Formyl-selective deuteration of aldehydes with D2O: Via synergistic organic and photoredox catalysis

Article abstract of DOI:10.1039/c9sc05132e

Formyl-selective deuteration of aldehydes is of high interest for labeling purposes and for optimizing properties of drug candidates. Herein, we report a mild general method for formyl-selective deuterium labeling of aldehydes with D₂O, an inexpensive deuterium source, via a synergistic combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and thiol catalysis. This highly efficient, scalable reaction showed excellent deuterium incorporation, a broad substrate scope, and excellent functional group tolerance and selectivity and is therefore a practical method for late-stage modification of synthetic intermediates in medicinal chemistry and for generating libraries of deuterated compounds.

Full text of DOI:10.1039/c9sc05132e

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Formyl-selective deuteration of aldehydes with
D2O via synergistic organic and photoredox
catalysis†
Cite this: DOI: 10.1039/c9sc05132e
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have been paid for by the Royal Society
of Chemistry
Jianyang Dong, Xiaochen Wang, Zhen Wang, Hongjian Song, Yuxiu Liu
*
and Qingmin Wang
Formyl-selective deuteration of aldehydes is of high interest for labeling purposes and for optimizing
properties of drug candidates. Herein, we report a mild general method for formyl-selective deuterium
labeling of aldehydes with D2O, an inexpensive deuterium source, via a synergistic combination of light-
driven, polyoxometalate-facilitated hydrogen atom transfer and thiol catalysis. This highly efficient,
scalable reaction showed excellent deuterium incorporation, a broad substrate scope, and excellent
functional group tolerance and selectivity and is therefore a practical method for late-stage modification
of synthetic intermediates in medicinal chemistry and for generating libraries of deuterated compounds.
Received 11th October 2019
Accepted 4th December 2019
DOI: 10.1039/c9sc05132e
rsc.li/chemical-science
via deoxygenative deuteration with synergistic photoredox and
organic catalysis (Scheme 1A).12 In terms of atom- and step-
Introduction
economy, the ideal protocol for preparing deuterated
Deuterium labeling has a range of applications, including in the
investigation of reaction mechanisms1 and the analysis of drug
absorption, distribution, metabolism, and excretion,2 as well as
in nuclear magnetic resonance spectroscopy3 and mass spec-
trometry.4 In recent years, interest in the incorporation of
deuterium atoms into patented drugs and drug candidates to
enhance their metabolism and pharmacokinetic properties has
burgeoned.5 In 2017, the US Food and Drug Administration
approved the rst deuterated drug, deutetrabenazine (Aus-
tedo),6 and the increasing demand for new deuterium-labeled
drugs has motivated the development of efficient deuteration
methods.7
Aromatic aldehydes are oen used as building blocks for
pharmaceutical synthesis owing to their versatile reactivity;8
indeed, they can be rapidly transformed to other compounds
via C–C and C–X bond forming reactions. The development of
an efficient protocol for constructing formyl-deuterated
aromatic aldehydes can be expected to increase the avail-
ability of deuterated lead compounds. Aromatic aldehydes
selectively labeled at the formyl position are traditionally
produced from the corresponding esters by means of reduc-
tion with LiAlD4 followed by oxidation,9 from the corre-
sponding amides by reaction with deuterated Schwartz's
reagent (obtained from LiAlD4),10 from aryl halides via Pd/Rh-
cocatalyzed reductive carbonylation,11 or from carboxylic acids
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin
300071, People's Republic of China. E-mail: wangqm@nankai.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9sc05132e
Scheme 1 Strategies for synthesizing deuterated aldehydes; (A) previous
methods to produce deuterated aldehydes through FG transformation;
(B) hydrogen isotope exchange (HIE) to produce deuterated aldehydes;
(C) hypothesis for the proposed deuteration; (D) our work.
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aromatic aldehydes would be direct hydrogen isotope
exchange (HIE) at the formyl C–H bond. In fact, a few protocols
for Ir- and Ru-catalyzed HIE at the formyl moiety have been
reported, although there is an intrinsic difficulty in controlling
the reactivity of the aryl ring moiety and formyl moiety
(Scheme 1B).13 Moreover, late-stage introduction of deuterium
into structurally complex aldehydes remains a challenge.
Given the importance of deuterated aldehydes, we were
interested in developing a method for efficient, atom- and
step-economical HIE with the goal of achieving formyl-
selective labeling of aldehydes with D2O, which is an inex-
pensive deuterium source. In addition, we wanted the new HIE
method to be useful for late-stage introduction of deuterium
into structurally complex aldehydes.
