ABSTRACT
The synthesis of new angular aza phenothiazinones, angular azaphenoxazines and their
derivatives are reported. Two key functional intermediates namely 2,6-diamino-4-chloropyrimidin-
5-thiol and 7-chloro-5,8-quinolinequinone were successfully synthesized from readily
available starting materials using such traditional organic methods as nitrosation, nitration,
halogenation, reduction, oxidation, direct thiocynation and base-catalyzed hydrolysis. The new
angular azaphenothiazinones and angular azaphenoxazinone were prepared by coupling the
requisite intermediates. Condensation reaction between 2,6-diamino-4-chloro-pyrimidin-5-thiol
or 2-aminothiophenol or 2-aminophenol and 7-chloro-5,8-quinolinequinone in the presence of
anhydrous sodium carbonate produced 10-amino-8-chloro-1,9,11-triaza-5Hbenzo[
a]phenothiazin-5-one,2291-aza-5H-benzo[a]- phenothiazin-5-one,231 1-aza-5Hbenzo[
a]phenoxazin-5-one233 respectively. Also by coupling 2,6-diamino-4-chloro-pyrimidin-5-
thiol with 2,3-dichloro-1,4-naphthoquinone in the presence of anhydrous sodium carbonate, 10-
amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one230 was obtained. These angular
azaphenothiazinones and angular azaphenoxazines were converted to their derivatives via
palladium, copper and nickel-catalyzed cross-coupling tandem reactions utilizing Mizoroki-Heck,
Buchwald-Hartwig and Yamamoto protocols. Palladium catalyzed cross-coupling reaction
between 10-amino-8-chloro-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one and four phenyl-iodo
derivatives utilizing Mizoroki-Heck protocol furnished four new compounds namely 10-amino-8-
chloro-6-(4-nitrophenyl)-1,9-11-triaza-5H-benzo[a]phenothiazin-5-one, 10-amino-8-chloro-6-(2-
hydroxyphenyl)-1,9,11-traiza-5H-benzo[a]phenothiazin-5-one, 10-amino-8-chloro-6-(4-
carboxyphenyl)-1,9,11-traiza-5H-benzo[a]phenothiazin-5-one and 10-amino-8-chloro-6-(2-
carboxyphenyl)-1,9,11-traiza-5H-benzo[a]phenothiazin-5-one.
Also palladium catalyzed Mizoroki-Heck cross coupling reactions with arylated iodo compounds
and 1-aza-5H-benzo[a]phenothiazin-5-one and 1-aza-5H-benzo[a]phenoxazin -5-one produced
vi
the following new compounds: 6-(4-nitrophenyl)-1-aza-5H-benzo[a]phenothiazin-5-one, 6-(2-
hydroxyphenyl)-1-aza-5H-benzo[a]phenothizin-5-one, 6-(4-carboxyphenyl)-1-aza-5H-benzo
[a]phenothiazin-5-one, 6-(2-carboxyphenyl)-1-aza-5H-benzo[a]phenothiazin-5-one, and 6(-(2-
hydroxyphenyl)-1-aza-5H-benzo[a] phenoxazin-5-one, 6-(4-nitrophenyl)-1-aza-5Hbenzo[
a]phenoxazin-5-one, 6-(4-carboxyphenyl)-1-aza-5H-benzo[a]phenoxazin-5-one and 6-(2-
carboxyphenyl)-1-aza-5H-benzo[a]phenoxazin-5-one respectively. The arylation of 10-amino-
6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one with some amide derivatives via
Buchwald-Hartwig nickel complex cross-coupling reactions gave five new compounds namely:
6-acetamido-10-amino-8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one, 6-benzamido-10-
amino-8-dichloro-9,11-diaza-5H-benzo[a] phenothiazin-5-one, 6-(4-nitrobenzamido)-10-amino-
6,8-dichloro-9,11-diaza-5H-benzo[a] phenothiazin-5-one, 6-phthalamido-10-amino-8-chloro-
9,11-diaza-5H-benzo[a]pheno- thiazin-5-one and 6-(2-hydrobenzamido)- 10-amino-8-chloro-
9,11-diaza-5H-benzo[a]phenothiazin-5-one.
