# A Review on Current Synthetic Methods of 4-Aminoquinazoline Derivatives

Authors: Soghra Khabnadideh; Sara Sadeghian
Journal: Journal of Chemistry
 (2022)

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## Abstract

Quinazoline scaffold and its various derivatives, as an important category of heterocyclic compounds, have received much attention for the design and development of new drugs due to their various pharmacological properties like anticancer, anticonvulsant, antidepressant, antibacterial, antifungal, antioxidant, anti-HIV, antileishmanial, anticoccidial, antimalarial, anti-inflammatory, antileukemic, and antimutagenic. Among the various substituted quinazolines, 4-aminoquinazoline scaffold, as a privileged structure in medicinal chemistry, is present in many approved drugs and biologically active compounds. Furthermore, 4-aminoquinazoline derivatives are often applied as key intermediates in the preparation of bioactive compounds. The current review focuses on the key methods for the preparation of 4-aminoquinazoline derivatives, including the nucleophilic substitution reaction, metal-catalyzed approaches, microwave irradiation methods, cyclocondensation, and direct amination methods.


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## Body

## 1. Introduction

Heterocycles containing nitrogen atom are an important category of the favorable structures in the field of medicinal chemistry [1]. Among the heterocyclic structures, quinazoline derivatives with a double-ring structure are one of the most significant scaffolds for the design and synthesis of a wide range of bioactive compounds [2]. Quinazoline derivatives have attracted much attention of the medicinal chemists due to their various biological properties like anticancer, anti-inflammatory, antidepressant, anticonvulsant, vasodilator, antihypertensive, antibacterial, antifungal, anti-HIV, antioxidant, antileishmanial, anticoccidial, antimalarial, antileukemic, and antimutagenic [2, 3]. Among the various substituted quinazolines, 4-aminoquinazoline scaffolds have great importance due to their diverse spectrum of therapeutic potential (Figure 1) [2, 4, 5]. According to the reports, 4-aminoquinazoline derivatives demonstrate a wide variety of biological activities like antimicrobial, anti-inflammatory, anticancer, and antihypertensive [1, 6]. 4-Aminoquinazoline, as a privileged core, is present in many approved drugs and biologically active compounds, such as bunazosin, prazosin, alfuzosin, trimetrexate, erlotinib, gefitinib, lapatinib, afatinib, and vandetanib (Figure 2) [1, 5–11]. Furthermore, 4-aminoquinazoline derivatives are often applied as key intermediates in the preparation of bioactive compounds.Figure 1
4-aminoquinazoline scaffolds.Figure 2
4-aminoquinazoline-based drugs.4-Aminoquinazoline derivatives exert their biological effects through a variety of targets such as DNA cleavage and p53 activation [12], aurora kinase inhibition [13], ERK inhibition [14], ErbB/HDAC inhibition [15], EGFR inhibition [16, 17], VEGFR-2 tyrosine kinase inhibition [18], and PDE1 inhibition [19].Therefore, the synthesis of 4-aminoquinazoline derivatives has attracted significant attention in recent years. The current review focuses on the new and improved synthetic pathways for the preparation of 4-aminoquinazoline derivatives including the nucleophilic substitution reaction, metal-catalyzed approaches, microwave irradiation methods, cyclocondensation approaches, and direct amination methods.


## 2. Synthetic Strategies of 4-Aminoquinazoline Derivatives

### 2.1. Nucleophilic Substitution Reaction

The first nucleophilic substitution reaction of quinazoline occurs at the more reactive C-4 position of the quinazoline ring. 4-Aminoquinazoline2, as an important core in the structure of several drugs and bioactive compounds, can be prepared from the nucleophilic substitution reaction of quinazoline 1 with sodamide (NaNH2) (Scheme 1).Scheme 1
Nucleophilic substitution reaction of quinazoline with sodamide (NaNH2).


### 2.2. Metal-Catalyzed Reactions

#### 2.2.1. Copper-Catalyzed Reactions

Yang et al. developed an efficient and simple copper-catalyzed approach to provide 4-aminoquinazoline6 and 2,4-diaminoquinazoline 7 analogues from the reaction of substituted 2-bromobenzonitriles 3 with amidines 4 or guanidine 5, with good yields (Scheme 2). The couplings of substituted 2-bromobenzonitriles with various amidines or guanidine were performed in DMF utilizing CuI as a catalyst, N, Nˊ-dimethylethylenediamine (DMEDA) as a ligand, and potassium carbonate (K2CO3) as a base, under nitrogen atmosphere at 80°C. The scope investigation of this system was carried out using different substituted 2-bromobenzonitriles, amidines, and guanidine. The results showed that the substitution type on the phenyl ring of 2-bromobenzonitriles affected the reactivity of the substrate. The existence of electron-withdrawing groups like NO2 on the phenyl ring increased the reaction rates compared to those with electron-neutral or electron-rich substituents. Moreover, aliphatic and aromatic amidines resulted in higher yields compared to guanidine because of high polarity of the guanidine derivatives. The proposed mechanism for this CuI-catalyzed method involves the Ullmann-type coupling reaction of the substituted 2-bromobenzonitriles with amidines or guanidine and subsequently, intramolecular nucleophilic addition of amino group to the ortho-cyano moiety (Figure 3). Readily available reactants, facile, one-pot cascade, practical, the use of mild conditions, economical, and good yield of products are the advantages of this method [1].Scheme 2
Copper-catalyzed synthesis of 4-aminoquinazoline and 2,4-diaminoquinazoline derivatives.Figure 3
The proposed mechanism for the synthesis of 4-aminoquinazoline and 2,4-diaminoquinazoline analogues using CuI as a catalyst.Yang et al. reported a very efficient copper-catalyzed procedure for the preparation of 2-substituted-4-aminoquinazoline derivatives11 from the reaction of 2-substituted benzimidamides 8 with various aldehydes 9 and sodium azide 10, in the presence of CuBr as a catalyst, L-proline as a ligand, and DMF as a solvent (Scheme 3). Further studies showed that CuBr and L-proline components were essential for this reaction and the use of other nitrogen sources like ammonium chloride, ammonium acetate, or ammonium hydroxide instead of NaN3 led to the unfavorable results. The substrate scope investigation of this copper-catalyzed system was performed using different 2-substituted benzimidamides and aldehydes. The results indicated that 2-iodo and 2-bromobenzimidamides substrates gave the target quinazolines in moderate to excellent yields while 2-fluoro and 2-chlorobenzimidamides did not produce products, despite increasing the reaction temperature. The reactivity order for the above compounds was as follows: aryl iodides > aryl bromides > aryl chlorides (fluorides). In addition, it was found that the electronic features of the groups on the phenyl ring of 2-substituted benzimidamides (R1) had negligible influence on the reaction yield. In the case of aldehydes, the type of substituents on the aromatic ring also does not have remarkable influence on the reactivity. So, a variety of aromatic aldehydes containing electron-donating (OH, OMe, Me, t-Bu), electron-neutral (H), and electron-withdrawing (NO2, Cl, Br) substituents afforded the corresponding quinazolines in moderate to good yields. Further investigations indicated that the large steric hindrance of the substituents on the aromatic ring had also an obvious effect on the reaction yields. So, 2,6-dimethylbenzaldehyde led to the target products in low yields (50%). In addition, it was found that alkyl aldehydes, 2-naphthaldehyde, 2-hydroxy-1-naphthaldehyde, 2-thienaldehyde, 2-furanaldehyde, and 3-pyridinaldehyde were well tolerated and afforded the corresponding products in good yields. Furthermore, in the case of ortho-halogenated benzimidamides, corresponding 2,6-disubstituted 4-aminoquinazolines were obtained in moderate to good yields. These results indicated that the electronic properties of the additional substituent on the ortho-halogenated benzimidamide had a limited effect on the reactivity. The probable mechanism of this copper-catalyzed system involves the SNAr substitution reaction between 2-halobenzimidamide 8 and NaN3 to produce 2-azidobenzimidamide 12. Afterwards, the copper-mediated denitrogenation of 12 in the existence of L-proline and trace H2O in DMF generates 2-aminobenzimidamide 15 using Cu(I) and Cu(III) complexes 13-14. The condensation of 15 with aldehyde provides Schiff base 16. An intramolecular nucleophilic addition of amidine nitrogen to imine carbon in 16 affords intermediate 17 which on subsequent oxidative dehydrogenation and amine-imine tautomerization forms the expected compound 11 (Figure 4). The advantages of this method are efficient, readily available reagents, mild reaction conditions, practical, one-pot cascade, wide substrate scope, operational simplicity, and low reaction temperature [20].Scheme 3
Synthesis of 2-substituted-4-aminoquinazolines in the presence of CuBr, L-proline, and DMF.Figure 4
The proposed mechanism for the synthesis of 2-substituted-4-aminoquinazoline derivatives in the presence of CuBr, L-proline, and DMF.Xu et al. described a new and effective copper-catalyzed approach for the preparation of 2-arylquinazolin-4-amines20 using readily available 2-arylindoles 18 and TMSN319. The reaction took place in acetonitrile and in the presence of Cu(OAc)2 as a catalyst, tert-butyl peroxybenzoate (TBPB) as an oxidant, H2O as an additive, and NaOH as a base, under argon atmosphere (Scheme 4). The scope examination of this method was performed using a variety of 2-arylindoles, under the optimized conditions. The results showed that indoles with methyl and halogen substituents (R′) at the C-5 and C-6 positions afforded the target products in satisfactory yields but indoles with electron-withdrawing substituents like NO2 and CF3 at the C-5 position could not produce the desired products. Further investigation revealed that the steric hindrance and the nature of groups present at the pyrrole ring (R) affected the yield of the reaction. Generally, the phenyl ring with substituents at the para position led to the higher yields compared to the phenyl ring with ortho- and meta-substitutions. Furthermore, the phenyl ring with electron-withdrawing substituents such as F and Cl gave better yields than the phenyl ring with electron-rich substituents, like methoxy, n-propyl, and t-butyl. In addition, 2-(pyridine-3-yl)-1H-indole provided the expected products in good yields, while 2-n-butyl-1H-indole resulted in very low yields. The suggested mechanism for this method is illustrated in Figure 5. The reaction of TMSN3 with TBPB in the existence of copper results in the formation of azidyl radical, through a single-electron transfer process. Afterwards, the addition of azidyl radicals to the C(3) of 18 generates the diazidation intermediate 22 which on intramolecular coupling of the carbon-centered radical with one azido group affords the aminyl radical 23. Intermediate 24 is obtained via the sequential reduction-protonation or H-abstraction. Then, the ring expansion in the presence of NaOH and denitrogenation of 25, affords intermediate 26 which on subsequent protonation and tautomerization forms the desired product 20. The significant advantages of this method are effective and mild conditions [4].Scheme 4
Synthesis of 2-arylquinazolin-4-amines in the presence of Cu(OAc)2 and TBPB.Figure 5
The plausible mechanism for the synthesis of 2-arylquinazolin-4-amines in the presence of Cu(OAc)2 and TBPB.Chen et al. reported a Cu-catalyzed approach for the direct conversion of cyclic amides to aromatic heterocyclic amines in DMF utilizing Cu(acac)2 as a catalyst and di-t-butyl peroxide (DTBP) as an oxidant. In this method, the direct amination of quinazolinones 27 with various amines 28 resulted in the 4-aminoquinazoline derivatives 29 (Scheme 5). The scope of the described method was examined using various primary and secondary alkylamines as well as different substituted quinazolin-4(3H)-ones. The results revealed that various amines like piperidine, methyl-substituted piperidines, pyrrolidine, azepane, cyclohexanamine, and linear and branched alkylamines afforded the corresponding quinazolines in moderate to excellent yields. But aromatic amines did not react with quinazolinones due to the low activities and also the possibility of oxidation. Furthermore, it was found that substituted quinazolin-4(3H)-ones with electron-donating and electron-withdrawing substituents afforded the target derivatives in good to excellent yields. In addition, 6-bromoquinazolinone and 6-iodoquinazolinone selectively reacted with amines to provide corresponding products but not the Ullman coupling products. Although, the results showed that halogens were more suitable for this reaction. Further investigations demonstrated that thieno [2, 3-d] pyrimidin-4-ol and electron-rich 6,7-diether substituted quinazolinones afforded the target quinazolines in 56–89% yields. The suggested mechanism for this reaction is illustrated in Figure 6. The significant advantages of this procedure are efficient, mild reaction conditions, environmentally friendly, and readily available starting materials [21].Scheme 5
Synthesis of 4-aminoquinazoline derivatives in the presence of Cu(acac)2 as a catalyst and DTBP.Figure 6
The proposed mechanism for the synthesis of 4-aminoquinazoline derivatives in the presence of Cu(acac)2 as a catalyst and DTBP.Huang et al. reported a new procedure for the preparation of 2-acyl-4-aminoquinazoline derivatives39 using 2-aminobenzonitriles 36, methyl ketones 37, and ammonium acetate (NH4OAc) 38 in the presence of I2/CuCl2 (Scheme 6). In this method, a methyl group was utilized as a new input to form target derivatives. The scope investigation of this process was carried out using various methyl ketones and a range of 2-aminobenzonitriles. The results indicated that aryl methyl ketones with electron-neutral (4-H); electron-donating (4-Me, 2-Me, 3-OMe, 4-OEt, 3,4-OCH2O, and 3,4-O(CH2)2O); electron-withdrawing (3-NO2, 4-SO2Me, and 4-CO2Me); and halogen (4-F, 4-Cl and 4-Br) groups on the benzene ring gave the expected products in good yields. In addition, heterocyclic methyl ketones and several substrates containing fused rings such as 1-naphthyl, 2-naphthyl, and 2-fluorenyl were also well tolerated and generated the target products in moderate to good yields. Furthermore, it was found that 2-aminobenzonitriles containing electron-rich (-Me, -OMe, and–di-OMe) and halogen (-F, -Cl, and -Br) substituents at the 4- and 5-positions of the phenyl ring reacted with methyl ketones and provided the expected products in moderate to good yields. The possible mechanism of this process is represented in Figure 7. The advantages of this method are operational simplicity, readily available materials, mild reaction conditions, and good functional group compatibility [5].Scheme 6
Synthesis of 2-acyl-4-aminoquinazoline derivatives in the presence of I2/CuCl2.Figure 7
The possible mechanism for the synthesis of 2-acyl-4-aminoquinazolines in the presence of I2/CuCl2.


#### 2.2.2. Palladium-Catalyzed Reactions

Wang et al. described a palladium catalyzed procedure for the production of a broad range of 4-amino-2-aryl(alkyl)quinazoline derivatives48 from N-arylamidines 46 and isonitriles 47, in the presence of CsCO3 and O2 as a base and oxidant, respectively (Scheme 7). The target quinazoline derivatives were obtained through palladium-catalyzed intramolecular aryl C-H amidination via incorporation of isonitrile under relatively mild condition in good yields. The substrate scope investigation of this method was performed using different N-aryl ring (R1)-substituted benzamidines under optimized reaction conditions. The results indicated that benzamidines with electron-donating substituents such as Me and OMe on the phenyl ring produced the target quinazolines in excellent yields except the benzamidine bearing a para-methoxy substituent which provided the target products in moderate yields. Benzamidines with electron-withdrawing substituents like F and Cl on the phenyl ring generated the target quinazolines in lower yields. These findings propose that an electrophilic aromatic substitution (SEAr) reaction may be involved in the activation process of the C(sp2)-H bond. Furthermore, the effect of benzamidine ring substituents (R2) was examined which demonstrated that the nature and steric hindrance of these substituents have a significant effect on the reaction yield. The aryl moieties bearing electron-donating substituents such as Me and OMe were more suitable for this reaction compared to electron-withdrawing substituents like Cl and Br. This observation showed that the electron density on amidine nitrogen plays a vital role in the complexation with the palladium. Moreover, it was found that the reaction yields are more sensitive towards ortho-substituents, which could be due to the steric interference with complexation of amidine nitrogen to the palladium. The benzamidine ring (R2) containing alkyl moieties such as t-butyl and cyclohexyl afforded the corresponding 2-alkyl-substituted 4-aminoquinazolines in moderate to good yields. Furthermore, the different substituted isonitriles (R3) were investigated. The results demonstrated that isopropyl and cyclohexyl isonitrile compared to t-butyl and aryl isonitriles are less efficient, a result which is related to the thermal stabilities of the isonitriles. The possible mechanism of the described reaction is shown in Figure 8. The coordination of isonitrile-ligated Pd (II) with amidine nitrogen in the presence of Cs2CO3 results in the generation of complex 49. Then, an intramolecular electrophilic substitution generates the cyclopalladation intermediate 50, which undergoes migratory insertion of the isonitrile. Subsequent reductive elimination of the intermediate 51 followed by tautomerization affords the target product 48 and Pd (0) species, which is reoxidized to Pd (II) using dioxygen. The advantages of this procedure are efficient, concise, environmentally benign, mild condition, good functionality tolerance, wide substrate scope, readily available starting materials, and high yield of products [22].Scheme 7
Synthesis of 4-amino-2-aryl(alkyl) quinazolines in the presence of Pd(OAc)2, CsCO3, and O2.Figure 8
The proposed mechanism for the synthesis of 4-amino-2-aryl(alkyl)quinazoline derivatives in the presence of Pd(OAc)2, CsCO3, and O2.Thanh et al. synthesized a set of 2-aryl-4-aminoquinazoline derivatives55 using 2-aryl-quinazolinones 52 via a three-step reaction in the presence of POCl3, NaN3, and H2/Pd (Scheme 8). In this process, the amide group of quinazolinones 52 were converted to the corresponding imine chloride 53 using POCl3 in moderate yields, which is subsequently converted into the intermediate 54 using NaN3 in good yields. Finally, the azide group of 54 was easily reduced to the amine group utilizing H2 and Pd/C and resulted in the target derivatives 55 in good yields. Generally, the results indicated that the electronic features and steric hindrance of the aryl ring had a negligible effect on the reaction yields [23].Scheme 8
Synthesis of 2-aryl-4-aminoquinazoline derivatives in the presence of POCl3, NaN3, and H2/Pd.


#### 2.2.3. Iron-Catalyzed Reaction

Yin et al. described an efficient procedure for the production of N4-substituted 2,4-diaminoquinazoline derivatives 58, 59 utilizing the commercially available 2-nitrobenzaldehydes 56, H2NCN, various amines, and Fe/HCl (Scheme 9). Preliminary studies showed that the oxidative cyanoimidation of 2-nitrobenzaldehydes and also the condensation with amine were carried out in excellent yields. Subsequently, the reductive intramolecular cyclization of 2-nitrobenzimidamides to generate diaminoquinazolines was conducted using Fe/HCl as a reductive agent in high yields. To examine the substrate scope of this method, different substrates includingsubstituted 2-nitrobenzaldehydes and different amines were tested, under optimized conditions. From the results, it was found that the type of substituents on the aryl ring of 2-nitrobenzaldehydes had a negligible effect on the reaction rate. Different 2-nitrobenzaldehydes with electron-withdrawing (Cl, Br) or electron-donating (OMe) groups provided cyanoimidates 57 in good yields. The reaction of various cyanoimidates with simple primary amines which were substituted with aliphatic chains or rings as well as the substitution containing the aryl groups gave the target products in excellent yields. In addition, the secondary amines also produced the desired products in good yields. The probable mechanism of this system is represented in Figure 9. This mechanism involves the tandem oxidative cyanoimidation, condensation of cyanoimidate with amine, and reductive intramolecular cyclization of 2-nitrobenzimidamides 60 to generate diaminoquinazolines 58 in the Fe/HCl medium. The advantages of this procedure are efficient, one-pot procedure, facile, readily available reactants, and high yield of products [24].Scheme 9
Synthesis of N4-substituted 2,4-diaminoquinazolines using 2-nitrobenzaldehydes in the presence of H2NCN and Fe/HCl.Figure 9
The proposed mechanism for the synthesis of N4-substituted 2,4-diaminoquinazolines in the presence of H2NCN and Fe/HCl.


#### 2.2.4. Rhodium (III)-Catalyzed Reaction

Ren et al. reported a novel rhodium (III)-catalyzed procedure for the preparation of 4-aminoquinazoline derivatives64 using N-arylbenzamidines 62 and 3-phenyl-1,4,2-dioxazol-5-ones 63 in the presence of AgOTf, Zn(OAc)2, and 4 Å MS in 1,2-dichloroethane (Scheme 10). The scope investigation of this method was performed using various substituted N-arylbenzamidines and 3-phenyl-1,4,2-dioxazol-5-ones under the optimized reaction conditions. The results demonstrated that the steric hindrance of the N-phenyl ring had a negligible effect on the reactivity. N-arylbenzamidines with both electron-donating (Me, OMe, Et, iPr, and tBu) and electron-withdrawing (F, Cl, Br) substituents at para-, ortho-, or meta-positions of the N-phenyl ring (R1), except the nitro-substituted, gave the target products in 53%–78% yields. In addition, it was observed that disubstituted N-arylbenzamidines were good substrates for this reaction with 74%–76% yields. Further investigations indicated that N-pyridyl and N-phenyl (4-benzyl) benzimidamides provided the desired quinazolines in moderate yields. In addition, N-arylbenzamidines with the substitution at the para- and meta-position of the C-phenyl ring (R2), except ortho-Cl and ortho-Me substitutions, converted into the desired products with 62%–78% yields. In the case of 3-phenyl-1,4,2-dioxazol-5-ones, the results showed that the steric hindrance of the phenyl ring had negligible influence on the reaction yield. Various para-, meta-, ortho-, and poly-substituted 1,4,2-dioxazol-5-ones could react with N-phenylbenzamidine to provide the corresponding products in good to excellent yields. Furthermore, it was found that the substrates with adamantine, naphthalene, bisphenyl, thiophene, and benzothiophene were well tolerated and afforded the corresponding derivatives with good yields. The significant advantages of this reaction are excellent regioselectivity, wide substrate scope, and cost-effective [25].Scheme 10
Synthesis of 4-aminoquinazoline derivatives using [Cp∗RhCl2]2, AgOTf, and Zn(OAc)2.


#### 2.2.5. Sn-Catalyzed Reaction

Patil et al. reported a rapid and facile method for the preparation of 4-amino-2-aryl quinazoline analogues68 using N-(2-cyanoaryl) amidoximes 67 in the presence of SnCl2 as a acatalyst and ethanol as a solvent (Scheme 11). N-(2-cyanoaryl) amidoximes 67 as key intermediates were prepared according to the previously reported method from the reaction of the corresponding anilines 65 and N-hydroxyimidoyl chlorides 66 in good yields [26]. The scope of this procedure was investigated using a range of aromatic and heteroaromatic N-(2-cyanoaryl) amidoximes under the optimized reaction conditions. The results indicated that N-(2-cyanoaryl) amidoximes with the electron-withdrawing or electron-neutral groups like H, Cl, and Br on the phenyl ring (R1) afforded the corresponding products in higher yields compared to those with electron-donating substituents such as Me. In addition, the existence of the phenyl ring with the electron-neutral (H) or electron-donating (p-CH3 and p-OCH3) groups at R2 position increased the reaction yields compared to those with electron-withdrawing (p-F and m-CN) and other substituents like o-NH2 and o-pyridyl. The advantages of this method are rapid, facile, and moderate to high yields [27].Scheme 11
Synthesis of 4-amino-2-aryl quinazoline derivatives using SnCl2.


#### 2.2.6. Zn-Catalyzed Reaction

Pujar et al. developed a procedure for the production of a new set of 2,4-disubstituted quinazoline analogues71 from commercially available anthranilic acid 69 (Scheme 12). In this reaction, key intermediates 70 were prepared by cyclization of anthranilic acid with aryl/heteroaryl amide under solvent-free condition in good yields. In the following step, the target quinazoline derivatives were obtained from the reaction of 70 with appropriate amines in the presence of zinc chloride (ZnCl2) with moderate yields. In this approach, various arylamides including phenyl, 3-pyridyl, and pyrazyl derivatives as well as diverse arylamines containing 4-OCH3 and 4-F substituents were tested and the results revealed that the type of substituents had no remarkable influence on the reaction yield [28].Scheme 12
Synthesis of 2,4-disubstituted quinazolines in the presence of ZnCl2.


#### 2.2.7. Dawson Heteropolyacid-Catalyzed Reaction

Bamoharram et al. reported a novel multicomponent procedure for the synthesis of 4-aminoquinazoline derivatives74 from 2-aminobenzonitrile 72, various acyl chlorides 73 and ammonium acetate 38 using Dawson-type heteropolyacids (HPAs) as efficient; eco-friendly and reusable heterogeneous inorganic catalysts; H6 P2M18O62 (M = WVI and MoVI); and mixed addenda forms (M = CoII, CuII, NiII, MnIII) (Scheme 13). The scope examination of this approach was performed using various acyl chlorides. The results showed that acetyl chloride and benzoyl chlorides with the electron-neutral (H) and electron-withdrawing (4-Cl and 4-NO2) groups at the phenyl ring led to the slightly better yields compared to those with electron-donating (4-Me, 4-OMe and 2-OMe) substituents. The suggested mechanism of this process is illustrated in Figure 10 which involves the condensation of 2-aminobenzonitrile with acyl chlorides to generate compound 75 which on further condensation with NH4OAc gives compound 76. An intramolecular electron transfer provides compound 77 which undergoes an intramolecular nucleophilic addition to afford intermediate 78. Subsequent aromatization of intermediate 78 leads to the target derivatives 74. The characteristic advantages of this multicomponent method are one-pot reaction, simple work-up, and good to excellent yields [29].Scheme 13
Synthesis of 4-aminoquinazoline derivatives in the presence of Dawson-type heteropolyacids (HPAs) catalysts.Figure 10
The proposed mechanism for the synthesis of 4-aminoquinazolines using HPAs as catalysts.


#### 2.2.8. Copper/Palladium-Catalyzed Reaction

Khabnadideh et al. prepared a new set of 2,4-diaminoquinazoline analogues81 using the commercially available 2-aminobenzonitrile 72 (Scheme 14). In this reaction, 2-aminobenzonitrile 72 was iodinated with iodine monochloride (ICl) to produce the iodide 79 which on cyclization with guanidine under solvent-free conditions gave 2,4-diaminoquinazoline 80 in high yield. Finally, Sonogashira or Heck coupling of 2,4-diaminoquinazoline with phenoxy derivatives resulted in the corresponding products 81 with moderate to good yields [30].Scheme 14
Copper/palladium-catalyzed synthesis of 2,4-diaminoquinazoline derivatives.


#### 2.2.9. Iron/Copper-Catalyzed Reaction

Jia et al. developed an efficient Fe/Cu catalyzed approach for the direct preparation of a series of 2-phenylquinazolin-4-amine derivatives84 using readily available ortho-halogenated benzonitriles 82 and various aryl aldehydes 83 as well as NaN310 as nitrogen source (Scheme 15). Investigations showed that FeCl3, CuI, and L-proline are essential reagents for this catalytic reaction and by increasing the amount of FeCl3 loading from 10 mol % to 30 mol %, the efficiency improved slightly. The scope examination of this procedure was performed using various ortho-halogenated benzonitriles and aryl aldehydes. The results demonstrated that both electron-neutral and electron-withdrawing substituents such as Me, F, and Cl on the phenyl ring of 2-bromobenzonitriles were suitable and afforded the desired quinazolines in moderate to good yields. Moreover, it was found that other ortho-halogenated benzonitriles like 2-fluoro, 2-chloro, and 2-iodobenzonitrile show good reactivity as well. In the case of aryl aldehydes, a range of aromatic aldehydes containing diverse substituents were examined and it was observed that aryl aldehydes with electron-donating (4-OMe, 4-OEt, 3,4-(OMe)2, 2-Me, 4-Me), electron-withdrawing (3-NO2, 3-Cl, 4-Cl), and electron-neutral (4-H) substituents gave the expected quinazolines in moderate to good yields. In addition, it was found that sterically hindered substrates like 1-naphthaldehyde, 2-naphthaldehyde, and heteroaryl aldehydes including furan-2-carbaldehyde, thiophene-2-carbaldehyde, and thiophene-3-carbaldehyde were suitable for this reaction. The proposed mechanism of this procedure is represented in Figure 11. The iron-mediated [3 + 2] cycloaddition of benzonitriles with NaN3 produces 85 which undergoes copper-catalyzed SNAr reaction and generates 86. Then, consecutive reduction, cyclization, oxidation, and copper-catalyzed denitrogenation of intermediates lead to the target derivative 84. The characteristic advantages of this approach are readily available starting reagents, substrate generality, and high efficiency [8].Scheme 15
Synthesis of 2-phenylquinazolin-4-amine derivatives in the presence of FeCl3, CuI, and L-proline.Figure 11
The proposed mechanism for the synthesis of 2-phenylquinazolin-4-amine derivatives in the presence of FeCl3, CuI, and L-proline.


### 2.3. Microwave Irradiation Methods

Seijas et al. described a solvent-free and efficient method for the production of 4-aminoquinazoline derivatives96 through fusing 2-aminobenzonitrile 72 with nitriles 95, under microwave irradiation (MW) conditions and utilizing 10% of potassium tert-butoxide (t-BuOK) as a base (Scheme 16). The scope investigation of this method was carried out utilizing several nitrile derivatives. The results showed that various nitriles containing phenyl-, 2-aminophenyl-, 2-furanyl-, 4-pyridyl-, and benzyl-moieties generated the target quinazoline derivatives in good to excellent yields. The characteristic advantages of this approach are short reaction time, high yields, absence of organic solvent, the use of catalytic amount of base, and an improvement over the previous method using traditional heating [31].Scheme 16
Synthesis of 4-aminoquinazoline derivatives using 2-aminobenzonitrile under microwave irradiation.David et al. prepared a new set of 4-aminoquinazoline analogues99 from the reaction of N-(2-cyanophenyl)-N,N-dimethylformamidine 97 with various amines 98 under microwave irradiation conditions (Scheme 17). This reaction carried out in acetic acid and acetonitrile. The scope exploration of this reaction was carried out using various substrates including substituted N-(2-cyanophenyl)-N, N-dimethylformamidine and different amines with a variety of electronic and steric substituents including benzylamines, aliphatic amine, and anilines under optimized conditions. The results indicated that all the tested substrates afforded the corresponding derivatives in high yields except the aniline with electron-poor substituent (Br) which generated the products in moderate yields. The significant benefits of this method are being simple, efficient, short time, one step, and having high yields [32].Scheme 17
Synthesis of 4-aminoquinazoline derivatives using N-(2-cyanophenyl)-N,N-dimethylformamidine under microwave irradiation conditions.Rad-Moghadam et al. described a microwave-promoted one-pot approach for the preparation of 2-alkyl-4-aminoquinazoline analogues101 (Scheme 18). The reaction of 2-aminobenzonitrile 72 with different orthoesters 100 and NH4OAc 38 under solvent-free condition resulted in desired products in good yields. In this case, in order to reduce the side reactions, excess amount of orthoesters is required. The scope of this method was investigated using different orthoesters under optimized conditions. According to the results, diverse orthoesters bearing H, methyl-, ethyl, n-propyl-, and n-butyl-groups gave the desired derivatives in excellent yields. The possible mechanism of the described process is including the initial formation of the amidine intermediate 102 from the reaction of 2-aminobenzonitrile with orthoesters and NH4OAc. Followed by nucleophilic attack of the amino group to the carbon atom of the nitrile group which leads to the formation of 4(3H)-iminoquinazoline intermediate 104 and subsequently tautomerize and resulted in the target product (Figure 12). It should be noted that in this method the intramolecular addition of amines to the nitrile group occurs easily and in nearly neutral conditions; while under conventional condition, this reaction requires harsh conditions and strong Lewis acids [33]. The advantages of this method are being one-pot, solvent free, operational simplicity, simple starting materials, mild condition, short reaction time, and high yields [34].Scheme 18
Synthesis of 2-alkyl-4-aminoquinazoline derivatives using 2-aminobenzonitrile under solvent-free and microwave irradiation condition.Figure 12
The proposed mechanism for the synthesis of 2-alkyl-4-aminoquinazoline derivatives using 2-aminobenzonitrile under microwave irradiation condition.Haghighijoo et al. described a rapid and convenient approach for the preparation of 4-aminoquinazoline derivatives109 using 2-amino-4,6-dicholorobenzoic acid 105 (Scheme 19). In this method, reaction of 2-amino-4,6-dicholorobenzoic acid 105 with formamide under microwave conditions resulted in intermediate 106, which on etherification with different alkoxy or morpholine generated 107. Then, the oxo group of 107 was substituted by chlorine in the presence of SOCl2 and led to the intermediate 108. Finally, the reaction of intermediate 108 with various anilines resulted in the corresponding products in moderate to good yields. The results indicated that all the tested substrates including alkoxy, morpholine, and various anilines with 2-CN; 3-CN; 2-Me-5-Cl; and 2,5-diethoxy substituents were well tolerated and generated the corresponding derivatives in moderate yields. The remarkable benefits of this approach are the cheap, readily available reagents, and good yields [35].Scheme 19
Synthesis of 4-aminoquinazoline derivatives using 2-amino-4,6-dicholorobenzoic acid under microwave irradiation condition.Song et al. obtained a new set of 4-aminoquinazoline derivatives112 from 2-amino-5-nitrobenzonitrile 110 and various anilines 111 in good to excellent yields, under microwave irradiation condition (Scheme 20). In this method, no solvent was required because DMF-DMA acted as both solvent and reagent. The substrate scope of this method was investigated using a series of anilines under optimized conditions. The results indicated that anilines with the halogen groups (F, Cl, and Br) at meta- or para- positions, except the Br group at the para-position, gave the target products in excellent yields. Furthermore, anilines with–C≡CH and CF3 groups at meta-position provided the target derivatives in good yields but anilines with electron-donating groups such as OH and Me gave low yields. The suggested mechanism for this system is illustrated in Figure 13. Initially, the reaction of 2-amino-5-nitrobenzonitrile with DMF-DMA leads to the formation of corresponding formamidine cation 114. Compound 114 undergoes electrophilic attack of the aniline 111 on the carbon of the cyano group and subsequent intramolecular electrophilic addition of nitrile nitrogen to enamine carbon results in the generation of intermediate 115. Then, aromatization and elimination of the dimethylamino moiety leads to the expected product 112. The advantages of this procedure are simple, one-pot cascade, short reaction time, environmentally friendly, and low volume of the organic solvent [36].Scheme 20
Synthesis of 4-aminoquinazoline derivatives using 2-amino-5-nitrobenzonitrile under microwave irradiation.Figure 13
The proposed mechanism for the synthesis of 4-aminoquinazoline derivatives using 2-amino-5-nitrobenzonitrile under microwave irradiation.Haghighijoo et al. obtained a new set of 4-aminoquinazoline derivatives119 with different substitutions using ortho-diflouro or ortho-dimethoxy anthranilic acid 116 under microwave irradiation conditions (Scheme 21). In this reaction, ortho-substituted anthranilic acid was reacted with formamide to produce intermediate 117 which was converted to the compound 118 in the presence of thionyl chloride (SOCl2). Finally, the reaction of 118 with aniline derivatives in 2-propanol and DMF afforded the desired products in good yields. The results showed that the substitution type on the phenyl ring of anthranilic acid and also various anilines with different substituents had negligible effects on the reaction yield. This method has some advantages like good yield of products, cleaner products, and easy work up [37, 38].Scheme 21
Synthesis of 4-aminoquinazolines derivatives usingortho-diflouro or ortho-dimethoxy anthranilic acid under microwave irradiation condition.


### 2.4. Metal-Catalyzed/Microwave Irradiation Methods

Tian et al. described a rapid and efficient iron-catalyzed method for the production of 4-amino-quinazoline analogous122 from the reaction of quinazoline-3-oxides 120 and carbodiimides 121 in the presence of FeCl3.6H2O as a catalyst and DMF as a solvent, under microwave irradiation conditions (Scheme 22). The scope investigation of this process was performed using a range of different quinazoline-3-oxides and carbodiimides under the optimized reaction conditions. The results demonstrated that different substituted quinazoline-3-oxides do not have a significant effect on the reaction yields but in the case of carbodiimides, aromatic carbodiimides afforded the target products in better yields compared to the aliphatic carbodiimides. The probable mechanism of this procedure (Figure 14) involves the [3 + 2] cycloaddition reaction between quinazoline-3-oxides 120 and carbodiimides 121 to generate intermediate 123, which might be unstable in the presence of Fe3+. Then, the rearrangement and aromatization of intermediate 124 under microwave irradiation gives 125, followed by the isomerization process which affords the target product 122. The advantages of this method are efficient, short reaction time, economic, environmentally benign, and good to excellent yields [6].Scheme 22
Synthesis of 4-aminoquinazoline derivatives in the presence of FeCl3.6H2O, under microwave irradiation conditions.Figure 14
The proposed mechanism for the synthesis of 4-aminoquinazolines in the presence of FeCl3.6H2O, under microwave irradiation conditions.Liu et al. reported a microwave irradiation procedure for the preparation of a novel set of fluorinated 2-alkylthio-4-aminoquinazoline derivatives128 in the presence of basic alumina as a solid-support agent and a solid base (Scheme 23). In this method, polyfluoro-benzenedicarbonitriles 126 and isothiouronium salts 127 were adsorbed onto basic alumina using ethanol and irradiated to obtain the corresponding derivatives in good yields. The scope investigation of this approach was performed using various substituted polyfluoro-benzenedicarbonitriles and isothiouronium salts under optimized reaction conditions. The results demonstrated that in the cases of polyfluoro-benzenedicarbonitriles, there were no significant differences in the reactivity and yields of corresponding products. In addition, the results revealed that the S alkyl/alkyl ethers isothiouronium salts led to the corresponding 2-alkylthio-4-aminoquinazoline derivatives in good yields. Moreover, it was found that isothiouronium salts with short carbon chain provided higher yields compared to the isothiouronium salts with a long carbon chain. Various isothiouronium salts with S-benzyl/naphthalen-2-ylmethyl/allyl/cyanomethyl moiety afforded the target quinazolines with good yields in shorter reaction time. Tetrafluoroterephthalonitrile were also tested to extend the scope of substrates. Tetrafluoroterephthalonitrile compared to the polyfluoro-benzenedicarbonitriles derivatives gave the corresponding products in moderate yields. The suggested mechanism of this microwave irradiation method is illustrated in Figure 15. The free isothiourea 129 is obtained from the adsorption reaction of its hydrogen halide with basic alumina. Subsequently, the nucleophilic aromatic substitution at o-fluoro of 126 affords intermediate 130. Afterwards, benzonitrile is activated by the surface O−H group on basic alumina followed by the N-nucleophilic amine attacks on the nitrile group to generate 132 which undergoes tautomerization to form the expected product 128. The significant advantages of this approach are efficient, environmentally benign, inexpensive, broad isothiourea substrate scope, and easily available materials [39].Scheme 23
Synthesis of fluorinated 2-alkylthio-4-aminoquinazolines under microwave irradiation.Figure 15
The proposed mechanism for the synthesis of fluorinated 2-alkylthio-4-aminoquinazolines under microwave irradiation.


### 2.5. Solid-Phase Method

Wilson reported a solid-phase method for the preparation of 2,4-diaminoquinazoline derivatives135 from the condensation of substituted 2-aminobenzonitriles 134 with various amines in good yields (Scheme 24). The substrate scope examination of this procedure was performed using different amines and substituted 2-aminobenzonitriles. According to the results, the secondary amines gave the corresponding products in average to good yields while the primary amines such as t-BuNH2 failed to produce the desired products. Furthermore, the lower yields of NH3 and (CH3)2NH could be due to interference with the cosolvent in which these amines were dissolved. In the case of substituted 2-aminobenzonitriles, all the tested substrates with alkyl (Me), alkoxy (OMe), and halogen (Cl, F) substituents, except the nitro-substituted, afforded the desired products in good yields. Probably in the case of nitro-substituted, even the thiourea resin has been formed but the second step which involved the guanidine formation or resin cleavage was unsuccessful. The plausible mechanism for this solid-phase method is represented in Figure 16. In this method, the carboxy polystyrene 136 is used to produce acyl isothiocyanate resin 133. Afterwards, substituted 2-aminobenzonitriles are added to the resin. The resin-bound guanidine 138 is generated by treatment of intermediate 137 with various amines and EDC (1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride)) under basic conditions. Optimal cleavage conditions are achieved by using trifluoroacetic acid (TFA) and water at 80°C to afford the final product 135. The advantage of this method is good purity [40].Scheme 24
Synthesis of 2,4-diaminoquinazoline derivatives using acyl isothiocyanate resin.Figure 16
The proposed mechanism for the synthesis of 2,4-diaminoquinazolines using acyl isothiocyanate resin.


### 2.6. Cyclocondensation Reactions

Yakhontov et al. synthesized a series of substituted 4-amino-2-methylquinazolines142 using anthranilic acid or 4-chloroanthranilic acid 139 (Scheme 25). In this method, the reaction of anthranilic acid or 4-chloroanthranilic acid with acetic anhydride resulted in the 2-methylbenzoxazinones-4(H) intermediates, which were then converted into the corresponding 2-methylquinazolones 140 using boiling 25% aqueous ammonia solution. The reaction of intermediates 140 with POCl3 in the presence of dimethylaniline led to the formation of 141 which then reacted with various amines and gave the target products in high yields. The results showed that anthranilic acid and 4-chloroanthranilic acid, as well as various aliphatic, aromatic, and aliphatic-aromatic amines were well tolerated and gave the corresponding products in high yields. The advantages of this method are efficient and high yields of products [41].Scheme 25
Synthesis of a series of substituted 4-amino-2-methylquinazolines in the presence of (CH3CO)2O, NH4OH, and POCl3.Tomisek et al. reported the synthesis of a series of 4-aminoquinazoline derivatives146 using 5-chloro-anthranilic acid 69 and anilines in the presence of acetic anhydride, NH3, and P2S5 (Scheme 26). In this process, 6-chloro-2-methyl-3,1-benzoxazin-4-one 143 was synthesized through heating anthranilic acid in anhydrous acetic anhydride. Then, the reaction of 143 with NH3 yielded 144. The cyclodehydration of 144 to the quinazolinone 145 was performed through heating in the NaOH solution. Finally, compound 146 was synthesized from the reaction of 6-chloro-2-methyl-4(3H)-quinazolinone 145 with aniline in the presence of P2S5 [42].Scheme 26
Synthesis of 4-aminoquinazoline derivatives in the presence of acetic anhydride, NH3, and P2S5.Sirisoma et al. synthesized a novel series of 4-aminoquinazoline derivatives150 using 2-aminobenzoic acid methyl ester 147 (Scheme 27). In this process, 2-aminobenzoic acid methyl ester was reacted with various nitriles including acetonitrile, propiononitrile, fluoroacetonitrile, and chloroacetonitrile and led to the synthesis of intermediates 148. Then, intermediates 148 reacted with distilled POCl3 in anhydrous toluene and diisopropylethylamine to produce 149. Finally, the reaction of 149 with substituted anilines in anhydrous isopropanol (IPA) in the presence of concentrated HCl led to the expected products 150 in moderate to good yields [43].Scheme 27
Synthesis of 4-aminoquinazoline derivatives using 2-aminobenzoic acid methyl ester in the presence of POCl3 and DIPEA.Hu et al. described an approach for the synthesis of a new series of 4-aminoquinazoline analogues154, 155, and 156 by utilizing 2-cyano-4-nitro-aniline 151, N, N-dimethylformamide dimethyl acetal 152, and different substituted anilines reagents (Scheme 28). The reaction of 2-cyano-4-nitro-aniline with N, N-dimethylformamide dimethyl acetal resulted in the key intermediate formamidine 153. Cyclization of the key intermediate 153 with various substituted anilines in acetic acid led to the formation of corresponding compounds 154. Reduction of compounds 154 in the presence of Fe/EtOH/AcOH generated 155. The alkyl substituted quinazolines 156 were prepared by alkylation of 154 with allyl bromide or 1-chloro-3-methylbut-2-ene in the presence of K2CO3 [44].Scheme 28
Synthesis of a new series of 4-aminoquinazolinone derivatives using 2-cyano-4-nitro-aniline.Wang et al. reported a new and efficient procedure for the preparation of 4-aminoquinazoline derivatives161 based on the conversion of indoline-2,3-dione 158 to formamidine (Scheme 29). Initially, different substituted anilines 157 reacted with chloral hydrate (Cl3CCHO) and hydroxylamine hydrochloride (HONH3Cl) to generate anilide derivatives. Then, Beckmann rearrangement was carried out in 95% of H2SO4 to prepare the key intermediate indole-2,3-dione 158. Condensation of indole-2,3-dione with hydroxylamine hydrochloride followed by heating in a solution of DMF and POCl3 yielded the compound 160. Finally, the target quinazoline derivatives were obtained from the reaction of the compound 160 with substituted anilines. The scope investigation of this procedure was carried out using various substituted anilines as starting reactants. The results demonstrated that anilines with electron-drawing substituents afforded the anilide derivatives in higher yields compared to the anilines with electron-donating substituents. Furthermore, anilines containing two electron-donating substituents on the benzene ring, gave lower yields compared to the other anilines. The advantages of this procedure are new, inexpensive starting material, simple, efficient, environmental friendly, and safe [45].Scheme 29
Synthesis of 4-aminoquinazoline derivatives using Cl3CCHO, HONH3Cl, and POCl3.Kamal et al. obtained a new set of 4-arylaminoquinazoline-2-carboxylic acid analogues164 in good yields from the reaction of (Z)-2-amino-N′-arylbenzimidamides 162 with various anhydrides 163 in dry ethanol under reflux conditions (Scheme 30). The scope of the described procedure explored using substituted (Z)-2-amino-N′-arylbenzimidamides and various anhydrides. The results revealed that various anhydrides including diphenic anhydride, phthalic anhydride, and succinic anhydride were successfully reacted with (Z)-2-amino-N′-arylbenzimidamides and afforded the corresponding quinazoline derivatives in high yields. According to the proposed mechanism, the nucleophilic attack of the amine group of 162 to the carbonyl group of 163 results in the formation of intermediate 165 which on subsequent rearrangement forms intermediate 166. Then, an intramolecular ring closure of 166 leads to the generation of 167, which is followed by losing a molecule of water and a 1,3-proton transfer to afford 164 (Figure 17) [46].Scheme 30
Synthesis of 4-arylaminoquinazoline-2-carboxylic acid analogues.Figure 17
The proposed mechanism for the synthesis of 4-arylaminoquinazoline-2-carboxylic acid derivatives.


### 2.7. Direct Amination Methods

Shen et al. developed an efficient direct amination of quinazolin-4(3H)-ones168 in the presence of hexachlorocyclotriphosphazene (HCCP), diisopropylethylamine (DIPEA), and various amines 169 for the preparation of 4-aminoquinazoline derivatives 170 in good yields (Scheme 31). The scope investigation of this method was performed using various primary and secondary amines, as well as a range of substituted quinazolin-4(3H)-ones under optimized reaction conditions. The results indicated that primary and secondary amines with low steric hindrance smoothly reacted with quinazolin-4(3H)-ones and produced the target products in good yields, while the reaction of sterically hindered amines such as tert-butylamine, gave low yields despite increasing the reaction temperature. Furthermore, nitrogen heterocycles, like pyrrolidine, piperidine, morpholine, and imidazole were also tested and afforded the desired products in high yields. Since anilines were much weaker nucleophiles compared to the alkylamines, no products were generated at room temperature, although moderate yields were obtained under reflux conditions. Anilines with electron-neutral and electron-donating substituents gave better yields compared to the anilines with electron-withdrawing substituents such as Cl. In the case of substituted quinazolin-4(3H)-ones, it was found that all the substituted quinazolin-4(3H)-ones with H, Me, Cl, and F substituents were suitable substrates for this process and afforded the corresponding products in good yields. Furthermore, 6,7-dimethoxyquinazolin-4(3H)-one with two methoxy groups, benzo[g]quinazolin-4(3H)-one and pyrido [2, 3-d] pyrimidin-4(3H)-one substrates were well tolerated and produced the corresponding products in 65–85% yield. This method has several advantages including mild, economical, and suitable for a broad range of amines. [47].Scheme 31
Synthesis of 4-aminoquinazoline derivatives in the presence of HCCP and DIPEA.Lockman et al. reported a synthetic route to provide the 4-aminoquinazoline derivatives173 from the reaction of 2-methyl-3H-quinazolin-4-one 171 with various amines (Scheme 32). Initially, the reaction of 171 with p-toluenesulfonyl chloride (TsCl) in the presence of triethylamine and a catalytic amount of dimethylaminopyridine (DMAP) in CH2Cl2 led to the quinazoline sulfonate ester intermediate 172 in excellent yield. In the following step, the reaction of the sulfonate ester intermediate with various amines in 2-propanol and CH2Cl2 led to the desired products in high yields. The scope of this method was investigated using a range of primary aliphatic and aromatic amines as well as secondary amines with different sizes and electronic properties. The results indicated that all the tested amines except the extremely hindered derivatives such as diisopropylamine and diphenylamine, afforded the expected derivatives in excellent yields [48].Scheme 32
Synthesis of 4-aminoquinazoline derivatives in the presence of TsCl, Et3N, and DMAP as catalyst.Chen et al. described an efficient one-pot procedure for the preparation of 4-(dimethylamino)quinazoline derivatives175 in high yields, via direct amination of quinazolin-4(3H)-ones 174 in the presence of readily available N, N-dimethylformamide (DMF) as the nitrogen source (Scheme 33). 4-Toluenesulfonyl chloride (TsCl) promotes the one-pot direct amination through effective activation of the C-OH bond at room temperature. Further investigation indicated that without TsCl no reaction occurred and for this process potassium tert-butoxide and DMF was the best base and solvent, respectively. Under the optimized reaction conditions, the scope examination of this method was performed using different substituted 2-arylquinazolin-4(3H)-ones. The results indicated that 2-arylquinazolin-4(3H)-ones with electron-neutral (H); electron-donating (Me, OMe, and NMe2); or electron-withdrawing (Cl, Br, CN, and CF3) substituents on the aryl group (R1) provided the target products are in good to excellent yields. Furthermore, quinazolinones containing H, Me, and Br groups on the phenyl ring (R2) were tested, which afforded the expected derivatives in good yields. 2-(1-Naphthyl)- and 2-heteroarylquinazolin-4(3H)-ones also gave the target compounds in moderate to high yields. Further investigation showed that 2-unsubstituted quinazolin-4(3H)-one and 2-cyclohexylquinazolin-4(3H)-one substrates did not react even with longer reaction time, which could be due to the difficulty of forming corresponding intermediates without the delocalization effect of the 2-aryl group. The suggested mechanism for this method is shown in Figure 18. Initially, the isomerization of quinazolinone 174 to quinazolin-4-ol 176 occurs. Afterwards, the reaction of quinazolinone with TsCl leads to the tosylate 177. The nitrogen atom of 177 attacks the carbonyl group of DMF to form intermediates 178, 179, 180, and 181. Finally, hydrolysis of 181 affords the target product 175. The significant advantages of this procedure are efficient, facile, one-pot cascade, mild conditions, cheap, and high yield of products [2].Scheme 33
Synthesis of 4-(dimethylamino) quinazolines via direct amination in the presence of TsCl, DMF, and t-BuOK.Figure 18
The proposed mechanism for the synthesis of 4-(dimethylamino) quinazolines via direct amination of quinazolin-4(3H)-one.Rahmannejadi et al. reported a simple and efficient approach for the preparation of 4-aminoquinazoline derivatives184 using 4-chloro-2-arylquinazolines 182 and various 2-substituted 5-chloroanilines 183 in DMF at 50°C with moderate to good yields (Scheme 34). The obtained results showed that various anilines with Me, OMe, and Cl substituents at R position were good substrates for this reaction. In addition, it was observed that the aryl groups with electron-withdrawing (F Cl, Br, and NO2) and electron-neutral (H) substituents on the quinazoline ring (Ar) gave the target products in good yields. The significant advantages of this reaction are selectivity, mild reaction conditions, good yields, and straightforward product isolation [49].Scheme 34
Synthesis of 4-aminoquinazoline derivatives in DMF solvent at 50°C.


## 2.1. Nucleophilic Substitution Reaction

The first nucleophilic substitution reaction of quinazoline occurs at the more reactive C-4 position of the quinazoline ring. 4-Aminoquinazoline2, as an important core in the structure of several drugs and bioactive compounds, can be prepared from the nucleophilic substitution reaction of quinazoline 1 with sodamide (NaNH2) (Scheme 1).Scheme 1
Nucleophilic substitution reaction of quinazoline with sodamide (NaNH2).


## 2.2. Metal-Catalyzed Reactions

### 2.2.1. Copper-Catalyzed Reactions

Yang et al. developed an efficient and simple copper-catalyzed approach to provide 4-aminoquinazoline6 and 2,4-diaminoquinazoline 7 analogues from the reaction of substituted 2-bromobenzonitriles 3 with amidines 4 or guanidine 5, with good yields (Scheme 2). The couplings of substituted 2-bromobenzonitriles with various amidines or guanidine were performed in DMF utilizing CuI as a catalyst, N, Nˊ-dimethylethylenediamine (DMEDA) as a ligand, and potassium carbonate (K2CO3) as a base, under nitrogen atmosphere at 80°C. The scope investigation of this system was carried out using different substituted 2-bromobenzonitriles, amidines, and guanidine. The results showed that the substitution type on the phenyl ring of 2-bromobenzonitriles affected the reactivity of the substrate. The existence of electron-withdrawing groups like NO2 on the phenyl ring increased the reaction rates compared to those with electron-neutral or electron-rich substituents. Moreover, aliphatic and aromatic amidines resulted in higher yields compared to guanidine because of high polarity of the guanidine derivatives. The proposed mechanism for this CuI-catalyzed method involves the Ullmann-type coupling reaction of the substituted 2-bromobenzonitriles with amidines or guanidine and subsequently, intramolecular nucleophilic addition of amino group to the ortho-cyano moiety (Figure 3). Readily available reactants, facile, one-pot cascade, practical, the use of mild conditions, economical, and good yield of products are the advantages of this method [1].Scheme 2
Copper-catalyzed synthesis of 4-aminoquinazoline and 2,4-diaminoquinazoline derivatives.Figure 3
The proposed mechanism for the synthesis of 4-aminoquinazoline and 2,4-diaminoquinazoline analogues using CuI as a catalyst.Yang et al. reported a very efficient copper-catalyzed procedure for the preparation of 2-substituted-4-aminoquinazoline derivatives11 from the reaction of 2-substituted benzimidamides 8 with various aldehydes 9 and sodium azide 10, in the presence of CuBr as a catalyst, L-proline as a ligand, and DMF as a solvent (Scheme 3). Further studies showed that CuBr and L-proline components were essential for this reaction and the use of other nitrogen sources like ammonium chloride, ammonium acetate, or ammonium hydroxide instead of NaN3 led to the unfavorable results. The substrate scope investigation of this copper-catalyzed system was performed using different 2-substituted benzimidamides and aldehydes. The results indicated that 2-iodo and 2-bromobenzimidamides substrates gave the target quinazolines in moderate to excellent yields while 2-fluoro and 2-chlorobenzimidamides did not produce products, despite increasing the reaction temperature. The reactivity order for the above compounds was as follows: aryl iodides > aryl bromides > aryl chlorides (fluorides). In addition, it was found that the electronic features of the groups on the phenyl ring of 2-substituted benzimidamides (R1) had negligible influence on the reaction yield. In the case of aldehydes, the type of substituents on the aromatic ring also does not have remarkable influence on the reactivity. So, a variety of aromatic aldehydes containing electron-donating (OH, OMe, Me, t-Bu), electron-neutral (H), and electron-withdrawing (NO2, Cl, Br) substituents afforded the corresponding quinazolines in moderate to good yields. Further investigations indicated that the large steric hindrance of the substituents on the aromatic ring had also an obvious effect on the reaction yields. So, 2,6-dimethylbenzaldehyde led to the target products in low yields (50%). In addition, it was found that alkyl aldehydes, 2-naphthaldehyde, 2-hydroxy-1-naphthaldehyde, 2-thienaldehyde, 2-furanaldehyde, and 3-pyridinaldehyde were well tolerated and afforded the corresponding products in good yields. Furthermore, in the case of ortho-halogenated benzimidamides, corresponding 2,6-disubstituted 4-aminoquinazolines were obtained in moderate to good yields. These results indicated that the electronic properties of the additional substituent on the ortho-halogenated benzimidamide had a limited effect on the reactivity. The probable mechanism of this copper-catalyzed system involves the SNAr substitution reaction between 2-halobenzimidamide 8 and NaN3 to produce 2-azidobenzimidamide 12. Afterwards, the copper-mediated denitrogenation of 12 in the existence of L-proline and trace H2O in DMF generates 2-aminobenzimidamide 15 using Cu(I) and Cu(III) complexes 13-14. The condensation of 15 with aldehyde provides Schiff base 16. An intramolecular nucleophilic addition of amidine nitrogen to imine carbon in 16 affords intermediate 17 which on subsequent oxidative dehydrogenation and amine-imine tautomerization forms the expected compound 11 (Figure 4). The advantages of this method are efficient, readily available reagents, mild reaction conditions, practical, one-pot cascade, wide substrate scope, operational simplicity, and low reaction temperature [20].Scheme 3
Synthesis of 2-substituted-4-aminoquinazolines in the presence of CuBr, L-proline, and DMF.Figure 4
The proposed mechanism for the synthesis of 2-substituted-4-aminoquinazoline derivatives in the presence of CuBr, L-proline, and DMF.Xu et al. described a new and effective copper-catalyzed approach for the preparation of 2-arylquinazolin-4-amines20 using readily available 2-arylindoles 18 and TMSN319. The reaction took place in acetonitrile and in the presence of Cu(OAc)2 as a catalyst, tert-butyl peroxybenzoate (TBPB) as an oxidant, H2O as an additive, and NaOH as a base, under argon atmosphere (Scheme 4). The scope examination of this method was performed using a variety of 2-arylindoles, under the optimized conditions. The results showed that indoles with methyl and halogen substituents (R′) at the C-5 and C-6 positions afforded the target products in satisfactory yields but indoles with electron-withdrawing substituents like NO2 and CF3 at the C-5 position could not produce the desired products. Further investigation revealed that the steric hindrance and the nature of groups present at the pyrrole ring (R) affected the yield of the reaction. Generally, the phenyl ring with substituents at the para position led to the higher yields compared to the phenyl ring with ortho- and meta-substitutions. Furthermore, the phenyl ring with electron-withdrawing substituents such as F and Cl gave better yields than the phenyl ring with electron-rich substituents, like methoxy, n-propyl, and t-butyl. In addition, 2-(pyridine-3-yl)-1H-indole provided the expected products in good yields, while 2-n-butyl-1H-indole resulted in very low yields. The suggested mechanism for this method is illustrated in Figure 5. The reaction of TMSN3 with TBPB in the existence of copper results in the formation of azidyl radical, through a single-electron transfer process. Afterwards, the addition of azidyl radicals to the C(3) of 18 generates the diazidation intermediate 22 which on intramolecular coupling of the carbon-centered radical with one azido group affords the aminyl radical 23. Intermediate 24 is obtained via the sequential reduction-protonation or H-abstraction. Then, the ring expansion in the presence of NaOH and denitrogenation of 25, affords intermediate 26 which on subsequent protonation and tautomerization forms the desired product 20. The significant advantages of this method are effective and mild conditions [4].Scheme 4
Synthesis of 2-arylquinazolin-4-amines in the presence of Cu(OAc)2 and TBPB.Figure 5
The plausible mechanism for the synthesis of 2-arylquinazolin-4-amines in the presence of Cu(OAc)2 and TBPB.Chen et al. reported a Cu-catalyzed approach for the direct conversion of cyclic amides to aromatic heterocyclic amines in DMF utilizing Cu(acac)2 as a catalyst and di-t-butyl peroxide (DTBP) as an oxidant. In this method, the direct amination of quinazolinones 27 with various amines 28 resulted in the 4-aminoquinazoline derivatives 29 (Scheme 5). The scope of the described method was examined using various primary and secondary alkylamines as well as different substituted quinazolin-4(3H)-ones. The results revealed that various amines like piperidine, methyl-substituted piperidines, pyrrolidine, azepane, cyclohexanamine, and linear and branched alkylamines afforded the corresponding quinazolines in moderate to excellent yields. But aromatic amines did not react with quinazolinones due to the low activities and also the possibility of oxidation. Furthermore, it was found that substituted quinazolin-4(3H)-ones with electron-donating and electron-withdrawing substituents afforded the target derivatives in good to excellent yields. In addition, 6-bromoquinazolinone and 6-iodoquinazolinone selectively reacted with amines to provide corresponding products but not the Ullman coupling products. Although, the results showed that halogens were more suitable for this reaction. Further investigations demonstrated that thieno [2, 3-d] pyrimidin-4-ol and electron-rich 6,7-diether substituted quinazolinones afforded the target quinazolines in 56–89% yields. The suggested mechanism for this reaction is illustrated in Figure 6. The significant advantages of this procedure are efficient, mild reaction conditions, environmentally friendly, and readily available starting materials [21].Scheme 5
Synthesis of 4-aminoquinazoline derivatives in the presence of Cu(acac)2 as a catalyst and DTBP.Figure 6
The proposed mechanism for the synthesis of 4-aminoquinazoline derivatives in the presence of Cu(acac)2 as a catalyst and DTBP.Huang et al. reported a new procedure for the preparation of 2-acyl-4-aminoquinazoline derivatives39 using 2-aminobenzonitriles 36, methyl ketones 37, and ammonium acetate (NH4OAc) 38 in the presence of I2/CuCl2 (Scheme 6). In this method, a methyl group was utilized as a new input to form target derivatives. The scope investigation of this process was carried out using various methyl ketones and a range of 2-aminobenzonitriles. The results indicated that aryl methyl ketones with electron-neutral (4-H); electron-donating (4-Me, 2-Me, 3-OMe, 4-OEt, 3,4-OCH2O, and 3,4-O(CH2)2O); electron-withdrawing (3-NO2, 4-SO2Me, and 4-CO2Me); and halogen (4-F, 4-Cl and 4-Br) groups on the benzene ring gave the expected products in good yields. In addition, heterocyclic methyl ketones and several substrates containing fused rings such as 1-naphthyl, 2-naphthyl, and 2-fluorenyl were also well tolerated and generated the target products in moderate to good yields. Furthermore, it was found that 2-aminobenzonitriles containing electron-rich (-Me, -OMe, and–di-OMe) and halogen (-F, -Cl, and -Br) substituents at the 4- and 5-positions of the phenyl ring reacted with methyl ketones and provided the expected products in moderate to good yields. The possible mechanism of this process is represented in Figure 7. The advantages of this method are operational simplicity, readily available materials, mild reaction conditions, and good functional group compatibility [5].Scheme 6
Synthesis of 2-acyl-4-aminoquinazoline derivatives in the presence of I2/CuCl2.Figure 7
The possible mechanism for the synthesis of 2-acyl-4-aminoquinazolines in the presence of I2/CuCl2.


### 2.2.2. Palladium-Catalyzed Reactions

Wang et al. described a palladium catalyzed procedure for the production of a broad range of 4-amino-2-aryl(alkyl)quinazoline derivatives48 from N-arylamidines 46 and isonitriles 47, in the presence of CsCO3 and O2 as a base and oxidant, respectively (Scheme 7). The target quinazoline derivatives were obtained through palladium-catalyzed intramolecular aryl C-H amidination via incorporation of isonitrile under relatively mild condition in good yields. The substrate scope investigation of this method was performed using different N-aryl ring (R1)-substituted benzamidines under optimized reaction conditions. The results indicated that benzamidines with electron-donating substituents such as Me and OMe on the phenyl ring produced the target quinazolines in excellent yields except the benzamidine bearing a para-methoxy substituent which provided the target products in moderate yields. Benzamidines with electron-withdrawing substituents like F and Cl on the phenyl ring generated the target quinazolines in lower yields. These findings propose that an electrophilic aromatic substitution (SEAr) reaction may be involved in the activation process of the C(sp2)-H bond. Furthermore, the effect of benzamidine ring substituents (R2) was examined which demonstrated that the nature and steric hindrance of these substituents have a significant effect on the reaction yield. The aryl moieties bearing electron-donating substituents such as Me and OMe were more suitable for this reaction compared to electron-withdrawing substituents like Cl and Br. This observation showed that the electron density on amidine nitrogen plays a vital role in the complexation with the palladium. Moreover, it was found that the reaction yields are more sensitive towards ortho-substituents, which could be due to the steric interference with complexation of amidine nitrogen to the palladium. The benzamidine ring (R2) containing alkyl moieties such as t-butyl and cyclohexyl afforded the corresponding 2-alkyl-substituted 4-aminoquinazolines in moderate to good yields. Furthermore, the different substituted isonitriles (R3) were investigated. The results demonstrated that isopropyl and cyclohexyl isonitrile compared to t-butyl and aryl isonitriles are less efficient, a result which is related to the thermal stabilities of the isonitriles. The possible mechanism of the described reaction is shown in Figure 8. The coordination of isonitrile-ligated Pd (II) with amidine nitrogen in the presence of Cs2CO3 results in the generation of complex 49. Then, an intramolecular electrophilic substitution generates the cyclopalladation intermediate 50, which undergoes migratory insertion of the isonitrile. Subsequent reductive elimination of the intermediate 51 followed by tautomerization affords the target product 48 and Pd (0) species, which is reoxidized to Pd (II) using dioxygen. The advantages of this procedure are efficient, concise, environmentally benign, mild condition, good functionality tolerance, wide substrate scope, readily available starting materials, and high yield of products [22].Scheme 7
Synthesis of 4-amino-2-aryl(alkyl) quinazolines in the presence of Pd(OAc)2, CsCO3, and O2.Figure 8
The proposed mechanism for the synthesis of 4-amino-2-aryl(alkyl)quinazoline derivatives in the presence of Pd(OAc)2, CsCO3, and O2.Thanh et al. synthesized a set of 2-aryl-4-aminoquinazoline derivatives55 using 2-aryl-quinazolinones 52 via a three-step reaction in the presence of POCl3, NaN3, and H2/Pd (Scheme 8). In this process, the amide group of quinazolinones 52 were converted to the corresponding imine chloride 53 using POCl3 in moderate yields, which is subsequently converted into the intermediate 54 using NaN3 in good yields. Finally, the azide group of 54 was easily reduced to the amine group utilizing H2 and Pd/C and resulted in the target derivatives 55 in good yields. Generally, the results indicated that the electronic features and steric hindrance of the aryl ring had a negligible effect on the reaction yields [23].Scheme 8
Synthesis of 2-aryl-4-aminoquinazoline derivatives in the presence of POCl3, NaN3, and H2/Pd.


### 2.2.3. Iron-Catalyzed Reaction

Yin et al. described an efficient procedure for the production of N4-substituted 2,4-diaminoquinazoline derivatives 58, 59 utilizing the commercially available 2-nitrobenzaldehydes 56, H2NCN, various amines, and Fe/HCl (Scheme 9). Preliminary studies showed that the oxidative cyanoimidation of 2-nitrobenzaldehydes and also the condensation with amine were carried out in excellent yields. Subsequently, the reductive intramolecular cyclization of 2-nitrobenzimidamides to generate diaminoquinazolines was conducted using Fe/HCl as a reductive agent in high yields. To examine the substrate scope of this method, different substrates includingsubstituted 2-nitrobenzaldehydes and different amines were tested, under optimized conditions. From the results, it was found that the type of substituents on the aryl ring of 2-nitrobenzaldehydes had a negligible effect on the reaction rate. Different 2-nitrobenzaldehydes with electron-withdrawing (Cl, Br) or electron-donating (OMe) groups provided cyanoimidates 57 in good yields. The reaction of various cyanoimidates with simple primary amines which were substituted with aliphatic chains or rings as well as the substitution containing the aryl groups gave the target products in excellent yields. In addition, the secondary amines also produced the desired products in good yields. The probable mechanism of this system is represented in Figure 9. This mechanism involves the tandem oxidative cyanoimidation, condensation of cyanoimidate with amine, and reductive intramolecular cyclization of 2-nitrobenzimidamides 60 to generate diaminoquinazolines 58 in the Fe/HCl medium. The advantages of this procedure are efficient, one-pot procedure, facile, readily available reactants, and high yield of products [24].Scheme 9
Synthesis of N4-substituted 2,4-diaminoquinazolines using 2-nitrobenzaldehydes in the presence of H2NCN and Fe/HCl.Figure 9
The proposed mechanism for the synthesis of N4-substituted 2,4-diaminoquinazolines in the presence of H2NCN and Fe/HCl.


### 2.2.4. Rhodium (III)-Catalyzed Reaction

Ren et al. reported a novel rhodium (III)-catalyzed procedure for the preparation of 4-aminoquinazoline derivatives64 using N-arylbenzamidines 62 and 3-phenyl-1,4,2-dioxazol-5-ones 63 in the presence of AgOTf, Zn(OAc)2, and 4 Å MS in 1,2-dichloroethane (Scheme 10). The scope investigation of this method was performed using various substituted N-arylbenzamidines and 3-phenyl-1,4,2-dioxazol-5-ones under the optimized reaction conditions. The results demonstrated that the steric hindrance of the N-phenyl ring had a negligible effect on the reactivity. N-arylbenzamidines with both electron-donating (Me, OMe, Et, iPr, and tBu) and electron-withdrawing (F, Cl, Br) substituents at para-, ortho-, or meta-positions of the N-phenyl ring (R1), except the nitro-substituted, gave the target products in 53%–78% yields. In addition, it was observed that disubstituted N-arylbenzamidines were good substrates for this reaction with 74%–76% yields. Further investigations indicated that N-pyridyl and N-phenyl (4-benzyl) benzimidamides provided the desired quinazolines in moderate yields. In addition, N-arylbenzamidines with the substitution at the para- and meta-position of the C-phenyl ring (R2), except ortho-Cl and ortho-Me substitutions, converted into the desired products with 62%–78% yields. In the case of 3-phenyl-1,4,2-dioxazol-5-ones, the results showed that the steric hindrance of the phenyl ring had negligible influence on the reaction yield. Various para-, meta-, ortho-, and poly-substituted 1,4,2-dioxazol-5-ones could react with N-phenylbenzamidine to provide the corresponding products in good to excellent yields. Furthermore, it was found that the substrates with adamantine, naphthalene, bisphenyl, thiophene, and benzothiophene were well tolerated and afforded the corresponding derivatives with good yields. The significant advantages of this reaction are excellent regioselectivity, wide substrate scope, and cost-effective [25].Scheme 10
Synthesis of 4-aminoquinazoline derivatives using [Cp∗RhCl2]2, AgOTf, and Zn(OAc)2.


### 2.2.5. Sn-Catalyzed Reaction

Patil et al. reported a rapid and facile method for the preparation of 4-amino-2-aryl quinazoline analogues68 using N-(2-cyanoaryl) amidoximes 67 in the presence of SnCl2 as a acatalyst and ethanol as a solvent (Scheme 11). N-(2-cyanoaryl) amidoximes 67 as key intermediates were prepared according to the previously reported method from the reaction of the corresponding anilines 65 and N-hydroxyimidoyl chlorides 66 in good yields [26]. The scope of this procedure was investigated using a range of aromatic and heteroaromatic N-(2-cyanoaryl) amidoximes under the optimized reaction conditions. The results indicated that N-(2-cyanoaryl) amidoximes with the electron-withdrawing or electron-neutral groups like H, Cl, and Br on the phenyl ring (R1) afforded the corresponding products in higher yields compared to those with electron-donating substituents such as Me. In addition, the existence of the phenyl ring with the electron-neutral (H) or electron-donating (p-CH3 and p-OCH3) groups at R2 position increased the reaction yields compared to those with electron-withdrawing (p-F and m-CN) and other substituents like o-NH2 and o-pyridyl. The advantages of this method are rapid, facile, and moderate to high yields [27].Scheme 11
Synthesis of 4-amino-2-aryl quinazoline derivatives using SnCl2.


### 2.2.6. Zn-Catalyzed Reaction

Pujar et al. developed a procedure for the production of a new set of 2,4-disubstituted quinazoline analogues71 from commercially available anthranilic acid 69 (Scheme 12). In this reaction, key intermediates 70 were prepared by cyclization of anthranilic acid with aryl/heteroaryl amide under solvent-free condition in good yields. In the following step, the target quinazoline derivatives were obtained from the reaction of 70 with appropriate amines in the presence of zinc chloride (ZnCl2) with moderate yields. In this approach, various arylamides including phenyl, 3-pyridyl, and pyrazyl derivatives as well as diverse arylamines containing 4-OCH3 and 4-F substituents were tested and the results revealed that the type of substituents had no remarkable influence on the reaction yield [28].Scheme 12
Synthesis of 2,4-disubstituted quinazolines in the presence of ZnCl2.


### 2.2.7. Dawson Heteropolyacid-Catalyzed Reaction

Bamoharram et al. reported a novel multicomponent procedure for the synthesis of 4-aminoquinazoline derivatives74 from 2-aminobenzonitrile 72, various acyl chlorides 73 and ammonium acetate 38 using Dawson-type heteropolyacids (HPAs) as efficient; eco-friendly and reusable heterogeneous inorganic catalysts; H6 P2M18O62 (M = WVI and MoVI); and mixed addenda forms (M = CoII, CuII, NiII, MnIII) (Scheme 13). The scope examination of this approach was performed using various acyl chlorides. The results showed that acetyl chloride and benzoyl chlorides with the electron-neutral (H) and electron-withdrawing (4-Cl and 4-NO2) groups at the phenyl ring led to the slightly better yields compared to those with electron-donating (4-Me, 4-OMe and 2-OMe) substituents. The suggested mechanism of this process is illustrated in Figure 10 which involves the condensation of 2-aminobenzonitrile with acyl chlorides to generate compound 75 which on further condensation with NH4OAc gives compound 76. An intramolecular electron transfer provides compound 77 which undergoes an intramolecular nucleophilic addition to afford intermediate 78. Subsequent aromatization of intermediate 78 leads to the target derivatives 74. The characteristic advantages of this multicomponent method are one-pot reaction, simple work-up, and good to excellent yields [29].Scheme 13
Synthesis of 4-aminoquinazoline derivatives in the presence of Dawson-type heteropolyacids (HPAs) catalysts.Figure 10
The proposed mechanism for the synthesis of 4-aminoquinazolines using HPAs as catalysts.


### 2.2.8. Copper/Palladium-Catalyzed Reaction

Khabnadideh et al. prepared a new set of 2,4-diaminoquinazoline analogues81 using the commercially available 2-aminobenzonitrile 72 (Scheme 14). In this reaction, 2-aminobenzonitrile 72 was iodinated with iodine monochloride (ICl) to produce the iodide 79 which on cyclization with guanidine under solvent-free conditions gave 2,4-diaminoquinazoline 80 in high yield. Finally, Sonogashira or Heck coupling of 2,4-diaminoquinazoline with phenoxy derivatives resulted in the corresponding products 81 with moderate to good yields [30].Scheme 14
Copper/palladium-catalyzed synthesis of 2,4-diaminoquinazoline derivatives.


### 2.2.9. Iron/Copper-Catalyzed Reaction

Jia et al. developed an efficient Fe/Cu catalyzed approach for the direct preparation of a series of 2-phenylquinazolin-4-amine derivatives84 using readily available ortho-halogenated benzonitriles 82 and various aryl aldehydes 83 as well as NaN310 as nitrogen source (Scheme 15). Investigations showed that FeCl3, CuI, and L-proline are essential reagents for this catalytic reaction and by increasing the amount of FeCl3 loading from 10 mol % to 30 mol %, the efficiency improved slightly. The scope examination of this procedure was performed using various ortho-halogenated benzonitriles and aryl aldehydes. The results demonstrated that both electron-neutral and electron-withdrawing substituents such as Me, F, and Cl on the phenyl ring of 2-bromobenzonitriles were suitable and afforded the desired quinazolines in moderate to good yields. Moreover, it was found that other ortho-halogenated benzonitriles like 2-fluoro, 2-chloro, and 2-iodobenzonitrile show good reactivity as well. In the case of aryl aldehydes, a range of aromatic aldehydes containing diverse substituents were examined and it was observed that aryl aldehydes with electron-donating (4-OMe, 4-OEt, 3,4-(OMe)2, 2-Me, 4-Me), electron-withdrawing (3-NO2, 3-Cl, 4-Cl), and electron-neutral (4-H) substituents gave the expected quinazolines in moderate to good yields. In addition, it was found that sterically hindered substrates like 1-naphthaldehyde, 2-naphthaldehyde, and heteroaryl aldehydes including furan-2-carbaldehyde, thiophene-2-carbaldehyde, and thiophene-3-carbaldehyde were suitable for this reaction. The proposed mechanism of this procedure is represented in Figure 11. The iron-mediated [3 + 2] cycloaddition of benzonitriles with NaN3 produces 85 which undergoes copper-catalyzed SNAr reaction and generates 86. Then, consecutive reduction, cyclization, oxidation, and copper-catalyzed denitrogenation of intermediates lead to the target derivative 84. The characteristic advantages of this approach are readily available starting reagents, substrate generality, and high efficiency [8].Scheme 15
Synthesis of 2-phenylquinazolin-4-amine derivatives in the presence of FeCl3, CuI, and L-proline.Figure 11
The proposed mechanism for the synthesis of 2-phenylquinazolin-4-amine derivatives in the presence of FeCl3, CuI, and L-proline.


