Tris(4-anisyl)phosphine as an efficient and practical reagent for the synthesis of (E)-2-benzylidenesuccinates

Article abstract of DOI:10.1002/cjoc.201090064

Condensation of maleic anhydride or dimethyl maleate with benzylaldehydes controlled by tris(4-anisyl)-phosphine to synthesize dimethyl (E)-2-benzylidenesuccinates has been systematically investigated. The protocol gives the product with high stereoselectivity in moderate to good yields under mild conditions. A plausible mechanism has been proposed.

Full text of DOI:10.1002/cjoc.201090064

FULL PAPER
Tris(4-anisyl)phosphine as an Efficient and Practical Reagent
for the Synthesis of (E)-2-Benzylidenesuccinates
Jiang, Huanfeng*(江焕峰)
Wang, Wei(王伟)
Liu, Weibing(刘卫兵)
Qiao, Chunli(乔春利)
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou,
Guangdong 510640, China
Condensation of maleic anhydride or dimethyl maleate with benzylaldehydes controlled by tris(4-anisyl)-
phosphine to synthesize dimethyl (E)-2-benzylidenesuccinates has been systematically investigated. The protocol
gives the product with high stereoselectivity in moderate to good yields under mild conditions. A plausible mecha-
nism has been proposed.
Keywords condensation, tris(4-anisyl)phosphine, dimethyl (E)-2-benzylidenesuccinate, mechanism
Introduction
Scheme 1
In the area of synthetic organic chemistry tremen-
dous progress has been made in the phosphine-involved
reactions including Wittig reaction,1 Wittig-Horner re-
action,2 and Horner-Wadsworth-Emmons reaction,3 in
the past decades, and some of these classic name reac-
tions have become powerful synthetic tools for the con-
struction of important synthons. Arylmethylidenesucci-
nates, one of the important synthons,4 have been em-
ployed to synthesize 1,4-diphenylbutadiene deriva-
tives,5a 2,3-butanediol,4a (Z)-methyl α-(acetoxy)acryl-
ates and (E)-β-aryl itaconate derivatives.4b However, a
considerable body of synthetic methods for aryl-
methylidenesuccinates has not been entirely satisfactory
because of such drawbacks as low yields, strong bases,
long reaction time, and expensive transition metal
compounds.6 Herein we wish to describe an efficient
and practical method to synthesize (E)-2-benzylidene-
succinates via tris(4-anisyl)phosphine-involved highly
selective succinylidenations of benzaldehydes with
maleic anhydride or dimethyl maleate. The reaction
does not require expensive reagents and special equip-
ment, while the mild reaction conditions and the
toleration of a range of functional groups are especially
noteworthy.
100 MHz, and the chemical shifts (δ) were referenced to
TMS. GC-MS was obtained using electron ionization
(EI). TLC was performed using commercially prepared
100—400 mesh silica gel plates (GF254), and visualiza-
tion was effected at 254 nm. All other chemicals were
purchased from Aldrich Chemicals.
Typical procedure for the reaction of maleic anhy-
dride with benzaldehyde
To a stirred mixture of maleic anhydride (98 mg, 1.0
mmol) and benzaldehyde (106 mg, 1.0 mmol), were
added 2 mL of methanol and tris(4-anisyl)phosphine
[P(p-MeOC6H4)3] (352 mg, 1.0 mmol) successively.
The mixture was stirred at 70 ℃ for 36 h in a round
bottom flask. After cooling, the resulting mixture was
then analyzed by GC-MS and subjected to isolation by
PTLC (GF254), eluted with a 10∶1 (V∶V) petroleum
ether-ethyl acetate mixture to give compound 3a (Table
1, Entry 1, Equation 1). The product was characterized
with 1H NMR spectra.
