solid supported pd-peppsi-ipentcl-10
TRANSCRIPT
Immobilization of Pd-PEPPSI-IPentCl
Speaker: Craig DaySupervisor: Michael Organ
N NN
SiO2
NN
PdCl ClN
Cl
Cl Cl
2
2010 Nobel Prize Winners
http://www.nobelprize.org/Cooper, T. W. J.; Campbell, I. B.; Macdonald, S. J. F. Angew. Chem. Int. Ed. 2010, 49, 8082
• 2010: 22% of all reactions in pharma are Pd-catalyzed couplings
• 2013: Buchwald-Hartwig amination most common reaction in pharma
3
General catalytic cycle
X M [PdCl2(PPh3)2]
LnPd0
LnPdII
R1
X
LnPdII
R1
R2
R2-MM-X
R1-XR1-R2
R1,R2= aryl, heteroaryl, alkylX= halide, pseudohalidesM= B(OR)2 (Suzuki-Miyaura),SnR3 (Stille), ZnR (Negishi), HNR2 (Buchwald-Hartwig)
Oxidativeaddition
Transmetallation
Reductiveelimination
Oxidative addition• Improved by electron rich metal
Transmetallation• Ease impacted by reactivity of nucleophilic partner
Reductive elimination• Reverse of oxidative addition• Improved by sterically bulky ligand
4
Phosphines N-Heterocyclic Carbenes(NHCs)
• σ-donating ligands - Increase e- density around metal centre- Easier oxidative addition- Difficult reductive elimination
• Easily oxidized• Measured with Tolman cone angle
• Electron-rich, neutral σ-donoring ligand
• Steric and electronic properties are tuneable
• Forms a very stable metal complex• Measured with percent buried
volume
PR
M
RR
NN
M
N N
IPr
Cl
P
Triphenylphosphine
PPh2
PPh2
BINAP
5
PEPPSI
• Pyridine-Enhanced Precatalyst Preparation Stabilization Initiation
NN
PdCl ClN
Cl
Pd-PEPPSI-IPr Pd-PEPPSI-IPent Pd-PEPPSI-IPentCl
NN
PdCl ClN
Cl
Cl Cl
NN
PdCl ClN
Cl
Increasing activity
6
Transition to heterogenous catalysis
• Solid Support− Economical (recovery of metal
and ligand)− Environmentally friendly− Reduce contamination
• Flow Applications− Improved heat transfer− Efficent mass transport and
mixing− Faster and safer reactions− Ease of scale-up
SiliaCat® immobilized DPP-Pd complex
• Silica− Cheap, widely available and
studied
• Phosphines− Easy to synthesize− Good catalyst− Suspected dissociation
mechanism− Leaching issues
7
NHC Immobilization
N N AdAd
O
SiO2
CuI
PVP
PVP = polyvinylpyridine
N N RR
PdCl ClNH
N N
OPdO
ClOO
S
SiOOOEt
S
SiO O
OEt
SiO2
(1) (2) (3)
1. Collinson, J.-M.; Wilton-Ely, J. D. E. T.; Díez-González, S. Chem. Commun. 2013, 49 (97), 11358–11360
2. Mennecke, K.; Kirschning, A. Synthesis 2008, (20), 3267–3272.3. Martínez, A.; Krinsky, J. L.; Peñafiel, I.; Castillón, S.; Loponov, K.; Lapkin, A.; Godard, C.; Claver,
C. Catal. Sci. Technol. 2014, 5 (1), 310–319.
Alters backbone of NHC Not attached to NHC ligand Impacts steric propertiesMade in-situ
8
Objective
• Advantages:− Robust − Tethered unit distant from metal centre− High yielding synthesis− Electronic properties of metal assumed to be the same− Preform metal complex for characterization
N NN
SiO2
NN
PdCl ClN
Cl
Cl Cl
9
1st generation: construction of aniline segments
NH2n-BuLi (1.1 equiv)
THF, r.t., 24 hr82%
Br
OEt
OEt(1.1 equiv.)
HN
OEt
OEt
NH2I2 (1.1 equiv.)
Et2O/Aq. NaHCO3
r.t., 2hr95%
NH2
I
Me3SiCCH (1.5 equiv.)Pd(PPh3)2Cl2 (2 mol%)
CuI (2 mol%)Et3N75%
NH2
TMS1 6 7
1 2
N O
OAc
1.HCOOH, Ac2O, r.t., 2hr
2.THF, r.t.
N
OEt
OEt
HClO4r.t., 3.5 hr
98%
O
ClO4
3
5
N
OO
4
HCOOH4 hr
51%
N NN
SiO2
NN
PdCl ClN
Cl
Cl Cl
10
Synthesis of protected immidazolium salt
N O
OAc
ClO4
5
NH2TMS
1.25 equiv.
CH2Cl2/Toluener.t., 18 hr
69%
N N
TMSClO4
N N
TMSClO4
SOCl2
CH2Cl2, rt, 30 min93%
DOWEX 1x4 chloride resin,(20-50 mesh),
CH2Cl2/Toluene/MeOH(80:15:5)
90%
N N
TMS
10
Cl
7
8
9
OH
N NN
SiO2
NN
PdCl ClN
Cl
Cl Cl
11
Final steps to immobilization
1) Cu2O, Toluene,110 oC, 48 hr
2) TBAF, THF,r.t, 5hr62%
N N
H
11
CuCl
MeCN, 40 oC, 16 hrN3 Si(OEt)3
86%
N N
CuCl
NN
N
(EtO)3Si
N N
PdN
NN
N(3-ClPy)2PdCl2
Toluene, 110 oC,48 hr61%
Cl
ClCl
(EtO)3Si
12
13
1) SiO2, toluene, 100 oC, 24 hr
2) HMDS, r.t., 24 hr
N N
PdN
NN
N
Cl
ClCl
SiO
O
OROTMS
0.3 mmol/gPd-PEPPSI-triazole
on SiO2
Flow applications• Screened in flow (Negishi)• Active for 14 hours
N NN
SiO2
NN
PdCl ClN
Cl
Cl Cl
12
Alkylation and decomposition
IPr IPent
NH2n-BuLi (1.1 equiv)
THF, r.t., 24 hr30%
Br
OEt
OEt(1.1 equiv.)
HN
OEt
OEtNH2n-BuLi (1.1 equiv)
THF, r.t., 24 hr82%
Br
OEt
OEt(1.1 equiv.)
HN
OEt
OEt
NH2
OMe
OMe
O
H
(1 equiv.)
CH2Cl2, MgSO4
N OMeMeO
Reducing Agent
THF, 24 hr
HN
OMe
OMe
1 2 16 18
1 14 15
N NN
SiO2
NN
PdCl ClN
Cl
Cl Cl
13
Reduction
N OMeMeO
Reducing Agent
Solvent, 24 hr
HN
OMe
OMe
14 15
Reducing agent
Equiv. Solvent Conversion(%)
Yield(%)
Borane 1.2 THF 100 41 + decomp.
NaCNBH3 1.1 CH2Cl2 100 49 + decomp.
Na(OAc)3BH
1.4 CH2Cl2 86 86
N NN
SiO2
NN
PdCl ClN
Cl
Cl Cl
14
2nd generation: construction of aniline segments
N O
OAc
NH2
OMe
OMe1.1 equiv.
N
OMe
OMe
HClO4r.t., 3.5 hr
50%
NH2I2 (1.1 equiv.)
Et2O/Aq. NaHCO3
r.t., 2hr93%
NH2
I
Me3SiCCH (1.5 equiv.)Pd(PPh3)2Cl2 (2 mol%)
CuI (2 mol%)Et3N98%
NH2
TMS16 22 23
ClO4
16 17 18
H
O
CH2Cl2, MgSO4
r.t, 24 hr98%
Na(AcO)3BH
CH2Cl2, r.t., 24 hr99%
HN
OMe
OMe
21
HCOOH 4 hr N
OO
20
1.HCOOH, Ac2O, r.t., 2hr
2.THF, r.t.
N
OMe
OMe
O
19
N NN
SiO2
NN
PdCl ClN
Cl
Cl Cl
15
Steric considerations
NH2TMS
N O
OAc
ClO4
21
1.25 equiv.
CH2Cl2/Toluener.t., 18 hr
NN
OH
TMSClO4
23
24
N NN
SiO2
NN
PdCl ClN
Cl
Cl Cl
16
Summary
• Robust, simple approach targeting complex anilines
• Proof of concept confirmed for transformations before joining segments
NH2
OMe
OMe1.1 equiv.
N
OMe
OMe
16 17 18
H
O
CH2Cl2, MgSO4
r.t, 24 hr98%
Na(AcO)3BH
CH2Cl2, r.t., 24 hr99%
HN
OMe
OMe
NH2TMS
N O
OAc
ClO4
21
1.25 equiv.
CH2Cl2/Toluener.t., 18 hr
NN
OH
TMSClO4
23
24
17
Acknowledgement
• Supervisor− Dr. Organ
• Committee− Dr. Orellana− Dr. Wilson
• Lab members− Greg Price, PhD