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TITLE PAGE
DEPARTMENT OF PURE AND INDUSTRIAL CHEMISTRY
FACULTY OF PHYSICAL SCIENCES,
UNIVERSITY OF NIGERIA, NSUKKA.
RESEARCH PROJECT (CHM 592)
PALLADIUM CATALYSED AMINATION OF A LINEAR
MONOAZAPHENOTHIAZINE
A RESEARCH PROJECT SUBMITTED IN PARTIAL
FULFILLMENT OF THE REQUIREMENT FOR THE
AWARD OF MASTER OF SCIENCE (M.Sc) IN ORGANIC
CHEMISTRY
BY
EGBUJOR, MELFORD CHUKA
PG/M.Sc/09/51552
SUPERVISOR: PROF. U.C OKORO.
DECEMBER, 2011.
2
CHAPTER ONE
INTRODUCTION
1.1 LINEAR PHENOTHIAZINES
Phenothiazine(1) also called dibenzothiazine or thiodiphenylamine is a
yellow crystalline compound soluble in hot acetic acid, benzene and
ether. It is a three ring structure compound in which two benzene rings
are joined by sulphur and nitrogen atom at nonadjacent positions. It is
obtained by fusing diphenylamine with sulphur.1
N
S
H
1
Phenothiazines belong to an important class of heterocyclic compounds
known for their pharmaceutical properties, phenothiazine is the active
component in sedatives, tranquilizer, antituberculotics or bactericides.
They are electron donor compounds with a low oxidation potential and
they can easily form radical cations. Lately, it has become very popular in
material science and in Biochemistry as marker for proteins and DNA.3
Research into phenothiazine and its derivatives has remained unabated
due to the wide range of application of this class of compounds as drugs,
pesticides, dyes, industrial antioxidants, thermal stabilizers etc.
Phenothiazine the parent compound of the large number of medicinal
compounds and thiazine dyes has been the subject of intensive study in
3
industries and universities. Variations in the structure of phenothiazine
have resulted in the synthesis of linear and non-linear derivatives of
phenothiazine.3
Linear phenothiazines are those phenothazines whose structures are
linear. For example, as a further variation of the phenothiazine structure,
systems in which a benzo group is fused unto one of the side rings of
phenothiazine leading to tetracyclic phenothiazine have been prepared
and are known as linear phenothiazines (2)
R1
R2
H
N
S
N
N
2
N
N
The importance of phenothiazine compounds as drugs has long been
recongnized. The pharmacological activitives of phenothiazine have been
attributed to the basic nitrogen of the ring which donates electrons to the
biological receptors by a charge transfer mechanism.2 Therefore the
synthesis of aza-analogues of phenothiazine has been of interest to
Chemists.2
Moreover within the last few decades several structural modifications of
the phenothiazine ring leading to linear aza phenothiazines have been
made4. Some of the useful compounds in these series are 1,4-
diazaphenothiazine(3),1,3,6-triazaphenothiazine(4),
4
1:3,4-triazaphenothiazine(5), 1,3,9-triazaphenothiazine(6), 2,3,6,7-
tetraazaphenothiazine(7), 2,3,7,8-tetrazaphenothiazine(9), 3,4,6,7-
tetraazaphenothiazine(10), 1,2,6,7-tetraazaphenothiazine(11)4
N
S
N
N
R2
R1
3 R3
R1
R2
4
N
HH
N N
N S
N
S N
N
R3
R2
N
HH
NCl CH3
5 6
N
SN
N
N
S N N
HH
NCl N
N
N
7 8
Cl
N
SN
N
HH
N
NN
N
Cl
NN
9 10N
SNN
NN
11
NS
NN
S
N
H
5
Phenothiazines constitute one of the largest classes of organic compounds
in official compendia. Over four thousand compounds have been
synthesized and about 100 have been used in clinical practice.5 Linear
phenothiazines derivatives such as 2,10-disubstituted phenothiazines(12)
are very important drugs which are widely used in psychiatric treatment
as tranquilizers6
S
N
R2
R1 12
Inventions and introduction of such phenothiazine derivatives into
treatment of mental diseases has changed the modern psychiatry. This
fact has improved the life style of patients and allowed quick
development of ambulatory system of treatment for such sickness.
The common use of phenothiazine has generated the need for fast and
reliable methods for quality control of phenothiazine pharmaceuticals and
monitoring them in clinical samples. 7-8
Phenothiazines especially, their linear derivatives are interesting from
analytical point of views due to their characteristic structure –the
presence of chemically active sulphur and nitrogen 9 atoms in positions 5
and 10 and substituents in position 2 and alkylamine side chain at 10-N
atom. Phenothiazine and its derivatives are characterized by low
ionization potentials. They are easily oxidized by different chemical,
6
electrochemical, photochemical, and enzymatic agents with the formation
of coloured oxidation product intermediate cation.
Linear phenothiazines have exhibited complexing properties due to the
presence of condensed three-ring aromatic system and amine nitrogen
atom in a side chain in position 10. They react with some metal ions or
thiocyanate complexes of metals forming coloured, hard soluble in water
but easily soluble in organic solvents compounds. Some organic
substance (eg picric, flavianic acid, pyrocatechol violet) have formed
with 2,10-disustituted phenothiazines coloured ion-association
compounds sparingly soluble in water, but quantitatively extracted into
organic phase. Phenothiazine as antipsychotic drugs act exclusively on
specific postsynaptic receptors and block the post synaptic dopamine
receptors 10
. Phenothiazine as antipsychotic drugs work on the positive
symptoms of psychosis such as hallucinations, delusions, disorganized
speech looseness of association, and bizarre behavior. It is important to
note that most of these antipsychotic drugs have linear phenothiazine
derivatives as their starting materials, e.g. 2-chlorophenothiazine (13) in
preparation of prochlorperazine, 2-trifluoromethyl phenothiazine (14) in
preparation of trifluoperazine, phenothiazine (1) in the preparation of
promazine etc.
7
Cl CF3
14
SS
13
N
H
N
H
Although, phenothiazine and its derivatives have many useful medicinal
properties, they have several undesirable side effects such as drowsiness,
lassitude, dryness of mouth etc. In the attempt to reduce these side
effects, some structural modifications were carried out. Some of the
earlier drugs of this type are chlorpromazine (largactil) (15),
promethazine (phenergan) (16) and diethazine (diparcol) (17) which are
used as tranquilizer, antihistamine and for the treatment of Parkinson’s
disease respectively 10
ClN
(CH2)3 N(CH3)2
15
S
N
CH2 CH(CH3)N(CH3)2
S 16
N
(CH2)2 N(C2H5)2
17
S
It has been shown by a further work on the therapeutic action of
chlorpromazine that its tranquilizing effects is due to the basic
phenothiazine ring which donates electrons to the biological receptor by
charge-transfer mechanism.11
This correlation between structure and
8
activity was made by Karreman, Isenberg and Szent-Gyorgyl.11
Thus
derivatives with annular nitrogen atoms were expected to be better drugs
than those without annular nitrogen. In support of this conclusion,
prothipendyl and isothipendyl, are better drugs than chlorpromazine(15)
and promethazine(16) respectively. 11
These interesting results aroused more interest in the study of aza-
analogues of phenothiazines.12
It is the interest in this class of
phenothiazine derivatives that prompted the present synthesis of the
following 3-anilino derivatives of 1-azaphenothiazine via Buchwald-
Hartwig amination protocol viz: 3-Anilino-1-azaphenothiazine(20),
3-(4-nitroanilino)-1-azaphenothiazine(21), 3-(4-hydroxyanilino1-
azaphenothiazine(22) and 3-(3-nitroanilino)-1-azaphenothiazine(23).14
N
S
N
S
OH
NO220
S
21
N
S
23NO2
22
H
N
N
H
N
H
N
H
N
H
N
H
N
H
H
N N
9
1.2 AMINATION REACTIONS
Amination is the process by which an amine group is introduced
into an organic molecule. This can occur in a number of ways
including reaction with ammonia or another amine such as in
reductive amination and the Mannich reaction. Most commonly,
amination reactions involve the use of the amine as the nucleophile
and the organic compound as the electrophile. However, this sense of
reactivity may be reversed for some electron-deficient amines,
including oxaziridines, hydroxylamines, oximes and other N-O
substrates when the amine is used as an electrophile, the reaction is
called electrophilic amination. Electron-rich organic substrates that
may be used as nucleophiles for this process include carbanions and
enolates. The palladium–catalyzed coupling of amines with aryl
halides or aryl alcohol derivatives is a typical amination reaction
known as Buchwald-Hartwig amination, it has matured from a
synthetic laboratory procedure to a technique that is widely used in
natural product synthesis as well as in other fields of academic interest
and in industry.14
The Buchwald–Hartwig amination is a chemical reaction used in
organic chemistry for the synthesis of carbon-nitrogen bonds via the
palladium-catalyzed cross coupling of amines(30) with aryl
halides(29). Though publications with similar focus were published
10
as early as 1983, credit for its development is typically awarded to
Stephen L. Buchwald and John F. Hartwig, whose publications
between 199459
and the late 200541
established the scope of the
transformation. The synthetic utility of the reaction stems primarily
from the short comings of typical methods (nucleophilic substitution,
reductive amination etc) for the synthesis of aromatic C-N bonds, with
most methods suffering from limited substrate scope and functional
group tolerance. The development of the Buchwald –Hartwig reaction
allowed for the facile synthesis of aryl amines(31) replacing to an
extent harsher methods (the Goldberg reaction, nucleophilic aromatic
substitution, etc) while significantly expanding the repertoire of
possible C –N bond formation.
