Cycloaddition of arynes with lodonium ylides: A mild and general route for the synthesis of benzofuran derivatives

Article abstract of DOI:10.1021/ol800051k

A mild and general cycloaddition of arynes with iodonium ylides protocol has been developed for the synthesis of benzofurans. In the presence of CsF, ortho-silyl aryltriflates were reacted with iodonium ylides smoothly at room temperature in moderate to good yields.

Full text of DOI:10.1021/ol800051k

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1525-1528
Cycloaddition of Arynes with Iodonium
Ylides: a Mild and General Route for
the Synthesis of Benzofuran Derivatives
Xiao-Cheng Huang,† Yi-Lin Liu,† Yun Liang,*,† Shao-Feng Pi,† Feng Wang,† and
Jin-Heng Li*,†,‡
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research
(Ministry of Education), Hunan Normal UniVersity, Changsha 410081, China, and
State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan UniVersity,
Changsha 410082, China
liangyun1972@126.com; jhli@hunnu.edu.cn
Received January 9, 2008
ABSTRACT
A mild and general cycloaddition of arynes with iodonium ylides protocol has been developed for the synthesis of benzofurans. In the presence
of CsF, ortho-silyl aryltriflates were reacted with iodonium ylides smoothly at room temperature in moderate to good yields.
Benzofuran moieties are widely presented in many naturally
occurring and biologically active compounds, which display
various pharmacological activities.1 For this reason, consider-
able efforts have been devoted to develop efficient methods
for their preparation.2-4 The majority of methods for
selectively constructing benzofurans include the transition
metal-catalyzed transformations.2 Although these transforma-
tions are efficient and general, two significant drawbacks
are usually presentedsthe requirement of harsh conditions
and the cost of the catalytic system.2
Caubere and co-workers have reported a new rout to the
preparation of benzofurans by the reactions of dihalo-
genobenzenes with cyclic ketones involving a benzyne
process, but harsh conditions including stronger bases
(NaNH2 combined with t-BuONa) were still required together
with low yields.3 Recently, much attention has been attracted
to apply ortho-silyl aryltriflates as the benzyne precursors
† Hunan Normal University.
(2) For selected reviews and papers on the synthesis of benzofurans by
transition metal-catalyzed transformations, see: (a) Alonso, F.; Beletskaya,
I. P.; Yus, M. Chem. ReV. 2004, 104, 3079. (b) Ziegert, R. E.; Torang, J.;
Knepper, K.; Brase, S. J. Comb. Chem. 2005, 7, 147. (c) Zeni, G.; Larock,
R. C. Chem. ReV. 2006, 106, 4644. (d) Boswell, D. E.; Landis, P. S.; Givens,
E. N.; Venuto, P. B. Ind. Eng. Chem. Prod. Res. DeV. 1968, 7, 215. (e)
Kozikowski, A. P.; Ma, D.; Du, L.; Lewin, N. E.; Blumberg, P. M. J. Am.
Chem. Soc. 1995, 117, 6666. (f) Hashmi, A. S. K.; Frost, T. M.; Bats, J.
W. Org. Lett. 2001, 3, 3769. (g) Carril, M.; SanMartin, R.; Tellitu, I.;
Dominguez, E. Org. Lett. 2006, 8, 1467. (h) Zhao, B.; Lu, X. Org. Lett.
2006, 8, 5987. (i) Gabriele, B.; Mancuso, R.; Salerno, G.; Costa, M. J.
Org. Chem. 2007, 72, 9278. (j) Oppenheimer, J.; Johnson, W. L.; Tracey,
M. R.; Hsung, R. P.; Yao, P.-Y.; Liu, R.; Zhao, K. Org. Lett. 2007, 9,
2361. (k) Nagamochi, M.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2007, 9,
2955. (l) De Luca, L.; Giacomelli, G.; Nieddu, G. J. Org. Chem. 2007, 72,
3955. (m) Liao, Y.; Smith, J.; Fathi, R.; Yang, Z. Org. Lett. 2005, 7, 2707.
(n) Bellur, E.; Langer, P. J. Org. Chem. 2005, 70, 7686. (o) Lu, B.; Wang,
B.; Zhang, Y.; Ma, D. J. Org. Chem. 2007, 72, 5337. (p) Nakamura, I.;
Mizushima, Y.; Yamagishi, U.; Yamamoto, Y. Tetrahedron 2007, 63, 8670.
‡ Hunan University.
(1) (a) Singh, S. N.; Fletcher, R. D.; Fisher, S. G.; Singh, B. N.; Lewis,
H. D.; Deedwania, P. C.; Massie, B. M.; Colling, C.; Layyeri, D. N. Engl.
J. Med. 1995, 333, 77. (b) Ka´lai, T.; Va´rbiro´, G.; Bogna´r, Z.; Pa´lfi, A.;
Hanto´, K.; Bogna´r, B.; Osz, E.; Su¨megi, B.; Hideg, K. Bioorg. Med. Chem.
2005, 13, 2629. (c) Proksch, P.; Proksch, M.; Towers, G. H. N.; Rodriguez,
E. J. Nat. Prod. 1983, 46, 331. (d) Chakrabarti, J. K.; Eggleton, R. J.;
Gallagher, P. T.; Harvey, J.; Hicks, T. A.; Kitchen, E. A.; Smith, C. W. J.
Med. Chem. 1987, 30, 1663. (e) Parodi, F. J.; Fischer, N. H.; Flores, H. E.
J. Nat. Prod. 1988, 51, 594. (f) Durani, N.; Jain, R.; Saeed, A.; Dikshit, D.
K.; Durani, S.; Kapil, R. S. J. Med. Chem. 1989, 32, 1700. (g) Tomaszewski,
Z.; Johnson, M. P.; Huang, X.; Nichols, D. E. J. Med. Chem. 1992, 35,
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10.1021/ol800051k CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/14/2008

in organic synthesis because ortho-silyl aryltriflates could
be readily converted into benzynes in situ under mild reaction
conditions.5-7 This prompted us to study the feasibility of
synthesizing benzofuran skeletons using ortho-silyl aryltri-
flates under mild conditions.2 After a series of trials, we were
delighted to find that benzofurans could be prepared smoothly
by treatment of ortho-silyl aryltriflates with iodonium ylides
under mild conditions.8 Herein, we wish to report our primary
results of the cycloadditions between arynes and iodonium
ylides to synthesize benzofurans (eq 1).
oxobutanoate (2a) was chosen as a model to screen the
optimal reaction conditions (Table 1). To our delight,
Table 1. Screening Optimal Conditionsa
entry
base
CsF
t (°C)
time (h)
isolated yield (%)
1
rt
rt
rt
rt
0
2.5
36
24
2.5
2.5
3.5
4.5
90
<5
0
65
trace
85
2b
3c
4d
5
CsF
TBAF
KF·2H2O
CsF
CsF
CsF
Initially, the reaction of 2-(trimethylsilyl)phenyl-trifluo-
romethanesulfonate (1a) with methyl 2-phenyliodonio-3-
6
7e
50
rt
88
(3) For papers on the synthesis of benzofurans from the reactions of
benzynes (from dihalogenobenzenes) with cyclic ketone enolates in the
presence of NaNH2 and t-BuONa, see: (a) Caubere, P.; Lalloz, L. J. Org.
Chem. 1975, 40, 2853. (b) Caubere, P.; Lalloz, L. J. Org. Chem. 1975, 40,
2859. (c) Bachelet, J.-P.; Caubere, P. J. Org. Chem. 1982, 47, 234. (d)
Inukay, Y.; Sonoda, T.; Kabayashi, H. Bull. Chem. Soc. Jpn. 1979, 52,
2657.
a Reaction conditions: 1a (0.12 mmol), 2a (0.1 mmol), and base (3 equiv)
in MeCN (3 mL) under argon atmosphere. b THF (3 mL) instead of MeCN.
c Messy results were observed, and no target product was determined by
GC-MS analysis. d 18-Crown-6 (3 equiv) was added. e 1a (1.2 mmol) and
2a (1 mmol).
(4) For selected recent papers on the synthesis of benzofurans by other
methods, see: (a) Miyata, O.; Takeda, N.; Naito, T. Org. Lett. 2004, 6,
1761. (b) Green, M. P.; Pichlmair, S.; Marques, M. M. B.; Martin, H. J.;
Diwald, O.; Berger, T.; Mulzer, J. Org. Lett. 2004, 6, 3131. (c) Fujita, M.;
Oshima, M.; Okuno, S.; Sugimura, T.; Okuyama, T. Org. Lett. 2006, 8,
4113. (d) Cheng, X.; Liu, X. J. Comb. Chem. 2007, 9, 906. (e) Fakhari, A.
R.; Nematollahi, D.; Shamsipur, M.; Makarem, S.; Hosseini, Davarani, S.
S.; Alizadeh, A.; Khavasi, H. R. Tetrahedron 2007, 63, 3894. (f) Wang,
S.; Gates, B. D.; Swenton, J. S. J. Org. Chem. 1991, 56, 1979. (g) Berard,
D.; Jean, A.; Canesi, S. Tetrahedron Lett. 2007, 48, 8238.
(5) (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211. (b) Himeshima, Y.; Kobayashi, H.; Sonoda, T. J. Am. Chem. Soc.
1985, 107, 5286. (c) Kessar, S. V. ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 4, p 483.
(6) For papers on the reactions of ortho-silyl aryltriflates with the active
methylene compounds, see: (a) Tambar, U. K.; Stoltz, B. M. J. Am. Chem.
Soc. 2005, 127, 5340. (b) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai,
A. Chem. Commun. 2005, 3292. (c) Yoshida, H.; Watanabe, M.; Ohshita,
J.; Kunai, A. Tetrahedron Lett. 2005, 46, 6729. (d) Tambar, U. K.; Ebner,
D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752. (e) Huang, X.;
Xue, J. J. Org. Chem. 2007, 72, 3965. (f) Liu, Z.; Shi, F.; Martinez, P. D.
G.; Raminelli, C.; Larock, R. C. J. Org. Chem. 2008, 73, 219. (g) Ramtohul,
Y. K.; Chartrand, A. Org. Lett. 2007, 9, 1029.
(7) For the other very recent papers on the application of ortho-silyl
