Benzylic compounds, lithium aluminum hydride

From intermediate 28, the construction of aldehyde 8 only requires a few straightforward steps. Thus, alkylation of the newly introduced C-3 secondary hydroxyl with methyl iodide, followed by hydrogenolysis of the C-5 benzyl ether, furnishes primary alcohol ( )-29. With a free primary hydroxyl group, compound ( )-29 provides a convenient opportunity for optical resolution at this stage. Indeed, separation of the equimolar mixture of diastereo-meric urethanes (carbamates) resulting from the action of (S)-(-)-a-methylbenzylisocyanate on ( )-29, followed by lithium aluminum hydride reduction of the separated urethanes, provides both enantiomers of 29 in optically active form. Oxidation of the levorotatory alcohol (-)-29 with PCC furnishes enantiomerically pure aldehyde 8 (88 % yield). 

Compound 203 (R1 = R2 = H, X = Br) underwent hydrazone exchange with hydrazine hydrate to give 2-amino-5-bromobenzophenone hydra-zone. The same benzotriazocine was ring-opened with lithium aluminum hydride to afford 2-benzyl-4-bromoaniline, while hydrolysis of the compound yielded 2-amino-5-bromobenzophenone (83CHE337). 

Brimacombe and How reduced methyl 3,4-0-isopropylidene-2,6-di-O-p-tolylsulfonyl-a-D-galactopyranoside with lithium aluminum hydride in tetrahydrofuran, to provide methyl 3,4-O-isopropylidene-2-0-p-tolylsulfonyl-a-D-fucopyranoside in 54% yield. In later reductions of closely related compounds, the solvent chosen was ether-benzene methyl 3-0-benzyl-2-deoxy-6-0-p-tolylsulfonyl-a-D-Ii/xo-hexopyranoside afforded the corresponding 6-deoxy compound which, on methylation, debenzylation, and acid hydrolysis, gave 2,6-dideoxy-4-O-methyl-D-Zi/Jco-hexose (chromose A). An improved synthesis of this sugar involved the reduction, in ether—benzene (1 1), ofmethyl 2-deoxy-4-0-methyl-3,6-di-0-p-tolylsulfonyl-a-D-/i/xo-hexopyranoside to methyl 2,6-dideoxy-4-0-methyl-a-D-Z /xo-hexopy-ranoside in 25% yield a synthesis of 3-0-acetyl-2,6-dideoxy-D-Z /xo-hexose (chromose D) was effected by way of reduction in ether-benzene (2 1) of methyl 2-deoxy-6-0-p-tolylsulfonyl-a-D-Zyxo-hexo-pyranoside to the corresponding 6-deoxy compound in 27% yield, followed by partial acetylation and acid hydrolysis. 

As mentioned before structure of 2-2 was proposed by spectral analyses, the position of methylenedioxyl group in isoquinoline of 2-2 is in position C-5—C-6, but it did not exclude its possibility in position C-7—C-8. A total synthesis was accomplished in order to confirm the structure and to derive more samples for pharmacological tests. Piperonal 2-4 was used as starting material. It was oxidized by silver oxide in basic condition to get 2-5, then amidized with dimethyl amine to 2-6 and directed ortho-lithiation with n-butyl-lithium in THF (tetrahydrofuran) to get homogeneous yellow solution, which upon treatment with methyl iodide afforded toluamide 2-7, the yield was 85%. The model synthesis study showed that lithiated toluamide 2-7 could condense with compound 2-14 to achieve the final product 2-2 through several steps (see below). The intermediate compound 2-14 could be synthesized starting from the same piperonal 2-4. It was reacted with cyclohexylamine to get Shiff base 2-8, the latter was reacted with 1.13 equiv. of n-butyllithium at -78°C, the metalated intermediate was carbethoxylated in situ by addition of excess ethyl chloroformate and the aldehyde 2-9 was obtained by extraction with dilute acid. Combination of 2-9 with equimolar of propane-1,3-dithiol a compound 2-10 was obtained, then 2-10 was reduced by lithium aluminum hydride and benzylated with benzyl bromide to 2-12. After treatment with bis(trifluoroacetoxy) iodobenzene, the obtained compound 2-13 was reacted with benzylamine to get the key compound 2-14. 

PROBLEM 16.44 As we saw on page 798, benzyl halides can be reduced by metal hydrides. Why can compound A not be reduced successfully with lithium aluminum hydride What reaction will complicate matters ... 

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