Alkyl methanesulfonates

Cleavage of the sulfonyl esters to the parent alcohols is accomplished in yields of 60-100% by treatment of the p-toluenesulfonates with 2-6 equivalents of sodium naphthalene in tetrahydrofuran at room temperature (yields 60-100%). Sodium naphthalene is prepared by stirring sodium with an equivalent amount or a slight excess of naphthalene in tetrahydrofuran for 1 hour at room temperature under an inert gas [701]. Benzenesulfonates and bromo-benzenesulfonates are also cleaved to the parent alcohols while alkyl methanesulfonates are reduced also to hydrocarbons [701]. 

A mixture of a solution of 0.300 g of an alkyl methanesulfonate or p-toluenesulfonate in 3-6 ml of 1,2-dimethoxyethane, 0.300 g of sodium iodide, 0.300 g of zinc dust, and 0.3 ml of water is stirred and refluxed for 4-5 hours. After dilution with ether the mixture is filtered the solution is washed with water, with 5% aqueous hydrochloric acid, with 5% aqueous solution of potassium hydrogen carbonate, with 5% aqueous solution of sodium thiosulfate and with water. After drying with anhydrous sodium sulfate the solution is evaporated and the residue worked up, giving 26-84% yield of alkane. 

Substituted 3,6-dialkoxy-2,5-dihydropyrazines are regioselectively metalated by strong alkyl-lithium bases, such as butyllithium, (l-methylpropyl)lithium, fcrf-butyllithium, or lithium diiso-propylamide, at the less substituted carbon atom (C5). Metalation proceeds at low temperatures (in general, below — 70 C) in THF as solvent. Electrophiles suitable for alkylation of the lithiated derivatives include alkyl iodides, bromides and chlorides, as well as alkyl methanesulfonates, 4-methylbenzenesulfonates and trifluoromethanesulfonates. The electrophile adds trans to the substituent at C2 in a highly stereoselective fashion, with typical diastereomeric excesses of greater than 90% (syn addition has been reported in only one case where a-methylphenyl alanine was used as chiral auxiliary and an alkyl trifluoromethanesulfonate as electrophile18). 

Alkylation of phthalimide anion can be carried out under solid-liquid phase-transfer conditions, using phosphonium salts or ammonium salts. In the reaction systems using hexadecyltributylphosphonium bromide, alkyl bromides and alkyl methanesulfonate are more reactive than alkyl chlorides. Octyl iodide is less reactive than the corresponding bromide and chloride. ( )-2-Octyl methanesulfonate was converted into (S)-2-octylamine with 92.5% inversion. Kinetic resolution of racemic ethyl 2-bromopro-pionate by the use of a chiral quaternary ammonium salt catalyst has been reported. Under liquid-liquid phase-transfer conditions, A -alkylation of phthalimide has been reported to give poor results. ... 

In contrast to the anion of diethyl phosphoramidate or trifluoromethanesulfonamide, which cannot be cleanly monoalkylated, - the anion of trifluoroacetamide (100) was monoalkylated by alkyl halides or alkyl methanesulfonate. The resulting A -alkylamides (101) were converted into primary amines by alkaline hydrolysis or reduction (NuBHa Scheme 42). Various primary amines were prepared from (100) with primary alkyl iodides or methanesulfonate, benzyl and allyl halides, a-bromocarbonyl compounds and 2,4-dinitrochlorobenzene. However, competitive elimination is a serious side reaction for less reactive primary alkyl chlorides and secondary halides or methanesulfonate. The synthesis of secondary amines from (100) has also been reported. ... 

Roos and his co-workers687 have described a general method of preparing simple alkyl toluenesulfonates. Pyridine has been used as acid-binding agent in the preparation of alkyl methanesulfonates,688 yields averaging 80%. 

A MECHANISM FOR THE REACTION ] Conversion of an Alcohol into a Mesylate (an Alkyl Methanesulfonate) 516... 

