Practical and Regioselective Synthesis of C-4-Alkylated Pyridines

被引:75
作者
Choi, Jin [1 ]
Laudadio, Gabriele [1 ]
Godineau, Edouard [2 ]
Baran, Phil S. [1 ]
机构
[1] Scripps Res, Dept Chem, La Jolla, CA 92037 USA
[2] Syngenta Crop Protect, Proc Res, CH-4332 Stein, Switzerland
关键词
C-H FUNCTIONALIZATION; NUCLEOPHILIC CHARACTER; MINISCI REACTIONS; ALKYL RADICALS; ARYLATION; INHIBITORS; ALKENE; MILD;
D O I
10.1021/jacs.1c05278
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The direct position-selective C-4 alkylation of pyridines has been a long-standing challenge in heterocyclic chemistry, particularly from pyridine itself. Historically this has been addressed using prefunctionalized materials to avoid overalkylation and mixtures of regioisomers. This study reports the invention of a simple maleate-derived blocking group for pyridines that enables exquisite control for Minisci-type decarboxylative alkylation at C-4 that allows for inexpensive access to these valuable building blocks. The method is employed on a variety of different pyridines and carboxylic acid alkyl donors, is operationally simple and scalable, and is applied to access known structures in a rapid and inexpensive fashion. Finally, this work points to an interesting strategic departure for the use of Minisci chemistry at the earliest possible stage (native pyridine) rather than current dogma that almost exclusively employs Minisci chemistry as a late-stage functionalization technique.
引用
收藏
页码:11927 / 11933
页数:7
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