Journal of Analytical and Applied Pyrolysis 96 (2012) 181–187 Contents lists available at SciVerse ScienceDirect Journal of Analytical and Applied Pyrolysis journa l h o me page: www.elsevier.com/locate/jaap Theoretical and experimental study on the reaction route for the FVP of 2-thioxohexahydroquinazolinones Walter J. Peláez a , Ana G. Iriarte a , Zsolt Szakonyi b , Ferenc Fülöp b , Gustavo A. Argüello a,∗ a INFIQC, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina b Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged Eötvös utca 6, Hungary a r t i c l e i n f o Article history: Received 7 July 2011 Accepted 9 April 2012 Available online 17 April 2012 Keywords: Flash vacuum pyrolysis 2-Thioxohexahydroquinazolinones Reactivity a b s t r a c t Structural and conformational analyses through the use of different spectrometric techniques as well as DFT calculations performed to analyze the results of FVP reactions on pure cis as well as pure trans 2- thioxo-hexahydroquinazolinones yielding isothiocyanates as main products have been carried out. With these, we could assess the specific tautomer/isomer/conformer that produces the products in each FVP reaction. It was confirmed that for both isomers, the reaction takes place from the thiol tautomer, and for the special case of the cis isomer, the conformer involved is the N(1)-in. © 2012 Elsevier B.V. All rights reserved. 1. Introduction In recent years, quinazolinones and their partially satu- rated analogs have come into the focus of interest because of their noteworthy pharmacological activity (e.g. nucleoside analogs with potential analgesic and anti-inflammatory effects or thymidylate synthase inhibitor activity) [1–7] due to the planar RNH C(S) NR C(O)R moiety [3a]. Quinazolinones present tautomerism [8]; therefore, under- standing its equilibrium properties and energetics is relevant for the study of molecular processes like thermal dissociation in the gas phase. Besides the existence of tautomers, there are other struc- tural features, given by the starting materials in the synthesis of quinazolinones. For trans fused rings there exists only one stable isomer whereas for cis fused ones, two distinct isomers (N(1)-in and N(1)-out) are present [3a]. These facts bring new variables when trying to rationalize the mechanism underlying the thermal reactivity shown in the gas phase. Usually, opening of the heterocyclic ring is the lowest- energy channel in the flash vacuum pyrolysis (FVP) thermal dissociation of cyclohexene-fused derivatives [9]. Nevertheless, at least six different structures (namely, trans/cis, N-in/N-out, NH/SH isomers) could in principle be responsible for the prod- ucts obtained. FVP afforded information and the results were interpreted as a concerted reaction, taking place from a cyclic four- centered transition state (TS4) originating from the thiol tautomer ∗ Corresponding author. Tel.: +54 351 433 4169. E-mail address: gaac@fcq.unc.edu.ar (G.A. Argüello). (SH), with the isothiocyanates as products (see Scheme 1) [9]. Kinetic data (mainly the entropies of activation) as well as theo- retical evidence reported for related compounds firmly indicated that the decomposition took place from the thiol tautomer. In the present work, we propose a thorough study of the whole energetics of the dissociation reaction through high level theo- retical calculations, paying special attention to the cis compound because is the one that can adopt more than one conformer. The study is further supported by the use of two experimental tech- niques, namely 1 H NMR spectroscopy and mass spectrometry, to shed some light into the operating mechanism. NMR spectra were recorded to get information about conformers (without a par- ticular interest in discriminating between tautomers), and mass spectra provided valuable information about tautomerism (with- out discriminating between conformers). All together, the three techniques ended-up in a straightforward comparison with the FVP results obtained [9]. 2. Results and discussion Pure cis and trans-2-thiohexahydroquinazolin-4(1H)-ones (1 and 2) were synthesized and selected for this study. The trans species adopts a unique backbone structure with all its angles at the optimal values and is thus more reluctant to react, as the results show in the temperatures needed for the FVP to take place. The difference in the reaction temperature between the cis and trans compounds is almost of 100 ◦ C. This is in agreement with the general trend found in other fused compounds like hyndrin- danes, decalines and pinanes [3]. The cis species, on the other hand, lies higher in energy than the trans counterpart (thus decomposing 0165-2370/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jaap.2012.04.004