Synthesis of Quinazoline and Quinazolinone Derivatives

*Heba E. Hashem*

#### **Abstract**

Active heterocyclic compounds are one of the main topics of interest for the medicinal chemists as they display a number of pharmacological activities. Nitrogen, sulfur, and oxygen containing five- and six-membered heterocyclic compounds have occupied enormous significance in the field of medicinal chemistry. The most important six-membered heterocyclic compounds are quinazoline and quinazolinone derivatives for their biological activities. The current chapter outlined the different methods for synthesis of quinazoline and quinazolinone derivatives that possess broad spectrum of biological activities.

**Keywords:** quinazoline, quinazolinone synthesis, six-membered heterocycles, biological activity

#### **1. Introduction**

Quinazoline (1,3-diazanaphthalene or 5,6-benzopyrimidine) and 4(3H) quinazolinone derivatives have a great interest in organic synthesis and medicinal chemistry fields as they possess a broad range of pharmacological activities. They exhibit antimicrobial [1], antimalarial [2], antioxidant [3], anti-inflammatory [4], anticonvulsant [5], antihypertensive [6], antidiabetic [7], and antitumor activities [8–10].

Many quinazolinone derivatives occurred naturally in various classes of the plant kingdom, microorganisms, and different animals (**Figure 1**). The first discovery of quinazolinone alkaloid is *febrifugine* which possesses antimalarial potential, extracted from the Chinese plant *aseru* (*Dichroa febrifuga* Lour) [11].

Quinazoline is a heterocyclic compound of two fused six-membered simple aromatic rings—benzene and pyrimidine ring. It is a yellow-colored compound, found usually in crystalline form. Its oxo-derivative (quinazolinone) is classified into three types according to the position and number of carbonyl group: 2(1H) quinazolinones, 4(3H)quinazolinones, and 2,4(1H,3H)quinazolinedione (**Figure 2**).

#### **2. Chemistry of quinazoline**

Quinazoline is a compound made up of two fused six-membered simple aromatic rings—benzene and pyrimidine ring. The properties of the pyrimidine ring were affected by the presence of fused benzene ring. The two nitrogen atoms are not equivalent, and the marked polarization of the 3,4-double bond is reflected

O-aminobenzaldehyde, ammonia, and formic acid. Quinazoline derivative can be easily oxidized in acidic medium at room temperature to give 3,4-dihydro-4-oxo quinazoline, while in alkaline medium using potassium permanganate will afford

The spectroscopic analysis of some synthesized quinazoline and quinazolinone derivatives was studied to investigate their structures including infrared, mass

Quinazoline derivatives found to give mainly three absorption bands in IR

correlated to C▬N, C=C, and C=N groups, while quinazolinone compounds showed 1680–1700 and 1640–1660 cm<sup>1</sup> corresponding to C=O and C=N groups [13, 14].

HNMR, and elemental analysis. The resulted data could be taken as

; these represented bands are

**3. Spectral characterization of quinazoline and quinazolinone**

standard for the new synthesized quinazoline analogue [13].

spectra: 1478–1517, 1566–1581, and 1612–1628 cm<sup>1</sup>

3,4-dihydro-6 4-oxo quinazoline (cf. **Figure 3**).

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

*Oxidation reaction of quinazoline at different medium.*

**derivatives**

**Figure 3.**

spectroscopy, <sup>1</sup>

**43**

**3.1 Infrared spectra**

**Figure 1.** *Structure of different quinazolinone alkaloids.*

#### **Figure 2.**

*Structure of quinazoline and different quinazolinone compounds.*

in the reactions of quinazoline. The properties of quinazoline derivatives depend on the following three factors:


The first synthesized quinazoline in laboratory was achieved by Gabriel in 1903 [12]. Most of quinazoline derivatives are stable in cold acidic or basic medium but can be destroyed at high temperature and undergo ring opening reaction, affording *Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

**Figure 3.** *Oxidation reaction of quinazoline at different medium.*

O-aminobenzaldehyde, ammonia, and formic acid. Quinazoline derivative can be easily oxidized in acidic medium at room temperature to give 3,4-dihydro-4-oxo quinazoline, while in alkaline medium using potassium permanganate will afford 3,4-dihydro-6 4-oxo quinazoline (cf. **Figure 3**).

## **3. Spectral characterization of quinazoline and quinazolinone derivatives**

The spectroscopic analysis of some synthesized quinazoline and quinazolinone derivatives was studied to investigate their structures including infrared, mass spectroscopy, <sup>1</sup> HNMR, and elemental analysis. The resulted data could be taken as standard for the new synthesized quinazoline analogue [13].

