Triphenylphosphine-catalysed one-pot synthesis of γ-butyrolactone derivatives and highly substituted enones via reaction of dimethyl acetylenedicarboxylate and aryl aldehydes

Article abstract of DOI:10.1016/j.tetlet.2010.02.004

The reaction between dimethyl acetylenedicarboxylate and various aryl aldehydes in the presence of triphenylphosphine leads to unsaturated γ-butyrolactone derivatives and highly substituted enones in fairly good yields at room temperature.

Full text of DOI:10.1016/j.tetlet.2010.02.004

Tetrahedron Letters 51 (2010) 1873–1875
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Tetrahedron Letters
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Triphenylphosphine-catalysed one-pot synthesis of c-butyrolactone
derivatives and highly substituted enones via reaction of dimethyl
acetylenedicarboxylate and aryl aldehydes
*
Mohammad Bayat , Hossein Imanieh, Fatemeh Hassanzadeh
Chemistry Department, Imam Khomeini International University, Qazvin, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction between dimethyl acetylenedicarboxylate and various aryl aldehydes in the presence of tri-
Received 17 September 2009
Revised 27 November 2009
Accepted 2 February 2010
Available online 6 February 2010
phenylphosphine leads to unsaturated
fairly good yields at room temperature.
c
-butyrolactone derivatives and highly substituted enones in
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Butenolide
Triphenylphosphine
Dimethyl acetylenedicarboxylate
Unsaturated
c
-butyrolactones or butenolides are important
zwitterionic species, we envisaged the possibility of trapping 1,3-
dipoles with aryl aldehydes. In the event we did not observe the
expected MCR product, instead the reaction afforded the corre-
structural units in natural products and are intermediates in organ-
ic synthesis.1–6 There has been considerable effort on the synthesis
of these compounds7–10 due to the discovery of many naturally
occurring cytotoxic or antitumour agents containing this structural
unit. They are typical products of a polyketide biosynthesis path-
way. Examples include the cardiotonic digitoxins from Digitalis
sp.11 and the antifungal agents (À)-incrustoporine12 and rofecoxib
(Scheme 1) for the treatment of rheumatoid arthritis.13 This ring
system has been the objective of synthetic projects in several lab-
oratories.1–6
sponding unsaturated
c-butyrolactones and highly substituted
enones with Ph3P playing a mediator role in the formation of a car-
bon–carbon bond between the aldehyde and DMAD.18,19
The one-pot three-component reactions of aryl aldehydes 1
with dimethyl acetylenedicarboxylate in the presence of Ph3P pro-
ceeded spontaneously at room temperature in CH2Cl2 and were
complete within 24 h. The 1H and 13C NMR spectra of the reaction
mixtures clearly indicated the presence of two products, namely,
Multicomponent reactions (MCRs) have emerged as a highly
valuable synthetic tool in the context of modern drug discov-
ery.14–17 In continuation of our general interest in MCRs involving
the unsaturated c-butyrolactone 2 and highly substituted enone
3 (Scheme 2). These products were separated by column chroma-
tography and identified as 2a–2g and 3a–3g based on their
O
O
O
O
HO
O
O
OH
S
O
O
R
H
Cardiotonic digitoxins
(-)-incrustoporine
rofecoxib
Scheme 1. Examples of pharmaceutically relevant butenolides.
* Corresponding author. Tel./fax: +98 281 3780040.
E-mail address: bayat_mo@yahoo.com (M. Bayat).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.004

