Organocatalytic Nitroaldol Reaction Associated with Deuterium-Labeling

Article abstract of DOI:10.1002/adsc.201701224

A deuterium-labeling reaction of nitroalkanes in deuterium oxide and the subsequent nitroaldol reaction have been accomplished under basic and organocatalytic conditions to provide the deuterium-labeled β-nitroalcohols in high yields and high deuterium contents. β-Deuterated β-nitroalcohols could be smoothly obtained from the reaction of nitroalkanes and various electrophiles using the easily-removal basic resin WA30. Furthermore, the asymmetric nitroaldol reaction using nitromethane and α-keto esters as electrophiles in the presence of a quinine-derived organocatalyst in deuterium oxide could provide the desired β-deuterated nitroalcohol derivatives with high enantioselectivities. (Figure presented.).

Full text of DOI:10.1002/adsc.201701224

Title: Organocatalytic Nitroaldol Reaction Associated with Deuterium-
Labeling
Authors: Tsuyoshi Yamada, Marina Kuwata, Ryoya Takakura,
Yasunari Monguchi, Hironao Sajiki, and Yoshinari Sawama
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701224
Link to VoR: http://dx.doi.org/10.1002/adsc.201701224

10.1002/adsc.201701224
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Organocatalytic Nitroaldol Reaction Associated with
Deuterium-Labeling
Tsuyoshi Yamada,a Marina Kuwata,a Ryoya Takakura,a Yasunari Monguchi,a Hironao
Sajiki,a* and Yoshinari Sawamaa*
a
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
E-mail: sawama@gifu-pu.ac.jp, sajiki@gifu-pu.ac.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
nitroalkane derivatives are expensive or cannot be
purchased. Since the nitroaldol reaction accompanied
by the deuterium-labeling of CH3NO2 has never been
developed, we herein report a direct deuteration
method of nitroalkanes in D2O and subsequent
nitroaldol reaction with various electrophiles to form
the corresponding -deuterated -nitroalcohol
derivatives using a heterogeneous basic resin, WA30,
as an easily handled organocatalyst, and a quinine-
derived organocatalyst for the enantioselective
synthesis.
Abstract. A deuterium-labeling reaction of nitroalkanes in
deuterium oxide and the subsequent nitroaldol reaction
have been accomplished under basic and organocatalytic
conditions to provide the deuterium-labeled -nitroalcohols
in high yields and high deuterium contents. -Deuterated -
nitroalcohols could be smoothly obtained from the reaction
of nitroalkanes and various electrophiles using the easily-
removal basic resin WA30. Furthermore, the asymmetric
nitroaldol reaction using nitromethane and -keto esters as
electrophiles in the presence of
a quinine-derived
organocatalyst in deuterium oxide could provide the
desired -deuterated nitroalcohol derivatives with high
enantioselectivities.
Keywords: deuterium-labeling; deuterium oxide;
enantioselectivity; organocatalysis; nitroaldol reaction
Deuterium-labeled compounds have been utilized in
various fields (e.g., the elucidation of metabolic
pathways and reaction mechanisms, surrogate
compounds for microanalyses of environmental
pollutants)[1], and heavy drugs (deuterium-labeled
medicines) have been recently spotlighted due to their
ability to prolong the duration of drug action based on
the isotope effect.[2] Therefore, the novel deuterium
incorporation methods into the desired positions of
compounds can be powerful tools to provide
deuterium-lableled functional materials and their
synthetic building blocks. Especially, the use of
deuterium oxide (D2O) as a deuterium source is
important from the viewpoint of green sustainable
chemistry and cost performance. Catalytic and/or
metal-free deuterium-labeling method are also useful
as an environmentally friendly method.[3,4] The
nitroaldol reaction (Henry reaction)[5] has been
widely utilized to synthesize various -nitroalcohol
derivatives, which could be transformed into
biologically-active compounds,[6] and deuterium-
labeled nitromethane (CD3NO2) has been used in
mechanistic studies to produce the deuterium-
incorporated products.[7] While CD3NO2 is
commercially available, other deuterium-labeled
Scheme 1. Organocatalytic nitroaldol reactions with
deuterium-labeling.
