**2. Synthetic methods of quinazolinones**

The number of synthetic methods of quinazolinone cores has intensely increased from year to year. These advancements in methods of synthesis lead to the access to new and effective quinazolinone compounds with augmented structural diversity starting from affordable and easily accessible substrates. In this chapter, we depict different methods of synthesis of quinazolinone derivatives from cheap and readily available starting precursors.

#### **2.1 Synthesis of quinazolinone compounds from 2-aminobenzoic acid**

Quinazolin-4(3*H*)-one (4) was synthesized by the reaction of formamide with 2-aminobenzoic acid at 125–130°C and cyclization of 2-aminobenzoic acid takes place as described in **Figure 2** [23]. Synthetic works started from esterification of 2-aminobenzoic acid and subsequently followed by reaction with isocyanates afforded 1,3-disubstituted quinazol-2,4(*1H, 3H*)-diones (5) [24] (**Figure 2**). 2-mercapto-3-substituted quinazolin-4(3*H*)-one derivatives (6) (**Figure 2**) have been synthesized through the interaction between 2-aminobenzoic acid and corresponding isothiocyanate reagent.

In 1960, Ried et al. reported [25–27] the reaction of imidates and 2-aminobenzoic acid in methanol at 80°C to afford the desired quinazolinones (7) in good yields (**Figure 2**).

A recently reported route, to the synthesis of 2-substituted quinazolin-4(3H) ones (7) under microwave conditions was reported by Rad-Moghadam and Mohseni [28]. This approach involves the condensation of 2-aminobenzoic acid, orthoesters and ammonium acetate which afford the 2-substituted-4(3H)-quinazolinone (7) **Figure 2**.

A solvent-free approach was reported by Li et al. [29] for the synthesis of 2,3-disubstituted-4(*3H*)-quinazolinones (8). The approach involves the interaction between 2-aminobenzoic acid, acyl chlorides and aromatic/aliphatic amines in the presence of SO3H-functionalized Brønsted acid ionic liquids as a catalyst under microwave irradiation (**Figure 2**). Langer and Döring [30] reported the reaction of 2-aminobenzoic acids with oxalic acid bis(imidoyl) chlorides to prepare quinazolinones (9) **Figure 2**.

**13**

(**Figure 3**).

**Figure 2.**

*Biological Activity of Quinazolinones*

*DOI: http://dx.doi.org/10.5772/intechopen.90621*

**2.2 Synthesis of quinazolinone compounds from 2-aminobenzamide**

*Synthesis of quinazolin-4(3H) one from 2-aminobenzoic acid.*

In 1962, Bake and Almaula [31] have reported the synthesis of 2-carboethoxyquinazoline-4(3H)-one **10** through the reaction of anthranilamide and diethyl oxalate (**Figure 3**). Shaterian and Rigi [32] reported a starch sulfate-catalyzed method for synthesis of 2-substituted-1,2,3,4-tetrahydro-4-quinazolinones **11** (**Figure 3**). Zhang and co-workers [33] reported a MnO2-catalyzed method for the synthesis of 2-substituted quinazolinones **12**. Anthranilamides undergo a-MnO2-catalyzed oxidative cyclization with alcohols using TBHP as an oxidant (**Figure 3**). Compound **12** could be obtained through the condensation of anthranilamide with an aldehyde in refluxing ethanol in the presence of CuCl2 [34]. Schiff base intermediate was first obtained and, in turn, is transformed into the 2-substituted quinazolinones **12**

In 1887, when Körner reported that the acylation of anthranilamide results in diamide intermediate which upon treatment with sodium carbonate or sodium

Quinazolin-4(3*H*) one compound **12** have been developed by Yang et al. via selective cleavage of the triple bond of ketoalkynes. A reasonable mechanism was suggested for this reaction (**Figure 3**). Michael addition of the amino group of the anthranilamide to the triple bond of the ketoalkyne generated the enaminone

hydroxide yielded 2-phenylquinazolin-4(3H)-one **12** (**Figure 3**) [35].

*Quinazolinone and Quinazoline Derivatives*

*Quinazolinone and quinazolinedione structures.*

**2. Synthetic methods of quinazolinones**

and readily available starting precursors.

responding isothiocyanate reagent.

linones [22].

**Figure 1.**

and 2,4(1H,3H)-quinazolinediones (**2**), 4(3H)-quinazolinones (**3**) are most prevalent and significant in medicinal chemistry possessing a multitude of pharmacological actions [21]. Quinazolinones are generally classified into four classes, 2-substituted quinazolinones, 3-substituted quinazolinones, 2,3-disubstituted quinazolinones and quinazolinone derivatives including fused quinazo-

The number of synthetic methods of quinazolinone cores has intensely increased from year to year. These advancements in methods of synthesis lead to the access to new and effective quinazolinone compounds with augmented structural diversity starting from affordable and easily accessible substrates. In this chapter, we depict different methods of synthesis of quinazolinone derivatives from cheap

**2.1 Synthesis of quinazolinone compounds from 2-aminobenzoic acid**

Quinazolin-4(3*H*)-one (4) was synthesized by the reaction of formamide with 2-aminobenzoic acid at 125–130°C and cyclization of 2-aminobenzoic acid takes place as described in **Figure 2** [23]. Synthetic works started from esterification of 2-aminobenzoic acid and subsequently followed by reaction with isocyanates afforded 1,3-disubstituted quinazol-2,4(*1H, 3H*)-diones (5) [24] (**Figure 2**). 2-mercapto-3-substituted quinazolin-4(3*H*)-one derivatives (6) (**Figure 2**) have been synthesized through the interaction between 2-aminobenzoic acid and cor-

In 1960, Ried et al. reported [25–27] the reaction of imidates and 2-aminobenzoic acid in methanol at 80°C to afford the desired quinazolinones (7) in good yields

A recently reported route, to the synthesis of 2-substituted quinazolin-4(3H) ones (7) under microwave conditions was reported by Rad-Moghadam and Mohseni [28]. This approach involves the condensation of 2-aminobenzoic acid, orthoesters and ammonium acetate which afford the 2-substituted-4(3H)-quinazolinone (7)

A solvent-free approach was reported by Li et al. [29] for the synthesis of 2,3-disubstituted-4(*3H*)-quinazolinones (8). The approach involves the interaction between 2-aminobenzoic acid, acyl chlorides and aromatic/aliphatic amines in the presence of SO3H-functionalized Brønsted acid ionic liquids as a catalyst under microwave irradiation (**Figure 2**). Langer and Döring [30] reported the reaction of 2-aminobenzoic acids with oxalic acid bis(imidoyl) chlorides to prepare quinazoli-

**12**

(**Figure 2**).

**Figure 2**.

nones (9) **Figure 2**.

**Figure 2.** *Synthesis of quinazolin-4(3H) one from 2-aminobenzoic acid.*

### **2.2 Synthesis of quinazolinone compounds from 2-aminobenzamide**

In 1962, Bake and Almaula [31] have reported the synthesis of 2-carboethoxyquinazoline-4(3H)-one **10** through the reaction of anthranilamide and diethyl oxalate (**Figure 3**). Shaterian and Rigi [32] reported a starch sulfate-catalyzed method for synthesis of 2-substituted-1,2,3,4-tetrahydro-4-quinazolinones **11** (**Figure 3**). Zhang and co-workers [33] reported a MnO2-catalyzed method for the synthesis of 2-substituted quinazolinones **12**. Anthranilamides undergo a-MnO2-catalyzed oxidative cyclization with alcohols using TBHP as an oxidant (**Figure 3**). Compound **12** could be obtained through the condensation of anthranilamide with an aldehyde in refluxing ethanol in the presence of CuCl2 [34]. Schiff base intermediate was first obtained and, in turn, is transformed into the 2-substituted quinazolinones **12** (**Figure 3**).

In 1887, when Körner reported that the acylation of anthranilamide results in diamide intermediate which upon treatment with sodium carbonate or sodium hydroxide yielded 2-phenylquinazolin-4(3H)-one **12** (**Figure 3**) [35].

