Project Abstract

<p> Synthesis of twelve O-arylated diazabenzo[a]phenoxazine-5-one and its<br>carbocyclic analogue is reported in 46 – 99 % yields. The intermediates<br>were prepared by anhydrous base catalyzed reaction of 2,3-dichloro-1,4-<br>naphthoquinone with 4,5-diamino-6-hydroxyl-2-mercaptopyrimidine and 2-<br>aminophenol. The O-arylation process occurred smoothly in non-polar<br>solvent, toluene with the inexpensive base, K2PO4 at 110oC. The<br>intermediates were combined with a variety of electron-deficient, electrically<br>neutral and electron-rich phenols in the presence of a catalyst combination of<br>Pd(OAc)2 and electron rich, bulky alkyldiarylphosphine ligand in which the<br>alkyl groups are tert-butyl (t-Buxphos), to furnish the arylated compounds.<br>Bulky yet basic nature of the phosphine ligand is thought to be responsible<br>for these transformations. The highest yields were obtained when the<br>intermediates coupled with electron rich phenols, with the carbocyclic<br>analogue giving better yields. IR, 1H NMR and 13C NMR spectra data,<br>confirmed the structures of all the synthesized compounds. The effect of the<br>synthesized compounds on bacteria and fungi growth was studied. The<br>studied compounds were found to be potent antibacterial and antifungal<br>agents as they showed significant biological activity against Escherichia<br>coli, Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and<br>Candida albicans. In addition, they may be useful as dyes in industries since<br>they absorb in the UV- visible region. <br></p>

Project Overview

<p> 1.0 INTRODUCTION<br>1.1 BACKGROUND OF STUDY:<br>Angular phenoxazines are defined as the polynuclear phenoxazines that<br>have non-linear arrangement ring system1. Angular phenoxazines and its aza<br>analogues constitute important classes of organic compounds because of their<br>wide range of commercial uses. They are used as dyes1 and drugs2. They exhibit<br>strong biological activities ranging from antidepressant3, antitumour4,<br>anticancer5, antibacterial6, and antituberculosis7 and schizophrenia agents8.<br>Among the several industrial applications of angular phenoxazine derivatives are<br>their use as acid-base indicator9, biological stains10, laser dyes11 and<br>chromophoric compounds12.<br>The report of the basic structure of the parent phenoxazine 1 prompted the<br>synthesis of several hundreds of derivatives, not only to improve their usefulness<br>but also to open up new area of applications.<br>N H<br>O<br>1<br>These structural modifications have given rise to benzo[a]phenoxazine 2,<br>benzo[c]phenoxazines 3, benzo[b]phenoxazine 4, benzo[j]phenoxazine 5,<br>2<br>benzo[i]phenoxazine 6 and benzo[h]phenoxazine 710 among others. These are all<br>carbocyclic phenoxazines.<br>N H<br>O<br>2 3<br>N H<br>O<br>N H<br>O<br>N H<br>O<br>4 5<br>N H<br>O<br>6 7<br>N H O<br>Structures 4 and 6 are linear phenoxazines while structures 2, 3, and 5 are<br>angular phenoxazines.<br>Phenoxazine compounds that have two benzo groups attached to<br>phenoxazine nucleus are called dibenzophenoxazines. These include compounds<br>8, 9, and 10.<br>3<br>N H<br>O<br>8<br>N H<br>O<br>9<br>10<br>N H<br>O<br>Some of the structures of angular phenoxazines are very complex. For example<br>compounds 1114, 1215,1316 and 1417.