Synthesis of 2-Fluoro-1,4-benzoxazines and 2-Fluoro-1,4-benzoxazepin-5-ones by Exploring the Nucleophilic Vinylic Substitution (S_NV) Reaction of gem-Difluoroenamides

Abstract

N-Benzoyl β,β-difluoroenamides and N-benzoyl fluoroynamides are novel structural units which have been explored as precursors in heterocyclic synthesis. The presence of two fluorine atoms at the β-position of the enamide moiety endows unique electrophilic reactivity. Treatment of these enamides with oxygen nucleophiles gives rise to a nucleophilic vinylic substitution (S(N)V) reaction, which was directed toward 2-fluoro-1,4-benzoxazines and 2-fluoro-1,4-benzoxazepin-5-ones. Furthermore, fluorinated ynamides, a new type of building block, were prepared in excellent yields for the first time. In this case, β-addition of nucleophiles across the triple bond is observed also.

gem‐Heteroatom‐Substituted Fluoroalkenes as Mimics of Amide Derivatives or Phosphates: A Comprehensive Review

“…At the same period, De Kimpe, Mangelinckx and co-workers studied the reactivity of β,β-difluoroenamides toward oxygenated nucleophiles via a nucleophilic vinylic substitution (S N V) reaction, leading to the expected products 5 and 6 in 4/1 ratio (Scheme 6). [21] Later in 2016, Cao's group developed an efficient synthesis of α-fluorovinyl pyrazolyl ethers, based on their previous strategy. [20], [22] gem-Difluoroalkenes and pyrazolin-5-ones reacted in presence of tBuOK as base in DMSO at 60 °C under inert atmosphere to produce relevant pyrazolone derivatives (Scheme 7).…”

“…A reactive enolate is generated in situ and reacted through a nucleophilic 5-endo-trig cyclization to furnish good to excellent yields of 5-fluorinated 2-alkylidene-2,3-dihydrofurans (Scheme 11). [28] In 2015, following their previously described procedure, [21] De Kimpe, Mangelinckx and co-workers designed specific substrates containing both the oxygen nucleophile and the electrophilic difluoroenamide moiety to develop an intramolecular S N V reaction. Six-or seven-membered monofluorinated 1,4benzoxazines (Scheme 12A) and 1,4-benzoxazepin-5-ones (Scheme 12B), both interesting bioactive heterocycles, [29] were synthesized in fair to good yields.…”

Synthesis of Monofluoroalkenes: A Leap Forward

“…In 2015, De Kimpe, Mangelinckx, and co-workers explored the nucleophilic vinylic substitution reaction of gem-difluoroenamides. 90 Under the optimized reaction conditions, (thio)phenolates and alkoxides act as nucleophiles to give the corresponding monofluoroalkenes. Then, an intramolecular variant was performed on more functionalized enamide molecules bearing the N-2,2-difluorovinyl and N-phenolate groups to give benzoxazines (4 examples, 70-86%, Scheme 70) or benzoxazepinones (5 examples, 62-88%).…”

“…De Kimpe, Mangelinckx, and co-workers used the nucleophilic addition of a phenoxide to a fluoroacetylene to obtain the corresponding cyclic monofluoroalkene (Scheme 96). 90 The 1-amido-2-fluoroacetylene was obtained in one step from a gem-bromodifluoro compound and the addition of TBAF allowed deprotection of the alcohol and its subsequent attack.…”

Base-Promoted Chemodivergent Formation of 1,4-Benzoxazepin-5(4H)-ones and 1,3-Benzoxazin-4(4H)-ones Switched by Solvents

“…Therefore, the synthetic approach to 1,4-benzoxazepin-5(4 H )-one ring has been well investigated. However, the known procedures for the formation of the seven-membered benzo-fused heterocycle either are multi-step with low atom-utilization or using uneasily available starting materials catalyzed by palladium complexes [33,34,35].…”