Initiators, Grignard reagents

Initially, Grignard reagents were considered to be nucleophiles reacting mainly in a polar fashion. However, early in the history of Grignard chemistry the concept originated that the reaction could have a radical character. In 1913 [26] and some years later in 1922 [27] the formation of alkenes and alkanes in the reaction of haloalkanes with Grignard reagents in diethyl ether (Scheme 2) had already been attributed to the intermediacy of what was named, /kr alkyls. 

In the presence of a catalytic amount of Cul, Grignard reagents convert acid chlorides chemoselectively to the corresponding ketones via a transiently formed cuprate reagent, which reacts competitively with the initial Grignard reagent. ... 

Solvent Preparation. The most critical aspect of the solvent is that it must be dry (less than 0.02 wt % of H2O) and free of O2. If the H2O content is above 0.02 wt %, then the reaction of Mg and RX does not initiate, except for an extremely reactive RX species, such as benzyl bromide. Although adventitious O2 does not retard the initiation process, the O2 reacts with the Grignard reagent to form a RMg02X species. Furthermore, upon hydrolysis, the oxidized Grignard reagent forms a ROH species that may cause purification problems. 

Addition of Grignard reagents and organolithium compounds to the pyridazine ring proceeds as a nucleophilic attack at one of the electron-deficient positions to give initially... 

A review of the literature prior to 1953 on reactions of pyridinium, quinolinium, and isoquinolinium salts is available (31). The reactions will be described here only briefly. The initial observation was that of Freund et al. (32-37), who found that treatment of various derivatives of hydra-stinine (15) with Grignard reagents yielded addition products, such as 16. 

Grignard reagents are normally prepared by the slow addition of the organic halide to a stirred suspension of magne.sium turnings in the appropriate solvent and with rigorous exclusion of air and moisture. The reaction, which usually begins slowly after an induction period, can be initiated by addition of a small crystal of iodine this penetrates the protective layer of... 

The conversion of a nitrile R —CN into a ketone R —CO—R demonstrates that polarized multiple bonds other than C=0 also react with Grignard reagents, and that such reactions are synthetically useful. Esters 22 and acid chlorides can react subsequently with two equivalents of RMgX the initially formed tetravalent product from the first addition reaction can decompose to a ketone that is still reactive, and reacts with a second RMgX. The final product 23 then contains two substituents R, coming from the Grignard reagent ... 

In an initial step, dibenzo[a,d] cyclohepten-5-one is reacted with the Grignard reagent of 3-di-methylaminopropyl chloride and hydrolyzed to give 5-(3-dimethylaminopropyl)-dibenzo[a,d] -[1,4] cycloheptatriene-5-ol. Then 13 g of that material, 40 ml of hydrochloric acid, and 135 ml of glacial acetic acid is refluxed for 314 hours. The solution is then evaporated to dryness in vacuo and added to ice water which is then rendered basic by addition of ammonium hydroxide solution. Extraction of the basic solution with chloroform and removal of the solvent from the dried chloroform extracts yields the crude product which when distilled in vacuo yields essentially pure 5-(3-dimethylaminopropylidene)-dibenzo[a/f ] [ 1,4] cycloheptatriene, BP 173°C to 177°C at 1.0 mm. 

The reversal of the stereoselectivity is attributed to the ability of chlorotrimethylsilane to trap the initially formed cuprate-enone complex, thereby suppressing equilibration of the diastereomeric complexes. The copper-catalyzed 1,4-addition of Grignard reagents to 5-substituted 2-cyclo-hexenone also proceeded with very high trans diastereoselectivity22. 

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