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OC 2 (FS 2013) Lecture 3 Prof. Bode
1
Redox Neutral Reactions and Rearrangements
1 Types of “Redox Neutral Organic Reactions” 1.1 Reactions with
no external reducing or oxidizing agent
In this case, one part of the starting material is oxidized
while the other is being reduced.
1.2 “Redox Disproportionation”
In this case, one starting material is oxidized while the other
starting material is being reduced.
2 Cannizzaro Reaction
3 Tishchenko Reaction
4 Meerwein-Ponndorf-Verley/Oppenauer
Meerwein-Ponndorf-Verley Reduction is the reverse reaction of
Oppenauer Oxidation
HOredox neutral
red.[O]O
OH
Me HO
H
redox neutral red.O
H O
Me[O]
H
O
aq. NaOH
Mechanism
Ar H
OOH
red.[O]
H
OH
H2 equivalent
O
OH
Ar H
O
O
(excess)
ArH
O
O
OH H2OAr
H
O
Ar
O
OH Ar OH2H
fromH2O
H
H
O
Al(OiPr)3O
O
Mechanism
Ar H
O Al(OiPr)3
H H red.
[O]
Ar H
OAl(OiPr)3
Ar
O
H
Ar
H
OAl(OiPr)3
Ar
O
H
Ar
O
O Ar
H
OAl(OiPr)3
Mechanism
R1 H
O Al(OiPr)3
red.[O]
R1
OAl
R2
OH R2
OOH
R1
OH
Me MeH
isopropanol
H
OHO
Me MeH
acetone
iPrO OiPr
R2R2
transferhydrogenation
then work-up
H+ work-up
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OC 2 (FS 2013) Lecture 3 Prof. Bode
2
5 NHC-Catalyzed Reactions Unlike other carbene or carbenoid
species which are high-energy intermediates, N-heterocyclic carbene
is a stable singlet carbene. The lone pairs of the heteroatoms
adjacent to the carbene carbon donate electron into the empty
p-orbital of the carbene carbon. Additionally, the N-substitution
provides kinetic stability.
5.1.1 Benzoin Reactions 5.1.1.1 Before there was an NHC
Cyanide ion catalyzed benzoin condensation
For mechanism: Lapworth, J. Chem. Soc., Trans. 1903, 83, 995
& 1904, 85, 1206
5.1.1.2 The thiamine variant:
In the benzoin reaction (and many other NHC-catalyzed
reactions), the aldehyde carbon undergoes a reversal in polarity
from an electrophilic center to being a nucleophilic center. This
concept is termed “umpolung” (Seebach ACIE 1979, 18, 239).
General Structures of nucleophilic carbenes
S N R'
thiazolylidene
N NR R'
imidazolylidene
NN NR R'
triazolylidene
XY N R
XY N R
H
XY N R
Base
carbene ylide
Ph H
O CN K
Ph CN
O
HPh CN
OHPh H
O
Ph CN
O
O
Ph
Ph CN
O
OH
Ph
Ph
O
OH
Ph
The benzoin condensation was the first organic reaction with its
mechanism fully elucidated.
CN
then H+
H
protontransfer
CN
OH
H2NN S
H3CNH3C
N base
HCl
thiamine
OH
R N S
H3C
HO
RN
S
H3C
ylide
carbene
OPh
HOH
R N S
H3C
PhO
H
OH
R N S
H3C
Ph OH
OH
R N S
H3C
PhHO
O
Ph
OH
R N S
H3C
PhOOH
Ph
PhPh
O
OH
OPh
H
R2 N S
R3R1
HCl
A general struture of thiazolium salt precatalyst
for benzoin reaction(R = alkyl or aryl)
Breslow intermediate
NHC-aldehydeadduct
base
base(protontransfer)
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OC 2 (FS 2013) Lecture 3 Prof. Bode
3
5.1.2 Stetter Reactions
The research program of Prof. Tom Rovis (Colorado State
University) has established the current state of the art for
Stetter reactions, especially the intramolecular variant:
5.1.3 Other NHC-Catalyzed Annulations γ-lactone synthesis via
