Basic Anion-Exchange Resin-Catalyzed Aldol Condensation of Aromatic Ketones with Aldehydes in Continuous Flow

Article abstract of DOI:10.1021/acs.oprd.9b00048

A general method for the aldol condensation of aromatic ketones with aldehydes was developed under continuous-flow conditions using a commercially available, strongly basic anion-exchange resin (A26) as catalyst. This procedure, in addition to exhibiting a wide substrate scope, promoted carbon-carbon bond formation under mild conditions using a quasi-stoichiometric ratio of starting reagents with good to excellent yields, thereby forming a limited amount of waste and allowing the process to be applied to sequential-flow systems. A proof of concept was developed in the first fully heterogeneously catalyzed two-step flow synthesis of donepezil, which is a blockbuster commercial anti-Alzheimer's drug.

Full text of DOI:10.1021/acs.oprd.9b00048

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Full Paper
Basic anion-exchange resin catalyzed aldol condensation
of aromatic ketones with aldehydes in continuous flow
Benjamin Laroche, Yuki Saito, Haruro Ishitani, and Shu Kobayashi
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 26 Mar 2019
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Organic Process Research & Development
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Basic anion-exchange resin catalyzed aldol condensation of
aromatic ketones with aldehydes in continuous flow
Benjamin Larochea, Yuki Saitoa, Haruro Ishitanib, Shū Kobayashi*a,b
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a. Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
b. Green & Sustainaible Chemistry Cooperation Laboratory, Graduate School of Science, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033 (Japan)
KEYWORDS: flow chemistry; aldol condensation; heterogeneous catalysis; C-C bond formation; flow fine synthesis.
ABSTRACT: A general method for the aldol condensation of aromatic ketones with aldehydes was developed under continuous-
flow conditions using a commercially available, strongly basic anion-exchange resin (A26) as catalyst. This procedure, in addition to
exhibiting a wide substrate scope, promoted carbon–carbon bond formation under mild conditions using a quasi-stoichiometric ratio
of starting reagents with good to excellent yields, thereby forming a limited amount of waste and allowing the process to be applied
to sequential-flow systems. A proof of concept was developed in the first fully heterogeneously catalyzed two-step flow synthesis of
donepezil, which is a blockbuster commercial anti-Alzheimer drug.
applications compared with solid-acid catalysts because of their
low stability and sensitivity to moisture, and because they often
require harsh conditions and the use of excess amounts of
reagents or catalysts. In parallel, anion-exchange resins have
been utilized as environmentally friendly and water-tolerant
heterogeneous base catalysts for various kinds of
transformations, including aldol condensation reactions.12
However, few examples of the application of heterogeneous
catalysis in industrially viable continuous-flow systems have
been reported.13 Recently, our group has demonstrated the
application of strongly basic ammonium hydroxide anion-
exchange resins for the flow synthesis of venlaflaxine,14 and for
the Knoevenagel condensation of aldehydes and ketones with
alkyl nitriles under continuous-flow conditions.15 Schütz and
colleagues also utilized a strongly basic anion-exchange resin,
A26, to catalyze the flow synthesis of -ionone through aldol
condensation, but an excess of acetone (9 equiv.) was required
and catalyst deactivation was observed after a 16 h operation.13a
Herein, we report a general basic anion-exchange resin
INTRODUCTION
The combination of heterogeneous catalysis with continuous-
flow chemistry is one of the most efficient strategies to promote
expeditious access to bioactive molecules in a sustainable way.1
First of all, heterogeneous catalysis allows easy and
inexpensive recovery of thermally stable catalysts while
avoiding the need for tedious separations and purifications of
intermediates or products from reaction mixtures.2 Then, flow
systems afford safe, scalable, and continuous production of
chemical entities.3 When coupled with atom-economical
transformations such as additions, hydrogenations,
condensations, or rearrangements, these combined strategies
are ideal from a green organic synthesis point of view towards
sustainable society, and they have recently attracted much
attention for the construction of multistep continuous-flow
systems.4
The base-catalyzed aldol condensation reaction between
enolates of carbonyl compounds and aldehydes or ketones, also
called Claisen–Schmidt condensation, is one of the most
fundamental and highly atom-economic C–C bond-forming
reactions.5 Brønsted bases such as NaOH, KOH, EtONa, or
quaternary ammonium bases are conventionally used as
catalysts for this transformation, allowing access to ,-
unsaturated carbonyl compounds, which are versatile building
blocks for synthetic methodologies, natural products, and drug
design.6 Despite the relatively straightforward nature of these
methods, issues associated with catalyst recovery and waste
treatment remain. As an alternative, heterogeneous catalysts
such as alumina,7 barium hydroxide,8 zeolite,9 hydrotalcites,10
or, more recently, metal-organic frameworks,11 have been
developed for aldol condensation reactions. Despite these
efforts, solid-base catalysts still have very limited industrial
catalyzed aldol condensation method with
a
quasi-
stoichiometric ratio of starting reagents in continuous-flow.
