Bromination and Diazo-Coupling of Pyridinethiones; Microwave Assisted Synthesis of Isothiazolopyridine, Pyridothiazine and Pyridothiazepines

Isothiazolopyridines, pyridothiazines and pyridothiazepines are important compounds that possess valuable biological activities. This paper reports on the synthesis of these compounds using both conventional chemical methods and modern microwave techniques. 3-Bromo-6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide, 5-arylazo-6-hydroxy-4-methyl-2-thioxo-1,2-dihydropyridine-3-carboxamides, 3,5-bis-arylazo-6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-caboxamide, 4-methyl-2,3,6,7-tetra-hydroisothiazolo[5,4-b]-pyridine-3,6-dione, 2,2'-(methylene-bis-(sulfanediyl))bis(4-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide), 2-hydroxy-5-methyl-4H-pyrido[3,2-e][1,3]-thiazine-4,7(8H)-dione and 2-arylmethylene-8-hydroxy-6-methyl-2,3,4,5-tetrahydropyrido-[3,2-f][1,4]thiazepine-3,5-diones have been prepared from 6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide. Some of these compounds were prepared using microwave-assisted reaction conditions, that provided higher yields in shorter times than the conventional methods.


Introduction
In continuation of our research groups' work in the field of synthetic organic chemistry [1][2][3][4][5]; we would like to report here on the annulation of isothiazole, 1,3-thiazine and 1,4-thiazepine ring systems to pyridine. Promising biological activities are reported in the literature concerning the targeted ring systems: Isothiazolo [5,4-b]pyridines could be used as analgesics [6,7] and as CNS and antimicrobial agents [8], pyrido [3,2-e] [1,3]thiazines could be used as CNS and antioxidant agents [9] and as analgesic agents [10] and pyrido [3,2-f]- [1,4]-thiazepines were used as calcium antagonists in both cardiac and smooth muscles [11] and as channel blockers for treatment of cardiovascular diseases [12]. Microwave-assisted technique offer several advantages over conventional methods of synthesis. Reduced reaction times [13][14][15], less effects on the environment and better reaction yields are some of the common advantages of using microwave irradiation. In the present research project, we used both the microwave technique as well as conventional methods to prepare the targeted compounds with expected biological activity.
Our preference for structure 3 for the reaction product was based on the comparison of both the 1 H-NMR and 13 C-NMR spectra (DMSO-d 6 ) of 2 and 3. In the 1 H-NMR spectrum of 2, there are two signals at δ 5.24 and δ 6.10 ppm corresponding to the pyridine-H3 and pyridine-H5, respectively. The 1 H-NMR spectrum of the reaction product revealed a signal at δ 6.12 ppm corresponding to the pyridine-H5. The 13 C-NMR spectrum of 2 showed two signals at δ 71.5 and δ 112.1 ppm corresponding to C3 and C5, respectively. The reaction product showed two signals at δ 91. 3 and 111.8 ppm corresponding to the same carbon atoms. The downfield shift of C3 indicates that bromination took place on this carbon atom, favouring structure 3 for the reaction product. The reaction product assigned structure 3 was most probably due to an initial protonation on the amide carbonyl that leads to higher activity of position 3 in compound 2, and so the formation of the kinetically controlled product 3 is favoured.
Attempts to couple compound 3 with benzenediazonium chloride to produce 4 have all failed, most probably due to lack of aromaticity in compound 3. In contrast to the reaction of bromine with compound 2, the latter compound coupled with some arenediazonium salts at position 5 to give the monoarylazo derivatives. Thus, treatment of 2 with equimolar amounts of some arenediazonium salts yielded 5-arylazo-6-hydroxy-4-methyl-2-thioxo-1,2-dihydropyridine-3-carboxamides 5a-c (Scheme 1). Structure 5 for the reaction product was based on a comparison between the 1 H-NMR spectra of 2 and 5a that revealed the disappearance of the signals at δ 5.24 & 6.10 ppm in 5a. The disappearance of the second one indicates that substitution takes place at position 5, while disappearance of the first one is due to tautomerization and appearance of a D 2 O exchangeable signal at δ 12.86 ppm. Also, the 13 C-NMR spectrum of compound 2 showed signals at 71.5 and 112.1, corresponding to C-3 and C-5, respectively. The same two carbons in 5a showed signals at 72.3 and 123.8, respectively. The downfield shift of C-5 signal indicates that substitution took place at this carbon atom. As further evidence, the monoarylazo derivatives 5a,b could be coupled with some arenediazonium salts to give bisarylazo derivatives (see below). An alternative ipso attack structure would have no aromaticity and would not undergo further coupling.
The selection of structure 11 was based firstly on the 1 H-NMR spectrum of the reaction product that showed two types of exchangeable protons at δ 7.92 and 11.10 ppm. Secondly, structure 11 behaves like a typical 2-hydroxypyridine and couples with arenediazonium salts to give the 7-arylazoderivatives 14, (see below). Moreover, compounds 11a,b could also be synthesized in a stepwise fashion. Thus, heating under reflux compound 2 with chloroacetic acid in acetic acid solution in the presence of sodium acetate, yielded 2-[(3-carbamoyl-6-hydroxy-4-methylpyridin-2-yl)thio]acetic acid (12, Scheme 3).
Our research group has recently [17][18][19] been interested in performing synthesis of some heterocyclic compounds under environmentally friendly, time saving microwave-assisted conditions. Accordingly, we re-synthesized the previously described compounds 8, 10, 11a,b, 12 and 13 under microwave conditions, aiming to increase reaction yields and reduce the reaction times. The results of these preparations indicated that reaction yields were increased by 17-23% compared to the conventional conditions. Reaction times were also significantly reduced. Table 1 summarizes the benefits of using microwave conditions for the synthesis of the above-mentioned compounds.

