Cyanothioacetamide in Heterocyclic Synthesis: A New Approach for the Synthesis of 2-Pyridothione and 2-Pyridazinothione Derivatives

Transcription

1 Cyanothioacetamide in Heterocyclic Synthesis: A New Approach for the Synthesis of 2-Pyridothione and 2-Pyridazinothione Derivatives R. M. M ohareb and S. M. Fahmy* Chemistry D epartm en t, Faculty o f Science, Cairo University, Giza, Egypt Z. N aturforsch. 41b, (1986); received July 8, 1985 Heterocyclic Synthesis, C yanothioacetam ide, Pyridazine Derivatives Cyanothioacetam ide (1) undergoes self condensation to give 4,6-diamino-3-cyano-2-pyridothione (2). The latter was utilised in synthesis of pyrido[2,3-c]pyrazole, pyrido[2,3-d]pyrim idine, bis-(pyridothione derivatives) through reaction with hydrazine hydrate, ethoxycarbonyl isothiocyanate and cinnam onitrile derivatives. Also 1 undergoes self dimerisation to give 13, the latter form the pyridazine derivative on coupling with benzenediazonium chloride. As a part of our program dealing with the scope and limitations of the use of activated nitriles in heterocyclic synthesis [1 3]. The title reagent seems very suitable for our purpose as it is known to be of high potential activity [4]. Recently we have reported for the self condensation of two moles of cyanothio acetam ide (1) in presence of sodium ethoxide to give 4,6-diamino-3-cyano-2-pyridothione (2). Now we found that 2 reacts with hydrazine hydrate to give the hydrazone derivative 3. On the o ther hand, conduct ing the reaction in dimethylform am ide instead of ethanol a pyrido[2,3-c]pyrazole derivative 4 is ob tained. Com pound 4 can also be obtained via refluxing of 3 in dim ethylform amide. Structures of com pounds 3 and 4 were established based on analytical and spectral data. 2 reacts with ethoxycarbonyl isothiocyanate to give a pyrido[2,3-d]pyrimidine derivative 6 through cyclisation of the non-isolable adduct 5. Structure of com pound 6 was established based on analytical and spectral data. 2 reacts with benzylidene m alononitrile (7) to give a product of molecular formula C9H 8SN6. Two pos sible isomeric structures 8 an 9 were proposed for the reaction product. Structure 9 was assigned for the reaction product based on spectral data in IR spectrum revealed only one CN stretching band at 2220 cm -1.!H N M R spectrum revealed the p re sence of six D 20 exchangeable protons four of which appear at d ppm, the other two at ppm assigned for the three am ino functions, * R eprint requests to Prof. D r. S. M. Fahmy. V erlag der Zeitschrift für N aturforschung, D-7400 Tübingen /86/ /$ 01.00/0 and a multiplet at < ppm corresponds for ylidene CH and phenyl protons. However, structure of compound 9 was strictly confirmed via identifica tion with an authentic sample prepared via reaction of 10 (recently we reported its synthesis [5]) with benzaldehyde. On the other hand, 2 reacts with benzylidene ethylcyanoacetate (11a) and ethoxym ethylene ethylcyanoacetate ( lib ) to give the corresponding bis(pyridothione) derivatives 12a and 12b, respectively; such ylidene group exchange has been previously re ported [6]. Structures of compounds 12 a and 12 b were established based on analytical and mass spec tra data ( cf. Tables I and II). On the other hand, compounds 12a and 12b found to coincide with authentic samples obtained via direct reaction of compound 2 with benzaldehyde or ethyl orthofor mate in 2:1 molecular ratio respectively. Cyanothioacetamide (1) seems to behave similar to m alononitrile, undergoes self dimerisation in basic medium [7]. Thus, 1 in alcoholic/triethylamine solu tion at room tem perature gives a product of m olec ular formula C6H 8N4S2. Two possible isomeric struc tures 13 and 14 are proposed. However, structure 13 was established for the reaction product based on IR spectrum which revealed the presence of one cyano group at 2220 cm-1. M oreover, 13 coupled with ben zenediazonium chloride in presence of sodium hy droxide to give the pyridazine derivative 16. The reaction takes place through interm ediate form ation of the nonisolable hydrazone derivative 15 and cyclisation similar to the reported literature [8]. 1 condenses with an equivalent am ount of acetylacetone in presence of piperidine as a catalyst to give the 2-pyridothione derivative 17. The latter com- Dieses Werk wurde im Jahr 2013 vom Verlag Zeitschrift für Naturforschung in Zusammenarbeit mit der Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.v. digitalisiert und unter folgender Lizenz veröffentlicht: Creative Commons Namensnennung 4.0 Lizenz. This work has been digitalized and published in 2013 by Verlag Zeitschrift für Naturforschung in cooperation with the Max Planck Society for the Advancement of Science under a Creative Commons Attribution 4.0 International License.

