Optimization of the selective monohydrolysis of diethyl 4-aryl-4H-pyran-3,5-dicarboxylates

Article abstract of DOI:10.3390/molecules16053845

A simple, efficient and eco-friendly procedure for the selective monohydrolysis of diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates under quaternary ammonium salt catalysis conditions is presented. The catalytic activities of various quaternary amm

Full text of DOI:10.3390/molecules16053845

Molecules 2011, 16, 3845-3854; doi:10.3390/molecules16053845
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Optimization of the Selective Monohydrolysis of Diethyl
4-Aryl-4H-pyran-3,5-dicarboxylates
Jiaojiao Duan, Xiaohui Song, Hong Yan * and Xiuqing Song
College of Life Science and Bio-engineering, Beijing University of Technology, Pingleyuan Street
Number 100, Chaoyang District, Beijing 100124, China
* Author to whom correspondence should be addressed; E-Mail: hongyan@bjut.edu.cn;
Tel.: +86-010-67396642; Fax: +86-101-67396642.
Received: 5 April 2011; in revised form: 15 April 2011 / Accepted: 18 April 2011 /
Published: 6 May 2011
Abstract: A simple, efficient and eco-friendly procedure for the selective monohydrolysis
of diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates under quaternary ammonium
salt catalysis conditions is presented. The catalytic activities of various quaternary
ammonium salts were investigated using different molar ratios of NaOH and water-organic
solvent mixtures. The results indicate that the combination of 1.0 equivalent of
tetraethyl-ammonium bromide (TEAB) with 1.2 equivalents of NaOH in a 10%
water-ethanol media at 40 °C displays remarkable selectivity for the monohydrolysis of
diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates. The utility of this process is
demonstrated by the monohydrolysis of a series of 4-aryl-4H-pyran-3,5-dicarboxylate esters
to afford the corresponding monoesters in 20–80% yields under the optimized conditions.
Keywords: monohydrolysis; 4-aryl-4H-pyran; quaternary ammonium salt; monoester;
symmetric diester
1. Introduction
The 4H-pyran moiety represents a privileged structure because many of its derivatives possess
useful pharmacological activities [1,2]. In recent years, polyfunctionalized 4H-pyrans and their
derivatives have been the subject of significant interest from the synthetic community and have been
widely recognized as versatile scaffolds with diverse biological activities [3,4]. Diethyl 2,6-dimethyl-
4-aryl-4H-pyran-3,5-dicarboxylates 1 represent an important class of 4H-pyrans that is widely used in

Molecules 2011, 16
3846
therapeutic areas, especially for the inhibition of the HIV-1 proteases [5-8]. The mono-carboxylic
acids, or monoesters 2 of compounds 1 hold potential biological activities similar to the biological
activity of 1, and are very versatile building blocks in organic synthesis. Diethyl 2,6-dimethyl-4-aryl-
4H-pyran-3,5-dicarboxylates 1 have routinely been efficiently synthesized by the reaction of aryl
aldehydes and 1,3-diketones catalyzed by ZnCl2 under ultrasound irradiation [9]. Here, we report the
synthesis of 4H-pyran hemiesters 2 by the selective monohydrolysis of symmetric diesters 1.
Ester hydrolysis is one of the most fundamental reactions in organic chemistry and commonly
referred to as alkaline hydrolysis or saponification. This method, using a base such as NaOH in
aqueous alcohol, has proven highly reliable for the hydrolysis of a single ester into a carboxylic acid
on large scales and at low cost. Unfortunately, it usually does not afford good results when applied to
diesters. In that case it typically produces complex mixtures of diacids, monoesters and the starting
diesters, and the separation of these product mixtures is often very difficult. One effective method for
the monohydrolysis of symmetric diesters utilizes enzymes [10-13]. The monohydrolysis of symmetric
diesters without the use of enzymes has proven to be a more challenging task. The only previously
reported non-enzymatic, selective monohydrolysis utilizes an aqueous NaOH solution with THF and
water as co-solvents [14-17]. Recently, quaternary ammonium salts have emerged as useful catalysts in
a number of organic transformations. Their cost, ready availability and inherent properties, such as
environmental compatibility, greater selectivity, operational simplicity, non-corrosive nature and ease
of reusability, make them highly practical choices for many applications [18-20]. We therefore became
interested in examining the behavior of quaternary ammonium ions as catalysts for the selective
monohydrolysis of diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates 1 in water-mediated
solvents (Scheme 1).
Scheme 1. Formation of 2 from 1 in the presence of TEAB catalyst.
R
R
R
1) EtOH/H2O,Cat.
