O CH2 O CH2 ROCH2 OH [CH2]2 CH2OR OH 2a [CH2] n 3a n = 2 ROH 4a R = Me 5a R = Et 6a R = Ac HO OH O O OH MeO OMe OH Ag2O C6H6 2a (70%) 4a (76%) 1a Ag2O MeOH J. Chem. Research (S), 1997, 74–75 J. Chem. Research (M), 1997, 0518–0529 Medium-sized Cyclophanes. Part 40.1 Generation of a Bis(o-quinone methide) from [n.2]Cyclophanes having a Spiro Skeleton and their Trapping Reaction with Nucleophiles and Dienophiles Takehiko Yamato,*a Jun-ichi Matsumoto,a Mitsuhiro Sato,a Koji Fujitaa 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 Spiro compounds 2, obtained from the oxidation of dihydroxy[n.2]metacyclophanes 1 with K3Fe(CN)6, readily generate a bis(o-quinone methide) 3 with mild heating which is trapped with nucleophiles and dienophiles to give diarylalkanes 4–6 and [4+2] cycloadducts 8, respectively.Quinone methides have been postulated as reactive intermediates in organic reactions for many years.2 A quinone methide with an unsubstituted methylene group has not been isolated except at low temperatures3 or in the case of highly hindered molecules.4 Filar and Winstein5 have shown the existence of a p-quinone methide in dilute solution. A quinone methide intermediate is usually identified from product studies. Balon6 has reported the oxidation of 4-substituted 2,6-dimethylphenols with various oxidizing agents such as silver oxide in methanol to form 4-substituted 2-methoxymethyl-6-methylphenols by trapping the o-quinone methide with the nucleophilic methanol.o-Quinone methide intermediate formation was subsequently confirmed by the formation of a [4+2] cycloadduct with reactive dienophiles to form chromane skeletons.7 We recently found that the oxidation of 5,13-di-tert-butyl- 8,16-dihydroxy[2.2]MCP (MCP=metacyclophane) 1a with K3Fe(CN)6 afforded the intramolecular O–C coupling product 2a having a spiro skeleton.8–11 Compound 2a corresponds to the intramolecular [4+2] cycloadduct of the bis(oquinone methide) 3a.Here we report the cycloreversion of 2 with mild heating to generate 3 and the reaction of 2 with alcohols, acetic acid and ethenes. The effects on strain with increasing methylene bridge length of the cycloreversion product are also investigated. Oxidation of 5,13-di-tert-butyl-8,16-dihydroxy[2.2]MCP 1a12 in refluxing benzene by Ag2O, as well as by aqueous K3Fe(CN)6, for 3 h afforded the intramolecular O–C coupling product 2a in 70% yield (Scheme 1).When methanol was used instead of benzene, an unexpected product 4a, which corresponds to a 1: 2-adduct of 3a and methanol, was obtained in 76% yield. The formation of 4a suggests that the spiro compound 2a produced in the oxidation of 1a by Ag2O reacted with methanol. Therefore, 2a was treated separately with methanol, ethanol and acetic acid.When 2a was treated with boiling methanol, the expected 4a, whose structure was determined by its spectral data, was obtained in 76% yield. Ethanol similarly reacted with 2a to give 5a in good yield. Compound 2a reacted with acetic acid to give diester 6a in good yield. 74 J. CHEM. RESEARCH (S), 1997 *To receive any correspondence (e-mail: yamatot@cc.saga-u. ac.jp). Scheme 1 Scheme 2 Table 1 Reaction of 2a with methanol, ethanol and acetic acid Reagent T/°C t/h Products (%)a MeOH EtOH HOAc reflux reflux 100–105 322 4a (76) 5a (96) 6a (84) aIsolated yields.O O R2 R1 R1 R2 R1 R2 benzene reflux, 24 h 2a [3a] a R1 = H, R2 = OEt b R1 = Me, R2 = Ph (96%) (99%) 8 OH EtOCH2 [CH2] n OH CH2OEt EtOH reflux 2 [3] a n = 2 b n = 3 c n = 4 d n = 5 5 The above results suggest the intermediate formation of the bis(o-quinone methide) 3a from the spiro metacyclophane 2a.In order to confirm this, reactions of 2a with electron- rich dienophiles3 such as ethyl vinyl ether (7a) and a-methylstyrene in refluxing benzene (7b) were