Synthesis of Quinazoline and Quinazolinone Derivatives

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.

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].

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 in the reactions of quinazoline. The properties of quinazoline derivatives depend on the following three factors: a. The nature of the substituents b. The presence of substituent whether they are in the pyrimidine ring or in the benzene ring c. The presence of conjugation in the pyrimidine ring 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  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).

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, 1 HNMR, and elemental analysis. The resulted data could be taken as standard for the new synthesized quinazoline analogue [13].

Infrared spectra
Quinazoline derivatives found to give mainly three absorption bands in IR spectra: 1478-1517, 1566-1581, and 1612-1628 cm À1 ; these represented bands are correlated to C▬N, C=C, and C=N groups, while quinazolinone compounds showed 1680-1700 and 1640-1660 cm À1 corresponding to C=O and C=N groups [13,14]. The 1 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 13 C NMR spectrum for quinazoline and quinazolinone derivatives is nearly the same, as it shows signals at δ 100-160 ppm region.

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.

Grimmel, Guinther, and Morgan's synthesis
From the reaction of o-amino benzoic acid with amine in the presence of phosphorus trichloride in toluene.

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.

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].

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].
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].

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][21][22].

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

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

Conclusion
Quinazoline and quinazolinone compounds which have a lot of considerable pharmacological interests can be synthesized by different methods, and the most attractive method was carried out starting from benzoxazinone derivatives.

Author details
Heba E. Hashem Department of Chemistry, College for Girls, Ain Shams University, Heliopolis, Cairo, Egypt *Address all correspondence to: hebahashem89@yahoo.com © 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.