Catalytic halodefluorination of aliphatic carbon–fluorine bonds

Abstract

RSC Adv. 6 (2016) 48, 42708-42712, http://dx.doi.org/10.1039/C6RA09429E ; Dep. Chem., Natl. Univ. Singapore, Singapore 117543, Singapore; Eng.) -M. Tismer 38-050

Nucleophilic Substitution of Aliphatic Fluorides via Pseudohalide Intermediates

“…A strategy that has recently been exploited to overcome poor reactivity and/or improve selectivity, has been to preinstall silyl groups on coupling partners prior to C−F functionalization ,,,,,. During the functional defluorination reaction, silyl fluoride byproducts act as thermodynamic sinks, driving reactivity.…”

“…Reaction with p ‐iodoaniline was also found to proceed at room temperature overnight to give the product 2 a in high yield (entry 3). Finally, iodide was employed to benchmark the reaction to previously reported halodefluorination reactions . The substitution of fluoride for iodide occurred much slower using TMSI than the pseudohalides, taking place over 12 hours to give a high yield of an iodide intermediate.…”

“…Similar reactivity preference has been observed in hydrogen‐bonding activated Friedel–Crafts alkylations using benzylic fluorides and aluminium‐catalyzed alkynyl couplings with benzylic fluorides . The ability to selectively target fluoride positions in the presence of alkyl chloro, bromo, and iodo motifs represents a distinct advantage of this methodology over previously reported halodefluorination approaches, and provides the possibility of orthogonal synthetic strategies.…”

“…Such catalysts have low functional group tolerance, with their reactivity either arrested or hindered in the presence of alcohol, amine, ester, carboxylic acid, carbonyl, ether, and nitrile groups ( inter alia). Furthermore, Lewis acid catalyst strategies that proceed by carbocation pathways are prone to rearrangement and elimination reactions and Friedel–Crafts reactivity, resulting in poor tolerance of arene solvents ,,,,,,. Indeed, C–F functionalization exploiting Friedel–Crafts reactivity also suffers from poor selectivity and low reactivity with arenes deactivated with electron‐withdrawing groups ,,,,…”

“…Retention of regiochemistry for primary positions ( 3 f – i ) in Lewis acid catalyzed fluoride substitution reactions is challenging in S N 1‐type substitutions . As such, we decided to benchmark the above descried reactions with other halide and pseudohalide sources to determine the origin of the high regioselectivity.…”