Cu Catalyzed Decarboxylative Coupling Reactions For The Synthesis Of C-3 Indole Derivatives

The indole derivatives are important organic structural motifs found in natural products and drugs.The most common approaches to access these compounds,especially C-3 indole derivatives,are transition-metal catalyzed cross-coupling reactions.Among which,decarboxylative coupling reaciton offers an atom-and step-economical modern synthetic protocol.Not only the substrate carboxylic acid is cheap and easy to obtain,but also the reaction by-products are few（only CO₂）and environmentally friendly.This strategy is now attracting increased attention of the chemist.In this paper,we have developed two types of copper-catalyzed decarboxylative coupling reactions of indoles for the synthesis of 3-（hetero）arylindoles and3-acylindoles.Thereafter,two kinds of drugs and their intermediates have been prepared efficiently and friendly by taking the above protocol.The details are summarized as follows:First,we mainly introduced the research progress of decarboxylative coupling reaciton,including decarboxylative arylation,acylation,olefination and alkynylation reaction.Besides,mechanochemistry and its application in organic synthesis were also briefly summarized.Then,a copper-catalyzed decarboxylative arylation reaction between indoles and potassium arylcarboxylate was developed.The reaction conditions,involving the catalysts,additives,solvents,reaction time and reaction temperature were systematically examined to obtain the optimal reaction conditions:Cu（OTf）₂（2.0 eq.）as catalyst,DMSO（1.5 mL）as solvent,heating at 120 ^oC for 4 h,which provided a cheap and efficient reaction system for the synthesis of 3-arylindole compounds.Subsequent synthesis of the key intermediates of the antimalarial drug ioneocryptolepine was achieved upon the developed method.Finally,the decarboxylative acylation of N-free indoles enabled by trace amount of copper catalyst and liquid-assisted grinding（LAG）was delivered.Through a detailed screening of the chemical conditions such as catalysts,oxidants,liquid additives（LAGs）and grinding aids,as well as the mechanical parameters such as milling frequency,time and milling-ball size,the optimal reaction conditions were obtained with Cu（OAc）₂·H₂O（20 mol%）as catalyst,MeCN（η=0.11）as LAGs,NaCl（3.0 g）as grinding auxiliary,O₂ as terminal oxidant,ball-milling at 750 rpm for120 min,and delivered a highly efficient and green synthesis of 3-acylindole derivatives.It has been verified that this new methodology was applicable to a gram-scale synthesis.Furthermore,possible reaction mechanism was proposed through a series of control experiments.Eventually,anticancer active drugs SCB01A and（6-methoxy-2-methyl-1H-indol-3-yl）（3,4,5-trimethoxyphenyl）methanone have been successfully prepared by the achieved mechanochemical protocol.