Functionalized Grignard Reagents and Their Applications
in New Amination Reactions
Evans Group Seminar November 9, 2004
Preparation of Functionalized Organomagnesium Reagents throughHalogen-Magnesium Exchange
iPrMgBrI MgBr
THF -40 °C to 0 °C
FG FG
MgBr
EtO2C
MgBr
EtO2C N NMe2
MgBr
NC (i-Pr)2NOC
MgBr MgBr
Br
OEtO2C MgBr
N
NC
MgBrN
MgBr
I
Ts
MgBr
CO2Et
NCMgClEtO2C
O O
O PhMgCl
recent review:P. Knochel et al. Angew. Chem. Int. Ed. 2003, 42, 4302.
Nitrofunctionalized Grignard Reagents
NO2R-MgX
I
NO2 NO2E+
ClMg E
NNu–O
O
- 1,2-, 1,4- and 1,6-addition or O-attack possible- Single-electron tranfer (SET)
and radical-anion coupling
New Amination Reactions using Arylmagnesium Reagents
NO2
I R-MgXN
OO
MgClNO2
EE+
NO2
INO2
Li E+
NO2
EPhLi (1.05 equiv.)
-100 °C, 3 minTHF:ether:pentane
4:1:1 16 - 69 %
C. E. Tucker, T. N. Majid and P.Knochel, J. Am. Chem. Soc., 1992, ,114, 3983.J. F. Cameron and J. M. Fréchet, J. Am. Chem. Soc.,1991, 113, 4303.
Nitro-Substituted Arylmagnesium Reagents
NO2I
FG
NO2MgCl
(CuCN·2LiCl)
E+
NO2E
up to 95 %
PhMgCl(1.05 equiv.)
-40 °C, 5 minTHF
(- PhI)FG: CO2Et, CN, I, NO2, OMe, H, Me, COPh, CONR2
FGFG
NO2
CN
OH
Ph
NO2 OH
Ph
O
Ph
NO2
CO2Et
Me
Me
NO2
94 %93 % 76 % 76 %
NO2 OH
Ph
EtO2C
NO2
MeO
NO2 OH
c-Hex
O2N
NO2
Ph
I
O
95 % 76 % 74 % 77 %
I. Sapountzis, P. Knochel Angew. Chem. 2002, 114, 1680; Angew. Chem. Int. Ed. 2002, 41, 1610.
Nitro-Substituted Heteroarylmagnesium Reagents
N
NO2
I -78 °C, 2 h
N
IO2N
NO2
N MgCl
-40 °C, 2 hN
O2NMgCl
N
NO2
OH
Ph
PhMgCl(1.05 equiv)
-78 °C, 5 minTHF(-PhI)
N
O2N
OHPhPhMgCl
(1.05 equiv)
-40 °C, 5 minTHF(-PhI)
PhCHO
PhCHO
55 %
78 %
N NH2
NO2
N I
NO2NaNO2; CuI
DMSO, HI50 °C, 30 min
63 %
m- and p-Nitro-Substituted Arylmagnesium Reagents
NO2
I
NO2
I
PhMgCl
PhMgCl
ClMg
NO2
MgCl
NO2
– 78 °C
– 78 °C
Nitro-Substituted Arylmagnesium Reagents
FGI
FGMgCl
O2N O2N
FGEPhMgCl E+
(CuCN·2LiCl)O2N
THF, -78 °C5 min
EtO2C
Ph
O
O2NO2N
OPh Et2NOC
O2N
Ph
O
54 - 94 %FG = CO2Et; CONR2; COPh; N=N-NR2; OTs; Boc2N
NO2
OTs
PhI
OH
NN
O2N
N
NO2
NBoc2
Ph
O
O2N
OMe
NO2
IOH
Ph
Me
61%58% 78%71%
94% 68%54% 78%
Nitro-Substituted Arylmagnesium Reagents in Negishi-cross coupling Reactions
EtO2C
INO2
EtO2C
ZnXNO2
EtO2C
NO21.) PhMgCl -40 °C, 10 min (-PhI)
2.) ZnBr2 -40 °C, 10 min
Pd(dba)2 (5 mol%)tfp (10 mol%)
-40 °C - rt, 2 h
78 %
EtO2C
NO2NO2NO2
NC
OMe
O2N
NO2CO2Et
68 %75 % 85 % O2N
NO2NO2
55 %
FG
NO2
I
MgBr
Me
Me
Me
NO2
ZnX
FG FG
NO2
Ar
1.)
-40 °C, 20 min
2.) ZnBr2 -40 °C, 10 min
ArI (1. 5 equiv)
Pd(dba)2 (5 mol%)tfp (10 mol%),-20 °C - rt, 3 h 55-85 %FG: CO2Et, CN, NO2, CO2NR2
m- and p-Nitro-Substituted Arylmagnesium Reagents in Negishi cross-coupling reactions
O2N
I
OOCO2Et
ZnX
O2N
INC
OTsNO2
NO2
OTsCN
NO2
O2N
CO2EtCN
1.) PhMgCl -78 °C, 10 min
2.) ZnBr2 -78 °C, 10 min
(2 equiv.)
Pd(dba)2 (5 mol%)tfp (10 mol%),-78 °C - rt, 5 h 83 %
I. Sapountzis, H. Dube, P. Knochel Adv. Synth. Catal. 2004, 346, 709.
73 % 77 %
Early Studies on Reactions between Nitroarenes and Organomagnesium Reagents
DDQ
NO2RMgX
NR
H
OMgXO N
H R
OMgXO
NH2R
NO2R
NO2
R
NH2
R
+
reduction
R= alkyl
NO2 MgX NXMgOO
reduction
NHO
G. Bartoli Acc. Chem. Res. 1984, 17, 109.Highlight: A. Ricci, M. Fochi Angew. Chem. Int. Ed. 2003, 42, 1444
The Bartoli Indole Synthesis
NO2R
MgX
MgXN OXMgO
R
OMgX
NOMgX
HR
C2H4
NXMg O
R
NOMgXXMg
RH3O+N
XMg O
HR
NHR
MgXNO
R
G. Bartoli, G. Palmieri, M. Bosco, R. Dalpozzo Tetrahedron Lett. 1989, 30, 2129.
Reducing the Hydroxylamine – Access to Diarylamines
One-Pot-Procedure desirable
Reduction conditions:Pd/C-NaBH4; Raney-Ni;Fe/AcOH; BEt3 in THF; SnCl2 in HCl;SnCl2 in EtOH; SmI2 in THF; various Lewis acids andNaBH4 in different solventsFeCl2 in THF + NaBH4
NO2
Br
MgCl
CO2Et
N
BrEtO2C
OH
HN
BrEtO2C
–20°CTHF, 1 h
+
New Amination Reaction using Aryl-Magnesium Reagents and Nitrobenzenes
ONAr2
O
Ar2 NOMgCl
OAr1
Ar2 NO
Ar1MgCl
Ar1MgCl
Ar1
NHAr2
Ar2 NAr1
OMgCl
1) Ar1MgCl (2 equiv.), THF, -20 °C2) FeCl2/NaBH4, -20 °C, 2 h
- Ar1OMgCl
FeCl2/NaBH4 -20 °C, 2 h
slow
fast
O2N
HNI
FG2
FG1 68-95 %( 2.3 equiv )
1) i-PrMgCl -20 °C, 0.5 h
2)
-20 °C, 2 h3) FeCl2/NaBH4, rt, 2 h
FG2FG1
FG: CO2Et, CN, I, NO2, OMe, H, F, Br, CF3, SMe, CONR2
New Amination Reactions using Arylmagnesium Reagents and Nitrobenzenes
EtO2C
HN
OTf
Br
HNNC
CO2Et
HN
F
HN
OMe
78 %
79 %
85 %
97 %
MeO
HN
SMe
MeO
HN CN
HN OMe
EtO2C
HN
Br73 %
79 %
72 %
92 %
I
HN
NMe2
HN
MeO
CF3
HN
HN Ph
HN
OMe
85 %
67 %
75%
94 %
I. Sapountzis, P. Knochel J. Am. Chem. Soc. 2002, 124, 9390
New Amination Reactions of Nitro-Heterocycles using Arylmagnesium Reagents
I
EtO2C O2N
N
S N
SHN
EtO2C( 2.3 equiv )
1) i-PrMgCl -20 °C, 0.5 h
2)
-20 °C, 2 h3) FeCl2/NaBH4, rt, 2 h
77 %
N
HN
EtO2C N
SHN
I
HN
N
PhN
HN
I
HN
NTos
N
HN
NN
75 %59 % 64 %
88 % 85 %44 %
Amination of Solid Phase Supported Nitrobenzenes using Arylmagnesium Reagents
O
ONO2
HO
OHN
HO
OHN
OMe
HO
OHN
Me
Me Me
HN
Ar
O
HO
92 % purityquant.