<br>N H<br>O NH<br>O<br>N H<br>O<br>O<br>11 HN<br>12<br>4<br>N H<br>O<br>N H<br>O<br>O S O<br>ONa<br>O S O<br>ONa<br>HO<br>OH<br>X<br>13<br>N H<br>O<br>N H<br>O<br>14<br>Phenoxazine derivatives produced by the fusion of the benzo group at ‘a’<br>position or 1, 2 bonds have been reported; 1518,1613 and 1719 which have been<br>used as dyestuff20 and good indicators21. They have been shown to exhibit<br>anticancer22, 23 and antibacterial activities24.<br>N H<br>Me2N O<br>KO3S SO3K<br>15<br>HCl<br>N H<br>O N+Et2N H2<br>Cl-<br>16<br>5<br>17<br>N H<br>N O + NHR3<br>HO<br>R<br>R<br>Replacement of one of the ring carbon atoms of angular phenoxazine analogues<br>with heteroatom such as oxygen, gives phenoxazines called<br>pyranophenoxazines13: 18, 19.<br>18<br>N H<br>O<br>O<br>N H<br>O<br>O<br>O<br>Cl<br>19<br>Variations in phenoxazines ring system because of replacement of one or<br>more CH groups by annular nitrogen have given rise to monoaza 20, diaza 21,<br>and triaza 22 analogues of phenoxazines. Compounds in each of these aza family<br>have been synthesized and reported25.<br>20<br>N<br>O<br>N<br>O<br>N N<br>H<br>O+ OH<br>21<br>6<br>22<br>N<br>N<br>N H<br>O<br>N<br>Some of these aza derivatives have substituents; 23 and 2426.<br>N N<br>O O<br>NH2<br>NHPh<br>N N<br>O O<br>R<br>Cl<br>R = NH2, NO2, NHOAc.<br>23<br>24<br>Several authors have reported cross coupling reactions used for the<br>synthesis of these derivatives27. Such coupling reactions includes Sonogashira<br>cross coupling reaction, Suzuki cross coupling reaction, Stille cross coupling<br>reaction, Buchwald-Hartwig cross coupling reaction and Heck-Mozoroki cross<br>coupling reaction. The discovery of these cross-coupling reactions constitutes<br>one of the most striking breakthroughs in organic chemistry, and it has brought<br>many benefits to organic chemists:<br>· It is extremely powerful and a general strategy for the formation of C – C<br>and C – hetero aromatic bonds.<br>7<br>· It has changed the methodology for the retro synthesis enabling the<br>Organic Chemists to shorten the synthetic procedure27,28<br>· The reaction has gained wide use in synthetic organic chemistry finding<br>application in many total synthesis and industrial preparation of numerous<br>pharmaceuticals 27, 29.<br>Several transition metal catalysts have been developed in response to the<br>increasing demand of these coupled products in chemical pharmaceutical<br>industries. The sole aim is to exert the highest turnover frequency27,28. Literature<br>has shown that palladium catalyzed cross coupling reactions and the Hartwig-<br>Buchwald coupling are the most frequently used routes for the formation of<br>carbon hetero aromatics bond 28. Buchwald group developed a series of catalyst<br>based butyl electron rich phosphine ligands that have attracted much attention<br>due to their ability to affect various C – C, C – N and C –O bond formation28.<br>Prominent amongst these are 2-(dicyclohexylphosphino)-2, 4, 6-<br>triisopropylbiphenyl(Xphos), 2-ditertiarybutylphosphino-1,2,3-triisopropyl<br>biphenyl(t-Buxphos), 2-dicyclohexylphosphino-21, 61-dimethoxybiphenyl<br>(Sphos), 2-dicyclohexylphosphino-21, 61-diisopropoxylbiphenyl(Ruphos) and 2-<br>(dicyclohexylphosphino)-3,6-dimethoxyl-21,41,61-triisopropyl-11,11-biphenyl<br>(Brettphos). Dialkylbiarylphosphine ligands and the pre catalysts derived from<br>them are commonly referred to as Buchwald ligands and pre catalysts<br>8<br>respectively. These reagents have developed into a highly valuable class of<br>compounds for palladium-catalysed reactions, and can be used for a broad range<br>of reactions. Palladium catalysed cross-coupling reactions have been tools for<br>C-C and C-heteroatom bond formation in academic and industrial settings 30, 31.