complex-induced proximity effect in directed ortho and remote metallation methodologies

February 5 2008Louis-Philippe Beaulieu

Complex-Induced Proximity Effect in Directed Ortho and Remote Metallation

Methodologies

Outline

2

1. Background Information

2. Complex-Induced Proximity Effect: The concept

Effect of Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions

Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations

3. Directed Ortho Metallation: Seminal Work

4. Directed Ortho Metallation: Methodological Aspects

Arylsulfonamide DoM Chemistry

Enantioselective Functionalization of Ferrocenes Via DoM

Background Information

3

Complex-Induced Proximity Effect (CIPE): The Concept

4 Beak, P. et al. J.Am.Chem.Soc. 1986, 19, 356-363

• The CIPE process requires kinetic removal of the β-proton in the presence of an α-proton which is ca. 10 pKa units thermodynamically more acidic

• The organolithium base is delivered with proper geometry to allow overlap between the HOMO of the β-C-H bond being broken and the LUMO of the π* orbital of the double bond

OiPr2N

HMe

H

s-BuLi OiPr2N

HMe

H

(LiBu)n OiPr2N

MeH

Li OiPr2N

MeH

MeMeI

O

iPr2N

H

CH2

MeH

(Li-Bu)n

FG

C H

+ (RLi)n

FG

C H

(LiR)n FG

C

Li

H

R

FG

C Li

E+

FG

C E

1 2 3 4 5

Complex-Induced Proximity Effect (CIPE): The Concept

5 Beak, P. et al. J.Am.Chem.Soc. 1986, 19, 356-363

Metallation Conditions Ratio 2:3

LDA-THF-HMPA 100:0

LDA-THF 40:60

HA

D

D

i) LDAii) H+

HA

+

D

DCO2Me CO2MeD CO2Me

1 2 3

• HMPA efficiently solvate cations and thus disrupts the oligomers of lithium base that constitute the preequilibrium complex

N

O

N

OBuLi

Li

N

O

N

OBuLi

OMe OMeLi

Bu

• In the case of the methoxy-substituted phenyloxazoline, no metalation occurs since the lithium base is complexed in a manner which holds the base away from the proton to be removed

CIPE : Kinetic Evidence for the Role of Complexes in the α’-Lithiations of Carboxamides

6

• The kinetics of the α’-lithiations in cyclohexane were determined by stopped-flow infrared spectroscopy• The interaction of ligands with sBuLi was investigated by cryoscopic measurements• Based on these investigations the reactive complex illustrated above was determined to have optimal reactivity

Beak, P. et al. J.Am.Chem.Soc. 1988, 110, 8145-8153

R

Li

Li

Li

RR

R

Li

LL

L

O Ar

N MeH

HH

R

Li

Li

Li

RR

R

Li

LL

L

O Ar

N MeH

HH

Ar N

O

Me

MeAr N

O

Me

Li

Ar = 2,4,6-triisopropylphenylL = 1 or TMEDAR = sBu

1 2

CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions

7

NBoc

s-BuLi

TMEDAN

OtBuO

Li

Me2SO4

N

OtBuO

Me

tBu tBu tBu

An orthogonal relationship between the lithio carbanion and the pi system of the amide is favorable:

• Allows for complexation of the lithium with the carbonyl oxygen•Relieves the possible repulsive interaction between the electron pairs of the carbanion and the pi system

Beak, P et al. Acc.Chem.Res. 1996, 29, 552-560


n R E+ E Time (h) Yield (cis:trans)

1 iPr Me3SnCl SnMe3 5 78: 0

1 iPr Me2SO4 Me 3 68:0

1 iPr PhMe2SiCl SiMe2Ph 4.5 43:0

2 tBu Me2SO4 Me 5 85:0

2 tBu PhMe2SiCl SiMe2Ph 5 50:10

8

NO

O

RR

sBuLi, TMEDAEt2O, -78C, 5h

n

NO

O

RRn

LiE+

NO

O

RRn

E



n R E+ E Time (h) Yield (cis:trans)

1 iPr Me3SnCl SnMe3 5 78: 0

1 iPr Me2SO4 Me 3 68:0

1 iPr PhMe2SiCl SiMe2Ph 4.5 43:0

2 tBu Me2SO4 Me 5 85:0

2 tBu PhMe2SiCl SiMe2Ph 5 50:10

9

NO

O

RR

sBuLi, TMEDAEt2O, -78C, 5h

n

NO

O

RRn

LiE+

NO

O

RRn

E


• The relative configuration of the stannane product was determined to be cis by X ray crystallography

