Iridium-catalyzed H/D exchange: Ligand complexes with improved efficiency and scope

Article abstract of DOI:10.1002/chem.201402078

Hydrogen isotope exchange (HIE) is one of the most attractive tools for the introduction of deuterium or tritium to an organic compound. Herein, iridium complexes with N,P-ligands, highly active catalysts for asymmetric double bond reductions, have been tested for their HIE capabilities. Electron-rich ligands, containing dicyclohexylphosphines or phosphinites, have been identified as excellent ligands for efficient deuterium incorporation. Substrates with strong directing groups, that is, pyridines, ketones, and amides, as well as weak ligating units, such as, nitro, sulfones, and sulfonamides, could be labeled efficiently. With the addition of tris(pentafluorophenyl) borane to the reaction mixture, also highly deactivating nitrile substituents were well tolerated in the reaction. Based on the excellent results obtained with the chiral ThrePhox ligand, a structurally simpler, achiral ligand was developed. The iridium complex containing this ligand, proved to be a powerful catalyst for HIE reactions. Uses beyond asymmetric catalysis: Iridium complexes with a wide variety of N,P-ligands were explored in hydrogen isotope exchange reactions (see scheme; pyr.=pyridine). Complexes with electron-rich ligands were found to be highly reactive, leading to efficient deuterium incorporation even in compounds bearing only weakly coordinating directing groups.

Full text of DOI:10.1002/chem.201402078

DOI: 10.1002/chem.201402078
Full Paper
&
Isotopic Labeling
Iridium-Catalyzed H/D Exchange: Ligand Complexes with
Improved Efficiency and Scope
Michael Parmentier,[a] Thomas Hartung,[b] Andreas Pfaltz,[a] and Dieter Muri*[b]
Abstract: Hydrogen isotope exchange (HIE) is one of the
most attractive tools for the introduction of deuterium or tri-
tium to an organic compound. Herein, iridium complexes
with N,P-ligands, highly active catalysts for asymmetric
double bond reductions, have been tested for their HIE ca-
pabilities. Electron-rich ligands, containing dicyclohexylphos-
phines or phosphinites, have been identified as excellent li-
gands for efficient deuterium incorporation. Substrates with
strong directing groups, that is, pyridines, ketones, and
amides, as well as weak ligating units, such as, nitro, sul-
fones, and sulfonamides, could be labeled efficiently. With
the addition of tris(pentafluorophenyl) borane to the reac-
tion mixture, also highly deactivating nitrile substituents
were well tolerated in the reaction. Based on the excellent
results obtained with the chiral ThrePhox ligand, a structural-
ly simpler, achiral ligand was developed. The iridium com-
plex containing this ligand, proved to be a powerful catalyst
for HIE reactions.
Introduction
leveraged a routine use of iridium complexes for tritium label-
ing and has also driven the development of new and more
active catalyst systems.[8m] These catalysts allow incorporation
of tritium preferentially in the ortho position to a directing
group tolerating a variety of different functionalities present in
the molecule. The incorporation should occur at a stable, that
is, non-exchangeable position to avoid back-exchange in
protic solvents under neutral, basic or acidic conditions with
the consequence of losing the label. To date, Crabtree’s cata-
lyst is still most widely used for these types of reactions
(Figure 1). Kerr’s catalyst shows improved reactivity and can
Isotopically labeled organic compounds are important tools in
the research and development of new therapeutic drug candi-
dates.[1] In particular, the demand for tritium-labeled radioli-
gands has constantly increased over the last years due to the
extended efforts in developing drugs for central nervous
system (CNS) targets associated with the exploration of the
corresponding receptors, performing translational studies for
the selection of suitable positron emission tomography (PET)
tracers, and for a rapid screening of drug candidates in preclin-
ical adsorption, distribution, metabolism, and excretion (ADME)
studies.[2] Moreover, compounds labeled with deuterium are of
high importance as internal standards in mass spectrometry or
for the investigation of reaction mechanisms.[3] Among the var-
ious existing labeling technologies,[4] transition-metal-catalyzed
hydrogen isotope exchange (HIE) is one of the most attractive
methods for the labeling of compounds with deuterium or tri-
tium.[5] This approach enables a direct labeling of the desired
compounds without laborious syntheses of adequately func-
tionalized precursors. Platinum complexes[6] have already been
applied to HIE in the sixties and the methodology was then
later extended by rhodium[7] and iridium complexes.[8] Especial-
ly the work of Heys[8b] and Hesk et al.[9] in the nineties has
Figure 1. Crabtree’s and Kerr’s catalyst.
even be used in catalytic amounts for substrates bearing only
weakly coordinating groups such as nitro units.[8m] Despite the
levels of effectiveness shown by these established Ir-centered
species, there is still room for improvement and for develop-
ment of new, selective, and effective iridium-based catalysts to
achieve tritium incorporation in high specific activities and
across a wider substrate range.
[a] Dr. M. Parmentier, Prof. Dr. A. Pfaltz
Department of Chemistry, University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Cationic iridium complexes bearing bidentate N,P ligands
have established themselves as very efficient and selective cat-
alysts for the enantioselective hydrogenation of functionalized
and unfunctionalized alkenes.[10] Considering the analogy to
Crabtree’s catalyst, we expected them to also catalyze HIE re-
actions. The accepted mechanism of the iridium-catalyzed HIE
[b] Dr. T. Hartung, Dr. D. Muri
Preclinical Chemistry Manufacturing Control
pRED, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124
4070 Basel (Switzerland)
E-mail: dieter.muri@roche.com
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402078.
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reaction involves an octahedral cyclometalated dideuteride IrIII
species such as 1 (Figure 2). Ligands around the metal center
stabilize the intermediates and influence the reactivity of the
catalyst by changing both the electron density and steric con-
al groups such as nitro-, sulfone, and sulfonamide (10, 11, 12)
were also investigated. Nitriles and pyridine-2-carbonyl deriva-
tives are structural motifs that are widely used in drug discov-
ery, and they can be considered as potential challenges to HIE
due to their binding abilities to the metal center. They signifi-
cantly reduce catalyst activity and, in most cases, even com-
pletely inhibit HIE.[14]
The high modularity of N,P-ligands allows the electronic
properties of the Ir catalysts to be varied, as both the nitro-
gen-containing part (oxazoline, oxazole, imidazoline, or pyri-
dine) and the phosphorus moiety (diaryl or dialkyl phosphine
or phosphinite) can be easily tuned. For our first screening, we
selected 15 Ir-based catalysts with different backbones and
electron densities to determine the most promising system
(Figure 4). Because of their previous use for asymmetric hydro-
Figure 2. Structures of cyclometalated IrIII intermediates bearing mono-
dentate or bidentate ligands.
gestion.[8f,g] In addition, the rate of the cyclometalation and re-
ductive elimination steps can be strongly affected by the elec-
tron density of the metal center and the trans influence of the
ligands.[11] IrIII species resulting from the Crabtree’s or Kerr’s cat-
alyst result in a trans relationship between the two monoden-
tate ligands (1, Figure 2).[8e,g,m,12] The use of bidentate N,P li-
gands leads to electronically and sterically different complexes
such as 2a or 2b (Figure 2),[13] which possibly could show en-
hanced catalytic activity in HIE reactions.
