Thesis Abstract

<p> Palladium-catalysed Suziki-Miyaura cross-coupling (SMC) reactions of 6-chloro-5H<br>benzo[a]phenothiazin-5-one, 11-amino-6-chloro-9-thio-5H-naphtho[2,1-b]pyrimido[5,4-e][1,4]<br>oxazin-5-one and 6-chloro-5H-naphtho[2,1-b]pyrido[2,3-e][1,4]oxazin-5-one with phenylboronic<br>acid and 3-nitophenylboronic acid were thoroughly investigated. The above intermediates were<br>prepared by the reactions of 2-aminothiophenol, 4,5-diamino-6-hydroxylpyrimidine-2-thiol and 2-<br>aminpyridin-3-ol respectively with 2,3-dichloronaphthalene-1,4-dione in a basic medium using<br>benzene/DMF as the solvent. Thereafter, each was subjected to the SMC reactions with<br>phenylboronic acid and 3-nitrophenyl boronic acid, refluxing for 7-8 h at 110 oC using<br>tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), SPhos, potassium phosphate (K3PO4), and<br>toluene as the catalyst, ligand, base and solvent correspondingly to yield 6-phenyl-5Hbenzo[<br>a]phenothiazin-5-one and 6-(3-nitrophenyl)-5H-benzo[a]phenothiazin-5-one;11-amino-9-<br>mercapto-6-phenyl-5H-naphtho[2,1-b]pyrimido[5,4-e][1,4]oxazin-5-one and 11-amino-9-<br>mercapto-6-(3-nitrophenyl)-5H-naphtho[2,1-b]pyrimido[5,4-e][1,4]oxazin-5-one; and 6-phenyl-<br>5H-naphtho[2,1-b]pyrido[2,3-e][1,4]oxazin-5-one and 6-(3-nitrophenyl)-5H-naphtho[2,1-<br>b]pyrido[2,3-e][1,4]oxazin-5-one. Structures of the compounds were characterized using<br>UV/visible spectrophotometry, FT-IR, 1H-NMR and 13C-NMR spectroscopy and elemental<br>analysis. Using Ciprofloxacin (antibacterial) and Ketoconazole (antifungal) as reference drugs, the<br>compounds were screened against six (6) micro-organisms, viz Bacillus subtitis, Staphylococcus<br>aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albican and Aspergillus niger; and<br>were found to show significant activity against some gram-positive bacteria. <br></p>

Thesis Overview

<p> 1.1 Background:<br>The emergence of new catalytic systems, utilizing palladacyclic complexes, electron-rich<br>trialkylphosphine ligands and the bulky biphenyl-based phosphines developed by Buchwald and<br>co-workers, 1 have virtually transformed the trend in organic synthesis. These have led to the<br>development of some novel compounds from unreactive aryl and heteroaryl chlorides that exhibit<br>strong actions against drug-resistant microbes and possess other potentials. However, the<br>applications of phenothiazine 1 and phenoxazine 2 compounds and their derivatives in drugs,<br>textile, agriculture and other related industries have long been recognized.<br>N<br>S<br>H<br>N<br>O<br>H<br>1 2<br>j<br>i<br>h<br>a<br>b<br>c<br>j<br>i<br>h<br>a<br>b<br>c<br>Phenothiazine , one of the most frequently encountered bioactive heterocycles in compounds of<br>biological interest,2 and its derivatives have been found to show tremendous biological activities<br>such as antiparkinsonian,3 anticonversant,4 antidepressant,5 neuroleptic,6 anti-inflamatory,7-9<br>antimalarial,10-12 antipsychotic,13-15 antimicrobial,16,17 anti-tubercular,18-21 antitumor,22,23<br>antihistaminic,24,25 analgesic, 26 prion disease drug27 . In textile, paint and plastic industries, they<br>are used as dyes and pigments28 and in agricultural industries as insecticides29. In petroleum<br>industries, they are used as antioxidants in lubricants and fuels30. It has been observed that some<br>phenothiazines inhibit intracellular replication of viruses including human immunodeficiency<br>2<br>viruses (HIV) 31. On the other hand, some have been reported to exhibit significant anticancer<br>activity32, 33.<br>Similarly, phenoxazine and related compounds have been reported to possess various biological<br>activities such as antiparkinsonian, 34,35 anticonvulsant,36 antihistamic,37 antihelmatic,38 antiviral,<br>39 antitumor,40 anticancer,41 antiparasitic,42 antibacterial43,44 and CNS depressant45. Other<br>applications include their use as antioxidants and biological stains,46 laser dyes,47 indicators48 and<br>especially as chromophoric compounds in host guest artificial protonic antenna system49.<br>1.2 STATEMENT OF THE PROBLEM<br>Although several synthetic routes to linear and angular phenoxazines and phenothiazines have<br>been reported50-54 methods are often not applicable for the preparation of a wide variety of their<br>derivatives with excellent yields and good pharmacological activity. Moreover, because of the<br>current indespensibility of phenothiazine and phenoxazine rings as valuable molecular templates<br>(scaffords) for the development of chemotherapeutic agents with high pharmacokinetic profile, it<br>becomes imperative to investigate elegant and facile reaction protocols to synthesized possible<br>derivatives with variety of functionalities.<br>1.3 OBJECTIVES OF THE STUDY<br>The specific objectives of this study are to:<br>i. To synthesize and characterize some benzo[a]phenothiazine and benzo[a]phenoxazine<br>compounds as intermediates.<br>ii. To convert the intermediates to their derivatives using palladium-SPhos catalyzed Suzuki<br>cross-coupling reaction.<br>iii. To characterize the synthesized compounds by spectroscopic methods (IR, UV, NMR and<br>elemental analysis).<br>iv. To screen the new compounds for antimicrobial properties.<br>3<br>1.4 JUSTIFICATION OF THE STUDY<br>The burgeoning pharmaceutical applications of phenothiazine and phenoxazine derivatives<br>stimulated us to explore facile reaction procedures for functionalization of these compounds60-70.<br>Hitherto, derivatizations of these compounds were accomplished by utilizing stoichiometric<br>reactions which are generally harsh and unfavourable to sensitive functional groups. Hence, the<br>extent of functionalization of these compounds under these conditions was limited. Although<br>various (hetero) chlorophenothiazines and chlorophenoxazines are relatively cheap and readily<br>available, their applications as coupling partners in Pd-catalyzed SMC reactions are rare.<br>Furthermore, since the discovery of monodendate, bulky and electron-rich<br>dialkylbiphenylphosphine ligands (of which SPhos is a part) used for cross-coupling of<br>electronically and/or sterically derived aryl chlorides and other substrates,66-68 none of them has<br>been tested on chlorophenothiazine and chlorophenoxazine. Our choice of SPhos is based on its<br>electronic and steric properties because it increases the electron density around palladium metal<br>and accelerates the oxidative addition of the substrate to the catalyst while its bulkiness and large<br>cone angle would accelerate the rate of reductive elimination68. Moreover, we chose Suzuki-<br>Miyaura protocol because of its so many advantages. Ultimately, the practicability of the<br>developed protocol was demonstrated in the synthesis of a total of six derivatives. Besides, to our<br>knowledge, these procedures were previously unknown and the synthesized compounds are new.<br>4 <br></p>