Hydroxy sulfonic acids formation

Sultones are the internal esters of hydroxy sulfonic acids and are the sulfur analogs of lactones. Sultones are demanded scaffolds in medicinal chemistry research. Biological studies on sultones are mainly concerned with their toxicological, skin sensitization, and antiviral activities [20]. Sultones are synthetically useful heterocycles which can react with a variety of compounds to introduce the alkylsulfonic acid function and therefore used as sulfoalkylating agents [21]. There have been several new developments for the synthesis of sultones which have also been applied in the total synthesis of natural products. In recent years, the palladium-catalyzed direct arylation of several aromatics via a C-H bond activation using aryl halides has led to successes. An intramolecular version of this reaction has allowed the synthesis of several biaryls via the formation of five- to seven-membered rings. Thus, the sultones should be synthesized by C-H activation via two pathways (Scheme 4.14). 

In contrast to phosphorus esters, sulfur esters are usually cleaved at the carbon-oxygen bond with carbon-fluorine bond formation Cleavage of esteri nf methanesulfonic acid, p-toluenesidfonic acid, and especially trifluoromethane-sulfonic acid (tnflic acid) by fluoride ion is the most widely used method for the conversion of hydroxy compounds to fluoro derivatives Potassium fluoride, triethylamine trihydrofluoride, and tetrabutylammonium fluoride are common sources of the fluoride ion For the cleavage of a variety of alkyl mesylates and tosylates with potassium fluoride, polyethylene glycol 400 is a solvent of choice, the yields are limited by solvolysis of the leaving group by the solvent, but this phenomenon is controlled by bulky substituents, either in the sulfonic acid part or in the alcohol part of the ester [42] (equation 29)... 

In further modifications of these norprogestins, reaction of norethindrone with acetic anhydride in the presence of p-toluene-sulfonic acid, followed by hydrolysis of the first-formed enol acetate, affords norethindrone acetate (41). This in turn affords, on reaction with excess cyclopentanol in the presence of phosphorus pentoxide, the 3-cyclopentyl enol ether (42) the progestational component of Riglovic . Reduction of norethindrone affords the 3,17-diol. The 33-hydroxy compound is the desired product since reactions at 3 do not show nearly the stereoselectivity of those at 17 by virtue of the relative lack of stereo-directing proximate substituents, the formation of the desired isomer is engendered by use of a bulky reducing agent, lithium aluminum-tri-t-butoxide. Acetylation of the 33,173-diol iffords ethynodiol diacetate, one of the most potent oral proves tins (44). ... 

Some green algae are able to use aromatic sulfonic acids (Figure 2.4a) (Soeder et al. 1987) and aliphatic sulfonic acids (Figure 2.4b) (Biedlingmeier and Schmidt 1983) as sources of sulfur. Cultures of Scenedesmus obliquus under conditions of sulfate limitation metabolized naphthalene-l-sulfonate to l-hydroxy-naphthalene-2-sulfonate and the gluco-side of naphth-l-ol (Kneifel et al. 1997). These results are consistent with formation of a 1,2-epoxide followed by an NIH shift. 

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. 

A problem that is characteristic of sulfuric acid-catalyzed alkylation is its capabihty to oxidize hydrocarbons. H2SO4 decomposes in the presence of isoalkanes to form water, SO2, and alkenes. This is a slow process, and so it occurs predominantly when the acid is in contact with hydrocarbons for a longer period. Higher temperatures favor the formation of SO2 (10). Some irreversible reactions between acid and hydrocarbons also take place during alkylation. Sulfone, sulfonic acid, and hydroxy groups have been detected in conjunct polymers produced with H2SO4 as the catalyst (8,96). Kramer (97) reported that... 

Sulfinic acids and sulfoxides are not particularly common, being readily oxidized to the sulfonic acids and sulfones, respectively. Sulfonic acids have high melting points and probably exist as zwitterions. They are amphoteric, but mainly display the characteristics of weak acids. The sulfonic acid group activates an adjacent halogen to nucleophilic displacement, and may itself be displaced, e.g. reaction of alkylamines with benzimidazole-2-sulfonic acid. Imidazolesulfonic acids resist esterification and acid chloride formation, and are only hydrolyzed by concentrated hydrochloric acid at 170 °C the 2-isomers are more resistant than the 4- or 5-isomers. Aqueous alkali converts the free acids into hydroxy derivatives. Sulfonyl chlorides are accessible via the thiols (Section 4.07.3.6.1) which react with ammonia to form sulfonamides, or are reduced by tin(II) chloride to thiols (77JHC889). 

