Convenient and Simple Esterification in Continuous-Flow Systems using g-DMAP

Article abstract of DOI:10.1002/cssc.201500919

The utility and applicability of polyethylene-g-polyacrylic acid-immobilized dimethylaminopyridine (g-DMAP) as a catalyst in a continuous-flow system were investigated for decarboxylative esterification. High catalytic activity toward acylation was provided by g-DMAP containing a flexible grafted-polymer structure. During decarboxylation, carboxylic acids and alcohols 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 reaction time under continuous-flow conditions, with a residence time of approximately 2 min. This highly efficient esterification procedure will provide more practical industrial applications.

Full text of DOI:10.1002/cssc.201500919

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)
E-mail: k.takeda@hamayaku.ac.jp
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201500919.
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Communications
Table 1. Continuous esterification process using various alcohols and car-
boxylic acids in the Boc2O/g-DMAP system, and comparison to corre-
sponding reactions conducted using a batch process.[a]
Table 2. Continuous esterification with N-protected amino acids and vari-
ous alcohols using a Boc2O/g-DMAP system under auxiliary base-free con-
ditions, and comparison to corresponding reactions under batch condi-
tions.[a]
Entry
R1ÀCOOH
R2ÀOH
Batch yield[b] [%]
Flow conv.[c] [%]
1[d]
2[d]
3[e]
4[e]
5[g]
Z-Pro
Z-Pro
Z-Pro
Boc-Pro[f]
Z-Phe
l-menthol
allyl
cinnamyl
benzyl
allyl
62
41
48
89
95
79
90
82
95
95
Entry
R1ÀOH
R2ÀCOOH
Batch
Flow
yield[b] [%] conv.[c] [%]
1
2
1-phenylethyl
1-phenylethyl
3-phenylpropanoic 99
cinnamic 81
92
87
3
3-phenylpropyl 3-phenylpropanoic 89
3-phenylpropyl cinnamic 85
3-phenylpropanoic 79
cinnamic 93
3-phenylpropanoic 64[f]
92
[a] g-DMAP (Lot No. 02,f=2.51 mmolgÀ1) with 0.12 mmol functionality
loaded in the reactor and used repeatedly. [b] R1ÀCOOH (0.1m), molar
ratios are same with flow conditions, g-DMAP (Lot No. 02, 3.3 mol%), RT,
24 h, isolated yield. [c] R1ÀCOOH (0.2m), determined by HPLC of crude
product. [d] X=1.3, Y=1.3. [e] X=1.5, Y=1.5. [f] N-(tert-butoxycarbonyl)-
d-proline [g] X=1.7, Y=1.7.
4[d]
5[d]
6
99[e]
84[e]
95
benzyl
benzyl
l-menthol
7
79[f,g,h]
[a] g-DMAP (Lot No. 01, f=2.54 mmolgÀ1) with 0.25 mmol functionality
was loaded and used repeatedly. [b] Alcohol (0.1m), molar ratios are
same with flow conditions, fresh g-DMAP (Lot No. 02, f=2.51 mmolgÀ1
,
3.3 mol%) was used, RT, 24 h, isolated yield. [c] Alcohol (0.6m), deter-
mined by HPLC of crude product. [d] Different Lot number catalyst was
used. [e] g-DMAP (Lot No. 02, f=2.51 mmolgÀ1) with 0.15 mmol function-
ality. [f] Solvent: ethyl acetate. [g] Flow rate: 20 mLminÀ1. [h] g-DMAP (Lot
No. 02, f=2.51 mmolgÀ1) with 0.11 mmol functionality.
The reaction was then performed under auxiliary-base-free
conditions. The auxiliary-base effect of NEt3 was determined
for esterification of N-(carbobenzyloxy)-d-proline (Z-Pro) with
allyl alcohol in a batch process (Scheme 2; Figure 2). In this
esterification with DMAP, NEt3 was important owing to the de-
protonation step in enhancing the nucleophilicity of carboxylic
acids for catalytic activity of DMAP.[11] As a result, in the ab-
sence of NEt3, the reaction proceeded more gradually than the
reaction under auxiliary-base conditions. However, this draw-
back was improved by employing the continuous-flow system,
which decreased the reaction time significantly. Several esterifi-
cation reactions between N-protected amino acids and alco-
hols without auxiliary base were investigated and compared
under batch and flow conditions at room temperature
(Table 2). In the continuous-flow
mation was reduced under a lower flow rate (20 mLminÀ1), the
conversion efficiency improved (Table 1, entry 7). However, the
batch reaction required 24 h, whereas the residence time in
the catalyst tube using the continuous-flow system was only
2 min at a flow rate of 40 mLminÀ1, demonstrating the advan-
tages of continuous-flow systems.[5] This suggests that Boc2O/
g-DMAP can be a beneficial coupling reagent for various sub-
strates if individual reaction conditions are optimized.
