Developing of novel methods for synthesis 1,3 - Benzazole using sulfur

Reacts with benzyl alcohol 101a, dibenzyl disulfide 102, phenylglycine

103, mandelic acid 104, or phenylglyoxalic acid 105 to synthesize

benzothiazole 111aa under the above optimum conditions. The performance of

the reaction was moderate to good. As can be seen, all of these reactions are

unbalanced redox. In the reaction between 109a, sulfur and benzyl alcohol 101a

are unbalanced redox type due to the synthesis of the compound benzothiazole

111aa, the -NO2 group of compound 109a requires 6e, S requires 2e while for

1eq 101a provide maximum 4e-. Similar to the reactions of 103, 104, 105,

when conducting the experiment, we see the formation of CO2, which means,

there will be decarboxyl reaction of compounds 103, 104, 105, respectively. a

reducing agent similar to benzyl alcohol 101a (compound 103, 104) and

bezadehyde (compound 105). That means, sulfur will act as a compensating

reducing agent 6e. Based on this result, we proceeded to synthesize

benzothiazole derivatives under optimal conditions by condensation

 between ochloronitrobenzene, benzyl alcohol and sulfur. Since benzyl alcohol is more

stable than benzaldehyde, the same 1.2 use as used with benzaldehyde is not

necessary.

