Letter pubs.acs.org/OrgLett
Formation of Phenalenone Skeleton by an Unusual Rearrangement Reaction Sayaka Sasaki,† Eriko Azuma,† Takahiro Sasamori,‡,∥ Norihiro Tokitoh,‡ Kouji Kuramochi,§ and Kazunori Tsubaki*,† †
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Shimogamo, Sakyo-ku, Kyoto 606-8522, Japan Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan § Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan ‡
S Supporting Information *
ABSTRACT: The frame rearrangement reaction of dinaphthyl ketones, possessing hydroxy groups at appropriate positions, into phenalenone derivatives under acidic conditions was discovered serendipitously. Although this rearrangement had limited scope, its mechanism was unusual, involving the division of naphthalene rings into one phenalenone ring and one benzene ring. The reaction mechanism was elucidated by direct determination of intermediate structures using 1H NMR measurements. The generated phenalenones are expected to be key intermediates toward natural products and functional materials.
X
anthone skeletons are widely found in natural products1 and are key structures in the construction of fluoresceintype dyes.2 We have studied the development of fluorescent dyes with xanthone skeletons and report an exhaustive synthesis of (di)benzoxanthones with benzene rings attached to one or both sides of the xanthone core. 3 These (di)benzoxanthones are often synthesized by dehydration condensation from corresponding diaryl ketones with two hydroxyl groups under acidic4 or basic conditions5 (Figure 1).
Scheme 1. Reaction of Dinaphthyl Ketone 1 under Basic and Acidic Conditions
Figure 1. Synthesis of xanthones through dehydration of diaryl ketones.
the generated phenalenones are found in various natural products6 and have also been studied as stable radical species with unique electronic and magnetic functions derived from the unique π-system.7 In this manuscript, we report insight into the rearrangement reaction and a new synthetic route toward phenalenone derivatives. To elucidate the reaction mechanism, we first synthesized four hydroxyl-group-deficient compounds 4−7, each lacking one of the hydroxyl groups in 1, and determined which hydroxy group was essential for rearrangement (Figure 2).8 The rearrangement conditions were applied for compounds 4−7, with the results shown in Table 1. When 4 was subjected
During our studies, when compound 1 was subjected to dehydration, the desired dibenzoxanthone 23 was afforded in 86% yield under basic conditions (Scheme 1). In contrast, under acidic conditions (such as methanesulfonic acid, 50 °C, 1 h), we noticed that a yellow fluorescent compound with a completely different framework was produced. The structure of this fluorescent compound was identified as phenalenone 3 after careful determination by NMR analysis. In this reaction, the two naphthalene rings in starting material 1 became disrupted, transforming into a benzene ring and tricyclic phenalenone ring. As no examples of such framework rearrangement reactions have been reported, we were interested in elucidating the reaction mechanism. Moreover, © 2017 American Chemical Society
Received: July 26, 2017 Published: August 28, 2017 4846
DOI: 10.1021/acs.orglett.7b02305 Org. Lett. 2017, 19, 4846−4849
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Organic Letters
conversely, the three hydroxyl groups at C7, C3′, and C6′ were essential for the rearrangement to occur. The rearrangement of compound 1 was completed within 1 h at 50 °C in methanesulfonic acid. We noticed the generation of an intermediate within 2 min at room temperature by TLC analysis after quenching an aliquot of the reaction mixture with water. Therefore, we attempted to isolate and identify the intermediate to help elucidate the reaction mechanism. The reaction was terminated with water, and the intermediate was extracted with ethyl acetate. The residue was treated again under rearrangement conditions, with formation of some amount of the desired phenalenone 3 observed. However, this result did not indicate the observed intermediate was a real intermediate for phenalenone 3. Because it was impossible to distinguish whether newly formed phenalenone 3 was produced from the intermediate or from the unreacted starting compound 1. The residue was treated with acetic anhydride and DMAP, and three compounds 20−22 were isolated (Scheme 2). Structures 20 and 21 were easily determined by
