Late-Stage β-C(sp3)-H Deuteration of Carboxylic Acids

Article abstract of DOI:10.1021/jacs.1c06474

Carboxylic acids are highly abundant in bioactive molecules. In this study, we describe the late-stage β-C(sp3)-H deuteration of free carboxylic acids. On the basis of the finding that C-H activation with our catalysts is reversible, the de-deuteration process was first optimized. The resulting method uses ethylenediamine-based ligands and can be used to achieve the desired deuteration when using a deuterated solvent. The reported method allows for the functionalization of a wide range of free carboxylic acids with diverse substitution patterns, as well as the late-stage deuteration of bioactive molecules and related frameworks and enables the functionalization of nonactivated methylene β-C(sp3)-H bonds for the first time.

Full text of DOI:10.1021/jacs.1c06474

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Late-Stage β‑C(sp3)−H Deuteration of Carboxylic Acids
Alexander Uttry, Sourjya Mal, and Manuel van Gemmeren*
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ABSTRACT: Carboxylic acids are highly abundant in bioactive molecules. In this study, we describe the late-stage β-C(sp3)−H
deuteration of free carboxylic acids. On the basis of the finding that C−H activation with our catalysts is reversible, the de-
deuteration process was first optimized. The resulting method uses ethylenediamine-based ligands and can be used to achieve the
desired deuteration when using a deuterated solvent. The reported method allows for the functionalization of a wide range of free
carboxylic acids with diverse substitution patterns, as well as the late-stage deuteration of bioactive molecules and related frameworks
and enables the functionalization of nonactivated methylene β-C(sp3)−H bonds for the first time.
ynthetic methods to introduce heavy hydrogen isotopes
Sinto organic molecules are a key technology. Despite the
apparent simplicity of such exchanges, efficient methods for the
late-stage deuteration of complex substrates are still scarce.1
Deuterated analogs are important in drug discovery processes
with applications including absorption, distribution, metabo-
lism, and excretion (ADME) studies.2 Isotopically labeled
compounds are used as internal standards,3 for the elucidation
of reaction mechanisms,4 as a design element to lower
metabolism rates in pharmacophores,5 and in many further
fields, like the investigation of proteomics6 or medicinal
imaging.7 While for some of these applications a quantitative
deuteration in a distinct position is strictly required, other
applications profit from a predictable regioselectivity, cost and
time efficiencies, and/or high overall deuteration degrees.8
Thus, while the development of deuteration methods should
strive for a maximum of reactivity and selectivity the threshold
defining success varies depending on the application envisaged.
Compared to the introduction of deuterium into arenes,
methods for aliphatic positions are limited.1d For small target
molecules with limited molecular complexity traditional
synthesis using prefunctionalized substrates can be used to
introduce deuterium.9,10 However, these approaches are
limited in their applicability to complex molecules such as
pharmacophores, since they result in multistep, time-
consuming procedures. In this context, the late-stage
deuteration of bioactive molecules becomes highly attractive
Figure 1. (A) Importance of late-stage deuteration. (B) Mechanism of
(Figure 1A). For example, this is evidenced by recent reports
the ligand-enabled carboxylate directed C(sp3)−H activation. Do =
on photocatalyzed deuterations based on HAT processes and
donor, E+ = electrophile. (C) Design of this study.
