HETEROCYCLES

Paper | Regular issue | Vol. 83, No. 8, 2011, pp. 1819-1830
Received, 6th May, 2011, Accepted, 16th June, 2011, Published online, 24th June, 2011.
DOI: 10.3987/COM-11-12247

■ Pyrido- and Quino-1,2,4-thiadiazine S,S-Dioxides from Reactions of 4-Chloro-3-pyridinesulfonyl- and 4-Chloro-3-quinolinesulfonyl Chlorides with O-Methylisourea

Elwira Chrobak, Michał Wlekliński, Andrzej Maślankiewicz,* Joachim Kusz, Maciej Zubko, and Ewa Michalik

Department of Organic Chemistry, Medical University of Silesia, Jagiellońska 4, 41-200 Sosnowiec, Poland

Abstract

Reaction of 4-chloro-3- pyridine- (or quinoline)sulfonyl chlorides (1) or (6) with O-methylisourea led to 4-chloro-3-pyridinesulfonyl-O-methylisourea (2a) or its quinoline analog 2b, respectively. Compounds 2a and 2b underwent dehydrochlorination to the title methoxy-pyrido or quino[4,3-e]-1,2,4-thiadiazine S,S-dioxides (3 and 7). X-Ray studies proved that both methoxy derivatives (3 and 7) exist as γazine-NH-tautomers. Reaction of N-H derivatives 3 and 7 with CH3I/CH3OK/DMF system proceeded at the pyridine-ring nitrogen and led to 7-methylpyrido derivative 4a or the 6-methylquino derivative 8a, respectively. After treatment with PhOP(O)Cl2 at 120-150 ºC compounds 4a or 8a were converted to chloro derivatives 4b or 8b, respectively, which were then transformed to aminothiadiazines 5a,b,c or 9a,b,c.

INTRODUCTION
Benzo- and heteroareno-fused 1,2,4-thiadiazine S,S-dioxides are promising candidates for drugs.1-9 The above mentioned compounds are usually obtained in the processes of 1,2,4-thiadiazine S,S-dioxides moiety formation.1,4,5,8-10 As concluded from a literature review5,11 and our previous study,12 a convenient short way leading to 1,2,4-thiadiazine S,S-dioxide derivatives consists in the reactions of ortho-chloroareno or heteroarenosulfonyl chlorides with appropriate R-C(=NH)-NH2 compounds such as amidines and guanidines. Since amino-de-chlorination at the chlorosulfonyl group is the first step in the transformations mentioned above, we turned to review the sulfonylation of other R-C(=NH)-NH2 compounds. As sulfonylation of S-alkylisothioureas appeared to be uneffective, the same treatment of O-alkylisoureas was reported as a good preparative source of sulfonylureas.13 This induced the present study on the reactions of 4-chloro-3-pyridinesulfonyl and 4-chloro-3-quinolinesulfonyl chlorides 1 or 6 with
O-methylisourea as a source of the title pyrido- and quino-1,2,4-thiadiazine S,S-dioxide derivatives 3, 4, and 5 or 7, 8, and 9, respectively.

RESULTS and DISCUSSION
Amination of γ-chloro-β-chlorosulfonylazine (pyridine or quinoline) (1) or (6)10,11,14 proceeded stepwise starting from the amino-de-chlorination at the chlorosulfonyl group followed by amino-de-chlorination at the γ-chloroazinyl position to give γ-amino-β-pyridinesulfonamides or γ-amino-β-quinolinesulfonamides, which were then subjected to cyclization to 1,2,4-thiadiazine S,S-dioxide derivatives.1,10,12 The same amino-de-chlorinations sequence was observed for the reaction of γ-chloro-β-chlorosulfonylpyridine (1) and its quinoline analog 6 with guanidines,12 this procedure was thus applied for reactions of 4-chloro-
3-pyridine- and 4-chloro-3-quinoline sulfonyl chlorides (1) or (6) with O-methylisourea. The reaction proceeded as sulfonylation and led to 4-chloro-3-pyridinesulfonyl-O-methylisourea (2a) or its quinoline analog 2b, respectively, in good yield. Compounds 2a and 2b were identified as sulfonamide-imino tautomers on the basis of 1H NMR spectra showing two non-identical NH signals. To perform the final amino-de-chlorination at the γ-chloroazinyl positions, azinesulfonyl-O-methylisoureas 2a or 2b were subjected to reaction with the Cs2CO3/methanol system, which gave the expected pyrido and quino-1,2,4-thiadiazine S,S-dioxides 3 or 7. The structure of 3 or 7 as γ-aminoazine tautomers was deduced from X-ray diffraction studies, presented in Figures 1 and 2.

