nghiên cứu tổng hợp, cấu trúc và tính chất một số dẫn xuất của quinolin trên cơ sở eugenol từ tinh dầu hương nhu bản tóm tắt tiếng anh

MINISTRY OF EDUCATION AND TRAINING HANOI NATIONAL UNIVERSITY OF EDUCATION ------ LE VAN CO RESEARCH SYNTHESIS, STRUCTURE AND PROPERTIES OF SOME QUINOLINE DERIVATIVES ON THE BASIS O

MINISTRY OF EDUCATION AND TRAINING

HANOI NATIONAL UNIVERSITY OF EDUCATION

- -

LE VAN CO

RESEARCH SYNTHESIS, STRUCTURE AND PROPERTIES

OF SOME QUINOLINE DERIVATIVES

ON THE BASIS OF EUGENOL FROM OCIMUM SANCTUM L OIL

SPECIALITY : ORGANIC CHEMISTRY Classification : 62.44.01.14

SUMMARY OF PHD THESIS

Advisor: Prof Dr Nguyen Huu Dinh

HA NOI, 2014

This thesis was completed in: Departments of Organic Chemistry –

Faculties of Chemistry – Hanoi National University of Education

Advisor: Prof Dr Nguyen Huu Dinh

Reviewer 1: Prof.Dr.Sc Nguyen Dinh Trieu

Hanoi University of Science – Vietnam National University

Reviewer 2: Prof.Dr.Sc Tran Van Sung

Vietnam Academy of Science and Technology

Reviewer 2: Assoc.Prof.Dr Dinh Thi Thanh Hai

Hanoi University of Pharmacy

This thesis will be dotted to the Council to perform thesis at the:

Departments of Organic Chemistry – Faculties of Chemistry – Hanoi National University of Education at the time hour October , 2014

This Thesis can be found at the Library of Hanoi National University of Education

or Central Library for Science & Technology

INTRODUCTION

1 Reasons for selecting topic

Chemistry of heterocyclic compounds is a strong growth sector and has created many compounds in practical applications In that field, quinoline heterocyclic plays an important role Many compounds containing a quinoline skeleton is used in various industries such as cosmetics, food, catalysts, dyes and especially in the pharmaceutical industry For example, quinine, cinchonine, chloroquine, pamaquine are used as anti-malarial drugs Several other derivatives of quinoline were applied to cure cancer as camptothecin, antibacterial, antifungal, anti-tuberculosis as bedaquiline

Notably, the diarylquinoline currently classified in one of ten new-generation antibiotic alternative for antibiotic resistant bacteria have been

Not only that, the kind of quinoline compounds also have many applications

in chemical analysis: Ferron, snazoxs, brombenzthiazo used as an indicator of some metals analysis by photometric method Many ligand complexes with quinoline compounds are more substituents have very good optical properties of interest in solar cell manufacturing

Recently, the organic synthesis group - Hanoi National University of Education

have discovered a new reaction: synthetic quinoline ring from quinone-aci compound prepared from eugenoxyaxetic acid It has opened a research synthesis

of new types of quinoline polysubstituted compounds However, this reaction is not stable, performance is low, and the reaction mechanism has not been elucidated The perfect way to create a new quinoline ring and metabolic studies of the products obtained new compounds not only theoretically significant but also the search for promising compounds have high biological activity and the ligand for complex research

Therefore, we selected topeak: “Research synthesis, structure and properties

of some quinoline derivatives on the basis of eugenol from Ocimum sanctum L Oil ”

2 The purpose and tasks of the thesis

– Complete method and study mechanism of the quinoline ring synthesis reaction from quinone-aci compound prepared from eugenol in basil oil

– Synthesis of some new quinoline polysubstituted compounds

– Study the relationship between the structure of the synthetic compound with their spectral properties

– Study the possibility of fluorescence of some kind hemixianin quinoline compounds

– Exploration of bioactive compounds synthesized

3 Research Methodology

● Synthesis: application of synthetic organic methods of traditional and innovative choice to suit each new object Focus on improving efficiency, reducing the amount of reactants, carefully refined to be clean nature

● Study structure: The structure of the synthetic compounds were identified

by IR, 1H NMR, 13C NMR, 2D NMR and MS spectrum coordination Some compounds was studied further UV-Vis, fluorescence emission spectra and single-crystal XRD The spectrums were analyzed in detail, the spectral data and the system were arranged to draw comment