2) H3O+
EtOOC
COOH
+
HOOC
COOH
EtOOC
COOEt
O
O
O
1
2
3
R = a: H; b: p-CH3; c: p-OCH3; d: p-Cl; e: m-Cl; f: p-F; g: p-NO2; h: m-NO2; i: m-Br;
j: m-NHCOCH3; k: 2,3,4- triOCH3
2. Results and Discussion
In order to study the behavior of quaternary ammonium salts as catalysts for the selective
monohydrolysis of diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates 1, and to determine the
optimal conditions with regard to the types of catalyst, equivalents of NaOH, solvents and reaction
temperature, an initial model study was carried out on the monohydrolysis of diethyl 2,6-dimethyl-4-
aryl-4H-pyran-3,5-dicarboxylate (1a).

Molecules 2011, 16
3847
The solvents ethanol and acetone used in classical ester hydrolysis were chosen for monohydrolysis
of 1a, and tetrahydrofuran and acetonitrile were also used in the co-solvent hydrolysis. The conditions
below were ascertained according to the reference [21-23]. These results presented in Table 1 were
obtianed under the conditions of 1.2 equivalents of NaOH and 1.0 equivalent of tetraethyl-ammonium
bromide (TEAB) as a catalyst in a 10% aqueous-organic solvent system at 40 °C.
Table 1. Solvent effects on the monohydrolysis of 1a using 1.2 equivalents of NaOH.
Temperature
Ratio a
2a:3a
61:39
70:30
63:37
78:22
81:19
75:25
42:58
50:50
45:55
36:64
41:59
34:66
Yield b (%)
Entry
Solvents
Time (h)
(°C)
25
40
55
25
40
55
25
40
55
25
40
55
2a
46
50
47
62
80
63
35
40
38
25
32
23
1
2
3
4
5
6
7
8
9
Tetrahydrofuran
Tetrahydrofuran
Tetrahydrofuran
Ethanol
4.5
5.0
5.0
4.0
4.0
4.0
5.0
5.0
5.0
6.0
5.5
6.0
Ethanol
Ethanol
Acetone
Acetone
Acetone
10
11
12
Acetonitrile
Acetonitrile
Acetonitrile
a Ratios based on HPLC analysis; b Isolated yields of 2a recrystallization from acetone.
In the monohydrolysis of 1a, the product ratios of 2a and 3a appeared to be higher in ethanol than
the other solvents at 40 °C, showing high partial selectivity. It seemed that the polar protic nature of
ethanol was beneficial for higher selectivity, whereas aprotic solvents were not as effective. The
efficacy of the ethanol was apparent in these reactions, as it appeared to increase the solubilities of the
diester 1 and monoester 2 and more efficiently disperse them in the reaction mixture. Other advantages
of ethanol as solvent include that it is somewhat more environmentally friendly and allows for
straightforward recovery of the catalyst by filtration through a short column of magnesium sulfate.
There was a great reason that ethanol provided a polar environment in which TEAB played a much
more obvious effect on monohydrolysis of 1a than other solvent.
Table 2. The effect of water-ethanol percentages on the monohydrolysis of 1a using
1.2 equivalents of NaOH.
% Water
(w/w%)
Ratio a
2a:3a
46:54
48:52
53:47
74:26
81:19
53:47
36:64
Yield b (%)
Entry
Time (h)
2a
35
38
48
65
80
50
28
1
2
3
4
5
6
7
0
1
5
12.0
9.0
5.5
5.5
4.0
3.5
3.5
8
10
15
20
a Ratios based on HPLC analysis; b Isolated yields of 2a recrystallization from acetone.

Molecules 2011, 16
3848
Regarding the selective monohydrolysis of 1a, the effect of the percentage of water (from 0%–20%)
in ethanol was also studied with 1.2 equivalents of NaOH and 1.0 equivalent of TEAB at 40 °C, as
depicted in Table 2. While increased water content was found to consistently enhance the rate of
hydrolysis, the optimal product ratio of 2a to 3a was observed in a 10% water-ethanol media. The
percentages were below or over 10%, the decreasing ratios of 2a and 3a were due to either less or
more exposure of the carboethoxy group to the aqueous NaOH, resulting in less reactivity to the diester
1a and higher reactivity to the diacid 3a, respectively.
The amount of NaOH used in the monohydrolysis proved to affect the selectivity for monoester 2a
under standard conditions significantly (Table 3). Low amounts of NaOH resulted in lower yields of
2a, along with lower ratios of 2a and 3a. Alternatively, excess NaOH led to increase in diacid 3a.
