A furan ring expansion approach to the synthesis of novel pyridazino-psoralen derivatives Jose ´ C. Gonza ´lez-Go ´mez, * Lourdes Santana and Eugenio Uriarte Departamento de Quı ´mica Orga ´ nica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain Received 3 January 2005; revised 21 February 2005; accepted 4 March 2005 Available online 23 March 2005 Abstract—A convenient preparation of the parent tetrahydrobenzodifuran 2 was developed from resorcinol. The oxidation of one or both furan rings of this key intermediate was accomplished with DDQ and the resulting benzodifuran was subsequently reacted with 3,6- dimethoxycarbonyl-1,2,4,5-tetrazine to afford the expected pyridazino-psoralen derivative in good yield. This simple method allowed the efficient preparation of a pyridazino-psoralen derivative with a formyl group at C-7, which was introduced by directed ortho-lithiation in the intermediate 2. An aminoalkyl side-chain was also introduced to the tetracyclic skeleton through the aldehyde functionality in a reductive amination process, which was accompanied by an unprecedented reduction of the pyridazine ring. q 2005 Elsevier Ltd. All rights reserved. 1. Introduction Psoralens form a group of natural or synthetic compounds that are of great pharmacological interest. 1 One of the most important applications of these compounds is in the field of photochemotherapy, where psoralens are capable of under- going photoaddition with thymine units present in DNA. 2 However, the utility of the most effective compounds in this class is limited by side-effects that are mainly related to their ability to cross-link the two strands of the DNA helix. 3 One of the most promising strategies to obtain monofunctional psoralens involves incorporating one of the reactive double bonds in a benzene nucleus by forming benzopsoralens (Fig. 1). This approach results in molecules that have a high propensity for intercalation and photoreaction with DNA and also helps to overcome some of the negative phototoxic effects. 4 With this information in mind, we embarked on the preparation of nitrogenated analogues of benzopsoralens reasoning that the inclusion of nitrogen atoms in the polycyclic skeleton may lead to improved interaction with DNA. 5 In particular, we were encouraged by the remarkable antiproliferative activity recently reported for pyrone side tetracyclic psoralen derivatives. 6 Prompted by this result and the widely used Diels–Alder of 1,2,4,5-tetrazines; 7 we focused on the development of a general synthetic route to novel pyridazino psoralens in which the pyridazine ring is attached to the pyrone nucleus of the psoralen skeleton. 8 In a preliminary attempt to fuse a pyridazine ring to psoralens using 3,6-dimethoxycarbonyl-1,2,4,5-tetrazine, we observed that the cycloaddition was accompanied by opening of the furan ring and concomitant expansion to a pyrone ring upon intramolecular transesterification. 9 We decided to exploit this interesting domino reaction path- way 10 to explore the use of benzodifuran derivatives to prepare these novel pyridazino-psoralens (Scheme 1). 2. Results and discussion An important intermediate in our synthetic proposal is the tetrahydrobenzodifuran 2 and the synthesis of this com- pound has been reported from 6-hydroxy-dihydrobenzo- furan in three steps. 11 Our initial goal was to develop a more convenient preparation of this intermediate and, in this respect, we envisaged a route based on a magnesium mediated cyclization process, which was reported by Nichols et al. for similar symmetrical benzodifuran derivatives. 12 The synthesis of this compound commenced with dialkylation of resorcinol using excess 1-bromo-2- 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.03.018 Tetrahedron 61 (2005) 4805–4810 Figure 1. Keywords: Psoralens; Benzofurans; Tetrazines; Diels–Alder; DNA intercalants. * Corresponding author. Tel.: C34 981563100; fax: C34 981594912; e-mail: jcgg1971@yahoo.es