Heteroatom Chemistry Volume 13, Number 2, 2002 A Facile One-Pot Regioselective Synthesis of [1,2,4]Triazolo[4,3-a]5(1 H )-pyrimidinones via Tandem Japp–Klingemann, Smiles Rearrangement, and Cyclization Reactions Ahmad S. Shawali, Magda A. Abdallah, Mosselhi A. N. Mosselhi, and Thoraya A. Farghaly Department of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt Received 14 February 2001; revised 23 July 2001 ABSTRACT: Coupling of active [(4-oxo-6-phenyl- 3H-pyrimidin-2-yl)thio]methine compounds (3) with diazotized anilines in the presence of base gave [1,2,4]triazolo[4,3-a]pyrimidines (7). The latter prod- ucts were also obtained by reactions of hydrazonoyl chlorides (10) with either 6-phenyl-2-thiouracil (1) or the 2-methylthio derivative 9. The mechanisms and the regiochemistry of the reactions studied are dis- cussed. C  2002 Wiley Periodicals, Inc. Heteroatom Chem 13:136–140, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10008 INTRODUCTION Tandem pericyclic reactions have attracted consid- erable attention within the past decade because of their utility in organic synthesis [1]. Other reac- tions in tandem have received little, if any, attention. We wish to disclose herein our finding that cou- pling of active [(4-oxo-6-phenyl-3 H-pyrimidin-2- yl)thio]methine compounds (3) with diazotized ani- lines afforded directly the respective 1 H-[1,2,4] triazolo[4,3-a]pyrimidin-5-ones via three in situ tan- dem reactions, namely, Japp–Klingemann, Smiles Correspondence to: Ahmad S. Shawali; e-mail: shawali@chem- sci.cairo.eun.eg. c  2002 Wiley Periodicals, Inc. rearrangement, and cyclization reactions. Such a sequence of reactions provides a facile one-pot regioselective synthesis of the title compounds. The latter compounds are of interest as many derivatives of [1,2,4]triazolo[4,3-a]pyrimidine (7) have been reported to be useful as calcium-channel blocking vasodilators and they have antihypertensive [2], car- diovascular [3,4], anxiolytic [5] activities, as well as being components in photographic materials [6]. RESULTS AND DISCUSSION Reaction of 6-phenyl-2-thiouracil (1), prepared as previously described [7], with the active chloro- methylene compounds 2A–C in ethanol in the presence of triethylamine at room temperature yielded the S-alkylated derivatives 3A–C, respectively (Scheme 1). The structure of the latter products were evidenced by their mass, IR, and 1 H NMR spectra (see Experimental). For example, their 1 H NMR spec- tra showed a singlet signal at δ-2.4 assignable to the methine hydrogen. The formation of 3A–C from 1 and 2A–C respectively is analogous to S-alkylation reactions exhibited by 2-thiouracil derivatives [8]. Next, reaction of 3 with diazotized anilines was investigated in ethanol in the presence of sodium ac- etate at low temperature (0–5 ◦ C). Based on the previ- ous literature on the Japp–Klingemann reaction [9], we anticipated that the products of this coupling re- action would be the thiohydrazonate esters (5) or 136