Halides, alkyl oxidation with DMSO

Silver salts are also utilized to perform nucleophilic additions to disulfide bonds to yield sulfenamides (146). If alkyl halides are treated with stoichiometric AgBF4 in dimethyl sulfoxide solvent (DMSO, solvent), the corresponding aldehydes/ ketones will form in good yields. This reaction is an alternative to the well-known Swern oxidation (147). In addition, silver can drive the formation of dialkylper-oxonium ions from alkyl halides, which then oxidizes sulfoxides or sulfides (148,149). In the presence of AgN03, sulfides can be oxidized into a-chloro sulfoxides by SO2CI2 (Fig. 36) (150). 

Acidic conditions for hydroxy deprotection can be avoided if benzyl-type ethers ate used as the blocking functions. They can be prepared from the alcohols by alkylation with benzyl halide/sodium hydride in DMSO or benzyl halide/silver(I) oxide in DMF (the silver salt does not cause acyl migration as a side... 

Oxidation. Oxidation of alkyl halides by DMSO requires high temperatures (100-150°), and yields are relatively low except for primary iodides (1, 303). Epstein and Ollinger11 find that halides can be oxidized to carbonyl compounds by DMSO at room temperature (4-48 hours) in the presence of silver perchlorate as assisting agent. Chlorides are relatively unreactive, but bromides and iodides are oxidized relatively easily. Yields are higher with primary halides than with secondary halides. Cyclohexyl halides are oxidized to only a slight extent to cyclohexanone, the main product being cyclohexene, formed by elimination. 

Alkyl halides are oxidized to carbonyl compounds by dimethyl sulfoxide (DMSO) at elevated temperatures (123). The drastic conditions can be obviated by introducing silver ion into the mixture (124—126). Alternatively, the halides may be converted to the corresponding tosylates (127) which are more susceptible to attack by DMSO. a-Bromoketones (128) and esters (129) yield the dicarbonyl compounds on standing with DMSO. 

In the Kornblum oxidation, a primary alkyl halide is oxidized to the aldehyde with DMSO and NaHC03, typically with microwave heating ... 

Alkyl halides are converted into carbonyl compounds by oxidation with 4-dimethylaminopyridine iV-oxide in the presence of diazabicycloundecane. This reagent is more reactive than pyridine N-oxide, and requires lower temperatures than the similar reaction using DMSO as oxidant. 

The direct oxidation of alkyl halides to carbonyl compounds by DMSO occurs in good yield under mild conditions in the presence of silver ion, which assists formation of the alkoxysulphonium intermediate silver perchlorate is the salt of choice, other salts competing nucleophilically with DMSO for the substrate. Oxidation of primary halides stops cleanly at the aldehyde stage, except when an excess of silver salt is present. As has been already described, sodium tetracarbonylferrate converts alkyl bromides into the homologous aldehydes this conversion is most successful with primary halides, n-decanal being obtained in 77% yield from n-nonyl bromide. 

Solvent effects Different solvents have different effects on the nucleophilicity of a species. Solvents with acidic protons are called protic solvents, usually O—H or N—H groups. Polar protic solvents, e.g. dimethyl sulph-oxide (DMSO), dimethyl formamide (DMF), acetonitrile (CH3CN) and acetone (CH3COCH3) are often used in 8 2 reactions, since the polar reactants (nucleophile and alkyl halide) generally dissolve well in them. 

The protected methyl glycoside 3 is converted to the corresponding aldehyde by Swern oxidation using oxalyl chloride activated DMSO. Further reaction with triethyl phosphonoacetate and sodium hydride -known as the Horner-Wadsworth-Emmons reaction - provides selectively the trans et /Tun saturated ester 4 in 72 % yield. This valuable alternative to the Wittig olefination protocol uses phosphonate esters as substrates which are readily available from alkyl halides and trialkyl phosphites via the Arbuzov rearrangement.9 co2Et Reaction of the phosphonate with a suitable base gives the... 

Note Colorless, odorless (when pure), hygroscopic liquid, powerful aprotic solvent dissolves many inorganic salts, soluble in water combustible readily penetrates the skin incompatible with strong oxidizers and many halogenated compounds (e.g., alkyl halides, aryl halides), oxygen, peroxides, diborane, perchlorates. Synonyms DMSO, methyl sulfoxide, sulfinylbismethane. 

With alkyl halide substrates, the first step of the oxidation is the Sn2 displacement of the halide with tosylate anion. Next the alkyl tosylate undergoes a second Sn2 reaction with the nucleophilic oxygen atom of the DMSO to form the alkoxysulfonium salt that undergoes deprotonation to give the alkoxysulfonium ylide, which upon a [2,3]-sigmatropic shift affords the carbonyl compound. In the case of a-halo carbonyl substrates, the deprotonation takes place at the more acidic a-carbon instead of the methyl group attached to the sulfur atom of the alkoxysulfonium salt. 

A tandem Kornblum ox/daf/on/imidazole formation reaction was used during the preparation of new fluorescent nucleotides by B. Fischer and co-workers.The adenosine monophosphate free acid was mixed with 10 equivalents of 2-bromo-(p-nitro)-acetophenone and dissolved in DMSO. The required pH value was maintained with the addition of DBU which also served as a base. The Kornblum oxidation of the alkyl halide yielded the glyoxal, which reacted in situ with the aromatic amine to form the desired imidazole derivative. 

Symmetrical disulfides (73) may be prepared by reaction of alkyl halides with disodium disulfide (Scheme 43). The product is contaminated with triand polysulfides owing to the presence of impurities in the disodium disulfide however, lower members of the series of dialkyl disulfides may be purified by fractional distillation. Disulfides can also be obtained from thiols by mild oxidation, e.g. by treatment with iodine or dimethyl sulfoxide (DMSO) (Scheme 44). In the reaction with iodine, the hydriodic acid formed must be removed, otherwise the disulfide is largely reduced back to the thiol by hydriodic acid which is a powerful reducing agent. Pure unsymmetrical disulfides are more difficult to prepare owing to their tendency to undergo disproportionation they can, however, be synthesised from thiols by treatment with imides (see p. 59) or sulfenyl halides (51) (Scheme 45). 

Related to these reactions is the oxidation of alkyl halides or tosylates to carbonyl compounds with dimethyl sulfoxide (or trimethylammonium A/-oxide). The reaction is effected simply by warming the halide (normally the iodide) or sulfonate in DMSO (or MeaNO), generally in the presence of a proton acceptor such as sodium hydrogen carbonate or a tertiary amine. Oxidation never proceeds beyond the carbonyl stage and other functional groups are unaffected. The reaction has been applied to benzyl halides, phenacyl halides, primary sulfonates and iodides and a limited number of secondary sulfonates. With substrates containing a secondary rather than primary halide or sulfonate elimination becomes an important side reaction and the oxidation is less useful with such compounds. 

It certainly demands quite extreme conditions, under which sodium hahdes, or still better, lithium halides or cyanides in a highly polar nonprotic medium such as DMSO or phospholine oxide [214,215,908,909] cleave the ester 130 under formation of alkyl halides. Alternatively, it succeeds in the presence of tertiary amines [910], in quinoline [911] or just in water in the presence of copper salts [912]. On the other hand boiling with 25% sulfuric acid [913] accomplished the same. 

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