A novel series of 2-substitutedguanidino-4-substitutedimine-6-sub-stitutedimino-1,3,5- thiadiazines (IIIa1 -e 5 ) have been recently synthesized by refluxing N-methylformamidino-N’- phenyliminothiocarbamide also called as 1-(N-substitutedcarbamimidoyl)3-{N-(E)- substitutedmethylidinecar-bamimidoyl}thiourea (Ia-e) with various isocyanodichloride (II1-5) in acetone-ethanol medium in 1:1 molar proportion. The structure of all the synthesized compounds was justified on the basis of chemical characteristics, elemental analysis and IR, NMR and mass spectral analysis. Keywords: Guanidine, 1,3,5-thiadiazines, acetone, ethanol et

P. V. Raut*, P. S. Bodakhe, S. A. Waghmare, D. T. Tayade

English

ZENODO

IAJPS 2017, 4 (12), 4644-4650                         P. V. Raut et al                           ISSN 2349-7750     w w w . i a j p s . c o m   Page 4644         CODEN [USA]: IAJPBB                         ISSN: 2349-7750    INDO AMERICAN JOURNAL OF  PHARMACEUTICAL SCIENCES                Available online at: http://www.iajps.com                                  Research Article  SYNTHESIS OF 2-SUBSTITUTEDGUANIDINO-4-SUBSTITUTED-IMINE-6-SUBSTITUTEDIMINO-1,3,5-THIADIAZINES P. V. Raut1*, P. S. Bodakhe2, S. A. Waghmare3, D. T. Tayade4 1Smt Sarda college Anjangaon (Surji), Dist. Amaravati (MS) 444728. 2Department of Chemistry, Vidya Bharti Mahavidhyalaya, Amravati 444606. 3Ghaulam Nabi Azad Arts, Comm. & Science College, Barshitakli Dist. Akola, (MS) 444401. 4Govt. Vid. Institute of Science and Humanities, Amravati (MS) 444606. Abstract: A novel series of 2-substitutedguanidino-4-substitutedimine-6-sub-stitutedimino-1,3,5-thiadiazines (IIIa1-e5) have been recently synthesized by refluxing N-methylformamidino-N’-phenyliminothiocarbamide also called as 1-(N-substitutedcarbamimidoyl)3-{N-(E)-substitutedmethylidinecar-bamimidoyl}thiourea (Ia-e) with various isocyanodichloride (II1-5) in acetone-ethanol medium in 1:1 molar proportion.  The structure of all the synthesized compounds was justified on the basis of chemical characteristics, elemental analysis and IR, NMR and mass spectral analysis. Keywords: Guanidine, 1,3,5-thiadiazines, acetone, ethanol etc. Corresponding author: P. V. Raut, Govt. Vid. Institute of Science and Humanities,  Amravati (MS) 444606. E- mail: pavanraut5@rediffmail.com  Please cite this article in press as P. V. Raut et al., Synthesis Of 2-Substitutedguanidino-4-Substituted-Imine-6-Substitutedimino-1,3,5-Thiadiazines, Indo Am. J. P. Sci, 2017; 4(12).    QR code   IAJPS 2017, 4 (12), 4644-4650                         P. V. Raut et al                           ISSN 2349-7750     w w w . i a j p s . c o m   Page 4645 INTRODUCTION: The literature survey reveals that when the heterocyclic compounds containing 1,3,5-thiadiazine as a parent nucleus then that molecule will enhance medicinal, pharmaceutical, agricultural and industrial activities of that drug1-9. Hence, nowadays the drug containing 1,3,5-thiadiazine nucleus are widely used in pharmaceutical, medicinal, biochemical and biotechnological fields. It has been reported that thiadiazine nucleus and its analogous possess10 antiviral, antifungal, antibacterial, anti-tuberculostatic