Novel Tunable CuX2-Mediated Cyclization Reaction of Cyclopropylideneacetic Acids and Esters for the Facile Synthesis of 4-Halomethyl-2(5H)-furanones and 4-Halo-5,6-dihydro-2H-pyran-2-ones

Article abstract of DOI:10.1021/ol026911q

(Matrix Presented) A mixture of cyclopropylideneacetic acids (or esters) and CuBr₂ (or CuI/I²) in aqueous acetonitrile afforded 4-substituted 2(5H)-furanones or 3,4 substituted 5,6 dihydro-2H-pyran-2-ones in moderate to good yields.

Full text of DOI:10.1021/ol026911q

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4419-4422
Novel Tunable CuX -Mediated
Cyclization Reaction of
2
Cyclopropylideneacetic Acids and
Esters for the Facile Synthesis of
4-Halomethyl-2(5H)-furanones and
4-Halo-5,6-dihydro-2H-pyran-2-ones
Xian Huang*,†,‡ and Hongwei Zhou†
Department of Chemistry, Zhejiang UniVersity (Campus Xixi), Hangzhou 310028,
P.R. China, and State Key Laboratory of Oganometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P.R. China
huangx@mail.hz.zj.cn
Received September 16, 2002
ABSTRACT
A mixture of cyclopropylideneacetic acids (or esters) and CuBr2 (or CuI/I2) in aqueous acetonitrile afforded 4-substituted 2(5H)-furanones or
3,4-substituted 5,6-dihydro-2H-pyran-2-ones in moderate to good yields. The selectivity of the reaction greatly depended on the reaction
temperature.
Methylenecyclopropanes (MCPs) are highly strained but
readily accessible molecules that have served as useful
Scheme 1
building blocks in organic synthesis.1 An attractive feature
of MCPs is the multiform reactive possibilities of the three
δ-bonds (two proximal and one distal bonds) in the cyclo-
propane ring. Recently, increasing attention has been paid
to the transition metal-catalyzed reactions of MCPs (Scheme
1), which have been usually employed for the construction
of complex and interesting organic molecules by inter-
molecular reaction.2-4
For intramolecular reactions, usually a phenolic hydroxyl
group2b or a C≡C or CdC bond3 is employed. In this paper,
† Zhejiang University (Campus Xixi).
we report the realization of a new concept in which the
proximal and distal C-C bonds were selectively cleaved with
‡ Chinese Academy of Sciences.
(1) Brandi, A.; Goti, A. Chem. ReV. 1998, 98, 589.
(2) (a) Camacho, D. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. Angew.
Chem., Int. Ed. 1999, 38, 3585. (b) Camacho, D. H.; Nakamura, I.; Saito,
S.; Yamamoto, Y. J. Org. Chem. 2001, 66, 270. (c) Tsukada, N.; Shibuya,
A.; Nakamura, I.; Yamamoto, Y J. Am. Chem. Soc. 1997, 119, 8123 (d)
Nakamura, I.; Saito, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 2661.
(e) Nakamura, I.; Siriwardana, A. I.; Saito, S.; Yamamoto, Y. J. Org. Chem.
2002, 67, 3445. (f) Nakamura, I.; Itagaki, H.; Yamamoto, Y. J. Org. Chem.
1998, 63, 6458. (g) Camacho, D. H.; Oh, B. H.; Nakamura, I.; Saito, S.;
Yamamoto, Y. Tetrahedron Lett. 2002, 43, 2903.
10.1021/ol026911q CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/15/2002