A study of the mechanism of the formation of guanosin-8-amine in the reaction of guanosine with hydroxylamine-O-sulfonic acid reveals that the reaction proceeds in three steps (1) electrophilic N7 amination by hydroxylamine-O-sulfonic acid, (2) nucleophilic C8 hydroxy-amination by NHjOH accompanied by elimination of the N7 amino group and aromatization and finally (3) the reduction of the C8 hydroxyamino group by NH2OH to give guanosin-8-amine. °... 

As discussed in Section 3.1.11.1, which covers the reductive cleavage of the 3-hydroxy sulfone derivatives to alkenes, the Julia reaction proceeds by the formation of an anion that is able to equilibrate to the thermodynamic mixture prior to elimination. Therefore, there is no inherent advantage in producing the erthyro- or threo-fi-hydroxy sulfone selectively fix>m the keto sulfone. The ( )/(Z)-mixture of alkenes should be the same. This method is used to produce alkenes in cases where the acid derivative is more readily available or more reactive. The reaction of the sulfone anion with esters to form the keto sulfone, followed by reduction with metal hydrides has been studied. The steric effects in the reduction do become important for the reaction to produce vinyl sulfones, which are formed from the anti elimination of the 3-hydroxy sulfone adduct, as mentioned in Section 3.1.11.6.2. Some examples of the use of esters are presented below. 

In the presence of aqueous ammonium bisulfite an equilibrium often exists between aromatic amines and aromatic hydroxy compounds. This reaction is called the Bucherer reaction 12 and its mechanism appears to involve the intermediate formation of a bisulfite addition complex. The mechanism which is most widely accepted is that of Fuchs and Stix,13 illustrated here with l-hydroxynaphthalcne-4-sulfonic acid ... 

Possible atmospheric reaction products are oxy-, hydroxy-, nitro- and hydroxynitro-PAH derivatives (Baek et al. 1991). Photochemical oxidation of a number of PAHs has been reported with the formation of nitrated PAHs, quinones, phenols, and dihydrodiols (Holloway et al. 1987 Kamens et al. 1986). Some of these breakdown products are mutagenic (Gibson et al. 1978). Reaction with ozone or peroxyacetyinitrate yields diones nitrogen oxide reactions yield nitro and dinitro PAHs. Sulfonic acids have also been formed from reaction with sulfur dioxide. 

Intorre and Martell (237) have also studied the formation of mixed chelate species in which the zirconium 1 1 complex with the hexa-dentate chelating ligands, ethylenediaminetetraacetic acid, iV-hydroxy-ethylethylenediaminetriacetic acid, and m7 s-cyclohexanediaminetetra-acetic acid, are shown to take up one mole of the bidentate ligands, l,2-dihydroxybenzene-3,5-disulfonate l,8-dihydroxynaphthalene-3,6-disulfonate 8-hydroxyquinoline-5-sulfonate, and acetylacetone (except ZrHEDTA), to form 8-coordinate 1 1 1 species. At least for the zir-conium-EDTA-l,2-dihydroxybenzene-3,5-disulfonate species, there is evidence for dimerization (230). Additionally, the Zr EDTA complex reacts with one mole of the bidentate ligands, 5-sulfosalicyclic acid, alizarin sulfonate, citric acid, and lactic acid to form 1 1 1 complexes tartaric acid and pyrophosphate ions form complexes which could not be identified. The zirconium-nitriloacetic acid complex in the presence of two moles of oxalic acid or l,2-dihydroxybenzene-3,5-sulfonate also forms 1 1 1 complexes in solution. 

Azo coupling of diazotized orthanilic acid with the sodium salt of IV-acetyl J acid (7-acetylamine-4-hydroxynaphthalene-2-sulfonic acid) (22) yields mainly coupling ortho to the hydroxy group. Substitution at both activated positions is significantly ster-ically hindered but ionization of the hydroxy group of (22) at higher pH causes additional electrostatic interaction on formation of the a-complex for substitution at the favoured position decreasing the rate of reaction. 

Since with stereochemically defined P-hydroxy carboxylic acids the configuration at the P-center is retained in the oxetanone product, the attack of PhS02Cl should occur at the COOH group (with formation of a mixed anhydride 7) rather than at the OH group (with formation of an O-sulfonate) of the educt [5] ... 

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