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Homogeneous Hydrogen
Transfer Chemistry
Professor Steve Marsden
Contents
 Introduction
 Catalytic Asymmetric Transfer Hydrogenation (CATHy) technology
 “Oxidant-free” oxidations
 Hydrogen-shuffling reactions
 Process perspectives
 Conclusions
Introduction
 Hydrogen – low molecular weight, needs to be transferred efficiently
 Avoid hazards/bespoke processing where possible
 Three reaction manifolds:
 Reduction (“In”)
 Oxidation (“Out”)
 Shuffling (“Shake it
all about”)
1. Catalytic Asymmetric Transfer
Hydrogenation (CATHy)
 Asymmetric reduction of ketones/imines
 Chiral alcohols/amines industrially important
 Classical synthesis: resolution (>50% waste)
Catalytic Asymmetric Transfer
Hydrogenation (CATHy)
 Transfer hydrogenation: uses soluble molecule as source of hydrogen
 Iso-propanol:
 Formate:
 Advantages: reduced hazards, scalability (homogeneous
– reduced mixing issues), standard kit (standard pressure)
CATHy examples
 Chiral amine (below right) – key intermediate in GSK’s Vestipitant
(anxiolytic, anti-emetic)
 Imine reduction route:
 Ketone reduction route:
CATHy examples
 Diltiazem – blockbuster anti-hypertensive
 Currently made by classical resolution of racemic intermediate
WASTE
 CATHy: enantioselective synthesis by Dynamic Kinetic Resolution
CATHy examples
 DKR:
2. Oxidation chemistry
 Oxidation: loss of hydrogen (Mw = 2)
 Frequently requires ‘heavy’ and undesirable reagents – hazards, waste
 Example: oxidative formation of heterocycles
XH
[O]
+
R'
R
X
O
R'
NH2
XH
X
R'
R'
N
R
R
N
R
H
N
H
 Common reagents: Pb(OAc)4, Mn(OAc)3, DDQ, PhI(OAc)2, Ag2O, MnO2
“Oxidant free” oxidations
 Use of homogeneous iridium catalyst: spontaneous loss of H2 gas
XH
+
R'
X
1% [Cp*IrI2]2
R
O
R'
toluene, reflux, 24 h
NH2
XH
X
R'
R'
N
R
R
H
N
H
Org. Lett., 2009, 11, 2039
R
N
H2
3. “Hydrogen-shuffling” chemistry
 Exchange of hydrogens – equilibration
 Use in racemisation of chiral amines (SCRAM):
NH
NH2
NH2
- H2
+ H2
+ H2
- H2
SCRAM: recycling valuable waste
 Example: classical resolution of Sertraline:
NHMe
NHMe
+
Ar
HO2C
Add
Ph
( = XH)
OH
NH2Me X
NH2Me X
+
Ar
Ar
crystalline
Ar = 3,4-dichlorophenyl
Ar
mother liquors
i) SCRAMTM; ii) KOtBu
 SCRAM facilitates recycling of late-stage unwanted enantiomer
SCRAMTM: Org. Proc. Res. Dev., 2007, 11, 642 and Tetrahedron Lett., 2007, 48, 1247
Recycling of sertraline: Org. Proc. Res. Dev., 2009, 13, 1370
Hydrogen-shuffling: new reactivity
 Changing oxidation state changes chemistry
 Catalysis can be employed for transient activation of unactive molecules
XH
unreactive
R1
XH
YH
R2
R1
R2
or
R1
R3
Mcat
"McatH2"
reactive
X
Y
X
or
R1
R2
R1
R2
R1
R3
Amine alkylation in water
 Coupling of amines/alcohols (no alkyl halides – PGIs)
R1
NH2
+
1% [Cp*IrI2]2
R3
HO
R1
H2O, 100oC, 10h
R2
R3
O
R3
R2
- H2O
R2
H
N
R1
R3
N
R2
 SCRAM facilitates this reaction in water
Chem. Commun., 2010, 1541 and Org. Proc. Res. Dev., 2010, 13, 1046
Process considerations
 Expensive precious metal catalysts (recycle)
 Separation of metal from APIs (to ppm levels)
 Solution: solid-supported catalysts
 Cp-STAR (TSB-funded) project (Leeds, Cambridge, Yorkshire Process
Technology, AstraZeneca, Pfizer)
 Patented technology allows supporting without loss of activity
Conclusions
 Hydrogen-transfer catalysis facilitates:
 Hydrogenations – without hydrogen
 Oxidations – without oxidants
 Hydrogen-shuffling – for unusual/unexpected reactivity
 Catalysts potentially readily separable and recyclable
Acknowledgments
 University of Leeds: Dr Mohamud Farah, Dr John Cooksey, Stephanie
Lucas, Andrea Barzano
 University of Bath: Prof Jon Williams, Dr Ourida Saidi
 EPSRC (EP/F038321/1) and TSB
Prof Steve Marsden
Prof John Blacker
Dr Paddy McGowan