#### **3.1 Infrared spectra**

Quinazoline derivatives found to give mainly three absorption bands in IR spectra: 1478–1517, 1566–1581, and 1612–1628 cm<sup>1</sup> ; these represented bands are correlated to C▬N, C=C, and C=N groups, while quinazolinone compounds showed 1680–1700 and 1640–1660 cm<sup>1</sup> corresponding to C=O and C=N groups [13, 14].

in the reactions of quinazoline. The properties of quinazoline derivatives depend on

b. The presence of substituent whether they are in the pyrimidine ring or in the

The first synthesized quinazoline in laboratory was achieved by Gabriel in 1903 [12]. Most of quinazoline derivatives are stable in cold acidic or basic medium but can be destroyed at high temperature and undergo ring opening reaction, affording

the following three factors:

**Figure 2.**

**42**

**Figure 1.**

benzene ring

a. The nature of the substituents

*Structure of different quinazolinone alkaloids.*

*Quinazolinone and Quinazoline Derivatives*

*Structure of quinazoline and different quinazolinone compounds.*

c. The presence of conjugation in the pyrimidine ring

The <sup>1</sup> HNMR spectra of quinazoline and quinazolinone derivatives are different from each other according to the presence of acidic proton and its position in the presented compound. In general the 1HNMR spectrum of the main quinazoline (I) represents multiple signals in the aromatic region δ 7–8 and two singlet signals for the two CH=N protons at δ 9–9.5 ppm, while quinazolinone (II) will show also signals of aromatic protons in the same region as well as one singlet signal for CH=N proton and one broad singlet signal at the down-field region for the NH proton at δ 12–13 ppm [13, 14].

On the other hand, the 13C NMR spectrum for quinazoline and quinazolinone derivatives is nearly the same, as it shows signals at δ 100–160 ppm region.

### **4. Synthesis of quinazoline and quinazolinone derivatives**

The synthesis of various quinazoline compounds is largely based on the substitution patterns of the 1,3-diazine moiety of the system. The first quinazoline derivative (2-cyano-3,4-dihydro-4-oxoquinazoline) was synthesized in 1869 by the reaction of cyanogens with anthranilic acid [15]. Many years later quinazoline was obtained by decarboxylation of the 2-carboxy derivative (quinazolinone) which can be synthesized more easily by a different method.

*4.1.3.2 Reaction with different aromatic amines*

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

(4) [18].

to the reaction medium [19].

*4.1.3.3 Reaction with hydrazine hydrate*

(10) [13].

**45**

It was stated by several authors that 2-substituted benzoxazinone reacted easily with primary aromatic amines, giving the corresponding quinazolones

On the other hand, reaction of benzoxazinone (5) with o-phenylenediamine gave quinazolinone derivative (6) or the fused quinazoline derivative (7) according

It was reported that benzoxazinone (8) reacted with hydrazine hydrate in ethanol and has the corresponding quinazolinone (9), while carrying out the same reaction in boiling acetic acid glacial afforded the fused quinazoline

#### **4.1 Synthesis of quinazolinone**

#### *4.1.1 Niementowski's synthesis*

From anthranilic acid and formamide.

#### *4.1.2 Grimmel, Guinther, and Morgan's synthesis*

From the reaction of o-amino benzoic acid with amine in the presence of phosphorus trichloride in toluene.

*4.1.3 From 3,1,4-benoxazones (acylanthranils) and amines*

Various quinazoline and quinazolinone derivatives can be synthesized from the reaction of benzoxazinone and different amine compounds in different media.

#### *4.1.3.1 Reaction with ammonium hydroxide*

When ammonium hydroxide reacted with benzoxazinone (1) over 1–3 h, it produced anthranilamides (2) which cyclizes to 4-quinazolones (3) under thermal conditions (240–280°C) or on heating with acetic anhydride [16, 17].

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

The <sup>1</sup>

*Quinazolinone and Quinazoline Derivatives*

12–13 ppm [13, 14].

HNMR spectra of quinazoline and quinazolinone derivatives are different

from each other according to the presence of acidic proton and its position in the presented compound. In general the 1HNMR spectrum of the main quinazoline (I) represents multiple signals in the aromatic region δ 7–8 and two singlet signals for the two CH=N protons at δ 9–9.5 ppm, while quinazolinone (II) will show also signals of aromatic protons in the same region as well as one singlet signal for CH=N proton and one broad singlet signal at the down-field region for the NH proton at δ

On the other hand, the 13C NMR spectrum for quinazoline and quinazolinone

derivatives is nearly the same, as it shows signals at δ 100–160 ppm region.

The synthesis of various quinazoline compounds is largely based on the substitution patterns of the 1,3-diazine moiety of the system. The first quinazoline derivative (2-cyano-3,4-dihydro-4-oxoquinazoline) was synthesized in 1869 by the reaction of cyanogens with anthranilic acid [15]. Many years later quinazoline was obtained by decarboxylation of the 2-carboxy derivative (quinazolinone) which

From the reaction of o-amino benzoic acid with amine in the presence of

Various quinazoline and quinazolinone derivatives can be synthesized from the reaction of benzoxazinone and different amine compounds in different media.

When ammonium hydroxide reacted with benzoxazinone (1) over 1–3 h, it produced anthranilamides (2) which cyclizes to 4-quinazolones (3) under thermal

conditions (240–280°C) or on heating with acetic anhydride [16, 17].

**4. Synthesis of quinazoline and quinazolinone derivatives**

can be synthesized more easily by a different method.

From anthranilic acid and formamide.

*4.1.2 Grimmel, Guinther, and Morgan's synthesis*

*4.1.3 From 3,1,4-benoxazones (acylanthranils) and amines*

*4.1.3.1 Reaction with ammonium hydroxide*

**44**

phosphorus trichloride in toluene.

**4.1 Synthesis of quinazolinone**

*4.1.1 Niementowski's synthesis*

#### *4.1.3.2 Reaction with different aromatic amines*

It was stated by several authors that 2-substituted benzoxazinone reacted easily with primary aromatic amines, giving the corresponding quinazolones (4) [18].

On the other hand, reaction of benzoxazinone (5) with o-phenylenediamine gave quinazolinone derivative (6) or the fused quinazoline derivative (7) according to the reaction medium [19].

#### *4.1.3.3 Reaction with hydrazine hydrate*

It was reported that benzoxazinone (8) reacted with hydrazine hydrate in ethanol and has the corresponding quinazolinone (9), while carrying out the same reaction in boiling acetic acid glacial afforded the fused quinazoline (10) [13].

#### *4.1.3.4 Reaction with different carbohydrazide*

Treatment of 2-substituted-3,1-benzoxazin-4-ones (11) with semicarbazide hydrochloride in dry pyridine is a good way to construct a third heterocyclic ring condensed with quinazoline (12) [18].

It was also reported that refluxing an equimolar amount of the benzoxazinone (8) with thiocarbonohydrazide in ethanol and in the presence of few drops of glacial acetic acid furnished quinazolinone (20) in the two isomers of thione and thiol form [13].

Isobutyrylanilides with urethane and phosphorus pentoxide in xylene gave 2-

propyl- and 2-isopropyl-3,4-dihydro-4-oxoquinazolines.

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

*4.1.4 Sen and Ray's synthesis*

**47**

The reaction of benzooxazinone (8) with 2-benzamido-3-phenylacrylohydrazide (13) glacial acetic acid in the presence of fused sodium acetate gave quinazoline derivative (14). In contrast, their reaction in pyridine afforded pyrazoloquinazoline derivative (15) [13].

Reaction of benzoxazinone (8) with cyanoacetohydrazide gave the corresponding cyano quinazolinone (16) which was reacted with different nucleophiles to give fused quinazoline and annulated quinazolinone derivatives (17–19) [13].

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

It was also reported that refluxing an equimolar amount of the benzoxazinone (8) with thiocarbonohydrazide in ethanol and in the presence of few drops of glacial acetic acid furnished quinazolinone (20) in the two isomers of thione and thiol form [13].

*4.1.4 Sen and Ray's synthesis*

Isobutyrylanilides with urethane and phosphorus pentoxide in xylene gave 2 propyl- and 2-isopropyl-3,4-dihydro-4-oxoquinazolines.

*4.1.3.4 Reaction with different carbohydrazide*

condensed with quinazoline (12) [18].

*Quinazolinone and Quinazoline Derivatives*

derivative (15) [13].