● Tested antibacterial activity, antifungal substance with some Gram (+) and Gram (-), yeasts, molds under successive dilution method Tested cytotoxicity of compounds for four cancer cell lines differ Tested the activity of antioxidant compounds In particular, tested the activity against malaria for 7-carboxymethoxy-

– Detect an abnormal nucleophilic reaction of N-metylquinolinium compounds: the

replacement of the carboxymethoxy group (OCH2COOH) by ankylamino group (RNH) Through extensive research this reaction, has proposed an unusual reaction mechanism

– Detect a reaction which occurs simultaneously with the replacement of the OCH2COOH group by the NHNH2 group and the replacement of Br atom by H atom On the basis of experimental and theoretical proposed the reaction mechanism of this unprecedented reaction

4.2 Study the structures and properties

– Have determined the structure of 60 new compounds type of quinoline polysubstituted by using coordinate spectroscopeak methods IR, 1H NMR, 13C NMR, HSQC, HMBC, NOESY and MS

– Provide reliable data on the chemical shift and constant spin-spin interactions of protons and carbons in a few series quinoline polysubstituted compounds

– Study UV-Vis and fluorescence emission spectra of 11 compounds kinds of alkylamino-1-methylquinolinium-3-sunfonate, sorbents in the visible range and fluorescence with λmax in the range of 505-674 nm

7-– Identified that, Q compound exhibits activity against malaria, but not strong;

QNO 2 has very weak cytotoxic activity; HzQBr has cytotoxic activity against cell carcinoma; A0 and Q have strong antibacterial activity; HzQBr has weak antibacterial, V5 has average antibacterial and R1 has weak antifungal

5 Layout of the thesis

The dissertation consists of 148 typed pages, printed on A4 paper with 26 diagrams, 59 photographs and 45 tables are distributed as follows: Introduction: 03 pages, 25 pages Overview, page 16 Experiments, Results and Discussion page 87, page 02 Conclusion, references 14 pages There is also 126 pages of appendix

CONTENTS OF THE THESIS

Have literature review of domestic and foreign research on the synthesis of homocyclic and heterocyclic compounds from with eugenol, the main constituent

of Ocimum sanctum L Oil and preliminary studies on the compounds containing a

quinoline ring Especially noticed a ring-closed reduction reaction of quinone-aci derivative creates a quinoline compound (detected by organic synthesis group -

Hanoi National University of Education ) is a new reaction should continued to refine

in order to open up a new direction research of polysubstituted quinoline

derivatives

Chapter 2 EXPERIMENTAL

2.1 SYNTHESIS Q AND SOME DERIVATIVES FROM Q

Scheme 1 Diagram synthetic Q and some derivatives from Q

Results synthesis derivatives of Q

Table 1 Structure and data synthesis of derivatives from Q

Order Notation R 1 /R 2 R 3 /R 4 Yield

12 QNHAc H/NHCOMe H/OH 50,0 x x x - x x

13 MeQBr Me/Br H/OH 66,8 x x x - x x

14 MeQNO 2 Me/NO2 H/OH - x x - - - -

14 14 13 2 9 12

2.2 THE REACTION OF QCHO WITH AMINO COMPOUNDS

Table 2 Structure and data synthesis of R1-R7 imins

Order Notation Y Yield

2.3 THE REACTION OF MeQBr WITH ANKYLAMINE

Table 3 Structure and data synthesis of S1-S8 compounds

Order Notation R Yield (%) R f **

Spectrums measurement and analysis

2.4 THE REACTION OF MeQNO 2 WITH ANKYLAMINE

Table 4 Structure and data synthesis of T1-T8 compounds

Order Notation R Yield (%) R f * Spectrums measurement and analysis

(Rf*: Thin-layer chromatography in solvent MeOH/CHCl3 (1:2))

2.5 THE SYNTHESIS AND REACTION OF QNHNH 2 CARBONYL COMPOUNDS

Table 5 Structure and data synthesis of V1-V13 hydrazons

Order Notation R 1 R 2 Yield

Chapter 3 RESULTS and DISCUSSION

3.1 Q: 7-CARRBOXYMETHOXY-6-HYDROXY-3-SULFOQUINOLINE

3.1.1 Complete the synthesis method of Q

By changing the molar ratio of the reactants, temperature, time of reaction stages and acidulating agent in stage 2, we have found conditions for synthesis

reaction Q with high and stability yield Compound Q was checked by IR, NMR

and MS spectroscopy, the results consistent with those previously published

Result analyzed single-crystal diffraction (Figure 1) also shows that Q has

structured in accordance with the expected formula

Figure 1 structure of Q determined by single-crystal XRD method

3.1.2 Study mechanisms reaction synthesis Q from A0

Through monitoring reaction progress by 1H NMR method, we propose a mechanism for the transformation from A0 to Q as Scheme 2

