Ruthenium-Catalyzed Deuteration of Aromatic Carbonyl Compounds with a Catalytic Transient Directing Group

Article abstract of DOI:10.1002/chem.202100468

A novel ruthenium-catalyzed C?H activation methodology for hydrogen isotope exchange of aromatic carbonyl compounds is presented. In the presence of catalytic amounts of specific amine additives, a transient directing group is formed in situ, which directs selective deuteration. A high degree of deuteration is achieved for α-carbonyl and aromatic ortho-positions. In addition, appropriate choice of conditions allows for exclusive labeling of the α-carbonyl position while a procedure for the preparation of merely ortho-deuterated compounds is also reported. This methodology proceeds with good functional group tolerance and can be also applied for deuteration of pharmaceutical drugs. Mechanistic studies reveal a kinetic isotope effect of 2.2, showing that the C?H activation is likely the rate-determining step of the catalytic cycle. Using deuterium oxide as a cheap and convenient source of deuterium, the methodology presents a cost-efficient alternative to state-of-the-art iridium-catalyzed procedures.

Full text of DOI:10.1002/chem.202100468

Accepted Article
Accepted Article
Title: Ruthenium-catalyzed Deuteration of Aromatic Carbonyl
Compounds with a Catalytic Transient Directing Group
Authors: Sara Kopf, Fei Ye, Helfried Neumann, and Matthias Beller
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
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.202100468
Link to VoR: https://doi.org/10.1002/chem.202100468
01/2020

10.1002/chem.202100468
Chemistry - A European Journal
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Ruthenium-catalyzed Deuteration of Aromatic Carbonyl
Compounds with a Catalytic Transient Directing Group
Sara Kopf,[a] Fei Ye,[a,b] HelfriedNeumann,*[a] and Matthias Beller*[a]
[a]
S. Kopf, Dr. F. Ye, Dr. H. Neumann, Prof. Dr. M. Beller
Leibniz-Institutfür Katalyse e. V., Rostock
Albert-Einstein-Straße 29a, 18059 Rostock(Germany)
E-mail: Matthias.Beller@catalysis.de
[b]
Dr. F. Ye
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, KeyLaboratoryof Organosilicon Material Technologyof
Zhejiang Province, Hangzhou Normal University. No. 2318, Yuhangtang Road, 311121, Hangzhou (P. R. China)
Supporting information for this articleis given via a link at theend of the document.
Abstract: A novel ruthenium-catalyzed C-H activation methodology
for hydrogen isotope exchange of aromatic carbonyl compounds is
presented. In the presence of catalytic amounts of specific amine
additives, a transient directing group is formed in situ, which directs
prevalence in biologically relevant compounds on the one hand,
as well as the presence of two potential labeling sites in their
structure on the other hand: While the slightly acidic α carbonyl
hydrogen atoms are subject to acid- or base-catalyzed hydrogen
selective deuteration. A high degreeof deuteration is achieved for α- isotope exchange (HIE),[5] the ketone moiety has also been
carbonyl and aromatic ortho-positions. In addition, appropriatechoice
of conditions allows for exclusive labeling of the α-carbonyl position
while a procedure for the preparation of merely ortho-deuterated
compounds is also reported. This methodology proceeds with good
functional group tolerance andcan be also applied for deuterationof
pharmaceutical drugs. Mechanistic studies reveal a kinetic isotope
effect of 2.2, showing that the C-H activation is likely the rate-
determining step of the catalytic cycle. Using deuterium oxide as a
cheap and convenient source ofdeuterium, the methodology presents
explored as a directing group in iridium-catalyzed ortho-selective
deuteration.[6] Having focused largely on unsubstituted
acetophenone and benzophenone as substrates, excellent
deuterium incorporation has been observed among others with
the so-called Kerr catalyst under deuterium gas atmosphere and
mild conditions(Scheme 1a).[6f]
a
cost-efficient alternative to state-of-the-art iridium-catalyzed
procedures.
