Comparison of Iridium(I) Catalysts in Temperature Mediated Hydrogen Isotope Exchange Reactions

Article abstract of DOI:10.1002/open.201900204

The reactivity and selectivity of iridium(I) catalysed hydrogen isotope exchange (HIE) reactions can be varied by using wide range of reaction temperatures. Herein, we have done a detailed comparison study with common iridium(I) catalysts (1–6) which will help us to understand and optimize the approaches of either high selectivity or maximum deuterium incorporation. We have demonstrated that the temperature window for these studied iridium(I) catalysts is surprisingly very broad. This principle was further proven in some HIE reactions on complex drug molecules.

Full text of DOI:10.1002/open.201900204

DOI: 10.1002/open.201900204
Full Papers
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Comparison of Iridium(I) Catalysts in Temperature
Mediated Hydrogen Isotope Exchange Reactions
Mégane Valero+, Anurag Mishra, Jennifer Blass, Remo Weck, and Volker Derdau*[a]
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The reactivity and selectivity of iridium(I) catalysed hydrogen
isotope exchange (HIE) reactions can be varied by using wide
range of reaction temperatures. Herein, we have done a detailed
comparison study with common iridium(I) catalysts (1–6) which
will help us to understand and optimize the approaches of either
high selectivity or maximum deuterium incorporation. We have
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demonstrated that the temperature window for these studied
iridium(I) catalysts is surprisingly very broad. This principle was
further proven in some HIE reactions on complex drug
molecules.
Introduction
as compared to parent molecules. Numerous HIE protocols
utilizing homogeneous or heterogeneous catalysts have already
been described.[3,12]
While there have been new HIE methods published lately
utilizing metals like iron,[13] cobalt[14] or ruthenium[15,16,17] the
state-of-the-art-procedure utilise iridium catalysts, such as those
explored by Crabtree 1,[18,19] Kerr 2,[20,21] Pfaltz 3,[22] Burgess 4,[23]
Ding 5[24] or Tamm 6.[25] (Scheme 1). Most of these catalysts are
In recent years CÀ H activation in the context of late stage
functionalization has become a strong tool in lead optimization
of bioactive molecules in the life science academia and
industry.[1] One fragment in this broader context of CH
functionalization[2] and applying the principles of chemical
modification of complex molecules at the latest possible time
point is the hydrogen isotope exchange (HIE). Due to its
simplicity the HIE method can be seen as the most fundamental
of all CH functionalization reactions. HIE reactions are an
elegant way for the incorporation of deuterium or tritium into
complex organic molecules circumventing the need for a
tedious total synthesis with several reaction steps.[3] Especially
for the synthesis of tritium labelled substances a labelling
procedure at the latest possible reaction step is minimizing
radioactive waste and decreases the handling time with the
radioactive products. Radioactive tritium labelled substances
are applied as tool compounds[4,5] e.g. for understanding tissue
distribution,[6] in covalent binding assays,[7] or for ADME
(Absorption Distribution Metabolism Excretion) profiling of new
drug candidates.[8] On the other hand deuterium labelled
compounds are utilized in pharmaceutical research as internal
standards for LC-MS/MS assay validation[9] for metabolic path-
way elucidation[10] and more recently also as “heavy drugs”.[11]
With deuterium or tritium labeling, the drug structures are not
changed which gives an exact chemical or biological behavior
[a] M. Valero,+ Dr. A. Mishra, J. Blass, R. Weck, Dr. V. Derdau
Sanofi-Aventis Deutschland GmbH, Integrated Drug Discovery, Isotope
Chemistry, Industriepark Höchst, Frankfurt, Germany
E-mail: Volker.Derdau@sanofi.com
[+] Mégane Valero is participant in the EU Isotopics consortium. The ISOTOPICS
project has received funding from the European Union’s Horizon 2020 re-
search and innovation programme under the Marie Sklodowska-Curie grant
Scheme 1. Common Iridium-catalysts (1--6) in directed HIE reactions.
commercially available and are nowadays applied regularly in
HIE reactions within industry laboratories.