Scheme 2 Reaction mechanism to form Q from A0

3.2 SYNTHESIS, STRUCTURE AND PROPERTIES OF SOME DERIVATIVES

OF Q

From the Q-key, by the methylation reaction, halogenated, nitrated,

acyl-esterified, hydrazide and condensation, have synthesized 14 new quinoline polysubstituted compounds

– IR spectra of derivatives of Q contains peaks characterize the main functional groups: OH, NH, CH, C=O, … accordance with structure are listed in tables 3.5 – 3.17 of the thesis

– 1H NMR, 13C NMR HSQC, HMBC and MS spectrum are shown in tables 3.5 - 3.17 of the thesis Spectral data showed that synthetic compounds have been structure accordance with the expected formula

- The results analyzed single-crystal diffraction EsQBr compound is shown in figure

2

Figure 2 Structure of EsQBr determined by single-crystal XRD diffraction

3.3 SPECTRA PROPERTIES AND STRUCTURE OF R1-R7 IMINES

3.3.1 Infrared spectrum (IR)

Some main absorbtion peak in the IR spectra of the imine R1-R7 are shown

in table 3:19 of the thesis

3.3.2 NMR and MS spectrum of R1-R7

Based on the chemical shift, constant spin-spin interaction and combined with 2D NMR spectral analysis, we have determined exactly the signal of the

proton resonances of the imines R1-R7, 1H NMR spectral data are listed in table 6

Table 6 Signals on the 1H NMR spectrum of R1-R7,  (ppm), J (Hz)

Y H2 H4 H8 H7a H5a H12 H16 H13 H15 H14 Others

s;1H

9,15 s;1H

7,42 s;1H

5,05 s;2H

9,92 s;1H

7,11 d;1H J=8

7,11 d;1H J=8

7,28 t;1H

J = 8

7,28 t;1H

J = 8

6,84 t;1H J=7,5

7,47 s;1H

5,04 s;2H

9,93

8,09 d;1H

J = 10

8,89 d;1H J=2,5

8,28 dd;1H J1=2,5 J2=9,5

s;1H

9,50 s;1H

7,30 s;1H

4,9 s;2H

9,8 s;1H

8,82 d;1H J=1.5

7,17 s;1H

4,85 s;2H

9,58

8,09 d;1H

J = 8

7,37 d;1H

J = 7.5

7,24 t;1H H12a: 2,46

s;1H

9,34 s;1H

7,25 s;1H

4,94 s;2H

9,72 d;1H J=9,5

R7

8,64 d;1H

J = 2

8,52 d;1H

J = 1,5

7,15 s;1H

4,23 s;2H

9,26 d;1H

J =

11

H11: 3,9 s;1H; H12e/H16e: 1,97 s; 2H H12a/H13a/H15a/H16a:1,4 m;4H;

H13e/H15e: 1,72 d; 2H; H14a: 1,25 d;1H H14e: 1,57 t;1H

The analysis NOESY spectrum of imine R6 not only helps to attribute all the

proton signals of R6 but also determined that the C=N double bond of R6 in E configuration (structure A in Figure 5) If R6 in E configuration - structure B (Figure

3), the H5a and H4 are away from each other should not be so strong signal

interaction

Figure 3 A number possible structures of R6

3.4 SPECTRA PROPERTIES AND STRUCTURE OF S1-S8

3.4.1 The reaction of MeQBr with ankylamines

When performing the reaction of QBr with ankylamines at room

temperature as well as heating reflux we have not carried out this reaction

substitution Br atom in position 5 Transforming QBr into MeQBr we hope that

the presence N+ in quinoline core will make it easy for nucleophilic substitution reaction with Br to form 5-ankylamino derivatives (5-RNH-Q) But Br atom had not been replaced so that the OCH2COOH group was replaced by RNH groups

forming 7-ankylamino derivatives S1-S8

In the reaction on the left side above Scheme, OR groups linked to aromatic was replaced by amine creating NHR group It is an unprecedented nucleophilic substitution reaction on the quinoline heterocyclic in particular and on general aromatic compounds

