NEW NICKEL COMPLEXES FOR TRIFLUOROMETHYLATION STUDIES A THESIS SUBMITTED TO THE GRADUATE DIVISION OF THE UNIVERSITY OF HAWAIʻI AT MĀNOA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN CHEMISTRY DECEMBER 2012 BY Hiromi Ichioka Thesis Committee: David Vicic, Chairperson Marcus A. Tius Philip Williams i NEW NICKEL COMPLEXES FOR TRIFLUOROMETHYLATION STUDIES A THESIS SUBMITTED TO THE GRADUATE DIVISION OF THE UNIVERSITY OF HAWAIʻI AT MĀNOA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN CHEMISTRY DECEMBER 2012 BY Hiromi Ichioka Thesis Committee: David Vicic, Chairperson Marcus A. Tius Philip Williams ii Acknowledgements I would like to thank the members of my thesis committee for spending their time to modify my thesis. I would like to appreciate Professor Vicic for overall advice. I would like to thank help and support from many individuals in the Chemistry Department, from faculty and staff. I would like to thank University of Hawaii for financial support in the form of teaching assistant. I would like to thank Professor Yamaguchi working together to synthesize bis-perfluoroalkyl nickel complexes. I would also like to appreciate Professor Shimada to experimentally help me and make good advice. iii Abstract We decided to prepare bis-perfluoroalkyl nickel complexes bearing a bipyridine ligand for investigation of the fundamental nickel perfluoroalkyl chemistry and reductive elimination of perfluoroethylene. Moreover, we envisioned a new precursor for investigation of Ar-CF3 reductive elimination. We have successfully demonstrated the syntheses of [(dtbpy)Ni(CF3)2] and [(dtbpy)Ni(CF2CF3)2] in moderate yields. The key intermediate nickel complex, [(tmeda)Ni(CF3)Br] allowed for the preparation of new complexes in good yields. iv Table of Contents Acknowledgement…………………………………………………………....……........... ii Abstract…………………………………………………………………………...……… iii List of Tables…………………………………………………………………………….. vii List of Figures……………………………………………………………………………. viii List of Schemes……………………………………………………………………........... ix List of Abbreviations…………………………………………………………………….. x New Nickel Complexes for Trifluoromethylation Studies 1.1. Introduction………………………………………………………………………….. 2 1.1.1. Fluorinated Organic Compounds………………………………….………….. 2 1.1.2. Trifluoromethyl Nucleophlic Attack…………………………………………. 4 1.1.3. Introduction of the Trifluoromethyl Group by Transmetalation…..………….. 6 1.1.4. Aryl Trifluoromethylations by Copper…………………..…………………… 8 1.1.5. Studies for Trifluoromethyl Palladium Complexes….....…………………….. 12 1.1.6. Studies for Trifluoromethyl Nickel Complexes………………………………. 16 1.1.7. Objectives …………………………………………………………………….. 18 1.2. Results and Discussion………………………………………………………………. 19 1.2.1. Preparation and Reactivity of a Nickel Bis-Alkoxide Complex……………… 19 1.2.2. Synthesis of a Bis-Trifluoromethyl Nickel Complex..…………………........... 24 1.2.3. Synthesis of a Bis-Methyl Nickel Complex………….…………………….…. 27 1.2.4. Synthesis of a Bis-Perfluoroethyl Nickel Complex…..………………………. 29 1.2.5. Visible Spectrum of New Nickel Complexes.…………………………........... 33 v 1.2.6. Studies for Reductive Elimination of a Bis-Trifluoromethyl Nickel Complex 35 1.2.7. Synthesis of the Key Intermediate for Aryl Trifluoromethyl Nickel Complexes to Explore the Possibility of Ar-CF3 Reductive Elimination, as Opposed to CF3-CF3 Reductive Elimination……………….. 37 1.2.8. Studies for Aryl Trifluoromethyl Nickel Complexes………………………… 43 1.3. Conclusion……………………………………………………………………........... 45 1.4. Experimental Section…………….………………………………………………….. 44 1.5. References…………………………………………………………………………… 55 vi List of Tables Table Page 1.1 Attempts of reductive elimination of 3 35 1.2 Failed attempts to prepare a phenyl trifluoromethyl nickel complex with an exchangeable ligand 38 1.3 Failed attempts to prepare an aryl trifluoromethyl nickel complex 41 1.4 Crystal data and structure refinement parameters for 9 48 1.5 Crystal data and structure refinement parameters for 3 50 1.6 Crystal data and structure refinement parameters for 13 53 vii List of Figures Figure Page 1.1 Fluorinated organic compounds 3 1.2 Ruppert’s reagent activated by anion 4 1.3 Nucleophilic attack of a trifluoromethyl on a ketone carbonyl 5 1.4 Proposed catalytic cycle for aryl trifluoromethylations 9 1.5 Generalized catalytic cycle for aryl trifluoromethylations 14 1.6 X-ray structure of 9 22 1.7 X-ray structure of 3 26 1.8 X-ray structure of 14 30 1.9 X-ray structure of 13 32 1.10 Experimental UV-vis spectra in THF 33 viii List of Schemes Scheme Page 1.1 Reaction of Ruppert’s reagent with an ester 5 1.2 Synthesis of trifluoromethyl titanium complex 6 1.3 Aryl trifluoromethylations by copper 8 1.4 Copper catalyzed aryl trifluoromethylations 8 1.5 Another example of copper catalyzed