Process Catalyst Mass Efficiency by Using Proline Tetrazole Column-Flow System

Article abstract of DOI:10.1002/chem.201705982

Generally, organocatalysts are not decomposed during chemical transformation, which is different from traditional metal catalysts. To improve catalytic processes efficiency, various studies have been applied to flow synthesis for organocatalysis. Furtherm

Full text of DOI:10.1002/chem.201705982

DOI: 10.1002/chem.201705982
Communication
&
Organocatalysis
Process Catalyst Mass Efficiency by Using Proline Tetrazole
Column-Flow System
Erika Nakashima* and Hisashi Yamamoto*[a]
synthesis,[5] moreover, performing heterogeneous catalysis in a
Abstract: Generally, organocatalysts are not decomposed
packed-bed reactor for continuous flow production has more
during chemical transformation, which is different from
distinct advantages, such as reduced catalyst consumption
traditional metal catalysts. To improve catalytic processes
leading to less waste, continuous production, and separation
efficiency, various studies have been applied to flow syn-
and reuse of catalysts without washing.[6] Still, heterogeneous
thesis for organocatalysis. Furthermore, many immobilized
organocatalyst flow synthesis has sometimes required huge
organocatalysts have been used for heterogeneous flow
amounts of silica, polymer, or other supported catalysts that
synthesis, which requires huge amounts of immobilized
take several steps to make. Herein, we report a completely dif-
catalyst and requires several steps to prepare. We took ad-
ferent approach for heterogeneous flow synthesis by using
vantage of organocatalysts with low-polarity organic sol-
excess proline tetrazole catalyst packed into an empty column,
vent and developed a flow system through a packed-bed
as a reactor with low polarity organic solvent to create condi-
column with simply proline tetrazole (5-(2-pyrrolidinyl)-1H-
tions for continuous use of the catalyst without consumption
tetrazole) for heterogeneous organocatalytic synthesis.
and loss of catalytic activity. This simple organocatalyst
Under ambient temperature, this heterogeneous organo-
packed-bed column would be suitable for long runs without
catalyst continuous flow-column system with ketones as a
changing the catalyst column. A number of reaction metrics
donor provides aldol, Mannich, and o-nitroso aldol reac-
associated with “greenness” in chemical reactions with respect
tions in up to quantitative yields with excellent enantio-
to raw material use or waste reduction, such as reaction yield,
and chemoselectivity values. Our heterogeneous-flow syn-
Trost’s atom economy,[7] Sheldon’s E factor,[8] GlaxoSmithKline
thesis provides extremely low process catalyst mass effi-
chemist’s reaction mass efficiency[9] and process mass intensi-
ciency and continuous production without changing the
ty,[10] life-cycle assessment have been defined to date. Howev-
packed-bed catalyst column.
er, there has been no metric adopted for evaluating consump-
tion of catalyst in flow synthesis, even for the heterogeneous
organocatalysts in a packed-bed flow synthesis that propose
A milestone report in 2000 describing a proline-catalyzed aldol
reaction opened a new avenue to asymmetric reactions by
using organocatalysts. This initially reported procedure for
aldol reactions used 20–30 mol% of catalyst.[1] To date, the re-
quired amount of catalyst has been reduced significantly to
0.1 mol%,[2] and we have recently been able to reduce the re-
quired proline catalyst loading to as low as 0.01 mol% (weight
ratio of catalyst/substrateꢀ0.001).[3] Meanwhile, flow reactors
have been accelerating a host of reactions and facilitating
scale up, and they are becoming an alternative to traditional
batch reactors for organocatalytic synthetic processes.[4] Gener-
ally, organocatalysts, such as proline and its derivatives, are rel-
atively insoluble in organic solvents, and very polar solvents,
such as DMSO, are required to improve reaction yield for ho-
mogenous synthesis in batch and flow. Homogeneous flow
synthesis could be expected as a key technology for green
continuous catalyst usage and production. Herein, we would
like to propose process catalyst mass efficiency (PCME) as the
preferred metric aimed to drive greater efficiencies in hetero-
geneous organocatalyst flow syntheses.
For a demonstration, proline tetrazole (5-(2-pyrrolidinyl)-1H-
tetrazole) developed by the Ley,[11] Arvidsson,[12] and our
group[3,13] was chosen as a heterogeneous organocatalyst,
which is completely insoluble in low-polarity organic solvents.
Previously, several homogenous and heterogeneous flow-
chemistry processes by using proline tetrazole were reported.
Seeberger and co-workers developed an excellent homogene-
ous flow system with 5–10 mol% proline tetrazole-catalyzed
aldol and Mannich reactions in DMSO,[5c] and Luisi reported a
homogeneous sustainable domino flow reaction with 12 mol%
proline tetrazole in DMSO.[5d] In a heterogeneous flow system,
Massi used prepared silica- or polymer-supported proline tetra-
zole in a packed-bed column with less polar solvents.[6c,e]
As a model study, simply using an excess of proline tetrazole
catalyst (270 mg) for a packed-bed column (I.D. 4.6ꢀ30 mm) as
a reactor for this heterogeneous flow system by using less
polar solvent, we successfully provided aldol product with ace-
tone and 4-nitrobenzaldehyde (71% yield, 34% enantiomeric
excess, ee) within five minutes reaction time (Scheme 1). Using
10 vol% of EtOAc slightly increased the yield (93% yield, 41%
[a] Dr. E. Nakashima, Prof. Dr. H. Yamamoto
Molecular Catalyst Research Center
Chubu University, 1200 Matsumoto, Kasugai, Aichi 487-8501 (Japan)
E-mail: e-nakashima@isc.chubu.ac.jp
hyamamoto@jsc.chubu.ac.jp
Supporting information and the ORCID identification numbers for the au-
thor(s) of this article can be found under https://doi.org/10.1002/
chem.201705982.
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laldehyde produced mono aldol products 1 f (74% isolated
yield) and 1g (63% isolated yield), respectively, with good
regio- and enantioselectivity values (n=0.05 mLminꢁ1). Addi-
tionally, scale up volume of the packed-bed catalyst column re-
actor ten times (I.D. 7.6ꢀ110 mm) with 2.7 g proline tetrazole
was continuously operated with a 52 mmol scale aldol reac-
tion, and gave product 1a<10 g (94% yield and 72% ee)
within 24 hours (n=0.366 mLminꢁ1).
This proline tetrazole packed-bed column was repeatedly
used ten times on ꢂ10 mmol scale with respect to aldol prod-
uct (Scheme 2, 1d). Nevertheless, the activity of the catalyst re-
mained the same, and thus 1d was obtained in high yield and
enantioselectivity (Figure 1).
Scheme 1. Influence of solvent and water for aldol reaction with acetone
and 4-nitrobenzaldehyde in a flow system.
ee). Moreover, a remarkable improvement in ee value was ob-
served by the 3 mol% addition of H2O (92% yield, 73% ee),
which has a similar effect to that previously reported for the
effect of adding a small amount of water in a batch reaction.[3]
The expansion of the scope of the heterogeneous flow
system to a broader range of substrate aldehydes in 10 vol%
EtOAc and 3 mol% H2O is shown in Scheme 2. In the case of
1a–d, excellent isolated yields were achieved, and the product
was simply collected by evaporation. Product yields of 1b and
c were improved by more than 15% compared with a batch
reaction.[3] Product 1d was obtained with extremely high enan-
tioselectivity (97% ee). When 2-naphthaldehyde was applied to
acetone, a 26% isolated yield and 68% ee were obtained for
1e (n=0.1 mLminꢁ1). For improving the product yield 1e,
slower flow speed can be effective: 49% isolated yield (n=
0.05 mLminꢁ1), 86% isolated yield (n=0.01 mLminꢁ1). Impor-
tantly, the reaction by using terephthalaldehyde and isophtha-
Figure 1. Repeated use of 270 mg proline tetrazole packed-bed column for
9.9 mmol scale aldol reaction with acetone and 2,6-dichlorobenzaldehyde.
