Keywords

1 Introduction

Quinazoline is a compound made up of a fused benzene ring and a pyrimidine ring (Figs. 13.1 and 13.2). Its chemical formula is C8H6N2. Quinazoline appears as a yellow crystalline substance. Any derivative of quinazoline may be described as a quinazoline compound.

Fig. 13.1
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Quinazoline

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Fig. 13.2
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Quinazolinone

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Quinazoline derivatives, which belong to the N-containing heterocyclic compounds, have caused universal concerns due to their wide and distinct biopharmaceutical activities. Researchers have already determined many therapeutic activities of quinazoline derivatives, including anticancer [1–4], anti-inflammatory [5, 6], antibacterial [7–10], analgesic [5, 9], antiviral [11], anti-cytotoxic [12], antispasmodic [9, 13], antituberculosis [14], antioxidant [15], antimalarial [16], antihypertensive [17], antiobesity [18], antipsychotic [19], antidiabetic [20], etc. Medicinal chemists synthesized a variety of quinazoline compounds with different biological activities by installing various active groups to the quinazoline moiety using developing synthetic methods. Potential applications of the quinazoline derivatives in fields of biology, pesticides, and medicine have also been explored. This chapter summarizes the representative synthetic methods, either traditional or novel, and categorized them as microwave-assisted reaction, metal-catalyzed reaction, ultrasound-promoted reaction, and phase-transfer catalysis. In addition, the bioactivity researches of quinazoline derivatives are also discussed in order to provide valuable reference for future synthesis and biological investigation of these compounds.

2 Naturally Occurring Quinazoline-Based Compounds

The quinazoline alkaloids form a small but important group of naturally occurring bases, which were isolated from a number of different families in the plant kingdom. Witt and Bergman [21] review the chemistry of quinazoline alkaloids, viz. chrysogine, luotonine A, tryptanthrin, febrifugine, and rutaecarpine. The only ­non-alkaloid ­naturally occurring quinazoline is the potent neurotoxin called tetrodotoxin, which was isolated from the Japanese puffer fish and from the California newt. Arborine was isolated by two Indian groups from Glycosmis arborea [22]. Vasicine was discovered in Adhatoda vasica [23] and was found to show bronchodilator activity. The bronchodilator activity of vasicine, vasicinone, and 3,4-dihydro-4-oxoquinazoline was studied in detail but was in no way comparable with known bronchodilator drugs [24].

Experiments in the USA and China during World War II led to the isolation of two compounds called febrifugine (Fig. 13.3) and isofebrifugine from Dichroa febrifuga with known antimalarial activity (a Chinese herb). Further studies suggested that it must be the diastereoisomers of febrifugine that posses the antimalarial properties. Baker and co-workers [25] studied the antimalarial activities of synthesized samples of dl-febrifugine and found only one-half activity than the naturally occurring compound. Further, they discovered that it was actually the isofebrifugine that possessed the antimalarial properties, but was highly toxic in isolation to the other compounds found in the naturally occurring alkaloid [26]. Finally, the antimalarial activity of febrifugine and many of its synthetic derivatives were confirmed by Hewitt and collaborators [27].

Fig. 13.3
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Febrifugine

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A hypotensive red alkaloid isolated from the Brazilian plant Hortia arborea England was called hortiamine. One of the most potent nonprotein neurotoxin tetrodotoxin was isolated from certain varieties of the Japanese puffer fish. Several quinazoline derivates show antimalarial properties against Plasmodium gallinaceum. The most effective was 6-chloro-2-ethyl-3,4-dihydro-4-oxo-3-p-pyrimidin-2′-ylsulfa-moylphenylquinazoline [28].

Cytotoxic alkaloids of the fumiquinazoline (Fig. 13.4) family have been isolated from different fungi including a strain of the fungus Aspergillus fumigatus, Acremonium sp., Ecteinascidia turbinata, and Neosartorya fischeri. The first total synthesis of fumiquinazolines has been described by Snider and Zheng [29].

