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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


-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


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


oxidativeaddition

KCl

22

OH

OH

150

151

OH

H

H

B

Fig3.4: Catalytic cycle for the preparation of 3-(4-hydroxyanilino)-1-

azaphenothiazine


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


oxidativeaddition

KCl

NO2

NO2

NO2

153

HN

H

Fig3.5: Catalytic cycle for the preparation of 3-(3-nitroanilino)-1-

azaphenothiazine


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



in an inert







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.



in an inert







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.



in an inert







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


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


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


N

S

23NO2

N

H

N

H


N

S

23NO2

N

H

N

H

82


N

SNO2

21

N

H

N

H


N

SNO2

21

N

H

N

H

v

83


CS

H

N N

14


CS

H

N N

14

84

85

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