ACS Catalysis
Letter
radical sensitive CC (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 CC double bond in 3am is observed.
TEMPO. The product was confirmed by ESI-MS analysis of
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
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sı
* Supporting Information
The Supporting Information is available free of charge at
General information and procedures, cost calculations,
further experimental results, and characterization data
AUTHOR INFORMATION
Corresponding Author
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Wei Wang − Department of Pharmacology and Toxicology,
College of Pharmacy, and BIO5 Institute, University of Arizona,
Tucson, Arizona 85721-0207, United States; orcid.org/
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
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:
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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REFERENCES
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Chem., Int. Ed. 2018, 57, 1758−1784. (b) Yang, J. Deuterium:
Discovery and Applications in Organic Chemistry; Elsevier: Amsterdam,
2229
ACS Catal. 2020, 10, 2226−2230