Chemical-Reductant-Free Electrochemical Deuteration Reaction using Deuterium Oxide

Article abstract of DOI:10.1002/anie.202005765

We report a method for the electrochemical deuteration of α,β-unsaturated carbonyl compounds under catalyst- and external-reductant-free conditions, with deuteration rates as high as 99 percent and yields up to 91 percent in 2 h. The use of graphite felt for both the cathode and the anode was key to ensuring chemoselectivity and high deuterium incorporation under neutral conditions without the need for an external reductant. This method has a number of advantages over previously reported deuteration reactions that use stoichiometric metallic reductants. Mechanistic experiments showed that O₂ evolution at the anode not only eliminates the need for an external reductant but also regulates the pH of the reaction mixture, keeping it approximately neutral.

Full text of DOI:10.1002/anie.202005765

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Accepted Article
Title: Chemical-Reductant-Free Electrochemical Deuteration Reaction
using Deuterium Oxide
Authors: Xu Liu, Ruoyu Liu, Jiaxing Qiu, Xu Cheng, and Guigen Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202005765
Link to VoR: https://doi.org/10.1002/anie.202005765

Angewandte Chemie International Edition
10.1002/anie.202005765
RESEARCH ARTICLE
Chemical-Reductant-Free Electrochemical Deuteration Reaction
using Deuterium Oxide
[
a]
[a]
[a]
[a,b]
and Guigen Li[a,c]
Xu Liu, Ruoyu Liu, Jiaxing Qiu, Xu Cheng*,
Dedicated to the 100th anniversary of the School of Chemistry and Chemical Engineering, Nanjing University
[
a]
X. Lu, R. Liu, J. Qiu, J. Dai, Prof. Dr. X. Cheng, Prof. Dr. G. Li. Institute of Chemistry and Biomedical Sciences, Jiangsu Key Laboratory of Advanced
Organic Materials, School of Chemistry and Chemical Engineering, National Demonstration Center for Experimental Chemistry Education, Nanjing
University, Nanjing, 210023, China. E-mail: chengxu@nju.edu.cn
[
[
b]
c]
Prof. Dr. Xu Cheng State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou,
310032, China
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, United States
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein, we report a protocol for electrochemical deuteration
of α,β-unsaturated carbonyl compounds under catalyst- and external-
reductant-free conditions with deuteration rates as high as 99% and
yields up to 91% in 2 h. The use of graphite felt for both the cathode
and the anode was key to ensuring chemoselectivity and high
deuterium incorporation under neutral conditions without the need for
an external reductant. This protocol has a number of advantages over
previously reported deuteration reactions that use stoichiometric
important to develop a protocol could fulfil the deuteration with
D
2
O in the absence of any external reductants.
Organic electrosynthesis recently underwent a dramatic
development and challenge transformations are achieved with
novel mechanism.[12] In these transformations, cathodic hydrogen
evolution is a highly efficient strategy to build molecules without
external oxidant.[ Inspired by these hydrogen evolution arts and
recently advances in electrochemical reduction reactions,[14] we
presumed that an electrochemical deuteration reaction using
deuterium oxide could be achieved without additional reductant.
In this approach, the oxygen could be released by an anodic
oxidation of basic species to fulfil the task as the reductant
alternative under neutral condition (Scheme 1c).
13]
metallic reductants. Mechanistic experiments showed that
O
2
evolution at the anode not only eliminated the need for an external
reductant but also regulated the pH of the reaction mixture, keeping it
approximately neutral.
Introduction
Replacement of hydrogen atom with deuteron brings additional
property and function to molecules. For example, the -
deuterated amino acid (Scheme 1a) was applied as label in
protein for NMR,[1] HDX-MS, X-ray crystallography,[3] and
Raman scattering microscopy.[ Also, -deuterated amino acid
has minimum derivation from its natural counterpart and could
provide enhanced metabolism profile in pharmaceutical
compounds.[ Recently, a number of innovative deuteration
protocols have been established with various deuterium reagents,
[2]
4]
5]
such as D
2
,[6] d6-DMSO,[7] d6-ethanol,[8] d3-acetonitrile,[9] and d6-
benzene.[
10]
2
As D O is the most readily available deuterium
source, the development of deuteration methods using D
directly would be highly desirable.
2
O
A number of arts of direct deuteration of organic molecules
[
11]
with H
2
O/D
2
O have been achieved.
In these cases, external
,[11e] Zn,[11k] Mn,[11m] or 304
[
11b]
reductants, for example Mg,
SmI
2
2
Scheme 1. Deuterated compounds and deuteration with D O as the deuterium
source. EWG: electron withdrawing group.
stainless steel,[11f] were required as electron donor (Scheme 1b).
However, another essential function of these reductants was
underrepresented. As water is the most stable storage of
hydrogen species, utilizing the deuterium in D
O need large Results and Discussion
2
amount energy input. So, it is necessary to couple a highly
energetic reductant to make the reaction happen, which will
produce unwanted basic species and limit functional compatibility.
As the nature uses photosynthesis to produce organic
compounds with only water and carbon dioxide, it is possible and
On the onset of our study, compound 1a bearing a terminal
epoxide was chosen as the model substrate (Table 1). With a
series of optimizations, we could achieve the deuteration of 1a to
saturated ester 2a in 71% yield and 95/97 () D incorporation
1
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
ratio. The epoxide remained intact (entry 1). Next, several
labile under basic hydrolysis conditions, could be obtained in good
yield. A variety of cinnamate-ester-containing natural products
were also subjected to this electrochemical deuteration
transformation. Specifically, L-menthol (2k), borneol (2l),
diacetone-D-glucose (2m), pregnenolone (2n), estrone (2o),
cholesterol (2p), diosgenin (2q), hydroxyl proline (2r), and
stavudine derivatives (2s) were prepared in moderate to good
yields and good deuterium incorporations. Cinnamates with
electron-withdrawing or electron-donating groups on the phenyl
rings gave good yields of the corresponding products (2t–2z)
along with good deuterium ratios. Naphthalene and heterocyclic
moieties were tolerated; good yields of desired compounds 2aa–
2ae were obtained. To our delight, aliphatic -unsaturated
compounds were also compatible with this protocol, furnishing
deuterated esters 2af–2ah, respectively. Trisubstituted esters
could be converted to desired products 2ai–2ak, respectively, in
good yields with high deuterium incorporation. Unsaturated
amides were also compatible substrates, affording 2al–2ap in
good yields with good deuterium incorporation. Substrates with
amine-protecting groups were examined. As expected, a Boc
group in product 2aq was tolerated, and we were pleased to find
that Cbz and alloc groups, which are readily removed under Pd-
catalyzed hydrogenation conditions, remained intact during this
electrochemical reaction (2ar and 2as). Deuterated amides
bearing a variety of functional groups (2at–2ay) were produced in
moderate to good yields with high deuterium incorporation.
Because acids might undergo Kolbe decarboxylation under basic
conditions, we thought it would be informative to test the
behaviour of some unsaturated acids under these conditions, and
we were pleased to find that deuterated acids were stable
throughout the reaction, affording 2az–2bb. No decarboxylative
side products were detected by GC-MS for any of the tested acids.
Three alkyne substrates were tested and found to afford fully
deuterated products 2bc –2be, respectively. A nitrile substrate
reported metal/D
2
O combinations were evaluated with 1a under
respective optimized conditions. It was found by using Pd(OAc)
2
as catalyst and 2.0 equiv Mn as terminal reductant (entry 2), 2a
was obtained in MeCN in 61% NMR yield and the deuterium
incorporation ratio was 22% and 77% respectively. [11m] If DMF
was used instead, Pd(OAc) /Mn/D O combination failed to give
2 2
the desired transformation and the substrate 1a decomposed
completely (entry 3). Other known protocols, such as
[
11k]
[11e]
NiCl
2
/Zn/D
2
O
(entry 4)
2 2
and SmI /D O (entry 5),
decomposed 1a and the reaction mixture turn quite basic. A
11b]
reaction using ZnCl
2
/Mg/D
2
O did not lead to the conversion. [
A
SUS304 ball milling protocol was also evaluated and no
conversion was observed (entry 7). [11f] We also evaluated the
other electrode materials. It is unexpected that Pt cathode did not
give conversion with other conditions remained unchanged (entry
8). When graphite rod was used both anode, the reaction only
gave trance conversion (entry 9). Such unusual anode effect in a
cathodic reduction was also observed recently by Waldvogel and
Rodrigo in their work of electrochemical reduction of nitrones. [14g]
.
Table 1. The comparison of deuteration protocols of substrate 1a
Entry[a]
Conditions[a]
Yield[b]
D
content
c]
(
α/β%)[
1
GF(+)/GF(-),
nBu NBF (0.5 equiv), DMF (5 mL),
V, rt
D
2
O
(20 equiv),
71%
95/97
4
4
6
2
3
4
D
2
O (80 equiv), Pd(OAc)
2
(5 mol%),
52%
22/77
1bf was converted to 2bf with moderate yield and more than one
Mn (2.0 equiv), MeCN (2 mL), rt
deuterium was detected at -position.
D
2
O (80 equiv), Pd(OAc)
2
(5 mol%),
decomposed
decomposed
Subsequently, we explored the synthetic applications of this
electrochemical deuteration reaction (Scheme 3). A series of
deuterium substituted amino acids were prepared (Scheme 3a),
like -amino acid derivative 2bg, -amino acid derivative 2bh, d2-
Mn (2.0 equiv), DMF (2 mL), rt
NiCl
2
6H
2
O
(10 mol%), Zn (2.0
O (3:1), 80 oC
equiv), Dioxane/D
2
DOPA precursor 2bi. A deuterated building block of CCR3
antagonist 2bj was synthesized. [15] With-unsaturated acid as
starting material, a d2-isobuprofen 2bk was prepared for the first
5
6
SmI2, THF/D
2
O (2.0 equiv), rt
decomposed
no reaction
ZnCl
2
(1.5 equiv), Mg (1.5 equiv),
2
time. A single step deuteration protocol with D O was applied to
D
2
O (2 mL)
prepare 2bl, a pharmacore in pain treatment with metabolic
stability enhanced by isotope effect, instead of original patent
deuteration sequence. [16]
2 4
protocol requiring a D O/EtOH/NaBD
7
8
9
SUS304 ball-milling
no reaction
no reaction
trace
Entry 1 with GF(+)/Pt(-)
Entry 1 with graphite rod(+)/GF(-)
Scaled-up syntheses were carried out with -methyl cinnamic
acid (1ba) as the substrate (Scheme 3b). Reactions in which 1ba
was more concentrated than that in Scheme 2 worked well at 15
g scale, giving carboxylic acid 2ba in 60% yield and deuterium
rate was almost identical to that obtained in 0.2 mmol scale.
[
a] conditions: 1a (0.2 mmol)，GF: graphite felt, DMF: N,N-dimethyl formamide,
THF: tetrahydrofuran. [b] isolated yield. [c] content of 100% indicates one D
atom on one carbon of 2a.
Subsequently, 2ba was converted to borane 3 (70%), [ alkyne
17]
[19]
alkyl benzothiazole 6 (47%), [20] and
4
(65%), [18] azide 5 (65%),
With the optimized conditions in hand, we explored the
alkyl caffeine 7 (35%). [ In all these transformations, the loss of
21]
substrate scope of the reaction by testing
unsaturated alkenes and alkynes (Scheme 2). Alkyl cinnamates
b–2i were obtained in good yields with high deuterium
incorporation. We were pleased to find that phenyl 2j, which is
a number of
deuterium was not observed.
2
2
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RESEARCH ARTICLE
Scheme 2 The substrate scope of electrochemical deuteration. [a] Conditions: 1 (0.2 mmol), nBu
4
NBF
4
(0.1 mmol), D
2
O (4.0 mmol), graphite felt (GF) electrodes,
DMF (5 mL), rt, isolated yields. [b] Reaction conditions: 1 (0.2 mmol), LiBF
4
2
(0.5 equiv), D O (40 equiv), GF electrodes, DMF (5 mL).
3
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RESEARCH ARTICLE
Scheme 4. Studies on the reaction species.
On the basis of these findings, a plausible pathway was
proposed in Scheme 5, for example, with 1c as substrate. First,
electron transfer from the cathode converts 1c to anionic radical
2
A, which immediately undergoes deuteration with D O to give
neutral radical B. A second cathodic reduction converts B to anion
C, and a second deuteration generates final product 2c. Because
of the large area and porous structure of the graphite felt cathode,
electron transfer and deuteration are highly concerted, and
therefore the lifetimes of intermediates A, B and C are so short
that side reactions, for example dimerization, do not occur. In
solution, the OD anions is in steady state and undergoes oxidation
Scheme 3. Synthetic applications of the electrochemical deuteration protocol.
BI: benziodoxolone, B pin : bis(pinacolate)diboron, DMSO: dimethylsulfoxide.
2 2
Finally, we carried out some mechanistic experiments. First,
cathodic cyclic voltammetry (CV) of a mixture of D O and ethyl
cinnamate (1c) (Scheme 4a) revealed that with a carbon cathode,
O was inert until −2.5 V (vs saturated calomel electrode, SCE),
2
to release oxygen and D
O might be oxidized directly at anode, giving oxygen, protonic
species and neutralized the basic species forming at cathode
path 2), a process proposed in the production of adiponitrile in
2
O at anode (path 1). Alternatively, the
D
2
D
2
whereas a peak for reduction of 1c was observed at −2.1 V (vs
SCE), suggesting that the reaction is initiated by electron transfer
to the substrate to yield an anionic radical, rather than by
(
divided cell. The overall effect on cathode and anode regulates
the pH not varying significantly.
+
reduction of a proton species, such as D . A square wave
voltammetry (SWV) experiment of 1c showed two separated
peaks, supporting an ECEC pathway. [14f] This possibility was
confirmed by the fact the no trace of hydrogen was detected when
H
2
O was subjected to a 6 V cell potential in the absence of 1c
(
see SI, section 7). In addition, because epoxide, a base-labile
group remained intact during the reaction (Table 1, entry 1), we
measured the pH of the reaction mixture, which did not vary
significantly from neutral (Scheme 4b). Lastly, we examined the
oxygen species generated in this electrochemical reaction using
18O-labelled water. By subjecting the gaseous effluent of a
reaction between 1c and H 1
PPh as a trapping reagent and Et
capture
experiment revealed that the amount of captured 18O was about
8O to a downstream reaction with
B as a catalyst, we could
2
as triphenylphosphine oxide (Scheme 4c). This
2
3
3
Scheme 5. Plausible pathway for electrochemical deuteration.
1
8
O
7
7% of the amount of 2c generated in the reaction; in contrast, if
Conclusion
substrate 1c was omitted from this electrolysis experiment, no 18
O
species were detected.
In summary, we have developed
electrochemical deuteration reactions on graphite felt electrodes.
The reaction used D O as the deuterium source and did not
a
protocol for mild
a) CV and SWV analysis of species in reaction
-0.05
1c
4
0
2
0.00
0.05
0.10
0.15
0.20
0.25
0.30
30
20
10
0
require either a transition-metal catalyst or a stoichiometric
reductant. At cathode, there was a selective reduction of substrate,
other than a hydrogen evolution process; At anode, the oxygen
evolution could not only avoid using of reactive reductant but also
Blank
D O (0.80 M)
2
1
1
c (0.04 M)
c (0.04 M) + D O (0.80 M)
2
-
consume the OD anion and regulate the pH level. Moderate to
-
3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.0
-1.2
-1.6
-2.0
-2.4
-2.8
-3.2
excellent yields and good to excellent deuterium incorporation
V vs SCE
V vs SCE
4
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
were achieved with this protocol. This deuteration reaction could
be scaled up to 15 g with good reproducibility. A number of
deuterated pharmaceutical compounds were prepared by means
of this protocol, and deuterated acid could serve as d2-synthon to
prepare a variety of compounds with no loss of deuterium.
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Acknowledgements
This work was supported by grants from the National Science
Foundation of China (no. 21572099) and the State Key
Laboratory Breeding Base of Green Chemistry-Synthesis
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Angewandte Chemie International Edition
10.1002/anie.202005765
RESEARCH ARTICLE
Entry for the Table of Contents
Insert graphic for Table of Contents here.
The first catalyst-free and chemical-reductant-free deuteration of alkene and alkynes is achieved with electrochemical approach with
graphite felt electrodes and deuterated water in undivided cell under neutral conditions. Up to 99% D incorporation and 91% yield can
be obtained at neutral condition and compatible with electron-rich alkene, heterocycles, epoxide, and protecting groups. A series of
d2- or d4 pharmaceutical compounds are prepared with this protocol.
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