Magnesium chloride reductive amination

Shortly after the product launch, the original process was modified (Scheme 2). Zinc chloride was removed from the coupling reaction, and ethyl bromopropionate was replaced with bromopropionic acid magnesium chloride salt. Most importantly, the resolution agent cinchonidine was replaced with A -alkylglucam-ine, which can be readily obtained from the reductive amination of o-glucose. 

Many studies of the addition of nucleophiles to palladium-allyl complexes have been conducted. Hayashi has shown that the additions of stabilized anions, such as malonate anions or amine nucleophiles, to chiral, non-racemic allyl complexes occur with inversion of configuration.Addition of excess phosphine and either diethyl malonate or dimethylamine to a chiral, non-racemic allyl complex results in nucleophilic attack with nearly complete inversion. The reaction with sodium dimethylmalonate is shown at the right of Equation 11.40. In contrast, nonstabilized carbanions such as allyl or phenyl magnesium chloride react with the same Ti -allylpalladium complex with retention of configuration as shown at the left of Equation 11.40. The stereochemistry from reaction of the Grignard reagents likely results from nucleophilic attack at the metal, followed by reductive elimination. 

Initially, we have considered the A -aluminum imines which may be obtained by DIBAH reduction of nitriles at -78 C in THF. Treatment of the aluminum imines thus obtained with 2 equivalents of alkyl or allyl lithium and benzyl and allyl magnesium chloride at room temperature fw 48 hours leads, after hydrolysis, to the expected primary amines CTable 4). The reaction appears to be quite general. In fact, aromatic as well as olizable aliphatic aluminum imines react with a variety of organometallic reagents to afford good to racellent yields of primary amines after hydrolysis. The stoichiometry of the... 

The reaction of formic acid or a variety of formic acid derivatives, such as formate salts and formamides, with ammonia or a variety of amines, as well as various amine derivatives and salts such as ammonium formate salts, and carbonyl compounds, results in the reductive alkylation of the amine in which the entering alkyl group is derived from the carbonyl compound. This reaction is known as the Leuckart reaction [30]. By proper selection of reagents, primary, secondary, and tertiary amines may be prepared. In general this reaction is carried out at elevated temperatures without further solvents. More recent work indicates that magnesium chloride and ammonium sulfate are particularly useful catalysts in the preparation of tertiary amines by the Leuckart reaction [31]. 

Metallic sodium. This metal is employed for the drying of ethers and of saturated and aromatic hydrocarbons. The bulk of the water should first be removed from the liquid or solution by a preliminary drying with anhydrous calcium chloride or magnesium sulphate. Sodium is most effective in the form of fine wire, which is forced directly into the liquid by means of a sodium press (see under Ether, Section II,47,i) a large surface is thus presented to the liquid. It cannot be used for any compound with which it reacts or which is affected by alkalis or is easily subject to reduction (due to the hydrogen evolved during the dehydration), viz., alcohols, acids, esters, organic halides, ketones, aldehydes, and some amines. 

The bimolecular reduction of aromatic nitro compounds, depending on reaction conditions, may produce azoxy compounds, azo compounds, hydrazo compounds (1,2-diarylhydrazines), benzidines, or amines. Whereas the reduction with zinc and sodium hydroxide leads to azo compounds, zinc and acetic acid/acetic anhydride produces azoxy compounds. Other reducing agents suggested are stannous chloride, magnesium with anhydrous methanol, a sodium-lead alloy in ethanol, thallium in ethanol, and sodium arsenite. 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

The less reactive magnesium reagent allows the complete reductive trimethylsilyla-tion of the nitrile function of benzonitrile. Hydrolysis of the obtained silazane into the ammonium chloride followed by its neutralization afforded the a-trimethylsilylbenzyl-amine (ASMA) in good yield.174... 

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