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Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1962 Olefins from carbonyls Development of new phosphorus-based cross- coupling reactions NICOLAS DANIELE D'IMPERIO ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6214 ISBN 978-91-513-1001-5 UPPSALA urn:nbn:se:uu:diva-419124 2020 Dissertation presented at Uppsala University to be publicly examined in Siegbahnsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, Friday, 30 October 2020 at 10:15 for the degree of Doctor of Philosophy. The examination will be conducted in English. Faculty examiner: Professor Carlos Romero-Nieto (University of Heidelberg, Organisch-Chemisches Institut). Abstract D'Imperio, N. D. 2020. Olefins from carbonyls. Development of new phosphorus-based cross- coupling reactions. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1962. 110 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-1001-5. Olefins, compounds containing C=C double bonds, are omnipresent in nature and serve as useful starting materials for various chemical modifications. Olefins are of crucial importance in Medicinal Chemistry and are also present in essential objects like dyes, polymers and plastics. Thus, developing methodologies for synthesizing olefins is at the heart of Organic Chemistry. In this regard, many reactions have been developed over the years for the production of olefins from different starting materials. To date only one reaction, namely the McMurry coupling, is available for constructing olefins from two carbonyls. This reaction is frequently applied in an academic context, but suffers many drawbacks that limit its wider use. This thesis offers innovative phosphorus-based methodologies for coupling two carbonyls into olefins. All the methods presented herein are based on a one-pot sequence in which a first carbonyl is transformed into a phosphaalkene (P=C double bond containing molecule) which, upon activation, reacts with a second carbonyl with formation of desired alkenes. The first two chapters of this thesis give a general overview on literature protocols for the formation of olefins, along with a comparison between P=C and C=C double bonds containing molecules. The third chapter is dedicated to the presentation of a new potential phosphorus-based coupling reagent. The studies presented in this chapter set the basis for the development of a new cross-coupling reaction of aldehydes to olefins. In the fourth chapter a new method for the one-pot synthesis of disubstituted alkenes from aldehydes is presented. The reactivity of phosphaalkene intermediates proved to be crucial in determining the reaction scope of the process. In the fifth chapter, a closer look into the E-Z stereoselectivity of the protocol is described. The following two chapters deal with more reactive phosphaalkenes. Studies on their chemical properties showed to be fundamental for developing an unprecedent cross-coupling of ketones and aldehydes to trisubstituted alkenes. In summary, this thesis represents the development of new phosphorus-based cross-couplings of carbonyls to olefins. Protocols for the stereoselective synthesis of disubstituted alkenes from two aldehydes, and trisubstituted olefins from ketones and aldehydes are presented. These innovative methodologies offer precious alternatives to the McMurry coupling. Keywords: olefins, carbonyl olefination, phosphaalkenes, stereoselective synthesis, Wittig, Horner-Wadsworth-Emmons, McMurry Nicolas Daniele D'Imperio, Department of Chemistry - Ångström, Synthetic Molecular Chemistry, 523, Uppsala University, SE-751 20 Uppsala, Sweden. © Nicolas Daniele D'Imperio 2020 ISSN 1651-6214 ISBN 978-91-513-1001-5 urn:nbn:se:uu:diva-419124 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-419124) To my unique family “The person who follows the crowd will usually go no further than the crowd. The person who walks alone is likely to find himself in places no one has ever seen before.” Albert Einstein List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I D’Imperio, N., Arkhypchuk, A., (2019) Reactivity patterns of benzhydryl(mesityl)phosphane oxide – a potential intermediate in carbonyl-carbonyl coupling reactions? Phosphorus, Sulfur Sil- icon Relat. Elem., 194: 575-579. DOI: 10.1080/10426507.2018.1543305. II D’Imperio, N., Arkhypchuk, A., Ott, S. (2018) One-pot intermo- lecular reductive cross-coupling of deactivated aldehydes to un- symmetrically 1,2-disubstituted alkenes. Org. Lett., 20: 5086- 5089. DOI: 10.1021/acs.orglett.8b01754. III D’Imperio, N., Arkhypchuk, A., Ott, S. (2020) E,Z-Selectivity in the reductive cross-coupling of two benzaldehydes to stilbenes under substrate control. Org. Biomol. Chem., 18: 6171-6179. DOI: 10.1039/d0ob01139h. IV