DOI: 10.1002/cssc.201500919
Communications
Convenient and Simple Esterification in Continuous-Flow
Systems using g-DMAP
Yoshinori Okuno, Shigeki Isomura, Anna Sugamata, Kaoru Tamahori, Ami Fukuhara,
Miyu Kashiwagi, Yuuichi Kitagawa, Emiri Kasai, and Kazuyoshi Takeda*[a]
The utility and applicability of polyethylene-g-polyacrylic acid-
immobilized dimethylaminopyridine (g-DMAP) as a catalyst in
a continuous-flow system were investigated for decarboxyla-
tive esterification. High catalytic activity toward acylation was
provided by g-DMAP containing a flexible grafted-polymer
structure. During decarboxylation, carboxylic acids and alco-
hols were converted cleanly using di-tert-butyl dicarbonate
(Boc2O) as a coupling reagent, which reduced by-products. In
addition, the use of Boc2O resulted in the formation of tert-
butyl esters. These esterifications dramatically reduced the re-
action time under continuous-flow conditions, with a residence
time of approximately 2 min. This highly efficient esterification
procedure will provide more practical industrial applications.
ous esterification reactions using a wide variety of carboxylic
acids and alcohols. As an extension of dimethylaminopyridine
(DMAP)-mediated esterification,[6] the esterification was report-
ed to proceed via an acylpyridinium salt after generation of
the mixed anhydride.[7] However, by-products of the coupling
reagents, such as dicyclohexylcarbodiimide/DMAP, hindered
esterification in a continuous-flow system.[8] Decarboxylative
esterification using the effective di-tert-butyl dicarbonate
(Boc2O)/DMAP system had the advantage of volatile by-prod-
ucts (Scheme 1).[9,10] Thus, herein a continuous-flow system
using g-DMAP for decarboxylative esterification in the Boc2O/
DMAP system was developed.
Polymer-immobilized reagents and catalysts have promoted
environmentally friendly and sustainable chemistry.[1,2] A variety
of catalysts for these syntheses were developed by introducing
functional groups into polystyrene supports.[3] However, the
ability of reagents to access the catalytic site can be difficult
owing to the closed framework of the cross-linked polystyr-
ene.[4] Therefore, attention focused on the use of graft poly-
mers to accumulate highly reactive side chains on the surface
of the trunk polymer. For example, polyethylene-g-polyacrylic
acid (PE-g-PAA) has flexible grafted chains on the chemostable
polyethylene trunk that can be functionalized.
A previous study reported PE-g-
Scheme 1. Decarboxylative esterification with Boc2O/g-DMAP.
PAA-supported dimethylaminopyri-
dine (g-DMAP) as a heterogeneous
Initially, decarboxylative esterification as a batch method
was investigated using 0.1m 1-phenylethyl alcohol, 1.5 equiva-
lents of 3-phenylpropanoic acid, 1.65 equivalents of Boc2O
and triethylamine (NEt3), and 3.3 mol% g-DMAP in toluene at
room temperature. Good activity was obtained (see the Sup-
porting Information for optimized conditions).
organocatalyst for continuous-flow
acylation systems (Figure 1).[5] The
g-DMAP possessed highly accessi-
ble reactive sites and chemical sta-
bility, owing to the structure of PE-
g-PAA. Acylation using g-DMAP
After the initial experiments, a continuous-flow system with
Boc2O/g-DMAP was investigated using several different alco-
hols and carboxylic acids. Batch and flow conditions were com-
pared using the same substrate ratio and solvent (Table 1).
Continuous-flow reaction conditions were based on previously
optimized values; sufficient time (ca. 60 min) was required to
replace the reaction solution, as the reactor was filled with sol-
vent before operation. The extent of conversion in the product
was determined periodically by HPLC using an internal stan-
dard. Esterification within the Boc2O/g-DMAP system under
both conditions was effective, demonstrating that g-DMAP can
be applied to continuous-flow systems and reused with differ-
ent substrates and solvents. Although the rate of product for-
with acid anhydride produced the
desired products in good yields.
The present study describes the
Figure 1. Structure of g-DMAP.
application of g-DMAP in continu-
[a] Y. Okuno, Dr. S. Isomura, A. Sugamata, K. Tamahori, A. Fukuhara,
M. Kashiwagi, Y. Kitagawa, E. Kasai, Prof. K. Takeda
Yokohama University of Pharmacy
Department of Medicinal Chemistry
601 Matano-cho, Totsuka-ku, Yokohama 245-0066 (Japan)
Supporting Information for this article is available on the WWW under
ChemSusChem 2015, 8, 3587 – 3589
3587
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