aryl trifluoromethylations 9 1.6 Well-defined trifluoromethyl copper complexes 10 1.7 Reaction of trifluoromethyl copper complexes and phenyl iodide 11 1.8 Attempts of reductive elimination of [(dppbz)Pd(o-tol)CF3] 12 1.9 Reductive elimination of [(Xantphos)Pd(Ph)CF3] 13 1.10 Reductive elimination of [(Brettphos)Pd(Ar)CF3] 14 1.11 Palladium catalyzed trifluoromethylations 15 1.12 Decomposition of [(dippe)Ni(Ar)(CF3)] 16 1.13 Reductive elimination of an aryl methyl nickel complex 17 1.14 The key step for nickel catalyzed cross coupling reactions 18 1.15 Initial synthesis of 3 19 1.16 Synthesis of aminoalcohol 6 20 1.17 Synthesis of 8 20 1.18 Synthesis of 9 21 1.19 Reactivity of 8 23 1.20 Synthesis of 3 24 ix 1.21 Synthesis of 12 27 1.22 Reductive elimination of 12 27 1.23 Failed synthesis of 13 29 1.24 Synthesis of 13 31 1.25 Synthesis of [(tmeda)Ni(Ph)X] 37 1.26 Stability of Mes nickel complexes toward dimerisation 40 1.27 Synthesis of 19 40 1.28 Synthetic pathway for an aryl trifluoromethyl nickel complex 41 1.29 Synthetic pathway for a variety of trifluoromethyl nickel complexes 42 1.30 Synthesis of 22 42 1.31 Preparation of [(tmeda)Ni(CF3)Ph] 43 1.32 Preparation of [(tmeda)Ni(CF3)Me] 44 x List of Abbreviations Ac acetyl acac acetylacetone Alk alkyl Ar aryl Brettphos 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl Bz benzyl bpy 2,2'-dipyridyl oC degrees Celsius 13C carbon-13 isotope cm-1 wave number COD 1,5-cyclooctadiene Cp cyclopentadienyl d doublet d day(s) dba dibenzylideneacetone DCM dichloromethane dippe 1,2-bis(diisopropylphosphino)ethane DMF N,N –dimethyl formamide DME dimethoxymethane DMI 1,3-dimethyl-2-imidazolidinone xi dppbz 1,4-bis(diphenylphosphino)butane dtbpy 4,4'-di-tert-butyl bipyridine eq equation eq. equivalent(s) 19F fluorine-19 isotope g gram(s) 1H proton isotope Hz hertz(s) J coupling constant (in Hz) λ lambda m mili- M molarity Me methyl MHz megahertz min minute(s) NFTP N-fluoro-2,4,6-trimethylpyridinium triflate NHC N-heterocyclic NMR nuclear magnetic resonance O Ortho Ph phenyl Phen phenanthroline rt room temperature s singlet xii TBAF tetra-n-butylammonium fluoride t-Bu tertiary butyl TCNE tetracyanoethylene TES tetraethylsilane Tf triflyl THF tetrahydrofuran TLC thin layer chromatography tmeda tetramethylethylenediamine TMS tetramethylsilane tol tolyl Ts tosyl UV ultraviolet Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene 1 New Nickel Complexes for Trifluoromethylation Studies 2 1.1. Introduction 1.1.1. Fluorinated Organic Compounds The number of naturally occurring fluorinated organic compounds is very few whereas inorganic fluorides are plentiful on earth. Therefore all fluorinated compounds are exclusively synthesized by organic or organometallic methodology. Today, fluorinated organic compounds have an essential role in pharmaceutical, veterinary, agrochemical, and material sciences. For example, fluorine and trifluoromethyl compounds can be found in commercially available pharmaceuticals such as Prozac, Celebrex, and Arava as shown in Figure 1.1.1-2 The introduction of a fluorine atom or trifluoromethyl group into an organic compound can alter the physical properties of organic molecules, and can also affect their conformational behavior, biological activity, and metabolic stability.3-5 Fluorine is the most electronegative element, and its small size makes it an interesting surrogate for a hydrogen atom.6 The trifluoromethyl or fluorine functional groups in biologically active compounds can modify the biological activities through improved lipophilicity and superior metabolic stability. Thus, the introduction of fluorine and trifluoromethyl groups in candidates for clinical drug development has become an important tool in drug development. Metal-mediated trifluoromethylations have been slowly developing, as discussed in section 1.4-6, whereas today the tremendous expansion of fluorinated compounds introduced by a wide scope of applications has been established by the field of organic chemistry.8 Only a few trifluoromethyl nickel complexes have been examined in trifluoromethylations (section 1.6). So nickel is one of the promising candidates to achieve nickel-catalyzed trifluoromethylations (section 1.7) 3 4 1.1.2. Trifluoromethyl Nucleophilic Attack The extensive study of fluorine chemistry has focused on developing new protocols to introduce trifluoromethyl groups into specific sites on target molecules. One of the most widely employed trifluoromethylation reagents is TMSCF3, or Ruppert's reagent as shown in Figure 1.2 which generates a trifluoromethyl anion equivalent by exposure to a fluoride anion.8-9 Low temperature NMR studies ( X = F ) and X-ray diffraction (X = CF3) support the formation of a five coordinated structure