Group Meeting12/7/2005

Narendra Ambhaikar Electrochemistry in Organic Synthesis

BrH

N

R2

COR1

N

COR1

CO2H

R2CO2H

R2=CH3, C5H11, (CH2)4CO2CH3

+

R1=H, CH3

NR

O

NR

O

anodic oxid.MeOH

!e!, !H+ +NuH, !H+N

R

O

NR

O

Nu

i) Kolbe and non-Kolbe oxidations of carboxylic acids

ii) Oxidation of amides

HNO

O

CH2Cl

C anodeconst. currentMeOH

HNO

O

CH2ClMeO

"-methoxy amide

NO

O

CH2Cl

HO

HO H

3 steps

NNH

N

O

Me N NC anodeEt4NOTsMeOH

(100%)

NNH

N

O

Me N N

OMe

s-BuLithen O2

(10-35%)

NNH

N

O

Me N NH

O

NNH

N

O

Me N NH

OOMe

C anodeNaOMeMeOH

(97%)

iv) Anodic oxidation of thioethers

N

SPh

Ph

O

N

SPh

Ph

OF

Pt anodeEt4NF.3HFMeCN

(70%)

N

N

S CO2Et

F

N

N

S CO2Et

Pt anodeEt4NF•3HFDME

(78%)

v) Introduction of F into biologically active molecules

OR

HO

OR

O

( )n

( )n

vi) Oxidation of alcohols and ethers

sproketal

Pt anodeLiBF4

NaOEt / EtOH

NH

HMe CO2H

O

!e!, Pt anodeNaOAc,MeOH/AcOH(84%)

NH

HMe OAc

ONH

CO2H

NCbz

CO2Me

MeO

protectionthen

-2e-,MeOHCu( )3

BF3•OEt2(80%)

NCbz

CO2Me

iii) Functionalization of proline

Celimene, C.; Dhimane, H.; La Bail, M.; Lhommet, G. Tetrahedron Lett. 1994, 35, 6105-6106.

(69%, 3 steps)

N

Me

H

n-Bu

ANODIC OXIDATIONS

Danielmeier, K.; Schierle, K.; Steckhan, E. Tetrahedron 1996, 52, 9743-9754.

!e!

(45-67%)

Becking, L.; Schafer, H. J. Tetrahedron Lett. 1988, 29, 2797-2800.

Mori, M.; Kagechika, K.; Sasai, H.; Shibasaki, M Tetrahedron 1991, 47, 5315-5340.

N

Me

O

H

S

CO2H

NHAc

(+)-PS-5 (antibiotic)

( )3

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.

Shono, T. Tetrahedron 1984, 40, 811-850.

Synthesis of O-alkyl, N-acyl hemiaminals

Electrochemical oxygenation versus anionic oxygenation

'' 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

pymetrozine O-alkyl, N-acyl hemiaminal

SO

O

R

SO

O

R

F(66-80%)

Pt anodeEt4NF•3HFDME

Hou, Y.; Higashiya, S.; Fuchigami, T. J. Org. Chem. 1997, 62, 8773-8776.

Dawood, K. M.; Higashiya, S.; Hou, Y.; Fuchigami, T. J. Org. Chem. 1999, 64, 7935-7939.

Higashiya, S.; Narizuka, S.; Konno, S.; Maeda, T.; Momota, K.; Fuchigami, T. J. Org. Chem. 1999,64, 133-137.

Marko, I. E. Tetrahedron Lett. 2000, 41, 4383-4387.

