4,6-Dinitro-7-(thiazol-2-ylamino)benzo[ c ][1,2,5] oxadiazole 1-oxide

: 4,6-Dinitro-7-(thiazol-2-ylamino)benzo[ c ][1,2,5]oxadiazole 1-oxide was synthesized by a S N Ar reaction between 7-chloro-4,6-dinitrobenzofuroxan and 2-aminothiazole. The structure of the newly synthesized compound (45% yield) was elucidated based on 1 H-NMR, 13 C-NMR, NOESY-1D, ESI-MS, UV-Vis, and FT-IR techniques.


Introduction
Aromatic substitution reactions (S E Ar and S N Ar) [1][2][3][4] are among the most important reactions in organic chemistry from both the synthetic and mechanistic points of view. In the latter case, the reaction course has been studied with a wide number of substrates and, in many cases, the reaction intermediates have been detected and isolated. For a long time, we have been studying this kind of reaction, coupling strongly activated neutral aromatics such as 1,3,5-triaminobenzenes with a series of electrophiles, both charged and neutral [5][6][7][8].
The presence of the benzofuroxanyl moiety is of particular interest in the medicinal and biological fields, due to its ability to release nitric oxide (NO) under physiological conditions [13,14].
In the framework of the recent increasing attention paid to the synthesis of hybrid structures able to nitric oxide (NO) release, we report the synthesis of 4,6-dinitro-7-(thiazol-2-ylamino) benzo[c][1,2,5]oxadiazole 1-oxide in mild conditions as a novel heterocyclic system incorporating furoxan and thiazole moieties of interest as a new potentially biologically active compound [16][17][18].

Discussion
It is known that 2-aminothiazole can behave as a tridentate nucleophile, with possible sites of attack localized on the exocyclic nitrogen atom, endocyclic nitrogen atom, and carbon atom in position 5. This characteristic makes possible, in principle, the formation of three different compounds ( Figure 1). To discriminate between the possible structures, we analyzed the 1 H-NMR spectrum, in which three signals in aromatic region were present-one singlet belonging to the benzofuroxanyl moiety and two doublets derived from the 2-aminothiazole moiety.
The presence of the two doublets permitted us to exclude the formation of compound C, where only one signal should be present for the thiazole moiety. In this context, it has to be noted that, when N,N-disubstituted 2-aminothiazole is used, only the product derived from this kind of attack was detected [11].
Since structures A and B cannot be easily distinguished by NMR spectroscopy, we planned to methylate the product (Scheme 2) and then analyze it through a NOESY-1D experiment in order to ascertain the structure.

Discussion
It is known that 2-aminothiazole can behave as a tridentate nucleophile, with possible sites of attack localized on the exocyclic nitrogen atom, endocyclic nitrogen atom, and carbon atom in position 5. This characteristic makes possible, in principle, the formation of three different compounds ( Figure 1).

Discussion
It is known that 2-aminothiazole can behave as a tridentate nucleophile, with possible sites of attack localized on the exocyclic nitrogen atom, endocyclic nitrogen atom, and carbon atom in position 5. This characteristic makes possible, in principle, the formation of three different compounds ( Figure 1). To discriminate between the possible structures, we analyzed the 1 H-NMR spectrum, in which three signals in aromatic region were present-one singlet belonging to the benzofuroxanyl moiety and two doublets derived from the 2-aminothiazole moiety.
The presence of the two doublets permitted us to exclude the formation of compound C, where only one signal should be present for the thiazole moiety. In this context, it has to be noted that, when N,N-disubstituted 2-aminothiazole is used, only the product derived from this kind of attack was detected [11].
Since structures A and B cannot be easily distinguished by NMR spectroscopy, we planned to methylate the product (Scheme 2) and then analyze it through a NOESY-1D experiment in order to ascertain the structure.  To discriminate between the possible structures, we analyzed the 1 H-NMR spectrum, in which three signals in aromatic region were present-one singlet belonging to the benzofuroxanyl moiety and two doublets derived from the 2-aminothiazole moiety.
The presence of the two doublets permitted us to exclude the formation of compound C, where only one signal should be present for the thiazole moiety. In this context, it has to be noted that, when N,N-disubstituted 2-aminothiazole is used, only the product derived from this kind of attack was detected [11].
Since structures A and B cannot be easily distinguished by NMR spectroscopy, we planned to methylate the product (Scheme 2) and then analyze it through a NOESY-1D experiment in order to ascertain the structure.

Discussion
It is known that 2-aminothiazole can behave as a tridentate nucleophile, with possible sites of attack localized on the exocyclic nitrogen atom, endocyclic nitrogen atom, and carbon atom in position 5. This characteristic makes possible, in principle, the formation of three different compounds (Figure 1). To discriminate between the possible structures, we analyzed the 1 H-NMR spectrum, in which three signals in aromatic region were present-one singlet belonging to the benzofuroxanyl moiety and two doublets derived from the 2-aminothiazole moiety.
The presence of the two doublets permitted us to exclude the formation of compound C, where only one signal should be present for the thiazole moiety. In this context, it has to be noted that, when N,N-disubstituted 2-aminothiazole is used, only the product derived from this kind of attack was detected [11].
Since structures A and B cannot be easily distinguished by NMR spectroscopy, we planned to methylate the product (Scheme 2) and then analyze it through a NOESY-1D experiment in order to ascertain the structure. The NOESY-1D spectrum (Figure 2) of the methylated compound, recorded by irradiating the methyl group signal (δ = 3.71), shows the presence of a signal at δ = 7.78, corresponding to one of the doublets of the thiazole moiety. From this finding, it has been possible to ascribe the structure Met-A to the product and then the structure A to compound 3. The same conclusion was gained by recording the NOESY-1D spectrum by irradiating the signal belonging at δ = 7.78 (see Figure S9).

Materials and Methods
The 1 H and 13 C spectra were recorded on an Inova 600 (Varian, Palo Alto, CA, USA) spectrometer operating at 600 MHz (for 1 H-NMR) and 150 MHz (for 13 C-NMR). Chemical shifts refer to the solvent for 1 H and 13 C-NMR (δ = 1.96 and δ = 118.26, respectively, for CD3CN; δ = 2.50 for 1 H-NMR in DMSO-d6). Signal multiplicities were established by Distortionless Enhanced by Polarization Transfer (DEPT90) experiments. Chemical shifts were measured in δ. J values are given in Hertz. Electron spray ionization mass spectra (ESI-MS) were recorded with a WATERS ZQ 4000 instrument (Waters Corporation, Milford, MA, USA). The IR spectrum was recorded with a Fourier transform spectrophotometer PerkinElmer FT-IR Spectrum Two (PerkinElmer, Waltham, MA, USA) in the 4000−800 cm −1 wavelength range using a NaCl cell. The UV/Vis spectrum was recorded using a PerkinElmer UV-Vis Lambda 12 spectrophotometer (PerkinElmer, Waltham, MA, USA). Chromatographic purifications (FC) were carried out on glass columns packed with silica gel (Merck grade 9385, 230−400 mesh particle size, 60 Å pore size) at medium pressure. Thin-layer chromatography (TLC) was performed on silica gel 60 F254-coated aluminum foils (Fluka, Darmstadt, Germany). 7-Chloro-4,6-dinitrobenzofuroxan was synthesized according to the literature [19], and 2aminothiazole was purchased by Sigma-Aldrich (Darmstadt, Germany).
Red plates, m.p. >300 °C (CH3Cl); 1  From this finding, it has been possible to ascribe the structure Met-A to the product and then the structure A to compound 3. The same conclusion was gained by recording the NOESY-1D spectrum by irradiating the signal belonging at δ = 7.78 (see Figure S9).

Materials and Methods
The 1 H and 13 C spectra were recorded on an Inova 600 (Varian, Palo Alto, CA, USA) spectrometer operating at 600 MHz (for 1 H-NMR) and 150 MHz (for 13 C-NMR). Chemical shifts refer to the solvent for 1 H and 13 C-NMR (δ = 1.96 and δ = 118.26, respectively, for CD 3 CN; δ = 2.50 for 1 H-NMR in DMSO-d 6 ).