Reactions of the Indole Magnesium Halides

In some instances the reactions of the indole Grignard reagents resemble those of simple aryl or alkyl magnesium halides, but in many eases they appear to reaet anomalously. 

A wide variety oi reaetion temperatures and times have been employed in carrying out these reactions in an extreme case tem-teratures of up to ca. 350° were employed. Under these conditions it is quite possible that the actual products isolated were formed as the result of seeondary reactions occurring after the primary products had been formed. Standard procedures for the working up of reaction mixtures obtained in Grignard reactions arc usually followed. 

Reactions with Organic Halogen Compounds 1. Alkyl Halides 

Oddo reported over 50 years ago that the interaction of methyl iodide with indole magnesium iodide at the reflux temperature of ether for 12 hours produced 3-methylindole (2). Rather surprisingly, 

Hoshino reported that a product, described as 3,3-dimethjd-indolenine (12), accompanied by some 1,3-dimethylindole (4) and a 

Hoshino, Proo. Imp. Acad. (Tokyo) 8, 171 (1932) Chem. Abstr. 26, 4814 

---

The reaction of the o-substituted nitrobenzene 1 with 3 moles of the vinyl magnesium halide 2 gives the 7-substituted indole 3 as the major product. 

Anisole and mixtures of diethyl ether with aromatic hydrocarbons have both been widely employed as solvents for these reactions. Ethers other than diethyl ether and anisole have also been successfully used (cf. refs. 14-17). Hcxamethylphosphorotriamide has recently been used as a solvent for indole Grignard reactions. Young and Mizianty have recently described the use of an aromatic magnesium halide (phenylmagnesium bromide) for the synthesis of indole magnesium bromide. 

Similar results have been obtained from the reaction of / -dialkylamin-oethyl halides with indole derivatives (Scheme 32). Alkylation of indolyl-magnesium iodide (152) with 2-chloro- 1-dimethylaminopropane (153) furnished the four products 154-157, whereas the reaction of the sodium salt of indole with 153 yielded the rearranged compound 157 as a major product, accompanied by 156. These results suggested that the aziridinium s t 158 is involved in this alkylation reaction as an intermediate. 

Table 11.1 lists some of the reaction conditions which have given prepara-tively useful yields of 3-alkylation. Entries 1-3 are typical alkylations using a magnesium salt and an alkyl halide. Even 2,3-disubstituted indoles are alkylated at C3 under these conditions (Entry 7). Entry 5 represents a more recently developed method in which an allylic alcohol and indole react in the... 

The preparation of indoles by the benzyne route is illustrated by the base-induced cyclization of the amino-alcohols (171 R = H or Me) to indole and 3-methylin-dole, respectively/ The photochemical reaction of o-bromo- or o-iodo-aniline with the enolates (172 R = H, Me, or PrO leads to indoles (173)/ The salt (174), generated by the action of lithium di-isopropylamide on o-tolyl isocyanide, serves as a source of diverse indole derivatives (i) it cyclizes spontaneously to 1-lithioindole, which forms 3-alkyl-indoles on treatment with alkyl halides in the presence of magnesium iodide, (ii) it reacts with allyl esters RC02CH2CH=CH2 (R = alkyl or aryl) to give the ketones (175), which cyclize... 

---