Acid-Catalysed Hydroaminations A thesis submitted to Cardiff University by Laura Henderson MChem (Hons.) In candidature of the degree of Doctor of Philosophy School of Chemistry Cardiff University UMI Number: U557419 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U557419 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Acknowledgments First of all I would like to thank Prof. David W. Knight, for all his support, great ideas and seemingly endless breadth of knowledge that made this project possible. Secondly, I would also like to thank Dr. Andrew C. Williams for all the support and advice he has given over the last three years. I am grateful to the many students whose have contributed towards this thesis; they were all a joy to work with. In particular, I want to thank Nena Christiansen, Jon Williams and Rhian Courtney for their work. I want to thank Dr Rob Jenkins, Robin Hicks and Dave Walker for all of their mass spec, and NMR support over the years. I also want to thank Dr John Brazier and Dr Jacky Yau for all the advice and help that they gave, and endless enthusiasm that they have shown. My time at Cardiff has been very enjoyable, mostly due to the wonderful people that work here. They have truly made coming to work every day a pleasure. Thank you very much to everyone in the playroom and in particular members of the Knight group: Andrew, Andy, Damian, Ian and Jess, for making the last three years fun. I would like to thank the EPSRC and Eli Lilly for the financial support and everyone at Eli Lilly who made my placement a highly enjoyable experience. And finally, I am incredibly grateful to the endless support and encouragement that my parents, Alan and Margaret, and my sister, Gemma, have given me. DECLARATION This work has not previously been accepted in substance for any degree and is not concurrently submitted in candidature for any degree. Signed . .0 7 ^ ^ 7 7 7 . ..... .................................. .. (candidate) Date ..S t.'/S C p . ...2 r Q .\?P STATEMENT 1 This thesis is being submitted in partial fulfilment of the requirements for the degree of PhD Signed . j0f7!rr77rr7 ... .v^~77rrr:. ................. (candidate) Date . .2 .0 1 0 STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. (candidate) Date. STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter- library loan, and for the title and summary to be made available to outside organisations. Signed ... (candidate) Date Abstract The Knight group has for some time been utilising the acid-catalysed hydroamination to synthesise pyrrolidines 140. This method was also utilised to produce poly-cyclic systems, of either a spiro- 220 or a fused-nature 12, through cascade reactions using a sulfonamide as a terminator. This was examined further to establish some scope and limitation. In particular, we have shown that the reaction is not limited to the formation of tertiary carbenium ions but could be implemented for cyclisations via secondary carbenium ions 155. The hydroamination was also shown to be most successful at forming highly hindered, bridged compounds 194, which would be difficult to synthesise through other means. The hydroamination reaction was then investigated in terms of its potential as a variant of the classical Pictet-Spengler reaction towards dihydroisoindoles 363 and tetrahydroisoquinolines 361. This was briefly explored in terms of the type of remote functional groups that would be compatible with this method. The formation of the isoindoles and isoquinolines was successful and further investigations of compatible functional groups need to be performed. The synthesis of the trisubstituted piperidine 447 was attempted using the acid-catalysed hydroamination method, believing that this would be a simple extension of the pyrrolidine synthesis. Unfortunately, this was not successful; instead the corresponding pyrrolidine 449 was isolated. This led us to further investigate the sensitivity of sterically crowded piperidines towards acid. Successful synthesis of trisubstituted piperidine 501 was achieved by changing the JV-protecting group. Contents Chapter 1 - Introduction to Acid-Catalysed Hydroaminations 1 1.1 Hydroamination Development 2 1.2 Bronsted Acid-Catalyzed Hydroamination of Alkenes and Alkynes 3 1.2.1. Intermolecular Bronsted Acid-Catalyzed Hydroamination of Alkenes 3 1.2.2. Intramolecular Bronsted Acid-Catalyzed Hydroamination of Alkenes 5 1.3. Development of Acid-Catalysed Hydroamination in the Knight Group 7 1.4. Conclusion 10 Chapter 2 - Acid-Catalysed Hydroaminations - Model Studies 11 2.1. Introduction 12 2.1.1. Intermolecular Methods for Pyrrolidine Formation 12 2.1.2. Intramolecular Methods to Afford Pyrrolidines 17 2.1.3. Reaction of Amino Alkenes 21 2.2. Background to Current Work 25 2.3. Results and Discussion 26 2.3.1. Simple Pyrrolidines 26 2.3.2. Terminal Double Bonds - Secondary vs. Primary Carbenium Ions 30 2.3.3. Investigations into Ring Opening and Re-closure 34 2.3.3.1. Investigations of the Mechanism 39 2.3.4. Transannular Cyclisations 40 2.3.5. Cascade & Fused Systems 42 2.3.6. Indene 44 2.3.7. O-N Compounds 47 2.3.7.1. Isoxazolidine vs. Morpholine 47 2.3.12. Transannular Cyclisations 53 2.3.7.3. 