Ag(i)-Mediated hydrogen isotope exchange of mono-fluorinated (hetero)arenes

Article abstract of DOI:10.1039/d0ob01273d

An efficient approach to install deuterium into mono-fluorinated (hetero)arenes by a Ag2CO3/Sphos-mediated HIE protocol with D2O as the deuterium source has been disclosed. This method showed a specific site selectivity of deuteration at the α-position of the fluorine atom, which is complementary to the existing transition metal-catalyzed HIE process.

Full text of DOI:10.1039/d0ob01273d

Organic &
Biomolecular Chemistry
View Article Online
View Journal
COMMUNICATION
Ag(I)-Mediated hydrogen isotope exchange of
mono-fluorinated (hetero)arenes†
Cite this: DOI: 10.1039/d0ob01273d
Guang-Qi Hu, En-Ci Li, Hong-Hai Zhang * and Wei Huang
Received 21st June 2020,
Accepted 11th August 2020
DOI: 10.1039/d0ob01273d
rsc.li/obc
1
2
An efficient approach to install deuterium into mono-fluorinated dine derivatives. Despite significant advances being made,
hetero)arenes by a Ag CO /Sphos-mediated HIE protocol with further expanding the substrate scope of simple (hetero)arenes
O as the deuterium source has been disclosed. This method for the HIE protocol is highly desirable.
showed a specific site selectivity of deuteration at the α-position Fluorinated arenes are one of the most prominent struc-
of the fluorine atom, which is complementary to the existing tran- tural motifs in drug candidates, occurring in 32 of 200 best-
(
2
3
D
2
1
3
sition metal-catalyzed HIE process.
selling drugs in 2018. Although the deuteration of fluoroar-
enes could be a useful approach to prepare deuterium-labeled
active pharmaceutical ingredients for absorption, distribution,
metabolism and toxicity studies, a preparative method for deu-
teration of mono-fluorinated (hetero)arenes via H/D exchange
Deuterated compounds are widely utilized as internal stan-
1
dards in mass spectrometry, for the mechanistic study in
2
chemical and biological processes, and for the investigation
of the structure and dynamics in soft matter through neutron
14
has rarely been explored. In addition, the cross-coupling
reaction by C–H activation of mono-fluorinated (hetero)arenes
also suffered from low efficiency and narrow substrate scope,
even when using monofluoroarenes as solvent. In our labora-
tory, we recently developed a new H/D exchange protocol with
a combination of Ag CO and a phosphine ligand as a catalyst
and demonstrated that the adoption of carbonate salts instead
of carboxylic salts as additives played a key role in achieving
H/D exchange of five-membered heteroarenes at room temp-
3
scattering. Due to the higher bond dissociation energy of the
C–D bond versus C–H bond, deuteration is commonly used to
alter the therapeutic profile and metabolic fate of drugs, while
retaining their original biochemical potency and selectivity.
Moreover, deuterated compounds have also found applications
in the production of advanced functional materials for organic
15
4
2
3
5
light-emitting devices and organic/polymer solar cells.
As one of the most efficient and straightforward strategies
for the synthesis of deuterated organic compounds, direct
hydrogen isotope exchange (HIE) has recently attracted great
16
erature. Herein, we report an efficient H/D exchange protocol
6
attention (Scheme 1). A common strategy to facilitate H/D
exchange processes and to control site selectivity focusses on
the use of directing groups containing N or O atoms to coordi-
7
,8
nate with a metal catalyst. However, the site-selective H/D
exchange protocol for simple (hetero)arenes lacking a coordi-
9
,10
nating group remains challenging.
In 2016, great advances
were made by the Chirik group using an iron complex as a
catalyst, affording deuterated arenes with special sterically con-
1
1
trolled site selectivity. Following this work, the same group
developed an H/D exchange protocol with a nickel complex as
a catalyst, selectively occurring at the α-position of simple pyri-
Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials
(
(
IAM), Jiangsu National Synergistic Innovation Center for Advanced Materials
SICAM), Nanjing Tech. University (Nanjing Tech.), 30 Puzhu Road, Nanjing 211816,
P. R. China. E-mail: iamhhzhang@njtech.edu.cn
Electronic supplementary information (ESI) available. See DOI: 10.1039/
†
d0ob01273d
Scheme 1 Deuteration via HIE.
This journal is © The Royal Society of Chemistry 2020
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
for the incorporation of deuterium into a wide range of mono- salt, which suggested that a silver salt is essential for this reac-
fluorinated (hetero)arenes with D O as the deuterium source. tion (Table 1, entry 17). The attempt to reduce the amount of
Ag CO and Sphos was unsuccessful. When the reaction was
JohnPhos, which has been found to be a robust catalytic conducted with 20 mol% of Ag CO and Sphos, the atom% of
2
Our study began with using a combination of Ag
2
CO
3
/
2
3
2
3
system for the H/D exchange protocol of five-membered het- deuterium incorporation was 36% at 80 °C and 72% at 120 °C
eroarenes. We found that products with only 5% deuterium (Table 1, entries 18 and 19). This result suggested that the
incorporation formed even at elevated temperature, which silver salt may serve as the catalyst for this reaction. Therefore,
suggested that the H/D exchange process is very slow under the optimal conditions were established with Ag CO /Sphos as
2
3
2 3
these conditions. We then screened the solvents for the reac- the catalyst and K CO as an additive in toluene at 90 °C.
tion and found that toluene is the best, affording 15% deuter- With the optimal reaction conditions in hand, we set out to
ium incorporation (see Table S1† for details). Concentration explore the generality of this method with respect to fluori-
played an important role in the H/D exchange process, as a nated arenes. As shown in Table 2, we found that a wide range
higher level of deuterium incorporation at 43% was achieved of functional groups including nitrile, ketone, alkoxyl, nitro,
using a smaller volume of toluene (Table 1, entry 1). The amide, alkynyl, alkyl, and halogen (Br) groups are compatible
choice of the phosphine ligand is crucial, and a high level of with the reaction conditions. The monofluoroarenes with sub-
deuterium incorporation at 91% was observed with Sphos as stituents at different positions are also examined. The mono-
the ligand (Table 1, entries 1–10). The examination of additives fluoroarenes with ortho-substitution are wide substrates for
2 3
showed that K CO is the best for the H/D exchange process, HIE, affording the desired products 2a–2d with moderate-to-
affording 91% deuterium incorporation (see Table S2† for high atom% deuterium incorporation. Interestingly, we found
details). These results also suggested that K CO can promote deuterium-labeling also occurring at the α position of the
2
3
the H/D exchange process. The atom% of deuterium incorpor- alkoxyl group of product 2d, suggesting that the alkoxy group
ation can be further increased by conducting the reaction at a may also promote the H/D exchange process. The monofluor-
slightly higher temperature (Table 1, entries 11 and 12). oarenes with para-substituents enabled the H/D exchange
2 3
Various silver salts other than Ag CO were examined and process to occur at both the α positions of the fluorine atom,
found to be less efficient, giving the product with lower deuter-
ium incorporation (Table 1, entries 13–16). In addition, no
deuterium incorporation was observed without adding a silver
a
Table 2 Deuteration of monofluoroarenes
Table 1 Reaction optimization
a
b
Entry
Ag salt
Ligand
D incorporation
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
2
2
2
2
2
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
O
3
3
3
3
3
3
3
3
3
3
3
3
JohnPhos
43%
26%
26%
6%
5%
15%
6%
90%
82%
91%
96%
96%
65%
1%
t-Bu
t-Bu
3
P
2
(2-MeC
6
H
4
)P
(o-MePh)
Ph
(p-OMePh)
3
P
3
P
3
P
3
(o-MePh) P
MePhos
DavePhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
0
1
2
3
4
5
6
7
8
9
c
d
AgBr
AgCl
AgOAc
None
1%
1%
0%
36%
72%
e
f
Ag
Ag
2
CO
CO
3
2
3
a
The reaction was conducted on 0.3 mmol of 1a, 6 mmol of D
0 mol% of Ag salt, 50 mol% of ligand and 0.3 mmol of K CO
2
O,
in
a
5
2
3
The reaction was conducted with compound 1 (1 mmol), D
CO (0.5 mmol), Sphos (0.5 mmol) and K CO (1 mmol)
and 20 mol% in 1 mL of toluene at 90 °C for 12 hours; deuterium incorporation was
2
O
b
c
d
e
toluene at 80 °C. Determined by GC-MS. 90 °C. 100 °C. 20 mol% (10 mmol), Ag
of Ag
of SPhos 120 °C.
2
3
2
3
f
2
CO
3
and 20 mol% of SPhos. 20 mol% of Ag
2
CO
3
1
b
estimated using H NMR spectra; isolated yield. Volatile liquid.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Organic & Biomolecular Chemistry
Communication
affording products with 73% to 95% deuterium incorporation of compounds 4d and 4g may be attributed to the volatile pro-
2e–2j). The H/D exchange process with meta-substituted perties and low boiling points of 4d and 4g. It is worth noting
monofluoroarenes showed site selectivity, possibly due to the that this Ag CO -mediated HIE protocol showed orthogonal
steric effect of phenyl groups (2k–2l). The use of 4,4′-difluoro- site selectivity to other metal catalysts, preferentially occurring
(
2
3
1
2
diphenyl and 4,4′-difluoro-benzophenone as starting materials at the 3, 4, and 5 positions of pyridine derivatives.
led to the H/D exchange of four C–H bonds, providing 65% Furthermore, we found that monofluoroquinoline and mono-
and 91% deuterium incorporation, respectively. In all cases, fluoropyrimidine derivatives are wide substrates (4h–4j), pro-
deuterium preferred to install at the ortho-position to the C–F viding a high level of deuterium incorporation even for the
bond, which is possibly due to the greater acidity of the C–H substrate with an amine group directly attached at the pyrimi-
1
7
bond ortho to the C–F bond. It is worth noting that the deu- dine ring. With the exception of the electron-deficient arenes,
teration of 4,4′-difluoro-benzophenone may lead to novel ultra- the H/D exchange of electron-rich 2-chloro-5-fluorobenzo[d]
long organic phosphorescent materials, since it is an impor- thiazole was also tested and it afforded a product with 90%
1
8
tant intermediate for organic phosphorescent materials.
deuterium incorporation, which further expands the scope of
Since nitrogen-containing heteroarenes are common struc- this reaction.
tural motifs in functional materials and bioactive compounds,
we next turned our attention to examine the H/D exchange Ag
To further demonstrate the specific site selectivity of this
CO -mediated H/D exchange protocol, we conducted the
2
3
process with monofluorinated nitrogen-containing heteroar- reaction with 2-(4-fluorophenyl)pyridine as the starting
enes as starting materials. As shown in Table 3, pyridine material. As shown in Scheme 2, the H/D exchange occurred at
derivatives with fluorine substituted at different positions are different positions with Ag
2
CO
3
/Sphos and a Ru complex as
1
9
wide substrates for the Ag CO -mediated H/D exchange reac- the catalyst, respectively. Based on this result, we prepared
2
3
tion, and excellent atom% deuterium incorporation is com- deuterium-labeled 2-(2,4-difluorophenyl)pyridine, which is a
monly observed with the exception of product 4c. The great key motif for a famous blue light-emitting material named
2
0
difference in atom% deuterium incorporation observed FIrpic. Deuterium-labeling of FIrpic is expected to prolong
2
1
between products 4a (94%) and 4c (55%) suggested that a the corresponding device’s lifetime.
steric effect may lead to the loss of efficiency in the H/D After establishing the utility of this Ag
2
3
CO -mediated H/D
exchange process. When a fluorine atom was installed at the exchange protocol on a wide range of monofluorinated
position meta to the pyridine nitrogen (compound 4d–4g), the (hetero)arenes, we attempted to apply this method to the late-
H/D exchange process preferentially occurred at the para-posi- stage deuterium-labelling of drug molecules. Although it is
2
tion over the ortho-positions, possibly due to the difference in challenging to introduce deuterium at the C(sp )–H bond in
1
7b
the pK
a
of the C–H bond at these positions.
The low yields the antipsychotic drug iloperidone by traditional metal-cata-
lyzed HIE protocols, the Ag CO -mediated H/D exchange on 5a
afforded 6a labeled at the fluorinated phenyl ring and methyl
group with high level of deuterium incorporation
Scheme 3).
We then investigated the mechanism. A mechanism invol-
2
3
a
a
Table 3 Deuteration of fluorinated nitrogen-containing heteroarenes
(
ving free radicals should be discounted, because the radical
inhibitor TEMPO has no negative effect on the reaction (see
the ESI† for details). Based on our experimental evidence and
1
6a,22
previous reports,
we proposed a plausible mechanism
pathway. First, the silver carbonate-mediated concerted meta-
a
The reaction was conducted with compound 3 (1 mmol), D
2
O
(
10 mmol), Ag
2
CO (0.5 mmol), Sphos (0.5 mmol) and K CO (1 mmol)
3
2
3
in 1 mL of toluene at 90 °C for 12 hours; deuterium incorporation was
estimated using H NMR spectra; isolated yield.
1
Scheme 2 Site selectivity of Ag CO -mediated HIE.
2
3
This journal is © The Royal Society of Chemistry 2020
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
Notes and references
1
(a) M. Waterstraat, A. Hildebrand, M. Rosler and
M. Bunzel, Development of a QuEChERS-Based Stable-
Isotope Dilution LC-MS/MS Method To Quantitate Ferulic
Acid and Its Main Microbial and Hepatic Metabolites in
Milk, J. Agric. Food Chem., 2016, 64, 8667; (b) J. Atzrodt and
V. Derdau, Pd- and Pt-catalyzed H/D exchange methods
and their application for internal MS standard preparation
from a Sanofi-Aventis perspective, J. Labelled Compd.
Radiopharm., 2010, 53, 674.
Scheme 3 Deuteration of iloperidone.
2
(a) E. M. Simmons and J. F. Hartwig, On the Interpretation
of Deuterium Kinetic Isotope Effects in C-H Bond
Functionalizations by Transition-Metal Complexes, Angew.
Chem., Int. Ed., 2012, 51, 3066; (b) R. E. McKinney and
R. A. Widenhoefer, Stereochemistry and Mechanism of the
Brønsted
Acid
Catalyzed
Intramolecular
Hydrofunctionalization of an Unactivated Cyclic Alkene,
Chem. – Eur. J., 2011, 17, 6170; (c) T. Giagon and
M. P. Meyer, Kinetic Isotope Effects in Asymmetric
Reactions, Chem. – Eur. J., 2010, 16, 10616; (d) L. A. Evans,
N. Fey, G. C. Lloyd-Jones, M. P. Munoz and P. A. Slatford,
Cryptocatalytic 1,2-Alkene Migration in a σ-Alkyl Palladium
Diene Complex, Angew. Chem., Int. Ed., 2009, 48, 6262.
(a) C. Shi, X. Zhang, C. H. Yu, Y. F. Yao and W. Zhang,
Geometric Isotope Effect of Deuteration in a Hydrogen-
Bonded Host-Guest Crystal, Nat. Commun., 2018, 9, 1;
Scheme 4 Plausible mechanism for Ag-mediated HIE.
3
lation deprotonation step leads to the C–H bond activation of
fluorinated arenes. Then, the H/D exchange may occur
between T2 and heavy water to form T3, followed by deuterium
incorporation and regeneration of silver carbonate (Scheme 4).
In summary, a general approach to install deuterium into
mono-fluorinated (hetero)arenes by H/D exchange is disclosed.
A wide range of fluorinated (hetero)arenes are found to be
compatible with this transformation, which widely expanded
the substrate scope of the H/D exchange protocol. In addition,
we applied this method for the deuterium-labelling of selected
commercial drugs and advanced functional materials. Further
work is underway in our laboratory to explore the scope of this
Ag CO -mediated HIE process and the isotope effect of deute-
(
b) S. Cantekin, D. W. R. Balkenende, M. M. J. Smulders,
A. R. A. Palmans and E. W. Meijier, The Effect of Isotope
Substitution on the Chirality of a Self-Assembled Helix,
Nat. Chem., 2011, 3, 42; (c) R. P. White, J. E. G. Lipson and
J. S. Higgins, Effect of Deuterium Substitution on the physi-
cal properties of polymer melts and blends,
Macromolecules, 2010, 43, 4287.
4
(a) J. Atzrodt, V. Derdau, W. J. Kerr and M. Reid,
Deuterium-
Applications in the life Sciences, Angew. Chem., Int. Ed.,
018, 57, 1758; (b) A. R. Navratil, M. S. Shchepinov and
and
Tritium-Labelled
Compounds:
2
2
3
E. A. Dennis, Lipidomics Reveals Dramatic Physiological
Kinetic Isotope Effects during the Enzymatic Oxygenation
of Polyunsaturated Fatty Acids Ex Vivo, J. Am. Chem. Soc.,
rated functional materials. These studies will be reported in
due course.
2018, 140, 235; (c) Y. Zhang, M. D. Tortorella, Y. Wang,
J. Liu, Z. Tu, X. Liu, Y. Bai, D. Wen, X. Lu, Y. Lu and
J. J. Talley, Synthesis of Deuterated Benzopyran Derivatives
Conflicts of interest
There are no conflicts to declare.
as
Pharmacokinetic Properties, ACS Med. Chem. Lett., 2014, 5,
162; (d) T. G. Gant, Using Deuterium in Drug Discovery:
Leaving the Label in the Drug, J. Med. Chem., 2014, 57,
595; (e) A. Katsnelson, Heavy drugs draw heavy interest
Selective
COX-2
Inhibitors
with
Improved
1
Acknowledgements
3
We thank the National Natural Science Foundation of China
from pharma backers, Nat. Med., 2013, 6, 656;
(f) N. A. Meanwell, Synopsis of Some Recent Tactical
Application of Bioisosteres in Drug Design, J. Med. Chem.,
2011, 54, 2529; (g) K. Sanderson, Big Interest in Heavy
Drug, Nature, 2009, 458, 269.
(Grant Numbers 21704041), Six Talent Peaks Project in Jiangsu
Province (Grant Number XCL-027) and Nanjing Scientific
Research Foundation for Returned Scholars for their support.
We thank Peter V. Bonnesen and Kunlun Hong (Oak Ridge
National Laboratory) for assistance in the preparation of the
manuscript.
5 (a) M. Shao, J. Keum, J. Chen, Y. He, W. Chen,
J. F. Browning, J. Jakowski, B. G. Sumpter, L. N. Ivanov,
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Organic & Biomolecular Chemistry
Communication
Y. Z. Ma, C. M. Rouleau, S. C. Smith, D. B. Geohegan,
K. Hong and K. Xiao, The Isotopic Effects of Deuteration
on Optoelectronic Properties of Conducting Polymers, Nat.
Commun., 2014, 5, 1; (b) R. Kabe, N. Notsuka, K. Yoshida
and C. Adachi, Afterglow Organic Light-Emitting Diode,
Adv. Mater., 2016, 28, 655; (c) T. D. Nguyen, G. Hukic-
Markosian, F. Wang, L. Wojcik, X. G. Li, E. Ehrenfreund
and Z. V. Vardeny, Isotope Effect in Spin Response of
π-Conjugated Polymer Films and Devices, Nat. Mater., 2010,
Catalyzed, Selective α,β-Deuteration of Bioactive Amines,
J. Am. Chem. Soc., 2012, 134, 12234; (e) Y. Chang,
A. Yesilcimen, M. Cao, Y. Zhang, B. Zhang, J. Z. Chan and
M. Wasa, Catalytic Deuterium Incorporation within
Metabolically Stale β-Amino C-H Bonds of Drug Molecules,
J. Am. Chem. Soc., 2019, 141, 14570; (f) J. S. Rowbotham,
M. A. Ramirez, O. Lenz, H. A. Reeve and K. A. Vincent,
Bringing biocatalytic deuteration into the toolbox of asym-
metric isotopic labelling techniques, Nat. Commun., 2020,
11, 1454; (g) W. J. Kerr, R. J. Mudd, M. Reid, J. Atzrodt and
9
, 345.
3
6
For selected reviews of H/D exchange, see: (a) J. Atzrodt,
V. Derdau, W. J. Kerr and M. Reid, C-H Functionalization
for Hydrogen Isotope Exchange, Angew. Chem., Int. Ed.,
V. Derdau, Iridium-Catalyzed Csp -H Activation for Mild
and Selective Hydrogen Isotope Exchange, ACS Catal., 2018,
8, 10895.
2
018, 57, 3022; (b) J. Atzrodt, V. Derdau, T. Fey and
9 (a) K. Park, T. Matsuda, T. Yamada, Y. Monguchi,
Y. Sawama, N. Doi, Y. Sasai, S. Kondo, Y. Sawama and
H. Sajiki, Direct Deuteration of Acrylic and Methacrylic
Acid Derivatives Catalyzed by Platinum on Carbon in
Deuterium Oxide, Adv. Synth. Catal., 2018, 360, 2303;
(b) W. N. Palmer and P. J. Chirik, Cobalt-Catalyzed
J. Zimmermann, The Renaissance of H/D Exchange, Angew.
Chem., Int. Ed., 2007, 46, 7744; (c) W. J. S. Lockley and
J. R. Heys, Metal-Catalysed Hydrogen Isotope Exchange
Labelling: a Brief Overview, J. Labelled Compd. Radiopharm.,
2
010, 53, 635; (d) A. Sattler, Hydrogen/Deuterium (HD)
3
Exchange Catalysis in Alkanes, ACS Catal., 2018, 8, 2296.
For selected publications on HIE of C(sp )–H, see:
Stereoretentive Hydrogen Isotope Exchange of C(sp )-H
2
7
Bonds, ACS Catal., 2017, 7, 5674; (c) M. Liu, X. Chen,
T. Chen and S. F. Yin, A Facile and General Acid-Catalyzed
Deuteration at Methyl Groups of N-Heteroarylmethanes,
Org. Biomol. Chem., 2017, 15, 2507; (d) Y. Sawama,
A. Nakano, T. Matsuda, T. Kawajiri, T. Yamada and
H. Sajiki, H-D Exchange Deuteration of Arenes at Room
Temperature, Org. Process Res. Dev., 2019, 23, 648;
(e) A. Palazzolo, S. Feuillastre, V. Pferfer, S. Garcia-Argote,
D. Bouzouita, S. Tricard, C. Chollet, E. Marcon,
D. A. Buisson, S. Cholet, F. Fenaille, G. Lippenss,
B. Chaudret and G. Pieters, Efficient Access to Deuterated
(
a) W. J. Kerr, M. Reid and T. Tuttle, Iridium-Catalyzed
Formyl-Selective Deuteration of Aldehydes, Angew. Chem.,
Int. Ed., 2017, 56, 7808; (b) W. J. Kerr, D. M. Lindsay,
M. Reid, J. Atzrodt, V. Derdau, P. Rojahn and R. Weck,
Iridium-Catalysed ortho-H/D and -H/T Exchange under
Basic Conditions: C-H Activation of Unprotected
Tetrazoles, Chem. Commun., 2016, 52, 6669; (c) R. Hey,
Investigation of [IrH (Me CO) (PPh ) ]BF as a Catalyst of
Hydrogen Isotope Exchange of Substrates in Solution,
J. Chem. Soc., Chem. Commun., 1992, 680; (d) S. Ma,
G. Villa, P. S. Thuy-Boun, A. Homs and J. Q. Yu, Palladium-
Catalyzed ortho-Selective C-H Deuteration of Arenes:
Evidence for Superior Reactivity of Weakly Coordinated,
2
2
2
3 2
4
and
Tritiated
Nucleobase
Pharmaceuticals
and
Oligonucleotides using Hydrogen-Isotope Exchange, Angew.
Chem., Int. Ed., 2019, 58, 4891.
Angew. Chem., Int. Ed., 2014, 53, 734; (e) H. Xu, M. Liu, 10 For selected publications on dehalogenative deuteration of
L. L. Li, Y. F. Cao, J. Q. Yu and H. X. Dai, Palladium-
Catalyzed Remote meta-C-H Bond Deuteration of Arenes
Using a Pyridine Template, Org. Lett., 2019, 21, 4887;
simple arenes, see: (a) V. Soulard, G. Villa, D. P. Vollmar
and P. Renaud, Radical Deuteration with D O: Catalysis
and Mechanistic Insights, J. Am. Chem. Soc., 2018, 140,
155; (b) H. Sajiki, T. Kurita, H. Esaki, F. Aoki, T. Maegawa
2
(
f) M. Valero, D. Bouzouita, A. Palazzolo, J. Atzrodt,
C. Dugave, S. Tricard, S. Feuillastre, G. Pieters, B. Chaudret
and V. Derdau, NHC-Stabilized Iridium Nanoparticles as
Novel Catalysts in Hydrogen Isotope Exchange Reactions of
Anilines, Angew. Chem., Int. Ed., 2020, 59, 3517.
2 2
and K. Hirotta, Complete Replacement of H by D via Pd/
C-Catalyzed H/D Exchange Reaction, Org. Lett., 2004, 6,
3521; (c) M. Kuriyama, N. Hamaguchi, G. Yano,
K.
Tsukuda,
K.
Sato
and
O.
Onomura,
3
8
For selected publications on HIE of C(sp )–H, see:
Deuterodechlorination of Aryl/Heteroaryl Chlorides
Catalyzed by a Palladium/Unsymmetrical NHC System,
J. Org. Chem., 2016, 81, 8934; (d) J. L. Koniarczyk, D. Hesk,
A. Overgard, I. W. Davies and A. McNally, A General
Strategy for Site-Selective Incorporation of Deuterium and
Tritium into Pyridines, Diazines, and Pharmaceuticals,
J. Am. Chem. Soc., 2018, 140, 1990; (e) K. Burglova,
S. Orochenkov and J. Hlavac, Efficient Route to Deuterated
Aromatics by the Deamination of Anilines, Org. Lett., 2016,
18, 3342; (f) R. Grainger, A. Nikmal, J. Cornella and
I. Larrosa, Selective deuteration of (hetero)aromatic com-
pounds via deuteron-decarboxylation of carboxylic acids,
Org. Biomol. Chem., 2012, 10, 3172.
(
a) M. Valero, R. Weck, S. Gussregen, J. Atzrodt and
V. Derdau, Highly Selective Directed Iridium-Catalyzed
Hydrogen Isotope Exchange Reactions of Aliphatic Amides,
Angew. Chem., Int. Ed., 2018, 57, 8159; (b) Y. Y. Loh,
K. Nagao, A. J. Hoover, D. Hesk, N. R. Rivera, S. L. Colletti,
I. W. Davies and D. W. C. MacMillan, Photoredox-Catalyzed
Deuteration and Tritiation of Pharmaceutical Compounds,
Science, 2017, 530, 1182; (c) L. V. A. Hale and
N. K. Szymczak, Stereoretentive Deuteration of α-Chiral
Amines with D
d) L. Neubert, D. Michalik, S. Bahn, S. Imm, H. Neumann,
J. Atzrodt, V. Derdau, W. Holla and M. Beller, Ruthenium-
2
O, J. Am. Chem. Soc., 2016, 138, 13489;
(
This journal is © The Royal Society of Chemistry 2020
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
1
1 (a) R. P. Yu, D. Hesk, N. Rivera, I. Pelczer and P. J. Chirik,
Iron-Catalysed Tritiation of Pharmaceuticals, Science, 2016,
Site-Selective Direct Allylation of Aryl C-H Bonds by Silver-
Mediated C-H Activation: A Synthetic and Mechanistic
Investigation, J. Am. Chem. Soc., 2016, 138, 15278;
(e) P. Ricci, K. Kramer, X. C. Cambeiro and I. Larrosa,
5
29, 195; (b) R. Arevalo and P. J. Chirik, Enabling Two-
Electron Pathways with Iron and Cobalt: From Ligand
Design to Catalytic Applications, J. Am. Chem. Soc., 2019,
Arene-Metal π-Complexation as a Traceless Reactivity
1
41, 9106.
Enhancer for C-H Arylation, J. Am. Chem. Soc., 2013, 135,
1
2 (a) H. Yang, C. Zarate, W. N. Palmer, N. Rivera, D. Hesk
13258.
and P. J. Chirik, Site-Selective Nickel-Catalyzed Hydrogen 16 (a) E. C. Li, G. Q. Hu, Y. X. Zhu, H. H. Zhang, K. Shen,
Isotope Exchange in N-Heterocycles and Its Application to
the Tritiation of Pharmaceuticals, ACS Catal., 2018, 8,
2 3
X. C. Hang, C. Zhang and W. Huang, Ag CO -Catalyzed
H/D Exchange of Five-Membered Heteroarenes at Ambient
Temperature, Org. Lett., 2019, 21, 6745; (b) L. Guo, C. Xu,
D. C. Wu, G. Q. Hu, H. H. Zhang, K. Hong, S. Chen and
X. Liu, Cascade alkylation and deuteration with aryl
iodides via Pd/norbornene catalysis: an efficient method
for the synthesis of congested deuterium-labeled arenes,
Chem. Commun., 2019, 55, 8567; (c) H. H. Zhang,
P. V. Bonnesen and K. Hong, Palladium-catalyzed Br/D
exchange of arenes: selective deuterium incorporation with
versatile functional group tolerance and high efficiency,
Org. Chem. Front., 2015, 2, 1071.
1
0210; (b) C. Zarate, H. Yang, M. J. Bezdek, D. Hesk and
P. J. Chirik, Ni(I)-X Complexes Bearing a Bulky -Diimine
Ligand: Synthesis, Structure and Superior Catalytic
Performance in the Hydrogen Isotope Exchange in
Pharmaceuticals, J. Am. Chem. Soc., 2019, 141, 5034.
3 (a) H. Mei, J. Han, S. Fustero, M. Medio-Simon,
D. M. Sedgwick, C. Santi, R. Ruzziconi and
V. A. Soloshonok, Fluorine-Containing Drugs Approved by
the FDA in 2018, Chem. – Eur. J., 2019, 25, 11797;
1
(b) E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly and
N. A. Meanwell, Applications of Fluorine in Medicinal 17 (a) S. I. Gorelsky, D. Lapointe and K. Fagnou, Analysis of
Chemistry, J. Med. Chem., 2015, 58, 8315; (c) J. Wang,
M. Sanchez-Rosello, J. L. Acena, C. Pozo, A. E. Sorochinsky,
S. Fustero, V. A. Soloshonok and H. Liu, Fluorine in
Pharmaceutical Industry: Fluorine-Containing Drugs
Introduced to the Market in the Last Decade (2001–2011),
Chem. Rev., 2014, 114, 2432; (d) N. A. McGrath,
the Concerted Metalation-Deprotonation Mechanism in
Palladium-Catalyzed Direct Arylation Across a Broad Range
of Aromatic Substrates, J. Am. Chem. Soc., 2008, 130, 10848;
(b) K. Shen, Y. Fu, J. N. Li, L. Liu and Q. X. Guo, What are
the pK values of C-H bonds in aromatic heterocyclic com-
a
pounds in DMSO, Tetrahedron, 2007, 63, 1568.
M. Brichacek and J. T. Njardarson, A Graphical Journey of 18 (a) W. Zhao, Z. He, J. W. Y. Lam, Q. Peng, H. Ma, Z. Shui,
Innovative Organic Architectures That Have Improved Our
Lives, J. Chem. Educ., 2010, 87, 1348.
