An Efficient One-Pot Synthesis of Bis Butenolides

Article abstract of DOI:10.1002/jhet.2469

3,3′,4,4′-Tetramethyl-5,5′-dioxo-2,2′-bifuran-2,2′(5H,5′H) diyl diacetate was obtained from the reaction between 2,3-dimethyl maleic anhydride and acetic anhydride in the presence of zinc in toluene. This easy synthetic route gave bis butenolide in excellent yield.

Full text of DOI:10.1002/jhet.2469

Month 2015
An Efficient One-Pot Synthesis of Bis Butenolides
a
b
*
Mohammad Bayat and Joseph M. Fox
aDepartment of Chemistry, Imam Khomeini International University, Qazvin, Iran
bBrown Laboratories, Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
*
E-mail: bayat_mo@yahoo.com
Received November 17, 2014
DOI 10.1002/jhet.2469
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
3,3′,4,4′-Tetramethyl-5,5′-dioxo-2,2′-bifuran-2,2′(5H,5′H) diyl diacetate was obtained from the reaction
between 2,3-dimethyl maleic anhydride and acetic anhydride in the presence of zinc in toluene. This easy
synthetic route gave bis butenolide in excellent yield.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
crystal X-ray analysis. An Oak Ridge Thermal Ellipsoid
Plot (ORTEP) diagram of 2 is shown in Figure 1.
Butenolides or γ-butyrolactones are important structural
units in natural products and are intermediates in organic
synthesis [1,2]. Compounds with butenolide substructures
have received much interest for their utility in synthesis
[3] and their prevalence in biologically active molecules
and natural products [4]. There has been considerable work
on the synthesis of these compounds [5,6] because of the
discovery of many naturally occurring cytotoxic or
antitumour agents containing this structural unit. Although
this ring system has been the objective of synthetic projects
in several laboratories [1–3], the number of different ap-
proaches is not large. A number of methods for preparing
butenolides involve the reaction of furan derivatives, in-
cluding asymmetric variants based on the Michael [7],
Mukaiyama Michael [8], vinylogous Mannich [9], and
aldol reactions [10].
Herein, we report an efficient synthetic route to 3,3′,4,
4′-tetramethyl-5,5′-dioxo-2,2′-bifuran-2,2′(5H,5′H) diyl
diacetate using 2,3-dimethylmaleic anhydride in the pres-
ence of zinc and acetic anhydride. The one-pot reaction
of 2,3-dimethylmaleic anhydride 1 proceeded at 86°C in
toluene and completed after 2days to afford bis butenolide
2 in excellent yield (Scheme 1).
Compound 2 has two stereogenic centers, and therefore,
two diastereomers are expected (Scheme 1). This result is
not in accord with the similar pathway that is known to
operate in the reduction of π-bond of unsaturated anhy-
drides. It seems that electron-donating groups like methyl
(increase Lowest Unoccupied Molecular Orbital (LUMO))
cause π-bonds to not be reduced by the Zn/Ac2O reagent.
The structures of bis butenolide 2 were deduced from their
IR, 1H NMR, and 13C NMR spectra, and by single-crystal
X-ray analysis. Unambiguous evidence for the structure
and stereochemistry of 2 was obtained from a single-
The 1H NMR spectrum of crude product clearly showed
both bis butenolide stereoisomers in a nearly 9: 1 ratio. The
1H NMR spectrum of bis butenolide (S,R)-2 consisted of a
singlet for the acetyl group at 1.98ppm and two methyl
proton signals at 1.95 and 2.05ppm (doublets, J=2.05Hz).
The corresponding signals for the minor diastereomer
(S,S)-2 were observed at 2.28 for the acetyl group and
two methyl proton signals at 2.45 and 2.58 ppm
(doublets, J = 1.94 Hz). The 1H decoupled 13C NMR
spectrum of bis butenolide (S,R)-2 showed eight sharp
signals in agreement with the proposed structure.
1
The H NMR spectrum of the crude reaction mixtures
obtained from 2-methylmaleic anhydride and acetic anhy-
dride was consistent with 2-methyl succinic anhydride 4
with the presence of only one diastereomer 5 (Scheme 2).
When the reaction was carried out with 2-methylmaleic
anhydride, both 4 and 5 were produced in 65 and 30%
yields, respectively.
We then switched our attention to maleic anhydride
(MA), In this case, we did not observe the expected bis
butenolide product as a major product; instead, the reaction
afforded the succinic anhydride (SA). We found that the re-
action of maleic anhydride is to be highly chemoselective,
and the reaction led to complete chemoselective reduction
of the C¼C bond and gave the SA in quantitative yield
1
(Scheme 3). The H NMR spectrum of SA consisted of a
singlet at 3.12 ppm. The 13C NMR spectrum of SA showed
two sharp signals at 28.4 and 170.6ppm in agreement with
the structure.
We studied the chemoselective reduction of MA
(Table 1). We examined the effect of MA, Zn, and Ac2O
concentrations on the conversion of MA to SA. It
was found that conversion became higher with the increas-
ing of Zn amount. In terms of the amount of Zn required
© 2015 HeteroCorporation