## 2.2.1. Copper-Catalyzed Reactions

Yang et al. developed an efficient and simple copper-catalyzed approach to provide 4-aminoquinazoline6 and 2,4-diaminoquinazoline 7 analogues from the reaction of substituted 2-bromobenzonitriles 3 with amidines 4 or guanidine 5, with good yields (Scheme 2). The couplings of substituted 2-bromobenzonitriles with various amidines or guanidine were performed in DMF utilizing CuI as a catalyst, N, Nˊ-dimethylethylenediamine (DMEDA) as a ligand, and potassium carbonate (K2CO3) as a base, under nitrogen atmosphere at 80°C. The scope investigation of this system was carried out using different substituted 2-bromobenzonitriles, amidines, and guanidine. The results showed that the substitution type on the phenyl ring of 2-bromobenzonitriles affected the reactivity of the substrate. The existence of electron-withdrawing groups like NO2 on the phenyl ring increased the reaction rates compared to those with electron-neutral or electron-rich substituents. Moreover, aliphatic and aromatic amidines resulted in higher yields compared to guanidine because of high polarity of the guanidine derivatives. The proposed mechanism for this CuI-catalyzed method involves the Ullmann-type coupling reaction of the substituted 2-bromobenzonitriles with amidines or guanidine and subsequently, intramolecular nucleophilic addition of amino group to the ortho-cyano moiety (Figure 3). Readily available reactants, facile, one-pot cascade, practical, the use of mild conditions, economical, and good yield of products are the advantages of this method [1].Scheme 2
Copper-catalyzed synthesis of 4-aminoquinazoline and 2,4-diaminoquinazoline derivatives.Figure 3
The proposed mechanism for the synthesis of 4-aminoquinazoline and 2,4-diaminoquinazoline analogues using CuI as a catalyst.Yang et al. reported a very efficient copper-catalyzed procedure for the preparation of 2-substituted-4-aminoquinazoline derivatives11 from the reaction of 2-substituted benzimidamides 8 with various aldehydes 9 and sodium azide 10, in the presence of CuBr as a catalyst, L-proline as a ligand, and DMF as a solvent (Scheme 3). Further studies showed that CuBr and L-proline components were essential for this reaction and the use of other nitrogen sources like ammonium chloride, ammonium acetate, or ammonium hydroxide instead of NaN3 led to the unfavorable results. The substrate scope investigation of this copper-catalyzed system was performed using different 2-substituted benzimidamides and aldehydes. The results indicated that 2-iodo and 2-bromobenzimidamides substrates gave the target quinazolines in moderate to excellent yields while 2-fluoro and 2-chlorobenzimidamides did not produce products, despite increasing the reaction temperature. The reactivity order for the above compounds was as follows: aryl iodides > aryl bromides > aryl chlorides (fluorides). In addition, it was found that the electronic features of the groups on the phenyl ring of 2-substituted benzimidamides (R1) had negligible influence on the reaction yield. In the case of aldehydes, the type of substituents on the aromatic ring also does not have remarkable influence on the reactivity. So, a variety of aromatic aldehydes containing electron-donating (OH, OMe, Me, t-Bu), electron-neutral (H), and electron-withdrawing (NO2, Cl, Br) substituents afforded the corresponding quinazolines in moderate to good yields. Further investigations indicated that the large steric hindrance of the substituents on the aromatic ring had also an obvious effect on the reaction yields. So, 2,6-dimethylbenzaldehyde led to the target products in low yields (50%). In addition, it was found that alkyl aldehydes, 2-naphthaldehyde, 2-hydroxy-1-naphthaldehyde, 2-thienaldehyde, 2-furanaldehyde, and 3-pyridinaldehyde were well tolerated and afforded the corresponding products in good yields. Furthermore, in the case of ortho-halogenated benzimidamides, corresponding 2,6-disubstituted 4-aminoquinazolines were obtained in moderate to good yields. These results indicated that the electronic properties of the additional substituent on the ortho-halogenated benzimidamide had a limited effect on the reactivity. The probable mechanism of this copper-catalyzed system involves the SNAr substitution reaction between 2-halobenzimidamide 8 and NaN3 to produce 2-azidobenzimidamide 12. Afterwards, the copper-mediated denitrogenation of 12 in the existence of L-proline and trace H2O in DMF generates 2-aminobenzimidamide 15 using Cu(I) and Cu(III) complexes 13-14. The condensation of 15 with aldehyde provides Schiff base 16. An intramolecular nucleophilic addition of amidine nitrogen to imine carbon in 16 affords intermediate 17 which on subsequent oxidative dehydrogenation and amine-imine tautomerization forms the expected compound 11 (Figure 4). The advantages of this method are efficient, readily available reagents, mild reaction conditions, practical, one-pot cascade, wide substrate scope, operational simplicity, and low reaction temperature [20].Scheme 3
Synthesis of 2-substituted-4-aminoquinazolines in the presence of CuBr, L-proline, and DMF.Figure 4
The proposed mechanism for the synthesis of 2-substituted-4-aminoquinazoline derivatives in the presence of CuBr, L-proline, and DMF.Xu et al. described a new and effective copper-catalyzed approach for the preparation of 2-arylquinazolin-4-amines20 using readily available 2-arylindoles 18 and TMSN319. The reaction took place in acetonitrile and in the presence of Cu(OAc)2 as a catalyst, tert-butyl peroxybenzoate (TBPB) as an oxidant, H2O as an additive, and NaOH as a base, under argon atmosphere (Scheme 4). The scope examination of this method was performed using a variety of 2-arylindoles, under the optimized conditions. The results showed that indoles with methyl and halogen substituents (R′) at the C-5 and C-6 positions afforded the target products in satisfactory yields but indoles with electron-withdrawing substituents like NO2 and CF3 at the C-5 position could not produce the desired products. Further investigation revealed that the steric hindrance and the nature of groups present at the pyrrole ring (R) affected the yield of the reaction. Generally, the phenyl ring with substituents at the para position led to the higher yields compared to the phenyl ring with ortho- and meta-substitutions. Furthermore, the phenyl ring with electron-withdrawing substituents such as F and Cl gave better yields than the phenyl ring with electron-rich substituents, like methoxy, n-propyl, and t-butyl. In addition, 2-(pyridine-3-yl)-1H-indole provided the expected products in good yields, while 2-n-butyl-1H-indole resulted in very low yields. The suggested mechanism for this method is illustrated in Figure 5. The reaction of TMSN3 with TBPB in the existence of copper results in the formation of azidyl radical, through a single-electron transfer process. Afterwards, the addition of azidyl radicals to the C(3) of 18 generates the diazidation intermediate 22 which on intramolecular coupling of the carbon-centered radical with one azido group affords the aminyl radical 23. Intermediate 24 is obtained via the sequential reduction-protonation or H-abstraction. Then, the ring expansion in the presence of NaOH and denitrogenation of 25, affords intermediate 26 which on subsequent protonation and tautomerization forms the desired product 20. The significant advantages of this method are effective and mild conditions [4].Scheme 4
Synthesis of 2-arylquinazolin-4-amines in the presence of Cu(OAc)2 and TBPB.Figure 5
The plausible mechanism for the synthesis of 2-arylquinazolin-4-amines in the presence of Cu(OAc)2 and TBPB.Chen et al. reported a Cu-catalyzed approach for the direct conversion of cyclic amides to aromatic heterocyclic amines in DMF utilizing Cu(acac)2 as a catalyst and di-t-butyl peroxide (DTBP) as an oxidant. In this method, the direct amination of quinazolinones 27 with various amines 28 resulted in the 4-aminoquinazoline derivatives 29 (Scheme 5). The scope of the described method was examined using various primary and secondary alkylamines as well as different substituted quinazolin-4(3H)-ones. The results revealed that various amines like piperidine, methyl-substituted piperidines, pyrrolidine, azepane, cyclohexanamine, and linear and branched alkylamines afforded the corresponding quinazolines in moderate to excellent yields. But aromatic amines did not react with quinazolinones due to the low activities and also the possibility of oxidation. Furthermore, it was found that substituted quinazolin-4(3H)-ones with electron-donating and electron-withdrawing substituents afforded the target derivatives in good to excellent yields. In addition, 6-bromoquinazolinone and 6-iodoquinazolinone selectively reacted with amines to provide corresponding products but not the Ullman coupling products. Although, the results showed that halogens were more suitable for this reaction. Further investigations demonstrated that thieno [2, 3-d] pyrimidin-4-ol and electron-rich 6,7-diether substituted quinazolinones afforded the target quinazolines in 56–89% yields. The suggested mechanism for this reaction is illustrated in Figure 6. The significant advantages of this procedure are efficient, mild reaction conditions, environmentally friendly, and readily available starting materials [21].Scheme 5
Synthesis of 4-aminoquinazoline derivatives in the presence of Cu(acac)2 as a catalyst and DTBP.Figure 6
The proposed mechanism for the synthesis of 4-aminoquinazoline derivatives in the presence of Cu(acac)2 as a catalyst and DTBP.Huang et al. reported a new procedure for the preparation of 2-acyl-4-aminoquinazoline derivatives39 using 2-aminobenzonitriles 36, methyl ketones 37, and ammonium acetate (NH4OAc) 38 in the presence of I2/CuCl2 (Scheme 6). In this method, a methyl group was utilized as a new input to form target derivatives. The scope investigation of this process was carried out using various methyl ketones and a range of 2-aminobenzonitriles. The results indicated that aryl methyl ketones with electron-neutral (4-H); electron-donating (4-Me, 2-Me, 3-OMe, 4-OEt, 3,4-OCH2O, and 3,4-O(CH2)2O); electron-withdrawing (3-NO2, 4-SO2Me, and 4-CO2Me); and halogen (4-F, 4-Cl and 4-Br) groups on the benzene ring gave the expected products in good yields. In addition, heterocyclic methyl ketones and several substrates containing fused rings such as 1-naphthyl, 2-naphthyl, and 2-fluorenyl were also well tolerated and generated the target products in moderate to good yields. Furthermore, it was found that 2-aminobenzonitriles containing electron-rich (-Me, -OMe, and–di-OMe) and halogen (-F, -Cl, and -Br) substituents at the 4- and 5-positions of the phenyl ring reacted with methyl ketones and provided the expected products in moderate to good yields. The possible mechanism of this process is represented in Figure 7. The advantages of this method are operational simplicity, readily available materials, mild reaction conditions, and good functional group compatibility [5].Scheme 6
Synthesis of 2-acyl-4-aminoquinazoline derivatives in the presence of I2/CuCl2.Figure 7
The possible mechanism for the synthesis of 2-acyl-4-aminoquinazolines in the presence of I2/CuCl2.


## 2.2.2. Palladium-Catalyzed Reactions

Wang et al. described a palladium catalyzed procedure for the production of a broad range of 4-amino-2-aryl(alkyl)quinazoline derivatives48 from N-arylamidines 46 and isonitriles 47, in the presence of CsCO3 and O2 as a base and oxidant, respectively (Scheme 7). The target quinazoline derivatives were obtained through palladium-catalyzed intramolecular aryl C-H amidination via incorporation of isonitrile under relatively mild condition in good yields. The substrate scope investigation of this method was performed using different N-aryl ring (R1)-substituted benzamidines under optimized reaction conditions. The results indicated that benzamidines with electron-donating substituents such as Me and OMe on the phenyl ring produced the target quinazolines in excellent yields except the benzamidine bearing a para-methoxy substituent which provided the target products in moderate yields. Benzamidines with electron-withdrawing substituents like F and Cl on the phenyl ring generated the target quinazolines in lower yields. These findings propose that an electrophilic aromatic substitution (SEAr) reaction may be involved in the activation process of the C(sp2)-H bond. Furthermore, the effect of benzamidine ring substituents (R2) was examined which demonstrated that the nature and steric hindrance of these substituents have a significant effect on the reaction yield. The aryl moieties bearing electron-donating substituents such as Me and OMe were more suitable for this reaction compared to electron-withdrawing substituents like Cl and Br. This observation showed that the electron density on amidine nitrogen plays a vital role in the complexation with the palladium. Moreover, it was found that the reaction yields are more sensitive towards ortho-substituents, which could be due to the steric interference with complexation of amidine nitrogen to the palladium. The benzamidine ring (R2) containing alkyl moieties such as t-butyl and cyclohexyl afforded the corresponding 2-alkyl-substituted 4-aminoquinazolines in moderate to good yields. Furthermore, the different substituted isonitriles (R3) were investigated. The results demonstrated that isopropyl and cyclohexyl isonitrile compared to t-butyl and aryl isonitriles are less efficient, a result which is related to the thermal stabilities of the isonitriles. The possible mechanism of the described reaction is shown in Figure 8. The coordination of isonitrile-ligated Pd (II) with amidine nitrogen in the presence of Cs2CO3 results in the generation of complex 49. Then, an intramolecular electrophilic substitution generates the cyclopalladation intermediate 50, which undergoes migratory insertion of the isonitrile. Subsequent reductive elimination of the intermediate 51 followed by tautomerization affords the target product 48 and Pd (0) species, which is reoxidized to Pd (II) using dioxygen. The advantages of this procedure are efficient, concise, environmentally benign, mild condition, good functionality tolerance, wide substrate scope, readily available starting materials, and high yield of products [22].Scheme 7
Synthesis of 4-amino-2-aryl(alkyl) quinazolines in the presence of Pd(OAc)2, CsCO3, and O2.Figure 8
The proposed mechanism for the synthesis of 4-amino-2-aryl(alkyl)quinazoline derivatives in the presence of Pd(OAc)2, CsCO3, and O2.Thanh et al. synthesized a set of 2-aryl-4-aminoquinazoline derivatives55 using 2-aryl-quinazolinones 52 via a three-step reaction in the presence of POCl3, NaN3, and H2/Pd (Scheme 8). In this process, the amide group of quinazolinones 52 were converted to the corresponding imine chloride 53 using POCl3 in moderate yields, which is subsequently converted into the intermediate 54 using NaN3 in good yields. Finally, the azide group of 54 was easily reduced to the amine group utilizing H2 and Pd/C and resulted in the target derivatives 55 in good yields. Generally, the results indicated that the electronic features and steric hindrance of the aryl ring had a negligible effect on the reaction yields [23].Scheme 8
Synthesis of 2-aryl-4-aminoquinazoline derivatives in the presence of POCl3, NaN3, and H2/Pd.


## 2.2.3. Iron-Catalyzed Reaction

Yin et al. described an efficient procedure for the production of N4-substituted 2,4-diaminoquinazoline derivatives 58, 59 utilizing the commercially available 2-nitrobenzaldehydes 56, H2NCN, various amines, and Fe/HCl (Scheme 9). Preliminary studies showed that the oxidative cyanoimidation of 2-nitrobenzaldehydes and also the condensation with amine were carried out in excellent yields. Subsequently, the reductive intramolecular cyclization of 2-nitrobenzimidamides to generate diaminoquinazolines was conducted using Fe/HCl as a reductive agent in high yields. To examine the substrate scope of this method, different substrates includingsubstituted 2-nitrobenzaldehydes and different amines were tested, under optimized conditions. From the results, it was found that the type of substituents on the aryl ring of 2-nitrobenzaldehydes had a negligible effect on the reaction rate. Different 2-nitrobenzaldehydes with electron-withdrawing (Cl, Br) or electron-donating (OMe) groups provided cyanoimidates 57 in good yields. The reaction of various cyanoimidates with simple primary amines which were substituted with aliphatic chains or rings as well as the substitution containing the aryl groups gave the target products in excellent yields. In addition, the secondary amines also produced the desired products in good yields. The probable mechanism of this system is represented in Figure 9. This mechanism involves the tandem oxidative cyanoimidation, condensation of cyanoimidate with amine, and reductive intramolecular cyclization of 2-nitrobenzimidamides 60 to generate diaminoquinazolines 58 in the Fe/HCl medium. The advantages of this procedure are efficient, one-pot procedure, facile, readily available reactants, and high yield of products [24].Scheme 9
Synthesis of N4-substituted 2,4-diaminoquinazolines using 2-nitrobenzaldehydes in the presence of H2NCN and Fe/HCl.Figure 9
The proposed mechanism for the synthesis of N4-substituted 2,4-diaminoquinazolines in the presence of H2NCN and Fe/HCl.


## 2.2.4. Rhodium (III)-Catalyzed Reaction

Ren et al. reported a novel rhodium (III)-catalyzed procedure for the preparation of 4-aminoquinazoline derivatives64 using N-arylbenzamidines 62 and 3-phenyl-1,4,2-dioxazol-5-ones 63 in the presence of AgOTf, Zn(OAc)2, and 4 Å MS in 1,2-dichloroethane (Scheme 10). The scope investigation of this method was performed using various substituted N-arylbenzamidines and 3-phenyl-1,4,2-dioxazol-5-ones under the optimized reaction conditions. The results demonstrated that the steric hindrance of the N-phenyl ring had a negligible effect on the reactivity. N-arylbenzamidines with both electron-donating (Me, OMe, Et, iPr, and tBu) and electron-withdrawing (F, Cl, Br) substituents at para-, ortho-, or meta-positions of the N-phenyl ring (R1), except the nitro-substituted, gave the target products in 53%–78% yields. In addition, it was observed that disubstituted N-arylbenzamidines were good substrates for this reaction with 74%–76% yields. Further investigations indicated that N-pyridyl and N-phenyl (4-benzyl) benzimidamides provided the desired quinazolines in moderate yields. In addition, N-arylbenzamidines with the substitution at the para- and meta-position of the C-phenyl ring (R2), except ortho-Cl and ortho-Me substitutions, converted into the desired products with 62%–78% yields. In the case of 3-phenyl-1,4,2-dioxazol-5-ones, the results showed that the steric hindrance of the phenyl ring had negligible influence on the reaction yield. Various para-, meta-, ortho-, and poly-substituted 1,4,2-dioxazol-5-ones could react with N-phenylbenzamidine to provide the corresponding products in good to excellent yields. Furthermore, it was found that the substrates with adamantine, naphthalene, bisphenyl, thiophene, and benzothiophene were well tolerated and afforded the corresponding derivatives with good yields. The significant advantages of this reaction are excellent regioselectivity, wide substrate scope, and cost-effective [25].Scheme 10
Synthesis of 4-aminoquinazoline derivatives using [Cp∗RhCl2]2, AgOTf, and Zn(OAc)2.


