Hydride Reducing Agents General Mechanism: ! ! ! • reduction of aldehydes & ketones O R O MHn R' R MHn-1 H OH H3O+ R' R H R' H • reduction of carboxylic acids & derivatives O R O MHn X R H MHn-1 O R X H H H O R H ML3 OH H3O+ H R H H Aluminum Hydrides 1. Lithium Aluminum Hydride (LiAlH4) ! ! • general H Li H H Al H H O H O O H Al H H k1 O H Al O H k2 H (fast) H H O k3 O H Al O O O H H k4 (slow) O O Al O O H H k1 > k2 > k3 > k4 LiAlH4 > LiAl(OR)H3 > LiAl(OR)2H2 > LiAl(OR)H 3 ROH H Aluminum Hydrides 1. Lithium Aluminum Hydride (LiAlH4) ! ! ! • reactivity - highly reactive, non-selective reducing agent - use with caution! Highly flammable solid! - one equivalent of LiAlH4 delivers 4 equivalents of hydride; still typically used in excess - reduces carboxylic acids, esters, lactones, acid chlorides, anhydrides, aldehydes, ketones, epoxides to give alcohols - reduces amides, lactams, nitriles, azides, aryl nitro groups to give amines - other reactive FG include: epoxides, alkyl halides, propargyl alcohols, etc. • examples O N Me H MeO N Me LiAlH4 THF O H 70% O H MeO O H OH Aluminum Hydrides 1. Lithium Aluminum Hydride (LiAlH4) ! ! ! • examples MeO2C MeO2C OH O HO O OH LiAlH4 THF, reflux H 72% H CO2H OH O CO Me 2 HO OH LiAlH4 THF, 65°C O 98% H O OH H O OTIPS O O O 1. LiAlH4, THF, rt 2. PhCOCl, Et3N, DMAP 90% O O OTIPS OBz Aluminum Hydrides 2. Trialkoxyaluminum hydrides: LiAl(OtBu)3H , LiAl(OMe)3H ! • reactivity - much less reactive than LiAlH4 - hindered, will reduce only most reactive FG (aldehydes, ketones, acid chlorides) • examples O O O Li(OtBu)3AlH Et2O, 0°C O O O O O O Li(OtBu)3AlH O EtO2C O Amberlite IR-20 benzene, 80°C HO THF, -10°C EtO2C O O O OHC OH O O O - LiAl(OtBu)3H can also be used to reduce acid chlorides to aldehydes O Aluminum Hydrides 3. Sodium Bis(2-Methoxyethoxy)aluminum Hydride (Red-Al, Vitride, SMEAH) • reactivity H - similar reactivity to LiAlH4 H • examples TBSO O S S RedAl toluene, -78°C TBSO OH S S 80% O BnO OH OH OH BnO + OH Red-Al DIBAL LiAlH4 150 : 1 1 : 13 1:1 BnO OMe O OMe Al Na - moisture sensitive, but not pyrophoric; thermally stable to 200°C O OH Aluminum Hydrides 4. Diisobutylaluminum Hydride (DIBAL, DIBAL-H) Al H • reactivity - strong reducing agent, but bulky sometimes see selectivity - reduces aldehydes, ketones, esters, epoxides to alcohol; lactones to lactols - pyrophoric liquid, typically purchased in solution • examples OTBS TBSO OTBS DIBAL CO2Me CH2Cl2, -78°C TBSO OH 93% O TBSO DIBAL OEt hexanes, -78°C O TBSO H 91% TBSO PMBO O TBSO Me N OMe O DIBAL THF 89% PMBO H Boron Hydrides 1. Sodium Borohydride (NaBH4) • general Na H H B H H k3 OR H B H H k3 k3 OR H B OR H OR H B OR OR k1 = k2 = k3 = k4 - requires activation: H R' δ+ O O H H B H H half life of NaBH4 at 25°C MeOH EtOH iPrOH tBuOH 30 min slow stable k3 OR RO B OR OR Boron Hydrides 1. Sodium Borohydride (NaBH4) • reactivity - selective reducing agent - reduces aldehydes and ketones to alcohols; imines to amines - carboxylic acids, esters, lactones, epoxides, nitirles and nitro groups do not react • examples O I HO I NaBH4 MeOH O OPiv O OPiv 99% O O O HO NaBH4 S S