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

9

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

10

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