Mechanistic Investigations for the Formation of Active Hexafluoroisopropyl Benzoates Involving Aza‐Oxyallyl Cation and Anthranils

Abstract

Herein, we report a multicomponent approach to access hexafluoroisopropyl activated esters using anthranil and aza-oxyallyl cation with hexafluoroisopropyl alcohol (HFIP) under mild reaction conditions. Activated (HFIP) esters synthesized via this approach serve as an important intermediate to obtain coveted 1,4-benzodiazepine-3,5-dione derivatives. The mechanism of the reaction was studied quantum mechanically using density functional theory (DFT) with functional M06-2X and 6-31G (d, p) basis set. Different pathways were investigated. Calculated results reveal probable involvement of two mechanisms in current transformation.

HFIP in Organic Synthesis

“… Alternative solvents such as DCM, THF, and dioxane all led to trace formation of product whereas HFIP led to a 90% yield. Singh and co-workers further investigated this reaction via computational and experimental methods …”

Aza‐oxyallyl Cations and Their Applications in (3+m) Cycloaddition Reactions

“…Benzodiazepines (BDZs) derivatives are important structural motifs in pharmaceuticals [49] . Recently, in 2020, two different research groups Singh et al [50a] . and Zhang et al [50b] .…”

“…Pathway I displayed ketene intermediate T is formed which further attacked by HFIP and gave desired product 103 a . Pathway II, showed hemiacetal V is formed by attack of HFIP; further hemiacetal V undergoes subsequent hydride transfer and deprotonation to set off product active HFIP ester 103 a [50a] . Zhang et al.…”

Heteroarylation of Congested α-Bromoamides with Imidazo-Heteroarenes and Indolizines via Aza-Oxyallyl Cations: Enroute to Dibenzoazepinone and Zolpidem Analogues

“…Recently, aza-oxyallyl cations have garnered significant attention as a three-unit synthon mostly for 3 + m cycloadditions . It is only recently we demonstrated the alkylative nature of this species by forming congested α-aminoamides . Therefore, in continuation of our research interest in the exploration of aza-oxyallyl cation chemistry, herein, we wish to report the direct heteroarylation of tertiary α-haloamides with imidazo-heteroarenes and 2-aryl indolizines via an aza-oxyallyl cation intermediate (eq 3, Figure ).…”