• In this structure, the carbonyl group is nearly coplanar to the C-Sn bond. Assuming the reaction with Me3SnCl proceeds with retention of configuration, the proton that is nearly coplanar with the carbonyl group would be favored for removal


10

NN

LiiPr iPr

Li

(Et2O)n

N

tBuO O

+ prelithiation complex

1

2

C

N

tBuO O

Li

dPdT

= k2[C] eqn 1

k2Kc

Kc = [C] [2i-C][1i-C]

eqn 2

Since [2i] [1] or [C]: Kc = [C] [2i][1i-C]

eqn 3

Solving for [C] and substitution into eqn 1:

dPdT

= k2Kc [2i][1i] [2i][1i-C]

eqn 4

If Kc large:dPdT

= eqn 5k2[1i]

3

Beak, P. et al. J. Org. Chem. 1995, 60, 7092-7093

• The observation of a large intermolecular isotope effect (˃30) between 1 and 1-d4 suggests that the deprotonation is the rate-determinating step

• The large value for Kc indicates that the equilibrium lies heavily on the side of the complex C


11

Competitive Efficiency in Carbamate-Directed Lithiations: Comparison of Constrained Carbamates and Boc Amines

N

Boc

N

Boc

KA

KB

kA

kB

+ sBuLi/TMEDA

A

B

+ sBuLi/TMEDA

prelithiationcomplex A

prelithiationcomplex B

N

N

OtBuO

Li

OtBuO

Li

• The magnitudes of both the equilibrium constants and the rate constants can affect the competitive efficiencies of the reactions compared


Substrate Pseudo-1st Order Competitive Efficiency

Second Order Competitive Efficiency

Dihedral Angles(HA, HB)(º)

Distance from carbonyl oxygen (HA, HB)(Å)

1 136, 14820, 97

2.64, 3.882.41, 3.44

3 4 20, 127 2.48, 3.78

235 68 36, 70 2.57, 3.16

330 920 20, 127 2.69, 3.96

705 4800 10, 96 2.66, 3.72

fast 19000 28, 77 2.78, 3.7012

N

Boc

HB

HA

N

HB

HA

Boc

NO

O

iPriPrHB

HA

N

OO

HA

HB

tBu

tBu

NHB

HA Boc

N

OO

HA

HB iPr

iPr


13

N

Boc

i) sBuLi, (-)-sparteineEt2O, -78°C, 6h

ii) iPr2CO, -78°C, 3h 55%

N

Boc

iPr

OHiPr

99:1 er

SEMCliPr2NEt

CH2Cl250C, 72 h

76%

N

Boc

iPr

OSEMiPr

i) sBuLi, (-)-sparteineEt2O, -78°C, 24h

ii) Me3SnCl, -78°C, 3h 25%

N

Boc

iPr

OSEMiPrMe3Sn

1) TBAF, THF, , 4 d 47%

2) NaH, THF, , 16 h 51%

NO

O

iPriPr

Me3Sn

Synthesis of the trans-organostannane

NO

O

RR

Li NO

O

RR

Li N Li

OtBuO

Evaluation of the effect of restricting the position of the carbamate carbonyl group on the configurational stability of a dipole-stabilized organolithium


Stannane Diamine Temp (ºC) Time (h) Yield (%) cis:trans

cis TMEDA -78 4 57 >99:1

cis TMEDA -40 1 44 >99:1

cis none -78 6 69 >99:1

cis none -40 5 21 >99:1

trans none -78 5 56 <1:99

trans none -40 1 24 2:1

trans TMEDA -78 1 44 1:1

trans TMEDA -78 6.5 21 >99:1

14

NO

O

iPriPr

Me3Sn

nBuLi

Et2O, -78°Ctime

NO

O

iPriPr

Li

Me2SO4

-78°CN

OO

iPriPr

Me


15

NO

O

iPriPr

Me3Sn

nBuLi

Et2O, -78°CN

OO

iPriPr

Li

Me2SO4

-78°CN

OO

iPriPr

Me

HN

O

HHHH

LiO

iPriPrH

NO

O

iPr

iPrH

H

H

H

H

Li

H

cis trans

• The cis organolithium is more thermodynamically stable given the better chelating interaction between the carbonyl oxygen and the lithium than the trans configuration

• Additional stabilization results from the orthogonal relationship between pi system and the, anion which is more accessible in the cis configuration


Solvent Temp (ºC) Time (h) Yield (%) e.r.