Visible-light-mediated photoredox catalysis has recently
emerged as a method for achieving organic transformations via
radical processes.14 Recently, MacMillan's group reported direct
HIE at a-amino C(sp3)–H bonds via a pathway involving
abstraction of a deuterium atom from a deuterium-labeled thiol
catalyst by an a-amino radical.15 We hypothesized that genera-
tion of acyl radicals from aldehydes by a hydrogen atom transfer
(HAT) photocatalyst in the presence of D2O and a thiol catalyst
would produce deuterated aldehydes.
Results and discussion
The proposed mechanism for formyl-selective deuteration of
aldehydes is shown in Scheme 2. In this mechanism photoex-
citation of tetrabutylammonium decatungstate (TBADT, 2) fol-
lowed by intersystem crossing produces triplet excited state 3,
which has a lifetime of 55 ns.19 Subsequent selective abstraction
of the formyl H atom of 2-naphthaldehyde (1a) affords singly
reduced decatungstate 4 and reactive nucleophilic formyl
radical 5. At the same time, thiol HAT catalyst 7 undergoes
exchange with D2O to give deuterated thiol 8, which serves as
the source of deuterium. Because of the gap between the re-
ported BDEs for typical formyl C–H and thiol S–H bonds, we
reasoned that HAT between polarity-matched radical 5 and
deuterated thiol 8 would furnish deuterated aldehyde 10a and
electrophilic thiol radical 9 [C(]O)–H BDE ¼ 94 kcal molꢀ1
;
S–H BDE ¼ 80 kcal molꢀ1 for 7]. The two catalytic cycles
converge when reduced decatungstate 4 undergoes a single-
electron transfer reaction with thiol radical 9 to regenerate
active HAT photocatalyst 2 and thiol HAT catalyst 7.
To test our mechanistic hypothesis, we began by exploring
deuteration reactions of 2-naphthaldehyde (1a) under various
conditions (Table 1). First, several thiol catalysts were screened
in the presence of 4 mol% of commercially available TBADT as
the HAT photocatalyst in 1 : 1 (v/v) dichloromethane/D2O under
irradiation with near-ultraviolet light (36 W 390 nm light-
emitting diodes; see the ESI†). To our delight, 2-naph-
thaldehyde (10a) with 94% deuterium incorporation was ob-
tained when 2,4,6-triisopropylbenzenethiol (7a, 40 mol%) was
used as the thiol catalyst (entry 1). Under the same conditions,
other thiols gave considerably lower deuterium incorporation
percentages (entries 2–4). The use of N-methyl-2-pyrrolidinone,
acetonitrile, or chloroform as the cosolvent also led to
decreased deuterium incorporation (entries 5–7). Reducing the
amount of TBADT or thiol 7a slightly decreased the deuterium
incorporation percentage (entries 8 and 9). Control experiments
showed that the reaction failed to proceed in the absence of the
HAT photocatalyst, the thiol catalyst, or light (entries 10–12).
With the optimized conditions in hand, we elucidated the
scope of the transformation with respect to the aldehyde.
Deuterated 2-naphthaldehyde 10a was isolated in 92% yield
We envisioned that polyoxometalates, many of which
possess high-energy excited states that can accomplish the
desired C–H abstraction,16 would be ideal HAT catalysts for the
proposed transformation. We were particularly interested in
the decatungstate anion ([W10O32]
4ꢀ), an efficient HAT pho-
tocatalyst that has been widely used for oxygenation, dehy-
drogenation, conjugate addition, and, more recently,
uorination and arylation of strong, unactivated aliphatic C–H
bonds, which have bond dissociation energies (BDEs) of up to
100 kcal molꢀ1 (for cyclohexane).17 To our knowledge, visible-
light polyoxometalate-facilitated HAT has not previously been
synergistically merged with thiol catalysis. Because aldehydes
have relatively low BDEs (94 kcal molꢀ1),12 we envisioned that
such a combination of catalytic processes would afford access
to a considerable variety of acyl radicals and deuterated alde-
hydes from abundant aldehyde feedstocks (Scheme 1C).