°
agreement N 675071*.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/open.201900204
As an introduction of a radioactive label in a metabolically
stable position is essential for the application of tritiated
compounds in in-vivo experiments, it is necessary to under-
stand the influence of the different directing groups in complex
molecules.[4] In comparison to 14C-labelling where a loss of the
© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons
Attribution Non-Commercial NoDerivs License, which permits use and dis-
tribution in any medium, provided the original work is properly cited, the
use is non-commercial and no modifications or adaptations are made.
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radioactive marker is most unlikely, the loss of tritium can
happen by phase 1 metabolic enzymatic transformation, like
e.g. hydroxylation. Therefore the prediction of the labelling
position in complex molecules would be of great benefit to
synthetic chemists[26] and avoid the necessity for many try and
error experiments. One parameter to trigger reactivity and
selectivity in HIE reactions is to study the effect of the reaction
temperature. Even though many details on the optimization of
reactions conditions in iridium catalysed HIE are already
reported,[27] there is still a lacking of head to head comparison,
therefore we concluded that a general comparison study with
the most commonly applied catalysts 1–6 could help to use the
optimized approach for either high selectivity or maximum
deuterium incorporation. This way unproductive HIE reactions
can be circumvented and hence it could be of great interest for
many scientists.
Table 1. Evaluations of iridium(I) catalysts 1–6 in a HIE reaction of 4-
1
2
3
4
5
6
7
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9
°
°
acetamido-acetophenone 7 at temperatures from À 80 C to 25 C in
dichloromethane.
Entry
catalyst
T ( C)
7A (D%)a
7B (D%)a
Dtotal
b
°
1
2
3
4
5
6
25
0
93
91
54
50
33
14
94
94
87
74
40
34
3.7
3.7
2.8
2.5
1.5
1.0
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À 15
À 30
À 60
À 80
7
8
9
10
11
25
0
À 15
À 30
À 60
92
30
10
0
99
87
70
38
34
3.8
2.3
1.6
0.8
0.7
0
Results and Discussion
We began our investigations with the HIE reactions of 4-
acetamido-acetophenone 7 with catalysts 1–6 in dichloro-
methane at various low temperatures. We had chosen this
model compound as the acetamido and the ketone directing
group were known to give good results in HIE reactions with
iridium catalysts.[20] Beside general deuterium introduction we
also evaluated the change in selectivity in the HIE reaction
between position A and B (Table 1). Interestingly, depending on
the used catalyst we observed strong differences in reactivities
and selectivities of the deuterated products of compound 7. At
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25
0
À 15
À 30
À 60
0
0
0
0
0
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20
10
0
1.0
0.4
0.2
–
0
–
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18
19
20
21
25
0
À 15
À 30
À 60
67
51
20
0
93
93
90
50
32
3.2
2.9
2.2
1.0
0.6
°
À 80 C only catalysts 1 (Crabtree, entry 6) showed reasonable
0
reactivity (>25%D incorporation), however with only low
selectivity in favour of position B (ketone directing group). The
other catalysts had increasing reactivity at lower temperatures
in the order of 6>2=4>5>3. For catalysts 2 (entry 10), 4
(entry 20) and 5 (entry 25) complete selectivity in favour of
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25
26
25
0
À 15
À 30
À 60
24
18
24
0
82
81
75
50
11
2.1
2.0
2.0
1.0
0.2
°
position B was observed at À 30 C. It is further noted that for
0
catalysts 1, 4, 5 and 6 there are no big differences in the
°
outcome of the HIE reaction of 25 or 0 C. These reactions
clearly indicate that HIE reactions at lower temperature have a
chance to change the reactions outcome and should be studied
more intensively in the future. Kerr et al. reported the different
free energy profiles for HIE reactions of aromatic compounds in
the gas phase with catalyst 2 (Scheme 2). While for acetophe-
non a ΔH activation energy in the transition state (8) of
18.13 kcal/mol (298 K) were calculated the value for acetanilide
of 23.04 kcal/mol (9) was reported[20c] which is 4.91 kcal/mol
energetically higher and in line with the observed selectivities
of all used catalysts in Table 1 and 2 showing the ketone
directing group of 7 the more HIE relevant one compared to
acetanilide. It looks like in principle all catalysts 1–6 could either
go through a five- or six-membered-ring transition state as both
positions were exchanged by deuterium in the products.
