Synthesis and reactivity of β,γ-dihalogenated unsaturated acids: Application to the synthesis of 4-substituted 5 H -furan-2-ones

Article abstract of DOI:10.1055/s-0030-1258324

β,γ-Dihalogenated unsaturated acids were prepared regio- and stereoselectively from allenic acid, and some aspects of their reactivities were studied. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258324

154
PAPER
Synthesis and Reactivity of b,g-Dihalogenated Unsaturated Acids: Application
to the Synthesis of 4-Substituted 5H-Furan-2-ones
Synthesis of
4.
L
5
H
-Furan-2-on
a
es mandé-Langle,a S. Inack Ngi,b E. Anselmi,b H. Allouchi,b A. Duchêne,b M. Abarbri,b J. Thibonnet*b
a
Laboratoire Groupe SUCRES, Unité Mixte 7565 CNRS, Université Henri Poincaré-Nancy 1, B.P. 239, 54506 Nancy-Vandoeuvre,
France
b
Laboratoire de Physicochimie des Matériaux et des Biomolécules, EA 4244, Faculté des Sciences et Techniques de Tours,
Parc de Grandmont, 37200 Tours, France
Fax +33(2)47367073; E-mail: jerome.thibonnet@univ-tours.fr
Received 14 September 2010; revised 1 October 2010
gioselectivity and increases the formation of by-products.
On the other hand, a low temperature (<0 °C) inhibits the
reaction. The optimal conditions were determined for 6
mmol of buta-2,3-dienoic acid diluted in Et2O (40 mL)
with 1.5 equivalents of XY (0.15 M, Et2O) at 4 °C for a
time period of 24 to 45 hours (Table 1).
Abstract: b,g-Dihalogenated unsaturated acids were prepared
regio- and stereoselectively from allenic acid, and some aspects of
their reactivities were studied.
Key words: a,b-unsaturated acids, halogenation, carboxylic acids,
cross-coupling, organometallic reagents
As expected with the use of aprotic solvents,4a the forma-
tion of by-product resulting from the addition of HX was
not noticed. The use of a small amount of acetic acid4a in-
creases the rate of the reactions even if the time of reac-
tions were important (15 to 48 h).
Dihalogenated systems are very useful building blocks in
organic chemistry. These compounds allow the develop-
ment of plurifunctional systems, if the reactivity of both
halogens is selectively controlled. Among these mole-
cules, those bearing an ester or acidic function are partic-
ularly interesting,1 but their synthesis constitutes a great
challenge. Our efforts were focused on the synthesis of
b,g-dihalogenated unsaturated acids. We have already
shown the usefulness of these moieties in the synthesis of
pyrroles.2 Only a few publications deal with the synthesis
of this kind of molecules3 while the greater part of the re-
ports concerns with the synthesis of the ester derivatives.4
In the case of dissymmetric dihalogens, the most elec-
tronegative halogen binds to the b-carbon while the other
one is localized on the g position. These results match
with those already published on the synthesis of the ester
homologue.4a The formation of g-butenolides 3 and 4 up
to 5% yield was also detected.
The E-stereoisomer is mainly obtained in all cases. The
structure of our products was confirmed by NOE-DIFF
and X-ray diffraction experiments. Data resulting from X-
ray diffraction experiments performed on compounds 2a
(Figure 1), 2b (Figure 2), 2c (Figure 3), and 2d (Figure 4)
are given. Details of the crystal structure analysis are list-
ed in Table 2.
The b,g-dihalogenated acids 2a–d were obtained by add-
ing symmetric (I2, Br2) and dissymmetric dihalogens (ICl,
IBr) directly to buta-2,3-dienoic acid, which can be pre-
pared via the method reported by Gaudemar5 (Scheme 1).
Several variables in our experimental conditions were
tested (temperature, solvent, concentration). Aprotic sol-
vents (MeCN, CH2Cl2, Et2O) were used to avoid HX ad-
dition on our substrate.4a Among them, Et2O led to the
best yields and selectivity. The reaction needs to be con-
ducted in dilute solution (0.15 M), protected from light to
avoid the formation of by-products.
These results obtained in term of selectivity can be ex-
plained by an internal control in transition state4a
(Scheme 2). The halonium bridge is formed on the same
side as the carboxylic function. This is favorized by the
stabilization of this bridge by the carbonyl function. The
subsequent attack by Y– ion is then directed preferentially
on the opposed side of the iodonium bridge on the most
electrophilic b-carbon.
The control of the temperature in the reaction is very im-
portant. A high temperature causes the lowering of the re-
I
X
X
X–Y, solvent
+
+
•
CO2H
CO2H
temp, time
O
O
Y
O
O
1
2a–d
main product
3
4
< 6%
Scheme 1 Synthesis of 3,4-dihalobut-2-enoic acids
SYNTHESIS 2011, No. 1, pp 0154–0160
x
x
.
