Triphosgene and Triphenylphosphine Oxide-Mediated Cascade Heterocyclization of N-Acylated Anilines: One-Pot Synthesis of 2,4-Dichloroquinolines

Abstract

A one-pot cascade chlorination/heterocyclization strategy has been developed for the synthesis of 2,4-dichlorosubstituted quinolines from acylated anilines using triphosgene and triphenylphosphine oxide. Obviating the conventional harsh conditions of chlorination, synthetic useful quinolines with moderate to good yields were obtained through this reaction. The mechanism study exhibited that the formation of a β-enamine intermediate plays a vital role in the generation of the final product.

One-Pot Synthesis of 4-Chloroquinolines via Bis(trichloromethyl) Carbonate and Triphenylphosphine Oxide-Mediated Cascade Reactions of N-Aryl Enaminones

“…Initially, a reactive ((chlorocarbonyl)­oxy)­triphenylphosphonium chloride (intermediate A ) is generated by the reaction between BTC and TPPO . Subsequently, enaminone 1 undergoes α-carbonylation mediated by A , generating acyloxytriphenylphosphonium salt, denoted as intermediate B . , Under the promotion of heating and chloride ions, intermediate B further sheds off TPPO and HCl affording ketene intermediate C , which rapidly undergoes a 6π-azaelectrocyclization providing the annulated intermediate D . Finally, in the presence of triphenylphosphine dichloride (TPPDC), derived from excessive A under thermal conditions by CO 2 extrusion, D undergoes dehydroxychlorination to produce the target product 4-chloroquinoline 2 through a enol intermediate E .…”

“…In the context of our studies on the chemistry of enaminones, we have achieved efficient synthesis of substituted 2,3-dihydrothieno­[3,2- c ]­pyridin-4­(5 H )-ones, 2,3-dihydrofuro­[3,2- c ]­pyridin-4­(5 H )-ones, 2,3-dihydrofuro­[3,2- c ]­pyridines, spiro-fused dihydrofuran-3­(2 H )-ones, and quinolin-4-ones . Very recently, a novel one-pot synthesis of 2,4-dichloroquinolines from α-substituted acetanilids was also realized by using the combination of triphosgene (BTC) and triphenylphosphine oxide (TPPO) as a dual chlorinating and carbonylation agent (Scheme h) . Preliminary mechanistic studies indicated the potential in situ formation of an enamine intermediate through the transformation.…”