Regiocontrolled Minisci Alkylations Guided by Phosphonium Ions

Significant improvements in the regioselectivity of Minisci alkylations have been enabled by adopting N-heteroaryl phosphonium salts as substrates for this textbook transformation. Minisci chemistry has been a workhorse synthetic protocol in industry and academia for decades since it generates more-complex N-heteroaryls such as pyridines by C–H alkylation of the latter species with abundant precursors like carboxylic acids. Its wide scope, robustness, and operational simplicity are also major advantages, but its regioselectivity is often poor and general solutions have been slow to emerge. This strategy draws on reliable regioselective methods to install phosphonium groups onto N-heteroarenes. We have demonstrated herein that C2-alkylation of easily accessible C4-PPh 3 +-containing pyridines and quinolines (and C4-alkylation of C2-PPh 3 +-containing quinolines) regiospecifically generates a range of alkylation patterns that have previously proven challenging for Minisci chemistry to access selectively – especially when using more-abundant alkyl sources. Moreover, the preliminary application of this strategy to further N-heteroarenes shows that sites less- or unreactive with alkyl radicals can be exclusively engaged by using the phosphonium group to block the preferred Minisci reaction site. Finally, after the alkylation, mild hydrolysis can tracelessly remove the PPh 3 + handle, or a suite of established substitutions can be used to enable regiospecific C–H/C–H difunctionalizations across the PPh 3 + installation/Minisci/PPh 3 + substitution sequence.