A Novel Methodology For The Construction Of Phenothiazine Drug Molecular Skeletons Via C-H Thiolation

Phenothiazine compounds are a class of nitrogen-containing and sulfur-containing tricyclic compounds.At least 100 phenothiazine drugs are mainly used as antipsychotics.They have also been successfully applied in the field of materials.Among the aryl sulfide units,the phenothiazines are of great importance and have gained attention due to their potential pharmacological and biological properties.Most of the synthesis methods are carbon-halogen bond coupling reactions,which is limited by substrate with various substitutions.Organic halides and pseudohalides do not exist widely in nature,and their preparation costs are relatively expensive.This type of reaction produces more by-products,which is not conducive to friendly environment,because the two reactants are generally organic halides and organic metal compounds.Hence,novel synthesis methods to prepare phenothiazine scaffolds with high atom efficiency,low reaction temperature and short reaction time was highly desirable.Transition-metal-catalyzed carbon-hydrogen(C-H)bond functionalization is considered as a powerful strategy for the construction of carbon-carbon(C-C)and carbon-heteroatom(C-N,C-O,C-S)bonds because of its remarkable atom-economy and sustainable environment.A one-pot reaction with step economic involves Rh(Ⅲ)-catalyzed C-H thiolation and relay Cu(Ⅱ)-catalyzed C-N amination of acetanilide and 2-bromothiophenol has been reported and several valuable phenothiazine products can be obtained.By screening different catalysts,oxidants,additives and solvents and other factors,the reaction conditions are optimized to obtain the most suitable reagents as[Cp*RhCl2]2,AgOAc,Cu(OTf)2 and toluene.Next,the applicability of the substrates of the acetanilide and 2-bromothiophenol substituted with different electron donating groups(-OMe,-Me,et al.)and electron withdrawing groups(-NO2,-CF3,-X,et al.)are investigated,and 23 compounds are synthesized.The electron donating group is better than the electron withdrawing group,and the para-reaction is better than the meta-position and better than the ortho-position.The gram-scale amplification experiment confirms that the reaction has the potential to expand production.In the intermolecular competition experiment,the ratio of the corresponding products of the electron-donating group and the electron-withdrawing group is 6.7:1,which proves once again that the electron donating groups are better than electron attracting groups in the reaction.The H/D exchange experiment measures that 20%of the adjacent H was replaced by D,which proves that the C-H bond is reversible.The KIE experiment measures KH/KD=2.16,which proves that the step of C-H activation is the speed-determining step of the reaction.Based on the research of the reaction,a possible reaction mechanism is proposed.This synthesis protocol proceeds from easily accessible material with demonstrates high atom economy and a broad substrate scope.Furthermore,the directing group can be easily removed,and chlorpromazine is provided in large-scale,thus this synthesis strategy can be developed as a facile access to phenothiazine derivatives.For the C-H thiolation reaction involved in the above synthesis method,further in-depth research has been carried out.Explore the use of ionic liquids(ILs)as the carrier of traditional catalysts to realize the effective and sustainable use of catalysts,and adopt an effective and recyclable sustainable development strategy to realize the sulfidation and selenization of C-H bonds.We establish an efficient and sustainable rhodium(Ⅲ)-catalyzed and ionic liquid-mediated C-S and C-Se formation from readily available starting material acetanilide with diaryl disulfides and diaryl diselenides.After optimizing the reaction conditions,the applicability of the substrates of the acetanilide、diaryl disulfides and diaryl diselenides substituted with different electron donating groups(-OMe,-Me,et al)and electron withdrawing groups(-NO2,-CF3,-X,et al.)are investigated,and 30 compounds are synthesized.The electron donating group is better than the electron withdrawing group,and the para-reaction is better than the meta-position and better than the ortho-position.The gram-scale amplification experiment confirms that the reaction has the potential to expand production.Recycling experiment also confirms that the catalytic system is recyclable.In the intermolecular competition experiment,the ratio of the corresponding products of the electron-donating group and the electron-withdrawing group is 5:3,which proves once again that the electron donating groups are better than electron attracting groups in the reaction.The H/D exchange experiment measures that 0%of the adjacent H was replaced by D,which proves that the C-H bond is irreversible.The KIE experiment measures KH/KD=2.09,which proves that the step of C-H activation is the speed-determining step of the reaction.Based on the research of the reaction,a possible reaction mechanism is proposed.The catalytic system of the synthesis method can be recycled,showing the idea of green synthesis.A one-pot reaction with step economic involves Rh(Ⅲ)-catalyzed C-H thiolation and relay Cu(Ⅱ)-catalyzed C-N amination of acetanilide and 2-bromothiophenol has been reported and several valuable phenothiazine products can be obtained.Also,We establish an efficient and sustainable rhodium(Ⅲ)-catalyzed and ionic liquid-mediated C-S and C-Se formation from readily available starting material acetanilide with diaryl disulfides and diaryl diselenides.Most importantly,they can be developed as a facile access to phenothiazine scaffold with potent biological activities in high atom economy,thus this strategy can be broadly applied to organic synthesis and medicinal chemistry.