Because of the potential of these bidentate N,P-ligands and
the great diversity and availability of the corresponding iridium
catalysts, we decided to study their use in isotope exchange
reactions. Here, we report improvements of the HIE reaction
with deuterium gas on representative classes of substrates cat-
alyzed by cationic iridium complexes bearing a bidentate N,P-
ligand.
Figure 4. Structures of selected ligands.
genation, all catalysts selected for the first investigations were
chiral. However, the HIE reaction does not require the use of
an enantiomerically pure catalyst and, therefore, an achiral
structurally simplified version of the most efficient catalysts
will also be presented in a second part including the synthesis
of the corresponding achiral N,P ligand.
Results and Discussion
As a starting point, we compiled a set of representative test
compounds (Figure 3). For a preliminary screening of catalysts
for ortho-directed HIE, classical model substrates such as 2-
phenylpyridine, acetophenone, acetanilide, and phenylbenz-
amide were chosen. 3,5-Disubstituted substrates 5 and 6 were
selected to explore steric and stereoelectronic effects of func-
tional groups on the arene ring. Weakly coordinating function-
In the initial experiments a set of model compounds were
treated with different iridium catalysts in the presence of deu-
terium gas under standard conditions: The substrate
(12.5 mmol) and Ir catalyst (0.625 mmol) were stirred in dry
CH2Cl2 (0.25 mL) under deuterium gas (1 bar)[15] for 4, 6, or
18 h. After the reaction, labile deuterium labels were re-ex-
changed by washing the crude mixture with aqueous ethanol.
The extent of deuterium incorporation in the model substrates
was determined by MS.
Using 2-phenylpyridine 3 as substrate, good deuterium in-
corporation could be obtained with most of the tested iridium
catalysts (Table 1). An average of 1 deuterium atom per mole-
cule could be incorporated (Dinc) in the ortho position of the
pyridine substituent using 5 mol% of the iridium catalyst de-
rived from the phenyloxazoline ligand 14b (Table 1, entry 2).
The less electron-rich diphenylphosphine derivative 14a led to
a lower incorporation level of 0.8 Dinc. A stronger influence of
the electronic properties of the phosphorus moiety was ob-
served for phenylimidazoline (PHIM) ligands 15a and 15b.
Figure 3. Structures of selected substrates.
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Table 1. Deuterium incorporation in 2-phenylpyridine 3 mediated by
different Ir complexes.
Entry
Ligand
Dinc
Entry
Ligand
Dinc
(D/molecule)[a]
(D/molecule)[a]
1
2
3
4
5
6
7
8
14a
14b
15a
15b
16a
16b
17a
17b
0.8
1.0
0.3
1.4
0.3
0.5
0.2
0.1
9
10
11
12
13
14
15
18a
18b
19a
19b
20a
20b
20c
0.9
1.1
1.3
1.4
0.1
1.0
1.3
Scheme 1. Deuterium incorporation in acetophenone derivatives 4–7, acet-
anilide 8, and benzanilide 9 mediated by Ir complexes.
[a] Average number of ortho-deuterium atoms incorporated per molecule
1
determined by GC-MS analysis and/or H NMR spectroscopy.
It is well known that cyano substituents can inhibit HIE
almost completely.[14] It was therefore no surprise that the stan-
dard reaction conditions, which were successfully applied for
the previously described acetophenone derivatives, led to dras-
tically different incorporation levels in 4-acetylbenzonitrile (7).
With all tested catalysts no H/D exchange was observed and
only starting material was recovered. To gain a better under-
standing of this failed H/D-exchange reaction, we decided to
investigate the effect of the catalyst loading and the interac-
tion of the nitrile with the catalyst in more detail (Table 2).
Whereas 15a, containing two ortho-tolyl substituents on the
phosphorus atom, led to 0.3 Dinc (Table 1, entry 3), the more
electron-rich dicyclohexyl phosphine analogue 15b brought
about 1.4 Dinc (entry 4). Up to 0.5 Dinc was obtained with more
rigid systems such as pyridine-phosphinite ligands 16 and 17.
Electron-rich phosphinite-containing derivatives such as Thre-
PHOX 18b or SimplePHOX 19b proved to be more active and
efficient deuterium incorporation up to 1.4 Dinc could be ach-
ieved (Table 1, entries 10 and 12). Finally, the NeoPHOX 20c
with trialkyl phosphine substituents allowed for the prepara-
tion of [D]-3, containing an average of 1.3 deuterium on the
phenyl ring (Table 1, entry 15).
Table 2. Catalyst loading effect on the HIE reaction on the 4-acetylbenzo-
nitrile 7.
A first conclusion from these screening results is that ligands
with an electron-rich phosphorus moiety are needed to ach-
ieve a good level of deuterium incorporation. Phosphinites or
trialkyl phosphines can be used and are suitable for the reac-
tion. Finally, the nitrogen-containing part of the backbone
could be imidazoline or oxazoline. Rigid pyridine-phosphinite
systems, which are known to be very efficient for asymmetric
hydrogenation reactions of olefins,[10d] led to low deuterium
levels. Taking into account all of these observations, we decid-
ed to proceed only with the most active electron-rich ligands
14b, 15b, 18b, 19a, 19b, 20b, and 20c.
Entry
Catalyst loading
[mol%]
Deuterium incorporation
(D/molecule)[a]
1
2
3
4
5
40
60
0
0.3
0.9
1.5
105
[a] Average number of ortho-deuterium atoms incorporated per molecule
determined by GC-MS analysis and/or H NMR spectroscopy.
1
With these catalysts in hand, we tested several other typical
model substrates for HIE such as acetophenone, acetanilide,
and benzanilide (Scheme 1). All catalysts led to almost quanti-
tative deuterium incorporation with a catalyst loading of
5 mol% and a reaction time of 6 h under standard conditions,
favoring a reaction path through a 5- or 6-membered iridacy-
cle. In the case of acetophenone, the catalyst containing
ligand 19b led to slightly diminished D incorporation. Sterical-
ly more demanding acetophenones 5 and 6 were investigated
as well. These substrates could be labeled as well to a similar
degree under standard reaction conditions. As expected, D in-
corporation in the para position of 6, which would involve a 4-
membered iridacycle, through coordination to a methoxy
group, was not observed.
The commercially available Ir complex containing 18b was
first chosen and 0.3 Dinc was observed with 40 mol% catalyst
loading after 18 h (Table 2, entry 2). Increasing the amount of
catalyst to 60 mol% resulted in increased isotope exchange of
0.9 Dinc (Table 2, entry 3). Finally, a slight excess of iridium cata-
lyst led to substantial incorporation of 1.5 Dinc (entry 4). These
results suggest a deactivation of the catalyst by the substrate
through strong coordination of the nitrile group to the metal
center. 1H NMR spectroscopic studies performed with the Ir
catalyst 21 and 10 equivalents of substrate supported this hy-
pothesis. Under 1 bar of hydrogen, the formation of an iridium-
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entry 1). Increasing both the re-
action temperature to 508C in
1,2-dichloroethene (DCE) and
the reaction time to 18 h did not
give
a better result (Table 3,
entry 2). However, performing
the reaction at 908C for 18 h in
chlorobenzene led to 3.4 Dinc
1
2
(Table 3, entry 4). H and H NMR
spectroscopic experiments
proved exchange at the phenyl
ring as well as incorporation into
the methyl group of the acetyl
moiety. This latter functionaliza-
tion is probably induced by the
Scheme 2. Studies of the inhibition of Ir complex 21 by 4-acetylbenzonitrile 7 (the counterion [PF6]À is omitted
for clarity).
(III)-dihydride complex containing two coordinated molecules
of acetylbenzonitrile was observed (Scheme 2).
keto–enol tautomerization that can occur at such a tempera-
ture. Under the same conditions, but in the absence of tris-
(pentafluorophenyl)borane only an incorporation of 0.1 Dinc
was observed (Table 3, entry 5). The complex derived from 18b
promoted the H/D exchange to 3.4 Dinc (Table 3, entry 6). Low-
ering the reaction temperature to 608C while simultaneously
increasing the catalyst loading to 10 mol% led to a Dinc of 1.3
(Table 3, entry 7). The reaction time seems to be crucial as only
0.7 Dinc was observed after 4 h (Table 3, entry 8). Also a slight
decrease in deuterium incorporation was observed when using
phenylimidazoline 15b (Table 3, entry 9) or SimplePHOX 19a
(Table 3, entry 12) as ligands. More than three deuterium
atoms were incorporated with the more electron-rich Neo-
PHOX complex 20b (Table 3, entry 10) and 20c (entry 11), re-
spectively. Finally, by using the iridium catalyst with the Sim-
plePHOX ligand 19b in the presence of 1.1 equivalents of the
tris(pentafluorophenyl)borane additive at 908C (Table 3,
entry 13), 4.4 deuterium atoms were incorporated adjacent to
the acetyl group in the aromatic ring and in the methyl group.
An advantage of tris(pentafluorophenyl)borane as additive is
the absence of any protons in the structure, thus avoiding the
generation of radioactive waste when tritium gas is used due
to potentially occurring phenyl-H/T exchange. On the other
hand, the ortho-directing effect of the chlorine in chloroben-
zene has to be monitored, as well as Cl/H exchange. Running
a reaction in the absence of substrate, no H/D exchange or re-
duction of chlorobenzene was observed, which clearly demon-
strated the suitability of this solvent for high-temperature HIE
reactions.
The iridium metal center is acting as Lewis acid toward the
nitrile group. Nuclear Overhauser effect (nOe) experiments
confirmed the geometry of the complex with two strong con-
tacts between the hydride cis to the phosphorus atom and the
proton ortho to the nitrile group in the phenyl ring as major
isomer (see the Supporting Information for details). With the
goal to develop a reaction using only catalytic amounts of the
metal complex, we decided to evaluate possible additives that
could block the nitrile group by formation of a complex. After
an extensive screening tris(pentafluorophenyl)borane was
identified as a suitable Lewis acid in this case. The results of
the HIE reaction of 7 in the presence of B(C6F5)3 are presented
in Table 3.
No deuterium incorporation was observed using the PHOX
ligand 14b in the presence of 1.1 equivalents of the borane
additive at room temperature for 6 h in CH2Cl2 (Table 3,
Table 3. Catalyst screening for the HIE reaction on the 4-acetylbenzo-
nitrile 7 in the presence of B(C6F5)3 as additive.
Entry
Ligand
Conditions
B(C6F5)3
[equiv]
Dinc
(D/molecule)[a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14b
14b
14b
14b
14b
18b
18b
18b
15b
20b
20c
19a
19b
CH2Cl2, 238C, 6 h
DCE, 508C, 18 h
PhCl, 238C, 18 h
PhCl, 908C, 18 h
PhCl, 908C, 18 h
PhCl, 908C, 18 h
PhCl, 608C, 18 h
PhCl, 908C, 4 h
PhCl, 908C, 18 h
PhCl, 908C, 18 h
PhCl, 908C, 18 h
PhCl, 908C, 18 h
PhCl, 908C, 18 h
1.1
1.1
1.1
1.1
–
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
0
0
0
The scope of the reaction was further explored by using
weakly coordinating functionalities such as sulfones, sulfon-
amides, and nitro groups (Scheme 3).
3.4
0.1
3.4
1.3[b]
0.7
2.3
3.2
3.1
1.4
4.4
These substrates required a more rigorous selection of cata-
lysts than the previously applied arenes. Whereas catalysts
with ligand 15b or 19a only led to low D incorporation,
almost complete conversion was observed with 20b as ligand
in the case of nitrobenzene 10 and methylphenylsulfone 11.
However, sulfonamide derivative 12 could not be efficiently la-
beled and the best result was obtained with 15b resulting in
0.4 Dinc.
[a] Average number of deuterium atoms incorporated per molecule de-
termined by GC-MS analysis and/or 1H NMR spectroscopy. [b] 10 mol% of
the catalyst was used.
Optimization of the reaction conditions for the labeling of
benzenesulfonamide 12 was performed by using the most effi-
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Scheme 4. H/D exchange on 13.
ane as additive in the reaction with the pyridine derivative 13
(Scheme 4).
