Facile SN2′ coupling reactions of Wittig reagents with dimethyl bromomethylfumarate: Synthesis of enes, dienes, and related natural products

Article abstract of DOI:10.1021/jo070728z

(Chemical Equation Presented) A new simple and efficient synthetic protocol with an ample scope has been demonstrated, by employing S_N2′ coupling reactions of a variety of Wittig reagents with dimethyl bromomethylfumarate to obtain the corresponding enes, dienes, and related natural and unnatural products.

Full text of DOI:10.1021/jo070728z

Facile SN2′ Coupling Reactions of Wittig Reagents with Dimethyl
Bromomethylfumarate: Synthesis of Enes, Dienes, and Related
Natural Products
Ramesh M. Patel and Narshinha P. Argade*
DiVision of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
np.argade@ncl.res.in
ReceiVed April 7, 2007
A new simple and efficient synthetic protocol with an ample scope has been demonstrated, by employing
SN2′ coupling reactions of a variety of Wittig reagents with dimethyl bromomethylfumarate to obtain the
corresponding enes, dienes, and related natural and unnatural products.
Introduction
The Wittig reagents also have been used for the preparation of
cyclopropane and cycloheptane derivatives.6 We envisaged that
the SN2′ coupling reactions of Wittig reagents with substrates
having appropriately placed leaving groups would be useful to
provide a convenient approach to attain a variety of enes and
dienes via the reductive removal of triphenylphosphine oxide
and the elimination of triphenylphosphine, respectively. Now,
we herein demonstrate an important new synthetic protocol to
synthesize several types of enes and dienes by taking the
advantage of Wittig chemistry (Schemes 1 and 2).
The SN2′ coupling reaction is a very important tool to form
new carbon-carbon bonds in synthetic organic chemistry,1 and
the propensity of Wittig reagents for SN2′ coupling reactions
has not been studied until recently.2 Enes and dienes are an
important class of compounds, and they find applications in the
preparation of dyes, UV screens, drugs, in Diels-Alder reac-
tions, and also for the synthesis of complex natural and unnatural
products.3 Several methods are known in the literature to design
enes and dienes.4 The application of a Wittig reaction to design
enes is a very standard, well-explored method in the literature.2,5
Results and Discussion
Dimethyl bromomethylfumarate (1) has been used for the
synthesis of several natural and unnatural products employing
SN2′ coupling reactions with a variety of carbanionic species.1,7
In this context, we decided to study the feasibility of SN2′
coupling reactions of Wittig reagents with the substrate 1.
Initially, we performed the reaction with equimolar amounts of
* Corresponding author. Tel.: 91-20-25902333; fax: 91-20-25902624.
(1) (a) Baag, M. M.; Puranik, V. G.; Argade, N. P. J. Org. Chem. 2007,
72, 1009. (b) Kar, A.; Argade, N. P. Synthesis 2005, 2995. (c) Kar, A.;
Gogai, S.; Argade, N. P. Tetrahedron 2005, 61, 5297. (d) Kar, A.; Argade,
N. P. J. Org. Chem. 2002, 67, 7131 and references cited therein.
(2) (a) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863. (b)
Murphy, P. J.; Brennan, J. Chem. Soc. ReV. 1988, 17, 1. (c) Walker, B. J.
Organophosphorus Reagents in Organic Synthesis; Cadogan, J. I. G., Ed.;
Academic Press: New York, 1979 and references cited therein.
(3) (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis,
G. Angew. Chem., Int. Ed. 2002, 41, 1668. (b) Deagostino, A.; Prandi, C.;
Zavattaro, C.; Venturello, P. Eur. J. Org. Chem. 2006, 2463 and references
cited therein.
(4) (a) Date, S. M.; Ghosh, S. K. Angew. Chem., Int. Ed. 2007, 46, 386.
(b) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; John
Wiley and Sons: New York, 1990. (c) Rappoport, Z. The Chemistry of
Dienes and Polyenes; John Wiley and Sons: New York, 1997; Vol. 1. (d)
Rappoport, Z. The Chemistry of Dienes and Polyenes; John Wiley and
Sons: New York, 2001; Vol. 2 and references cited therein.
