An efficient synthesis of highly substituted furans via the electrophilic cyclization of 1-(1-alkynyl)-cyclopropyl ketones

Article abstract of DOI:10.1016/j.tetlet.2008.02.081

The electrophilic cyclization of 1-(1-alkynyl)-cyclopropyl ketones offers an efficient and straightforward route to highly substituted furans under extremely mild reaction conditions. Iodine, NIS, and PhSeBr have proven successful as electrophiles in this

Full text of DOI:10.1016/j.tetlet.2008.02.081

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Tetrahedron Letters 49 (2008) 2359–2362
An efficient synthesis of highly substituted furans via the
electrophilic cyclization of 1-(1-alkynyl)-cyclopropyl ketones
Xian Huang a,b,*, Weijun Fu a, Maozhong Miao a
a Department of Chemistry, Zhejiang University (Xixi Campus), Hangzhou 310028, PR China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, PR China
Received 27 November 2007; revised 1 February 2008; accepted 15 February 2008
Available online 19 February 2008
Abstract
The electrophilic cyclization of 1-(1-alkynyl)-cyclopropyl ketones offers an efficient and straightforward route to highly substituted
furans under extremely mild reaction conditions. Iodine, NIS, and PhSeBr have proven successful as electrophiles in this process.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Electrophilic cyclization; Furans; Cyclopropanes; Iodine
Furans represent an important class of heterocyclic
compounds as they are pivotal skeletons in many biol-
ogically active natural products as well as numerous
pharmacologically interesting compounds.1 A variety of
compounds with furan units have been used as flavor, fra-
grance substances, insecticides, and antileukemic agents.2
Moreover, furans also found wide utility as synthetic inter-
mediates or synthons for numerous functional groups such
as carboxylic acids, b-keto-esters, and aromatics.3 As a
result, development of new and efficient methodologies
for the synthesis of polysubstituted furans from simple,
readily available starting materials remains an important
research theme in organic chemistry despite many strate-
gies already existed.4,5
Cyclopropanes are key intermediates in many synthetic
strategies because of their easy availability and high reac-
tivity.6 One of the useful reactivities of cyclopropanes is
ring opening by nucleophiles when the cyclopropane is
activated by one or more electron-withdrawing groups to
serve as homo-Michael acceptors.7 Recently, Schmalz
reported an interesting Au(I)-catalyzed cyclization of 1-
(1-alkynyl)-cyclopropyl ketones with nucleophiles, leading
to substituted furans.8 The employed Au(I) catalyst is sug-
gested to facilitate the reaction by a dual function as both a
Lewis acid and coordination reagent with alkynes. As an
alternative to transition metal-catalyzed cyclizations of
unsaturated frameworks,9 electrophilic cyclizations have
been frequently utilized to construct a wide range of carbo-
cycles and heterocycles.10 Noteworthy in these protocols is
that the installation of electrophilic groups could facilitate
further elaboration of the obtained products. With these
considerations in mind and in our ongoing efforts to
explore the chemistry of cyclopropane derivatives,11 herein
we wish to present our preliminary results in the electro-
philic cyclization of 1-(1-alkynyl)-cyclopropyl ketones 1
using I+ or PhSe+ as electrophilic species to afford an effi-
cient synthesis of substituted halofurans and chalcogenyl
furans, which would be very useful intermediates for access
to other furan derivatives since they could be further
elaborated to amplify complexity via a variety of carbon–
carbon or carbon–heteroatom bond formation reactions
(Scheme 1).12
We initially examined the electrophile-induced cycli-
zation of 1-phenylethynyl-bicyclo[4.1.0]heptan-2-one 1a
with 1.5 equiv of methanol, 1.1 equiv of I2, and 1.1 equiv
of NaHCO3 in CH2Cl2 at room temperature. The reaction
*
Corresponding author. Fax: +86 571 88807077.
E-mail address: huangx@mail.hz.zj.cn (X. Huang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.081

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X. Huang et al. / Tetrahedron Letters 49 (2008) 2359–2362
Table 2
R3
R3
Iodocyclization of 1-(1-alkynyl)-cyclopropyl ketonesa
R3
O
O
E
R4
O
R3
E+
R3
R1
R2
R1
R2
R1
O
Nu_
I
O
1.1equiv. I2
r.t.
