Investigation of the use of enolate ions to induce ortho-lithiation in aromatic systems: A new type of cyclization reaction

Directed ortho Metalation (DoM) reactions constitute a very useful tool in the repertoire of the synthetic organic chemist in its use to generate polysubstituted aromatic systems. In this dissertation, a novel reaction is reported between benzoate esters and aryl acetonitriles in the presence of excess LDA. This yields 3-amino-indenones in modest to good yields. It was shown that the less than anticipated yields were due to the attack of LDA on the esters to generate the N,N-diisopropylbenzamide. The DMG in this reaction is the enolate ion of the intermediate keto-nitrile. However the yields increase dramatically when the keto-nitriles (synthesized independently by condensation in the presence of sodium hydride) are subjected to the action o LDA. This reaction was successful with pyridyl esters and naphthalene esters on one side, and pyridyl acetonitriles, alkyl nitriles, benzoylmalononitrile, and phenylthioacetonitriles on the other. The reaction failed with furan and thiophene carboxylate esters.;The 3-amino-indenones when hydrolyzed in boiling acidic water, generated the corresponding biologically active 1,3-indandiones in high yields.;In an attempt to determine if the enolate was the true DMG in this reaction, several related nitriles were synthesized. Some evidence to confirm this view was obtained when it was found that neither an enol ether of a keto-nitrile system nor a nitrile lacking an enolate component would undergo cyclization.;A really surprising finding was that benzoyl acetonitrile wouldn't cyclize to 3-amino-indenone. Several ideas were explored in an attempt to explain this failure. Ultimately however it was found that a dianion is formed at the side chain and this appears to discourage further deprotonation of the aromatic ring. Some experiments to confirm this then were carried out. 2-Bromobenzoyl acetonitrile was synthesized and treated separately with LDA and t-BuLi. No cyclic product was formed. The lack of cyclization was very surprising, considering that an anion at the phenyl ring ought to be formed because of the metal-halogen exchange. 2-Bromobenzoyl acetonitrile in which the side chain was di-deuterated was then synthesized. When treated with t-BuLi, it was shown that the anion transferred to the side chain by observing a deuterium shift to the phenyl ring!! When a similar experiment was performed with benzoyl acetonitrile that was di-deuterated at the side chain, no anion transfer was observed. This proves that in 2-bromobenzoyl acetonitrile, the first deprotonation is followed by a metal-halogen exchange, which then equilibrates to form the dianion at the side chain. In benzoyl acetonitrile, the first deprotonation seems to be followed by a second direct side chain deprotonation and no ortho deprotonation occurs or intervenes.