Nucleophilic Imines and Electrophilic o-Quinone Methides, a Three-Component Assembly of Assorted 3,4-Dihydro-2H-1,3-benzoxazines

Abstract

A one-pot method for joining three separate components leading to an assortment of N-substituted 3,4-dihydro-2H-1,3-benzoxazines is described. The method involves the addition of a Grignard reagent to an o-OBoc salicylaldehyde in the presence of an imine. With a variety of components, 15 examples are presented, including the diastereoselective incorporation of chiral imines.

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

“…Fruitful combinations of salicylic aldehydes, Grignard reagents, and dihydrooxazoles, followed by aqueous bicarbonate are shown in Figure . The trend among yields for the aromatic cores 1 – 4 (Table , entries 1–5) reflected of our earlier observations in which similar o -QMs have been generated and intercepted by either organometallic species, alkenes, imines, or other carbon nucleophiles . Salicylaldehydes displaying electron donating substituents (C2–C4) usually provide stable o -QM species leading to better controlled reactions, whereas the o -QM derived from compound 1 (-R = -H) (entry 4, Table ) without donating substituents resulted in moderate self-destruction and lower overall yields (entry 4, 49%) .…”

“…Originally, we had postulated that introduction of 4,5-dihydrooxazoles should deliver the corresponding tricyclic 1,3-benzoxazine adduct as opposed to the earlier bicyclic adducts observed for imines (Scheme : ii ) . When this result failed to transpire, we paused to consider the inherent reactivity of 4,5-dihydrooxazoles with electrophilic reagents (Scheme ).…”

“…We recently described a synthetic method involving ortho -quinone 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-2 H -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 4,5-dihydrooxazoles should deliver the corresponding tricyclic 1,3-benzoxazine 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 4,5-dihydrooxazoles 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 ).…”