Regioselective monoalkylation of dimethyl alkylidenesuccinates: Simple approach to dialkyl-substituted maleic anhydrides including chaetomellic acid A

Article abstract of DOI:10.1055/s-0030-1260013

Natural and nonnatural dialkylmaleic anhydrides were readily prepared from dimethyl alkylidenesuccinates by sodium hexamethyldisilazide-induced selective monoalkylation followed by base-catalyzed hydrolysis. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260013

1804
PAPER
Regioselective Monoalkylation of Dimethyl Alkylidenesuccinates: Simple
Approach to Dialkyl-Substituted Maleic Anhydrides Including Chaetomellic
Acid A
Regioselective
A
lk
m
ylation of
D
imethy
e
l
A
lkyliden
s
esuccinate
h
s
A. Kshirsagar, 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 10 February 2011; revised 25 March 2011
natural products have been reported in recent times, in-
Abstract: Natural and nonnatural dialkylmaleic anhydrides were
readily prepared from dimethyl alkylidenesuccinates by sodium
hexamethyldisilazide-induced selective monoalkylation followed
by base-catalyzed hydrolysis.
cluding several from our research group.13,14 In continua-
tion of our studies on cyclic anhydride chemistry,14,15 we
felt that the selective alkylation of readily available di-
methyl alkylidenesuccinates would provide a robust and
general approach to the target compounds. With this per-
spective, we report our results on simple and efficient syn-
theses of natural and nonnatural dialkylmaleic
anhydrides.
Key words: esters, alkylations, furans, heterocycles, maleic anhy-
drides
Maleic anhydrides and their derivatives are potentially
useful as building blocks for the synthesis of a diverse
range of structurally interesting, complex, bioactive, nat-
ural and nonnatural products or polymers with the tailored
material characteristics.1 Recently, large number of alky-
lated methyl-substituted maleic anhydrides has been iso-
lated as bioactive natural products, and we surmise that
these might be produced naturally by condensation of
suitable long-chain acids with pyruvic acid (Figure 1).2–12
Many well-designed product-specific syntheses of these
Dimethyl alkylidenesuccinates can be readily obtained by
treatment of dimethyl maleate with trialkylphosphine and
aldehydes16 or with 1,8-diazabicyclo[5.4.0]undec-7-ene
and nitroalkanes.17 As shown in Table 1, the reactions of
an in situ generated Wittig adduct from dimethyl maleate
and tributylphosphine with variety of aldehydes at room
temperature provided the desired (E)-dimethyl alkyli-
denesuccinates (2a–g) in 68–78% yields within 24–30
hours.
O
O
O
O
O
O
O
O
O
O
O
O
12
chaetomellic acid A anhydride
(ras farnesyl protein transferase
inhibitor)5
2-ethyl-3-methylmaleic anhydride
(flavoring agent)2
2-hexyl-3-methylmaleic anhydride
(flavoring agent)3
2-octyl-3-methylmaleic anhydride
(flavoring agent)4
COOH
OH
O
O
O
O
COOH
R
4
12
6
O
O
O
O
O
O
O
O
itaconitin (activity unknown)8
aspergillus acid A [R = (CH2)3OAc]
aspergillus acid B [R = Ac]
(S)-aspergillus acid C [R = CH(OH)Me]
(S)-aspergillus acid D [R = CH(OAc)Me]
(activity unknown)6
maleic anhydride segment of
tautomycin (antifungal & antibiotic)7
chaetomellic acid B anhydride
(ras farnesyl protein transferase
inhibitor)5
O
O
O
O
O
COOH
O
O
O
O
COOH
COOH
O
O
O
O
graphenone (activity unknown)9
2-carboxymethyl-3-hexylmaleic
anhydride (in vitro activity against
Gram-positive bacteria)11
telfairic anhydride (activity unknown)10
2-(2-carboxyethyl)-3-hexylmaleic
anhydride (activity unknown)12
Figure 1 Naturally occurring dialkyl-substituted maleic anhydrides
SYNTHESIS 2011, No. 11, pp 1804–1808
x
x.
x
x
.
2
0
1
1
Advanced online publication: 20.04.2011
DOI: 10.1055/s-0030-1260013; Art ID: Z18711SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Regioselective Alkylation of Dimethyl Alkylidenesuccinates
1805
silazide. As summarized in Table 2, the carbanionic spe-
cies generated from compounds 2a–g reacted smoothly
with methyl iodide, allyl bromide, benzyl bromide, or
methyl bromoacetate to give the required monoalkylated
products 3a–j in 79–93% yields. Unfortunately, however,
the allylic carbanionic species generated from substrates
3b and 3h failed to react with a secondary halide (2-bro-
mopropane) under similar conditions.
