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

3. 4       1,4-Bis(2-hydroxy–3,5–ditert–butylbenzyl)piperazine……………..44

3. 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

3. 5. 2       3-(2–Aminopyrazino)–1,9–diazaphenoxazine……………………..45

3. 5. 3      3-(2-Aminopyridino)–1,9–diazaphenoxazine……………………….46

3. 5. 4      3–(2–Aminophenyl)–1,9–diazaphenoxazine………………………..46

3. 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 and functionalisation 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.