An Efficien t Syn th esis of
4-Ha lo-5-h yd r oxyfu r a n -2(5H)-on es via th e
Sequ en tia l Ha lola cton iza tion a n d
γ-Hyd r oxyla tion of 4-Ar yl-2,3-a lk a d ien oic
Acid s
Shengming Ma,* Bin Wu, and Zhangjie Shi
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. China
masm@mail.sioc.ac.cn
Received October 23, 2003
F IGURE 1. Molecular structure of 2a .
Abstr a ct: 4-Halo-5-hydroxyfuran-2(5H)-ones were synthe-
sized via the efficient sequential halolactonization-hydroxy-
lation reaction of 4-aryl-2,3-allenoic acids with I2 or CuX2
(X ) Br or Cl) in moderate to good yields. The structures of
the products were established by the X-ray single-crystal
diffraction study of 3-methyl-4-iodo-5-phenyl-5-hydroxyl-
2(5H)-furanone (2a ). A rationale for this reaction was
discussed based on some brief mechanistic study.
SCHEME 1
sis of R,â-butenolides,2e and reaction of lithium E-â-
bromo-â-lithioacrylates with aldehydes.2f Herein, we wish
to report an interesting and efficient halolactonization-
hydroxylation reaction of 4-aryl-2,3-allenoic acids.
During the course of our project aimed at the synthesis
of optically active 4-iodobutenolide3 from the optically
active 1:1 salt of (L)-(-)-cinchonidine with 2,3-allenoic
acid, to our surprise, racemic 4-iodo-5-hydroxy-2(5H)-
furanone (2a ) was formed in THF:DMF (3:1) (eq 1).
5-Hydroxyfuran-2(5H)-ones are an important class of
compounds because they often occur in natural products
and exhibit a broad range of biological activities.1 These
compounds are considered as antimutagen, bactericides,
cytotoxicity, antitumor agents, allergy inhibitors, stimu-
latory agents, cyclooxygenase inhibitors, phospholipase
A2 inhibitors, etc.1 Recently, much attention has been
focused on the efficient and diverse synthesis of these
compounds, particularly 4-halo-5-hydroxy-2(5H)-fura-
nones. The typical synthetic strategies include acid-
catalyzed cyclization of ketonic acids,1k,i autoxidation of
the corresponding lactones in air,2a,b rearrangement
reactions of R-phenylsulfinylacrylates,2c oxidation with
chromium trioxide in acetic acid,2d bromination-hydroly-
The structure of 2a was unambiguously determined
by the X-ray single-crystal diffraction study (Figure 1).4
From this results, we envisioned that a γ-hydroxylation
followed the lactonization reaction.
This result prompted us to investigate the possibility
of direct synthesis of 5-hydroxy-2(5H)-furanones via the
cyclization-hydroxylation of 2,3-allenoic acids (Scheme
1).
It is known that slow γ-hydroxylation of butenolides
may be accomplished via the treatment of furan-2(5H)-
ones with oxygen.2a,b We initiated this study with the
reaction of 2-methyl-4-phenyl-2,3-butadienoic acid with
various bases in THF/DMF (2:1) at room temperature.
Among the bases screened, the use of NaOH, K2CO3, Na2-
CO3, Cs2CO3, Li2CO3, NaOAc, Et3N, and pyridine gave
(1) (a) Kakinuma, K.; Koike, J .; Ishibashi, K.; Takahashi, W.; Takei,
H. Agric. Biol. Chem. 1986, 50, 625. (b) Tasdemir, D.; Concepcio´n, G.
P.; Mangalindan, G. C.; Harper, M. K.; Hajdu, E.; Ireland, C. M.
Tetrahedron 2000, 56, 9025. (c) Uchida, M.; Koike, Y.; Kusano, G.;
Kondo, Y.; Nozoe, S.; Kabuto, C.; Takemoto, T. Chem. Pharm. Bull.
1980, 28, 92. (d) Ko¨nig, G. M.; Wright, A. D.; Franzblau, S. G. Planta
Med. 2000, 66, 337. (e) Ko¨nig, G. M.; Wright, A. D.; Sticher, O.;
Angerhofer, C. K.; Pezzuto, J . M. Planta Med. 1994, 60, 532. (f) Gnabre,
J . N.; Pinnas, J . L.; Martin, D. G.; Mizsak, S. A.; Kloosterman, D. A.;
Baczynskyj, L.; Nielsen, J . W.; Bates, R. B.; Hoffmann, J . J .; Kane, V.
V. Tetrahedron 1991, 47, 3545. (g) Yoneyama, K.; Takeuchi, Y.;
Ogasawara, M.; Konnai, M.; Sugimoto, Y.; Sassa, T. J . Agric. Food
Chem. 1998, 46, 1583. (h) Resch, M.; Steigel, A.; Chen, Z.-l.; Bauer, R.
J . Nat. Prod. 1998, 61, 347. (i) Reynolds, L. J .; Morgan, B. P.; Hite, G.
A.; Mihelich, E. D.; Dennis, E. A. J . Am. Chem. Soc. 1988, 110, 5172.
(j) J iang, Z.; Yu, D.-Q. J . Nat. Prod. 1997, 60, 122. (k) Patt, W. C.;
Edmunds, J . J .; Repine, J . T.; Berryman, K. A.; Reisdorph, B. R.; Lee,
C.; Plummer, M. S.; Shahripour, A.; Haleen, S. J .; Keiser, J . A.; Flynn,
M. A.; Welch, K. M.; Reynolds, E. E.; Rubin, R.; Tobias, B.; Hallak,
H.; Doherty, A. M. J . Med. Chem. 1997, 40, 1063.
(2) (a) Lacey, R. N. J . Chem. Soc. 1954, 822. (b) Berg, A. S.; Kolsaker,
P. Acta Chem. Scand. Ser. B 1978, 32, 665. (c) Yamagiwa, S.; Sato,
H.; Hoshi, N.; Kosugi, H.; Uda, H. J . Chem. Soc., Perkin Trans. 1 1979,
570. (d) Pelter, A.; Al-Bayati, R. I. H.; Ayoub, M. T.; Lewis, W.;
Pardasani, P.; Hansel, R. J . Chem. Soc., Perkin Trans. 1 1987, 717.
(e) de March, P.; Font, J .; Gracia, A.; Qingying, Z. J . Org. Chem. 1995,
60, 1814. (f) Caine, D.; Ukachukwu, V. C. Tetrahedron Lett. 1983, 24,
3959.
(3) (a) Ma, S.; Shi, Z.; Yu, Z. Tetrahedron Lett. 1999, 40, 2393. (b)
Ma, S.; Shi, Z.; Yu, Z. Tetrahedron 1999, 55, 12137.
(4) Crystal data for compound 2a : C11H9O3I, MW ) 316.09, mono-
clinic, space group P2(1)/n, Mo KR, final R indices [I > 2σ(I)], R1 )
0.045, wR2 ) 0.057, a ) 12.900 (5) Å, b ) 7.216 (2) Å, c ) 13.626 (3)
Å, R ) 90.00°, â ) 116.23 (2)°, γ ) 90.00°, V ) 1137.8 (6) Å3, T ) 293
K, Z ) 4, reflections collected/unique 2681/2561 (Rint ) 0.0196, no
observation [I > 2σ(I)] 1868; parameters 137.
10.1021/jo0355698 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/21/2004
J . Org. Chem. 2004, 69, 1429-1431
1429