Experimental
All the reactions were carried out in a round bottom
flask equipped with a magnetic stir bar. Solvents and all
1
reagents were used as received. H NMR spectra were
recorded in CDCl3 at 400 MHz and 13C NMR spectra at
*
E-mail: jianghf@scut.edu.cn; Tel.: 0086-020-87112906; Fax: 0086-020-87112906
Received August 11, 2009; revised September 18, 2009; accepted October 28, 2009.
Project supported by the National Natural Science Foundation of China (Nos. 20625205, 20772034 and 20932002) and Guangdong Natural Science
Foundation (No. 07118070).
Chin. J. Chem. 2010, 28, 263— 268
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Jiang et al.
FULL PAPER
Table 1 Synthesis of (E)-2-benzylidenesuccinates using 1 and benzaldehydes 2a
Entry
1
Benzaldehyde
Product
Eq. 1 yieldb/%
42
Eq. 2 yieldc/%
81
66
2
3
4
5
66
30
53
38
60
97
96
6
7
39
42
47
33
55
73
61
59
52
57
8
9
10
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Chin. J. Chem. 2010, 28, 263— 268

Tris(4-anisyl)phosphine for the Synthesis of (E)-2-Benzylidenesuccinates
Continued
Eq. 2 yieldc/%
Entry
11
Benzaldehyde
Product
Eq. 1 yieldb/%
85
89
a All the reactions were carried out using 1 mmol of 1, 1.0 mmol of 2, and 1.0 equiv. of P(p-MeOC6H4)3 in methanol (2.0 mL) at 70 ℃
(Eq. 1) and in acetonitrile (2.0 mL) at 80 ℃ (Eq. 2) for 36 h. b Isolated yield for Eq. 1. c Isolated yield for Eq. 2.
Typical procedure for the reaction of dimethyl
maleate with benzaldehyde
succinate (Table 1, Entry 5) Yield: Eq. 1 38%, Eq. 2
96%; H NMR (CDCl3, 400 MHz) δ: 7.88 (s, 1H), 7.59
1
(d, J＝2 Hz, 2H), 7.51 (d, J＝2 Hz, 2H), 3.82 (s, 3H),
3.72 (s, 3H), 3.47 (s, 2H); 13C NMR (CDCl3, 100 MHz)
δ: 171.2, 167.3, 140.4, 135.7, 132.0, 131.8, 131.6, 129.2,
127.3, 125.7, 123.7, 52.4,－52.3, 33.3; IR (KBr) v: 2958,
To a stirred mixture of dimethyl maleate (72 mg, 0.5
mmol) and benzaldehyde (53 mg, 0.5 mmol), were
added 2 mL of acetonitrile and tris(4-anisyl)phosphine
[P(p-MeOC6H4)3] (176 mg, 0.5 mmol) successively.
The mixture was stirred at 80 ℃ for 36 h in a round
bottom flask. After cooling, the resulting mixture was
then analyzed by GC-MS and subjected to isolation by
PTLC (GF254), eluted with a 10∶1 (V∶V) petroleum
ether-ethyl acetate mixture to give compound 3a (Table
1, Entry 1, Equation 2).
1
1666, 1452, 778, 701 cm ; MS (70 eV) m/z (%): 302
(M＋, 96), 270 (100), 242 (94), 189 (49). Anal. calcd for
C14H13F3O4: C 55.63, H 4.34; found C 55.47, H 4.36.
(E)-Dimethyl
2-(4-fluorobenzylidene)succinate
1
(Table 1, Entry 6)7e Yield: Eq. 1 39%, Eq. 2 73%; H
NMR (CDCl3, 400 MHz) δ: 7.85 (s, 1H), 7.11—7.27 (m,
4H), 3.80 (s, 3H), 3.70 (s, 3H), 3.52 (s, 2H); 13C NMR
(CDCl3, 100 MHz) δ: 171.6, 167.8, 142.3, 138.3, 134.8,
129.7, 128.5＋, 126.0, 52.2, 52.1, 33.4; MS (70 eV) m/z
(%): 252 (M , 39), 220 (58), 192 (48), 133 (100).
