PalladiumCatalyzed Sonogashira Synthesis of Mono- and Bisalkynylated Derivatives of Quinoline-5,8-Dione and their Antimicrobial Activity

ABSTRACT

The synthesis of five mono- and five bis-alkynylated derivatives of quinoline-5,8-diones is reported. The intermediate 6,7-dibromoquinoline-5,8-dione was obtained by nitrosation of 8- hydroxyquinoline, followed by reduction and subsequent bromination and oxidation. The coupling reaction of 6,7-dibromoquinoline-5,8-dione via palladium-catalyzed Sonogashira cross-coupling gave the alkynylated products. The chemical structures of the products were confirmed using spectroscopic methods which include UV-visible spectrophotometry, Fourier Transform-Infrared (FT-IR) spectroscopy, 1H and 13C-NMR spectroscopy. The antimicrobial properties of the synthesized products were determined on Escherichia Coli 1, Escherichia Coli 12, Klebsiella Pneumonia, Pseudomonas aeruoginosa and Staphylococcus aureus using the agar-diffusion method. Results showed significant improvement in antibacterial activities compared with ampicillin and gentamycin.

Table of Contents.

Title Page ----------------------------------------------------------------------------------------------- i

Approval page----------------------------------------------------------------------------------------------- ii

Certification------------------------------------------------------------------------------------------------ iii

Dedication--------------------------------------------------------------------------------------------------- iv

Acknowledgement----------------------------------------------------------------------------------------- v

Abstract----------------------------------------------------------------------------------------------------- vi

Table of Contents------------------------------------------------------------------------------------------ vii

List of Abbreviations ------------------------------------------------------------------------------------- x

List of Tables ---------------------------------------------------------------------------------------------- xi

List of figures --------------------------------------------------------------------------------------------- xii

Chapter One: Introduction

1.0: Background of Study ------------------------------------------------------------------------------- 1

1.1: Tandem Catalysis ------------------------------------------------------------------------------------ 5

1.2: Sonogashira Cross-Coupling Reaction ----------------------------------------------------------- 6

1.3: Statement of Problem. ------------------------------------------------------------------------------ 7

1.4: Objectives of Study. ------------------------------------------------------------------------------ 7

1.5: Justification of Study ------------------------------------------------------------------------------ 9

Chapter Two: Literature Review.

2.0: Sonogashira Cross-Coupling Reactions. ---------------------------------------------------------- 10

2.1: Mechanism of Sonogashira Cross-Coupling Reaction. ----------------------------------------- 11

2.1.1: General Mechanism of Sonogashira Cross-Coupling Reaction. ---------------------------- 11

2.1.2: General Mechanism for Copper-free Sonogashira Cross-Coupling Reaction. ----------- 13

2.1.3: Limitation of Sonogashira Reaction. --------------------------------------------------------- 15

2.1.4: Mono-alkynylated Derivatives under Copper and Solvent Conditions. --------------------- 17

2.1.5: Mono-alkynylated Derivatives under Copper-free Conditions. -------------------------------- 25

2.1.6: Mono-alkynylated Derivatives under Copper-, Amine-, and Solvent-free Conditions. ----- 27

2.1.7: Bis-alkynylated Compounds. ---------------------------------------------------------------------- 28

2.1.8: Quinoline-5,8-dione Analogues. ------------------------------------------------------------- 34

Chapter Three: Experimental Section.

3.0: General ------------------------------------------------------------------------------ 40

3.1: Synthesis of key intermediates ------------------------------------------------------------ 40

3.1.1: 5-nitroso-8-hydroxyquinoline hydrochloride ------------------------------------------------- 40

3.1.2: 5-Amino-8-hydroxyquinoline hydrochloride -------------------------------------------------- 41

3.1.3: 6,7-dibromoquinoline-5,8-dione. ------------------------------------------------------------------ 42

3.2: General Procedure for the preparation of mono-alkynylated derivatives of 6,7-dibromoquinoline-5,8-diones. ---------------------------------------------------- 43

3.2.1: 7-Bromo-6-(3-hydroxyprop-1-yn-1-yl) quinoline-5,8-dione --------------------------------- 43

