Electrophilic cyclization of 2-(1-alkynyl)-2-alken-1-ones using the I 2/K3PO4 system: An efficient synthesis of highly substituted iodofurans

Article abstract of DOI:10.1021/ol051659i

(Chemical Equation Presented) The electrophilic cyclization of 2-(1-alkynyl)-2-alken-1-ones in the presence of various alcohols or carbon-based nucleophiles offers an efficient and straightforward route to highly substituted iodofurans under extremely mil

Full text of DOI:10.1021/ol051659i

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4609-4611
Electrophilic Cyclization of
2-(1-Alkynyl)-2-alken-1-ones Using the
I2/K3PO4 System: An Efficient Synthesis
of Highly Substituted Iodofurans
Yuanhong Liu* and Shaolin Zhou
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, People’s Republic of China
yhliu@mail.sioc.ac.cn
Received July 14, 2005
ABSTRACT
The electrophilic cyclization of 2-(1-alkynyl)-2-alken-1-ones in the presence of various alcohols or carbon-based nucleophiles offers an efficient
and straightforward route to highly substituted iodofurans under extremely mild reaction conditions. The iodo derivatives are potential synthetic
intermediates for amplification of molecular complexity.
The furan rings widely occur as key structural subunits in
numerous natural products, which can find a variety of
applications as pharmaceuticals, flavor and fragrance com-
pounds.1 Furthermore, highly substituted furans are of
significant interest since they are useful and versatile
synthetic intermediates for access to heterocyclic and acyclic
compounds.2 As a consequence, much attention has been paid
to the synthesis of furan derivatives either by traditional
methods3 or by transition-metal-catalyzed reactions, including
cyclization of allenyl ketones4 and 3-alkyn-1-ones,5 cyclo-
isomerizations of (Z)-2-en-4-yn-1-ols,6 Pd-catalyzed cycliza-
tion of (Z)-2-iodoalk-2-enyl ketones,7 etc. Recently, Larock
reported an interesting AuCl3-catalyzed cyclization of 2-(1-
alkynyl)-2-alken-1-ones leading to substituted furans8 (eq 1).
(3) For recent reviews, see: (a) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.;
Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998,
54, 1955-2020. (b) Keay, B. A. Chem. Soc. ReV. 1999, 28, 209-215.
(4) (a) Ma, S.; Zhang, J.; Lu, L. Chem.sEur. J. 2003, 9, 2447-2456.
(b) Ma, S.; Zhang, J. Chem. Commun. 2000, 117-118. (c) Hashmi, A. S.
K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem., Int. Ed. 2000,
39, 2285-2288. (d) Marshall, J. A.; Bartley, G. S. J. Org. Chem. 1994, 59,
7169-7171. (e) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1991, 56, 960-
969. (f) Hashmi, A. S. K.; Ruppert, T. L.; Kno¨fel, T.; Bats, J. W. J. Org.
Chem. 1997, 62, 7295. For a recent review, see: (g) Brown, R. C. D. Angew.
Chem., Int. Ed. 2005, 44, 850.
(5) (a) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. J. Org. Chem.
1991, 56, 5816-5819. (b) Arcadi, A.; Cacchi, S.; Larock, R. C.; Marinelli,
F. Tetrahedron Lett. 1993, 34, 2813-2816.
(6) (a) Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64,
7687-7692. (b) Seiller, B.; Bruneau, C.; Dixneuf, P. H. J. Chem. Soc.,
Chem. Commun. 1994, 493.
(1) (a) Katritsky, A. R. AdVances in Heterocyclic Chemistry; Academic
Press: New York, 1982. (b) Sargent, M. V.; Dean, F. M. In ComprehensiVe
Heterocyclic Chemistry; Katrizky, A. R., Rees, C. W., Eds.; Pergamon
Press: New York, 1984; Vol. 4, pp 599-656. (c) Nakanishi, K. Natural
Products Chemistry; Kodansha: Tokyo, 1974. (d) Bird, C. W.; Cheeseman,
G. W. H. ComprehensiVe Organic Chemistry; Pergamon: New York, 1984.
(e) Vernin, G. The Chemistry of Heterocyclic FlaVouring and Aroma
Compounds; Ellis Harwood: Chichester, U.K., 1982.
(2) (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795-819. (b) Maier, M.
In Organic Synthesis Highlights II; Waldmann, H., Ed.; VCH: Weinheim,
Germany, 1995; pp 231-242. (c) Benassi, R. In ComprehensiVe Hetero-
cyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996; Vol. 2, pp 259-295.
(7) Lou, F.-T.; Bajji, A. C.; Jeevanandam. A. J. Org. Chem. 1999, 64,
1738-1740.
10.1021/ol051659i CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/14/2005

In a more recent study, the analogous cyclization reaction
has been achieved using Cu(I) catalyst in DMF.9 The metal
salt employed was suggested to facilitate the reaction by a
dual function as both a Lewis acid and coordination reagents
with alkynes. However, in these reactions, an air-sensitive
catalyst or high-temperature reaction were required.9 In our
ongoing efforts to develop new methodologies for the
synthesis of heterocycles, we have succeeded in the con-
struction of fully substituted 5-ylidene-2,5-dihydrofurans with
high regio- and stereoselectivity through electrophilic cy-
clization of (Z)-enynols.10 Halofurans are important deriva-
tives that provide further structural elaboration by a variety
of C-C, C-N, or C-S bond-forming reactions.11
(3h, 88%), afforded iodinated furan 2a in reasonable yields
at room temperature. Interestingly, when K3PO4 was em-
ployed as a base, the desired product was isolated in 94%
yield within 30 min.
The use of organic base of Et3N resulted in the formation
of 2a in low (18%) yield. Thus, we chose the following
reaction conditions for furan formation: 1.5 equiv of
methanol, 1.1 equiv of I2, and 1.1 equiv of K3PO4 in CH2-
Cl2 stirred at room temperature for an appropriate time. The
results are summarized in Table 1. In most cases, the ring-
closure products of 2a-2m were obtained in good to high
yields within 30 min. We first investigated the scope of
nucleophiles. It was found that, in addition to methanol, a
variety of alcohols could be used as effective nucleophile
for this reaction. Treatment of 2a with phenol resulted in
the formation of 2b with a phenoxy group in 80% yield.
The reaction of 1a with propargylic alcohol or allylic alcohol
afforded 2c and 2d in 99 and 88% yield, respectively. Bulky
alcohols, such as L-borneol reacted, with 1a smoothly to give
2e in 91% yield. Not only alcohols but also carbon
nucleophiles of silyl enol ether (Table 1, entry 8) or an
electron-rich aromatic compound, like N,N-dimethylaniline
(Table 1, entry 9), can be used, furnishing iodocyclization
products 2h and 2i with a newly formed carbon-carbon bond
in 47 and 60% yield, respectively. The present I2/K3PO4-
based methodology worked well with substrates bearing an
aromatic ring as well as a vinylic group at the end of alkyne
moiety (Table 1, entry 7) to produce the cyclization products.
In contrast to the results of AuCl3-catalyzed reaction,8 alkyne
of 1d bearing a TMS group reacted smoothly with I2 to afford
2,3-diiodo-substituted furan 2j in 60% yield in which
desilylation-iodination easily occurred under the standard
reaction conditions. The appearance of a methyl substituent
on the alkene moiety in 1e did not influence the efficiency
of this reaction (Table 1, entry 11), in which the correspond-
ing product 2k was formed in 64% yield. When 2-alkynyl-
cyclopentenone 1f was employed, the cyclopenta[b]furan
In this paper, we report the cyclization of 2-(1-alkynyl)-
2-alken-1-ones12 by a more convenient and efficient approach
involving electrophilic cyclization using a wide range of
nucleophiles for the synthesis of 3-iodofuran derivatives. This
procedure generally produces good to excellent yields of
iodofurans in a short reaction time.
Electrophile-promoted cycloaddition of unsaturated com-
pounds has proven to be an elegant synthetic route to the
wide variety of halogenated heterocyclic compounds.13
However, most of the recent reports focused on arylalkynes
bearing ortho-related heteroatomic nucleophiles,14 whereas
only limited reports have been presented in the literature by
employing other type of alkynes.10,12,15 Here, we found that
alkyne 1 readily undergoes electrophilic cyclization in the
presence of a wide range of nucleophiles under mild reaction
conditions (eq 2). We began our investigation with 1a bear-
ing a phenyl group at the end of an alkyne moiety. The
reaction of 1a in CH2Cl2 with methanol, iodine, and
carbonate bases, such as NaHCO3 (15 h, 51%) or Na2CO3
(8) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126,
11164-11165.
(9) Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2005, 70, 4531-
4534.
(10) Liu, Y. H.; Song, F. J.; Cong, L. Q. J. Org. Chem. 2005, 70, 6999-
7002.
(11) (a) Chinchilla, R.; Najera, C.; Yus, M. Chem. ReV. 2004, 104, 2667-
2722. (b) Tanabe, Y.; Wakimura, K.; Nishii, Y.; Muroya, Y. Synthesis 1996,
388-392. (c) For C-C bond formation, see: (c) Lin, S.-Y.; Chen, C.-L.;
Lee, Y.-J. J. Org. Chem. 2003, 68, 2968-2971. (d) Bach, T.; Kru¨ger, L.
Eur. J. Org. Chem. 1999, 2045-2057. (e) Alvarez-lbarra, C.; Quiroga, M.
L.; Toledano, E. Tetrahedron 1996, 52, 4065-4078. For C-N bond
formation, see: (f) Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org.
Chem. 2003, 68, 2861-2873. (g) Padwa, A.; Crawford, K. R.; Rashatasa-
khon, P.; Rose, M. J. Org. Chem. 2003, 68, 2609-2617. (h) Crawford, K.
R.; Padwa, A. Tetrahedron Lett. 2002, 43, 7365-7368. For C-S bond
formation, see: (i) Arroyo, Y.; Rodriguez, J. F.; Sanz-Tejedor, M. A.;
Santos, M. Tetrahedron Lett. 2002, 43, 9129-9132.
(12) A 5-endo-dig electrophilic cyclization of 5-alkynyl-2′-deoxyuridines
with NBS or NIS has been reported: Rao, M. S.; Esho, N.; Sergeant, C.;
Dembinski, R. J. Org. Chem. 2003, 68, 6788-6790.
(13) (a) Harding, K. E.; Tinger, T. H. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
4, p 463. (b) Mulzer, J. In Organic Syntheis Highlights; VCH: Weinheim,
Germany, 1991; p 157. (c) Rousseau, G.; Robin, S. Tetrahedron 1998, 54,
13681-13736. (d) Lotagawa, O.; Inoue, T.; Taguchi, T. ReV. Heteroatom
Chem. 1996, 15, 243.
(14) (a) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002,
67, 3437-3444. (b) Zhang, X.; Marino, A. C.; Yao, T.; Larock, R. C. Org.
Lett. 2005, 7, 763-766. (c) Barluenga, J.; Vazquez-Villa, H.; Ballesteros,
A.; Gonzalez, J. M. J. Am. Chem. Soc. 2003, 125, 9028-9029. (d) Yue,
D.; Della, C. N.; Larock, R. C. Org. Lett. 2004, 6, 1581-1584. (e) Arcadi,
A.; Cacchi, S.; Giuseppe, S. D.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002,
4, 2409-2412 and references therein. (f) Yue, D.; Larock, R. C. Org. Lett.
2004, 6, 1037-1040. (g) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez,
J. M. Angew. Chem., Int. Ed. 2003, 42, 2406-2409. (h) Yao, T.; Larock,
R. C. J. Org. Chem. 2005, 70, 1432-1437. (i) Knight, D. W.; Redfern, A.
L.; Gilmore, J. J. J. Chem. Soc., Perkin Trans. 1 2002, 622-628. (j)
Nishizawa, M.; Takao, H.; Yadav, V. K.; Imagawa, H.; Sugihara, T. Org.
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Org. Lett., Vol. 7, No. 21, 2005

