A novel construction of dibenzofuran-1,4-diones by oxidative cyclization of quinone-arenols

Article abstract of DOI:10.1021/ol070951i

A novel oxidative cyclization of quinone-arenols 5 leading to products 6 with a dibenzofuran-1,4-dione structure, which forms the core of several natural products, has been developed and applied to the synthesis of violet-quinone (4).

Full text of DOI:10.1021/ol070951i

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2807-2810
A Novel Construction of
Dibenzofuran-1,4-diones by Oxidative
Cyclization of Quinone-arenols
Tetsuya Takeya,*,† Hiromu Kondo, Tsuyoshi Otsuka, Kazuho Tomita,
Iwao Okamoto, and Osamu Tamura*
Showa Pharmaceutical UniVersity, 3-3165 Higashi-tamagawagakuen, Machida,
Tokyo 194-8543, Japan
tamura@ac.shoyaku.ac.jp
Received April 24, 2007
ABSTRACT
A novel oxidative cyclization of quinone-arenols 5 leading to products 6 with a dibenzofuran-1,4-dione structure, which forms the core of
several natural products, has been developed and applied to the synthesis of violet-quinone (4).
Heterocyclic ring-fused quinone systems are found in many
biologically and pharmacologically active compounds.1
Among them, the dibenzofuran-1,4-dione core 1 is found in
several natural products of biological importance, such as
cytotoxic popolohuanone E (2),2 antipruritic balsaminone A
(3),3 violet-quinone (4),4 and other natural quinones.5 (Figure
1). The biological activities of corresponding synthetic
compounds have also been examined.6 Several methods have
been reported for the construction of the structure 1 by
cyclization of 2,2′-biquinones,7 coupling reaction of dichloro-
quinones with phenols,6,8 transition metal-mediated cycliza-
tion,9 and lithiation-mediated cyclization.10 In addition, much
effort has been directed to the synthesis of cytotoxic
popolohuanone E (2),7c,8b,c and the 8-O-methyl derivative of
2 was synthesized by Katoh et al.8c However, synthesis of 2
itself has not yet been accomplished.
† Deceased, June 19, 2006.
(1) Cheng, C. C. Progress of Medicinal Chemistry; Ellia, G. P., West,
G. B., Eds.; Elsevier: Amsterdam, The Netherlands, 1988; Vol. 25, pp 35-
83.
(2) Carney, J. R.; Scheuer, P. J. Tetrahedron Lett. 1993, 34, 3727-3730.
(3) Ishiguro, K.; Ohira, Y.; Oku, H. J. Nat. Prod. 1998, 61, 1126-1129.
(4) Sankaram, A. V. B.; Reddy, V. V. N.; Sidhu, G. S. Phytochemistry
1981, 20, 1093-1096.
(5) (a) Xu, M.; Deng, Z.; Li, M.; Li, J.; Fu, H.; Proksch, P.; Lin, W. J.
Nat. Prod. 2004, 67, 762-766. (b) Puder, C.; Wagner, K.; Vettermann, R.;
Hauptmann, R.; Potterat, O. J. Nat. Prod. 2005, 68, 323-326. (c) Kayser,
O.; Kiderlen, A. F.; Laatsch, H.; Croft, S. L. Acta Trop. 2000, 77, 307-
314.
(6) (a) Cheng, C. C.; Dong, Q.; Liu, D. F.; Luo, Y. L.; Liu, L. F.; Chen,
A. Y.; Yu, C.; Savaraj, N.; Chou, T. C. J. Med. Chem. 1993, 36, 4108-
4112. (b) Hejaz, H. A. M.; Woo, L. W. L.; Purohit, A.; Reed, M. J.; Potter,
B. V. L. Bioorg. Med. Chem. 2004, 12, 2759-2772. (c) Lee, K.; Park, Y.;
Park, S.; Hwang, J.; Lee, S.; Kim, G.; Park, W.; Lee, S.; Jeong, D.; Kong,
J.; Kang, H.; Cho, H. Bioorg. Med. Chem. Lett. 2006, 16, 737-742.
Figure 1. Natural products having a dibenzofuran-1,4-dione core.
10.1021/ol070951i CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/20/2007

In the course of our research aimed at synthesizing 2-4,
we sought an efficient method for the construction of the
core structure 1. Herein, we report a novel oxidative
cyclization of quinone-arenols 5 with benzo-1,4-quinone (7)
or chloranil (8) in the presence of molecular oxygen (O2),
leading to cyclization products 6 having the dibenzofuran-
1,4-dione core structure 1 (Scheme 1). This cyclization
reaction was also applied to an efficient synthesis of 4.
Table 1. Preparation of Quinone-arenols 5 from Hydroquinone
Monomethylethers 9
Scheme 1. Oxidative Cyclization of Quinone-arenols 5
Our research began with preparation of the starting 2,2′-
quinonearenols 5 via a two-step sequence involving oxidative
dimerization of hydroquinone monomethyl ethers 9 and
monodemethylation of the resulting [2,2′]arenylidene-1,1′-
diones 10 (Scheme 2, Table 1).7b,11,12 Thus, the 2,2′-
Scheme 2. Preparation of Quinone-arenols 5
followed by O-monodemethylation of the [2,2′]binaphtha-
lenylidene-1,1′-diones 10a and 10b with SnO2 (entries 1 and
2). Similarly, [2,2′]biphenyl-1,4-diones 5c-e were also
prepared from the corresponding phenols 9c-e (entries 3-5)
(see Supporting Information).13
quinonenaphthols 5a and 5b were readily prepared by
oxidative dimerization of the corresponding 1-naphthols 9a
and 9b with benzoquinone (7) and chloranyl (8), respectively,
With the substrates 5a-e in hand, we next examined the
key oxidative cyclization of 5 using benzoquinone (7) or
chloranyl (8) as an oxidant (Scheme 1, Table 2). After
screening various solvents and temperatures for cyclization
of 5a, the best result was obtained by heating in toluene with
7. Thus, the quinone-naphthol 5a, on heating with 7 (1.1
equiv) in toluene at 100 °C under argon, underwent oxidative
cyclization with consumption of 7 to give 6a in 76% yield
along with some polymeric precipitates (entry 1). To clarify
hydroquinone formation from benzoquinone (7) during the
reaction, the reaction mixture was treated with acetic
anhydride (Ac2O) in the presence of Mg(ClO4)214 to furnish
hydroquinone diacetate in 80% yield from 7. This result
shows that 7 acts as an oxidant, accepting two hydrogen
(7) (a) Buchan, R.; Musgrave, O. C. J. Chem. Soc., Perkin Trans. 1 1980,
90-92. (b) Ogata, T.; Okamoto, I.; Kotani, E.; Takeya, T. Tetrahedron
2004, 60, 3941-3948. (c) Anderson, J. C.; Denton, R. M.; Wilson, C. Org.
Lett. 2005, 7, 123-125.
(8) (a) Shand, A. J.; Thomson, R. H. Tetrahedron 1963, 19, 1919-1937.
(b) Ueki, Y.; Itoh, M.; Katoh, T.; Terashima, S. Tetrahedron Lett. 1996,
37, 5719-5722. (c) Katoh, T.; Nakatani, M.; Shikita, S.; Sampe, R.;
Ishiwata, A.; Ohmori, O.; Nakamura, M.; Terashima, S. Org. Lett. 2001,
3, 2701-2704.
(9) (a) Martinez, E.; Martinez, L.; Estevez, J. C.; Estevez, R. J.; Castedo,
L. Tetrahedron Lett. 1998, 39, 2175-2176. (b) Chang, H.; Chou, T.; Savaraj,
N.; Liu, L. F.; Yu, C.; Cheng, C. C. J. Med. Chem. 1999, 42, 405-408. (c)
Martinez, E.; Martinez, L.; Treus, M.; Estevez, J. C.; Estevez, R. J.; Castedo,
L. Tetrahedron 2000, 56, 6023-6030. (d) Martinez, A.; Fernandez, M.;
Estevez, J. C.; Estevez, R. J.; Castedo, L. Tetrahedron 2005, 61, 1353-
1362. (e) Miguel del Corral, J. M.; Castro, M. A.; Gordaliza, M.; Martin,
M. L.; Gamito, A. M.; Cuevas, C.; San Feliciano, A. Bioorg. Med. Chem.
2006, 14, 2816-2827.
(10) Azevedo, M. S.; Alves, G. B. C.; Cardoso, J. N.; Lopes, R. S. C.;
Lopes, C. C. Synthesis 2004, 1262-1268.
(11) (a) Takeya, T.; Otsuka, T.; Okamoto, I.; Kotani, E. Tetrahedron
2004, 60, 10681-10693. (b) Takeya, T.; Kondo, H.; Otsuka, T.; Doi, H.;
Okamoto, I.; Kotani, E. Chem. Pharm. Bull. 2005, 53, 199-206.
(12) Hewgill, F. R.; Greca, B. L.; Legge, F.; Roga, P. E. J. Chem. Soc.,
Perkin Trans. 1 1983, 131-134.
(13) The intermediate 10c for the preparation of 5c was obtained in only
40% yield by oxidative dimerization, crystallization, and collection by
filtration. The low yield may be due to low crystallinity of 10c.
(14) Chakraborti, A. K.; Sharma, L.; Gulhane, R.; Shivani, S. Tetrahedron
2003, 59, 7661-7668.
2808
Org. Lett., Vol. 9, No. 15, 2007

popolohuanone E (2).8b In contrast to the high-yield forma-
tion of 6e, it was reported that debenzylation of 11 followed
by oxidation with a large excess of 2,3-dichloro-5,6-dicyano-
1,4-quinone (DDQ) in a short time gave the quinone-phenol
5f instead of the dibenzofuranquinone derivative 6f (Scheme
3).15 Indeed, reaction of 5e with DDQ gave only 34% yield
Table 2. Oxidative Cyclization of Quinone-arenols 5a-e
Leading to Dibenzofuranquinones 6a-ea
Scheme 3. Debenzylation and Oxidation of 11
of the cyclization product 6e along with unidentified byprod-
ucts probably due to overreaction, although the reaction time
(1 h) was much shorter than that with 7 or 8 (Table 2, entry
12).
These facts implied that selection of the oxidant might be
very important for efficient cyclization of 5 without an
undesired side reaction, and prompted us to employ cyclic
voltammetry of 5 to examine this point. The measurements
suggested a correlation of the oxidation potentials (Eox) of 5
as donors with the reduction potentials (Ered) of benzoquinone
(7) and chloranil (8) as acceptors for efficient cyclization
(Table 3, see also Table 2). For example, 7 (-0.59 V)11b
a Unless otherwise noted, all reactions were carried out by using substrate
(1 mmol), benzoquinone (7), or chloranil (8) (1.1 equiv) in O2-saturated
toluene at 100 °C in a sealed tube. b The reaction was conducted under an
argon atmosphere. c The starting material 5b (40%) was recovered. d The
starting material 5c (32%) was recovered.
Table 3. Oxidation Potentials (Eox) of 5a-e and Reduction
Potentials (Ered) of 7 and 8
5 (Eox, V)a
7 and 8 (Ered, V)a
atoms from 5a. Next, a similar reaction was conducted in
the presence of O2. The use of O2 resulted in an improvement
of the yield of 6a (84%) and prevented the formation of
undesired polymeric precipitates (entry 2). In addition,
hydroquinone diacetate (62%) was again obtained by expo-
sure of the reaction mixture to Ac2O. Although the exact
role of O2 remains unclear, O2 might partially act for
recycling benzoquinone (7) and for preventing the undesired
polymerization of 5a. The reaction of 5a with chloranil (8)
was less clean, giving 6a in 54% yield (entry 3). Cyclization
of 5b was examined under similar conditions (entries 4 and
5). Although the cyclization of 5b required a prolonged
reaction time, reaction with 8 afforded an excellent yield
(97%) of 6b (entry 5). We next applied our method to 5c-e
as shown in entries 6-11. In all cases, the cyclizations
proceeded to afford the corresponding dibenzofuranquinones
6a-c in good to high yields. In addition, entries 6-11 show
that the use of 8 gave better results than in the case of 7
(entries 7, 9, and 11 versus entries 6, 8, and 10). It should
be noted that 6e has a substituent pattern similar to that of
5a (+0.85)
5b (+0.93)
5c (+1.04)
5d (+0.92)
5e (+1.14)
7 (-0.59)
8 (-0.08)
a See ref 16.
with a lower redox potential is a more suitable acceptor in
the reaction of 5a (+0.85 V) (observed below Eox ) +0.9
V). In contrast, 8 (-0.08 V)11b having a higher redox
potential is a more suitable acceptor for the reaction of 5b
(15) Benbow, J. W.; Martinez, B. L.; Anderson, W. R. J. Org. Chem.
1997, 62, 9345-9347.
(16) Potentials (V) are versus Ag/AgCl; all substrates were measured in
the range of about 0.0-2.0 V. The oxidation potentials of anodic current
(E) were obtained by cyclic voltammetry of 0.1 mM solutions of the
substrates in an argon-saturated solvent (CH2Cl2) containing 0.1 M
n-Bu4NClO4 as a supporting electrolyte at a Pt electrode. The voltage scan
rate in cyclic voltammetry was 100 mV s-1 at 23 °C. Eox ) the first half-
wave oxidation potential.11b
Org. Lett., Vol. 9, No. 15, 2007
2809

