Synthesis of natural fimbrolides

Article abstract of DOI:10.1055/s-2007-983755

Starting from citraconic anhydride, a three-step approach to fimbrolide congener is reported by taking the advantage of a regioselective Grignard reaction with an anhydride, followed by a dehydrative cyclization and double bromination-dehydrobromination s

Full text of DOI:10.1055/s-2007-983755

2198
PAPER
Synthesis of Natural Fimbrolides
Synthesisof
N
atur
i
a
l
Fimb
s
rolide
s
han P. Haval, Narshinha P. Argade*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411008, India
E-mail: np.argade@ncl.res.in
Received 7 March 2007; revised 12 May 2007
O
O
Me
O
OH
Abstract: Starting from citraconic anhydride, a three-step approach
to fimbrolide congener is reported by taking the advantage of a re-
gioselective Grignard reaction with an anhydride, followed by a de-
hydrative cyclization and double bromination–dehydrobromination
sequence. Starting from N-(4-tolyl)maleimide, an eight-step synthe-
sis of two natural fimbrolides is reported with good yields via the
synthesis of requisite butylmaleic anhydride, its regioselective
Grignard coupling reaction, and a bromination–dehydrobromina-
tion pathway.
Me
H
Me
Me
H
i
O
O
+
H
OH
Me
4a
O
O
3
4b
(for 4b)
ii
(for 4a)
ii
Key words: butylmaleic anhydride, regioselective Grignard cou-
pling, butenolides, bromination, fimbrolides
H
O
O
H
Me
H
Me
Br
Me
H
iii
O
O
O
Fimbrolides (1) have been isolated from the red marine
algae Delisea fimbriata; they are bromobutenolides with
interesting antifungal and antimicrobial properties.1
Pulchralides (2) appear to be the [2+2] cycloadducts of the
fimbrolides 1 and they have been isolated from antarctic
macroalgae2 (Figure 1). The natural fimbrolides 1 are lim-
ited in availability and to date four syntheses of 1 have
been described in the literature by oxidative cyclodehy-
dration of dibromo-2-butyllevulinic acid,3,4 treatment of a
suitable b-lithiocarboxylate with acetic anhydride as the
key step,5 and treatment of a g-monosubstituted allenic es-
ter with N-bromosuccinimide in water.6 In continuation of
our studies on the synthesis of structurally interesting and
biologically important natural and unnatural products us-
ing cyclic anhydrides as potential precursors,7 we herein
report the synthesis of fimbrolides starting from N-aryl-
maleimide 7 via butylmaleic anhydride (12) (Schemes 1
and 2).
H
Br
O
H
H
6
5b
5a
Scheme 1 Reagents and conditions: (i) MeMgI (1.10 equiv), Et2O,
–20 °C, 2 h (4a: 68%, 4b: 8%); (ii) P2O5, benzene, reflux, 5 h (5a:
88%, 5b: 85%); (iii) (a) Br2 (2.20 equiv), CCl4, 0 °C to r.t., 10 h, (b)
Et3N (2.20 equiv), CHCl3, 0 °C to r.t., 5 h (68%).
We decided to use butylmaleic anhydride (12) as precur-
sor for the synthesis of fimbrolides. To confirm the feasi-
bility of our proposal, we initially used the readily
available citraconic anhydride (3) for model studies
(Scheme 1). The regioselective nucleophilic addition of
methylmagnesium iodide to citraconic anhydride (3) at
–20 °C furnished a mixture of lactols 4a and 4b in
~88:12 ratio with 76% yield. Separation of 4a and 4b by
column chromatography (silica gel) followed by the phos-
phorus pentoxide induced dehydration gave the buteno-
lides 5a and 5b in 88% and 85% yields, respectively.
Reaction of compound 5a with 2.20 equivalents of bro-
R1
R1
R
Br
Br
Br
R2
O
O
O
O
O
O
R3
R2
Br
Br Br
fimbrolide (1a): R1 = R2 = H
pulchralide A (2a): R = R1 = OAc, R2 = R3 = H
pulchralide B (2b): R = R1 = R2 = R3 = H
pulchralide C (2c): R = OAc, R1 = R2 = R3 = H
fimbrolide (1b): R1 = H, R2 = Br
acetoxyfimbrolide (1c): R1 = OAc, R2 = H
hydroxyfimbrolide (1d): R1 = OH, R2 = H
Figure 1 Fimbrolides and pulchralides
SYNTHESIS 2007, No. 14, pp 2198–2202
x
x.
x
x
.
