Design, Synthesis And Characterization Of Novel Heterocyclic-fused Containing Of 6-bromoquinoline Skeleton

Quinoline derivatives are found in many natural products as a very important family of heterocyclic compounds, and show a broader range of biological and pharmacological activities. Especially, those containing heteroatoms fused to a quinoline ring are known to display significant biological activity. Therefore, the study has important implications for the synthesis and properties of fused heterocyclic polycyclic quinoline compounds. In this thesis, we selected ethyl 6-bromo-2-(chloromethyl)-3-carboxylate as a starting compound to synthesize a variety of 6-bromoquinoline-fused heterocyclic compounds. The thesis was mainly consisted of seven parts.In the first part, the synthesis of 6-bromoquinoline and its derivatives are reviewed on the basis of a survey of previous literatures.In the second part, study on the synthesis of ethyl 6-bromo-2-(chloromethyl)quinoline-3- carboxylatethe(1): The compound was first prepared by the reduction reaction of o-nitrobenzaldehyde followed by acetylation of the arising 2-amino group. The resulting was then underwent the halogenation reaction with N-chlorosuccinimide using eco-friendly PEG-400 as solvent at room temperature. Subsequently, the compound were subjected to the Friedl?nder condensation reaction with 4-chloroacetoacetate with the presence of chlorotrimethylsilane(TMSCl) as catalyst to achieve the synthesis of the desired title compounds, namely ethyl 6-bromo-2-(chloromethyl)quinoline-3-carboxylates(1). The structure was confirmed by IR, IR、1H NMR、13C NMR、ESI-MS and HR-MS spectra.In the third part, a novel and facile synthesis of 2-(benzofuran-2-yl)-6-bromoquinoline-3-carboxylic acid: The title compounds were prepared by ethyl 6-bromo-2-(chloromethyl)- 3-carboxylate(1) with various substituted salicylaldehydes, the yields of compounds 2a-i are 60.5-85.4% repectaly. The structure was confirmed by IR, 1H NMR, 13 C NMR, ESI-MS and HR-MS spectra.In the fourth part, a variety of structurally new 7-bromo-2,3-dihydro-1H-pyrrolo[3,4-b] quinolin-1-one derivates were synthesized: The synthesis mainly relied on a one-pot reaction procedure of ethyl 6-bromo-2-(chloromethyl)quinoline-3-carboxylate(1) with anilines, hydrocarbylamines and diamines in refluxing ethanol. Giving the corresponding 7-bromo-2- phenyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one derivates(3a-j), 7-bromo-2,3-dihydro-1H- pyrrolo[3,4-b]quinolin-1-one derivates(3k-n), 2,2’-bis(7-bromo-2,3-dihydro-1H-pyrrolo[3,4-b] quinolin-1-one) derivates(3o-q). All these newly-synthesized compounds 3a-q are novel and their structures were confirmed by IR, 1H NMR, 13 C NMR, ESI-MS and HR-MS spectra.In the fifth part, a series of novel(E)-6-bromo-2-styrylquinoline-3-carboxylic acid(4a-z, 5a-d) were synthesized by a three-step one-pot procedure which involved the Ylide from the reaction between the starting compound(1) and triethyl phosphite followed by the Wittig-Horner reaction with aromatic or heteroaromatic aldehydes and subsequent basic hydrolysis. Compound 4a, 4b could be further treated by PPA Regent to give the corresponding 2-bromo-12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one(4a’, 4b’) via intramolecular cyclization reaction. Compound 4e, 4k could be further treated by Eaton’s Regent to give the corresponding 8-bromo-3-phenyl-3,4-dihydro-1H-pyrano[4,3-b]quinolin-1-one(4e’, 4k’) via intramolecular cyclization reaction. All these newly-synthesized compounds 4a-z, 5a-d, 4a’, 4b’, 4e’, 4k’ are novel and their structures were confirmed by IR, 1H NMR, 13 C NMR, ESI-MS and HR-MS spectra.In the sixth part, 6-bromo-2-((naphthalen-1-yloxy)methyl)quinoline-3-carboxylic acid(6a) and 6-bromo-2-((naphthalen-2-yloxy)methyl)quinoline-3-carboxylic acid(6b) were sythesized by a one-pot method of ethyl 6-bromo-2-(chloromethyl)quinoline-3-carboxylate(1) with α-naphthol and β-naphthol respectively. Compounds 10-bromonaphtho[2’,1’:6,7]oxepino [3,4-b]quinolin-7(14H)-one(7a) and 12-bromonaphtho[1’,2’:6,7]oxepino[3,4-b]quinolin-15(8H)-one(7b) were prepared by the intramolecular Friedel-Crafts acylation reactions of 6a and 6b under the PPA condition. The compounds 7a and 7b could be further treated under basic conditions to undergo 1,2-Witting rearrangement and atmospheric oxidation giving the corresponding naphthyridine dione Compounds 10-bromonaphtho[2,1-b]acridine-7,14-dione(8a) and 11-bromonaphtho[1,2-b]acridine-7,14-dione(8b). All these newly-synthesized compounds 6a, 6b, 7a, 7b, 8a, 8b are novel and their structures were confirmed by IR, 1H NMR, 13 C NMR, ESI-MS and HR-MS spectra.