Deuteration of Formyl Groups via a Catalytic Radical H/D Exchange Approach

Article abstract of DOI:10.1021/acscatal.9b05300

H/D exchange at formyl groups represents the straightforward approach to C-1 deuterated aldehydes. This transformation has been recently realized by transition metal and NHC carbene catalysis. Mechanistically, all of these processes involve an ionic pathway. Herein, we report a distinct photoredox catalytic, visible light mediated neutral radical approach. Selective control of highly reactive acyl radical in the energy barrier surmountable, reversible reaction enables driving the formation of deuterated products when an excess of D₂O is employed. The power of the H/D exchange process has been demonstrated for not only aromatic aldehydes but also aliphatic substrates, which have been difficult in transitional metal catalyzed H/D exchange reactions, and for selective late-stage deuterium incorporation into complex structures with uniformly high deuteration level (>90%).

Full text of DOI:10.1021/acscatal.9b05300

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Letter
Deuteration of Formyl Groups via a Catalytic Radical H/D Exchange
Approach
Yueteng Zhang, Peng Ji, Yue Dong, Yongyi Wei, and Wei Wang*
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ABSTRACT: H/D exchange at formyl groups represents the
straightforward approach to C-1 deuterated aldehydes. This trans-
formation has been recently realized by transition metal and NHC
carbene catalysis. Mechanistically, all of these processes involve an ionic
pathway. Herein, we report a distinct photoredox catalytic, visible light
mediated neutral radical approach. Selective control of highly reactive
acyl radical in the energy barrier surmountable, reversible reaction
enables driving the formation of deuterated products when an excess of
D2O is employed. The power of the H/D exchange process has been
demonstrated for not only aromatic aldehydes but also aliphatic substrates, which have been difficult in transitional metal catalyzed
H/D exchange reactions, and for selective late-stage deuterium incorporation into complex structures with uniformly high
deuteration level (>90%).
KEYWORDS: aldehyde, deuteration, H/D exchange, photoredox, radical reaction
mong isotopes, deuterium perhaps has the broadest
impact on almost every subdiscipline in the life, chemical,
b) mainly work for aromatic aldehydes. More recently, we13
and Bertrand and Yan14 have developed more efficient NHC
carbene promoted HDE processes (Scheme 1c). Mechanisti-
cally, all of these HDE transformations rely on the ionic
reaction pathway.
A
material, and nuclear sciences and beyond.1 The recent surge
in applications of deuterated pharmaceutical agents has been
witnessed by the FDA approval of the first deuterated drug,
Austedo (deutetrabenazine), in 20172 and the large number of
emerging deuterated drug candidates.1c,d,2,3 This has spurred
considerable interest in developing synthetic methods that
enable efficient generation of deuterated building blocks.4,5
Given the broad availability and synthetic versatility of
aldehydes, C-1 deuterated aldehydes can provide quick access
to a wide range of highly valued and structurally diverse
deuterated building blocks and to pharmaceutically relevant
structures.6 Several methodologies have been reported for their
synthesis (Scheme 1). Conventional methods rely on the
reduction and/or oxidation sequence but use expensive
A radical process for direct HDE offers an alternative route.
Implementing the distinct neutral radical process for direct
HDE requires the in situ generation of an aldehyde derived acyl
radical. A process using acyl radical as a key intermediate has
been nicely realized by Xie and coworkers for the synthesis of
C-1 deuterated aldehydes (Scheme 1a).10 In their studies, acyl
radicals are produced from carboxylic acid precursors using
visible light mediated photoredox deoxygenation with
phosphines. Furthermore, direct abstraction of formyl hydro-
gen with photoredox strategy has been successfully used by
Glorius and us for new bond formation recently.15,16 These
processes, involving new bond connection, are generally
kinetically controlled and irreversible. It is recognized that
the realization of the reversible acyl radical17 involved
chemistry for HDE process must overcome the challenge
that the control of intrinsic reversibility enables manipulation
of the equilibrium to achieve synthetically useful yields of the
desired product. Moreover, achieving the thermodynamic
control process could be complicated by an undesired
7
deuterated reducing agents such as LiAlD4 and Cp2ZrDCl.8
Recently, more cost-effective approaches using cheap, safe, and
readily handled D2O as the deuterium source have been
elegantly realized from aryl iodides,9 carboxylic acids,10 or
benzyl halides11 by Denmark, Xie, and Sheng, respectively
(Scheme 1a). Direct hydrogen−deuterium exchange (HDE)
processes with aldehydes without requiring additional func-
tional group transformation represent an even more syntheti-
cally efficient strategy. Tuttle and Newman12 independently
reported Ir and Ru catalyzed HDE reactions (Scheme 1b).
