R¢ S R¢ 15 S 6 S 9 R S syn-conformer R 18 anti-conformer XCH2 CH2X R HSCH2 CH2SH OMe + S 3 4a 15 6 S 18 OMe syn-5 9 R R = H, X = Br (67%) i R = Me, X = Br R = Br, X = Cl R = NO2, X = Br R = But, X = Br a b c d e R = H R = Me R = Br R = NO2 R = But a b c d e (61%) (41%) (67%) (60%) 192 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 192–193 J. Chem. Research (M), 1997, 1323–1343 Medium-sized Cyclophanes. Part 44.1 Synthesis and Stereochemical Assignments of 9-Substituted 2,11-Dithia[3.3]metacyclophanes Takehiko Yamato,*a Mitsuaki Shigekuni,a Hidetsugu Kunugidaa and Yoshiaki Naganob aDepartment of Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi, Saga-shi, Saga 840, Japan bTohwa Institute of Science, Tohwa University, 1-1 Chikushigaoka, Minami-ku, Fukuoka 815, Japan Various syn- and anti-9-substituted 2,11-dithia[3.3]metacyclophanes are obtained by the coupling reaction of the corresponding 2,6-bis(bromomethyl)benzenes and 1-substituted 2,6-bis(sulfanylmethyl)-4-tert-butylbenzenes under highly diluted conditions in 10% ethanolic KOH in the presence of a small amount of NaBH4.For many years various research groups have been attracted by the structures of the [3.3]MCP ([3.3]MCP=[3.3]metacyclophane) skeleton.2,3c When both internal substituents of a [3.3]phane are H, the molecule may be mobile. Mitchell and his co-workers demonstrated in 1970 that 9,18-dimethyl- 2,11-dithia[3.3]MCP exists in syn- and anti-conformers (see Fig. 1), which do not interconvert below 200 °C.4a V�ogtle and Schunder5 have made extensive studies of syn–anti conversions in other dithia[3.3]MCPs, especially in relation to the size of the substituents. When electron-withdrawing groups such as halo, nitro and cyano are present, the yields of the syn isomers increase substantially. Very bulky groups, such as tert-butyl, decrease the yields of syn isomers. Although the effect on the ratio of syn and anti conformers of dithia[3.3]MCPs was reported, it is still not clear what the effects are, not only with respect to the properties of the internal substituents, but also of having unsymmetrically substituted benzene rings arising from charge-transfer-type interactions between the two benzene rings as well as from the steric effects of the substituents at the 6- and 15-positions.All the previously studied compounds have been internally unsubstituted or methyl-substituted dithia[3.3]MCPs and it is surprising that there are very few reports on the preparation of 9-methoxy analogues.We report here the synthesis and stereochemical assignments of 9-methoxy-2,11-dithia[3.3]- MCPs. The substituent effects on the syn and anti conformations are also discussed. The cyclizations of 5-substituted 1,3-bis(halomethyl)benzenes 3a–e with 4-tert-butyl-2,6-bis(sulfanylmethyl)anisole 4a6,7a,b,e were carried out at high dilution in 10% ethanolic KOH and in the presence of a small amount of NaBH4, giving syn-9-methoxy-2,11-dithia[3.3]MCPs 5a–e in 41–67% yields, respectively (Scheme 1).In contrast, when the cyclizations of 5-substituted 1,3-bis (halomethyl)benzenes 3a–e with 4-tert-butyl-2,6-bis(sulfanylmethyl) toluene 4b were carried out under similar conditions, 3a–c and 3e gave exclusively the anti-9-methyl- 2,11-dithia[3.3]MCPs 6a–c and 6e in 60–71% yields, respectively whereas 3d gave only syn-9-methyl-15-nitro- 2,11-dithia[3.3]MCP syn-6d.Depending on the OMe and Me substitution, different yields (inversion of selectivity) of antiand syn-conformers were formed. Thus 9-methoxy analogues are exclusively formed as syn-conformers, but 9-methyl analogues are formed as anti-conformers. On treatment of 4-substituted 2,6-bis(bromomethyl)anisoles 8a–d with 4a, mixtures of anti- and syn-2,11- dithia[3.3]MCPs 5h–k were obtained, except for 6,15-di-tertbutyl- 2,11-dithia[3.3]MCP 5l. By careful column