Group Meeting12/7/2005

Narendra Ambhaikar Electrochemistry in Organic Synthesis

BrH

O

Me

Me

Me

OTBS

OTBS

TBDPSO

Me

O

TBDPSO

Me

O

Me

HOTBS

Me

Me

RVC anode (0.2 mA)2,6-lutidine, LiClO420% MeOH/CH2Cl22.44 F/mol(70%)

O

R1

O

Br

TMSO

R1

O OO

R1

R2

Mg, CuITMSCl

C anode, LiClO4

i-PrOH/MeCN2,6-lutidineconst. current

+

Sythesis of [6-7-5] guanacastepene core (Trauner, 2005)

Total synthesis of (±)-alliacol A (Moeller, 2003)

Me

O OH

O

Me

Me

O

Alliacol A

Me

O

TBSO

MeMe

TBSO

Me

O

Me

Me

TBSO

O

MeO

HRVC anodecarbon cathode0.4 M LiClO4

MeOH/CH2Cl2 (1:4)2,6-lutidine, RT15-20 mA, 2.2 F/mole

TsOH, RT(88%)

Me

O

Me

Me

HO

O HMe

O

Me

Me

O

MeO

H a) I2, PPh3, Im

DCM/Tol, 85 oC (87%)

b) AgNO3

THF/MeOH, RT (92%)

Nuc-H

X

( )nNuc-H

X

( )nNuc

X

( )n

Nuc

X

( )n Y

[O]

+ solvent (YH)

!H+!H+[O]

Intramolecular anodic olefin coupling reactions

These reactions reverse the polarity of the electron rich olefin to be oxidized, transforming it into an electrophile

(70%)O

TBDPSO

Me

O

Me

HOTBS

Me

Me

MeO

H

HCl, H2O, THF (85%)

O

MeO

MeO

OMe

NMe

OMe

MeO

MeO

OMe

NMe

OMe

MeO

MeO

OMe

NMe

OMe

MeO

MeO

OMe

NMe

H- e-

H2O

Electrooxidative cyclization of (±)-Laudanosine (Miller, 1971)

1.1 VLiClO4

Na2CO3

(52%)

-e-

- ROH

- 2H+

ANODIC OXIDATIONS

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.

Hughes, C. C.; Miller, A. K.; Trauner, D. Org. Lett. 2005, 7, 3425-3428.Whitehead, C. R.; Sessions, E. H.; Ghiviriga, I.; Wright. D. L. Org. Lett. 2002, 4, 3763-3765.

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.

O

MeMe

TBSO

P(OEt)2

O

O

O

+

i) NaH (92%)

ii) Me2Cu(CN)Li2 TBSCl, (91%)

( )n( )n( )n

n = 1 R1 = H, R2 = Me (64%)n = 1 R1 = Me, R2 = H (78%)n = 1 R1 = H, R2 = Me (64%)n = 2 R1 = Me, R2 = H (76%)n = 2 R1 = H, R2 = Me (65%)

R2 R2

OO

R1

R2

( )n

Two-step annulation for assembly of polycyclic systems

1N HCl Oi-Pr

H

BrH

Group Meeting12/7/2005

Narendra Ambhaikar Electrochemistry in Organic Synthesis

BrH

I OMe

O

+

Pd(OAc)2n-Bu4NBr

DMF/H2O/Et3N

RT, 3.5 hOMe

O

(82%)

Electrochemical Heck Reaction

- Requires no ligand and no high temperatures

Trapping of N-centered radicals and radical cations

NH Ph

MeR

i) n-BuLi, THFii) Pt anode, THF, HMPA0.25 M LiClO4

1.2 F/mole, !10oCNMeR

Ph

(66-85%)R = H, Me, Ph

Anodic oxidation of NO3-: Nitrate radical formation

R2

R1

R3

Pt anodeLiNO3

CH3CN/H2O/Et2ON O

R2

R1

R3

Me

(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+

Oxidation of ethers using an 'Electroauxiliary'

Y EA!e!

Y EA- EA+

!e!Y -EA

+

Nu Y Nu

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 over-oxidation of the product.

Electrochemical Nozaki-Hiyama-Kishi coupling

Catalytic amounts of chromium (7%) and nickel (3%) are generated from a pre-electrolysis of a stainless steel rod make it environmentally friendly.

