Efficient synthesis of new butenolides by subsequent reactions: Application for the synthesis of original iminolactones, bis-iminolactones and bis-lactones

Article abstract of DOI:10.1016/j.tet.2010.12.062

We have developed the synthesis of twenty four new iminolactones, bis-iminolactones and bis-lactones by subsequent esterification-condensation or addition-condensation reactions according to two strategies from α-hydroxyketones. The X-ray diffraction data of a bis-iminolactone is described and present an interesting helical column packing.

Full text of DOI:10.1016/j.tet.2010.12.062

Tetrahedron 67 (2011) 1540e1551
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of new butenolides by subsequent reactions: application for
the synthesis of original iminolactones, bis-iminolactones and bis-lactones
,b,
Nawel Cheikh a c, Nathalie Bar a, Nourredine Choukchou-Braham b, Bachir Mostefa-Kara b,
,
Jean-Franc¸ ois Lohier a, Jana Sopkova d, Didier Villemin a
*
a
ꢀ
ꢀ
Laboratoire de Chimie Moleculaire et Thioorganique, UMR CNRS 6507, INC3M, FR 3038, ENSICAEN et Universite de Caen Basse-Normandie, 14050 Caen, France
Laboratoire de Catalyse et Synthese en Chimie Organique, Faculte des Sciences, Universite Abou-Bakr Belkaid, BP 119, 13000 Tlemcen, Algeria
b
c
ꢁ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Universite de Bechar, Faculte des Sciences et Technologies, BP 417, 08000 Bechar, Algeria
d
ꢀ
ꢀ
Centre d’Etudes et de Recherche sur le Medicament de Normandie (CERMN), Universite de Caen, boulevard Henri Becquerel, F-14032 Caen, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 October 2010
Received in revised form 18 December 2010
Accepted 21 December 2010
Available online 30 December 2010
We have developed the synthesis of twenty four new iminolactones, bis-iminolactones and bis-lactones
by subsequent esterificationecondensation or additionecondensation reactions according to two strat-
egies from
a-hydroxyketones. The X-ray diffraction data of a bis-iminolactone is described and present
an interesting helical column packing.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
N-Substituted cyanoacetamide
Iminolactone
Butenolide
Diamine
Bis-iminolactone
Bis-lactone
1. Introduction
CHO
OH
C6H5
C6H5
Amberlite (OH-)
+
Functionally substituted derivatives of 2,5-dihydrofurans (but-
2-en-4-olides) constitute an important class of many natural and
synthetic products.1,2 They possess a wide range of biological
activities, which include antibacterial,3 antibiotic,4 antifungal,5
pesticides,6 anti-inflammatory7 and analgesic.8 These properties
have been responsible for considerable interest in the synthesis of
substituted butenolides.9,10
Iminolactones are an important class of heterocyclic compounds
due to their potential biological properties and were essentially
known in coumarin series. They are precursor agents for the prepa-
rationofawidespectrumofnaturalcompounds.11 However, thereare
only a few methods reported for the synthesis of iminolactones12e16
compared to the butenolides.9,10 Iminocoumarines are obtained by
the reaction of a nitrile with salicylic aldehyde or 2-hydrox-
yacetophenones under acidebase conditions (Fig. 1).13e15 The hy-
drolysis of iminolactones with aqueous hydrochloric acid produces
butenolides.16
CN
O
NH
Fig. 1. An example of synthesis of iminocoumarins.14
In our laboratory, we have described the synthesis of iminoar-
ylbutenolides
(3-aryl-2-imino-4-methyl-2,5-dihydrofurans)17,18
obtained by an one pot condensation reaction between different
-hydroxyketone and acetonitrile compounds, catalysed by sodium
ethoxide in ethanol under classical conditions or microwave irra-
diation. The hydrolysis of these iminolactones afforded corre-
sponding butenolides in good yields.
In the present work, we report in the first part a generic
methodology for the synthesis of five-membered iminolactones
(iminodihydrofurans) from various amines and their conversion
into the corresponding butenolides (2,5-dihydrofurans) by a simple
hydrolysis (Fig. 2).
In the second part, in view of synthesizing new heterocycles, we
present simple protocols for preparing two series of bis-lactone
derivatives (Fig. 3). These bis-lactone derivatives could be good
candidates as chelating and bis-alkylating agents. Generally the
butenolidecytotoxicitywasattributed totheirreactivity towardsthe
cysteine residues of functional proteins forming covalent bond via
a
* Corresponding author. Fax: þ33 231452877; e-mail addresses: n_cheikh@ya-
hoo.fr (N. Cheikh), sopkova@pharmacie.unicaen.fr (J. Sopkova), didier.villemin@
ensicaen.fr (D. Villemin).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.062

N. Cheikh et al. / Tetrahedron 67 (2011) 1540e1551
1541
R
Z
R
Z
However, secondary amine required longer reaction time (24 h) at
room temperature and the reaction were incomplete. The cyanoa-
cetamide 2d was formed in 37% yield (Table 1).
Next, iminolactone compounds (N-alkyl-2,5-dihydro-2-imino-
furan-3-carboxamides) 3aed were obtained, in cascade reaction,
R1
R2
R1
R2
NH
O
O
O
iminolactone
(iminodihydrofuran)
butenolide
(2,5-dihydrofuran)
from
a-hydroxyketone 1 and N-substituted cyanoacetamide de-
rivatives 2aed in the presence of a catalytic amount of sodium
ethoxide in ethanol at room temperature for 6e24 h (Table 2).
The spontaneous cyclisation between the hydroxyl group of
compound 1 and the cyano group of intermediate 2 followed by
a Knoevenagel21 reaction led to iminolactone derivatives in good
yields (75e96%). The ease of ring formation was probably due to the
Fig. 2. Generic structures of butenolide, iminolactone.
reverse Michael type addition.19 In the literature, bis-iminolactones
have been the subject of only one report20 for bis-iminocoumarins
synthesis.
Fig. 3. Generic structures of bis-lactones.
2. Results and discussion
presence of a gem-diakyl moiety producing a ThorpeeIngold con-
formational effect.22,23 The supposed mechanism is described in
Scheme 1.
The simple and easy synthesis of iminolactones (N-alkyl-2,5-
dihydro-2-iminofuran-3-carboxamides) 3aed begins with the
preparation of N-substituted cyanoacetamide derivatives 2aed. The
latter were easily obtained by direct condensation of ethyl cyanoa-
cetate with primary amines at room temperature in the presence of
a catalytic amount of sodium ethoxide in ethanol. The reaction was
carried out also in solvent free conditions with KF-alumina (Al2O3/
KF) for 1 h and gave similar isolated yields (85e90%) (Table 1).
The readily treatment of iminolactones 3aed with concentrated
hydrochloric acid lead to the hydrolysis of the imino group
affording the corresponding lactones 4aed in quantitative yields
(Table 2). The structures of iminolactones 3aed and lactones 4aed
were determined unambiguously by IR, 1H NMR, 13C NMR and mass
spectra. Namely, the C]N absorptions of the imino group observed
in IR (1674e1681 cmꢀ1) are lower than C]O absorptions of the
lactone (1732e1748 cmꢀ1). This indicates clearly the formation of
iminolactones. The different chemical shifts values in 13C NMR
spectra and the melting points also confirmed the formation of two
different products.
In the second part of our work, we developed an easy and effi-
cient method for preparation of various bis-lactone derivatives,
which are new potential chelating compounds. We have in-
vestigated herein the synthesis of two types of new bis-lactones
7 and 9 (Fig. 4).
Table 1
Synthesis of cyanoacetamide derivatives 2aed
O
CN
R
R'
R'
EtONa / EtOH
N
+
N
R
H
or Al2O3 / KF
rt
CO2Et
CN
2a-d
2a: R = H, R' = cyclohexyl
2b: R = H, R' = benzyl
2c: R = H, R' = tetrahydrofurfuryl
2d: R, R' = piperidinyl
The bis-lactones 7 and 9 differ from the nature (amide or C]C
bond, respectively) and the position (3 or 4, respectively) of the
group, which binds to the spacer.
Entry
1
R
R0
Product
Yield [%]
The synthesis of bis-lactones 7aee was based on the following
procedure: a direct and simple condensation of different diamines
with 2 equiv of ethyl cyanoacetate in the presence of a catalytic
amount of basic catalyst afforded bis-cyanoacetamides 5aed in
isolated yields (75e85%) at room temperature from primary
amines. However with secondary amine, the reaction yield is lower
(5e 39%) and needs higher temperature (80 ꢁC) during a longer time
(Table 3).
O
90a
2a
H
Cyclohexyl
N
H
CN
CN
O
85a
2
3
H
H
Benzyl
N
H
2b
Then, the Knoevenagel condensation of bis-cyanoacetamides
5aee with 2 equiv of a-hydroxyketone 1 in the presence of the
O
sodium ethoxide in ethanol afforded the bis-iminolactones 6aee in
isolated yields (58e96%). The hydrolysis of the bis-iminolactones
6aee in the presence of hydrochloric acid (3 M) gave the bis-lactones
7aed. In the case of compound 6e the bis-lactone was not obtained
in this condition, a hydrolysis occurred followed by an esterification
in ethanol to furnish the butenolide ester 8a.
Following this successful synthesis, several substituted bis-imin
olactones and bis-lactones were prepared (Table 4).
The new bis-iminolactone 6a was obtained, crystallized and it
was possible to carry out by the X-ray crystallography study. This
O
87a
2c
Tetrahydrofurfuryl
N
H
CN
O
37b
4
Piperidinyl
N
2d
CN
a
1 h, rt.
24 h, rt.
b

1542
N. Cheikh et al. / Tetrahedron 67 (2011) 1540e1551
Table 2
Synthesis of iminolactones 3aed and their corresponding lactones 4aed
O
O
O
O
R'
R'
R'
EtONa / EtOH
rt
N
R
N
R
N
R
HCl (3M)
+
OH
O
CN
O
NH
O
1
2a-d
3a-d
4a-d
Entry
1
R
R0
Product
Yield [%]
96a
O
3a
H
Cyclohexyl
N
H
O
O
O
O
NH
O
94a
75a
93b
N
H
3b
3c
2
3
4
H
H
Benzyl
NH
O
O
N
H
Tetrahydrofurfuryl
NH
O
N
Piperidinyl
3d
4a
NH
O
99c
5
H
Cyclohexyl
N
H
O
O
O
O
O
O
98c
99c
95c
N
H
4b
4c
6
7
H
Benzyl
O
O
O
N
H
H
Tetrahydrofurfuryl
O
O
N
8
Piperidinyl
4d
O
a
6 h, rt.
24 h, rt.
: 5 h, reflux EtOH.
b
c
The structure of the crystal is very original and shows a supra-
O
CONHR
N
O
CONHR
R1
R2
R1
R2
molecular arrangement in an infinite helical column (Fig. 6). The
querying of the Cambridge Structural Database (CSD, Version 5.24,
Allen & Kennard, 1993) showed that actually, there is not available
structure of similar compounds. Furthermore, the arrangement of
compound in an infinite helical column in the crystal is not com-
mon. These columns are connected between them along a axis by
a weak CeH /O interaction between H13A from C13 methyl group
and O7. Two methyl hydrogen from two neighbouring molecules of
one column interact with the same oxygen of the second column.
In the crystal structure N8 is situated in the proximity of hy-
drogen H9 of atom N9. The contact distance between N8 and H9 is
+
C
N
O
O
1
2
CONHR
NH
O
O
CONHR
NH
R1
R2
R1
R2
O
Scheme 1. Mechanism of formation of 2-imino-4-methyl-2,5-dihydrofurans.
ꢂ
2.095e2.110A, indicating formation of an intramolecular hydrogen
structure of 6a confirms the formation of iminolactone with
ketonitriles. To our knowledge, it is the first structure of a bis-
iminolactone described in literature.
b-
bond. With this hydrogen bond, the six atoms N8, C2, C4, C6, N9
and H9 form a pseudo-six-membered ring. Formation of the
pseudo-six-membered ring is accompanied by a delocalization of
The ORTEP diagram is shown in Fig. 5:
p
electrons. So, in reality the compound behaves as a compound

N. Cheikh et al. / Tetrahedron 67 (2011) 1540e1551
1543
O
O
R1
R1
R2
R2
O
O
R1
R1
R2
O
O
O
O
R2
O
O
9
7
Fig. 4. Structures of bis-lactones 7 and 9.
Table 3
Synthesis of bis-cyanoacetamide derivatives 5aee
O
O
CN
EtONa / EtOH
2
N
R
N
R
RHN
NHR
+
CO2Et
CN
CN
5a-e
Entry
1
Diamine
Product
Yield [%]
O
O
O
85a
74a
78a
H2N(CH2)3NH2
H2N(CH2)6NH2
5a
N
H
N
H
CN
CN
O
2
3
5b
5c
N
H
N
H
4
CN
CN
O
O
H2N(CH2)3O(CH2)4O(CH2)3NH2
1,3-H2NCH2C6H4CH2NH2
N
O
O
N
3
4
3
H
H
CN
CN
CN
CN
O
O
75a
39b
5d
4
N
H
N
H
O
O
5e
N
N
5
H
N
N H
CN
NC
a
2 h, rt.
12 h, reflux EtOH.
b
Table 4
Synthesis of bis-iminolactone and bis-lactone derivatives
O
O
O
O
O
O
O
EtONa
EtOH
2
HCl
+
O
O
O
O
OH
CN
CN
NH
O
HN
O
5a-e
6a-e
7a-d
1
Entry
1
Yield [%]
96a
Product
O
O
N
H
N
H
6a
eHN(CH2)3NHe
eHN(CH2)6NHe
O
O
O
NH
O
HN
O
93a
80a
6b
N
N
H
2
3
4
H
O
NH
O
HN
O
N
O
O
N
3
eHN(CH2)3O(CH2)4O(CH2)3NHe
6c
3
4
H
H
O
O
NH
HN
(continued on next page)

1544
N. Cheikh et al. / Tetrahedron 67 (2011) 1540e1551
Table 4 (continued )
Entry
Yield [%]
70a
Product
O
O
N
H
N
H
4
1,3-HNCH2C6H4CH2NHe
6d
O
O
NH
HN
O
O
N
N
5
6e
N
N
58b
94c
98c
88c
90c
0c
NH
HN
O
O
O
O
N
H
N
6
eHN(CH2)3NHe
eHN(CH2)6NHe
7a
H
O
O
O
O
O
O
O
O
N
H
N
H
7
7b
4
O
O
O
O
O
N
O
O
N
H
8
eHN(CH2)3O(CH2)4O(CH2)3NHe
1,3-HNCH2C6H4CH2NHe
3
4
3
7c
H
O
O
O
O
O
O
N
H
N
H
9
7d
O
O
O
O
O
N
N
10
N
N
7e
O
O
O
O
a
12 h, rt.
6 h, reflux EtOH.
5 h, reflux EtOH.
b
c
code: ꢀxþ1, ꢀy, ꢀz) related by inversion centre. Thus, the in-
termolecular hydrogen-bonded molecules form infinite helical col-
umnalong thec axis. Thesecolumns areconnected betweenthem by
a weak CeH /O interaction between H13A from C13 methyl group
and O7. The disorder is situatedon the aliphatic chain connecting the
rings and it includes five atoms. The two conformations are the same
probability of appearance, since this disorder is 50%.
Finally, we developed a synthesis of bis-lactones of type 9. In
this case, the methyl group in position 4 of 2,5-dihydrofurans is
acid, vinylogue to the methylene of the malonate derivatives,24 so it
can easily be deprotonated and condensed with arylaldehyde.17 In
a similar manner, we report an efficient synthesis of bis-lactones of
type 9 from readily available aromatic dialdehyde (meta or para).
As shown in Table 5, the bis-lactones 9aeg were synthesized in
two steps from different a-hydroxyketones 1aec. In the first step
we prepared lactones 8aed according to a simple and easy method
without solvent.10 The condensation of 2 equiv of these lactones
with an equivalent of terephtalaldehyde or isophtalaldehyde in the
presence of 1 equiv of triethylamine in solvent free reaction con-
ditions afforded the bis-lactones 9aeg in good yields after heating
at 80 ꢁC during 5 h (Table 5).
Fig. 5. ORTEP diagram of the X-ray crystal structure of compound 6a with thermal
ellipsoids at 50% probability.
3. Conclusion
with a bicycle on each extremity and the folded conformation of
compound observed in the crystal is a result of
teraction occurring between the bicycles.
