Sodium aluminum hydride reduction

The mechanism of lithium aluminum hydride reduction of aldehydes and ketones IS analogous to that of sodium borohydride except that the reduction and hydrolysis... 

Methylindole has also been prepared by lithium aluminum hydride reduction of 1-methylindoxyl. Compounds giving rise to NH absorption in the infrared (indole, skatole) can be completely removed by refluxing the crude 1-methylindole over sodium for 2 days and then distilling the unreacted 1-methylindole from the sodio derivatives and tarry decomposition products. 

Mescaline, a hallucinogenic amine obtained from the peyote cactus, has been synthesized in two steps from 3,4,5-trimethoxybenzyl bromide. The first step is nucleophilic substitution by sodium cyanide. The second step is a lithium aluminum hydride reduction. What is the structure of mescaline ... 

Lithium aluminum hydride reduction of pyridinium salts is very similar to sodium horohydride reduction and gives similar products, but the ratio of 1,2- and 1,4-dihydro- or tetrahydropyridines differs considerably (5). Isoquinolinium salts are reduced hy sodium borohydride or lithium aluminum hydride in a manner identical to pyridinium salts (5). Quino-linium salts are reduced by sodium borohydride to give primarily tetra-hydroquinolines (72) as shown by the conversion of 33 to 34 and 35. When lithium aluminum hydride is used, the product is usually the dihydroquinoline (73) as shown in the conversion of 36 to 37 and 38. 

Thus the critical synthetic 1,6-dihydropyridine precursor for the unique isoquinuclidine system of the iboga alkaloids, was generated by reduction of a pyridinium salt with sodium borohydride in base (137-140). Lithium aluminum hydride reduction of phenylisoquinolinium and indole-3-ethylisoquinolinium salts gave enamines, which could be cyclized to the skeletons found in norcoralydine (141) and the yohimbane-type alkaloids (142,143). 

Woodward s strychnine synthesis commences with a Fischer indole synthesis using phenylhydrazine (24) and acetoveratrone (25) as starting materials (see Scheme 2). In the presence of polyphosphor-ic acid, intermediates 24 and 25 combine to afford 2-veratrylindole (23) through the reaction processes illustrated in Scheme 2. With its a position suitably masked, 2-veratrylindole (23) reacts smoothly at the ft position with the Schiff base derived from the action of dimethylamine on formaldehyde to give intermediate 22 in 92% yield. TV-Methylation of the dimethylamino substituent in 22 with methyl iodide, followed by exposure of the resultant quaternary ammonium iodide to sodium cyanide in DMF, provides nitrile 26 in an overall yield of 97%. Condensation of 2-veratryl-tryptamine (20), the product of a lithium aluminum hydride reduction of nitrile 26, with ethyl glyoxylate (21) furnishes Schiff base 19 in a yield of 92%. 

Lithium aluminum hydride reduction of oxychelerythrine (232) gave 6-hydroxydihydrochelerythrine (235), recrystallization of which in methanol afforded 6-methoxydihydrochelerythrine (agoline) (236). Both compounds have been isolated from plants, but they are probably artifacts arising during isolation. On reduction with sodium borohydride or dehydration with 10% hydrochloric acid, 235 was converted to dihydrochelerythrine (203) or chelerythrine (205), respectively (130,131). 

Corynantheidol (255) has been prepared by Hanaoka et al. (155), who started from piperideine derivative 268 and tryptophyl bromide (197). The key cyclization step, resulting in indolo[2,3-a]quinolizine 270 as the major product besides 271, was carried out by mercuric acetate oxidation in the presence of the disodium salt of ethylenediaminetetraacetic acid (EDTA), followed by sodium borohydride reduction. Finally, lithium aluminum hydride reduction of 270 provided ( )-corynantheidol in good yield (155). 

