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Organic Chemistry IV Organic Chemistry IV Organometallic Chemistry for Organic Synthesis Prof. Paul Knochel LMU 2014 1 OCIV Prüfung: Freitag 11. Juli 2014 9-11 Uhr Baeyer HS Wiederholungsklausur: Donnerstag 11. September 2014 12-14 Uhr Baeyer HS 2 Recommended Literature 1. F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry, Fifth Edition Part A and Part B, Springer, 2008, ISBN-13: 978-0-387-68346-1 2. R. Brückner, Organic Mechanisms, Springer, 2010, ISBN: 978-3-642- 03650-7 3. L. Kürti, B. Czako, Strategic applications of named reactions in organic synthesis, Elsevier, 2005, ISBN-13: 978-0-12-429785-2 4. N. Krause, Metallorganische Chemie, Spektrum der Wissenschaft, 1996, ISBN: 3-86025-146-5 5. R. H. Crabtree, The organometallic chemistry of transition metals, Wiley- Interscience, 2005, ISBN: 0-471-66256-9 6. M. Schlosser, Organometallics in Synthesis – A manual, 2nd edition, Wiley, 2002, ISBN: 0-471-98416-7 7. K. C. Nicolaou, T. Montagnon, Molecules that changed the world, Wiley- VCH, 2008, ISBN: 978-527-30983-2 8. J. Hartwig, Organotransition Metal Chemistry: From Bonding to Catalysis, Palgrave Macmillan, 2009, ISBN-13: 978-1891389535 9. P. Knochel, Handbook of Functionalized Organometallics, Volume 1 und 2, Wiley-VCH, 2005, ISBN-13: 978-3-527-31131-6 3 Importance of organometallics 4 Industrial production Industrial annual production of various organometallics Organometallic production [T / year] Si 700 000 Pb 600 000 Al 50 000 Sn 35 000 Li 900 5 Organometallic reagents and catalysts for the organic synthesis organometallic reagents: CO2Me ZnCl CH2 AlMe2 BuLi Cp2Ti HClZrCp2 Cl MgBr O Me Tebbe reagent Schwarz reagent organometallic catalysts: Mes N N Mes Pd(PPh3)4 CpCo(CO)2 RhCl(CO)2 ClRh(PPh3)3 2 Cl Ru Wilkinson's catalyst Cl Ph PCy3 Grubbs II catalyst Cp 6 Historic point of view 1757 - Louis Cadet de Gassicourt (parisian apothecary) E. Frankland (1848), University of Marburg, initial goal: synthesis of an ethyl radical Universität Marburg (1848) 2/3Tl 2 Na 2/3Et Tl Et2Zn 2Et Na 3 -Zn(0) -Zn(0) 7 Organometallic chemistry of the XIX century Frankland 1848, 1863 O OH Et O Et O Et Et-I + Zn Et Zn Et + O Et Et O O Beilstein 1862, Saytzeff 1870, Wagner 1875 O OH Et O Et O Et Et-I + Zn + O Et Et O O Barbier 1899 O OH ++Me-I Mg Me O Et Et Ph. Barbier Comptes Rendus de l'Académie des Sciences, 1899, 128, 110 8 Organometallic chemistry of the XIX century H Mg H I I Et H H Mg O H H Et O O Et Et Et Et Mg Ph-CHO OH Br MgBr ether Ph reactif de Grignard V. Grignard Comptes Rendus de l'Académie des Sciences, 1900, 130,1322 9 Reactivity of the Grignard reagents 10 Historic point of view Victor Grignard (1900) Karl Ziegler (1919) 11 Historic point of view first transition metal organometallics: Hein (1919) 12 Historic point of view 1951 : synthesis of ferrocene Pauson (Scotland) 7. August 1951 Miller 11. June 1951 H H FeCl + 2 300 °C MgBr (C5H5)2Fe + Fe Smp.: 172 °C G. Wilkinson 1952 structural proposal by Pauson correct structure by G. Wilkinson and R. B. Woodward G. Wilkinson, R. B. Woodward J. Am. Chem. Soc. 1952, 74, 2125 Fe R.B. Woodward J. Am. Chem. Soc. 1952, 74, 3458 ferrocene FeCl3 MgBr+ R. B. Woodward 13 H. Sitzmann J. Am. Chem. Soc. 1993, 115, 12003 radical formation Goal of the lecture main goal of this course: applications of organometallic compounds in modern organic synthesis Y.-H. Chen, Angew. Chem. Int. Ed. 2008, 47, 7648. 14 General synthetic methods for preparing organometallic reagents classification according to starting materials direct synthesis via an oxidative addition and halogen-metal exchange 15 Classification according to starting materials transmetalation 16 Classification according to starting materials metalation 17 Classification according to starting materials carbometalation and hydrometalation 18 Synthesis starting from organic halides direct synthesis - oxidative addition driving force of the reaction: 19 Direct Synthesis - Oxidative Addition examples: O O Mg BuBr BuMgBr Bu2Mg + Br2Mg1 O O ether H 2CrCl + CrCl Br + 2 Me CrCl2 3 pure E-isomer E/Z-mixture 20 Direct Synthesis - Oxidative Addition mechanism: P. Knochel Tetrahedron Lett. 1986, 27, 5091 21 Activation of the metal: the Rieke-approach activation of the metal: R. D. Rieke, Science 1989, 246, 1260 Mg + PhOH PhO Br 20 °C, 5 min PhO MgBr Mg* CO2 PhO MgBr PhO CO2H -78°C, 1h 70% Activation of lithium: formation of soluble Li-sources: 22 P.P. Freeman, L.L. Hutchinson J. Org. Chem. 1983, 48, 4705 Mechanism of the metal insertion Br Li Li Li-DBB (2 equiv.) + 80: 20 loss stereochemical information H.M. Walborsky: J. Am. Chem. Soc. 1989, 11, 1896 radical mechanism 23 Preparation of functionalized organometallics O O Zn, THF 25 °C, 6h O O I ZnI O O P. Knochel, J. Org. Chem. 1988, 53, 2390 P. Knochel, Org. React. 2001, 58, 417. A. Krasovskiy, V. Malakhov, A. Gavryushin, P. Knochel, Angew. Chem. Int. Ed. 2006, 45, 6040. 24 Preparation of functionalized organometallics Br MgBr SMe Mg, LiCl MeSO2SMe THF, -10 °C, 20 min OBoc OBoc OBoc 91% 92% 2 2 2 2 2 F. Piller, P. Knochel Chem. Eur. J. 2009, 15, 7192 25 Preparation of functionalized organometallics activation of Al using LiCl and TiCl4, BiCl3, PbCl2 or InCl3 T. Blümke, Y.-H. Chen, P. Knochel Nature Chemistry, 2010, 2, 313 A. Metzger, P. Knochel Org. Lett. 2008, 10, 1107 26 Extension to insertion reactions to C-S bonds S. Rychnosvsky J. Org. Chem. 1989, 54, 4982; J. Org. Chem. 1990, 95, 5550 27 The Halogen-Metal-Exchange driving force: the most stable carbanion is always formed R HC C CH3 CH2R HC R CR3 2 Csp C 3 sp Csp 28 The Halogen-Metal-Exchange 1939: the Wittig-Gilman reaction Br THF Li + BuLi + BuBr -78 °C tBuLi Bu Bu Br 2equiv. Li + + tBuH tBuLi Bu + H LiBr Li + Br + H Li tBuLi MeOH I + 2MeOH Li H 2 equiv. 