∂
Efficient Catalytic Syntheses of Organoboronate Esters
Ubiquitous building blocks for the fine chemical and pharmaceutical industries
∂ Chemistry Initiative
NORSC Sustainable
Ramside Hall, Durham
24th April 2012
Patrick Steel
Department of Chemistry, Durham University, UK
p.g.steel@durham.ac.uk
Why make aryl boronates?
∂
Hall, Boronic Acids, Wiley-VCH, 2nd Ed 2011
Why make aryl boronates?
• Non-toxic
• Tolerant to air and water
• Stable in the absence of a catalyst
∂
• React under mild conditions
• Reaction by-product is inert and benign to humans
Hall, Boronic Acids, Wiley-VCH, 2nd Ed 2011
Classical Aryl Boronate Synthesis
a Sustainable Chemistry Challenge?
F
H2N
Br
1. i. n-BuLi (2 eq.), THF, 0 °C
ii. TMSCl
2. i. t-BuLi (2.2 eq.), Et2O, -78 °C
ii. B(OMe)3 (xs), -78 °C
iii. 0.1N aq HCl
F
H2N
B(OH)2
45 %
Asher et al., Tetrahedron Lett., 2003, 44, 7719
∂
NEt2
O
MeO
O
NEt2
i. s-BuLi, TMEDA, THF, -78 °C
ii. B(OMe)3
O
MeO
B(OH)2
iii. 10 % aq. HCl
88 %
Snieckus et al., J. Org. Chem., 2009, 74, 4094
O
Functional Group Tolerant Aryl Boronate Synthesis
Pd(dppf)Cl2 (3 mol%), KOAc (3 eq.),
B2pin2 (1.1 eq.)
O
O
O
Br
B
DMSO, 80 °C, 1 h
O
80 %
Ishiyama, Miyaura et al., J. Org. Chem., 1995, 60, 7508
∂
CuI (10 mol%), nBu3P (13 mol%),
KOtBu (1.5 eq.), B2pin2 (1.5 eq.)
O
Br
B
O
THF, 25 °C, 24 h
69 %
Kleeberg, Marder et al., Angew. Chem. Int. Ed., 2009, 48, 5350
Iridium Catalysed Arene C-H Borylation
∂
Mkhalid, Barnard, Marder, Murphy, Hartwig, Chem. Rev., 2010, 110, 890
Iridium Catalysed Arene C-H Borylation
∂
Mkhalid, Barnard, Marder, Murphy, Hartwig, Chem. Rev., 2010, 110, 890
Iridium Catalysed Borylation – An Atom Economical Process
∂
Iridium Catalysed Borylation – An Atom Economical Process
∂
Iridium Catalysed Borylation – An Atom Economical Process
∂
‘One-pot’ Transformations from Arenes
S
i. [Ir(OMe)(cod)]2 (1.5 mol%), dtbpy (3 mol%)
HBpin (1.5 eq) hexanes, 25 ˚C, 0.5h
S
CF3
ii. removal of volatiles
iii. aq. K3PO4•nH2O, 4-BrC6H4CF3, Pd(PPh3)4 (2 mol%)
DME, 80 ˚C, 8 h
85%
Maleczka, Smith et al., Tetrahedron, 2008, 64, 6103
∂
CO2Me
i. [Ir(OMe)(cod)]2 (1.5 mol%), dtbpy (3 mol%)
B2pin2 (0.5 eq) hexane (1 vol) 25 ˚C, 4h
Cl
Cl
ii. aq. K3PO4; 4-BrC6H4CO2Me, PdCl2(dppf) (3 mol%)
DMF (2 vol), 60 ˚C, 2 h
Cl
96%
Cl
Ishiyama, Miyaura et al., Tetrahedron, 2008, 64, 4967
One-pot C-H Borylation/Suzuki-Miyaura Cross-Coupling
O
[Ir(OMe)(cod)]2 (1.5 mol%), dtbpy (3 mol%)
B
O
B2pin2 (1 equiv), solvent, 80 ˚C, 6 h
∂
Solvent
Temp ( ˚C)
Time (h)
GC-MS Conversion (%)
DMF
80
6
0
1,4-dioxane
80
6
25
MeCN
80
6
37
2-MeTHF
80
6
85
MTBE
80
6
100
Peter Harrisson
One-pot C-H Borylation/Suzuki-Miyaura Cross-Coupling
CO2Me
O
[Ir(OMe)(cod)]2 (1.5 mol%)
dtbpy (3 mol%)
B
Pd(dppf)Cl2 (3 mol%)
KOH (5 eq)
O
B2pin2 (1 eq)
MTBE
80 ˚C, 6 h
4-MeO2CC6H4I (1.2 eq)
MTBE - H2O, 80 ˚C, 3 h
∂
Peter Harrisson
90%
One-pot C-H Borylation/Suzuki-Miyaura Cross-Coupling
CO2Me
O
[Ir(OMe)(cod)]2 (1.5 mol%)
dtbpy (3 mol%)
B
Pd(dppf)Cl2 (3 mol%)
KOH (5 eq)
O
B2pin2 (1 eq)
MTBE
80 ˚C, 6 h
4-MeO2CC6H4I (1.2 eq)
MTBE - H2O, 80 ˚C, 3 h
∂
Peter Harrisson
90%
One-pot C-H Borylation/Suzuki-Miyaura Cross-Coupling
CO2Me
O
[Ir(OMe)(cod)]2 (1.5 mol%)
dtbpy (3 mol%)
B
Pd(dppf)Cl2 (3 mol%)
KOH (5 eq)
O
B2pin2 (1 eq)
MTBE
80 ˚C, 6 h
4-MeO2CC6H4I (1.2 eq)
MTBE - H2O, 80 ˚C, 3 h
∂
Peter Harrisson
90%
One-pot C-H Borylation/Suzuki-Miyaura Cross-Coupling
∂
Peter Harrisson
Microwave Accelerated “One-Pot” Biaryl Synthesis
∂
Peter Harrisson
Challenges for Ir-Catalysed Arene C-H Borylation
Regiocontrol
[Ir(OMe)(cod)]2
dtbpy
R
R
Bpin
B2pin2
80 ˚C
R
R
Rbig
R
∂
R
R
2
Rsmall
1
Challenges for Ir-Catalysed Arene C-H Borylation
Carboxylic
Acid
Vs. Boronic
Acid:
Heterocyclic
Organoboronic
Acids
Chemical Space Comparison
Green = Available
Red = Non Available
MeO
Phenyl Aromatic Space
Heterocyclic Ar Space
CO2H
∂
N
OH
OH
MeO
B
CO2H
N
B
N
OH
OH
N
Carboxylic acids open up more heterocyclic design space!
Data – Courtesy David Blakemore Pfizer - Neusentis
Challenges for the Synthesis of Heterocyclic Boronate Esters
1
2
N
H
N
H
N
TIPS
N
Bpin
[Ir(OMe)(cod)]2 (2.5 mol%)
dtbpy (5 mol%)
B2pin2 (0.5 eq)
N
hexanes, 80 ˚C
Bpin
∂
N
+
N
1:1
[Ir(OMe)(cod)]2 (1.5 mol%)
dtbpy (3 mol%)
B2pin2 (2 eq)
N
MTBE, mW, 80 ˚C
Bpin
Bpin
Bpin
N
Bpin
N
89% 1 : 1
Challenges for the Synthesis of Heterocyclic Boronate Esters
1
2
N
H
N
H
N
TIPS
N
Bpin
[Ir(OMe)(cod)]2 (2.5 mol%)
dtbpy (5 mol%)
B2pin2 (0.5 eq)
N
hexanes, 80 ˚C
Bpin
∂
N
+
N
1:1
[Ir(OMe)(cod)]2 (1.5 mol%)
dtbpy (3 mol%)
B2pin2 (2 eq)
N
MTBE, mW, 80 ˚C
Bpin
Bpin
Bpin
N
Bpin
N
89% 1 : 1
Quinoline Boronate Esters
∂
Peter Harrisson
Where Now for ‘Cleaner Greener’ Aromatic C-H Borylation?
Other sequential chemistries
Faster more effective Catalysts.
Better ligand sets to control regiochemistry.
∂
Where Now for ‘Cleaner Greener’ Aromatic C-H Borylation?
∂
Where Now for ‘Cleaner Greener’ Aromatic C-H Borylation?
Other sequential chemistries
Faster more effective Catalysts.
Better ligand sets to control regiochemistry.
∂
Cheaper metals than “Ir” – Cu????
Alkyl Boronate Esters via Cu-Catalysed C-X Activation
∂
Hazmi Tajuddin
2012 Durham Lectures
Prof John Hartwig
University of California, Berkeley
∂
Monday 14th May
Tuesday 15th May
Wednesday 16th May
Department of Chemistry, Durham University
All Lectures Commence at 4pm – Visitors Welcome
For Further Details p.g.steel@durham.ac.uk
Understanding and Optimising Chemical Processes
2nd & 3rd July 2012
Department of Chemistry
Durham University
This two-day programme provides delegates with an opportunity to augment
their process knowledge using Principal Components Analysis (PCA) and
Design of Experiments (DoE) methodologies to expand process
understanding, establish and develop capability, ensure robust and in-control
∂
processes, improve quality and reduce operational and environmental costs.
Keynote Speaker
Martin Owen
Product Development, GlaxoSmithKline, Stevenage
Further Information & Registration
Contact: Matthew Linsley, ISRU, Newcastle University
matthew.linsley@newcastle.ac.uk
29
Acknowledgements
Prof Todd Marder
Peter Harrisson
Hazmi Tajuddin
Bianca Bitterlich
Prof Lei Liu (Tsinghua University, Beijing)
∂
Alan Kenwright (NMR)
Jackie Mosely (MS)
Andrei Batsanov (X-ray)
James Morris (Syngenta)
Aoife Maxwell (GSK)
Lena Shukla (GSK)
Understanding and Optimising Chemical Processes
2nd & 3rd July 2012
Department of Chemistry
Durham University
This two-day programme provides delegates with an opportunity to augment
their process knowledge using Principal Components Analysis (PCA) and
Design of Experiments (DoE) methodologies to expand process
understanding, establish and develop capability, ensure robust and in-control
∂
processes, improve quality and reduce operational and environmental costs.
Keynote Speaker
Martin Owen
Product Development, GlaxoSmithKline, Stevenage
Further Information & Registration
Contact: Matthew Linsley, ISRU, Newcastle University
matthew.linsley@newcastle.ac.uk
31
∂