x
x
.2
0
1
0
Advanced online publication: 15.11.2010
DOI: 10.1055/s-0030-1258324; Art ID: Z23110SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 4-Substituted 5H-Furan-2-ones
155
Table 1 Addition of X–Y to Buta-2,3-dienoic Acid
Entry
1
X–Y
Time (h)/Temp (°C) Product
Ratio 2/3/4
Ratio (E)-2/(Z)-2 Yield (%)
Br
Br–Br
48/4
15/4
48/4
2a
2b
2c
100:0:0
65/35
85/15
83/17
80
75
70
CO2H
Br
I
2
3
I–I
100:0:0
94:2:4
CO2H
I
I
I–Cl
CO2H
CO2H
Cl
I
4
I–Br
48/4
2d
90:5:5
60/40
62
Br
Figure 1 ORTEP drawing and labeling scheme for 2a (ellipsoids
are set at 50% probability). Bond lengths [Å]: C4–C3, 1.484(6); C4–
Br1, 1.953(4); C3–C2, 1.320(5); C3–Br2, 1.907(4); C2–C1 1.471(5);
C1–O1, 1.214(5); C1–O2, 1.318(5); angles [°]: C3–C1–Br1,
110.9(3); C2–C3–C4, 128.4(3); C2–C3–Br2, 117.1(3); C4–C3–Br2,
114.5(3); C3–C2–C1, 124.0(4); O1–C1–O2, 122.8(3); O1–C1–C2,
124.5(3); O2–C1–C2, 112.7(3).
Figure 3 ORTEP drawing and labeling scheme for 2c (ellipsoids
are set at 50% probability). Bond lengths [Å]: C4–C3, 1.484(4); C4–
I2, 1.992(6); C4–I1, 2.193(3); C3–C2, 1.329(3); C3–Cl2, 1.742(2);
C2–C1, 1.465(3); C1–O1, 1.217(3); C1–O2, 1.320(3); angles [°]: C3–
C4–I2, 109.5(2); C3–C4–I1, 111.12(16); C2–C3–C4, 127.9(2); C2–
C3–Cl2, 117.94(19); C4–C3–Cl2, 114.17(18); C3–C2–C1, 125.0(2);
O1–C1–O2, 122.8(2); O1–C1–C2, 125.5(2); O2–C1–C2, 111.7(2).
Figure 2 ORTEP drawing and labeling scheme for 2b (ellipsoids
are set at 50% probability). Bond lengths [Å]: C1–O2, 1.230(10); C1–
O1, 1.300(10); C1–C2, 1.474(11); C2–C3, 1.304(10); 0.93; C3–C4,
1.508(10); C3–I1, 2.108(7); C4–I2, 2.155(8); angles [°]: O2–C1–O1,
123.0(8); O2–C1–C2, 124.4(8); O1–C1–C2, 112.6(7); C3–C2–C1,
124.8(7); C3–C2–H2, 117.6; C1–C2–H2, 117.6; C2–C3–C4,
128.2(7); C2–C3–I1, 117.2(5); C4–C3–I1, 114.6(6); C3–C4–I2,
110.4(5).
Figure 4 ORTEP drawing and labeling scheme for 2d (ellipsoids
are set at 50% probability). Bond lengths [Å]: I1–C4, 2.137(6); Br1–
C3, 1.893(6); O2–C1, 1.306(7); O1–C1, 1.234(7); C1–C2, 1.458(9);
C3–C2, 1.335(8); C3–C4, 1.468(8); angles [°]: O1–C1–O2, 122.3(6);
O1–C1–C2, 124.5(6); O2–C1–C2, 113.2(5); C2–C3–C4, 128.1(5);
C2–C3–Br1, 117.1(4); C4–C3–Br1, 114.8(4); C3–C2–C1, 124.8(5);
C3–C4–I1, 110.8(4).
Synthesis 2011, No. 1, 154–160 © Thieme Stuttgart · New York

156
S. Lamandé-Langle et al.
PAPER
Table 2 Crystal and Structure Refinement Parameters of 2a, 2b, 2c, and 2d
Parameter
formula
formula weight
temperature
crystal system
space group
a (Å)
2a
2b
2c
2d
C4H4Br2O2
243.89
293(2)
monoclinic
P21/n
C4H4I2O2
675.74
C4H4ClIO2
246.42
293(2)
monoclinic
P21/c
C4H4BrIO2
581.76
293(2)
monoclinic
C2/c
293(2)
monoclinic
C2/c
5.1993(1)
10.4791(3)
12.1849(4)
90
24.586(5)
7.410(5)
8.606(5)
90.000(5)
101.504(5)
90.000(5)
1536.4(14)
8
4.8806(1)
8.8071(2)
16.0278(4)
90
24.756(2)
7.2482(7)
8.2277(8)
90
b (Å)
c (Å)
a (°)
b (°)
91.678(1)
90
96.833(2)
90
101.389(3)
90
g (°)
V (Å3)
663.60(3)
4
684.04(3)
4
1447.3(2)
4
Z
r
calc. (g/cm3)
2.441
2.921
2.393
2.67
m (mm–1)
F(000)
12.124
456
8.109
4.983
9.863
1200
456
1056
q range (°)
index ranges
3.35–28.67
2.88–28.16
2.64–28.66
2.93–28.63
0 ≤ h ≤ 6,
0 ≤ k ≤ 14,
16 ≤ l ≤ 16
–32 ≤ h ≤ 27,
–9 ≤ k ≤ 7,
–11 ≤ l ≤ 9
–6 ≤ h ≤ 6,
–10 ≤ k ≤ 11,
–21 ≤ l ≤ 20
–33 ≤ h ≤ 27,
–8 ≤ k ≤ 9,
11 ≤ l ≤ 9
reflections collected
independent reflections
data/restraints/parameters
goodness-of-fit on F2
Rint
5880
7729
6682
5557
1646
1801
1669
1810
1646/0/74
1.154
1801/0/74
1.018
1669/0/83
1.042
1810/0/74
1.08
–
0.0677
0.0385
0.0524
final R indices [I > 2s(I)]
R indices (all data)
R1 = 0.0372
wR2 = 0.0856
R1 = 0.0491
wR2 = 0.1209
R1 = 0.0267
wR2 = 0.0614
R1 = 0.0449
wR2 = 0.1072
Y
Y
OH
CO2H
OH
O
OH
•
+
X
•
•
δ
O
X
X
O
X
Y
δ
Y
Scheme 2 Plausible mechanism for the formation of 3,4-dihalobut-2-enoic acids
Reactivity of (E)-3,4-Diiodobut-2-enoic Acid
in a variety of natural products,7 which are medically im-
portant compounds.8 Several of these compounds are drug
The lactonization of (E)-3,4-diiodobut-2-enoic acid (2b) active principles, for example Rofecoxib (Vioxx®)9 or
was investigated (Scheme 3). It yields 4-iodo-5H-furan-2- Benfurodil hemisuccinate (Eucilat®).10
one (3),6 which is one of the principal by-products report-
As expected, a basic medium or a catalytic amount of pal-
ed earlier in the synthesis of 3,4-dihalobut-2-enoic acids
ladium is sufficient to induce the cyclization, even if the
2a–d (cf. Scheme 1). 5H-Furan-2-one moiety is prevalent
use of an excess of n-BuNH2 had a detrimental effect to
Synthesis 2011, No. 1, 154–160 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Substituted 5H-Furan-2-ones
157
basic
conditions
Table 3 Synthesis of 4-Iodo-5H-furan-2-one (3)
O
I
O
Entry Conditions
Yield
10
CO2H
I
I
2b
3
1
2
3
4
5
6
DMF, 24 h, 40 °C
Scheme 3 Synthesis of 4-iodo-5H-furan-2-one
n-BuNH2 (1 equiv), DMF, 5 h, 50 °C
n-BuNH2 (2 equiv), DMF, 5 h, 50 °C
K2CO3 (1 equiv), DMF, 5 h, 50 °C
PdCl2(PPh3)2 (5 mol%), DMF, 24 h, 60 °C
66
38
the reaction. Actually, a mixture of unknown by-products
was obtained mainly. The best conditions are given in
Table 3 (entries 5–7). These conditions are very interest-
ing, since they are conditions of Stille and Suzuki cross-
coupling, respectively. The most interesting conditions
are described in entry 7. These palladium-free conditions
led to the best yield of 4-iodo-5H-furan-2-one (3).
37
69
Pd(PPh3)4, toluene–H2O–EtOH, Na2CO3 (1 M),
2 h, 40 °C
68
7
toluene–H2O–EtOH, Na2CO3 (1 M), 2 h, 40 °C
75
Considering the above results, the one-pot reaction of or-
ganotin and organoboronic acid derivatives with 3,4-dih-
alobut-2-enoic acids was investigated. Our plan was to
achieve in one operation the cyclization and the cross-
coupling on the vinylic iodide, in order to obtain 4-substi-
tuted 5H-furan-2-ones of type 5 (Scheme 4).11 Thus, the
reactions were carried out and a new possibility was found
to acquire 4-substituted 5H-furan-2-ones in a one-pot re-
action in average yields. The results given in Table 4
show that we were able to perform the cyclization and the
subsequent Stille and Suzuki cross-couplings.
RM
O
I
I
O
"Pd"
CO2H
R
2b
5
O
O
I
Scheme 4 Synthesis of 4-substituted-5H-furan-2-ones
Table 4 Synthesis of 4-Substituted 5H-Furan-2-ones
Entry
1
Organometallic
Methoda
Product
Yield (%)
54
Reference
6b
A
5a
–
–
SnBu3
O
O
Me3Si
6b
2
3
Me3Si
A
A
5b
5c
52
SnBu3
O
O
4
SnBu3
52
–
4
O
O
Ph
11n
11p
11n
4
5
6
PhB(OH)2
B
B
B
5d
5e
5f
68
–
–
–
O
O
4-MeC6H4
4-MeC6H4B(OH)2
4-MeOC6H4B(OH)2
60
O
O
4-MeOC6H4
59
O
O
t-Bu
7
t-Bu
B
5g
62
–
B(OH)2
O
O
a Condtions A: 2b, PdCl2(PPh3)2 (0.03 equiv), RSnBu3 (1.3 equiv), DMF, 80 °C. Condtions B: 2b, RB(OH)2 (1.3 equiv), Pd(PPh3)4 (0.03 equiv),
Na2CO3, EtOH, toluene, 80 °C.
Synthesis 2011, No. 1, 154–160 © Thieme Stuttgart · New York

158
S. Lamandé-Langle et al.
PAPER
IR (KBr): 3065, 1702, 1617 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.85 (s, 2 H), 6.46 (s, 1 H), 8.70
In summary, we have developed a new way to produce
b,g-dihalogenated unsaturated acids by direct halogena-
tion of buta-2,3-dienoic acid. The dihalogenated acids ob- (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 31.4, 124.8, 144.5, 168.1.
