Lithium aluminium hydride alcohols

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. 

Trimethylene dibromide (Section 111,35) is easily prepared from commercial trimethj lene glycol, whilst hexamethylene dibromide (1 O dibromohexane) is obtained by the red P - Br reaction upon the glycol 1 6-hexanediol is prepared by the reduction of diethyl adipate (sodium and alcohol lithium aluminium hydride or copper-chromium oxide and hydrogen under pressure). Penta-methylene dibromide (1 5-dibromopentane) is readily produced by the red P-Brj method from the commercially available 1 5 pentanediol or tetra-hydropyran (Section 111,37). Pentamethylene dibromide is also formed by the action of phosphorus pentabromide upon benzoyl piperidine (I) (from benzoyl chloride and piperidine) ... 

Potassium and sodium borohydride show greater selectivity in action than lithium aluminium hydride thus ketones or aldehydes may be reduced to alcohols whilst the cyano, nitro, amido and carbalkoxy groups remain unaffected. Furthermore, the reagent may be used in aqueous or aqueous-alcoholic solution. One simple application of its use will be described, viz., the reduction of m-nitrobenzaldehyde to m-nitrobenzyl alcohol ... 

Thiazole acids may undergo many different types of reduction. Chemical reduction of thiazolecarboxy lic acids and of their derivatives to yield the corresponding alcohols can be accomplished with lithium aluminium hydride in ether solution (53). 

Reduction with sodium in alcohol was unsuccessful (54). The introduction of lithium aluminium hydride has provided an elegant method for the reduction of thiazole esters to hydroxythiazoles for example, ethyl 2-methyl-4-thiazolecarboxylate (11 with lithium aluminium hydride in diethyl ether gives 2-methyl-4-(hydroxymethyl)thiazole (12) in 66 to 69% yield (Scheme 7) (53),... 

The purification of diethyl ether (see Chapter 4) is typical of liquid ethers. The most common contaminants are the alcohols or hydroxy compounds from which the ethers are prepared, their oxidation products (e.g. aldehydes), peroxides and water. Peroxides, aldehydes and alcohols can be removed by shaking with alkaline potassium permanganate solution for several hours, followed by washing with water, concentrated sulfuric acid [CARE], then water. After drying with calcium chloride, the ether is distilled. It is then dried with sodium or with lithium aluminium hydride, redistilled and given a final fractional distillation. The drying process should be repeated if necessary. 

The Mitsunobu reaction was also applied to the synthesis of [ 1,2,4]triaz-ino[4,5-n]indoles (84AG517). Thus, reaction of the 2-acylindoles 127 with sodium borohydride in methanol or with lithium aluminium hydride in tetrahydrofuran gave the corresponding alcohols 128. Their cyclization with diethyl azodicarboxylate in the presence of triphenyl-phosphine gave the triazinoindoles 129. Acid treatment of the latter afforded 130 (Scheme 30). 

Lithium aluminium hydride reduces carboxylic esters to give 2mol of alcohol. The reaction is of wide scope and has been used to reduce many esters. Where the interest is in obtaining R OH, this is a method of hydrolyzing esters. Lactones... 

Lithium aluminium hydride Higuchi and co-workers100 introduced it as a titrant, usually in tetrahydrofuran (previously liberated from peroxide), for the titration of alcohols and phenols according to the overall reaction... 

In the synthesis of methyl corydalate (55) Nonaka et al. (65) used the methiodide of (-t-)-tetrahydrocorysamine (65) as substrate and the Hofmann degradation method for ring opening (Scheme 16). The methine base (66) on hydroboration afforded alcohol 67, identical with a product obtained from 55 by lithium aluminium hydride reduction. 

Brown, H. C., and Ch. J. Shoaf Selective Reductions. III. Further Studies of the Reaction of Alcohols with Lithium Aluminium Hydride as a Route to the Lithium Alkoxyaluminiumhydrides. J. Amer. chem. Soc. 

Because of their interest in physiologically active selenophenes, Magde-sieva and co-workers147 I4S have prepared some a-amino alcohols (115). Ketones (114) were nitrosated and the oximes thus obtained were reduced with lithium aluminium hydride. 

