion of arynes into the C-O o-bond of epoxides. The reaction was carried out in the presence of CsF in MeCN, and the dihydrobenzofurans 76 were formed as a single regioisomer (Scheme 33) [56]. The reaction can be rationalized as the initial addition of epoxide oxygen on aryne generating the zwitterionic intermediate 77 followed by cyclization of 77 to furnish 76. In this reaction, the 2-aryl dihydrobenzofuran 78 was not detected presumably due to the enhanced stability of the positive charge at the benzylic position resulting from the cleavage of zwit-terion 77. 

Later, Yu and Davies further elaborated this fascinating reaction in the enantioselective synthesis of highly functionalized 2,3-dihydrobenzofurans (Scheme 3.31) [60]. Through a rhodium-catalyzed enantioselective intermolec-ular C-H insertion and following palladium-catalyzed C-H activation/C-O cyclization sequence, a variety of 2,3-dihydrobenzofurans were synthesized with a high regio-, diastereo-, and enantioselectivity. 

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