Despite these impressive studies, it is recognized that
significant synthetic challenges are associated with the difficulty
of controlling chemoselectivity of nonselective deuteration of
aromatic rings and the unsatisfactory deuteration level (14−
84%). Furthermore, the reported protocols (Schemes 1a and
Received: December 9, 2019
Revised: January 21, 2020
Published: January 23, 2020
https://dx.doi.org/10.1021/acscatal.9b05300
© XXXX American Chemical Society
ACS Catal. 2020, 10, 2226−2230
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Letter
Scheme 1. Methods for the Synthesis of C-1 Deuterated
Aldehydes
Scheme 2. A Plausible Mechanism
Table 1. Optimization of the Reaction Conditions
decarbonylation process (Scheme 2).18,19 Studies indicate that
the decarbonylation process is unfavored.20 With these in
mind, it is possible to realize the strategy of combining a
thermodynamic approach with the use of one of the reaction
components in a large excess. Furthermore, the stronger C−D
bond (bond dissociation energy (BDE) of C−H as 338 kJ/mol
and C−D as 341.4 kJ/mol) also could enhance the C−D bond
formation. The investigation from MacMillan and coworkers of
an elegant photoredox mediated hydrogen isotope exchange
(HIE) for selective deuteration and tritiation of α-C−H bonds
of amines made our new HDE with a formyl group possible.5b
Herein, we report the results of the study which lead to a
visible light mediated photoredox catalytic H/D exchange at
formyl groups (Scheme 1d). In the preparation of this
manuscript, a similar work was reported by Wang and
coworkers.21
Our investigation began with a model deuteration reaction
of p-tolualdehyde with D2O in the presence of a photocatalyst
and a hydrogen atom transfer (HAT) catalyst. 9,10-
Phenanthrenequinone 2a used as a HAT photocatalyst in
our previous study16 gave 23% deuterium incorporated
product 3a (Table 1, entry 2). Switching to the photoredox
catalytic system of 4CzIPN as photosensitizer (PS) and methyl
2-mercaptoacetate 2b as HAT gave slightly improved
deuterium incorporation (40%, Table S1), but the results
were not reproducible. In our extensive reaction optimization
effort (Table S1), we accidently found that an impurity of
sodium dodecyl sulfate (SDS) from the detergent contami-
nated reaction flask could generate reproducible results (40%
D incorporation). We surmised that SDS might serve as a
more effective HAT. Glorius et al. found that benzoyloxy
radical PhCOO•, produced from PhCO2Na in the presence of
e
b
d
entry
variation of standard conditions
none
yield (%)
D ratio (%)
a
c
1
95 (91 )
89
97
23
95
82
16
<5
<5
<5
<5
ND
2
3
2a instead of 4CzIPN and PhCO2Na
2b instead of 2d
87
4
2c instead of 2d
91
5
6
7
MeCN instead of EtOAc
DMF instead of EtOAc
without PhCO2Na
93
94
93
8
without 2d
93
9
10
no light or no photocatalyst
open to air
95
<5
a
Standard reaction conditions: 1a (0.2 mmol), 4CzIPN (5 mol %),
sodium benzoate (30 mol %), 2d (30 mol %), D2O (40 equiv),
anhydrous EtOAc (0.2 M), 5 W blue LED strip, N2, 36 h. Isotope
exchanged 2d of 1 M anhydrous EtOAc solution was prepared by
following procedure: dissolve 2d (1.0 mmol) in 1.0 mL of anhydrous
EtOAc followed by adding D2O (10 mmol, 1/10 molar ratio of 2d/
D2O); after 1 h stirring, the top EtOAc layer was separated and used
b
c
d
in the reaction. 1H NMR yield. Isolated yield. D (deuteration) %
e
determined by 1H NMR. All solvents are anhydrous. ND: not
detected.
