Tổng hợp và tính chất của một số hợp chất 2,4-Dihydroxyquinolin thế có chứa hợp phần đường

Header Page of 126 I HC QUC GIA H NI TRNG I HC KHOA HC T NHIấN DNG THANH NGA TNG HP V TNH CHT CA MT S HP CHT 2, 4-DIHYDROXYQUINOLIN TH Cể CHA HP PHN NG LUN VN THC S KHOA HC Chuyờn ngnh: Húa Hu C Mó s : 60440114 H Ni 2017 Footer Page of 126 Header Page of 126 I HC QUC GIA H NI TRNG I HC KHOA HC T NHIấN DNG THANH NGA TNG HP V TNH CHT CA MT S HP CHT 2, 4-DIHYDROXYQUINOLIN TH Cể CHA HP PHN NG LUN VN THC S KHOA HC Chuyờn ngnh : Húa Hu c Mó s :60440114 Cỏn b hng dn: GS TS Nguyn ỡnh Thnh H Ni - 2017 Footer Page of 126 Header Page of 126 LI CM N hon thnh lun ny, trc tiờn cho em gi li cam n chõn tiGS TS Nguyn ỡnh Thnh a giao ti, tn tỡnhhng dnv ch bo em sut thi gian thc hin lun tt nghip Em cng xin chõn thnh cm n cỏc Thy, cụ b mụn Hoỏ Hu C, cỏc anh ch, cỏc bn v cỏc em phũng Tng Hp Hu C I ó luụn to iu kin, ng viờn, trao i v giỳp em hon thnh lun vntt nghip ny H Ni, thỏng nm 2017 Hc viờn Dng Thanh Nga [Type text] Footer Page of 126 Page 59 Header Page of 126 CC K HIU VIT TT 13 : 13carbon C-Nuclear Magnetic Resonance (Ph cng hng t ht nhõn carbon-13) C NMR DMSO-d6 : Dimethyl sulfoxide c deuteri húa nc : im núng chy IR : Infrared Spectroscopy (Ph hng ngoi) MS : Mass Spectrometry (Ph lng) H NMR :1H-Nuclear Magnetic Resonance(Ph cng hng t ht nhõnproton) : chuyn dch húa hc [Type text] Footer Page of 126 Page 59 Header Page of 126 DANH MC BNG BNG 3.1 Kt qu ph IR ca mt s hp cht 2-methylquinolin-4(1H)-on th 51 BNG 3.2 Kt qu ph IR ca mt s dn xut ca hp cht 2-methylquinolin-4(1H)-on th 55 BNG 3.3.Kt qu ph IR ca mt s dn xut ca hp cht 4-cloro-2-methylquinolin-4(1H)-on th 56 [Type text] Footer Page of 126 Page 59 Header Page of 126 DANH MC HèNH Hỡnh 3.1.Ph IR ca 4-hydroxyquinolin-2-on 44 Hỡnh 3.2.Ph IR ca 4-hydroxy-7-methylquinolin-2-on 45 Hỡnh 3.3.Ph 1H NMR ca 4-hydroxy-7-methylquinolin-2-on 46 Hỡnh 3.4 Ph 13C NMR ca 4-hydroxy-7-methylquinolin-2-on .47 Hỡnh 3.5 Ph 1H NMR ca hp cht 4-propynyloxyquinolin-2(1H)-on 48 Hỡnh 3.6 Ph 1H NMR ca 7-methyl-4-propynyoxyquinolin-2-on .49 Hỡnh 3.7 Ph 13C NMR ca 7-methyl-4-propynyloxylquinolin-2-on .50 Hỡnh 3.8.Ph IR ca 2-methylquinolin-4-on 52 Hỡnh 3.9.Ph IR ca 2,8-dimethylquinolin-4(1H)-on 52 Hỡnh 3.10.Ph 1H NMR ca hp cht 2-methylquinolin-4(1H)-on 53 Hỡnh 3.11.Ph 13C NMR ca hp cht 2-methylquinolin-4(1H)-on .54 Hỡnh 3.12 Ph IR ca 2,8-dimethyl-4-cloroquinolin 55 Hỡnh 3.13 Ph IR ca hp cht 4-azido-2,8-dimethylquinolin 57 Hỡnh 3.14 Ph 1H NMR ca hp cht 4-azido-2,8-dimethylquinolin 58 Hỡnh 3.15 Ph 13C NMR ca hp cht 4-azido-2,8-dimethylquinolin .59 Hỡnh 3.16 Ph 1H NMR ca hp cht 4-azido-2,6-dimethylquinolin .60 Hỡnh 3.17 Ph 13C NMR ca hp cht 4-azido-2,6-dimethylquinolin 61 Hỡnh 3.18 Ph 1H NMR caPhn ng click gia 4-azido-2-methylquinolin vi propagyl Tetre-O-acetyl--Dglucopyranoside 63 Hỡnh 3.19 Ph C NMR caPhn ng click gia 4-azido-2-methylquinolin vi propagyl Tetre-O-acetyl--Dglucopyranoside 64 [Type text] Footer Page of 126 Page 59 Header Page of 126 MC LC M U CHNG TNG QUAN 10 1.1 TNG QUAN V QUINOLIN 10 1.1.1 Gii thiu v quinolin 10 1.1.2 Tớnh cht ca quinolin 10 1.1.3 Tng hp quinolin 11 1.2 TNG QUAN V CC 2-METHYLQUINOLIN-4(1H)-ON TH 14 1.2.1 Gii thiu v cỏc 2-methylquinolin-4(1H)-on v dn xut 14 1.2.2 Tớnh cht húa hc 15 1.2.3 Phn ng tng hp 2-methylquinolin-4(1H)-on v dn xut 18 1.2.1 Hoat tớnh sinh hc 19 1.3 TễNG QUAN Vấ PHAN NG CLICK 20 1.3.1 Gii thiu 20 1.3.2 Tng quan tỡnh hỡnh nghiờn cu 21 1.4 Tng hp 4-hydroxyquinolin 27 1.4.1 Tng hp t ethyl oxaloacetate 27 1.4.2 Tng hp t ester ethyl ethoxylmethylenemalonic 28 1.4.3 Tng hp t hp cht thm ortho disubstituted 28 1.4.4 Tng hp t ethyl acetoacetat 29 CHNG PHN THC NGHIM Error! Bookmark not defined 2.1 TNG HP 2, 4-DIHYDROXYQUINOLIN THError! Bookmark not defined 2.1.1 Tng hp 2, 4-dihydroxyquinolin Error! Bookmark not defined 2.1.2 Tng hp 7-methyl-2,4-dihydroxyquinolinError! Bookmark not defined 2.2 TNG HP 4-PROPYNYLOXYQUINOLIN-2-ON THError! Bookmark not defi 2.2.1 Tng hp 4-propargyloxyquinolin-2-onError! Bookmark not defined 2.2.2 Tng hp 7-methyl-4-propargyloxyquinolin-2-onError! Bookmark not defined 2.3 TNG HP MT S HP CHT -ENAMIN CA ETHYL ANILINOCROTONATE TH Error! Bookmark not defined 2.4 TNG HP MT S HP CHT CA CC 2METHYLQUINOLIN-4-ON TH Error! Bookmark not defined 2.4.1 Tng hp 2-methylquinolin-4-on Error! Bookmark not defined [Type text] Footer Page of 126 Page 59 Header Page of 126 2.4.2 Tng hp 2,8-dimethylquinolin-4-on Error! Bookmark not defined 2.4.3 Tng hp 2,6-dimethylquinolin-4-on Error! Bookmark not defined 2.4.4 Tng hp 8-methoxy-2-methylquinolin-4-onError! Bookmark not defined 2.5 TNG HP DN XUT 4-CLORO-2-METHYLQUINOLIN THError! Bookma 2.5.1 Tng hp 2-methy-4-clorolquinolin Error! Bookmark not defined 2.5.2 Tng hp 2,6-dimethyl-4-cloroquinolinError! Bookmark not defined 2.5.3 Tng hp 2,8-dimethyl-4-cloroquinolinError! Bookmark not defined 2.5.4 Tng hp 8-methoxyl-2-methyl-4-cloroquinolinError! Bookmark not defined 2.6 TNGHP CC 4-AZIDO-2-METHYL-QUINOLIN THError! Bookmark not d 2.6 Tng hp 4-azido-2-methylquinolin Error! Bookmark not defined 2.6.2 Tng hp 4-azido-2,8-dimethylquinolinError! Bookmark not defined 2.6.3 Tng hp 4-azido-2,6-dimethylquinolinError! Bookmark not defined 2.6 Tng hp 8-methoxy-4-azido-2-methylquinolinError! Bookmark not defined 2.7 PHN NG CLICK CA 4-AZIDO-2-METHYLQUINOLITH VI PROPARGYL TETRA-O-ACETYL--D-GLUCOPYRANOSIDEError! Bookmark not def Chng KT QU V THO LUN Error! Bookmark not defined 3.1 TNG HP 4-HYDROXYQUINOLIN-2(1H)-ON THError! Bookmark not define 3.1.1 Tng hp 4-hydroxyquinolin-2(1H)-onError! Bookmark not defined 3.1.2 Tng hp 4-hydroxy-7-methylquinolin-2(1H)-onError! Bookmark not defined 3.2 TNG HP MT S 4-PROPARGYLOXYQUINOLIN-2(1H)-ON TH Error! Bookmark not defined 3.2.1 Tng hp 4-propargyloxyquinolin-2-onError! Bookmark not defined 3.2.2 Tng hp 7-methyl-4-propargyloxyquinolin-2-onError! Bookmark not defined 3.3 TNG HP CC 2-METHYLQUINOLIN-4-ON THError! Bookmark not define 3.3.1 iu ch enamin Error! Bookmark not defined 3.3.2 Phn ng úng vũng cỏc enamin Error! Bookmark not defined 3.3.3 Ph hng ngoi ca cỏc hp cht ca 2-methylquinolon-4(1H)-on th Error! Bookmark not defined 3.3.4 Ph cng hng t ca cỏc hp cht ca 2-methylquinolon4(1H)-on thError! Bookmark 3.4 TNG HP MT S 4-CLORO-2-METHYLQUINOLINError! Bookmark not de 3.5 TNG HP MT S 4-AZIDO-2-METHYLQUINOLINError! Bookmark not def [Type text] Footer Page of 126 Page 59 Header Page of 126 3.5.1 Ph hng ngoi cỏc dn sut ca cỏc hp cht ca 2-metylquinolon4(1H)-on th Error! Bookmark not defined 3.5.2.Ph cng hng t ca 4-azido-2,8-dimethylquinolinError! Bookmark not define 3.5.3 Ph cng hng t ca 4-azido-2,6-dimethylquinolinError! Bookmark not defin 3.6 PHN NG CLICK CA 4-AZIDO-2-METHYLQUINOLIN VI PROPAGYL TETRA-O-ACETYL--D-GLUCOPYRANOSIDEError! Bookmark not defin KT LUN TI LIU THAM KHO PH LC [Type text] Footer Page of 126 Error! Bookmark not defined 30 Error! Bookmark not defined Page 59 Header Page 10 of 126 M U T thi xa xa, ngi ta ó bit iu ch v s dng mt s hp cht hu c i sng nh: gim, cht mu hu c, ru ethylic Ngy cựng vi s phỏt trin manh m ca khoa hc k thut núi chung v húa hc núi riờng, húa hc v tng hp cỏc cht hu ccng ngy cng phỏt trin nhm tao cỏc hp cht phc v cho i sng ca ngi, c bit l cỏc hp cht cú hoat tớnh sinh hc cao i vi c th ngi v sinh vt Cỏc hp cht ny ngy cng tr nờn cú ý ngha quan trng v c ỏp dng vo lnh vc y hc cha tr cỏc cn bnh him nghốo, nõng cao sc khe cho ngi v ng vt Nh chỳng ta ó bit, quinolin-4(1H)-on l hp cht hu c i t dn xut ca quinolone vi hoat tớnh sinh hc cao Chng han nh chng viờm, khỏng nm, khỏng khun, cú thuc chng co git, gim au [6,17] Ngoi cỏc dn xut ca quinolone c s dng nh cht xỳc tỏc, cht c ch n mũn, cht bo qun õy cũn l hp cht trung gian quỏ trỡnh tng hp cỏc cht cú hoat tớnh sinh hc cao Chớnh vỡ vy hp cht ny ó c cỏc nh khoa hc nghiờn cu v gn thờm cỏc nhúm th khỏc c nhng hp cht cú hoat tớnh sinh hc a dang phong phỳ Mt s dn xut ca quinolone c phõn lp t thiờn nhiờn, hoc cng cú th tng hp theo phng phỏp tng hp ton phn Vi mc ớch gúp phn vo vic nghiờn cu v lnh vc húa hc ca cỏc monosaccharide cú cha d vũng, bn lun ny, em ó ó tin hnh nghiờn cu tng hp mt s dn xut ca 4-azido-2-methylquinolin, l hp cht chỡa khoỏ cho cỏc chuyn hoỏ tip theo thc hin mc ớch ny, lun thac s khoa hcca em ó thc hin mt s nhim v chớnh sau: + Tng hp mt s 2, 4-dihydroxyquinolin th + Tng hp mt s dn xut ca 2, 4-dihydroxyquinolin th + Tng hp mt s 2-methylquinolin-4-on th + Tng hp mt s dn xut ca2-methyl-4-cloroquinolin + Tng hp mt s dn xut ca 4-azido-2-methylquinolin [Type text] Footer Page 10 of 126 Page 59 Header Page 27 of 126 50],hoc phn ng polymer hoỏ tng hp cỏc polymer mach thng di [49] Kiu cng hp vũng hoỏ 1,3-lng cc Huisgen trờn lai c phõn loai thnh cỏc loai sau: + Phn ng cng hp vũng hoỏ azide-alkyn c xỳc tỏc bng Cu(I) (CuAAC, Cu(I)-catalyzed Azide-Alkyne Cycloaddition) gia azide v alkyn tao thnh mt d vũng canh, 1,2,3-triazol th 1,4-di thay vỡ gm c ng phõn th 1,5-di phn ng cng hp 1,3-lng cc di tỏc dng ca nhit ca Huisgen N N N R R Đồng phân 1,4 N N R N R Đồng phân 1,5 + Phn ng cng hp vũng hoỏ azide-alkyn c xỳc tin bng sc cng vũng (SPAAC, Strain-promoted Azide-Alkyne Cycloaddition), phn ng loai ny, thay vỡ s dng Cu(I) hoat hoỏ alkyn, ngi ta s dng mt alkyn cú sc cng, nh difluorocyclooctyn, ú cỏc nhúm th gem-difluor hỳt electron manh v trớ propargylic hoat ng cựng vi sc cng vũng lm mt n nh ỏng k alkyn + Phn ng cng hp vũng hoỏ alkyn-nitron c xỳc tin bng sc cng vũng ca cỏc cyclooctyn th diaryl cú sc cng, bao gm dibenzylcyclooctyn (DIBO) ó c s dng phn ng vi cỏc 1,3-nitron (SPANC, Strain-promoted AlkyneNitrone Cycloaddition) cho cỏc N-alkyl isoxazolin [58] + Phn ng ca cỏc alken cú sc cng [59], chng han, cỏc trans-cycloalken (thng l cỏc cycloocten) v cỏc alken cú sc cng nh oxanorbornadien c s dng phn ng click vi mt s tỏc nhõn nh cỏc azide, tetrazin v tetrazol Loai phn ng ny bao hm s cng hp vũng hoỏ [3+2] ca alken v azide [61], phn ng Diels-Alder nghch o ca alken v tetrazin [62, 63] v phn ng photoclick ca alken v tetrazol [6468] Trong s cỏc kiu phn ng click tao d vũng 1,2,3-triazol thỡ phn ng ca cỏc alkyn u mach vi cỏc azide, c bit l cỏc azide hu c c cỏc nh [Type text] Footer Page 27 of 126 Page 59 Header Page 28 of 126 tng hp hu c quan tõm bi vỡ s d dng xy ca phn ng vi hiu sut cao Ngoi cỏc hp cht kiu O-, S- v N-glucoside ca monosaccharide vi cỏc amin d vũng (indol, imidazol, quinolin, quinazolin, pyrimidin, pyridin, ) [6973], cỏc glycosylamin [74-78], v ó c quan tõm nghiờn cu c v mt lý thuyt cng nh thc nghim [79], thi gian gn õy ó cú mt s cụng b cp n phn ng click cỏc monosaccharide [25, 27],trong ú, natri azide c s dng lm hp phn azide thay vỡ azide hu c thụng thng, phn ng vi cỏc O-propargyl glycoside T nm 1999, húa hc click ó kớch thớch nhiu quan tõm cỏc lnh vc nghiờn cu khỏc nhau, c s dng nhiu lnh vc, t vi in t n vic gn nhón virus iu tr bnh ung th Mc dự nhu cu v vt liu húa cht mi v hoat tớnh sinh hc phõn t tip tc phỏt trin, cỏc nh húa hc ó hu nh khụng bt u khỏm phỏ cỏc úng gúp rng ln ca hp cht cú hoat tớnh [71].Trong bi cnh ca s yờu cu liờn tc v cỏc loai thuc tt hn thi gian ngn hn, nh húa y hc phi i mt vi nhim v khú khn ca vic tng hp cỏc phõn t mi, kt hp vi hoat tớnh cao v tớnh chn lc cao, ging thuc v cỏc tớnh cht dc lc tt Cỏc dc phm tim nng da trờn 1,2,3-triazol bao gm hp cht chng ung th CAI [72], dn xut nucleoside lm cht c ch enzyme chộp ngc, c gi l TSAO, [73] cỏc khỏng sinh -lactum Tazobactum, cephalosporine Cefatrizine (Hỡnh 1.2), v.v [Type text] Footer Page 28 of 126 Page 59 Header Page 29 of 126 Hỡnh 1.2.Mt s dc phm tim nng trờn c s 1,2,3-triazol Ngc lai vi xu hng nghiờn cu ngy cng phỏt trin trờn th gii, Vit Nam, vic nghiờn cu phn ng click tng hp d vũng 1,2,3-triazol cha c cp n nhiu 1.4 Tng hp 4-hydroxyquinolin 1.4.1 Tng hp t ethyl oxaloacetate NH2 + H5C2OOC CH CO COOC 2H5 CH2Cl2 CH3COOH H5C2OOC CH Solution NH C COOC2H5 Jnert sovent 250o OH OH C N [Type text] Footer Page 29 of 126 CH CH OH- , -H2O C CH Heat N COOC 2H5 Page 59 Header Page 30 of 126 Anilin ngng t vi ethyl oxaloacetate acid acetic loóng hoc dung dch methylene chloride tao -carbethoxyl--anilinoacerylate (2)(16) Sau ú úng vũng bng cỏch hn hp vo Dowtherm ó lm núng trc ú tao 4-hydroxy2-cacbethoxylquinolin, tip theo kh cacboxyl bng cỏch un núng bi Dowtherm nhit cao thu c 4-hydroxyquinolin 1.4.2 Tng hp t esterethyl ethoxylmethylenemalonic H5C6 NH2 + H5C2 O CH C (COOC 2H5)2 OH (H 5C2OOC) C NH 240-50oc CH N OH (COOC 2H5)2 CH i) OH- CH ii) -CO2 CH N CH Gould v Jocobs ó gii thiu ethyl ethoxylmethylenemalonic nh mt thnh phn -keto ester catng hp Conrad-Limpuch Tng hp ny sau ú thy phõn tao 4-hydroxyquinolin-3-carboxylic acid Sau ú l phn ng kh cacboxyl b un núng nhit cao 1.4.3 Tng hp t hp cht thm ortho disubstituted COOR OH ' OEt + R Ph Me OEt N C6H õy l loai tng hp dnh mt quinoline ca mt cu trỳc v õy l li th nht ca phng phỏp ny so vi cỏc loai khỏc ca phng phỏp Nhng nhc im ln ca loai hỡnh nyl khú khn ca synthesising cỏc vt liu Liementowski ó bỏo cỏo rng acid anthranilic un núng vi acetophenone tao 2-phenyl-4hydroxyquinoline Sn lng phn ng ny ớt v nú cú th c ci thin nuanthranilic acid v xeton c thay th ln lt bi methyl anthranilate v ketal ca keton Khi acid anthranilic ó c s dng v trớ ca ester "nng sut ó c xung vỡ cỏc phn ng kh carboxyl ca acid anthranilic theo cỏc iu kin [Type text] Footer Page 30 of 126 Page 59 Header Page 31 of 126 ca phn ng Tuy vy s ngng t gia acid anthranilic v propiophenone tao 2phenyl-3-methyl- hydroxyquinoline cho nng sut cao hn 1.4.4 Tng hp t ethylacetoacetat OC 2H5 OC CH C NH re te om o r at tu era mp -H 2O NH2 + C2H5OH H O,H+ anhyd 130-40OC CaSO4 at 14 0-60 o C H3C COCH COOC 2H5 CH3 -C H OH H3C HO C CH CO NH Mt ester -keto nh ethylacetoacetat cú th phn ng vi amin thm bng mt hai cỏch nh hỡnh di õy cú kh nng ngng t nhit phũng nu thc hin vi s hin din ca mt acid Lm phỏt sinh mt cht xỳc tỏc Anil nu nú thc hin tai mc n im sụi tng ng ca hn hp phn ng an ton v anilide c hỡnh thnh anil (p -anilinocrotonic esterr) un núng n 240o-250oC mụi trng tr nh du hoc Dowtherm tao ra4-hydroxy-quinoline OH OC OC2H5 C NH -C2H5OH CH CH3 to CH N C CH3 Phn ng ny thng c gi l Conrad-Limpach Cỏc anilide v si m bng acid sulfuric m c v dnh mt dn xut 2hydroxyquinoline Phn ng ny l thng c gi l tng hp Knorrls Mt s ester S-keto khỏc ó c s dng Conrad-Limpach loai tng [Type text] Footer Page 31 of 126 Page 59 Header Page 32 of 126 hp Trong s ny oxaloacetate ethyl v ethyl ethoxymethylenemalonate c c bit cp c s dng gn õy hn vic tng hp 2s3 ~ khụng th -4 - dn xut hydroxyquinoline cn thit cho vic tng hp aminoquinolines quan trng iu tr [Type text] Footer Page 32 of 126 Page 59 Header Page 33 of 126 TI LIU THAM KHO Ting Vit 1.Nguyn ỡnh Thnh (2010), C s húa hc hu c, NXB hc Quc Gia H Ni, H Ni 2.Nguyn ỡnh Thnh (2011), Cỏcphng phỏp ph ng dng húa hc, NXB Khoa hc v K thut, H Ni 3.Nguyn Minh Tho (2001), Tng hp hu c, NXB hc Quc Gia H Ni, H Ni Nguyn Minh Tho (2001), Húa hc cỏc hp cht d vũng, NXB Giỏo dc, H Ni Trn Th Thu Thy, Ngụ Ngc Thng, inh Th H, Nguyn Quyt Chin, Stephanie Legoupy, Tng hp cỏc dn xut triazolo-cyclobutane nucleosidecú cha vũng piperazine, Tp Hoỏ hc,52(1) 19-23 (2014) Vng Vn Trng, Nghiờn cu chit tỏch v chuyn húa zerumbone mt s cõy thuc thuc h Gng (Zingiberaceae) Vit Nam v kho sỏt hot tớnh gõy c t bo ung th, Lun ỏn Tin s Hoỏ hc, H Ni (2016), 169 tr Ting Anh B Bhudevi, P Venkata Ramana, Anwita Mudiraj & A Ram Reddy(2009)Vol 48B, Synthesisof 4-hydroxy-3-formylideneamino-1H/methyl/phenylquinolin2-ones, Indian Journal of Chemistry, pp 255-260 Bhupendra Mistry , Smita Jauhari , (2010), Synthesis and characterization of some quinoline based azetidinones and thiazolidinones as antimicrobial agents, Archives of Applied Science Research 2(6), pp 332-343 Carla Prata, Nathalie Mora, Jean-Michel Lacombe, Jean-Claude Maurizis, Bernard Pucci, (1999), Synthesis and surface-active properties of glycosyl carbamates and thioureas, Carbohydrate Research 321(1-2), pp 4-14 El-hossain ali mohamed, (1991), On step synthesis of 4-hydroxycarbostyrils VI, Jour Chem Soc Pak Vol 13, pp 166-168 Farhalulah, Diptesh Sil, Brajendra K Tripathi, Arvi K Srivastava, (2004), Synthesis and glucose-6-phosphatase inhibitory activity of alkanoic acid [Type text] Footer Page 33 of 126 Page 59 Header Page 34 of 126 esterrs, Bioorganic & Medicinal Chemistry Letters, 14(10), pp 2571-2574 10 Giorgos Athanasellis, Georgia Melagraki, Haralambos Chatzidakis, Antreas Afantitis, Anastasia Detsi, Olga Igglessi-Markopoulou, John Markopoulos, (2004), Novel Short-Step Synthesis of Funtionalized -Phenyl-hydroxybutenoates and their cyclization to 4-hydroxycoumarins via the Nhydroxybenzotriazole methodology, Synthesis11, pp 1775-1782 11.Li Qing-han , Zhao Zhi-gang , Chen Shu-hua , (2007) , Efficient synthesis of thiosemecarbasene under microwave irradiation, Chemical Research and Appication 9, pp 1011-1016 12.Li Z G , Wang Q M , Huang J M , (2001), The Preparation of Organic Intermediates, 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Sự cộng hợp vào liên kết bội carbon-carbon R R X [X] R R + Sản phẩm phụ (X = O, NR,+SR,+NR) (Sự tạo thành vòng ba cạnh) EWG EWG EWG + EWG EWG EWG (EWG: Nhóm hút electron) (Một số cộng hợp Michael)... [Type text] Footer Page 25 of 126 Page 59 Header Page 26 of 126 Sự cộng hợp vòng hoá R N N N + R R Cu(I) CH N N N R (Sự cộng hợp vòng hoá 1,3-lưỡng cực azide alkyn cuối mạch) Sự m vòng nucleophil... defined 2.1.1 Tng hp 2, 4-dihydroxyquinolin Error! Bookmark not defined 2.1.2 Tng hp 7-methyl-2,4-dihydroxyquinolinError! Bookmark not defined 2.2 TNG HP 4-PROPYNYLOXYQUINOLIN-2-ON THError!