Iron-catalyzed isopropylation of electron-deficient aryl and heteroaryl chlorides

Sanderson, James N. and Dominey, Andrew P. and Percy, Jonathan M. (2017) Iron-catalyzed isopropylation of electron-deficient aryl and heteroaryl chlorides. Advanced Synthesis and Catalysis. ISSN 1615-4150

[img] Text (Sanderson-etal-ASC2017-Iron-catalyzed-isopropylation-of-electron-deficient-aryl-and-heteroaryl-chlorides)
Accepted Author Manuscript

Download (2MB)


    Traditional methods for the preparation of secondary alkyl-substituted aryl and heteroaryl chlorides challenge both selectivity and functional group tolerance. This contribution describes the use of statistical design of experiments to develop an effective procedure for the preparation of isopropyl-substituted (hetero)arenes with minimal isopropyl to n-propyl isomerization. The reaction tolerates electronically diverse aryl chloride coupling partners, with excellent conversion observed for strongly electron-deficient aromatic rings, such as esters and amides. Electron-rich systems, including methyl- and methoxy-substituted aryl chlorides, were found to be less reactive. Furthermore, the reaction was found to be most successful when heteroaryl chlorides were submitted to the cross-coupling protocol. By mapping substituent effects on reaction selectivity, we were able to show that electron-deficient aryl chlorides are essential for efficient coupling, and use electronic structure calculations to predict the likelihood of successful coupling through the estimation of the electron affinity of each aryl chloride. Moderate isolated yields were achieved with selected aryl chlorides, and moderate to good isolated yields were obtained for all the heteroaryl chlorides coupled. Excellent selectivity was observed when a 2,6-dichloroquinoline was used, allowing mono-substitution on a challenging substrate.