This heterogeneous flow system by using excess proline tet-
razole catalyst (270 mg) for a packed-bed column was further
extended to aldol, Mannich, and o-nitro aldol reactions with
cyclohexanone as a donor. Aldol product 2 was obtained in
95% yield, and excellent diastereometric ratio with 92% ee for
the anti-isomer when 2,6-dichlorobenzaldehyde was utilized as
substrate (Scheme 3). Mannich reaction with a-iminoglyoxylate
Scheme 3. Aldol reaction of 2,6-dichlorobenzaldehyde with cyclohexanone.
and cyclohexanone in MeCN was achieved in excellent enan-
tioselectivity at ambient temperature and pressure. b-Amino
ketone 3 was obtained in 72% yield and excellent diastereo-
metric ratio with >99% ee for the syn-isomer (Scheme 4). Fur-
thermore, the o-nitroso aldol reactions by using this heteroge-
neous flow system gave products in good yield and excellent
chemoselectivity values at ambient temperature (Scheme 5).
Optimal results were obtained in the reaction of nitrosoben-
zene with an excess of cyclohexanone (4a: 63% yield, >99%
ee), and in the case of 2-nitrosotoluene with an excess of cyclo-
hexanone, 92% yield and >99% ee were achieved (4b).
Solubility of proline tetrazole in organic solvent is very low,
which helped to reduce leaching of the catalyst from the
column, although substrates and products are freely soluble in
Scheme 2. Screening of aromatic aldehydes with water addition in the pres-
ence of proline tetrazole in a flow system.
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Scheme 4. Mannich reaction of a-iminoglyoxylate with cyclohexanone.
Scheme 5. o-Nitoroso aldol reaction of nitroso derivatives with cyclohexa-
none.
organic solvent, which provides smooth flow in the column
during reaction (Table 1).
Figure 2. Proposed reaction pathway.
During the process in the column, a small quantity of dis-
solved proline tetrazole reacts with the ketone, producing en-
amine and water. The enamine reacts with aldehyde to form
an iminium cation intermediate. Finally, it is quenched by
water, giving aldol products and regenerating the catalyst
(Figure 2).
An example of how process catalyst mass efficiency is com-
puted follows: Mannnich reaction using 1.0 g of polystyrene-
supported hydroxyproline gave product (90% yield, 7.8 mmol;
Eq. (2)).[6a]
1000 ½mgꢃ
A number of reaction metrics, such as atom economy and E
factor, are applied to raw materials usage or waste reduction,
and these are suitable for commitment to green chemistry. Un-
fortunately, these metrics are not sufficient to evaluate the cat-
alyst performance during repeated or continuous use of an or-
ganocatalyst for a packed-bed heterogeneous flow synthesis.
Herein, we propose a new metric for additional evaluation of
catalyst mass efficiency in heterogeneous flow synthesis. Pro-
cess catalyst mass efficiency (PCME) is defined as the actual
mass of catalyst used or catalyst consumption in the process
relative to desired product [Eq (1)].
ð2Þ
PCME ¼
¼ 127:8
7:82 ½mmolꢃ
A heterogeneous flow system process catalyst mass efficien-
cy is computed as follows: aldol reaction by the consumption
of 0.052 mg of proline tetrazole during 5 mmol production
[Eq. (3)].
0:052 ½mgꢃ
ð3Þ
PCME ¼
¼ 0:0104
5 ½mmolꢃ
Silica-supported,[14] polymer-supported,[15]
peptide-catalyzed[16] organocatalysts are
used in packed-bed column reactors for
heterogeneous flow synthesis. Our work
shows extremely low process catalyst mass
intensity compared with several polymer-
Total catalyst mass in packed bed column or catalyst consumption ½mgꢃ
PCME ¼
Moles of product
ð1Þ
supported or immobilized organocatalyst (Table 2).