1874
M. Bayat et al. / Tetrahedron Letters 51 (2010) 1873–1875
O
CO2Me
MeO
O
CO2Me
H
O
Ar
MeO2C
CH2Cl2
r.t.
PPh3
+
MeO2C
CO2Me
+
+
Ar
Ar
H
O
1
2
3
Aldehyde
Ar
Yield (%) of 2
Yield (%) of 3
1a 4-Nitrophenyl
1b 4-Chlorophenyl
1c 4-Bromophenyl
1d 4-Methylphenyl
1e 4-Methoxyphenyl
48
52
50
70
75
55
52
45
40
38
25
20
35
40
1f
3-Nitrophenyl
1g 2,6-Dichlorophenyl
Scheme 2.
elemental analyses and their IR, 1H and 13C NMR spectral data. The
mass spectra of the products displayed molecular ion peaks at
appropriate m/z values.
In terms of the amount of Ph3P required for the reaction of aryl
aldehydes 1 and DMAD to afford compounds 2 and 3, the best re-
sults were obtained using a stoichiometric amount (1 mmol). In
the absence of Ph3P, no products formed, whilst in the presence
of 10–20 mol % of Ph3P, the products were obtained in low yields
(<30%).
CHO
COOMe
H
O
+
PPh3
DMAD
+
COOMe
OHC
OH
5
Scheme 4.
Supplementary data
The 1H NMR spectrum of 2a exhibited two singlets identified as
methoxy groups at d 3.69 and d 4.33 along with a sharp singlet for
the methine proton at d 6.07. The 13C NMR spectrum of 2a showed
11 distinct resonances in agreement with the structure of methyl
2-(4-nitrophenyl)-2,5-dihydro-4-methoxy-5-oxofuran-3-carboxyl-
ate.20 The 1H NMR spectrum of 3a showed the presence of two
singlets due to the methoxy groups at d 3.66 and d 3.79 along with
a sharp singlet for the olefinic proton at d 7.13. The 13C NMR spec-
trum of E-3a showed 11 distinct resonances in agreement with the
proposed structure. The 1H and 13C NMR spectra of 2b–2g were
similar to those of 2a, and the spectra of 3b–3g were similar to
those of 3a except for the substituted phenyl ring, which exhibited
characteristic resonances with appropriate chemical shifts.
In the reaction of Ph3P and DMAD with o-hydroxybenzalde-
hyde, the initially formed phosphorane ylide underwent
addition–cyclisation as a result of an intramolecular Wittig reac-
tion.21 Thus 2H-chromene 4 was formed in excellent yield (85%)
(Scheme 3).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.004.
References and notes
1. Grieco, P. A. Synthesis 1975, 67.
2. Gammill, R. B.; Wilson, C. A.; Bryson, T. A. Synth. Commun. 1975, 5, 245.
3. Newaz, S. S. Aldrichim. Acta 1977, 10, 64.
4. Hoffmann, H. M.; Rabe, R. J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94.
5. Petragnani, N.; Ferraz, H. M. C.; Silva, G. V. J. Synthesis 1986, 157.
6. Sarma, J.; Sharma, R. P. Heterocycles 1986, 24, 441.
7. Rao, Y. S. Chem. Rev. 1976, 76, 625.
8. Bossio, R.; Marcaccini, S.; Pepino, R.; Torroba, T. Synthesis 1993, 783.
9. Bossio, R.; Marcaccini, S.; Pepino, R. Liebigs Ann. Chem. 1994, 5, 527.
10. Marcaccini, S.; Pepino, R.; Marcos, C. F.; Polo, C.; Torroba, T. J. Heterocycl. Chem.
2000, 37, 1501.
11. (a) Repke, K. R. H.; Megges, R.; Weiland, J.; Schon, R. Angew. Chem., Int. Ed. Engl.
1995, 34, 282; (b) Beck, B.; Magnin-Lachaux, M.; Herdtweck, E.; Dömling, A.
Org. Lett. 2001, 3, 2875.
12. Zapf, S.; Anke, T.; Sterner, O. Acta Chem. Scand. 1995, 49, 233.
13. Scott, L. I.; Lamb, H. M. Drugs 1999, 3, 499.
The addition of p-hydroxybenzaldehyde to DMAD in the pres-
ence of Ph3P leads to product 5 in 60% yield (Scheme 4).
In conclusion, the three-component reaction of aryl aldehydes
with dimethyl acetylenedicarboxylate in the presence of Ph3P pro-
14. Applications of Multicomponent Reactions in Drug Discovery; Bienayme, H., Zhu,
J., Eds.Lead Generation to Process Developments; Wiley-VCH: Weinheim, 2005.
15. Dondoni, A.; Massi, A. Acc. Chem. Res. 2006, 39, 451.
16. Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.;
Balagopal, L. Acc. Chem. Res. 2003, 36, 899.
17. Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709.
18. Nair, V.; Sreekanth, A. R.; Vinod, A. U. Org. Lett. 2001, 3, 3495.
19. (a) Nair, V.; Sreekanth, A. R.; Vinod, A. U. Org. Lett. 2002, 4, 2807; (b) Schreiber,
S. L. Science 2000, 287, 1964.
vides a simple entry to the synthesis of unsaturated c-butyrolac-
tone derivatives and highly substituted enone compounds of
potential synthetic interest and possible candidates for Diels–Alder
reactions. The present procedure carries the advantage that not
only the reaction is performed under neutral conditions but also
the reagents can be mixed without any activation or modification.
20. Typical procedure for the preparation of methyl 2,5-dihydro-4-methoxy-2-(4-
nitrophenyl)-5-oxofuran-3-carboxylate (2a) and dimethyl 2-(4-nitrobenzoyl)-
butenedioate (3a). To
a stirred solution of 4-nitrobenzaldehyde (0.151 g,
1 mmol) and triphenylphosphine (0.262 g, 1 mmol) in CH2Cl2 (10 ml) was
added dimethyl acetylendicarboxylate (0.142 g, 1 mmol) in CH2Cl2 (2 ml), at
room temperature, over 10 min via a syringe. The reaction mixture was stirred
at room temperature for 24 h. The solvent was removed under reduced
pressure and the residue was purified by column chromatography (Merck silica
gel 60, 70–230 mesh) using hexane/EtOAc (8:2) as eluent. The solvent was
evaporated to afford the products 2a and 3a.
CHO
OH
COOMe
COOMe
+
DMAD
+
PPh3
O
4
Methyl 2,5-dihydro-4-methoxy-2-(4-nitrophenyl)-5-oxofuran-3-carboxylate (2a).
Yellow oil, (0.140 g, 48%). IR (KBr) (m
max/cmÀ1): 1775 and 1682 (C@O), 1637
Scheme 3.