5^z>o-Isoxazolidines 54 2.4. Conclusion 57 Chapter 3 - A Hydroamination Variant of the Pictet-Spengler Reaction 58 3.1. Introduction 59 3.1.1 Development of the Pictet-Spengler Reaction 59 3.1.2. Tetrahydroisoquinolines 59 3.1.3. Pictet-Spengler Reaction of Indoles 64 3.1.4. Conclusion 67 3.2. Hypothesis 69 3.3. Results and Discussion 70 3.3.1. Proposed Synthetic Route 70 3.3.2. Suzuki Reaction 71 3.3.3. Cyclisations 74 3.3.3.1. Dihydroisoindoles 74 3.3.3.2. Tetrahydroisoquinolines 79 3.4. Remote Functional Groups 83 3.4.1. Alternatives to Suzuki 84 3.5. Conclusion 90 Chapter 4 - Ring-Contraction of Piperidines 93 4.1. Introduction 94 4.2. Results and Discussion 99 4.2.1. Ring-Contraction of Piperidines 99 4.2.2. Synthesis towards Piperidines 110 4.3. Conclusion 115 Chapter 6 - Experimental 117 6.1. General Details 118 6.2. General Procedures 119 6.3. Experimental Data 120 References 206 Appendix 220 Abbreviations Abbreviations in this text are: Ac Acetyl APCI Atmospheric Pressure Chemical Ionisation Aq. Aqueous Ar Aromatic Boc Butoxycarbonyl 9-BBN 9-Borabicyclo[3.3.1]nonane Cone. Concentrated Cbz Benxyl carbamate DBU 1,8-Diazobicyclo[5.4.0]undec-7-ene DCM Dichloromethane d.e. Diastereomeric excess DIAD Diisopropyl azodicarboxylate DMAP Dimethylaminopyridine DMF A^A-Dimethylformamide dtbpf Di-fer/-butyl phosphine ferrocene e.e. Enantiomeric excess Eq. Equivalents El Electro Ionisation ES Electro Spray hr Hour hrs Hours HRMS High Resolution Mass Spectrometry IR Infra red LDA Lithium diisopropylamine LRMS Low Resolution Mass Spectrometry m.p. Melting point M Molar (moles L'1) mins Minutes MsCl Mesyl chloride/ methanesulfonyl chloride NMR Nuclear Magnetic Resonance Ns / nosyl para-N itrobenzenesulfonyl z-Pr fro-Propyl Ppm Parts per million Py Pyridine r.t. Room temperature Sat. Saturated TBAF tetra-H-Butylammonium fluoride TBS tert-Butylsilyl THF Tetrahydrofiiran TLC Thin Layer Chromatography TfOH Trifluoromethane sulfonic acid PCy3 Tricyclohexylphosphine TsNHBoc iV-(fer/-Butoxycarbonyl)-/?-toluenesulfonamide Ts / tosyl p -T oluenesulfonyl TsCl p-T oluenesulfonyl chloride Chapter 1 1 Chapter 1 Introduction to Acid-Catalysed Hydroamination “Hydroamination is a highly atom-economical process in which an amine N-Hfunctionality is added to an unsaturated carbon-carbon linkage."1 1.1. Hydroamination Development Nitrogen-containing saturated heterocyclic systems are important core structures in organic chemistry because of their presence in many natural products; making the development of simple procedures for the formation of heterocycles, such as pyrrolidines and piperidines, highly desirable. Other nitrogen containing compounds including amines, enamines and imines, are valuable and commercially important bulk chemicals, speciality chemicals and pharmaceuticals.4 Amongst various synthetic routes, hydroamination, the direct formation of a new carbon-nitrogen bond by addition of an amine to an unsaturated carbon-carbon bond, is of particular significance.5 The reaction offers a potentially atom-efficient pathway starting from readily accessible alkenes and alkynes. 6'7'w ° The hydroamination of alkenes is more difficult compared to that of alkynes because of the lower reactivity and electron density of carbon-carbon double bonds.11 A particular challenge is the reversal of stereochemistry to obtain the anti-Markovnikov product.12 During recent years, hydroamination became a widely explored operation in the synthesis of nitrogen heterocycles and complex nitrogenous molecules in general. The Markovnikov addition of protected amines to alkynes is also now an established synthetic strategy. In early studies, hydroaminations were mostly triggered by alkali and lanthanide metals, followed by a shift in focus to the use of zirconium, titanium5,13 and late transition metal catalysts.14 Most of these are employed as homogenous catalysts, though new strategies for the immobilisation of these have gained and will undoubtedly continue to gain increased importance.103 Acid-catalysed hydroaminations have been developed from related, well studied methods of carbon-oxygen bond formation using acid catalysts.