Microwave-assisted synthesis and crystal structure of novel 2-dichloromethyl-1,3-dioxolanes

Article abstract of DOI:10.3987/COM-12-12628

An efficient synthesis of 2-dichloromethyl-1,3-dioxolane derivatives with microwave-assisted addition reaction was developed. The intermediate 1,3-dioxolanes 2 were obtained by exposing to microwave radiation with glycol at the present of anhydrous CuSO

Full text of DOI:10.3987/COM-12-12628

HETEROCYCLES, Vol. 87, No. 2, 2013
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HETEROCYCLES, Vol. 87, No. 2, 2013, pp. 407 - 415. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 14th November, 2012, Accepted, 19th December, 2012, Published online, 27th December, 2012
DOI: 10.3987/COM-12-12628
MICROWAVE-ASSISTED SYNTHESIS AND CRYSTAL STRUCTURE OF
NOVEL 2-DICHLOROMETHYL-1,3-DIOXOLANES
Fei Ye, Ying Li, Ying Fu,* Shuang Gao, and Li-Xia Zhao
Department of Applied Chemistry, College of Science, Northeast Agricultural
University, Harbin, 150030, P.R. China; email: fuying@neau.edu.cn
Abstract – An efficient synthesis of 2-dichloromethyl-1,3-dioxolane derivatives
with microwave-assisted addition reaction was developed. The intermediate
1,3-dioxolanes 2 were obtained by exposing to microwave radiation with glycol at
the
present
of
anhydrous
CuSO4.
A
series
of
novel
2-dichloromethyl-1,3-dioxolane derivatives 3 were synthesized by carbenes
insertion of dioxolanes 2 and chloroform with TEBA used as phase transfer
1
catalyst. The structures of the compounds were characterized by IR, H-NMR,
13C-NMR spectroscopy, and elemental analysis. The configuration of 3f was
determined by X-ray crystallography.
A recent spur of interest in dioxolane derivatives acting as biological materials and intermediates in
organic synthesis reflects a compelling need for convenient synthetic routes for them.1 Depending on the
structure of subsitiuents, they have been found to be of interest due to antifungal,2 antibacterial,3
antiallodynic,4 anticonvulstant ones,5 and so on. In particular, 2-dichloromethyl-1,3-dioxolane derivatives
have been investigated for used as herbicide safeners which protect crops from the injury by herbicides.6
Substituents changing at the dioxolane has showed significant safety activity,7 which encouraged us to
synthesize novel 2-dichloromethyl-1,3-dioxolane derivatives with better biological activity.
Several approaches had been developed to dioxolane derivatives with PTSA,8 EPZG,9 CdI2,10 choline
13
chloride·xZnCl2 (x = 1-3),11 trimethylsilylbromide12 or ZrO(OTf)2 used as catalysts. But most of these
methods required harsh reaction conditions, expensive catalysts, or resulted in poor yields.
Microwave-assisted organic synthesis, as one of the most convenient and efficient paths to obtain organic

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HETEROCYCLES, Vol. 87, No. 2, 2013
compounds, could achieve fast, clean and high-yield transformation.14 While, there were few reports on
microwave-assisted synthesis of 2-dichloromethyl-1,3-dioxolanes. In this study we described the two-step
synthesis of 2-dichloromethyl-1,3-dioxolane derivatives 3 by microwave-irradiated acetalization and
insertion of dichlorocarbene into the α-C-H bond in corresponding dioxolanes 2 (Scheme 1).15
R
O
O
CuSO
MV
OH
TEBA
4
OH
R
CHO
+
CHCl
+
3
Cl
Cl
O
O
50% NaOH aq.
R
2a-f
1a-f
3a-f
O
n-C H
3 7
c:R=
b:R=
Me
a:R=
S
O N
e:R=
f:R=
2
d:R=
OMe
Scheme 1. Route for synthesis of 2-dichloromethyl-1,3-dioxolanes
The synthesis of compounds 2 was performed by the cyclization of aldehydes 1 with glycol in the
presence of anhydrous CuSO4 under microwave radiation (600W). The reaction conditions and physical
data were summarized in Table 1. The reaction went smoothly under microwave radiation and afforded
products 2 in moderate isolated yields 35.7-57.5%. The conjugation effect of aryl and carbonyl might lead
the acetalization easier. The yield of 2c was lower than others due to the substituent was alkyl on position
2. However, the yield of 2d was the lowest, which was mainly caused by the instability of thiophene.
Table 1. Intermediate 1,3-dioxolanes 2a-f
Refluxing
Microwave-irradiated
Yield
(%)
Intermediate
Product Status
Temperature (°C)
Time (min)
2a
2b
2c
2d
2e
105
105
95
24
24
24
50
60
57.5
45.0
43.4
35.7
50.6
colorless oil
light yellow oil
colorless oil
90
light yellow oil
light green solid
100
2f
100
60
54.2
colorless oil

