Synthesis and mass spectrometric fragmentation pattern of 6-(4-chlorophenyl)-N-aryl-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amines

Pavlo V. Zadorozhnii; Vadym V. Kiselev; Ihor O. Pokotylo; Oxana V. Okhtina; Aleksandr V. Kharchenko

doi:10.1515/hc-2018-0082

Article Open Access

Synthesis and mass spectrometric fragmentation pattern of 6-(4-chlorophenyl)-N-aryl-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amines

Pavlo V. Zadorozhnii , Vadym V. Kiselev , Ihor O. Pokotylo , Oxana V. Okhtina and Aleksandr V. Kharchenko

Published/Copyright: September 18, 2018

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From the journal Heterocyclic Communications Volume 24 Issue 5

Abstract

The mass spectrometric fragmentation of 6-(4-chlorophenyl)-N-aryl-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amines was studied under fast-atom bombardment (FAB) conditions. To simplify the interpretation of the mass spectra, a number of new 4H-1,3,5-oxadiazine derivatives containing polyisotopic elements (Cl and Br) in the arylamine substituent were synthesized. It was shown that fragmentation occurs in two main patterns.

Keywords: 1,3,5-oxadiazonium cation; FAB; fragmentation; 4H-1,3,5-oxadiazine; mass spectra

Introduction

Derivatives of 1,3,5-oxadiazines are of interest in medical chemistry, pharmaceutical industry and agriculture [1], [2]. Effective antibacterial and antifungal agents have been found among the representatives of this class of compounds [3], [4], [5], [6], [7], [8], [9], [10]. The antitumor drug ‘synthazin’ has been developed [11], [12], [13]. A large number of pesticides have been synthesized as well [14], [15], [16], [17].

For the synthesis of 4H-1,3,5-oxadiazine derivatives, the [4+2] cycloaddition reactions [[16], [[18], [19], [20], [21], [22], [23], [24], [25] are most often used, in addition to the intramolecular cyclization of bisamidals [26], [27], [28] and certain thioureas 29]. In studies on the synthesis of 1,3,5-oxadiazines, the structure of the products was confirmed mainly by ¹H NMR, ¹³C NMR and IR spectroscopy, and in some cases by X-ray diffraction analysis [20], [[29], [30]. MS data were used primarily to confirm the molecular weight of synthesized compounds 9], [10], [25], [29]. Only in two reports 23], [[24] the fragmentation patterns of 2-(dialkylamino)-6-phenyl-4H-1,3,5-oxadiazin-4-ones and 2-aryl-6-(2-aryl-4,4-bis(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-5-yl)-4,4-bis(trifluoromethyl)-4H-1,3,5-oxadiazines have been suggested. This work is devoted to the determination of the fragmentation pattern of 6-(4-chlorophenyl)-N-aryl-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amines 4, the synthetic chemistry of which was developed earlier 29].

Results and discussion

Compounds 4 were prepared by the dehydrosulfation reaction of N-amidoalkylated thioureas 3 [31] which are the products of the addition reaction of aromatic amines 2 to 4-chloro-N-(2,2,2-trichloro-1-isothiocyanatoethyl)benzamide 1 [32] with dicyclohexylcarbodiimide (DCC) (Scheme 1). In addition to compounds 4a–e, 4g, 4l and 4n synthesized previously, a series of new derivatives of 4H-1,3,5-oxadiazines 4f, 4h–k and 4m were prepared. These compounds contain polyisotopic elements (Cl and Br) in the arylamine substituent, which greatly simplifies interpretation of their mass spectra.

Scheme 1

Synthesis of 4H-1,3,5-oxadiazine derivatives 4.

The structure of the products was confirmed by spectral studies. For example, in the IR spectra of compounds 4, intense absorption bands related to symmetric and antisymmetric stretching vibrations of the N=C-O-C=N group are observed in the region of 1732–1717 cm⁻¹ and 1653–1645 cm⁻¹ [33]. In the ¹H NMR spectra of these compounds, the signal of the methine proton (5.8–5.6 ppm) adjacent to the trichloromethyl group is manifested as a singlet, while for their precursors 3 the corresponding signal is in the form of a double-doublet (7.5–7.2 ppm). The proton of the amino group in compounds 4 appears in the region of 10.1–9.0 ppm in the form of a singlet, which confirms ring closure with the participation of both amide and thiourea fragments. In the ¹³C NMR spectra of compounds 4 in the region of 152–145 ppm, carbon signals of two imino groups are observed, with no signals for C=S (182–180 ppm) and C=O (165–164 ppm) carbons that are characteristic for the starting thioureas 3.