Arylation of 10-amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one using some
substituted anilines via Buchwald-Hartwig protocol with palladium acetate (Pd(OAc)2 gave five
new derivatives namely: 10-amino-8-chloro-6-((4-nitrophenyl) amino)-9,11-diaza-5Hbenzo[
a]phenothiazin-5-one, 10-amino-6-((4-bromophenyl)amino) -8-chloro-9,11-diaza-5Hbenzo[
a]phenothiazin-5-one, 10-amino-8-chloro-6-((3-nitrtophenyl)amino)-9,11-diaza-5Hbenzo[
a]phenothiazin-5-one, 10-amino-8-chloro-6-((4-chlorophenyl)amino)-9,11-diaza-5Hbenzo[
a]phenothiazin-5-one and 10-amino-6-((2-chlorophenyl)amino-9,11-diaza-5Hbenzo[
a]phenothiazin-5-one. Similarly arylation of 10-amino-6,8-dichloro-9,11-diaza-5H-benzo-
[a]phenothiazin-5-one with Pd(OAc)2 and some heterocyclic amines gave new derivatives
namely: 10-amino-8chloro-6-(pyrimidin-2-ylamino)-9,11-diaza-5H-benzo[a]phenothiazin-5-one
and 10-amino-8-chloro-6-(4-methylpyridylamino)-(9,11-diaza-5H-benzo[a]- phenothiazin-5-one.
Copper-catalyzed N-arylation reaction between 10-amino-8-chloro-1,9,11-triaza-5Hbenzo[
a]phenothiazin-5-one and potassium aryltriolborates utilizing Yamamoto reaction protocol
gave 8-chloro-10-(phenylamido)-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one 8-chloro-10-((3-
chlorophenyl)amino)-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one and 10-((4-
bromophenyl)amino-1,9-11-triaza-5H-benzo[a]phenothiazin-5-one. Similarly N-arylation of 10-
amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one, using copper complex and
potassium aryltriolborates furnished 6,8-dichloro-10-(phenylamino)-9,11-diaza-5Hbenzo[
a]phenothiazin-5-one, 6,8-dichloro-10-((3-chlorophenyl)amino)-9,11-diaza-5Hbenzo[
a]phenothiazin-5-one and 10-((4-bromophenyl)amino)-6,8-dichloro-9,11-diaza-5Hvii
benzo[a]phenothiazin-5-one. Structure elucidation of the synthesized compounds were done by
UV-visible, IR, ′HNMR 13CNMR spectroscopy and elemental analysis. The infrared (IR) spectra
of these angular azaphenothiazinones and phenoxazinones showed decrease in the C=O
absorption band from the expected 1690cm-1 to values ranging from 1682 – 1601cm-1 which were
due to ionic resonance effects. Compounds produced from Buchwald-Hartwig cross-coupling
reactions using palladium catalysts gave yields of 41 -80%. Nickel complex catalyzed Buchwald-
Hartwig reactions gave yields ranging from 71 – 78%. Derivatives obtained by employing
Mizoroki-Heck cross-coupling reaction protocol via palladium complex yields between 69 –
86%. Compounds obtained from copper catalysis via potassium phenyltriolborates gave yields 22
– 64%. As a a result of extended conjugation in these new angular azaphenothiazinones and
phenoxazinones scaffolds, they are intensely coloured and their colours range from yellow to
deep red through reddish brown to dark brown. Antimicrobial screening of these new compounds
showed significant biological activity against Bacillus subtilis, Staphylococcus aureus,
Escherichia coli, Enterococus faecalis, pseudomonas aerugionsa, Candida albicaus and
Aspergillus niger.