Introduction
Being an elegant approach to label a compound without
altering its physical properties, structure, or biological function,
the selective exchange of hydrogen for its heavier isotope
[1]
deuterium continues to be of interest for many scientists.
Especially in the context of medicinal chemistry, the introduction
of deuterium as a bioisostericreplacement of protium in specific,
metabolically labile or racemization prone positions of drug
candidates such as α carbonyl positionscan mitigate deleterious
pathways thanks to the kinetic isotope effect (KIE).[2] The
formation of potentially toxic metabolites is thereby prevented
while a more generalimprovement of the absorption,distribution,
metabolism and excretion (ADME) properties of the drug
candidate is possible at the same time.[2] The development of
selective hydrogen isotope exchange (HIE) methodologies can
further be important for the preparation of starting materials for
KIE studies relevant for the investigation of reaction
mechanisms.[3] Here, substrates with deuteration ortho to a
functional group can be interesting.[4] In contrast, the preparation
of MSstandardsfor metabolism studiesrequiresthe incorporation
of several deuterium atoms at once rather than selective
deuteration to avoid overlap of unlabeled and labeled compounds
in the mass spectrum.[1b] For this purpose, acetophenone
derivatives are particularly attractive substrates, given their
Scheme 1. Homogeneous transition metal-catalyzed HIE of aromatic ketones.
1
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Although it would be worth investigating scope and
functionalgroup tolerance of these methodologiesfurther, the use
of alternative transition metal catalysts as well as cheaper
deuterium sources is also appealing. However, attempts to
replace iridium by ruthenium[7] or palladium[8] for ketone-directed
HIE have been met with only limited success so far.[9] In spiteof
deliveringmoderate deuterium incorporations for benzophenones
(Scheme 1b), these methodologies showed reduced or no
reactivity for acetophenone derivatives.[7a,8] Moreover, using
deuterated trifluoroacetic acid as deuterium source, concomitant
electrophilicaromaticsubstitution hampers the ortho-selectivityof
the directed palladium-catalyzed approach (Scheme 1c).[8]
Interestingly, Plietkerand co-workers achieved moderate to
good deuteration levels in acetophenone derivatives under
ruthenium catalysis in the presence of (over)stoichiometric
amounts ofzincadditives(Scheme 1d).[7b] An alternative concept
for homogeneous ruthenium-catalyzed aromatic HIE makes use
of nitrogen containing directing groups.[7,10] Circumventing the
need to pre-synthesize such directing groups, we recently
reported a manganese-catalyzed deuteration of benzaldehydes
in the presence of catalytic amine additives that form a transient
directing group (TDG) in situ.[11] Thisconcept had previously been
shown to be effective under ruthenium catalysisamong others[12]
for the alkylation,[13] amination,[14] and radicaldifluoroalkylation[15]
of aromatic aldehydes, but can also be used for the C–H
functionalization of ketones when using palladium[16] and
that the TDG is needed forthistransformation (Table 1, entry 6).
In this context, it is worth mentioning that previous attempts to
deuterate aldehydes under ruthenium catalysis but without a
transient directing group strategy had failed.[7a] Lowering the
temperature to 80 °C diminished the deuterium incorporation
significantly whereas the recovery of deuterated aldehyde was
reduced at elevated temperature(Table 1, entries7 and 8). Lastly,
the scale of the reaction can be increased 10-fold without affecting
deuterium incorporation and yield (Table 1, entry 9).
Table 1. Ruthenium-catalyzed and TDG-mediated o-
selective HIEof o-nitrobenzaldehyde.[a]
Entry
Variation
D [%][b]
92
0
Yield [%][c]
75
1
2
3
4
5
6
7
8
9
none
no [Ru][d]
n.d.
n.d.
n.d.
85
1.25 mol% [Ru]2
0.5 mol% [Ru]2
10 mol% 5
no 5
84
52
91
0
[17]
rhodium catalysts. Building on this knowledge and aiming
n.d.
n.d.
65
towardsa cost-efficient procedure forthe deuteration of ketones,
we wish to report herein a novel useful ruthenium-catalyzed
deuteration of aromatic aldehydesand ketones(Scheme 1e).
80 °C
35
91
90
120 °C
10 mol% 5, 5 mmol scale
84
Results and Discussion
[a] 0.5 mmol scale. Further optimization details can be found in the SI. [b]
Determined by 1H NMR usingthe aldehydeor m/p-resonancesas reference. [c]
Isolated yields. [d]120 °C, 24 h.
Inspired by
the work on ruthenium-catalyzed
functionalization of aromatic aldehydes in the presence of
anilines,[13a] we investigated the deuteration of o-
nitrobenzaldehyde as model substrate with 10 eq. of deuterium
oxide as deuteriumsource in the presence of common ruthenium
catalysts. While cyclometalated ruthenium complexes as
developed in our group[18] as well as NHC ligated metathesis
catalystsperformed well, the best resultswere achieved with the
simple and commercially available ruthenium chloride p-cymene
dimer (Table 1, entry 1). Notably, the addition of p-chlorobenzoic
acid and silver hexafluoroantimonate are necessary to activate
the ruthenium complex. Alternative ruthenium precursors such as
ruthenium chloride or dodecacarbonyl ruthenium(0) were not
effective and the addition of various phosphine ligands slowed
down the reaction. In the absence of the ruthenium catalyst no
reaction took place although high deuteration was still obtained
with a catalyst loading as low as 1.25 mol% (Table 1, entries2-4).
Notably, the exact substitution pattern of the transient directing
group plays a minor role. A good balance between a sufficiently
stable imine intermediate and good catalytic turnover isachieved
with electron-deficient anilines such as o- and p-
aminobenzotrifluoride aswell as2-methyl-3-trifluoromethyl aniline
5. Further, the isolation of deuterated aldehyde could be improved
without impacting the deuterium incorporation by decreasingthe
aniline loading to 10 mol% which lowered the amount of
remaining imine after the reaction (Table 1, entry 5). No
deuteration takes place in the absence of the aniline, confirming
Having established optimal reaction conditions for the
ruthenium- and aniline-catalyzed deuteration of aldehydes, we
explored the scope of this transformation, particularly seeking to
address some of the limitations of our previously published
manganese-catalyzed HIE reaction which showed diminished
reactivity for sterically hindered substrates and did not tolerate
free hydroxy groups.[11] Besides, slightly modified reaction
conditions were needed for electron-deficient substrates. This
new methodology on the other hand appears to be remarkably
robust, delivering excellent deuterium incorporations and yields
for both electron-deficient and electron-rich (hetero)arenes under
unchanged conditions (Scheme 2). Moreover, free hydroxy
groupsas in vanillin are tolerated and even the sterically hindered
tert-butylbenzaldehyde isdeuterated smoothly.
Interestingly, in the case of naphthaldehyde and
benzothiophene-3-carboxaldehyde, both ortho- and peri-
positions are deuterated, whereas our previously reported
methodologyfurnished exclusive labeling in the ortho-position.
Encouraged by these results, we attempted the TDG-
enabled deuteration of aromatic ketones. Under the optimized
conditionsvide supra but in the absence of catalyticamines, only
12% deuterium incorporation in the ortho-positions of
acetophenone was observed, confirming the challenging nature
of HIE on this type of substrates (Table 2, entry 1). However,
2
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adding 20 mol% of aniline 5 as TDG, the deuteration efficiency
was raised significantly (Table 2, entry 2). In contrast to the
reaction on aldehydes, other anilines including o- and p-
aminobenzo-trifluoride afforded moderate to low deuterium
incorporation whereas m-aminobenzotrifluoride delivered very
good results comparable to 5. We explain this different behavior
by the lower reactivityof ketonescompared to aldehydestowards
imine formation, requiring more nucleophilic amines. Finally, a
deuteration degree of 90% could be obtained after raising the
temperature and increasing theamount of deuterium oxide (Table
2, entry 3). Under these conditions, high deuteration levels are
additionally achieved in the α-carbonyl position, furnishing an
overallincorporation offive deuterium atomspermolecule.
arenes afforded very good deuterium incorporation, whereas
electron-deficient acetophenone derivativeswere somewhat less
feasible substrates.
Table 3. Amine- and silver-catalyzed α-carbonyl
deuteration.[a]
Entry
Variation
none
D (α) [%][b]
1
2
3
93
62
46
no AgSbF6
no 5
[a] 0.5 mmol scale. [b] Determined by 1H NMR using the resonance for the p-
position as reference.
However, using 50 mol% rather than 20 mol% of the TDG,
the deuterium incorporation of trifluoromethyl-substituted ketone
20 increased markedly. It can thus be deduced that the lower
deuterium incorporation observed under standard conditions can
be explained by the short-lived nature of the correspondingimine
intermediateratherthan factorsinvolving the C-H activation step.
Furthermore, the reaction is compatible with reactive
functional groups such as free alcohols (16), tertiary as well as
free amino groups (31 and 17), unprotected heterocycles (27),
and thioethers (31).[19] Highly electron-rich substrates such as
compounds 17 and 28 engage in concomitant deuteration by
electrophilic aromatic substitution, affording perdeuterated
products. Increasing the chain length of acetophenone (23) and
including branched structures (24) led to decreased deuterium
incorporation. It thus appears that increased steric hindrance on
this side of the ketone substrate interferes with either imine
formation or coordination to the ruthenium catalyst.
Scheme 2. Scope of aldehydes (0.5 mmol scale). Deuterium incorporations
were determined by 1H NMR using the aldehyde or m/p-resonances as
reference and are indicated in square brackets. Yields are given under the
structures.
Table 2. Ruthenium- and TDG-catalyzed o-selective HIE of
acetophenone.[a]
If exclusive labeling in the ortho-position is desired, the
deuterated compounds can simply be reacted with water under
silver and amine catalysis, thus reversing the deuteration of the
methyl group (21-d2).
Entry
Variation
D (o) [%][b]
D (α) [%][b]
Mass spectrometric analysis of the isolated deuterated
products showed that in almost all cases no non-deuterated
compounds were present, rendering the herein presented
procedure relevant for the preparation of isotopicallylabeled LC-
MS standards. Besides, the preparation of deuterated
pharmaceuticals is also feasible as demonstrated in the
successful deuteration of marketed drugs ketoprofen (32) and
fenofibrate (33).
1
2
3
no TDG
12
74
90
46
86
90
none
120 °C, 20 eq. D2O
[a] 0.5 mmol scale. Further optimization details can be found in the SI. [b]
Determined by 1H NMR usingthe resonancefor the p-position as reference.
In agreement with previous reports,[13a] it can be proposed
that the ruthenium catalyst is activated by silver-mediated halide
abstraction and coordination of the p-chlorobenzoicacid additive.
At the same time, acid-catalyzed condensation of aniline and
aldehyde or ketone to the imine intermediate takes place,
preparing for subsequent coordination to ruthenium followed by
C-H activation. For o-nitrobenzaldehyde, we measured a kinetic
isotope effect (KIE) of 2.2, indicating that the C-H activation is
likely the rate-determining step of the reaction. Its reverse finally
leads to the deuterated product while the excess of deuterium
oxide along with the KIEenable high conversions.
As shown by control experiments (Table 3), this latter
reaction likely proceeds via an amine-mediated enamine
formation and requiresthe Lewis acidicsilversalt or the benzoic
acid derivative as a catalyst. Indeed, in the absence of the
ruthenium catalyst, ketones are solely deuterated in α-position.
Finally, a broad range of acetophenone derivatives could be
successfullyconverted to the ortho- and α-deuterated analogues
using this newly developed methodology (Scheme 3).
Substituents in ortho-, meta-, and para-positions were all
tolerated and deuteration levels appeared to be only slightly
affected by steric effects. Especially electron-rich and neutral
3
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Scheme 3. Ruthenium-catalyzed HIE in the presence of a TDG: Scope of ketones. Deuterium incorporationswere determinedby 1H NMR using the resonances
for the p-position as reference and is indicated in square brackets. Yields are given under the structures. [a] 50 mol% TDG used. [b] 4 days reaction time. [c] 4
consecutive deuterationcycles.
DCE (900 µL) and D2O (100 µL) were added. Liquid aldehydes were also
added at this stage. The reaction mixture was subsequently heated to
100 °C and stirred at this temperature for 16 hours. The resulting
Conclusion
suspension was diluted with DCM, washed with an aqueous saturated
solution of sodium bicarbonate (20 mL), and extracted with DCM (2x
In conclusion, we have demonstrated a novel ruthenium-
catalyzed hydrogen isotope exchange reaction of aromatic
aldehydes and ketones using the cheapest deuterium source as
a viable alternative to the more expensive state-of-the art iridium-
catalyzed methodologies. Using a catalytic transient directing
group strategy, the difficulties in the C-H activation of such
substrates could be mitigated. Furthermore, appropriate choice of
reaction conditionsallowsforselective deuteration in eitherortho-
or α-positions or at both sites at the same time. The importance
of this methodology in the context of drug design and metabolism
studies is showcased by the successfulpreparation of deuterated
analoguesof marketed drugs.
20 mL). The combined organic layers were washed with distilled water
(20 mL), dried over sodium sulfate and concentrated. The deuterated
products were then purified by silica column chromatography with eluent
systems of pentane and ethyl acetate.
Representative procedure for the deuteration of ketones. The ketone
(0.5 mmol), p-chlorobenzoic acid (39 mg, 0.25 mmol, 0.5 eq.), 2-methyl-3-
trifluoromethyl-aniline (18 mg, 0.1 mmol, 20 mol%), dichloro(p-
cymene)ruthenium(II) dimer (7.7 mg, 12.5 µmol, 2.5 mol%), and silver
hexafluoroantimonate (34 mg, 0.1 mmol, 20 mol%) were weighed into a
25 mL pressure-resistant Schlenk tube equipped with a magnetic stirring
bar. The Schlenk tube was evacuated and backfilled with argon three times.
DCE (300 µL) and D2O (200 µL) were added. Liquid ketones were also
added at this stage. The reaction mixture was subsequently heated to
120 °C and stirred at this temperature for 16 hours. The resulting
suspension was diluted with DCM, washed with an aqueous saturated
solution of sodium bicarbonate (20 mL), and extracted with DCM (2x
20 mL). The combined organic layers were washed with water (20 mL),
dried over sodium sulfate and concentrated. The deuterated products were
then purified by silica column chromatography with eluent systems of
pentane and ethyl acetate.
Experimental Section
Representative procedure for the deuteration of aldehydes: The
aldehyde (0.5 mmol), p-chlorobenzoic acid (39 mg, 0.25 mmol, 0.5 eq.), 2-
methyl-3-trifluoromethyl-aniline (8.8 mg, 50 µmol, 10 mol%), dichloro(p-
cymene)ruthenium(II) dimer (7.7 mg, 12.5 µmol, 2.5 mol%), and silver
hexafluoroantimonate (34 mg, 0.1 mmol, 20 mol%) were weighed into a
25 mL pressure-resistant Schlenk tube equipped with a magnetic stirring
bar. The Schlenk tube was evacuated and backfilled with argon three times.
