Aromatization of IMDAF adducts in aqueous alkaline media{ Fedor I. Zubkov,* Inga K. Airiyan, Julya D. Ershova, Timur R. Galeev, Vladimir P. Zaytsev, Eugeniya V. Nikitina and Alexey V. Varlamov Received 17th February 2012, Accepted 20th February 2012 DOI: 10.1039/c2ra20295f In this paper, we propose a simple synthesis of isoindoline-4-carboxylic acids by means of the aromatization of 3a,6-epoxyisoindoles in alkaline media. The method is facile from an experimental point of view: a short-term (0.5–2h) reflux of epoxyisoindoles in 5% aqueous solutions of alkali leads to the target products in 40–90% yields. The absence of by-products, ease of isolation of the target products and applicability to acidophobic group bearing substrates favorably distinguishes the proposed procedure from previously utilized acid-catalyzed methods. The proposed strategy has been successfully utilized for isoindole containing compounds and nuevamine-type alkaloids. Introduction Isoindole chemistry is a thriving and relatively new area of organic chemistry; nevertheless, numerous synthetic approaches toward isoindoles have been proposed in the literature. 1 This advance is due to the large amount of biologically active isoindole-containing compounds found in nature 2 (for example, lennoxamine, aristoyagonine, nuevamine, chilenine and some other alkaloids). Of all the isoindole fragment construction methods, the one that has attracted the most attention of our group over the last decade 3 is a two-step approach based on the IMDAF (intramolecular Diels–Alder reaction of furans) 4 reaction. The advantages of the method are cheap starting materials, wide chemical diversity (substituted furfurals can be used as the starting materials and various alkenyl halides, anhydrides and chlorides of a,b-unsaturated acids can be used in the acylation step) and the simplicity of the experimental procedure. We have been trying to apply this approach for syntheses of isoindole-containing alkaloids and alkaloid-like compounds, particularly nuevamine and its derivatives (Fig. 1). We encoun- tered problems in the final step of the route for our model compounds (see Results and discussion): aromatization of the 7-oxabicyclo[2.2.1]heptene fragment to 10,12a-epoxyisoin- dolo[1,2-a]isoquinoline using acid catalysis and common proce- dures was not successful. The IMDAF approach towards isoindolines (Fig. 2) was suggested for the first time by Yugoslav (now Croatian) chemists in 1964. 5 The authors proposed a number of reagents to be utilized in the final step as dehydrating agents: HBr/AcOH, H 2 SO 4 /AcOH and diluted H 2 SO 4 . This approach turned out to be so effective that it is still being widely used 6 and improved. 7 Thereupon, the method was extended to aromatization of the 3a,6-epoxy-2-benzofuran core. 8 In addition to the above-mentioned reagents, H 3 PO 4 , 3 HCl, 6a p-TSA 6g,7a and BF 3 ?OEt 2 9 are also effective tools for this transformation. Two more methods 7 of aromatization of 3a,6- epoxyisoindoles have been proposed: a protic ionic liquid based approach 7b (CF 3 SO 3 H/ionic liquid/microwave irradiation), and a method utilizing the K 10 -Fe 3+ catalyst coated on montmor- illonite clay. 7c Most of the mentioned conditions lead to good yields of the target isoindoles. However, all cited methods involve acid catalysis. It should be noted that proton or Lewis acids can produce unpredictable but often very interesting side transfor- mations of the 7-oxabicyclo[2.2.1]heptene fragment. 5f,6e,9 See for example, the unexpected rearrangement of 2,3,7,7a-tetrahydro- 3a,6-epoxyisoindol-1-ones to furo[2,3-c]pyrrolo[3,4-b]pyrrole- 2,4,6-triones in 85% H 3 PO 4 . 9 Another limitation of the described methods is their nonapplicability to the synthesis of isoindoles bearing acidophobic substituents (furyl, allyl, pyrrolyl, etc.) There are a few studies on the aromatization of the 7-oxabicyclo[2.2.1]heptene moiety in strong alkaline media. As an illustration, a very limited number of publications on the aromatization of similar systems with metal–organic compounds and alcoholates can be mentioned. 8a,10 Dehydrative aroma- tization of 3-oxo-1,3-dihydro-2-benzofuran-4-carboxylic acids takes place in a 3M NaOMe solution 8a and aromatization of 7-oxabicyclo[2.2.1]heptanes can be carried out using t-BuLi. 10a Aromatization of epoxyisoindolyl phosphonates 10b can be performed in different conditions (H 3 PO 4 , TFA), but NaOMe/ MeOH leads to several by-products. We present a newly developed effective procedure of aromatization of 3a,6-epoxyisoindoles in 5% alkali aqueous solution, which was successfully utilized for the synthesis of nuevamine derivatives. To the best of our knowledge, this is the first time dilute aqueous alkaline solutions have been used as Department of Organic Chemistry, Peoples’ Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow, Russia. E-mail: fzubkov@sci.pfu.edu.ru { Electronic Supplementary Information (ESI) available: full physico- chemical and spectral data of all synthesized compounds. See DOI: 10.1039/c2ra20295f/ RSC Advances Dynamic Article Links Cite this: RSC Advances, 2012, 2, 4103–4109 www.rsc.org/advances PAPER This journal is ß The Royal Society of Chemistry 2012 RSC Adv., 2012, 2, 4103–4109 | 4103