TABLE OF CONTENTS
Title page i
Certification ii
Dedication iii
Acknowledgement iv
Abstract vi
Table of contents ix
List of tables xvi
List of figures xvii
Abbreviations xxii
CHAPTER ONE
Introduction 1
1.0 Background of study 1
1.1 Transition metal catalyzed tandem reactions 11
1.2 Statement of the problem 14
1.3 Objectives of the study 14
1.4 Justification of the study 15
CHAPTER TWO
Literature Review 16
2.1 Non-aza Angular phenothiazines and phenoxazines 16
2.1.1 Angular phenoxazines 35
2.1.2 Angular Aza-phenothiazines and phenoxazines 46
2.1.3 Angular azaphenoxazines 62
2.2 Tandem reactions 67
ix
2.3 Mizoroki-Heck reactions 68
2.4 Buchwald-Hartwig Amination 79
2.5 Yamamoto Copper-Mediated N-arylation reactions 96
CHAPTER THREE
EXPERIMENTAL SECTION
3.1.1 GENERAL REAGENT INFORMATION 98
3.1.2 GENERAL ANALYTICAL INFORMATION 98
3.2.0 SYNTHESIS OF KEY INTERMEDIATES 99
3.2.1 2,6-Diamino-4-chloro-5-thiocyanto-pyrimidine 99
3.2.2 2,6-Diamino-4-chloro-pyrimidin-5-thiol 100
3.2.3 8-Hydroxy-5-nitrosoquinoline hydrochloride 101
3.2.4 8-Hydroxy-5-nitroquniline 102
3.2.5 7-Choloro-8-hydroxyquninoline 103
3.2.6 5-Amino-7-choloro,8-hydroxyquinoline 104
3.2.7 7-Chloro-5,8-quinolinequinone 105
3.3.0 SYNTHESIS OF NEW ANGULAR PHENOTHIAZINES
AND PHENOXAZINE 106
3.3.1 10-Amino-8-chloro-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one, 229 106
3.3.2 10-Amino-6,8-dichloro-9,11-triaza-5H-benzo[a]phenothiazin-5-one, 230 107
3.3.3 1-Aza-5H-benzo[a]phenothiazin-5-one, 231 108
3.3.4 1-Aza-5H-benzo[a]phenoxazin-5-one, 232 108
3.4.0 Preparation of bis-(triphenylphosphine)dichloronickel(II)
complex, (Ph3P)2Nicl2 109
3.5.0 Preparation of 1,4-bis(2-hydroxyl-3,5-ditertbutylbenzyl) piperazine,
x
C34H54N2O2 110
3.6.0 Synthesis of Aryltriolborates 110
3.6.1 Potassiumphenyltriolborate 110
3.6.2 Potassium 4-bromophenyltrioborates 111
3.7.0 GENERAL METHOD FOR THE MIZOROKI-HECK
REACTION 111
3.7.1 10-Amino-8-chloro-6(4-nitrophenyl)1,9,11-triaza-5Hbenzo[
a] phenothiazin-5-one, 233a 112
3.7.2 10-Amino-8-chloro-6(2-hydroxyphenyl)-1,9,11-triaza-5Hbenzo[
a] phenothiazin-5-one 233b 113
3.7.3 10-Amino-8-chloro-6(4-carboxyphenyl)-1,9,11-triaza-5Hbenzo[
a] phenothiazin-5-one, 233c 114
3.7.4 10-Amino-8-chloro-6(2carboxyphenyl)-1,9,11-triaza-5Hbenzo[
a] phenothiazin-5-one, 233d 115
3.7.5 6-(4-nitrophenyl)-1-aza-5H-benzo[a]-phenothiazin-5-
one, 234a 116
3.7.6 6-(2-hydroxyphenyl)-1-aza-5H-benzo[a]phenothiazin-5-one,
234b 117
3.7.7 6-(4-carboxyphenyl)-1-aza-5H-benzo[a]phenothiazin-5-one 234c 118
3.7.8 6-(2-carboxyphenyl)-1-aza-5H-benzo[a]phenothiazin-5-one, 234d 119
3.7.9 6–(2–Hydroxyphenyl)–5H–benzo[a]–phenoxazin-5-one, 235a 120
3.7.10 6–(4–Nitrophenyl)–1-aza-5H–benzo[a]–phenoxazin-5-one, 235b 121
3.7.11 6-(4-carboxyphenyl)-1-aza-5H-benzo[a]phenoxazin-5-one, 235c 122
xi
3.7.12 6-(2-carboxyphenyl)-1-aza-5H-benzo[a]phenoxazin-5-one, 235d 123
3.8.0 GENERAL METHOD FOR TH E PALLADIUM CATALYZED CARBONNITROGEN
CROSS COUPLING REACTIONS (AMINATION) 124
3.8.1 10-Amino-8-chloro-6-((4-nitrophenyl)-amino)-9,11-diaza-
5H-benzo[a]phenothiazin-5-one, 237a 125
3.8.2 10-Amono-6-((4-bromophenyl)amino)-8chloro,9,11-diaza-5H-benzo[a]
phenothiazin-5-one, 237b 126
3.8.3 10-Amono-8-chloro-6-((3-nitrophenyl)-amino)-9,11-diaza-
5H-benzo[a]phenothiazin-5-one, 237c 127
3.8.4 10-Amono-8-chloro-6-((4-chlorophenyl)-amino)-9,11-diaza-
5H- benzo[a]phenothiazin-5-one, 237d 128
3.8.5 10-Amono-8-chloro-6-((2-chlorophenyl)-amino)-9,11-diaza-
5H- benzo[a]phenothiazin-5-one, 237e 129
3.8.6 10-Amino-8-chloro-6-(pyrimidin-2-ylamino)-9,11-daiza-5H- benzo[a]
phenothiazin-5-one, 238a 130
3.8.7 10-Amino-8-chloro-6-(4-methylpyrimylamino)-9,11-daiza-5H-benzo[a]
phenothiazin-5-one, 238b 131
3.9.0 Representative procedure for (Ph3P)2NiCl2 complex catalyzed amidation
reactions 132
3.9.1 6-Acetamido-10-amino-8-chloro-9,11-diaza-5H-benzo[a]-
phenothiazin-5-one, 236a 132
3.9.2 6-benzamido-10-amino-8-chloro-9,11-diaza-5H-benzo[a]-
phenothiazin-5-one, 236b 133
xii
3.9.3 6-(4-nitrobenzamido-10-amino-8-chloro-9,11-diaza-5Hbenzo[
a]phenothiazin-5-one, 236c 134
3.9.4 6-phthalamido-10-amino-8-chloro-9,11-diaza-5Hbenzo[
a]- phenothiazin-5-one, 236d 135
3.9.5 6-(2-hydroxybenzamido)-10-amino-8-chloro-9,11-diaza-
5H-benzo- [a]phenothiazin-5-one, 236e 136
3.10.0 REPRESENTATIVE PROCEDURE FOR COPPER(II)
CATALYZED N-ARYLATION USING ARYLTRIOLBORATES 137
3.10.1 10-(phenylamino)-1,9,11-triaza-5H-benzo[a] phenothiazin-
5-one, 239a 137
3.10.2 10-((3-chlorophenyl)amino)-1,9,11-triaza-5H-benzo[a]phenothiazin
-5-one, 239b 138
3.10.3 10-((4-bromo-phenyl)amino)-8-chloro-1,9,11-triaza-5Hbenzo-
[a]phenothiazin-5-one, 239c 139
3.10.4 6,8-dichloro-10-((phenylamino)-9,11-diaza-5H-benzo[a]
phenothiazin-5-one, 240a 139
3.10.5 6,8-dichloro-10-((3-chlorophenyl)amino)-9,11-diaza-5Hbenzo
[a]phenothiazin-5-one, 240b 140
3.10.6 10-((4-bromophenyl)amino)-6,8-dichloro-9,11-diaza-5Hbenzo
[a]phenothiazin-5-one, 240c 141
3.11.1 EVALUATION OF THE SYNTHESIZED ANGULAR
AZA-PHENOTHIAZINONES AND ANGULAR
AZA-PHENOXAZINONE FOR ANTIMICROBIAL 141
xiii
3.11.2 DETERMINATION OF MINIMUM INHIBITORY
CONCENTRATION (MIC) 142
CHAPTER FOUR
4.0 Results and discussion 144
4.1 2,6-Diamino-4-chloro-5-thiocynatopyrimide 144
4.2 2,6-Diamino-4-chloro-pyrimidine-5-thiol 145
4.3 8-Hydroxy-5-nitrosoquinoline hydrochloride 146
4.4 8-Hydroxy-5-nitroquinoline 146
4.5 7-Chloro-8-hydroxy-5-nitroquinoline 147
4.6 5-Amino-7-chloro-8-hydroxyquinoline 147
4.7 7-Chloro-5,8-quinolinequinone 148
4.8 10-Amino-8-chloro-1,9,11-triaza-5-benzo[a]phenothiazin-5-one 148
4.9 10-Amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazine-5-one 151
4.10 1-Aza-5H-benzo[a] phenothiazin-5-one 153
4.11 1-Aza-5H-benzo[a]phenoxazin -5-one 155
4.12 Palladium catalyzed synthesis of some derivatives of 10-amino-8-chloro-
1,9,11-triaza-5H-benzo[a]phenothiazin-5-one (Mizoroki-Heck) 157
4.13 Palladium catalyzed synthesis of some derivatives
of 1,aza-5H-benzo[a]phenothiazin-5-one (Mizoroki-Heck) 162
4.14 Palladium complex catalyzed synthesis of some derivatives
of 1,aza-5H-benzo[a]phenoxazin-5-one (Mizoroki-Heck) 166
xiv
4.15 Nickel catalyzed synthesis of some derivatives of 10-
amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one
(Buchwald-Hartwig amidation reactions) 169
4.16 Palladium-catalyzed synthesis of some derivatives of 10-
amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one
(Buchwald-Hartwig amination reactions) 173
4.17 Palladium-catalyzed synthesis of some derivatives of 10-
amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one
using heterocyclic amines (Buchwald-Hartwig amination) 178
4.18 Copper-catalyzed synthesis of some derivatives of 10-
amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one
(Yamamoto et al) 181
4.19 Copper-catalyzed synthesis of some derivatives of 10-
amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one
(Yamamoto et al) 184
4.20 Antimicrobial screening test of the synthesized angular phenothiazinones
and phenoxazines 188
4.21 Conclusion 196
REFERENCES 198
APPENDIX 225
xv
CHAPTER ONE
INTRODUCTION
1.0 Background of study:
In the last few decades, the chemistry of phenothiazine 1, phenoxazine 2 and their
derivatives have been of great interest to organic chemists.
S
N
H
1
O
N
H
2
Much earlier, Bernthsen in 18831,2 accidentally discovered phenothiazine parent
ring 1 and eight years later the same researcher reported2 the first parent ring of
phenoxazine2.
All these discoveries were made during his classical studies on the structure of
thiazine dyes. Some phenothiazine derivatives, notably Lauth’s Violet 3 and Methylene
Blue 41 were commercially available as dyes even before the discovery of the parent
phenothiazine3.
S
N
H2N NH2
Cl
3
+
S
N
NMe2
Cl
4
+
Me2N
A lot of structural modifications have been carried out since the discovery of
parent compounds 1 and 2 in search of compounds with improved properties. Hence
2
subsequent variations in their parent structure have given rise to a large number of
derivatives of pharmaceutical and industrial interests.
Initial attempts were made on side-chains and N-alkyl-aminoalkyl derivatives
which were used in medicine, agriculture and industry.
Phenothiazine and its derivatives including many other organosulphur compounds
find their greatest applications in medicine4, pesiticides5, dyes and pigments, 6,7,8,
industrial antioxidants9,10, in gasoline and other petroleum lubricants; thermal
stabilizers11, acid-base indicators6, sensitizers for photocopying materials, polymerization
retardants6 and also very popular in material science as marker for proteins and
deoxyribonucleic acid (DNA) 12(a-c) to mention a few.
In medicine, phenothiazine derivatives possess several biological activities
including antibacteria 13-14and antifungal22-24, antipsychotic15-16 and anti-inflammatory17-
18, antiparkinsonian activities19, anti-tubercular20-21, anticonvulsant25, anti-worm26 for
livestock and cardiovascular27 activities among others.
Similarly phenoxazine and its numerous derivatives have been shown to possess a
broad spectrum of pharmacological activities. Notably among them are tranquilizing
agents28, antitumor29-30 antimicrobial31, anti-inflammatory32, antiviral33, insecticidal
properities34, antituberculosis35-36, sedative and central nervous system (CNS)
depressant37.
Although phenothiazine derivatives have many useful medicinal properties, they
also have several undesirable side effects such as dryness of mouth, drowsiness,
lassitude38, etc. Many phenoxazine derivatives, in addition to their marked
pharmacological effects, also display high levels of toxicity 39-40.
3
In the effort to control these side effects, some structural modifications were
carried out. This led to the synthesis of some important drugs like promethazine 5,
chlorpromazine 6, diethazine 7 and propiomazine 841-42.
N
S
CH2-CH-N(CH3)2
CH3
5
N
S
Cl
(CH2)3N(CH3)2
6
N
S
(CH2)2N(C2H5)2
7
N
S
CH2CH-N(CH3)2
CH3
COCH2CH3
8
N
S
(CH3)2 N- (CH2)3
9
These drugs are also clinically useful in the chemotherapy of mental and
emotional disturbance 42. In addition to the main neuroleptic action of phenothiazine
family, other biological activities of importance to their cancer chemopreventive effect
were also documented in the literature43-45
4
More report by Karreman et al46 on the therapeutic action of phenothiazine
derivatives showed that promazine 9 and chlorpromazine 6 and their tranquilizing effect
is due to the basic nitrogen of phenothiazine ring that releases electrons to the biological
receptor by charge transfer mechanism37. Hence the derivatives of phenothazine with
annular nitrogen atoms were found to be better drugs than those without annular nitrogen
atoms. This inferred that prothipendyl 10 and isothipendyl 11 which are derivatives of 1-
azaphenothiazine analogue of promazine are more potent than promethazine 5,
chlorpromazine 6 and diethazine 7 in the treatment of mental disorders especially in acute
psychosic complicated with latent epilepsy47.
S
N N
(CH2)3 – N(CH3)2
10
S
N N
(CH2) CH – N(CH3)2
CH3
11
Further search for more potent drugs led to molecular modification of linear
phenothiazine leading to aza-phenothiazine ring systems. This resulted in the preparation
of derivatives in which a benzo group is fused onto one of the side rings leading to the
tetracyclic aza-phenothiazine 1247. Before then, four monoaza1, ten diaza38 and four
triaza49-50, phenothiazine ring systems were prepared and characterized.
5
S
N
N
H
12
R1 R3
R2
R1,R2 R3 = any substituent such as -NH2, -NMe2, X(Cl, Br, I) etc.
As an extension of these works, Okafor et al47 successfully synthesized 1,4,6,8-
tetraazabenzo[b] phenothiazine ring system 13 (48,51) as a new ring in these series. The
name of the new ring is quinozaline,[2,3-b]1[1,4]pyrimido[5,6-e]thiazine.
N
N
S
N
N
N
H 1
R1
2 R3
3
11
12
13
14
6 5 1
7
8
9 10
4
13
Phenoxazine 2 is a useful antioxidant9 although it is inferior to phenothiazine 1.
However, its derivative, 2-amino-3H- phenoxazin-3-one 14 exhibits marked inhibiting
action on the growth of some selected species of Clostridium botulinum 51-53
O
N NH2
O
14
Many polycyclic compounds containing a phenoxazine ring system are used as
biological stains, fabric dyes and light emitting materials in dye lasers such as cresyl
violet and nile blue26a – b
Further works on the synthesis of different structural modification led to the
fusion of the benzene ring in the [a] position of the parent ring of phenothiazine 1 and
6
phenoxazine 2. This resulted in the formation of angular or non-linear
benzo[a]phenothiazine6 and benzo[a]phenoxazine1 of types 15 and 16.
S
N
H
A B C
D
15
O
N
H
A B C
D
16
Okafor53 – 55,58 reported that compounds 15 and 16 were the earliest and simplest
modifications of parent phenothiazine and phenoxazine. Meldola Blue 17 a derivative of
the angular phenoxazine 16 was commercially available as a blue dye long before the
parent phenoxazine and phenothiazine were discovered by Bernthsen2.
O
N
Me2N
+ Cl
17
S
N
H
18
The earliest recorded report of an angular phenothiazine was made in 1890 by
Kym55a, who synthesized benzo[a]phenothiazine 18 in 40% yield. This was done by
heating 1-anilinonaphthalene 19 with sulphur at elevated temperatures. Shirley55b later
improved the yield by adding catalytic amount of iodine to achieve a 71% yield. These
compounds were used as drugs, thermal stabilizers and dyes 60. More derivatives of
angular phenothiazine 20 and phenoxazine 21 were also synthesized subsequently.
7
N
H
19
S
N
O
R
O
N
O
20 21
R2
R1
R = R1 = Et2N, R2 = H, and R1 = Et2N, R2 = PhNHCO]
Further structures in which the ring A or D of the non-linear systems 15 and 16
have been replaced by pyridine or pyrimidine fragments giving rise to the aza-analogues
of angular phenothiazine and phenoxazine which have been synthesized such as 22, 23
and 241, 48,60.
X
N
H N
22
X
N
H
N
23
X
N
H
2N
24
X = O or S
The first aza analogues of angular phenothiazine 25 and 26 were reported by
Okafor60 by heating a mixture of suitably substituted o-amniopyridinethiol and 2,3,-
dichloro-1,4-naphthoquinone in chloroform following a similar procedure by Agarwal
8
and Mital58b using o-aminothiophenol. Other examples are: 1-azabenzo[a]phenothiazine
27 and 8,10-diaza-5H-benzo[a]phenothiazin-5-one 28.
N S
N H
R
Cl
O
25
N
N
S
N
NH2
Cl
O
26
R = H,Cl, OMe
S
N
H N
27
N
N
S
N
O
28
Further variation of these angular azaphenothiazines was achieved by Okafor et
al47. by replacing the ring sulphur with oxygen leading to angular azaphenoxazine 29.
This was obtained by treating 2-amino-3-pyridinol 30 with a stoichiometric amount of
2,3-dichloro-1,4-naphthoquinone 31 in chloroform in the presence of anhydrous sodium
carbonate or sodium acetate to get an orange solid (97%), m.p 232-2330C.
9
N
O
N
Cl
O
29
N NH2
OH
30
Cl
Cl
O
O
31
Prior to Okafor’s report58a, Noelting59 in 1922 reported the synthesis of 4-azaanalogue
32. He obtained the blue dye by the reaction of 8-hydroxyquinoline 33 with ohydroxy-
N,N-dimethylaniline hydrochloride 34 in the presence of a trace of zinc. This
product is a good blue mordant dye for cotton mordanted with tannin and fixed by iron,
aluminum or chromium mordant.
O
N N
O
32
N
OH
33
NMe2
OH
34
HCl
Interest in the aza-analogues of phenoxazine derivatives has grown tremendously
since the dawn of the 20th century. Some angular aza-phenoxazines especially the
10
pyridol[3,2-a]phenoxazines occur in nature. Among them are rhodommatin 3561-63 and
xanthommatin 36 which are responsible for the coloration in the wings of insects of the
Lepidoptera family and in the eyes of the butterfly-papilio xuthus as examined by some
Japanese workers.63
O
N NH
O
C
O O 2C-CH-CH2
NH3
H
CO2H
O
O
OH
OH
HOH2C
OH
+
35
Further variations in the structure of non-linear aza phenothiazines and
phenoxazines were observed and in an effort to synthesize new dyes, pigments and drugs,
Okafor63 and Okoro64-65et al synthesized new non-linear and three(Y)-branched azaphenothiazine
and aza-phenoxazine systems represented as 37,38,39.
O
N N
HO
O2C-CH-CH2-C=O
NH3
CO2H
O
+
36
11
N
S
N
S
N
N
37
N
S
N
S
N
N
H2N
35
38
N
O
N
S
N
R
39
R = H, Cl, OMe
1.1 Transition metal catalyzed tandem reactions
Tandem reactions constitute a fascinating branch of organic chemistry. It is an
organic reaction in which several bonds are formed in sequence without isolating the
intermediates or changing reaction conditions or adding reagent66. It allows the synthesis
of complete multinuclear molecule from single precursor and that may be the reason why
some researchers called it a one-pot synthesis. This is because everything that is
necessary for the reaction must be incorporated into the starting materials.
There are undeniable benefits of tandem reactions which have been established
and have been recounted on numerous occasions. These include: atom economy,
economy of time, labour, resource management, minimal waste generation and functional
12
group tolerant of the starting partner67. Tandem reactions have wide applications mostly
in transition metal-catalyzed organic synthesis. They have been used extensively in both
the ring synthesis and the functionalisation of heterocycles68-74.
For more than two decades palladium-catalyzed cross-coupling reactions have
blossomed into extraordinarily powerful tools for carbon-carbon and carbon-heteroatom
bond formation and research in this field continues apace72,75-76. Palladium catalyst
occupies a special place followed by the nickel and most recently the soluble copper
complexes which serve as a convinenent replacement of Ullman harsh reaction
conditions77-78. Despite that, palladium has the advantage of being compatible with many
functional groups including its synthetic versatility. It is an ideal catalyst for tandem
reactions79.
Among the palladium – catalyzed C-C bond formation reactions, the Mizoroki-
Heck has undoubtedly found the most applications in tandem processes especially in
intramolecular reactions80-82.