Acknowledgements
We acknowledge the support from the European Union (Flow
Chemistry for Isotope Exchange, FLIX, 862179), the BMBF and
4
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[16] a) J. Xu, Y. Liu, Y. Wang, Y. Li, X. Xu, Z. Jin, Org. Lett. 2017, 19, 1562-
1565; b) J. Wang, C. Dong, L. Wu, M. Xu, J. Lin, K. Wei, Adv. Synth.
Catal. 2018, 360, 3709-3715.
the State of Mecklenburg-Western Pommerania. Fei Ye thanks
the NationalNatural Science Foundation of China (No. 21801056)
for financial support. We thank Dr. Wolfgang Baumann for the
measurement of 2H NMR spectra and the whole analytical team
of LIKAT for their kind support.
[17] A. E. Hande, V. B. Ramesh, K. R. Prabhu, Chem. Commun. 2018, 54,
12113-12116.
[18] P. Piehl, R. Amuso, E. Alberico, H. Junge, B. Gabriele, H. Neumann, M.
Beller, Chem. Eur. J. 2020, 26, 6050-6055.
[19] Substrates 16 and 17 engage in some side reactions and thus give
somewhat diminished, but nevertheless synthetically useful yields of
deuterated products.
Keywords: C-H activation • hydrogen isotope exchange •
ketones• ruthenium • transientdirecting group
[1]
a) J. Atzrodt, V. Derdau, W. J. Kerr, M. Reid, Angew. Chem. Int. Ed. 2018,
57, 3022-3047; Angew. Chem. 2018, 130, 3074-3101; b) J. Atzrodt, V.
Derdau, W. J. Kerr, M. Reid, Angew. Chem. Int. Ed. 2018, 57, 1758-
1784; Angew. Chem. 2018, 130, 1774-1802.
[2]
[3]
[4]
T. Pirali, M. Serafini, S. Cargnin, A. A. Genazzani, J. Med. Chem. 2019,
62, 5276-5297.
E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51, 3066-
3072; Angew. Chem. 2012, 124, 3120-3126.
Recent examples: a) Q. Dherbassy, J.-P. Djukic, J. Wencel-Delord, F.
Colobert, Angew. Chem. Int. Ed. 2018, 57, 4668-4672; Angew. Chem.
2018, 130, 4758-4762; b) R. A. Jagtap, C. P. Vinod, B. Punji, ACS Catal.
2019, 9, 431-441.
[5]
a) C. Rappe, W. H. Sachs, Tetrahedron 1968, 24, 6287-6290;b) J. Yao,
R. F. Ervilia, J. Am. Chem. Soc. 1994, 116, 11229-11233; c) C.
Berthelette, J. Scheigetz, J. Label. Compd. Radiopharm. 2004, 47, 891-
894; d) M. Zhan, T. Zhang, H. Huang, Y. Xie, Y. Chen, J. Label. Compd.
Radiopharm. 2014, 57, 533-539; e) Y. Chang, T. Myers, M. Wasa, Adv.
Synth. Catal. 2020, 362, 360-364; f) K. I. Galkin, E. G. Gordeev, V. P.
Ananikov, Adv. Synth. Catal. 2021, 363, 1368-1378.
[6]
a) J. R. Heys, A. Y. L. Shu, S. G. Senderoff, N. M. Phillips, J. Label.
Compd. Radiopharm. 1993, 33, 431-438; b) D. Hesk, P. R. Das, B. Evans,
J. Label. Compd. Radiopharm. 1995, 36, 497-502;c) G. J. Ellames, J. S.
Gibson, J. M. Herbert, A. H. McNeill, Tetrahedron 2001, 57, 9487-6597;
d) J. A. Brown, S. Irvine, A. R. Kennedy, W. J. Kerr, S. Andersson, G. N.