91 % purityquant.
98 % purityquant.
1. Ar-MgX (10 equiv) (THF, -20 °C, 2 h)
2. EtOH (0.5 mL)3. FeCl2 (5 equiv)4. NaBH4 (2.5 equiv) (rt, 2 h)5. TFA/CH2Cl2/H2O= 9:1:1
O
O O
HO
1.) iPrMgCl (10 Äq.) THF, –20 °C, 2 h
2.) THF, 2x 5 mL3.) PhNO24.) EtOH (0.5 mL)5.) FeCl2 (5 Äq.) NaBH4 (2.5 Äq.) RT, 2 h6.) TFA/CH2Cl2/H2O= 9:1:1
I OH
95% purity quant.
New Amination Reactions using Arylmagnesium Reagents and Nitrobenzenes
ClMg
NO2
FG
-20 °C, 2 h
2) FeCl2, NaBH4 -20 °C, 2 h
1)
2.3 equiv of ArMgXor
4.6 equiv of ArMgX
HN
HN
HN
NO2
FG
O2N
FG
FG
HN
HN
CN
44%
HN
HN
EtO2C CO2Et
HN NO2
HN
NO2
72 % 67 % 63 %
HN NO2
MeO68 %
HN
HN
95%I. Sapountzis, P. Knochel Synlett 2004, 955
New Amination Reactions using Arylmagnesium Reagents and Amino- or Hydroxy-Substituted Nitrobenzenes
OH
O2Nn
N
NO2
BocHN NBocHN
O2N
BocHN
O2N
O
NH
RO2NS
NNHBoc
O2N
R
Possible scaffolds that were of interest for Aventis:
Addition of various aromatic Grignard reagents:
N
HN
BocHN
Ph
73%
HN
Ph
88%
O
NHR
HN
CN
Ph
68%HO
Reduction and Amination saves one step for most of these substrates
Application in Removal of p-Nitrobenzyl Protecting Group
ClMg
NO2-20 °C, 2 h
2) FeCl2, NaBH4 -20 °C, 2 h3) CF3COOH 0.02 M in DCM 0 °C, 1h
1)
OBr
OH
Br80 %
ClMg
NO2
NEt -20 °C, 2 h
2) FeCl2, NaBH4 -20 °C, 2 h3) CF3COOH 0.02 M in DCM 0 °C, 1h
1)
70 %
PMBEt
Ph
NHEt PMB
Et
Ph
with N. Gommermann
see also: O. J. Plante, S. L. Buchwald and P. H Seeberger J. Am. Chem. Soc. 2000, 122, 7148.