Interestingly, 1.0 equivalent of NaOH was not enough to maximize the ratio of 2a and 3a. In a
relatively short reaction time, 1.2 equivalents of NaOH was preferable to 1.5 and 2.0 equivalents of
NaOH, whereas the ratio of 2a and 3a was higher than those of the 1.5 and 2.0 equivalents of NaOH.
Table 3. The effect of NaOH stoichiometry on the monohydrolysis of 1a.
Ratio a
2a:3a
51:49
52:48
60:40
73:27
81:19
43:57
25:75
Yield b (%)
Entry
NaOH equiv.
Time (h)
2a
34
35
43
70
80
41
23
1
2
3
4
5
6
7
0.1
0.3
0.5
1.0
1.2
1.5
2.0
10.0
9.5
8.0
6.0
4.0
4.5
3.5
a Ratios based on HPLC analysis; b Isolated yields of 2a recrystallization from acetone.
Four catalysts were used to investigate the effect on the monohydrolysis of 1a: PEG-400
(polyethylene glycol-400), β-CD (β-cyclodextrins), tetraethyl-ammonium bromide (TEAB) and
tetrabutyl-ammonium bromide (TBAB) under standard conditions (Table 4).
Table 4. The effect of catalysts on the monohydrolysis of 1a using 1.2 equivalents of NaOH.
Ratio a
2a:3a
40:60
46:54
37:63
81:19
75:25
Yield b (%)
Entry
Catalyst
Time (h)
2a
34
45
34
80
65
1
2
3
4
5
None
PEG-400
β-CD
TEAB
TBAB
12.0
8.0
8.5
4.0
4.0
a Ratios based on HPLC analysis; b Isolated yields of 2a recrystallization from acetone.
Either in the absence of a catalyst or with PEG-400, β-CD and TBAB used as catalyst, the yields of
and selectivities for 2a were lower, with lower 2a:3a ratios. However the purity of 2a was higher when
the reaction was carried out in the presence of TEAB. Only TBAB displayed even comparable
catalytic activity to TEAB. Presumably, the shorter alkyl substitutes of TEAB make it more

Molecules 2011, 16
3849
hydrophilic, and thus more soluble, than TBAB, explaining the improved outcome [24]. In this
selective monohydrolysis, the mechanisms of TEAB appear to be a surfactant and a cation source of an
ion pair. As a surfactant, TEAB forms micelles in 10% water-ethanol media and gives carboxylate
anion by coordinating with hydroxide. The subsequent nucleophilic attack forms the carboxyl group
functionality and regenerates the TEAB in the aqueous NaOH media. As the cation of an ion pair,
TEAB provides Q+ in forming ion pairs with the carboxyl anion of monoesters to slow down the
second hydrolysis reaction [22].
The amount of TEAB catalyst played a crucial role in the selective monohydrolysis of 1a under
standard conditions (Table 5). The optimal quantity of TEAB proved to be 1.0 equivalent of 1a, and the
purity of 2a was better in a 80% conversion. The reason was that quaternary cation associated with the
carboxylate anion of monoester was more than unassociated with anion. The generation of ion pairs of
monoester 2a with Q+ resulted the further hydrolysis of 1a to diacid 3a subsequently. When more than
1.0 equivalent of TEAB was used, the ratios of 2a and 3a decreased, particularly when greater than 2.0
equivalents of TEAB were used; in this case, the major product was diacid 3a.
Table 5. The effect of TEAB stoichiometry on the monohydrolysis of 1a using
1.2 equivalents of NaOH.
TEAB
Equiv.
0.5
1.0
1.5
Ratio a
2a:3a
60:40
81:19
72:28
26:74
10:90
Yield b(%)
Entry
Time (h)
2a
43
80
67
25
9
1
2
3
4
5
5.5
4.0
3.5
3.5
3.5
2.0
2.5
a Ratios based on HPLC analysis; b Isolated yields of 2a recrystallization from acetone.
In order to analyze the scope of the methodology, different substituted dicarboxylate products 1b–k
were used under the following conditions: 10% water-ethanol media, 1.2 equivalents of NaOH and
1.0 equivalent of TEAB at 40 °C, as shown in Table 6.
Table 6. Monohydrolysis yields for a variety of 4-aryl-4H-pyrans 2 using 1.2 equivalents of NaOH.
Ratio a
2:3
Substrate
R
Yield b(%)
Melting point (°C)
1b
1c
1d
1e
1f
1g
1h
1i
p-CH3
p-OCH3
p-Cl
m-Cl
p-F
p-NO2
m-NO2
m-Br
72:28
52:48
69:31
58:42
75:25
50:50
46:54
65:35
20:80
45:55
69
51
66
54
69
49
40
62
20
42
123.6–124.7
110.3–112.0
141.8–143.1
132.1–133.4
137.4–139.1
110.1–111.7
121.4–121.9
161.4–162.7
181.2–183.2
149.1–150.4
1j
1k
m-NHCOCH3
2,3,4-triOCH3
a Ratios based on HPLC analysis; b Isolated yields of 2.