In the crystal, the packing is principally mediated by electrostatic
interactions. The neighbouring molecules are linked by pair of two
symmetry equivalent hydrogen bonds, N8eH8/O1 (symmetry
p
-stacking in-
In conclusion, we have developed two simple and efficient routes
for the synthesis of various iminolactone, bis-iminolactone and bis-
lactone derivatives from simple and readily available starting ma-
terials. The bis-lactones were easily synthesized either by hydrolysis
of bis-iminolactones or by solvent free cascade reaction between

N. Cheikh et al. / Tetrahedron 67 (2011) 1540e1551
1545
spectra were recorded on a QTOF Micro (Waters) spectrometer with
electrospray ionization (ESI, positive mode), lockspray PEG, infusion
introduction at 5 m
L/min, a source temperature of 80 ꢁC and des-
olvation temperature of 120 ꢁC.
4.2. General procedure 1:synthesis of cyanoacetamides 2aed
A mixture of a solution of sodium ethoxide (0.1 mmol) in ethanol
(3 mL), ethyl cyanoacetate (10 mmol) and amine (10 mmol) was
stirred at room temperature. The reaction time is 1 h for primary
amines and 24 h for secondary amine 2d. The precipitate obtained
was separated by filtration, washed with diethylether and recrys-
tallised in ethanol to provide a white solid of cyanoacetamides.
4.2.1. 2-Cyano-N-cyclohexylacetamide 2a. The general procedure 1,
using (1.13 g, 10 mmol) of ethyl cyanoacetate and (0.99 g, 10 mmol)
of cyclohexylamine, gave the compound 2a (1.49 g, 90%) as a white
solid, mp 122e123 ꢁC. 1H NMR (DMSO-d6)
d
8.13 (1H, qt, 3J¼7.5 Hz,
NH), 3.58 (2H, s, CH2CN), 3.48e3.56 (1H, m, CH), 1.09e1.79 (10H, m,
5CH2). 13C NMR (DMSO-d6)
d 160.9, 116.2, 48.4, 32.0, 25.0, 24.8, 24.3.
EIMS m/z (% relative abundance): 167 (MþH, 52), 85 (100), 83 (56).
HRMS (ES-QTOF) Calcd for C9H15N2O MþH 167.1184. Found
167.1186. IR nmax (neat/cmꢀ1): 3276, 2261, 1646.
4.2.2. 2-Cyano-N-benzylacetamide 2b. The general procedure 1,
using (1.13 g, 10 mmol) of ethyl cyanoacetate and (1.07 g, 10 mmol)
of benzylamine, gave the compound 2b (1.47 g, 85%) as a white
solid, mp 119e120 ꢁC. 1H NMR (DMSO-d6)
d
8.81 (1H, t, 3J¼4.9 Hz,
NH), 7.27e7.41 (5H, m, Harom), 4.35 (2H, d, 3J¼5.8 Hz, CH2Ph), 3.76
(2H, s, CH2CN). 13C NMR (DMSO-d6)
d 162.2, 138.5, 128.6, 127.3,
127.0, 116.2, 42.7, 25.3. EIMS m/z (% relative abundance): 175 (MþH,
12), 97 (18), 91 (100). HRMS (ES-QTOF) Calcd for C10H11N2O MþH
175.0871. Found 175.0873. IR nmax (neat/cmꢀ1): 3302, 2255, 1644.
4.2.3. 2-Cyano-N-((tetrahydrofuran-2-yl)methyl)acetamide 2c. The
general procedure 1, using (1.13 g, 10 mmol) of ethyl cyanoacetate
and (1.01 g, 10 mmol) of tetrahydrofurfurylamine, gave the com-
pound 2c (1.46 g, 87%) as a white solid, mp 89e90 ꢁC. 1H NMR
Fig. 6. A view of the electrostatic interactions in the crystal packing of 6a.
(DMSO-d6)
d
8.37 (1H, 3J¼7.0 Hz, NH), 3.66 (2H, s, CH2CN),
3.55e3.60 (2H, m, CH2), 3.64e3.69 (1H, m, CH), 3.13e3.23 (2H, m,
dialdehyde and a,b-insaturated g-lactones. Both methods are ef-
CH2NH),1.47e1.93 (4H, m, 2CH2). 13C NMR (DMSO-d6)
d 162.2, 116.1,
fective and allowed us to obtain twenty four new heterocyclic
compounds, not described previously, with very good yields. Finally,
we present herein the first X-ray diffraction data of a bis-imino-
lactone, which shows an interesting helical column packing.
76.8, 67.1, 43.1, 28.3, 25.3, 25.1. EIMS m/z (% relative abundance):
169 (MþH, 37), 151 (39), 97 (40), 85 (100). HRMS (ES-QTOF) Calcd
for C8H13N2O2 MþH 169.0977. Found 169.0981. IR nmax (neat/cmꢀ1):
3279, 2254, 1641.
4. Experimental section
4.1. General methods
4.2.4. 3-Oxo-3-(piperidin-1-yl)propanenitrile 2d. The general pro-
cedure 1, using (1.13 g, 10 mmol) of ethyl cyanoacetate and (0.85 g,
10mmol)ofpiperidine, gavethecompound2d(0.56g, 37%)asawhite
solid, mp 86e87 ꢁC. 1H NMR (DMSO-d6)
d 4.02 (2H, s, CH2CN), 3.45
All commercial reagents were purchased from Acros, Aldrich
and Sigma and were used as received without further purification.
Reactions were monitored by TLC until no starting material
remained. TLC was performed using Silica gel 60 F254 percolated
aluminum sheets.
(2H, t, 3J¼5.6 Hz, CH2N), 3.32 (2H, t, 3J¼5.6 Hz, CH2N), 1.44e1.63 (6H,
m, 3CH2). 13C NMR (DMSO-d6)
d 160.9, 116.2, 46.4, 42.5, 25.6, 25.0,
24.7, 23.8. EIMS m/z (% relative abundance): 153 (MþH,100),112 (70),
85 (100). HRMS (ES-QTOF) Calcd for C8H13N2O MþH 153.1028. Found
153.1023. IR nmax (neat/cmꢀ1): 2987, 2263, 1640.
Melting points were recorded on a Kofler apparatus and are un-
corrected. IR spectra were obtained with solids or neat liquids with
a Fourier transform PerkineElmer Spectrum One with ATR accessory.
Only significant absorptions are listed. NMR spectra were recorded at
250MHzfor1HNMRand62.9MHzfor13CNMRwitha‘BrukerAC250’
4.3. General procedure 2:synthesis of N-alkyl-2,5-dihydro-2-
imino-4,5,5-trialkylfuran-3-carboxamide 3aed
A mixture of 3-hydroxy-3-methylbutan-2-one 1 (10 mmol) and
the substituted cyanoacetamides 2aed (10 mmol) with a solution
of sodium ethoxide (0.5 mmol) in ethanol (10 mL) was stirred at
room temperature. After evaporation of the solvent, the residue
was acidified with 6 M aqueous HCl. The mixture was neutralised
with a solution of potassium carbonate (10%), then extracted with
CH2Cl2 (3ꢂ25 mL). The combined organic layers were dried on
spectrophotometer in CDCl3 and DMSO-d6. Chemical shifts (d) are
expressed in parts per million (ppm) and are referenced to the in-
ternal deuterated solvents with tetramethylsilane as the internal
standard. Data are reported as follows: multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, qt¼quintuplet, dd¼doublet of
doublet, dt¼doublet of triplet, m¼multiplet, br s¼broad signal). Mass

1546
N. Cheikh et al. / Tetrahedron 67 (2011) 1540e1551
Table 5
Synthesis of bis-lactones 9
Y
Y
Y
4
3
O
Y
R1
R2
Et3N
R1
R2
2
O
OHC
CHO
+
+
O
O
O
R1
R2
OH
R1
R2
80 °C
5
CO2Et
O
1
O
1a-c
9a-g
8a-d
p / m
a: R1 = R2 = Me
b: R1 = Me, R2 = Et
c: R1 = R2 = -(CH2)5-
a: R1 = R2 = Me, Y = CO2Et
: p / m-phenyl
b: R1 = Me, R2 = Et, Y = CO2Et
c: R1 = R2 = -(CH2)5-, Y = CO2Et
d: R1 = R2 = Me, Y = COMe
Entry
1
Dialdehyde
Product
Yield [%]
48
CO2Et
EtO2C
O
O
O
O
9a
9b
CO2Et
EtO2C
O
O
2
3
40
35
O
O
CHO
CHO
CO2Et
EtO2C
O
O
O
O
O
O
9c
O
O
4
O
67
O
9d
9e
9f
CO2Et
EtO2C
O
O
5
6
81
73
O
O
CO2Et
EtO2C
CHO
O
O
O
O
CHO
CO2Et
EtO2C
O
O
7
70
O
O
9g
MgSO4, filtered and concentrated in vacuum. The recovered solid
was recrystallised in ethanol to provide compounds 3aed.
