Michael Additions of Highly Basic Enolates toortho-Quinone Methides

Abstract

A protocol by which ketone or ester enolates and ortho-quinone methides (o-QMs) are generated in situ in a single reaction flask from silylated precursors under the action of anhydrous fluoride is reported. The reaction partners are joined to give a variety of β-(2-hydroxyphenyl)-carbonyl compounds in 32–94% yield in a single laboratory operation. The intermediacy of o-QMs is supported by control experiments utilizing enolate precursors and conventional alkyl halides as competitive alkylating agents and the isolation of 1,5-dicarbonyl products resulting from conjugate additions that do not restore the aromatic system.

A Strategy toward Icetexane Natural Products

“…We originally intended to employ the enolate–OQM coupling reaction developed in our laboratories [9] to join a vinyl-bearing silylenol ether derived from 4,4-dimethyl-2-cyclohexen-1-one with a highly functionalized tert -butyldimethylsilyloxybenzyl chloride under the action of tetramethylammonium fluoride (Scheme 1). The central seven-membered ring of the monomeric icetexanes would then be completed by a ring-closing metathesis reaction; [10] our proposed two-step strategy is distinctly different from prior efforts and would represent the most convergent synthesis of these natural products to date.…”

“…We observed similar complications with other ketophenol substrates during our development of the enolate–OQM coupling reaction but unlike those simpler systems, we were unable to develop conditions under which the open ketophenol 6 could be captured. [9] …”

“…Following the alkylation events, the vinyl groups were joined under the action of the Grubbs second generation catalyst [9] in straightforward ring-closing metathesis reactions to give the corresponding seven-membered rings 19 and 20 , featuring the core structure of monomeric icetexane natural products in 92 % and 85 % yield, respectively. Alternatively, rigorous separation of the alkylation products proved unnecessary; the mixture of alkylation products could be subjected to the ring closing metathesis reaction directly to give the cycloheptenes in 32 % and 48 % yield, respectively, over two steps.…”

Iodine‐Mediated Direct Generation of o‐Quinone Methides at Room Temperature: A Facile Protocol for the Synthesis of ortho‐Hydroxybenzyl Thioethers

“…Subsequently, Schneider's group has employed o ‐QMs along with β‐diketones to synthesize 4 H ‐chromenes by Michael addition followed by a dehydration reaction strategy . In 2015, Chain and co‐workers reported the synthesis of β‐(2‐hydroxyphenyl)‐carbonyl compounds by the Michael addition reaction between o ‐QMs and ketone or ester enolates . Kang and co‐workers developed the synthesis of diaryl phosphonates through the Michael addition of trialkylphosphites onto in situ generated ortho ‐quinone methides …”

“…[22] In 2015, Chain and co-workers reported the synthesis of b-(2-hydroxyphenyl)carbonyl compounds by the Michael addition reaction between o-QMs and ketone or ester enolates. [23] Kang and coworkers developed the synthesis of diaryl phosphonates through the Michael addition of trialkylphosphites onto in situ generated ortho-quinone methides. [24] From this tremendously diversef unctionalization of in situ generated o-QMs in conjugate addition reactions, [20][21][22][23][24] we envisagedthat the iodine-assisted method could unmask the aromatic system to generate o-QMs under mild conditions with controllable rate to access Michael addition reactions.…”