Chemoselective synthesis of novel thiatriazolophanes

Article J. Braz. Chem. Soc., Vol. 19, No. 1, 42-52, 2008. Printed in Brazil - ©2008 Sociedade Brasileira de Química 0103 - 5053 $6.00+0.00 Chemoselective Synthesis of Novel Thiatriazolophanes Madhukar S. Chande,* Kiran A. Puthamane, Pravin A. Barve, Rahul R. Khanwelkar and Deepak S. Venkataraman Department of Chemistry, The Institute of Science, 15, Madam Cama Road, Mumbai 400 032, India Bis-[4-alquil/aril-5-tia-1,2,4-triazóis] foram preparados pela fusão de diácidos e tiosemicarbazidas, pela condensação de hidrazidas ácidas aromáticas com isotiocianato. A alquilação quimiosseletiva destes bis-[4-alquil/aril-5-tia-1,2,4-triazóis] com 1,W-dihaloalcanos na presença de hidróxido de potássio em metanol aquoso, proporcionou N-alquil/aril tiatriazolofanos inéditos. Bis-[4-alkyl/aryl-5-thia-1,2,4-triazoles] were prepared by fusion of diacids and thiosemicarbazides by condensation of aromatic acid hydrazides with isothiocyanate. Chemoselective alkylation of these bis-[4-alkyl/aryl-5-thia-1,2,4-triazoles] with 1,W-dihaloalkanes in presence of potassium hydroxide in aqueous methanol afforded novel N-alkyl/aryl thiatriazolophanes. Keywords: 4-alkyl/aryl-5-thia-1,2,4-triazoles, 1,W-dihaloalkanes, N-alkyl/aryl thiatriazolophanes, chemoselectivity Introduction Crown compounds have generated considerable interest during the last three decades because of their ability to form stable complexes with a variety of metal and organic cations and anions.1 They also have wide applications in phase transfer catalysis.2 In recent years various structural changes have been made to the basic “crown ether” structure in order to enhance the selective activity of the ligands.3 These changes involve the insertion of aromatic and/or heterocyclic ring systems into the macrocycles. Incorporation of heterocyclic subunit provides rigidity to the macrocycle and contributes in increasing the stability of complexes formed with both metals and organic cations.3 The development of crown compounds especially macrocyclic compounds containing heterocyclic subunit has gained importance due to their wide range of applications. Several reviews and monographs have been published which highlight their synthesis and application in synthetic organic chemistry as phase transfer catalysts and in analytical chemistry as ligand for complexation.2,4 *e-mail: In recent years, attention has been increasingly paid to the synthesis of bisheterocyclic compounds, which exhibit various biological activities. 5 including antibacterial, antifungicidal, tuberculostatic and plant growth regulative properties. Bisheterocyclic compounds displayed much better antibacterial activity than heterocyclic compounds.6 Various 1,2,4-triazoles are found to be associated with diverse pharmacological activities such as antiasthmatic,7 antiviral (ribavirin),8 antifungal (fluconazole),9 antimicrobial,10 antibacterial,11 insecticidal,11,12 amoebicidal,13 hypnotic,14 cytotoxic, 15 and hypotensive 16 activities. This moiety was also found in potent agonist and antagonist receptor ligands,17 in HIV-1 protease inhibitors18 and in thrombin inhibitors.19 Along with these significant pharmaceutical uses, 1,2,4-triazole derivatives are effectively used in polymers, dyestuff, photographic chemicals and agricultural chemicals.20 We have previously reported the chemoselective synthesis of novel oxadiazolophanes21 and N-aminotriazolophanes.22 In continuation of this ongoing program in the synthesis of novel macrocyclic ligands21,22 their computational studies21,22 and their application as phase transfer catalyst (PTC),22 we now report a facile chemoselective synthesis of novel N-alkyl/aryl thiatriazolophanes. Vol. 19, No. 1, 2008 Chande et al. Results and Discussion The present work describes a versatile synthetic strategy for the chemoselective synthesis of novel N-alkyl/aryl thiatriazolophanes. Obtained heterophanes would be similar to lariat ether23 with N-alkyl/aryl groups as side arm. The study of the stereochemistry of these compounds is of interest as the two N- alkyl/aryl groups would be either cis or trans to each other depending on the alkyl chain joining the two heterocyclic units and the thermodynamic stability of the molecule. There are many methods described in the literature for the synthesis of N-substituted-1,2,4-triazoles,20 but none of them concerns the synthesis of heterophanes. Bis N-alkyl/ aryl thiatriazoles 3a-c were prepared in good yield by direct fusion of adipic acid 1 with thiosemicarbazides 2a-c, according to Xu method24 (Scheme 1). This compound 3 containing thioamido groups has an amphoteric nature and can exist in tautomeric forms 3A and 3B. On alkylation of 3 with 1,W-dihaloalkane, multiple products could form depending on the reactions conditions. Reaction of compounds 3a-c with diiodoalkanes 4a-f in aq. methanol (80%) in the presence of potassium hydroxide as a base gave only products 5a-n chemoselectively in good yield (Scheme 1, Table 1). The reaction was carried out in large excess of solvent to ensure intramolecular cyclisation (high dilution condition). The elucidation of structures 5a-n was accomplished on the basis of their spectral data and elemental analysis (Table 1). For example, reaction of 3a with 1,2 diiodoethane 4b resulted in the formation of the desired Reagents and conditions: (a) 140 oC, fusion; (b) KOH, aq. MeOH (80%), 80 oC. Scheme 1. Synthesis of N-alkyl/aryl thiatriazolophanes 5. 43 N-ethylthiatriazolophane 5b, confirmed on the basis of NMR spectra. 1H NMR spectrum of the compound showed triplet at D 4.10 for S-CH2 group of ethane chain. Absence of peak for C=S in 13C NMR spectrum confirmed the chemoselectivity of S-alkylation. It showed signal for S-CH2 carbon at 32.1 ppm. From the above data compound 5c was identified as 14,64-diethyl-7,11dithia-1,6(3,5)-di-(1,2,4-triazola)cycloundecaphane. 25 The other thiatriazolophanes 5a-n were similarly synthesized and characterized. In order to improve the solubility of the thiatriazolophanes, it was thought to incorporate a phenyl nucleus into the structure, which would also help in complexation by PTC. Hence, the scope of the previous reaction was extended to the synthesis of benzotriazolophanes 9 (Scheme 2). Bistriazoles 8 was synthesized in high yield, by reacting isophthalic acid dihydrazide 6 with phenyl/o-tolyl isothiocyanates 7. The reaction of 8a-b with 4a-g in aqueous methanol (80%) in the presence of potassium hydroxide as a base gave desired benzotriazolophanes 9a-l chemoselectively in moderate yield (Scheme 2, Table 1). Structures of the products were confirmed on the basis of spectral data and elemental analysis (Table 1). For example, reaction of 8a with 1,2-diiodoethane 4b resulted in the formation of desired benzotriazolophane 9a, confirmed on the basis of NMR spectra. 1H NMR spectrum of the compound showed triplet at D 3.46 for S-CH2 group of ethane chain. Absence of peak for C=S in 13C NMR spectrum confirmed the chemoselectivity (...truncated)