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