Zinc chloride is a Lewis acid catalyst that promotes cellulose esterification. However, because of the large quantities required, this type of catalyst would be uneconomical for commercial use. Other compounds such as titanium alkoxides, eg, tetrabutoxytitanium (80), sulfate salts containing cadmium, aluminum, and ammonium ions (81), sulfamic acid, and ammonium sulfate (82) have been reported as catalysts for cellulose acetate production. In general, they require reaction temperatures above 50°C for complete esterification. Relatively small amounts (<0.5%) of sulfuric acid combined with phosphoric acid (83), sulfonic acids, eg, methanesulfonic, or alkyl phosphites (84) have been reported as good acetylation catalysts, especially at reaction temperatures above 90°C. 

In laboratory preparations, sulfuric acid and hydrochloric acid have classically been used as esterification catalysts. However, formation of alkyl chlorides or dehydration, isomerization, or polymerization side reactions may result. Sulfonic acids, such as benzenesulfonic acid, toluenesulfonic acid, or methanesulfonic acid, are widely used in plant operations because of their less corrosive nature. Phosphoric acid is sometimes employed, but it leads to rather slow reactions. Soluble or supported metal salts minimize side reactions but usually require higher temperatures than strong acids. 

Reactions of ar>l or alkyl bis(siloxy)isopropyl ethers with tetrabutyl-ammoninm fluoride-mesyl fluoride reagent lead to replacement of one siloxy group by fluorine and dehydrosiloxylation, providing an efficient access to fluoroisopropenyl ethers, which are useful as specific building blocks in drug design The reactions proceed via the intermediate allyl methanesulfonates [30, 31] (equation 23)... 

In contrast to phosphorus esters, sulfur esters are usually cleaved at the carbon-oxygen bond with carbon-fluorine bond formation Cleavage of esteri nf methanesulfonic acid, p-toluenesidfonic acid, and especially trifluoromethane-sulfonic acid (tnflic acid) by fluoride ion is the most widely used method for the conversion of hydroxy compounds to fluoro derivatives Potassium fluoride, triethylamine trihydrofluoride, and tetrabutylammonium fluoride are common sources of the fluoride ion For the cleavage of a variety of alkyl mesylates and tosylates with potassium fluoride, polyethylene glycol 400 is a solvent of choice, the yields are limited by solvolysis of the leaving group by the solvent, but this phenomenon is controlled by bulky substituents, either in the sulfonic acid part or in the alcohol part of the ester [42] (equation 29)... 

British investigators (Haddow and Timmis 1951) synthesized and studied esters of the methanesulfonic acid. The most active derivative was the dimethylsulfonic ester of 1,4-butanedione, known as busulfan. Busulfan interacts with the thiol groups of proteins and amino acids some of its metabolites can alkylate the thiols of cysteine, peptides and proteins. Busulfan exerts selective cytotoxic activity in hematopoietic bone marrow cells and inhibits the formation of granulocytes and platelets. It slightly affects the lymphoid tissue. 

Methanesulfonic acid is too powerful a catalyst for (9-alkylation with the vinyl ether, causing explosive polymerisation of the latter on multimolar scale. Dichloroacetic acid is a satisfactory catalyst on the 3 g mol scale. 

Interestingly, treatment of diene 215a with methanesulfonic acid afforded 216 as a single diastereomer in 88% yield, the structure of which was confirmed by X-ray analysis (Scheme 60). The transformation of 216 into 217 started with an alkylation, followed by reductive desulfurization and triazene formation to afford compound 217 in 92% yield. Upon treatment with diiodomethane, triazene 217 was smoothly converted to aryl iodide 218 in 75% yield. Pd-catalyzed intramolecular Heck coupling of 218 led to the desired product 219b in 62% yield. 

Workers at Merck recently reported three variants for pyridine formation in conjunction with the synthesis of COX-2-Specific inhibitor 8 (Scheme 1). Acid catalyzed annulation (path a) was achieved in 72% with 2 equivalents of methanesulfonic acid and four equivalents of 2-chloro-3-aminoacrolein. Base-promoted annulation between 7 and 2,3-dichloroacrolein provided 8 in 58% yield. Finally, base-promoted annulation with 2-chloro-iV,jV-dimethyl-armnotrimethinium hexafluorophosphate afforded 8 in 97% yield . Other alkylation-based strategies for pyridine formation include the work of Manna <00BMC1883> and Parra <00S273>. 

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