Studies on Regioselective Alkylation of N-Heteroarene Using 1,1-Diborylalkanes as Alkylating Sources

Abstract

The regioselective, direct alkylation of electron-deficient N-heteroarenes is, in principle, a powerful and efficient way of accessing alkylated N-heteroarenes that are important core structures of many biologically active compounds and pharmaceutical agents. Especially methyl group, which is the smallest carbohydrate functional group consisted by one carbon and three hydrogen, can cause significant difference in bioactive work. In chapter I, a general overview of alkylation in electron-deficient N-heteroarene is introduced. In chapter II, we report base-promoted transition-metal-free regioselective alkylation of pyridine N-oxide using 1,1-diborylalkane as an alkylating reagents. The reaction showed the new usefulness of using α-borylcarbanion nucleophile. The synthetic utility of the developed method is demonstrated by the sequential C-H arylation and methylation of pyridine N-oxides. The reaction also can be applied for thedirect introduction of amethyl group to 9-O-methylquinine N-oxide, thus it can serve as apowerful method for late-stagefunctionalization. In chapter III, we report a direct C2- or C4-selective primary and secondary alkylation of pyridines and quinolines using 1,1-diborylalkanes and dimethylzinc. While substituted pyridines and quinolines exclusively afford C2-alkylated products, simple pyridine delivers C4-alkylated pyridine with excellent regioselectivity. The reaction scope is remarkably broad, and a range of C2- or C4-alkylated electron-deficient N-heteroarenes are obtained in good yields. Experimental and computational mechanistic studies implicate that ZnMe2 serves not only as an activator of 1,1-diborylalkanes to generate (α-borylalkyl)methylalkoxy zincate, which acts as a Lewis acid to bind to the nitrogen atom of the heterocycles, controls the regioselectivity and also as an oxidant for rearomatizing the dihydro-N-heteroarene intermediates to release the product.