Grignard reagents side reactions

But apart from unexpected side reactions, various well-known competing reactions, such as reduction, conjugated addition, and enolization reactions, may well hinder the studies of mechanistic aspects of Grignard reagent reactions. In view of all such unknown factors, it may not come as a surprise that in one of the latest publications on some mechanistic aspects of Grignard reagent addition reactions, in the Journal of Organic Chemistry, the authors started their report with the remark that... 

RM can be a traditional Grignard reagent or an organolithium, 2inc, aluminum, or mercury compound. The Grignard route is employed commercially for production of tertiary phosphines, even though these reactions are subject to side reactions. Yields are often low, eg, 40—50% for (C4H )2P prepared via a Grignard reaction (18). A phosphoms—carbon bond can form from the metathetical reaction of a phosphoms haUde and a pseudohaUde salt. 

When both a-positions of the oxime possess active hydrogen, the regiochemistry of the Hoch-Campbell reaction prefers the side with more available hydrogens— indicating the process is kinetically controlled. In case of oxime 36, azirine 37 was not formed. Instead, azirine 38 was obtained exclusively. Addition of the third equivalent of the Grignard reagent delivered aziridine 39 as a mixture of two diastereomers. 

Grignard reagents that contain a /3-hydrogen—e.g. 15—can reduce a carbonyl substrate by transfer of that hydrogen as a side-reaction. The so-called Grignard reduction is likely to proceed via a six-membered cyclic transition state 16 the alkyl group of alkylmagnesium compound 15 is thereby converted into an alkene 17. 

This reaction can be used for the synthesis of hydrocarbons but it may also take place as a side-reaction during generation of a Grignard reagent from an alkyl halide and magnesium, then leading to formation of undesired side-products. 

To anticipate briefly, shortening the length of the side chain in the phenothiazines from three to two carbon atoms changes I he activity of the products from neuroleptics to antihistaminic iigents. A rather similar effect is seen in the tricyclic antidepressants. Reaction of ketone, 27, with the Grignard reagent I rom 4-chloro-l-methylpipyridine (35) affords the tertiary alco-liol, 36. Dehydration gives the antihistamine, cyproheptadine (37). ... 

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). ... 

Ullmann condensation of the sodium salt of p-chlorothiophe-nol (31) with 2-iodobenzoic (32) acid gives 33. Cyclization by means of sulfuric acid affords the thioxanthone, 34. Reaction with the Grignard reagent from 3-dimethylaminopropyl chloride affords the tertiary carbinol (35). Dehydration by means of acetic anhydride affords chlorprothixene as a mixture of geometric isomers, 36. (Subsequent work showed the Z isomer-chlorine and amine on the same side—to be the more potent compound.) Chlorprothixene is said to cause less sedation than the phenothiazines. ... 

Reaction of the ester with methyl Grignard reagent completes construction of the side chain (111). Photolysis... 

Next to the formation of Grignard reagents, the most important application of this reaction is the conversion of alkyl and aryl halides to organolithium compounds, but it has also been carried out with many other metals, (e.g., Na, Be, Zn, Hg, As, Sb, and Sn). With sodium, the Wurtz reaction (10-93) is an important side reaction. In some cases, where the reaction between a halide and a metal is too slow, an alloy of the metal with potassium or sodium can be used instead. The most important example is the preparation of tetraethyl lead from ethyl bromide and a Pb—Na alloy. 

A methyl group can be placed on cobalt in dicyano[cobyrinic acid heptamethyl ester] when it is treated with excess methyl magnesium iodide (the ester side chains being converted into tertiary alcohol groups). The alkylation could also be achieved using lithium alkyls (176). Presumably this reaction would be successful with any corrinoid which is soluble in solvents compatible with Grignard reagents. 

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