2
0
0
7
Advanced online publication: 03.07.2007
DOI: 10.1055/s-2007-983755; Art ID: Z05807SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Natural Fimbrolides
2199
Ar
N
H
O
H
O
O
n-Pr
H
H
ii
n-Pr
iii
i
ArHN
HO
n-Bu
O
Ar
N
Ar
N
H
O
O
O
O
8
9
7
10
iv
O
O
O
Me
O
OH
n-Bu
H
n-Bu
H
n-Bu
n-Bu
vi
v
HO
HO
O
O
+
H
H
OH
Me
O
O
O
13b
13a
11
12
(for 13a)
vii
vii (for 13b)
O
O
O
O
H
n-Bu
n-Bu
Br
n-Bu
Br
H
n-Bu
O
+
O
viii
H
O
H
H
Br
Br
H
Br
H
O
14b
14a
1b
1a
Ar = p-tolyl
Scheme 2 Reagents and conditions: (i) Ph3P (1.00 equiv), PrCHO (1.50 equiv), THF, reflux, 10 h (90%); (ii) aq 2 M LiOH, THF, 0 °C to r.t.,
5 h (93%); (iii) cyanuric chloride (1.10 equiv), Et3N (3.00 equiv), CH2Cl2, 0 °C to r.t., 8 h (85%); (iv) HCl–AcOH (1:1), reflux, 66 h (96%); (v)
Ac2O, 60 °C, 3 h (90%); (vi) MeMgI (1.10 equiv), Et2O, –20 °C, 2 h (13a: 62%, 13b: 9%); (vii) P2O5, benzene, reflux, 5 h (14a: 90%, 14b:
87%); (viii) (a) Br2 (2.20/3.30 equiv), CCl4, 0 °C to r.t., 10 h, (b) Et3N (2.20/3.30 equiv), CHCl3, 0 °C to r.t., 5 h (1a: 37/15%, 1b: 18/41%).
mine at 0 °C followed by the treatment with triethyl- are quite stable in organic solvents, but they have a pro-
amine, yielded exclusively the dibromobutenolide 6 in pensity to undergo polymerization during the course of
68% yield, by the addition of two molecules of bromine to isolation and also in the neat form. The structural assign-
two different C=C bonds followed by a double dehydro- ment of 14a and 14b was done on the basis of NMR spec-
bromination pathway.
tral data and as expected the b-hydrogen in 14a was more
deshielded (d = 7.03) than the a-hydrogen in 14b
(d = 5.99). At this stage, to obtain the fimbrolides, we sys-
tematically studied the bromination reactions of 14a at
0 °C with 2.20 and 3.30 equivalents of bromine in carbon
tetrachloride. In these reactions, we always ended up with
the formation of a mixture of the fimbrolides 1a and 1b
via the addition–elimination pathway together with a
quantity of gummy material. Using 2.20 equivalents of
bromine, 1a was formed as the major product, while 1b
was formed as the major product with the use of 3.30
equivalents of bromine. In these reactions, both the addi-
tion of bromine to the C=C bonds and the elimination of
hydrogen bromide were instantaneous, but to ensure com-
plete dehydrobromination, the use of triethylamine was
necessary. Herein, all our attempts to obtain exclusively
1a or 1b met with failure and forced conditions resulted in
the formation of a polymeric gum. Thus, the obtained
mixture of 1a, 1b, and polymeric gum was initially fil-
tered through a silica gel column to remove the impurities
and then the remaining mixture of 1a and 1b was separat-
We decided to prepare butylmaleic anhydride (12) using
our own method8 and obtained butylisomaleimide 10
from the maleimide 7 in three steps (Scheme 2). The acid-
catalyzed hydrolysis of the isomaleimide 10 followed by
acetic anhydride induced dehydrative cyclization of the
thus-formed butylmaleic acid 11 gave the anhydride 12 in
90% yield. The regioselective reaction of methylmagne-
sium iodide with anhydride 12 at –20 °C again produced
a mixture of lactols 13a and 13b in ~85:15 ratio with 71%
yield. Herein, as expected, the nucleophilic addition of the
Grignard reagent took place predominantly at the unhin-
dered carbonyl carbon, thus providing 13a as the major
product. It was difficult for us to lower the temperature in
order to achieve higher regioselectivity as below –20 °C
the anhydride 12 started separating out as a sticky solid.
