Sulfonic esters, nucleophilic displacement

The preparation of esters can be classified into two main categories (1) carboxy-late activation with a good leaving group and (2) nucleophilic displacement of a caiboxylate on an alkyl halide or sulfonate. The latter approach is generally not suitable for the preparation of esters if the halide or tosylate is sterically hindered, but there has been some success with simple secondaiy halides and tosylates (ROTs, DMF, K2CO3, 69-93% yield). ... 

An alternative procedure for the introduction of the fluorine substituent in secondary positions of carbohydrates consists in nucleophilic displacement of sulfonic esters. Walden inversion always accompanies such displacements, and the success of this method may be attributed to two factors. 

Secondly, the factors controlling nucleophilic displacements of sulfonic esters had already been determined to a considerable extent, and have been described in reviews in this Series103,104 and, in addition, the steric and polar factors governing such displacements have been summarized qualitatively,101 and will therefore not be discussed here in any detail. This accumulated knowledge made possible the prediction of the course of such fluoride displacements. 

By selection of an appropriate derivative the hydroxyl group can become activated towards displacement (via an 8 2 exchange process) with a suitably chosen nucleophile. Conversion to the sulfonate ester (SO2R) [115] promotes displacement by either an acetate ( OAc) (sequence Dl) or phthalimide nucleophile (Sequence D2), whilst the trimethylsilyl derivative facilitates introduction of fluorine (Sequence E) [116]. 

Nucleophilic displacement using [ F] fluoride works well in aUphatic systems where reactive haUdes or sulfonates esters can undergo substitution at unhindered sites. In order to introduce a F fluorine atom in a secondary or tertiary position, a two steps strategy was developed. It involves a F-bromofluorination of alkenes, followed by reductive debromination (n-BujSnH, AIBN). [ F]BrF is usually generated in situ from [ F]potassium fluoride and l,3-dibromo-5,5-dimethylhydantoin (DBH) in sulfuric acid. This methodology was successfully applied to label steroids at the 11 and 6a positions [245] (Scheme 60) and to prepare [ F]fluorocyclohexanes [246]. 

SCHEME 42. The physical basis of Richardson s rules for nucleophilic displacement of carbohydrate sulfonic esters (1969). 

Deoxyhalogeno sugars are susceptible to nucleophilic attack, leading either to displacement, elimination, or anhydro-ring formation. The ease of displacement decreases in the order I > Br> Cl > F the iodo and bromo derivatives have, therefore, been especially utilized in such reactions, although several reactions with chlorodeoxy sugars have now been reported as a result of the increased availability of these compounds. The approach delineated in Section 11,1 (see p. 227) for predicting the reactivity of sulfonic esters can be expected also to be applicable, in an approximate and qualitative way,... 

Problem 13.17 How does sulfonate ester formation from suifonyl chloride resemble nucleophilic displacements of alkyl halides "d... 

Bimolecular, nucleophilic-displacement reactions of sulfonic esters of carbohydrates have been reviewed.77,78... 

Nucleophilic Displacement Reactions of lmidazole-1-Sulfonate Esters... 

J. M. Sugihara and W. J. Teerlink, Stereochemical effects in the nucleophilic displacement reactions of primary carbohydrate benzene sulfonate esters with sodium iodide, J. Org. Chem. 29 550 (1964). 

The final example in this section features a rare instance where the electrophilic center is s -hybridized carbon, as most cyclative cleavages involve the attack of carbonyl derivatives. Oxazolidinones are formed cyclatively18 by the displacement of a sulfonate ester by an acylsulfonamide (Fig. 5). In a variant19 of this cyclization, a quasi-meso bis-sulfonate partitions into a pair of quasi-enantiomeric sulfonates, one resin bound and the other cleaved, depending on the direction of intramolecular cyclization. The resin-bound enantiomer can then be displaced by an external nucleophile. 

The selective nucleophilic displacement of one ortho nitro group from 2,4,6-trinitrotoluene by esters of mercap-toacetic acid followed by oxidation leads to 2-(alkoxycarbonyl)methylsulfonyl compounds. These sulfones react with aromatic aldehydes under Knoevenagel conditions to produce thiochroman 1,1-dioxides 477, probably via a stilbene and a subsequent intramolecular Michael addition. Activating groups other than nitro are compatible with the route (Scheme 167) <2003RJ0397>. 

The resistance of the furoxan ring to chemical attack allows derivatives to be prepared via the reactions of the substituents (Section 4.22.3.4). Carboxylic acids are available by permanganate oxidation of methyl derivatives or by hydrolysis of the corresponding esters reaction with ammonia affords carboxamides. Acylfuroxans provide a source of hydroxyalkyl compounds by reduction, and oximes, for example, via nucleophilic addition. Acylation and oxidation of aminofuroxans allows the amide and nitro derivatives to be prepared. Nucleophilic displacements of nitro substituents can take place, but can be somewhat hazardous on account of the explosive nature of these compounds. Alkoxy derivatives are formed with sodium alkoxide, while reaction with thiolate anions yields sulfides, from which sulfones can be synthesized by peracid oxidation. Nitrofuroxans have also been reduced to... 

OH" is not a satisfactory leaving group. A sufficient activation is needed to allow nucleophilic displacements. Tosylates, mesylates, triflates, sulfates and other esters of sulfuric and sulfonic acids are suitable leaving groups for this purpose. They are generally easy to make and stable enough for isolation or purification. Isolation of a stable intermediate often gives cleaner reactions and products. 

The generation of an alkene by the reaction of a v/c-disulfonate ester with iodide (the Tipson-Cohen reaction) has been known since 1943 and in some cases it has proved useful where other methods have failed, as in the preparation of the spirocyclic triene (54 Scheme 22). The mechanism probably involves an initial nucleophilic displacement to give an iodohydrin sulfonate, which then undergoes iodide-induced elimination to the alkene. Methanesulfonates can be used as well as arenesulfonates. 

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