Trimethyl Orthoformate as a Highly Selective Mono-C-Methylating Agent for Arylacetonitriles

Abstract

The mono-C-methylation of arylacetonitriles (ArCH2CN, 1) to produce 2-arylproprionitriles [ArCH(CH3)CN, 2] represents a valuable reaction especially from a pharmaceutical standpoint. In fact, a number of compounds 2 are key intermediates for the synthesis of nonsteroidal analgesics of the hydratropic acid (2-arylpropanoic acid) class.1 Common well-known examples are Ibuprofen, Ketoprofen, and Naproxen (Chart 1). However, synthetic procedures for the direct monomethylation of 1 fail with classical alkylating agents (methyl halides and dimethyl sulfate) because mixtures of monoand dimethylated products are always obtained (Scheme 1).2 For instance, the alkylation of phenylacetonitrile with CH3I is reported with a monoto dimethyl selectivity of 84%, at a conversion of 86%.3 Although a number of multistep alkylation methods have been developed for the preparation of 2-arylpropanoic acids,1 the achievement of an effective one-pot procedure still represents a challenging task and may deserve attention from both the economical standpoint and the synthetic feasibility. Concerning this, a very efficient procedure is the ruthenium-catalyzed reductive methylation of active methylene compounds carried out at 135-230 °C with paraformaldehyde.4 However, we extensively reported that direct highly selective mono-C-methylations of CH2acidic compounds (YCH2X) can also be performed by the use of dimethyl carbonate (DMC) as a methylating agent, without any metal catalyst.5-11 Thus, at 180-210 °C in the presence of weak bases (K2CO3), aryland aroxyacetonitriles, methyl aryland aroxyacetates (Y ) Ar, ArO; X ) CN, CO2CH3), and R-methylene sulfones (Y ) Ar, X ) SO2Ar, SO2R) yield the corresponding mono-Cmethyl derivatives with selectivities >99% at a complete substrate conversion. In addition, the procedure is a true environmentally benign one: DMC is a nontoxic reagent, the base can be used catalytically, and neither organic nor inorganic byproducts are formed and need to be disposed of.12,13