Copper-Catalyzed Benzylic sp3C-H Amination Reaction of Amidines: Synthesis of Quinazoline Derivatives

Abstract

Quinazoline motif is an important heterocyclic framework, which widely exists in many biologically active molecules and natural products. Although numerous synthetic efforts have been made for the preparation of quinazoline de- rivatives in recent years, it is still highly desirable to search for a more convenient and efficient approach. As part of our ongoing interest in transition-metal-catalyzed C—H functionalization, herein, we report a novel copper-catalyzed synthesis of quinazoline derivatives from amidines. During these transformations, the selectivity of benzylic sp 3 C—H over aryl sp 2 C—H bond was efficiently realized. Various 2-arylquinazoline derivatives were obtained in moderate to good yields. A representa- tive procedure for the copper-catalyzed construction of quinazolines from amidines is as following: N-(o-tolyl)benzimidamide (1a, 0.4 mmol, 89.7 mg), Cu(OTf)2 (0.04 mmol, 13.8 mg) and Ag2CO3 (0.8 mmol, 219 mg) were added to a 25 mL sealed tube, followed by addition of DMF (2 mL). The mixture was stirred at 140 ℃ for 10 h. After cool- ing to room temperature, the mixture was poured into ice-water and extracted with CH2Cl2 (15 mL×3). The combined or- ganic layers were dried (Na2SO4), filtered over Celite, evaporated in vacuo. The residue was purified by a shot flash silica gel column chromatography (petroleum ether/ethyl acetate, V∶V=15∶1) to afford the product 2a (71%, 62.4 mg). Keywords copper; N-arylamidines; C—N bond formation; quinazoline derivatives