This method allowed the continuous formation in good to
excellent yields of a large panel of ,-unsaturated carbonyl
compounds with a limited amount of chemical waste by
implementing a key solvent system that enabled the catalyst
activity to be maintained for more than 5 days without any
deactivation. The method’s application to the heterogeneously
catalyzed two-step flow synthesis of donepezil, an anti-
Alzheimer drug, is also described.
RESULTS AND DISCUSSION
Our investigations began with the screening of heterogeneous
base catalysts for the aldol condensation between -tetralone 1a
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and benzaldehyde 2a as model substrates under batch
Page 2 of 8
for this transformation (entries 6, 9, and 10, respectively),
whereas DMF gave unsatisfactory results (entry 11). The
reaction was also performed at lower temperature in EtOH for
18 h (entry 12), and only -hydroxyl intermediate 4aa was
observed in 42% yield along with a diastereoisomeric ratio of
36:64, showing that the formation of ,-unsaturated ketone
3aa was governed by the temperature of the reaction mixture
(thermodynamic product). It is also important to highlight that
these conditions included a slight excess of electrophile, which
was relatively promising at this stage compared with previous
reports that required excess amounts of nucleophiles.13a
1
2
3
4
5
6
7
8
conditions (Table 1).
Table 1. Preliminary investigations under batch conditions
O
O
O
O
OH
Catalyst (50 mg)
Solvent (1 mL)
3 h, 25 °C
1a
2a
1.2 equiv.
3aa
4aa
0.3 mmol
9
Yield 3aa
Yield 4aa
(dr)[%]a
0
Entry
Catalyst
Solvent
THF
THF
THF
THF
THF
THF
THF
[%]a
0
10
11
12
13
14
15
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17
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1
2
3
4
5
6
7
SiO2-NH2
SiO2-DNH
MgO
Encouraged by these preliminary outcomes, a flow system was
designed as follows. A 0.1 M solution of ketone 1a and 1.05
equivalents of aldehyde 2a in an appropriate solvent were
pumped at 0.15 mL/min into a bed reactor packed with 7 g of
prewashed A26 catalyst and heated at 60 C with an aluminum
block. The resulting crude solution was then collected,
evaporated, and analyzed by 1H NMR spectroscopy (Figure 1).
Toluene solvent was initially preferred because the use of THF
gave lower yields, and EtOH was discarded because of
solubility issues (see the Supporting Information (SI) for the
optimization experiments). Similar to the batch system, the
selective formation of ,-unsaturated ketone 3aa was found to
be controlled by the temperature of the flow reactor, affording
84% yield of enone 3aa after 18 h operation with complete
selectivity at 60 C. However, investigations of the process
lifetime with toluene as the sole solvent revealed a dramatic
reduction in yield after 28 h operation (75% yield), indicating a
deactivation of the basic resin catalyst. To address this
fundamental issue, we discovered that cosolvent systems had a
tremendous effect on the catalyst lifetime.
0
<5
0
0
0
CaO
0
KF/Al2O3
A26 (type I)
0
0
0
75
23
IRA910
(type II)
18 (50:50)
8
WA30
(tertiary
amine)
THF
0
0
9
A26
A26
A26
A26
EtOH
Toluene
DMF
62
63
49
0
0
10
11
12b
0
O
O
O
13 (54:46)
42 (36:64)
0.15 mL/min
A26 (7 g)
EtOH
10 x 100 mm SUS
1a
1 equiv.
Solvent (0.1M)
2a
3aa
60 °C
1.05 equiv.
a Yield based on 1H NMR analysis using 1,4-di-tert-butylbenzene as internal
standard; b Reaction was performed at –40 C for 18 h.
H2N
90
SiO2
PS
PS
PS
SiO2
OH
OH
NMe3
OH
NH2
N
N
80
70
60
50
40
30
20
10
0
N
H
SiO2-NH2
SiO2-DNH
Type I (A26)
Type II (IRA910)
Tertiary amine (WA30)
TOF: 0.09 h-1
STY: 354 g/(L·day)
Batch reactions were initially performed at 25 C for 3 h at 0.3
M concentration in THF relative to 1a, using 50 mg of
heterogeneous catalysts. First, amine functionalized SiO2 were
investigated, but no catalytic activity was observed,
undoubtedly because of their low basicity (Table 1, entries 1
and 2). Surprisingly, conventional solid-base catalysts such as
MgO, CaO, or KF/Al2O3 were also found to be unsuccessful
(entries 3–5). Nevertheless, we were pleased to observe
outstanding activity of type I polystyrene (PS)-supported
ammonium hydroxide resin (A26), affording a 75% yield of the
desired enone 3aa, without any trace of -hydroxyl
intermediate 4aa (entry 4). Inspired by this result, different
types of basic resins were investigated, such as type II (IRA910)
and supported tertiary amine (WA30, entries 7 and 8). The
lower basicity of these catalysts led to lower yields of the
desired product 3aa, along with the formation of 18% of
intermediate 4aa for IRA910 (entry 8). A screening of
industrially viable solvents was then achieved using A26 as
catalyst (entries 9–11). THF, EtOH, and toluene were suitable
Time [h]
0
20
40
60
80
100
120
Toluene
Toluene/EtOH (9:1)
THF/EtOH (9:1)
Toluene/EtOH (7:3)
Toluene/EtOH (9:1) (A26: 10g/10 x 150 mm SUS)
Figure 1. Cosolvent optimization and lifetime investigation
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Gratifyingly, mixing toluene with 10% EtOH overcame the
Electron-withdrawing substituted aromatic aldehydes such as
para-bromo (2b) and chloro (2c) benzaldehyde afforded high
yields of the corresponding ,-unsaturated ketone 3ab and 3ac
(85–87 and 82–84%, respectively, entries 2 and 3). For the case
of para-fluorobenzaldehyde 2d (entry 4), only 60–61% yield of
the desired product was obtained because of the formation of
para-ethoxybenzaldehyde, derived from aromatic nucleophilic
substitution of the fluorine in the presence of EtOH under basic
conditions.16 Interestingly, such undesired secondary reaction
did not occur when ortho-fluorobenzaldehyde (2e) was used,
furnishing an almost perfect outcome (entry 5). The effect of
electron-donating substituents showed that ortho-substituted
aromatic aldehydes were more reactive than the corresponding
para-isomers (entries 6–10). This unusual superior reactivity of
ortho-substituted aromatic aldehydes was further studied and
was suspected to arise from specific interactions of the
ammonium counteranion with ortho-substituted substrates.17
To continue, the catalytic system was found to be tolerant to
other heteroaromatics, such as 2-thiophene (entry 13) and 2-
furyl (entry 14) compounds, as well as acetal-containing
piperonal, although the yields remained moderate (52–59%,
entry 15). Aliphatic aldehyde 4-formylcyclohexene was also
successful, giving about 90% of the desired product 3ap (entry
16). Except where otherwise stated, it is notable that no
intermediates or by-products were formed during the aldehyde
screening, and that most of the desired compounds could be
isolated by simple recrystallization in EtOH (see SI for more
details).
1
2
3
4
5
6
7
8
catalyst deactivation, affording an average yield of 78–83% of
compound 3aa continuously between 25 and 80 h. As
representative comparison, using the same ratio of EtOH with
THF as the main solvent showed lower reactivity and shorter
lifetime, highlighting the importance of toluene for this
transformation. Although increasing the ratio of EtOH to 30%
was found to be efficient to reduce the time to access the steady
state (77% yield after only 3 h operation), a gradual decrease in
yield associated with lower solubility of 3aa in higher
concentration of EtOH was observed. An acceptable way to
accelerate the process was to increase the catalyst amount to 10
g, along with the reactor length (10  150 mm SUS), affording
81–84% yield of the desired product from 6 h operation to more
than 5 days without any sign of catalyst deactivation (TOF: 0.09
h–1 and STY: 354 g/(L·day)).
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With these optimized conditions in hand, we embarked on an
assessment of the substrate scope by varying the benzaldehyde
substituents (Table 2, entries 2–10).
Table 2. Substrate scope of aldehydes in continuous flow
O
O
O
0.15 mL/min
R1
R1
H
A26 (10 g)
1a
2a-p
15 x 100 mm SUS
3aa-3ap
1 equiv.
1.05 equiv.
Temp (°C)
0.1 M in toluene/EtOH 9:1
Entry
Aldehyde (2a–p)
Product
3aa
Yield (3) [%]a
81–84
85–87
82–84
60–61
91–94
75–80
83
The substrate scope was further investigated by varying the
ketone substrates (Table 3, entries 1–12). In contrast with -
tetralone 1a, acyclic acetophenone 1b and acetonaphthone 1c
required only 25 C to promote the aldol condensation with
benzaldehyde 2a in high yields (about 90% for both cases,
entries 1 and 2). However, the affinity of acyclic substrates 1b
and 1c for lower temperatures went along with loss of
selectivity, furnishing some -hydroxyl intermediates and 1,4-
addition products in small but noticeable amounts. It is
noteworthy that reactivity and selectivity were lowered when
acyclic substrates were submitted to higher temperature. As an
example for entry 1 substrates, the yield of 3ab dropped to 55-
59% at 60 °C and 8-10% of 1,4-adduct 5ab was formed. The
need for higher temperatures in cyclic ketones series can be
streamlined by the steric hindrance caused by the cyclic strain.
This hypothesis was confirmed when 5,6-dimethoxy-1-
indanone (1d) was submitted to the aldol condensation with
benzaldehyde 2a; in this case the reaction indeed required 60
C to achieve quantitative yield of the desired product 3da
(entry 3). The electronic and steric effects on acetophenone-
type substrates were also investigated (Table 3, entries 4–8).
Electron-donating substituents such as 4-methyl or 4-
methoxyacetophenone required slightly higher reaction
temperature to give high yields of ,-unsaturated ketones 3ea
and 3fa (40 C, 91–92% and 81%, respectively, entries 4 and
5), while giving also small amounts of -alcohol intermediates.
In contrast, ortho-methoxyacetophenone 1g showed a high
yield with complete selectivity (88–89%, entry 6), highlighting
that steric hindrance at the ortho-position did not affect the
outcome of the reaction and even accelerated the dehydration
step.
1
2
2a
R1: 4-Br-C6H4 (2b)
R1: 4-Cl-C6H4 (2c)
R1: 4-F-C6H4 (2d)
R1: 2-F-C6H4 (2e)
3ab
3
3ac
4
3ad
5
3ae
6
R1: 2-OMe-C6H4 (2f)
R1: 3-OMe- C6H4 (2g)
R1: 4-OMe- C6H4 (2h)
R1: 2-Me-C6H4 (2i)
R1: 4-Me-C6H4 (2j)
R1: 2-pyridyl (2k)
R1: 4-pyridyl (2l)
3af
3ag
3ah
3ai
7
8
46
9
84
10
11
12
13
14
15
16
3aj
62–67
92–95
74–78
92–93
94–97
52–59
88–90
3ak
3al
R1: 2-thiophene (2m)
R1: 2-furyl (2n)
3am
3an
3ao
3ap
Piperonal (2o)
4-formylcyclohexene
(2p)
a
1
Yield based on H NMR analysis using 1,2,4,5-tetramethylbenzene as
internal standard.
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Page 4 of 8
Table 3. Substrate scope of ketones in continuous-flow
thiophene methyl ketone (1k) afforded the best results at 25 C
1
2
3
4
5
6
(about 87% yield for both, entries 9 and 10), while furyl methyl
ketone (1l) required 0 C (entry 11), essentially to reduce the
formation of 1,4-adduct 5la (13% of 5la was formed at 25 °C).
Finally, the conjugated 4-phenyl-3-buten-2-one 1m was
converted into the desired compound 3ma at 25 C in 70–73%
yield, along with 7% of aldol product 4ma (entry 12).
O
OH
Ph
R1
O
O
O
4
0.15 mL/min
R1
R2
H
O
Ph
A26 (10 g)
R1
Ph
O
R1
3
1a-m
2a
1.05 equiv.
15 x 100 mm SUS
1 equiv.
R1
Ph
Temp (°C)
0.1 M in toluene/EtOH 9:1
5
7
8
9
Following up the substrate scope investigations and considering
the outstanding results obtained with cyclic aromatic ketones,
we embarked upon a continuous-flow synthesis of donepezil
(6), which is a best-selling anti-Alzheimer drug that acts as a
reversible acetylcholinesterase inhibitor. While several
pathways have been developed, the initial and more direct
synthetic route to donepezil included an aldol condensation
between 5,6-dimethoxy-1-indanone (1d) and aldehyde (2q),
followed by a chemoselective enone reduction.18 Our synthetic
method using A26 as heterogeneous catalyst was thereby
applied for the aldol condensation of 1d and 2q (Scheme 1).
Reoptimization of the reaction conditions was required for this
highly valuable synthetic drug (see details in SI). Although the
concentration, the starting materials ratio, and the flow rate
were kept, much effort was devoted to finding an appropriate
solvent system to achieve the best outcomes. Ultimately, using
THF as the solvent was necessary to dissolve the almost
insoluble intermediate 3dq, while isopropanol (iPrOH) was
required to prevent A26 deactivation.
T
Ketone
Entry
Yield
Yield
Yield
(3) [%]b (4) [%]b (5) [%]b
[C]a
(1a–m)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2
R1: Ph;
25
86–90
92–94
7
3
2
2
R2: CH3 (1b)
R1: 1-
25
naphthyl;
R2: CH3 (1c)
3
4
5
6
5,6-
dimethoxy-1-
indanone (1d)
60
40
40
40
Quant.
91–92
81
0
5
6
0
0
0
0
0
R1: 4-Me-
C6H4;
R2: CH3 (1e)
R1: 4-OMe-
C6H4;
R2: CH3 (1f)
O
MeO
O
1.0 equiv.
0.15 mL/min
R1: 2-OMe-
C6H4;
88–89
MeO
MeO
MeO
1d
A26 (7 g)
R2: CH3 (1g)
O
3dq
55 °C
 10 x 100 mm
SUS column
1.05
Ph
equ
iv.
