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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
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
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
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 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
O S O
O R O R
e–
S S + R R1
O R1 O R1
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
Electron-Donating
• destabilises α-anion
Na(0), NH3,
EtOH
MeO MeO MeO
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
• 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
Cl Ti Cl
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
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 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
74
• 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
O LnSm
O LnSmO
SmI2, THF / HMPA, CO2Me CO2Me
0˚C 1 min.
89 %
O O OMe
SmL n
• lactonisation
O O
LnSmO
CHO
SmI2, THF /
O O
HMPA, 0˚C
O 91 % O
OH
H
H H
Other Reductions
Conjugated Systems
97 %
Mechanism
R OEt SmI2 R OEt EtOH R OEt
e–
O O O
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
PhSO2
5 SmI2, THF /
DMPU / MeOH Ph N
Ph N Dpp
Dpp 91 %
• nucleophilic addition
Anionic–Anionic
I OH OH
O SmI2
O OH
O
Cl
Cl