Halogen/magnesium displacement

An ester of alanine with an arylaliphatic alcohol has shown promise as a non-tricyclic antidepressant. It may be speculated that the hindered milieu of the ester linkage protects the compound from hydrolysis by endogenous esterases. The preparation starts by reaction of pheny-lacctate 83 with methyl magnesium iodide to give tertiary carbinol 84. Acylation with 2-bromo-]>ropionyl bromide leads to ester 85 displacement of halogen with ammonia leads to alaproclate ( 6) [211. 

A chlorocarbonyl group ortho to a fluorine atom activates the halogen towards nucleophilic displacement. In the synthesis of a number of polyfluorinated chromones the 1,3-diketo side-chain is introduced using ethyl acetoacetate in the presence of magnesium ethoxide. Cyclization occurs on addition of sulfuric acid (70JOC930). 

Nucleophilic replacement of hydrogen on an isoxazole (cf. the Chichibabin reaction) is unknown, and only a few examples of replacement of substituents such as halogen have been reported.1,151 The activated methoxy group in compound 45 is displaced by dimethylamine, and even by phenyl-magnesium bromide, in which case the product is 46.152... 

Many di-Grignard reagents can be prepared routinely from the corresponding halo compounds, provided the halogens are sufficiently separated, for example, (42), X(CH2)4X, or m- and /t-dihalo aromatics. Precautions such as dilution, low temperature, and active magnesium (particularly Mg anthracene) may be important for a good yield, particularly where the halide is easily displaced, for example benzylic. 

The chemical reactivity of the thiocyano groups in these chelate rings has not been investigated, but the halogen atoms in the 3-halo metal acetylacetonates have been found to be quite inert and their behavior is different from that of aryl halides, since treatment of the tris(3-bromo-2,4-pentanediono)chromium(III) chelate with magnesium or lithium in benzene or tetrahydrofuran resulted in no reaction. Attempted nucleophilic displacement of the bromine atoms in this chelate by azide, acetate, nitrate, and iodide ions in hot dimethylformamide also failed. In most of these... 

Selective positional reduction is also possible as in the formation of 4-bromophenol from 2,4-dibromophenol and triphenylphosphine [59] and of 1, 4-dibromobenzene from 1, 2, 4-tribromobenzene and KOBu in dimethylsulphoxide [60]. Illustrative of recent methods for halogen displacement is the reduction of chlorobenzene with magnesium in isopropanol [61] and the photochemical reduction of p-chlorophenol to phenol (also in isopropanol) [62]. 

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