Fig. 13.4
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Fumiquinazoline

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3 Microwave Methodology of Quinazolines Synthesis

3.1 Microwave-Assisted Synthesis of Quinazoline Compounds

Microwave-assisted organic synthesis is becoming popular with organic chemists, and comprehensive chapters have become available in recent years. Microwave heating is very convenient to use in organic synthesis. The heating is instantaneous, very specific, and there is no contact required between the energy source and the reaction vessel. Recent interest has been focused on “dry media” synthesis and particularly on solvent-free procedures using various mineral oxides and solvent-less reactions with neat reactants in the absence of a catalyst or solid support. Furthermore, the diversity-generating potential of multicomponent reactions (MCRs) has been recognized and their utility in preparing libraries to screen for functional molecules is well appreciated. Consequently, the design of novel MCRs is an important field of research. In this section, some selected literature examples of quinazoline synthesis by these methodologies are discussed.

Compared to traditional heating methods, microwave heating could expand the reaction range as well as shorten the reaction time from a few days or hours to a few minutes. Thus, when applied in fields of organic synthesis, pharmaceutical chemistry, and high-throughput chemistry, microwave heating shows greater advantage than traditional heating methods [30–33].

Luo et al. reported the first microwave-assisted synthesis of new quinazoline derivates containing α-aminophosphonate [34]. In their method, N′-(substituted-2-cyanophenyl)-N, N-dimethyl-formamidine derivatives, and dialkyl amino(phenyl) were adopted as the raw materials to react in 4:1 volume ratio of isopropanol to acetic acid solvent for 20 min under microwave irradiation (100 psi) and obtained 24 quinazoline compounds, two of which had similar activity as commercial reagent ningnanmycin (Scheme 13.1).

figure a

Scheme 13.1

Tu et al. reported a fast one-pot, microwave-assisted synthesis of polysubstituent imidazo[1,2-a]quinoline, pyrimido [1,2-a]quinoline, and quinolino[1,2-a]quinazoline derivatives [35]. They explored the optimal reagent, volume, and heating temperature by testing different reagents under different reaction times and temperatures. Then, under optimal conditions (2.0 ml glycol), several aldehydes were separately made to react with various enaminones and malononitrile to obtain different products (Scheme 13.2).

figure b

Scheme 13.2

In the synthetic research conducted by Kidwai et al. [36], the target compounds quinazoline derivatives were obtained by heating an equimolar amount of aldehyde, 5,5-dimethyl-1,3-cyclohexanedione (dimedone), and urea/thiourea under microwave irradiation in the absence of solvent and catalyst (Scheme 13.3).

figure c

Scheme 13.3

3.2 Niementowski Quinazoline Synthesis

The striking improvement in the Niementowski quinazoline synthesis has been fulfilled using microwave irradiation (Scheme 13.4). Using microwave irradiation and/or Appel’s salt, new efficient routes to various substituted and fused quinazolines have been developed by Besson et al. [37, 38].

figure d

Scheme 13.4

3.3 MultiComponent One-Pot Synthesis of Quinazolines

One-pot synthesis of 4(3H)-quinazolinones from amines and formic acid (or orthoesters) was developed, and recently, more detailed procedures using inorganic solid support and neat one-pot procedures under microwave irradiation have been developed by Dandia et al. [39] (Scheme 13.5) and Liu et al. [40]. Also facile one-pot synthesis of 2,4(1H,3H)-quinazolinediones has been developed recently as a green chemical procedure.

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Scheme 13.5

4 Ultrasound-Promoted Synthesis of Quinazoline

In critical synthesis, ultrasonic assistance is needed to meet the high requirements for temperature and pressure. For instance, in Bischler cyclization, the most traditional synthetic methods for quinazoline derivatives, high temperature (above 120 °C) and high pressure are needed for at least 5 h in saturated ammonia alcohol solution. Various syntheses applying this method contain the passage of ammonia through a mixed melt of the amino compound and sodium acetate at a temperature higher than 160 °C in which ultrasonic promotion is demanded.

Zhang et al. [41] reported an ultrasound-assisted synthesis of novel quinazoline derivatives (Scheme 13.6), including a four-step synthesis of quinazoline core and the optimization of the Bischler cyclization [42].

figure f

Scheme 13.6

We had an interest in utilizing 2-phosphoranylideneamino-benzoyl derivatives as building blocks, particularly in view of anthranilic acids as important biological precursors of various alkaloids such as glomerine, vascine, and microbial products like tryptanthrin and anthramycine.

