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Recent Approaches for the Synthesis of Imidazoquinazolines and Benzimidazoquinazolines

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Ayesha Rafiq, Sana Aslam, Matloob Ahmad, Muhammad Jawwad Saif, Sami A. Al-Hussain and Magdi E.A. Zaki

Submitted: 30 April 2023 Reviewed: 16 May 2023 Published: 09 November 2023

DOI: 10.5772/intechopen.1001896

Recent Advances on Quinazoline IntechOpen
Recent Advances on Quinazoline Edited by Ali Gamal Al-Kaf

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Recent Advances on Quinazoline

Ali Gamal Al-Kaf

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Abstract

Heterocyclic ring systems are gaining attention due to their pivotal role in drug design and medicinal chemistry. Quinazolines are nitrogen-containing heterocyclic pharmacophoric units found in abundance in natural and pharmaceutical products. Imidazoquinazolines and benzimidazoquinazolines are fused tricyclic and tetracyclic heterocyclic moieties, respectively. Different isomeric forms of imidazoquinazolines and benzimidazoquinazolines exhibited a plethora of biological applications such as antitumor, antimicrobial, antioxidant, anti-inflammatory, antitubercular, anticancer, antihypertensive, anticonvulsant, antiviral, antimalarial, antiapoptotic, anti-proliferative activities, etc. This chapter addressed the recent synthetic strategies for medicinally privileged scaffolds; imidazoquinazolines and benzimidazoquinazolines. The synthetic routes of various isomeric forms of above-mentioned heterocycles have also been discussed.

Keywords

  • Quinazoline
  • Imidazoquinazoline
  • Benzimidazoquinazoline
  • synthetic methodologies
  • medicinal importance

1. Introduction

Heterocycles gain much attention because of their vast applications in biology [1, 2, 3] and material sciences [4, 5]. Heterocycles possessed a lot of medicinal benefits [6, 7, 8, 9] and played an important role in drug design and development. Among the heterocycles, quinazoline is a bicyclic N-containing heterocycle that possesses a broad range of pharmaceutical applications, such as anti-inflammatory [10], antimicrobial [11], anticonvulsant [12], antimalarial [13], antitubercular [14], antioxidant [15], antihypertensive [16], antiviral [17] activities, etc.

Imidazole and benzimidazole are heterocyclic moieties and important pharmacophores in medicinal chemistry. Imidazole is a five-membered aromatic heterocycle that exhibits a number of biological applications, such as antibacterial [18], anticancer [19], antiepileptic [20], antitubercular [21] activities, etc. Benzimidazoles are privileged structures related to their roles in medicinal chemistry, e.g., they play their role in antibacterial [22], antidiabetic [23], antiviral [24], antiulcer [25] activities, etc. Drugs containing quinazoline, imidazole, and benzimidazole are given in Figure 1.

Figure 1.

Quinazoline, imidazole, and benzimidazole-based drugs.

Imidazoquinazoline and benzimidazoquinazoline moieties play significant roles as active biological agents. Imidazoquinazoline I is a PI3K inhibitor [26], imidazoquinazoline II is antiapoptotic [27] and benzimidazoquinazoline III is antitumor [28] in its action (Figure 2).

Figure 2.

Biologically active analogues.

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2. Imidazoquinazoline

Imidazoquinazoline is a fused tricyclic structure containing imidazole and quinazoline and has three nitrogen atoms in its molecular architecture. It is an important scaffold in drug molecules such as antithrombotic and anticardiotonic agents [29]. Certain derivatives of imidazoquinazolines show a plethora of biological applications, i.e., antitumor [30], anticonvulsant [31], antihypertensive [32], etc.

Structures of imidazoquinazoline and their different isomeric forms are given in Figures 3 and 4.

Figure 3.

Structure of Imidazoquinazoline.

Figure 4.

Different isomeric forms of Imidazoquinazoline.

2.1 Imidazo[1,2-c]quinazoline

Imidazo[1,2-c]quinazoline gains much attention for its synthesis because of its large-scale applications in pharmaceuticals as well as in material sciences. Imidazo[1,2-c] quinazolines play pivotal roles as anti-inflammatory [33], antimicrobial [34], antiapoptotic [35], anticancer agents [36], and as efficient dopants in OLEDs [37]. Following are the different synthetic strategies of imidazo [1,2-c]quinazoline.

