A Protocol for the Ortho-Deuteration of Acidic Aromatic Compounds in D2O Catalyzed by Cationic RhIII

Article abstract of DOI:10.1021/acs.orglett.9b02618

Methods to catalytically introduce deuterium in synthetically useful yields ortho to a carboxylic acid directing group on arenes typically requires D₂ or high catalyst loadings, which makes using these approaches cost prohibitive for large-scale synthesis (equipment and reagent costs respectively). Herein, we present a simplified approach using low catalyst loadings of cationic Rh^III and D₂O as both deuterium source and solvent and show its application to H/D exchange on various carboxylic acid substrates.

Full text of DOI:10.1021/acs.orglett.9b02618

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Protocol for the Ortho-Deuteration of Acidic Aromatic Compounds
in D2O Catalyzed by Cationic RhIII
Alyssa L. Garreau, Hanyang Zhou, and Michael C. Young*
Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, The University of Toledo, Toledo, Ohio
43606 United States
S
* Supporting Information
ABSTRACT: Methods to catalytically introduce deuterium in synthetically useful
yields ortho to a carboxylic acid directing group on arenes typically requires D2 or high
catalyst loadings, which makes using these approaches cost prohibitive for large-scale
synthesis (equipment and reagent costs respectively). Herein, we present a simplified
approach using low catalyst loadings of cationic RhIII and D2O as both deuterium source
and solvent and show its application to H/D exchange on various carboxylic acid
substrates.
elective incorporation of deuterium into organic com-
were performed in triplicate, and the average yield/deuteration
1
Spounds is vital for a variety of applications, including was reported. The reaction was run for 24 h at 90 °C, resulting
kinetic isotope experiments,2 internal standards for analytical
applications,3 and labeled probes for studying metabolomics.4
Exchanging H for D can also lead to modified pharmacological
properties.5 Unsurprisingly, a number of synthetic methods
have been developed to replace hydrogen atoms with
deuterium. These include stoichiometric directed metalation,6
per-deuteration of aromatic7 or aliphatic8 C−H bonds, and
catalytic directed metalation9 strategies. Most of these methods
achieve site-selective H/D exchange (HDE) using either excess
in 98% deuteration at C6 as determined by 1H NMR (Table 1,
1). This also led to 92% deuteration at the C2 position,
suggesting that steric blocking of the 2-position is not as viable
an approach as it is in other C−H activation reactions.17 The
catalyst loading could be dropped to only 0.25 mol % without
a significant decrease in the level of deuteration at C6, although
deuteration at C2 became less favorable (2), consistent with
previous observations.18 Using RhCl3·3H2O (3) gave poor
conversion, probably due to the rate of catalyst decomposition
without the stabilizing cp* ligand.13
10
D2 or acetic acid-d4.11 There are reports that make use of
Halide dimers of Rh or Ir19 cyclopentadienyl-based catalysts
were not as effective (4 and 5), showing good C6 deuteration,
but reduced HDE at C2. Ru was completely ineffective (6 and
7).20 Despite precedence in similar reactions using acetic acid-
d4, we found that Pd(OAc)2 was not effective in our system
(8).11 Unsurprisingly, no deuteration was observed in the
absence of transition-metal catalyst (9). Changing the identity
of the base also had a detrimental effect (10−12). We found
that the reaction was not complete at shorter reaction times
(13 and 14), while lowering the temperature led to decreased
levels of deuteration (15 and 16). Raising the temperature
leads to lower levels of HDE (17), probably due to catalyst
decomposition. Meanwhile, at the lower temperature of 70 °C,
the reaction will continue to give slightly higher levels of HDE
if left beyond 24 h (18), even at lower catalyst loadings (19).
Using our optimized conditions, we were able to isolate the
model substrate in 93% yield with the previously observed 98%
site-selective C−H deuteration of aryl carboxylic acids with
D2O as the deuterium source, typically using Group VIII
metals,12 but these struggle from numerous challenges,
including catalyst decomposition,13 the need for cosolvents,14
or conversion into a better directing group.15 The ability to use
solely D2O as solvent and as a deuterium source while using
low catalyst loading would lead to a straightforward way to
prepare ortho-deuterated aromatic carboxylic acids in a more
sustainable and straightforward fashion and at larger scale and
lower cost with common laboratory equipment.
