Transesterification Reactions Catalyzed by a Recyclable Heterogeneous Zinc/Imidazole Catalyst

Article abstract of DOI:10.1002/adsc.201600229

We report the development of a universal and recyclable heterogeneous zinc/imidazole catalyst. The catalyst is recoverable through simple filtration and can be reused at least five times, retaining its catalytic activity. Leached zinc species were not responsible for the observed catalysis based on the hot filtration test and ICP-MS analysis. The heterogeneous zinc catalyst also promotes chemoselective transesterification over amidation. (Figure presented.).

Full text of DOI:10.1002/adsc.201600229

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DOI: 10.1002/adsc.201600229
Transesterification Reactions Catalyzed by a Recyclable
Heterogeneous Zinc/Imidazole Catalyst
Daiki Nakatake,a Ryo Yazaki,a Yoshimasa Matsushima,b and Takashi Ohshimaa,*
a
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan
Fax : (+81)-092-642-6654; phone: (+81)-092-642-6650; e-mail: ohshima@phar.kyushu-u.ac.jp
Corporate Research and Development Division, Takasago International Corporation, 1-4-11 Nishi-yawata, Hiratsuka,
b
Kanagawa 254-0073, Japan
Received: February 26, 2016; Revised: March 25, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600229.
Abstract: We report the development of a universal
and recyclable heterogeneous zinc/imidazole cata-
lyst. The catalyst is recoverable through simple fil-
tration and can be reused at least five times, retain-
ing its catalytic activity. Leached zinc species were
not responsible for the observed catalysis based on
the hot filtration test and ICP-MS analysis. The het-
erogeneous zinc catalyst also promotes chemoselec-
tive transesterification over amidation.
velopment of alternative heterogeneous transesterifi-
cation catalysts that operate under milder conditions
is in great demand.
We previously reported that combined use of m-
oxo-tetranuclear zinc cluster Zn4(OCOCF3)6O (1)[9]
(Figure 1) with a catalytic amount of N-heteroaromat-
ic compounds, such as DMAP, significantly facilitated
Keywords: chemoselective process; heterogeneous
catalysis; recyclable catalyst; transesterification;
zinc
Esters are a common functional group found in natu-
ral products, drugs, and functional materials.[1] For the
industrial scale production of esters, catalytic transes-
terification of lower esters is a highly advantageous
method due to its high atom-economy compared with
traditional methods using carboxylic acids under stoi-
chiometric amounts of condensation reagents or
highly reactive acyl chlorides or anhydrides.[2] In addi-
tion, transesterification can be performed under
almost neutral conditions, allowing for high functional
group compatibility. Considerable research efforts are
therefore devoted to the development of robust and
practical catalysts for transesterification, especially
heterogeneous catalysts. Heterogeneous catalysts
have several advantages, including high stability, reus-
ability, and turnover number (TON), and ease of
product purification.[3] Several metal oxides or doped
metal oxides, such as CaO,[4] MgO,[5] ZrO2,[6] SnO2
[7]
and zeolite,[8] have been used as heterogeneous cata-
lysts for transesterification. Although these metal
oxide catalysts are inexpensive and recyclable, they
have narrow functional group compatibility due to
Figure 1. The structures of Zn4(OCOCF3)6O (1) and octahe-
dral zinc complex 2 prepared from Zn(OCOCF3)2 and
their inherent acidic or basic character. Thus, the de- bis(imidazole) ligand 3.
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Table 1. Evaluation of zinc catalysts.[a]
the transesterification reaction rate through in situ
generation of more active lower-nuclear Zn species.[9c]
Moreover, we recently developed the highly reactive
octahedral zinc complex 2 supported by a designed bi-
s(imidazole) ligand 3.[10] The high stability of zinc
complex 2 enabled the practical use of 2 for transes-
terification reactions without strict concern regarding
air and moisture. The highly crystalline nature of 2
stemming from its infinite network structure, howev-
er, limits the applicability of 2 in organic solvents.
Herein we report the development of a practical and
recyclable zinc/imidazole catalyst immobilized on
polystyrene resin as a highly active and chemoselec-
tive heterogeneous catalyst for transesterification and
transcarbonation reactions in a variety of organic sol-
vents.
Entry Zinc catalyst
Yield [%]
1
2
3
4
5
6
Zn(OCOCF3)2
19
21
38
97
Zn4(OCOCF3)6O (1)
zinc/bis(imidazole) complex (2)
Zn(OCOCF3)2 +NMI[b]
heterogeneous zinc/imidazole catalyst (6) 97
imidazole resin (5)
N.D.
[a]
Reaction conditions: 7a (0.5 mmol), 8a (0.6 mmol), tolu-
ene (1.0 mL), reflux (oil bath temp.=1208C). Yields
were determined by GC analysis using nonadecane as an
internal standard.