Table 1 Synthesis of Dimethyl (2E)-2-Alkylidenesuccinates
MeOOC
MeOOC
RCHO, n-Bu3P
THF, r.t.
R
MeOOC
MeOOC
1
2a–g
Entry
RCHO
Time (h) Product Yield (%)
1
2
3
4
5
6
7
MeCH2CHO
24
24
24
24
30
30
24
2a
2b
2c
2d
2e
2f
72
78
71
68
74
72
76
The base-catalyzed hydrolysis of two different ester units
in compounds 3b, 3d, 3f, and 3h to give the corresponding
dicarboxylic acids, followed by acetic anhydride-induced
ring closure and concomitant exocyclic to endocyclic car-
bon–carbon double-bond isomerization gave the corre-
sponding dialkylated maleic anhydrides 4a–d in 73–91%
yields (Table 3); product 4d is a precursor of maculalac-
tones A–C.18 Base-catalyzed hydrolysis of triester 3i fol-
lowed by acidification with hydrochloric acid gave the
natural product 4e in 65% yield through isomerization of
the carbon–carbon double bond followed by instanta-
neous dehydrative ring closure. The analytical and spec-
tral data obtained for all the above-mentioned natural
products were in complete agreement with the reported
data.3,5,11,14a,18d More distinctively, starting from dimethyl
maleate (1), the naturally occurring ras FPTase inhibitor
chaetomellic acid A anhydride (4b) was obtained in three
straightforward steps with 53% overall yield.
Me(CH2)4CHO
Me(CH2)8CHO
Me(CH2)12CHO
PMBO(CH2)2CHO
PMBO(CH2)3CHO
PhCHO
2g
We devised a systematic plan for studying the base-cata-
lyzed alkylation of our prospective precursors 2a–g, with
the aim of developing a new and simple approach to a di-
verse range of dialkylmaleic anhydrides. In principle, the
action of a base on substrates 2a–f should form reactive
allylic carbanions at either the a-position of the ester unit
or the g-position of a,b-unsaturated systems with effective
extended delocalization of the p-cloud. In our hands, the
use of sodium hydride as the base for generating carban-
ions from substrates 2a and 2d resulted in excessive de-
composition of the starting materials. The best results
were obtained by using sodium hexamethyldisilazide
(1.20 equiv) as the base in tetrahydrofuran as solvent at
–78 °C; this produced the allylic carbanion regioselective-
ly at the a-position of the ester unit of the substrates 2a–f.
As expected, substrate 2g also formed the corresponding
allylic carbanion on treatment with sodium hexamethyldi-
In summary, we have demonstrated a new general proto-
col for the synthesis of natural and unnatural symmetrical/
unsymmetrical dialkyl-substituted maleic anhydrides
through regioselective generation of carbanions from
dimethyl alkylidenesuccinates, followed by selective
monocondensation with primary alkyl halides, allyl ha-
lides, benzyl halides, or activated alkyl halides, and sub-
sequent base-catalyzed hydrolysis and ring closure with
the exocyclic to endocyclic carbon–carbon double-bond
rearrangement. We feel that the present approach to di-
alkylmaleic anhydrides is noteworthy and will be useful
for producing a focused library of derivatives and conge-
ners for studies of structure–activity relationships.
Table 2 Regioselective Monoalkylation of Dimethyl (2E)-2-Alky-
lidenesuccinates
(i) NaHMDS, THF
MeOOC
MeOOC
MeOOC
R1
R1
–78 °C, 30 min
(ii) R2X, 45 min
Table 3 Synthesis of Natural and Nonnatural Dialkylmaleic Anhy-
drides
R2
3a–j
MeOOC
2a–g
O
(i) KOH, THF–H2O (1:1)
MeOOC
Entry R1
R2X
MeI
MeI
MeI
MeI
MeI
MeI
Product Yield (%)
R1
R1
r.t., 2 h
O
(ii) Ac2O, reflux, 2 h
MeOOC
3b,d,f,h,i
R2
1
2
Et
3a
3b
3c
3d
3e
3f
93
91
85
88
85
81
82
92
86
79
R2
O
(CH2)4Me
(CH2)8Me
(CH2)12Me
(CH2)2OPMB
(CH2)3OPMB
(CH2)4Me
Ph
4a–d
4e (R2 = CH2COOH)
3
Entry
R1
(CH2)4Me
R2
Product
4a
Yield (%)
4
1
Me
83
89
73
91
65
5
2
(CH2)12Me
(CH2)3OPMB
Ph
Me
4b
6
3
Me
4c
7
CH2=CHCH2Br
3g
3h
3i
4
Bn
4d
8
BnBr
5a
(CH2)4Me
CH2CO2Me
4e
9
(CH2)4Me
(CH2)8Me
MeO2CCH2Br
MeO2CCH2Br
a Reaction conditions: (i) aq KOH, THF–MeOH (1:2), reflux, 2 h; (ii)
H+/HCl.