Quinazolin-4(3*H*) one compound **12** have been developed by Yang et al. via selective cleavage of the triple bond of ketoalkynes. A reasonable mechanism was suggested for this reaction (**Figure 3**). Michael addition of the amino group of the anthranilamide to the triple bond of the ketoalkyne generated the enaminone

intermediate which upon acid catalyzed intramolecular cyclization with subsequent C-C bond cleavage afforded final product **12**.

#### **2.3 Synthesis of quinazolinone compounds from o-substituted aniline**

Yan et al. [36] reported a C(sp3)-H oxidative amination, tandem condensation oxidation, catalyzed by iodine method to access quinazolinone compound **13** (**Figure 4**).

Natte and co-workers [37] reported the reaction of 2-iodoanilines, amines and trimethyl orthoformate catalyzed by Pd/C afforded quinazolin-4(3*H*) one compounds **13** (**Figure 4**).

#### **Figure 3.**

*Synthesis of quinazolin-4(3H) one from 2-aminobenzamide.*

**15**

**Figure 5.**

*Synthesis of spiroquinazolinones.*

*Biological Activity of Quinazolinones*

**16** (**Figure 4**) [39].

ethanol) (**Figure 5**).

(**Figure 6**).

*DOI: http://dx.doi.org/10.5772/intechopen.90621*

**2.4 Synthesis of spiroquinazolinones**

**2.5 Synthesis of heterocycle-fused quinazolinones**

(phenylamino) quinazolin-4(3H)-ones (**Figure 6**).

tophenone and isatoic anhydrides (**Figure 6**).

phine and isocyanates (**Figure 6**).

Mizuno et al. [38] synthesis of qiunazolin-2,4-(1*H*,3*H*) ones (2,4-dihydroxyquinazolines) **15** using 2-aminobenzonitriles starting materials in the presence of carbon dioxide and suitable base. The reaction first generates the carbamate salts followed by nucleophilic cyclisation via attack of the carbamate oxygen onto the cyano group with subsequent rearrangement into an intermediate that is protonated yielding the desired 2,4-dihydroxyquinazoline **15** (**Figure 4**). Also, amidation of anthranilamide with 3-phenylacryloyl chloride with subsequent oxidative ring closure using base catalyst revealed 2-styryl-4(3*H*) quinazolinone

Revathy and Lalitha [39] reported a method of *p*-Toluene sulfonic acid-catalyzed synthesis of spiroquinazolinones **17** using anthranilamide and with ketones as starting materials (**Figure 5**). Tajbakhsh et al. [40] reported a H3PO3-catalyzed method for synthesis of spiro2,3-dihydroquinazolin-4(1*H*)-ones **18** using isatoic anhydride, hydrazides and cyclic ketones, in the presence of H3PO3 catalyst (20 mol %, in

Yang et al. [41] reported the synthesis of tricyclic quinazolinones **19** using

Reddy et al. [42] reported a CuI/DMSO-catalyzed domino oxidative method for the synthesis of tryptanthrin compound **20** through the interaction of 2-aminoace-

Foldesi et al. [43] reported the synthesis of the tetracyclic pyrrolotriazepinoquinazolinone derivative **21** the interaction between 1-aryl-4-(methylsulfanyl)-5Hpyrrolo[2,1-d] [1, 2, 5] triazepines and anthranilic acid under reflux in acetic acid

Yuan et al. [44] developed a process to prepare 1H-pyrimido[2,1-b]quinazoline-2,6-dione derivatives **22.** The product was accessed through a tandem aza-Wittig/ nucleophilic addition/intramolecular cyclization/isomerization reaction of (E)-methyl 2-((2-azidobenzamido)methyl)-3-phenylacrylate with triphenylphos-

Wang and Ganesan [45] reported the synthesis of luotonin A, **23** through the reaction of anthranilic acid with 1*H*-pyrrolo[2,3-b]quinolin-2(3*H*)-one (**Figure 6**).

formic acid-catalyzed intramolecular cyclization of 3-(2-aminoalkyl)-2-

**Figure 4.**

*Synthesis of quinazolinone compounds from* o*-substituted aniline.*

*Quinazolinone and Quinazoline Derivatives*

(**Figure 4**).

pounds **13** (**Figure 4**).