Characterization data for products
(E)-Dimethyl 2-benzylidenesuccinate (Table 1,
1
Entry 1)7a Yield: Eq. 1 42%, Eq. 2 81%; H NMR
(E)-Dimethyl
2-(4-chlorobenzylidene)succinate
(CDCl3, 400 MHz) δ: 7.88 (s, 1H), 7.24—7.39 (m, 5H),
3.80 (s, 3H), 3.70 (s, 3H), 3.52 (s, 2H); 13C NMR
(CDCl3, 100 MHz) δ: 171.6, 167.8, 142.1, 134.9, 129.0,
128.9, 128.6＋, 125.8, 52.2, 52.1, 33.4; MS (70 eV) m/z
(%): 234 (M , 29), 174 (39), 115 (100), 91 (21).
1
(Table 1, Entry 7)7f Yield: Eq. 1 42%, Eq. 2 61%; H
NMR (CDCl3, 400 MHz) δ: 7.82 (s, 1H), 7.35 (d, J＝4
Hz, 2H), 7.25 (d, J＝2 Hz, 2H), 3.80 (s, 3H), 3.71 (s,
3H), 3.48 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 171.4,
167.5, 140.9, 135.0, 133.3, 130.3, 128.9, 126.4, 52.4,
52.3, 33.4; MS (70 eV) m/z (%): 268 (M＋, 58), 236 (70),
149 (85), 115 (100).
(E)-Dimethyl
2-(4-nitrobenzylidene)succinate
1
(Table 1, Entry 2)7b Yield: Eq. 1 66%, Eq. 2 66%; H
NMR (CDCl3, 400 MHz) δ: 8.24 (d, J＝4 Hz, 2H), 7.89
(s, 1H), 7.49 (d, J＝4 Hz, 2H), 3.83 (s, 3H), 3.73 (s, 3H),
3.46 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 171.0,
197.0, 147.7, 141.4, 139.6, 129.7, 129.0, 123.9, 52.6,
52.－4, 33.4; IR (KBr) v: 2958, 1657, 1497, 1437, 708
(E)-Dimethyl
2-(4-bromobenzylidene)succinate
1
(Table 1, Entry 8)7d Yield: Eq. 1 47%, Eq. 2 59%; H
NMR (CDCl3, 400 MHz) δ: 7.79 (s, 1H), 7.49 (d, J＝2
Hz, 2H), 7.19 (d, J＝4 Hz, 2H), 3.80 (s, 3H), 3.71 (s,
3H), 3.47 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 171.3,
167.5, 140.9, 133.7, 131.9, 130.5, 126.5, ＋123.2, 52.4,
52.2, 33.4; MS (70 eV) m/z (%): 312 (M , 43) , 280
(71), 253 (90), 194 (100).
＋
1
cm ; MS (70 eV) m/z (%): 279 (M , 5), 247 (100), 219
(40), 145 (86).
(E)-Dimethyl 2-(3-nitrobenzylidene)succinate (Ta-
1
ble 1, Entry 3)7c Yield: Eq. 1 30%, Eq. 2 60%; H
(E)-Dimethyl
2-(2-bromobenzylidene)succinate
NMR (CDCl3, 400 MHz) δ: 8.20 (d, J＝2 Hz, 2H), 7.89
(s, 1H), 7.55—7.60 (m, 2H), 3.83 (s, 3H), 3.74 (s, 3H),
3.48 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 171.0,
167.0, 147.5, 139.4, 136.5, 134.7, 129.8, 128.6, 123.＋7,
123.6, 52.6, 52.4, 33.4; MS (70 eV) m/z (%): 279 (M ,
8), 247 (100), 173 (80), 145 (86).
