Ultrasound-Assisted Methyl Esterification of Carboxylic Acids ACatalyzed by Polymer-Supported Triphenylphosphine

Article abstract of DOI:10.1055/s-0034-1381117

A convenient and efficient sonochemical method for methyl esterification of carboxylic acids catalyzed by polymer-supported triAphenylphosphine (PS-Ph₃P) is reported. In the presence of 1:0.1:2 molar ratio of 2,4,6-trichloro-1,3,5-triazine/PS-Ph₃P/Na₂CO₃, methyl esters of various carboxylic acids bearing reactive hydroxyl groups as well as acid-or base-labile functionalities could be rapidly prepared (within 10-20 min) in good to excellent yields without necessity to pre-activate the acids. Using the polymer-bound phosphine also allows easy isolation of the products which, in most of the cases, were obtained in high purities without column chromatography.

Full text of DOI:10.1055/s-0034-1381117

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©
Georg Thieme Verlag Stuttgart · New York
2015, 26, 2006–2008
2006
letter
Synlett
S. Jaita et al.
Letter
Ultrasound-Assisted Methyl Esterification of Carboxylic Acids
Catalyzed by Polymer-Supported Triphenylphosphine
Subin Jaita
Wong Phakhodee
Mookda Pattarawarapan*
Department of Chemistry and Center of Excellence for Innovation
in Chemistry, Faculty of Science, Chiang Mai University,
Chiang Mai 50200, Thailand
mookdap55@gmail.com
Received: 16.04.2015
Accepted after revision: 09.06.2015
Published online: 09.07.2015
boxylic acids and methanol since the starting materials are
inexpensive, easy to handle, and readily available. The well-
known classical approach for such transformation is the
DOI: 10.1055/s-0034-1381117; Art ID: st-2015-d0276-l
9
Fisher esterification. This acid-catalyzed reaction is, how-
Abstract A convenient and efficient sonochemical method for methyl
esterification of carboxylic acids catalyzed by polymer-supported tri-
phenylphosphine (PS-Ph P) is reported. In the presence of 1:0.1:2 molar
ratio of 2,4,6-trichloro-1,3,5-triazine/PS-Ph P/Na CO , methyl esters of
various carboxylic acids bearing reactive hydroxyl groups as well as
acid- or base-labile functionalities could be rapidly prepared (within 10–
ever, reversible and requires removal of water and/or use of
a large excess of alcohol to achieve high conversions. In-
compatibility with acid-sensitive functionalities also limits
its use to those simple carboxylic acids.
Alternatively, carboxylic acids may be converted into
other more active species such as acid halides, anhydrides,
or active esters before treatment with alcohols. In addition
to commercially available coupling reagents, some exam-
3
3
2
3
20 min) in good to excellent yields without necessity to pre-activate the
acids. Using the polymer-bound phosphine also allows easy isolation of
the products which, in most of the cases, were obtained in high purities
without column chromatography.
ples of acid-activating systems including 2,4,6-trichloro-
Key words esterification, carboxylic acids, esters, phosphorus, che-
moselectivity
10
1
,3,5-triazine (TCT) and its derivatives, Ph P/trichloroiso-
3
11
imidazole carbamate/urea,12 Ph P-I /
cyanuric acid,
imidazole,
3
2
13
14
15
POCl -DMAP,
Ph P-I /cat. Zn(OTf) ,
and
3
3
2
2
6
Methyl esterification of carboxylic acids is an important
synthetic process which has been used in various applica-
tions such as in the synthesis of biodiesels, fragrance mate-
Mitsunobu-type reagents1 have been developed for esteri-
fication of carboxylic acids. Nevertheless, the methods still
suffer limitations such as requirement of an additional acti-
vation step, costly reagents, long reaction times, and/or
harsh reaction conditions.
1
rials, and surfactants. Moreover, the method is generally
applied in facilitating the purification and characterization
of structurally complex molecules as well as in the protec-
tion of carboxyl group(s) during a synthetic sequence.2
Thus, numerous methods for generating methyl esters have
been developed to achieve high conversion with functional-
group compatibility under mild conditions.
Generally, methyl esters can be prepared either by
methylation of the carboxyl oxygen or through nucleophilic
substitution on the carboxyl carbon by methanol. In the
Ultrasonic technology has become a highly attractive
energy source for organic reactions due to the safety and
simplicity of the instrumental set-up.17 Due to the cavita-
tion effect which leads to enhancement in mass-transfer
rate and mixing between the phases, reactions carried out
under ultrasonic irradiation have often been reported with
higher yields, better selectivity, and shorter reaction times
in comparison with the traditional stirring methods.
3
former method, apart from the direct use of iodomethane,
In our ongoing studies with the TCT/Ph P-mediated nu-
3
18
4
various reagents such as diazomethane (CH N ), trimethyl-
cleophilic substitution of carboxylic acids, we herein re-
2
2
5
6
silyldiazomethane (TMSCHN ), dimethyl sulfate, polymer-
port a facile, convenient, and economical approach for rapid
conversion of carboxylic acids into their methyl ester deriv-
atives using a combination of TCT, polymer-supported
triphenylphosphine (PS-Ph P), and Na CO under ultrasonic
2
7
8
supported methyl sulfonate, and dimethyl carbonate have
been applied as electrophilic methyl-group equivalents.
A relatively more straightforward method toward meth-
yl esters is through the direct condensation between car-
3
2
3
irradiation. The reaction is most likely to proceed via the
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Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2006–2008

