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

O O O OH OH OH
e– H+ e– H+
R R1 R R1 R R1 R R1 R R1 R R1
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 (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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 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 OH
Li(0), NH3
Et 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
e– O
O O
+
R1 R1
R R1

• Sulfones are another important group that can be cleaved by hydrogenolysis

O S O
O R O R
e–
S S + R R1
O R1 O R1

• it is possible that sulfone is

reduced to sulfide first (cf SmI2)

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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 H H
SO2 Tol
Na2HPO4, Na–Hg,
MeOH / THF
N Pr N Pr
H Cbz H Cbz
• Note: MeOH essential in order to prevent β-elimination (cf the Julia Reaction)

PhSO2 • no proton source

Na / NH3
60 % Ph N
Ph
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 α-anion
Na(0), NH3,
EtOH
RO2C RO2C RO2C

Electron-Donating
• destabilises α-anion
Na(0), NH3,
EtOH
MeO MeO MeO

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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 Use in Synthesis

Li, EtOH, MeO R

MeO
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
CO2H • Wittig
CO2tBu
H
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 (g.rowlands@sussex.ac.uk) 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% TiCl 3,
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
4 R3SiCl Cl
• problem is reducing
• replace with strong Si–O bond strong Ti=O bond
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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 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 SmL n
H R R1
R O

OH

Ln
SmL n Sm
O O O

R1 R1
H H
R R

O
• selectivity believed
• all other reductants to result from
failed to give good yield co-ordination to axial
and / or selectivity oxygen
Use in Synthesis
R R
H 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 (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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• stereochemistry Evans-Tishenko-Type Reaction
controlled by • Diastereoselective transfer-hydrogen-like reaction
alcohol only
O
OH O
R1CHO, cat. SmI2, THF R1 O OH
R 85-95 %
• stereochemistry R
independant of
other substituents O
OH O
R1CHO, cat. SmI2, THF R1 O OH
R
R

Transition state
• chelation of the two oxygens
results in diastereoselectivity
O
H R1

O O
Sm
• selective reduction
of ketone only Carbonyl Reduction
• SmI2 can reduce carbonyl group by direct electron-transfer
• thermodynamic product
O HO
2 SmI 2, THF / H2O
H 97 %, 86 % d.e. H
OTBS OTBS
H H
CO2Me CO2Me

Mechanism

Sm(III)L n Sm(III)L n
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 SmI 2, THF
81 %, 92 % d.e. OH
TBSO
TBSO CHO
OH

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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 Reductive Radical Couplings
• The ketyl radical produced can also be used in other radical couplings

O LnSm
O LnSmO
SmI2, THF / HMPA, CO2Me CO2Me
0˚C 1 min.
89 %

O O OMe
SmL n
• lactonisation
O O

• Radical cascades are also possible

LnSmO
CHO
SmI2, THF /
O O
HMPA, 0˚C
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 (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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 Halides
Br 2.5 SmI 2, 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 SmI 2, 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

O2 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 (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
78
 Anionic–Radical

TMS TMS • ketyl radical

TMS
addition
SmI2, THF /
O TBSO OH
TBSO HMPA
CO2Et
81 % TBSO
Br

• nucleophilic addition

Anionic–Anionic

I OH OH

O SmI2
O OH
O
Cl
Cl

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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