1
(Table 1, Entry 9)4b Yield: Eq. 1 33%, Eq. 2 52%; H
NMR (CDCl3, 400 MHz) δ: 7.86 (s, 1H), 7.60 (d, J＝4
Hz, 1H), 7.18—7.31 (m, 3H), 3.82 (s, 3H), 3.70 (s, 3H),
3.37 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 171.4,
167.2, 141.4, 135.4, 132.8, 130.2, 129.9, 127.4,＋123.9,
52.4, 52.3, 33.5; MS (70 eV) m/z (%): 312 (M , 40),
280 (74), 253 (84), 194 (100).
(E)-Dimethyl 2-(4-trifluoromethyl)benzylidene)-
succinate (Table 1, Entry 4)7d Yield: Eq. 1 53%, Eq. 2
1
(E)-Dimethyl
2-(4-iodobenzylidene)succinate
97%; H NMR (CDCl3, 400 MHz) δ: 7.87 (s, 1H), 7.62
1
(Table 1, Entry 10) Yield: Eq. 1 55%, Eq. 2 57%; H
NMR (CDCl3, 400 MHz) δ: 7.78 (s, 1H), 7.71 (d, J＝4
Hz, 2H), 7.05 (d, J＝2 Hz, 2H), 3.80 (s, 3H), 3.72 (s,
3H), 3.47 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 171.3,
167.5, 141.0, 137.8, 134.3, 130.6, 126.6, 35.1, 52.4,
52.3, 33.4; IR (KBr) v: 2957, 1659, 1500, 739, 699
(d, J＝4 Hz, 2H), 7.42 (d, J＝4 Hz, 2H), 3.81 (s, 3H),
3.71 (s, 3H), 3.46 (s, 2H); 13C NMR (CDCl3, 100 MHz)
δ: 171.2, 167.2, 140.5, 138.5, 130.3, 129.1, 127.9, 125＋.5,
123.7, 52.4, 52.2, 33.3; MS (70 eV) m/z (%): 302 (M ,
90), 270 (100), 183 (95), 115 (83).
(E)-Dimethyl 2-(3-trifluoromethyl)benzylidene)-
Chin. J. Chem. 2010, 28, 263— 268
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Jiang et al.
FULL PAPER
cm ; MS (70 eV) m/z (%): 360 (M , 80), 300 (27), 262
(100). Anal. calcd for C13H13IO4: C 43.35, H 3.64;
found C 42.76, H 3.70.
＋
－1
sides, when the reaction was carried out at room tem-
perature, it afforded 3a in poor yield (Table 2, Entry
10).
(E)-Dimethyl 2-(pentafluorophenylmethylidene)-
succinate (Table 1, Entry 11) Yield: Eq. 1 85%, Eq. 2
With these optimized conditions in hand, we next
explored the scope of the process by studying a wide
variety of benzaldehydes as substrates. As outlined in
Table 1 (Eq. 1), a wide range of benzaldehydes were
condensed with maleic anhydride 1a in moderate to
good isolated yields with high stereoselectivity (Table 1,
Entries 1—11). The reaction appeared quite sensitive
with respect to the steric and electronic contribution of
the substituent on the benzene ring of the benzaldehydes.
As revealed in Entries 2—5, benzaldehydes with a
para-electron-withdrawing group can be successfully
employed in this reaction to produce the corresponding
(E)-2-benzylidenesuccinate derivatives. For example,
2,3,4,5,6-pentafluorobenzaldehyde afforded dimethyl
(E)-2-(pentafluorophenylmethylidene)succinate in 85%
isolated yield (Table 1, Entry 11). While meta-electron-
withdrawing-substituted (Table 1, Entries 3 and 5),
para- or ortho-halogen-substituted benzylaldehydes
were used (Table 1, Entries 6—10), the reaction gave
relatively poor yields.
1
89%; H NMR (CDCl3, 400 MHz) δ: 7.43 (s, 1H), 3.84
(s, 3H), 3.66 (s, 3H), 3.31 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ: 169.9, 166.0, 145.1, 142.7, 142.6, 139.0,
136.5, 133.7, 125.3, 109.6, 52.7,－52.2, 34.4; IR (KBr) v:
1
2958, 1657, 1497, 1437, 708 cm ; MS (70 eV) m/z (%):
324 (M＋, 30), 264 (50), 205 (100). Anal. calcd for
C13H9F5O4: C 48.16, H 2.80; found C 48.38, H 2.81.
