Tóm tắt tiếng anh: Nghiên cứu tổng hợp, cấu trúc và khảo sát hoạt tính sinh học của một số hợp chất chứa dị vòng Benzothiazol.

MINISTRY OF EDUCATION AND TRAINING
HANOI NATIONAL UNIVERSITY OF EDUCATION

NGUYEN THI NGOC MAI

STUDY ON SYNTHESIS, STRUCTURES AND BIOLOGICAL ACTIVITY
EVALUATION OF SOME DERIVATIVES
CONATING BENZOTHIAZOLE AND BENZOXAZOLE

Major: ORGANIC CHEMISTRY
Code: 9.44.01.14

ABSTRACT OF DOCTORAL THESIS IN CHEMISTRY

Ha Noi, 12/2021


The Research Works is completed at: Hanoi National University of
Education

Supervisor: 1. Dr. Duong Quoc Hoan
2. Dr. Trinh Thi Huan

Reviewer 1: Prof. Pham Quoc Long
Institute of Natural Products Chemistry
Reviewer 2: Prof. Nguyen Hai Nam
Hanoi University of Pharmacy
Reviewer 3: Assoc. Prof. Vu Quoc Trung
Hanoi National University of Education

The thesis is defended before Board of Thesis Examiners at Institutional

level met in Hanoi National University of Education at ………on
……………………..

The thesis can be found at the library: National Library, Hanoi
or the Library of Hanoi National University of Education


INTRODUCTION
1. Reasons for choosing the topic
Benzothiazole heterocyclic derivatives have an important role in many
fields, especially in synthetic chemistry, medicine and pharmaceuticals due to
their diverse biological activities such as antibacterial, antifungal, anticancer etc.
Many benzothiazole heterocyclic compounds are used in drugs such as: Riluzole
used in antidepressant, Zopolrestat used to treat diabetic complications and
Ethoxazolamide used as treatment for glaucoma, diuretics, duodenal ulcers etc.
Many benzothiazole derivatives currently in clinical trials have shown the
importance of this heterocycle.
Besides, benzoxazole is a heterocyclic compound commonly found in
nature as well as in synthesis. Benzoxazole is found in the chemical structure of
several pharmaceutical products such as: anti-inflammatory drug
Flunoxaprofen, antibiotic Calcimycin, analgesic, antipyretic and antiinflammatory Benoxaprofen etc. Benoxaprofen heterocyclic derivatives have
also received significant attention from scientists due to its diverse biological
activities such as anticancer, antibacterial, anticonvulsant.
However, researches on these two heterocycles in Vietnam are few,
unsystematic and just stop at synthesis without much attention to their
biological activities. The synthesis and study of benzothiazole derivatives
containing both amino and hydroxyl functional groups not only increase the
conversion capacity to form new derivatives but also increase the active
resonance capacity. Therefore, this research direction is still open, promising
new, interesting and useful results in terms of theory and practice.

Thus I chose this topic: “Study on synthesis, structures and biological
activity evaluation of some derivatives containing benzothiazole and
benzoxazole”.
2. Objective of the thesis
The study focuses on synthesis, structure udentification and oriented
conversion to form some new derivatives containing benzothiazole and
benzoxazole heterocycles with many substituents from the starting materials 4hydroxybenzaldehyde and vanillin, in order to search for compounds with high
biological activity or other applications.
3. Mission of the thesis
+ Deriving from the first two substances, 4-hydroxybenzaldehyde and
vanillin, synthesize some "key substances" of o-aminophenol type.
+ Transforming the "key substance" into new sets of compounds
containing benzothiazole and benzoxazole heterocycles.
+ Studying the properties and determining the structures of new
compounds by modern IR, NMR and MS spectroscopy methods.
+ Exploring tested antimicrobial, antioxidant, anti-cancer and plant
growth-stimulating activities of several new compounds to search for
1


compounds with high biological activity.
4. Scientific and practical significance of the thesis
- Completing 02 processes for synthesizing benzothiazole heterocyclic
derivatives according to the principle of green chemistry from the two starting
substances, 4-hydroxybenzaldehyde and vanillin, which are: i) close the
benzothiazole heterocyclic ring containing the benzothiazole heterocycle, which
occurs in both amino and hydroxyl functional groups; ii) N-formylation of the
amine group, this reaction occurs only in the amine functional group. During
the synthesis process, there are several stages using microwave energy
irradiation that shorten the reaction time, save solvents and increase the

efficiency of the reaction.
- Providing accurate data on IR, NMR and MS spectra of complex
heterocyclic compounds for scientific research and training high quality human
resources for society.
- Some compounds containing the N-formamide-type benzothiazole
heterocycle and hydroxamic acid exhibit good cytotoxicity comparable to the
control, while the o-aminophenol-type compounds exhibit high antioxidant
activity, which helps orienting the search for new compounds with potential for
practical application.
CONTENTS OF THE THESIS
CHAPTER 1. OVERVIEW
The overview covered the following:
1.1. Benzothiazole heterocycle overview
1.1.1. Benzothiazole heterocycle synthesis method
1.1.2. Biological activity of compounds containing benzothiazole heterocycle
1.2. Benzoxazole heterocycle overview
1.2.1. Benzoxazole heterocycle synthesis method
1.2.2. Biological activity of compounds containing benzoxazole heterocycle
CHAPTER 2. EXPERIMENT
2.1. Chemicals and equipment
2.1.1. Chemicals
2.1.2. Instruments and equipment in the laboratory
2.1.3. Methods for isolation of product
2.1.4. Equipment for studying properties and structures
2.2. Methods to detect biological activity
2.2.1. Antimicrobial activity
2.2.2. Antioxidant activity
2.2.3. Cytotoxic activity
2.2.4. Plant growth stimulant activity
2

2.3. Substance synthesis
2.3.1. General synthetic figure
2.3.2. Synthesis “key substances”
R

SH

R
OH

OH

HNO3 /AcOH

1giê

OHC

OHC

NO2

1A,1B

2A,2B

o-aminothiophenol
MW, 3-4 phót

kh«ng dung m«i

R
S

NH2

OH

MW, 3-4 phót
kh«ng dung m«i

N

D·y A: R=H
D·y B: R=OCH3

R

Na2S2O4/EtOH

6 giê
R

S

R

S
OH

N

S

AcOH

OH
O

N

OH

8h

N
4A,4B

6A,6B HN

7A,7B

NO2

3A,3B

NH2

Figure 2.4. Synthesis “key substances”

2.3.3. Synthesis of benzazole series
R

R

S

S

OH Ar-CHO, AcOH, MW
N

O

N

4A (R=H)
4B (R=OCH3)

N

NH2

Ar

Benzazole 4A1-4A6 (R=H); 4B1-4B13(R=OCH3)

Figure 2.5. Synthesis of benzazole series
2.3.4. Synthesis of N-formamide 5A, 5B
R

R

S
OH
N
4A: (R=H)
4B: (R=OCH3)

DMF

S

MW

N

OH

NH2

5A: (R=H)
5B: (R=OCH3)

NH
O
H

Figure 2.6. Synthesis of N-formamide series
2.3.5. Synthesis of ester, carboxylic acid and hydroxamic acid series

a. Synthesis of ester series 6AE, 6BE, 7AE, 7BE
R
S
OH

R

ClCH2COOEt
K2CO3/KI/DMF

O

N
6A
6B
7A
7B

O

S
O

N

R1
(R=H, R1=NHCOCH3)
(R=OCH3, R1=NHCOCH3)
(R=H, R1=H)
(R=OCH3, R1=H)

6AE
6BE
7AE
7BE

R1
(R=H, R1=NHCOCH3)
(R=OCH3, R1=NHCOCH3)
(R=H, R1=H)
(R=OCH3, R1=H)

Figure 2.7. Synthesis of ester series
b. Synthesis of carboxylic acid series 8A1, 8B1, 8B2
3


R

R

O

S
O

S

NaOH/HCl

O

O
O

N

OH

N

R1
6AE (R=H, R1=NHCOCH3)
6BE (R=OCH3, R1=NHCOCH3)
7BE (R=OCH3, R1=H)

