Transition-Metal-Free, Selective Reductive Deuteration of Terminal Alkynes with Sodium Dispersions and EtOD- d1

Article abstract of DOI:10.1021/acs.orglett.8b01036

A transition-metal-free single electron transfer reaction has been developed for the synthesis of [D₃]-alkenes from terminal alkynes using sodium dispersions as the electron donor and EtOD-d₁ as the deuterium source. Both reagents ar

Full text of DOI:10.1021/acs.orglett.8b01036

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transition-Metal-Free, Selective Reductive Deuteration of Terminal
Alkynes with Sodium Dispersions and EtOD‑d1
Minhui Han, Yuxuan Ding, Yuhao Yan, Hengzhao Li, Shihui Luo, Adila Adijiang, Yun Ling, and Jie An*
College of Science, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China
S
* Supporting Information
ABSTRACT: A transition-metal-free single electron transfer
reaction has been developed for the synthesis of [D3]-alkenes
from terminal alkynes using sodium dispersions as the electron
donor and EtOD-d1 as the deuterium source. Both reagents are
cost-effective and bench-stable. This practical method exhibits
remarkable terminal alkyne selectivity and exclusive alkene selectivity. Excellent deuterium incorporations and yields were
achieved across a broad range of terminal alkynes without olefin isomerization. Of note, this reaction is highly solvent dependent.
n-Hexane provides unique enhancement to this reductive deuteration process.
elective deuterium substitution of physiologically active
compounds can result in longer half-lives and improve safety
Scheme 1. Strategies for the Synthesis of [D3]-Alkenes8
S
due to higher stability of C−D bonds than C−H bonds.1 With
the recent renaissance of deuterated drugs, a considerable
amount of deuterium-containing agents have entered clinical
trials (Figure 1a).1 In 2017, the US Food and Drug
Figure 1. (a) Selected examples of deuterated drugs advanced to clinical
trials, (b) deutetrabenazine, and (c) deuterium-labeled internal
standard.3b
Administration (FDA) awarded a new chemical entity to the
first deuterated drug, deutetrabenazine, which is recognized as a
different orphan drug for the treatment of chorea versus
tetrabenazine (Figure 1b). In addition, deuterium labeled
compounds have been widely used as metabolic or pharmaco-
kinetic probes,2 internal standards in analytical chemistry,3 and
tools for elucidation of reaction mechanisms4 (Figure 1c).
Terminal alkenes are useful building blocks as well as valuable
end products, present in a plethora of pharmaceuticals,
agrochemicals, and natural products. H/D exchange and
reductive deuteration are two strategies generally employed for
the selective introduction of deuterium into the vinyl groups.
Transition metal catalyzed postsynthetic H/D exchange5 is a
universal strategy, albeit it often requires harsh reaction
conditions and suffers from poor regioselectivity and low
deuterium incorporations (Scheme 1A). As alkenes are typically
synthesized by semihydrogenation of the corresponding
alkynes,6 reductive deuteration represents a more straightfor-
ward strategy.7 In fact, transition-metal-catalyzed semireduction
of terminal alkynes in the presence of D2 gas,7b,d,e organosilanes/
D2O,7a or CO/D2O7c have resulted in better regioselectivity and
higher deuterium incorporations than H/D exchange (Scheme
1B). However, if [D3]-alkene is the designed product, [D1]-
alkynes have to be used as the corresponding starting materials
(Scheme 1B).7b Unfortunately, over-reduction associated with
the reduction process makes this strategy less synthetically
attractive. In addition, expensive transition-metal catalysts,
reductants, and deuterium sources employed in both of these
strategies (Scheme 1A,B) have thus far restricted industrial
applications.
Previously, we have demonstrated the alkali-metal-mediated
single electron transfer (SET) as an emerging strategy for the
reductive deuteration of carboxylic esters and activated alkenes.9
Herein, we report the first selective SET reductive deuteration of
Received: April 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
alkynes mediated by sodium dispersions and the readily available
ROD-d1. Both reagents, i.e., the electron and deuterium donor,
are bench-stable and commercially available. This strategy is
amenable to scale-up, and the application of Na dispersions in
industry synthesis has already been demonstrated.
Table 1. Optimization Studies in the Reductive Deuteration of
Alkynes
a
Traditionally, alkyne reduction can be achieved by dissolved
alkali metal in either liquid ammonia or HMPA (Birch
conditions).10 As the soluble electride derived from Na and
liquid NH3 is a very powerful reductant, both internal and
terminal alkynes and even aromatic or heteroaromatic moieties
are reduced via an outer sphere electron transfer process.
Additionally, toxic ammonia, tedious experimental procedures,
and the problems associated with over-reduction and olefin
isomerization have made this classical method less attractive.
Furthermore, direct reduction of alkynes by a sodium lump is
impractical, as this heterogeneous reaction is extremely slow.
In this study, we report that commercially available sodium
dispersions (particle size 5−10 μm) with high specific surface
area significantly increase the rate of alkyne reduction and,
remarkably, reduce terminal alkynes with high selectivity via an
inner sphere electron transfer process (Scheme 1C). We show
that in the presence of a deuterium donor unlabeled terminal
alkynes can be directly converted into [D3]-alkenes in a single
step by sodium dispersions. This reaction involves two processes:
(i) reductive deuteration of the triple bond and (ii) the H/D
exchange of the terminal hydrogen. We found that subjecting a
terminal alkene, dec-1-ene, to Na/EtOD-d1 led to no detectable
H/D exchange, which indicates that H/D exchange happened
before the reduction via the formation of an acetylide anion. Our
method shows the following advantages compared with other
reductive deuterations of alkynes: (a) excellent terminal alkyne
selectivity, (b) using all hydrogen alkyne as the starting material
to synthesized [D3]-alkene in a single step, and (c) much cheaper
and more convenient to use reagents and reaction conditions.
On the basis of this observation, the reaction conditions were
optimized using an unactivated terminal alkyne 1a (Table 1).
Excellent yield and deuterium incorporation were obtained using
10 equiv of sodium dispersion/deuterium donor in hexane at 0
°C (entry 4). Significantly, the side reaction between deuterium
donors and sodium to generate deuterium gas was relatively slow,
compared to the electron transfer process. In addition, the use of
sodium dispersions obviates the hazards associated with
traditional alkali metal-mediated reactions. Traditional sodium-
mediated reactions, for example, Bouveault−Blanc reduction,
normally require reflux conditions and may result in excessive
foaming and even fire. This reaction was found to be highly
solvent dependent (entries 4−7). In n-hexane, sodium dispersion
exhibits uniquely enhanced reductive ability toward terminal
alkynes, whereas in THF, Et2O, or toluene, the yields dropped
dramatically from >98% to <5% (entries 5−7). We hypothesize
that solvents with higher dielectric constant, such as THF, would
facilitate an outer sphere electron transfer process,11 while
solvents with low dielectric constants, such as hexanes, should
favor the inner-sphere mechanism. As expected, a sodium lump
led to much lower conversion (entry 8). Finally, variations in the
addition order resulted in lower deuterium incorporation (entry
9).
b
b
Na
ROH
yield
[D] at positions 1, 2,
entry (equiv)
(equiv)
solvent
hexane
(%)
and 3 (%)
1
2
3
4
5
6
7
8
9
4.0
EtOD-d1
(4.0)
77
63, 48, 72
6.0
EtOD-d1
(6.0)
hexane
hexane
hexane
THF
79
84
98
<5
<5
<5
19
98
74, 50, 82
91, 71, 88
96, 82, 96
8.0
EtOD-d1
(8.0)
10.0
10.0
10.0
10.0
10.0
10.0
EtOD-d1
(10.0)
EtOD-d1
(10.0)
EtOD-d1
(10.0)
Et2O
EtOD-d1
(10.0)
toluene
hexane
hexane
c
EtOD-d1
(10.0)
d
EtOD-d1
(10.0)
72,70,82
a
Conditions: sodium dispersions in oil (29 wt %, particle size 5−10
μm) was added to a solution of 1a (0.50 mmol, 1.0 equiv) and EtOD-
b
d1 at 0 °C, and stirred for 20 min under N2. Determined by 1H NMR.
c
d
Sodium lump. EtOD-d1 was added 20 min after the addition of
sodium.
the developed conditions, which is in contrast to the classic
Birch-reduction.
This method is compatible with a broad range of functional
groups, including aromatic rings (1c, 1g−1j), tertiary amines
(1d, 1e), ethers (1f−1j, 1m−1n), and amides (1l). The removal
of benzylic protecting groups from alcohols (1f) and amines (1e)
was not detected. Terminal alkynes with increasing steric
demand at the α-carbon were suitable substrates for the
reduction (1b, 1m). Over-reduction and olefin isomerization
were not observed, except for stabilized benzyl radicals, which is a
significant advantage compared to the traditional Na/NH3
system. As an exception, phenyl-substituted alkyne 1n was fully
reduced to alkane. Halides (1g−1j) were reduced with >90%
deuterium incorporations without the use of additional reagents,
which suggests a potential in the selective halogen-deuterium
exchange. The ester group (1k) was sequentially converted to the
α,α-dideuterio alcohol with high deuterium incorporation. It is
noteworthy that scaling up this reaction (from 0.50 to 10 mmol)
had little influence on the yield and deuterium incorporation (1c,
Table 2). Unactivated internal alkynes (1q, 1r, 1s) are very stable
under the reaction conditions. Note that, while 1,2-diphenyle-
thyne (1o) can undergo reduction, this process likely involves an
aryl radical pathway. Finally, full selectivity in the reduction of
terminal alkynes in the presence of internal alkynes was achieved
in both intermolecular (eq 1) and intramolecular (1p, Table 2)
competition reactions.
Next, the optimized conditions were applied to the selective
reductive deuteration of different classes of alkynes (Tables 2). A
broad range of terminal alkynes were converted to the
corresponding [D3]-alkenes with excellent deuterium incorpo-
ration and in high yields. Remarkably, unactivated internal
alkynes and aromatic groups were found to be very stable under
B
DOI: 10.1021/acs.orglett.8b01036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
from deprotonated terminal alkyne may easily be adsorbed onto
the surface of the positively charged sodium particles. Under
heterogeneous conditions, electron transfer only occurs on the
surface of the sodium particle. Thus, the ET process may be
accelerated after deprotonation. However, it is noteworthy that
this reaction is significantly slower than most other sodium-
mediated SET reactions, such as Birch reduction or Bouveault−
Blanc reduction. Monitoring of the present reaction demon-
strated a t1/2 of about 10 min. Decreasing the reaction time to 3
min led to significantly lower conversions. The kinetic isotope
effect determined using 1c (kH/kD = 1.2 0.1) demonstrated
that deuterium transfer is unlikely to be the rate determining step
of this reaction.12 Moreover, cleavage of the methoxy group in
1m revealed that the radical anion intermediate derived from the
first electron transfer (Scheme 1C) is relatively stable, suggesting
that the second electron transfer might be the slow step of this
reaction.
Table 2. Reductive Deuteration of Terminal Alkynes by Na/
EtOD-d1
a
As extremely useful building blocks, terminal [D3]-alkenes can
be used for the construction of complex deuterium-containing
labels via well-established methods including cross-metathesis,
epoxidation, ozonolysis, cyclopropanation, Sharpless dihydrox-
ylation, and Wacker oxidation. Taking 2f as an example, we
demonstrated that high deuterium incorporation content is well-
preserved after derivatization by Sharpless dihydroxylation (eq
2) or olefin metathesis (eq 3).
To further explore the synthetic utility of this new deuteration
method, [D5]-pefurazoate was synthesized using the route
illustrated in Scheme 2. Pefurazoate is a marketed imidazole-
Scheme 2. Synthesis of [D5]-Pefurazoate9
containing fungicide used for seed treatment. As shown, high,
site-specific deuterium incorporation was achieved in the final
product, which constitutes an attractive target for isotope
dilution analysis. The antifungal activity of [D5]-pefurazoate
will be evaluated and compared with the all hydrogen analogues
in our further studies.
a
Isolated yields. Percentage of exchanged protons at the specified
b
position are indicated in brackets, determined by 1H NMR. 10.0
mmol scale.
High terminal selectivity may result from two possible
scenarios: (a) steric hindrance of the internal alkyne and (b)
deprotonation/activation pathway. An acetylide anion derived
In summary, we have developed a practical reductive
deuteration method of terminal alkynes mediated by sodium
C
DOI: 10.1021/acs.orglett.8b01036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01036.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jie_an@cau.edu.cn.
ORCID
Jie An: 0000-0002-1521-009X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Key Research and Development Plan of
China (2017YFD0200504) and the National Natural Science
Foundation of China (No. 21602248, 21711530213) for
financial support.
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D
DOI: 10.1021/acs.orglett.8b01036
Org. Lett. XXXX, XXX, XXX−XXX