Methyl fluorosulfonate

For both azole and benzazole rings the introduction of further heteroatoms into the ring affects the ease of quaternization. In series with the same number and orientation of heteroatoms, rate constants increase in the order X = 0requires stronger reagents and conditions methyl fluorosulfonate is sometimes used (78AHC(22)71). The 1-or 2-substituted 1,2,3-triazoles are difficult to alkylate, but methyl fluorosulfonate succeeds (7IACS2087). 

The first use of chiral oxazolines as activating groups for nucleophilic additions to arenes was described by Meyers in 1984. " Reaction of naphthyloxazoline 3 with phenyllithium followed by alkylation of the resulting anion with iodomethane afforded dihydronaphthalene 10 in 99% yield as an 83 17 mixture of separable diastereomers. Reductive cleavage of 10 by sequential treatment with methyl fluorosulfonate, NaBKi, and aqueous oxalic acid afforded the corresponding enantiopure aldehyde 11 in 88% yield. 

Cleavage of the chiral auxiliary is effected in a three-step procedure commencing with quatemization of the nitrogen with methyl fluorosulfonate, methyl trlfluoromethanesulfonate, or trimethyloxonium tetrafluoroborate. Reduction of the corresponding iminium salt 19 with NaBH4 and acidic hydrolysis of the resulting product affords substituted aldehyde 5 without epimerization of either stereocenter. 

The ketones 1 and 3, or compounds with a similar structure, have been used for the preparation of methoxy derivatives of 1-benzoxepin. In the standard procedure for methylation, the 1-benzoxepinone is deprotonated by potassium tert-butoxide and subsequently reacted with methyl fluorosulfonate at low temperature.16 173 - 175 The yields are generally high. 

The different reactivity of the ketone functions has also been demonstrated by the reaction of 2,7-dimethyl-4-phenyl-l-benzoxepin-3,5(2f/,4//)-dione with diazomethane which gives a mixture of the two monomelhylated products 10 and 11. In both compounds, the second methyl group is introduced by deprotonation with potassium tm-butoxide followed by the addition of methyl fluorosulfonate.177... 

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

Amino-3,5-dimethylisoxazole (372, R = H) gave an iV-tosyl derivative (372, R = tosyl), which by treatment with methyl fluorosulfonate followed by perchloric acid gave the salt 371, R = R = R = Me, R = tosyl, X = C104. Attempts to isolate the meso-ionic sul-fonamidate (370, R = R = R = Me, R = tosyl) by treatment of the salt with potassium hydroxide or triethylamine were unsuccessful, but spectroscopic evidence for its formation in solution has been offered. 

The reaction of 3-hydroxymethyIpyridine 1-oxide with methyl fluorosulfonate and potassium cyanide provides a direct method for 2,6-dicyanation (75JOC2092). However, the generality of this method is limited by the need for a 3-substituent that can form an anhydrobase. In this example (Scheme 138) the anhydrobase is formed by methylation of the 3-hydroxymethyl group followed by elimination either during or subsequent to attack by the second mole of cyanide. The use of such a powerful methylating agent overcomes... 

Cyclization of the diazonium salt (442) followed by treatment with base and then with acid gave (443 R1 = C02H) which was decarboxylated to give (443 R1 = H) (77MI51803). These products show typical phenylhydrazone unreactivity to alkylation at N-l but treatment of (443 R1 = H, R = Me) with methyl fluorosulfonate gave a relatively stable quaternary salt via methylation at N-2 this isomerized in acid to give l-imino-3-methylquinazolin-4-one (444) (79JHC1411). 

Both reagents are powerful methylating agents, reacting with O, N, and S. Read precautions carefully. The Methyl fluorosulfonate (Magic Methyl) is no longer commercially avai lable. Methyl triflate is extremely (sometimes violently) reactive towards amines. Except for extremely hindered or unactivated amines, not generally required for the task. 

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... 

Naphthyridines (see Sections II and V,D). Diquaternary salts of 1,5-25,165 ( 57), 1,6-,25 1,7-,25 1,8-25 ( 8), and 2,7-25 naphthyridines have been prepared by the action of methyl sulfate165 or methyl fluorosulfonate.25l,8-Naphthyridine does not react with methyl sulfate to give a diquaternary salt but does so with 1,2-dibromoethane to give 58,166 an interesting observation. 

Triazoles (see Section II). 1-Substituted 1,2,3-triazoles (64) readily undergo quaternization at N-3.171,172 Quantitative data are not available, but the fact that methyl fluorosulfonate is required to quaternize isomeric structures 65 suggests that they are much less reactive than 64.173 Since the two isomers show large differences in basicity,174 it seems likely that the large separation in reactivity is not primarily due to... 

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). 

An extensive study on the use of benzothiazoles as carbonyl equivalents has been conducted (78TL5, 9). The 2-lithiobenzothiazole (576) readily adds to carbonyl compounds to furnish on dehydration of the carbinol a vinylbenzothiazole (578). The benzothiazole nucleus can then be unmasked by a sequence of reactions involving (a) Af-methylation with methyl fluorosulfonate, (b) addition of either hydride (NaBKU) or an organometallic (MeLi) to afford the iV-methylbenzothiazoline and (c) hydrolysis of the crude Af-methylbenzothiazo-line (e.g. AgN03). A representative example is shown in Scheme 126. 

The hydroxyl group of ethyl 2-hydroxy-4-oxo-4//-pyrimido[2,l-a]-isoquinoline-3-carboxylate (20) was methylated with methyl iodide in dry boiling acetone for 5 h in the presence of potassium carbonate, with dimethyl sulfate in methylene chloride in methanol in the presence of Triton B at 20°C for 18 h, with methyl fluorosulfonate in 2.5 M sodium hydroxide at 20°C for 5 h, and with diazomethane in a mixture of diethyl ether and methylene chloride at 20°C for 3 h to give the 2-methoxy derivative (89AJC2161). The hydroxy group of 3-hydroxymethyl-4//-pyrimido[2,l-b]-isoquinolin-4-one was alkylated and acylated with 2-(diethylamino)ethyl chloride in dimethylformamide in the presence of sodium hydroxide, and with acetic anhydride in boiling chloroform in the presence of triethylamine and a few drops of 4-dimethylaminopyridine, respectively (86EUP 166439). 

Treatment with mercuric chloride or methyl fluorosulfonate before the oxidation step initiated the migration of a second alkyl group from boron to carbon, and a synthesis of tertiary alcohols was thus at hand [284]. 

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