Reduction by lithium aluminium hydride

To meet the needs of the advanced students, preparations have now been included to illustrate, for example, reduction by lithium aluminium hydride and by the Meerwein-Ponndorf-Verley method, oxidation by selenium dioxide and by periodate, the Michael, Hoesch, Leuckart and Doebner-Miller Reactions, the Knorr pyrrole and the Hantzsch collidine syntheses, various Free Radical reactions, the Pinacol-Pinacolone, Beckmann and Arbusov Rearrangements, and the Bart and the Meyer Reactions, together with many others. 

TABLE l. Structural features of sulphones in relation to their reduction by lithium aluminium hydride... 

W. G. Brown, Reductions by Lithium Aluminium Hydride, Organic Reactions, Vol. VI, S. 469, John Wiley Sons, New York 1951. 

In an approach toward a synthesis of tetraponerine 37, Gevorgyan first synthesized the fully aromatic tricyclic system 49 and then reduced it over two steps, first via hydrogenation under pressure (50 psi) to give 36 followed by a second reduction by lithium aluminium hydride of the amidinium salt (Scheme 1) <2002OL4697, 2004JOC5638>. 

Amino-4-methoxy-l-methoxymethylnaphthalene 120, obtained from the chloromethyl derivative 111, is transformed into azide 121. The latter undergoes photolytic heterocyclization to the labile 5-methoxyben-zo[cd]indole 117 which, on reduction by lithium aluminium hydride followed by acetylation, is converted into the stable l-acetyI-5-methoxy-l, 2-dihydrobenzo[o/]indole 119 (R = OMe) [71JCS(C)721]. The reduction of methyl or phenyl 8-nitro-1 -naphthyl ketones by hydrogen and platinum dioxide or by iron in acetic acid leads to a mixture of products (59M634). 

Similar results were also obtained with diborane, followed by acid treatment148. Reduction by lithium aluminium hydride is effective in reducing the double bond of enaminones, leaving the carbonyl group untouched, as it acts via 1,4-addition149,150 (Scheme 107). 

Reductive deoxygenation-rearrangement of 2-yne-l,4-diols to 1,3-dienes is a useful synthetic procedure since a large variety of ynediols are available in a few steps by sequential reaction at both ends of acetylene with aldehydes. Acetylenic 1,4-diols can be deoxygenated reductively by lithium aluminium hydride to form conjugated dienes of high stereoisomeric purity (equation 9). A modification to this procedure is the use of acetylenic 1,4-diol mono-THP derivative. Allenic tertiary alcohols which are intermediates in the reaction can be separated and subjected to reductive elimination rearrangement... 

Catalytic hydrogenation gives a mixture of partially reduced products (enamine and allylamine) and/or saturated amine depending on the conditions used . Partial reduction also occurs on treatment with lithium in ammonia . Dienamines are resistant to reduction by lithium aluminium hydride which therefore provides a means for selective reduction of a less reactive carbonyl group in polyfunctional molecules (Scheme 13). 

Reduction by lithium aluminium hydride (LAH) or addition of phenylmagnesium bromide transforms the aroyl groups in 3-aroyl-3,4-dihydro-l,2,3-benzotriazin -ones 93b and 93c into more hydrolyzable 3-(1-hydroxy-1-arylalkyl) groups. Accordingly, the parent benzotriazinone 3 is reached in both cases prior to or during aqueous workup <1%OJOC1501>. 

In this context, Alvarez et al. synthesized a boranophosphinate 18, analogue of AZT (Scheme 2) [22]. The formation of the phosphorus-boron motif required six steps, starting from the stable thymine phosphonate 14. A full reduction by lithium aluminium hydride followed by partial oxidation mediated by hydrogen peroxide afforded the //-phosphinic acid 16. After the introduction of the azide group, azido-//-phosphinate 17 undergoes a borylation and desilylation to yield to the boranophosphinate 18. 

Oxymercuration followed by borohydride reduction of 6-methylenebicyclo-[3,l,l]heptane (166) gave the alcohols shown in Scheme 8. Similar reaction with 5-methylenebicyclo[2,l,l]hexane gave entirely monocyclic products. Stereochemical aspects are discussed for the formation and reduction of epoxides of 2-methylene- and 3-methylene-bicyclo[3,l,l]heptanes, the hydrobora-tion-oxidation of 3-methylenebicyclo[3,l,l]heptanes, and reduction by lithium aluminium hydride and diborane of bicyclo[3,l,l]heptanones. ... 

Boron forms a whole series of hydrides. The simplest of these is diborane, BjH. It may be prepared by the reduction of boron trichloride in ether by lithium aluminium hydride. This is a general method for the preparation of non-metallic hydrides. 

