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University of Bath
PHD Conversion of Alcohols into Amines by Borrowing Hydrogen
Hamid, Malai
Award date:
2008
Awarding institution:
University of Bath
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Conversion of Alcohols into Amines
by Borrowing Hydrogen
Malai Haniti Sheikh Abdul Hamid
A thesis submitted for the degree of Doctor of Philosophy
Department of Chemistry
University of Bath
November 2008
COPYRIGHT
Attention is drawn to the fact that copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the prior written consent of the author. This thesis may be made available for consultation within the University Library and may be photocopied or lent to other libraries for the purposes of consultation.
Signed ............................................. Date .............................................
CONTENTS
CHAPTER 1........................................................................
1. INTRODUCTION........................................................................
..............................1
1.1 A
......................................1 1.2 SYNTHESIS OF AMINES........................................................................ ....................3
1.2.1 Synthesis of Secondary Amines.......................................................................6
1.2.2 Synthesis of Tertiary Amines........................................................................
...8
1.3 TRANSITION METAL-CATALYSED TRANSFER HYDROGENATION...........................12
1.4 N-ALKYLATION OF AMINES WITH ALCOHOLS.......................................................22 1.5 ..................................36 CHAPTER 2........................................................................
2. RESULTS AND DISCUSSION I........................................................................
....42
2.1 B
..........................42
2.2 R
ESEARCH
....................46
2.3 I
RIDIUM-CATALYSED N-ALKYLATION OF AMINES WITH PHENETHYL ALCOHOL BY BORROWING HYDROGEN........................................................................ .............47
2.4 R
UTHENIUM-CATALYSED N-ALKYLATION OF PRIMARY AMINES WITH PRIMARY ALCOHOLS BY BORROWING HYDROGEN..............................................................50 2.4.1 N-Alkylation of Primary Alkyl and Aromatic Amines with Benzyl Alcohol and Phenethyl Alcohol........................................................................ ........61 2.4.2 N-Alkylation of Aniline with Primary Alcohols..........................................64
2.5 CHAPTER SUMMARY........................................................................
................70
2.6 R
............................71 CHAPTER 3........................................................................
3. RESULTS AND DISCUSSION II........................................................................
..73
3.1 A
3.2 BACKGROUND........................................................................
..........................73
3.3 I
NITIAL STUDIES........................................................................ .......................75
3.4 R
UTHENIUM-CATALYSED N-ALKYLATION OF PRIMARY ALCOHOLS WITH
SECONDARY AMINES BY
BORROWING HYDROGEN..............................................84 3.5 RUTHENIUM-CATALYSED SYNTHESIS OF DIMETHYLAMINES BY BORROWING ......................................87
3.5.1 Initial Studies........................................................................
......................87 3.5.2 Ruthenium-Catalysed Synthesis of N,N-Dimethylamines from Alcohols by Borrowing Hydrogen........................................................................ ..........95
3.6 C
HAPTER SUMMARY........................................................................ ..............100
3.7 R
..........................101 CHAPTER 4........................................................................ 4. ...........................103
4.1 I
.......................103
4.2 T
HE ROLE OF THE RECEPTOR........................................................................ .104
4.3 A
..............................105 4.3.1 Synthesis of Piribedil........................................................................ ........107 4.3.2 Ruthenium-Catalysed Synthesis of Piribedil by Borrowing Hydrogen.....109
4.4 A
NTIHISTAMINES OF H
1 RECEPTOR ANTAGONISTS........................................111 4.4.1 Synthesis of Antergan and Tripelennamine..............................................114 4.4.2 Synthesis of Corresponding Alcohols of Antergan and Tripelennamine by Conventional Methods and Borrowing Hydrogen Methodology..............115 4.4.3 Ruthenium-Catalysed Synthesis of Antergan and Tripelennamine by Borrowing Hydrogen........................................................................ ........117
4.5 C
HAPTER SUMMARY........................................................................ ..............120
4.6 C
ONCLUSION AND FUTURE DIRECTIONS........................................................120
4.8 R
..........................123 CHAPTER 5........................................................................