transition metal catalyzed protocols.11 Further recent reports
include the stereoretentive α-deuteration of amino acids or the
selective stereoretentive deuteration of C(sp3)−H bonds in
benzylic positions.12
Received: June 22, 2021
Published: July 19, 2021
Carboxylic acids are among the most common functional
groups in drug molecules and organic molecules overall.13
Consequently, methods for the regioselective C−H activation/
functionalization of carboxylic acids possess tremendous
application potential. After pioneering work by Yu et al.,14
several research groups developed ligand-enabled trans-
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formations giving access to a range of useful transforma-
tions.15,16 This approach could be extended to distal γ-
C(sp3)−H functionalization reactions17 and enantioselective
transformations using strained rings.18
used for the C(sp3)−H activation of carboxylic acids (Table
1).16b−d,g,17c,18a Ligands L1−L5 gave low but measurable levels
of de-deuteration (entries 2−6). Ethylenediamine-derived
ligand L6 developed by Yu gave the first encouraging result,
with an overall de-deuteration of 11% (entry 7).18 On the basis
of this observation, we prepared a series of ethylenediamine-
based ligands, varying the structure of the amide. In related
studies ethylenediamine ligands bearing the NHAc-protecting
group proved to facilitate the CMD step in enantioselective
arylations of free carboxylic acids.18 We discovered that the
reactivity for the de-deuteration could be increased signifi-
cantly when changing this group to a more bulky isopropyl
substituent L7 (entry 8). Further systematic variation resulted
in highly active ligands L8 and L9 (entries 9 and 10).
Carboxylic acids and derivatives have also been used as
directing groups to enable the ortho-deuteration of aromatic
substrates.19 This includes a report on the ortho-deuteration of
phenylacetic acids derivatives by Yu, in which the authors also
observed the deuteration of the benzylic positions α to the
carboxylic acid,19b presumably through a deprotonation/
reprotonation mechanism. With carboxylic acids as directing
groups (DG), the only reports for the deuterations of
C(sp3)−H bonds have remained limited to heterogeneously
catalyzed protocols for simple fatty acids, enabling an
unselective deuteration under harsh conditions.8,20 Regiose-
lective C(sp3)−H deuterations of carboxylic acid derivatives
were achieved indirectly via exogenous directing groups,21 but
direct regioselective deuterations of free carboxylic acids have
remained elusive to date.
a
Table 1. Ligand Screening
Carboxylate-directed C(sp3)−H functionalizations are de-
scribed to occur via transition state TS-1 in which the ligand
acts as an internal base for the concerted metalation−
deprotonation (CMD) step (Figure 1B).22 The C−H activated
palladacycle 2 can undergo further functionalization with a
range of electrophilic coupling partners. Mechanistic inves-
tigations on such systems showed through de-deuteration
experiments that under suitable conditions the C−H activation
step is reversible.16g,17a−c
We envisioned a deuteration of aliphatic carboxylic acids
based on this mechanism. Key to such a method would be to
reversibly and efficiently form intermediate 2 while at the same
time avoiding side reactions leading to catalyst or substrate
decomposition (Figure 1C). Considering the correlation
between a deuteration of regular substrates in deuterated
solvents and the reverse de-deuteration of labeled compounds
in regular solvents,23 we reasoned that it should be possible to
optimize de-deuteration processes when ultimately aiming to
develop a deuteration method. This generally applicable
strategy offers substantial advantages. In particular, the
optimization studies could be performed with regular solvents
including 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) which we
assumed would be required, due to its well-documented
unique properties in C−H activation processes.24 Screening
would be more robust, because the acidic proton of the
substrate and potential contaminations with proton sources
such as water would exert no detrimental effect. Another
attractive feature is that new catalytic activities could be
uncovered: Since the C−H activation step is separated from
any subsequent transformation, the discovery of catalyst
systems that activate challenging positions is not affected by
the performance of the same catalyst in the subsequent steps of
the model reaction. Such single-step screenings have been used
successfully in the discovery of new photochemical trans-
formations25 and are expected to prove useful in C−H
activation. Finally, taking the kinetic isotope effect (KIE) into
account, catalysts developed in this way should even perform
better when used for deuteration. Importantly, while de-
deuterations have been used to gain mechanistic insights and
drive mechanism-based catalyst improvement,26 to the best of
our knowledge, the proposed screening of reaction conditions
in the reverse reaction has not been reported.
b
b
entry
ligand
yield 4 (%)
de-deuteration (%)
1
2
3
4
5
6
7
8
9
10
none
L1
L2
L3
L4
L5
L6
L7
L8
L9
L9
82
87
91
87
92
91
89
90
93
93
92
<5
<5
<5
<5
<5
<5
11
32
73
80
c
11
68
a
b
Reactions were performed on a 0.1 mmol scale. Yields and degrees
1
of de-deuteration were determined by H-NMR spectroscopy using
c
1,3,5-trimethoxybenzene as internal standard. No Ag2CO3.
Interestingly, the analogous ligand with a simple benzamide
group gave no activity. Presumably, substituents in the 2- and
6-position are required to either force the arene out of the
amide plane, thereby altering the ligand properties, or to
prevent an intramolecular C−H activation leading to catalyst
deactivation. Substitution on the backbone or at the tertiary
amine of the ligands gave no further improvements.27 The
optimized protocol employs catalytic amounts of silver
carbonate. Notably, silver is not essential, although the
reaction proceeds with reduced efficiency in its absence
(entry 11). Silver can thus not be part of the catalyst, but
presumably acts as a Lewis acid accelerating the reaction and/
or as an oxidant preventing catalyst decomposition via Pd(0)
formation.28 A condition-based sensitivity assessment showed
that the method tolerates variations in parameters that
negatively affect many C−H activation methods.27,29
Encouraged by these considerations, we initiated our
investigation by screening ligands classes L1−L6 commonly
We proceeded to investigate the scope of this protocol
(Scheme 1). The carboxylic acid substrates were generally
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a
Scheme 1. Scope of Carboxylic Acids−Structural Variations and Functional Group Tolerance
a
Positions with less than 10% D incorporation are not explicitly depicted but reflected in the DTotal value.27 Light green is used to denote positions
b
in which C−H deuteration is observed and likely to occur through a mechanism other than directed C−H activation. Isolated after esterification.
c
No Ag2CO3.
reisolated in good to excellent yields, the majority of products
being obtained in yields above 70%. We began our
investigation with pivalic acid (5), and the conditions
identified in the de-deuteration screening indeed enabled us
to incorporate very high amounts of deuterium (Dtotal = 7.8).
Substrate 6 with a longer alkyl chain led to an interesting
observation. Besides the expected methyl groups, we also
observed deuterium incorporation in the β-methylene position
with similar efficiency. This is remarkable, since such
nonactivated methylene positions are typically outside the
range of carboxylate-directed C−H activation catalysts. In fact,
to the best of our knowledge, this constitutes the first report on
a Pd-catalyzed β-methylene C−H activation/functionalization
of an unbiased carboxylic acid. TBS-protected alcohol 7 and
remote second carboxylic acid moiety 8 were well-tolerated,
although the second carboxylate was found to hinder
deuteration in the methylene-position.27 With phenyl residue
9, we observed that besides the expected β-methyl- and β-
methylene positions, deuteration also occurred on the arene to
a small extent. Since this arene deuteration cannot be
carboxylate-directed, we investigated the nature of this
nondirected deuteration. Undirected deuterations of arenes
can be catalyzed by Lewis acids or heterogeneous catalysts.30
Multiple experiments indicated that our reaction system is
homogeneous in nature, which implies a Lewis acid catalyzed
deuteration by silver or palladium. With 3,5-trifluoromethly-
ated substrate 10, an aliphatic C−H deuteration was observed
exclusively. Various other carboxylic acids bearing electron-
poor arenes (11−15) gave high levels of deuterium
incorporation (up to Dtotal = 8.5). Deuterium incorporation
occurred in the ortho positions of the arene, presumably
through a carboxylate directed pathway.19b,31 Interestingly, the
remote carboxylate directed deuteration outcompetes weak to
moderate directing groups directly attached to the arene (12,
14, and 15). Phenylacetic acid derivative 16 was deuterated
efficiently even in remote positions (DTotal = 9.2), indicating a
combination of directed and nondirected C−H functionaliza-
tion. Lactic acid derivative 17, a model substrate for drug
molecules of the fibrate class, required a silver-free protocol to
control the degradation of the starting material, and we
obtained the deuterated compound [2H]17 in 69% yield.