As shown in Scheme 1, imidazole is readily at-
tached to a commercially available cross-linked Mer-
rifield resin 4 (Cl loading=2.40 mmolgÀ1) under stan-
dard basic conditions. The imidazole content of resin
5 was determined to be 1.99 mmolgÀ1 by elemental
[b]
NMI=N-methylimidazole.
analysis. For complexation of imidazole resin 5 and yield (entries 1 and 2). Our developed zinc/bis(imida-
zinc salt, the zinc/imidazole ratio and solvent selection zole) complex 2, which potentially has higher catalytic
were crucial for obtaining high catalytic activity.[11] activity than Zn4(OCOCF3)6O, also exhibited poor
The use of four equivalents of imidazole to zinc ions catalytic performance due to its low solubility in tolu-
under THF reflux conditions was optimal, and the ene (entry 3). The combined use of Zn(OCOCF3)2
zinc content of 6 was determined to be 0.399 mmolgÀ1 and N-methylimidazole (NMI) (zinc/NMI=1/4)
by ICP-MS analysis. We also investigated the immobi- showed a high catalytic performance (entry 4). The
lization of a previously developed m-substituted newly developed heterogeneous zinc/imidazole cata-
bis(imidazole) unit[10] on Merrifield resin in place of lyst 6 was completely insoluble during the course of
an imidazole unit, but the catalytic activity was much the reaction, but had comparable catalytic per-
lower than that of zinc/imidazole catalyst 6.[11] In ad- formance as the homogeneous zinc/NMI catalyst, and
dition, a silica-gel supported imidazole ligand gave product 9aa was observed in 97% yield (entry 5).[12]
only unsatisfactory results.[11]
With newly prepared heterogeneous zinc/imidazole (entry 6).
No product was observed by using imidazole resin 5
catalyst 6 in hand, 6 and other zinc catalysts were ap-
To confirm further applicability of our heterogene-
plied to transesterification in toluene for a short reac- ous zinc/imidazole catalyst 6 in various other reac-
tion time (Table 1). Both Zn(OCOCF3)2 and tions (solvents), we next examined the reaction scope
Zn4(OCOCF3)6O afforded the product 9aa in low (Scheme 2). While heterogeneous zinc/imidazole cata-
lyst 6 was insoluble in all solvents, catalyst 6 effective-
ly delivered the desired products quantitatively in all
the reactions: acetylation in ethyl acetate, deacetyla-
tion in methanol, and methoxycarbonylation in di-
methyl carbonate,[13] within a short reaction time.
When other zinc catalysts shown in Table 1 were
used, lower yields were obtained, except for a homo-
geneous catalyst comprising Zn(OCOCF3)2 and NMI
(up to 42% yield, see the Supporting Information for
details), thus highlighting the wide applicability of the
present heterogeneous catalyst 6.
We evaluated the stability of the present heteroge-
neous catalyst 6 by water-addition control experi-
ments (Scheme 3).[10] In the presence of five equiva-
lents of water, Zn4(OCOCF3)6O (1) provided the
product 9aa in moderate yield even after prolonged
reaction time. In sharp contrast, heterogeneous zinc
catalyst 6 afforded similar results as the previously de-
Scheme 1. Preparation of heterogeneous zinc/imidazole cat-
alyst 6.
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Scheme 4. Recovery and recuse experiments.
simple filtration.[11] Therefore, to demonstrate the re-
cyclability of heterogeneous zinc/imidazole catalyst 6,
recovery-reuse
experiments
were
performed
(Scheme 4). To measure the catalytic activity, each re-
action was quenched after 1 h with ~80% yield (pro-
longed reaction time resulted in the completion of the
reactions, >99% yield). The simply recovered hetero-
geneous zinc catalyst 6 retained high catalytic activity,
even after five runs (76%–81% yield).
The recyclability of heterogeneous zinc catalyst 6
was also demonstrated in acetylation, deacetylation,
and transcarbonation (Scheme 5). In all the reactions,
complete conversions were observed after five runs
and catalytic activity was retained. It is noteworthy
that significant deactivation was not observed, even
when using highly coordinative alcohol as the solvent,
verifying the wide solvent tolerance of catalyst 6.
To confirm that the insoluble catalyst promotes the
reaction under heterogeneous conditions, we conduct-
Scheme 2. Reaction scope using heterogeneous zinc/imida-
zole catalyst 6.
Scheme 3. Reaction profiles in the presence of water.
veloped highly stable zinc complex 2 and the product
9aa was obtained in quantitative yield after 21 h, dem-
onstrating that the high stability of the present heter-
ogeneous catalyst 6.
Because the present heterogeneous zinc catalyst 6
was highly stable, 6 was storable on the bench without
strict concern regarding air and moisture, and after
Scheme 5. Recovery and recuse experiments in various reac-
the reaction catalyst 6 was easily recovered through tions.
