A selective and cost-effective method for the reductive deuteration of activated alkenes

Article abstract of DOI:10.1016/j.tetlet.2017.05.092

A new single electron transfer reaction for the reductive deuteration of activated alkenes has been developed for the selective synthesis of α,β-dideuterio compounds. A cheap, stable and commercially-available sodium dispersion with high specific surface

Full text of DOI:10.1016/j.tetlet.2017.05.092

Accepted Manuscript
A Selective and Cost-Effective Method for the Reductive Deuteration of Acti-
vated Alkenes
Hengzhao Li, Bin Zhang, Yanhong Dong, Ting Liu, Yuntong Zhang, Haiyu Nie,
Ruoyan Yang, Xiaodong Ma, Yun Ling, Jie An
PII:
S0040-4039(17)30696-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.092
TETL 48985
Reference:
Tetrahedron Letters
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Revised Date:
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29 May 2017
31 May 2017
Please cite this article as: Li, H., Zhang, B., Dong, Y., Liu, T., Zhang, Y., Nie, H., Yang, R., Ma, X., Ling, Y., An,
J., A Selective and Cost-Effective Method for the Reductive Deuteration of Activated Alkenes, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.092
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A Selective and Cost-Effective Method for
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Hengzhao Li, Bin Zhang, Yanhong Dong, Ting Liu, Yuntong Zhang, Haiyu Nie, Ruoyan Yang, Xiaodong Ma,
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1
Tetrahedron Letters
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A Selective and Cost-Effective Method for the Reductive Deuteration of
Activated Alkenes
Hengzhao Li, Bin Zhang, Yanhong Dong, Ting Liu, Yuntong Zhang, Haiyu Nie, Ruoyan Yang, Xiaodong
Ma, Yun Ling and Jie An*
College of Science, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, China.
a
ARTICLE INFO
ABSTRACT
Article history:
Received
A new single electron transfer reaction for the reductive deuteration of activated alkenes has
been developed for the selective synthesis of α,β-dideuterio compounds. A cheap, stable and
commercially-available sodium dispersion with high specific surface area is employed as the
electron donor to replace the traditionally used sodium/liquid ammonium system. Deuterium
source is provided by EtOD-d1. Excellent yields and deuterium incorporations were obtained
across a broad range of activated alkenes with good functional group tolerance. This method
provided a cheap, efficient and operationally-simple method for the synthesis of deuterium
labeled compounds.
Received in revised form
Accepted
Available online
Keywords:
Reductive deuteration
Activated alkene
2009 Elsevier Ltd. All rights reserved
.
Deuterium-Labeled Compound
Single electron transfer reaction
A: Transition Metal-Catalyzed Post-synthesis H/D Exchange7a
Deuterium labelled compounds have been broadly employed
as metabolic or pharmacokinetic probes1, analytical standards in
O
O
[8] [8] [2]
2
[Cp*(PMe3)IrCl2] cat.
mass spectrometry
and powerful tools for mechanistic
ONa
( )6
investigations of organic reactions3. While deuterated compounds
have been extensively studied in non-clinical settings, recent
advances have further focused attention on deuterium substituted
medicines, which is reflected by the emergence of new
companies working in this field, and the recent entry of several
deuterated drugs into clinical trials4 . Because of the primary
kinetic isotope effect, the carbon–deuterium bonds are more
stable to chemical or enzymatic cleavage relative to the carbon–
hydrogen bonds. Deuterium labelling is therefore expected to
improve the half-life and toxicity profiles of medicines5 and some
other bioactive compounds, such as agrochemicals6 . However,
the application of deuterium labelled bioactive compounds is
restricted by the limitation of synthetic methodologies and, more
importantly, the cost of the deuterated compounds.
ONa
D2O, 135 oC, 40 h
[83] [8] [8] [7]
Numbers in brackets indicate percentage of exchanged protons at the specified position
B: Reductive Deuteration Mediated by Low-Valent Transition
Metal Compounds9c
D
O
O
SmI2/D2O
rt, THF
Ph
OH
77%
Ph
OH
D
C: Traditional Dissolving Metal Reduction of Activated Alkenes11a
over-reduced
by-products
AG
AG
Na/NH3
Na lump
+
+
R
AG
R
R
AG
R
AG
D: This Work
R
Na dispersion
D
EtO -d1, Et2O
D
up to 95% yield
up to 98% [D]
7
Post synthesis H/D-exchange and reductive deuteration
8
AG
R
AG
R
rt, 10 min
mediated by alkali metal deuterides (e.g. NaBD4 and LiAlD4) are
the most frequently used methods to introduce deuterium into a
compound, which, however, either suffer from low selectivity
and harsh reaction conditions (A, Fig. 1), or require expensive
reagents. Recently, single electron transfer (SET) reaction
became an emerging strategy in reductive deuterations (B, Fig.
1).9 Previously, our group has reported a SET reaction for the
selective synthesis of α,α-dideuterio alcohols10.
D
AG=activating group
Figure 1. A) Transition metal-catalyzed H/D exchange. B) Reductive
deuteration mediated by low-valent transition metal compounds. C)
Traditional dissolving metal reduction of activated alkenes. D) This work:
reductive deuteration of activated alkenes mediated by sodium dispersion.
Activated alkenes can be reduced by alkali metals, low-valent
transition metal compounds, metal hydrides and organohydride.
Electrochemical processes and catalytic hydrogenations are also
In order to develop a cost-effective method for the selective
synthesis of α,β-dideuterio compounds, herein we report the first
reductive deuteration reaction of alkenes mediated by sodium and
EtOD-d1 (D, Fig. 1)
11
used for this purpose . Among them, alkali metal/liquid
ammonium mediated reaction requires only cheap reagents, and
always lead to relatively higher atom economy (C, Fig. 1).
However, the use of liquid ammonium has restricted the
application of this method. Given that Na/NH3 is a strong
reducing agent, the formation of over-reduced by-products was

2
Tetrahedron
detected in same cases. Alternatively, in the heterogeneous
higher cost of i-PrOD-d1, EtOD-d1 was considered as a better
deuterium donor. As we expected, using sodium lump instead of
sodium dispersions led to a significantly lower yield of 2a (Table
1, entry 12) and the formation of the dimerized by-product was
detected.
reaction without liquid ammonium, electron is transferred from
the metal surface to the substrate and the radical anion
intermediates must diffuse to metal surface before the second
electron transfer can occur. Due to the slow rate of the second
electron transfer, significant amount of the dimerized by-product
formed via 5 was always observed11a (C, Fig. 1).
With the optimal conditions identified (Table 1, entry 4), the
scope of this reductive deuteration reaction was examined (Table
2). A broad range of activated alkenes can be successfully
employed as substrates for this reductive deuteration reaction to
furnish the corresponding dideuterated compounds in good yields
and deuterium incorporations15, including derivatives of cinnamic
acid, α,β-unsaturated amides and conjugated alkenes. It is
noteworthy that amides, carboxylate acids 2l, un-activated
alkenes 2f, phenyl ethers 2j and aromatic rings are stable under
the reaction conditions. And a variety of halogens are also
compatible, providing synthetic handles for further elaboration
(2g, 2h and 2k). However, chlorine substitution on the para-
position of the phenyl ring (2i) was reduced under the conditions,
which was possible formed via intermediate 2i’, albeit the
corresponding fluoride 2k is much more stable. Interestingly,
chlorine substitution on the ortho position of the phenyl ring was
stable under the tested conditions (2g). Furthermore, preliminary
results also demonstrated that the reductive deuterations of 1,4-
diene and activated alkyne can also be achieved using this
method (Table 3), which suggest the potential application of this
electron transfer protocol for the selective introduction of
deuterium into unsaturated compounds.
The rate of heterogeneous reaction increases with the
increasing of surface area of the solid phase. Given that various
bench-stable sodium dispersions with very high special surface
area have become commercially available, we proposed that a
highly efficient deuteration reduction of alkenes can be achieved
by using sodium dispersions/ROD-d1 system in a suitable organic
solvent (D, Figure 1). As this method requires only cheap
reagents and is operationally-simple, it compares favorably with
other reductive deuteration reactions mediated by metal
deuterides12, SmI2/D2O9c, and catalytic deuteration reactions13.
Table 1. Optimization of the Reductive Deuteration Mediated
a
by Na/ROD-d1
entry
Na
(eq.)
ROD-d1 (eq.) solvent
yield b
C1
[D]b
C2
[D]b
1
2.0
2.0
2.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
hexane
THF
Et2O
Et2O
Et2O
Et2O
58%
56%
73%
87%
51%
39%
80%
86%
90%
89%
91%
>98%
79%
93%
92%
90%
96%
>98%
2
3.0
Table 2. Reductive Deuteration of Activated Alkenes
a
Mediated by Na/EtOD-d1
3
3.0
4
3.0
5
6.0
6
9.0
7
3.0
complicated mixtures
8
3.0
31%
66%
91%
38%
28%
75%
80%
87%
81%
91%
76%
80%
90%
80%
94%
9
CD3OD 3.0
iPrOD-d1 3.0
D2O 3.0
3.0
10
11
12c
aConditions: 1a (0.50 mmol, 1.0 equiv), Na dispersions in oil (40 wt%,
particle size 5-10 µm), solvent (2.5 mL), rt, 10 min, ROD-d1 was first added
followed by Na dispersion. bDetermined by 1H NMR. cSodium lump was used
instead of sodium dispersions.
In this study, sodium dispersion in oil (particle size 5-10 µm,
40 wt%) was employed as the electron-donor as it is a bench-
stable and commercially-available reagent which is easy to
handle in an open atmosphere14. To our delight, the initial trial
with sodium dispersions in oil (2.0 equiv) and EtOD-d1 (2.0
equiv) lead to the formation of 2a in a promising 58% yield and
high deuterium incorporations at both C1 and C2 positions
(Table 1, entry 1). The reduction of amide group was not
observed. Higher yields were achieved by using more sodium
dispersions (Table 1, entries 3 and 4). Increasing the amount of
deuterium donor equivalents resulted in a greater degree of D
incorporation up to 98% (Table 1, entries 5 and 6). However,
excess EtOD-d1 accelerated the side reaction with sodium and,
therefore, led to a lower yield of 2a. This reaction was
significantly influenced by the nature of solvent. The best result
was obtained with Et2O. Different deuterium donors were also
screened (Table 1, entries 9-11). The use of i-PrOD-d1 led to a
similar result as EtOD-d1. The reactions with D2O and CD3OD
afforded lower yields of 2a, which may due to the fast side
reaction between the deuterium donors and sodium. Given the
aConditions: 1 (0.50 mmol, 1.0 equiv), ROD-d1 (3.0 equiv.), Na dispersions in
oil (3.0 equiv), Et2O (2.5 mL), rt, 10 min; isolated yield; D incorporation
determined by 1H NMR.

3
improved the rate of the second electron transfer in the alkene
Table 3. Reductive Deuteration of 1,4-Diene and Alkyne
a
reduction process and provided an attractive alternative to the
traditional homogenous Na/NH3 system. Compared with other
known reductive deuterations mediated by low-valent transition
metal compounds, such as SmI2, and alkali metal deuterides, this
new method is lower costing, safer, and with higher atom
economy. The potential application of this protocol in the
reductive deuteration of alkynes, polyenes and halides has also
been demonstrated and will be further investigated.
Mediated by Na/EtOD-d1
entry
substrate
product
yield (%)
62
1
2
95
Acknowledgments
aConditions: 1 (0.50 mmol, 1.0 equiv), ROD-d1 (3.0 or 6.0 equiv.), Na
dispersions in oil (3.0 or 6.0 equiv), Et2O (2.5 mL), rt, 10 min; isolated yield;
D incorporation determined by 1H NMR.
We thank NSFC (Nos. 21602248, 31272075 and 51302310)
and Chinese Universities Scientific Fund for financial support.
A possible mechanism for this transformation is presented in
Scheme 1. The dimerized product, formed via 5, was not detected
in any of the reactions mediated by sodium dispersions. However,
using sodium lump instead of sodium dispersion led to the
formation of 5 as the by-product (Table 1, entry 13), which
indicated that the specific surface area of sodium metal was
crucial to this reaction and the second electron transfer 3→4 was
possibly the rate determine step of this reaction. A primary
kinetic isotope effect kH/kD of 1.0 was determined for 1o. And
kH/kD of 1.3 (C1) and 1.0 (C2) was detected for 1a. The results
reveal that, for both activated alkenes, the deuterium transfer is
not involved in the rate limiting step3a. If EtOD-d1 was used to
quench the reaction 10 min after the addition of sodium,
complicated mixtures was formed (eq. 1), which indicated that
the second electron transfer is difficult to occur without a proton
donor. The products obtained from the sequential addition of
EtOD-d1 and EtOH (and verse vice) (Eq. 2 and 3) indicated that 1
→3 might be a proton coupled electron transfer process16 and
anion at C1 position is protonated at a later stage.
Supplementary Material
Experimental procedures and compound characterization data (PDF).
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4
Tetrahedron
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