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re used with equal equivalent. N-methylmorpholine (4 eq) is used as a base because it is believed to be suitable for this purpose in previous studies [121a, b]. We selected the ratio of the starting substances o-chloronitrobenzene: S: aldehyde: N-methylmorpholine (1: 1: 1: 4) to optimize the reaction conditions around this ratio. Response time is 16 hours. 3.1.1. Optimization of the benzothiazole synthesis * Survey reaction temperature Bảng 3.1. Effect of temperature on the reaction efficiency of the synthesis 2- Phenylbenzo[d]thiazole Nhiệt độ (°C) Hiệu suất % 100 0 110 20 120 25 130 40 140 30 0 10 20 30 40 50 100 110 120 130 140 ye ild ( % ) temperature 0C Figure 3.1. Survey reaction temperature synthesis of 2-Phenylbenzo[d]thiazole From the graph of reaction temperature, we see that at 100 oC, the reaction does not happen. When the reaction temperature increases, the reaction begins at 110 °C with an efficiency of 20%. Continue to increase the reaction temperature at 120 oC, 130 oC, 140 oC, the yield is 25%, 40% and 30% respectively. Thus, it 4 can be seen that, with the ratio of the initial substances o-chloronitrobenzene: S: aldehyde: N-methylmorpholine (1: 1: 1: 4) at 130 oC, the reaction reaches the highest efficiency of 40%. Therefore, the ratio o-chloronitrobenzene: S: aldehyde: N-methylmorpholine (1: 1: 1: 4) is not the optimal ratio of the reaction. If benzaldehyde acts as a reducing agent, the reaction efficiency is up to 25%. This is explained, in the synthesis of benzothiazole from o- chloronitrobenzene, to reduce the NO2 group requires 6e, while 1 aldehyde equivalent gives only 2e. However, the actual efficiency of the reaction was 40%. This proves that sulfur can act both as a reaction participant, and as an additional reducing agent e- missing in this synthesis. This suggests us to increase the sulfur equivalent to 2 eq as an additional reducing agent e- (Figure 3.2). Figure 3.2. Role of sulfur in e- compensation We proceeded to increase the amount of sulfur to 2 equivalents. The reaction was conducted for 16 h at 130 °C. Reaction efficiency increased by 65%. Thus, with the use of 2 sulfur-equivalent, 111aa benzothiazole synthesis improved. Next, we investigate response time. * Survey response time Table 3.2: Effect of time on reaction efficiency of 2-Phenylbenzo[d]thiazole synthesis Time (h) Yield % 2 0 4 0 6 3 8 10 10 30 12 40 14 60 16 65 17 62 18 55 5 Figure 3.3. Investigation of reaction time 2-Phenylbenzo[d]thiazole From the survey response time graph we see that. During the period from 4 h to 8 h the reaction did not occur or occurred with low efficiency (10%). Continuing to prolong the reaction time, we found that the longer the reaction time, the higher the reaction efficiency, the highest yield of 65% when the reaction lasted 16 h. When prolonged up to 18 h, response efficiency reached 55%. Thus, with the top ratio o-chloronitrobenzene: S: aldehyde: N- methylmorpholine (1: 2: 1: 4) the reaction time for the highest performance (65%) is 16 h at 130 oC. As can be seen, it is reasonable to increase sulfur to act as an e- supplemental reducing agent. Investigated at 130 oC temperature, reaction time 16 h and using 3 sulfur equivalents, the reaction produced a 111aa benzothiazole product with an efficiency of 72%. Benzadehyde is susceptible to oxidation under reaction conditions as well as during storage. To compensate for this deficiency, we increased the amount of benzaldehyde to 1.2 eq to compensate for its loss due to self-oxidation during storage and undesirable oxidation during the reaction. The result increases reaction efficiency by 80%. The amount of N-methymorpholine is also an important parameter for the success of the reaction. If N-methylmorpholine is reduced to 3 equivalents, the yield is reduced to 73%. Using a stronger base such as 3-picoline (pKa = 5,63) instead of N-methylmorpholine (pKa = 7.61) resulted in a 30% reduction in reaction efficiency. Thus, with the top ratio o-chloronitrobenzene: S: aldehyde: N-methylmorpholine (1: 2: 1.2: 4), the maximum yield of 16 h at 130 oC is the optimal condition for the process. benzothiazole fusion according to this method. To confirm the successful synthesis of 111aa benzothiazole, we demonstrated the structure of this compound by nuclear magnetic resonance spectroscopy NMR: 1H, 13C as follows: 6 Figure 3.4. 1H spectrum of compound 111aa On the 1H spectrum of compound 111aa, the full proton resonance signal appears in the molecule. The resonant signal in the multiplet low field region at 8.08-8.12 ppm of 3H at position H3, H12, H9 is attached to the benzene ring, in addition, the doublet-doublet signal is in the range 7.90-7.92 ppm (d, J = 8 Hz, 1H) at position H6 and a multiplet signal in the range 7.49-7.51 (m, 4H) are assigned to positions H4, H5, H10, H11. Triplet signal at about 7.38-7.41 ppm (t, J = 7.5 Hz, 1H) at position H13. Figure 3.5. 