2 Table I. List of the compounds 3, 4, 6, 9, 12a, b; 13, and 21. Compound Cryst. solvent Colour Yield [%] m.p. [ C] Molecular formula Analysis found (calcd) C [%] H [%] N [%] S [% ] 3 Ethanol yellow 70 >300 Q H 8N ( ) 4 Dioxan orange 65 (a) >300 c 6h 8n (b) ( ) 6 Dioxan yellow c 8h 5n 5o s ( ) 9 Dioxan yellow c 16h 12n 6s ( ) 12 a DMF orange 57 (a) Ci9H]6NgS (b) ( ) 12 b Dioxan orange 52 (a) c 15h 16n 8s (b) ( ) 13 Dioxan yellow 80 >300 c 6h 8n 4s ( ) 16 DMF brown c 12h 9n 5s ( ) 17 Ethanol yellow 80 >300 c 8h 8n 2s ( ) 18 a Ethanol yellow CgH10N ( ) 18 b Dioxan orange C14H 14N ( ) 19 DMF yellow 72 >300 c 6h 5n 3o s ( ) 21 Ethanol white c 4h 5n 3o s ( ) OH NH2 CN h n ^ ^ y ^ T 1 N H HN OEt C-0 NH, r T CNl s N N S Ph-CH=C(CN)2 cha I CN 12a: x=ph b : x=oet 10 Chart 1

3 R. M. M ohareb S. M. Fahmy Cyanothioacetamide in Heterocyclic Synthesis 107 Table II. IR and H NMR spectra of the compounds Compound IR [cm"1] H NMR [ppm] (three N H,); 2980 (CH2); 2220 (CN) and 1625 (NH2 deformation) (three NH2); 2980 (CH2) and 1630 (NH2 deformation) (O H ); (NH2, NH), 2220 (CN); 1635 (NH2 deformation) and (two C=S) (three N H,); (aromatic CH and exocyclic CH); 222~0 (CN); 1630 (NH, deformation and (C =S)) 12 a (four N H 2); 3050 (aromatic CH); 2220 (two sym CN); 1635 (NH, deformation) and (C =S) 12b (four NH2); 2980, 2895 (CH2, CH3); 2220 (two sym CN); 1650 (NH, deformation) and (C =S) (three N H,); 2980 (CH,); 2220 (CN); 1635 (NH, deformation) and (two C=S) (two N H,); 3050 (aromatic CH); 2220 (CN); 1635 (NH, deformation) and (two C=S) (ring CH): 2980 (two CH,); 2220 (CN); 1205 (C=S) 18 a (N H NH); 3040 (ring CH); 2980 (two CH3); 2220 (CN); 1630 (NH, deformation) 18 b (N H); 3050 (aromatic and ring CH); 2980 (two C H,) and 222 (CN) (O H ); (N H,); 3040 (ring CH,); 2220 (CN); (C =S) (2 N H,); 2890 (CH); 2220 (CN); 1680 (C = 0 ) and 1190 (C =S) 5.61 (s, 2H, NH,); (2 s, 4H, 2 N H 2) and 6.98 (s, 2H, CH,) 5.55 (s, 2H, N H,); 9.0 (s, 1H, O H ) and ppm (br, 2 s, 2H, 2 NH) (m, 4H, 2 N H,); 6.18 (s, 2H, N H,) and (m, 6H, exocyclic CH, C6H 5) 4.10 (s, 2H, CH,); 4.89 (s, 2H, N H,); (2 s, 4H, 2 NH,) 4.89 (s, 2H, NH2); 6.14 (s, 2H, NH2) and 7.38 (m, 5H, C6H 5) 1.16, 1.24 (2 s, 6H, 2C H ); 6.01 (s, 2H, N H,); 7.11 (m, 2H, ring CH); 9.36 (s, br, 1H, NH) 1.18, 1.24 (2 s, 6 H, 2 CH 3); (m, 7H, pyridine C-3, C-5 and C6H S); (2 s, br, 2H, 2 NH) 4.68 and 5.19 (2 s, 4 H, 2 N H,); 6.25 (s, 1H, CH) pound reacts with hydrazine hydrate and phenylhydrazine to give the hydrazone derivatives 18 a and 18b, respectively. 1 was found to react with ethyl cyanoacetate in presence of a catalytic amount of piperidine to give the 2-pyridothione derivative 19. Moreover, reaction of 1 with cyanoacetamide in sodium ethoxide solution gave the same product 19 which seems to proceed via loss of ammonia from the nonisolable acyclic adduct react with trichloroacetamide to give a product of the molecular formula C4H 5N 0 5. Two possible isomeric structures are possible, 21 and 22. Structure 21 is established for the reaction product based on *H NMR which revealed the presence of 4 D 20 exchangeable protons assigned for two NH2 groups at < and < ppm and a singlet at < ppm for CH proton. Experimental All melting points are uncorrected. IR spectra were recorded on a Pye-Unicam Spectrophotometer. H NMR spectra on a Varian EM-90 MHz Spectrometer. The Microanalytical data were performed by the Microanalytical D ata U nit at Cairo U niversity. 