A Three-Component Synthesis of (1,3-Oxazol-2-yl)-1,2-dihydro(iso)quinoline and its further Structural Diversifications

Abstract

A Reissert-type three-component synthesis of 1,3-oxazol-2-yl-1,2-dihydro(iso)quinoline is developed using a-isocyano b-phenyl propionamide as an isonitrile input. The structure of this multicomponent adduct is further diversified taking advantage of the rich chemistry of oxazole.Quinoline and isoquinoline derivatives are important classes of hetertocycles. 1 Their ubiquitous occurrence in nature and their wide spectrum of biological activities make them the prime targets in medicinal chemistry and the search of new and efficient synthetic routes has attracted attention of synthetic chemists for years. 2 For the functionalization of quinolines, isoquinolines and related aromatic azines, the Reissert reaction remained one of the most powerful tools. 3 The reaction can be considered as a multicomponent reaction (MCR) 4 where adducts are formed from an azine, an acyl chlorides and sodium cyanide via a N-acyliminium intermediate.The ability of isonitrile to undergo facile a-addition with a nucleophile and an electrophile under mild conditions made it a popular reactant for the development of novel MCRs. The eminent example is the classic Ugi four-component reaction which converts an aldehyde, an amine, an acid and an isonitrile into a-acetamidoamide in one step with good to excellent yield. 5 Recently, Lavilla and coworkers extended the Ugi-4CR to (iso)quinoline and demonstrated that N-acylated aromatic azine, is susceptible to nucleophilic attack of isocyanide leading, after hydrolysis, to the a-carbamoylated 1,2-dihydroazine. 6,7 On the other hand, Mironov et al. have independently developed a three-component synthesis of 2,3-dihydro-10H-pyrrolo[2,1-a]isoquinoline-1-one by reaction of isoquinoline, gem-diactivated olefines and isocyanides. 8 Earlier, Morel and his co-workers developed a three-component synthesis of fused imidazolium and dihydropyrimidinium salt by reaction of methylchlothioimidate, pyridine and isocyanides. 9,10 Based on these observations, we report herein a three-component synthesis of (1,3-oxazol-2-yl)-1,2-dihydro(iso)quinoline by exploiting the unique reactivity of a-isocyano acetamides. 11 Further structural-diversification of this adduct is also delineated based on the chemical reactivity of oxazole. Scheme 1As shown in the Scheme 1, the reaction of isoquinoline (1), methyl chloroformate (2) and morpholinyl-a-isocyano-b-phenylpropionamide (3) under slightly modified Lavilla's conditions (CH 2 Cl 2 , -40°C, 4 Å molecular sieves) 12 provided the expected compound 4 in 76%. 13