A new method for the synthesis of 4H-1,3,5-oxadiazine derivatives

Introduction

Azines are of immense importance in medicinal chemistry and in the pharmaceutical industry. They are widely used in agriculture and in the production of polymers, semiconductors and dyes. Compounds containing a 1,3,5-oxadiazine ring that exhibit pronounced antibacterial, antifungal [1], [2], [3], [4], [5], antitumor [6] and insecticidal [7], [8] activities, are of special importance.

Though there are several preparative approaches for the synthesis of 1,3,5-oxadiazine derivatives, many such compounds remain difficult to synthesize. In most cases, the reactions of [4+2] cycloaddition of heterodienes to dienophiles [9], [10], [11], cyclodehydration of polyfluoro-containing bisamidales [12] and introduction of an oxygen atom into the imidazole ring by the Baeyer-Villiger reaction are used for the synthesis of these structures [13].

Another approach includes the use of N-(2,2,2-trichloro-1-(3-arylthioureido)ethyl)amides of carboxylic acids [14], [15], which, due to the advantageous arrangement of the two reaction sites (amide and thioureide), are suitable for closing six-membered rings. For obtaining 4H-1,3,5-oxadiazine derivatives, 4-chloro-N- (2,2,2-trichloro-1-(3-arylthioureido)ethyl)benzamides were used as starting materials. In these compounds, the p-chlorophenyl substituent promotes amide-imide tautomerism [16], facilitating ring closure.

Results and discussion

The addition reaction of amines 2 to 4-chloro-N-(2,2,2-trichloro-1-isothiocyanatoethyl)benzamide (1) [14], [15] furnished a series of N-amidoalkylated derivatives of thioureas 3 (Scheme 1). Thioureas 3 can be of interest in medicinal chemistry [17], [18], [19].

Scheme 1

In this work, compounds 3 were successfully used in the synthesis of new 4H-1,3,5-oxadiazine derivatives. First, dehydrosulfurization of thioureas 3 was conducted at reflux in anhydrous acetonitrile with a 10% excess of dicyclohexylcarbodiimide (DCC) [20] for 50−60 min. During the reaction, the initially colorless solution turned bright yellow because of the formation of dicyclohexylthiourea. This reaction is assumed to involve the formation of intermediate carbodiimide 4 [14] followed by cyclization leading to the closure of the 1,3,5-oxadiazine ring (Scheme 2). Products 5 were obtained in acceptable yields and easily purified.

Scheme 2

The structure of compounds 5a–h was confirmed by spectral analysis. For example, in the IR spectra, strong absorption bands at 1725–1735 cm⁻¹ and 1645–1655 cm⁻¹ are observed. This absorption can be attributed to the symmetric and antisymmetric valence vibrations of a group -N=C-O-C=N- with certainty [21]. In the ¹H NMR spectra, the signal of the methine proton located at a trichloromethyl group appears as a singlet at 5.70–5.50 ppm, which is in a stronger field compared to 7.40–6.00 ppm for compounds 3. A singlet for the amino group is observed at 10.20–8.70 ppm. This result is consistent with the participation of both amide and thiourea fragments in the cyclization. There are no signals of carbons C=S and C=O, typical for the starting thioureas, in the ¹³C NMR spectra of compounds 5 near 180 and 165 ppm. Instead, carbon signals of two imino groups located in the range of 153–144 ppm can be seen. Because of the relative instability of compounds 5, electron-impact mass spectra were uninformative. The intensity of the molecular ion peak does not exceed 1.0% in each case, and for some compounds, the molecular ion peak is not observed at all. The mass spectra recorded under fast-atom bombardment conditions are more informative. The molecular structure of compound 5d was confirmed by an X-ray diffraction (XRD) study (Figure 1).

Figure 1

Molecular structure of 6-(4-chlorophenyl)-N-(2,5-dimetoxyphenyl)-4-(trichloro-methyl)-4H-1,3,5-oxadiazin-2-amine (5d) obtained from XRD data.

The oxadiazine ring is approximately flat [22], [23] to within 0.02 Å, and the N(3) atom also adopts a near-planar configuration with the sum of N-centered bond angles of 359(2)°. Both N(3)-C(2) 1.356(2) Å and N(3)-C(11) 1.405(2) Å bonds are slightly elongated compared to typical values of 1.339 Å and 1.353 Å, respectively [24], but are typical for arylamine derivatives of oxazole [25]. The {C(2), (N(3)-H(3), C(11)} fragment is almost coplanar with the oxadiazine ring and the {C(11)…C(16)} benzene moiety; the interfacial angles are 2.4° and 4.5°, respectively. That arrangement facilitates π-conjugation of the N(3) lone pair with the C(2)=N(2) moiety and the aromatic ring. The relative position of the ring is additionally stabilized by intramolecular hydrogen bonds. Both methoxy groups are deviated from the {C(11)…C(16)} benzene ring plane. The C(12)-C(13)-O(2)-C(17) torsion angle is 29.2(2)°. The C(11)-C(16)-O(3)-C(18) torsion angle of 14.1(2)° is slightly reduced due to the N(3)-H(3)…O(3) hydrogen bond. The p-chlorophenyl substituent is slightly rotated around the oxadiazine ring with the interfacial angle of 156(2)°, despite the presence of the attractive intramolecular contact C(6)-H(6)…N(1) 2.59 Å, for which the van der Waals radii sum is 2.67 Å. The C(1)-C(5) bond of 1.481(2) Å is elongated compared to a typical value of 1.463 Å [25], which indicates weakening of the π-conjugation between those rings.

Conclusion

A new method for the synthesis of 4H-1,3,5-oxadiazines based on the dehydrosulfurization reaction of readily available N-amidoalkylated thioureas 3 was developed. It allows obtaining cyclization products with acceptable yields and high degrees of purity.

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 was carried out with a beam of argon atoms having an energy of 8 keV. EI mass spectra were recorded using a Kratos MS 890 spectrometer with direct sample injection into ion source; the temperature of the ionization chamber was 180–250°C and the ionization energy of the electrons was 70 eV. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded for solutions in DMSO-d₆ on a Varian VXR-400 spectrometer. Elemental analysis was performed on a LECO CHNS-900 instrument. Control of the reactions and the purity of compounds were performed by TLC on Silufol UV-254 plates eluting with chloroform/acetone (3:1).

Supporting information

XRD data for compound 5d are given in the online supplement.