Silver Catalyzed Decarboxylative Direct C2-alkylation Of Benzothiazole With Carboxylic Acids

In recent years, transition-metal-catalyzed and photo-catalyzed decarboxylativecross-coupling reactions using simple carboxylic acids as coupling partners have beenwidely studied in organic synthesis as novel methods for formation of variouscarbon–carbon and carbon–heteroatom bonds. Since carboxylic acids ascross-coupling components are non-toxic, low cost, stable and structurally diverse,extensive studies have been accomplished in this area. Despite the significantadvances, the reactions reported in the literature were mainly focused ondecarboxylative cross-coupling reactions of aromatic, α-oxo-, alkenyl and alkynylcarboxylic acids involving the breaking of Csp—COOH or Csp2—COOH bonds. Butfew transition metal catalyzed decarboxylative coupling reactions involving thebreaking of Csp3—COOH bonds were reported. In particular, the alkylation ofbenzothiazoles and benzoxazoles using saturated aliphatic carboxylic acid asalkylating reagent is never reported. According to the literature most of the successfuldirect C H alkylation of benzothiazoles and benzoxazoles were performed usingtransition metals as catalysts and alkyl halides, Grignard reagents, N-Tosylhydrazonesand potassium alkyltrifluoroborates as alkylating reagents under very harsh reactionconditions. Therefore, further developments for more general alkylationmethodologies are strongly desired. Herein, we report silver catalyzed alkylation ofbenzothiazoles with carboxylic acid through direct decarboxylative cross-couplingreaction, in which a wide range of carboxylic acids including secondary or tertiaryα-substituted, cyclic and acyclic carboxylic acids which even could bare a variety offunctional groups were employed as the alkylation reagents.NR2AgNO3, K2S2O8NR2R1H+HOOCR3R1R3XR4(H)CH2Cl2-H2O, r.t.,8hXR4(H)1X=S, O23The main contents of this paper are as follows: Firstly, the progress and applications of decarboxylative cross-coupling reactionswere introduced and summarized. Then we optimized the reaction conditions of thetransition-metal-catalyzed decarboxylative cross-coupling reaction of benzothiazolesand carboxylic acids; And then the scope of this reaction were investigated; Finally,the mechanism of this reaction was studied by designed experiments.1. The reaction conditions were optimized from the respects such as catalyst,oxidant, the ratios of reactants, solvent, and the reaction time with the templatereaction of pivalic acid and benzothiazole. The optimum reaction conditions are:benzothiazole react with2equiv of carboxylic acid,20mol%of AgNO3,4equiv ofK2S2O8in CH2Cl2-H2O (v/v=1:1) at room temperature for8h.2. Under the optimized conditions, the scope and regularity of this reaction wereinvestigated by testing various benzothiazoles, thiazoles, benzoxazoles andcarboxylic acids. Found that secondary or tertiary α-substituted carboxylic acidswitch also could bare various functional groups such as hydroxyl group, an etherbond, an amide bond are preferably used in the reaction, while the methyl-, nitro-,halo-substituted benzothiazole, thiazole, benzoxazole can be well applied. And30coupled compounds were synthesized with structural elucidation by NMR andHR MS. And the single crystal of2-tert-butyl-6-nitro-benzothiazole was analysedby X-Ray diffraction.3. Finally, we studied the mechanism of this reaction with designed experiments,finding the free radical mechanism.