Palladium-catalyzed cross-coupling reactions of 4-tosyl-2(5H)-furanone with boronic acids: A facile and efficient route to generate 4-substituted 2(5H)-furanones

Article abstract of DOI:10.1021/jo020640f

An efficient and facile synthesis of 4-substituted 2(5H)-furanones using palladium catalyzed cross-coupling reactions between 4-tosyl-2(5H)-furanone and boronic acids is reported herein.

Full text of DOI:10.1021/jo020640f

P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin g
Rea ction s of 4-Tosyl-2(5H)-fu r a n on e w ith
Bor on ic Acid s: A F a cile a n d Efficien t
Rou te to Gen er a te 4-Su bstitu ted
2(5H)-F u r a n on es
J ie Wu,*,† Qiang Zhu,† Lisha Wang,† Reza Fathi,‡ and
Zhen Yang*,‡,§
F IGURE 1. Butenolide chemistry.
The Aaron Diamond AIDS Research Center, Rockefeller
University, 455 First Avenue, New York, New York 10016,
VivoQuest, Inc., 711 Executive Blvd., Suite Q,
Valley Cottage, New York 10989, and College of Chemistry
and Molecular Engineering, Peking University,
Beijing 100871, P. R. China
quently is utilized as a key intermediate to construct
complex molecules and also appears as a substructure
in peptide analogues and HIV-1 protease inhibitors.2h,i
In our ongoing combinatorial synthesis of natural
product-like molecular libraries,4d we were interested in
integrating this important fragment into our library
synthesis either as a structural subunit or as a synthon
to elaborate further complexity.
z.yang@vivoquest.com
Received October 8, 2002
Synthetically, to generate 4-substituted 2(5H)-furanone
is more challenging than its corresponding 3- or 5-sub-
stituted 2(5H)-furanone.3 Currently, the most frequently
used methods for synthesizing 4-substituted 2(5H)-fura-
none derivatives are based on the transition metal-
catalyzed coupling methods.3 For example, the first
Suzuki reaction of tetronic acid triflate with 9-alkyl-9-
BBN (51% yield) was adopted by Grigg3p during the total
synthesis of (-)-isoseiridine, and later the reaction of
Abstr a ct: An efficient and facile synthesis of 4-substituted
2(5H)-furanones using palladium catalyzed cross-coupling
reactions between 4-tosyl-2(5H)-furanone and boronic acids
is reported herein.
As a privileged fragment, 4-substituted 2(5H)-furanone
is a ubiquitous subunit in many butenolide-containing
natural products with remarkable biological activities.1
For example, butenolide A (see Figure 1),1f which was
isolated from P. syringae pv. tomato, shows an interesting
antimicrobial activity; Rubrolides B,1g,h a family of bio-
logically active marine ascidian (tunicate) metabolites
that have been isolated from Ritterella rubra and Syn-
oicum blochmanni, are potent antibiotics and show
moderate but selective inhibition of protein phosphatases
1 and 2A, significant cytotoxicity against P-388 suspen-
sion cultures of mouse lymphoid neoplasm and monolayer
cultures of human lung carcinoma (A-549), human colon
carcinoma (HT-29), and human melanoma (MEL-28). As
a valuable synthetic intermediate,2a-g butenolide fre-
(2) For example: (a) Renard, M.; Ghosez, L. A. Tetrahedron 2001,
57, 2597. (b) Concellon, J . M.; Riego, E.; Bernad, P. L. Org. Lett. 2002,
4, 1303. (c) Makabe, H.; Hattori, Y.; Tanaka, A.; Oritani, T. Org. Lett.
2002, 4, 1083. (d) Chio, Y.; Choo, H.; Chong, Y.; Lee, S.; Olgen, S.;
Schinazi, R. F.; Chu, C. K. Org. Lett. 2002, 4, 305. (e) Roush, W. R.;
Limberakis, C.; Kunz, R. K.; Barda, D. A. Org. Lett. 2002, 4, 1543. (f)
Ghosh, N.; McKee, S. P.; Thompson, W. J .; Darke, P. L.; Zugory, J . C.
