Asymmetric Synthesis of 2,3‐Dihydrobenzofurans by a [4+1] Annulation Between Ammonium Ylides and In Situ Generated o‐Quinone Methides

Abstract

A highly enantio‐ and diastereoselective [4+1] annulation between in situ generated ammonium ylides and o‐quinone methides for the synthesis of a variety of 2,3‐dihydrobenzofurans has been developed. The key factors controlling the reactivity and stereoselectivity were systematically investigated by experimental and computational means and the energy profiles obtained provide a deeper insight into the mechanistic details of this reaction.

Organocatalytic Asymmetric Synthesis of Tetrahydrofuran and 1,2‐Dihydrobenzofuran Scaffolds

“…One year later Waser's group also established similar kind of asymmetric [4+1] cyclization reaction of ammonium ylides 152 and in situ generated o ‐quinone methides ( o ‐QMs) from 151 for the synthesis of 2,3‐dihydrobenzofurans . In this protocol, initially, the cinchona alkaloids 35 reacted with ammonium salts 152 which allows the generation of in situ chiral ammonium ylide 35 which participated in the [4+1] cyclization reaction with o ‐QMs to obtain product 153 with control of both the relative and the absolute configuration (Scheme ).…”

Ammonium Ylide Mediated Cyclization Reactions

“…The syntheses of dihydrobenzofurans 88 by the addition of onium ylides to in situ generated o -quinone methides 89 have recently received much attention. [57–60] Approximately a year ago, we reported the first highly asymmetric synthesis of dihydrobenzofurans 88 by using a chiral ammonium ylide strategy. [57] After screening different chiral ammonium salts, we realized that quinidine-based salts 92 serve to achieve high enantio- and diastereoselectivities for this formal [4+1] annulation reaction, in which quinone methide 89 and ylide 91 are both generated in situ under basic reaction conditions (Scheme 24A).…”

“…Scheme 23), as the formation of the ammonium salt turned out to be slow under the reaction conditions relative to the decomposition of 90 . [57]…”

Enantioselective Catalytic [4+1]‐Cyclization of ortho‐Hydroxy‐para‐Quinone Methides with Allenoates

“…Interestingly however, their applicability for asymmetric [4+1]‐cyclizations to access dihydrobenzofurans 1 has so far been rather limited, with highly asymmetric protocols still being rare (Scheme B) . Two years ago we reported the first highly enantioselective synthesis of compounds 1 by reacting preformed chiral ammonium ylides with in situ formed o ‐QMs 2 . More recently we found that the highly functionalized allenoates 4 can undergo a very unique (and up to then unprecedented) formal [4+1]‐cyclization with acceptors 2 in the presence of a stoichiometric amount of PPh 3 (Scheme C) .…”