Methanesulfonyl Chloride

MeSO2Cl

[124-63-0]  · CH3ClO2S  · Methanesulfonyl Chloride  · (MW 114.56)

(synthesis of methanesulfonates;1 generation of sulfene)

Alternate Name: mesyl chloride.

Physical Data: bp 60 °C/21 mmHg; d 1.480 g cm-3.

Solubility: insol water; sol alcohol, ether.

Form Supplied in: liquid of 98% or 99+% purity.

Handling, Storage, and Precautions: highly toxic; corrosive; lachrymator; moisture sensitive; store in a cool dry place.

Methanesulfonates.

The most common use of methanesulfonyl chloride is for the synthesis of sulfonate esters from alcohols. This can be readily accomplished by treatment of an alcohol with mesyl chloride in the presence of a base (usually Triethylamine or Pyridine).1 The methanesulfonates formed are functional equivalents of halides. As such they are frequently employed as intermediates for reactions such as displacements, eliminations, reductions,2 and rearrangements.3 Selective mesylation of a vicinal diol is a common method of preparation of epoxides.4 Alkynyl mesylates can be used for the synthesis of trimethylsilyl allenes.5 Oxime mesylates undergo a Beckmann rearrangement upon treatment with a Lewis acid.6 Aromatic mesylates have been used as substrates for nucleophilic aromatic substitution.7 Mesylates are more reactive than tosylates toward nucleophilic substitution, but less reactive toward solvolysis.

Protection of Alcohols.

In addition to being used as a halide equivalent, methanesulfonates have also been used as protecting groups for alcohols and phenols. The use of methanesulfonate as a protecting group for alcohols is mainly limited to carbohydrate synthesis due to the lability of the methanesulfonate group toward nucleophilic attack. The sulfonate ester is stable to acidic conditions and can be cleaved by Sodium Amalgam.8

Protection of Amines.

Amines also react with mesyl chloride to form the corresponding sulfonamide. The sulfonamide group is one of the most stable nitrogen-protecting groups, with good stability to both acidic and basic conditions. The sulfonamide can be cleaved back to the amine by Lithium Aluminum Hydride or dissolving metal reductions.9 In addition to treatment of amines with mesyl chloride, other reports for the preparation of sulfonamides include a Reissert-type reaction of mesyl chloride with phthalazine10 and addition of mesyl chloride to lactim ethers (eq 1).11

Chlorination.

Methanesulfonyl chloride can effect the direct chlorination of various substrates. The most notable of these reactions is the selective chlorination of the C-6 primary hydroxy group of carbohydrates (eq 2).12 Under these conditions, 2-furyl alcohol (eq 3)13 and guanine N-oxide (eq 4)14 can also be chlorinated directly.

Meyers developed a procedure for the direct conversion of allylic alcohols to allylic chlorides that is general for a variety of terpenes (eq 5).15 Primary alcohols give yields in the 85% range. A single example of a secondary alcohol produced the chloride in 50% yield. Certain allylic alcohols also undergo stereospecific chlorination under the conditions normally employed for mesylate formation (eq 6).16

Under Lewis acid catalysis, mesyl chloride reacts with unactivated benzenes to produce the aromatic chloride and only trace amounts of the corresponding sulfone (eq 7).17 Mesylates have also been used as intermediates for the transformation of alcohols into halides.

Interconversion of Carboxylic Acid Derivatives.

Methanesulfonyl chloride is employed in the activation of carboxylic acids for the preparation of anhydrides (eq 8),18 nitriles (eq 9),19 amides (eq 10), and esters (eq 11).20

Eliminations.

Alkene formation by elimination can also be achieved with mesyl chloride. This is general for a variety of substrates. Peterson reported the elimination of b-hydroxy silanes to give predominantly trans-alkenes upon treatment with mesyl chloride (eq 12).21 In a similar manner, b-hydroxy phenylselenates can also be eliminated (eq 13).22

Corey reported a mild elimination of iodohydrins by activation with mesyl chloride (eq 14).23 The major advantage of this method over traditional methods is that the use of a strong reducing agent (Zinc or Tin(II) Chloride) is avoided.

The direct elimination of tertiary alcohols by treatment with mesyl chloride has also been reported.24 A variety of acid sensitive functional groups including silyl ethers and acetals are stable to these reaction conditions (eq 15). Mixtures of cis and trans and internal and terminal alkenes are formed in all cases where possible (eq 16).

The synthesis of a-methylene lactones25 and ketones26 via the elimination of a mesylate has also been reported (eqs 17 and 18). In these cases, the pyridine or triethylamine is sufficiently basic to induce elimination under standard mesylate forming conditions.

Heterocycles.

Sulfene, generated by the treatment of methanesulfonyl chloride with base, undergoes [2 + 2], [3 + 2], and [4 + 2] cycloadditions to produce four-, five-, and six-membered heterocycles, respectively. Alkynyl amines27 and enamines28 both undergo [2 + 2] cycloadditions with sulfene to produce four-membered cyclic sulfones (eqs 19 and 20).

Five-membered sultones can be formed by reaction of a-hydroxy ketones with sulfene (eq 21).29 Sulfene adds in a [4 + 2] manner across azadienes (eq 22)30 and enones (eq 23).31

Addition Across Alkenes and Alkynes.

In the presence of a catalyst (usually Copper or ruthenium), methanesulfonyl chloride adds across alkenes and alkynes to produce b-chloro sulfones.32 The stereochemistry of the product of addition across phenylacetylene depends on the reaction conditions used. In the absence of an added hydrochloride salt, the cis addition product predominates (eq 24), whereas the trans product is favored when the salt is added (eq 25).

TMS-substituted alkenes and alkynes are especially useful in these reactions (eqs 26 and 27).33 Using this methodology, allylic sulfones can be prepared (eq 28). Kamigata reported only minor success in inducing chirality into this reaction by the use of optically active ruthenium catalysts (eq 29).34

Synthesis of Vinyl and Allyl Sulfones.

In addition to the methods presented above, vinyl and allyl sulfones have been prepared by the palladium-catalyzed cross coupling of vinyl- and allylstannanes with sulfonyl chlorides (eq 30).35

Acyliminium Cyclizations.

Formation of acyliminium ions by treatment of a-hydroxy amides with methanesulfonyl chloride is a mild way of effecting acyliminium ion cyclizations. Under these conditions, allylstannanes (eq 31)36 and cyclic vinyl sulfides (eq 32)37 undergo addition to the iminium ion generated. The allylstannane cyclizes with a high degree of endo selectivity.

Lactone Inversion.

Lansbury demonstrated the use of mesyl chloride for lactone inversion in his synthesis of aromatin (eq 33).38 This method is superior to the classical methods since the problems of racemization and relactonization are overcome.

Rearrangement of Thioacetals to Aldehydes.

Sato et al. reported the rearrangement of a-hydroxy thioacetals to a-sulfenyl aldehydes (eq 34).39 The thioacetals are prepared by the addition of the anion of methoxy(phenylthio)methane to aldehydes and ketones. This reaction is general for alkyl, allyl, and aromatic carbonyl compounds.

Related Reagents.

Methanesulfonyl Chloride-Dimethylaminopyridine.


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Valerie Vaillancourt & Michele M. Cudahy

The Upjohn Co., Kalamazoo, MI, USA



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