R1
8A1 (R=H, R1=NHCOCH3)
8B1 (R=OCH3, R1=NHCOCH3)
8B2 (R=OCH3, R1=H)

Figure 2.8. Synthesis of carboxylic acid series
c. Synthesis of hydroxamic acid series 9B1, 9A2, 9B2
R

O

S
O

O

N

R
S

H2N-OH.HCl

HN OH

O

MeOH/THF

R1

O

N
R1
9B1 (R=OCH3, R1=NHCOCH3)
9A2 (R=H, R1=H)
9B2 (R=OCH3, R1=H)

6BE (R=OCH3, R1=NHCOCH3)
7AE (R=H, R1=H)
7BE (R=OCH3, R1=H)

Figure 2.9. Synthesis of hydroxamic acid series

2.3.6. Synthesis of hydrazide-hydrazone series
a. Synthesis of hydrazide series 10A, 10B, 11A, 11B
R

O

S
O

O

R
H2N-NH2.H2O
C2H5OH

N

O

S
O
N

R1

NH
H2N

R1

6AE (R=H, R1=NHCOCH3)
6BE (R=OCH3, R1=NHCOCH3)
7AE (R=H, R1=H)
7BE (R=OCH3, R1=H)

10A (R=H, R1=NHCOCH3)
10B (R=OCH3, R1=NHCOCH3)
11A (R=H, R1=H)
11B (R=OCH3, R1=H)

Figure 2.10. Synthesis of hydrazide series
b. Synthesis of hydrazone series
 Hydrazone series 10A1-10A8
HN N
S
N
10A

ArCHO
O CH2 C NH NH2
O
NH C CH3
O

DMF, CH3COOH

Ar

S
N

10A1-10A8 HN

O
O
CH3

Figure 2.11 (a). Synthesis of hydrazone series 10A1-10A8
 Hydrazone series 10B1-10B8
4

O


OCH3

OCH3 HN N

S
O CH2 C NH NH2
O
NH C CH3
O

N
10B

Ar

S

ArCHO
DMF, CH3COOH

O
O

N

O

HN

10B1-10B8

CH3

Figure 2.11(b). Synthesis of hydrazone series 10B1-10B8
 Hydrazone series 11A1-11A16
S
OCH2CONHNH2
N

Ar

S

ArCHO

HN N

O

DMF, CH3COOH

N

11A

O

11A1-11A16

Figure 2.11(c). Synthesis of hydrazone series 11A1-11A16
 Hydrazone series 11B1-11B8
OCH3

OCH3
S

ArCHO

O CH2 C NH NH2
O

N
11B

HN N
Ar

S
O

DMF, CH3COOH

O

N
11B1-11B8

Figure 2.11(d). Synthesis of hydrazone series 11B1-11B8
2.3.7. Synthesis of benzoxazoles from nitrovanillin
a. Synthesis of o-nitrophenols from nitrovanillin
HO
H3CO
CHO
nitrovanillin (2B)

NO2

NO2

NO2
Ar - NH2
MW
4-10 phút; DMF

HO

HO

H
N

NaBH4

H3CO
12B1-12B7

N

H3CO

Ar

Ar

13B1-13B7
O

O
O

NO2

NO2

HO

O

N

R

15B1-15B7

Ar

O

LiOH

O

R
14B1-14B7

O
N

Ar

Figure 2.12. Synthesis of o-nitrophenol series from nitrovanillin
b. Synthesis of o-aminophenol 16B1
5


NO2

NH2

HO

O

HO

O

Na2S2O4
N

H3CO

C2H5OH

15B1

N

H3CO
16B1

Cl

Cl

Figure 2.13. Synthesis of o-aminophenol 16B1
c. Synthesis of benzoxazole 18B1, 18B2
OCH3

NH2
HO

O

O

O

ArCHO/KCN/DMF

R

N

N

H3CO
16B1

18B1 (R=OCH3)
18B2 (R=OH)

Cl

Cl

N

Figure 2.14. Synthesis of benzoxazole 18B1, 18B2
CHAPTER 3. RESULTS AND DISCUSSION
3.1. Synthesis and structure of two key substances 4A and 4B
To synthesize the two key substances 4A and 4B from the two starting
substances, 4-hydroxybenzaldehyde and vanillin, three stages are required,
including the closing of the benzothiazole ring to form compounds 3A and 3B.
Benzothiazole cyclization reaction to form substances 3A, 3B is carried out by
condensing aromatic aldehydes with 2-aminothiophenol with household
microwave irradiation. This synthesis method has many outstanding advantages
such as: i) no solvent nor catalyst is required; ii) the reaction occurs in a very
short time, only about 4-6 minutes; iii) very high efficiency, above 95%. The
absence of solvents and catalysts for the reaction partially saves cost and limits
waste to the environment, so it meets the requirements of green chemical
synthesis [5]. The mechanism of the benzothiazole ring-closing reaction is
Figure 3.1 [61, 80].
+

O

H
N
Ar
H

(III)

(II)

(VI)

SH
OH

chuyÓn H+

H
N
H2 Ar

Ar

NH2
(I)

SH
O

H

SH

H
S

H

N

Ar
(VII)

S

H

[O]

N
H

Ar

-H2O

H

-H2O

(IV)

chuyÓn proton

SH

toC

N

Ar

(V)
S
Ar
N
(VIII)

Figure 3.1. Benzothiazole ring-closing mechanism
There are many agents used to reduce the –NO2 group to –NH2 group such
as Fe/HCl; Zn/NH4Cl; Na2S2O4/NaOH etc. and usually done in acidic or base
6


environment. However, compounds 3A and 3B have both the –OH group and –
NO2 group at ortho position, so when performing the reduction reaction in the
base medium, the result is obtained in the form of phenolate salt and when
reducing in acid medium, the obtained result exists in the form of ammonium
salt of the amine, which is difficult to separate and derive. Through literature
review, Siddiqui et al. successfully reduced 4-carbomethoxy-2-nitrophenol to 4carbomethoxy-2-aminophenol by reducing agent Na2S2O4/C2H5OH [88].
Compounds 3A, 3B have similar structure to 4-carbomethoxy-2-nitrophenol, so
when applying similar reaction conditions, the desired products 4A and 4B
were obtained with high efficiency (> 80%), Na2S2O4 is pretty cheap and easy
to find. In particular, compound 4A was isolated for the first time in pure form,
and compound 4B, although isolated by Vu Thi Anh Tuyet's group as a free oaminophenol, the procedure is complicated and has more stage (3 stages):
reduction with HCl/Fe agent to obtain the product as ammonium salt,
acetylation and hydrolysis [8]. This shows that the reduction method in neutral
medium applied above is more efficient compared to the reduction method of
previous authors: simple procedure, few stages, high reaction efficiency, and
cheap reducing agent.
The results of 4A and 4B synthesis are presented in Table 3.1, the results
of spectral analysis to determine their structures are presented in Table 3.2 –

Table 3.5, below are the results of 1H NMR and 13C NMR spectral data of 4A
and 4B.
Table 3.3. 1H NMR signal of 4A and 4B (δ (ppm), J (Hz))
Symbol
H2
H3
H4
H5
H9
H10
H13
H14
OH
NH2

4A
8.04 (dd, J = 0.5; 7.5, 1H)
7.37 (td, J = 1.5; 7.5, 1H)
7.56 (t, J = 1.5; 7.5, 1H)
7.94 (d, J = 8.0, 1H)
7.39 (d, J = 7.5, 1H)
6.77 (d; J = 8.0; 1H)
7.18 (dd, J = 2.0; 8.0, 1H)
10.10 (s, 1H)
4.84 (s, 2H)

4B
8.06 (d, J = 8.0, 1H)
7.49 (t, J = 8.5; 1.5, 1H)
7.39 (t, J = 8.5; 1.5, 1H)

7.96 (d, J = 8.0, 1H)
7.09 (d, J = 2.0, 1H)
7.02 (d, J = 2.0, 1H)
3.87 (s, 3H)
8.95 (s, 1H)
4.99 (s, 2H)

Table 3.4. 13C NMR signal of 4A and 4B, δ (ppm)
Symbol
4A
4B

C1
C2
134.0
121.9
135.7
122.7

C3
C4
124.6
126.2
125.6
127.5

C5
C6
122.0
153.7

122.9
154.9

C7
C8
168.3
124.5
171.3
137.5

7

C9
C10
116.4
114.4
102.2
149.2

C11
C12
147.3
137.3
138.4
126.0

C13
C14
112.3
110.1

56.6


3.2. Synthesis and structure identification of benzazole series 4A1-4A6 and
4B1-4B13
The synthesis of compounds 4A1-4A6 and 4B1-4B13 (these are
compounds containing both benzothiazole and benzoxazole heterocycles,
collectively referred to as benzazoles) was carried out under microwave
irradiation from 2 starting amines 4A and 4B. The influence of home
microwave energy level on the reaction efficiency was investigated during the
synthesis of compound 4B1. In 150 watt mode, the reaction took 26 minutes but
was unfinished and the efficiency was only 46%. When the power level was set
at 280 watts, after refining the efficiency reached 80% after 19 minutes of
irradiation. At 400 watts, the reaction ended quickly in just 6 minutes and the
desired product efficiency is 92%. Both 600 watts and 800 watts reduce
efficiency due to overheating (Table 3.6).
Table 3.6. Optimizing the energy of home microwave oven
No.
Power level (watts)
Time (minutes)
Efficiency (%)*
1
150
26
46
2
280
19
80
3

400
6
92
4
600
4
26
5
800
2
burnt
*
after refining; reaction conditions: 4B1 (308 mg, 1 mmol), benzaldehyde (116 mg, 1,1
mmol) and HOAc (2 ml) irradiated with a microwave oven at different power levels.

Applying the above optimization process, 19 benzazoles including 4A14A6 and 4B1-4B13 were synthesized with the maximum efficiency of 92%.
The results were published in the journal Letters in Organic Chemistry.
Thus, the process of performing the reaction to synthesize benzazoles has
many advantages: (i) easy to implement, (ii) environmentally friendly due to
minimal use of solvent, (iii) energy- and time-saving since it is fast and clean,
(iv) easy experimental handling: irradiation of the reaction mixture, adding
ethanol to the post-reaction mixture to form crystals, filtering and drying, (v)
using laboratory equipment readily available and cheap.
The mechanism of benzazole formation consists of two stages:
Stage 1:
H

H
O

H
O H

H

Ar

C O H

Ar

Ar

Stage 2:
OH

OH
H

H
H O C

NH2

Ar
(A)

H
O

(C)

Ar
C
N
H
H

(D)

H
O Ar
C
N H
H

N
H2

OH
H

ChuyÓn proton

Ar
OH
(B)

O

Ar

[O]

O

H

-H2O

N

C

+

N

-H

(E)

N
H

t0

Ar
-H2O
OH2

Ar

H

Figure 3.2. Mechanism of benzazole formation
The data on appearance, color, crystallization solvent, melting point and
8


reaction yield of the benzazole series are presented in Table 3.7. Results of
spectral analysis of benzazole series 4A1-4A6; 4B1-4B13 presented in Table 3.9
to Table 3.13 have demonstrated that their structure is consistent with the
predicted formula.
Table 3.9. 1H NMR signal of 4A1-4A6 (δ (ppm), J (Hz))
Symbol
H2
H3
H4
H5
H9
H10
H13
H16
H17
H18
H19
H20
H21
Other

H

4A1

4A2

4A3

4A4

4A5

4A6

8.1
d, J7.5, 1H
7.4
t, J7.5, 1H
7.5
t, J7.5, 1H
8.09
d, J7.5, 1H
8.13
dd, J8.5, 1.5, 1H
7.9
d, J8.0, 1H
8.39
d, J1.5, 1H
8.09
d, J8.5, 1H

7.00
d, J8.5, 1H
-

8.16
d,J7.5, 1H
7.47
t,J7.5, 1H
7.56
t, J7.5, 1H
8.13
d, J8.5, 1H
8.09
d, J8.0, 1H
7.92
d;J 7.5; 1H
8.40
s, 1H
7.71
s, 1H
-

8.17
td, J1.5, 7.0, 1H
7.49
t, J8.0, 1H
7.58
td, J1.0, 8.0, 1H
8.17
td, J1.5, 7.0, 1H

8.09
d, J8.0, 1H
7.99
d, J8.5, 1H
8.44
d, J1.0, 1H
8.13
d, J8.0, 1H
7.45
d, J8.0, 1H
-

8.15
d, J8.0, 1H
7.45
t, J7.0, 1H
7.54
t, J7.0, 1H
8.15
d, J8.0, 1H
8.07
d, J 7.5, 1H
7.90(s, 1H)

8.16
d,J7.5, 1H
7.47
t, J 7.5, 1H
7.56
t, J7.5, 1H

8.09
d, J8.0, 1H
8.15
d, J8.0, 1H
7.94
d;J 7.5; 1H
8.40
s, 1H
7.70
s, 1H
-

7.00
d, J8.5, 1H
8.09
d, J8.5, 1H
-

7.02
d, J8.0, 1H
7.72
d, J8.0, 1H
3.92
s,1H
-OH
10.04 (s, 1H)

8.2
d, J8.5, 1H
7.47

t, J7.5, 1H
7.56
t, J7.5, 1H
8.18
d, J7.5, 1H
8.09
d, J 8.0, 1H
7.99
d, J8.0, 1H
8.47
s, 1H
8.25
d, J7.5, 1H
7.65
t, J7.5, 1H
7.66
d, J8.5, 1H
7.65
t, J7.5, 1H
8.25
d, J7.5, 1H
-

7.45
d, J8.0, 1H
8.13
d, J8.0, 1H
2.43 (s, 3H)

7.15

d, J8.0, 1H
8.13
d, J9.0,1H
3.86 (s, 3H)

-OH
10.37 (s, 1H)

-

-

8.13
s, 1H
8.13
d, J9.0, 1H
7.15
d, J 8.0, 1H
-

-

7.20
d, J8.0, 1H
7.84
d, J8.0, 1H
3.87 (s,3H)
3.91 (s,3H)
-

Table 3.10. 13C NMR signal of 4A1-4A6 (δ (ppm)
Symbol
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21/C22

4A1
134.6
122.3
125.5
126.7
122.8

153.6
167.1
129.8
124.3
111.5
152.0
142.7
117.8
164.3
116.6
129.6
116.2
161.3
116.2
129.6
-

4A2
134.5
122.2
125.4
126.6
122.7
153.5
167.0
129.8
124.3
111.4
151.9
142.6

117.7
164.2
116.7
121.5
148.0
150.9
116.0
110.7
55.7

4A3
134.6
122.2
125.4
126.6
122.8
153.5
166.8
132.3
125.9
111.5
152.0
142.2
117.8
163.7
125.9
127.4
129.3
125.0
130.0

129.3
-

9

4A4
134.5
122.2
124.8
126.6
122.8
153.5
166.9
130.0
125.5
111.5
152.0
142.6
118.2
163.9
123.1
129.9
127.4
142.3
127.4
129.9
21.15

4A5
134.6

122.2
125.4
126.6
122.8
153.5
166.9
129.9
124.5
111.5
151.9
142.5
118.2
163.8
117.9
129.4
114.8
162.5
114.8
129.4
55.50

4A6
134.8
122.2
125.4
126.6
122.8
153.5
166.9
129.9

125.4
111.6
152.0
142.5
117.8
163.9
118.1
109.0
149.0
152.3
111.9
121.2
55.6/55.7


Table 3.11. 1H NMR spectral data of 4B1-4B13 ( (ppm), J (Hz))
O
9 10
1 S
7 8
11

3
4

6 N

5

Symbol

Ar

H2

H3

H4

7.39,
td, J
7.5,
1.0
7.39,
td, J
8.0,
1.0
7.39,
td, J
8.0,
1.0
7.39,
td,
J7.5,
1.5
7.40,
td,
J8.0,
1.0

