Grignard reagents with aromatic rings

Lukes studied the reaction of N-methyl lactams with Grignard reagents. With the five- (39-42) and six-membered (43-47) rings, 2,2-dialkylated bases (16, = 1,2) are formed as by-products in addition to the l-methyl-2-alkyl pyrrolines (15, = 1) or l-methyl-2-alkyl piperideines (15, =2). Aromatic Grignard reagents afford only the unsaturated bases, probably because of steric factors (48,49). Separation of enamines and 2,2-dialkylated amines from each other can be easily achieved since the perchlorates of the enamines and the picrates of 2,2-dialkylated bases crystallize readily. Therefore enamines can be isolated as crystalline perchlorates and the 2,2-dialkylated bases as crystalline picrates. Some authors who repeated the reactions isolated only pyrrolines (50,57) or, by contrast, 2,2-dialkylated bases (52). This can be explained by use of unsuitable isolation techniques by the authors. 

A most remarkable reaction of Grignard reagents with a l-(oxazolidin-2-yl)naphthalene has been described, in which addition to the aromatic ring occurs, whereas organolithium, organocerium or organocopper reagents all attack the oxazolidine 2-position [20] ... 

Aromatic carboxylic acids can be prepared by oxidation of the corresponding benzyl alcohols and benzaldehydes. An aromatic methyl group is also sufficiently activated by the aromatic ring for it to be oxidized to the acid under vigorous conditions, such as heating with chromium(VI) oxide. Other conventional methods include the hydrolysis of aromatic nitriles and the carboxylation of aromatic Grignard reagents with carbon dioxide. 

Grignard reagents can be made to react with aromatic rings under appropriate conditions. Both addition and substitution are observed, and the mixture of products depends on the reaction conditions, substitution being the result of addition, followed by elimination [1,27]. The factors affecting 1,2- versus 1,4-addition for hindered aryl ketones (leading to ring-alkylated products) have been reviewed by Fuson [28]. 

The reactions of Grignard reagents with nitroarenes has provoked considerable study by Bartoli and co-workers, who have developed this procedure as a method for the alkylation of aromatic nitro compounds. They have found that an excess of the Grignard is required, first, to form an adduct that adds a second mole of Grignard reagent to the aromatic ring [Eq. (12) 29,30]. 

Organic acids can be prepared in many ways, four of which are described here (1) oxidation of primary alcohols or aldehydes, (2) oxidation of alkyl side chains on aromatic rings, (3) reaction of Grignard reagents with carbon dioxide, and (4) hydrolysis of alkyl cyanides (nitriles). 

When the additional nitrogen atom is included in one of the aromatic rings, on the other hand, there is obtained a compound with antihistaminic properties. Reaction of the Grignard reagent from 4-chlorobromobenzene with pyridine-2-aldehyde gives the benzhydrol analog (12). The alcohol is then converted to its sodium salt by means of sodium, and this salt is alkylated with W-C2-chloroethyl)dimethylamine. Carbinoxamine (13) is thus obtained. ... 

Use of benzotriazole in the preparation of diphenylmethanes and triphenylmethanes has been reviewed." Benzotriazole is condensed with an aldehyde and then allowed to react with naphthols to form a diphenyl-methane benzotriazole derivative such as 69 (Scheme 9). The benzotriazole moiety in 69 is displaced by a Grignard reagent to give triphenylmethanes.79 100 This method allows for the preparation of triarylmethanes which contain three different aromatic rings. Compounds 70-72 are prepared by this method. 

The chemistry of benzo[Z>]furan-2(3//)-one (395) which exists in the keto form, is that expected of the lactone of 2-hydroxyphenylacetic acid. Grignard reagents bring about the expected ring opening. Condensations may be effected at the 3-position, especially with aromatic aldehydes. Methylation with iodomethane and potassium carbonate in DMF furnishes the 3-methyl and the 3,3-dimethyl compound. Methylation, with diazomethane,... 

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