Application of iridium pincer complexes in hydrogen isotope exchange reactions

Article abstract of DOI:10.1016/j.jorganchem.2007.09.009

Iridium pincer complex catalyzed hydrogen to deuterium exchange could be achieved using aromatic and heteroaromatic substrates. The reactions proceed under mild conditions and with high regioselectivity. The efficiency of the hydrogen isotope exchange rea

Full text of DOI:10.1016/j.jorganchem.2007.09.009

Available online at www.sciencedirect.com
Journal of Organometallic Chemistry 692 (2007) 5529–5531
www.elsevier.com/locate/jorganchem
Communication
Application of iridium pincer complexes in hydrogen isotope
exchange reactions
a
a
b,
a,
*
Annika Traff , Goran N. Nilsson , Kalman J. Szabo *, Ludvig Eriksson
´
´
´
¨
¨
a
AstraZeneca R&D Mo¨lndal, SE-431 83 Mo¨lndal, Sweden
Stockholm University, Arrhenius Laboratory, Department of Organic Chemistry, SE-106 91 Stockhom, Sweden
b
Received 17 August 2007; received in revised form 6 September 2007; accepted 12 September 2007
Available online 20 September 2007
Abstract
Iridium pincer complex catalyzed hydrogen to deuterium exchange could be achieved using aromatic and heteroaromatic substrates.
The reactions proceed under mild conditions and with high regioselectivity. The efficiency of the hydrogen isotope exchange reaction
depends on the electronic properties of the pincer complex catalyst.
Ó 2007 Elsevier B.V. All rights reserved.
Keywords: Pincer complexes; Iridium; Catalysis; Deuterium; Hydrogen isotope exchange
Attrition or high failure rate has emerged as a central
problem of modern drug development and therefore the
design of drugs with optimal potency and pharmacokinetic
properties as well as increased safety profile poses a major
challenge. Absorption, distribution, metabolism, excretion
and toxicology (ADMET) studies are widely used in drug
discovery and development to help obtain an optimal
balance of properties necessary to convert lead compounds
into drugs that are safe and effective in humans. In order to
decrease the attrition rate most pharmaceutical industries
have moved towards front-loading of ADMET studies into
the discovery phase to address possible clinical liabilities.
Deuterium and tritium isotope labelled compounds are
widely used in the ADMET studies. Hydrogen isotope
exchange (HIE) reactions offer a very attractive synthetic
tool to access deuterium and tritium labelled compounds.
The most important advantage of the HIE techniques is
that these procedures do not require special precursors,
hydrogen atoms of drug molecules can be directly
exchanged with deuterium or tritium. Currently the most
common catalysts employed for hydrogen isotope
exchange reactions are iridium-based organometallic com-
plexes, such as Crabtree’s catalyst 1 (Scheme 1) [1].
Although, Crabtree’s catalyst and other commonly
employed organo-iridium complexes have an excellent per-
formance [2] in hydrogen isotope exchange processes, use
of these complexes impose certain synthetic limitations as
well. One problem is the relatively low stability of these
complexes, which are prone to form catalytically inactive
di- and trimeric iridium species. Another problem arises
from the coordinative interactions between the iridium
atom of the complex and the functionalities of the labelled
substrate [2,3]. These difficulties could be avoided by appli-
cation of robust and highly selective iridium complexes in
the HIE reactions. A possible solution for the above-men-
tioned problems would be application of the so-called
pincer complexes as catalysts [4–6]. These complexes are
known to be highly stable and easily tunable for selective
organic transformations [5–13]. The synthesis of the first
iridium PCP pincer complex was reported by Moulton
and Shaw [7]. Several research groups, such as Jensen
and co-workers [8], Goldman and co-workers [9], Leitner
and Six [10], Brookhart and co-workers [11], employed
these complexes as catalysts in dehydrogenation reaction
of hydrocarbons. Recently, Hartwig and co-workers [13]
reported a new application of iridium PCP-pincers for
*
Corresponding authors. Tel.: +46 317064836.
E-mail address: ludvig.eriksson@astrazeneca.com (L. Eriksson).
0022-328X/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2007.09.009