HETEROCYCLES, Vol. 87, No. 2, 2013
409
The target compounds 3 were obtained by insertion of dichloromethyl in corresponding dioxolanes 2 with
chloroform by stirring 24-28 h at 0-5 °C, TEBA used as the phase transfer catalyst. The process was
monitored by thin-layer chromatography. Low temperature was employed for the reaction being
exothermic. The structures of all the compounds 2 and 3 were supported by MS, IR, 1H-NMR, 13C-NMR
spectral data and elemental analysis.
The IR spectra of compounds 3a-f showed bands at 1007-1283 cm-1 due to C-O, which confirmed the
formation of dioxolane. The 1H-NMR spectra of 3a-f exhibited a single signal in the range δ 5.51-6.11 for
the proton of -CH-Cl2. For the asymmetry of dioxolane with different substituents at position 2, the four
13
hydrogen atoms of dioxolane splited at δ 4.24-4.37 and 3.94-4.14 ppm. In the C-NMR spectra, the
signals observed in the region of δ 74.58-76.63 ppm accounted for the carbon of -CH-Cl2, and δ
66.68-67.45 ppm accounted for the two carbon of -O-CH2-CH2-O-. The elemental analysis of 3a-f agreed
with the molecular formulas of these compounds.
Finally, the single crystal of 3f was obtained by dissolving it in ethanol and light petroleum, followed by
slow evaporation. The X-ray data were collected on a Bruker AXS II CCD area-detector diffractometer
with Mo-Kα graphite-monochromated radiation (λ = 0.71073 Å) at 293(2) K. The structure was solved by
direct method using SHELXS-97, and refined by full matrix least squares on F2, SHELXL-97.16 The
molecular structure and the packing view of 3f were shown in Figure 1 and Figure 2, respectively. The
dioxolane was in an envelope conformation with the C atom forming the flap. The bond lengths and bond
angles of the dioxolane were both normal (Table 2). In the crystal structure, molecules were linked by
weak intermolecular C—H…O hydrogen bonds to form one-dimension chains (Figure 2), which
stabilized the crystal structure. No significant π-π interactions were found in the crystal structure.
Figure 1. Molecular structure for compound 3f at 30% probability level

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HETEROCYCLES, Vol. 87, No. 2, 2013
Figure 2. Packing view of the compound 3f
Table 2. Selected bond lengths (Å) and angles (°) with their standard deviations relevant to 3f
C1-O3
1.371(3)
1.425(3)
1.419(2)
1.417(4)
1.392(4)
1.776(3)
123.1(2)
120.1(2)
107.83(18)
109.85(16)
107.11(18)
106.3(3)
109.25(12)
116.5(2)
C6-C8
1.523(3)
1.407(3)
1.541(3)
1.461(5)
1.772(2)
C7-O3
C8-O1
C8-O2
C8-C11
C9-C10
C11-Cl1
C9-O1
C10-O2
C11-Cl2
O3-C1-C2
C5-C6-C8
O1-C8-O2
O2-C8-C6
O2-C8-C11
O1-C9-C10
Cl1-C11-Cl2
O3-C1-C6
C1-C6-C8
121.67(19)
110.68(19)
109.47(18)
111.76(18)
107.6(2)
O1-C8-C6
O1-C8- Cl1
C6-C8-C11
O2-C10-C9
C8-C11-Cl2
C8-C11-Cl1
110.80(17)
110.73(16)