Figure 2. Four hydroxyl-group-deficient compounds 4−7.8
Table 1. Attempted Rearrangement Conditions for Compounds 4−7
Scheme 2. Isolation of Compounds 20−22
NMR, while compound 22 was resolved by X-ray analysis. Compound 20 was an acetylated product of starting compound 1, while compound 21 was simply the cyclization product of 1, containing a xanthone skeleton. Compound 22 was the product of a transannular interaction between the two naphthalene rings followed by removal of the carbonyl oxygen at the junctional position. The formation mechanism of compound 22 is discussed later. Finally, we attempted to directly access the intermediates using 1H NMR measurements.10 In methanesulfonic acid, the reaction proceeded too quickly, even at room temperature, to observe the intermediates, so trifluoroacetic acid (TFA) was used as the acidic solvent instead. The reaction proceeded slowly in TFA, allowing the intermediates to be tracked by 1H NMR. Time-course NMR measurements showed that signals attributed to the starting material gradually diminished and that signals apparently attributed to intermediates became larger. The best time period to observe the intermediates was 43−48 h, during which COSY and NOESY spectra were recorded. Two intermediates were observed by NMR, one with 11 protons (named 11H-intermediate) and another with 10 protons (named 10H-intermediate). In the NOESY measurements, negative correlations were observed between the two
to rearrangement conditions, a retro-Friedel−Crafts reaction took place, and fragmental products 8 and 9 were isolated in 60% and 50% yields, respectively.9 From compound 5, three products (10−12) were isolated after converting the corresponding hydroxyl groups to MOM groups. RetroFriedel−Crafts products 10 and 11 and simple cyclized xanthone 12 were obtained in yields of 20%, 15%, and 59%, respectively. Compound 6 afforded compounds 13 (7%), 14 (4%), 15 (9%), 16 (14%), and 17 (11% yield). The generation of compounds 16 and 17 indicated that, although the transannular reaction between C8 and C1′ had proceeded, the cleavage reaction toward phenalenone and benzene rings had not occurred. From compound 7, phenalenone 18 was isolated in 36% yield. These results showed that the hydroxyl group at C2 did not participate in the rearrangement and, 4847
DOI: 10.1021/acs.orglett.7b02305 Org. Lett. 2017, 19, 4846−4849
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Organic Letters intermediates. These negative correlations indicated that interrelated signals could be interconverted, such as in keto− enol tautomerism. From these NMR measurements, we clearly determined the structures of two intermediates that were interconvertible (Figure 3). Therefore, the key signals were two
Scheme 3. Proposed Rearrangement Mechanism
Figure 3. Structures of intermediates and their1H NMR spectra. Conditions: CDCl3/CF3CO2H = 1/6, 600 MHz, 27 °C.
ester moiety. The product is expected to be a key intermediate for natural products and electronic materials (Scheme 4). Scheme 4. Removal of Side Chain by Baeyer−Villiger Oxidation
doublets at δ 5.30 (ascribed to Hh) and 4.38 ppm (Hi) for the 11H-intermediate and a singlet signal at δ 5.23 ppm (Hh′) for the 10H-intermediate. The signals at 5.30 and 4.38 ppm had a vicinal relationship, while those at 5.30 ppm for the 11Hintermediate and 5.23 ppm for the 10H-intermediate were exchangeable. These signals were ascribed to interconversion between −CO−CHi−CHh (two doublets) and −C(OH) C−CHh′− (one singlet) arrangements.11 Based on the structures of two intermediates, the plausible reaction mechanism of this rearrangement reaction is as follows (Scheme 3). Thus, the mechanism consists of the following five steps: (1) protonation at C4′ position, (2) C−C bond formation between C8 and C1′ by participation of hydroxyl group at C7, (3) deprotonation at C8 with recovery of aromaticity at the lower left ring, (4) protonation at the C8a′ with participation of hydroxyl group at 6′, and (5) bond cleavage between 1′ and 8a′ with recovery of aromaticity at the lower right ring by assisting the hydroxyl group at C3′. Since step (4) should be the rate-limiting step, two intermediates (10and 11H-intermediate) positioning before the transition state were confirmed in NMR experiments. In addition, when under weak acidic conditions, it was inferred that generation of deacetyl 22 was caused by protonation to C2′ of the 10Hintermediate followed by a 1,2-hydride shift and E1cb dehydration reaction. Finally, compound 3, produced by the rearrangement reaction, was transformed into a simple phenalenone skeleton 2512 through a Baeyer−Villiger oxidation and hydrolysis of the