system using an HPLC pump, all
reagents were placed together
in a flask. Catalytic activity for
the esterification of Z-Pro with
unsaturated and secondary alco-
hols in the batch process was
improved dramatically through
the use of this continuous-flow
system (Table 2, entries 1–3).
Scheme 2. The esterification of Z-Pro with allyl alcohol using the Boc2O/g-DMAP system.
These results suggest that g-DMAP plays an important role in
esterification, not only as a highly nucleophilic base catalyst,
but also through enhancement of the nucleophilicity of the
carboxylic acids as an auxiliary base.
Finally, the efficacy of the Boc2O/g-DMAP system for tert-
butyl esterification of various carboxylic acids was investigated
(Table 3).[9,12] As indicated in Scheme 1(b), Boc2O reacted with
carboxylic acids to afford mixed carbonic–carboxylic anhy-
drides (3) with one equivalent of tert-butyl alcohol (tBuOH).
The mixed carbonic–carboxylic anhydrides (3) then underwent
nucleophilic attack by g-DMAP, resulting in formation of the
acylpyridinium salt and its corresponding tert-butyl ester, ac-
Figure 2. Effect of NEt3 on esterification of Z-Pro with allyl alcohol using the
Boc2O/g-DMAP system in a batch process.
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Table 3. Continuous tert-butyl esterification of various carboxylic acids in
the Boc2O/g-DMAP system.[a]
Keywords: acylation
esterification · graft polymer
·
dialkyl dicarbonate
·
dmap
·
[1] P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Practice, Oxford
Science Publications, 1998.
Entry R1-COOH
Boc2O [equiv.] Solvent Flow Conv.[b] [%]
[2] a) C. Ayats, A. H. Henseler, M. A. Pericµs, ChemSusChem 2012, 5, 320–
325; b) J. Lu, P. H. Toy, Synlett 2011, 5, 659–662; c) C. Ó. Dµlaigh, S. A.
Corr, Y. Gun’ko, S. J. Connon, Angew. Chem. Int. Ed. 2007, 46, 4329–
4332; Angew. Chem. 2007, 119, 4407–4410; d) K. Takeda, Reagent for Or-
ganic Synthesis-Reagents for Glycoside, Nucleotide, and Peptide Synthesis
(Ed.: D. Crich), Wiley, UK, 2006, p. 521; e) K. Takeda, Reagent for Organic
Synthesis-Reagents for High-Throughput Solid-Phase and Solution-Phase
Organic Synthesis (Ed.: P. Wipf), Wiley, UK, 2005, 272; f) M. Benaglia, A.
Puglisi, F. Cozzi, Chem. Rev. 2003, 103, 3401–3429; g) N. E. Leadbeater,
M. Macro, Chem. Rev. 2002, 102, 3217–3274.
[3] a) T. V. Khamatnurova, D. E. Bergbreiter, Polym. Chem. 2013, 4, 1617–
1624; b) J. Lu, P. H. Toy, Synlett 2011, 12, 1723–1726; c) J. Lu, P. H. Toy,
Chem. Rev. 2009, 109, 815–838; d) E. Alza, X. C. Camberio, C. Jimeno,
M. A. Pericàs, Org. Lett. 2007, 9, 3717–3720; e) K. E. Price, B. P. Mason,
A. R. Bogdan, S. J. Broadwater, J. L. Steinbacher, D. T. McQuade, J. Am.
Chem. Soc. 2006, 128, 10376–10377.
[4] T. Mizota, S. Tsuneda, K. Saito, T. Sugo, Ind. Eng. Chem. Res. 1994, 33,
2215–2219.
[5] Y. Okuno, S. Isomura, T. Kamakura, F. Sano, K. Tamahori, T. Goto, T. Haya-
shida, Y. Kitagawa, A. Fukuhara, K. Takeda, ChemSusChem 2015, 8,
1711–1715.