NBn
92_95% yield
TOFA26: 0.13 h-1
7
8
R1: 4-F-C6H4;
25
25
78–81
89
6–7
6–7
2–3
4
N
R2: CH3 (1h)
2q
STY: 972 g/(L·day)
0.1 M (THF/iPrOH, 9:1)
R1: 4-Br-
C6H4;
+2% H2O
Pd-DMPSi/Al2O3
(0.027 mmol)
R2: CH3 (1i)
O
MeO
Al2O3 (6.4 g)
9
R1: 2-pyridyl;
25
25
87
4
6
7–8
7
MeO
25 °C
R2: CH3 (1j)
 10 x 100 mm
Glass column
H2
N
6
(15 mL/min)
Donepezil (
)
Ph
10
R1: 2-
87–88
92_95% yield for 30 h
TOFPd: 31.2 h-1
thiophene;
STY: 488 g/(L·day)
Productivity: 7.7 g/day
R2: CH3 (1k)
Scheme 1. Two-step continuous synthesis of donepezil (6)
11
12
R1: 2-furyl;
0
82–84
70–73
6
7
8
0
R2: CH3 (1l)
Interestingly, it was discovered that the addition of 2% water to
the starting material solution tremendously accelerated the time
to reach the steady state: i.e., a 95% yield of 3dq was obtained
after only 3 h operation (6 h was needed without water).
Gratifyingly, telescoping the enone 3dq formation with
sequential-flow hydrogenation using our previously reported
Pd-DMPSi/Al2O3 heterogeneous catalyst at 25 C allowed us to
selectively produce 7.7 g per day of donepezil (6) continuously
for more than 30 h, without any trace of ketone reduction or
debenzylation products.19 Scale-up of the process in an
industrial setting is currently ongoing between our laboratory
and industrial collaborators.
4-phenyl-3-
buten-2-one
(1m)
25
a The optimal temperatures were selected by trial and error in flow; b Yield
based on 1H NMR analysis using 1,2,4,5-tetramethylbenzene as internal
standard.
Electron-withdrawing substituents such as para-fluoro (1h) and
para-bromoacetophenone (1i) displayed a higher reactivity,
requiring only 25 C to convert the ketone starting material into
the desired product in good-to-high yields, but with lower
selectivities (entries 7 and 8). Reactions with acetophenones
bearing heteroaromatic substituents were also conducted, but
these were again accompanied by -alcohol and 1,4-adduct
formation (entries 25–27). Interestingly, 2-pyridyl (1j) and
CONCLUSION
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A solid-base catalyzed aldol condensation method was
For all flow reactions, yields were measured by 1H NMR
spectroscopy relying on the initial concentration of starting
materials (0.1 M). As a standard procedure, 2 mL of the
resulting reaction solution (0.1 M x 2 mL = 0.2 mmol) were
collected using a graduated pipette. After concentration by
rotary evaporator and high-vacuum for approximately 10 min
(0.2 mmHg), internal standard was added and weighted
precisely, and the resulting mixture was analyzed by 1H NMR
spectroscopy in CDCl3. Integration of the desired product peak
against internal standard peak afforded the reaction yield. For
the accuracy of the results, yield range were given by three
measurements taken between 6 and 24h of run.
1
2
3
4
5
6
7
8
developed in continuous flow using a commercial strongly
basic ammonium hydroxide-supported ion-exchange resin,
A26. The wide diversity of substrates highlighted the versatility
of this method, which provided 29 ,-unsaturated ketones with
high yields and selectivities, especially for cyclic aromatic
ketones. A proof of concept was demonstrated for an
unprecedented fully heterogeneous catalyzed two-step
continuous-flow synthesis of donepezil, which is one of the top
100 best-selling synthetic drugs of the global pharmaceutical
market.
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EXPERIMENTAL SECTION
General procedure A: basic resin preparation (for batch
and flow systems). Prior to use, commercially available basic
resins were washed using a Kiriyama funnel (or a Büchner
funnel) and a filter paper with distilled water (3 times), EtOH
(3 times), and the reaction solvent (3 times), and added in the
reaction vessel or packed into the flow reactor without drying
(wet conditions). For the optimal conditions of aldol
condensation under flow conditions (10 g of A26 resin), the
order of catalyst wash was as follows: 3  20 mL of H2O, 3 
20 mL of EtOH, 3  20 mL of toluene/EtOH (9:1). For the
optimal conditions of donepezil flow synthesis (7 g of A26
resin): 3  15 mL of H2O, 3  15 mL of EtOH, 3  15 mL of
THF/iPrOH (9:1) + 2% H2O.