(5) (a) Wittig, G.; Geissler, G. Justus Liebigs Ann. Chem. 1953, 580,
44. (b) Wittig, G.; Scho¨llkopf, U. Chem. Ber. 1954, 87, 1318.
(6) (a) Freeman, J. P. J. Org. Chem. 1966, 31, 538. (b) Bestmann, H. J.;
Seng, F. Angew. Chem., Int. Ed. 1962, 1, 116. (c) Grieco, P. A.; Finkelhor,
R. S. Tetrahedron Lett. 1972, 13, 3781. (d) Fujimoto, T.; Tekeuchi, Y.;
Kai, K.; Hotai, Y.; Ohta, K.; Yamamoto, I. Chem. Commun. 1992, 1263.
(7) (a) Kariem, H.; Abdullah, M. I.; Amri, H. Tetrahedron Lett. 2003,
44, 553. (b) Beji, F.; Lebreton, J.; Villieras, J.; Amri, H. Synth. Commun.
2002, 32, 3273. (c) Beji, F.; Lebreton, J.; Villieras, J.; Amri, H. Tetrahedron
2001, 57, 9959.
10.1021/jo070728z CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/01/2007
4900
J. Org. Chem. 2007, 72, 4900-4904

Facile SN2′ Coupling Reactions of Wittig Reagents
SCHEME 1. SN2′ Coupling Reactions of Wittig Reagents with 1, Synthesis of Enes and Dienesa
a (i) Wittig reagent, -100 °C to rt, 3 h [3a-g/5a-i : (60-66%)/(8-85%)]; (ii) Wittig reagent, -100 °C, 3 h, then H2O at -100 °C [3a-g/5a-i :
(15-20%)/(50-85%)].
TABLE 1. Synthesis of Variety of Enes 5 and Dienes 3 from Dimethyl Bromomethylfumarate (1)
a Obtained mixtures of enes and dienes were separated by silica gel column chromatography, and the isolated yields are in parentheses. Overall conditions:
(i) Wittig reagent, -100 °C to rt; (ii) Wittig reagent, -100 °C, H2O.
1 and the Wittig reagent benzylidenetriphenylphosphorane at
0 °C in THF, and upon quenching with water at the same
temperature, we obtained the column separable mixture of ene
5a and diene 3a in a 2:3 ratio with 30% yield (Scheme 1). On
confirmation of the feasibility of SN2′ coupling reactions of
Wittig reagents with substrate 1, we performed several experi-
ments using different bases to generate the ylides (n-BuLi, NaH,
NaCH2SOCH3, KOBu-t, and DBU) and solvents (THF, ether,
1,4-dioxane, THF-dioxane, and THF-HMPA) at different tem-
peratures (-100, -78, -40, -20, and 0 °C and rt) to selectively
obtain the enes and dienes with high yields. In the SN2′ coupling
reaction of 1 with Wittig reagents, the best result was obtained
when n-BuLi was used as a base to generate the ylide and by
performing the reaction in THF at -100 °C and then quenching
the reaction at room temperature after 3 h (68% yield, 3a/5a )
88:12). When the same reaction of compound 1 with the Wittig
reagent was quenched at -100 °C with water after 3 h, we
obtained the opposite selectivity, and the ene 5a was obtained
as a major product and diene 3a as a minor product (68% yield,
3a/5a ) 26:74). These experiments very clearly revealed that
(i) in the formation of dienes, the Wittig reagent couples with
1 in a SN2′ fashion, which is followed by an instantaneous
abstraction of the acidic methine proton by the conjugate base,
the bromide anion, with anti-elimination of PPh3 to yield the
diene 3a with exclusive E-geometry of the newly formed
carbon-carbon double bond and (ii) in the same reaction on
quenching with water at -100 °C, the reductive removal of
POPh3 takes place with the formation of ene 5a as a major
product.8 To confirm that in the formation of enes the hydrogen
atom at the benzylic position comes from water, we quenched
the reaction at -100 °C with D2O and obtained the correspond-
ing deuterium incorporated compound 6 in 48% yield. In the
(8) (a) Bestmann, H. J. Angew. Chem., Int. Ed. 1965, 77, 609. (b)
Meisenheimer, J.; Casper, J.; Ho¨ring, M.; Lauter, W.; Lichtenstadt, L.;
Samuel, W. Justus Liebigs Ann. Chem. 1926, 449, 213. (c) Fentonu, G.
