LITERATURE REVIEW
Introduction
Over the years, heterocyclic chemistry, especially quinazoline or quinazolinone frameworks are nitrogen heterocycles compounds which have been considerable attention in organic synthesis and pharmaceutical chemistry Nowadays, many studies of synthesizing quinazoline and quinazolinone derivatives in general and 2 – arylquinazoline derivatives in particular have been published; some of which have been patented with wide applicability, high efficiency and diversity of product structures [1]
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.
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,
5 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 120 o C
(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 2- 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)
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]
7 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
8 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 60 o C 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 o C 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
10 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 CuCl/DABCO/4-OH-TEMPO catalytic system in oxygen environment and acetonitrile solvent at 80 o C, after reacting for 2 hours that developed 2-arylquinazoline from 2-aminobenzyl amine and benzadehyde (Scheme 1.8a) [62] By 2017, N-oxyl radical ABNO in oxygen as catalysts was found for oxidation condition synthesizing quinazoline derivatives from 2- aminobenzylamines and correlative aldehyde derivatives by Ma’ Group This method was 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
Approaches organic synthesis using sulfur-mediated catalysts
In recent year, numerous excellent research has been investigated via a transition- 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]
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 35 0 C, 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 o- 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 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.
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
21 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.
The synthesis of quinazolinones
1.5.1 The C 2 activation and Csp 2 –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(sp 2 )–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 sp 2 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 KO t Bu 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 KO t Bu 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 1-[2-(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 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 palladium- catalyzed carbonylative coupling reaction, successfully generating different kinds of 2- 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
27 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)
28 [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-
29 tetrahrydroisoquinoline giving different substituents in excellent yield (scheme 1.29d) [107]
Scheme 1 29 The synthesis reaction of quinazolinone
Pyrido-Fused quinazolinone derivatives were generated through the amination and annulation reaction of arenes with 2- aminopyridines by Liu and co-workers through using Cu(OAc)2 catalyst in DMSO solvent with numerous substituents (scheme 1.30a) [108] At that time, a research from Xie’s Group were published that 1,2,3,4-tetrahydroisoquinoline and 2-aminobenzyl alcohol were reacted to form quinazolinones scaffold in the presence of Co-catalyst, molecular O2 and 4-nitrobenzoic acid as the additive in p-xylene solvent (scheme 1.30b) [109] In 2019, according to Arachchige’s Group, quinazoline and quinazolinone derivatives were successfully resulted from the coupling reaction of 2- aminophenyl ketones and 2-aminobenzamides with amines, via ligand-promoted, ruthenium-catalyzed in 1,4-dioxane (scheme 1.30c) [110] At the same year, Quinazolinones were obtained from oxidative cyclization reaction of 2-aminobenzamide, Xie’s Group had utilized (NH4)2S2O8 as the oxidant in DMSO solvent with different substituents (scheme 1.30d) [111]
Scheme 1 30 The reaction of synthesis quinazolinone derivatives.
Our approach
The synthesis of quinazolinones scaffold has attreacted numerous interest for both organic chemistry and pharmaceutical area As a result, synthesizing quinazolinone derivatives have been attracted from many researchers However, a lot of methods in the past have shown numerous limitations in using unavailable and unstable and highly toxic reactants causing environmental damage as well as harsh conditions To resolve this problem, our group reported a method to form quinazolinone derivatives from available materials and using copper –catalyzed reaction
EXPERIMETAL
Materials and instrumentals
All reagents and starting materials were obtained commercially from supplier (Sigma–Aldrich, Across, and Merck) without any further purification unless otherwise noted Besides, the derivatives of 2-nitrobenzyl alcohol and phenylacetic acid were used in the reaction to form 2-aryl- quinazoline derivatives which were synthesized by our research team
Gas chromatographic analyses (GC) were performed using a Shimadzu GC 2010Plus equipped with flame ionization detector (FID) and an SPB–5 column (length 30 m, inner diameter = 0.25 mm, film thickness = 0.25 m) The temperature program for
GC analysis: held samples at 100 o C for 1 minutes then heated sample from 100 to 280 o C at 40 o C/min and finally held them at 280 o C for 4.5 minutes Nitrogen was used as carrier gas and its inlet pressure was set constantly at 147 kPa Inlet and detector temperatures were set constantly at 280 o C Biphenyl was used as an internal standard to calculate reaction yield
GS–MS analyses were performed on a Shimadzu GCMS–QP2010Ultra with a ZB– 5MS column (length = 30 m, inner diameter = 0.25 mm, film thickness = 0.25 m) and using He as carrier gas The temperature program for GC–MS analysis held samples at
50 o C for 2 min; heated samples from 50 to 280 o C at 10 o C/min and held them at 280 o C for
10 mins Inlet temperature was set constantly at 280 o C MS spectra was compared with the spectra gathered in the NIST library
Nuclear magnetic resonance (NMR) spectra ( 1 H and 13 C) were recorded on a Bruker
AV 500 spectrometer using residual solvent peaks as references at Faculty of Chemistry – University of Science – Hanoi National University
Reaction procedure for synthesis quinazolines derivatives 32 1 The general procedure for quinazoline derivatives synthesis reaction 32
2.2.1 The general procedure for quinazoline derivatives synthesis reaction
To a dry 4-mL vial containing a magnetic stirring bar was added 2-nitrobenzyl alcohol (15.3 mg, 0.1 mmol), phenylacetic acid (40.8 mg, 0.3 mmol), DABCO (33.6 mg, 0.25 mmol), urea (18 mg, 0.3 mmol), S catalyst (9.6 mg, 0.3 mmol), DMSO solvent (0.3 ml) and biphenyl (15.4 mg, 0.1 mmol) as an internal standard The reaction tube was then tightly capped and stirred at 140 o C for 2 hours After the reaction was completed, the reaction tube was cooled to room temperature, quenched with brine and organic components were then extracted into ethyl acetate (3×1 mL), washed with saturated aqueous NaHCO3 solution (1 mL), dried over anhydrous Na2SO4 and the sample was analysed using GC with reference to biphenyl The GC yield of main product 2- phenylquinazolines after reaction was calculated based on the calibration curve from the
Scheme 2 1 General procedure of synthesis quinazolines
Table 2 1 List of substances and vendors
2-nitrobenzyl alcohol (97%) C7H7NO3 Acros biphenyl C12H10 Acros
Phenylacetic aicd (95%) C8H8O2 Sigma – Aldrich urea (NH2)2CO Xilong Chemical
Dimethyl sufoxide (CH3)2SO Merck ethyl acetate C4H8O2 Chemsol VN
To isolate the products, a typical reaction was carried out After completion of the reaction, the mixture was cooled to room temperature The organic components were then extracted into ethyl acetate (3×2 mL), washed with NaHCO3 solution (10% in water, 3x1 mL) and dried over anhydrous Na2SO4 The combined organic extracts were concentrated in vacuo and purified by column chromatography on silica gel with hexane/ethyl acetate
(ethyl acetate/hexane = 1:5 to 1:2) solvent system to afford the product 2- phenylquinazoline (17.9 mg, 89%) as yellowish crystals The product identity was further determined by GC-MS, 1 H-NMR and 13 C-NMR spectra
2.2.3 Gram-scale reaction for quinazoline
To demonstrate the practical application of synthetic method 2-aryl quinazoline derivatives (gram-scale), the experiment was conducted through following conditions: the mixture of 2-nitrobenzyl alcohol (0.61g, 4 mmol), phenylacetic acid (1.36 g, 10 mmol), DABCO (1.12 g, 10 mmol), urea (0.72 g, 12 mmol), DMSO solvent (12 ml) added into a flask 25 mL containing S catalyst (0.32g, 10 mmol) The reaction was carried out at 140 0 C in an oil bath for 2 hours and was monitored by TLC At the end of the reaction, the flask
34 was cooled to room temperature, DMSO solvent were added into mixture in order to dissolve all the organic compounds The mixture was extracted with ethyl acetate and saturated solution NaCl (10 mL) The organic phase is dried over anhydrous with Na2SO4, then removing solvent and the product was recrystallization in acetone solvent.
