A Recyclable Hydrophobic Anchor-Tagged Asymmetric Amino Thiourea Catalyst

Article abstract of DOI:10.1002/cctc.201800714

A novel, recyclable, thiourea-based asymmetric organocatalyst containing a hydrophobic anchor has been developed. The chemical nature of the hydrophobic anchor contributes to the desirable characteristics of the recyclable catalyst. The hydrophobic anchor

Full text of DOI:10.1002/cctc.201800714

Accepted Article
Title: A recyclable hydrophobic anchor-tagged asymmetric amino
thiourea catalyst
Authors: Takahisa Jichu, Tsubasa Inokuma, Keisuke Aihara, Taiki
Kohiki, Kodai Nishida, Akira Shigenaga, Ken-ichi Yamada,
and Akira Otaka
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To be cited as: ChemCatChem 10.1002/cctc.201800714
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10.1002/cctc.201800714
ChemCatChem
COMMUNICATION
A recyclable hydrophobic anchor-tagged asymmetric amino
thiourea catalyst
Takahisa Jichu†, Tsubasa Inokuma†, Keisuke Aihara, Taiki Kohiki, Kodai Nishida, Akira Shigenaga
Ken-ichi Yamada and Akira Otaka*[a]
A
novel recyclable thiourea-based, asymmetric organocatalyst
containing a hydrophobic anchor has been developed. The chemical
nature of the hydrophobic anchor contributes to the desirable
characteristics of the recyclable catalyst. The hydrophobic anchor-
tagged thiourea catalyst is highly soluble in less polar solvents
compatible to the amino thiourea catalyst-mediated asymmetric
reactions, but sparingly soluble in polar solvents used for recycle
process. This asymmetric catalyst delivers a catalytic performance
comparable to that of a parent catalyst and can be readily recycled
from reactions.
Access to a wide variety of chiral compounds requires that
asymmetric catalysts perform well in the construction of chiral
centers. Amongst known efficient asymmetric catalysts,
organocatalysts have attracted attention increasingly because
they are cost-effective, less toxic, and operationally simple
compared with conventional metal catalysts.1 Amino thiourea
Scheme 1. Concept of recycling of the hydrophobic anchor-tagged catalyst.
In comparison with the asymmetric metal catalysts, a weak
point of organocatalysts is that relatively large amounts of the
catalyst load must be used. Because of this, recyclable
organocatalysts have been designed to extend the synthetic
utility of organocatalysts.3 Recyclable thiourea catalysts that
have been developed to date have an insoluble resin support,4a,b
a polyethyleneglycol (PEG) moiety,4a or a fluorocarbon carrier4c,d
as shown in Figure 1. A poly styrene-type insoluble resin support
in a catalyst 2 allows for easy recovery of the catalyst from a
reaction, typically by filtration, but the two-phase reaction using a
resin-supported catalyst generally results in reduced catalytic
activity. PEG as a carrier can be used in solution and leads to a
more favourable reaction outcome. A drawback of PEG catalysts
such as 3 is that difficulties in the control of the solubility can
lead to low efficiency in the recovery. Recently, catalysts 4 and 5
with a perfluoroalkyl chain were independently developed by
Cai4c and Miura.4d Such fluorine-containing catalysts have a high
affinity for fluorine-containing solvents or silica gel. These
features allow the fluoroalkyl catalyst to be separated by
extractive or chromatographic work-up using fluorine-containing
solvent. Such solvents may however be expensive.
catalysts
are
dual-activating
organocatalysts
which
simultaneously activate both an electrophile and a nucleophile in
a highly enantioselective reaction, affording a chiral product.2
For example, Takemoto’s thiourea catalyst 1 has been applied
to a variety of asymmetric reactions (Figure. 1).2c
In this context, we envisioned that the use of a hydrophobic
anchor tag consisting of an extended alkyl chain as a carrier
could be used in the development of a novel recyclable catalyst
which can overcome the drawbacks mentioned above.
Hydrophobic anchors have been independently developed by
Tamiaki and Chiba and Takahashi for use in peptide synthesis.5
Generally, such anchors enhance the solubility of the tagged
molecules in less polar solvents such as CH2Cl2, CHCl3, toluene,
and THF but lead to the precipitation of the tagged molecules in
polar solvents, including MeOH and MeCN. The less polar
solvents are suitable for reactions catalysed by thiourea and
precipitation-inducing polar solvents can solubilize a wide variety
of organic molecules involved in the reaction. We speculated
Figure 1. Recyclable thiourea catalysts.
[a]
Dr. T. Jichu, Dr. T. Inokuma, Dr. K. Aihara, T. Kohiki, K. Nishida, Dr.