<br>However, palladium sources can have significant problems in generating active<br>catalyst32. For example, stable Pd (0) sources such as Pdn(dba) contains<br>dibenzyldeneacetone (dba) ligands that can impede the catalytic cycle. These Pd<br>species can also contain varying degrees of free dba and palladium nanoparticles<br>33. As researchers explore cross-coupling reactions that are more complex, the<br>method for generation of the catalytically active LnPd (0) species has often<br>proven to be vital to the success of cross-coupling reactions 32. Pd (II) sources<br>such as Pd (OAc) 2 and PdCl2 need to be reduced to Pd (0) in situ before entering<br>a Pd (0) – Pd (II) cross-coupling cycle. The palladium (II) sources are usually<br>reduced using ligands. t-Buxphos has been found to be excellent supporting<br>ligand for pd-catalyzed C – O bond forming reactions33 due to the presence of<br>monophosphine in the structure. Consequently, Buchwald catalyst, which is<br>combination of palladium complex and Buchwald ligand (t-Buxphos), was used<br>in this study.<br>9<br>1.2 Statement of problem<br>Although a wide range of linear and angular phenoxazine compounds<br>have been synthesized, only a limited number of their derivatives have been<br>prepared. Furthermore, their biological activities are understudied. Because of<br>this, parent phenoxazine 1 has been continuously modified in this direction to<br>open new area of application.<br>N<br>O<br>1<br>Benzo[a]phenoxazine 26 and diazabenzo[a]phenoxazine nucleus 25 have<br>been known for years but their chemistry remains poorly developed 34<br>N<br>N<br>N<br>O O<br>Cl<br>NH2<br>HS<br>25<br>Still more grossly under studied is the O-arylated angular phenoxazines.<br>Before now, no significant work has been done using Buchwald catalyst to Oarylate<br>diazaphenoxazine and related carbocyclic analogue. Interest in this type<br>of ring system made us to synthesize twelve new phenoxazines nucleus, which<br>are O-arylated using Buchwald catalyst.<br>N<br>O O<br>26 Cl<br>10<br>1.3 Objectives of the study<br>The objectives of this work therefore are to<br>· Synthesize angular diazaphenoxazine and related carbocyclic<br>analogue compound of the type 2 and 3.<br>N<br>N<br>N<br>O O<br>NH2<br>HS<br>Cl<br>N<br>O O<br>25 26 Cl<br>· O-Arylate the angular diazaphenoxazine and the related carbocyclic<br>analogue using Buchwald catalyst as shown below:<br>N<br>N<br>N<br>O O<br>Cl<br>NH2<br>HS N<br>N<br>N<br>O O<br>NH2<br>O<br>HS<br>OH<br>+ X<br>X<br>Pd(OAc)2 / L<br>k3PO4<br>toluene, 110 0c<br>H2O, 8hrs<br>25 27<br>28<br>11<br>N<br>O<br>Cl<br>O<br>+<br>OH<br>x<br>N<br>O<br>O<br>O<br>x<br>Pd(OAc)2/L<br>K3PO4<br>Toluene,110oc<br>H2O,8hrs<br>26 27<br>29<br>X = H, Me, isopropyl, methoxy, chlorine, and benzene ring<br>L = t-Buxphos.<br>· Characterize the compounds synthesized using UV, IR and NMR<br>spectrophotometer.<br>· Carry out antimicrobial screening on the new phenoxazine scaffold.<br>1.4 Justification for the study<br>The study provides new and facile route of making novel polycyclic ring<br>systems thereby extending methods available for obtaining phenoxazine<br>derivatives. Thus, it generates new area for further research. The newly<br>synthesized compounds could be useful as potent antimicrobial agents in<br>medicine and may be used as dyes in the industries since they show absorption<br>in UV-visible region. <br></p>