homoenolate addition
Bode JACS 2004, 126, 8126 & Glorius ACIE 2004, 43, 6205
5.1.4 Internal Redox Reactions - Epoxy aldehyde
Bode JACS, 2004, 126, 8126
Ph
O
H
Ph
OH
N
S
R1
R3
R2
Ph
OH
N
S
R1R2
R3
OPh
Ar
O
PhAr
O
Ph
N
S
R1R3
R2
S
N
Me
Me
HO
O
PhAr
SN Me
Me
HO
Ph
O
Ph
OAr
- NHC
1,4-addition
O
O CO2Et20 mol% cat
20 mol% base
xylenes, 25 oC, 24 h O
O CO2Et
N N
N
OMe
O BF4-
R1 H
O
H
O
R2
+
base (7 mol %)THF/t-BuOH
RT
O
R2
R1
ON N MesMesCl
(8 mol %)
R1 H
O
R1
O
N
N
Mes
Mes
H
R1
OH
N
N
Mes
Mes
R1
OH
N
N
Mes
Mes
homoenolate
H
O
R2
R1
OH
N
N
Mes
Mes
R2 O
activated carboxylate
R1
O
N
N
Mes
Mes
R2 O
N
N Mes
Mes
OR2
R1
O
Mechanism
enolate
base(proton
transfer)
base(proton
transfer)
R1
R2
OO
H R3OH R1
R2
O
OR3
OH
10 mol % NHC
8 mol % base
+
S
N
Bn
Me
Me
Cl–
redox-neutral
oxidized
reduced
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OC 2 (FS 2013) Lecture 3 Prof. Bode
4
- Mechanism:
- An application to natural product synthesis:
Vosburg OL, 2009, 11, 2217
- Redox esterification from α-bromoaldehyde was concurrently
reported:
Rovis, JACS, 2004, 126, 9518
6 Other nucleophilic catalysis 6.1.1 Baylis-Hillman reaction
O
R1HO
S
N
Bn
Me
Me
OH
R1O
S
N
Bn
Me
Me
S
NBn
Me
Me
R2
R2
O
R1
O
S
N
Bn
Me
Me
R2
H
O
R1
HO
S
N
Bn
Me
Me
O
R1
OH
S
N
Bn
Me
Me
R2
R2
O
R1
OH
OR3
R2
O
R1O
H
R2
S
N
Bn
Me
Me
H
base
R3O
base(protontransfer)
base(protontransfer)
H
R3O
HAcO
Me
O
Me
O S N Bn
MeMe
baseEtOH
OEtAcO
Me
OH
Me
OO
Me H O
Me
MeMe
83% (+)-davanone
Cl
R1H
O
Br
R3OH(20 mol %) R1
OR3
O
R2R2
NN N Ph
BF4
Et3N (1 eq)
55−91%
OMe
OO
Ph H OMe
OOH
Ph
NN
DABCO
Mechanism
X
O
NR3
X
O
NR3
O
R'HX
O
NR3
R'
OH
NR3
X
O
R
ONR3
H NR3 X
O
R'
OHNR3
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OC 2 (FS 2013) Lecture 3 Prof. Bode
5
6.1.2 Rauhut-Currier reaction
6.1.3 Others
PPh3 catalyzed cycloaddition of N-Tosyl-substituted imines with
allenes
7 Alkyne and Alkene Hydration
7.1 Alkyne Hydration
- Mercuric ion-catalyzed hydration of alkynes goes with
Markovnikov orientation. - The Hg2+ salt acts as a catalyst to
accelerate the rate of reaction; the nucleophile (e.g. H2O) will
attack the most stabilized carbocation it formed.
7.2 Alkene Hydration
The orientation of hydration to alkenes with aqueous acid is
followed by Markovnikov's rule
O
EtO OEt
O 1 equiv Bu3P
MeCN, 40 oC, 3 hr EtO
O
OEt
O
Mechanism
R
O
PR3
R
O
PR3
O
RR
O
PR3
R
OH PR3
H
R
O
R
OH
R
O
R
Oketo-enoltautomerism
•COOMe
NTs
PPh3
benzener.t.
N
COOMe
Ts
Mechanism
398%
PPh3COOMe
TsN Ph
COOMePPh3
N
Ph3P COOMe
Ts
Ph
N
Ph3P COOMe
Ts
Ph
PPh3
1 2
1
2
3
R HH2O, H2SO4Hg(OAc)2 R
OH
enol tautomer
R
O
keto tautomerMarkovnikov product
R2R1Hg2+
R2
Hg+
HOH
R1
O R2
Hg+
HH
HOH
R1
O R2
Hg+
H H3O+
+ H3O+R1
O R2
H
Hketo-enol
tautomerism O
R1R2
Mechanism
+ Hg2+, H2Ocarbocation oxonium ion Markovnikovproduct
R1
Me H3PO4H2O, 250 oC
(Markovnikov product)
MeOH
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OC 2 (FS 2013) Lecture 3 Prof. Bode
6
8 Nef Reaction
9 Rearrangements 9.1 Pinacol Rearrangements 9.1.1 Pinacol to
pinacolone
- The group that stabilizes a positive charge better migrates
first.
