Me Me Me Me Br H [CH2] n PhCH2NMe3Br3 – Br in CH2Cl2 room temp. (5 min) H b; n = 3 c; n = 4 [CH2] n 1 b; n = 3 c; n = 4 cis-3 + (2) Me Me Br H Br H Me Me OAc H Br H Me Me H AcO OAc H [CH2] n b; n = 3 c; n = 4 cis-5 Me cis-3 Me b; n = 3 c; n = 4 OAc H OAc [CH2] n H 4 [CH2] n trans-5c + AgOAc– HOAc b; n = 3 c; n = 4 [CH2] n + 190 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 190–191 J. Chem. Research (M), 1997, 1301–1322 Medium-sized Cyclophanes. Part 42.1 Synthesis of [2.n]Metacyclophan-1-ones and [2.n]Metacyclophane- 1,2-diones Takehiko Yamato,*a Koji Fujita,a Seiji Idea and Yoshiaki Naganob aDepartment of Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi 1, Saga-shi, Saga 840, Japan bTohwa Institute of Science, Tohwa University, 1-1 Chikushigaoka, Minami-ku, Fukuoka 815, Japan Acetolysis of 10-endo, 11-exo-dibromo-6,14-di-tert-butyl-9,17-dimethyl[3.2]metacyclophane cis-3b afforded the corresponding 10,11-diacetoxy derivative cis-5b with retention of configuration, whereas in the case of [4.2]metacyclophane cis-3c the same stereoselectivity was not observed: the diacetoxy derivatives 5 were converted into a 10,11-dione 10b and a 11,12-dione 10c via hydrolysis followed by Swern oxidation of dihydroxy derivatives 7b and 7c.For many years various research groups have been attracted by the chemistry and spectral properties of the [2.2]MCP ([2.2]MCP=[2.2]metacyclophane) skeleton.2,3 Its conformation, which has been elucidated by X-ray measurements,4 is frozen into a chair-like non-planar form. Many attempts have been made directly to introduce functional groups into the methylene groups of [2.2]MCPs, but these have failed because of deviation of the benzyl carbon atom from the plane of the benzene ring.5g Singler and Cram have reported that bromination of [2.2]paracyclophan-1-ene with bromine affords the corresponding cis-adduct.6 Recently, we have reported that di-tertbutyl( dimethyl)[2.n]MCP-1-enes 1b,c when treated with an equimolar amount of benzyltrimethylammonium tribromide (BTMA Br3) in methylene dichloride9a afford the cis-adducts 3b,c to the bridged double bond in 90 and 95% yield, respectively [eqn. (2)].These results indicate the first success in the introduction of two bromo groups into the methylene groups of dimethyl[n.2]MCPs. We undertook the present work in order to extend the novel reaction mentioned above. We report here on the acetolysis of bromine adducts with silver acetate in acetic acid and the conversion into the 10,11-dione 10b and 11,12-dione 10c via hydrolysis followed by Swern oxidation of the dihydroxy derivatives 7.Acetolysis of 10-endo,11-exo-dibromo-6,14-di-tert-butyl- 9,17-dimethyl[3.2]MCP cis-3b with silver acetate in acetic acid at 60 °C for 30 min afforded the corresponding 10-acetoxy derivative 4b with complete retention of configuration in 90% yield. A prolonged reaction time (to 12 h) and higher reaction temperature (to 90 °C) furnished complete acetolysis to afford 10-endo,11-exo-diacetoxy-6,14-di-tert-butyl- 9,17-dimethyl[3.2]MCP cis-5b with complete retention of configuration at the 10,11 positions in the bridged cyclophane ring.In contrast, in the case of the [4.2]metacyclophane cis-3c the same stereoselectivity was not observed under either set of reaction conditions. Thus, 11,12-bis(endo-acetoxy)- 7,15-di-tert-butyl-10,18-dimethyl[4.2]MCP trans-5c was obtained in 30 and 40% yields along with 4c and cis-5c, respectively.These results can be attributed to the nature of the cyclophane structure, like in the acetolysis of 1,2-dibromo[2.2]paracyclophane. 10a The stereoselectivity of the acetolysis decreases with increasing the length of the methylene bridges and the distances between the two aromatic rings. Acetates 4 and cis-5 were easily converted into the corresponding alcohols 6 and cis-7 by hydrolysis with alcoholic KOH at 50 °C for 15 min in almost quantitative yields.Attempted oxidation of monools 6b and 6c with pyridinium chlorochromate12 carried out in a methylene dichloride *To receive any correspondence (e-mail: yamatot@cc.saga-u. ac.jp). Table 1 Acetolysis of cis-3 with AgOAc in acetic acida Temp. Time Run Substrate (T/°C) (t/h) Products (%) 1234 cis-3b cis-3b cis-3c cis-3c 60 90 60 90 0.5 12 0.5 12 4b (90) cis-5b (87) 4c (60), trans-5c (30) cis-5c (50), trans-5c (40) aIsolated yields are shown. Scheme 1Me Me OH H X H [CH2] n b X = Br, n = 3 c X = Br, n = 4 6 b X = OH, n = 3 c X = OH, n = 4 cis-7 Me Me [CH2] n b X = Br, n = 3 c X = Br, n = 4 8 b X = H, n = 3 c X = H, n = 4 9 Me Me O [CH2] n b n = 3 c n = 4 10 O X H O Me N N Me H2N H2N in EtOH, room temp., 24 h (quant.) 10b 12b J.CHEM. RESEARCH (S), 1997 191 solution at room temperature for 1 h led to the expected monoketones 8b and 8c as a single product in 61 and 90% yields, respectively.Monoketones 8b and 8c were easily converted into the corresponding 9b and 9c by reduction with zinc powder in acetic acid at 80 °C for 15 min. In contrast, an attempted oxidation of the cis-diol cis-7b to the 11,12-dione 10b with pyridinium chlorochromate carried out in a methylene dichloride solution under the same reaction conditions as described above failed. Only the cleavage reaction product, 1,3-bis(5-tert-butyl-3-formyl-2-methylphenyl) propane 11b, was obtained in quantitative yield.This finding seems to support the strained nature of the diketone 10b compared to the monoketones 8b and 9b, in spite of these having the same ring size. Fortunately, Swern oxidation13 of cis-7b succeeded in affording the desired [3.2]diketone 10b in quantitative yield. However, 10b was found to be labile during silica gel column chromatography, and on refluxing in hexane it gave only intractable mixtures. Thus, a trapping reaction of diketone 10b with o-phenylenediamine was attempted, in which the crude diketone 10b was treated with o-phenylenediamine in ethanol at room temperature for 24 h to afford in almost quantitative yield the desired [3.2]MCP 12b having a quinoxaline skeleton (Scheme 3).Similarly, in the case of [4.2]MCP, Swern oxidation of the cis-diol cis-7c also succeeded in affording the desired diketone 10c in 70% yield as stable colourless prisms. This finding seems to support the notion that the strain of the [3.2]diketone 10b compared to the [4.2]diketone 10c increases as the length of the methylene bridge decreases.The low frequency in the IR spectrum (1700 cmµ1 for 9b and 1696 cmµ1 for 9c) in comparison with that of the reference compound, 5-tert-butyl-2,3-dimethylbenzyl 5-tert-butyl- 2,3-dimethylphenyl ketone (1685 cmµ1), presumably and in analogy with the corresponding paracyclophane analogue, 10a,14 reflects expanded OCC bond angles rather than conjugation. Bathochromic shifts were observed in the cyclophane ketones 9b,c and the diketone 10b, which are ascribed to a transannular interaction between the two benzene rings and an increase in the strain of these systems.15 The lack of an acetophenone-type chromophore in the UV spectrum of the MCP ketones confirms the non-planarity of the aromatic ring and carbonyl group. In conclusion, we have demonstrated that acetolysis o f 1 0 - e n d o , 1 1 - e x o - d i b r o m o - 6 , 1 4 - d i - t e r t- b u t y l - 9 , 1 7 - d i m e t h y l - [3.2]MCP cis-3b affords the corresponding 10,11-diacetoxy derivative 5b with retention of configuration, whereas in the case of [4.2]MCP 3c the same stereoselectivity is not observed.The present results of the stereoselective acetolysis of bromine adducts of [2.n]MCP-1-enes will open up new mechanistic aspects for cyclophane chemistry. Also, diacetoxy derivatives 5 were converted into the 10,11-dione 10b and the 11,12-dione 10c via hydrolysis followed by Swern oxidation of the dihydroxy derivatives 7.Further studies on the chemical properties of the monoketone 9 and diketone 10 are now in progress. Techniques used: 1H NMR, IR, mass spec. References: 15 Schemes: 3 Fig. 1: UV absorption spectra of [n.2]MCP ketones 9b, 9c and reference compound 13 in cyclohexane Fig. 2: UV absorption spectra of [n.2]MCP diketone 10c and reference compound benzil 14 in cyclohexane Table 2: 1H NMR data for [2.n]MCP-1-ones 8, 9 and [2.4]MCP- 1,2-dione 10c Received, 2nd September 1996; Accepted, 3rd March 1997 Paper E/6/06019F References 1 Part 41: T. Yamato, K. Fujita, N. Shinoda, K. Noda, Y. Nagano, T. Arimura and M. Tashiro, Research on Chemical Intermediates, 1996, 22, 871. 2 R. W. Griffin, Jr., Chem. Rev., 1963, 63, 45. 3 D. J. Cram, Acc. Chem. Res., 1971, 4, 204. 4 C. J. Brown, J. Chem. Soc., 1953, 3278. 5 (g) B. H. Smith, Bridged Aromatic Compounds, Academic Press, New York, 1964. 6 R. E. Singler and D. J. Cram, J. Am. Chem. Soc., 1972, 94, 3512. 9 (a) T. Yamato, J. Matsumoto, S. Ide, K. Suehiro, K. Kobayashi and M. Tashiro, Chem. Ber., 1993, 126, 447. 10 (a) R. E. Singer and D. J. Cram, J. Am. Chem. Soc., 1971, 93, 4443. 12 G. Piancatelli, A. Scettri and M. D’Auria, Synthesis, 1982, 245. 13 A. J. Mancuso, S. L. Huang and D. Swern, J. Org. Chem., 1978, 43, 2480. 14 D. J. Cram and R. C. Helgeson, J. Am. Chem. Soc., 1966, 88, 3515. 15 Cyclophanes, ed. P. M. Keehn and S. M. Rosenfield, Academic Press, New York, 1983, vol. 1, ch. 6, p. 428. Scheme 3