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. 2015 May 1;17(9):2278-81.
doi: 10.1021/acs.orglett.5b00972. Epub 2015 Apr 23.

Michael Additions of Highly Basic Enolates to ortho-Quinone Methides

Robert S Lewis  1 , Christopher J Garza  1 , Ann T Dang  1 , Te Kie A Pedro  1 , William J Chain  1   2
Affiliations

Michael Additions of Highly Basic Enolates to ortho-Quinone Methides

Robert S Lewis et al. Org Lett. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
X-ray crystallographic structures for o-QM-enolate products.
Figure 2
Figure 2
An open transition state model for the union of (E)-o-QMs and enolates with no ion bridging between reaction partners.
Scheme 1
Scheme 1
(a) Selected Prior Examples of Reactions Involving o-QMs and Enolates; (b) Nucleophilic Alkylation of o-QMs by Discrete Enolatesa aTBS = tert-butyldimethylsilyl, TMS = trimethylsilyl, TMAF = tetramethylammonium fluoride, Np = 2-naphthyl, PMP = para-methoxyphenyl, NR4F = cinchona alkaloid salt.
Scheme 2
Scheme 2
Conversion of O-Silylated Phenolic Benzyl Halides to ortho-Quinone Methides as Described by Rokita and Co-workers
Scheme 3
Scheme 3
Michael Additions of Enolates to o-QMsa aYields of isolated products; reactions were performed on a 1.0 mmol scale (TMAF). bProduct was isolated as a mixture of cyclic hemiacetal diastereomers. cYield based on recovered starting material. dProduct was isolated as a mixture of diastereomers (1.1:1 mixture with respect to the benzylic stereogenic center). eProduct characterized as the corresponding methyl ether.
Scheme 4
Scheme 4
Evidence for the Intermediacy of o-QMs: (a) Control Experiment with Conventional Alkyl Halide; (b) Unexpected Michael Addition Regiochemistry
See this image and copyright information in PMC

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