Thus, acylation of N-methylamides with 2-azidobenzoyl chloride (readily available from 2-azidobenzoic acid [43]) forms imides which upon treatment with triphenylphosphine (TPP) in the course of consecutive Staudinger reaction/intramolecular aza-Wittig reaction yields exclusively 3-methylquinazolin-4(3H)-ones quantitatively (Scheme 13.7) [44, 45]. This procedure provides simple and efficient quinazolinone annelation of amides and lactams.

figure g

Scheme 13.7

Safari et al. [45] successfully demonstrated for the first time that Cu powder and ultrasound 300 w/H2O could be used as an excellent and efficient catalyst for convenient synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives under solvent-free conditions and microwave irradiation (Scheme 13.8). The protocol proves to be efficient and environmentally benign in terms of easy workup, high yields, and ease of recovery of catalyst. In addition, the present method is superior in terms of green media, the amount of catalyst, and reaction time.

figure h

Scheme 13.8

Bharathi et al. [46] successfully synthesized the TiO2 nanoparticles using aqueous Annona squamosa peel extract (Scheme 13.9). These synthesized TiO2 nanoparticles were characterized using UV, XRD, and TEM and used as a catalyst for 2,3-dihydro-3-methyl-2-phenylquinazolin-4(1H)-one analogue synthesis.

figure i

Scheme 13.9

Muthukrishnan et al. [47] discovered that the EtOAc fraction of Glycosmis pentaphylla leaf extract inhibits the juvenile hormone III biosynthesis in vitro of corpora allata from 3-day-old females of the field cricket Gryllus bimaculatus. The bioactive compound responsible for this activity was identified as the quinazolone alkaloid arborine. This alkaloid also exhibited larvicidal activity against the mosquito.

Derivatives of 2-methyl-3-(o-tolyl)-4(3H)-quinazolone (Scheme 13.10) bearing new substituents on the 2-methyl group have been synthesized. It was established that most substitutions at this position reduce or remove the CNS-depressant activity of methaqualone [48].

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Scheme 13.10 Aza-Diels–Alder reaction

Imino-Diels–Alder reaction [49] containing the coupling of imine and electron-rich alkene gradually became a powerful tool for the synthesis of quinazoline derivatives [50]. In Povarov imino-Diels–Alder reaction, aniline and ethyl glyoxalate were chosen as substrates. And two molecules of α-iminoesters, which were obtained from the condensation of aniline and ethyl glyoxalate, were hypothesized to form the direct additive product. Cascade imino-Diels–Alder reaction conducted by Chen et al. [51] (Scheme 13.11) was extended from the Povarov imino-Diels–Alder reaction. In this research, researchers chose the same substrates as in the Povarov imino-Diels–Alder reaction, adopted various kinds of Lewis acids as catalysts, and finally produced quinazoline derivatives. Iron powder was determined as the optimized catalyst with highest yields.

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Scheme 13.11 Aza-Wittig reaction

Aza-Wittig reaction, which generally precedes in cascade with easy operation under mild reaction conditions, is widely used in the synthesis of N-heterocycles [52]. He et al. reported a kind of tandem Staudinger–Aza-Wittig–nucleophilic addition reaction to synthesize indolo[1,2-c]quinazolines recently [53]. Results showed that the nitrogen evolution through the Staudinger reaction halted during the initial 2 h and surprisingly produced the final product indolo[1,2- c]quinazolines directly from the reaction mixture (Scheme 13.12).

figure l

Scheme 13.12

A synthetic method for 2-alkoxy-3H-quinazolin-4-ones was reported by Ding et al. in 2004 [54]. In this study, 12 novel 2-alkoxy-3H-quinazolin-4-ones were synthesized from carbodiimide, which was obtained from aza-Wittig reaction of iminophosphorane with aromatic isocynate (Scheme 13.13).

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Scheme 13.13

5 Water-Mediated Quinazoline Synthesis

Organic reactions in water, without the use of any harmful organic solvents, are of great interest because water is nontoxic, nonflammable, abundantly available, and inexpensive. Thus, water as the reaction medium is generally considered a cheap, safe, and environmentally benign alternative to synthetic solvents. Furthermore, because of the low solubility of common organic compounds in water, the use of water as a solvent often makes the purification of products very easy by simple filtration or extraction.

A convenient and clean water-mediated synthesis of a series of indolo[1,2-c]quinazoline derivatives was reported using alternative nonconventional energy sources. The products are obtained in shorter times with excellent yields (78–89 %) from the MCR of 2-aminobenzimidazole, malononitrile, and carbonyl compounds [55]. In their research, 2-(2-halophenyl)-1H-indoles and (aryl)methanamines were adopted as raw materials to generate corresponding Schiff base via the Ullmann reaction. Then, gas as oxidant, 3 equiv K2CO3 as base, and 10 mol% Cu(OAc)2 as catalyst were revealed as the optimum conditions to conduct aerobic oxidative C–H amination under solvent-free conditions or water (Scheme 13.14).

figure n

Scheme 13.14

Jiang et al. also reported a one-pot synthesis of 5,12-dihydroindolo[2,1-b]quinazolines [56]. N-(2-bromobenzyl)-2-iodoani-line and malononitrile were adopted as the raw materials to afford the desired compound through copper-catalyzed intramolecular C–N coupling reaction (Scheme 13.15).

figure o

Scheme 13.15

Dabiri and Mostafa reported [57] a rapid, efficient, and one-pot procedure for the synthesis of mono- and di-substituted (3H)-quinazolin-4-ones in the presence of an AlCl3/ZnCl2 mixture supported on silica gel, under solvent-free conditions or water.

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Scheme 13.16

An efficient and eco-friendly method is reported for the synthesis of 2-substituted-2,3-dihydroquinazolin- 4(1H)-ones from direct cyclocondensation of anthranilamide with aldehydes and ketones using N-propylsulfamic acid supported on magnetic Fe3O4 as a recoverable and recyclable nanocatalyst in good to excellent yields in water (Scheme 13.17). The characteristic advantages of this catalyst are rapid, simple, and efficient separation using an appropriate external magnet, which minimizes the loss of catalyst during separation and is reusable without significant loss of activity up to ten cycles.

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Scheme 13.17

The procedure does not involve the use of any additional reagent/catalyst, produces no waste, and represents a green synthetic protocol with high atom economy. The combination of microwave irradiation, ultrasonic irradiation, and aqueous-mediated conditions using MCRs lead to enhanced reaction rates, higher yields of pure products, easier workup, and sometimes selective conversions. Consequently, this protocol should be welcome in these environmentally aware days.

6 Metal-Catalyzed Synthesis of Quinazoline Derivatives

In 1993, several catalytic methods have been developed for the synthesis of 4(3H)-quinazolinones via transition-metal catalyzed reductive N-heterocyclization. For example, palladium-catalyzed cyclocarbonylations of halides with appropriate reactants provided regioselective synthesis of 4(3H)-quinazolinone derivatives and indoloquinazolines [58]. Also, selenium-catalyzed reductive N-heterocyclization to quinazolinones has been developed. Copper-catalyzed heteroannulation with alkynes has been developed as highly region- and stereoselective route to 2-(2-arylvinyl)-1,2,3,4-tetrahydroquinazolin-4-ones by Kundu et al. [59] (Scheme 13.18). Recently, condensation of anthranylamide with various aldehydes to 4-quinazolinones has been found to give excellent yields in the presence of cupric chloride. For synthesis of quinazoline derivatives, various coupling reactions have been utilized after synthesis of quinazoline-2,4(1H,3H)-diones via palladium-catalyzed oxidative coupling. For example, synthesis of diarylquinazolines by iron-catalyzed cross-coupling reaction and diaminoquinazolinones by palladium-catalyzed amination have been developed.

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Scheme 13.18

6.1 Titanium-Catalyzed Reaction

A convenient method for the synthesis of 3-substituted quinazolin-4(3H)- ones using the convergent reactions of formic acid, a primary amine, and isatoic anhydride under solvent-free conditions and with brief microwave irradiation is described.

Natural and synthetic molecules with the core of quinazoline ring system show a wide range of biological activities [60–64]. The chemotherapeutic use of quinazoline alkaloids may date back to the ancient Chinese treatment of malaria with the herbal preparations from Dichroa febrifuja [65]. At present, some synthetic quinazoline-based drugs such as metolazone, quinethazone, and prazosin have acquired medicinal approval for their unique pharmacological indices and many others are under clinical evaluation [66–71]. In this synthesis, a series of quinazoline derivatives were afforded by adopting anhydrous THF as solvent and the TiCl4–Zn system as reducing agent. Several representative synthetic routes were selected [72, 73]. In many such cases, the role of solvents as heat dispersants are no longer needed. The so-called solvent-free reactions are eco-friendly and, in view of green chemistry’s desire for avoiding solvent hazards, are in demand (Scheme 13.19).