The EI-MS for many compounds 4 are not informative because the peak intensity for the molecular ion does not exceed 1% of the base peak and, for some compounds, the peak of the molecular ion is not observed at all. The absence of a molecular ion peak in the EI mass spectra of many 1,3,5-oxadiazine derivatives has been previously noted [3]. Accordingly, in this study the mass spectra were recorded in a fast-atom bombardment (FAB) mode. In these mass spectra, with the exception of compound 4d, the molecular ion is manifested by the protonated form [MH]⁺. Protonation is also characteristic for some fragment ions. The presence of polyisotopic elements (Cl and Br) in 4H-1,3,5-oxadiazines 4 in the arylamine substituent greatly facilitates interpretation of the mass spectra. At the beginning of this work, elimination of the HCl (pathway A) or CHCl₃ (B) molecule, as well as cleavage of the oxadiazine ring (C) or (D), could be predicted (Figure 1). It turned out that the elimination of the HCl molecule for the molecular ion of 1,3,5-oxadiazines 4 is not preferred and intensity of the peaks [MH-36]⁺ in most cases does not exceed 5% of the base peak. Moreover, for compounds 4d, 4e and 4n these peaks are not observed at all. Only for compounds 4f and 4h, the intensity of this peak is about 10%. Elimination of the chloroform molecule was observed for all compounds, probably because of the thermodynamic stability of the aromatic 1,3,5-oxadiazonium cation [MH-118]⁺ formed (Scheme 2). The intensity of the peaks [M-118]⁺, in some cases reaches 25–30%, and for the compound 4n it is 53%. Most likely, the fragmentation pathway B proceeds under thermodynamic control. The second stage of the decomposition pathway B is the elimination of HCN and ArNHCN. The resulting two isotopic cations [p-ClC₆H₄CO]⁺ are characterized by high intensity peaks. At the third stage, the elimination of the CO molecule from the cations [p-ClC₆H₄CO]⁺ is observed. Thereafter, the isotopic cations [p-ClC₆H₄]⁺ undergo fragmentation according to the classical scheme for the corresponding aromatic compounds.

Figure 1

Possible fragmentation pattern of 4H-1,3,5-oxadiazines 4.

Scheme 2

Fragmentation patterns B, C and the hypothetical pathway D of 4H-1,3,5-oxadiazines 4.

The fragmentation pathway C is the most characteristic (Scheme 2). Obviously, the process takes place under kinetic control with the rupture of the weakest bonds. The intensities of the [MH-p-ClC₆H₄CN]⁺ peaks range from 10% to 50% of the base peak, and for compound 4c this peak amounts to 100%. Elimination of the ArCN fragment in the mass spectra of 4H-1,3,5-oxadiazine derivatives has been observed earlier [23], [[24]. In the second stage of the decomposition pathway C, the molecules of chloroform and hydrogen cyanide are eliminated. The peak for the resultant ion [OCNHAr]⁺ is of high intensity and for compound 4b it reaches 100%. In the third stage of the cleavage, the molecule of HNCO is eliminated, after which the [Ar]⁺ ion formed undergoes fragmentation according to the classical scheme for the corresponding aromatic compounds. It is noteworthy that the thermal decomposition of 4H-1,3,5-oxadiazines occurs according to a similar scheme 34]. Fragmentation pathway D was not observed. This is probably due to the greater stability of the resulting (E)-1-aryl-3-(2,2,2-trichloroethylidene)urea (pathway C) than the stability of the anticipated molecule of (E)-4-chloro-N-(2,2,2-trichloroethylidene)benzamide (pathway D).

Conclusion

Several 4H-1,3,5-oxadiazine derivatives were synthesized and their fragmentation under FAB conditions was studied. The most characteristic fragmentation pattern involves fragmentation of the 1,3,5-oxadiazine ring followed by cleavage of the resulting (E)-1-aryl-3-(2,2,2-trichloroethylidene)urea.

Experimental

IR spectra were recorded in KBr pellets using a Spectrum BX II spectrometer. FAB mass spectra were recorded on a VG7070 instrument. Desorption of ions from the samples in meta-nitrobenzyl alcohol or 3-mercaptopropane-1,2-diol was carried out with a beam of argon atoms having an energy of 8 keV. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded for solutions in DMSO-d₆ on a Varian VXR-400 spectrometer. EA was performed on a LECO CHNS-900 instrument. Control of the reactions and the purity of compounds were performed by thin layer chromatography (TLC) on Silufol UV-254 plates eluting with chloroform/acetone (3:1).