13C spectrum of compound 111aa On the 13C-NMR spectrum of the compound 111aa, it shows the resonance signal of 14 carbon atoms, at the resonant C1 position δ = 168.1 ppm (C7), 135.1 ppm (C8), 133.6 ppm (C2), the The difference between the two CH 7 resonant groups at 129.1 ppm (C9, C12) and 127.6 ppm (C10, C11), 126.3 ppm (C5), 125.2 ppm (C4), pair 123.2 and 121.6 ppm (C3 and C6). Thus, we have succeeded in synthesizing benzothiazole 111aa by the above method. The 1H NMR, 13C NMR data of 1,3-benothiazole derivatives (from 111aa to 111de) are described in the thesis. Next, to evaluate the reactivity of o-halonitrobenzene in benzothiazole synthesis by this method. We reacted with o-fluoronitrobenzene, o-bromonitrobenzene and o-iodonitrobenzene under optimized conditions that were successfully applied to other o-halonitrobenzenes to provide 111aa benzothiazole for high efficiency of 76%, respectively. 77% and 81%. 3.1.2. Synthesis of benzothiazole derivatives with the above optimal conditions With the above optimal reaction conditions, we conducted a benzothiazole fusion from o-chloronitrobenzene with different aldehydes. Different 110b-s aldehydes (Figure 3.6) are reacted with o-chloronitrobenzene 109a. Figure 3.6. Aldehyde derivatives from 110b to 110s These aldehydes are all available in the market at a low cost. Many different substituents including electron repellant groups (OMe, OH) and electron aspirating potential groups (CF3, CN, NO2), different substituent positions in the aromatic ring of aldehydes 110 are possible with reaction (benzothiazole 111ad-111al) with an efficiency of between 62% and 74% (Figure 3.7). Thus, it can be seen that our method is suitable for different potential groups including electron repulsive potential groups and electron 8 attraction potential groups. Compared with other methods, our benzothiazole synthesis method is more widely applied and therefore will not be limited by the structure of the starting substances as well as the synthetic benzothiazole derivatives. Figure 3.7. The 111ab-111al benzothiazole compounds are synthesized To identify these structures, we choose substance 111al as a representative. 111al structure will be demonstrated by nuclear magnetic resonance spectroscopy NMR: 1H, 13C 9 Figure 3.8. 1H NMR spectrum of compound 111al On the 1H spectrum of compound 111al appeared eight proton resonance signals present in the molecule. The resonant signal in the low- field area, the multiplet form at 8.92-8.93 ppm of proton at the H9 position is attached to the benzene ring, the multiplet form at 8.41-8.43 ppm of H at the H13 position, the multiplet form at 8.32-8.34 (m, 1H) H11 is attached to benzene ring, doublet form at 8.11-8.13 ppm at H6 position on benzothiazole, doublet form at 7.94-7.95 ppm of proton at H3 on benzothiazole, triplet form at 7.67-7.70 ppm of proton at position H12 position was attached to benzene ring, multiplet form at 7.53-7.56 ppm H4, and 7.44-7.47 ppm were assigned to proton at H4 and H5 attached to benzothiazole ring. Figure 3.9. Spectrum 13C NMR compound 111al On the 13C-NMR spectrum of the 111al compound that fully shows the resonance signals of 14 carbon atoms, at the resonant C1 position δ = 164.9 ppm (C7), 148.8 ppm (C10), 135.3 ppm (C8), 135.2 ppm (C2), CH resonant group signal at 133.0 ppm (C13), 130.1 ppm (C12), 126.9 ppm (C5), 126.1 ppm (C4), 125.2 (C11), 123.8 (C9), 122.4 ppm (C3), 121.8 ppm (C6). Thus, we successfully synthesized benzothiazole compounds when changing the different substituents of aldehydes. Through the synthesis of 111al, we found that 111al compound with -NO2 group was still used when using 110l m-Nitrobenzaldehyde as the first agent of the reaction. Although the -NO2 group is easily reduced under reaction conditions, it proves that the reaction does not follow the same mechanism as before [65-66]. 10 Figure 3.10. Benzothiazole synthesis reaction via imine-mediated compound In this reaction, only the nitro group of 109a is affected, indicating that reduction of this nitro group will not be the first step of the reaction so the reaction will occur via an endolecular mechanism. Initial substances were performed for both naphthaldehyde (96m-n) as well as heterocyclic aromatic aldehydes (110o-s) to synthesize benzothiazole (111am- 111hm) with high efficiency from 60% to 76% (Figure 3.11). Figure 3.11. Benzothiazole compounds 111am, 111an, 111ao and 111ap Reactions with all three isomers of pyridinecarboxaldehyde resulting in pyridylbenzothiazole (111aq-111as) did not show any noticeable difference in reactivity. In comparison with previous methods [75], our method has successfully performed this layer under milder conditions such as the reaction only need to be conducted at 130 oC compared to 275 oC. Our method also does not need to use solvents, while previous studies use expensive solvents [75]. Figure 3.12. Pyridylbenzothiazole 111aq-111as When optimizing the conditions for benzothiazole fusion, benzaldehyde is used 1 eq to 1.2 eq. To prove this ratio is suitable, we conducted a benzothiazole fusion from a compound containing 2 groups of -CHO (96t) with the amount of 0.5 quantitative use. The results have synthesized a bis- benzothiazole 111at compound with an efficiency of 67% (Figure 3.13). This proves that the use of 1 equivalent of benzaldehyde is reasonable for this reaction. 