Improved synthesis of diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylate under ultrasound irradiation

Article abstract of DOI:10.1016/j.ultsonch.2009.09.006

Diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates (1) have been synthesized by the reaction of aryl aldehyde and 1,3-diketone catalyzed by ZnCl₂ under ultrasound irradiation. The effects of changes in the ultrasonic power, temperature, an

Full text of DOI:10.1016/j.ultsonch.2009.09.006

Ultrasonics Sonochemistry 17 (2010) 367–369
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Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Improved synthesis of diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylate
under ultrasound irradiation
1
1
*
Cheng-Liang Ni , Xiao-Hui Song , Hong Yan , Xiu-Qing Song, Ru-Gang Zhong
College of Life Science and Bio-engineering, Beijing University of Technology, Pingleyuan Street No. 100, Chaoyang District, Beijing 100124, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates (1) have been synthesized by the reaction of
aryl aldehyde and 1,3-diketone catalyzed by ZnCl2 under ultrasound irradiation. The effects of changes
in the ultrasonic power, temperature, and reaction time are discussed. With the optimized reaction con-
ditions, various aryl aldehydes were used to synthesize 4H-pyrans (1) under the influence of ultrasound
irradiation. Compared with the conventional thermal methods, the remarkable advantages of this
method are the simple experimental procedure, shorter reaction time and high yield of product.
Ó 2009 Elsevier B.V. All rights reserved.
Received 4 November 2008
Received in revised form 1 September 2009
Accepted 21 September 2009
Available online 26 September 2009
Keywords:
4-Aryl-4H-pyran
Ultrasound
Synthesis
Aryl aldehyde
1,3-Diketone
1. Introduction
irradiation are playing an increasing role in process chemistry,
especially in cases where classical methods require drastic condi-
4H-pyrane and its derivatives are known as an important class
of heterocyclic compounds in the pharmaceutical as well as syn-
thetic chemistry [1,2]. A number of compounds containing the
4H-pyrane moiety are being developed in wide range of therapeu-
tic areas [3–5], especially in the inhibition of the HIV-1 proteases
[6]. Numerous methods have been reported for the synthesis of
4H-pyrane. Diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxyl-
ates (1) was produced via the reaction between the corresponding
aldehyde and 1,3-diketone in 16 h with a yield of 30–50%, utilizing
ZnCl2 as a catalyst, acetic anhydride as the solvent, and column
chromatography to purify the product [7–9]. To simplify the exper-
imental procedures, the reaction was exposed to microwave irradi-
ation for nearly 30 min, and the isolated yield did not increase
significantly (<50%) [10] for the decomposition of ethyl acetoace-
tate [11].
tions or prolonged reactions times. As part of our program to inves-
tigated organic reactions amenable to sonochemistry, we report
the ultrasound-assisted synthesis of diethyl 2,6-dimethyl-4-aryl-
4H-pyran-3,5-dicarboxylates (1) (Scheme 1). The general proce-
dure for synthesis of 1 is the reaction of aldehyde and 1,3-diketone
in 16 h with a yield of 30–50%, ZnCl2 was used as a catalyst, and
acetic anhydride was the solvent. In our procedure the reactions
were performed in an ultrasonic processor (GEX750-5C, USA).
The effects of changes in the ultrasonic power, temperature, and
reaction time are discussed. Our methodology offers several advan-
tages including mild reaction conditions, good yields of products as
well as a simple experimental and isolation procedure which
makes it a useful and attractive process for the synthesis of these
compounds.
Ultrasound irradiation has been established as an important
technique in synthetic organic chemistry. It has been used as an
efficient heating source for organic reactions. Shorter reaction time
is the main advantage of ultrasound-assisted reactions. Simple
experimental procedure, very high yields, increased selectivity
and clean reactions of many ultrasound-induced organic transfor-
mations offers additional conveniences in the field of synthetic or-
ganic chemistry [12–14]. The beneficial effects of ultrasound
2. Method
2.1. Apparatus and analysis
Melting points were determined by an X-5 instrument (made in
China), and uncorrected. IR spectra were taken on a VERTEX70
(made in German) spectrometer by ATR. NMR spectra were mea-
sured on a Bruker AV 400 MHz (made in German) spectrometer.
