Quinazoline Derivatives: Synthesis and Bioactivities Dan Wang and Feng Gao*

Wang and Gao Chemistry Central Journal 2013, 7:95 http://journal.chemistrycentral.com/content/7/1/95 REVIEW Open Access Quinazoline derivatives: synthesis and bioactivities Dan Wang and Feng Gao* Abstract Owing to the significant biological activities, quinazoline derivatives have drawn more and more attention in the synthesis and bioactivities research. This review summarizes the recent advances in the synthesis and biological activities investigations of quinazoline derivatives. According to the main method the authors adopted in their research design, those synthetic methods were divided into five main classifications, including Aza-reaction, Microwave-assisted reaction, Metal-mediated reaction, Ultrasound-promoted reaction and Phase-transfer catalysis reaction. The biological activities of the synthesized quinazoline derivatives also are discussed. Keywords: Quinazoline derivative, Synthesis, Bioactivity Introduction including Oxidative cyclization, Reagent refluxing and Quinazoline derivatives, which belong to the N-containing One-pot synthesis. In addition, the bioactivity researches heterocyclic compounds, have caused universal concerns of quinazoline derivatives were also discussed in order to due to their widely and distinct biopharmaceutical activities. provide valuable reference for the future synthesis and Researchers have already determined many therapeutic biological investigation of these compounds. activities of quinazoline derivatives, including anti-cancer [1-4], anti-inflammation [5,6], anti-bacterial [7-10], anal- gesia [5,9], anti-virus [11], anti-cytotoxin [12], anti-spasm Review [9,13], anti-tuberculosis [14], anti-oxidation [15], anti- Synthetic methods malarial [16], anti-hypertension [17], anti-obesity [18], Aza-reaction anti-psychotic [19], anti-diabetes [20], etc. Medicinal Aza-Diels-Alder reaction Imino-Diels-Alder reaction chemists synthesized a variety of quinazoline compounds [21] containing the coupling of imine and electron-rich with different biological activities by installing various alkene gradually became a powerful tool for the synthesis active groups to the quinazoline moiety using develop- of quinazoline derivatives [22]. In Povarov imino-Diels- ing synthetic methods. And the potential applications of Alder reaction, aniline and ethyl glyoxalate were chosen the quinazoline derivatives in fields of biology, pesti- as substrates. And two molecules of α-iminoesters, which cides and medicine have also been explored. This review were got from the condensation of aniline and ethyl summarized the representative synthetic methods, either glyoxalate, were hypothesized to form the direct additive traditional or novel, and categorized them into five main product. Cascade Imino-Diels-Alder reaction conducted classifications, including Aza-reaction, Microwave-assisted by Chen et al. [23] was extended from the Povarov Imino- reaction, Metal-catalyzed reaction, Ultrasound-promoted Diels-Alder reaction. In this research, researchers chosed reaction and Phase-transfer catalysis. Besides, three other the same substrates as in the Povarov Imino-Diels-Alder kinds of reactions were also listed out, which were either reaction, and adopted various kinds of Lewis acid as cata- designed as supplementary methods in most experi- lysts, then the reagents were refluxed in toluene for one ments or used as the main methods in some researches, day, and finally produced quinazoline derivatives 3. CuBr2 was determined as the optimized catalyst with highest yields (Scheme 1). * Correspondence: [email protected] Department of Chinese Traditional Herbal, Agronomy College, Sichuan Agricultural University, No. 211, Huiming Road, Wenjiang Region, Chengdu 611130, P. R. China © 2013 Wang and Gao; licensee Chemistry Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Wang and Gao Chemistry Central Journal 2013, 7:95 Page 2 of 15 http://journal.chemistrycentral.com/content/7/1/95 O O N NH2 O O CuBr2 R R + O N Toluene / reflux O O 1 2 R 3 Scheme 1 Synthesis of derivatives 3 by cascade imino-Diels-Alder reaction. Aza-Wittig reaction Aza-Wittig reaction, which gener- synthesis of 3H-quinazolin-4-ones by aza-Wittig reaction ally precedes in cascade with easy operation under mild [27]. Compounds such as Type 11 were adopted as sub- reaction conditions, is widely used in the synthesis of N- strates to react quantitatively with per fluoro-tagged heterocycles [24]. He et al. reported a kind of tandem phosphine 12 to obtain iminophosphoranes 13. Then Staudinger–Aza-Wittig–Nucleophilic addition reaction to these intermediates converted directly into the desired synthesize indolo[1,2-c]quinazolines recently [25]. The quinazoline derivatives through intramolecular aza-Wittig main synthetic procedure of this research was using reaction. The reactions were preceded in toluene as azides 4 and triphenylphosphine to react in toluene for solvent and trifluorotoluene as co-solvent (Scheme 4). 