Palladium–catalyzed Sonogashira Synthesis of Mono- And Bisalkynylated Derivatives of Quinoline-5,8-dione and their Antimicrobial Activity
Palladium–catalyzed 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, 1 H 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 CONTENT
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
INTRODUCTION
The chemistry of quinoline-5,8-dione as a functionality is a developing field because of its various biological activities.
Quinoline-5,8-dione 1, the parent functionality of a large number of medicinal compounds have been of great interest to drug researchers due to its biological functions as antifungal, antibacterial, antiparasitic and antitumor agents.
Streptonigrin and Lavendamycin are known antibiotic, antitumor agents containing the quinoline-5,8-dione functional group.
Since the discovery of the parent compound, many structural modifications have been carried out in search of compounds with improved biological activities. Thus, subsequent variations in the parent structure have given rise to a large number of derivatives of medicinal interest.
Substituted quinoline-5,8-diones are useful antifungicides and antibactericides whereas some of the polynuclear quinones built on the dihaloquinoline quinine scaffold are useful tuberculostatic and cytostatic substances.
A number of alkylene-imino quinones have been prepared which are capable of inhibiting the growth of tumor nuclei. Some hydroxyl and amino-quinoline-quinones possess marked amoebicidal activity. Padwa’s group reported the synthesis of quinoline-5,8-dione analogues 2 and 3 using two different methods.
The first method used 7-aminoquinolinediones directly as coupling partners to synthesize compound. The second method looked at synthesizing the quinoline-5,8- dione after the cross-coupling step to obtain compound.
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CSN Team.