7.56,
td, J
7.0,
1.0
7.50,
td,
J7.0,
1.0
7.50,
td, J
7.5,
1.0
7.49,
td, J
7.0,
1.5
7.51,
td,
J7.5,
1.0

13 12

21

O
14
Ar
N

H5

H9

H13

H16

H17

H18

H19

H20

H21

H22

Other
H

8.08,
d,
J8.0

7.81,
d,
J1.0

8.01,
d,
J1.0

8.30,
m

7.53,
m

7.56,
m

7.53,
m

8.30,
m

4.19,
s

-

-

8.08,
d, J
8.0

7.79,
d,
J1.0

7.99,
d,
J1.0

8.18,
d,
J8.5

7.34,
d,
J8.0

-

7.34,
d,
J8.0

8.18,
d,
J8.5

4.18,
s

2.45,
s

-

8.08,
d, J
8.0

7.85,
d,
J1.0

8.08,
d,
J1.0

-

7.58,
dd, J
8.0,
1.5

7.46,
td,
J8.0,
2.0

7.44,

td, J
8.0,
1.5

8.20,
dd, J
7.5,
1.5

4.19,
s

-

-

8.07,
d,
J8.5

7.79,
d,
J1.0

7.98,
d,
J1.5

8.21,
d,

J8.5

7.50,
d,
J8.5

-

7.50,
d,
J8.5

8.21,
d,
J8.5

4.17,
s

-

-

8.08,
d,
J7.5

7.84,
d,
J1.5

8.02,
d,
J1.5

9.11,
t, J1.5

-

8.39,
td, J
7.5,
1.0

7.73,
t,
J7.5

8.60,
td,
J8.5,
1.0

4.20,
s

-

-

8.48,
d,
J9.0

4.18
(s,
3H,
H21)
;

-

-

4B1

7.91,
d, J
7.5

4B2

7.91,
d, J
8.0

4B3

7.91,

d,
J7.5

4B4

7.90,
d,
J8.0

4B5

7.92,
d,
J8.0

4B6

8.19,
d,
J8.5

7.49,
t,
J8.0

7.58,
t,
J8.0

8.12,

d,
J8.5

7.85,
s

8.13,
s

8.48,
d,
J9.0

8.45,
d,
J9.0

-

8.45,
d,
J9.0

4B7

8.14,
d,
J8.0

7.55,

t,
J7.5
7.55,
td,
J8.5,
1.5
7.49,
td,
J7.0,
1.0
7.56,
t,
J7.0
7.50,
td, J
8.0,
1.0

8.08,
d,
J8.0

7.71,
s

7.95,
s

8.05,
d,

J8.5

6.98,
d,
J8.5

-

6.98,
d,
J8.5

8.05,
d,
J8.5

4.13,
s

-

10.38
(s, OH)

8.08,
d,
J7.5

7.75,
d,

J1.0

8.01,
d,
J1.5

7.60,
t, J1.5

-

7.04,
d,
J8.5

7.42,
t,
J7.5

7.64,
d,
J7.5

4.14,
s

-

9.98 (s,
OH)

8.07,
d,
J7.5

7.77,
d,
J1.5

7.96,
d,
J1.5

8.23,
td,
J9.5,
2.5
8.17,
d,
J8.5

-

8.05,
d,
J1.5

7.03,
td,
J9.5,

2.5
7.8,
d,
J8.0

3.89,
s

7.78,
d,
J1.0

7.03,
td,
J9.5,
2.5
7.8,
d,
J8.0

4.18,
s

8.08,
d,
J8.5

8.23
(td,
J9.5,

2.5
8.17,
d,
J8.5

4.15,
s

-

-

8.08,
d, J
8.5

7.80,
s

7.97,
s

7.72,
s

-

-

8.10,

d,
J1.5

4.18,
s

4.04,
s

6.40, s,
OH)

7.52,
t,
J8.0

7.77,
d,
J7.5

4.18,
s

3.89,
s

-

8.2,
t,

J8.0

8.8,
d,
J7.0

3.94,
s

-

-

4B9

7.90,
d,
J7.5

4B10

8.15,
d,
J8.5

7.46,
t,
J7.5
7.47,
td,

J8.0,
1.0
7.38,
td,
J8.0,
1.0
7.48,
t,
J7.5

4B11

7.91,
d,
J8.0

7.40,
t,
J8.0

4B12

8.10,
d,
J8.0

7.45,
t,
J7.5

7.54,
t,
J8.0

8.06,
d,
J8.0

7.72,
d,
J2.0

7.97,
d,
J2.0

7.67,
d,
J1.5

-

4B13

8.08,
d,
J8.0

7.42,
t,

J7.5

7.50,
t,
J8.0

7.9,
d,
J8.0

7.40,
m

7.37,
m

10.12,
s

-

8.14,
d,
J8.0

4B8

Table 3.11.

13

-

7.19,
dd, J
8.0,
2.0
9.08,
d,
J3.0

C NMR spectral data of 4B1-4B13 [ (ppm)]
O
9 10
1 S
7 8
11

3
4
5

Symb
ol

-

6 N

13 12

N

21
O
14
Ar

C1,
C2

C3,
C4

C5,
C6

C7,
C8

C9,
C10

C11,
C12

C13,
C14

C15,

C16

C17,
C18

C19,
C20

C21,
C22

4B1

135.2
121.6

125.2
126.4

123.2
154.1

167.9
131.4

107.0
145.2

141.9
144.2

112.5
164.1

126.7
127.9

128.9
131.9

128.9
127.8

56.6
-

4B2

135.2
121.6

125.2
126.3

123.2
154.1

167.9
131.3

106.8
145.1

141.8
144.3

112.4
164.3

123.9
127.9

129.7
142.5

129.7
127.9

56.7.
21.7

Ar

10


4B3

135.2
121.6

125.3
126.4

123.2
154.1

167.8
133.7

107.5
145.2

141.7
143.8

112.9
161.8

125.7
132.5

131.5.
132.2

126.9
131.9

56.8
-

4B4

135.2
121.6

125.3
126.4

123.2
154.1

167.7
131.5

107.1
145.1

141.8
144.1

112.4
163.1

125.1
129.3

129.1
138.2

129.1
129.3

56.6
-

4B5

135.2
121.7

125.4
126.5

123.3
154.1

167.5
131.9

107.6
145.3

142.0
143.8

112.6
161.6

128.5

122.7

148.8,
126.1

130.2
133.2

56.7
-

No spectral data available due to poor solubility in DMSO at 373 K

4B6
134.5
122.2

125.4
130.4

122.7
153.4

167.1
130.4

106.4
144.6

140.9

143.9

110.9
163.8

116.5
116.1

129.5
161.2

129.5
116.1

56.4
-

134.6
122.3

125.6
126.7

122.8
153.4

167.0
130.6

106.9

144.8

141.2
143.6

111.4,
163.4

126.9
113.8

157.9
119.5

130.7
118.2

56.5
-

4B9

135.2
121.6

125.2
126.3

123.2
154.1

168.0,
131.2

106.7
145.0

141.7
144.4

112.2
164.2

114.4
129.7

119.2
162.6

119.2
129.7

56.6
55.5

4B10

135.2
121.8

125.1
126.3

122.5
153.2

166.5,
130.7

107.5
143.4

141.1
144.6

111.1
162.3

124.9
129.0

132.1
125.6

132.1
129.0

56.5
-

4B11

135.2
121.6

125.1
126.4

123.2
154.1

167.8
131.5

106.9
145.1

141.8
144.1

112.2
162.9

119.5
109.0

147.5
146.6

108.7

125.3

58.5
56.8

4B12

134.3
121.6

125.0
126.1

122.4
153.1

166.5
130.5

107.3
144.5

140.9
143.3

111.0
162.8

126.8
111.9

159.4
118.0

130.0
119.4

56.3
55.1

4B13

134.5
122.2

125.1
126.6

122.4
153.4

167.2
130.5

106.4
148.6

140.5
143.6

111.5
154.3

124.0
131.5

154.3

124.5
136.3

56.2
-

4B7
4B8

3.3. Synthesis and structure of N-formamides 5A and 5B
N-formylation plays an important role in organic synthesis such as
protecting amine functional groups and in pharmaceutical chemistry, so many
methods of formamide synthesis have been researched and developed. In which
one interesting method is to use N,N-dimethylformamide (DMF) in combination
with suitable agent for N-formyl synthesis such as imidazole and DMF [95];
P2O5 and DMF[17]; POCl3 and DMF [18]; [Ni(quin)2], DMF and imidazole [93].
Microwave irradiation also has the effect of supporting the N-formylation
process such as using ester, DMF under microwave irradiation to create Nformyl from amine in 5 minutes [110]; using HCOOH/SiO2 heterogeneous
catalyst in solvent-free conditions, or using HCOOH under the effect of
microwaves, can also create N-formamides from amines or alcohols [13, 25].
With the above basis, use amine 4A to react with DMF using common
catalysts such as HCl, AcOH, TsOH or silica gel. The reaction mixture was

