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 r[r]
(1)GRADUATE UNIVERSITY SCIENCE AND TECHNOLOGY -
Nguyen Le Anh
PROJECT NAME
Developing of novel methods for synthesis 1,3-benzazole using sulfur
Major: Organic Chemistry Code: 44 01 14
SUMMARY OF CHEMITRY DOCTORAL THESIS
Ha noi– 2021
VIETNAM ACADEMY OF SCIENCE AND TECHNOLOGY MINISTRY OF EDUCATION
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INSTRODUCTION 1 The urgency of the thesis
Benzazoles is one of the important compounds, representing a group of heterocyclic compounds with many interesting biological activities 1,3-benzazoles derivatives have been shown to be active against cancer, bacteria and mold [1, 2] In recent years, research into new methods of synthesizing derivatives of 1,3-benzazoles has attracted the attention of many scientists in the world Up to now, most of the 1,3-benzazoles synthesis methods have been based on a condensation oxidation reaction that uses the oxidizing effect of oxygen and is catalyzed with different metals However, the use of oxygen as an oxidizer has some drawbacks, such as the often poorly selective reaction, requiring the presence of a metal catalyst, sometimes expensive, and the complicated catalytic-type product refining process The manipulation of gaseous oxygen requires special reactors, especially at high temperatures and high pressures Recently, sulfur is being studied for use in many condensation oxidation reactions Using sulfur as a condensate oxidation reaction agent or catalyst has several advantages such as sulfur as a solid, non-hygroscopic, durable, and non-toxic Compared to oxygen, it is easy to use the exact amount of sulfur in a reaction even at high temperatures In addition, reactions with sulfur can be catalyzed with inexpensive metals and no significant toxicity such as iron, molybdenum With the above advantages, sulfur chemistry is an appropriate method with a green, environmentally friendly approach
Therefore, in order to research and develop some new simple, environmentally friendly methods using sulfur, we have implemented the thesis with the name ‘‘Developing of novel methods for synthesis 1,3-benzazole using sulfur’’
2 The research objectives of the thesis
- Successfully studied a new multi-component reaction to synthesize 1,3-benzothiazoles using a sulfur agent
- New reaction for synthesis of 1,3-benzoxazoles using a sulfur catalyst 3 Research content
- Construction of conditions and optimization of 1,3-benzothiazole fusion from o-chloronitrobenzen, aldehydes, sulfur
- Synthesis of different derivatives of 1,3-benzothiazole under optimal conditions
- Construction of conditions and optimization of new reaction for synthesis 1,3-benzoxazoles from o-aminophenol, aldehyde, sulfur
- Synthesis of various derivatives 1,3-benzoxazole
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- Reaction products are cleaned by column chromatography The structure of the product is determined by modern spectroscopic methods such as: NMR, HR-MS, X-ray
CHAPTER OVERVIEW 1.1 Overview of benzazole compounds
1.2 Benzazole compounds in nature
1.2.1 Benzazole compounds were extracted from Streptomyces 1.2.2 Benzazole compounds were isolated from marine organisms
1.3 The compounds contain semi-synthetic benzazole frames 1.4 Benzazole synthesis methods not use sulfur
1.4.1 Methods of benzoxazole synthesis
1.4.1.1 Synthesis of benzoxazole with condensation of o-Aminophenol and Aldehyde or diketone
1.4.1.2 Synthesis of benzoxazole from o-Aminophenol and carboxylic acid or ester 1.4.1.3 Synthesis of benzoxazole from o-aminophenol with diaryl acetylene
1.4.1.4 Synthesis of benzoxazole from anilines compounds 1.4.1.5 Synthesis of benzoxazole from aryne
1.4.1.6 Synthesis of benzoxazole from Schiff base
1.4.1.7 Multi-component reaction for synthesis of benzoxazole 1.4.2 Synthesis of benzothiazole
1.4.2.1 Synthesis of benzothiazole from o-aminothiophenol with aldehyde, ketone, carboxylic acid and acyl chloride
1.4.2.2 Synthesis of benzothiazole from 2-aminothiophenol with CO2
1.5 Synthesis benzazole use sulfur
1.5.5 Synthesis of benzoxazole
1.5.5.1 From o-nitrophenol 1.5.5.2 From o-aminophenol
CHAPTER EXPERIMENT 2.1 Chemicals and equipment
2.1.1 Chemicals 2.1.2 Equipment
2.2 Method of determining the cleanliness and studying the structure of the product
2.2.1 Thin layer chromatography 2.2.2 Column chromatography
2.2.3 Method of determining structures
2.3 Synthesis of benzothiazoles 2.4 Synthesis of benzoxazoles
CHAPTER RESULTS AND DISCUSSION 3.1 Synthesis of benzothiazoles
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We constructed a reaction model in which three starting materials o-chloronitrobenzene 109a, aldehyde 110a and elemental sulfur were 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
110 20
120 25
130 40
140 30
0 10 20 30 40 50
100 110 120 130 140
ye
ild (
%)
temperature 0C
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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 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 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 equivalents The reaction was conducted for 16 h at 130 °C Reaction efficiency increased by 65% Thus, with the use of 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
4
6
8 10
10 30
12 40
14 60
16 65
17 62
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Figure 3.3 Investigation of reaction time 2-Phenylbenzo[d]thiazole
From the survey response time graph we see that During the period from h to 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 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 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
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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 = 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
