Three-component Ugi reaction: synthesis of 2-(1- (cyclohexanecarbonyl)cyclohexyl)-2-aza spiro[4.5]decan-3-one derivatives

Recently, a new version of the isocyanide-based Ugi three-component coupling reaction (3CC) using an aldehyde and acid has been developed as a bi-functional substrate [1,2]. Intermolecular versions of the Ugi reaction have also been reported, where two of the four functional groups are present on the same molecule. The possibility of generating β- lactam rings using β-amino acids as bifunctional compounds is known as the Ugi-4-centre-3- component reaction (U-4C-3CR) [3]. This reaction proceeds through a seven-membered ring intermediate to give the β-lactam derivative via a ring-contraction step.Gabapentin (GBP) is an antiepileptic drugin order to increase the biologicallyactivity of GBP, we have developed a simple synthetic method for the efficient preparation of new 2-(1- (cyclohexanecarbonyl)cyclohexyl)-2-azaspiro[4.5]decan-3-onederivatives using a Ugi-three-component reaction involving GBP, various ketones and cyclohexylisocyanide in ethanol (scheme 1). Experimentals: A mixture of 2-(1-(aminomethyl)cyclohexyl)acetic acid (1 mmol), cyclohexanone (1 mmol) and cyclohexylisocyanide (1 mmol) in ethanol (4 mL) was stirred at 50 °C for the appropriatetime. The progress of the reaction was monitored by TLC. Upon completion, solvent was removed under reduced pressure and the crude product was purified by washing with n-hexane and diethyl ether to afford the pure 2-(1-(cyclohexanecarbonyl)cyclohexyl)-2-azaspiro[4.5]decan-3-one. Results and Discussion:The scope and generality of this process are illustrated with respect to GBP and different ketones.In all the cases, the reactions were clean and provided the desired 2-(1-(cyclohexanecarbonyl)cyclohexyl)-2-azaspiro[4.5]decan-3-one derivatives in good yields. All products were fully characterized and confirmed by NMR, IR and elemental analysis