Abstract
New N-dichloroacetyl-5-aryl-1,3-oxazolidines 4 were synthesized by cycloaddition reaction of an aryl substituted hydroxyalkylamine 1 with aldehyde or ketone 2, followed by acylation, without isolation of the intermediate product 3. The structures of compounds 4 were determined by spectral and elemental analyses. The structure of 4b was determined by an X-ray crystallographic analysis. The bioassay results demonstrate that these compounds could alleviate chlorsulfuron injury to maize.
Introduction
1,3-Oxazolidines are prominent heterocyclic compounds that are used not only as intermediates in the synthesis of various organic compounds [1, 2] but also as ligands to catalyze asymmetric synthesis [3, 4]. N-Dichloroacetyloxazolidines are also an important class of oxazolidine derivatives that exhibit extensive biological activities [5–7]. It is known in agricultural biochemistry that N-dichloroacetyloxazolidines affect herbicide absorption, metabolism, and target enzyme activity [8–10]. In addition, N-dichloroacetyloxazolidines act as a herbicide safener by increasing the activities of glutathione-S-transferase (GST) to catalyze the conjugation of glutathione (GSH) with some herbicides [11].
Several general methods for the synthesis of various 1,3-oxazolidines have been reported. 1,3-Oxazolidine-2,4-diones have been synthesized by the reaction of readily available α-ketols and isocyanates [12]. Tetrahydro-2H-oxazolothiazoles have been prepared by intramolecular 1,3-dipolar cycloaddition reaction [13]. Darabantu et al. synthesized diastereoselectively 1,3-oxazolidines in the presence of α,α,α-trimethylolaminomethane (TRIS) and related aminopolyols [14, 15]. There are limited reports on the preparation of 5-phenyl-1,3-oxazolidines by cyclocondensation of phenylethanolamines with cyclohexanone or another ketone in the presence of K2CO3 [16, 17]. In this report, we describe a convenient one-pot synthetic approach to a novel series of N-dichloroacetyl-5-aryl-1,3-oxazolidine derivatives. The reaction is carried out without isolation of the intermediate product and in the absence of any catalyst (Scheme 1). Bioassay was carried out for determining the safener activities of the compounds.
Results and discussion
Products 4 were obtained in moderate yields by using cycloaddition and acylation reactions [18]. It can be concluded that the presence of a substituent at the para position of the aryl group does not significantly affect the yields of the products. The yield of the second acylation step is affected by steric effects of substituents R1 and R2 at position 2 of 1,3-oxazolidine.
The structures of compounds 4a–l were confirmed by elemental analysis and spectroscopic techniques. In particular, 1H NMR spectra of 4a–l exhibit the characteristic singlet around δ 6.05 for the Cl2CH moiety. In the 13C NMR spectra of the synthesized compounds, the signals observed in the region δ 95–100, δ 65–70, and δ 50–55 account for the three carbon atoms of the oxazolidine ring.
The single crystal of 4b was obtained by slow evaporation of the solution in ethanol and light petroleum. The molecular structure and the packing view of 4b are shown in Figures 1 and 2, respectively. All bond lengths and angles are in the expected ranges.
Molecular structure for compound 4b at 30% probability level.
Packing view of the compound 4b.
Compounds 4a–l were evaluated for their protection of maize in vivo against injury by chlorsulfuron, a sulfonylurea herbicide, at a concentration of 2 μg/kg. Most of the compounds showed notable herbicidal safener activities by increasing GST and acetolactate synthase (ALS) activities. Compound 4c exhibits a relatively higher effect on GSH and GST than others, whereas the effect of compound 4i is the most profound.
Conclusion
The current work affords a facile strategy of the synthesis of a series of novel N-dichloroacetyl-5-aryl-1,3-oxazolidines. All compounds exhibit safener activities to chlorsulfuron.
Experimental
Infrared (IR) spectra were taken on a KJ-IN-27G infrared spectrophotometer using KBr pellets. 1H NMR spectra (300 MHz) and 13C NMR spectra (75 MHz) were recorded on a Bruker Avance 300 MHz nuclear magnetic resonance spectrometer in CDCl3 (unless stated otherwise). Elemental analysis was performed on a Flash EA1112 elemental analyzer. X-Ray diffraction data were collected on a Bruker AXS II CCD area-detector diffractometer, Mo Kα. Melting points were determined on a Beijng Taike melting point apparatus (X-4) and are uncorrected. All reagents were of analytical grade. Reactions and products were routinely monitored by thin layer chromatography (TLC) on silica gel.
Typical procedure for the synthesis N- dichloroacetyl-5-aryl-1,3-oxazolidine 4a–l
Aryl substituted hydroxyalkylamine 1 (0.025 mol) and aldehyde or ketone 2 (0.030 mol) were added to benzene (35 mL) and the mixture was stirred briefly at 33–35°C followed by heating under reflux with azeotropic removal of water with benzene. Then the mixture was cooled to 0°C and treated with sodium hydroxide solution (33%, 0.03 mol). Afterwards, dichloroacetyl chloride (0.030 mol) was added dropwise with stirring and cooling in an ice bath. Stirring was continued for 2 h. The organic phase was washed with water and dried over anhydrous magnesium sulfate. The crude products were crystallized from a mixture of ethyl acetate and light petroleum.
N-Dichloroacetyl-5-(2′-thienyl)-2,2-dimethyl-1,3-oxazolidine (4a)
White crystals; yield 65%; mp 107–109°C; IR: ν 3250–2900 (C-H), 1681 (C=O), 1415 (Cl2HC-CO-), 1217 cm-1 (N-C-O); 1H NMR: δ 7.36–7.38 (m, 1H, Ar-H), 7.15 (d, J = 3.5 Hz, 1H, ArH), 7.03 (m, 1H, ArH), 6.05 (s, 1H, Cl2CH), 5.40 (m, 2H, NCH2), 3.73 (t, J = 9.7 Hz, 1H, OCH), 1.75 (s, 3H, CH3), 1.70 (s, 3H, CH3); 13C NMR: δ 159.5, 139.5, 126.9, 126.4, 126.4, 97.0, 72.7, 67.0, 52.9, 25.4, 23.5. Anal. Calcd for C11H13Cl2NO2S: C, 45.05; H, 4.47; N, 4.78; S, 10.91. Found: C, 45.12; H, 4.42; N, 4.71; S, 10.85.
N-Dichloroacetyl-5-phenyl-2,2-dimethyl-1,3-oxazolidine (4b)
White crystals; yield 85%; mp 110–111°C; IR: ν 3250–2900 (C-H), 1610 (C=O), 1417 (Cl2HC-CO-), 1244 cm-1 (N-C-O); 1H NMR: δ 7.43 (m, 5H, ArH), 6.06 (s, 1H, Cl2CH), 5.18, 4.26 (m, 2H, NCH2), 3.54–3.60 (t, J = 9.7 Hz, 1H, OCH), 1.80 (s, 3H, CH3), 1.72 (s, 3H, CH3); 13C NMR: δ 159.6, 136.7, 129.0, 128.8, 128.8, 126.4, 126.4, 96.9, 76.5, 67.0, 52.9, 25.4, 23.3. Anal. Calcd for C13H15Cl2NO2: C, 54.35; H, 5.27; N, 4.88. Found: C, 54.31; H, 5.24; N, 4.92.
N-Dichloroacetyl-5-(p-chlorophenyl)-2,2-dimethyl-1,3-oxazolidine (4c)
White crystals; yield 84%; mp 87–89°C; IR: ν 3022–3100 (C-H), 1672 (C=O), 1515 (Cl2HC-CO-), 1218 cm-1 (N-C-O); 1H NMR: δ 7.38 (m, 4H, ArH), 6.04 (s, 1H, Cl2CH), 5.15, 4.26 (m, 2H, NCH2), 3.46 (t, J = 9.9 Hz, 1H, OCH), 1.77 (s, 3H, CH3), 1.70 (s, 3H, CH3); 13C NMR: δ 159.6, 135.3, 134.7, 129.0, 129.0, 127.7, 127.7, 97.0, 75.8, 67.0, 52.7, 25.4, 23.3. Anal. Calcd for C13H14Cl3NO2: C, 48.60; H, 4.40; N, 4.36. Found: C, 48.69; H, 4.49; N, 4.28.
N-Dichloroacetyl-5-(p-methylphenyl)-2,2-dimethyl-1,3-oxazolidine (4d)
White crystals; yield 86%; mp 96–98°C; IR: ν 3018–2958 (C-H), 1670 (C=O), 1545 (Cl2HC-CO-), 1215 cm-1 (N-C-O). 1H NMR (CDCl3): δ 7.29 (m, 2H, ArH), 6.91 (m, 2H, ArH), 6.04 (s, 1H, Cl2CH), 5.18 (m, 2H, NCH2), 3.80 (s, 3H, CH3), 3.49–3.56 (t, J = 9.9 Hz, 1H, OCH), 1.75 (s, 3H, CH3), 1.68 (s, 3H, CH3); 13C NMR: δ 160.1, 159.6, 128.5, 127.9, 127.9, 114.2, 114.2, 96.7, 76.2, 67.0, 55.4, 52.9, 25.4, 23.3. Anal. Calcd for C14H17Cl2NO2: C, 55.80; H, 5.69; N, 4.65. Found: C, 55.89; H, 5.73; N, 4.58.
N-Dichloroacetyl-5-(p-methoxyphenyl)-2,2-dimethyl-1,3-oxazolidine (4e)
White crystals; yield 88%; mp 79–81°C; IR: ν 3022–3000 (C-H), 1672 (C=O), 1514 (Cl2HC-CO-), 1247 cm-1 (N-C-O); 1H NMR: δ 7.27 (m, 4H, ArH), 6.06 (s, 1H, Cl2CH), 4.23 (m, 2H, NCH2), 3.52–3.58 (t, J = 9.9 Hz, 1H, OCH), 2.38 (s, 3H, CH3), 1.78 (s, 3H, CH3), 1.70 (s, 3H, CH3); 13C NMR: δ 159.6, 138.9, 133.6, 129.5, 129.5, 126.4, 126.4, 96.8, 76.4, 67.0, 52.9, 25.4, 23.3, 21.3. Anal. Calcd for C14H17Cl2NO3: C, 52.99; H, 5.40; N, 4.42. Found: C, 53.08; H, 5.46; N, 4.34.
N-Dichloroacetyl-5-(2′-furyl)-2,2-dimethyl-1,3-oxazolidine (4f)
White crystals; yield 91%; mp 98–99°C. IR: ν 3250–3000 (C-H), 1674 (C=O), 1423 (Cl2HC-CO-), 1139 cm-1 (N-C-O); 1H NMR: δ 7.44 (m, 1H, ArH), 6.46 (d, J = 3.3 Hz, 1H, ArH), 6.38 (m, 1H, ArH), 6.05 (s, 1H, Cl2CH-), 5.18 (m, 2H, NCH2), 3.97 (m, 1H, OCH), 1.69 (s, 3H, CH3), 1.64 (s, 3H, CH3); 13C NMR: δ 159.6, 149.0, 143.6, 110.6, 110.0, 96.9, 69.9, 67.0, 48.9, 25.3, 23.5. Anal. Calcd for C11H13Cl2NO3: C, 47.65; H, 4.73; N, 5.05. Found: C, 47.69; H, 4.71; N, 5.02.
N-Dichloroacetyl-5-(2′-furyl)-2-methyl-2-n-propyl-1,3-oxazolidine (4g)
White crystals; yield 84%; mp 149–151°C; IR: ν 3083–2989 (C-H), 1681 (C=O), 1423 (Cl2HC-CO-), 1143 cm-1 (N-C-O); 1H NMR: δ 7.47 (m, 1H, Ar-H), 6.49 (m, 1H, Ar-H), 6.40 (m, 1H, Ar-H), 6.08 (s, 1H, Cl2CH), 4.20 (m, 2H, N-CH2), 3.90 (t, J = 9.9 Hz, 1H, O-CH), 1.64 (s, 3H, CH3), 1.32 (m, 4H, CH2-CH2), 0.93 (m, 3H, CH3); 13C NMR: δ 159.5, 148.8, 143.7, 110.6, 110.1, 98.8, 69.8, 67.1, 49.9, 39.1, 22.9, 16.1, 13.9. Anal. Calcd for C13H17Cl2NO3: C, 51.14; H, 5.62; N, 4.59. Found: C, 51.21; H, 5.56; N, 4.54.
N-Dichloroacetyl-5-(2′-furyl)-2,2-diethyl-1,3-oxazolidine (4h)
White crystals; yield 74%; mp 68–70°C; IR: ν 3050–2979 (C-H), 1660 (C=O), 1417 (Cl2HC-CO-), 1168 cm-1 (N-C-O); 1H NMR: δ 7.47 (m, 1H, Ar-H), 6.48 (m, 1H, Ar-H), 6.40 (m, 1H, Ar-H), 6.11 (s, 1H, Cl2CH), 4.26 (m, 2H, N-CH2), 3.97 (t, J = 9.9 Hz, 1H, O-CH), 1.82–2.36 (m, 4H, 2 × CH2), 0.88–0.99 (m, 6H, 2 × CH3); 13C NMR: δ 159.5, 149.4, 143.6, 110.6, 109.9, 102.1, 70.7, 67.1, 50.2, 29.3, 28.0, 8.3, 7.0. Anal. Calcd for C13H17Cl2NO3: C, 51.14; H, 5.62; N, 4.59. Found: C, 51.18; H, 5.68; N, 4.48.
N-Dichloroacetyl-5-(2′-furyl)-1,3-oxazolidine (4i)
Yellow oil; yield 64%; IR: ν 3050–3000 (C-H), 1690 (C=O), 1450 (Cl2HC-CO-), 1200 cm-1 (N-C-O); 1H NMR: δ 7.47 (m, 1H, Ar-H), 6.43 (m, 2H, Ar-H), 6.08 (s, 1H, Cl2CH-), 5.11–5.41 (m, 3H, N-CH2-O and CH-O), 3.88–4.18 (m, 2H, N-CH2); 13C NMR: δ 160.4, 149.2, 143.6, 110.6, 109.7, 79.7, 74.1, 66.0, 47.4. Anal. Calcd for C9H9Cl2NO3: C, 43.37; H, 3.64; N, 5.62. Found: C, 43.29; H, 3.74; N, 5.74.
N-Dichloroacetyl-5-(2′-furyl)-2-phenyl-1,3-oxazolidine2(4j)
White crystals; yield 61%; mp 78–79°C; IR: ν 3250–2900 (C-H), 1681 (C=O), 1421 (Cl2HC-CO-), 1168 cm-1 (N-C-O); 1H NMR: δ 7.45 (m, 8H, ArH), 6.53 (s, 1H, Cl2CH), 6.13 (s, 1H, H-C), 5.39 (t, J = 6.04 Hz, 1H, O-CH), 4.38, 4.21 (m, 2H, N-CH2); 13C NMR: δ 160.9, 149.9, 143.5, 137.1, 129.5, 129.3, 129.3, 126.5, 126.5, 110.6, 109.5, 90.1, 72.3, 66.3, 48.5. Anal. Calcd for C15H13Cl2NO3: C, 55.38; H, 4.03; N, 4.31. Found: C, 55.42; H, 4.01; N, 4.35.
N-Dichloroacetyl-5-(2′-furyl)-2-methyl-2-phenethyl-1,3-oxazolidine (4k)
White crystals; yield 77%; mp 114–116°C; IR: ν 3090–3000 (C-H), 1688 (C=O), 1411 (Cl2HC-CO-), 1232 cm-1 (N-C-O); 1H NMR (DMSO-d6): δ 7.75 (m, 1H, Ar-H), 7.17 (m, 5H, Ar-H), 7.02 (s, 1H, Cl2CH), 6.66 (d, J = 3.3 Hz, 1H, Ar-H), 6.51 (m, 1H, Ar-H), 4.23 (m, 2H, N-CH2), 3.79 (t, J = 9.8 Hz, 1H, CH-O), 2.07–2.69 (m, 4H, 2 × CH2), 1.57 (s, 3H, CH3); 13C NMR (DMSO-d6): δ 160.0, 149.6, 144.6, 141.9, 128.9, 128.9, 128.6, 128.6, 126.3, 111.2, 110.8, 97.4, 69.5, 67.8, 49.8, 38.8, 29.2, 23.1. Anal. Calcd for C18H19Cl2NO3: C, 58.84; H, 5.22; N, 3.81. Found: C, 58.72; H, 5.28; N, 3.74.
N-Dichloroacetyl-2-(2′-furyl)-1-oxa-4-aza-spiro-4,5-noncane (4l)
White crystals; yield 88%; mp 105–108°C; IR: ν 2927–2864 (C-H), 1670 (C=O), 1421 (Cl2HC-CO-), 1137 cm-1 (N-C-O); 1H NMR: δ 7.47 (m, 1H, Ar-H), 6.48 (m, 1H, Ar-H), 6.40 (m, 1H, Ar-H), 6.05 (s, 1H, Cl2CH), 4.14 (m, 1H, N-CH2), 3.93–3.99 (t, J = 9.5 Hz, 1H, O-CH), 2.25–2.62 (m, 10H, (CH2)5); 13C NMR: δ 159.8, 149.4, 143.5, 110.6, 109.8, 98.6, 69.7, 67.2, 49.0, 33.2, 30.5, 24.5, 23.0, 23.0. Anal. Calcd for C14H17Cl2NO3: C, 52.99; H, 5.40; N, 4.42. Found: C, 52.87; H, 5.42; N, 4.50.
X-Ray data collection and structure refinement
X-Ray data were collected on a Bruker AXS II CCD area-detector diffractometer using graphite monochromated Mo Kα radiation (λ = 0.071073 nm) at 298(2) K. The structure was solved by direct methods using SHELXS-97, and refined by full matrix least squares on F2 using full-matrix least-squares procedures [19]. Minimum and maximum, final electron density were -0.616 and 0.401 eÅ-3. Symmetry equivalent reflections were used to optimize crystal shape and size. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 808806. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: + 44-1223-336033, e-mail: deposit@ccdc.cam. ac.uk).
This work was supported by the National Nature Science Foundation of China (No. 31101473), the Natural Science Foundation of Heilongjiang Province (B201212), 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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