M. Bayat et al. / Tetrahedron Letters 51 (2010) 1873–1875
1875
(C@C), 1214 (C–O). 1H NMR (CDCl3): d = 3.69 (3H, s, OMe), 4.33 (3H, s, CO2Me),
(
m
max/cmÀ1): 1727 and 1682 (C@O), 1437 (C@C), 1214 (C–O). 1H NMR (CDCl3):
3
3
3
6.07 (1H, s, CH), 7.50 (2H, d, JHH = 8.2 Hz, CHarom), 8.23 (2H, d, JHH = 8.2 Hz,
CHarom). 13C NMR (CDCl3): d = 52.52 and 60.35 (2OCH3), 78.28 (CH), 121.62
(C@C–OMe), 123.97 and 128.39 (4CHarom), 130.05 and 148.33 (2Carom), 148.53
(C@C–OMe), 161.11 and 166.00 (2C@O). MS (m/z, %): 293 (M+, 21), 278 (3), 264
(26), 234 (37), 150 (41), 143 (100), 115 (25), 83 (15), 59 (22). Anal. Calcd for
C13H11NO7 (293.23): C, 53.25; H, 3.78; N, 4.78. Found: C, 53.3; H, 3.8; N, 4.8.
Dimethyl 2-(4-nitrobenzoyl)-butenedioate (3a). Red oil, (0.132 g, 45%). IR (KBr)
d = 3.66 and 3.79 (6H, s, 2OMe), 7.13 (1H, s, C@CH), 8.04 (2H, d, JHH = 8.0 Hz,
CHarom), 8.32 (2H, d, JHH = 8.0 Hz, CHarom). 13C NMR (CDCl3): d = 52.79 and
3
53.50 (2OCH3), 131.39 (C@CH), 124.10, 129.58, 129.92, 150.63 (6Carom), 144.42
(C@CH), 162.98 and 164.20 (2C@O ester), 190.79 (C@O). MS (m/z, %): 293 (M+,
16), 278 (10), 262 (9), 150 (100), 104 (22), 92 (12), 76 (20), 59 (13). Anal. Calcd
for C13H11NO7 (293.23): C, 53.25; H, 3.78; N, 4.78. Found: C, 53.3; H, 3.7; N, 4.8.
21. Yavari, I.; Ramazani, A.; Yahya-zadeh, A. Synth. Commun. 1996, 26, 4495.