Hydrogenation, Transfer Hydrogenat- ion and Hydrogen Transfer Reactions Catalyzed by Iridium Complexes. Xu Quan ©Xu Quan, Stockholm University 2015 ISBN 978-91-7649-255-0 Printed in Sweden by Holmbergs, Malmö 2015 Distributor: Department of Organic Chemistry, Stockholm University To my parents and Ling Jin 谨以此论文献给我的父母和妻子 Abstract The work described in this thesis is focused on the development of new bi- dentate iridium complexes and their applications in the asymmetric reduction of olefins, ketones and imines. Three new types of iridium complexes were synthesized, which included pyridine derived chiral N,P-iridium complexes, achiral NHC complexes and chiral NHC-phosphine complexes. A study of their catalytic applications demonstrated a high efficiency of the N,P-iridium complexes for asymmetric hydrogenation of olefins, with good enantioselec- tivity. The carbene complexes were found to be very efficient hydrogen transfer mediators capable of abstracting hydrogen from alcohols and subse- quently transfer it to other unsaturated bonds. This hydrogen transferring property of the carbene complexes was used in the development of C–C and C–N bond formation reactions via the hydrogen borrowing process. The complexes displayed high catalytic reactivity using 0.5–1.0 mol% of the catalyst and mild reaction conditions. Finally chiral carbene complexes were found to be activated by hydrogen gas. Their corresponding iridium hydride species were able to reduce ketones and imines with high efficiency and enantioselectivity without any additives, base or acid. i List of Publications This thesis is based on the following publications, which are referred to in the text by their Roman numerals. I. Iridium Catalysts with Chiral Bicyclic Pyridine-Phosphane Ligands for the Asymmetric Hydrogenation of Olefins. Xu Quan, Vijay Singh Parihar, Milan Bera, and Pher G. Andersson. European Journal of Organic Chemistry, 2014, 140–146. II. Highly Enantioselective Iridium Catalyzed Hydrogenation of α, β Unsaturated Esters. Jia-Qi Li, Xu Quan, and Pher G. An- dersson. Chemistry-A European Journal, 2012, 10609–10616. III. Chiral Hetero- and Carbocyclic Compounds from the Asym- metric Hydrogenation of Cyclic Alkenes. J. Johan Verendel, Jia- Qi Li, Xu Quan, Byron Peters, Taigang Zhou, Odd R. Gautun, Thavendran Govender, and Pher G. Andersson. Chemistry-A Euro- pean Journal, 2012, 6507–6513. IV. C-C Coupling of Ketones with Methanol Catalyzed by a N- Heterocyclic Carbene-Phosphine Iridium Complex. Xu Quan, Sutthichat Kerdphon, and Pher G. Andersson. Chemistry-A Euro- pean Journal, 2015, 3576–3579. V. C-N Coupling of Amides with Alcohols Catalyzed by N- Heterocyclic Carbene-Phosphine Iridium Complexes. Sut- thichat Kerdphon, Xu Quan, Vijay Singh Parihar, and Pher G. An- dersson. Journal of Organic Chemistry (Submitted) VI. Highly Active Cationic NHC, Phosphine Iridium Catalysts for Base Free Asymmetric Hydrogenation of Ketones. Xu Quan, Sutthichat Kerdphon, Janjira Rujirawanich, Suppachai Krajangsri, and Pher G. Andersson. (Manuscript) Manuscript not included in this thesis: VII. The Thiazole, Imidazole and Oxazole Based N, P-Ligands for the Palladium Catalyzed Cycloisomerization of 1,6-Enynes. Xu Quan, Jianguo Liu, Wangchuk Rabten, Simone Diomedi, and Pher G. Andersson. (Manuscript) ii Abbreviations * Stereogenic center Ac Acetyl Ar Aryl - BArF Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate BINAL-H 1,1’-Bi-2-naphtolaluminum hydride Bu Butyl BuLi Butyl lithium t-Bu tert-Butyl Cat. Catalyst COD 1,5-Cyclooctadiene Conv. Conversion Cp* Pentamethylcyclopentadienyl Cy Cyclohexyl DCM Dichloromethane DIBAL Di-iso-butylaluminum hydride DMF Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1’-Bis(diphenylphosphino)ferrocene dppp 1,3-Bis(diphenylphosphino)propane ee Enantiomeric excess equiv. Equivalent Et Ethyl i-Pr iso-Propyl LDA Lithium di-iso-propylamine L Ligand m Meta Me Methyl Mes Mesityl NHC N-heterocyclic carbene o Ortho S Solvent Tol Tolyl p Para iii Ph Phenyl PHOX Phosphinooxazolines Py Pyridine r.t. Room temperature THF Tetrahydrofuran iv Contents 1. Introduction ............................................................................................. 1 1.1 Catalysis1 .............................................................................................................. 1 1.2 Chirality ................................................................................................................. 2 1.3 Asymmetric Hydrogenation .................................................................................. 4 1.4 Hydrogen Transfer Alkylation ............................................................................... 7 1.5 Aim of this Thesis ................................................................................................. 