The stereoselective total synthesis of both ( )-corynantheidine (61) (170,171) (alio stereoisomer) and ( )-dihydrocorynantheine (172) (normal stereoisomer) has been elaborated by Szdntay and co-workers. The key intermediate leading to both alkaloids was the alio cyanoacetic ester derivative 315, which was obtained from the previously prepared ketone 312 (173) by the Knoevenagel condensation accompanied by complete epimerization at C-20 and by subsequent stereoselective sodium borohydride reduction. ( )-Corynantheidine was prepared by modification of the cyanoacetate side chain esterification furnished diester 316, which underwent selective lithium aluminum hydride reduction. The resulting sodium enolate of the a-formyl ester was finally methylated to racemic corynantheidine (171). 

The pyridine ring is easily reduced in the form of its quaternary salts to give hexahydro derivatives by catalytic hydrogenation [446], and to tetrahydro and hexahydro derivatives by reduction with alane aluminum hydride) [447], sodium aluminum hydride [448], sodium bis 2-methoxyethoxy)aluminum hydride [448], sodium borohydride [447], potassium borohydride [449], sodium in ethanol [444, 450], and formic acid [318]. Reductions with hydrides give predominantly 1,2,5,6-tetrahydro derivatives while electroreduction and reduction with formic acid give more hexahydro derivatives [451,452]. 

If the quaternary nitrogen is a member of a ring, the ring is cleaved. 3-Benzyl-2-phenyl-A, A -dimethylpyrrolidinium chloride was cleaved by hydrogenation over Raney nickel at 20-25° almost quantitatively to 2-benzyl-4-dimethylamino-l-phenylbutane [722]. Reduction of methylpyridinium iodide (and its methyl homologs) with sodium aluminum hydride gave 24-89% yields of 5-methylamino-l,3-pentadiene (and its methyl homologs) in addition to A -methyl dihydro- and tetrahydropyridine [448]. 

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],... 

Thiochroman-4-ones are reduced to thiochroman-4-ols by sodium borohydride6 and lithium aluminum hydride.50 Lithium aluminum hydride reduction of thiofiavan-4-ones (27) forms the 2,4-ws-thiofiavan-4-ols (28) as in Eq. (8). By contrast, deamination of 2,4-cis-4-aminothio-flavans (29) with nitrous acid produced the trans- alcohol (30) as shown in Eq. (9).50 The alcohols obtained by the hydride reductions have... 

Attempts to synthesize C-terminal peptide aldehydes using other reductive techniques are less successful. 24"29 The reduction of a-amino acid esters with sodium amalgam and lithium aluminum hydride reduction of tosylated a-aminoacyldimethylpyrazoles resulted in poor yields. 26,29 The Rosemond reduction of TV-phthaloyl amino acid chlorides is inconvenient because the aldehyde is sensitive to hydrazine hydrate that is used to remove the phthaloyl group. 27 28 jV -Z-Protected a-aminoacylimidazoles, which are reduced to the corresponding aldehydes using lithium aluminum hydride, are extremely moisture sensitive and readily decomposed. 25 The catalytic reduction of mixed carbonic/carboxylic acid anhydrides, prepared from acylated a-amino acids, leads to poor reproducibility and low yields. 24 The major problems associated with these techniques are overreduction, racemization, and poor yields. 

The lithium aluminum hydride reduction of l-acetyloxy-2-oxindole (287) gave a polymer, but that of the 1-methoxy analogue (288) yielded [78JCS(P1)1117] 1-methoxyindole. Application of this method (83H1797) led to a valuable synthesis of lespedamine 291. Alkylation of 288 by 1,2-dibromoethane and sodium hydride gave a 3,3-spiro derivative, which dimethylamine converted to 289. Reduction with lithium aluminum hydride now gave 290, as a mixture of isomers, which was dehydrated instantly by acid to 291 (see Section 1II,E). 

The last of the butyl isomers, the tert-butyl compound, was made from a much more obvious starting material. This is the commercially available tert-butyl hydroquinone. It was methylated in sodium hydroxide with methyl iodide, and then carried through the above sequence (benzaldehyde. mp 124 °C from cyclohexane, nitrostyrene, yellow crystals from methanol, mp 95-96.5 °C, and lithium aluminum hydride reduction) to give 2,5-dimethoxy-4-(l,l-dimethylethyl)amphetamine hydrochloride (DOTB, mp 168 °C). Rats trained in a process called the Sidman Avoidance Schedule gave behavior that suggested that DOTB had no activity at all, and in human trials, doses of up to 25 milligrams were totally without effect. 