Molecules 2011, 16
3850
In general, the selective monohydrolysis of symmetric diesters 1 was successful and the
corresponding monoesters 2 were obtained in 20–80% yields. The effects of substituents on the aryl
ring of 4-aryl-4H-pyrans showed no discernable pattern. That is, for electron-withdrawing groups such
as p-F and p-NO2, the yields of monoesters 2f and 2g (69% and 49%, respectively) with ratios of 2 and
3 (75:25 and 50:50, respectively) were similar to those of 2b and 2c (69% and 51%, respectively) with
ratios of 2 and 3 (72:28 and 52:48, respectively), which have electron-donating groups (p-CH3 and
p-OCH3, respectively). An increase in the yields of 2 was observed with the electron-withdrawing
groups of p-Cl and p-NO2 (66% and 49%, respectively) with ratios of 2 and 3 (69:31 and 50:50,
respectively) in comparison to m-Cl, m-NO2 (54% and 40%, respectively) with ratios of 2 and 3 (58:42
and 46:54, respectively). The lowest yield was observed with m-NHCOCH3 (2j) with the lowest ratio
of 2j and 3j (20:80), likely due to its decreased solubility and susceptibility to hydrolysis of the acetyl
amino group in alkaline water-ethanol media.
3. Experimental
3.1. General
Melting points were determined using an X-5 apparatus (open capillaries, uncorrected values).
1H- and 13C-NMR spectra were acquired at ambient temperature (25 °C) in CDCl3 on a Bruker AV 400
spectrometer (400 and 100.6 MHz, respectively). Infrared spectra were recorded on a Bruker
VERTEX70 instrument as potassium bromide pellets. Mass spectra were recorded on an Agilent
G3250AA LC/MSD TOF system. The reaction process and the products were routinely monitored by
HPLC (Waters 600, UV 2487 dual absorbance detector) with a C-18 column (4.6 × 250 mm; eluent:
acetonitrile-H2O = 65:35; 25 °C; flow rate = 1 mL/min; UV detection at 220 nm). The chemical agents
used in this study were all commercially available; diesters 1 were prepared according to our
previously described method [9].
3.2. General Procedure for the Synthesis of Compounds 2
A mixture of 1 (1.0 mmol) and TEAB (0.36 g, 1.0 mmol) was dissolved in ethanol (20 mL) and
water (1.75 mL). The reaction mixture was stirred with the evolution of heat; to this mixture was added
dropwise with stirring 1.0 M NaOH aqueous solution in the amount indicated in Tables 1–6 (0.1, 0.3,
0.5, 1.0, 1.2, 1.5 and 2.0 equivalents) until the mixture temperature reached 40 °C. The reaction
mixture was stirred until complete consumption of the starting diester 1 was observed by TLC. The
solution was then poured into water (150 mL) and acidified to pH 1–2 with 6.0 M HCl at 5–10 °C. A
fine white precipitate was formed and filtered off, washed with ice water until reaching pH 7 and dried
under vacuum.
5-(ethoxycarbonyl)-2,6-dimethyl-4-aryl-4H-pyran-3-carboxylic acid (2a). Yield (0.24 g, 80%), Mp
98.3–100.0 °C. IR: 705, 1191, 1626, 1664, 1709, 2372, 2981, 3432 cm−1. 1H-NMR: δ = 1.21–1.23 (t, 3 H,
CH2CH3), 2.38 (s, 6 H, CH3), 4.10–4.13 (m, 2 H, CH2CH3), 4.75 (s, 1 H, Ar–CH), 7.15 (d, J = 8.8 Hz,
2 H, Ar–H), 7.27 (d, J = 8.8 Hz, 2 H, Ar–H), 10.40–13.05 (s, 1 H, COOH). 13C-NMR: δ = 14.2, 15.6,

Molecules 2011, 16
3851
41.8, 61.7, 106.6, 107.3, 125.8, 128.7, 129.1, 142.2, 156.6, 159.4. HRMS: m/z [M + K]+ calcd for
C17H18O5K: 341.1218; found: 341.1220.
