New method for synthesizing 2 arylquinazoline and quinazolinone

In terms of analysing published studies and quinazoline synthesis, the synthetic methodology of 2-arylquinazoline derivatives may be classified into four groups: i Coupling reaction to f

VIETNAM NATIONAL UNIVERSITY–HO CHI MINH CITY

HO CHI MINH UNIVERSITY OF TECHNOLOGY

-

NGUYEN KHANH DUYEN

NEW METHOD FOR SYNTHESIZING

2-ARYLQUINAZOLINE AND QUINAZOLINONE

Major: Chemical Engineering

Number: 8520301

MASTER THESIS

HO CHI MINH CITY, SEPTEMBER 2020

ACKNOWLEGDMENT

At first, I would like to express my sincere gratitude to all teachers of Faculty of Organic Chemistry of Ho Chi Minh city University of Technology, especially Prof Dr Phan Thanh Son Nam and Dr Nguyen Thanh Tung – my supervisors

Besides, I also want to thank to co-workers – Pham Hoang Phuc, Nguyen Xuan Khang – whose expertise, understanding, generous guidance and support made it posible for me to work on my topic It was a pleasure working with them

In addition, I want to say thanks to Minh Duy, Hoang Khang and others - my lab member, who always accompany and support me during my studying time at Manar laboratory

Finally, I would like to show my respect and gratitude to my family – who always support and help me complete my thesis effectively

NGUYEN KHANH DUYEN

ABSTRACT

In this master thesis, I would like to present two new protocol that obtained heterocylclic containing nitrogen compounds, especially quinazoline and quinazolinone compounds

In the first work, using sulfur as promoter for the synthesizing reaction arylquinazoline that has more advantages compared to previous works such as short reaction time, using sulfur has lower toxicity than traditional transition – metal catalysts, low usage amount; at the same time, the applicability of the reaction system has been demonstrated through a variety of 2-arylquinazoline derivatives synthesized based on a wide variety of agents

2-In the second study, a novel C–H bond activation of isoquinoline and 2-aminobenzyl alcohol was explored to form quinazolinone derivatives using copper salt catalyst Mentioned reaction has more advantages compared to previous works such as short reaction time, using transition – metal catalysts This reaction was successfully developed

on various derivatives

TÓM TẮT LUẬN VĂN

Luận văn trình bày hai phương pháp mới để tổng hợp khung quinazoline và quinazolinone Phần thứ nhất của luận văn giới thiệu phương pháp tổng hợp quinazoline

sử dụng lưu huỳnh làm tác nhân phản ứng, phản ứng này thể hiện nhiều ưu điểm như không

sử dụng kim loại chyển tiếp, ít độc hại hơn so với các phương pháp truyền thống khác, bên cạnh đó phản ứng còn tổng hợp được số lượng lớn nhóm thế của 2-phenylquinazoline

Trong phản ứng thứ hai, một phương pháp dùng để tổng hợp khung quinazolinone được giới thiệu, phương pháp này có nhiều cải tiến khi sử dụng xúc tác là muối đồng với thời gian phản ứng ngắn và phương pháp thành công trên nhiều loại nhóm thế khác nhau

DECLARATION

I guarantee this is my own research work with the scientific guidance of Prof Dr Phan Thanh Son Nam and Dr Nguyen Thanh Tung The research contents, results in this topic are honest and unpublished in any form before The data in tables for analysis and comment are collected by the author from various sources in the reference section

In addition, the thesis also uses some comments and assessments as well as data from other authors and other organizations which are cited and annotated

If any fraud is found, I will take full responsibility for the content of my thesis HCM University of Technology is not related to violation of copyright caused by me during the implementation process (if any)

Ho Chi Minh city, September 2020

NGUYEN KHANH DUYEN

TABLE OF CONTENTS

ACKNOWLEGDMENT i

ABSTRACT ii

DECLARATION iii

TABLE OF CONTENTS iv

LIST OF ABBREVIATIONS vi

LIST OF FIGURE vii

LIST OF SCHEMES viii

LIST OF TABLES xi

CHAPTER 1: LITERATURE REVIEW 1

1.1 Introduction 1

1.2 The synthesis of quinazolines 4

1.3 Approaches organic synthesis using sulfur-mediated catalysts 17

1.4 The aim and objectives of our approach 20

1.5 The synthesis of quinazolinones 21

1.5.1.The C2 activation and Csp2 –N coupling reaction in organic synthesis 21 1.5.2.Advanced in the synthesis of quinazolinones 26

1.6 Our approach 30

CHAPTER 2: EXPERIMETAL 31

2.1 Materials and instrumentals 31

2.2 Reaction procedure for synthesis quinazolines derivatives 32

2.2.1.The general procedure for quinazoline derivatives synthesis reaction 32

2.2.2.Isolated product procedure 33

2.2.3.Gram-scale reaction for quinazoline 33

2.3 Reaction procedure of reaction forming quinazolinones 34

2.3.1.The general procedure for synthesis of quinazolinones derivatives 34

2.3.2.Isolated product procedure 34

CHAPTER 3: RESULTS AND DISCUSSION 36

3.1 Studies of reaction conditions of quinazolines 36

3.2 Effect of different substituents of the reaction 47

3.3 Control experiments and proposed mechanism 54

3.4 Studies of reaction conditions of quinazolinones 59

3.4.1.Study of many different conditions on the yield of quinazolinones product 59

