An Efficient and Scalable One-Pot Double Michael Addition-Dieckmann Condensation for the Synthesis of 4,4-Disubstituted Cyclohexane β-Keto Esters

Abstract

A simple, scalable, and efficient one-pot methodology for the synthesis of 4,4-disubstituted cyclohexane beta-keto esters from benzylic nitriles or esters and methyl acrylate promoted by potassium tert-butoxide is described. The process relies on a tandem double Michael addition-Dieckmann condensation reaction, which results in the formation of three discrete carbon-carbon bonds in a single pot, including a quaternary center. The method allows for the convenient and rapid synthesis of a variety of 4-aryl-4-cyano-2-carbomethoxycyclohexanone and 4-aryl-2,4-biscarbomethoxycyclohexanone building blocks for use in natural products synthesis and medicinal chemistry.

Quantification and Theoretical Analysis of the Electrophilicities of Michael Acceptors

“…When 13 and 1a (2 equiv) were combined at low temperature in THF with potassium tert -butoxide as the base, cyclic β-keto ester 16 was formed by a 2-fold Michael addition with subsequent Dieckmann condensation (Scheme , for the detailed mechanism see Supporting Information). Analogous 4,4-disubstituted cyclohexane β-keto esters were previously obtained when phenylacetonitriles or phenylacetates were treated with 1a (2 equiv) under basic conditions ( t BuOK, THF, rt) …”

High-yielding method for preparation of carbocyclic or N-containing heterocyclic β-keto esters using in situ activated sodium hydride in dimethyl sulphoxide

“…The compounds are very often prepared by the acylation of preformed ketone enolate anions using reagents such as Weinreb amides (4), alkyl-cyanoformates (5,6) or 1-Boc-imidazole (7), as well as alkyl carbonates at elevated temperature (8)(9)(10)(11). Dieckmann condensation (12) of various diesters provides good yields of 5-and 6-membered carbocyclic (13)(14)(15) or heterocyclic β-keto esters (16)(17)(18)(19)(20)(21) while acyclic analogues result from Claisen ester condensation (22) typically after prolonged heating in aromatic solvents with alkoxides. Alternatively, the acylation is promoted by Lewis acids (23,24).…”

Successful Strategies for Mitigation of a Preclinical Signal for Phototoxicity in a DGAT1 Inhibitor

“…In order to access oxabicyclooctane containing analogues such as 10 and 12 , the synthetic strategy utilized key intermediate 13 , which was built up from methyl 2-(4-bromophenyl) acetate (Scheme ). A double Michael–Dieckmann cyclization–decarboxylation sequence was used to construct the corresponding cyclohexanone . Overall reduction of the resulting methyl ester to the neopentyl alcohol followed by Horner–Wadsworth–Emmons olefination afforded the desired substrate for the intramolecular oxa-Michael addition, which proceeded smoothly with base to give key bromide intermediate 13 .…”

“…A double Michael− Dieckmann cyclization−decarboxylation sequence was used to construct the corresponding cyclohexanone. 29 Overall reduction of the resulting methyl ester to the neopentyl alcohol followed by Horner−Wadsworth−Emmons olefination afforded the desired substrate for the intramolecular oxa-Michael addition, which proceeded smoothly with base to give key bromide intermediate 13. 28 The structure of the oxabicyclooctane ring system was confirmed in the solid state by X-ray crystallographic analysis (ORTEP of 13 shown in Scheme 1).…”