Nilsson, Chem. Commun. 2008, 1115-1117;e) A. R. Cochrane, S. Irvine,
W. J. Kerr, M. Reid, S. Andersson, G. N. Nilsson, J. Label. Compd.
Radiopharm. 2013, 56, 451-454;f)J. A. Brown, A. R. Cochrane, S. Irvine,
W. J. Kerr, B. Mondal, J. A. Parkinson, L. C. Paterson, M. Reid, T. Tuttle,
S. Andersson, G. N. Nilsson, Adv. Synth. Catal. 2014, 356, 3551-3562,
g) M. Parmentier, T. Hartung, A. Pfaltz, D. Muri, Chem. Eur. J. 2014, 20,
11496-11504; h) K. Jess, V. Derdau, R. Weck, J. Atzrodt, M. Freytag, P.
G. Jones, M. Tamm, Adv. Synth. Catal. 2017, 359, 629-638.
a) L. Piola, J. A. Fernández-Salas, S. Manzini, S. P. Nolan, Org. Biomol.
Chem. 2014, 12, 8683-8688; b)P. Eisele, F. Ullwer, S. Scholz, B. Plietker,
Chem. Eur. J. 2019, 25, 16550-16554.
[7]
[8]
[9]
R. Giles, G. Ahn, K. W. Jung, TetrahedronLett. 2015, 56, 6231-6235.
Concerning directing groups other than ketones, both ruthenium and
palladium-catalyzed methodologies have been demonstrated as viable
alternatives to iridium-catalyzed HIE. See ref. 7a and: a) V. Müller, R.
Weck, V. Derdau, L. Ackermann, ChemCatChem 2020, 12, 100-104; b)
S. Ma, G. Villa, P. S. Thuy-Boun, A. Homs, J.-Q. Yu, Angew. Chem. Int.
Ed. 2014, 53, 734-737; Angew. Chem. 2014, 126, 753-756.
[10] L.-L. Zhao, W. Liu, Z. Zhang, H. Zhao, Q. Wang, X. Yan, Org. Lett. 2019,
21, 10023-10027.
[11] S. Kopf, H. Neumann, M. Beller, Chem. Commun. 2021, 57, 1137–1140.
[12] a) P. Gandeepan, L. Ackermann, Chem 2018, 4, 199-222;b) S. StJohn-
Campbell, J. A. Bull, Org. Biomol. Chem. 2018, 16, 4582-4595; c) B. Niu,
K. Yang, B. Lawrence, H. Ge, ChemSusChem 2019, 12, 2955-2969; d)
J. I. Higham, J. A. Bull, Org. Biomol. Chem. 2020, 18, 7291-7315.
[13] a) F. Li, Y. Zhou, H. Yang, D. Liu, B. Sun, F.-L. Zhang, Org. Lett. 2018,
20, 146-149; b) Z.-Y. Li, H. H. C. Lakmal, X. Qian, Z. Zhu, B. Donnadieu,
S. J. McClain, X. Xu, and X. Cui, J. Am. Chem. Soc. 2019, 141, 15730-
15736; c) G. Li, Q. Liu, L. Vasamsetty, W. Guo, J. Wang, Angew. Chem.
Int. Ed. 2020, 59, 3475-3479; Angew. Chem. 2020, 132, 3503-3507.
[14] O. K. Rasheed, Synlett 2018, 29, 1033-1036.
[15] Y. Cheng, Y. He, J. Zheng, H. Yang, J. Liu, G. An, G. Li, Chin. Chem.
Lett., doi:10.1016/j.cclet.2020.09.044.
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Entry for the Table of Contents
Everything is transient …: The combination of a ruthenium catalyst with amines enablesthe C-H activation and deuterationof
aromatic carbonyl compounds in a generalmanner. Using D2O as a convenient source of deuterium, high deuteration levelswere
achieved and the application ofthismethodology forthe preparation of deuterated pharmaceuticalswas demonstrated.
Institute and/orresearcher Twitter usernames: @likat_rostock, @sarakopf1
6
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