aryltriflates in organic sysnthesis, see: (a) Xie, C.; Zhang, Y. Org. Lett.
2007, 9, 781. (b) Bhuvaneswari, S.; Jeganmohan, M.; Cheng, C.-H. Org.
Lett. 2006, 8, 5581. (c) Shen, Y.-M.; Grampp, G.; Leesakul, N.; Hu, H.-
W.; Xu, J.-H. Eur. J. Org. Chem. 2007, 3718. (d) Yoshida, H.; Morishita,
T.; Fukushima, H.; Ohshita, J. i.; Kunai, A. Org. Lett. 2007, 9, 3367. (e)
Beltran-Rodil, S.; Pena, D.; Guitian, E. Synlett 2007, 1308. (f) Xie, C.;
Zhang, Y.; Huang, Z.; Xu, P. J. Org. Chem. 2007, 72, 5431. (g) Yoshida,
H.; Mimura, Y.; Ohshita, J.; Kunai, A. Chem. Commun. 2007, 2405. (h)
Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 3323. (i) Yoshida,
H.; Fukushima, H.; Morishita, T.; Ohshita, J.; Kunai, A. Tetrahedron 2007,
63, 4793. (j) Liu, Z.; Larock, R. C. Angew. Chem., Int. Ed. 2007, 46, 2535.
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treatment of ortho-silyl aryltriflate 1a with iodonium ylide
2a and CsF in MeCN at room temperature afforded the
corresponding benzofuran (3) in a 90% yield (entry 1).
However, a trace amount of the target product 3 was
observed using THF as the medium (entry 2). Two other
fluoride-containing bases, TBAF and KF, were subsequently
tested, and the results showed that they both were less
effective than CsF (entries 3 and 4). It was found that no
target product 3 was observed using TBAF (entry 3), and
the yield of 3 was reduced to 65% in the presence of KF
even with the aid of 18-crown-6 (entry 4). Finally, the
reaction temperatures were examined, and it turned out that
room temperature gave the best yield (entries 1, 5, and 6). It
is noteworthy that high yield is still isolated after 4.5 h when
1.2 mmol of 1a was reacted with 1 mmol of 2a and 3 mmol
of CsF in MeCN at room temperature (entry 7).
With the standard reaction conditions in hand, a variety
of arynes and iodonium ylides were surveyed to investigate
scope of the cycloaddition reaction (Table 2).9,10 The results
demonstrated that the yield and selectivity were affected by
the structures of the two reaction partners to some extent.
(9) The structure of the isomers of the products 4, 10, and 17 was
determined according to H-H COSY spectroscopy of 4, and the authorita-
tive 5-H and/or 8-H shift data of benzofurans in ref 2o. The structure of
the isomers of 20 was assigned according to the authoritative 1H NMR
data, see: (a) Sidduri, A.; Rozema, M. J.; Knochel, P. J. Org. Chem. 1993,
58, 2694. (b) Chatterjea, J. N. J. Indian Chem. Soc. 1957, 34, 347.
(10) Typical experimental procedure for the cycloaddition reactions of
ortho-silyl aryltriflates (1) and iodonium ylides (2). A mixture of ortho-
silyl aryltriflate 1 (0.12 mmol), iodonium ylide 2 (0.1 mmol), and CsF (3
equiv) in MeCN (3 mL) was stirred at room temperature for the indicated
time until complete consumption of starting material as monitored by TLC
and GC analysis. Then, the mixture was washed with brine and extracted
with diethyl ether. The combined organic layers were dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The residue was then
purified by flash column chromatography to afford the pure product (hexane/
ethyl acetate).
(8) For a papers on the generation of intermediate A and E from iodonium
ylides, see: Moriarty, R. M.; Prakash, O.; Vaild, R. K.; Zhao, L. J. Am.
Chem. Soc. 1989, 111, 6443.
1526
Org. Lett., Vol. 10, No. 8, 2008

Table 2. Cycloadditions of 2-Trimethylsilyltriflates (1) with Iodonium Ylides (2) in the Presence of CsFa
a Reaction conditions: 1 (0.12 mmol), 2 (0.1 mmol), and CsF (3 equiv) at room temperature in MeCN (3 mL) under argon atmosphere. b Isolated yield.
The ratio was given in the parenthesis.
Org. Lett., Vol. 10, No. 8, 2008
1527

As listed in Table 2, the reactions between the other three
ortho-silyl aryltriflates, 1b-d, and ylide 2a, respectively,
were also conducted smoothly under the standard conditions
(entries 1-3). 4-Methyl-2-(trimethylsilyl)phenyltrifluo-
romethanesulfonate (1b) treated with ylide 2a, for example,
afforded two regioselective products, methyl 2,6-dimethyl-
benzofuran-3-carboxylate and methyl 2,5-dimethylbenzofu-
ran-3-carboxylate, in a 1:1.3 ratio and an 81% total yield
(entry 1).9 Substrate 1d, a bulky ortho-silyl aryltriflate, also
successfully underwent the cycloaddition reaction with ylide
2a providing high yield (entry 3). Subsequently, a number
of 2-phenyliodonio-3-oxobutanoates, 2b-i, were evaluated,
and they all were found to be suitable substrates for the
reaction with ortho-silyl aryltriflates under the standard
conditions (entries 4-12). Substrate 2c bearing a bulky
isopropoxy group, for instance, was treated with ortho-silyl
aryltriflate 1a and CsF smoothly at room temperature in an
85% yield (entry 5). Substrate 2g or 2h containing a halo
group was also tolerated well under the same conditions
(entries 10 and 11). We were happy to observe that
3-phenyliodonio-2,4-diones, 2j-k, could also react with
ortho-silyl aryltriflates efficiently in moderate yields (entries
13-18). 3-phenyliodonio-pentane-2,4-dione (2h), for ex-
ample, was treated with ylides 1a-d, respectively, to afford
the corresponding products 16-19 in 43-70% yields (entries
13-16).9 Although the yield was low in the reaction of
substrate 1a with ylide 2j, an interesting tricycles product
21 was constructed (entry 18). Interestingly, the reaction of
1a with 2-phenyliodonio-3-oxo-3-phenylpropanenitrile (2k)
was conducted smoothly in a 29% yield under the standard
conditions (entry 19).
Scheme 1. Working Mechanism
ties of 2c and 2d, such as the steric effect and electron effect,
are affected the regioselectivity to some extent. Study of the
accurate mechanism is in progress.
In summary, we have developed a mild and general
cycloaddition of benzynes with iodonium ylides protocol for
the synthesis of benzofurans. In the presence of CsF, ortho-
silyl aryltriflates successfully underwent the cycloaddition
reaction with iodonium ylides at room temperature to afford
the corresponding benzofurans in moderate to good yields.
Work to probe the detailed mechanism and apply the reaction
in organic synthesis is currently underway.
A working mechanism as outlined in Scheme 1 was
proposed for the present reaction on the basis of the
previously reported mechanism.4-8 ortho-Silyl aryltriflate 1
can be readily conversed into benzyne B in situ with the aid
of CsF.4-7 Subsequently, nucleophilic addition of intermedi-
ate A with benzyne B to yield intermediate C, followed by
intramolecular cycloaddition of intermediate C to afford
intermediate D7 or intermediate E.8 Finally, intermediate D
or intermediate E undergoes reductive elimination to generate
the desired benzofurans and PhI.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (No. 20572020), New Century
Excellent Talents in University (No. NCET-06-0711), Spe-
cialized Research Fund for the Doctoral Program of Higher
Education (No. 20060542007), Fok Ying Tung Education
Foundation (No. 101012), and State Key Laboratory of
Chemo/Biosensing and Chemometrics Foundation (No.
2006016) for financial support.
A pathway was also provided to elucidate the reason of
the observed high regioselectivities of the products using
ortho-silyl aryltriflates 2c and 2d. Generally, an anion F is
generated from the cleavage of the C-Si bond, and a cation
G from the cleavage of the C-O bond, which results in the
high regioselectivity in the reactions of ylides with 2c or
2d. Compared the selectivity using substrate 2b, the proper-
Supporting Information Available: Analytical data and
spectra (1H and 13C NMR) for all the products 3-22; typical
procedure for the cycloaddition of ortho-silyl aryltriflates
with iodonium ylides. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL800051K
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Org. Lett., Vol. 10, No. 8, 2008