J . Org. Chem. 1993, 58, 1025. (g) Wender, P. A.; Ihle, N. C.; Correia,
C. R. D. J . Am. Chem. Soc. 1988, 110, 5904. (h) Hanessian, S.; Park,
H.; Yang, R. Y. Synlett 1997, 351. (i) Hanessian, S.; Park, H.; Yang,
R. Y. Synlett 1997, 353. (j) Sulikowski, G. A.; Agnelli, F.; Spencer, P.;
Koomen, J . M.; Russell, D. H. Org. Lett. 2002, 4, 1447.
(3) (a) Lattmann, E.; Hoffmann, H. M. R. Synthesis 1996, 155. (b)
Knight, D. W. Contemp. Org. Synth. 1994, 1, 287. (c) Marshall, J . A.;
Wolf, M. A. J . Org. Chem. 1996, 61, 3238. (d) Xiao, W.-J .; Alper, H. J .
Org. Chem. 1997, 62, 3422. (e) Marshall, J . A.; Wolf, M. A. J . Org.
Chem. 1997, 62, 367. (f) J oh, T.; Nagata, H.; Takahashi, S. Inorg. Chim.
Acta. 1994, 220, 45. (g) Forgione, P.; Wison, P. D.; Fallis, A. G.
Tetrahedron Lett. 2000, 41, 17. (h) Reginato, G.; Capperucci, A.;
Degl’Innocenti, A.; Mordini, A.; Pecchi, S. Tetrahedron 1995, 51, 2129.
(i) Hoffmann, H. M. R.; Gerlach, K.; Lattmann, E. Synthesis 1996, 164.
(j) Hollingworth, G. J .; Sweeney, J . B. Tetrahedron Lett. 1992, 33, 7049.
(k) Hollingworth, G. J .; Perkins, G.; Sweeney, J . B. J . Chem. Soc.,
Perkin Trans. 1 1996, 1913. (l) Maon, R.; Richecoeur, A. M. E.;
Sweeney, J . B. J . Org. Chem. 1999, 64, 328. (m) Ma, S.; Shi, Z. J . Org.
Chem. 1998, 63, 6387. (n) Boukouvalas, J .; Lachance, N.; Ouellet, M.;
Trudeau, M. Tetrahedron Lett. 1998, 39, 7665. (o) Ma, S.; Shi, Z.; Yu,
Z. Tetrahedron Lett. 1999, 40, 2393. (p) Grigg, R.; Kennewell, P.; Savic,
V. Tetrahedron 1994, 50, 5489. (q) Honda, T.; Mizutani, H.; Kanai, K.
J . Org. Chem. 1996, 61, 9374. (r) Yao, M.-L.; Deng, M.-Z. J . Org. Chem.
2000, 65, 5034. (s) Ma, S. Chin. J . Org. Chem. (Youji Huahue) 2001,
21, 833 and references therein. (t) Mehta, G.; Sengupta, S. Tetrahedron
Lett. 1996, 37, 8625. (u) Rossi, R.; Bellina, F.; Biagetti, M. Synth.
Commun. 1999, 29, 3415. (v) Bella, M.; Piancatelli, G.; Pigro, M. C.
Tetrahedron 1999, 55, 12387. (w) Rossi, R.; Bellina, F.; Raugei, E.
Synlett 2000, 1749.
† Rockefeller University.
‡ VivoQuest, Inc.
§ Peking University.
(1) (a) Bohlmann, F.; Zdero, C.; King, R. M.; Robinson, H. Phy-
tochemistry 1981, 20, 2545. (b) Gadir, S. A.; Smith, Y.; Tada, A. A.;
Thaller, V. J . Chem. Res., Synop. 1986, 102. (c) Brima, T. S. US Patent
4,968,817, 1990; Chem. Abstr. 1991, 114, 185246y. (d) Tanabe, A. J pn.
Kokai Tokkyo. Koho J P 63,211,276 [88,211,276], 1988; Chem. Abstr.