1
General. H and 13C NMR spectra were recorded with JEOL
ECX-600, ECA-500, and ECX-400 spectrometers in CDCl3
(7.24 and 77.0 ppm). IR spectra were measured with a JASCO
FT/IR-610 spectrometer. High-resolution mass spectrometry
was carried out with a JEOL JMS-T100TD (DART) using PEG
(Avg. mol. Wt 400) as internal standard. Preparative thin-layer
chromatography was performed using a glass plate with
Wakogel B-5F.
SiO2-NH2 and SiO2-DNH were purchased from Chromatorex
and dried under vacuum (0.1 mmHg) at rt for 1 h prior to use.
MgO and CaO were prepared prior to use from Mg(OH)2 and
Ca(OH)2, respectively, by calcination at 600 C for 3 h.
KF/Al2O3 was prepared according to a reported procedure.20
A26 catalyst was purchased from Sigma-Aldrich and washed
by following general procedure A prior to use. IRA910
(chlorine form) was purchased from Organo and submitted to
counteranion exchange prior to use. For this, an aqueous
solution of NaOH (0.1 M, 50 equiv. relative to Cl loading) was
added to the crude resin and the mixture was stirred at room
temperature overnight. A rotary evaporator was utilized as
stirring instrument to promote mild stirring and avoid polymer
decomposition at atmospheric pressure. The resulting resin was
filtered over a Kiriyama funnel and washed by following
general procedure A. WA30 was purchased from Mitsubishi
Chemical and washed by following general procedure A prior
to use. Toluene, THF, and DMF were purchased from Wako
Pure Chemical Industries, Ltd. as anhydrous solvents and used
without further purification. EtOH (99%) was purchased from
Wako Pure Chemical Industries, Ltd. and used directly. All
aldehydes were purchased from Tokyo Chemical Industry Co.,
Ltd. and distilled prior to use (liquid ones) except otherwise
stated. All ketones were purchased from Tokyo Chemical
Industry Co., Ltd. and used directly.
General procedure B: aldol condensation under batch
conditions. Into an oven-dried reaction tube (10 mL) was added
ketone (1 equiv. 0.3 mmol), aldehyde (1.2 equiv., 0.36 mmol),
solvent (1 mL) and the catalyst (50 mg). The reaction mixture
was purged three times with argon and stirred for 3 h at the
specified temperature. The catalyst was then removed by
filtration, and the filtrate was concentrated under reduced
pressure. The resulting crude mixture was analyzed and the
1
yields were calculated by H NMR analysis using 1,4-di-tert-
butylbenzene as internal standard.
General procedure C: aldol condensation under flow
conditions. The prewashed basic resin catalyst was packed into
a flow reactor (10 g (wet), 10  150 mm, SUS column) and
conditioned with the reaction solvent at the reaction flow rate
(0.15 mL/min) and temperature for approximately 1 h. During
this time, ketone (25 mmol, 1 equiv.) and aldehyde (26.25
mmol, 1.05 equiv.) were mixed in a 250 mL volumetric flask
and dissolved in 9:1 toluene/EtOH solvent system. The
resulting 0.1 M reservoir solution of starting materials was then
pumped at 0.15 mL/min into the flow reactor containing the
basic resin. Yields were measured over time by 1H NMR
spectroscopic analysis using 1,2,4,5-tetramethylbenzene as
internal standard.
A dual pump KP-22 (FLOM, Inc.) and aluminum block heaters
(EYELA, LCR-300 systems) were used for flow reactions.
PTFE tubes (ID 1.0 mm, OD 1.58 mm, 1/16 in.) and SUS
columns (EYELA, stainless) were utilized for flow reactions.
Hydrogen gas was generated by electrolysis from round silence
hydrogen generator RHG-200, and regulated by a mass-flow
controller MC3000E connected with another digital mass-flow
controller RP-300. Pd-DMPSi/Al2O3, Pd-DMPSi/SiO2, and Pd-
DMPSi/BC-Celite catalysts were prepared according to our
reported procedures.4c,14,19 Al2O3 (alumina, activated, about 75
m/ca. 200 mesh), utilized as diluting agent for donepezil flow
synthesis was purchased from Wako Pure Chemical Industries,
Ltd and used directly.
General procedure D: two-step flow synthesis of donepezil.
Aldol condensation. Prewashed A26 catalyst was packed into a
flow reactor (7 g (wet), 10  100 mm, SUS column) and
conditioned at 0.15 mL/min with the reaction solvent
(THF/iPrOH 9:1 + 2% H2O) at 55 C for approximately 1 h.
During this time, 5,6-dimethoxy-1-indanone (1d) (4.81 g, 25
mmol) and 1-benzylpiperidine-4-carbaldehyde (2q) (5.34 g,
26.25 mmol) were mixed into a 250 mL volumetric flask and
dissolved in 9:1 THF/iPrOH solvent system. To this solution
was added 2% of distilled water (5 mL) and the resulting
reservoir solution was pumped at 0.15 mL/min into the flow
Precisions on 1H NMR yield measurements
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Page 6 of 8
Reactions. ACS Catal., 2014, 4 (3), 870-891. (c) Climent M. J.,
reactor containing the basic resin at 55 C. The outlet pipe was
connected to the second flow reactor for hydrogenation after 3
h operation.
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Compounds through Multistep Continuous Flow with
Heterogeneous Catalysts. Org. Lett. 2016, 18 (6), 1346-1349.
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Continuous-Flow Synthesis of (R)- and (S)-Rolipram Using
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(d) Angelini T., Bonollo S., Ballerini E., Lanari D., Maggi R.,
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Ketones. J. Flow. Chem. 2015, 4 (1), 40-43.
Enone reduction and connection of the two reactors. The flow
reactor for enone reduction was prepared in parallel to the aldol
condensation part. A 10  100 mm diameter SUS column was
packed with a previously prepared mixture of Pd-DMPSi/Al2O3
(Pd loading: 0.1 mmol/g, 270 mg, 0.027 mmol) and alumina
(activated, 6.4 g). Optimized solvent system (THF/iPrOH 9:1 +
2% H2O) was flowed at 0.15 mL/min at 25 C for 15 min into
the column before connecting a H2 stream (15 mL/min) through
a T-shape mixer. The resulting set-up was run for at least 1 h
before connecting the aldol condensation flow. The yields were
measured by 1H NMR spectroscopy using 1,2,4,5-
tetramethylbenzene as internal standard.
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ASSOCIATED CONTENT
Supporting information available including: (1) Optimization
studies for the aldol condensation in continuous-flow; (2)
Optimization studies for donepezil flow synthesis; (3)
Characterization data including 1H NMR and 13C NMR spectra.
AUTHOR INFORMATION
Corresponding Author
* shu_kobayashi@chem.s.u-tokyo.ac.jp
ACKNOWLEDGMENTS
This work was partially supported by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science
(JSPS), Global COE Program, The University of Tokyo, the
Ministry of Education, Culture, Sports, Science and Technology
(MEXT), the Japan Science and Technology Agency (JST), and
Japan Agency for Medical Research and Development (AMED).
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SYNOPSIS TOC
H2
Pd-DMPSi/Al2O3
O
(15 mL/min)
O
O
(0.027 mmol)
MeO
0.15 mL/min
Ph
MeO
MeO
A26 (7 g)
Al2O3 (6.4 g)
MeO
N
25 °C
55 °C
1.0 equiv.
1.0
5 e
qui
Donepezil
Anti-Alzheimer
N
v.
29 examples in flow
mild conditions
up to 100% yield
lifetime >5 days
application to Donepezil
Ph
0.1 M (THF/iPrOH, 9:1)
A26:
92-95% yield for 30 h
Productivity: 7.7 g/day
PS
N
OH
+2% H2O
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