Microwave Assisted Synthesis and Unusual Coupling of Some Novel Pyrido[3,2-f][1,4]thiazepines

3-Amino-3-thioxopropanamide (1) reacted with ethyl acetoacetate to form 6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide (2), which reacted with α-haloketones 3 to produce 2,3-disubstituted-8-hydroxy-6-methyl-2H,5H-pyrido[3,2-f]-[1,4]thiazepin-5-ones 4a-c. Benzoylation of 4c led to the formation of the dibenzoate derivative 9. Compounds 4a-c could be prepared stepwise through the formation of S-alkylated derivatives 10a-c. Compounds 2, 4a-c, 9 and 10a-c were prepared using microwave as a source of heat, and gave better yields in shorter times than those achieved by traditional methods. Coupling of 4a-c with arenediazonium chlorides proceeded unusually to give the 6-hydroxy-4-methyl-2-(arylazo)thieno[2,3-b]pyridin-3(2H)-one ring contraction products 14. Structures of the newly synthesized compounds were proven by spectral and chemical methods.

This product was found to be different in all aspects (m.p., mixed m.p. and IR) from the reaction product 4c, obtained by the reaction between 2 and 3c in acetic acid. Our original aim was to synthesize the thiazolopyridine-8-carbonitrile 8 by reacting 6 with phenacyl bromide in polyphosphoric acid, and then to hydrolyze product 8 to obtain 5c. Instead we found that hydrolysis of the carbonitrile group into carboxamide took place directly and 5c was eventually obtained (Scheme 2). A further confirmation of structure 4 could be obtained by reacting 4c, as a representative, with an excess of benzoyl chloride in pyridine to obtain the dibenzoate derivative 9. It is clear that benzoylation is only possible for compound 4c and not for structure 5. When 2 was reacted with each of 3a-c by boiling in ethanolic potassium hydroxide, the S-alkylated derivatives 10a-c were obtained in poor yields. Compounds 10a-c could be cyclized by heating with acetic anhydride in pyridine to give 4a-c, respectively (Scheme 1).

Scheme 2.
Independent route for the formation of 5c.
Our research group has recently [12] been interested in performing synthesis of some heterocyclic compounds under the environmentally friendly, time saving microwave-assisted conditions. Accordingly, we re-synthesized the previously described compounds 2, 4a-c, 9 and 10a-c under microwave conditions, aiming to increase reaction yields and reduce the reaction times. The results of these preparation indicated that reaction yields increased by 20-30% compared to the traditional conditions. Reaction times were also significantly reduced. Table 1 summarizes the benefits of using microwave conditions for the synthesis of the above-mentioned compounds.
Compound 4c underwent bromination upon treatment with bromine in acetic acid to give 7-bromo-6-methyl-3-phenyl-4,5,8,9-tetrahydropyrido[3,2-f] [1,4]thiazepine-5,8-dione (11) (Scheme 3) The occurrence of bromination at C7 was proved by studying 1 H-NMR spectrum of 11, which revealed the disappearance of the signal that originally existed in 4c at δ6.30 ppm. On the other hand, coupling of 4a-c with arenediazonium chlorides in pyridine/potassium hydroxide took place in an unexpected manner to produce 14a-c. As an example, treatment of 4a or 4c with benzenediazonium chloride gave one and the same reaction product. The mass spectrum and elemental analysis of the reaction product showed that its molecular formula was C 14 H 11 N 3 O 2 S, and could be formulated to be 6-hydroxy-4-methyl-2-(phenylazo)thieno [2,3-b]pyridin-3(2H)-one (14a). If coupling took place at either C2 or C7 with no further modification, we would have obtained compounds 15a or 16a, respectively, each of which has the molecular formula C 16 H 14 N 4 O 2 S or 15b or 16b, which would have the molecular formula C 21 H 16 N 4 O 2 S. As a possible sequence for the formation of 14a from 4a,c, the latter compounds firstly underwent coupling at position 2 to give the corresponding 2-arylazo derivative, 12. Compound 12 underwent hydrolysis and gave 13 which underwent cyclization followed by deacylation to give 14a, as shown in Scheme 3.
Surprisingly, coupling of 4b with benzenediazonium chloride yielded the same reaction product 14a. The reaction may have proceeded firstly via coupling at position 2 to give the corresponding 2-phenylazo derivative 17 which underwent deacylation (Japp-Klingemann reaction) to give compound 12a. The latter compound underwent hydrolysis then cyclization followed by deacylation to give 14a as described in Scheme 4.

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) was prepared according to a literature procedure [10].
Method B: The same reactants of method A were heated in the microwave apparatus at 500 w and 140 °C for 15 min. The reaction mixture was treated in a similar manner to method A to afford compound 2. Compound 2 was obtained as white crystals in 55% yield (Method A) and 82% yield
Method B: The same reactants of method A were heated in microwave at 500 w and 140 °C for 30 min. The reaction mixture was treated in a similar manner to method A to give compounds 4a-c. [3,2- (7) Compound 6 (1.66 g, 0.01 mol, [11]) was dissolved in a warm ethanolic potassium hydroxide solution [prepared by dissolving 0.56 g (0.01 mol) of potassium hydroxide in 50 mL of ethanol]. Then 3c (1.99 g, 0.01 mol) was added. The mixture was refluxed for two hours, then cooled and poured into water. The solid so-formed was filtered off and recrystallized from dilute dimethylformamide to obtain white crystals in 73% yield, m.p. 211-212 °C. 1
Method B: The same reactants of method A were heated in microwave at 500 w and 90 °C for 5 min. The reaction mixture was treated in a similar manner to method A to obtain compounds 10a-c.    [3,2-f] [1,4]thiazepine-5,8(4H,9H)-dione (11) To a solution of 4c (2.84 g, 0.01 mol) in glacial acetic acid (50 mL), bromine (0.5 mL, 0.01 mole) was added dropwise with stirring at room temperature under sunlight. The mixture was then stirred at water bath 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 dilute dimethylformamide to afford 11 as white crystals in 73% yield; m.p. 310-311 °C.

Conclusions
Several new 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.