Study On The Reaction Of Ethyl 6-chloro-2-(Chloromethyl) Quinoline-3-carboxylate As Substrate

Quinoline and its derivatives as typical nitrogen heterocyclic compounds are found in many alkaloids.They occupy a very important position in medicinal chemistry and display a wide spectrum of biological and pharmacological activity.Especially,6-chloroquinoline compounds share potent biological properties with quinoline compounds.Moreover,6-chloroquinolines are also wide applied in the fields of organic ligand,pesticide other than the medical field.Because of the presence of the derivativable chloro functional group,there is much synthetic interest in the synthesis and application of these derivatives.In this thesis,we selected ethyl 6-chloro-2-(chloromethyl)quinoline-3-carboxylate as the substrate to conduct the reaction with a series of compounds(such as amines,phenols,and so on)to synthesize successfully a veriety of 6-chloroquinoline-based compounds.The thesis is mainly consisted of eight parts as follows:In the first part,a literature survey concerning the quinoline and their derivatives was conducted,and their biological and pharmaceutical activities were reviewed.In the second part,ethyl 6-chloro-2-(chloromethyl)quinoline-3-carboxylate(1)as the starting compound was subjected to the reaction with various amines including aromatic amines 2a-2j,aliphatic amines 2k-2n,and diamines 2o-2s to give the corresponding N-aryl-3a-3j,N-alkyl-substituted 3k-3n,and symmetrical N,N'-alkyl(aryl)-bridged 3o-3s 7-chloropyrrolo[3,4-b]quinolin-1-one derivatives,respectively.Fluorescence spectra of compounds 3a-3s showed that compounds 3a-3j,3r,3s owned good fluorescence properties.In the third part,the starting compound 1 reacted with phenol or substituted phenols 4a-4o,quinolin-8-ol(4p),5,7-dichoroquinoline-8-ol(4q),and [1,1?-binaphthalene]-2,2?-diol(4r)in one-pot procedure with presence of potassium carbonate as the base and acetonitrile as solvent to give corresponding 6-chloro-2-(phenoxymethyl)quinoline-3-carboxylic acids 5a-5o,6-chloro-2-((quinolin-8-yloxy)methyl)quinoline-3-carboxylic acids(5p,5q),2,2?-(([1,1?-binaphthalene]-2,2?-diylbis(oxy))bis(methylene))bis(6-chloroquinoline-3-carboxyl ic acid)(5r).In the fourth part,a facile synthesis of 2-(benzofuran-2-yl)-6-chloroquinoline-3-carboxylic acid derivatives 7a-7o has been described,involving ultrasound-assisted three-step one-pot reaction of ethyl 6-chloro-2-(chloromethyl)quinoline-3-carboxylate(1)with corresponding salicylaldehydes 6a-6h,2-hydroxy-1-naphthaldehyde(6i)or 1-(2-hydroxyphenyl)ethanones 6j-6o in the presence of K2CO3 as acid-binding agent,MeCN as solvent and PEG-400 as phase transfer catalyst,with good yields ranging 61.5-78.3%.In the fifth part,the synthesis of a series of novel(E)-6-chloro-2-arylvinylquinoline-3-carboxylic acid derivatives 9a-9f' had been achieved through a simple and efficient one-pot reaction of ethyl 6-chloro-2-(chloromethyl)quinoline-3-carboxylate(1)with various aromatic aldehydes 8a-8f',involving the reaction of 1 with triethyl phosphate followed by the Wittig-Horner reaction with various aromatic aldehydes using NaH/DMF system and subsequent basic hydrolysis,with good yields ranging 54.8-83.6%.In the sixth part,ethyl 6-chloro-2-(chloromethyl)quinoline-3-carboxylate(1)as substrate was subjected to the Williamson reaction with 1-naphthol(10a)or 2-naphthol(10b)to give corresponding 6-chloro-2-((naphthalene-1/2-yloxy)methyl)quinoline-3-carboxylic acid(11a,11b)via a two-step one-pot procedure.Subsequently,the resulting 11 a,11b were treated with PPA at 135 oC to give the cyclized products 10-chloronaphtho[2',1':6,7]oxepino[3,4-b]quinolin-7(14H)-one(12a)and 12-chloronaphtho[1',2':6,7]oxepino[3,4-b]quinolin-15(8H)-one(12b)via the intramolecular Friedel-Crafts acylation reaction.Compounds 12 a,12b were further treated under basic conditions to undergo 1,2-Wittig rearrangement and atmospheric oxidation,giving the corresponding 10-chloronaphthoacridine-7,14-dione(13a,13b).In the seventh part,ethyl 6-chloro-2-(chloromethyl)quinoline-3-carboxylate(1)was first treated with ethyl 2-hydroxyacetate to afford ethyl 6-chloro-2-((2-ethoxy-2-oxoethoxy)methyl)quinoline-3-carboxylate(14)via Williamson reaction,which was then underwent the Claisen condensation reaction to afford ethyl 7-chloro-4-oxo-3,4-dihydro-1H-pyrano[3,4-b]quinoline-3-carboxylate(15)with the use of EtONa as the base.Further,compound 15 was underwent the hydrolysis and decarboxylation reaction under acidic condition to give 7-chloro-1H-pyrano[3,4-b]quinolin-4(3H)-one(16).Finally,the obtained latter was conducted the Friedlander reaction with o-amino aryl carbonyl compounds 17a-17 c in the presence of EtONa as base to synthesize 2-chloro-6H-pyrano[3,2-b:5,4-b']diquinoline derivatives 18a-18 c,with good yields of 64.8-70.5%.In the eighth part,7-chloro-1H-pyrano[3,4-b]quinolin-4(3H)-one(16)was performed the Pfitzinger raction with various substituted indoline-2,3-diones 19a-19 l to obtain the corresponding 2-chloro-6H-pyrano[3,2-b:5,4-b']diquinoline-8-carboxylic acid derivatives 20a-20 l with good yields ranging 61.8-67.7% using EtOH as the solvent and KOH as the base.Structure of synthesized compounds 3a-3s,5a-5r,7a-7o,9a-9f?,11 a,11b,12 a,12b,13 a,13b,14,15,16,18a-18 c,20a-20 l characterized by IR,1H NMR,13 C NMR and HRMS spectra.