General procedure for the synthesis of new substituted thioureas 3f, 3h–k and 3m

The isothiocyanate 1 (3.44 g, 0.01 mol), prepared according to the method reported in [32], was dissolved in 15–18 mL of acetonitrile. Then, the solution was stirred vigorously and treated portion-wise, to avoid overheating, for 7–10 min, with 0.01 mol of the appropriate amine 2. After the stirring was stopped, the mixture was left at room temperature for 24 h. The resultant precipitate was filtered off, washed with acetonitrile (2×3 mL), dried for 24 h at room temperature and then for 5 h at 100°C. Product 3 was crystallized from MeCN.

N-(1-(3-(2-Bromophenyl)thioureido)-2,2,2-trichloroethyl)-4-chlorobenzamide (3f)

Pale yellow solid; yield 87% (4.49 g); mp 211–213°C; R_f 0.74; IR: ν_max 3282, 3235, 3068, 3052 (NH), 2944, 2853 (CH), 1657 (C=O), 1594, 1537, 1507, 1482, 1331, 1297, 1136, 1014, 903, 821, 804, 725, 633, 590 cm⁻¹; ¹H NMR: δ 10.16 (s, 1H, NH), 9.40 (d, J=7.3 Hz, 1H, NH), 8.20 (br. s, 1H, NH), 7.91–7.89 (m, 2H, H_arom.), 7.71–7.69 (m, 1H, H_arom.), 7.63–7.61 (m, 2H, H_arom.), 7.56–7.52 (m, 2H, H_arom.), 7.42–7.39 (m, 1H, H_arom.), 7.22 (dd, J=7.8, 7.3 Hz, 1H, CH); ¹³C NMR: δ 182.2 (C=S), 164.7 (C=O), 137.0, 136.8, 132.6, 131.9, 130.1, 129.5, 128.5, 128.3, 127.8, 120.6, 101.6 (CCl₃), 70.5 (CH); FAB-MS: m/z (%) 514 (4) [MH]⁺. Anal. Calcd for C₁₆H₁₂BrCl₄N₃OS (516.06): C, 37.24; H, 2.34; Br, 15.48; Cl, 27.48; N, 8.14; S, 6.21. Found: C, 37.26; H, 2.36; Br, 15.50; Cl, 27.50; N, 8.15; S, 6.19.

N-(1-(3-(4-Bromophenyl)thioureido)-2,2,2-trichloroethyl)-4-chlorobenzamide (3h)

Pale yellow solid; yield 84% (4.33 g); mp 210–212°C; R_f 0.66; IR: ν_max 3279, 3199 (NH), 3093, 3063, 3002, 2944, 2852, 2777 (CH), 1637 (C=O), 1596, 1537, 1505, 1485, 1396, 1332, 1273, 1136, 1068, 1013, 897, 800, 723, 650, 602, 500 cm⁻¹; ¹H NMR: δ 10.57 (s, 1H, NH), 9.25 (d, J=7.3 Hz, 1H, NH), 8.08 (d, J=9.8 Hz, 1H, NH), 7.89–7.87 (m, 2H, H_arom.), 7.62–7.47 (m, 7H, 6H_arom.+CH); ¹³C NMR: δ 180.4 (C=S), 164.6 (C=O), 137.8, 136.8, 131.8, 131.6, 129.4, 128.5, 125.1, 117.0, 101.5 (CCl₃), 70.1 (CH); FAB-MS: m/z (%) 515 (2) [M+2H]⁺. Anal. Calcd for C₁₆H₁₂BrCl₄N₃OS (516.06): C, 37.24; H, 2.34; Br, 15.48; Cl, 27.48; N, 8.14; S, 6.21. Found: C, 37.21; H, 2.31; Br, 15.45; Cl, 27.51; N, 8.18; S, 6.18.

4-Chloro-N-(2,2,2-trichloro-1-(3-(2-chlorophenyl)thioureido)ethyl)benzamide (3i)

Pale yellow solid; yield 85% (4.01 g); mp 214–216°C; R_f 0.67; IR: ν_max 3289, 3238, 3053 (NH), 2943, 2813 (CH), 1659 (C=O), 1594, 1538, 1505, 1480, 1331, 1296, 1132, 1014, 903, 802, 733, 665, 601, 499 cm⁻¹; ¹H NMR: δ 10.18 (s, 1H, NH), 9.35 (s, 1H, NH), 8.23 (d, J=7.3 Hz, 1H, NH), 7.91–7.89 (m, 2H, H_arom.), 7.63–7.53 (m, 5H, H_arom.), 7.38–7.27 (m, 2H, H_arom.+ CH); ¹³C NMR: δ 182.1 (C=S), 164.7 (C=O), 136.8, 135.6, 131.9, 129.6, 129.5, 129.5, 129.4, 128.5, 127.8, 127.2, 101.6 (CCl₃), 70.5 (CH); FAB-MS: m/z (%) 470 (9), [MH]⁺. Anal. Calcd for C₁₆H₁₂Cl₅N₃OS (471.60): C, 40.75; H, 2.56; Cl, 37.58; N, 8.91; S, 6.80. Found: C, 40.71; H, 2.53; Cl, 37.61; N, 8.95; S, 6.78.

4-Chloro-N-(2,2,2-trichloro-1-(3-(4-chlorophenyl)thioureido)ethyl)benzamide (3j)

Pale yellow solid; yield 88% (4.15 g); mp 207–209°C; R_f 0.61; IR: ν_max 3281, 3196, 3093, 3064 (NH), 3003, 2945, 2850, 2779 (CH), 1637 (C=O), 1596, 1505, 1485, 1330, 1273, 1137, 1092, 1014, 898, 800, 725, 656, 605 cm⁻¹; ¹H NMR: δ 10.62 (s, 1H, NH), 9.27 (d, J=6.4 Hz, 1H, NH), 8.10 (d, J=8.8 Hz, 1H, NH), 7.90–7.88 (m, 2H, H_arom.), 7.61–7.50 (m, 5H, H_arom.), 7.45–7.42 (m, 2H, H_arom.+CH); ¹³C NMR: δ 180.5 (C=S), 164.6 (C=O), 137.4, 136.9, 131.8, 129.4, 128.9, 128.6, 128.5, 124.8, 101.6 (CCl₃), 70.1 (CH); FAB-MS: m/z (%) 470 (6), [MH]⁺. Anal. Calcd for C₁₆H₁₂Cl₅N₃OS (471.60): C, 40.75; H, 2.56; Cl, 37.58; N, 8.91; S, 6.80. Found: C, 40.77; H, 2.54; Cl, 37.60; N, 8.94; S, 6.79.

4-Chloro-N-(2,2,2-trichloro-1-(3-(2,4-dichlorophenyl)thioureido)ethyl)benzamide (3k)

Pale yellow solid; yield 87% (4.40 g); mp 212–214°C; R_f 0.72; IR: ν_max 3412, 3291, 3245 (NH), 3092, 2943 (CH), 1651 (C=O), 1595, 1531, 1482, 1330, 1297, 1138, 1099, 1015, 803 cm⁻¹; ¹H NMR: δ 10.23 (s, 1H, NH), 9.40 (d, J=8.8 Hz, 1H, NH), 8.37 (d, J=8.6 Hz, 1H, NH), 7.91–7.89 (m, 2H, H_arom.), 7.72–7.67 (m, 2H, H_arom.), 7.62–7.60 (m, 2H, H_arom.), 7.52 (dd, J=8.8, 8.6 Hz, 1H, CH), 7.45–7.43 (m, 1H, H_arom.); ¹³C NMR: δ 182.2 (C=S), 164.8 (C=O), 136.8, 134.9, 131.9, 131.0, 130.7, 130.3, 129.5, 128.9, 128.5, 127.3, 101.5 (CCl₃), 70.5 (CH); FAB-MS: m/z (%) 504 (3), [MH]⁺. Anal. Calcd for C₁₆H₁₁Cl₆N₃OS (506.04): C, 37.98; H, 2.19; Cl, 42.03; N, 8.30; S, 6.34. Found: C, 37.95; H, 2.20; Cl, 42.07; N, 8.34; S, 6.30.

4-Chloro-N-(2,2,2-trichloro-1-(3-(3,4-dichlorophenyl)thioureido)ethyl)benzamide (3m)

Pale yellow solid; yield 80% (4.05 g); mp 211–213°C; R_f 0.68; IR: ν_max 3280, 3212, 3089 (NH), 2940, 2852, 2760 (CH), 1646 (C=O), 1595, 1503, 1329, 1298, 1145, 1121, 1014, 932, 835, 719, 655 cm⁻¹; ¹H NMR: δ 10.70 (s, 1H, NH), 9.26 (d, J=7.3 Hz, 1H, NH), 8.21 (d, J=9.3 Hz, 1H, NH), 7.99 (s, 1H, H_arom.), 7.90–7.88 (m, 2H, H_arom.), 7.64–7.60 (m, 3H, H_arom.), 7.52–7.43 (m, 2H, H_arom.+CH); ¹³C NMR: δ 180.5 (C=S), 164.6 (C=O), 138.7, 136.9, 131.7, 130.7, 130.5, 129.4, 128.5, 126.5, 124.2, 122.9, 101.4 (CCl₃), 70.0 (CH); FAB-MS: m/z (%) 504 (16), [MH]⁺. Anal. Calcd for C₁₆H₁₁Cl₆N₃OS (506.04): C, 37.98; H, 2.19; Cl, 42.03; N, 8.30; S, 6.34. Found: C, 38.01; H, 2.16; Cl, 42.04; N, 8.31; S, 6.29.

General procedure for the synthesis of new 4H-1,3,5-oxadiazines 4f, 4h–k and 4m

DCC (1.13 g, 5.5 mmol) was added to a thiourea 3 (5 mmol) in acetonitrile (20 mL), and the mixture was heated under reflux for 50–60 min. As the reaction progressed, the precipitate of thiourea 3 gradually dissolved, and the solution turned yellow due to formation of dicyclohexylthiourea. After completion, the solution was filtered while hot, and the filtrate was left at room temperature for 24 h. The precipitated crystals were filtered off and washed with acetonitrile (2×5 mL), then dried and crystallized from the appropriate solvent indicated below.

6-(4-Chlorophenyl)-N-phenyl-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amine (4a)

FAB-MS: m/z (%) 402 (27) [MH]⁺, 366 (4) [MH-36]⁺, 284 (25) [MH-118]⁺, 265 (43) [MH-137]⁺, 148 (50), 139 (100) [p-ClC₆H₄CO]⁺, 120 (64) [C₆H₄NHCO]⁺, 111 (18) [p-ClC₆H₄]⁺, 107 (30), 89 (34), 65 (16), 55 (8), 50 (18).

6-(4-Chlorophenyl)-N-(2,4-dimethylphenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amine (4b)

FAB-MS: m/z (%) 430 (14) [MH]⁺, 394 (2) [MH-36]⁺, 312 (9) [MH-118]⁺, 293 (49) [MH-137]⁺, 165 (8), 147 (100) [2,4-diCH₃C₆H₃NHCO]⁺, 139 (55) [p-ClC₆H₄CO]⁺, 120 (49), 111 (12) [p-ClC₆H₄]⁺, 106 (31) [2,4-diCH₃C₆H₃]⁺, 88 (31), 76 (54), 65 (8).

6-(4-Chlorophenyl)-N-(2-methoxyphenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amine (4c)

FAB-MS: m/z (%) 432 (22) [MH]⁺, 396 (3) [MH-36]⁺, 313 (21) [MH-118]⁺, 295 (100) [MH-137]⁺, 195 (12), 167 (11), 150 (59) [2-CH₃OC₆H₄NHCO]⁺, 139 (75) [p-ClC₆H₄]⁺, 123 (38), 106 (80) [CH₃OC₆H₄]⁺, 88 (51), 76 (41), 61 (43).

6-(4-Chlorophenyl)-N-(2,5-dimethoxyphenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amine (4d)

FAB-MS: m/z (%) 461 (14) [M]⁺, 343 [M-118]⁺, 324 (100) [M-137]⁺, 180 (67) [2,5-diCH₃OC₆H₃NHCO]⁺, 165 (46), 148 (28), 137 (90) [2,4-diCH₃OC₆H₃]⁺, 124 (25), 120 (29), 115 (10), 107 (56), 95 (17), 89 (50), 77 (49), 69 (13), 63 (29), 55 (17), 51 (39).

6-(4-Chlorophenyl)-N-(4-methoxy-2-nitrophenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amine (4e)

FAB-MS: m/z (%) 477 (10) [MH]⁺, 359 (6) [MH-118]⁺, 340 (29) [MH-137]⁺, 307 (78), 280 (20), 274 (14), 259 (8), 243 (10), 226 (14), 195 (17) [2-NO₂-4-CH₃OC₆H₃NHCO]⁺, 166 (21), 152 (40) [2-NO₂-4-CH₃OC₆H₃]⁺, 139 (100) [p-ClC₆H₄CO]⁺, 120 (54), 111 (19) [p-ClC₆H₄]⁺, 107 (90), 89 (88), 77 (80), 62 (52), 50 (17).

N-(2-Bromophenyl)-6-(4-chlorophenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amine (4f)

Pale yellow crystals; yield 40% (0.96 g); mp 148–150°C (from MeCN); R_f 0.62. IR: ν_max 3435, 3384, 3281 (NH), 3089, 3066, 2952, 2891, 2855 (CH), 1732 (-N=C-O-C=N-), 1653 (C=N), 1594, 1535, 1439, 1400, 1318, 1288, 1210, 1135, 1086, 1012, 824, 772, 751, 728, 700, 665, 615, 514 cm⁻¹; ¹H NMR: δ 9.17 (s, 1H, NH), 8.07–8.06 (m, 2H, H_arom.), 7.87 (m, 1H, H_arom.), 7.69–7.66 (m, 3H, H_arom.), 7.42–7.38 (m, 1H, H_arom.), 7.14–7.11 (m, 1H, H_arom.), 5.62 (s, 1H, CH). ¹³C NMR: δ 152.2 (C=N), 146.3 (C=N), 137.6, 132.7, 129.8, 129.0, 128.9, 128.0, 127.9, 126.3, 126.1, 117.1, 103.0 (CCl₃), 79.3 (CH); FAB-MS: m/z (%) 480 (10) [M+H]⁺, 444 (12) [MH-36]⁺, 362 (5) [MH-118]⁺, 343 (21) [MH-137]⁺, 311 (17), 286 (10), 242 (21), 215 (75), 200 (55), 181 (61), 165 (40), 148 (100), 139 (89) [p-ClC₆H₄CO]⁺, 123 (32), 105 (48), 89 (67), 79 (48), 75 (54). Anal. Calcd for C₁₆H₁₀BrCl₄N₃O (481.98): C, 39.87; H, 2.09; Br, 16.58; Cl, 29.42; N, 8.72. Found: C, 39.85; H, 2.10; Br, 16.60; Cl, 29.41; N, 8.75.

N-(3-Bromophenyl)-6-(4-chlorophenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amine (4g)

FAB-MS: m/z (%) 480 (25) [MH]⁺, 444 (4) [MH-36]⁺, 362 (25) [MH-118]⁺, 343 (27) [MH-137]⁺, 249 (8), 234 (7), 198 (35) [3-BrC₆H₄NHCO]⁺, 171 (10), 165 (11), 146 (58), 139 (100) [p-ClC₆H₄CO]⁺, 124 (13), 120 (22), 115 (7), 106 (27), 89 (45), 76 (37), 67 (9), 61 (21), 52 (19).

N-(4-Bromophenyl)-6-(4-chlorophenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amine (4h)

White crystals; yield 53% (1.28 g); mp 172–174°C (from MeCN); R_f 0.87; IR: ν_max 3418, 3247 (NH), 3097, 2911, 2885, 2856 (CH), 1717 (N=C-O-C=N), 1646 (C=N), 1595, 1537, 1489, 1400, 1326, 1287, 1250, 1213, 1131, 1090, 823, 798, 770, 731, 603, 492 cm⁻¹; ¹H NMR: δ 9.92 (s, 1H, NH), 8.05–8.03 (m, 2H, H_arom.), 7.71–7.67 (m, 4H, H_arom.), 7.52–7.50 (m, 2H, H_arom.), 5.71 (s, 1H, CH); ¹³C NMR: δ 152.2 (C=N), 145.0 (C=N), 138.2, 137.2, 128.9, 128.8, 128.0, 120.8, 117.3, 103.0 (CCl₃), 79.3 (CH); FAB-MS: m/z (%) 480 (9) [M+H]⁺, 446 (9) [MH-36]⁺, 362 (6) [MH-118]⁺, 343 (16) [MH-137]⁺, 307 (19), 242 (38), 215 (76), 200 (49), 181 (70), 165 (43), 157 (87), 147 (61), 139 (100), 123 (42), 109 (64), 89 (89), 75 (55), 60 (79). Anal. Calcd for C₁₆H₁₀BrCl₄N₃O (481.98): C, 39.87; H, 2.09; Br, 16.58; Cl, 29.42; N, 8.72. Found: C, 39.84; H, 2.11; Br, 16.62; Cl, 29.45; N, 8.74.