R2
NuH
+
R1
R1
Nu
Nu
E = I, PhSe
R2
R2
1
Nu
Scheme 1.
1
2
Entry
R1/R2
R3
NuH
2, Yieldsb (%)
1
2
3
4
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
C6H5
C6H5
C6H5
C6H5
MeOH
I2
i-PrOH
t-BuOH
2a, 92
2b, 74
2c, 88
2d, 0
proceeded smoothly to give the ring expanded bicyclic
cycloheptafuran 2a in 52% yield along with some 2b in
20% yield (Table 1, entry 1). It can be inferred that I2
was served as both an electrophile and a nucleophile in this
reaction. Considering the competing reaction between
MeOH and I2, we then tried to use an excess of MeOH
to get the desired iodofuran 2a. Interestingly, when
10.0 equiv of MeOH was utilized and 3.0 equiv of
NaHCO3 was employed as a base, the desired product 2a
was isolated in 92% yield, without any of compound 2b
being formed (Table 1, entry 3). NIS as an electrophile
was also tested, but gave inferior results (Table 1, entry 7).
With the optimized conditions in hand, we next investi-
gated the annulation reaction of various cyclopropyl
ketones 1.13 The results are summarized in Table 2. Treat-
ment of 1a with secondary alcohol i-PrOH under the opti-
mized conditions gave the product 2c in 88% yield (Table 2,
entry 3). However, in the case of tert-butyl alcohol the reac-
tion could not proceed as expected, indicating that tertiary
alcohols are not suitable nucleophiles in this reaction
(Table 2, entry 4). Employing NIS as an electrophile, the
reaction of propargylic alcohol with 1a proceeded
smoothly to afford product 2e in 67% yield (Table 2, entry
5). When the reaction was carried out without any MeOH,
2e, 67c
OH
5
–(CH2)3–
C6H5
6
7
8
9
10
a
–(CH2)3–
C6H5/H
4-CH3OC6H4/H
n-C3H7/H
C4H9
C6H5
C6H5
C6H5
C6H5
MeOH
2f, 78
2g, 86
2h, 90
2i, 81
2j, 85
I2
I2
I2
I2
2-CH3OC6 H4/H
Unless noted, all of the reaction was carried out using I2 (1.1 equiv),
nucleophile (10 equiv) and NaHCO3 (3 equiv) at room temperature for
2 h.
b
Isolated yields.
NIS was used.
c
compound 2b was isolated in 74% yield (Table 2, entry 2).
The methodology worked well with substrates bearing an
alkyl substituent at the end of alkyne moiety to produce
the cyclization products (Table 2, entry 6). For the mono-
cyclic 1-(1-alkynyl)-cyclopropyl ketones, unfortunately,
alcohols could not serve as nucleophiles in these reactions
and the products, which are obviously formed by nucleo-
philic attack of iodide were obtained in good yields (Table
2, entries 7–10).
Table 1
Electrophile-induced cyclization of 1a
Ph
Ph
Ph
O
O
I
I
O
1.1 electrophile
r.t.
CH3OH
+
+
OMe
I
1a
2a
2b
Entry
Electrophile
Nucleophile
Solvent
Yield of 2ab (%)
1
2
3
4
5
6
7
a
I2
I2
I2
I2
I2
I2
NIS
1.5 CH3OH
3.0 CH3OH
10.0 CH3OH
CH3OH
10.0 CH3OH
10.0 CH3OH
10.0 CH3OH
CH2Cl2
CH2Cl2
CH2Cl2
CH3OH
CH2Cl2
CH3CN
CH2Cl2
52
73
92
85
83c
67
71
Reaction conditions: a solution of 0.5 mmol of 1a, 1.1 equiv of electrophile, the nucleophile indicated and 3.0 equiv of NaHCO3 in 5 mL of solvent was
stirred at room temperature for 2 h.
b
Isolated yield.
3.0 equiv of Na2CO3 was used.
c

X. Huang et al. / Tetrahedron Letters 49 (2008) 2359–2362
2361
Table 3
gen onto the cation 4 led to the formation of intermediate
5, which could be attacked by the nucleophile in a regio-
selective homo-Michael-type addition to afford furan
derivative 2 or 3.
In summary, we have demonstrated that electrophilic
cyclization of 1-(1-alkynyl)-cyclopropyl ketones affords
highly substituted furans in good to excellent yields under
mild conditions. The iodo or phenylselenenyl derivatives
are potential synthetic intermediates. Further investigation
on the scope and limitations of this electrophilic cyclization
is underway.
Reaction of 1-(1-alkynyl)-cyclopropyl ketones with PhSeBra
R3
R3
O
SePh
O
1.2 equiv. PhSeBr
NuH
+
R1
R2
R1
r.t.
R2
Nu
1
3
Entry
R1/R2
R3
NuH
3, Yieldsb (%)
1c
2
3
4
5
6
7
a
–(CH2)3–
–(CH2)3–
–(CH2)3–
C6H5/H
4-CH3OC6H4/H
n-C3H7/H
C6H5
C6H5
C4H9
C6H5
C6H5
C6H5
C6H5
MeOH
Br
Br
Br
Br
3a, 41
3b, 78
3c, 75
3d, 67
3e, 82
3f, 70
3g, 81
Acknowledgments
This work was supported by the National Natural
Science Foundation of China (20732005, 20472072) and
Academic Foundation of Zhejiang Province.
Br
Br
2-CH3OC6H4/H
Unless noted, all of the reaction was carried out using PhSeBr
(1.2 equiv) at room temperature for 1 h.
Supplementary data
b
Isolated yields.
10.0 equiv of MeOH was used.
c
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.02.081.
Moreover, we also examined a similar electrophilic cycli-
zation reaction of cyclopropyl ketones 1 with PhSeBr.14
The results are summarized in Table 3. Treatment of 1a
with 10.0 equiv of methanol, 1.2 equiv of PhSeBr, and
3.0 equiv of NaHCO3 in CH2Cl2 at room temperature gave
the desired tetrasubstituted furan 3a in 41% yield along
with some 3b in 35% yield (Table 3, entry 1). When the
reaction was carried out without any bases, the product
3b was isolated in 78% yield without any of tetrasubstituted
furan 3a being formed (Table 3, entry 2). For other cyclo-
propyl ketones, the reaction with bromine anion serving as
a nucleophile proceeded efficiently to give the cyclization
products in good yields (Table 3, entries 3–7).
References and notes
1. (a) Sargent, M. V.; Dean, F. M. In Comprehensive Heterocyclic
Chemistry; Katrizky, A. R., Rees, C. W., Eds.; Pergamon Press: New
York, 1984; Vol. 4; (b) Hou, X. L.; Yang, Z.; Wong, H. N. C. In
Progress in Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L.,
Eds.; Pergamon: Oxford, 2002; Vol. 14; (c) Donnelly, D. M. X.;
Meegan, M. J. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon: New York, 1984; Vol. 4.
2. (a) Nakanish, K. Natural Products Chemistry; Kodansha, Ltd: Tokyo,
1974; (b) The Chemistry of Heterocyclic Flavoring and Aroma
Compounds; Vernin, G., Ed.; Ellis Horwood: Chichester, 1982; (c)
Kubo, I.; Lee, Y. W.; Nakanishi, K.; Chapya, A. J. Chem. Soc.,
Chem. Commun. 1976, 949; (d) Schulte, G.; Schener, P. J.; McConnel,
O. Helv. Chim. Acta 1980, 63, 2159.
3. (a) Meyers, A. I. Heterocycles in Organic Synthesis; Wiley-Inter-
science: New York, 1974; (b) Maier, M. In Organic Synthesis
Highlights II; Waldmann, H., Ed.; VCH: Weinheim, 1995; (c)
Benassi, R. In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996; (d) Lipshutz, B. H. Chem. Rev. 1986, 86, 795; (e) Heaney, H.;
Ahn, J. S.. In Comprehensive Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996;
Vol. 2.
On the basis of the results obtained above, a plausible
reaction mechanism is depicted in Scheme 2. The addition
of I+ or PhSe+ to the triple bond of 1 would form the
bridged intermediate cation 4. The anti attack of the oxy-
R3
R3
E+
O
O
E+
R1
R1
4. For recent reviews, see: (a) Brown, R. C. D. Angew. Chem., Int. Ed.
2005, 44, 850; (b) 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; (c) Keay, B. A. Chem. Soc. Rev. 1999, 28, 209.
R2
R2
1
4
R3
5. For recent examples, see: (a) Ma, S.; Yu, Z. Angew. Chem., Int. Ed.
2002, 41, 1775; (b) Ma, S.; Zhang, J.; Lu, L. Chem. Eur. J. 2003, 9,
2447; (c) Ma, S.; Zhang, J. Chem. Commun. 2000, 117; (d) Hashmi, A.
S. K.; Schwarz, L.; Choi, J. H.; Frost, T. M. Angew. Chem., Int. Ed.
2000, 39, 2285; (e) Sromek, A. W.; KelJin, A. V.; Gevorgyan, V.
Angew. Chem., Int. Ed. 2004, 43, 2280; (f) Yao, T.; Zhang, X.; Larock,
R. C. J. Am. Chem. Soc. 2004, 126, 11164; (g) Patil, N. T.; Wu, H.;
Yamamoto, Y. J. Org. Chem. 2005, 70, 4531; (h) Gabriele, B.;
Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64, 7687; (i) Lou, F. T.;
Bajji, A. C.; Jeevanandam, A. J. Org. Chem. 1999, 64, 1738.
R3
O
O
E
R1
R2
E
R1
R2
NuH
Nu
3
2
5
or
Scheme 2.

2362
X. Huang et al. / Tetrahedron Letters 49 (2008) 2359–2362
6. For selected recent examples, see: (a) Han, Z.; Uehira, S.; Tsuritani,
T.; Shinokubo, H.; Oshima, K. Tetrahedron 2001, 57, 987; (b) Alper,
P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira, E. M. Angew.
Chem., Int. Ed. 1999, 38, 3186; (c) Lautens, M.; Han, W. J. Am.
Chem. Soc. 2002, 124, 6312; (d) Lautens, M.; Han, W.; Liu, J. H. C. J.
Am. Chem. Soc. 2003, 125, 4028; (e) Scott, M. E.; Han, W.; Lautens,
M. Org. Lett. 2004, 6, 3309; (f) Lim, Y. H.; McGee, K. F.; Sieburth, S.
M. J. Org. Chem. 2002, 67, 6535; (j) Yang, Y. H.; Shi, M. J. Org.
Chem. 2005, 70, 10082.
J. J. Org. Chem. 2003, 68, 2968; (d) Bach, T.; Kruger, L. Eur. J. Org.
Chem. 1999, 2045; (e) Alvarezlbarra, C.; Quiroga, M. L.; Toledano, E.
Tetrahedron 1996, 52, 4065. For C–N bond formation, see: (f)
Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003,
68, 2861; (g) Padwa, A.; Crawford, K. R.; Rashatasakhon, P.; Rose,
M. J. Org. Chem. 2003, 68, 2609; (h) Crawford, K. R.; Padwa, A.
Tetrahedron Lett. 2002, 43, 7365.; For C–S bond formation, see: (i)
Arroyo, Y.; Rodriguez, J. F.; Sanztejedor, M. A.; Santos, M.
Tetrahedron Lett. 2002, 43, 9129.
7. (a) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 3147;
(b) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 4333;
(c) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip, Y. C.; Tanko, J.;
Hudlicky, T. Chem. Rev. 1989, 89, 165; (d) Danishefsky, S. Acc.
Chem. Res. 1979, 12, 66.
13. Typical procedure for the synthesis of 2: To a solution of 1-(1-alkynyl)-
cyclopropyl ketones 1 (0.5 mmol) in 5 mL of CH2Cl2 was added
MeOH (5 mmol), NaHCO3 (1.5 mmol), and I2 (0.55 mmol). The
resulting mixture was stirred at room temperature for 2 h. The
reaction mixture was then diluted with ether, washed with saturated
Na2S2O3 and dried over MgSO4. The solvent was removed under
reduced pressure and the residue was purified by flash chromato-
graphy on silica gel. Compound 2a. IR (neat): 2928, 1094, 951,
763 cmÀ1. 1H NMR (CDCl3, 400 MHz): 7.96–7.99 (m, 2H), 7.39–7.43
(m, 2H), 7.29–7.33 (m, 1H), 3.42 (s, 3H), 3.33–3.37 (m, 1H), 2.78–2.90
(m, 3H), 2.55–2.60 (m, 1H), 2.15–2.17 (m, 1H), 1.97–1.99 (m, 1H),
1.78–1.82 (m, 1H), 1.61–1.65 (m, 1H). 13C NMR (CDCl3, 100 MHz):
152.5, 148.5, 130.4, 128.1, 127.5, 125.8, 119.5, 78.7, 70.5, 56.1, 35.3,
31.7, 28.1, 22.1. MS (70 eV): m/z (%) = 368 (100) [M+]. Anal. Calcd
for C16H17IO2: C, 52.19; H, 4.65. Found: C, 52.37; H, 4.79.
8. Zhang, J. L.; Schmalz, H. G. Angew. Chem., Int. Ed. 2006, 45, 6704.
9. For leading reviews, see: (a) Bruneau, C. Angew. Chem., Int. Ed. 2005,
´
44, 2328; (b) Mendez, M.; Mamane, V.; Furstner, A. Chemtracts
¨
2003, 16, 397; (c) Echavarren, A. M.; Nevado, C. Chem. Soc. Rev.
2004, 33, 431.
10. For selected examples, see: (a) Worlikar, S. A.; Kesharwani, T.; Yao,
T.; Larock, R. C. J. Org. Chem. 2007, 72, 1347; (b) Yao, T.; Larock,
R. C. J. Org. Chem. 2003, 68, 5936; (c) Zhang, X.; Campo, M. A.;
Yao, T.; Larock, R. C. Org. Lett. 2005, 7, 763; (d) Zhang, X.; Sarkar,
S.; Larock, R. C. J. Org. Chem. 2006, 71, 236; (e) Sniady, A.; Wheeler,
K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769; (f) Barluenga, J.;
Trincado, M.; Marco-Arias, M.; Ballesteros, A.; Rubio, E.; Gonzalez,
J. M. Chem. Commun. 2005, 2008; (g) Hessian, K. O.; Flynn, B. L.
Org. Lett. 2003, 5, 4377; (h) Huang, Q.; Hunter, J. A.; Larock, R. C.
J. Org. Chem. 2002, 67, 3437; (i) Yue, D.; Larock, R. C. Org. Lett.
2004, 6, 1037.
14. Typical procedure for the synthesis of 3: To a solution of 1-(1-alkynyl)-
cyclopropyl ketones 1 (0.5 mmol) in 5 mL of CH2Cl2 was added
PhSeBr (0.6 mmol). The resulting mixture was stirred at room
temperature for 1 h. The solvent was removed under reduced pressure
and the residue was purified by flash chromatography on silica gel.
1
Compound 3b. IR (neat): 2928, 1601, 1439, 735, 688 cmÀ1. H NMR
11. (a) Huang, X.; Zhou, H. W. Org. Lett. 2002, 4, 4419; (b) Huang, X.;
Zhou, H. W.; Chen, W. L. J. Org. Chem. 2004, 69, 839; (c) Zhou, H.
W.; Huang, X.; Chen, W. L. Synlett 2003, 2080; (d) Fu, W. J.; Huang,
X. Synlett 2007, 321.
12. (a) Chinchilla, R.; Najera, C.; Yus, M. Chem. Rev. 2004, 104, 2667;
(b) Tanabe, Y.; Wakimura, K.; Nishii, Y.; Muroya, Y. Synthesis 1996,
388. For C–C bond formation, see: (c) Lin, S. Y.; Chen, C. L.; Lee, Y.
(CDCl3, 400 MHz): 7.97–7.99 (m, 2H), 7.14–7.38 (m, 8H), 4.21–4.26
(m, 1H), 3.24–3.25 (m, 1H), 2.86–3.00 (m, 3H), 2.49–2.52 (m, 1H),
2.21–2.25 (m, 1H), 2.01–2.06 (m, 1H), 1.71–1.74 (m, 1H). 13C NMR
(CDCl3, 100 MHz): 153.4, 152.9, 132.3, 130.5, 129.3, 128.7, 128.3,
127.9, 126.2, 126.0, 122.2, 106.0, 52.2, 41.7, 35.5, 28.2, 25.2. MS
(70 eV): m/z (%) = 446 (100) [M+]. Anal. Calcd for C21H19BrOSe: C,
56.52; H, 4.29. Found: C, 56.22; H, 4.40.