2.1.1 One-pot exhaustive dehydrogenation

An expedient way to synthesize imidazo [1,2-c]quinazoline is the reaction of o-cyanoaniline (1) with phenylenediammine (2) in xylene under reflux to get an intermediate (3). The aminophenyl imidazole (3), when reacted with various aldehydes, resulted in the formation of 2,3,5,6-tetrahydroimidazoquinazoline (4a-h) in good yields. The aminophenyl imidazole (3) treated with imidates in boiling toluene afforded dihydroimidazoquinazolines (5a-b). The imidazo [1,2-c] quinazolines (4a-h) and (5a-b), when underwent the oxidative dehydrogenation conditions, i.e., potassium permanganate and silica gel, using acetonitrile at room temperature separately, afforded the respective targeted products (6a-i) in high yields [38]. A similar study was carried out by Claudi et al. following exhaustive dehydrogenation [39].

2.1.2 Ullmann coupling reaction

Imidazo[1,2-c]quinazolines (9a-p) were synthesized in moderate yields through a tandem reductive amination reaction. The reaction of 2-(2-bromophenyl)-4,5-disubstituted-1H-imidazole (7) with dimethyl acetamide (8) in the presence of CuI, tert-butylhydroperoxide, and p-toluenesulphonic acid at 130°C for 10 h afforded a series of desired products [40]. The Ullmann-type C–N coupling reactions in a tandem fashion were also observed by Nandwana et al. [41, 42].

2.1.3 Conventional or oxidative coupling

Imidazo[1,2-c] quinazolines (12a-l) can be prepared via one-pot, catalyst-free, and environment-friendly synthesis using ionic liquids as a solvent in excellent yields by the reaction of imidazolyl anilines (10a-g) with various aromatic aldehydes (11a-g) [43]. The formation of imidazo [1,2-c]quinazoline through oxidative coupling catalyzed by AgOTf was studied by Wu et al. [44].

2.1.4 Intramolecular C-N coupling

Imidazo[1,2-c] quinazolines were synthesized by Bagal, S. K. et al. The SNAr reaction was shown between chloroquinazolines (13a-e) and aminooxetane (14), using K2CO3 in acetonitrile to afford (15a-e). Intramolecular cyclization reactions were observed in (15a-e) during reflux in methanol, and finally, imidazo [1,2-c] quinazolines (16a-e) were achieved in 15–57% yields [45]. Imidazo[1,2-c]quinazoline synthesis through intramolecular C-N coupling was also practiced by Khoza et al. [46].

2.2 Imidazo[1,5-c]quinazline

Imidazo[1,5-c]quinazoline possesses a novel imidazo-N-heterocyclic skeleton. The following is the metal-free tandem approach to synthesizing it:

2.2.1 Oxidative domino sp3 C–H amination

An oxidative domino synthesis pathway for the formation of imidazo [1,5-c] quinazolines is the n-Bu4NI catalyzed reaction of 4-methyl-2-phenyl-quinazoline (17) with various benzylamines (18a-n) using tert-butylhydroperoxide, acetic acid, and DMSO yielded imidazo [1,5-c] quinazolines (19a-n) in high yields. Similarly, by following the same reaction conditions, various 4-methyl-2-substituted quinazolines (17’a-p) were reacted with benzylamine (18′) to give (19’a-n) in poor to high yields. Imidazo[1,5-c]quinazoline can also be prepared from amino acids. 4-methyl-2-phenyl-quinazoline (17) got reacted with various amino acids (20-c) under the same conditions and yielded various imidazo [1,5-c] quinazolines (21a-c) in poor to good yields (23–83%) [47].

2.3 Imidazo[2,1-b]quinazoline

Imidazo[2,1-b]quinazoline is an imidazole-blend quinazoline molecule. These types of heterocycles have applications in luminophores, optical lasers, and optoelectronics [48, 49]. Following is the synthetic approach to afford imidazo[2,1-b]quinazoline.

2.3.1 Cascade reaction

A cascade microwave-promoted reaction involving Claisen-Schmidt, aza-Michael, and cyclization reactions in the formation of imidazo[2,1-b]quinazoline was reported. Claisen–Schmidt reaction was observed between various active methylene ketones (22) and numerous aromatic aldehydes (23) using KOH and ethanol, resulting in the formation of a series of chalcones (24). These chalcones (24) underwent aza-Michael and cyclization reactions with benzimidazole (25), using KOH as a base and microwave irradiation as a catalytic tool in DMF to afford the targeted product (26) [50]. Imidazo[2,1-b]quinazoline was synthesized by Devipriya & her coworkers under UV-light in a cascade fashion [51].

