sp3 C–H alkylation of fluorenes catalyzed by o-phenylene-bridged noninnocent bis-azopyridyl complexes of copper

Abstract

Herein, employing bio-inspired phenylene-bridged redox noninnocent bis-azopyridyl copper complexes, namely, [1]: [(L)CuCl₂] and [2]: [(L)CuCl], an efficient sp³ C–H alkylation of fluorenes using alcohols as alkylating agents is reported, yielding alkylated fluorenes. Complex [2] was a better catalyst than complex [1]. The catalytic protocol employing [2] was very efficient and versatile across various fluorenes and benzyl alcohols. It also showed very good functional-group tolerance for both alcohols and fluorenes under lower base loadings and lower reaction temperatures. The protocol was also very effective in the synthesis of various fluorene-derived drug analogues of benflumetol. Mechanistic investigations by various spectroscopic techniques, control experiments, deuterium labelling studies, ¹H NMR kinetic analyses and DFT calculations revealed that a ligand radical–containing Cu(I) complex acted as the catalyst over the course of the reaction. Thus, complex [2] in the presence of KO^tBu generated K⁺[(L)˙⁻Cu^I(OCH₂Ph)]˙⁻ (A) as the active catalyst, in which the two redox noninnocent azopyridine moieties of the ligand participated in alcohol dehydrogenation, leading to the formation of the intermediate catalyst K⁺[(HL)²˙⁻Cu^I(OCHPh)]˙⁻ (B). Subsequently, upon the reaction of B with the deprotonated fluorene, the electronically rich new intermediate D was formed, which facilitated the hydrogenation of the alkenylated fluorenes to yield alkylated fluorenes at comparatively lower temperatures.