C-C bond cleavage afforded final product **12**.

*Synthesis of quinazolin-4(3H) one from 2-aminobenzamide.*

*Synthesis of quinazolinone compounds from* o*-substituted aniline.*

intermediate which upon acid catalyzed intramolecular cyclization with subsequent

Yan et al. [36] reported a C(sp3)-H oxidative amination, tandem condensation oxidation, catalyzed by iodine method to access quinazolinone compound **13**

Natte and co-workers [37] reported the reaction of 2-iodoanilines, amines and trimethyl orthoformate catalyzed by Pd/C afforded quinazolin-4(3*H*) one com-

**2.3 Synthesis of quinazolinone compounds from o-substituted aniline**

**14**

**Figure 4.**

**Figure 3.**

Mizuno et al. [38] synthesis of qiunazolin-2,4-(1*H*,3*H*) ones (2,4-dihydroxyquinazolines) **15** using 2-aminobenzonitriles starting materials in the presence of carbon dioxide and suitable base. The reaction first generates the carbamate salts followed by nucleophilic cyclisation via attack of the carbamate oxygen onto the cyano group with subsequent rearrangement into an intermediate that is protonated yielding the desired 2,4-dihydroxyquinazoline **15** (**Figure 4**). Also, amidation of anthranilamide with 3-phenylacryloyl chloride with subsequent oxidative ring closure using base catalyst revealed 2-styryl-4(3*H*) quinazolinone **16** (**Figure 4**) [39].

### **2.4 Synthesis of spiroquinazolinones**

Revathy and Lalitha [39] reported a method of *p*-Toluene sulfonic acid-catalyzed synthesis of spiroquinazolinones **17** using anthranilamide and with ketones as starting materials (**Figure 5**). Tajbakhsh et al. [40] reported a H3PO3-catalyzed method for synthesis of spiro2,3-dihydroquinazolin-4(1*H*)-ones **18** using isatoic anhydride, hydrazides and cyclic ketones, in the presence of H3PO3 catalyst (20 mol %, in ethanol) (**Figure 5**).

### **2.5 Synthesis of heterocycle-fused quinazolinones**

Yang et al. [41] reported the synthesis of tricyclic quinazolinones **19** using formic acid-catalyzed intramolecular cyclization of 3-(2-aminoalkyl)-2- (phenylamino) quinazolin-4(3H)-ones (**Figure 6**).

Reddy et al. [42] reported a CuI/DMSO-catalyzed domino oxidative method for the synthesis of tryptanthrin compound **20** through the interaction of 2-aminoacetophenone and isatoic anhydrides (**Figure 6**).

Foldesi et al. [43] reported the synthesis of the tetracyclic pyrrolotriazepinoquinazolinone derivative **21** the interaction between 1-aryl-4-(methylsulfanyl)-5Hpyrrolo[2,1-d] [1, 2, 5] triazepines and anthranilic acid under reflux in acetic acid (**Figure 6**).

Yuan et al. [44] developed a process to prepare 1H-pyrimido[2,1-b]quinazoline-2,6-dione derivatives **22.** The product was accessed through a tandem aza-Wittig/ nucleophilic addition/intramolecular cyclization/isomerization reaction of (E)-methyl 2-((2-azidobenzamido)methyl)-3-phenylacrylate with triphenylphosphine and isocyanates (**Figure 6**).

Wang and Ganesan [45] reported the synthesis of luotonin A, **23** through the reaction of anthranilic acid with 1*H*-pyrrolo[2,3-b]quinolin-2(3*H*)-one (**Figure 6**).

**Figure 5.** *Synthesis of spiroquinazolinones.*

**Figure 6.** *Synthetic methods of heterocycle-fused quinazolinones.*
