Dimethyl sulfate aprotic, polar

With proof-of-concept on the direct methylation in hand, the optimization of the methylation with respect to regioselectivity, yield and isolation conditions was initiated to eliminate the use of 1,4-dioxane and LiH (Table 6.3). Under similar reagent/base conditions (Me2S04, LiOt-Bu), better selectivity was observed in nonpolar solvents (entries 2 and 3) than in polar (entry 1) and aprotic solvents (entries 4 and 5). Mel was a better methylation reagent than dimethyl sulfate under otherwise the same reaction conditions (entries 5 and 7). 

Ternary and secondary alcohols are less acidic than primary alcohols. Methylation of HOCCfCH OH with Me2S04 and alkali hydroxide in aqueous medium, analogous to die procedure for HG=CCH20CH3 (exp. 2.1), is therefore expected to give a poor result. In the aprotic DMSO, however, the concentration of the alkoxide HC=CC(CH3>20K will be sufficient, while the alkylation will proceed smoothly in this strongly polar solvent. Undoubtedly, pan of the dimethyl sulfate will react with KOH to give methanol (which may further react to dimethyl ether). Therefore, an excess of Me2S04 and KOH is used. 

Hydroxybenzo[6]thiophenes exist as oxo tautomers and are referred to as thiooxindoles. O- Alkylation of thiooxindole is favoured in polar aprotic solvents thus NaH/HMPT/Me2S04 gives a 90% yield of 2-methoxybenzo[6]thiophene. Treatment of thiooxindole with two equivalents of NaOH and dimethyl sulfate, or... 

The O-alkylation of carboxylates is a useful alternative to the acid-catalyzed esterification of carboxylic acids with alcohols. Carboxylates are weak, hard nucleophiles which are alkylated quickly by carbocations and by highly reactive, carbocation-like electrophiles (e.g. trityl or some benzhydryl halides). Suitable procedures include treatment of carboxylic acids with alcohols under the conditions of the Mitsunobu reaction [122], or with diazoalkanes. With soft electrophiles, such as alkyl iodides, alkylation of carboxylic acid salts proceeds more slowly, but in polar aprotic solvents, such as DMF, or with non-coordinating cations acceptable rates can still be achieved. Alkylating agents with a high tendency to O-alkylate carboxylates include a-halo ketones [42], dimethyl sulfate [100,123], and benzyl halides (Scheme 6.31). 

After selective generation of the syn- or anH -enolate of an amide, it is usually reacted with a haloalkane, often the iodide. Allylic and benzylic bromides also react satisfactorily, and dimethyl and diethyl sulfate have also been used in some cases. A solution of the alkylating agent in an ethereal solvent, usually tetrahydrofuran, is added to the enolate, usually at low temperature. A polar, aprotic cosolvent, such as hexamethylphosphoric triamide, is frequently used as an additive in the alkylation step. The use of this suspected carcinogen is prohibited in some countries, which limits the usefulness of many of the reactions described below. However, similarly effective in many cases are some ureas, such as the commercially available 1,3-dimethyl-3,4,5,6-tetrahydro-2(l//)-pyrimidinone (DMPU)12. 

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