Palladium–catalyzed sonogashira synthesis of mono- and bisalkynylated derivatives of quinoline-5,8-dione and their antimicrobial activity
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
: Introduction1.0: 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
viii
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
ix
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
x
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
Thesis 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.
Thesis Overview
1.0: INTRODUCTION
1.0: Background of Study
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 agents1. Streptonigrin and
Lavendamycin are known antibiotic, antitumor agents containing the quinoline-5,8-dione
functional group1
N
O
O
1
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 substances2. A number of alkylene-imino quinones have been
prepared which are capable of inhibiting the growth of tumor nuclei3. Some hydroxyl and
amino-quinoline-quinones posses marked amoebicidal activity4.
2
Padwa’s group5 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 2. The second method looked at synthesizing the quinoline-5,8-
dione after the cross coupling step to obtain compound 3. The synthesis is very similar to the
method Behforouz had published in 19971.
N
O
O
H2N Cl N
O
O
ACHN
N
CH3 3
2
The importance of the quinoline-5,8-dione prompted Behforouz1 to report the synthesis
of the analogue 4.
N CH3
O
O
H2N
4
Also in the year 1984, Kende and Ebetion6 reported the synthesis of lavendamycin methyl
ester 5, another analogue of quinoline-5,8-dione in a total of nine steps with an overall yield of
2%.
3
In 2010, Behforouz7, reported a study of the biological activities on the quinoline-5,8-diones
analogues 6. The compounds were synthesized through Pictet-Spendgler condensation of
quinolinedione aldehydes with trypophans.
HN
N
N
O
O
R1HN
R2
COR3
R4
R5
6
(R1 =CH3CO, CH3 (CH2)2, HCO, etc. R2 = H, Cl; R3 = OCH3, NH2, N[(CH2CH2)2]. R4 = H,
CH3. R5 = H, OH).
Padwa5 reported the synthesis of another new quinolinequinone derivative 7 from 8-hydroxytetra-
azole [1, 5-a] quinoline.
HN
N
N
O
O
CO2CH3 H2N
CH3
5
4
As a further variation in the structure of quinoline-5,8-dione in an effort to synthesize
new antifungal drugs, Chung12 synthesized new quinolinequinones with substitution at C-6 and
C-7 as represented as structures 8, 9, 10 and 11.
N
NH
X
O
O
R1
R2
R3 N
NH
SCH3
O
O
R1
R2
R3
N
NH
O
O
R1
R2
R3 SCN
N
O
O
X
S
R4
8 9
10
11
( R1 R2, R3 are the same or different and a halogen atom, or aceto group and R4 is C-1 to C-20
alkyl groups and X = a halogen atom8 ).
Among all the prepared quinolinequinones only 6,7-dichloro, 12 and 6,7-dibromo- 13
derivatives derived from the highly antibacterial 8-hydroxyquinoline 142 have been found to
possess antimicrobial activities comparable with those of 2,3-dichloro-1,4-naphthoquinoline 159.
N
O
O
Br N3
7
5
N
Cl
Cl
O
O
N
O
O
Br
Br N
OH
O
O
Cl
Cl
12 13 14
15
1.1: TANDEM CATALYSIS
The term tandem catalysis represents processes in which “the sequential transformation of
the substrate occurs via two (or more) mechanistically distinct processes”10. There are three types
of tandem catalysis namely:
(a) Orthogonal tandem catalysis: In this type of tandem catalysis, there are two or more
mechanistically distinct transformations, two or more functionally and ideally non-interfering
catalysts and all catalysts present from the outset of the reaction.
(b) Auto-tandem catalysis: Here, there are two or more mechanistically distinct transformations
which occur via a single catalyst precursor; both catalytic cycles occur spontaneously and there
is cooperative interaction of all species present at the outset of the reaction.
(c) Assisted tandem catalysis: In this type, two or more mechanistically distinct transformations
are promoted by a single catalytic species and the addition of a reagent is needed to trigger a
change in catalyst function10.
Transition metal catalyzed reactions are probably the most important area in organometallic
chemistry11. Interestingly, palladium catalyzed processes are the vastly applied process. It
typically utilizes only 1-5mol% of the catalyst12. The catalytic system is generally composed of a
6
metal and a ligand11. For most reactions, the active catalyst is the zerovalent metal, that is Pd(0)
and can be added as such, as a stable complex such as tetrakis(triphenylphosphine) Pd(PPh3)3
13.
