Grignard reaction, addition of methyl

Grignard reaction, addition of methyl-magnesium bromide to thiophos-phoryl chloride, 45,102 Grignard reagents, synthesis and utility of unsolvated, 47, 116 titration of, 48, 48... 

The low yields, which are observed among styrenyl adducts, reflect a combination of the poor reactivity of the styrene at the low temperature of the reaction. For example, the combination of t-butyl Grignard with the 2,4-bis-OBoc-benzyl alcohol 15 affords the corresponding benzopyran 50 in only 50% yield even when carried out in the presence of 5-10 equivalents of the styrene (method H, Fig. 4.27).27 Yields for substituted benzopyran styrene adducts are still lower (method G, Fig. 4.27). For example, addition of methyl lithium to 2,4-bis-OBoc-benzylaldehyde 5 followed by the addition of the dienophile and magnesium bromide affords benzopyran 51 in a paltry 27% yield. Method F is entirely ineffective in these cases, because the methyl Grignard reagent competes with the enol ether and with styrene 1,4-addition of methyl supercedes cycloaddition. 

Sandin and Fieser developed an efficient synthesis of the potently carcinogenic 9,10-dimethyl-l,2-benzanthracene from 1,2-benzanthraquinone (1) involving addition of methyl Grignard reagent, reaction of the adduct (2) with hydriodic acid to give the 9-methyl-10-iodomethyl derivative (3) and reduction with stannous chloride in dioxane-hydrochloric acid. 

Quinoxaline readily reacts with Grignard reagents. Addition of two molecular proportions of allylmagnesium bromide and of 3-(dimethylamino)propylmagnesium chloride, and hydrolysis of the initial adducts, gives the tetrahydroquinoxalines 2 and 3, respectively. The 1 1 adducts 4, 5, and 6 are obtained from the reaction of quinoxaline with diphenylcyclopropenone, diphenylcyclopropenethione, and methyl phenylhydrazonochloroacetate in the presence of triethylamine, respectively. In the latter case the presumed intermediate is the dipolar... 

The synthesis of the sterically hindered 2-ketoesters succeeded in a simple fashion and in excellent yields by the esterification of ethyl oxalyl chloride with the lithium salt of 2,6-di-f rt-butyl-4-methoxyphenol followed by the chemose-lective nucleophilic addition of methyl or ethyl Grignard reagents to the unsym-metrical ethyl aryl oxalate. Reaction with (S)-l-amino-2-(methoxymethyl)pyrro-... 

In addition, the higher reactivity of esters relative to ketones is unusual and opposite to that observed with Grignard reactions. Extension of this atypical reactivity resulted in the development of methods for selective ketone synthesis. Addition of benzoyl chloride or methyl benzoate to phenylytterbium iodide (in... 

With l,4,6-triene-3-ones, addition occurs exclusively at the 1,2-double bond to yield la-methyl-A -S-ketones. Grignard reaction and reacetylation of 17)5-acetoxyandrosta-l,4,6-trien-3-one (23) gives the la-methyl-4,6-dien-3-one (24) in a crude yield of 85%. ° ... 

Reaction of estrone methyl ether with methyl Grignard reagent followed by Birch reduction and hydrolysis of the intermediate enol ether affords the prototype orally active androgen in the 19-nor series, normethandrolone (69). ° (Note that here again the addition of the methyl group proceeded stereoselectively by approach from the least hindered side.) The preparation of the ethyl homolog starts by catalytic reduction of mestranol treatment of the intermediate, 70, under the conditions of the Birch reduction and subsequent hydrolysis of the intermediate enol ether yields norethandrolone (71). ... 

Generally, in contrast to 2-substituted cyclopentanones, the diastereoselectivity of addition reactions to 3-substituted cyclopentanones is nearly independent of the nucleophile and the substituent in the 3-position. Thus, addition of various Grignard reagents, including ethynyl reagents, to 3-methyl- and 3-ferf-butylcyclopentanone leads to almost the same ratio of diastereomers (Table 3)3,4 6, 27,2s... 

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