A! Aalto university School of Chemical Technology KE-4.4120 Synthetic Organic Chemistry 13. Reduction Prof Ari Koskinen C318 © Ari Koskinen Catalytic hydrogenation A! Aalto university School of Chemical Technology Finely divided metals, such as Ni, Pd, Pt, Rh (usually adsorbed on a solid support) can be used for chemoselective reductions. The ”mechanisms” for these reductions are obscure and difficult to discern because most of these reactions are heterogenous. © Ari Koskinen Double bond reductions © Ari Koskinen A! Aalto university School of Chemical Technology Catalytic Reductions © Ari Koskinen A! Aalto university School of Chemical Technology Catalytic hydrogenations of double bonds © Ari Koskinen A! Aalto university School of Chemical Technology Selective reductions A! Aalto university School of Chemical Technology Alkynes can be selectively hydrogenated to Z alkenes by using a poisoned Pd catalyst: A similar catalyst can also be used for hydrogenolysis of acid chlorides to aldehydes (Rosenmund): The name Lindlar reduction is often used for partial reductions of alkynes to alkenes. The Lindlar catalyst (Pd poisoned with Pb on CaCO3) is but one of many systems that also work. © Ari Koskinen Reductive amination © Ari Koskinen A! Aalto university School of Chemical Technology Reductions with diimide © Ari Koskinen A! Aalto university School of Chemical Technology Review: Pasto, D. J.; Taylor, R. T. Org. React. 1991, 40, 91-155. Wolff-Kischner Reduction © Ari Koskinen A! Aalto university School of Chemical Technology Reduction of Enones: Alkene Walk © Ari Koskinen A! Aalto university School of Chemical Technology Meerwein-Ponndorff-Verley A! Aalto university School of Chemical Technology Reversible: Oppenauer oxidation © Ari Koskinen Meerwein, H.; Schmidt, R. Liebigs Ann. Chemie 1925, 444, 221–238. Verley, A. Bull. Soc. Chim. Fr. 1925, 37, 537. Catalytic MPV Reduction A! Aalto university School of Chemical Technology RuCl2.(PPh3)3 catalyst to substrate ratio: 1: 5000 © Ari Koskinen Noyori R, Angew. Chem. Int. Ed. 2001, 40, 40. Dissolving metal reductions (Birch) A! Aalto university School of Chemical Technology © Ari Koskinen Birch reductions: regioselectivity © Ari Koskinen A! Aalto university School of Chemical Technology Enolates via Birch Reduction A! Aalto university School of Chemical Technology Mander, L. Tetrahedron Lett. 1981, 22, 4115. See also: Uda Chem. Commun. 1982, 502. Simple alkylation: Mander, L. Tetrahedron Lett. 1982, 23, 1095. © Ari Koskinen Hydride Reducing Agents Aldehyde Ketone Acid chloride Lactone Epoxide Ester Acid Acid salt tert-Amide Nitrile Nitro Olefin 1 2 3 4 5 6 7 8 9 10 © Ari Koskinen A! Aalto university School of Chemical Technology 1 2 3 4 5 6 7 8 9 10 Complete reduction in 1 h Reduction takes place in inert solvent Only partial reduction in 1 h Insignificant reduciton in 1 h NaBH4 in EtOH Li(t-BuO)3AlH LiBH4 Al(BH4)3 B2H6 Sia2BH in THF 9-BBN in THF AlH3 in THF Li(MeO)3AlH in THF LiAlH4 in THF Brown, H.C. Chem. Engng. News March 5, 1979, 24. Reductions with LiAlH4 Rate decreases rapidly as more alkoxy groups accumulate around Al. The intermediates are stable (do not disproportionate!). © Ari Koskinen A! Aalto university School of Chemical