(+0.93 V) (observed above Eox ) +0.9 V). This makes it
possible to readily select an effective acceptor for future
oxidative cyclizations of a wide variety of quinone-arenols
5, leading to the corresponding dibenzofuranquinones 6.
The present oxidative cyclization was applied to the
synthesis of violet-quinone (4) (Scheme 4). The quinone-
MgBr2-iodide-mediated selective demethylation of the C4-
and C11-OMe groups of 6g afforded the natural product 4
in 81% yield and mp of 332-335 °C. All physical data of
the synthetic compound 4 were identical with those of an
authentic sample.4,7b
As mentioned above, we have developed a simple method
for the synthesis of dibenzofuranquinones 6, which is the
core structure of the natural products 2-4, utilizing a novel
oxidative cyclization of the quinone-arenols 5. As an
application of this method to natural product synthesis, a
facile synthesis of 4 was accomplished, confirming the
synthetic utility of the present cyclization. Toward the
synthesis of popolohuanone E (2), since it was reported that
8-O-methyl group could not be removed under the conditions
compatible with exocyclic methylenes,8c examination of the
protective group of C8-oxygen functionality should be indeed
indispensable for the synthesis of 2. The preparation method
of cyclization-precursor for 2 should be also examined
because the yield of precursor 5e was moderate. Despite the
considerations of above, the present oxidative cyclization
would be very attractive as an option for the construction of
the skeleton of 2.
Scheme 4. Synthesis of Violet-quinone (4)
Acknowledgment. This research was supported by a
Grant-in-aid from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 5a-e, 5g,
6a-e, 6g, 10a-d′, 10g, and 4; 1H NMR spectra of
compounds 5c-e and 10c,d′. This material is available free
of charge via the Internet at http://pubs.acs.org.
arenol 5g was readily prepared from 9g via a two-step
sequence similar to that used for the preparation of 9a:
oxidative dimerization with 7 followed by selective mono-
demethylation with SnO2. On the basis of the above
information, oxidative cyclization of 5g (Eox ) +0.82 V)
was carried out by using 7 (Ered ) -0.59 V) as an oxidant
in the presence of O2, affording 6g in high yield. Finally,
OL070951I
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