[6] a) I. Dhimitruka, J., Jr. StantaLucia, Org. Lett. 2006, 8, 47–50; b) I. Shiina,
M. Kubota, R. Ibuka, Tetrahedron Lett. 2002, 43, 7535–7539; c) J. Inana-
ga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.
[7] Y. Okuno, S. Isomura, A. Nishibayashi, A. Hosoi, K. Fukuyama, M. Ohoba,
K. Takeda, Synth. Commun. 2014, 44, 2854–2860.
1
2
3[d]
4[d]
Z-Pro
Z-Phe
1.5
2.0
Toluene (a) 88[c]
tBuOH
THF
(a) 79
2-Phenylbutyric acid 2.0
Abietic acid 2.0
(a) 81[d]
(a) nd[d,e]
(b)>99[d]
THF
[a] g-DMAP (Lot No. 02,f=2.51 mmolgÀ1) with 0.25 mmol functionality
loaded in the reactor and used repeatedly. [b] R1ÀCOOH (0.2m), deter-
mined by HPLC of crude product. [c] 76 h. [d] g-DMAP (Lot No. 02,f=
2.51 mmolgÀ1) with 0.22 mmol functionality loaded in the reactor and
used repeatedly. [e] Not determined.
companied by CO2 evolution. High conversion of N-(carboben-
zyloxy)-d-phenylalanine (Z-Phe) occurred using tBuOH (Table 3,
entry 2) indicating that tBuOH functions as solvent and nucleo-
philic reagent. In abietic acid, which is a sterically hindered car-
boxylic acid, a tert-butyl carbonic abietic anhydride intermedi-
ate was formed without formation of the tert-butyl ester.
In conclusion, a useful continuous-flow system was devel-
oped using coupling reactions involving Boc2O/g-DMAP for de-
carboxylative esterification with carboxylic acids and alcohols.
This continuous-flow system not only reduced the production
of by-products, but also dramatically decreased the reaction
time because of the graft-polymer-supported catalyst. Howev-
er, further optimization is needed for the reactions. These re-
sults suggest a broad scope for graft-polymer-supported cata-
lysts in flow systems.
[8] a) B. Neises, W. Steglich, Angew. Chem. Int. Ed. Engl. 1978, 17, 522–523;
b) A. Hassner, V. Alexanian, Tetrahedron Lett. 1978, 19, 4475–4478.
[9] K. Takeda, A. Akiyama, H. Nakamura, S. Takizawa, Y. Mizuno, H. Takayana-
gi, Y. Harigaya, Synthesis 1994, 1063–1066.
[10] a) U. Ragnarsson, L. Grehn, RSC Adv. 2013, 3, 18691–18697; b) L.
Gooßen, A. Dçhring, Synlett 2004, 2, 263–266; c) Y. Basel, A. Hassner,
Tetrahedron Lett. 2002, 43, 2529–2533; d) Y. Basel, A. Hassner, J. Org.
Chem. 2000, 65, 6368–6380; e) S. Kim, J. I. Lee, Y. C. Kim, J. Org. Chem.
1985, 50, 560–565.
Acknowledgements
[11] a) A. Sakakura, K. Kawajiri, T. Ohkubo, Y. Kosugi, K. Ishihara, J. Am. Chem.
Soc. 2007, 129, 14775–14779; b) T. Mukaiyama, S. Funasaka, Chem. Lett.
2007, 36, 326–327; c) S. Xu, I. Held, B. Kempf, H. Mayr, W. Steglich, H.
Zipse, Chem. Eur. J. 2005, 11, 4751–4757; d) A. C. Spivey, S. Arseniyadis,
Angew. Chem. Int. Ed. 2004, 43, 5436–5441; Angew. Chem. 2004, 116,
5552–5557.
We thank Dr. K. Nagai of the School of Pharmaceutical Sciences,
Kitasato University, for providing the MS spectra and elemental
analysis. We also thank Mr. J. Kanno and Dr. S. Aoki of Ebara
Clean Environment Co. Ltd. for pertinent advice and generous
support. We wish to acknowledge valuable discussions with Prof.
M. Otsuka of Graduate school of Pharmaceutical Sciences, Kuma-
moto University. This research was supported by Dia Pharma-
ceutical Co. Ltd., and Yokohama University of Pharmacy.
[12] L. Gooßen, A. Dçhring, Adv. Synth. Catal. 2003, 345, 943–947.
Received: July 8, 2015
Published online on October 1, 2015
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