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Letter
a
a PS, could selectively and efficiently abstract the hydrogen
atom from the formyl group.15 Therefore, we probed
PhCO2Na. To our delight, a level of 95% D-incorporation
and 87% yield were obtained (entry 3). Without PhCO2Na,
almost no deuteration product was detected (entry 7).
Screening of thiol HAT catalysts revealed triisopropylsilane-
thiol 2d to be optimal one (entry 1 vs 3 and 4) and variation of
reaction media led to the choice of ethyl acetate (entry 1 vs 5
and 6). In control studies, HAT 2d (entry 8), light, and
photocatalyst (entry 9) are necessary for the deuteration
process. When the reaction is open to air, p-tolualdehyde was
oxidized to benzoic acid (entry 10). The efforts on the
optimization of the reaction led to the optimal reaction
conditions as follows: 4CzIPN (5 mol %) as photoredox
promoter, PhCO2Na (30 mol %) and triisopropylsilanethiol
(2d, 30 mol %) as HAT and D2O (40 equiv) in anhydrous
EtOAc (0.2 M) by 5 W blue LED strip under N2 at rt. To
reduce the introduction of extra protium in the reaction as
much as possible, isotope exchanging of 2d was performed by
stirring 2d solution of anhydrous EtOAc with 10 equiv D2O
for 1 h.
Scheme 3. Reaction Scope for Aromatic Aldehydes
Based on these results, a possible reaction mechanism is
proposed (Scheme 2). Irradiation of photocatalyst 4CzIPN by
visible light generates the excited state 4CzIPN*, which
oxidizes sodium benzoate 5 to give benzoyloxy radical 7 for a
subsequent HAT. The key acyl radical 4 is formed by
abstraction of a hydrogen from aldehyde precursor 1. Then,
the second HAT process between resulting acyl radical 4 and
deuterated thiol 10 delivers deuterated aldehyde product 3 and
concurrent generation of thiyl radical 8. Finally, the thiyl
radical is reduced by the 4CzIPN•− to give the thiolate 9 and
4CzIPN to complete the redox cycle. The more basic thiolate
anion 9 serves as an internal base to deprotonate the benzoic
acid (pKa = 10) to regenerate HAT catalysts 5 and 2d. The
latter HAT catalyst can be transformed to deuterated thiol 10
by HDE with D2O. It is also possible that 9 can be directly
protonated to give 10.
a
See the Supporting Information for detailed reaction conditions.
1
Isolated yields (Y); D% determined by H NMR spectroscopy.
a
Scheme 4. Reaction Scope for Aliphatic Aldehydes
With the optimized protocol in hand, the scope of the
deuteration process was probed. The methodology serves as a
mild, general approach for the synthesis of a wide array of
deuterated aromatic aldehydes in good yields (up to 99%) and
with uniformly high levels (90−98%) of deuterium incorpo-
ration (Scheme 3). In general, the substrates of aromatic ring
containing electron donating groups (MeO, AcO, AcHN,
morpholine) gave slightly better results. It is believed that their
enhancement in the nucleophilicity of acyl radical provides
higher reactivity in the electrophilic HAT process. Notably,
various functional groups such as free hydroxy (3j and 3k),
halogen substituents (3g, 3h, 3i), ester (3l, 3s), and allylic
(3m) can be tolerated by the deuteration protocol. Moreover,
heteroaromatic aldehydes underwent deuteration smoothly to
afford desired products (3p, 3q, 3r).
Having demonstrated the capacity of the aromatic aldehydes
to participate in this radical engaged deuteration process, we
turned our attention to aliphatic aldehyde substrates, which
have remained an unsolved synthetic challenge for their C-1
deuteration (Scheme 4). Gratifyingly, aliphatic aldehydes are
competent substrates, affording the corresponding C-1
deuterated products (3t−3aa) in 52−99% yields and with
uniformly high level of D-incorporation (93−98%) under the
optimized mild reaction conditions (Scheme 3). It is
noteworthy that under the mild reaction conditions, the
formation of decarbonylated side products is minimized.
a
See the Supporting Information for detailed reaction conditions.
1
Isolated yields (Y); D% determined by H NMR spectroscopy.
Nonetheless, in many cases, D-incorporation into other acidic
C−H positions, in particular the enolizable α-position, is
observed. Again, a wide array of functional groups such as
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radical sensitive CC (3aa, 3am), amide (3ab), ketone (3ac),
ester (3ad), and cyanide (3ae and 3af) are tolerated.
