Applications of the Grignard Reaction

When twelve moles of phenylmagnesium bromide acted on tetraacetyl-D-gluconolactone in a mixture of ether and benzene, 1,1-C-diphenyl-D-glucitol (IX), could be isolated in ten to twelve percent yield. In 

When l,2 3,4-diisopropylidene-l-D-arabinosecarboxylic acid (XIY), reacted with four moles of methylmagnesium iodide two products were obtained37 in a ratio of seven to one, l-C-methyI-2,3 4,5-diisopro-pylidene-D-glucosone (XV), and l,l-C-dimethyI-2,3 4,5-diisopropyli-dene-jS-D-fructose (XVI). The further reaction of methylmagnesium 

2 and 3 in XIX and XX was indicated by their reducing properties, but the experimental evidence offered in support of the furanose ring 

Similar investigations were conducted on XXII. Its partial hydrolysis produced two products, l,l-C-diphenyl-2,3-isopropylidene-D-fructo-furanose (XXV), and l,l-C-diphenyl-2,3-isopropylidene-D-fructopyra-nose (XXVI). Both XXV and XXVI were non-reducing, establishing the involvement of the reducing carbon atom with an acetone residue. 

When benzylmagnesium chloride reacted with XIV, 1,1-C-dibenzyl-2,3 4,5-diisopropylidene-D-fructose (XXIX), was obtained,38 but a product analogous to XV was not observed. XXIX was similarly subjected to partial hydrolysis, and the structures of the hydrolytic products were deduced by similar reasoning. The rather complex nature of the hydrolysis products in the above studies suggests the desirability that the structures proposed by Ohle be examined more extensively by modern methods. 

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This method is merely an application of the Grignard reaction but is a lot less troublesome because it uses really common chemicals. This method can be done as it was done in the reference where a phenylbutene was made using a bromopropane ( bromo-propane and bromoethane are cheap to purchase or can be made... 

Further applications of the Grignard reaction are given under Reactions XIV., XXII., XXXIV. (6), XLIII., LX. See also Ann. Rep., 1932, 99. 

Reaction XLIII. (b) Formation of Ethyl Esters by the Action of Ethyl Chloroformate on Magnesium Alkyl Halide in Dry Ethereal Solution (Grignard).—This is another mode of application of the Grignard reaction to the synthesis of esters. It is more direct than the previous method. 

Hi l.illy introduced a major medical advance in the treatment of pain in the late )5o with the introduction of Darvon" (propoxyphene. 26) xs. This demonstrates the application of the Grignard reaction to provide a terliary substituted alcohol. 

An interesting application of the Grignard reaction leads to 2-deoxy-D-ribose from 2,3-0-isopropylidene-D-glyceraldehyde and allylmagnesium bromide 181). 

Methyl Bromide.—The simplest alkyl bromide is prepared in an esentially similar way (Bygden, J. pr. Ghem., 1911, 83, 421). Since it boils at 4-5° it is difficult to keep in stock, but its direct application in the Grignard reaction, in place of the dearer iodine compound, is very much to be recommended. Uses analogous to those of ethyl bromide. 

The reliability of the Grignard reaction and its broad scope of application warrants utilization of the retrosynthetic disconnection of C-C bonds adjacent to the hydroxyl-bearing carbon as a routine procedure in the analysis of practical synthetic pathways. 

Grignard Reaction.— The magnesium alkyl compounds had been known but not used in synthetic reactions until 1899 when Barbier and in 1900 Grignard used them in this way. Since then the applications of the general reaction have been very numerous. It is known as the Grignard Reaction and may be illustrated as follows ... 

Banno, T., Hayakawa, Y., Umeno, M. Some applications of the Grignard cross-coupling reaction in the industrial field. J. Organomet. Chem. 2002, 653, 288-291. 

The stereoselectivity of the Wittig reaction depends, not only on the substituents, but also on the conditions under which the reaction is effected. The presence of lithivun salts tends to favour the fJ-alkene, so reactions in which the Z-alkene is desired are often carried out using sodium or potassium bases. It is possible to obtain high yields of the fJ-alkene from a non-stabilized phosphonium ylide by deprotonation, then reprotonation of the intermediate oxaphosphetane or betaine. An especially useful application of the Wittig reaction is in the formation of exo-cyclic double bonds. Thus, cyclohexanone and (methylene)triphenylphosphorane give (methylene)cyclohexane, whereas the use of the Grignard reaction followed by dehydration leads to the endocyclic isomer. 

An additional important application of the Kharasch reaction is in the synthesis of polyaryls. For example, 2,5-dibromopyridine (140) was transmetallated upon treatment with isopropylmagnesium bromide to give the corresponding Grignard reagent 141, which subsequently underwent the Kharasch reaction affording the polypyridine (PPy) in 76% yield [43], respectively. Scheme 11. 

Allylamines have received much attention in the recent literature, a trend which appears to be continuing. a-sec-Allylamines have been rarely reported but a recent disclosure describes their syn-thesis via application of the Bruylants reaction. The method is versatile in that either enals can be converted to vinyl amino-nitriles prior to reaction with a Grignard reagent, or vinyl Grignard reagents can be reacted with a-aminonitriles (Scheme 15). Yields of the products were moderate to good. 

Thus it appears that several publications from the first years of application of the Grignard reagent, in which the versatility of the one-step Barbier reaction was well demonstrated, did not m et with the response they merited. 

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