On the other hand, a Pd(ll) pre-catalyst such as palladium acetate, together with a ligand (or
as a pre-formed catalyst) can be used and has the benefit of better stability for storage14. An
initial step, reduction of Pd(ll) to Pd(0), is required before the catalytic cycle can start15. This
reduction is usually brought about by a component of the reaction as shown below, but
sometimes separate reducing agents such as DIBAH can be used16.
PdX2 + Ph3P +H2O Pd(0)+ Ph3PO +2HX
X= halide. M= any metal, R= any type of organic moiety.
The ligand is the main variable in the catalyst system. Phosphines can be varied in steric
bulk or in their donor strength, increasing in the electron density on the metal and thus, the
reactivity of the catalyst to less reactive substrate such as chlorides. Steric bulk decreases the
number of ligands that can coordinate to the metal atom, thereby increasing its reactivity by
accelerating reductive elimination11.
1.2: Sonogashira Cross-coupling reaction
Carbon-carbon bond formation is a very important reaction in organic synthesis. The array
of transition-metal-catalyzed cross-coupling reactions can easily be considered nowadays
cornerstones in the field of organic synthesis17, 18, 19. Palladium-catalyzed Sonogashira crosscoupling20,
21 is one of the most powerful and straightforward methods for the formation of
carbon-carbon bonds in organic synthesis21, 22, 23. Other methods which have been used for the
same purpose includes Suzuki-Miyaura reaction, Stille reactions, Hiyama reactions, Negishi
7
reactions to mention but a few. Among them, the palladium-catalyzed Sonogashira sp2-sp
coupling reaction between aryl or alkenyl halides or triflates and terminal alkynes, with or
without the presence of a copper (1) cocatalyst, has become the most important method to
prepare arylalkynes and conjugated enynes, which are precursors for natural products,
pharmaceuticals, and molecular organic materials22, 24. Traditionally, these cross-coupling
reaction rely on the presence of both palladium and copper to contribute to catalysis25, although
much effort of late has gone into effecting such C-C bond constructions in the absence of one21,26
or the other metal21, 27 or by virtue of alternative methodologies that accomplish the same net
aryl-alkynes bond 21, 28.
1.3: STATEMENT OF PROBLEM
Though there are various alkylated derivatives of quinoline-5,8-diones with reported
biological properties, the synthesis of its alkynylated derivatives is yet unknown. In fact, no
significant work has been reported on using the Sonogashira cross-coupling reaction to extend
the conjugation of halogenated quinoline-5,8-diones. It is the interest in these type of
compounds and their medicinal value that informs the quest for the synthesis of new mono-and
bis-alkynylated quinoline-5,8-diones.
1.4: Objectives of Study.
The objectives of this work therefore were to:
1. Synthesize functional halogenated quinoline-5,8-dione intermediates of the structure 13:
8
N
O
O
Br
Br
13
2. Convert the halogenated quinoline-5,8-dione (13) to the relevant derivatives (131E1-5) and
(132E1-5) respectively via palladium-catalyzed Sonogashira cross-coupling reaction under
copper-, amine-, and solvent-free conditions. (Schemes 3 and 4 where R1= aryl, alkyl, alkoxy,
etc.)
N
O
O
Br
Br
+ R CH 1
3 mol%,PdCl2(PPh3)2
TBAF,800C,N2 N
O
O
R1
Br
13 (131E1-5)
Scheme 1: Palladium-catalyzed Sonogashira synthesis of mono-alkynylated quinoline-5,8-diones
under copper-, amine-, and solvent-free Conditions.
N
O
O
Br
Br
+ R CH 1
3 mol%,PdCl2(PPh3)2
TBAF,800C,N2 N
O
O
R1
R1
2
13 (132E1-5)
9
Scheme 2: Palladium-catalyzed Sonogashira synthesis of bis-alkynylated quinoline-5,8-diones
under copper-, amine-, and solvent-free Conditions.
3. Characterize the mono- and bis-alkynylated derivatives of quinoline-5,8-diones (131E1-5) and
(132E1-5) respectively, with Uv-visible, IR, 1H-NMR and 13C-NMR spectroscopy
4. Evaluate the antimicrobial activities of the new alkynylated quinoline-5,8-diones.
1.5: Justification of the Study
The wide therapeutic applications of quinoline-5,8-diones derivatives and unavailability of
its alkynylated derivatives in the literature necessitates this research.
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