In conclusion, we have successfully demonstrated a new and
general heterogeneous organocatalyst in packed-bed
Table 1. Leaching proline tetrazole from packed-bed column.[a]
a
Solvent
Leaching proline tetrazole [mg][b]
column for a continuous flow system. This simple column-flow
system sheds new light on organocatalysts. Organocatalysis
has high functionality, greenness, and robustness, while having
the drawback of requiring very high catalyst loading. However,
this issue can be solved by the present bed-type column
system, and it makes possible continuous synthesis by using
the organocatalyst without any loss by using solvent that does
not dissolve the catalyst. Therefore, to evaluate the catalyst ef-
ficiency for a packed-bed column flow synthesis, analyzing the
precise amount of consumed catalyst is a crucial factor. In par-
acetone
EtOAc
0.080
<0.001
0.095
0.052
0.658
90:10 acetone/EtOAc
90:10 acetone/EtOAc+H2O 3 mol%
DMF
MeCN
<0.001
[a] Empty column was filled with proline tetrazole (270 mg), and the
amount of solvent that is required for 5 mmol of aldol, Mannich, and o-ni-
troso products flowing through the column. [b] Calculated by NMR spec-
troscopy.
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Table 2. PCME in heterogeneous organocatalytic flow reaction.
Heterogeneous organocatalytic flow reaction
PCME
127.8
Polystyrene-supported hydroxyproline for
Mannich reaction
Silica-supported proline for aldol reaction
Silica-supported proline for
a-aminoxylation reaction
Polystyrene-supported proline catalyst for
aldol reaction
Polystyrene-supported pyrrolidine for
Mannich reaction
Polymer-supported primary amino acid-derived
catalyst for three-component Mannich reaction
Polystyrene-immobilized peptide for conjugate
addition reaction
377.4
16.3
30.7
7.6
95.8
20.0
0.01
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Non-supported proline tetrazole
ticular, the organocatalyst packed-bed column flow system
using proline tetrazole has given high catalytic process efficien-
cy and afforded products in excellent yields and high enantio-
and chemoselectivity values to various transformations includ-
ing aldol, Mannich, and o-nitroso aldol reactions.
Acknowledgements
We express our appreciation to the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan for generously pro-
viding financial support (Grant No. 17H06142). In addition, this
work was supported in part by a Grant for Environmental Re-
search Project from the Sumitomo Foundation. E.N. would like
to thank the Ministry of Education, Culture, Sports, Science and
Technology, Japan for the Grant-in-Aid for Young Scientists (B)
(No. 17K18217).
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Conflict of interest
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The authors declare no conflict of interest.
Keywords: aldol reactions · heterogeneous continuous flow ·
Mannich reaction · o-nitroso reaction · organocatalysis ·
synthetic methods
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Version of record online: && &&, 0000
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COMMUNICATION
&
Organocatalysis
E. Nakashima,* H. Yamamoto*
&& – &&
Process Catalyst Mass Efficiency by
Using Proline Tetrazole Column-Flow
System
An organocatalyst packed-bed
quantitative yields with excellent enan-
tio- and chemoselectivity values. This
heterogeneous flow synthesis provides
extremely low process catalyst mass effi-
ciency and continuous production with-
out changing the packed-bed catalyst
column (see scheme).
column-flow system by using proline or-
ganocatalysis was successfully con-
structed for aldol, Mannich, and o-ni-
troso reactions. Under ambient temper-
ature, this heterogeneous organocata-
lyst continuous flow process with ke-
tones as a donor has provided up to
Chem. Eur. J. 2018, 24, 1 – 5
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These are not the final page numbers! ÞÞ