TETRAHEDRON LETTERS Tetrahedron Letters 44 (2003) 5781–5784 Pergamon The first nucleophilic aromatic substitution of suitably activated 2-methoxyfurans with Grignard reagents M. Rosaria Iesce,* M. Liliana Graziano, Flavio Cermola, Stefania Montella and Lucrezia Di Gioia Dipartimento di Chimica Organica e Biochimica, Universita ` degli Studi di Napoli Federico II, Complesso Universitario Monte S. Angelo, via Cinthia, I -80126 Napoli, Italy Received 6 June 2003; accepted 7 June 2003 Abstract—The reaction of 2-methoxyfuroates 1 with Grignard reagents 2 leads to tertiary alcohols or S N Ar products depending on the position of the alkoxycarbonyl group. OMe-Displacement occurs only for 3-substituted derivatives. It takes place even for 3-acetyl-2-methoxyfuran while the presence of a further ester function at 4 position induces the formation of the sole 4-tertiary alcohol. The OMe-substitution has been verified for a wide range of furans and Grignard reagents and low yields have been found only in the reactions with the benzylic and allylic reagents which are delocalized anions. A mechanistic interpretation is given. © 2003 Elsevier Ltd. All rights reserved. The furans are versatile building blocks in organic synthesis for the preparation of many compound types. 1 This versatility is due to the double nature of 1,4-diene and of aromatic compound. So, furans undergo easy [4+2] cycloaddition as well as electrophilic aromatic substitution, both reactions representing key steps in the syntheses of products of applicative and biological interest. 1,2 Conversely, the nucleophilic aro- matic substitution occurs with difficulty even in the halogen-substituted derivatives. 2,3 In the latter cases, the introduction of powerful electron-withdrawing groups, as the nitro substituent or the carboxy or carbalkoxy function, greatly facilitates the reaction. 3 Here we report the first nucleophilic substitution by Grignard reagents of 2-methoxyfurans activated by carb- alkoxy or carbonyl substituents. The OMe-displace- ment by Grignard reagents has been reported to occur in the benzene 4 and naphthalene 5 derivatives when suit- ably substituted with nitro, 5a ester 4a,5b or oxazoline 4b,5c groups. The reaction of 2-methoxyfurans 1a, 6 1b, 6 1c 7 and 1d 6 bearing an ester function at 3-, 4-, 5- or at 3- and 4-positions with EtMgBr (2a) was carried out under classical protocols and the results are reported in Scheme 1. 8 Unexpectedly, furan 1a gave the OMe-sub- stituted derivative 3a in addition to little amount of 4a, deriving from OMe-substitution followed by addition of the Grignard reagent to the 3-methoxycarbonyl func- tion. In the other cases the reaction led exclusively to the tertiary alcohols 5 9 and 6 and, for 1d, to lactone 8 evidently via the undetected furan 7. The peculiar behaviour of 3-substituted furan 1a prompted us to examine the scope of the reaction by using several combinations of 3-methoxycarbonyl-2- methoxyfurans (1e–g, 6 1h, 10 1i 10 ) and Grignard reagents (2b–f). The reaction was also carried out on 3-acetyl derivative 1j. 6 As shown in Table 1, 8 the OMe-displace- ment prevails definitely over the addition to the alkoxy- carbonyl group, even to the carbonyl group (entry 7). However, in the latter case, substitution is followed by addition to the highly reactive carbonyl function so that the main product is the furan 4g. The reaction mixtures are generally clean. As an exception, the reaction of 1a with the benzyl derivative 2e led to a complex mixture of products among which the only identified compound was 3k (20% yield with a purity of 85%). It is notewor- thy that the allylic reagent 2f gave both the S N Ar product 3l and the tertiary alcohol 9l with a large excess of the latter (15: 85 molar ratio). The results can be easily interpreted on the basis of Meyers’ hypothesis 4b assuming that the OMe displace- ment proceeds via an addition–elimination sequence in which the metal forms a strong complex with the Keywords : 2-methoxyfuroates; Grignard reagents; nucleophilic aro- matic substitution. * Corresponding author. Tel: +39-81-674334; fax: +39-81-674393; e-mail: iesce@unina.it 0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0040-4039(03)01430-8