Reactions of 5-mercaptoazoles and pyridine-2-thiones with acetylenic esters. Selectivity of the formation of novel fused thiazin-4-ones and thiazolidin-4-ones

Abstract

A systematic study of the reactions of dimethyl acetylenedicarboxylate (DMAD) and methyl propynoate with 5-mercaptoazoles and pyridine-2-thiones has been carried out and as a result, a number of novel imidazo[1,5-b]thiazin-4-ones 6a,b, pyrazolo[1,5-b] thiazin-4-ones 15a–f, imidazo[1,5-b]thiazol-4-ones 7a,b and thiazolo[3,2-a]pyridines 21a–c have been prepared. The influence of the size of the ring of the starting “cyclic” thioamides on the size of the fused ring in the reaction products has been established. The preferred formation of a six-membered thiazine ring took place in the reactions of 5-mercaptoazoles. In contrast, the five membered thiazolidine ring is formed in reactions of pyridine-2-thiones. In both cases the product is a five-membered ring fused to a six-membered heterocycle.

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Introduction

The reactions of thioureas, thiosemicarbazides and thioamides with electron poor acetylenes are known as convenient and effective methods to prepare thiazolidin-4-ones and thiazin-4-ones.^1–12 The most probable mechanism of these reactions involves the addition of the sulfur atom of the thiocarbamoyl moiety onto the triple bond of the acetylenes, followed by cyclocondensation of the intermediate vinylthioimidates of type 2via elimination of a molecule of methanol. Reactions of thioamides of various natures with DMAD have been shown to occur via one of two possible mechanisms where generally the α-situated ester group participates in the cyclization leading to a five-membered thiazolidine ring 3.^{3,4,6,10–12} An alternative possibility for the cyclization of intermediate 2 (R² = H) involves the reaction of the β-ester group to afford a thiazin-4-one ring.^4,6,10

In previous work, we have shown that novel 2,5-dimethylenethiazolidin-4-one derivatives can be prepared by reaction of malonthioamide derivatives with DMAD¹¹ and a new synthetic approach to conjugated bicyclic heterocycles has been elaborated based on a similar reaction of heterocyclic thioamides.¹² Reactions of heterocyclic compounds where an endocyclic thioamide group is present with DMAD and methyl propynoate have only been reported once.⁴ In order to find a general synthetic method to thiazin-4-ones and thiazolin-4-ones fused to azole and azine rings we have studied the reactions of 5-mercaptoimidazoles, -pyrazoles, -1,2,3-triazoles and tetrahydropyridine-2-thiones with DMAD and methyl propynoate.

Results and discussion

Reaction of 5-mercaptoimidazole-4-carboxamide 5a with DMAD in principle could give both thiazine 6a and thiazolidine 7a rings. We have found that this reaction in methanol at room temperature results in the exclusive formation of fused thiazine 6a in 66% yield. However, a mixture of thiazine 6a and thiazolidine 7a in a ratio of 7 to 3 was obtained when sodium methoxide was used as a catalyst. It should be noted that compound 5a did not react with methyl propynoate in either circumstances.

The respective thiazin-4-one and thiazolin-4-one structures of products 6a and 7a are confirmed by their ¹H and ¹³C NMR spectral data (Experimental section, Table 1). The ¹H NMR spectra for both products are very similar but all signals of thiazine 6a are shifted 0.14–0.18 ppm downfield in comparison with those of 7a. The signals in the ¹³C NMR spectra are also very similar for both isomeric products 6a and 7a. The ¹H coupled ¹³C NMR spectra of 6a and 7a show doublet signals at 119.0 and 118.8 ppm, respectively, with similar ¹J_CH coupling constants of 175 Hz, which is typical for CC units. The final decision in favor of the thiazolidine structure for 7a and thiazine for 6a can be made after considering the magnitudes of the ¹³C–¹H coupling constants in the ¹³C NMR spectra.^2,11,12 The C₆ and C₄ signals of 7a are found in the coupled spectrum as doublets with ²J_C6–H5 coupling constants of 1.4 Hz and ³J_C4–H5 of 4.8 Hz. This shows the presence of an exocyclic double bond in the structure of thiazolidine 7a. In contrast to this, the coupled spectrum of 6a contains a doublet signal for C₄ with a ²J_C4–H5 coupling constant of 1.4 Hz, which confirms the structure of 6a as thiazin-4-ones.

