Synthesis, structure and reactions of the most twisted amide

Abstract

Details are reported of the synthesis, properties and reactions of 3,5,7-trimethyl-1-azatricyclo[3.3.1.1^3,7]decan-2-one, 7 (the “most twisted amide”). Its spectroscopic properties show clearly that 7 is a ketone rather than an amide, albeit a ketone with a tertiary amino group directly attached to the carbonyl carbon. The amino group is basic (pK_a ∼ 5.2) and nucleophilic, while the CO group reacts normally as a ketone, giving the corresponding twisted enamine with the methylene Wittig reagent and acetals under standard conditions. As expected, 7 is rapidly hydrolysed to the bicyclic amino acid 15, but, remarkably, hydrolysis is readily reversible under mild acidic conditions, and in methanol the amino acid is converted to the twisted amide in 80% yield. This cyclisation of the amino acid is an extraordinarily efficient intramolecular reaction: the effective molarity of the amine nucleophile is estimated at 10¹² M: the carboxylate anion thus acting as an efficient acylating agent for both secondary and tertiary amine groups. The hydrate of the conjugate acid, typically a high-energy intermediate in amide hydrolysis, is stable in dilute aqueous acid and as the crystalline hydrochloride.