Sulfones, alkylation sulfonyl halides

Sulfonate esters are especially useful substrates in nucleophilic substitution reactions used in synthesis. They have a high level of reactivity, and, unlike alkyl halides, they can be prepared from alcohols by reactions that do not directly involve bonds to the carbon atom imdeigoing substitution. The latter aspect is particularly important in cases in which the stereochemical and structural integrity of the reactant must be maintained. Sulfonate esters are usually prepared by reaction of an alcohol with a sulfonyl halide in the presence of pyridine ... 

Other sulfonyl halides that form alkyl sulfonates include ... 

The sulfonyl halides (ArSOjCl) convert the alcohol into a sulfonate (ArSOjOR), which is a better leaving group than the hydroxyl group. This allows a range of nucleophilic substitutions to be carried out, many of which parallel those found with alkyl halides. Alkyl halides such as iodides are formed by the nucleophilic substitution of the sulfonate by an iodide ion. The reaction in this case proceeds with inversion of configuration. Treatment of the sulfonate esters with bases such as sodium methoxide or collidine (2,4,6-trimethylpyridine), or even just heating them, can lead to the elimination of toluene-4-sulfonic acid and the formation of an alkene. 

Alkyl halides or alkyl sulfates, treated with the salts of sulhnic acids, give sul-fones. A palladium catalyzed reaction with a chiral complexing agent led to sul-fones with modest asymmetric induction.Alkyl sulhnates R SO—OR may be side products. " Sulfonic acids themselves can be used, if DBU (p. 1530) is pre-sent. Sulfonyl halides react with allylic halides in the presence of AICI3 Fe and wit benzyl hlaides in the presence of Sm/HgCla. " " Sulfones have also been prepared by treatment of alkyl halides with tosyUiydrazide. " ... 

Sulfonyl chlorides as well as esters and amides of sulfonic acids can be hydrolyzed to the corresponding acids. Sulfonyl chlorides can by hydrolyzed with water or with an alcohol in the absence of acid or base. Basic catalysis is also used, though of course the salt is the product obtained. Esters are readily hydrolyzed, many with water or dilute alkali. This is the same reaction as 10-4, and usually involves R —O cleavage, except when R is aryl. However, in some cases retention of configuration has been shown at alkyl R, indicating S—O cleavage in these cases. Sulfonamides are generally not hydrolyzed by alkaline treatment, not even with hot concentrated alkali. Acids, however, do hydrolyze sulfonamides, but less readily than they do sulfonyl halides or sulfonic esters. Of course, ammonia or the amine appears as the salt. However, sulfonamides can be hydrolyzed with base if the solvent is HMPA. ... 

Sulfonic esters are most frequently prepared by treatment of the corresponding sulfonyl halides with alcohols in the presence of a base. This procedure is the most common method for the conversion of alcohols to tosylates, brosylates, and similar sulfonic esters. Both R and R may be alkyl or aryl. The base is often pyridine, which functions as a nucleophilic catalyst, as in the similar alcoholysis of carboxylic acyl halides (16-61). Propylenediamines have also been used to facilitate tosylation of an alcohol. Silver oxide has been used, in conjunction with KI. Primary alcohols react the most rapidly, and it is often possible to sulfonate selectively a primary OH group in a molecule that also contains secondary or tertiary OH groups. The reaction with sulfonamides has been much less frequently used and is limited to A,A-disubstituted sulfonamides that is, R— may not be hydrogen. However, within these limits it is a useful reaction. The nucleophile in this case is actually RO . However, R may be hydrogen (as well as alkyl) if the nucleophile is a phenol, so that the product is RS020Ar. Acidic catalysts are used in this case. Sulfonic acids have been converted directly to sulfonates by treatment with triethyl or trimethyl orthoformate, HC(OR)3, without catalyst or solvent and with a trialkyl phosphite, P(OR)3. ... 

Sulfonyl halides Primary alkyl halides Sulfonate esters Peroxides... 

Many types of reactive molecules are well known to medicinal chemists acyl halides, aldehydes, aliphatic esters, aliphatic ketones, alkyl halides, anhydrides, alpha-halocarbonyl compounds, aziridines, 1,2-dicarbonyl compounds, epoxides, halopyrimidines, heteroatom-heteroatom single bonds, imines, Michael acceptors and (l-heterosubstituted carbonyl compounds, perhalo ketones, phosphonate esters, thioesters, sulfonate esters, and sulfonyl halides, to name a few [14]. This is not to say that these functionalities are not useful - some even appear in approved drugs -but all of these can react covalently with proteins, and thus should be regarded with suspicion. However, molecules can react covalently with proteins even if they do not contain functionalities that raise alarm. Jonathan Baell has referred to these as pan assay interference compounds, or PAINS, and has published a list of moieties to watch out for, as well as strategies to detect them [15, 16]. 

Preparation of sulfonate esters is accomplished by treatment of a carbohydrate with a pyridine solution of an aryl or alkyl sulfonyl chloride (RSO2CI) or with 50% sodium hydroxide and the sulfonyl chloride at room temperature. Under these conditions, all of the hydroxyl groups may be esterified except those on the reducing (anomeric) carbons which are replaced by halide atoms. Thus, D-glucose gives tetra-O-tosyl-D-glucopy-ranosyl chloride. The primary hydroxyl group seems to be more easily esterified than the secondary hydroxyls (116). 

Synthesis and Stability. Sulfonate esters are conveniently prepared from precursor sulfonyl halides and the appropriate alcohol or alkoxide [Eq. (3) ] this synthetic pathway is particularly suitable for the introduction of a C label into the alkylating moiety since radioactive primary alcohols can be readily synthesized. ... 

An advantage that sulfonate esters have over alkyl halides is that their prepara tion from alcohols does not involve any of the bonds to carbon The alcohol oxygen becomes the oxygen that connects the alkyl group to the sulfonyl group Thus the configuration of a sulfonate ester is exactly the same as that of the alcohol from which It was prepared If we wish to study the stereochemistry of nucleophilic substitution m an optically active substrate for example we know that a tosylate ester will have the same configuration and the same optical purity as the alcohol from which it was prepared... 

The alkylation of sulfur-stabilized anions has been the subject of an excellent recent review633. Anions adjacent to a wide range of sulfur functionalities may be alkylated readily, the most common being sulfoxide and sulfone a-anions. In the synthesis of retinoic acid derivatives and vitamin A634-636, a-sulfonyl anions have been alkylated with an co-acetoxy-containing allyl halide in good yield (equation 96). 

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

Reaction of Sulfonyl-Stabilized Oxiranyllitbiums. Reaction of sulfonyl-stabilized oxiranyllitbiums with primary alkyl halides gives acceptable yields of products. More reactive alkyl triflates give generally better yields but, due to the instability of oxiranyl-lithiums, yields are often not reproducible when electrophiles are added to a solution of the preformed oxiranyllitbiums. It is recommended that the alkylation reaction be carried out by an in situ trapping method. Treatment of a solution of epoxy sulfone (1.0 equiv) and triflate (1.5 equiv) in THE-DMPU (or HMPA) at — 100 °C under argon with n-BuLi (1.0 equiv) followed by stirring... 

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