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

INTRODUCTION 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, NOsteroid 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 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 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 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 New contributions of the study 5.1 Synthesis: * Starting from eugenol in basil essential oil, a total of 64 new compounds have been synthesized corresponding to series of compounds including: Chain of compounds containing heterocyclic furoxan (A series, 18 substances), series of compounds containing both furoxan and quinoline heterocyclic rings (series B, 18 substances), series containing quinazoline heterocyclic ring (range D, 12 substances), Chain of compounds containing heterogeneous quinoline ring group (range E, substances), the compound sequence which are derivative of quinoline-5,6-dione (G series, substances) * 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 and 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 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: pages Literature review: 26 pages Experiment section: 21 pages Results and discussions: 96 pages Conclusion: pages References: 13 pages There are also appendices (152 pages) including 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 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: Comment [H1]: acetonitrile Scheme 3.1 Summary scheme of range A compounds b Synthesis Microwave oven were used to perform the reactions: radiate the reaction mixtures with microwave for minute each time, use TLC to monitor the reactions, and repeat the radiation After every 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 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: Scheme 3.2 Mechanism of the reaction that produced amide A15 A16-A18 compounds: For succinic anhydride, there was no product formed when the reaction was carried out in ethanol or pyridine solvents Therefore, PhOMe was used instead of ethanol that allowed to increase the reaction temperature The results showed that when the reaction was conducted at 120°C for h, the product was amide A16, and when the reaction was conducted at 140°C, a mixture of two imide isomers of position N → O, when a reaction of 120 °C for h, the product was imide and the N → O group was not isomerized to the A17 position The causes of the formation of imides and amides from A0 and succinic anhydride are explained in the following scheme: Scheme 3.3 The process of forming and metabolizing amide and imide from succinic anhydride c General results Table 3.1 Summary result data for compounds of A1 - A18 Compound A1 A2 Crystalline solvents Ethanol : dioxane 1:1 Ethanol : dioxane 1:1 Ethanol A4 Ethanol : dioxane 1:1 A5 Ethanol A6 A7 Ethanol Dioxane Dioxane : water 1:1 Ethanol: water 1:1 A9 A10 A12 A13 A14 Ethanol A15 Ethanol A16 Ethanol A17 Ethanol A18 Methanol A11 Small dark red crystals Small yellow crystals yellowish brown crystals Small yellowish brown crystals Small red crystals Small dark red crystals Small red crystals Small yellow crystals Small red crystals Dioxane Ethanol: water 1:1 Ethanol Ethanol Melting temprature (oC) Small red crystals A3 A8 Colour and shape Small yellowish brown crystals Orange-yellow crystals orange red crystals Yellow needle-shaped crystals Yellow needle shaped crystals white needle-shaped crystals Brown needle shaped crystals Brown needle shaped crystals Yield % 210 - 211 85 195 - 196 81 200 - 201 79 175 - 176 54 195 - 196 45 210 - 211 154 - 155 87 71 188 - 189 85 174 - 175 73 205-206 70 187 - 188 82 195- 196 191-192 80 80 185-186 80 178-179 74 168-169 54 173-174 65 166-169 60 Analyzed spectrum IR, 1H , 13C, HSQC, HMBC IR, MS, 1H , 13C, HSQC, HMBC, IR, 1H , 13C, HSQC, HMBC, MS IR, 1H , 13C, HSQC, HMBC IR, 1H IR, 1H , 13C IR, H , 13C, HMBC IR, 1H , 13C, HSQC, HMBC IR, 1H , 13C, HMBC, MS IR, 1H , 13C, HMBC, MS IR, 1H, 13C IR, 1H IR, 1H IR, 1H IR, 1H, 13C IR, 1H, 13C IR, 1H, 13C, HMBC IR, 1H, 13C 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 1H NMR spectral data of A1-A18 substances H3 H6 6.81 s 6.50 s H7a H7b 3.75 s 3.67 s H10 OH/NH(H11) 2.17 s 5.34 s H12 H13 - A1 7.37 s 7.81 s 4.03 s 3.92 s 2.14 s 14.56 s 7.11 d;J = A2 7.28 s 7.47 s 3.91 s 3.91 s 1.95 s 10.23 s 6.77 s Compound Ar A0 - H14 H15 8.01 d; J = 9.5 7.88d; J=9 6.70 dd;J=2.0;7 H16 H17 7.50 t;J=7.5 7.66 t; J = 7.5 7.31 d; J=8.0 2.61 s H18 - 8.69 d J = 8.5 - A3 7.26 s 7.63 s 3.99 s 3.91 s 1.97 s 7.06 s A4 7.34 s 7.55 s 3.95 s 3.93 s 2.24 s 10.57 s A5 7.35 s 7.78 s A6 7.33 s 7.5 s A7 8.86 d J=3 7.50 t J=8.0 6.75 d J=8.5 7.62 d (che) 7.65 d (che) 8.19 d J=8.0 6.94 dJ=8.5 7.22 d J = 1.5; 8.0 - 7.30 d; J = 1.5 2.02 s - 2.01 s 10.74 s 7.1 d;J = 7.42 d;J = 2.5;9.5 - 7.30 d; J = 2.5 - - 3.93 s 3.92 s 1.99 s 3.34 s 8.29d;J = 2.5 7.89 dd; J = 2.5;9.0 7.29;J = 9.0 - 7.37 s 7.80 s 3.96 s 3.94 s 2.04 s 8.00 s 7.15 d;J=7.0 7.98 dd J=7.0; - 8.01 s 2.50 A8 7.25 s 7.47 s 3.91 s 3.90 s 1.96 s - 7.63 dJ=8.5 6.82 dJ=8.5 6.82 d J=8.5 7.63 dJ=8.5 3.04 s - A9 7.26 s 7.49 s 3.92 s 3.90 s 1.98 s - 8.19 d J=2.5 - 6.73d J=8.5 7.57dd J=9;2.5 - - A10 7.21 s 7.62 s 3.97 s 3.88 s 1.98 s 8.40 s 7.76 dJ=9.0 6.72 d J=7.5 - 8.72 s 7.57 dd J=8;3.5 9.14 d J=8.5 A11 7.22 s 7.46 s 3.88 s 3.90 s 1.96 s - 7.93 s - 6.48 s 7.53 s 10.0 s - A12 7.18 s 7.26 s 3.91 s 3.94 s 2.10 s 8.80 s 7.58 dJ=1.5 - 7.94 dJ=1.5 - A13 7.15 s 7.23 s 3.92 s 3.83 s 2.07 s 8.79 s 8.32 d J=1.5 - 7.26d;J=9.0 7.97 dd J =2.0;9.0 - A14 7.15 s 7.18 s 3.99 s 3.91 s 2.08 s 8.77 s 8.15 dd J=3.0;1.0 7.43 dd J=5.0;1.0 7.65 dd J=5.0;3.0 - - A15 7.11 s 7.38 s 3.82 s 3.79 s 2.01 s 10.03 s 6.42 d;J=12 6.29 d;J=12 - - - 6.79 s 6.95 s 7.08 s 7.31 s 3.84 s 3.73 s 3.85 s 3.82 s 2.80 m 3.01 m 2.73 m 2.73 m - - - - - 6.89 s 6.33 s 3.67 s 3.66 s 2.30 s 7.85 s 2.10 s 2.14 s 6.17 s J =6 (4.4 dd J= 6) A16 A17 A18 3.95 s 3.94 s 7.37d J=7.5 7.24 t J= 7.5 7.3 d J=7.5 - - In 1H 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 In the 1H 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 13C 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 quinoline-2carbaldehyde B2 with SeO2 We optimized the reaction conditions by changing reaction temperature and time 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 h To obtain only B3 (which is predicted to be quinoline-2carboxylic acid) the amount of SeO2 was doubled and the reaction time was increased to h at 100 oC The esters from quinoline-2-carboxylic acid B3 are synthesized by the traditional methods c General results Table 3.3 Summary result data for compounds from B1 - B18 Compound Crystalline solvents B1 B2 B3 B4 B5 B6 B7 B8 B9 Ethanol Ethanol dioxane Ethanol Ethanol Ethanol Ethanol Toluene Toluene B10 Toluene B11 B12 B13 Toluene Ethanol Ethanol B14 Ethanol B15 B16 B17 B18 Ethanol Ethanol Ethanol Ethanol Melting temperature (oC) Yield % White needle-shaped crystals Yellow needle-shaped crystals Dark yellow needle-shaped crystals White needle-shaped crystals White needle-shaped crystals White needle-shaped crystals White needle-shaped crystals white Dark yellow needle-shaped crystals Dark yellow needle-shaped crystals Dark yellow needle-shaped crystals 179 - 180 219 - 220 250 - 251 179-180 184-185 180-181 190-191 278 217 85 80 79 60 71 78 80 75 68 224 70 Dark yellow needle-shaped crystals Light yellow needle-shaped crystals Light yellow needle-shaped crystals Light yellow needle-shaped crystals 220 230-231 202 60 80 80 217-218 80 Light yellow needle-shaped crystals Light yellow needle-shaped crystals Light yellow needle-shaped crystals Light yellow needle-shaped crystals 225 252 220 223 74 54 65 60 Colour and hape Analyzed spectrum IR, 1H , 13C, HMBC, MS IR, 1H , 13C, HMBC IR, 1H , 13C, IR, 1H , 13C IR, 1H, 13C, MS IR, 1H , 13C IR, 1H , 13C IR, H , 13C, HMBC IR, 1H , 13C, HMBC, IR, 1H , 13C, HMBC, HSQC, MS IR, 1H, 13C IR, 1H ,13C IR, 1H , 13C IR, 1H , 13C, HMBC, HSQC, MS IR, 1H, 13C IR, 1H, 13C IR, 1H, 13C IR, 1H, 13C 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 1H 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 2methylquinoline - The 1H NMR spectrum of B2 has the signal integrating for one hydrogen of the aldehyde proton at =10.01 ppm and no longer has the proton signal at = 2.61 ppm with the intensity of three protons Table 3.4 1H NMR signal of compounds B1 - B7; δ, ppm; J, Hz Compound X 2a B1 CH3 2a H C O 2a OH C O B2 B3 H3 H7 7.50 d;J =8.5 7.92 s H4 H12a 8.42 d; J=9.0 2.06 s H5a H6a 4.00 s 4.00 s H2a H13 2.61 s - H14 H15 H16 H17 8.05 d;J=9.0 8.18 s 8.74 d; J=8.5 2.11 s 4.09 s 4.05 s 10.01 s - - - 8.19 d;J=9.0 8.14 s 8.70 d;J=9.0 2.14 s 4.09 s 4.06 s - - - B4 13 2a OCH C O 8.18 d;J=8.5 8.15 s 8.72 d;J=8.5 2.14 s 4.08 s 4.05 s 3.93 s - - B5 13 14 2a OCH 2CH3 C O 8.18 d;J=9.0 8.15 s 8.74 d;J=9.0 2.16 s 4.08 s 4.05 s 4.39 m 1.34 t - - B6 13 14 15 16 2a OCH 2CH2CH2CH3 C O 8.17 d;J=8.5 8.15 s 8.71 d;J=8.5 2.14 s 4.07 s 4.05 s 4.34 t 1.71 m 1.42 m 0.95 m - B7 13 14 15 16 2a OCH 2CH2CHCH3 