Metal and Non-Metal Catalyzed Beta-Alkylation of Secondary Alcohols: Scope and Mechanism

Abstract

Hydrogen Borrowing has emerged as an advantageous synthetic methodology due to its green chemistry nature. The concept of in–situ temporary alcohol oxidation followed by functionalization and reduction has been utilized to yield various functional groups with great success. Implementation of this methodology for making secondary alcohols is a relatively new development in that field. In this work a commercially available catalyst, RuCl2(PPh3)3, was used as catalyst and a protocol was developed for β-alkylation of secondary alcohols with primary alcohols via hydrogen borrowing. The system was optimized for aromatic substrates with electron donating and withdrawing groups on both the primary and secondary alcohol under aerobic conditions garnering yields ranging from 66–100%. The same catalyst was used for aliphatic primary alcohols and secondary aromatic alcohols giving yields from 75–100%. The catalyst gave low yields when heterocyclic aromatic substrates or aliphatic secondary alcohols were used.

A second system was developed for the same transformation catalyzed by potassium tert- butoxide under aerobic conditions and without use of a transition metal. This protocol was limited to aromatic primary and secondary alcohols but gave high yields for substrates bearing electron donating or withdrawing groups on either alcohol. The yields were comparable to the ruthenium catalyzed system with RuCl2(PPh3)3, ranging from 66–100%. A mechanistic investigation revealed that the catalysis is initiated by oxygen and the enone intermediate produces catalytic turnover by acting as the hydrogen carrier. Transfer hydrogenation between the enone and the deprotonated alcohols is mediated by the potassium in a direct hydrogen transfer.

The third system utilized for this transformation introduced a newly designed ruthenium catalyst, [Ru(terpy)(en)Cl][BPh4]. Two synthetic routes for making this catalyst were developed starting from Ru(terpy)Cl3 with a reducing agent, either triethylamine or zinc, in the presence of the ethylenediamine ligand to give relatively good yields ~50%. The catalyst was tested for hydrogen borrowing with both aromatic and aliphatic alcohols. The new catalyst emerged as an exceptional catalyst for aliphatic substrates for either primary or secondary aliphatic alcohols providing higher than previously reported yields of 62–100%.

The combination of these three protocols widens the scope of this reaction enhancing the synthetic value of this methodology and approach to synthesis of secondary alcohols.