Acid-Catalyzed Formal Cycloaddition of α,β-Unsaturated Carbonyls with Epoxides: Dioxepines or Acetals? Veronica Santacroce, Emanuele Paris, Giovanni Sartori, Raimondo Maggi, and Giovanni Maestri* Clean Synthetic Methodology Group, Dipartimento di Chimica, Universita ̀ degli Studi di Parma, Parma I-43124, Italy * S Supporting Information ABSTRACT: It has been recently reported that the reaction of α,β-unsaturated carbonyl derivatives with epoxides in the presence of a homogeneous acid catalyst readily delivers the corresponding dioxepines via formal (4 + 3) cycloaddition. We report herein that the same apparent reactivity can be triggered via heterogeneous catalysis. Characterization of products by means of NMR correlation experiments and DFT modeling revealed, however, that products are the acetals of the unsaturated reagent rather than the desired heterocycles. C atalytic cycloadditions are a powerful synthetic tool for the straightforward construction of complex polycyclic frameworks from readily available precursors. 1 Regarding medium-sized rings, their broad domain of applications pushed the development of a variety of elegant methods to access seven-membered cyclic cores by either a (4 + 3) or a (5 + 2) strategy. 1 While extremely efficient protocols exist to form carbocycles, the incorporation of heteroatoms within the ring remains synthetically challenging. 2 1,4-Dioxepines are well-known for their biological properties (Scheme 1), 3 and their preparation usually requires substrate prefunctionalization and multistep syntheses, ultimately affect- ing the panel of readily accessible motifs and the environmental cost of the process. 4 Recently introduced has been the possibility to synthesize these heterocycles by formal cyclo- addition between an α,β-unsaturated carbonyl compound and an epoxide in the presence of a Lewis acid as homogeneous catalyst (Scheme 2, left). 5 As part of our ongoing interest toward the use of zeolites as an efficient tool to develop eco-friendly synthetic processes, 6 we wished to develop a catalytic synthesis of dioxepines via formal (4 + 3) cycloaddition using these heterogeneous solid acids. On the basis of our studies, we report herein that products of these reactions are vinyl acetals rather than the originally proposed dioxepines (Scheme 2, right). As a model reaction, we attempted the synthesis of the reported dioxepine 3 5 by stirring 3 mmol of ketone 1a with 1.1 equiv. of cyclohexene oxide 2a in the presence of a catalytic amount of a solid acid at 30 °C for 8 h (Scheme 3). Epoxide 2a was slowly added to the reaction mixture (0.55 mmol/h) to minimize its decomposition under acidic conditions. 7 Upon optimization of reaction parameters, we were then delighted to observe formation of the product described as 3 as a single diastereomer in 68% yield using zeolite HY-360 as catalyst. No reaction took place in the absence of the catalyst, and lower yields were achieved increasing the pace of epoxide addition. The product is relatively sensitive to moisture, slowly decomposing to a mixture of starting ketone and trans-1,2- cyclohexandiol. A comparable selectivity toward the product (62%) was achieved using BF 3 etherate as catalyst. 5 The heterocycle that we synthesized reproduced all the spectroscopic data reported for dioxepine 3 ( 1 H and 13 C NMR, IR, and MS; Figure 1 presents relevant captions of key 1 H and 13 C NMR resonances). We were, however, puzzled by the attribution of the surprisingly large coupling constant of 15.9 Hz observed in the 1 H NMR to the interaction between the benzylic and vinylic protons of 3 (highlighted in purple and Received: July 1, 2014 Published: August 5, 2014 Scheme 1. 1,4-Dioxepine Core in Natural Products Scheme 2. Comparison of Possible Outcomes Reacting Epoxides with α,β-Unsaturated Carbonyls Scheme 3. 1,4- vs 1,2-Addition in the Reaction of Epoxide 2a with α,β-Unsaturated Ketone 1a Note pubs.acs.org/joc © 2014 American Chemical Society 8477 dx.doi.org/10.1021/jo501458n | J. Org. Chem. 2014, 79, 8477-8480