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Digitally Signed by: Content manager’s Name
DN : CN = Weabmaster’s name
O= University of Nigeria, Nsukka
OU = Innovation Centre
Nwamarah Uche
FACULTY OF PHYSICAL SCIENCES
DEPARTMENT OF PURE AND INDUSTRIAL CHMISTRY
TANDEM AMIDATION CATALYSIS IN THE SYNTHESIS OF
DIAZAPHENOXAZINECARBOXAMIDES OF PHARMACEUTICAL INTEREST
EDOKA OBIANUJU ORRITTA
PG/MSC/10/57249
2
TANDEM AMIDATION CATALYSIS IN THE SYNTHESIS
OF DIAZAPHENOXAZINECARBOXAMIDES OF
PHARMACEUTICAL INTEREST
BY
EDOKA OBIANUJU LORRITTA
PG/MSC/10/57249
DEPARTMENT OF PURE AND INDUSTRIAL CHEMISTRY
UNIVERSITY OF NIGERIA, NSUKKA.
MAY 2013
3
TITLE PAGE
UNIVERSITY OF NIGERIA, NSUKKA
FACULTY OF PHYSICAL SCIENCES
DEPARTMENT OF PURE AND INDUSTRIAL CHMISTRY
CHM 592, RESEARCH (PROJECT)
TANDEM AMIDATION CATALYSIS IN THE SYNTHESIS OF DIAZAPHENOXAZINE CARBOXAMIDES
OF PHARMACEUTICAL INTEREST
A RESEARCH PROJECT SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENT FOR THE
AWARD OF MASTER OF SCIENCE (M.Sc) DEGREE IN ORGANIC CHEMISTRY
BY
EDOKA, OBIANUJU LORRITA
PG/M.Sc/10/57249
PROJECT SUPERVISOR: PROF. U.C. OKORO
4
APPROVAL PAGE
This work has been approved by the Department of Pure and Industrial Chemistry, University of Nigeria Nsukka
_________________________ ________________________
PROF. U.C OKORO DR. A. E. OCHONOGOR
Project Supervisor Head of Department
Date______________________ Date_________________
5
6
CERTIFICATION
This is to certify that the research work titled “Tandem amidation catalysis in the syntheses of diazaphenoxazine
carboxamides of pharmaceutical interest” was carried out by Edoka, Obianuju Lorrita. (PG/M.Sc/10/572) and has
been approved by the undersigned as having met the standard of the Department of Pure and Industrial Chemistry
University of Nigeria, Nsukka submitted in partial fulfillment of the requirements for the award of M.Sc in Organic
Chemistry.
_________________________ ________________________
PROF. U.C OKORO Dr. A. E. Ochonogor
Project Supervisor Head of Department
Date______________________ Date_________________
7
DEDICATION
This project is dedicated to Almighty God, the Great I am that I am, the
Immortal and Invisible, who brought me where I am today and provided for
me. May His name be praised forever in Jesus name.
8
ACKNOWLEDGEMENT
I wish to express my sincere gratitude to God Almighty for His love and abundant grace that ensured the
accomplishment of this work. My special appreciation goes to my supervisor Prof. U. C. Okoro for his moral and
material support that made this work a success. His tireless effort, encouragement, provision of essential chemicals
as well as keen interest at every stage in the work cannot be over emphasized. He connected me to his friend in UK
for the analysis of my product using NMR machine.
My profound gratitude goes to Mr. and Mrs. Clifford Amah and family for their spiritual and material support. My
deepest gratitude goes to Mr. and Mrs. Christian Emodi and family for their care both spiritually and materially,
may the Lord reward all of you in Jesus name. I also appreciate Anya Christian for his assistance in sourcing
materials from internet. Again my special regard and thanks goes to Mr. and Mrs. Isaac Ugwu, Mr. and Mrs. Peter
Ikeh and Mercy Oraka for their prayers and support.
Finally, my deepest gratitude goes to Florence, Peace, Ada, Christy, Tochi, Joy and Onyekachi for their care and
support towards the success of this work. This report will be incomplete if I fail to thank members of my fellowship
for their prayers and care. May Almighty God reward all of you in Jesus name Amen.
9
ABSTRACT
Tandem amidation catalyzed synthesis of linear diazaphenoxazine carboxamide derivatives is reported. This was
achieved by the reaction of 2-amino-3-hydroxypyridine and 2,3,5-trichloropyridine in aqueous basic medium which
gave 3-chloro-1,9-diazaphenoxazine as white solid crystals. 3-Chloro-1,9-diazaphenoxazine was then subjected to
Buchwald-Hartwig amidation coupling reaction with various amides namely formamide, phthalamide, 4-
nitrobenzamide, benzamide and acetamide via water promoted catalyst preactivation protocol to afford the
following, 3-amido derivatives of 1,9-diazaphenoxazine namely 3-formamido-1,9-diazaphenoxazine, 3-
phthalamido-1,9-diazaphenoxazine, 3-(4-nitrobenamido)-1,9-diazaphenoxazine, 3-benzamido-1,9-
diazaphenoxazine and 3-acetamido-1,9-diazaphenoxazine. The compounds were characterized using UV-visible,
FTIR, 1HNMR and
13CNMR spectroscopy.
10
LIST OF ABREVIATIONS
DMF: N,N-dimethyl formamide
DMAC: N,N-dimethyl acetamide
DMSO: Dimethyl sulfoxide
DMEDA: N,N-dimethyl ethylenediamine
DIBAH: Diisobutyl aluminum hydride
CNS: Central nervous system
WBC: White blood cell
KBr: Potassium bromide
UV: Ultraviolet
IR: Infrared
NMR: Nuclear magnetic resonance
TMSO: Trimethylsulfoxide
11
CHAPTER ONE
1.0 INTRODUCTION
1.1TANDEM CATALYSIS
The term tandem catalysis represents processes in which “sequential transformation of the
substrate occurs via two (or more) mechanistically distinct processes”1 and there is no need to
isolate the individual intermediates as the entire reaction takes place in one pot.
Types of tandem catalysis
There are three types of tandem catalysis
Orthogonal tandem catalysis: In this type of catalysis, there are two or more mechanistically
distinct transformations, two or more functionally and ideally non-interfering catalysts with all
catalysts present from the outset of the reaction, as shown in Scheme 1.
Scheme 1
Substrate A Product AMechanism B Mechanism A Mechanism B Product B
Catalyst B Catalyst A Catalyst B
Auto-tandem catalysis: In this type of catalysis, there are two or more mechanistically distinct
transformations which occur via a single catalyst precursor; both catalytic cycles occur
12
spontaneously and there is cooperative interaction of all species present at the outset of the reaction
as shown on Scheme 2
Scheme 2
Product AMechanism A Mechanism B Product B
Catalyst A
Substrate A
Catalyst A
(A)
Assisted tandem catalysis: In this type, two or more mechanistically distinct transformations are
promoted by a single catalytic species while the addition of a reagent is needed to trigger a change
in catalyst function,2 as shown in Scheme 3.
Scheme 3
Catalyst B
Product AMechanism A Mechanism B Product B
Catalyst A
Substrate A
trigger
1.2 TANDEM REACTIONS
In so far as one of the fundamental objectives of organic synthesis is the construction of complex
molecules from simpler ones, the importance of synthetic efficiency becomes immediately
apparent and has been well recognized. The increase in molecular complexity that necessarily
accompanies the course of a synthesis provides a guide (and a measure) of synthetic efficiency. As
13
a goal, one would like to optimally match the change in molecular complexity at each step with
reaction of comparable synthetic complexity.
Thus, the creation of many bond, rings and stereocenters in a single transformation is a necessary
(although not sufficient) condition for high synthetic efficiency. The ultimate, perfect match would
constitute a single-step synthesis. More realistically, especially In view of the desire for general
synthetic methods, the combination of multiple reactions in single operations increase molecular
complexity is a powerful means to enhance synthetic efficiency.
The concept for reactions in tandem as a strategy for the rapid construction of complex structures is
well-known and has been reviewed1. In addition, a recent international attention, and books
dedicated to tandem reaction3 and multi component cyclizations have now appeared. Within the
universe of tandem reactions, the constellation of consecutive pericyclic reactions is still vast.
Consecutive pericyclic reactions involving at least one cycloaddition have enjoyed extensive
application in synthesis as exemplified by tandem benzocyclobutene opening, Diels-Alder
reactions4, Danheiser
’s aromatic annulation
5, electrocyclic opening of 1,3-dipolar cycloaddition and
endiandric acid cascade6.
1.3 DEFINITION OF TANDEM REACTIONS
The dictionary definition of tandem as “one behind the other” is in itself, insufficient since every
reaction sequence would then be a tandem reaction. However, a rigorous and all encompassing
definition of tandem or sequential reactions is very difficult to formulate because of the continuum
of chemical reactivity. In other words we must decide what constitutes a reactive intermediate or a
14
stable, isolable entity which given the circumstances of reactant structure or reaction conditions,
undergoes a secondary transformation .What is unique about the type of tandem process
exemplified by tandem pericyclic reaction is the structural change that accompanies the initial
reaction and the creation of an intermediate with the necessary functionality to perform the second
reaction .Furthermore, if the process involves sequential addition of reagents the second reagent
has to be included into the product. In addition, new bonds and stereocenters have to be created in
the second reaction.
There is an all-encompassing definition of tandem as reactions that occur one after the other, and
use the modifiers cascade (domino), consecutive, and sequential to specify how the two (or more)
reactions follow. Thus, the family tandem cycloaddition reaction can be divided into three
categories with the following definitions.
Tandem cascade cycloadditions: In this, the reactions are intrinsically coupled, that is, each
subsequent stage can occur by virtue of the structural change brought about by the previous step
under the same reaction conditions7.
In tandem cascade cycloadditions, both processes take place without the agency of additional
components or reagents. Everything necessary for both reactions is incorporated in the starting
materials .The product of the initial stage may be stable under the reaction conditions; however, the
intermediate cannot be an isolable species but rather is converted to the tandem product upon
workup. The classic examples of tandem cascade cycloadditions are “pincer”(path a) and
“domino” (path b) modes of Diels-Alder reactions which have served as the corner stone in the
15
synthesis of the formidable pagodane and dodecahedrane8 structures respectively, as shown in
Scheme 4
Scheme 4
(4 + 2)
(4 + 2)
(4 + 2)
(4 + 2)
H
CO2Me
CO2Me
CO2Me
CO2Me
H
MeO2C
"pincer mode"
MeO2C
path a
CO2MeMeO
2C
path a
CO2Me
CO2Me
"domino mode"
Tandem consecutive cycloaddtion, are reactions where the first cycloaddition is necessary but not
sufficient for the tandem process, i.e external reagents or changes in reaction conditions are also
required to facilitate propagation9.
16
Tandem consecutive reactions differ from cascade reactions in that the intermediate is an isolable
entity. The intermediate contains the required functionally to perform the second reaction, but
additional promotion10
in the form of energy (heat or light) is necessary to overcome the activation
barriers. Many examples of such consecutive cycloadditions have been documented10
. A
particularly illustrative example is shown in Scheme 5.
Scheme 5
OMe
OMe
+(2 + 2)
OMe
(4 + 2)
OMe
O
O
MeO
Cl
Cl
Cl O
O
hv
Cl
O
O
ClCl
ClCl
ClCl
Cl
MeOCl
The [4+2] cycloaddition produces a new olefin which is poised for an intramolecular [2+2]
cycloaddition. Although, the first reaction is necessary, it is not sufficient for the tandem process,
and a change in conditions (photochemical activation) is required.
Another example shown in Scheme 6 illustrates the problem of rigorous definition11
while the first
[4+2] cycloaddition is not strictly necessary in that the second [4+2] process are already present in
the precursor, the important structural consequences of intra molecularity is probably equally
significant for the success of the tandem process as shown in scheme 6.
17
Scheme 6
CH3 CH2
OR CH3
OR
OPh
CH2
Ph O
[4+2]
OR
OPh
CH3
heat
[4+2]
Tandem sequential cycloadditions are reactions wherein the second stage requires the addition of
the cycloaddition partners or another reagent.
Tandem sequential cycloadditions require the addition of the second component for the tandem
process to occur in a separate step. To qualify as a tandem reaction, the first stage must create
the functionality in the product to enable it to engage the second reaction. The intermediate may be
isolable, though this is not a necessity. This class of reaction is not as well recognized as the
previous ones, but it is nonetheless clearly illustrated in the synthesis of vernolepin and
vernomenin by Danishefsky12
(Scheme7)
Scheme 7
[4 + 2] [4 + 2]
H
CO2Me
TMSO
MeO
O
OH
CO2Me
18
Components of tandem [4+2]/[3+2] cycloaddition
The design of a tandem [4+2]/[3+2] cycloaddition process for nitroalkenes can be understood by
recognizing the central role played by nitrates (Scheme 8). Early studies on the use of nitroalkenes
as heterodienes (vide infra) led to the development of a general, high yielding, and stereoselective
method for the synthesis of cyclic nitronates. These dipoles are well-known to undergo 1,3-dipolar
cycloadditions (vide infra); however, synthetic applications of this process are rare. This is
undoubtedly due to the lack of general methods for the preparation of nitronates and their
instability. Thus, as illustrated in Scheme 8, the potential for a powerful tandem process is
formulated in the combination of an inverse electron demand [4+2] cycloaddition of a donor
dienophile (D denotes electron withdrawing group). The resulting tandem process can construct
four new bonds, up to four new rings, and up to six new stereogenic centers (three of which bear
hetero atoms).
19
Scheme 8
R2
R1
N+ O
-O CH3
CH3
nitro alkene
ON
CH3
CH3
R2
R1
O-
*
**
*
*
[4+2]
Lewis acid
nitronate
RO
Y+
N+OH
X
nitronate
[4+2]
ZZ
R
Y+
NO
Z
ZX
nitroso acetal
DA N
+ O-
O A N+ DOO
-
NDOO
A *
* * *
*
*
1.4 BUCHWALD-HARTWIG AMINATION
The Buchwald-Hartwig amination is an organic process describing a coupling reaction between an
aryl halide and an amine in the presence of base and a palladium catalyst which results in the
formation of a new carbon-nitrogen bond 13
.
The first example of a Buchwald-Hartwig amination reaction was realized in Kiev, Ukraine, in
1985, by Yagupolskii et al14
. Polysubstituted activated chloroarenes and anilines underwent C-N
coupling reaction catalyzed by one mole percent of [PdPh2(PPh3)2] in moderate yield.
20
Buchwald-Hartwig amination usually requires a catalytic process containing four components to
generate the C-N bond15
.
Solvents: The solvent used in Buchwald-Hartwig coupling play two important roles which are to
dissolve the coupling partners as well as being part of the base and allowing for a respective
temperature window for the reaction and also plays a crucial role in stabilizing intermediates in the
catalytic cycle16
.
Ligands: ligand stabilizes the palladium precursor in solution and also raises the electron density at
the metal to facilitate oxidative addition as well as provide sufficient bulkiness17
to accelerate
reductive elimination in the catalytic system.
Palladium precursor: palladium facilitates the reaction by acting as a catalyst in the reaction.
Bases: A base deprotonate the amine substrate prior to or after coordination to the palladium
centre.
1.5 LINEAR PHENOXAZINE
Phenoxazine 1 is the parent compound of a large number of useful organic dyes which have been
extensively studied due to the wide range of application of these compounds as acid-base and
redox indicators18
. The parent ring phenoxazine 1 was first synthesized by Bernthsen19
in 1887
soon after his pioneer work on phenothiaziine in 1879.
21
N
O
H
1
N
O
R2
NH2
O
R1
N
O
COpeptide
NH2
O
CO peptide
CH3 CH323
There are numerous naturally occurring phenoxazine derivatives. These have beer classified as
Ommochromes, Fungalmetalolites, Questiomycins, and Actiomycins. Phenoxazine derivatives of
type 2 are responsible for the coloration in microorganisms such as wood-rotting fungi and
moulds20
. The actinomycins, which are groups of very toxic antibiotics obtained from certain
species of the genus Streptomyces19
are complex chromopeptide derivatives21
of phenoxazine 3.
Many of them have been isolated and they differ mainly in the peptide chain. In small dies,
actinomycin antibiotic show anti-tumor activities in the treatment of Hodgkin’s disease, a cancer-
like disease of the lympthatic system20
.
Following repeated reports on the pharmacological properties of phenoxazine, attention was
diverted from their dyeing properties to a study of biological activities. From tests carried out with
laboratory animals and man, it was found that many phenoxazine derivatives showed pronounced
pharmacololgical properties as central nervous system depressants, sedatives, antiepileptics,
herbicides, tranquilizers, anti-tumor, antibacterial spasmolytic, anthelminthic and parasticidal
agents19,20,21
.
Furthermore, early improvement on the structure of phenoxazine involves change in the side chain
and the 10-alkylamino group. However, nowadays interest is being showed on the modifications on
22
the pheoxazinwe ring itself through replacement of one benzo groups with furan, pyrrole, pyridine
and pyrazine ring as the case may be. The modification could also involve expansion of the
oxazine ring leading to oxazepines and oxazocines
N
O
H
4
N
O
H
N N
O
H NO2
NO2
NN
O
H NO2
NO2
N
ON
H NO2
N
N
O
H NO2
NO2
Cl N
O
N
N
H
Cl
Cl N
N
O
N
H5 6
7
8 910 11
N
O NN
CH3
Cl
12
Compounds 4 and 5 are described as “linear phenoxazines” because of the linear arrangement of
the ring system22
. Consequently, polynuclear phenoxazines with a straight arrangement of the ring
systems are generally referred to as linear phenoxazines. There are also structures which
incorporates additional annular nitrogen atom(s). These are known as the aza analogues. Aza
analogues which bear one nitrogen atom is called mono aza analogues as shown in structures 6, 7,
8 and 9 above. Compounds 6, 7, 8 and 9 are known as 1-azaphenoxazine, 2-azaphenoxazine, 3-
azaphenoxazine and 4-azaphenoxazine, respectively, because of the position of the additional
annular nitrogen atom22
.
Further, there are also sometimes where two nitrogen atoms are added in the ring. These are called
diazaphenoxazines as shown in compounds 10, 11 and 12 above. Compounds 10, 11 and 12 are
called 1,4-diazaphexazine, 1,9-diazaphenoxazine and 3,4-diazaphenoxazine, respectively, because
of the position of the added annular nitrogen.
23
1.6 STATEMENT OF THE PROBLEM
The unending pharmaceutical applications of phenoxazine derivatives and unavailability of the
chemistry of 1,9-diazaphenoxazine-3-carboxamide derivatives in literature informed this research.
1.7 OBJECTIVES OF THE STUDY
I. To synthesize 3-chloro-1,9-diazaphenoxazine by a condensation reaction.
II. To use this systhesized diazaphenoxazine to couple the following amides: formamide,
phthalamide, 4-nitrobenzamide, benzamide and acetamide via the Buchwald-Hartwig
tandem amination protocol.
III. To use combined information from Uv-visible, IR and NMR (13
C and 1H) in the assignment
of structures of the synthesized 1,9- diazaphenoxzine-3-carboxamides.
1.8 JUSTIFICATION OF THE STUDY
Interest in naturally occurring and synthetic phenoxazine derivatives as pharmaceuticals prompted
the synthesis of new rings derived from phenoxazine with consistent reports on improved
pharmacological applications. Thus it is necessary to synthesize more compounds of phenoxazine
derivatives to increase the available raw materials for pharmaceutical industries.
24
CHAPTER TWO
2.0 LITERATURE REVIEW
2.1 TANDEM CATALYSIS (TRANSITION METAL CATALYZED AMIDATION AND
AMINATION REACTIONS)
A large body of literature regarding the coupling of carbonic acid amides has been accumulated in
the last twenty years. Intramolecular cyclization of bromo-substituted, amide-functionalized arenes
as reported in 1999 by Buchwald23
using either DPEPhos or XantPhos in combination with bases
such as Cs2CO3 and K2 CO3, to perform efficient cyclization43
as shown in Scheme 9
Scheme 9
( )n
N
Bn
O
BrO
NHBn( )n
Pd catalyst, ligand
base, toluene, 100oC
79-95%
An intermolecular coupling of carbamates with aryl bromides using P(t-Bu)3 was reported by
Hartwig in 199924
. This system allowed for the arylation of t-butyl carbamate at 1000C giving the
product in 62–86% yield as shown in Scheme 10
Scheme 10
R
Br
+ NH2 OBu-t
O
Pd(dba)2
P(t-Bu)3, 100oC
N OBu-t
H
OR
25
In 2000, Buchwald25
outlined the intermolecular coupling of amides with aryl halides using
XantPhos as the ligand. Using this procedure, carbamates and sulfonamides were also found to be
viable substrates for the coupling reaction. Moreover the scope was extended from aryl halides to
aryltriflates as coupling partners26
. The amidation proceeds at 45-1100 C using 1-4 mol% of
catalyst, as shown in Scheme 11
Scheme 11
X
R O
+HN R
2
R1
X = Br, OTf, l
Pd(OAc)2, XantPhos
CS2CO
3, 1,4-dioxane
R O
N
R1
R2
Further examples of the coupling of cyclic carbamates and urea were provided by Ghosh,27
who
developed an efficient method for the first intermolecular cross – coupling of oxazolidinones with
aryl chlorides using Pd2(dba)3,Cs2CO3 or K3PO4 as base and Buchwald’s biaryl ligands, as shown
below in Scheme 12.
Scheme 12
X
R
+OHN
RR
O
21
BR2
XON
RR
O
21
Pd2dba
3. Cs
2CO
3, toluene
R
26
Scheme 13
Br
R
SR
O
NH
1+Pd(OAc)
2, ligand
Cs2CO
3, toluene, 110oC
R
SR
O
1N
In 2000, Bolm28
reported the N-arylation of sulfoximines with a wide range of aryl bromides in
high yield employing chelating ligands such as BINAP, DPPF and DPEPhos as show in Scheme 13
above .
Regarding the arylation of hydrazines an intramolecur example was reported by Zhu29
, as shown in
Scheme 14.
Scheme 14
N
BrNH
Ac
Pd(OAc)2 DPEPhos
Cs2CO
3, toluene, 110oC N
N
Ac97%
In 2003, Evindar et al30
reported an intramolecular quanidinylation. Using Pd(PPh3)4 almost
quantitative yields could be achieved, nevertheless the complementary copper iodide-catalyzed
process was found to be superior as Shown in Scheme 15.
27
Scheme 15
N NR
R
HN
BrR
R4
3
2
1
Cul, 1,10-Phen, or
Pd(PPh3)4
Cs2CO3, DME, 80oC
N
N
N
R
R
R1
2
3
R4
The simplest amine is ammonia. Nevertheless, C-N coupling reactions with this substrate have not
been reported to be successful. Due to this, palladium catalyzed aminations with ammonia
equivalents have been used to achieve this transformation. Maes et al31
reported several examples,
using ammonia surrogate as an alternative for classical nucleophilic substitutions on a
chloropyridazine as shown in Scheme 16.
Scheme 16
N N
O
MeO Cl
NH
Ph Ph
Pd(OAc)2, BINAP,
K2CO3, toluene, 110oC
N N
O
MeO NPh
Ph
88%
Ferreira et al32
employed the reagent for the synthesis of 6-amino-benzo[b]thiophenes using
BINAP as the ligand and Cs2 CO3 as the base. Interestingly, the use of NaOMe as base gave even
better results. The amino derivatives were hydrolyzed with HCl in THF to give the parent amine
Scheme 17.
28
Scheme 17
SBr
NH
Ph Ph
SH
2N
71%1) Pd2dba3, BINAP
NaOMe, toluene, 100oC
2) 2N HCl/THF,rt
In 2001, Hartwig as well as Buchwald reported new ammonia equivalents that show broad
versatility. LHMDS was used by Hartwig 33
to achieve the conversion of aryl bromides and even
aryl chlorides to the parent anilines. The reaction is catalyzed by Pd(dba)2 and P(t-Bu)3 and can be
run with a little as 0.2 mol% of catalyst.
Scheme 18
RX
+
RNH
2LiN
Me3Si SiMe
3
1) Pddba2/P(t-Bu)3
2) HCl neutralization
X = Cl, Br
Subsequently, Yang et al23
also reported the use of LHMDS and an even more versatile reagent,
LHMDS in combination with amino triphenylsilane. In this study, Buchwald’s 2-dicyclo-
hexylphosphinobiphenyl system proved to be good ligands for the transformation. The addition of
the less bulky amino triphenylsilane now allowed also the amination of ortho-substituted aryl
halides Scheme 19.
29
Scheme 19
X
R
+ Ph3SiNH
2
1) Pd2dba3, LHMDS, toluene
2) H+
NH2
R
X = Cl, Br
PCyz
An interesting application of C-N coupling as a strategy for the protection of hydroxyl groups in
sugars was reported by Buchwald et al25
. By converting the free hydroxyl group to a para-halide
substituted benzylic ether, an anchor for C-N coupling is formed. Amination with a suitable amine
yields a labile protecting group that can easily be cleaved by Lewis or protic acids. By employing
4-chloro-, 4-bromo- or 4-iodo-substituted benzylic ethers, orthogonal protection is possible while
the protecting groups can be removed sequentially. This strategy, has found application in the
synthesis of trisaccharides. The general methodology is illustrated in Scheme 20.
Scheme 20
R-OH
Br
Br
NaH, DMF Br
ROPd2dba3, NaOt-Bu
ligand, HNR1R
2 NR1R
2
RO
Lewis or protic acidNR
1R
2
RO
La3+
ROH
30
In 2007, Loones34
and co-workers reported regio selective tandem metal- catalyzed imination wit
2-chloro-3- iodo-quinoline(67) and amino [benzo] (di) azine (68), as shown in Scheme 21.
Scheme 21
N
N
NH2N
I
Br
+Pd(OAc)2, Xantphos 97
Cs2CO3, toluene
reflux N
N
N (N)
67 68108
Again, Loones34
and co-workers reacted 2,3-dibromoquinoline with amino[benzo](d1) azine (68).
This reaction achieved selective C-2 intermolecular palladium-catalyzed amination in Scheme 22.
Scheme 22
N
N
NH2N
Br
Br
+Pd(OAc)2, Xantphos 97
Cs2CO3, DMF
reflux
N N
N (N)
69 68109
Zhang35
and co-workers developed amination of chloro methylnaphthalene (70) and chloromethyl
anthracene (71) derivatives to produce naphthylamine (72) and anthrylamine (73) in a good yield
via palladium catalyzed protocol as shown in Schemes 23 and 24 respectively. These aminaton
reactions proceeded smoothly under mild conditions in the presence of Pd(PPh3)4 as catalyst.
31
Scheme 23
R4
R3
Cl
+ H N
R2
R1
R4
R3
N
R2
R1
Pd(PPh3)4, base
solvent
70
110
72
Scheme 24
R3
Cl
R
+ H N
R2
R1
R3
N
R2
R1
R
Pd(PPh3)4, base
solvent
71
110
73
2.2 LINEAR PHENOXAZINE AND THEIR AZA ANALOGUES
A review of the chemistry of phenoxazines has been undertaken by Pearson36
, Ramage37
,
Schaefer38
, Okafor39
and many others.
The synthesis of azaphenoxaine compounds involves the condensation of suitably substituted
halonitropyridine (11) with 2-amino-3-hydroxypyridine (12). The resulting intermediate product
was further treated with a strong base, thus forming the anticipated aza phenoxazine.
32
Scheme 25
NO2 ph
(11) (12)(13) (14) (15)
N
OH
CH3
N
BrH
2N
Cl
N
OH
NH2
N Cl
N OH
3-Bromo-4-chloro-5-aminopyridine (13) was successfully used in place of the halo nitropyridine
(11) to achieve the synthesis of aza phenoxazines. The use of 2-amino-hydroxypyridine (12) in
place of 2-aminophenol (15) has also been reported39
. Unlike 2-aminomercaptopyridine
derivatives required for azaphenothiazine synthesis and formed through thiazolopyridine40
or
hydroxypridine41
compounds in extended steps, these 2-aminohydroxypyridines are more readily
accessible. Compound 12 is conveniently obtained by nitration of 2-amino pyridine, followed by
separation of the isomers and diazotization and hydrolysis of the diazonium salt of the o-isomer.
Reduction of the resulting 2-hydroxynitropyridine gave a good yield of 12. Picryl chloride (16) and
2,4,6-trinitroanisole(17) have also been used in place of halodinitropyridines, provided that the
others reactions is of type 12.
2.2.2 Monoazaphenoxazines
2.2.2.1 1-Azaphenoxazine
7,9-Dinitro-1-azaphenoxazine (19) was synthesized by Plazek and Rodewald42
by condensing 3-
hydroxy-2-aminopyridine with picryl chloride (16). The condensation product was further treated
33
with alcoholic base, yielding the isolated product (19). It was proposed that the 2-aminopyridyl
phenyl ether (18) was formed, followed by the Smiles rearangement43
of the diaryl ether to the
corresponding 2-hydroxypyridylaniline (20). In excess base, cyclization of this intermediate was
achieved leading to the isolated product, as shown below in Scheme 26.
Scheme 26
NO2
NO2
(12) NO2
NO2
(16)
+
(18)
NO2
NO2
NO2
Cl
O2N
N
O2N
N
O
H
- NO2
N N
O
H
N NH2
O
O2N
(19) (20)
N
OH
NH2
The overall yield was adversely limited by the poor yield of the precursor (12), which was obtained
by the nitration of 3-hydroxypyridine with a mixture of concentrated nitric and sulfuric acids,
followed by reduction of the nitro group, as shown in Scheme 27
34
Scheme 27
NO2
NO2
1.
2.
N
OH
N
OH
NH2
SnCl2/HCl
N
OH
H2SO
4
N
OH
O
Fe, HgCl2
N
OH
HNO3
H2SO
4 NH4OH
HNO3
O
An improved yield of compound (12) was obtained by Lewicka and Plazek44
who nitrated 3-
hydroxy-1-pyridine oxide with mixed acids followed by reduction and deoxygenation with iron
and mercuric chloride.
When 2- chloro -3, 5-dinitropyridine (21) was treated with 2-aminophenol in ethanolic sodium
ethoxide, red crystals of (3,5-dinitro-2-pyridyl)-2-hydroxyaniline (22) were formed . As a possible
explanation, it was postulated that the amino hydrogen in compound 22 entered into strong
hydrogen bonding with the strongly negative oxygen of the 3-NO2 group, leading to the formation
of a six-membered chelate of high stability. The stability of this chelate ring, (24), is sufficiently
high to exclude cyclization to form (23) in the alcoholic medium.
35
Scheme 28
N N
H
O2NOHNO2
N
O
N
O2N
H
CH3CH2 O-
NH
O-
R
2223
24
The cyclization of the tertiary amine 25, in this case was successful because the replacement of the
amino hydrogen in 22 with a methyl group removes possibility of formation of a strong chelate
ring which might prevent cyclization. This result below is therefore an evidence for the
interpretation above.
Scheme 29
NO2
N
O2N
N
O
N N
OO2N
CH3
-
CH3
(25) (26)
A number of side chain derivatives were also reported. For example, Moore and Marascia45
obtained 7, 9- dinitro-4-methyl-3- phenyl-1- azaphenoxazine (28) by reacting 2-amino-3-hydroxy -
4-methyl-5-phenylpyridine (27) with picryl chloride (16) in ethanolic sodium ethoxide as shown in
Scheme 27. The pyridine precursor was obtained by a novel method introduced by some Polish
36
workers46
and further developed by Moore and co-workers45
. In this method the substituted
hydroxypyridine 27 was coupled with p-nitrobenzene diazonium chloride (16) in a slightly alkaline
medium, followed by reductive cleavage of the azopyridine (31) with hydrogen and palladium in
acetic acid medium.
Scheme 30
N
OH
NH2
CH3
Ph
+
NO2
Cl
O2N
NO2
N
CH3
Ph
NH2
O
O2N
NO2
NO2
N
CH3
Ph O-
NH
O2N
NO2
NO2
N
O
NH
NO2
NO2
CH3
Ph
Na, EtOH
27
16
28
Takahashi and Yoneda47
used alkylation in the presence of sodamide or sodium hydroxide in
dioxane, DMF, DMAC or DMSO to obtain 10-alkylamino-alkyl derivative (34) in Scheme 31.
37
Scheme 31
OH
NH
NEt Et
+N
NO2O2N N
O2N NO2NH
NEt Et
O
NN
NEt Et
NO2O-
O2N
O
N N
NEt Et
NO2
31
2132
33
34
2.2.2.2 2-Azaphenoxazine
In continuation of the search for compounds of medicinal interest, Petrow and Rewald48
pioneered
research on azaphenoxazine structures related to methylene blue, a phenothiazine derivate which
was first demonstrated by Gutamann and Ehrlich49
as an antimalarial agent. Model experiments on
the synthesis of 2- azaphenoxazine were carried out by these investigators. The preparation occurs
with 3-amino-4-hydroxypyridine (12) was condensed with picryl chloride (16).This reaction led to
the formation of intensely coloured compounds which contained chlorine and exploded on
warming. These results therefore lead to the conclusion that, in these reactions, picryl chloride
attacks the ring nitrogen preferentially and not anticipated hydroxyl group of compound 12.
However, when picryl chloride was replaced by 2,4,6- trinitroanisole (17), a product reported as
38
2,4,6—trinitrophenyl-(4 –hydroxy -3-pyridyl) amine (35) was isolated in 70%yield, purified and
then treated with alcoholic potassium hydroxide yielding brilliant red needles of 7,9-dinitro-2-
azaphenoxazine (30) in good yield. There was no physical or chemical evidence in support of the
assigned intermediate structure, 35. Although petro12
claimed that the isolated intermediate is a
diarylamine 35, it is more likely that 2,4,6-trinitrophenyl-(3-amino-4-pyridly) ether (36)was first
formed, followed by Smiles rearrangement the presence of a base to give 35 which then cyclized
to the isolated 2-azaphenoxazine derivative, (30) as shown in Scheme 32.
Scheme 32
+
NO2O2N
NO2
OMe
12
16
36
35
30
N
NH2
OH
O2N NO2
N
ONO2
NH2
NNH
NO2O-
O2N
O2N
N
O
NH
NO2
CH3
2.2.2.3. 3-Azaphenoxazine
In addition to 1-aza-2-azaphenoxazine derivatives, the 3-aza analog has also been synthesized.
Both the parent compound and side chain derivatives have been reported. 1-Nitro-3-
azaphenoxazine (32), the first known compound in the series, was obtained by treating 3,5-dinitro-
4-chloropyrine50
(33) with 2-aminophenol (34) in the presence of anhydrous sodium acetate in
39
methylated spirit. Petrow and Rewald48
reported that an isolable diarylamine, (37), was formed,
followed by cyclization to the desired product, on further treatment with alcoholic base. No
evidence was give to support the assigned structure (35). It is proposed that biaryl
ether (36) was initially formed followed by Smiles rearrangement to compound 35 when treated
with alcoholic base. The latter product, readily cyclized to compound (32) in the presence of excess
base as shown in Scheme 33. It is likely that the compound reported in literature48
as 35 is
compound 36 because of the greater nucleophilic power of the phenoxide ion when compared
to the anilino group ( compound 34 in an alkaline medium) and because of the greater
stability of 2-aminophenylnitropyridyl sulfide (37) compared to 2-mercaptophenyl
nitropyridyllamines (38) in alkaline medium.
Scheme 33
NO2+
NO2
NO2
NO2
(32)
(33) (34)(36) (35)
N
O2N
OH
N
NO
N
N
O O2N
NH2 N
O2N
O
OH
NH2
H
-
H
In most cases intermediate of type 37 were isolated unlike o-mercaptodiarylamine
(38) which readily cyclized once formed to the azaphenothiazine compound51
.
40
(37)(38)
NH2
O2N
S
N
SH O2N
N
N
H
Takahashi51
has also prepared compound 32 by condensing 3-bromo-4-chloro-5-
nitropyridine (13) with o- aminophenol (34) as shown as Scheme 34 followed by
cyclization of the diarylamine intermediate with piperidine base . Since bromine is the
leaving group in the cyclization of compound 40, the possible chelate ring formation
between the nitro and amino groups in 40 brought its bromine and hydroxyl groups close
enough (structure 41) to effect the intramolecular condensation of 40 to 32 in the basic
medium.
Scheme 34
+
NO2(13) (34)
(39)
NO2
NO2
(32)(40)
Br H2N
O
N
Br O
N
NN
NO
OHH
2N
-H
N
O2N
Cl
Br
H
41
Catalytic reduction of red crystals of compound 32 with pallladized charcoal gave hydrochloride of
1-amino-3-azaphenoxazine 42, identical with the product reported by Petrow and Rewald48
.
(41)+
Br O
N
N
N HOO -
-
(42)
N
NO
NH3H
+Cl
-
The parent compound, 3-azaphenoxazine 43 was prepared by condensation of benzyl 2-
hydroxyaniline (44), with 4-chloro -3- nitropyrdine hydrochloride (45) followed by cyclization
of the diarylamine 47, in aqueous base to 10-benzyl-3-azaphenoxazine (48). When 3-
azaphenoxazine was treated with 3-dimethylaminopropylchloride in 50% aqueous sodium
hydroxide alkylation took place in the 3-position instead of the usual 10-alkylation . The
compound, (3-dimethyl aminopropyl)-3-azaphenoxazine (49) thus obtained, reduces high arterial
blood pressure and is therefore an effective anti-hypertensive agent.
42
Scheme 35
N
Cl
NHCH2Ph
OHH
NO2
+Cl
-
+N
O
NH O2N
CH2
Ph
N
O O2N
CH2
Ph
-
NO
CH2
Ph
N
NO
NH
NO
N
CH2
CH2
CH2
NMeMe
Me2N(CH
2)
3Cl
Dioxane
(45)(44)
(46) (47)
(48)(43)(49)
1-Nitro-3-azaphenoxazine was readily reduced with stannous chloride in concentrated hydrochloric
acid to 1-amino -3-azaphenoxazine hydrochloride (42), melting above 300oC unlike the 2-aza
analog, the free base 52, obtained by neutralization of an aqueous solution compound 42 with
ammonia solution, was sufficiently stable to be isolated in the pure state as white needles, melting
at 258-2590C. It was further converted to 3-azaphenoxazine-9,10-diazole (51) by treatment with
cold aqueous sodium nitrite. This reaction is characteristic of 2-aminodiphenylamine and was
shown to take place in structurally related systems such as aminoacridine and 1,3-diamino
phenothiazinium chloride.
43
NO2
(51) (52)
O
N
N N
O
N
O2N
H
The orientation in 3-azaphenoxazine was also investigated. Nitration of compound 32 with fuming
nitric acid in glacial acetic acid gave a dinitro derivative which was formulated as 1,7-dinitro-3-
azaphenoxazine (52) by analogy with the product obtained by nitration of phenoxazine.
4-Azaphenoxazine
The synthesis of 4-azaphenoxazine51
follows the general pattern already described for 1-aza, 2-aza,
and 3-aza-phenoxazines. Here, 3-amino-2-hydroxy-5-chloropyridine (17) in excess base, the
following steps were formulated for the over all reaction, leading to 2-chloro-7, 9-dinitro-4-
azaphenoxazine (56) as shown in Scheme 36.
Scheme 36
+
NO2O2N
NO2
OMe
55
17
56
N
NH2Cl
OH O2N NO2
NO
NO2
NH2Cl
N
NH
NO2O-
O2N
O2N
Cl
N O
NH
NO2
CH3
Cl
44
2.2.3 Diazaphenoxazine
2.2.3.1 3, 4-Diazaphenoxazine
Very few compounds of this new heterocyclic ring system are known. Reports of known
diazaphenoxazine compounds exist mainly in the patent literature50
. Two derivatives; 10-alkyl- and
10-dialkylaminoalkyl-2-oxo-2,3-dihydro-3,4-diazaphenoxazine (64), were reported by Bonder52
in
a USSR patent, without details of methods of preparation, properties and uses. Gortinskaya53
and
co-workers obtained in good yields some 2,10-disubstituted -3,4-diazaphenoxazine (76) of
biological interest by condensing 2-methylaminophenol (65) in alcoholic triethylamine as shown in
Scheme 37.
Scheme 37
+N
N
ClCl
Cl
64
65
NHCH3
OH NN
Cl
O
NHCH3
Cl
NN
N
O-
Cl
CH3
Cl
O
N
NN
CH3
-
Cl
Cl
..
N
O NN
CH3
Cl
74
75
76
2.2.3.2 1, 4-Diazaphenoxazine.
1,4-Diazaphenoxazine Reports on the interesting pharmacological activities of 3,4-
diazaphenoxazines prompted the synthesis of other isomeric diazaphenoxazine4.
45
The second aza-phenoxazine ring in this series the 1,4-diazaphenoxazine (57) prepared by
refluxing a mixture of 2,3,5,6-tetra chloropyrazine (58) with the sodium salt of o-amino phenol
(60) and cyclized with or without rearrangement to the desired compound, 57, by refluxing with
sodium hydroxide in isopyropyl alcohol for a half hour period.25
The sequence of reactions
involved is given in Scheme 38.
Scheme 38
N
N Cl
Cl
NH2
ONa
+
Cl
Cl
NH2
N
N Cl
Cl
Cl
OO
N
N
N Cl
Cl
H
(58)(59)
(60)(57)
Okafor54
reported the synthesis of 1,4-diazaphenoxazine (77) and 1,4-diazaphenoxazine[b] (78)
and their derivatives. 2,3-dichloropyrazine (79) obtained by the action of excess sulfyryl
chloride on 2-chloropyrazine in N,N-dimethyl formamide (DMF) as a solvent. The resulting
compound (79), was subsequently treated with the sodium salt of 2-aminophenol (80) in aqueous
N,N-dimethylacetamide (DMAC) to afford a creamy white product, according to Scheme 39.
Scheme 39
+
(79) (80)(77)
+N
N Cl
Cl O
N
N
N
H
NH2
O Na-
46
Replacing 2,3-dichloropyrazine (79) with 2,3-dichloroquinoxaline (81), leads to the formation of
the tetracyclic 1,4-diazabenzo [b] phenoxazine (78) as shown in Scheme 40.
Scheme 40
++
(81) (80) (78)
NH2
O Na O
N
N
N
N
N Cl
Cl-
H
2.2.3.2 1,9-Diazaphenoxazine
In addition to the preparation of 3,4-diaza-and 1,4-diazaphenoxazines, the synthesis of 1,9-
diazaphenoxazine (61) was also reported52
. This is the only known diazaphenoxazine in which the
nitrogens are in different rings. The reaction leading to the parent heterocycle involves the acid-
catalysed condensation of 2-amino-3-hydroxypyridine (12) with 2-chloro 3-nitropyridine (11) in
dilute sulfuric acid as shown in Scheme 38. The diaryl amino compound (62), obtained in 45%
yield after neutralization with concentrated ammonia, was converted to 1,9- diazaphenoxazine (61)
in 31% yield by refluxing with potassium hydroxide in dimethyl sulfoxide for 10 h54
. The reactions
involved are shown in Scheme 41.
47
Scheme 41
+N Cl
NO2
12 11
N
OH
NH2
NN NH
O2NOH
N NH
O
N
61
H3O+
KOH, DMSO
62
1,9-Diazaphenoxazine, obtained in an overall yield 14%, is the second azaphenoxazine whose
parent compound is now known. It is a microcrystalline compound melting at 245-246oC. The
ultraviolet spectrum had three intense absorption maxima 338, 217 and 210 nm. Most phenoxazine
compound show characteristic absorption maxima between 318 and 338 nM55
. 1, 9-
diazaphenoxazine (61) and its precursor (62), were tested in mice and rats for their effect on the
central nervous system. Both compounds showed both analgesic and CNS antidepressant
properties by as much as 1.9o compared to 0.8
o in chloropromazine
56.
NITRO, AMINO, N-ACETYL AND N-ALKYL PHENOXAZINES
The syntheses of nitro, amino, N-acetyl and N-alkyl phenoxazine derivatives were reported by
Maas and coworkers57
. They synthesized 3,7-dinitrophenoxazine (82) by nitration of
Phenoxazine with NaNO2 in the presence of glacial acetic acid at room temperature, shown in
Scheme 42.
48
Scheme 42
N
O
H
N
O
H
N
O
H
N
O
H
N
O
H
O2N
NH2NH
2HN2
NO2NO2
HClHCl2
(I) NaNO2, CH
3COOH, acetone
(II) NaOH
Fe, HCl 25%
EtOH, reflux, 1hFe, HCl 25%EtOH, reflux, 1h
(1)
(82) (83)
(84)(85)
When the reaction condition was varied, a mixture of 3-nitrophenoxazine (83) and 3,7-
dinitrophenoxazine (82) were obtained, respectively. Reduction of 3-nitrophenoxazine (83) and
3,7-dinitrophenoxazine in the presence iron with hydrochloric acid in ethanol yielded the amino
hydrochlorides (85) and (84) in reaction and 78% after purification respectively.
Oxidation of diamino hydrochloride (85) in the presence of methanolic silver nitrate at room
temperature yielded the oxonine (86), as shown in Scheme 43.
49
Scheme 43
O
N
NH2NH2
H
2HCl
O
N
NH2
+
AgNO3, CH3OH/H2O
1/2 h, rtNO3
-
8586
The pure product 86 was isolated in 66% yield as a red solid by recrystallization, using appropriate
solvent. Purification by chromatography gave very low yield due to decomposition and difficulties
in extracting the dye from the column material57
.
Acylation of 3,7-diaminophenoxazine dihydrochloride (85) with acetyl chloride proceeded under
nitrogen in dry chloromethane with excess triethylamine at room temperature to give the N-
acylated compound (87) as brown solid in 91% yield after purification by flash chromatography
on alumina as shown in Scheme 44.
Scheme 44
O
N
NH2NH2
H
2HCl
85
87
CH3COCl (3 equiv)
Et3N, CH2Cl2, 1 h, rt
O
N
O
NH
CH3O
NH
CH3
CH3 O
Furthermore, oxidation of compound (87) in ethanolic silver nitrate at room temperature gave
compound (88) as dark-green solid in 60% yield as shown in Scheme 45.
50
Scheme 45
87
O
N
O
NH
CH3O
NH
CH3
CH3 O
O
N
O
N+
CH3O
NH
CH3
HNO3
-
88
AgNO3, EtOH
8 h, rt
Again reduction of compound 88 with LiAIH4 under nitrogen in dry tetrahydrofuran gave 3,7-bis
(ethyl amino) phenoxazium nitrate (89) in 53% yield as shown in Scheme 46.
Scheme 46
AgNO3, EtOH/H2O, 8 h, rt
O
N
O
N+
CH3O
NH
CH3
HNO3
-
88
O
N
N+
CH3
NH
CH3
HNO3
-
89
LiAlH4 (2 equiv), THF, 15 h
The high solubility of compound (88) in methanol is low due to its ionic character57
. The oxidized
product (86), (87) and (89) has different spectra from the non-oxidize products due to
delocalization of the π-electrons in the former group of compounds.
2.2.5 2-Amino 4,4α-DIHYDRO-4α-DIMETHYL-3-H-PHENOXAZINE -3-ONE.
51
Shimamoto co-workers58
synthesized 2-amino-4,4α-dihydro-4α,7-dimethyl-3H-phenoxazine-3-one
(90) by the reaction between 2-amino-5-methylphenol (91) with bovine hemolysates as shown in
Scheme 47.
Scheme 47
O
N NH2
CH3
H3C O
NH2
OHH3C
HbO2
MetHb NH
OH3C
+
NH2
OHH3C
(91)(92) (91) (90)
Biological evaluation of compound (90) showed that it may be used to treat different types of
leukemia58
. This was shown by examining its effect on the proliferation of the human leukemia
cell lines. Compound 90 inhibited proliferation and induced apopotos in all the leukemia cell lines
tested.
52
CHAPTER THREE
3.0 EXPERIMENTAL
3.1 GENERAL
All reactions were carried out under nitrogen atmosphere. Melting points were determined with a
Fischer Johns melting point apparatus and are uncorrected. UV and visible spectra were recorded
in ethanol on a Unicon UV- 2500PC spectrophotometer using matched 1cm quartz cells,
absorptions were measured in nanometer (nm). IR Spectra were recorded on 8400s Fourier
Transform Infrared (FTIR) spectrophotometer and are reported in wave numbers (cm-1). UV -
visible and IR analysis were done at the National Research Institute for Chemical Technology
(NARICT), Zaria, Kaduna State, Nigeria. Nuclear magnetic resonance (1H-NMR and
13C-NMR)
spectra were determined using a Jeol 400MHz spectrometer at Strathclyde University, Scotland.
Chemical Shifts are reported in (δ) scale. All reagents used were of technical grade. 2-Amino- δ -
hydroxypyridine, 2,3,5-trichloropyridine, Pd(OAc)2, piperazine, formaldehyde, 2,4-di-tert- butyl
phenol were purchased from Sigma. Potassium hydroxide, acetamide, benzamide, 4-
nitrobezamide, phthalamide, formamide, potassium carbonate, 1,4-dioxane, methanol and ethanol
were purchased from Aldrich in sure-seal bottles and were used without further purifications.
3.2 1,4-Bis (2- hydroxyl-3,5-di-tert-butyl benzyl)piperazine.
The ligand was prepared according to the method of Mohanty et al
59. A mixture of piperazine (2.2
g, 25.54 mmol) and 5.3 mL of 40% aqueous formaldehyde solution (75.36 mmol) dissolved in
53
methanol (40 mL) was heated to reflux for 2 h to obtain a clear solution. The clear solution was
allowed to cool. Then 2,4-di-tert-butyl phenol (10.3 g, 50.4 mmol) solution in methanol was added
to the clear solution and refluxed for a further 12 h. The resulting product was cooled to room
temperature and filtered to obtain1, 4-bis piperazine ligand as white crystalline solid which melts
above 260oC (lit above 250
oC).
3.3 3- Chloro-1,9-diazaphenoxazine.
This compound was prepared according to the procedure given by Fors60
. Into a 250 mL two
necked flask which was equipped with magnetic stirrer was added potassium hydroxide (3 g, 53.6
mmol) dissolved in distilled water (50 mL). 2-Amino-3-hydroxypyridine (12) (4 g, 36.4 mmol)
was added to the flask and heated until it dissolved. Then 2,3,5-trichloropyridine (93) (3.2 g, 18.88
mmol) in 1,4- dioxane (50 mL) was added drop by drop for 15 min. The entire mixture was
refluxed for 4 h at 80oC. It was poured into a beaker and allowed to cool. Then it was filtered and
the residue air dried and recrystallized with aqueous ethanol as white solid crystals of 3-chloro-1,9-
diazaphenoxazine (94) (4.4 g, 72%) with a melting point of 480C. UV-visible (ethanol) λmax: 204
(logε 3.01), 211.5 (logε 3.02), 222.5 (logε 3.05) nm. IR (KBr) cm-1
: 3394 (N-H stret), 1650 (C=C
stret), 1429 (C-H bending), 1053 (C-O-C), 761 (m-substituted aromatic ring). 1H-NMR (DMSO) δ:
8.6 (s, 1H, NH), 8.4 (s, 5H, ArH). 13
CNMR (DMSO) δ: 128-132 (Ar-C)
54
3.4 General Procedure for Preparing Phenoxazine Carboxamides
These compounds were prepared according to the procedure developed by Anderson and co-
workers61
. 1,4-Bis (2-hydroxyl-3,5-di-tert-butyl benzyl)piperazine (0.016 g, 0.003 mmol) and
palladium acetate (0.002 g, 0.001 mmol) were placed in a 100 mL two necked flask. Nitrogen gas
was introduced for 30 sec, 2 mL of water was added and the mixture heated for 2 min at 80oC. The
catalyst pre-activation was monitored visually by colour change from yellow to black. Then 3-
chloro-1,9-diazaphenoxazine (94) (0.208 g, 1.0 mmol), potassium carbonate (0.193 g, 1.4 mmol)
and 3-substituted carboxamide derivatives (1.2 mmol ) in DMF (2 mL) were mixed with toluene
(2mL) and evacuated with nitrogen gas for another 30 sec. The entire mixture was heated under
reflux with stirring for 2 h at 110oC in an oil bath under nitrogen atmosphere. The crude product
obtained was cooled at room temperature, air dried and recrystallized from aqueous ethyl acetate.
3.4.1 3-Formamido-1,9-diazaphenoxazine
3-Formamido-1,9-diazaphenoxazine (99) was obtained as an ash solid, yield 0.168 g (78.7%), mp
200oC. UV-visible (ethanol) λmax: 280.5 nm (logε 2.36). IR (KBr) cm
-1: 3855 and 3741(2 N-H
stret), 1685 (C=O stret), 1534 (C=N stret); 1HNMR (DMSO) δ: 5.2 (s, b, 1H, NH), 7.2 (m, 2H, Ar-
H). 13
CNMR (DMSO) δ: 170 (C=O), 130-147 (Ar-C)
3.4.2 3-Phthalamido-1,9-diazaphenoxazine
3-Phthalamido-1,9-diazaphenoxazine (100) was obtained as an ash solid, yield 0.209 g, (54.6%),
mp 247oC. UV-visible (ethanol) λmax : 282.5 nm (logε 2.91). IR (KBr) cm
-1: 3393 and 3297 (2 N- H
55
stret), 1008 (C-O-C stret), 3137 (ArC- H), 1449 (C=N stret), 845-722 (p-disubstituted aromatic
ring). 1HNMR (DMSO) δ: 5.25 (s, b, 1H, NH), 7.0–6.6 (m, 2H, Ar-H).
13CNMR (DMSO) δ: 128-
150 (Ar-C).
3.4.3 3-(4-Nitrobenzamido)-1,9-diazaphenoxazine
3-(4-Nitrobenzamido)-1,9-diazaphenoxazine (101) was obtained as an ash solid, yield 0.357 g,
(87.8%), mp 310oC. UV-visible (ethanol) λmax : 280.5 nm (logε 2.91). IR (KBr) cm
-1: 3741and
3855 (2 N-H stret), 1664 (C=O), 1535 (C=N stret). 1HNMR (DMSO) δ: 8.4 (s, 2H, NH), 8.6 (s,
5H, Ar-H). 13
CNMR (DMSO) δ: 100-150 (Ar-C).
3.4.4 3-Benzamido-1,9-diazaphenoxazine
3.4.4 3- Benzamido-1,9-diazaphenoxazine (102) was obtained as a reddish-brown solid, yield
0.242 g, (68.5%), mp 129oC. UV-visible (ethanol) λmax : 307.50 nm (logε 2.32). IR (KBr) cm
-1 3740
and 3365 (2 N-H stret), 3178 (ArC-H), 1646 (C=O), 1400 (C-H bending), 1021 (C-O-C stret), 785
(p-disubstituted aromatic ring), 665 (m-substituted aromatic ring). 1HNMR (DMSO) δ: 8.0 (s, b,
1H, NH) 8.5 (m, 5H, Ar-H), 7.3 (Ar-H). 13
CNMR (DMSO) δ: 130-146 (Ar-C).
3.4.5 3-Acetamido-1,9-diazaphenoxazine
3-Acetamido-1,9-diazaphenoxazine (103) was obtained as a yellow solid, yield 0.222 g, (79.6%),
mp 310oC. UV-visible (ethanol) λmax: 218 (logε 3.04), 225 (logε 3.05), 232.5(logε 3.06), 283.5
(logε 2.78) nm. IR (KBr) cm-1
3736 and 3394 (2 N-H stret), 1655 (C=O stret), 1452 (C-H bending)
56
1058 (C-O-C stret), 773 (p-disubstituted aromatic ring). 1HNMR (DMSO) δ: 2.5 (s, 3H, CH3), 8.0
(s, b, 2H, NH), 8.2 (m, 4H, Ar-H). 13
CNMR (DMSO) δ: 132-142 (Ar-C), 157 (C=O).
57
CHAPTHER FOUR
4.0 RESULTS AND DISCUSSION
4.1 3-Chloro-1,9-diazaphenoxazine
Compound 94 was prepared by condensation reaction between 2-amino-3-hydroxypyridine
(12) with 2,3,5-trichloropyridine (93) in 1,4-dioxane in aqueous basic medium for 4 h, 3–chloro-
1,9–diazaphenoxazine (94) was obtained as a white solid crystal which melts at 48oC as shown in
Scheme 48 below.
Scheme 48
N
OH
NH2
N
N
O
N N
ClCl
Cl Cl
+
KOH, 1,4-dioxane
reflux 4h,
1
2
3
45
6
7
8
9 H
(12) (94)(93)
The proposed mechanism for the preparation of 3-chloro 1,9-diazaphenoxazine is shown in
Scheme 49 below.
Scheme 49
58
N
O
NH2
NCl
Cl Cl-HCl
N
O
NH2
N
Cl Cl N
O
N
N
Cl Cl
H
H+
N
O
N
Cl
H
Cl
-HClN
N
N N
Cl
HN
H
(12a)(93)
(95)(96)
(94)(97)
The first step in the mechanism is the abstraction of a proton from the hydroxyl group of the
pyridine (12) by the base. The ion formed mounts a nucleophilic attack on the halogen atom of the
pyridine (93) to form the oxide. The oxide undergoes Smiles rearrangement and loses HCl to form
3-chloro-1,9-diazaphenoxazine (94). The assigned structure is supported by spectral analysis. The
absorption band in the UV-visible at 284 nm (logε 2.78) is consistent with the observed colour.
The absorption band at 3394 cm-1
in the infrared is due to N-H of phenoxazine moiety, the bands at
1532 cm-1
is due to C=N stretch, 1053 cm-1
is due to C-O-C, 761 is due to p-substituted aromatic
ring. In 1HNMR, the peak at 88.6 (s, b, 1H) is due to N-H proton which is consistent with the
assigned structure. In the 13
CNMR, the peaks at 129-134 are due to aromatic 169 is due to carbonyl
carbon.
4.2 3-Formamido–1,9–diazaphenoxazine
The catalyst preactivation was monitored visually by colour change from yellow to black. On
stirring an activated solution of 1,4-bis [2-hydroxy-3,5-di-tert butyl benzyl]piperazine, palladium
acetate and 3-chloro-1,9-diazaphenoxazine (94), potassium carbonate and formamide (98) in 2 mL
59
DMF mixed with 2 mL toluene for 2 h at 110oC over oil bath, 3-formamido-1,9-diazaphenoxazine
(99) was obtained as an ash solid as shown in Scheme 50.
Scheme 50
9499
N
O
N N
H
Cl
+NH2 H
O
N
O
NH
N
N
H
H
O0.001 mmol Pd(OAc)2
0.003 mmol piperazine ligand
K2CO3, DMF/toluene
0.04 mmol H2O, 110oC, 2 h
98
The assigned structure is supported by spectral analysis. The absorption band in the ultra violet
visible at 280.50 nm (logε 2.49) is consistent with the phenoxazine compounds 19
. The absorption
band at 3855 cm-1
and 3741 cm -1
are due to N-H stretch of amines, the band at 1685 cm-1
is due to
C=O stretch while the band at 1534 cm-1
is assigned to C=N stretch. In 1HNMR, the peak at 86.5
(s, b, 1H) is assigned to the N-H, while that 8.7-8.0 (m, 4H) is due to C6 –C9 protons. The signal at
130-147 in the 13-CNMR are assigned to the aromatic carbons. The signal at 170 is assigned to the
carbonyl carbon.
4.3 3-Phthatalamido-1,9-diazaphenoxazine
The catalyst preactivation was monitored visually by colour change from yellow to black. On
stirring an activated solution of 1,4-bis(2-hydroxy-3,5-di-tert butyl benzyl )piperazine and
palladium acetate in a two necked 100 mL flask for 2 min at 800C, 3-chloro-1,9-diazaphenoxazine
(100), potassium carbonate and phthalamide (104) in 2 mL DMF mixed with 2 mL toluene was
60
added. On stirring for 2 h at 1100C, 3-phthalamido-1,9-diazaphenoxazine (100) was obtained as an
ash solid as shown in Scheme 51.
Scheme 51
94100
N
O
N N
H
Cl
+
0.001 mmol Pd(OAc)2
0.003 mmol piperazine ligand
K2CO3, DMF/toluene
0.04 mmol H2O, 110oC, 2 h
N
O
O
H
104
N
O
O
N
O
NH
N
The assigned structure is supported by spectral analysis. The absorption band in the UV-visible at
282.50 nm (logε 2.91) is consistent with phenoxazine ring19
. The infrared spectrum at3393 cm-1
and 3297 cm-1
is due to N-H stretch of amine, the band at 1008 cm-1
is assigned to C-O-C while the
bands at 845 cm-1
and 722 cm-1
are due to p-disubstitution, the band at 1585 cm-1
is due to C=C
stretch of aromatic compounds. The signal at δ 5.25 (s, b, 1H) in the 1HNMR is due to N-H, while
the peak at δ7.7-7.5 (m, 4H) are due to the C6-C9 protons. The signals at δ 128-150 in 13
CNMR are
assigned to aromatic carbons.
4.4 3-(4-Nitrobenzamido)-1,9-diazaphenoxazine
When a solution of 1,4-bis (2-hydroxy-3,5-di-tert butyl benzyl)piperazine and palladium acetate
was preactivated in a 100 mL two necked flask for 2 min at 80oC, while monitoring it visually by
colour change from yellow to black, 3-chloro-1,9-diazaphenoxazine 94, potassium carbonate and
4-nitrobenzamide (105) in 2 mL DMF mixed with 2 mL toluene was added. On stirring for 2 h at
61
110oC, 3-(4-nitrobenzamido)-1,9-diazaphenoxazine (101) was obtained as an ash coloured solid as
shown in Scheme 52.
Scheme 52
94101
N
O
N N
H
Cl
+
0.001 mmol Pd(OAc)2
0.003 mmol piperazine ligand
K2CO3, DMF/toluene
0.04 mmol H2O, 110oC, 2 h
105
NO2
O
NH2
NH
O
N
O
NH
N
NO2
The assigned structure is supported by spectral analysis. The band at 280.5 nm is characteristic of
phenoxazine compounds. The infrared absorption bands at 3741 cm-1
is due to N-H stretch of
amines, the band at 1664 cm-1
is due to C=O stretching frequencies, the vibration at 1536 cm-1
is
due to C=N stretch. In the HNMR, the signal at δ 8.5 (m, 4H) is due to the C6-C9 protons. In the
13-CNMR, the peaks between δ 129 and 150 are due to aromatic carbons.
4.5 3-Benzamido-1,9-diazaphenoxazine
The catalyst pre activation was monitored visually by colour change from yellow to black. On
stirring an activated solution of 1,4-bis (2-hydroxy-3,5-di-tert butyl benzyl)piperazine ligand,
palladium acetate and 3-chloro-1,9-diazaphenoxazine (94) in a two necked flask, potassium
carbonate and benzamide (106) in 2 mL DMF mixed with 2 mL toluene for 2 h at 110oC, 3-
benzamido-1,9-dizaphenoxazine (102) was obtained as reddish-brown solid as shown in Scheme
53.
62
Scheme 53
94102
N
O
N N
H
Cl
+
0.001 mmol Pd(OAc)2
0.003 mmol piperazine ligand
K2CO3, DMF/toluene
0.04 mmol H2O, 110oC, 2 h
106
O
NH2
NH
O
N
O
NH
N
The assigned structure is supported by spectral analysis. The absorption band in the UV-visible at
307.50 nm (logε 2.32) is characteristic of phenoxazine compounds. The absorption band at 3365
cm-1
is due to N-H of the phenoxazine compounds, band at 1021 cm-1
is due to C-O-C, band at
1645 cm-1
is due to C=O stretching, band at 784 cm-1
is due to p-disubstitution. In 1HNMR, the
peak at δ 6.7 (s, b, 1H) is due to the C6-C9 protons. The peaks at δ 130-147 are due to aromatic
carbons. The peak at δ 160 is assigned to the carbonyl carbon.
4.6 3-Acetamido-1,9-diazaphenoxazine
The catalyst pre activation was monitored visually by colour change from yellow to black. On
stirring an activated solution of 1,4-bis (2-hydroxy-3,5-di-tert butyl benzyl)piperazine ligand,
palladium acetate and 3-chloro-1,9-diazaphenoxazine (94) in a two necked flask, potassium
carbonate and acetamide (107) in 2 mL DMF mixed with 2 mL toluene for 2 h at 110oC, 3-
acetamido-1,9-dizaphenoxazine (103) was obtained as yellow solid as shown in Scheme 54.
63
Scheme 54
94103
N
O
N N
H
Cl
+
0.001 mmol Pd(OAc)2
0.003 mmol piperazine ligand
K2CO3, DMF/toluene
0.04 mmol H2O, 110oC, 2 h
107
O
NH2 CH3
NH
O
N
O
NH
N
CH3
Spectral analysis supports the assigned structure. The UV-visible band at 283.50 nm (logε 2.78) is
characteristic of phenoxazine compounds19
. The infrared absorption band at 3394 cm-1
is due to N-
H, the band at 1655 cm-1
is due to C=O, the band at 1058 cm-1
is assigned to C-O-C while the band
at 773 cm-1
is due to m-substituted aromatic ring. In 1HNMR, the peak at δ 8.3 is due to C6-C9
protons while that at δ 2.5 is due to methyl protons. In 13
CNMR, the peaks at δ 132-143 are due to
the aromatic carbons. The peak at δ 157 is assigned to the carbonyl carbon.
The mechanism for the preparation of the 3-chloro-1,9-diazaphenoxazine carboxamides 99-103,
proceeds through the following steps as shown in Scheme 55.
The first step in this catalytic cycle is the oxidative addition of Pd(0) to the aryl halide to form
organo palladium species which then reacts with the base (K2CO3) to form the organo palladium
complex. Reductive elimination results in the formation of the desired product (C-N bond), while
the Pd(0) catalyst is regenerated.
64
Scheme 55
Pd(OAc)2 + Ln
LnPd(0)
N N
O
N
H
Cl
oxidative addition
LnPdII-Cl
N
N
O
N
H
-
K2CO3
KCl
LnPdII-NO3
NN
O
N
H
-
HCO3
-
N N
O
N
H
NH X
O
NH2X
O
NN
O
N
H
NH
O X
PdIILn
reductive elimination
1.4- bis(2-hydroxy-3,5-di-tert-butylbenzyl)piperazine.
The ligand was prepared accordinjg to the method of Mohanty et al59
. A mixture of piperazine and
40 percent aqueous formaldehyde solution dissolved in methanol was heated under reflux for 2 h,
then cooled, and refluxed with a solution of 2,4-di-tert-butyl phenol for further 12 h in methanol.
On cooling the reaction mixture to room temperature, the ligand appeared as colourless crystals of
melting point 260oC (lit above 250
oC)
65
Scheme 56
NH
NH
+ HCHO
N
OH
CH3
CH3CH3
CH3
N
CH3
CH3
CH3
CH3
OH
6667
Table 1: summary of cross coupling of 3-chloro-1,9-diazaphenoxazine with amides
N NH
O
N
Cl
+NH2 X
O
N NH
O
N
N X
O
H
0.001 mmol Pd(OAc)2
0.003 mmol piperazine ligand
K2CO3, DMF, toluene
110oC, 2 h
entry amide product colour Yield
(%)
1
HNH H
O
98
N NH
O
N
N
H
H
O
99
Ash solid 78.7
66
2
N
O
O
H
104
N NH
O
N
N
H
O
N
O
O100
Ash solid 54.6
3 O
NH2
NO2
105
N NH
O
N
N
H
O
NO2101
Ash solid 87.8
4 O
NH2
106
N NH
O
N
N
H
O
102
Reddish-
brown
68.5
5
CH3
O
NH2
107
103
N NH
O
N
N
H
CH3
O
yellow 79.6
67
CHAPTER FIVE
5.0 Conclusion
The synthesis of 3-chloro-1,9-diazaphenoxazine carboxamide derivatives were achieved in two
stages. The first stage is the condensation of 2-amino-3-hydroxypyridine and 2,3,5-
trichloropyridine in basic medium to afford 3-chloro-1,9-diazaphenoxazine (94). Then the second
stage involved Buchwald-Hartwig tandem amination reaction of the 3-chloro-1,9-
diazaphenoxazine with substituted amides to furnish the substituted amido derivatives of 1,9-
diazaphenoxazine (99-103). The structures assigned to the compounds were supported by spectral
analysis using UV-visible, FTIR, 1HNMR and
13CNMR.
68
REFERENCES
1. Fogg, D.E and Santos, E.N. (2004): Tandem Reaction in Organic Synthesis:
Rutheniun and Palladium Catalysis. Coord. Chem. Rev. 248, 2365
2. She, Z; Niu, D; Chen, L; Gunawan, M.A; Shanja, X; Hersh, W.H. and Chen, Y. (2012)
Synthesis of Trisubstituted isoxazoles by Palladium (II)-Catalyzed Cascade Cyclization-
Alkenylation of 2-Alkyn-1-one O-methyl oximes. J. Org. Chem. 77(7), 3627-3633
3. Mashkoskii, M. D. and Roshchina, L. F. (1971): Action of Azaphen (Antidepressant)
on the bioelectric activity of the brain. Farmakol. Toksikol, 34, 144
4. Gulbenk, A.H; Horne, D.J. and Johnson, H.(1972): (Dew chem…co) U.S. patent,
3(663)543 Chem. Abstra. 77, 4850
5. Rodig, O.R; Collier, R.E. and Schlatzer R.K. (1964): Pyridine Chemistry. The Smiles
Rearrangement of the 3-Amino-2,2-dipyridyl sulfide system. J. org. Chem. 29, 2652
6. Okafor ,C.O (1976): Studies in the Heterocyclic series xi. Reactions of 2-amino-3-
hydroxypyridine with 2-chloro -3-nitropyridine .J. Heterocyclic Chem.13 ,107-110
7. Okafor ,C.O.(1974):Synthesis of Dipyrido[3,2-b:2 ,31-e][1,4] Oxazine (1,9-
Diazaphenoxazine). J. Chem.Soc.Chem.Commun 878
8. Nemoto, T; Ohshima, T. and Shibasak, M. (2003): Diels-Alder Reaction in the Synthesis
Of pagodane and dodecahedrane structures. Tetrahedron 59, 6889-6897
9. Carey, F.A. (2000): Organic Chemistry 4th edition McGraw-Hill companies Inc. 546-553.
69
10. Gomez,I; Alonso, E; Ramon, D.J. and Yus, M.(2000): Naphthalene- catalyzed Lithiation
of Chlorinated Nitrogenated Aromatic Heterocycles and Reaction with Electrophiles.
Tetrahedron.56, 4043-4052
11. Wolfe, J.P and Buchwald, S.L. (2004): Palladium Catalyzed Amination of Aryl Halides
and Aryl Triflates. Org. Synth. Coll. 10, 423
12. Danishefsky, L.A; Knolker, H.J; Knoll, J.S. (2003): Synthesis of vernolepin and
vernomenin. Chem. Comm. 1170-1186
13. Newman, M.S; Perry, C.Y. (1963): The Synthesis Of New Heterocyclic Compounds From
3,4-Dichlorocoumarins. J. Org. Chem. 28, 166-170
14. Schlummer, B. and Schnolz, U. (2004): Palladium catalyzed C-N and C-O coupling. A
pratical guide from an industrial vantage point Adv. Synth. Catal. 346, 1599-1626.
15. Paul, F; Path, J. and Hartwig, J.F. (1994): Palladium-Catalyzed formation of carbon-
Nitrogen Bonds Reaction intermediate and catalyst improvement in the Hetero-cross-
Coupling of Aryl Halides and Amides J. Am. Chem. Soc. 116, 5969-5970
16. Christensen, H; Kiil, D.K; Nielsen, O. and Michael, B. (2006): Effect of solvents
on the Product Distribution Rate of a Buchwald-Hartwig Amination Reaction. Org.
Process Res. Dev. 10(4), 762-769
17. Yin, J. and Buchwald, S.L. (2002): Palladium-Catalyzed Coupling of amides and aryl
Chlorides. J. Am. Chem. Soc. 124, 6043-6048
70
18. Horton, J.K; Thimmaiah, K.N; Harwood, F.C; Kutte, S.J.F. and
Houghton, P.J. (1993): Pharmacological characterization of N-substituted Phenoxazine
Directed toward Reversing Vinca Alkaloid Resistance in Multiting Resistant Cancer cells
Pharmocol. Abstra.44, 552-559.
19. Okafor, C.O. (1977): Studies in the Heterocyclic series xii. The Chemistry and Application of
Phenoxazine and Related compounds. An International Journal for Revisions And
Communications in Heterocyclic Chemistry. 7(1), 392-393.
20. Fries, K. and Ochwat, P. (1923): Dichloro-2,3-naphthochinon Chem. Abstra. 1291(56B), 3334.
21. Okafor, C.O. (1986): A New Type Angular Phenoxazine Ring Systerm. Tetrahedron. 42,
2771-2775.
22. Wolfe, J.P. and Buchwald, S.L. (2004): Palladium Catalyzed Amination of Aryl Halides and
Triflates Org. Khim. Synth. Cok. 10, 423.
23. Yang, B.H; Buchwald, S,L. (1999): Palladium-Catalyzed Amination of Aryl Halides and aryl
Triflates. Org. Lett.1, 35 - 37
24. Hartwig, J.F; Kawatsura, S.L; Hauk, K.H; Shaughnessy, L. (1999): Palladium-Catalyzed
coupling of amides and sulfonamides. Org. Chem. 64, 5575-5580.
25. Plante, O.J; Buchwald, S.L; Seeberge, P.H. (2000): Carbon-Nitrogen Amination with
hydroxyl group and 4-bromo-substitu ted benzylic ethers J. Am. Chem. Soc. 122, 7148-7149
26. Kondratenko, N.B; Kolomejeev, A.A; Mogilevskaya, B.O; Varlamova, N.M. and
vagupolskii L.M.(1986) : Poly(nitro and bifluoromethylsulphonyl) substituted
71
diphenylamines, Zh. Org. khim. 22(8), 1721-1729.
27. Ghosh, A; Sieser, J.E; Rioa, M; Cai, W; Rivera-Ruiz, L. (2003): Palladium- catalyzed
Coupling Carbamates and Urea. Org. Lett. 5, 2207-2210
28. Bolm, C; Hilde, J.P. (2000): Palladium-Catalyzed Coupling of Aryl Halides with
Sulfoximines. Angew. Chem. Int. Ed. 38, 2419-2421
29. Zhu, Y.M; Katayama, H and Kiryu, Y. (2002): Palladium-Catalyzed Coupling Reaction with
Non-amine Nucleophiles. Tetrahedron lett. 43, 3570-3580.
30. Evindar, G; Batey, R.A. (2003): Synthesis of Indoles and Carbazoles. Org. Lett. 5, 133-138
31. Maes, B.U.W; Kosrij, J; Lemiere, G.L.F. (2002): Palladium-Catalyzed Coupling for Ammonia
Surrogate For Nucleophilic Substitution. J. Heterocyclic Chem. 39, 535- 543.
32. Ferreira, I.C.F.R; Queiroz, M.J.R.P; Kirsch, G. (2003): Synthesis of 6-aminobiazo[b]
thiophenes via Tandem Catalysis. Tetrahedron Lett. 59, 975-981.
33. Breitler, S; Oldenhuis, N.J; Fors, B.P and Buchwald, S.L. (2011): Synthesis of Unsymmetrical
Diarylureas via Palladium-Catalyzed C-N Cross-Coupling Reaction. Organic Letter, 13(12),
3262-3265.
34. Loones, K.T; Maes, B.U. and Dommisse, R.A. (2007): Synthesis of Pyrido[21,1
1,:2,3]
Imidazo [4,5-b] quinoline and Pyrido[11,1
1:1,2] Imidazo[4,5-b] quinoline and their Benzo
72
and Aza analogs via Tandem Catalysis. Tetrahedron, 63 1085-1089
35. Zhhang, S; Wang, Y; FengxandBao, M. (2012): Palladium-Catalyzed Amination chloromethyl
naphthalene and chloromethyl anthracene Derivatives with various Amines. J.
Am. Chem. Soc. 134(12), 5492-5495
36. Pearson, D.E. (1957): Heterocyclic Chemistry, John Wiley and Sons Inc. New York 642-
726.
37. Ramage, G.R; Rodd, E.H. and Landqiust, J.K. (1960): “The Chemistry of Carbon
Compounds” Vol iv Part c, “Heterocyclic Compounds” Elsevier Publishers Inc. London
1491- 1502.
38. Schaefer, w. (1964): “Progress in Organic Chemistry” Vol vi, Butterworth Publishers and Co,
Ltd. London 135–163.
39. Okafor, C.O. (1986): A New Type of Angular Phenoxazine Ring System. Tetrahedron. 42,
2771-2775
40. Okafor, C.O. (1967): Studies in the heterocyclic series, V. The Chemistry of Some Pyrido[2,3-
d] thiazole Systems. J. Med. Chem. 10, 126
41. Caldwell, W.T. and Kornfeld, E.C. (1942): The chemistry of substituted 2-sulfonamido-5-
aminopyridines. J. Am. Chem. Soc. 64, 1695.
73
42. Plazek, E. and Rodewald, Z. (1936): The Chemistry of pyridine and its derivatives. Rocz,
chem. 16, 502.
43. Rodig, O.R; Collier, R.E. and Schlatzer R.K. (1964): Pyridine Chemistry. The Smiles
Rearrangement of the 3-Amino-2,2-dipyridyl sulfide system. J. org. Chem. 29, 2652
44. Lewicka, K. and Plazek, E.(1959): The Nitration of 3-Hydroxypyridine-N-Oxide. Rec. Trav.
Chim. Pays-Bas.78, 644
45. Moore, J.A. and Marascia, F.J (1959): The preparation and Reaction of 2-Amino-5-
hydroxypyridines: the formation of an Azaquinone. J. Am. Chem. Soc 81, 6049.
46. Bojarska-Dahlig, H. and Urbanski, T. (1922): Phenolic Reactions of 3-Hydroxypyridines Pra.
Placowek Nauk-Badaw. Min. Przem. Chem. 1
47. Takahashi, T. and Yoneda, F. (1958): Synthesis of Heterocyclic compounds of Nitrogen.
Azaphenoxazine Derivatives. Chem. Pharm. Bull. 6,378.
48. Petrow, V.A and Rewald, E.L. (1945): New synthesis of Heterocyclic compounds Part
iii. Azaphenoxazines. J. Chem. Soc. 40, 313
49. Guttman, A. and Ehrlich, H. (1891): Diazaphenothiazine sulfoxides. Berlin kiln.
Wochenschr. 28, 593
50. Okafor, C.O. (1971): Studies in the Heterocyclic series iv Azaphenoxazine and Related
Naturally Occuring compounds. Int. J. Sulfur Chem. B.6(4), 345.
51. Takahashi, T. and Maki, Y. (1958): Sulfur containing pyyidine Derivatives. Lvi. Smiles
74
Rearrangement of Pyridine Derivatives and Synthesis of Benzopyrido and Dipyrido-1,4-
thiazine Derivative. Chem. Pharm. Bull, 6, 369.
52. Bondar, L.N; Gortinskaya, T.V; Savitskaya, N.V. and Chukina, M.N. (1967): 10-Alkyl-
and 10-diaikylamino alkyl-2-oxo-2,3-dihydro-3,4-diazaphenoxazines. USSR Patent,
208, 688
53. Gortinskaya, T.V; Shchukina, M .N; Savitskaya, N.V; Nyrkova, V.G; Mashkovskii, M.D;
Polezhaeva, A.I; Bonda, L.N. and Andryushina, T. F. (August 1, 1970): 3,4-
Diazaphenoxazines. French patent 1(576), 534
54. Okafor , C.O. (1981): Studies in the Heterocyclic series x x. 1,4-Diazaphenoxazine and
Related Compounds. J. heterocyclic Chem. 118, 1445.
55. Lonescu, M; Tietze, L.M and Mantsch, H.(1967): ”Advanced Heterocyclic Series” Vol.
8, Academic Press Inc. New York, 83-113
56. Okafor,C.O; Steeberg,M.L and Buckley, J.P.(1976):New CNS-depressants derived from 1,9-
Diazaphenoxazine and two isomeric Triazaphenothiazine Ring Systems. Eurp. J. Med. Chem.
10.
57. Maas,H; Khatyr,A.and Calzaferri,G.(2003):Phenoxazine Dyes in Zeolite, Synthesis and
Properties. Microporous And Mesoporous Materials. 65,233-242.
58. Isabelle, T. and Carsten, B.(2012).Transition-metal free intramolecular N-arylations. Org Lett.
14(7), 1892-1895.
75
59. Mohanty, S; Punji, B; and Balakvishn, M.S. (2008):An inexpensive and highly stable
Iigand1,4-bis (2-hydroxy-3,5-di-tert-butylbenzyl) piperazine for Mizoroki-Heck at room
temperature. Suzuki-Miyaura cross-coupling reactions. Tetrahedron. 64, 240-247.
60. Fors, B.P; Krattiger, P; Strieter, E. and Buchwald, S.L. (2003): Water-Mediated
Preactivation An Efficient Protocol for C-N Cross - Coupling Reactions .J.Am, Chem.
Soc 125. 6653
61. Anderson, K.W; Tundel, R.E; Ikawa, T; Altman, R.A; Buchwald, S.L. (2006): Palladium-
Catalyzed Tandem Amination Reaction for the synthesis of 4-Quinolones Angew. Chem.
Int. Ed. 45, 6523
62. Abayomi, L.A; Terry, L.A; White, S.F. Warner, P.J. (2006): Chemistry of Tandem Reactions
Biosens. Bioelectron. 21, 2176-2179
63. .