5-Amino-3-( diethylamino )-5 H-benzo [ 4 , 5 ] imidazo [ 1 , 2-b ] [ 1 , 2 , 4 , 6 ] thiatriazine 1 , 1-Dioxide

In the quest for discovery of novel bioactive molecules, new heterocyclic ring systems provide templates for exploration of uncharted chemical space. Herein, we describe the synthesis of a new benzo[4,5]imidazo[1,2-b][1,2,4,6]thiatriazine derivative from readily available 1,2-diaminobenzimidazole and N,N-diethyl-N′-chlorosulfonyl chloroformamidine. The product structure, confirmed by X-ray crystallography, bears an exocyclic NH2 group, which should enable synthesis of an extended range of derivatives of this unusual scaffold.


Introduction
The immense biological and industrial significance of heterocyclic compounds [1] ensures that considerable research effort continues to be directed toward the discovery of convenient and efficient synthetic routes to such molecules.Importantly, the construction of new heterocyclic ring systems can provide templates and building blocks for exploration of uncharted chemical space, which is free of competing intellectual property claims.

Introduction
The immense biological and industrial significance of heterocyclic compounds [1] ensures that considerable research effort continues to be directed toward the discovery of convenient and efficient synthetic routes to such molecules.Importantly, the construction of new heterocyclic ring systems can provide templates and building blocks for exploration of uncharted chemical space, which is free of competing intellectual property claims.
In the syntheses outlined in Scheme 1, the 2-aminobenzimidazoles 2 acted as 1,3-bis-nucleophiles in reactions with the 1,3-bis-electrophilic dichlorides 1 to produce six-membered ring products, the fused thiatriazines 3 (and 4), which are representatives of very rare ring systems.We envisaged that replacement of 2-aminobenzimidazoles 2 with 1,2-diaminobenzimidazole (5) (readily produced from 2 (R 3 =H) by N-amination [4]) in a similar reaction to those outlined in Scheme 1 might result in the production of a new fused seven-membered ring system via the action of 5 as a 1,4-bis-nucleophile.
In the syntheses outlined in Scheme 1, the 2-aminobenzimidazoles 2 acted as 1,3-bisnucleophiles in reactions with the 1,3-bis-electrophilic dichlorides 1 to produce six-membered ring products, the fused thiatriazines 3 (and 4), which are representatives of very rare ring systems.
We envisaged that replacement of 2-aminobenzimidazoles 2 with 1,2-diaminobenzimidazole (5) (readily produced from 2 (R 3 =H) by N-amination [4]) in a similar reaction to those outlined in Scheme 1 might result in the production of a new fused seven-membered ring system via the action of 5 as a 1,4-bis-nucleophile.

Results and Discussion
Treatment of 5 [4] with N,N-diethyl-N′-chlorosulfonyl chloroformamidine 1a [2] in N,N′-dimethylpropyleneurea (DMPU) in the presence of Hünig's base at room temperature afforded the 5-amino-benzo [4,5] imidazo[1,2-b][1,2,4,6]thiatriazine derivative (6) as the major product.The crude product, obtained as a precipitate directly from the reaction mixture by simple addition of ethyl acetate and water, was a ~7:1 mixture of 6 and an isomeric compound, presumably the 10-aminobenzo [4,5] NMR and mass spectral analyses alone did not allow an unambiguous structural assignment for fused thiatriazine 6; however, a signal at 5.88 ppm integrating for 2H in the 1 H-NMR spectrum of 6 was indicative of an NH2 group, thereby narrowing the possibilities to either of structures 6 or 7.An unequivocal determination of the structure of 6 was achieved via X-ray crystallography (Figures 1  and 2).In the 1 H-NMR spectrum of the crude product (see Supplementary Materials), an additional minor resonance at 5.80 ppm, also indicative of an NH2 group, suggested that the minor isomer had structure 7. Neither of the expected seven-membered ring products 8 or 9 were observed.No obvious additional spots were noted during thin-layer chromatography (TLC) analysis of the mother liquor.NMR and mass spectral analyses alone did not allow an unambiguous structural assignment for fused thiatriazine 6; however, a signal at 5.88 ppm integrating for 2H in the 1 H-NMR spectrum of 6 was indicative of an NH 2 group, thereby narrowing the possibilities to either of structures 6 or 7.An unequivocal determination of the structure of 6 was achieved via X-ray crystallography (Figures 1 and 2).In the 1 H-NMR spectrum of the crude product (see Supplementary Materials), an additional minor resonance at 5.80 ppm, also indicative of an NH 2 group, suggested that the minor isomer had structure 7. Neither of the expected seven-membered ring products 8 or 9 were observed.No obvious additional spots were noted during thin-layer chromatography (TLC) analysis of the mother liquor.The crystal structure of 6 shows linear chain packing, formed by hydrogen bonding between the exocyclic amino groups and sulfonyl oxygen atoms of adjacent molecules (Figure 2).The polynucleophilicity of 5 allows for either the 1,3-NCN or 1,4-NCNN bis-nucleophilic modes of reaction with dielectrophilic reagents and both types of reaction of 5 with 1,3-bis-electrophiles are described in the literature.For example, treatment of 5 with either of N-arylitaconimides or Narylmaleimides in refluxing 2-propanol in the presence of catalytic amounts of acetic acid afforded 10-amino-tetrahydropyrimido[1,2-a]benzimidazole derivatives, the products of a 1,3-NCN reaction [5,6].Similarly, treatment of 5 with malonic or β-ethoxymethylenemalonic acid derivatives gave pyrimido[1,2-a]benzimidazole derivatives, again from a 1,3-NCN reaction [7].However, reactions of diamine 5 as a 1,4-NCNN bis-nucleophile with β-dicarbonyl compounds, under acid catalysis, to provide 1,2,4-triazepino[2,3-a]benzimidazoles, were also reported [8].
It appears that, in the present work, the reaction of diamine 5 with dichloride 1a under basic conditions, favors the 1,3-NCN bis-nucleophilic mode of reaction, affording the 5-aminobenzo [4,5] The free NH2 moiety on the newly formed and rare fused [1,2,4,6]thiatriazine ring system of 6 should offer prospects for various N-substitution reactions.Such synthetic chemistry, in addition to the ring NH substitution methodology previously demonstrated on compounds 3 [3], should enable the production of an extended range of derivatives of this unusual scaffold, with potential application in bioactive molecule discovery projects.The crystal structure of 6 shows linear chain packing, formed by hydrogen bonding between the exocyclic amino groups and sulfonyl oxygen atoms of adjacent molecules (Figure 2).The crystal structure of 6 shows linear chain packing, formed by hydrogen bonding between the exocyclic amino groups and sulfonyl oxygen atoms of adjacent molecules (Figure 2).The polynucleophilicity of 5 allows for either the 1,3-NCN or 1,4-NCNN bis-nucleophilic modes of reaction with dielectrophilic reagents and both types of reaction of 5 with 1,3-bis-electrophiles are described in the literature.For example, treatment of 5 with either of N-arylitaconimides or Narylmaleimides in refluxing 2-propanol in the presence of catalytic amounts of acetic acid afforded 10-amino-tetrahydropyrimido[1,2-a]benzimidazole derivatives, the products of a 1,3-NCN reaction [5,6].Similarly, treatment of 5 with malonic or β-ethoxymethylenemalonic acid derivatives gave pyrimido[1,2-a]benzimidazole derivatives, again from a 1,3-NCN reaction [7].However, reactions of diamine 5 as a 1,4-NCNN bis-nucleophile with β-dicarbonyl compounds, under acid catalysis, to provide 1,2,4-triazepino[2,3-a]benzimidazoles, were also reported [8].
It appears that, in the present work, the reaction of diamine 5 with dichloride 1a under basic conditions, favors the 1,3-NCN bis-nucleophilic mode of reaction, affording the 5-aminobenzo [4,5] The free NH2 moiety on the newly formed and rare fused [1,2,4,6]thiatriazine ring system of 6 should offer prospects for various N-substitution reactions.Such synthetic chemistry, in addition to the ring NH substitution methodology previously demonstrated on compounds 3 [3], should enable the production of an extended range of derivatives of this unusual scaffold, with potential application in bioactive molecule discovery projects.The polynucleophilicity of 5 allows for either the 1,3-NCN or 1,4-NCNN bis-nucleophilic modes of reaction with dielectrophilic reagents and both types of reaction of 5 with 1,3-bis-electrophiles are described in the literature.For example, treatment of 5 with either of N-arylitaconimides or N-arylmaleimides in refluxing 2-propanol in the presence of catalytic amounts of acetic acid afforded 10-amino-tetrahydropyrimido[1,2-a]benzimidazole derivatives, the products of a 1,3-NCN reaction [5,6].Similarly, treatment of 5 with malonic or β-ethoxymethylenemalonic acid derivatives gave pyrimido[1,2-a]benzimidazole derivatives, again from a 1,3-NCN reaction [7].However, reactions of diamine 5 as a 1,4-NCNN bis-nucleophile with β-dicarbonyl compounds, under acid catalysis, to provide 1,2,4-triazepino[2,3-a]benzimidazoles, were also reported [8].
It appears that, in the present work, the reaction of diamine 5 with dichloride 1a under basic conditions, favors the 1,3-NCN bis-nucleophilic mode of reaction, affording the 5-amino-benzo [4,5] The free NH 2 moiety on the newly formed and rare fused [1,2,4,6]thiatriazine ring system of 6 should offer prospects for various N-substitution reactions.Such synthetic chemistry, in addition to the ring NH substitution methodology previously demonstrated on compounds 3 [3], should enable the production of an extended range of derivatives of this unusual scaffold, with potential application in bioactive molecule discovery projects.

Materials and Methods
All chemicals were commercially available except those whose synthesis is described.The reaction mixture was monitored by TLC using commercial aluminium-backed TLC plates (Merck Kieselgel 60 F254, Darmstadt, Germany).The plates were observed under UV light at 254 nm.The melting point was determined using a Büchi B-545 apparatus and is uncorrected.High resolution mass spectrometric analyses were performed on a Thermo Scientific Q Exactive mass spectrometer (Thermo Scientific, Waltham, MA, USA) fitted with an ASAP ion source (M&M Mass Spec consulting) [9].The design and method of ionisation have been described previously [10,11].Positive and negative ions were recorded in an appropriate mass range at 140,000 mass resolution.The APCI probe was used without flow of solvent.The nitrogen nebulizing/desolvation gas used for vaporization was heated to 350 • C. The sheath gas flow rate was set to 25, the auxiliary gas flow rate to 5 and the sweep gas flow rate to 2 (all arbitrary units).The discharge current was 4 mA and the capillary temperature was 320 • C. The UV-vis spectrum was collected in methanol solution on a Lambda 1050 UV-Vis-NIR Spectrometer (Perkin Elmer, Waltham, MA, USA) with a standard detector in the 250-800 cm −1 range.The IR spectrum was collected from a solid sample on a laminated diamond in the 4000-600 cm −1 range with a resolution of 4 cm −1 using a Nicolet 6700 FT-IR spectrometer (Thermo Scientific, Waltham, MA, USA). 1 H and 13 C-NMR spectra were recorded on a Bruker Av400 instrument (Bruker Biospin, Rheinstetten, Germany) at 400 and 100.6 MHz, respectively.Deuterated dimethyl sulfoxide (DMSO-d 6 ) was used as the solvent and also as an internal lock.LC-MS analyses were performed on a Waters Acquity UPLC i-Class (Waters Corporation, Milford, MA, USA) with QDa performance mass detector with adjustment-free atmospheric pressure ionisation (API) electrospray (ES) interface.Positive and negative ions were recorded simultaneously with full scan analysis in m/z range 50 to 1000.High purity nitrogen (>95%) nebulizing/desolvation gas was used for vapourization with the pressure regulated at 650-700 kPa.The probe temperature was set at 600 • C, the source temperature at 120 • C, the cone voltage was 10 V whilst the capillary voltage was 0.8 kV for both positive and negative ion modes.The chromatographic conditions were as follows: column-Waters Acquity UPLC BEH C 18 (50 × 2.1 mm, 1.7 µm particle size); flow rate-0.4mL/min; column temperature 30 • C; mobile phase A-100% Milli-Q Water with 0.1% formic acid; mobile phase B-100% acetonitrile with 0.1% formic acid; gradient-95% A to 100% B over 4.5 min, hold at 100% B for 1 min, change to 95% A over 0.5 min, then hold for 1 min.MS data were collected for the complete 7 min run.Spectral analysis was from 190 to 350 nm with chromatograms extracted using a wavelength of 254 nm.A mixture of 5 [4] (0.74 g, 5 mmol), the dichloro compound 1a [2] (1.52 g, 6.5 mmol), N,N-diisopropylethylamine (2.25 mL, 13 mmol), and DMPU (5 mL) was stirred at room temperature for 6 h.Ethyl acetate (15 mL) was added with stirring, followed by water (30 mL), and the mixture was stirred vigorously for a few min.The precipitate was collected by filtration and washed sequentially with water, ethyl acetate, and diethyl ether to afford a mixture of compounds 6 and 7 (~7:1, 687 mg, 45%) as an off-white solid.A sample (100 mg) was recrystallized from aqueous 1,2-dimethoxyethane to afford the title compound 6 (61 mg) as small, off-white, nacreous plates, melting point 273-275

Figure 1 .
Figure 1.Crystal structure of 6.The molecular diagram is shown with 50% thermal ellipsoids.Only one of the two unique molecules is shown.The other molecule is essentially the same as that shown, apart from the relative orientations of the ethyl groups of the NEt2 substituent at C3.

Figure 2 .
Figure 2. Stick plot of the linear chain crystal packing of 6.

Figure 1 .
Figure 1.Crystal structure of 6.The molecular diagram is shown with 50% thermal ellipsoids.Only one of the two unique molecules is shown.The other molecule is essentially the same as that shown, apart from the relative orientations of the ethyl groups of the NEt 2 substituent at C3.

Molbank 2018 , 6 Figure 1 .
Figure 1.Crystal structure of 6.The molecular diagram is shown with 50% thermal ellipsoids.Only one of the two unique molecules is shown.The other molecule is essentially the same as that shown, apart from the relative orientations of the ethyl groups of the NEt2 substituent at C3.

Figure 2 .
Figure 2. Stick plot of the linear chain crystal packing of 6.

Figure 2 .
Figure 2. Stick plot of the linear chain crystal packing of 6.