ABSTRACT
Synthesis of twelve O-arylated diazabenzo[a]phenoxazine-5-one and its
carbocyclic analogue is reported in 46 – 99 % yields. The intermediates
were prepared by anhydrous base catalyzed reaction of 2,3-dichloro-1,4-
naphthoquinone with 4,5-diamino-6-hydroxyl-2-mercaptopyrimidine and 2-
aminophenol. The O-arylation process occurred smoothly in non-polar
solvent, toluene with the inexpensive base, K2PO4 at 110oC. The
intermediates were combined with a variety of electron-deficient, electrically
neutral and electron-rich phenols in the presence of a catalyst combination of
Pd(OAc)2 and electron rich, bulky alkyldiarylphosphine ligand in which the
alkyl groups are tert-butyl (t-Buxphos), to furnish the arylated compounds.
Bulky yet basic nature of the phosphine ligand is thought to be responsible
for these transformations. The highest yields were obtained when the
intermediates coupled with electron rich phenols, with the carbocyclic
analogue giving better yields. IR, 1H NMR and 13C NMR spectra data,
confirmed the structures of all the synthesized compounds. The effect of the
synthesized compounds on bacteria and fungi growth was studied. The
studied compounds were found to be potent antibacterial and antifungal
agents as they showed significant biological activity against Escherichia
coli, Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and
Candida albicans. In addition, they may be useful as dyes in industries since
they absorb in the UV- visible region.
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TABLE OF CONTENTS
CHAPTER ONE
1.0 INTRODUCTION 1
1.1 BACKGROUND OF STUDY 1
1.2 Statement of problem 9
1.3 Objectives of the study 10
1.4 Justification for the study 11
CHAPTER TWO
2.0 LITERATURE REVIEW 12
2.1 Buchwald-Hartwig C–O Coupling Reactions 12
2.2 Mechanism of Buchwald-Hartwig C-O coupling reactions 22
2.3 Factors influencing the performance of a given C-O coupling
reactions 24
2.4 Angular phenoxazines 35
2.4.1 Benzophenoxazine ring system 35
2.4.2 Dibenzophenoxazine ring system 38
2.4.3 Aza analogues of benzo[a]phenoxazines 42
2.5 Applications of angular phenoxazines 47
CHAPTER THREE
3.0 EXPERIMENTAL SECTION 57
x
3.1 GENERAL REAGENT INFORMATION 57
3.2GENERAL ANALYTICAL INFORMATION 57
3.2.1 Synthesis of 11-amino-6-chloro-9-mercapto-8,10 –
diazabenzo[a]phenoxazin-5-one 3 58
3.2.2 Synthesis of 6-Chlorobenzo[a]phenoxazin-5-one 26 59
3.3 General procedure for Pd-catalyzed coupling
of angular diazabenzo[a]phenoxazine and related
carbocyclic analogue with phenols 60
3.4 Synthesis of 9-mecapto-11-amino-6-(4-methylphenoxyl)
-8,10-diazabenzo[a]phenoxazine-5-one 28a 61
3.5 Synthesis of 11-amino-9-mercapto-6-(phenoxyl)-8,10-
diazabenzo [a]phenoxazine-5-one 28b 62
3.6 Synthesis of 11-amino-9-mecaptho-6-(4-chlorophenoxy)
8,10-diazabenzo[a]phenoxazin-5-one 28c 63
3.7 Synthesis of 11-amino-9-mercapto-6-(2-aminophenoxyl)-
8,10-diazabenzo[a]phenoxazin-5-one 28d 64
3.8 Synthesis of 11-amino-9-mercapto-6-(4-isopropyl
phenoxy) benzo[a]phenoxazin-5-one 28e 65
3.9 Synthesis of 11-amino-9-mercapto-6-(naphthoxyl)
benzo[a] phenoxazin-5-one 28f 66
3.10 Synthesis of 6-(4-methoxyl phenoxyl) benzo[a]phenoxazine
xi
-5-one 29a 67
3.11 Synthesis of 6-phenoxylbenzo[a]phenoxazin-5-one 29b 68
3.12 Synthesis of 6-(4-chlorophenoxyl)-benzo[a]phenoxazine-5-one 29c 69
3.13 Synthesis of (2-aminophenoxyl)benzo[a]phenoxazin-5-one 29d 70
3.14 Synthesis of 6-(4-isopropylphenoxyl)benzo[a]phenoxazin-5-one 29e 71
3.15 Synthesis of 6-(1-naphthoxyl)benzo[a]phenoxazine-5-one 29 f 72
3.16 Antimicrobial screening of the novel compounds 72
3.17 Determination of minimum inhibitory concentration (MIC)
of the new compounds 74
CHAPTER FOUR
4.0 RESULTS AND DISCUSSION 75
4.1 General consideration of yield of the described products 75
4.2 Proposed catalytic cycle 86
4.3. UV/VIS spectroscopy results of the synthesized angular
phenoxazine derivatives 89
4.4 Confirmation of the structures of the diazaphenoxazine and
related carbocyclic anologue derivatives using IR spectroscopic data 91
4.5. NMR interpretation of angular diazaphenoxzines and related
carbocyclic analogues synthesized 105
4.6. Biological activity of the novel angular diazaphenoxazine
and benzophenoxazine derivatives 116
Conclusion 121
REFERENCES 122
xii
APPENDIX
CHAPTER ONE
1.0 INTRODUCTION
1.1 BACKGROUND OF STUDY:
Angular phenoxazines are defined as the polynuclear phenoxazines that
have non-linear arrangement ring system1. Angular phenoxazines and its aza
analogues constitute important classes of organic compounds because of their
wide range of commercial uses. They are used as dyes1 and drugs2. They exhibit
strong biological activities ranging from antidepressant3, antitumour4,
anticancer5, antibacterial6, and antituberculosis7 and schizophrenia agents8.
