ELECTRON TRANSFER REDUCTIONS (S.E.T. / DISSOLVING METAL / RADICAL) • Reduction is the addition of electrons to a substrate Dissolving Metal Alkali Metal
• Transfer of electron from valence shell to substrate xs1 ® xs0+ R ® R•– (radical anion) • Normally a second transfer occurs to give the anion which gains proton from solvent
Reduction of Carbonyl Compounds Mechanism
OH O e– O O H+ OH e– OH H+ 1 1 1 R R1 1 1 R R R R R R R R R R H
• pinacol reaction: O O OH OH potential side-reaction H+ • choice of metal can R R R R favour coupling (vide R1 R1 R1 R1 infra) Selectivity • Hydrogen normally adds to give the thermodynamic product
O O O O H H Li(0), NH3, EtOH 93 % O HO
• Enones behave in a similar manner OH OH
H Li(0), NH3 H R R H H O O
OH OH
H MeI H R R H H H H O HO Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 69 Reduction of Alkynes
• Complimentary to hydrogenation • Dissolving metal reduction gives predominantly trans akenes
Mechanism
( ) H e– R H+ R R R R R
e– • electrons repel and stay as far apart as possible H R H+ R R R ( ) Hydrogenolysis • Single bonds can be reduced as well • O-benzyl and N-benzyl groups can be readily cleaved by dissolving metal
OH Li(0), NH OH Et 3 Et O Et O Et H Et O H Et O BnO HO • benzyl group removed • benzylic radical stabilised Proposed Mechanism by delocalisation
R R O O e– O 1 1 + R R R R1
• Sulfones are another important group that can be cleaved by hydrogenolysis
O S O O O R e– R S S + R R1 1 1 O R O R
• it is possible that sulfone is reduced to sulfide first (cf SmI2)
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 70 H H SO2Tol Na2HPO4, Na–Hg, MeOH / THF N Pr N Pr H Cbz H Cbz • Note: MeOH essential in order to prevent b-elimination (cf the Julia Reaction)
PhSO2 • no proton source
Na / NH3 Ph Ph 60 % N N Dpp NHDpp Dpp Ph The Birch Reduction • Partial reduction of an aromatic system utilising dissolving metal General Mechanism
e–
EtO H
H H H H H H Na(0), NH3, EtOH
e– H H H H H H H H EtO H
H H
• Note: conjugated diene (1,3-cyclohexadiene) thermodynamically more stable • But 1,4-diene formed in preference • Reason for formation of the kinetic product not entirely understood Substituent Effect Electron-Withdrawing • stabilises a -anion Na(0), NH3, EtOH RO2C RO2C RO2C
Electron-Donating • destabilises a -anion Na(0), NH3, EtOH MeO MeO MeO
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 71 Use in Synthesis
Li, EtOH, MeO MeO R O O O NH3 O H Et H H H MeO H Et OH • Grignard • deprotection • ozonolysis • ozonolysis • transesterification • protection
R R O O O O H Et OHC MeO O H Et Reductive Alkylation (a useful extension) • The anion intermediate can be readily trapped with a suitable electrophile
Br OMe
Birch OMe reduction OMe
CO2H CO2 CO2H OMe • iodolactonisation radical cyclisation • reduction • deprotection • Wittig CO2H CO tBu H 2 H I
O O
O O • And of course, an asymmetric variant
MeO MeO O O
N Birch N MeI
OMOM OMOM
• hydrolysis • iodolactonisation • reduction
H I
O O O MOMO O
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 72 Titanium Promoted Reductions The Pinacol Coupling and McMurry Reaction • Not just alkali metals that are good at promoting electron transfer • Titanium has been shown to be very good at promoting the pinacol reaction • Titanium is very oxophilic and can deoxygenate the diol to give an alkene • Known as the McMurry reaction
R R [Ti]O O[Ti] R R O O [Ti] [Ti] R R
• pinacol proceeds via • McMurry could diradical (vide supra) proceed via diol • Note: possible that McMurry proceeds via a carbenoid C=[Ti] (deoxygenation proir to coupling) • Titanium can be used in catalytic quantities
OH O 3 % Cp2TiCl2, Zn, Ar MgBr, TMSCl Ar Ar H 90 % OH • And of course, an asymmetric variant utilising the catalyst below
Cl Ti Cl
• The McMurry reaction can also be achieved catalytically O Ph Ph 10 mol% TiCl3, Zn, TMSCl NH N CF3 88 % H
O CF3 • stoichiometric reductant Proposed Catalytic Cycle readilt reduces Ti–Cl bond
2 ZnCl2 2 [TiCl] diketone 2 Zn
2 TiCl3