In order to prepare these macrocycles it was necessary to synthesize the previously unknown o -bis(phosphino)benzene (IV). Lithium aluminum hydride reduction of the o-bis(phosphonate) III gave IV in 50% yield (31P NMR, 6 -123.8 ppm, Jpy = 207 Hz). The phosphonate III could be obtained in modest yields by the photo-activated nucleophilic aromatic substitution by sodium diethyl-phosphite on o-chloroiodobenzene in liquid ammonia solution (4). 

The reduction of 2-substituted-isoquinolinium salts has been reported by Torossian65 with potassium borohydride in water, by Mirza,68 and by Durmand et al.,87,68 using sodium borohydride in aqueous methanol to yield 1,2,3,4-tetrahydroisoquinolines. The reduction of the second double bond appears to arise from a mechanism similar to that leading to tetrahydropyridines from pyridinium ions (see Section I). Mirza66 (see also Bose60) found that the reduction of berberine (60) with sodium borohydride could be stopped at the 1,2-dihydro-intermediate (61), and Karrer and Brook70 showed that the 1,2-dihydroisoquinoline formed by the lithium aluminum hydride reduction of l-phenyl-2-methylisoquinolinium iodide (62) could be further reduced to the 1,2,3,4-tetrahydroisoquinoline (63) with sodium borohydride in methanol. Awe et al.71,72 and Huffman73... 

The synthesis of the zero-valent, 1,3-cyclohexadiene benzene ruthenium complex 196a has been mentioned as a coproduct of the cyclohexadienyl complex 236a in the reduction of the benzene ruthenium dication 235 with lithium aluminum hydride. Reduction of 235 with sodium borohydride in THF, however, gives only the air-sensitive, yellow-green ruthenium(O) complex 196a (118). This reaction has been generalized to... 

Lithium aluminum hydride reduction of epiquinamine, as expected, afforded 3-epicinchonamine, mp 168°, [a]D +48° (EtOH), also obtainable along with cinchonamine by the sodium-ethanol reduction of apoquinamine (23). Finally, it was shown in 1945 that, on heating quinamine or dihydroquinamine above its melting point, formaldehyde was evolved, and this was taken as evidence for the presence of a 2-hydroxymethyl on an indole a-carbon (15). In the light of the true structure, the writer would like to suggest that this aldehyde is formed by pyrolysis of a 1,3-glycol, that is, a retro Prins reaction (25). 

Reduction of 2-(4-pyridyl)propenol (60)51 with sodium in ethanol and the aluminum hydride reduction of 4-isopropylpyridine48 afford the same product, 4-isopropyl-3-piperideine (61). 

Somewhat less useful is the aluminum hydride reduction of quaternary pyridinium salts. Reduction of the salts may be more conveniently performed by the use of sodium borohydride (see Section II, B, 6). Moreover, the aluminum hydride reductions of some dialkyl-pyridinium salts are accompanied by reductive cleavage of the pyridine ring,77 For example, methiodides of 2,5-dimethylpyridine,77 2-methyl-5-ethylpyridine,77 and 2-ethyl-5-methylpyridine61 afford mixtures of the corresponding tetrahydro and hexahydro bases along with a secondary amine, viz., 5-methylaminomethyl-2,4-hexadiene, 5-methylaminomethyl-2,4-heptadiene, and 7-methylamino-6-methyl-2,4-heptadiene, respectively. 

In contrast to aluminum hydride reductions (see Section II, B, 4), no ring openings have been observed in reductions of quaternary pyridinium salts by means of sodium borohydride. Whenever possible, both isomeric tetrahydropyridines are formed, as it may be seen from the following examples (aluminum hydride, electrolytic, and formic acid reductions are included for comparison). 

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