Iodocyclization of ethoxyethyl ethers to alkynes: A broadly applicable synthesis of 3-iodobenzo[b]furans

Article abstract of DOI:10.1021/ol8020463

(Chemical Equation Presented) A wide variety of 3-iodobenzo[b]furans were readily prepared by iodocyclization of 2-alkynyl-1-(1-ethoxyethoxy)benzenes with the I(coll)₂PF₆-BF₃-OEt₂ combination. Aryl-, vinyiic-, a

Full text of DOI:10.1021/ol8020463

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4967-4970
Iodocyclization of Ethoxyethyl Ethers to
Alkynes: A Broadly Applicable
Synthesis of 3-Iodobenzo[b]furans
Takashi Okitsu, Daisuke Nakazawa, Rie Taniguchi, and Akimori Wada*
Department of Organic Chemistry for Life Science, Kobe Pharmaceutical UniVersity,
4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan
a-wada@kobepharma-u.ac.jp
Received September 2, 2008
ABSTRACT
A wide variety of 3-iodobenzo[b]furans were readily prepared by iodocyclization of 2-alkynyl-1-(1-ethoxyethoxy)benzenes with the
I(coll)2PF6-BF3·OEt2 combination. Aryl-, vinylic-, and alkyl-substituted alkynes undergo iodocyclization in good to excellent yields. The mechanism
of the reaction is also discussed.
The benzo[b]furans are attractive synthetic target molecules
due to the wide spectrum of their biological activities in
natural and unnatural compounds.1 Numerous efficient
methods for the synthesis of the benzo[b]furans have been
developed.2,3 Among them, iodocyclization of 2-alkynylphe-
nol derivatives is a powerful method for the construction of
3-iodobenzo[b]furans due to the potential for further func-
tionalization at the C-I bond by metal-catalyzed cross-
coupling.3
Arcadi et al. reported the synthesis of 3-iodobenzo[b]furans
by iodocyclization of 2-alkynylphenols (eq 1).3a However,
their method requires a series of protecting and deprotecting
steps for the preparation of 2-alkynylphenols, which are also
relatively unstable. Larock and Colobert et al. reported the
iodocyclization of 2-alkynylanisoles, which are stable and
more easily prepared in fewer steps than in Arcadi’s
procedure (eq 2).3b,c Although the 2-aryl-3-iodobenzo[b]-
furans were successfully synthesized by these methodologies,
the application for 2-alkyl derivatives has been limited due
(2) (a) Tsai, T.-W.; Wang, E.-C.; Huang, K.-S.; Li, S.-R.; Wang, Y.-F.;
Lin, Y.-L.; Chen, Y.-H. Heterocycles 2004, 63, 1771–1781. (b) Hercouet,
A.; Corre, M. L. Tetrahedron Lett. 1979, 2145–2148. (c) Akiyama, S.;
Akimoto, H.; Nakatsuji, S.; Nakashima, K. Bull. Chem. Soc. Jpn. 1985,
58, 2192–2196. (d) Seemuth, P. D.; Zimmer, H. J. Org. Chem. 1978, 43,
3063–3064. (e) Dai, D.-M.; Lai, K.-W. Tetrahedron Lett. 2002, 43, 9377–
9380. (f) Manojit, P.; Venkataraman, S.; Koteswar, R. Y. Tetrahedron Lett.
2003, 44, 8221–8225. (g) Hu, Y.; Nawoschik, K. J.; Liao, Y.; Ma, J.; Fathi,
R.; Yang, Z. J. Org. Chem. 2004, 69, 2235–2239. (h) Liang, Y.; Tang, S.;
Zhang, X.-D.; Mao, L.-Q.; Xie, Y.-X.; Li, J.-H. Org. Lett. 2006, 8, 3017–
3020. (i) Bates, C. G.; Saejueng, P.; Murphy, J. M.; Venkataraman, D. Org.
Lett. 2002, 4, 4727–4729. (j) Carril, M.; SanMartin, R.; Tellitu, I.;
Dom´ınguez, E. Org. Lett. 2006, 8, 1467–1470. (k) Willis, M. C.; Taylor,
D.; Gillmore, A. T. Org. Lett. 2004, 6, 4755–4757. (l) Kraus, G. A.; Zhang,
N.; Verkade, J. G.; Nagarajan, M.; Kisange, P. B. Org. Lett. 2000, 2, 2409–
2410. (m) Akai, S.; Morita, N.; Iio, K.; Nakamura, Y.; Kita, Y. Org. Lett.
2000, 2, 2279–2282. (n) Miyata, O.; Takeda, N.; Naito, T. Org. Lett. 2004,
6, 1761–1763.
(1) (a) Dean, F. M. The Total Synthesis of Natural Products; ApSimon,
J., Ed.; Wiley: New York, 1973; Vol. 1, pp 467-562. (b) Cagniant, P.;
Cagniant, D. In AdVances in Heterocyclic Chemistry; Katritzky, A. R.,
Boulton, A. J., Eds.; Academic Press: New York, 1975; Vol. 18, pp
337-482. (c) Dean, F. M.; Sargent, M. V. In ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford,
UK, 1984; Vol. 4, pp 531-596. (d) ComprehensiVe Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, UK, 1996; Vol. 2, pp 259-321.
(3) (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett
1999, 1432–1434. (b) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005,
70, 10292–10296. (c) Colobert, F.; Castanet, A.-S.; Abillard, O. Eur. J.
Org. Chem. 2005, 3334–3341.
10.1021/ol8020463 CCC: $40.75
Published on Web 10/03/2008
2008 American Chemical Society

to 1,2-addition of I2 to alkynes. In addition, carcinogenic
and volatile halomethanes (MeI or MeCl) can be formed in
the reactions by these earlier methods. Therefore, we sought
a safer, more general procedure for the efficient synthesis
of both 2-aryl- and 2-alkyl-3-iodobenzo[b]furans.
Table 1. Optimization of Iodocyclization of 1a
entry [I+] source additive (equiv)
time
2a (yield, %)
1
2
3
4
5
6
7
8
9a
I2
I2
ICl
NIS
IPy2BF4
I(coll)2PF6
I(coll)2PF6
I(coll)2PF6
I(coll)2PF6
NIS
none
NaHCO3 (2)
none
none
none
2 h
2 h
10 min
23 h
20 h
3
0
84
43
96
92
98
quant
51
40
Herein, we report an iodocyclization of ethoxyethyl ethers
to alkynes for the synthesis of 3-iodobenzo[b]furans. The
advantages of our method are as follows: (1) ethoxyethyl
ether serves not only as the protecting group but also as a
directing group for the preparation of precursors for iodocy-
clization; (2) the synthesis requires a reasonable number of
steps from starting material to 3-iodobenzo[b]furans; (3) the
title compounds are afforded not only in short reaction time
(10 min) but also in high yields without the generation of
hazardous halomethanes; and (4) 2-alkyl-3-iodobenzo[b]-
furans can also be obtained in good yields.
none
24 h
BF3·OEt2 (4)
BF3·OEt2 (2)
BF3·OEt2 (1)
BF3·OEt2 (2)
10 min
10 min
24 h
10
10 min
a 1 equiv of I(coll)2PF6 was added.
decrease of the nucleophilicity of the counteranion would
suppress the addition reaction. Therefore, N-iodosuccinimide
(NIS), bis(pyridine) iodonium tetrafluoroborate (IPy2BF4),
and bis(2,4,6-collidine)iodonium hexafluorophosphate
(I(coll)2PF6) were examined as iodinating reagents, and
IPy2BF4 and I(coll)2PF6 provided superior yields of 2a
(entries 4-6). IPy2BF4 was more expensive than I(coll)2PF6,
so the latter reagent was used for further optimization.7 We
found that BF3·OEt2 as an additive enhanced the reaction
rate to afford 2a in quantitative yield within only 10 min
(entries 7 and 8).8 A diminishment of reagent equivalents
or the combination of NIS-BF3·OEt2 in place of
I(coll)2PF6-BF3·OEt2 decreased the yields of 2a (entries 9
and 10). To the our best knowledge, this is the first report
of an iodocyclization with an ethoxyethyl ether serving as
an oxygen nucleophile toward alkynes.9
2-Alkynyl-1-(1-ethoxyethoxy)benzenes 1, the precursors
for iodocyclization, were prepared by the conversion of
2-iodophenol to the ethoxyethyl ether4 followed by Sono-
gashira coupling with terminal alkynes (Scheme 1).5 Notably,
Scheme 1. Preparation of the Precursors in Iodocyclizaton
Once the optimized conditions were established as in entry
8 (Table 1), various substrates were next examined (Table
2). Other acetal-type protecting groups, such as MOM
(methoxymethyl) and THP (tetrahydropyranyl) ethers, were
effective, but the yields were less than with the ethoxyethyl
ether derivative (entries 1 and 2). When the substituent on
the alkyne was aryl and vinylic, with sp2 carbon centers,
2-aryl- and 2-vinylic-3-iodobenzo[b]furans were obtained in
high to excellent yields (entries 3-5). The presence of
substituents on the aromatic core did not influence the
iodocyclizations (entries 6 and 7). It is noteworthy that alkyl-
the ethoxyethyl ether could be used as a directing group.6
Thus, R-lithiation of 1-(1-ethoxyethoxy)naphthalene and
iodination with I2 followed by Sonogashira coupling with
phenylacetylene afforded a naphthol derivative 1h (see the
Supporting Information).
We first examined the reaction of 1a toward the iodinating
reagents (Table 1). Each reaction was performed with 2 equiv
of the iodinating reagents in a 0.1 M CH2Cl2 solution of 1a
at room temperature. Whereas I2 was poor for the iodocy-
clization, ICl afforded 2a in good yield (entries 1-3).
However, in each case, 1,2-addition of I2 or ICl across the
alkyne occurred as a side reaction. We considered that a
(7) The price per gram is 10300 yen for IPy2BF4 and 2560 yen for
I(coll)2PF6; source Aldrich catalogue 2007-2008.
(8) IPy2BF4 can be activated by Lewis acid; see: Barluenga, J.; Campos,
P. J.; Gonza´lez, J. M.; Sua´rez, J. L. J. Org. Chem. 1991, 56, 2234–2237.
(b) Barluenga, J.; Trincado, M.; Rubio, E.; Gonza´lez, J. M. Angew. Chem.,
Int. Ed. 2003, 42, 2406–2409. (c) Barluenga, J.; Trincado, M.; Marco-Arias,
M.; Ballesteros, A.; Rubio, E.; Gonza´lez, J. M. Chem. Commun. 2005, 2008–
2010.
(4) Fukuzawa, A.; Sato, H.; Masamune, T. Tetrahedron Lett. 1987, 28,
4303–4306.
(5) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467–4470.
(9) For PtCl2-catalyzed carboalkoxylation of o-alkynylphenyl acetals,
see: Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005,
127, 15022–15023.
(6) MOM ether as a directing group: Townsend, C. A.; Bloom, L. M.
Tetrahedron Lett. 1981, 22, 3923–3924.
4968
Org. Lett., Vol. 10, No. 21, 2008

Table 2. Synthesis of 3-Iodobenzo[b]furans 2a-n by Iodocyclizationa
a EE: ethoxyethyl, conditions: I(coll)2PF6 (2 equiv), BF3·OEt2 (2 equiv), CH2Cl2, rt, 10 min. b Conditions: I(coll)2PF6 (4 equiv), BF3·OEt2 (4 equiv),
CH2Cl2, rt, 10 min.
(sp3 carbon center-)substituted alkynes 1i-l were also
applicable in these reaction conditions (entries 8-11). To
Scheme 2. Plausible Reaction Mechanism
our best knowledge, only one example of the synthesis of a
2-alkyl-3-iodobenzo[b]furan has been reported.3a Thus, our
novel reaction conditions may afford a more widely adaptable
synthetic route to 2-alkyl-3-iodobenzo[b]furans. Of the alkyl
substituents, not only primary but also tertiary alkyl groups
were allowed. Our method was also acceptable in a gram
scale procedure (entry 9, see the Supporting Information).
Even the substrate containing an oxygen function at the
terminal alkyne 1l afforded 2l in moderate yield. Further-
more, double-iodocyclization was achieved by using 4 equiv
of I(coll)2PF6 and BF3·OEt2 (entries 12 and 13).
Based on the outcomes of these reactions, we developed
a plausible reaction mechanism for the iodocyclization
(Scheme 2). From the reaction of I(coll)2PF6 and BF3·OEt2,
active iodonium species A is generated.8 The anti attack of
the electrophile and the oxygen of the ethoxyethyl ether on
the alkyne gives intermediate B, which undergoes the loss
Org. Lett., Vol. 10, No. 21, 2008
4969

