Organic & Biomolecular Chemistry PAPER Cite this: Org. Biomol. Chem., 2016, 14, 7490 Received 19th May 2016, Accepted 5th July 2016 DOI: 10.1039/c6ob01099g www.rsc.org/obc A rare γ-pyranopyrazole skeleton: design, one-pot synthesis and computational study† Muhammed Üçüncü, a Ceren Cantürk, a Erman Karakuş, a Hüseyin Zeybek, a Uğur Bozkaya, b Emine Soydaş, c Ertan Şahin c and Mustafa Emrullahoğlu* a Drawing upon a consecutive amide coupling and intramolecularcyclisation pathway, a one-pot, straight- forward synthetic route has been developed for a range of pyrazole fused γ-pyrone derivatives. The reaction mechanism proposed for the chemoselective formation of γ-pyranopyrazole is furthermore fully supported by experimental and computational studies. Heterocyclic compounds bearing a pyrone scaffold (e.g., 4-pyrone or γ-pyrone) exhibit an array of biological and pharmacological activities. 1 Since the biological activity of the pyrone ring is closely linked to the core structure’s substitution pattern, incorporating other ring motifs into the pyrone skeleton could greatly contribute to the parent molecule’s bio- logical activity. 2 In terms of biological diversity, constructing ring-fused pyrone derivatives has attracted significant attention; however, despite widespread interest in and efforts toward con- structing new pyrone derivatives, ring-fused pyrone derivatives remain extremely rare, 3 given the lack of practical and effective synthetic protocols and guidelines for their construction. Representing an unusual example of a fused pyrone ring, the pyranopyrazole ring system can participate in diverse bio- logical activities including analgesic, anti-inflammatory, antimicrobial, fungicidal, and cytotoxic activities. 4 Certain derivatives of pyranopyrazoles have been evaluated for their affinity to bind with bovine brain adenosine receptors. 5 At the same time, the γ-pyranopyrazole ring system is photoactive and apt to undergo photochemical reactions such as photo- dimerization and photocleavage. 6 The general method for preparing the known pyrano[3,2-c] pyrazole skeleton relies on a two-step synthetic process, which Gelin et al. have described (Fig. 1). 7 Over the years, improved versions of the method have been published, 8 most of which however still employ harsh reaction conditions (i.e., refluxing in acetic or sulphuric acid). Deng et al. have recently intro- duced an elegant approach to the same γ-pyranopyrazole skele- ton that relies on a tandem cyclisation process employing certain diazo compounds as starting materials. 9 Nevertheless, other concise methods of constructing new γ-pyrone structures with potential biological activities continue to be in demand. In response, we herein report a straightforward, one-pot synthetic protocol for constructing γ-pyranopyrazoles with a rare structural skeleton. This rare γ-pyranopyrazole skeleton differs from the common skeleton insofar as the nitrogen of the pyrazole ring is located on the bridge of the fused ring system (Fig. 1). To the best of our knowledge, only one report has described the preparation of this skeleton, namely as a low-yield by-product that remains to be thoroughly investigated. 10 As part of our continued interest in synthesizing fluorescent labelling molecules, we have outlined a synthetic approach for preparing 1,5-diazabicyclo [3.3.0]octadienediones (D) (9,10- dioxabimanes) (Scheme 1). We proposed a two-step synthetic pathway, first involving a classical amide coupling between pyrazolone (A) and 2-propiolic acid (B) (Scheme 1). Compound C was anticipated to cyclize in an intramolecular hydroamina- tion process to yield the expected bimane structure (D). Surprisingly, however, instead of producing bimane (D), compound C cyclized unexpectedly from the oxygen atom over the alkyne to yield compound E:a γ-pyrone derivative fused with a pyrazole ring. We thus experimentally investigated the Fig. 1 Structure of γ-pyrone and γ-pyranopyrazole. † Electronic supplementary information (ESI) available: Experimental pro- cedures, characterization of new compounds, spectral data, computational results and crystallographic data. CCDC 1456335. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ob01099g a Department of Chemistry, Faculty of Science, İzmir Institute of Technology, Urla, 35430 Izmir, Turkey. E-mail: mustafaemrullahoglu@iyte.edu.tr b Department of Chemistry, Hacettepe University, Ankara 06800, Turkey c Department of Chemistry, Atatürk University, Erzurum 25240, Turkey 7490 | Org. Biomol. Chem. , 2016, 14, 7490–7494 This journal is © The Royal Society of Chemistry 2016 Open Access Article. Published on 05 July 2016. Downloaded on 04/02/2017 11:20:02. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online View Journal | View Issue