Lithium carboxylic acid reduction

Reactions of Nitriles Nitriles undergo acidic or basic hydrolysis to amides, which may be further hydrolyzed to carboxylic acids. Reduction of a nitrile by lithium aluminum hydride gives a primary amine, and the reaction with a Grignard reagent gives an imine that hydrolyzes to a ketone. 

Zsadon and Horvath-Otta have investigated some of the simple reactions of tabersonine (28) and vincadifformine (2) (185,186). Zinc and hydrochloric acid in methanol gave the 2,16-dihydro derivatives 274 and 74, which could be hydrolyzed to the corresponding carboxylic acids. Reduction of the dihydro esters with lithium aluminum hydride gave the carbinols 345 and 78. 

Aldehydes and Ketones from Carboxylic Acids. Reduction of the derived acylimidazole (2) with Lithium Aluminum Hydride achieves conversion of an aliphatic or aromatic carboxylic acid to an aldehyde (eq 6). DiisobutyUduminum Hydride has also been used, allowing preparation of a-acylamino aldehydes fromiV-protected amino acids. Similarly, reaction of... 

REDUCTION OF CARBOXYLIC ACIDS Reduction With Lithium Aluminum Hydride Reduction with Diborane... 

Lithium aluminium hydride, LiAlH, is a very active reducing agent, and is used particularly for the ready reduction of carboxylic acids (or their esters) to primary alcohols R-COOH -> R CH,OH. 

The less hindered f/ans-olefins may be obtained by reduction with lithium or sodium metal in liquid ammonia or amine solvents (Birch reduction). This reagent, however, attacks most polar functional groups (except for carboxylic acids R.E.A. Dear, 1963 J. Fried, 1968), and their protection is necessary (see section 2.6). 

Reductions carried out with lithium aluminium hydride are not always so successful. As noted by Sprague (46) the esters of 2-aminothiazole carboxylic acids behave somewhat differently with AlLiH4 (55). 

Lithium aluminum hydride reduction (Sec tion 15 3) Carboxylic acids are reduced to primary alcohols by the powerful reducing agent lithium aluminum hydride... 

The Rosenmund reduction is usually applied for the conversion of a carboxylic acid into the corresponding aldehyde via the acyl chloride. Alternatively a carboxylic acid may be reduced with lithium aluminum hydride to the alcohol, which in turn may then be oxidized to the aldehyde. Both routes require the preparation of an intermediate product and each route may have its advantages over the other, depending on substrate structure. 

Compared to the lithium enolates of l and 5, the higher stereoselectivity obtained by the Mukaiyama variation is, in general, accompanied by reduced chemical yields. The chiral alcoholic moieties of the esters 3 and 7 can be removed either by reduction with lithium aluminum hydride (after protection of the earbinol group) or by aqueous alkaline hydrolysis with lithium hydroxide to afford the corresponding carboxylic acid. In both cases, the chiral auxiliary reagent can be recovered. 

The same nonpolar conformation can be achieved by conversion to bicyclic structures. 1,4-Cyclo-addition of ethylene to anthracene-9-carboxylic acid gives acid 68. Successive conversion to the N-methylamide, via the acid chloride, followed by reduction with lithium aluminum hydride produced... 

Reduction of carboxylic acids are the most difficult, but they can be accomplished with the powerful reducing agent lithium aluminum hydride (LiAlH4, abbreviated LAH). 

The final step is to convert the carboxylic acid into a primary alcohol by heating it with lithium aluminium hydride (LiAlH ) dissolved in ether (ethoxyethane). This is a reduction reaction and delivers the target molecule, propan-l-ol. 

Free acids require still an additional hydride equivalent because their acidic hydrogens combine with one hydride ion of lithium aluminum hydride forming acyloxy trihydroaluminate ion. Complete reduction of free carboxylic acids to alcohols requires 0.75 mol of lithium aluminum hydride. The same amount is needed for reduction of monosubstituted amides to secondary amines. Unsubstituted amides require one full mole of lithium aluminum hydride since one half reacts with two acidic hydrogens while the second half achieves the reduction. 

The reduction of free acids to alcohols became practical only after the advent of complex hydrides. Lithium aluminum hydride reduces carboxylic acids to alcohols in ether solution very rapidly in an exothermic reaction. Because of the presence of acidic hydrogen in the carboxylic acid an additional equivalent of lithium aluminum hydride is needed beyond the amount required for the reduction. The stoichiometric ratio is 4 mol of the acid to 3 mol of lithium aluminum hydride (Equation 12, p. 18). Trimethylacetic add was reduced to neopentyl alcohol in 92% yield, and stearic acid to 1-octadecanol in 91% yield. Dicarboxylic sebacic acid was reduced to 1,10-decanedioI even if less than the needed amount of lithiiun aluminum hydride was used [968]. 

Reduction of aromatic carboxylic acids to alcohols can be achieved by hydrides and complex hydrides, e.g. lithium aluminum hydride 968], sodium aluminum hydride [55] and sodium bis 2-methoxyethoxy)aluminum hydride [544, 969, 970], and with borane (diborane) [976] prepared from sodium borohydride and boron trifluoride etherate [971, 977] or aluminum chloride [755, 975] in diglyme. Sodium borohydride alone does not reduce free carboxylic acids. Anthranilic acid was reduced to the corresponding alcohol by electroreduction in sulfuric acid at 20-30° in 69-78% yield [979],... 

The classical preparation of alkyllithium compounds by reductive cleavage of alkyl phenyl sulfides with lithium naphthalene (stoichiometric version) was also carried out with the same electron carrier but under catalytic conditions (1-8%). When secondary alkyl phenyl sulfides 73 were allowed to react with lithium and a catalytic amount of naphthalene (8%) in THF at —40°C, secondary alkyllithium intermediates 74 were formed, which finally reacted successively with carbon dioxide and water, giving the expected carboxylic acids 75 (Scheme 30) °. 

The CD fragment 1s synthesized starting with resolved bicyclic acid 129. Sequential catalytic hydrogenation and reduction with sodium borohydride leads to the reduced hydroxy acid 1. The carboxylic acid function is then converted to the methyl ketone by treatment with methyl-lithium and the alcohol is converted to the mesylate. Elimination of the latter group with base leads to the conjugated olefin 133. Catalytic reduction followed by equilibration of the ketone in base leads to the saturated methyl ketone 134. Treatment of that intermediate with peracid leads to scission of the ketone by Bayer Villiger reaction to afford acetate 135. The t-butyl protecting... 

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