Synthesis and Properties of a New Member of the Calixnaphthalene Family: A C 2 -Symmetrical endo-Calix[4]naphthalene Sultan Chowdhury and Paris E. Georghiou* Department of Chemistry, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador A1B 3X7, Canada parisg@mun.ca Received June 11, 2002 Abstract: The synthesis of a new endo-calix[4]naphthalene is described. The reaction sequence involves the cyclocon- densation of a key bisnaphthylmethane intermediate (8) with formaldehyde. This key intermediate (8) is formed using a modified Suzuki-Miyaura Pd-catalyzed cross- coupling reaction between bromomethylnaphthyl (6) and naphthylboronic acid (7), both of which can be derived from 2-hydroxynaphthoic acid. Calix[n]arenes constitute an important class of com- pounds that have been widely used as “molecular bas- kets” in supramolecular complexation studies and in a variety of other applications. 1,2 In general, the depth of the basket or cavity in a cone conformer of an unsubsti- tuted calix[4]arene as measured from the phenolic oxygen atom to the distal hydrogen atom on the para hydrogen atom is approximately 5.3 Å. In an analogous unsubsti- tuted endo-calix[4]naphthalene such as 1, however, the comparable distance is 7.5 Å (Figure 1). 3 Calix[4]- naphthalenes such as 1 can therefore be thought of as deeper and electron-richer “molecular baskets” than the corresponding calix[4]arenes. Such calixnaphthalenes have been shown to be capable of complexing 4 with C 60 and also of forming a dimer in the solid state. 5 To date, there have only been a few calix[n]naphtha- lenes that have been reported. 5-7 In this paper, we report the synthesis of the newest member of the calix[4]- naphthalene family, the C 2 -symmetrical endo-calix[4]- naphthalene 2 and its alkoxy derivatives. The synthetic route includes the use of directed ortho metalation conditions and a modified 8 Suzuki-Miyaura 9 Pd-cata- lyzed cross-coupling reaction to produce key intermedi- ates. A simple retrosynthetic approach can be envisioned for a convergent synthesis of 2 (or its derivatives) via a “2 + 2” cross-coupling of synthons such as 3 (or 3a) with 4 and/or 4a (Scheme 1) using different metal-assisted or catalyzed carbon-carbon bond-forming methodologies, in particular, the modified Suzuki-Miyaura coupling reac- tion. 8,9 We have previously demonstrated that it is possible to achieve Pd-catalyzed cross-coupling between phenyl- or naphthylboronic acids and benzyl bromides, iodides, or bromomethylnaphthalenes to form methylene- bridged products in synthetically useful yields. 8 However, until now, this methodology had not been tested for the “2 + 2” cross-coupling reactions between diboronic acids such as 3 (or 3a), with 4 and/or 4a, as envisioned, for example, in Scheme 1. Both synthons 3 (or 3a) and 4 (or 4a) can be derived from the common intermediates bis(2-methoxy-3-naph- thyl)methane (5) or its O-methoxymethyl analogue, 5a. These latter intermediates, in turn, could be synthesized in 89% and 79% yields, respectively, using the modified Suzuki-Miyaura Pd-catalyzed reaction between 3-bro- momethyl-2-methoxynaphthalene (6) 5 and naphthylbo- ronic acids 7 or 7a. To efficiently produce the correspond- ing diboronic acid synthon 3 or 3a, however, the alkoxy groups in 5 or 5a, respectively, needed to first be removed (Scheme 2). This was achieved using BBr 3 in CH 2 Cl 2 to afford 8 in 95% yield. Bromination with Br 2 in acetic acid formed 9, which was then converted to the MOM- protected compound 9a, both steps affording near- quantitative yields. Double ortho-lithiation using n-BuLi (2.2 equiv) in THF at -78 °C followed by the in situ addition of trimethyl borate and subsequent hydrolysis furnished the desired diboronic acid synthon 3a. The second required synthon, 4, was synthesized from 5 by reaction with aqueous formaldehyde in HBr-acetic acid solution in 77% yield. (1) For a recent review, see: Gutsche, C. D. In Calixarenes 2001; Asfari, Z., Bohmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer Academic Publishers: Dordrecht, The Netherlands, 2001. (2) Calixarenes in Action; Mandolini, L., Ungaro, R., Eds.; Imperial College Press: London, England, 2000. (3) Molecular modeling calculations were performed using the PC SPARTAN Pro program from Wavefunction, Inc., Irvine, CA. (4) Georghiou, P. E.; Mizyed, S.; Chowdhury, S. Tetrahedron Lett. 1999, 40, 611. Mizyed, S.; Georghiou, P. E.; Ashram, M. J. Chem. Soc., Perkin Trans. 2 2000, 277. For complexation studies of C 60 with the related hexahomotrioxacalix[3]naphthalenes, see: Mizyed, S.; Miller, D. O.; Georghiou, P. E. J. Chem. Soc., Perkin Trans. 1 2001, 1916. (5) Georghiou, P. E.; Ashram, M.; Clase, H. J.; Bridson, J. N. J. Org. Chem. 1998, 63, 1819. (6) (a) Georghiou, P. E.; Ashram, M.; Li, Z.; Chaulk, S. G. J. Org. Chem. 1995, 60, 7284 and references therein. (b) For an earlier reference to the synthesis of 1, see also: Andreetti, G. D.; Bo ¨hmer, V.; Jordon, J. G.; Tabatabai, M.; Ugozzoli, F.; Vogt, W.; Wolff, A. J. Org. Chem. 1993, 58, 4023. (c) See also Ashram, M.; Mizyed, S.; Georghiou, P. E. J. Org. Chem. 2001, 66, 1473 for references to some other calixnaphthalenes. (7) For examples of a recently reported different class of calixnaph- thalene: (a) Shorthill, B. J.; Granucci, R. G.; Powell, D. R.; Glass, T. E. J. Org. Chem. 1998, 63, 3748. (b) Shorthill, B. J.; Glass, T. E. Org. Lett. 2000, 2, 577. (8) Chowdhury, S.; Georghiou, P. E. Tetrahedron Lett. 1999, 40, 7599. (9) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. FIGURE 1. Cone conformer of endo-calix[4]naphthalene (1) as determined by molecular modeling. 6808 J. Org. Chem. 2002, 67, 6808-6811 10.1021/jo026045v CCC: $22.00 © 2002 American Chemical Society Published on Web 08/29/2002