10
3j
Synthesis 2011, No. 11, 1804–1808 © Thieme Stuttgart · New York

1806
U. A. Kshirsagar, N. P. Argade
PAPER
The1H NMR spectra were recorded on Bruker NMR spectrometers
operating at 200, 400 and 500 MHz, respectively, with TMS as an
internal standard. The 13C NMR spectra were recorded on the same
instruments operating at 50, 100 and 125 MHz. The IR spectra were
recorded on a Shimadzu FT-IR spectrometer. Column chromato-
graphic separations were carried out on silica gel (60–120 mesh).
Commercially available dimethyl maleate, NaHMDS, and n-Bu3P
were used.
4.44 (s, 2 H), 6.80–6.95 (m, 2 H), 6.97 (t, J = 8 Hz, 1 H), 7.20–7.30
(m, 2 H).
13C NMR (CDCl3, 50 MHz): d = 29.6, 32.2, 52.0 (2 C), 55.2, 67.9,
72.7, 113.7, 126.8, 129.2, 130.1, 142.3, 159.2, 167.1, 171.1.
Anal. Calcd for C17H22O6: C, 63.34; H, 6.88. Found: C, 63.46; H,
7.16.
Dimethyl (2E)-2-{4-[(4-Methoxybenzyl)oxy]butylidene}succi-
nate (2f)
Dimethyl (2E)-2-Propylidenesuccinate (2a)17d; Typical Proce-
dure
IR (CHCl3): 1740, 1712, 1653 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.76 (quint, J = 8 Hz, 2 H), 2.30
(q, J = 8 Hz, 2 H), 3.37 (s, 2 H), 3.46 (t, J = 8 Hz, 2 H), 3.68 (s, 3
H), 3.75 (s, 3 H), 3.81 (s, 3 H), 4.42 (s, 2 H), 6.80–6.95 (m, 2 H),
6.97 (t, J = 8 Hz, 1 H), 7.20–7.32 (m, 2 H).
13C NMR (CDCl3, 50 MHz): d = 25.5, 28.3, 31.9, 51.83, 51.85, 55.1,
68.7, 72.5, 113.6, 125.7, 129.1, 130.3, 145.2, 159.0, 167.2, 171.2.
n-Bu3P (1.30 mL, 5.21 mmol) was slowly added by syringe to a
stirred soln of dimethyl maleate (1, 0.50 g, 3.47 mmol) and EtCHO
(0.20 g, 3.47 mmol) in THF (1 mL) at r.t. under N2. The mixture was
stirred for 24 h and then diluted with CH2Cl2 (15 mL). 35% aq H2O2
(5 mL) was added to oxidize unreacted n-Bu3P, and the mixture was
stirred for additional 30 min. The organic layer was washed with
H2O (10 mL), sat. aq NaHCO3 (10 mL), and brine (10 mL) then
dried (Na2SO4) and concentrated. The residue was purified by col-
umn chromatography [silica gel, PE–EtOAc (85:15)] to give a thick
oil; yield: 0.47 g (72%).
Anal. Calcd for C18H24O6: C, 64.27; H, 7.19. Found: C, 63.92; H,
7.27.
Dimethyl (2E)-2-Benzylidenesuccinate (2g)16b
IR (neat): 1742, 1723, 1653 cm–1.
IR (CHCl3): 1733, 1715, 1641 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.03 (t, J = 8 Hz, 3 H), 2.17 (quint,
J = 8 Hz, 2 H), 3.32 (s, 2 H), 3.65 (s, 3 H), 3.71 (s, 3 H), 6.93 (t, J = 4
Hz, 1 H).
13C NMR (CDCl3, 50 MHz): d = 12.8, 22.2, 31.8, 51.8, 51.9, 124.6,
147.4, 167.3, 171.2.
1H NMR (CDCl3, 200 MHz): d = 3.55 (s, 2 H), 3.74 (s, 3 H), 3.84
(s, 3 H), 7.30–7.50 (m, 5 H), 7.92 (s, 1 H).
13C NMR (CDCl3, 50 MHz): d = 33.3, 52.0, 52.1, 125.7, 128.5,
128.8, 128.9, 134.8, 142.0, 167.6, 171.5.
Dimethyl (3E)-2-Methyl-3-propylidenesuccinate (3a); Typical
Procedure
Dimethyl (2E)-2-Hexylidenesuccinate (2b)17b
IR (neat): 1733, 1715, 1657 cm–1.
A 1 M soln of NaHMDS in THF (1.30 mL, 1.30 mmol) was added
to a stirred soln of alkylidenesuccinate 2a (0.20 g, 1.08 mmol) in
THF (5 mL) at –78 °C, and reaction mixture was stirred at –78 °C
for 30 min. MeI (0.07 mL, 1.08 mmol) was then added dropwise at
–78 °C, and the mixture was stirred at –78 °C for 45 min. The reac-
tion was quenched with sat. aq NH4Cl (2 mL), and the mixture was
concentrated in vacuo. The residue was dissolved in EtOAc (20
mL), and the organic layer was washed with H2O (10 mL) and brine
(10 mL), dried (Na2SO4), and concentrated in vacuo. The residue
was purified by column chromatography [silica gel, PE–EtOAc
(85:15)] to give a thick oil; yield: 0.20 g (93%).
1H NMR (CDCl3, 400 MHz): d = 0.89 (t, J = 8 Hz, 3 H), 1.25–1.37
(m, 4 H), 1.46 (quint, J = 8 Hz, 2 H), 2.19 (q, J = 8 Hz, 2 H), 3.36
(s, 2 H), 3.68 (s, 3 H), 3.75 (s, 3 H), 6.98 (t, J = 8 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): d = 13.8, 22.3, 28.0, 28.8, 31.3, 32.0,
51.8, 51.9, 125.1, 146.1, 167.3, 171.2.
Dimethyl (2E)-2-Decylidenesuccinate (2c)
IR (CHCl3): 1736, 1718, 1655 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.88 (t, J = 8 Hz, 3 H), 1.26 (br s,
12 H), 1.45 (quint, J = 8 Hz, 2 H), 2.18 (q, J = 8 Hz, 2 H), 3.36 (s,
2 H), 3.68 (s, 3 H), 3.75 (s, 3 H), 6.98 (t, J = 8 Hz, 1 H).
IR (CHCl3): 1746, 1715, 1643 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.07 (t, J = 8 Hz, 3 H), 1.32 (d,
J = 8 Hz, 3 H), 2.20 (d quint, J = 8, 4 Hz, 2 H), 3.59 (q, J = 8 Hz, 1
H), 3.65 (s, 3 H), 3.71 (s, 3 H), 6.83 (t, J = 8 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): d = 13.0, 15.8, 21.8, 37.5, 51.7, 51.9,
131.5, 145.5, 166.9, 174.1.
13C NMR (CDCl3, 50 MHz): d = 14.0, 22.6, 28.4, 28.9, 29.2, 29.25,
29.34, 29.4, 31.8, 32.0, 51.87, 51.91, 125.2, 146.2, 167.4, 171.3.
Anal. Calcd for C16H28O4: C, 67.57; H, 9.92. Found: C, 67.19; H,
9.65.
Dimethyl (2E)-2-Tetradecylidenesuccinate (2d)
Anal. Calcd for C10H16O4: C, 59.98; H, 8.05. Found: C, 60.37; H,
7.69.
IR (CHCl3): 1735, 1718, 1654 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.88 (t, J = 6 Hz, 3 H), 1.26 (br s,
20 H), 1.45 (quint, J = 8 Hz, 2 H), 2.18 (q, J = 8 Hz, 2 H), 3.36 (s,
2 H), 3.69 (s, 3 H), 3.75 (s, 3 H), 6.98 (t, J = 8 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): d = 14.0, 22.6, 28.4, 28.9, 29.26, 29.29,
29.34, 29.5, 29.6 (4 C), 31.9, 32.0, 51.87, 51.91, 125.1, 146.2,
167.4, 171.3.
Dimethyl (2E)-2-Hexylidene-3-methylsuccinate (3b)15b
IR (neat):1742, 1730 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.85 (t, J = 8 Hz, 3 H), 1.20–1.35
(m, 4 H), 1.29 (d, J = 6 Hz, 3 H), 1.43 (quint, J = 6 Hz, 2 H), 2.14
(dq, J = 8, 4 Hz, 2 H), 3.56 (q, J = 6 Hz, 1 H), 3.61 (s, 3 H), 3.67 (s,
3 H), 6.80 (t, J = 8 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): d = 13.8, 15.7, 22.3, 28.1, 28.4, 31.4,
37.5, 51.5, 51.7, 131.9, 144.1, 166.8, 174.0.
Anal. Calcd for C20H36O4: C, 70.55; H, 10.66. Found: C, 70.27; H,
10.46.
Dimethyl (2E)-2-{3-[(4-Methoxybenzyl)oxy]propylidene}succi-
nate (2e)
Dimethyl (2E)-2-Decylidene-3-methylsuccinate (3c)
IR (CHCl3): 1734, 1726, 1647 cm–1.
IR (CHCl3): 1740, 1714, 1657 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.88 (t, J = 6 Hz, 3 H), 1.26 (br s,
12 H), 1.34 (d, J = 6 Hz, 3 H), 1.46 (quint, J = 6 Hz, 2 H), 2.19 (dq,
1H NMR (CDCl3, 200 MHz): d = 2.48 (q, J = 8 Hz, 2 H), 3.37 (s, 2
H), 3.54 (t, J = 6 Hz, 2 H), 3.66 (s, 3 H), 3.74 (s, 3 H), 3.80 (s, 3 H),
Synthesis 2011, No. 11, 1804–1808 © Thieme Stuttgart · New York

PAPER
Regioselective Alkylation of Dimethyl Alkylidenesuccinates
1807
J = 7, 4 Hz, 2 H), 3.60 (q, J = 8 Hz, 1 H), 3.66 (s, 3 H), 3.72 (s, 3
H), 6.85 (t, J = 8 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): d = 14.0, 15.8, 22.6, 28.51, 28.53, 29.2,
29.3, 29.36, 29.43, 31.8, 37.6, 51.7, 51.9, 131.9, 144.3, 166.9,
174.2.
13C NMR (CDCl3, 50 MHz): d = 35.9, 45.2, 52.0, 52.2, 126.1,
128.06, 128.11, 128.15, 128.19, 129.1, 130.4, 135.0, 138.9, 142.9,
167.0, 173.1.
Trimethyl (3E)-Non-3-ene-1,2,3-tricarboxylate (3i)17a
IR (CHCl3): 1735, 1650 cm–1.
Anal. Calcd for C17H30O4: C, 68.42; H, 10.13. Found: C, 68.13; H,
9.81.
1H NMR (CDCl3, 200 MHz): d = 0.89 (t, J = 6 Hz, 3 H), 1.20–1.40
(m, 4 H), 1.47 (quint, J = 6 Hz, 2 H), 2.14–2.40 (m, 2 H), 2.44 (dd,
J = 12, 6 Hz, 1 H), 3.21 (dd, J = 16, 8 Hz, 1 H), 3.66 (s, 3 H), 3.69
(s, 3 H), 3.73 (s, 3 H), 4.13 (dd, J = 8, 6 Hz, 1 H), 6.95 (t, J = 8 Hz,
1 H).
13C NMR (CDCl3, 50 MHz): d = 13.9, 22.4, 28.2, 28.7, 31.5, 35.2,
39.4, 51.8, 51.9, 52.3, 129.2, 146.8, 166.6, 172.4, 172.6.
Dimethyl (3E)-2-Methyl-3-tetradecylidenesuccinate (3d)15b
IR (CHCl3): 1739, 1712, 1646 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.88 (t, J = 6 Hz, 3 H), 1.26 (br s,
20 H), 1.34 (d, J = 8 Hz, 3 H), 1.47 (quint, J = 6 Hz, 2 H), 2.19 (dq,
J = 7, 4 Hz, 2 H), 3.61 (q, J = 8 Hz, 1 H), 3.66 (s, 3 H), 3.73 (s, 3
H), 6.86 (t, J = 8 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): d = 14.1, 15.9, 22.7, 28.6, 29.3, 29.36,
29.40, 29.5, 29.6 (5 C), 31.9, 37.6, 51.8, 52.0, 131.9, 144.4, 166.9,
174.2.
Trimethyl (3E)-Tridec-3-ene-1,2,3-tricarboxylate (3j)
IR (CHCl3): 1735, 1646 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.88 (t, J = 8 Hz, 3 H), 1.26 (br s,
12 H), 1.46 (quint, J = 8 Hz, 2 H), 2.13–2.40 (m, 2 H), 2.44 (dd,
J = 12, 6 Hz, 1 H), 3.21 (dd, J = 18, 8 Hz, 1 H), 3.66 (s, 3 H), 3.69
(s, 3 H), 3.72 (s, 3 H), 4.12 (dd, J = 8, 8 Hz, 1 H), 6.95 (t, J = 8 Hz,
1 H).
13C NMR (CDCl3, 50 MHz): d = 14.0, 22.6, 28.5, 28.7, 29.2, 29.3,
29.35, 29.43, 31.8, 35.2, 39.4, 51.75, 51.78, 52.2, 129.2, 146.7,
166.5, 172.4, 172.5.
Dimethyl (2E)-2-{3-[(4-Methoxybenzyl)oxy]propylidene}-3-
methylsuccinate (3e)
IR (neat): 1740, 1716, 1648 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.34 (d, J = 6 Hz, 3 H), 2.50 (dq,
J = 8, 2 Hz, 2 H), 3.55 (t, J = 6 Hz, 2 H), 3.60 (q, J = 6 Hz, 1 H),
3.64 (s, 3 H), 3.73 (s, 3 H), 3.81 (s, 3 H), 4.46 (s, 2 H), 6.86–6.93
(m, 3 H), 7.21–7.30 (m, 2 H).
13C NMR (CDCl3, 50 MHz): d = 15.7, 29.2, 37.8, 51.7, 51.9, 55.2,
68.0, 72.7, 113.7, 129.2, 130.1, 133.5, 140.3, 159.2, 166.6, 173.9.
Anal. Calcd for C19H32O6: C, 64.02; H, 9.05. Found: C, 63.64; H,
8.94.
3-Hexyl-4-methylfuran-2,5-dione (4a);14i Typical Procedure
20% aq KOH (5 mL) was added to a stirred soln of diester 3b (100
mg, 0.42 mmol) in THF (5 mL), and the mixture was stirred at r.t.
for 2 h. The solvent was removed in vacuo and the residue was acid-
ified to pH 2 with 2 M HCl. The mixture was extracted with Et2O
(3 × 10 mL) and the organic layer was washed with brine (10 mL),
dried (Na2SO4), and concentrated in vacuo. Ac2O (5 mL) was added
to the residue and the mixture was refluxed for 2 h. The mixture was
then concentrated in vacuum and the residue was purified by col-
umn chromatography [silica gel, PE–EtOAc (8:2)] to give a thick
oil; yield: 68 mg (83%).
Anal. Calcd for C18H24O6: C, 64.27; H, 7.19. Found: C, 63.87; H,
6.94.
Dimethyl (2E)-2-{4-[(4-Methoxybenzyl)oxy]butylidene}-3-
methylsuccinate (3f)
IR (CHCl3): 1735, 1715, 1647 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.34 (d, J = 6 Hz, 3 H), 1.77
(quint, J = 8 Hz, 2 H), 2.18–2.42 (m, 2 H), 3.48 (t, J = 6 Hz, 2 H),
3.62 (q, J = 6 Hz, 1 H), 3.66 (s, 3 H), 3.73 (s, 3 H), 3.81 (s, 3 H),
4.42 (s, 2 H), 6.80–6.93 (m, 3 H), 7.21–7.30 (m, 2 H).
13C NMR (CDCl3, 50 MHz): d = 15.8, 25.3, 28.6, 37.6, 51.7, 51.9,
55.2, 68.9, 72.6, 113.8, 129.2, 130.4, 132.5, 143.4, 159.2, 166.8,
174.1.
IR (neat): 1765, 1655 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.90 (m, 3 H), 1.15–1.45 (m, 6 H),
1.45–1.70 (m, 2 H), 2.08 (s, 3 H), 2.46 (t, J = 7 Hz, 2 H).
13C NMR (CDCl3, 50 MHz): d = 9.4, 12.0, 22.4, 24.4, 27.6, 29.0,
31.3, 140.5, 144.7, 165.8, 166.4.