2 R3Si-O-SiR3 Ti O 2 Product Cl 4 R3SiCl • problem is reducing • replace with strong Si–O bond strong Ti=O bond Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 73 Samarium Diiodide SmI2 (Kagan's reagent)
• An amazingly versatile reagent • A powerful single-electron reducing agent • To list all its reactions would be time consuming so just give an overview • SmI2 reactivity is readily modulated by varying solvent, co-catalyst and other conditions making it incredibly flexible Preparation • Although commercially available you are recommended to prepare it freshly • Mix (CH2)I2 (recrystallised) & Sm in THF (0.1 M limiting solubity) (CARE: exotherm) • Dark blue solution within 3 hrs Reductions • Will not deal with reactions that have a second metal present Carbonyl Reductions • Mild and selective, ketones and aldehydes can be reduced in the presence of other carbonyl functionality • Catalytic SmI2 can replace aluminum alkoxides in the Meerwein-Ponndorf-Verley reaction General Mechanism OH + SmI2
OH O
R1 H SmLn R R1 R O
H
OH
Ln SmLn Sm O O O
1 R1 H R H R R
• selectivity believed O • all other reductants to result from failed to give good yield co-ordination to axial and / or selectivity oxygen Use in Synthesis
R H R H H H H O SmI2 0.1 eq, H O iPrOH 10 eq, THF H PMBO O PMBO O H 98 %, 97 % e.e. H O OH Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 74 • stereochemistry Evans-Tishenko-Type Reaction controlled by • Diastereoselective transfer-hydrogen-like reaction alcohol only O OH O 1 1 R CHO, cat. SmI2, THF R O OH R 85-95 % • stereochemistry R independant of other substituents O OH O 1 R CHO, cat. SmI2, THF R1 O OH R R
Transition state • chelation of the two oxygens results in diastereoselectivity O H R1
O O • selective reduction Sm of ketone only Carbonyl Reduction
• SmI2 can reduce carbonyl group by direct electron-transfer • thermodynamic product
O HO 2 SmI2, THF / H2O H 97 %, 86 % d.e. H OTBS OTBS H H CO2Me CO2Me Mechanism
Sm(III)Ln Sm(III)Ln O SmI2 O SmI2 O + e– + e– H OH R R1 R R R1 R1
Pinacol Reaction • The ketyl radical intermediate (shown above) is the same as that found in the pinacol reaction (vide supra) • SmI2 can mediate the pinacol reaction • Many examples of the intramolecular pinacol • Potentially this could occur either via the diradical species or an ionic species
CO2Me CO2Me COMe 2 SmI2, THF 81 %, 92 % d.e. OH TBSO TBSO CHO OH
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 75 Reductive Radical Couplings • The ketyl radical produced can also be used in other radical couplings
LnSm O O LnSmO CO2Me SmI2, THF / HMPA, CO2Me 0˚C 1 min. 89 %
O O OMe SmL • lactonisation n O O
• Radical cascades are also possible
LnSmO CHO SmI , THF / O 2 HMPA, 0˚C O O 91 % O
OH H
H H Other Reductions Conjugated Systems
SmI2, THF, EtOH O CO2Et CO2Et N 97 % Mechanism
R OEt SmI2 R OEt EtOH R OEt e– O O O
• Note: conjugated ketones give a mix of 1,4- & 1,2-reduction • Note: conjugated aldehydes give polymers
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 76 Halides Br 2.5 SmI2, THF, MeCN, HMPA, iPrOH 98 %
• Reaction proceeds via a radical intermediate • Again can be used as a radical precursor
TMS TMS
Br 3 SmI2, THF / HMPA, rt 3 hrs
O O
I 1. 2.5 SmI2, THF / HMPA / tBuOH BnO O Et O O Et 2. H2CrO4
-Carbonyl Functionality
O O
X SmI2, THF, MeOH
X = halide 100 % X = sulfide 76 % X = sulfone 88 % • Even normally poor leaving groups such as hydroxyl can be reduced • deoxygenation O O O O
SmI2, THF
MEMO OTBS MEMO OTBS HO
H H O O
• Sulfones amd Sulfoxides can be readily reduced to their analogous sulfides
O 2 2 SmI2, THF / S S Ph Ph HMPA, rt Ph Ph 99 % • Sulfones can be reductively cleaved (presumably via the sulfide)
PhSO2
5 SmI2, THF / DMPU / MeOH Ph N Ph N Dpp Dpp 91 %
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 77 Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 78 Anionic–Radical
TMS TMS • ketyl radical addition TMS SmI , THF / 2 O TBSO HMPA TBSO OH CO Et 2 81 % TBSO Br
• nucleophilic addition
Anionic–Anionic
I OH OH
O SmI2 O OH O Cl Cl
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 79