Halogen Magnesium Exchange Günther Scheid Supergroupmeeting Princeton 04/21/2004
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