Facile and Efficient Sulfenylation Method Using Quinone Mono-O,S-Acetals under Mild Conditions Masato Matsugi, † Kenji Murata, † Kentoku Gotanda, † Hisanori Nambu, † Gopinathan Anilkumar, † Keita Matsumoto, ‡ and Yasuyuki Kita* ,† Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan, and Research Center, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Omiya, Saitama 330-8530, Japan kita@phs.osaka-u.ac.jp Received December 5, 2000 A novel sulfenylation method induced by aromatization of quinone mono-O,S-acetals is described. These sulfenylation reagents readily react with silyl enolethers or electron rich aromatic compounds to give sulfenylation products under mild conditions. In particular, O,S-acetal 2j, which possesses a pentafluorophenylthio function, is the most effective reagent from the standpoint of the adaptability for various substrates. Introduction It is important to effectively introduce sulfur into organic compounds, since many biologically active com- pounds contain sulfur functions. 1 Furthermore, the sulfur function has great versatility as a foothold for the construction of various target molecules. 2 Many sulfeny- lation methods have been studied to date 3 that include electrophilic substitution with sulfur-containing electro- philes such as sulfenyl chloride, sulfenylamines, thiosul- fonates, disulfides, nucleophilic substitution of aryl ha- lides with metal mercaptides, replacement reactions via diazonium intermediates, and coupling reactions via a radical cation. However, these approaches usually require basic, acidic, or heating conditions during the sulfenyla- tion process except for in limited cases, 3q and until now, a mild sulfenylation reaction under neutral conditions was not readily available. We have already reported that various quinone mono- O,S-acetals 2, which are intermediates in the aromatic Pummerer-type rearrangement, could be easily isolated in high yields, 4 and recent preliminary communications 5 showed that these quinone mono-O,S-acetals 2 readily aromatize by reaction with some nucleophiles giving sulfenylation products under mild conditions. In this paper, we present the full account of these studies along with the efficient sulfenylation of various substrates. The starting quinone mono-O,S-acetals 2a-j were readily prepared from the corresponding sulfoxides 1 by the reported method 4 using 1-ethoxy vinylesters (Table 1). 6,7 Result and Discussion We first examined the ability of quinone mono-O,S- acetals 2a-e to undergo sulfenylation of cyclic silyl enol * To whom correspondence should be addressed. † Osaka University. ‡ Taisho Pharmaceutical Co., Ltd. (1) For recent reviews, see: (a) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041-2114. (b) Faulkner, D. J. Nat. Prod. Rep. 1995, 12, 223-269. (2) (a) Trost, B. M. Chem. Rev. 1978, 78, 363-382. (b) Akai, S.; Takeda, Y.; Iio, K.; Takahashi, K.; Fukuda, N.; Kita, Y. J. Org. Chem. 1997, 62, 5526-5536. (c) Kita, Y.; Iio, K.; Kawaguchi, K.; Fukuda, N.; Takeda, Y.; Ueno, H.; Okunaka, R.; Higuchi, K.; Tsujino, T.; Fujioka, H.; Akai, S. Chem. Eur. J. 2000, 6, 3897-3905. (d) Akai, S.; Morita, N.; Iio, K.; Nakamura, Y.; Kita, Y. Org. Lett. 2000, 2, 2279-2282. (3) For examples: (a) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976, 98, 4887-4902. (b) Scholz, D. Synthesis 1983, 944-945. (c) Bischoff, L.; David, C.; Martin, L.; Meudal, H.; Roques B.-P.; Fournie ´-Zaluski, M.-C. J. Org. Chem. 1997, 62, 4848-4850. (d) Foray, G.; Pen ˜e ´n ˜ ory, A. B.; Rossi, R. A. Tetrahedron Lett. 1997, 38, 2035-2038. (e) Tanaka, T.; Azuma, T.; Fang, X.; Uchida, S.; Iwata, C.; Ishida, T.; In, Y.; Maezaki, N. Synlett 2000, 33-36. (f) Bottino, F.; Fradullo, R.; Pappalardo, S. J. Org. Chem. 1981, 46, 2793-2795. (g) Criatau, H. J.; Chabaud, B.; Chene, A.; Christol, H. Synthesis 1981, 892-894. (h) Oae, S.; Shinhana, K.; Kim, Y. H. Chem. Lett. 1979, 939- 942. (i) Atkinson, J. G.; Hamel, P.; Girard, Y. Synthesis 1988, 480- 481. (j) Anzai, K. J. Heterocycl. Chem. 1979, 16, 567-569. (k) Bates, D. K.; Tafel, K. A. J. Org. Chem. 1994, 59, 8076-8080. (l) Tomita, K.; Terada, A.; Tachikawa, R. Heterocycles 1976, 4, 733-737. (m) Franco, F.; Greenhouse, R.; Muchowski, J. M. J. Org. Chem. 1982, 47, 1682- 1688. (n) Hocker, J.; Ley, K.; Merten, R. Synthesis 1975, 334-335. (o) Hartke, K.; Teuber, D.; Gerber, H.-D. Tetrahedron 1988, 44, 3261- 3270. (p) Pagnoni, U. M.; Pinetti, A. J. Heterocyclic Chem. 1993, 30, 617-621. (q) Kita, Y.; Takada, T.; Mihara, S.; Whelen, B. A.; Tohma, H. J. Org. Chem. 1995, 60, 7144-7148. (4) Kita, Y.; Takeda, Y.; Matsugi, M.; Iio, K.; Gotanda, K.; Murata, K.; Akai, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 1529-1531. (5) (a) Matsugi, M.; Gotanda, K.; Murata, K.; Kita, Y. Chem. Commun. 1997, 1387-1388. (b) Matsugi, M.; Murata, K.; Nambu, H.; Kita, Y. Tetrahedron Lett. 2001, 42, 1077-1080. (6) (a) Kita, Y.; Maeda, H.; Omori, K.; Okuno, T.; Tamura, Y. J. Chem. Soc., Perkin Trans. 1 1993, 2999-3005. (b) Shibata, N.; Matsugi, M.; Kawano, N.; Fukui, S.; Fujimori, C.; Gotanda, K.; Murata, K.; Kita, Y. Tetrahedron: Asymmetry 1997, 8, 303-310. (7) Quinone mono-O,S-acetals (2a-j) are stable for several months during storage in a refrigerator. Table 1. Preparation of Quinone Mono-O,S-acetals 2 2434 J. Org. Chem. 2001, 66, 2434-2441 10.1021/jo001710q CCC: $20.00 © 2001 American Chemical Society Published on Web 03/15/2001