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25
0
À 15
À 30
À 60
À 80
65
86
70
21
0
94
91
92
79
48
13
3.2
3.6
3.3
2.0
1.0
0.3
0
Conditions: substrate 1 (10 mg), catalyst (5 mol%), D2 (1 atm), dichlor-
omethane (5 mL), 4 h; a determined by 1H-NMR, b determined by LC-MS.
°
5 showed their highest deuteration efficiency at 75–100 C with
nearly full deuteration of the aromatic positions (entry 3, 8, 19,
24). Remarkably no H/D exchange at the C(sp3)-positions were
observed, neither at the ketone or acetanilide methyl-groups.
Catalyst 3 and 6 were the most sensitive ones in relation to
Next, we studied the HIE reaction of our model compound
°
7 at elevated temperatures up to 130 C (Table 2). Therefore we
had to change the solvent to chlorobenzene due to the low
°
boiling point of dichloromethane. Interestingly, catalyst 1, 2, 4,
heat. Above 50 C the deuterium introduction decreased
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significantly indicating that the HIE activity of these catalysts
drops due to undesired side reactions. These results clearly
indicate that higher temperatures are having a strong effects
on the outcome of the HIE reaction and should be studied
more intensively as optimization parameter in the future.
1
2
3
4
5
Even though we know that a full picture on the efficiency
and reactivity of the different catalysts 1–6 can’t be given by a
HIE reaction of just a single substrate we believe that together
with a lot of different literature examples[20,22,29] a general
statement can be made. Even though these ligated iridium
catalysts seem to be remarkable stable at higher temperatures
methodological studies at elevated temperature are still few in
6
7
8
9
Scheme 2. Simplified transition states in the HIE reaction of acetophenon
and acetanilide with a iridium catalyst. DFT calculation values of catalyst
2.[20c]
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Table 2. Evaluations of iridium(I) catalysts 1–6 in a HIE reaction of 4-
°
number.[23,28] Furthermore to our knowledge there is only one
acetamido-acetophenone 7 at temperatures from 25 to 130 C in
chlorobenzene.
[29]
°
study on HIE reactions at À 20 C reaction temperature.
Entry
catalyst
T ( C)
DA (%)–7c
DB (%)–7c
Dtotal
d
°
Nevertheless the overview in Figure 1 should only be seen as a
1
2
3
4
5
25
50
87
84
99
15
13
94
99
99
68
64
3.6
3.7
4.0
1.8
1.6
75
100
130
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7
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9
25
50
75
100
130
94
90
98
52
0
92
99
99
81
47
3.8
3.8
4.0
2.7
1.0
10
11
12
13
14
15
25
50
75
100
130
0
0
0
0
0
45
48
35
0
0.9
1.0
0.7
0.1
0
0
Figure 1. Graphical overview in which temperature window the catalysts 1–6
are efficiently working (threshold 25%D) for HIE reactions with compound 7;
yellow star is showing highest deuterium incorporation
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19
20
25
50
75
100
130
63
58
62
98
49
97
99
99
99
84
3.0
3.2
3.3
4.0
2.9
principal direction in which kind of temperature window the
catalysts were reactive and no significant decomposition of the
catalyst was observed.
Finally we were interested to demonstrate how the knowl-
edge about different HIE reactivities and deuterium introduc-
tion efficiencies of these iridium catalysts 1–6 can influence the
project planning. Therefore we identified five more complex
examples where we wanted to apply different labelling
conditions.