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Scheme 13.19

6.2 Palladium-Catalyzed Reaction

Palladium-catalyzed coupling reaction, which plays a vital role in the pharmaceutical industry, is widely applied in the chemical synthesis industry and laboratories as an efficient method for the formation of C–C and C–heteroatom bond. Qiu et al. [74] determined the optimum conditions for the palladium-catalyzed three-component synthesis of quinazolino[3,2-a]quinazolines as follows: amine (3.0 equiv), isocyanide (3.0 equiv), carbodiimide (0.2 mmol), Pd(OAc)2 (5 mol%), and Cs2CO3 (3.0 equiv) in 3.0 ml toluene (Scheme 13.20).

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Scheme 13.20

6.3 Organometallic Reagents

Various quinazolines from 2-aminobenzonitrile using organometallic reagents have been developed by Bergman et al. [75–76]. The topical synthetic methodologies such as iminophosphorane-mediated synthesis (aza-Wittig methodology), microwave-assisted synthesis, solid-phase synthesis, and application of organometallic reagents, etc. will be discussed retrospectively, focusing on the pathways to quinazoline, quinazoline-4-one (Scheme 13.21), and their derivatives.

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Scheme 13.21

6.4 PTSA-catalyzed Reaction

Rossi et al. have utilized the tandem aza-Wittig/electrocyclization principle for synthesis of quinazoline ring starting from N-imidoyl iminophosphorane [77]. Other unique synthetic strategies with N-vinyliminophosphoranes and benzotriazolyl derivatives (Scheme 13.22) have also been developed demonstrating the maturity and excellent prospects of iminophosphorane-mediated syntheses.

figure v

Scheme 13.22

Quinazolines and their spiro derivatives are also available via MCRs in water. The three-component condensation of isatoic anhydride, primary amines, and aromatic aldehydes or isatin to give 2,3-dihydroquinazolin-4(1H)-ones or spirooxindole derivatives (Scheme 13.23) was performed in water using ethylenediamine diacetate (EDDA) as catalyst [78].

figure w

Scheme 13.23

7 Antimalarial Activity

Several bio-active natural products such as febrifugine (Fig. 13.5) and isofebrifugine (Fig. 13.6) contain quinazolinone moieties with potential antimalarial [79] activity.

Fig. 13.5
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(+)-febrifugine

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Fig. 13.6
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(+)-iso febrifugine

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Quinazolinone derivatives attract widespread attention due to the diverse biological activities associated with them. Rutaecarpine (Fig. 13.7) and luotonine A [80] (Fig. 13.8) are the two natural quinazoline-fused compounds exhibiting very potent pharmacological values.

Fig. 13.7
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Rutaecarpine

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Fig. 13.8
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Luotonine

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8 Conclusions

Conventional synthetic methods for quinazoline derivatives, still in general use, including microwave-assisted reaction, ultrasound-promoted reaction, metal-mediated reaction, water reaction, and phase-transfer catalysis reaction for the synthesis of this important heterocyclic compounds are discussed. It could be seen from the examples compiled above that some novel synthetic methods are in constant development and different methods are adopted in the synthesis of different quinazoline analogues. On the other hand, it is known that substituents at different positions affect the activity differently. By careful observation of the recent researches, substituted quinazoline analogues remain a majority among the products. However, with the deepening and development of researches, substituent groups at other positions are also achieved and studied increasingly, such as the construction of N-heterocyclic quinazolines by introduction of active groups into the 3-position of the quinazoline core. It is worth mentioning that N-heterocyclic quinazolines with more rigid and complicated structures were synthesized successively, some of which showed excellent biodynamic derivatives. In addition, it could be drawn from the research progress discussed above that enhancement of activity by the splicing method of installing various active groups is and will still be the main method for drug design and reconstruction of quinazoline derivatives. We hope that the information contained here encourages the readers to make use of these green protocols for the efficient and eco-friendly construction of novel heterocyclic frameworks.