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Table 2. Substrate scope in acetylation.[a]
Figure 2. Hot filtration test.
ed a hot filtration test. The heterogeneous reaction
mixture was filtered to remove catalyst 6 after 60 min
(54% conversion), and the resulting filtrate was fur-
ther heated under reflux conditions. Even after an ad-
ditional 300 min, however, conversion to the product
9aa remained unchanged, suggesting that leached zinc
species did not catalyze the reaction at all
(Figure 2).[14]
We next investigated the substrate scope in an ace-
tylation reaction (Table 2), which cannot be catalyzed
by the previously developed poorly soluble zinc/bis-
ACHTUNGTRENNUNG(imidazole) complex 2. Cinnamyl alcohol (8b) and
geraniol (8c) were smoothly converted into the corre-
sponding acetates in high yield (entries 2 and 3).[15]
Nitro and bromo groups were tolerated during the re-
actions and the desired products were obtained in ex-
cellent yield (entries 4 and 5). The mildness of the
present catalysis was demonstrated by using sub-
strates with a variety of protecting groups (MOM,
TES, Piv) (entries 6–8). A secondary alcohol on cho-
lesterol was applicable with a prolonged reaction time
(entry 9). High functional group compatibility was
highlighted by using abacavir (8j), an antiretroviral
medication for the prevention and treatment of HIV/
AIDS. The O-acetylation of abacavir (8j) was ach-
ieved chemoselectively over N-acetylation and the de-
sired product 10j was isolated in 98% yield
[a]
Reaction conditions:
908C. Isolated yields are shown.
8 (1.0 mmol), EtOAc (2.0 mL),
Scheme 6. Chemoselective acetylation of abacavir (8j).
(Scheme 6). This result clearly suggested that hetero- lective reactions using highly coordinative amino alco-
geneous zinc catalyst 6 can be applied to chemoselec- hols remain a difficult task. Although a decreased cat-
tive transesterification of amino alcohol over amida- alytic activity was observed after the fourth run, the
tion.[11,16] We next checked the recyclability of the catalyst could be used at least three times without sig-
present heterogeneous catalyst 6 on chemoselective nificant loss of activity at this stage.
acetylation of highly coordinative abacavir (8j)
Finally, we applied the present zinc catalysis to
(Scheme 7). Recovery-reuse experiments of chemose- a protection-deprotection sequence of a 1,2-diol
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(5.0 mol% zinc). Solvent (2.0 mL) was added to the flask via
syringe, followed by the addition of starting materials
(1.0 mmol) at room temperature. The reaction mixture was
then heated under an argon atmosphere. The resulting
crude reaction mixture was applied to GC analysis or puri-
fied flash column chromatography to determine the product
yield.
Acknowledgements
This work was financially supported by Scientific Research
on Innovative Area 2707 Middle molecular strategy and Plat-
form for Drug Discovery, Informatics, and Structural Life
Science from MEXT.
Scheme 7. Recovery and recuse experiments using highly co-
ordinative abacavir (8j).
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In conclusion, we developed highly practical heter-
ogeneous zinc/imidazole catalyst 6. Catalyst 6 was ef-
fective in a broad spectrum of solvents, such as tolu-
ene, ethyl acetate, methanol, and dimethyl carbonate,
with enhanced catalytic activity. The recyclability of
catalyst 6 was also demonstrated by recovery-reuse
experiments, and catalyst 6 promoted various reac-
tions in various solvents at least five times without
loss of the activity. Studies on the further application
of the heterogeneous zinc catalyst to a continuous
flow process are in progress.
Experimental Section
General Procedure for Transesterification Reactions
An oven-dried Schlenk flask equipped with a magnetic stir-
ring bar and reflux condenser was charged with zinc catalyst
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[10] D. Nakatake, Y. Yokote, Y. Matsushima, R. Yazaki, T.
Ohshima, Green Chem. 2016, 18, 1524.
[11] See the Supporting Information for details.
[12] On the basis of our previous work (ref.[10]), the highly
active octahedral zinc complex would be formed by the
use of 4 equiv. of imidazole unit to zinc ions.
[15] When acetylated products 10b and 10c were also sub-
jected to the deacetylation conditions in methanol,
quantitative conversions were observed. In addition,
methoxycarbonated products were cleanly obtained
using cinnamyl alcohol (8b) and geraniol (8c). See the
Supporting Information for details.
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tion by ICP-MS analysis and found that only 0.3% of
zinc ion was detected in the filtrate.
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Transesterification Reactions Catalyzed by a Recyclable
Heterogeneous Zinc/Imidazole Catalyst
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Adv. Synth. Catal. 2016, 358, 1 – 7
Daiki Nakatake, Ryo Yazaki, Yoshimasa Matsushima,
Takashi Ohshima*
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