C CH3 O 17 8.17 d;J=9.0 8.15 s 8.72 d;J=9.0 2.13 s 4.08 s 4.05 s 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 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 H3 H7 7.50 d;J=8.5 7.92 s H4 H12a 8.42 dJ=9.0 2.06 s H5a H6a 4.00 s 4.00 s H2a H2b 2.61 s - H14 H15(15a) - H16 H17 - H18 H16b B8 8.02 d; J=8.5 7.97 s 8.57 dJ=9.0 2.12 s 4.08 s 4.06 s 7.62 dJ=16 7.80 dJ=16.5 8.24 d J=9.0 7.98 d J=9.0 7.98 d J=9.0 8.24 dJ=9.0 - B9 8.00 d; J=9.0 7.97 s 8.56 dJ=9.0 2.12 s 4.07 s 4.05 s 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 8.16dd J=8.0;1.5 - B10 7.89 d; J=9.0 7.97 s 8.57 dJ=8.5 2.11 s 4.07 s 4.05 s 7.47d; J = 16 7.99dJ =15.5 8.02 d J=8.0 7.60t J=8.0 7.77t J=7.5 8.07d J=8.5 - B11 8.01 d; J=9.0 7.98 s 8.56 dJ=8.5 2.10 s 4.04 s 4.03 s 7.62d J=16.5 7.77d J=16.5 8.00 d J=2.0 -(3.98 s) - 7.89 d J=2.0 2.35 s KH B1 X 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-2methyl-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 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 phydroxy 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: Comment [H2]: Sơ đồ phải bổ sung giải phóng ammoniac Cơng thức khôgn xoay tự thế, không khoa học Scheme 3.8 Reaction mechanism explains the formation of D12 from D2 c General results Table 3.7 Some data of compounds D1 - D12 Compound Crystalline solvents D1 Ethanol D2 Ethanol D3 Ethanol Ethanol : nước 1:1 D4 D5 Ethanol D6 Ethanol D7 Ethanol D8 Ethanol D9 Ethanol D10 Ethanol D11 Ethanol D12 Ethanol Colour and shape Brown needle-shaped crystals Yellow needle-shaped crystals Red needle-shaped crystals Yellow needle-shaped crystals White needle-shaped crystals Yellow needle-shaped crystals Orange small needle crystals Yellow needle-shaped crystals Small dark yellow crystals Needle-shaped crystals, yellow Yellow needle-shaped crystals Yellow needle-shaped crystals Melting temperature (oC) Yield % Analyzed spectrum 167 - 168 60 IR, 1H , 13C, HMBC, HSQC, NOESY, ESI MS 185- 186 60 IR, 1H , 13C, HMBC 151 80 IR, 1H , 13C, HMBC 253- 254 80 IR, 1H , 13C, HMBC 236-240 60 IR, 1H , 13C, HMBC 189 76 IR, 1H , 13C 191 70 IR, 1H, 13C, MS 195 80 IR, 1H , 13C 186 - 187 75 IR, 1H , 13C 190-191 78 IR, 1H , 13C, HMBC 187-188 79 IR, 1H , 13C, HMBC, 288 55 IR, 1H , 13C, HMBC, HSQC, MS 3.3.2 Structure D1 is a new and unusual compound compared to expected synthesis Its structure IR, 1H, 13C and MS spectra of D1 (see Experimental) was associated with The proton and carbon signals of D1 were assigned by using NOESY, HSQC and HMBC spectra The results of single crystal X-ray diffraction analysis showed that the structure of D1 consists of benzene ring agglomerated with pyrimidine ring, classified as a quinazoline ring heterocyclic type, IUPAC name is 4- (1chloro-1-nitroethyl) - 6,7-dimethoxy-2-methylquinazoline The results (Fig.3.1) shown that D1 was in triclinic system, group P1 (No.2) is indecated in the lattice parameters of a: 7.0601; b: 9.6243; c: 10.4481 (Pond); α: 105.830; β: 91.367; γ: 92.375 (degrees): Figure 3.1 The structure of D1 and the D1 arrangement in the base lattice cell on XRD Figure 3.1 shows the C2 carbon atom in two different configurations in each base cell of compound D1 containing a pair of enantiomers In other words, D1 was existed as a racemate The analysis results of the NMR and MS spectra (Figures 3.26, 3.27 in the thesis) in Table 3.27 were consistent with the structure of D1 according to single crystal XRD Table 3.8 Results of NMR spectrum analysis of D1 No 2/4 5/6 7/8 9/10 2a 4a/4b 6a/7a 13 H NMR spectrum,  (ppm) -/7.08 / - / 7.44 -/2.76 s - / 2.64 3.86 / 3.99 C NMR spectrum,  (ppm) 106.4 / 157.3 100.3 / 150.0 155.9 / 107.3 150.1 / 113.2 25.5 104.0 / 29.8 55.7 / 56.4 In the IR spectrum of D2, the difference compared to that of D1 is a strong absorption range at 1691 -1 cm , which characterizes the stretching vibration of the C = O group connected with aromatic ring, however, vibration of the NH group does not appear Unlike the IR spectrum of D1, the IR spectrum of D4 is characterized by the strong absorption at 1671 cm-1, which is typical for the conjugated carbonyl C = O group, while in the D5 spectrum, the absorption at 3450 cm-1 is indicated for hydrogen bonded OH group IR spectra data of D1-D5 compounds are given in table 3.29 of the dissertation An important the difference of the 13 C NMR spectra between of D2 and D1 is the appearance of signals at δ=202.5 ppm that is specific to the C = O group of aromatic ketones The results of NMR spectroscopy analysis of D2 are shown in table 3.28 of the thesis The most important difference is that the 1H NMR spectra of both D4 and D5 no longer has methyl group signals attached to saturated carbon as in D1 1H NMR spectral data of D1-D5 compounds are given in table 3.9 Table 3.9 1H NMR signal of compounds D1 - D5; δ, ppm; J, Hz Compound D1 D2 H5 7.08 s 7.95 s H8 7.44 s 7.34 s H6a 3.86 s 3.90 s H7a 3.99 s 3.98 s H2a 2.76 s 2.76 s H4b 2.64 s 2.74 s H12/16 - H13/15 - H14 - 7.29 s 7.38 s 7.46 s D3 D4 D5 13 7.93 s 7.04 s 7.35 s 3.89 s 3.84 s 3.90 s 3.97 s 3.87 s 3.93 s 2.72 s 2.30 s 2.62 s 2.47 s - 7.39 d; J=8 - 7.29 d; J=8 - 6.90 t J=8 - C NMR spectral data of D1-D5 compounds are given in table 3.31 of the dissertation Spectral data show that synthesized compounds are structured in accordance with the expected formulae IR spectrum of α,β unsaturated-ketone compounds D6-D11 has strong absorption band that is a characteristic of C = O group conjugated with C = C ethylenic group IR spectra data of substances D6 - D11 are listed in table 3.33 of the dissertation Data of 1H NMR and 13C NMR spectra of D6-D11 compounds are given in tables 3.34 and 3.35 of the dissertation Spectral data show that synthesized compounds are structured in accordance with the expected formulae The IR spectrum of the D12 at 2500 - 3500 cm-1 range is enhanced, indicating that the compound D12 exists of intramolecular hydrogen bonds The two peaks are sharp at 3514 and 3239 cm-1 corresponding to the valence stretching of the OH and NH groups The typical IR spectrum of D12 is shown in table 3.36 of the dissertation Analysis of 1H, 13 C and HMBC spectra (Figure 3.2) shows that D12 is an isoquinoline type compound Table 3.10 1H NMR signal of compounds D6– D12; δ, ppm; J, Hz Compound -X D2 D6 D7 11 12 13 D8 16 15 14 14a N(CH3)2 11 13 D9 16 15 12 14 NO2 11 16 12 15 13 14 14a OCH3 D10 D11 11 12 13 D12 16 15 14 Cl H5 H8 7.95 s 7.34 s 7.84 s 7.39 s H6a H7a 3.90 s 3.98 s 4.00 s 3.91 s H4b H2a 2.76 s 2.74 s 7.80 d; J=15.5 2.81 s H4c H14 - H12/H16 H13/H15 H14a - - 7.90 d; J=15.5 - 7.49 d 7.81 d - 7.74 s 7.35 s 3.98 s 3.87 s 7.51 d; J=15.5 2.78 s 7.67 d; J=15.5 - 7.61d; J=7.0 6.74 d; J=7.0 3.00 s - 7.89 s 7.39 s 3.99 s 3.92 s 7.91 d J = 16 2.81 s 8.07 d; J = 16 - 8.08 d J = 9.0 8.28 d J=9 - 8.09 s 7.31 s 4.06 s 4.04 s 7.85 d J=16 2.93 s 7.87 d J=16 - 7.66 d J= 7.81 d J=8.5 3.87 s - 7.95 s 7.41 s 4.00 s 3.94 s 7.92 d J=16 2.81 s 8.10 d; J=16 7.74 d; J=8.0 7.54 d J= 8.12 dd; J=8.0;1 7.85 td; J=8.0;1 4.18 m 1.41 t 7.84 s 7.40 s 4.00 s 3.91 s 7.81 d J=16 2.81 s 7.91 d J=16 - 8.11 d; J=9.0 7.86; d J =9 - 7.28s 3.96s 3.96s 2.36s 2.73s - 7.85d; J = 8.5 6.78d; J = 8.5 - Figure 3.2 HMBC spectrum of D12 3.4 SYNTHESIS AND STRUCTURAL STUDY OF SERIES E 3.4.1 Synthesis of E compounds a Synthetic scheme : Scheme 3.9 General synthetic Scheme of E compounds b Synthesis Quinolincarbaldehyde and ketone condensation reactions are usually carried out under gentle conditions with either a dilute alkaline or a dilute acid condition In addition, E0 was also stirred with acetophenone under the same conditions but the condensation reaction did not occur To explain the observation, it is assumed that in the phenolic HO group at position of E0 is deprotonized into O-group in alkaline environment, which pushes the electron to reduce the reactivity of the CH=O group, so condensation in a strong acidic environment as described in section 2.6 of the dissertation In the first cases in Table 3.39, α, βunsaturated ketones were obtained in about 68-75% yield In the following three cases, it is necessary to increase the heating time from15 to 20 h to obtain a product of 1,5-diketone with 30-38% yield c General results Table 3.11 Composite results data of E1-E8 Compound Aryl methyl ketone Decomposition temperature (oC)/ Time (h) Crystalline solvent Colour and Shape E1 MeCOPh 80/12 DMF:H2O:MeOH 1:1:2 Yellow metallic E2 p-MeCOPhMe 80/12 DMF:H2O:EtOH 1:2:1 E3 p-MeCOPhOH 70/8 E4 p-MeCOPhOMe 70/8 E5 p-MeCOPhOEt 70/8 DMF:H2O:EtOH 1:4:1 E6 p-MeCOPhBr 80/15 DMF:H2O:EtOH 2:1:1 E7 p-MeCOPhNO2 80/20 DMF:H2O:EtOH 1:2:1 E8 p-MeCOPhCl 80/15 DMF:H2O:EtOH 1:4:1 DMF:H2O:EtOH 1:3:1 DMF:H2O:EtOH 1:4:1 Yield % Analyzed spectrum 68 IR, 1H , 13C, 70 IR, 1H , 13C, HMBC, MS 75 IR, 1H , 13C 72 IR, 1H , 13C, HMBC 75 IR, 1H , 13C, HMBC 35 IR, 1H , 13C, HSQC, HMBC, MS 30 IR, 1H, Red needleshape crystals, red Yellow needleshape crystals, Orange eedleshape crystal, Orange yellowish needle shape crystals Light yellow needleshapecrystals