Bromine-induced facile synthesis of butenolides and spirobutenolides from sterically congested tetrasubstituted dialkyl alkylidene succinates

Article abstract of DOI:10.1055/s-0029-1219233

Starting from sterically congested tetrasubstituted dialkyl alkylidene succinates, facile general approach to several dialkyl substituted butenolides and spirobutenolides with the generation of quaternary carbon center has been demonstrated via bromine-in

Full text of DOI:10.1055/s-0029-1219233

1188
PAPER
Bromine-Induced Facile Synthesis of Butenolides and Spirobutenolides from
Sterically Congested Tetrasubstituted Dialkyl Alkylidene Succinates
S
ynthesis of Bute
a
nolides and
m
Spirobutenolides esh M. Patel, Narshinha P. Argade*
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411 008, India
Fax +91(20)25902629; E-mail: np.argade@ncl.res.in
Received 26 November 2009; revised 8 December 2009
tion, palladium-catalyzed arylation, and photocyclization
Abstract: Starting from sterically congested tetrasubstituted di-
alkyl alkylidene succinates, facile general approach to several di-
alkyl substituted butenolides and spirobutenolides with the
generation of quaternary carbon center has been demonstrated via
methodologies.4,5 All these studies indicate that the devel-
opment of new potential routes to g-butenolides is still a
challenging task of current interest. In continuation of our
bromine-induced dealkylative regioselective intramolecular cy- studies on cyclic anhydrides to bioactive natural and un-
natural products,6 we recently synthesized the tetrasubsti-
clization and dehydrobromination pathway. The mechanistic as-
pects involved in the formation of butenolides have been also
described in brief.
tuted dialkyl alkylidene succinates and systematically
studied their bromination reactions. Our preliminary stud-
ies on halogenation of dimethyl 2-(propan-2-ylidene)suc-
cinate (2a) revealed the formation of methyl 2,2-
Key words: alkylidene succinates, bromine, intramolecular cy-
clizations, butenolides, spirobutenolides
dimethyl-5-oxo-2,5-dihydrofuran-3-carboxylate (6a) as
the product, instead of the corresponding expected dihalo
The natural and unnatural g-butenolides are an important
class of compounds that find major applications in organ-
ic, medicinal, and polymer chemistry, and a broad range
of biological properties have been conferred on them.1–5
Moreover, the two important pesticides spirodiclofen and
spiromesifen used to keep a control on severe crop dam-
aging pests (Tetranychus urticae, Panonychus ulmi, and
Bemisia tabaci), also possess spirobutenolide skeletons
(Figure 1).2
compound. We prepared a systematic plan to completely
explore our observed fact with a perspective to develop a
new general route to g-butenolides. In this context, we
herein report our results on the synthesis of target mole-
cules (Scheme 1).
R3
R3
O
O
O
Br
Br
R1O
R1O
R1O
R1O
R4
R1O
R4
i
iia
O
R2
R2
R1
O
O
R2
O
O
O
1
[4a–j]
O
O
2a–l [and 2m (n = 5)]
– R1Br
O
O
O
O
(n = 5)
i
ii
R3
O
O
R3
R4
R4
O
Cl
Cl
spirodiclofen
Br
R1O
iib, c
R1O
spiromesifen
MeO
MeO
O
O
R2
Figure 1 Pesticidal spirobutenolides of commercial interest
R2
– HBr
O
O
O
6a–j
R1 = Me, Et; R2 = H, Me, CH2CO2Me;
R3 = R4 = dialkyl, CH2(CH2)nCH2 (n = 1–5)
[5a–g,i,j] and 5h (84%) .
3m (75%)
Basically, the diverse range of g-butenolide skeletons has
been designed by employing new carbon–oxygen bond
construction reactions and metal-catalyzed carbon–car-
bon bond formations. A very large number of such g-
butenolides has been synthesized during the past century
using several elegant synthetic strategies.3 Methods for
the construction of such type of building blocks with a
quaternary carbon center are of special interest to organic
chemists due to their presence in natural products.4
Scheme 1 Synthesis of butenolides and spirobutenolides via the
bromination of tetrasubstituted C=C bonds. Reagents and conditions:
(i) (a) t-BuOK, t-BuOH, R2COR3, 25 °C, 45 min, (b) MeOH or EtOH,
H+/H2SO4, reflux, 8 h (50–78%); (ii) (a) Br2 (1.5 equiv), CCl4, 25 °C,
8 h, (b) Et3N (1.5 equiv), 25 °C, 2 h (82–88%, 44% for 6d), (c) Et3N
(1.5 equiv), reflux, 2 h (84% for 6h and 82% for 6i).
