Rhodium(III)-catalyzed regioselective C2-amidation of indoles with N-(2,4,6-trichlorobenzoyloxy)amides and its synthetic application to the development of a novel potential PPARγ modulator

被引:37
作者
Shi, Jingjing [1 ]
Zhao, Guanguan [1 ]
Wang, Xiaowei [1 ]
Xu, H. Eric [1 ,2 ]
Yi, Wei [1 ]
机构
[1] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, VARI SIMM Ctr,Ctr Struct & Funct Drug Targets, Shanghai 201203, Peoples R China
[2] Van Andel Res Inst, Lab Struct Sci, Program Struct Biol & Drug Discovery, Grand Rapids, MI 49503 USA
关键词
C-H AMIDATION; N BOND FORMATION; CARBENOID FUNCTIONALIZATION; AMINATION; ALKENYLATION; (HETERO)ARENES; ARYLATION; ALKENES; ARENES; LIGAND;
D O I
10.1039/c4ob00637b
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
A new and efficient method for the direct regioselective C2-amidation of various functionalized indoles with several N-(2,4,6-trichlorobenzoyloxy) amides via Rh(III)-catalyzed C-H activation/N-O cleavage/C-N formation using the pyrimidyl group as a readily installable and removable directing group has been developed. With this method, a variety of valuable 2-amido indoles can be easily prepared under mild conditions with broad functional group tolerance and excellent region-/site-specificities. Application of this strategy to the synthesis of target compound 6 as a novel PPAR gamma modulator was also demonstrated. The results from biological evaluation showed that compound 6 had a partial PPAR gamma agonistic activity and a strong PPAR gamma binding affinity with an IC50 value of 120.0 nM, along with a less pronounced adipocyte differentiation ability compared to the currently marketed anti-diabetic drug rosiglitazone, suggesting that further development of such a compound might be of great interest.
引用
收藏
页码:6831 / 6836
页数:6
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