A. Shigenaga, Prof. Dr. A Otaka
Institute of Biomedical Sciences and Graduate School of
Pharmaceutical Sciences
Tokushima University
Tokushima 770-8505, Japan
E-mail: aotaka@tokushima-u.ac.jp
that
a hydrophobic anchor-tagged thiourea catalyst could
† Equally contributed.
function as an ideal recyclable asymmetric catalyst. Reaction
protocols that could be envisioned are shown in Scheme 1.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cctc.201800714
ChemCatChem
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indicated that the synthesized tagged catalyst 6 satisfies the first
criteria for use as a recyclable catalyst.
Table 1. Solubility of catalyst 6 in various solvents.
entry
solvent
solubility (mM)[a]
4 ºC
141
20 ºC
156
30 ºC
177
1
2
3
4
5
6
CHCl3
CH2Cl2
toluene
THF
6.39
1.46
4.48
N.D.
N.D.
7.53
1.71
4.70
N.D.
N.D.
30.9
39.5
32.4
0.10
0.06
Scheme 2. Syntheis of recyclable hydrophobic anchor-tagged catalyst 6 and
resin-bound catalyst 14.
MeOH
MeCN
A
hydrophobic anchor-tagged thiourea catalyst should
provide a homogeneous reaction mixture in less polar solvents
and thus participate in an asymmetric reaction with efficiency
[a] Determined from UV absorbance in solution.
comparable to that of
a conventional thiourea catalyst.
Replacement of the reaction solvent by polar solvents dissolves
the reactants and causes precipitation of the recyclable catalyst.
After removal of the catalyst by filtration, the filtrate is subjected
to the appropriate purification steps.
Initially, an amino thiourea catalyst 6 possessing an O-
alkylated gallic acid unit as a hydrophobic anchor was designed
(Scheme 2). Using the known benzoyl chloride 7,6 commercially
available 5-amino-1-pentanol was reacted in CHCl3 to afford the
hydroxyalkyl benzamide 8. Esterification of this benzamide 8
with a benzoic acid derivative 9 was achieved by the action of
(benzotriazol-1-yloxy)
tripyrrolidino-phosphonium
hexafluorophosphate (PyBOP) in CHCl3 to give the ester 10,
whose nitro group was then reduced to an amino group with
SnCl2·H2O in CHCl3. The resulting aniline derivative 11 was
converted to the corresponding isothiocyanate 12 by reaction
with 1,1’-thiocarbonyldiimidazole (TCDI) in CHCl3.
The
synthesis was completed by coupling of 12 with the chiral
diamine 13 in CHCl3 to yield the desired hydrophobic anchor-
tagged amino thiourea catalyst 6. In all these reactions, CHCl3
was used as the solvent because the newly introduced
hydrophobic anchor unit facilitated solubilisation of the organic
materials. Furthermore, precipitation of the tagged molecules
including the final product 6 by the addition of the polar solvents
enabled the easy, one-step separation of excess reagents.
Catalyst 6 was obtained in 75% isolated yield over five steps
from 7. To compare the efficacy of 6 with a polystyrene-linked
counterpart, a recyclable catalyst 14 was prepared through
amide-linking of the known thiourea 154a to polystyrene resin.7
Having obtained the hydrophobic anchor-tagged catalyst 6,
we determined its solubility in various solvents to assess its
utility as a recyclable catalyst. Solubility was calculated on the
basis of the UV absorbance of 6 (Table 1). The tagged catalyst 6
was readily soluble in CHCl3 at temperatures from 4 °C to 30 °C
(entry 1, Figure 2-a). The solubility of 6 in CHCl3, toluene, or
THF was affected by changes in temperature and facilitated its
practical use as an asymmetric organocatalyst at 30 °C (entries
2–4). The catalyst 6 on the other hand, is practically insoluble in
the polar solvents (entries 5–6, Figure 2-b). These data clearly
Figure 2. Catalyst 6 is soluble in CHCl3, but recovered from MeCN..
In comparison with the parent catalyst 1 and the resin-
bound recyclable catalyst 14, the performance of the
hydrophobic anchor-tagged catalyst 6 was evaluated by its
application to the aza-Henry reaction (Table 2).8 Attempted aza-
Henry reaction of 0.1 mmol of an N-Boc imine (16) with 10
equivalents of nitromethane 17 in CH2Cl2 at 30 °C in the
presence of 10 mol% of catalyst 6 or 1 proceeded efficiently,
yielding the desired product 18 (entries 1 and 2). Additionally,
the use of MeCN as a recycling solvent allowed for efficient
recovery of the used catalyst. Removal of CH2Cl2 followed by
addition of MeCN led to the precipitation of the catalyst 6.
Removal by filtration of the insoluble catalyst led to recovery of 6
in 99% yield. On the other hand, the conventional resin-
supported catalyst 14 under the same reaction conditions totally
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10.1002/cctc.201800714
ChemCatChem
COMMUNICATION
failed to afford 18 (entry 3). Generation of 18 using 14 as
catalyst required increases in both catalysis load (30 mol%) and
reaction time (6 days) but the chemical yield (15%) remained
low (entry 4). Screening the other less polar solvents (CHCl3,
toluene, and THF) revealed that CH2Cl2 was the best solvent for
the examined aza-Henry reaction (entries 5–7). The use of
CHCl3 or toluene resulted in reduced chemical yields although
optical yields were comparable to that of using CH2Cl2. The one-
gram (4.9 mmol) scale reaction also proceeded smoothly to
result in reaction outcomes comparable to those of 0.1 mol scale
reaction (entry 8).
Figure 3. Recycling and reuse of 6 in aza-Henry reaction of 16.
Application of the recyclable catalyst 6 to an asymmetric
Michael reaction was next examined (Scheme 3). The reaction
of nitrostyrene 19a or 19b with acyclic dicarbonyl compounds
such as diethyl malonate 209 or acetylacetone 2110 in the
presence of 30 mol% of catalyst 6 in toluene at 30 °C proceeded
smoothly to yield desired Michael adducts 24a-d in high
chemical and optical yields. The reaction with cyclic-type
nucleophiles 2211 and 2312 in CH2Cl2 also proceeded in an
enantioselectively, generating desired products 24e-f and 24g-h
in high chemical yields.
Table 1. Asymmetric aza-Henry reaction.[a]
entry
catalyst
solvent
catalyst
yield
ee
recovery (%)[b]
(%)[c]
(%)[d]
1
2
6
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
toluene
THF
99
---
99
99
95
99
99
99
77
76
91
90
---
89
90
91
---
91
3
14
14
6
N.R.
15
4[e]
5
69
6
6
30
7
6
N.R.
81
8[f]
6
CH2Cl2
[a] Unless otherwise noted, reactions were carried out using 16 (0.1 mmol),
17 (1.0 mmol) and solvent (1.0 mL). [b] Recovered by using MeCN. [c]
Isolated yield. [d] Determined by chiral HPLC analysis (chiralpak IC3, flow
rate 1.0 ml/min, hexane/2-propanol = 85/15). [e] 30 mol% of 14 was used
and the reaction was performed for 6 days. [f] Reaction was carried out
using 16 (4.9 mmol), 17 (49 mmol) and CH2Cl2 (49 mL).
Scheme 3. Asymmetric Michael addition of nitrostyrenes with several
nucleophiles catalysed by 6.
We next examined recycling of the used catalyst 6 (Figure
3). In the first recycle of 6 in the same aza-Henry reaction of 16
with 17, the desired product was obtained in 72% chemical and
91% optical yields with 99% recovery of the catalyst. The
reaction outcomes observed subsequently were comparable to
those of the first run. Two further additional runs of the reaction
were carried out with no loss of the catalytic activity. Although
further trials have yet to be performed, obtained data for the
recycling showed that the catalyst 6 could be a potential
recyclable catalyst in terms of both activity and recyclability.
In summary, development of a hydrophobic anchor-tagged
asymmetric recyclable thiourea catalyst has been achieved.
Chemical features of the hydrophobic anchor allowed for both
the facile recycling and efficient preparation of the tagged
catalyst. Use of a less polar homogeneous reaction solution of
recyclable catalyst contributes to the high performance of the
tagged thiourea catalyst. The recyclable catalyst exhibits
catalytic activity comparable to that of the conventional soluble
thiourea catalysts. The application of the hydrophobic anchor
has to date been limited to amino thiourea catalysts, but other
types of recyclable organocatalysts containing a hydrophobic
anchor unit are under investigation.
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Acknowledgements
This research was supported in part by a Grant-in-Aid for
Scientific Research (KAKENHI). T.J. is grateful for SUNBOR
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Keywords: organocatalyst • amino thiourea • asymmetric
catalyst • hydrophobic anchor • recyclable catalyst
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Takahisa Jichu, Tsubasa Inokuma,
Keisuke Aihara, Taiki Kohiki, Kodai
Nishida, Akira Shigenaga, Ken-ichi
Yamada, Akira Otaka*
Page No. – Page No.
A recyclable hydrophobic anchor-
tagged asymmetric amino thiourea
catalyst
Catalyst comes back: A novel recyclable thiourea-based, asymmetric
organocatalyst containing a hydrophobic anchor has been developed. The
hydrophobic anchor-tagged thiourea catalyst is highly soluble in less polar solvents
compatible to the amino thiourea catalyst-mediated asymmetric reactions, but
insoluble in polar solvents so that the catalyst can be readily recycled only by
simple filtration.
This article is protected by copyright. All rights reserved.