MS were determined on Esquire 6000 spectrometer (made in Ger-
man). Sonication was performed in a GEX750-5C ultrasonic proces-
sor (made in USA) equipped with a 3 mm wide and 140 mm long
* Corresponding author. Tel.: +86 010 67396211; fax: +86 101 67392001.
E-mail address: hongyan@bjut.edu.cn (H. Yan).
1
The authors contributed equally to this work.
1350-4177/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2009.09.006

368
C.-L. Ni et al. / Ultrasonics Sonochemistry 17 (2010) 367–369
Table 1
The ultrasound yields of 1d under ambient conditions.
R
O
O
ZnCl2, Ac2O
U. S.
O
O
Temp (°C)
Time (min) Power (W)
30
50
70
50
R
+
O
O
O
50 100
150
50
100
150
100
150
CHO
O
10
30
50
32.1 47.2 46.9 77.3 78.3 74.5 76.5 77.7 77.2
39.7 52.3 53.1 64.6 88.5 74.7 83.3 86.1 76.9
42.5 55.4 57.6 85.3 88.5 76.3 86.2 85.7 72.7
1
R= a: H; b: 4-CH3; c: 4-Br; d: 4-OCH3; e: 4-Cl; f: 3-Cl; g: 4-F; h: 4-NO2; i: 3-NO2; j:
4-OH; k: 3-Br; l: 3-NHCOCH3; m: 4-NHCOCH3; n: 2,3,4-triOCH3; o: 2,4,5-triOCH3.
Scheme 1.
Compound 1e: white solid, 1H NMR (CDCl3, 400 MHz): d = 1.22
(t, 6H, 2CH2CH3), 2.37 (s, 6H, 2CH3), 4.10 (m, 4H, 2CH2CH3), 4.74 (s,
1H Ar-CH), 7.20 (d, 2H, J = 8.4 Hz, Ar-H), 7.29 (d, 2H, J = 8.4 Hz, Ar-
H).
probe, which was immersed directly into the reaction mixture. The
operating frequency was 24 kHz and the output power was
0–750 W through manual adjustment.
Compound 1f: white solid, 1H NMR (CDCl3, 400 MHz): d = 1.23
(t, 6H, 2CH2CH3), 2.39 (s, 6H, 2CH3), 4.11 (m, 4H, 2CH2CH3), 4.74
(s, 1H, Ar-CH), 7.14–7.17 (m, 4H, Ar-H).
Compound 1g: white solid, 1H NMR (CDCl3, 400 MHz): d = 1.20
(t, 6H, 2CH2CH3), 2.35 (s, 6H, 2CH3), 4.09 (m, 4H, 2CH2CH3), 4.73 (s,
1H, Ar-CH), 6.91 (m, 2H, Ar-H), 7.20 (m, 2H, Ar-H).
2.2. Typical procedure
Compound 1h: yellow solid, 1H NMR (CDCl3, 400 MHz): d = 1.20
(t, 6H, 2CH2CH3), 2.38 (s, 6H, 2CH3), 4.08 (m, 4H, 2CH2CH3), 4.86 (s,
1H, Ar-CH), 7.41 (d, 2H, J = 8.7 Hz, Ar-H), 8.10 (d, 2H, J = 8.7 Hz, Ar-
H).
A
mixture of benzaldehyde (0.06 mol), ethyl acetoacetate
(0.12 mol), in acetic anhydride (9.0 mL) was irradiated by an ultra-
sonic processor at 50 °C and 100 W. After the indicated time (see
Table 2), the mixture was cooled to the room temperature, ice
water was added and the solution was neutralized (pH 7–8) by
an aqueous solution of NaOH. The organic phase was extracted
with dichloromethane, washed with water and dried with Na2SO4.