Reaction procedure of reaction forming quinazolinones
2.3.1 The general procedure for synthesis of quinazolinones derivatives
To a 12-mL screw-cap vial was added isoquinoline (0.3 mmol, 3.0 equiv.), CuCl2
(20 mol%), TsOH.H2O (20 mol%) and DMF (1.5 mL) The reaction tube was flushed with
O2, tightly capped and stirred at room temperature for 10 min Then, 2-aminobenzyl alcohol (0.1 mmol, 1.0 equiv.) was added in three portions and the resulting mixture was stirred at 100 0 C for 12 h Upon completion of the reaction, the mixture was cooled to room temperature and diphenyl ether (17.2 mg, 0.1 mmol) as an internal standard was added The organic components were then extracted into ethyl acetate (2.0 mL), washed with NaHCO3 solution (5% in water, 1.0 mL) and brine (1.0 mL), dried over anhydrous Na2SO4 and analyzed by GC with reference to diphenyl ether To isolate the corresponding product, the combined organic extracts were concentrated in vacuo and purified by column chromatography on silica gel with n-hexane/ethyl acetate solvent system to give pure product The product identity was further confirmed by GC-MS, 1 H NMR and 13 C NMR
Scheme 2 2 General procedure of synthesis quinazolinones
To isolate the quinazolinone products, a typical reaction was carried out After completion of the reaction, the mixture was cooled to room temperature The organic
35 components were then extracted into ethyl acetate (3×2 mL), washed with NaHCO3 solution (10% in water, 3x1 mL) and dried over anhydrous Na2SO4 The combined organic extracts were concentrated in vacuo and purified by column chromatography on silica gel with hexane/ethyl acetate (ethyl acetate/hexane = 1:5 to 1:2) solvent system to afford the product quinazolinones (19.9 mg, 81%) and quinazolinones as yellowish crystals The product identity was further determined by GC-MS, 1 H-NMR and 13 C-NMR spectra
RESULTS AND DISCUSSION
Studies of reaction conditions of quinazolines
Elemental sulfur mediated were used for the model reaction between 2-nitrobenzyl alcohol (1a) and phenylacetic acid (2a) to generate 2-phenylquinazoline (3aa) as main product Initial investigations revealed that the domino reaction between 2-nitrobenzyl alcohol and phenylacetic acid produced the major product 3aa in the presence of S8, DABCO as base, urea additives under DMSO solvent (scheme 3.1) The final conditions of the reaction are investigated through alternating each factor, including: reaction temperature, catalyst and amount of them, type of base agent and amount of base agent, type of solvent or amount of solvent, reaction time The application of reaction is also expanding on various derivatives of phenylacetic acid (2a) and 2-nitrobenzyl alcohol (1a) The detail data of experiment are shown in Appendix 5
Scheme 3 1 Reaction model to investigate synthesis of quinazoline
3.1.1 Effect of temperature on reaction synthesis of quinazolines
The temperature is the important factor to be investigated because it is directly related thermodynamic factor of reaction Based on previous studies, temperature factor was studied from 80 0 C to 140 0 C in 2 hours The reaction used 0.1 mmol agent with 1a: 2a molar ratio of 1: 3, 2.5 equivalent of elemental sulfur, 2.5 equivalent of DABCO and 3 equivalent of urea additives in DMSO solvent
Scheme 3 2 Investigation of the temperature on reaction
Table 3 1 Melting temperature of some agents used in the reaction
The result illustrated that, as anticipated, increasing the reaction temperature led to significant improvement in the yield of the expected product At 80 0 C, the performance of
3aa products was less than 10% after 12 hours When the temperature rose up to 110 0 C, the reaction efficiency increased by 20% and reached 60% at 120 0 C If the reaction temperature was 140 0 C, best result was achieved for the reaction with 71% yield 3aa being obtained after 4h This can be explained by the low temperature, the solids did not melt, so the phase difficultly contacted, affecting process the transfer chemical reaction was like not take place To save energy, the reaction temperature was kept at 140 0 C for further investigation
Figure 3 1 Effect of base on reaction synthesis of quinazolines
According to a study of Nguyen et al 2014 reported the condensation reaction between 2-nitroaniline derivatives and phenylacetic acid, the base agents were greatly influenced on the condensation reaction [112] Therefore, the different kinds of base were the next factor to be investigated The reaction used 0.1 mmol agent with 1a: 2a molar ratio of 1: 3, 2.5 equivalent of elemental sulfur, 2.5 equivalent of DABCO and 3 equivalent of urea additives in DMSO solvent The detail data of experiment are shown in Appendix 5
Scheme 3 3 Investigation of base on reaction
Figure 3 2 The yield of main product in various kinds of base
The survey of Nguyen et al or Guntreddi et al, the strength and boiling temperature of the base have key role in the reaction [67,112] Experimental results have shown that the tertiary amine or amidine such as [DBUH]OAc gived better yield than primary amine and secondary amine; pyridine and other related base agents such as 2-aminopyridine or morpholine exhibited very poor reactivity According to previous studies, the elimination process of acid carboxyl group usually happened in the form of carboxylate, so the base agent needed to have sufficient strength to completely separate the carboxylic acid proton [60,67,120] Besides, boiling temperature was also essential factor that directly affected the activity of base types Due to the reaction performed under stirring at high temperatures and evaporate partially, so these agents may show poor activity in the reaction For the case of using the DBU base, although this was a very strong organic base; However, with low boiling point, only about 80 0 C, DBU illustrated only about 9% yield of product Similarly, ionic liquid [DBUH]OAc had the same activity as DBU but melting point temperature was slightly higher (180 0 C in a vacuum), so the yield of 3aa product was 30%
In addition, some inorganic bases such as Li2CO3, K2CO3 and NaOAc were also studied in reaction Only NaOAc agent produced less than 30% 3aa products, with the other base agents, 3aa products were only recognized 10% Among all the base agents,
DABCO has been demonstrated as the base agent for the most efficient, thanks to their superiority in performance of the main product In addition, the use of DABCO was more economical than other similar activity organic bases such as N,N’-dimethylpiperazine; or ionic liquid [DBUH]OAc, but they was very high cost
Figure 3 3 The effect of DABCO on the reaction
The effect of DABCO was the next parameter to be investigated on the process, the reactions were conducted at 120 0 C for 12 hours; use molar ratio 1a: 2a corresponding to 1: 3; DABCO was studied at 0.5 eqv, 1 eqv, 1.5 eqv, 2 eqv, 2.5 eqv, 3 eqv in the presence of 3 equivalent S8, 2.5 equivalent of urea in DMSO solvent
The Figure 3.3 showed that bases had a significant impact on the yield of synthesizing quinazoline The yield of 3aa product was 24% when using 0.5 equivalent
0.5 eqv 1 eqv 1.5 eqv 2 eqv 2.5 eqv 3 eqv
41 DABCO When DABCO was increased to 2.5 equivalents, the GC yield of the product reached 70% However, this yield slightly decreased when DABCO rose up to 3 equivalents This may be because when the amount of base was too high, the proton transported to the nitro group while the reduction process was unfavorable [120] In addition, the presence of a large amount of amine with a strong nucleotide like DABCO may cause the Lewis acid centers in the catalyst that was inactivated as a result the connection between the substance and the catalyst in the system might reduce [113,114] Totally, the amount of DABCO will be used at 2.5 equivalent in the next investigation
3.1.2 Effect of nitrogen sources on reaction synthesis of quinazolines
Nitrogen source was the next factor to be investigated at 120 0 C for 2 hours; using molar ratio 1a: 2a corresponding to 1: 3; many nitrogen sources was used in the reaction such as NH4OAc, NH4HCO3, NH3 of 30% and urea in the presence of 3 equivalent S8, 5 equivalent of urea in DMSO solvent The result was represented in Figure 3.4
Scheme 3 4 Investigation of additives on reaction
Figure 3 4 The effect of different kinds of nitrogen source on reaction
According to the results, it can be predicted that a certain amount of ammonia can be added to the system to create a balanced shift in the direction of the formation of product Some nitro sources such as NH4OAc, NH4HCO3, NH3 solution in water (25-30%), urea which were added to the system with the content of 0.5 mmol Finally, our group selected urea additives agent in study reaction conditions
NH4OAc NH4HCO3 30% aq NH3 urea No nitrogen source
Figure 3 5 Effect of urea amount on the yield of product
The effect of urea amount was observed at 140 0 C for 4h; with molar ratio 1a: 2a corresponding to 1: 3; in the presence of S8, 2.5 equivalents of DABCO under DMSO solvent When the urea amount increased from 0.5 to 3 equivalents, the yield of the main reaction tended to increase (Figure 3.5) The amount of urea over 3 equivalents did not increase the performance, so 3 equivalent urea was the best choice in next investigation
3.1.3 Effect of the ratio of reactants on reaction
In previous redox systems, reducing agents of nitro groups were often excessively used in the redox reaction For the reducing cyclization of the o-nitroacetophenone derivatives and aldehyde derivatives, Yu and co-workers used 3.0 equivalents of H3NBH3 on Ni/ Pd catalysts [115]; Wang and co-workers synthesized quinazoline derivatives from (E)-2- nitrobenzaldehyde O-methyl oxime with 3.0 equivalents of reducing agent as alcohol or benzylamine on Pd/ dppf catalyst [64] The effect of molar ratio of reactants was performed at 140 0 C for 2 hours; in the presence of S8, DABCO 2.5 equivalent, 3 equivalent of urea under DMSO solvent (Figure 3.6)
0.5 eqv 1 eqv 2 eqv 3 eqv 4 eqv 5 eqv 6 eqv 8 eqv
Figure 3 6 Effect of different molar ratio of starting reactants
In terms of the economic area, the use of 1a as a limiting agent will be more beneficial, since 1a was a much higher cost than 2a; Moreover, when the molar ratio of phenylacetic acid 2a was increased to 2.5 equivalent, the performance lifted from 40% to 67% Thus, the final molar ratio of 1a: 2a was selected being 1: 2.5 and this ratio also demonstrated the effective elemental sulfur
3.1.4 Effect of the amount of elemental sulfur on reaction
According to a study on nitro-oxidation reactions using Fe/ S catalysts, Nguyen group suggested a mixture of Fe (10 mol%) and S (10 mol%) for oxygen condensation reaction between 2-nitroaniline or 2-nitrophenol derivatives and methyl hetarene derivatives [116]; while a mixture of FeCl2.4H2O (5 mol%) and S (40 mol%) were used as a catalyst for condensation and decarboxylate between 2-nitroaniline derivatives and arylacetic acid in order to synthesize benzimidazole derivatives [115]; or a mixture of FeCl3.6H2O (5 mol%) and S (20 mol%) was utilized for the condensation reaction between 2-nitroaniline and phenethylamine derivatives [117] Thus, it was necessary to investigate the suitable amount of sulfur for the reaction between 1a and 2a
Figure 3 7 The effect of amount of elemental sulfur on yield of product
Effect of different substituents of the reaction
The application of synthesizing different 2-phenylquinazoline derivatives, the reaction system was aimed to investigate variety of different substituents of 2-nitrobenzyl alcohol and phenylacetic acid with the reaction conditions described in Table 3.2 The reaction between 2-nitrobenzyl alcohol (1a) and different phenylacetic acid derivatives in order to formed 2-phenylquinazoline derivatives with isolated yield ranging from 47% to 89%
In general, common functionalities were tolerated under the reaction conditions the quinazoline derivatives were gained with either electron-rich (3ab-ad and 3ai) or electron- deficient arylacetic acids (3aj) that giving good performance Coupling reaction between 2-nitrobenzyl alcohol and halogenated phenylacetic acid that may incompatible with elemental sulfur-mediated [67], so the yield of products (3af-ag) are slightly increase However, the reaction between 1-naphthylacetic acid reacted and 2-nitrobenzyl alcohol,
48 which achieved the quinazoline product (3ak) in 70% yield Thiophene-derived quinazolines 3al and 3am and the indole-derived quinazoline 3aq were developed through nearly unchanging the reaction conditions, so the compatibility of heterocycles was proved in this reaction
Especially, this reaction was scale-up to 4 mmol, without the significant changing in yield Besides, our strategy still depicted some limitation The substrate contained a nitro, hydroxy or unprotected indole functionality which were not suitable for this reaction The desired product also did not find in the synthesis reaction of cinnamic acid derivatives and aliphatic carboxylic acids
Table 3 2 Synthesis of 2-arylquinazoline derivatives from different substituents of phenylacetic acid derivatives and 2-nitrobenzyl alcohol
Entry Reactant 1 Reactant 2 Product Yield b
71 a Reaction condition: 2-nitrobenzyl alcohol (0.1 mmol, 1 equivalent); phenylacetic acid derivatives (0.3 mmol, 3 equivalent); DABCO (0.25 mmol, 2.5 equivalent); urea (0.3 mmol, 3 equivalent); sulfur (3 mmol); DMSO solvent; 140 0 C, 4 hours b Isolated yield by column chromatography on silica gel c Reaction time: 4h
The scope of the 2-nitrobenzyl alcohol was next studied (Table 3.3) The coupling reaction between aryl(2-nitrophenyl)methanols and phenylacetic acid was successful with good yield of quinazolines 3ba and 3bg Howerver, 1-(2-Nitrophenyl)ethanol gave smaller
51 amount of the quinazoline with 13% of isolated yield product 3ca Reactions of substituted 2-nitrobenzyl alcohols were also attempted Dimethoxy and methylenedioxy derivatives showed moderate to good yields of the quinazolines 3da and 3ea, at 67% and 42 %, respectively Coupling reaction of 3-chloro-2-nitrobenzyl alcohol gave a complex mixture and with nearly no having quinazoline product Besides, expanding the reaction scope with respect to the 2-nitrobenzyl alcohol are developing with 2-picoline and 4-picoline reactants
Table 3 3 Synthesis of 2-arylquinazoline derivatives from different substituents of 2- nitrobenzyl alcohol and phenylacetic acid
Entry Reactant 1 Reactant 2 Product Yield b
42 a Reaction condition: DMSO solvent, 140 0 C, 4h; 2-nitrobenzyl alcohol derivatives (0.1 mmol, 1 equiv.); arylacetic acid derivatives (0.3 mmol, 3 equiv.); DABCO (0.25 mmol, 2.5 equiv.); urea (0.3 mmol, 3 equiv.); sulfur (0.3 mmol, 3 equiv) b Isolated yield by chromatography on silica gel
We next paid attention to the condensation of various benzylic synthons (Table 3.4) When esters of phenylacetic acids were used, the reaction proceeded much more slowly than that of phenylacetic acid (Table 3.4, entries 1 and 2) Because a relatively high yield of 3aa was obtained by the reaction of phenylglyoxylic acid, this compound might be a key intermediate for the transformation (entry 3) Benzaldehyde coupled with 2- nitrobenzyl alcohol to afford 3aa in 64% yield (entry 4) Other compounds with unsubstituted C–H bonds gave 3aa in low yields, presumably due to oxidation problem
(entries 5–7) Notably, the activated sp 3 C–H bonds in 2-picolines or their isosteres were inert under our conditions
Table 3 4 Study of benzyl coupling partner a
Entry Benzylic coupling partner Yield of 3aa (%)
7 Mandelic acid 35 a 1a (0.1 mmol), benzylic coupling partner (0.25 mmol), sulfur (0.25 mmol, 32 g/mol), DABCO (0.25 mmol), urea (0.3 mmol), DMSO (0.3 mL), 140 °C, 2 h.
