UNIVERSITÀ DEGLI STUDI DELL’INSUBRIA Dipartimento di Scienza e Alta Tecnologia Dottorato di Ricerca in Scienze Chimiche – XXVI ciclo SYNTHESIS AND FUNCTIONALIZATION OF INDOLE SKELETON COMPOUNDS VIA NITROSOARENE-ALKYNE CYCLOADDITIONS Supervisor : Dr. Andrea PENONI Co-supervisor : Prof. Giovanni PALMISANO Ph.D. dissertation by GABRIELLA IERONIMO Index GENERAL INTRODUCTION ..................................................................................................................... 7 1 INDOLES ...................................................................................................................................... 9 2 REFERENCES ........................................................................................................................... 12 CHAPTER 1 – INDOLE SYNTHESES..................................................................................................... 15 1 INTRODUCTION .............................................................................................................................. 17 1.1 Disconnection “a” .................................................................................................................... 17 1.1.1 Fischer Indole Synthesis ............................................................................................................. 18 1.1.2 Bailey-Liebeskind Indole Synthesis ............................................................................................. 21 1.1.3 Bischler-Möhlau Indole Synthesis ................................................................................................ 21 1.1.4 Gassman Indole and Oxindole Synthesis .................................................................................... 22 1.1.5 Murphy Indole Synthesis ............................................................................................................. 23 1.2 Disconnection “b” .................................................................................................................... 24 1.2.1 Madelung Indole Synthesis ......................................................................................................... 24 1.2.2 Fürstner Indole Synthesis ............................................................................................................ 25 1.2.3 Saegusa Indole Synthesis ........................................................................................................... 27 1.2.4 Wender Indole Synthesis ............................................................................................................ 28 1.3 Disconnection “c” .................................................................................................................... 29 1.3.1 Bartoli Indole Synthesis ............................................................................................................... 29 1.3.2 Cadogan-Sundberg Indole Synthesis .......................................................................................... 31 1.3.3 Castro Indole Synthesis .............................................................................................................. 32 1.3.4 Engler Indole Synthesis............................................................................................................... 33 1.3.5 Hegedus Indole Synthesis ........................................................................................................... 33 1.3.6 Larock Indole Synthesis .............................................................................................................. 35 1.3.7 Cacchi Indole Synthesis .............................................................................................................. 36 1.3.8 Leimgruber-Batcho Indole Synthesis ........................................................................................... 37 1.3.9 Makosza Indole Synthesis ........................................................................................................... 37 1.3.10 Reissert Indole Synthesis ............................................................................................................ 39 1.4 Disconnection “d” .................................................................................................................... 40 1.4.1 Hemetsberger Indole Synthesis ................................................................................................... 40 1.4.2 Nenitzescu Indole Synthesis ....................................................................................................... 41 1.5 Syntheses of N-hydroxy indoles.............................................................................................. 42 1.5.1 Acheson Synthesis ..................................................................................................................... 42 1.5.2 Somei Syntheses ........................................................................................................................ 43 1.5.3 Wong Synthesis .......................................................................................................................... 45 1.5.4 Nicolaou Synthesis ..................................................................................................................... 45 1.5.5 Wojciechowski Synthesis ............................................................................................................ 46 1.5.6 Zhao Synthesis of N-alkoxyindoles .............................................................................................. 46 1.6 References ............................................................................................................................. 48 CHAPTER 2 – RESULTS AND DISCUSSION ........................................................................................ 53 2 BACKGROUND : NITROSO COMPOUNDS AND ALKYNES AS STARTING MATERIALS .................................. 55 3 Index 2.1 From nitro- to nitrosoaromatics ............................................................................................... 55 2.2 Synthesis of 3-arylindoles ....................................................................................................... 58 2.2.1 Synthesis of nitrosoarenes .......................................................................................................... 58 2.2.2 Synthesis of arylalkynes .............................................................................................................. 59 2.2.3 Synthesis of 3-arylindoles under alkylating conditions .................................................................. 60 2.2.4 Synthesis of polycyclic compounds ............................................................................................. 62 2.3 Synthesis of 3-aroylindoles ..................................................................................................... 64 2.3.1 Synthesis of aroylalkynes ............................................................................................................ 65 2.3.2 Synthesis of 3-aroylindoles from arylalkynones............................................................................ 69 2.3.3 Synthesis of 3-aroylindoles from more complex aromatic alkynones ............................................ 72 2.4 References ............................................................................................................................. 77 CHAPTER 3 : CONCLUSIONS ............................................................................................................... 81 3 CONCLUSIONS .............................................................................................................................. 83 3.1 References ............................................................................................................................. 85 CHAPTER 4 : EXPERIMENTAL SECTION ............................................................................................. 87 4.1 Synthesis of nitrosoarenes ...................................................................................................... 90 4.2 Synthesis of 3-arylindoles ....................................................................................................... 91 4.2.1 Synthesis of alkynes ................................................................................................................... 92 4.2.2 Synthesis of 3-arylindoles ........................................................................................................... 93 4.2.3 Synthesis of polycyclic compounds ............................................................................................. 96 4.3 Synthesis of 3-aroylindoles ..................................................................................................... 98 4.3.1 Synthesis of alkynones................................................................................................................ 98 4.3.2 Synthesis of propargylamides.................................................................................................... 106 4.3.3 Synthesis of 3-aroylindoles........................................................................................................ 107 4.4 References ........................................................................................................................... 120 4 List of abbreviations List of abbreviations Me methyl Ar aryl (substituted aromatic ring MeOH methanol aq aqueous MS mass spectrometry Bn benzyl NMR nuclear