Halogen Magnesium Exchange

Günther Scheid

Supergroupmeeting Princeton 04/21/2004

2

3Why? … or what is wrong with…

Mg E+Br

R Et2O or THF

MgBr

R

E

R

tBuLi

-78ºC

E+Br

R Et2O or THF

Li

R

E

R

4Two Early Examples

EtMgBr

Et2O, 20ºC

Br MgBr+ EtBr

iPrMgCl

-78ºC

TMSClHCBr3 HBr2CMgCl HBr2CSiMe3

C. Prévost, Bull. Soc. Chim. Fr. 1931, 1372.J. Viléra, Bull. Soc. Chim. Fr. 1967, 1520.

5Functionalized Aryl Reagents I

iPrMgBr

THF, 25ºC

I

OMe

MgBr

OMe OMe

H2N CO2EtNCO2Et

CO2Et

Boc

then HCl, Et2O

CO2Et

higher temp. for e--rich substrates

iPrMgBr

THF, -20ºC

I

CO2Me

MgBr

CO2Me

RCHO

THF, -20ºC

CO2Me

HO R

R = p-CN-C6H4R = c-C6H11

83%72%stable for several

hours below -10ºC

L.Boymond, P. Knochel et al., ACIEE 1998, 37, 1701.P. Knochel et al. ACIEE 2003, 42, 4302.

6Functionalized Aryl Reagents II

iPrMgBr

THF, -20ºC

N

CO2Et

CuCN 2LiI

II

NMe2

N

CO2Et

MgBrI

NMe2

ICO2Et

then ZnCl2, EtOH, 80ºC

HN

CO2Et

I

O

78%

iPrMgBrTHF, -10ºCN

N

I

Ph

71%

Ph

CuCN 2LiIthen

BrOMe

cat. H2SO4

MeOH

N

N

Ph

Ph

OMe

NH

NH2

D.M. Lindsay, P. Knochel et al., Org. Lett. 2002, 4, 1819.P. Knochel et al. ACIEE 2003, 42, 4302.

7Functionalized Aryl Reagents III - free amines

PhMgCl

-25ºC, 10min

NH2

CN

CuCN 2LiIII

NHMgCl

CN

MgClI

65%

-30ºC, 5min

iPrMgCl HN OSiMe3Me3Si

NH2

CN

NH2I

PhMgCl

-25ºC, 10min

NH2

CN

INHMgCl

CN

MgCl

64%

-30ºC, 5min

iPrMgCl HN OSiMe3Me3Si

NH2

CN

OH

G.Varchi, P. Knochel et al., Chem. Commun. 2003, 396.P. Knochel et al. ACIEE 2003, 42, 4302.

8Functionalized Aryl Reagents IV - directing groups

THF, -10ºC,1.5h

68%

iPrMgBrNBrNC

NMe2

Br

Br/Mg exchange is significantly slower than I/Mg exchange!!!

NMgBrNC

NMe2

Br

NNC

NMe2

Br

OHBu

BuO

OMe

Br

BrOMe

Br

MgBr

90%

iPrMgBrOMe

Br

CO2H

THF, 40ºC, 2h

CO2

P. Knochel et al. ACIEE 2003, 42, 4302.

9Functionalized Aryl Reagents V

THF, -30ºC, 1h

75%

iPrMgBrCO2Me

I

Cl

CO2Me

MgBr

ClPhN=C=O

CO2Me

N

O

Ph

O

CO2Et

I

83%

iPrMgCl

THF, -20ºC, 1h

OTs

O

CO2Et

MgCl

OTs

CuCN 2LiI

CO2Et

O

T. Delacroix, P. Knochel et al., JOC 2000, 65, 8108..

10Functionalized Aryl Reagents VI - cyclizations

40ºC, 1hc-C6H11MgCl

then CuI (10mol%)

OOBr

Br Br

BrO

BrH

H

70%

-20ºC, 0.5h78%N

Br

O

NPh

Cl

BrI

N

Br

OBr

Cl

OMe

MgBr

H. Nishiyama et al., JOC 1992, 57, 407.M. Poirier, F. Chen et al., Org. Lett. 2001, 3, 3795.

11Functionalized Aryl Reagents VII - Magnesiates

THF, -40ºC, 0.5h

85%

CN

Br

CNCN CN

MgBu Li

Br

NBr Br THF, -40ºC, 0.5h N NMgBu Li

Br Br

Bu3MgLiDMF

NBrO

94%

Bu3MgLi

K. Oshima, J.Organomet. Chem. 1999, 575, 1.K. Kitagawa, K. Oshima et al. ACIEE 2000, 39, 2481.

12Functionalized Aryl Reagents VIII - Nitroarenes

-80ºC, 5min94%

INO2

CO2Et

MgClNO2

CO2EtCN CN

NO2

CO2EtCN

HO Ph

90%

PhMgCl PhCHO

-40ºC, 30sec

NO2I

PhMgCl

NC

NO2MgCl

NC

1) ZnBr22) [Pd(dba)2] (5mol%) tfp (10mol%)

NO2

NC

CO2Et

CO2Et

I

73%

I. Sapountzis, P.Knochel, ACIEE 2002, 41, 1610.

13Heteroaryl Reagents I

-40ºC, 30min

94%

N

I

N

MgCl

N

HO R

iPrMgBr RCHO

Cl Cl Cl

-80ºC, 10min

81%

N N

Br

N N

Br

N N

BriPrMgBr

I MgBr

Br

CuCN 2LiI

M.Abarbi, P.Knochel, JOC 2000, 65, 4618.

