Formation of Phenalenone Skeleton by an Unusual Rearrangement Reaction

Article abstract of DOI:10.1021/acs.orglett.7b02305

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.

Full text of DOI:10.1021/acs.orglett.7b02305

Letter
pubs.acs.org/OrgLett
Formation of Phenalenone Skeleton by an Unusual Rearrangement
Reaction
†
†
‡,∥
Norihiro Tokitoh, Kouji Kuramochi,§
‡
Sayaka Sasaki, Eriko Azuma, Takahiro Sasamori,
,†
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
1
structures using H NMR measurements. The generated phenale-
nones are expected to be key intermediates toward natural products
and functional materials.
1
anthone skeletons are widely found in natural products
Scheme 1. Reaction of Dinaphthyl Ketone 1 under Basic and
Acidic Conditions
X
and are key structures in the construction of fluorescein-
type dyes. 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. These
2
3
(
di)benzoxanthones are often synthesized by dehydration
condensation from corresponding diaryl ketones with two
4
5
hydroxyl groups under acidic or basic conditions (Figure 1).
Figure 1. Synthesis of xanthones through dehydration of diaryl
ketones.
the generated phenalenones are found in various natural
products and have also been studied as stable radical species
6
with unique electronic and magnetic functions derived from the
unique π-system. In this manuscript, we report insight into the
rearrangement reaction and a new synthetic route toward
phenalenone derivatives.
During our studies, when compound 1 was subjected to
dehydration, the desired dibenzoxanthone 2 was afforded in
6% yield under basic conditions (Scheme 1). In contrast,
7
3
8
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,
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
8
group was essential for rearrangement (Figure 2).
The rearrangement conditions were applied for compounds
−7, with the results shown in Table 1. When 4 was subjected
4
Received: July 26, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02305
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Organic Letters
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
8
Figure 2. Four hydroxyl-group-deficient compounds 4−7.
Table 1. Attempted Rearrangement Conditions for
Compounds 4−7
(
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.
to rearrangement conditions, a retro-Friedel−Crafts reaction
Finally, we attempted to directly access the intermediates
1
10
took place, and fragmental products 8 and 9 were isolated in
using H NMR measurements. 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
9
6
0% and 50% yields, respectively. 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
1
slowly in TFA, allowing the intermediates to be tracked by H
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
(
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,
B
DOI: 10.1021/acs.orglett.7b02305
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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
1
Figure 3. Structures of intermediates and their H NMR spectra.
ester moiety. The product is expected to be a key intermediate
for natural products and electronic materials (Scheme 4).
Conditions: CDCl /CF CO H = 1/6, 600 MHz, 27 °C.
3
3
2
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
1H-intermediate and a singlet signal at δ 5.23 ppm (Hh′) for
1
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)
1
1
C−CHh′− (one singlet) arrangements.
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 (10-
and 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 10H-
intermediate followed by a 1,2-hydride shift and E1cb
dehydration reaction.
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 hydroxyl-
group-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
Finally, compound 3, produced by the rearrangement
reaction, was transformed into a simple phenalenone skeleton
1
2
2
5 through a Baeyer−Villiger oxidation and hydrolysis of the
C
DOI: 10.1021/acs.orglett.7b02305
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as a key intermediate for the synthesis of natural products and
promising electronic materials.
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.
ASSOCIATED CONTENT
■
(
6) (a) Ho
̈
lscher, 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
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02305.
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.
Experimental details, H and 13C NMR spectra of new
1
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.
(7) (a) Mukherjee, A.; Sau, S. C.; Mandal, S. K. Acc. Chem. Res. 2017,
X-ray data for compound 22 (CIF)
5
(
0, 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,
22, 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−
441.
AUTHOR INFORMATION
Corresponding Author
■
1
*E-mail: tsubaki@kpu.ac.jp.
2
ORCID
(
8) For the synthesis of compounds 4−7, see the Supporting
Takahiro Sasamori: 0000-0001-5410-8488
Kouji Kuramochi: 0000-0003-0571-9703
Kazunori Tsubaki: 0000-0001-8181-0854
Present Address
Information.
(9) Bacci, J. P.; Kearney, A. M.; Van Vranken, D. L. J. Org. Chem.
2
(
005, 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
∥
Graduate School of Natural Sciences, Nagoya City University.
Notes
°
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.; Bras
b) Winter, D. K.; Sloman, D. L.; Porco, J. A., Jr. Nat. Prod. Rep. 2013,
■
(
̈
e, S. Chem. Rev. 2012, 112, 3717−3776.
(
3
0, 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,
1
0963−10972.
3) Azuma, E.; Kuramochi, K.; Tsubaki, K. Tetrahedron 2013, 69,
694−1699.
4) (a) Vandana, T.; Prasad, K. J. R. Indian J. Chem., Sect. B 2005, 44,
15−818. (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.;
(
1
(
8
(
(
D
DOI: 10.1021/acs.orglett.7b02305
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