Synthesis of γ-benzopyranone by TfOH-promoted regioselective cyclization of o-alkynoylphenols

Article abstract of DOI:10.1021/ol2016934

Regioselective cyclization of o-alkynoylphenols forming γ-benzopyranones has been demonstrated. Trifluoromethanesulfonic acid (TfOH) induced 6-endo cyclization of o-alkynoylphenols without forming 5-exo cyclized benzofuranone derivatives to provide the corresponding γ-benzopyranones in high yields.

Full text of DOI:10.1021/ol2016934

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4526–4529
Synthesis of γ-Benzopyranone by
TfOH-Promoted Regioselective Cyclization
of o-Alkynoylphenols
Masahito Yoshida, Yuta Fujino, and Takayuki Doi*
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba,
Aramaki, Aoba-ku, Sendai 980-8578, Japan
doi_taka@mail.pharm.tohoku.ac.jp
Received June 23, 2011
ABSTRACT
Regioselective cyclization of o-alkynoylphenols forming γ-benzopyranones has been demonstrated. Trifluoromethanesulfonic acid (TfOH)
induced 6-endo cyclization of o-alkynoylphenols without forming 5-exo cyclized benzofuranone derivatives to provide the corresponding
γ-benzopyranones in high yields.
γ-Benzopyranone-containing natural products such as
nobiletin (1) and pluramycin A (2) exhibit a wide range of
biological activities, especially, anti-inflammatory, antimi-
crobial, antitumoric, and cytotoxic (Figure 1).1 Several
approaches to the synthesis of a γ-benzopyranone skeleton
have been reported, for example, acid-catalyzed cyclization
of 1,3-dione derivatives prepared from 2-hydroxyaceto-
phenones2 and oxidative cyclization of 2-hydroxychalcones.3
The γ-benzopyranone system with substituents at the
C2 position can also be synthesized by 6-endo-digonal
cyclization of o-alkynoylphenols 3.4 In general, cycli-
zation of o-alkynoylphenols predominantly provides
(1) (a) Martens, S.; Mithofer, A. Phytochemistry 2005, 66, 2399–
2407. (b) Veitch, N. C.; Grayer, R. J. Nat. Prod. Rep. 2008, 25, 555–611.
(c) Crozier, A.; Jaganath, I. B.; Clifford, M. N. Nat. Prod. Rep. 2009, 26,
1001–1043. (d) Sequin, U. Fortschr. Chem. Naturst. 1986, 50, 57–122.
Figure 1. γ-Benzopyranone-containing natural products and
(e) Hansen, M. R.; Hurley, L. H. Acc. Chem. Res. 1996, 29, 249–258.
possible mode of the cyclization of o-alkynoylphenol.
(2) (a) Baker, W. J. Chem. Soc. 1933, 1381–1389. (b) Mahal, H. S.;
Venkataraman, K. J. Chem. Soc. 1934, 1767–1769. (c) Zembower, D. E.;
Zhang, H. J. Org. Chem. 1998, 63, 9300–9305. (d) Asakawa, T.; Hiza, A.;
γ-benzopyranones4via6-endo-digonalcyclization(patha),
while a substantial amount of benzofuranone 5, formedvia
5-exo-digonal cyclization (path b), is also observed.5 Sev-
Nakayama, M.;Inai, M.; Oyama, D.; Koide, H.; Shimizu, K.; Wakimoto,
T.; Harada, N.; Tsukada, H.; Oku, N.; Kan, T. Chem. Commun. 2011, 47,
2868–2870.
(3) (a) Chen, F. C.; Chang, C. T.; Chen, C. Y.; Hung, M.; Lin, Y. C.
eral studies on cyclization of o-alkynoylphenols revealed
that a mixture of γ-benzopyranones 4 and benzofuranones
J. Org. Chem. 1962, 27, 310–312. (b) Zhang, F.-J.; Lin, G.-Q.; Huang,
Q.-C. J. Org. Chem. 1995, 60, 6427–6430. (c) Joo, Y. H.; Kim, J. K.;
Kang, S. H.; Noh, M. S.; Ha, J. Y.; Choi, J. K.; Lim, K. M.; Lee, C. H.;
Chung, S. Bioorg. Med. Chem. Lett. 2003, 13, 413–417.
(4) (a) Baldwin, J. K. J. Chem. Soc., Chem. Commun. 1976, 734–736.
(b) Baldwin, J. K.; Cutting, J.; Dupont, W.; Kruse, L.; Siberman, L.;
Thomas, R. C. J. Chem. Soc., Chem. Commun. 1976, 736–738.
(5) (a) Garcıa, H.; Iborra, S.; Primo, J.; Miranda, M. A. J. Org.
Chem. 1986, 51, 4432–4436. (b) Brennan, C. M.; Johnson, C. D.;
McDonnell, P. D. J. Chem. Soc., Perkin Trans. 2 1989, 957–961.
r
10.1021/ol2016934
Published on Web 08/03/2011
2011 American Chemical Society

