LiAlH4, reaction with acetates

Carboxyl redution. A sample of pennethylated PI (5 mg) was carboxyl-reduced by a modification of the method described by Lindberg and Lbnngren [9], as follows. The methylated fraction was solubilized and added a mixture of LiAlH4 (25 mg) in THF (5 mL) at 20 °C for 4 h. and refluxed during 1 h. The excess of reagent was destroyed with ethyl acetate (5-6 drops) and water (10 drops) and the pH of the mixture adjusted to neutrality with acetic acid. The insoluble residue was removed by centrifugation. The reduced fi action was precipitated with EtOH. The reaction was monitored by l.r. specroscopy. Hydrolysis products were analysed by GC-MS as methyl alditol acetates... 

Mannich bases. A nonacidic and regioselective route to Mannich bases (3) from ketones (or esters) involves reaction with DMF dimethyl acetal (1) at 110° to form an enaminone, which is reduced by LiAlH4 to the Mannich base.1 Example ... 

Subsequent reaction with lithium aluminium hydride afforded the chiral cryptand 10 in only 15 % yield 43. However, LiAlH4 could not be replaced by a more powerful agent, like diborane which will cleave the acetal group. 

For the preparation of 4-(1.2.3.4-tetrahydroquinolino)-phenol 17 three different procedures were worked out [Eqs. (6)-(8)]. 17 was prepared by reacting N-p-methoxyphenyl-anthranilic acid with acetic anhydride and subsequent saponification to l-p-methoxyphenyl-4-hydroxy-2-quinolone, reaction withPOCl3 to form l-p-methoxyphenyl-4-chloro-2-quinolone, hydrogenation to l-(p-methoxy-phenyl)-3.4-dihydro-2-quinolone, splitting the ether with HBr to l-(p-hydroxy-phenyl)3.4-dihydro-2-quinolone, and reduction with LiAlH4 [Eq. (6)J. Another synthetic possibility was the reaction of p-anilinophenol with (3-propiolactone and subsequent cyclization to l-(p-acetoxyphenyl)2.3-dihydro-4-quinolone 18. The next step, the Wolff-Kishner reduction, led directly to the desired product [Eq. (7)]. The third way, the direct amination of p-iodoanisole with 1.2.3.4-tetrahydro-quinoline and the subsequent splitting of 4-(1.2.3.4-tetrahydro-quinolino)-anisol with HBr was the best one [Eq. (8)]. Saponification of l-(p-acetoxyphenyl>2.3-... 

In a study related to the conformational properties of the cyclohexane-fused six-membered heterocycles, new bicyclic dithiolanes, 285-/ra r (Scheme 52) and 285-crr (not shown), were prepared along the reaction pathway, as precursors used further for the syntheses of 2-methyl substituted and unsubstituted /ra r-fused 4a,5,6,7,8,8a-hexahydro-2//,4//-1,3-benzodithiines, exemplified by structure 288-/ra ir (R=R = H) <2002JOC1910>. Thus, ditosylation of cis-Z-hydroxymethyl cyclohexanol 284, and subsequent reaction with sodium sulfide and sulfur, provided a mixture of new bicyclic products 285 and 286, albeit in very low yields, with configurational inversion at C-1. These were reduced by LiAlH4 to provide /ra r-2-mercaptomethyl cyclohexanethiol 2 l-trans. Upon acetalization or transacetalization, the desired 2SS-trans derivative was obtained. The same methodology with the precursor 2E4-trans was extended to the preparation of the r-fused bicyclic compounds 285-288. 

LiAlH4) of the product afforded an aminomethylquinolizidine (19) which, on reaction with glutaric anhydride followed by acetic anhydride, afforded ( )-lamprolobine (20).2 2... 

The excess of LiAlH4 can be decomposed with moist ether or, carefully, with sodium carbonate solution or water. For larger batches the decomposition is effected by a reagent that does not evolve hydrogen on reaction with LiAlH4 ethyl acetate is very suitable, since its reduction product (ethanol) rarely interferes in subsequent working up. 

N-Alkylation of amides. Benzotriazol-l-ylmethylation on the nitrogen atom of an amide is accomplished in refluxing acetic acid. Benzotriazole can then be displaced by reaction with an organometallic reagent (R2Zn, etc.). On LiAlH4 reduction A -methylamines are obtained. 

A solution of 0.105 mol of BuLi in 69 ml of hexane is placed in the flask. TMEDA (0.12 mol, 13.9 g, dried by distillation from LiAlH4 in a partial vacuum) is added over a few minutes. An additional amount of 50 ml of hexane or pentane is added, after which the solution is cooled to — 40 °C. The S,S-acetal (0.10 mol, 10.8 g, see Exp. 21) is then introduced over a few s, after which the cooling bath is removed. The temperature rises to 0-10 °C within a few minutes. After an additional 5 min (at 10 °C) the desired co-solvent (Et20 or THF, usually 80 ml) is added to the thick suspension with cooling below 0 °C. The resulting suspension (in the case of Et20) or solution (in the case of THF) should be immediately cooled to below — 40 °C, after which the reaction with the desired compound is carried out. 

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