29 93% The Halogen-Metal-Exchange mechanism: R1 I R2 R1 I + R2 Li R1 Li + R2 I Li H. J. Reich, A. W. Sanders, A. T. Fiedler, M. J. Bevan J. Am. Chem. Soc. 2002, 124, 13386 30 The Halogen-Metal-Exchange : tolerance of functional groups 31 The iodine- magnesium-exchange: compatibility with a nitro group 32 A secondary iodine/lithium exchange on cyclohexyl iodides 33 A secondary iodine/lithium exchange on cyclohexyl iodides 34 A secondary iodine/lithium exchange on cyclohexyl iodides 35 Acyclic systems: stereospecific I/Li exchange reaction Acyclic systems: stereospecific I/Li exchange and reactions with C-electrophiles O tBuLi OMe ANTI R N 2.2 equiv; 0.2 M Me OTBS OTBS OTBS O (2.5 equiv) I added slowly in 10 min Li R -100 oC, Me Me 74% Me 3:2 hexane/Et2O (dr = 98:2) >dr= 96:4 O OMe tBuLi R N SYN 2.2 equiv; 0.2 M Me OTBS OTBS O OTBS (2.5 equiv) added slowly in 10 min Li I R -100 oC, Me 75% Me >dr=6:94 Me 3:2 hexane/Et2O (dr = 3:97) OTBS OTBS OTBS OTBS OTBS OTBS O H O H O Ph O Ph O CF3 O CF3 80 % yield 70 % yield 66 % yield 68 % yield 67 % yield 65 % yield dr = 92:8 dr =9:91 dr =97:3 dr =6:94 dr =96:4 dr =5:95 G. Dagousset, K. Moriya, R. Mose, G. Berionni, K. Karaghiosoff, P. Knochel in press, 2013 Stereoconvergent synthesis of Li-reagents 1. tBuLi, -50°C, 15 min 1. tBuLi, -50°C, 15 min hexane / Et2O=4:1 hexane / Et2O=4:1 TBSO I TBSO I 2. Me2S2 TBSO SMe 2. Me2S2 Stereoretention dr =97:3 dr =96:4 Stereoinversion dr =97:3 anti syn 58-60 % 1. tBuLi, -50°C, 15 min TBSO I TBSO E TBSO Li TBSO Li hexane / ether = 4 : 1 dr =50:50 2. E+ SiPh3 O O TBSO O TBSO B SBu TBSO CHO TBSO TBSO CO2Et TBSO + + + + + + E = Cl-CO Et E = E = Pin-OMe E =Bu2S2 E =DMF E =DMF 2 SiPh3 60 % 74 % 67 % 67 % 63 % 73 % dr =94:6 dr =92:8 dr =96:4 dr =96:4 dr =99:1 dr =97:3 D. Didier, K. Moriya, 2014 The iodine/zinc-exchange catalysis of the halogen-metal exchange F. Kneisel, P. Knochel Angew. Chem. Int. Ed. 2004, 43, 1017 39 The Halogen-Metal-Exchange indole-synthesis NMe2 1) iPrMgBr THF, -20 °C, N 5min EtO2C I I OMe 2) Br N Me H I . CO2Et CuCN 2LiCl 90% -20 °C, 30 min 3) H+ D. M. Lindsay, W. Dohle, A. E. Jensen, F. Kopp, P. Knochel Org. Lett., 2002, 4 , 1819 CN CN iPrMgCl LiCl PhCHO NC OH -7 °C, 3 h 0°C Br MgCl Ph 81% Cl Li iPrMgCl LiCl i-Pr Mg Cl A. Krasovskiy, P. Knochel Angew. Chem. Int. Ed. 2004, 43, 3333 40 Transmetalation a) the most stable carbanion is linked to the most electropositive metal 41 Transmetalation W. C. Still, J. Am. Chem. Soc. 1980, 102, 1201 42 Transmetalation b) 43 Transmetalation E. Nakamura, I. Kuwajima J. Am. Chem. Soc. 1984, 106, 3368 44 Transmetalation T. Imamoto, Y. Sugiyura, N. Takiyama, Tetrahedron Lett. 1984, 25, 4233 OH O HO MgCl MgCl LaCl3 2LiCl 0°C,0.5h 93% A. Krasovskiy, F. Kopp, P. Knochel Angew. Chem. Int. Ed. 2006, 45, 497 45 Transmetalation M. Reetz, D. Seebach Angew. Chem. 1983, 95, 12 A. Maercker, M. Theis, A. Kos, P. Schleyer, Angew.
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