The use of 1.1 equivalents of B(C6F5)3 significantly increased
the incorporation of deuterium up to 2.1 Dinc. Unfortunately,
NMR spectroscopic analysis of the product [D]-13 revealed
that the deuterium incorporation occurs exclusively at the
methyl group. Deuteration of the methyl group could be ex-
plained by formation of a 4- or 5-membered iridacycle through
coordination of the catalyst with the ketone or the pyridine N
atom, respectively, followed by CÀH insertion. Alternatively,
deuterium incorporation could occur through boron enolate
formation and subsequent D+ transfer from an acidic iridium
deuteride species to the enolate.[16] The addition of a stoichio-
metric amount of rhodium black to the reaction mixture, as
described by Schou, neither improved the deuteration level
nor changed the labeling position.[17]
Scheme 3. Scope extension of the HIE reaction.
cient ligands 15b, 18b, 20b, and 20c identified above and by
varying both solvent and temperature (Table 4).
After 6 h at room temperature in dichloromethane, an aver-
age of 0.4 deuterium per molecule could be incorporated
Table 4. Optimization of the reaction conditions for H/D exchange on 12
mediated by Ir complexes.
Development of an achiral Ir catalyst
Entry
Ligand
Conditions
Dinc
(D/molecule)[a]
Our investigation of iridium complex-catalyzed H/D exchange
reactions with different substrate classes revealed that Thre-
PHOX 18b is one of the most efficient N,P-ligands for this pro-
cess leading to very good results in general. For that reason
we aimed at designing an achiral N,P-ligand based on struc-
ture of 18b. First, the impact of each part of the skeleton of
18b on the HIE reaction was evaluated by choosing acetanilide
1
2
3
4
5
6
7
8
15b
15b
15b
20b
20b
20b
20c
18b
CH2Cl2, 238C, 6 h
DCE, 508C, 18 h
PhCl, 908C, 18 h
CH2Cl2, 238C, 6 h
DCE, 508C, 18 h
PhCl, 908C, 18 h
PhCl, 908C, 18 h
PhCl, 908C, 18 h
0.4
0.5
1.5
0.3
0.7
1.8
1.9
1.9
8
as test substrate under standard reaction conditions
(Table 5).
As previously observed, the electronic properties of the
[a] Average number of deuterium atoms incorporated per molecule de-
termined by GC-MS analysis and/or H NMR spectroscopy.
1
phosphinite moiety were crucial as replacement of the cyclo-
hexyl groups by two phenyl groups resulted in complete loss
of activity (Table 5, entries 1 vs. 2). Removing the methyl group
on the oxazole ring and replacing the gem-dibenzyl by a gem-
dimethyl group slightly lowered the efficiency (Table 5,
entry 3). We were pleased to find that the use of achiral ligand
23, resembling 18b, led to high deuterium incorporation
levels at only 3 mol% catalyst loading (Table 5, entry 4).
when using 15b as ligand (Table 4, entry 1). Increasing the
temperature to 508C in dichloroethane improved the result to
0.5 Dinc (Table 4, entry 2). As already observed in the case of
acetylbenzonitrile, the use of chlorobenzene at 908C for 18 h
led to the best level of H/D exchange with an average of
1.5 Dinc (Table 4, entry 3). Iridium catalysts with 18b, 20b, and
20c as ligands led to almost quantitative D incorporation at
more elevated temperatures. NMR spectroscopic analysis
showed that deuterium incorporation occurred in the ortho
position to the sulfonamide group.
A straightforward synthetic route was designed to synthe-
size catalyst 26 (Scheme 5). The oxazole ring was formed by
using a procedure described by Wang, providing ketone 24 in
70% yield.[18] Addition of 2 equivalents of methylmagnesium
bromide afforded the tertiary alcohol 25 in 84% yield. Treat-
ment of the alcoholate of 25 with dicyclohexylchlorophos-
phine led to the corresponding phosphinite derivative 23,
which was used without further purification to avoid oxidation
of the phosphine moiety. The desired Ir complex 26 was ob-
tained in 25% yield based on 25 after complexation with [IrCl-
(cod)]2 (cod=1,5-cyclooctadiene) followed by anion exchange
Strong complexation of the metal center between the nitro-
gen atom and the carbonyl group can be expected in the case
of HIE attempts with 2-keto-substituted pyridines, a structural
motif quite common in drugs and drug-like molecules. As
a model substrate for this class of compounds we selected
acetylpyridine 13. Based on our results in the HIE with acetyl-
benzonitrile 7, we decided to use tris(pentafluorophenyl)bor-
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Table 5. Influence of phosphine ligands on the HIE of 8.
Table 6. Scope of the HIE reaction mediated by achiral Ir complex 26.
Entry
Substrate
Conditions
B(C6F5)3
[equiv]
Dinc
Entry
1
Ligand
Dinc
(D/molecule)[a]
(D/molecule)[a]
1
2
3
4
5
6
7
8
9
3
4
5
6
7
8
9
10
11
12
CH2Cl2, 238C, 6 h
CH2Cl2, 238C, 6 h
CH2Cl2, 238C, 6 h
CH2Cl2, 238C, 6 h
PhCl, 908C, 18 h
CH2Cl2, 238C, 6 h
CH2Cl2, 238C, 6 h
CH2Cl2, 238C, 6 h
CH2Cl2, 238C, 6 h
PhCl, 908C, 18 h
–
–
–
–
1.1
–
–
–
–
1.3
2.0
2.1
2.0
2.4
1.8
3.9
0.4
0
18b
1.5
2
3
4
18a
22
0
1.3
1.5[b]
10
–
0.3
[a] Average number of deuterium atoms incorporated per molecule de-
termined by GC-MS analysis and/or H NMR spectroscopy.
1
23
Conclusion
[a] Average number of deuterium atoms incorporated per molecule de-
termined by GC-MS analysis and/or 1H NMR spectroscopy. [b] 3 mol% of
catalyst.
Investigation of the hydrogen isotope incorporation reaction
with various substrates catalyzed by iridium complexes re-
vealed the suitability of bidentate N,P-ligands for this transfor-
mation. Highly electron-rich ligands, preferably dicyclohexyl-
phosphines or phosphinites, are necessary to achieve high
deuteration levels. ThrePHOX 18b, NeoPHOX 20c, SimplePHOX
19b, and PHIM 15b ligands were identified as the backbone
of choice for the catalyst enabling both broad tolerance of
substrate functionality and high efficiency. In most cases, excel-
lent deuterium incorporation was observed when 5 mol% of
an Ir catalyst derived from one of these ligands was used.