3.2.2: 7-Bromo-6-(3-hydroxy-3-methyl-but-1-yn-1-yl) quinoline-5,8-dione ------------------- 43

3.2.3: 7-Bromo-6-(Phenyl ethynyl) quinoline-5,8-dione. ------------------------------------------- 44

3.2.4: 7-Bromo-6-(Oct-1-yn-1-yl) quinoline-5,8-dione. ------------------------------------------- 44

3.2.5: 7-Bromo-6-(hex-1-yn-yl) quinoline-5,8-dione. ----------------------------------------------- 44

3.3: General Procedure for the preparation of Bis-alkynylated derivatives of 6,7-dibromoquinoline-5,8-diones. ---------------------------------------------- 45

3.3.1: 6,7-bis-(3-hydroxyprop-1-yn-1-yl) quinoline-5,8-dione. ----------------------------------- 45

3.3.2: 6,7-bis-(3-hydroxy-3-methyl-but-1-yn-1-yl) quinoline-5,8-dione. --------------------- 45

3.3.3: 6,7-bis-(Phenyl ethynyl) quinoline-5,8-dione. ------------------------------------------- 46

3.3.4: 6,7-bis-(oct-1-yn-1-yl) quinoline-5,8-dione. --------------------------------------------- 46

3.3.5: 6,7-bis-(hex-1-yn-yl) quinoline-5,8-dione. ------------------------------------------------ 46

3.4: Antimicrobial Activity. --------------------------------------------------------------------- 47

3.4.1: Sensitivity Testing of Compounds. ------------------------------------------------------- 47

3.4.2: Minimum Inhibitory Concentration (MIC) Testing of Compounds. ------------------- 48

Chapter Four:

4.0 Results and Discussion. ------------------------------------------------------------------------- 49

4.1: 5-nitroso-8-hydroxyquinoline hydrochloride --------------------------------------------- 50

4.2: 5-Amino-8-hydroxyquinoline hydrochloride --------------------------------------------- 51

4.3: 6,7-dibromoquinoline-5,8-dione. --------------------------------------------------- 53

4.4: Palladium Catalyzed Synthesis of mono-and bis-alkynylated derivatives of 6,7-dibromoquinoline-5,8-diones (131E1-5 and 132E1-5).---------------- 55

4.4.1: 7-Bromo-6-(3-hydroxyprop-1-yn-1-yl) quinoline-5,8-dione. -------------------------- 55

4.4.2: 7-Bromo-6-(3-hydroxy-3-methyl-but-1-yn-1-yl) quinoline-5,8-dione. ---------------- 56

4.4.3: 7-Bromo-6-(Phenyl ethynyl) quinoline-5,8-dione. ----------------------------------- 57

4.4.4: 7-Bromo-6-(Oct-1-yn-1-yl) quinoline-5,8-dione. ----------------------------------- 58

4.4.5: 7-Bromo-6-(hex-1-yn-yl) quinoline-5,8-dione. ----------------------------------- 59

4.4.6: 6,7-bis-(3-hydroxyprop-1-yn-1-yl) quinoline-5,8-dione. --------------------------------- 60

4.4.7: 6,7-bis-(3-hydroxy-3-methyl-but-1-yn-1-yl) quinoline-5,8-dione. -------------------- 61

4.4.8: 6,7-bis-(Phenyl ethynyl) quinoline-5,8-dione. -------------------------------------------- 62

4.4.9: 6,7-bis-(oct-1-yn-1-yl) quinoline-5,8-dione. --------------------------------------------- 63

4.4.10: 6,7-bis-(hex-1-yn-yl) quinoline-5,8-dione. --------------------------------------------- 64

4.5: The Cross Mechanistic Features. ----------------------------------------------------------- 65

4.6: Antimicrobial Activity Evaluation. -------------------------------------------------------- 69

4.6.1: Results of Sensitivity testing of compounds. -------------------------------------------- 70

4.6.2: Results of Inhibition Zone Diameter (IZD). ---------------------------------------------- 71

4.6.3: Results of Minimum Inhibitory Concentration (MIC). --------------------------------- 72

4.6.4: Conclusion. ---------------------------------------------------------------------------------- 76

References ------------------------------------------------------------------------------------------ 77