11 Figure 3.13. Synthesis of bis-benzothiazole 111at from aldehyde 96t Subsequent evaluation of a series of 109b-h o-chloronitrobenzenes was performed. The reaction is done with both the group of substances with electron repellent group (Me, MeO) and electron attraction group (CF3) in para position of initial Cl group (Figure 3.14). Figure 3.14. Benzothiazoles 111ba, 111ca, 111da were synthesized A question posed when performing the o-chloronitrobenzen reaction is that with chloronitrobenzen containing more than one chlorine atom, do other chlorine groups attack with sulfur or not? To explore this further the reaction was performed with 109e-g having more than one -Cl substituent group. The results showed that, only Cl atom at the ortho position was attacked by sulfur, the remaining group was still intact (Figure 3.15). Figure 3.15. Benzothiazoles 111ea, 111fa, 111ga were synthesized Redox condensation of 2-chloro-3-nitropyridine 109h to form 111ha benzothiazole was also successfully performed with efficiency of 61%. Figure 3.16. Structure compound of 111ah The application of this multi-component desensitizing oxidation is applied to the synthesis of benzothiazole PMX 610 (Figure 3.17), identified as a potent and selective anti-tumor agent [123]. 12 Figure 3.17. Structure compound of PMX 610 Both the 109iI o-chloro derivatives and the 109iF o-fluoro derivatives reacted with sulfur and veratraldehyde 110e with good performance (76%). Continuing further research on the role of sulfur in the redox reaction between o-chloronitrobenzene 109a and sulfur, we have selected a number of reducing compounds for the phenylmethine radical of benzothiazole 111aa through the oxidation process. (Figure 3.18). Figure 3.18. Synthesis benzothiazole 111aa from reducing compounds to phenylmethine radical Reacts with benzyl alcohol 101a, dibenzyl disulfide 102, phenylglycine 103, mandelic acid 104, or phenylglyoxalic acid 105 to synthesize benzothiazole 111aa under the above optimum conditions. The performance of the reaction was moderate to good. As can be seen, all of these reactions are unbalanced redox. In the reaction between 109a, sulfur and benzyl alcohol 101a are unbalanced redox type due to the synthesis of the compound benzothiazole 111aa, the -NO2 group of compound 109a requires 6e, S requires 2e while for 1eq 101a provide maximum 4e-. Similar to the reactions of 103, 104, 105, when conducting the experiment, we see the formation of CO2, which means, there will be decarboxyl reaction of compounds 103, 104, 105, respectively. a reducing agent similar to benzyl alcohol 101a (compound 103, 104) and bezadehyde (compound 105). That means, sulfur will act as a compensating reducing agent 6e. Based on this result, we proceeded to synthesize benzothiazole derivatives under optimal conditions by condensation between o- chloronitrobenzene, benzyl alcohol and sulfur. Since benzyl alcohol is more stable than benzaldehyde, the same 1.2 use as used with benzaldehyde is not necessary. The successful synthesis of benzothiazole derivatives from o- 13 chloronitrobenzene, benzyl alcohol proves that sulfur is the compensatory reducing agent 6e (Figure 3.19). Figure 3.19. Synthesis benzothiazole from benzyl alcohol We have successfully synthesized benzothiazole 111ab, 111ad, 111ae, 111au and 111av derivatives with yields of 52%, 85%, 31% and 63%, respectively. With benzyl alcohol having p-trifluoromethyl substituent, it is less suitable for this reaction (efficiency reaches 31%). The reaction of 2,6- dimethanolpyridine 101v demonstrated the diversity of this method, resulting in a new compound bis-benzothiazole 111av with good efficiency (68%). To demonstrate the 111av new compound structure, we used nuclear magnetic resonance method 1H, 13C and high resolution mass spectrometry HRMS. Figure 3.20. 1H NMR spectrum of compound 111av 14 On the 1H spectrum of compound 111av appeared 6 proton resonance signals. The doublet signal at 8.44 ppm is assigned to position H3 on the benzothiazole branch, the doublet form at 8.11 ppm is assigned to the H9 position on the pyridine branch, the triplet form at 8.00 ppm is the H6 position of the benzothiazole branch, the doublet form at 7.98 ppm is the H10 position on the pyridine branch, the multiplet form at 7.55-7.49 ppm is the H5 position on the benzene ring of the benzothiazole branch, the multiplet form at 7.46-7.41 is the H4 position on the benzene ring of the benzothiazole clade. Figure 3.21. 