N-Methylation
Methylation of sodium (or potassium) salts of 2-methyl-(1H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (11) and 2-dimethylamino-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (12) proceeded at the endocyclic nitrogen of the pyridine-ring and led to 6-methyl derivatives.12 Methylation of sodium (or potassium) salts of 3-dimethylaminopyrido-1,2,4-thiadiazine dioxide (10), proceeded also at the endocyclic nitrogen of the pyridine-ring to form 7-methyl derivative.12

The same regioorientation during methylation was observed in this work for potassium salts of 2-methoxy-(1H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (7) and 3-methoxy-(4H)-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (3), which underwent transformation to 6-methyl derivative 8a or 7-methyl derivative 4a. (Schemes 1 and 2). Although alkylation of sodium (or potassium) salts of pyrido and quinothiadiazine S,S-dioxides 3 or 7 may formally follow through the nitrogen anionic forms I, II, III, the least hindered pyridine-ring nitrogen anion III appears to be the most reactive nucleophilic agent.

The structure of 4a and 8a and the position of the newly-introduced N-CH3 group was concluded from HSQC and HMBC experiments as presented in Scheme 5.

The synthesis of the pyrido- and quino-1,2,4-thiadiazine S,S-dioxides 4a or 8a, presented above (Schemes 1 and 2) provides easy access to the 1,2,4-thiadiazine derivatives fused with a 1,4-dihydropyridine or a 1,4-dihydroquinoline unit. Transformation of methoxy substituent at thiadiazine ring of compounds 4a or 8a into more active leaving group is however necessary for further functionalization of pyrido- and quino-1,2,4-thiadiazine S,S-dioxides 4a or 8a, as a first step to the preparation of biologically active compounds. For this purpose, methoxy derivatives 4a or 8a, were subjected to demethoxy-chlorination. Although no reaction was observed in a boiling POCl3/Et3N x HCl system, in the reaction with PhOP(O)Cl2/Et3N x HCl system the compounds 4a (120 ºC) or 8a (150 ºC) were converted to chlorothiadiazines 4b or 8b, respectively. Finally, reactions of chlorothiadiazines 4b or 8b with amines led to aminothiadiazines 5a,b,c or 9a,b,c, respectively.
1H NMR spectra of n-butylamino derivatives 5b and 9b show resonances of the alkyl and aromatic protons of two species having very similar coupling patterns in the ratio of 1:0.3 (as deduced from the intensities of α-methylene protons as well as from α-azinyl protons). This observation could be interpreted in terms of restricted rotation about the exocyclic amine bond taking into account that in the case of numerous unsymmetrical N-alkyl(aryl)guanidines hindered rotation can give rise to cis- and trans-rotational isomers18 and that the electronic structure of the guanidine part of compounds 5b and 9b should be described with mesomeric formulae A, B, C and D (see Scheme 6).

CONCLUSIONS
The title pyrido- and quino[4,3-e]-1,2,4-thiadiazine S,S-dioxides 3, 7 are easily available in a two-step process starting from reaction of O-methylisourea with 4-chloro-3-pyridine-(and quinoline)sulfonyl chlorides (1) and (6) followed by cyclization of the O-methylsulfonylisoureas 2a,b to compounds 3, 7. Although both 1,2,4-thiadiazine S,S-dioxides exist in the form of 4thiadiazinic NH-tautomers, the potassium salts of 3, 7 were methylated outside the thiadiazine ring at the pyridine ring nitrogen, which led to 7-methyl derivative 4a or 6-methyl derivative 8a, respectively. Transformation of methoxythiadiazines 4a, 8a to chlorothiadiazines 4b, 8b followed by amination of the latter to aminothiadiazines 5a,b,c or 9a,b,c opens a new route to 1,2,4-thiadiazine S,S-dioxide derivatives fused with 1,4-dihydropyridine or 1,4-dihydroquinoline unit.

EXPERIMENTAL
Melting points were taken in open capillary tubes and are uncorrected. All NMR spectra were recorded on a Bruker AVANCE 400 spectrometer operating at 400.22 MHz and 100.64 MHz for 1H and 13C nuclei, respectively, in DMSO-d6 solutions with tetramethylsilane (δ 0.0 ppm) as internal standard. Two-dimensional 1H-13C HSQC and HMBC experiments were performed using standard Bruker software HSQCGP and HMBCGP, respectively, and the following parameters: the spectral widths in F2 and F1 were ca 5 kHz for 1H and 16.7 kHz for 13C, the relaxation delay was 1.5 s, the refocusing in the HSQC experiment was 1.7 ms and the delay for long-range evolutions was 50 ms in 1H/13C HMBC. 2D spectra were acquired as 2048 x 1024 hypercomplex files, with 1-4 transients. EI MS spectra were determined on a Finnigan MAT 95 spectrometer at 70 eV. TLC analyses were performed employing Merck’s SiO2 oxide 60 F254 neutral (type E) plates and using CHCl3/EtOH mixture (3 : 1, v/v) as an eluent.
O-Methylisourea hydrochloride was commercial product. 4-Chloro-3-pyridinesulfonyl chloride (1)10,15 and 4-chloro-3-quinolinesulfonyl chloride (6) were prepared as described previously.14

Sulfonylation of O-methylisourea hydrochloride to N1-(4-chloro-3-pyridinesulfonyl)-O-methylisourea (2a) and to N1-(4-chloro-3-quinolinesulfonyl)-O-methylisourea (2b):
A suspension of 4-chloro-3-quinolinesulfonyl chloride (1) (0.52 g, 2 mMol) in 4 mL of acetone and a solution of O-methylisourea hydrochloride 0.22 g (2 mMol) in water (1.3 mL) were stirred at -5 ºC and aqueous NaOH (160 mg + 0.75 mL of water) was added in three portions. Each portion was added once the mixture became neutral (pH~7). The mixture was kept in refrigerator at 0 ºC for 16 h. The solid was filtered off and washed with cold acetone. Sulfonyl-O-methylisourea 2a (53%) and 2b (50%) were recrystallized from methanol or ethanol.
N1-(4-Chloro-3-pyridinesulfonyl)-O-methylisourea (2a):
mp 153-156 ºC (MeOH), decomp. EIMS (70 eV): m/z (%) = 249 (23.5, M+), 250 [(7.8, (M + 1)+], 251 [(8.9, (M + 2)+]. 1H NMR (DMSO-d6), δ: 3.68 (s, 3H, OCH3), 7.48 (bs, 1H, NH), 7.63 (d, 3J = 5.3 Hz, 1H, H5), 8.48 (bs, 1H, NH), 8.73 (d, 3J = 5.6Hz, 1H, H6), 9.11 (s, 1H, H2). Anal. Calcd for C7H8ClN3O3S: C 33.67, H 3.23, N 16.83. Found: C 33.94, H 3.07, N 16.80.
N1-(4-Chloro-3-quinolinesulfonyl)-O-methylisourea (2b):
mp 181-183 ºC (EtOH), decomp. EIMS (70 eV): m/z (%) = 299 (89.6, M+), 301 [34.6, (M+2)+]. 1H NMR (DMSO-d6), δ: 3.64 (s, 3H, OCH3), 7.52 (bs, 1H, NH), 7.82-7.86 (m, 1H, Harom), 7.95-7.99 (m, 1H, Harom), 8.12-8.14 (m, 1H, Harom), 8.36-8.39 (m, 1H, Harom), 8.45 (bs, 1H, NH), 9.34 (s, 1H, H-2). Anal. Calcd for C11H10ClN3O3S: C 44.08, H 3.36, N 14.02. Found: C 44.53, H 3.17, N 14.04.

Cyclization of N1-(4-chloro-3-pyridinesulfonyl)-O-methylisourea (2a) and N1-(4-chloro-3-quinolinesulfonyl)-O-methylisourea (2b) to 3-methoxy-(4H)-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (3) and 2-methoxy-(1H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (7):
Pyridinesulfonyl-O-methylisourea 2a or quinolinesulfonyl-O-methylisourea 2b (3 mMol), cesium carbonate (1.45 g, 4.5 mMol) and 20 mL of dry methanol were placed in a steel autoclave. It was kept in an oil-bath at 110 ºC for 3 h. The mixture was cooled down to rt, transferred to distillation flask and then concentrated to dryness under vaccum. The residue was dissolved in water (ca. 9 mL for 2a, 30 mL for 2b) and acidified at 0 ºC with formic acid up to pH ~ 3. The solid was filtered off, washed with cold water and dried on air. Crude thiadiazines 3 or 7 were recrystallized from methanol (or acetone) to give pyridothiadiazine 3 (0.38 g, 60%) or quinothiadiazine 7 (0.55 g, 70%).
3-Methoxy-(4H)-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (3)
mp 158-160 ºC decomp. (MeOH). EIMS (70 eV): m/z (%) = 213 (94.1, M+), 156 (100). 1H NMR (DMSO-d6), δ: 3.93 (s, 3H, OCH3), 7.19 (d, 3J = 5.6 Hz, 1H, H5), 8.64 (d, 3J = 5.6Hz, 1H, H6), 8.92 (s, 1H, H8), 12.57 (bs, 1H, NH). Anal. Calcd for C7H7N3O3S x H2O: C 36.36, H 3.92, N 18.17. Found: C 36.50, H 4.0, N 17.81.
2-Methoxy-(1H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (7)
mp 139-140 ºCdecomp. (acetone). EIMS (70 eV): m/z (%) = 263 (100, M+). 1H NMR (DMSO-d6), δ: 3.95 (s, 3H, OCH3), 7.75-7.79 (m, 1H, Harom), 7.95-7.99 (m, 1H, Harom), 8.02-8.04 (m, 1H, Harom), 8.67-8.69 (m, 1H, Harom), 9.19 (s, 1H, H-5). Anal. Calcd for C11H9N3O3S x H2O: C 46.97, H 3.94, N 14.94. Found: C 46.53, H 3.87, N 14.80.

N-Methylation of 3-methoxy-(4H)-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (3) and 2-methoxy-(1H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (7):
Potassium methoxide (0.150 g, ca. 2.1 mM) was added on stirring to the suspension of 2 mmol of pyridothiadiazine 1,1-dioxide 3 or quinothiadiazine 4,4-dioxide 7 in dry DMF (5 mL). The mixture was stirred for 5-10 min until the mixture became clear. Then, a solution of methyl iodide (0.8 mL, ca. 2 mMol) in DMF (2.5 mL) was added dropwise for 15 min and the mixture was stirred at rt for 20 h. The solid was filtered off, washed with cold water and dried on air. It was boiled with EtOH to give 3-methoxy-7-methylpyridothiadiazine 1,1-dioxide 4a (240 mg, 52%) or 2-methoxy-6-methylquino
thiadiazine 4,4-dioxide 8a (380 mg, 69%).
3-Methoxy-7-methyl-(7H)-pyrido[4,3-e]-1.2.4-thiadiazine 1,1-dioxide (4a)
mp 253-254 ºC (EtOH), decomp. EIMS (70 eV): m/z (%) = 227 (43.5, M+). 1H NMR (DMSO-d6), δ [δC for carbons from single bond and / long range proton-carbon correlations]: 3.77 [(s, 3H, CH3O); 54.3 (CH3O)/ 163.4 (C3)], 4.05 [(s, 3H, CH3N); 45.5 (CH3N)/ 142.1 (C8), 143.4 (C6)], 7.2 [(d, 3J=7.2 Hz, 1H, H5); 120.1 (C5)/ 119.5 (C8a), 143.4 (C6)], 8.27 [(dd, 3J=7.2 Hz, 4J=1.6 Hz, 1H, H6); 143.4 (C6)/ 45.5 (CH3N), 120.1 (C5), 142.1 (C8), 157.9 (C4a)], 9.08 [(d, 4J=1.6 Hz, 1H, H8); 142.1 (C8)/ 45.5 (CH3N), 119.5 (C8a), 143.4 (C6), 157.9 (C4a)]. Anal. Calcd for C8H9N3O3S: C 42.28, H 3.99, N 18.49. Found: C 42.48, H 3.88, N 18.28.
2-Methoxy-6-methyl-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (8a)
mp 263-266 ºC (DMF). EIMS (70 eV): m/z (%) = 277 (54.4, M+), 183 (100). 1H NMR (DMSO-d6), δ [δC for carbons from single bond and / long range proton-carbon correlations]: 3.88 [(s, 3H, CH3O); 54.5 (CH3O)/ 163.0 (C2)], 4.28 [(s, 3H, CH3N); 42.7 (CH3N)/ 138.6 (C6a), 145.1 (C5)], 7.81 [(m, 1H, H9); 127.9 (C9)/ 118.5 (C7), 123.9 (C10a)], 8.06 [(m, 1H, H8); 134.1 (C8)/ 138.6 (C6a), 125.4 (C10)], 8.11 [(m, 1H, H7); 118.5 (C7)/123.9 (C10a), 127.9 (C9), 157.1 (C10b)], 9.41 [(s, 1H, H5); 145.1 (C5)/ 42.7 (CH3N), 111.8(C4a), 138.6 (C6a), 157.1 (C10b)]. Anal. Calcd for C12H11N3O3S: C 51.98, H 4.00, N 15.15. Found: C 52.07, H 3.95, N 15.16.

Reaction of methoxy-azino-thiadiazines 4a or 8a with phenyl dichlorophosphate leading to chloro-azino-thiadiazines 4b or 8b
Suspension of 1 mMol of methoxy derivative 4a or 8a and triethylamine hydrochloride (15 mg) in phenyl dichlorophosphate (1 mL, ca. 6.8 mMol) was stirred at 120 ºC for 4a or 150 ºC for 8a (both oil-bath temperature) for 4 h. The mixture was cooled down to rt and poured into 10 g of the mixture of water and ice and then neutralized with 25 % ammonia to pH~6.7. The solid was filtered off, washed with water and dried on air. Crude product was boiled with EtOH. Hot solution was decanted off to leave 3-chloro-7-methyl-(7H)-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (4b) (145 mg, 62%) or 2-chloro-6-methyl-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (8b) (230 mg, 82%).
3-Chloro-7-methyl-(7H)-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (4b)
mp 330 ºC decomp. (EtOH). EIMS (70 eV): m/z (%) = 231 (34, M+), [11.2, (M + 2)+]. 1H NMR (DMSO-d6), δ: 4.15 (s, 3H, CH3N), 7.49 (d, 3J=7.1 Hz, 1H, H5), 8.54 (dd, 3J=7.1 Hz, 4J=1.5 Hz, 1H, H6), 9.38 (d, 4J=1.5 Hz, 1H, H8). Anal. Calcd for C7H6ClN3O2S: C 36.29, H 2.61, N 18.14. Found: C 36.62, H 2.97, N 17.42.
2-Chloro-6-methyl-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (8b)
mp 281-284 ºC (EtOH), decomp. EIMS (70 eV): m/z (%) = 281 (100, M+), 282 [12.9, (M + 1)], 283 [35.5, M + 2)]. 1H NMR (DMSO-d6), δ: 4.40 (s, 3H, CH3N), 7.90-7.94 (m, 1H, Harom), 8.14-8.19 (m, 1H, Harom), 8.24-8.26 (m, 1H, Harom), 8.73-8.76 (m, 1H, Harom), 9.71 (s, 1H, H5). Anal. Calcd for C11H8ClN3O2S: C 46.90, H 2.86, N 14.92. Found: C 46.54, H 3.10, N 14.57.

Amination of 3-chloro-7-methyl-(7H)-pyrido[4,3-e]-1.2.4-thiadiazine 1,1-dioxide (4b) and 2-chloro-6-methyl-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (8b):
a) with aqueous ammonia or with aqueous dimethylamine
Chloropyridothiadiazine 4b or chloroquinothiadiazine 8b (1 mmol), and 5 mL of conc. aqueous ammonia or 4 mL of 40 % aqueous Me2NH solution was placed in a steel autoclave. It was heated in an oil-bath at 100 ºC for 2 h. The mixture was cooled down to rt, transferred to distillation flask and an exces of NH3 or Me2NH was then distilled off under vaccum. The solid was filered off, washed with cold water and boiled with EtOH. Hot solution was decanted off to leave amino derivatives 5a (181 mg, 85%) or 9a (228 mg, 87%), or dimethylamino derivatives 5c (180 mg, 79%) and 9c (256 mg, 88%).
b) with n-butylamine
Chloropyridothiadiazine 4b or chloroquinothiadiazine 8b (1 mmol) and n-butylamine (4 mL) was refluxed for 1 h. Excess of n-butylamine was then evaporated to dryness under reduced pressure from water bath. The residue was cooled down to rt and triturated with water (4 mL). The solid was filtered off, washed with cold water and dried on air to give crude 5c (220 mg) or crude 9c (280 mg). Products were purified by column chromatography ((SiO2, CHCl3/EtOH, 3:1, v/v) and recrystallized from ethanol to give 5b (205 mg, 77%) or 9b (237 mg, 75%).
3-Amino-7-methyl-(7H)-pyrido[4,3-e]-1.2.4-thiadiazine 1,1-dioxide (5a)
mp 316-319 oC (EtOH). EIMS (70 eV): m/z(%) = 212 (45, M+), 148 (100). 1H NMR (DMSO-d6), δ: 3.93 (s, 3H, NCH3), 6.86 (d, 3J=7.2 Hz, 1H, H5), 6.9 (bs, 2H, NH2), 8.01 (dd, 3J=7.2 Hz, 4J=1.6 Hz, 1H, H6), 8.73 (d, 4J=1.7 Hz, 1H, H8). Anal. Calcd for C7H8N4O2S: C 39.62, H 3.80, N 26.40. Found: C 39.23, H 3.76, N 25.81.
3-Butylamino-7-methyl-(7H)-pyrido[4,3-e]-1.2.4-thiadiazine 1,1-dioxide (5b)
mp 219-222 oC (EtOH). EIMS (70 eV): m/z(%) = 268 (6.9, M+), 133 (100). 1H NMR spectrum contains the spectral lines of the same functional groups of two species A and B in the ratio 1:0.3, despite the fact that the product seems to be chromatographically homogeneous. 1H NMR (DMSO-d6), species A δ: 0.86-0.90 (m, 3H, CH3), 1.25-1.34 (m, 2H, CH2), 1.42-1.49 (m, 2H, CH2), 3.11-3.16 (m, 2H, CH2), 3.90 (s, 3H, NCH3), 6.78 (d, 3J=7.3 Hz, 1H, H5), 7.51-7.53 (m-t, 1H, NH), 7.96 (dd, 3J=7.3 Hz, 4J=1.7 Hz, 1H, H6), 8.67 (d, 4J=1.7 Hz, 1H, H8), species B δ: 0.86-0.90 (m, 3H, CH3), 1.25-1.34 (m, 2H, CH2), 1.42-1.49 (m, 2H, CH2), 3.29-3.30 (m, 2H, CH2), 3.94 (s, 3H, NCH3), 6.96 (d, 3J=7.2 Hz, 1H, H5), 7.25-7.30 (m-t, 1H, NH), 8.44 (dd, 3J=7.2 Hz, 4J=1.7 Hz, 1H, H6), 8.75 (d, 4J=1.7 Hz, 1H, H8). Anal. Calcd for C11H16N4O2S: C 49.24, H 6.01, N 20.88. Found: C 49.02, H 5.96, N 20.51.
3-Dimethylamino-7-methyl-(7H)-pyrido[4,3-e]-1.2.4-thiadiazine 1,1-dioxide (5c)
mp 261-263 ºC (EtOH). Mp and 1H NMR spectrum in DMSO-d6 were identical with the reported data.3
2-Amino-6-methyl-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (9a):
mp 324-325 oC (EtOH). EIMS (70 eV): m/z(%) = 262 (100, M+). 1H NMR (DMSO-d6), δ: 4.15 (s, 3H, NCH3), 7.15 (bs, 2H, NH2), 7.70-7.74 (m, 1H, Harom), 7.95-7.97 (m, 2H, Harom , NH), 8.66-8.68 (m, 1H, Harom), 9.06 (s, 1H, H5). Anal. Calcd for C11H10N4O2S: C 50.37, H 3.84, N 21.36. Found: C 50.05, H 3.93, N 20.99.
2-Butylamino-6-methyl-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (9b):
mp 209-212 oC (EtOH). EIMS (70 eV): m/z(%) = 318 (7.1, M+), 183 (100). 1H NMR spectrum contains the spectral lines of the same functional groups of two species A and B in the ratio of 1:0.3, despite the fact that the product seems to be chromatographically homogeneous. 1H NMR (DMSO-d6), species A δ: 0.86-0.93 (m, 3H, CH3), 1.30-1.39 (m, 2H, CH2), 1.49-1.56 (m, 2H, CH2), 3.20-3.23 (m, 2H, CH2), 4.12 (s, 3H, NCH3), 7.68-7.72 (m, 1H, Harom), 7.77-7.80 (m, 1H, Harom), 7.92-7.95 (m, , 2H, Harom , NH), 8.63-8.65 (m, 1H, Harom), 8.99 (s, 1H, H5); species B δ: 0.86-93 (m, 3H, CH3), 1.30-1.39 (m, 2H, CH2), 1.49-1.56 (m, 2H, CH2), 3.47-3.52 (m, 2H, CH2), 4.17 (s, 3H, NCH3), 7.55-7.58 (m, 1H, Harom), 7.74-7.76 (m, 1H, Harom), 7.98-7.99 (m, 2H, Harom , NH), 8.71-8.73 (m, , 1H, Harom), 9.09 (s, 1H, H5) . Anal. Calcd for C15H18N4O2S: C 56.58, H 5.70, N 17.60. Found: C 56.71, H 5.51, N 17.59.
2-Dimethylamino-6-methyl-(6H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (9c):
mp 283-286 ºC (EtOH). Mp and 1H NMR spectrum in DMSO-d6 were identical with the reported data.3

X-Ray structure analysis
The diffraction data were collected with a four – circle Xcalibur diffractometer with Sapphire3 CCD detector using graphite monochromated Mo Kα radiation. The intensity data were collected and processed using Oxford Diffraction CrysAlis Software16 The crystal structures were solved by direct methods with the program SHELXS-9717 and refined by full-matrix least-squares method on F2 with SHELXL-97.17
Crystals of 3-methoxy-(4H)-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (3) semi-DMSO solvate were obtained by slow evaporation of DMSO solution at room temperature. Crystal data for 3: monoclinic, space group P21/c, a = 8.2579(1) Å, b = 16.0022(2) Å, c = 15.7348(2) Å, α = 90º, β = 92.093(1)°, γ = 90º, V = 2077.88(4) Å3, Z = 4, dx = 1,613 Mg m-3, T = 100(1) K, Data were collected for a crystal of dimensions 0.48 x 0.16 x 0.16 mm3. Final R indices for 3385 reflections with I > 2σ(I) and 313 refined parameters are R1= 0.0255, wR2= 0.0681 (R1= 0.0279, wR2= 0.0690 for all 3674 data).
Crystals of 2-methoxy-(1H)-quino[4,3-e]-1,2,4-thiadiazine 4,4-dioxide (7) hydrate were grown by slow evaporation from acetone – water (5 : 1, v/v) solution at room temperature. Crystal data for 7: monoclinic, space group P21/c, a = 20.0087(3) Å, b = 8.8774(1) Å, c = 20.1801(4) Å, α = 90°, β = 139.600(1)°, γ = 90°, V = 2323.18(8) Å3, Z = 8, dx = 1,608 Mg m-3, T = 100(1) K, Data were collected for a crystal of dimensions 0.32 x 0.24 x 0.17 mm3. Final R indices for 6823 reflections with I > 2σ(I) and 376 refined parameters are R1= 0.0322, wR2= 0.0954, (R1= 0.0463 and wR2= 0.0980 for all 9195 data). Crystallographic data for compounds 3 and 7 have been deposited with Cambridge Crystallographic Data Centre (CCDC deposition numbers 802223 and 802222 respectively) Copies of the data can be obtained upon request from CCDC, 12 Union road, Cambridge CB2 1EZ, UK).

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