Selectfluor^TM‐Mediated Tandem Fluorination and 1,3‐Carbonyl Migration in ortho‐Carbonyl Anilines: Charge‐Transfer‐Enabled ortho‐Selectivity

Abstract

An unprecedented tandem ortho‐selective fluorination and 1,3‐carbonyl migration in ortho‐carbonyl anilines using selectfluorTM as the sole reagent is reported. The reaction is transition‐metal free, does not require any pre‐functionalization, takes place under ambient conditions, and yields ortho‐fluoroanilide derivatives in moderate to good yields. SelectfluorTM serves the dual purpose of fluorine source and assists 1,3‐carbonyl migration. The formation of proposed charge transfer (CT) complex between ortho‐carbonyl aniline (donor) and selectfluorTM (acceptor), and its role in enabling the observed ortho‐selectivity is supported by experimental and computational investigations. The single‐electron‐transfer (SET) in the complex results in the formation of (2‐amino‐3‐fluorophenyl)(phenyl)methanone intermediate, which on subsequent 1,3‐carbonyl migration forms ortho‐fluoroanilide in presence of F+ or in‐situ generated H+.

N-(2,4-Difluorophenyl)-2-fluorobenzamide

“…It is noted from a CSD review that 2-chloro-N-(4-chloro-2-fluorophenyl)benzamide or XEHZOD crystallizes in space group Pna2 1 and differs by replacing the two F atoms (in Fo24) with two Cl atoms [3,20]. The 2-bromo-N-(2,4-dichlorophenyl)benzamide or ZAJWUF structure in space group Pbca is another related crystal structure [21].…”

“…Analysis of a benzamide search [C 13 H 8 X 3 O 1 N 1 formula; X = F, Cl, Br, I and C 6 CONHC 6 skeleton] and reviewing various trihalide (X) combinations shows that the majority are chloroderivatives. The chloro-derivatives provide ten CSD structural 'hits' and structures, as listed by CANYAV, CANYEZ [3,22], ENUKAA [23], JOFHAO [24], KODTUT [25], LAQ-DOY [26], XEHZOD [20], YODDUR [27], YOVMIG [28] and ZAJWUF [21].…”

“…The benzamide crystal structures reported in the Cambridge Structural Database [3] facilitate analysis of physicochemical research trends and patterns. Ongoing research is directed towards the development of larger n × m benzamide isomer grids and correlating properties such as melting points, spectroscopic and structural data [3][4][5][6][7][8][9][10][20][21][22][23][24][25][26][27][28]. Even when analyzing relatively small molecules such as benzamides, there are gaps in our structural knowledge where crystal structure prediction can potentially be used to fill the spaces [29].…”