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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
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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
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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
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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
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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, 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
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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,
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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
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On the 1H spectrum of compound 111av appeared 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
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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
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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
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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
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%
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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
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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)
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2 - -
3 7.38-7.34 (m, 2H) 7.39-7.36(m,2H) 7.80-7.77 (m, 1H) 7.80-7.78(m,1H) 7.61-7.55 (m, 1H) 7.61-7.55 (m,4H) 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
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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% (Figure 3.32)
Figure 3.32 Structure of 114pa
The reaction was conducted under the above optimum conditions with 2-aminophenol containing different substituents The results were obtained with the desired benzoxazole derivatives with an efficiency of 72% to 90% (Figure 3.33)
Figure 3.33 Structure of 114ab to 114af
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dichloromethane/H2O system and filtered through silica gel When conducting
benzoxazole fusion reactions following this method, there is no change in pressure even though H2S is a byproduct of the reaction This proves that this
toxic gas is trapped in the reaction medium Check the raw mixture of the reaction with 1H NMR, see on 1H NMR spectrum with a peak at 2.12 ppm as
the position of dimethyl sulfide (Figure 3.34)
Figure 3.34 1H NMR spectra of the crude mixture of fusion 114fa While the exact mechanism of this process is not fully understood, we propose that H2S reacts with DMSO to regenerate sulfur and release dimethyl
sulfide (Figure 3.35) [124]
Figure 3.35 The reaction of DMSO with H2S
On the basis of these and previous works, a mechanism is proposed as described in Figure 3.36
DMSO
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Figure 3.36 Reaction mechanism proposed to synthesize benzoxazole With the aid of the sulfide anion from sodium sulfide as a Lewis base catalyst to open the sulfur ring, highly nucleophilic polysulfide A anions are formed and participate in the addition of imine B generated from the condensation of andehyde 112a with 2-aminophenol 113a The formed polysulfide-amide C may undergo a proton transition to provide phenolate D, which is cyclized to benzoxazoline E Ultimately the hydrogen sulfide removal produces 114aa product
CONCLUDE The main results of the thesis are as follows:
1 A new multi-component reaction synthesizing 1,3-benzothiazole derivatives using a sulfur agent has been successfully studied Performance conditions:
- Ratio of o-chloronitrobenzene : S : aldehyde : N-methylmorpholine (1 : : 1.2 : 4)
- The reaction time on 16h at130 oC
- Yeild (61% to 80%.)
Application for synthesis 30 benzothiazoles compound with different substituents (group push e: -OMe, -OH electron suction group: -CN, -CF3, NO2, bulky substituents such as naphthalene, heterocyclic groups such as thiophen, indole, pyridine, halogen substituents -F, -Cl) Including 02 new compounds are 111at (1,3-Bis(benzo[d]thiazol-2-yl)benzene) and 111av (2,6-Bis(benzo[d]thiazol-2-yl)pyridine)
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X-ray spectroscopy of the N-methylmorpholine.SO3 complex was obtained
Thereby, clarifying and proposing the mechanism of the new multi-component reaction
In particular, this new reaction has been applied in the successful synthesis of PMX 610 compound with strong anti-tumor properties
2 A new reaction for synthesis of 1,3-benzoxazole using sulfur such as oxydative catalyst Performance conditions:
- Ratio of aldehyde : 2-aminophenol : S : Na2S.5H2O : DMSO (1 : : : 0.1 : 1.5)
- Time for reaction on 16 h at 70 oC - Yeild (40% to 78%)
A new synthesis of 1,3-benzoxazole has been successfully studied using sulfur as an oxidation catalyst Implementation conditions: Applied this new method successfully to synthesize 21 benzoxazole compounds with different substituents (e: -Me, -OMe, -OH push groups, e: -CN, -NO2, bulky substituents such as
naphthalene, halogen substituents such as -F, -Br, -Cl)
A mechanism for 1,3-benzoxazole fusion has been proposed
NEW CONTRIBUTIONS OF THE THESIS
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PUBLICATIONS
1 Le Anh Nguyen, Anh Quoc Ngo, Pascal Retailleau, Thanh Binh Nguyen, Elemental Sulfur as Polyvalent Reagent in Redox Condensation with o-Chloronitrobenzenes and Benzaldehydes: Three-Component Access to 2-Arylbenzothiazoles, Green Chem., 2017,19, 4289-4293
2 Le Anh Nguyen, Thai Duy Dang, Quoc Anh Ngo, Thanh Binh Nguyen,
Sulfur-Promoted Synthesis of Benzoxazoles from 2-Aminophenols and Aldehydes, Eur J Org Chem., 2020, 25, 3818-3821