Et2O -78 1 65 89:11

Et2O -78 2 53 82:18

Et2O -78 3 76 80:20

Et2O -78 5 33 65:35

Et2O -78 6.5 54 61:39

Et2O -78 8 20 55:45

Et2O/TMEDA -78 10 66 90:10

Et2O/TMEDA -40 1 50 46:54

16

nBuLi

Et2O, -78°C

Me2SO4

-78°CN SnMe3

BocN Li

OtBuO

N Me

Boc

(S)e.r. 95:5

CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations

17

Possible reaction pathways:

FG

C H

+ (RLi)n

FG

C H

(LiR)n FG

C

Li

H

R

FG

C Li

E+

FG

C E

1 2 3 4 5


18Beak, P. et al. J.Am.Chem.Soc, 1999, 121, 7553-7558

Possible reaction pathways:

H

HX Y

+D

DX Y

RLi H

LiX Y

+D

LiX Y

1 1-d2 4 4-d1

H

DX Y

RLi H

LiX Y

+D

LiX Y

1-d1 4 4-d1

Intramolecular effect Intermolecular effect

Kinetically enhanced metallation

Complex-induced proximity effect


19

Intramolecular isotope effect: kH/kD = [2-d1]/[2]

Ph N N

O

H

MeMe

D H i) 1.8 equiv sBuLi/TMEDA

THF, -78°Cii) CO2

N

NMe

Me

O

O

Ph

+

HN

NMe

Me

O

O

PhD

62%

kH/kD 20

1-d1 2-d12

Ph N N

O

H

MeMe

H H

Ph N N

O

H

MeMe

D D

i) 1.25-1.8 equiv sBuLi/TMEDA

THF, -78°Cii) CO2

6-60%

k'H/k'D 5-6

N

NMe

Me

O

O

Ph

+

HN

NMe

Me

O

O

PhD

2-d12

+

1-d2

1 1-d2 + 1

Intermolecular isotope effect: k’H/k’D = log([1]/[1]i) log([1-d2]/[1-d2]i)

• The relative concentrations of 1 and 1-d2 change as a function of time , and consequently so does the relative forward velocities

, assuming the reaction is first order in substrate


Substratek’H/k’D

IntermolecularkH/kD

Intramolecular

5-6 >20

>20 >30

>20 >20

20

Ph N N

O

H

MeMe

(D)HH(D)

O NiPr2

(D)H H(D)

O NHiPr2

(D)H H(D)



IntermolecularkH/kD

Intramolecular

5-6 >20

>20 >30

>20 >20

21

Ph N N

O

H

MeMe

(D)HH(D)

O NiPr2

(D)H H(D)

O NHiPr2

(D)H H(D)

Limitations

Intramolecular isotope effect:

kH/kD = [2-d1]/[2]

• Precise determination of the isotope effect is complicated by the low occurrence of 2

• A different value of intra- and intermolecular kinetic isotope effect precludes a one-step mechanism

• Reaction pathway b, d or f might best describe the reaction profile



IntermolecularkH/kD

Intramolecular

5-6 >20

>20 >30

>20 >20

22

Ph N N

O

H

MeMe

(D)HH(D)

O NiPr2

(D)H H(D)

O NHiPr2

(D)H H(D)

Limitations

Intramolecular isotope effect:

kH/kD = [2-d1]/[2]

• Precise determination of the isotope effect is complicated by the low occurrence of 2

Intermolecular isotope effect:

k’H/k’D = log([1]/[1]i) ([1-d2]/[1-d2]i)

• High conversions of 1 and very low conversions of 1-d2 complicate the determination of the isotope effect

• However qualitatively k’H/k’D would be large in value



IntermolecularkH/kD

Intramolecular

5-6 >20

>20 >30

>20 >20

23

Ph N N

O

H

MeMe

(D)HH(D)

O NiPr2

(D)H H(D)

O NHiPr2

(D)H H(D)

• Similar values of inter- and intramolecular kinetic isotope effects does not allow to distingsh between kinetically enhanced metallation and CIPE.

• However, if the deprotonations of all three substrates can be described similarly, then the two benzamide substrates may follow reaction pathway e.

