Nitriles directed lithiation

Nitriles will direct lithiation with non-nucleophilic bases such as LiTMP, particularly in conjuction with another nitrile group . The nitriles presumably act by an acidifying effect alone—no intramolecular N-Li coordination is possible in the intermediate (Scheme 60). 

Lithiation of both A/-phenyl- and 0-phenyl-urethanes has been reported. The ortho lithiadon of /V-r-bu-toxycaibonylaniline and subsequent addition to carbonyls, nitriles and several other electrophiles was first reported by Muchowski in 1980. In some cases the adduct cyclized by attacking the urethane carbonyl. Typical examples are shown in Scheme 17. Lithiation of an /V-r-butoxycarbonylaniline derivative served as one of two directed lithiation steps in Snieckus synthesis of anthramycin (17 Scheme 18). Treatment of phenothiazines with 2 equiv. of butyllithium affords an A(,o-dilithium species, but reaction with electrophiles occurs at both sites. Katritzky has shown that the sequence of N-lithiadon, car-bonation and o-lithiation protects the nitrogen from alkylation (Scheme 19). ... 

Careful choice of reaction conditions allows 2-lithiation even in the presence of groups susceptible to attack by the reagent. At — 100°C in THE 4,5-dicyano-l-methylimidazole forms the 2-lithio compound at — 80°C butyllithium attacks one of the nitrile functions <92JHCI09I>. Even 4- and 5-chloroimidazoles can be 2-lithiated, as can 4-bromoimidazole, but when the 2-position is blocked halogen-metal exchange and direct lithiation can occur elsewhere <94JMC332>. 

Halogeno compounds have been prepared by direct halogena-tion or by Sandmeyer reaction on 4-aminoisothiazoles. As expected from general considerations, a halogen atom in the 4-position is less reactive than one in the 5-position, but nitriles are obtained in good yield with cuprous cyanide at elevated temperatures. With butyllithium, lithiation occurs exclusively in the 5-position, and no evidence of halogen displacement has been obtained. ... 

The use of thienyl Grignard reagents, and more recently lithiated thiophenes, has been extensive and can be illustrated by citing formation of oxythiophenes, either by reaction of the former with f-butyl perbenzoate or the latter directly with bis(trimethylsilyl) peroxide or via the boronic acid, the synthesis of thiophene carboxylic acids by reaction of the organometallic with carbon dioxide, the synthesis of ketones, by reaction with a nitrile, or alcohols by reaction with aldehydes, by the reaction of 2-lithiothiophene with A -tosylaziridine, and by syntheses of thieno[3,2- ]thiophene and of dithieno[3,2- 2, 3 - /]thiophene. Some of these are illustrated below. 

Several routes to /3-keto-acids, -esters, and -nitriles, based on the acylation of malonate derivatives, have been reported. The dianion of monoethyl malonate is acylated by acid chlorides to give -keto-esters in a one-pot synthesis,and the lithio-derivative of bis(trimethylsilyl) malonate reacts with acid chlorides, giving /3-keto-acids directly.The magnesium derivatives of monomethyl or mono-thioalkyl esters of malonic acid give j8-keto-esters or -thioesters respectively in high yield under virtually neutral conditions with acid imidazolides. Similarly, the trimethylsilyl ester of cyanoacetic acid, after lithiation, reacts with mixed anhydrides to give high yields of j8-keto-nitriles. ... 

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