Compounds with strongly coordinating substituents such as
acetylbenzonitrile 7 and acetylpyridine 13 are known to be
problematic substrates for the HIE process. NMR spectroscopic
studies showed that the nitrile group of 7 strongly coordinated
to the Ir center, resulting in loss of catalytic activity. Based on
these observations, the process was modified by addition of
tris(pentafluorophenyl)borane, which prevents deactivation of
the catalyst by binding to the nitrile group of the substrate,
and thus permits high deuterium incorporation levels. Unfortu-
nately, 2-acetylpyridine was exclusively labeled at the methyl
group. Deuterium incorporation
with
sodium
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate
(NaBArF).
With the achiral Ir complex 26 in hand, the efficiency of this
new catalyst for HIE was evaluated. Substrates 3–12 were then
tested under the optimal reaction conditions previously estab-
lished in the presence of 5 mol% of catalyst (Table 6).
We were pleased to see high deuterium incorporation with
most of the tested substrates. For example, complete H/D ex-
change at the ortho position occurred with the acetophenone
derivatives after 6 h (Table 6, entries 2–4). The use of B(C6F5)3 as
an additive for the functionalization of acetylbenzonitrile 7 was
successful and Dinc of 2.4 was observed (Table 6, entry 5). Sur-
prisingly, whereas nitrobenzene 10 led to excellent results with
the use of 18b as ligand (Scheme 3), low H/D exchange oc-
curred with the achiral ligand 26 under the same reaction con-
ditions (Table 6, entry 8).
in the aromatic ring remains
a challenge in that case. The ex-
cellent results obtained with the
chiral ThrePHOX ligand 18b
prompted us to develop a struc-
turally simpler achiral analogue
23. The Ir complex 26 derived
from this ligand, which was
readily prepared in a short syn-
thetic sequence, proved to be
a very efficient catalyst in the hy-
drogen isotope exchange reac-
Scheme 5. Synthesis of achiral Ir catalyst 26.
tion of a wide range of sub-
Chem. Eur. J. 2014, 20, 11496 – 11504
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the appropriate temperature for 18, 6, or 4 h. The solvent was then
removed by bubbling argon through the solution and the crude
reaction mixture was analyzed by GC/MS (EI) and/or NMR spectros-
copy.
strates. Results obtained with this catalyst on drug-like mole-
cules will be reported in due course.
Typical H/D exchange procedure using tris(pentafluorophenyl)-
boron as an additive: The substrate stock solution in PhCl
(1 equiv, 0.250 mL, 0.05m) was added to a vial (2.5 mL) containing
tris(pentafluorophenyl)boron (1.1 equiv, 13.75 mmol, 7.4 mg). After
stirring the mixture for 10 min at RT, the catalyst (5 mol%,
0.625 mmol) was added to the vial, which was then placed in
a high-pressure reactor. The equipment was first pressurized to
2.2 bar with deuterium gas and the pressure released to 1 bar. This
procedure was then repeated twice. The reaction was performed
under 1 bar D2 atmosphere at 908C for 18, 6, or 4 h. The solvent
was then removed by bubbling argon through the solution and
the crude reaction mixture was analyzed by GC/MS (EI) and/or
NMR spectroscopy.
Experimental Section
General information
Working techniques: Commercially available reagents were pur-
chased from Acros, Aldrich, or Fluka and used as received. The sol-
vents were collected from a purification column system (PureSolv,
Innovative Technology Inc.) or purchased from Aldrich or Fluka in
sure/sealed bottles over molecular sieves. Column chromatograph-
ic purifications were performed on Fluka silica gel 60 (Buchs, parti-
cle size 40–63 nm). The eluents were of technical grade and dis-
tilled prior to use. The dichloromethane was purchased from Al-
drich (ꢀ99.5%, over molecular sieves).
Melting points: Melting points were determined on a Bꢁchi 535
apparatus and are uncorrected.
1H NMR spectroscopic data of deuterated products [D]-3 to
[D]-13
Thin-layer chromatography: TLC plates were obtained from Mach-
rey-Nagel (Polygram SIL/UV254, 0.2 mm silica with fluorescence in-
dicator). UV light (254 nm) or basic permanganate solution were
used to visualize the respective compounds.
2-Phenylpyridine (3): 1H NMR (400 MHz; CDCl3, 258C, TMS): d=
8.71 (d, J=4.7 Hz, 1H), 8.00 (d, J=7.1 Hz, 2H), 7.79–7.73 (m, 2H),
7.52–7.41 (m, 3H), 7.26–7.23 ppm (m, 1H). Deuterium incorpora-
tion was quantified by integration of the signal at d=8.00 ppm
using the signal at d=7.79–7.73 ppm as a reference.
NMR spectroscopy: 1H NMR spectra were measured either on
a Bruker Avance 400 (400 MHz) a Bruker Avance 500 (500 MHz)
spectrometer or a Bruker AV 600 (600 MHz). 13C NMR spectra are
measured on a Bruker AV 600 (150 MHz). The chemical shifts (d)
are given in ppm. The chemical shift d values were corrected to
the signals of the deuterated solvents: d=7.26 (1H NMR) and
77.16 ppm (13C NMR) for CDCl3; d=2.05 for [D6]acetone, and
2.50 ppm for [D6]DMSO. 31P NMR spectra are calibrated relative to
85% phosphoric acid (d=0 ppm). 13C and 31P spectra were record-
1
Acetophenone (4): H NMR (400 MHz; CDCl3, 258C, TMS): d=7.95
(d, J=8.0 Hz, 2H), 7.54 (t, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 2H),
2.58 ppm (s, 3H). Deuterium incorporation was quantified by inte-
gration of the signal at d=7.95 ppm using the signal at d=
2.58 ppm as a reference.
3,5-Dimethylacetophenone (5): 1H NMR (400 MHz; CDCl3, 258C,
TMS): d=7.57 (s, 2H), 7.20 (s, 1H), 2.58 (s, 3H), 2.37 ppm (s, 6H).
Deuterium incorporation was quantified by integration of the
signal at d=7.57 ppm using the signal at d=7.20 ppm as refer-
ence.
1
1
ed H-decoupled. The assignment of H and 13C signals was accom-
plished, when needed, by two-dimensional correlation experiments
(COSY and HSQC). Multiplets are assigned as: s (singlet), d (dou-
blet), t (triplet), q (quartet), sept (septet), and m (multiplet). Broad
signals are assigned with: br (broad).