14Heteroaryl Reagents II

-40ºC, 60min

iPrMgClN

I

EtO OEt

NC N

MgCl

EtO OEt

NCN

EtO OEt

NCDMF

OH

25ºC, 30min

iPrMgBr

N N

BrBr

Br

N N

BrBr

N N

CO2EtBr

OEt

CuCN 2LiClBr

OEt-40ºC, 2h

iPrMgBr

NCCO2Et

OEt

57% 55%

M.Bergauer, P.Gmeiner, Synthesis 2001, 2281.M.Abarbi, P.Knochel, JOC 2000, 65, 4618..

15Functional Group Tolerance

OI MgBr

-30ºC, 1h

OBrMg1) ZnBr22) [Pd(dba)2] (5mol%) tfp (10mol%)

CO2Me

I

O

CO2Me

64%

no hydride transfer reduction withneopentylmagnesium bromide!!!

MgBr

-50ºC, 0.5h

ZnBr2

77%O

MeO2C I

O

MeO2C MgBr

CO2Et

Br

O

MeO2C CO2Et

F.F. Kneisel, P.Knochel, Synlett 2002, 11, 1799.

16Alkenyl Magnesium Reagents I

-70ºC, 12h

iPrMgClEtO2C

O

Ph

I

EtO2C

O

Ph

MgBr

PhCHO EtO2C

O

Ph

PhHO

THF, -78ºC

iPrMgCl

CuBr Me2S55%

O

O

OI

O

O

OClMg

THF/HMPA-78ºC to rt

CHO

O

O

OO

M.Rottländer, P.Knochel, JOC 1999, 64, 1080.J.-F. Briére, R.H. Blaauw et al. Eur. JOC 2001, 12, 2371.

17Alkenyl Magnesium Reagents II

R

R

Br

EWG iPrMgBr

THF, -40ºC

15 to 60min

R

R

MgBr

EWG

R

R

E

EWGE

EWG = CN, SO2Ph, CO2tBu, CONEt2

iPrMgCl 62%I

ClTHF

MgCl

Cl

OMgCl

CN

tBuLi

CN

HHO

P. Knochel et al. ACIEE 2003, 42, 4302.F.F. Fleming et al. Org.Lett. 2002, 4, 2493.

18Alkyl Grignard Reagents and Carbenoids I

iPrMgBr

THF, -40ºC15min

EtO2C I EtO2C MgBr

CuCN 2LiCl

PhCOClEtO2C

Ph

O

EtMgCl

85%BuO

OI

O

BuO

MgBrI2

O

BuO

IDME

radical cyclization!

V.A. Vu, P. Knochel et al. ACIEE 2002, 41, 351.A. Inoue, K. Oshima et al. Org.Lett. 2000, 2, 651.

19Alkyl Grignard Reagents and Carbenoids II

iPrMgCl

Et2O, -50ºC10min

EtO2C Br EtO2C MgCl EtO2C IBr Br BrI2

85%

iPrMgCl

Et2O, -50ºC10min

EtO2C I EtO2C MgCl EtO2C BrI I I

BrBr

Cl Cl

Cl Cl

80%

V.A. Vu, P. Knochel et al. ACIEE 2002, 41, 351.

20Alkyl Grignard Reagents and Carbenoids III

THF, -78ºC15min

PhCHO

60%Tol

Cl

SO

Cl

BrMg

ClPh

OH

Ph Ph

Me2AlCl

Ph

97%ee93%ee

EtMgBr

R.W. Hoffmann, P.G. Nell, ACIEE 1999, 38, 338.

21Bisaryl Amine Synthesis without Pd

NO

NMe2

PhMgClN

HO

NMe2

Ph

FeCl2/NaBH4

2h

HN

NMe2

Ph

NO

NMe2

NHO

NMe2

FeCl2/NaBH4

2h

HN

NMe2

Ph

MgBr

CO2Et

CO2Et

72%

73%

F.Koop, P.Knochel, Synlett 2003, 885.

22Bisaryl Amine Synthesis without Pd

NaNO2, HBF4N2

CO2Et

TsNa

HN

ZnAcOH/TFA (5:1)

CO2Et

71%

Ts

CO2Et

NH2BF4

CH2Cl2

NN

CO2Et

Ts

N

I

Ph

CO2Et

A

iPrMgClTHF, -20ºC, 1h

then A

1) allyl iodide

2)N

N

Ph

CO2Et

CO2Et

N

HN

Ph

CO2Et

I. Sapountzis, P.Knochel, ACIEE 2004, 897.

23Total Synthesis (“complex”) Substrates I

-78ºC to -15ºCiPrMgBr

O

O

MeOOTBS

MeO

TMS O

NBr OTf

O

HO

MeOOTBS

MeO

TMS

O

N OTf

O

N OTf

tBuLi O

N OTf

O

O

O

OH

Et2NH did not catalyze the rearrangement of the intermediate Lithiated compound

then

A.B. Smith III et al., JACS 2001, 123, 10942.

24Total Synthesis (“complex”) Substrates II

K.C. Nicolaou et al., ACIEE 1998, 37, 2717.

25Summary

Halogen Magnesium exchange allows the Synthesisof organomagnesium reagents with many more functionalgroups than previously thought.

The mild reaction conditions are the key for assuring high functional group tolerance.

26Problem

N

SO2N I

MgCl

A

FeCl2/NaBH4

B-20ºC

C

27Problem

N

SO2N I

MgCl

A

FeCl2/NaBH4 C

-20ºC N

SN

ClMgO

ArO

N

SNO

I

MgCl

N

SNHO

Ar

N

SHN

I

B

28Problem

N

SO2N I

MgCl

A

FeCl2/NaBH4 C

-20ºC N

SN

ClMgO

ArO

N

SNO

I

MgCl

N

SNHO

Ar

N

SHN

I

B