Directed Ortho Metallation: Seminal Work

24

Oi) nBuLi

Et2O, -78°C, 20hii) CO2

O

CO2

+

O O O

19% 40%

DMG

(RLi)n or(RLi)nLm DMG

(RLi)n

nH

-(RH)n DMG

nLi

E+DMG

E

DMG = Directed Metallation Group

Bebb, R.L. et al. J.Am.Chem.Soc. 1939, 61, 109-112

Seminal Discovery (1939)

Mechanism

Directed Ortho Metallation: Directed Metallation Groups

25Beak, P. et al. J.Org.Chem. 1979, 44, 24, 4464-4466

N

O

+i) nBuLi (1 equiv)

THF, -100°Cii) MeIDMG

N

O

+

DMG

Me

Me

DMG = SO2NMe2,SO2NHMe, CON(iPr)2, CONEt2, CONHMe, CH2NMe2

CONEt2

DMG

i) sBuLi/TMEDA

THF, -100°Cii) MeOD

CONEt2

DMG

D

DMG = p-SO2NEt2, p-SO2NHMe, p-CO2H, p-CH2NMe2, m-CH3, p-CH3, o-Cl, m-Cl, p-Cl

Beak, P. et al. J.Org.Chem. 1979, 44, 24, 4463-4464

OCO2NR2

SO2tBu SOtBu

CONR2 CON R

SO2NR2 SO2N-R

CO2-

OMOM

N-Boc N-COtBu

(CH2)nNR2, n = 1,2

F

NR2

N

OIncreasingDMG Power

Beak, P. et al. Angew.Chem.Int.Ed. 2004, 43, 2206-2225

Directed Ortho Metallation: Methodological Aspects

26

CONEt2

OMe

i) sBuLi/TMEDAii) TMSCl

CONEt2

OMe

TMS

i) sBuLi/TMEDAii) ClCONEt2

CONEt2

OMe

TMS

CONEt2i) sBuLi/TMEDAii) ClCONEt2

CONEt2

OMe

TMS

CONEt2Et2NOC

i) sBuLi/TMEDAii) MeI

(78%)

(66%)(74%)(94%)

CONEt2

OMe

TMS

CONEt2Et2NOC

Me

Snieckus, V. et al. J.Org.Chem. 1989, 54, 4372-4385

Iterative DoM Reactions: The "Walk-Along-The-Ring" Sequence


27 Snieckus, V. et al. Org.Let. 2005, 7, 13, 2523-2526

Silyl Group Functionalization : ipso-Halodesilylation Reactions

Compd Hal+/solvent/temp X Yield (%)

2 ICl/CH2Cl2/rt Cl 86

2 NCS/MeCN/reflux Cl 70

2 Br2/CH2Cl2/0°C-rt Br 92


3 NCS/MeCN/reflux Cl 65



4 NCS/MeCN/reflux Cl NR


DMG

TMS

DMG

X

R

Hal+

2, 3, 4 5, 6, 7

2, 5: DMG = OCONEt2; 3, 6: DMG = CONEt2; 4, 7: DMG = SO2NEt2



Silyl Group Functionalization : ipso-Borodesilylation Reactions

DMG R Yield (%)

CONEt2 H 76

N-cumyl amide H 95

OCONEt2 H 85

OCONEt2 6-TMS 89

SO2NHEt H 90

R

DMG

TMS

i) BX3 (1.2 equiv) CH2Cl2, rt, 2h

ii) Pinacol (4 equiv), EtOAc

X = Cl, Br

R

DMG

B

O

O



Silyl Group Functionalization : in situ ipso-Borodesilylation and Suzuki Cross-Coupling Reactions

DMG ArX Yield (%)

PhBr 76 (80)

3-Br-Py 83(58)

PhBr 76

R

DMG

TMS

BX3 (1.2 equiv) CH2Cl2, rt, 2h

R

DMG

BX2

ArX

Pd(PPh3)4Na2CO3

R

DMG

Ar

CONEt2

TMS

OCONEt2

TMS

OCONEt2

TMS

TMS


30

OCONR2

R'i) RLi, -78°C

ii) RT

OH

CONR2

1) PG

2) RLi3) E+

OPG

CONR2

R' R'