Technology Reductive coupling: toremifene © Ari Koskinen A! Aalto university School of Chemical Technology Reductions with LiAlH4 and LiBH4 © Ari Koskinen A! Aalto university School of Chemical Technology Aldehydes or ketones from esters Carboxylate salts can give ketones with organolithium compounds: © Ari Koskinen A! Aalto university School of Chemical Technology Synthesis of aldehydes or ketones with Weinreb amides © Ari Koskinen A! Aalto university School of Chemical Technology Reductions with i-Bu2AlH (DIBAL-H) A! Aalto university School of Chemical Technology © Ari Koskinen Red-Al reductions • • Versatile reducing agent for epoxides, esters etc. Easier to dispense and safer to handle than LiAlH4 © Ari Koskinen A! Aalto university School of Chemical Technology Reductions with borohydrides A! Aalto university School of Chemical Technology NaBH4 • mild reducing agent, primarily for aldehydes and ketones • does not (usually) reduce esters • good solvent is EtOH, reacts with H2O and MeOH (the reagent should be kept dry!). • requires activation of the C=O by hydrogen bonding (hence alcoholic solvents!) • very slow reductions in nonprotic solvents (THF, diglyme) • available from Finnish Chemicals (Äetsä) LiBH4 • more reactive than NaBH4: Li+ activates C=O by coordination! • readily reduces esters © Ari Koskinen Reductions with NaBH4 Likely mechanism: NB! © Ari Koskinen A! Aalto university School of Chemical Technology NaBH4 © Ari Koskinen A! Aalto university School of Chemical Technology Rapoport J. Org. Chem. 1963, 28, 3261. BH3 in situ: NaBH4/I2 and NaBH4/H2SO4 A! Aalto university School of Chemical Technology © Ari Koskinen Reductions with borohydrides A! Aalto university School of Chemical Technology NaCNBH3 (sodium cyanoborohydride) • very mild: CN is a good electron withdrawing group => reduces reactivity • toxic! can generate HCN • relatively stable in water • dream reagent for reductive amination: © Ari Koskinen C. F. Lane, Synthesis, 1975, 135-146. Reductions with NaCNBH3 © Ari Koskinen A! Aalto university School of Chemical Technology Ha, J.D.; Cha, J.K. J. Am. Chem. Soc. 1999,121,10012. Alkene Walk © Ari Koskinen A! Aalto university School of Chemical Technology Reductions with borane (BH3) A! Aalto university School of Chemical Technology © Ari Koskinen Trialkylborohydrides • Very bulky and selective reducing agents, exclusive equatorial hydride delivery with cyclohexanones; also prefer conjugate addition: © Ari Koskinen A! Aalto university School of Chemical Technology Super Hydride: LiBHEt3 © Ari Koskinen A! Aalto university School of Chemical Technology 1,2- vs. 1,4-addition to C=C-C=O Borohydrides often give conjugate addition: With aprotic solvents, the reaction may stop at the enolate stage. © Ari Koskinen A! Aalto university School of Chemical Technology NaBH4 and Cu or Co A! Aalto university School of Chemical Technology NaBH4 together with CuCl gives clean 1,4-reduction: So does CoCl; in this case the reaction has also been rendered enantioselective: © Ari Koskinen Effect of metal salts: cyclohexenone A! Aalto university School of Chemical Technology © Ari Koskinen Effect of metal salts: cyclopentenone A! Aalto university School of Chemical Technology