3J¼5.8 Hz, CH2Ph), 2.33 (3H, s, CH3), 1.32 (6H, s, 2CH3). 13C NMR
(CDCl3)
d 172.1, 167.6, 162.0, 138.5, 128.7, 127.5, 127.1, 119.0, 88.6,
42.7, 24.9, 12.6. EIMS m/z (% relative abundance): 259 (MþH, 54),
241 (14), 224 (10), 214 (20), 199 (43), 196 (25), 185 (16), 181 (14),
157 (22), 152 (26), 135 (27), 106 (32), 91 (100). HRMS (ES-QTOF)
Calcd for C15H19N2O2 MþH 259.1447. Found 259.1447. IR nmax
(neat/cmꢀ1): 3256, 3063, 2850, 1674, 1644, 1552.
4.3.1. N-Cyclohexyl-2,5-dihydro-2-imino-4,5,5-trimethylfuran-3-car-
boxamide 3a. The general procedure 2, using (1.02 g, 10 mmol) of
3-hydroxy-3-methylbutan-2-one and (1.66 g, 10 mmol) of 2-cy-
ano-N-cyclohexylacetamide 2a in the presence of sodium ethoxide
(0.01 g, 0.5 mmol), gave, in 6 h, compound 3a (2.40 g, 96%) as
yellow solid, mp<50 ꢁC. 1H NMR (CDCl3)
d
9.51 (1H, d, 3J¼5.0 Hz,
4.3.3. N-((Tetrahydrofuran-2-yl)methyl)-2,5-dihydro-2-imino-4,5,5-
trimethylfuran-3-carboxamide 3c. The general procedure 2, using
(1.02 g, 10 mmol) of 3-hydroxy-3-methylbutan-2-one and (1.68 g,
10 mmol) of 2-cyano-N-((tetrahydrofuran-2-yl)methyl)acetamide
2c in the presence of sodium ethoxide (0.01 g, 0.5 mmol), gave, in
6 h, compound 3c (1.89 g, 75%) as yellow solid, mp 64e65 ꢁC. 1H
CONH), 6.80 (1H, s, C]NH), 3.82e3.89 (1H, m, NHCH), 2.36 (3H, s,
CH3), 1.84e1.89 (2H, m, CH2), 1.65e1.66 (2H, m, CH2), 1.50e1.52
(2H, m, CH2), 1.37 (6H, s, 2CH3), 1.26e1.35 (4H, m, 2CH2). 13C NMR
(CDCl3)
d 171.4, 167.8, 161.1, 119.0, 88.4, 47.3, 32.6, 29.2, 25.7, 24.6,
12.5. EIMS m/z (% relative abundance): 251 (MþH, 100), 234 (23),
169 (28), 152 (73), 151 (79). HRMS (ES-QTOF) Calcd for C14H23N2O2
MþH 251.1760. Found 251.1761. IR nmax (neat/cmꢀ1): 2978, 2854,
1674, 1640, 1552.
NMR (CDCl3)
d 9.76 (1H, s, CONH), 6.96 (1H, s, C]NH), 4.02e4.09
(1H, m, CH), 3.74e3.91 (2H, m, CH2), 3.33e3.56 (2H, m, NHCH2),
2.38 (3H, s, CH3), 1.84e1.94 (4H, m, 2CH2), 1.38 (6H, s, 2CH3). 13C
NMR (CDCl3)
d 175.7, 168.1, 159.2, 119.8, 98.5, 76.6, 67.1, 42.9, 28.6,
4.3.2. N-Benzyl-2,5-dihydro-2-imino-4,5,5-trimethylfuran-3-carbox-
amide 3b. The general procedure 2, using (1.02 g, 10 mmol) of
3-hydroxy-3-methylbutan-2-one and (1.74 g, 10 mmol) of 2-cy-
ano-N-benzylacetamide 2b in the presence of sodium ethoxide
(0.01 g, 0.5 mmol), gave, in 6 h, compound 3b (2.42 g, 94%) as
25.1, 23.0, 13.3. EIMS m/z (% relative abundance): 253 (MþH, 48),
236 (15), 235 (10), 153 (31), 152 (100), 135 (35). HRMS (ES-QTOF)
Calcd for C13H21N2O3 MþH 253.1552. Found 253.1554. IR nmax (neat/
cmꢀ1): 3181, 3049, 2668, 1681, 1627, 1551.
yellow solid, mp 56e58 ꢁC. 1H NMR (CDCl3)
d
9.93 (1H, s, CONH),
4.3.4. (5-Ethyl-2-imino-4,5-dimethyl-2,5-dihydrofuran-3-yl)(piper-
7.16e7.26 (5H, m, Harom), 6.87 (1H, s, C]NH), 4.47 (2H, d,
idin-1-yl)methanone 3d. The general procedure 2, using (1.02 g,

N. Cheikh et al. / Tetrahedron 67 (2011) 1540e1551
1547
10 mmol) of 3-hydroxy-3-methylpentan-2-one and (1.52 g,
10 mmol) of 3-oxo-3-(piperidin-1-yl)propanenitrile 2d in the
presence of sodium ethoxide (0.01 g, 0.5 mmol) gave, in 24 h,
115.5, 89.0, 48.1, 32.2, 25.3, 23.1,12.1. EIMS m/z (% relative abundance):
238 (MþH, 82). HRMS (ES-QTOF) Calcd for C13H20NO3 MþH 238.1438.
Found 238.1440. IR nmax (neat/cmꢀ1): 2972, 1748, 1629.
compound 3d (2.19 g, 93%) as viscous liquid. 1H NMR (CDCl3)
d 5.29
(1H, s, C]NH), 3.56 (4H, t, 3J¼5.2 Hz, 2CH2), 2.20 (3H, s, CH3), 1.80
4.5. General procedure 4: synthesis of bis-cyanoacetamides
5aee
(6H, s, 2CH3), 1.56e1.60 (6H, m, 3CH2). 13C NMR (CDCl3)
d
168.4,
162.3, 159.9, 114.1, 91.3, 48.1, 32.2, 25.0, 18.4, 11.6. EIMS m/z (% rel-
ative abundance): 237 (MþH, 100). HRMS (ES-QTOF) Calcd for
C13H21N2O2 MþH 237.1598. Found 237.1591. IR nmax (neat/cmꢀ1):
3322, 2987, 2901, 1676, 1641.
A mixture of a solution of sodium ethoxide (1 mmol) in ethanol
(3 mL), ethyl cyanoacetate (10 mmol) and the diamine (5 mmol)
was stirred. The white precipitate obtained was separated by fil-
tration, rinsed with diethylether and recrystallised in ethanol to
provide bis-cyanoacetamides 5aee.
4.4. General procedure 3: hydrolysis of iminolactones 3aed in
butenolides 4aed
4.5.1. Bis-(2-cyanoacetamide)-N,N0-propylidene 5a. The general
procedure 4, using ethyl cyanoacetate (1.13 g, 10 mmol) and pro-
panediamine (0.37 g, 5 mmol), gave in 2 h at room temperature,
compound 5a (0.88 g, 85%) as white solid, mp 159e160 ꢁC. 1H NMR
To a solution of HCl (3 M, 2 mL) was added N-alkyl-2,5-dihydro-
2-imino-4,5,5-trialkylfuran-3-carboxamide 3aed (2 mmol) in
ethanol (5 mL). After being refluxed for 5 h, the mixture was
evaporated and the obtained residue was extracted with CH2Cl2
(3ꢂ20 mL). The combined organic layers were dried on MgSO4,
filtered and concentrated in vacuum to give butenolides 4aed, after
recrystallisation in ethanol.
(DMSO-d6)
d 8.25 (2H, s, 2NH), 3.64 (4H, s, 2CH2CN), 3.11 (4H, q,
3J¼6.7 Hz, CH2CH2CH2), 1.59 (2H, m, 3J¼6.9 Hz, CH2CH2CH2). 13C
NMR (DMSO-d6) d 162.6, 116.2, 36.9, 28.5, 25.2. EIMS m/z (% relative
abundance): 209 (MþH, 100), 142 (90), 125 (62). HRMS (ES-QTOF)
Calcd for C9H13N4O2 MþH 209.1039. Found 209.1040. IR nmax (neat/
cmꢀ1): 3287, 3092, 2927, 2257, 1649, 1561.
