O
ANODIC OXIDATIONS
i) Kolbe and non-Kolbe oxidations of carboxylic acids
Me
R2
CO2H
!e!
N
N
R2=CH3, C5H11,
COR1
(45-67%)
(CH2)4CO2CH3
COR1
R1=H, CH3
Becking, L.; Schafer, H. J. Tetrahedron Lett. 1988, 29, 2797-2800.
H
Me
CO2H
NH
O
H
Me
OAc
H
Me
NH
O
S
N
O
NHAc
CO2H
O
R
O
!e!, !H+
N
R
N
H
(69%, 3 steps)
O
R
+NuH, !H+
N
C anode
const. current
MeOH
N
HN
O
3 steps
O
N
HO
CH2Cl
HO
H
CH2Cl
N
H
O
pymetrozine
N
Cbz
CO2Me
N
Me
n-Bu
SPh
F
O
N
(70%)
Ph
C anode
Et4NOTs
MeOH
(100%)
s-BuLi
then O2
N
N
N
H
S
R
N
O
O
(66-80%)
Butora, G.; Reed, J. W.; Hudlicky, T.; Brammer, L. E. Jr.; Higgs, P. I.; Simmons, D. P.; Heard, N. E.
J. Am. Chem. Soc. 1997, 119, 7694-7701.
S
F
O
O
Higashiya, S.; Narizuka, S.; Konno, S.; Maeda, T.; Momota, K.; Fuchigami, T. J. Org. Chem. 1999,
64, 133-137.
vi) Oxidation of alcohols and ethers
HO
O-alkyl, N-acyl hemiaminal
(10-35%)
F
R
Pt anode
Et4NF•3HF
DME
O
N
N
CO2Et
S
OMe
Me
Pt anode
Et4NF•3HF
DME
N
S
CO2Et
(78%)
Dawood, K. M.; Higashiya, S.; Hou, Y.; Fuchigami, T. J. Org. Chem. 1999, 64, 7935-7939.
N
Electrochemical oxygenation versus anionic oxygenation
N
Ph
N
Danielmeier, K.; Schierle, K.; Steckhan, E. Tetrahedron 1996, 52, 9743-9754.
N
( )3
BF3•OEt2
(80%)
v) Introduction of F into biologically active molecules
O
"-methoxy amide
N
N
Cbz
Hou, Y.; Higashiya, S.; Fuchigami, T. J. Org. Chem. 1997, 62, 8773-8776.
O
MeO
CH2Cl
N
O
( )3 Cu
CO2Me
Pt anode
Et4NF.3HF
MeCN
SPh
N
Synthesis of O-alkyl, N-acyl hemiaminals
Me
MeO
O
Shono, T. Tetrahedron 1984, 40, 811-850.
O
N
H
NH
H
protection
then
CO2H -2e-,MeOH
Nu
HN
N
(97%)
N
iv) Anodic oxidation of thioethers
O
O
N
Celimene, C.; Dhimane, H.; La Bail, M.; Lhommet, G. Tetrahedron Lett. 1994, 35, 6105-6106.
ii) Oxidation of amides
N
O
Me
iii) Functionalization of proline
!e!, Pt anode
NaOAc,
MeOH/AcOH
(84%)
anodic oxid.
MeOH
N
H
NH
O
OMe
C anode
NaOMe
MeOH
'' The anionic oxygenation protocol was abandoned for safety considerations and the
general unpredictability of hazards, as well as complexity of the reaction mixtures'' Hudlicky and coworkers
(+)-PS-5 (antibiotic)
Mori, M.; Kagechika, K.; Sasai, H.; Shibasaki, M Tetrahedron 1991, 47, 5315-5340.
R
N
N
N
R2CO2H
+
Group Meeting
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Electrochemistry in Organic Synthesis
Narendra Ambhaikar
R
O
( )n
Pt anode
LiBF4
NaOEt / EtOH
Marko, I. E. Tetrahedron Lett. 2000, 41, 4383-4387.