Reduction of 124, 125, and 126 with either sodium borohydride or lithium aluminium hydride followed by methylation of the unstable alcohol obtained gave the methyl ethers 130,131, and 132 respectively. Comparisons between the NMR spectra of the methyl ethers 130 and 131 and the homoannulenes 127 and 128 indicated that 130 and 131 are paratropic like the 16 7r-electron methyl ether 114. The methyl ether 132 is atropic. 

Oxidative coupling55 of the acetylenic alcohol 146 under Eglinton conditions followed by acidic treatment of the product gave the aldehydes 147 (37%) and 148 (8%). Wittig reaction of aldehyde 147 and the bisphosphonium salt 120 with 1,5-diazabicyclo[4.3.0]non-5-ene as base gave the [21]annulenone 149. This on reduction with lithium aluminium hydride-aluminium chloride gave the homoannulene... 

Nonmetallic systems (Chapter 11) are efficient for catalytic reduction and are complementary to the metallic catalytic methods. For example lithium aluminium hydride, sodium borohydride and borane-tetrahydrofuran have been modified with enantiomerically pure ligands161. Among those catalysts, the chirally modified boron complexes have received increased interest. Several ligands, such as amino alcohols[7], phosphino alcohols18 91 and hydroxysulfoximines[10], com-plexed with the borane, have been found to be selective reducing agents. 

A particularly interesting property of lithium aluminium hydride is its ability to reduce carboxylic acids and its derivatives to primary alcohol. 

Although lithium aluminium hydride does not reduce alkenes or acetylene hydrocarbons, it reduces allylic alcohols and their acetylenic counterparts. Thus cinnamic acid is reduced to dihydrocinnamyl alcohol. 

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. 

By reduction of aldehydes and ketones Aldehydes and ketones are reduced to the corresponding alcohols by addition of hydrogen in the presence of catalysts (catalytic hydrogenation). The usual catalyst is a finely divided metal such as platinum, palladium or nickel. It is also prepared by treating aldehydes and ketones with sodium borohydride (NaBH4) or lithium aluminium hydride (LLAIH4). Aldehydes yield primary alcohols whereas ketones give secondary alcohols. 

Carboxylic acids are reduced to primaiy alcohols by lithium aluminium hydride or better with diborane. Diborane does not easily... 

We have already noted the ability of complex metal hydrides like lithium aluminium hydride and sodium borohydride to reduce the carbonyl group of aldehydes and ketones, giving alcohols (see Section 7.5). These reagents deliver hydride in such a manner that it appears to act as a nucleophile. However, as we have seen, the aluminium hydride anion is responsible for transfer of the hydride and... 

Reduction of the 19-tosylates (28) and (30) with lithium aluminium hydride gave the 5,10-methano-compound (29) and the alcohol (31) respectively. Vicinal dibromo-steroids are converted readily into olefins when treated with silver salts in the presence of amines. Diaxial bromohydrins are converted into the epoxides under these conditions. 

Reduction of cycloalkane-condensed 2-phenyl-5,6-dihydro-4//-l,3-benzoxazines 144 with lithium aluminium hydride (LAH) afforded A -benzyl-substituted 2-(aminomethyl)cycloalkanols 145 in a reductive ring opening via the ring-chain tautomeric tetrahydro-l,3-oxazine intermediates. Catalytic reduction of 1,3-oxazines 144 under mild conditions in the presence of palladium-on-carbon catalyst similarly resulted in formation of the A -benzyl-1,3-amino alcohols 145. When the catalytic reduction was performed at elevated temperature at hydrogen pressure of 7.1 MPa, the N-unsubstituted 2-(aminomethyl)cycloalkanols 146 were formed in good yields (Scheme 22) <1998SC2303>. 

These intermediates were used to synthesize optically pure ephedrines and amphetamines without recourse to resolution, since the chirality of the amino acid educt was entirely conserved throughout the process. The reduction of (S)-2-(ethoxycarbo-nyl)amino-propiophenone (74) first produced a mixture of alcohols (75a, b) Lithium aluminium hydride reduction then produced the desired secondary amino alcohols (76a, b). Table 1 illustrates the reduction scheme and the diastereomer ratios obtained "K... 

---