D’Imperio, N., Arkhypchuk, A., Mai, J., Ott, S. (2019) Triphen- yphosphaalkenes in chemical equilibria. Eur. J. Inorg. Chem., 1562-1566. DOI: 10.1002/ejic.201801322. V Arkhypchuk, A., D’Imperio, N., Ott, S., (2019) Triarylalkenes from the site-selective reductive cross-coupling of benzophe- nones and aldehydes. Chem. Commun., 55: 6030-6033. DOI: 10.1039/c9cc02972a. Reprints were made with permission from the respective publishers. Contribution report Paper I Performed half of the synthetic work and characterizations of the synthesized products. Contributed to the discussion of the project and to the writing of the manuscript and the supporting information. Paper II Performed most of the synthetic work and the characterizations. Contributed to the design of the project. Wrote the manuscript and the sup- porting information with feedback from S. Ott. Paper III Performed most of the synthetic work and the characterizations. Wrote the manuscript and the supporting information with feedback from S. Ott. Paper IV Performed a major part of the work. Major contribution to the in- terpretation of the results. Contributed to the design of the project. Wrote the manuscript and the supporting information with feedback from S. Ott. Paper V Contributed to the design and discussion of the project and, partially, in the writing of the manuscript. Contents 1. Introduction .............................................................................................. 11 2. Background .............................................................................................. 13 2.1 Formation of C=C bonds .................................................................... 13 2.1.1 Carbonyl olefinations ................................................................ 14 2.1.2 Wittig and related phosphorus olefination reactions ................ 15 2.1.3 Phosphorus free olefination reactions ...................................... 22 2.2 Phosphorus as the Carbon copy ......................................................... 26 2.2.1 Comparison of P=C and C=C double bonds ............................ 26 2.2.2 Stabilization of phosphaalkenes ............................................... 27 2.2.3 Synthetic pathways towards phosphaalkenes ........................... 29 2.2.4 Reactivity and applications of phosphaalkenes ........................ 31 3. Reactivity patterns of a potential new olefinating reagent (Paper I) ...... 34 3.1 Alkenes from two carbonyl compounds – the McMurry reaction .... 34 3.2 Novel methodology for aldehyde-aldehyde couplings via phosphaalkene intermediates ....................................................................... 35 3.3 Reducing the size of the phosphorus protecting group ...................... 37 3.4 A new potential coupling reagent - preparation and reactivity ......... 38 3.4.1 Planning a new broader cross-coupling reaction ..................... 38 3.4.2 Synthesis of benzhydryl(mesityl)phosphine oxide .................. 39 3.4.3 Reactivity study of benzhydryl(mesityl)phosphine oxide ....... 40 3.4.4 Conclusions and outlook ........................................................... 42 4. Development of a new reductive cross-coupling of deactivated aldehydes (Paper II) .......................................................................................... 43 4.1 Modification of the previous method ................................................. 43 4.2 The phospha-Peterson reaction .......................................................... 45 4.3 Phosphaalkenes as electrophiles ......................................................... 48 4.4 HWE-type olefinating reagents .......................................................... 49 4.5 Optimization of the phospha-Peterson reaction ................................. 50 4.6 Bridging low- and high-valent phosphorus chemistry ...................... 53 4.7 Study of the olefination step ............................................................... 55 4.8 Development of the new one-pot procedure ...................................... 58 4.9 Substrate scope of the new method .................................................... 60 4.10 Advantages and limitations ........................................................... 63 4.11 Conclusions .................................................................................... 65 5. E-Z selectivity of the new cross-coupling procedure (Paper III) ........... 66 5.1 Introduction ......................................................................................... 66 5.2 Synthesis of E- and Z- alkenes; results and discussion ...................... 67 5.3 Conclusions ........................................................................................
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