W.; Ingold, C. K. J. Chem. Soc. 1929, 2342.
J. Org. Chem, Vol. 72, No. 13, 2007 4901

Patel and Argade
SCHEME 2. Synthesis of Symmetrical and Unsymmetrical
Dienesa
SCHEME 4. Heck Coupling Reactions of Enes, Synthesis of
Prasanthalinea
a (i) Wittig reagent, -100 °C to rt, 3 h.
SCHEME 3. Heck Coupling Reactions of Dienes, Synthesis
of Gulbulina
a (i) ArI, Pd(OAc)2, Cy2NH, H2O, 120 °C, 24 h (E/Z ) 82:18, 88%).
base due to the electron deficient nature of the phosphorus atom
in those two cases.
Then, we studied the SN2′ coupling reactions of relatively
more reactive phosphoranes generated from phosphonium salts
of methyl iodide and allyl bromide with 1 and exclusively
obtained the corresponding diene 3j and dimethyl ester of
fulgenic acid (3k),9 respectively, but in 31 and 54% yields
(Scheme 2). Herein, as the ylides are relatively more reactive,
the further refinements in reaction conditions for the improve-
ment of yields of 3j and 3k are essential.
We decided to use both enes and dienes for the short and
efficient synthesis of natural products (()-gulbulin (from
Himantandra baccata Bail)10 and (()-prasanthaline (from
Jatropha gossypifolia Linn).11 The dienes 3a,c on Heck coupling
reactions12 with appropriate halides gave the (E,E)-dienes 7a,c
1
as a major product in 86% yield (E/Z ) 94:6, by H NMR).
The five-step conversion of diene 7c to (()-gulbulin (8c) has
been shown in the literature (Scheme 3).13 Similarly, Heck
coupling reactions12 of enes 5a,c with appropriate halides gave
the corresponding desired diesters 9a,c in 88% yield (E/Z )
a (i) ArI, Pd(OAc)2, Cy2NH, H2O, 120 °C, 24 h (E/Z ) 94:6, 86%).
reactions of the Wittig reagent with 1, we tried our best to
exclusively obtain diene 3a by using super dry THF and also
by adding TEA as an external base for the elimination of PPh3,
but all our attempts were met with failure, and we always ended
up with the isolation of ene 5a as a minor product. We strongly
believe that under the complete absence of moisture, the present
reaction will provide the diene 3a as an exclusive product. We
also feel that the preparation of substrate 1 using higher alcohols
and similar less activated substrates may not demand such a
lower temperature for the effective SN2′ coupling reactions of
the Wittig reagents.
1
82:18, by H NMR). The reduction of two ester groups in ene
9c followed by an in situ acylation of the formed intermediate
1,4-diol provided the natural product (()-prasanthaline (10c),
which has been discussed in the literature (Scheme 4).14
Conclusion
In summary, we have demonstrated an unprecedented SN2′
coupling reaction of Wittig reagents to selectively obtain the
(9) (a) Deshpande, S. G.; Argade, N. P. Synthesis 1999, 1306. (b)
Tarnchompoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron Lett.
1987, 28, 6671 and references cited therein.
(10) Hughes, G. K.; Ritchie, E. Aust. J. Chem. 1954, 7, 104.
(11) Chatterjee, A.; Das, B.; Chakrabarti, R.; Bose, P.; Budziekiwics,
H.; Banerji, A.; Banerji, J. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 1988, 27, 740.
(12) (a) Heck, R. F.; Nolly, J. P. J. Org. Chem. 1972, 37, 2320. (b)
Heck, R. F. Palladium Reagents in Organic Synthesis; Academic Press:
London, 1985.
(13) Datta, P. K.; Yau, C.; Hooper, T. S.; Yvon, B. L.; Charlton, J. L. J.
Org. Chem. 2001, 66, 8606.