Among the several industrial applications of angular phenoxazine derivatives are
their use as acid-base indicator9, biological stains10, laser dyes11 and
chromophoric compounds12.
The report of the basic structure of the parent phenoxazine 1 prompted the
synthesis of several hundreds of derivatives, not only to improve their usefulness
but also to open up new area of applications.
N H
O
1
These structural modifications have given rise to benzo[a]phenoxazine 2,
benzo[c]phenoxazines 3, benzo[b]phenoxazine 4, benzo[j]phenoxazine 5,
2
benzo[i]phenoxazine 6 and benzo[h]phenoxazine 710 among others. These are all
carbocyclic phenoxazines.
N H
O
2 3
N H
O
N H
O
N H
O
4 5
N H
O
6 7
N H O
Structures 4 and 6 are linear phenoxazines while structures 2, 3, and 5 are
angular phenoxazines.
Phenoxazine compounds that have two benzo groups attached to
phenoxazine nucleus are called dibenzophenoxazines. These include compounds
8, 9, and 10.
3
N H
O
8
N H
O
9
10
N H
O
Some of the structures of angular phenoxazines are very complex. For example
compounds 1114, 1215,1316 and 1417.
N H
O NH
O
N H
O
O
11 HN
12
4
N H
O
N H
O
O S O
ONa
O S O
ONa
HO
OH
X
13
N H
O
N H
O
14
Phenoxazine derivatives produced by the fusion of the benzo group at ‘a’
position or 1, 2 bonds have been reported; 1518,1613 and 1719 which have been
used as dyestuff20 and good indicators21. They have been shown to exhibit
anticancer22, 23 and antibacterial activities24.
N H
Me2N O
KO3S SO3K
15
HCl
N H
O N+Et2N H2
Cl-
16
5
17
N H
N O + NHR3
HO
R
R
Replacement of one of the ring carbon atoms of angular phenoxazine analogues
with heteroatom such as oxygen, gives phenoxazines called
pyranophenoxazines13: 18, 19.
18
N H
O
O
N H
O
O
O
Cl
19
Variations in phenoxazines ring system because of replacement of one or
more CH groups by annular nitrogen have given rise to monoaza 20, diaza 21,
and triaza 22 analogues of phenoxazines. Compounds in each of these aza family
have been synthesized and reported25.
20
N
O
N
O
N N
H
O+ OH
21
6
22
N
N
N H
O
N
Some of these aza derivatives have substituents; 23 and 2426.
N N
O O
NH2
NHPh
N N
O O
R
Cl
R = NH2, NO2, NHOAc.
23
24
Several authors have reported cross coupling reactions used for the
synthesis of these derivatives27. Such coupling reactions includes Sonogashira
cross coupling reaction, Suzuki cross coupling reaction, Stille cross coupling
reaction, Buchwald-Hartwig cross coupling reaction and Heck-Mozoroki cross
coupling reaction. The discovery of these cross-coupling reactions constitutes
one of the most striking breakthroughs in organic chemistry, and it has brought
many benefits to organic chemists:
· It is extremely powerful and a general strategy for the formation of C – C
and C – hetero aromatic bonds.
7
· It has changed the methodology for the retro synthesis enabling the
Organic Chemists to shorten the synthetic procedure27,28
· The reaction has gained wide use in synthetic organic chemistry finding
application in many total synthesis and industrial preparation of numerous
pharmaceuticals 27, 29.
