ABSTRACT
The synthesis of ten new alkynylated derivatives of angular phenoxazine and alkynylated naphthoquinone was thoroughly investigated. The first intermediate, 6-chloro-5H– benzo[a]phenoxazin-5-one was obtained by the condensation of 2-aminophenol with 2,3- dichloro-1,4- naphthoquinone in the presence of anhydrous sodium tricarbonate (IV) . Thereafter, the intermediate and 2,3-dichloro-1,4-naphthoquinone were each suggested to Sonogashira cross–coupling reaction under copper-, amine-, and solvent free conditions at 80
oC with five different terminal alkynes using PdCL2(PPh3)2 and tetrabutylammonium
trihydrate (TBAF.3H2O) as the catalyst and ligand respectively to afford the alkynylated angular phenoxazines and alkynylated naphthoquinone derivatives in good to excellent yield . Structures of synthesized compounds were confirmed with Uv-visible, Fourier Transform – Infrared (FT-IR), 1H-NMR and 13C-NMR spectroscopy. The synthesized compounds were screened against five (5) micro-organisms viz: Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli 1 and Escherichia coli 12 using agar well diffusion technique. The results showed significant improvement in antimicrobial activities compared with gentamycin and ampicillin (standard drugs).
CHAPTER ONE
1.0 INTRODUCTION
The chemistry of phenoxazine and its derivatives have been of considerable interest over the years because of their important and impressive number of applications1 particularly as dyes and drugs2,3. Phenoxazines are a pharmaceutically important class of tricyclic nitrogen- oxygen heterocycles4. They show tremendous pharmacological activities as anti-epileptic5, antitumour6,7, anticancer8, antituberculosis9, antibacterial10,11, anthelminthic12, spasmolytic, central nervous system (C.N.S) depressants,13,14 herbicides tranquilizers, sedatives15 and
parasiticidal agents16. Other applications of phenoxazine derivatives include their use as
antioxidants17, biological stains18,19, acid-base indicators20, and bromometric and stannometric redox indicators21-25. Phenoxazine itself has been used as a stabilizer for the polymerization of vinylpyridines26, polyethylene and polystyrene27. Some of its derivatives were also reported as having radioprotective and antioxidative actions28.
Naphthoquinones are secondary metabolites largely found in plants, micro-organisms, and some animals29. These compounds have been widely used as colourants for comestics30, fabrics31, foods and for pharmacological activities such as antitumor, anti-inflammatory, antibacterial, antiviral, antiproliferative, antiparasitic, cytotoxic activities and others32-34. They can be prepared synthetically and are widely produced by the chemical industry as organic dyes35. The scientific community has explored the biological and toxicological
activities of napthoquinones in attempts to discover and develop new drugs.
1.1 BACKGROUND OF THE STUDY
Since the discovery of the parent ring phenoxazine 1, which was synthesized first by
Bernthsen36 in 1887, many structural modifications have been carried out to enhance its biological activities, minimize undesirable effects37 and open new areas of applications.
Such molecular modifications had yielded derivatives such as compounds 2, 3, 4, 5, 6 and 7.
Compounds 2, 3, 4, and 5 are described as “angular” phenoxazines because of the non-linear arrangement of the ring systems38. These possess fused rings at positions a39, c40, h and j bonds of the phenoxazine.
There are also systems in which naphthalene is attached to two different positions in the parent compound. Such structures include dibenzo[a,h]phenoxazine 841,
dibenzo[a,i]phenoxazine 9 and dibenzo[a, j]phenoxazine 10.
There are variations of “angular” phenoxazine in which one of the ring carbon atoms has been replaced with oxygen, known as benzopyrano[3,4-b]benzoxazine 11, and structures in which the attached benzene ring possesses a substituent. Example of the later is compound
Many derivatives of non-linear phenoxazine formed by fusion of benzene ring in the [a] position have been reported. These compounds such as 2 have been used as dye stuff and suitable indicators42.
A number of intermediates including naphthoquinones 13 derivatives have been used for the synthesis of non- linear phenoxazines. Naphthoquinone 13 and its derivatives have been the subject of much research due to their pharmacological activities. Quinone and naphthoquinone fragments are often encountered in natural biologically active compounds. Natural naphthoquinone derivatives
found in plants, such as 2-hydroxy-1,4-naphthoquinone, have antibacterial effect on several species of aerobic and anaerobic organism43-44. Some 1,4-naphthoquinone derivatives possess biological activities45-46. 2-Hydroxy-1,4-naphthoquinone 83 (Lawsone) is a naphthoquinone dye isolated from leaves of Lawsonia inermis, the Henna plant used for preparing decorative hair and skin dyes. It also demonstrates antimicrobial and antioxidant effects43. Baker and co- workers in 1990 isolated naphthoquinone from culture extracts of Fusarium oxysporum and Fusarium solani47. Brandelli and co-workers in 2004 also reported that the presence of an imino group instead of a keto group in the position 1 or 4 in 1,4-naphthoquinone results in the loss of antimicrobial activity48. This may indicate that both free groups are required for full activity49. The incidence of bacterial infections is an important and challenging problem due to the emerging new infectious diseases and increasing multi-drug resistance of microbial pathogens50. For critically ill people with a compromised immune system including AIDS patients, burn victims, individuals undergoing chemotherapy as well as organ transplant recipients taking immunosuppressive drugs, fungal infections are a serious concern51.