In the literature review mentioned, the nucleophile substitution on the 7thposition of quinoline ring is difficult Although there are also a number of studies have been done a number of nucleophilic reactions with halogenated in 7th position

of quinoline ring, but have not found substitute reaction -OR group (ether) linked to the quinoline ring particular and general aromatic The fact that the alkyl aryl ether RO-Ar is inert with nucleophilic agents such as Cl-, OH-, amine, Because in -O-

Ar, the effect of -p conjugated, R-O group sustainable linked with aromatic should

be so difficult to replace

When cleavage linked RO-Ar with HI, the OR group is not replaced (not leave), the group OAr is leaving group as HO-Ar We have the following scheme illustrates

The reaction (3) is essentially SN2 reaction at saturated carbon atom (𝐶 ) not nucleophilic reaction of aromatic compounds (SNAr) Such the replacement

reaction OCH2COOH group with ankylamine as presented above is a clearly abnormal response unprecedented

To explain this unusual reaction we propose a mechanism similar to the

SNAr mechanism (or addition-elimination mechanism) as described in scheme 3

3.4.2 Infrared spectrum (IR) of S1-S8

IR spectra of MeQBr have characteristic absorption peaks of C=O bond at

1754 cm-1, also on the spectra of S1-S8 only remaining absorption peaks of C=C,

C=N bond of quinoline ring at 1540-1610 cm-1; in the 3000-3500 cm-1, absorption

peaks on IR spectra of MeQBr blended to form absorption band, but on the spectrum of S1-S8, there is a clear separation of the two amino fluctuated with

medium intensity Some absorption peaks on the IR spectra of the series S1-S8 are listed in Table 3.24 of the thesis

3.4.3 NMR spectrum of S1-S8

Based on the chemical shift, constant spin-spin interaction and combined with 2D NMR spectral analysis, we have determined exactly the signal of the

proton resonances of S1-S8 compounds, 1H NMR spectral data are listed in table 7

Table 7 Signals on the 1H NMR spectrum of S1-S8,  (ppm), J (Hz)

H1 H2 H4 H8 H11 H12 H13 H11’ (**) H12’ (**) H13’ (**) Others

s;3H

8,35 s;1H

8,36 s;1H

6,39 s;1H

2,99 d;3H

8,75 s;1H

6,71 s;1H

3,01 d;3H

J = 1

8,26 d;1H

J = 1

6,46 s;1H

2,83 q;2H

J = 7

1,14 t;3H

J = 7

-

3,42 m;2H

J = 7

1,26 t;3H

J = 1

8,75 s;1H

6,78

1,27 t;3H

8,25 s;1H

6,4 s;1H

2,74 t;2H

J = 7,5

1,56 m;2H

J = 7,5

0,90 t;3H

J = 7,5

Bị che lấp

1,70 m;2H

J = 7,5

0,96 t;3H

8,74 s;1H

6,77 s;1H

3,40 d;2H

J = 6

1,70 q;2H

J = 7,5

0,96 t;3H

J = 1

8,28 s;1H

6,53 s;1H

4,63 d;2H

J = 6

H12/H16/H13’/H17’ (**)

: 7,43 t; 4H; J = 7,5 H13/H14/H15: 7,35 t, 3H; J = 7,5

H14’/H16’ (**)

: 7,39 t; 2H; J = 7,5;

H5’ (**) : 7,26 t; 1H; J = 7,5

NH: 7,79

s;3H

9,05 d;1H

J = 1

8,75 s;1H

6,81 s;1H

4,70 d;2H

J = 6

H12/H16: 7,47 d; 2H; J = 7,5 H13/H15: 7,36 dd; 2H; J1 = 8;J2 = 2 H14: 7,27 t; 1H; J = 7,5

NH: 8,37

s;3H

8,34 d;1H

J = 1

8,27 s;1H

6,51 s;1H

3,45 q;2H

J = 5,5

3,69 t;2H

J = 1

8,75 s;1H

6,88 s;1H

3,52 q;2H

J = 5,5

3,71 t;2H

6,59 s;1H

3,71 q;2H

J = 6

3,19 t;2H

7,01 s;1H

3,79 q

J = 6,5

3,10 dd;2H J1 = 5,5 J2 = 6,5

J = 7

1,35 s;2H

1,63 s;2H

H14:

3,11 s; 2H

H12e/H16e: 1,97 m;2H;

H14e: 1,64d;1H; H14a:1,21 m;1H H13e/H15e: 1,77 m;2H;

NH: 7,13