**46**

Treatment of 2-substituted-3,1-benzoxazin-4-ones (11) with semicarbazide hydrochloride in dry pyridine is a good way to construct a third heterocyclic ring

The reaction of benzooxazinone (8) with 2-benzamido-3-phenylacrylohydrazide (13) glacial acetic acid in the presence of fused sodium acetate gave quinazoline derivative (14). In contrast, their reaction in pyridine afforded pyrazoloquinazoline

Reaction of benzoxazinone (8) with cyanoacetohydrazide gave the corresponding cyano quinazolinone (16) which was reacted with different nucleophiles to give fused

quinazoline and annulated quinazolinone derivatives (17–19) [13].

#### *4.1.5 From 2-aminobenzylamine*

Reaction of 2-aminobenzylamine with butyrolactone further condensed with benzaldehyde afforded 3-(2-chlorobenzylidene)-1,2,3,9-tetrahydropyrrolo-2-quinazoline.

### **5. Biological importance of quinazoline derivatives**

As we mentioned above, the important biological activity of quinazoline and quinazolinone skeletons in various fields depends mainly on the substituents of quinazoline compounds. Different substituted quinazoline compounds are found to be active as antihypertensive, antineoplastic, antidepressant, and antipsychotic, and others are effective against analgesic, antipsychotic, antiarrhythmic, cancer, and other activities [20–22].

#### **5.1 Anticancer**

It was reported that 3-substituted quinazolin-4(3H)-ones and 3,4-dihydroquinazolin-2-(1H)-one derivatives possess broad spectrum antitumor activities toward different cell (**Figure 4**) [23].

Also, different quinazoline derivatives containing thiosemicarbazide moiety possess antitumor activity (**Figure 5**) [24].

#### **5.2 Antibacterial activity**

It was reported that some novel substituted iodoquinazoline derivatives possess remarkable activity toward Gram-negative bacteria *E. coli* (**Figure 6**) [25].

#### **5.3 Antiviral agents**

A series of Schiff bases of some 2-phenyl quinazoline-4(3)H-one derivatives have shown great activity as antiviral agents (**Figure 7**) [26].

**5.4 Antimutagenic activity**

*Quinazoline derivatives with antibacterial activity.*

**Figure 5.**

**Figure 6.**

**Figure 7.**

**49**

**5.5 Antioxidant activity**

The (S)-4-aminoquinazoline alcohols performed great antimutagenic activity when tested by using *Salmonella typhimurium* and *E. coli* WP2uvrA tester strains at

Some novel thiazoloquinazoline derivatives are investigated for antioxidant activity by DPPH radical assay, nitric oxide scavenging activity, and hydrogen

0.01, 0.1, and 1 lg/plate concentrations (**Figure 8**) [27].

*Different schiff base of quinazolinone with antiviral activity.*

*Quinazoline derivatives bearing thiosemicarbazide possess anti-tumor activity.*

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

**Figure 4.** *Anti-tumor quinazolinone derivatives.*

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

*4.1.5 From 2-aminobenzylamine*

*Quinazolinone and Quinazoline Derivatives*

other activities [20–22].

**5.2 Antibacterial activity**

**5.3 Antiviral agents**

**Figure 4.**

**48**

*Anti-tumor quinazolinone derivatives.*

toward different cell (**Figure 4**) [23].

possess antitumor activity (**Figure 5**) [24].

**5.1 Anticancer**

Reaction of 2-aminobenzylamine with butyrolactone further condensed with benzaldehyde afforded 3-(2-chlorobenzylidene)-1,2,3,9-tetrahydropyrrolo-2-quinazoline.

As we mentioned above, the important biological activity of quinazoline and quinazolinone skeletons in various fields depends mainly on the substituents of quinazoline compounds. Different substituted quinazoline compounds are found to be active as antihypertensive, antineoplastic, antidepressant, and antipsychotic, and others are effective against analgesic, antipsychotic, antiarrhythmic, cancer, and

It was reported that 3-substituted quinazolin-4(3H)-ones and 3,4-dihydroquinazolin-2-(1H)-one derivatives possess broad spectrum antitumor activities

Also, different quinazoline derivatives containing thiosemicarbazide moiety

It was reported that some novel substituted iodoquinazoline derivatives possess

A series of Schiff bases of some 2-phenyl quinazoline-4(3)H-one derivatives

remarkable activity toward Gram-negative bacteria *E. coli* (**Figure 6**) [25].

have shown great activity as antiviral agents (**Figure 7**) [26].

