Enantioselective C (SP3) - H amidation of thioamide catalyzed by angelw: CO (III) / chiral carboxylic acid

Transition metal catalyzed C-H functionalization has been widely concerned in organic synthesis because it can synthesize functional molecules in a more atom and step-by-step economic way The trivalent 9-group metals with cyclopentadienyl (CPX) ligands exhibit remarkable catalytic properties, and have universal applicability for guided group assisted C-H activation / functionalization Due to the lack of empty coordination sites of external chiral ligands, the control of enantioselective catalysis is a long-standing problem under the catalysis of CP x m (III) (M = Co, Rh, IR) At present, the carefully designed chiral CP x ligands have become an efficient solution After the pioneering work of Cramer group, many kinds of chiral CPX ligands and their metal complexes have been reported, and they have been used in enantioselective C-H functionalization (scheme 1a and 1b) However, previous studies on 9 groups of metals only focused on enantioselective C (SP 2) - H functionalization, and more challenging C (SP 3) - H functionalization has not been reported Recently, Professor Shigeki Matsunaga and Dr Tatsuhiko Yoshino of Hokkaido University in Japan reported the synergistic catalysis of C (SP 3) - H amidation of thioamides by chiral carboxylic acids and non chiral cpxco (III) Relevant articles were published on angelw Chem Int ed (DOI: 10.1002 / anie 201812215) (source: angelw Chem Int ed.) before, Dixon and seayad research group reported the C (SP 3) - H amidation of thioamide catalyzed by Cp * CO (III) (angelw Chem Int ed 2017, 56, 16550) The results of quantum chemical calculation show that the C-H bond breaking step is carried out by the external carboxylate assisted cooperative metallization (CMD) mechanism Based on the above results, the author began to study the amidation reaction of thioamide 1a and dioxazolone 2a in the hope that chiral carboxylic acids can promote enantioselective synergistic metallization process (Table 1) The effects of a series of chiral TERT leucine derivatives, cpxco (III) catalysts, additives and solvents on the reaction results were investigated The optimum reaction conditions were as follows: using Nonchiral CO (III) complex 4B as catalyst, chiral carboxylic acid 5F as ligand, ms13x as additive, o-dichlorobenzene as solvent, 82% yield and 92 / 8 Er value 3aa 。
(source: angelw Chem Int ed.) next, the author first examined the scope of application of thioamide 1 (Table 2) The corresponding product 3AA - 3KA (entries 1-11) was obtained from thioamide with various substituents in α position with good yield and excellent enantioselectivity Acyl thioamide also showed good enantioselectivity in the reaction Then, the substrate range of dioxazolone 2 was investigated by thioamide for 1 h and 1 h The substrate 2 with electron acceptor and electron donor can be compatible with the reaction, and the target product 3AB - 3AI (entries 12-15) can be obtained in 63% - 90% yield and 91 / 9-94 / 6 er In addition to aromatic dioxazones, heteroaromatic and aliphatic dioxazones also have good enantioselectivity (entries 16-19) (source: angelw Chem Int ed.) in order to prove the practicability of the reaction, the author carried out a gram scale reaction of 1a and 2a, and successfully obtained 3AA, the yield was 92%, er value was 93 / 7 (scheme 3) Under the conditions of Ag 2CO 3 and NiCl 2 / NaBH 4, the product 3AA can be converted into amide 6 and amine 7, respectively In addition, 3 AA was methylated and reduced to obtain chiral β - aminoaldehyde 8 in 73% yield (source: angelw Chem Int ed.) finally, the author proved that the C-H activation step of the reaction was irreversible by H / D exchange experiment, and further confirmed that the enantioselectivity of the reaction was determined by the C-H bond breaking step of the enantioselectivity (scheme 4) (source: angelw Chem Int ed.) in a word, Professor Shigeki Matsunaga and Dr Tatsuhiko Yoshino have realized the asymmetric C (SP 3) - H amidation of thioamide 1 and dioxazolone 2 by using the combination of chiral carboxylic acid 5F and Nonchiral CO (III) complex 4B Through the enantioselective activation of C (SP 3) - H, we have constructed a variety of products with good enantioselectivity, thus providing a synthetic block with quaternary carbon chiral center.