利用金屬和非金屬催化劑合成具有生物活性之分子

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(1)SYNTHESIS OF BIOACTIVE MOLECULES BY METAL AND NON-METAL CATALYSIS. A Dissertation Submitted to the National Taiwan Normal University for the Degree of Doctor of Philosophy in Chemistry. Submitted by Donala Janreddy 898420145. Advisor Prof. Dr. Ching-Fa Yao. Department of Chemistry National Taiwan Normal University Taipei – 11677 TAIWAN, R.O.C. December 2013.

(2) TABLE OF CONTENTS Page Abbreviations. i-iv. Abstract. v-xi. Part-I Part-I, Section-A: Overview on “Indole Nucleus” Reactions I.A.1. Introduction to indole nucleus. 1. I.A.2. Indole synthesis. 2. I.A.3. Indole nucleus synthesis. 3. I.A.3.1. Indole nucleus from monofunctionalized arene precursors. 4. I.A.3.2. Indole nucleus from bifunctional arene precursors. 5. I.A.4. Recent advances in the synthesis of free N-H 2,3-disubstituted indole nucleus through cascade/tandem reactions (from bifunctional arene precursors). 6. I.A.5. References. 15. Part-I, Section-B: An Easy Access to Carbazolones and 2,3-Disubstituted Indoles I.B.1. Introduction. 21. I.B.2. Review of literature. 22. I.B.3. Results and discussion. 25. I.B.4. Conclusions. 32. I.B.5. Experimental section. 33. I.B.6. References. 41.

(3) Part-I, Section-C: The PdCl2-Catalyzed Sequential Heterocyclization/Michael Addition Cascade in the Synthesis of 2,3-Disubstituted Indoles I.C.1. Introduction. 44. I.C.2. Review of literature. 44. I.C.3. Results and discussion. 48. I.C.4. Conclusions. 59. I.C.5. Experimental section. 59. I.C.6. References. 69. Part-II Part-II, Section-A: Overview on 2-Aryl benzoxazoles and 1,2,3-Triazoles. II.A.1. Introduction to 2-aryl benzoxazole. 71. II.A.2. Benzoxazole synthesis. 72. II.A.2.1. 2-aryl benzoxazole synthesis. 72. II.A.2.2. Recent developments in the synthesis of 2-aryl benzoxazoles via transition-metal-catalyzed cyclization of ortho-haloanilides. 73. II.A.3. Overview on the synthesis of 1,2,3-triazoles. 78. II.A.3.1. Introduction to 1,2,3-triazoles. 78. II.A.3.2. 1,2,3-triazole synthesis. 78. II.A.3.3. Recent advances in the synthesis of 1,2,3-triazoles. 79. via azide- alkene cycloaddition II.A.4. References. 83. Part-II, Section-B: One-Pot Tandem Synthesis of 2-Aryl benzoxazole Derivatives via Copper-Catalyzed C–N and C–O Bond Formation II.B.1. Introduction. 87.

(4) II.B.2. Review of literature. 87. II.B.3. Results and discussion. 90. II.B.4. Conclusions. 100. II.B.5. Experimental section. 100. II.B.6. References. 113. Part-II,. Section-C:. Copper. (I)-Catalyzed. Aerobic. Oxidative. Azide–Alkene. Cycloaddition: An Efficient Synthesis of Substituted 1,2,3-Triazoles. II.C.1. Introduction. 115. II.C.2. Review of literature. 115. II.C.3. Results and discussion. 118. II.C.4. Conclusions. 124. II.C.5. Experimental section. 125. II.C.6. References. 135. Part-III. Part-III, Section-A: Overview on Naphthalenes. III.A.1. Introduction. 138. III.A.2. Naphthalene synthesis. 140. III.A.3. Recent advances in the synthesis of naphthalene derivatives from o-alkynyl-substituted carbonyl compounds. 141. III.A.4. References. 146.