5 is obtained and their ratio is highly dependent on the
reaction conditions as well as the substituents on the
substrate.6
Therefore, we are interested in developing a versatile
method for the synthesis of γ-benzopyranones from
o-alkynoylphenols. WehereinreportthatTfOH-promoted
cyclization of o-alkynoylphenols exclusively produced
γ-benzopyranones.
To achieve the regioselective cyclization of o-alkynoyl-
phenol 6, we postulated the production of R,β-unsaturated
ketone 7 by 1,4-addition of triflic acid (TfOH) to
o-alkynoylphenol 6 (Scheme 1). Vasilyev et al. reported
that ynoates underwent 1,4-addition of TfOH to yield
corresponding vinyl triflates 7.7 Vinyl triflate 7 should be
a good Michael acceptor such that intramolecular 1,
4-addition of the phenolic hydroxy group, followed by
the elimination of TfOH, would exclusively afford benzo-
pyranone 9. This integrated synthesis of a γ-benzopyra-
none skeleton would be useful because the above two
reactions can be performed in a single one-pot operation.8
The 5-membered ring product aurone (12a) was not ob-
served under these reaction conditions (Table 1, entry 1,
11a:12a = >99:1).9 On the other hand, no reaction
proceeded in the presence of other Brønsted acids. In
addition, weaker acids such as trifluoroacetic acid, p-
toluenesulfonic acid, camphor sulfonic acid, acetic acid,
and formic acid gave no reaction (entries 3À7). Inter-
estingly, bis(trifluoromethanesulfonyl)imide (Tf2NH),10
which is a stronger acid than TfOH, gave a trace amount
of the product (entry 2).
When the reaction was conducted at rt, vinyl triflate 13
was isolated in 41% yield accompanied by 11a (23%)
(Scheme 2). Then, 13 was quantitatively converted to 11a
with heating at 40 °C without formation of 12a. According
to the above investigation, note that the TfOH-promoted
cyclization of alkynoylphenol 10a proceeded via an inter-
mediate 13; therefore the desired 6-endo cyclized product
11a was regioselectively afforded.
Table 1. Investigation of the Cyclization of o-Alkynoylphenol
10a under Acidic Conditions
Scheme 1. TfOH-Promoted Regioselective Cyclization of
o-Alkynoylphenols
temp time ratio of
yield of
entry reagenta solvent (°C) (h) 11a:12ab 6-endo 11a (%)c
1
2
3
4
5
6
7
TfOH
Tf2NH
TFA
(CH2Cl)2 40
(CH2Cl)2 40
(CH2Cl)2 40
10
24
24
24
24
24
24
>99:1
>99:1
À
80
5
0
p-TsOH (CH2Cl)2 40
À
0
CSA
(CH2Cl)2 40
(CH2Cl)2 40
À
0
AcOH
À
0
HCOOH (CH2Cl)2 40
À
0
We initially examined the regioselectivity of the cycliza-
tion of o-alkynoylphenol 10a. Treatment of 10a with 1
equiv of TfOH at 40 °C in 1,2-dichloroethane provided the
6-membered ring product flavone (11a) in 80% yield.
a 100 mol % of Brønstedacid was used. b The ratio of 11a and 12a was
determined by crude 1H NMR. c Isolated yield.
(6) (a) Alvaro, M.; Garcia, H.; Iborra, S.; Miranda, M. A.; Primo, J.
Tetrahedron 1987, 43, 143–148. (b) McGarry, L. W.; Detty, M. R. J. Org.
Chem. 1990, 55, 4349–4356. (c) Ciattini, P. G.; Morera, E.; Ortar, G.; Rossi,
S. S. Tetrahedron 1991, 47, 6449–6456. (d) Torii, S.; Okumoto, H.; Xu,
L. H.; Sadatake, M.; Shostakovsky, M. V.; Ponomaryov, A. B.; Kalini,
V. N. Tetrahedron 1993, 49, 6773–6784. (e) Nakatani, K.; Okamoto, A.;
Yamanuki, M.; Saito, I. J. Org. Chem. 1994, 59, 4360–4361. (f) Nakatani,
K.; Okamoto, A.; Saito, I. Tetrahedron 1996, 52, 9427–9446. (g) Uno, H.;
Sakamoto, K.; Honda, E.; Ono, N. Chem. Commun. 1999, 1005–1006.
(h) Bhat, A. S.; Whetstone, J. L.; Brueggemeier, R. W. Tetrahedron Lett.
1999, 40, 2469–2472. (i) Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765–1768.
(j) Bhat, A. S.; Whetstone, J. L.; Brueggemeier, R. W. J. Comb. Chem. 2000,
2, 597–599. (k) Huang, X.; Tang, E.; Xu, W.-M.; Cao, J. J. Comb. Chem.
2005, 7, 802–805. (l) Zhou, C.; Dubrovsky, A. V.; Larock, R. C. J. Org.
Chem. 2006, 71, 1626–1632. (m) Likhar, P. R.; Subhas, M. S.; Roy, M.;
Roy, S.; Kantam, M. L. Helv. Chim. Acta 2008, 91, 259–264. (n) Kraus,
G. A.; Wie, J.; Thite, A. Synthesis 2008, 15, 2427–2431. (o) Yamaguchi, S.;
Kobayashi, M.; Harada, S.; Miyazawa, M.; Hirai, Y. Bull. Chem. Soc. Jpn.
2008, 81, 863–868.
Scheme 2. Reaction Pathway from 10a to 11a by TfOH-Pro-
moted Cyclization
(9) Aurone 12a was prepared by treatment with a catalytic amount of
AgCl; see: Jong, T.-T.; Leu, S.-J. J. Chem. Soc., Perkin Trans. 1 1990,
423–424.
(7) Vasilyev, A. V.; Walspurger, S.; Chassaing, S.; Pale, P.; Sommer,
J. Eur. J. Org. Chem. 2007, 5740–5748.
(8) In classification of reaction integration, tandem reaction is cate-
gorized as a time and space integration by the Yoshida group; see: Suga.,
S.; Yamada, D.; Yoshida, J. Chem. Lett. 2010, 39, 404–406.
(10) (a) Foropoulos, J.; DesMarteau, D. D. Inorg. Chem. 1984, 23,
3720–3723. (b) Koppel, I. A.; Taft, R. W.; Anvia, F.; Zhu, S.; Hu, L.;
Sung, K.; DesMarteau, D. D.; Yagupolskii, L. M.; Yagupolskii, A. Y.;
Ignat’ev, N. V.; Kondratenko, N. V.; Volkonskii, A. Y.; Vlasov, V. M.;
Notario, R.; Maria, P. J. Am. Chem. Soc. 1994, 116, 3047–3057.
Org. Lett., Vol. 13, No. 17, 2011
4527