13C NMR spectrum of compound 111av On the 13C spectrum of substance 111av appears 10 carbon resonance signals. Where the fourth carbon at position C1 on the benzothiazole branch is the signal at 154.6 ppm, and in the 168.8 ppm region it is the carbon 4 position at the C8 position of the carbon 4 position on the pyridine branch. 15 Figure 3.22. HR-MS spectrum of compound 111av High resolution mass spectrometry, we found peak 346.0466 consistent with molecular formula C19H12N3S2 [M + H]+ (Figure 3.22). From these analysis results, we conclude that compound 111av has been successfully synthesized. To evaluate the range of this reaction with aliphatic aldehydes, we performed a benzothiazole fusion from o-halonitrobenzen with aliphatic aldehydes under the above optimum conditions. The results show that the current conditions are not suitable for aldehyde aliphatic. For example, the reaction of 95a with hexanal leads to a complex mixture. From this preliminary result, one hypothesis is that the reaction with a sulfur atom produces a benzothiazole molecule with three oxygen atoms and one HCl molecule as a byproduct (Figure 3.23). Figure 3.23. Equations for benzothiazole fusion While the HCl is trapped as the N-methylmorpholinium chloride salt, the oxygen atoms are fixed by the components of the reaction. Sulfur acts as an oxygen recovered, fixing these oxygen atoms to sulfur oxides. These sulfur oxides obviously cannot exist in free form in the reaction medium because of their interaction with other components in this mixture. When excess N- methylmorpholine is used, SO3 complexes with this nitrogen base. This type of compound has previously been reported to be easily prepared by mixing their original components and hydrolyzed to sulfate when treated with water [122]. For a more in-depth look at the nature of these oxidized sulfur compounds, the raw mixture was further analyzed and two important clues were obtained. First, the aqueous layer obtained from treating a coarse mixture with water in an inert medium (to avoid aerobic oxidation) gives a positive result for a sulfate test (aqueous BaCl2/HCl solution). Second, during the purification of the crude mixture by chromatography, a polarity containing different amounts of compound X is obtained that is contaminated with N-methylmorpholine. From this section, a number of crystals were obtained and their structures determined by X-ray diffraction method (Figure 3.24). 16 Figure 3.24. Structure X-ray of X A mechanism is proposed as shown in Figure 3.25. Figure 3.25. Proposed mechanism for benzothiazole synthesis The reaction is thought to begin with the attack of the reversible A complex between sulfur and N-methylmorpholine on benzaldehyde 110a to form zwitterion (bipolar ions) B. The subsequent fragmentation of B leads to polythiobenzoat C, this reaction with o-chloronitrobenzene 109a to produce o- nitro polysulfide D. Although the detailed mechanism of D to the final 111aa benzothiazole is not clear at this time, the redox redox process. The potential occurs through the gradual transfer of oxygen atoms from the nitro group to an internal sulfur atom of the polysulfur chain D. Nitrososulfoxide E formation followed by a series of related redox reactions up to the elimination of N- methylmorpholine aided by an SO3 molecule results in benzothiazole 111aa. 3.2. Synthesis benzoxazoles Figure: 17 We constructed a reaction model in which three starting materials o- aldehyde 112a, 2-aminophenol 113a and elemental sulfur were used in equal amounts. Na2S.5H2O has been chosen to catalyze sulfur because it has been found suitable for this purpose in previous studies [125, 126]. We selected the ratio of the starting aldehyde: 2-aminophenol: S: Na2S.5H2O: DMSO (1: 1: 1: 0.1: 1.5) substances to optimize the reaction conditions around this ratio. Response time is 16 hours. 3.2.1. Optimization of the benzoxazole synthesis * Survey reaction temperature Table 3.2. Effect of temperature on performance of benzoxazole fusion Temperature (°C) Yeild % 90 67 80 69 70 72 60 0 Figure 3.26. Investigating the effect of temperature on synthesis benzoxazole From the graph of investigating the effect of temperature on synthesis benzoxazole, it showed that at a high temperature of 90 oC, the reaction efficiency is only 67% worse when reducing the reaction temperature to 80 oC (69%). and the most efficient reaction at 70 oC reaction occurred with an efficiency of 72%. Reducing the reaction temperature further to 60 °C, the reaction does not occur (only the first substance involved in the reaction is obtained). Thus, provided the ratio of the initial aldehyde: 2-aminophenol: S: Na2S.5H2O: DMSO (1: 1: 1: 0.1: 1.5) substances at 70 oC, the highest obtained reaction efficiency is 72%. * Replace DMSO with DMAc, DMF for reaction 18 Using the above conditions to change DMSO by DMAc, the reaction of DMF does not occur. Based on these results, DMSO is selected for the benzoxazole fusion following this method. Next, with the above conditions (aldehyde: 2-aminophenol: S: Na2S.5H2O: DMSO (1: 1: 1: 0.1: 1.5) at 70 oC), continue to investigate the amount of DMSO needed when performing the reaction. benzoxazole synthesis. Table 3.3: Effects of amount of DMSO used on efficiency of synthesis benzoxazole DMSO (ml) Yeild (%) DMSO (0,1 ml) 72 DMSO (0,2 ml) 62 DMSO (0,05 ml) 65 Figure 3.27. Investigation of the amount of DMSO in synthesis benzoxazole From the survey graph of DMSO amount of benzoxazole fusion shows that using 0.1 ml of DMSO is suitable for the reaction to occur with high efficiency (72%), with 0.2 ml or 0.05 ml of DMSO, difference the yield is 62% and 65%, respectively. In the absence of DMSO, reaction did not occur. * Sulfur activation catalytic investigation by Na2S.5H2O, NMM, NMP, Pyridine, DIPEA, K2CO3, Na2CO3 The reaction is carried out with Na2S.5H2O as a sulfur activation catalyst. In addition, NMM, NMP, Pyridine, DIPEA, K2CO3, Na2CO3 were also selected for the survey. Results showed that, with organic bases (NMM, NMP, Pyridine, DIPEA), the reaction obtained a complex mixture, no sign of the benzoxazole product needed to synthesize. With K2CO3, Na2CO3 reaction does not occur, the reaction mixture is the first substance. With this result, Na2S.5H2O is a suitable catalyst for sulfur activation in our reaction. Conducted the reaction without Na2S.5H2O catalyst, the reaction did not occur. The amount of sulfur is also one of the important factors in the synthesis of benzoxazole by this method. With the conditions examined above (aldehyde: 19 2-aminophenol: S: Na2S.5H2O: DMSO (1: 1: 1: 0.1: 1.5) at 70 oC), the reaction is carried out with a reduction of S to 0.5 By contrast, the efficiency of the reaction is reduced (efficiency obtained under this condition is 42%), when no reactive sulfur is used. Thus, the optimal condition of the reaction is aldehyde: 2-aminophenol: S: Na2S.5H2O: DMSO (1: 1: 1: 0.1: 1.5) at 70 °C. To demonstrate the successful synthesis of benzoxazole by the method Here, we use nuclear magnetic resonance method 1H and compare with relevant documents in the determination of the structure of benzoxazole: On the 1H-NMR spectrum of substance 114aa showed that the resonance signals of protons are shown as follows: the resonance signal in the low field multiplet form at 8.29-8.25 ppm of 2H at the H9 and H12 positions, the signal at 7.80-7.77 ppm (m, 1H) in H4 position, signal at 7.61-7.55 ppm (m, 1H) in H5 position, signal at 7.54-7.52 ppm (m, 3H) in H10, H11 position , H13, signal at 7.38-7.34 ppm (m, 2H) at position H3, H6. Figure 3.28. 1H- NMR spectrum of 114aa Table 3.4. Compare the 1H spectrum data, for the 114aa compound with 2- phenyl-benzoxazole [111] C 114aa 2-phenyl benzoxazole [111] H, ppm (J, Hz) (500MHz, CDCl3) H, ppm (J, Hz) (400MHz, CDCl3) 1 - - 20 2 - - 3 7.38-7.34 (m, 2H) 7.39-7.36(m,2H) 4 7.80-7.77 (m, 1H) 7.80-7.78(m,1H) 5 7.61-7.55 (m, 1H) 7.61-7.55 (m,4H) 6 7.38-7.34 (m, 2H) 7.39-7.36 (m,2H 7 - - 8 - - 9 8.29-8.25 (m,2H) 8.29(d, J= 4.0 Hz, 2H) 10 7.54-7.52 (m,3H) 7.61-7.55 (m,4H) 11 7.54-7.52 (m,3H) 7.61-7.55 (m,4H) 12 8.29-8.25 (m,2H) 8.29(d,J=4.0Hz, 2H) 13 7.54-7.52 (m,3H) 7.61-7.55 (m,4H) Thus, the 1H NMR spectral data obtained for the 114aa compound are consistent with the structure of 2-phenylbenzo[d]oxazole and consistent with the results published earlier [111]. The 1H NMR spectral data of 1,3-benzoxazole compounds (from 114aa to 114db) are described in the thesis. 3.2.2. Synthesis of benzoxazole derivatives under optimal conditions With optimal conditions on hand, we synthesized this benzazole with 2- aminophenol and aldehydes. With electron repulsive groups (Me, OMe, OH, CN), the desired benzoxazole derivatives are obtained with an efficiency of 40% to 75%) or electron absorbent group (NO2) (Figure 3.29). Figure3.29. 1,3-benzoxazole compounds from 114ba to 114la With the 4-F, 4-Cl, 4-Br halogen substituents of aldehydes, the desired benzoxazole product is obtained with an efficiency of 55-78% (Figure 3.30). 21 Hình 3.30. 1,3-benzoxazole compounds from 114ca to 114oa In addition, with bulkier aldehyde (Naphthaldehyde), benzoxazole 114ma is obtained with a 70% efficiency (Figure 3.31). Figure 3.31. Structure of 114ma Especially in our reaction conditions, the work with aldehyde aliphatic also synthesizes the desired benzoxazole (114pa) with an efficiency of 70% (Figur

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