A facile, aqueous phase green synthetic protocol for the synthesis of 5,9b-dihydro-1H-[1,2,4]triazino[5,6-b]indole-3-ols/5,9b-dihydro- 1H-[1,2,4]triazino[5,6-b]indole-3-thiols K. Ramesh, S. Narayana Murthy, K. Karnakar, Y. V. D. Nageswar ⇑ Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India article info Article history: Received 6 June 2011 Revised 22 June 2011 Accepted 26 June 2011 Available online 13 July 2011 Keywords: Isatin Semicarbazide/thiosemicarbazide b-Cyclodextrin Water abstract 5,9b-Dihydro-1H-[1,2,4]triazino[5,6-b]indole-3-ols/5,9b-dihydro-1H-[1,2,4]triazino[5,6-b]indole-3-thiols were synthesized for the first time in water under neutral conditions by using isatin, semicarbazide/ thiosemicarbazide, mediated by b-cyclodextrin in excellent yields. b-Cyclodextrin has been recovered and reused without any loss of catalytic activity. Ó 2011 Elsevier Ltd. All rights reserved. Over the years synthetic heterocyclic chemistry is providing impetus to the development of new drug scaffolds through itera- tive manipulation of functional groups around the rudimentary skeletal systems. Among these, heterocyclic compounds have been given special emphasis due to a wide variety of medicinal and bio- logical properties associated with them 1 (Fig. 1). 2 In view of this, globally researchers started exploring simple and novel one-pot procedures to obtain potential new molecular entities, 3 belonging to a broad range of heterocyclic systems. 5,9b-Dihydro-1H- [1,2,4]triazino[5,6-b]indole-3-ols/5,9b-dihydro-1H-[1,2,4]triaz- ino[5,6-b]indole-3-thiols and their analogues exhibit varied bio- logical activities/medicinal applications such as antimicrobial, 4–8 antiviral, 9 antihypertensive, 9,10 blood-platelet aggregation inhibi- tory, 10,11 and analgesic 12 activities. In addition, 3-arylidene-and 3-alditol-1-ylidenehydrazino-1,2,4-triazino[5,6-b]indoles showed antitumor activity against P388 lymphocytic leukemia in mice 13 and antibacterial activity. 14,15 Recently Ivachtchenko et al., re- ported the synthesis of 5H-[1,2,4]triazino[5,6-b]indole-3-thiol by using isatin, and thiosemicarbazide mediated by base followed by acid. 16 In view of different biological activities associated with various 5,9b-dihydro-1H-[1,2,4]triazino[5,6-b]indole-3-ols/5,9b-dihydro- 1H-[1,2,4]triazino[5,6-b]indole-3-thiol derivatives and in continu- ation of our interest in the use of cyclodextrins as mild and efficient biomimetic catalysts in promoting various transforma- tions, 17 we have attempted a novel aqueous phase synthesis of 5,9b-dihydro-1H-[1,2,4] triazino[5,6-b]indole-3-ols/5,9b-dihydro- 1H-[1,2,4] triazino[5,6-b]indole-3-thiols by the reaction of isatin derivatives with semicarbazide/thiosemicarbazide under neutral conditions involving supramolecular catalysis using b-cyclodex- trin. Cyclodextrins (CDs) are cyclic oligosaccharides possessing hydrophobic cavities, which bind substrates selectively and cata- lyze chemical reactions with high selectivity. They catalyze reac- tions by supramolecular catalysis involving reversible formation of host–guest complexes by non-covalent bonding as seen in en- zymes. We describe, herein, the first aqueous phase synthesis of a 5,9b-dihydro-1H-[1,2,4] triazino[5,6-b]indole-3-ols/5,9b-dihy- dro-1H-[1,2,4] triazino[5,6-b]indole-3-thiol derivatives demon- strating the remarkable catalytic activity of b-cyclodextrin (Schemes 1 and 2). In general, the reaction was carried out by the in situ formation of b-CD complex of isatin in water followed by the addition of semicarbazide/thiosemicarbazide and stirring at 50–55 °C to give the corresponding a 5,9b-dihydro-1H- [1,2,4]triazino[5,6-b]indole-3-ols/5,9b-dihydro-1H-[1,2,4] triazi- no[5,6-b]indole-3-thiols in high yields (80–90%). These reactions 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.06.098 ⇑ Corresponding author. Tel.: +91 40 27191654; fax: +91 40 27160512. E-mail address: dryvdnageswar@gmail.com (Y.V.D. Nageswar). N N N N S H N Figure 1. Polycyclic fused heteroaromatic skeleton with good biological activities. Tetrahedron Letters 52 (2011) 4734–4737 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet