Hydroquinone and benzoquinone-catalyzed aqueous Knoevenagel condensation

Article abstract of DOI:10.1039/d0ob01397h

A Knoevenagel condensation of various aldehydes with malononitrile effectively proceeded in the presence of hydroquinone/benzoquinone mixed catalysts at room temperature in H2O. Furthermore, γ-deuterium-labeled α,β-unsaturated nitrile derivatives were als

Full text of DOI:10.1039/d0ob01397h

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DOI: 10.1039/D0OB01397H
COMMUNICATION
Hydroquinone and Benzoquinone-Catalyzed Aqueous
Knoevenagel Condensation
a
a
a
a
a
Ryoya Takakura, Kaho Koyama, Marina Kuwata, Tsuyoshi Yamada, Hironao Sajiki* and
Received 00th January 20xx,
Accepted 00th January 20xx
a
Yoshinari Sawama*
DOI: 10.1039/x0xx00000x
A
Knoevenagel condensation of various aldehydes with accomplished to give γ-deuterated α,β-unsaturated nitriles with
malononitrile effectively proceeded in the presence of high deuterium contents.
hydroquinone/benzoquinone mixed catalysts at room temperature The Knoevenagel condensation between decanal (1a; 0.25
o
in H
2
O. Furthermore, γ-deuterium-labeled α,β-unsaturated nitrile mmol) and malononitrile (2.5 mmol) in H
2
O for 3 h at 25 C
derivatives were also constructed via a deuteration of an aliphatic without any catalyst could proceed to give 2-
aldehyde in D O using a basic resin and the subsequent decylpropanedinitrile (2a) in a low yield (14%, Table 1, entry 1).
2
Knoevenagel condensation.
The reaction efficiency slightly improved by adding HQ (0.1
equiv.) bearing weak acidic aromatic hydroxyl groups within the
molecule (entry 2). BQ indicated a higher catalyst activity to give
The Knoevenagel condensation of aldehydes with active
methylene compounds to provide α,β-unsaturated products
has been widely utilized in various fields, such as the fine
chemical and pharmaceutical industries. The Knoevenagel
condensation is generally catalyzed by bases (e.g., organic
2
a in 60% yield (entry 3). It is noteworthy that the combined use
of a catalytic amount of HQ and BQ further efficiently promoted
the desired reaction. The starting substrate (1a) was
quantitatively converted to 2a within 3 h (entry 4), while the
conversion was incomplete after a 1.5 h reaction (entry 6).
Furthermore, the reactivity could be maintained even if only
1
2
3
4
amines, ammonia, ammonium salts), amino acids and acids
5
in organic solvents. On the other hand, the solvent-free or
aqueous6
-11
reactions were recently spotlighted from the
0
.05 equiv. of each HQ and BQ was used (entry 5). Decreasing
viewpoint of safety and green sustainability. Although ionic
the use of malononitrile from 10 to 5 equiv. led to the lower
yields of 2a (entry 7). Knoevenagel condensation also
proceeded under the air to give 2a in good yield (entry 8). The
present reaction smoothly proceeded in H O, but the reaction
2
efficiency significantly dropped in organic solvents [MeOH, N,N-
dimethylformamide (DMF), tetrahydrofuran (THF), n-hexane or
6
7
liquids, well-defined heterogeneous catalysts (e.g., polymer,
8
9
magnetic nanoparticles, metal-organic frameworks ), or bases
1
0
[
e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
1,4-
1
1
diazabicyclo[2.2.2]octane (DABCO) ] were used in the aqueous
Knoevenagel condensation, heating was frequently required,
and the applicable substrates were limited. In particular, there
were few examples when aliphatic aldehydes were used as the
substrates. Therefore, the development of a convenient and
mild method bearing a broad substrate scope is still desired. We
now report the hydroquinone (HQ) and benzoquinone (BQ)-
catalyzed Knoevenagel condensation, which is applicable to a
2 2
CH Cl ] (entries 4 vs. 9-13). Quinhydrone (QH; HQ-BQ complex),
which forms based on the hydrogen bonding and π-π
interaction between HQ and BQ, has been frequently used in
12
electrochemistry. No product was obtained under solvent-
free conditions (entry14). The addition of QH instead of the
combined use of HQ and BQ gave the desired α,β-unsaturated
nitrile (2a) in 85% yield (entry 15).
2
wide range of aromatic and aliphatic aldehydes, in H O at room
temperature. Moreover, the Knoevenagel reaction with a
combination of basic resin-catalyzed deuterium-labeling of
aliphatic aldehydes in deuterium oxide (D O) has also been
2
Various combinations of the hydroquinone and benzoquinone
derivatives were next evaluated by the Knoevenagel reaction of
1
a in H
reaction could efficiently proceed by the use of the simple
unsubstituted) HQ and BQ (Table 1 entry 4; Table 2, entry 1),
the case of 2-methoxybenzoquinone, 2-chlorobenzoquinone or
,4-cyclohexanedione instead of BQ caused lower catalyst
2
O at room temperature for 3 h (Table 2). While the
(
a. Laboratory of Organic Chemistry, Gifu Pharmaceutical University
-25-4 Daigakunishi, Gifu 501-1196, Japan
E-mail: sajiki@gifu-pu.ac.jp, sawama@gifu-pu.ac.jp
Electronic Supplementary Information (ESI) available: [details of any
1
1
†
activities (entries 2-4). Meanwhile, 2-methoxy or 2-
chlorohydroquinone instead of HQ moderately catalyzed the
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Page 2 of 5
COMMUNICATION
Journal Name
Knovenagel condensation to give 2a in good yields (entries 5
and 6). Resorcinol, catechol, or phenol as a co-catalyst of BQ
was ineffective (entries 7-9). The use of 1,4-dimethoxybenzene
instead of HQ significantly decreased the yield of 2a (entry 10).
OH
Cl
O
O
View Article Online
DOI: 10.1039/8D00OB01397H
6
7
HO
O
O
OH
OH
65
OH
Table 1. Optimization of the Knoevenagel condensation of decanal (1a).a
O
O
O
8
9
1
41
62
36
OH
O
OH
OH
O
O
O
+
HO
(HQ; X equiv.)
O
CN
CN
CHO
8
(BQ; Y equiv.)
CN
CN
2a
8
solvent, rt, time, Ar
OMe
1
a
0
entry
X
Y
solvent
Time (h)
Yield (%)b
MeO
3
3
3
3
3
1
3
3
3
3
3
3
3
3
3
14
32
60
99
97
70
72
81
15
47
10
30
10
trace
85
1
2
3
4
5
6
7c
–
–
H
H
H
H
H
H
H
H
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
a
Reaction conditions: 1a (0.25 mmol), malononitrile (10 equiv.), H
2
O (1 mL), rt, 3
h. b Isolated yield after silica-gel column chromatography.
0.1
–
–
0.1
0.1
0.05
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
–
The addition of butylhydroxytoluene (BHT) or galvinoxyl as a
radical scavenger did not completely suppress the Knoevenagel
condensation of 1a (Scheme 1, eq. 1) and the reaction of 1a
under dark conditions also smoothly proceeded (eq. 2). Based
on these results, the radical pathway of the reaction mechanism
can be ruled out. According to the results shown in Table 1, for
entries 1-4, the basicity based on the lone pair of carbonyl
groups of BQ mainly facilitates the Knovenagel condensation,
and the acidity of HQ partially and additively assists the reaction
progress. A plausible reaction mechanism is shown in Scheme
0.1
0.05
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
–
.5
8d
9e
MeOH
DMF
1
1
1
1
1
1
0
1
2
3
THF
1
, eq. 3. HQ-catalyzed nucleophilic addition of malononitrile
n-hexane
activated by BQ to aldehyde (1) gives a cyanohydrin A. The
consecutive dehydration provides α,β-unsaturated nitrile (2).
CH
2 2
Cl
4
–
BQ (0.1 equiv.)
HQ (0.1 equiv.)
5f
2
H O
CN Radical scavenger (1 equiv.)
CHO
8
CN
CN
(
(
1)
2)
8
H2O (1 mL), rt, 3 h, Ar
a
b
CN
a (0.25 mmol) 10 eq.
Reaction conditions: 1a (0.25 mmol), malononitrile (10 equiv.), solvent (1 mL), rt.
Isolated yield after silica-gel column chromatography. 5 equivs. of malononitrile
were used. The reaction was carried out under air conditions. Decanal dimethyl
acetal was also obtained in 60% yield. 0.1 equiv. of quinhydrone (QH; a complex
2
a
1
c
Radical scavenger: BHT
; 1a/2a = 60/40 (%)
d
e
Galvinoxyl ; 1a/2a = 18/52 (%)
f
BQ (0.1 equiv.)
HQ (0.1 equiv.)
CN
CN
a: 78%
recovered 1a: 6%)
of HQ and BQ) was used instead of the HQ and BQ combination.
CHO
8
CN
CN
8
H2O (1 mL), rt, 3 h, Ar, dark
2
1
a (0.25 mmol) 10 eq.
(
NC
NC
NC
NC
Table 2. Effect of additives.a
H
O
O
(BQ)
additive A (0.1 equiv.)
additive B (0.1 equiv.)
HO
O
R
OH
BQ
CN
CN
CHO
8
CN
CN
2a
H
8
(HQ)
H2O, rt, 3 h, Ar
O
OH
OH2
O
1
a
CN
CN
CN
(3)
R
R
H
R
H
CN
CN
+
CN
entry additive A
additive B
yield (%)b
2
H /H O
1
A
2
OH
O
Scheme 1. Mechanistic studies and proposed reaction mechanism.
1
99
HO
(HQ)
OH
O
(BQ)
O
Various substrates, such as aromatic and aliphatic aldehydes,
were applicable under the HQ and BQ-dually-catalyzed reaction
2
3
4
5
42
77
28
83
HO
HO
HO
HO
O
O
O
O
OMe
1
3,14
conditions (Table 3).
The Knoevenagel condensation of
OH
OH
O
aromatic aldehydes bearing electron-donating or electron-
withdrawing groups on aromatic nuclei efficiently proceeded to
give the corresponding products in high yields (2b–2n). A
tetrahydropyranyl (THP) ether as an acid-labile acetal-type
protecting group of 2o was tolerant under present reaction
conditions. Heteroaromatic aldehydes, such as furfural (1p),
Cl
O
OH
O
OMe
pyrrole-2-carboxaldehyde
(1q),
and
2-
2
| J. Name., 2012, 00, 1-3
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Journal Name
thiophenecarboxaldehyde (1r), were also applicable as product (2a-d
COMMUNICATION
) was obtained in 49% yield with a 95% D content
2
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substrates. Aliphatic aldehydes bearing an olefin, hydroxy (entry 1). Deuteration hardly proceededDwOIi:t1h0o.1u0t39W/DA03O0B0(e13n9t7rHy
group, tert-butyldimethylsilyl (TBS) ether, etc., were also 2). Meanwhile, the removal of WA30 by filtration before the HQ
smoothly transformed into α,β-unsaturated nitriles (2s–2v) in and BQ-catalyzed Knoevenagel reaction improved the yield of
good to high yields. Aliphatic aldehydes containing a hydroxyl 2a-d
group or its protecting form were also reacted with could undergo α-deuteration and the subsequent Knoevenagel
malononitrile to provide the corresponding condensation in the presence of WA30 even without HQ and
2
while maintaining a high D content (entry 3). Although 1a
alkylidenemalononitriles in good yields (2w and 2x).
2
BQ, the chemical yield of 2a-d had significantly decreased
(
entry 4). Under the optimized reaction conditions (Table 4,
Table 3. Scope of substrates.a
entry 3), aliphatic aldehydes (1a, 1t, and 1x) were transformed
into the corresponding γ-deuterated α,β-unsaturated nitriles in
moderate yields with high D contents (Scheme 2).
OH
O
CN
CN
HO
O
CN
CN
CHO
R
R
H2O, rt, 3 h, Ar
Table 4. Application to synthesis of γ-deuterated α, β-unsaturated nitriles.
1
2
CN
NC CN (10 equiv.)
HQ (0.1 equiv.)
BQ (0.1 equiv.)
R1
CN
D D
CHO
D D CN
CN
2a-d2
Additive
CHO
7
R1 =
D O (1 mL)
7
rt, 3 h
2-OMe (2b)
: 89%
: 94%
: 97%
: 95%
: 96%
: 94%b
2-Me (2h)
3-Me (2i)
4-Me (2j)
2-NO2 (2k)
3-NO2 (2l)
: 93%
: 98%
: 92%
: quant.
: 28%
2
7
rt, 24 h
1
a
3
4
2
3
4
-OMe (2c)
-OMe (2d)
-Cl (2e)
entry additive
D content (%)b
yield (%)c
1
2
3
4
WA30 (20 mg)
95
0
97
95
49
60
63
24
–a
WA30 (20 mg)b
WA30 (20 mg)d
-Cl (2f)
-Cl (2g)
4-NO2 (2m) : 73%b,c
NC
a
2
Reaction conditions: 1a (0.25 mmol), WA 30 (20 mg) and D O (1 mL) were used
at rt for the first step. Then, malononitrile (10 equiv.; 2.50 mmol), HQ (0.1 equiv.;
.25 mmol) and BQ (0.1 equiv.; 0.25 mmol) were used at rt for the second step.
CN
CN
O
b
0
CN
CN
CN
2p: quant.
HO
THPO
1
The D content of 2a-d
2
was determined based on the integral value of H NMR
2
n: 84%
2o: 70%b
NC
c
d
analysis. Isolated yield after silica-gel column chromatography. The reaction was
carried out in the absence of HQ and BQ.
NC
CN
NH
S
CN
CN
CN
2
q: 82%
2r: 95%
2s: 66%
D D
D D
CHO
CHO
CHO
CHO
7
7
7
7
CN
CN
t: 80%
CN
CN
CN
1a
1t
WA30
1a-d2
1t-d2
or
or
D D
8
CN
D O
2
TBSO
TBSO
2
2v: 99%
CHO
rt, 24 h
then filtration
CHO
2
u: 80%
4
4
1x
1x-d2
HO
CN
CN
TBSO
CN
CN
9
7
96
OH
O
D D CN
CN
2a-d2: 63% or
D D CN
5
5
2
w: 77%c
2x: 69%
HO
O
7
7
CN
NC
CN
2t-d2: 44%
9
7
CN
CN
a
rt, 3 h
D D
Reaction condtion: 0.25 mmol 1, 10 eq. malononitrile, 0.1 eq. HQ, 0.1 eq. BQ, 1
O, rt, 3 h. The reaction was stirred for 6 h. 0.5 eq. of hydroquinone and
benzoquinone were added.
TBSO
b
c
mL H
2
4
2
x-d2: 51%
Scheme 2. Synthesis of γ-deuterium-labeled α,β-unsaturated nitrile
derivatives.
Deuterium-labeled compounds are widely utilized in various
scientific fields, such as human metabolism analyses, reaction
mechanistic studies, heavy drugs, neutron contrast scattering
1
5
Conclusions
We have achieved
analyses, etc. Therefore, various synthetic methods have been
1
6
developed. We have also recently reported the hydrogen (H)-
deuterium (D) exchange reaction of an acidic proton of alkynes
a simple and green Knoevenagel
condensation catalyzed by the mixed use of BQ and HQ in H
2
O
2
and nitromethane, etc., in deuterium oxide (D O) as an easily
at room temperature. A wide variety of aldehydes were
smoothly transformed into the corresponding α,β-unsaturated
nitrile derivatives. In addition, the efficient synthetic method to
construct γ-deuterated α,β-unsaturated nitriles via the basic
1
7
available deuterium source under weak basic conditions. We
have newly developed a basic resin (WA30)-catalyzed
deuteration of the a-position of aliphatic aldehydes and
subsequent Knoevenagel reaction to provide the γ-deuterated
α,β-unsaturated nitrile (Table 4). After stirring 1a and WA30 in
2
resin-catalyzed deuteration of aliphatic aldehydes in D O and
consecutive Knoevenagel reaction was also developed. Because
the present method is the first example using a combination of
BQ and HQ as a catalyst in organic synthesis, novel and
2
D O for 24 h at room temperature, malononitrile, HQ, and BQ
were added to the reaction mixture. The reaction mixture was
further stirred for 3 h at room temperature and the desired
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
2
007, 46, 7744; (d) J. M. Herbert, J. LabVeielwleAdrticlCeoOmnlinpe.
beneficial synthetic information can be provided to many
organic chemists.
Radiopharm. 2010, 53, 658.
DOI: 10.1039/D0OB01397H
1
1
6 (a) J. Atzrodt, V. Derdau, W. J. Kerr and M. Reid, Angew. Chem.
Int. Ed. 2018, 57, 3022; (b) Y. Sawama, Y. Monguchi and H.
Sajiki, Synlett 2012, 23, 959; (c) Y. Sawama, K. Park, T. Yamada
and H. Sajiki, Chem. Pharm. Bull. 2018, 66, 21.
7 (a) Y. Yabe, Y. Sawama, Y. Monguchi and H. Sajiki, Chem. Eur.
J. 2013, 19, 484; (b) T. Yamada, K. Park, Y. Monguchi, Y.
Sawama and H. Sajiki, RSC Adv., 2015, 5, 92954; (c) T. Yamada,
M. Kuwata, R. Takakura, Y. Monguchi, H. Sajiki and Y. Sawama,
Adv. Synth. Catal. 2018, 360, 637.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This study was supported by a Grant-in-Aid for JSPS Research
Fellows from the Japan Society for the Promotion of Science
(JSPS, Number: 18J23126 for R. T.)
Notes and references
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016, 844, 30099.
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2 S. Rosini and E. Siebert, Electrochim Acta 2004, 49, 525.
3 The Knoevenagel condensation could proceed without
catalyst as shown in Table 1, entry 1. The comparison of
reactivities using some aldehydes with or without HQ and BQ
is described in SI.
1
1
4 Dimethyl malonate, ethyl cyanoacetate and acetonitrile
instead of malononitrile as nucleophiles resulted in no
reaction.
5 (a) T. Pirali, M. Serafini, S. Cargnin and A. A. Genazzani, J. Med.
Chem. 2019, 62, 5276; (b) J. Atzrodt, V. Derdau, W. J. Kerr and
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V. Derdau, T. Fey and J. Zimmermann, Angew. Chem. Int. Ed.
4
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0OB01397H
Table of Contents
OH
O
CN
CN
HO
O
CN
CN
CHO
R
R
H2O, rt
・
Green solvent
2
6 examples
R = (Het)Ar, alkyl
・ Wide scope of substrates
up to 99% yield
Aqueous Knoevenagel condensation of various aldehyde with malononitrile could efficiently
proceed using hydroquinone and benzoquinone as mixed catalysts.