Sulfates nucleophilic displacement

O- Alkylation is comparable to A/-alkylation, but since the sodium salts are water-soluble it is most convenient to treat the phenol or naphthol in aqueous caustic solution with dimethyl sulfate or diethyl sulfate. These are comparatively expensive reagents, and therefore, alkoxy groups are introduced at a prior stage by a nucleophilic displacement reaction whenever possible. 

Historically, simple Vz-alkyl ethers formed from a phenol and a halide or sulfate were cleaved under rather drastic conditions (e.g., refluxing HBr). New ether protective groups have been developed that are removed under much milder conditions (e.g., via nucleophilic displacement, hydrogenolysis of benzyl ethers, and mild acid hydrolysis of acetal-type ethers) that seldom affect other functional groups in a molecule. 

Although the foregoing reactions involve dehalogenation by reduction or elimination, nucleophilic displacement of chloride may also be important. This has been examined with dihalomethanes using HS at concentrations that might be encountered in environments where active anaerobic sulfate reduction is taking place. The rates of reaction with HS exceeded those for hydrolysis and at pH values above 7 in systems that are in equilibrium with elementary sulfur, the rates with polysulfide exceeded those with HS. The principal product from dihalomethanes was the polythio-methylene HS (CH2-S) H (Roberts et al. 1992). 

Various alkylamino-artemisinins 155 were synthesized by the nucleophilic displacement of bromoartemisin 149, which was prepared in situ from 148 (Scheme 19), followed by reaction with alkylamines <2004AGE1381>. A more direct route involved treatment of 29a firstly with a mixture of NaBr and TMSCl and then with the amine <2006AGE2082>. HFIP can be used as an additive in the amination step to increase the yield <2005AGE2060>. Similar aminoartemisinins 155 (where NRR = NHAr) were prepared by reacting 29a with anilines, in the presence of a catalytic amount of pyridinium sulfate in pyridine, in good yields (e.g., Ar = Ph, 93% 72% ... 

Alkyl and aryl azides are prepared by the nucleophilic displacement by azide ion on halide, sulfate, phenyldiazonium, hydroxyl, nitrate, iodoxy, alkoxy, and tosylate groups [6]. Sodium azide is the most useful and practical reagent. The use of silver azide is not necessary in most cases. Some examples from the literature [8-33] employing these methods are shown in Table I. 

The use of cyclic sulfates in synthetic applications has been limited in the past because, although cyclic sulfites are easily prepared from diols, a convenient method for oxidation of the cyclic sulfites to cyclic sulfates had not been developed. The experiments of Denmark [70] and of Lowe and co-workers [71 ] with stoichiometric ruthenium tetroxide oxidations and of Brandes and Katzenellenbogen [72a] and Gao and Sharpless [68] with catalytic ruthenium tetroxide and sodium periodate as cooxidant have led to an efficient method for this oxidation step. Examples of the conversion of several diols (67) to cyclic sulfites (68) followed by oxidation to cyclic sulfates (69) are listed in Table 6D.7. The cyclic sulfite/cyclic sulfate sequence has been applied to 1,2-, 1,3-, and 1,4-diols with equal success. Cyclic sulfates, like epoxides, are excellent electrophiles and, as a consequence of their stereoelectronic makeup, are less susceptible to the elimination reactions that usually accompany attack by nucleophiles at a secondary carbon. With the development of convenient methods for their syntheses, the reactions of cyclic sulfates have been explored, Most of the reactions have been nucleophilic displacements with opening of the cyclic sulfate ring. The variety of nucleophiles used in this way is already extensive and includes H [68], [68,73-76], F" [68,72,74], PhCOCT [68,73,74], NOJ [68], SCN [68],... 

Alternatively, the remaining sulfate ester of 70 may serve as a leaving group for a second nucleophilic displacement reaction. When this displacement is by an intramolecular nucleophile, a new ring is formed, as was first shown in the synthesis of a cyclopropane with malonate as the nucleophile [68] and of aziridines with amines as the nucleophiles [76]. The concept is further illustrated in the double displacement on (/J,/ )-stilbenediol cyclic sulfate (72) by benzamidine (73) to produce the chiral imidazoline 74 [79]. Conversion of the imidazoline (74) to (.V,.S )-stilbenediaminc 75 demonstrates an alternative route to optically active 1,2-diamines. Acylation of 75 with chloroacetyl chloride forms a bisamide, which, after reduction with diborane, is cyclized to the enantiomerically pure trans-2,3-diphenyl- 1,4-diazabicy-clo[2.2.2]octane (76) [81],... 

With two-electron oxidants, sulfate may form through direct oxygen transfer (p. 366), or by nucleophilic displacement on sulfur ... 

A scale-up synthesis of isosteric phosphonate analogue (178) of mannose-6-phosphate (M6P) has been perfonned via regioselective nucleophilic displacement of the protected 4,6-cyclic sulfate precursor (179) by lithiated dialkyl methylphosphonates in the key step. ... 

As already discussed (Sec. 17.5), phenols are converted into ethers by reaction in alkaline solution with alkyl halides methyl ethers can also be prepared by reaction with methyl sulfate. In alkaline solutions a phenol exists as the phenoxide ion which, acting as a nucleophilic reagent, attacks the halide (or the sulfate) and displaces halide ion (or sulfate ion). 

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. 

Alkyl halides, alkyl sulfonates, and alkyl sulfates undergo nucleophilic displacement by aqueous sulfite to afford sulfonic acid salts under very mild conditions.This chemistry is traditionally referred to as... 

A large water-soluble group such as sulfate or glucuronate is transferred onto the drug by a nucleophilic displacement reaction (steps a and b of scheme). 

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