Sulfonic esters displacement

The selectivity of the reduction of methyl a-DL-ald-2-enopyranosid-4-ulose 326 and, consequently, the low availability of the 2,3-unsatu-rated pyranosides of the a-threo (329) configuration, required the inversion of the configuration of C-4 (C-5 in the glyeulopyranosides) for completion of several syntheses. The benzoic acid-diethyl azodicar-boxylate-triphenylphosphine reagent was reported to effect the esterification specifically, with inversion of the configuration the yields were significantly higher than those obtained in the two-step, sulfonic-ester, displacement procedure.229... 

Nucleophilic Displacement. - Sulfonate ester displacement reactions continue to be widely applied in amino-sugar syntheses. The 3-amino-S-thioglucofuranose derivative 20 was obtained from the corresponding allofuranose 3-mesylate by displacement with azide ion and reducdon (liAlHJ (see also section 2.6)." The 2,3-epimino-a-D-lyxopyranoside 21 was prepared in 11 steps from diacetoneglucose via 3-azido-3-deoxy-1.2-O-isoprc ylidene-a-D-glucofriranose. Key steps were... 

The reaction of alcohols with acyl chlorides is analogous to their reaction with p toluenesulfonyl chloride described earlier (Section 8 14 and Table 15 2) In those reactions a p toluene sulfonate ester was formed by displacement of chloride from the sulfonyl group by the oxygen of the alcohol Carboxylic esters arise by displacement of chlonde from a carbonyl group by the alcohol oxygen... 

The most common leaving groups are sulfonate esters and halides. For the sake of convenience, the discussion of certain dehalogenation reactions is also included in this section even though they may not involve 8 2 type displacement. Benzylic alcohols are also known to be displaced by hydrides or deuterides, but there is no evidence for the application of these reactions to the steroid field. 

Only one of these methods, namely the reaction of halides with lithium aluminum deuteride, is a true displacement reaction, following the same course as the previously discussed displacement of sulfonate esters (section Vl-A). Thus, lithium aluminum deuteride treatment of 7a- and 7jS-bromo-3 -benzoyloxy-5a-cholestanes (195) and (196) gives the corresponding deuterium labeled cholestanols (197) and (198) respectively." ... 

The Preparation of Halodeoxy Sugars by Displacement of Sulfonate Esters... 

Another deviation from the normal displacement reaction of primary tosylates occurs in nucleoside derivatives (39, 81) where cyclonucleosides and anhydronucleosides are formed by participation of a nitrogen atom (as in purine nucleosides) and oxygen atom (as in pyrimidine nucleosides ), respectively. Iodonucleosides can result from these reactions only if these cyclic compounds are prone to attack by iodide ion. Several new examples of unexpected reactions during the solvolysis of sulfonate esters in sugar derivatives have been recorded in the past few years (2, 4,5,7,15,44,62,63,94). 

The use of tetra-n-butylammonium fluoride (54) in an aprotic solvent such as acetonitrile may be more advantageous. Foster and colleagues (19, 37) have effected an SN2 type of reaction using this reagent in the conversion of l,2 5,6-di-0-isopropylidene-3-0-p-tolylsulfonyl-D-allofura-nose into the C-3 epimeric fluorodeoxy derivative. Note that whereas potassium fluoride is ineffective in displacing secondary sulfonate esters in sugars, tetra-n-butylammonium fluoride is capable of effecting a displacement with Walden inversion even in a furanose drivative. 

The group of Caddick has described the synthesis of functionalized sulfonamides by microwave-assisted displacement of pentafluorophenyl (PFP) sulfonate esters with amines (Scheme 6.159) [306]. Their ease of handling due to their higher crystallinity, along with their long shelf-life and their ability to react under aqueous reaction conditions, makes these an attractive alternative to sulfonyl chlorides. The microwave-assisted reaction of alkyl PFP esters with amines is a facile process which proceeds cleanly and in good yields with a number of different amines, including primary, secondary, and sterically hindered amines, and anilines. Optimum condi-... 

Another example of the fact that primary displacement of sulfonic esters is not always facile101,103-105 is the discovery that vigorous conditions were required for fluorination of l,2 3,5-di-0-isopropylidene-6-0-(methylsulfony])-a-D-galactofuranose with potassium fluoride dihydrate in methanol,85,88 and a comparatively long reaction-time was necessary for the fluorination of the 6-O-p-tolylsulfonyl derivative with tetrabutylammonium fluoride in acetonitrile.106... 

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]. 

Displacement of sulfonate esters with nitrate anion... 

The displacement of both halides and nitro groups from polynitroarylenes has been covered in Sections 4.8.1 and 4.8.2. The centres of low electron density induced by electron-withdrawing nitro groups also allow the displacement of many other groups, including hydrogen, alkoxy, aryloxy, sulfonate ester etc. 

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,... 

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