Nghiên cứu tổng hợp, cấu trúc và chuyển hóa một số dãy hợp chất furoxan, quinoline và quinazoline nhiều nhóm thế từ eugenol trong tinh dầu hương nhu tt tiếng anh

Researches on heterocyclic compounds synthesized from natural compounds in plant essential oils have attracted much attention of scientists.. The previous furoxan, quinoline, and quinazo

1 The necessity of the study

Heterocyclic chemistry plays a very important role in organic chemistry Currently, the increase in the number of organic compounds is mainly due to heterocyclic compounds Researches on heterocyclic compounds synthesized from natural compounds in plant essential oils have attracted much attention of scientists These heterocyclic compounds have both specific structural parts of natural compounds and new structural components Therefore, they could be highly bioactive, and could be applied in pharmacy and medicine

Furoxan heterocyclic compounds (1,2,5-oxadiazole-2-oxide) have NO-releasing properties when they enter the human body NO molecules have effects on the nervous system that controls blood vessel elasticity Therefore, they are promising in treatment of cardiovascular diseases Currently, several compounds that can release NO, including either monocyclic compounds or heterocyclic compounds associated with the furoxan ring, have been used in clinical trials such as NO-aspirin, NO-steroid and NO-ursodeoxycholic acid

Compounds containing quinoline heterocycle have a wide range of bioactive activities Many

of those have been used as antibiotics, antibacterial drugs, antimalarial drugs, and some other derivatives have been used as anti-tuberculosis drugs Moreover, quinoline-containing compounds also have many applications in analytical chemistry metal analysis by photometric and fluorescent methods

Quinazoline and quinazolinone compounds have gained many attentions in medicine due to their wide range of biological activities Numerous quinazoline- and quinazolinone-contaning compounds have antihypertensive, anti-inflammatory, anti-HIV, antiviral and anticancer activity due to their inhibitory effects on thymidylate synthase, poly- (ADP-ribose) polymerase (PARP) and thyrosine kinase Currently, some antihypertensive drugs such as (1- (4-Amino-6,7-dimethoxy-2-quinazolinyl) -4- (1,4-benzodioxan-2-ylcarbonyl) -piperazine monomethane-sul fonate with brand name doaosinemesylate), obesity medication such as ((RS) -dimethoxy-2- [4- (tetra hydrofuran-2-ylcarbonyl) piperazin-1-yl] -quinazolin-4-amine brand name terazosine) and blood pressure medication, such as ( 2-[4- (2-furoyl)piperazin-1-yl]-6,7-dimethoxyquinazolin-4-amine with the commercial name prazosin) having a quinazoline structure have been brought to market

The previous furoxan, quinoline, and quinazoline heterocyclic compounds were mostly synthesized from products of the chemical industry, mainly from petrochemical technology The synthesis of those heterocyclic compounds from plant essential oil resources, which are renewable materials, is consistent with the green chemistry Current research directions still attract a little attention, therefore, the studies on heterocyclic compounds synthesized from plant essential oils are relatively rare

Due to those reasons mentioned above, the research topic: "Research on synthesis, structure and transformation of some series of substituted furoxan, quinolines and quinazolines from eugenol in Ocimum sanctum L oil " was chosen

2 Aims and objectives

- Aims

Synthesis and transformation of new substituted furoxans, quinolines and quinazolines starting from natural products to look for compounds with high biological activities or for other applications

- Objectives:

+ Synthesize number of key substances from eugenol in basil essential oil

+ Transform the synthetic key substances into new derivatives

+ Study the properties and determine the structure of synthesized compounds

+ Investigate antibacterial, antifungal and cytotoxic activities to search for compounds with high biological activities

3 Research methods

+ Synthesis of substances: Applying traditional organic synthetic methods which were selected and improved to suit each new objects Focusing on improving performance, reducing the amounts of starting materials, careful purification by recrystallization

+ Structural study: The synthesized substances were structurally studied by spectroscopic methods such

as IR, 1H- NMR and 13C-NMR spectroscopy; Molecular weights of most of new compounds were measured by MS spectroscopy In each series of substances with similar structures, some substances with complex structures were selected to studied with 2D NMR spectra

