A Chelating Nucleophile Plays a Starring Role: 1,8-Naphthyridine-Catalyzed Polycomponent α,α-Difluorination of Acid Chlorides

Abstract

A dually activated ketene enolate, generated from an acid chloride, the unusual chelating nucleophile (1,8-naphthyridine), and a Lewis acid, reacts to afford a host of α,α-difluorinated products in the presence of a benchtop-stable fluorinating agent (Selectfluor). The use of this method to synthesize otherwise difficult to make products is highlighted along with computational and spectroscopic support for the proposed chelate.

Catalyzed and Promoted Aliphatic Fluorination

“…Almost a decade ago, as players in the midst of what could be arguably termed a “golden era of asymmetric α-halogenation”, our lab reported a tricomponent, catalytic, asymmetric α-fluorination of acid chlorides using N -fluorobenzenesulfonamide (NFSI) . The development of this reaction proved to be quite interesting, but nevertheless challenging, and necessitated the judicious and sometimes counterintuitive juggling of three catalysts: a cinchona alkaloid derivative such as benzoylquinidine (BQd) to impart enantioselectivity; a Lewis acid (usually Li + ) to activate the fluorinating agent; and finally, a transition-metal complex in order to form a stabilized zwitterionic enolate (Scheme ).…”

Photoinduced regioselective difluorination of secondary inert C(sp3)–H bonds in sulfonamides via 1,5-hydrogen-atom transfer

“…Among various methods, [16][17][18][19][20][21][22][23][24][25][26] direct C(sp 3 )-H difluorination that can introduce two fluorine atoms at once is especially desirable for forming diverse molecules and functionalizing complex substrates at a late stage, which can avoid pre-functionalization and reduce the generation of harmful waste. 27,28 Previous studies have mainly focused on substrates with active C(sp 3 )-H bonds adjacent to iminyl, 29 carbonyl, [30][31][32][33] aryl 31,[33][34][35][36][37][38] or hetero-aryl 39 groups (Fig. 1B).…”

Gram-Scale Synthesis of 1,8-Naphthyridines in Water: The Friedlander Reaction Revisited

“…The medicinal properties of naphthyridines and their derivatives are the major driving forces to synthesize them on a large scale. Among naphthyridines, 1,8-naphthyridines ( 1 , Figure A) and their derivatives are used as drugs for antimicrobial activities (nalidixic acid, 2 ), − HIV inhibitor ( 3 ), antibacterial activities (gemifloxacin, 4 ), , antitumor activity (vosaroxin, 5 ), etc. − The 1,8-naphthyridine derivatives can also act as monodentate, bidentate, or binucleating bridging ligands ( 6 , Figure A). − They also exhibit excellent thermally activated delayed fluorescence (TADF) and high photoluminescence quantum yield ( 7 ), which make them suitable blue organic light-emitting diodes (OLEDs). It is worth mentioning that the extensively substituted 1,8-naphthyridines and less substituted ones are used as probes to monitor the structure and function of enzymes and proteins.…”