The CeCl3-mediated reduction is known as the Luche reduction. © Ari Koskinen NaBH4 and Cu or Co A! Aalto university School of Chemical Technology NaBH4 together with CuCl gives clean 1,4-reduction: So does CoCl; in this case the reaction has also been rendered enantioselective: © Ari Koskinen Conjugate Reductions: ’CuH’ Premix timea Time Ratio of 5:6:7 Y (%)b keto:alc. 1 1h 1.5 h 94:6:0 79:8 2 1.5 h 4h 96:4:0 65:5 3 2h 50 min 91:8:1 83:7 4 4h 55 min 96:4:0 95:3 5 1.5 h 9h 92:6:2 82:9 6 1h 15 min 48:50:2 43:49 7 2h 3.5 h 54:46:0 43:36 8 1h 35 min 49:49:2 42:43 9 1h 18 h 10:81:9 9:71 Entry © Ari Koskinen Ligand A! Aalto university School of Chemical Technology Andrejs Pelss J. Org. Chem. 2009, 74, 7598-7601. Hydrosilylation of enones © Ari Koskinen A! Aalto university School of Chemical Technology Andrejs Pelss J. Org. Chem. 2009, 74, 7598-7601. Hydrosilylation © Ari Koskinen A! Aalto university School of Chemical Technology Andrejs Pelss J. Org. Chem. 2009, 74, 7598-7601. Nucleophilic attack to cyclohexanones © Ari Koskinen A! Aalto university School of Chemical Technology Selectivity for equatorial attack © Ari Koskinen A! Aalto university School of Chemical Technology Brown, H. C. et al. J. Am. Chem. Soc. 1970, 92, 709; 1972, 94, 7159; 1976, 98, 3383. Stereoselectivity in Cyclic Ketone Reduction axial attack R1 t Bu O R2 R1 LiAlH4 t Bu OH R2 + R1 OH R2 t Bu equatorial attack R1 = R 2 = H 92 : 8 R1 = Me; R 2 = H 83 : 17 R1 = R 2 = Me 53 : 47 Cherest, M.; Felkin, H. Tetrahedron Lett. 1968, 2205. Unhindered ketones and reagents: Hindered ketones and reagents: Axial attack to give equatorial alcohol Equatorial attack to give axial alcohol Wigfield, D.C. Tetrahedron 1979, 35, 449. Kruger, D.; Sopchik, A.E.; Kingsbury, C.A. J. Org. Chem. 1984, 49, 778. Caro, B.; Boyer, B.; Lamaty, G.; Jacquen, G. Bull. Chim. Soc. Fr. II 1983, 281. Greeves, N. Comprehensive Organic Synthesis, Pergamon Press, 1990. © Ari Koskinen A! Aalto university School of Chemical Technology Selectivity for Equatorial Attack O O O O O Aalto university School of Chemical Technology O Me Me Me Me Me Me Me reference NaBH 4 30 14 - 14 52 26 1 LiAlH 4, THF 24 16 - 10 80 23 1 NiCRA 7 - 5 6 1 - 2 LiMeBH3 13 5.7 4.5 1.7 66 - 3 LiBuBH 3 - 8 6 2 - - 4 K9-tBu-9-BBN-H 99.5 98 94 98.5 99 - 5 K9-OThx-9-BBN-H 98.5 90 85.5 87 99.9 - 6 LiSia 3BH 99.7 99.6 99 99.4 - 99.5 7 Li(MeCp) 3BH 99.5 99 98 99.4 - - 8 LiMes 2BH 2 99 99 94 94 - 98 8 Li sBu 3BH 99.3 95 90 96.5 99.8 99.3 1 © Ari Koskinen A! References: 1Caro, B.; Boyer, B.; Lamaty, G.; Jaquen, G. Bull. Chim. Soc. Fr. II 1983, 218. 2Caubere, P. et al. Tetrahedron Lett. 1988, 29, 1379. 3Kim, S.; Moon, Y.C.; Anh, K.H. J. Org. Chem. 1982, 47, 3311. 4Kim. S.; Lee, S.J.; Kang, H.J. Synth. Comm. 1982, 12, 723. 5Cha, J.S. et al. Tetrahedron Lett. 1988, 29, 1069. 6Brown, H.C. et al. J. Org. Chem. 1985, 50, 549. 7Krishnamurthy, S.; Brown, H.C. J. Am. Chem. Soc. 1976, 98, 3383. 8Hooz, J. et al. J. Am. Chem. Soc. 1974, 96, 274. Reagent Control in Cyclic Enone Reduction A! Aalto university School of Chemical Technology Each isomer uncontaminated by the other one! © Ari Koskinen Amann, A.; Ourisson, G.; Luu, B. Synthesis, 1987, 1002.
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