(5) Part-III, Section-B: Molecular Iodine Mediated Regioselective Switching Reaction for the Construction of Naphthalenes and Iodo-Substituted Isochromenes from 2-(2phenylethynyl)-Morita-Baylis-Hillman Adducts III.B.1. Introduction. 149. III.B.2. Review of literature. 149. III.B.3. Results and discussion. 150. III.B.4. Conclusions. 161. III.B.5. Experimental section. 161. III.B.6. References. 169. Part-III,. Section-C:. PdCl2-Catalyzed. Aerobic. Oxidative. Intermolecular. [4+2]. Cycloaddition Reaction of 2-Alkynyl Benzaldehydes with Electron-Deficient Terminal Alkenes: An Efficient Synthesis of Naphthalenes. III.C.1. Introduction. 173. III.C.2. Review of literature. 174. III.C.3. Results and discussion. 175. III.C.4. Conclusions. 180. III.C.5. Experimental section. 181. III.C.6. References. 188. X-ray Crystallographic Data. 192. 1H. 206. and 13C NMR Spectral Copies. References. 374.

(6) Abbreviations Å. Angstrom. Ac2O. Acetic anhydride. AcOH. Acetic acid. AgNO3. Silver nitrate. AgOTf. Oxo(trifluoromethylsulfonyl)silver. AlCl3. Aluminium chloride. Ar. Aryl. aq.. Aqueous. B-H. Baylis-Hillman. BF3.Et2O. Boron trifluoride diethyl etherate. (R)-BINAP. 2,2'-bis(Dipenylphosphino)-1,1'-binaphthyl. Bn. Benzyl. Boc. Butyloxycarbonyl. Bu. Butyl. n-BuLi. n-Butyllithium. t-Bu. tert-Butyl. t-BuOH. tert-Butanol. br. Broad (IR). brs. Broad singlet (NMR). Bz. Benzoyl. o. C. Degree celsius. Cat.. Catalyst. CDCl3. Chloroform (deuterated). Cm. Centimeter. CH2ClCH2Cl. 1,2-Dichloroethane. CH3NO2. Nitromethane. Cs2CO3. Cesium carbonate. d. Doublet (NMR). d. Day(s). dd. Doublet of doublet. DABCO. 1,4-Diazabicyclo[2.2.2]octane i.

(7) DBU. 1,8-Diazabicyclo[5.4.0]undec-7-ene. DCE. 1,2-Dichloroethane. DCM. Methylene chloride. DEAD. Diethyl azodicarboxylate. DIEPA. N,N-Diisopropylethyl amine. DMF. N,N-Dimethylformamide. DMSO. Dimethyl sulfoxide. EI. Electron impact. Et. Ethyl. Et3N. Triethyl amine. EtOAc. Ethyl acetate. Et2O. Diethyl ether. EtOH. Ethanol. equiv.. Equivalent(s). FAB. Fast atom bombardment. Fe. Iron powder. FT. Fourier transform. H. Hour (s). hν. Irradiation with light. HBr. Hydrogen bromide. HCl. Hydrochloric acid. H2O. Water. HRMS. High resolution mass spectrometry. Hz. Hertz. IBX. o-Iodoxybenzoic acid. InBr3. Indium tribromide. iProAc. Isopropyl acetate. IR. Infrared spectrometry. KBr. Potassium bromide (IR). K2CO3. Potassium carbonate. KF. Potassium fluoride. KOH. Potassium hydroxide. LRMS. Low resolution mass spectrometry. M. Moles per liter ii.

(8) Me. Methyl. Me2NH. Dimethylamine. Me2SO4. Dimethyl sulfate. Mg. Milligram. MgSO4. Magnesium sulfate. MHz. Megahertz. Min. Minutes. mL. Milliliter(s). mmol. Millimole(s). MnO2. Manganese dioxide. mol. Mole(s). mp. Melting point. MS. Mass spectrometry. MVK. Methyl vinyl ketone. MW. Microwave. μL. Microliter (s). N. Equivalents per liter (Normality). NaCl. Sodium chloride. Na2CO3. Sodium carbonate. NaH. Sodium hydride. NaHCO3. Sodium bicarbonate. NBS. N-Bromosuccinimide. NCS. N-Chlorosuccinimide. NH4Cl. Ammonium chloride. NaIO4. Sodium periodate. NIS. N-Iodosuccinimide. NMM. N-Methylmorpholine. NMR. Nuclear magnetic resonance. NH2NH2. Hydrazine. NH4OAc. Ammonium acetate. Na2SO4. Sodium sulfate. Ni2B. Nickel boride. Nu. Nucleophile. OAc. Acetate iii.

