Ring-closing metathesis for the synthesis of 2H- and 4H-chromenes Willem A. L. van Otterlo, * E. Lindani Ngidi, Samuel Kuzvidza, Garreth L. Morgans, Simon S. Moleele and Charles B. de Koning Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, 2050 Johannesburg, South Africa Received 31 May 2005; revised 20 July 2005; accepted 4 August 2005 Available online 26 August 2005 Abstract—Six 4H-chromenes were synthesized from substituted phenols using vinylstannylation and ring-closing metathesis (RCM) as key steps. In addition, a different approach involving amongst other steps, an aryl allyl isomerization and RCM afforded a set of seven 2H-chromenes from phenolic precursors. q 2005 Elsevier Ltd. All rights reserved. 1. Introduction Compounds in which a benzene and pyran ring are fused together with various levels of saturation and oxidation are very common in Nature. 1 The 1-benzopyrans include structural skeletons such as chromane 1,4H-chromene 2 and 2H-chromene 3 as depicted in Figure 1. As a class of compounds the 4H-chromenes 2 (also known as 4H-1-benzopyrans) are rather unusual and only a few examples of natural products containing this structure have been isolated. 2 An example of a naturally occurring 4H-chromene is 7-hydroxy-6-methoxy-4H-chromene 4, which was efficiently synthesized by De Korte and co- workers (Fig. 2). 3 This natural product, which reportedly has interesting organoleptic properties, was isolated from the plant Wisteria sinensis along with the related compound, 6,7-dimethoxy-4H-chromene 5. 2 In contrast to the paucity of 4H-chromene examples, the literature abounds with vast numbers of papers reporting the isolation and synthesis of naturally occurring 2H-chromenes 3. 1 Examples reported recently include compounds 6 and 7, both isolated from the leaf essential oil of Calyptranthes tricona (Fig. 2). 4 The chromene skeletons have also elicited pharmaceutical interest as structural elements in drug-like compounds. Examples of artificial compounds bearing the 2H-chromene motif include 6-fluoro-2H-chromene 8, 5 which exhibited the highest 5-HT 1A receptor affinity among a series of novel 6-fluorochromane derivatives; and 6-substituted 2H-chro- menyl compound 9, 6 which was tested for potential antidiabetic activity as a Na C -glucose co-transporter inhibitor (Fig. 3). In addition, a series of hypoglycemic benzenesulfonylsemicarbazides with potential application in the treatment of diabetes mellitus included substituted 2H-chromene 10. 7 In recent years, the ring-closing metathesis (RCM) reaction 8 has been used to synthesize both the 2H- 9 and 4H-chromene 10 classes. Methodology for the synthesis of the 2H-chromenes normally involves the RCM of an Tetrahedron 61 (2005) 9996–10006 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.08.020 Figure 1. Figure 2. Keywords: 2H-chromenes; 4H-chromenes; Ring-closing metathesis; Isomerization. * Corresponding author. Tel.: C27 11 717 6707; fax: C27 11 717 6749; e-mail: willem@aurum.chem.wits.ac.za