Anionic Rearramgement


Snieckus, V. et al. J.Am.Chem.Soc. 1985, 107, 6312-6315

OCONEt2

R

OCONEt2

R

Et2NOCi) sBuLi/TMEDA

ii) MeI

OMe

R

Et2NOC CONEt2i) sBuLi/TMEDA

ii) RTii) MeI/K2CO3

i) sBuLi/TMEDA

ii) MgBr2

ii) Allyl bromide

OMe

R

Et2NOC CONEt2 6N HCl

OH

R

HO2CO

O OH

R

O

O

NH

OHO2C

Ph

R = H ochratoxin BR = Cl ochratoxin A

R = HR = Cl

R = H (89%)R = Cl (77%)

R = H (59%)R = Cl (42%)

R = H (55%)R = Cl (38%)

R = H (50%)R = Cl (49%)

Aspergillus ochraceus and Penicillium viridicatum

Fungal toxic metabolites from strains of


31

Remote Aromatic Metalation

• X-ray crystal structure data for N,N-Diisopropyl 2-phenyl-6-(1’-naphtyl)benzamide shows an approximately orthogonal amide carbonyl with respect to the central aromatic ring

CONiPr2

BuLi or LDAN

O

iPr

iPr Li

H

Ar1

Ar2

OH

Ar1

Ar2

BCl3

OHO

MeO

OMeMe

CONEt2iPrO

i) sBuLi/TMEDA THF/ -78°C

ii) B(OnBu)3CONEt2

iPrO

B(OnBu)2

PdCl2(dppf)2K3PO4/DMF/RT

MeO

iPrO

OMe

CONEt2iPrO

MeO

iPrO

OMe

I

(50%)

(94%)

i) LDA/THF 0°C RT

ii) BCl3/CH2Cl2 0°C

(58%)

Dengibsinin


N-Cumyl Benzamide, Sulfonamide and Aryl o-Carbamate DMG


O2S

NH

Ph

Me Me

OMeN

O

Ph

Me MeTMS

OH

TMS

1) TFA2) 10% NaOH/ EtOHO

MeN

O

Ph

Me Me

i) sBuLi/TMEDA THF, -78°C, 2h

ii) -78°C rt

OHMeN

O

Ph

Me Me(82%)

TFE

reflux / 11h

OH

NHMe

O

NH

O

Ph

Me Me

TMS

TFA, rt, 15 min (83%)

NH2

O

E orBF3·OEt2CH2Cl2, rt, 2 h (86%)

TMS

TFA, rt, 15 min (82%)

O2S

NH2

TMS

i) sBuLi/TMEDA THF, -78°C, 2h

ii) TMSCl

(87%)

(79%)

(70%)

N-Cumyl Arylsulfonamide DoM Chemistry

33

SNH

Ph

O O

E

E = TMSTFA, rt, 10 min

(85%)

SNH2

O O

TMS

E = Hi) NaH, DMF 0°C RT

ii) EtI (91%)

SNEt

Ph

O O

i) sBuLi, THF, -78°Cii) TMSCliii) 10:1 TFE/AcOH

(72%)

SNHEt

O O

TMSCl

E = ICu powderDMF, 105°C, 25h

SNH

Ph

O O

)2

E =OH

Ph PhTFA, rt, 10 min

NHS

OO

Ph Ph

(99%)

E = CHO

NS

OO

PhOH

PDC, DMF

(67%)N

SO

O

PhO


N-Cumyl Arylsulfonamide DoM Chemistry

34 Snieckus, V. et al. J.Org.Chem. 2007, 72, 3199-3206

SEt2NOCO O

NH

Ph

R

i) nBuLi/TMEDA THF, -78°C, 1h

ii) I2

SEt2NOCO O

NH

Ph

RI

R = Ph (53%)R = OMe (62%)

Pd(PPh3)4, PhB(OH)22M Na2CO3, DME

90°C, 24h

R = Ph (76%)R = OMe (82%)

SEt2NOCO O

NH

Ph

RPh

1) TFA, rt, 10 min2) AcOH, reflux 12h3) HCl

R = Ph (79%)R = OMe (83%)

RPh

S

HN O

OO

NS

OO

O N

O

Me

OHHH

-O2C+R3N

SNH

Ph

O O

I+,XCoupl

1

+CONEt22

I+,XCoupl

3

Merck carbapenem-typeantibacterial agents


35Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891

SO2NEt2R

iPr2Mg (2.25 equiv)5 mol% [Ni(acac)2]

Et2O / rtR

H

Entry R Yield (%)

1 H (74)

2 2-Me (74)

3 3-Me (94)

4 4-Me (56)

5 2-CONEt2 60(64)