Table 1 ¹³C NMR spectra

N	Chemical shifts (ppm), multiplicity						Coupling constants/Hz
	C2	C4	C5	C6	C7	Others	J C5–H5	J C4–H5	J C8–H8	J C6–H5
6a	124.2 d	156.4 d	118.8 d	143.5 s	162.5 s	54.3 q (OCH3), 133.1 s (C9), 133.9 d (C8H), 162.0 s (C10)	175.0	<1.0	223.0
6b	127.6 d	156.8 d	119.0 d	144.3 s	162.2 s	54.3 q (OCH3), 133.2 s (C9), 134.9 d (C8H), 163.5 s (C10)	174.0	1.5	224.0
7a	124.2 d	156.4 d	118.8 d	143.5 d	162.0 s	54.3 q (OCH3), 127.6 s (C9), 134.0 d (C8H), 186.6 s (C10)	175.0	4.8	222.2	1.4
7b	127.6 d	158.2 d	112.7 d	144.3 s	160.1 s	54.3 q (OCH3), 127.6 s (C9), 132.7 d (C8), 187.3 s (C10)	174.0	3.3	220.0
15a	124.1	154.5	122.4	141.3	162.0	11.7 (C14), 54.3 (OCH3), 54.7 (OCH3), 114.8 (C11), 124.1 (C12), 125.4 (C8), 135.6 (C13), 145.9 (C10), 152.8 (C9)
15b	125.8	154.5	122.1	141.8	161.8	11.7 (C14), 21.0 (CH3), 54.3 (OCH3), 121.8 (C11), 130.1 (C12), 136.5 (C8), 141.8 (C13), 149.8 (C10), 153.1 (C9)
15c	127.0 s	155.3 br s	122.7 d	142.1 s	162.7 s	12.6 q (Me), 54.2 q (OCH3), 136.5 s, 154.1 s (Cpyrazole), 123.5 d, 130.5 d, 132.3 s, 152.6 s (Ar)	173.6
15d	125.9 s	154.9 d	122.6 d	142.1 s	161.9 s	12.0 q (Me), 54.3 q (OCH3), 136.5 s, 154.6 s (Cpyrazole), 123.5 d, 129.4 d, 137.2 s, 150.6 s (Ar)	174.1	0.6
15e	127.2	154.6	122.9	141.8	161.9	11.8 (C14), 14.2 (CH3), 54.5 (OCH3), 61.2 (OCH2), 123.0 (C11), 130. (C12), 136.0 (C8), 141.6 (C13), 153.8 (C9), 153.8 (C10), 165.2 (COOEt)
15f	126.4 d	155.1 d	118.8 d	137.9 dd		12.0 q (Me), 136.5 s, 153.5 s (Cpyrazole), 123.4 d, 129.5 d, 137.0 s, 150.8 s (Ar)	173.1	10.6		2.3
19	122.6	154.6	121.8	141.2	162.2	11.8 (C14), 53.9 (OCH3), 119.2 (C8), 151.7 s (C9), 121.8 (C11), 131.4 (C12), 132.4 (C13), 149.8 (10)
21a	137.7	166.1	113.7	143.1	166.2	52.3 (OCH3), 66.0 (C10), 109.7 (C8), 119.2 (CN), 127.2, 127.6, 128.6, 144.9 (Ar), 147.6 (C11), 164.5 (C12)
21b	137.7	166.0	114.5	144.3	166.1	52.4 (OCH3), 34.6 (C9), 65.7 (C10), 109.6 (C8), 119.1 (CN), 147.9 (C11), 147.3, 125.2, 125.5 d, 127.0 (Cthienyl), 164.5 (C12)
21c	142.0 d	164.3 d	115.8 d	142.3 s	165.9 q	13.7 and 61.2 q (OCH2CH3), 52.5 q (OCH3), 35.1 d, 65.7 m, 106.7 d, 147.6 d (Cpyr), 118.7 s (CN), 147.2 m, 127.0 d, 125.2 d, 125.1 d (Cthienyl)	172.8	5.6

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In contrast to 5a, 5-mercapto-1,2,3-triazole-4-carboxamide does not react with DMAD and methyl propynoate. All our attempts to involve this compound in these reactions failed. We have shown that 5-mercapto substituted imidazole-4-thiocarboxamides can react with DMAD to form 2-imidazolylthiazolidines.¹² Therefore, we expected from the reaction of thioamide 5b with DMAD the formation of the products of type 6–9 from the condensation with both the exocyclic and endocyclic thioamide groups.

We have found that reaction of 5b with DMAD in methanol, either with or without sodium methoxide, affords a mixture of thiazine 6b and thiazolidine 7b in a ratio of 9 to 1 in 50% yield. The ¹H and ¹³C NMR spectra of products 6b, 7b are very similar to those of 7a and 7b (See Table 1). The downfield shift (0.5– 0.6 ppm) of the signals of C₈–H of 6b, 7b in comparison with the conjugated imidazolylthiazolidines¹² also confirmed the formation of fused imidazoles in this reaction. The ¹³C NMR spectra of 7a and 7b contain signals at 186.8 and 187.3 ppm corresponding to signals of the unchanged thioamide groups.

We have found that 5-mercapto-1,2,3-triazole-4-thiocarboxamides 10 are less active in the reaction with DMAD in comparison with 5-mercaptoimidazoles. Triazoles, that are unsubstituted at the ring nitrogen did not react either with DMAD or methyl propynoate. On the other hand 1-R-5-mercapto-1,2,3-triazoles reacted with both DMAD and methyl propynoate to form vinyl sulfide derivatives 11. The presence of two ester groups and a vinyl moiety in compounds 11 was confirmed by the presence of two signals in their ¹H NMR spectra at 3.45–3.76 ppm, signals at 6.69 and 6.70 in spectra of 11a,b respectively and of doublet signals at 6.10 and 7.25 with vicinal coupling constant of 8.6 Hz in spectra of 11c. We did not manage to react compounds 11a–c with a further equivalent of DMAD, although 11c smoothly reacted with o-nitrophenacyl bromide to give 2-triazolylthiazole 12 in 74% yield.

Indeed, reaction of DMAD with 5-mercaptoazole-4-thiocarboxamides 5b,10a,b preferably occurs with participation of the endocyclic thioamide group, similar to the reaction of these compounds with alkylating agents.^13,14 This can be rationalized by the existence of 5b,10 in a zwitterionic tautomeric form where the negative charge is located at the 5-sulfur atom which should enhance an electrophilic attack to this center.

In the reaction of 4-arylhydrazonopyrazole-5-thiones 13 with esters of acetylenecarboxylic acids one can theoretically expect the formation at least 4 products 15–18 because both thioamide and hydrazono groups of 13 are known to react with DMAD.^10–12,15 If we suppose that the most nucleophilic sulfur atom reacts first with the acetylene to form an intermediate vinylthioimidate of type 14 then the direction of its cyclization will govern the composition of the products 15–18.

We have found that compounds 13a–f readily react with DMAD and methyl propynoate to form 15a–f as the only products in good yields. The assignments of the structures of compounds 15 as pyrazolo[1,5-b]thiazin-4-ones follows from the analysis of their ¹H and ¹³C NMR spectra and from the reaction of 15d with sodium dithionite. Mass spectra, and decoupled ¹H and ¹³C NMR spectra did not allow one to make a difference between structures 15–18. At the same time, the similarity of the NMR spectra for the products obtained in the reaction of DMAD and methyl propynoate allowed us to assume that the same type of product was formed in both types of reactions. The spectrum of 15f shows two doublets as an AB system with a coupling constant of 10.6 Hz which is typical for a CH=CH moiety. The C₄ and C₇ signals in the coupled spectrum of 15d are found at δ = 154.9 ppm as doublets with a ²J_C4–H5 coupling constant of 0.6 Hz and at 161.9 ppm with ³J_C7–H5 of 3.8 Hz, respectively. These data allowed us to rule the structures 16 and 17 out of consideration, since one should observe an AB system in their spectra with a geminal constant of 18–22 Hz and a higher magnitude (2–5 Hz) for the coupling constant J_C4–H5.

An additional argument in favor of structure 15 was made from reduction of compound 15d by sodium dithionite. The arylhydrazino derivative 19 was obtained, and hydrazines are typical reduction products of arylazo compounds. This finally eliminates structures 17 and 18.

Thus, the novel imidazo[1,5-b]thiazin-4-ones 6a,b, pyrazolo[1,5-b]thiazin-4-ones 15a-f and imidazo[1,5-b]thiazole-4-ones 7a,b have been prepared by reactions of 5-mercaptoazoles with DMAD and methyl propynoate.

To study whether the size of the ring formed in the reaction of endocyclic thioamides with acetylene carboxylic esters depends on the type of ring in the starting compounds, we have carried out the reaction of 3,4-dihydropyridine-2(1H)-thiones 20a–c with DMAD.

Reaction of 2(1H)-pyridinethiones with DMAD is known to give thiazolo[3,2-a]pyridinium salts. At the same time, the reaction of 2(1H)-pyridinethiones with methyl propynoate results in the acyclic condensation products.^16–18 3,4-Dihydropyridin-2(1H)-ones have not been reacted with acetylene carboxylic acids so far.

By analogy with the reactions of malonthioamides and with the chemistry of the 5-mercaptoazoles mentioned above, one can expect the formation of both pyridothiazoles of type 21 and pyridothiazines 22 from the reaction of compounds 20 with DMAD. We have found that the reaction of pyridinethiones 20a–c with DMAD in chloroform in the presence of triethylamine selectively affords thiazolo[3,2-a]pyridines 21a–c in good yields. The structure assignment of the compounds prepared follows from their NMR spectra. ¹H NMR spectra of 21a–c show signals at 6.65–6.78 ppm and the coupled ¹³C NMR spectrum of 21c contains doublets of C₄ with a ³J_CH coupling constant of 5.6 Hz with the vinyl proton, and of C₇ with a ²J_CH coupling constant of less than 1.0 Hz with the same vinyl proton. This is in accordance with the presence of an exocyclic double bond in the structures of compounds 21a–c. Furthermore, the magnitude of the constant ³J_C4–H5 confirms the (Z)-configuration of this bond.

Conclusion

The data obtained allows us to make some conclusions. The size of the rings formed in the reactions of cyclic thioamides with acetylenecarboxylic esters depends on the size of the starting heterocycle. Thus, a five-membered thiazolidine ring condenses onto the pyridine ring and a six-membered thiazine ring is fused onto a five-membered azole ring. In contrast to all reactions of thioamides of various structures,^9–12 including reactions of pyridinethiones with DMAD where the thiazolidin-4-ones are formed exclusively, the reactions of 5-mercaptoazoles with acetylenecarboxylic esters lead to the preferred formation of a six-membered thiazine ring. This exception to the general rule can be explained by the increased ring strain for two fused five-membered rings compared to a situation where a six-and five-membered ring are fused. This also implies that the reactions are under thermodynamic rather than kinetic control.

Experimental

General

¹H and ¹³C spectra were recorded at 400 and 100 MHz, respectively on a Bruker AMX 400 with SiMe₄ as an internal reference in ether DMSO-d₆ + CCl₄ or CDCl₃ solutions. Mass spectra were obtained on a Varian MAT 311A instrument using the electron impact ionization technique (40–200 °C, 70 eV). Reactions were monitored by TLC (Silufol^®) on aluminium foil plates) in CHCl₃–EtOH (9 : 1), CHCl₃–EtOH–NH₄OH (15 : 8 : 1), acetone–hexane (3 : 5) visualized under UV light. All solvents were distilled prior to use.

General procedure. For reaction of 5-mercaptoazoles and pyridine-2-thiones with esters of acetylenecarboxylic and propiolic acids.

Method A. The acetylenecarboxylic ester (0.0015 mol) was added to a suspension of mercaptoheterocycle (0.001 mol) in methanol (10 mL). The reaction mixture was stirred at room temperature for 2–20 h until, according to TLC, all the starting materials had disappeared. On cooling, a precipitate was formed, that was filtered off and crystallized from methanol to afford the pure product.

Method B. The acetylenecarboxylic ester (0.0015 mol) was added to a solution of mercaptoheterocycle (0.001 mol) and sodium methoxide in methanol, which was prepared from Na (23 mg, 0.001 mol) and methanol (5 mL). The reaction mixture was stirred at room temperature for 8–10 h until, according to TLC, all the starting materials had disappeared. On cooling, a precipitate was formed, which was filtered off and the product was extracted with hot methanol. After cooling, the precipitate was collected.

Method C. The acetylenecarboxylic ester (0.0015 mol) was added to a suspension of mercaptoheterocycle (0.001 mol) in methanol (10 mL) or chloroform (10 mL) with triethylamine (0.001 mol). The reaction mixture was stirred at room temperature for 1–3 h until, according to TLC, all the starting material had disappeared. On cooling, a precipitate was formed, which was filtered off and crystallized from methanol to afford the pure product.

8-Carbamoyl-2-methoxycarbonyl-4-oxo-4H-imidazo[5,1-b][1,3]thiazine (6a). From 5-mercaptoimidazole-4-carboxamide 5a¹⁹ and DMAD. Yield 66% (method A), 43%. (method B). Yellow crystals, mp 218–221 °C. Mass spectrum, m/z (%): 253 (50) M⁺˙. Found, %: C 42.55; H 2.90; N 16.93; S 12.21. C₉H₇N₃O₄S. Calcd, %: C 42.69; H 2.79; N 16.60; S 12.65; δ_H (DMSO-d₆) 3.97 (3H, s, OCH₃), 7.24 (1H, s, = C₍₅₎H), 7.63 (1H, s, NH), 7.83 (1H, s, NH), 8.80 (1H, s, = C₍₈₎H).

Methyl 2-(7-carbamoyl-3-oxoimidazo[5,1-b]thiazol-2-ylidene) acetate (7a). From 5-mercaptoimidazole-4-carboxamide 5a and DMAD, method B. The precipitate, that was insoluble in hot methanol, was washed by methanol and dried. Yellow crystals, yield 60%. Mp 252–262 °C (decomp.). Mass spectrum, m/z (%): 253 (100) M⁺˙.Found, %: C 42.60; H 2.70; N 16.04; S 12.23. C₉H₇N₃O₄S. Calcd, %: C 42.69; H 2.79; N 16.60; S 12.65; δ_H (DMSO-d₆) 3.79 (3H, s, OCH₃), 7.07 (1H, s, = C₍₅₎H), 7.45 (1H, s, NH), 7.65 (1H, s, NH), 8.63 (1H, s, = C₍₈₎H).

2-Methoxycarbonyl-4-oxo-8-thiocarbamoyl-4H-imidazo[5,1-b][1,3]thiazine (6b) and methyl (3-oxo-7-thiocarbamoylimidazo[5,1-b]thiazol-2-ylidene) acetate (7b). Obtained as a mixture from 5-mercaptoimidazole-4-thiocarboxamide 5b¹⁹ and DMAD, yield 48% (method B). Yellow crystals, mp 268–270 °C (decomp.). Mass spectrum, m/z (%): 269 (100) M⁺˙. Found, %: C 40.40; H 2.69; N 15.29; S 23.88. C₉H₇N₃O₃S₂. Calcd, %: C 40.14; H 2.62; N 15.60; S 23.81; 6bδ_H (DMSO-d₆) 3.97 (3H, s, OCH₃), 7.27 (1H, s, = C₍₅₎H), 8.86 (1H, s, = C₍₈₎H), 9.41 (1H, s, NH), 9.70 (1H, s, NH); 7bδ_H (DMSO-d₆) 3.76 (3H, s, OCH₃), 6.93 (1H, s, = C₍₅₎H), 8.70 (1H, s, = C₍₈₎H), 9.42 (1H, s, NH), 9.70 (1H, s, NH).

Dimethyl 2-(3-methyl-5-thiocarbamoyl-3H-[1,2,3]triazol-4-ylthio)but-2-enedioate (11a). From 1-methyl-5-mercapto-1,2,3-triazole-4-thiocarboxamide 10a²⁰ and DMAD, yield 43% (method A). Yellow crystals, mp 175–178 °C. Mass spectrum, m/z (%): 316 (60) M⁺˙. Found, %: C 37.70; H 3.91; N 17.72; S 20.65. C₁₀H₁₂N₄O₄S₂. Calcd, %: C 37.97; H 3.82; N 16.70; S 20.27; δ_H (DMSO-d₆) 3.48 (3H, s, OCH₃), 3.76 (1H, s, OCH₃), 4.08 (3H, s, NCH₃), 6.69 (1H, s, =CH), 9.50 (1H, s, NH), 9.72 (1H, s, NH).

Dimethyl 2-(5-thiocarbamoyl-3-phenyl-3H-[1,2,3]triazol-4-ylthio)but-2-enedioate (11b). From 1-phenyl-5-mercapto-1,2,3-triazole-4-thiocarboxamide 10b²⁰ and DMAD, yield 44% (method A). Yellow crystals, mp 100–105 °C (ethanol). Found, %: C 47.85; H 3.91; N 14.44; S 17.32. C₁₅H₁₄N₄O₄S₂. Calcd, %: C 47.61; H 3.73; N 14.81; S 16.93; δ_H (DMSO-d₆) 3.45 (3H, s, OCH₃), 3.74 (3H, s, OCH₃), 6.70 (1H, s, =CH), 7.20–7.45 (5H, m, Ph), 9.53 (1H, s, NH), 9.79 (1H, s, NH).

Methyl 2-(3-methyl-5-thiocarbamoyl-3H-[1,2,3]triazol-4-ylthio)acrylate (11c). From 1-methyl-5-mercapto-1,2,3-triazole-4-thiocarboxamide 10a and methyl propynoate, yield 43% (method A). Yellow crystals, mp 167–170^oC (from ethanol). Mass spectrum, m/z (%): 258 (71) M⁺˙. Found, %: C 36.78; H 4.0; N 22.14. C₈H₁₀N₄O₂S₂. Calcd, %: C 37.2; H 3.88; N 21.71; δ_H (DMSO-d₆) 3.78 (3H, s, OCH₃), 4.04 (3H, s, NCH₃), 6.10(1H, d, J = 8.6 Hz, =CH), 7,25 (1H, d, 8.6, =CH), 9.56 (1H, s, NH), 9.80 (1H, s, NH).

Methyl 2-{3-methyl-5-[4-(2-nitrophenyl)thiazol-2-yl]-3H-[1,2,3]triazol-4-ylthio}acrylate (12). 0.245 g (0.001 mol) o-nitrophenacyl bromide was added to a suspension of 0.316 g (0.001 mol) triazole 11c in 10 mL ethanol. The reaction mixture was refluxed for 1 h. After cooling, the precipitate was filtered off. The product was crystallized from ethanol. Yield 74%, mp 180–183 °C. Found, %: C 47.62; H 3.50; N 17.74; S 16.32. C₁₆H₁₅N₅O₄S₂. Calcd, %: C 47.63; H 3.25; N 17.36; S 15.88; δ_H (DMSO-d₆) 3.79 (3H, s, OCH₃), 4.14 (3H, s, NCH₃), 6.19(1H, d, J = 9.6, =CH), 7.40 (1H,d, J = 9.6 Hz, =CH), 7.73 (1H, t, ArH), 8.15–8.22 (1H, m, ArH), 8.35–8.41 (1H, m, ArH), 8.50 (1H, s, H_thiazole), 8.77 (1H, t, ArH).

5-Methoxycarbonyl-3-(4-methoxyphenylazo)-2-methyl-7-oxo-7H-pyrazolo[5,1-b][1,3]thiazine (15a). From pyrazole 13a and DMAD in methanol by method C, yield 73%, mp 218–220 °C. Found, %: C, 53.81; H, 4.01; N, 15.71; S, 9.00. C₁₆H₁₄N₄O₄S. Calcd, %: C, 53.63; H, 3.91; N, 15.64; S, 8.94; δ_H (DMSO-d₆) 2,59 (3H, s, Me), 3.89 (3H, s, OMe), 4.0 (3H, s, COOMe), 7.33 (1H, s, C₍₅₎H), 7.81 and 7.04 (4H, AA′XX′, J = 9.3 Hz, ArH).

5-Methoxycarbonyl-2-methyl-7-oxo-3-p-tolylazo-7H-pyrazolo[5,1-b][1,3]thiazine (15b). From pyrazole 13b and DMAD in methanol by method C, yield 80%, mp 183–185 °C. Found, %: C, 56.25; H, 4.12; N, 16.52; S, 9.50. C₁₆H₁₄N₄O₃S. Calcd, %: C, 56.14; H, 4.09; N, 16.37; S, 9.36; δ_H (DMSO-d₆) 2,44 (3H, s, Me), 2.70 (3H, s, Me), 3.99 (3H, s, COOMe), 7.36 (1H, s, C₍₅₎H), 7.74 and 7.33 (4H, AA′XX′, J = 8.0 Hz, ArH).

5-Methoxycarbonyl-2-methyl-7-oxo-3-phenylazo-7H-pyrazolo[5,1-b][1,3]thiazine (15c). From pyrazole 13c and DMAD by method C, yield 69%, mp 198–200 °C. Found, %: C, 55.01; H, 3.71; N, 17.07; S, 9.81. C₁₅H₁₂N₄O₃S. Calcd, %: C, 54.85; H, 3.66; N, 17.15; S, 9.76; δ_H (DMSO-d₆) 2,71 (3H, s, Me), 3.99 (3H, s, COOMe), 7.52 (1H, s, C₍₅₎H), 7.3–7.26 (3H, m, ArH), 7.84 (2H, dd, J = 8.3, J = 2.3 Hz, ArH).

3-(4-Chlorophenylazo)-2-methyl-7-oxo-7H-pyrazolo[5,1-b][1,3]thiazine-5-carboxylic acid methyl ester (15d). From pyrazole 13d and DMAD by method C, yield 85%, mp 224–226 °C. Found, %: C, 49.83; H, 3.10; N, 15.37; S, 8.75. C₁₅H₁₁ClN₄O₃S. Calcd, %: C, 49.66; H, 3.03; N, 15.45; S, 8.83; δ_H (DMSO-d₆) 2.71 (3H, s, Me), 3.99 (3H, s, COOMe), 7.39 (1H, s, C₍₅₎H), 7.85 and 7.54 (4H, AA′XX′, J = 8.8 Hz, ArH).

3-(4-Ethoxycarbonylphenylazo)-5-methoxycarbonyl-2-methyl-7-oxo-7H-pyrazolo[5,1-b][1,3]thiazine (15e). From pyrazole 13e and DMAD by method C, yield 71%, mp 195–197 °C. Found, %: C, 53.82; H, 3.93; N, 14.10; S, 7.93. C₁₈H₁₆N₄O₅S. Calcd, %: C, 54.00; H, 4.00; N, 14.00; S, 8.00; δ_H (DMSO-d₆) 1.41 (3H, t, 7.0, CH₂CH₃), 2.72 (3H, s, Me), 4.00 (3H, s, COOMe), 4.37 (2H, q, J = 7.0 Hz, OCH₂), 7.39 (1H, s, C₍₅₎H), 8.09 and 7.88 (4H, AA′XX′, J = 8.5 Hz, ArH).

3-(4-Chlorophenylazo)-2-methyl-7H-pyrazolo[5,1-b][1,3]thiazin-7-one (15f). From pyrazole 13d and methyl propynoate in ethanol by method C, yield 73%, mp 248–249 °C. Found, %: C, 51.40; H, 3.11; N, 18.10; S, 10.71. C₁₈H₁₆N₄O₅S. Calcd, %: C, 51.23; H, 2.96; N, 18.39; S, 10.51; δ_H (CDCl₃) 2.81 (3H, s, Me), 7.73 and 6.85 (2H, AA′XX′, J = 10.6 Hz, C₍₅₎H +C₍₆₎H), 7.84 and 7.49 (4H, AA′XX′, J = 8.4 Hz, ArH).

5-Methoxycarbonyl-2-methyl-7-oxo-3-(2-phenylhydrazino)-7H-pyrazolo[5,1-b][1,3]thiazine (19). A mixture of sodium dithionite (0.4 g, 0.0023 mol) and azo compound 15c (0.3 g, 0.0009 mol) in acetone (40 mL) and water (10 mL) was refluxed for 3 hours. The solvents were evaporated and the residue was crystallized from MeOH–DMF. Yield 30%, mp 175–176 °C. Found, %: C, 54.55; H, 4.24; N, 16.97; S, 9.70. C₁₅H₁₄N₄O₃S. Calcd, %: C, 54.40; H, 4.11; N, 17.14; S, 9.91; δ_H (DMSO-d₆) 2.34 (3H, s, Me), 3.88 (3H, s, COOMe), 6.82 (1H, dd, J = 7.5, J = 7.3 Hz, H₁₇), 6.84 (2H, d, J = 7.5 Hz, H₁₃, H₁₄), 7.01(1H, s, C₍₅₎H), 7.14 (2H, dd, J = 7.5, J = 7.3 Hz, H₁₅H₁₆), 7.44 (1H, s, NH), 7.80 (1H, s, NH).

Methyl (5-amino-8-carbamoyl-3-oxo-7-phenyl-6-cyano-7H-thiazolo[3,2-a]pyridin-2-ylidene)acetate (21a). From pyridinethione 20a²¹ and DMAD in chloroform, yield 42% (method C). Yellow crystals, mp 305–307 °C. Found, %: C 56.56; H 3.75; N 14.60; S 8.95. C₁₈H₁₄N₄O₄S. Calcd, %: C 56.54; H 3.69; N 14.69; S 8.41; δ_H (DMSO-d₆) 3.81 (3H, s,OCH₃), 4.76 (1H, s, CH), 6.66 (1H, s, C₍₅₎H), 7.25–7.35 (5H, m, ArH), 7.27 (2H, s NH₂).

Methyl (5-amino-8-carbamoyl-3-oxo-7-thienyl-6-cyano-7H-thiazolo[3,2-a]pyridin-2-ylidene)acetate (21b). From pyridinethione 20b²¹ and DMAD in chloroform, yield 71% (method C). Yellow crystals, mp 292–295 °C. Found, %: C 49.55; H 3.02; N 14.93; S 16.00. C₁₆H₁₂N₄O₄S₂. Calcd, %: C 49.48; H 3.11; N 14.42; S 16.51; δ_H (DMSO-d₆) 3.80 (3H, s, OCH₃), 5.18 (1H, s, CH), 6.67 (1H, s, =C₍₅₎H), 6.92–6.94 (1H, m, H_thienyl), 7.03–7.04 (1H, m, NH), 7.28–7.31 (2H, m, H_thienyl), 7.33 (1H, s, NH), 7.43 (2H, s, NH₂).

Methyl (5-amino-8-ethoxycarbonyl-3-oxo-7-thienyl-6-cyano-7H-thiazolo[3,2-a]pyridin-2-ylidene)acetate (21c). From pyridinethione 20c²² and DMAD in chloroform, yield 48% (method C). Yellow crystals, mp 249–252 °C. Found, %: C 51.98; H 3.55; N 10.51; S 14.95. C₁₈H₁₅N₃O₅S. Calcd, %: C 51.79; H 3.62; N 10.06; S 15.36; δ_H (DMSO-d₆) 1.21 (3H, t, CH₃), 3.83 (3H, s, OCH₃), 4.18 (2H, q, CH₂), 4.86 (1H, s, CH), 6.77 (1H, s, =C₍₅₎H), 6.90–6.95 (2H, m, H_thienyl), 7.25–7.30 (1H, m, H_thienyl), 7.35 (2H, s, NH₂).

General method for the synthesis of arylazopyrazolethiones 13a-e

Arylazopyrazolones²³ (0.004 mol) were refluxed about 30 min in toluene (50 mL) with Lawesson's reagent (0.0022 mol). The solution was cooled and the solid filtered off. The product was crystallized from ethanol.

4-(4-Methoxyphenylazo)-5-methyl-2,4-dihydropyrazole-3-thione (13a). Yield 81%, mp 201–202 °C. Mass spectrum, m/z (%): 248 (78) M⁺˙.Found, %: C 53.45; H 4.77; N, 22.58; S, 12.90. C₁₁H₁₂N₄OS. Calcd, %: C 53.21; H 4.87; N, 22.67; S, 13.00; δ_H (DMSO-d₆) 2.26 (3H, s, Me), 3.89 (3H, s, OMe), 7.52 and 7.01 (4H, AA′BB′, J = 8.8 Hz, ArH), 12.99 (1H, s, NH), 16.78 (1H, s, NH).

4-(4-Methylphenylazo)-5-methyl-2,4-dihydropyrazole-3-thione (13b). Yield 85%, mp 190–193 °C. Mass spectrum, m/z (%): 232 (50) M⁺˙.Found, %: C 56.69; H 5.37; N, 24.14; S, 13.79. C₁₁H₁₂N₄S. Calcd, %: C 56.87; H 5.21; N, 24.03; S, 13.86; δ_H (DMSO-d₆) 2.38 (3H, s, Me), 2.53 (3H, s, Me), 7.59 and 7.27 (4H, AA′BB′, J = 8.8 Hz, ArH), 13.00 (1H, s, NH), 16.70 (1H, s, NH).

4-Phenylazo-5-methyl-2,4-dihydropyrazole-3-thione (13c). Yield 83%, mp 171–172 °C. Mass spectrum, m/z (%): 218 (75) M⁺˙. Found, %: C 55.15; H 4.80; N, 25.69; S, 14.68. C₁₀H₁₀N₄S. Calcd, %: C 55.03; H 4.62; N, 25.71; S, 14.90; δ_H (DMSO-d₆) 2.26 (3H, s, Me), 7.27 (1H, dd, J-7.5, J = 7.3 Hz, ArH), 7.44 (2H, dd, J = 7.5, J = 7.3 Hz, ArH), 7.56 (2H, d, J = 7.7 Hz, ArH), 13.03 (1H, s, NH), 16.58 (1H, s, NH).

4-(4-Chlorophenylazo)-5-methyl-2,4-dihydropyrazole-3-thione (13d). Yield 93%, mp 205–208 °C. Mass spectrum, m/z (%): 252 (85) M⁺˙. Found, %: C 47.33; H 3.88; N, 22.18; S, 12.67. C₁₀H₉ClN₄S. Calcd, %: C 47.53; H 3.59; N, 22.11; S, 12.80; δ_H (DMSO-d₆) 2.30 (3H, s, Me), 7.75 and 7.56 (4H, AA′BB′, J = 8.8 Hz, ArH), 13.10 (1H, s, NH), 16.55 (1H, s, NH).

4-(4-Ethoxycarbonylphenylazo)-5-methyl-2,4-dihydropyrazole-3-thione (13e). Yield 85%, mp 195–197 °C. Mass spectrum, m/z (%): 290 (89) M⁺˙.Found, %: C 54.01; H 4.98; N, 19.31; S, 11.09. C₁₃H₁₄N₄O₂S. Calcd, %: C 53.78; H 4.86; N, 19.54; S, 11.35; δ_H (DMSO-d₆) 1.38 (3H, q, J = 7.0 Hz, CH₂CH₃), 2.26 (3H, s, Me), 4.32 (2H, q, J = 7.0 Hz, CH₂CH₃), 8.02 and 7.60 (4H, AA′BB′, J = 9.0 Hz, ArH), 13.21 (1H, s, NH), 16.43 (1H, s, NH).

Acknowledgements

W. D. thanks the F. W. O.-Vlaanderen, the Ministerie voor Wetenschapsbeleid and the University of Leuven for financial support. V. S. B. and V. A. B. thank the Russian Foundation for Basic Research (grant 01-03-33173) and CRDF (grant Rec 005).

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