Synthetic Access to α-Oxoketene Aminals by the Nucleophilic Addition of Enol Silane-Derived Palladium(II) Enolates to Carbodiimides

Abstract

Synthetically important α-oxoketene aminal intermediates can now be accessed from readily available and inexpensive carbodiimides as starting materials via the nucleophilic addition of palladium enolates derived from enol silane precursors. This operationally simple method features mild reaction conditions, including open air atmosphere, ligand-free metal catalysis, broad substrate scope, and multi-gram scalability. Select synthetic applications that take advantage of the enamine character of α-oxoketene aminals and involve C-nucleophilic additions to electrophilic systems, including an α,β-unsaturated ester, an azo dicarboxylate, an aralkyl halide, and an aldehyde, are demonstrated.

Developing a transition-metal-free green protocol for the electrophilic hydrazination of silyl enol ethers using diazo electrophiles with EtOH–H2O as a safe solvent

“…[20][21][22] Taking advantage of the unique function of silyl enol ethers as masked enolate precursors of ketones, aldehydes and esters, the development of numerous synthetic protocols involving the construction of new C-C, C-N, C-O, C-S and C-x (x = halogen) bonds has been reported over the last three decades. [23][24][25][26][27][28][29][30][31][32] Specifically, silyl enol ethers serve as the preferred reagents to generate enolate equivalents in a regio-and stereo-selective manner, which has empowered their utility as versatile synthetic intermediates in the construction of building blocks of interest to pharmaceutical chemistry to generate diverse scaffolds and drug-like compounds for a range of therapeutic targets.…”

Examining the Scope of Deriving β-Aryl Enones from Enol Silanes as Ketone Equivalents via Pd(II)-Mediated Sequential Dehydrosilylation and Arylation

“…The limited number of existing methods to transform saturated ketones to β-aryl enones and the limitations associated with these protocols spurred us to design and develop an alternative approach based on a retrosynthetic strategy relying upon silyl enol ethers as substrates, taking advantage of their function as masked enol equivalents of saturated ketones (Scheme ). In the forward synthetic direction, enol silanes would be expected to fulfill the role of acting as synthetic equivalents of saturated ketones by undergoing dehydrosilylation with the in situ generation of α,β-unsaturated ketones that would then be arylated in a one-pot process. − We were particularly interested in exploring silyl enol ethers as versatile reagents in a continuation of our earlier research that took advantage of their nucleophilic character to enable C–C and C–N bond formation with quinone, carbodiimide, and azodicarboxylate electrophilic systems. − Importantly, silyl enol ethers (a) are readily prepared from keto, aldehyde, and ester precursors; (b) are the reagents of choice for the regio- and stereo-selective generation of enolate equivalents; (c) undergo a diverse range of synthetic reactions, including aldol condensations, Michael additions, and [4 + 2] cycloadditions; and (d) find use as synthetic building blocks in pharmaceutical chemistry to generate drug-like compounds of diverse architecture. − Herein, we report for the first time the synthesis of β-arylated enone derivatives from enol silanes through the sequential generation of an enone in situ and the ensuing arylation with arylboronic acids or aryl halides in a convenient, one-pot process using modular Pd­(II)/Pd(0) catalytic systems (Scheme , eq 3).…”