6 4-CONEt2 58(67)

7 2-N(Me)Ph 53

8 4-N(Me)Ph 18

9 2-OMe (97)

10 2-OCH2Ph 68

11 2-OiPr 59

12 3-OMe (91)

13 4-OMe (18)

14 2-TMS (48)

15 4-TMS (76)

16 2-(p-MeO-C6H4) 90

17 4-(p-MeO-C6H4) 85



SO2NEt2R


Et2O / rtR

H

Entry R Yield (%)

1 H (74)

2 2-Me (74)

3 3-Me (94)

4 4-Me (56)

5 2-CONEt2 60(64)

6 4-CONEt2 58(67)

7 2-N(Me)Ph 53

8 4-N(Me)Ph 18

9 2-OMe (97)

10 2-OCH2Ph 68

11 2-OiPr 59

12 3-OMe (91)

13 4-OMe (18)

14 2-TMS (48)

15 4-TMS (76)

16 2-(p-MeO-C6H4) 90

17 4-(p-MeO-C6H4) 85

• Large ortho substituents and para-substituted electron-donating groups promote lower yields



SO2NEt2R


Et2O / rtR

H

Entry R Yield (%)

1 H (74)

2 2-Me (74)

3 3-Me (94)

4 4-Me (56)

5 2-CONEt2 60(64)

6 4-CONEt2 58(67)

7 2-N(Me)Ph 53

8 4-N(Me)Ph 18

9 2-OMe (97)

10 2-OCH2Ph 68

11 2-OiPr 59

12 3-OMe (91)

13 4-OMe (18)

14 2-TMS (48)

15 4-TMS (76)

16 2-(p-MeO-C6H4) 90

17 4-(p-MeO-C6H4) 85

• Large ortho substituents and para-substituted electron-donating groups promote lower yields

• Groups ortho to the sulfonamide that are capable of metal coordination enhance the yield significantly

SO2NEt2R


Et2O / rtR

H

OMe OMe

R = 4-N(Me)Ph (77%)R = 4-OMe (87%)


38 Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891

Entry

R R’ Yield (%)

1 2-OMe Me (60)

2 2-OMe Ph 52

3 4-OMe Ph 79

4 2-(p-MeO-C6H4) Ph 65

5 4-(p-MeO-C6H4) Ph 72

6 2-Me Ph (69)

7 4-Me Ph (80)

8 2-TMS Ph (73)

9 4-TMS Ph (84)

SO2NEt2R

R'MgX (4.5 equiv)5 mol % [Ni(acac)2] / dppp

PhMe / refluxR

R'

• Electronic effects seem to have little influence on the yields of products

SO2NEt2X

MeO-C6H4-ZnCl[Pd(PPh3)4]

THF / reflux

SO2NEt2MeO

PhMgBr[Ni(acac)2]

dppp

PhMe / reflux

Ph

MeO

a: 2-I (85%)b: 4-Br (89%)

a: 2-MeO-C6H4 (65%)b: 4-MeO-C6H4 (72%)


39 Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891

L2NiX2

2 MgX2

2 RMgX

L2NiR2

R-R

Ar-SO2NEt2

L2NiAr

SO2NEt2

L2NiAr

RL2NiR'

R

1

2

3

4

5

RMgX

MgXSO2NEt2

Ar-SO2NEt2

Ar-SO2NEt2

Ar-R

• The reduction of 6 by [D7]iPr2Mg and the regiospecific cross-coupling of aryl sulfonamides with aryl Grignard reagents suggest that the cross-coupling reaction proceeds through the catalytic cycle of the Corriu-Kumada- Tamao reaction

SO2NEt2

TMS

OMe

OMe

2.25 equiv [D7]iPr2Mg5 mol% [Ni(acac)2]

Et2O / rt

D

TMS

OMe

OMe

6 7


40 Snieckus, V. et al. Synlett 2000, 9, 1294-1296

Me

SO2NHEti) nBuLi (2.1 equiv)THF, 0°C 30 min

ii) I2 (1.1 equiv)THF, -78°C 30 min

Me

SO2NHEt

I

1) [(PPh3)2PdCl2] (2 mol%) CuI (1 mol %) (1.2 equiv) rt, 2h

2) K2CO3 (0.1 equiv) MeOH, rt, 10 min

TMS

Me

SO2NHEt

50% aq. KOH18-crown-6CH2Cl2

Br (equiv) Me

SO2N

EtGrubbs I (10 mol %)0.002 M CH2Cl2

Me

NEtSO O

OO O

Toluene80°C, 2h

Me

NEtSO O

O

O

O

H

(86%) (84%)

(63%)

(40%)

(61%)


41 Snieckus, V. et al. J.Am.Chem.Soc. 1996, 118, 685-686

Entry E+ E Yield (%) ee (%)

1 TMSCl TMS 96 98

2 MeI Me 91 94

3 Et2CO Et2C(OH) 45 99

4 Ph2CO Ph2C(OH) 91 99

5 ClCH2OCH3 CH2OCH3 62 81

6 I2 I 85 96

7 (PhS)2 PhS 90 98

8 (PhSe)2 PhSe 92 93

9 Ph2PCl Ph2P 82 90

10 B(OMe)3 B(OH)2 89 85

N

N

H

H

(-)-sparteine (1.2 equiv) -78°C, Et2O

i) nBuLi (1.2 equiv)

ii) E+

FeCONiPr2

E

FeCONiPr2




1 TMSCl TMS 96 98

2 MeI Me 91 94



5 ClCH2OCH3 CH2OCH3 62 81

6 I2 I 85 96

7 (PhS)2 PhS 90 98


9 Ph2PCl Ph2P 82 90

10 B(OMe)3 B(OH)2 89 85

• The (S) absolute configuration was established by single-crystal X-ray crystallographic analysis

• Since the sp2-hybridized ferrocenyl carbanions are configurationally stable, the enantioselective induction must occur at the deprotonation and not the electrophile substitution step

• On this basis, the configurational outcome of the other 1,2-disubstituted ferrocenes was assigned to be S

• The enantiomeric excess was determined by comparison with racemic products generated by deprotonation with nBuLi using chiral HPLC

N

N

H

H



ii) E+

FeCONiPr2

E

FeCONiPr2



FeCONiPr2

EE = TMS

i) nBuLi, -78°C, THF

ii) Ph2COFe

CONiPr2

TMS

OH

Ph Ph

(72%)

Pd(PPh3)4 (2 mol %)aq. Na2CO3 (6 equiv)DME, reflux, 48h

B(OH)2

OMeMeO

FeCONiPr2

OMeMeO

+FeCONiPr2

E = I

(31% 96% ee)(67%)(1.6 equiv)


44 Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631




3 Bu3SnCl Bu3Sn 58 82

4 Ph2PCl Ph2P 53 97

5 (PhS)2 PhS 71 89


7 I2 I 70 89

8 MeI Me 71 92

N

N

H

H



ii) E+ (6 equiv)

FeCONiPr2

E

FeCONiPr2

CONiPr2 CONiPr2



Entry ee 1 (%) R E+ E Yield (%)

dl : meso

ee (%)

1 0 TMS TMSCl TMS 86 51:49 72

2 a TMS TMSCl TMS 75 84:16 91

3 97 Ph2P Ph2PCl Ph2P 45 >95:5 98

4 89 PhS (PhS)2 PhS 60 99:1 97

FeCONiPr2

R

N

N

H

H



ii) E+ (6 equiv)

FeCONiPr2

R

FeCONiPr2

CONiPr2 CONiPr2

+

R

E

dl meso

CONiPr2

E

a CSP HPLC enantiomeric resolution was not feasible, [α]23578 +67.5 (c 0.54, CHCl3)



FeCONiPr2

CONiPr2

X

B(OH)2

OMeMeO

PhBr (1.3 equiv)

X = I X = SnnBu3

Pd(PPh3)4 ( 10 mol%)aq. Na2CO3 (6 equiv)DME, reflux, 5 d

(1.6 equiv)

PdCl2(dppf) (30 mol %)CuO (8 equiv)DMF, 150°C, 18 h

FeCONiPr2

CONiPr2

Ph

FeCONiPr2

CONiPr2

FeCONiPr2

CONiPr2

FeCONiPr2

CONiPr2

I

+ +

MeO OMe

(20%, 89% ee) (70%) (35%) (51%)



Ph Ph

OAc

+ CH(CO2Me)2

[Pd(3-C3H5)Cl]2 (2.5 mol%)AcOK (4 mol %)BSA (3 equiv)Dimethyl malonate (3 equiv)DCM, rt, 10h

FeCONiPr2

PPh2

CONiPr2Ph2P

(10 mol%)

Ph Ph

MeO2C CO2Me

(96%, 84% ee (R))