(9) OsO4. Osmium tetroxide. Pd/C. Palladium over charcoal. Pd(PPh3)2Cl2. Bis(triphenylphosphine)palladium(II)dichloride. Pd(PPh3)4. Tetrakis(triphenylphosphine)palladium(0). Pd(OAc)2. Palladium(II)acetate. PdCl2. Palladium(II)chloride. Ph2CO. Benzophenone. Ph. Phenyl. ppm. Parts per million. q. Quartet (NMR). Rf. Retention factor. rt. Room temperature. s. Singlet (NMR). Sc(OTf)3. Scandium triflate. SiO2. Silicon dioxide. SN2. Substitution nucleophilic bimolecular. t. Triplet (NMR). TBAF. Tetrabutylammonium fluoride. TFA. Trifluoroacetic acid. TFAA. Trifluoroacetic anhydride. THF. Tetrahydrofuran. TLC. Thin layer chromatography. TMSN3. Trimethylsilyl azide. UV. Ultraviolet. Zn. Zinc powder. iv.

(10) ABSTRACT OF THE THESIS SYNTHESIS OF BIOACTIVE MOLECULES BY METAL AND NONMETAL CATALYSIS Keywords: Metal and non-metal, naphthalenes, indole nucleus, 1,2,3-triazoles. The content of this dissertation is divided into three parts. The part I is subdivided into three sections. Section A, illustrate the overview, classification and synthetic approaches on ‘indole nucleus’ reactions and related literature review. Section B demonstrate the ‘An Easy Access to Carbazolones and 2,3-Disubstituted Indoles’ by a Fe/AcOH-mediated intramolecular reductive N-heteroannulation of 3-hydroxy-2-(2-nitrophenyl)enones. Section C, describes the synthesis of ‘2,3-disubstituted indoles’ via cascade reaction of 2-N-unprotected-2-alkynylanilines and various electron-deﬁcient alkenes in the presence of PdCl2. Part II deals with the synthesis of 2-aryl benzoxazole derivatives and 1,2,3-triazoles by using transition metal catalyzed reactions. Part II is subdivided into three sections. Section A, deals with overview, classification and synthetic approaches of 2-aryl benzoxazole derivatives. This section also describe the overview on 1,2,3- triazole derivatives, classification and synthetic approaches from azide and alkenes. Section B, represents an efficient synthesis of 2-aryl benzoxazole derivatives having an amine or amide functionality in the aryl group at the ortho position via Copper-catalyzed tandem C–N and C–O bond formation. Section C, deals with the novel synthesis of substituted 1,2,3-triazoles via Copper(I)-catalyzed aerobic oxidative azide– alkene cycloaddition. Part III deals with the synthesis of naphthalene by using non-metal, transition metal catalyzed reactions and their application towards diversity oriented synthesis. Part III is subdivided into three sections. Section A, deals with overview and synthetic approaches towards naphthalene derivatives. Section B, describes an efficient synthesis of naphthalenes and iodo-substituted isochromene derivatives via reaction of 2-(2-phenylethynyl)-Morita-Baylis-Hillman adducts using molecular iodine. The resulting iodo-substituted-derivatives utilized to couple with a array of boronic acid (Suzuki coupling), activated alkene (Heck coupling) and alkyne (Sonogashira reaction). Section C, demonstrates an efficient synthesis of naphthalenes via PdCl2-catalyzed. aerobic. oxidative. intermolecular. benzaldehydes and electron-deficient terminal alkenes. v. cycloaddition. between. 2-alkenyl.

(11) PART-I Part-I, Section-A: Overview on “Indole Nucleus” reactions This section describes the overview, classification and synthetic approaches of “indole nucleus”. This section also involves the literature survey of the “2,3-disubstituted indole derivative” reactions through cascade/tandem process.. Part-I, Section-B: An Easy Access to Carbazolones and 2,3-Disubstituted Indoles This section disclose a simple and efficient synthetic protocol for the synthesis of library of carbazol-4-ones, 3,4-dihydrocyclopental-indol-1-one, indeno-indole and 2,3-disubstituted indole derivatives via Fe/AcOH-mediated N-heteroannulation. In addition, this approach enables easy access to indolocarbazolone and indoloquinolinone derivatives. Furthermore, the conventional Fe/AcOH system is much more cost effective than existing methods involving transition metals. Hence, short reaction time, high yield, economical viability, and the ready availability and accessibility of starting materials are salient features of this method. Furthermore, this method is also applicable to the synthesis of indolocarbazolone derivatives and the natural product precursor of cryptosanguinolentine.. Scheme 1. Synthesis of carbazol-4-ones, 3,4-dihydrocyclopental-indol-1-one and 2,3disubstituted indole derivatives via Fe/AcOH-mediated N-heteroannulation.. vi.

