Studies on Syntheses of2-dialkylaminoquinoline and Dialkyl Quinolin-2-yl Phosphonate Derivatives |
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Author | KeDianDian |
Tutor | ZhaoYuFen; ChenXiaoZuo |
School | Zhengzhou University |
Course | Organic Chemistry |
Keywords | quinoline cross dehydrogenative coupling 2-dialklyaminoquinolines dialkyl quinolin-2-yl phosphonates and mechanism |
CLC | O626.323 |
Type | Master's thesis |
Year | 2013 |
Downloads | 13 |
Quotes | 0 |
Quinoline derivatives represent a large and important class of heterocyclic compounds, and are widely distributed in the nature. With a wide spectrum of chemical activities and good capability to react with other materials to generate a variety of different derivatives, they demonstrate significant applications on many fields including pharmaceutical industry, dyestuffs, and molecular biology etc. As one category of this big family, aminoquinolines have relatively higher bioactivities and2-aminoquinoline derivatives are especially important in that they have been proven to possess a collection of pharmaceutical activities such as anti malarial, antibacterial, protease inhibitor, anthelmintic, antiprotozoal, antidepressant, antihypertensive, anti-Alzheimer disease, and anticancer, anti-HIV, antioxidant etc. This high incidence of pharmacological activities among2-aminoquinolines has spontaneously stimulated many research efforts to prepare compounds of this structure type. While numerous synthetic approaches have been developed for2-aminoquinoline synthesis, the most common synthetic methods involve Chichibabin-type amination from amine alkali, Substitution of2-prefunctionalized quinolines by an amine, and Cycloaddition with anilines as starting materials. However, these methods are mostly unsatisfactory with some drawbacks. Herein, we demonstrate a novel phosphorus reagent participated method for synthesis of2-dialkylaminoquinolines with mild conditions, convenient operation and devoidness of poisonous reagents.The developments of novel, highly efficient and selective synthesis methods are of great significance for Organic Chemistry."Classical" syntheses are generally based on transformation of different functional groups. The direct reactions between some inert bonds such as C-H bonds will profoundly improve overall synthesis efficiency by abatement of pre-functionalization steps. Thus, these methods will be an important strategy for boost of synthetic efficiency. In2003, Professor Chao-Jun Li of McGill University firstly demonstrated concept of Cross Dehydrogenative Coupling (CDC) reaction. Such a coupling reaction would eliminate the prefunctionalization of reactants through forthright employing of non-prefunctionalized reactants and thus make the synthetic procedures shorter, greener and more economical, and will greatly enrich the methods of synthesis for variant C-C(C-X) bonds containing compounds. Meanwhile,2-quinolyphosphonate derivatives have been reported to possess a variety of biological activities and thus are of potential use as therapeutic agents on clinic. In this paper, we first summarized recent developments of CDC reactions, and subsequently proposed a simple and efficient method for direct construction of sp2C-N bond for synthesis of dialkyl quinolin-2-yl phosphonates. The main contents are as follows:(1) With quinolines-N-oxides and tertiary amine employed as reaction substrates, and H-phosphonates and carbon tetrachloride as auxiliary ingredients, a series of2-dialklyaminoquinolines has been efficiently synthesized. Meanwhile, the investigations of optimal reaction conditions regarding the necessity of auxiliaries, influences of reactants’usage, solvents and reaction temperature, are carried out with a selected model reaction. After that, we proposed a reasonable mechanism, and in succession an experiment was further designed to verify the hypothesis through31P-NMR spectra tracking. The results show that the auxiliaries including H-phosphonates and CCl4are indispensable in this reaction. And this method for direct construction of sp2C-N bond to synthesize2-dialklyaminoquinolines is superior to others due to its mild conditions and easy operation etc. With optimal conditions in hand, sixteen2-dialklyaminoquinolines were ultimately synthesized with structural elucidations by ESI-MS, NMR.(2) Base on the principle and method of CDC reaction, using air as a green and economical oxidant, quinolines and a range of H-phosphonates were reacted without metal catalysts to generate a series of dialkyl quinolin-2-yl phosphonates. Initially, the feasibility of this designed protocol was investigated; and reaction conditions were subsequently examined from several aspects, including choice of oxidants and catalysts, solvents and temperature. With optimal reaction conditions in hand, target compounds of dialkyl quinolin-2-yl phosphonates were obtained followed by two by-products:tetra-alkyl (1,2,3,4-tetrahydroquinoline-2,4-diyl) bis (phosphonate) and tetra-alkyl quinoline-2,4-diylbis (phosphonate). This CDC approach for direct construction of sp2C-P bond is advantageous in terms of simple reaction condition, devoidness of pre-functionalized reactants, and green chemistry ideology with sustainable air employed as oxidant. This method for synthesis of dialkyl quinolin-2-yl phosphonates is of great importance for further exploration and study. Herein, seven dialkyl quinolin-2-yl phosphonates were synthesized with structural elucidations by NMR, ESI-MS and other by-products were confirmed by ESI-MS and P-NMR etc.