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 phenale-
nones 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 fluorescein-
type dyes.2 We have studied the development of fluorescent
Scheme 1. Reaction of Dinaphthyl Ketone 1 under Basic and
Acidic Conditions

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).

Figure 1. Synthesis of xanthones through dehydration of diaryl

ketones.
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,
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
Received: July 26, 2017
Published: August 28, 2017

© 2017 American Chemical Society 4846 DOI: 10.1021/acs.orglett.7b02305

Org. Lett. 2017, 19, 4846−4849
Organic Letters
Figure 2. Four hydroxyl-group-deficient compounds 4−7.8
Table 1. Attempted Rearrangement Conditions for
Compounds 4−7
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. Retro-
Friedel−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
Letter
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
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 measure-
ments, negative correlations were observed between the two
DOI: 10.1021/acs.orglett.7b02305
Org. Lett. 2017, 19, 4846−4849
Organic Letters Letter

intermediates. These negative correlations indicated that Scheme 3. Proposed Rearrangement Mechanism
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

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

doublets at δ 5.30 (ascribed to Hh) and 4.38 ppm (Hi) for the Oxidation
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 11H-
intermediate 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 In conclusion, a new rearrangement reaction was developed,
lower right ring by assisting the hydroxyl group at C3′. Since in which phenalenone derivatives can be obtained in one step
step (4) should be the rate-limiting step, two intermediates (10- from the corresponding dinaphthyl ketones possessing three
and 11H-intermediate) positioning before the transition state hydroxyl groups at appropriate positions. The mechanism of
were confirmed in NMR experiments. In addition, when under the rearrangement reaction was elucidated using hydroxyl-
weak acidic conditions, it was inferred that generation of group-deficient derivatives, trapping deacetyl 22 by quenching
deacetyl 22 was caused by protonation to C2′ of the 10H- the reaction with water at the midway point and determining
intermediate followed by a 1,2-hydride shift and E1cb the acetylated structure by X-ray analysis, and measuring the
dehydration reaction. intermediates directly in trifluoroacetic acid by NMR. Although
Finally, compound 3, produced by the rearrangement the substrate scope of this rearrangement is narrow, the
reaction, was transformed into a simple phenalenone skeleton phenalenone skeleton product, which was conveniently
2512 through a Baeyer−Villiger oxidation and hydrolysis of the synthesized using this rearrangement reaction, is widely used
4848 DOI: 10.1021/acs.orglett.7b02305
Org. Lett. 2017, 19, 4846−4849
Organic Letters Letter

as a key intermediate for the synthesis of natural products and Jiang, H.; Portelli, V. J. Aust. J. Chem. 1990, 43, 1291−1295. (d) Ojida,
promising electronic materials. 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.
ASSOCIATED CONTENT Lett. 2007, 9, 2393−2396.
(6) (a) Hölscher, D.; Schneider, B. Phytochemistry 2005, 66, 59−64.
*
S Supporting Information
(b) Julianti, E.; Lee, J.-H.; Liao, L.; Park, W.; Park, S.; Oh, D.-C.; Oh,
The Supporting Information is available free of charge on the K.-B.; Shin, J. Org. Lett. 2013, 15, 1286−1289. (c) Rukachaisirikul, V.;
ACS Publications website at DOI: 10.1021/acs.or- Rungsaiwattana, N.; Klaiklay, S.; Phongpaichit, S.; Borwornwiriyapan,
glett.7b02305. K.; Sakayaroj, J. J. Nat. Prod. 2014, 77, 2375−2382. (d) Intaraudom,
C.; Nitthithanasilp, S.; Rachtawee, P.; Boonruangprapa, T.; Prabpai, S.;
Experimental details, 1H and 13C NMR spectra of new Kongsaeree, P.; Pittayakhajonwut, P. Phytochemistry 2015, 120, 19−27.
compounds, and COSY and NOESY spectra of 10H and (e) Gao, S.-S.; Duan, A.; Xu, W.; Yu, P.; Hang, L.; Houk, K. N.; Tang,
11H intermediates (PDF) Y. J. Am. Chem. Soc. 2016, 138, 4249−4259.
X-ray data for compound 22 (CIF) (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.
AUTHOR INFORMATION (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,
Corresponding Author 122, 4825−4826. (d) Paira, R.; Singh, B.; Hota, P. K.; Ahmed, J.; Sau,
*E-mail: tsubaki@kpu.ac.jp. S. C.; Johnpeter, J. P.; Mandal, S. K. J. Org. Chem. 2016, 81, 2432−
ORCID 2441.
(8) For the synthesis of compounds 4−7, see the Supporting
Takahiro Sasamori: 0000-0001-5410-8488 Information.
Kouji Kuramochi: 0000-0003-0571-9703 (9) Bacci, J. P.; Kearney, A. M.; Van Vranken, D. L. J. Org. Chem.
Kazunori Tsubaki: 0000-0001-8181-0854 2005, 70, 9051−9053.
(10) Genaev, A. M.; Salnikov, G. E.; Shernyukov, A. V.; Zhu, Z.;
Present Address Koltunov, K. Y. Org. Lett. 2017, 19, 532−535.
∥
Graduate School of Natural Sciences, Nagoya City University. (11) After confirming the formation of the intermediates in TFA,
Notes methanesulfonic acid was superadded to the solution and heated to 50
°C. The desired phenalenone 3 was afforded in 85% yield.
The authors declare no competing financial interest.

