Site-selective deuterated-alkene synthesis with palladium on boron nitride

Article abstract of DOI:10.1002/chem.201203337

Heavy stuff: A triethylamine-mediated H-D exchange reaction for the conversion of unlabeled alkynes (1) into [D₁]alkynes ([D ₁]-1) in a mixture of D₂O/THF has been developed. Furthermore, the efficient preparation of site-

Full text of DOI:10.1002/chem.201203337

DOI: 10.1002/chem.201203337
Site-Selective Deuterated-Alkene Synthesis with Palladium on Boron Nitride
Yuki Yabe, Yoshinari Sawama, Yasunari Monguchi, and Hironao Sajiki*[a]
Deuterium (2H or D)-labeled compounds are utilized in
various scientific fields,[1–5] and many deuterium-labeling
methods have therefore been developed.[6–14] Deuterium-la-
beled alkenes are widely available as starting materials for
the construction of a wide variety of deuterated target com-
pounds because of their remarkable features as building
blocks. Although direct H–D exchange reactions of unla-
beled alkenes with a deuterium source are regarded as the
most straightforward approach to the synthesis of deuterat-
ed alkenes ([Dn]alkenes), the site- and regioselective intro-
Scheme 1. Regioselective preparation of deuterated alkenes by using the
Pd/BN catalyst under a D2 or H2 atmosphere.
duction of the desired number of deuterium atoms with high
deuterium efficiency remains challenging.[9] Among the step-
wise syntheses of [Dn]alkenes,[10] the site-selective reductive
deuteration of an alkyne or [D1]alkyne can be useful for the
synthesis of the desired [Dn]alkene.[11–14] [D1]- and
[D2]alkenes could be prepared from terminal propargylic
compounds by using homogeneous metal hydride or deuter-
ide reagents ([Cp2ZrHCl] or [Cp2ZrDCl]; Cp=cyclopenta-
dienyl,[11] boron,[12a] and aluminum[12b] reagents) followed by
an aqueous workup by using D2O or H2O. Deuterated 4-me-
thoxystyrene analogues were efficiently synthesized from 4-
ethynylanisole by homogeneous Rh-catalyzed semi-deutero-
genation under an atmosphere of H2 or D2.[13] cis-Deuterat-
ed alkenes were prepared by use of the Lindlar catalyst for
partial reductive deuteration of 1,2-disubstituted alkynes by
using D2 gas generated by the electrolysis of D2O in a spe-
cial flow reactor (H-cube).[14] Although these methods
enable the incorporation of the desired number of deuteri-
um atoms into suitable alkynes, an efficient and widely ap-
plicable method for the synthesis of monosubstituted
[Dn]alkene compounds from monosubstituted aromatic and
aliphatic alkynes remains challenging because of the ready
over-reduction of in situ generated alkenes to alkanes. We
now report a new deuterium-labeling method for terminal
alkynes, which yields [D1]alkynes, and the highly selective
and systematic synthesis of terminal [D1]-, [D2]-, and
[D3]alkenes from unlabeled terminal alkynes or [D1]alkynes
by palladium on boron nitride catalyzed[15] partial reduction
(semihydrogenation[16] or semideuterogenation) with H2 or
D2 gas (Scheme 1).
Theoretically, terminal alkynes (1) can be transformed
into the [D2]alkene by deuterogenation with D2 gas on a
heterogeneous palladium catalyst such as Pd/C. However,
the generated [D2]alkenes are easily and further deutero-
genated to [D4]alkane derivatives, even when using the Lin-
dlar catalyst.[17–19] Moreover, D2 gas is quite expensive and
not easily obtainable because of the complicated acquisition
process, on account of limited production as a consequence
of its combustible nature and import restrictions because it
is considered a strategic material.
We have developed an efficient semihydrogenation of
monosubstituted alkynes to alkenes by using Pd/BN (boron
nitride supported Pd catalyst) in the presence of an appro-
priate amine such as diethylenetriamine [DETA; Eq. (1)][15]
and D2 gas generated by the method described in refer-
ence [8] [Pd/C in D2O, the cheapest deuterium source, is stir-
red under an atmosphere of H2 at room temperature;
Eq. (2)]. However, in contrast to our expectations, the
Pd/BN-catalyzed deuterogenation of 4-ethynylanisole (1a)
in the presence of DETA in MeOH at room temperature
under in situ generated D2 gas gave the [D3]alkene
([D3]-2a) in low D efficiencies [Eq. (3)]. This result indicat-
ed that the Pd/BN-catalyzed cis-addition of D2 gas to the
alkyne (1a) proceeded after the preliminary H–D exchange
reaction of the relatively acidic unlabeled alkyne (1a) to the
corresponding [D1]alkyne ([D1]-1a) because the D content
at the cis-positions of [D3]2a was nearly equal.
[a] Y. Yabe, Dr. Y. Sawama, Dr. Y. Monguchi, Prof. Dr. H. Sajiki
Laboratory of Organic Chemistry, Gifu Pharmaceutical University
1-25-4 Daigaku-nishi, Gifu 501-1196 (Japan)
Fax : (+81)58-230-8109
E-mail: sajiki@gifu-pu.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203337.
484
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Chem. Eur. J. 2013, 19, 484 – 488

COMMUNICATION
The H–D exchange reaction of the unlabeled alkyne to a
[D1]alkyne derivative ([D1]-1) has generally been performed
by the formation of metal acetylide by using relatively
strong bases (e.g., nBuLi[20] or a Grignard reagent[21]) and
subsequent workup by using deuterium sources, such as
D2O and MeOD. The acidic protons in DETA and MeOH
may cause the reverse D–H exchange reaction, resulting in
the low D incorporation observed.[22] Therefore, the reaction
was carried out under aprotic conditions by using a Et3N/
D2O/THF solvent system. Reactions under these conditions
proceeded effectively and various aromatic and aliphatic al-
kynes were deuterated with excellent D incorporations and
isolated in high yields at room temperature (Figure 1).[23]
Figure 2. Preparation of [D3]alkenes: [a] Prepared by the method report-
ed in reference [8]. [b] 0.06 mol% of 0.3% Pd/BN was used.
[D1]Alkenes ([D1]-2) could be prepared by the Pd/BN-cat-
alyzed semihydrogenation of [D1]-1 under an H2 atmos-
phere. Although the semihydrogenation of [D1]-1a by using
the H2/Pd/BN/pyridine combination gave [D1]-2a with a sat-
isfactory D content (92%), a small amount of D (7%) was
introduced into the E-position relative to the aromatic ring
on the terminal sp2-carbon atom (Table 1, entry 1). The Pd/
BN-catalyzed semihydrogenation in 2,6-lutidine as the sol-
vent (Table 1, entry 2) failed. However, the use of only
1.0 equivalent of 2,6-lutidine (relative to the amount of [D1]-
1a) as an additive in pyridine (1 mL) efficiently suppressed
D incorporation at the E-position (only 2%, Table 1,
entry 3). Other pyridine derivatives, such as 2-picoline, 2-
methoxypyridine, and quinoline, were less effective inhibi-
Table 1. Optimization of [D1]alkene preparation.
Figure 1. Synthesis of [D1]alkyne compounds.
Entry Additive
Solvent
Time [h] Product Yield [%]
The acidic protons of DETA and MeOH can also de-
crease the D efficiency of Pd/BN-catalyzed semideuteroge-
nation of [D1]alkynes ([D1]-1) to [D3]alkenes ([D3]-2) with
D2 [see q. (3)], as is the case for the preparation of
[D1]alkynes ([D1]-1, Figure 1). Consequently, pyridine was
chosen as the solvent to maintain the D efficiency of the re-
action. As a result, compounds [D3]-2 were effectively pre-
pared from [D1]-1 with high D efficiencies and isolated in
near quantitative yields with an extremely low catalyst load-
ing (0.03 mol%) of Pd/BN (Figure 2). Because Pd/BN is an
extremely mild catalyst for hydrogenation, the totally che-
moselective semihydrogenation of alkynes in the presence
of nitro, benzyl ether, benzyl alcohol, and tert-butyldimethyl-
silyl (TBS) ether functionalities is possible.[15] Therefore, the
1
2
3
–
pyridine
3
6
3
99
n.r.
98
–
2,6-lutidine
pyridine
–
2,6-lutidine
4
5
6
7
8
2-MeO-pyridine
quinoline
pyridine
pyridine
pyridine
4
8
99
79
2-picoline[a]
24
3
67
MS4ꢁ, 2,6-lutidine pyridine
MS4ꢁ, 2,6-lutidine pyridine
61
present
Pd/BN-catalyzed
semideuterogenation
of
[D1]alkynes in pyridine gave various aromatic and aliphatic
[D3]alkenes, but left the other reducible functionalities
intact ([D3]-2c, [D3]-2d, [D3]-2e, and [D3]-2 f).
3
99[b]
[a] 2 Equivalents. [b] 0.1 mol% of Pd/BN catalyst was used.
Chem. Eur. J. 2013, 19, 484 – 488
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485

H. Sajiki et al.
tors of E-deuteration (Table 1, entries 4–6). Fortunately, the
addition of 4 ꢁ molecular sieves (MS4ꢁ) not only improved
the D efficiency at the Z-position (up to 95% D), but also
completely suppressed the incorporation of D at the E-posi-
tion, resulting in isolation of [D1]-2a in moderate yields
(Table 1, entry 7). The semihydrogenation of [D1]-1a could
be forced to completion by use of a larger amount of Pd/BN
(0.1 mol%), quantitatively yielding [D1]-2a (Table 1,
entry 8). The exact mechanistic role of the additives applied
is not clear and, therefore, detailed investigations into the
effect of 2,6-lutidine and MS4ꢁ are underway.
The Pd/BN-catalyzed semihydrogenation of [D1]alkynes
in pyridine in the presence of 2,6-lutidine and MS4ꢁ could
be adapted to prepare various [D1]alkenes ([D1]-2) in high
D efficiencies and yields (Figure 3). The nitro group and
benzyl and TBS ethers are tolerated very well under the re-
action conditions.
Figure 4. Preparation of [D2]alkenes: [a] Prepared by the method report-
ed in reference [8]. [b] 0.05 mol% of 0.3% Pd/BN was used.
[c] 0.20 mol% of 0.3% Pd/BN was used.
Scheme 2. Synthesis of deuterated allylsilane derivatives: [a] Prepared by
the method reported in reference [8].
Figure 3. Syntheses of various [D1]alkene compounds.
The preparation of [D2]alkenes ([D2]-2) was also accom-
plished starting from unlabeled alkynes (1) with the Pd/BN–
MS4ꢁ–2,6-lutidine–pyridine system under an atmosphere of
D2 gas prepared by the method described in reference [8] in-
stead of H2 gas. Unfortunately, D incorporation at the unde-
sired Z-position, relative to the aromatic ring, on the termi-
nal sp2-carbon atom was not completely suppressed because
of the inevitable pyridine/2,6-lutidine-mediated H–D ex-
change reaction of 1 to [D1]-1 prior to the reductive semi-
deuterogenation of 1 to [D2]-2 (Figure 4).
Lastly, we applied the systematic preparation methods for
deuterated alkenes developed herein to the synthesis of deu-
terium-labeled allylsilanes, which are the key reactive re-
agents in the construction of deuterium-labeled frameworks
of a wide variety of functionalized organic compounds.
These deuterium-labeled materials may be synthesized by
Sakurai–Hosomi allylation[24] or Hiyama cross-coupling,[25]
and in the synthesis of physiologically significant heterocy-
cles, such as tetrahydropyran[26] and tetrahydrofuran.[27] As
shown in Scheme 2, dimethylphenylpropargylsilane (1g) un-
derwent semideutrogenation by using the Pd/BN–MS4ꢁ–
2,6-lutidine–pyridine system under a D2 atmosphere, pre-
pared as described in reference [8], to afford [D2]-2g regio-
selectively with efficient D atom incorporation. After prepa-
ration of [D1]-1g by the Et3N-mediated H–D exchange reac-
tion of unlabeled 1g in D2O/THF at 508C, the Pd/BN-cata-
lyzed semihydrogenation and semideuterogenation gave
[D1]-2g and [D3]-2g, respectively, in high yields and D effi-
ciencies.
In conclusion, we have developed a new Et3N-mediated
H–D exchange reaction of alkynes (1) to prepare
[D1]alkynes ([D1]-1) in a mixture of D2O and THF at room
temperature and a method for the Pd/BN-catalyzed regiose-
lective systematic preparation of various deuterated termi-
nal alkenes from unlabeled alkynes or deuterated alkyne de-
rivatives in excellent yields and with high D contents and re-
gioselectivities. A variety of reducible functionalities, such as
nitro groups, benzyl ethers, TBS ethers, and silanes, are well
tolerated under the reaction conditions described and the
wide variety of deuterated products obtainable by this
method are expected to be useful building blocks for new
deuterated materials including, but not limited to, deuteri-
um-labeled drugs, deuterated polymers, and tracers.
486
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Deuterated-Alkene Synthesis
COMMUNICATION
[7] For selected recent papers on direct deuteration of various com-
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Experimental Section
Typical procedure for the deuteration of alkynes (Figure 1): Et3N
(1.1 mmol) was added to a solution of an alkyne (1 mmol) in D2O/THF
(1:1 mL) at room temperature under an argon atmosphere and the reac-
tion mixture was stirred for the appropriate duration, as indicated in
Figure 1. The resulting mixture was diluted with Et2O or hexanes (2 mL)
and separated into two layers. The aqueous layer was then further ex-
tracted with Et2O or hexanes (2 mLꢂ2). The combined organic layers
were dried over Na2SO4 and concentrated under vacuum to give analyti-
cally pure product.
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2008, 9, 1467; n) T. Kurita, K. Hattori, S. Seki, T. Mizumoto, F.
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Typical procedure for the synthesis of [D3]alkenes (Figure 2): A flask
was charged with a mixture of the substrate (0.25 mmol) and Pd/BN
(0.3%; 0.03 mol% of the substrate) in pyridine (1 mL). After the reac-
tion flask was depressurized, previously prepared D2 (further details are
provided in the Supporting Information) was allowed to flow into the re-
action flask. After stirring for 6 h at room temperature, the resulting mix-
ture was diluted with Et2O or hexanes (5 mL) and then filtered through a
pad of Celite. The filtrate separated into two layers and was treated with
1m aqueous HCl (20 mL). The organic layer was separated and washed
with H2O (10 mL). The combined organic layers were dried over Na2SO4
and concentrated under vacuum to give the analytically pure product.
Keywords: alkenes · alkynes · deuterium · palladium ·
regioselectivity
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Received: September 18, 2012
Published online: December 7, 2012
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