of the ethoxyethyl group to afford the 3-iodobenzo[b]furans.
The oxonium ions C and D are trapped by 2,4,6-collidine to
afford collidinium salts E and F.10 Intermediates A-F were
confirmed by SIMS study of the reaction mixture of 1a (see
the Supporting Information). More- over, instead of generat-
ing hazardous halomethanes,3b,c our method produced highly
polar compounds E and F together, which are stable and
easily removable by column chromatography on silica gel.
Thus, our synthetic method for 3-iodobenzo[b]furans was
totally safe and applicable to various substrates.
Scheme 3. Cyanation of 2a
The 3-iodobenzo[b]furans can be further functionalized
by palladium-catalyzed coupling reactions at the C-I bond.
Arcadi et al. have reported the Sonogashira coupling reaction,
Heck reaction, and methoxycarbonylation of 2a.3a We also
elaborated a cyanation of 2a by Pd(OAc)2 and K4[Fe(CN)6],
a nontoxic cyanide source, to yield 3-cyanobenzo[b]furan 3
in 86% yield (Scheme 3).11 The nitrile group could then
utilized for further transformations.12
In summary, we have constructed 3-iodobenzo[b]furans
through the iodocyclization of ethoxyethyl ether to alkynes.
The substituents on alkyne, sp-, sp2-, and sp3-carbon center
were available. These iodo derivatives have the possibility
for further functionalization by metal-catalyzed cross-
coupling. This research provides a new synthetic method for
natural and unnatural compounds containing the benzofuran
skeleton. Further investigations into the scope and limitations
of the iodocyclization are ongoing.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Encouragement of Young Scientists from
the Ministry of Education, Culture, Sports, Science and
Technology and a grant from the Second Project for
Advanced Research and Technology by Kobe Pharmaceutical
University.
Supporting Information Available: Experimental details
and characterization data of compounds 1a-n, 2a-n, and
3. Copies of 1H and 13C NMR spectra of all new compounds
and SIMS spectra of the reaction mixture. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) (a) Fujioka, H.; Okitsu, T.; Sawama, Y.; Murata, N.; Li, R.; Kita,
Y. J. Am. Chem. Soc. 2006, 128, 5930–5938. (b) Fujioka, H.; Okitsu, T.;
Ohnaka, T.; Sawama, Y.; Kubo, O.; Okamoto, K.; Kita, Y. AdV. Synth.
Catal. 2007, 349, 636–646.
(11) Weissman, S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005, 70,
1508–1510.
(12) Rappoport, Z., Ed. Chemistry of the Cyano Group; John Wiley &
Sons: London, 1970.
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Org. Lett., Vol. 10, No. 21, 2008