Sulfonate ester, formation from sulfonyl

Problem 13.16 How does sulfonate ester formation from sulfonyl chloride resemble nucleophilic displacements of alkyl halides ... 

Sulfonate ester, formation from sulfonyl chloride and alcohol, 67, 78, 84, 145 Sulfonation, benzoic acid, 269 phenol, 104 o-xylene, 47... 

Section 7.8). Other classes of derivatives are thus most conveniently prepared from the sulfonyl chloride. Reaction with an alcohol leads to formation of a sulfonate ester. Two common sulfonyl chloride reagents employed to make sulfonate esters from alcohols arep-toluenesulfonyl chloride, known as tosyl chloride, and methanesulfonyl chloride, known as mesyl chloride (see Section 6.1.4). Note the nomenclature tosyl and mesyl for these groups, which may be abbreviated to Ts and Ms respectively. 

A primary or secondary amine attacks a sulfonyl chloride and displaces chloride ion to give an amide. Amides of sulfonic acids are called sulfonamides. This reaction is similar to the formation of a sulfonate ester from a sulfonyl chloride (such as tosyl chloride) and an alcohol (Section 11-5). 

The second concealed ElcB elimination is disguised in the mechanism of formation of methanesulfonates (mesylates). When we introduced sulfonate esters in Chapter IS, and revisited them on p. 391 of this chapter, we avoided (uncharacteristically, you may say) explaining the mechanism by which they are formed from sulfonyl chlorides. This was deliberate because, while TsCl reacts with alcohols by the mechanism you might predict, the reaction with MsCl involves an elimination step. 

In Figure 11.2, a sulfonate ester is the leaving group, and reaction with a nucleophile breaks the weaker C-0 bond to generate a sulfonate anion (26). This anion is resonance stabilized and quite stable, which means it is relatively unreactive as a nucleophile. The combination of a weak C-0 bond and the stability and poor reactivity of the sulfonate anion makes sulfonate esters good leaving groups. The most common sulfonate esters (see Chapter 20, Section 20.11) are those derived from methanesulfonic acid, benzenesulfonic acid, or 4-methylbenzenesulfonic acid. Formation of sulfonate esters from sulfonic acids or sulfonyl chlorides will be discussed in Section 11.7.3 and in Chapter 20,... 

The formation of halogenation products from Grignard reagents and sulfonic acid anhydrides is the result of an oxidative reaction pathway . This side-reaction can be reduced by using sulfonic acid esters, however, in these cases alkylations as well as twofold sulfonylations (cf. corresponding results with sulfonyl fluorides ) are competing (equations 64 and 65). 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

---