Microwave-assisted synthesis and bioactivity of novel 2,2,4,5- tetrasubstituted 3-dichloroacetyl-1,3-oxazolidines

Article abstract of DOI:10.3987/COM-11-12326

An efficient one-pot synthesis of 2,2,4,5-tetrasubstituted 3-dichloroacetyl-1,3-oxazolidines under microwave irradiation was developed. The intermediate oxazolidines were attained by the reaction of amino alcohol with aldehyde or ketone in refluxing benzene with microwave-assisted cycloaddition, and then the acylation followed with dichloroacetyl chloride and NaOH acting as the attaching acid agent. All the compounds were characterized by IR, ¹H-NMR, ¹³C-NMR and elemental analysis. The preliminary biological test shows that these compounds could protect maize against injury caused by acetochlor to a certain extent.

Full text of DOI:10.3987/COM-11-12326

HETEROCYCLES, Vol. 83, No. 11, 2011
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HETEROCYCLES, Vol. 83, No. 11, 2011, pp. 2607 - 2613. © 2011 The Japan Institute of Heterocyclic Chemistry
Received, 3rd August, 2011, Accepted, 5th September, 2011, Published online, 14th September, 2011
DOI: 10.3987/COM-11-12326
MICROWAVE-ASSISTED SYNTHESIS AND BIOACTIVITY OF NOVEL
2,2,4,5-TETRASUBSTITUTED
OXAZOLIDINES
3-DICHLOROACETYL-1,3-
Ying Fu, Lei Yang, Fei Ye,* and Shuang Gao
Department of Applied Chemistry, College of Science, Northeast Agricultural
University, Harbin, 150030, P. R. China; email: yefei@neau.edu.cn
Abstract – An efficient one-pot synthesis of 2,2,4,5-tetrasubstituted
3-dichloroacetyl-1,3-oxazolidines under microwave irradiation was developed.
The intermediate oxazolidines were attained by the reaction of amino alcohol with
aldehyde or ketone in refluxing benzene with microwave-assisted cycloaddition,
and then the acylation followed with dichloroacetyl chloride and NaOH acting as
1
the attaching acid agent. All the compounds were characterized by IR, H-NMR,
13C-NMR and elemental analysis. The preliminary biological test shows that these
compounds could protect maize against injury caused by acetochlor to a certain
extent.
In recent years, oxazolidine derivatives are important target compounds because they are found to possess
useful biological activities and pharmacological activities.1 They are also utilized as chiral synthons in
asymmetric syntheses of biological active compounds or their synthetic intermediates.2 In particular,
3-dichloroacetyl oxazolidine derivatives display significant herbicide safener properties.3
Recently, some papers were published on the synthesis of oxazolidines. A general synthetic method for
the synthesis of 1,3-oxazolidines was the condensation of β-amino alcohols with carbonyl compounds in
the presence of an acid catalyst.4 Several other catalytic methods using transition metals as catalysts have
been developed. For example, Yamamoto and Shim showed the Pd-catalyzed [3+2] cycloaddition of
vinylic oxiranes with imines,5 and the reaction of β-amino alcohols with nitrile derivatives catalyzed by
Pd/C or Rh/C under hydrogen was reported.6 In addition, 1,3-oxazolidines were synthesized from imines
and epoxides catalyzed by samarium compounds.7 All these methods suffered the disadvantages of low
efficiency, expensive catalysts, and unsatisfactory yields. Microwave technology played an important role
in synthesis with it’s rapidly form of heating. It was one of the most convenient and efficient paths to
promote organic reaction. There were many synthetic chemists who utilized microwave to achieve fast,

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HETEROCYCLES, Vol. 83, No. 11, 2011
clean and high-yielding transformations,8 which prompted us to investigate the synthesis of
3-dichloroacetyl oxazolidines by microwave irradiation. With the survey of references, there were few
reports on the microwave-assisted synthesis of 2,2,4,5-tetrasubstituted 3-dichloroacetyl oxazolidines.
Here we extended our earlier work9 and developed a microwave-irradiated method to synthesize novel
2,2,4,5-tetrasubstituted 3-dichloroacetyl-1,3-oxazolidines starting from the amino alcohol, aldehyde or
ketone and dichloroacetyl chloride (Scheme 1).
R4
R3
R4
R3
O
O
Cl2CHCOCl
R3CH CHR4
HN
C6H6
O
+ R1 C R2
Cl2HCC N
R1
O
0-5 °C, 33% NaOH aq
MW, 800W
NH2
OH
R2
R1
R2
4a-h
Yield: 61-86%
1
2
3a-h
a)R1=R2=Et, R3=R4=Me; b)R1=R2= R3=Me, R4=Et; c)R1=H, R2=nPr, R3=Me, R4=Et;
d)R1=R3=Me, R2=nPr, R4=Et; e)R1=R2=R4=Et, R3=Me; f)R1=H, R2=Ph, R3=Me, R4=Et;
g)R1=R2=Me, R3=R4=Et; h)R1=R2=R3=R4=Et
Scheme 1. Route for synthesis of the title compounds
A mixture of amino alcohol 1 and aldehyde or ketone 2 in benzene was stirred for 15 min at 33 °C, then
refluxed to remove water irritated by MW (800 W) for 15 min, the corresponding oxazolidine derivatives
3 were obtained. For the condensation was a reversible process, numerous methods for binding of the
liberated water or its removal from the reaction mixture were proposed in order to increase the yields of
oxazolidines. Usually, azeotropic distillation was used10 or drying agents were added.11 The possible
process was depicted in Scheme 2, and there was equilibrium between open-chain and cyclic tautomers.12
Even very small amount of water in the system strongly affected the state of reversible equilibrium. With
the rapid heating mode of microwave irradiation, water was produced and removed from the reaction
system right away. Microwave-assisted heating shortened the reflux time.
R4
R3
HN
R1
O
R2
O
R3CH CHR4
- H2O
oxazolidine
C R2
1
+
R
NH2
OH
R2
R4CH CHN=C R1
OH R3
imine
Scheme 2. Equilibrium between open-chain and cyclic tautomers

HETEROCYCLES, Vol. 83, No. 11, 2011
2609
The ratio of the open-chain and cyclic tautomers considerably changed, depending on the solvent polarity:
the fraction of the open-chain tautomer increased in more polar solvents. Stabilization of the open-chain
form by polar solvents was explained by formation of a strong hydrogen bond involving the hydroxy
group. For the polarity of oxazolidine was lower than imine, the nonpolar solvent was benefit to the
formation of oxazolidine. Thus benzene was employed as solvent.
The steric hindrance effect on positions 2 and 4 hindered the acylation of dichloroacetyl chloride with 3,
which made the yield of 4h lower than 4a and 4e. With the alkaline conditions, oxazolidine easily
transfered to the imine especially for the substitute was H at position 2.13 If there were some substitutes
on the oxazolidine ring, the ratio of cyclic tautomers was increased.14 Thus, the yields of 4c and 4f were
lower than other compounds.
The structures of all the novel compounds 4a-h were elucidated by elemental analysis and spectroscopic
technique data. In their IR spectra a characteristic carbonyl band at around 1670 cm-1 proved the presence
of p-π conjunction between N atom and O=C. 1H-NMR spectra of compounds 4a−h gave a characteristic
of Cl2CH- with single signal in the δ 6.05 ppm range. For the asymmetry of the oxazolidine ring, the one
hydrogen of -N-CH-C splited in multiplet at δ 3.9−4.0 ppm. δ 3.6−3.7 ppm range accounted for the one
13
hydrogen of -C-CH-O-. In the C-NMR spectra of the synthesized compounds, the signals observed in
the region δ160 ppm accounting for the carbon of Cl2C-, δ 95-100 ppm, δ 80−85 ppm, and δ 60−65 ppm
accounting for the signals of the three carbons of oxazolidine ring, which also confirm the formation of
oxazolidines.
The bioactivity determination of the novel 3-dichloroacetyl oxazolidine derivatives was carried out on
corn from the injury of acetochlor.15 The results were listed in Table 1. The recovery rates of the growth
index could be attained over 50% with 25 mg/kg of the 4a−h when the concentration of acetochlor in the
soil was 20 mg/kg. Among the compounds tested, 4f showed the best activity against the injury of
acetochlor.
In conclusion, we have developed an efficient, fast and convenient method for the microwave-assisted
preparation of 2,2,4,5-tetrasubstituted 3-dichloroacetyl-1,3-oxazolidines. This method offers short
reaction time and good yields. The preliminary bioactivity results showed that compound 4f attained the
best herbicide safener activity of these novel compounds.

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Table 1. Effect of detoxification of compounds 4a-h to growth index of corna,b,c
Recovery of
Recovery of
Recovery of
Recovery of root
weight (%)
64.88
Compound
plant height (%) plant weight (%) root length (%)
4a
4b
4c
4d
4e
4f
81.69
81.89
72.44
65.16
62.99
86.02
71.65
60.43
71.85
74.26
67.42
55.58
54.18
80.76
66.40
50.20
81.37
84.06
77.64
62.32
60.46
89.86
76.81
56.52
65.76
59.68
54.40
52.71
76.69
4g
4h
56.45
50.22
a
data are means of three replicates
Treated with compounds - Treated with acetochlor
Contrast - Treated with acetochlor
b
Recovery Rate(%) 
cwater treated was used as contrast
EXPERIMENTAL
1
The Infrared (IR) spectra were taken on a KJ-IN-27G infrared spectrophotometer (KBr). The H-NMR
13
spectra and C-NMR spectra were recorded on a Bruker Avance 300MHz nuclear magnetic resonance
spectrometer with CDCl3 as the solvent and TMS as the internal standard. The elemental analysis was
performed on FLASH EA1112 elemental analyzer. The automatic microwave synthesizer was XH-100B
of Beijing Xianghu Company. The melting points were determined on Beijng Taike melting point
apparatus (X-4) and uncorrected. All the reagents were of analytical reagents grade.
Preparation of 2,2,4,5-tetrasubstituted 3-dichloroacetyl-1,3-oxazolidines.
General Procedure: amino alcohol (1, 0.026 mol), aldehyde or ketone (2, 0.026 mol) and benzene (25
mL) were stirred for 15 min under room temperature. Then, the mixture was heated to reflux under
microwave irradiation (800 W) for 15 min and water was stripped off, followed by cooling to 0−4 °C
and addition of 3 mL of 33% sodium hydroxide solution. Afterwards 3 mL (0.031 mol) of dichloroacetyl
chloride was added dropwise with stirring and cooling in an ice bath. Stirring was continued for 1 h. The
organic phase was washed until pH = 7. The organic layer was dried over magnesium sulfate anhydrous
and vacuum distillation solvent. Compound 4b−d and 4f were separated on silica gel by column
chromatography [V (EtOAc): V (light petroleum) = 1:12]. The other crude products were recrystallized
with EtOAc and light petroleum until the white crystals were obtained. The physical and spectra data of
the compounds 4a−h are as follows:

HETEROCYCLES, Vol. 83, No. 11, 2011
2611
3-Dichloroacetyl-4,5-dimethyl-2,2-diethyl-1,3-oxazolidine (4a). Yield 80%. White solid, mp 63-64 °C.
1
IR (KBr, cm-1) ν: 3033-2883 (CH), 1674 (C=O), 1415 (Cl2HC-CO-), 1099 (N-C-O). H-NMR (CDCl3)
δ: 6.17 (s, 1H, Cl2CH-), 4.32-4.38 (m, 1H, N-CH-C), 3.90-3.99 (m, 1H, C-CH-O), 2.16-2.33 (m, 2H,
C-CH2-C), 1.88-1.93 (m, 2H, C-CH2-C), 1.23-1.43 (m, 6H, 2×CH3-C), 0.82-0.94 (m, 6H, 2×CH3-C);
13C-NMR (CDCl3) δ: 160.24, 100.39, 72.54, 65.42, 55.55, 27.55, 27.34, 16.42, 14.35, 8.32, 8.13. Anal.
Calcd for C11H19Cl2NO2: C 49.42, H 7.17, N 5.24. Found: C 49.45, H 7.14, N 5.29.
3-Dichloroacetyl-2,2,4-trimethyl-5-ethyl-1,3-oxazolidine (4b). Yield 86%. White solid, mp 64-65 °C.
IR (KBr, cm-1) ν: 3028-2870 (C-H), 1666 (C=O), 1409 (Cl2HC-CO-), 1134 (N-C-O); 1H-NMR (CDCl3)
δ: 6.13 (s, 1H, Cl2CH-), 3.79-4.05 (m, 2H, N-CH-C and C-CH-O), 1.59-1.68 (m, 8H, 2×CH3-C and
13
C-CH2-C), 1.22-1.44 (m, 3H, CH3-C-N), 0.98-1.04 (m, 3H, CH3-C-C); C-NMR (CDCl3) δ: 160.57,
95.37, 84.29, 65.47, 55.55, 27.34, 26.67, 21.95, 16.10, 9.99. Anal. Calcd for C10H17Cl2NO2: C 47.42, H
6.77, N 5.53. Found: C 47.36, H 6.74, N 5.60.
3-Dichloroacetyl-4-methyl-5-ethyl-2-n-propyl-1,3-oxazolidine (4c). Yield 61%. Yellow oil. IR (KBr,
cm-1) ν: 2964-2870 (C-H), 1666 (C=O), 1417 (Cl2HC-CO-), 1188 (N-C-O); 1H-NMR (CDCl3) δ: 6.07 (s,
1H, Cl2CH-), 5.13-5.34 (m, 1H, N-CH-O), 3.77-4.14 (m, 2H, N-CH-C and C-CH-O), 1.74-2.33 (m, 2H,
C-CH2-C), 1.40-1.53 (m, 4H, 2×C-CH2-C), 1.21-1.24 (m, 3H, CH3-C-N), 0.92-1.04 (m, 6H,
2×CH3-C-C); 13C-NMR (CDCl3) δ: 161.15, 90.39, 81.58, 55.37, 54.77, 35.96, 22.01, 17.76, 15.45, 13.93,
10.35. Anal. Calcd for C11H19Cl2NO2: C 49.42, H 7.17, N 5.24. Found: C 49.46, H 7.20, N 5.18.
3-Dichloroacetyl-2,4-dimethyl-5-ethyl-2-n-propyl-1,3-oxazolidine (4d). Yield 71%. White solid, mp
68-69 °C. IR (KBr, cm-1) ν: 3030-2870 (C-H), 1670 (C=O), 1411 (Cl2HC-CO-), 1135 (N-C-O);
1H-NMR (CDCl3) δ: 6.11 (s, 1H, Cl2CH-), 3.75-4.02 (m, 2H, C-CH-N and C-CH-O), 1.60-1.82 (m, 5H,
CH3-C-CH2), 1.38-1.52 (m, 5H, CH3-C-N and CH2-C-O), 1.18-1.20 (m, 2H, C-CH2-C), 0.86-1.01 (m,
13
6H, 2×CH3-C-C); C-NMR (CDCl3) δ: 160.64, 99.22, 84.36, 65.54, 57.40, 40.81, 27.54, 24.65, 22.16,
17.54, 14.25, 10.38. Anal. Calcd for C12H21Cl2NO2: C 51.23, H 7.53, N 4.98. Found: C 51.26, H 7.58, N
4.94.
3-Dichloroacetyl-4-methyl-2,2,5-triethyl-1,3-oxazolidine (4e). Yield 76%. White solid, mp 48-49 °C.
IR (KBr, cm-1) ν: 3033-2880 (C-H), 1662 (C=O), 1415 (Cl2HC-CO-), 1130 (N-C-O); 1H-NMR (CDCl3)
δ: 6.16 (s, 1H, Cl2CH-), 3.96-4.07 (m, 1H, C-CH-N), 3.60-3.75 (m, 1H, C-CH-O), 1.89-2.35 (m, 4H,
2×C-CH2), 1.65-1.70 (m, 2H, C-CH2-C), 1.23-1.44 (m, 3H, CH3-C-N), 0.78-1.06 (m, 9H, 2×C-CH3 and
13
CH3-C-C-O); C-NMR (CDCl3) δ: 160.19, 100.23, 83.62, 65.30, 54.97, 27.50, 27.20, 22.11, 16.28,
10.53, 8.39, 8.20. Anal. Calcd for C12H21Cl2NO2: C 51.23, H 7.53, N 4.98. Found: C 51.18, H 7.56, N
4.92.
3-Dichloroacetyl-4-methyl-5-ethyl-2-benzyl-1,3-oxazolidine (4f). Yield 66%. Yellow oil. IR (KBr,
1
cm-1) ν: 2966-2875 (C-H), 1677 (C=O), 1413 (Cl2HC-CO-), 1166 (N-C-O); H-NMR (CDCl3) δ:

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HETEROCYCLES, Vol. 83, No. 11, 2011
7.32-7.49 (m, 5H, C6H5-), 6.10 (s, 1H, Cl2CH-), 5.46 (s, 1H, CH-Ar), 4.25-4.50 (m, 1H, C-CH-N),
3.95-4.02 (m, 1H, C-CH-O), 1.59-1.73 (m, 2H, C-CH2-C), 1.35-1.44 (m, 3H, CH3-C-N), 0.97-1.06 (m,
3H, CH3-C-C-O); 13C-NMR (CDCl3) δ: 160.97, 136.36, 130.75, 129.87, 129.87, 127.43, 127.43, 90.17,
82.15, 64.50, 56.16, 21.79, 13.68, 10.43. Anal. Calcd for C14H17Cl2NO2: C 55.80, H 5.69, N 4.65.
Found: C 55.72, H 5.75, N 4.60.
3-Dichloroacetyl-2,2-dimethyl-4,5-diethyl-1,3-oxazolidine (4g). Yield 75%. White solid, mp 62-63 °C.
IR (KBr, cm-1) ν: 3050-2880 (C-H), 1670 (C=O), 1409 (Cl2HC-CO-), 1142 (N-C-O); 1H-NMR (CDCl3)
δ: 6.13 (s, 1H, Cl2CH-), 3.98-4.12 (m, 1H, C-CH-N), 3.70-3.82 (m, 1H, C-CH-O), 1.51-1.83 (m, 10H,
2×C-CH2-C and 2×CH3-C), 0.96-1.06 (m, 6H, 2×CH3-C-C); 13C-NMR (CDCl3) δ: 160.44, 95.20, 79.15,
65.87, 60.97, 27.24, 23.67, 22.47, 21.83, 11.12, 10.98. Anal. Calcd for C11H19Cl2NO2: C 49.42, H 7.17,
N 5.24. Found: C 49.36, H 7.21, N 5.22.
3-Dichloroacetyl-2,2,4,5-tetraethyl-1,3-oxazolidine (4h). Yield 70%. White solid, mp 53-54 °C. IR
(KBr, cm-1) ν: 2980-2870 (C-H), 1662 (C=O), 1411 (Cl2HC-CO-), 1130 (N-C-O); 1H-NMR (CDCl3) δ:
6.08 (s, 1H, Cl2CH-), 3.96-4.02 (m, 1H, C-CH-N), 3.65-3.72 (m, 1H, C-CH-O), 1.59-1.88 (m, 8H,
13
4×C-CH2-C), 0.96-1.06 (m, 6H, CH3-C-C-N and CH3-C-C-O), 0.79-0.90 (m, 6H, 2×CH3-C); C-NMR
(CDCl3) δ: 160.53, 99.93, 79.02, 65.93, 60.96, 27.86, 27.16, 24.78, 21.94, 11.84, 11.03, 8.38, 8.24. Anal.
Calcd for C13H23Cl2NO2: C 52.86, H 7.85, N 4.75. Found: C 52.85, H 7.81, N 4.72.
ACKNOWLEDGEMENTS
This work was supported by the National Nature Science Foundation of China (No. 31101473) and
Research Science Foundation in Technology Innovation of Harbin (No. 2010RFQYN108).
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