Phenylacetic acid (18) underwent isotope exchange in the
ortho positions alongside moderate levels of nondirected
deuteration on the remaining arene and in the relatively acidic
α-position.19b Such deuteration in acidic α-positions has been
observed in the literature and results from simple acid−base
reactions. 2-Methylhexanoic acid (4) showed that the
deuteration of protons in the β-methylene position occurs
diastereoselectively, with the major product resulting from the
reaction via the sterically less encumbered palladacycle (d.r. =
3:1). Analogously, for 1-methyl-1-cyclohexanecarboxylic acid
(19), only the geometrically easily accessible β-methylene
protons underwent H/D exchange. Encouraged by the high
activity of our system toward β-methylene positions, we used
2,2-dipropylpentanoic acid (20) to achieve deuteration
exclusively in such positions. Even for unactivated hexanoic
acid (21), high levels of deuterium incorporation were
observed. Finally, we used isononanoic acid 22 to investigate
the reactivity toward γ-C(sp3)−H positions and observed a
moderate deuterium incorporation.
Next, we applied our method to the late-stage deuteration of
bioactive molecules and related frameworks, for which an
alternative de novo synthesis of a deuterated analog would be
highly challenging (Scheme 2). Using gemfibrozil (23), we
obtained deuterated compound [2H]23 in good yield and
deuteration efficiency. For (+)-camphoric acid (24), we
observed deuteration exclusively in the β-methyl group. For
this substrate, γ-methyl and β-methylene deuteration are
disfavored since the intermediate palladacycles would be
strained bicycles. The Trolox-ether 25 showed good
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a
Scheme 2. Scope of Bioactive Compounds
a
b
Positions with less than 10% D incorporation are not explicitly depicted but reflected in the DTotal value.27 Ligand L9, Ag2CO3 (0.25 equiv).
c
d
Ligand L8, Ag2CO3 (1.0 equiv) Ligand L9, no Ag2CO3.
regioselectivity. OTBS-protected pentacyclic triterpenoid
enoxolone 26 could likewise be deuterated. Interestingly, the
deuteration exclusively occurred in the methyl and the
sterically less hindered methylene positions. Dehydroabietic
acid (27), was selectively deuterated at the β-methyl position.
Ibuprofen 28 could be deuterated under slightly modified
conditions using ligand L8 and increased silver loading.
Ibuprofen analogues flurbiprofen (29), ketoprofen (30), and
fenoprofen (31) could be deuterated with moderate to high
degrees of deuterium incorporation (Dtotal up to 3.9) using
mild reaction conditions. Clofibric acid (32), ciprofibrate (33),
clinofibrate (34), and bezafibrate (35) as representatives for
the fibrate class showed moderate but useful deuterium
incorporation (Dtotal = 1.4−2.2). The herbicide fenoprop
(36) could also be deuterated. Valproic acid (37) delivered the
all-cis deuterated compound [2H]37 as the major diastereomer.
We concluded our investigation using amino acids. (S)-N-
Phthaloyl-protected alanine (38) gave a high degree of β-
methyl deuteration, without a measurable loss of stereo-
chemical information. α-Methylated amino acids such as 39
and 40 are also viable substrates. Finally, simple dipeptide 41
could be deuterated selectively at the C-terminus.32
Scheme 3. Selected Examples Employing D2O as Source of
Deuterium
a
Since the optimized reaction conditions require HFIP-d1 as
source of deuterium, we developed a convenient method for its
synthesis from cheap starting materials.33 Alternatively, our
optimization studies revealed a second set of reaction
conditions based with D2O as deuterium source (Scheme 3).
These conditions enable the hydrogen isotope exchange in
the methyl positions of α-quaternary substrates as well as the
ortho positions of arenes with comparable efficiency. In
contrast, for β-methylene positions and generally for α-
nonquaternary acids, we observed low to moderate degrees
of deuterium incorporation. While these results remain less
a
Positions with less than 10% D incorporation are not explicitly
depicted but are reflected in the DTotal value.27 Ligand L9, Ag2CO3
(0.25 equiv). Ligand L8, Ag2CO3 (1.0 equiv) Ligand L9, no
Ag2CO3.
b
c
d
efficient than the use of HFIP-d1, they may prove useful for
practitioners without access to this solvent. Literature results in
which D2O was replaced with T2O or HTO imply that with
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Int. Ed. 2018, 57, 3022−3047. (d) Valero, M.; Derdau, V. Highlights
of Aliphatic C(sp3)−H Hydrogen Isotope Exchange Reactions. J.