Control experiments and proposed mechanism
Firstly, the reaction between 2-nitrobenzyl alcohol (1a) and phenylacetic acid (2a), in the presence of urea generated 2-phenylquinazoline product (3aa) A summary of the results of our extensive screening test of the reactions conditions was presented in Table
3.5 From some previous reports, the use of an excess of elemental sulfur was required to attain a reasonable yield of 3aa (Table 3.5, entry 1) However, there was not dramatically change the yield when using of more than 3 equivalents of sulfur (entry 2) With utilizing of one equivalent of elemental sulfur, 38% yield of the quinazoline 3aa was obtained (entry 3) Omission of elemental sulfur observed no product (entry 4) With various nitrogen source, urea shown the best performance comparision to ammonium salts such as NH4OAc or NH4HCO3 (entries 5 and 6) Some common solvents like DMF and 1,4-dioxane gave the product in lower yields than that obtained in DMSO (entries 7 and 8) This observation was also approriated with that reported by Nguyen and co-workers If N-methylpiperidine was used as the base, a 40% yield of 3aa was obtained (entry 9) Moreover, the use of a catalytic mixture of iron and a group VI element such as sulfur or selenium afforded 3aa in moderate yields (entries 10 and 11) Reactions at temperatures below 140 0 C delivered significantly lower yields of 3aa (entries 12 and 13) When the reaction was investigated under an oxygen atmosphere, the quinazoline 3aa was represented in 73% yield (entry 13) Notably, the reaction could be reacted under air without a significant loss of yield (entry 14)
Table 3 5 Reaction conditions and control experiments
(equiv./mol%) Base (equiv.) Additive
12 FeCl 3 (20 mol%) DABCO (2.5 ) Urea (3) DMSO 14
56 aStandard reaction conditions: 2-nitrobenzyl alcohol (1a, 0.1 mmol), phenylacetic acid (2a, 0.25 mmol), sulfur (0.3 mmol, 32 g/mol), DABCO (0.25 mmol), urea (0.3 mmol), DMSO (0.5 mL), 140 °C, 4 h, under argon Yields by GC with diphenyl ether as internal standard
(1) TEMPO (1 equiv): 37% aYields were determined by GC analysis with diphenyl ether as internal standard
To understand the mechanism, from the scheme 3.5 we carried out some test experiments When the reaction between 2-nitrobenzyl alcohol and phenylacetic acid in standard conditions and TEMPO; the formation of quinazoline might involve a radical transformation because the yield of the quinazoline 3aa dramatically decreased when using the radical quencher TEMPO (Scheme 3.5, eq 1) When thiobenzaldehyde was utilized, the yield of 3aa resulted in 71% yield (Scheme 3.5, eq 2) with the presence of phenylacetic acid and elemental sulfur Moreover, the reaction of 2-nitrobenzaldehyde and 2a afforded quinazoline 3aa in 78% yield (Scheme 3.5, eq 3), confirming the presence of thiobenzadehyde and 2-nitrobenzaldehyde intermediate during the course of the reaction When 2-nitrobenzylamine was used as a substrate, the product 3aa was observed in 57% yield without an addition of urea (Scheme 3.5, eq 4), the reason may be slower oxidation of the C–N bond Besides, the precursors from reduction of the nitro group of 1a also reacted with phenylacetic acid (2a) The reaction of 2-aminobenzyl alcohol gave 3aa in 81% yield (Scheme 3.5, eq 5), whereas the use of the (2-nitrosophenyl)methanol intermediate afforded quinazoline 3aa in 65% yield (Scheme 3.5, eq 6)
Based on the above results and previous studies [74,120], a possible mechanism is proposed (Scheme 3.6) Initially, DABCO base and elemental sulfur complexation converted an active sulfur species that then combined with a phenylacetate anion from 2a to gain a benzyl polysulfide [74] In the presence of the DABCO–sulfur complex, this adduct was decomposed to form thiobenzaldehyde (4) or experienced single-electronbased fragmentation in order to afford benzylic radical (9) Besides, 2-nitrobenzyl alcohol (1a) undergone the process to generate 2- nitrosobenzaldehyde (10) The condensation of (10) and NH3 from urea that continuously followed by addition route to the benzyl radical (9) and dehydration resulted the bisimine (13) A nonradical pathway mightnot be completely ruled out, the reason is that when addition of a radical quencher such as TEMPO in this reaction still gave a small amount of 3aa The intermediate (7) might attain when reduction
59 of 1a which could go through an imine condensation and oxidation to furnish (13)
Electrocyclization of (13) followed by oxidation gives the desired quinazoline 3aa From the optimization results suggested that the combination of elemental sulfur and DMSO solvent accounts for the successful oxidation.
2 Synthesis of substituted derivatives of 2,4-disubstituted quinazoline
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]
7 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.
3 Synthesis of 2-(1H-indol-1-yl)quinazoline derivatives via Buchwald-
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).
4 Aggregation of carbazole – quinazoline by Ullmann – Goldberg using
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
8 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 60 o C 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]
5 Synthesis of quinazoline derivatives via Ullmann-Goldberg coupling
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 o C using Cu2O catalyst in 40 hours (Scheme 1.6) [49].
6 Synthesis of quinazoline derivatives from o-bromobenzyl (pseudo)halides and amidine derivatives via Ullmann-Goldberg coupling reaction
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
10 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).
7 Synthesis of 2-arylquinazoline derivatives via cyclization of N-
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 CuCl/DABCO/4-OH-TEMPO catalytic system in oxygen environment and acetonitrile solvent at 80 o C, after reacting for 2 hours that developed 2-arylquinazoline from 2-aminobenzyl amine and benzadehyde (Scheme 1.8a) [62] By 2017, N-oxyl radical ABNO in oxygen as catalysts was found for oxidation condition synthesizing quinazoline derivatives from 2- aminobenzylamines and correlative aldehyde derivatives by Ma’ Group This method was not used transition metal catalysts (Scheme 1.8b) [54]
8 Synthetic reaction of 2-arylquinazoline derivatives from 2-
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]
9 Synthesis of quinazoline derivatives from 2-aminobenzylamines and
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]
10 Synthesis of quinazoline derivatives from 2-aminobenzylamine and
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]
11 Synthesis of quinazoline derivatives from 2-aminobenzylamines and
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].
12 Synthesis of quinazoline derivatives from 2-aminobenzyl alcohol
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
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.
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 transition- 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]
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].
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 35 0 C, 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 o- 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 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
21 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
1.5.1 The C 2 activation and Csp 2 –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(sp 2 )–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 sp 2 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 KO t Bu 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 KO t Bu 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 1-[2-(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 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 palladium- catalyzed carbonylative coupling reaction, successfully generating different kinds of 2- 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
27 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-
18 Reactions using elemental sulfur in 2018
In 2019, Nguyen group synthesized hexaazatrinaphthylene derivatives from o- 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 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]
19 Reactions using elemental sulfur in 2019
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].
20 Using elemental sulfur in organic synthesis in 2020
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
21 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
1.5.1 The C 2 activation and Csp 2 –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(sp 2 )–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 sp 2 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 KO t Bu 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 KO t Bu 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 1-[2-(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 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 palladium- catalyzed carbonylative coupling reaction, successfully generating different kinds of 2- 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
27 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)
28 [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-
29 tetrahrydroisoquinoline giving different substituents in excellent yield (scheme 1.29d) [107]
Scheme 1 29 The synthesis reaction of quinazolinone
22 C2 activation reaction of quinoline structures in organic synthesis.23
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].
