A novel simple pyrolytic approach towards anhydronucleosides Alya Al-Etaibi, Saad Makhseed, Nouria A. Al-Awadi * and Yehia A. Ibrahim * Chemistry Department, Faculty of Science, Kuwait University, PO Box 5969, Safat 13060, Kuwait Received 8 September 2004; revised 2 November 2004; accepted 8 November 2004 Abstract—An interesting novel gas phase thermal intramolecular substitution reaction was discovered, which led to the conversion of the 2-b-D-N-glucosyl, 2-b-D-N-galactosyl and 2-b-D-N-ribosyl derivatives of 3-thioxo-2,3-dihydro-1,2,4-triazin-5(4H)-ones into their corresponding 3,2 0 -anhydro-b-D-mannosyl, 3,2 0 -anhydro-b-D-talosyl and 3,2 0 -anhydro-b-D-arabinosyl derivatives. The struc- tures of these new anhydroglycosyls were determined by NMR experiments and by X-ray crystallography. Ó 2004 Elsevier Ltd. All rights reserved. There exists considerable interest in the synthesis of 2,2 0 - and 2,3 0 -anhydronucleosides due to the possibility that these compounds can be attacked by nucleophiles at the C-2 0 or C-3 0 positions affording compounds with anti-AIDS activity. 1 To the best of our knowledge the first reported method for the synthesis of 2,2 0 -anhydro- nucleosides involved treating 1-3 0 ,5 0 -O-isopropylidene- 2 0 -O-methanesulfonyl-b-D-xylofuranosylthymine with sodium hydroxide in refluxing ethanol to afford the cor- responding 2,2 0 -anhydronucleoside. 2 Recently, 1d,f,g,3–5 the action of bases (NaHCO 3 /DMF, PhCOONa or DBU) on the the appropriate 2 0 -O-phenyloxycarbonyl or 2 0 -O-methanesulfonyl derivatives of nucleosides have been used to promote anhydrization. Additionally, heating 2 0 -deoxy-2 0 -iodonucleosides in DMF with di-n- butyltin oxide gave the corresponding anhydronucleo- sides. 6 2,2 0 -Anhydrothionucleosides have also been investigated and some synthetic methods have been reported. 7a,b Moreover, a method has been reported for the synthesis of arabino-6-aza-2-thio-2,2 0 -anhydro- uridine. 8 The chemistry and diverse applications of heterocyclic glycosyl derivatives have received much attention due to their pronounced biological activity. Recently 9 we re- ported a simple selective synthesis of 2-glycosyl deriva- tives of 1,2,4-triazine-3,5(2H,4H)-diones and their thiones (6-azauracil derivatives), which possess potential biological activity as cytotoxic, antiviral, enzyme inhibi- ting, immunosuppressive, antiphlogestic and bacterio- static agents. 10,11 Extension of this methodology enabled a direct selective synthesis of 2-N-glycosyls of 1,2,4-triazole-3(2H)-thione, which are also of consider- able biological interest. 12 Scheme 1 illustrates the crucial step in our synthetic methods, which depends on selec- tive protection–deprotection via the arylideneamino group. In our previous work we have shown that re- moval of the benzonitrile leads to efficient selective syn- thesis of the desired 2-glycosyl derivatives (e.g., 2a) upon pyrolysis of the arylideneamino derivatives (e.g., 1, Scheme 1) at ca. 180–200 °C. We have also studied the kinetics of the triazole derivatives, which involves six- membered transition state concerted hetero-retro-ene elimination reactions. 13 During our kinetic studies of the pyrolysis of the 2-glucosyl-4-arylideneamino-3-thi- oxo-2,3-dihydro-1,2,4-triazin-4(5H)-ones 1 we found that heating 1 at a temperature above 220 °C led to the formation of the expected N-glucosyl derivative 2a in addition to another product, which was identified as 3,2 0 -anhydro-2-(3,4,6-tri-O-acetyl-b-D-mannosyl)-3- mercapto-1,2,4-triazin-5(2H)-one 3a. The yield of the latter was optimal at 270 °C. This finding represents an interesting, new, easy pyrolytic synthetic access to anhy- droglycosyl derivatives. This gas phase pyrolytic approach has been extended to the synthesis of 3,2 0 - anhydro-b-D-talosyl and 3,2 0 -anhydro-b-D-arabinosyl derivatives of 3-mercapto-1,2,4-triazin-5(2H)-ones. The formation of 3a presumably involves elimination of acetic acid from 2a. This presumption was substantiated by pyrolyzing 2a and this indeed gave 3a with the opti- mum yield (87%) obtained by heating at 270 °C for 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.11.050 Keywords: Pyrolysis; Nucleosides; Anhydronucleosides; 1,2,4- Triazines. * Corresponding authors. Tel.: +965 9464215; fax: +965 4816482; e-mail addresses: nouria@kuc01.kuniv.edu.kw; yehiaai@kuc01. kuniv.edu.kw Tetrahedron Letters 46 (2005) 31–35 Tetrahedron Letters