New procedures for the selective synthesis of 22H)-pyranone derivatives and 3-aryl-4-iodoisocoumarins Matteo Biagetti, p Fabio Bellina, Adriano Carpita, Paolo Stabile and Renzo Rossi p Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy Received 4 March 2002; revised 5 April 2002; accepted 2 May 2002 Abstract Ð5-Iodo-22H)-pyranone derivatives have been selectively synthesized by reaction of stereode®ned methyl 2-en-4-ynoates with iodine in MeCN, CH 2 Cl 2 orC 6 H 6 at 208C Method C) or by treatment of these esters with ICl in CH 2 Cl 2 at 208C Method B). Methods B and C proved also to be suitable for the preparation of 3-aryl-4-iodoisocoumarins from the corresponding methyl 2-arylethynyl)benzoates. Interestingly, the high selectivity of iodolactonization of stereode®ned methyl 2-en-4-ynoates by Method B allowed preparation in moderate yields of 22H)-pyranone derivatives by a one-pot sequence of iodolactonization and Stille-type reactions. q 2002 Elsevier Science Ltd. All rights reserved. 1. Introduction Iodolactonization of alkynoic acids 1 is a process much less investigated and employed in synthetic organic chemistry than iodolactonization of alkenoic acids 2 or alkyl alkeno- ates. 3 Nevertheless, it has found utility in the preparation of ®ve-membered halolactone analogues of a-aminoacids that have value as inhibitors of serine proteases. 4 On the other hand, until a few years ago no data were available on iodo- lactonization of stereode®ned enynoic acids, but recently, in the course of our studies on the synthesis of biologically active, naturally-occurring oxygen-containing heterocycles and their analogues, 5 we developed convenient protocols for the synthesis of natural and unnatural 5,6-disubstituted and 6-substituted 22H)-pyranones, 7 and 8, which involved iodolactonization of 5-substituted Z)-2-en-4-ynoic acids 1 Scheme 1). 6,7 In particular, we found that reaction of compounds 1 with 3.0 equiv. of iodine and 3.0 equiv. of NaHCO 3 in MeCN at 208C Method A) or with 1.0 equiv. of ICl in CH 2 Cl 2 at 208C Method B) provides mixtures of E)-5-1-iodoylidene)-25H)-furanones 3 and 6-substituted 5-iodo-22H)-pyranones 4 in which these last compounds are the major products Scheme 1). 6 We also found that compounds 4, which are available in 63±72% yield by chro- matographic separation from iodides 3, are able to undergo Stille-type reactions with a variety of organotin derivatives to give 5,6-disubstituted 22H)-pyranones 7 in moderate to good yields Scheme 1). 6 One of these compounds, i.e. 5-1- butynyl)-6-methyl-22H)-pyranone 7a), was then used as a direct precursor to two substances produced by fungal culture LL-11G219, which function as androgen ligands, i.e. Z)-5-1-butenyl)-6-methyl-22H)-pyranone 11) and 5-butyl-6-methyl-22H)-pyranone 12). 6 In continuation of these investigations we then discovered that 6-alkyl-5-iodozinc-22H)-pyranones 13, which are easily available from iodides 4 by insertion of activated zinc metal on their carbon-iodine bond, undergo Pd-cata- lyzed reaction either with activated alkenyl halides or with activated and deactivated hetero)aryl halides to provide compounds 7 in fair to good yields Scheme 1). 7 Moreover, we observed that acidic hydrolysis of the above-mentioned organozinc derivatives gave in satisfactory yields 6-substi- tuted 22H)-pyranones 8 including two natural products Scheme 1). 7 More recently, we examined the possibility of accessing 3,5,6-trisubstituted and 3,6-disubstituted 22H)-pyranones of general formula 9 and 10, respectively, starting from 5-substituted E)-2-bromo-2-en-4-ynoic acids 2 by a chemistry similar to that successfully used to prepare compounds 7 and 8 and we found that iodolactonization of carboxylic acids 2 using Methods A or B allows prepara- tion of 6-substituted 3-bromo-5-iodo-22H)-pyranones 6 in yields ranging from 30 to 75%. 8 These dihalides were then converted into compounds 9 by two consecutive Stille- type reactions Scheme 1). 8 On the other hand, selective reduction of dihalides 6 to the corresponding 6-substituted 3-bromo-22H)-pyranones 14 followed by a Tetrahedron 58 2002) 5023±5038 Pergamon TETRAHEDRON 0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved. PII: S0040-402002)00469-6 Keywords: iodine heterocycles; pyrones; isocoumarins; Stille coupling; palladium catalysis. p Corresponding authors. Tel.: 139-50-918214; fax: 139-50-918260; e-mail: rossi@dcci.unipi.it