23 Coupling reaction via C –H activation in 2016
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 KO t Bu 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]
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 KO t Bu 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]
25 C2 activation and Csp 2 –N coupling reaction from 2018 to 2019
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 1-[2-(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 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 palladium- catalyzed carbonylative coupling reaction, successfully generating different kinds of 2- 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
27 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)
28 [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-
29 tetrahrydroisoquinoline giving different substituents in excellent yield (scheme 1.29d) [107]
Scheme 1 29 The synthesis reaction of quinazolinone
Pyrido-Fused quinazolinone derivatives were generated through the amination and annulation reaction of arenes with 2- aminopyridines by Liu and co-workers through using Cu(OAc)2 catalyst in DMSO solvent with numerous substituents (scheme 1.30a) [108] At that time, a research from Xie’s Group were published that 1,2,3,4-tetrahydroisoquinoline and 2-aminobenzyl alcohol were reacted to form quinazolinones scaffold in the presence of Co-catalyst, molecular O2 and 4-nitrobenzoic acid as the additive in p-xylene solvent (scheme 1.30b) [109] In 2019, according to Arachchige’s Group, quinazoline and quinazolinone derivatives were successfully resulted from the coupling reaction of 2- aminophenyl ketones and 2-aminobenzamides with amines, via ligand-promoted, ruthenium-catalyzed in 1,4-dioxane (scheme 1.30c) [110] At the same year, Quinazolinones were obtained from oxidative cyclization reaction of 2-aminobenzamide, Xie’s Group had utilized (NH4)2S2O8 as the oxidant in DMSO solvent with different substituents (scheme 1.30d) [111]
Scheme 1 30 The reaction of synthesis quinazolinone derivatives
The synthesis of quinazolinones scaffold has attreacted numerous interest for both organic chemistry and pharmaceutical area As a result, synthesizing quinazolinone derivatives have been attracted from many researchers However, a lot of methods in the past have shown numerous limitations in using unavailable and unstable and highly toxic reactants causing environmental damage as well as harsh conditions To resolve this problem, our group reported a method to form quinazolinone derivatives from available materials and using copper –catalyzed reaction
All reagents and starting materials were obtained commercially from supplier (Sigma–Aldrich, Across, and Merck) without any further purification unless otherwise noted Besides, the derivatives of 2-nitrobenzyl alcohol and phenylacetic acid were used in the reaction to form 2-aryl- quinazoline derivatives which were synthesized by our research team
Gas chromatographic analyses (GC) were performed using a Shimadzu GC 2010Plus equipped with flame ionization detector (FID) and an SPB–5 column (length 30 m, inner diameter = 0.25 mm, film thickness = 0.25 m) The temperature program for
GC analysis: held samples at 100 o C for 1 minutes then heated sample from 100 to 280 o C at 40 o C/min and finally held them at 280 o C for 4.5 minutes Nitrogen was used as carrier gas and its inlet pressure was set constantly at 147 kPa Inlet and detector temperatures were set constantly at 280 o C Biphenyl was used as an internal standard to calculate reaction yield
GS–MS analyses were performed on a Shimadzu GCMS–QP2010Ultra with a ZB– 5MS column (length = 30 m, inner diameter = 0.25 mm, film thickness = 0.25 m) and using He as carrier gas The temperature program for GC–MS analysis held samples at
50 o C for 2 min; heated samples from 50 to 280 o C at 10 o C/min and held them at 280 o C for
10 mins Inlet temperature was set constantly at 280 o C MS spectra was compared with the spectra gathered in the NIST library
Nuclear magnetic resonance (NMR) spectra ( 1 H and 13 C) were recorded on a Bruker
AV 500 spectrometer using residual solvent peaks as references at Faculty of Chemistry – University of Science – Hanoi National University
2.2 Reaction procedure for synthesis quinazolines derivatives
2.2.1 The general procedure for quinazoline derivatives synthesis reaction
To a dry 4-mL vial containing a magnetic stirring bar was added 2-nitrobenzyl alcohol (15.3 mg, 0.1 mmol), phenylacetic acid (40.8 mg, 0.3 mmol), DABCO (33.6 mg, 0.25 mmol), urea (18 mg, 0.3 mmol), S catalyst (9.6 mg, 0.3 mmol), DMSO solvent (0.3 ml) and biphenyl (15.4 mg, 0.1 mmol) as an internal standard The reaction tube was then tightly capped and stirred at 140 o C for 2 hours After the reaction was completed, the reaction tube was cooled to room temperature, quenched with brine and organic components were then extracted into ethyl acetate (3×1 mL), washed with saturated aqueous NaHCO3 solution (1 mL), dried over anhydrous Na2SO4 and the sample was analysed using GC with reference to biphenyl The GC yield of main product 2- phenylquinazolines after reaction was calculated based on the calibration curve from the
Scheme 2 1 General procedure of synthesis quinazolines
Table 2 1 List of substances and vendors
2-nitrobenzyl alcohol (97%) C7H7NO3 Acros biphenyl C12H10 Acros
Phenylacetic aicd (95%) C8H8O2 Sigma – Aldrich urea (NH2)2CO Xilong Chemical
Dimethyl sufoxide (CH3)2SO Merck ethyl acetate C4H8O2 Chemsol VN
To isolate the products, a typical reaction was carried out After completion of the reaction, the mixture was cooled to room temperature The organic components were then extracted into ethyl acetate (3×2 mL), washed with NaHCO3 solution (10% in water, 3x1 mL) and dried over anhydrous Na2SO4 The combined organic extracts were concentrated in vacuo and purified by column chromatography on silica gel with hexane/ethyl acetate
(ethyl acetate/hexane = 1:5 to 1:2) solvent system to afford the product 2- phenylquinazoline (17.9 mg, 89%) as yellowish crystals The product identity was further determined by GC-MS, 1 H-NMR and 13 C-NMR spectra
2.2.3 Gram-scale reaction for quinazoline
To demonstrate the practical application of synthetic method 2-aryl quinazoline derivatives (gram-scale), the experiment was conducted through following conditions: the mixture of 2-nitrobenzyl alcohol (0.61g, 4 mmol), phenylacetic acid (1.36 g, 10 mmol), DABCO (1.12 g, 10 mmol), urea (0.72 g, 12 mmol), DMSO solvent (12 ml) added into a flask 25 mL containing S catalyst (0.32g, 10 mmol) The reaction was carried out at 140 0 C in an oil bath for 2 hours and was monitored by TLC At the end of the reaction, the flask
28 Synthesizing of quinazolinone derivatives in 2015
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-
29 tetrahrydroisoquinoline giving different substituents in excellent yield (scheme 1.29d) [107].
29 The synthesis reaction of quinazolinone in 2016 and 2017
Pyrido-Fused quinazolinone derivatives were generated through the amination and annulation reaction of arenes with 2- aminopyridines by Liu and co-workers through using Cu(OAc)2 catalyst in DMSO solvent with numerous substituents (scheme 1.30a) [108] At that time, a research from Xie’s Group were published that 1,2,3,4-tetrahydroisoquinoline and 2-aminobenzyl alcohol were reacted to form quinazolinones scaffold in the presence of Co-catalyst, molecular O2 and 4-nitrobenzoic acid as the additive in p-xylene solvent (scheme 1.30b) [109] In 2019, according to Arachchige’s Group, quinazoline and quinazolinone derivatives were successfully resulted from the coupling reaction of 2- aminophenyl ketones and 2-aminobenzamides with amines, via ligand-promoted, ruthenium-catalyzed in 1,4-dioxane (scheme 1.30c) [110] At the same year, Quinazolinones were obtained from oxidative cyclization reaction of 2-aminobenzamide, Xie’s Group had utilized (NH4)2S2O8 as the oxidant in DMSO solvent with different substituents (scheme 1.30d) [111]
30 The reaction of synthesis quinazolinone derivatives in 2018 and 2019
The synthesis of quinazolinones scaffold has attreacted numerous interest for both organic chemistry and pharmaceutical area As a result, synthesizing quinazolinone derivatives have been attracted from many researchers However, a lot of methods in the past have shown numerous limitations in using unavailable and unstable and highly toxic reactants causing environmental damage as well as harsh conditions To resolve this problem, our group reported a method to form quinazolinone derivatives from available materials and using copper –catalyzed reaction
All reagents and starting materials were obtained commercially from supplier (Sigma–Aldrich, Across, and Merck) without any further purification unless otherwise noted Besides, the derivatives of 2-nitrobenzyl alcohol and phenylacetic acid were used in the reaction to form 2-aryl- quinazoline derivatives which were synthesized by our research team
Gas chromatographic analyses (GC) were performed using a Shimadzu GC 2010Plus equipped with flame ionization detector (FID) and an SPB–5 column (length 30 m, inner diameter = 0.25 mm, film thickness = 0.25 m) The temperature program for
GC analysis: held samples at 100 o C for 1 minutes then heated sample from 100 to 280 o C at 40 o C/min and finally held them at 280 o C for 4.5 minutes Nitrogen was used as carrier gas and its inlet pressure was set constantly at 147 kPa Inlet and detector temperatures were set constantly at 280 o C Biphenyl was used as an internal standard to calculate reaction yield
GS–MS analyses were performed on a Shimadzu GCMS–QP2010Ultra with a ZB– 5MS column (length = 30 m, inner diameter = 0.25 mm, film thickness = 0.25 m) and using He as carrier gas The temperature program for GC–MS analysis held samples at
50 o C for 2 min; heated samples from 50 to 280 o C at 10 o C/min and held them at 280 o C for
10 mins Inlet temperature was set constantly at 280 o C MS spectra was compared with the spectra gathered in the NIST library
Nuclear magnetic resonance (NMR) spectra ( 1 H and 13 C) were recorded on a Bruker
AV 500 spectrometer using residual solvent peaks as references at Faculty of Chemistry – University of Science – Hanoi National University
2.2 Reaction procedure for synthesis quinazolines derivatives
2.2.1 The general procedure for quinazoline derivatives synthesis reaction
To a dry 4-mL vial containing a magnetic stirring bar was added 2-nitrobenzyl alcohol (15.3 mg, 0.1 mmol), phenylacetic acid (40.8 mg, 0.3 mmol), DABCO (33.6 mg, 0.25 mmol), urea (18 mg, 0.3 mmol), S catalyst (9.6 mg, 0.3 mmol), DMSO solvent (0.3 ml) and biphenyl (15.4 mg, 0.1 mmol) as an internal standard The reaction tube was then tightly capped and stirred at 140 o C for 2 hours After the reaction was completed, the reaction tube was cooled to room temperature, quenched with brine and organic components were then extracted into ethyl acetate (3×1 mL), washed with saturated aqueous NaHCO3 solution (1 mL), dried over anhydrous Na2SO4 and the sample was analysed using GC with reference to biphenyl The GC yield of main product 2- phenylquinazolines after reaction was calculated based on the calibration curve from the
1 General procedure of synthesis quinazolines
Table 2 1 List of substances and vendors
2-nitrobenzyl alcohol (97%) C7H7NO3 Acros biphenyl C12H10 Acros
Phenylacetic aicd (95%) C8H8O2 Sigma – Aldrich urea (NH2)2CO Xilong Chemical
Dimethyl sufoxide (CH3)2SO Merck ethyl acetate C4H8O2 Chemsol VN
To isolate the products, a typical reaction was carried out After completion of the reaction, the mixture was cooled to room temperature The organic components were then extracted into ethyl acetate (3×2 mL), washed with NaHCO3 solution (10% in water, 3x1 mL) and dried over anhydrous Na2SO4 The combined organic extracts were concentrated in vacuo and purified by column chromatography on silica gel with hexane/ethyl acetate
(ethyl acetate/hexane = 1:5 to 1:2) solvent system to afford the product 2- phenylquinazoline (17.9 mg, 89%) as yellowish crystals The product identity was further determined by GC-MS, 1 H-NMR and 13 C-NMR spectra
2.2.3 Gram-scale reaction for quinazoline
To demonstrate the practical application of synthetic method 2-aryl quinazoline derivatives (gram-scale), the experiment was conducted through following conditions: the mixture of 2-nitrobenzyl alcohol (0.61g, 4 mmol), phenylacetic acid (1.36 g, 10 mmol), DABCO (1.12 g, 10 mmol), urea (0.72 g, 12 mmol), DMSO solvent (12 ml) added into a flask 25 mL containing S catalyst (0.32g, 10 mmol) The reaction was carried out at 140 0 C in an oil bath for 2 hours and was monitored by TLC At the end of the reaction, the flask
34 was cooled to room temperature, DMSO solvent were added into mixture in order to dissolve all the organic compounds The mixture was extracted with ethyl acetate and saturated solution NaCl (10 mL) The organic phase is dried over anhydrous with Na2SO4, then removing solvent and the product was recrystallization in acetone solvent
2.3 Reaction procedure of reaction forming quinazolinones
2.3.1 The general procedure for synthesis of quinazolinones derivatives
To a 12-mL screw-cap vial was added isoquinoline (0.3 mmol, 3.0 equiv.), CuCl2
(20 mol%), TsOH.H2O (20 mol%) and DMF (1.5 mL) The reaction tube was flushed with
O2, tightly capped and stirred at room temperature for 10 min Then, 2-aminobenzyl alcohol (0.1 mmol, 1.0 equiv.) was added in three portions and the resulting mixture was stirred at 100 0 C for 12 h Upon completion of the reaction, the mixture was cooled to room temperature and diphenyl ether (17.2 mg, 0.1 mmol) as an internal standard was added The organic components were then extracted into ethyl acetate (2.0 mL), washed with NaHCO3 solution (5% in water, 1.0 mL) and brine (1.0 mL), dried over anhydrous Na2SO4 and analyzed by GC with reference to diphenyl ether To isolate the corresponding product, the combined organic extracts were concentrated in vacuo and purified by column chromatography on silica gel with n-hexane/ethyl acetate solvent system to give pure product The product identity was further confirmed by GC-MS, 1 H NMR and 13 C NMR.
2 General procedure of synthesis quinazolinones
To isolate the quinazolinone products, a typical reaction was carried out After completion of the reaction, the mixture was cooled to room temperature The organic
35 components were then extracted into ethyl acetate (3×2 mL), washed with NaHCO3 solution (10% in water, 3x1 mL) and dried over anhydrous Na2SO4 The combined organic extracts were concentrated in vacuo and purified by column chromatography on silica gel with hexane/ethyl acetate (ethyl acetate/hexane = 1:5 to 1:2) solvent system to afford the product quinazolinones (19.9 mg, 81%) and quinazolinones as yellowish crystals The product identity was further determined by GC-MS, 1 H-NMR and 13 C-NMR spectra
3.1 Studies of reaction conditions of quinazolines
Elemental sulfur mediated were used for the model reaction between 2-nitrobenzyl alcohol (1a) and phenylacetic acid (2a) to generate 2-phenylquinazoline (3aa) as main product Initial investigations revealed that the domino reaction between 2-nitrobenzyl alcohol and phenylacetic acid produced the major product 3aa in the presence of S8, DABCO as base, urea additives under DMSO solvent (scheme 3.1) The final conditions of the reaction are investigated through alternating each factor, including: reaction temperature, catalyst and amount of them, type of base agent and amount of base agent, type of solvent or amount of solvent, reaction time The application of reaction is also expanding on various derivatives of phenylacetic acid (2a) and 2-nitrobenzyl alcohol (1a) The detail data of experiment are shown in Appendix 5.
1 Reaction model to investigate synthesis of quinazoline
3.1.1 Effect of temperature on reaction synthesis of quinazolines
The temperature is the important factor to be investigated because it is directly related thermodynamic factor of reaction Based on previous studies, temperature factor was studied from 80 0 C to 140 0 C in 2 hours The reaction used 0.1 mmol agent with 1a: 2a molar ratio of 1: 3, 2.5 equivalent of elemental sulfur, 2.5 equivalent of DABCO and 3 equivalent of urea additives in DMSO solvent
2 Investigation of the temperature on reaction
Table 3 1 Melting temperature of some agents used in the reaction
The result illustrated that, as anticipated, increasing the reaction temperature led to significant improvement in the yield of the expected product At 80 0 C, the performance of
3aa products was less than 10% after 12 hours When the temperature rose up to 110 0 C, the reaction efficiency increased by 20% and reached 60% at 120 0 C If the reaction temperature was 140 0 C, best result was achieved for the reaction with 71% yield 3aa being obtained after 4h This can be explained by the low temperature, the solids did not melt, so the phase difficultly contacted, affecting process the transfer chemical reaction was like not take place To save energy, the reaction temperature was kept at 140 0 C for further investigation
Figure 3 1 Effect of base on reaction synthesis of quinazolines
According to a study of Nguyen et al 2014 reported the condensation reaction between 2-nitroaniline derivatives and phenylacetic acid, the base agents were greatly influenced on the condensation reaction [112] Therefore, the different kinds of base were the next factor to be investigated The reaction used 0.1 mmol agent with 1a: 2a molar ratio of 1: 3, 2.5 equivalent of elemental sulfur, 2.5 equivalent of DABCO and 3 equivalent of urea additives in DMSO solvent The detail data of experiment are shown in Appendix 5.
3 Investigation of base on reaction
Figure 3 2 The yield of main product in various kinds of base
The survey of Nguyen et al or Guntreddi et al, the strength and boiling temperature of the base have key role in the reaction [67,112] Experimental results have shown that the tertiary amine or amidine such as [DBUH]OAc gived better yield than primary amine and secondary amine; pyridine and other related base agents such as 2-aminopyridine or morpholine exhibited very poor reactivity According to previous studies, the elimination process of acid carboxyl group usually happened in the form of carboxylate, so the base agent needed to have sufficient strength to completely separate the carboxylic acid proton [60,67,120] Besides, boiling temperature was also essential factor that directly affected the activity of base types Due to the reaction performed under stirring at high temperatures and evaporate partially, so these agents may show poor activity in the reaction For the case of using the DBU base, although this was a very strong organic base; However, with low boiling point, only about 80 0 C, DBU illustrated only about 9% yield of product Similarly, ionic liquid [DBUH]OAc had the same activity as DBU but melting point temperature was slightly higher (180 0 C in a vacuum), so the yield of 3aa product was 30%
In addition, some inorganic bases such as Li2CO3, K2CO3 and NaOAc were also studied in reaction Only NaOAc agent produced less than 30% 3aa products, with the other base agents, 3aa products were only recognized 10% Among all the base agents,
DABCO has been demonstrated as the base agent for the most efficient, thanks to their superiority in performance of the main product In addition, the use of DABCO was more economical than other similar activity organic bases such as N,N’-dimethylpiperazine; or ionic liquid [DBUH]OAc, but they was very high cost
Figure 3 3 The effect of DABCO on the reaction
The effect of DABCO was the next parameter to be investigated on the process, the reactions were conducted at 120 0 C for 12 hours; use molar ratio 1a: 2a corresponding to 1: 3; DABCO was studied at 0.5 eqv, 1 eqv, 1.5 eqv, 2 eqv, 2.5 eqv, 3 eqv in the presence of 3 equivalent S8, 2.5 equivalent of urea in DMSO solvent
The Figure 3.3 showed that bases had a significant impact on the yield of synthesizing quinazoline The yield of 3aa product was 24% when using 0.5 equivalent
0.5 eqv 1 eqv 1.5 eqv 2 eqv 2.5 eqv 3 eqv
41 DABCO When DABCO was increased to 2.5 equivalents, the GC yield of the product reached 70% However, this yield slightly decreased when DABCO rose up to 3 equivalents This may be because when the amount of base was too high, the proton transported to the nitro group while the reduction process was unfavorable [120] In addition, the presence of a large amount of amine with a strong nucleotide like DABCO may cause the Lewis acid centers in the catalyst that was inactivated as a result the connection between the substance and the catalyst in the system might reduce [113,114] Totally, the amount of DABCO will be used at 2.5 equivalent in the next investigation
3.1.2 Effect of nitrogen sources on reaction synthesis of quinazolines
Nitrogen source was the next factor to be investigated at 120 0 C for 2 hours; using molar ratio 1a: 2a corresponding to 1: 3; many nitrogen sources was used in the reaction such as NH4OAc, NH4HCO3, NH3 of 30% and urea in the presence of 3 equivalent S8, 5 equivalent of urea in DMSO solvent The result was represented in Figure 3.4.
