Synthetic Study On Privileged Heterocycles Based On Ugi Four-Component Reaction And Microwave-Assisted Post Annulation

Privileged heterocycles are capable of interaction with multiple receptors and they play an important role in pharmaceutical research and development.Generation of libraries of privileged heterocyclic compounds in a timeless and cost-effective manner is an essential component of drug research programs.The Ugi four-component reaction(U-4CR) has been widely used as a robust synthetic method for creation of structural diversity.It is the main theme of this thesis research to establish microwave-assisted,metal-catalyzed annulation reactions,which are able to convert the linear U-4CR products into cyclic scaffolds.It is expected that this study makes contribution to the post-Ugi annulation methodologies applicable to the efficient assembling of privileged heterocycles.Chapter 1 briefly introduces the isocyanide-based Ugi four-component reaction and its variants along with other types of multicomponent reactions.The literature examples on use of U-4CR with various post annulation reactions are covered.It is followed by a brief mention on the advantage of microwave-assisted organic synthesis (MAOS) in a temperature-control manner.The importance of privileged structures is then illustrated with the examples taken from the literature and those synthesized from 2-aminophenols in our laboratories.Chapter 2 provides an overview on Heck reaction and its applications in synthesis of complex molecules.Preparation of 3-arylideneindolin-2-ones by various approaches is discussed,including intramolecular Heck reaction(IMHR) and other types of metal-catalyzed annulation.The main effort presented in this chapter concerns with microwave-assisted IMHR of aryl triflates.After optimization of the catalyst system,a "U-4CR-IMHR" sequence has been established for generation of 3-arylideneindolin-2-ones.Starting from 2-aminophenols,the U-4CR forms the functionalized phenol products,which are transformed into the corresponding triflates. The latter undergo IMHR by using 5 mol%each of Pd(OAc)₂ and(±)-BINAP in MeCN at 180℃for 30-60 min under microwave heating to produce 3-arylideneindolin-2-ones.The yields for the IMHR are 52-77%with the product E/Z selectivity of 70:30-90:10.It is found advantageous for microwave-assisted IMHR which requires less catalyst loading and short reaction time.Chapter 3 describes an attempted investigation on Pd-catalyzed intramolecular direct arylation and intramolecular amidation on the scaffolds of 3-arylideneindolines and 3-arylideneindolin-2-ones.Although positive results are not obtained,it is found that the U-4CR products formed from 2-aminophenols are able to undergo Cu-catalyzed intramolecular Ullmann etherification,resulting in formation of 6/7/6-tricyclic heterocycles.This observation forms the basis for development of a "U-4CR-Ullmann" sequence and the details are given in Chapter 4.By using 2-bromobenzaldehyde and 2-bromobenzoic acid,respectively,in the U-4CR with 2-aminophenols,the U-4CR products are subjected to Cu-catalyzed intramolecular Ullmann etherification under controlled microwave heating.Two series of heterocycles,i.e.dibenz[b,f][1,4]oxazepine-11(10H)-carboxamides and dibenz[b,f] [1,4]oxazepin-11(10H)-ones are synthesized.For the Ullmann reaction,10 mol%CuI and 30 mol%N,N-dimethylglycine(DMG) hydrochloride are used as the catalyst with 2 equivalents of Cs₂CO₃ as the base.The reaction is heated in dioxane at 150℃for 30 min to afford the products in 64-100%yields.Scope of the microwave-assisted intramolecular Ullmann reaction is excellent.The experimental section,characterization of all new compounds,cited references,and copies of original ¹H and ¹³C NMR spectra are found at the end of the thesis.