Light yellow needle- shape, crystals Light yellow needle- shape, crystals 38 H , 13C, HSQC 3.4.2 Structure of compounds E1-E5 In the IR spectra of E1 - E5 compounds, there are additional absorption bands of the OH group, the CH group, the C=C aromatic group, the C=O carboxyl group The strong absorption of the C=O carboxyl group which conjugates with C=C ethylenic group is at 1637 - 1646 cm-1 The results of IR spectrum analysis of E1 – E5 compounds are presented in table 3.40 of the dissertation The 1H NMR spectra of E1 –E5 no longer have the proton signal of the –CHO group, the number of aromatic proton signals is instead of in E0, in which the appearance of two pairs of protons with J = 15 - 16 Hz is attributed for H5a and H5b This shows that the aldol condensation of between E0 and pC2H5OC6H4COCH3 occurred to form CH=CH group in trans configuration Data of 1H NMR spectra of E1 –E5 are presented in Table 3.41 of the dissertation The changes of chemical shifts of protons H5a of E1-E5 compoundsis decreased morethan that of E0; the H4 signal of E0 is in weaker field than H2, on the other hand,the α, β-unsaturated products behaved in the opposite maner (this is confirmed through HMBC spectrum analysis) Table 3.12 1H NMR signal of E1-E5, δ (ppm), J (Hz) Compound H2 H4 H5a E0 9.91 d J=2 9.00 s 10.72s E1 9.16 d J =2 9.16 s E2 9.00s 8.78s E3 9.13 s 8.96 s E4 9.15s 8.99s E5 9.15s 8.99s 8.21 d J=16 8.21d J=16 8.14 d J=15.5 8.15d J=16 8.16d; J=16 H5b 8.06 d J=16 8.07d; J=16 8.02 d J=15.5 8.05d; J=16 8.06d J=16 H7a H8 5.11 s 7.63 s 5.09 s 7.53 s 5.06s 7.48 s 5.08 s 7.51s 5.09 s 7.53 s 5.09s 7.53 s H12 H16 H13 H15 H14a H14b 8.06d J= 8.0 7.96d; J=7.5 7.97 d J=8 8.07d J=8.5 8.06d J=7.5 7.61 d J=7.5 7.40d; J=8 6.92 d J=8 7.12d J=8.5 7.11d J=8.0 2.41s 3.85s 4.16m 1.37 tJ=7 Table 3.12 shows that the chemical shifts of proton H5a of compounds E1-E5 is much lower than that of E0; the H4 signal of E0 is in weaker field than H2; in the α, β-unsaturated products, the opposite pattern is found (this is confirmed through HMBC spectrum analysis); The proton signals of E1-E5 are similar because of the same types of α, β-unsaturated compounds with trans configuration as predicted Results of 13C NMR spectral analysis of E1-E5 compounds are listed in Table 3.42 of the dissertation The number of none-equivalent Cs and their chemical shift are completely consistent with the formula of each compound, Table 3.42 Spectrum MS The molecular formula of E2 is C21H17NO8S with M = 443 au In its MS spectrum, the peak at 444 au has very small intensity, only about 5% compared to the base peak at 364 au, whosethe intensity is 100% Thus, unstable pseudo-ion [M + H]+ molecules have been formed and decomposed as follows: In E2 -MS spectral, there was no peak at 442 au (M-H+), but peak at 362 au is 100% intensity Thus, similar to the spectra + MS, the unstable pseudo-molecular ions [M-H] - were formed and decomposed as follows: Comment [H3]: thiếu J=? The results of 13CNMR spectrum analysis of E1-E5 compounds are listed in Table 3.42 The chemical shift of none-equivalent Cs is listed in Table 3.42 These is completely consistent with the formula of each compound Table 3.12 Table of signals 13C NMR of E1-E5, δ (ppm) E0 E1 E2 E3 E4 E5 C2 C3 141.1 141.9 140.9 133.2 143.4 135.8 141.2 132.5 141.0 133.0 141.0 132.0 C4 C5 134.0 113.4 140.2 115.1 139.9 114.6 140.1 115.4 140.2 115.4 140.0 115.3 C5a C5b 191.2 134.6 128.4 134.8 127.6 133.4 128.5 133.8 128.5 133.6 128.4 C5c C6 157.3 189.6 149.4 189.2 148.8 187.5 148.9 187.7 149.1 187.6 148.9 C7 C7a 152.6 65.8 152.4 65.9 150.8 65.6 152.1 65.8 152.3 65.8 152.2 65.8 C7b C8 168.9 108.4 169.1 89.2 169.4 108.0 169.2 105.0 169.1 89.2 168.9 104.0 C9 C10 136.5 122.0 137.2 123.2 140.8 122.4 137.7 127.9 137.0 123.1 137.0 123.0 C11 C14 137.6 133.4 135.2 143.7 129.0 162.4 130.4 163.4 130.1 162.2 C12 C16 129.0 129.0 129.5 129.5 131.0 131.0 130.8 130.8 130.6 130.6 C13 C15 128.4 128.4 128.4 128.4 115.6 115.6 114.3 114.3 114.6 114.6 C14a C14b 21.2 55.6 63.6 14.4 3.4.3 Structure of compounds E6-E8 Some key absorption bands on the IR spectrum of E6 –E8 are listed in Table 3.43 of the dissertation Figure 3.3 A part of 1H NMR spectrum and structure of E6 H NMR spectra of E6 - E8 are quite similar but different from that of E1-E5 The two interesting anomalies in the proton spectrum of E6 (Figure 3.3) are as follows: Firstly, the signal of methylene protons (2 CH2 groups) is represented by two doublets of doublet while these methylene group