Exploring an altogether different ligand architecture, Lockley reported the application of hexafluoroacetylacetonate (hfacac)-ligated Ir(I) complex, 46, in ortho-HIE
(Scheme 13) [8, 10, 22, 90–92]. This catalyst has been successfully applied in the
labeling of benzylic amines, benzoic acids, and primary sulfonamides, where few
other Ir-based HIE catalysts have succeeded. The catalyst is one of the few iridium
HIE catalysts operational in highly polar solvents such as DMF (desirable for poorly
soluble drug molecules) and displays different labeling regioselectivities depending
on the choice of isotope source (D 2 or D 2 O; see 47 ! 48 vs. 47 ! 49).
In the early 2000s, increasing interest in Crabtree’s catalyst, 15, in HIE was
paralleled with investigations by other researchers to improve efficiency and
Ir
PR 3
PR 3
X
R =
Ir
R 2
P
P
R 2
X
Ir
PF 6
(5 mol%)
T 2 , DCM, rt
Fe
P
Cy 2
R 2
P
O
OMe
N
N
O
H
N
N
O
T
T
[ 3 H] 2 -AZ12320927
R = 3,5-dimethyl-4-methoxyphenyl
n
R = Ph (n=1)
Ph (n = 3)
Ir
LPh 3
LPh 3
X
L= N, P, As, Sb
Ph
Ph 2 Me
o-Tol
m-Tol
p-TolO
Cy
NMe 2
2-furyl
C 6 F 5
OEt
n-Bu
i-Bu
t-Bu
Bn
Ph 2 OMe
p-C 6 H 4 F
p-C 6 H 4 Cl
p-C 6 H 4 OMe
41
O
OMe
N
N
O
H
N
N
O
AZ12320927
Selected recent example
Scheme 11 An overview of bis-phosphine-ligated iridium catalysts applied in HIE
DG
DG
D
D
D 2 (8 eq.), DCM, r.t., 1 h
7 examples reported
+ tritiation experiments
X
X
Ir
PCy 3
N
PF 6
43
N
O
(56)
44
45
N
H
O
PPh 2 , DCM
(i)
(ii) DCM washes
P
Ph 2
Ph 2
P
Ir
PF 6
15
42
N
{27}
(21)
{17}
(68)
{73}
(18)
{36}
%D and Catalyst Key
{} = 42 (1.6 mg)
() = 15 (2 mol%)
[] = 22 (2 mol%)
[0]
[45]
[79]
[0]
[Ir]
Selected examples
Scheme 12 Polymer-supported iridium catalyst in ortho-HIE
Iridium Catalysts for Hydrogen Isotope Exchange
281