## 2.2.5. Sn-Catalyzed Reaction

Patil et al. reported a rapid and facile method for the preparation of 4-amino-2-aryl quinazoline analogues68 using N-(2-cyanoaryl) amidoximes 67 in the presence of SnCl2 as a acatalyst and ethanol as a solvent (Scheme 11). N-(2-cyanoaryl) amidoximes 67 as key intermediates were prepared according to the previously reported method from the reaction of the corresponding anilines 65 and N-hydroxyimidoyl chlorides 66 in good yields [26]. The scope of this procedure was investigated using a range of aromatic and heteroaromatic N-(2-cyanoaryl) amidoximes under the optimized reaction conditions. The results indicated that N-(2-cyanoaryl) amidoximes with the electron-withdrawing or electron-neutral groups like H, Cl, and Br on the phenyl ring (R1) afforded the corresponding products in higher yields compared to those with electron-donating substituents such as Me. In addition, the existence of the phenyl ring with the electron-neutral (H) or electron-donating (p-CH3 and p-OCH3) groups at R2 position increased the reaction yields compared to those with electron-withdrawing (p-F and m-CN) and other substituents like o-NH2 and o-pyridyl. The advantages of this method are rapid, facile, and moderate to high yields [27].Scheme 11
Synthesis of 4-amino-2-aryl quinazoline derivatives using SnCl2.


## 2.2.6. Zn-Catalyzed Reaction

Pujar et al. developed a procedure for the production of a new set of 2,4-disubstituted quinazoline analogues71 from commercially available anthranilic acid 69 (Scheme 12). In this reaction, key intermediates 70 were prepared by cyclization of anthranilic acid with aryl/heteroaryl amide under solvent-free condition in good yields. In the following step, the target quinazoline derivatives were obtained from the reaction of 70 with appropriate amines in the presence of zinc chloride (ZnCl2) with moderate yields. In this approach, various arylamides including phenyl, 3-pyridyl, and pyrazyl derivatives as well as diverse arylamines containing 4-OCH3 and 4-F substituents were tested and the results revealed that the type of substituents had no remarkable influence on the reaction yield [28].Scheme 12
Synthesis of 2,4-disubstituted quinazolines in the presence of ZnCl2.


## 2.2.7. Dawson Heteropolyacid-Catalyzed Reaction

Bamoharram et al. reported a novel multicomponent procedure for the synthesis of 4-aminoquinazoline derivatives74 from 2-aminobenzonitrile 72, various acyl chlorides 73 and ammonium acetate 38 using Dawson-type heteropolyacids (HPAs) as efficient; eco-friendly and reusable heterogeneous inorganic catalysts; H6 P2M18O62 (M = WVI and MoVI); and mixed addenda forms (M = CoII, CuII, NiII, MnIII) (Scheme 13). The scope examination of this approach was performed using various acyl chlorides. The results showed that acetyl chloride and benzoyl chlorides with the electron-neutral (H) and electron-withdrawing (4-Cl and 4-NO2) groups at the phenyl ring led to the slightly better yields compared to those with electron-donating (4-Me, 4-OMe and 2-OMe) substituents. The suggested mechanism of this process is illustrated in Figure 10 which involves the condensation of 2-aminobenzonitrile with acyl chlorides to generate compound 75 which on further condensation with NH4OAc gives compound 76. An intramolecular electron transfer provides compound 77 which undergoes an intramolecular nucleophilic addition to afford intermediate 78. Subsequent aromatization of intermediate 78 leads to the target derivatives 74. The characteristic advantages of this multicomponent method are one-pot reaction, simple work-up, and good to excellent yields [29].Scheme 13
Synthesis of 4-aminoquinazoline derivatives in the presence of Dawson-type heteropolyacids (HPAs) catalysts.Figure 10
The proposed mechanism for the synthesis of 4-aminoquinazolines using HPAs as catalysts.


## 2.2.8. Copper/Palladium-Catalyzed Reaction

Khabnadideh et al. prepared a new set of 2,4-diaminoquinazoline analogues81 using the commercially available 2-aminobenzonitrile 72 (Scheme 14). In this reaction, 2-aminobenzonitrile 72 was iodinated with iodine monochloride (ICl) to produce the iodide 79 which on cyclization with guanidine under solvent-free conditions gave 2,4-diaminoquinazoline 80 in high yield. Finally, Sonogashira or Heck coupling of 2,4-diaminoquinazoline with phenoxy derivatives resulted in the corresponding products 81 with moderate to good yields [30].Scheme 14
Copper/palladium-catalyzed synthesis of 2,4-diaminoquinazoline derivatives.


## 2.2.9. Iron/Copper-Catalyzed Reaction

Jia et al. developed an efficient Fe/Cu catalyzed approach for the direct preparation of a series of 2-phenylquinazolin-4-amine derivatives84 using readily available ortho-halogenated benzonitriles 82 and various aryl aldehydes 83 as well as NaN310 as nitrogen source (Scheme 15). Investigations showed that FeCl3, CuI, and L-proline are essential reagents for this catalytic reaction and by increasing the amount of FeCl3 loading from 10 mol % to 30 mol %, the efficiency improved slightly. The scope examination of this procedure was performed using various ortho-halogenated benzonitriles and aryl aldehydes. The results demonstrated that both electron-neutral and electron-withdrawing substituents such as Me, F, and Cl on the phenyl ring of 2-bromobenzonitriles were suitable and afforded the desired quinazolines in moderate to good yields. Moreover, it was found that other ortho-halogenated benzonitriles like 2-fluoro, 2-chloro, and 2-iodobenzonitrile show good reactivity as well. In the case of aryl aldehydes, a range of aromatic aldehydes containing diverse substituents were examined and it was observed that aryl aldehydes with electron-donating (4-OMe, 4-OEt, 3,4-(OMe)2, 2-Me, 4-Me), electron-withdrawing (3-NO2, 3-Cl, 4-Cl), and electron-neutral (4-H) substituents gave the expected quinazolines in moderate to good yields. In addition, it was found that sterically hindered substrates like 1-naphthaldehyde, 2-naphthaldehyde, and heteroaryl aldehydes including furan-2-carbaldehyde, thiophene-2-carbaldehyde, and thiophene-3-carbaldehyde were suitable for this reaction. The proposed mechanism of this procedure is represented in Figure 11. The iron-mediated [3 + 2] cycloaddition of benzonitriles with NaN3 produces 85 which undergoes copper-catalyzed SNAr reaction and generates 86. Then, consecutive reduction, cyclization, oxidation, and copper-catalyzed denitrogenation of intermediates lead to the target derivative 84. The characteristic advantages of this approach are readily available starting reagents, substrate generality, and high efficiency [8].Scheme 15
Synthesis of 2-phenylquinazolin-4-amine derivatives in the presence of FeCl3, CuI, and L-proline.Figure 11
The proposed mechanism for the synthesis of 2-phenylquinazolin-4-amine derivatives in the presence of FeCl3, CuI, and L-proline.


## 2.3. Microwave Irradiation Methods

Seijas et al. described a solvent-free and efficient method for the production of 4-aminoquinazoline derivatives96 through fusing 2-aminobenzonitrile 72 with nitriles 95, under microwave irradiation (MW) conditions and utilizing 10% of potassium tert-butoxide (t-BuOK) as a base (Scheme 16). The scope investigation of this method was carried out utilizing several nitrile derivatives. The results showed that various nitriles containing phenyl-, 2-aminophenyl-, 2-furanyl-, 4-pyridyl-, and benzyl-moieties generated the target quinazoline derivatives in good to excellent yields. The characteristic advantages of this approach are short reaction time, high yields, absence of organic solvent, the use of catalytic amount of base, and an improvement over the previous method using traditional heating [31].Scheme 16
Synthesis of 4-aminoquinazoline derivatives using 2-aminobenzonitrile under microwave irradiation.David et al. prepared a new set of 4-aminoquinazoline analogues99 from the reaction of N-(2-cyanophenyl)-N,N-dimethylformamidine 97 with various amines 98 under microwave irradiation conditions (Scheme 17). This reaction carried out in acetic acid and acetonitrile. The scope exploration of this reaction was carried out using various substrates including substituted N-(2-cyanophenyl)-N, N-dimethylformamidine and different amines with a variety of electronic and steric substituents including benzylamines, aliphatic amine, and anilines under optimized conditions. The results indicated that all the tested substrates afforded the corresponding derivatives in high yields except the aniline with electron-poor substituent (Br) which generated the products in moderate yields. The significant benefits of this method are being simple, efficient, short time, one step, and having high yields [32].Scheme 17
Synthesis of 4-aminoquinazoline derivatives using N-(2-cyanophenyl)-N,N-dimethylformamidine under microwave irradiation conditions.Rad-Moghadam et al. described a microwave-promoted one-pot approach for the preparation of 2-alkyl-4-aminoquinazoline analogues101 (Scheme 18). The reaction of 2-aminobenzonitrile 72 with different orthoesters 100 and NH4OAc 38 under solvent-free condition resulted in desired products in good yields. In this case, in order to reduce the side reactions, excess amount of orthoesters is required. The scope of this method was investigated using different orthoesters under optimized conditions. According to the results, diverse orthoesters bearing H, methyl-, ethyl, n-propyl-, and n-butyl-groups gave the desired derivatives in excellent yields. The possible mechanism of the described process is including the initial formation of the amidine intermediate 102 from the reaction of 2-aminobenzonitrile with orthoesters and NH4OAc. Followed by nucleophilic attack of the amino group to the carbon atom of the nitrile group which leads to the formation of 4(3H)-iminoquinazoline intermediate 104 and subsequently tautomerize and resulted in the target product (Figure 12). It should be noted that in this method the intramolecular addition of amines to the nitrile group occurs easily and in nearly neutral conditions; while under conventional condition, this reaction requires harsh conditions and strong Lewis acids [33]. The advantages of this method are being one-pot, solvent free, operational simplicity, simple starting materials, mild condition, short reaction time, and high yields [34].Scheme 18
Synthesis of 2-alkyl-4-aminoquinazoline derivatives using 2-aminobenzonitrile under solvent-free and microwave irradiation condition.Figure 12
The proposed mechanism for the synthesis of 2-alkyl-4-aminoquinazoline derivatives using 2-aminobenzonitrile under microwave irradiation condition.Haghighijoo et al. described a rapid and convenient approach for the preparation of 4-aminoquinazoline derivatives109 using 2-amino-4,6-dicholorobenzoic acid 105 (Scheme 19). In this method, reaction of 2-amino-4,6-dicholorobenzoic acid 105 with formamide under microwave conditions resulted in intermediate 106, which on etherification with different alkoxy or morpholine generated 107. Then, the oxo group of 107 was substituted by chlorine in the presence of SOCl2 and led to the intermediate 108. Finally, the reaction of intermediate 108 with various anilines resulted in the corresponding products in moderate to good yields. The results indicated that all the tested substrates including alkoxy, morpholine, and various anilines with 2-CN; 3-CN; 2-Me-5-Cl; and 2,5-diethoxy substituents were well tolerated and generated the corresponding derivatives in moderate yields. The remarkable benefits of this approach are the cheap, readily available reagents, and good yields [35].Scheme 19
Synthesis of 4-aminoquinazoline derivatives using 2-amino-4,6-dicholorobenzoic acid under microwave irradiation condition.Song et al. obtained a new set of 4-aminoquinazoline derivatives112 from 2-amino-5-nitrobenzonitrile 110 and various anilines 111 in good to excellent yields, under microwave irradiation condition (Scheme 20). In this method, no solvent was required because DMF-DMA acted as both solvent and reagent. The substrate scope of this method was investigated using a series of anilines under optimized conditions. The results indicated that anilines with the halogen groups (F, Cl, and Br) at meta- or para- positions, except the Br group at the para-position, gave the target products in excellent yields. Furthermore, anilines with–C≡CH and CF3 groups at meta-position provided the target derivatives in good yields but anilines with electron-donating groups such as OH and Me gave low yields. The suggested mechanism for this system is illustrated in Figure 13. Initially, the reaction of 2-amino-5-nitrobenzonitrile with DMF-DMA leads to the formation of corresponding formamidine cation 114. Compound 114 undergoes electrophilic attack of the aniline 111 on the carbon of the cyano group and subsequent intramolecular electrophilic addition of nitrile nitrogen to enamine carbon results in the generation of intermediate 115. Then, aromatization and elimination of the dimethylamino moiety leads to the expected product 112. The advantages of this procedure are simple, one-pot cascade, short reaction time, environmentally friendly, and low volume of the organic solvent [36].Scheme 20
Synthesis of 4-aminoquinazoline derivatives using 2-amino-5-nitrobenzonitrile under microwave irradiation.Figure 13
The proposed mechanism for the synthesis of 4-aminoquinazoline derivatives using 2-amino-5-nitrobenzonitrile under microwave irradiation.Haghighijoo et al. obtained a new set of 4-aminoquinazoline derivatives119 with different substitutions using ortho-diflouro or ortho-dimethoxy anthranilic acid 116 under microwave irradiation conditions (Scheme 21). In this reaction, ortho-substituted anthranilic acid was reacted with formamide to produce intermediate 117 which was converted to the compound 118 in the presence of thionyl chloride (SOCl2). Finally, the reaction of 118 with aniline derivatives in 2-propanol and DMF afforded the desired products in good yields. The results showed that the substitution type on the phenyl ring of anthranilic acid and also various anilines with different substituents had negligible effects on the reaction yield. This method has some advantages like good yield of products, cleaner products, and easy work up [37, 38].Scheme 21
Synthesis of 4-aminoquinazolines derivatives usingortho-diflouro or ortho-dimethoxy anthranilic acid under microwave irradiation condition.


## 2.4. Metal-Catalyzed/Microwave Irradiation Methods

Tian et al. described a rapid and efficient iron-catalyzed method for the production of 4-amino-quinazoline analogous122 from the reaction of quinazoline-3-oxides 120 and carbodiimides 121 in the presence of FeCl3.6H2O as a catalyst and DMF as a solvent, under microwave irradiation conditions (Scheme 22). The scope investigation of this process was performed using a range of different quinazoline-3-oxides and carbodiimides under the optimized reaction conditions. The results demonstrated that different substituted quinazoline-3-oxides do not have a significant effect on the reaction yields but in the case of carbodiimides, aromatic carbodiimides afforded the target products in better yields compared to the aliphatic carbodiimides. The probable mechanism of this procedure (Figure 14) involves the [3 + 2] cycloaddition reaction between quinazoline-3-oxides 120 and carbodiimides 121 to generate intermediate 123, which might be unstable in the presence of Fe3+. Then, the rearrangement and aromatization of intermediate 124 under microwave irradiation gives 125, followed by the isomerization process which affords the target product 122. The advantages of this method are efficient, short reaction time, economic, environmentally benign, and good to excellent yields [6].Scheme 22
Synthesis of 4-aminoquinazoline derivatives in the presence of FeCl3.6H2O, under microwave irradiation conditions.Figure 14
The proposed mechanism for the synthesis of 4-aminoquinazolines in the presence of FeCl3.6H2O, under microwave irradiation conditions.Liu et al. reported a microwave irradiation procedure for the preparation of a novel set of fluorinated 2-alkylthio-4-aminoquinazoline derivatives128 in the presence of basic alumina as a solid-support agent and a solid base (Scheme 23). In this method, polyfluoro-benzenedicarbonitriles 126 and isothiouronium salts 127 were adsorbed onto basic alumina using ethanol and irradiated to obtain the corresponding derivatives in good yields. The scope investigation of this approach was performed using various substituted polyfluoro-benzenedicarbonitriles and isothiouronium salts under optimized reaction conditions. The results demonstrated that in the cases of polyfluoro-benzenedicarbonitriles, there were no significant differences in the reactivity and yields of corresponding products. In addition, the results revealed that the S alkyl/alkyl ethers isothiouronium salts led to the corresponding 2-alkylthio-4-aminoquinazoline derivatives in good yields. Moreover, it was found that isothiouronium salts with short carbon chain provided higher yields compared to the isothiouronium salts with a long carbon chain. Various isothiouronium salts with S-benzyl/naphthalen-2-ylmethyl/allyl/cyanomethyl moiety afforded the target quinazolines with good yields in shorter reaction time. Tetrafluoroterephthalonitrile were also tested to extend the scope of substrates. Tetrafluoroterephthalonitrile compared to the polyfluoro-benzenedicarbonitriles derivatives gave the corresponding products in moderate yields. The suggested mechanism of this microwave irradiation method is illustrated in Figure 15. The free isothiourea 129 is obtained from the adsorption reaction of its hydrogen halide with basic alumina. Subsequently, the nucleophilic aromatic substitution at o-fluoro of 126 affords intermediate 130. Afterwards, benzonitrile is activated by the surface O−H group on basic alumina followed by the N-nucleophilic amine attacks on the nitrile group to generate 132 which undergoes tautomerization to form the expected product 128. The significant advantages of this approach are efficient, environmentally benign, inexpensive, broad isothiourea substrate scope, and easily available materials [39].Scheme 23
Synthesis of fluorinated 2-alkylthio-4-aminoquinazolines under microwave irradiation.Figure 15
The proposed mechanism for the synthesis of fluorinated 2-alkylthio-4-aminoquinazolines under microwave irradiation.