only gives signal in the 13 C NMR spectrum and cross peaks on the HSQC spectrum Secondly, the singlet (singlet) at  = 7.94 ppm (1H),  = 2.87 ppm (3H) and  = 2.71ppm (3H) proves that there is a DMF molecule attached to a diketone The strong infrared absorption band at 1632 cm-1 (Table 3.44) is suitable for that observation On the HMBC spectrum (Appendix E) of E6, the H17 signal of DMF has a cross peak with C12 of phenyl group This can only be explained by the assumption that the π-π interaction between the electron systems π of the phenyl groups and the C = O group of DMF helped to create the molecular complex E6 On 1H spectrum of E7, there is a signal of DMF similar to that of E6, indicating that it is also a complex molecule On the 1H spectrum of E8, there is no signal of DMF, proving that it does not form complex molecules The results of NMR spectroscopy analysis of E6, E7 and E8 are listed in Table 3.13 Table 3.13 13C NMR and 1H NMR signals of E6 - E8 (ppm, Hz) Location E6 H NMR E7 2/4 9.25 s / 9.60 s 9.18 s / 9.40 s 3/8 5/6 5a/5c - / 7.40 s -/4.76 / 4.05 dd; J= 16; 3.68 dd; J= 16; - / 7.94 s 5.00 s / -/-/-/7.79 d;J= 7.79 d;J= 7.65 d;J= 7.65 d;J= 2.87 s /2.71 s - / 7.37 s -/4.70 / 4.07 dd; J= 16; 3.83 dd; J= 16; - / 7.87 s 4.99 s / -/-/-/8.09 d; J= 8.09 d; J= 8.27 d; J= 8.27 d; J= 2.90 s / 2.75 s 5b 5b’ 7/17 7a/7b 9/10 11/14 11’/14’ 12+16 12’+16’ 13+15 13’+15’ 18/19 3.5 SYNTHESIS AND STRUCTURE OF SERIES G 3.5.1 Synthesis of G1 - G7 compounds a General scheme 13 E8 8.76 s/ 9.20 J= 1.5 -/7.47s -/3.57 dd; J= 17; 3.47 dd; J= 17; 5.09 s/ -/-/-/7.95 d;J= 7.76 d;J= 9.5 7.52 d;J= 7.49 d;J= -/- C NMR E6 139.5/99.4 124.3/147.4 28.2/198.0 E8 131.3/ 143.0 140.1/101.6 117.8/147.1 27.1/196.5 41.0 46.5 - - 153.5/162.3 65.8/168.9 134.4/124.7 135.4/127.4 -/129.8 -/131.8 -/35.8/30.8 151.6/65.7/169.1 135.0/120.6 138.3/128.8 133.5/128.5 130.1 126.1 128.7 128.6 -/- 138.7/137.7 Scheme 3.10 Synthetic scheme of G series compounds b Synthesis When G0 reacts with semicarbazide hydrochloride in methanol, the semicarbazone G2 is not obtained as expected, but G1 compound with high yield (70%) Compound G2 is collected by working up the reaction mixture with pyridine solution in water Surprisingly, the reaction of G0 with thiosemicarbazide in methanol did not give thiosemicarbazone, G3 compound was with 50% yield instead The formation of G3 can be explained by the thiosemicarbazide which is added at1.4 positions of G0 and then the addition product is enolized into G3 Ethane-1,2-diaminium G4 salt was obtained by stirring G0 with ethylenediamine The product G4 was isolated in methanol but it can be well soluble in water Treatment of G4 with NaOH solution followed by HCl solution gave quinoxaline G5 When G0 was slowly added into the benzene and 1,2-diamine solution, it formed complex G6 in 35% yield Treatment of G6 with concentrated HCl solution yielded quinoxaline G7 The order of the reactants was reversed: gradually added benzene and 1,2-diamine to the G0 solution to avoid excessiveness of amine during the reaction that gave G7 in higher yield 3.5.2.Synthesis of G8 a Synthetic scheme b Synthesis When the coupling reaction of QN2+Cl- with some aromatic amines (PhNH2, p-MeOPhNH2, Me2NPh) created a precipitate, after re-crystallization in EtOH/H2O 1:1, was a metallic dark yellow crystal denoted G8 c General results Table 3.14 General data of substances G1-G8 Compound Crystalline solvents Ethanol : water 1:1 Ethanol : water 2:1 Ethanol : water 1:1 Ethanol : water 1:1 Ethanol : water 2:1 Ethanol : water 1:1 G1 G2 G3 G4 G5 G6 G7 Ethanol G8 Ethanol : water 1:1 Colour and Shape Decomposition temperature (oC) Yield % Analysed spectrum 275 69 IR, 1H , 13C, HMBC, HSQC, NOESY, ESI MS 255 58 IR, 1H , 13C, HMBC 265 55 IR, 1H , 13C, HMBC 260 38 IR, 1H , 13C, HMBC 250 55 IR, 1H , 13C, HMBC 250 35 IR, 1H , 13C 280 87 IR, 1H, 13C, MS - 64 IR, 1H , 13C, X-ray Dark yellow crystals Pale brown crystals pale yellow crystals Dark brown crystals Pale green crystals Blue crystals Dark yellow needle crystals Dark yellow crystals 3.5.2 Structure of G1 - G7 compounds Data of IR spectra of G1 - G7 are shown in table 3.46 of the thesis Spectral data 1H and 13C are shown in tables 3.15 and 3.16 below Table 3.15 1H NMR signal of G0 - G7 compounds; δ, ppm; J, Hz H2 8.80 d J=2 8.76 d; J= 8.88 d; J =2 8.91 d; J= 8.97 d; J= 9.17 s H4 8.16 d J=2 8.49 d; J= 8.42 d; J= 8.68 d; J= 9.01 d; J= 9.45 s G6 9.16 d; J= G7 9.26 d; J= Compound G0 G1 G2 G3 G4 G5 H8 H7a H12 H13 H14 H15 Khác 6.62 s 4.75 s - - - - - 6.88 s 4.85 s - - - 4.86 s 5,84 s NH 5,84 s NH 8.81 s NH - 4,87 s 8.81 s NH 5.04 NH 6.76 s 4.50 s 3.31 s - - 7.51 s 5.12 s 7.54 s NH 7.53 s NH 10.11 s OH 9.14 d; J =2 9.17 s - 6,36 s 9.45 s OH 14.09 s NH 10.46 s OH 9.12 d; J= 9.13 s - - 9.59 d; J= 7.46 s 5.20 s 8.42 dd; J= 8; 4J= 8.06 m 8.10 m 9.71 d; J= 7.49 s 5.23 s 8.43 dd J= 8; 4J =2 8.10 m 8.11 m 8.48 dd; J= 8;4J= 8.50 dd; J= 8;4J =2 6.97 m 6.86 m - Comment [H4]: bảng khác nên theo kiểu bảng Table 3.16 13C NMR spectral data of G1-G7 compounds; δ, ppm C2 C3 C4 C5 C6 C7 C7a C7b C8 C9 C10 C11 C12 C13 C14 C15 C16 G1 G2 G3 G4 G5 G6 G7 145.5 137.9 125.8 138.7 132.8 151.2 65.5 169.9 100.5 142.2 115.2 159.8 - 152.1 140.7 131.5 179.9 127.9 154.2 62.5 169.4 102.6 155.2 121.6 159.5 - 147.0 139.6 126.6 144.0 136.2 155.0 69.8 167.2 102.7 141.8 117.9 171.7 - 148.4 135.9 130.1 1389.9 134.9 154.1 67.6 174.8 107.1 149.0 119.9 144.8 145.7 36.64 - 149.4 140.6 129.1 140.5 136.2 154.5 65.5 169.6 108.4 148.4 120.6 145.3 145.6 - 149.4 140.7 129.3 141.1 137.4 154.1 65.3 169.5 109.1 149.7 121.1 142.1 129.5 131.3 131.7 129.3 141.8 146.6 141.1 132.1 140.5 137.2 155.9 65.6 169.2 105.8 147.2 120.2 142.0 129.6 131.9 132.2 129.3 141.9 3.5.3 Structure of G8 In order to confirm the structure of G8, which was elucidated by the single crystal X-ray diffraction method (The crystal size is 0.2 x 0.1 x 0.07 mm3) The single crystal X-ray diffraction of G8 is shown in Figure 3.4 that is completely consistent with the G8 structure and matches withIR and NMR methods Figure 3.1 The structure and bond length (Å) of G8 and its single crystal X-ray diffraction Figure 3.4 also shows that G8 is a crystalline diazoquinoline compound with three H2O molecules Therefore on its IR spectrum (appendix G) the region above 3000 cm-1 has many strong absorption peaks and on its 1H NMR spectrum (appendix G) the resonance peaks of the water is very Some of the comments are given from Figure 3.4 are: i) The bond length of G8 (1.100 Å) is almost equal to the triple bond length of the nitrogen molecule (1.097632 Å) ii) The C5N bond length of G8 (1.353 Å) is close to the average value of the C = N double bond in organic compounds (1.30Å) iii) G8 C6O bond length (1.24 Å) is close to the average value of C = O double bond in organic compounds (1.23 Å) iv) The length of the bonds to create pyridine core(except for the common bond between the two rings of sides) is close to the C-C bond length in aromatic ring (1.39 Å), while the length of the bonds creates 6membered ring with diazo group (except for C7C8 bond) is much larger than the C-C bond length in aromatic rings and close to the single bond length that is between double bonds (C =C-C = C 1.42Å) The above comments show that the electron structure of G8 needs to be expressed by two limiting (resonance) formulas in which the C5N and NN bonds bears a characteristic part of the double bond as follows: 3.6 EXAMINING BIOLOGICAL ACTIVITY OF SOME COMPOUNDS 3.6.1 Anti-microbial activity Among the synthesized compounds, 20 samples were tested for their antimicrobial activity The tested microorganisms includes Gram (-) bacteria: Escherichia coli (EC), Pseudomonas aeruginosa (PA), Salmonella enterica, Gram (+) bacteria: Bacillus subtillis (BS), Staphylococcus aureus (SA) ), Lactobacillus fermentum (LF) and some fungi The results are presented in Table 3.49 of the dissertation The results from Table 3.49 show that the compound D5 has strong antifungal activity against C albicans with MIC value of 17.19 g/ml; meanwhileA4 and A5 exhibited moderate A.niger antifungal activity with MIC value of 50 µg/ml Compound A6 exhibited moderate activity against B subtilis with MIC value of 50 µg/ml The antibacterial ability of Gram+ of compound E3 is weak with MIC value of 112 g/ml for B.subtillis and MIC = 124.3 g/ml with S.aureus 3.6.2 Cytotoxic activity Three out of the synthesized compoundswere screened cytotoxic test: D5 (symbol of sample Q1), D6 (symbol of symbol QN2) and D8 (model of symbol QN5) Celllines tested include: Hep-G2: liver cancer; LU-1: lung cancer; KB: carcinoma and MCF-7: breast cancer Results are shown in table 3.51 Table 3.17 Results of exploration of cytotoxic activity No Compound Label D3 Qhy(Y4) D4 B2 D5 Q1 D6 QN2B D8 QN5 D12 QN4 Ellipticine IC50 (g/ ml) KB Hep - G2 MCF-7 LU-1 1.23 8.0 24 3.24 >128 32 0.31 1.25 41.79 4.37 0.80 0.38 3.57 12.0 0.85 32 0.54 1.84 94.95 4.41 0.41 The results showed that the compound D5 showed moderately cytotoxic