MS (EI): m/z (%) = 244 [M+].
tained are useful building blocks to prepare the 5H-furan-
2-one moiety. The use of Stille, Suzuki, or palladium-free
Suzuki like conditions on the acids allowed us to synthe-
size 4-iodo-5H-furan-2-one and 4-substituted 5H-furan-
2-ones in average yields.
Z-Isomer
1H NMR (200 MHz, CDCl3): d = 4.32 (s, 2 H), 6.76 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 36.9, 122.0, 136.8, 168.4.
All reactions were carried out under argon atmosphere in dried
glassware. THF and Et2O were dried and freshly distilled from so-
dium/benzophenone. Flash chromatography was carried out with
Merck silica gel (silica gel, 230–400 mesh). 1H NMR spectra were
recorded on a Bruker AC 200 (200 MHz) NMR spectrometer, using
CDCl3 as solvent. Data, reported using the residual solvent proton
resonance of CDCl3 (dH = 7.25 ppm) as internal reference, were as
follows (in order): chemical shift (d in ppm relative to Me4Si), mul-
tiplicity (s, d, t, q, m, br for singlet, doublet, triplet, quartet, multip-
let, broad) and coupling constants (J in Hz). 13C NMR was recorded
at 50 MHz on the same instruments, using the CDCl3 solvent peak
at (dC = 77.0 ppm as reference. Mass spectra were obtained on a
Hewlett Packard (engine 5989A) in direct introduction mode (70
eV). IR spectra were recorded on a Perkin-Elmer Spectrum One
spectrophotometer. Melting points were uncorrected. Vinyltributyl-
tin and isobutenyltributyltin were prepared from vinylmagnesium
bromide and isobutenylmagnesium bromide and bis(tributyltin)ox-
ide, respectively.12 (E)-1-Trimethylsilyl-2-tributylstannylethylene13
was prepared by hydrostannation of trimethylsilylacetylene; other
vinyltin reagents were prepared by hydrostannation of the corre-
sponding terminal alkynes under radical conditions (AIBN) and
used as a thermodynamic mixture of E- and Z-isomers.
(E)-3,4-Diiodobut-2-enoic Acid (2b)
Yield: 75%; yellowish solid; mp 150–152 °C (CH2Cl2).
IR (KBr): 3071, 1683, 1592 cm–1.
1H NMR (200 MHz, CDCl3): d = 5.08 (s, 2 H), 6.64 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 10.9, 125.5, 131.1, 168.3.
MS (EI): m/z (%) = 254 (M – 84, 68), 226 (61), 211 (12), 210 (41),
180 (100), 152 (40), 128 (18), 127 (58), 99 (45), 84 (24), 83 (52), 55
(55), 53 (76), 45 (24), 43 (16), 39 (59), 38 (28), 37 (18).
Z-Isomer
1H NMR (200 MHz, CDCl3): d = 4.62 (s, 2 H), 6.73 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 17.5, 117.8, 127.2, 169.2.
(E)-3-Chloro-4-iodobut-2-enoic Acid (2c)
Yield: 70%; yellowish solid; mp 92–93 °C (CH2Cl2).
IR (KBr): 3054, 1694, 1622 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.75 (s, 2 H), 6.17 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 1.9, 119.1, 155.5, 169.7.
MS (EI, 70 eV): m/z (%) = 248 (2), 246 (5), 127 (14), 121 (10), 119
(32), 93 (4), 91 (14), 83 (19), 55 (24), 45 (26), 39 (100), 38 (38), 37
(21).
X-ray Crystallography14
Suitable single crystals of 2a, 2b, 2c, and 2d were mounted on a
glass fiber. Data collections were carried out at r.t. on a Bruker-
Nonius KappaCCD diffractometer equipped with graphite-mono-
chromated Mo(Ka) radiation (l = 0.71073 Å). Cell parameters
were retrieved and refined using DENZO-SMN software15 on all re-
flections. Data reductions were performed with the DENZO-SMN
software. An empirical absorption correction based on the symme-
try-equivalent reflections was applied to each data set using the
SORTAV program.16 The structure were solved either by SIR9217
or SHELXS-9718 and refined with the SHELXL-97 program.19 The
hydrogen atoms were placed in geometrically idealized positions
and constrained to ride on their parent atoms.
Z-Isomer
1H NMR (200 MHz, CDCl3): d = 4.18 (s, 2 H), 6.40 (s, 1 H).
(E)-3-Bromo-4-iodobut-2-enoic Acid (2d)
Yield: 62%; yellowish solid; mp 122–123 °C (CH2Cl2).
IR (KBr): 3084, 3047, 1683, 1605 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.93 (s, 2 H), 6.40 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 4.8, 123.2, 147.3, 169.3.
MS (EI): m/z (%) = 292 (5), 290 (5), 211 (10), 165 (21), 163 (22),
137 (11), 135 (12), 127 (12), 84 (26), 55 (16), 45 (24), 40 (12), 39
(100), 38 (32), 37 (15).
3,4-Dihalobut-2-enoic Acids 2a–d; General Procedure
A dry round-bottomed double-necked flask (25 mL) equipped with
a dropping funnel was charged with a solution of buta-2,3-dienoic
acid (1; 0.5 g, 0.006 mol) in anhyd Et2O (40 mL). A solution of X–
Y (0.0072 mol) in a minimum of anhyd Et2O was added dropwise
to the solution of 1 via the dropping funnel at 0 °C (in the case of
IBr addition, a 1 M commercial solution of dihalogen in CH2Cl2 was
used). The mixture was stirred for 15 h or 48 h at 4 °C protected
from the light, and was then hydrolyzed with aq 1 M solution of
Na2S2O3 until the mixture was decolored (for the addition reactions
of Br2, sat. aq NaHSO3 was used to destroy the excess of Br2). The
organic phase was separated and the aqueous phase was extracted
with Et2O (3 × 15 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated at r.t. under reduced pressure.
The compound obtained was purified by crystallization from
CH2Cl2 (Table 1).
Z-Isomer
1H NMR (200 MHz, CDCl3): d = 4.86 (s, 2 H), 6.47 (s, 1 H).
4-Iodo-5H-furan-2-one (3)
A mixture of 3,4-diiodobut-2-enoic acid (2b; 0.68 g, 2 mmol),
EtOH (3 mL), H2O (0.9 mL), toluene (4 mL) and aq Na2CO3 (2.5
mL, 1 M) was stirred at 40 °C for 2 h. The solvent was removed in
vacuo. Sat. aq NH4Cl (10 mL) was added and the aqueous layer was
extracted with Et2O (3 × 15 mL). The organic phase was washed
with brine (10 mL), dried (MgSO4), filtered, and concentrated in
vacuo. Recrystallization from petroleum ether (bp 40–60 °C)–Et2O
gave 36b (315 mg, 75%) as white needles; mp 109–110 °C.
IR (KBr): 1774, 1729, 1585 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.86 (d, J = 1.9 Hz, 2 H), 6.57 (t,
J = 1.9 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 77.8, 117.3, 128.4, 170.2.
(E)-3,4-Dibromobut-2-enoic Acid (2a)
Yield: 80%; yellowish solid; mp 134–136 °C (CH2Cl2).
Synthesis 2011, No. 1, 154–160 © Thieme Stuttgart · New York

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Synthesis of 4-Substituted 5H-Furan-2-ones
159
MS (EI, 70 eV): m/z (%) = 210 (59), 152 (13), 127 (17), 83 (100),
55 (32), 39 (69).
13C NMR (50 MHz, CDCl3): d = 14.3, 20.3, 22.5, 28.1, 31.5, 71.9,
73.7, 108.7, 121.8, 148.7, 174.1.
MS (EI, 70 eV): m/z (%) = 178 (2), 163 (10), 149 (22), 136 (20), 122
(11), 121 (15), 119 (21), 107 (12), 106 (15), 105 (51), 93 (25), 92
(42), 91 (89), 81 (25), 79 (56), 78 (23), 77 (41), 68 (15), 67 (16), 66
(15), 65 (28), 64 (20), 63 (67), 62 (14), 57 (16), 55 (88), 53 (13), 51
(40), 50 (17), 42 (24), 41 (100), 39 (51).
4-Substituted 5H-Furan-2-ones 5; General Procedure
Stille Procedure: A dry Schlenk tube (25 mL) equipped with a
teflon-coated magnetic stirrer was charged with (E)-3,4-diiodobut-
2-enoic acid (2b; 0.68 g, 2 mmol), PdCl2(PPh3)2 (0.06 mmol, 0.03
equiv), and freshly distilled DMF (3 mL). The mixture was stirred
at r.t. for 15 min, and the respective organotin reagent (2.6 mmol,
1.3 equiv) was added. The mixture was stirred again at 80 °C for 24
h, followed by the addition of another portion of PdCl2(PPh3)2 (0.03
equiv). After cooling, the mixture was filtered over a Celite pad.
The solvent was evaporated and the residue was treated with EtOAc
(3 mL) and aq 1 M KF (3 mL). The mixture was vigorously stirred
for 2 h, then filtered over a Celite pad, and extracted with Et2O
(3 × 10 mL). The organic portions were combined, washed with
brine (10 mL), and dried (MgSO4). After evaporation of the solvent,
the crude product was purified by flash chromatography on silica
gel to give the desired 5H-furan-2-ones (Table 4).
4-Phenyl-5H-furan-2-one (5d)11n
Yield: 68%; white solid; mp 90–91 °C.
IR (KBr): 3110, 3057, 1786, 1749, 1625, 1578 cm–1.
1H NMR (200 MHz, CDCl3): d = 5.23 (d, J = 1.7 Hz, 2 H), 6.38 (t,
J = 1.7 Hz, 1 H), 7.48–7.53 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 71.5, 113.4, 126.9 (2 C), 129.7 (2
C), 130.0, 132.2, 164.4, 174.4.
MS (EI, 70 eV): m/z (%) = 160 (52), 132 (10), 131 (100), 103 (60),
102 (43), 77 (29), 76 (14), 63 (10), 51 (36), 50 (15).
Suzuki Procedure: A dry Schlenk tube (25 mL) equipped with a
teflon-coated magnetic stirrer and containing EtOH (3.2 mL), H2O
(0.9 mL), and toluene (4.0 mL) was charged with (E)-3,4-diiodobut-
2-enoic acid (2b; 0.68 g, 2 mmol) and the respective boronic acid
(2.6 mmol, 1.3 equiv). Aq 1 M Na2CO3 (2.5 mL) and Pd(PPh3)4
(0.06 mmol, 0.03 equiv) were added, and then the mixture was
stirred at 80 °C for 2 h. The reaction was quenched with aq NH4Cl
(10 mL). The residue was diluted with Et2O (15 mL) and filtered
through a Celite pad. The organic solvents were evaporated from
the filtrate and the aqueous medium obtained was extracted with
Et2O (3 × 20 mL). The organic portions were combined and dried
(MgSO4). After evaporation of the solvent, the crude product was
purified by flash chromatography on silica gel to give the desired
5H-furan-2-ones (Table 4).
4-p-Tolyl-5H-furan-2-one (5e)11p
Yield: 60%; white solid; mp 117–118 °C.
IR (KBr): 3055, 1787, 1755, 1744, 1623 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.42 (s, 3 H), 5.20 (d, J = 1.7 Hz,
2 H), 6.32 (t, J = 1.7 Hz, 1 H), 7.28 (d, J = 8.1 Hz, 2 H), 7.41 (d,
J = 8.1 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 21.9, 71.4, 112.2, 126.8 (2 C),
127.3, 130.4 (2 C), 142.9, 164.5, 174.6.
MS (EI, 70 eV): m/z (%) = 174 (77), 146 (11), 145 (100), 117 (37),
116 (31), 115 (56), 91 (12), 65 (12), 51 (10), 39 (14).
4-(4-Methoxyphenyl)-5H-furan-2-one (5f)11n
Yield: 59%; white solid; mp 107–108 °C.
IR (KBr): 3057, 1786, 1751, 1625 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.87 (s, 3 H), 5.20 (d, J = 1.7 Hz,
2 H), 6.24 (d, J = 1.7 Hz, 1 H), 6.97 (d, J = 8.9 Hz, 2 H), 7.46 (d,
J = 8.9 Hz, 2 H).
4-Vinyl-5H-furan-2-one (5a)6b
Yield: 54%; orange oil.
IR (NaCl): 3102, 1781, 1744, 1643, 1583 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.98 (d, J = 1.7 Hz, 2 H), 5.60 (d,
J = 10.8 Hz, 1 H), 5.61 (d, J = 17.8 Hz, 1 H), 5.96 (br s, 1 H), 6.69
(dd, J = 17.8, 10.8 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 70.8, 116.7, 123.7, 128.3, 162.5,
174.2.
13C NMR (50 MHz, CDCl3): d = 55.9, 71.4, 110.9, 115.1 (2 C),
122.6, 128.6 (2 C), 162.8, 164.2, 174.9.
MS (EI, 70 eV): m/z = 190 (100), 161 (93), 133 (44), 132 (56), 118
(14), 117 (31), 103 (12), 90 (15), 89 (52), 77 (23), 63 (38), 51 (22),
39 (19).
MS (EI): m/z (%) = 110 (40), 81 (100), 53 (84), 52 (57), 51 (23), 50
(17), 39 (16).
(4E)-3,3-Dimethylbut-1-enyl-5H-furan-2-one (5g)
Yield: 62%; yellow oil.
IR (NaCl): 1778, 1747, 1645, 1594 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.11 (s, 9 H), 4.97 (d, J = 1.5 Hz,
2 H), 5.88 (d, J = 1.5 Hz, 1 H), 6.11 (d, J = 16.4 Hz, 1 H), 6.34 (d,
J = 16.4 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 29.2 (3 C), 34.5, 71.0, 114.5,
117.1, 152.0, 163.4, 174.6.
4-[(2-Trimethylsilyl)vinyl]-5H-furan-2-one (5b)6b
Yield: 52%; orange oil.
IR (NaCl): 3102, 1779, 1745, 1627, 1566 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.14 (s, 9 H), 4.97 (d, J = 1.6 Hz,
2 H), 5.92 (br s, 1 H), 6.36 (d, J = 19.3 Hz, 1 H), 6.84 (d, J = 19.3
Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = –2.9 (3 C), 69.6, 114.5, 132.8,
141.6, 161.8, 175.5.
MS (EI, 70 eV): m/z (%) = 166 (54), 151 (23), 123 (37), 121 (24),
109 (47), 107 (100), 105 (17), 96 (37), 95 (33), 93 (53), 91 (74), 81
(12), 79 (58), 77 (56), 70 (31), 67 (40), 65 (27), 55 (36), 53 (29), 51
(32), 43 (32), 41 (82), 39 (65).
MS (EI, 70 eV): m/z (%) = 182 (19), 167 (20), 139 (13), 123 (22),
111 (18), 83 (10), 73 (100), 59 (25), 45 (16), 43 (15).
Hept-4-ynyl-5H-furan-2-one (5c)
Yield: 48%; orange oil.
IR (NaCl): 2226, 1780, 1750, 1610 cm–1.
Acknowledgment
1H NMR (200 MHz, CDCl3): d = 0.92 (t, J = 6.9 Hz, 3 H), 1.26–
1.65 (m, 6 H), 2.46 (t, J = 6.9 Hz, 2 H), 4.78 (d, J = 1.8 Hz, 2 H),
6.10 (s, 1 H).
We thank the CNRS and MRT for providing financial support, the
‘Service d’analyse chimique du Vivant de Tours’ for recording
NMR and mass spectra, and the ‘Laboratoire de Cristallochimie’ of
Marseille University for X-ray diffraction analysis.
Synthesis 2011, No. 1, 154–160 © Thieme Stuttgart · New York

160
S. Lamandé-Langle et al.
PAPER
PCT Int. Appl. WO9500501, 1995; Chem. Abstr. 1996, 124,
55954. (h) Tan, L.; Chen, C.-Y.; Larsen, R. D.; Verhoeven,
T. R.; Reider, P. J. Tetrahedron Lett. 1998, 39, 3961.
(9) Forgione, P.; Wilson, P. D.; Fallis, A. G. Tetrahedron Lett.
2000, 41, 17.
(10) (a) Vallat, J.-N.; Grossi, P.-J.; Boucherle, A.; Simiand, J.
Eur. J. Med. Chem. 1981, 16, 409. (b) Schmitt, J.; Sugnet,
M.; Salle, J.; Comoy, P.; Callet, G.; LeMeur, J. Chim. Ther.
1966, 1, 305.
References
(1) (a) Rossi, R.; Bellina, F.; Biagetti, M.; Mannina, L.
Tetrahedron Lett. 1998, 39, 7799. (b) Rossi, R.; Bellina, F.;
Mannina, L. Tetrahedron Lett. 1998, 39, 3017. (c) Wang,
Y.; Burton, D. J. J. Org. Chem. 2006, 71, 3859.
(2) Lamandé-Langle, S.; Abarbri, M.; Thibonnet, J.; Duchêne,
A.; Parrain, J.-L. Chem. Commun. 2010, 46, 5157.
(3) Allan, R. D.; Johnston, G. A. R.; Twitchin, B. Aust. J. Chem.
1980, 33, 1115.
(11) For some synthesis of 4-substituted 5H-furan-2-ones, see:
(a) Hollingworth, G. J.; Sweeney, J. B. Tetrahedron Lett.
1992, 33, 7049. (b) Hollingworth, G. J.; Sweeney, J. B.
Synlett 1993, 463. (c) Trost, B. M.; McIntosh, M. C. J. Am.
Chem. Soc. 1995, 117, 7255. (d) Hollingworth, G. J.;
Perkins, G.; Sweeney, J. B. J. Chem. Soc., Perkin Trans. 1
1996, 1913. (e) Hoffmann, H. M. R.; Gerlach, K.; Lattmann,
E. Synthesis 1996, 164. (f) Hollingworth, G. J.; Richecoeur,
A. M. E.; Sweeney, J. B. J. Chem. Soc., Perkin Trans. 1
1996, 2833. (g) Gerlach, K.; Hoffmann, H. M. R.;
Wartchow, R. J. Chem. Soc., Perkin Trans. 1 1998, 3867.
(h) Trost, B. M.; Hachiya, I.; McIntosh, M. C. Tetrahedron
Lett. 1998, 39, 6445. (i) Ma, S.; Shi, Z. J. Org. Chem. 1998,
63, 6387. (j) Rossi, R.; Bellina, F.; Biagetti, M.; Mannina, L.
Tetrahedron Lett. 1998, 39, 7599. (k) Rossi, R.; Bellina, F.;
Biagetti, M. Synth. Commun. 1999, 29, 3415. (l) Rossi, R.;
Bellina, F.; Raugei, E. Synlett 2000, 1749. (m) Trost, B. M.;
Gunzner, J. L.; Yasukata, T. Tetrahedron Lett. 2001, 42,
3775. (n) Wu, J.; Zhu, Q.; Wang, L.; Fathi, R.; Yang, Z.
J. Org. Chem. 2003, 68, 670. (o) Tang, Z.-Y.; Hu, Q.-S.
Adv. Synth. Catal. 2004, 346, 1635. (p) Kagabu, S.;
Shimizu, Y.; Chinatsu, I.; Moriya, K. Synthesis 1992, 830.
(12) (a) Seyferth, D.; Stone, F. G. A. J. Am. Chem. Soc. 1957, 79,
515. (b) Saihi, M. L.; Pereyre, M. Bull. Soc. Chim. Fr. 1977,
1251.
(4) (a) Tendil, J.; Verny, M.; Vessière, R. Bull. Soc. Chim. Fr.
1972, 4027. (b) Faust, G.; Verny, M.; Vessière, R. C. R.
Acad. Sci. Paris 1975, 281, 193. (c) Tendil, J.; Verny, M.;
Vessière, R. Bull. Soc. Chim. Fr. 1977, 565. (d) Natsias, K.;
Hopf, H. Tetrahedron Lett. 1982, 23, 3673. (e) Welch, S.
C.; Gruber, J. M. J. Org. Chem. 1982, 47, 385.
(5) (a) Prevost, C.; Gaudemar, M.; Honiberg, J. C. R. Acad. Sci.
Paris 1950, 230, 1186. (b) Eglinton, G.; Jones, E. R. H.;
Mansfield, G. H.; Whiting, M. C. J. Chem. Soc. 1954, 3197.
(c) Gaudemar, M. Ann. Chim. 1956, 1, 161.
(6) (a) Reginato, G.; Capperucci, A.; Degl’Innocenti, A.;
Mordini, A.; Pecchi, S. Tetrahedron 1995, 51, 2129.
(b) Lattmann, E.; Hoffmann, H. M. R. Synthesis 1996, 155.
(c) Ma, S.; Shi, Z.; Yu, Z. Tetrahedron Lett. 1999, 40, 2393.
(d) Ma, S.; Shi, Z.; Yu, Z. Tetrahedron 1999, 55, 12137.
(7) (a) Bohlmann, F.; Zdero, C.; King, R. M.; Robinson, H.
Phytochemistry 1981, 20, 2425. (b) Gadir, S. A.; Smith, Y.;
Tada, A. A.; Thaller, V. J. Chem. Res., Synop. 1986, 102.
(c) Miao, S. C.; Andersen, R. J. J. Org. Chem. 1991, 56,
6275. (d) Paquette, L. A.; Ezquerra, J.; He, W. J. Org. Chem.
1995, 60, 1435. (e) Wang, T. Z.; Pinard, E.; Paquette, L. A.
J. Am. Chem. Soc. 1996, 118, 1309. (f) Rodriguez, A. D.;
Shi, J.-G.; Huang, S.-D. J. Org. Chem. 1998, 63, 4425.
(g) Takayama, H.; Kuwajima, T.; Kitajima, M.; Nonato, M.
G.; Aimi, N. Heterocycles 1999, 50, 75. (h) Xu, L.-P.; Gou,
D.; Liu, J.-S.; Zheng, J.-H.; Koike, K.; Jia, Z.-H.; Nikaido,
T. Heterocycles 1999, 51, 605. (i) Mikayado, M.; Kato, T.;
Ohno, N.; Yoshioka, H.; Ohshio, H. Agric. Biol. Chem.
1977, 41, 57. (j) Knight, D. W. Contemp. Org. Synth. 1994,
1, 287. (k) Figadère, B. Acc. Chem. Res. 1995, 28, 359.
(l) Zapf, S.; Anke, T.; Sterner, O. Acta Chem. Scand. 1995,
49, 233. (m) Gibson, C. L.; Handa, S. Tetrahedron:
Asymmetry 1996, 7, 1281. (n) Freer, A. A.; Kirby, G. W.;
Rao, G. V.; Cain, R. B. J. Chem. Soc., Perkin Trans. 1 1996,
2111. (o) Gamard, P.; Sâuriol, F.; Benhamou, N.; Belanger,
R. R.; Paulitz, T. C. J. Antibiot. 1997, 50, 742.
(13) Cunico, R. F.; Clayton, F. J. Org. Chem. 1976, 41, 1480.
(14) Crystallographic data for the structural analysis have been
deposited with the Cambridge Crystallographic Data Center
under CCDC Nos. 702136 (compound 2d), 745342
(compound 2c), 745343 (compound 2a), and 785338
(compound 2b). Copies of this information may be obtained
free of charge from The Director, CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (1223)336033; e-mail:
deposit@ccdc.cam.ac.uk or www.http://
www.ccdc.cam.ac.uk].
(15) Otwinowsky, Z.; Minor, W. Processing of X-ray Diffraction
Data Collected in Oscillation Method Mode, In Methods in
Enzymology Vol. 276: Macromolecular Crystallography,
Part A; Carter, C. W. Jr.; Sweet, R. M., Eds.; Academic
Press: New York, 1997, 307–326.
(16) Blessing, R. H. J. Appl. Crystallogr. 1997, 30, 421.
(17) Altamore, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi,
A.; Burla, M. C.; Polidori, G.; Camalli, M. J. Appl.
Crystallogr. 1994, 27, 435.
(18) Sheldrick, G. M. Acta Crystallogr., Sect A 1990, 46, 467.
(19) Sheldrick, G. M. SHELXL-97, Program for the Refinement
of Crystal Structures; University of Göttingen: Germany,
1997.
(8) (a) Tanabe, A. Jpn Kokai Tokkyo Koho JP 63211276
[88211276], 1988; Chem. Abstr. 1989, 110, 94978.
(b) Brima, T. S. US Patent 4968817, 1990; Chem. Abstr.
1991, 114, 185246. (c) Lee, G. C. M. Eur. Patent Appl. EP
372940, 1990; Chem. Abstr. 1990, 113, 191137. (d) Lee, G.
C. M.; Garst, M. E. PCT Int. Appl. WO9116055, 1991;
Chem. Abstr. 1992, 116, 59197. (e) Cerri, A.; Mauri, P.;
Mauro, M.; Melloni, P. J. Heterocycl. Chem. 1993, 30,
1581. (f) Oomura, Y.; Shiraishi, T.; Takeoka, J. Jpn Kokai
Tokkyo Koho, JP 07196491 [95196491], 1995; Chem.
Abstr. 1995, 123, 246850. (g) Ducharme, Y.; Gauthier, J.
Y.; Prasit, P.; Leblanc, Y.; Wang, Z.; Leger, S.; Therien, M.
Synthesis 2011, No. 1, 154–160 © Thieme Stuttgart · New York