CuX25 followed by applying an COOH or COOEt group as
the intramolecular nucleophile to trap the in situ-generated
organometallic intermediate.
Scheme 4
As a first attempt, we used cyclopropylideneacetic acid
(1a) as the starting point. When the reaction of 1a with CuBr2
was conducted in 2:1 EtOH/H2O or 2:1 acetone/H2O, no
product was obtained; interestingly, 4-bromomethyl-2(5H)-
furanone (3a) was isolated in 54% for the reaction in CH3-
CN at 60 °C. Further screening demonstrated that 4:1 CH3-
CN/H2O was the more suitable reaction medium, and the
reaction at the higher reaction temperature (85 °C) afforded
a good yield of 3a (Scheme 2).
We chose ester 2a to examine the temperature effect. The
1H NMR spectra of the reaction mixture showed that the
reaction was sensitive to the reaction temperature. The
reaction afforded 3b and 4a in different ratios at the
temperature range from 60 to 85 °C (Table 1).
Scheme 2
Table 1. Temperature Effect of the Reaction of 1b with
a
CuI/I2
entry
temp (°C)
time (h)
product
yield (%)
Because the synthesis of 2-substituted cyclopropylidene-
acetic acids was not well documented and we obtained them
from the corresponding esters,6 we managed to directly use
ethyl cyclopropylideneacetate (2a) as the starting material.
The result showed that a similar reaction occurred, and the
yield was satisfactory (Scheme 3).
1
2
3
4
5
60
65
70
78
85
14
14
14
12
10
3b
63
3b/4a
3b/4a
3b/4a
4a
53 (10:1)
50 (2.6:1)
52 (1:2)
49
a CH3CN/H2O (4:1) was the reaction medium.
Scheme 3
Then we examined the effect of the R-substituent by
studying the reaction of R-methyl-substituted cyclopropy-
lidenepropanoic acid (1b) with CuBr2 or CuI/I2; to our
surprise, no reaction was observed at 60 °C, while at 85 °C,
only six-membered lactones, i.e., 3-methyl-4-bromo-5,6-
dihydro-2H-pyran-2-one (4b) and 3-methyl-4-iodo-5,6-di-
hydro-2H-pyran-2-one (4c), were formed using CuBr2 or CuI/
I2, respectively (Scheme 5).
It is interesting to note that the reaction of 1a with CuI/I2
in 4:1 CH3CN/H2O afforded 4-iodomethyl-2(5H)-furanone
(3b) and/or 4-iodo-5,6-dihydro-2H-pyran-2-one (4a) at vari-
ous temperatures (Scheme 4).
Scheme 5
(3) (a) Nakamura, I.; Oh, B. H.; Saito, S.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2001. 40, 1298. (b) Lautens, M.; Ren, Y.; Delanghe, P. H. M. J.
Am. Chem. Soc. 1994, 116, 8821. (c) Oh, B. H.; Nakamura, I.; Saito, S.;
Yamamoto, Y. Tetrahedron Lett. 2001, 42, 6203. (d) Lautens, M.; Ren, Y.
J. Am. Chem. Soc. 1996, 118, 9597. (e) Lautens, M.; Ren, Y. J. Am. Chem.
Soc. 1996, 118, 10668. (f) Corlay, H.; Lewis, R. T.; Motherwell, W. B.;
Shipman, M. Tetrahedron 1995, 51, 3303
(4) (a) Suginome, M.; Matsuda, T.; Ito, Y. J. Am. Chem. Soc. 2000, 122,
11015. (b) Lautens, M.; Meyer, C.; Lorenz, A. J. Am. Chem. Soc. 1996,
118, 10676. (c) Bessmertnykh, A. G.; Blinov, K. A.; Grishin, Y. K.;
Donskaya, N. A.; Tveritinova, E. V.; Yur’eva, N. M.; Beletskaya, I. P. J.
Org. Chem. 1997, 62, 6069
(5) (a) Rodebaugh, R.; Debenham, J. S.; Freiser-Reid., B.; Synder., J. P.
J. Org. Chem. 1999, 64, 1758. (b) Uemura, S.; Okazaki, H.; Okano, M. J.
Chem. Soc., Perkin Trans. 1 1978, 1278.
A series of ethyl 2-alkyl-substitued cyclopropylidene-
acetates were chosen as substrates, and 4-halo-5,6-dihydro-
2H-pyran-2-ones were obtained highly selectively (Table 2).
The reaction of ethyl 2-allyl-cyclopropylideneacetate (2f)
with CuX2 afforded 6-bromo-4,5,6,7-tetrahydro-3H-cyclo-
(6) Kortmann, I.; Werstermann, B. Synthesis 1995, 931-933.
4420
Org. Lett., Vol. 4, No. 25, 2002

Table 2. Synthesis of 4-Halo-5,6-dihydro-2H-pyran-2-onesa
Table 3. Distal and Proximal Cleavages of Aryl-Substituted
Methylenecyclopropanes and the Temperature Effect
yield (%)
substrate
temp (°C)
time (h)
X
9
10
8a
8b
8c
8c
8c
8c
8ca
85
85
85
75
65
55
45
8
14
10
15
22
30
48
Br
Br
I
I
I
87
72
88
81
84
78
52
0
17
0
0
0
entry
R
X
time (h)
product (yield %)
1
2
3
4
5
6
7
8
Me (2b)
Me (2b)
Et (2c)
Br
I
Br
I
Br
I
Br
I
30
30
31
31
30
30
35
35
4b (81)
4c (71)
4d (83)
4e (77)
4f (80)
4g (76)
4h (76)
4i (70)
I
I
4
9
Et (2c)
n-Pr (2d )
n-Pr (2d )
Bn (2e)
Bn (2e)
a Recovery of 8c ) 25%.
cyclopropylideneacetic acid 1a provides two possible ways
to cleave cyclopropane ring and may form two organocopper
coordination complexes 11 and 13.8,4a In complex 11, the
a Reaction temperature ) 85 °C; CuBr2 (4 equiv), I2 (4 equiv), CuI (0.1
equiv).
penta[c]-pyran-1-one (5a) and 6-iodo-4,5,6,7-tetrahydro-3H-
cyclopenta[c]-pyran-1-one (5b) indicating the possibility of
intermediate 6.7 Intermediate 6 gave bicyclic copper inter-
mediate 7, which upon intramolecular insertion afforded
6-halo-4,5,6,7-tetrahydro-3H-cyclopenta[c]-pyran-1-one (5)
via oxidative cleavage with CuX2 (Scheme 6).
Scheme 7
Scheme 6
hydroxy oxygen atom acting as an intramolecular nucleophile
attacks the γ-position of complex 11 to undergo lactonization
to give 12 and a molecule of HX. Oxidative cleavage of 12
with CuX2 affords 4-halomethyl-2(5H)-furanone 3.8 In
complex 13, the hydroxy oxygen atom attacks the δ-position
instead, to form vinylic copper intermediate 14, and gives a
molecule of HX. Intermediate 14 leads to 4-halo-5,6-dihydro-
2H-pyran-2-one after oxidative cleavage by CuX2 (Scheme
8). For the reaction of carboxylates, the carbonyl oxygen
may act as the nucleophile.9
Although the Nickel(0)-catalyzed intermolecular dimer-
ization and Michael reaction of ethyl cyclopropylidene-
acetates were reported,10 to the best of our knowledge, no
similar intramolecular cyclization has been documented. In
conclusion, we have developed a novel, convenient, and
efficient method for the synthesis of 4-substitued 2(5H)-
furanones and 3,4-substituted-5,6-dihydro-2H-pyran-2-ones.
Both furanones and pyranones are important classes of
Furthermore, the reaction of aryl-substituted methylene-
cyclopropanes with CuX2 afforded 2,4-dihalo-1-alkenes (9)
and 2,2-dihalomethyl-1- alkenes (10), indicating the pos-
sibility of two ways to cleave the cyclopropane ring (Scheme
7). Further screening showed that benzylenecyclopropane
(8c) has similar whereas weaker temperature effect compared
to 1b (Table 3).
Ito has proposed a metalcyclic intermediate mechanism
to explain the selective distal or proximal C-C bond
cleavage of MCPs via Pd- and Pt-catalyzed silaboration,4a
and Ma has proposed a coordination copper-complex mech-
anism for the CuX2-mediated cyclization reaction of 2,3-
allenoic acids.8 Considering the similarity of the cyclopro-
pane ring with the CdC bond, we suggest the possibility of
a coppercyclic intermediate mechanism for the reaction. Due
to the fact that 3b could not be transformed to 4a under the
same conditions, it is concluded that 3b and 4a were formed
by parallel reaction routes. The coordination of CuX2 to
(9) (a) Ma, S.; Wu, S. L. Tetrahedron Lett. 2001, 42, 4075. (b) Ma, S.;
Xie, H. X. J. Org. Chem. 2002, 67, 3801.
(10) (a) Kawasaki, T.; Saito, S.; Yamamoto, Y. J. Org. Chem. 2002, 67,
4911. (b) Notzel, M. W.; Tamm, M.; Lahahn, T.; Notemeyer, M.; de
Meijere, A. J. Org. Chem. 2000, 65, 3850. (c) Zorn, C.; Goti, A.; Brandi,
A.; Johnsen, K.; Notemeyer, M.; de Meijere, A. J. Org. Chem. 1999, 64,
755. (d) Notzel, M. W.; Rauch, K.; Labahn, T.; de Meijere, A. Org. Lett.
2002, 4, 839. (e) Notzel, M. W.; Labahn, T.; Es-sayed, M.; de Meijere, A.
Eur. J. Org. Chem. 2001, 3025. (f) Zorn, C.; Anichini, B.; Goti, A.; Brandi,
A.; Kozhushkov, S. I.; de Meijere, A.; Citti, L. J. Org. Chem. 1999, 64,
7846.
(7) Jousseaume, B.; Duboudin, J. G. Synth. Commun. 1979, 9, 53.
(8) Ma, S.; Wu, S. L. J. Org. Chem. 1999, 64, 9314.
Org. Lett., Vol. 4, No. 25, 2002
4421

Scheme 8
compounds because they are pivotal skeletons in many
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (20272050)
and the Doctoral Foundation of the National Education
Ministry of China.
natural products with an unusual range of biological activi-
ties11 and can be obtained from moderate to good yields by
the reaction of cyclopropylideneacetic acids (or esters) and
CuBr2 (or CuI/I2) in aqueous acetonitrile. The reaction
mechanism, influence of temperature on selectivity, and
synthetic application of this methodology are being inves-
tigated in our laboratory.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds prepared. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Watanabe, H.; Watanabe, H.; Usui, T.; Kondoh, M.; Osada, H.;
Kitahara, T. J. Antibiot. 2000. 53, 540. (b) Takeda, Y.; Okeda, Y.; Masuda,
T.; Hirata, E.; Shieato, T.; Takushi, A.; Yu, Q.; Otsuka, H. P. K.: Warkentin,
J. Chem. Pharm. Bull. 2000, 48, 752. (c) Brady, S. F.; Clardy, J. J. Nat.
Prod. 2000, 63, 1447. (d) Topol, I.; Burt, S. K.; Rashin, A. A.; Erickson,
J. W. J. Phys. Chem. A 2000, 104, 866.
OL026911Q
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Org. Lett., Vol. 4, No. 25, 2002