M. Bayat and J. M. Fox
Vol 000
Scheme 1. Synthesis of bis butenolide. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Table 1
Effect of amount of Zn and Ac2O on the synthesis of 2.
Entry
MA (mM)
Zn (mM)
Ac2O (mM)
Yield (%)
1
2
3
4
5
6
7
1
1
1
1
1
1
1
0.1
0.2
0.3
0.1
3
0.1
0.2
0.3
3
0.1
1
trace
trace
trace
trace
trace
35
1
13
7
100
Table 2
Metal effect on the synthesis of 2.
Entry MA (mM)
Metal (mM)
Ac2O (mM) Yield (%)
1
2
3
4
1
1
1
1
Zn(OAc)2 (13)
Zn (13)
Fe (13)
—
—
7
0
0
0
0
Cu (13)
7
Figure 1. X-ray crystal structure (ORTEP) of 2. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
for the reaction of MA to afford SA, the best results
were obtained in the presence of 13 mM of Zn and 7 mM
of acetic anhydride. In the absence of Zn, no products
formed whilst in the presence of 10–30 mol% of Zn;
the products were obtained in low yields (gave SA in only
5–10% yield).
We examined the chemoselective reduction of MA
using Zn (OAc)2 or only Zn in toluene (Table 2); in the
same conditions, no products formed. Neither Fe nor Cu
dust promoted the reaction under similar conditions (entries
3 and 4).
We investigated suitable α,β unsaturated carbonyl com-
pounds for the chemoselective reduction as alternatives to
this reduction. We were pleased to find that with a variety
of compounds, the expected chemoselective reduction
takes place, again in quantitative yields. The reactions of
fumaric acid 6 or maleic acid 7 in toluene gave SA in quan-
titative yield in the same way (Scheme 4). SA is used as an
intermediate in chemical, pharmaceutical, and food indus-
tries. The analysis of literatures on hydrogenation of MA
shows that the most papers refer to catalytic studies at
temperature over 200°C by batch process [11].
Scheme 2. Synthesis of γ-butyrolactone. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
Scheme 4. Synthesis of succinic anhydride by using fumaric acid and
maleic acid. [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
An Efficient One-Pot
Scheme 5. Synthesis of N-substitutedsuccinimide. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
3,3′,4,4′-tetramethyl-5,5′-dioxo-2,2′-bifuran-2,2′(5H,5′H) diyl
diacetate (S,R)-2. Yield: 0.159g (90%), Colorless crystal,
m.p. 258–260°C (dec.). 1H NMR (CDCl3): δ = 1.91
(6H, d, J = 2 Hz, 2 CH3), 1.98 (6H, s, 2 OAc), 2.05
(6H, d, J = 2 Hz, 2 CH3). 13C NMR (CDCl3): δ= 8.9
(CH3), 12.2 (CH3CO), 21.3 (CH3), 103.6 (C), 129.5
and 153.6 (C¼C), 166.8 and 170.2 (C¼O).
3,3′,4,4′-tetramethyl-5,5′-dioxo-2,2′-bifuran-2,2′(5H,5′H) diyl
The broad potential scope for this chemoselective reduc-
tion is further examined by using maleimide derivatives.
The reaction of maleimide or N-substitutedmaleimide 7 in
the same condition proceeds smoothly to produce the
succinimide or N-substitutedsuccinimide 8 compounds in
fairly good yields (Scheme 5). Although numerous exam-
ples of metal reductions methods appear in the literature
[12], no broad study of the scope of this method for the
preparation of N-alkyl succinimides has been reported.
In conclusion, the reaction of 2,3-dimethyl maleic anhy-
dride with Zn in the presence of acetic anhydride provides
a simple one-pot entry into the synthesis of stable bis
butenolide compounds of potential interest. The simplicity
of the present procedure makes it an interesting alternative
to other approaches. SA generated by using maleic anhy-