5. EXPERIMENTAL........................................................................
.........................126
5.1 G
ENERAL EXPERIMENTAL METHODS.............................................................126
5.2 E
XPERIMENTAL PROCEDURES FOR CHAPTER 2...............................................127
5.3 E
XPERIMENTAL PROCEDURES FOR CHAPTER 3...............................................147
5.4 E
XPERIMENTAL PROCEDURES FOR CHAPTER 4...............................................169
5.5 R
..........................175 APPENDICES .................................................................... ....................................... 176
Acknowledgements
ACKNOWLEDGMENTS
My heartiest thank you goes out to Professor Jonathan Williams for his constant support and excellent supervision over the last three years. Thank you for the excitement we shared when things went well and comforting me when things didn't. You've been such an inspiration to me! I would also like to thank all the members of the Williams group as well as the Bull group especially Slatto, Sonia, Gareth A., Nathan, Simon, Tracy, Hannah, Nik, Gareth
L., Iwan, Mike, Andy, Paul, Liana, Ory and
James for the fun times we've had in the
lab. I shall miss working in the Williams lab so much. Thank you Anneke, Sheila, Mary, Hilary and all staff at the University of Bath for making my time in Bath run smoothly. A special thank you to John Lowe for answering all my NMR questions. I am very grateful to His Majesty's Government of Brunei Darussalam and Universiti Brunei Darussalam for giving me this opportunity to pursue my research at the
University of Bath.
A big thank you to my family especially my
parents and two daughters Hana and Zahra for their love, support and understanding in everything that I do. Thank you to my sister Zeiti for spoiling me all the time and finally to my husband, Sufri I love you and thank you for everything. And I dedicate this to my late father-in-law, Pg Ali Pg Hj Osman. i
Synopsis
SYNOPSIS
This thesis describes the development of a more economical catalytic system for the N- alkylation of amines by "borrowing hydrogen" and its application in the synthesis of a variety of amines including the dopamine agonist Piribedil and the antihistamine agents
Antergan and Tripelennamine.
Chapter 2 describes the development of the ruthenium-catalysed N-alkylation of primary amines with primary alcohols by "borrowing hydrogen". Chapter 3 describes the application of the ruthenium-catalysed N-alkylation of secondary amines with primary alcohols by "borrowing hydrogen". The ruthenium- catalysed synthesis of dimethylamines by "borrowing hydrogen" is also described and a mechanistic proposal for the N-alkylation of alcohols with amines has been proposed. Chapter 4 describes the role of amines in pharmaceuticals and the ruthenium-catalysed synthesis of Piribedil, Antergan and Tripelennamine by "borrowing hydrogen". ii
Abbreviations
Abbreviations
Å Angstrom
Abs. Absolute
acac Acetylacetone anhyd. Anhydrous
Ar Aryl group
atm Atmospheres bmim 1-butyl-3-methylimidazolium
Bn Benzyl
Bz Benzoyl
b.p. Boiling point
BINAP 2,2'-Bis(diphenylphos
phino)-1,1'-binapthyl
Boc t-butyloxycarbonyl
c Concentration
COD 1,5-Cyclooctadiene
COT 1,3,5,7-Cyclooctatetraene
Cp* Pentamethylcyclopentadienyl
crotyl trans-but-2-en-1-yl dba Dibenzylidene acetone
DBU 1,8-diazabicyclo[5.4.0]undecene-7
DEAD Diethyl azodicarboxylate
dippf 1,1'-Bis(diisopropylphosphino)ferrocene
DMF N,N-Dimethylfomamide
DMSO Dimethylsulfoxide
DPEphos (Oxydi-2,1-phenylene)bis(diphenylphosphine) dppe 1,1'-Bis(diphenylphosphino)ethane dppf 1,1'-Bis(diphenylphosphino)ferrocene dppp
1,1'-Bis(diphenylphosphino)propane
ee Enantiomeric excess equiv. Equivalent
ESI Electrospray Ionisation
Et Ethyl
Et 3
N Triethylamine
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