While the nitroaldol reaction is generally carried
out under basic conditions in organic solvents, water
(H2O) has also been used as a solvent in a few reports
related to the metal-free nitroaldol reactions.[8] We
first investigated the nitroaldol reaction between 0.25
mmol of benzaldehyde (1a) and 2.5 mmol of
CH3NO2 in D2O (1 mL) under relatively mild basic
condi tions (Table 1). After stirring CH3NO2 and
K2CO3 (40 mol%) in D2O for 2 h at room temperature,
1a was added to the mixture. After further stirring for
12 h at room temperature, the desired -bisdeuterated
-nitroalcohol (2a-d2) was obtained in 88% yield
with 90% D content. Et3N was also effective to
produce 2a-d2 with a high D efficiency (entry 2),
while the use of quinoline led to the decrease in both
the D content and yield (entry 3). On the other hand,
the basic resin WA30 (10 mg, 38 wt% toward 1a,
Mitsubishi Chemical Corp.), which is a polystyrene
polymer possessing tertiary amine residues on the
fundamental skeleton, effectively catalyzed the
1
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10.1002/adsc.201701224
Advanced Synthesis & Catalysis
present nitroaldol reaction in association with
deuterium-labeling to form 2a-d2 with a 96% D
content (entry 4), and the increased use of D2O (2
mL) further improved the reaction efficiency to
provide 2a-d2 with a nearly quantitative D content
(entry 5). A 20-times scale-up test could also be
allowed with a high D content and yield (entry 6). It
is an important feature that WA30 is easily-
eliminated from the reaction media by a simple
filtration. Additional investigation results using other
bases are detailed in the Supporting Information.
WA30 could be reused to give 2a-d2 with good
deuterium contents, although the slight reduction in
the isolated yield was observed (entry 7; the results of
the repeated uses (five times) are described in
Supporting Information). During the first stirring in
the presence of WA30 without 1a, CH3NO2 was
effectively deuterated into CD3NO2 within 2 h with a
quite satisfactory D content (eq. 1).
decanal and the following nitroaldol reaction between
CD3NO2 and the partially -deuterated decanal.
Nitroethane (EtNO2) and nitropropane (n-PrNO2)
were also available for the present reaction, and the
corresponding mono-deuterated products (3-d1 and 4-
d1)
were
obtained
as
diastereomixtures.
(5) and ethyl
Trifluoromethylacetophenone
benzoylformate (7) were also effectively reacted with
the in situ-generated CD3NO2 to give the -
bisdeuterated -nitroalcohols (6-d2 and 8-d2) with
good
D
efficiencies. The -bisdeuterated -
nitroamine derivative (10-d2) could be obtained from
(E)-N-benzylideneaniline (9) in a moderate yield
along with generation of the -bisdeuterated -
nitroalcohol (2a-d2) via the hydrolyzed benzaldehyde
(1a).
Table 2. Scope of substrates under WA30-catalyzed
conditions.[a]
Table 1. Nitroaldol reactions associated with deuterium-
labeling.
D content yield
entry base
(%)
90
86
32
96
99
96
93
(%)
88
1
K2CO3 (40 mol%)
Et3N (40 mol%)
quinoline (40 mol%)
WA30 (10 mg)
WA30 (10 mg)
WA30
2
100
22
3
4
88
5[a]
6[b]
7
75
84
Reused WA30
78
[a] 2 mL of D2O was used.
[b] 5 mmol of 1a, 200 mg of WA30 and 20 mL of D2O were
used.
Various electrophiles and nitroalkane derivatives
were next investigated (Table 2). 4-Bromo-, 4-
methoxycarbonyl-, 4-methoxy-, 4-nitro-, 3-nitro- and
2-nitro-benzaldehyde derivatives (1b–1g) were all
smoothly transformed into the corresponding -
bisdeuterated -nitroalcohols (2b-d2–2g-d2) based on
the coupling of the in situ-generated CD3NO2 with
excellent D efficiencies and good to high yields.
Naphthylaldehyde (1h) and heteroaromatic aldehydes
(1i and 1j) were also good substrates. Decanal was
converted to the tetradeuterated nitroalcohol (2k-d4)
via the initial WA30-catalyzed α-deuteration of
[a]
The reaction was carried out using CH3NO2 and an
aldehyde (1) unless otherwise noted.
[b] 1 mL of D2O was used.
[c] K2CO3 (20 mol%) was added.
[d] At 50 oC for the second step.
[e] 20 mg of WA30 was used.
[f] EtNO2 was used instead of CH3NO2.
[g] n-PrNO2 was used instead of CH3NO2. The first step was
for 24 h.
2
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10.1002/adsc.201701224
Advanced Synthesis & Catalysis
[h] The product was obtained as a diastereomixture.
