An environmentally benign nano CuO catalyzed “on-water” strategy has been developed for one-pot synthesis of isoindolo[2,1-a]quinazolines by a three-component coupling of isatoic anhydride, 2-carboxybenzaldehyde and amines in high yields. Aryl, heteroaryl and alkyl amines reacted very well under the present reaction conditions. Water plays a major role to accelerate this transformation through hydrogen bond mediated ‘electrophile–nucleophile dual activation’. The catalyst can be reused several times without significant loss of catalytic activity. The present method produces no waste, and represents a green synthetic protocol.