We studied the SN2′ coupling reactions of several other Wittig
reagents generated from the phosphonium salts of corresponding
benzyl bromides with 1 and obtained the corresponding enes
5a-g and dienes 3a-g, proving the generality of the present
approach (Table 1, entries 1-7). Surprisingly, the Wittig
reagents generated from phosphonium salts of ortho- and para-
nitrobenzyl bromides, on SN2′ condensations with 1, exclusively
furnished corresponding enes 5h,i in 85% yield under both
reaction conditions (Table 1, entries 8 and 9). We feel that this
could be a result of higher stability of the unisolable intermedi-
ates 2h,i and the nonavailability of bromide anion as a conjugate
(14) Banerji, J.; Bose, P.; Das, B. Indian J. Chem., Sect. B: Org. Chem.
Incl. Med. Chem. 1989, 28, 711.
4902 J. Org. Chem., Vol. 72, No. 13, 2007

Facile SN2′ Coupling Reactions of Wittig Reagents
(1:9) as an eluent to obtain major product 3g (60%) and minor
product 5g (10%) as thick oils. H NMR (CDCl3, 200 MHz) δ
corresponding enes and dienes, which is a pivotal new applica-
tion of Wittig reagents. Herein, the enes have been obtained by
using the Wittig reagents rather than the corresponding Grignard
reagents, while dienes have been obtained with the recovery of
triphenylphosphine. We feel that the use of Wittig reagents in
the place of Grignard reagents in the synthesis of enes will
positively widen the scope of SN2′ coupling reactions. The use
of alkyl halides and benzyl halides instead of the corresponding
aldehydes to obtain these products is an added advantage. We
also feel that our present protocol is general and that the Wittig
reagents will undergo SN2′ coupling reactions with a variety of
other activated substrates to provide the corresponding enes,
dienes, related natural (Lignan family) products, and unnatural
products including several useful fulgides.15 The present ap-
proach also is useful for intramolecular cyclizations in the
construction of carbocycles and heterocycles.
1
3.77 (s, 3H), 3.81 (s, 3H), 5.60 (d, J ) 2 Hz, 1H), 6.40 (d, J ) 2
Hz, 1H), 6.95-7.10 (m, 2H), 7.20-7.40 (m, 2H), 7.89 (s, 1H);
13C NMR (CDCl3, 50 MHz) δ 52.3, 52.4, 115.8 (d, J ) 22 Hz),
122.5 (d, J ) 13 Hz), 123.9 (d, J ) 3 Hz), 130.29 (d, J ) 3 Hz),
130.34, 130.97 (d, J ) 9 Hz), 131.01 (d, J ) 2 Hz), 134.3 (d, J )
4 Hz), 135.9, 160.5 (d, J ) 250 Hz), 166.3, 166.7; IR (CHCl3)
νmax 1719, 1641, 1620, 1437 cm-1. Anal. Calcd for C14H13FO4:
C, 63.63; H, 4.96. Found: C, 63.44; H, 4.89. (The C-F couplings
observed in the 13C NMR spectrum are in parentheses.)
(E)-Dimethyl 2-Allylidene-3-methylenesuccinate (3j). The
similarly obtained crude product was purified by column chroma-
tography using a mixture of ethyl acetate/petroleum ether (1:9) as
1
an eluent to obtain 3j (54%) as a thick oil. H NMR (CDCl3, 200
MHz) δ 3.74 (s, 6H), 5.50 (dd, J ) 10 Hz and 2 Hz, 1H), 5.65 (d,
J ) 2 Hz, 1H), 5.68 (d, J ) 16 Hz, 1H), 6.42-6.64 (m, 1H), 6.54
(d, J ) 2 Hz, 1H), 7.34 (d, J ) 12 Hz, 1H); 13C NMR (CDCl3, 50
MHz) δ 52.0, 52.1, 126.6, 129.3, 130.3, 132.2, 135.0, 141.5, 166.2,
166.8; IR (CHCl3) νmax 1717, 1624, 1437 cm-1. Anal. Calcd for
C10H12O4: C, 61.22; H, 6.16. Found: C, 61.09; H, 6.24.
Experimental Section
Preparation of Different Triphenylphosphonium Salts. To a
stirred solution of triphenylphosphine (2.62 g, 10.00 mmol) in
benzene (10 mL) at 0 °C was added benzylbromide (1.67 mL, 14.00
mmol) in a dropwise fashion under argon atmosphere. Stirring was
continued for 24 h at room temperature. The formed salt was
filtered, washed with ether and petroleum ether, respectively, dried
under vacuum, and stored in a desiccator over phosphorus pentoxide
(4.30 g, 99%). All other triphenylphosphonium salts were prepared
similarly.
