Lead organomagnesiums

The reaction with organolithium or organomagnesium reagents 9 leads to formation of /3-aminoalcohols 10 ... 

The much simpler steroid, 253, was fortuitously found to fulfill this role when injected into animals. Its lack of oral activity was overcome by incorporation of the 7a-thioacetate group. Reaction of the ethisterone intermediate, 77b, with a large excess of an organomagnesium halide leads to the corresponding acetylide salt carbonation with CO2 affords the carboxyllic acid, 251. This is then hydrogenated and the hydroxy acid cy-clized to the spirolactone. Oppenauer oxidation followed by treatment with chloranil affords the 4,6-dehydro-3-ketone (254). Conjugate addition of thiolacetic acid completes the synthesis of spironolactone (255), an orally active aldosterone antagonist. ... 

Organomagnesium and organolithium compounds are strongly basic and nucleophilic. Despite their potential to react as nucleophiles in SN2 substitution reactions, this reaction is of limited utility in synthesis. One limitation on alkylation reactions is competition from electron transfer processes, which can lead to radical reactions. Methyl and other primary iodides usually give the best results in alkylation reactions. 

FIGURE 4.16 Method D organomagnesium reactions leading to monoalkylated products. 

There were several problems to address in developing the conversion of the unsaturated acyl imidazolide 18 to these ketones. The acetylacetonate ligand was found to add to 18 leading to more than 2% of a by-product, believed to be 59 (Figure 3.7), which proved difficult to remove. The reaction also consumes far more organomagnesium reagent than should be necessary 5 equiv are required for complete conversion (the theoretical is 2.0). Also, the reaction provided best results when carried out at low temperature (-35 °C). 

The use of organomagnesium reagents as bases leads to complexation of the nitrile imines (e.g., 141), which has been found to have a strong effect in promoting syn selectivity in reactions with methyl 2-(l-hydroxyalkyl)acrylates via coordination of the metal atom with the alcoholic oxygen (e.g., leading to the formation of 142). Lithium complexation had little effect (78). 

Many monomeric organomagnesium amide solvates may be transformed on heating under vacuum. In some instances this leads to simple desolvation of the complexes and in turn gives rise to dimerization or even further aggregation Another outcome... 

O-Benzyllactaldehyde dimethylhydrazone 230 allows a substrate control in the addition reaction of organomagnesium halides, leading almost exclusively to the 5yn-isomer 231 (equation 155) . The resulting hydrazide can be reduced on Raney Ni to the corresponding iyw-aminoalcohol 232. The stereoselective Grignard addition to a similar A-formyl hydrazone 233 proceeds with 92% diastereoselectivity (equation 156). The silylation of the amide nitrogen by TMSCl provides the pure iyw-adduct . 

Organomagnesium and organolithium compounds can add both 1,2 and 1,4 to alkenones, and the relative importance of each mode of addition depends on the structure of the reactants. This sort of dual behavior can be a nuisance in synthetic work because it leads to separation problems and low yields. Organocopper compounds are a great help in this situation because they show a very high selectivity for 1,4 addition and add to unsaturated ketones in excellent yield ... 

The Grignard Reaction is the addition of an organomagnesium. halide (Grignard reagent) to a ketone or aldehyde, to form a tertiary or secondary alcohol, respectively. The reaction with formaldehyde leads to a primary alcohol. 

The addition of mild nucleophiles occurs preferentially in a (as described below) but with hydride, organomagnesium, or organolithium reagents addition in y can also be observed, leading to isolable y-pyrans. 

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