Green Synthesis of 6‐Aryl‐5,6‐dihydrobenzo[4,5]imidazo[1,2‐c]quinazoline Derivatives in Ionic Liquid under Catalyst‐free Conditions

Abstract

in Wiley Online Library (wileyonlinelibrary.com).Using ionic liquids as green media, a series of 6-arylbenzo [4,5]imidazo [1,2-c]quinazoline derivatives is synthesized via a reaction of 2-(1H-benzo [d]imidazol-2-yl)aniline and benzaldehydes in the air. While the intermediate products of 6-aryl-5,6-dihydrobenzo[4,5]imidazo [1,2-c]quinazolines were obtained in high yields at the same conditions under nitrogen protection.J. Heterocyclic Chem., 55, 166 (2018). INTRODUCTIONBenzoimidazole is a very useful heterocycle for its histamine receptor antagonist. A well-known example is astemizole (Fig. 1, left) [1], which is the secondgeneration antihistamine drug that has a long duration of action. It also has better selectivity to the H1 receptor and is clinically used to treat hay fever urticaria, allergic rhinitis, and allergic conjunctivitis. Quinazolines are also an important class of bicyclic heterocyclic compounds that are famous for their anti-tumor activity. Lapatinib (Fig. 1, right) [2], which is a marked anti-cancer drug, is a dual tyrosine kinase inhibitor that interrupts the HER2/neu and epidermal growth factor receptor pathways. It is usually used for the treatment of patients with advanced or metastatic breast cancer and other solid tumors.Benzoimidazoquinazoline is a tetracyclic heterocycle containing three nitrogen atoms whose derivatives may possess novel bioactive activities for screening. It was reported that they were usually obtained by a condensation of 1H-benzo [d]imidazol-2-amine, aldehydes, and dimedone [3]; or 1H-benzo [d]imidazol-2-amine and 2-halogenated benzaldehydes [4]; or two-step reaction of isatoic anhydride, o-phenylenediamine, and aldehydes [5]. In addition, treatment of 2-(1H-benzo[d]imidazol-2-yl) aniline with various kinds of benzaldehydes also is a more efficient procedure. However, it should be noted that they were all treated in flammable organic solvents with moderated yields, such as HOAc [6] and CH 3 OH [7]. Thus, a simple, efficient, and especially green method to synthesize benzoimidazoquinazolines would be attractive.Room temperature ionic liquids, especially those based on the 1-N-alkyl-3-methylimidazolium cation, have shown great promise as attractive alternative to conventional solvents for its unique property of no vapor pressure. Therefore, they have been used widely as green medium in chemistry for many organic reactions [8] RESULTS AND DISCUSSIONTreatment of 2-(1H-benzo[d]imidazol-2-yl)aniline (1) and 3-chlorobenzaldehyde (2a) in ionic liquids of [BMIm]BF 4 (Scheme 1) at 80°C resulted in the corresponding 6-(3-chlorophenyl)-5,6-dihydrobenzo [4,5] imidazo[1,2-c]quinazoline (3a) in 96% yield.Using the conversion of 1 and 3-chlorobenzaldehyde 2a as a model reaction, several parameters including reaction temperature and ionic liquids were explored as shown in Table 1. A mixture of 3a and 4a was detected by TLC in ionic liquids of [BMIm]BF 4 at room temperature (Table 1, entry 1). It was found that the reaction temperature played a key role in the conversion, and 3a wit...

Recent Approaches for the Synthesis of Imidazoquinazolines and Benzimidazoquinazolines

“…Benz [4,5]imidazo [1,2-c]quinazolines (34a-I) can be prepared by green synthesis using ionic liquids by reacting benzimidazolyl anilines (32a-c) with various aldehydes (33a-l) in a catalyst-free environment in good to excellent yields [61]. Another facile access to afford [4,5]imidazo [1,2-c]quinazolines (36a-n) is the I 2 -catalyzed oxidative cross-coupling reaction between anilines (32a-c) and various aromatic methyl ketones (35a-n) in moderate to good yields [62].…”