3.4.2.The result of synthesis reaction quinazolinone derivatives 65

CONCLUSION 67

REFERENCES 69

APPENDICES 78

NMR Nuclear Magnetic Resonance

PXRD Powder X-ray Diffraction

LIST OF FIGURE

Figure 1 1 Quinazoline and its isomers 2

Figure 1 2 Quinazoline and its derivatives with biological activity 3

Figure 1 3 The 2-arylquinazoline derivatives have applications in luminescent and bioactive materials 4

Figure 1 4 The analysis of synthesis of 2-arylquinazoline substituted-derivatives via breaking C2-bond 5

Figure 3 1 Effect of base on reaction synthesis of quinazolines 38

Figure 3 2 The yield of main product in various kinds of base 39

Figure 3 3 The effect of DABCO on the reaction 40

Figure 3 4 The effect of different kinds of nitrogen source on reaction 42

Figure 3 5 Effect of urea amount on the yield of product 43

Figure 3 6 Effect of different molar ratio of starting reactants 44

Figure 3 7 The effect of amount of elemental sulfur on yield of product 45

Figure 3 8 Effect of different solvent on the yield of product 46

Figure 3 9 The effect of different promoters on quinazolines synthesis 47

Figure 3 10 Effect of temperature on the yield of quinazolinone product 60

Figure 3 11 Effect of different types of acid on the yield of quinazolinone product 61

Figure 3 12 The molar ratio effect on the yield of main product 62

Figure 3 13 The various kinds of catalyst effect on yield of product 63

Figure 3 14 Effecting the amount of catalyst on reaction 63

Figure 3 15 Effect of different solvent on synthesis of quinazolinone 64

LIST OF SCHEMES

Scheme 1 1 Coupling reaction of 2-cloroquinazoline and arylboric acid by using

Pd catalysts 6Scheme 1 2 Synthesis of substituted derivatives of 2,4-disubstituted quinazoline via Suzuki coupling reaction of a) Prabhakar and co-workers b) Kakad and co-workers 6Scheme 1 3 Synthesis of 2-(1H-indol-1-yl)quinazoline derivatives via Buchwald-Hartwig coupling reaction using Ni catalysts 7Scheme 1 4 Aggregation of carbazole – quinazoline by Ullmann – Goldberg using CuCl catalysts 7

Scheme 1 5 Synthesis of quinazoline derivatives via Ullmann-Goldberg coupling

reaction from 2-halobenzaldehydes and amidine derivatives 9

Scheme 1 6 Synthesis of quinazoline derivatives from o-bromobenzyl (pseudo)halides and amidine derivatives via Ullmann-Goldberg coupling reaction.

9

Scheme 1 7 Synthesis of 2-arylquinazoline derivatives via cyclization of

N-arylamidine and carbonyl equivalent derivatives 10Scheme 1 8 Synthetic reaction of 2-arylquinazoline derivatives from 2-aminobenzylamines and benzaldehydes using redox catalytic system in the presence

of oxygen 11Scheme 1 9 Synthesis of quinazoline derivatives from 2-aminobenzylamines and benzyl alcohols 12Scheme 1 10 Synthesis of quinazoline derivatives from 2-aminobenzylamine and equivalent benzaldehyde 13Scheme 1 11 Synthesis of quinazoline derivatives from 2-aminobenzylamines and equivalent derivatives of benzaldehyde without transition metal catalysts 14Scheme 1 12 Synthesis of quinazoline derivatives from 2-aminobenzyl alcohol derivatives and benzonitriles 14

Scheme 1 13 Synthesis of quinazoline derivatives from benzylamine derivatives.

15

Scheme 1 14 General process to synthesize 2-arylquinazoline derivatives 16

Scheme 1 15 Synthesis of quinazolines towards hydrogen transfer strategy 16

Scheme 1 16 Synthesis arylbenzothiazole derivatives by Guntreddi and co-workers 17

Scheme 1 17 Using elemental sulfur in organic synthesis in 2017 18

Scheme 1 18 Reactions using elemental sulfur in 2018 19

Scheme 1 19 Reactions using elemental sulfur in 2019 20

Scheme 1 20 Using elemental sulfur in organic synthesis in 2020 20

Scheme 1 21 C-H coupling reaction were reported in 2013 22

Scheme 1 22 C2 activation reaction of quinoline structures in organic synthesis.23 Scheme 1 23 Coupling reaction via C –H activation in 2016 23

Scheme 1 24 C2 selective and C –N bond formation reaction in 2017 25

Scheme 1 25 C2 activation and Csp2–N coupling reaction from 2018 to 2019 26

Scheme 1 26 The reaction synthesis of quinazolinone in 2011 26

Scheme 1 27 The synthesis reaction of quinazolinone in 2013 and 2014 27

Scheme 1 28 Synthesizing of quinazolinone derivatives in 2015 28

Scheme 1 29 The synthesis reaction of quinazolinone in 2016 and 2017 29

Scheme 1 30 The reaction of synthesis quinazolinone derivatives in 2018 and 2019 30

Scheme 2 1 General procedure of synthesis quinazolines 32

Scheme 2 2 General procedure of synthesis quinazolinones 34

Scheme 3 1 Reaction model to investigate synthesis of quinazoline 36

Scheme 3 2 Investigation of the temperature on reaction 37

Scheme 3 3 Investigation of base on reaction 38

Scheme 3 4 Investigation of additives on reaction 41

Scheme 3 5 Mechanistic studies 56

Scheme 3 6 Plausible mechanism 58

Scheme 3 7 Reaction model to investigate synthesis of quinazolinone 59

Scheme 4 1 Optimal condition of synthetic reaction of 2-phenylquinazoline from 2-nitrobenzyl alcohol and phenylacetic acid 67

