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TtitleNickel-mediated, Heterogeneous Cross-Couplings.
Bruce H. Lipshutz
University of California
Santa Barbara, CA USA
Department of Chemistry & Biochemistry
Phone: 805-893-2521; Fax: 805-893-8265; E Mail: [email protected]
WWW: http://www.chem.ucsb.edu/~lipshutzgroup/
Making Bonds Almost for Free
KEYS
Heterogeneous catalysis
Benefits:
Heterogeneous Catalysis
workup
recycling
environment
economics
Disadvantages: reaction rates
(1) dramatically increase rates
Potential for Microwave-assisted Reactions
(2) allow for use of (heat, air, and moisture)
sensitive organometallics at high temperatures
Potential for MW Reactions
JOC cover
Ni/C couplingsSuzuki
Time frame for reactions: 6 - >24 h
RZnX
RB(OH)2
RMgX
Negishi
Kumada
aminesBuchwald/Hartwig
Heterogeneous couplings catalyzed by Ni/C
reductions
Cl
R
Me2NH•BH3
+
Review: Lipshutz, B.H. Adv. Synth. Catal. 2001, 343, 313.
Negish Ni/C
n-C6H13ZrCp2Cl
CF3
C6H13-n
CF3
I
Negishi couplings catalyzed by Ni/C & accelerated by µW
95% (isolated)
1-octyne + Cp2Zr(H)Cl
+
no Ph3P
Ni/C, THF, , 24 h
no Ph3P
µW, 200°C, 10 min
Ni/C, THF
70% conversion
Table Zr couplings
OTBSClCp2Zr
OTIPSClCp2Zr
OTIPSClCp2Zr
OTIPSClCp2Zr
OTIPSClCp2Zr
OTIPSClCp2Zr
ICF3
I
OMe
BrF
Br
Me
Me
ClCF3
ClOO
Negishi couplings catalyzed by Ni/C & accelerated by µW
86
75
76
77
vinyl zirconoceneentry aryl halide time (min) yield (%)
83
831
2
3
4
5
6
15
40
30
20
15
10
Cl
CNCN
ZnCl
OMe
Cl
O
O
THF, 60°, 16 h
5% Ni / C, Ph3P
ClZn
+
Lipshutz, B. H.; Blomgren, P. A. J. Am. Chem. Soc. 1999, 121, 5819.
(92%)
Negishi couplings: organozinc reagents
+
OMe(82%)
O
O
THF, 60°, 24 h
5% Ni / C, Ph3P
Negishi Zn
Negishi MW-1CN
CN
ZnCl
ZnCl
(75%; isolated)180°, 30 min
+15% Ni / C, Ph3P
(90%; isolated)
Cl
CN
Cl
180°, 30 min
CN
ZnCl
F
CHO
Negishi couplings: catalyzed by Ni/C, accelerated by µW
Cl
CHO
15% Ni / C, Ph3P
F
(80%; isolated)
µW, dioxane
15% Ni / C, Ph3P
180°, 30 min
+
+µW, dioxane
µW, dioxane
Negishi MW -2ZnCl
ZnCl
Cl
Cl
ZnCl
ClMeO
CO2Et CO2Et
F F
OMe
OMe
OMe
OMe
µW, dioxane
+
(93%; isolated)150°, 15 min
8% Ni / C, Ph3P
150°, 15 min
8% Ni / C, Ph3P
(92%; isolated)
µW, dioxane
µW, dioxane
(75%; isolated)
15% Ni / C, Ph3P
more examples...
+
Negishi couplings: catalyzed by Ni/C, accelerated byµW
+
200°, 30 min
OMe
Negishi MW -3n-Bu-ZnCl
Cl
Cl
ZnCl
MeO
OTs
µW, dioxane
(96%; isolated)
150°, 30 min
Negishi couplings: catalyzed by Ni/C, accelerated by µW
70°, 30 min
more examples...
8% Ni / C, Ph3P
+
(91%; isolated)
8% Ni / C, Ph3P
(85%; isolated)
O
n-Bu
µW, dioxane
O
CN
EtO
CNO
15% Ni / C, Ph3P
+
MeO CHO 150°, 15 min
MeO
MeO CHO
EtOZnCl
O
+
µW, dioxane
Aminations ConvCH3
H3C Cl
NH-n-C6H13F
CH3
ClFH2N-n-C6H13
N OH H3C N OLiO-t-Bu
LiO-t-Bu
5% Ni / C, 2.5% dppf
(76%)
+
Aminations of aryl chlorides catalyzed by
(91%)
Lipshutz, B. H.; Ueda, H. Angew. Chem. Int. Ed. 2000, 39, 4492.
+
PhMe, 110°, 46 h
dioxane, , 47 h
10% Ni / C, 20% dppf
Ni/C
Aminations Ni/C + mW
F3C I
NFBrF
H3C
N
H
LiO-t-Bu, dioxane
H2N-C4H9 NH-C4H9LiO-t-Bu, dioxane
IF3C N
H
LiO-t-Bu, dioxane
N
CF3
µW, 200°, 10 min
5% Ni / C, 2.5% dppf
5% Ni / C, 2.5% dppf+
µW, 200°, 10 min (92%)
+
(80%)
Aminations of aryl halides: catalyzed by Ni/C, accelerated by µW
+
µW, 200°, 10 min
5% Ni / C, 2.5% dppf
(88%)
Aminations Ni/C + mW-ClCl
LiO-t-Bu, dioxane
LiO-t-Bu, dioxane
N
NCN
O
H
N
NC
O
Cl
NC N
H
CN
10% Ni / C, 5% dppf
µW, 200°, 10 min
+
µW, 200°, 10 min
10% Ni / C, 5% dppf
(95%)
+
(84%)
Aminations of aryl halides: catalyzed by Ni/C, accelerated byµW
Amination 3
µW, 180°, 10 min
+
N
H
LiO-t-Bu, dioxane
Aminations of aryl chlorides: catalyzed by Ni/C, accelerated by µW
+
5% Ni / C, 10% dppf
µW, 200°, 10 min
10% Ni / C, 5% dppf
(92%)
ClCN
NCN
LiO-t-Bu, dioxane
Cl
CF3
N
NH2
N
NHF3C
(85%)
Electron-rich + drugLiO-t-Bu, dioxane
Cl
NH
OMeO NMeOO
Br
F
NO
O
OTBDPS
NH
O
LiO-t-Bu, dioxane
N
F
NO
O
OTBDPS
electron-rich
O
Aminations of aryl halides: catalyzed by Ni/C, accelerated by µW
+
N
F
NO
10% Ni / C, 10% dppf
(86%)
O
µW, 200°, 30 min
+
NHAc
O
µW, 200°, 40 min
(86%)
10% Ni / C, 20% dppf
linezolid (antibacterial)Zyvox
Suzuki Conv
dioxane, , 18-24 h
Suzuki couplings of aryl chlorides catalyzed by Ni/C
+
Lipshutz, B. H.; Sclafani, J. A.; Blomgren, P. A. Tetrahedron 2000, 56, 2139.
K3PO4
O
Cl B(OH)2
(88%)
O
N
(84%)
OMe
(78%)
(85%)
O
S
6-10% Ni / C, 4 Ph3P
CN
Suzuki MW-1
KF, LiOH, dioxane
CN
CN
Cl81% isolated
+ 2% Ni / C, 12% Ph3P
Suzuki couplings catalyzed by Ni/C, µW accelerated
B(OH)2
O
µW, 200°C, 35 min
CF3
Cl
2% Ni / C, 12% Ph3P
B(OH)2
O
O
CF3
O
80% isolated
+KF, LiOH, dioxane
µW, 200°C, 35 min
Suzuki MW-2
KF, dioxane
CF3Cl
88% isolated
91% isolated
µW, 180°C, 35 min
2% Ni / C, 12% Ph3P
Suzuki couplings catalyzed by Ni/C, µW accelerated
B(OH)2
CF3
+
OMeB(OH)22% Ni / C, 12% Ph3P
O
Br
84% isolated
O
OMe
B(OH)2
OMe
KF, LiOH, dioxane
µW, 200°C, 35 min
CoQ MW model
O
O
MeO
MeO H
OTs
MeO
MeO H
(CoQ10)
OTs
MeO
MeOCl Me2Al
Me2AlOTIPS
OTs
MeO
MeOOTIPS
THF
H
µW, 200°C, 20 min
The MODEL
9
10
+
Application of µW technology to a practical problem: coenzyme Q
10
10
4% Ni / C, 2 Ph3P
(82%)
CoQ the real
O
O
MeO
MeO H
OTs
MeO
MeO H
(CoQ10)
OTs
MeO
MeOCl Me2Al
9
9
10
+
Application of µW technology to a practical problem: coenzyme Q
10
10
5% Ni / C, 2 Ph3PTHF
(80%)
H
Me2Al H
OTs
MeO
MeO H
µW, 200°C, 20 min
10
The REAL
14 h (85%)
conventional:
summarySummary
• Ni / C; rapid cross-couplings under µW conditions
• Ni / Cg; reagent for reductions of aryl OH groups
New technologies for heterogeneous catalysis
organo Ni chemistry
Acknowledgements
Acknowledgements
National Institutes of Health
Amgen, Biotage
Ni/C
Bryan Frieman
Ben Taft
Pierce Lee
Ni/Cg
Bryan Frieman
Tom Butler
Vladimir Kogan
Danielle Nihan
Peter Blomgren
Takashi Tomioka
Joe Sclafani
Hiroshi UedaStefan TaslerSteven Pfeiffer
current
former
Will Chrisman