O
R
O
( )n
sproketal
B
r
H
Group Meeting
12/7/2005
Electrochemistry in Organic Synthesis
Narendra Ambhaikar
ANODIC OXIDATIONS
Total synthesis of (±)-alliacol A (Moeller, 2003)
Electrooxidative cyclization of (±)-Laudanosine (Miller, 1971)
OMe
O
OMe
MeO
Me
Me
MeO
1.1 V
LiClO4
Na2CO3
TBSO
(52%)
NMe
O
i) NaH (92%)
P(OEt)2 ii) Me Cu(CN)Li
2
2
TBSCl, (91%)
+ O
Me
Me
O
RVC anode
carbon cathode
0.4 M LiClO4
MeO
O
TBSO
MeO
TsOH, RT
(88%)
O
OMe
OMe
MeO
Me
NMe
MeO
OMe
H
Me
Me
MeOH/CH2Cl2 (1:4)
2,6-lutidine, RT
15-20 mA, 2.2 F/mole
O
TBSO
O
Me
TBSO
MeO
-e-
H2O
- e-
- ROH
H
- 2H+
NMe
Me
O
OMe
H
Me
Me
O
MeO
OMe
Me
Me
NMe
MeO
O
Me
O
OH
a) I2, PPh3, Im
DCM/Tol, 85 oC (87%)
b) AgNO3
THF/MeOH, RT (92%)
O
H
Me
Me
Me
O
HO
MeO
O
Alliacol A
Miller, L.; Stermitz, F. R.; Falck, J. R. J. Am. Chem. Soc. 1971, 93, 5941-5942.
Miller, L. L.; Stermitz, F. R.; Falck, J. R. J. Am. Chem. Soc. 1973, 95, 2651-2656.
Mihelcic, J.; Moeller, K. J. Am. Chem. Soc. 2003, 125, 36-37.
Asymmetric synthesis: Mihelcic, J.;Moeller J. Am. Chem. Soc. 2004, 126, 9106-9111.
Intramolecular anodic olefin coupling reactions
These reactions reverse the polarity of the electron rich olefin to be oxidized, transforming it into an electrophile
X
X
X
[O]
( )n
!H+
( )n
( )n
Nuc
Nuc-H
Nuc-H
[O]
+ solvent (YH)
!H+
Sythesis of [6-7-5] guanacastepene core (Trauner, 2005)
X
Y
( )n
Me
Me
Me
Nuc
Two-step annulation for assembly of polycyclic systems
R1
( )n
Mg, CuI
TMSCl
Br
+
R2
O
O
R1
( )n
TMSO
R2
O
C anode, LiClO4
i-PrOH/MeCN
2,6-lutidine
const. current
O
( )n
R1 = H, R2 = Me
R1 = Me, R2 = H
R1 = H, R2 = Me
R1 = Me, R2 = H
R1 = H, R2 = Me
(64%)
(78%)
(64%)
(76%)
(65%)
OTBS
RVC anode (0.2 mA)
2,6-lutidine, LiClO4
20% MeOH/CH2Cl2
2.44 F/mol
(70%)
Me
Me
Me
O
H
MeO
HCl, H2O, THF
Oi-Pr
O
Me
Me
Me
Whitehead, C. R.; Sessions, E. H.; Ghiviriga, I.; Wright. D. L. Org. Lett. 2002, 4, 3763-3765.
TBDPSO
R2
O
O
Hughes, C. C.; Miller, A. K.; Trauner, D. Org. Lett. 2005, 7, 3425-3428.
OTBS
O
(85%)
R1
( )n
Me
H
TBDPSO
(70%)
O R2H
O
1N HCl
n=1
n=1
n=1
n=2
n=2
OTBS
TBDPSO
R1
Me
H
Me
OTBS
O
Br
H
Oxidation of ethers using an 'Electroauxiliary'
Y
!e!
EA
Y
EA
Group Meeting
12/7/2005
Electrochemistry in Organic Synthesis
Narendra Ambhaikar
Electrochemistry in organometallic reactions
+
- EA+
Y
!
!e
Nu
-EA
Y
Nu
Electrochemical Heck Reaction
I
Y = heteroatom, EA = electroauxiliary, a group that is attached to a substrate to
reduce its oxidation potential. Enables oxidation of the substrate. It also avoids overoxidation of the product.
OMe
+
O
Pd(OAc)2
n-Bu4NBr
DMF/H2O/Et3N
RT, 3.5 h
O
OMe
(82%)
EA
C anode
Bu4NBF4
O
C7H15
SnBu3
electrolysis
Bu4NClO4
Y
O
C7H15
F
EA = TMS (68%, cis/trans 55:45)
EA = SnBu3 (83%, cis/trans 74:26)
EA = SMe (64%, cis/trans 87:13)
Y = O, R = H (55%)
Y = O, R = F (80%)
Y = NCO2Me, R = H (54%)
Y
R
R
Yoshida, J.; Maekawa, T.; Murata, T.; Matsunaga, S.; Isoe, S. J. Am. Chem. Soc. 1990, 112, 19621970. Yoshida, J.; Ishichi, Y.; Isoe, S. J. Am. Chem. Soc. 1992, 114, 7594-7595.
i) n-BuLi, THF
ii) Pt anode, THF, HMPA
0.25 M LiClO4
1.2 F/mole, !10oC
Ph
NH
Me
Tian, J.; Moeller, K. D. Org. Lett. 2005, 7, 5381-5383.