5-(ethoxycarbonyl)-2,6-dimethyl-4-p-tolyl-4H-pyran-3-carboxylic acid (2b). Yield (0.22 g, 69%), Mp
1
123.6–124.7 °C. IR: 933, 1191, 1621, 1699, 2373, 2982, 3430 cm−1. H-NMR: δ = 1.19–1.23 (t, 3 H,
CH2CH3), 2.32 (s, 3 H, CH3), 2.38 (s, 6 H, CH3), 4.09–4.11 (m, 2 H, CH2CH3), 4.75 (s, 1 H, Ar–CH),
7.10 (d, J = 8.8 Hz, 2 H, Ar–H), 7.15 (d, J = 8.8 Hz, 2 H, Ar–H), 11.00-12.98 (s, 1 H, COOH).
13C-NMR: δ = 14.2, 15.6, 24.3, 41.8, 61.7, 106.6, 107.3, 129.0, 135.4, 139.2, 156.6, 159.4, 167.2,
171.3. HRMS: m/z [M + Na]+calcd for C18H20O5Na: 339.1326; found: 339.1322.
5-(ethoxycarbonyl)-4-(4-methoxyphenyl)-2,6-dimethyl-4H-pyran-3-carboxylic acid (2c): Yield (0.17 g,
51%), Mp 110.3–112.0 °C. IR: 932, 1180, 1625, 1715, 2371, 2982, 3433 cm−1; 1H-NMR: δ = 1.12–1.24
(t, 3 H, CH2CH3), 2.36 (s, 6 H, CH3), 3.77 (s, 3 H, OCH3), 4.07–4.13 (m, 2 H, CH2CH3), 4.77 (s, 1 H,
Ar–CH), 6.98 (d, J = 8.8 Hz, 2 H, Ar–H), 7.35 (d, J = 8.8 Hz, 2 H, Ar–H), 11.10–13.90 (s, 1 H,
13
COOH). C-NMR: δ = 14.1, 18.5, 19.1, 37.2, 55.1, 60.3, 107.6, 108.8, 113.4, 129.3, 137.4, 157.8,
158.3, 160.4, 166.5, 171.3. HRMS: m/z [M − H]+ calcd for C18H20O6: 331.1323; found: 331.1319.
4-(4-chlorophenyl)-5-(ethoxycarbonyl)-2,6-dimethyl-4H-pyran-3-carboxylic acid (2d): Yield (0.23 g,
66%), Mp 141.8–143.1 °C. IR: 853, 1180, 1655, 1718, 2372, 2983, 3436 cm−1; 1H-NMR: δ = 1.21–1.24
(t, 3 H, CH2CH3), 2.37 (s, 6 H, CH3), 4.09–4.13 (m, 2 H, CH2CH3), 4.71 (s, 1 H, Ar–CH), 6.87 (d,
13
J = 8.8 Hz, 2 H, Ar–H), 7.27 (d, J = 8.8 Hz, 2 H, Ar–H), 11.3 (s, 1 H, COOH). C-NMR: δ = 14.1,
18.5, 19.1, 37.2, 55.1, 60.3, 107.6, 108.8, 113.4, 129.3, 137.4, 157.8, 158.3, 160.4, 166.5, 172.2.
HRMS: m/z [2M – CH3]+ calcd for C17H17ClO5: 687.2383; found: 687.2388.
4-(3-chlorophenyl)-5-(ethoxycarbonyl)-2,6-dimethyl-4H-pyran-3-carboxylic acid (2e): Yield (0.18 g,
54%), Mp 132.1–133.4 °C. IR: 853, 1188, 1656, 1718, 2372, 2983, 3433 cm−1; 1H-NMR: δ = 1.23–1.27
(t, 3 H, CH2CH3), 2.39 (s, 6 H, CH3), 4.10–4.17 (m, 2 H, CH2CH3), 4.76 (s, 1 H, Ar–CH), 7.09 (d,
13
J = 8.8 Hz, 2 H, Ar–H), 7.38 (d, J = 8.8 Hz, 2 H, Ar–H), 10.40–13.40 (s, 1 H, COOH). C-NMR:
δ = 14.1, 18.5, 19.1, 37.2, 55.1, 60.3, 107.6, 108.8, 113.4, 129.3, 137.4, 157.8, 158.3, 163.4, 165.4,
176.3. HRMS: m/z [M − H]+ calcd for C17H17ClO5: 335.0821; found: 335.0821.
5-(ethoxycarbonyl)-4-(4-fluorophenyl)-2,6-dimethyl-4H-pyran-3-carboxylic acid (2f): Yield (0.22 g,
1
69%), Mp 137.4–139.1 °C. IR: 849, 1128, 1192, 1710, 2372, 2983, 3152, 3425 cm−1; H-NMR:
δ = 1.18–1.21 (t, 3 H, CH2CH3), 2.39 (s, 6 H, CH3), 4.06–4.11 (m, 2 H, CH2CH3), 4.72 (s, 1 H, Ar–CH),
6.98 (d, J = 8.8 Hz, 2 H, Ar–H), 7.25 (d, J = 8.8 Hz, 2 H, Ar–H), 11.70–12.80 (s, 1 H, COOH).