1
3,5-Dimethoxyacetophenone (6): H NMR (400 MHz; CDCl3, 258C,
Mass spectrometry (MS): Mass spectra were measured on a Shi-
madzu spectrometer (electron ionization (EI)). ESI MS spectra were
measured on a Finnigan MAT LCQ. The signals are given in mass-
to-charge ratios (m/z). The fragments and relative intensities are
given in brackets. High-resolution MS (HRMS) were measured on
an Agilent QTOF 6520.
TMS): d=7.06 (d, J=2.4 Hz, 2H), 6.62 (t, J=2.4 Hz, 1H), 3.81 (s,
6H), 2.55 ppm (s, 3H). Deuterium incorporation was quantified by
integration of the signal at d=7.06 ppm using the signal at d=
6.62 ppm as reference.
1
4-Acetylbenzonitrile (7): H NMR (400 MHz, CDCl3, 258C, TMS): d=
8.02–8.07 (m, 2H), 7.75–7.81 (m, 2H), 2.65 ppm (s, 3H). Deuterium
incorporation was quantified by integration of the signal at d=
7.75–7.81 and 2.65 ppm using the signal at d=8.02–8.07 ppm as
reference.
Gas chromatography (GC): Gas chromatograms were recorded on
Carlo Erba HRGC Mega2 Series 800 (HRGS Mega2) instruments.
Separations on achiral phases were performed on a Restek Rtx-
1701 (30 mꢂ0.25 mmꢂ0.25 mmol).
1
Acetanilide (8): H NMR (400 MHz; CDCl3, 258C, TMS): d=7.54 (s,
Commercially available compounds and iridium complexes: Sub-
strates 3–13 were purchased from Acros, Aldrich, or Fluka and
used as received without further purifications. Iridium complexes
arising from ligands 14a, 14b, 15a, 15b, 16a, 16b, 17a, 17b,
18a, 18b, 19a, 19b, 20a, 20b, 20c, 22 and iridium complex 21
were synthesized according to literature procedures.[10e,19]
1H), 7.50 (d, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 7.10 (t, J=
7.4 Hz, 1H), 2.17 ppm (s, 3H). Deuterium incorporation was quanti-
fied by integration of the signal at d=7.50 ppm using the signal at
d=2.17 ppm as a reference.
Benzanilide (9): 1H NMR (400 MHz; [D6]acetone, 258C, TMS): d=
9.49 (s, 1H), 7.99 (dd, J=7.0, 1.2 Hz, 2H), 7.85 (d, J=7.5 Hz, 2H),
7.59–7.48 (m, 3H), 7.35 (m, 2H), 7.11 ppm (tt, J=7.4, 1.1 Hz, 1H).
Deuterium incorporation was quantified by integration of the
signal at d=7.99 and 7.85 ppm using the signal at d=7.11 ppm as
a reference.
Procedures
Typical H/D exchange procedure: A vial (2.5 mL) was charged
with a stirring bar and the catalyst (5 mol%, 0.625 mmol). The sub-
strate stock solution in CH2Cl2 (1 equiv, 0.250 mL, 0.05m) was
added to the vial, which was placed in a high-pressure reactor. The
equipment was first pressurized to 2.2 bar with deuterium gas and
the pressure released to 1 bar. This procedure was then repeated
twice. The reaction was performed under 1 bar D2 atmosphere at
1
Nitrobenzene (10): H NMR (400 MHz; CDCl3, 258C, TMS): d=8.25
(dd, J=7.7, 1.1 Hz, 2H), 7.71 (tt, J=7.4 Hz, 1.1 Hz, 1H) and
7.56 ppm (t, J=7.4 Hz, 2H). Deuterium incorporation was quanti-
fied by integration of the signal at d=8.25 ppm using the signal at
d=7.71 ppm as reference.
Chem. Eur. J. 2014, 20, 11496 – 11504
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Methylphenylsulfone (11): 1H NMR (400 MHz; [D6]DMSO, 258C,
TMS): d=7.93–7.97 (m, 2H), 7.65–7.69 (m, 1H) 7.56–7.61 (m, 2H),
3.07 ppm (s, 3H). Deuterium incorporation was quantified by inte-
gration of the signal at d=7.93–7.97 ppm using the signal at d=
7.56–7.61 ppm as reference.
1H NMR (500 MHz, CD2Cl2, 258C, TMS): d=8.52 (d, J=7.08 Hz, 2H),
7.75–7.71 (m, 9H), 7.65 (m, 2H), 7.56 (s, 4H), 5.07–5.18 (m, 1H),
4.73–4.81 (m, 1H), 3.28–3.41 (m, 2H), 243–2.65 (m, 2H), 2.57 (s,
3H), 2.35 (s, 3H), 2.10–2.33 (m, 5H), 1.59–2.01 (m, 13H), 1.16–1.48
(m, 10H), 0.97–1.14 (m, 2H), 0.50–0.67 ppm (m, 1H); 13C{1H} NMR
N-Methyl benzenesulfonamide (12): 1H NMR (400 MHz, CDC13,
258C, TMS): d=7.88 (d, J=6.7 Hz, 2H), 7.57–7.61 (m, 3H), 4.40 (m,
1H), 2.67 ppm (d, J=5.4 Hz, 3H). Deuterium incorporation was
quantified by integration of the signal at d=7.88 ppm using the
signal at d=7.57–7.61 ppm as a reference.
2-Acetylpyridine (13): 1H NMR (400 MHz, CDCl3, 258C, TMS): d=
8.69 (brd, J=4.1 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.84 (td, J=7.7,
1.7 Hz, 1H), 7.49–7.30 (m, 1H), 2.73 ppm (s, 3H). Deuterium incor-
poration was quantified by integration of the signal at d=8.69 and
2.73 ppm using the signal at d=7.84 ppm as a reference.
