Dudley Benzylation Reagent

Aldrich ChemFiles 2007, 7.3, 3.

 Benzyl ethers and derivatives are among the most widely used protecting groups in organic synthesis. Cleavage can be effected under a variety of conditions including hydrogenolysis, oxidation, and acid decomposition. Typically, protection of alcohols in the form of a benzyl ether requires harsh reaction conditions. Williamson ether synthesis necessitates strongly basic conditions to generate an alkoxide nucleophile (Figure 1). Alternatively, trichloroacetimidate reagents can be employed in the presence of triflic acid (HOTf) as a promoter. Many complex alcohols are incompatible with these strongly basic or acidic conditions. For example, b-hydroxy esters are prone to elimination, epimerization at the a-carbon, or retro-aldol reactions under acid or base catalysis. Additionally, resident protecting groups on the alcohol substrate may be incompatible with non-pH-neutral reactions. Under acidic conditions, trimethylsilyl (TMS) ethers are easily cleaved, while acetals can undergo migration in polyol systems. Bulkier silyl protecting groups can undergo migration in the presence of base.

Figure 1

Professor Gregory Dudley and co-workers at Florida State University have developed a pre-activated pyridinium salt for the mild benzylation of alcohols under neutral conditions.1 The salt is bench-stable, can be handled in air (Figure 2), and simple reaction conditions are employed. Simply heating the alcohol in the presence of the salt provides the desired benzyl ether. Heterogeneous MgO serves to neutralize the mildly acidic hydroxypyridine generated during the protection reaction. The resultant pyridinone byproduct is water soluble, and thus, easily removed (Scheme 1).

Figure 2

Scheme 1

As shown in Table 1, a variety of primary, secondary, and tertiary alcohols underwent clean and high-yielding benzylation. 1,2- Dichloroethane (DCE), benzene, toluene, and benzotrifluoride (BTF) are viable solvents for the reaction. BTF is a low-cost, moderately volatile solvent that is an environmentally friendly alternative to chlorinated solvents. Notably, the labile stereogenic center of optically pure methyl 3-hydroxy-2-methylpropionate survived the reaction conditions unaltered (entry 6). Trimethylsilylethanol (entry 7) is subject to Peterson elimination under acidic or basic conditions, and its benzyl ether had not been reported previously. Attempts to generate the benzyl ether derivative with benzyl trichloroacetimidate did not provide any of the desired product. However, use of the pyridinium reagent cleanly provided the alcohol in 100% conversion.

Table 1

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  1. (a) Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923. (b) Poon, K. W. C. et al. Synlett 2005, 3142.

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