4 Investigation of additives on reaction
Figure 3 4 The effect of different kinds of nitrogen source on reaction
According to the results, it can be predicted that a certain amount of ammonia can be added to the system to create a balanced shift in the direction of the formation of product Some nitro sources such as NH4OAc, NH4HCO3, NH3 solution in water (25-30%), urea which were added to the system with the content of 0.5 mmol Finally, our group selected urea additives agent in study reaction conditions
NH4OAc NH4HCO3 30% aq NH3 urea No nitrogen source
Figure 3 5 Effect of urea amount on the yield of product
The effect of urea amount was observed at 140 0 C for 4h; with molar ratio 1a: 2a corresponding to 1: 3; in the presence of S8, 2.5 equivalents of DABCO under DMSO solvent When the urea amount increased from 0.5 to 3 equivalents, the yield of the main reaction tended to increase (Figure 3.5) The amount of urea over 3 equivalents did not increase the performance, so 3 equivalent urea was the best choice in next investigation
3.1.3 Effect of the ratio of reactants on reaction
In previous redox systems, reducing agents of nitro groups were often excessively used in the redox reaction For the reducing cyclization of the o-nitroacetophenone derivatives and aldehyde derivatives, Yu and co-workers used 3.0 equivalents of H3NBH3 on Ni/ Pd catalysts [115]; Wang and co-workers synthesized quinazoline derivatives from (E)-2- nitrobenzaldehyde O-methyl oxime with 3.0 equivalents of reducing agent as alcohol or benzylamine on Pd/ dppf catalyst [64] The effect of molar ratio of reactants was performed at 140 0 C for 2 hours; in the presence of S8, DABCO 2.5 equivalent, 3 equivalent of urea under DMSO solvent (Figure 3.6)
0.5 eqv 1 eqv 2 eqv 3 eqv 4 eqv 5 eqv 6 eqv 8 eqv
Figure 3 6 Effect of different molar ratio of starting reactants
In terms of the economic area, the use of 1a as a limiting agent will be more beneficial, since 1a was a much higher cost than 2a; Moreover, when the molar ratio of phenylacetic acid 2a was increased to 2.5 equivalent, the performance lifted from 40% to 67% Thus, the final molar ratio of 1a: 2a was selected being 1: 2.5 and this ratio also demonstrated the effective elemental sulfur
3.1.4 Effect of the amount of elemental sulfur on reaction
According to a study on nitro-oxidation reactions using Fe/ S catalysts, Nguyen group suggested a mixture of Fe (10 mol%) and S (10 mol%) for oxygen condensation reaction between 2-nitroaniline or 2-nitrophenol derivatives and methyl hetarene derivatives [116]; while a mixture of FeCl2.4H2O (5 mol%) and S (40 mol%) were used as a catalyst for condensation and decarboxylate between 2-nitroaniline derivatives and arylacetic acid in order to synthesize benzimidazole derivatives [115]; or a mixture of FeCl3.6H2O (5 mol%) and S (20 mol%) was utilized for the condensation reaction between 2-nitroaniline and phenethylamine derivatives [117] Thus, it was necessary to investigate the suitable amount of sulfur for the reaction between 1a and 2a
Figure 3 7 The effect of amount of elemental sulfur on yield of product
These reactions were conducted at 120 0 C for 8 hours, using molar ratio of starting material of 1a: 2a corresponding to 1: 2.5; 2.5 equivalents of DABCO base, the amount of urea was 3 equivalents in the presence of different amount of sulfur from 1 to 6 equivalents in DMSO solvent When the amount of sulfur raised to 3 equivalents, the yield of 3aa product obtained 72% but instantly decreased to 54% at 6 equivalents
3.1.5 Effect of solvent on reaction synthesis of quinazolines
In many cases, the solvents had a great influence on the performance of the reaction This depended on the reaction agent and the main product, and also on the nature of the catalyst [118-119] For this reason, it was necessary to research the impact of several different solvents on the reaction The investigating solvents included protic and aprotic polar The reaction was conducted at 120 0 C for 8 hours, using a molar ratio of 1a: 2a being 1: 2.5, the amount of DABCO base used was 2.5 equivalent The amount of urea was 3 equivalents and in the presence of 3 equivalent sulfur in different solvents with the result shown on Figure 3.8
1 eqv 2 eqv 3 eqv 4 eqv 5 eqv 6 eqv
Figure 3 8 Effect of different solvent on the yield of product
According to the results, polar solvents such as aromatic solvents, ether and carbonate are not suitable for reaction of synthesis quinazoline derivatives High polar solvents such as DMSO and DMF gave the yield of 3aa nearly 70% and 30%, respectively
As a result, DMSO solvent was 0.3 mL in the synthesis of quinazoline
3.1.6 Effect of different catalyst on reaction
The reaction was also conducted at 140 0 C for 2 hours, using molar ratio of 1a: 2a being 1: 2.5, the amount of DABCO base was 2.5 equivalent, 3 equivalents of urea in the presence of various catalysts and DMSO solvent The results of reaction were depicted on
Figure 3 9 The effect of different promoters on quinazolines synthesis
3.2 Effect of different substituents of the reaction
The application of synthesizing different 2-phenylquinazoline derivatives, the reaction system was aimed to investigate variety of different substituents of 2-nitrobenzyl alcohol and phenylacetic acid with the reaction conditions described in Table 3.2 The reaction between 2-nitrobenzyl alcohol (1a) and different phenylacetic acid derivatives in order to formed 2-phenylquinazoline derivatives with isolated yield ranging from 47% to 89%
In general, common functionalities were tolerated under the reaction conditions the quinazoline derivatives were gained with either electron-rich (3ab-ad and 3ai) or electron- deficient arylacetic acids (3aj) that giving good performance Coupling reaction between 2-nitrobenzyl alcohol and halogenated phenylacetic acid that may incompatible with elemental sulfur-mediated [67], so the yield of products (3af-ag) are slightly increase However, the reaction between 1-naphthylacetic acid reacted and 2-nitrobenzyl alcohol,
48 which achieved the quinazoline product (3ak) in 70% yield Thiophene-derived quinazolines 3al and 3am and the indole-derived quinazoline 3aq were developed through nearly unchanging the reaction conditions, so the compatibility of heterocycles was proved in this reaction
Especially, this reaction was scale-up to 4 mmol, without the significant changing in yield Besides, our strategy still depicted some limitation The substrate contained a nitro, hydroxy or unprotected indole functionality which were not suitable for this reaction The desired product also did not find in the synthesis reaction of cinnamic acid derivatives and aliphatic carboxylic acids
Table 3 2 Synthesis of 2-arylquinazoline derivatives from different substituents of phenylacetic acid derivatives and 2-nitrobenzyl alcohol
Entry Reactant 1 Reactant 2 Product Yield b
71 a Reaction condition: 2-nitrobenzyl alcohol (0.1 mmol, 1 equivalent); phenylacetic acid derivatives (0.3 mmol, 3 equivalent); DABCO (0.25 mmol, 2.5 equivalent); urea (0.3 mmol, 3 equivalent); sulfur (3 mmol); DMSO solvent; 140 0 C, 4 hours b Isolated yield by column chromatography on silica gel c Reaction time: 4h
The scope of the 2-nitrobenzyl alcohol was next studied (Table 3.3) The coupling reaction between aryl(2-nitrophenyl)methanols and phenylacetic acid was successful with good yield of quinazolines 3ba and 3bg Howerver, 1-(2-Nitrophenyl)ethanol gave smaller
5 Mechanistic studies
(1) TEMPO (1 equiv): 37% aYields were determined by GC analysis with diphenyl ether as internal standard
To understand the mechanism, from the scheme 3.5 we carried out some test experiments When the reaction between 2-nitrobenzyl alcohol and phenylacetic acid in standard conditions and TEMPO; the formation of quinazoline might involve a radical transformation because the yield of the quinazoline 3aa dramatically decreased when using the radical quencher TEMPO (Scheme 3.5, eq 1) When thiobenzaldehyde was utilized, the yield of 3aa resulted in 71% yield (Scheme 3.5, eq 2) with the presence of phenylacetic acid and elemental sulfur Moreover, the reaction of 2-nitrobenzaldehyde and 2a afforded quinazoline 3aa in 78% yield (Scheme 3.5, eq 3), confirming the presence of thiobenzadehyde and 2-nitrobenzaldehyde intermediate during the course of the reaction When 2-nitrobenzylamine was used as a substrate, the product 3aa was observed in 57% yield without an addition of urea (Scheme 3.5, eq 4), the reason may be slower oxidation of the C–N bond Besides, the precursors from reduction of the nitro group of 1a also reacted with phenylacetic acid (2a) The reaction of 2-aminobenzyl alcohol gave 3aa in 81% yield (Scheme 3.5, eq 5), whereas the use of the (2-nitrosophenyl)methanol intermediate afforded quinazoline 3aa in 65% yield (Scheme 3.5, eq 6)
6 Plausible mechanism
Based on the above results and previous studies [74,120], a possible mechanism is proposed (Scheme 3.6) Initially, DABCO base and elemental sulfur complexation converted an active sulfur species that then combined with a phenylacetate anion from 2a to gain a benzyl polysulfide [74] In the presence of the DABCO–sulfur complex, this adduct was decomposed to form thiobenzaldehyde (4) or experienced single-electronbased fragmentation in order to afford benzylic radical (9) Besides, 2-nitrobenzyl alcohol (1a) undergone the process to generate 2- nitrosobenzaldehyde (10) The condensation of (10) and NH3 from urea that continuously followed by addition route to the benzyl radical (9) and dehydration resulted the bisimine (13) A nonradical pathway mightnot be completely ruled out, the reason is that when addition of a radical quencher such as TEMPO in this reaction still gave a small amount of 3aa The intermediate (7) might attain when reduction
59 of 1a which could go through an imine condensation and oxidation to furnish (13)
Electrocyclization of (13) followed by oxidation gives the desired quinazoline 3aa From the optimization results suggested that the combination of elemental sulfur and DMSO solvent accounts for the successful oxidation
3.4 Studies of reaction conditions of quinazolinones
3.4.1 Study of many different conditions on the yield of quinazolinones product
Quinazolinone were generated via two steps, isoquinoline (0.3 mmol, 3.0 equiv.), CuCl2 (20 mol%), TsOH.H2O (20 mol%) and DMF (1.5 mL) was added in vial with flushed
O2, at room temperature for 10 min Then, 2-aminobenzyl alcohol (0.1 mmol, 1.0 equiv.) was added and reacted at 100 0 C for 12 h Initial investigations show that 2-aminobenzyl alcohol (4a) and isoquinoline (5a) were reacted to gain the major product 9aa in the presence of CuCl2 catalyst, TsOH.H2O, under DMSO solvent (scheme 3.1) The final conditions of the reaction are investigated through alternating each factor, including: reaction temperature, catalyst and amount of them, type of acid agent and amount of them, type of solvent or amount of them and reaction time The application of reaction is also expanding on various derivatives of 2-aminobenzyl alcohol (4a) and isoquinoline (5a).
7 Reaction model to investigate synthesis of quinazolinone
The temperature is the important factor to be investigated because it is directly related thermodynamic factor of reaction Based on previous studies, temperature factor was studied from 80 0 C to 140 0 C in 12 hours The reaction used 0.1 mmol agent, with 4a:
5a molar ratio being 1: 2, 20 mol% of CuCl2 and 0.2 equivalent of acid TsOH.H2O in DMF solvent
Figure 3 10 Effect of temperature on the yield of quinazolinone product
The results show that, when the temperature increased the GC yield of the 9aa product increases At 80 0 C, the performance of 9aa products was nearly 30% after 12 hours When the temperature rose up to 100 0 C, the reaction efficiency increased and reached 52% at 100 0 C If the reaction temperature was 120 0 C, the reaction efficiency was 51% This may be explained by the low temperature, the solids did not melt, so the phase difficultly contacted so affecting process the transfer chemical reaction was like not take place In addition, when done at higher temperatures in the presence of solvents, the yield of product was highest at 100 0 C Thus, the reaction temperature was kept at 100 0 C for further investigation
Figure 3 11 Effect of different types of acid on the yield of quinazolinone product
The results show on Graph 3.11 that acid had a significant impact on the synthesis of quinazolinone The performance of 9aa product is 68% when using TsOH.H2O 0.2 equivalent, increasing the amount of TsOH.H2O to 1 equivalent, the GC yield of the product slightly decreased to 66% However, this yield of quinazolinone slightly decreased when the amount of acid rose up 1 equivalent This may be because when the amount of acid is too high, the H + might selectively react with amino group of reagent Totally, the amount of acid TsOH.H2O will be used at 0.2 equivalent for the investigation
Figure 3 12 The molar ratio effect on the yield of main product
In terms of the economic area, using 4a as a limiting agent will be more beneficial; Moreover, the molar ratio of isoquinoline 5a increased to 3 equivalents, the performance lifted from 32% to 64% Thus, the final molar ratio of 4a: 5a was selected corresponding to 1: 3 for final conditions
Figure 3 13 The various kinds of catalyst effect on yield of product
Figure 3 14 Effecting the amount of catalyst on reaction
Figure 3.13 and 3.14 was shown that CuCl2 gave highest yield for the synthesis of quinazolinone The performance of 9aa product was 64% when using CuCl2 (20 mol%), increasing the amount of catalyt to 30 mol%, the GC yield of the product slightly decreased to 58% Finally, CuCl2 (20 mol%) catalyst was used to result the quinazolinone product
Figure 3 15 Effect of different solvent on synthesis of quinazolinone
In many cases, the solvents have a great influence on the performance of the product
So, it was necessary to research the impact of several different solvents on the reaction [118-119] For this reason, many solvents included protic and aprotic polar solvent The reaction was conducted at 120 0 C for 12 hours, using a molar ratio of 4a: 5a being 1: 3, the amount of TsOH.H2O was 0.2 equivalent, the amount of CuCl2 was 20 mol% in different solvents with the shown in Figure 3 15
3.4.2 The result of synthesis reaction quinazolinone derivatives
The application of synthesizing different quinazolinone and tetrahydroquinazolinone derivatives, the reaction was investigated in various of different substituents of 2-aminobenzyl alcohol and isoquinoline with the reaction conditions described in Table 3.6
Table 3 6 Synthesis of 2-arylquinazoline derivatives from different substituents of phenylacetic acid derivatives and 2-nitrobenzyl alcohol
Entry Reactant 1 Reactant 2 Product Yield b
88 a Reaction conditions: 2-aminoarylmethanols 1 (0.2 mmol, 1.0 equiv.), isoquinolines 2
(0.6 mmol, 3.0 equiv.), CuCl2 (20 mol%), TsOH.H2O (20 mol%), DMF (3.0 mL), 100 o C,
In this thesis, synthetic reaction of 2-phenylquinazoline was synthesized from 2- nitrobenzyl alcohol and phenylacetic acid The main product 2-phenylquinazoline afforded 80% in GC yield (78% in isolated yield) after 4 hours reaction at 140 o C using 3 equivalents of sulfur; in the presence of 2.5 equivalents of DABCO base and 3 equivalents of urea as nitrogen source
In addition, the potential application of the reaction system was also extended to different 2-nitrobenzyl alcohol derivatives and phenylacetic acid derivatives, giving isolated yield ranging from 47% to 90%.
1 Optimal condition of synthetic reaction of 2-phenylquinazoline from 2-nitrobenzyl alcohol and phenylacetic acid
nitrobenzyl alcohol and phenylacetic acid
Quinazolinone derivatives were also delivered through the reaction of 2- aminobenzyl alcohol (0.1 mmol, 1.0 equiv.) and isoquinoline (0.3 mmol, 3.0 equiv.) with catalyst CuCl2 (20 mol%), additives TsOH.H2O (20 mol%) and DMF (1.5 mL) solvent Moreovers, the reaction system was successfull to different derivatives of 2-aminobenzyl alcohol and isoquinoline, isolated yield of products was from 42% to 91%
2 Synthetic reaction of quinazolinone from 2-aminobenzyl alcohol and isoquinoline
In the future, we aim to futher applying S-promoter/ DABCO/ Urea system to synthesize more heterocycle structure as well as organic chemistry synthesizing, moreover, we also focus studies using Copper-catalyzed to generate more heterocycle containing nitrogen and expanding developing more quinazoline and quinazolinone derivatives
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Appendix 1: GC yield calculation 81Appendix 2: Calibration curve data 81Appendix 3: Calibration curve with reference to biphenyl 82Appendix 4: GC result of reaction synthesizing of 2-phenyl quinazoline 82Appendix 5: MS spectrum of 2-phenylquinazoline 83Appendix 6: Optimization data of synthetic reaction of 2-arylquinazoline 83Appendix 7: 1 H-NMR spectrum of 3aa 86Appendix 8: 13 C-NMR spectrum of 3aa 87Appendix 9: 1 H-NMR spectrum of 3ab 88Appendix 10: 13 C-NMR spectrum of 3ab 89Appendix 11: 1 H-NMR spectrum of 3ac 90Appendix 12: 13 C-NMR spectrum of 3ac 91Appendix 13: 1 H-NMR spectrum of 3ad 92Appendix 14: 13 C-NMR spectrum of 3ad 93Appendix 15: 1 H-NMR spectrum of 3ae 94Appendix 16: 13 C-NMR spectrum of 3ae 95Appendix 17: 1 H-NMR spectrum of 3af 96Appendix 18: 13 C-NMR spectrum of 3af 97Appendix 19: 1 H-NMR spectrum of 3ag 98Appendix 20: 13 C-NMR spectrum of 3ag 99Appendix 21: 1 H-NMR spectrum of 3ah 100Appendix 22: 13 C-NMR spectrum of 3ah 101Appendix 23: 1 H-NMR spectrum of 3ai 102Appendix 24: 13 C-NMR spectrum of 3ai 103Appendix 25: 1 H-NMR spectrum of 3aj 104Appendix 26: 13 C-NMR spectrum of 3aj 105Appendix 27: 1 H-NMR spectrum of 3ak 106
79 Appendix 28: 13 C-NMR spectrum of 3ak 107Appendix 29: 1 H-NMR spectrum of 3al 108Appendix 30: 13 C-NMR spectrum of 3al 109Appendix 31: 1 H-NMR spectrum of 3am 110Appendix 32: 13 C-NMR spectrum of 3am 111Appendix 33: 1 H-NMR spectrum of 3aq 112Appendix 34: 13 C-NMR spectrum of 3aq 113Appendix 35: 1 H-NMR spectrum of 3ba 114Appendix 36: 13 C-NMR spectrum of 3ba 115Appendix 37: 1 H-NMR spectrum of 3bg 116Appendix 38: 13 C-NMR spectrum of 3bg 117Appendix 39: 1 H-NMR spectrum of 3ca 118Appendix 40: 13 C-NMR spectrum of 3ca 119Appendix 41: 1 H-NMR spectrum of 3da 120Appendix 42: 13 C-NMR spectrum of 3da 121Appendix 43: 1 H-NMR spectrum of 3ea 122Appendix 44: 13 C-NMR spectrum of 3ea 123Appendix 45: Calibration curve data 124Appendix 46: Calibration curve with reference to diphenyl ether 124Appendix 47: Optimization data of synthetic reaction of 8H-isoquinolino[1,2- b]quinazolin-8-one 125Appendix 48: 1 H-NMR spectrum of 9aa 130Appendix 49: 13 C-NMR spectrum of 9aa 131Appendix 50: 1 H-NMR spectrum of 9ab 132Appendix 51: 13 C-NMR spectrum of 9ab 133Appendix 52: 1 H-NMR spectrum of 9ac 134Appendix 53: 13 C-NMR spectrum of 9ac 135Appendix 54: 1 H-NMR spectrum of 9ad 136Appendix 55: 13 C-NMR spectrum of 9ad 137