Moreover, the reaction can be applied to generate aliphatic
deuterated aldehydes, which contain synthetically and bio-
logically relevant heterocycles, including pyridine (3ag), indole
(3ah), furan (3ai), thiophene (3aj), and pyrimidine (3ak).
Finally, aliphatic aldehydes bearing long chain also work
smoothly (3al and 3am). It is found that isomerization of the
cis CC double bond in 3am is observed.
TEMPO. The product was confirmed by ESI-MS analysis of
the crude reaction mixture (Scheme 5d) (SI, Section 6).
In summary, we developed a visible light mediated,
organocatalyzed HDE process for directly converting readily
accessible aldehydes to their 1-deutero counterparts using D2O
as the deuterium pool. Distinct from the established transition
metal catalyzed ionic HDE processes, this organophotoredox
catalytic radical strategy was successfully realized. Notably, this
approach not only enables direct HDE of aromatic aldehydes
without deuteration on the aromatic ring but also for aliphatic
aldehydes and selective late-stage deuterium incorporation into
complex structures with uniformly high level (>90%) of
deuterium incorporation. We anticipate that the approach will
enable facile access to a wide range of deuterated structures,
which are highly valuable in the fields of biological, medicinal,
and organic chemistry.
The capacity of the mild deuteration methodology is also
demonstrated in selective C-1 deuteration of aldehyde
functionality in complex pharmaceutically relevant structures
(Scheme 5a). Native ursodeoxycholic aldehyde, mycophenolic
Scheme 5. Deuteration of Aldehyde Moiety in Structurally
Complex Structures, Gram Scale Synthesis, Recycling and
a
Reuse of D2O, and Intermediate Trapping Study
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.9b05300.
General information and procedures, cost calculations,
further experimental results, and characterization data
for compounds 3 (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Wei Wang − Department of Pharmacology and Toxicology,
College of Pharmacy, and BIO5 Institute, University of Arizona,
Tucson, Arizona 85721-0207, United States; orcid.org/
0000-0001-6043-0860; Email: wwang@
pharmacy.arizona.edu
Authors
Yueteng Zhang − Department of Pharmacology and Toxicology,
College of Pharmacy, and BIO5 Institute, University of
Arizona, Tucson, Arizona 85721-0207, United States
Peng Ji − Department of Pharmacology and Toxicology, College
of Pharmacy, and BIO5 Institute, University of Arizona,
Tucson, Arizona 85721-0207, United States
Yue Dong − Department of Pharmacology and Toxicology,
College of Pharmacy, and BIO5 Institute, University of
Arizona, Tucson, Arizona 85721-0207, United States
Yongyi Wei − Department of Pharmacology and Toxicology,
College of Pharmacy, and BIO5 Institute, University of
Arizona, Tucson, Arizona 85721-0207, United States
a
See the Supporting Information for detailed reaction conditions.
1
Isolated yields (Y); D% determined by H NMR spectroscopy.
aldehyde, and marketed drug indomethacin derived aldehydes
are selectively deuterated in good yield and with high
deuteration (3an−3ap). Furthermore, ribose amino acid
tryptophan and dipeptide Phe-Gly aldehyde derivatives can
be labeled by deuterium with high level deuterium decoration
(91−96%, 3aq−3as).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.9b05300
The method can be used in a gram-scale synthesis of C-
1deuterated aldehydes. In comparison to the small-scale
process, as shown using p-tolualdehyde 1a as an example,
the gram-scale counterpart 3a is formed in a similar yield and
with a comparable level of D-incorporation, although reduced
amounts of reagents and catalysts (only 20 equiv of D2O, 1.5
mol % 4CzIPN, 20 mol % PhCO2Na, and 8 mol %
triisopropylsilanethiol) are used (Scheme 5b). Furthermore,
the recovered D2O containing solvent can be used in a second
and third reaction without causing a significant decrease in
yield and D-incorporation level (Scheme 5c). These studies
demonstrate that the cost for the synthesis of deuterated
aldehyde products can be further reduced. Finally, to verify the
proposed mechanism, the formed acyl radical was trapped by
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support was provided by the NIH (5R01GM125920-
03).
■
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