The solvent was removed under reduced pressure to afford 1. The
crude products were purified by recrystallation (ethyl acetate and
petroleum ether) with enough purity for spectral analysis.
Compound 1a: white solid, 1H NMR (CDCl3, 400 MHz): d = 1.20
(t, 6H, 2CH2CH3), 2.36 (s, 6H, 2CH3), 4.09 (m, 4H, 2CH2CH3), 4.75 (s,
1H, Ar-CH), 7.13–7.26 (m, 5H, Ar-H).
Compound 1i: yellow solid, 1H NMR (CDCl3, 400 MHz): d = 1.21
(t, 6H, 2CH2CH3), 2.41 (s, 6H, 2CH3), 4.11 (m, 4H, 2CH2CH3), 4.88 (s,
1H, Ar-CH), 7.41–8.12 (m, 4H, Ar-H).
Compound 1j: white solid, 1H NMR (CDCl3, 400 MHz): d = 1.29
(t, 6H, 2CH2CH3), 2.42 (s, 6H, 2CH3), 4.18 (m, 4H, 2CH2CH3), 4.80
(s, 1H, Ar-CH), 6.80 (d, 2H, J = 8.8 Hz, Ar-H), 7.15 (d, 2H,
J = 8.8 Hz, Ar-H), 8.22 (s, 1H, Ar-OH).
Compound 1k: white solid, IR (ATR, cmÀ1): 2973, 1678, 1544,
1412, 1190, 1137, 1023, 790; 1H NMR (CDCl3, 400 MHz): d = 1.23
(t, 6H, 2CH2CH3), 2.39 (s, 6H, 2CH3), 4.12 (m, 4H, 2CH2CH3), 4.73
(s, 1H, Ar-CH), 7.10–7.31 (m, 4H, Ar-H); MS: 410 (M+1).
Compound 1l: brown solid, IR (ATR, cmÀ1): 3299, 2980, 1705,
1609, 1552, 1485, 1369, 1189, 1126, 1026, 779; 1H NMR (CDCl3,
400 MHz): d = 1.22 (t, 6H, 2CH2CH3), 2.16 (s, 3H, COCH3), 2.37 (s,
6H, 2CH3), 4.11 (m, 4H, 2CH2CH3), 4.76 (s, 1H, Ar-CH), 7.00–7.23
(m, 4H, Ar-H), 7.47 (s, 1H, NHCOCH3); MS: 410 (M+23).
Compound 1m: brown solid, IR (ATR, cmÀ1): 3296, 2979, 1703,
1554, 1408, 1188, 1125, 1023, 778; 1H NMR (CDCl3, 400 MHz):
d = 1.21 (t, 6H, 2CH2CH3), 2.15 (s, 3H, COCH3), 2.36 (s, 6H, 2CH3),
4.10 (m, 4H, 2CH2CH3), 4.74 (s, 1H, Ar-CH), 6.98–7.48 (m, 4H, Ar-
H), 7.12 (s, 1H, NHCOCH3); MS: 388(M+1).
Compound 1b: white solid, 1H NMR (CDCl3, 400 MHz): d = 1.21
(t, 6H, 2CH2CH3), 2.28 (s, 3H, Ar-CH3), 2.35 (s, 6H, 2CH3), 4.08 (m,
4H, 2CH2CH3), 4.70 (s, 1H, Ar-CH), 7.04 (d, 2H, J = 8.0 Hz, Ar-H),
7.12 (d, 2H, J = 8.0 Hz, Ar-H).
Compound 1c: white solid, 1H NMR (CDCl3, 400 MHz): d = 1.22
(t, 6H, 2CH2CH3), 2.37 (s, 6H, 2CH3), 4.11 (m, 4H, 2CH2CH3), 4.73 (s,
1H, Ar-CH), 7.12 (d, 2H, J = 8.4 Hz, Ar-H), 7.36 (d, 2H, J = 8.4 Hz, Ar-
H).
Compound 1d: white solid, 1H NMR (CDCl3, 400 MHz): d = 1.27
(t, 6H, 2CH2CH3), 2.36 (s, 6H, 2CH3), 3.77 (s, 3H, OCH3), 4.10 (m, 4H,
2CH2CH3), 4.71 (s, 1H, Ar-CH), 6.80 (d, 2H, J = 8.8 Hz, Ar-H), 7.28 (d,
2H, J = 8.8 Hz, Ar-H).
Table 2
The yields of 1 under ultrasonic irradiation.
Entry
R
Time (min)/yielda (%)
Time (h)/yield (%)
Mp (°C)
Mp (°C)
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
H
4-CH3
4-Br
4-OCH3
4-Cl
3-Cl
4-F
4-NO2
3-NO2
4-OH
3-Br
3-NHCOCH3
4-NHCOCH3
2,3,4-triOCH3
2,4,5-triOCH3
35/89.4
20/80.8
35/71.2
30/88.5
40/87.2
45/80.3
45/83.1
45/90.0
40/84.9
50/79.2
40/78.2
55/70.7
60/74.7
50/78.2
50/75.0
24/48.4 [9]
16/13.1 [8]
14/50.8b
21/36.7 [9]
16/49.8 [8]
11/50.2b
13/52.7b
13/58.7b
24/44.4b
15/46.2b
–
74.0–74.7
81.9–82.2
81.3–81.8
83.0–84.6
63.2–64.8
62.2–63.8
69.9–71.5
84.5–85.9
88.6–89.6
140.6–142.1
70.8–72.1
110.1–111.9
135.7–136.2
97.2–97.7
99.0–100.1
74.0–75.0 [9]
79.0–84.0 [8]
81.2 [20]
84.0–85.0 [9]
63.0–66.0 [8]
62.5–63.2 [20]
68.9–69.9 [20]
84.5–86.8 [20]
89.0 [9]
106.0 [9]
–
–
–
–
–
–
–
–
–
a
Isolated yield.
Synthesised based on the method of Urbahns [8,9,15].
b

C.-L. Ni et al. / Ultrasonics Sonochemistry 17 (2010) 367–369
369
Compound 1n: white solid, IR (ATR, cmÀ1): 2979, 2935, 1706,
1620, 1487, 1369, 1286, 1188, 1095, 1038, 793; 1H NMR (CDCl3,
400 MHz), d = 1.23 (t, 6H, 2CH2CH3), 2.33 (s, 6H, 2CH3), 3.91 (t,
9H, 3OCH3), 4.14 (m, 4H, 2CH2CH3), 4.82 (s, 1H, Ar-CH), 6.51 (d,
1H, J = 8.8 Hz, Ar-H), 6.80 (d, 1H, J = 8.8 Hz, Ar-H); MS: 443 (M+23).
Compound 1o: white solid, IR (ATR, cmÀ1): 2982, 2833, 1704,
1627, 1513, 1462, 1291, 1191, 1080, 1031, 812; 1H NMR (CDCl3,
400 MHz), d = 1.23 (t, 6H, 2CH2CH3), 2.37 (s, 6H, 2CH3), 3.89 (t,
9H, 3OCH3), 4.14 (m, 4H, 2CH2CH3), 4.81 (s, 1H, Ar-CH), 6.42 (s,
1H, Ar-H), 6.71 (s, 1H, Ar-H); MS: 421 (M+1), 443 (M+23).
We also examined the synthesis of 3-bromobenzaldehyde (1k),
3-acetamidobenzaldehyde (1l), 4-acetamidobenzaldehyde (1m),
2,3,4-trimethoxyl-benzaldehyde (1n), 2,4,5-trimethoxylbenzalde-
hyde (1o) under ultrasound. Compounds 1k, 1l, 1m, 1n, and 1o
were obtained in yields 70–78% in 40–60 min, and no significant
formation was observed under literature conditions even after
16 h.
As shown in Table 2, a series of 1 were synthesized by ultrasonic
irradiation in a simple experimental procedure, with a short reac-
tion time, high yield, and ease of product isolation. The compounds
1a–1j were characterized by 1H NMR and matched with literatures.
The compounds 1k, 1l, 1m, 1n and 1o were characterized by 1H
NMR, IR and MS spectrum, respectively.
3. Results and discussion
In order to obtain the optimum experimental conditions, the
reaction of 4-methoxy benzaldehyde with ethyl acetoacetate un-
der ultrasonic irradiation has been considered as a standard model
reaction (Table 1). To determine the appropriate time of the reac-
tion, we investigated the model reaction at different times (10,
30, 50 min). The product was formed in lower yield at 10 min,
and higher at 30 min and 50 min. This indicates that 30 min was
sufficient for the result. When the reaction was at 50 and 70 °C,
the product was in similar yields after 30 min. When the reaction
4. Conclusion
The diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates
(1) have been synthesized under ultrasound irradiation. The pres-
ent method has many advantages to those reported in the litera-
ture, the procedure is carried out in a shorter time, easier
work-up and good yields, especially the generality to the various
substituted 4H-pyrans.
was performed with an ultrasonic power of 50 W,
a lower
yield was achieved, with starting material remaining. The reaction
yield was improved under sonication at 100 and 150 W. The
best yield for 1d was obtained by ultrasonic irradiation at a tem-
perature of 50 °C and a power of 100 W. The product was obtained
within 30 min in 88.5% yield. In conventional method, the yield 1d
was gained in 36.7% after heating 16 h at 60 °C [15]. It was ob-
served that the reaction under ultrasonic irradiation had signifi-
cantly improved yields.
Acknowledgements
The authors are grateful for financial support of National Natu-
ral Sciences Foundation (No. 20872009), Natural Sciences Founda-
tion of Beijing (No. 200710005002), Key Projects in the National
Science & Technology Pillar Program during the 11th Five-Year
Plan Period (No. 2008ZX10001-015) and the Ph.D. Graduate Inno-
vention Fund of BJUT (No. bcx-2009-087).
The advantages on the synthesis of 1d by such ultrasound is fre-
quently attributed to cavitation (mechanical) effects, the physical
processes that creates, enlarges, and implodes gaseous and va-
por-phase cavities in an irradiated liquid. Cavitation induces very
high local temperatures and pressure inside the bubbles (cavities),
leading to a turbulent flow in the liquid and enhanced mass trans-
fer, thus producing a variety of high energy species in solution [16–
18]. It has been observed that a favorable acceleration in reaction
rate occurs when compared to classical conditions (i.e. under re-
flux). The addition of catalytic amounts of ZnCl2 further facilitates
the reaction, thereby indicating a synergistic effect of ultrasound
on the tri-phase catalyst system. However, the successful reaction
with sonication in the absence of catalyst indicates that ultrasound
can indeed substitute for a phase transfer catalyst, thereby provid-
ing an attractive alternative for the nucleophilic substitution reac-
tions [19].
To establish the generality with respect to the aryl aldehydes
under the influence of ultrasound irradiation, various aryl alde-
hydes were used for the synthesis of 4H-pyran (1) with substituents
such as –Cl, –OH, –NO2, –Me, –OMe and so on. Under the optimized
conditions previously described, the reaction of the aryl aldehydes
under the influence of ultrasound irradiation was carried out. The
corresponding 4H-pyrane (1) were formed in excellent yields. The
results are summarized in Table 2. It was observed that 1 was
formed faster (20–60 min) with yields of 70–90% using ultrasound.
This is compared with the time required (11–24 h) and yields
(40–60%) under thermal processing (Table 2, entries 1a–1j).
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