Ruthenium-Catalyzed ortho- And meta-H/D Exchange of Arenes

Article abstract of DOI:10.1021/acs.orglett.9b03955

Ruthenium-catalyzed aromatic H/D exchange in [D₄]acetic acid has been developed. By using N-heteroarenes as directing groups, both ortho and meta positions are selectively deuterated with high levels of D incorporation. Moreover, this strategy provides an alternative way to achieve meta-C-H activation.

Full text of DOI:10.1021/acs.orglett.9b03955

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ruthenium-Catalyzed ortho- and meta-H/D Exchange of Arenes
Liang-Liang Zhao, Wei Liu, Zengyu Zhang, Hongyan Zhao, Qi Wang, and Xiaoyu Yan*
Department of Chemistry, Renmin University of China, Beijing 100872, China
S
* Supporting Information
ABSTRACT: Ruthenium-catalyzed aromatic H/D exchange in [D4]acetic
acid has been developed. By using N-heteroarenes as directing groups, both
ortho and meta positions are selectively deuterated with high levels of D
incorporation. Moreover, this strategy provides an alternative way to achieve
meta-C−H activation.
Scheme 1. Metal-Catalyzed Selective C−H Deuteration
ncorporation of deuterium atoms into a specific molecule
Ihas been an advanced research focus in recent years, for the
broad application of deuterated compounds in studying
biological and chemical processes1 and mass spectrometry.2
In particular, the special ability to change the ADME
properties of the known drug candidates has paved the way
for numerous breakthroughs in pharmacokinetics as well as in
pharmaceutical industry. In 2017, the first deuterated drug,
deutetrabenazine, was approved by the Food and Drug
Administration, which pointed out a clearer pathway for the
development of deuterated compounds in clinical medicine.3
Generally, most of simple deuterium-labeled compounds can
be accessed through multistep synthetic routes from
deuterated precursors. However, when it comes to complex
molecule structures or specific deuterium labeling positions, a
direct hydrogen isotope exchange (HIE) method would be the
optimal choice. Although transition metal-catalyzed H/D
exchange protocols have been well established,4 challenges in
regioselective hydrogen isotope exchange remain. Deuteration
of ortho-C−H of arenes assisted by various directing groups
with Ir,5 Pd,6 Rh,7 or Ru8 as the catalyst has been extensively
explored (Scheme 1a); nevertheless, remote C−H bond
deuteration of arenes remains elusive. In 2016, Chirik and
co-workers disclosed a Fe-catalyzed strategy that allowed for
deuteration and tritiation at selective and complementary
positions to existing previously reported transition metal
catalysis strategies.9 Very recently, the groups of Maiti10 and
Dai11 independently reported a novel palladium-catalyzed
selective meta-C−H bond H/D exchange of arenes. In these
strategies, to restrain ortho-C−H activation and to realize meta-
C−H bond deuteration efficiently, a meticulously designed
long-reaching directing template is introduced into the
substrates (Scheme 1b).
Assisted by Directing Groups
and benzylation.20 Radical trapping and isotope labeling
experiments were carried out to explore the reaction
mechanism. These results revealed that the ortho-C−H
bonds were easily deuterated in D2O,16,17b,18a,b because of
ortho-C−H bond activation enabled by cyclometalation.
Nevertheless, addition to the meta position of the cyclo-
metalated intermediate proceeded through a radical pathway
(Scheme 1c), rather than SEAr proposed in the very
beginning.12 Thus, it was difficult to achieve ruthenium-
catalyzed deuteration of the meta-C−H bond due to the
challenging radical H/D exchange. We envisioned that the
SEAr pathway would be preferred while increasing the electron
density of the metal center as well as using a polar deuterated
Ruthenium-catalyzed functionalization of the meta-C−H
bond has been an advanced topic due to the relatively simple
catalytic system and starting materials, because of pioneering
work reported by Frost12 and Ackermann13 in 2011. After
years of research, ruthenium-catalyzed meta-C−H functional-
ization had been well studied,14 such as sulfonation,12,15
bromination,16 alkylation,17 nitration,18 difluoroalkylation,19
Received: November 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03955
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Screening of Reaction Conditions for Deuteration of 1
b
c
entry
catalyst
ligand
solvent
additive
o/m
yield (%)
1
2
3
4
5
6
7
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
Ru(PPh3)3Cl2
Ru(PPh3)2ClCp
Ru3CO12
−
CH3COOD
CH3COOD
CH3COOD
CH3COOD
CH3COOD
CH3COOD
CD3COOD
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
−
69/10
75/12
67/75
72/65
75/12
81/9
77
77
76
65
88
81
80
MesCOOH
PPh3
−
−
PPh3
[RuCl2(p-cymene)]2
PPh3
AgOAc
93/84
a
Reaction conditions: 1a (0.2 mmol), [Ru] (5 mol %), ligand (15 mol %), additive (15 mol %), and solvent (0.8 mL) in a sealed tube, 150 °C, 24
b
c
1
h. Deuterium incorporation determined by H NMR spectroscopic analysis. Isolated yields.
solvent to achieve meta-C−H H/D exchange (see the
Supporting Information for details). Herein, we report
ruthenium-catalyzed ortho- and meta-H/D exchange reaction
with PPh3 as the ligand in [D4]acetic acid. The reaction is
accomplished with high levels of D incorporation with various
N-heteroarenes as directing groups.
Scheme 2. Deuteration of the ortho- and meta-C−H Bond of
a,b
1-Phenylpyrazole Derivatives
We began our study of the H/D exchange reaction of 1a in
[D1]acetic acid with [RuCl2(p-cymene)]2 as the catalyst and
AgOAc as the chloride scavenger. The ortho-C−H bond was
deuterated by 69%, while 10% meta deuteration was detected
(Table 1, entry 1). This inspiring result initiated us to explore
an efficient way to achieve a high level of deuterium
incorporation at ortho and meta positions simultaneously. We
assumed that the addition of an electron-rich ligand would
increase the electron density of the cyclometalated inter-
mediate, which may be beneficial for H/D exchange at meta
positions via the SEAr pathway. MesCOOH, widely used in
other reports as a ligand, was tested to serve as a ligand but
proved to be ineffective for meta-C−H deuteration (entry 2).
Impressively, 75% deuterium incorporation at meta positions
as well as 67% at ortho positions of the benzene ring was
observed when PPh3 was used as the ligand under the same
conditions (entry 3). Other [Ru] catalysts for meta-C−H
activation were subsequently applied to the reaction (entries
4−6). Ru(PPh3)3Cl2 showed a slightly lower catalytic activity
with 65% and 72% deuterium incorporation at the meta and
ortho positions, respectively. However, Ru(PPh3)2ClCp and
Ru3CO12 were not suitable for this reaction system, while trace
deuterium atoms were introduced at the meta positions. The
level of deuterium incorporation was 93% when [D4]acetic
acid was used (entry 7). The yields at meta and ortho positions
were increased to 84%, and we should note that moderate H/
D exchange of the directing group was also observed in the
meantime.
a
b
Standard reaction conditions, isolated yield. Deuterium incorpo-
ration determined by 1H NMR spectroscopic analysis shown in
brackets. CH2Br2 used as an internal standard for deuteration
analysis.
c
deuterium incorporation at meta positions then those of
electron-withdrawing halide groups, which further supported
the SEAr process in achieving meta-C−H bond activation. Only
27% meta-C−H was deuterated for 2g, probably due to the
decreased electron density of the benzene ring. A strong
electron-donating methoxy group at the ortho position gave
97%, 74%, and 91% deuteration at positions C3, C5, and C6,
respectively (2h). The lower level of deuteration at position
C5 compared with that at position C3 is probably due to the
steric effect during SEAr deuteration of a ruthenacycle
intermediate. 3,4- and 2,4-dimethyl-substituted 2i and 2j
delivered only 12% and 15% deuteration, respectively, at the
position C5 for the same reason. Substituents at the pyrazole
moiety were also investigated (2k and 2l), and both electron-
donating and -withdrawing substituents gave excellent
With the optimized reaction conditions in hand, we
investigated the substrate scope with pyrazole as the directing
group under the best conditions (Scheme 2). Substituents at
the benzene ring had little influence on the results for the
deuteration rate at ortho positions; all examples gave more than
90% D incorporation (2a−2j). Steric hindrance and electronic
properties of the substituents at the para position had a strong
influence on meta H/D exchange (2a−2f). Only 52%
deuteration at the meta position was observed when a bulky
tert-butyl was substituted at the para position (2c). Electron-
donating groups, like methyl and methoxy, delivered better
B
DOI: 10.1021/acs.orglett.9b03955
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
deuteration at the ortho and meta positions, although a
relatively lower yield of 2l.
Scheme 4. Deuteration of the ortho- and meta-C−H Bond
a,b
Directed by Other N-Heterocycles
We next devoted our efforts to investigate the application of
this protocol to 2-phenylpyridine derivatives (Scheme 3). The
Scheme 3. Deuteration of the ortho- and meta-C−H Bond of
a,b
2-Phenylpyridine Derivatives
a
b
Standard reaction conditions, isolated yield. Deuterium incorpo-
ration determined by 1H NMR spectroscopic analysis shown in
brackets.
a
b
Standard reaction conditions, isolated yield. Deuterium incorpo-
ration determined by 1H NMR spectroscopic analysis shown in
brackets. CH2Br2 used as an internal standard for deuteration
c
analysis.
a variety of substituents were tolerated and the reaction gave
good to excellent D incorporation at the ortho and meta
positions. Various N-heteroarenes were also competent as the
directing group. More importantly, this strategy represents a
new way for Ru-catalyzed meta-C−H bond activation of
arenes, instead of the radical process. Further investigations are
still in progress in this area.
substrate applicability was similar to those of 2-phenylpyrazole
directives. All examples gave excellent deuteration at ortho
positions of the benzene ring; moreover, inevitable deuteration
of the directing group occurred. Electron-donating groups at
the para position afforded >90% deuterium incorporation at
the meta position (2m and 2n), while electron-withdrawing
halide groups gave lower deuteration rates (2o and 2p).
However, meta-substituted derivatives (2q and 2r) afforded
poor deuterium incorporation at the other meta position, even
though a strong electron-donating methoxyl group that was
introduced did not significantly improve the result. Only 20%
meta-C−H bonds were exchanged with deuterium in the case
of 2s.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03955.
Experimental procedures, characterization of new
compounds, and NMR spectra (PDF)
Nitrogen heterocyclic compounds found broad applications
in biological and pharmaceutical science. To demonstrate
whether other nitrogen heterocyclic arenes are competent with
respect to this method as directing groups to achieve multiple-
site deuteration, several nitrogen heterocyclic arene derivatives
were synthesized as shown in Scheme 4. Benzimidazole
derivatives 2t and 2u were well suited to this method, giving
>90% deuteration at the ortho and meta positions with high
yields, while imidazole derivative 2v gave degressive deutera-
tion at the meta positions. To our delight, pyrimidine and
pyrazine derivatives (2w−2y) also proved to be good directing
groups as high levels of deuterium incorporation were
detected. However, substrates with 1,2,4-triazole, 1,2,3-triazole,
and oxazole as directing groups delivered poor deuteration at
meta positions but excellent deuteration at ortho positions as
well as the N-heterocyclic arene section (2z, 2aa, and 2ab).
In summary, we have disclosed a new method for selective
ortho-C−H and meta-C−H H/D exchange of arenes catalyzed
by Ru with PPh3 and AgOAc as the additive and [D4]acetic
acid as the deuterium source and solvent. In this novel strategy,
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yanxy@ruc.edu.cn.
ORCID
Xiaoyu Yan: 0000-0003-3973-3669
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation of China (21602249).
■
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DOI: 10.1021/acs.orglett.9b03955
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