9 2. Development of Pyridine Based N, P-Iridium Catalysts for the Asymmetric Hydrogenation of Olefins (Paper I) ........................................... 10 2.1 Synthesis of Novel Pyridine Derived Ligands and their Iridium Complexes ....... 12 2.2 Evaluation of the Iridium Catalysts in Asymmetric Hydrogenation ..................... 14 2.3 Conclusion .......................................................................................................... 17 3. Asymmetric Hydrogenation of α-Substituted Conjugated Esters (Paper II) .............................................................................................................. 18 3.1 Catalyst Screening ............................................................................................. 20 3.2 Study of the Substrate Scope ............................................................................. 21 3.3 Conclusion .......................................................................................................... 25 4. Synthesis of Chiral Heterocyclic Compounds by Iridium Catalyzed Hydrogenation (Paper III) ............................................................................. 26 4.1 Asymmetric Hydrogenation of Conjugated Lactones and Ketones .................... 26 4.2 Asymmetric Hydrogenation of 2-Substituted Quinolines .................................... 27 4.3 Conclusion .......................................................................................................... 28 5. Iridium Catalyzed Alkylation of Ketones and Amides with Alcohols, via Hydrogen Transfer Reactions (Paper IV and V) .......................................... 29 5.1 Methylation of Ketones with Methanol (Paper IV) .............................................. 30 5.1.1 Catalyst screening and optimization .......................................................... 30 5.1.2 Study of substrate scope ............................................................................ 32 5.1.3 Mechanistic study ....................................................................................... 35 5.2 N-Alkylation of Amides with Alcohols (Paper V) ................................................. 37 5.2.1 Study of reaction conditions ....................................................................... 37 5.2.2 Study of substrate scope ............................................................................ 39 5.3 Conclusion .......................................................................................................... 43 6. Chiral Bidentate NHC, Phosphine-Iridium Complexes and their Catalytic Activities in Hydrogenation Reactions (Paper VI) ........................................ 44 6.1 A Class of Novel Bidentate Chiral NHC, Phosphine-Iridium Complexes. ........... 45 6.2 Evaluation of Chiral NHC-P Iridium Complexes ................................................. 47 6.2.1 Hydrogenation of alkenes .......................................................................... 47 6.2.2. Hydrogenation of ketones and imines ....................................................... 48 6.3 Conclusion .......................................................................................................... 58 7. Concluding Remarks and Outlook ........................................................ 59 Contribution List ........................................................................................... 60 Acknowledgments ........................................................................................ 62 Summary in Swedish ................................................................................... 64 References ................................................................................................... 65 1. Introduction 1.1 Catalysis1 Catalysis is the process that facilitates a chemical reaction, and was first introduced by Jöns Jacob Berzelius in 1835.2 A catalyst is an additive that triggers and participates in the reaction to make the reaction go faster by decreasing the activation energy, without itself being consumed. It does not change the equilibrium of reaction system, but accelerates the reaction by stabilizing the transition state. As it is not included in the product, only sub- stoichiometric amounts of catalyst can be enough to accelerate a reaction, thus generating less waste. In addition, the catalyst can often be used to con- trol the chemo-, regio-, stereo- and enantioselectivity of a reaction. Generally, catalysis is classified as being either homogeneous or heteroge- neous. In homogeneous catalysis, the catalyst and reactants are in the same phase; whereas for heterogeneous catalysis, the catalyst is in a different phase from the reactant. Homogeneous catalysis often provides good reactiv- ity