Electrochemical Nozaki-Hiyama-Kishi coupling
O
Ph
N
Me
R
R = H, Me, Ph
FG
+
A
OH
3% bipy, DMF
e-, Fe/Cr/Ni anode
(50-80%)
A
Durandetti, M. I.; Nedelec, J.-Y.; Perichon, J. Org. Lett. 2001, 3, 2073-2076.
Electrochemical Ni catalyzed coupling between aryl halides and "-chloroesters
Anodic oxidation of NO3-: Nitrate radical formation
R1
R3
Pt anode
LiNO3
CH3CN/H2O/Et2O
FG
Catalytic amounts of chromium (7%) and nickel (3%) are generated from a preelectrolysis of a stainless steel rod make it environmentally friendly.
(66-85%)
Tokuda, M.; Fujita, H.; Miyato, T.; Suginome, H. Tetrahedron 1993, 49, 2413-2426.
R2
X
A = H, CF3, CO2Me, CN
X = Cl, Br, FG = electron donating or withdrawing
Trapping of N-centered radicals and radical cations
R
- Requires no ligand and no high temperatures
R
Br
R2
R3
R1
N
O
Me
A
+
Cl
CO2Me
A = F, CF3, MeO, CN, Me,COMe
R = H, Me
Ni cathode
Zn/Al anode
Bu4NBF4
NiBr2Bipy
R
A
CO2Me
(51-85%)
(69-77%)
Generation of NO3•, then its addition to olefin to form the most substituted radical, then further
oxidation to carbocation and finally trapping by MeCN to form oxazole after loss of NO2+
Shono, T.; Chuankamnerkarn, M.; Kaekawa, G.; Ishifune, M.; Kashimura, S. Synthesis 1994, 895-897.
Durandetti, M.; Nedelec, J.-Y.; Perichon, J. J. Org. Chem. 1996, 61, 1748-1755.
BrH
B
r
H
NC
Electrochemical Reductions
NC
OTBDPS i) 9-BBN
ii) PCC
O
+e-
CHO
Group Meeting
12/7/2005
Electrochemistry in Organic Synthesis
Narendra Ambhaikar
CHO
EWG
H
EWG
EWG
Me
(85%) Me
Me
OTBDPS +2e , CH2(CO2Me)2
n-Bu4NBr, MeCN
(90%)
O
Me
+e
O
O
cyclization
H
-1.85 V, DMF,
n-Bu4NBr
(65-80%)
CO2Me
Br
CO2Me
OTBDPS
Total synthesis of 1-sterpurene (Little, 1986)
H
Me
Me
CH(CO2Me)2
Formal total synthesis of quadrone (Little, 1990)
Me
H
Me
Me
H
Me
1-sterpurene
e-, Cu electrode
CH2(CO2Et)2
0.9 M Et4NOTs
MeCN/H2O
CO2Me
O
Me
H
O
[2+2]
CO2Me
CO2Me
H
58% (11.6:1 trans:cis)
H
+2e-, CH2(CO2Me)2
n-Bu4NBr, MeCN
(89%)
Me Me
Me
H
O
H
Na, TMSCl
(4.9 eq)
PhMe, !
Me
Me
(58%)
H
O
OH
i) MsCl, Et3N
(75%)
ii) LiBr, Li2CO3
Me Me
quadrone
O
H
Me
Me
H
O
CO2Me
Me
Me OH
CO2Me
O
CN
Me
Me Me
Kende's intermediate
e-, Sn/C, i-PrOH,
Et4NOTs
4 F/mol (70%)
Me
HO
quadrone
Little, R. D. Chem. Rev. 1996, 96, 93-114.
O
O
EWG
EWG
EWG
Me
-
O
OH
OH
OTBDPS
Me
H
overall
transformation
NC
Me
Me
HO
Me
Me
i) LAH (95%)
CO2Me ii) TBDPSCl (96%)
H
h"
H
O
H2C CH2
H
Me
Me
Me
H
i) MeLi
ii) PCC (2 eq)
(71%)
O
H
Me
Me
H
i) MeLi
(60%)
ii) SOCl2, Py
iii) PCC (100%)
iii) (EtO)2POCH2CN (76%)
H
Me
Me
Sowell, G. C.; Wolin, R. L.; Little, R. D. Tetrahedron Lett. 1990, 31, 458-485.
Group Seminar by Carlos Guerrero on 'Quadrone'
Me
Me
Yield and selectivity of the electroreductive cyclization increased
in the presence of CeCl3 (73%, 14.8:1).
H
Me
1-sterpurene
Moens, L.; Baizer, M.; Little, D. J. Org. Chem. 1986, 51, 4497-4498.
Br
H
O