Scheme 4 2 Synthetic reaction of quinazolinone from 2-aminobenzyl alcohol and isoquinoline 68

LIST OF TABLES

Table 2 1 List of substances and vendors 33

Table 3 1 Melting temperature of some agents used in the reaction 37Table 3 2 Synthesis of 2-arylquinazoline derivatives from different substituents of phenylacetic acid derivatives and 2-nitrobenzyl alcohol 48Table 3 3 Synthesis of 2-arylquinazoline derivatives from different substituents of 2-nitrobenzyl alcohol and phenylacetic acid 51Table 3 4 Study of benzyl coupling partnera 53Table 3 5 Reaction conditions and control experiments 55Table 3 6 Synthesis of 2-arylquinazoline derivatives from different substituents of phenylacetic acid derivatives and 2-nitrobenzyl alcohol 65

CHAPTER 1: LITERATURE REVIEW

The name “quinazoline” originates from Chinese quinine medicinal plant, with scientific name is Dichroa febrifuga Lour of Saxifragaceae family coming from China [2] The quinazoline compound is isolated from the tree named febrifugine which is used to synthesize antimalarial agents The formula of C8H6N2 is a basic structure of the quinazoline and formed by a combination of benzene and pyrimidine heterocycle This structure has extremely valuable advantages of quinazoline due to the fact that pyrimidines are one of the most important structure in the heterocyclic compounds containing nitrogen They have in the nucleic acid component and pyrimidine that significantly reduce the risk

of elimination of quinazoline derivatives when introduced into living organisms [3]

The figure for research relating to the quinazoline scaffold is continuously increasing to now The SciFinder® database updated more than 8200 scientific articles and patents related to the quinazoline framework and its derivatives; with more than 670,000 isolated compounds containing quinazoline frames, synthesized and determined structures, more than 40,000 quinazoline derivatives bioavtivities have been demonstrated These statistics have proved the potential application as well as the importance in expanding

number of approaches to synthesize this structure [4] Figure 1.1

Figure 1 1 Quinazoline and its isomers

In 1869, Griess conducted the reaction of cyanogens with anthranilic acid making 2-cyano-3,4-dihydro-4-oxoquinazoline or bicyanoamido benzoyl which is the first quinazoline derivative [5] Until 1903, when Gabriel and his co-workers carried out further studies, at that time the name “Quinazoline” was proposed and widely used until these days With many essential roles in pharmacological area, they became one of the most popular structure in medical research From 1980 to now, many researchers have claimed more than 50 derivatives of this compound, it has numerous biological activities such as inhibiting lung cancer cells of dacomitinib, alfuzosin curing prostate hypertrophy, trimetrexate supporting the process of treating AIDS, prazocin helping lower blood pressure, linagliptin in diabetes treatment, anagrelide reducing thrombocytopenia syndrom, erlotinib inhibits kinase enzyme and letermovir with antiviral ability [6-13]

Figure 1 2 Quinazoline and its derivatives with biological activity

In this study, we concentrated on the protocol of synthesizing derivatives having aryl group at the second position of quinazoline scaffold 2-arylquinazoline derivatives were reported to have diverse biological activities such as antimicrobial, antiviral, anti-tuberculosis and malaria, inhibition of topoisomerase I enzymes, preventing the formation

of membranes of HIV-1 virus and selectively inhibiting CHK2 protein at the same time, which offered a high potential of developing various types of anticancer agents In addition, some of the studied 2,4-diarylquinazoline compounds were capable of fluorescing in solid state, thereby opening new research directions to study new luminescent material families [14-26]

Figure 1 3 The 2-arylquinazoline derivatives have applications in luminescent and

bioactive materials

1.2 The synthesis of quinazolines

According to SciFinder® statistics, since 2010, over 700 articles and the studies of synthesis of 2-arylquinazoline, 4 -arylquinazoline and 2,4-diarylquinazoline have been published in prestigious journals In terms of analysing published studies and quinazoline synthesis, the synthetic methodology of 2-arylquinazoline derivatives may be classified into four groups: i) Coupling reaction to forming C–C and C–N bonds using transition metal catalysts; ii) Cyclization reaction forming quinazoline structures from arylamidine

or carboxamide derivatives; iii) Condensation reaction between of 2-aminbenzylamine and carbonyl; iv) Condensation reaction between nitro compounds and equivalent derivatives

of carbonyl towards hydrogen converting path under transition metal catalysts or phosphine [27]

1.2.1 Synthesis of quinazoline derivatives through the coupling reaction of C–C or C–N

bonds

Biaryl structures or conjugated aromatic were existed in many polymer molecules, organic ligands and pharmaceuticals The synthetic methodologies of these structures gained a great attention of organic chemistry all over the world In terms of the synthesis

of aromatic multi-ring derivatives by forming C–C linkages, Suzuki-Miyaura coupling reaction with Pd catalysts have more advantages than the similar ones [28] For instance,

the Hiyama coupling reaction with organosilicon agents under Pd catalysts required reagents containing ion activated flouride, which led to eliminate directly some silicon functional groups (such as groups protecting silyl ether), simultanously, ion flouride affects functional groups such as acid or ester [29]; Kumada-Negishi coupling reaction with Grignard and organozinc reagents in the presence of Pd or Ni catalysts, had a drawback when producing a huge amount of metal-contaminated wastes like Mg and Zn In addition, the mentioned organometallic reagents were not suitable for functional groups containing labile protons [30] Therefore, Suzuki-Miyaura coupling reaction brings many outstanding advantages such as mild reaction condition, compatibility with various kinds of substituents or functional groups, commercially available reagents, non-toxic byproducts and products are easy to remove impurities and unwanted elements [31]

Figure 1 4 The analysis of synthesis of 2-arylquinazoline substituted-derivatives via

breaking C2-bond

In 2006, Henriksen and co-workers successfully synthesized 2-arylquinazoline derivative from 2-chloroquinazoline, from Suzuki – Miyaura coupling reaction with different arylboronic acid reagents under PdCl2(PPh3)2 and microwave irradiation at 120oC

(scheme 1.1) The reaction was done in short time from 10 to 15 minutes, the yield of main

product was given about 63% to 79% However, the number of substituents and its efficiency was low, the relatively high equivalent weight of base was used in this reaction [32]

Scheme 1 1 Coupling reaction of 2-cloroquinazoline and arylboric acid by using Pd

catalysts

In 2016, study of Kakad [29] and Prabhakar [30] and co-workers introduced that arylquinazoline derivatives could be synthesized with high performance that based on Suzuki coupling reaction using PdCl2(PPh3)2 and Pd(PPh3)4 catalytic (Scheme 1.2)

2-Scheme 1 2 Synthesis of substituted derivatives of 2,4-disubstituted quinazoline via Suzuki

coupling reaction of a) Prabhakar and co-workers b) Kakad and co-workers

In addition, Buchwald-Harwig C-N bond-forming coupling reaction played an important role in multi–ring construction organic synthesis [35-38], in which Palladium/phosphine catalytic system performed high activity [39-42] Moreover, C–N bond formation via Ullmann – Goldberg coupling reaction have also gained significant achievements [43-47]

In 2015, N-heteroarylindole and N-heteroarylcarbazole derivatives were described

by Rull and co-workers via Buchwald-Hartwig coupling reaction using [(Ipr)Ni(styrene)2]

catalytic system and t-BuOLi base in 1,4-dioxane solvent without phosphine ligands as

other previous Pd–catalyzed methods [45] (scheme 1.3) However, the number of

derivatives was still limited and the synthesis of indole and carbazole containing halogen functional groups were not formed in the reaction

Scheme 1 3 Synthesis of 2-(1H-indol-1-yl)quinazoline derivatives via Buchwald-Hartwig

coupling reaction using Ni catalysts

Zhao and co-workers in 2016 carried out Ullmann-Goldberg coupling reaction to achieved heteroarylcarbazole and N-heteroarylquinazoline derivatives, resulting 90% yield

of the desired product was attained in a short time, CuCl catalysts were used with

1-methylimidazole ligands in toluene solvent and t-BuOLi base [44] (scheme 1.4)

Scheme 1 4 Aggregation of carbazole – quinazoline by Ullmann – Goldberg using CuCl

catalysts

In general, the method to synthesize quinazoline derivatives through direct coupling forming C-C or C-N links based on Suzuki – Miyaura, Buchwald-Hartwig and Ullmann-Goldberg reaction that could be shown in high yield and many different substituents Nevertheless, all these methods have their own limitations such as using expensive, rare and precious metal catalysts as palladium and phosphine organic ligands having complex structures and high cost According to green chemistry, it is essential for developing more synthetic methods of quinazoline scaffolds by applying more efficient catalysts and

reactants and improving economic via inexpensive materials, chemically stable and commercially available reagents

1.2.2 Synthesis of quinazoline derivatives through the cyclization reaction from

arylamidine and carboxamide derivatives

In 2010, Truong and co-workers delivered a method synthesizing

2-arylquinazolines via Ullmann-Goldberg coupling reaction, 2-iodobenzaldehyde and

benzamidine derivatives were reacted under methanol solvent at 60oC using CuI catalysts

(Scheme 1.5a) [46] In 2011, a similar reaction was represented by Vypolzov and co –

workers, which utilized CuI catalytic system together with L-proline liands in DMSO

solvent; the main product were formed with high yield in 1 hour (Scheme 1.5b) [47] At

the same time, the synthetic method of quinazoline derivatives from 2-bromobenzaldehyde were introduced by Raut and co–workers in 2017, using nano – Cu2O catalyst in ethylene glycol solvent, under microwave irradiation with the yield ranging from 81% to 96% in 2

minutes (Scheme 1.5c) [48]

Scheme 1 5 Synthesis of quinazoline derivatives via Ullmann-Goldberg coupling reaction

from 2-halobenzaldehydes and amidine derivatives

Synthesizing quinazoline derivatives by using the Ullmann-Goldberg coupling reaction from amine derivatives in the absence of aldehydes were also a way to attract much attentions In 2012, Malakar and co-workers reported that performing 2-

arylquinazoline derivatives were synthesized from o-bromobenzylbromides and

benzamidines in water at 100 oC using Cu2O catalyst in 40 hours (Scheme 1.6) [49]

Scheme 1 6 Synthesis of quinazoline derivatives from o-bromobenzyl (pseudo)halides and

amidine derivatives via Ullmann-Goldberg coupling reaction

In 2014, Zhang and co-workers aimed to achieve 2,4-diarylquinazoline through redox condensation reaction between amidines and benzaldehydes using nano-CuO

catalysts and air as oxidants (Scheme 1.7a) [50] According to the research from Li and

co-workers in 2018, they have replaced unstable and toxic benzaldehydes by benzyl

alcohols that were more stable and environmental friendly reagent than benzadehyde [58]

