REDUCTIONS • Invaluable process • Can be used to remove functionality from a molecule • A versatile method for introducing stereocentres • Formally reduction is the gain of electrons but it is more easy to visualise it as the gain of hydrogen (although this far from mechanistically correct) Metal Hydrides • The most common metal hydrides are lithium aluminium hydride (LiAlH4) and sodium borohydride (NaBH4) • There are differences mechanistically • In many cases the lithium cation is vital for reaction • number of repetitions • lithium activates depends on sterics of carbonyl the carbonyl Li H H Al Li Al H 2 H3Al d+ O O O H2Al Od– R R d– H d+ H H R H R R R R R 4 • addition of a crown compound • each addition is slower can prevent reduction by • alkoxide electron-withdrawing removing lithium group so reduces reactivity of hydride • In NaBH4 reactions cation is not important but solvent can be • not concerted Solv O H R HH H Solv O H O H B O Solv OH R1 H H3B O Solv H R R1 • multiple reductions occur • alkoxide makes hydride less reactive Chemoselectivity • LiAlH4 – very reactive, will reduce most carbonyl functionality • Care should be taken as it will react with acidic protons (RCO2H, RCH2OH, RCH2NH2) • NaBH4 – much milder, can be used to selectivily reduce aldehydes, ketones and acid chlorides in the presence of other functionality • Properties of both reagents can be altered by the addition of substituents • Some of these will be discussed below Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 45 Lithium Aluminium Hydride LiAlH4 General • All carbonyl groups are reduced • Many other functional groups are reduced • Reaction with acidic protons generates H2: 3 LiAlH4 + 4 RCO2H LiAl(OCH2R)4 + 2 LiAlO2 + 4 H2 Amides • Behave unpredictably (in my opinion) • hemiketal H or aminol N OH R1 R2 H O R1 3 + N R H O R2 O AlL3 H R O • hydrolysis 1 LiAlH R 4 R1 N R N R 2 H R R2 H2Al H 1 1 R R R N R N R2 R2 H • Which path is followed is a result of sterics and electronics around the amine • Personally I have found it is also effected by solvent, temperature, day of the month Enones • Another problematic functional group H H • 1,4-addtion • 1,2-addition H Al H R1 O R1 O R1 OH R2 R R2 R R2 R H • Very dependant on the exact structure of the enone • Advisable to choose a different reagent Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 46 Epoxides O R1 H OH LiAlH4 R1 R R2 R R2 • Hydride normally delivered to the least hindered end • Epoxides are more readily reduced than esters • Epoxides are less readily reduced than aldehydes / ketones 1. LiAlH4, Et2O, rt OH O + 2. H3O O 95 % O Nitriles Transformation R C N R NH2 Postulated Mechanism Li H AlH3 H N AlH3 N N AlH2 C H R R 2 R • quite franky a little bit of a mystery where the proton comes from H • I would prefer lithium cation H being present until w/u N AlH2 R NH2 H R 2 • Nitriles are easily introduced to a molecule • Nitriles are useful in aiding C–C formation by stabilising anions Ph Ph Ph K NC N O N O NC N O pH 3.0 LDA Ph Ph Ph I Me N OH LiAlH4 NC N O O H2N NC N Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 47 Nitro Group Transformation R NO2 R NH2 Example O NO NO NH MeO 2 NH4OAc 2 LiAlH4 2 + Ar Ar Hydrogenolysis Transformation R X R X = halide, sulfonate ester, good leaving group Examples Cl C8H17 O C8H17 LiAlH , reflux, N N O 4 26 hrs 72 % Cl O O • selective protection O O of least hindered primary alcohol OH OH OH OTs OH TsCl, Pyr LiAlH4 Ease of Reduction of Functional Groups with LiAlH4 RCHO RCH2OH Easiest 1 1 RCHOR RCH2OHR RCOCl RCH2OH 1 1 RCH CHR RCH2 CHR O OH 1 1 RCO2R RCH2OH + R OH RCO2H RCH2OH 1 1 RCH2NR 2 or (RCH2OH RCONR 2 1 + HNR 2) RCº N RCH2NH2 Hardest Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 48 Alkoxyaluminate Reducing Systems • By altering both the sterics and electronics of the substituents on LiAlH4 it is possible to tune the reactivity of metal hydrides • The addition of alkoxides reduces the reactivity of the hydride due to their electron-withdrawing properties • This enables chemoselective reactions LiAlH(OEt)3 • Reduces nitriles to aldehydes H O LiAlH(OEt)3 