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[2,1-b]pyrido[2,3-e][1,4]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 oC using
tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), SPhos, potassium phosphate (K3PO4), and
toluene as the catalyst, ligand, base and solvent correspondingly to yield 6-phenyl-5Hbenzo[
a]phenothiazin-5-one and 6-(3-nitrophenyl)-5H-benzo[a]phenothiazin-5-one;11-amino-9-
mercapto-6-phenyl-5H-naphtho[2,1-b]pyrimido[5,4-e][1,4]oxazin-5-one and 11-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[2,1-
b]pyrido[2,3-e][1,4]oxazin-5-one. Structures of the compounds were characterized using
UV/visible spectrophotometry, FT-IR, 1H-NMR and 13C-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.

 

TABLE OF CONTENTS

 

Title page – – – – – – – – – – – i
Certification – – – – – – – – – – – ii
Dedication – – – – – – – – – – – iii
Acknowledgement – – – – – – – – – – iv
Abstract – – – – – – – – – – – v
Table of Contents – – – – – – – – – – vi
List of Figures – – – – – – – – – – – viii
List of Tables – – – – – – – – – – – x
Abbreviations – – – – – – – – – – – xi
CHAPTER ONE
1.0 Introduction – – – – – – – – – – 1
1.1 Background of study – – – – – – – — – 1
1.2 Statement of problem – – – – – – – – – – 2
1.3 Objectives of study – – – – – – – – – – 2
1.4 Justification of study – – – – – – – – – 3
CHAPTER TWO
2.0 Literature Review – – – – – – – – – – 4
2.1 Angular Phenothiazines – – – – – – – – – 4
2.2 Aza-Analogues of angular Phenothiazines – – – – – – – 8
2.3 Angular Phenoxazines – – – – – – – – – – 12
2.4 Aza-Analogues of Angular Phenoxazines – — – – – – 18
2.5 Suzuki-Miyaura Cross Coupling Reaction – – — – – – – 25
CHAPTER THREE
3.0 Experimental Section – – – – – – – – – 53
vii
3.1 Materials and Method – – – – – – – – 53
3.2 Synthesis of Angular Phenothiazine and Phenoxazine Intermediates – – 53
3.2.1 6-chloro-5H-benzo[a]phenothiazin-5-one – – – – – – 53
3.2.2 11-amino-6-chloro-9-mercapto-5H-naphtho[2,1-b]pyrimido[5,4-e][1,4]oxazin-5-one 54
3.2.3 6-chloro-5H-naphtho[2,1-b]pyrido[2,3-e][1,4]oxazin-5-one – – – – 55
3.3 The General Procedure for Suzuki Cross-Coupling Reactions – – – – 55
3.3.2 Synthesis of Derivatives of 6-chloro-5H-benzo[a]phenothiazin-5-one – – 56
3.3.2.1 6-phenyl-5H-benzo[a]phenothiazin-5-one – – – – – – 56
3.3.3.2 6-(3-nitrophenyl)-5H-benzo[a]phenothiazin-5-one, – – – – – 56
3.3.3 Synthesis of Derivative of 11-amino-6-chloro-9-mercapto-5H-naphtho[2,1-b]pyrimido
[5,4- e][1,4]oxazin-5-one – – – – – – – – – 57
3.3.3.1 11-amino-9-mercapto-6-phenyl-5H-naphtho[2,1-b]pyrimido[5,4-e][1,4]oxazin-5-one – 57
3.3.3.2 11-amino-9-mercapto-6-(3-nitrophenyl)-5H-naphtho[2,1-b]pyrimido[5,4-e][1,4]
oxazin-5-one- – – – – – – – – 57
3.3.4 Synthesis of the Derivatives of 6-chloro-5H-naphtho[2,1-b]pyrido[2,3-e][1,4]oxazin-5-one 58
3.3.4.1 6-phenyl-5H-naphtho[2,1-b]pyrido[2,3-e][1,4]oxazin-5-one – – – – 58
3.3.4.2 6-(3-nitrophenyl)-5H-naphtho[2,1-b]pyrido[2,3-e][1,4]oxazin-5-one – – – 59
3.4 Antimicrobial Screening – – – – – – – – – 59
3.4.1 General Sensitivity Testing of Compounds – – – – – – 60
3.4.2 Minimum Inhibitory Concentration (MIC) testing – – – – – 60
CHAPTER FOUR
4.0 Results and discussion- – – – – – – – – 61
4.1 Synthesis of the intermediates – – – – – – – – 61
4.2 Coupled products via Suzuki cross coupling reactions – – – – – 63
4.6 Antimicrobial Activity Result – – – – – – – – 68
CHAPTER FIVE
5.0 Conclusion – – – – – – – – – – 73
References – – – – – – – – – – 74
Appendixes- – – – – – – – – – 90

 

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.
N
S
H
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H
1 2
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i
h
a
b
c
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i
h
a
b
c
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 neuroleptic,6 anti-inflamatory,7-9
antimalarial,10-12 antipsychotic,13-15 antimicrobial,16,17 anti-tubercular,18-21 antitumor,22,23
antihistaminic,24,25 analgesic, 26 prion disease drug27 . In textile, paint and plastic industries, they
are used as dyes and pigments28 and in agricultural industries as insecticides29. In petroleum
industries, they are used as antioxidants in lubricants and fuels30. It has been observed that some
phenothiazines inhibit intracellular replication of viruses including human immunodeficiency
2
viruses (HIV) 31. On the other hand, some have been reported to exhibit significant anticancer
activity32, 33.
Similarly, phenoxazine and related compounds have been reported to possess various biological
activities such as antiparkinsonian, 34,35 anticonvulsant,36 antihistamic,37 antihelmatic,38 antiviral,
39 antitumor,40 anticancer,41 antiparasitic,42 antibacterial43,44 and CNS depressant45. Other
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 system49.
1.2 STATEMENT OF THE PROBLEM
Although several synthetic routes to linear and angular phenoxazines and phenothiazines have
been reported50-54 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.
ii. To convert the intermediates to their derivatives using palladium-SPhos catalyzed Suzuki
cross-coupling reaction.
iii. To characterize the synthesized compounds by spectroscopic methods (IR, UV, NMR and
elemental analysis).
iv. To screen the new compounds for antimicrobial properties.
3
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 compounds60-70.
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,66-68 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 elimination68. 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 and the synthesized compounds are new.
4

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