microwave irradiated at 380W for an appropriate time. The progress of the
reaction was monitored by TLC in the n-hexane/ethyl acetate solvent system
(1:1). The experiments show that, when using HCl as a catalyst, the obtained
products are only shown as traces on TLC, when using TsOH as a catalyst,
although the efficiency may reach 70%, the refining is more complicated, a
base solution is required to wash off TsOH, after washing off the excess amine
with an acid solution. Experimental results are presented in Table 3.14.
11


Table 3.14. Experimental conditions for N-formamide creation
NO.

Reaction

Catalyst

1
2
3
4

4A + DMF
4A + DMF
4A + DMF
4A + DMF

AcOH
HCl
TsOH

Silica gel

Time
Efficiency
(minutes)
7
92%
20
5%
20
70%
20
22%

The above table has shown that the optimal conditions for the reaction to
create N-formamide from compound 4A were selected using amine + DMF +
AcOH, the mixture was microwave irradiated in medium level (380W-450W).
To verify this experimental procedure, amine 4B is also processed in the same
way as amine 4A, yielding N-formamide 5B. The structures of 5A and 5B were
identified by IR, NMR and MS spectra. This procedure opens up a new method
to generate N-formamide from free amine in a simple, efficient and effective
way using home microwave irradiation, which has been successfully applied
and synthesized a series of twenty N-formamide and the results were published
in the Journal of Chemistry. The advantage of this method is that it is
selectively formylated to the amine group but not to the –OH phenol phenol
functional group, especially selective to weak nucleophilic amine groups such
as p-nitroaniline.
The reaction mechanism to generate N-formamide:
H

O

O

H

Het:

N

N

H

-OAc

R
Het

S

O H

O

N

R

R

OH

NH2

Het
H3C

O H
H

H3C

N CH3

R
-NH(CH3)2

R
OH

Het

OH
H
N
H
O H
H N
H3C
CH3

H2N

N
H3C

Het

OH
OH

-AcOH

Het

OH

O H
N
H

H

AcO

HN CHO
5A (R=H); 5B (R=OCH3)

Figure 3.3. Mechanism of N-formamide 5A and 5B formation
The spectral analysis results of 5A and 5B are presented in Table 3.17

and Table 3.18. Below is the resonance signal of the protons and carbon of 5A
and 5B.

12


Table 3.17. Proton and carbon resonance data of compounds 5A and 5B
H
H2
H3
H4
H5
H9
H10
H13
H14
OH
NH
H15

5A
δ (ppm), J (Hz)
8.08 (d, J = 8.0, 1H)
7.40 (td, J = 8.0;
J = 1.0, 1H)
7.50 (td, J = 8.0;
J = 1.0, 1H)
8.00 (d, J = 8.0, 1H)
7.69 (dd, J = 8.5,
J = 2.0, 1H)

7.04 (d, J = 8.5, 1H)
8.94 (d, J = 2.0, 1H)
8.37 (d, J = 1.5, 1H)
10.84 (s, 1H)
9.76 (s, 1H)
-

C
C1
C2
C3

δ (ppm)
134.1
122.1
124.9

H
H2
H3

C4

126.4

H4

C5
C6
C7

C8
C9

122.3
153.6
167.4
123.6
123.9

H5
H9

5B
δ (ppm), J (Hz)
8.08 (d, J = 8.0,1H)
7.40 (td, J = 8.0, 1.0,
1H)
7.50 (td, J = 8.0, 1.0,
1H)
8.02 (d, J = 8.0, 1H)
7.46 (d, J = 2.0, 1H)

C10
C11
C12
C13
C14
C15

115.3

149.6
126.6
119.0
160.3
-

H10
H13
H14
OH
NH
H15

8.59 (d, J = 2.0, 1H)
8.37 (d, J = 2.0, 1H)
10.08 (s, 1H)
9.31 (s, 1H)
3.95 (s, 3H)

C
C1
C2
C3

δ (ppm)
134.2
122.1
123.5

C4

126.4

C5
C6
C7
C8
C9

122.2
153.6
167.6
125
105.6

C10
C11
C12
C13
C14
C15

147.8
138.8
126.9
112.8
160.4
56.1

3.4. Synthesis and structure of the carboxylic acid series

3.4.1. Synthesis of carboxylic acid series
a. Acetylation of the amine group of 4A and 4B
According to the authors Vu Thi Anh Tuyet and Nguyen My Linh, to
acetylate the NH2 group of compound 4B to form compound 6B, two steps are
required. Step 1: acetylation of both –OH group and –NH2 group by Ac2O agent in
DMF solvent and Et3N catalyst. Step 2: hydrolyze the ester functional group with
LiOH (in MeOH:H2O = 4:1), leaving the amide functional group [5, 9]. In this
thesis, the method of synthesizing 6B from 4B has been improved, shortened to one
stage by refluxing amine 4B in the residual acetic acid for 6 hours, the reaction
efficiency reached 87%. Using the same procedure with amine 4A, we obtained
amide 6A (light brown needle-shaped crystals) with 85% efficiency.
b. Synthesis of esters
Using Finkelstein reaction to perform etherification with NaI and K2CO3
catalysts, instead of using acetone solvent, we use DMF. Since the boiling point
of acetone is lower than that of DMF, the reaction is easier to occur and with
higher efficiency. NaI has the role of providing I- for the halogen exchange
reaction to form a C-I bond, in which I- is more easily replaced than Cl-, so the
reaction also occurs more easily.
c. Hydrolyzed ester form acid carboxylic
Conducting the hydrolysis reaction of the esters will obtain the
corresponding carboxylic acid series 8A1, 8B1, 8B2. The synthesis results are
presented in Table 3.19. The spectrum analysis results presented in Table 3.20
13


to Table 3.22 have shown that their structure is consistent with the predicted
formula.
3.5. Synthesis and structure identification of hydroxamic acid series
Hydroxamic acids are obtained when the corresponding esters react with
hydroxyamine. Synthesis results of hydroxamic acid series 9B1, 9A2, 9B2 are

presented in Table 3.23. The spectral analysis results presented in Tables 3.24 to
Table 3.27 have shown that the hydroxamics’ structure is consistent with the
predicted formula.
3.6. Synthesis and structure identification of hydrazide series
A series of four hydrazides 10A, 10B, 11A and 11B is formed when the
corresponding esters react with hydrazine hydrate. This reaction is fast with
simple procedure, the product is easy to refine, and high yield.
Synthetic results of hydrazide series are presented in Table 3.28. The
spectrum analysis results are presented in Table 3.29-3.32.
Table 3.30. 1H NMR spectral data of 10A, 10B, 11A 11B (δ (ppm); J (Hz))
H
H2
H3
H4
H5
H9
H10
H12
H13
H14
H10a
H12b
NHa
NHb
NH2

10A
8.11
d, J = 8.0, 1H
7.43

td, J = 1.0, 8.0, 1H
7.52
td, J= 1, J=8.5, 1H
8.03
d, J = 8.0, 1H
7.78
dd, J = 2.0, 8.5, 1H
7.21
d, J = 9.0, 1H
-

