Chapter 18: Catalytic C-H Functionalization

Y. Shimizu

18.1. Overview
C-H activation: Catalytic or stoichiometric reactions of transition metal complexes with the unreactive C-H bondsof alkanes, arenes, or alkyl chains to form products containing a new metal-carbon bond.
(Fiedel-Crafts reaction or ortho lithiation are not C-H activation.)
major challenge:

selective activation
catalytic process
terminal C-H bond functionalization (sec. or tert. C-H: radical approach)methane to methanol

Difficulties
The reactions are thermodynamically unfavored in many cases.
Oxidation by many oxidizing reagents is downhill.

cat.
R-H + AThe products are typically more reactive than the reactants.
Protect the products by steric or electronic effect.

R-FG + B
reactive site

18.2. 18.3. Oxidations
Platinum catalyst
Shilov's system
H-D exchange

primary C-H selectivefunctionalization

Pt(Ⅳ) as oxidant : impractical
Periana's improvement

H2SO4: corrosive...
remarkable stability
EWG: prevent the further reaction
cf. Polyoxometallate (H4PV2Mo10O40) can act as a mediator of oxidation by O2.

mechanism
see chapter 6via -complex
see chapter 11Nbackside attack
on a paltinum methyl

OPNPtNNMeH

turnover limiting
step

Directed functionalizations
Role of directing group
trigger C-H bond cleavage
regioselective functionalization
Sames (Shilov's system)

acetoxylation

amination

halogenation

mechanistic insite
PdX2

Pd

Pd()

oxidation

Pd()

reductive
elimination

C-H
activation

reductive
elimination
XAr

Ar-PdX

Pd
Y
alternativelyPd( ) speciesYoxidation

18.4. Carbonylation of Arenes and Alkanes
oxidative carbonylation
stoichiometric in Pd by Fujiwara

catalytic in Pd
sp2 C-H

sp3 C-Halkylative carbonylation
linear selective

mainly by Ru

directed reaction
reductive
elimination

C-H
activation

sp3 C-Holefininsertion

carbonyl
insertion

direct carbonylation to aldehyde
endothermic process (thermal conditions were inefficient)
Photochemical processes partially succeeded the reaction.

A radical trap inhibited the formation of the branched aldehyde.

alternative use of isocyanide (weaker multiple bond)18.5. Dehydrogenation
Early works by Crabtree and Felkinhigh temperature condition
catalyst stability limits turnover numbers

Pincer complex

thermaly stable complex
applicable to polymers and amines

mechanism

faster for POCOP cat.

most stablespecies for PCP cat.
(resting state)

faster for primary C-H
see chapter 6

POCOP cat.
most reactive
dehydrogenation cat. + olefin metathesis cat. = alkane metathesis

most stablespecies for POCOP cat.
(resting state)18.6. Hydroarylation
overview
Murai et al. 1993
pioneering work

synthesis of lithospermic acidmechanism
reversible
insertion

C-H
activation
ortho EWG
accelerate the process
resembles to migration process (by calc.)

Scope
DG part: imine, pyridine, carbonyl, heterocycles
imine

heterocycle

ketonepyridinecatalyst
ketone DG: RuH2(CO)(PPh3)3, [RuH2(H2)(PCy3)2], [Cp*Rh(C2H3SiMe3)2]
imine DG: Ru3(CO)12, [Rh(PPh3)3Cl]
pyridine DG: [RhCl(COE)] + PCy3
alkynesmore likely via electrophilic substitution

without directing grouphydroarylation
anti-Markovnikov selectivity

oxidative arylation

alternative to the Heck reaction

mechanism

oxidative hydrogen migration

18.7. Functionalization of Alkanes and Arenes with Main Group Reagents
Borylation of Alkanes
Hartwig's land mark reaction
sp3
terminal C-H slective
less hindered position
not at the position of heteroatom

sp2

heteroatom

Ir catalized borylation of arenes
little electronic preference
controlled by steric effects
complements to electrophilic substitutions

mechanism
Rh cat.

isolated (catalytically active)

Ir cat.

turnover limiting
step

16e

R=H :isolated(catalytically active)
p-orbital on boron assists in the C-H bond cleavage step (chapter 6)silylation of C-H bonds
with DG

hydrogen acceptor

without hydrogen acceptor

without DG

via Cp*Rh(SiEt3)2

via -bond metathesis

18.8. Hydroacylation
mechanism
decarbonylation
is problematicCOLnRh RH

poisoning thecatalyst cycle
LnRhCOR H

Rh cat.

Co cat.

The use of cationic Rh complex
containing chelating ligand
suppresses poisoning of thecatalyst by decarbonylation.

intramolecular
asymmetricdirecting group

NRhO

stable metallacycle

imine derivative
stable metallacycle+
less favorable de-insertionof an isocyanide

18.9. Functionalization of C-H Bonds by Carbene Insertions

secondary C-H > tertially C-H > primary C-H

bond energy
steric factor

favorable at sites that stabilize a buildup positive charge(favored: to O, N disfavored: to ester, OAc)
aliphatic C-H > aromatic C-HCu catalyst
The first work was conducted with copper complexes.
intramolecularintermolecular

Rh catalyst
intramolecular reaction
asymmetric reaction

for total synthesis

intermolecular reaction(see Mr. Takasu's lit. seminar (D2))

major problem: self coupling to form olefins
N2Ar
Donor

CO2R-Donor- -acceptor type carbenoids have moderate reactivity.
It worked well for intermolecular C-H functionalization.

Acceptor
to heteroatom

for total synthesis

18.10. H/D Exchange
Label compounds directly from natural products or synthetic
products.