(12) Scheme 2. Synthesis of indeno-indole derivatives from 3-hydroxy-2-(2-nitrophenyl)-1Hinden-1-one derivatives.. Part-I, Section-C: The PdCl2-Catalyzed Sequential Heterocyclization/Michael Addition Cascade in the Synthesis of 2,3-Disubstituted Indoles. This section describes a simple and facile protocol on cascade reaction of 2-N-unprotected-2alkynylanilines and various electron-deficient alkenes using PdCl2 and Pd(OAc)2/LiCl catalytic systems. The presence of catalytic PdCl2 produces 2,3-disubstituted indole derivatives whereas in the presence of Pd(OAc)2/LiCl catalytic system produces N-alkylated-2alkynylaniline derivatives. The mechanism for the formation of 2,3-disubstituted indole derivatives is explained based on experimental outcome. This method offers a mild and easy method to access a variety of 2,3-disubstituted indole derivatives in moderate to good yields. Furthermore, a variety of functional groups readily tolerated under the reaction conditions employed.. Scheme 3. Synthesis of 2,3-disubstituted indole derivatives and N-alkylated-2-alkynylaniline derivatives via cascade reaction.. PART-II Part-II, Section-A: Overview on 2-Aryl benzoxazoles and 1,2,3-Triazoles The section deals with overview, classification and importance of 2-aryl benzoxazoles and 1,2,3-triazoles. This section also involves the literature survey for the synthesis 2arylbenzoxazoles and 1,2,3-triazoles. vii.

(13) Part-II, Section-B: One-Pot Tandem Synthesis of 2-Aryl benzoxazole Derivatives via Copper-Catalyzed C–N and C–O Bond Formation This section describes a practical and efficient synthesis of 2-aryl benzoxazole derivatives having an amine or amide functionality in the aryl group at the ortho position through a coppercatalyzed tandem C–N/C–O coupling strategy using readily available substrates. A wide range of nitrogen nucleophiles was investigated in this protocol, which can be used to produce a variety of 2-aryl benzoxazole derivatives in moderate to good yields. This method is simple, handy and most of the reactions were performed under ligand-free conditions.. Scheme 4. Synthesis of 2-arylbenzoxazole derivatives via copper-catalyzed tandem C–N/C– O coupling.. Part-II, Section-C: Copper (I)-Catalyzed Aerobic Oxidative Azide–Alkene Cycloaddition: An Efficient Synthesis of Substituted 1,2,3-Triazoles This section disclose a novel, copper (I)-promoted azide–alkene aerobic oxidative cycloaddition protocol for the regioselective synthesis of 1,4-disubstituted/1,4,5-trisubstituted 1,2,3-triazoles by using azides and various electron-deficient olefins under an oxygen atmosphere. The mechanism for the formation of 1,2,3-triazole derivatives is explained based on experimental results. A wide range of terminal and internal electron-deficient alkenes and azides were used in this reaction, which can be produces substituted 1,2,3-triazole derivatives viii.

