Dr. Pere Romea Department of Organic Chemistry Rouen Cathedral Claude Monet, 1892-94 7. Reductions Organic Synthesis 2014-2015 Autumn Carbon Backbone & Functional Groups The synthesis of an organic compound must pay attention to ... Carbon backbone Functional groups (Chapters 2–4 ) Functional Group Interconversion (FGI) I. Nucleophilic Substitutions Electrophilic Additions to C=C Addition-Eliminations on Carboxylic Acids and Derivatives II. Reductions Mechanism!!! III. Oxidations Pere Romea, 2014 2 Reductions & Oxidations Redox: electronic, e–, interchange Reduction: gain Oxidation: loss OH + 0 e– Hydration R + H2O R (RC2H3) (RC2H5O) O OH + 2 e– R + 2 H R Reduction (RC2H3O) (RC2H5O) O + 0 e– Hydration R H + H2O R (RC2H) (RC2H3O) O – 2 e– R + H2O R + 2 H Oxidation (RC2H3) (RC2H3O) 3 Pere Romea, 2014 Reductions & Oxidations Redox: interchange of H or O Reduction: gain of H/loss of O Oxidation: gain of O/loss of H H HH reduction H reduction H R H R R + H + H H HH OH O O oxidation oxidation H R H – H R H + O R OH Reduction H OH O O O 1 H 1 H 1 2 1 2 1 2 R R2 R R2 R R R OR R O OR Alkane 2ary Alcohol Ketone Ester Carbonate Oxidation 4 Pere Romea, 2014 Reductions & Oxidations Standard Reduction Potentials Remember that ΔGo = – n F ΔEo Eo(V) Li+ + e– Li –3.04 Reduction Na+ + e– Na –2.71 – – H2 + 2e 2 H –2.25 Sm3+ + e– Sm2+ –1.55 Zn2+ + 2e– Zn –0.76 Sn2+ + 2e– Sn –0.13 + – 2 H + 2e H2 0 Cu2+ + e– Cu+ 0.16 Fe3+ + e– Fe2+ 0.77 Ag+ + e– Ag 0.80 Oxidation – – Cl2 + 2e 2 Cl 1.36 Pere Romea, 2014 5 Reductions Reductive processes: a) Dissolving metal reductions b) Radical reductions c) Reductions with hydrides d) Catalytic hydrogenations e) Carbonyl deoxigenation reactions Chap. 23 Different Chaps. mainly Pere Romea, 2014 6 Dissolving Metal Reductions Lithium or sodium metals give very easily the electron from the valence shell slow Li + NH3 Li + e [NH3]n NH2 + 1/2 H2 Blue solution Colorless solution Electrons are the simplest reducing agents and they reduce any funtional group with a low-energy π* orbital : BIRCH REDUCTION ALKYNE REDUCTION CARBONYL REDUCTION Pere Romea, 2014 7 Birch Reduction Birch reduction converts phenyl groups in 1,4-cyclohexadienes H H Li or Na NH3 / ROH H H H H H H H H H H H H e ROH H H H H H H H H H e H H H H H H H H H H H H ROH H H H H H H H H H H 8 Pere Romea, 2014 Birch Reduction The reduction proceeds with a remarkable regioselectivity .... EWG EWG EDG EDG Li Li NH3 / ROH NH3 / ROH EWG: CO2R, CN, NO2 EDG: OMe, NR2, Alkyl OMe OMe OMe O Li H H3O NH3 / EtOH 80% CO2H CO2 CO2H Li H3O NH / EtOH 3 90% 9 Pere Romea, 2014 Alkyne Reduction Alkynes are converted into E-alkenes stereoselectively H Li or Na 2 1 2 R2 R1 R2 R R R1 NH3 or Z Alkene Lindlar HMPT/ t-BuOH E Alkene H H M NH or ROH 1) M 1 2 1 2 3 2 R2 R R R R 1 R R1 R 2) NH3 or ROH H H R1 R2 Na NH3 liq, –33 °C 86% 10 Pere Romea, 2014 Carbonyl Reduction Carbonyl groups can be reduced to alcohols O O O OH OH M ROH 1) M 2) ROH H Ketyl radical anion For a synthetic point of view this procedure is not very important. It is more useful the reduction of unsaturated carbonyl groups O O OH 1) 2 M 1) 2 M 2) 2 ROH 2) 2 ROH H H 1) Li, NH3 liq 2) NH Cl O 4 O H 99% trans 11 Pere Romea, 2014 SmI2 Reductions Samarium diiodide (SmI2) is a single-electron reducing agent particularly useful in C-C bond formations and transformations of several functional groups Nicolaou, K. C. ACIE 2009, 48, 7140; Procter, D. J. ACIE 2012, 51, 9238 Sm + ICH2I SmI2 + 1/2 H2C=CH2 Sm + ICH2CH2I SmI2 + H2C=CH2 Eo 1.55 V Sm (II) Sm (III) + e– The reactivity of SmI2 is significantly affected by the choice of solvent. It reduces organic halides, aldehydes, ketones and α-functionalized carbonyls 12 Pere Romea, 2014 SmI2 Reductions Organic halides can be reduced to hydrocarbons HX R X + SmI2 R H + SmI2X SmI2 HX R X Sm(II) R R SmI2 R H –SmI2X –SmI2X Sm(III) Sm(III) SmI2 H H THF / HMPA, i-PrOH, rt H H Cl 99% Corey, E. J. JACS 1987, 109, 6187 Br O O SmI2 O O THF, HMPA, i-PrOH, rt 99% 13 SmI2 Reductions Aldehydes and ketones can be reduced to alcohols O OH HX R1 R2 + SmI2 R1 R2 H Sm(II) Sm(III) H Sm(III) H O O O O O HX SmI2 HX H H R3SiO R3SiO O O SmI2 PMBO O PMBO O THF, i-PrOH O OH 98% Evans, D. A. JACS 1990, 112, 7001 14 Pere Romea, 2014 Radical Reductions Alkyl bromides and iodides are easily reduced to the corresponding alkanes through a free-radical process with n-Bu3SnH. In + Bu3SnH Bu3Sn + In–H Bu3Sn + R–X Bu3SnH + R R + Bu3SnH Bu3Sn + R–H A parallel transformation involves a radical-promoted deoxygenation of O-thiocarbonate derivatives of alcohols in a two-step process named Barton-McCombie reaction S OH O SMe 1) NaH, CS2 2) MeI S S–SnBu3 O SMe O SMe H Bu3Sn Bu3SnH – MeSCOSSnBu 3 15 Radical Reductions OTIPS OTIPS I HO HO O O H OMe H Bu3SnH, AIBN H OMe H TIPSO O THF, Δ TIPSO O H H OPMB OTIPS OPMB OTIPS Cl OPMB 70% Cl OPMB Kishi, Y. ACIE 1998, 37, 137 The radical generated during the dehalogenation reaction can undergo a tandem radical cyclization Bu3Sn Br H H Bu3SnH, AIBN PhH, Δ H H 61% – Bu3SnBr Bu3SnH H H H H H H Curran, D. TL 1985, 26, 4991 16 Pere Romea, 2014 Hydride Transfer Formal addition of H– to a double or a simple bond H A B + H H A B H A B H H A B + H H A + B B H Hydrides, M–H, used for the reduction of organic compounds B are from three elements close in the periodic table: boron, aluminum, and silicon Their reactivity fairly depends on the element: Al Si aluminium hydrides are more active than the boron counterparts, and these more than the silicon ones 17 LiAlH4: A General Reducing Agent? Lithium aluminum hydride, LiAlH4, the strongest reducing agent? Li Li Li Li O O O O OH + H 2 1 1 H R1 OR2 R1 OR 2 R1 H R H R H – OR H H H H Al H Stable? Al H H H H H Li Li – O O O R2N is a very poor leaving group 2 3 2 3 R1 NR2R3 R1 NR R R1 H + R R NLi H H AlH Stable? Al 3 H H H AlH 3 2 3 2 3 Li O NR R NR R 2 3 R1 NR R R1 H R1 H H H H Al H H 18 H Pere Romea, 2014 LiAlH4: A General Reducing Agent? – LiAlH4 is commercially available, very sensitive to water. – Dry ethereal solvents are required. – LiAlH4 is a very strong & non chemoselective reductor. LiAlH4 O O 1 1 X R R2 O R 1 1 R X R C N R O H OH 1 R1 NR2R3 R R1 R 2 OH H H R1 R1 OH H H H H 1 R1 NR2R3 R NH2 19 Pere Romea, 2014 LiAlH4: A General Reducing Agent? O N N H H LiAlH4 MeO MeO THF O O H 70% H O OH O t-Bu O HO H HO H MeO2C LiAlH4 MeO2C HO CO H THF 2 OH H 72% H MeO MeO LiAlH CN 4 MeO MeO NH2 Et2O 85% 20 Pere Romea, 2014 LiAlH4: A General Reducing Agent? MsO O LiAlH4 OH Et2O, ta 77% LiAlH4 I Et2O, ta 94% O t-Bu OH OH LiAlH O 4 t-Bu t-Bu Et2O, ta t-Bu H t-Bu LiAlH4 O Et O, ta t-Bu t-Bu O 2 t-Bu OH H OH 21 Pere Romea, 2014 LiAlH4: A General Reducing Agent? LiAlH4 can even be active on propargylic and homopropargylic alcohols … OH LiAlH O H2Al O H O H H OH 4 Al R R Al H – H2 H H R H H R H R H O O OH LiAlH4 OH THF, ta Ph Ph 95% OMe OMe HO HO LiAlH4 THF, Δ 85% 22 Pere Romea, 2014 LiAlH(OR)3: Selective C=O Reduction LiAlH4 + 3 ROH LiAlH(OR)3 + 3 H2 – Alkoxyde ligands, OR, reduce the reactivity of aluminum hydride: they become more chemoselective – The presence of one or two H– permet to tune the reactivity O O O O CHO LiAlH(Ot-Bu)3 OH CO2Me THF, –10 °C CO2Me O O O O 1) LiAlH(OEt)3, THF, 0 °C N H H 2) H+ OH 77% O OH O Red-Al™ O NaAlH2(OCH2CH2OCH3)2 CO2t-Bu CO2t-Bu Hexà, –70 °C OTHP OTHP OTHP OTHP 23 Pere Romea, 2014 i-Bu2AlH: Selective XC=O Reduction A highly selective reducing agent to aldehydes: i-Bu2AlH (DIBAL or DIBALH) i-Bu Al i-Bu H i-Bu i-Bu Al Al(i-Bu)2 O O H O O + H3O 2 R1 OR2 R1 OR2 R1 OR R1 H H Somehow stable at low T CO2Me DIBAL CHO O O N Toluè, –78 °C N Boc Boc 76% O O DIBAL CN CHO Et2O, –78 °C HO t-Bu HO t-Bu 56% Cl O Cl O DIBAL Me TBSO N TBSO H CH2Cl2, –78 °C OMe Pere Romea, 2014 82% 24 NaBH4: Reduction of C=O Sodium borohydride, NaBH4, the mildest agent? H H The boron atom has no The boron atom cannot B + E E B H electron pairs available H H H accept 10e (octet rule) H H H O O OH H2O o ROH B H + R H R H R H H H –BH3 H H – Sodium borohydride is a solid very easy to handle and commercially available – The reductions with NaBH4 are carried out in methanol, ethanol, or even water at 0 °C or room temp – NaBH4 reduces aldehydes and ketones to the corresponding alcohols.