binder, j. t.; cordier, c. j.; fu, g. c. j. am. chem . soc. 2012 , asap
DESCRIPTION
Catalytic Enantioselective Cross-Couplings of Secondary Alkyl Electrophiles with Secondary Alkylmetal Nucleophiles. Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem . Soc. 2012 , ASAP. « CRAZY » COUPLINgS !!. Lea Constantineau November 21, 2012. - PowerPoint PPT PresentationTRANSCRIPT
Catalytic Enantioselective Cross-Couplings of Secondary Alkyl Electrophiles with Secondary
Alkylmetal Nucleophiles
Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP
Lea ConstantineauNovember 21, 2012
R1
Br
R n
IZnracemic
R1
R
O
N
t-Bu
N
(S)-1
n
10% NiBr2.glyme
13% (S)-1
1.2 CsI or MgI2CH2Cl2 / dioxane
-30 °C
R2 Mn+2D
MnLn
R2
D
M2YX-M2-Y
R2
D
R1 R1
homocoupling
hydrideelimination
R2
LnMn+2
D
X
R2
D
M2Y
R2
D
D
proto-demetalation
LnMn+2
X
R1
XR1
hydrideelimination
R1
R1
R1
oxidativeaddition
transmetalation
reductive elimination
n is oxidation state
The Challenges of C(sp3)-C(sp3) Cross-Coupling
21) Jana,R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417.
Slow oxidative addition: Homocoupling or β-elimination of the electrophile Spontaneous decomposition of alkyl organometallics via β-elimination or proto-demetalation Slow transmetalation: needs of additives
Slow oxidative addition: Homocoupling or β-elimination of the electrophile Spontaneous decomposition of alkyl organometallics via β-elimination or proto-demetalation Slow transmetalation: needs of additives
C(sp3)-C(sp3) Cross-Couplings in Total Synthesis
3
O
OHHO
Zoapatanol1O
B-alkyl Suzuki-Miyaura Coupling
1) Raghavan, S.; Babu, V. S. Chem. Eur. J. 2011, 17, 8487. 2) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem. Soc. 2002, 124, 14983. 3) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756.
Gambierol2
B-alkyl Suzuki-Miyaura Coupling
OHO
O
O
O
H
OH
H H H O
O
O
O HHH
HHHMeMe
H MeMe
HMe
OH
Fluvirucininie A13
Me
OH
MeEt
NH
O
First Negishi Coupling
Second Negishi coupling
Examples of asymmetric Cross-Coupling with Alkylzinc Reagents
41) Fisher, C; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594. 2) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756.
RBrZn
racemic
10% NiCl2.glyme
13% (S,S)-Pybox
DMI/THF (7:1)
0 °C
R1, R = alkyl 51-90% yield77-96% ee
R1
Br 1.3 equiv
NBn
O
Ph
R1
R
NBn
O
Ph
NN
O
DMI
(S,S)-pybox
N
N
OO
N
iPr iPr
RBrZn
racemic
5% NiCl2.glyme
5.5% (S,S)-BnCH2-pybox
4.0 equiv NaCl
DMA/DMF (1:1), -10 °C
R1= alkyl, COR, CONR2
R2 ,R = alkyl
54-95% yield69-98% ee
R2
Br
R1
1,2 equiv
R2
R
R1
(S,S)-BnCH2-pybox
N
N
OO
N
BnBn
First Asymmetric Negishi Cross-Coupling
MeN
O
Ph
PhMe
O
O
85% ee63% yield
MeN
O
Ph
Ph
90% ee54% yield
EtN
O
Ph
Ph
91% ee74% yield
OTBS4
EtN
O
Ph
Ph
90% ee63% yield
N6
EtN
O
Ph
Ph
84% ee70% yield
EtN
O
Ph
Ph
69% ee51% yield
CN4
n-BuN
O
Ph
Ph
90% ee64% yield
2
FN
O
Ph
Ph
OMe
88% ee83% yield
Ph
2
Only one Example of a Secondary-Secondary Cross-Coupling
5Zultanski, S. L.; Fu, G.C. J. Am. Chem. Soc. 2011, 133, 15362.
(9-BBN)
10% Ni.glyme
12%
KOtBu(1.4 equiv)
n-hexanol (1.8 equiv)
Et2O/hexanes (1:1)
r.t.
RR1
Cl
N
O
R1
R
N
OMeHN
Ph Ph
NHMePh
Ph
Ph
Ph
Cross-Couplings of Secondary Alkyl Electrophiles with Primary Alkylzinc Nucleophiles
61) Arp, F.O.; Fu, G.C. J. Am. Chem. Soc. 2005, 127, 10482. 2) Krasovskiy, A.; Knochel, P. Synthesis 2006, 890.
RR1BrZn
racemic
R
(S,S)-pybox
10% NiBr2.glyme
13% (S,S)-pybox
N,N-dimethylacetamide
0 °C
Br
N
N
OO
N
i-Pr i-Pr
R1
R1 = primary alkyl47-89% yield
90% ee
1.6 equiv
R1
Br
R n
IZnracemic
R1R
nSame condition
<5% yield<80% ee
Alkylzinc reagents synthesis by Knochel’s method
Optimization of the Reaction
7
R1
Br
Rn
IZnracemic
R1R
n
10% NiBr2.glyme
13% (S)-1
1.2 CsI or MgI2CH2Cl2 / dioxane
-30 °C1.8 equiv
entry variation from the “Standard” conditions ee (%) yield (%)
1 (S)-4 instead of (S)-1 78 84
2 none 95 91
3 no NiBr2.glyme - <2
4 no (S)-1 - 9
5 no CsI 93 69
6 r.t. 72 20
7 5% NiBr2.glyme, 6.5% (S)-1 93 64
8 (S,S)-pybox instead of (S)-1 - <2
9 (S,S)-5 instead of (S)-1 55 9
O
N
t-Bu
N
(S)-1
O
N
t-Bu
N
(S)-4
N
OO
N
i-Pr i-Pr(S,S)-5
(S,S)-pybox
N
N
OO
N
i-Pr i-Pr
1) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP. 2) Choi, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 9102. 3) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756.
Cross-Couplings of Secondary Alkyl Electrophiles with Secondary Alkylzinc Nucleophiles
8Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP
R1
Br
R n
IZn
racemic
R1R
O
N
t-Bu
N
(S)-1
n
10% NiBr2.glyme
13% (S)-1
1.2 CsI or MgI2CH2Cl2 / dioxane
-30 °C
1.8 equiv
Scope of the Reaction
9
R1
Br
Rn
IZnracemic
R1R
n
10% NiBr2.glyme
13% (S)-1
1.2 CsI or MgI2CH2Cl2 / dioxane
-30 °C1.8 equiv
O
N
t-Bu
N
(S)-1
1) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP.
95% ee91% yield
95% ee72% yield
93% ee75% yield
87% ee48% yield
F
95% ee86% yield
MeOEt
91% ee65% yield
BnO
96% ee74% yield
95% ee80% yield
Et
91% ee51% yield
F3C
Ph92% ee
74% yield
Cl
91% ee74% yield
I
Et
92% ee68% yield
Br98% ee
79% yield
95% ee54% yield
O
Et
87% ee60% yield
Et
84% ee52% yield
MeO
Cross-Couplings of Secondary Alkyl Electrophiles with Acyclic Secondary Alkylzinc Nucleophiles
101) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP. 2) Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 7532.
BrMe Me
IZn
racemic
MeMe10% NiBr2
.glyme
13% (S)-1
1.2 CsI or MgI2CH2Cl2 / dioxane
-30 °C1.8 equiv
Bn Bn Bn
Me
76 : 24branched59% ee
linear9% ee
O
N
t-Bu
N
(S)-1
Br
IZn
racemic
MeMe10% NiBr2
.glyme
13% (S)-1
1.2 CsI or MgI2CH2Cl2 / dioxane
-30 °C1.8 equiv
Bn BnBn
Me
62 : 38 branched76% ee
linear9% ee
Me
First time that a branched product is formed from a linear alkylmetal compound.2
Possible Mechanism for Nickel-catalyzed Secondary-Secondary Cross-Couplings
11Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP 2) Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 7532.
L*NiI-XRR1
oxidativeaddition
transmetalationreductive elimination
IZn R
L*NiI
MeL*NiI
Me
Me
R1 Br
L*NiIII R1
R
Br
R = i-Pr or n-Pr
O
N
t-Bu
N
L*
L*NiI
Me
HH
H
L*NiI
H
Me
L*NiI CH2
HMe
L*NiIMe
H
L*NiI
H
Me
HH
-hydride elimination
-hydride elimination
-migratory insertion
-migratory insertion
branchedlinear
Isomerisation: β-hydride elimination and β-migratory insertion
Use of a bidentate, rather than tridentate, ligand
Transmetalation occuring before oxidative addition (NiI catalyzed)
Isomerisation: β-hydride elimination and β-migratory insertion
Use of a bidentate, rather than tridentate, ligand
Transmetalation occuring before oxidative addition (NiI catalyzed)
Syn Selective mechanism
121) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP.
R1
Br
racemic
R1
10% NiBr2.glyme
13% L*
1.2 CsI or MgI2CH2Cl2 / dioxane
-30 °C
D
D ZnI
95% yield97% ee
Five isomersD and 1-phenylethyl: trans
L*NiI L*NiI
H
L*NiI
L*NiI
-hydride elimination
-hydride elimination
-migratory insertion
-migratory insertion
D
D
D
H L*NiIH L*NiIH L*NiIH L*NiIH
D D D D D
The β-hydride elimination and β-migratory insertion are Syn specific D always trans from the Nickel
Reaction with 0.5 equiv of cyclopentene did not give incorporation of unlabeled cyclopentane
The β-hydride elimination and β-migratory insertion are Syn specific D always trans from the Nickel
Reaction with 0.5 equiv of cyclopentene did not give incorporation of unlabeled cyclopentane
Conclusion
13
New enantioselective cross-coupling of secondary electrophiles with secondary alkylzinc reagents.
New class of ligand was used (Usually Negishi reactions are done with Pybox ligand).
Discovery of a unusual isomerization: formation of a branched product from a linear alkylzinc reagents.
O
N
t-Bu
N
(S)-1
Br
IZn
racemic
MeMe10% NiBr2
.glyme
13% (S)-1
1.2 CsI or MgI2CH2Cl2 / dioxane
-30 °C1.8 equiv
Bn BnBn
Me
62 : 38 branched76% ee
linear9% ee
Me
R1
Br
Rn
IZnracemic
R1
R
n
10% NiBr2.glyme
13% (S)-1
1.2 CsI or MgI2CH2Cl2 / dioxane
-30 °C1.8 equiv
Entry Ar alkyl alkyl1 ee (%) yield (%)
1 ph Me 80 68
3 ph n-Bu 82 64
5 Me 66 62
6Et
85 74
First Asymmetric Suzuki-Miyaura Cross-Coupling of an Unactived Secondary Alkyl Halide
14
(9-BBN)
10% Ni(cod)2
12% (R,R)-1
KOtBu(1.2 equiv)iBuOH (2.0 equiv)
iPr2O, 5 °C
alkyl1Ar
alkyl
Br
Aralkyl
alkyl1
MeHN NHMe
F3C CF3
(R,R)-1
Ph
OTBS
OTBSO
O
O
OMe
OMe
Saito, B. Fu, G. C. J. Am. Chem. Soc. 2008, 130, 6694.
β-hydride elimination and β-migratory insertion
15
L*NiI
Me
HH
H
L*NiI
H
Me
L*NiI
H
Me
L*NiI CH2
HMe
L*NiIMe
H
L*NiI
H
Me
HH
-hydride elimination
-hydrideelimination
-migratory insertion-migratory insertion
branched
linear
Use of a bidentate, rather than tridentate, ligand Transmetalation occuring before oxidative addition
Use of a bidentate, rather than tridentate, ligand Transmetalation occuring before oxidative addition
1) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP. 2)
16
17
C(sp3)-C(sp3) Cross-Couplings in Total Synthesis
18
O
OHHO
Zoapatanol1O
B-alkyl Suzuki-Miyaura Coupling
1) Raghavan, S.; Babu, V. S. Chem. Eur. J. 2011, 17, 8487. 2) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem. Soc. 2002, 124, 14983
Gambierol2
B-alkyl Suzuki-Miyaura Coupling
OHO
O
O
O
H
OH
H H H O
O
O
O HHH
HHHMeMe
H MeMe
HMe
OH
alkyl1R
alkyl
Br
Ralkyl
Suzuki-MiyauraCross-Coupling
9-BBN alkyl1