Reaction of Organomagnesium Compounds

Recent topics related to halogen-magnesium exchange reactions and organomag-nesium-mediated radical reachons will be discussed in subsequent sections. 

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In this chapter it has become clear that knowledge about the structures of organomagnesium compounds both in the solid state and in solution is often a pre-requisite for a better understanding of the reaction pathways involved in reactions of organomagnesium compounds. For the design of new synthetic pathways for the synthesis of new organic products this knowledge is of particular importance. 

Early investigations of reactions of organomagnesium compounds with ketenes are described, as illustrated by the example of mesitylketene described by Rappoport and... 

T. Holm, I. Crossland, Mechanistic Features of the Reactions of Organomagnesium Compounds, in Grignard Reagents—New Developments (H. G. Richey, Jr., Ed.), John Wiley Sons, Chichester, 2000, 1-26. 

The complexities of their constitution in solution make studies of the mechanism of reactions of organomagnesium compounds extraordinarily difficult. Few reactions have stimulated such a wealth of elegantly planned and meticulously executed experiments as those of Grignard reagents with carbonyl compounds (see Section 6.1). Fortunately an admittedly grossly oversimplified rationale for the reactivity of organomagnesium compounds, and in particular for the influence of solvation, is adequate for most applications in organic synthesis. In a monomeric, unsolvated species (2),... 

A number of reactions of organomagnesium compounds, giving rise to new organomagnesium compounds, are covered in other chapters. They include addition to carbon-carbon multiple bonds (see Chapter 4), addition to isonitriles (see Section 5.4), addition to carbon monoxide (see Section 6.5), thiophilic addition to carbon-sulfur double bonds (see Chapter 7) and addition to carbenes (see Section 9.1). 

Early investigations of reactions of organomagnesium compounds with nitro compounds led to mixtures of products, and gave little indication that they might be useful [5]. However, it has now been established that with two equivalents of an alkylmagnesium halide in THF, nucleophilic addition to the ring of a variety of nitroaromatic compounds occurs, as summarized in Table 4.1. The product of the addition is a nitronate anion, which may be converted into various products, as illustrated by the example of 2-nitronaphthalene. 

In contrast, reactions of organomagnesium compounds with pyridinium salts are more useful than those of organolithium compounds. Unsubstituted pyridinium salts have a somewhat greater tendency towards 4-alkylation than pyridine itself [5], and with a bulky N-substituent, 4-alkylation predominates. If the N-substituent is also a good leaving group, a viable general synthesis of 4-substituted pyridines results [6],... 

In other cases, however, the initial adduct is stable, and its hydrolysis product is isolable, and is a useful intermediate for further transformations. For example, the products from reactions of organomagnesium compounds with p-oxoketene dithioacetals may be transformed into a variety of... 

The reactions of organomagnesium compounds with acyl derivatives, R COX, where X represents a good leaving group, follow a common pattern ... 

Syntheses of tertiary alcohols by reactions of organomagnesium compounds with... 

Similar considerations apply to reactions of organomagnesium compounds with formate esters (leading to aldehydes), chloroformates or carbonates (leading to esters) or carbamoyl chlorides (leading to amides) ... 

Reactions of organomagnesium compounds with a,[3-unsaturated esters show a somewhat greater tendency to conjugate addition than reactions with a,(3-unsaturated ketones (see p. 124). However, copper(i) catalysis may be beneficial even in cases where conjugate addition is the main uncatalysed reaction [30] ... 

Reactions of organomagnesium compounds with /V,/V-disubstituted amides differ from those of other acyl derivatives (Section 6.2) in that the initial adducts are much more stable. However, although examples are known where a carbinolamine may be isolated following careful hydrolysis, acid hydrolysis without special precautions usually gives the... 

Synthesis of aldehydes and ketones by reactions of organomagnesium compounds... 