Much of the work in HDE catalyzed by Group VIII metals
has focused on low-valent species, or the free metal halide salts.
Based on the precedent of C−H activation of benzoic acids to
form new C−C bonds using RhIII catalysts,16 we set out to
determine the optimal conditions for our desired C−H
deuteration reaction on 3-(trifluoromethyl)benzoic acid as
the model substrate using RhIII precatalysts and determined
that the best system involved using 1.0 mol % of the cationic
complex [Rh(cp*)(MeCN)3](SbF6)2 with 1.1 equiv of NaOAc
as base and ∼200 equiv of D2O as the solvent. All reactions
Received: July 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02618
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization Study of the C−H Deuteration of 3-
(Trifluoromethyl)benzoic Acid (0.26 mmol Scale)
Scheme 1. Scope of the C−H Deuteration of ipso-Aryl and
Heteroaryl Carboxylic Acids (0.30 mmol Scale)
C6C2 deuteration
entry
deviation from optimized conditions
(%)
1
2
none
98/92
97/67
[Rh(cp*)](MeCN)3]SbF6)2 as catalyst
(0.25 mol %)
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
RhCl3·3H2O as catalyst (1 mol %)
[Rh(cp*)Cl2]2 as catalyst (1 mol %)
[Ir(cp*)Cl2]2 as catalyst (1 mol %)
[Ru(cp*)(cod)Cl] as catalyst (1 mol %)
[Ru(PPh3)2Cl2] as catalyst (1 mol %)
Pd(OAc)2 as catalyst (1 mol %)
no catalyst
NaHCO3 as base (1.2 equiv)
Cs2CO3 as base (1.2 equiv)
Na2CO3 as base (1.2 equiv)
6 h reaction time
4/6
98/73
98/81
<4/< 4
<4/< 4
<4/< 4
<4/< 4
65/17
35/9
65/17
97/50
98/88
98/90
95/61
93/42
98/69
91/39
12 h reaction time
80 °C reaction temperature
70 °C reaction temperature
100 °C and 0.25 mol % RhIII catalyst loading
70 °C and 48 h reaction time
70 °C, 48 h, and 0.25 mol % RhIII catalyst
loading
deuteration at C6 and 92% deuteration at C2 (Scheme 1, 1a).
1
The percent deuteration was determined using H NMR and,
2
when needed, an internal standard as well as H NMR (to
assess nondirected HDE). Notably, shifting the CF3 group to
the ortho or para position had a profound effect on the level of
deuteration (1b and 1c). Gratifyingly, the poor levels of
deuteration could be improved simply by increasing the
catalyst loading. The same was true for a 3,5-bis-CF3-
substituted substrate (1d). Our method was effective on a
variety of halogenated substrates containing fluorine (1e),
chlorine (1f), iodine (1g and 1h), and bromine (1i)
substituents. The ortho-iodide gave a small amount of
inseparable byproducts, likely due to competitive reaction at
the ortho-iodide. Even a nitrile substituent could be tolerated in
the reaction (1j).
The reaction is not limited to simple benzoic acids, and both
2-naphthoic (1k) and 1-naphthoic (1l) acids gave relatively
high levels of deuteration ortho to the directing group. In
addition to β-C−H activation, substrate 1l also showed
deuteration at the γ-position.21 Aliphatic substituents on
benzoic acid were also tolerated, both at the para-position
(1m and 1n) as well as at the ortho-position (1o). In contrast
to substrate 1l, the o-CH3 does not undergo γ-C−H activation.
While low-valent metals or radical intermediates will often
cleave sensitive cyclopropyls, the RhIII used in this trans-
formation was able to catalyze the transformation while
preserving a sensitive o-cyclopropyl ring (1p). Performing
the reaction on 4-acetamidobenzoic acid gave effective ortho-
deuteration to the carboxylic acid but also lower levels of
deuteration ortho to the acetamide (1q). Trifluoromethoxy
substituents (1r and 1s) are tolerated as is a bis-methoxy-
substituted ring (1t).
a
b
2 mol % of catalyst used. 1H NMR taken directly in D2O from the
crude reaction mixture.