Modern organic synthesis has been greatly improved by the use of reactions catalyzed by transition metal complexes especially palladium, and this has led to the development of new methods of constructing carbon-carbon bonds and carbon-heteroatom bonds52-55. The transition metal-catalyzed C-C bond forming reactions have gained increasing importance over the last decade. The development and finetuning of reaction parameters for known and newly discovered metal–catalyzed transformations have had an important impact on
successes in the synthesis of natural and non-natural biologically active compounds and as theoretically interesting molecules of high complexity56a-c. In addition, process development for valuable intermediates in the pharmaceutical and agrochemical industry as well as
research towards new materials have benefited a great deal.
The increasing popularity of processes harnessing coupled catalysis is highlighted by the number of recent reviews in this area, especially the well-documented work on Pd- catalyzed C-C bond formation57-60. One of the most general and widely used palladium– catalyzed cross–coupling reactions is the alkynylation of the aryl halides using terminal
alkynes, generally known as the Sonogashira cross–coupling reaction61a-c. Other palladium
catalyzed coupling reactions that have changed the face of organic synthesis include Heck- Mizoroki coupling reaction, Buchwald-Hartwig coupling reaction, Suzuki- Miyaura reaction and Negishi reaction.
There are two different approaches to the application of transition metal- catalyzed reactions to the chemistry of heterocyclic compounds62a-c. One of them, involves the building of the heterocyclic backbone whereas in the other aspect, the heterocyclic fragment is used as
one of the reaction components. These examples are given in (i) and (ii) below, respectively.
ABSTRACT
The synthesis of ten new alkynylated derivatives of angular phenoxazine and alkynylated naphthoquinone was thoroughly investigated. The first intermediate, 6-chloro-5H– benzo[a]phenoxazin-5-one was obtained by the condensation of 2-aminophenol with 2,3- dichloro-1,4- naphthoquinone in the presence of anhydrous sodium tricarbonate (IV) . Thereafter, the intermediate and 2,3-dichloro-1,4-naphthoquinone were each suggested to Sonogashira cross–coupling reaction under copper-, amine-, and solvent free conditions at 80
oC with five different terminal alkynes using PdCL2(PPh3)2 and tetrabutylammonium
trihydrate (TBAF.3H2O) as the catalyst and ligand respectively to afford the alkynylated angular phenoxazines and alkynylated naphthoquinone derivatives in good to excellent yield . Structures of synthesized compounds were confirmed with Uv-visible, Fourier Transform – Infrared (FT-IR), 1H-NMR and 13C-NMR spectroscopy. The synthesized compounds were screened against five (5) micro-organisms viz: Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli 1 and Escherichia coli 12 using agar well diffusion technique. The results showed significant improvement in antimicrobial activities compared with gentamycin and ampicillin (standard drugs).
CHAPTER ONE
1.0 INTRODUCTION
The chemistry of phenoxazine and its derivatives have been of considerable interest over the years because of their important and impressive number of applications1 particularly as dyes and drugs2,3. Phenoxazines are a pharmaceutically important class of tricyclic nitrogen- oxygen heterocycles4. They show tremendous pharmacological activities as anti-epileptic5, antitumour6,7, anticancer8, antituberculosis9, antibacterial10,11, anthelminthic12, spasmolytic, central nervous system (C.N.S) depressants,13,14 herbicides tranquilizers, sedatives15 and
parasiticidal agents16. Other applications of phenoxazine derivatives include their use as
antioxidants17, biological stains18,19, acid-base indicators20, and bromometric and stannometric redox indicators21-25. Phenoxazine itself has been used as a stabilizer for the polymerization of vinylpyridines26, polyethylene and polystyrene27. Some of its derivatives were also reported as having radioprotective and antioxidative actions28.
Naphthoquinones are secondary metabolites largely found in plants, micro-organisms, and some animals29. These compounds have been widely used as colourants for comestics30, fabrics31, foods and for pharmacological activities such as antitumor, anti-inflammatory, antibacterial, antiviral, antiproliferative, antiparasitic, cytotoxic activities and others32-34. They can be prepared synthetically and are widely produced by the chemical industry as organic dyes35. The scientific community has explored the biological and toxicological
activities of napthoquinones in attempts to discover and develop new drugs.
