ABSTRACT
Palladium-catalysed Suziki-Miyaura cross-coupling (SMC) reactions of 6-chloro-5H benzo[a]phenothiazin-5-one, 11-amino-6-chloro-9-thio-5H-naphtho[2, 1-b]pyrimido[5,4-e][1,4] oxazin-5-one and 6-chloro-5H-naphtho[2,l-b]pyrido[2,3-e][l,4]oxazin-5-one with phenylboronic acid and 3-nitophenylboronic acid were thoroughly investigated. The above intermediates were prepared by the reactions of 2-aminothiophenol, 4,5-diamino-6-hydroxylpyrimidine-2-thiol and 2- aminpyridin-3-ol respectively with 2,3-dichloronaphthalene-1,4-dione in a basic medium using benzene/DMF as the solvent. Thereafter, each was subjected to the SMC reactions with phenylboronic acid and 3-nitrophenyl boronic acid, refluxing for 7-8 h at 110 C using tris(dibenzylideneacetone)dipalladium(0) (Pd(dba)), SPhos, potassium phosphate (K,PO,), and toluene as the catalyst, ligand, base and solvent correspondingly to yield 6-phenyl-5H• benzo[a]phenothiazin-5-one and 6-(3-nitrophenyl)-5H-benzo[a]phenothiazin-5-one; 1 l-amino-9- mercapto-6-phenyl-5H-naphtho[2, 1–b]pyrimido[5,4-e][1,4]oxazin-5-one and 1 l-amino-9- mercapto-6-(3-nitrophenyl)-5H-naphtho[2, 1–b]pyrimido[5,4-e][1,4]oxazin-5-one; and 6-phenyl-
5H-naphtho[2, 1-b]pyrido[2,3-e][1,4]oxazin-5-one        and       6-(3-nitrophenyl)-5H-naphtho[2, l• b]pyrido[2,3-e][1,4]oxazin-5-one.  Structures  of  the  compounds  were  characterized  using UV/visible  spectrophotometry,  FT-IR,  ‘H-NMR  and  ‘C-NMR  spectroscopy  and  elemental analysis.  Using Ciprofloxacin (antibacterial) and Ketoconazole (antifungal) as reference drugs, the compounds were screened against six (6) micro-organisms, viz: Bacillus subtitis, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli,  Candida albican and Aspergillus  niger; and were found to show significant activity against some gram-positive bacteria.
CHAPTER ONE
1.1 Background:
The emergence of new catalytic systems, utilizing palladacyclic complexes, electron-rich trialkylphosphine ligands and the bulky biphenyl-based phosphines developed by Buchwald and co-workers, 1 have virtually transformed the trend in organic synthesis. These have led to the development of some novel compounds from unreactive aryl and heteroaryl chlorides that exhibit strong actions against drug-resistant microbes and possess other potentials. However, the applications of phenothiazine 1 and phenoxazine 2 compounds and their derivatives in drugs, textile, agriculture and other related industries have long been recognized.
Phenothiazine , one of the most frequently encountered bioactive heterocycles in compounds of biological interest,2 and its derivatives have been found to show tremendous biological activities
such as antiparkinsonian,3 anticonversant,4 antidepressant, 5 neuro leptic,6 anti-inflamatory,””
ant1mallaer:iao,
antipsychotic,” antimicrobial,’
anti-tubercu1.ar, 18-21
ant1· tumor,22 “23
antihistaminic, analgesic, ” prion disease drug’. In textile, paint and plastic industries, they are used as dyes and pigments and in agricultural industries as insecticides”. In petroleum industries, they are used as antioxidants in lubricants and fuels”. It has been observed that some phenothiazines inhibit intracellular replication of viruses including human immunodeficiency
2
viruses (HIV) ‘. On the other hand, some have been reported to exhibit significant anticancer activity’33
Similarly, phenoxazine and related compounds have been reported to possess various biological activities such as antiparkinsonian, anticonvulsant,” antihistamic,’ antihelmatic,” anti•
vIra3, 9
ant1.,tumor,40
anti. cancer,41
ant1.parasi.t.ic,42
antiiba:
ctera:,143.’44
and CNS depressant.A5 .
applications include their use as antioxidants and biological stains,46 laser dyes,47 indicators48 and especially as chromophoric compounds in host guest artificial protonic antenna system”.
1.2 STATEMENT OF THE PROBLEM
Although several synthetic routes to linear and angular phenoxazines and phenothiazines have been reported”” methods are often not applicable for the preparation of a wide variety of their derivatives with excellent yields and good pharmacological activity. Moreover, because of the current indespensibility of phenothiazine and phenoxazine rings as valuable molecular templates (scaffords) for the development of chemotherapeutic agents with high pharmacokinetic profile, it becomes imperative to investigate elegant and facile reaction protocols to synthesized possible derivatives with variety of functionalities.
1.3 OBJECTIVES OF THE STUDY
The specific objectives of this study are to:
i. To synthesize and characterize some benzo [a]phenothiazine and benzo [a]phenoxazine compounds as intermediates.
11. To convert the intermediates to their derivatives using palladium-SPhos catalyzed Suzuki cross-coupling reaction.
111. To characterize the synthesized compounds by spectroscopic methods (IR, UV, NMR and elemental analysis).
1v. To screen the new compounds for antimicrobial properties.
1.4 JUSTIFICATION OF THE STUDY
The  burgeoning  pharmaceutical  applications  of phenothiazine  and  phenoxazine  derivatives stimulated us to explore facile reaction procedures  for functionalization  of these compounds70 Hitherto,  derivatizations  of these  compounds  were  accomplished  by  utilizing  stoichiometric reactions which are generally harsh and unfavourable  to sensitive functional groups.  Hence,  the extent of functionalization  of these  compounds  under  these  conditions  was  limited.  Although various  (hetero)  chlorophenothiazines  and chlorophenoxazines  are relatively  cheap and readily available,  their  applications  as  coupling  partners  in  Pd-catalyzed  SMC  reactions  are  rare. Furthermore,  since the  discovery  of monodendate,  bulky  and  electron-rich dialkylbiphenylphosphine  ligands  (of  which  SPhos  is  a  part)  used  for  cross-coupling  of electronically and/or sterically derived aryl chlorides and other substrates,        none of them has been tested on chlorophenothiazine  and chlorophenoxazine.  Our choice of SPhos is based on its electronic and steric properties because it  increases  the electron density around palladium  metal and accelerates the oxidative addition of the substrate to the catalyst while its bulkiness and large cone angle would  accelerate  the rate  of reductive  elimination”,  Moreover,  we chose  Suzuki• Miyaura  protocol  because  of its  so  many  advantages.  Ultimately,  the practicability  of the developed protocol was demonstrated in the synthesis of a total of six derivatives.  Besides,  to our knowledge, these procedures were previously unknown
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THE UTILITY OF SUZUKI-MIYAURA CROSS-COUPLING REACTION IN THE SYNTHESIS OF ANGULAR BENZO[A]PHENOTHIAZINE AND BENZO[A]PHENOXAZINE DERIVATIVES AND THEIR ANTI-MICROBIAL SCREENING>
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