Abstract:
A metal-free catalytic “one-pot” synthesis for a biologically relevant molecular architecture, pyrrolo1,2-
α (
iso)quinolines, is developed. Based on our previous studies on the synthesis of indolizines and imidazopyridines, the key reaction involved in this study is promoted by an amine and
N-heterocyclic carbene (NHC) relay catalysis via Michael addition-3+2 cycloaddition of azaarenes and
α,
β-unsaturated aldehydes. The reactions between azaarenes (0.2 mmol) and
α,β-unsaturated aldehydes (0.4 mmol) are sequentially catalyzed by the amine (10%, mol fraction) and NHC catalyst (20%, mol fraction) in the presence of 4-dimethylaminopyridine (DMAP) as the base (0.1 mmol) and (diacetoxyiodo)benzene (PIDA) as the oxidant (0.3 mmol) in toluene at room temperature. The first Michael addition step is catalyzed by the amine catalyst for 4 h at room temperature to give the Michael-addition product. Without any further work-up, NHC catalyst, DMAP and PIDA are added into the solution for an additional 18 h at room temperature. In this latter step, cycloaddition and aromatization takes place to give pyrrolo1,2-
αquinoline products. The “one-pot” reactions proceed smoothly for a variety of substituted and more conjugated quinolines, including those with tethered neutral, electron-withdrawing and electron-donating groups at 4, 6, 7-positions of quinolines. Ethyl 2-(benzofquinolin-3-yl)acetate also tolerates the reaction condition to afford the quinoline product in 75% yield. The substitution of the
α,
β-unsaturated aldehyde structures with electron-donating and withdrawing groups on the phenyl ring also successfully produces the corresponding quinoline products in moderate-to-good yields. Moreover, isoquinoline is also tolerated to give the corresponding isoquinoline product in 72% yield. Hetero quinoline-ethyl 2-(quinoxalin-2-yl)acetate also works well to afford ethyl 1-formyl-2-phenylpyrrolo1,2-
αquinoxaline-3-carboxylate in 56% yield.