1989, 110, 94978q. (e) Lee, G. C. M. Eur. Pat. Appl. EP 372,940, 1990;
Chem Abstr. 1990, 113, 191137j. (f) Midland, S. L.; Sims, J . J . J . Org.
Chem. 1995, 60, 1118. (g) Miao, S. W.; Andersen, R. J . J . Org. Chem.
1991, 56, 6275. (h) Ortega, M. J .; Zubia, E.; Ocafia, J . M.; Naranjo, S.;
Salva, J . Tetrahedron 2000, 56, 3963. (i) Ducharme, Y.; Gauthier, J .
Y.; Prasit, P.; Leblanc, Y.; Wang, Z.; Leger, S.; Therien, M. PCT Int.
Appl. WO 95 00,501, 1995; Chem. Abstr. 1996, 124, 55954y. (j) Lee, G.
C. M.; Garst, M. E. PCT Int. Appl. WO 91 16,055, 1991; Chem. Abstr.
1992, 116, 59197m. (k) Honda, T.; Mizutani, H.; Kanai, K. J . Org.
Chem. 1996, 61, 9374. (l) Bellina, F.; Anselmi, C.; Viel, S.; Mannina,
L.; Rossi, R. Tetrahedron 2001, 57, 9997 and references therein. (m)
For pyrroxanthin, see: J ohansen, J . E.; Svec, W. A.; Liaaen-J ensen,
S.; Haxo, F. T. Phytochemistry 1974, 13, 2261. (n) For dihydroxerulin,
xerulin, and xerulinic acid, see: Kuhnt, D.; Anke, T.; Besl, H.; Bross,
M.; Herrmann, R.; Mocek, U.; Steffan, B.; Steglich, W. J . Antiobiot.
1990, 43, 1413. (o) For (-)-dysiolide, see: Gunaskera, G. P.; McCarthy,
P. J .; Kelly Borges, M.; Lobkovsky, E.; Clardy, J . J . Am. Chem. Soc.
1996, 118, 8759. (p) For (-)-seiridin, see: Sparapano, L.; Evidente,
A.; Ballio, A.; Graniti, A.; Randazzo, G. Experientia 1986, 42, 627.
(4) (a) Tallarico, J . A.; Depew, K. M.; Pelish, H. E.; Westwood, N.
J .; Lindsley, C. W.; Shair, M. D.; Schreiber, S. L.; Foley, M. A. J . Comb.
Chem. 2001, 3, 312. (b) Pelish, H. E.; Westwood, N. J .; Feng, Y.;
Kirchhausen, T.; Shair, M. D. J . Am. Chem. Soc. 2001, 123, 6740. (c)
http://iccb.med.harvard.edu. (d) Liao, Y.; Reitman, M.; Zhang, Y.; Fathi,
R.; Yang, Z. Org. Lett. 2002, 4, 2607. (e) Liao, Y.; Fathi, R.; Reitman,
M.; Zhang, Y.; Yang, Z. Tetrahedron Lett. 2001, 42, 1815.
10.1021/jo020640f CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/14/2002
670
J . Org. Chem. 2003, 68, 670-673

SCHEME 1. Tosyla te-Ba sed Su zu k i Cou p lin g
Rea ction
alkenylboronic acid with tetronic acid triflate (48% yield)
was described by Honda3q in the preparation of syributin.
Very recently, Deng3r reported the palladium-catalyzed
reactions of 4-triflate-2(5H)-furanone with cyclopropyl-
boronic acids in the presence of AsPh3 as a ligand (63-
85% yields). Also, Boukouvalas3n and Rossi3w reported the
coupling reactions by using 4-bromo-2(5H)-furanone as
the substrate. However, the preparation of 4-bromo-
2(5H)-furanone suffers harsh conditions, and highly toxic
tin reagents were employed in the couplings. Another
problem associated with the aforementioned synthetic
methods is the stability of tetronic acid-derived triflate,
which cannot be stored under normal conditions based
on our experience.
Our desire to build up a furanone-based combinatorial
library promoted us to search for a more facile method.
The criteria for this replacement selection included the
following considerations: (a) it must be stable at room
temperature and in different solvents; (b) the reaction
conditions must be very mild in order to be compatible
with diversified substrates and our selected solid sup-
port;4 and (c) the reaction should be reasonably fast at
room temperature with high yield.
Recently, we have witnessed the important progress
of using aryl sulfonates as electronphiles for the cross-
coupling reactions.5 In this field, we also reported the
applications of 4-hydroxycoumarin-derived 4-tosyl-cou-
marin as a unique replacement for its corresponding
triflate in the transition metal-catalyzed cross-coupling
reactions with acetylenes, organozinc reagents, and aryl-
boronic acids, respectively.6
The structural similarity of 4-hydroxycoumarin and
tetronic acid led us to envisage that the 4-tosyl-2(5H)-
furanone might be an ideal alternative for its correspond-
ing triflate, since the 4-tosyl group attached to the
electron-withdrawing R,â-unsaturated double bond in
4-tosyl-2(5H)-furanone may enhance its oxidative addi-
tion to the transition metals.
We therefore focused our attention on exploring the
possibility of using 4-tosyl-2(5H)-furanone as a substrate
in the palladium-catalyzed cross-coupling reaction. To
permit an application of the above coupling reactions in
drug discovery, it is of utmost importance to overcome
the necessity of using highly toxic reagents. Due to the
innocuous nature of boronic acids, which are generally
nontoxic and thermally, air-, and moisture-stable, aryl-
boronic acids would be the starting materials of choice,
particularly for small-scale reaction. Thus, initial studies
were carried out with 2-methoxyphenylboronic acid and
4-tosyl-2(5H)-furanone 1 (Scheme 1).
4-Tosyl-2(5H)-furanone 1 was prepared by simply
mixing tetronic acid (1.0 equiv), tosyl chloride (1.0 equiv)
and triethylamine (1.2 equiv) in dichloromethane at room
temperature (See Experimental Section). As was ex-
pected, in contrast to the corresponding triflate, which
is known to exhibit lability, 1 was remarkably stable as
a crystalline solid, which could be stored at room tem-
perature under air without protection from light. Under
standard Suzuki conditions that we selected previously
(PdCl2(PPh3)2, THF, sodium carbonate),6a compound 1
underwent coupling reaction with o-methylphenylboronic
acid to provide a 59% yield of desired product 2b as
expected. After further screening of different palladium
catalysts and bases, 95% yield of 2b was eventually
obtained by combining potassium fluoride7 and 5 mol %
PdCl2(PPh3)2 in a mixed solvent of THF-H2O at 60 °C
for 12 h. The ideal amount of catalyst is 5 mol %;
however, with a significantly lower catalyst loading, the
corresponding product with good yield was obtained by
prolonging the reaction time to 48 h [PdCl2(PPh3)2 (0.5
mol %), 60 °C, 92% yield]. Most importantly, this reaction
can proceed even at room temperature to give 90% yield
of coupling product, although the reaction needs 48 h to
go to completion.
Encouraged by these results, the scope of this reaction
was investigated by using various boronic acids and
substrate 1. The results are shown in Table 1.
From the results listed in Table 1, we can make the
following observations. (1) Tosylate 1 can couple with all
the selected boronic acids to provide the corresponding
products in moderate to good yields. (2) Both electron-
rich and electron-poor arylboronic acids gave similar
yields (entries 2-5). (3) When 2-thiopheneboronic acid
and 2-benzothiopheneboronic acid were coupled with 1,
only moderate yields of 49 and 48%, respectively, were
obtained (entries 8 and 9). This may be due to a
deteriorating effect of the sulfur on the palladium catalyst
during the process of the reaction, which could cause the
reduction of the efficiency of the catalyst. To broaden
synthetic application of compound 1, its coupling reaction
with an alkenylboronic acid (entry 11) was also evalu-
ated. As expected, 61% yield of desired product 2k was
obtained with retention of the double bond stereochem-
1
istry as evidenced from the H NMR spectrum.
However, when the 3-phenyl-4-tosyl-2(5H)-furanone 3
was utilized as a substrate to couple with the boronic
acids, only a trace amount of the desired product was
detected, presumably due to the steric effect of C-3 phenyl
group (Scheme 2). The reaction was still inactive even
though different phosphine ligands such as PtBu3 and
PCy3 were added in the reaction.
Product 2 can be easily transformed to 4-substituted
5-[1-(aryl)methylidene]-2(5H)-furanones, another key sub-
unit in natural products. For example, the reaction of
compound 2c with 4-chlorobenzaldehyde afforded the
corresponding product 5a in almost quantitative yield at
room temperature by using a literature method8 (Scheme
3).
(5) (a) Lakshman, M. K.; Thomson, P. F.; Nuqui, M. A.; Hilmer, J .
H.; Sevova, N.; Boggess, B. Org. Lett. 2002, 4, 1479. (b) Percec, V.;
Bae, J . Y.; Hill, D. H. J . Org. Chem. 1995, 60, 1060. (c) Kobayashi, Y.;
Mizojiri, R. Tetrahedron Lett. 1996, 37, 8531. (d) Zim, D.; Lando, V.
R.; Dupont, J .; Monteiro, A. L. Org. Lett. 2001, 3, 3049. (e) Schio, L.;
Chatreaux, F.; Klich, M. Tetrahedron Lett. 2000, 41, 1543.
(7) Littke, A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000, 122,
4020 and references therein.
(6) (a) Wu, J .; Wang, L.; Fathi, R.; Yang, Z. Tetrahedron Lett. 2002,
43, 4395. (b) Wu, J .; Liao, Y.; Yang, Z. J . Org. Chem. 2001, 66, 3642.
(8) Bellina, F.; Anselmi, C.; Viel, S.; Mannina, L.; Rossi, R. Tetra-
hedron 2001, 57, 9997 and references therein.
J . Org. Chem, Vol. 68, No. 2, 2003 671

TABLE 1. P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin g
Rea ction s of 1 w ith Va r iou s Bor on ic Acid sa
SCHEME 3
make it an ideal synthon for organic synthesis, and
further reports will be forthcoming.
Exp er im en ta l Section
P r oced u r e for Syn th esis of 4-Tosyl-2(5H)-fu r a n on e (1).
To a solution of tetronic acid (1.00 g, 10 mmol) and p-toluene-
sulfonyl chloride (2.00 g, 10.5 mmol) in dichloromethane (50 mL)
was added triethylamine (1.67 mL, 12 mmol) under air at room
temperature. The reaction mixture was stirred at room temper-
ature for 2 h. Following completion of the reaction as monitored
by TLC, the reaction mixture was concentrated to a residue that
was purified by flash chromatography (silica gel, 4/1 (v/v) hexane/
ethyl acetate) to give the corresponding product 1 (98% yield)
as a white solid: 1H NMR (500 MHz, DMSO-d6) δ (ppm) 2.45
(s, 3H), 4.89 (s, 2H), 5.98 (s, 1H), 7.56 (d, J ) 8.5 Hz, 2H), 8.03
(d, J ) 8.5 Hz, 2H); 13C NMR (125.7 MHz) δ (ppm) 22.0, 68.5,
99.9, 129.5, 130.4, 131.4, 148.2, 169.9, 171.7; MS [C11H10O5S],
m/z (M+ + 1) calcd 255, found 255.
Gen er a l P r oced u r e for Syn th esis of 4-Su bstitu ted 2(5H)-
F u r a n on es. To a solution of 4-tosyl-2(5H)-furanones (64 mg,
0.25 mmol), PdCl2(PPh3)2 (8.8 mg, 5 mol %), and boronic acid
(1.2 equiv) in THF (2 mL) was added potassium fluoride (2.0 M
in water, 2 mL) under a nitrogen atmosphere. The reaction
mixture was stirred at 60 °C overnight. Following completion
of the reaction as monitored by TLC, the reaction mixture was
diluted with ethyl acetate (20 mL) and separated. The solution
was dried and filtered, and the filtrate was concentrated to a
residue that was purified by flash chromatography (silica gel,
4/1 (v/v) hexane/ethyl acetate) to give the corresponding product.
4-Phenyl-2(5H)-furanone (2a ),9 4-(2-methoxyphenyl)-2(5H)-
furanone (2b),10 4-(4-methoxyphenyl)-2(5H)-furanone (2c),9 4-(4-
chlorophenyl)-2(5H)-furanone (2d ),9 4-(4-fluorophenyl)-2(5H)-
furanone (2e),11 and 4-thiophen-2-yl-5H-furan-2-one (2h )9 are
reported in the literature as known compounds.
4-Ben zofu r a n -2-yl-5H-fu r a n 2-on e (2f): 52% yield as a
colorless oil; 1H NMR (500 MHz, DMSO-d6) δ (ppm) 5.37 (s, 2H),
6.60 (s, 1H), 7.33 (t, J ) 7.0 Hz, 1H), 7.47 (t, J ) 7.0 Hz, 1H),
7.59 (s, 1H), 7.67 (d, J ) 8.0 Hz, 1H), 7.78 (d, J ) 7.5 Hz, 1H);
13C NMR (125.7 MHz) δ (ppm) 70.6, 111.3, 112.3, 113.0, 123.3,
124.7, 128.1, 128.2, 147.7, 154.3, 155.7, 173.8; MS [C12H8O3],
m/z (M+ + 1) calcd 201, found 201.
a
Conditions: 4-tosyl-2(5H)-furanone (0.5 mmol), boronic acid
(1.2 equiv), PdCl2(PPh3)2 (5 mol %), THF (2.0 mL), KF (2.0 M in
water, 2.0 mL), 60 °C. Isolated yield based on 4-tosyl-2(5H)-
furanone.
b
SCHEME 2
2′H-[2,3′]Bifu r a n yl-5′-on e (2g): 80% yield as a colorless oil;
1H NMR (500 MHz, DMSO-d6) δ (ppm) 5.24 (s, 2H), 6.32 (s, 1H),
6.72-6.74 (m, 1H), 7.15 (d, J ) 9.0 Hz, 1H), 8.00 (s, 1H); 13C
NMR (125.7 MHz) δ (ppm) 70.3, 109.7, 113.6, 115.6, 146.2, 147.6,
154.1, 174.1; MS [C8H6O3], m/z (M+ + Na) calcd 173, found 173.
4-Ben zo[b]th iop h en -2-yl-5H-fu r a n -2-on e (2i): 48% yield
as a colorless oil; 1H NMR (500 MHz, DMSO-d6) δ (ppm) 5.43
(s, 2H), 6.55 (s, 1H), 7.40-7.50 (m, 2H), 7.94 (t, J ) 10.0, 8.0
Hz, 2H), 8.06 (d, J ) 8.0 Hz, 1H); 13C NMR (125.7 MHz) δ (ppm)
71.7, 113.6, 123.6, 125.8, 126.1, 127.5, 127.6, 133.0, 139.8, 141.0,
159.0, 173.8.
In conclusion, we have reported herein the efficient and
facile synthesis of 4-substituted 2(5H)-furanones using
cross-coupling reactions between 4-tosyl-2(5H)-furanone
(derived from commercially available tetronic acid) and
boronic acids. The superiority of 4-tosyl-2(5H)-furanone
versus its corresponding triflate in terms of its stability,
the synthetic reagent cost, and easy preparation should
4-Ben zo[1,3]d ioxol-5-yl-5H-fu r a n -2-on e (2j): 61% yield as
a colorless oil; 1H NMR (500 MHz, DMSO-d6) δ (ppm) 5.29 (s,
(9) Kagabu, S.; Shimizu, Y.; Ito, C.; Moriya, K. Synthesis 1992, 830.
(10) Taniguchi, T.; Nagata, H.; Kanada, R. M.; Kadota, K.; Takeuchi,
M.; Ogasawara, K. Heterocycles 2000, 52, 67.
(11) MacMillan, J . H.; Washburne, S. S. J . Heterocycl. Chem. 1975,
12, 1215.
672 J . Org. Chem., Vol. 68, No. 2, 2003

2H), 6.11 (s, 2H), 6.59 (s, 1H), 7.04 (d, J ) 8.5 Hz, 1H), 7.20 (d,
J ) 8.0 Hz, 1H), 7.38 (d, J ) 1.5 Hz, 1H); 13C NMR (125.7 MHz)
δ (ppm) 71.7, 102.6, 107.7, 109.3, 111.4, 122.8, 124.5, 148.8,
150.8, 165.3, 174.6.
6.43 (s, 1H), 6.60 (s, 1H), 7.12 (d, J ) 7.0 Hz, 2H), 7.52 (d, J )
7.0 Hz, 2H), 7.63 (dd, J ) 7.0, 2.0 Hz, 2H), 7.84 (dd, J ) 7.0, 2.0
Hz, 2H); 13C NMR (125.7 MHz) δ (ppm) 56.2, 112.1, 114.1, 115.3,
122.6, 129.6, 131.2, 132.7, 132.8, 134.3, 148.5, 158.3, 161.9, 168.8;
MS [C18H13ClO3], m/z (M++1) calcd 313, found 313.
5-(4-Cyan o-ben zyliden e)-4-(4-m eth oxy-ph en yl)-5H-fu r an -
2-on e (5b): 1H NMR (500 MHz, DMSO-d6) δ (ppm) 3.84 (s, 3H),
6.52 (s, 1H), 6.69 (s, 1H), 7.12 (d, J ) 9.0 Hz, 2H), 7.64 (d, J )
9.0 Hz, 2H), 7.90 (d, J ) 8.5 Hz, 2H), 8.00 (d, J ) 8.0 Hz, 2H);
13C NMR (125.7 MHz) δ (ppm) 56.2, 111.3, 111.4, 115.1, 115.4,
119.4, 122.4, 131.2, 131.6, 133.3, 138.4, 150.1, 158.2, 162.1, 168.6;
MS [C19H13NO3], m/z (M++1) calcd 304, found 304.
4-Hex-1-en yl-5H-fu r a n -2-on e (2k ): 61% yield as a colorless
1
oil; H NMR (500 MHz, DMSO-d6) δ (ppm) 0.87 (t, J ) 7.5 Hz,
3H), 1.27-1.34 (m, 2H), 1.36-1.41 (m, 2H), 2.16-2.22 (m, 2H),
5.05 (s, 2H), 5.98 (s, 1H), 6.26-6.32 (m, 1H), 6.45 (d, J ) 16.0
Hz, 1H); 13C NMR (125.7 MHz) δ (ppm) 14.4, 22.3, 30.7, 32.9,
71.3, 113.5, 122.0, 142.8, 164.4, 174.5.
Gen er a l P r oced u r e for th e Syn th esis of (Z)-4-(4-Meth -
oxyph en yl)-5-[1-(4-su bstitu ted-ph en yl)m eth yli-den e]-2(5H)-
fu r a n on e 5. A solution of compound 2c (0.25 mmol) in dichlo-
romethane (3.0 mL) was sequentially treated with tert-butyl-
dimethylsilyl trifluoromethanesulfonate (1.2 equiv), diisopropyl-
ethylamine (3.0 equiv), and benzaldehyde (1.2 equiv), and the
resulting mixture was stirred for 2 h at room temperature under
argon. DBU (2.0 equiv) was then added, and the mixture was
stirred at room temperature. Following completion of the reac-
tion, the reaction mixture was filtered through a short pad of
silica gel and the filtrate was concentrated to a residue that was
purified by flash chromatography (silica gel, 6/1 (v/v) hexane/
ethyl acetate) to give the corresponding product 5.
Ack n ow led gm en t. We thank Professor David Ho
for his encouragement and invaluable advice during the
course of this research. Financial support from Vivo-
Quest, Inc., is gratefully acknowledged.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of the compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
5-(4-Ch lor o-ben zyliden e)-4-(4-m eth oxy-ph en yl)-5H-fu r an -
2-on e (5a ): 1H NMR (500 MHz, DMSO-d6) δ (ppm) 3.84 (s, 3H),
J O020640F
J . Org. Chem, Vol. 68, No. 2, 2003 673