Chlorine secondary alcohols

Bromine or chlorine dissolved in hexamethylphosphoric triamide [680-31-9] (HMPT) with a base, eg, NaH2PO, present, oxidizes primary and secondary alcohols to carbonyl compounds in high yield (38). 

Dipyridiue-chromium(VI) oxide2 was introduced as an oxidant for the conversion of acid-sensitive alcohols to carbonyl compounds by Poos, Arth, Beyler, and Sarett.3 The complex, dispersed in pyridine, smoothly converts secondary alcohols to ketones, but oxidations of primary alcohols to aldehydes are capricious.4 In 1968, Collins, Hess, and Frank found that anhydrous dipyridine-chromium(VI) oxide is moderately soluble in chlorinated hydrocarbons and chose dichloro-methane as the solvent.5 By this modification, primary and secondary alcohols were oxidized to aldehydes and ketones in yields of 87-98%. Subsequently Dauben, Lorber, and Fullerton showed that dichloro-methane solutions of the complex are also useful for accomplishing allylic oxidations.6... 

DMSO or other sulfoxides react with trimethylchlorosilanes (TCS) 14 or trimefhylsilyl bromide 16, via 789, to give the Sila-Pummerer product 1275. Rearrangement of 789 and further reaction with TCS 14 affords, with elimination of HMDSO 7 and via 1276 and 1277, methanesulfenyl chloride 1278, which is also accessible by chlorination of dimethyldisulfide, by treatment of DMSO with Me2SiCl2 48, with formation of silicon oil 56, or by reaction of DMSO with oxalyl chloride, whereupon CO and CO2 is evolved (cf also Section 8.2.2). On heating equimolar amounts of primary or secondary alcohols with DMSO and TCS 14 in benzene, formaldehyde acetals are formed in 76-96% yield [67]. Thus reaction of -butanol with DMSO and TCS 14 gives, via intermediate 1275 and the mixed acetal 1279, formaldehyde di-n-butyl acetal 1280 in 81% yield and methyl mercaptan (Scheme 8.26). Most importantly, use of DMSO-Dg furnishes acetals in which the 0,0 -methylene group is deuter-ated. Benzyl alcohol, however, affords, under these reaction conditions, 93% diben-zyl ether 1817 and no acetal [67]. 

In another procedure, oxidation is carried out in the presence of chloride ions and ruthenium dioxide [31]. Chlorine is generated at the anode and this oxidises ruthenium to the tetroxide level. The reaction medium is aqueous sodium chloride with an inert solvent for the alkanol. Ruthenium tetroxide dissolves in the organic layer and effects oxidation of the alkanol. An undivided cell is used so that the chlorine generated at the anode reacts with hydroxide generated at the cathode to form hypochlorite. Thus this electrochemical process is equivalent to the oxidation of alkanols by ruthenium dioxide and a stoichiometric amount of sodium hypochlorite. Secondary alcohols are oxidised to ketones in excellent yields. 1,4- and 1,5-Diols with at least one primary alcohol function, are oxidised to lactones while... 

Another method that provides chlorides from alcohols with retention of configuration involves conversion to a xanthate ester, followed by reaction with sulfuryl chloride. This method is thought to involve collapse of a chlorinated adduct of the xanthate ester. The reaction is useful for secondary alcohols, including stoically hindered structures.8... 

Oxidation and Reduction.—A number of selective oxidation procedures have been reported. Trichloroacetaldehyde on dehydrated chromatographic alumina converts the diol (15) into the 3/3-hydroxy-17-ketone (68%)." Primary alcohols are reported to be less readily oxidized than secondary alcohols by this reagent. Similarly, bromine or chlorine with HMPA oxidizes secondary alcohols more readily than primary alcohols. Thus the diol (16) was converted into the ketol (17)... 

Subsequent reduction of the prochiral ketone with diborane in THF and chlorination of the resulting secondary alcohol 9 provided a reactive benzylic chloride that underwent subsequent nucleophilic displacement with 4-trifluoromethylphenoxide to give 10. Von Braun degradation of the V,V-dimethyl amine in 10, via the V-cyano intermediate 11, gave racemic fluoxetine (4). 

With primary or nonsterically hindered secondary alcohols, method A led exclusively to the formation of chlorinated sugars [68]. The mildness and efficiency of this chlorination method was used to advantage in the synthesis of a dichloro aminoglycoside, a precursor of seldomycin factor 2 [68] (Scheme 7). 

In 1980, Stevens et al.10 reported that a plain solution of sodium hypochlorite, which is easily available as swimming pool chlorine , is able to efficiently oxidize secondary alcohols in a solution in acetic acid, while primary alcohols react very slowly. Two years later, this research team published11 a more detailed account on the ability of NaOCl/AcOH to perform the selective oxidation of secondary alcohols in the presence of primary ones. Stevens oxidant became one of the standard reagents for the selective oxidation of secondary alcohols.12... 

Other reagents, providing a source of electrophilic halogen, able to selectively oxidize secondary alcohols include molecular chlorine,13 molecular bromine,13c 3-iodopyridine dichloride,13a trichloroisocyanuric acid (TCIA),14 the complex HOF MeCN15 and tetraethylammonium trichloride.16... 

The method given here is essentially that of Meerwein and his pupils Schmidt5 and von Bock.3 The theory of the reaction and applications are also discussed by Dworzack 4 and by Ver-ley.6 A number of patents have appeared covering this reaction, in some of which a secondary alcohol such as isopropyl alcohol 7 is used in place of ethyl alcohol. Trichloroethyl alcohol is one of the chlorination products of alcohol and is found in the high-boiling fractions in the production of chloral.8 It was prepared by Garzarolli-Thurnlackh 9 and by Delacre10 by the action of diethylzinc on chloral. 