EtOH-CH2Cl2 S S Boron Hydrides 2. Lithium Borohydride (LiBH4) • reactivity - reduces aldehydes, ketones, esters, lactones, epoxides - does not react with carboxylic acids, amides, nitriles, etc. - can attenuate reactivity by choice of solvent: in ether > THF > 2-propanol - reacts violently with water • examples HO Me MeO2C CO2H HO Me LiBH4 81% HO F CO2H F O2N H N O O N H CO2Me OTBS O2N LiBH4 H N MeOH-THF-Et2O 83% O OH O N H OTBS Boron Hydrides 3. Sodium Borhydride / CeCl3: Luche Reduction • reactivity - selectively reduces α,β-unsaturated carbonyl compounds to allylic alcohols - also good for readily enolizable ketones • examples N H N NaBH4, CeCl3 H N H MeCN-MeOH 78% H MeO2C N H H MeO2C O OH O OH OH + NaBH4 NaBH4, CeCl3 51 : 49 >99 : 1 Boron Hydrides 4. Borane (BH3) • reactivity - very selective: CO2H ≈ CHO > ketone >> CO2R ≈ CN - also reacts with alkenes and alkynes • examples HO2C O O BH3•SMe2 THF HO O O Boron Hydrides 5. Sodium Cyanoborohydride (NaCNBH3) • reactivity - very mild reducing agent; less reactive than NaBH4 - stable in aqueous solution at pH >3 • examples O O CO2Me CO2Me MeCN-H2O 96% NH2 Me N Me MeO2C MeO2C OAc O NaCNBH3, H2C=O O MeO2C TsNHNH2 EtOH OAc N TsN OtBu OAc O O OtBu OtBu O TsNHNH2 NaCNBH3 79% NaCNBH3 Boron Hydrides 6. Lithium Triethylborohydride (LiEt3BH): Super Hydride • reactivity - very powerful reducing agent stronger than LiAlH4 - excellent reagent for reduction of sulfonates & epoxides • examples OTs LiEt3BH BnO THF OH BnO OH 92% O OH LiEt3BH THF HO HO H Br H H LiEt3BD THF H D Boron Hydrides 7. Lithium or Potassium Tri-s-butylborohydride (Li(sBu)3BH, K(sBu)3BH): L/K-Selectride • reactivity M+ HB - bulky reducing agents 3 - reduce aldehyde & ketones, but not carboxylic acid derivatives • examples O OH K(sBu)3BH O N O R O THF, -78°C N CO2Et BPSO CO2Et BPSO O Li(sBu)3BH O THF, -78°C O O HO O K(sBu)3BH THF, -78°C O O O R Boron Hydrides 8. Zinc Borohydride ( Zn[BH4]2 ) • reactivity - prep (in ether): NaBH4 + ZnCl2 Zn(BH4)2 - ether solution of Zn(BH4)2 is neutral good for base sensitive compounds • examples O OBn Zn(BH4)2 ether OH OBn Boron Hydrides 9. Sodium Triacetoxyborohydride ( NaBH(OAc3 ) • reactivity - also known with tetraalkylammonium counterions Me4NBH(OAc)3 - selective reduction of aldehydes in presence of ketones - hydroxyl directed reduction of ketones • examples O O CHO Me4NBH(OAc)3 benzene, reflux OH 77% O HO OH Ph Me4NBH(OAc)3 benzene, reflux HO Ph Silyl Hydrides 1. Triethylsilane / Wilkinson’s Catalyst (Et3SiH / (Ph3P)3RhCl) • reactivity - selective 1,4-reduction of enones • examples O Et3SiH (Ph3P)3RhCl OSEt3 H3O+ O Other Reductions of Carbonyls 1. Meerwein-Pondorf-Verely Reduction (MPV) - reverse of Openauer oxidation - equilibrium determined by choice of solvent OH Al(OiPr)3 O R H OH R' R O Al(OiPr)3 R' Other Reductions of Carbonyls 2. Clemmensen Reduction O Zn(Hg) HCl CO2H MeO CO2H MeO 68% 3. Wolff-Kishner Reduction N N N O N Cl Ph N N CHO H2NNH, KOtBu EtOH, reflux H N CH3 O N Cl 91% Ph H 4. Raney-Nickel O Et HS N SH BF3•OEt2 81% S Et S Ni(Ra) N iPrOH, 70°C 78% Et N
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