10B
8.13
d, J = 8.0, 1H
7.45
t, J = 7.5, 1H
7.52
t, J = 7.5, 1H
8.01
d, J = 8.0, 1H
8.57
s, 1H
-

8.79 (s, 1H)

7.47 (s, 1H)

4.70 (s, 2H)
2.18 (s, 3H)

9.55 (s, 1H)
9.62 (s, 1H)
4.41 (s, 2H)

4.56 (s, 2H)
3.95 (s, 3H)
2.19 (s, 3H)
9.45 (s, 1H)
10.43 (s, 1H)
4.34 (s, 2H)

-

11A
8.11
dd, J = 8.0, 0.5, 1H
7.43
td, J = 8.5; 1.5, 1H
7.52
td, J = 8.5; 1.5, 1H
8.01
d, J = 8.0, 1H
8.03
d, J = 9.0, 1H
7.14
td, J = 9.0, 2.0, 1H
7.14
td, J = 9.0, 2.0, 1H
8.03
d, J = 9.0, 1H

4.60 (s, 2H)
9.39 (s, 1H)
4.34 (s, 2H)

11B
8.10
d, J = 8.0, 1H
7.44
td, J = 1.5, 8.0, 1H
7.52
td, J = 1.0, 8.5, 1H
8.02
d, J = 8.0, 1H
7.67
d, J = 2.0, 1H
7.08
d, J = 8.5, 1H
7.59
dd, J = 2.0, 8.0 1H
4.57 (s, 2H)
3.91 (s, 3H)
9.24 (s, 1H)
4.34 (s, 2H)

Table 3.31. 1H NMR spectral data of 10A, 10B, 11A 11B δ (ppm);
C
C1
C2
C3
C4

C5
C6
C7

10A
134.3
122.2
125.1
126.5
122.5
153.6
166.1

10B
134.4
122.2
125.4
126.6
122.7
153.4
167.0

14

11A
134.2
122.1
125.0
126.4
122.4

153.5
166.8

11B
134.4
122.2
125.3
126.6
122.6
153.6
166.4


125.9
123.4
112.9
149.9
128.1
120.7
67.1
168.7
166.9
23.9

C8
C9
C10
C11
C12
C13

C14
C15
C10a
C12a
C12b

128.8
112.0
152.3
139.3
133.3
105.4
70.9
168.6
56.1
168.6
24.1

126.0
128.7
115.4
160.2
115.4
128.7
66.2
166.1
-

126.6
109.9

150.0
149.5
120.7
113.9
67.1
167.1
55.8
-

3.7. Synthesis and structure of hydrazide - hydrazone series
To synthesize the 4 hydrazide - hydrazone series 10A1-10A8; 10B1-10B8;
11A1-11A16 and 11B1-11B8 a condensation reaction must be conducted
between corresponding hydrazides 10A, 10B, 11A and 11B with aromatic
aldehydes, in the presence of the catalyst AcOH. The reaction is carried out by
microwave irradiation in a short time from only 5-30 minutes (compared with
the conventional reflux heating method which requires 2-3 hours) and the
efficiency is very high (>90%). The results of hydrazide - hydrazone synthesis
are presented in Table 3.33 – 3.36.
The 1H NMR spectra of all these hydrazide - hydrazones are quite
complex, consisting of 2 sets of signals, one with strong intensity and one with
weak intensity, sometimes separate and sometimes intertwined, which makes it
difficult to analyze (Figure 3.20).

NHa

2
3

1

4
5

S

6 N

7

8

18
17

HN N

9 10

14 15
11

O
O
12
O
13
HN
NHb
12a
CH3

H19,H21

20 NO

2

16
22

21

H12b
H18,H22
H14

12b

H12b'

NHa
H14'

NHa'

H16
H5

H16'

19

NHb
NHb'

H13

H13'

H4

H2
H9

H10

H3
H10'

H9'

Figure 3.20. 1H NMR spectrum of 10A1
Hydrazide - hydrazone 10A1 in solution may be exit 4 isomer, 2 E/Z
imine isomers (-N=CH-) and 2 cis/trans (-N-C(O) amide. When studying the
hydrazides - hydrazones formed from the condensation reaction between
substituent hydrazides and aromatic aldehydes Wyrzykiewicz et al.
demonstrated that in solution the hydrazides - hydrazones usually exist in the
geometrical form E imine [106].
15

H
H
O

Ar'

C
H2

N
C

C
N

Ar

Ar
H

ChËm

O

Ar'

O

C

H2

Nhanh

Ar'

O

O

Nhanh

C
N
C
H2

Cis, E

Ar=

NO2
N

H
N
C

H

Trans, Z

Trans, E

Ar

N
C

C
N

H
H
O

ChËm
Ar'

O

C
N
C
H2

Ar
N
C

H

Ar'=
O
C NH
H3C

S

O

Cis, Z

Besides, compound 10A1 was spectroscopically measured in d6-dimethyl
sulfoxide solvent, the E imine isomer undergoes a rapid conversion of the
cis/trans amide equilibrium in which the cis amide conformation is preferred
[68]. Therefore, it can be confirmed that the form of hydrazide - hydrazone
10A1 in DMSO-d6 measuring solution is cis amide E imine corresponding to
the strong signal set, while the weaker signal set is trans amide Z imine [21].
The results of NMR, HRMS and MS spectral analysis of the hydrazide hydrazones presented in Table 3.38 – Table 3.49 have shown that their
structure is consistent with the predicted formula.
The four series of hydrazide - hydrazone synthesized above are all very
insoluble in common organic solvents, so the product is not recrystallized, but
only washed several times with hot alcohol until the impurities are gone, thus
the most effective method to verify the structure is based on HRMS highresolution mass spectrometry. In the above four series of hydrazide hydrazones, a representative substance is selected in each series to measure
HRMS, the samples are 10A1, 10B2, 11A2 and 11B1, the remaining
substances in the series are measured MS normally. Spectral measurement
results are listed in the appendix, the results of HRMS analysis of the four
hydrazones selected to represent each series are presented in Table 3.48 and
the normal MS results of the remaining substances are presented in Table

3.49. Compound 10A1 has the predicted formula of C24H19O5N5S,
corresponding to the molecular ion peak on the +HRMS spectrum of
C24H20O5N5S+ calculated as 490.1174 au. The measured value on the +HRMS
spectrum of 10A1 (Figure 3.23) is 490.1178 au, which proves that compound
10A1 has a structure as originally expected. For the remaining substances, the
measured +HMRS or -HRMS spectra have a matching value of 2 to 3 decimal
figures compared with the calculated value (see Table 3.48). Particularly, the HRMS spectrum of compound 11B1 is often accompanied by the M+Clvalue, according to calculations this molecular ion peak would have a value of
497.0697 au while the measured value is 497.0664 au.
16


3.8. Synthesis and structure of benzoxazoles from nitrovanillin
3.8.1. Synthesis of o-nitrophenols
3.8.1.1. Synthesis
From nitrovanillin (2B), conducting condensation reaction with aromatic
amines to obtain 7 Schiff bases 12B1-12B7, the results of synthesizing this
series have been published in the Journal of Science - Ho Chi Minh City
University of Education [27]. From the Schiff bases, conduct reduction to
obtain 7 secondary amines, 13B1-13B7, the results of synthesizing this series of
substances have been published by the research team in the Journal of
Chemistry [26]. From the series of secondary amines, conducting acetylation
reaction with Ac2O using microwave irradiation to obtain a series of
compounds 14B1-14B7. Hydrolysis of 14B1-14B7 with LiOH yields a series of
N-acetyl (o-nitrophenol type) 15B1-15B7.
3.8.1.2. Structure identification
NMR spectra of substances 15B1-15B7 are presented in the appendix, the
results of spectral analysis are included in Table 3.51 and Table 3.52. A special
feature on the 1H NMR spectrum of the o-nitrophenol series is that the two H8
protons of 15B2 have completely different chemical shifts at δ = 5.5 ppm and at δ
= 4.2 ppm respectively (denoted as H8a and H8b) with separation constant J = 14

Hz characterizes the spin-spin interaction of the 2 gem-hydrogen. In the remaining
substances (15B1, 15B3, 15B4, 15B5, 15B6 and 15B7), the signal of 2 protons H8
is shown as a single fringe, intensity 2H (Figure 3.24).