Quinolinium dichromate (17) shows the solubility profile common to most chromium based oxidants—sparingly soluble in chlorinated solvents, but more soluble in more polar solvents. It has been mainly used in dichloromethane at reflux, or in DMF at 30 C to oxidize primary alcohols. Secondary alcohols are also oxidized reasonably well. 

Dimethyl sulfoxide and chlorine form highly reactive intermediates which are of some limited use as oxidants for alcohols. These intermediates are related to those derived from the reaction of the halogens with dimethyl sulfide and probably have a structure such as (27). When formed at -45 "C they allow the oxidation of primary and secondary alcohols to aldehydes and ketones when used in a two-fold excess. For very simple alcohols the reaction proceeds in yields of greater than 90%, but there are considerable drawbacks if some types of additional functionality are present in the molecule, e.g. alkenes react very rapidly to form vicinal dichlorides. 

OxUatiou of primary and secondary alcohals to carbonyl compounds. Corey and Kim report that the complex of N-chlorosuccinimide and dimethyl sulfide is somewhat superior to the complex of dimethyl sulfide and chlorine (this volume) for oxidation of primary and secondary alcohols the formation of hydrogen chloride is avoided and yields are generally higher. The procedure is illustrated for the oxidation of 4-r-butyl-cyclohexanol (2) to 4-r-butylcyclohexanonc (4). The complex (1) is prepared by addition of dimethyl sulfide (4.1 mmole) to a stirred solution of NCS (3.0 mmole) in toluene at 0° under argon. The mixture is cooled to -25° and a solution of 4-r-butylcyclo-hexanol (2.0 mmole, mixture of cis and trans) in toluene is added dropwise. The stirring is continued for 2 hr. at — 25° and then triethylamine (3.0 mmole) in toluene is added dropwise. The ketone (4) is obtained in almost quantitative yield. As in oxidation with the complex of dimethyl sulfide and chlorine, an intermediate sulfoxonium complex (3) is involved. 

Oxidation of primary and secondary alcohols to carbonyl compounds, Treatment of dimethyl sulfide in carbon tetrachloride at 0° with 1 eq. of chlorine in the same solvent results in rapid formation of the partially insoluble complex (I). This complex has been used by Corey and Kim for oxidation of primary and secondary alcohols. In a typical... 

There is an alternative oxidant for secondary alcohols that is just as efflcientand much safer from an environmental standpoint 5.25% (0.75 M) sodium hypochlorite solution available in the grocery store as household bleach. The mechanism of the reaction is not clear. It is not a free radical reaction the reaction is much faster in acid than in base elemental chlorine is presumably the oxidant and hypochlorous acid must be present. It may form an intermediate alkyl hypochlorite ester, which, by an Ej elimination, gives the ketone and chloride ion. 

Oxidations by chlorine are limited to only few types of compounds. In organic solvents and pyridine [681] or hexamethylphosphoramide (HMPA) [682] as cosolvents, primary alcohols are oxidized to aldehydes and secondary alcohols to ketones [681, 682]. Secondary alcohols are oxidized in preference to primary alcohols [681]. Many oxidations with chlorine are carried out in aqueous media and involve sulfur-containing compounds. Mercaptans [683], alkyl thiolcarboxylates [683], thiocyanates [684], isothioureas [684], disulfides [655], and sulfinic acids [656] are transformed into sulfonyl chlorides. The chlorination of dimethyl disulfide in acetic anhydride yields methanesulfinyl chloride [657]. 

Halogens and their oxygen-containing compounds are useful and selective oxidants for secondary alcohols. The addition of a chlorine solution in carbon tetrachloride to a chloroform solution of 5a-cholestane-3p,19-diol below 30 °C gives a 77% yield of 5a-cholestan-19-ol-3-one after 15 min [681]. 

Similar selectivity is found with chlorine (or bromine) in the presence of hexamethylphosphoric triamide (HMPA). The addition of solutions of chlorine in chloroform to stirred solutions of the alcohols in a mixture of HMPA, dichloromethane, and an aqueous solution of sodiunfdihydrogen phosphate at 0-5 °C results in very good yields of ketones. Competitive experiments with equimolar mixtures of primary and secondary alcohols show a 95-97% predominance of ketones over aldehydes [682]. 

Like chlorine, bromine is used to convert secondary alcohols into ketones. A convenient way is to apply the addition product of 2 mol of bromine with l,4-diazabicyclo[2,2,2]octane (Dabco), a nonhygroscopicyellow solid, prepared by mixing carbon tetrachloride solutions of bromine and Dabco. The compound decomposes at 155-160 °C [726]. Oxidation with this addition product is carried out in acetonitrile solution at 50 °C and results in 50 and 71% yields of cyclopentanone and cyclohexanone, respectively, but very low yields of 2-pentanone [726]. 

A general rule is that allylic alcohols are more readily oxidized than saturated secondary alcohols [975], and these, in turn, are more readily oxidized than saturated primary alcohols [681, 741, 1041, 1152], Ceric sulfate [741], ceric ammonium nitrate [741], chlorine [681], sodium hypochlorite [1152], and 2,3-dichloro-5,6-dicyano-p-benzoquinone [975] are successfully used for this purpose (equations 287-289). 

This has, for example, been achieved using strains of Sacchawmyces cerevisiae. These strains reduce the ketone to a secondary alcohol only if the chlorine on position 2 is in the R configuration. Thus ... 

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