OX

FGA

OH

A FG+

3% bipy, DMFe-, Fe/Cr/Ni anode(50-80%)

A = H, CF3, CO2Me, CNX = Cl, Br, FG = electron donating or withdrawing

O

EA

C7H15

C anode

Bu4NBF4

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

SnBu3

R

Y

R

Y = O, R = H (55%)

Y = O, R = F (80%)

Y = NCO2Me, R = H (54%)

electrolysisBu4NClO4

A

Br

A = F, CF3, MeO, CN, Me,COMe

R = H, Me

Cl CO2Me

R

+ ACO2Me

RNi cathodeZn/Al anodeBu4NBF4NiBr2Bipy

(51-85%)

Durandetti, M.; Nedelec, J.-Y.; Perichon, J. J. Org. Chem. 1996, 61, 1748-1755.

Durandetti, M. I.; Nedelec, J.-Y.; Perichon, J. Org. Lett. 2001, 3, 2073-2076.

Tian, J.; Moeller, K. D. Org. Lett. 2005, 7, 5381-5383.

Electrochemical Ni catalyzed coupling between aryl halides and "-chloroestersTokuda, M.; Fujita, H.; Miyato, T.; Suginome, H. Tetrahedron 1993, 49, 2413-2426.

Shono, T.; Chuankamnerkarn, M.; Kaekawa, G.; Ishifune, M.; Kashimura, S. Synthesis 1994, 895-897.

Yoshida, J.; Maekawa, T.; Murata, T.; Matsunaga, S.; Isoe, S. J. Am. Chem. Soc. 1990, 112, 1962-1970. Yoshida, J.; Ishichi, Y.; Isoe, S. J. Am. Chem. Soc. 1992, 114, 7594-7595.

Electrochemistry in organometallic reactions

Group Meeting12/7/2005

Narendra Ambhaikar Electrochemistry in Organic Synthesis

BrH

Electrochemical Reductions

O

Me

e-, Sn/C, i-PrOH, Et4NOTs4 F/mol (70%)

OHMe

Br CO2Me

CO2Me-1.85 V, DMF, n-Bu4NBr(65-80%)

CH(CO2Me)2

+2e-, CH2(CO2Me)2n-Bu4NBr, MeCN (89%)

quadrone

CHO

EWG

+e-CHO

EWG

cyclization

EWG

O

H

EWG

O

+e-

EWG

O

H

EWG

OH

overall transformation

Me

H

Me

Me

H

1-sterpurene

Total synthesis of 1-sterpurene (Little, 1986)

Me

Me

HMe

OH

[2+2]Me

H

Me

Me

H

OH

CO2Me

CO2Mee-, Cu electrode CH2(CO2Et)20.9 M Et4NOTsMeCN/H2O CO2Me

CO2Me Na, TMSCl (4.9 eq)PhMe, !

Me

Me

H

HOH

O

58% (11.6:1 trans:cis)

Me

Me

H

H

O

i) MsCl, Et3Nii) LiBr, Li2CO3

(58%)

(75%)

i) MeLiii) PCC (2 eq)

(71%)

Me

Me

HMe

OH

H2C CH2

Me

H

Me

Me

H

OH

Me

i) MeLiii) SOCl2, Py

(60%)

Me

H

Me

Me

H

1-sterpurene

Me

H

Yield and selectivity of the electroreductive cyclization increased

in the presence of CeCl3 (73%, 14.8:1).

h"

Moens, L.; Baizer, M.; Little, D. J. Org. Chem. 1986, 51, 4497-4498.

Formal total synthesis of quadrone (Little, 1990)

OO

Me Me

O

O

CO2Me

Me Me

HO

CO2Me

MeMe

i) LAH (95%)

ii) TBDPSCl (96%)

iii) PCC (100%)

iii) (EtO)2POCH2CN (76%)

MeMe

NC

OTBDPS

MeMe

NC

OTBDPS

H

O

i) 9-BBNii) PCC

(85%)

+2e-, CH2(CO2Me)2n-Bu4NBr, MeCN (90%)

MeMe

NC

OTBDPS

Me Me

HO

OH

CN

OTBDPS

Me Me

OO

quadrone

Sowell, G. C.; Wolin, R. L.; Little, R. D. Tetrahedron Lett. 1990, 31, 458-485. Group Seminar by Carlos Guerrero on 'Quadrone'

Little, R. D. Chem. Rev. 1996, 96, 93-114.Kende's intermediate