Separation of 13a and 13b by column chromatography
(silica gel) followed by phosphorus pentoxide induced de-
hydration gave the expected butenolides 14a and 14b in
90% and 87% yield, respectively. During the isolation of
14a and 14b, we noticed that the butenolides 14a and 14b
Synthesis 2007, No. 14, 2198–2202 © Thieme Stuttgart · New York

2200
K. P. Haval, N. P. Argade
PAPER
ed by HPLC using the known procedure.1c The analytical
and spectral data obtained for 1a and 1b were in complete
agreement with the reported data.3–6 Starting from male-
imide 7, the fimbrolides 1a and 1b were obtained in eight
steps with 13% and 14% overall yield, respectively. A re-
ported attempt to convert fimbrolide into pulchralide pho-
tochemically was unsuccessful, thus supporting their
biotic genesis.2
3-Methyl-5-methylenefuran-2(5H)-one (5a); Typical Procedure
A suspension of 4a (700 mg, 5.47 mmol) and P2O5 (2.33 g, 16.41
mmol) in benzene (20 mL) was refluxed for 5 h. The mixture was
filtered through Celite and the residue was washed with benzene
(2 × 20 mL). The organic layer was concentrated in vacuo and the
obtained crude product was purified by column chromatography
(silica gel, PE–EtOAc, 9:1) to give 5a (530 mg, 88%) as a yellowish
thick oil.
IR (CHCl3): 1771, 1653 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.03 (d, J = 2 Hz, 3 H), 4.77 (d,
J = 4 Hz, 1 H), 5.11 (t, J = 2 Hz, 1 H), 7.06 (d, J = 2 Hz, 1 H).
In summary, we have demonstrated a facile synthesis of
two natural fimbrolides, starting from butylmaleic anhy-
dride, taking the advantage of a regioselective Grignard
coupling reaction and an instantaneous bromination–de-
hydrobromination process. We feel that our present ap-
proach is general in nature and will be useful for the
synthesis of several other suitably substituted butyrolac-
tone congeners for structure–activity relationship studies.
Anal. Calcd for C6H6O2: C, 65.45; H, 5.49. Found: C, 65.32; H,
5.55.
4-Methyl-5-methylenefuran-2(5H)-one (5b)
Obtained using the typical procedure for 5a as a yellowish thick oil;
yield: 85%.
IR (CHCl3): 1767, 1655 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.18 (d, J = 2 Hz, 3 H), 4.91 (dd,
J = 4, 1 Hz, 1 H), 5.15 (dd, J = 4, 2 Hz, 1 H), 6.00 (sextet, J = 2 Hz,
1 H).
Commercially available citraconic anhydride, p-toluidine, P2O5, bu-
tyraldehyde, Ac2O, MeI, Br2, and Ph3P were used. Freshly recrys-
tallized cyanuric chloride (from CCl4) was used. The petroleum
ether (PE) used had boiling range 60–80 °C. Melting points are un-
corrected. Column chromatographic separations were carried out on
silica gel (60–120 mesh). FT-IR spectra were recorded on a FT-IR-
Anal. Calcd for C6H6O2: C, 65.45; H, 5.49. Found: C, 65.51; H,
5.53.
1
(Z)-4-Bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one
(6); Typical Procedure
8300 Shimadzu spectrometer. H NMR spectra were recorded in
CDCl3 using TMS as internal standard and in DMSO-d6 on a Bruker
AC 200 NMR spectrometer (200 MHz). 13C NMR spectra were re-
corded on Bruker AC 200, Bruker AC 400, and Bruker DRX 500
NMR spectrometers (50 MHz, 100 MHz, and 125 MHZ respective-
ly).
A soln of Br2 (0.21 mL, 3.99 mmol) in CCl4 (5 mL) was added to
the soln of 5a (200 mg, 1.82 mmol) in CCl4 (10 mL) at 0 °C. The
mixture was stirred at r.t. for 10 h and then the solvent was removed
in vacuo. The obtained residue was dissolved in CHCl3 and Et3N
(0.56 mL, 3.99 mmol) was added at 0 °C. The mixture was further
stirred at r.t. for 5 h. The solvent was removed in vacuo and the ob-
tained crude product was purified by column chromatography (sili-
ca gel, PE–EtOAc) to give pure 6 (330 mg, 68%) as a colorless
solid; mp 69–70 °C (PE–EtOAc).
IR (CHCl3): 1786, 1638, 1609 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.16 (s, 3 H), 6.22 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 11.6, 90.6, 112.2, 149.5, 152.0,
163.5.
5-Hydroxy-3,5-dimethylfuran-2(5H)-one (4a) and 5-Hydroxy-
4,5-dimethylfuran-2(5H)-one (4b); Typical Procedure
A fresh soln of MeMgI in Et2O was prepared as follows: A soln of
MeI (1.40 g, 9.82 mmol) in anhyd Et2O (30 mL) was added at 0 °C
to Mg turnings (1.18 g, 49.10 mmol) in anhyd Et2O (10 mL) under
argon with constant stirring in 3 equal portions with 10-min inter-
vals. The mixture was further stirred at 0 °C for 30 min. This freshly
generated Grignard reagent was added in a dropwise fashion to a
soln of citraconic anhydride (3, 1.00 g, 8.92 mmol) in anhyd Et2O
(15 mL) under argon atmosphere at –20 °C, and the mixture was
further stirred at the same temperature for 2 h. The reaction was
quenched by the addition of sat. aq NH4Cl (20 mL) and EtOAc (50
mL) was added to the mixture. The separated organic layer was
washed with brine, dried (Na2SO4), and concentrated in vacuo. The
obtained residue was purified by column chromatography (silica
gel, PE–EtOAc, 9:1) to give 4a (780 mg, 68%) and 4b (90 mg, 8%).
Anal. Calcd for C6H4Br2O2: C, 26.90; H, 1.50; Br, 59.65. Found: C,
27.10; H, 1.44; Br, 59.67.
3-Butylidene-1-(4-tolyl)pyrrolidine-2,5-dione (8)
A soln of N-(4-tolyl)maleimide (7, 2.00 g, 10.70 mmol) and Ph3P
(2.80 g, 10.70 mmol) in THF (50 mL) was stirred at r.t. for 30 min.
To the mixture was added butyraldehyde (1.16 g, 16.04 mmol) and
it was gently refluxed for 10 h. The THF was removed in vacuo at
50 °C and the residue was purified by column chromatography (sil-
ica gel, PE–EtOAc, 9:1) to give 8 (2.34 g, 90%); as a colorless solid;
mp 90–92 °C (PE–EtOAc).
4a
Colorless solid; mp 98–99 °C (PE–EtOAc).
IR (CHCl3): 3385, 1767, 1751, 1709 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.63 (s, 3 H), 1.85 (d, J = 2 Hz, 3
H), 5.01 (br s, 1 H), 6.84 (q, J = 2 Hz, 1 H).
IR (Nujol): 1773, 1709, 1676 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.99 (t, J = 8 Hz, 3 H), 1.58 (sex-
tet, J = 8 Hz, 2 H), 2.23 (q, J = 8 Hz, 2 H), 2.39 (s, 3 H), 3.39 (s, 2
H), 6.95 (t, J = 8 Hz, 1 H), 7.20 (d, J = 8 Hz, 2 H), 7.29 (d, J = 8 Hz,
2 H).
Anal. Calcd for C6H8O3: C, 56.25; H, 6.29. Found: C, 56.31; H,
6.13.
4b
MS: m/z = 243, 228, 214, 133, 95, 67, 53.
Yellowish thick oil.
Anal. Calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76. Found: C,
73.92; H, 7.15; N, 5.69.
IR (neat): 3354, 1744, 1670, 1647 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.64 (s, 3 H), 2.09 (d, J = 2 Hz, 3
H), 4.96 (br s, 1 H), 5.74 (q, J = 2 Hz, 1 H).
3-(4-Tolylcarbamoyl)hept-3-enoic Acid (9)
To a soln of 8 (2.00 g, 8.23 mmol) in THF (25 mL) was added aq 2
M LiOH (4 mL) in a dropwise fashion at 0 °C and the mixture was
Anal. Calcd for C6H8O3: C, 56.25; H, 6.29. Found: C, 56.09; H,
6.22.
Synthesis 2007, No. 14, 2198–2202 © Thieme Stuttgart · New York

PAPER
Synthesis of Natural Fimbrolides
2201
stirred at r.t. for 5 h. THF was removed in vacuo and the aqueous
layer was acidified with aq 2 M HCl till pH 4 and extracted with
EtOAc (3 × 50 mL). The combined organic layers were washed
with H2O and brine and dried (Na2SO4). Concentration of the organ-
ic layer in vacuo gave 9 (1.99 g, 93%) as a colorless solid; mp 140–
142 °C (PE–EtOAc).
1H NMR (200 MHz, CDCl3): d = 0.96 (t, J = 8 Hz, 3 H), 1.42 (sex-
tet, J = 8 Hz, 2 H), 1.64 (quintet, J = 8 Hz, 2 H), 2.54 (dt, J = 8, 2
Hz, 2 H), 6.60 (t, J = 2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.6, 22.2, 25.6, 28.9, 128.4,
153.8, 164.0, 165.9.
Anal. Calcd for C8H10O3: C, 62.33; H, 6.54. Found: C, 62.40; H,
6.47.
IR (Nujol): 3283, 1682, 1657, 1597 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 6 Hz, 3 H), 1.50 (sex-
tet, J = 8 Hz, 2 H), 2.31 (s, 3 H), 2.15–2.40 (m, 2 H), 3.39 (s, 2 H),
6.46 (t, J = 6 Hz, 1 H), 7.13 (d, J = 8 Hz, 2 H), 7.40 (d, J = 8 Hz, 2
H), 8.07 (br s, 1 H).
3-Butyl-5-hydroxy-5-methylfuran-2(5H)-one (13a) and
4-Butyl-5-hydroxy-5-methylfuran-2(5H)-one (13b)
Obtained by using the typical procedure for 4a and 4b in 62% and
9% yield, respectively.
Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C,
68.89; H, 7.40; N, 5.28.
13a
Yellowish thick oil.
IR (CHCl3): 3462, 1755, 1609 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 8 Hz, 3 H), 1.28–1.60
(m, 4 H), 1.70 (s, 3 H), 2.28 (dt, J = 8, 2 Hz, 2 H), 3.26 (br s, 1 H),
6.82 (t, J = 2 Hz, 1 H).
4-Butyl-5-(4-tolylimino)furan-2(5H)-one (10)
To a slurry of 9 (1.50 g, 5.75 mmol) in CH2Cl2 (25 mL) was added
Et3N (2.40 mL, 17.24 mmol) in a dropwise fashion with constant
stirring at 0 °C. To the resulting mixture was added a soln of cyanu-
ric chloride (1.16 g, 6.22 mmol) in CH2Cl2 (25 mL) and the mixture
was further stirred under an argon atmosphere at r.t. for 8 h. The
mixture was concentrated in vacuo and the residue was dissolved in
EtOAc (50 mL). The organic layer was washed with H2O, 5% aq
NaHCO3, brine, and dried (Na2SO4). The EtOAc layer was concen-
trated in vacuo and the crude product was purified by column chro-
matography (silica gel, PE–EtOAc, 9:1) to give pure 10 (1.19 g,
85%) as a yellowish thick oil.
13C NMR (100 MHz, CDCl3): d = 13.7, 22.3, 24.6, 24.9, 29.3, 104.1,
136.4, 146.5, 171.2.
Anal. Calcd for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.61; H,
8.32.
13b
IR (neat): 1798, 1682, 1622 cm–1.
Yellowish thick oil.
IR (CHCl3): 3381, 1744, 1670 cm –1
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 8 Hz, 3 H), 1.30–1.50
(m, 2 H), 1.50–1.70 (m, 2 H), 1.63 (s, 3 H), 2.20–2.45 (m, 2 H), 5.71
(t, J = 2 Hz, 1 H).
1H NMR (200 MHz, CDCl3): d = 0.99 (t, J = 8 Hz, 3 H), 1.46 (sex-
tet, J = 8 Hz, 2 H), 1.70 (quintet, J = 8 Hz, 2 H), 2.37 (s, 3 H), 2.67
(dt, J = 8, 2 Hz, 2 H), 6.31 (t, J = 2 Hz, 1 H), 7.19 (d, J = 8 Hz, 2 H),
7.35 (d, J = 8 Hz, 2 H).
.
13C NMR (125 MHz, CDCl3): d = 13.6, 20.9, 22.2, 25.8, 29.3, 120.9,
125.2, 129.3, 137.0, 140.9, 150.0, 159.6, 167.0.
Anal. Calcd for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.56; H,
8.07.
Anal. Calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76. Found: C,
73.88; H, 7.15; N, 5.67.
3-Butyl-5-methylenefuran-2(5H)-one (14a)
Obtained using the typical procedure for 5a in 90% yield as a yel-
lowish thick oil.
IR (CHCl3): 1773, 1655 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 8 Hz, 3 H), 1.37 (sex-
tet, J = 8 Hz, 2 H), 1.50–1.66 (m, 2 H), 2.38 (t, J = 8 Hz, 2 H), 4.77
(d, J = 2 Hz, 1 H), 5.11 (d, J = 2 Hz, 1 H), 7.03 (t, J = 2 Hz, 1 H).
2-Butylmaleic Acid (11)
A soln of 10 (1.00 g, 4.12 mmol) in glacial AcOH–concd HCl (1:1,
20 mL) was refluxed for 66 h. The mixture was allowed to reach r.t.,
concentrated in vacuo, and the thus obtained residue was dissolved
in 5% aq NaHCO3 (40 mL). The aqueous layer was washed with
EtOAc (2 × 50 mL). The aqueous layer was acidified with aq 2 M
HCl till pH 4 and then extracted with EtOAc (3 × 50 mL). The com-
bined organic layers were washed with H2O and brine and dried
(Na2SO4). Concentration of the organic layer in vacuo gave 11 (680
mg, 96%) as a colorless solid; mp 163–164 °C (PE–EtOAc).
Anal. Calcd for C9H12O2: C, 71.03; H, 7.94. Found: C, 70.92; H,
7.89.
4-Butyl-5-methylenefuran-2(5H)-one (14b)
Obtained using the typical procedure for 5a in 87% yield as a yel-
lowish thick oil.
IR (CHCl3): 1773, 1657 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.96 (t, J = 8 Hz, 3 H), 1.42 (sex-
tet, J = 8 Hz, 2 H), 1.63 (quintet, J = 8 Hz, 2 H), 2.49 (dt, J = 8, 2
Hz, 2 H), 4.93 (dd, J = 3, 2 Hz, 1 H), 5.16 (dd, J = 2, 2 Hz, 1 H),
5.99 (t, J = 2 Hz, 1 H).
IR (Nujol): 2700–2500, 1690, 1647 cm–1.
1H NMR (200 MHz, CDCl3/DMSO-d6): d = 0.94 (t, J = 8 Hz, 3 H),
1.48 (sextet, J = 8 Hz, 2 H), 2.17 (q, J = 8 Hz, 2 H), 2.56–2.63 (m,
2 H), 6.90 (t, J = 8 Hz, 1 H).
13C NMR (125 MHz, CDCl3/DMSO-d6): d = 12.6, 20.5, 29.5, 31.0,
125.5, 143.4, 167.5, 171.4.
Anal. Calcd for C8H12O4: C, 55.81; H, 7.02. Found: C, 55.74; H,
7.13.
Anal. Calcd for C9H12O2: C, 71.03; H, 7.94. Found: C, 70.91; H,
7.88.
3-Butylfuran-2,5-dione (12)
(Z)-4-Bromo-5-(bromomethylene)-3-butylfuran-2(5H)-one (1a)
and 4-Bromo-3-butyl-5-(dibromomethylene)furan-2(5H)-one
(1b)
Obtained using the typical procedure for 6, the bromination of 14a
(70 mg, 0.46 mmol) with Br2 (162 mg, 1.01 mmol). Purification was
by filtration through a column of silica gel and this was followed by
HPLC separation1c to give 1a (53 mg, 37%) and 1b (32 mg, 18%).