(125.8 MHz, CD2Cl2, 258C, TMS): d=162.54 (s), 162.17 (q, JCF
=
50.1 Hz, BArF), 146.81 (s), 138.57 (s), 135.16 (m, BArF), 133.97 (s),
129.88 (s), 129.35 (s), 129.07 (qq, JCF =31.1 Hz, JCB =2.5 Hz, BArF),
124.92 (q, JCF =273 Hz, BArF), 124.43 (s), 117.83 (sept., JCF =3.8 Hz,
BArF), 98.16 (d, JCP =9.2 Hz), 91.41 (d, JCP =12.9 Hz), 78.56 (d, JCP
4.9 Hz), 67.45 (s), 61.38 (s), 40.31 (s), 39.99 (s), 38.69 (d, JCP =2.8 Hz),
36.41 (d, JCP =36.3 Hz), 33.9 (s), 32.59 (s), 29.09 (s), 28.58 (dd, JCP
3.96, 1.33 Hz), 28.48 (s), 27.16 (d, JCP =10.8 Hz), 26.92 (d, JCP
12.5 Hz), 26.58 (d, JCP =6.9 Hz), 26.73 (s), 26.40 (brs), 26.33 (d, JCP
6.7 Hz), 24.44 (s), 13.28 ppm (s); 31P{1H} NMR (162 MHz, CD2Cl2,
258C): d=112.46 ppm; MS (+ESI) m/z (%): 716.3 (M+, 6.5), 715.3
(M+, 35.4), 714.3 (M+, 100), 713.4 (M+, 31.8), 712.2 (M+, 58.5);
IR (neat): n˜ =2933, 2860, 1699, 1544, 1485, 1452, 1353, 1271, 1114,
1001, 900, 885, 839, 763, 744, 711, 669, 576 cmÀ1; HRMS-QTOF: m/z
calcd for [C33H48IrNO2P]+: 714.3046; found: 714.3063; m/z calcd for
[C32H12BF24]À: 863.0691; found: 863.0717.
=
=
=
=
The 1H NMR spectroscopic data of deuterated products [D]-3 to
[D]-6 and [D]-8 to [D]-13 were consistent with the literature[8f,17,20]
.
Further characterizations of [D]-7 including 1 H, 2 H, and 13C NMR
spectra and detailed results of the NOE study of Ir complex 21
with compound 7 are provided in the Supporting Information.
Synthesis of achiral Ir complex 26
Acknowledgements
2-(5-Methyl-2-phenyloxazol-4-yl)propan-2-ol (25): A solution of
oxazole 24 (0.66 mmol, 1 equiv) in Et2O (3 mL) was added dropwise
The authors thank Dr. Michelangelo Scalone for helpful scientif-
ic discussions.
to
a solution of methylmagnesium bromide (3m in ether,
1.33 mmol, 2 equiv) at room temperature, and the mixture was
stirred overnight. The reaction was quenched with a 20% sulfuric
acid solution (20 mL) and then extracted with Et2O. The ether layer
was washed with a 5% sodium bicarbonate solution (15 mL) and
dried over anhydrous magnesium sulfate. Evaporation of the sol-
vent provided a yellow residue that was subjected to column chro-
matography using a 20% EtOAc-hexane mixture as eluent (Rf =
0.18). The desired product was obtained as yellow oil in 84% yield.
M.p. 678C; 1H NMR (400 MHz, CDCl3, 258C, TMS): d=7.97 (d, J=
6.0 Hz, 2H), 7.41 (d, J=6.0 Hz, 3H), 2.81 (s, 1H), 2.48 (s, 3H),
1.60 ppm (s, 6H); 13C{1H} NMR (100 MHz, CDCl3, 258C, TMS): d=
158.4, 141.9, 130.0, 129.8, 128.6 (2C), 127.8, 126.0 (2C), 69.3, 30.0
(2C), 11.9 ppm; IR (neat): n˜ = =3303, 2975, 2920, 1622, 1556, 1487,
1448, 1359, 1336, 1286, 1190, 1159, 1134, 1099, 1066, 1001, 962,
916, 852, 775, 725, 690, 659, 619 cmÀ1; HRMS-QTOF: m/z calcd for
[C13H16NO2]+: 218.1176 [M+H]+; found: 218.1173.
Keywords: CÀH activation
· deuterium · homogeneous
catalysis · isotopic labeling · synthetic methods
[1] G. Lappin, S. Temple, Radiotracers in Drug Development, CRC, Florida,
2006.
[2] W. J. S. Lockley, A. McEwen, R. Cooke, J. Labelled Compd. Radiopharm.
2012, 55, 235–257.
[3] For a review on H/D exchange, see: J. Atzrodt, V. Derdau, T. Fey, J. Zim-
mermann, Angew. Chem. 2007, 119, 7890–7911; Angew. Chem. Int. Ed.
2007, 46, 7744–7765.
[4] a) M. Saljoughian, P. G. Williams, Curr. Pharmaceut. Des. 2000, 6, 1029–
1056; b) M. Saljoughian, Synthesis 2002, 1781–1801; c) R. Voges, R.
Heys, T. Moenius, Preparation of Compounds Labelled with Tritium and
Carbon-14, Wiley, New York, 2009.
[5] For recent reviews, see: a) Special issue dedicated to Metal-Catalyzed
Hydrogen Isotope Exchange, J. Label. Compd. Radiopharm. (Eds.: W. J. S.
Lockley, J. R. Heys), Wiley, Chichester, 2010, 53, pp. 635–762; b) R.
Voges, J. R. Heys, T. Moenius, Preparation of Compounds Labelled with
Tritium and Carbon-14, Wiley, New York, 2009, pp. 60–107.
[6] J. L. Garnett, R. J. Hodges, J. Am. Chem. Soc. 1967, 89, 4546–4547.
[7] a) M. R. Blake, J. L. Garnett, I. K. Gregor, W. Hannan, K. Hoa, M. A. Long,
J. Chem. Soc. Chem. Commun. 1975, 930–932; b) W. J. S. Lockley, Tetra-
hedron Lett. 1982, 23, 3819–3822; c) W. S. J. Lockley, J. Labelled Compd.
Radiopharm. 1984, 21, 45–57; d) W. S. J. Lockley, J. Labelled Compd. Ra-
diopharm. 1985, 22, 623–630; e) D. Hesk, J. R. Jones, W. S. J. Lockley, J.
Pharm. Sci. 1991, 80, 887–890.
[8] a) R. H. Crabtree, E. M. Holt, M. Lavin, S. M. Morehouse, Inorg. Chem.
1985, 24, 1986–1992; b) R. Heys, J. Chem. Soc. Chem. Commun. 1992,
680–681; c) J. R. Heys, A. Y. L. Shu, S. G. Senderoff, N. M. Phillips, J. La-
belled Compd. Radiopharm. 1993, 33, 431–438; d) A. Y. L. Shu, W. Chen,
J. R. Heys, J. Organomet. Chem. 1996, 524, 87–93; e) J. G. Ellames, S. J.
Gibson, J. M. Herbert, W. J. Kerr, A. H. McNeill, Tetrahedron Lett. 2001, 42,
6413–6416; f) P. W. C. Cross, J. G. Ellames, J. S. Gibson, J. M. Herbert,
W. J. Kerr, A. H. McNeill, T. W. Mathers, Tetrahedron 2003, 59, 3349–
3358; g) J. G. Ellames, J. S. Gibson, J. M. Herbert, W. J. Kerr, A. H. McNeill,
J. Labelled Compd. Radiopharm. 2004, 47, 1–10; h) M. B. Skaddan, C. M.
Yung, R. G. Bergman, Org. Lett. 2004, 6, 11–13; i) C. M. Yung, M. B. Skad-
dan, R. G. Bergman, J. Am. Chem. Soc. 2004, 126, 13033–13043; j) R. N.