Moreover, owing to the gaps between the BDEs of C(]O)H
bonds (94 kcal molꢀ1), aryl C–H bonds (113 kcal molꢀ1), and
S–H bonds (80–88 kcal molꢀ1), the decatungstate anion
([W10O32]
4ꢀ) would be unable to abstract a hydrogen atom
from the aryl C–H bond,17g allowing us to achieve formyl
labeling without the formation of aryl-labeled by-products
(Scheme 1C). In contrast, the nucleophilic acyl radical would
readily undergo HAT from the thiol catalyst to form a deuter-
ated aldehyde, owing to the gap between the BDEs of the C–H
and S–H bonds and a polarity matching effect (Scheme 1C).18
We recognized that the choice of a suitable thiol catalyst would
be heavily inuenced by thermodynamic factors, particularly
the BDE of the thiol bond relative to that of the acyl C–H bond,
as well as its pKa relative to that of water. Herein, we describe
a general strategy for formyl-selective deuteration of aldehydes
with D2O mediated by the synergistic combination of light-
driven, polyoxometalate-facilitated HAT and thiol catalysis
(Scheme 1D).
Scheme 2 Proposed mechanism.
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Table 1 Optimization of conditions for the catalytic formyl-selective
smoothly transformed into the corresponding deuterated
aldehydes (10p and 10q). Moreover, electron-rich aldehydes
were also reactive (10r–10v, 88–95% deuterium incorporation).
Intriguingly, several relatively sensitive yet versatile functional
groups—boronic esters (10w and 10x), an alkyne (10y), and an
alkene (10z)—tolerated the deuteration conditions well, which
shows the potential utility of this protocol for synthetic and
medicinal chemistry applications. Polysubstituted aldehydes
were also suitable substrates (10aa and 10bb). Being aware of
the important role of heteroaromatic moieties in the scaffolds
of pharmaceutical compounds, we were pleased to nd that N-
and S-heterocycles were also tolerated under our deuteration
conditions (10cc–10gg). In addition, the reaction was amenable
to scale up; when it was carried out on a 9 mmol scale, 10i was
isolated in 93% yield with no decrease in deuterium
incorporation.
In addition to aromatic aldehydes, aliphatic aldehydes are
also interesting because they constitute an even greater part of
the –CHO family. However, few radical-based tools for conve-
nient modication of aliphatic aldehydes have been developed.
This is particularly true for branched aldehydes, which tend to
undergo decarbonylation under radical conditions.22 However,
when we subjected linear and branched aldehydes to our
protocol, we found that all of them underwent formyl deutera-
tion to afford the desired products (10hh–10mm, 90–98%
deuterium incorporation), and no products of CO dissociation
were observed. However, a limitation of this reaction was also
uncovered. That is, deuteration also takes place at the a-posi-
tions of formyl.
deuteration reactiona
Entry
Deviation from standard conditions
Deuterationb (%)
1
2
3
4
5
6
7
8
None
94
63
71
78
13
38
62
77
80
<5
<5
<5
7b instead of 7a
7c instead of 7a
7d instead of 7a
NMP instead of DCM
MeCN instead of DCM
CHCl3 instead of DCM
2 mol% of TBADT
20 mol% of 7a
No TBADT
9
10
11
12
No 7a
No light
a
Reaction conditions, unless otherwise noted: 1a (0.3 mmol), TBADT
(0.012 mmol), 7a (0.12 mmol), and 1 : 1 (v/v) DCM/D2O (3.0 mL) under
b
an Ar atmosphere. Deuterium incorporation was determined by
integration of the residual formyl proton in the 1H NMR spectrum.
DCM ¼ dichloromethane and NMP ¼ N-methyl-2-pyrrolidinone.
This excellent functional group tolerance suggested that
the protocol would be useful for the synthesis of structurally
complex deuterated aldehydes, and indeed we were pleased to
nd that deuterated aldehydes derived from menthol, preg-
nenolone, ibuprofen, and fenbufen derivatives (10nn–10qq)
could be accessed with uncompromised reactivities. In addi-
tion, the reaction of adapalene, an antiacne drug, afforded
corresponding deuterated aldehyde 10rr with high deuterium
incorporation. These examples conrmed the potential utility
of our protocol for practical late-stage modication of
synthetic intermediates in medicinal chemistry applications
(Table 2).
Because aldehydes are versatile functional groups that
undergo a wide variety of organic transformations, the protocol
reported herein can be used to access libraries of deuterated
compounds (Scheme 3A). For example, deuterium-labeled
aldehyde 10i readily underwent reduction, reductive amina-
tion, and Horner–Wadsworth–Emmons olenation to deliver
deuterated alcohol 11, deuterated amine 12,7a and b-deuterated,
a,b-unsaturated ester 13. Importantly, 13 has not been accessed
by direct labeling of the corresponding cinnamate ester.23
Deuterium could also be incorporated into pharmaceutical
molecules and advanced materials, as indicated by the
successful Suzuki coupling reaction of 10i to afford 14 and the
Sonogashira coupling reaction of 10i to provide 15, which is
difficult to obtain by currently available methods.
aer purication by column chromatography, indicating that
decomposition and side-product formation were minimal. 6-
Methoxy-2-naphthaldehyde was also a suitable substrate, giving
10b in 90% yield with 92% deuterium incorporation. 1-Naph-
thaldehyde gave a product (10c) with lower deuterium incor-
poration (90%) than 10a, presumably because the 1-position is
more sterically hindered than the 2-position. We also tested
benzaldehydes bearing substituents with various electronic and
steric properties to obtain deuterated products 10d–10bb.
Specically, benzaldehydes with electronically neutral func-
tional groups, such as isopropyl, t-butyl, and phenyl, worked
well under the optimal conditions, giving high yields with
excellent deuterium incorporation (10d–10f, 93%). Halogenated
molecules account for approximately 50% of the market-leading
drugs because they are less susceptible to oxidation by cyto-
chrome P450.20 Furthermore, they offer a valuable platform for
generating molecular complexity through cross-coupling reac-
tions.21 Therefore, we were encouraged to nd that benzalde-
hydes bearing uoro, chloro, bromo, and iodo atoms gave the
corresponding products (10g–10k) with high deuterium incor-
poration (90–96%). Triuoromethyl and triuoromethoxy
groups, which have oen been shown to improve the activity of
pharmaceutical leads, were compatible with our protocol,
showing good deuterium incorporation (10l–10o, 95–97%)
regardless of their position on the benzene ring. Benzaldehydes
with other electron-withdrawing groups (ester and cyano) were
In a further demonstration of the utility of this catalytic
formyl-deuteration method, we used it to synthesize silyl-
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Table 2 Exploration of substrate scopea
a
Reactions were performed on a 0.3 mmol scale, unless otherwise noted. b Some sites in compounds 10hh, 10jj, 10kk, 10ll and 10mm (shown in
their structures, with the deuteration percentage in square brackets) are deuterated. Isolated yields are given. See the ESI for experimental details.
1
Deuterium incorporation was determined by integration of the residual formyl proton in the H NMR spectra.
protected phenol 10tt, which is an intermediate in the synthesis 10tt, which employs stoichiometric quantities of reagents and
of enantiopure d1-benzyl alcohols, in a single, high-yielding step requires ve steps from aldehyde 1ss.24
and with a high deuterium incorporation from aldehyde 1tt
Having explored the substrate scope and utility of the
(Scheme 3B).24 This method is superior to the existing route to reaction, we conducted mechanistic studies to support the
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light and recuperation of reactivity on further illumination
(Fig. S3†). This indicates that light was essential for this
transformation, and any chain propagation process should be
short-lived.
Conclusions
In conclusion, we have developed a mild protocol for selective
direct HIE at the formyl C–H bonds of both aromatic and
aliphatic aldehydes with D2O as an inexpensive deuterium
source mediated by synergistic visible-light polyoxometalate-
facilitated HAT catalysis and thiol catalysis. The high effi-
ciency, broad substrate scope, excellent functional group
tolerance, and mild conditions make this protocol practical for
late-stage modication of pharmaceutical intermediates and for
obtaining libraries of deuterated compounds.
Conflicts of interest
Scheme 3 Transformations of deuterated aldehyde 10i and improved
synthetic route to deuterium-labeled aldehyde 10tt; (A) 10i is used to
access libraries of deuterated compounds; (B) improved synthetic
route to deuterium-labeled aldehyde 10tt.
There are no conicts to declare.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21732002 and 21672117) and the PhD Candidate
Research Innovation Fund of the College of Chemistry, Nankai
University for generous nancial support for our research.
proposed pathway shown in Scheme 2. When radical scav-
enger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was
present in the reaction mixture, deuterium incorporation was
markedly decreased (to 10%), and the radical-trapping
product 2,2,6,6-tetramethylpiperidin-1-yl-2-naphthoate (16)
was isolated in 12% yield (Scheme 4A). When benzyl acrylate
(17) was used as a radical scavenger, benzyl 4-(naphthalen-2-
yl)-4-oxobutanoate-2-d (18) was isolated (Scheme 4B). These
results suggest that acyl radical 5 was generated. When we
used 4-pyridinecarboxaldehyde (1uu) as the substrate, we
isolated by-product 19 (84% yield), which was generated by
a radical coupling reaction of acyl radical 20 and thiol radical
21 (Scheme 4C). These experiments clearly point to a radical
pathway. Furthermore, the light on/off experiments illustrated
a total interruption of the reaction process in the absence of
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