(14) in moderate-to-excellent yields. This method is an easy and convenient alternative to the existing methodologies for the synthesis of substituted 1,2,3-triazole derivatives.. Scheme 5. Synthesis of 1,4-disubstituted/1,4,5-trisubstituted 1,2,3-triazoles via copper(I)promoted azide–alkene aerobic oxidative cycloaddition.. PART-III Part-III, Section-A: Overview on Naphthalenes The section describes the overview, importance and synthetic approaches of naphthalene derivatives. This section also include the literature survey for the synthesis of naphthalene derivatives from 2-alkynylbenzaldehyde.. Part-III, Section-B: Molecular Iodine Mediated Regioselective Switching Reaction for the Construction of Naphthalenes and Iodo-Substituted Isochromenes from 2-(2-phenylethynyl)-Morita-Baylis-Hillman Adducts This section demonstrates a synthetic methodology for the construction of naphthyl ketones and iodo-substituted isochromene derivatives via iodine mediated regioselective switching reaction of 2-(2-phenylethynyl)-Morita-Baylis-Hillman adducts. In the presence of molecular iodine afford the formation of naphthalene derivatives whereas in the presence of I2/K3PO4 system, produces the iodo-substituted 1H-isochromene and 1,3-dihydroisobenzofuran derivatives. The possible mechanisms for this reaction were proposed based on the experimental outcome. This protocol offers a mild and easy access to variety of substituted naphthalene derivatives and 1H-isochromene derivatives in moderate-to-good yields.. ix.

(15) Scheme 6. Outline of the synthetic route to naphthalene and iodo-substituted isochromene derivatives.. Part-III, Section-C: PdCl2-Catalyzed Aerobic Oxidative Intermolecular [4+2] Cycloaddition Reaction of 2-Alkynyl Benzaldehydes with Electrondeficient Terminal Alkenes: An Efficient Synthesis of Naphthalenes This section describes a simple and efficient synthetic protocol for the synthesis of library of naphthyl ketone derivatives through PdCl2-catalyzed aerobic oxidative intermolecular [4+2] cycloaddition reaction of 2-alkenyl benzaldehydes to electron-deficient alkenes. This method involves the intermolecular [4+2] cycloaddition of 2-alkynyl benzaldehydes to alkenes followed by aerobic oxidative aromatization in tandem process and the mechanism was proposed based on experimental results. The mild reaction conditions, good functional group tolerance, and broad range of naphthalene derivatives are salient features of this protocol.. Scheme 7. Synthesis of naphthyl ketone derivatives through tandem PdCl2-catalyzed aerobic oxidative intermolecular [4+2] cycloaddition reaction of 2-alkenyl benzaldehydes to electrondeficient terminal alkenes.. x.

(16) 中文摘要利用金屬和非金屬催化劑合成具有生物活性之分子. 關鍵字: 金屬及非金屬, 萘, 吲哚環, 1,2,3-三唑.. 本論文的內容被分為三個章節，第一章節可被細分為三個部分，A部分主要是對於吲哚(indole)環的反應進行概述、分類及合成方法和相關文獻的說明。B部分的標題為「 Carbazolones和2,3-disubstituted Indoles的簡易方法」，內容是介紹一個利用Fe/AcOH催化分子內還原3-hydroxy-2-(2-nitrophenyl)enones的含氮雜環化反應。C部分介紹2,3disubstituted Indole在PdCl2催化下進行2-N-unprotected-2-alkynylanilines和多樣缺電子烯類的級聯反應(cascade reaction)。. 第二章節介紹利用過渡金屬催化2-arylbenzoxazole衍生物和1,2,3-triazoles的合成。第二章節可被細分為三個部分，A部分主要是對於2-arylbenzoxazole衍生物進行概述、分類及合成方法的說明。此部分也對1,2,3-triazoles衍生物進行概述、分類及以azide和 alkenes合成的方法說明。B部分介紹透過銅催化C-N和C-O鍵形成級聯反應，使2arylbenzoxazole衍生物在芳香基團的鄰位上有胺或醯胺官能基的有效合成方法。C部分介紹一個新穎方法為透過銅催化在有氧環境下進行azide-alkene的氧化環加成反應。. 第三章節介紹利用非金屬、過渡金屬催化合成naphthalene及其多元性導向的應用。第三章節可被細分為三個部分。A部分是naphthalene衍生物的概論及其合成方法。B部分描述一個有效率利用碘分子和2-(2-phenylethynyl)-Morita-Baylis-Hillman催化 naphthalenes和iodo-substituted isochromene衍生物的合成。而iodo-substituted-derivatives 則可以用來進行一連串的耦合反應如用硼酸、活化烯類、炔類分別可進行Suzuki coupling、Heck. reaction。C部分介紹一個以PdCl2催化2-. coupling、Sonogashira. alkenylbenzaldehydes和缺電子烯類在有氧環境下分子間氧化環加成來合成naphthalenes 的的有效路徑。. xi.

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