Directed Iridium-Catalyzed Hydrogen Isotope Exchange Reactions of Phenylacetic Acid Esters and Amides

Article abstract of DOI:10.1002/chem.201901449

For the first time, a catalytic protocol for a highly selective hydrogen isotope exchange (HIE) of phenylacetic acid esters and amides under very mild reaction conditions is reported. Using a homogeneous iridium catalyst supported by a bidentate phosphine-imidazolin-2-imine P,N ligand, the HIE reaction on a series of phenylacetic acid derivatives proceeds with high yields, high selectivity, and with deuterium incorporation up to 99 %. The method is fully adaptable to the specific requirements of tritium chemistry, and its effectiveness was demonstrated by direct tritium labeling of the fungicide benalaxyl and the drug camylofine. Further insights into the mechanism of the HIE reaction with catalyst 1 have been provided utilizing DFT calculations, NMR studies, and X-ray diffraction analysis.

Full text of DOI:10.1002/chem.201901449

A Journal of
Accepted Article
Title: Directed Iridium-Catalyzed Hydrogen Isotope Exchange
Reactions of Phenylacetic Acid Esters and Amides
Authors: Mégane Valero, Daniel Becker, Kristof Jess, Remo Weck,
Jens Atzrodt, Thomas Bannenberg, Volker Derdau, and
Matthias Tamm
This manuscript has been accepted after peer review and appears as an
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201901449
Link to VoR: http://dx.doi.org/10.1002/chem.201901449
Supported by

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COMMUNICATION
Directed Iridium-Catalyzed Hydrogen Isotope Exchange
Reactions of Phenylacetic Acid Esters and Amides
Mégane Valero,[a,#] Daniel Becker,[b,#] Kristof Jess, Remo Weck, Jens Atzrodt, Thomas
[b]
[a]
[a]
[b]
[a, ]
[b, ]
Bannenberg, Volker Derdau, * and Matthias Tamm *
Directed aromatic HIE of phenylacetic derivatives:
Yu et al.
Abstract: For the first time, a catalytic protocol for highly selective
hydrogen isotope exchange (HIE) of phenylacetic acid esters and
amides under very mild reaction conditions is reported. Using a
homogeneous iridium catalyst supported by a bidentate phosphine-
imidazolin-2-imine P,N ligand, the HIE reaction on a series of
1
0 mol%Pd(OAc)2
H
D
Na CO (1.5 equiv.)
D
D
2
3
OH
[D ]acetic acid
OH
XR
4
O
120 °C, 12 h
O
H
D
phenylacetic acid derivatives proceeds with high yields, high
selectivity and with deuterium incorporation up to 99%. The method is
fully adaptable to the specific requirements of tritium chemistry, and
its effectiveness was demonstrated by direct tritium labeling of the
fungicide benalaxyl and the drug camylofine. Further insights into the
mechanism of the HIE reaction with catalyst 1 have been provided
utilizing DFT calculation, NMR-studies and X-ray diffraction analysis.
R
R
Hoover et al.
1
0 eq.
tBu
tBu
H
H
N
N
XR
or JohnPhos
O
II
O
/T
D
D /T
2
Pd
2
Cs CO
2
3
(4 eq. Pd)
X = O, NH
11 examples D/T
rt, 18 h
Our work:
Hydrogen isotope exchange (HIE) – the most fundamental of all
C-H functionalization processes – has become a broadly utilized
D/T
N
N
1
XR
H
N
+
P
Ir
XR
O
strategy for the incorporation of deuterium or tritium into complex
organic molecules.2,3 In drug discovery, radioactive tritium tracers
O
/T
1
D
BArF24-
4
H
10 mol%
/T
are increasingly utilized as discovery tools, in covalent binding
19 esters (49-91 %D)
10 amides (75-99 %D)
5
6
D
2
2
assays, for tissue distribution studies, for in-vivo profiling of new
drug candidates and for other life science applications.3,7,8 Based
on homogeneous or heterogeneous catalysis, numerous HIE
X = N, O
chlorobenzene
rt, 2 h
2 complex tritium compds.
methods have already been described.1,2,9 Besides an ongoing
Scheme 1. Known aromatic HIE reactions in comparison to our work for
3
active research for C(sp )-H activation/deuteration,10 particularly
selective CH-activation/deuteration in phenylacetic acid esters and amides;
–
BArF24 = tetrakis[bis(3,5-trifluoromethyl)phenyl]borate.
the selective ortho-directed HIE of aromatic substrates with
commercial Crabtree's 11 and Kerr's catalyst 12 , 13 have been
investigated and successfully applied for many years. Some of
the existing limitations with these classical HIE catalysts could
recently be overcome by introduction of a new generation of
iridium catalysts containing bidentate ligands with examples from
Pfaltz14 and Burgess.15 We have also contributed to this field by
developing the new P,N-ligated iridium catalyst 1, which
demonstrated unique reactivity features and an unprecedented
HIE transition state flexibility involving 5-, 6- and even 4-
membered rings.16 As a consequence, 1 allowed to extend the
scope of ortho-directed HIE reactions to various tertiary
sulfonamides, sulfonylurea, anisoles, phosphonamides and even
N-Boc-protected anilines.
Despite this recent progress, the selective labeling of
phenylacetic acid derivatives still presents an unsolved challenge
for catalytic HIE. This interesting structural motif is present in
many life science products such as pharmaceutical drugs, e.g.,
clopidogrel, ibuprofen, naproxen etc., or fungicides like benalaxyl.
In 1996, Heys studied the HIE performance of several iridium(I)
complexes such as [Ir(COD)(PCy
tricyclohexylphosphine, py = pyridine, “Crabtree’s catalyst”),
Ir(COD)(PPh ]BF and [Ir(COD)(dppe)]BF (COD 1,5-
cycloctadiene, dppe diphenylphosphinoethane), and low
deuterium introduction of only up to ca. 7% was found for the
model substrate ethyl phenylacetate (3), which was ascribed to
the lower preference for formation of six-membered metallacyclic
intermediates upon oxidative insertion into the activated ortho-C–
H bond. It was also shown that the latter complex containing the
chelating dppe ligand was generally more effective at labeling
substrates requiring the formation of six-membered metallcycles.
Deuteration as well as tritiation of methyl (6-methoxynaphth-2-
yl)acetate was also achieved, albeit with low deuterium (12%) and
3
)(py)]BF
4
(PCy
3
=
[
3
)
2
4
4
=
=
[
[
[
a]
b]
#]
M. Valero, R. Weck, Dr. Jens Atzrodt, Dr. V. Derdau, Sanofi-Aventis
Deutschland GmbH, R&D, Integrated Drug Discovery, Industriepark
Höchst, 65926 Frankfurt am Main (Germany)
E-mail: Volker.Derdau@sanofi.com
D. Becker, Dr. Kristof Jess, Dr. Thomas Bannenberg, Prof. Dr.
Matthias Tamm, Technische Universität Braunschweig, Hagenring
-1
30, 38106 Braunschweig (Germany)
tritium (7 Ci mmol ) incorporation and high catalyst loadings (150
mol%).17 Based on heterogeneous catalysis, Sajiki developed an
unselective method for labeling of all aromatic protons with
palladium and platinum on charcoal at 180 °C in D
2
O.18 The first
selective method was reported by Yu in 2014, who discovered a
palladium-catalyzed HIE reaction of phenylacetic acids with
E-Mail: m.tamm@tu-bs.de
Both authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201901449
COMMUNICATION
deuterated acetic acid as deuterium source (Scheme 1). 19
Recently, this approach was further improved by Hoover,20 who
generated substrate-palladium complexes, which were reduced
subsequently by deuterium or tritium. However, while Yu’s acetic
towards the substitution pattern at the aryl ring. While meta-
substitution in 3-tolylacetic acid methyl ester 6 gave 45%D and
55%D, respectively, the corresponding para- or ortho-substituted
analogues gave better deuterium incorporation (85%D and
acid method requires harsh reaction conditions (high temperature, 94%D). This was also observed in the halogenated substrates 11
low pH) and employs a hydrogen isotope source that is not
compatible with the requirements of tritium chemistry.21 Hoover’s
protocol is non-catalytic and requires a potentially troublesome
precursor synthesis together with tedious removal of excess
palladium and ligand. In order to circumvent these shortcomings,
we became interested in developing an improved catalytic HIE
and 12. Interestingly, this trend was not observed for the hydroxyl-
substituted esters 8–10, indicating that not only steric but also
electronic factors exert influence on the outcome of the HIE
reaction. Increasing the reaction time to 24 h for compounds with
lower deuterium incorporation like 3, 4 or 6 had no positive effect
on the final deuteration results.
method under very mild reaction conditions with D
hydrogen isotope source.
2 2
/T as
[
63]
[98]
[99]
[
98]
H
N
N
N
[63]
[
33]
We initiated our HIE studies by examining the deuteration of
methyl phenylacetate (2) as model substrate under one
atmosphere D pressure. By varying the reaction parameters
2
O
O
O
1
4, 88%
15, 97%
[79]
16, 97%
[96]
[
13]
such as catalyst amount, solvent and temperature, optimal
conditions were identified to be 10 mol% catalyst loading of 1 in
chlorobenzene at room temperature. Under these conditions, a
high degree of deuterium incorporation (90%) was observed for
the ortho-position in the presence of catalyst 1, while a screening
with other established and commercially avalable iridium catalysts
afforded only low levels of deuteration (< 3%D, see the
Supporting Information, Table S1).