The base-catalyzed Stobbe condensation of dimethyl suc-
cinate with acetone, isobutyl methyl ketone, cyclobu-
They have been synthesized by using an excellent iodide-
catalyzed methyl–oxygen bond cleavage in 2-methoxy-
furans, metal-catalyzed carbonylation, oxidative cycliza-
tanone,
cyclopentanone,
cyclohexanone,
4-tert-
butylcyclohexanone, cycloheptanone, a-tetralone, and
benzophenone, followed by esterification of the formed
intermediate monoesters,7 respectively furnished the cor-
responding desired starting materials, the dimethyl alkyl-
SYNTHESIS 2010, No. 7, pp 1188–1194
Advanced online publication: 20.01.2010
DOI: 10.1055/s-0029-1219233; Art ID: Z25809SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
0

PAPER
Synthesis of Butenolides and Spirobutenolides
1189
idene succinates 2a, 2c–g and 2j–l in 50–78% yields.8 functionalities to form the corresponding dimethyl cy-
Similarly, the condensation of diethyl succinate with ace- clooctyl fumarate.
tone, condensation of dimethyl methylsuccinate with cy-
clohexanone and condensation of trimethyl propane-
On having all these potential starting materials 2a–l in
hand, we studied their reactions with bromine to obtain
1,2,3-tricarboxylate with cyclohexanone, respectively
the desired butenolides. The reactions of dialkyl alky-
furnished the required starting materials 2b, 2h, and 2i in
lidene succinates 2a–c with bromine in CCl4 at room tem-
52–69% yields. In our hands, the Stobbe condensation of
perature directly furnished the corresponding butenolides
dimethyl succinate with cyclooctanone directly furnished
6a–c in 82–84% yields. During these studies, we noticed
that the addition of triethylamine after an eight-hour reac-
tion time provides the desired products with slight im-
the product 3m8c via the expected intermediate 2m. We
feel that, herein the selective exocylic to endocyclic C=C
bond migration is notable, as the double bond in the inter-
provement in yields (86–88%) (Table 1).
mediate 2m does not get in conjugation with the two ester
Table 1 Synthesis of Butenolides 6a–j
Entry
Ketones
Dialkyl alkylidines
Butenolides
O
O
MeO
MeO
MeO
O
1
O
O
O
2a (69%)
O
6a (88%)
O
EtO
EtO
EtO
O
2
3
4
5
O
O
O
2b (69%)
O
6b (87%)
O
MeO
MeO
MeO
O
O
O
O
2c (62%)
O
6c (86%)
O
O
MeO
MeO
MeO
O
O
O
2d (74%)
O
6d (44%)
O
O
MeO
MeO
MeO
O
O
O
6e (82%)
2e (52%)
O
O
O
MeO
MeO
MeO
6
O
O
O
6f (85%)
2f (60%)
Synthesis 2010, No. 7, 1188–1194 © Thieme Stuttgart · New York

1190
R. M. Patel, N. P. Argade
PAPER
Table 1 Synthesis of Butenolides 6a–j (continued)
Entry
Ketones
Dialkyl alkylidines
Butenolides
O
O
O
MeO
7
MeO
MeO
O
O
O
6g (84%)
2g (56%)
O
O
O
MeO
MeO
MeO
8
9
O
O
O
6ha (84%)
2h (53%)
O
O
O
MeO
MeO
MeO
O
O
O
OMe
O
MeO
O
2i (52%)
6i (82%)
O
O
O
MeO
MeO
10
MeO
O
O
O
2j (50%)
6j (83%)
O
O
O
MeO
MeO
MeO
11
12
O
O
O
6k (not obtained)
2k (72%)
O
Ph
O
Ph
Ph
O
Ph
MeO
MeO
MeO
O
Ph
Ph
O
O
6l (not obtained)
2l (78%)
a Possesses antifungal and C1 esterase inhibitor activities.9
As expected, the substrates 2d–j, obtained by using cyclic bromine–triethylamine under the standard reaction condi-
ketones, on sequential treatment with bromine in CCl4 and tions and we were unable to obtain products 6k and 6l
triethylamine gave the expected spirobutenolides prod- (Table 1). The analytical and spectral data obtained for all
ucts 6d–j in 82–85% yields, except for 6d. In the case of the g-butenolides were in complete agreement with the as-
conversion of 2d to 6d, though we got the expected prod- signed structures. In the 1H NMR spectra of 6a–g and 6j,
uct, the yield was only 44% while the remaining was de- the characteristic vinylic proton singlet appeared at d =
composed material, probably originated by an in situ ~6.57.
cleavage of the cyclobutane ring during the course of re-
In an attempt to study the mechanistic aspects involved in
action. As expected, in the bromination reaction of 2g, we
the conversion of compounds 2a–j to 6a–j, we noticed
got an inseparable, nearly 1:1 mixture of diastereomers of
that the methine proton in the compound 5h is not easily
accessible to the base at room temperature for the last de-
6g. The substrates 2k and 2l, wherein the tetrasubstituted
C=C bonds are in conjugation with the aromatic ring,
hydrobromination process. Hence, we could successfully
remained unreacted in our hands in the presence of
isolate the corresponding intermediate saturated bromo-
Synthesis 2010, No. 7, 1188–1194 © Thieme Stuttgart · New York

PAPER
Synthesis of Butenolides and Spirobutenolides
1191
in t-BuOH (5 mL) in a dropwise fashion under argon with constant
stirring. After stirring the reaction mixture for 10 min, a solution of
acetone (696 mg, 12.0 mmol) in t-BuOH (5 mL) was added drop-
wise under argon and the mixture was stirred for 45 min at 25 °C.