Limitations of Amination Reactions using Arylmagnesium Reagentsand Nitrobenzenes
MgCl
CO2Et
NO2HN
CO2Et
FG FG
MgCl
NO2
NO2HN
NO2
FG FG
MgCl
Me
Me
Me
NO2FG
NN
HN
Me
Me Me
FG
traces
main product
FG
FG
Only Arylmagnesium Reagents
2 equiv. of Grignard needed
New Amination Reactions
Ar1 Ar2HN
Ar1 NH2
Ar1 NH Ar2
Ar2 X
X+
+
a
Ar1 NH
b
Ar1 NO
O
Ar2 Met
MgXAr2
+
+
Problems:leaving groupelectron poor aromatics
Pd-catalyzed:Ligand and Base tuningside reactions
Electrophlic Amination Reactions
NCF3
CF3CF3
F3C
OTs
S N3
ON
O
OO
N
N3
Ts N3
K. Narasaka
B. M. Trost
Synthetic equivalents for NH2
Kabalka
J. P. Genet V. Snieckus
O
ON
Li
OTsMe
MeMe
Ph2PO
ONR2
G. Boche
E. Erdik, M. Ay, Chem. Rev. 1989, 89, 1947
New Amination Reactions
Ar1 Ar2HN
Ar1 NH2
Ar1 NH Ar2
Ar2 X
X+
+
a
Ar1 NH
b
Ar1 NO
O
Ar2 Met
MgXAr2
+
+
Problems:leaving groupelectron poor aromatics
Pd-catalyzed:Ligand and Base tuningside reactions
Ar1 NO
Ar1 NN SO2Tol
New Amination Reactions using Arylmagnesium Reagents and Aryl-p-Tolylazo Sulfones
Acid Base Approx. pKa
ArSO3H ArSO3- -6.5
Ar3NH+ Ar3N -5 F3CCOOH F3CCOO- -1.0 Ar2NH2
+ Ar2NH 1 ArNH3
+ ArNH2 3-5 ArNR2H+ ArNR2 3-5 HCOOH HCOO- 3.77 CH3COOH CH3COO- 4.76 NH4
+ NH3 9.24 R3NH+ R3N 10-11
R
Zn
Ar1N N
TsAr2
RNH
Ar2
Ar1
R = H, Me, allyl, benzyl, Tos, Ms, Ac
still difficult
H
Ar1
N NTs
Ar2R
H
Zn
NHAr2
Ar1
easy
(AcOH : TFA 5 : 1)
Ar1N N
SO2Tol
Ar1N N
TsAr2
MgXNH
Ar2
Ar1
Ar2MgX reductive
cleavagevery difficult
various reduction conditionseverything that is reported
in literature failed
New Amination Reactions using Arylmagnesium Reagents and Aryl-p-Tolylazo Sulfones
Ar1 NH2 Ar1 N2TsNa
CH2Cl2, RT
NaNO2
HBF4, RT Ar1N N
TsBF4
> 80% yield
1) Ar2MgX (1.1 eq) -20°C, 1h
2) C3H7I, NMP 20 °C, 3 h3) solvent evaporation
N NTsAr1
Ar2Ar1N N
Ts Zn
AcOH:TFA5:1
Ar1HN Ar2
63-86%overall yield
I. Sapountzis, P. Knochel Angew. Chem. Int. Ed. 2004, 43, 897
New Amination Reactions using Arylmagnesium Reagents and Aryl-p-Tolylazo Sulfones
HN
EtO2C Br
68 %
HN
EtO2C CN64 %
HN
EtO2C Br
83 %
HN
EtO2C
Br80 %
I
HN
EtO2C
63 %
HN
Me BrMe
Me
69 %
N
HN
CO2Et
Ph
CO2Et
71 %
Fe
HN
Br
58 %
Cl
HN
59 %
HN
OMeOTf
MeO
HN
CO2Et
HN CF3
MeOCF3
81 %92 %
62 %
Cl
ClMeO
New Amination Reactions using Arylmagnesium Reagents and Aryl-p-Tolylazo Sulfones
1) –20 °C, 1h2) allyl iodide, NMP 20 °C, 3 h
solvent evaporation3) Zn, AcOH 75 °C, 10 min
1) –20 °C, 1h2) allyl iodide, NMP 50 °C, 24 h
solvent evaporation3) Zn, AcOH 75 °C, 15 min
MgBr
N2Ts
R
N2Ts
CO2Et
IZn Me
HN
EtO2C
Me
HN
R
R = CO2Et, Br R = CO2Et; 62%R = Br; 67%
55
62%
New Amination Reactions using Arylmagnesium Reagentsand Aryl-p-Tolylazo Sulfones
HN
CO2Et
TfONN
Ts
CO2Et
TfO
N
HN
OMeN
NN
Ts
OMe
microwave
ZnAcOH/TFA 5:1
5 bar, 1h
overall yield 85%
microwave
ZnAcOH/TFA 5:1
5 bar, 2 h
overall yield 60%
HN
FG
NHN
Ts
FG
Raney-Nickel/ H2 (1 atm)
EtOH/ r.t. 12 h- 48h
FG: CO2Et FG: OMe FG: H
FG: H, OMe, CO2Et 96%88%76%
Challenging substrates
N
N
OEtO2CMgX
N
NR
I
N
N
NH2
Br
SMgX
HNF3C
CF3
CO2Et
some kinds of heterocycles
very electron-poor systemse.g.:
NH2
NH2
XMg
N
SMgX
N
triarylamines are not possiblee.g.:
1,2 Dehydrobenzene Formation via I/Mg Exchange Reaction
NO2
RO
I
SO
OOF3C Ar
O
O Ar
O
O Ar
O
OAr
O
NO2
RO
ClMg
Me OAr
PhMgCl
R=
I
OTf
O2N
PhMgCl
MgCl
OTf
O2N O2NTHF–78 °C–PhI
decomposition
New Amination UsingSelective Benzyne Formation via I/Mg Exchange Reaction
LGI
LGMgCl NAr2
MgX
ArN
Ar
MgX
?
NAr2
EE+
FG FG FG FG FG
OTfI
O OTfLi O
2.) nBuLi -78 °C
1.)
K. Suzuki Synlett 2000, 520.
Selective 1,2 Dehydrobenzene Formation via I/Mg Exchange Reaction
OTsI
OTsMgCl
OTs OH
Ph
95 %
iPrMgCl
-78 °C
PhCHO
-78 °C
OTsI
OTsMgCl
OO
iPrMgCl
-78 °C2 h
-78°C to RT 78 %2 h
OTsI
OTsMgCl
OO
iPrMgCl
-78 °C30 min
-78°C to RTFG FG FG FG
FG: CO2Me, CN FG = CO2Me: 73 %, 15 h CN : 77 %, 24 h
Selective 1,2 Dehydrobenzene Formation via I/Mg Exchange Reaction
ORI
CO2Me
ORMgCl
CO2Me CO2Me
OO
CO2Me
iPrMgCl
–78 °C –78 °C - RT
–78 °C
OR
CO2Me
OH
PhPhCHO
O2S
Cl
O2S
CF3
CF3
O2S
CH3
O2S
Cl
Cl
Me
Me
Me
O
OSO2MeSO2CF3SO2CH2CF3
R =
Selective 1,2 Dehydrobenzene Formation via I/Mg Exchange Reaction
ArO2SOI
ArO2SOMgCl
ArO2SO OH
PhiPrMgCl
-78 °CFG FG FG
PhCHO
-78 °C
FG = CO2Me, CN, CF3, Hal, [ NO2 (PhMgCl)]
Ar= 4-Chlorphenyl
Ar= 4-Chlorphenyl
ArO2SO OH
Ph
F3C
ArO2SO OH
Ph
CO2Me
ArO2SO OH
Ph
CN
ArO2SO OH
PhI
CN
ArO2SO OH
Ph
91 % 93 %95 % 95 %68 %
ArO2SO OH
Ph
NO2
95 %
Selective 1,2 Dehydrobenzene Formation via I/Mg Exchange Reaction
-78°C to RT
ArO2SOI i-PrMgCl
-78 °CFG
OArO2SO
MgCl
FG FG
FG = CO2Me, CN, CF3, Hal, NO2
Ar= 4-Chlorphenyl
FG
CO2Me
O
CN
O
NO2
OO
CO2MeO
89 %71% 78 %78 % 58 %
OTBSEtO
94 %
CO2Me
I
I. Sapountzis, W. Lin, M. Fischer, P. Knochel Angew. Chem. Int. Ed. 2004, 43, 4364.
New Amination Using Selective 1,2 Dehydrobenzene Formation via I/Mg Exchange Reaction
-78°C to RT
ArO2SOI
i-PrMgCl
-78 °C
NEt2
H
ArO2SOMgCl 1.) Et2NMgCl
2.) H+
75 %
-78°C to RT
ArO2SOI
i-PrMgCl
-78 °C
SPh
I
-78°C to RT
ArO2SOI i-PrMgCl
-78 °C
SCHO
Br
ArO2SOMgCl
ArO2SOMgCl
1.) PhSMgCl
2.) I2
81 %
1.) Br-PhSMgCl
2.) DMF
75 %W. Lin
Summary
• Functionalized Nitrophenylmagnesium Reagents
• Electrophilic Aminations using Nitrobenzenes or Arylazosulphones
•Preparation of Functionalized Benzynes via I/Mg Exchange
FGMgCl
O2N
NO2MgCl
FG
HN
FG2FG1
NO2
FG1 Ar1N N
Ts
NR
FG
R
FG
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