COUPLING OF 2-ARYL-4-CHLORO-3-IODOQUINOLINE DERIVATIVES WITH TERMINAL

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1 Student number: I declare that REGIOSELECTIVITY OF PALLADIUM-CATALYZED SONOGASHIRA CROSS- COUPLING OF 2-ARYL-4-CHLORO-3-IODOQUINOLINE DERIVATIVES WITH TERMINAL ALKYNES is my own work and that all the sources that I have used or quoted have been indicated and acknowledged by means of complete references. SIGNATURE DATE (MS H.R MAKELANE) i

2 This thesis is dedicated to my mother, N. E Machimane and my sister, T. H Nkuna ii

3 ACKNOWLEDGEMENTS The work presented in this thesis would not have been possible without the assistance of a number of people and institutions. I would like to give thanks to the following: To my supervisor Prof M.J Mphahlele for his support, guidance, and encouragement throughout this project. The University of South Africa and the National Research Foundation (NRF) for financial support. The Phalabora Foundation and PROTEC for financial assistance, motivation and support. My colleagues, friends and family for their support and motivation. My parents and my sister for their extraordinary encouragement, guidance and support throughout my studies. Above all, to the almighty God be the glory. iii

4 ABSTRACT Sonogashira cross-coupling of 2-aryl-4-chloro-3-iodoquinoline derivatives with stoichiometric amount of terminal alkynes in the presence of bis(triphenylphosphine)palladium(ii)chloride and copper iodide in triethylamine afforded the 3-(alkynyl)-2-aryl-4-chloroquinoline, exclusively. On the other hand, the 2-aryl-4-chloro-3-iodoquinolines with excess (2.5 equiv.) of terminal alkynes in the presence of PdCl 2 (PPh 3 ) 2 -CuI catalyst mixture and NEt 3 in dioxane-water (3:1 v/v) afforded the 2-aryl-3,4-bis(alkynyl)quinoline derivatives in a one-step operation. Further transformation of the 2-aryl-3-(alkynyl)-4-chloroquinoline via Suzuki cross-coupling reaction with boronic acid derivatives in the presence of tetrakis(triphenylphosphine)palladium and tricyclohexylphosphine as a ligand in dioxane-water (3:1 v/v) afforded the 2,4-diaryl-3- (alkynyl)quinolines in moderate to high yields. The 2-aryl-3-(alkynyl)-4-chloroquinolines were also transformed to the corresponding 2-aryl-4-(methylamino)-3-(alkynyl)quinoline derivatives using methylamine in ethanol under reflux. Keywords: 2-aryl-4-chloro-3-iodoquinoline, Sonogashira cross-coupling reaction, Suzuki crosscoupling reaction, amination, 2,3,4-trisubstituted quinolines iv

5 TABLE OF CONTENT Declaration Dedication Acknowledgements Abstract i ii iii iv CHAPTER 1: INTRODUCTION 1.1 Background Natural distribution of polysubstituted quinolines and their biological applications Known synthetic methods for the preparation of polysubstituted quinoline derivatives Classical methods for the direct synthesis of polysubstituted quinoline Skraup synthesis of quinolines Friedlander synthesis of substituted quinolines Doebner-von Miller synthesis of quinolines Combes synthesis of quinolines Indirect methods for the synthesis of polysubstituted quinolines Cyclization methods Quinolinols or 4-quinolones as precursors Methods involving 4-haloquinolines or tosylquinoline derivatives Application of organometallic reagents in the synthesis of polysubstituted quinolines Application of Stille coupling in quinoline synthesis Application of Negishi coupling in quinoline synthesis Application of Hiyama coupling in quinoline synthesis Application of Heck coupling in quinoline synthesis Application of Suzuki coupling in quinoline synthesis Application of Sonogashira coupling in quinoline synthesis Structure-activity relationship of 2,3,4-trisubstituted quinoline derivatives Research problem and hypothesis Aims and objectives of this investigation 32 v

6 CHAPTER 2: RESULTS AND DISCUSSION 2.1 Synthesis of substrates Synthesis of N-benzoyl-2-aminoacetophenone derivatives Synthesis of 2-arylquinoline-4(H)-one derivatives Synthesis of 2-aryl-3-iodoquin-4(H)-one derivatives Synthesis of 2-aryl-4-chloro-3-iodoquinoline derivatives Regioselective synthesis of 2-aryl-4-chloro-3-(alkynyl)quinoline derivatives One-pot synthesis of 2-aryl-3,4-bis(alkynyl)quinoline derivatives Suzuki cross-coupling of 2-aryl-4-chloro-3-(alkynyl)quinoline derivatives Amination of 2-aryl-4-chloro-3-(alkynyl)quinoline derivatives 57 CHAPTER 3: CONCLUSIONS 60 CHAPTER 4: EXPRERIMENTAL 4.1 General Preparation of N-benzoyl-2-aminoacetophenone derivatives Preparation of 2-arylquinolin-4(1H)-one derivatives Preparation of 2-aryl-3-iodoquinolon-(1H)-one derivatives Preparation of 2-aryl-4-chloro-3-iodoquinoline derivatives Preparation of 2-aryl-4-chloro-3-(alkynyl)quinoline derivatives Preparation of 2-aryl-3,4-bis(alkynyl)quinoline derivatives Preparation of Suzuki cross-coupling of 2-aryl-4-chloro-3-(alkynyl)quinoline derivatives Preparation of 2-aryl-4-(methylamino)-3-(alkynyl)quinoline derivatives X-ray crystal structure solution and refinement 91 CHAPTER 5: REFERENCES 93 APPENDIX Selected Mass Spectra 98 X-Ray Crystallographic Data 100 vi