(E)-Dimethyl 2-Benzylidene-3-methylenesuccinate (3a). To a
stirred solution of benzyltriphenylphosphonium bromide (866 mg,
2.00 mmol) in THF (25 mL) at -100 °C was added n-BuLi (1.34
mL, 2.00 mmol) in a dropwise fashion under argon atmosphere.
The reaction mixture was allowed to reach 0 °C. Then, the reaction
mixture was added to a stirred solution of 1 (569 mg, 2.40 mmol)
in THF (20 mL) at -100 °C under argon atmosphere in a dropwise
fashion. The reaction mixture was allowed to reach room temper-
ature, and the reaction was then quenched with water. The reaction
mixture was extracted with ethyl acetate (30 mL × 4), and the
combined organic layer was washed with brine and dried over Na2-
SO4. Concentration of the organic layer in vacuo followed by silica
gel column chromatographic purification of the residue using a
mixture of ethyl acetate/petroleum ether (1:9) as an eluent provided
the major product 3a (296 mg, 60%) and minor product 5a (39
mg, 8%) as thick oils. 1H NMR (CDCl3, 200 MHz) δ 3.75 (s, 3H),
3.80 (s, 3H), 5.68 (d, J ) 2 Hz, 1H), 6.49 (d, J ) 2 Hz, 1H),
7.28-7.35 (m, 3H), 7.35-7.45 (m, 2H), 7.81 (s, 1H); 13C NMR
(CDCl3, 50 MHz) δ 52.2, 52.3, 128.4, 128.5, 129.3, 130.0, 130.6,
134.3, 136.0, 141.8, 166.4, 167.2; IR (CHCl3) νmax 1717, 1630,
1618, 1497 cm-1. Anal. Calcd for C14H14O4: C, 68.28; H, 5.73.
Found: C, 68.13; H, 5.92.
Dimethyl 2,3-Dimethylenesuccinate (3k). The similarly ob-
tained crude product was purified by column chromatography using
a mixture of ethyl acetate/petroleum ether (1:9) as an eluent to
obtain 3k (31%) as a thick oil. 1H NMR (CDCl3, 200 MHz) δ 3.77
(s, 6H), 5.82 (d, J ) 2 Hz, 2H), 6.30 (d, J ) 2 Hz, 2H); 13C NMR
(CDCl3, 50 MHz) δ 52.1, 127.8, 138.4, 166.1; IR (CHCl3) νmax
1719, 1618, 1437 cm-1. Anal. Calcd for C8H10O4: C, 56.47; H,
5.92. Found: C, 56.34; H, 6.06.
Dimethyl 2-Benzyl-3-methylenesuccinate (5a).2c To a stirred
solution of benzyltriphenylphosphonium bromide (866 mg, 2.00
mmol) in THF (25 mL) at -100 °C was added n-BuLi (1.34 mL,
2.00 mmol) in a dropwise fashion under argon atmosphere. The
reaction mixture was allowed to reach 0 °C. Then, the reaction
mixture was added to a stirred solution of 1 (521 mg, 2.00 mmol)
in THF (20 mL) at -100 °C under argon atmosphere in a dropwise
fashion. Stirring was continued for a further 3 h at the same
temperature. The reaction was then quenched with water. The
reaction mixture was extracted with ethyl acetate (30 mL × 4),
and the combined organic layer was washed with brine and dried
over Na2SO4. Concentration of the organic layer in vacuo followed
by silica gel column chromatographic purification of the residue
using a mixture of ethyl acetate/petroleum ether (1:9) as an eluent
provided major product 5a (248 mg, 50%) and minor product 3a
1
(89 mg, 18%) as thick oils. H NMR (CDCl3, 200 MHz) δ 2.96
(dd, J ) 14 and 8 Hz, 1H), 3.25 (dd, J ) 14 and 8 Hz, 1H), 3.63
(s, 3H), 3.75 (s, 3H), 3.83 (t, J ) 8 Hz, 1H), 5.67 (s, 1H), 6.31 (s,
1H), 7.10-7.35 (m, 5H); 13C NMR (CDCl3, 50 MHz) δ 37.4, 48.8,
52.0, 52.1, 126.4, 127.5, 128.3, 128.9, 137.6, 138.7, 166.4, 173.0;
IR (CHCl3) νmax 1740, 1721, 1632 cm-1. Anal. Calcd for
C14H16O4: C, 67.73; H, 6.50. Found: C, 67.58; H, 6.41.
3-[Deutero(phenyl)methyl]-4-methylenehexane-2,5-dione (6).
Compound 6 was prepared by using the same procedure as
described previously, and the reaction was quenched with D2O.
The crude product was purified by column chromatography using
a mixture of ethyl acetate/petroleum ether (1:9) as an eluent to
obtain major product 6 (48%) and minor product 3a (21%) as thick
oils. 1H NMR (CDCl3, 200 MHz) δ 2.95 (d, J ) 8 Hz, 0.8H), 3.18-
3.25 (m, 0.2H), 3.63 (s, 3H), 3.75 (s, 3H), 3.79-3.90 (m, 1H),
5.67 (s, 1H), 6.31 (s, 1H), 7.10-7.35 (m, 5H); 13C NMR (CDCl3,
100 MHz) δ 37.1 (t, J ) 10 Hz), 48.7, 52.0, 52.1, 126.4, 127.5,
128.3, 128.9, 137.6, 138.7, 166.4, 173.0; IR (CHCl3) νmax 1734,
1719, 1636, 1634 cm-1. (The C-D coupling observed in 13C NMR
spectrum are in parentheses.)
(E)-Dimethyl 2-(3,4-Dimethoxybenzylidene)-3-methylenesuc-
cinate (3c). The similarly obtained crude product was purified by
column chromatography using a mixture of ethyl acetate/petroleum
ether (1:4) as an eluent to obtain major product 3c (65%) and minor
product 5c (10%) as thick oils. 1H NMR (CDCl3, 200 MHz) δ 3.73
(s, 3H), 3.79 (s, 3H), 3.81 (s, 3H), 3.88 (s, 3H), 5.76 (d, J ) 2 Hz,
1H), 6.56 (d, J ) 2 Hz, 1H), 6.82 (d, J ) 8 Hz, 1H), 6.98-7.10
(m, 2H), 7.74 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 52.3 (2
carbons), 55.6, 55.8, 110.7, 112.5, 124.5, 125.7, 127.0, 130.5, 136.5,
141.6, 148.5, 150.2, 166.5, 167.4; IR (CHCl3) νmax 1717, 1636,
1601, 1514 cm-1. Anal. Calcd for C16H18O6: C, 62.74; H, 5.92.
Found: C, 62.83; H, 6.04.
(E)-Dimethyl 2-(2-Fluorobenzylidene)-3-methylenesuccinate
(3g). The similarly obtained crude product was purified by column
chromatography using a mixture of ethyl acetate/petroleum ether
Dimethyl 2-(3,4-Dimethoxybenzyl)-3-methylenesuccinate (5c).
The similarly obtained crude product was purified by column
chromatography using a mixture of ethyl acetate/petroleum ether
(1:4) as an eluent to obtain major product 5c (60%) and minor
product 3c (15%) as thick oils. 1H NMR (CDCl3, 200 MHz) δ 2.89
(15) Yokoyama, Y. Chem. ReV. 2000, 100, 1717-1739.
J. Org. Chem, Vol. 72, No. 13, 2007 4903

Patel and Argade
(dd, J ) 14 and 6 Hz, 1H), 3.16 (dd, J ) 14 and 8 Hz, 1H), 3.63
(s, 3H), 3.77 (s, 3H), 3.85 (s, 6H), 3.70-3.90 (m, 1H), 5.70 (s,
1H), 6.31 (s, 1H), 6.60-6.85 (m, 3H); 13C NMR (CDCl3, 50 MHz)
δ 37.3, 48.9, 52.0, 52.1, 55.8 (2 carbons), 111.2, 112.2, 121.0, 127.3,
131.3, 137.8, 147.7, 148.8, 166.3, 173.0; IR (CHCl3) νmax 1734,
1717, 1636 cm-1. Anal. Calcd for C16H20O6: C, 62.33; H, 6.54.
Found: C, 62.47; H, 6.70.
(2E,3E)-Dimethyl 2,3-Bis(3,4-dimethoxydibenzylidene)succi-
nate (7c). The similarly obtained crude product was purified by
column chromatography using a mixture of ethyl acetate/petroleum
ether (3:7) as an eluent to obtain 7c (E/Z 94:6, 86%) as a thick oil.
1H NMR (CDCl3, 200 MHz) δ 3.71 (s, 6H), 3.75 (s, 6H), 3.86 (s,
6H), 6.80 (d, J ) 8 Hz, 2H), 7.08-7.20 (m, 4H), 7.90 (s, 2H); 13
C
NMR (CDCl3, 50 MHz) δ 52.1, 55.4, 55.6, 110.6, 111.6, 124.2,
124.4, 127.3, 142.0, 148.5, 150.3, 167.5; IR (CHCl3) νmax 1709,
1628 cm-1. Anal. Calcd for C24H26O8: C, 65.15; H, 5.92; Found:
C, 65.23; H, 6.00.
Dimethyl 2-(2-Fluorobenzyl)-3-methylenesuccinate (5g). The
similarly obtained crude product was purified by column chroma-
tography using a mixture of ethyl acetate/petroleum ether (1:9) as
an eluent to obtain major product 5g (52%) and minor product 3g
(E)-Dimethyl 2-Benzyl-3-benzylidenesuccinate (9a).16 The
similarly obtained crude product was purified by column chroma-
tography using a mixture of ethyl acetate/petroleum ether (1:9) as
1
(18%) as thick oils. H NMR (CDCl3, 200 MHz) δ 3.06 (dd, J )
14 and 8 Hz, 1H), 3.29 (dd, J ) 14 and 8 Hz, 1H), 3.65 (s, 3H),
3.75 (s, 3H), 3.60-3.85 (m, 1H), 5.62 (s, 1H), 6.28 (s, 1H), 6.90-
7.25 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ 30.7 (d, J ) 2 Hz),
47.6 (d, J ) 2 Hz), 52.07, 52.11, 115.2 (d, J ) 22 Hz), 123.9 (d,
J ) 4 Hz), 125.6 (d, J ) 16 Hz), 127.9, 128.3 (d, J ) 9 Hz), 131.3
(d, J ) 5 Hz), 137.4, 161.2 (d, J ) 244 Hz), 166.2, 172.7; IR
(CHCl3) νmax 1730, 1720, 1634 cm-1. Anal. Calcd for C14H15FO4:
C, 63.15; H, 5.68. Found: C, 63.04; H, 5.79. (The C-F couplings
observed in 13C NMR spectrum are in parentheses.)
1
an eluent to obtain 9a (E/Z 82:18, 88%) as a thick oil. H NMR
(CDCl3, 200 MHz) δ 2.98 (dd, J ) 14 and 10 Hz, 1H), 3.42 (dd,
J ) 14 and 4 Hz, 1H), 3.73 (s, 3H), 3.84 (s, 3H), 4.00 (dd, J ) 10
and 4 Hz, 1H), 6.81-6.92 (m, 3H), 7.06-7.16 (m, 3H), 7.18-
7.31 (m, 4H), 7.76 (s, 1H); 13C NMR (CDCl3, 50 MHz) δ 35.9,
45.3, 52.0, 52.2, 126.1, 128.08, 128.12, 128.16, 128.20, 129.1,
130.4, 135.0, 138.9, 142.9, 167.0, 173.1; IR (CHCl3) νmax 1738,
1715, 1643, 1603 cm-1. Anal. Calcd for C20H20O4: C, 74.06; H,
6.22. Found: C, 73.89; H, 6.17.
Dimethyl 2-Methylene-3-(4-nitrobenzyl)succinate (5h). The
similarly obtained crude product was purified by column chroma-
tography using a mixture of ethyl acetate/petroleum ether (1:9) as
an eluent to obtain 5h (85%) as a thick oil. 1H NMR (CDCl3, 200
MHz) δ 3.07 (dd, J ) 14 and 8 Hz, 1H), 3.34 (dd, J ) 14 and 8
Hz, 1H), 3.64 (s, 3H), 3.77 (s, 3H), 3.70-3.90 (m, 1H), 5.66 (s,
1H), 6.32 (s, 1H), 7.34 (d, J ) 8 Hz, 2H), 8.13 (d, J ) 8 Hz, 2H);
13C NMR (CDCl3, 125 MHz) δ 37.2, 48.4, 52.2 (2 carbons), 123.5,
127.8, 129.8, 137.2, 146.6, 146.7, 166.1, 172.2; IR (CHCl3) νmax
1732, 1713, 1630, 1607 cm-1. Anal. Calcd for C14H15NO6: C,
57.33; H, 5.16; N, 4.78. Found: C, 57.38; H, 5.19; N, 4.69.
(2E,3E)-Dimethyl 2,3-Dibenzylidenesuccinate (7a).16 A mixture
of 3a (246 mg, 1.00 mmol), phenyl iodide (0.074 mL, 0.66 mmol),
dicyclohexyl amine (0.20 mL, 1.00 mmol), and the catalyst Pd-
(OAc)2 (6.7 mg, 3 mol %) in water (3 mL) was heated at 120 °C
for 24 h. Then, the reaction mixture was cooled and diluted with
EtOAc (40 mL). The organic layer was washed with 2 N HCl (30
mL × 2) and water (30 mL × 2) and dried over Na2SO4. The
organic layer was concentrated in vacuo followed by column
chromatography purification using ethyl acetate/petroleum ether (1:
9) to afford pure product 7a (182 mg, E/Z 94:6, 86%) as a thick
(E)-Dimethyl 2-(Benzo[d][1,3]dioxal-5-ylmethyl)-3-(3,4-dime-
thoxybenzylidene)succinate (9c). The similarly obtained crude
product was purified by column chromatography using a mixture
of ethyl acetate/petroleum ether (1:4) as an eluent to obtain 9c (E/Z
1
82:18, 88%) as a thick oil. H NMR (CDCl3, 200 MHz) δ 2.91
(dd, J ) 14 and 10 Hz, 1H), 3.37 (dd, J ) 14 and 4 Hz, 1H), 3.66
(s, 3H), 3.73 (s, 3H), 3.81 (s, 6H), 4.05 (dd, J ) 10 and 4 Hz, 1H),
5.94 (s, 2H), 6.38 (dd, J ) 6 and 2 Hz, 1H), 6.46 (dd, J ) 8 and
2 Hz, 1H), 6.48 (d, J ) 2 Hz, 1H), 6.66 (d, J ) 6 Hz, 1H), 6.67
(s, 1H), 6.73 (d, J ) 8 Hz, 1H), 7.63 (s, 1H); 13C NMR (CDCl3,
50 MHz) δ 35.6, 45.4, 51.9, 52.2, 55.3, 55.8, 101.2, 108.1, 108.4,
110.8, 111.8, 121.1, 122.5, 128.8, 129.6, 131.4, 142.3, 147.3, 147.5,
147.6, 148.5, 167.0, 173.0; IR (CHCl3) νmax 1738, 1715, 1630, 1605
cm-1. Anal. Calcd for C23H24O8: C, 64.48; H, 5.65. Found: C,
64.53; H, 5.48.
Acknowledgment. R.M.P. thanks CSIR, New Delhi, for the
award of a research fellowship.
1
oil. H NMR (CDCl3, 200 MHz) δ 3.70 (s, 6H), 7.15-7.30 (m,
Supporting Information Available: The tabulated analytical
and spectral data for the compounds 3b, 3d-f, 5b, 5d-f, and 5i.
1H NMR, 13C NMR, and DEPT spectra of 3a-c, 3e, 3g, 3j,k, 5a-
i, 6, 7a, 7c, 9a, and 9c. This material is available free of charge
via the Internet at http://pubs.acs.org.
6H), 7.30-7.45 (m, 4H), 7.88 (s, 2H); 13C NMR (CDCl3, 50 MHz)
δ 52.4, 126.6, 128.5, 129.4, 129.5, 134.5, 142.9, 167.3; IR (CHCl3)
νmax 1709, 1638, 1605, 1435 cm-1. Anal. Calcd for C20H18O4: C,
74.52; H, 5.63; Found: C, 74.62; H, 5.55.
(16) Andersson, J.; Eberson, L. NouVeau J. Chim. 1977, 1, 413.
JO070728Z
4904 J. Org. Chem., Vol. 72, No. 13, 2007