Sensitive alcohols

Lithium ethoxyacetylide appears superior to the magnesium reagent for avoiding further transformations of particularly sensitive alcohols produced in this reaction. 

Me3Si)20, PyH TsO, PhH, mol. sieves, reflux, 4 days, 80-90% yield. These mildly acidic conditions are suitable for acid-sensitive alcohols. 

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... 

The inclusion of DMAP to the extent of 5-20 mol % in acylations by acid anhydrides and acyl chlorides increases acylation rates by up to four orders of magnitude and permits successful acylation of tertiary and other hindered alcohols. The reagent combination of an acid anhydride with MgBr2 and a hindered tertiary amine, e.g., ( -Pr)2NC2H5 or 1,2,2,6,6,-pentamethylpiperidine, gives an even more reactive acylation system, which is useful for hindered and sensitive alcohols.105... 

Olah and co-workers ° conducted a comprehensive study into the use of N-nitropyridinium salts for nitration. Such salts are easily prepared from the slow addition of the appropriate heterocyclic base to an equimolar suspension of nitronium tetrafluoroborate in acetonitrile. Olah studied the effect on nitration of changing both the structure of the heterocyclic base and the counter ion. Three of these salts (20, 21, 22) illustrated above have been synthesized and used for the 0-nitration of alcohols with success. Transfer nitrations with Al-nitropyridinium salts are particularly useful for the preparation of nitrate esters from acid-sensitive alcohols and polyols because conditions are essentially neutral. 

An extremely mild method for the synthesis of nitrate esters from easily oxidized or acid-sensitive alcohols involves the decomposition of a nitratocarbonate (29). The nitratocar-bonate is prepared in situ from metathesis between a chloroformate (reaction between phosgene and an alcohol) and silver nitrate in acetonitrile in the presence of pyridine at room temperature. Under these conditions the nitratocarbonate readily decomposes to yield the corresponding nitrate ester and carbon dioxide. Few examples of these reactions are available in the literature and they are limited to a laboratory scale. 

Note. Two procedures are given. Procedure A is the simplest to perform, but B is preferred for sensitive alcohols and in cases where elimination to give olefins is expected, for example, with all tertiary and many secondary alcohols. Procedure A is best for sterically hindered alcohols, for example, neopentyl alcohol. 

The methods described above are applicable to almost any alcohol. Procedure A is best for sterically hindered alcohols and procedure B is especially useful for sensitive alcohols where rearrangement or alkene formation is likely. The submitter s... 

PTC methods for the oxidation of water-insoluble acid-sensitive alcohols have been described which use an aqueous sulphuric acid solution of potassium dichromate, dichloromethane and catalytic amounts of tetrabutylammonium hydrogen sulphate.103... 

Instead of a steam bath or a water bath, an electrically heated oil bath is suitable. This permits easy regulation of the rate of distillation. However, the temperature of the bath should not exceed 95-100° when isopropyl alcohol is the solvent if possible dehydration of a sensitive alcohol is to be avoided. For this same reason, a burner, hot plate, or sand bath is not recommended for heating. Especially at the end of the reduction, superheating of the concentrated alkoxide solution may bring about dehydration or other decomposition of the product. 

Goedde HW, Agarwal DP. Aldehyde dehydrogenase polymorphism molecular basis and phenotypic relationship to alcohol sensitivity. Alcohol Alcohol 1987 (suppl l) 47-54. 

Crabb DW, Dipple KM, Thomasson HR. Alcohol sensitivity, alcohol metabolism, risk of alcoholism, and the role of alcohol and aldehyde dehdrogenase genotypes. J Lab Clin Med 1993 122 234-240. 

Other C=S-containing esters derived from alcohols can also be defunctionalized in a similar fashion. Imidazolylthiocarbonic esters, which in contrast to xanthates can be synthesized under neutral conditions, are one example. This is important for the reduction of base-sensitive alcohols. Figure 1.41 shows a reaction of this type. If the corresponding xanthate was pre-... 

Zinc halides are used in a modified Mitsunobu983 procedure based on diethyl azodicar-boxylate and triphenylphosphine, for the conversion of sensitive alcohols to alkyl halides (equation 154)984. 

Chromic acid is best avoided if acid-sensitive alcohols are to be oxidized, and an alternative reagent for these is PCC (pyridinium chlorochromate), which can be used in dichloromethane. 

It will oxidize even very sensitive alcohols to carbonyl compounds—few others, for example, would give a cis-a,p-unsaturated aldehyde from a as-allylic alcohol without isomerizing it to trans, or producing other byproducts. 

Cesium fluoride reacts with epoxides to form cesium alcoholates that can be transformed into a plethora of ethers and esters in good yield, for example, reaction of 12 to give 13. Methyl-ation with iodomethane is common. For sensitive alcohols silver oxide is the base of choice." No elimination to the a,)S-unsaturated sulfoxides was reported, when alcohols 14 were treated w ith iodomethane in dimethylformamide to give ethers 15." ... 

For ntoro sensitive alcohols, pyridinium chlorochromate is often used because Ute ro-action is milder and occurs at lower teinperaturos. 

The alkoxide (27) is the initial product of addition to the carbonyl group (Scheme 3). Workup with aqueous acid generates alcohol (28) and water-soluble magnesium salts. However, with sensitive alcohols this workup may lead to dehydration. Milder workup can be achieved by acidifying with aqueous aimnonium chloride, or by hydrolyzing with a minimal amount of water, and attempting to filter or... 

The THP group is a widely used protecting group it is readily introduced by reaction of the enol ether dihydropyran with an alcohol in the presence of an acid catalyst, such as TsOH, BF3 OEt2, or POCI3. For sensitive alcohols such as allylic alcohols, PPTS (pyridinium p-toluenesulfonate) is used as a catalyst for tetrahydropy-ranylation. As an acetal, the THP group is readily hydrolyzed under aqueous acidic conditions with AcOH-THF, TsOH, PPTS-EtOH, or Dowex-H (cation exchange resin). 

Tosylate esters may be prepared in the absence of pyridine as solvent by converting the hydroxyl group to a lithium salt by addition of methyl or butyllithium. The resultant lithium alkoxide is then treated with tosyl chloride. This approach is recommended for the preparation of tosylates from very sensitive alcohols, provided that they do not contain other functional groups that react with the alkyl lithium reagents. 

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