15B4
15B2

15B3

15B1

15B6
15B5

15B7

Figure 3.24. Signals of H8 protons of substances
The above "strange" phenomenon can be explained by two reasons: (i)
Pyramidal inversion of the nitrogen configuration in tetrahedral form when the
amide group has an electron-withdrawing group such as a halogen, O, N, S on
the nitrogen atom [27]. (ii) restricted rotation around the Ar-N bond.
In the case of compound 15B2, on the N atom that does not contain an
electron-absorbing group, it does not reduce the resonance nature of N with C =
17


O in the amide group, leading to the nitrogen atom not carrying a tetrahedral
nature, so the N atom does not exist in a pyramidal form. Therefore, the
appearance of two non-equivalent proton signals of H-8 is not related to the
pyramidal transition. Besides, the naphthyl group directs the aromatic ring

towards H-8 causing anisotropy effect, the anti form is preferred [57].
Furthermore, Shvo et al. established two systems to separate the two
phenomena of pyramidal inversion and limited rotation around the Ar-N bond
and confirmed the nonequivalence of the diastereotopic protons of the benzyl
methylene group in N. -benzyl-N-(o-tolyl)acetamide is due to limited rotation
around the Ar-N bond. In addition, one more demonstration of the chemical
shift disequivalence of the methylene protons (H-8) of 15B2 is that their signals
are always sharp, sharp fringes even when measured at room temperature
(298K). ) or measured at high temperature (373K) (Figure 3.25) [86].

HO

3

NO2 10
H3C

5

H3CO
7

3

N

1
2

O

9

6
8

15B2

11

12
13

20
19

14
15

18

16
17

298K

373K

Figure 3.25. H8's signal in 15B2 at two temperatures
The spectral analysis results of 15B1-15B7 presented in Tables 3.51-3.54

have shown that their structure is consistent with the predicted formula.
3.8.2. Series of o-aminophenols and derivatives
3.8.2.1. Synthesis
Applying the method of reducing o-nitrophenol compounds with
Na2S2O4/C2H5OH agent similar to when synthesizing 2 compounds 4A and 4B
(section 3.1.1), 15B1 has been reduced to obtain o-aminophenol-type
compound 16B1 (the structure of 16B1 was identified through IR, NMR, MS
spectroscopy). The spectral analysis results of 16B1 presented in Table 3.57
have shown that their structure is consistent with the predicted formula.
Conducting the benzoxazole ring-closing reaction from 16B1 with
aromatic aldehydes, two benzoxazole derivatives 18B1 and 18B2 were
obtained. The mechanism of the benzoxazole ring-closing reaction is Figure
3.4. The spectral analysis results of 18B1 and 18B2 are presented in Table 3.59
and Table 3.60 below
18


Table 3.59. Spectral analysis results of compound 18B1
7

OCH3

10
12
13

9
11

O2

N
8

14

Cl

1

Proton
H2
H6
H7

1

3

4

6

5

19
18

O
N

20

24

OCH3

23 22

18B1

16
15

13

H NMR
δ (ppm), J (Hz)
6.82 (s, 1H)
7.09 (s, 1H)
3.94 (s, 3H)

21

17

C NMR
Carbon δ (ppm)
135.1
C1

108.1
C2
143.9
C3
138.1
C4
143.2
C5
111.0
C6
56.1
C7

H8

4.95 (s, 2H)

C8

51.5

H10
H12
H13
H15
H16
H17
H18
H19
H20

H21
H22
H23
H24

1.87 (s, 3H)
7.26 (d, J = 8.5, 1H)
7.40 (d, J = 8.5, 1H)
7.40 (d, J = 8.5, 1H)
7.26 (d, J = 8.5, 1H)
8.07 (d, J = 8.5, 1H)
7.13 (d, J = 8.5, 1H)
7.13 (d, J = 8.5, 1H)
8.07 (d, J = 8.5, 1H)
3.85 (s, 3H)

C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21
C11

C23
C24

169.3
23.9
141.3
129.9
129.3
131.9
129.3
129.9
162.5
118.6
129.3
114.7
162.1
114.7
129.3
55.4

HMBC
x: has mixed spectrum with
H2xC8; H2xC6; H2xC4;H2xC3
H6xC8; H6xC2; H6xC4
H7xC3
H8xC2; H8xC6; H8xC1; H8xC11;
H8xC9
H12xC16; H12xC14; H12xC11
H13xC15; H13xC11; H15xC14
H15xC13; H15xC11; H15xC14

H16x C12; H14xC14; H14xC11
H19xC21; H19xC23; H19xC20
H20xC18; H20xC22; H20xC21
H22xC18; H22xC20; H22xC21
H23xC19; H23xC21; H23xC20
H24xC21

3.9. Biological activities of substances
3.9.1. Tested antimicrobial activity
Table 3.61. Results of tested antimicrobial activity of some substances
No
.

Sample
symbol

1
2
3
4
5
6
7
8
9

4B5 (T6f)
5A (H19.1)
5B (H19.3)
8B1 (La)

9B1 (Lb)
9A2 (Lb1)
10A
10B
11A

Minimum inhibitory concentration ( MIC, µg/ml)
Bacterium
Bacterium
Mold
Yeast
Gr(-)
Gr(+)
P.
B.
S.
F.
S.
C.
E.
A.
aeruginos subtili arueu
oxyspor cevevisia albican
coli
niger
a
s
s
um
e

s
200
-

200
200
200

-

-

19

-

-

200
-

-


10
11
12
13
14
15

16
17
18
19
20

11B
10A1
10A3
10A5
10A7
11A3 (H19.11)
11A11 (H19.8)
11A12
(H19.12)
11A14
(H19.10A)
15B1
16B1

200
200
-

200
200
-

200
-

-

-

-

200
-

200
200

150
-

150
-

200
-

-

200
200
-

-

-

-

-

-

-

-

Test results have shown that:
- Samples 4B5, 5A, 5B, 8B1, 9B1, 9A2, 10A1, 11A3, 11A11, 11A12,
11A14 did not exhibit any antimicrobial activity against tested bacterial and
fungal strains.
- The remaining samples exhibited tested antimicrobial activity against at
least 1 bacterial strain or 1 fungal strain with MIC values between 150-200
g/mL.
3.9.2. Antioxidant activity
Among the synthesized substances, 10 samples were selected to test the
antioxidant activity by DPPH method, including the following samples: 4
samples of o-nitrophenol and o-aminophenol (4A, 4B, 15B1, 16B1); 2 samples
of N-formamide (5A, 5B) 3 samples of benzazole (4A1, 4A2, 4A6) and 1
sample of benzoxazole 18B2. The test results are presented in Table 3.62.
Table 3.62. Test results of antioxidant activity of some substances
Sample symbol
No.