**5. Biological importance of quinazoline derivatives**

**Figure 5.** *Quinazoline derivatives bearing thiosemicarbazide possess anti-tumor activity.*

**Figure 6.** *Quinazoline derivatives with antibacterial activity.*

**Figure 7.**

*Different schiff base of quinazolinone with antiviral activity.*

#### **5.4 Antimutagenic activity**

The (S)-4-aminoquinazoline alcohols performed great antimutagenic activity when tested by using *Salmonella typhimurium* and *E. coli* WP2uvrA tester strains at 0.01, 0.1, and 1 lg/plate concentrations (**Figure 8**) [27].

#### **5.5 Antioxidant activity**

Some novel thiazoloquinazoline derivatives are investigated for antioxidant activity by DPPH radical assay, nitric oxide scavenging activity, and hydrogen

**References**

[1] Grover G, Kini SG. Synthesis and evaluation of new quinazolone

derivatives of nalidixic acid as potential antibacterial and antifungal agents. European Journal of Medicinal Chemistry. 2006;**41**:256-262

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

> European Journal of Medicinal Chemistry. 2011;**46**:2043-2057

quinazoline scaffold. Journal of Medicinal Chemistry. 2010;**53**:

1862-1866

800-845

2017;**41**:106-111

115-121

[9] Chilin A, Conconi MT, Marzaro G, Guiotto A, Urbani L, Tonus F, et al. Exploring epidermal growth factor receptor (EGFR) inhibitor features: The role of fused dioxygenated rings on the

[10] Sagiv-Barfi I, Weiss E, Levitzki A. Design, synthesis, and evaluation of quinazoline T cell proliferation inhibitors. Bioorganic & Medicinal Chemistry. 2010;**18**:6404-6413

[11] Wattanapiromsakul C, Forster PI, Waterman PG. Alkaloids and limonoids

from *Bouchardatia neurococca*: Systematic significance.

[12] Gabriel S. Synthesis and

Phytochemistry. 2003;**64**:609-615

pharmacological evaluation of 3-alkyl/ aryl–2-methylquinazolin-4-one

derivatives. Bernoulli Society. 1903;**36**:

[13] Hemdan MM, Youssef ASA, El-Mariah FA, Hashem HE. Synthesis and antimicrobial assessments of some quinazolines and their annulated systems. Journal of Chemical Research.

[14] Zeinab F, Nasrin R, Razieh S, Kamiar Z, Mohammad A, Soghra K. Synthesis of some novel dibromo-2 arylquinazolinone derivatives as cytotoxic agents. Research in

Pharmaceutical Sciences. 2019;**14**(2):

[15] Armarego WLF. A Text Book of Quinazolines. 1963. pp. 1-320

[16] Essawy A, El-Hashash MA, El-Gendy AM, Hamed MMM. Synthesis

[2] Verhaeghe P, Azas N, Gasquet M, Hutter S, Ducros C, Laget M, et al. Synthesis and antiplasmodial activity of

quinazolines. Bioorganic & Medicinal Chemistry Letters. 2008;**18**:396-401

[3] Roopan SM, Maiyalagan T, Khan FN.

[4] Smits RA, Adami M, Istyastono EP, Zuiderveld OP, van Dam CME, de Kanter FJJ, et al. Synthesis and QSAR of quinazoline sulfonamides as highly potent human histamine H4receptor inverse agonists. Journal of Medicinal Chemistry. 2010;**53**:2390-2400

[5] Georgey H, Abdel Gawad N, Abbas S. Synthesis and anticonvulsant activity of

[6] Jain KS, Bariwal JB, Kathiravan MK, Phoujdar MS, Sahne RS, Chauhan AK, et al. Recent advances in selective alpha1-adrenoreceptor B.S. antagonists as antihypertensive agents. Bioorganic & Medicinal Chemistry. 2008;**16**:

[7] Malamas MS, Millen J. Quinazoline acetic acids and related analogues as aldose reductase inhibitors. Journal of Medicinal Chemistry. 1991;**34**:

[8] Shallal HM, Russu WA. Discovery, synthesis, and investigation of the antitumor activity of novel

piperazinylpyrimidine derivatives.

some quinazolin-4-(3H)-one derivatives. Molecules. 2008;**13**:

new 4-aryl-2-trichloromethyl

Solvent-free syntheses of some quinazolin-4(3H)-ones derivatives. Canadian Journal of Chemistry. 2008;

**86**:1019

2557-2569

4759-4800

1492-1503

**51**

**Figure 8.** *Antimutagenic activity of amino quinazoline derivative.*

**Figure 9.** *Antioxidant activity of different quinazoline.*

peroxide scavenging activity and possess high potent antioxidant activity (**Figure 9**) [28].