Considering heteroaromatics, 2-furoic acid showed high
levels of deuteration at C3 (1u). The electronically biased
HDE at C5 also occurred with 53% exchange.22 Similarly, 3-
furoic acid underwent high levels of exchange at C2 and C4,
while medium HDE was observed at C5 (1v). In the case of 2-
thiophene carboxylic acid, high levels of deuteration were
observed at C3 as expected, but comparatively little at C5 (1w),
reflecting the decreased reactivity of thiophenes for C−H
activation.23 Similarly, 3-thiophene carboxylic acid showed
high levels of exchange at C2 and C4, with very little at C5 (1x).
No significant HDE was observed for any of the pyridine
carboxylic acids (1y−1aa).
B
DOI: 10.1021/acs.orglett.9b02618
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We considered that this method should also be viable for
vinylic acids and began studying the reaction on cinnamic
acids. Notably, RuII catalysts are known for promoting HDE on
vinylic acids in the presence of either CD3OD or D2O.24
Simple cinnamic acid showed almost complete deuteration at
the β-carbon (Scheme 2, 2a). Low levels of deuteration were
intermixed with oligomerization products of acrylic acid (2i).
While methacrylic acid (2j) was stable to the conditions, only
low levels of HDE were observed. It is unclear whether the
enrichment of deuterium at the trans-β-hydrogen is due to
isomerization of the alkene (installation at the cis-position and
subsequent isomerization) or undirected C−H activation at
the trans-β-hydrogen. Poor levels of deuteration were also
observed for crotonic (2k) and 2,4-hexadienoic (2l) acids,
suggesting that perhaps the arene in the cinnamic acids is
critical for C−H activation.
Scheme 2. Scope of the C−H Deuteration of Vinyl
Carboxylic Acids (0.30 mmol Scale)
We next wondered if other acidic functional groups might
also participate in the reaction. The reaction with 4-
chlorobenzene sulfamide25 (Scheme 3, entry 3a) showed no
Scheme 3. Scope of the C−H Deuteration of Various Acidic
Substrates (0.30 mmol scale)
a
b
c
3 mol % of catalyst used. 5 mol % of catalyst used. 1H NMR taken
a
1H NMR taken directly in D2O from crude reaction mixture.
d
directly in D2O from crude reaction mixture. Substrate underwent
oligomerization.
sign of HDE. Even p-toluenesulfonic acid gave only trace
conversion to the deuterated product (3b). Using a
phosphonic acid gave slightly improved but still poor levels
of deuteration (3c). We next tried simple acrylamide (3d), and
although it did not oligomerize like acrylic acid in our method,
no HDE was observed. We next questioned whether or not the
carboxylic acid could be moved further away from the arene
and still direct C−H activation effectively.26 When we
subjected 3-(trifluoromethyl)phenylacetic acid to the reaction
conditions, we observed 79% deuteration, but surprisingly at
the α-position (3e). This may be a consequence of exchange
promoted by the more acidic α-carbon rather than a C−H
activation pathway. Meanwhile, only trace HDE was observed
on the arene. When we explored the reaction on 2-(4-
isobutylphenyl)propanoic acid (ibuprofen, 3f), either the
decreased acidity or increased sterics was able to shut down
the α-HDE, leading to slightly increased but still low levels of
exchange on the arene. Interestingly, running the reaction in a
1:1 mixture of CD3OD/D2O completely shut down the HDE
(see the Supporting Information). Considering the increased
rigidity of phenylglyoxylic acid, we considered it might be a
viable substrate but found similarly poor conversion (3g).
We considered that acetylsalicylic acid (aspirin) might make
for a nice application of this method on an obvious biologically
relevant molecule. When the reaction was attempted under the
standard conditions, acetylsalicylic acid was deuterated at the
C6 position almost quantitatively (Scheme 4, 1ab). However,
under the conditions, the acetyl group was completely
hydrolyzed. When the reaction temperature was lowered to
80 or 70 °C, lower levels of deuteration were observed, but still
also observed at the α-carbon. Similar results were observed for
a 3-(trifluoromethyl)-substituted cinnamic acid (2b). Using
either a 3-nitro- (2c) or 4-bromo-2-fluoro-substituted cinnamic
acid (2d), low levels of HDE were observed. 4-Methylcinnamic
acid was also tested but gave only moderate levels of HDE at
Cβ (2e). Surprisingly, use of extra catalyst did not significantly
or consistently improve the deuteration for this more poorly
soluble example as it did in the cases of 1b−1d. Using a larger
iPr-substituent led to higher levels of HDE (2f), even though it
was also insoluble. In this case, increasing the catalyst loading
did have a slight impact on improving the deuteration at both
Cβ and Cα.