21
22
23
24
25
25
50
75
100
130
35
79
79
96
8
85
99
99
98
93
2.4
3.6
3.6
3.9
1.8
26
27
28
29
30
25
50
75
100
130
56
23
30
8
87
63
35
26
0
3.0
1.7
1.4
0.8
0.0
One interesting example for the different reactivity of
iridium catalysts is described in Scheme 3. With catalyst 6 at
0
°
25 C we have obtained selectively deuterium incorporation in
the aromatic position A of phenylacetic amide 10.[30] Interest-
ingly with catalyst 2a we obtained no deuterium introduction
Conditions: substrate 7 (1 mg), catalyst (5 mol%), D2 (1 atm), C6D5Cl
(0.5 mL), 4 h c determined by 1H NMR, d determined by LC-MS (we have not
found any significant decomposition products)
°
at all at 25 C. However, when we increased the temperature to
°
80 C we observed deuteration in both positions A and B,
indicating that by increasing the temperature the transitions
states for both CH-activation pathways for C(sp2)- and C(sp3)-
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°
Scheme 3. HIE reaction of phenylacetic glycine amide derivative 10 with two iridium catalysts (5 mol%). No deuterated product with catalyst 2a at 25 C and
°
catalyst 6 at 80 C.
carbons are possible to be passed through. The labelling of
glycine C(sp3)-positions with catalyst 2 has been demonstrated
earlier by us already.[28a] With catalyst 6 we obtained only traces
of deuterated product due to the prior described instability of
like clopidogrel, naproxene, camylofine, etc. and labelling of
these compounds is still challenging.[30]
In a third example we have studied the deuteration of
celecoxib 12 (Scheme 5), a COX-2 selective nonsteroidal anti-
inflammatory drug (NSAID) to treat arthritis. With catalyst 6 we
observed in the HIE reaction at 0 C only exchange in the B-
position (62%D) directed by the sulfonamide group, while with
catalyst 1 we found the product labelled at the A-position (78%
D) only. At 80 C this selectivity of catalyst 1 was reduced to 3:1
°
the catalyst at temperatures above 50 C. Unfortunately, we
°
haven’t found a catalyst or conditions to selectively introduce
deuterium at the C(sp3)-position (B) only of 10 until now.
In this context we tried the HIE reaction of diclofenac
°
methylester 11,
inflammatory diseases such as gout or arthritis, which was only
deuterated by applying catalyst 5 at 100 C (Scheme 4). No
deuteration was observed at 80 C degree and below with
a
NSAID drug used to treat pain and
(60%D for position A and 20%D for B). The total amount of
°
°
catalyst 5, as with all other tested catalysts 1–4 at temperatures
°
25–100 C. This is a remarkable result as phenyl acetic acids
derivatives are core structures in a variety of important drugs,
Scheme 4. HIE reaction of diclofenac 11 with five different iridium catalysts;
Scheme 5. HIE reaction of celecoxib 12 with three different iridium catalysts
°
no reactivity at < =80 C with catalysts 1–5.
and temperatures
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°
°
Scheme 6. HIE reaction of glibenclamide 13 with two different iridium catalysts 4, 5 at 100–120 C; no reactivity of catalysts 4, 5 at 25 C.
°
°
Scheme 7. HIE reaction of apixaban 14 with two different iridium catalysts 4, 5 at 100 C, no reactivity at 25 C.
°
introduced deuterium did not change compared to 0 C.
overall four deuterium atoms, however all three possible
positions A, B and C were deuterated.
2
°
Interestingly, applying catalyst 4 at 100 C both C(sp )-positions,
A and B, were exchanged completely (92%D) indicating how
catalyst and temperature can trigger the HIE reaction outcome.
Next we performed HIE reactions with glibenclamide 13 Conclusions
(Scheme 6), an inhibitor of the ATP-sensitive potassium chan-
nels (KATP) which is an inhibitory regulatory subunit of the
sulfonylurea receptor 1 (SUR1) in pancreatic beta cells to treat
We have demonstrated that by applying the optimized
combination of iridium catalysts and reaction temperatures
different HIE reaction outcomes can be achieved. Notably the
temperature window for most studied iridium catalysts 1–6 is
surprisingly broad and we hope that they are applied more
specifically and with greater success in the future. To use the
right catalyst with the ideal reaction conditions is the trigger to
either increase the selectivity or the deuterium incorporation.
While rising the reaction temperature to a maximum prior
facing catalyst decomposition is the key for maximum deute-
rium incorporation into the target molecule, on the other hand
decreasing the temperature can circumvent not wanted side
reactions (hydrogenation) or substrate decomposition and
therefore triggers either regioselectivity and catalyst activity.
°
diabetes mellitus type 2. With catalyst 5 at 100 C selectively
only position A was deuterated, while with catalyst 4, as
reported before,[23a] both positions A and B (59%D and 83%D)
with favoring of deuterated position B was obtained. Both
°
catalysts (4,5) showed no reactivity in reactions at 25 C.
Finally we studied the HIE reaction of apixaban 14
(Scheme 7), a reversible direct inhibitor of factor Xa to prevent
stroke, with two different iridium catalysts at the same temper-
°
ature (100 C). Interestingly, with catalyst 5 only deuteration of
position C was observed, with a total of one deuterium
introduced into the molecule. In comparison the HIE reaction
with catalyst 4 generated a highly deuterated product with
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Our studies give a first aid which catalysts can be applied if very Conflict of Interest
1
2
3
4
5
6
7
8
heat sensitive substrates are used. Furthermore, we believe that
evaluating selectivity and reactivity of different catalysts in a
comparison study of a reaction class can make the prediction of
CH-functionalization reaction more reliable and understandable
which could enable a greater probability of success with HIE
reactions to increase effectiveness and reduce the number of
reactions needed.
The authors declare no conflict of interest.
Keywords: hydrogen isotope exchange · deuterium · iridium
catalysis · CÀ H functionalization · homogeneous catalysis
9
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All chemicals were used as commercially available, unless specified
otherwise. Deuterium (99.9%D) was purchased from Sigma Aldrich
1
in 12 L bottles. H-NMR spectra were obtained on a Bruker Avance
300 spectrometer (Bruker, Rheinstetten, Germany). The chemical
shifts are shown in ppm in reference to the shift of the residual
proton of DMSO-d6 (δ 2.50 ppm) or CDCl3 (δ 7.27 ppm). NMR-peaks
were assigned to respective protons using a combination of NMR
prediction software and 2D-NMR experiments. The NMR-spectra
shown are the reference for the starting material and the product
of the hydrogen-deuterium exchange. LC-MS analysis was done on
an Agilent 1100 series HPLC. Using positive ESI mode, the mass of
the compounds was recorded before and after deuteration. The
results were normalized against the natural occurring isotopes
found in the reference spectra. All reactions were carried out in a
Radleys Carousel 12 parallel synthesizer.
HIE reaction method A: Substrate (10 mg, 1 eq) and catalyst (5 mol
%, 0.05 eq) were dissolved in dichloromethane (DCM) for a total
volume of 3 ml and added to a flask equipped with a stirring bar.
The flasks were sealed. The flasks were then evacuated until
bubbling started and filled with deuterium gas, this was repeated
thrice. The flasks were sealed and the reactions were run in D2
atmosphere while stirring (500 rpm). After four hours the reaction
was stopped by evacuation of the flask and evaporation of DCM.
The products were analyzed by LC-MS and 1H NMR.
HIE reaction method B: Catalysts (5 mol%, 0.05 eq) were dissolved
in chlorobenzene-D5 for a total volume of 0.4 ml and added to a
flask equipped with a stirring bar. The flasks were sealed. The flasks
were then evacuated until bubbling started and filled with
deuterium gas, this was repeated thrice. The flasks were sealed and
the reaction was run in D2 atmosphere while stirring (300 RPM, at
various temperature as specified), 1 h). After 1 h, substrate 7 (1 mg,
1 eq) in 0.5 mL chlorobenzene-d5 were added in the reaction
mixture and the reaction was further continued for another 2 h at
respective temperatures. Finally, the reactions were stopped by
evacuation of the flask and the products were analysed directly by
1H NMR and LC-MS.
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compounds 10–14 please look the supporting information.
Acknowledgements
We thank the European Union’s Horizon 2020 research and
innovation program under the Marie Sklodowska-Curie grant
agreement no. 675071 for funding.
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ChemistryOpen 2019, 8, 1183–1189
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© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA

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Manuscript received: June 11, 2019
ChemistryOpen 2019, 8, 1183–1189
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© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA