A direct approach to 5-hydroxybenzofurans via a platinum-catalyzed domino rearrangement/5-endo-dig cyclization reaction of quinols

Article abstract of DOI:10.1021/jo901937u

(Chemical Equation Presented) A highly efficient and atom-economical construction of 2-substituted 5-hydroxybenzofurans was accomplished by employing a platinum-catalyzed domino dienone-phenol rearrangement/5-endo-dig cyclization reaction of quinols beari

Full text of DOI:10.1021/jo901937u

pubs.acs.org/joc
interest on the facile construction of heterocycles under mild
A Direct Approach to 5-Hydroxybenzofurans
via a Platinum-Catalyzed Domino
Rearrangement/5-endo-dig Cyclization
Reaction of Quinols
conditions,3 we envisioned that subsequent cyclization after
the rearrangement would occur to form a bicyclic product, 4
or 5 if the starting quinol 1 has an appropriate electrophilic
group.
Ikyon Kim,* Kyungsun Kim, and Jungeun Choi
SCHEME 1. General Plan for the Synthesis of Bicycles via a
Tandem Rearrangement/Cyclization Sequence
Medicinal Chemistry Research Center, Korea Research
Institute of Chemical Technology, Daejeon 305-600,
Republic of Korea
ikyon@krict.re.kr
Received September 8, 2009
Along this line, we anticipated that quinols bearing an
alkyne unit 6 would rearrange to either 7 or 8, setting the
stage for the subsequent intramolecular cyclization to pro-
vide 5- or 6-hydroxybenzofuran (Scheme 2). Since both types
of substitution patterns are frequently found in a number of
natural products and pharmaceuticals, we decided to explore
the feasibility of this strategy. To the best of our knowledge,
no examples on the dienone-phenol rearrangement of the
quinols containing an alkyne moiety have been disclosed yet.
Here we wish to communicate our preliminary result on the
atom-economical synthesis of benzofurans4 featuring a dom-
ino rearrangement/intramolecular 5-endo-dig ring closure
reaction5 of quinols 6.
A highly efficient and atom-economical construction of
2-substituted 5-hydroxybenzofurans was accomplished
by employing a platinum-catalyzed domino dieno-
ne-phenol rearrangement/5-endo-dig cyclization reac-
tion of quinols bearing alkynes.
Transformation of 4,4-disubstituted cyclohexadienones to
3,4-disubstituted phenol derivatives via bond migration,
known as the dienone-phenol rearrangement, has been a
useful strategy for the synthesis of highly substituted phe-
nols.1 In particular, depending on the reaction conditions,
this rearrangement of quinol 1 results in either hydroquinone
2 or resorcinol 3 (Scheme 1).2 As part of our continued
SCHEME 2. Domino Dienone-Phenol Rearrangement/
5-endo-dig Cyclization
(1) (a) Metlesics, W.; Wesseley, F.; Budzikiewicz, H. Tetrahedron 1959, 6,
345. (b) Miller, B. Acc. Chem. Res. 1975, 8, 245. (c) Whiting, D. A. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: New York, 1991; Vol. 3, p 803. (d) In Strategic Applications of Named
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Reactions in Organic Synthesis; K€urti, L., Czarko, B., Eds.; Academic Press:
Oxford, UK, 2005; p 142 (e) In Name Reactions; Li, J.-J., Ed.; Springer: New
York, 2006; p 202.
(2) (a) Goodwin, S.; Witkop, B. J. Am. Chem. Soc. 1957, 79, 179.
2-Arylbenzofurans constitute
products displaying a variety of interesting biological
activities including anticancer, antimicrobial, and
a class of natural
(b) Hecker, E.; Meyer, B. Chem. Ber. 1964, 97, 1926–1940. (c) Planas, A.;
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Tomas, J.; Bonet, J.-J. Tetrahedron Lett. 1987, 28, 471. (d) Tian, G. R.; Mori,
A.; Kato, N.; Takeshita, H. Bull. Chem. Soc. Jpn. 1989, 62, 506. (e) Uno, H.;
Shiraishi, Y.; Matsushima, Y.; Yayama, A.; Suzuki, H. Bull. Chem. Soc. Jpn.
1991, 64, 842. (f) Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1992, 114,
1824. (g) Hart, D. J.; Kim, A.; Krishnamurthy, R.; Merriman, G. H.; Waltos,
A.-M. Tetrahedron 1992, 48, 8179. (h) Frimer, A. A.; Marks, V.; Sprecher,
M.; Gilinsky-Sharon, P. J. Org. Chem. 1994, 59, 1831. (i) Pitsinos, E. N.;
Moutsos, V. I.; Vageli, O. Tetrahedron Lett. 2007, 48, 1523.
(3) (a) Kim, I.; Lee, G. H.; No, Z. S. Bull. Korean Chem. Soc. 2007, 28,
685. (b) Kim, I.; Choi, J.; Won, H. K.; Lee, G. H. Tetrahedron Lett. 2007, 48,
6863. (c) Kim, I.; Won, H. K.; Choi, J.; Lee, G. H. Tetrahedron 2007, 63,
12954. (d) Kim, I.; Kim, S. G.; Kim, J. Y.; Lee, G. H. Tetrahedron Lett. 2007,
48, 8976. (e) Choi, J.; Lee, G. H.; Kim, I. Synlett 2008, 1243. (f) Kim, I.; Na,
H.-K.; Kim, K. R.; Kim, S. G.; Lee, G. H. Synlett 2008, 2069. (g) Kim, I.;
Choi, J.; Lee, S.; Lee, G. H. Synlett 2008, 2334. (h) Kim, I.; Lee, S.-H.; Lee, S.
Tetrahedron Lett. 2008, 49, 6579.
(4) For selected reviews and synthetic methods, see: (a) Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, UK, 1996; Vol. 2, p 259. (b) Kadieva, M. G.; Oganesyan,
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E. T. Chem. Heterocycl. Compd. 1997, 33, 1245. (c) McCallion, G. D. Curr. Org.
Chem. 1999, 3, 67. (d) Kraus, G. A.; Kim, I. Org. Lett. 2003, 5, 1191. (e) Lu, K.;
Luo, T.; Xiang, Z.; You, Z.; Fathi, R.; Chen, J.; Yang, Z. J. Comb. Chem. 2005, 7,
958. (f) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292. (g) Huang,
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(5) For some examples on domino rearrangement/cyclization reactions,
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2003, 2305. (b) Schobert, R.; Gordon, G. J.; Bieser, A.; Milius, W. Eur. J.
Org. Chem. 2003, 3637. (c) Pennicott, L.; Lindell, S. Synlett 2006, 463.
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8492 J. Org. Chem. 2009, 74, 8492–8495
Published on Web 10/14/2009
DOI: 10.1021/jo901937u
r
2009 American Chemical Society

Kim et al.
JOCNote
antioxidant activities.6 For example, as shown in Figure 1,
3-(γ,γ-dimethylpropenyl)moracin M was known to exhibit
modest cyclooxygenase inhibitory activity whereas moracin
O was recently reported to strongly inhibit hypoxia-induced
HIF-1R accumulation in human hepatocellular carcinoma
cell line Hep3B cells.
TABLE 1. Screening of the Reaction Conditions
entry catalysta
solvent
i-PrOH
i-PrOH
temp (°C) time (h) yield (%)b
1
2
PtCl2
CuI
80
80
80
80
80
80
80
80
80
80
50
80
50
80
40
40
40
rt
5
24
24
24
24
24
24
24
24
34
24
24
24
34
48
96
48
3
60
NRc
CMd
NR
NR
NR
NR
CM
CM
30
3
4
CuCl2 i-PrOH
ZnCl2 i-PrOH
5
6
7
InCl3
BiCl3
AuCl3 t-PrOH
i-PrOH
i-PrOH
8
9
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtBr2
PtI2
MeOH
EtOH
t-PrOH
dioxane
dioxane:H2O (1:1)
toluene
DME
DME:MeOH (20:1)
DME:MeOH (20:1)
DME:MeOH (20:1)
DME:MeOH (20:1)
DME
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CM
23
CM
25
86
70
NR
60
75
78
76
62
FIGURE 1. Some representative 2-arylbenzofuran natural pro-
ducts.
The requisite quinols for this study were easily prepared
from the nucleophilic addition of lithium acetylides to 1,4-
benzoquinones. Optimal reaction conditions were screened
with 6a. Initial screening of the catalysts revealed that PtCl2
is capable of promoting this domino sequence, furnishing the
desired benzofuran product in 60% yield (Table 1, entries
1-7). Comparison of the NMR data of the product with the
literature values7 indicates that the product isolated from
the reaction mixture is 5-hydroxy-2-phenylbenzofuran 9a.
Later, its structure was unambiguously established on the
basis of X-ray crystallographic analysis of O-methylated
analogue, 9a0.8,9 No isomeric 6-hydroxy-2-phenylbenzo-
furan10 was observed from the crude NMR analysis.
It turned out that solvent also plays a crucial role in this
process. While the reaction in either MeOH or EtOH at 80 °C
gave a complex mixture, use of i-PrOH led to 60% of
9a (Table 1, entries 1, 8, and 9). A rather low yield of 9a,
however, was obtained in t-BuOH (Table 1, entry 10).
Interestingly, no product was isolated in dioxane whereas
the mixed solvent system (dioxane:H2O, 1:1) afforded the
desired product albeit in low yield (Table 1, entries 11 and
12). No desired product was obtained in toluene at 50 °C
PtCl4
PtCl4
PtCl4
rt
rt
rt
rt
3
6
24
24
24
e
DME
f
PtCl4e DME
PtCl4e THF
PtCl4
EA
rt
60
a10 mol % catalyst loading unless otherwise noted. bIsolated yield.
cNo reaction. dComplex mixture. e5 mol %. f1 mol %.
(Table 1, entry 13). Although longer reaction time is re-
quired, we found that lowering the reaction temperature is
beneficial.11 In particular, we were able to obtain 9a in 86%
yield by using a mixed solvent (DME:MeOH, 20:1) after 48 h
at 40 °C (Table 1, entries 14 and 15). Other Pt(II) salts (PtBr2
and PtI2) were examined under these conditions, displaying
lower reactivities than PtCl2 (Table 1, entries 16 and 17).
Surprisingly, PtCl4 was found to induce this domino se-
quence at room temperature, furnishing 9a in 60-75% yields
(Table 1, entries 18 and 19). Even 5 or 1 mol % catalyst
loading of PtCl4 was effective without compromising the
yield (Table 1, entries 20 and 21). It seemed that superior
reactivity of PtCl4 to PtCl2 might be, in part, ascribed to the
solubility issues as PtCl4 is completely soluble in DME
whereas PtCl2 is not. Solvents such as THF or EA can be
used although the yield was a little lower than that in DME
(Table 1, entries 22 and 23).
(6) (a) Demizu, S.; Kajiyama, K.; Takahashi, K.; Hiraga, Y.; Yamamoto,
S.; Tamura, Y.; Okada, K.; Kinoshita, T. Chem. Pharm. Bull. 1988, 36, 3474.
(b) Basnet, P.; Kadota, S.; Terashima, S.; Shimizu, M.; Namba, T. Chem.
Pharm. Bull. 1993, 41, 1238. (c) Su, B.-N.; Cuendet, M.; Hawthorne, M. E.;
Kardono, L. B. S.; Riswan, S.; Fong, H. H. S.; Mehta, R. G.; Pezzuto, J. M.;
Kinghorn, A. D. J. Nat. Prod. 2002, 65, 163. (d) Dat, N. T.; Jin, X.; Lee, K.;
Hong, Y.-S.; Kim, Y. H.; Lee, J. J. J. Nat. Prod. 2009, 72, 39. (e) Kapche, G.
D. W. F.; Fozing, C. D.; Donfack, J. H.; Fosto, G. W.; Amadou, D.; Tchana,
A. N.; Bezabih, M.; Moundipa, P. F.; Ngadjui, B. T.; Abegaz, B. Phyto-
chemistry 2009, 70, 216. (f) Ni, G.; Zhang, Q.-J.; Zheng, Z.-F.; Chen, R.-Y.;
Yu, D.-Q. J. Nat. Prod. 2009, 72, 966.
Mechanistically, an alkyne moiety in 6a migrates to the
adjacent carbon to generate alkynone A,12 which undergoes
cyclization with the aid of Pt salt13 to give benzofuran 9a
(11) Benzofuran product seemed unstable to high temperature.
(7) (a) Domschke, G. J. Prakt. Chem. 1966, 32, 144. (b) Csekei, M.;
Novak, Z.; Timari, G.; Kotschy, A. ARKIVOC 2004, 285. (c) Alvey, L.;
Prado, S.; Huteau, V.; Saint-Joanis, B.; Michel, S.; Koch, M.; Cole, S. T.;
Tillequin, F.; Janin, Y. L. Bioorg. Med. Chem. 2008, 16, 8264.
(12) For the cyclization of alkynones, see: (a) Fukuda, Y.; Shiragami, H.;
Utimoto, K.; Nozaki, H. J. Org. Chem. 1991, 56, 5816. (b) Sromek, A. W.;
Kel’in, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2004, 43, 2280. (c) Yao,
T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164. (d) Patil, N.
T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2005, 70, 4531. (e) Kirsch, S. F.;
(8) 9a0 was prepared in a quantitative yield upon exposure of 9a to MeI
and Cs2CO3 in acetone at rt. See the Supporting Information for spectral
data of 5-methoxy-2-phenylbenzofuran (9a0). See also: Duan, X.-F.; Zeng,
J.; Zhang, Z.-B.; Zi, G.-F. J. Org. Chem. 2007, 72, 10283.
ꢀ
Binder, J. T.; Liebert, C.; Menz, H. Angew. Chem., Int. Ed. 2006, 45, 5878.
(f)Zhang, J.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2006, 45, 6704. (g) Zhang,
G.; Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 1814. (h) Xiao,
Y.; Zhang, J. Angew. Chem., Int. Ed. 2008, 47, 1903. (i) Sniady, A.; Morreale,
M. S.; Wheeler, K. A.; Dembinski, R. Eur. J. Org. Chem. 2008, 3449.
(13) (a) Nakamura, I.; Bajracharya, G. B.; Wu, H.; Oishi, K.; Mizushima,
Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 15423.
(b) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127,
(9) CCDC 739254 contains the supplementary crystallographic data for
compound 9a0. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
(10) McAllister, G. D.; Hartley, R. C.; Dawson, M. J.; Knaggs, A. R.
J. Chem. Soc., Perkin Trans. 1 1998, 3453.
€
15022. (c) Furstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024.
J. Org. Chem. Vol. 74, No. 21, 2009 8493

Kim et al.
JOCNote
(Scheme 3). The exact role of Pt salt in the dienone-phenol
rearrangement is not clear at this point but it presumably
induces the migration by its action as a Lewis acid to
coordinate to the dienone carbonyl oxygen as well as to the
alkyne group. Notably, this cascade event occurs predomi-
nantly despite the presence of a sensitive functional group
such as hydroxyl in 6a, which is both propargylic and allylic.
SCHEME 4
SCHEME 3. Proposed Mechanism
an alkyne unit, 11 and 12,16 were submitted to these condi-
tions to provide 13 and 14, implying this procedure should be
useful for the synthesis of substituted 1,4-hydroquinones or
benzoquinones (Scheme 5).
SCHEME 5
Having found the optimal conditions, the reaction scope
was examined with several quinols. As shown in Table 2, a
number of aryl groups at the R position of 6 were tolerated
under the reaction conditions (Table 2, entries 1-6). It
should be mentioned that 5-methoxybenzofuran was also
obtained as a minor product under condition A.14,15 Hetero-
cycle-containing benzofuran 9h was produced from the cor-
responding quinol 6h (Table 2, entry 7). 5-Hydroxybenzo-
furans containing alkyl groups at the C2 position were
constructed in good yields as well (Table 2, entries 8-12).
Exposure of 6n and 6o to these conditions also led to
the corresponding benzofurans 9n and 9o, respectively
(Scheme 4).
The basic benzofuran skeleton constructed by these methods
can be further elaborated toward the synthesis of benzofuran-
based natural products, which is briefly demonstrated in
Scheme 6. For example, demethylation of 9c with BBr3 gave a
5-hydroxy regioisomer of moracin M in 86% yield. In addition,
methylation of 9b furnished corsifuran C in excellent yield.17
SCHEME 6. Further functionalization
TABLE 2. Synthesis of Various 5-Hydroxybenzofurans
entry
substrate (R)
4-MeOPh
3,5-(MeO)2Ph
product
yield (%)a,b
1
2
6b
6c
9b
9c
75 (A)
81 (A)
85 (B)c
80 (A)
81 (B)
83 (B)
92 (A)
86 (A)
73 (A)d
77 (A)d
78 (A)d
79 (A)
69 (A)
3
4
5
6
7
8
9
10
11
12
4-MePh
4-FPh
3-FPh
6-methoxynaphthalen-2-yl
thiophen-3-yl
phenethyl
n-butyl
tert-butyl
cyclohexenyl
cyclopentyl
6d
6e
6f
6g
6h
6i
6j
6k
6l
9d
9e
9f
9g
9h
9i
9j
9k
9l
In conclusion, we have developed the direct synthesis of
2-substituted 5-hydroxybenzofurans from alkyne-containing
quinols using a Pt-catalyzed domino dienone-phenol rearran-
gement/intramolecular 5-endo-dig cyclization reaction se-
quence. This is the first example of the dienone-phenol
rearrangement of quinols bearing alkynes. Also noteworthy is
that this event was successfully coupled with the subsequent
5-endo-dig ring formation to allow for a ready access to a
number of 5-hydroxybenzofurans having alkyl groups as well
as aryl groups at the C2 position in good to excellent yields,
which is unprecedented in the literature. Efforts to search for
other catalytic systems to induce hydroxyl migration and to
employ quinols for the construction of other carbo- and hetero-
cycles are currently in progress, and will be reported soon.
6m
9m
aMethod A: PtCl2 (10 mol %), DME/MeOH (20:1), 40 °C. Method B:
PtCl4 (5 mol %), DME, rt. bIsolated yield. c1 mmol scale. d50 °C.
To see if either simple alkyl or aryl group rearrangement
could occur under these conditions, two quinols not having
(14) To directly obtain 5-methoxybenzofuran as the major product, use of
MeOH as the sole solvent resulted in a complex mixture.
Experimental Section
(15) For example, 2(3-fluorophenyl)-5-methoxybenzofuran (9f0) was iso-
lated as a minor product by treatment of 6f with PtCl2. The structure of 9f0
was confirmed by X-ray crystallographic analysis. CCDC 739253 contains
the supplementary crystallographic data for compound 9f0. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
General Procedure for the Synthesis of 2-Substituted 5-Hydro-
xybenzofurans: Method A:. To a stirred solution of the quinols
(17) Spectral data of synthetic sample are in good agreement with those of
€
natural corsifuran C. See: von Reuss, S. H.; Konig, W. A. Phytochemistry
2004, 65, 3113.
(16) For the preparation of 11 and 12, see: Felpin, F.-X. Tetrahedron
Lett. 2007, 48, 409.
8494 J. Org. Chem. Vol. 74, No. 21, 2009

Kim et al.
JOCNote
bearing an alkyne unit 6 (0.2 mmol) in DME/MeOH (20:1, 2
mL) was added PtCl2 (10 mL). After being stirred at 40 °C for 48
h, the mixture was concentrated in vacuo and purified by flash
column chromatography (hexanes:ethyl acetate:methylene
chloride = 10:1:2) to afford 2-substituted 5-hydroxybenzofuran
9. Method B: To a stirred solution of the quinols bearing an
alkyne unit 6 (0.2 mmol) in DME (2 mL) was added PtCl4 (5 mol
%). After being stirred at rt for 6 h, the mixture was concen-
trated in vacuo, and purified by flash column chromatography
(hexanes:ethyl acetate:methylene chloride = 10:1:2) to afford
2-substituted 5-hydroxybenzofuran 9.
NMR (75 MHz, (CD3)2CO) δ 157.2, 154.6, 150.3, 131.5, 131.0,
129.8, 129.4, 125.5, 114.2, 112.1, 106.4, 102.4; MS (EI) m/z 210
(Mþ, 100), 181 (98), 165 (29), 152 (99), 127 (40), 105 (57), 76 (46);
HRMS (EI) calcd for [C14H10O2]þ m/z 210.0681, found
210.0683.
Acknowledgment. We thank Korea Research Institute of
Chemical Technology for supporting this work.
Supporting Information Available: Spectral data and copies
of 1H and 13C NMR spectra of compounds 9, 13-15,
and synthetic corsifuran C, and CIF files of 9a0 and 9f0. This
material is available free of charge via the Internet at http://
pubs.acs.org.
5-Hydroxy-2-phenylbenzofuran (9a):. 1H NMR (300 MHz,
(CD3)2CO) δ 8.18 (br s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.49 (t,
J = 7.2 Hz, 2H), 7.40 (d, J = 7.7 Hz, 2H), 7.17 (d, J = 0.8 Hz,
1H), 7.06 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 2.5, 8.8 Hz, 1H); 13
C
J. Org. Chem. Vol. 74, No. 21, 2009 8495