臺灣博碩士論文加值系統

本論文主要是探討一鍋化反應之應用於1,3-dipolar cycloaddition及Hetero-Diels-Alder reaction反應，簡易合成出1,2,4-triazoles和pyrazole等衍生物。
論文的第一部分是探討用以one-pot方式將一系列aldehydes, oxime, 和nitrile (imidate)等起始物與hydrazonoyl hydrochlorides進行1,3-dipolar cycloaddition反應，得到相應的1,2,4-triazoles產物。將合成出的1,2,4-triazoles化合物再送測三株腫瘤細胞株(NCI- H226，TW-01和Jurkat)，其中以triazolic環在N-1含有trifluoromethane官能基以及triazolic環的C-5位置所具有的五圓環基團，包括cyclopentyl, 3-furyl, 3-thienyl, 和 2-pyrrolyl等五圓環，對NCI- H226具有的顯著選擇性抑制效果。
本論文的第二部分，是利用封管條件下將maleimides與pyrazoylimines進行one-pot Aza-Diels–Alder反應，得到一系列高產率pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine產物。依據實驗結果，產物的產率與pyrazoylimines上的N,N-disubstitutedamidinyl的取代基團所造成之torsion conformation成正向關係。
第三部分我們使用5-aminopyrazoles 與 ethyl nitrite或sodium nitrite在一鍋反應，得到5-amino-4-hydroxyiminopyrazoles 和 (E)-N1-aryl-3-aryl-4-[(substituted pyrazolyl)diazenyl]pyrazoles相對產物。相關產物皆經光譜構造鑑定，並進一步經X光單晶繞射驗證其結構。針對5-amino-4-hydroxyiminopyrazoles互變異構體的結構，初次被X光單晶繞射儀的加以證實，而非為先前文獻報導的5-amino-4-nitrosopyrazoles結構。

In this dissertation, we focus on one-pot reaction to prepare the derivatives of 1,2,4-triazoles, and pyrazoles through 1,3-dipolar cycloadditions and hetero-Diels-Alder reaction. First, we developed the efficient one-pot reaction via 1,3-dipolar cycloaddition synthesis method by reacting hydrazonoyl hydrochlorides with a series of aldehydes, oxime, imidate or nitrile to give the corresponding 1,2,4-triazoles. Various of reactants such as 1,2,4-triazole comounds, containing trifluoromethyl group on N-1 phenyl group or possessed the five-membered ring groups including cyclopentyl, 3-furyl, 3-thienyl, and 2-pyrrolyl on the C-5 position of the triazolic ring, possessed the significant selective inhibitory activity against NCI-H226 cancer cells.
In the second part of this dissertation, a modified synthetic method of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridines was developed through an Aza-Diels–Alder reaction of pyrazoylimines with maleimides under the sealed tube condition. Based on the controlling study, the yields for Aza-Diels–Alder reaction seemed proportional to the suitable torsion conformation of pyrazoylimine which was modulated by N,N-disubstitutedamidinyl moiety. The versatile sealed tube technique was also proven to promote the yields of in the Aza-Diels–Alder cycloaddition reaction.
5-Amino-4-hydroxyiminopyrazoles and (E)-N1-aryl-3-aryl-4-[(substituted pyrazolyl)diazenyl]pyrazoles were successfully and conveniently synthesized and studied as the corresponding products by treating 5-aminopyrazoles with ethyl nitrite in the third part. All of 5-amino-4-hydroxyiminopyrazole and (E)-N1-aryl-3-aryl-4-[(substituted pyrazolyl)diazenyl]pyrazole compounds were fully identified by spectroscopic methods. Based on the further single-crystal X-ray diffraction study (ORTEP) resonamce 5-amino-4-hydroxyiminopyrazole structure was identified in the first time and presented as opposed to a 5-amino-4-nitrosopyrazoles tautomer.

Publication List II
Abbreviations IV
Contents V
Chart List VIII
Chart of Figure VIII
Chart of Scheme X
Chart of Table XI
中文摘要 XII
Abstract XIII
Chapter 1. Introduction 1
1.1 The biological activity and tradition synthesis of 1,2,4-triazole derivatives 1
1.1.1 The biological activity of 1,2,4-triazole derivatives 1
1.1.2 The tradition synthesis of 1,2,4-triazole derivatives 5
1.2 The biological activity and synthesis of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives via Diels-Alder reaction of pyrazole derivatives 8
1.2.1 Antitumor of Pyrazolone Derivatives 8
1.2.2 Sedation of Pyrazolone Derivatives 10
1.2.3 The synthesis of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives via Diels-Alder reaction 13
1.3 The physicochemical properties of 5-amino-4-hydroxyiminopyrazoles and diazenes 16
1.3.1 The physicochemical properties of 5-amino-4-nitrosopyrazole 16
1.3.2 The physicochemical properties of diazene 18
1.4 The advantage of one-pot reaction 19
Chapter 2. Research Approach 20
Chapter 3. Results & Discussion 23
3.1 Synthesis of 1,2,4-triazoles from reactional of aldehydes or oxime with hydrazonoyl hydrochlorides via 1,3-dipolar cycloaddition reaction 23
3.1.1 Chemistry 23
3.1.2 Proposed mechanism 32
3.1.3 Biological Evaluation of 3,5-disubstituted 1,2,4-triazoles derivatives 33
3.2 Investigation of 1,2,4-triazoles from nitriles with hydrazonoyl hydrochlorides via 1,3-dipolar cycloaddition 37
3.3 Synthesis of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives via Aza-Diels–Alder reaction: evaluation of torsion effect of pyrazoylimines 42
3.4 Synthesis and structural identification of 5-amino-4-hydroxyiminopyrazoles and (E)-N1-aryl-3-aryl-4-[(substituted pyrazolyl)diazenyl] pyrazoles from 5-aminopyrazoles with ethyl nitrite or sodium nitrite. 50
Chapter 4. Conclusion 56
Chapter 5. Experimental Section 61
5.1 General Procedure 61
5.1.1 Material 61
5.1.2 Instrument 63
5.1.3 Investigation of 1,2,4-triazole using aldehydes, oxime, nitrile and imidate with hydrozonoyl hydrochloride 64
5.1.4 Investigation of Pyrazolo[3,4-b]pyrrolo[3,4-d]pyridines Using Pyrazoylimines with Various Amides and Maleimide 77
5.1.5 Synthesis diazenylpyrazole and 5-amino-4-hydroxyiminopyrazole by pyrazole 83
5.2Cell lines 89
5.3Growth inhibition assay 90
Reference 91
Appendix 99

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