2 h at room temperature, and then heating at reflux After the reaction, desired products 15 were separated for 6–24 h. Results showed that the nitrogen evolution through solid-extraction on fluorous reversed-phase sil- through the Staudinger reaction halted during the ini- ica gel, for that the unreacted iminophosphoranes 13 tial 2 h, and surprisingly produced the final product and phosphane oxide 14 would leave the perfluoro tag indolo[1,2- c]quinazolines 6 directly from the reaction on silica gel, thus make the products be washed off mixture (Scheme 2).A synthetic method for 2-alkoxy- effectively. In this way, it was made possible for simple 3H-quinazolin-4-ones was reported by Ding et al.in segregation of quinazolin-4-ones even with unquantitative 2004 [26]. In this study, twelve novel 2-alkoxy-3H- cyclization reaction. quinazolin-4-ones were synthesized from carbodiimide 8, which was obtained from aza-Wittig reaction of Microwave-assisted synthesis iminophosphorane 7 with aromatic isocynate (Scheme 3). Compared to traditional heating methods, microwave Sophie Barthelemy et al. applied perfluoroalkyl-tagged heating could expand reaction range as well as shorten triphenylphosphine in a fluorous biphasic system for the the reaction time from a few days or hours to a few R3 R3 O O OH O R3 O O R1HN R HN 1 Ph3P R1HN N N N R2 R2 N O N R2 N O 3 Ph P 4 3 5 6 Scheme 2 Synthesis of indolo[1,2-c]quinazolines 6 from azides 4. O COOEt COOEt ArNCO NaOR COOEt Ar N PPh3 NHAr C NAr N N N C N OR OR 7 8 910 Scheme 3 Synthesis of 2-alkoxy-3H-quinazolin-4-ones. Wang and Gao Chemistry Central Journal 2013, 7:95 Page 3 of 15 http://journal.chemistrycentral.com/content/7/1/95 O O P Rf O O O 3 R2 N R3 12 N R3 N R2 R2 O P Rf + N3 Rf = CH2CH2C8F17 N 3 N R3 R1 R1 P R1 11 13 (Ph-Rf )3 14 15 Scheme 4 Synthesis of 3H-quinazolin-4-ones via aza-Wittig reaction. minutes. Thus, when applied in fields of organic syn- In the synthetic research conducted by Kidwai et al. thesis, pharmaceutical chemistry and high-throughput [34], the target compounds quinazoline derivatives 28 chemistry, microwave heating shows greater advantage were obtained by heating an equimolar amount of alde- than traditional heating methods [28-31]. hyde 25, 5,5-dimethyl-1,3-cyclohexanedione (dimedone) Luo et al. reported the first microwave-assisted 26 and urea/thiourea 27 under microwave irradiation in synthesis of new quinazoline derivates containing α- the absence of solvent and catalyst (Scheme 7). aminophosphonate [32]. In their method, N’-(substituted- Hazarkhani et al. adopted isatoic anhydride and 2- 2-cyanophenyl)-N,N-dimethyl-formamidine derivatives and aminobenzimi-dazole as the raw materials, DMAC as dialkyl amino (phenyl) were adopted as the raw materials solvent in their starting research and got 2-amino-N-(1-H - to react in 4:1 volume ratio of isopropanol to acetic acid benzimidazol-2-yl) benzamideundermicrowaveirradiation solvent for 20 min under microwave irradiation (100°C, [35]. Then they discovered that this novel amide has three 100 psi), and obtained twenty-four quinazoline compounds nucleophilic sites to condense with different electrophilic 18, two of which had similar activity as commercial reagent compounds, which made it applicable for the synthesis of Ningnanmycin (Scheme 5). numerous quinazolinone based targets, and was applied in Tu et al. reported a fast, one-pot, microwave-assisted syn- the following synthesis. thesis of polysubstituent imidazo[1,2-a]quinoline, pyrimido Amides (5 mmol), triethylorthoformate (7.5 mmol), p- [1,2-a]quinoline and quinolino[1,2-a]quinazoline derivatives tolue-nesulfonic acid (0.25 mmol) and DMAC (1–2 ml) [33]. They explored the optimal reagent, volume and were mixed in a tall beaker covered with stem-less fun- heating temperature by testing different reagents under nel, and heated for 4 min under 600 w microwave power different reaction time and temperature. Then under the in a microwave oven, then interrupted in between with a optimal conditions (2.0 mL glycol and 120°C),several alde- cooling procedure. After that, the reaction mixture was hydes were separately reacted with various enaminones cooled to room temperature and poured into a large vol- and malononitrile to obtain different products (Scheme 6). ume of water for precipitation. Then the precipitate was OR3 OR3 O O P OR3 P OR3 CN i-PrOH / AcOH NH NH2 MW,20 min R R1 + R2 2 CH N N R1 16 17 18 N Scheme 5 Synthesis of quinazoline compounds containing α-aminophosphonat. O O R CN HN O R RCHO R1 CN R' O 19 R2HN R1 N NH COOH 21 R1 23 N NH + R1 O ethylene glycol, MW ethylene glycol, MW 120 ,5-8min NC CN 120 ,5-8min R2 O One-Pot One-Pot R' 24 20 22 Scheme 6 Microwave-assisted one-pot synthesis of quinazoline compounds. Wang and Gao Chemistry Central Journal 2013, 7:95 Page 4 of 15 http://journal.chemistrycentral.com/content/7/1/95 O O R H2N NH2 MW NH + + R-CHO Solvent and Catalyst free O X N X 27 H 25 26 28 X=O,S O R= Cl O N Cl Scheme 7 Solvent-catalyst-free microwave-assisted synthesis of quinazolines.

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