Similarly, the use of 3.30 equivalents of bromine furnished 1a (21
A soln of 11 (600 mg, 3.49 mmol) in Ac2O (15 mL) was heated at
60 °C for 3 h. The mixture was concentrated under vacuum to give
a crude residue that on careful column chromatography (silica gel,
PE–EtOAc, 9:1) gave pure 12 (480 mg, 90%) as a yellowish thick
oil.
IR (CHCl3): 1844, 1773, 1638 cm–1.
Synthesis 2007, No. 14, 2198–2202 © Thieme Stuttgart · New York

2202
K. P. Haval, N. P. Argade
PAPER
mg, 15%) and 1b (73 mg, 41%). The analytical and spectral data ob-
tained for 1a and 1b were in complete agreement with the reported
data.3–6
References
(1) (a) Kazlauskas, R.; Murphy, P. T.; Quinn, R. J.; Wells, R. J.
Tetrahedron Lett. 1977, 18, 37. (b) McCombs, J. D.; Blunt,
J. W.; Chambers, M. V.; Munro, M. H. G.; Robinson, W. T.
Tetrahedron 1988, 44, 1489. (c) Nys, R. D.; Coll, J. C.;
Bowden, B. F. Aust. J. Chem. 1992, 45, 1625. (d) Wright,
A. D.; Nys, R. D.; Angerhofer, C. K.; Pezzuto, J. M.;
Gurrath, M. J. Nat. Prod. 2006, 69, 1180.
(2) Ankisetty, S.; Nandiraju, S.; Win, H.; Park, Y. C.; Amsler,
C. D.; McClintock, J. B.; Baker, J. A.; Diyabalanage, T. K.;
Pasaribu, A.; Singh, M. P.; Maiese, W. M.; Walsh, R. D.;
Zaworotko, M. J.; Baker, B. J. J. Nat. Prod. 2004, 67, 1295.
(3) Beechan, C. M.; Sims, J. J. Tetrahedron Lett. 1979, 20,
1649.
1a
Pale yellow oil.
IR (neat): 1790, 1621 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.92 (t, J = 7 Hz, 3 H), 1.26–1.42
(m, 2 H), 1.49–1.65 (m, 2 H), 2.39 (t, J = 7 Hz, 2 H), 6.25 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 13.5, 22.4, 29.2, 25.1, 91.0, 149.9,
130.1, 133.9, 166.2.
Anal. Calcd for C9H10Br2O2: C, 34.87; H, 3.25; Br, 51.55. Found:
C, 34.72; H, 3.19; Br, 51.42.
(4) Manny, A. J.; Kjelleberg, S.; Kumar, N.; Nys, R. D.; Read,
R. W.; Steinberg, P. Tetrahedron 1997, 53, 15813.
(5) Caine, D.; Ukachukwu, V. C. J. Org. Chem. 1985, 50, 2195.
(6) March, P. D.; Font, J.; Gracia, A.; Qingying, Z. J. Org.
Chem. 1995, 60, 1814.
(7) (a) Baag, M. M.; Sahoo, M. K.; Puranik, V. G.; Argade, N.
P. Synthesis 2007, 457. (b) Baag, M. M.; Puranik, V. G.;
Argade, N. P. J. Org. Chem. 2007, 72, 1009. (c) Mondal,
M.; Puranik, V. G.; Argade, N. P. J. Org. Chem. 2007, 72,
2068; and references cited in these references 7a–c.
(8) (a) Haval, K. P.; Mhaske, S. B.; Argade, N. P. Tetrahedron
2006, 62, 937. (b) Haval, K. P.; Argade, N. P. Tetrahedron
2006, 62, 3557.
1b
Pale yellow oil.
IR (neat): 1780, 1622 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.93 (t, J = 7 Hz, 3 H), 1.29–1.45
(m, 2 H), 1.50–1.64 (m, 2 H), 2.40 (t, J = 7 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 13.6, 22.2, 25.9, 28.8, 81.5, 128.3,
138.1, 144.7, 164.9.
Anal. Calcd for C9H9Br3O2: C, 27.80; H, 2.33; Br, 61.64. Found: C,
27.73; H, 2.41; Br, 61.50.
Acknowledgment
K.P.H. thanks CSIR, New Delhi, for the award of a research fel-
lowship.
Synthesis 2007, No. 14, 2198–2202 © Thieme Stuttgart · New York