Ir complex 26: In a glovebox, alcohol 25 (0.187 mmol, 1 equiv), di-
cyclohexylchlorophosphine (0.191 mmol, 1.02 equiv), KH (25 to
35% wt, 0.374 mmol, 2 equiv), and a magnetic stir bar were added
to a dry Schlenk tube. Outside the glovebox, THF (2 mL) was
added under an argon atmosphere. The mixture was stirred at
room temperature overnight. The solvent was removed in vacuo.
The Schlenk tube was transferred back to the glovebox, and the
residue was suspended in toluene (2 mL, dry, degassed) and fil-
tered over a disposable HPLC-syringe filter (CHROMAFIL O-20/15
MS, pore size 20 mm). The remaining solid on the filter was rinsed
with toluene (2ꢂ2 mL). After removing the filtrate from the glove-
box, it was concentrated in vacuo, and the crude ligand was dis-
solved in CH2Cl2 (3 mL). This solution was added dropwise under
stirring to a solution of [IrCl(cod)]2 (0.0954 mmol, 0.51 equiv) in
CH2Cl2 (1 mL). The resulting solution was heated at reflux for 1 h
and cooled down to room temperature. NaBArF (0.206 mmol,
1.1 equiv) was added and the mixture was stirred for 30 min at
room temperature. Silica gel was added and the solvent was re-
moved in vacuo. Filtration over silica gel (40 g; hꢂd: 15ꢂ2.5 cm,
1st: 150 mL of Et2O 2nd: 200 mL of CH2Cl2/Et2O 1:1) led to the de-
sired iridium complex in 25% yield as an orange solid. M.p. 1808C;
Chem. Eur. J. 2014, 20, 11496 – 11504
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Full Paper
Garman, M. J. Hickey, L. P. Kingston, B. McAuley, J. R. Jones, W. J. S. Lock-
ley, A. N. Mather, D. J. Wilkinson, J. Labelled Compd. Radiopharm. 2005,
48, 75–84; k) J. Krꢁger, B. Manmontri, G. Fels, Eur. J. Org. Chem. 2005,
1402–1408; l) M. B. Skaddan, R. G. Bergman, J. Labelled Compd. Radio-
pharm. 2006, 49, 623–634; m) J. A. Brown, S. Irvine, A. R. Kennedy, W. J.
Kerr, S. Andersson, G. N. Nilsson, Chem. Commun. 2008, 1115–1117.
[9] D. Hesk, P. R. Das, B. Evans, J. Labelled Compd. Radiopharm. 1995, 36,
497–502.
tritium gas under high pressure needs special equipment which is usu-
ally not accessible to isotope laboratories. Furthermore, high pressure
leads to increased consumption of expensive tritium and larger
amounts of radioactive waste.
[16] Cationic iridium hydride complexes, which are formed upon treatment
of [IrI(cod)] precatalysts with dihydrogen, are known to be strong
Brønsted acids; see: D. Y. Zhu, Y. Fan, K. Burgess, J. Am. Chem. Soc.
2010, 132, 6249–6253.
[10] a) A. Pfaltz, Acc. Chem. Res. 1993, 26, 339–345; b) G. Helmchen, A.
Pfaltz, Acc. Chem. Res. 2000, 33, 336–345; c) A. Pfaltz, W. Drury, Proc.
Natl. Acad. Sci. USA 2004, 101, 5723–5726; d) S. Bell, B. Wustenberg, S.
Kaiser, F. Menges, T. Netscher, A. Pfaltz, Science 2006, 311, 642–644;
e) S. J. Roseblade, A. Pfaltz, Acc. Chem. Res. 2007, 40, 1402–1411.
[11] P. G. Jessop, R. H. Morris, Coord. Chem. Rev. 2001, 121, 155–284.
[12] a) D.-H. Lee, J. Chen, J. W. Faller, R. H. Crabtree, Chem. Commun. 2001,
213–214; b) R. H. Crabtree, J. W. Faller, M. F. Mellea, J. M. Quirk, Organo-
metallics 1982, 1, 1361–1366; c) X. Li, P. Chen, J. Faller, R. Crabtree, Or-
ganometallics 2005, 24, 4810–4815.
[17] S. C. Schou, J. Labelled Compd. Radiopharm. 2009, 52, 376–381.
[18] C. Wan, J. Zhang, S. Wang, J. Fan, Z. Wang, Org. Lett. 2010, 12, 2338–
2341.
[19] For example, see: a) A. Pfaltz, J. Blankestein, R. Hilgraf, E. Hçrmann, S.
McIntyre, F. Menges, M. Schçnleber, S. P. Smidt, B. Wꢁstenberg, N. Zim-
mermann, Adv. Synth. Catal. 2002, 344, 33–44; b) A. Pfaltz, S. Bell, in
Handbook of Homogeneous Hydrogenation Vol. 2 (Eds.: J. G. de Vries,
C. J. Elsevier), Wiley-VCH, Weinheim, 2007, 1029–1072, and references
cited therein; c) Two Ir(ThrePHOX) complexes (derived from ligands
18a and 18b) are commercially available from Strem, Inc. (catalog no.
77-5009, 77-5019).
[13] For computational study on octahedral organometallic compounds,
see: I. Tubert-Brohman, M. Schmid, M. Meuwly, J. Chem. Theory Comput.
2009, 5, 530–539.
[20] G. J. Ellames, J. S. Gibson, J. M. Herbert, A. H. McNeill, Tetrahedron 2001,
57, 9487–9497.
[14] R. Salter, J. Labelled Compd. Radiopharm. 2010, 53, 645–657.
[15] The pressure was restricted to 1 bar. The procedure should be adapta-
ble to a reaction with tritium gas on a tritium manifold, in which usual-
ly reactions are run at ambient or even reduced pressure. Handling of
Received: February 7, 2014
Published online on July 10, 2014
Chem. Eur. J. 2014, 20, 11496 – 11504
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11504
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim