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.
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 Mechanism B A Mechanism A Product 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
11
spontaneously and there is cooperative interaction of all species present at the outset of the reaction
as shown on Scheme 2
Scheme 2
Mechanism A Product 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
Mechanism A Product 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
12
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 annulation5, 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
13
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
14
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
MeO2C CO2Me
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.
15
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
Cl
Cl
Cl
Cl
Cl
Cl
Cl
MeO
Cl
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.
16
Scheme 6
H3C CH2
OR H3C
OR
Ph O
H2C
Ph O
[4+2]
OR
Ph O
H3C
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
O
H
CO2Me
17
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).
18
Scheme 8
R2
R1
N+ O- O CH3
CH3
nitro alkene
O
N
CH3
CH3
R2
R1
O-
*
* *
*
*
[4+2]
Lewis acid
nitronate
R
O
Y+
NHO +
X
nitronate
[4+2]
Z Z
R
Y+
O N
Z
Z X
nitroso acetal
D
A N+ O- O A NO + O D –
N
O O D
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.
19
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.
20
N
O
H
1
N
O
R2
NH2
O
R1
N
O
COpeptide
NH2
O
CO peptide
2 CH3 CH3
3
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 cancerlike
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
21
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
N
N
O
H NO2
NO2
N
O
N
H NO2
N
N
O
H NO2
NO2
Cl N
O
N
N
H
Cl
Cl N
N
O
N
H
5 6 7
8 9
10 11
N
O N
N
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.
22
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 (13C 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.
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