Carboxylic acids dissolving metal reduction

Dissolving metal reductions of the benzene rings are especially important with functional derivatives of benzene such as phenols, phenol ethers and carboxylic acids (pp. 80, 82,93 and 140). 

Extension of the dissolving metal reduction of enones to a,[3-unsaturated carboxylic acid esters converts the ester moiety to an amide. However, a, 3-unsaturat-ed esters undergo double bond reduction on treatment with magnesium in methanol. ... 

Then the carboxylic acid was converted (via the acid chloride) to the diazoketone (Chapter 9), and decomposition of the latter via the carbene and insertion produced the substituted cyclopropane. Next, the keto group was converted to a methylene unit via the Wittig, and thermolysis generated the third cyclopentyl ring. Dissolving metal reduction and epimerization in sodium ethoxide set the stage for conversion of the ester to an alkyl group. 

Dissolving metal reduction cleaved the N-benzyl group and acid hydrolysis opened the lactam ring to give ethyl 3-amino-4-ethenylcyclohexane-l-carboxylate, 7.57.42... 

Dissolving metal reduction of the oxime and hydrolysis gave lR,3R-3-aminocyclo-pentane-1-carboxylic acid, 7.41. An identical approach was used to prepare cyclohexane derivatives. Reaction of 7.129 " with hydroxylamine76b.77 nd subsequent... 

The solubility of alkali metals in THF can be increased by the presence of crown compounds, and blue solutions containing Na-K alloy suspended in THF in the presence of catalytic 18-crown-6 have been used to reduce organic molecules. Products are not always the same as from conventional dissolving metal reductions for example benzoic acid is reduced to cyclohexane carboxylic acid. 

Although Smh is more chemoselective than traditional dissolving metal reagents, it does react with sulfoxides, epoxides, the conjugated double bonds of unsaturated ketones, aldehydes and esters, alkyl bromides, iodides and p-toluenesulfonates. It does not, however, reduce carboxylic acids, esters, phosphine oxides or alkyl chlorides. In common with most dissolving metal systems, ketones with an a-hetero substituent suffer loss of the substituent rather than reduction of the carbonyl group. ... 

Several related reactions involve reduction of cyclic carboxylic acid derivatives to masked aldehydes which resist further reduction but can be converted into the required aldehydes by acid hydrolysis. In a series of papers, it was established that carboxylic acids could be converted into dihydro-1,3-thiazines or dihydro-1,3-oxazines which could be reduced by NaBH4 in weakly acidic ethanol. Thus, as shown in Scheme 20, dihydro-1,3-thiazines (41) were reduced to tetrahydro-1,3-thiazines (42) in yields of 66-84%. The resulting tetrahydro compounds could be hydrolyzed to aldehydes by aqueous acid. - In a later publication, these workers showed that there was little evidence for ring opening during reduction and that other methods of reduction e.g. hydrogenation over Pt, Pd or Rh or use of dissolving metals such as Zn, Sn or Na) were totally unsuccessful. In closely similar work, reduction of 5,6-dihydro-4W-... 

Aromatic acids are reduced by metal-ammonia solutions very much more readily than simple hydrocarbons and ethers. In contrast to the normal requirements for the latter derivatives, it is often possible to achieve reduction with close to stoichiometric quantities of metal. The addition of aromatic carboxylic acids to liquid ammonia (or vice versa) results in the immediate precipitation of the ammonium salt. As the metal is added, however, the precipitate usually dissolves as reduction proceeds, especially if lithium is used. If reduction is carried out in carefully dried, redistilled ammonia, as little as 2.2 mol of lithium are consumed in some cAses, thereby demonstrating that the substrate is reduced much more readily than the ammonium ions, which instead react with the intermediates from reduction of the substrate. However, protonation by NH4 is not essential since reduction proceeds equally well on preformed metal car-boxylates (although low solubility is then often a problem). The addition of an alcohol is not necessary, but it may serve as a useful buffer and can often improve solubility. The presence of alcohol can nevertheless be deleterious, since it facilitates isomerization of the initially formed 1,4-dihydro isomer to the 3,4-isomer and in this way affords the possibility of further reduction. ... 

Many other examples of chemoselective enone reduction in the presence of other reducible functionalities have been reported. For instance, the C—S bonds of many sulfides and thioketals are readily cleaved by dissolving metals. " Yet, there are examples of conjugate reduction of enones in the presence of a thioalkyl ether group." " Selective enone reduction in the presence of a reducible nitrile group was illustrated with another steroidal enone. While carboxylic acids, because of salt formation, are not reduced by dissolving metals, esters" and amides are easily reduced to saturated alcohols and aldehydes or alcohols, respectively. However, metal-ammonia reduction of enones is faster than that of either esters or amides. This allows selective enone reduction in the presence of esters"" and amides - -" using short reaction times and limited amounts of lithium in ammonia. 

Apart from catalytic hydrogenation and dissolving metal methods, very few other techniques exist for the reduction of the pyrrole ring. However, one example is the improved use of hypophosphorus acid that has been described by Scott and coworkers in a reduction of pyrrole-2-carboxylic acid to the prolyl hydroxylase inhibitor (5)-3,4-dehydroproline (after resolution) (equation 10). r,—A i, HI, AcOH, H3PO2... 

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