HETEROCYCLES, Vol. 87, No. 2, 2013
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EXPERIMENTAL
The IR spectra were taken on a KJ-IN-27G infrared spectrophotometer in KBr pellets. The 1H NMR and
13C NMR spectra were recorded on Bruker AVANVE 300 MHz and 400 MHz, with CDCl3 as the solvent
and TMS as the internal standard. The elemental analysis was performed on FLASH EA1112 elemental
analyzer. The melting points were determined on a Beijing Taike melting point apparatus(X-4) and are
uncorrected. The automatic microwave synthesizer was XH-100B of Beijing Xianghu Company. All the
reagents were of analytical reagents grade.
General procedure for the preparation of 2-substituted-1,3-dioxolanes (2a-f)
A mixture of aldehyde (1, 0.1 mol), glycol (0.15 mol), CuSO4 (1.5 g) and cyclohexane (40 mL) was
exposed to microwave radiation (600 W) for 24-60 min with refluxing and removing water. The reaction
mixture was cooled and washed with water until the organic phase was colorless. The organic layer was
extracted with EtOAc (3 × 50 mL) and dried over anhydrous MgSO4. Evaporation of the solvent under
reduced pressure gave the crude products. Compound 2d and 2f were purified on silica gel by column
chromatography [V (EtOAc): V (light petroleum) = 1:30] and compound 2e was crystallized with EtOAc
and light petroleum until the light green crystal was obtained. The other crude products were separated
under reduced pressure. The spectra data of the compounds 2a-f were as follows:
2-p-Methylphenyl-1,3-dioxolane (2a). Yield 57.5%. Colorless oil, IR (KBr, cm-1): ν 2953-2885 (C-H),
1224-1022 (C-O); 1H-NMR (CDCl3, 300 MHz): δ 7.20-7.40 (m, 4H, Ar-H), 5.81 (s, 1H, -CH-), 4.13-4.16
(m, 2H, -O-CH2-), 4.04-4.07 (m, 2H, -CH2-O-), 2.38 (s, 3H, -CH3); 13C-NMR (CDCl3, 75 MHz): δ 139.09,
134.94, 129.07, 129.07, 126.41, 126.41, 103.83, 65.30, 65.30, 21.33. Anal. Calcd for C10H12O2: C 73.13,
H 7.37. Found: C 73.21, H 7.31.
2-(α-Furyl)-1,3-dioxolane (2b). Yield 45.0%. Light yellow oil, IR (KBr, cm-1): ν 3124-2892 (C-H),
1
1225-1014 (C-O); H-NMR (CDCl3, 300 MHz): δ 7.44-7.45 (m, 1H, Ar-H), 6.46-6.48 (m, 1H, Ar-H),
6.37-6.38 (m, 1H, Ar-H), 5.95 (s, 1H, -CH-), 4.13-4.18 (m, 2H, -O-CH2-), 4.02-4.05 (m, 2H, -CH2-O-);
13C-NMR (CDCl3, 75 MHz): δ 151.03, 143.22, 110.17, 108.81, 97.75, 65.20, 65.20. Anal. Calcd for
C7H8O3: C 59.98, H 5.76. Found: C 59.90, H 5.85.
2-n-Propyl-1,3-dioxolane (2c). Yield 43.4%. Colorless oil, IR (KBr, cm-1): ν 2996-2770 (C-H),
1
1213-1023 (C-O); H-NMR (CDCl3, 300 MHz): δ 4.84-4.88 (t, J=4.8 Hz, 1H, -CH-), 3.95-4.00 (m, 2H,
-O-CH2-), 3.85-3.88 (m, 2H, -CH2-O-), 1.62-1.69 (m, 2H, C-CH2-C-), 1.42-1.50 (m, 2H, -C-CH2-C),
13
0.94-0.99 (t, J=7.3 Hz, 3H, -CH3); C-NMR (CDCl3, 75 MHz): δ 104.54, 64.84, 64.84, 35.99, 17.48,

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14.09. Anal. Calcd for C6H12O2: C 62.02, H 10.42. Found: C 62.10, H 10.36.
2-(α-Thienyl)-1,3-dioxolane (2d). Yield 35.7%. Light yellow oil, IR (KBr, cm-1): ν 3106-2888 (C-H),
1
1212-1071 (C-O); H-NMR (CDCl3, 400 MHz): δ 7.31-7.33 (m, 1H, Ar-H), 7.16-7.17 (d, J=3.2 Hz, 1H,
Ar-H), 6.98-7.00 (m, 1H, Ar-H), 6.11 (s, 1H, -CH-), 4.10-4.16 (m, 2H, -O-CH2-), 3.96-4.04 (m, 2H,
13
-CH2-O-); C-NMR (CDCl3, 100 MHz): δ 141.73, 126.67, 126.37, 126.27, 100.26, 65.22, 65.22. Anal.
Calcd for C7H8O2S: C 53.84, H 5.17, S 20.49. Found: C 53.92, H 5.23, S 20.41.
2-p-Nitrophenyl-1,3-dioxolane (2e). Yield 50.6%. Light green solid, mp 91-93 °C. IR (KBr, cm-1): ν
1
3084-2895 (C-H), 1292-1080 (C-O); H-NMR (CDCl3, 400 MHz): δ 8.24-8.26 (d, J=8.8 Hz, 2H, Ar-H),
13
7.66-7.68 (d, J=8.4 Hz, 2H, Ar-H), 5.91 (s, 1H, -CH-), 4.10-4.12 (m, 4H, -O-CH2-CH2-O); C-NMR
(CDCl3, 100 MHz): δ 148.45, 144.98, 127.43, 127.43, 123.60, 123.60, 102.27, 65.50, 65.50. Anal. Calcd
for C9H9NO4: C 55.37, H 4.65, N 7.18. Found: C 55.42, H 4.71, N 7.09.
2-o-Methoxyphenyl-1,3-dioxolane (2f). Yield 54.2%. Colorless oil, IR (KBr, cm-1): ν 2952-2885,
1
1285-1027 (C-O); H-NMR (CDCl3, 400 MHz)：δ 7.35-7.58 (m, 2H, Ar-H), 6.91-7.00 (m, 2H, Ar-H),
6.20 (s, 1H, -CH-), 4.12-4.17 (m, 2H, -O-CH2-), 4.01-4.05 (m, 2H, -CH2-O-), 3.87 (s, 3H, -CH3);
13C-NMR (CDCl3, 100 MHz): δ 157.77, 130.32, 126.75, 125.92, 120.47, 110.77, 99.33, 65.31, 65.31,
55.64. Anal. Calcd for C10H12O3: C 66.64, H 6.72. Found: C 66.58, H 6.79.
General procedure for the preparation of 2-dichloromethyl-1,3-dioxolanes (3a-f)
50% NaOH aq. was dropped into mixture of 0.05 mol dioxolane 2, CHCl3 (60 mL), anhydrous Na2SO4
(30 g), and TEBA (2 g) at 0 °C with vigorous stirring over a period of 24-28 h. Then 100 mL water and
100 mL Et2O were added into the mixture. The aqueous layer was extracted with 50 mL Et2O for five
times. The organic layers were combined and washed with water until pH=7 and dried over anhydrous
MgSO4. The ether was removed by distillation. Compounds 3a-b and 3d were distilled under reduced
pressure. The other crude products were purified on silica gel by column chromatography [V (EtOAc): V
(light petroleum) = 1:30]. The physical and spectra data of the compounds 3a-f were as follows:
2-Dichloromethyl-2-p-methylphenyl-1,3-dioxolane (3a). Yield 30.7%. White solid, mp 56-57 °C; IR
1
(KBr, cm-1): ν 3016-2870 (C-H), 1226-1023 (C-O); H-NMR (CDCl3, 300 MHz): δ 7.45-7.48 (m, 2H,
Ar-H), 7.18-7.21 (m, 2H, Ar-H), 5.83-5.84 (s, 1H, -CHCl2), 4.26-4.30 (m, 2H, -CH2-O-), 3.97-4.01 (m,
2H, -O-CH2-), 2.37 (s, 3H, -CH3); 13C-NMR (CDCl3, 75 MHz): δ 139.15, 134.33, 128.75, 128.75, 127.00,
127.00, 109.15, 75.55, 66.68, 66.68, 21.31. Anal. Calcd for C11H12Cl2O2: C 53.65, H 4.92. Found: C
53.81, H 4.88.