[i] 5 was used as the substrate.
[j] 7 was used as the substrate.
of the hydroxy group using the combination of mesyl
chloride (MsCl) and Et3N into the corresponding -
nitrostyrene (11-d1) and the Pd/C-catalyzed hydrogen
transfer reaction using ammonium formate as a
hydrogen source into the -aminoalcohol (12-d2) with
retention of the D contents (eq. 4).
[k] 9 was used as the substrate.
The stepwise addition of CH3NO2 and
benzaldehyde (1a) shown in Table 1 was not essential,
and the -bisdeuterated -nitroalcohol (2a-d2) could
be obtained with satisfactory 92% D contents by the
mixed use of CH3NO2 and 1a in D2O from the outset
of the reaction (eq. 2). Furthermore, the WA30-
catalyzed direct deuteration of unlabeled -
nitroalcohols (2a or 2c) produce the only a 31% yield
of 2a-d2 or only a 19% D efficiency of 2c-d2 (eq. 3).
2a preferentially underwent the retroaldol reaction to
give benzaldehyde, which resulted in low yield of 2a-
d2. Meanwhile, the reason for the lower deuterium
efficiency of 2c was unclear. Three equilibrium
reactions in the nitoroaldol reaction associated with
deuterium labeling, such as the deuteration (H-D
exchange reaction) of CH3NO2 vs. the reverse D-H
exchange reaction (path A), nitroaldol vs. retroaldol
reactions between 1 and 2 (path B and B’) and the
direct H-D exchange vs. D-H exchange reactions of 2
(path C) can be proposed (Scheme 2). The excess use
of D2O toward CH3NO2 facilitates the generation of
CD3NO2 which is also sufficiently generated to
promote the subsequent nitroaldol reaction of 1 into
the deuterium-labeled nitroalcohol product (2-d2).
Additionally, 2-d2 can be directly obtained from the
non-labeled 2. The stability of the C-D bonds based
on the isotope effect also contributes to preferentially
generate the deuteration processes (paths A and C).
Consequently, the deuterium-labeled nitroalcohol
product (2-d2) with high deuterium contents is
available.
The asymmetric nitroaldol reaction accompanied
by the deuterium-labeling using a chiral basic
organocatalyst in D2O was also investigated (Table 3).
The enantioselective nitroaldol reactions without the
deuterium-labeling step in aqueous media have been
accomplished using transition metal-based chiral
catalysts.[9] Although the organocatalytic nitroaldol
reactions using cinchona alkaloid derivatives were
also reported in the literature, organic solvents
(CH2Cl2 and THF) were always required.[10] We
chose quinine and quinidine derivatives bearing
tertiary amine and quinoline moieties within the
molecule, which facilitates the desirable asymmetric
nitroaldol reaction associated with the deuterium-
labeling process in D2O as shown in Table 3. While
quinine (cat. 1a) and its derivatives (cat. 1b and cat.
1c) were inefficient (entries 1-3), the cat. 1d [R1 = H,
R2 = benzoyl (Bz)]-catalyzed nitroaldol reaction of
CH3NO2 and ethyl benzoylformate (7) in D2O could
efficiently proceed to form the desired product (R)-8-
d2[11] in high yield, D content and ee (entry 4).[12] The
use of the benzoyl quinidine derivative (cat. 2) also
effectively provided (S)-8-d2 (entry 5). The tertiary-
butyl benzoylformate (13a) was a more suitable
substrate to improve the enantioselectivity to produce
14a-d2 in 94% ee (entry 6).
Table 3. Application to asymmetric reaction using
benzoylformate (7 or 13a).
Scheme 2. Proposed reaction mechanism of WA30-
catalyzed deuteration of CH3NO2 and subsequent
nitroaldol reaction.
D
(%)
content yield
(%)
entry catalyst
R
ee
The generated deuterium-labeled product 2a-d2
could undergo a further transformation by elimination
1
Et
89
98
12
cat. 1a
3
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10.1002/adsc.201701224
Advanced Synthesis & Catalysis
2
3
4
5
6
Et
Et
Et
Et
84
93
94
91
93
7
66
cat. 1b
cat. 1c
cat. 1d
cat. 2
35
98
94
93
90
90[a]
tBu 93
94
cat. 1d
[a] (S)-8-d2 was obtained as the principal product.
tertiary-Butyl benzoylformate derivatives (13b–
13i) bearing various functionalities, such as methoxy,
siloxy, fluoro, ethoxycarbonyl and nitrile groups, on
the
aromatic
ring
were
efficiently
and
enantioselectively reacted with the in situ-generated
CD3NO2 in the presence of cat. 1d to give the
corresponding chiral -bisdeuterated -nitroalcohol
products (14b-d2–14i-d2) with high D contents and
excellent ee values (Table 4). 13j and 13k bearing
naphthalene- (13j) and thiophene- (13k) rings also
underwent the asymmetric nitroaldol reaction with
deuterium labeling to provide the desired products
(14j-d2 and 14k-d2) in good to excellent
enantioselectivities. Although the reaction of the
cyclohexyl (13l) and phenylalkynyl (13m) derivatives
also
stereoselectively
proceeded,
their
enantioselectivities were slightly decreased.[13]
Because the cat. 1d-catalyzed reaction of 13a in H2O
instead of D2O gave the non-labeled chiral -
nitroalcohol product (14a) with an excellent ee (eq. 5),
the present metal-free methodology is also useful as a
simple asymmetric reaction without the deuterium-
labeling process from view point of green sustainable
chemistry. Furhtermore, cat. 1d recovered after the
reaction could be reused without decreasing the
catalytic activity (eq. 6).
[a] The second step was for 48 h.
[b]19% of the substrate was recovered.
Table 4. Organocatalytic and asymmetric nitroaldol
reaction associated with deuterium labeling.
In conclusion, we have developed the efficient
synthetic method to construct -deuterated -
nitroalcohols by the base-catalyzed deuteration of
nitroalkanes in D2O and the consecutive nitroaldol
reaction in a one-pot manner. The present reaction
could be heterogeneously catalyzed by the easily-
eliminable WA30 to give the corresponding -
deuterated -nitroalcohol derivatives (2–4, 6, 8).
Furthermore, a quinine-derived organocatalyst (cat.
1d) allowed the highly enantioselective reaction of α-
keto ester derivatives (7 and 13) to efficiently provide
the desired chiral deuterium-labeled products (8 and
14). The present unprecedented methodology can
easily provide various -deuterated -nitroalcohol
products, as deuterium-labeled synthetic building
blocks.
Experimental Section
Experimental Details WA30-catalyzed reaction: A solution
of a nitroalkane (2.5 mmol, 134 μL) and WA30 (10 mg) in
D2O (1 mL) was stirred at rt for 2 h. An aldehyde (1: 0.25
4
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10.1002/adsc.201701224
Advanced Synthesis & Catalysis
mmol) was added to the reaction mixture and stirred for 12
h. The reaction mixture was filtered and the filtrate was
extracted with Et2O (5 mL x 2). The combined organic
layers were dried over Na2SO4, and concentrated in vacuo.
The crude residue was purified by silica-gel column
chromatography to give the -deuterated -nitroalcohol 2-
dx.
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Palomo, M. Oiarbide, A. Mielgo, Angew. Chem. Int. Ed.
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[6] a) J. C. Borah, S. Gogoi, J. Boruwa, B. Kalita, N. C.
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46, 7581–7582; c) A. Cochi, T.-X. Metro, D. G. Padro,
J. Cossy, Org. Lett. 2010, 12, 3693–3595.
Asymmetric reaction: A solution of CH3NO2 (2.5 mmol,
134 μL) and cat. 1d (5 mol%) in D2O (1 mL) was stirred at
rt for 24 h. An acylformate (7 or 13) (0.25 mmol) was
added to the reaction mixture at 0 °C and stirred for 24 h.
The reaction mixture was directly purified by silica-gel
column chromatography to produce 14-d2.
Acknowledgements
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We thank the Mitsubishi Chemical Corporation for the kind gift
of WA30. This work was partially supported by Grant-in-Aid for
Scientific Research (C) from the Japan Society for the Promotion
of Science (JSPS: 16K08169 for Y.S.) and a Grant-in-Aid from
JSPS (15J01556 to T.Y.).
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[11] The absolute configuration of (R)- or (S)-8-d2 was
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5
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Advanced Synthesis & Catalysis
COMMUNICATION
Organocatalytic Nitroaldol Reaction Associated
with Deuterium-Labeling
Adv. Synth. Catal. Year, Volume, Page – Page
Tsuyoshi Yamada, Marina Kuwata, Ryoya
Takakura, Yasunari Monguchi, Hironao Sajiki*,
and Yoshinari Sawama*
6
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