H3O CN N Al(OEt)3 iPr H LiAlH(OtBu)3 • Will reduce ketones, aldehydes and acid chlorides but little else • Allows good selectivity • only ketone reduced • ester untouched O O O O O OH LiAlH(OtBu)3 H H H H H H AcO AcO • both ketones reduced • bromide untouched O OH LiAlH(OtBu)3 O HO H H Br Br Sodium Bis(2-methoxyethoxy)aluminium Hydride (Red-Al) H O O Na Al O H O • Similar selectivity to LiAlH4 • But more stable and soluble (so why it is sold as the most viscous gum known to mankind is anyones guess) • Can achieve 1,4-reductions in the presence of CuBr • Probably proceeds via the copper hydride • copper very useful for 1,4-additions O Red-Al, CuBr O O O (CH2)4OTHP (CH2)4OTHP O O Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 49 Sodium Borohydride NaBH4 • Much less powerful reducing reagent • Selective for aldehydes, ketones and acid chlorides • Does not touch epoxides, esters, acids and nitriles O OMe O OTBS TBSO O O O O OTBS O CO2Me O • lactone survives NaBH4 O OMe O OTBS TBSO O O O O OTBS O CO2Me • ketone reduced OH • ozonolysis cleaves • reduce only aldehyde electron-rich double bond and not ester • allows lactone formation OH 1. O3, MeOH H3O O TMSO 2. NaBH4 O H H H TMSO2C • NaBH4 can reduce imides but only as far as the aminol • Allows an elegant route to bicyclic alkaloids O O O OH N NaBH4 N CF3CO2H O N SiMe3 SiMe3 Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 50 Substituents on Boron Super Hydride LiBHEt3 • Addition of electron-donating groups (inductive effect) increases reducing power • One of the best reducing reagents • Especially good at hydrogenolysis (superior to LiAlH4) Ph Ph HO 1. MeSO2Cl, Et3N 2. LiBHEt3 K & L–Selectride (K or Li BH( )3) • Very reactive hydride donors due to inductive effect • Bulk makes them very good at diastereoselective reactions (substrate control) • existing stereocentres control formation of new stereocentre tBu tBu tBu O O O Si Si Si tBu tBu tBu O O O DMP L-Selectride PMBO PMBO 95 % 2 steps PMBO OH O OH N O N O N O OMe OMe OMe Sodium Cyanoborohydride NaBH3CN • Very unreactive therefore very selective • Will reduce iodides, bromides and tosylates in HMPA even in the presence of carbonyls • Ketones can be reduced BUT in acid media (ph 3-4) O O H H NaBH3CN, O O H H HPMA, 70˚C 1 hr H H 70 % O O I Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 51 Effect of Counterions / Additives • Changing the counter-cation can have a profound effect on the reactivity of NaBH4 • Addition of LiBr, AlCl3 or ZnCl2 results in more powerful reducing agent (due to higher ionic potential) • Addition of CeCl3 (Luche Reduction) gives very selective 1,2-reduction of conjugated aldehydes and ketones O OH NaBH4•CeCl3 MeOH N3 CO2Me N3 CO2Me • Two reasons: Co-ordination of the carbonyl and cerium result in increased hardness and more d+ character thus more reactive to "H–" Tethering effect "intramolecularises reaction" • Reaction is under kinetic control (irreversible) H H H B H Ce O • Use of Ni2+ or Co2+ results in a reversible complexation and a thermodynamically controlled reaction which results in predominantly 1,4-reduction Borane / Diborane B2H6 • Very reactive • But also strong Lewis acid • Co-ordinates to electron-rich centres which alters its properties considerably • Complimentary to LiAlH4 (reverses much of its reactivity) O H O H BH3 OH CO2H O O O O RCO2H RCH2OH Easiest RCOR1 CHOHR1 RCN RCH2NH2 1 1 RCO2R RCH2OH + R OH RCOCl inert Hardest Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 52 Diisobutylaluminium Hydride DIBAL-H (iBu2AlH) • Strong reducing agent • But frequently possible to use it to reduce only one "oxidation state" • Esters can be reduced to aldehydes N N N DIBAL-H H -78˚C H 76 % H H N N N H H H H H H CO2Me HO O HO HO O • Lactones reduced to lactols O OH HO DIBAL-H Wittig H O O (CH2)3CO2H -78˚C 80 % C5H11 C5H11 C5H11 THPO H H H OTHP OTHP OTHP OTHP OTHP • Nitriles to aldehydes iBu2Al O N N + H DIBAL-H H H O O 3 O O O O O H H H MECHANISM FOR DIBAL-H REDUCTIONS • The mechanism of the DIBAL-H reduction different to that of other metal hydride reagents • Primarily because it is a Lewis acid.