2.4 Imidazo[4,5-g]quinazoline

Imidazo[4,5-g]quinazoline was discovered as traces in the long-term storage of 5-aminobenzimidazole. Following is the reported multicomponent reaction involved in the synthesis of imidazo[4,5-g]quinazoline.

2.4.1 Reductive coupling

Imidazo[4,5-g]quinazoline was synthesized by a novel multicomponent reaction that involved a series of reactions, i.e., Schiff base formation, Diels-Alder reaction, deflourination, and dehydrogenation. The substituted dinitrobenzenes (27) were dehydrogenated using Pd/C as a dehydrogenating agent in THF, ethanol, and ammonium formate to afford (28). The intramolecular hetero-Diels-Alder reaction was observed, followed by Schiff base formation in compounds (28) with various aldehydes (29), resulting in the formation of (30). These substituted-benzimidazoles (30) underwent deflourination and dehydrogenation reactions followed by Schiff base formation with a variety of aldehydes (29) to afford targeted products (31) in poor to moderate yields [52]. Reductive amination to prepare imidazo[4,5-g]quinazoline as ATP site inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor was practiced by Rewcastle et al. [53].

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3. Benzimidazoquinazoline

Benzimidazoquinazoline is a fused tetracyclic structure containing benzimidazole and quinazoline, having three nitrogen atoms in its molecular architecture. Benzimidazoquinazoline derivatives act as potent immunosuppressors [54] and possess promising antitumor activity [55] as well.

Structures of benzimidazoquinazoline and their different isomeric forms are given in Figures 5 and 6.

Figure 5.

Structure of benzimidazoquinazoline.

Figure 6.

Different isomeric forms of benzimidazoquinazoline.

3.1 Benz[4,5]imidazo[1,2-c]quinazoline

Benzo[4,5]imidazo[1,2-c]quinazoline is a planar heteroacene that possesses both benzimidazole and quinazoline structures fused together via a shared bond. Benz[4,5]imidazo[1,2-c]quinazoline derivatives showed a wide range of biological applications, i.e., antimicrobial [56], antiviral [57], anticancer [58], anticonvulsant [59], and anti-inflammatory [60]. Following are the different synthetic methods reported in the literature to afford benz [4,5]imidazo[1,2-c]quinazoline.

3.1.1 Conventional or oxidative coupling

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 I2-catalyzed oxidative cross-coupling reaction between anilines (32a-c) and various aromatic methyl ketones (35a-n) in moderate to good yields [62]. An efficient protocol was reported to synthesize benz[4,5]imidazo[1,2-c]quinazolines (38a-i) in moderate to good yields by cobalt-catalyzed isocyanide insertion reactions by reacting anilines (32a-c) with various isocyanides (37a-d) using sodium acetate, K2S2O8, and Cu(OAc)2.4H2O under reflux [63].

A domino synthetic approach for benz[4,5]imidazo[1,2-c]quinazoline formation was the reaction of benzimidazolyl anilines (39a-d) with ethynyl benzene (40) using I2 and CuI as catalysts in DMSO at 120°C to afford the desired products (41a-d) in moderate to good yields [64]. Highly functionalized benz[4,5]imidazo[1,2-c]quinazolines (43a-d) were synthesized under metal-free, photocatalytic conditions by reacting benzimidazolyl (39a-d) with trialky amine (42a-d) using eosin Y (EY) as a catalyst in aqueous acetonitrile in the presence of blue LED at room temperature for 27–50 h to obtain the desired products [65].

3.1.2 Intramolecular C-N coupling via C-X activation

Another approach to synthesize benz[4,5]imidazo[1,2-c]]quinazolines (45a-s) was the cycloamination reaction between substituted anilinoquinazolines (44) and phenyliodine bis(triflouroacetate) (PIFA) using Cu(OTf)2 in TFA in poor to good yields [66]. Bioactive Erlotinib analogues containing the benz[4,5]imidazo[1,2-c]quinazoline (46a-n) moiety were synthesized by the metal-free intramolecular amination reaction of anilinoquinazolines (44) with hexafluoroisopropyl alcohol (HFIP), using phenyliodide diacetate as a catalyst at 40°C for half an hour to afford the targeted product [67].