Only poor HDE was observed for a methylene dioxycin-
namic acid (2g), while a dimethoxy cinnamic acid (2h) gave
much higher levels of deuteration. To address potential
insolubility issues, we looked at addition of both CD3OD
and DMSO-d6 as cosolvents to the reaction of 2e and 2a (see
the Supporting Information). Increasing amounts of DMSO-d6
lowered the amount of HDE, while CD3OD dramatically
increased the HDE on 2e, but led to a slight decrease for 2a.
Using a 1:1 mixture of CD3OD/D2O led to improved HDE for
1c, 2d, and 2g, but not for 2c, suggesting 2c’s poor
performance in the HDE reaction may be due to factors
other than solubility.
Since the method could work on a variety of cinnamic acids,
we considered that simpler vinylic acids might also be suitable
substrates. However, performing the transformation on acrylic
acid gave a complex mixture of possibly deuterated products
C
DOI: 10.1021/acs.orglett.9b02618
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Letter
(at least one substrate).27 An internal concerted metalation-
deprotonation step will then lead to C−H activation of the
substrate. The protonated carboxylic acid ligand can then
undergo HDE with the solvent, followed by deuteration of the
Rh−C bond, though direct deuterolysis by solvent is also
plausible. Ligand exchange between deutero and protio
substrates would then be expected to give turnover.
Scheme 4. HDE on the Drug Acetylsalicyclic Acid (0.30
mmol Scale)
a
b
Reaction performed at 80 °C. Reaction performed at 70 °C.
In conclusion, we have developed a simple protocol where
aromatic acids can undergo C−H exchange with deuterium,
using only D2O as a solvent as well as a source of deuterium.
Compared with other methods, this is operationally simple
without the need for D2 gas, or a preinstalled functional group
other than hydrogen to replace with deuterium,28 while
utilizing in most cases attractively low loadings of a readily
commercially available catalyst. Notably, the reaction can be
easily scaled up while maintaining comparable levels of
deuteration, making it useful for affordable scale up. Future
work in this area may focus on developing catalysts capable of
more efficient HDE using fewer equivalents of D2O, HDO, or
even HTO.
with concomitant loss of the Ac group, suggesting that
deuteration from salicylic acid followed by installation of the
Ac group would be preferable to prepare aspirin-6-d.
Interestingly, no exchange was observed at C3 ortho to the
phenol.
To demonstrate scalability, we performed the HDE for 1s
but now at 50 times the initial scale (Scheme 5). Due to the
Scheme 5. Scale-up of the C−H Deuteration of 2-
(Trifluoromethoxy)benzoic Acid and 3-Iodobenzoic Acid
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02618.
1
Experimental details and procedures as well as H, 13C
2
NMR, mass spectrometry, and selected H NMR data
(PDF)
cost of the RhIII catalyst, we performed the reaction using a
reduced catalyst loading (0.25 mol %), and found that
significant deuteration could still be achieved. We also
performed the reaction on 3-iodobenzoic acid at 1.5 mmol
scale, or 10 times the initial scale. This time we used the same
catalyst loading (1 mol %), and found only slight decrease in
the level of deuteration.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michael.young8@utoledo.edu.
ORCID
Michael C. Young: 0000-0002-3256-5562
Notes
We propose for the mechanism (Figure 1) that cationic RhIII
first undergoes ligand exchange to install two eq of carboxylate
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge start-up funding from The University of
Toledo as well as funding from the ACS Herman Frasch
Foundation (830-HF17) in partial support of this work. A.L.G.
wishes to acknowledge funding through The University of
Toledo’s Office of Undergraduate Research (USRCAP).
Zhiqiang (Mark) Wang at the Environmental Analysis Service
Center, University of Cincinnati, is acknowledged for
collecting high-resolution mass spectrometry data. We are
grateful to Dr. Yong-Wah Kim (UToledo) for useful
2
discussions and assistance performing H NMR and to Dr.
Samantha L. Schachermeyer (UToledo) for testing the
reproducibility of this chemistry. Mr. Daniel Liu (UToledo)
is thanked for proofreading the manuscript. ChemRxiv is
acknowledged for posting a preliminary version of this
manuscript as a preprint (8292296).29
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Figure 1. Proposed mechanism for C−H deuteration using RhIII.
D
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