Other transition metal catalyzed cross-coupling reactions that have revolutionized
synthetic strategies include:
i. Buchwald-Hartwig coupling reaction
ii. Suzuki-Miyaura cross-coupling reactions.
iii. Sonogashira reactions of arylalide using terminal alkynes
iv. Stille cross-coupling reactions of arylhalides using stannanes
v. Migita-kosugi cross-coupling reactions using organotin substances and
vi. Negishi palladium-catalyzed cross-coupling reactions using allyl-alkenyl
substrates among others. These interesting studies opened the new way for reactions
13
which brought about the recognition of Richard Heck, Akira Suzuki and El-ich
Negishi who were the receipients of 2010 Nobel Prize83 in chemistry.
Mizoroki-Heck cross-coupling reations have been applied to diverse array of
fields ranging from natural products and to material science, including biologically
important molecules82. Several reviews of Mizoroki-Heck cross-coupling reaction have
been published in literature84-86.
Similarly, transition metal catalyzed amination and amidation are reactions which
utilize Buchwald-Hartwig protocols for the formation of carbon-nitrogen bonds. The
success of these reactions is tremendous and has found its use in the synthesis of natural
products, material science products and nitrogen containing ligands81.
A plethora of reports has appeared during the last few years regarding the
application of the C-N coupling methodology for the synthesis of natural products or
active ingredients for pharmaceutical or agricultural use. These reactions were
traditionally performed with aryliodides under Goldberg who modified Ullmann harsh
cross-coupling reaction conditions of stiochiometric copper and high reaction
temperature3, 5,86-88. More advances in this area have allowed for the reactions of amides
and aryliodides or arylbromides using catalytic amount of copper under mild reaction
conditions 89-91.
Owing to the frequent occurrence of N-arylamines, N-arylanilines and N-aryl
imidazoles in pharmaceutically and agriculturally interesting compounds Yammamoto et
al96-98, carried out copper-catalyzed N-arylation with potassium aryltriolborate in the
presence of a reoxidant, trimethylamine N-oxide, a catalytic amount of Cu(OAC)2;
molecular sieves, toluene solvent and at room temperature. Hence they discovered and
14
reported that aryltriolborates are better aryl donors than traditional boronic acids and
trifluoroborates for copper(II)-catalyzed.
1.2 Statement of the problem
Phenothiazines and phenoxazines are compounds of great importance in
pharmaceutical, 7 agricultural8 and textile industries9,10,11. The most reported methods of
their synthesis have been based on classical procedures in which several intermediates
were prepared in order to get the finished products. There is however, loss of time,
material and resources in these processes due to difficulties in isolation and purification
of the required intermediates. Furthermore, most of these methods do not tolerate some
functional groups in the starting materials thereby limiting the functionalisation of the
final products. Hence, there is need to explore other methods of synthesizing the
functionalised angular phenothiazines and phenoxazines which will circumvent or
ameliorate these problems. Synthesis of these compounds employing Mizoroki-Heck,
Buchwald-Hartwig and Yamamoto transition metal-catalyzed tandem cross-coupling
reactions are viable options.
1.3 Objectives of the study
The main objective of this study is to synthesize new derivatives of phenothiazine and
phenoxazine using transition metal-catalyzed tandem reactions, and evaluate them for
antimicrobial activities.
The specific objectives of this work therefore were to:
i. synthesize functionalised organic intermediates leading to the synthesis of new
angular phenothiazine and phenoxazine compounds.
15
ii. convert the angular phenothiazine and phenoxazine compounds to their
derivatives via Mizoroki-Heck, Buchwald-Hartwig cross-coupling reactions and
copper-mediated N-arylation with aryltriolborates (Yamamoto et al)
iii. characterize the synthesized compounds and
iv. carry out antimicrobial screening on the new phenothiazine and phenoxazine
moieties.
1.4 Justification for the study
Phenothiazines and phenoxazines have been known for their usefulness and
applicability in different fields of human endeavour but their methods of preparation have
remained poorly developed54. There is also scarcity of works on their syntheses and
applications in most chemical literature. Our use of transition metal- catalyzed tandem
reactions in synthesizing alkenyl, amino and aryl derivatives of phenothiazines and
phenoxazines will help provide such information.
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