Synthesis of functionalized allylic, propargylic and allenylic compounds Selective formation of CB, CC, CCF3 and CSi bonds Tony Zhao © Tony Zhao, Stockholm 2015 Cover picture: Lukas Erritsø Hansen ISBN 978-91-7649-189-8 Printed in Sweden by E-print AB 2015 Distributor: Department of Organic Chemistry, Stockholm University ii iii iv Abstract This thesis is focused on the development of new palladium and copper- mediated reactions for functionalization of alkenes and propargylic alcohol derivatives. The synthetic utility of the 1,2-diborylated butadienes synthe- sized in one of these processes has also been demonstrated. We have developed an efficient procedure for the synthesis of allenyl boronates from propargylic carbonates and acetates. This was achieved by using a bimetallic system of palladium and copper or silver as co-catalyst. The reactions were performed under mild conditions for the synthesis of a variety of allenyl boronates. Furthermore, the synthesis of 1,2-diborylated butadienes was achieved with high diastereoselectivity from propargylic epoxides. The reactivity of the 1,2-diborylated butadienes with aldehydes was studied. It was found that the initial allylboration reaction proceeds via an allenylboronate intermediate. The allenylboronate reacts readily with an additional aldehyde to construct 2-ethynylbutane-1,4-diols with moderate to high diastereoselectivity. We have also studied the copper-mediated trifluoromethylation of propar- gylic halides and trifluoroacetates. It was also shown that a transfer of chiral- ity occurred when an enantioenriched starting material was used. In the last part of the thesis, we have described a method for palladium- catalyzed functionalization of allylic CH bonds for the selective synthesis of allylic silanes. The protocol only works under highly oxidative conditions which suggest a mechanism involving high oxidation state palladium inter- mediates. v vi List of Publications This thesis is based on the following papers, which will be referred to by Roman numerals IIV. Reprints were made with the kind permission from the publishers. I. Borylation of Propargylic Substrates by Bimetallic Catalysis. Syn- thesis of Allenyl, Propargylic and Butadiene Bpin Derivatives Tony S. N. Zhao, Yuzhu Yang, Timo Lessing, Kálmán, J. Szabó Journal of American Chemical Society, 2014, 136, 7563-7566 II. Stereoselective Synthesis of 1,4-Diols by a Tandem Allylboration- Allenylboration Sequence Tony S. N. Zhao, Jian Zhao, Kálmán, J. Szabó Organic Letters, 2015, 17, 2290-2293 III. Trifluoromethylation of Propargylic Halides and Trifluoroace- tates Using (Ph3P)3Cu(CF3) Reagent Tony S. N. Zhao, Kálmán, J. Szabó Organic Letters, 2012, 14, 3966–3969 IV. Palladium-Catalyzed Oxidative Allylic C−H Silylation Johanna, M. Larsson, Tony S. N. Zhao, Kálmán, J. Szabó Organic Letters, 2011, 13, 1888–1891 vii Contents Abstract ............................................................................................................. v List of Publications ........................................................................................ vii Contents ..........................................................................................................viii Abbreviations ................................................................................................... x 1. Introduction .................................................................................................. 1 1.1 Transition metal-catalyzed allylic substitution ........................................ 1 1.2 Transition metal-catalyzed propargylic substitution ............................... 2 1.3 Reactions of allyl and allenyl boronates with aldehydes......................... 3 1.4 Trifluoromethylation of organic compounds ........................................... 4 1.5 Objectives of the thesis .............................................................................. 4 2. Borylation of propargylic alcohol derivatives (Paper I) ........................... 5 2.1 Method development for synthesis of α,γ-substituted allenyl boronates ........................................................................................................... 7 2.2 Synthesis of α,γ-substituted and α-substituted allenyl boronates ......... 11 2.3 Method development for synthesis of γ-substituted allenyl boronates 13 2.4 Stereochemistry of the formation of allenyl boronate ........................... 16 2.5 Borylative opening of propargylic epoxides; synthesis of 1,2-diborylated butadienes............................................................................. 17 2.6 Proposed catalytic cycle .......................................................................... 21 2.6.1 Proposed catalytic cycle for the borylation of propargylic carbonates ....................................................................................................... 21 2.6.3 Proposed catalytic cycle for the borylation of propargylic epoxides 22 2.7 Summary and conclusions for borylation of alcohol derivatives.......... 24 3. Sequential addition of 1,2-diborylated butadienes to aldehydes (Paper II) ......................................................................................................... 25 3.1 Method development for the synthesis of 2-ethynylbutane-1,4-diols from (mono)aldehydes ................................................................................... 26 3.2 Synthesis of 2-ethynylbutane-1,4-diols from aldehydes ....................... 27 3.3 Synthesis of 1,4-dihydroxytetralin derivatives from dialdehydes and 1,2,-diborylated butadienes ........................................................................... 29 3.4 Determination of relative stereochemistry of the 1,4-diol products ..... 32 3.5 Mechanism of the sequential allylboration-allenylboration reaction ... 33 3.6 Summary and conclusion for addition of 1,2-diborylated butadienes to aldehydes ........................................................................................................ 35 viii 4. Cu-mediated trifluoromethylation of propargylic alcohol derivatives (Paper II) ......................................................................................................... 36 4.1 Initial experiments ................................................................................... 37 4.2 Synthesis of trifluoromethylated allenylic and propargylic compounds ......................................................................................................................... 38 4.3 Stereochemistry of the trifluoromethylation reaction ............................ 42 4.4 Investigation of a possible radical mechanism ...................................... 42 4.5 Study of the thermal rearrangement of 20b ........................................... 43 4.6 Proposed mechanism ............................................................................... 44 4.7 Recent publications for the synthesis of trifluoromethylated propargylic and allenylic compounds ............................................................................... 44 4.8 Summary and conclusions for trifluoromethylation of propargylic substrates......................................................................................................... 45 5. Palladium-catalyzed oxidative CH silylation (Paper III) ...................... 46 5.1 Background .............................................................................................. 46 5.1.1 Previous palladium-catalyzed methods for the synthesis of allylic silanes .............................................................................................................. 46 5.1.2 Previous allylic CH functionalization developed in the group ........ 47 5.2 Development of palladium-catalyzed CH silylation ........................... 48 5.3 Synthesis of allylic silanes – scope and limitations ............................... 48 5.4 Mechanistic investigation and proposed catalytic cycle for the silylation of alkenes ....................................................................................... 50 5.5 Conclusions and summary for CH functionalized silylation of alkenes ......................................................................................................................... 52 6. Concluding remarks and outlook .............................................................. 53 X. Acknowledgements ................................................................................... 54 Y. Vetenskaplig sammanfattning .................................................................. 56 Z. References .................................................................................................. 57 ix Abbreviations Abbreviations and acronyms are used in agreement with standards of the subject.† Only nonstandard and unconventional ones that appear in the thesis are listed here. BQ 1,4-benzoquinone bpy 2,2’-bipyridine CMD concerted metallation-deprotonation DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DPEPhos bis(2-diphenylphosphinophenyl)ether dppb 1,4-bis(diphenylphosphino)butane dr diastereomeric ratio HSQC heteronuclear single quantum correlation IPr 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene L.A. Lewis acid LG leaving group M.S. molecular sieves Nu nucleophile Piv pivaloyl pin pinacolato PTS polyoxyethanyl α-tocophery sebacate TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy Tf trifluoromethanesulfonyl TRIP 3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-bi-2-naphthol cyclic monophosphate