dride, maleic acid, or fumaric acid in highly efficient
chemoselective reduction. We envisage broad potential ap-
plications for it that can be utilized for suitable substrates
such as α,β unsaturated carbonyl compounds to afford the
corresponding compounds. We hope that this methodology
will be useful for production of SA in industrial scales.
diacetate (S,S)-2.
Yield: 0.017 g (10%),White powder,
m.p. 248–250°C (dec.). 1H NMR (CDCl3): δ = 2.28
(6H, s, 2 OAc), 2.45 (6H, d, J = 1.94 Hz, 2 CH3), 2.58
(6H, d, J = 1.94 Hz, 2 CH3). 13C NMR (CDCl3): δ= 9.2
(CH3), 12.1 (CH3CO), 20.0 (CH3), 104.3 (C), 129.1
and 153.5 (C¼C), 167.4 and 170.0 (C¼O).
2-methylsuccinic anhydride (4). Yield: 0.074g (65%),1H
NMR (CDCl3): δ= 1.45 (3H, d, J = 6.5 Hz, CH3), 3.15
(2H, m, CH2), 3.21 (1H, m, CH). 13C NMR (CDCl3):
δ =16.1 (CH3), 35.4 (CH2), 35.8 (CH), 170.1 and 170.5
(2C¼O).
3′,4,4′-tetramethyl-5,5′-dioxo-2,2′-bifuran-2(5H)yl acetate
1
(5). Yield: 0.046g (30%), White solid, H NMR (CDCl3):
δ =1.25 (6H, d, 2 CH3), 2.12 (6H, s, 2 OAc), 7.31
(2H, br s, =CH). 13C NMR (CDCl3): δ= 16.8 (CH3), 38.3
and 66.3, 128.2 and 128.6 (C¼C), 177.4 and 180.9 (2C¼O).
Sccinic anhydride (SA). Yield: 0.100 g (100%),White
1
solid, m.p. 128–130°C. H NMR (400MHz, Acetone-d6):
δ = 3.12 (4H, s, CH). 13C NMR (151 MHz, CDCl3):
δ = 28.4 (CH) and 170.6 (C¼O).
Succinimide (8a). Yield: 0.099g (100%),White solid,
1
m.p. 123–125°C. H NMR (600 MHz, CDCl3): δ= 2.89
(4H, s, CH2), 8.95 (1H, br s, NH). 13C NMR (151MHz,
EXPERIMENTAL
CDCl3): δ =29.9 (CH2), 177.9 (C¼O).
N-methyl succinimide (8b). Yield: 0.113 g (100%), White
Maleic anhydride, 2,3-dimethylmaleic anhydride and
other reagents and solvents used in this work were ob-
tained from Aldrich chemical Co. and used without further
purification. NMR spectra were recorded with a Bruker
DRX-300 AVANCE instrument (400 MHz for 1H and
100MHz. for 13C) with CDCl3 as solvent. Chemical shifts
are given in ppm (δ) relative to internal TMS, and coupling
constant (J) are reported in hertz (Hz). Melting points were
measured with an electrotherma1 9100 apparatus. IR spec-
tra were measured with Bruker Tensor 27 spectrometer.
solid, m.p. 70–72°C. 1H NMR (600 MHz, CDCl3): δ= 2.71
(4H, s, CH2), 2.99 (3H, s, CH2). 13C NMR (151MHz,
CDCl3): δ =24.6 (CH2), 28.2 (NCH3), 177.3 (C¼O).
N-phenyl succinimide (8f).
Yield: 0.175 g (100%),
White solid, m.p. 154–156°C. 1H NMR (300MHz,
CDCl3): δ =2.86 (4H, s, CH2), 7.15–7.49 (5H, m, arom.).
Acknowledgments. We thank the University of Delaware for
supporting this work. We thank Dr. Glenn Yap for x-ray
crystallography and Robert Panish for mass spectroscopy
(Delaware).
Typical procedure for preparation of bis butenolide 2.
A
solution of 2,3-dimethylmaleic anhydride (0.126g, 1mM)
in toluene (6 mL) and Ac2O (0.7 mL, 7mM) was warmed
to 40°C, and heating was pursued until complete
dissolution of the solid. Activated Zn dust (0.8 g, 13mM)
was then added in one portion. The mixture was
mechanically stirred at 86°C for 48 h; under N2; vigorous
stirring is recommended in order to maintain the zinc in
suspension. It was then allowed to cool to r.t. and filtered
through a Celite pad. The solid was washed several times
with toluene, and the combined filtrate and washings
were evaporated under reduced pressure to afford the
product.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet