Synthesis of novel azaxanthones derived from N-hydroxyazoles Jesper L. Kristensen, Per Vedsù ² and Mikael Begtrup p Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark Received 11 October 2001; accepted 10 January 2002 Abstract ÐThe synthesis of a new class of azaxanthones is presented. The N± O functionality of 1-hydroxypyrazole and 1-hydroxy-1,2,3- triazole was used to direct metalation and subsequently incorporated in the new ring systems. q 2002 Published by Elsevier Science Ltd. 1. Introduction The regioselective functionalisation of 1-hydroxypyrazole and 1-hydroxy-1,2,3-triazole was reported recently. 1±4 We sought to incorporate the N ± O functionality in a new and distinct group of heterocyclic systems using these protocols. The xanthone is an ubiquitous structural motif found in numerous natural products, and substituted derivatives have a broad spectrum of biological activities. 5±10 The azaxanthones 1a and 1b in Scheme 1 were chosen as the target molecules. 2. Retrosynthetical analysis We speculated that the compounds could be prepared via two different approaches, see Scheme 2. In route A, the central ring would be constructed via an intramolecular nucleophilic aromatic substitution. Route B involves an anionic intramolecular ring closure, analogous to the recent synthesis of substituted xanthones reported by Snieckus. 11±13 3. Synthesis of 1a and 1bÐroute A 1-(Benzyloxy)pyrazole 2a and 1-benzyloxy-1,2,3-triazole 2b were acylated in 82 and 71% yield, respectively via our metalation/transmetalation/cross-coupling protocols, followed by debenzylation, see Scheme 3. The crucial ring closure via displacement of the 2-¯uoro substituent proceeded under very mild conditions: treating 4a and 4b with 2 equiv. K 2 CO 3 in DMF at 508C for 30 min gave full conversion to the desired azaxhanthones 1a and 1b. 14 Suitable crystals of 1b were obtained, and an X-ray structure con®rmed the structural assignment (Fig. 1). 15 Although the synthesis proceeds very smoothly it requires four individual steps: benzylation, acylation, debenzylation and ring closure. Thus, a shorter synthesis would be desirable. When ortho-lithiated aryl carbamates are warmed to rt an anionic Fries rearrangement produces the corresponding salicylamides, see Scheme 4. 16 If the lithiated pyrazole 5 depicted in Scheme 4 could be generated, a similar rearrangement would give 4a, thereby circumventing the Tetrahedron 58 (2002) 2397±2404 Pergamon TETRAHEDRON 0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd. PII: S0040-4020(02)00034-0 Scheme 1. The target azaxanthones. Scheme 2. Retrosynthetical analysis. Routes A and B. Keywords: azaxanthones; cyclisations; anionic ring closure. p Corresponding author. Tel.: 145-35-30-60-00; fax: 145-35-30-60-40; e-mail: begtrup@dfh.dk ² Current address: Novo Nordisk A/S, Medicinal Chemistry Research, DK- 2760 Ma Êlùv, Denmark.