Anal. Calcd for C19H26O6: C, 65.13; H, 7.48. Found: C, 65.43; H,
7.90.
Dimethyl (3E)-2-Allyl-3-hexylidenesuccinate (3g)
3-Methyl-4-tetradecylfuran-2,5-dione (4b; Chaetomellic AcidA
Anhydride)14i
IR (CHCl3): 1743, 1716, 1644 cm-1.
IR (neat): 1770, 1680 cm–1.
1H NMR (CDCl3, 500 MHz): d = 0.90 (t, J = 10 Hz, 3 H), 1.26–1.36
(m, 4 H), 1.77 (quint, J = 10 Hz, 2 H), 2.10–2.25 (m, 2 H), 2.36–
2.45 (m, 1 H), 2.81–2.88 (m, 1 H), 3.57 (dd, J = 10, 5 Hz, 1 H), 3.66
(s, 3 H), 3.72 (s, 3 H), 4.98 (dd, J = 10, 2 Hz, 1 H), 5.03 (dd, J = 15,
5 Hz, 1 H), 5.66–5.76 (m, 1 H), 6.94 (t, J = 10 Hz, 1 H).
13C NMR (CDCl3, 125 MHz): d = 13.9, 22.4, 28.2, 28.8, 31.5, 34.4,
43.1, 51.8, 52.0, 116.8, 129.5, 135.8, 145.8, 166.9, 173.2.
1H NMR (CDCl3, 200 MHz): d = 0.88 (t, J = 7 Hz, 3 H), 1.15–1.45
(br s, 22 H), 1.46–1.69 (m, 2 H), 2.07 (s, 3 H), 2.45 (t, J = 7 Hz, 2
H).
13C NMR (CDCl3, 50 MHz): d = 9.6, 14.3, 22.9, 24.6, 27.7, 29.0–
31.0 (9 C), 32.1, 140.6, 144.9, 166.0, 166.4.
3-{4-[(4-Methoxybenzyl)oxy]butyl}-4-methylfuran-2,5-dione
Anal. Calcd for C15H24O4: C, 67.14; H, 9.01. Found: C, 66.83; H,
9.40.
(4c)
IR (CHCl3): 1822, 1764, 1613 cm–1.
Dimethyl (3E)-2-Benzyl-3-benzylidenesuccinate (3h)15g
1H NMR (CDCl3, 200 MHz): d = 1.55–1.80 (m, 4 H), 2.05 (s, 3 H),
2.48 (t, J = 8 Hz, 2 H), 3.46 (t, J = 6 Hz, 2 H), 3.81 (s, 3 H), 4.43 (s,
2 H), 6.89 (d, J = 10 Hz, 2 H), 7.26 (d, J = 12 Hz, 2 H).
13C NMR (CDCl3, 50 MHz): d = 9.5, 24.1, 24.4, 29.4, 55.2, 69.1,
72.6, 113.7, 129.3, 130.3, 140.7, 144.3, 159.1, 165.8, 166.2.
IR (CHCl3): 1735, 1715, 1637 cm–1.
1H NMR (CDCl3, 200 MHz): d = 2.98 (dd, J = 14, 10 Hz, 1 H), 3.41
(dd, J = 14, 6 Hz, 1 H), 3.73 (s, 3 H), 3.84 (s, 3 H), 4.00 (dd, J = 10,
6 Hz, 1 H), 6.80–6.92 (m, 4 H), 7.05–7.17 (m, 2 H), 7.18–7.31 (m,
4 H), 7.75 (s, 1 H).
Anal. Calcd for C17H20O5: C, 67.09; H, 6.62. Found: C, 67.37; H,
6.96.
Synthesis 2011, No. 11, 1804–1808 © Thieme Stuttgart · New York

1808
U. A. Kshirsagar, N. P. Argade
PAPER
3,4-Dibenzylfuran-2,5-dione (4d)18d
(13) (a) Dardennes, E.; Labano, S.; Simpkins, N. S.; Wilson, C.
Tetrahedron Lett. 2007, 48, 6380. (b) Alizadeh, A.;
Movahedi, F.; Esmaili, A. A. Tetrahedron Lett. 2006, 47,
4469. (c) Kishorebabu, N.; Periasamy, M. Tetrahedron Lett.