+ Analyze the spectra, systematize the data and draw conclusions

+ Select some typical compounds to explore antimicrobial activities and cytotoxicity

4 Scientific and practical significances of the study

- Opening the direction of synthesizing a number of heterocyclic compounds according to the principles of green chemistry by synthesizing key substances from eugenol

- Providing accurate data sources on IR, NMR, MS spectra of complex heterocyclic compounds for scientific research and chemistry teaching

- Several synthetic quinazoline compounds have shown high cytotoxicity Their structures help guide the search for more active compounds

5 New contributions of the study

* Some abnormal reactions have been investigated whose reaction mechanisms were proposed, leading

to a new synthesis method They are: Synthesis of quinazoline ring (compound D1) by transforming

furoxan ring and acetamido group at the positions 1 and 2 of the benzene ring; Creation a carbonyl

ketone group (compound D2) by reducing the nitro group at the same position at the branch; Preparation of diazo compound G8 by reaction in the reversed order of normal diazoni salt preparation 5.2 Structural study:

* The structures of 64 new compounds have been determined by combining IR, 1H NMR, 13C NMR, HMBC, NOESY, X-RAY and MS spectra

* Identify the structures and explain the formation of many new and unexpected compounds obtained from unprecedented reactions, namely: 4- (1-chloro-1-nitroethyl-6,7-dimethoxy-2-methylquinazoline

(D1); 5,6-dimethoxy-2-methyl-3-H-indole-3-one (D4) from the hydrolysis reaction of D1; isoquinoline D12 compound from quinazoline D2 compound; magnetic??? G3 compound additive thiosemicarbazide reaction to quinolin-5,6-dione G0; molecular complexes G6 and G7 from diamine reaction with G0; diazo G8 compound from reaction of diazoni salt with amine

5.3 Bioactive tests: The micro-antibiotic activity of some new compounds was moderate and weak Notably, compound D8 exhibited high cytotoxic activity against three strains of liver, breast and lung

cancers at test concentrations with an IC50 value of 0.80; 0.85; 4.41 g/ml; Compound G1 showed

antioxidant activity on DPPH with IC50 = 9.8 μg/mL

6 Structure of the dissertation

The dissertation consists of 147 A4 typed pages with 50 tables, 98 fugires and schemes which are distributed as follows:

Introduction: 2 pages

Literature review: 26 pages

Experiment section: 21 pages

Results and discussions: 96 pages

Conclusion: 2 pages

References: 13 pages

There are also appendices (152 pages) including 5 sections A, B, D, E, G

CONTENTS OF THE DISSERTATION Chapter 1: LITERATURE REVIEW

Domestic and international documents on the general research of furoxan rings, quinazoline and quinoline rings have been reviewed The results show that there are only a very few studies on transformation of furoxan, quinazoline and quinoline compounds synthesized from eugenol in basil essential oil

Chapter 2: EXPERIMENT

The synthesized substances were prepared as shown in diagram 2.1 The several first substances for 5 series of research compounds were synthesized according to the constrained Scheme 2.1 In Scheme 2.1, substances A0, Q0, E0 and G0 are substances published by other authors, substances B1, D1 are the key substances which are novel compounds

Scheme 2.1 General diagram of the study compounds

CHAPTER 3: RESULTS AND DISCUSSIONS 3.1 SYNTHESIS AND STRUCTURAL STUDY OF SERIES A

3.1.1 Synthesis of A-range compounds

a Synthetics scheme:

Scheme 3.1 Summary scheme of range A compounds

Comment [H1]: acetonitrile

b Synthesis

Microwave oven were used to perform the reactions: radiate the reaction mixtures with microwave for

1 minute each time, use TLC to monitor the reactions, and repeat the radiation After every 2 minutes, check the TLC until all the starting materials have been consumed, then stopped the reactions Spectral analysis showed that the products had the expected structures

A15 compound: The reaction of Ao with maleic anhydride was performed in ethanol in the presence

of concentrated H2SO4 as catalyst The progress of the reaction was monitored by TLC which shown that the amount of product increased gradually After 8 h, there were no starting materials Let the reaction mixture cool down to room temperature The desired product was obtained as yellow needles,

The double bond in A15 has trans configuration which is different from the original cis configuration

of maleic anhydride This can be explained as followed: the carbonium cation rotates freely around the single bond, which helps the acylium ion to have a more stable trans configuration and it is more convenient to attack the NH2 group right next to the bulky furoxan group of A0

We expected the A15 amide reaction mechanism to be as follows:

following scheme:

Scheme 3.3 The process of forming and metabolizing amide and imide from succinic anhydride

3.1.2 The structure of the A-range compounds

- IR spectrum of A1-A18 no longer has absorption band of the NH2 group Some main absorption ranges on

IR spectrum of A1-A18 are given in tables 3.3, 3.9 and 3.11 of the thesis.1H NMR spectra data of A1-A18

substances are summarized in Table 3.2

Table 3.2 1

H NMR spectral data of A1-A18 substances

H6 H7a H7b

H10 OH/NH(H11)

H12 H13

H14 H15

H16 H17

H18

6.50 s 3.75 s 3.67 s

2.17 s 5.34 s

2.14 s 14.56 s

1.95 s 10.23 s

- 6.77 s

- 6.70

A3

7.63 s 3.91 s 7.06 s 7.50 t J=8.0 6.75 d J=8.5 7.65 d (che) J=8.0

7.55 s 3.95 s 3.93 s

2.24 s 10.57 s

2.04 s 8.00 s

1.96 s

-

7.63 dJ=8.5 6.82 dJ=8.5

1.98 s 8.40 s

7.53 s

7.26 s 3.91 s 3.94 s

2.10 s 8.80 s

2.07 s 8.79 s

2.08 s 8.77 s

- 8.15 dd

J=3.0;1.0

- 7.43 dd

2.30 s 7.85 s

2.80 m 3.01 m

-

7.31 s 3.85 s 3.82 s

2.10 s

-

2.73 m 2.73 m

-

6.33 s 3.67 s 3.66 s

2.14 s

6.17 s J =6 (4.4 dd J= 6)

-

7.37d J=7.5

7.24 t J= 7.5

In H NMR spectrum of the amine A0, the chemical shift of the proton H3 is larger than that of the

proton H6 Interesting, in azo compounds, the chemical shift of the proton H3 is smaller than that of the proton

H6 This may be because in A0, the methyl group donates electron density by hyperconjugation to the C6

position, while in the azo compound, the diazo group N = N attracts electron density from the C6 position (I, C> + C) The chemical shift of the methyl protons at the C4 position of the furoxan ring (H10: 1.96-2.24 ppm) is smaller than that of the methyl protons attached to the aromatic rings (2.3 ppm) This may be due to the anisotropic effect of the N → O group This indicates that the N → O group is close to the methyl group but not

-to the phenyl group

In A0, the chemical shift of the C4 is smaller than that of the C6 but in the azo compounds, the

opposite was found This is due not only to the different electronic effects of the NH2 and –N = N- groups, but also to the bulky azo component that caused the furoxan ring to be perpendicular to the plane of the benzene ring which makes the effect of the +C effect of furoxan to the C4 position of the azo compound is no longer the same

as in A0

Inthe 1

H NMR spectrum of the amide A15, synthesized from A0 and maleic anhydride, there are two

doublets with splitting constants of JH12,H13 = 12.0 Hz, showing that the acrylamito group has trans configuration which differs from the original cis configuration of maleic anhydride

- The 13

C NMR spectroscopic data of the series A are given in the tables 3.5, 3.6 and 3.13 All the spectroscopic

data were in accordance with the expected structures of the synthesized compounds

- The ESI MS spectra of the four compounds A1, A4, A5 and A6 give pseudo-molecular peaks suitable for

calculated molecule weights

3.2 SYNTHESIS AND STRUCTURAL STUDY OF THE SERIES B

3.2.1 Summary of the compounds in series B

a General scheme:

Scheme 3.4 Synthetic scheme of the series B

b Synthesis

The quinoline B1 was synthesized from A0 following the Döebner – Miler method The procedure

was improved from the traditional method as follows: the reaction was performed in toluene – HCl

heterogeneous system in which the actetaldehyde was replaced with paraldehyde The desired product B1 was

obtained with 85% yield as white crystals B1 is insoluble in water but well soluble in common organic solvents

This is an important key substance, opening up a diverse synthesis of the derivatives containing both furoxan and quinoline heterocycles

The mechanism of the Döebner – Miler reaction is as follows: Paraldehyde is the trimer of acetaldehyde In acidic medium, paraldehyde is gradually decomposed into acetaldehyde which underwent the aldol condensation to yield crotonaldehyde Crotonaldehyde then took part in the reaction with amine and was converted to the quinoline ring

The B1 compound thus formed is a 2-methylquinoline compound which was oxidized to carbaldehyde B2 with SeO2 We optimized the reaction conditions by changing reaction temperature and time

quinoline-2-The results of the investigation summarized in table 3.16 show that the synthesis of quinoline-2-carbaldehyde B2 gave highest yield when performed at 90 °C for 4 h To obtain only B3 (which is predicted to be quinoline-2-

carboxylic acid) the amount of SeO2 was doubled and the reaction time was increased to 5 h at 100 oC

The esters from quinoline-2-carboxylic acid B3 are synthesized by the traditional methods

Yield

1H , 13C, HMBC, HSQC,

MS

1

MS

3.2.2 Structure of compounds in series B

- Main IR absorption bands of B1-B18 are given in tables 3.17, 3.20 and 3.24 The IR spectrum of B1 no longer

has absorption band of the NH2 group The IR spectrum of B2 has the absorption band of the aldehyde carbonyl group, substances B3 - B7 have the typical absorption bands for the acid and ester C = O groups (C = O ester >

C = O acid), the α, β-unsaturated ketones B12 - B18 have absorption band for C = O group in conjugation with

the C = C ethylenic group

- The H NMR spectrum of B1 has three downfield protons with chemical shift greater than 7.0 ppm, while in amine A0 there are only two aromatic protons in the benzene ring with smaller chemical shifts The upfield range in the spectrum of B1 differs from that in A0 which has an additional signal with an intensity of 3H at δ=

2.61 ppm, proving that the ring reaction according to Doebner - Miller method has occurred, affording methylquinoline

H5a H6a

H2a H13

H14 H15

H16 H17

- 3.93 s

- 4.39 m

- 4.34 t

1.71 m 1.42 m

- 4.37 t

1.62 m 1.75 m

0.93 m 0.93 m

- The 1H NMR spectra of the alkenes from B8 to B11 showed that in the sp2 range, the number of protons is not

three as in the key substance B1 but at least 3 more protons appear, in which two peaks with coupling constants

of 15 - 16,5 Hz corresponding to a trans C-C double bond

Table 3.5 1H NMR signal of compounds B8 - B11; δ, ppm; J, Hz

H7

H4 H12a

H5a H6a

H2a H2b

H14 H15(15a)

H16 H17

H18 H16b

7.62 dJ=16 7.80 dJ=16.5

8.24 d J=9.0 7.98 d J=9.0

7.60d J=16.5 7.82d J=16.5

8.50 t J=1.5

-

8.19 d J=8.0 7.71 t J=8.0

7.47d; J = 16 7.99dJ =15.5

-

8.02 d J=8.0

7.60t J=8.0 7.77t J=7.5

7.62d J=16.5 7.77d J=16.5

- The H NMR spectra of the compounds from B12 - B18 showed no signal of the aldehyde proton (typically at

about 10 ppm), and there were 10 signals of aromatic protons in accordance with the number of aromatic protons

in the predicted formula There are always two signal olefinic protons with coupling constant larger than 12 Hz

This indicated that the Aldol condensation between the aldehyde B2 and various ketones occurred and yielded

trans- products.+ When changing from aldehyde B2 to α, β-unsaturated ketone in general, the chemical shift of

both H7 and H4 was decreased

+ The chemical shift of H3 increased significantly in comparison to that in B2, except for compound B18, the chemical shift of H3 is almost unchanged compared to the original B2 aldehyde

+ The chemical shifts of H2a and H2b are abnormal Normally, for α, β-unsaturated ketone δ (Hα) <δ (Hβ) due

to – C effect of the C = O group Accordingly, for αβ-unsaturated ketone B12-B18, δ (2Hb) <δ (2Ha) But for α, β-unsaturated ketone B14, the HMBC spectrum showed the opposite: δ (2Hb)> δ (2Ha) (Figure 3.24, cross-peak