[
92]
H
N
N
N
[
22]
O
O
O
O
O
O
1
7, 66%
95]
18, 95%
19, 96%
29]
[
[
H
[98]
N
N
[29]
[
13]
O
O
N
N
[
87]
[68]
[49]
20, 61%
21, 67%
O
O
O
O
[
99]
[75]
H
N
H
O
O
O
N
O
2
, 83%
3, 78%
4, 81%
O
O
Cl
O
[45]
2
3, 98%
[
85]
22, 94%
O
O
O
O
O
O
Scheme 3. HIE reaction with various phenylacetic amides; conditions: catalyst
(10 mol%), 1 atm D , chlorobenzene 1 mL, rt, 2 h; all reactions repeated at
least twice.
[
55]
[94]
1
2
5
, 87%
6, 91%
7
, 82%
OH
[
82]
[76]
O
HO
O
[26]
O
Under the general reaction conditions, ortho-directed
deuteration of a variety of phenylacetic amides (14–23) was also
achieved with high yields, good selectivity and high to excellent
deuterium incorporation of up to 99%D (Scheme 3). In nearly all
reactions of the N-methyl amides 14, 15, 17, 18, 20 and 21, we
observed additional deuteration at the N-methyl group with 13–
O
O
O
HO
[95]
9, 91%
[
52]
8
, 89%
1
0, 91%
[
[
[
85]
77]
87]
[22]
[40]
[53]
[
[
15]
16]
[76]
[
9]
O
X
O
O
33%D (15, 63%D) as observed previously for alkylamines
containing directing groups, e.g., pyridine and pyrimidine. 22
Interestingly, these aliphatic labeling side reactions could be
completely avoided by introduction of larger N-substituents like in
amides 16, 19, 22 and 23, indicating that excellent selectivity and
deuterium incorporation can be achieved. Unfortunately, we
observed no HIE reaction with primary amides or free
phenylacetic acids under these reaction conditions.
O
O
O
X
[86][73][72]
N
1
1
1
1a (X = F), 32%
1b (X = Cl), 90%
1c (X = Br), 88%
12a (X = F), 75%
12b (X = Cl), 89%
12c (X = Br), 95%
13, 82%
Scheme 2. HIE reaction with various phenylacetic acid esters; conditions:
catalyst 1 (10 mol%), 1 atm D , chlorobenzene 1 mL, rt, 2 h; all reactions
2
repeated at least twice.
We further examined the scope and limitations of this method
with the more complex drug-like substrates 24–28 (Scheme 4).
For the ibuprofen derivatives 24a–e, we observed no HIE product
for the primary amide 24a,23 but good to excellent deuterium
introduction for secondary and tertiary amides 24b–d (81–96%D).
The corresponding ester 24e (32%D) afforded lower deuteration
Under these optimized conditions, catalyst 1 promoted ortho-
directed deuteration of a variety of phenylacetic acid esters (2–
13) with high yields, good selectivity and good to high deuterium
incorporation of up to 95%D (Scheme 2). Interestingly, the
efficiency of the HIE reaction depended strongly on the size of the
ester function, resulting in decreasing deuterium incorporation
levels in the order methyl (2, 87%D) > ethyl (3, 68%D) > isopropyl
efficiency compared to the amides 24b–d.
A remarkable
selectivity and deuterium incorporation of 99%D was achieved for
drug-like compound 2524 without labeling of the other aromatic
ring systems. For both naproxen esters 26a (75%D) and 26b
(
4, 49%D). Additionally, the HIE reaction was somewhat sensitive
(
76%D), deuteration results are identical, but interestingly, only
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COMMUNICATION
the 3-position reacted. Ester 26b was also converted into the
corresponding acid (naproxen) under basic conditions without
significant loss of deuterium (for details see Supporting
Information). Surprisingly, next to the expected aromatic labeling
Methyl phenylacetate (12) was chosen as model substrate, and
its binding to a cationic iridium(I) complex fragment [(P,N)IrD
2
]+
afforded complex IN1 as the first stationary point on the potential
energy surface (Figure 1, left). Substrate binding in intermediate
IN1 involves the carbonyl oxygen atom and an agostic ortho-C–H
bond, which adopts an axial position trans to the phosphorus atom
(
(
72%D), we also observed deuteration in the benzylic position
64%D) of camylofine 27a, a phosphodiesterase type IV inhibitor
to treat stomach ache. This almost 1:1 ratio was completely
reduced in favor of the aromatic position by methylation of the
secondary amine function in 27b, indicating that free NH groups
have a significant effect on activity and selectivity of catalyst 1.
and points between the two equatorial deuterium atoms. In
analogy to other mechanistic studies,1
3c, 26
C–H activation
represents the rate-determining step and leads to the HD complex
IN2 through -bond metathesis via transition state TS1. IN2 is
destablized by only 6.6 kcal mol-1 relative to IN1 despite the
formation of a less favorable six-membered metallacycle.17
Hydride fluxionality27 involving TS2 gives IN3 with a rotated HD
ligand, which allows elimination and C–D bond formation through
TS3 to furnish IN4, which contains the ortho-deuterated substrate
Finally, we compared the results of deuteration and tritiation
for two examples. While selective deuteration in the aromatic
position with 72%D was found in the HIE reaction of camylofine
27a under the optimized conditions, we observed 26%T
incorporation (32 Ci/mmol specific activity in total) with 4.3 eq. of
tritium gas. Benalaxyl 28, a fungicide which inhibits the RNA
polymerase I and is used in crop protection of potato and grape
farming was deuterated selectively in the ortho-position with
2
-d (Figure 1, right). To confirm that C–H activation represents the
rate-determining step, the kinetic isotope effect (KIE) 28 was
studied theoretically and experimentally for the deuteration of 2
6 3 2
and for the hydrogenation of dideuterated (2,6-C H D )C(O)OMe
96%D. Despite an expected kinetic isotope effect (D vs. T) and a
(
2-d ), respectively (see the Supporting Information, Scheme S3,
2
much lower tritium pressure (60 mbar, 5.5 eq. vs. atmospheric
deuterium pressure), a specific activity of 14 Ci/mmol was
obtained, which was more than sufficient for the planned in-vitro
Figures S5 and S6). The calculated and experimental KIE values
of 3.5 and 3.5(3) are identical within the experimental error and
also in good agreement with the values derived from related
reactions.26 These findings substantiate our mechanistic proposal,
and the low activation barriers associated with the C–H and C–D
activation steps confirm the observed high catalytic activtiy of 1.
3
studies with H-benalaxyl (28-T). To the best of our knowledge,
Heys reported the only other example of iridium-mediated direct
tritium labeling of complex phenylacetic amides; however, this
protocol required the use of 3.0–4.2 eq. of Crabtree’s catalyst.25
While Heys has shown that arylacetates resisted efficient
iridium-catalyzed HIE, the related substrates N-phenylacetamide,
MeC(O)NHPh, and phenyl acetate, MeC(O)OPh, gave markedly
2
better results, indicating that replacing the bridging unit CH by
NH or O is favorable to achieve ortho-deuteration via the
formation of a six-membered metallcycle.17 Therefore, the profile
for the C–H activation step (IN1→TS1→IN2) was also calculated
for these substrates, revealing the expected lower activation
barriers and significant stabilization of the corresponding
intermediates, expecially for the acetamide (NH) derivative, which
can be ascribed to conjugation within the NH- and O-bridged
metallacycles (see the Supporting Information, Figure S7).
Occassionally,
a blue colouration of the solution was
observed under the HIE reaction conditions described above,
hinting at the formation of a new iridium species. A dark blue
complex was isolated by stirring a solution of 1 in CH
2
Cl
2
and
1
toluene under dihydrogen atmosphere, and its H NMR spectrum
gave rise to a characteristic highfield multiplet at –28.14 ppm that
collapsed to a singlet by phosphorus decoupling and could be
assigned to two hydrogen atoms per ligated iridium atom by
accurate integration.29 These findings are in agreement with the
2
composition [(P,N)IrH ][BArF24] as also confirmed by elemental
analysis. Single crystals of this species were obtained by slow
diffusion of hexane into a saturated dichloromethane solution, and
X-ray diffraction analysis afforded the molecular structure of the
2 2 4 2
dicationic diiridium complex [(P,N) Ir H ][BArF24] (29, Figure 2).
The positions of two bridging hydrogen atoms could be refined,
whereas two additional hydrogen atoms are expected to reside in
terminal positions at each iridium atom presumably in a trans-
Scheme 4. HIE reaction with various drug-like phenylacetic acid esters and
amides; conditions: catalyst 1 (10 mol%), 1 atm D
0 mbar tritium (T ) pressure.
2
, chlorobenzene 1 mL, rt, 2 h;
6
2
orientation above and below the Ir
2 2
H plane as found in related
systems.30 To verify the presence of terminal hydrides, an IR
2 2
spectrum of 29 was recorded in CH Cl solution, which revealed
a sharp signal at 2307 cm-1 (see the Supporting Information,
Figure S3), which is in good agreement with the calculated IR
Density functional theory (DFT) calculations were performed
to rationalise the experimentally observed high activity of
pre-)catalyst 1 in the deuteration of phenylacetic acid derivatives.
(
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COMMUNICATION
0
Figure 1. Potential energy profile for ortho-deuteration of phenyl acetic methylester (2) with iridium catalyst 1, scaled to Gibbs free energy (ΔG ). All theoretical
calculations were performed according to the Density Functional Theory (DFT) method M06/6-311G(d,p) for all main group elements and a “Stuttgart 1997
ECP” – double-ξ basis set with an effective core potential – for the 5d transition metal iridium. For the stationary points, all hydrogen atoms, except for those
involved in the reaction pathway, were omitted for clarity, and only a rudimentary N–C–C–P–C2 skeleton of the P,N ligand is shown.
stretching frequency of 2341 cm-1 (in the gas phase) and the
2 2 4 2
Figure 2. ORTEP diagram of the dication in the complex [(P,N) Ir H ][BArF24]
(29); all hydrogen atoms except for the bridging ones have been omitted for
clarity; the positions of the expected terminal hydrides could not be refined.
corresponding values reported for other iridium complexes
bearing terminal hydrides.31 The Ir–Ir distance is 2.5978(4) Å and
falls in the range observed for related bimetallic iridium(III)
2 4
complexes featuring an Ir H moiety with bridging and terminal
3
0
hydrogen atoms. However, the observation of only one highfield
H NMR resonance at –28.14 ppm indicates fast exchange
In conclusion, we have developed the first efficient catalytic
protocol for ortho-selective hydrogen isotope exchange (HIE) of
pharmacologically important phenylacetic acid esters and amides
under very mild reaction conditions. This method is fully adaptable
to the specific requirements of tritium chemistry, which is
demonstrated by direct tritium labeling of benalaxyl and
camylofine. DFT calculations and kinetic studies give insights into
the mechanism of the HIE reaction and explain the observed high
activity and selectivity of catalyst 1, which is remarkable
considering the required formation of six-membered non-
conjugated metallacycles upon ortho-C–H activation. Therefore,
one of the longstanding challenges in iridium-catalyzed C–H
functionalization and HIE has been solved, and we believe that
our findings will stimulate further application of 1 and related
catalysts in this field.
1
between terminal and bridging positions on the NMR time scale,
which could not be resolved by a variable-temperature NMR study
in the range from 298 to 183 K (see the Supporting Information,
Figure S2). Nevertheless, further studies are required to elucidate
the hydrogen exchange mechanism in this system. Interestingly
attempts to perform HIE on substrate 2 in the presence of
complex 29 in chlorobenzene at room temperature afforded only
marginal deuterium incorporation, indicating that this complex is
not part of the catalytic cycle, but represents a deactivated form
or an overly stabilized resting state, respectively.
Acknowledgements
H1
N1i
P1
Mégane Valero is participant in the EU Isotopics consortium. The
ISOTOPICS project has received funding from the European
Union’s Horizon 2020 research and innovation programme under
the Marie Sklodowska-Curie grant agreement No. 675071. The
authors would like to thank Dr. Martin Sandvoss for analytical
support, Dr. Dirk Bockfeld for the crystal structure determination
of 29 and Dr. Kerstin Ibrom for analytical support and valuable
discussions.
Ir1
Ir1i
P1i
N1
H1i
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Keywords: hydrogen isotope exchange • C-H activation •
iridium • homogeneous catalysis • kinetic isotope effect
1
2
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Chemistry - A European Journal
10.1002/chem.201901449
COMMUNICATION
Layout 2:
COMMUNICATION
Mégane Valero, Daniel Becker, Kristof
Jess, Remo Weck, Jens Atzrodt,
Thomas Bannenberg, Volker Derdau,*
and Matthias Tamm*
Page No. – Page No.
Directed Iridium-Catalyzed Hydrogen
Isotope Exchange Reactions of
Phenylacetic Acid Esters and Amides
Mild, selective and efficient: The first efficient iridium-catalyzed protocol for ortho-
selective iridium-catalyzed deuteration and tritiaton of pharmacologically important
phenylacetic acid esters and amides has been developed, which proceeds
smoothly despite the formation of unfavorable non-conjugated six-membered
metallacyclic intermediates.
This article is protected by copyright. All rights reserved.