A three-component coupling process based on vicarious nucleophilic substitution (VNS(AR))-alkylation reactions: an approach to indoprofen and derivatives.
The intermediate anion derived from the vicarious nucleophilic substitution (VNS) of hydrogen reacts with a series of alkyl halides to generate the corresponding alpha-alkylated conventional VNS product in a one-pot process. This one-pot VNS-alkylation reaction offers a convenient route to a range alpha-substituted nitrobenzyl phosphine oxides, sulfones, and esters via a three-component coupling reaction. Reactions of alpha-chloroethyl phenyl sulfone (14) and ethyl 2-chloropropionate (16) with nitrobenzene followed by subsequent addition of an alkylating agent give a series of sulfones and esters bearing an alpha-aryl quaternary center. The VNS-alkylation protocol has been applied to the synthesis of derivatives of Indoprofen from nitrobenzene using readily available inexpensive starting materials. Indoprofen itself was prepared using the conventional VNS reaction in four steps and 24% overall yield from nitrobenzene.
Lawrence
Nicholas J
NJ
Department of Chemistry, University of Manchester Institute of Science and Technology, Manchester M60 1QD, U.K. Lawrencenj1@cardiff.ac.uk
Liddle
John
J
Bushell
Simon M
SM
Jackson
David A
DA
D000478:Alkylation; D002384:Catalysis; D002625:Chemistry, Organic / Q000379:methods; D002855:Chromatography, Thin Layer; D004952:Esters / Q000737:chemistry; D007216:Indoprofen / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009578:Nitrobenzenes / Q000138:chemical synthesis* / Q000737:chemistry*; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry; D013450:Sulfones / Q000737:chemistry
D004952:Esters; D009578:Nitrobenzenes; D011422:Propionates; D013450:Sulfones; C449959:chloroethyl phenylsulfone; D007216:Indoprofen; C449960:ethyl 2-chloropropionate