Practical generation of 3,5‐dimethoxybenzyllithium: application to the synthesis of 5‐substituted‐resorcinols

Abstract

Reductive lithiation of 3,5-dimethoxybenzyl methyl ether was successfully performed with lithium wire and a catalytic amount of naphthalene in dry tetrahydrofuran at −15 • C, leading to the quantitative generation of 3,5-dimethoxybenzyllithium. This organometallic compound, which can be stored for at least 24 h, was trapped with a variety of different electrophiles, including, besides aldehydes, non-functionalized and functionalized alkyl halides and an epoxide. Accordingly, it is a useful intermediate in the synthesis of 5-substituted natural and non-natural resorcinols.

Benzylic Organometals via Reductive Metalation Procedures

“…Practical applications of these findings include the development of synthetic procedures allowing the one-pot transformation of arylmethyl methyl ethers (31, R = H) into 2-arylpropanoic acids (34) (Scheme 13) [37b], as well as a new synthetic approach to the synthesis of the dimethyl ethers 5-substituted resorcinols (37-39), via a practical generation of 3,5-dimethoxybenzylithium (36) (Scheme 14) [41].…”

Functionalized organolithium compounds in total synthesis

“…149 In addition, this reductive lithiation has recently been applied to 3,5-dimethoxybenzyl methyl ether, also for the synthesis of some natural resorcinols. 150 Another example of the use of these types of organolithium reagents is the dibenzyllithium compound 352, which has been employed in the total synthesis of the secolignan (G)-peperomin. 151 …”

Reductive lithiation of alkoxy-substituted benzyl methyl ethers and connection with cross-coupling reactions

“…1 -5 Interestingly, the presence of strong electron donor substituents on the aromatic ring does not affect the efficiency of this procedure. 1,4 Indeed, this reaction shows unique features in the generation of stable solutions of methoxy-substituted benzyllithium derivatives both in terms of regioselectivity and mildness of reaction conditions. 6 -8 With the aim to expand the synthetic utility of this reaction, and following our interest in the development of highly regioselective strategies for the synthesis of polysubstituted aromatic compounds, we developed a synthetic protocol leading to the synthesis of dicarbo-substituted benzenes by a reaction sequence connecting our reductive lithiation procedure to well known and versatile reactions, i.e.…”