investigated. The expected [4+2] cycloadducts, 8a and 8b, were obtained in 96 and 99% yield, respectively.The reaction of 2a with electron-deficient dimethyl acetylenedicarboxylate did not give the expected cycloadduct; instead a complex mixture of unidentified products was obtained. In conclusion, the spiro compound 2a is a convenient precursor of the bis(o-quinone methide) 3a, generated after mild heating of 2a.These novel ring fissions, generating bis(o-quinone methide) intermediate 3a after mild heating of 2a, might occur as a result of releasing the strain in the spiro compound 2a. Thus, there is substantial interest in investigating the effects on strain of increasing the length of the methylene bridge of spiro [n.2]cyclophanes by the formation of bis(oquinone methide) intermediates. W h e n 5 p, 6 - d i - t e r t - b u t y l - 3 p, 8 - p r o p a n o s p i r o [ c h r o m a n e - 2,1p-cyclohexa-3p,5p-dien]-2p-one 2b was treated with boiling ethanol for 2 h, the expected product 5b derived from a bis(oquinone methide) intermediate was obtained in 13% yield along with 87% recovery of the starting compound.Prolonged reaction times led to complete formation of 5b. Similar treatment of the larger-ring-sized spiro compound 2c (n=4) with boiling ethanol afforded only 5c in 16% yield, while with the larger-ring spiro compound 2d only recovered starting material was obtained.Although Biali et al.14 reported the preparation of bis- (spirodienone) derivatives of p-tert-butylcalix[4]arene and various reactions in protic media, the present novel ring fission to generate bis(o-quinone methide) intermediates has not been observed so far. Therefore, the above results suggest that the effects of strain in [n.2]cyclophanes having a spiro skeleton 2 do exist. Thus, the generation of a bis(oquinone methide) on mild heating is possible for [2.2]cyclophane 2a and [3.2]cyclophane 2b having a spiro skeleton and can be attributed to the strain of a medium ring which can be released by conversion into the strain-free bis(o-quinone methides) 3a and 3b.We conclude that the spiro compounds 2 obtained in the oxidation of dihydroxy[n.2]MCPs 1 with K3Fe(CN)6, readily generate a bis(o-quinone methide) 3 on mild heating, which is trapped with methanol, ethanol and acetic acid to give diarylalkanes.Techniques used: 1H NMR, IR, MS, VPC References: 14 Tables: 2 Schemes: 5 Received, 13th August 1996; Accepted, 18th November 1996 Paper E/6/05667I References cited in this synopsis 1 Part 39: T. Yamato, K. Fujita, T. Ando, S. Ide, Y. Nagano and M. Tashiro, J. Chem. Res., 1996, (S) 264; (M) 1434. 2 A. B. Turner, Quart. Rev., 1964, 28, 347. 3 (b) A. Merrijan, B. A. Shoulders and P. D. Gardner, J. Org. Chem., 1963, 28, 2148. 4 A. Bistrzycki and C. Herbst, Chem. Ber., 1903, 36, 2335. 5 L. J. Filar and S. Winstein, Tetrahedron Lett., 1960, 25, 9. 6 D. A. Balon, J. Org. Chem., 1970, 35, 715. 7 D. A. Balon, J. Org. Chem., 1970, 35, 3666. 8 M. Tashiro, T. Yamato, S. Horie and S. Mataka, Chem. Pharm. Bull., 1984, 32, 1641. 9 T. Yamato, J. Matsumoto, K. Tokuhisa, K. Suehiro, S. Horie and M. Tashiro, J. Org. Chem., 1992, 57, 6368. 10 T. Yamato, J. Matsumoto, K. Tokuhisa, K. Suehiro and M. Tashiro, J. Chem. Soc., Chem. Commun., 1992, 865. 11 T. Yamato, K. Fujita, J. Matsumoto, M. Sato, Y. Nagano and M. Tashiro, J. Chem. Res. (S), 1996, 262. 12 (b) M. Tashiro, K. Koya and T. Yamato, J. Am. Chem. Soc., 1982, 104, 3707. 14 A. M. Litwak, F. Grynszpan, O. Aleksiuk, S. Cohen and S. E. Biali, J. Org. Chem., 1993, 58, 393. J. CHEM. RESEARCH (S), 1997 75 Scheme 3 Scheme 5 Table 2 Reaction of 2 with EtOH Substrate 2 t/h Products 5 (%)a Recovd. a bbc d 22 36 36 36 (100) (13) (100) (16) (0) (0) (87) (0) (84) (100) aYields were determined from 1H NMR spectroscopy.