HETEROCYCLES, Vol. 87, No. 2, 2013
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2-Dichloromethyl-2-(-α-furyl)-1,3-dioxolane (3b). Yield 15.1%. White solid, mp 43-44 °C; IR (KBr,
1
cm-1): ν 3014-2883 (C-H), 1283-1007 (C-O); H-NMR (CDCl3, 300 MHz): δ 7.34-7.51 (m, 3H, Ar-H),
13
5.52 (s, 1H, -CHCl2), 4.26-4.32 (m, 2H, -CH2-O-), 3.97-4.06 (m, 2H, -O-CH2-); C-NMR (CDCl3, 75
MHz): δ 150.56, 142.41, 109.44, 107.21, 96.35, 75.81, 64.79, 64.79. Anal. Calcd for C8H8Cl2O3: C 43.25,
H 3.63. Found: C 43.21, H 3.77.
2-Dichloromethyl-2-n-propyl-1,3-dioxolane (3c). Yield 39.5%. White solid, mp 85-86 °C, IR (KBr,
1
cm-1): ν 2900-2830 (C-H), 1224-1039 (C-O); H-NMR (CDCl3, 300 MHz): δ 5.63 (s, 1H, -CHCl2),
4.20-4.24 (m, 2H, -O-CH2-), 4.06-4.11 (m, 2H, -CH2-O-), 1.92-1.98 (m, 2H, -CH2-), 1.39-1.47 (m, 2H,
13
-CH2-), 0.93-0.98 (t, J=7.4 Hz, 3H, -CH3); C-NMR (CDCl3, 75 MHz): δ 111.22, 75.04, 67.02, 67.02,
35.75, 16.07, 14.14. Anal. Calcd for C7H12Cl2O2: C 42.42, H 6.11. Found: C 42.48, H 6.05.
2-Dichloromethyl-2-(-α-thienyl)-1,3-dioxolane (3d). Yield 21.1%. White solid, mp 49-50 °C; IR (KBr,
1
cm-1): ν 3113-2899 (C-H), 1278-1020 (C-O); H-NMR (CDCl3, 400 MHz): δ 7.36-7.38 (m, 1H, Ar-H),
7.25-7.28 (m, 1H, Ar-H), 7.03-7.06 (m, 1H, Ar-H), 5.89 (s, 1H, -CHCl2), 4.28-4.35 (m, 2H, -CH2-O-),
13
4.11-4.19 (m, 2H, O-CH2-); C-NMR (CDCl3, 100 MHz): δ 140.23, 127.30, 126.96, 126.87, 108.23,
74.97, 67.06, 67.06. Anal. Calcd for C8H8Cl2O2S: C 40.34, H 3.39, S 13.44. Found: C 40.48, H 3.41, S
13.29.
2-Dichloromethyl-2-p-nitrophenyl-1,3-dioxolane (3e). Yield 32.6%. White solid, mp 102-103 °C; IR
1
(KBr, cm-1) ν 3119-2901, 1307-1049 (C-O); H-NMR (CDCl3, 400 MHz): δ 8.24-8.27 (m, 2H, Ar-H),
7.82 (m, 1H, Ar-H), 7.28 (s, 1H, Ar-H), 5.83 (s, 1H, -CHCl2), 4.34-4.35 (m, 2H, -O-CH2-), 4.02-4.03 (m,
13
2H, -CH2-O-); C-NMR (CDCl3, 100 MHz): δ 148.54, 144.05, 128.56, 128.56, 123.10, 123.10, 108.59,
74.58, 66.97, 66.97. Anal. Calcd for C10H9Cl2NO4: C 43.32, H 3.27, N 5.06. Found: C 43.30, H 3.24, N
5.09.
2-Dichloromethyl-2-o-methoxyphenyl-1,3-dioxolane (3f). Yield 45.8%. White solid; mp 95-96 °C; IR
1
(KBr, cm-1): ν 3028-2839 (C-H), 1282-1020 (C-O); H-NMR (CDCl3, 400 MHz): δ 7.62-7.64 (m, 2H,
Ar-H), 6.95-7.00 (m, 2H, Ar-H), 6.67 (s, 1H, -CHCl2), 4.36-4.37 (m, 2H, O-CH2-), 4.08-4.09 (m, 2H,
13
-CH2-O-), 3.92 (s, 3H, -CH3); C-NMR (CDCl3, 100 MHz): δ 156.63, 130.70, 128.14, 125.94, 120.57,
111.75, 109.50, 74.67, 66.98, 66.98, 55.95. Anal. Calcd for C11H12Cl2O3: C 50.38, H 4.62. Found: C 50.29,
H 4.71.

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SUPPLEMENTARY MATERIAL
Crystallographic data for the structural analysis of 3f has been deposited with the Cambridge
Crystallographic Data Centre (CCDC 892488). Copies may be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; by quoting the publication citation and the deposit
numbers. [Fax: (+44) 1223-336-033; E-mail: deposit@ccdc.cam.ac.uk, http://www.ccdc.cam.ac.uk]
ACKNOWLEDGEMENTS
This work was supported by the National Nature Science Foundation of China (No. 31101473), the
Science and Technology Research Project of Heilongjiang Education Department (No. 12521002), and
the Research Science Foundation in Technology Innovation of Harbin (2012RFXXN002).
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