4.4.1. N-Cyclohexyl-2,5-dihydro-4,5,5-trimethyl-2-oxofuran-3-car-
boxamide 4a. The general procedure 3, using (0.50 g, 2 mmol) of
N-cyclohexyl-2,5-dihydro-2-imino-4,5,5-trimethylfuran-3-car-
boxamide 3a, yielded 4a (0.49 g, 99%) as yellow solid, mp
4.5.2. Bis-(2-cyanoacetamide)-N,N0-hexylidene 5b. The general
procedure 4, using ethyl cyanoacetate (1.13 g, 10 mmol) and 1,6-
hexanediamine (0.58 g, 5 mmol), gave in 2 h at room temperature,
compound 5b (0.92 g, 74%) as white solid, mp 149e150 ꢁC. 1H NMR
80e81 ꢁC. 1H NMR (CDCl3)
d
8.12 (1H, d, 3J¼5.7 Hz, CONH),
3.81e3.93 (1H, m, CH), 2.47 (3H, s, CH3), 1.69e1.92 (4H, m, 2CH2),
1.55e1.59 (2H, m, CH2), 1.47 (6H, s, 2CH3), 1.24e1.40 (4H, m, 2CH2).
(DMSO-d6)
d 8.25 (2H, s, 2NH), 3.63 (4H, s, 2CH2CN), 3.08 (4H, q,
13C NMR (CDCl3)
d
174.3, 169.9, 154.5, 111.8, 81.1, 42.0, 27.2, 20.0,
3J¼6.6 Hz, 2CH2), 1.28e1.45 (8H, m, 4CH2). 13C NMR (DMSO-d6)
19.1, 18.7, 7.4. EIMS m/z (% relative abundance): 252 (MþH, 57), 171
(10), 170 (100). HRMS (ES-QTOF) Calcd for C14H22NO3 MþH
252.1607. Found 252.1600. IR nmax (neat/cmꢀ1): 3334, 2981, 2854,
1733, 1666, 1641.
d 161.8, 116.2, 38.9, 28.6, 25.9, 25.2. EIMS m/z (% relative abun-
dance): 251 (MþH, 100), 184 (90), 167 (18). HRMS (ES-QTOF) Calcd
for C12H19N4O2 MþH 251.1508. Found 251.1511. IR nmax (neat/cmꢀ1):
3287, 3066, 2868, 2259, 1648, 1544.
4.4.2. N-Benzyl-2,5-dihydro-4,5,5-trimethyl-2-oxofuran-3-carbox-
amide 4b. The general procedure 3, using (0.52 g, 2 mmol) of
N-benzyl-2,5-dihydro-2-imino-4,5,5-trimethylfuran-3-carboxami
de 3b, yielded 4b (0.50 g, 98%) as yellow solid, mp 83e84 ꢁC. 1H
4.5.3. 1,4-Bis-(2-cyanoacetamido)-N-bis-(propyloxy)butane 5c. The
general procedure 4, using ethyl cyanoacetate (1.13 g, 10 mmol) and
4,9-dioxa-1,12-dodecanediamine (1.02 g, 5 mmol), gave in 2 h at
room temperature, compound 5c (1.31 g, 78%) as white solid, mp
NMR (CDCl3)
d
8.55 (1H, s, NH), 7.20e7.34 (5H, m, Harom), 4.53 (2H,
100e102 ꢁC. 1H NMR (DMSO-d6)
d 8.29 (2H, s, 2NH), 3.63 (4H, s,
d, 3J¼5.9 Hz, CH2), 2.48 (3H, s, CH3), 1.46 (6H, s, 2CH3). 13C NMR
2CH2CN), 3.30e3.46 (8H, m, 4CH2), 3.14 (4H, q, 3J¼6.6 Hz, 2CH2NH),
(CDCl3)
d 180.5, 171.3, 160.9, 137.9, 128.8, 127.7, 127.4, 117.1, 86.8,
1.66 (4H, m, 3J¼6.5 Hz, 2CH2), 1.55 (4H, m, 2CH2). 13C NMR (DMSO-
42.8, 24.2,13.0. EIMS m/z (% relative abundance): 260 (MþH, 46), 91
(100). HRMS (ES-QTOF) Calcd for C15H18NO3 MþH 260.1287. Found
260.1285. IR nmax (neat/cmꢀ1): 3348, 3031, 2931, 1732, 1659, 1644.
d6) d 161.9, 116.2, 69.8, 67.3, 36.4, 29.0, 26.0, 25.2. EIMS m/z (% rel-
ative abundance): 339 (MþH, 83), 125 (100). HRMS (ES-QTOF)
Calcd for C16H27N4O4 MþH 339.2032. Found 339.2034. IR nmax
(neat/cmꢀ1): 3262, 3096, 2804, 2255, 1651, 1571.
4.4.3. 2,5-Dihydro-N-((tetrahydrofuran-2-yl)methyl)-4,5,5-trimethyl-
2-oxofuran-3-carboxamide 4c. The general procedure 3, using N-
((tetrahydrofuran-2-yl)methyl)-2,5-dihydro-2-imino-4,5,5-tri-
methylfuran-3-carboxamide 3c (0.50 g, 2 mmol), yielded 4c
4.5.4. 1,3-Bis-((2-cyanoacetamido)-N-methyl)benzene 5d. The gen-
eral procedure 4, using ethyl cyanoacetate (1.13 g, 10 mmol) and
m-xylylenediamine (0.68 g, 5 mmol), gave in 2 h at room tem-
perature, compound 5d (1.01 g, 75%) as white solid, mp
(0.50 g, 99%) as yellow solid, mp 90e92 ꢁC. 1H NMR (CDCl3)
d 8.38
(1H, s, NH), 4.01e4.05 (1H, m, CH), 3.72e3.90 (2H, m, CH2),
3.33e3.53 (2H, m, CH2NH), 2.46 (3H, s, CH3), 1.53e1.95 (4H, m,
170e172 ꢁC. 1H NMR (DMSO-d6)
d
8.81 (2H, t, 3J¼5.4 Hz, 2NH),
7.18e7.37 (4H, m, Harom), 4.31 (4H, d, 3J¼5.7 Hz, 2CH2Ph), 3.73
2CH2), 1.46 (6H, s, 2CH3). 13C NMR (CDCl3)
d
179.0, 170.2, 160.2,
(4H, s, 2CH2CN). 13C NMR (DMSO-d6)
d 162.1, 138.7, 128.4, 126.3,
116.3, 85.7, 75.6, 67.3, 41.6, 27.8, 24.9, 23.1, 11.9. EIMS m/z (% rel-
ative abundance): 254 (MþH, 65), 236 (19), 182 (20), 171 (70), 170
(100), 153 (46), 152 (12). HRMS (ES-QTOF) Calcd for C13H20NO4
MþH 254.1392. Found 254.1391. IR nmax (neat/cmꢀ1): 3342, 2979,
2872, 1735, 1666, 1648.
126.0, 116.2, 42.5, 25.2. EIMS m/z (% relative abundance): 271
(MþH, 87), 205 (13), 187 (100). HRMS (ES-QTOF) Calcd for
C14H15N4O2 MþH 271.1195. Found 271.1198. IR nmax (neat/cmꢀ1):
3288, 3080, 2800, 2258, 1647, 1549.
4.5.5. 3-(4-(3-oxopropanenitrile)piperazin-1-yl)-3-oxopropaneni-
trile 5e. The general procedure 4, is used with ethyl cyanoacetate
(1.13 g, 10 mmol) and piperazine (0.43 g, 5 mmol). The mixture was
refluxed during 12 h to obtain 5e (0.43g, 39%) as white solid, mp
4.4.4. 5-Ethyl-4,5-dimethyl-3-(piperidine-1-carbonyl)furan-2(5H)-
one 4d. The general procedure 3, using (5-ethyl-2-imino-4,5-di-
methyl-2,5-dihydrofuran-3-yl)(piperidin-1-yl)methanone 3d (0.50 g,
2 mmol), yielded 4d (0.46 g, 97%) as yellow solid, mp 60e61 ꢁC. 1H
240e241 ꢁC. 1H NMR (DMSO-d6)
4CH2). 13C NMR (DMSO-d6)
relative abundance): 221 (MþH, 100), 180 (14), 154 (28). HRMS (ES-
d
4.09 (4H, s, 2CH2CN), 3.43 (8H, s,
NMR (CDCl3)
d
3.59 (4H, t, 3J¼5.3 Hz, 2CH2), 2.22 (3H, s, CH3),1.78 (6H,
d 161.8, 116.0, 45.0, 24.8. EIMS m/z (%
s, 2CH3),1.56e1.60 (6H, m, 3CH2).13C NMR (CDCl3)
d 170.3,168.8,161.0,

1548
N. Cheikh et al. / Tetrahedron 67 (2011) 1540e1551
QTOF) Calcd for C10H13N4O2 MþH 221.1039. Found 221.1038. IR nmax
(6H, s, 2CH3), 1.46 (12H, s, 4CH3). 13C NMR (CDCl3)
d 171.8, 166.1,
(neat/cmꢀ1): 2975, 2900, 2260, 1646, 1465.