1.1 BACKGROUND OF THE STUDY
Since the discovery of the parent ring phenoxazine 1, which was synthesized first by
Bernthsen36 in 1887, many structural modifications have been carried out to enhance its biological activities, minimize undesirable effects37 and open new areas of applications.
Such molecular modifications had yielded derivatives such as compounds 2, 3, 4, 5, 6 and 7.
Compounds 2, 3, 4, and 5 are described as “angular” phenoxazines because of the non-linear arrangement of the ring systems38. These possess fused rings at positions a39, c40, h and j bonds of the phenoxazine.
There are also systems in which naphthalene is attached to two different positions in the parent compound. Such structures include dibenzo[a,h]phenoxazine 841,
dibenzo[a,i]phenoxazine 9 and dibenzo[a, j]phenoxazine 10.
There are variations of “angular” phenoxazine in which one of the ring carbon atoms has been replaced with oxygen, known as benzopyrano[3,4-b]benzoxazine 11, and structures in which the attached benzene ring possesses a substituent. Example of the later is compound
Many derivatives of non-linear phenoxazine formed by fusion of benzene ring in the [a] position have been reported. These compounds such as 2 have been used as dye stuff and suitable indicators42.
A number of intermediates including naphthoquinones 13 derivatives have been used for the synthesis of non- linear phenoxazines. Naphthoquinone 13 and its derivatives have been the subject of much research due to their pharmacological activities. Quinone and naphthoquinone fragments are often encountered in natural biologically active compounds. Natural naphthoquinone derivatives
found in plants, such as 2-hydroxy-1,4-naphthoquinone, have antibacterial effect on several species of aerobic and anaerobic organism43-44. Some 1,4-naphthoquinone derivatives possess biological activities45-46. 2-Hydroxy-1,4-naphthoquinone 83 (Lawsone) is a naphthoquinone dye isolated from leaves of Lawsonia inermis, the Henna plant used for preparing decorative hair and skin dyes. It also demonstrates antimicrobial and antioxidant effects43. Baker and co- workers in 1990 isolated naphthoquinone from culture extracts of Fusarium oxysporum and Fusarium solani47. Brandelli and co-workers in 2004 also reported that the presence of an imino group instead of a keto group in the position 1 or 4 in 1,4-naphthoquinone results in the loss of antimicrobial activity48. This may indicate that both free groups are required for full activity49. The incidence of bacterial infections is an important and challenging problem due to the emerging new infectious diseases and increasing multi-drug resistance of microbial pathogens50. For critically ill people with a compromised immune system including AIDS patients, burn victims, individuals undergoing chemotherapy as well as organ transplant recipients taking immunosuppressive drugs, fungal infections are a serious concern51.
Modern organic synthesis has been greatly improved by the use of reactions catalyzed by transition metal complexes especially palladium, and this has led to the development of new methods of constructing carbon-carbon bonds and carbon-heteroatom bonds52-55. The transition metal-catalyzed C-C bond forming reactions have gained increasing importance over the last decade. The development and finetuning of reaction parameters for known and newly discovered metal–catalyzed transformations have had an important impact on
successes in the synthesis of natural and non-natural biologically active compounds and as theoretically interesting molecules of high complexity56a-c. In addition, process development for valuable intermediates in the pharmaceutical and agrochemical industry as well as
research towards new materials have benefited a great deal.
The increasing popularity of processes harnessing coupled catalysis is highlighted by the number of recent reviews in this area, especially the well-documented work on Pd- catalyzed C-C bond formation57-60. One of the most general and widely used palladium– catalyzed cross–coupling reactions is the alkynylation of the aryl halides using terminal
alkynes, generally known as the Sonogashira cross–coupling reaction61a-c. Other palladium
catalyzed coupling reactions that have changed the face of organic synthesis include Heck- Mizoroki coupling reaction, Buchwald-Hartwig coupling reaction, Suzuki- Miyaura reaction and Negishi reaction.
There are two different approaches to the application of transition metal- catalyzed reactions to the chemistry of heterocyclic compounds62a-c. One of them, involves the building of the heterocyclic backbone whereas in the other aspect, the heterocyclic fragment is used as
one of the reaction components. These examples are given in (i) and (ii) below, respectively.
This material content is developed to serve as a GUIDE for students to conduct academic research
SYNTHESES CHARACTERIZATION AND ANTIMICROBIAL ACTIVITIES OF ALKYNYLATED ANGULAR PHENOXAZINES AND ALKYNYLATED NAPHTHOQUINONES
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