## 2.5. Solid-Phase Method

Wilson reported a solid-phase method for the preparation of 2,4-diaminoquinazoline derivatives135 from the condensation of substituted 2-aminobenzonitriles 134 with various amines in good yields (Scheme 24). The substrate scope examination of this procedure was performed using different amines and substituted 2-aminobenzonitriles. According to the results, the secondary amines gave the corresponding products in average to good yields while the primary amines such as t-BuNH2 failed to produce the desired products. Furthermore, the lower yields of NH3 and (CH3)2NH could be due to interference with the cosolvent in which these amines were dissolved. In the case of substituted 2-aminobenzonitriles, all the tested substrates with alkyl (Me), alkoxy (OMe), and halogen (Cl, F) substituents, except the nitro-substituted, afforded the desired products in good yields. Probably in the case of nitro-substituted, even the thiourea resin has been formed but the second step which involved the guanidine formation or resin cleavage was unsuccessful. The plausible mechanism for this solid-phase method is represented in Figure 16. In this method, the carboxy polystyrene 136 is used to produce acyl isothiocyanate resin 133. Afterwards, substituted 2-aminobenzonitriles are added to the resin. The resin-bound guanidine 138 is generated by treatment of intermediate 137 with various amines and EDC (1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride)) under basic conditions. Optimal cleavage conditions are achieved by using trifluoroacetic acid (TFA) and water at 80°C to afford the final product 135. The advantage of this method is good purity [40].Scheme 24
Synthesis of 2,4-diaminoquinazoline derivatives using acyl isothiocyanate resin.Figure 16
The proposed mechanism for the synthesis of 2,4-diaminoquinazolines using acyl isothiocyanate resin.


## 2.6. Cyclocondensation Reactions

Yakhontov et al. synthesized a series of substituted 4-amino-2-methylquinazolines142 using anthranilic acid or 4-chloroanthranilic acid 139 (Scheme 25). In this method, the reaction of anthranilic acid or 4-chloroanthranilic acid with acetic anhydride resulted in the 2-methylbenzoxazinones-4(H) intermediates, which were then converted into the corresponding 2-methylquinazolones 140 using boiling 25% aqueous ammonia solution. The reaction of intermediates 140 with POCl3 in the presence of dimethylaniline led to the formation of 141 which then reacted with various amines and gave the target products in high yields. The results showed that anthranilic acid and 4-chloroanthranilic acid, as well as various aliphatic, aromatic, and aliphatic-aromatic amines were well tolerated and gave the corresponding products in high yields. The advantages of this method are efficient and high yields of products [41].Scheme 25
Synthesis of a series of substituted 4-amino-2-methylquinazolines in the presence of (CH3CO)2O, NH4OH, and POCl3.Tomisek et al. reported the synthesis of a series of 4-aminoquinazoline derivatives146 using 5-chloro-anthranilic acid 69 and anilines in the presence of acetic anhydride, NH3, and P2S5 (Scheme 26). In this process, 6-chloro-2-methyl-3,1-benzoxazin-4-one 143 was synthesized through heating anthranilic acid in anhydrous acetic anhydride. Then, the reaction of 143 with NH3 yielded 144. The cyclodehydration of 144 to the quinazolinone 145 was performed through heating in the NaOH solution. Finally, compound 146 was synthesized from the reaction of 6-chloro-2-methyl-4(3H)-quinazolinone 145 with aniline in the presence of P2S5 [42].Scheme 26
Synthesis of 4-aminoquinazoline derivatives in the presence of acetic anhydride, NH3, and P2S5.Sirisoma et al. synthesized a novel series of 4-aminoquinazoline derivatives150 using 2-aminobenzoic acid methyl ester 147 (Scheme 27). In this process, 2-aminobenzoic acid methyl ester was reacted with various nitriles including acetonitrile, propiononitrile, fluoroacetonitrile, and chloroacetonitrile and led to the synthesis of intermediates 148. Then, intermediates 148 reacted with distilled POCl3 in anhydrous toluene and diisopropylethylamine to produce 149. Finally, the reaction of 149 with substituted anilines in anhydrous isopropanol (IPA) in the presence of concentrated HCl led to the expected products 150 in moderate to good yields [43].Scheme 27
Synthesis of 4-aminoquinazoline derivatives using 2-aminobenzoic acid methyl ester in the presence of POCl3 and DIPEA.Hu et al. described an approach for the synthesis of a new series of 4-aminoquinazoline analogues154, 155, and 156 by utilizing 2-cyano-4-nitro-aniline 151, N, N-dimethylformamide dimethyl acetal 152, and different substituted anilines reagents (Scheme 28). The reaction of 2-cyano-4-nitro-aniline with N, N-dimethylformamide dimethyl acetal resulted in the key intermediate formamidine 153. Cyclization of the key intermediate 153 with various substituted anilines in acetic acid led to the formation of corresponding compounds 154. Reduction of compounds 154 in the presence of Fe/EtOH/AcOH generated 155. The alkyl substituted quinazolines 156 were prepared by alkylation of 154 with allyl bromide or 1-chloro-3-methylbut-2-ene in the presence of K2CO3 [44].Scheme 28
Synthesis of a new series of 4-aminoquinazolinone derivatives using 2-cyano-4-nitro-aniline.Wang et al. reported a new and efficient procedure for the preparation of 4-aminoquinazoline derivatives161 based on the conversion of indoline-2,3-dione 158 to formamidine (Scheme 29). Initially, different substituted anilines 157 reacted with chloral hydrate (Cl3CCHO) and hydroxylamine hydrochloride (HONH3Cl) to generate anilide derivatives. Then, Beckmann rearrangement was carried out in 95% of H2SO4 to prepare the key intermediate indole-2,3-dione 158. Condensation of indole-2,3-dione with hydroxylamine hydrochloride followed by heating in a solution of DMF and POCl3 yielded the compound 160. Finally, the target quinazoline derivatives were obtained from the reaction of the compound 160 with substituted anilines. The scope investigation of this procedure was carried out using various substituted anilines as starting reactants. The results demonstrated that anilines with electron-drawing substituents afforded the anilide derivatives in higher yields compared to the anilines with electron-donating substituents. Furthermore, anilines containing two electron-donating substituents on the benzene ring, gave lower yields compared to the other anilines. The advantages of this procedure are new, inexpensive starting material, simple, efficient, environmental friendly, and safe [45].Scheme 29
Synthesis of 4-aminoquinazoline derivatives using Cl3CCHO, HONH3Cl, and POCl3.Kamal et al. obtained a new set of 4-arylaminoquinazoline-2-carboxylic acid analogues164 in good yields from the reaction of (Z)-2-amino-N′-arylbenzimidamides 162 with various anhydrides 163 in dry ethanol under reflux conditions (Scheme 30). The scope of the described procedure explored using substituted (Z)-2-amino-N′-arylbenzimidamides and various anhydrides. The results revealed that various anhydrides including diphenic anhydride, phthalic anhydride, and succinic anhydride were successfully reacted with (Z)-2-amino-N′-arylbenzimidamides and afforded the corresponding quinazoline derivatives in high yields. According to the proposed mechanism, the nucleophilic attack of the amine group of 162 to the carbonyl group of 163 results in the formation of intermediate 165 which on subsequent rearrangement forms intermediate 166. Then, an intramolecular ring closure of 166 leads to the generation of 167, which is followed by losing a molecule of water and a 1,3-proton transfer to afford 164 (Figure 17) [46].Scheme 30
Synthesis of 4-arylaminoquinazoline-2-carboxylic acid analogues.Figure 17
The proposed mechanism for the synthesis of 4-arylaminoquinazoline-2-carboxylic acid derivatives.


## 2.7. Direct Amination Methods

Shen et al. developed an efficient direct amination of quinazolin-4(3H)-ones168 in the presence of hexachlorocyclotriphosphazene (HCCP), diisopropylethylamine (DIPEA), and various amines 169 for the preparation of 4-aminoquinazoline derivatives 170 in good yields (Scheme 31). The scope investigation of this method was performed using various primary and secondary amines, as well as a range of substituted quinazolin-4(3H)-ones under optimized reaction conditions. The results indicated that primary and secondary amines with low steric hindrance smoothly reacted with quinazolin-4(3H)-ones and produced the target products in good yields, while the reaction of sterically hindered amines such as tert-butylamine, gave low yields despite increasing the reaction temperature. Furthermore, nitrogen heterocycles, like pyrrolidine, piperidine, morpholine, and imidazole were also tested and afforded the desired products in high yields. Since anilines were much weaker nucleophiles compared to the alkylamines, no products were generated at room temperature, although moderate yields were obtained under reflux conditions. Anilines with electron-neutral and electron-donating substituents gave better yields compared to the anilines with electron-withdrawing substituents such as Cl. In the case of substituted quinazolin-4(3H)-ones, it was found that all the substituted quinazolin-4(3H)-ones with H, Me, Cl, and F substituents were suitable substrates for this process and afforded the corresponding products in good yields. Furthermore, 6,7-dimethoxyquinazolin-4(3H)-one with two methoxy groups, benzo[g]quinazolin-4(3H)-one and pyrido [2, 3-d] pyrimidin-4(3H)-one substrates were well tolerated and produced the corresponding products in 65–85% yield. This method has several advantages including mild, economical, and suitable for a broad range of amines. [47].Scheme 31
Synthesis of 4-aminoquinazoline derivatives in the presence of HCCP and DIPEA.Lockman et al. reported a synthetic route to provide the 4-aminoquinazoline derivatives173 from the reaction of 2-methyl-3H-quinazolin-4-one 171 with various amines (Scheme 32). Initially, the reaction of 171 with p-toluenesulfonyl chloride (TsCl) in the presence of triethylamine and a catalytic amount of dimethylaminopyridine (DMAP) in CH2Cl2 led to the quinazoline sulfonate ester intermediate 172 in excellent yield. In the following step, the reaction of the sulfonate ester intermediate with various amines in 2-propanol and CH2Cl2 led to the desired products in high yields. The scope of this method was investigated using a range of primary aliphatic and aromatic amines as well as secondary amines with different sizes and electronic properties. The results indicated that all the tested amines except the extremely hindered derivatives such as diisopropylamine and diphenylamine, afforded the expected derivatives in excellent yields [48].Scheme 32
Synthesis of 4-aminoquinazoline derivatives in the presence of TsCl, Et3N, and DMAP as catalyst.Chen et al. described an efficient one-pot procedure for the preparation of 4-(dimethylamino)quinazoline derivatives175 in high yields, via direct amination of quinazolin-4(3H)-ones 174 in the presence of readily available N, N-dimethylformamide (DMF) as the nitrogen source (Scheme 33). 4-Toluenesulfonyl chloride (TsCl) promotes the one-pot direct amination through effective activation of the C-OH bond at room temperature. Further investigation indicated that without TsCl no reaction occurred and for this process potassium tert-butoxide and DMF was the best base and solvent, respectively. Under the optimized reaction conditions, the scope examination of this method was performed using different substituted 2-arylquinazolin-4(3H)-ones. The results indicated that 2-arylquinazolin-4(3H)-ones with electron-neutral (H); electron-donating (Me, OMe, and NMe2); or electron-withdrawing (Cl, Br, CN, and CF3) substituents on the aryl group (R1) provided the target products are in good to excellent yields. Furthermore, quinazolinones containing H, Me, and Br groups on the phenyl ring (R2) were tested, which afforded the expected derivatives in good yields. 2-(1-Naphthyl)- and 2-heteroarylquinazolin-4(3H)-ones also gave the target compounds in moderate to high yields. Further investigation showed that 2-unsubstituted quinazolin-4(3H)-one and 2-cyclohexylquinazolin-4(3H)-one substrates did not react even with longer reaction time, which could be due to the difficulty of forming corresponding intermediates without the delocalization effect of the 2-aryl group. The suggested mechanism for this method is shown in Figure 18. Initially, the isomerization of quinazolinone 174 to quinazolin-4-ol 176 occurs. Afterwards, the reaction of quinazolinone with TsCl leads to the tosylate 177. The nitrogen atom of 177 attacks the carbonyl group of DMF to form intermediates 178, 179, 180, and 181. Finally, hydrolysis of 181 affords the target product 175. The significant advantages of this procedure are efficient, facile, one-pot cascade, mild conditions, cheap, and high yield of products [2].Scheme 33
Synthesis of 4-(dimethylamino) quinazolines via direct amination in the presence of TsCl, DMF, and t-BuOK.Figure 18
The proposed mechanism for the synthesis of 4-(dimethylamino) quinazolines via direct amination of quinazolin-4(3H)-one.Rahmannejadi et al. reported a simple and efficient approach for the preparation of 4-aminoquinazoline derivatives184 using 4-chloro-2-arylquinazolines 182 and various 2-substituted 5-chloroanilines 183 in DMF at 50°C with moderate to good yields (Scheme 34). The obtained results showed that various anilines with Me, OMe, and Cl substituents at R position were good substrates for this reaction. In addition, it was observed that the aryl groups with electron-withdrawing (F Cl, Br, and NO2) and electron-neutral (H) substituents on the quinazoline ring (Ar) gave the target products in good yields. The significant advantages of this reaction are selectivity, mild reaction conditions, good yields, and straightforward product isolation [49].Scheme 34
Synthesis of 4-aminoquinazoline derivatives in DMF solvent at 50°C.


## 3. Conclusion

Quinazoline is a heterocycle structure of great importance in the field of medicinal chemistry that is present in the structure of various FDA-approved drugs like prazosin, alfuzosin, trimetrexate, erlotinib, gefitinib, and vandetanib, as well as clinical candidates and biologically active molecules. Among the various substituted quinazolines, 4-aminoquinazoline scaffolds have great importance due to their diverse spectrum of therapeutic potential. In this review, we have presented a wide range of new, efficient, extremely mild condition, and operational simplicity synthetic strategies to provide various 4-aminoquinazoline derivatives using readily available and inexpensive starting reagents. According to the reports, several strategies have been used successfully to prepare this scaffold, including the nucleophilic substitution reaction, metal-catalyzed approaches, microwave irradiation methods, cyclocondensation approaches, and direct amination. This review is also focused on the description of reaction conditions, substrate scope, and mechanism of the reactions. We hope that this review provide insight to medicinal chemist for the design and development of novel methods for the synthesis of 4-aminoquinazoline derivatives.



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