(Scheme 1.7b) Moreover, condensation reaction between N-arylamidine derivatives and

some 1-carbon equivalent derivatives were attempted to gain 2-arylquinazoline derivatives

in common solvents such as DMSO, DMF, NMP, DMAc or TMEDA (tertiary amine); Cu(OTf)2 catalyst and selectflour by Lv’ Group [52] (Scheme 1.7c)

Scheme 1 7 Synthesis of 2-arylquinazoline derivatives via cyclization of N-arylamidine

and carbonyl equivalent derivatives

1.2.3 Synthesis of quinazoline derivatives through condensation reaction between

2-aminobenzylamine derivatives and carbonyl equivalent derivatives

In 2012, Han and co – workers had established a method using OH-TEMPO catalytic system in oxygen environment and acetonitrile solvent at 80oC, after reacting for 2 hours that developed 2-arylquinazoline from 2-aminobenzyl amine and

CuCl/DABCO/4-benzadehyde (Scheme 1.8a) [62] By 2017, N-oxyl radical ABNO in oxygen as catalysts

was found for oxidation condition synthesizing quinazoline derivatives from aminobenzylamines and correlative aldehyde derivatives by Ma’ Group This method was

2-not used transition metal catalysts (Scheme 1.8b) [54]

Scheme 1 8 Synthetic reaction of 2-arylquinazoline derivatives from 2-aminobenzylamines

and benzaldehydes using redox catalytic system in the presence of oxygen

Besides, tetrehydroquinazoline derivatives were also investigated by utilizing hydrogen transferring catalytic systems or electron transferring or photocatalytic systems The benzyl alcohol derivatives were used as alternative reagents in many cases instead of benzaldehyde due to its commercial popularity, low toxicity and higher chemical stability

As a result, Zhao and co – workers published the synthetic method of 2-arylquinazoline derivatives in 2013, via the reaction between 2-aminobenzyl alcohols and primary alcohols under FeCl3 and TBHP oxidants, with good yield of main product (Scheme 1.9a) [55] By

2018, Gujjarappa’ Group have also verified a method to gain quinazoline derivatives using

simple organocatalyst such as 3-nitropyridines, pyridine N-oxide and vitamin B3 with the

presence of oxygen in air like oxidants (Scheme 1.9b) [53]

Scheme 1 9 Synthesis of quinazoline derivatives from 2-aminobenzylamines and benzyl

alcohols

In 2014, the reaction of arylbromides and 2-aminobenzylamines using Pd catalysts and CO as a carbonyl source were attracted by Chen and co-workers, which generated these quinazoline frameworks These products were found with high yield, however, this method related Pd – scarce metal catalysts and toxic CO source at high pressure which is dangerous

(Scheme 1.10a) [57] At the same moment, 2-arylquinazoline derivatives was aggregated

by Li and co-workers via condensation reaction between 2-aminobenzylamines and

benzonitrile (Scheme 1.10b) [58] Moreover, Chen and co – workers carried out the

reaction to form quinazoline scaffolds, which was the application of decarboxylation reaction of phenylacetic acid and using FeCl3/O2 catalytic system in DMF solvent [59]; or

by Yan and co – workers under Cu(OAc)2/O2 in NMP solvent There have many advantages in this methodologies due to the chemical stability and commercial popularity

of phenylacetic acids; the nontoxic by – products are CO2, with 90% isolated yield

(Scheme 1.10c) [61]

Scheme 1 10 Synthesis of quinazoline derivatives from 2-aminobenzylamine and

equivalent benzaldehyde

In 2016, 2-arylquinazoline derivatives were investigated by Tiwari and co-workers

via condensation reaction between 2-aminobenzylamines and benzylamine derivatives or

its N-substituted derivatives The reaction reacted under iodine catalysts in oxygen without

solvent and in the direction of not using transition metals (Scheme 1.11a) [65] After that,

these methods have been improved the drawbacks towards C–C bonds cleavage of aryl

methyl ketone derivatives which was more stable (Scheme 1.11b) [66] By 2018, From

,,-trihalotoluene derivatives in H2O, Chatterjee and co-workers explored a method of producing 2-arylquinazoline derivatives, only by-product was NaCl or NaBr However,

,,-trihalotoluene were commercially unavailable as a limitation of this method

(Scheme 1.11c) [23]

Scheme 1 11 Synthesis of quinazoline derivatives from 2-aminobenzylamines and equivalent derivatives of benzaldehyde without transition metal catalysts

Because 2-aminobenzylamine derivatives were low chemical stability, easy to be oxidized in oxygen to form imine selfcoupled – products hindering storing and refining materials In 2017, to modify the previous disadvantages, a synthetic method 2-arylquinazolines was developed by Parua and co–workers from 2-aminobenzyl alcohols

via using Ni catalyst system, which were cheaper than ruthernium and irridium (Scheme 1.12a) [56] However, in the same year of 2017, Yao’ Group found that the 2-

arylquinazoline products can be synthesized from 2-aminobenzyl alcohols and nitrile derivatives using CsOH.H2O base, given high performance without transition metal

catalysts (Scheme 1.12b) [61]