2006, 47, 2107. (d) Bellesia, F.; Danieli, C.; De Buyck, L.;
Galeazzi, R.; Ghelfi, F.; Mucci, A.; Orena, M.; Pagnoni, U.
M.; Parsons, A. F.; Roncaglia, F. Tetrahedron 2006, 62,
746. (e) De Buyck, L.; Danieli, C.; Ghelfi, F.; Pagnoni, U.
M.; Parsons, A. F.; Pattarozzi, M.; Roncaglia, F.
IR (CHCl3): 1769 cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.78 (s, 4 H), 7.05–7.20 (m, 4 H),
7.20–7.35 (m, 6 H).
13C NMR (CDCl3, 50 MHz): d = 29.9, 127.1, 128.6, 128.8, 134.9,
142.7, 165.6.
2-(4-Hexyl-2,5-dioxo-2,5-dihydrofuran-3-yl)acetic Acid (4e)14c
20% aq KOH (5 mL) was added to a stirred soln of triester 3i (100
mg, 0.34 mmol) in 1:2 THF–MeOH (5 mL) and the mixture was
stirred and refluxed for 2 h. The mixture was then concentrated in
vacuo and the residue was acidified to pH 2 with 2 M HCl. The mix-
ture was extracted with Et2O (3 × 10 mL) and the organic layer was
washed with brine (10 mL), dried (Na2SO4), and concentrated in
vacuo. The residue was purified by column chromatography [silica
gel, PE–EtOAc (7:3)] to give a thick oil; yield: 52 mg (65%).
Tetrahedron 2005, 61, 2871. (f) Brown, G. D.; Wong, H.-F.
Tetrahedron 2004, 60, 5439. (g) Kurono, M.; Isobe, M.
Tetrahedron 2004, 60, 1773. (h) Spiegel, D. A.; Njardarson,
J. T.; McDonald, I. M.; Wood, J. L. Chem. Rev. 2003, 103,
2691. (i) Nicolaou, K. C.; Zhong, Y. L.; Baran, P. S.; Jung,
J.; Choi, H. S.; Yoon, W. H. J. Am. Chem. Soc. 2002, 124,
2202. (j) Adlington, R. M.; Baldwin, J. E.; Cox, R. J.;
Pritchard, G. J. Synlett 2002, 820. (k) Bellina, F.; Rossi, R.
Synthesis 2002, 2729. (l) Tan, Q.; Danishefsky, S. J. Angew.
Chem. Int. Ed. 2001, 40, 647. (m) Chen, C.; Layton, M. E.;
Sheehan, S. M.; Shair, M. D. J. Am. Chem. Soc. 2000, 122,
7424. (n) White, J. D.; Kim, J.; Drapela, N. E. J. Am. Chem.
Soc. 2000, 122, 8665. (o) Yoshimitsu, T.; Yanagisawa, S.;
Nagaoka, H. Org. Lett. 2000, 2, 3751; and references cited
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IR (neat): 1820, 1771, 1718, 1216, 925, 670 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.89 (t, J = 8 Hz, 3 H), 1.15–1.45
(m, 6 H), 1.60 (quint, J = 8 Hz, 2 H), 2.50 (t, J = 8 Hz, 2 H), 3.57 (s,
2 H), 8.60 (br s, 1 H).
13C NMR (CDCl3, 50 MHz): d = 13.9, 22.4, 24.9, 27.5, 29.1 (2 C),
31.3, 135.5, 148.1, 165.1 (2 C), 173.0.
(14) (a) Haval, K. P.; Argade, N. P. J. Org. Chem. 2008, 73,
6936. (b) Easwar, S.; Argade, N. P. Synthesis 2006, 831.
(c) Kar, A.; Argade, N. P. Tetrahedron 2003, 59, 2991.
(d) Kar, A.; Argade, N. P. J. Org. Chem. 2002, 67, 7131.
(e) Kar, A.; Argade, N. P. Tetrahedron Lett. 2002, 43, 6563.
(f) Mangaleswaran, S.; Argade, N. P. J. Org. Chem. 2001,
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Soc., Perkin Trans. 1 2001, 1764. (h) Deshpande, A. M.;
Natu, A. A.; Argade, N. P. Synthesis 2001, 702.
Acknowledgment
U.A.K. thanks CSIR, New Delhi, for the award of research fel-
lowship. N.P.A. thanks the Department of Science and Technology,
New Delhi, for financial support.
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Synthesis 2011, No. 11, 1804–1808 © Thieme Stuttgart · New York