Thông tin tóm tắt về những đóng góp mới của luận án tiến sĩ: Nghiên cứu tổng hợp các hợp chất dị vòng 1,3-benzazole sử dụng lưu huỳnh

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]

GRADUATE UNIVERSITY SCIENCE AND TECHNOLOGY

-

Nguyen Le Anh

PROJECT NAME Developing of novel methods for synthesis 1,3-benzazole

AND TRAINING

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 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

1,3-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 benzothiazoles using a sulfur agent

1,3 New reaction for synthesis of 1,31,3 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

- Applied to the scale of 10 mmol and 100 mmol in the synthesis of benzoxazoles with the new optimized reaction

1,3 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 1 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 do 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 CO 2

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 2 EXPERIMENT 2.1 Chemicals and equipment

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 Phenylbenzo[d]thiazole

2-Nhiệt độ (°C) Hiệu suất %

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

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

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:

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

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

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

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 field area, the multiplet form at 8.92-8.93 ppm of proton at the H9 position

low-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]

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

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]

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-