3.1.3 Ullmann N-arylation reaction

An easy way found to synthesize benz[4,5]imidazo[1,2-c]quinazolines (50a-f) was the Ullmann N-arylation reaction. The tandem reaction between o-cyanoanilines (47a-f) and diaryl iodonium salt (48) using Cu(OTf)2 as a catalyst in DCE at 110°C afforded intermediates (49a-f). The further treatment of quinazolin-4(3H)-imines (49a-f) with CuI resulted in the formation of desired products [68].

3.1.4 Directed arylic C-H amidation

Another efficient protocol reported to synthesize benz[4,5]imidazo[1,2-c]quinazolines (53a-n) was the reaction between N-tosyl-2-phenyl benzimidazoles (51a-n) and phenyl dioxolone (52) using Rh(III) catalyst in the presence of silver bis(triflimide) in DCE to afford the targeted product in 71–99% yields [69]. Directed arylic C-H amidation approach aided by Rh(III) catalyst was adopted by Xu and his colleagues to synthesize benz[4,5]imidazo[1,2-c]quinazolines [70].

3.1.5 Double C-H functionalization

A metal-free pathway for the synthesis of benz[4,5]imidazo[1,2-c]quinazoline was reported by Xiaojing, T. et al. Accordingly, the desired products (56a-w) can be obtained in 56–94% yields by reacting N-cyanobenzimidazoles (54a-w) with (55a-h) under oxidative conditions in the presence of tert-butyl peroxybenzoate [71]. Double C-H functionalization approach assisted by visible-light photoredox catalysis was executed by Xu et al. [72].

3.2 Benz[4,5]imidazo[1,2-a]quinazoline

Here are the methods for the synthesis of another isomer, benz[4,5]imidazo[1,2-a] quinazoline, reported in the established literature;

3.2.1 Transition metal-free tandem process

One-pot regioselective synthesis of benz[4,5]imidazo[1,2-a]quinazoline was reported by Fang, S. et al. Anilinobenzimidazole (25) showed a reaction with various aromatic aldehydes bearing halogen groups and a nitro group (57a-o) in DMF to afford the targeted products (58a-j) in 59–97% yields [73]. Transition metal-free coupling reaction to form benzimidazoquinazoline was carried out by Kim et al. under recyclable magnetic MOF-199 catalysis [74].

3.2.2 Intramolecular C: N bond formation

Benz[4,5]imidazo[1,2-a]quinazolines can be prepared from N-(2-benzimidazolyl)-2-aminobenzamides (59a-c) and o-halogenated aromatic aldehydes (60). When both moieties showed a reaction using CuI/L-proline in the presence of base Cs2CO3, the desired products (61a-n) can be achieved in good yields [75]. Another synthetic approach was the metal-free microwave-assisted reaction, which was designed by using the same reactants in DMF at 130°C to get the benz[4,5]imidazo[1,2-a]quinazoline (62a-j) in 38–77% yields [76].

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4. Conclusion

The fused heterocyclic moieties tend to achieve the top of the list position in drug design because of their wide range of pharmacological applications. In this context, this chapter is focused on the different synthetic approaches of imidazoquinazolines and benzimidazolquinazolines. These biological scaffolds were prepared by a large number of synthetic routes that are summarized in this chapter. These routes include Ullmann cross-coupling reaction, Claisen–Schmidt reaction, Aza–Michael reaction, cyclization reaction, Cu(OTf)2 catalyzed reaction, Iodine-mediated oxidative annulation reaction, oxidative and nonoxidative C-N coupling reaction, photoredox catalyzed synthesis, metal-free synthesis, green synthesis, microwave mediated synthesis, oxidative domino synthesis, transition metal-free and transition metal-catalyzed tandem processes. These synthetic strategies will be helpful in bringing novelty to the synthesis of bioactive compounds and in exploring a new area of medicinal research.

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Written By

Ayesha Rafiq, Sana Aslam, Matloob Ahmad, Muhammad Jawwad Saif, Sami A. Al-Hussain and Magdi E.A. Zaki

Submitted: 30 April 2023 Reviewed: 16 May 2023 Published: 09 November 2023

© The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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