80 Appendix 56: 1 H-NMR spectrum of 9ae 138Appendix 57: 13 C-NMR spectrum of 9ae 139Appendix 58: 1 H-NMR spectrum of 9ca 140Appendix 59: 13 C-NMR spectrum of 9ca 141Appendix 60: 1 H-NMR spectrum of 9aq 142Appendix 61: 13 C-NMR spectrum of 9aq 143
The GC yield of the reaction was determined through the ratio of the peak area of the product to that of the internal standard, which was calculated as follows:
Where Sproduct and Sinternal standard are respectively the peak areas of 3aa and biphenyl measured on GC chromatogram
Sinternal standard × 1.0424 + 0.0008) ×n product × 100% n product o Where: nproduct (mol): mole of product obtained, n o product (mol): calculated mole of product when reaction yield equals 100%, ninternal standard (mol): mole of biphenyl in the sample
Peak area ratio Molar ratio
Appendix 3: Calibration curve with reference to biphenyl
Appendix 4: GC result of reaction synthesizing of 2-phenyl quinazoline
Appendix 5: MS spectrum of 2-phenylquinazoline
Appendix 6: Optimization data of synthetic reaction of 2-arylquinazoline
Appendix 7: 1 H-NMR spectrum of 3aa
Appendix 8: 13 C-NMR spectrum of 3aa
Charaterization Data for (3aa) 121 2-phenylquinazoline
Prepare as shown in the general experimental procedure and was purified by silica gel column chromatography using hexane/ethyl acetate (5:1, v/v) as eluent: white solid, 82% yield 1 H-NMR (500 MHz, CDCl3, ppm) δ 9.47 (d, J = 0.7 Hz, 1H), 8.66 – 8.58 (m, 2H), 8.09 (d, J = 8.5 Hz, 1H), 7.97 – 7.87 (m, 2H), 7.65 – 7.57 (m, 1H), 7.57 – 7.48 (m, 3H)
Appendix 9: 1 H-NMR spectrum of 3ab
Appendix 10: 13 C-NMR spectrum of 3ab
Charaterization Data for 2-( o -Tolyl)quinazoline (3ab) 121
Prepare as shown in the general experimental procedure and was purified by silica gel column chromatography using hexane/ethyl acetate (5:1, v/v) as eluent: white solid, 90% yield 1 H-NMR (500 MHz, DMSO-d 6 , ppm) δ 9.71 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H), 8.08 – 8.03 (m, 2H), 7.92 (d, J = 7.3 Hz, 1H), 7.77 (ddd, J = 8.0, 4.9, 3.1 Hz, 1H), 7.44 – 7.33 (m, 3H), 2.58 (s, 3H) 13 C-NMR (125 MHz, DMSO-d 6 , ppm) δ 163.4, 161.1, 150.0, 138.7, 137.5, 135.1, 131.6, 131.2, 129.7, 128.34, 128.31, 128.1, 126.3, 123.0, 21.5
Appendix 11: 1 H-NMR spectrum of 3ac
Appendix 12: 13 C-NMR spectrum of 3ac
Charaterization Data for 2-( p -Tolyl)quinazoline (3ac) 121
Prepare as shown in the general experimental procedure and was purified by silica gel column chromatography using hexane/ethyl acetate (5:1, v/v) as eluent: white solid, 80% yield 1 H-NMR (500 MHz, CDCl3, ppm) δ 9.45 (s, 1H), 8.51 (d, J = 8.2 Hz, 2H), 8.07 (d, J = 8.5 Hz, 1H), 7.95 – 7.86 (m, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 2.45 (s, 3H) 13 C-NMR (125 MHz, CDCl3, ppm) δ 161.2, 160.4, 150.8, 140.9, 135.4, 134.0, 129.4, 128.6, 128.5, 127.1, 127.0, 123.5, 21.5
Appendix 13: 1 H-NMR spectrum of 3ad
Appendix 14: 13 C-NMR spectrum of 3ad
Charaterization Data for 2-(2,5-Dimethylphenyl)quinazoline (3ad) 121
Prepare as shown in the general experimental procedure and was purified by silica gel column chromatography using hexane/ethyl acetate (8:1, v/v) as eluent: white solid, 79% yield 1 H-NMR (500 MHz, DMSO-d 6 , ppm) δ 9.71 (s, 1H), 8.21 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 3.5 Hz, 2H), 7.82 – 7.76 (m, 1H), 7.75 (s, 1H), 7.25 (dd, J = 11.3, 4.5 Hz, 2H), 2.53 (s, 4H), 2.38 (s, 3H) 13 C-NMR (125 MHz, DMSO-d 6 , ppm) δ 163.5, 161.1, 150.0, 138.4, 135.2, 135.1, 134.4, 131.65, 131.61, 130.4, 128.33, 128.30, 128.2, 123.0, 21.1, 21.0 HRMS (ESI) m/z calcd for C16H15N2 + (M+H) + 235.1230, found 235.1227
Appendix 15: 1 H-NMR spectrum of 3ae
Appendix 16: 13 C-NMR spectrum of 3ae
Charaterization Data for 2-(2-Chlorophenyl)quinazoline (3ae) 121
Prepare as shown in the general experimental procedure and was purified by silica gel column chromatography using hexane/ethyl acetate (6:1, v/v) as eluent: white solid, 68% yield 1 H-NMR (500 MHz, CDCl3, ppm) δ 9.54 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 8.00 – 7.95 (m, 1H), 7.84 – 7.81 (m, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.56 – 7.54 (m, 1H), 7.45 – 7.39 (m, 2H) 13 C-NMR (125 MHz, CDCl3, ppm) δ 162.0, 160.3, 150.4, 138.3, 134.4, 132.9, 131.8, 130.6, 130.3, 128.7, 128.7, 127.2, 126.9, 123.3
Appendix 17: 1 H-NMR spectrum of 3af
Appendix 18: 13 C-NMR spectrum of 3af
Charaterization Data for 2-(3-Chlorophenyl)quinazoline (3af) 121
Prepare as shown in the general experimental procedure and was purified by silica gel column chromatography using hexane/ethyl acetate (5:1, v/v) as eluent: white solid, 73% yield 1 H-NMR (500 MHz, DMSO-d 6 , ppm) δ 9.74 (s, 1H), 8.53 (ddd, J = 8.6, 4.8,
1.7 Hz, 2H), 8.21 (d, J = 8.2 Hz, 1H), 8.13 – 8.04 (m, 2H), 7.83 – 7.75 (m, 1H), 7.66 – 7.60 (m, 2H) 13 C-NMR (125 MHz, DMSO-d 6 , ppm) δ 162.0, 158.8, 150.2, 140.1, 135.5, 134.2, 131.2, 131.0, 128.7, 128.45, 128.38, 128.1, 127.1, 124.0
Appendix 19: 1 H-NMR spectrum of 3ag
Appendix 20: 13 C-NMR spectrum of 3ag Charaterization Data for 2-(4-Chlorophenyl)quinazoline (3ag) 121
Prepare as shown in the general experimental procedure and was purified by silica gel column chromatography using hexane/ethyl acetate (4:1, v/v) as eluent: white solid, 60% yield 1 H-NMR (500 MHz, CDCl3, ppm) δ 9.45 (s, 1H), 8.61 – 8.53 (m, 2H), 8.07 (d,
J = 8.4 Hz, 1H), 7.96 – 7.87 (m, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.52 – 7.48 (m, 2H) 13 C-NMR (125 MHz, CDCl3, ppm) δ 160.5, 160.1, 150.7, 136.9, 136.5, 134.3, 129.9, 128.8, 128.6, 127.5, 127.2, 123.6
Appendix 21: 1 H-NMR spectrum of 3ah
Appendix 22: 13 C-NMR spectrum of 3ah
Charaterization Data for 2-(2-Methoxyphenyl)quinazoline (3ah) 122
Prepare as shown in the general experimental procedure and was purified by silica gel column chromatography using hexane/ethyl acetate (1:1, v/v) as eluent: white solid, 75% yield 1 H-NMR (500 MHz, DMSO-d 6 , ppm) δ 9.67 (s, 1H), 8.21 – 8.16 (m, 1H), 8.04 (d, J = 3.5 Hz, 2H), 7.80 – 7.75 (m, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.50 (d, J = 0.7 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.10 (t,
J = 7.4 Hz, 1H), 3.79 (s, 3H) 13 C-NMR (125 MHz, DMSO-d 6 , ppm) δ 162.4, 160.9, 157.9, 150.2, 135.0, 131.7, 131.1, 129.5, 128.3, 128.1, 123.2, 120.7, 112.7, 56.2 One carbon signal could not be located
Appendix 23: 1 H-NMR spectrum of 3ai
Appendix 24: 13 C-NMR spectrum of 3ai
Charaterization Data for 2-(4-Methoxyphenyl)quinazoline (3ai) 121
Prepare as shown in the general experimental procedure and was purified by silica gel column chromatography using hexane/ethyl acetate (3:1, v/v) as eluent: white solid, 79% yield 1 H-NMR (500 MHz, DMSO-d 6 , ppm) δ 9.65 (s, 1H), 8.53 (d, J = 8.9 Hz, 2H), 8.14 (d, J = 8.0 Hz, 1H), 8.01 (dd, J = 4.5, 1.8 Hz, 2H), 7.70 (ddd, J = 8.0, 5.4, 2.5 Hz, 1H), 3.87 (s, 4H) 13 C-NMR (125 MHz, DMSO-d 6 , ppm) δ 162.1, 161.6, 160.2, 150.4, 135.2, 130.4, 130.3, 128.3, 128.2, 127.7, 123.5, 114.6, 55.8
Appendix 25: 1 H-NMR spectrum of 3aj
Appendix 26: 13 C-NMR spectrum of 3aj
Charaterization Data for 2-(4-(Trifluoromethyl)phenyl)quinazoline (3aj) 121
Prepare as shown in the general experimental procedure and was purified by silica gel column chromatography using hexane/ethyl acetate (5:1, v/v) as eluent: white solid, 70% yield 1 H-NMR (500 MHz, DMSO-d 6 , ppm) δ 9.77 (s, 1H), 8.76 (d, J = 8.3 Hz, 2H), 8.22 (d, J = 8.0 Hz, 1H), 8.14 – 8.05 (m, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.80 (t, J = 7.3 Hz, 1H) 13 C-NMR (125 MHz, DMSO-d 6 , ppm) δ 162.1, 158.8, 150.2, 141.7, 135.6, 131.1 (q,
Appendix 27: 1 H-NMR spectrum of 3ak
Appendix 28: 13 C-NMR spectrum of 3ak
Charaterization Data for 2-(Naphthalen-1-yl)quinazoline (3ak) 122