In conclusion, a new rearrangement reaction was developed, in which phenalenone derivatives can be obtained in one step from the corresponding dinaphthyl ketones possessing three hydroxyl groups at appropriate positions. The mechanism of the rearrangement reaction was elucidated using hydroxylgroup-deficient derivatives, trapping deacetyl 22 by quenching the reaction with water at the midway point and determining the acetylated structure by X-ray analysis, and measuring the intermediates directly in trifluoroacetic acid by NMR. Although the substrate scope of this rearrangement is narrow, the phenalenone skeleton product, which was conveniently synthesized using this rearrangement reaction, is widely used 4848
DOI: 10.1021/acs.orglett.7b02305 Org. Lett. 2017, 19, 4846−4849
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Jiang, H.; Portelli, V. J. Aust. J. Chem. 1990, 43, 1291−1295. (d) Ojida, A.; Nonaka, H.; Miyahara, Y.; Tamaru, S.; Sada, K.; Hamachi, I. Angew. Chem., Int. Ed. 2006, 45, 5518−5521. (e) Kogan, K.; Biali, S. E. Org. Lett. 2007, 9, 2393−2396. (6) (a) Hölscher, D.; Schneider, B. Phytochemistry 2005, 66, 59−64. (b) Julianti, E.; Lee, J.-H.; Liao, L.; Park, W.; Park, S.; Oh, D.-C.; Oh, K.-B.; Shin, J. Org. Lett. 2013, 15, 1286−1289. (c) Rukachaisirikul, V.; Rungsaiwattana, N.; Klaiklay, S.; Phongpaichit, S.; Borwornwiriyapan, K.; Sakayaroj, J. J. Nat. Prod. 2014, 77, 2375−2382. (d) Intaraudom, C.; Nitthithanasilp, S.; Rachtawee, P.; Boonruangprapa, T.; Prabpai, S.; Kongsaeree, P.; Pittayakhajonwut, P. Phytochemistry 2015, 120, 19−27. (e) Gao, S.-S.; Duan, A.; Xu, W.; Yu, P.; Hang, L.; Houk, K. N.; Tang, Y. J. Am. Chem. Soc. 2016, 138, 4249−4259. (7) (a) Mukherjee, A.; Sau, S. C.; Mandal, S. K. Acc. Chem. Res. 2017, 50, 1679−1691. (b) Kubo, T. Chem. Rec. 2015, 15, 218−232. (c) Morita, Y.; Ohba, T.; Haneda, N.; Maki, S.; Kawai, J.; Hatanaka, K.; Sato, K.; Shiomi, D.; Takui, T.; Nakasuji, K. J. Am. Chem. Soc. 2000, 122, 4825−4826. (d) Paira, R.; Singh, B.; Hota, P. K.; Ahmed, J.; Sau, S. C.; Johnpeter, J. P.; Mandal, S. K. J. Org. Chem. 2016, 81, 2432− 2441. (8) For the synthesis of compounds 4−7, see the Supporting Information. (9) Bacci, J. P.; Kearney, A. M.; Van Vranken, D. L. J. Org. Chem. 2005, 70, 9051−9053. (10) Genaev, A. M.; Salnikov, G. E.; Shernyukov, A. V.; Zhu, Z.; Koltunov, K. Y. Org. Lett. 2017, 19, 532−535. (11) After confirming the formation of the intermediates in TFA, methanesulfonic acid was superadded to the solution and heated to 50 °C. The desired phenalenone 3 was afforded in 85% yield. (12) Laundon, B.; Morrison, G. A. J. Chem. Soc. C 1971, 1694−1704.
as a key intermediate for the synthesis of natural products and promising electronic materials.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02305. Experimental details, 1H and 13C NMR spectra of new compounds, and COSY and NOESY spectra of 10H and 11H intermediates (PDF) X-ray data for compound 22 (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Takahiro Sasamori: 0000-0001-5410-8488 Kouji Kuramochi: 0000-0003-0571-9703 Kazunori Tsubaki: 0000-0001-8181-0854 Present Address ∥
Graduate School of Natural Sciences, Nagoya City University.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are grateful to Prof. Hajime Iwamoto (Niigata University) for useful suggestions for the synthesis of 8-bromo2-naphthol and Ms. Kyohko Ohmine (ICR, Kyoto University) for the NMR measurements. This study was carried out using the Fourier transform ion cyclotron resonance mass spectrometer and the NMR in the Joint Usage/Research Center at the Institute for Chemical Research, Kyoto University. This study was supported in part by KAKENHI (No. 15K14931) and Grant-in-Aid from the Tokyo Biochemical Research Foundation.
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DOI: 10.1021/acs.orglett.7b02305 Org. Lett. 2017, 19, 4846−4849