The mixture was concentrated in vacuo. The obtained residue was
dissolved in H2O (50 mL) and the aqueous layer was washed with
EtOAc (2 × 20 mL). The aqueous layer was acidified to pH 2 using
aq 2 N HCl (20 mL). The acidified aqueous layer was extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed
with H2O (25 mL), brine (25 mL), dried (Na2SO4), and concentrated
in vacuo, and the dried residue was dissolved in MeOH (30 mL). To
the above solution was added concd H2SO4 (1 mL) and the mixture
was refluxed for 8 h with constant stirring. The mixture was allowed
to reach 25 °C and concentrated in vacuo. The obtained residue was
dissolved in EtOAc (50 mL) and the organic layer was washed with
lactone 5h in 84% yield. The isolated intermediate 5h, in
the presence of triethylamine as the base, under reflux
conditions gave the desired product 6h in quantitative
yield. Based on the isolated intermediate 5h, we surmise
that during the course of the bromination reaction, the bro-
monium ion intermediates 4a–j, as depicted in Scheme 1,
are formed. In the proposed intermediates 4a–j, the bulk-
ier bromide anion is unable to approach the quaternary
carbons to form the expected dibromides. Hence the lone
pair on the relatively smaller oxygen atom, intramolecu-
larly and regioselectively, attacks the bromonium bridge
to form the g-lactone. The simultaneous bromide anion-
induced dealkylation takes place to cancel the positive
charge on an oxygen atom to form the intermediate prod- 5% aq NaHCO3 (25 mL), brine (25 mL), and dried (Na2SO4). Con-
centration of the organic layer in vacuo followed by silica gel col-
umn chromatographic purification of the resulting residue using
ucts 5a–j, which on dehydrobromination yield the target
compounds 6a–j.
EtOAc–PE (1:9) as eluent afforded the pure product 2a as a thick
The corresponding substrate 710 with a trisubstituted C=C
bond, upon bromination, exclusively gave the corre-
sponding dibromo compound 8 in 68% yield, while it re-
mained unreacted with iodine (Scheme 2); these results
directly support both our proposed strategy and described
mechanistic pathway.
oil8 (1.28 g, 69%).
IR (neat): 1728, 1642 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.86 (s, 3 H), 2.14 (s, 3 H), 3.38
(s, 2 H), 3.67 (s, 3 H), 3.71 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 23.2 (2 C), 35.1, 51.4, 51.8, 120.2,
149.8, 168.2, 171.8.
Anal. Calcd for C9H14O4: C, 58.05; H, 7.58. Found: C, 58.16; H,
7.71.
O
Br
O
H
Br
Br2, CCl4
25 °C, 8 h
MeO
MeO
MeO
MeO
Diethyl 2-(Propan-2-ylidene)succinate (2b)
Compound 2b was obtained from diethyl succinate (1.74 g, 10.0
mmol) and acetone (696 mg, 12.0 mmol) using the same procedure
described above for 2a, as a thick oil7 (1.48 g, 69%).
O
O
7
8 (68%)
Scheme 2 Bromination of trisubstituted C=C bond
IR (neat): 1738, 1719, 1642 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (t, J = 7 Hz, 3 H), 1.27 (t,
J = 7 Hz, 3 H), 1.86 (s, 3 H), 2.14 (s, 3 H), 3.36 (s, 2 H), 4.13 (q,
J = 7 Hz, 2 H), 4.18 (q, J = 7 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 14.2, 23.2, 23.3, 35.5, 60.2, 60.7,
120.7, 148.9, 167.9, 171.5.
In summary, we have demonstrated a simple and efficient
general approach to gem-dialkyl-substituted quaternary
butenolides by taking advantage of bromine stimulated
structural rearrangement of sterically congested tetrasub-
stituted dialkyl alkylidene succinates. We feel that an in
situ dealkylative intramolecular cyclization process in-
volved in the present approach along with the formation
of oxygen–carbon bond, is noteworthy.
(E)-Dimethyl 2-(4-Methylpentan-2-ylidene)succinate (2c)
Compound 2c was obtained from dimethyl succinate (1.46 g, 10.0
mmol) and 4-methylpentan-2-one (1.20 g, 12.0 mmol) using the
same procedure described above for 2a, as a thick oil (1.41 g, 62%).
IR (CHCl3): 1743, 1720, 1630 cm–1.
Melting points are uncorrected. The1H NMR spectra were recorded
on 200 MHz, 300 MHz, and 500 MHz NMR spectrometer using
TMS as an internal standard. The 13C NMR spectra were recorded
on 200 NMR spectrometer (50 MHz) and 500 NMR spectrometer
(125 MHz). The IR spectra were recorded on an FT-IR spectrome-
ter. Elemental analyses were obtained by using Flash EA 1112 se-
ries and Elementar Vario EL analyzer at NCL, Pune. Column
chromatographic separations were carried out on silica gel (60–120
mesh). Commercially available dimethyl succinate, diethyl succi-
nate, dimethyl methylsuccinate, trimethyl propane-1,2,3-tricaboxy-
late, isopropyl methyl ketone, cyclobutanone, cyclopentanone,
cyclohexanone, tert-butylcyclohexanone, cycloheptanone, cyclooc-
tanone, a-tetralone, benzophenone, and t-BuOK were used. Petro-
leum ether (PE) used refers to the fraction boiling in the range 60–
80 °C.
