Alkylating agents methyl fluorosulfonates

Benzothiepins react with strong alkylating agents, such as methyl fluorosulfonate (caution toxic), to give the corresponding 1-benzothiepinium salts 2.88... 

By changing the reactivity of the alkylating agent, it is possible to vary the magnitude of an ortho steric effect. Thus, the reactivity of 2-substituted pyridines toward Mel in acetone is linearly related on a logarithmic scale to the reactivity of the same substrates toward methyl fluorosulfonate in benzene. The fluorosulfonate is about 104 times more reactive than the iodide, and so the transition state for quaternization occurs earlier. The earlier transition state gives rise to a smaller steric effect the slope of the plot demonstrating the dependence of the steric effect on reactivity is 0.69.76... 

A7-Acyl derivatives of heterocycles can often be quatemized by hard alkylating agents, such as trialkyloxonium fluoroborates406 or methyl fluorosulfonate.364 The quaternary salt is not usually isolated, but N-alkylated derivatives are obtained whose structures are generally different from those obtained by alkylation of anions (Sections IV,C,2). This method, due to Olofson and Kendall,406 has been used with success in azapentalenes [Eqs. (34) and (35)1, where the products 384 and 385 are different from those obtained by alkylation of the anions 361 and 364, respectively (Scheme 16). 

The quaternization of 1-substituted imidazoles is usually easy unless steric factors intervene, or strongly electron-attracting groups are present, for example, 1-acylimidazoles can only be alkylated at N(3) with powerful alkylating agents such as methyl fluorosulfonate or trialkyloxonium fluoroborates. Trimethyloxonium fluoroborate does not methylate 1-dimethylaminosulfonylimidazole. Regiospecific synthesis of 3-substituted L-histidines can be achieved by alkylation of Ar-/-butoxycarbonyl-l-phenacyl-L-histidinc methyl ester at N(3), followed by reductive removal of the phenacyl group (Scheme 15). 

Alkylation. Methyl fluorosulfonate is a convenient and powerful alkylating agent. It alkylates amines, amides, nitriles, and ethers. 

A mixture of fluorosulfonic acid and dimethyl sulfate distilled in glass -> methyl fluorosulfonate. Y > 80%. - Fluorosulfonic acid esters are excellent alkylating agents. F. e. and listing of good alkylating agents s. M. G. Ahmed et al., Chem. Commun. 1968, 1533. 

Note Alkyl fluorosulfonates are extremely powerful alkylating agents. Their high reactivity may therefore result in non-specific alkylation. Among the possible side reactions, alkylation of aromatic substances and O-alkylation by ether cleavage may be cited [74]. However, methylation of a partially acetylated substrate was reported [75] to have occurred in excellent yield without migration of the acetyl groups. Numerous data for this type of alkylation are available in the literature [74 -84]. 

In addition to diazomethane and trialkyloxonium salts, methyl fluorosulfonate, Me0S02F, may be used as an alkylating agent. Similarly, instead of LiR, many other nucleophilic lithium compounds may be utilized. 

In spite of their great thermodynamic stability, carbene anions are reactive toward a variety of carbon electrophiles. Allylic and benzylic halides react with carbene anions at 0° to give alkylated carbene complexes (W. R. Bruns-void and C. P. Casey, unpublished results, 1975). Methyl fluorosulfonate acts as an efficient methylating agent of carbene anions (Casey ei al., 1972). 

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