Copper‐Catalyzed One‐Pot Synthesis of 3‐(N‐Heteroarenyl)acrylonitriles through Radical Conjugated Addition of β‐Nitrostyrene to Methylazaarenes

Abstract

A simple procedure for the copper‐catalyzed synthesis of 3‐(N‐heteroaryl)acrylonitriles was developed. Using a combination of Lewis and Brønsted acids, this one‐pot procedure undergoes via a radical conjugated addition and dehydration processes, without isolation of any intermediate, affording the acrylonitriles. This diastereoselective approach allowed the synthesis of a broad scope of quinazoline derivatives (22 examples) with moderate to good yields and good functional‐group tolerance and could be extended to other N‐heterocyles such as quinolines and isoquinolines. Based on control experiments, a mechanistic proposal for this new transformation is also presented.

Copper-Catalyzed Synthesis of Pyrrolo[1,2-c]quinazolines and Pyrrolo[2,1-a]isoquinolines and Antiplasmodial Evaluation

“…We began our studies with the optimization of the reaction conditions, using trans -β-methyl-β-nitrostyrene ( 1a ) and 4-methylquinazoline 2a as model substrates. Based on our previous reports, we initially used CuI (10 mol %) and HCl 0.5 M (10 mol %) in N , N -dimethylformamide (DMF), in which the desired product 3a was obtained in 54% yield (Table , entry 1). Then, we performed a screening of solvents using CuI as a catalyst.…”

“…In our previous study, the 1,4-addition of nitroolefins to 4-methylquinazolines was found to occur through a radical mechanism . In order to contribute with the mechanism pathway of this new method, we performed the reaction between trans -β-methyl-β-nitrostyrene ( 1a ) and 4-methylquinazoline ( 2a ) in the presence of (2,2,6,6-tetramethylpiperidin-1-yl)­oxyl (TEMPO) (Scheme ).…”

“…We have previously reported a Cu­(I)-catalyzed one-pot Michael addition/dehydration cascade reactions, using β-nitroolefins and 2-methyl-azaarenes, furnishing 3-( N -hetero­arenyl)­acrylonitriles and pyrrolo­[1,2- c ]­quinazolines as minor products . Based on these results, we envisioned that the presence of an alkyl group in β-position of the β-nitrostyrene could avoid the elimination reaction that leads to the acrylonitrile.…”