Nucleophilic Addition of 4,5-Dihydrooxazole Derivatives to Base Generated o-Quinone Methides: A Four-Component Reaction

Abstract

A novel method for joining four components together in a single pot leading to an assortment of N-amino-benzylated phenols is described. The method involves the addition of different Grignard reagents to various o-OBoc salicylaldehydes in the presence of assorted 4,5-dihydrooxazoles, followed by aqueous workup. Seventeen examples are presented with varied (-R, -R′ -R″, -R‴, -R⁗, and C n ) substituents.W e recently described a synthetic method involving orthoquinone methides (o-QMs), which are base generated by the addition of assorted Grignard reagents to various ortho-OBoc salicylaldehydes and observed to undergo reaction with the sp 2 nitrogen atom of various imine nucleophiles and afford the corresponding 3,4-dihydro-2H-1,3-benzoxazines in good yields and diastereoselectivities (Scheme 1: i). 1 As a multi three-component reaction (M3CR) 2 comprised of a salicylaldehyde, a Grignard reagent, and an imine, this earlier process enables the rapid exploration of benzylic amine substrate space. 3 Herein, we report an unexpected M4CR from replacement of the imine with dihydro-4,5-oxazole derivatives followed by hydrolytic workup of a zwitterionic intermediate.Originally, we had postulated that introduction of 4,5dihydrooxazoles should deliver the corresponding tricyclic 1,3benzoxazine adduct as opposed to the earlier bicyclic adducts observed for imines (Scheme 1: ii). 1 When this result failed to transpire, we paused to consider the inherent reactivity of 4,5dihydrooxazoles with electrophilic reagents (Scheme 2). We found the literature bursting with examples of cationic ring opening polymerization, and reports of block copolymer formation leading to polyamides via a pseudo-living oxazolinum terminus thermodynamically driven toward amide formation (Scheme 2: i). 4 These were instigated by the addition of a small amount of an electrophilic initiator, which included an assortment of Brønsted or Lewis acids, as well as alkylation or acylation reagents under neat conditions. These reactions afforded poly-N-acylethylenimines of tunable molecular weight that were bioisosteric with polypeptides. In addition, several nonpolymerizing ring openings of dihydrooxazole have been noted at reduced temperatures. These required that the electrophile and nucleophile be introduced