Elemental sulfur mediated was reacted in redox condensation of benzyl chlorides and o-chloronitrobenzenes for the synthesis of 2-substituted benzothiazoles under metal- free condition, this research was proposed by Wang and co-worker in 2017(scheme 1.17a) [69]. In this year, Jing and co-workers introduced base-promoted sulfur-mediated in cyclization of proparginic amine as substrate with TFben (benzene-1,3,5-triyl triformate) and sulfur powder using DBU solvent at 350C, this reaction resulted 91% yield of cycling product (scheme 1.17b) [70]. At the same time, 2-substituted benzothiazoles were developed by Wang’s group from o-idoaniline, arylacetic acid and elemental sulfur in the presence of Cu(OAc)2.H2O as catalyst and K2CO3 as base using DMSO solvent with high yield (scheme 1.17c) [71]. Moreover, Li and co-workers generated the same product from 2-aminobenzenethiol and arylacetylenes using elemental sulfur, DMF solvent in air, the desired product could be established in 81% isolated yield (scheme 1.17d) [68].
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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].
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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].
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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
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synthesized by various methods. However, most of these methods show numerous limitations about using unavailable, unstable, expensive and highly toxic reactants causing environmental damage or using transition metal. For these reasons, it is necessary to report a new method to synthesize quinazoline derivatives utilizing available materials such as elemental sulfur, 2-nitrobenyzyl alcohol and phenylacetic acid.
1.5. The synthesis of quinazolinones
1.5.1. The C2 activation and Csp2 –N coupling reaction in organic synthesis N-containing organic structure frequently present in natural products, pharmaceuticals, bioactive molecules and other important materials [77]. Developing many approaches in order to synthesize these units which paid attention of numerous researchers. As a result, C–H bond activation reaction to form C–N bond through transition-metal-catalyzed had become essential producing N–containing compounds method [78].
In 2013, Liu’s group have reported the reaction C–N heteroarylation of pyridines in the presence of transition metal-catalyzed Pd(OAc)2, ligand and AgOAc as the oxidant; the cross-coupling transformation afforded moderate to good yield with different functional groups (scheme 1.21a) [77]. At the same year, imidazo[1,2-a]pyridines coumpounds were synthesized from pyridines and acetophenone oxime acetate through oxidative coupling the C–N bond by Huang and co-workers, with CuI as the catalyst, Li2CO3 and DMF solvent with high yield (scheme 1.21b) [78]. In this direction, Singh’ group had successfully developed an efficient cross-coupling reaction arylation of various heteroarenes via functionalization of C(sp2)–H using iron-catalyzed, oxidant agents at room temperature (scheme 1.21c) [80]. Moreover, pyridines derivatives were generated through dehydrogenative cross-coupling reactions between a sp2 C–H bond of pyridine and C–H bond of ether under the Sc(OTf)3 catalyst and DTBP oxidant by Salman and co-workers (scheme 1.21d) [81].
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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].
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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.
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In 2017, the C–H arylation coupling reaction between thiazole and aryl diazonium were reported by Ahmed’s group, through arylation at the C2 position of thiazole process and under 1,10-phenanthroline ligand, base KOtBu and DMSO solvent with various derivatives (scheme 1.24a) [87]. Moreover, Zeng and co-workers have demonstrated the direct C –H arylation of pyridine using the transition-metal-catalyzed; The main product 2,6-diarylpyridines were successfully identified by the reaction between pyridine and 1- bromo-4-methylbenzene in the presence of Pd catalyzed, K2CO3 base and DMAc solvent with high yield (scheme 1.24b) [88]. At the same time, Inturi’ group have published method synthesis 4,3-fused 1,2,4-triazoles via one-pot multicomponent domino reaction of pyridine, benzaldehyde and p-Toluensulfonhydrazide in oxidant condition, the main product as well as various derivatives were generated with excellent yield (scheme 1.24c) [89]. In this year, the regioselective arylamination of heterocyclic N–oxides were carried out by Biswas and co-workers with using CuI catalyst in 1,4-dioxane (scheme 1.24d) [90].
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Scheme 1.24. C2 selective and C –N bond formation reaction in 2017.
The C–H functionalization reaction of uncativated arenes to gain biaryl product were developed by Ahmad’s group in 2018, with high yield (scheme 1.25a) [91]. At that time, the C–C cross coupling reaction between 2-iodothiophene and benzene in the presence of KOtBu and ligand were proposed by Banik’s group (scheme 1.25b) [92].
Besides, the desired product 2-(1H-benzo[d][1,2,3]triazol-1-yl)quinoline and derivatives were synthesized from quinoline and 1H-benzotriazole as the nucleophilic reagent in MeCN solvent by Xie’s group, this reaction was shown in functionalization of C2 activation of N–heterocycles under metal and base-free conditions (scheme 1.25c) [93]. In 2019, N-fused imidazo 6,11-dihydro β-carboline derivatives were generated by Satyam and co-workers, using H2O solvent at room temperature with high yield and various derivatives (scheme 1.25d) [94].
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Scheme 1.25. C2 activation and Csp2–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
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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)
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[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-
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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].
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Scheme 1. 30. The reaction of synthesis quinazolinone derivatives.
1.6. 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.
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CHAPTER 2: EXPERIMETAL
2.1. 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 100oC for 1 minutes then heated sample from 100 to 280oC at 40oC/min and finally held them at 280oC 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 280oC. 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 50oC for 2 min; heated samples from 50 to 280oC at 10oC/min and held them at 280oC for 10 mins. Inlet temperature was set constantly at 280oC. MS spectra was compared with the spectra gathered in the NIST library.
Nuclear magnetic resonance (NMR) spectra (1H and 13C) were recorded on a Bruker AV 500 spectrometer using residual solvent peaks as references at Faculty of Chemistry – University of Science – Hanoi National University.
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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 140oC 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 GC analysis result.
Scheme 2. 1. General procedure of synthesis quinazolines.
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Table 2. 1. List of substances and vendors.
Substances Formula Vendor
2-nitrobenzyl alcohol (97%) C7H7NO3 Acros
biphenyl C12H10 Acros
Phenylacetic aicd (95%) C8H8O2 Sigma – Aldrich
urea (NH2)2CO Xilong Chemical
1,4-Diazabicyclo[2.2.2]octane (99%) C6H12N2 Sigma – Aldrich
Sulfur S8 Sigma – Aldrich
Dimethyl sufoxide (CH3)2SO Merck
ethyl acetate C4H8O2 Chemsol VN
2.2.2. Isolated product procedure
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, 1H-NMR and 13C-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 1400C in an oil bath for 2 hours and was monitored by TLC. At the end of the reaction, the flask
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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 1000C 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, 1H NMR and 13C NMR.
Scheme 2. 2. General procedure of synthesis quinazolinones.
2.3.2. Isolated product procedure
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
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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, 1H-NMR and 13C-NMR spectra.
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CHAPTER 3: RESULTS AND DISCUSSION
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.
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 800C to 1400C 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.