Table 1. Iodocyclization of 2-(1-Alkynyl)-2-alken-1-ones
On the basis of the results obtained above, a plausible
reaction mechanism is shown in eq 4,16 which involves (i)
cyclic iodonium ion 4 formation through coordination of the
triple bond with an iodine cation; (ii) the anti attack of the
oxygen onto the iodonium ion led to the formation of
intermediate 5; (iii) 1,4-addition of a nucleophile to the C-C
double bond to afford furan derivative 2.
In summary, we have demonstrated that electrophilic
cyclization of 2-(1-alkynyl)-2-alken-1-ones17 with a various
nucleophiles using the I2/K3PO4 system yields highly sub-
stituted halofurans in good to excellent yields under ex-
tremely mild conditions. The iodo derivatives are potential
synthetic intermediates for amplification of molecular com-
plexity. Further investigation into the scope and limitations
of this electrophilic cyclization is underway.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (Grant No.20402019), Chinese
Academy of Science, and the Science and Technology
Commission of Shanghai Municipality for financial support.
Supporting Information Available: Experimental details
and characterization data of compounds 2a-2m. Copies of
1H and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Unless noted, all of the reaction was carried out using I2 (1.1 equiv)
and K3PO4 (1.1 equiv) at room temperature for 30 min. b Two isomers were
obtained in the ratio of 1:1. c The reaction was carried out for 3 h using I2
(3 equiv) and K3PO4 (3 equiv).
OL051659I
derivative 2l was obtained in 59% yield. Acyclic 2-alken-
1-one 1g also underwent a smooth annulation reaction with
MeOH to produce furan 2m in 50% yield. The utility of
3-iodofurans produced by this chemistry as useful synthetic
intermediate for further elaboration was briefly investigated
by Pd-catalyzed Sonogashira reaction of 2a, which afforded
alkynylated product 3 in 41% yield.
(16) (a) Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli,
F. Org. Lett. 2002, 4, 2409-2412. (b) Ren, X.-F.; Turos, E. Tetrahedron
Lett. 1993, 34, 1575-1578.
(17) During our manuscript reviewing, electrophile-induced coupling of
2-(1-alkynyl)-2-alken-1-ones and nucleophiles using excess amount of I2
(3 equiv), NaHCO3 (3 equiv), and nucleophile (8 equiv) was reported: Yao,
T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005, web release date: Aug
20, 2005.
Org. Lett., Vol. 7, No. 21, 2005
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