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S. Jaita et al.
Letter
formation of triazinephosphonium chloride (I) which un-
dergoes displacement with a carboxylate anion to provide
an acyloxytriazine II. This reactive species then further re-
acts with methanol to afford the desired methyl ester with
concomitant release of the hydroxyl derivative of TCT
Nicotinic acid also reacted efficiently (Table 1, entry 11). 4-
Hydroxybenzoic acid containing a reactive phenolic hy-
droxy group provided the respective product in moderate
yield indicating good chemoselectivity of the method (Table
1, entry 12). The sonochemical conditions were also appli-
cable to α,β-unsaturated acids as well as aliphatic acids (Ta-
ble 1, entries 13–16). Methyl ester derivatives of β-aryl ac-
ids were afforded in high yields without decarboxylation as
may be observed under Fischer esterification conditions
(Scheme 1).
Cl
N
Ph2P
N
N
(
Table 1, entries 15 and 16).22
Cl
Cl
O-Methylation of N-protected α-amino acids was also
attempted. N-Benzoyl glycine and Boc-Gly-OH reacted
readily to give the desired products without removal of the
acid-sensitive benzoyl or Boc groups (Table 1, entries 17
and 18). Similarly, Fmoc-Gly-OH (Table 1, entry 19) was
converted into its corresponding methyl ester in good yield.
Cl
Cl
Ph
N
N
Ph2P
O
Cl
N
P
Ph
I
Table 1 Methyl Esterification of Carboxylic Acids
Cl
R
N
OMe
O
MeOH
N
N
O
O
+
TCT, PS-PPh3
R
O
Na
+
MeOH
R1
OH
R1
OH
Cl
N
O
OMe
Na2CO3, ))), 50 °C
N
R
O
Entry
R1CO
2
H
Time (min) Yield (%)a
Purity (%)c
II
Cl
N
Cl
1
2
PhCOOH
6 4
4-MeC H COOH
10
10
10
20
10
30
20
20
20
20
20
20
10
10
20
10
20
20
10
90
98
92
82
99
85
97
94
92
96
100
100
100
100
100
98
Scheme 1 Proposed mechanism for TCT/PS-Ph P-catalyzed methyl es-
terification
3
3
4-MeOC
2-MeOC
6
6
H
4
COOH
COOH
4
H
4
Since alcohols are weaker nucleophiles than carboxylate
ions, a one-step condensation procedure in which carboxyl-
ic acids were activated in the presence of methanol and in-
organic bases was investigated. In a preliminary study, it
was found that the methyl ester of 4-methylbenzoic acid
5
3,4-(MeO) C H COOH
2
6
3
6
3-Me
2
NC
6
H
4
COOH
7
4-ClC
2-ClC
6
6
H
4
4
COOH
COOH
100
100
100
100
95
8
H
(
0.271 mmol) could be obtained in 98% yield after ten min-
9
2-IC
4-O
6
H
4
COOH
utes sonication of the acid in methanol (0.5 mL) at 50 °C in
the presence of 1:0.1:2 molar ratio of TCT/PS-Ph P/Na CO .
10
11
12
2
NC COOH
6 4
H
3
2
3
Although other carbonate bases including K CO and Cs CO
nicotinic acid
80
2
3
2
3
gave comparative yields, Na CO was selected as the base
70b
2
3
4-HOC H COOH
88
6
4
for further investigation due to its lower cost and ready
availability.
13
14
15
PhCH=CHCOOH
Ph(CH COOH
2-MeOPhCH COOH
4-HOPhCH COOH
82
97
90
77b
100
100
100
90
2 4
)
Reaction in the absence of the phosphine catalyst gave a
complex mixture which provided only 27% of the corre-
sponding ester. Under vigorous stirring at 50 °C, the corre-
sponding ester was obtained in 35% yield. Thus a significant
improvement in both the product yield and the reaction
rate results from using catalytic quantities of the polymer-
bound phosphine under ultrasonic irradiation.
2
16
17
2
b
benzoylglycine
Boc-Gly-OH
87
92
80b
18
95
19
Fmoc-Gly-OH
85b
93
a
Unless otherwise indicated, the yield was obtained after filtration of the
crude reaction through a short pad of silica, followed by solvent evapora-
tion.
Yield obtained after column chromatography.