1

2
3
4
5
6
7
8
9
10

Prototype (+) / [acid ascorbic]
Prototype (-) / [DPPH/EtOH+DMSO]
4A
4B
15B1
16B1
5A
5B
18B2
4A1
4A2
4A6

Free radical
neutralization
capacity (SC, %)*
87.53±0.3
0±0
83.92±0.7
88.52±0.2

69.49±0.5
80.69±0.6
36.38±0.8
36.85±1.4
45.77±0.8
80.78  0.91
78.87  1.02
82.21  0.77

SC50
(µg/ml)
11.5
12.23
22.96
24.01
14.81
≥50
≥50
47.26
116.85
209.87
104.32

Maximum sample test concentration 50 µg/ml
The results of antioxidant activity test have shown that:
- Five samples 4A1, 4A2, 4A6, 5A and 5B did not exhibit any antioxidant
activity in vitro when tested for free radical neutralization by the DPPH method
within the test concentration range.
20

- The remaining five samples including 4A, 4B, 15B1, 16B1 and 18B2 all
showed antioxidant activity in vitro when testing the capacity to neutralize free
radicals by DPPH method with SC50 from 12,23-47,26 µg/mL.
3.9.3. Cytotoxic activity of substances
Among the synthesized substances, seven samples were selected for
cytotoxicity testing, including: 04 samples of substance 8B1, 9A2, 9B1, 9B2 to
test the activity on KB cell line (carcinoma cells), test results on KB cell line
are presented in Table 3.63 and 03 samples 5A, 5B and 9B2 were tested for
activity on 4 cell lines Hep-G2 (liver cancer cells), MCF-7 (breast cancer cells),
A549 (lung cancer cells), HGC 27 (gastric cancer cells), the test results are
presented in Table 3.64.
Table 3.63. Anticancer activity of 8B1, 9A2, 9B1 and 9B2 on KB line
No.
1
2
3
4
5

Sample symbol
8B1 (La)
9A2 (L1b)
9B1 (Lb)
9B2 (L2b)
Ellipticine (ĐC)

IC50 value, µg/mL
>128
13.12

71.86
80.69
0.45

Table 3.63 has shown that:
Sample 8B1 (La) showed no activity against the KB cancer cell line at the
test concentrations.
Samples 9A2, 9B1 and 9B2 exhibited activity against the KB cell line
with IC50 values of 13.12; 71.86 and 80.69 µg/mL, respectively.
Table 3.64. Anticancer activity of substances 5A, 5B, 9B2
No.
1
2
3
4

Sample
symbol
5A
5B
9B2
Paclitaxel
(ĐC)

A549
>100
>100
3.23
49.13

Cell line (IC50 value, µg/mL)
HepG2
MCF7
>100
18.18
25.82
24.81
15.09
5.51
42.01
37.91

HGC-27
>100
30.65
99.04
61.23

Table 3.64 has shown that all 3 samples showed high activity against 1 to
4 tested cell lines. Specifically:
- Compound 5A showed activity on 01 MCF7 cell line with IC50 value =
18.18 µg/mL.
- Compound 5B showed activity on 02 cell lines MCF7, HepG2 and HGC27 with IC50 values of 24.81 µg/mL, 25.82 µg/mL and 30.65 µg/mL.
- Compound 9B2 showed activity on 04 cell lines MCF7, HepG2, A549
and HGC-27 with IC50 values of 5.51 µg/mL; 15.09 µg/mL và 3.23
µg/mL; 99.04 µg/mL.
3.9.4. Plant growth stimulant activity
a. Plant growth stimulant activities of 9A2 and 9B2 on some maize varieties
The plant growth stimulant activity of 2 compounds 9A2 and 9B2 was
tested on 5 maize varieties LVN092, LVN17, VN556, VN5885, DL668. The test

21


results are shown through the average stem length and average root length of
the maize varieties when stimulated with compounds 9A2 and 9B2 after 10 and
15 days of growing in the growth chamber compared with the tested, presented
in Table 3.65.
Based on Table 3.65, we can see that increasing the concentration of
derivative 9A2 will reduce the growth of maize varieties. Especially, at the
concentration of 10-3M, the young plants of LVN092 variety showed difficulties in
growing and gradually dying, yellowing, poor root development because the plants
had difficulty absorbing water at this concentration. At the tested concentrations,
maize varieties LVN17, VN556, VN5885 do not had much difference in stem height,
but the DL668 variety had a much lower stem height than the other varieties.
However, the DL668 had better root length than the other varieties.
At all concentrations of derivative 9B2, maize varieties LVN092, LVN17,
VN556, VN5885, DL668 showed growth inhibition. Although variation was not
as pronounced as that of derivative 9A2, at all concentrations the stem and root
heights were lower than that of the control samples (Table 3.66). Increasing the
concentration of derivative 9B2 reduced the growth ability of maize varieties,
all had better developed roots than the stem.
b. Plant growth stimulant activities of 9A2 and 9B2 on some rice varieties
The growth stimulant activity of 2 compounds 9A2 on BACTHOM7
variety and 9B2 on OM18 variety has been tested, the test results are presented
in Table 3.67 and Table 3.68.
Table 3.67 shows that at the test concentrations 10-3 M and 10-4 M of
compound 9A2, both exhibited growth inhibition against BACTHOM7 variety,
but at lower concentrations (10-5, 10-6, 10-7 M) growth stimulation for plants and
roots was exhibited, especially at the concentration of 10 -6 M after 15 days, the
length of the stem was significantly higher than that of the control (145.79%).

Table 3.68 shows that, at all tested concentrations of 9B2, after 10 days,
the root length of the OM18 rice variety was more developed than that of the
control, especially at the concentration of 10-7M-10-5 M. Most of the stem
lengths showed a decrease in growth rate compared to the control (except at the
concentration of 10-5M). After 15 days of testing, most of the stem and root
length were reduced compared to the control (except at the concentration of 10 5
M), especially at concentration 10-3M, starting from day 8 onwards, the plants
gradually withered and died after 10 days of testing.

22


CONCLUSION
After a period of conducting the thesis, we have obtained the following
results:
1. i. From the two starting substances, 4-hydroxybenzaldehyde and
vanillin, using the combination of various reactions, some of which were
supported by microwave irradiation, 5 "key substances" have been synthesized:
2-amino-4-(benzo[d]thiazol-2-yl)phenol (4A); 2-amino-4-(benzo[d]thiazol-2yl)-6-methoxyphenol (4B); 4-(benzo[d]thiazol-2-yl)phenol (7A); 2-amino-4(benzo[d]thiazol-2-yl)phenol
(7B)
and
N-(3-amino-4-hydroxy-5methoxybenzyl)-N-(4-chlorophenyl)acetamide (16B1). In which compounds
4A, 4B, 16B1 are o-aminophenol-type compounds with high reactivity and
good antioxidant activity.
ii. From the "key substances" mentioned in conclusion 1, 06 series of
substances containing benzothiazole and benzoxazole heterocycles have been
synthesized, specifically as follows: benzazole series 4A1-4A6 and 4B1-4B13
(19 substances); N-formamide series 5A, 5B (2 substances); Carboxylic acid
series 8A1, 8B1, 8B2 (3 substances); Hydroxamic acid series 9B1, 9A2, 9B2 (3
substances); Hydrazide series 10A, 10B, 11A, 11B (4 substances); Hydrazide hydrazone series 10A1-10A8; 10B1-10B8; 11A1-11A16 and 11B1-11B8 (40

substances).
iii. From nitrovanillin (2B), were synthesized the "key substance" 16B1 of oaminophenol-type was obtained and two benzoxazoles 18B1-18B2.
2. Structures of the 83 new compounds have been identified by IR, 1H
NMR, 13C NMR, 2D NMR, HRMS and MS spectra. By using HSQC
spectroscopy, HMBC has accurately attributed each signal on the 1H NMR and
13
C NMR spectra of the synthesized compounds, as well as showing the
dependence between the spectral properties and the chemical structure of the
substances in the hydrazide-hydrazone series 10A1-10A8; 10B1-10B8, 11A111A16; 11B1-11B8 and o-nitrophenol series 15B1-15B7.
3. i. The antimicrobial activity of 20 compounds has been tested, the results
showed that, there are 09 compounds showing moderate and weak activity
against some bacterial and fungal strains with IC50 =150-200 µg/mL.
ii. Antioxidant activity of 10 compounds 4A, 4B, 4A1, 4A2, 4A6, 5A, 5B,
15B1, 16B1, 18B1 has been tested by DPPH method. The results showed that
05 compounds 5A, 5B, 4A1, 4A2, 4A6 did not show any antioxidant activity at
the test concentrations, 01 compound 18B1 showed weak antioxidant activity
with IC50 of 47.26 µg/mL, 04 compounds 4A, 4B, 15B1 and 16B1 showed
moderate and high antioxidant activity at test concentrations with IC 50 of 12.23;
22.96; 14.81 and 24.01 g/mL.
iii. Cytotoxic activity of 07 compounds has been tested, including: 04
compounds (8B1, 9A2, 9B1, 9B2) on KB cancer line, 03 compounds (5A, 5B,
9B2) on 4 lines: Hep-G2 (liver cancer cells), MCF-7 (breast cancer cells), A549
23