Note. Both tetramethylene glycol (1 4-butanediol) and hexamethylene glycol (1 6 hexaiiediol) may be prepared more conveniently by copper-chromium oxide reduction (Section VI,6) or, for small quantities, by reduction with lithium aluminium hydride (see Section VI,10). 

Some of the functional groups which are reduced by lithium aluminium hydride, the reduction product together with the theoretical mols of reducing agent required (in parenthesis) are listed below —... 

Hydroxyalkylthiazoles are also obtained by cyclization or from alkoxyalkyl-thiazoles by hydrolysis (36, 44, 45, 52, 55-57) and by lithium aluminium hydride reduction of the esters of thiazolecarboxylic acids (58-60) or of the thiazoleacetic adds. The Cannizzaro reaction of 4-thiazolealdehyde gives 4-(hydroxymethyl)-thiazole (53). The main reactions of hydroxyalkyl thiazoles are the synthesis of halogenated derivatives by the action of hydrobroraic acid (55, 61-63), thionyl chloride (44, 45, 63-66), phosphoryl chloride (52, 62, 67), phosphorus penta-chloride (58), tribromide (38, 68), esterification (58, 68-71), and elimination that leads to the alkenylthiazoles (49, 72). 

Two contrasting conclusions have been reported in the reactions of lithium aluminium hydride in THF with phosphine oxides and phosphine sulphides respectively. The secondary oxide, phenyl-a-phenylethylphos-phine oxide (42), has been found to be racemized very rapidly by lithium aluminium hydride, and this observation casts some doubt on earlier reports of the preparation of optically active secondary oxides by reduction of menthyl phosphinates with this reagent. A similar study of the treatment of (/ )-(+ )-methyl-n-propylphenylphosphine sulphide (43) with lithium aluminium hydride has revealed no racemization. These results have been rationalized on the basis of the preferred site of attack of hydride on the complexed intermediate (44), which, in the case of phosphine oxides (X = O), is at phosphorus, and in the case of the sulphides (X = S), is at sulphur. Such behaviour is comparable to that observed during the reduction of phosphine oxides and sulphides with hexachlorodisilane. ... 

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. 

Ozonolysis of alkene 446 in the presence of acetaldehyde afforded diketone 448 through the intermediacy of 447. Ring expansion through Beckmann rearrangement took place when bis-oxime 449 was mesylated and warmed in aqueous tetrahydrofuran (THF). The bis-lactam so formed gave piperidinediol 450 on reduction with lithium aluminium hydride, and this compound was transformed into ( )-sparteine by treatment with triphenylphosphine, CCI4, and triethylamine (Scheme 105) <20050BC1557>. 

Azatriquinadiene (2,3-dihydroazatriquinacene) 39 has been efficiently synthesized from enamine 389. Enamine 389 on treatment with bromine followed by aqueous work-up afforded the tetrabromohemiaminal 390. Dehydrohalogenation of 390 with potassium hexamethyldisilazide (KHMDS) and compound 391 on reduction with lithium aluminium hydride yielded the target molecule azatriquinadiene 39 in good overall yield (Scheme 85) <2000JOC7253>. 

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... 

The l.d. 50 for mice of this compound was 15 mg./kg. Some of the higher members of this series show an alternation of toxicity, as do also the mercaptans produced by reduction of the thiocyanates by lithium aluminium hydride. Thus F(CH2)nSH was toxic when n was even. 

Basic solid liquid two-phase conditions with f-butyl peroxide and N-benzylquininium chloride convert cyclohex-2-enone preferentially into the 2(S),3(S)-oxirane (20% ee) which, upon purification and treatment with hydrazine, yields (S)-cyclohex-2-enol [7]. This reaction contrasts with the direct reduction of cyclohex-2-enone to the /J-isomer by lithium aluminium hydride in the presence of quinine [20]. 

Complete control of the diastereoselectivity of the synthesis of 1,3-diols has been achieved by reagent selection in a one-pot tandem aldol-reduction sequence (see Scheme l). i Anti-selective method (a) employs titanium(IV) chloride at 5°C, followed by Ti(OPr )4, whereas method (b), using the tetrachloride with a base at -78 °C followed by lithium aluminium hydride, reverses the selectivity. A non-polar solvent is required (e.g. toluene or dichloromethane, not diethyl ether or THF), and at the lower temperature the titanium alkoxide cannot bring about the reduction of the aldol. Tertiary alkoxides also fail, indicating a similarity with the mechanism of Meerwein-Ponndorf reduction. 

Estradiol is formed by lithium aluminium hydride reduction of the ketone. We can formulate this simply as hydride acting as the nucleophile, though hydride delivery by LAH is strictly more complex than this. Unless you are specifically asked for details, treat LAH as a source of hydride ion. 

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