161.2, 139.1, 128.6, 126.4, 126.0, 118.0, 88.3, 41.6, 24.3, 12.1. EIMS m/z
(% relative abundance): 439 (MþH, 47), 422 (13), 288 (100), 271
(15). HRMS (ES-QTOF) Calcd for C24H31N4O4 MþH 439.2345. Found
439.2362. IR nmax (neat/cmꢀ1): 3259, 1674, 1643, 1552.
4.6. General procedure 5: synthesis of bis-iminolactones 6aee
A mixture of 3-hydroxy-3-methylbutan-2-one 1 (20 mmol) and
the substituted bis-cyanoacetamides (10 mmol) with a solution of
sodium ethoxide (1 mmol) in ethanol (10 mL) was stirred. After
evaporation of the solvent, the residue was acidified with 6 M
aqueous HCl. The mixture was neutralised with potassium car-
bonate, then extracted with CH2Cl2 (3ꢂ30 mL). The combined or-
ganic layers were dried on MgSO4, filtered and concentrated in
vacuum. The obtained solid was recrystallised in ethanol to provide
bis-iminolactones 6aee.
4.6.5. 3,4-Bis-(5-ethyl-2-imino-4,5-dimethyl-2,5dihydrofuran-3-yl)
(piperazin-1-yl)methanone 6e. The general procedure 5, is used
with 3-hydroxy-3-methylpentan-2-one (2.04 g, 20 mmol) and 3-
(4-(3-oxopropanenitrile)piperazin-1-yl)-3-oxopropanenitrile 5e
(2.20 g, 10 mmol) in the presence of sodium ethoxide (0.02 g,
1 mmol). The mixture was refluxed during 6 h to give compound
6e (2.17 g, 58%) as yellow solid, mp 188e189 ꢁC. 1H NMR (CDCl3)
d
5.28 (2H, s, 2C]NH), 3.20 (8H, s, 4CH2), 2.19 (6H, s, 2CH3), 1.28
(12H, s, 4CH3). 13C NMR (CDCl3)
d
170.6, 166.7, 161.2, 117.8, 82.0,
4.6.1. N,N0-Propan-10,30-bis-(2,5-dihydro-2-imino-4,5,5-trime-
thylfuran-3-carboxamide) 6a. The general procedure 5, using
3-hydroxy-3-methylbutan-2-one 1 (2.04 g, 20 mmol) and bis-(2-
cyanoacetamide)-N,N0-propylidene 5a (2.08 g, 10 mmol) in the
presence of sodium ethoxide (0.02 g, 1 mmol), gave in 12 h at room
temperature, 6a (3.61 g, 96%) as yellow solid, mp 128e129 ꢁC. 1H
44.5, 23.6, 13.8. EIMS m/z (% relative abundance): 389 (MþH,
100). HRMS (ES-QTOF) Calcd for C20H29N4O4 MþH 389.2184.
Found 389.2165. IR nmax (neat/cmꢀ1): 3318, 2987, 2901, 1678,
1643.
NMR (CDCl3)
d
9.61 (2H, s, 2CONH), 6.91 (2H, s, 2C]NH), 3.41 (4H,
4.7. General procedure 6: hydrolysis of bis-iminolactones
6aed to bis-butenolides 7aed
q, 3J¼6.8 Hz, CH2CH2CH2), 2.38 (6H, s, 2CH3), 1.85 (2H, m, 3J¼6.9 Hz,
CH2CH2CH2), 1.39 (12H, s, 4CH3). 13C NMR (CDCl3)
d 171.7, 167.7,
162.2, 118.9, 88.5, 36.5, 29.3, 24.6, 12.5. EIMS m/z (% relative abun-
dance): 377 (MþH, 40), 360 (08), 252 (14), 226 (69), 209 (24), 208
(100). HRMS (ES-QTOF) Calcd for C19H29N4O4 MþH 377.2189. Found
377.2196. IR nmax (neat/cmꢀ1): 3307, 3190, 1677, 1643, 1552.
To a solution of HCl (3 M, 2 mL) was added bis-iminolactone
6aed (1 mmol) in ethanol (5 mL). After being refluxed for 5 h, the
mixture was evaporated and the residue obtained was extracted
with CH2Cl2 (3ꢂ20 mL). The combined organic layers were dried on
MgSO4, filtered and concentrated in vacuum to give after recrys-
tallisation in ethanol, bis-butenolides 7aed.
4.6.2. N,N0-Hexan-10,60-bis-(2,5-dihydro-2-imino-4,5,5-trime-
thylfuran-3-carboxamide) 6b. The general procedure 5, using
3-hydroxy-3-methylbutan-2-one 1 (2.04 g, 20 mmol) and bis-(2-
cyanoacetamide) N,N0-hexylidene 5b (2.50 g, 10 mmol) in the
presence of sodium ethoxide (0.02 g, 1 mmol), gave in 12 h at room
temperature, 6b (3.88 g, 93%) as white solid, mp 119e120 ꢁC. 1H
4.7.1. N,N0-Propan-10,30-bis-(2,5-dihydro-4,5,5-trimethyl-2-ox-
ofuran-3-carboxamide) 7a. The general procedure 6, using N,
N0-propan-10,30-bis-(2,5-dihydro-2-imino-4,5,5-trimethylfuran-3-
carboxamide) 6a (0.37 g, 1 mmol), yielded 7a (0.35 g, 94%) as white
NMR (CDCl3)
d
9.66 (2H, s, 2CONH), 8.03 (2H, s, 2C]NH), 3.21 (4H,
solid, mp 145e146 ꢁC. 1H NMR (CDCl3)
d 8.31 (2H, s, 2NH), 3.42 (4H,
q, 3J¼6.5 Hz, 2CH2), 2.36 (6H, s, 2CH3), 1.47e1.52 (4H, m, 2CH2), 1.41
q, 3J¼6.5 Hz, 2CH2), 2.48 (6H, s, 2CH3), 1.85 (2H, m, 3J¼6,6 Hz, CH2),
(12H, s, 4CH3), 1.21e1.26 (4H, m, 2CH2). 13C NMR (CDCl3)
d
171.4,
1.48 (12H, s, 4CH3). 13C NMR (CDCl3)
d 180.1, 171.3, 161.2, 117.2, 86.7,
166.1, 161.0, 118.0, 88.0, 37.8, 28.8, 26.1, 24.1, 12.0. EIMS m/z (% rel-
ative abundance): 419 (MþH, 35), 402 (16), 268 (100). HRMS (ES-
QTOF) Calcd for C22H35N4O4 MþH 419.2658. Found 419.2673. IR
nmax (neat/cmꢀ1): 3256, 1674, 1641, 1554.
36.7, 29.4, 24.2, 12.9. EIMS m/z (% relative abundance): 379 (MþH,
90), 361 (25), 210 (100). HRMS (ES-QTOF) Calcd for C19H27N2O4
MþH 379.1855. Found 379.1869. IR nmax (neat/cmꢀ1): 3340, 2982,
2875, 1729, 1662, 1647, 1531.
4.6.3. N,N0-Bis-(propyloxy)butan-bis-(2,5-dihydro-2-imino-4,5,5-tri-
methylfuran-3-carboxamide) 6c. The general procedure 5, using
3-hydroxy-3-methylbutan-2-one 1 (2.04 g, 20 mmol) and 1,4-bis-
4.7.2. N,N0-Hexan-10,60-bis-(2,5-dihydro-4,5,5-trimethyl-2-oxofuran-
3-carboxamide) 7b. The general procedure 6, using N,-N0hexan-
10,60-bis(2,5-dihydro-2-imino-4,5,5-trimethylfuran-3-carbox-
amide) 6b (0.42 g, 1 mmol), yielded 7b (0.41 g, 98%) as white solid,
(2-cyanoacetamido)-N-bis-(propyloxy)butane
5c
(3.38
g,
10 mmol) in the presence of sodium ethoxide (0.02 g, 1 mmol),
mp 130e131 ꢁC. 1H NMR (DMSO-d6)
d
8.17 (2H, t, 3J¼5.5 Hz,
gave in 2 h at room temperature, 6c (4.05 g, 80%) as viscous liquid.
2CONH), 3.24 (4H, q, 3J¼6.5 Hz, 2CH2NH), 2.38 (6H, s, 2CH3),
1.49e1.54 (4H, m, 2CH2), 1.46 (12H, s, 4CH3), 1.20e1.32 (4H, m,
1H NMR (CDCl3)
d 9,66 (2H, s, 2NH), 8.03 (2H, s, 2C]NH), 2.35 (6H,
s, 2CH3), 1.70 (6H, m, 3J¼6.2 Hz, 3CH2), 1.55 (8H, m, 4CH2), 1.40
2CH2). 13C NMR (DMSO-d6)
d 178.7, 170.2, 160.2, 117.6, 86.5, 38.0,
(12H, s, 4CH3), 1.18e1.20 (6H, m, 3CH2). 13C NMR (CDCl3)
d
171.4,
28.8, 26.0, 23.7, 12.4. EIMS m/z (% relative abundance): 421 (MþH,
100), 403 (14), 252 (94), 182 (14). HRMS (ES-QTOF) Calcd for
C22H33N2O6 MþH 421.2339. Found 421.2318. IR nmax (neat/cmꢀ1):
3343, 2982, 2859, 1730, 1664, 1647, 1536.
166.0, 161.1, 118.1, 88.0, 69.8, 67.5, 35.2, 29.1, 25.9, 24.3, 12.0. EIMS
m/z (% relative abundance): 507 (MþH, 80), 490 (15), 356 (100),
339 (29), 209 (60). HRMS (ES-QTOF) Calcd for C26H43N4O6 MþH
507.3183. Found 507.3182. IR nmax (neat/cmꢀ1): 3260, 3070, 2863,
1675, 1642, 1561.
4.7.3. N,N0-Bis-(propyloxy)butan-bis-(2,5-dihydro-4,5,5-trimethyl-2-
oxofuran-3-carboxamide) 7c. The general procedure 6, using of
N,N0-bis-(propyloxy)butan-bis-(2,5-dihydro-2-imino-4,5,5-trime-
thylfuran-3-carboxamide) 6c (0.51 g, 1 mmol), yielded 7c (0.45 g,
4.6.4. N,N0-Metaxylyl-bis-(2,5-dihydro-2-imino-4,5,5-trime-
thylfuran-3-carboxamide) 6d. The general procedure 5, using
3-hydroxy-3-methylbutan-2-one 1 (2.04 g, 20 mmol) and 1,3-bis-
((2-cyanoacetamido)-N-methyl)benzene 5d (2.70 g, 10 mmol) in
the presence of sodium ethoxide (0.02 g, 1 mmol), gave in 2 h at
room temperature, 6d (3.06 g, 70%) as white solid, mp 125e126 ꢁC.
88%) as viscous liquid. 1H NMR (CDCl3)
d
8.24 (2H, t, 3J¼5.4 Hz,
2NH), 2.39 (6H, s, 2CH3), 1.70e1.78 (6H, m, 3CH2), 1.52e1.58 (8H, m,
4CH2), 1.47 (12H, s, 4CH3), 0.88e1.21 (6H, m, 3CH2). 13C NMR
(CDCl3)
d 178.9, 170.2, 160.3, 117.5, 86.5, 69.9, 67.8, 35.9, 29.0, 25.9,
1H NMR (CDCl3)
d
10.07 (2H, t, 3J¼5.4 Hz, 2CONH), 8.12 (2H, s, 2C]
23.7, 12.4. EIMS m/z (% relative abundance): 509 (MþH, 98), 210
NH), 7.28e7.41 (4H, m, Harom), 4.50 (4H, d, 3J¼5.8 Hz, 2CH2), 2.42
(100). HRMS (ES-QTOF) Calcd for C26H41N2O8 MþH 509.2863.

N. Cheikh et al. / Tetrahedron 67 (2011) 1540e1551
1549
Found 509.2875. IR nmax (neat/cmꢀ1): 3340, 3070, 2863, 1733, 1664,
1650, 1537.
(3ꢂ30 mL). The combined organic layers were washed with water,
dried on MgSO4, filtered and concentrated. The obtained residue
was distilled to provide 3-acetyl-4,5,5-trimethyl-5H-furan-2-one
8d (1.01 g, 30% yield) as colourless liquid, bp: 94 ꢁC/5 mtorr. 1H NMR
4.7.4. N,N0-Metaxylyl-bis-(2,5-dihydro-4,5,5-trimethyl-2-oxofuran-
3-carboxamide) 7d. The general procedure 6, using N,N0-metaxylyl-
bis-(2,5-dihydro-2-imino-4,5,5-trimethylfuran-3-carboxamide) 6d
(0.44 g, 1 mmol), yielded 7d (0.39 g, 90%) as white solid, mp
(CDCl3)
d
2.56 (3H, s, COCH3), 2.35 (3H, s, C]CeCH3), 1.50 (6H, s, 2
195.2, 180.1, 169.2, 123.5, 85.5, 27.9, 24.0,
CH3). 13C NMR (CDCl3)
d
12.5. HRMS (ES-QTOF) Calcd for C9H13O3 MþH 169.0865. Found
140e141 ꢁC. 1H NMR (CDCl3)
d
8.66 (2H, t, 3J¼2.5 Hz, 2NH),
169.0864. IR nmax (neat/cmꢀ1): 1755, 1688, 1627.
7.24e7.33 (4H, m, Harom), 4.50 (4H, d, 3J¼6.0 Hz, 2CH2), 2.42 (6H, s,
2CH3), 1.50 (12H, s, 4CH3). 13C NMR (CDCl3)
d 179.2, 170.1, 160.4,
4.9. General procedure 8: synthesis of the bis-lactones from
139.0, 128.4, 126.2, 126.0, 117.5, 86.6, 41.7, 23.7, 12.5. EIMS m/z (%
relative abundance): 441 (MþH, 82), 272 (100). HRMS (ES-QTOF)
Calcd for C24H29N2O6 MþH 441.2026. Found 441.2021. IR nmax (neat/
cmꢀ1): 3339, 2978, 2868, 1731, 1666, 1650, 1531.
the bis-aldehydes 9aeg
A mixture of ethyl 4,5,5-trialkyl-2-oxo-2,5-dihydrofuran-3-car-
boxylate (4 mmol), dialdehyde (2 mmol) and triethylamine
(4 mmol) was heated to 80 ꢁC for 5 h. The solid obtained was
washed several times with diethylether and some drops of meth-
anol to provide yellow solid 9aeg.
4.8. General procedure 7: synthesis of ethyl 4-methyl-5,5-
dialkyl-2-oxo-2,5-dihydrofuran-3-carboxylate 8aec
A mixture of a-hydroxyketone (20 mmol) and ethyl malonate
4.9.1. Ethyl 4-(4-(2-(4-(ethoxycarbonyl)-2,5-dihydro-2,2-dimethyl-5-
oxofuran-3yl)vinyl)styryl)-2,5-dihydro-5,5-dimethyl-2-oxofuran-3-
carboxylate 9a. The general procedure 8, using ethyl 4,5,5-trimethyl-
(4 mmol) was adsorbed on KF-alumina (3 g) and then stirred at
room temperature without solvent for 3 h. The mixture was
extracted with diethylether (3ꢂ20 mL). The combined organic
layers were subsequently washed with water, dried on MgSO4,
filtered and concentrated in vacuum.