N-(2-Chlorophenyl)-6-(4-chlorophenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amine (4i)

White crystals; yield 68% (1.49 g); mp 135–137°C (from MeCN); R_f 0.69. IR: ν_max 3402, 3285 (NH), 3190, 3096, 2929, 2898, 2853 (CH), 1729 (-N=C-O-C=N-), 1651 (C=N), 1596, 1536, 1488, 1443, 1316, 1211, 1135, 1089, 1013, 838, 749, 700, 503 cm⁻¹; ¹H NMR: δ 9.00 (br. s, 1H, NH), 8.07 (d, J=7.8 Hz, 2H, H_arom.), 7.95 (m, 1H, H_arom.), 7.63 (d, J=7.8 Hz, 2H, H_arom.), 7.51–7.49 (m, 1H, H_arom.), 7.37–7.33 (m, 1H, H_arom.), 7.19–7.16 (m, 1H, H_arom.) 5.63 (s, 1H, CH); ¹³C NMR: δ 152.3 (C=N), 146.0 (C=N), 137.6, 134.4, 129.5, 129.1, 128.8, 128.0, 127.3, 125.5, 125.3, 124.8, 103.0 (CCl₃), 79.3 (CH); FAB-MS: m/z (%) 436 (8) [MH]⁺, 400 (3) [MH-36]⁺, 318 (7) [MH-118]⁺, 299 (17) [MH-137]⁺, 186 (14), 139 (100) [p-ClC₆H₄CO]⁺, 98 (32), 83 (43), 54 (36). Anal. Calcd for C₁₆H₁₀Cl₅N₃O (437.53): C, 43.92; H, 2.30; Cl, 40.51; N, 9.60. Found: C, 43.89; H, 2.32; Cl, 40.55; N, 9.63.

N,6-bis(4-Chlorophenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amine (4j)

White crystals; yield 38% (0.83 g); mp 151–153°C (from MeCN); R_f 0.73; IR: ν_max 3419, 3281 (NH), 3189, 3093, 2929, 2880 (CH), 1723 (-N=C-O-C=N-), 1645 (C=N), 1597, 1537, 1492, 1402, 1322, 1286, 1132, 1088, 1013, 826, 770, 731, 703, 606, 494 cm⁻¹; ¹H NMR: δ 9.91 (s, 1H, NH), 8.04 (d, J=8.3 Hz, 2H, H_arom.), 7.74–7.68 (m, 4H, H_arom.), 7.38 (d, J=8.8 Hz, 2H, H_arom.), 5.71 (s, 1H, CH); ¹³C NMR: δ 152.3 (C=N), 145.0 (C=N), 137.6, 137.3, 128.9, 128.8, 128.5, 128.1, 126.1, 120.0, 103.0 (CCl₃), 79.3 (CH); FAB-MS: m/z (%) 436 (9) [M+H]⁺, 400 (3) [MH-36]⁺, 318 (4) [MH-118]⁺, 299 (13) [MH-137]⁺, 208 (10), 186 (20), 139 (100) [p-ClC₆H₄CO]⁺, 125 (17), 98 (36), 83 (42), 54 (36). Anal. Calcd for C₁₆H₁₀Cl₅N₃O (437.53): C, 43.92; H, 2.30; Cl, 40.51; N, 9.60. Found: C, 43.94; H, 2.28; Cl, 40.49; N, 9.62.

6-(4-Chlorophenyl)-N-(2,4-dichlorophenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amine (4k)

White crystals; yield 52% (1.23 g); mp 164–166°C (from EtOH); R_f 0.89; IR: ν_max 3412, 3279 (NH), 3093, 2974, 2916 (CH), 1724 (N=C-O-C=N), 1645 (C=N), 1594, 1527, 1390, 1336, 1292, 1212, 1134, 1091, 1012, 805, 730 cm⁻¹; ¹H NMR: δ 9.36 (s, 1H, NH), 8.11 (d, J=7.3 Hz, 2H, H_arom.), 7.94–7.92 (m, 1H, H_arom.), 7.69–7.67 (m, 3H, H_arom.), 7.47–7.67 (m, 1H, H_arom.), 5.66 (s, 1H, CH); ¹³C NMR: δ 152.1 (C=N), 146.1 (C=N), 137.7, 133.6, 129.8, 129.1, 128.9, 128.4, 127.9, 127.4, 126.3, 125.7 (arom.), 102.8 (CCl₃), 79.2 (CH). FAB-MS: m/z (I, %) 470 (2) [MH]⁺, 434 (5) [MH-36]⁺, 352 (5) [MH-118]⁺, 333 (6) [MH-137]⁺, 215 (43), 187 (30) [2,4-diCl-C₆H₃NHCO]⁺, 179 (26), 163 (16), 145 (76) [C₆H₃Cl₂]⁺, 139 (100) [p-ClC₆H₄CO]⁺, 123 (33), 109 (51), 89 (44), 75 (24), 60 (47). Anal. Calcd for C₁₆H₉Cl₆N₃O (471.97): C, 40.72; H, 1.92; Cl, 45.07; N, 8.90. Found: C, 40.69; H, 1.90; Cl, 45.11; N, 8.94.

6-(4-Chlorophenyl)-N-(2,5-dichlorophenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amine (4l)

FAB-MS: m/z (%) 470 (14) [MH]⁺, 434 (3) [MH-36]⁺, 368 (9), 352 (30) [MH-118]⁺, 333 (22) [MH-137]⁺, 317 (10), 299 (10), 280 (14), 226 (10), 206 (10), 188 (26) [2,4-diCl-C₆H₃NHCO]⁺, 160 (24), 145 (74) [C₆H₃Cl₂]⁺, 139 (100) [p-ClC₆H₄CO]⁺, 124 (30), 120 (39), 115 (18), 111 (16) [p-ClC₆H₄]⁺, 107 (84), 89 (93), 77 (86), 62 (46), 51 (18).

6-(4-Chlorophenyl)-N-(3,4-dichlorophenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amine (4m)

White crystals; yield 67% (1.58 g); mp 159–161°C (from MeCN); R_f 0.89. IR: ν_max 3415, 3285 (NH), 3185, 3102, 2926, 2877 (CH), 1723 (N=C-O-C=N), 1649 (C=N), 1588, 1531, 1476, 1395, 1315, 1128, 1089, 1013, 810, 730, 610 cm⁻¹; ¹H NMR: δ 10.09 (s, 1H, NH), 8.23 (s, 1H, H_arom.), 8.03 (d, J=8.3 Hz, 2H, H_arom.), 7.69 (d, J=8.3 Hz, 2H, H_arom.), 7.58–7.56 (m, 1H, H_arom.), 7.52–7.50 (m, 1H, H_arom.), 5.75 (s, 1H, CH); ¹³C NMR: δ 152.1 (C=N), 144.9 (C=N), 138.4, 137.7, 131.0, 130.5, 129.0, 128.8, 127.9, 123.8, 119.8, 118.5, 102.8 (CCl₃), 79.2 (CH); FAB-MS: m/z (%) 470 (7) [MH]⁺, 434 (4) [MH-36]⁺, 352 (5) [MH-118]⁺, 333 (18) [MH-137]⁺, 299 (17), 232 (9), 215 (14), 187 (28) [2,4-diCl-C₆H₃NHCO]⁺, 161 (19), 145 (95) [C₆H₃Cl₂]⁺, 139 (100) [p-ClC₆H₄CO]⁺, 112 (42), 91 (72), 79 (70), 56 (45). Anal. Calcd for C₁₆H₉Cl₆N₃O (471.97): C, 40.72; H, 1.92; Cl, 45.07; N, 8.90. Found: C, 40.74; H, 1.94; Cl, 45.05; N, 8.95.

Butyl 4-((6-(4-chlorophenyl)-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-yl)amino)benzoate (4n)

FAB-MS: m/z (%) 502 (22) [MH]⁺, 384 (53) [MH-118]⁺, 369 (9) [MH-137]⁺, 329 (11), 238 (50), 220 (73) [n-BuOC(O)C₆H₄NHCO]⁺, 193 (30), 181 (20), 164 (79), 146 (63), 139 (100) [p-ClC₆H₄CO]⁺, 120 (84), 115 (21), 111 (18), 107 (74), 89 (88), 76 (66), 62 (51), 55 (53).

Supplementary material (online only)

FAB spectra

Acknowledgments

The authors thank Dr. Alexandr V. Mazepa (A. V. Bogatsky Physico-Chemical Institute, Odessa, Ukraine) for assistance in the mass spectrometric studies.

References

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hc-2018-0082).

Received: 2018-05-23

Accepted: 2018-08-14

Published Online: 2018-09-18

Published in Print: 2018-10-25

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Keywords for this article

1,3,5-oxadiazonium cation; FAB; fragmentation; 4H-1,3,5-oxadiazine; mass spectra

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