Several transition metal catalysts have been developed in response to the
increasing demand of these coupled products in chemical pharmaceutical
industries. The sole aim is to exert the highest turnover frequency27,28. Literature
has shown that palladium catalyzed cross coupling reactions and the Hartwig-
Buchwald coupling are the most frequently used routes for the formation of
carbon hetero aromatics bond 28. Buchwald group developed a series of catalyst
based butyl electron rich phosphine ligands that have attracted much attention
due to their ability to affect various C – C, C – N and C –O bond formation28.
Prominent amongst these are 2-(dicyclohexylphosphino)-2, 4, 6-
triisopropylbiphenyl(Xphos), 2-ditertiarybutylphosphino-1,2,3-triisopropyl
biphenyl(t-Buxphos), 2-dicyclohexylphosphino-21, 61-dimethoxybiphenyl
(Sphos), 2-dicyclohexylphosphino-21, 61-diisopropoxylbiphenyl(Ruphos) and 2-
(dicyclohexylphosphino)-3,6-dimethoxyl-21,41,61-triisopropyl-11,11-biphenyl
(Brettphos). Dialkylbiarylphosphine ligands and the pre catalysts derived from
them are commonly referred to as Buchwald ligands and pre catalysts
8
respectively. These reagents have developed into a highly valuable class of
compounds for palladium-catalysed reactions, and can be used for a broad range
of reactions. Palladium catalysed cross-coupling reactions have been tools for
C-C and C-heteroatom bond formation in academic and industrial settings 30, 31.
However, palladium sources can have significant problems in generating active
catalyst32. For example, stable Pd (0) sources such as Pdn(dba) contains
dibenzyldeneacetone (dba) ligands that can impede the catalytic cycle. These Pd
species can also contain varying degrees of free dba and palladium nanoparticles
33. As researchers explore cross-coupling reactions that are more complex, the
method for generation of the catalytically active LnPd (0) species has often
proven to be vital to the success of cross-coupling reactions 32. Pd (II) sources
such as Pd (OAc) 2 and PdCl2 need to be reduced to Pd (0) in situ before entering
a Pd (0) – Pd (II) cross-coupling cycle. The palladium (II) sources are usually
reduced using ligands. t-Buxphos has been found to be excellent supporting
ligand for pd-catalyzed C – O bond forming reactions33 due to the presence of
monophosphine in the structure. Consequently, Buchwald catalyst, which is
combination of palladium complex and Buchwald ligand (t-Buxphos), was used
in this study.
9
1.2 Statement of problem
Although a wide range of linear and angular phenoxazine compounds
have been synthesized, only a limited number of their derivatives have been
prepared. Furthermore, their biological activities are understudied. Because of
this, parent phenoxazine 1 has been continuously modified in this direction to
open new area of application.
N
O
1
Benzo[a]phenoxazine 26 and diazabenzo[a]phenoxazine nucleus 25 have
been known for years but their chemistry remains poorly developed 34
N
N
N
O O
Cl
NH2
HS
25
Still more grossly under studied is the O-arylated angular phenoxazines.
Before now, no significant work has been done using Buchwald catalyst to Oarylate
diazaphenoxazine and related carbocyclic analogue. Interest in this type
of ring system made us to synthesize twelve new phenoxazines nucleus, which
are O-arylated using Buchwald catalyst.
N
O O
26 Cl
10
1.3 Objectives of the study
The objectives of this work therefore are to
· Synthesize angular diazaphenoxazine and related carbocyclic
analogue compound of the type 2 and 3.
N
N
N
O O
NH2
HS
Cl
N
O O
25 26 Cl
· O-Arylate the angular diazaphenoxazine and the related carbocyclic
analogue using Buchwald catalyst as shown below:
N
N
N
O O
Cl
NH2
HS N
N
N
O O
NH2
O
HS
OH
+ X
X
Pd(OAc)2 / L
k3PO4
toluene, 110 0c
H2O, 8hrs
25 27
28
11
N
O
Cl
O
+
OH
x
N
O
O
O
x
Pd(OAc)2/L
K3PO4
Toluene,110oc
H2O,8hrs
26 27
29
X = H, Me, isopropyl, methoxy, chlorine, and benzene ring
L = t-Buxphos.
· Characterize the compounds synthesized using UV, IR and NMR
spectrophotometer.
· Carry out antimicrobial screening on the new phenoxazine scaffold.
1.4 Justification for the study
The study provides new and facile route of making novel polycyclic ring
systems thereby extending methods available for obtaining phenoxazine
derivatives. Thus, it generates new area for further research. The newly
synthesized compounds could be useful as potent antimicrobial agents in
medicine and may be used as dyes in the industries since they show absorption
in UV-visible region.
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