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TANDEM AMINATION CATALYSIS IN THE SYNTHESIS OF DIAZAPHENOXAZINE COMPOUNDS OF PHARMACEUTICAL INTEREST

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

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

 

 

LIST OF FIGURES

Fig 1:Uv-visible spectrum for 3-(2-amino-3-nitropyridino)-1,9-diazaphenoxazine……………………………………………………………………………………………….66

Fig 2:Uv-visible spectrum for 3-(2-aminopyrazino)-1,9-diazaphenoxazine………….67

Fig 3:Uv-visible spectrum for 3-(2-aminopyridino)-1,9-diazaphenoxazine…………..68

Fig 4:Uv-visible spectrum for 3-(2-aminophenyl)-1, 9-diazaphenoxazine…………..69

Fig 5:Uv-visible spectrum for 3-chloro-1, 9-diazaphenoxazine …………………………..70

Fig 6:Uv-visible spectrum for 3-anilino-1,9-diazaphenoxazine…………………………….71

Fig 7:IR spectrum for 3-chloro-1,9-diazaphenoxazine………………………………..……….72

Fig 8:IR spectrum for 3-(2-amino-3-nitropyridino)-1,9-diazaphenoxazine…………..73

Fig 9:IR spectrum for 3-(2-aminopyrazino)-1,9-diazaphenoxazine………….…………..74

Fig 10:IR spectrum for 3-(2-aminopyridino)-1,9-diazaphenoxazine…………………….75

Fig 11:IR spectrum for 3-(2-aminophenyl)-1,9-diazaphenoxazine……………………….76

Fig 12:IR spectrum for anilino-1,9-diazaphenoxazine………………………………………….77

Fig 13:1H-NMR Spectrum for 3-chloro-1,9-diazaphenoxazine……………………………..78

Fig 14:1H-NMR Spectrum for 3-(2-amino-3-nitropyridino)-1,9-diazaphenoxazine……………………………………………………………………………………………….79Fig 15:1H-NMR Spectrum for 3-(2-aminopyrazino)-1,9-diazaphenoxazine………….80

Fig 16:1H-NMR Spectrum for 3-(2-aminopyridino)-1,9-diazaphenoxazine…………..81

Fig 17:1H-NMR Spectrum for 3-(2-aminophenyl)-1,9-diazaphenoxazine……………..82

Fig 18:1H-NMR Spectrum for 3-anilino-1,9-diazaphenoxazine…………………………….83

Fig 19:13C-NMR Spectrum for 3-chloro-1,9-diazaphenoxazine…………………………….84

Fig 20:13C-NMR Spectrum for 3-(2-aminopyrazino)-1,9-diazaphenoxazine…..…….85

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.

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