9.1.2 Stereospecific pinacol rearrangements
9.1.3 Synthesis of enantiopure quaternary carbons
Semipinacol rearrangement of 2,3-aziridino alcohols
Mechanism
R2
R1
R3
OH HH
R1R2 H
HR3
+
HOH
R2 H
HR3
OR1
HH
HOH
R2 H
HR3R1
HO
- H2O - H3O+
H
Me
NONa
O H2SO4
H2O
Me
OH
Mechanism
R2
R1
NO
OR2
R1
NHO
OR2
R1
NHO
OHR2
R1
NHO
OHHOH R1 R2
OH2N2O2 N2O
O
HH
+ H+ + H+ P.T. + H+
-H2O -H2O
HO OH
Me MeMe Me
pinacol
aq. H2SO4- H2O
O
Me
Me
MeMe
HO OH
R2 R3R1 R4
Mechanism
pnacolone
H HO OH
R2 R3R1 R4
H- H2O HO
R2R1
R4
R3
[1,2]-alkyl shiftR1
OH
R4
R2R3
- HR1
OR4
R2R3
H3C Ph
O
S
H3C Ph
OH
OHS
MsCl, Et3N
CH2Cl20 oC, 10 min
H3C Ph
OH
MsOS
Et3Al
CH2Cl2-78 oC, 10 min
93%99% e.e.
OHNTs
Et MeZnBr2
CH2Cl2, r.t.
Me O
Et
NHTs
NTs
R1
OHR2
Lewis acidN
R1
OHR2
TsLA
R2
OH
NTs
LA
R1
–
- LA
O
R2
NHTs
R1
Mechanism
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OC 2 (FS 2013) Lecture 3 Prof. Bode
7
9.2 Benzil rearrangement
9.3 Favorskii rearrangement
9.4 Payne rearrangement
O
O
KOH
H2O, MeOH, heat
OH
R
OR
O
benzil
OHR
OO
ROH R
O
R
O
OK HCl OH
O
OH
R
HO
ROH
O
O
OH3O+
R
HO
ROH
O
Mechanism
- H2O
OCl NaOH
O OH
OHXR1R2
R1XR2
O
R1O
R2 R1R2O OR
R1
R2
OH
OBase
HOR H
protontransfer
Mechanism
- X–
O
CH3
H CH3O
H3C
H H
OHH3C CH3
H3COH
0.5 N NaOH
O
R2
R1H
OO
R2
R1H
O O
R2
R1 OH OH
R2
R1 OBase 3-exo-tet
- HBase
+ HBase
- Base
Mechanism
R1 O
OHR2
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OC 2 (FS 2013) Lecture 3 Prof. Bode
8
10 Advanced Topic (Optional)
10.1 Ir catalyzed redox neutral C-C bond coupling
More information: Krische Org. Process Res. Dev., 2011, 15,
1236
10.2 Chemoselective Keto-Acid-Hydroxyl-Amine Ligation
Bode ACIE 2006, 45, 1248
10.3 Gold-catalyzed cycloisomerization of bis-homopropargylic
diols under a mild condition
Michelet & Genêt JACS 2005, 127, 9976
OAc OH
R
IrO
O
NO2
PPh2
Ph2P
2.5 to 5%
Cs2CO3; m-NO2BzOHTHF; 110oC
OH
R
[Ir3+]
OH
R
[O]
O
R
[Ir3+]
OH
R
H2N
H2NHN
ONH
OPh
O
O
OHMe
HOHN
NH
O
Me
COOH
O
HN
Ph
OH
O H2N
H2NHN
ONH
OPh
O
HN
MeNH
O
Me
COOH
O
HN
Ph
OH
O+
aq. DMF40 oC
- CO2- H2O
HO
HOPh
H
AuCl (2 mol %)
MeOH, r.t.30 min
O
O
Ph
Me99%
HO
HO R
H
O [Au]H
R
HO
O[Au]–
R
HO
[Au]
H+
H+
O
O
R
Me
Mechanism