■
(12) Laundon, B.; Morrison, G. A. J. Chem. Soc. C 1971, 1694−1704.

ACKNOWLEDGMENTS
The authors are grateful to Prof. Hajime Iwamoto (Niigata
University) for useful suggestions for the synthesis of 8-bromo-
2-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 spec-
trometer 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.

■ REFERENCES
(1) (a) Masters, K. S.; Bräse, S. Chem. Rev. 2012, 112, 3717−3776.
(b) Winter, D. K.; Sloman, D. L.; Porco, J. A., Jr. Nat. Prod. Rep. 2013,
30, 382−391. (c) Wei, X.; Liang, D.; Wang, Q.; Meng, X.; Li, Z. Org.
Biomol. Chem. 2016, 14, 8821−8831. (d) Tang, Y. X.; Fu, W. W.; Wu,
R.; Tan, H. S.; Shen, Z. W.; Xu, H. X. J. Nat. Prod. 2016, 79, 1752−
1761.
(2) (a) Urano, Y.; Kamiya, M.; Kanda, K.; Ueno, T.; Hirose, K.;
Nagano, T. J. Am. Chem. Soc. 2005, 127, 4888−4894. (b) Yang, Y.;
Lowry, M.; Schowalter, C. M.; Fakayode, S. O.; Escobedo, J. O.; Xu,
X.; Zhang, H.; Jensen, T. J.; Fronczek, F. R.; Warner, I. M.; Strongin,
R. M. J. Am. Chem. Soc. 2006, 128, 14081−14092. (c) Kim, S. H.;
Gunther, J. R.; Katzenellenbogen, J. A. Org. Lett. 2008, 10, 4931−4934.
(d) Li, J.; Hu, M.; Yao, S. Q. Org. Lett. 2009, 11, 3008−3011.
(e) Katori, A.; Azuma, E.; Ishimura, H.; Kuramochi, K.; Tsubaki, K. J.
Org. Chem. 2015, 80, 4603−4610. (f) Yamagami, A.; Ishimura, H.;
Katori, A.; Kuramochi, K.; Tsubaki, K. Org. Biomol. Chem. 2016, 14,
10963−10972.
(3) Azuma, E.; Kuramochi, K.; Tsubaki, K. Tetrahedron 2013, 69,
1694−1699.
(4) (a) Vandana, T.; Prasad, K. J. R. Indian J. Chem., Sect. B 2005, 44,
815−818. (b) Mottram, L. F.; Maddox, E.; Schwab, M.; Beaufils, F.;
Peterson, B. R. Org. Lett. 2007, 9, 3741−3744.
(5) (a) Bichan, D. J.; Yates, P. Can. J. Chem. 1975, 53, 2054−2063.
(b) Sundholm, E. G. Tetrahedron 1978, 34, 577−586. (c) Elix, J. A.;

4849 DOI: 10.1021/acs.orglett.7b02305

Org. Lett. 2017, 19, 4846−4849