G. Bai, J. Hao and B. Z. Tang, Rational Molecular Design
for Achieving Persistent and Efficient Pure Organic Room-
Temperature Phosphorescence, Chem, 2016, 1, 592;
(b) N. Gan, H. Shi, Z. An and W. Huang, Recent Advances
1
4 For preparation of deuterated fluoroarenes via lithium
reagents, please see: (a) V. H. Mai and G. I. Nikonov,
Hydrodefluorination of Fluoroaromatics by Isopropyl
Alcohol Catalyzed by a Ruthenium NHC Complex. An
Unusual Role of the Carbene Ligand, ACS Catal., 2016, 6,
in
Polymer-Based
Metal-Free
Room-Temperature
Phosphorescent Materials, Adv. Funct. Mater., 2018, 28,
1802657.
7
956; (b) K. N. Plessel, A. C. Jones, D. J. Wherit, 19 L. Piola, J. A. Fernandez-Salas, S. Manzini and S. P. Nolan,
R. M. Maksymowicz, E. T. Poweleit and H. J. Reich, A Rapid
Injection NMR Study of the Reaction of Organolithium
Reagents with Esters, Amides, and Ketones, Org. Lett.,
Regioselective ruthenium catalysed H-D exchange using
D O as the deuterium source, Org. Biomol. Chem., 2014, 12,
2
8683.
2
015, 17, 2310. For base mediated H/D exchange, please 20 (a) S. Lamansky, P. Djurovich, M. Murphy, F. Abdel-Razzaq,
see: (c) V. Salamanca and A. C. Albeniz, Deuterium
Exchange between Arenes and Deuterated solvents in the
Absence of a Transition Metal: Synthesis of D-Labeled
Fluoroarenes, Eur. J. Org. Chem., 2020, 3206.
5 For cross-coupling by C–H activation of fluorinated arenes,
please see: (a) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord
and F. Glorius, Beyond Directing Groups: Transition-Metal-
Catalyzed C-H Activation of Simple Arenes, Angew. Chem.,
Int. Ed., 2012, 51, 10236; (b) M. He, J. F. Soule and
H. E. Lee, C. Adachi, P. Burrows, S. R. Forrest and
M. E. Thompson, Highly Phosphorescent bis-
Cyclometalated Iridium Complexes: Synthesis,
Photophysical Characterization and Use in Organic Light
Emitting Diodes, J. Am. Chem. Soc., 2001, 123, 4304;
(b) T. Tsuboi, H. Murayama, S. J. Yeh, M. F. Wu and
C. T. Chen, Photoluminescence characteristics of blue
1
3
+
phosphorescent Ir -compounds FIrpic and FIrN4 doped in
mCP and SimCP, Opt. Mater., 2008, 31, 366.
H. Doucet, Reactivity of Para-Substituted Fluorobenzenes 21 (a) P. Wang, F. F. Wang, Y. Chen, Q. Niu, L. Lu,
in Palladium-catalyzed Intermolecular Direct Arylations,
ChemCatChem, 2015, 7, 2130; (c) A. Hfaiedh, H. B. Ammar,
J. F. Soule and H. Doucet, Palladium-catalyzed regio-
selective C-H bond arylations at the C3 position of ortho-
substituted fluorobenzenes, Org. Biomol. Chem., 2017, 15,
H. M. Wang, X. C. Gao, B. Wei, H. W. Wu, X. Cai and
D. C. Zou, Synthesis of all-deuterated tris(2-phenylpyridine)
iridium for highly stable electrophosphorescence: the “deu-
terium effect”, J. Mater. Chem. C, 2013, 1, 4821; (b) H. Tsuji,
C. Mitsui and E. Nakamura, The hydrogen/deuterium
isotope effect of the host material on the lifetime of
7
447; (d) S. Y. Lee and J. F. Hartwig, Palladium-Catalyzed,
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Organic & Biomolecular Chemistry
Communication
organic light-emitting diodes, Chem. Commun., 2014, 50,
Palladium-Catalyzed Arene and Heteroarene C-H
Functionalization Reactions, Organometallics, 2017, 36,
165; (c) C. Y. He, Q. Q. Min and X. Zhang, Palladium-
Catalyzed Aerobic Dehydrogenative Cross-Coupling of
Polyfluoroarenes with Thiophenes: Facile Access to
Polyfluoroarene-Thiophene Structure, Organometallics,
2012, 31, 1335.
1
4870.
2
2 (a) D. Whitaker, J. Bures and I. Larrosa, Ag(I)-Catalyzed C-H
Activation: The Role of the Ag(I) Salt in Pd/Ag-Mediated
C-H Arylation of Electron-Deficient Arenes, J. Am. Chem.
Soc., 2016, 138, 8384; (b) M. D. Lotz, N. M. Camasso,
A. J. Canty and M. S. Sanford, Role of Silver Salts in
This journal is © The Royal Society of Chemistry 2020
Org. Biomol. Chem.