5530
A. Tra¨ff et al. / Journal of Organometallic Chemistry 692 (2007) 5529–5531
Table 2
R
Ir
R
Deuteration of substrates mediated by catalyst 2, 3, 4 and Crabtree’s
catalyst 1a
PF6
Ir
N
Deuterium atom incorporationb
Cy3P
AgSbF6
AgCl
Entry
Substrate
O
O
O
O
Cl
1
2
3
4
tBu2P
PtBu2
tBu2P
Ir
PtBu2
1
1.9
1.7
1.0
0.8
N
H
1
SbF6
H
2a R= H
3a R= OMe
4a R= C6F5
2b-4b
5a
NH
2
3.7
0.8
0.6
1.0
Scheme 1.
O
6a
nitrogen–hydrogen bond activation in ammonia. Consider-
ing the fact that iridium pincer complexes perform well in
carbon–hydrogen and nitrogen–hydrogen bond activation
processes, it is appealing to attempt HIE processes with
these catalysts. We have now found that iridium pincer
complexes 2a–4a [11] (Scheme 1) are promising catalysts
in these reactions. Pincer complexes 2a–4a were prepared
according to the procedure reported by Brookhart and
co-workers [11]. Although, complex 2a showed some HIE
activity (entry 1, Table 1 and Scheme 2), it was found that
the pincer complex catalysts can be efficiently activated
[11,14] by exchange of the chloride counter ion with a
weakly coordinating anion via exchange with silver salts.
The best results could be achieved by conversion of 2a with
AgSbF6 providing 2b as active HIE catalyst (entry 4, Table
1 and Scheme 1).
3
4
a
3.9
1.9
0
0
0
0
0
Me2N
O
7
0.05
O
HN
8
The transformations were performed using 20 lmol catalyst, 20 lmol
AgSbF6 for 2–4 and 40 lmol substrate in CH2Cl2 employing 1 atm deu-
terium gas. All reactions were conducted for 4 h at room temperature.
Average number of deuterium atoms incorporated per molecule
determined by LC–MS.
b
ilar using phenyl pyridine (5a) as substrate (entry 1, Table
2). The hydrogen exchange process catalyzed by 2b takes
place with a high regioselectivity at the ortho hydrogens
in 5a (Scheme 1) as formation of 5b could be detected by
1H NMR analysis of the reaction mixture. The deuterium
incorporation to N-phenylbenzamide 6a was less extensive
with pincer complex catalyst 2b than with 1 (0.8 versus 3.7
atom, entry 2, Table 2). Interestingly, however, the deute-
rium incorporation with 2b takes place regioselectively at
the 20 and 60 ortho positions of 6a affording product 6b
(Scheme 3). On the other hand, Crabtree’s catalyst 1 medi-
ates the hydrogen exchange for all the four ortho positions
(2,6,20 and 60) in 6a (entry 2, Table 2). For the catalytic
HIE reaction of substrates 7 and 8 catalyst 1 clearly outper-
forms pincer complex 2b (Table 2). In order to study the
electronic effects of the para substituents (R) in the pincer
complex catalyst, we have studied the deuterium atom
In a typical reaction, the corresponding substrate (5a–b,
7 or 8, 40 lmol) in 1 mL CH2Cl2 was added to a mixture of
2a [11] (20 lmol) and AgSbF6 (20 lmol) under argon. Sub-
sequently, the reaction mixture was saturated with deute-
rium gas and stirred for 4 h at room temperature. We
have also compared the efficiency of the pincer complex
catalysts 2b and Crabtree’s catalyst 1 in the HIE reactions
under identical reaction conditions. The extent of deute-
rium incorporation with 1 and 2b appeared to be very sim-
Table 1
Activation of complex 2a by different silver agents in hydrogen isotope
exchange reaction (Scheme 1)
Entry
Activation agent
Dna
1
2
3
4
5
a
–
0.7
0.8
1.0
1.7
0.8
AgOCOCF3
AgBF4
AgSbF6
AgSbF6 + H2O
H
H
D
D
0.5e q 2b,D 2
Figures presented are the average number of deuterium atoms incor-
porated per molecule determined by LC–MS and 1H NMR.
NH
O
NH
O
CH2Cl2, 4h@rt
6b
6a
Ln
H
D
6
Ir
H
N
6'
2'
0.5e q 2b,D 2
N
N
CH2Cl2, 4h@rt
2
LnIr
O
H
D
5b
5a
6c
Scheme 3.
Scheme 2.

A. Tra¨ff et al. / Journal of Organometallic Chemistry 692 (2007) 5529–5531
5531
lective exchange reaction of the H20 and H60 ortho hydro-
gens of 6a (Scheme 3). A possible explanation [15,16] for
this regioselectivity of 2b is a preferential formation of a
five-membered ring intermediate of the iridium atom with
the nitrogen atom and carbon atom 60 (upper part of 6c).
Crabtree’s catalyst 1 mediates the exchange of these ortho
protons (i.e. H20 and H60) as well as the ortho protons of
the aniline part (i.e. H2 and H6), thus exchange a total
of four protons (entry 2, Table 2). This indicates that 1 is
able to react via the above described five membered ring
intermediate, and also via a six-membered intermediate
involving the iridium atom, the carbon atom C6 and the
carbonyl oxygen (lower part of 6c) [15,16].
D
O
O
tBu2P
Ir
PtBu2
FG
10b
H
9a
reductive
elimination
oxidative
addition
O
O
H
O
O
tBu2P
PtBu2
H
Ir
tBu2P
Ir
PtBu2
D
9e
D
D
9b
FG
In summary, we have shown for the first time that irid-
ium pincer complexes 2a–4a are able to catalyze HIE
exchange for aromatic substrates 5a and 6a under mild
conditions. The exchange reaction takes place with a high
regioselectivity for labelling of 6a. Our studies also suggest
that the catalytic activity and selectivity of the pincer com-
plex catalysts can be fine tuned by changing of the elec-
tronic properties of the complex. Considering the above
application of iridium pincer complexes represent an inter-
esting alternative for the use of mono and bidentate iridium
complexes for HIE reaction of drug like molecules.
reductive
elimination
isomerization
HD
substrate coordination
and CH-activation
O
O
O
O
D
tBu2P
Ir
PtBu2
tBu2P
PtBu2
Ir
H
D
9c
H
9d
FG
FG
10a
Acknowledgements
Scheme 4.
The author thank Dr. Claes Landersjo¨ for NMR-assis-
tance and AstraZeneca R&D Mo¨lndal for providing mate-
rials and facilities for the project. This work was also
supported by the Swedish Research Council (VR).
incorporation with the methoxy substituted pincer complex
3b and the pentafluoro phenyl substituted complex 4b
(Scheme 1). Using 5a as substrate, application of both elec-
tron donating (3b) and electron withdrawing (4b) substitu-
ents in 2b leads to a decrease of the catalytic activity (entry
1, Table 2) in H/D exchange. Similarly, the methoxy com-
plex 3b is less efficient for HIE with 6a than with 2b, how-
ever, complex 4b appeared to be somewhat more reactive in
deuterium exchange with 6a than with the parent complex
2b (entry 2, Table 2). Similarly to 2b complexes 3b and 4b
are inactive for HIE of substrates 7 and 8.
References
[1] R. Crabtree, Acc. Chem. Res. 12 (1979) 331.
[2] R. Salter (Ed.), Synthesis and Applications of Isotopically Labelled
Compounds, Wiley, New York, 2001.
[3] G.J. Ellames, Tetrahedron 57 (2001) 9487.
[4] D. Morales-Morales, C.M. Jensen (Eds.), The Chemistry of Pincer
Compounds, Elsevier, Amsterdam, 2007.
Skaddan and Bergman [17] studied the mechanistic
aspects of the iridium catalyzed HIE reactions, showing
[17] that the non-selective HIE reaction proceeds via irid-
ium (III)/iridium (V) intermediates. Based on these results
a plausible catalytic cycle is proposed for the above pre-
sented (Schemes 2 and 3 and Table 2) pincer complex cat-
alyzed processes (Scheme 4). Accordingly, the activated
intermediate 9a undergoes oxidative addition with deute-
rium gas affording complex 9b. Subsequently, reductive
elimination of HD provides deutero complex 9c, which oxi-
datively activates the carbon hydrogen bond of the aro-
matic substrate 10a to form complex 9d. After
isomerization of 9d to 9e a reductive elimination affords
the deuterated product 10b recovering catalyst 9a. Conver-
sion of 9c to 9d is probably the most interesting step of the
catalytic cycle determining the regioselectivity of the HIE
process. As we pointed out complex 2b induces a regiose-
[5] J.T. Singleton, Tetrahedron 59 (2003) 1837.
[6] D. Milstein, M. van der Boom, Chem. Rev. 103 (2003) 1759.
[7] C.J. Moulton, B.L. Shaw, J. Chem. Soc., Dalton Trans. (1976)
1020.
[8] M. Gupta, C. Hagen, R.J. Flesher, W. Kaska, C.M. Jensen, J. Chem.
Soc., Chem Commun. (1996) 2083.
[9] K. Wang, M.E. Goldman, T.J. Emge, A.S. Goldman, J. Organomet.
Chem. 518 (1996) 55.
[10] W. Leitner, C. Six, Chem. Ber./Receueil. 130 (1997) 555.
[11] I. Go¨ttker-Schnetmann, P. White, M. Brookhart, J. Am. Chem. Soc.
126 (2004) 1804.
[12] K. Zhu, P.D. Achord, X. Zhang, K. Krogh-Jespersen, A.S. Goldman,
J. Am. Chem. Soc. 126 (2004) 13044.
[13] J. Zhao, A.S. Goldman, J.F. Hartwig, Science 307 (2005) 1080.
[14] D. Morales-Morales, R. Redo´n, C. Yung, C.M. Jensen, Inorg. Chim.
Acta 357 (2004) 2953.
[15] M. Lavin, E.M. Holt, R.H. Crabtree, Organomtallics 8 (1989) 99.
[16] A.Y.L. Shu, W. Chen, J.R. Heys, J. Organomet. Chem. 524 (1996)
87.
[17] M.B. Skaddan, R.G. Bergman, J. Am. Chem. Soc. 126 (2004) 13033.