Scheme 1.12 Synthesis of quinazoline derivatives from 2-aminobenzyl alcohol derivatives

and benzonitriles

By using benzylamine derivatives, the method of synthesizing 2-arylquinazoline

derivatives from o-carbonylaniline or correlative alcohols was conducted in many studies

In 2017, Gopalaiah and co – workers used FeBr2 catalysts and oxygen in chlorobenzene solvents to synthesize 2-arylquinazoline derivatives from benzylamine derivatives

(scheme 1.13a) [66] In the research direction without using transition metals, the method

of synthesis 2-arylquinazoline from 2-aminobenzylamine derivatives using I2 was

developed by Yan and co – workers (scheme 1.13b) [63]

Scheme 1 13 Synthesis of quinazoline derivatives from benzylamine derivatives

In conclusion, 2-arylquinazoline derivatives can be easily generated by various methodologies However, these methods have their own drawbacks like using expensive transition metal catalyst and deriving from the aryl halide derivative with high toxic as well

as utilizing amidine derivatives which are very active agents In many recent years, synthetic method of quinazoline from nitro containing agents in the direct way as starting materials to the final products have also interested many researchers Quinazolines have experienced redox processes: reduction of aromatic nitro compouds to form aromatic amine frames, oxidation of condensed products to form quinazoline scaffolds

Scheme 1 14 General process to synthesize 2-arylquinazoline derivatives

In 2014, Wang and co – workers aggregated 2-arylquinazoline derivatives based on

hydrogen transfer reaction between (E)-2-nitrobenzaldehyde O-methyl oxime derivatives

and benzyl alcohols/benzylamines under Pd(OAc)2/dppf in anisole solvents (Scheme

1.15a) [64] Tang and co – workers in 2016 established a directly method to obtain

4-methyl-2-phenylquinazoline derivatives from o-nitroacetophenones and benzylamine

derivatives or DL--phenylglycines via hydrogen transfer on Pd/C catalysts in water

(Scheme 1.15b) [65] Although there were advantages such as high product efficiency,

repeated catalytic reuse, these methods are limited due to using expensive catalysts based

on Pd

Scheme 1 15 Synthesis of quinazolines towards hydrogen transfer strategy

1.3 Approaches organic synthesis using sulfur-mediated catalysts

In recent year, numerous excellent research has been investigated via a metal-catalyzed approach to form arylquinazolines structure; however, these reactions often require the use of metal catalysts, excess additives [67] Elemental sulfur is readily accessible as a stable solid, widely exists in nature, and due to its nontoxicity [68]

transition-In 2015, Guntreddi and co-workers developed the method which used a model reaction of o-chloronitrobenzene and phenylacetic acid in the presence of element sulfur, the study led to the formation of desired product 2-arylbenzothiazole in 75% isolated yield

(scheme 1.16) [67]

Scheme 1 16 Synthesis arylbenzothiazole derivatives by Guntreddi and co-workers

Elemental sulfur mediated was reacted in redox condensation of benzyl chlorides and o-chloronitrobenzenes for the synthesis of 2-substituted benzothiazoles under metal-

free condition, this research was proposed by Wang and co-worker in 2017(scheme 1.17a)

[69] In this year, Jing and co-workers introduced base-promoted sulfur-mediated in cyclization of proparginic amine as substrate with TFben (benzene-1,3,5-triyl triformate) and sulfur powder using DBU solvent at 350C, this reaction resulted 91% yield of cycling

product (scheme 1.17b) [70] At the same time, 2-substituted benzothiazoles were

developed by Wang’s group from o-idoaniline, arylacetic acid and elemental sulfur in the presence of Cu(OAc)2.H2O as catalyst and K2CO3 as base using DMSO solvent with high

yield (scheme 1.17c) [71] Moreover, Li and co-workers generated the same product from

2-aminobenzenethiol and arylacetylenes using elemental sulfur, DMF solvent in air, the

desired product could be established in 81% isolated yield (scheme 1.17d) [68]

Scheme 1 17 Using elemental sulfur in organic synthesis using sulfur-mediated catalyst

In 2018, Wang and co-workers reported the method using elemental sulfur in order

to converted amides from N-alkoxyamides in the presence of DABCO and DMSO with

excellent yield (scheme 1.18a) [72] In this year, methyl ketoximes and methyl

N-heteroarenes were utilized to synthesize bis-heteroanunulation by Huang and co-workers, this approach used CuBr as catalyst, base Cs2CO3, DMSO solvent and elemental sulfur

giving in a satisfactory yield (72%) (scheme 1.18b) [79] In addition,

imidazo[1,5-a]pyridiens were developed by Sheng and co-workers via elemental sulfur mediated, ethyl 2-(pyridi-2-yl)acetate and benzylamine like starting materials in DMSO with high yield

(scheme 1.18c) [73]

Scheme 1 18 Reactions using elemental sulfur

In 2019, Nguyen group synthesized hexaazatrinaphthylene derivatives from phenylenediamine and cyclohexanone in the presence of sulfur in DMSO and Bronsted acid (H+ cat), this desired product was delivered in high yield (scheme 1.19a) [74] At the

o-same time, Dibenzo[d,f][1,3]diazepines were introduced by Tikhonova group via using elemental sulfur-mediated, H2O solvent, Et3N base through cyclocondensation reaction of 2,2’-biphenyldiamines and 2-chloroacetic acid, this protocol presented that affordable

adapting to a large-scale synthesis and excellent yield (scheme 1.19b) [78] Addition, Xing

and co-worker published the strategy which was accomplished 2-substituted benzothiazole from the reaction between 1-methyl-4nitrobenzene and phenylmethanol in the presence of sulfur with FeCl3 as catalyst, additive NH4I, KHCO3 base and NMP solvent in 80% isolated

yield with high levels of regioselectivity (scheme 1.19c) [76]