Few examples of reactions of organomagnesium compounds with lactams have been reported [A, E]. On the other hand, reactions with cyclic imides (and carbamate analogues [18, 19]), as illustrated by the following examples, have some promise in synthesis ... 

Analogous reactions of organomagnesium compounds with ketenes, giving enolates, also appear to be general [A] ... 

The reaction of organomagnesium compounds with carbon dioxide to give carboxylates, and thence carboxylic acids, was one of the first to be reported by Grignard [4], and Grignard also observed the important side-reactions leading to ketones and t-alcohols [5] ... 

Reactions of organomagnesium compounds with a,(3-unsaturated dithioesters are somewhat unpredictable, 1,2-, 1,4-carbophilic and thiophilic addition having been observed [6], With a,(3-unsaturated thioamides [7] and imidothioesters [6], however, 1,4-carbophilic addition appears to predominate. 

The most generally useful reactions of organomagnesium compounds with thiocarbonyl compounds are those with carbon disulfide and with isothiocyanates. The former can be used to prepare a variety of compounds by further reactions of the dithiocarboxylate initially formed, and the latter is a good general method for synthesizing thioamides ... 

Reactions of organomagnesium compounds with carbon disulfide... 

The usual reactions of organomagnesium compounds with esters, amides and nitriles are those described in Sections 5.3, 6.2 and 6.3. However, factors such as steric hindrance and stability of leaving group may lead to reactions resulting in overall nucleophilic displacement. Most of them are of limited applicability (see Ref. [39] for examples involving carbamate), but two warrant coverage. 

Catalysed reactions of organomagnesium compounds with allylic acetates are potentially useful in synthesis, but lack of regioselectivity may be a problem ... 

Reactions of organomagnesium compounds with dialkyl sulfates or alkyl sulfonates often give satisfactory yields of the products of displacement of sulfate or sulfonate. Side-reactions have been observed, but they can often be avoided for example, an excess of the sulfate or sulfonate should be used with Grignard reagents, as some is consumed by nucleophilic attack by halide ion [A]. The dialkyl sulfates are reactive, but hazardous. Toluenesulfonates (tosylates) are less reactive, but their reactions are catalysed by copper complexes the reactions of trifluoromethanesulfonates (triflates) are catalysed by nickel complexes. Reactions of Grignard reagents with secondary tosylates appear to follow an Sn2 mechanism, with inversion of configuration [43],... 

Reactions of organomagnesium compounds with thioethers usually take other pathways, and uncatalysed reactions involving displacement of thiolate are rare. On the other hand, several examples of nickel(n)-catalysed reactions have been described, and analogous reactions of selenoethers have also been reported, e.g. 

The nickel-catalysed reaction of organomagnesium compounds with dithioacetals, in which the initial substitution leads to elimination, giving a substituted alkene, is potentially useful [23, 24], as in the following procedure. Elimination of [3-alkoxy or alkylthio groups from the... 

Reactions of organomagnesium compounds with sulfoxides often result in ligand exchange [31], and may be complicated by a- or ortho metallation. However, in some cases, notably with 2-pyridyl aryl sulfoxides, reactions with arylmagnesium halides give useful yields of products from displacement of the aryl sulfoxido group [32, 33], e.g. [32]... 

Reactions of Organomagnesium Compounds with Proton Donors... 

Reactions of organomagnesium compounds with amines give a number of useful reagents. A preparation and use of a bromomagnesium dialkylamide has already been described (see p. 49), and others are listed in Table 10.1. (Note that in most cases the products listed in Table 10.1 were not isolated, and their constitution was not established.) The final entry in Table 10.1 is noteworthy, as bromomagnesio derivatives of pyrroles and indoles may be used as carbon nucleophiles in the synthesis of pyrrole and indole derivatives. In the case of pyrroles, N-, 2- and/or 3 substituted products may be obtained, and the conditions favouring one or another have been extensively studied [10]. In the example shown in the... 

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