+ HN
R3
R2
X
pd catBase
ligand
N
R3
R2R1R1
29 3031
Over the course of its development, several generations of catalyst
system have been developed, with each system allowing greater scope
in terms of coupling partners and milder conditions, allowing virtually
any amine to be coupled with a wide variety of aryl coupling partners.
Because of the ubiquity of aryl C-N bonds in pharmaceuticals15
and
natural products, the reactions has gained wide use in synthetic
organic chemistry, finding application in many total syntheses and the
11
industrial preparation of numerous pharmaceuticals16,17
. Also the
development of bidentate phosphine ligands such as diphenyl
phosphinobinapthyl (BINAP) and diphenylphosphino ferrocene
(DPPF) as ligands for the Buchwald Hartwig amination provided the
first reliable extension to primary amine and allowed efficient
coupling of aryl iodides and triflates.
O
Br
+ H2N C6H13
Pd2 (dba)3
BINAP
NaOtBuToluene, 80oC
HN
O
C6H13
95%
3332
Another amination reaction of importance is the Mannich reaction
with involves the condensation of a CH- activated compound (usually
an aldehyde or ketone)(35) with a primary or secondary amine (or
ammonia)(36) and a non-enolizable aldehyde or ketone(35) to yield
aminoalkylated derivative known as mannich base(37) 11,
R1
R3
R2
R4 R5
OO
+ HN (HCl) acid (cat) or base (cat)
R3R2R1N
R6
R7
R4R5
O
3435
R6
R7
enolizablecarbonyl compound
aldehyde or Ketone
non-enolizable 1o
37 manmich base
solvent-HOH
or 2o amine orits hydrodichloride
R1 =H, alkyl, aryl, R
2-3 =H, alkyl, aryl, R
4-5=H, alkyl, aryl R
6= H,
alkyl, OH, NH2 R7=H, alkyl; solvent =ROH< H2O, AcOH.
12
Among all the methods of amination, reductive amination 14
is one
of the oldest, but most powerful and widely used synthetic
transformation to access different kinds of amines. Reductive
amination, where a mixture of an aldehyde or ketone and an amine is
treated with a reductant in one –pot fashion, is one of the most useful
and versatile methods for the preparation of amines and related
functional compounds in chemical and biological systems18
. The
reaction of aldehydes or ketones(38) with ammonia and amines
(primary or secondary)(39) in presence of a reducing agent to give
primary, secondary or tertiary amines respectively, is known as
reductive amination of the carbonyl compounds or reductive
alkylation of the amines.
R1
R2
O + H N
R3
R4
R2
R1
HO
N
R1
N +
R3
R4
[H]
41
R2R4
R1
carbonyl compound AmineAddition product
Iminium ion
R2 N42
R3
R4
alkyl amine
R1
H
The reaction involves the initial formation addition product(40) as
an aminol intermediate or carbinol amine, which under the suitable
reaction conditions dehydrates to form an imine. The imine on
protonation forms an iminium ion(41) that subsequently on reduction
results in the respective alkylated amine(42).
13
CHAPTER TWO
LITERATURE REVIEW
2.1 LINEAR PHENOTHIAZINES
Bernthsen’s interest in methylene blue (44), Lauth’s violet (43) and
related phenothiazinoid dyes led him to investigate the preparation of
the parent phenothiazine ring(1). His success in 1883 by the simple
thionation of diphenylamine opened a new chapter in the chemistry of
useful heterocyclic compounds as several phenothiazine derivatives of
very useful applications 19
NH2H2NS(CH3)2N
43 44
N+
S+
N(CH3)2
In the past, phenothiazines were mainly used in the dye industry
where they constitute an important class of sulphur dyes. Additionally,
they were found to be useful antioxidants and have also shown several
chemotherapeutic effects. As one of the most useful heterocyclic rings
so far known, extensive structural modifications of phenothiazine and
its derivatives are still in progress in an attempt to improve their
biological activities and to reduce the undesirable side effects18
.
Despite reports which showed enhanced pharmacological values of the
heterocyclic analogues of benzenoid drugs, basically no report was
made on the heterocyclic analogues of this compound until about the
14
middle of the 20th century when Petrow and rewald
8 reported the
synthesis of 3-azaphenothiazine system. This discovery led to the
research into other nitrogen heterocyclic analogues of phenothiazine.
Within the last few decades, many more new aza phenothiazine rings
and new products derived from them have been reported20
. These
compounds have continued to show interesting chemotherapeutic
effects which is probably responsible for their publications in
classified literature as patents. Among these derivatives are the linear
azaphenothiazine compounds which have great pharmaceutical
importance21
.
In a systematic attempt to synthesis these compounds, all the six
isomeric diazaphenothiazines, 1,2-diaza, 2,3-diaza, 3,4-diaza, 1,3-
diaza and 2,4-diazaphenothiazines were reported previously.22
The
synthesis of the remaining 1,4-diazaphenothiazine(47) was achieved
by Okafor5 in 1981. This was accomplished by condensing an alkaline
mixture of 2-aminothiophenol(45) with 2,3-dicloropyrazine(46)
SH
NH2
+
Cl
Cl
R
R
N R
RNS
474645
N
H
N
N
Alkylation of these 1,4-diazaphenothiazine with benzyl bromide,
dimethylaminopropryl chloride and morpholinopropyl chloride in the
15
presence of strong base afforded the corresponding 10-alkyl-6,7,8,9-
tetrahydro -1, 4-diazaphenothiazine.
At a concentration of 100ppm 10-(3-dimethyl-aminopropyl)-
6,7,8,9 – tetrahydro-1,4-diazaphenothiazine gave 100% control of
staphylococcus aureus, candida albicans among others.18
All the earlier reports on the aza analogs of phenothiazine were
concerned with the chemistry and biological properties of only the
monoaza and diazaphenothiazines.23
There was no report what so ever
on any of the twenty four isomeric triazaphenothiazine systems. In
1973, however, Okafor and co-workers23
ventured into the synthesis
of the first set of compounds in these series and successfully achieved
the preparation of 1,3,6-triazaphenothiazine(50) derivatives thereby
opening the new chapter on linear phenothiazine chemistry 23
.
They obtained these compounds in yields varying from 11% to
95% by acid catalysed condensation of 3-aminopyridin-2(IH)-thiones
(48) with 4,5-dihalogenopyrimidines (49).
NH2
+
ClN
N
SR2
R3
Br
S
48 49 50
R3
R2
R1
R1 N
H
N
H
N
N N
16
These 1, 3, 6-triazaphenothiazines were tested in mice and rats for
their effects on the central nervous system. The test results showed
that the derivatives studied have appreciable CNS-depressant
activities. All investigated compounds had antipyretic activity. They
decrease body temperature in some cases by as much as 1.9o
compared to 0.8o in chlorpromazine(15).
In addition to the reports on 1,3,6-triazaphenothiazines, Kaji and
his co-workers54
have also reported the synthesis of another
triazaphenothiazine ring system. When 6-halogeno-1,3,4-triazine-3,5
(2H,4H)-dione(52) was refluxed in an alkaline solution of
2-aminothiophenol(51), 6-(2-aminophenylthio)-1 ,3,4-triazine-
3,5(2H,4H)-dione(53) was obtained. Cyclization of the diaryl
sulphide(53), was achieved by refluxing in acetic acid for 1.5 hours.
This led to 29% yield of 1,3,4-triazaphenothiazine-2(1H)-one(54).
Compound(54) was converted through the tautomer(55) to the
chloroderivative(56) by the action of phosphorus oxychloride and
phosphorus pentachloride in the presence of diethylaniline.
17
NH2
S
O O
N
53
OO
Cl NNH
NH2
SH
OO
55
NS
PhNEt2POCl3PCl5
54
S NN
56
H
NN
H
N
H
N
N
S
N
NN
51 52
N
N
H
Cl
The third isomeric triazaphenothiazine, 1,3,9-triazaphenothiazine
derivatives(59) was reported by Okafor22
via the acid catalysed
condensation of 3-mercapto-2-aminopyridine(58) with 4,5-
dihalogenopyrimidine(57).
Cl R2 CH3NH2
CH3
R3
R2
SN
Br
N +
R3
59
58
57
NS-
N
H
N
H
N.
N
18
In tests with mice and rats, these derivatives of 1,3,9-
triazaphenothiazine showed CNS- depressant activities in doses of
1-4mg/kg, they also showed antipyretic activities.
On further research, replacement of the benzene ring in
phenothiazine with pyridazine leading to tetrazaphenothiazines was
accomplished by Wise and Castle55
who successfully synthesized five
out of thirty five possible isomeric tetra azaphenothiazine rings.
In these reactions, 4-amino-5-chloropyridazine(60) was converted to
4-aminopyridazine-5-thiol(61) in 58% yield by heating with sodium
hydrosulfide under pressure. This product was then treated with 3,4,
6-trichloropyridazine(62) at -10o to -50
o in ethanolic sodium
hydroxide. The resulting dipyridazinyl sulfide (63) was refluxed in the
presence of glacial acetic acid and gave 8-chloro-2,3,6,7-
tetrazaphenothiazine (65).
19
N
N
Cl
NH2
NaSH
under pressure
NH2
SHCl
Cl Cl
NN
62
KOHEtOH
ClSH
NN
Cl
gl . ACOH
S
NH2 NN
Cl
Cl
..
NN
N
N
HN Cl
65
6463
N
N
N
N
S
Similarly, by stirring a mixture of 4, 5-dichloropyridazine (66) and 5 –
aminopyridazine-6 (1H)- thione (67) at room temperature in the presence
of alcoholic potassium hydroxide, 2,3,6,7-tetraazaphenotiazine (68) was
isolated in 55% yield. It is a white compound melting at 184-185OC
23.
N
N
Cl
Cl
S
NH2
N
N
S
686766
+
NN
N
H
NN
Furthermore, it was also reported by Wise and Castle55
that if 4-(5-
aminopyridazinyl-4-thiol) -3, 6-dichloropyridazine (69), obtained by base
catalyzed condensation of 61 and 62 were treated with concentrated
hydrochloric acid, a chlorotetrazaphenothiazine (70) melting at 256-257o
was obtained23
.
20
S N
NNH2 Cl
Cl
NN
N
Conc
Cl
NN
7069
NHCl N
H
S
The unsubstituted 2,3,7,8-tetraazaphenothiazine was obtained in 66%
yield by treating compound 61 with71 in the presence of alcoholic KOH
at room temperature. It is a colourless solid melting at 167-168oC
18.
N
NNH2
ClN
N
N
N
N
N
Cl
61 7172
Alc. KOH
R.T
+
SH S
N
H
Similarly, the compound 3,4,6,7-tetraazaphenothiazine (75) was obtained
in 60% yield by stirring for 24 hours, an alcoholic mixture of compound
73 and 3,4-dichloropyridazine(74) in the presence of potassium
hydroxide. It is a crystalline compound melting at 179-180o.18
NN
NH2
Cl
NN
N
NN
ClAlc. KOH
+
SH S
NH2Cl
N
73 74
NN S
HN
NN
NN S
HN
Cl N
N
75
Also, Wise and Castle55
in utilizing the case of cylization of suitably
substituted diaryl sulfides heated the dipyridazinyl sulfide(76) in
concentrated hydrochloric acid at 90o for 4 hours to obtain compound 77.
21
It was isolated in 61% yield and it melted at 256-258oC. The UV
spectrum is different from those of related compounds24
. The compound
was therefore identified as 3-chloro-1,2,6,7-tetrazaphenothiazine
N
N
NS
NH2Cl
NN
N S
N
Cl
Conc HCl
Cl
7776
NN
H
It is very important to note that apart from linear azaphenothiazines, there
are many other phenothiazines used as dyes 25
and many that have
pharmaceutical importance. For example hydrophenothiazine which is
prepared by reacting 2-aminothiophenol(45) with 2-bromocyclohexanone
(78) in an inert atmosphere gave 1,2,3,4-tetrahydro-3H-phenothiazine
hydrobromide(79), which was converted to 1,2,3, 4-tetrahydro
phenothiazine(80) by treatment with a base under nitrogen atmosphere
followed by vacuum distillation and crystallization.
NH2
SSH+
O
Br
7845
N2 AtmBr -
N2Atm HO -
+
80
79
N
H
N
H
22
The structure of compound(80) which melted at 55-60o(bp.133-
135oC)
18 was established by a study of its infrared and NMR spectra.
Compound 80 and related compounds were shown to have enaminic
character and this property was used to rationalize its
disproportionation to a mixture of 1,2,3,4,4a,10a
hexahydrophenothiazine
S
80 81
S S
H+
+
N
H
N
H
N
H
Another important class of linear phenothiazines are 2,10-disubstituted
phenothiazines which are useful redox indicators and
spectrophotometric reagents.17
The radical cations, which are stable
enough under acidic conditions, exhibit quite intense colour. This
property allows employing phenothiazines as redox indicators in many
redoxometric determinations16
. The values of reduction potentials of
some phenothiazine established by Madej Wardman and Gowda
Ahmed17
are given below
23
Table 1
Phenothiazines Reduction potential
Chlorpromazine 860
Promethazine 925
Diethazine 845
Thioridazine 789
Propericizine 966
Trifluoperazine 880
Prochloperazine 799
Butaperazine 865
These linear phenothiazines have been used as indicators for
complexometric determination of iron(II) with disodium versenate.
They form with Fe(II) ions coloured oxidation products (red, orange
or blue). The addition of disodium versenate to the titrated solution
containing iron (II) solution and phenothiazine as indicator has caused
a change of the test solution in end point of titration as shown below
Table 2
Colourless-red colourless-orange colourless-blue
Chlorpromazine propericizine Thioridazine
Diethazine trifluoperazine
Promethazine prochlorperazine
Butaperazine
The usefulness of phenothiazine (chlorpromazine, promazine,
perphenazine, methopromazine), as redox indicators in chromatometric
determination of K4[Fe(CN)6] has been described by Puzanowska-
24
Tarasiewicz et al.16
Phenothiazines indictors are superior to conventional
indicators (eg ferroin, variamin blue). They give sharper end point and act
over a wide range of acidity than other conventional indicators. Based on
information gathered in the present review, it can be concluded that iron
(III) ion and its anionic complexes are valuable reagents useful in an
analysis of phenothiazines. The mild oxidation potential of iron (III) and
K3[Fe(CN)6] allows quantification of phenothiazines in batch and flow
systems. The proposed methods are characterized by simplicity, sensivity,
and good precision 16
.
Linear phenothiazines are chemically constituted by a lipophilic,
linearly fused cyclic system having a hydrophilic basic amino alkyl
chain. Linear phenothiazines function as antipsychotic drugs.
STRUCTURE ACTIVITY RELATIONSHIPS OF PHENOTHIAZINES
N
S
H1
2
3
456
7
8
9
10
Phenothiazines are the derivatives of phenothiazine tricyclic
heterocyclic moiety. The central ring possesses nitrogen and sulphur
heteroatoms.
1. Substitution at the second position of phenothiazine increases
antipsychotic activity. Example is chlorpromazine.
25
2. Substitution at the 3-position of phenothiazine nucleus increases
antipsychotic activity.
3. Substitution at 1 and 4 positions of phenothiazine nucleus reduces
the antipsychotic activity
4. Phenothiazines must have a nitrogen-containing side-chain
substituent on the ring nitrogen for antipsychotic activity. The ring
and side-chain nitrogen must be separated by a three carbon chain.
5. The side chains are either aliphatic, piperazine or piperidine
derivatives. Piperazine side chains confer the greatest potency and
the highest pharmacological selectivity.
6. Fluphenazine and long chain alcohols form stable, highly lipophilic
esters, which possess markedly prolonged activity.
7. Substitution on the side chain with a large or polar groups such as
phenyl, dimethylamino or hydroxyl results in loss of tranquilizing
activity.
8. The phenothiazines produce a lesser degree of CNS depression
than the barbiturates or benzodiazepines.11
Promazine(82),10-(3-(dimethylamino)-propyl) phenothiazine) is prepared
by condensing 3-chloro-N,N-dimethyl propylamine(81) with
phenothiazine (1) in presence of sodium hydride
26
N
SS
+ Cl-CH2CH2CH2N
CH3
CH3
NaH
CH2-CH2-CH2 N
CH3
CH3
81 82
N
H
It is presented as a hydrochloride salt. Promazine hydrochloride is
white or slightly yellow crystalline powder, and is freely soluble in water
and chloroform. It is unstable in air. It is used as antipsychotic drug and
it is also used to control nausea and vomiting.
Another important antipsychotic drug is triflupromazine (81), which is a
fluorinated phenothiazine derivative. Chemically, triflupromazine is
10-[3-(dithylamino)propyl]-2-(trifluoromethyl)phenothiazine. It is
synthesized by condensing 2-(trifluoromethyl)phenothiazine(83) with (3-
chloropropyl)dimethylamine(81) in dry benzene in presence of sodamide.
N
S
+ Cl-CH2CH2CH2N
CH3CH2-CH2-CH2
N
CH3NaNH/dry benzene
83
N
HCH3
CH3
CF3
CF3
S81
84
It is presented as a hydrochloride salt. Triflupromazine
hydrochloride is white crystalline powder. It is freely soluble in water,
alcohol and insoluble in ether. Triflupromazine is used to treat psychotic
disorder and also possesses antiemetic properties .
Similarly, prochlorperazine (87) is a phenothiazine derivative associated
with piperazine. Chemically, prochlorperazine is 3-chloro-10-[3-(4-
27
methyl-1-piperazinyl)phenothiazine. It is presented as meleate and
mesylate salts. Prochlorperazines is prepared by refluxing 1-(3-
chloropropyl)-4-methylpiperazine (80) with 2-chlorophenothhiazine (85)
in presence of sodamide in toluene.
Cl
+ H3C N N CH2 CH2 CH2Cl
8685
S NaNH2/Toluene
CH2CH2CH2N N CH3
Cl
87
N
H
N
S
Also trifluoperazine (88) an antipsychotic drug is a fluorinated
phenothiazine derivative. It also possesses a piperazine nucleus.
Chemically, trifluoperazine is 10-[3-(4-methylpiperazine -1-yl) propyl] -
2-trifluoromethylmethylphenothiazine (83). It is prepared by refluxing 2-
trifluoromethylphenothiazine (83) and 3-(4-methylpiperazineyl)propyl
chloride (86) in presence of sodamide as a base.
28
+ N N
86
CH2CH2CH2 N N
CH3
83
ClCH2CH2CH2
CH3
CF3
88
CF3
NaNH2
S
N
N
S
H
Trifluoperazine occurs as hydrochloride salt. Trifluoperazine
hydrochloride is a white to pale yellow crystalline powder. It is freely
soluble in water and should be protected from light and moisture. It has
been used to control psychotic disorder. It is effective to control excessive
anxiety, tension, aggressiveness and agitation.
2:2 TRANSITION METAL CATALYZED REACTIONS
A coupling reaction in organic chemistry is a catch-all term for a variety
of reactions where two hydrocarbon fragments are coupled with the aid
of a metal catalyst26
. In one important reaction type a main group
organic metallic compound of the type RM (R= organic fragment, M=
main group centre) reacts with an organic halide of the type R1X with
formation of a new carbon-carbon bond in the product R-R1.
Contributions to coupling reactions by Ei-ichi Negishi and Akira Suzuki
29
were recognized with the 2010 Nobel Prize in Chemistry, which was
shared with Richard F. Heck.
Broadly speaking, two types of coupling reaction are recognized.
(1) Cross couplings involves reaction between two different
partners for example bromobenzene(PhBr) and vinyl chloride to
give styrene (PhCH=CH2).
(2) Homocouplings couple two identical partners, for example, the
conversion of iodobenzene (PhI) to biphenyl (Ph-Ph).
Transition metal catalyzed couplings usually begin with oxidative
addition of one organic halide to the catalyst. Subsequently, the second
partner undergoes transmetallation, which places both coupling partners
on the same metal centre. The final step is reductive elimination of the
two coupling fragments to regenerate the catalyst and give the organic
product. Unsaturated organic groups couple more easily in part because
they add readily. The intermediates are also less prone to beta-hydride
elimination. In one computational study, unsaturated organic groups were
shown to undergo much easier coupling reaction on the metal centre. The
rates for reductive elimination followed the following orders: vinyl-
vinyl> phenyl-phenyl> alkynyl-alkynyl> alkyl-alkyl. The activation
barriers and the reaction energies for unsymmetrical R-R1 couplings were
found to be close to the averages of the corresponding values of the
30
symmetrical R-R and RI-R
I coupling reactions; for example; vinyl-
vinyl>vinyl-alkyl>alkyl-alkyl.
The most popular transition metal catalyst is palladium27
but some
processes use nickel and cooper. A common catalyst is tetrakis
(triphenylphosphine)palladium(0). Palladium-catalyzed reactions have
several advantages including functional group tolerance, low sensivity of
organopalladium compounds towards water and air.
The leaving group X in the organic partner is usually bromide,
iodide or triflate. Ideal leaving group is chloride, since organic chlorides
are cheaper than related compounds. The main group metal in the
organometallic partner usually is tin, zinc, or boron.
Considering the operating conditions, while many coupling reations
involve reagents that are extremely susceptible to presence of water or
oxygen, it is unreasonable to assume that all coupling reactions need to be
performed with strict exclusion of water. It is possible to perform
palladium–based coupling reactions in aqeous solutions using the water-
soluble sulfonated phosphines made by the reactions of triphenyl
phosphine with sulphuric acid27
. In general, the oxygen in the air is more
able to disrupt coupling reactions, because many of these reactions occur
via unsaturated metal complexes in nickel and palladium cross
couplings. A zero-valent complex with two vacant sites (or labile ligands)
reacts with the carbon halogen bond to form a metal halogen and a metal
31
carbon bond. Such a zerovalent complex with labile ligands or empty
coordination sites is normally very reactive toward oxygen.
SOME TRANSITION–METAL COUPLING TYPES
Reaction Year Reactant A I React B I Homo/cross Catalys Remark
Glaser coupling 1869 RC CH SP RC CH
SP Hom CU O2 as H-
acceptor
Ullmann
reaction
19
01
Ar-X SP
2 Ar-X
SP
2 Homo Cu High
temperature
Cadiot-chod
Kiewicz
coupling
1957 RC CH SP RC CX
SP Cross Cu Requires base
Castro-stephens
coupling
1963 RC CH SP Ar-X
SP
2 Cross Cu
Cassar reaction 1970 Alkene SP
2 R-X
SP
3 Cross Pd Requires base
Kumada
coupling
1972 Ar-mgBr S
P2,
SP
3 Ar-X
SP
2 Cross Pd or
Ni.
Heck reaction 1972 Alkene S
P2
R-X SP
2 Cross Pd Requires base
Somogashira
coupling
1975 RC CH SP R-X
SP
3
SP
2
Cross Pd and
Cu
Requires base
Negishi
coupling
1977 R Zn X SP
3
SP
2
R-X SP
3
SP
2
Cross Pd or Ni
Stille cross
coupling
1978 R-SnR3 SP
3
sp2s
p
R-X SP
3
SP
2
Cross Pd
Suzuki reaction 1979 R-B(OR)2 SP
2 R-X
SP
3
SP
2
Cross Pd Requires base
Hiyana coupling 1988 R-SiR3 SP
2 R-X
SP
3
SP
2
Cross Pd Requires base
Buchwald-
Hartwig
Reaction
1994 R2N-
RSnR3
SP
3 R-X
SP
2 Cross Pd N-C coupling,
Second
generation
32
Free amine
One method for palladium catalyzed cross-coupling reactions of aryl
halides (90) with fluorinated arenes(89) was reported.58
It is unusual in
that it involves C-H functionalisation at an electron deficient arenes
FF
F H
FF
+
Br
8990
Pd(OAC)2 (5mo/%)
K2CO3. DMA, 120OC
FF
F
FF91
98% yield
BU2PH3. HBF4
2.3 AMINATION REACTION
Clearly most researchers interested in the palladium–catalyzed
aromatic C-N coupling are attracted by the tool of a bond formation
between amines and aromatic halides or sulfonic acid esters. The first
example of a palladium catalyzed C-N cross coupling reaction was
published in 1983 by Migita and coworkers56
and described a reaction
between several aryl bromides and N,N-diethylamino–tributyltin using
1mol% PdCl2[p(o-tolyl)3]2. Though several aryl bromides were tested,
only electronically neutral, sterically unencumbered substrates gave good
yields
NBr + BU3Sn
R 9293
PdCL2[P(O-tolyl)3)2
C6H5CH3, 100OCN
R
94 16-18% yield
33
Then, in 1984, Dale L. Boger and James S. Panek63
reported an example
of Pd(0)
-mediated C-N bond formation in the context of their work on the
synthesis of lavendamycin(96) which utilized stocichiometric Pd(PPh3)4.
MeO2C CO2Me
H2N
Br
1.5eq Pd(PPh3)4
THF, 80OC, 21hrsHN
MeO2C CO2Me
84%96
95
In February of 1994, the Hartwig group59
published a systematic study of
the palladium compounds involved in the original Migita paper, their
findings indicated that the d10
complex Pd[p)o-Tglyl)3]2 was the active
catalyst (with the corresponding chloride entering the catalytic cycle via
in situ reduction) and supported a catalytic cycle involving oxidation
addition of the aryl bromide.
34
(O-Tolyl)3P-Pd-P(O-Tolyl)3
BrR
98
R=Me,Et
(O-Tolyl)3p Br
Pd
Br
Pd
R
P(O-Tolyl)3
9980-90%
R
Bu3SnNMe2
NMe2
100 R 90%
In May of the same year, the Buchwald group58
published an
extension of the Migita paper offering two major improvements over the
original paper. First, transamination of Bu3SnNEt2 followed by argon
purge to remove the volatile diethylamine allowed extension of the
methodology to a variety of secondary amines (both cyclic and acyclic)
and primary anilines. Secondly, the yield for election rich and election
poor arenes was improved via minor modification to the reactions
procedure (higher catalyst loading, higher temperature, longer reaction
time), although no orthosubstituted aryl groups were included in this
publication.
35
Bu3SnNEt2HNR2
ArpurgeHNEt2
BU3SnNR2
R
NR2
Br
R
PdCl2[P(O-Tolyl)3]2
55-58%
101
The following year, studies from each lab showed that the couplings
could be conducted with free amines in the presence of a bulky base
(KOtBu in the Buchwald publication,58
LiHMDS in the Hartwing
publication60
), allowing for organotin-free coupling. Though these
improved conditions proceeded at a faster rate, the substrate scope was
limited almost entirely to secondary amine due to competitive
dehalogenation of the bromoarenes
Br + HNR2
PdCl2[P(O-Tolyl)3]2or PD[PO-Tolyl)3]2
or Pd(dba)2/2P(O-Tolyl)3
NaOtBu or LiHMDsR
Toluene or THF
NR2
102R
92
25-100o C
These results established the so-called “first generation” of Buchwald-
Hartwig catalyst system. 28,29
. The following years saw development of
more sophisticated phospines ligands that allowed extension to a larger
variety of amines and aryl groups. Aryl iodides, chlorides, and triflates
36
eventually became suitable substrates, and reactions run with weaker
bases at room temperature were developed.
The amination reaction mechanism has been demonstrated to proceed
through steps similar to those known for palladium catalyzed C-C
coupling reactions,30
namely oxidative addition, palladium amide
formation (rather than transmetalltion), and finally reductive elimination.
In addition to this, an unproductive side reaction can complete with
reductive elimination where in the amide undergoes beta hydride
elimination to yield the hydrodehalogenated arene and an imine product.
Over the course of the development of this reaction, there has been a
great deal of work to determine the exact palladium species 29
responsible
for each of these steps, with several mechanistic revisions occurring as
more data was generated. These studies have revealed a divergent
reaction pathways depending on whether monodentate or chelating
phosphine ligands are employed in the reaction 31
.
37
Ar H + NR1
+ LPd
R11
Ar NRR1
Pd
H
L A r
NR L Pd
LPd
L Pd
Pd Ar
NR1
R
H
XBase
Base HX
Ar
X
Pd
L
XAr
L2Pd
HNRR1
R11
L
Reductiveelimination
NHRR1
Ar
Ar- X
Oxidative addition
palladiumamine forma tion
Fig 2.3: Buchwald-Hartwig Amination Catalytic Cycle
For monodentate ligand systems, monophosphine palladium (11)
species which is an equilibrium with the halogen dimer. The stability of
this dimer decreases in the slow reaction of aryl iodides with the first –
generation catalyst system. Amine ligation followed by deprotonation by
base produces the palladium amide. (chelating systems have been shown
to undergo these two steps in reverse order, with base complexation
preceding amide formation). This key intermediate reductively eliminates
to produce the product and regenerate the catalyzed 32
. However, a side
reaction can occur wherein -hydride elimination followed by reductive
38
elimination produces the hydrodehalogenated arene and the
corresponding imine.
For chelating ligands, the monophosphine palladium species is not
formed; oxidative addition, amide formation and reductive elimination
occur from L2Pd complexes. The Hartwig group found that reductive
elimination can occur from either a four-coordinate bisphosphine or
three-coordinate monophosphine aryl palladium amido complex.
Eliminations from the three- coordinate compounds are faster. Therefore,
-hydrogen elimination occurs slowly from arylpalladium complex
containing chelating phosphine while reductive elimination can still occur
from these four-coordinate species
Despite progress made thus far, ammonia remains one of the most
challenging coupling partners for Buchwald–Hartwig amination reactions
due to its tight binding with palladium complexes. Several strategies
have been developed to overcome this based on reagents that serve as
ammonia equivalent61
. The use of benzophenone imine or silylamide can
overcome this limitation, with subsequent hydrolysis furnishing the
primary aniline.
39
R
102
NH
PhPh
Pd(OAC)2
BINAP R
R
R
N Ph
Ph
N(siMe3)2
103
104
105
H3O+
H+orF-
H+orF-
NH2THF,65OC
P(tBu)3,LiHMDS
Toluene, 90oC
pd2(dba)3
Ph3SiNH2, LiHMDS
Tluene, 65oC
R
Cs2CO3
Pd2(dba) 3
NHSiPh3
Notably, the Hartwig group has recently developed a catalyst system that
can directly couple ammonia using a Josiphos-type ligand33
2.4 AMIDATION REACTION
Metal-catalyzed amidation reaction of aryl halides or pseudo halide are an
attractive method for synthesizing N-arylamides. These reactions were
traditionally performed with aryl iodides under Goldberg-modified
Ullman64
cross-coupling conditions using stoichiometric Cu and high
reaction temperature. Recent advances in this area have allowed for the
reaction of amides and aryl iodides or arylbromides to be performed
using catalytic amounts of Cu under milder conditions. Pd-based catalyst
system using phosphine ligands have also been developed33
, which
allow for the coupling of amides with aryl sulfonates, arylbromides and
most recently, aryl chlorides. These methods have been proven to be
useful to synthetic chemists and have been widely used in both industrial
and academic laboratories. Aryl chlorides are generally the most
40
attractive substrates for cross-coupling reactions because they are less
expensive and more readily available. Below is the amidation reaction for
the cross-coupling of acetamide (108) and 2-chlorotoluene (107)
Cl H2N
O
Me
1mol%Pd, 1.2mol%, ligand
solvent, base, 110oC, 40mins
Me108
O
MeNH
Me109107
Buchwald and his co-workers in 200836
, investigated the
application of water-mediated catalyst preactivation to amidation reaction
of aryl chlorides. Their research group recently reported an efficiently
catalyst system for this transformation utlilizing the combination of
Pd2(dba)2 and ligand. It has been proposed that with
biarydialkylphosphine ligands26
the rate-limiting step in amidation
reaction is the “transmetallation” (amide binding and /or deprotonation).
With a preactivation of Pd(OAc)2 a more active catalyst system could be
achieved, because there would be no dba present in the reaction to
compete for binding at the Pd centre.
They also considered cross-coupling reactions of amides with
3-chloropyridine, which have been difficult in the past. When the
preactivation protocol was employed, formamide, nicotinamide, and
2-pyrrolidinone(34) were all successfully coupling with 3-chloropyridine,
in 3hours using 1mol% Pd.35, 36
41
O
O
+
R3N(H)R2
Cl
3mol% ligand
4mo% H2O, 110oC 3h
R3NR2
112
R1
R1110 111
1mol%Pd(OAc)2
k2 PO4, t-BuOH
Reactions involving systhesis of amides include Beckmann
rearrangement and Chan-Lam coupling.
OR1R1
NH
H2SO4 conc
NOH R
113
114
Beckmann rearrangement
R
Ar B(OH)2+ HY R Cu(OAc)2
CH2Cl2,r.t Ar
: NR;O,S,
NCOR
NSO2R117116115 R
YY
Recent literature are as follows:
In 2006, Buchwald, Tundel and Anderson57
carried out a microwave –
assisted palladium –catalyzed C-N bond –forming reactions with aryl/
heteroaryl nonaflates and amines using soluble amine base which resulted
in good to excellent yields of arylamides in short reactions times.
42
Ar +
Ar
117116115
ONF H2NO
R
2.5mol%Pd2dba3
0.1 equ XantPhos
2.5 eq MTBDtoluene, MW 150or 175oC, 30min
Ar
R
O
120
NF: SO2(CF2)3CF3
XantPhos:PPh2
PPh2
O
N
NN
MTBD;
N
H
Also in 2006, A.G. Myers and his co-workers65
carried out the reaction of
N,N-dialkylformamide dimethyl acetal(122), with primary amides (121)
which produced N’-acyl-N, N-dialkylformamidine(123) as intermediates.
In the presence of certain Lewis acid additives efficient acyl transfer for
amide occurs, providing new and useful methods for amide exchange
such as
tran
R NH2
O
1.25eq
122
CH2Cl2, 23oC
2-5h
NiPr2
NR
O
NiPr2
2eq NH
R11
R1
0.5eq.Zrd4
23oC,1h
R N
R1
125123
121
O
RII
MeO
MeO
samidation.
In 2008, Y. Zhao and his co-workers47
carried out a convinent and
efficient iron –catalyzed aminobromination of alkenes which was
developed using inexpensive FeCl2 as the catalyst, amides/sulfonamides
43
and NBS as nitrogen and bromine sources, respectively, under mild
conditions.
R1
1.2eq
+ H2N RII
0.1eq
1.1eq NBS
FeCl2
EtOAc, r.l, 6h
RR
NRII
RI 128
126 127
Br
Moreover, in 2010, I.V Aksenova and co-workers45
carried out the
reaction of aromatic compounds with nitroethane (120) in polyphosphoric
acid which allows the synthesis of acetamides in good yields. The
corresponding amines can be obtained in situ upon hydrolysis of the
acetamides.
Ar H + O2NPolyphosphoric acid
(PPA) 110oC, 3-5h
Ar
NH
1.1eq
131
130129
O
Also in the same 2010, S.L Buchwald and co-workers38
carried out a
palladium–catalyzed cross-coupling reactions of amides and aryl
mesylates (132) which allows the transformation of array of aryl and
heteroaryl mesylates into the corresponding N-aryl amides in good yields.
H2N R
O1mol.%Pd(OAc)2
2.2mol%ligand
8mol%H2O,1.2eq (S2CO3
t-BuoA, 110oC 24hr.
ArNH
R
O
133121
132
Ar OMs +
44
2.5 BUCHWALD-HARTWIG CROSS COUPLING REACTION
The direct Pd-catalyzed C-N and C-O bond formation between aryl
halides or trifluoromethanesulfontes and amines (1o and 2
o aliphatic or
aromatic amines, imides, amides, sulfonamides, sulfoximines) or between
aryl halides or triflates and alcohols (aliphatic alcohols and phenols) in
the presence of a stoichiometric amount of base is known as the
Buchwald-Hartwig cross-coupling 36
.
R
X + H2NRI
PdCl2 (dPPf) (cat)
NaOt-Bu
dioxane100oC
R
NHRI
135134
R=Alkyl, CN, COR, RI= Alkyl, Aryl,
XR
+ NaO
+ -Pd(OAc)2 or Pd2(dba)3
base
RO
RII
136
R11
RII = 1
0, 2
0, or 3
0 aliphatic or aromatic. Ligand = BINAP, dppf, dba,
P(o-Tol)3
Base= NaOt-Bu, LHMDS, K2CO3, Cs2CO3
The advantages of Buchwald-Hartwig cross coupling reaction include
the use of stoichiometric amounts of heat and moisture –sensitive
tributyltin amides as coupling partners 37
.
In 1995, S. Buchwald and J. Hartwig58,60
concurrently discovered that the
aminotin species can be replaced with the free amine if one uses a strong
45
base which generates the corresponding sodium amide in situ by
deprotonating the Pd-coordinated amine. The temperature of the reaction
can be some times as low as 25oC.
M
+
Ot-Bu
M-XLnPd(II)
O-tBu
Ar
+
LnPd(II)
X
Ar
HNR2
HOt-Buk
LnPd(II)
NR2
Ar
Ar-NR3
reductiveelimination
LnPd(o)
Ar-Xoxidativeaddition
HNR2
LnPd(II)
X
Ar
MOt-Bu
+ -HOt-But Mx
Fig 2.5: Buchwald-Hartwig Coupling Reaction Catalytic Cycle
The first step in the catalytic cycle is the oxidative addition of Pd(0) to
the aryl halide (or sulfonate). In the second step the Pd (II) aryl amide can
be formed either by direct displacement of the halide (or sulfonate) by the
amide via a Pd(II)
- alkoxide intermediate. Finally, reductive elimination
results in the formation of the desired C-N bond and the Pd(o)
catalyst is
regenerated.38,39
46
Some of the recent literature are as follows:
In 2010, M. Lautens and G.Newman40
carried out a Pd(0)
-catalyzed C-N
bond forming reaction which enables the synthesis of brominated indoles
(138) in the presence of PtBu3 as phosphine ligand. The bulky ligand
serves to prevent inhibition of the catalyst by facilitating reversible
oxidative addition in the product C-Br bond40
R
N
Br
BrNH2
137
RBr
H138
5mol%Pd(OAc)2
6mol% Pt Bu3
2eq K2CO3
toluene, 100oC, 14h
Buchwald and co-worker26
recently improved the method for the Pd-
catalyzed coupling of phenols (139) with aryl halides.
Ar X + HO Ar1
1-3mol%Pd (OAC)2
3mol-%ligand
2eq K3 K3PO4
tolluene, 100oC 1-24xhr
ArO
Ar1
139
Similarly in 2010, S. Buchawld and P. Fors38
carried out a multiligand
base palladium –catalyzed C-N cross –coupling reactions 38
Ar X + HN Ar N
1mol% precatalyst1mol% ligand
1.4eq NaOtBudioxane 110oC, 24h.
R
R1
R
R1
Buchwald also developed an air and thermally stable one-component
catalyst for amination of aryl chloride. 41,42
47
Ar + Ar N
RI
RII
RI
RII
Cl H N2mol% catalyst
1.5 eq NaOtaBu, KO+toluene, 60 or 120oC2-20h.
48
CHAPTER THREE
RESULTS AND DISCUSSION
Most of the reports on the synthesis of linear azaphenothiazines ring
systems involved the reaction between o-aminothiophenol and
pyridines.43
The general success of this method especially with regard to
the synthesis of azaphenothiazine derivatives has motivated interest in
linear monoazaphenothiazine synthesis. This led us to the palladium-
catalyzed amination of linear monoazaphenothiazines.
3.1 3-CHLORO-1-AZAPHENOTHIAZINE.
For the synthesis of 3-chloro-1-azaphenothiazines(142),
2-aminothiophenol(140) and 2,3, 5-trichloropyridine(141) were utilized .
+
NH2Cl
Cl
ClSH ClS
H
N NKOH
DMF140
141142
N
The reaction mechanism follows “Smiles Rearrangement” in which there
is an intramolecular nucleophilic aromatic substitution in alkaline
solution resulting in the migration of the aromatic system from one
hetroatom to another, as represented in scheme 1.
49
SCHEME 1
N
NH2
SH
N
Cl
S
NH2 NCl
Cl
..
N
Cl
64
KOH
DMF
ClCl
Cl
Cl
NSH
N
H
S
Cl
NH
142
This mechanism is consistent with earlier observations in the literature.52
The synthesis of compound 142 was achieved by the reaction of 2-
aminothiophenol(40) and 2,3,5-trichloropyridine(14) in the presence of
potassium hydroxide and DMF.52
Compound 142 serves as an important
arylchloride intermediate in the synthesis of derivatives of this ring
system.
The assigned structure is supported by spectral analysis. In the infra red,
the absorption band at 3440-3060cm-1
is due to N-H stretching, 1607cm-1
is due to the C=N of pyridine ring, while the absorption band at 746cm-1
is due to C-Cl stretching. The absorption band in the UV-Visible at
309.2nm(l2.490) and 360nm(2.556) are consistent with the pyridine
50
structure. 1HNMR(CDCl3),δ7.05-6.30(6H,m,Ar-H), 4.0(1H,s,N-H).
13CNMR(CDCl3),δ147.4,146.9,146.4,135.8,130.0,128.6,126.7,126.1,119.
1,118.8,115.4 (11C,m,Ar-C).
Elemental analysis data calculated for C11H7N2ClS; C,56.30, H,3.00,
N,11.90, Cl,15.14, S,13.65. Analysis found: C,56.40, H,3.01, N,11.78,
Cl,15.20, S,13.61.
3.2 3-ANILINO-1-AZAPHENOTHIAZINE
When a mixture of 3-chloro-1-azaphenothiazine (142), aniline and
K2CO3 reacted with an activated palladium catalyst solution , at 110oC,
3-anilino-1-azaphenothiazine (20) was obtained as a dark tan solid
product melting at 117o-118
oC.
N
S
143
Cl
NH2
144
3mol%ligand
K2CO3. t-BuOH
4mol% H2O,110oC, 12h
SN
H20
+
N
H
N
H
1mol%Pd(OAc)2
The reaction proceeds by the mechanism represented in a catalytic cycle
shown in scheme 2
51
SCHEME 2
LnPd(o)
Pd(OAc)2 +2Ln
H2ON
S
N
NH
LnPd(II)NH
S
N N
HCO3
NH2
K2CO3
KCl
LnPd(II)
N N
S
Cl
oxidative addition
reductiveelimination
-hydrideelimination
20
LnPd(II)
N
S
N
Cl145
147
146
B
CO3
H
N
S
H
HH
H
Fig3.2 Catalytic cycle for the preparation of 3-anilino-1-
azaphenothiazine
The first step in the reaction mechanism is the oxidative addition of
palladium(0) to 3-chloro-1-azaphenothiazine(143) to form compound
145. In the second step, the palladium(II)- aryl carbonate (146) was
formed by direct displacement of the chloride group. Compound 146
reacts with aniline to give palladium(II)-arylcarbonate (147). Finally,
reductive elimination of compound 147 results in the formation of 3-
anilino-1-azaphenothiazine(20) and the catalyst was regenerated.
The assigned structure is supported by spectral analysis.
The absorption band at 3437-3057cm-1
in the infra red is due N-H bond,
52
1608cm-1
is due to C=N of pyridine moiety while absorption band at
745cm-1
is due to C-S-C. UV-Visible, λmax (ethanol)
237nm(log =2.375), 261.8nm(2.418), 307nm(2.487), 409.8nm(2.613).
1HNMR (CDCl3),δ7.79-6.30 (9H,m,Ar-H), 4.0(2H,s,N-H).
13C-NMR
(CDCl3),δ147.4, 146.7,141.9,137.5,136.0,134.1,130.0 ,129.3,
126.1,119.1,118.8,118.5,115.1,112.7(16C,m,Ar-C)
3.3 3-(4-NITROANILINO)-1-AZAPHENOTHIAZINE
When a mixture of 3-chloro-1-azaphenothiazine(142), 4-nitroaniline, and
potassium carbonate reacted with an activated palladium catalyst
solution, refluxed for 2 hours at 110oC, 3-(4-nitroanilino)-1-
azaphenothiazine(21) was obtained as grey solid melting at 97-98oC.
Cl
N
S
N
143
+
NH2
NO2
1mol%Pd(OAc)2
3mol%ligand
K2CO3 t-BuOH
4mol%H2O,11OOC, 2hrs
H
N
S
N
H
150
N
H
NO2
21
The reaction mechanism for preparation of compound (21) is represented
in scheme 3
53
SCHEME3
LnPd(o)
Pd(OAc)2 +2Ln
H2ON
S
N
NH
LnPd(II)NH
S
N N
HCO3
NH2
K2CO3
LnPd(II)
N
S
Cl
-hydrideelimination LnPd(II)
S
N
Cl145
146
21
NO2
143
HN N
S
KClCO3
NO2
NO2
149
HN
HN
H
B
H
147
Fig3.3: Catalytic cycle for the preparation of 3-(4-nitroanilino)-1-
azaphenothiazine
The first step in the reaction mechanism is the oxidative addition of
palladium (0) to 3-chloro-1-azaphenothiazine(143) to form compound
(145). In the second step, the palladium (II)-aryl carbonate (146) was
formed by direct replacement of the chloride group. Compound 146
reacted with (147) to give palladium (II)- aryl carbonate(149). Finally,
reductive elimination of compound 149 resulted in the formation of 3-(4-
nitroanilino)-1-azaphenothiazine(21) and the catalyst was regenerated.
54
The assigned structure is supported by spectral analysis. In the infra red
spectra, the absorption band at 3476-3064cm-1 is due to N-H bonding,
1612cm-1
is due to C=N of pyridine, 1307cm-1
is due to –NO2 while
747cm-1
is due to C-S-C. UV-Visible λmax (ethanol), 210.4nm(log
=2.323),246nm(2.391), 310nm(2.491),370.4nm(2.569),497.8nm(2.70)
1HNMR (CDCl3),δ7.94-6.30(8H,m,Ar-H), 4.0(2H,s,N-H).
13C-NMR
(CDCl3),δ152.8,147.4,141.9,138.4,137.5,136.0,134.1,130.0,126.1,124.4,
119.1,118.8,116.0,115.4,112.7(15C,m,Ar-C).
3.4. 3-(4-HYDROXYANILINO)-1-AZAPHENOTHIAZINE
When a mixture of 3-chloro-1-azaphenothiazine (142), 4-hydroxyaniline,
and K2CO3 reacted with an activated palladium catalyst solution, refluxed
for 2 hours at 110oC, 3-(4-hydroxyanilino)-1-azaphenothiazaine(22) was
obtained as a resin melting at 99-99.5oC
Cl
+
NH21mol%Pd(OAC)2
3mol%ligand
143
SNHK2CO3, t-BuOH
4mol%H2O 110oC
2hrsOH150
22
OH
N
H
N
H
NN
The reaction proceeds by the mechanism represented in a catalytic cycle
shown in scheme 4
55
SCHEME 4
LnPd(o)
Pd(OAc)2 +2Ln
H2ON
S
N
NH
LnPd(II)NH
S
N N
HCO3
NH2
K2CO3
LnPd(II)
N
S
Cl
-hydrideelimination
LnPd(II)S
N
Cl
147
146
HN N
S
CO3
HN
HN
reductiveelimination
oxidativeaddition
KCl
22
OH
OH
150
151
OH
H
H
B
Fig3.4: Catalytic cycle for the preparation of 3-(4-hydroxyanilino)-1-
azaphenothiazine
The first step in the reaction mechanism is the oxidative addition of
palladium (0) to 3-chloromonoazaphenothiazine(143) to form compound
(145). In the second step, the palladium(II)- aryl carbonate (146) was
formed by direct replacement of the chloride group. Compound 146
reacted with 4-hydroxyaniline(148) to give palladium (II)-aryl amine
(151). Then, reductive elimination of compound (151). Results in the
formation of 3-(4-hydroxyanilino)-1-azaphenothiazine (22) and the
catalyst was regenerated.
56
The assigned structure is supported by spectral analysis. The
absorption band in the infra red at 3432-3063cm-1
is due to N-H and O-H
stretching, 746cm-1
is due C-S-C while the absorption band at 1615cm-1
is
due to C=N of pyridine ring. UV-Visible λmax (ethanol), 237.4nm
(log =2.375), 307.4nm(2.488), 378nm(2.577), 496.2nm(2.692).
1HNMR (CDCl3),δ 7.79-6.29 (8H,m,Ar–H), 4.0(2H,s,N-H),5.0(1H,s,OH).
13C-NMR(CDCl3), δ 147.4, 147.3, 141.9, 139.3, 137.5, 136.0, 134.1,
130.0, 126.1, 119.1, 118.8, 116.5, 115.4, 112.7(14C,m,Ar-C).
3.5 3-(3-NITROANILINO)-1- AZAPHENOTHIAZINE
On reacting a mixture of 3-chloro-1-azaphenothiazine, 3-nitroaniline,
K2CO3 with an activated palladium catalyst solution, refluxed for 2 hours
at 110oC, 3-(3-nitroanilino)-1-azaphenothiazine(23) was obtained as a
grey solid melting at 89oC-90
oC.
Cl
+
NH2 1mol%Pd(OAC)2
3mol%lignd
SK2CO3, t-BuOH
4mol%H2O 110oC
2hrs
N
NO2
152
23NO2
N
S
NN
N
H
H H
The reaction mechanism for the preparation of compound(23) is
represented in scheme 5
SCHEME 5
57
LnPd(o)
Pd(OAc)2 +2Ln
H2O
S
N
NH
LnPd(II)NH
S
N N
HCO3
NH2
K2CO3
LnPd(II)
N
S
Cl
B-hydrideelimination
LnPd(II)S
N
Cl
147
146
HN N
S
CO3
HN
HN
reductiveelimination
oxidativeaddition
KCl
NO2
NO2
NO2
153
HN
H
Fig3.5: Catalytic cycle for the preparation of 3-(3-nitroanilino)-1-
azaphenothiazine
The first step in the reaction mechanism is the oxidative addition of
palladium(0) to 3-chloro-1-azaphenothiazine(143) to form compound
(145). In the second step, the palladium (II)-aryl carbonate was formed
by direct replacement of the chloride group. Compound 146 react with 3-
nitroaniline (152) to give palladium (II)-aryl amine (153). The, reductive
elimination of compound (153) results in the formation of 3-(3-
nitroanilino)-1-azaphenothiazine (23) and the catalyst was regenerated36
.
The assigned structure is supported by spectral analysis. The absorption
bands in the infra red at 3768-3074cm-1
is due to N-H bonding 1337cm-1
58
is due to –NO2, 742cm-1
is due to C-S-C and the absorption band at 1613-
1506cm-1
is due to C=N of pyridine moiety. UV-Visible λmax (ethanol),
212nm(log =2.326), 248.2nm(2.395), 307nm(2.487), 360nm (2.556).
1HNMR (CDCl3), δ 7.79-6.30(10H,m,Ar-H), 4.0(2H,s,N-H).
13C-NMR
(CDCl3), δ 149.2, 147.6, 147.1, 141.9, 137.5, 136.0, 134.1, 130.2,130.0,
126.1, 119.1, 118.8, 115.4, 113.6, 112.7, 110.2 (16C,m,Ar-C).
59
CHAPTER FOUR
EXPERIMENTAL
4.1 GENERAL
Melting points of the compounds synthesized were determined using
electrothermal melting point apparatus in open capillaries and are
uncorrected. Ultraviolet-visible spectra were recorded on a UNICO-
UV2102 PC spectrophotometer (Pure and Industrial Chemistry
Department, UNN) using matched 1cm quarts cells. The solvent was
ethanol and absorption maxima are given in nanometers (nm); the figures
in parenthesis are the log values. Infrared spectra data was obtained on
a Magna –IR system 750 spectrophotometer(NARICT,Zaria, Kaduna
State) using KBr discs and absorptions were given in per-centimeter (cm-
1). Nuclear Magnetic Resonance(
1H-NMR and
13C-NMR) were
determined using varian NMR mercury 200BB spectrophotometer
(Obafemi Awolowo University, Ile Ife). Chemical shifts are reported in δ
scale(neat). Elemental analysis was carried out to determine the
percentage abundance of the elements present.
4.2 3-CHLORO-1-AZAPHENOTHIAZINE
2-aminothiophenol (2g,18mmoles) was placed in the reaction flask
containing (1.79g,44mmoles) of potassium hydroxide in 50ml of
60
water.The mixture was warmed until the material dissolved at a
temperature of about 85oC. 2,3,5-Trichloropyridine (2.97g,20mmoles) in
50ml of DMF was added in drops during a period of 15minutes. The
entire mixture was refluxed with stirring for 4 hours. It was later poured
into a beaker, diluted with water to the 500ml mark and cooled, filtered
and the residue recrystallized from ethanol52
. Greenish yellow crystals of
3-chloro-1-azaphenothiazine (4.81g, 52% yield) were obtained melting at
161-161.5oC. IR(KBr), Vmax 3438cm
-1 (N-H stret), 3049cm
-1 (Ar-C-H),
1615cm-1
(C=C of aromatic rings), 1483-1417cm-1
(C=N stret), 1350cm-1
-1305cm-1
(monosubstituted Cl),756cm-1
(C-S-C).
UV-Visible, λmax (ethanol), 309.2nm(log =2.490), 291nm(2.464),
360nm(2.556). 1HNMR(CDCl3),δ7.05-6.30(6H,m,Ar-H), 4.0(1H,s,N-H).
13CNMR(CDCl3), δ147.4, 146.9, 146.4, 135.8, 130.0, 128.6, 126.7, 126.1,
119.1, 118.8, 115.4 (11C,m,Ar-C).
Analysis calculated for C11H7N2ClS; C,56.30, H,3.00, N,11.90, Cl,15.14,
S,13.65. Analysis found: C,56.40, H,3.01, N,11.78, Cl,15.20, S,13.61.
4.3. 3-ANILINO-1-AZAPHENOTHIAZINE
This compound was prepared according to water–mediated catalyst
preactivation procedure of Buchwald and coworkers36
in an inert
atmosphere. Preactivation of palladium acetate catalyst was done by
heating Pd(OAc)2 (0.0022g, 0.01mmol), water (2ml) and piperazine
ligand(1.60g,0.03) for 1 minute in t-BuOH (2mL). The activation was
61
monitored visually by colour change until a black catalyst solution was
observed. Then the activated catalyst solution was transferred into a
250ml three-necked round bottomed flask containing 3-chloro-1-
azaphenothiazine (2.34g,1.0mmol), K2CO3(0.19g,1.4mmol), aniline
(1.12g,1.2mmol), equipped with a magnetic stirrers and quick fit
thermometer. The solution was heated to 110oC for I minute and refluxed
for 2 hours. A solid product was obtained which on recrystallization with
ethyl acetate gave 3-anilino-1-azaphenothiazine as a dark tan solid
in(0.26g 95%) yield, melting at 117-117.5oC. IR (KBr), Vmax 3440-
3060cm-1
(N-H stret), 3210-2950cm-1
(C=C-H), 1610cm-1
(C=N),
1360cm-1
(C-N), 745cm-1
(C-S-C). UV-Visible, λmax
(ethanol),237nm(log 2.375),261.8nm(2.418),
307nm(2.487),409.8nm(2.613) 1
HNMR (CDCl3),δ7.79-6.30 (9H,m,Ar-
H), 4.0(2H,s,N-H). 13
C-NMR (CDCl3),δ147.4, 146.7,141.9 ,137.5,136.0,
134.1,130.0 ,129.3, 126.1,119.1,118.8,118.5,115.1,112.7(16C,m,Ar-C).
Analysis calculated for C17H13N3S: C,70.10, H,4.47, N,14.43, S,11.00.
Analysis found: C,69.89, H,4.50, N,14.48, S,11.13.
4.4 3-(4-NITROANILINO) -1-AZAPHENOTHIAZINE
62
This compound was prepared according to water–mediated catalyst
preactivation procedure of Buchwald and coworkers36
in an inert
atmosphere. Preactivation of palladium acetate catalyst was done by
heating Pd(OAc)2 (0.0022g, 0.01mmol), water (2ml) and piperazine
ligand(1.60g,0.03) for 1 minute in t-BuOH (2mL). The activation was
monitored visually by colour change until a black catalyst solution was
observed. Then the activated catalyst solution was transferred into a
250ml three-necked round bottomed flask containing 3-chloro-1-
azaphenothiazine (2.34g,1.0mmol), K2CO3(0.19g,1.4mmol),
4-nitroaniline (0.131g,1.2mmol), equipped with a magnetic stirrer and
quick fit thermometer. The solution was heated to 110oC for I minute and
refluxed for 2 hours. A solid product was obtained which on
recrystallization with ethyl acetate gave 3-(4-nitroanilino)-1-
azaphenothiazine as a grey solid in(2.59g, 96%) yield, melting at 97-
98oC. IR (KBr), Vmax 3070cm
-1 (N-H), 3230-2940cm
-1 (C=C-H, C-H
stret), 1620cm-1
(C=N) 1310cm-1
(C-N), 1307cm-1
(-NO2), 747cm-1
(C-S-
C). UV-Visible,λmax(ethanol),210.4nm(log =2.323),246nm(2.391),
310nm(2.491),370.4nm(2.569),497.8nm(2.70). 1HNMR (CDCl3), δ
7.94-6.30(8H,m,Ar-H), 4.0(2H,s,N-H). 13
C-NMR (CDCl3), δ 152.8,
147.4, 141.9, 138.4,137.5, 136.0,134.1, 130.0, 126.1, 124.4, 119.1,
118.8, 116.0, 115.4, 112.7(15C,m,Ar-C). Analysis calculated for
63
C17H12N4SO2: C,60.71, H,3.57, N,16.67, S,9.52. Analysis found: C,60.80,
H,3.61, N,16.60, S,9.49.
4.5. 3-(4-HYDROXYANILINO)-1-AZAPHENOTHIAZINE.
This compound was prepared according to water–mediated catalyst
preactivation procedure of Buchwald and coworkers36
in an inert
atmosphere. Preactivation of palladium acetate catalyst was done by
heating Pd(OAc)2 (0.0022g, 0.01mmol), water (2ml) and piperazine
ligand(1.60g,0.03) for 1 minute in t-BuOH (2mL). The activation was
monitored visually by colour change until a black catalyst solution was
observed. Then the activated catalyst solution was transferred into a
250ml three-necked round bottomed flask containing 3-chloro-1-
azaphenothiazine (2.34g,1.0mmol), K2CO3(0.19g,1.4mmol),
4-hydroxyaniline (0.13g,1.2mmol), equipped with a magnetic stirrers and
quick fit thermometer. The solution was heated to 110oC for I minute and
refluxed for 2 hours. A solid product was obtained which on
recrystallization with ethyl acetate gave 3-(4-hydroxyanilino)-1-
azaphenothiazine as a resin in (0.26g,95%) yield, melting at 117-118oC.
IR (KBr), Vmax, 3440-3070cm-1
(N-H, O-H stret), 3070-3940cm-1
(C=C-
H. C-H stret), 2390cm-1
(C=C, C=N) 1360cm-1
(C-N), 746cm-1
(C-S-
C).UV-Visible λmax (ethanol),237.4nm(log =2.375), 307.4nm(2.488),
64
378nm(2.577), 496.2nm (2.692). 1HNMR (CDCl3),δ 7.79-6.29
(8H,m,Ar–H), 4.0(2H,s,N-H),5.0(1H,s,O-H). 13
C-NMR(CDCl3), δ
147.4, 147.3, 141.9, 139.3, 137.5, 136.0, 134.1, 130.0, 126.1, 119.1,
118.8, 116.5, 115.4, 112.7(14C,m,Ar-C).
Analysis calculated for C17H12N3SO: C,66.67, H, 3.92, N, 13.73, S,10.46.
Analysis found: C,66.70, H,3.80, N,13.81, S,10.50.
4:6 3-(3-NITROANILINO)-1-AZAPHENOTHIAZINE.
This compound was prepared according to water–mediated catalyst
preactivation procedure of Buchwald and coworkers36
in an inert
atmosphere. Preactivation of palladium acetate catalyst was done by
heating Pd(OAc)2 (0.0022g, 0.01mmol), water (2ml) and piperazine
ligand(1.60g,0.03) for 1 minute in t-BuOH (2mL). The activation was
monitored visually by colour change until a black catalyst solution was
observed. Then the activated catalyst solution was transferred into a
250ml three-necked round bottomed flask containing 3-chloro-1-
azaphenothiazine(2.34g,1.0mmol), K2CO3(0.19g,1.4mmol),
3-nitroaniline (0.17g,1.2mmol), equipped with a magnetic stirrers and
quick fit thermometer. The solution was heated then to 110oC for I
minute and refluxed for 2 hours. A solid product was obtained which on
recrystallization with ethyl acetate gave 3-(3-nitroanilino)-1-
azaphenothiazine as a grey solid in (2.75g, 95%) yield, melting point 88-
65
89oC. IR (KBr), Vmax 3770-3084cm
-1 (N-H), 3210-2950cm
-1 (C-H
stret), 1620-1510cm-1
(C=C, C=N stret), 1340cm-1
(C-N), 1337cm-1
(-
NO2), 742cm-1
(C-S-C). UV-Visible λmax (ethanol),
212nm(log =2.326), 248.2nm (log2.395), 307nm (log2.487), 360nm
(log2.556). 1HNMR (CDCl3), δ 7.79-6.30(10H,m,Ar-H), 4.0(2H,s,N-H).
13C-NMR (CDCl3), δ 149.2, 147.6, 147.1, 141.9, 137.5, 136.0,
134.1,130.2,130.0, 126.1, 119.1, 118.8, 115.4, 113.6, 112.7,
110.2(16C,m,Ar-C). Analysis calculated for C17H12N4SO2: C,60.71,
H,3.57, N,16.67, S,9.52. Analysis found: C,60.79, H,3.49, N,16.64,
S,9.48.
66
CONCLUSION
Palladium catalyzed amination of linear monoazaphenothiazines was
carried out by Buchwald-Hartwig amination reaction protocol using 3-
chloro-1-azaphenothiazine as the aryl intermediate. The Buchwald
amination reaction using 3-chloro-1-monoazaphenothiazine as the
arylchloride intermediate. The cross- coupling amino partners include
aniline, 3-nitroaniline, 4-nitroaniline and 4-hydroxyaniline which resulted
in the synthesis of 3-anilino-1-azphenthiazine, 3-(3-nitroanilino)-1-
azaphenothiazine, 3-(4-nitroanilino)-1-azaphenothiazine and 3-(4-
hydroxyanilino)-1-azaphenothiazine respectively.The next frontier is to
investigate the possible biological activities of these phenothiazine
derivatives.
67
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73
INDEX
INFRARED SPECTROSCOPY
3-(4-hydroxyanilino)-1-azaphenothiazine
N
SOH
22
N
H
N
3-anilino-1-azaphenothiazine
20
S
H
N
H
N N
74
N
S
23NO2
N
H
N
H
N
SNO2
21
N
H
N
H
3-(3-Nitroanilino)-1-azaphenothiazine
3-(4-Nitroanilino)-1-azaphenothiazine
75
3-Chloro-1-azaphenothiazine
CS
H
N N
14
76
UV-VISIBLE SPECTROSCOPY
3(4-hydroxyanilino)-1-azaphenothiazine
N
SOH
22
N
H
N
3-anilino-1-azaphenothiazine
20
S
H
N
H
N N
77
3-(3-Nitroanilino)-1-azaphenothiazine
N
S
23NO2
N
H
N
H
3(4-Nitroanilino)-1-azaphenothiazine
N
SNO2
21
N
H
N
H
78
3-chloro-1-azaphenothiazine
CS
H
N N
14
79
1H-NMR AND
13C-NMR SPECTROSCOPY
3-(4-Hydroxyanilino)-1-azaphenothiazine
N
SOH
22
N
H
N
N
SOH
22
N
H
N
80
3-Anilino-1-azaphenothiazine
20
S
H
N
H
N N
3-Anilino-1-azaphenothiazine
20
S
H
N
H
N N
81
3-(3-Nitroanilino)-1-azaphenothiazine
N
S
23NO2
N
H
N
H
3-(3-Nitroanilino)-1-azaphenothiazine
N
S
23NO2
N
H
N
H
82
3-(4-Nitroanilino)-1-azaphenothiazine
N
SNO2
21
N
H
N
H
3-(4-Nitroanilino)-1-azaphenothiazine
N
SNO2
21
N
H
N
H
v
83
3-chloro-1-azaphenothiazine
CS
H
N N
14
3-chloro-1-azaphenothiazine
CS
H
N N
14
84
85