chromatography (silica gel, Wako C-300), two conformers, anti (anti- 5) and syn-2,11-dithia[3.3]MCP (syn-5), were easily *To receive any correspondence (e-mail: yamatot@cc.saga-u.ac.jp). Fig. 1 Syn- and anti-conformers of dithia[3.3]metacyclophanes Scheme 1 Reagents and conditions: i, KOH, EtOH, NaBH4, high dilutionMeO S S OMe OMe S S OMe anti-5 R R OMe CH2X XCH2 R syn-5 a b c d e 8 R = H, X = Br R = Me, X = Cl R = Cl, X = Cl R = Br, X = Br R = But, X = Cl + 4a i h i j k l R = H R = Me R = Cl R = Br R = But (17%) (31%) (12%) (25%) (56%) (74%) (40%) (27%) (13%) (0%) 19 : 81 56 70 34 0 anti : syn + 44 : 30 : 66 : 100 : R S– K+ S R O Me K+ –S X R S Me K+ –S R¢ X R¢ R S Steric interaction and p–p stacking interaction X Through-space interaction CH–p interaction J.CHEM. RESEARCH (S), 1997 193 separated. The 1H NMR spectrum of 5l shows this product to exist exclusively as the anti conformer. This result might be attributed to the bulkiness of the tert-butyl groups which would inhibit formation of syn-5l.Accordingly, the proportion of syn conformer is observed to increase with decreasing bulkiness of the substituents at the 15-position. These findings suggest that in the case of the 9-methoxy analogues the through-space interaction between the nonbonding electron pairs of the oxygen atom of the methoxy group and the opposite aromatic p-electrons of the anticonformer may disfavour the formation of this conformer. In contrast, in the case of a 9-methyl analogue the aromatic p–p interaction between the two opposite benzene rings and the steric crowding at the internal positions 9 and 18 may inhibit the formation of the syn-conformer in the [3.3]MCP system, while in turn the CH–p interaction9 between the methyl and the opposite aromatic p-electrons may favour the formation of an anti-conformer during the cyclization process.CH–p interactions involving aliphatic CH moieties are well documented9 as being either conformation-controlling intramolecular processes or involving crystal-structure-controlling intermolecular forces, especially for inclusion complexes of calixarene derivatives.10g In conclusion, we have demonstrated for the first time a through-space interaction between the non-bonding electron pairs of the oxygen atom of the methoxy group and the opposite aromatic p-electrons which may disfavour the formation of the anti-conformer during the coupling reaction of the corresponding 2,6-bis(bromomethyl)benzenes and 4-tertbutyl- 2,6-bis(sulfanylmethyl)anisole 4a to afford syn- 9-methoxy-2,11-dithia[3.3]MCPs 5 exclusively.Techniques used: 1H NMR, IR, mass. spec. References: 10 Schemes: 5 Fig. 2: Steric effect on the reaction intermediate for the cyclization to form syn-2,11-dithia[3.3]MCPs Received, 18th November 1996; Accepted, 4th March 1996 Paper E/6/07798F References cited in this synopsis 1 Part 43: T. Yamato, H. Kamimura, T. Furukawa, F. Zhang and Y. Nagano, J. Org. Chem., submitted for publication. 2 K. Meurer and F. V�ogtle, Top. Curr. Chem., 1985, 127, 1. 3 (c) F. V�ogtle, Cyclophane Chemistry, Wiley, Chichester, 1993. 4 (a) R. H. Mitchell and V. Boekelheide, Tetrahedron Lett., 1970, 1197. 5 F. V�ogtle and L. Schunder, Chem. Ber., 1969, 102, 2677. 6 M. Tashiro and T. Yamato, Org. Prep. Proced. Int., 1981, 13, 1. 7 (a) M. Tashiro and T. Yamato, J. Org. Chem., 1981, 46, 1543; (b) M. Tashiro, K. Koya and T. Yamato, J. Am. Chem. Soc., 1982, 104, 3707; (e) M. Tashiro, A. Tsuge, T. Sawada, T. Makishima, S. Horie, T. Arimura, S. Mataka and T. Yamato, J. Org. Chem., 1990, 55, 2404. 9 M. Nishio and M. Horita, Tetrahedron, 1989, 45, 7201. 10 (g) K. Kobayashi, Y. Asakawa, Y. Kikuchi, H. Toi and Y. Aoyama, J. Am. Chem. Soc., 1993, 115, 2648. Scheme 4 Reagents and conditions: i, KOH, EtOH, NaBH4, high dilution Fig. 3 Reaction intermediate for the cyclization to form [