13C-NMR: δ = 14.1, 18.5, 19.2, 37.3, 60.4, 107.4, 108.5, 114.7, 114.9, 129.8, 129.9, 140.8, 158.3,
160.4, 162.8, 166.3, 172.3. HRMS: m/z [M – CH3]+ calcd for C17H17FO5: 305.1561; found: 305.1556.
5-(ethoxycarbonyl)-2,6-dimethyl-4-(4-nitrophenyl)-4H-pyran-3-carboxylic acid (2g): Yield (0.16 g,
49%), Mp 110.1–111.7 °C. IR: 874, 1167, 1347, 1624, 1721, 2349, 2938, 3077, 3462 cm−1. 1H-NMR:
δ = 1.18–1.21 (t, 3 H, CH2CH3), 2.39 (s, 6 H, CH3), 4.06–4.11 (m, 2 H, CH2CH3), 4.84 (s, 1 H,
Ar–CH), 7.26 (d, J = 8.8 Hz, 2 H, Ar–H), 7.42 (d, J = 8.8 Hz, 2 H, Ar–H), 10.90–13.20 (s, 1 H,

Molecules 2011, 16
3852
13
COOH). C-NMR: δ = 14.1, 18.6, 19.2, 38.3, 60.7, 106.4, 107.5, 123.4, 129.3, 146.7, 152.3, 159,
161.7, 165.8, 171.5. HRMS: m/z [M − H]+ calcd for C17H17NO7: 335.0831; found: 335.0830.
5-(ethoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-4H-pyran-3-carboxylic acid (2h): Yield (0.13 g,
40%), Mp 121.4–121.9 °C. IR: 900, 1221, 1348, 1652, 1703, 2372, 2952, 3091, 3348 cm−1. 1H-NMR:
δ = 1.19–1.22 (t, 3 H, CH2CH3), 2.30 (s, 6 H, CH3), 4.11–4.17 (m, 2 H, CH2CH3), 4.89 (s, 1 H,
Ar–CH), 7.21 (d, J = 8.8 Hz, 2 H, Ar–H), 7.42 (d, J = 8.8 Hz, 2 H, Ar–H), 10.84–12.40 (s, 1 H,
13
COOH). C-NMR: δ = 14.1, 18.6, 19.2, 38.6, 62.7, 106.4, 107.5, 123.4, 129.3, 146.7, 152.3, 160.3,
162.7, 165.8, 175.4. HRMS: m/z [M]+ calcd for C17H17NO7: 336.0815; found: 336.0816.
4-(3-bromophenyl)-5-(ethoxycarbonyl)-2,6-dimethyl-4H-pyran-3-carboxylic acid (2i): Yield (0.24 g,
62%), Mp 161.4–162.7 °C. IR: 900, 1221, 1380, 1628, 1700, 2372, 2952, 3091, 3348 cm−1. 1H-NMR:
δ = 1.22–1.25 (t, 3 H, CH2CH3), 2.34 (s, 6 H, CH3), 4.09–4.15 (m, 2 H, CH2CH3), 4.73 (s, 1 H,
Ar–CH), 7.10 (s, J = 8.8 Hz, 2 H, Ar–H), 7.15-7.35 (m, J = 8.8 Hz, 3 H, Ar–H), 11.40–13.20 (s, 1 H,
13
COOH). C-NMR: δ = 14.2, 17.6, 28.3, 38.2, 61.7, 106.6, 107.3, 125.4, 128.3, 146.2, 156.3, 159.4,
160.7, 165.4, 174.3. HRMS: m/z [M + Na]+ calcd for C17H17BrO5Na: 403.0315; found: 403.0315.
4-(3-acetamidophenyl)-5-(ethoxycarbonyl)-2,6-dimethyl-4H-pyran-3-carboxylic acid (2j): Yield (0.07
g, 20%), Mp 181.2–183.2 °C. IR: 888, 1188, 1330, 1652, 1717, 2345, 2983, 3061, 3425 cm−1.
1H-NMR: δ = 1.20–1.24 (t, 3 H, CH2CH3), 2.16 (s, 3 H, NHCOCH3), 2.34 (s, 6 H, CH3), 4.07–4.14
(m, 2 H, CH2CH3), 4.92 (s, 1 H, Ar–CH), 6.94–7.23 (m, 4 H, Ar–H), 7.44 (s, 1 H, NHCOCH3), 11.60–13.50
13
(s, 1 H, COOH). C-NMR: δ = 14.2, 18.6, 22.9, 41.8, 60.7, 106.6, 107.3, 118.4, 124.3, 128.7, 138.3,
142.4, 156.6, 165.8, 167.2, 173.3. HRMS: m/z [M + Na]+ calcd for C19H21NO6Na: 382.1464; found:
382.1455.
5-(ethoxycarbonyl)-2,6-dimethyl-4-(2,3,4-trimethoxyphenyl)-4H-pyran-3-carboxylic acid (2k): Yield
(0.16 g, 42%), Mp 149.1–150.4 °C. IR: 793, 1048, 1147, 1189, 1291, 1397, 1494, 1645, 1724, 2935,
1
3037, 3444 cm−1. H-NMR: δ = 1.21–1.25 (t, 3 H, CH2CH3), 2.32 (s, 6 H, CH3), 3.84 (t, 9 H, OCH3),
4.08–4.16 (m, 2 H, CH2CH3), 4.77 (s, 1 H, Ar–CH), 7.20 (d, J = 8.8 Hz, 1 H, Ar–H), 7.34 (d, J = 8.8 Hz,
13
1 H, Ar–H), 10.95-12.70 (s, 1 H, COOH). C-NMR: δ = 14.2, 17.6, 41.7, 56.5, 61.7, 106.6, 107.5,
113.4, 128.4, 139.1, 145.8, 157.6, 167.2, 171.3, 174.4. HRMS: m/z [M + Na]+ calcd for C21H27O8Na:
415.1527; found: 415.1526.
4. Conclusions
In summary, experiments were designed to study and optimize the selective monohydrolysis of
symmetric diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylate diesters 1 for the preparation of
5-(ethoxycarbonyl)-2,6-dimethyl-4-aryl-4H-pyran-3-carboxylic acid monoesters 2. The main parameters
that affected the yields of monoesters 2 were investigated, and the optimal conditions were established
as a 10% water-ethanol media in the presence of a 1.0 equiv. TEAB, with the following molar ratios
for NaOH: 1a = 1.2:1 at 40 °C. This reaction represents a unique, flexible and simple method for the
monohydrolysis of diesters to afford monoesters in 20–80% yields under the optimized condition.

Molecules 2011, 16
3853
Acknowledgements
This work was financially supported by the National Natural Sciences Foundation (Number
20872009) and the Natural Sciences Foundation of Beijing (Number 200710005002).
References
1. Zamocka, J.; Misikova, E.; Durinda, J. Preparation, structure elucidation and activity of some
[(5-hydroxy- or 5-methoxy-4-oxo-4H-pyran-2-yl) methyl]-2-alkoxycarbanilates. Pharmazie 1991,
46, 610.
2. Wang, J.L.; Liu, D.; Zhang, Z.J.; Shan, S.; Han, X.; Srinivasula, S.M.; Croce, C.M.; Alnemri, E.S.;
Huang, Z. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces
apoptosis of tumor cells. Proc. Natl. Acad. Sci. USA 2000, 97, 7124-7129.
3. Hatakeyama, S.; Ochi, N.; Numata, H.; Takano, S. A new route to substituted
3-methoxycarbonyldihydropyrans; enatioselective synthesis of (−)-methyl elenolate. J. Chem.
Soc. Chem. Commun. 1988, 17, 1202-1204.
4. González, R.; Martín, N.; Seoane, C.; Marco, J.L.; Albert, A.; Cano, F.H. The first asymmetric
synthesis of polyfunctionalized 4H-pyrans via Michael addition of malononitrile to 2-acyl
acrylates. Tetrahedron Lett. 1992, 33, 3809-3812.
5. Li, A.H.; Ji, X.D.; Kim, H.S.; Melman, N.; Jacobson, K.A. Pyran template approach to the design
of novel A3 adenosine receptor antagonists. Drug Dev. Res. 1999, 48, 171-177.
6. Urbahns, K.; Horvath, E.; Stasch, J.P.; Mauler, F. 4-Phenyl-4H-pyrans as IKCa channel blockers.
Bioorg. Med. Chem. Lett. 2003, 13, 2637-2639.
7. Witte, E.C.; Neubert, P.; Roesch, A. 7-(Piperazinylpropoxy)-2H-1-benzopyran-2-ones. DE patent
3427985, 1986.
8. Yan, H.; Ni, C.L.; Wang, H.Q. Preparation of 3,9-dioxapentacyclo[6.4.0.02,7.04,11.05,10]
dodecane derivatives as anti-AIDS agents. CN patent 101041662, 2007.
