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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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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, 1b]pyrimido[5,4-e][1,4]oxazin-5-one         and         1 l-amino-9- mercapto-6-(3-nitrophenyl)-5H-naphtho[2, 1b]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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