3-Cyano-4,6-diam ino-2-hydrazono-pyridine (3) To a solution of compound 2 (0.01 mol) in ethanol hydrazine hydrate (0.01 mol) is added. The reaction

4 108 R. M. M ohareb S. M. Fahmy Cyanothioacetamide in Heterocyclic Synthesis mixture is heated under reflux for 3 h then poured into ice/water containing few drops of hydrochloric acid. The solid product, so formed, is collected by 3,4,6-Triam ino-5-hydro-pyrido[2',3 '-cjpyrazole (4) M ethod (a): To a solution of compound 2 (0.01 mol) in DMF (20 ml), hydrazine hydrate (0.01 mol) is added. The whole mixture is heated under reflux for 4 h then evaporated in vacuo. The remaining solid product is triturated with dilute ethanol then collected by M ethod (b): A solution of compound 3 (0.01 mol) in DM F (30 ml) is heated under reflux for 2 h then poured into ice/water. The resulting solid product is collected by 5-Amino-6-cyano-2,7-dithiono-4-hydroxyp yrido[2',3'-d]pyrim idine (6) A solution of ethoxycarbonyl isothiocyanate (prepared by mixing ethylchloroformate (0.01 mol) in dry acetone with ammonium thiocyanate (0.01 mol) and heating in water bath for 20 min) is added to a stirred solution of compound 2 (1.6 g, 0.01 mol) in acetone (30 ml). The whole mixture is heated under reflux in water bath for 2 h then evaporated in vacuo. The remaining product is triturated with alcohol then collected by 3-Cyano-6-phenylylidine-4,5,7-triamino-2-thionop yrid o[2',3'-bfpyridine (9) M ethod (a): To a solution of compound 2 (1.6 g, 0.01 mol in ethanol (30 ml) containing triethylamine ( '/ 2 ml) benzylidene malononitrile (0.01 mol) is added. The whole mixture is heated under reflux for 3 h then left to cool. The reaction product is precipitated by adding ice/water and collected by filtration (yield 69%). M ethod (b): To a solution of compound 10 (0.01 mol) in ethanol containing '/2 ml of piperidine, benzaldehyde (0.01 mol) is added. The reaction mixture is heated under reflux for 3 h then poured into

5 R. M. M ohareb S. M. Fahmy Cyanothioacetamide in Heterocyclic Synthesis 109 ice/water containing few drops of hydrochloric acid. The solid product, so formed on standing, is collected by filtration (yield 80%). Synthesis o f bis(pyridothione) derivatives 12a and 12 b M ethod (a): To a solution of compound 2 (0.01 mol) in absolute ethanol (30 ml) containing triethylamine (Vi ml) each of 11a or l i b (0.01 mol) is added. The reaction mixture is heated under reflux for 3 h then evaporated in vacuo. The solid product, so formed, is triturated with water then collected by M ethod (b): To a solution of compound 2 (0.01 mol) in dimethylformamide (30 ml) containing piperidine ('A ml) each of benzaldehyde or ethylorthoform ate (0.01 mol) is added. The reaction mixture is heated under reflux for 30 min then poured into ice/water containing few drops of hydrochloric acid. The solid product, so formed is collected by 3-Am ino-2,4-dithiocarbam ido-crotononitrile (13) To a solution of cyanothioacetamide (0.05 mol) in ethanol (50 ml), triethylamine (1 ml) is added. The reaction mixture is left over night at room tem perature with constant stirring. The whole mixture is then re fluxed for 1 h then left to cool. The solid product, so formed on standing is collected by 4-Am ino-5-cyano-3-thiocabamido-l-phenyl-6-thionopyridazine (16) To a stirred solution of compound 13 (0.01 mol) in ethanol (50 ml) containing sodium hydroxide (10 ml, 5%) benzene diazonium chloride (prepared by mixing sodium nitrite (0.01 mol) to the appropriate quantity of aniline in hydrochloric acid with cooling) is added. The reaction mixture is left at room tem perature for 4 h and the solid product, so formed, is collected by 3-Cyano-4,6-dimethyl-2-thiono-pyridine (17) To a solution of cyanothioacetamide (1) (0.01 mol) in absolute ethanol (30 ml) containing triethylamine (1 ml) acetylacetone (0.01 mol) is added. The reaction mixture is heated under reflux for 1 h then poured into ice/water. The solid product, so formed is collected by 3-Cyano-4,6-dimethyl-2-hydrazono-pyridine derivatives 18 a and 18 b To a solution of compound 17 (0.01 mol) in ethanol (30 ml) hydrazinehydrate or phenylhydrazine (0.01 mol) is added. The reaction mixture is heated under reflux for 1 h then poured into ice/water containing few drops of hydrochloric acid. The solid product, so formed, is collected by 4 - A m ino-3-cyano-5-hydroxy-2-thiono-pyridine (19) To a solution of compound 1 (0.01 mol) in absolute ethanol (30 ml) containing '/2 ml of piperidine, ethyl cyanoacetate or cyanoacetamide (0.01 mol) is added. The reaction mixture is heated under reflux for 3 h then left to cool. The solid product, so formed, is collected by a-cyano-a-thiocarbamido-acetamide (21) To a solution of compound 1 (0.01 mol) in acetic acid (50 ml) containing sodium acetate (5 g), trichloroacetamide (0.01 mol) is added. The whole mixture is heated under reflux for 4 h then poured into ice/water. The solid product, so formed, is collected by [1] S. M. Fahmy and R. M. M ohareb, Synthesis 6, 478 (1983). [2] S. M. Fahmy, S. O. Abd Allah, and R. M. M ohareb, Synthesis 11, 976 (1984). [3] S. M. Fahmy and R. M. M ohareb, Liebigs Ann. Chem. 1985, [4] H. Howard. A. Koth, R. V. Lindsay, and R. E. Putnam. J. Am. Chem. Soc. 80, 3924 (1958). [5] S. M. Fahmy and R. M. M ohareb, Tetrahedron (1985), in press. [6] M. R. H. Elmoghayar, M. K. A. Ibraheim, A. H. H. Elgandour, and M. H. Elnagdi, Synthesis 1981, 635. [7] E. C. Taylor and K. S. H artke, J. Org. Chem. 113,125 (1948). [8] S. M. Fahmy, N. M. Abed, R. M. M ohareb, and M. H. Elnagdi. Synthesis 6, 490 (1972).