9. Ni, C.L.; Song, X.H.; Yan, H.; Song, X.Q.; Zhong, R.G. Improved synthesis of diethyl
2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylate under ultrasound irradiation. Ultrason. Sonochem.
2010, 17, 367-369.
10. Iding, H.; Wirz, B.; Rosa-Maria, R.S. Chemoenzymatic preparation of non-racemic N-Boc-
piperidine-3,5-dicarboxylic acid 3-methyl esters and their 5-hydroxymethyl derivatives.
Tetrahedron: Asymmetry 2003, 14, 1541-1545.
11. Guanti, G.; Narisano, E.; Podgorski, T.; Thea, S.; Williams, A. Enzyme catalyzed monohydrolysis
of 2-aryl-1,3-propanediol diacetates. A study of structural effects of the aryl moiety on the
enantioselectivity. Tetrahedron 1990, 46, 7081-7092.
12. Guanti, G.; Banfi, L.; Narisano, E. Enzymes in organic synthesis: Remarkable influence of
a π system on the enantioselectivity in PPL catalyzed monohydrolysis of 2-substituted
1,3-diacetoxypropanes. Tetrahedron: Asymmetry 1990, 1, 721-724.
13. Rodrigues, D.S.; Mendes, A.A.; Filice, M.; Roberto, F.L.; Guisan, J.M.; Palomo, J.M. Different
derivatives of a lipase display different regioselectivity in the monohydrolysis of per-O-acetylated
1-O-substituted-β-galactopyranosides. J. Mol. Catal. B: Enzym. 2009, 58, 36-40.

Molecules 2011, 16
3854
14. Niwayama, S.; Wang, H.Z.; Hiraga, Y.; Clayton, J.C. Influence of co-solvents in the highly
efficient selective monohydrolysis of a symmetric diester. Tetrahedron Lett. 2007, 48, 8508-8510.
15. Satomi, N.; Hanjoung, C. Practical large scale synthesis of half-esters of malonic acid.
Chem. Pharm. Bull. 2009, 57, 508-510.
16. Satomi, N.; Hanjoung, C.; Masoud Z.M.; Bruce R.W. Remote exo/endo selectivity in selective
monohydrolysis of dialkyl bicyclo[2.2.1]heptane-2,3-dicarboxylate derivatives. J. Org. Chem.
2010, 75, 3775-3780.
17. Niwayama, S. Highly efficient selective monohydrolysis of symmetric diesters. J. Org. Chem.
2000, 65, 5834-5836.
18. Chary, M.V.; Keerthysri, N.C.; Vupallapati, S.V.N.; Lingaiah, N.; Kantevari, S.
Tetrabutylammonium bromide (TBAB) in isopropanol: An efficient, novel, neutral and recyclable
catalytic system for the synthesis of 2,4,5-trisubstituted imidazoles. Catal. Commun. 2008, 9,
2013-2017.
19. Bhalerao, D.S.; Mahajan, U.S.; Chaudhari, K.H.; Akamanchi, K.G. O-Iodoxybenzoic acid- and
tetraethylammonium bromide-mediated oxidative transformation of primary carboxamides to
one-carbon dehomologated nitriles. J. Org. Chem. 2007, 72, 662-665.
20. Uchiyama, Y.; Fujinami, M.; Sawada, T.; Lsao, T. Observation of dynamic molecular behavior in
a phase transfer catalytic reaction at a liquid/liquid interface by using the time-resolved
quasi-elastic laser scattering method. J. Phys. Chem. B 2000, 104, 4699-4702.
21. Wu, W.J.; Ding, H.Y.; Li, Q.R. Synthesis of 2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-
1,4-dihydropyridine-3-carboxylic acid. J. Guangdong Pharm. 2008, 24, 493-495.
22. Hasegawa, T.; Yamamoto, H. A selective partial hydrolysis of dimenthyl ester using dry
tetrabutylammonium hydroxide. Synlett 1999, 1, 84-86.
23. Sirovski, F.; Gorokhova, M.; Ruban, S. Phase-transfer catalysis: kinetics and mechanism of
dichlorocyclopropane formation in liquid/liquid and solid/liquid systems. J. Mol. Catal. A-Chem.
2003, 197, 213-222.
24. Lygo, B.; Crosby, J.; Lowdon, T.R.; Peterson, J.A.; Wainwright, P.G. Studies on the
enantioselective synthesis of α-amino acids via asymmetric phase-transfer catalysis. Tetrahedron
2001, 57, 2403-2409.
Sample Availability: Sample of compounds 2a-2k are available from authors.
© 2011 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).