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Aryne reaction with triuoromethyl ketones in three modes: CC bond cleavage, [2+2] cycloaddition and O-arylationw
Hiroto Yoshida,* Yu Ito, Yunito Yoshikawa, Joji Ohshita and Ken Takaki
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Received 13th May 2011, Accepted 17th June 2011 DOI: 10.1039/c1cc12820e Triuoromethyl ketones were found to be coupled with arynes in three modes depending upon their substitution patterns, namely CC bond cleavage, [2+2] cycloaddition and O-arylation. Construction of carbon skeletons via insertion reactions of unsaturated hydrocarbons into CC single bonds has received considerable attention, because it enables dual carboncarbon bond-forming processes to take place all at once, providing molecules of structural complexity in a straightforward manner. Eorts have hitherto been devoted mainly to developing the insertion reactions through activation of CC bonds with transition metal catalysis,1 and the transformations have proven to be applicable even to such strain-free CC bonds as CCN (nitriles)2 and CC(O)R (b-dicarbonyl compounds).3 On the other hand, we have already reported that arynes can be smoothly inserted into strain-free CC bonds (active methylene compounds4 and uorenyl ketones)5 without the aid of a transition metal catalyst, providing a direct method for constructing multisubstituted aromatic skeletons.6 Because the successful CC bond cleavage reactions are triggered by generation of carbanionic species via deprotonation of acidic CH moieties (Scheme 1),46 we envisaged that other CC bonds would be cleaved and added across arynes according to this protocol by enhancement of the CH acidity using uorous functional groups of high electronegativity. Herein we report that a C(methylene)C(carbonyl) bond of benzyl ketones can be smoothly added to arynes by introducing a triuoromethyl moiety, aording diverse triuoroacetophenone derivatives bearing a benzyl substituent at the ortho position. Furthermore, modes of the reaction were found to change from the CC bond cleavage to [2+2] cycloaddition or O-arylation depending upon a substituent of triuoromethyl ketones. We rst carried out the reaction of benzyne,7 generated in situ from 1a with KF/18-Crown-6, with benzyl triuoromethyl ketone (2a) in THF and observed that benzyne was smoothly inserted into the methylenecarbonyl bond to aord 2 0 -benzyl-2,2,2-triuoroacetophenone (3aa) in 60% yield (Scheme 2). Benzyl triuoromethyl ketones bearing an electron-donating (methoxy, 2b) or an electron-withdrawing (triuoromethyl, 2c) group could also take part in the reaction to provide the respective products (3ab and 3ac) in 55% or 63% yield, and furthermore the methylenecarbonyl bond of chloro(uoro)benzyl triuoromethyl ketone (2d) could be cleaved and added across benzyne. Although a carbanionic

Scheme 1 A scenario for the CC bond cleavage reaction using triuoromethyl ketones. Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University, Higashi-Hiroshima 739-8527, Japan. E-mail: yhiroto@hiroshima-u.ac.jp; Fax: +81-82-424-5494; Tel: +81-82-424-7724 w Electronic supplementary information (ESI) available: Experimental procedure including spectroscopic and analytical data. See DOI: 10.1039/c1cc12820e

Scheme 2 CC bond cleavage reaction of benzyl triuoromethyl ketones with benzyne.

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Scheme 3 ketones.

O-arylation or [2+2] cycloaddition using triuoromethyl

species would be involved as a key intermediate in the CC bond cleavage reaction (vide infra, Scheme 6), a CBr bond in 2e or 2f remained intact throughout the process, demonstrating the high chemoselectivity of the present reaction. In marked contrast, steric congestion around a methylene moiety totally retarded the CC cleavage. Thus, treatment of triuoromethyl mesitylmethyl ketone (2g) with benzyne solely gave enol ether 3ag, whose stereochemistry was determined to be Z by an NOE experiment and a 3JCH coupling constant (Scheme 3).8 It should be noted that the reaction using triuoromethyl phenethyl ketone (2h) or decyl triuoromethyl ketone (2i) produced a benzocyclobutenol (3ah or 3ai) in a stereoselective manner,9 demonstrating that substituents in ketones signicantly aect the course of the reaction. Increasing the CH acidity with a triuoromethyl moiety is indispensable for a successful reaction, and thus the desired insertion product was not formed at all in the reaction using benzyl n-butyl ketone of structural similarity to 2a (Scheme 4).10 Variously substituted aryl triuoromethyl ketones were synthesized in a straightforward manner by the reactions using substituted arynes. As depicted in Scheme 5, symmetrical arynes including 4,5-dimethylbenzyne (from 1b) and 2,3-naphthalyne (from 1c) reacted with 2e to aord the respective insertion products (3be and 3ce). Furthermore, the high regioselectivity in the reaction of an unsymmetrical aryne should be noted: the benzyl moiety of 2e was exclusively introduced into the less congested site of 3-methoxybenzyne (from 1d), aording a 53% yield of 3de.11 As depicted in Scheme 6, [2+2] cycloaddition between an aryne and an enolate, generated in situ via deprotonation of a triuoromethyl ketone by a uoride ion,12 takes place rst to give a benzocyclobutene (4). Subsequent ring-opening of 4 that provides a diarylmethyl anion (5), followed by protonation, aords a CC bond cleavage product. The formation of 3ah

Scheme 5 CC bond cleavage reaction of 2e with substituted arynes.

Scheme 6 Plausible pathways for the reaction of arynes with triuoromethyl ketones.

Scheme 4 Reaction of benzyl n-butyl ketone with benzyne.

can be explained by protonation of 4, implying that the ringopening step depends totally on the generation of the stable diarylmethyl anion. On the other hand, steric hindrance in the enolate of 2g induced by the mesityl moiety inhibits the [2+2] cycloaddition, which results in nucleophilic attack of the oxygen moiety on benzyne to give 3ag. The perfect stereoselectivity observed in the reaction of 2g is attributable to stereoselective formation of the respective enolate, whose mesityl moiety is located cis to the oxygen moiety. The same conguration of the enolate of 2h (or 2i) also led to the exclusive formation of 3ah (or 3ai), and importantly these results suggest the concerted nature of the [2+2] cycloaddition.13,14 In conclusion, we have demonstrated that benzyl triuoromethyl ketones serve as excellent substrates for a CC bond cleavage reaction, and that reaction modes can distinctly be switched into [2+2] cycloaddition or O-arylation depending upon the substitution patterns, resulting in stereoselective formation of a benzocyclobutenol or an enol ether. Further studies on novel CC bond cleavage reactions with arynes and on synthetic application of the present reaction are in progress.
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This work was nancially supported by The Kurata Memorial Hitachi Science and Technology Foundation. We thank Central Glass Co. Ltd. for a generous gift of triuoromethanesulfonic anhydride, and Dr Tomoko Amimoto, the Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University, for HRMS measurement.

Notes and references

1 For recent reviews, see: (a) T. Kondo and T. Mitsudo, Chem. Lett., 2005, 1462; (b) Y. J. Park, J.-W. Park and C.-H. Jun, Acc. Chem. Res., 2008, 41, 222; (c) M. Murakami and T. Matsuda, Chem. Commun., 2011, 47, 1100. 2 (a) Y. Nakao, S. Oda and T. Hiyama, J. Am. Chem. Soc., 2004, 126, 13904; (b) Y. Nishihara, Y. Inoue, M. Itazaki and K. Takagi, Org. Lett., 2005, 7, 2639; (c) Y. Nakao, T. Yukawa, Y. Hirata, S. Oda, J. Sato and T. Hiyama, J. Am. Chem. Soc., 2006, 128, 7116; (d) Y. Kobayashi, H. Kamisaki, R. Yanada and Y. Takemoto, Org. Lett., 2006, 8, 2711; (e) Y. Nakao, A. Yada, S. Ebata and T. Hiyama, J. Am. Chem. Soc., 2007, 129, 2428; (f) Y. Nakao, Y. Hirata, M. Tanaka and T. Hiyama, Angew. Chem., Int. Ed., 2008, 47, 385; (g) Y. Hirata, T. Yukawa, N. Kashihara, Y. Nakao and T. Hiyama, J. Am. Chem. Soc., 2009, 131, 10964; (h) Y. Hirata, A. Yada, E. Morita, Y. Nakao, T. Hiyama, M. Ohashi and S. Ogoshi, J. Am. Chem. Soc., 2010, 132, 10070. 3 (a) Y. Kuninobu, A. Kawata and K. Takai, J. Am. Chem. Soc., 2006, 128, 11368; (b) Y. Kuninobu, A. Kawata, M. Nishi, H. Takata and K. Takai, Chem. Commun., 2008, 6360; (c) Y. Kuninobu, A. Kawata, M. Nishi, S. S. Yudha, J. J. Chen and K. Takai, Chem.Asian J., 2009, 4, 1424.

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4 (a) H. Yoshida, M. Watanabe, J. Ohshita and A. Kunai, Chem. Commun., 2005, 3292; (b) H. Yoshida, M. Watanabe, J. Ohshita and A. Kunai, Tetrahedron Lett., 2005, 46, 6729; (c) H. Yoshida, M. Watanabe, T. Morishita, J. Ohshita and A. Kunai, Chem. Commun., 2007, 1505. 5 H. Yoshida, T. Kishida, M. Watanabe and J. Ohshita, Chem. Commun., 2008, 5963. 6 Similar insertion reactions of arynes into b-ketoesters have been reported by Stoltz, see: (a) U. K. Tambar and B. M. Stoltz, J. Am. Chem. Soc., 2005, 127, 5340; (b) U. K. Tambar, D. C. Ebner and B. M. Stoltz, J. Am. Chem. Soc., 2006, 128, 11752. 7 Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett., 1983, 1211. 8 See ESIw for details. 9 The stereochemistry of the benzocyclobutenols was also determined by NOE experiments. See ESIw for details. 10 Although 1a was completely consumed, almost all of the ketone remained intact in this case. 11 Similar regioselectivities were observed in the CC bond cleavage reactions with 3-methoxybenzyne. See ref. 4 and 5. 12 We have already demonstrated that a uoride acts as a base for the formation of a carbanion from malononitrile. See ref. 4c. 13 For stereospecicity in the [2+2] cycloaddition between benzyne and ketene silyl acetals, see: T. Hosoya, T. Hasegawa, Y. Kuriyama and K. Suzuki, Tetrahedron Lett., 1995, 36, 3377. 14 We proposed stepwise [2+2] cycloaddition to reach benzocyclobutene intermediates in our previous papers (ref. 4 and 5), however, the results described herein imply that the previous reactions may also proceed through concerted [2+2] cycloaddition. At present, we have no decisive evidence for whether the [2+2] cycloaddition proceeds concertedly or stepwise in the previous reactions.

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Chem. Commun.