ABSTRACT

 

The synthesis and characterization of five new linear diazaphenoxazine compounds is reported. The key intermediate, 3-chloro-1-9-diazaphenoxazine, was prepared via a base catalyzed reaction of 2-amino-3-hydroxypyridine with 2,3,5-trichloropyridine in aqueous 1, 4-dioxane.

Five 3-amino derivatives of the key intermediate were prepared via Buchwald – Hartwigamination coupling reaction between 3-chloro-1,9-diazaphenoxazine and various heterocyclic amines, under the catalytic influence of palladium acetate.

The assignment of structures to the synthesized compounds was done by the use of combined information from Uv-vis, IR, and NMR spectra.

 

TABLE OF CONTENTS

Title page…………………………………………………………………………………………………….i

Approval page………………………………………………………………………………………………………ii

Certification…………………………………………………………………………………………………………iii

Dedication……………………………………………………………………………………………………………iv

Acknowledgement………………………………………………………………………………………………..v

Abstract……………………………………………………………………………………………………………….vi

Table of contents………………………………………………………………………………………………..vii

CHPTER ONE…………………………………………………………………………………………………………1

1.0  Introduction…………………………………………………………………………………………….…….1

1.1 Background of study………………………………………………………………………………….……3

1.2 Statement of the problem………………………………………………………………………….…..5

1.3 Objectives of the study…………………………………………………………………………………..6

1.4 Justification of the study………………………………………………………………………………..6

CHAPTER TWO…………………………………………………………………………………………………….7

2.0  LiteratureReview………………………………………………………………………………………….7

2.1  TandemAmination and Amidation………………………………………………………………..7

2.2  LinearPhenoxazines……………………………………………………………………………….……19

2.2.1  Non-azaanalogues of phenoxazines…..……………………………………………….…..20

2.2.1.1Benzo[b]phenoxazine……………………………………………………………………………..20

2.2.1.2   2-Amino-4,4α-dihydro-4α,7-dimethyl-3H-Phenoxazine-3-one………………22

2.2.2       Aza analogues of phenoxazines……………………………………………………………23

2.2.2.1         1-Azaphenoxazine……………………………………………………………………………24

2.2.2.2         2-Azaphenoxazine……………………………………………………………………………27

2.2.2.3        3–Azaphenoxazine……………………………………………………………………………28

2.2.2.4        4–Azaphenoxazine……………………………………………………………………………33

2.2.2.5       3,4-Diazaphenoxazine……………………………………………………………………….34

2.2.2.6       1,4-Diazaphenoxazine…………..…………………………………………………………..35

2.2.2.7       1,9-Diazaphenoxazine ………………………………………………………………………37

2.2.3           Nitro, Amino, N-Acetyl and N-Alkyl Phenoxazines…………………………….38

CHAPTER THREE………………………………………………………………………………………………..42

3.0        Experimental……………………………………………………………………………….…………42

3.1       General Information……………………………………………………………………………….42

3.2        3-Chloro-1,9-diazphenoxazine………………………………………………………………..43

3.3         Preparations of Single Crystals of 3-Chloro-1,9-diazaphenoxazine ………..43

3. 4 1,4-Bis(2-hydroxy–3,5–ditert–butylbenzyl)piperazine…………………..………..44
4. 5 General Procedure for the Synthesis of 3-AminoDerivativesof 1,9-Diazaphenoxazine……………………………………………………………………………………..……….44
5. 5. 1 3-(2-Amino-3–nitropyridino)-1,9-diazaphenoxazine……………………………..45
6. 5. 2 3-(2–Aminopyrazino)–1,9–diazaphenoxazine……………………………………..45
7. 5. 3 3-(2-Aminopyridino)–1,9–diazaphenoxazine……………………………………….46
8. 5. 4 3–(2–Aminophenyl)–1,9–diazaphenoxazine………………………………………..46
9. 5. 5 3–Anilino-1,9–diazaphenoxazine………………………………………………………..46

CHAPTER FOUR …………………………………………………………………………………………………47

4.0       Results and Discussion ……………………………………………………………………………47

4.1        3–Chloro–1,9-diazaphenoxazine ……………………………………………………………47

4.2        1,4–Bis(2–hydroxy–3,5-ditert–butylbenzyl)piperazine …………………………..49

4.3       Catalyst Preactivation …………………………………………………………………………….49

4.4      3–(2–Amino-3–nitropyridino)-1,9-diazaphenoxazine ………………………………49

4.5      3–(2–Aminopyrazino)-1,9–diazaphenoxazine…………………………………………50

4.6      3–(2–Aminopyridino)-1,9–diazaphenoxazine………………………………….………..51

4.7       3–(2–Aminophenyl)–1,9–diazaphenoxazine………………………………….…………52

4.8         3–Anilino–1,9–diazaphenoxazine………………………………………………..…………52

CHAPTER FIVE ……………………………………………………………………………………………………54

5.0   Conclusion …………………………………………………………………………………………….……54

REFERENCES…………………………………………………………………………………….…..55

 

 

CHAPTER ONE

1.0   INTRODUCTION

Phenoxazine(1) is a compound analogous in structure to phenothiazine(2) with

oxygen in place of sulphur.Its other systematic names are 10H-phenoxazine and 2,2,5,6-dibenzo-1,4-oxazine¹.They are tricyclic nitrogen-oxygen heterocycles². Owing to the wide range of application of phenoxazine compounds, the synthesis of their derivatives and isolation of the natural phenoxazines have been a subject of great interest over the years³. Phenoxazine compounds have a wide range of applications, particularly as drugs and dyes.

 

The naturally occurring phenoxazine derivatives have been classified as Ommochromes, fungal metabolites, Questiomycins and Actinomycins⁴.

Phenoxazines are generally grouped into linear phenoxazines and angular phenoxazines. The linear phenoxazine, as the name implies, has a linear arrangement of rings like compounds 3 and 4 below.

 

 

 

Angular phenoxazines have their skeleton extended by adding fused benzene rings to a, c, h or j faces such as compounds 5, 6, 7, and 8 below.

 

 

 

 

There are still other structural arrangements with additional annular nitrogen atom(s). Where additional one, two or three nitrogen atom(s) are added, they are known as monoaza, diaza or triaza analogues respectively. Examples are below;

 

TANDEM CATALYSIS

Tandem catalysis is the application of transition metal complexes as catalyst. Tandem catalysis has led to the development of simple and efficient methods of carbon-carbon and carbon-heteroatom bond formation⁵. Transition metal catalysed reactions have been used extensively in both ring synthesis andfunctionalisation of heterocycles⁶. As well as completely new modes of reactivity, variants of older synthetic methods have been developed using the milder and more selective processes that involve the use of transition metal catalysts⁷.

 

Although there are many processes catalyzed by a range of transition metals, palladium-catalyzed processes vastly outnumber the others such as Ni, Rh, Cu, Fe.⁸

The rate, yield and scope of palladium-catalyzed cross-coupling reactions are influenced by both the reaction parameters and the choice of ligands, allowing for a wide substrate scope through judicious choice of these parameters⁸.

 

• BACKGROUND OF STUDY

The naturally occurring phenoxazine derivatives are numerous⁹. TheOmmochromes such as xanthommatin(9) are acidic pigments found in different arthropods and are responsible for the colouration in the wings, cuticle and eyes of insects¹⁰.

 

 

 

Some fungal metabolites derived from phenoxazine ring have been isolated from various wood-rotting fungi and from moulds. The colouration in these organisms has been attributed to these phenoxazine derivatives of type 10^11-13.

 

With the exception of the actinomycin antibiotics which have antibacterial and anti-tumor activities, these naturally occurring phenoxazines are notparticularly useful compounds.

Interest in the naturally occurring phenoxazines    has declined considerably giving way to a systematic synthesis of phenoxazineanalogs modeled after the biologically active azaphenothiazines¹⁴.

Following reportson the pharmacological activities of phenoxazine, attention was  diverted form their dyeing properties to a study of their biological  activities.^15-17 From tests carried out in laboratory animals and in man, it was found that many phenoxazine derivatives showed pronounced pharmacological activities as CNS depressants¹⁸, sedatives¹⁹, antiepileptics²⁰, tranquilizers²¹, antituberculosis²², anti- tumour²³, antibacterial²⁴, spasmolytic²⁵, anthelminthic²⁶ and parasiticidal agents²⁷.

1.2      STATEMENT OF THE PROBLEM

It was interest to ascertain if tandem catalysis procedures  could be extended to C- substituted side chain derivatives  of diazaphenoxazine. The extension would validate the generality of optimized tandem molecular amination protocols in terms of substrate scope.

To the best of our knowledge, there is practically no report of the synthesis of side chain amino derivatives of diazaphenoxazine through tandem catalysis.Thus, a concise application of tandem methodologies would allow access to five hitherto unknown heterocyclic scaffolds of the diazaphenoxazine type shown below.

 

 

1.3      OBJECTIVES OF THE STUDY

The specific objectives of this study were to:

(i) Synthesize the key intermediate, 3- chloro-1 9- diazaphenoxazine.

(ii) Prepare single crystals of this intermediate for X-ray analysis.

(iii) Transfrom 3-chloro-1,9- diazaphenoxazine to varions 3- substituted aminoheterocyclic derivatives via Buchwald – Hartwig tandem amination protocol.

(iv) Characterize the new derivatives using spectroscopic techniques.

 

1.4    JUSTIFICATION OF THE STUDY

Among the motivations  to carry out the research work is the wide range of application of phenoxazine derivatives^18-27 and the need to synthesize new derivatives which may have better and desirable properties.

 

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