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, ‘H and ‘C-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
CHAPTER ONE
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 agents’. Streptonigrin and Lavendamycin are known antibiotic, antitumor agents containing the quinoline-5,8-dione functional group 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 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 posses 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 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 1997′.
Cl ACHN
The importance of the quinoline-5,8-dione prompted Behforouz’ to report the synthesis of the analogue 4.
Also in the year 1984, Kende and Ebetion” 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
In 2010, Behforouz’, 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.
(R’=CH,CO, CH, (CH») HCO, etc. R= H, CI; R’= OCH,, NH N[(CH,CH)»]. R= H,
CH3 R= H, OH).
Padwareported the synthesis of another new quinolinequinone derivative 7 from 8-hydroxy•
tetra-azole [1, 5-a] quinoline.
As a further variation in the structure of quinoline-5,8-dione in an effort to synthesize new antifungal drugs, Chung’ synthesized new quinolinequinones with substitution at C-6 and C-7 as represented as structures 8, 9, 10 and 11.
| -° |
(R‘R, Rare the same or different and a halogen atom, or aceto group and R is C-1 to C-20 alkyl groups and X = a halogen atom”).
Among all the prepared quinolinequinones only 6,7-dichloro, 12 and 6,7-dibromo- 13 derivatives derived from the highly antibacterial 8-hydroxyquinoline 14 have been found to possess antimicrobial activities comparable with those of 2,3-dichloro-1,4-naphthoquinoline 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””. 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 function”
Transition metal catalyzed reactions are probably the most important area in organometallic chemistry”. Interestingly, palladium catalyzed processes are the vastly applied process. It typically utilizes only 1-5mol% of the catalyst’. The catalytic system is generally composed of a
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(PPh,),”.
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 storage”. An initial step, reduction of Pd(ll) to Pd(0), is required before the catalytic cycle can start’. 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 used”
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 synthesis! I8. I Palladium-catalyzed Sonogashira cross• coupling?’ is one of the most powerful and straightforward methods for the formation of carbon-carbon bonds in organic synthesis.22. 23, Other methods which have been used for the same purpose includes Suzuki-Miyaura reaction, Stille reactions, Hiyama reactions, Negishi
reactions to mention but a few. Among them, the palladium-catalyzed Sonogashira sp-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 materials?· ? Traditionally, these cross-coupling reaction rely on the presence of both palladium and copper to contribute to catalysis, although much effort oflate has gone into effecting such C-C bond constructions in the absence of one’2° or the other meta or by virtue of alternative methodologies that accomplish the same net aryl-alkynes bond3′.28
1.3: STATEMENT OF PROBLEM
Though there are vanous 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:
2. Convert the halogenated quinoline-5,8-dione (13) to the relevant derivatives (131El-5) and (132El-5) respectively via palladium-catalyzed Sonogashira cross-coupling reaction under copper-, amine-, and solvent-free conditions. (Schemes 3 and 4 where R’= aryl, alkyl, alkoxy,
etc.)
Scheme 1: Palladium-catalyzed Sonogashira synthesis of mono-alkynylated quinoline-5,8-diones under copper-, amine-, and solvent-free Conditions.
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 (13 lEl-5) and
(132E1-5) respectively, with U-visible, IR, ‘H-NMR and ‘C-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 resea
This material content is developed to serve as a GUIDE for students to conduct academic research
PALLADIUM -CATALYZED SONOGASHIRA SYNTHESIS OF MONO-AND BIS• ALKYNYLATED DERIV ATIVES OF QUINOLINE-5,8-DIONE AND THEIR ANTIMICROBIAL ACTIVITY
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