From reduction of carboxylic acids

From reduction of carboxylic acids and acyl derivatives Sodium borohydride, 278 Sodium cyanoborohydride-Tin(II) chloride, 280... 

From oxidative cleavage of 1,2-diols and 1,2-amino alcohols Dibutyltin oxide, 95 By reaction of alkyl halides with sulfur-stabilized carbanions Methylthiomethyl p-tolyl sulfone, 192 From reduction of carboxylic acids Vilsmeier reagent, 341 From terminal alkenes by addition reactions... 

Section 15.3 Alcohols can be prepared from carbonyl compounds by reduction of carboxylic acids and esters. See Table 15.3. 

The reduction of carboxylic acids to the aldehydes is catalyzed by reduced viologen accepting tungsten containing enzymes from Clostridium thermoaceticum and Clostridium, formicoaceticum. This reaction is reversible [73-75] ... 

The biocatalytic reduction of carboxylic acids to their respective aldehydes or alcohols is a relatively new biocatalytic process with the potential to replace conventional chemical processes that use toxic metal catalysts and noxious reagents. An enzyme known as carboxylic acid reductase (Car) from Nocardia sp. NRRL 5646 was cloned into Escherichia coli BL21(DE3). This E. coli based biocatalyst grows faster, expresses Car, and produces fewer side products than Nocardia. Although the enzyme itself can be used in small-scale reactions, whole E. coli cells containing Car and the natural cofactors ATP and NADPH, are easily used to reduce a wide range of carboxylic acids, conceivably at any scale. The biocatalytic reduction of vanillic acid to the commercially valuable product vanillin is used to illustrate the ease and efficiency of the recombinant Car E. coli reduction system." A comprehensive overview is given in Reference 6, and experimental details below are taken primarily from Reference 7. 

Reduction then proceeds by successive transfers of hydride ion, H e, from aluminum to carbon. The first such transfer reduces the acid salt to the oxidation level of the aldehyde reduction does not stop at this point, however, but continues rapidly to the alcohol. Insufficient information is available to permit very specific structures to be written for the intermediates in the lithium aluminum hydride reduction of carboxylic acids. However, the product is a complex aluminum alkoxide, from which the alcohol is freed by hydrolysis ... 

Reduction of carboxylic acids to aldehydes. 2 3-Acyllhiazolidine-2-thiones (2) can be prepared by reaction of l,3-thiazolidine-2-thione (1) with carboxylic acids directly (using 2-chloro-l-methylpyridinium iodide, 8, 95-96) or with acid chlorides (triethylamine or DCC). They can also be prepared from reaction of the thallium salt of 1 with an acid chloride. Yields by all four methods are 70-95%. The amides are reduced to aldehydes by either DIBAH or, generally in higher yield, by NaBH4 (90-98% yield). 

Also in the cathodic reduction of carboxylic acids, electrolysis is in competition with catalytic methods. However, catalytic hydrogenations in this area do not always proceed so smoothly that electrochemical processes are without any prospects from the outset. 

Industrial work on the reduction of carboxylic acids was focused on the search for an electrochemical synthesis of glyoxylic add from oxalic acid ... 

Until about 1950, reduction of carboxylic acids and their derivatives to aldehydes was not straightforward, and even one of the best methods, the Rosenmund hydrogenation of acid chlorides, required very careful control of both the reaction conditions and preparation of catalyst. The advent of aluminum and boron hydrides and their ready commercial availability transformeKl the situation to such an extent that the formation of aldehydes from carboxylic acids, acid chlorides, esters, amides, nitriles and similar groups in the presence of other reducible functional groups has become a relatively easy operation on both small and large scale. 

There have been two major approaches towards achieving selective reduction of carboxylic acid derivatives to aldehydes (or derivatives) by hydrides. Firstly, hydride reagents themselves have been modified as, for example, sodium borohydride and sodium cyanoborohydride. Sometimes these modifications have led to finely tuned reducing agents, as with the dimethyl sulfide adduct of thexylbromoborane (see later). Secondly, the type of carboxylic acid derivative has been modified for the optimum yield of aldehyde. For example, amides have been made from an assortment of amines in efforts to maximize yields of aldehyde. Best yields of aldehydes are obtained usually by a combination of modified hydride reagent with a modified carboxylic acid derivative. 

In a later development by Bedenbaugh et methylamine was used as solvent and lithium as electron donor. No proton donor was required, suggesting that the lithium salt (28) of hemiaminal (27) is stable under the reaction conditions (both aldehydes and aldimines are reduced by the reagent cf. the analogous reduction of carboxylic acids, Section 1.12.2 and Scheme 2). Yields of aldehydes produced by this method are shown in Table 8. It is notable that only tertiary amides are reduced satisfactorily. A major limitation of the reaction is the substantial formation of side products resulting from transamid-ation by the methylamine solvent (/. e. RCONHMe from RCONR 2). 

Hydroxymethylpyrazines may be prepared by reduction of carboxylic acid derivatives. Thus reduction of 2-amino-3-methoxycarbonylpyrazine with lithium aluminum hydride in tetrahydrofuran gave 2-amino-3-hydroxymethylpyrazine (1074, 1075) the imide from 23-dicarboxypyrazine (20) with sodium borohydride in tetrahydrofuran gave 2-carbamoyl-3-hydroxymethylpyrazine (21), and the methylcarbamoyl analogue was prepared similarly (1076). 

Aldehydes. The reduction of carboxylic acid derivatives such as esters and nitriles is stopped at the aldehyde stage with the modified sodium aluminum hydride. The reagent is prepared from NaAlH2Et2 and piperidine in THF-toluene at 0°C. Interestingly, acid chlorides can be converted to aldehydes by treatment with piperidine and then with NaAlH2Et2- ... 

Reduction of acids or esters to aldehydes. Diaminoaluminum hydrides, particularly those derived from secondary cyclic amines such as N-methyl-piperazine or morpholine, are useful for reduction of carboxylic acids or esters to aldehydes, without contamination by the corresponding alcohols. The reduction is carried out in refluxing THF (6-20 hr.). In general, 2 moles of reagent are used for each mole of substrate. The reduction is applicable to both aromatic and aliphatic esters. Yields are in the range of 50-85%,... 

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