C3xH2a and pattern C2xH2b) We assumed that the –C effect of C = N in the quinoline ring is opposite to that

of C = C, which is the cause of the abnormal chemical shifts

Table 3.6 1H NMR signal of compounds B12 - B18; δ, ppm; J, Hz

H7

H4 H12a

H5a H6a

H2a H2b

H14/

H18

H15/

H17 H16(a) H16b

7.69 d J=15.5 8.22 d J=16

7.71 d J=16 7.80 d J=16

7.43 d; J = 16 8.21 d;J =16

7.72 d J=15.5 8.18 d J=16

7.69 d;J=15.5 8.22 d;J =16

8.13 d;

J=8.5

7.10 d

J=8.5 4.18qJ=7 1.38 tJ=7

7.72 d;J=15 8.10 d;J=15

- The ESI-MS spectra of the three compounds B1, B5 and B6 give pseudo-molecular peaks suitable for the

calculated molecular weights

3.3 SYNTHESIS AND STRUCTURAL STUDY OF SERIES D

3.3.1 Summary of series D

a Synthetic Scheme :

Scheme 3.5 Summary scheme of series D

b Synthesis

Acetylation A0 produced 3-methyl-4- (2-acetamido-4,5-dimethoxy-phenyl) furoxan Am The reaction between

Am and DMF-POCl3 (Wilsmeier-Haack agent) did not give quinoline type compounds as expected by Wilsmeier-Haack

method but heterocyclic quinazoline D1 was obtained The formation of D1 was explained as in scheme 3.6

Scheme 3.6 Explanation of the quinazolin D1 ring formation from Am

The quinazoline ring as shown in the scheme 3.6 above is an unprecedented reaction The right

conditions for this abnormal reaction were found to become a synthetic method of quinazoline D1 with the yield

of 64 % Interestingly, the reaction of quinazoline D1 with Na2S2O4 did not stop at reduction of nitro group into

amino group, as soon as it wasconverted to methylketone D2 as shown in scheme 3.7 The structure of D2 is

determined on the basis of analyzing its spectra, in addition, its structure was further confirmed by the reaction

of D2 with C6H5NHNH2HCl to create phenylhydrazone D3

Scheme 3.7 The formation of D2 from D1

Interestingly, a yellow needle-shaped D4 compound was obtained by boiling D1 with 10%

NaOH solution in 95% ethanol after crystallizing The spectral analysis showed that D4 was

5,6-dimethoxy-2-methyl-3H-indol-3-one On the other hand, when boiling D1 with KClO3 in a solution of HCl at 50 °C, oxidation

product D5 as a white needle-shaped crystal wasobtained indicating that branch was oxidized

Because 4-acetyl-2-methyl-6,7-dimethoxyquinazoline (D2) is a new ketone, it was further investigated

its reaction to aldehyde in presence ether HO- or H+ catalysts In acidic environment, condensation reaction

occurred to obtain 6 unsaturated α, β-ketones D6 - D11, while in alkaline environment, similar products were not

obtained However, in case of p-OHC6H4CH=O reaction with D2 in alkaline environment, product D12 was

obtained as an isoquinoline type compound.The formation of compound D12 from quinazoline D2 and

p-hydroxy benzaldehyde is unpredictable under the aldol-croton condensation reaction, This can be explained as

follows: When heated in an alkaline environment, D2 is hydrolyzed to break the pyrimidine ring to produce

ammonia, the ammonia will condense with the C = O group to form imine II The NH group of imine is added to

the C = O group of p-hydroxybenzaldehyde to form III which is protonized and then split the water to create IV

carbocataion The carbocation acts as an electrophilic agent that attacks the ortho position compared to methoxy

to create compound V, the carbonyl group of V is protonized to produce carbocationVI and then continue to

separate H+ from to form compound D12 according to the scheme below:

Scheme 3.8 Reaction mechanism explains the formation of D12 from D2

Comment [H2]: Sơ đồ phải bổ sung giải phóng

ra ammoniac Công thức khôgn được xoay tự

do thế, không khoa học