1H NMR (200 MHz, CDCl3): d = 0.90 (d, J = 6 Hz, 6 H), 1.75–2.00
(m, 1 H), 2.07 (d, J = 8 Hz, 2 H), 2.10 (s, 3 H), 3.41 (s, 2 H), 3.67
(s, 3 H), 3.72 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 21.7, 22.5, 27.2, 35.1, 45.6, 51.4,
51.9, 121.2, 152.0, 168.4, 172.0.
Anal. Calcd for C12H20O4: C, 63.14; H, 8.83. Found: C, 62.81; H,
8.51.
Dimethyl 2-Cyclobutylidenesuccinate (2d)
Compound 2d was obtained from dimethyl succinate (1.46 g, 10.0
mmol) and cyclobutanone (840 mg, 12.0 mmol) using the same pro-
cedure described above for 2a, as a thick oil (1.47 g, 74%).
IR (CHCl3): 1737, 1710, 1680 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.06 (quint, J = 8 Hz, 2 H), 2.82
(t, J = 8 Hz, 2 H), 3.15 (s, 2 H), 3.15 (t, J = 8 Hz, 2 H), 3.69 (s, 3 H),
3.71 (s, 3 H).
Dimethyl 2-(Propan-2-ylidene)succinate (2a); Typical Proce-
dure
To a stirred solution of t-BuOK (1.22 g, 10.0 mmol) in t-BuOH (10
mL) was added a solution of dimethyl succinate (1.46 g, 10.0 mmol)
13C NMR (50 MHz, CDCl3): d = 16.4, 30.9, 32.9, 33.7, 51.3, 51.9,
117.3, 164.2, 167.0, 171.8.
Synthesis 2010, No. 7, 1188–1194 © Thieme Stuttgart · New York

1192
R. M. Patel, N. P. Argade
PAPER
Anal. Calcd for C10H14O4: C, 60.59; H, 7.12. Found: C, 60.40; H,
7.30.
1H NMR (200 MHz, CDCl3): d = 1.50–1.75 (m, 6 H), 2.24–2.35 (m,
2 H), 2.36 (dd, J = 17, 6 Hz, 1 H), 2.44–2.55 (m, 2 H), 3.09 (dd,
J = 17, 8 Hz, 1 H), 3.67 (s, 3 H), 3.68 (s, 3 H), 3.69 (s, 3 H), 4.17
(dd, J = 9, 6 Hz, 1 H).
Dimethyl 2-Cyclopentylidenesuccinate (2e)
Compound 2e was prepared from dimethyl succinate (1.46 g, 10.0
mmol) and cyclopentanone (1.10 g, 12.0 mmol) using the same pro-
cedure described above for 2a, as a thick oil8 (1.10 g, 52%).
IR (CHCl3): 1736, 1693, 1643 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.60–1.82 (m, 4 H), 2.40 (t, J = 6
Hz, 2 H), 2.82 (t, J = 6 Hz, 2 H), 3.35 (s, 2 H), 3.68 (s, 3 H), 3.72 (s,
3 H).
13C NMR (50 MHz, CDCl3): d = 26.3, 28.0, 28.2, 31.9, 32.9, 35.8,
41.3, 51.4, 51.8, 52.2, 122.2, 152.8, 168.3, 172.3, 172.9.
Anal. Calcd for C15H22O6: C, 60.39; H, 7.43. Found: C, 60.25; H,
7.76.
Dimethyl 2-Cycloheptylidenesuccinate (2j)
Compound 2j was obtained from dimethyl succinate (1.46 g, 10.0
mmol) and cycloheptanone (1.34 g, 12.0 mmol) using the same pro-
cedure described above for 2a, as a thick oil (1.20 g, 50%).
IR (CHCl3): 1741, 1717, 1652 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.40–1.80 (m, 8 H), 2.36 (t, J = 6
Hz, 2 H), 2.71 (t, J = 6 Hz, 2 H), 3.38 (s, 2 H), 3.67 (s, 3 H), 3.71 (s,
3 H).
13C NMR (50 MHz, CDCl3): d = 25.5, 26.9, 34.2, 34.5, 35.8, 51.3,
51.9, 116.6, 165.3, 167.5, 172.0.
Anal. Calcd for C11H16O4: C, 62.25; H, 7.60. Found: C, 62.35; H,
7.98.
Dimethyl 2-Cyclohexylidenesuccinate (2f)
Compound 2f was obtained from dimethyl succinate (1.46 g, 10.0
mmol) and cyclohexanone (1.18 g, 12.0 mmol) using the same pro-
cedure described above for 2a, as a thick oil8 (1.36 g, 60%).
IR (CHCl3): 1742, 1710, 1635 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.52–1.72 (m, 6 H), 2.18–2.28 (m,
2 H), 2.58–2.68 (m, 2 H), 3.39 (s, 2 H), 3.68 (s, 3 H), 3.73 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 26.2, 27.2, 28.5 (2 C), 33.7, 34.0,
34.8, 51.4, 51.9, 120.1, 158.2, 168.4, 172.0.
Anal. Calcd for C13H20O4: C, 64.98; H, 8.39. Found: C, 64.60; H,
7.90.
(E)-Dimethyl 2-[3,4-Dihydronapthalen-1(2H)-ylidene]succi-
nate (2k)
Compound 2k was obtained from dimethyl succinate (1.46 g, 10.0
mmol) and a-tetralone (1.75 g, 12.0 mmol) using the same proce-
dure described above for 2a, as a thick oil (1.97 g, 72%).
13C NMR (50 MHz, CDCl3): d = 26.2, 27.9, 28.1, 32.3, 32.4, 34.6,
51.4, 51.8, 117.2, 155.2, 168.8, 171.8.
Anal. Calcd for C12H18O4: C, 63.70; H, 8.02. Found: C, 63.59; H,
7.72.
IR (CHCl3): 1740, 1707, 1619 cm–1.
Dimethyl 2-(4-tert-Butylcyclohexylidene)succinate (2g)
Compound 2g was obtained from dimethyl succinate (1.46 g, 10.0
mmol) and 4-tert-butylcyclohexanone (1.85 g, 12.0 mmol) using
the same procedure described above for 2a, as a thick oil (1.58 g,
56%).
1H NMR (200 MHz, CDCl3): d = 1.85 (quint, J = 6 Hz, 2 H), 2.56
(t, J = 6 Hz, 2 H), 2.75 (t, J = 6 Hz, 2 H), 3.56 (s, 2 H + 3 H), 3.71
(s, 3 H), 7.05–7.25 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 22.2, 28.7, 29.5, 36.2, 51.7, 52.1,
120.9, 125.1, 127.8, 128.0, 128.5, 135.4, 139.8, 145.2, 171.1, 171.3.
IR (CHCl3): 1741, 1705, 1652 cm–1.
Dimethyl 2-(Diphenylmethylene)succinate (2l)
1H NMR (200 MHz, CDCl3): d = 0.85 (s, 9 H), 1.05–1.35 (m, 4 H),
1.80–2.05 (m, 4 H), 2.55–2.68 (m, 1 H), 3.40 (s, 2 H), 3.68 (s, 3 H),
3.73 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 27.5, 28.4, 28.7, 32.0, 32.2, 32.4,
34.7, 47.7, 51.5, 51.9, 117.0, 155.4, 168.9, 171.9.
Compound 2l was obtained from dimethyl succinate (1.46 g, 10.0
mmol) and benzophenone (2.18 g, 12.0 mmol) using the same pro-
cedure described above for 2a, as a solid (2.42 g, 78%); mp 82–
84 °C (Lit.8 mp 78–80 °C).
IR (CHCl3): 1739, 1712, 1620 cm–1.
Dimethyl 2-Cyclohexylidene-3-methylsuccinate (2h)
1H NMR (200 MHz, CDCl3): d = 3.47 (s, 2 H + 3 H), 3.70 (s, 3 H),
Compound 2h was obtained from dimethyl 2-methylsuccinate (1.60
g, 10.0 mmol) and cyclohexanone (1.18 g, 12.0 mmol) using the
same procedure described above for 2a, as a thick oil (1.27 g, 53%).
IR (CHCl3): 1743, 1726, 1632 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.32 (d, J = 8 Hz, 3 H), 1.50–1.75
(m, 6 H), 2.24 (t, J = 6 Hz, 2 H), 2.30–2.60 (m, 2 H), 3.64 (q, J = 8
Hz, 1 H), 3.67 (s, 3 H), 3.70 (s, 3 H).
7.05–7.20 (m, 4 H), 7.20–7.40 (m, 6 H).
13C NMR (50 MHz, CDCl3): d = 37.9, 51.5, 51.9, 124.5, 127.8 (2
C), 128.2, 128.3, 128.5, 128.9, 140.3, 141.7, 151.7, 169.8, 171.5.
Anal. Calcd for C19H18O4: C, 73.53; H, 5.85. Found: C, 73.70; H,
5.52.
(E)-Dimethyl 2-Cyclooct-1-enylsuccinate (3m)
Compound 3m was obtained from dimethyl succinate (1.46 g, 10.0
mmol) and cyclooctanone (1.51 g, 12.0 mmol) using the same pro-
cedure described above for 2a, as a thick oil8 (1.91 g, 75%).
IR (CHCl3): 1739, 1654 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.45 (br s, 8 H), 2.00–2.30 (m, 4
H), 2.49 (dd, J = 17, 6 Hz, 1 H), 2.96 (dd, J = 16, 10 Hz, 1 H), 3.51
(dd, J = 11, 4 Hz, 1 H), 3.67 (s, 3 H), 3.69 (s, 3 H), 5.58 (t, J = 8 Hz,
1 H).
13C NMR (50 MHz, CDCl3): d = 16.4, 26.4, 28.0, 28.2, 31.6, 32.9,
39.6, 51.3, 52.0, 124.7, 150.0, 169.0, 174.5.
Anal. Calcd for C13H20O4: C, 64.98; H, 8.39. Found: C, 64.64; H,
8.70.
Trimethyl 1-Cyclohexylidenepropane-1,2,3-tricarboxylate (2i)
Compound 2i was obtained from trimethyl propane-1,2,3-tricarbox-
ylate (2.18 g, 10.0 mmol) and cyclohexanone (1.18 g, 12.0 mmol)
using the same procedure described above for 2a, as a thick oil (1.55
g, 52%).
13C NMR (50 MHz, CDCl3): d = 26.0, 26.2, 26.3, 27.8, 29.0, 29.4,
35.6, 48.7, 51.8, 52.0, 128.8, 136.5, 172.5, 173.8.
IR (CHCl3): 1740, 1630 cm–1.
Synthesis 2010, No. 7, 1188–1194 © Thieme Stuttgart · New York

PAPER
Synthesis of Butenolides and Spirobutenolides
IR (CHCl3): 1761, 1726, 1630 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.13 (quint, J = 10 Hz, 2 H), 2.55–
2.65 (m, 2 H), 2.77–2.85 (m, 2 H), 3.94 (s, 3 H), 6.55 (s, 1 H).
1193
Methyl 10-Bromo-9-methyl-8-oxo-7-oxaspiro[5,4]decane-10-
carboxylate (5h)
Compound 5h was obtained from 2h (480 mg, 2.00 mmol) using the
same procedure described for 6a (see below), but in the absence of
Et3N, as a thick oil (513 mg, 84%).
13C NMR (125 MHz, CDCl3): d = 13.3, 31.8 (2 C), 52.7, 89.0,
125.9, 157.5, 161.6, 169.8.
IR (CHCl3): 1790, 1756 cm–1.
Anal. Calcd for C9H10O4: C, 59.34; H, 5.53. Found: C, 59.59; H,
5.70.
1H NMR (200 MHz, CDCl3): d = 1.31 (d, J = 6 Hz, 3 H), 1.50–1.80
(m, 8 H), 1.80–1.95 (m, 1 H), 2.04 (dd, J = 13, 6 Hz, 1 H), 3.25 (q,
J = 6 Hz, 1 H), 3.81 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 8.9, 22.0, 22.2, 24.7, 31.1, 34.9,
47.2, 53.6, 71.5, 86.8, 167.0, 173.4.
Methyl 7-Oxo-6-oxaspiro[4,4]non-8-ene-9-carboxylate (6e)
Compound 6e was obtained from 2e (424 mg, 2.00 mmol) using the
same procedure described above for 6a, as a thick oil5a (322 mg,
82%).
Methyl 2,2-Dimethyl-5-oxo-2,5-dihydrofuran-3-carboxylate
(6a); Typical Procedure
IR (CHCl3): 1767, 1730, 1630 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.75–2.10 (m, 6 H), 2.20–2.45 (m,
2 H), 3.88 (s, 3 H), 6.62 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 25.2, 37.0, 52.6, 97.1, 126.8, 158.2,
161.4, 170.1.
To a stirred solution of 2a (372 mg, 2.00 mmol) in CCl4 (25 mL)
was added a solution of Br2 (480 mg, 3.00 mmol) in CCl4 (5 mL) in
a dropwise fashion and the reaction mixture was stirred for 8 h at 25
°C. Then, Et3N (303 mg, 3.00 mmol) was added dropwise and the
mixture was further stirred for 2 h at 25 °C. The mixture was con-
centrated in vacuo. The obtained residue was dissolved in EtOAc
(50 mL), the organic layer washed with H2O (25 mL), brine
(25 mL), and dried (Na2SO4). Concentration of the organic layer in
vacuo, followed by silica gel column chromatographic purification
of the resulting residue using EtOAc–PE (1:9) as eluent afforded the
pure product 6a, as a thick oil5a (299 mg, 88%).
IR (CHCl3): 1764, 1730, 1633 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.63 (s, 6 H), 3.88 (s, 3 H), 6.58
(s, 1 H).
13C NMR (50 MHz, CDCl3): d = 25.1, 52.6, 87.2, 126.1, 160.9,
161.2, 169.8.
Anal. Calcd for C10H12O4: C, 61.22; H, 6.16. Found: C, 61.27; H,
6.04.
Methyl 8-Oxo-7-oxaspiro[5,4]dec-9-ene-10-carboxylate (6f)
Compound 6f was obtained from 2f (452 mg, 2.00 mmol) using the
same procedure described above for 6a, as a white solid (357 mg,
85%); mp 94–96 °C.
IR (CHCl3): 1761, 1732, 1628 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.20–1.45 (m, 1 H), 1.45–1.85 (m,
7 H), 2.05–2.25 (m, 2 H), 3.88 (s, 3 H), 6.60 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.9, 24.2, 33.5, 52.6, 89.1, 126.3,
161.0, 161.4, 170.1.
Anal. Calcd for C11H14O4: C, 62.85; H, 6.71. Found: C, 63.03; H,
6.88.
Ethyl 2,2-Dimethyl-5-oxo-2,5-dihydrofuran-3-carboxylate (6b)
Compound 6b was obtained from 2b (428 mg, 2.00 mmol) using the
same procedure described above for 6a, as a thick oil (320 mg,
87%).
IR (CHCl3): 1770, 1725, 1633 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.36 (t, J = 8 Hz, 3 H), 1.62 (s, 6
H), 4.33 (q, J = 8 Hz, 2 H), 6.57 (s, 1 H).
Methyl 3-tert-Butyl-8-oxo-7-oxaspiro[5,4]dec-9-ene-10-carbox-
ylate (6g)
Compound 6g was obtained from 2g (564 mg, 2.00 mmol) using the
same procedure described above for 6a, as a yellow solid (447 mg,
84%, 1:1 mixture of diastereomers); mp 86–88 °C.
13C NMR (50 MHz, CDCl3): d = 14.0, 25.1, 62.0, 87.2, 125.9,
IR (CHCl3): 1767, 1731, 1629 cm–1.
160.8, 161.3, 169.9.
1H NMR (200 MHz, CDCl3): d = 0.88 (s, 9 H), 0.99 (s, 9 H), 1.00–
1.90 (m, 14 H), 2.03–2.30 (m, 4 H), 3.87 (s, 6 H), 6.48 (s, 1 H), 6.59
(s, 1 H).
Anal. Calcd for C9H12O4: C, 58.69; H, 6.57. Found: C, 58.73; H,
6.49.
13C NMR (50 MHz, CDCl3): d = 21.8, 23.0, 27.4, 27.7, 32.4, 32.8,
33.0, 34.1, 43.0, 46.2, 52.6, 52.7, 89.0, 89.8, 125.4, 126.5, 161.0,
161.4, 161.8, 162.5, 170.1, 170.3.
Methyl 2-Isobutyl-2-methyl-5-oxo-2,5-dihydrofuran-3-carbox-
ylate (6c)
Compound 6c was obtained from 2c (456 mg, 2.00 mmol) using the
same procedure described above for 6a, as a thick oil (365 mg,
86%).
IR (neat): 1767, 1731, 1633 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.87 (d, J = 10 Hz, 3 H), 0.90 (d,
J = 10 Hz, 3 H), 1.55 (sept, J = 8 Hz, 1 H), 1.61 (s, 3 H), 1.84 (dd,
J = 14, 6 Hz, 1 H), 1.98 (dd, J = 14, 6 Hz, 1 H), 3.89 (s, 3 H), 6.62
(s, 1 H).
Methyl 9-Methyl-8-oxo-7-oxaspiro[5,4]dec-9-ene-10-carboxy-
late (6h)
Compound 6h was obtained from 2h (480 mg, 2.00 mmol) using the
same procedure described above for 6a, however, after addition of
Et3N, the reaction mixture was refluxed for 2 h to obtain 6h, as a
white solid (376 mg, 84%); mp 92–94 °C (Lit.9 mp 94 °C).
IR (CHCl3): 1760, 1723, 1660 cm–1.
13C NMR (50 MHz, CDCl3): d = 23.7, 24.0, 24.1, 25.0, 45.5, 52.6,
1H NMR (200 MHz, CDCl3): d = 1.15–1.37 (m, 1 H), 1.38–1.55 (m,
2 H), 1.60–1.85 (m, 5 H), 2.05–2.25 (m, 2 H), 2.16 (s, 3 H), 3.88 (s,
3 H).
13C NMR (50 MHz, CDCl3): d = 11.3, 22.1, 24.3, 33.7, 52.2, 87.8,
136.5, 151.8, 162.9, 172.2.
89.7, 126.8, 160.3, 161.4, 170.1.
Anal. Calcd for C11H16O4: C, 62.25; H, 7.60. Found: C, 62.33; H,
7.40.
Methyl 6-Oxo-5-oxaspiro[3,4]oct-7-ene-8-carboxylate (6d)
Compound 6d was obtained from 2d (198 mg, 1.00 mmol) using the
same procedure described above for 6a, as a thick oil5a (80 mg,
44%).
Anal. Calcd for C12H16O4: C, 64.27; H, 7.19. Found: C, 64.33; H,
7.08.
Synthesis 2010, No. 7, 1188–1194 © Thieme Stuttgart · New York

1194
R. M. Patel, N. P. Argade
PAPER
Dimethyl 8-Oxo-7-oxaspiro[5,4]dec-9-ene-9-methylene-10-di-
carboxylate (6i)
Compound 6i was obtained from 2i (596 mg, 2.00 mmol) using the
same procedure described above for 6a; however, after addition of
Et3N, the reaction mixture was refluxed for 2 h to obtain 6i, as a
white solid (463 mg, 82%); mp 104–106 °C.
IR (CHCl3): 1762, 1748, 1728, 1664 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.15–1.40 (m, 1 H), 1.45–1.90 (m,
7 H), 2.05–2.30 (m, 2 H), 3.69 (s, 2 H), 3.71 (s, 3 H), 3.87 (s, 3 H).
Ramos, A.; Pozuelo, J. M.; Domínguez, M. T. Org. Biomol.
Chem. 2004, 2, 1864. (e) Seitz, M.; Reiser, O. Curr. Opin.
Chem. Biol. 2005, 9, 285.
(2) Nauen, R.; Bretschneider, T.; Elbert, A.; Fischer, R.;
Tiemann, R. Pestic. Outlook 2003, (December), 243.
(3) (a) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M. J. Am. Chem. Soc. 2008,
130, 7202. (b) Boukouvalas, J.; Loach, R. P. J. Org. Chem.
2008, 73, 8109. (c) Boto, A.; Hernández, D.; Hernández, R.
J. Org. Chem. 2008, 73, 5287. (d) Yamaguchi, A.;
Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10, 2319.
(e) Lebel, H.; Parmentier, M. Org. Lett. 2007, 9, 3563.
(4) Hyde, A. M.; Buchwald, S. L. Org. Lett. 2009, 11, 2663; and
references cited therein.
(5) (a) Geraghty, N. W. A.; Hernon, E. M. Tetrahedron Lett.
2009, 50, 570. (b) Zhao, Y.-M.; Gu, P.; Tu, Y.-Q.; Fan, C.-
A.; Zhang, Q. Org. Lett. 2008, 10, 1763. (c) Greco, G. E.;
Gleason, B. L.; Lowery, T. A.; Kier, M. J.; Hollander, L. B.;
Gibbs, S. A.; Worthy, A. D. Org. Lett. 2007, 9, 3817.
(d) Ma, S.; Lu, L.; Lu, P. J. Org. Chem. 2005, 70, 1063.
(e) Robertson, J.; Meo, P.; Dallimore, J. W. P.; Doyle, B. M.;
Hoarau, C. Org. Lett. 2004, 6, 3861. (f) Yoneda, E.;
Kaneko, T.; Zhang, S.-W.; Onitsuka, K.; Takahashi, S. Org.
Lett. 2000, 2, 441. (g) Harrowven, D. C.; Hannam, J. C.
Tetrahedron 1999, 55, 9341.
13C NMR (50 MHz, CDCl3): d = 22.1, 24.3, 30.6, 33.6, 52.4, 52.5,
88.4, 132.9, 154.7, 162.1, 169.0, 171.0.
Anal. Calcd for C14H18O6: C, 59.57; H, 6.43. Found: C, 59.70; H,
6.35.
Methyl 9-Oxo-8-oxaspiro[6,4]undec-10-ene-11-carboxylate (6j)
Compound 6j was obtained from 2j (480 mg, 2.00 mmol) using the
same procedure described above for 6a, as a white solid (372 mg,
83%); mp 70–72 °C.
IR (CHCl3): 1767, 1732, 1634 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.50–2.00 (m, 10 H), 2.10–2.33
(m, 2 H), 3.87 (s, 3 H), 6.51 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 22.9, 28.1, 37.3, 52.6, 92.4, 125.0,
161.6, 162.3, 170.5.
(6) (a) Haval, K. P.; Argade, N. P. J. Org. Chem. 2008, 73,
6936. (b) Wakchaure, P. B.; Easwar, S.; Puranik, V. G.;
Argade, N. P. Tetrahedron 2008, 64, 1786. (c) Baag, M.
M.; Puranik, V. G.; Argade, N. P. J. Org. Chem. 2007, 72,
1009.
Anal. Calcd for C12H16O4: C, 64.27; H, 7.19. Found: C, 64.43; H,
7.28.
(7) Thomas, C. J.; Wolak, M. A.; Birge, R. R.; Lees, W. J.
J. Org. Chem. 2001, 66, 1914.
Acknowledgment
(8) (a) Gupta, G.; Banerjee, S. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1990, 29, 787. (b) Asiri, A. M.;
Salem, A.-J. S. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 1999, 38, 488. (c) Lee, W.-W. W.; Gan, L.-M.;
Loh, T.-P. Synlett 2005, 2473.
R.M.P. thanks CSIR, New Delhi for the award of a research fel-
lowship. N.P.A. thanks Department of Science and Technology,
New Delhi for financial support.
(9) Paris, J.; Gouet, E.; Payard, M.; Reboul-Salze, S.; Hartmann,
L.; Tronche, P. Eur. J. Med. Chem. 1982, 17, 563; and
references cited therein.
(10) Ballini, R.; Bosica, G.; Damianl, M.; Righi, P. Tetrahedron
1999, 55, 13451.
References
(1) (a) Rao, Y. S. Chem. Rev. 1976, 76, 625. (b) Avetisyan, A.
A.; Dangyan, M. T. Russ. Chem. Rev. 1977, 46, 643.
(c) Figadère, B. Acc. Chem. Res. 1995, 28, 359. (d) Braña,
M. F.; García, M. L.; López, B.; de Pascual-Teresa, B.;
Synthesis 2010, No. 7, 1188–1194 © Thieme Stuttgart · New York