Lithium aluminum hydride, reduction carbonyls

The chemical reduction of enamines by hydride again depends upon the prior generation of an imonium salt (111,225). Thus an equivalent of acid, such as perchloric acid, must be added to the enamine in reductions with lithium aluminum hydride. Studies of the steric course (537) of lithium aluminum hydride reductions of imonium salts indicate less stereoselectivity in comparison with the analogous carbonyl compounds, where an equatorial alcohol usually predominates in the reduction products of six-membered ring ketones. 

The homology between 22 and 21 is obviously very close. After lithium aluminum hydride reduction of the ethoxycarbonyl function in 22, oxidation of the resultant primary alcohol with PCC furnishes aldehyde 34. Subjection of 34 to sequential carbonyl addition, oxidation, and deprotection reactions then provides ketone 21 (31% overall yield from (—)-33). By virtue of its symmetry, the dextrorotatory monobenzyl ether, (/ )-(+)-33, can also be converted to compound 21, with the same absolute configuration as that derived from (S)-(-)-33, by using a synthetic route that differs only slightly from the one already described. 

An important example of this type of reaction is the formation of esters, which was discussed previously in connection with the reactions of alcohols in Section 15-4D. Similar addition-elimination mechanisms occur in many reactions at the carbonyl groups of acid derivatives. A less obvious example of addition to carboxyl groups involves hydride ion (H 0) and takes place in lithium aluminum hydride reduction of carboxylic acids (Sections 16-4E and 18-3C). 

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 product of a lithium aluminum hydride reduction of a cinnamic acid or ester 1 is highly dependent on the solvent. The product of exclusive carbonyl reduction, cinnamyl alcohol 2, was obtained in hydrocarbon solvents (pentane, hexane or benzene) even under prolonged reflux. 3-Phenylpropanol 3, resulting from carbonyl and C-C double bond reduction was produced in diethyl ether. However, phenylcyclopropane 4 was obtained in tetrahy-drofuran or 1,2-dimethoxyethane, notably after prolonged reflux. 

The lithium aluminum hydride reductive method to cleave tosyl groups is also convenient and will likewise reduce any carbonyl groups present in the macrocycle at the same time. Isolation of the products of this cleavage reaction is relatively easy. 

The introduction of iV-substituents in aminoborneols is also possible by lithium aluminum hydride reduction of amides formed with activated carboxylic acids44, e.g., (S)-iV-(benzyloxy-carbony])proline. Compounds of this type 39-41 have been used as catalysts in the enantiose-lective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.). 

Vincatine (mp 111-112°) gave a molecular ion at m/e 370, in agreement with a molecular formula of C22H30N2O3. The IR spectrum showed carbonyl absorptions at 1705 and 1735 cm-1 and the UV spectrum indicated the presence of a 2-oxindole. Four aromatic protons were observed in the PMR spectrum together with JV-methyl (3.20 ppm) and carbomethoxyl (3.62 ppm) groups. Lithium aluminum hydride reduction gave a diol 164 but acetylation of this compound gave only a monoacetyl derivative. The structure of vincatine (163) was deduced on the basis of a rationalization of the mass spectra of the parent compound and its various derivatives, particularly the ions at m/e 297, 211, 182, and 124 in the parent compound (Scheme 3) and the base peak at m/e 184 (165) in the mass spectrum of the diol. 

C. Lithium Aluminum Hydride Reduction of Non-Carbonyl Heteroatom Functional Groups... 

Chart IV) lithium aluminum hydride reduction of XXIV ceases after removal of the lactam carbonyl, the ether oxygen being unaffected. The original paper should be consulted for a detailed discussion of the many interesting reactions hinted at in Chart V. The full paper should also be compared with the preliminary communication. 

But this is all with the normal-propyl compound. There is a rich collection of misinformation and potential discovery that is associated with the isopropyl isomer. This structural isomer, 2,5-dimethoxyl-4-(i)-propylamphetamine is properly called DOIP for des-oxy-iso-propyl. It has been synthesized and explored in animals and, to a modest extent, in man. The synthesis has proceeded from 2,5-dimethoxyacetophenone by the addition of a methyl group to the carbonyl followed by reduction to the hydrocarbon. Aldehyde formation, nitropropene synthesis with nitroethane, and lithium aluminum hydride reduction are uneventful, providing the hydrochloride salt DOIP, which has a mp of 183-184 °C as an analytical sample. Animal tests (such as rabbit hyperthermia assays), have indicated that the isopropyl compound DOIP is less potent than the... 

In the reduction of a carbo>grl group, two hydrogens from LiAlH4 are delivered to the carbonyl group. The hydrogen on the hydroxyl group of the product is provided by water or by aqueous acid during workup. The mechanism of lithium aluminum hydride reduction of carbo>qrl derivatives is presented in Section 18.10. 

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