and anti-helminthic properties. Several thiadiazines are widely used in the treatment of cancer11 and anti-HIV12-13 drugs. They are also used in agriculture14 as like fungicidal15, insecticidal16. These 1,3,5-thiadiazines are also effective against copper corrosion17-18 and used in lubricating oil19. The important reactions of substituted isocyanodichlorides have been briefly investigated by some researchers20-30. In the view of utility and significances of these compounds in various fields and as a part of wider programme in the synthesis of nitrogen, nitrogen and sulphur containing heteroacycles and heterocycles to developed an alternative route for the synthesis of six member heterocycles in this laboratory, it is quite interesting to investigate the cyclisation of 1-(N-substitutedcarbamimidoyl)3-{N-(E)-substitutedmethylidinecarbamimidoyl}-thiourea  (Ia-f) with N-substitutedisocyanodichlorides (IIa-d) in acetone-ethanol medium to synthesise 2-substitutedguanidino-4-substitutedimine-6-substitutedimino-1,3,5-thiadiazines (IIIa1-e5).    The tentative reaction and mechanism for the formation of product is depicted below,  R NHCNNHCH C HN C NHR'NHSN SNR NCHCClClN R"N R"HN C NHR'NHWhere R, R' & R"  = -methyl, -ethyl, -allyl, -phenyl+(V)1-(N-substitutedcarbamimidoyl)3-{N-(E)-substitutedmethylidenecarbamimidoyl}thiourea(VII)Substitutedisocyanodichlorides2-Substitutedguanidino-4-substitutedimine-6-substitutedimino-1,3,5-thiadiazines1-Substituted-3-[(2Z)-2-(substitutedimino)-4-{[(E)-substituted-methylidene]amino}2H-1,3,5-thiadiazin-6-yl]guanidinesOR(VIII) EXPERIMENTAL: Synthesis of 2-substitutedguanidino-4,6-susbstitutedlimino-1,3,5-thiadiazine (IIIa1-e5): A reaction mixture of N-substitutedformamidino-N’susbtitutediminothio-carbamide (Ia-e) (0.1M) with substitutedisocyanodichloride (II1-5) (0.1M)  in 1:1 molar ratio was refluxed on water bath in 50% acetone-ethanol (15 ml) medium for 2 hours. During heating evolution of hydrochloride gas was clearly noticed. After distillation of excess of acetone-ethanol dark brown colour product was isolated this on basification with dilute ammonium hydroxide lemon yellow crystals were afforded, yield, m.p. recorded.  RESULT AND DISCUSSION: Synthesis of 2-phenylguanidino-4-methylimino-6-phenylimino-1,3,5-thia-diazine (IIIa1): A reaction mixture of N-methylformamidino-N’-phenylimino-thiocarbamide (Ia) with phenylisocyanodichloride (II1) in 1:1 molar ratio was refluxed on water bath in acetone-ethanol medium for 4 hours. During heating evolution of hydrochloride gas was clearly noticed. After distillation of excess of acetone-ethanol ivory coloured product was isolated this on basification with dilute ammonium hydroxide lemon yellow crystals were afforded, yield 82%, m.p. 1280C. The probable mechanism of the formation of (IIIa1) is depicted below (Scheme-II).  Properties of (IIIa1): 1) It was lemon yellow crystalline solid having m.p.1280C. 2) It gave positive test for nitrogen and sulphur and negative test for chlorine. 3) It does not desulphurized when boiled with alkaline plumbite solution which clearly indicates that sulphur is not free and gets cyclised. 4) It was soluble in benzene, acetic acid, DMF and DMSO. 5) Elemental analysis: The result of elemental analysis is given in Table No. 1.1   IAJPS 2017, 4 (12), 4644-4650                         P. V. Raut et al                           ISSN 2349-7750     w w w . i a j p s . c o m   Page 4646 Table No-1.1 Elements Found (%) Calculated (%) Carbon 58.90 59.5041 Hydrogen 04.29 04.6832 Nitrogen 26.54 26.9972 Sulphur 08.78 08.8154  Table No.-1.2. Absorption observed cm-1 Assignment Absorption Expected cm-1 3185.10 ArC-H32 stretching 3150-3000 1637.7 C=N33 stretching 1750-1450 1254.30 C-N34 stretching 1360-1000 725.37 C-S34 stretching 800-600 668.34 Mono-substituted ph-ring  800-600 3376.8 NH Stretching  3500-3000 1507.18 Ar C=C stretching  1600-1450  6) From the analytical data the molecular formula was found to be C18H17N7S1. 7) IR Spectrum of compound: IR spectrum of compound was carried out in KBr pellets and reproduce on Plate No. PVR-8, an important absorption are correlated as follows in Table No.-1.2.  8) PMR-Spectrum: The PMR spectrum24,36 of compound was carried out in CDCl3 and DMSO-d6 and reproduced on PMR Plate No. PVR-8. This spectrum distinctly displayed the signals due to Ar-protons at δ 6.6253-8.4541ppm, NH protons at δ 3.1786-4.8738 ppm, =NH protons at δ 3.1786-3.7665 ppm,  -CH proton at δ 2.1345-2.6119 ppm and –CH3 protons at δ 1.2024-1.5318 ppm. 9) Mass spectrum:-  The Mass analysis of the compound was carried out and reproduced on Mass Plate No. PVR-8. The fragmentation occurs during the analysis is given in Mass Scheme-I. PVR 8 (363)N SNN N+NHNCH2M+ = 269NHNNHNHM+1 = 253N SNNCH3NHNHNNHN SNNCH3NHNHNHNHM+1 = 288N SNNCH3NH2NHM+1 = 170CH3NN SNNM+ = 151  From the above properties and spectral analysis of the compound (IIIa1) was assigned the structure as 2-methylguanidino-4-methylimine-6-phenylimino-1,3,5-thiadiazines (IIIa1). CHN CNHNHNHN(VIIIa)NN SH3C Synthesis of 2-phenylguanidino-4-phenylimine-6-phenylimino-1,3,5-thiadi-azine (IIIa3): IAJPS 2017, 4 (12), 4644-4650                         P. V. Raut et al                           ISSN 2349-7750     w w w . i a j p s . c o m   Page 4547   Ph NHCNNHCH C HN C NHPhNHSCClClN PhN SNPh NCHN PhHN C NHPhNHWhere R, R' & R"  = -methyl, -ethyl, -allyl, -phenyl+1-(N-phenylcarbamimidoyl)3-{N-(E)-phenylidenecarbamimidoyl}thioureaPhenylisocyanodichlorides(Vp) (VIId)(VIIId)2-Phenylgaunidino-4-phenylimine-6-phenylimino-1,3,5-thiadiazine  Scheme-II A reaction mixture of N-phenylformamidino-N’-phenylimino-thiocarbamide (Ic) with phenylisocyanodichloride (IId) in 1:1 molar ratio was refluxed acetone-ethanol medium for 2 hours. During heating evolution of hydrochloride gas was clearly noticed. After distillation of excess of acetone-ethanol dark brown colour product was isolated this on basification with dilute ammonium hydroxide afforded lemon yellow crystals, yield 72%, m.p. 2400C. The probable mechanism of the formation of (IIIa3) is depicted below (Scheme-II).  Properties of (IIIa3): 1) It was lemon yellow crystalline solid having m.p.2400C. 2) It gave positive test for nitrogen and sulphur. 3) It does not desulphurized when boiled with alkaline plumbite solutions which clearly indicate that sulphur is not free as in (IIIa3) and gets cyclised. 4) It was soluble in benzene, acetic acid, DMF and DMSO. 5) From the analytical data the molecular formula was found to be C23H19N7S1. 6) IR Spectrum of compound: IR spectrum of compound was carried out in KBr pellets and reproduce on Plate No. PVR-7, an important absorption are correlated as follows in Table no-1.5.  10) Elemental analysis:  The result of elemental analysis is given in Table No.1.4  Table 1.4  Elements Found (%) Calculated (%) Carbon 66.98 67.3170 Hydrogen 03.51 04.3902 Nitrogen 19.75 20.4878 Sulphur 07.49 07.8      Table 1.5  Absorption observed (cm-1) Assignment Absorption Expected (cm-1) 3176.0 ArC-H32 stretching 3150-3000 1635.0 C=N33 stretching 1750-1450 1254.30 C-N34 stretching 1360-1000 723.14 C-S34 stretching 800-600 668.12 Mono-substituted –ph ring  800-600 3376.8 NH Stretching  3500-3000 1504.1 Ar C=C stretching  1600-1450 IAJPS 2017, 4 (12), 4644-4650                         P. V. Raut et al                           ISSN 2349-7750     w w w . i a j p s . c o m   Page 4648 7) PMR-Spectrum: The PMR spectrum24,36 of compound was carried out in CDCl3 and DMSO-d6 and reproduced on PMR Plate No. PVR-7. This spectrum distinctly displayed the signals due to Ar-protons at δ 6.647-8.1570 ppm, NH protons at δ 3.5515 ppm, =NH protons at δ 2.5627-2.5850 ppm,  and  -CH proton at δ 2.1134 ppm. 8) Mass spectrum:-  The Mass analysis of the compound was carried out and reproduced on Mass Plate No. PVR-7. The fragmentation occurs during the analysis is given in Mass Scheme-II. N NN NH2SHH5C6CHNN SN NHN C6H5HNNHPVR 7 425H5C6CHNN SNNHNHNHNHH5C6NN SNNM+1 215M+ 351M+1 207NHN NHNHNNHM+1= 169 DIMERNHNNHNHm+1=253NHNNH2M=85, M+1=86Nm+1=104 NHNNH2+M+ 146  iTS NOT NH 2 From the above properties and spectral analysis of the compound (IIIa3) was assigned the structure as 2-phenylguanidino-4-phenylimine-6-phenylimino-1,3,5-thiadiazine (IIIa3). N SNPh NCHN PhHN C NHPhNH(VIIId)2-Phenylgaunidino-4-phenylimine-6-phenylimino-1,3,5-thiadiazine    Similarly, N-ethylformamidino-N’-phenyliminothiocarbamide (Ib), N-3-nitrophenylformamidino-N’-phenyliminothiocarbamide (Id), N-4-nitrophenylformamidino-N’-phenyliminothiocarbamide (Ie) and N-3-p-dimethylphenyl- formamidino-N’-phenyliminothiocarbamide (If) were interacted with phenylisocyanodichloride (II2)  to isolate 2-   phenylguanidino-4-ethylimino-6-phenylimino-1,3,5-thiadiazine (IIIa2), 2-phenylguanidino- 4-(3-nitro)phenylimine-6-phenylimino-1,3,5-thiadiazine(IIIa4),2-phenylgua-nidino-4-(4-nitro)phenylimine-6-phenylimino-1,3,5-thiadiazine(IIIa5) and  2-phenylguanidino-4-(3-p-dimethyl)phenylimine-6-phenylimino-1,3,5-thiadiazine (IIIa6) respectively by above mentioned method in Experiment No. 3-30 and enlisted in Table No.-1.7.  IAJPS 2017, 4 (12), 4644-4650                         P. V. Raut et al                           ISSN 2349-7750     w w w . i a j p s . c o m   Page 4649 Table No.-1.7  Expt No Comp No Substitued isocyanodi- chloride 2-Phenylguanidino-4-substitutedimine-6-substitutedimino-1,3,5-thiadiazine Yield % M.P. 0C 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 (Ib) (Id) (Ie) (If) (Ia) (Ib) (Ic) (Id) (Ie) (If) (Ia) (Ib) (Ic) (Id) (Ie) (If)  (Ia) (Ib) (Ic) (Id) (Ie) (If) (Ia) (Ib) (Ic) (Id) (Ie) (If) Phenyl...... Phenyl...... Phenyl...... Phenyl...... Methyl...... Methyl...... Methyl...... Methyl...... Methyl...... Methyl...... Ethyl...... Ethyl...... Ethyl...... Ethyl...... Ethyl...... Ethyl...... t-butyl.... t-butyl.... t-butyl.... t-butyl.... t-butyl.... t-butyl.... p-Cl-Ph... p-Cl-Ph... p-Cl-Ph... p-Cl-Ph... p-Cl-Ph... p-Cl-Ph... ......4-ethylimine-6phenyl.................. ......4-(3-nitro)phenylimine-6-phenyl.... ......4-(4-nitro)phenylimine-6-phenyl..... ......4-(3-p-dimethyl)phenylimine-6phenyl..... ......4-methylimine-6-methyl..................... ......4-ethylimine-6-methyl........................ ......4-phenylimine-6-methyl..................... ......4-(3-nitro)phenylimine-6-methyl..... ......4-(4-nitro)phenylimine-6-methyl..... .....4-(3-p-dimethyl)phenylimine-6-methyl..... ......4-methylimine-6-ethyl........................ ......4-ethylimine-6-ethyl........................... ......4-phenylimine-6-ethyl....................... ......4-(3-nitro)phenylimine-6-ethyl..... ......4-(4-nitro)phenylimine-6-ethyl..... .......4-(3-p-dimethyl)phenylimine-6-ethyl..... ......4-methylimine-6-t-butyl..................... ......4-ethylimine-6-t-butyl......................... ......4-phenylimine-6-t-butyl...................... ......4-(3-nitro)phenylimine-6-t-butyl.... ......4-(4-nitro)phenylimine-6-t-butyl.... ......4-(3-p-dimethyl)phenylimine-6-t-butyl..... ......4-methylimine-6-(p-Cl)-phenyl............ ......4-ethylimine-6-(p-Cl)-phenyl.............. ......4-phenylimine-6-(p-Cl)-phenyl............ .....4-(3-nitro)phenylimine-6-(p-Cl)phenyl... ..4-(4-nitro)phenylimine-6-(p-Cl)-phenyl..  ..4-(3-p-dimethyl)phenylimine-6-(p-Cl)-phenyl.. 82 80 76 75 85 82 80 78 78 75 84 82 78 75 76 74 75 72 72 68 65 66 68 65 64 63 62 62 192 204 215 189 178 197 210 235 203 183 155 168 244 276 279 230 256 234 278 145 167 174 234 201 185 214 248 199  REFERENCES: 1.Tayade D.T. and Waghmare S.A., synthesis and characterization of 5-substituted series of 3-(4-chlorophenyl)-2,4-dithio-1,3,5-triazines containing chalcone moieties.,Int. Res. J. Pharm., 2016; 7(6):96-98. 2.Blotny G., Recent applications of 2,4,6-trichloro- 1,3,5-triazine and its derivatives in organic synthesis., Tetrahedron, 2006; 62:9507-9522.  3.Nishigaki S., Yoneda U.H., Tsumoto H. and Jiorinaga A.I., Synthetic Antibacterials. I. Nitrofurylvinyl-s-triazine Derivatives., J. Am. Chem. Soc., 1969; 12:39-42.  4.Barker J.J., Antibacterial drug discovery and structure based design. Drug Disc. Today., 2006, 11, 391-404.  5.Srinivas K., Srinivas U., Bhanuprakash K., Harakishore K., Murthy U.S.N. and Rao V.J., Synthesis and antibacterial activity of various substituted s-triazines., Eur. J. Med. Chem., 2006; 41: 1240-1246.  6.Wise R., Hart T., Cars O., Helmuth R., Huovinen P., Sprenger M. and Streulens M., Antimicrobial resistance is a major threat to public health. BMJ., 1998; 317: 609-610.    IAJPS 2017, 4 (12), 4644-4650                         P. V. Raut et al                           ISSN 2349-7750     w w w . i a j p s . c o m   Page 4650 7.Patel R. B., Chikhalia K. H., Pannecouque C. and Clercq Erik de., Synthesis of Novel PETT Analogues: 3,4-Dimethoxy Phenyl Ethyl 1,3,5- Triazinyl Thiourea Derivatives and their Antibacterial and Anti-HIV Studies., J. Braz. Chem. Soc., 2007; 18(2): 312-321,  8.Raval J.P., Desai J.T., Desai C.K. and Desai K.R., A comparative study of microwave assisted and conventional synthesis of 2,3-dihydro-2-aryl-4-[4- (2–oxo–2H–chromen–3–yl)–1,3-thiazol–2– ylamino]-1,5–benzothiazepines and its antimicrobial activity, ARKIVOC, 2008, xii, 233- 244.  9.Gubernator K. and Bohm H.J., Structure-Based Ligand Design, Methods and Principles in Medicinal Chemistry. Wiley-VCH Publishers, Weinheim, 1998, 15-95.  10.Raval J.P. and Desai K. R., Synthesis of 3-Phenyl4[4(mnitrophenyl)N2(2’arylureido/arylthioureido-4’-N-morpholino-striazin)-benzo-[6,7]coumarins and their Applicatiions., E-J. Chem., 2004; 01(5): 211 – 215.  11.Singh B.K., Mishra M., Saxena N., Yadav G.P., Maulik P.R., Sahoo M.K., Gaur R.L., Murthy P.K., Tripathi R.P., Synthesis of 2-sulfanyl-6-methyl- 1,4-dihydropyrimidines as a new class of antifilarial agents, Eur. J. Med. Chem.,2008; 43(12): 2717-2723.  12.Weiner David B. and William V., Chemical and structural approaches to rational drug design. Boca Raton, CRC, FL, 1994, 12-85.  13.Thruston J.T., Dudley J.R., Kaiser D.W., Henbleikner I., Schaefer F.C. and Holm-Hensen D., Cyanuric Chloride Derivatives. I. Aminochloro-s-triazines. J. Am. Chem. Soc., 1951; 73: 2981-2983.  14.Kumar A., Srivastava K., Raja Kumar S., Puri S.K., Chauhan Prem M.S., Synthesis and bioevaluation of hybrid 4-aminoquinoline triazines as a new class of antimalarial agents., Bioorg. Med. Chem. Lett., 2008; 18(24):6530-6533.  15.Raval J.P. and Desai K.R., A Comparative study of Microwave assisted and Conventional Synthesis of novel 2-(4-diethylamino-2-hydroxyphenyl)-3- substituted-thiazolidin-4-one derivatives. Chemija (Accepted, MS.No.08-30).  16.Kumar A., Menon S. K., Fullerene derivatized striazine analogues as antimicrobial agents., Eur. J. Med. Chem.,2009; 44(5): 2178-2183.  17.Tayade D.T. and Waghmare S.A., synthesis and characterization of (2e) -1- [4- (2, 4-dithio-3-ethylimino-5-substitutedimino-1,3,5-triazino-6-yl)aminophenyl]-3-(3,4-dimethoxyphenyl) prop -2- en-1-one., Haya: Saudi J. Life Sci., 2016;1(2):72-75. 18.Tayade D. T. and Waghmare S. A., synthesis and characterization of (2e)-1-{4-[2,4-dithio-3-(2-methylpropan-2-yl)imino-5-substitutedimino-1,3,5-triazino6yl]aminophenyl}3(3,4dimethoxyphenyl)prop-2-en-1-one., European Journal of Pharmaceutical and Medical Research, 2016; 3(7): 433-435. 19.Waghmare S.A.  and Tayade D.T., Synthesis and Characterization of 5-Substituted Derivatives of 2, 4-Dithio-3-phenyl-6-chalcone-1,3,5-Triazines,  IJCPS, 2016; 4(8): 286–288. 20.Tayade D.T., Thombare R.D. & Waghmare S.A.  synthesis of 5-{(4- amino-n- [2-(diethylamino)ethyl]-o-anisamido- 5-yl}- amino-3- substitutedimino-7-substitutedimino-1,2,4,6- trithiazepines.,  IAJPS, 2017; 4(11): 1-5. 

SYNTHESIS OF 2-SUBSTITUTEDGUANIDINO-4-SUBSTITUTED-IMINE-6-SUBSTITUTEDIMINO-1,3,5-THIADIAZINES

https://zenodo.org/record/1069718/files/3.Corrected%20Proofs.pdf

SYNTHESIS OF 2-SUBSTITUTEDGUANIDINO-4-SUBSTITUTED-IMINE-6-SUBSTITUTEDIMINO-1,3,5-THIADIAZINES

Abstract

Similar works

Full text

Available Versions

ZENODO