on epithelial cancer cells with IC50 value of 24 g/ml and did not show cytotoxic activity against others at the test concentrations Compound D6 has a relatively strong cytotoxic activity with IC50 = 3.24 g / ml, IC50 = 4.37 g/ml for the two cell types of epithelial and liver cancer In particular, the compound D8 exhibits cytotoxic activity against three cancer types of liver, breast and lung cancer at the test concentration with the IC50 value of 0.80; 0.85; 4.41 g/ml respectively Meanwhile, the control sample has an IC50 value for each type of 0.28; 0.41 and 0.42 g/ml respectively Thus, the compound D8 has high cytotoxic activity for two cancers of the liver and breast cancer 3.6.3 DPPH antioxidant activity Among the synthesized compounds, we have tested the antioxidant activity of two samples G1 and G3 Resveratrol is used as a reference standard The inhibitory concentration of 50% DPPH (2,2-diphenyl-1picrylhydrazyl) of G1, G3 and resveratrol was 9.8; 256 and 7.5 μg/mL Thus, G1 compound exhibits antioxidant activity on DPPH with IC50 = 9.8 μ/mL CONCLUSION After a period of carrying out the study, we have obtained some results as follows: From eugenol in basil essential oil, via different reactions we have synthesized "key substances", that are, 3methyl-4- (2-amino-4,5-dimethoxyphenyl) furoxan (A0) ; 8- (3-methylfuroxan-4-yl) -2-methyl-5,6- dimethoxyquinoline (B1); 4- (1-chloro-1-nitroethyl) -6,7-dimethoxy-2-methylquinazoline (D1); 2- (5-formyl -6hydroxy-3-sulfoquinolin-7-yloxy)acetic acid (E0) and 2-(5,6-dioxo-3-sulfoquinolin-7-yloxy)acetic acid (G0) Of the synthesized compounds, B1 is a new compound containing both furoxan and quinoline ring, while D1 is a new compound containing quinazoline heterocyclic ring that was synthesized by the new method for the first time From the "key" substances mentioned in conclusion 1, five series of 64 new heterocyclic compounds have been synthesized as shown below: i) A number of furoxan ring compounds (A-range) including: azo compounds A1 - A11, azomethine A12 - A14, amide, imide and benzylamino compounds A15 - A18 ii) A range of compounds containing simultaneously furoxane and quinoline ring (B-range) including: Quinoline B1, aldehyde B2, acid B3, ester B4 - B7, alkene B8 - B11 and ketone compounds α, β-unsaturated B12 - B18 iii) A range of derivatives from quinazoline D1 (D-range) includes: Quinazoline ring compounds D1 - D3, D5, compounds α, β-ketone unsaturated D6 - D11; indole derivatives D4 and derivatives of isoquinoline D12 iv) Range of quinoline substituents (E-range) including ketones α, β-unsaturated E1 - E5 and 1,5-diketone E6 E8 v) Quinoline-5,6-dione derivative range (G-range) including compounds G1 - G8 By combining IR, MS, 1D NMR, 2D NMR and single-crystal X-ray diffraction methods, the structures of the synthesized compounds were determined Moreover, the formation of many novel compounds obtained from the abnormal reactions were explained: Quinazoline D1 was formed by furoxan ring and acetamido group transformation; 5,6-dimethoxy-2-methyl-3-H-indole-3-one D4 from D1 via hydrolysis reaction; isoquinoline D12 from quinazoline D2; G3 compound from thiosemicarbazide plus reaction into quinolin-5,6-dione (G0); molecular complexes G6 and G7 from diamine reaction with G0; diazo compound G8 from the reaction of diazoni salt with amine The structures of 64 new compounds were determined by IR, 1H NMR, 13 C NMR, 2D NMR, MS spectroscopic methods Based on the HSQC and HMBC spectrum analyses, each signal on the 1H NMR and 13C NMR spectrum of newly synthesized compounds has been correctly assigned - Antimicrobial activity of 20 compounds was tested The results showed that the antimicrobial activities of some new compounds was from weak to moderate - Tested the cytotoxic activity of new compound samples on all four cancer cell types In which, compound D8 shows high cytotoxic activity against three strains of liver, breast and lung cancers at test concentrations with IC50 values of 0.80, respectively; 0.85; 4.41 g/ml - Tested the antioxidant activity of two samples G1 and G3, the result of G1 compound shows the antioxidant activity on DPPH with IC50 = 9.8 μg/ml ... 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. .. (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???... furoxan and quinoline heterocyclic rings (series B, 18 substances), series containing quinazoline heterocyclic ring (range D, 12 substances), Chain of compounds containing heterogeneous quinoline