PALLADIUM -CATALYZED SONOGASHIRA SYNTHESIS OF MONO-AND BIS• ALKYNYLATED DERIV ATIVES 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,   ‘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

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