Results and discussion
Our studies were initiated by the reaction of 1.0
equiv. of PPh3 to a solution of maleic anhydride, ben-
zaldehyde and 2 mL of methanol at 70 ℃ for 12 h
(Scheme 1, Entry 1 in Table 2), and the reaction resulted
in dimethyl (E)-2-benzylidenesuccinate, which was de-
1
termined via H, 13C NMR spectra and literature.7
Encouraged by this result, we examined the reaction
in detail under different conditions in an attempt to in-
crease the yield. The representative results are summa-
rized in Table 2. Among the additives examined in
methanol, organic-phosphine compounds especially
tris(4-anisyl)phosphine showed good activity for this
reaction (Table 2, Entries 4—6), however organic- ni-
trogen compounds, such as pyridine (Py) and
1,4-diazabicyclo(2.2.2)octane (DABCO), showed no
activity for the condensation (Table 2, Entries 2 and 3).
When the reaction time was prolonged from 12 to 36 h
(Table 2, Entries 6 and 8), the yield was increased from
48% to 70%, while when prolonged to 48 h, the yield
was not raised further (Table 2, Entries 8 and 9). Be-
This protocol appeared to be well suitable for di-
methyl maleate, and the results showed that the corre-
sponding (E)-2-benzylidenesuccinates could be obtained
in good to excellent isolated yields (Table 1, Eq. 2). It is
interesting that the substituent groups on phenyl ring of
benzaldehydes have little effect on the reaction ste-
reo-selectivity, however dimethyl maleate proved to be
a viable reaction partner in this protocol due to higher
yields of the desired target compounds (Table 1, Entries
1—11).
The plausible mechanism for the formation of the
Table 2 Condition optimization for the synthesis of dimethyl (E)-2-benzylidenesuccinatea
Entry
Additive (1.0 equiv.)
Temperature/℃
Time/h
12
Yieldb/%
15
1
2
PPh3
70
Py
70
70
70
70
70
70
70
70
r.t.
12
12
12
12
12
24
36
48
36
none
none
23
3
DABCO
(n-Bu)3P
4
5
Tribenzo[d][1,3]dioxol-5-ylphosphine
Tris(4-anisyl)phosphine
Tris(4-anisyl)phosphine
Tris(4-anisyl)phosphine
Tris(4-anisyl)phosphine
Tris(4-anisyl)phosphine
41
6
48
7
57
8
70
9
71
10
trace
a Reaction conditions: maleic anhydride 1a (0.25 mmol), benzaldehyde 2a (0.25 mmol), methanol (2 mL); b GC yield.
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Chin. J. Chem. 2010, 28, 263— 268

Tris(4-anisyl)phosphine for the Synthesis of (E)-2-Benzylidenesuccinates
Scheme 2 Proposed route to synthesize (E)-2-benzylidenesuccinates
benzylidenesuccinate compounds was depicted in
Scheme 2. The reaction could be triggered by nucleo-
philic addition of tris(4-anisyl)phosphine to the elec-
tron-deficient double bond to produce zwitterionic I,
and then involved with nucleophilic attack of the car-
banion of intermediate I on the carbon-oxygen double
bond of benzaldehydes to form II, which is swiftly
transformed to III. Subsequently, (p-MeOC6H4)3P＝O
was eliminated from the intermediate III to form an-
other zwitterionic IV, which quickly resulted in the tar-
get compound 3 due to the intramolecular hydrogen
transfer.
In summary, we have described the reaction of ben-
zaldehydes with maleic anhydride or dimethyl maleate
controlled by P(p-MeOC6H4)3 to give (E)-2-benzylide-
nesuccinates with high stereoselectivity in moderate to
good yields under mild conditions. To the best of our
knowledge, this protocol opened up a direct way for the
synthesis of (E)-2-benzylidensuccinates, which are very
important potential organic intermediates in organic
synthesis.
1075.
3
4
(a) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc.
1961, 83, 1733.
(b) Wang, X. Q.; He, F. K. Chin. J. Chem. 2003, 21, 805.
(c) Elise, C.; Isabelle, G. Synlett 2009, 263.
(a) Bilenko, V.; Jiao, H. J.; Spannenberg, A.; Fischer, C.
Eur. J. Org. Chem. 2007, 758.
(b) Liu, Y.; Sandoval, C. A.; Yamaguchi, Y. I.; Zhang, X.;
Wang, Z.; Kato, K.; Ding, K. L. J. Am. Chem. Soc. 2006,
128, 14212.
(c) Kapferer, T.; Brueckner, R. Eur. J. Org. Chem. 2006,
2119.
(d) Boaz, N. W.; Mackenzie, E. B.; Debenham, S. D.; Large,
S. E. J. Org. Chem. 2005, 70, 1872.
(e) Korostylev, A.; Selent, D.; Monsees, A. Tetrahedron:
Asymmetry 2003, 14, 1905.
(f) Boaz, N. W.; Debenham, S. D.; Mackenzie, E. B.; Large,
S. E. Org. Lett. 2002, 4, 2421.
(g) Suprakas, S. R.; Mamookho, E. M. Polymer 2009, 50,
4635.
5
6
(a) Hiroshi, S.; Tsuyoshi, Q.; Hiroshi, Q.; Akio, Q. Chem.
Pharm. Bull. 2006, 54, 1686.
References
1
(a) Wittig, G.; Schöllkopf, U. Ber. Bunsen-Ges. Phys. Chem.
1954, 87, 1318.
(b) Momose, T. F.; Tanabe, G.; Tsujimori, H. K.; Muraoka,
O. Chem. Pharm. Bull. 1992, 40, 2525.
(b) Christopher, J. O.; Jennifer, L. Angew. Chem., Int. Ed.
2009, 48, 6836.
(a) Johnson, W. S.; Daub, G. H. Org. React. 1953, 6, 1.
(b) Gordaliza, M.; Migueldel, J. M.; Corral, M. A.; Castro,
M. A.; Salinero, A. Synlett 1996, 1201.
(c) McNulty, J.; Das, P. Tetrahedron Lett. 2009, 50, 5737.
(a) Horner, L. Chem. Ber. 1959, 92, 1499.
(b) Chen, Z. B.; Shou, W. G.; Wang, Y. G. Synthesis 2009,
2
(c) Cameron, A. F.; Duncanson, F. D.; Freer, A. A.; Arm-
strong, D. W.; Ramage, R. J. Chem. Soc., Perkin Trans. 2
Chin. J. Chem. 2010, 28, 263— 268
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
267

Jiang et al.
FULL PAPER
1975, 1030.
[Chem. Abstr. 2006, 146, 358685].
(d) Linke, S.; Kurz, J.; Lipinski, D.; Gau, W. Liebigs Ann.
Chem. 1980, 542.
(d) Shen, Y. C.; Zhang, Z. H. J. Chem. Res., Synop. 1998,
10, 642.
7
(a) Hiroshi, S.; Tsuyoshi, O.; Hiroshi, O.; Akio, O. Chem.
Pharm. Bull. 2006, 54, 1686.
(e) Hideya, M. Tetrahedron 2006, 62, 8539.
(f) McComble, S. W.; Luchaco, C. A. Tetrahedron Lett.
1997, 33, 5775.
(b) Ding, H. F.; Cheng, M. Org. Lett. 2005, 7, 2125.
(c) Donate, P. M.; Jimenez, R. R. BR 2004003135, 2006
(E0908113 Pan, B.; Fan, Y.)
268
www.cjc.wiley-vch.de
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