Labelled Compd. Radiopharm. 2020, 63, 266−280.
further optimization our method may be adapted for a late-
stage tritiation of carboxylic acids.34
In summary, we have achieved a regioselective late-stage
C(sp3)−H deuteration of free carboxylic acids. The reaction
was developed using a screening approach in which we first
optimized the reverse reaction, a strategy that we expect will
prove useful for the development of other challenging
transformations. Importantly, we discovered that ethylenedi-
amine-derived ligands with 2,6-disubstituted benzamide groups
as internal base enable unprecedented β-methylene C(sp3)−H
activations of unbiased carboxylic acids. The late-stage
deuteration method developed in this study enables the
isotope labeling of diverse bioactive molecule frameworks and
is thus expected to prove valuable in medicinal chemistry and
organic synthesis.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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Optimization of reaction conditions, preparative proce-
dures, and analytical data for the compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
(4) Simmons, E. M.; Hartwig, J. F. On the Interpretation of
Deuterium Kinetic Isotope Effects in C−H Bond Functionalizations
by Transition-Metal Complexes. Angew. Chem., Int. Ed. 2012, 51,
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Svensson, T. H.; Cenci, M. A.; Schilström, B. Deuterium Substitutions
in the L-DOPA Molecule Improve its Anti-Akinetic Potency without
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Herbst, F.-A.; Schmidt, F.; Richnow, H.-H.; Seifert, J. Insights from
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■
Manuel van Gemmeren − Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Munster, 48149 Munster,
̈ ̈
Germany; orcid.org/0000-0003-3080-3579;
Email: mvangemmeren@uni-muenster.de
Authors
Alexander Uttry − Organisch-Chemisches Institut Westfälische
Wilhelms-Universität Munster, 48149 Munster, Germany
Sourjya Mal − Organisch-Chemisches Institut Westfälische
Wilhelms-Universität Munster, 48149 Munster, Germany
̈
̈
̈
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c06474
Author Contributions
All authors have given approval to the final version of the
manuscript.
Funding
We gratefully acknowledge financial support from the SFB 858,
the Emmy Noether Program and the WWU Mu
Notes
(8) Atzrodt, J.; Derdau, V. 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, 674−685.
(9) (a) Murray, A.; Lloyd Williams, D. Organic Synthesis with
Isotopes, Part 2; Interscience Publishers, 1958. (b) Simon, H.
Deuterium Labeling in Organic Chemistry. In Deuterium Labeling in
Organic Chemistry; Appleton-Century-Crofts, 1971.
̈
nster
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank all members of our MS and NMR department for
their excellent service. We thank S. Bognar, M. Farizyan, and
Dr. M. Letzel for helpful scientific discussions and T.
̈
Dunnebacke for optical rotation measurements. Furthermore,
we thank Prof. F. Glorius for his generous support.
(10) For selected examples, see (a) Fontana, E.; Venegoni, S.
Syntheses of (R,S)-Naproxen and its 6-O-Desmethylated Metabolite
Labelled with 2H. J. Labelled Compd. Radiopharm. 2008, 51, 239−241.
̈
(b) Hsieh, C.-T.; Otvös, S. B.; Wu, Y.-C.; Mándity, I. M.; Chang, F.-
R.; Fulöp, F. Highly Selective Continuous-Flow Synthesis of
̈
Potentially Bioactive Deuterated Chalcone Derivatives. ChemPlu-
sChem 2015, 80, 859−864. (c) Upshur, M. A.; Chase, H. M.; Strick,
B. F.; Ebben, C. J.; Fu, L.; Wang, H.; Thomson, R. J.; Geiger, F. M.
Vibrational Mode Assignment of α-Pinene by Isotope Editing: One
Down, Seventy-One To Go. J. Phys. Chem. A 2016, 120, 2684−2690.
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