from the intermediate B. Therefore, addition of 1 equiv of
TfOH is necessary to complete the reaction.
With the optimal reaction conditions for 6-endo cycliza-
tion of o-alkynoylphenol in hand, we evaluated the various
substrates in TfOH-promoted regioselective cyclizaton.
Cyclization of the substrates 10bÀd possessing methoxy
groups on the right benzene ring (Table 2, entries 1À3) was
easily completed within 4 h and yielded the corresponding
6-endo cyclized products 11bÀd in excellent yields; this was
presumably because of the electron-donating effect of the
methoxy group at the para-position on the right benzene
ring. Except for 10e, substrates 10fÀh bearing methoxy
groups on the left benzene ring were also cyclized under the
same reaction conditions to provide the corresponding
products 11fÀh (entries 5À7). In the cyclization of 10e,
which has no methoxy group on the right benzene ring, a
higher temperature (80 °C) was necessary because the
electron-donating effect of the methoxy group strongly
decreased the electrophilicity of the carbonyl group (entry 4).
The cyclization of substrates 10iÀl, which contain a meth-
oxy group at one of the meta-positions, was also selectively
performed to yield 11iÀl in moderate yields (entries 8À11).
Although TfOH also induced 6-endo cyclization in the case
of substrates 10m and 10n, demethylation of the methoxy
group was observed to provide 5-hydroxy derivatives 11m
(71%, entry 12) and 11n (73%, entry 13), respectively.12 In
the cyclization of the substrates 10oÀq possessing alkyl
groups instead of the aromatic ring, the reaction was not
completed even at 80°C. After extensiveinvestigations, the
reaction smoothly proceeded at 150 °C under microwave
irradiation leading to the corresponding 6-endo cyclized
γ-benzopyranones 11oÀq in moderate yields (67À75%,
entries 14À16).
Figure 2. Selected 1H NMR spectra (6.7À8.5 ppm) of the
reaction of 10a under the TfOHÀCD2Cl2 conditions. (A) Sub-
strate 10a; (B) 0 h (10a with TfOH); (C) after 5 h, with blue
arrows indicating the signal of intermediate A (vinyl triflate 13);
(D) after 10 h; (E) isolated 11a.
When the regioselective cyclization of o-alkynoylphenol
10a using 0.5 equiv of TfOH was performed, 11a was
produced in 41% yield with recovery of 10a (47%). As it
was speculated that the cyclization proceeded stoichiome-
trically, the time course of the cyclization of 10a was moni-
tored by 1H NMR spectroscopy in CD2Cl2 (Figure 2). The
substrate 10a and the mixture of 10a with 1 equiv of TfOH
Scheme 3. Plausible Mechanism of TfOH-Mediated Cyclization
of o-Alkynoylphenol 10a
1
were initially measured. It was found that the H NMR
spectrum of the above mixture was completely distinguish-
able from that of substrate 10a (Figure 2A and B). There-
fore, we expected that 10a was easily converted to the
complex using TfOH by coordination with the carbonyl
group. Substrate 10a was consumed in 5 h; considerable
amounts of intermediates A, B (see Scheme 3) and a cyc-
lized product were observed (Figure 2C). After 10 h, the
reaction was completed and a single product was detected
by 1H NMR (Figure 2D). The spectrum of the product in
the reaction mixture was not identical to that of isolated
11a (Figure 2D and E). Notably, when the product was
generated, the color of the reaction mixture gradually
turned from yellow to dark red.11 It is suggested that
flavylium salt 14 would be generated under the reaction
conditions by coordination of TfOH (Scheme 3). Accord-
ing to the above observations, it should be noted that 14
was immediately formed by elimination of the TfOÀ ion
In summary, we have demonstrated the regioselective
cyclization of o-alkynoylphenols in acidic media. It was
found that the 6-endo cyclization was induced by TfOH to
afford γ-benzopyranone derivatives in moderate to excel-
lent yields without forming 5-exo cyclized benzofuranone
(12) Demethylation of the methoxy group under acidic conditions
€
has been observed; see: Schonberg, A.; Badran, N. J. Am. Chem. Soc.
1951, 73, 2960–2961.
(11) Flipescu, N.; Chakrabarti, S. K.; Trassoff, P. G. J. Phys. Chem.
1973, 77, 2276–2282.
4528
Org. Lett., Vol. 13, No. 17, 2011

Table 2. TfOH-Promoted Regioselective Cyclization: Substrate Scope
a The reaction was conductedat 80 °C. b Demethylation of the methoxy group was observed. c The reaction was conductedat 150 °C under microwave
irradiation.
derivatives. Using this methodology, the library synthesis
of γ-benzopyranone-based natural product derivatives is
currently underway in our laboratory.
MEXT. We also thank the Circle for the Promotion of
Science and Engineering for financial support.
Supporting Information Available. Experimental pro-
cedures and compound characterization data for 10aÀq,
11aÀq, 12a, and 13. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Scientific Research on Innovative
Areas “Reaction Integration” (No. 2105, 22106503) from
Org. Lett., Vol. 13, No. 17, 2011
4529