Purity of the isolated product after the filtration method based on GC–
The one-step condensation between methanol and a se-
ries of carboxylic acids including aromatic acids, α,β-unsat-
urated acid, aliphatic acids, as well as N-protected α-amino
b
c
19–21
acids was further evaluated.
According to Table 1, ben-
MS.
zoic acids with either electron-donating groups or electron-
withdrawing substituent(s) gave the corresponding methyl
esters in good to excellent yields although electron-defi-
cient and sterically hindered acids required slightly longer
times for completion of the reaction (Table 1, entries 1–10).
It is noted that we did not observe any residual TCT after
reaction which could be due to the formation of monosub-
stituted acyloxytriazine II or possibly methanolysis of the
unreacted TCT. Since most methyl esters are less polar than
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S. Jaita et al.
Letter
other unreacted carboxylic acids (if any) and the byprod-
uct(s) from TCT, isolation of the ester products could be
readily conducted by filtration through a short silica plug.
With this procedure, only the polar components are re-
tained on the silica gel, while the desired methyl esters are
isolated in high purities (>95% based on GC–MS). Neverthe-
less, flash chromatography was necessary in the cases
where the reaction gave high polarity products (Table 1, en-
tries 17–19) or complex mixtures (Table 1, entries 12 and
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In summary, using a TCT/PS-Ph P/Na CO combination,
3
2
3
methyl esters of carboxylic acids could be rapidly prepared
in a single step without requirement for an additional acid
pre-activation reaction. Under the weakly basic conditions,
the reaction is compatible with a range of carboxylic acids
including those containing a reactive hydroxyl group and
N-protected α-amino acids bearing acid- or base-sensitive
protecting groups. This easy-to-operate sonochemical
method offers an excellent alternative to the existing esteri-
fication procedures with additional benefits in terms of
functional-group compatibility and selectivity. Investiga-
tions into the scope of the methodology with a series of al-
cohols are currently under way.
(
14) Chen, H.; Xu, X.; Liu, L.; Tang, G.; Zhao, Y. RSC Adv. 2013, 3,
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Acknowledgment
(e) Suprarukmi, D. D.; Sudrajat, B. A.; Widayat, Procedia Envi-
The Center of Excellence for Innovation in Chemistry (PERCH-CIC),
and the National Research University Project under Thailand’s Office
of the Higher Education Commission, Chiang Mai University are
gratefully acknowledged for financial support.
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(19) General Procedure
The carboxylic acid (0.271 mmol), TCT (0.050 g, 0.271 mmol),
PS-Ph P (0.009 g, 0.027 mmol, loading 3.0 mmol/g), and Na CO
3
3
2
References and Notes
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f
1
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3
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f
1
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3
(d, J = 7.6 Hz, 2 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.31 (t, J = 7.6 Hz, 2
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(
(
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©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2006–2008