Lithium alkoxyaluminum hydride

Reduction of o /i-unsatin-ated lactams, S,6-dihydro-2-pyridones, with lithium aluminum hydride, lithium alkoxyaluminum hydrides and alane gave the corresponding piperidines. 5-Methyl-5,6-dihydro-2-pyridone (with no substituent on nitrogen) gave on reduction with lithium aluminum hydride in tetrahydrofuran only 9% yield of 2-methylpiperidine, but l,6-dimethyl-5,6-dihydro-2-pyridone and 6-methyl-l-phenyl-5,6-dihydro-2-pyridone afforded 1,2-dimethylpiperidine and 2-methyl-1-phenylpiperidine in respective yields of 47% and 65% with an excess of lithium aluminum hydride, and 91% and 92% with alane generated from lithium aluminum hydride and aluminum chloride in ether. Lithium mono-, di- and triethoxyaluminum hydrides also gave satisfactory yields (45-84%) [7752]. 

Based on the accompanying kinetic data and an observation that lithium cation is essential in the lithium aluminum hydride reduction,5 Ashby and Boone proposed that the reduction would occur via a six-membered transition state in which the lithium cation is involved4 (Scheme 4.II). Because the aluminum in the boat transition state TS-boat is proximal to the carbonyl oxygen, the boat transition state might be of lower energy than the chairlike transition state TS-chair. Furthermore, the boatlike transition state would be a favored states as it results in direct formation of the lithium alkoxyaluminum hydride intermediate. 

The enantioselective reduction of unsymmetrical ketones to produce optically active secondary alcohols has been one of the most vibrant topics in organic synthesis.8 Perhaps Tatchell et al. were first (in 1964) to employ lithium aluminum hydride to achieve the asymmetric reduction of ketones9 (Scheme 4.IV). When pinacolone and acetophenone were treated with the chiral lithium alkoxyaluminum hydride reagent 3, generated from 1.2 equivalents of 1,2-0-cyclohexylidene-D-glucofuranose and 1 equivalent of LiAlHzt, the alcohol 4 was obtained in 5 and 14% ee, respectively. Tatchell improved the enantios-electivity in the reduction of acetophenone to 70% ee with an ethanol-modified lithium aluminum hydride-sugar complex.10... 

Asymmetric reduction of (5s)-sulfmimine 110 with diisobutylaluminum hydride (DIBAL) afforded a diastereomeric mixture of sulfinamides 111 in 92% yield and in a ratio of 96 4.34 Use of sodium boron hydride, lithium aluminum hydride, or lithium alkoxyaluminum hydride resulted in lower optical yields.33,34,75 The sul-finyl group can be removed by treating 111 with trifluoroacetic acid (TFA) and methanol to give a-phenylethyl amine (112). 

Chiral lithium alkoxyaluminum hydride complexes can be used to obtain optically active allylic alco-hols. " These reagents are more selective than the polymer-supported LiAlfL and LiAlRt-monosac-charide complexes. ... 

I he keto function in compound 10 is reduced with lithium aluminum hydride in THF to a secondary alcohol. In the course of this reaction one of the melhoxy groups in the ortho-position is also cleaved. It appears reasonable to explain this by an oriho effect the alcohol group forms an intermediate alkoxyaluminum hydride complex 37 that coordinates with one of the methoxy groups, which is thereby activated toward nucleophilic attack by hydride. A chelate complex protects the product from cleavage of the second ortho-methoxy group. 

A general method for the synthesis of 2-deoxyaldoses utilizes a reaction sequence involving the formation and subsequent reduction of ketene dithioacetal intermediates (Scheme 10). Reduction of ketene diethyl dithioacetal 12 with lithium aluminum hydride proceeds via the alkoxyaluminum hydride salt involving the 3-hydroxyl group. Several deoxy hexoses and pentoses were prepared by this method, and also their 2-deuterio analogues.45... 

A comparison of four tri-f-alkoxyaluminum hydrides revealed that lithium tris[(3-ethyl-3-pen-tyl)oxy]aluminum hydride, prepared from LAH and 3-ethyl-3-pentanol, was the most selective for reduction of aldehydes over ketones of all types. Even the less reactive benzaldehyde was reduced in THE at -78 C faster than cyclohexanone (97.7 2.3). A good correlation between the steric demands of the reducing agent and the observed chemoselectivity was observed. 

Addition of lithium aluminum hydride to an aldehyde or ketone furnishes initially an alkoxyaluminum hydride, which continues to deliver hydride to three more carbonyl groups, in this way reducing a total of four equivalents of aldehyde or ketone. Work-up with water consumes excess reagent, hydrolyzes the tetraalkoxyaluminate to aluminum hydroxide, A1(0H)3, and releases the product alcohol. 

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