Tsuji-Trost allylation

Applications in asymmetric synthesis



Asymmetric alkylation of benzaldehyde

H

O

+ Et2Zni) 5 mol %

solvent, rt, 2-3 dii) HCl/H2O

FeCONiPr2

R

CONiPr2Et

OH

*

Entry R ee of ligand

Solvent Yield (%) ee (%)

1 Ph2C(OH) 96 Hexane 98 61(S)

2 Ph2C(OH) 96 PhMe 98 12(R)

3 Ph2C(OLi) 95 PhMe 70 47(S)

4 Et2C(OH) 90 Hexane 37 60(S)

5 2,4-di(MeO)Ph 89 PhMe 43 90(S)


49 Snieckus, V. et al. Adv.Synth.Catal. 2003, 345, 370-382

Entry E+ E Yield (%) 2

Yield (%) 3

ee (%) 3

1 MeI Me 87 99 96(R)

2 DMF CH2OCH3a 75 80 95(R)

3 TMSCl TMS 69 99 95(R)

4 Ph2PCl Ph2P N.D. 61 N.D.

5 (MeS)2 MeS 89 99 88(R)

6 ICH2CH2I I 72 99 96(R)b

Fe

EtN

O

Ph

Me MeFe

EtN

O

Ph

Me Me

i) 1.2 equiv nBuLi/(-)-sparteine 6:1 Et2O:PhMe/ -78°C

ii) E+

CF3CH2OH

reflux, 5-12 h

E

Fe

NHEt

O

E

1 2a-f 3a-f

a Product aldehyde was reduced with NaBH4 to give the corresponding alcohol, which was methylated using NaH/MeIb Absolute stereochemistry was established by single crystal X-ray analysis



Fe

NHEt

O

TMS i) 2.2 equiv nBuLi/TMEDA THF, -78°C -10°C

ii) I2 (32%)

Fe

NHEt

O

TMS

I

TBAF

THF, rt Fe

NHEt

OI

(89%, 94% ee)

Latent Silicon Protection Route



Fe

NHEt

O

E i) NaH, DMF 0°C rt

ii) R-XFe

EtN

O

IR

1 2a (R = Me, 90%)2b (R = allyl, 77%)

2a (R = Me)

1) BH3SMe2

THF, reflux

2) 10% NaOHreflux(76%)

Fe

EtN

IR

4

(E = I)

2b (R = allyl)

Pd(PPh3)4 (3 mol %)NEt3 (12 equiv)

MeCN, 95°C, 48 h(47%)

Fe

NEt

O

5

i) 2.6 equiv TF2O 6.0 equiv Py -40°C 0°C, 1.5 h

ii) MeOH, rt, 12 hiii) NH4Cl

Fe

E

3a-c

CO2Me

Entry E Yield (%) ee (%)

1 Me 50(92) 96

2 TMS 49(92) 93

3 I 26(94) 96



Fe

EtN

O

Ph

Me Me Fe

EtN

O

Ph

Me Me

i) nBuLi/(-)-sparteine (1.2 equiv) 6:1 Et2O:PhMe/ -78°C

ii) DMF

CHO1) TMSCH2MgCl (2.5 equiv.) Et2O, rt

2) NH4Cl3) NaH, THF, reflux

Fe

EtN

O

Ph

Me Me

1) CF3CH2OH reflux, 10.5 h

2) NaH, DMF3) Allyl bromide

(89 %) (61 %) (90%)

Fe

NEt

O

1) Grubbs I (16 mol %) CH2Cl2, reflux

2) Pd/C/H2 MeOH (73%, 91% ee)

Fe

NEt

O

i) sBuLi (1.2 equiv) TMEDA 1:1 Et2O: THF, -78°C

ii) Ph2PCl (87%)

Fe

NEt

OPPh2

Conclusion

53

• Thinking beyond thermodynamic acidity leads to new synthetic methodologies for remote functionalization

• CIPE provides a heuristic model to discover new modes of C-H activation

• The involvement of CIPE in directed ortho and remote metallation allows the synthesis of complex aromatic systems with ease

• Combination of several methodologies to DoM and DreM expands the versatility of this synthetic strategy

complex-induced proximity effect in directed ortho and remote metallation methodologies

Documents

concepteffect of effect

carbonyl group

cipe process

directed aryl

preequilibrium complex

reactive complex

oligomers of lithium

organolithium base