博士論文 / Efficient synthesis of valuable heterocyclic compounds using multi-component reactions 多成分反応を利用した高付加価値ヘテロ環化合物の効率的合成法に関する研究

著者

Jalli Venkataprasad / 九州工業大学 / 博士（工学）

書誌事項

タイトル: Efficient synthesis of valuable heterocyclic compounds using multi-component reactions
タイトル別名: 多成分反応を利用した高付加価値ヘテロ環化合物の効率的合成法に関する研究
著者名: Jalli Venkataprasad
学位授与大学: 九州工業大学 (大学ID:0071) (CAT機関ID:KI000844)
取得学位: 博士（工学）
学位授与番号: 甲工第436号
学位授与年月日: 2017-03-24

注記・抄録

Synthetic protocols involving easy handling process, atom economy, ambient reaction conditions, short reaction times, inexpensive and less hazardous catalyst always have been attractive. Multi-component reaction is a chemical reaction, in which three or more starting materials react to form the product in an atom economy manner and ease of access to complex molecules in one-pot certainly belong to this class. A contemporary challenge in the world is environmental pollution. Multi component reactions are certainly one of the solutions for this problem due to the less release of chemical wastage compared with classical bicomponent reaction protocols and it is being considered as one of the green technology. I have also tried to use water as a reaction solvent to synthesize heterocyclic compounds because water is cheaper, green solvent and highly abundant in nature. I have synthesized various valuable heterocyclic compounds using multicomponent reactions. Compounds possessing pyrrolo[2,3-c]pyridone backbone have been used to control the cell proliferation in breast cancer and p38 kinase inhibitors. Wang Le et. al., also have reported molecules having pyrrolo[2,3-c]pyridone backbone as BRD4 receptor inhibitors to control breast cancer. Considering the importance of these molecules, we have demonstrated an efficient, mild and multicomponent protocol for the synthesis of novel heterocyclic compounds possessing pyrrolo[2,3-c]pyridone backbone by using Ugi four component reaction and post condensation of Ugi adduct. This method offers several advantages such as easy handling procedure, atom economy, short reaction time and huge molecular library can be synthesized by changing the substituents on four independent starting materials. In previous reported methods for pyrrolo[2,3- c]pyridones, expensive metal catalysts were used, where as in present method we used inexpensive PTSA catalyst. Various anilines substituted with Iodo, bromo, chloro, methyl, methoxy at different positions on aniline were used in Ugi 4CR. And also phenyl glyoxylic acids substituted with methoxy, ethoxy, methyl and chloro were used in combinations with t-butyl and cyclohexyl isocyanides. In all cases the reaction proceeded smoothly and yielded the corresponding pyrrolo[2,3-c]pyridone derivatives in good to excellent yields. Considering these advantages we hope this methodology will be useful for medicinal chemists in drug discovery process. All the products were characterized by using NMR (1H and 13C) spectroscopy and FAB mass. One of the products was further characterized with X-ray diffraction analysis. Coumarin analogs having both coumarin and furan heterocycles have gained the considerable attention of researchers due to their significant properties as anti-leishmania panamensis, dyes and fluorescent sensors. Coumarin analogs with furan heterocycle isolated from the plants origin such as microminutin, micromelin, psoralen, 8-methoxypsoralen have important properties in medicinal chemistry and bio photochemistry. It is well documented that by introducing a heteroaromatic substituent at 3-position the absorption and emission maxima of coumarin scaffold can be improved because of extended πconjugation and consequently their optoelectronic properties can be improved. Based on this phenomenon a variety of 3-heteroaryl coumarin derivatives have been synthesized and evaluated for their optoelectronic properties. Considering the broad range of applications of furyl coumarin derivatives, we have demonistrated an efficient and facile synthesis of 3-furyl coumarin derivatives by reaction of 4- chloro-3-formylcoumarin, secondary amines, dialkyl acetylenedicarboxylates and diversely substituted isocyanides using four component one pot reaction. All the products were isolated as yellow color fluorescent solids by column chromatography in quantitative yield and characterized with 1H NMR, C13 NMR, IR and FAB mass. Spiro compounds having dipyrrole namely Amathaspiramide A, Mytraginine psuedoindoxyl as shown below was proven to have prominent antiviral and anticancer properties. Very few reports were there in the literature for the synthesis of spiro [indole-2,2’- pyrroles] bearing spiro carbon at C-2 position. Considering this as an opportunity, we have developed an efficient and facile method for the synthesis of novel spiro[indole-2,2'-pyrroles] from N-methyl-3-isatin imines, t-butyl isocyanide and dialkyl acetylenedicarboxylate has been achieved by [3+2] cyclo addition reaction. The notable advantages of this protocol are operational simplicity, easily available starting materials, available diversity of each component, catalyst free and easy work procedure employed. We believed in this protocol will help in developing novel spiro heterocyclic compounds using C-2 carbon atom of isatin. All the products were purified by column chromatography as yellow solids and confirmed with 1H NMR, 13CNMR, FAB mass, IR. One of the compound was further confirmed with X-ray analysis. Imidazo[1,2-a]pyridines have been valuable to organic and medicinal chemists due to the interesting structure and numerous applications in pharmaceutical Industry. The molecules possessing imidazo[1,2-a]pyridine core structure have been used as anticancer, antiinflammatory, antibacterial, antiprotozonal and antiviral agents. Additionally, they were also used for the treatment of gastric disease and heart disease. They have been found in drug candidates such as Minodronic acid used for the treatment of osteoporosis, Zolpidem used for the treatment of insomnia and some brain disorders, Zolmidine used for the treatment of peptic ulcers and gastro esophageal reflux disease and Olprinone used for the treatment of acute heart failure. Considering these applications, New coumarin derivatives having imidazo[1,2-a]pyridine heterocycle moiety were synthesized by the condensation of 4-morpholino-3-formyl coumarin, diversely substituted 2-amino pyridine and isocyanides under catalyst free, water mediated reaction conditions. All the products were characterized by using IR, NMR (1H and 13C) spectroscopy and HRMS spectrometry. Product 4b was further characterized with X-ray diffraction analysis. All the products have showed UV-Visible absorbance in between 234 nm to 248 nm and emissions were observed in between 412 nm to 544 nm.

九州工業大学博士学位論文学位記番号:工博甲第436号学位授与年月日:平成29年3月24日

1. Introduction|2. Efficient synthesis of novel pyrrolo[2,3-c]pyridone derivatives using Ugi forcomponent reaction followed by condensation reaction|3. One pot four component synthesis of novel 3-furyl coumarin derivatives|4. Synthesis of novel spiro[indole-2,2’-pyrroles] using isocyanide|5. Catalyst free, water mediated synthesis of 2,3-disubstituted imidazo[1,2-a]pyridines derivatives using three-component reaction and evaluation of their

photophysical properties

平成28年度

九州工業大学博士学位論文（要旨）学位記番号：工博甲第436号学位授与年月日：平成29年3月24日