General
Melting points were determined in open glass capillaries on a Gallenkamp melting point apparatus and are uncorrected. IR spectra (KBr discs) were recorded on a Shimadzu FTIR-8201PC spectrophotometer. 1 H-NMR and 13 C-NMR spectra were recorded on a Varian Mercury 300 MHz and Varian Gemini 200 MHz spectrometers using TMS as an internal standard and DMSO-d 6 as solvent. Chemical shifts were expressed as δ (ppm) units. Mass spectra were recorded at 70 eV on a Shimadzu GCMS-QP1000EX using an inlet type injector. All reactions were followed by TLC (silica gel, aluminum sheets 60 F254, Merck). The Microanalytical Center of Cairo University performed the microanalyses. Microwave reactions were performed with a Millstone Organic Synthesis Unit (MicroSYNTH with touch control terminal) with a continuous focused microwave power delivery system in a pressure glass vessel (10 mL) sealed with a septum under magnetic stirring. The temperature of the reaction mixture was monitored using a calibrated infrared temperature control under the reaction vessel, and control of the pressure was performed with a pressure sensor connected to the septum of the vessel. 3-Amino-3-thioxopropanamide [monothiomalonamide (1)] and 6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide (2) were prepared according to literature procedures [16,17]. Reported 1 H-NMR and 13 C-NMR of 2 [14] are given for comparison: 1

5-Arylazo-6-hydroxy-44-methyl-2-thioxo-1,2-dihydropyridine-3-carboxamides 5a-c
General procedure: To a cold solution of 2 (1.84 g, 0.01 mole) in pyridine (50 mL), containing 0.3 g potassium hydroxide, the arenediazonium chloride (0.01 mole) [prepared by adding concentrated hydrochloric acid (3 mL) to aromatic amine (0.01 mol) at 0 °C and treating the resulting hydrochloride with a cold solution of sodium nitrite (0.69 g, 0.01 mol) in water (5 mL)] was added dropwise with stirring at 0 °C. The coupling mixture was stirred at room temperature for two hours and then diluted with water (30 mL). The resultant crude product thus precipitated was collected by filtration, washed with water, dried and crystallized from the proper solvent.   13

3,5-Bis-arylazo-6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamides 6a-d
Route A: To a cold solution of 5 (0.01 mole) in pyridine (50 mL), containing potassium hydroxide (0.3 g), the arenediazonium chloride (0.01 mole) [prepared by adding concentrated hydrochloric acid (3 mL) to aromatic amine (0.01 mol) at 0 °C and treating the resulting hydrochloride with a cold solution of sodium nitrite (0.69 g, 0.01 mol) in water (5 mL)] was added dropwise with stirring at 0 °C. The coupling mixture was stirred at room temperature for two hours and then diluted with water (30 mL). The resultant crude product thus precipitated was collected by filtration, washed with water, dried and crystallized from the proper solvent.    Route B: To a cold solution of 2 (0.92 g, 0.005 mole) in pyridine (50 mL), containing potassium hydroxide (0.3 g), the arenediazonium chloride (0.01 mole) [prepared by adding concentrated hydrochloric acid (3 mL) to aromatic amine (0.01 mol) at 0 °C and treating the resulting hydrochloride with a cold solution of sodium nitrite (0.69 g, 0.01 mol) in water (5 mL)] was added dropwise with stirring at 0 °C. The coupling mixture was stirred at room temperature for two hours and then diluted with water (30 mL). The resultant crude product thus precipitated was collected by filtration, washed with water, dried and crystallized. Compound 6c was thus obtained in 93% yield and matched the same compound prepared by Route A in every aspect (m.p., mixed m.p. and IR spectrum). Compound 6d was thus obtained in 96% yield and matched the same compound prepared by Route A in every aspect (m.p., mixed m.p. and IR spectrum). [5,4-b]pyridine-3,6-dione (7) To a solution of 2 (1.84 g, 0.01 mole) in ethanol (50 mL), in the presence of potassium hydroxide (0.56 g, 0.01 mole), potassium ferricyanide (2.5 g, 0.01 mol) was added dropwise with stirring at room temperature. The mixture was then stirred at room temperature for two hours and then diluted with cold water (30 mL). The resultant crude product thus precipitated was collected by filtration, washed with water, dried and crystallized from dimethylformamide to afford 7 in 80% yield as a white powder; m.p. 292 °C; IR ν: 3420 (NH) and 1681 and 1636 (2 CO); 1 H-NMR: 2.42 (s, 3H, CH 3 ), 6.11 (s, 1H, pyridine-H5), 11.37 (br.s, 2H, 2 NH, D 2 O exchangeable); 13

2,2'-(Methylene-bis(sulfanediyl))bis(4-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide) (8)
Method A: To a solution of 2 (1.84 g, 0.01 mol) in ethanol (50 mL) in the presence of potassium hydroxide (0.56 g, 0.01 mol), methylene iodide (0.53 mL, 0.005 mol) was added dropwise with stirring at room temperature. The mixture was then stirred under reflux for two hours and then diluted with cold water (30 mL). The resultant crude product thus precipitated was collected by filtration, washed with water, dried and crystallized from dioxane to afford 8. Method B: The same reactants of method A were heated under microwaves at 500 W and 140 °C for 5 min. The reaction mixture was treated in a similar manner to method A to give compound 8.

Conclusions
Several new isothiazolopyridines, pyridothiazines and pyridothiazepines have been synthesized using both traditional methods and microwave assisted conditions. The latter methods proved much more efficient in reducing reaction times as well as increasing the overall yield of the reactions. Structures of the newly synthesized compounds were proven by both spectral and chemical methods.