Scheme 1 19 Reactions using elemental sulfur

In 2020, elemental sulfur was utilized in the reaction forming imidazoheterocycles from phenylimidazopyridine and N-methylaniline as starting substrates in DMSO by Gou

and co-workers, with 80% the isolated yield of product (scheme 1.20) [75]

Scheme 1 20 Using elemental sulfur in organic synthesis

1.4 The aim and objectives of our approach

Quinazoline scaffolds, especially 2-arylquinazoline derivatives have been studied

to play important role in many applications in biomedical engineering, pharmaceutical chemistry synthesis, agrochemical synthesis and material engineering As a result, quinazoline derivatives in general and 2-arylquinazolines in particular have been

synthesized by various methods However, most of these methods show numerous limitations about using unavailable, unstable, expensive and highly toxic reactants causing environmental damage or using transition metal For these reasons, it is necessary to report

a new method to synthesize quinazoline derivatives utilizing available materials such as elemental sulfur, 2-nitrobenyzyl alcohol and phenylacetic acid

1.5 The synthesis of quinazolinones

1.5.1 The C2 activation and Csp2 –N coupling reaction in organic synthesis

N-containing organic structure frequently present in natural products, pharmaceuticals, bioactive molecules and other important materials [77] Developing many approaches in order to synthesize these units which paid attention of numerous researchers As a result, C–H bond activation reaction to form C–N bond through transition-metal-catalyzed had become essential producing N–containing compounds method [78]

In 2013, Liu’s group have reported the reaction C–N heteroarylation of pyridines in the presence of transition metal-catalyzed Pd(OAc)2, ligand and AgOAc as the oxidant; the cross-coupling transformation afforded moderate to good yield with different functional

groups (scheme 1.21a) [77] At the same year, imidazo[1,2-a]pyridines coumpounds were

synthesized from pyridines and acetophenone oxime acetate through oxidative coupling the C–N bond by Huang and co-workers, with CuI as the catalyst, Li2CO3 and DMF solvent

with high yield (scheme 1.21b) [78] In this direction, Singh’ group had successfully

developed an efficient cross-coupling reaction arylation of various heteroarenes via functionalization of C(sp2)–H using iron-catalyzed, oxidant agents at room temperature

(scheme 1.21c) [80] Moreover, pyridines derivatives were generated through

dehydrogenative cross-coupling reactions between a sp2 C–H bond of pyridine and C–H bond of ether under the Sc(OTf)3 catalyst and DTBP oxidant by Salman and co-workers

(scheme 1.21d) [81]

Scheme 1.21 C-H coupling reaction were reported using transition metal catalyst

In 2014, Zhu and co-workers have given the method condensation of quinoline N –oxide and piperidine via direct C–N bond amination by using CuI catalyst, toluene, under

air with high yield (scheme 1.22a) [82] Besides, the alkylation of heterocycles between

isoquinoline and aliphatic aldehydes were explored by Tang’ group in 2015, the direct heterocyclic C(sp)2 –H bond activation was observed to form product under the TBP

oxidant agents, solvent in medium yield (scheme 1.22b) [83] At that time, the

cross-dehydrogenative C–N bond formation between quinoline and 1H-benzo[d][1,2,3]triazole was represented by Sun’ group using copper-catalyzed, selectflour oxidants, K2CO3 base and CH3NO2 solvent successfully given various derivatives (scheme 1.22c) [84]

Scheme 1.22 C2 activation reaction of quinoline structures in organic synthesis

In 2016, Ruch and co-workers have shown the arylation of pyrimidines via C–C bond formation process involving C–X functional activation of heteroarenes; this reaction was carried out by using acetonitriles as solvent, K2CO3 base and UV irradiation with good

yield (scheme 1.23a) [85] At the same year, cross-dehydrogenative coupling reaction of

pyridines and benzoxazoles were represented by Yamada’s group, C–H bond formation of two heterocyclic have been successful in this reaction with using palladium acetate catalyst

and oxidant agents (scheme 1.23b) [86]

Scheme 1.23 Coupling reaction via C –H activation

In 2017, the C–H arylation coupling reaction between thiazole and aryl diazonium

were reported by Ahmed’s group, through arylation at the C2 position of thiazole process

and under 1,10-phenanthroline ligand, base KOtBu and DMSO solvent with various

derivatives (scheme 1.24a) [87] Moreover, Zeng and co-workers have demonstrated the

direct C –H arylation of pyridine using the transition-metal-catalyzed; The main product

2,6-diarylpyridines were successfully identified by the reaction between pyridine and

1-bromo-4-methylbenzene in the presence of Pd catalyzed, K2CO3 base and DMAc solvent

with high yield (scheme 1.24b) [88] At the same time, Inturi’ group have published

method synthesis 4,3-fused 1,2,4-triazoles via one-pot multicomponent domino reaction of

pyridine, benzaldehyde and p-Toluensulfonhydrazide in oxidant condition, the main

product as well as various derivatives were generated with excellent yield (scheme 1.24c)

[89] In this year, the regioselective arylamination of heterocyclic N–oxides were carried

out by Biswas and co-workers with using CuI catalyst in 1,4-dioxane (scheme 1.24d) [90]

Scheme 1.24 C 2 selective and C –N bond formation reaction in 2017

The C–H functionalization reaction of uncativated arenes to gain biaryl product

were developed by Ahmad’s group in 2018, with high yield (scheme 1.25a) [91] At that

time, the C–C cross coupling reaction between 2-iodothiophene and benzene in the presence of KOtBu and ligand were proposed by Banik’s group (scheme 1.25b) [92]

Besides, the desired product 2-(1H-benzo[d][1,2,3]triazol-1-yl)quinoline and derivatives were synthesized from quinoline and 1H-benzotriazole as the nucleophilic reagent in MeCN solvent by Xie’s group, this reaction was shown in functionalization of C2

activation of N–heterocycles under metal and base-free conditions (scheme 1.25c) [93] In

2019, N-fused imidazo 6,11-dihydro β-carboline derivatives were generated by Satyam and co-workers, using H2O solvent at room temperature with high yield and various

derivatives (scheme 1.25d) [94]

Scheme 1.25 C2 activation and Csp 2 –N coupling reaction

1.5.2 Advanced in the synthesis of quinazolinones

Nitrogen–containing compounds play essential role in many fields, especially theses structure like quinazolinone derivatives founding in many natural products and pharmaceutical drugs So, the development of efficient methodology for synthetic quinazolinone scaffolds has become interest issue In 2006, F Pellón and co-workers have reported a route to synthesize 11H-pyrido[2,1-b]quinazoline-11-one through the Ullmann condensation of 2-chlorobenzoic acid and 2-aminopyridine using DMF solvent, with high

yield (scheme 1.26a) [95] After that, various protocols have been published for synthesis

of quinazolinones as well as its derivatives, in 2011, quinazolinone scaffold were generated

by Maity’s group via condensation of 2-aminopyridine and 0-bromobenzyl bromide in DMF solvent, CuI catalyst and K2CO3 base; this reaction was successful in different

substituted products in excellent yields (scheme 1.26b) [96]

Scheme 1 26 The reaction synthesis of quinazolinone using Copper catalyst

In 2013, acridin-9(10H)-one were synthesized from (phenylamino)phenyl]ethanone by Yu and co-workers; A efficient copper-catalyzed aerobic oxidative C–H and C–C functionalization process has been publish to form

1-[2-acridone derivatives, with high yield (scheme 1.27a) [97] After one year, Chen’s Group

have proposed a new method to form fused quinazolinone scaffolds via catalyzed carbonylative coupling reaction, successfully generating different kinds of 2-

palladium-aminopyridines and 2-bromoflourobenzene substituents (scheme 1.27b) [98] At that time,

approach synthesis of 11H-pyrido[2,1-b]quinazolin-11-one also were reported by Liang’s

Group through palladium-catalyzed C–H pyridocarbonylation of N-aryl-2aminopyridines

(scheme 1.27c) [99] In 2014, the main product

6-methyl-11H-pyrido[2,1-b]quinazolin-11-one were resulted by Sun and co-workers, a direct method for the domino reaction were

developed via copper-catalyzed tandem aerobic oxidative annulation from

2-(2-bromophenyl)-N-(3-methylpyridin-2-yl)acetamide that the use of CuI catalyst and

1,10-phen as catalyst, KOAC as base, TBAB as additive in DMF solvent, given high yield of

quinazolinone derivatives (scheme 1.27d) [100]

Scheme 1 27 The synthesis reaction of quinazolinone through transition metal catalyst

In 2015, Chen’s Group have investigated the protocol for the synthesis of

11H-pyrido[2,1-b]quinazolin-11-ones by the carbonylation of N-phenylpyridin-2amine with

DMF using Pd(OAc)2, K2S2O8 as oxidant with HOAc as co-solvent (scheme 1.28a) [101]

In the same year, the synthetic method of fused azoacridone derivatives were represented

by Li’s Group followed via substitution reaction between anthranilic acid and

2,4-dichloropyrimidines in POCl3 solvent with various given derivatives (scheme 1.28b)

[102] Besides, the main product 11H-pyrido[2,1-b]quinazolin-11-one were gained through direct functionalization of the C–H bond by Chen and co-workers in 2015, using Pd/C-catalyzed carbonylation cyclization reaction of N-arylpyridin-2-amine derivatives

(scheme 1.28c) [103]

Scheme 1.28 Synthesizing of quinazolinone derivatives by Pd-catalyst

In 2016, Yang and co-workers have reported the method to produce pyridoquinazolone scaffolds through condensation reaction of pyridines and anthranilic

acids with good yields (scheme 1.29a) [104] At that time, the main product

11H-pyrido[2,1-b]quinazolin-11-one were synthesized by Liu’s Group via the reaction between isatin and 2-bromopyridine, using Cu(OAc)2.H2O as catalyst, NaHCO3 as base, DMF as

solvent in generally numerous substituents (scheme 1.29b) [105] Moreover, Rao and

co-workers have investigated the direct carbonylation to generate pyrido-Fused Quinazolinones from the N-phenylpyridin-2-amine in DMF using Palladium/silver

bimetallic catalysis under oxygen environment (scheme 1.29c) [106] In 2017, the new

method to synthesize tetrahydro-5h-isoquinolino[2,1-g][1,6]naphthyridine structure was represented by Li’s Group; An efficient Lewis acid-catalyzed C –C bond formation was successfully investigated between 2-methylquinoline-3-carbaldehyde and 1,2,3,4-