2-oxo-2,5-dihydrofuran-3-carboxylate 8a (0.79 g,
4
mmol),
teraphtalaldehyde (0.27 g, 2 mmol) and triethylamine (0.40 g,
4 mmol), gave 9a (0.47 g, 48%) as yellow solid, mp decomposed
around 267 ꢁC. 1H NMR (CDCl3)
d
7.95 (2H, d, 3J¼17.0 Hz, 2CH]
CHePh), 7.63 (4H, s, Harom), 7.20 (2H, d, 3J¼17.0 Hz, 2CH]CHePh),
4.42 (4H, q, 3J¼7.1 Hz, 2CH2CH3), 1.74 (12H, s, 4CH3), 1.42 (6H, t,
4.8.1. Ethyl 2,5-dihydro-4,5,5-trimethyl-2-oxofuran-3-carboxylate 8a.
The general procedure 7, using 3-hydroxy-3-methylbutan-2-one
(2.04 g, 20 mmol), ethyl malonate (3.20 g, 20 mmol) and 3 g of Al2O3/
KF, yielded 8a (3.25 g, 82%) as colourless needles, mp<50 ꢁC. 1H NMR
3J¼7.1 Hz, 2CH2CH3). 13C NMR (CDCl3)
d 171.6, 166.9, 162.3, 141.0,
137.2, 128.7, 128.5, 119.2, 84.1, 61.6, 27.0, 14.2. EIMS m/z (% relative
abundance): 495 (MþH, 94), 467 (100), 449 (47). HRMS (ES-QTOF)
Calcd for C28H31O8 MþH 495.2019. Found 495.2000. IR nmax (neat/
cmꢀ1): 1747, 1702, 1610, 1574.
(CDCl3)
d
4.34 (2H, q, 3J¼7.1 Hz, CH2), 2.35 (3H, s, C]CeCH3),1.50 (6H,
s, 2CH3), 1.37 (3H, t, 3J¼7.1 Hz, CO2CH2CH3). 13C NMR (CDCl3)
d 180.4,
167.4, 161.8, 118.4, 85.4, 61.4, 24.4, 14.2, 13.2. EIMS m/z Mþ 198 (12),
183(8), 155 (100). HRMS (ES-QTOF) Calcd for C10H15O4 MþH
199.0970. Found 199.0972. IR nmax (neat/cmꢀ1): 1774, 1718, 1654.
4.9.2. Ethyl 4-(4-(2-(4-(ethoxycarbonyl)-2-ethyl-2,5-dihydro-2-met
hyl-5-oxofuran-3-yl)vinyl)styryl)-5-ethyl-2,5-dihydro-5-methyl-2-
oxofuran-3-carboxylate 9b. The general procedure 8, using ethyl 5-
ethyl-4,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate 8b (0.85
g, 4 mmol), teraphtalaldehyde (0.27 g, 2 mmol) and triethylamine
(0.40 g, 4 mmol), gave 9b (0.42 g, 40%) as yellow solid, mp
4.8.2. Ethyl 5-ethyl-2,5-dihydro-4,5-dimethyl-2-oxofuran-3-carbox-
ylate 8b. The general procedure 7, using 3-hydroxy-3-methyl-
pentan-2-one (2.32 g, 20 mmol), ethyl malonate (3.20 g, 20 mmol)
and 3 g of Al2O3/KF, yielded 8b (3.18 g, 75%) as colourless liquid, bp
128 ꢁC/5 mtorr.1H NMR (CDCl3)
d
4.36 (2H, q, 3J¼7.1 Hz, CO2CH2CH3),
220e222 ꢁC. 1H NMR (CDCl3)
d
7.98 (2H, d, 3J¼16,9 Hz, 2CH]
2.31 (3H, s, C]CeCH3), 1.96 (1H, dq, 2J¼14.8 Hz, 3J¼7.4 Hz, C(Me)
CHaHbCH3),1.75 (1H, dq, 2JHH¼14.8 Hz, 3J¼7.4Hz, C(Me)CHaHbCH3),
1.48 (3H, s, CeCH3), 1.38 (3H, t, 3J¼7.1 Hz, CO2CH2CH3), 0.81 (3H, t,
CHePh), 7.63 (4H, s, Harom), 7.19 (2H, d, 3J¼16.9 Hz, 2CH]CHePh),
4.42 (4H, q, 3J¼7.1 Hz, 2OCH2CH3), 1.96e2.17 (4H, m, 2CH2CH3), 1.71
(6H, s, 2CCH3), 1.43 (6H, t, 3J¼7.1 Hz, 2OCH2CH3), 0.85 (6H, t,
3J¼7.4 Hz, CCH2CH3).13C NMR (CDCl3)
d 179.3,167.5,161.4,119.1, 87.7,
3J¼7.3 Hz, 2CH2CH3). 13C NMR (CDCl3)
d 170.5, 167.3, 162.1, 140.5,
61.1, 23.0, 22.9,14.00,13.6, 7.1. EIMS m/z Mþ 212 (4),183(33),169 (55),
137 (100). HRMS (ES-QTOF) Calcd for C11H17O4 MþH 213.1127. Found
213.1126. IR nmax (neat/cmꢀ1): 1772, 1716, 1652.
137.2, 128.7, 119.3, 118.6, 86.9, 61.6, 32.6, 25.9, 14.2, 7.6. EIMS m/z (%
relative abundance): 523 (MþH, 55), 495 (100), 477 (77), 449 (14),
431 (18). HRMS (ES-QTOF) Calcd for C30H35O8 MþH 523.2332.
Found 523.2308. IR nmax (neat/cmꢀ1): 1746, 1702, 1607, 1574.
4.8.3. Ethyl 4-methyl-2,5-dihydro-5,5-pentamethylene-2-oxofuran-
3-carboxylate 8c. The general procedure 7, using 1-(1-hydroxy-
cyclohexyl)ethanone (2.84 g, 20 mmol), ethyl malonate (3.20 g,
20 mmol) and 3 g of Al2O3/KF, yielded 8c (4.09 g, 86%) as white
4.9.3. Ethyl 4-(4-(2-(4-(ethoxycarbonyl)-2,5-dihydro-2,2-pentameth
ylene-5-oxofuran-3yl)vinyl)styryl)-2,5-dihydro-5,5-pentamethylene-
2-oxofuran-3-carboxylate 9c. The general procedure 8, using ethyl
4-methyl-2-oxo-1-oxa-spiro[4,5]dec-3-ene-3-carboxylate 8c (0.95
g, 4 mmol), teraphtalaldehyde (0.27 g, 2 mmol) and triethylamine
(0.40 g, 4 mmol), gave 9c (0.40 g, 35%) as yellow solid, mp
solid, mp 67e68 ꢁC. 1H NMR (CDCl3)
d
4.35 (2H, q, 3J¼7.2 Hz,
OCH2CH3), 2.32 (3H, s, C]CeCH3), 1.65e1.85 (8H, m, 4 CH2),
1.50e1.54 (2H, m, CH2), 1.37 (3H, t, 3J¼7.2 Hz, OCH2CH3). 13C NMR
209e210 ꢁC. 1H NMR (CDCl3)
d
7.82 (2H, d, 3J¼16.9 Hz, 2CH]
(CDCl3)
d 180.3, 167.6, 161.8, 118.4, 87.1, 61.9, 32.9, 24.4, 21.5, 14.1,
13.4. EIMS m/z Mþ 238 (40), 193(36), 192 (39), 181 (49), 137 (100).
HRMS (ES-QTOF) Calcd for C13H19O4 MþH 239.1283. Found
239.1280. IR nmax (neat/cmꢀ1): 1756, 1708, 1636.
CHePh), 7.68 (4H, s, Harom), 7.34 (2H, d, 3J¼16.9 Hz, 2CH]CHePh),
4.41 (4H, q, 3J¼7.1 Hz, 2CH2CH3), 1.74e2.09 (20H, m, 10CH2), 1.41
(6H, t, 3J¼7.1 Hz, 2CH2CH3). 13C NMR (CDCl3)
d 171.2, 167.3, 162.5,
140.9,137.2,128.6,128.5,119.2, 86.3, 61.6, 35.6, 24.6, 22.0,14.2. EIMS
m/z (% relative abundance): 575 (MþH, 64), 547 (100), 529 (84).
HRMS (ES-QTOF) Calcd for C34H39O8 MþH 575.2645. Found
575.2632. IR nmax (neat/cmꢀ1): 1745, 1709, 1612, 1574.
4.8.4. Synthesis of 3-acetyl-4,5,5-trimethyl-5H-furan-2-one 8d.
3-Hydroxy-3-methylbutan-2-one (2.04 g, 20 mmol) and tert-butyl
acetylacetonate (3.16 g, 20 mmol) was added to a mixture of so-
dium ethoxide (2 mmol) in ethanol (2 mL). The whole was refluxed
for 4 h. The solvent was removed by evaporation and aqueous HCl
(18%) was added. The mixture was extracted with diethylether
4.9.4. 4-(4-(2-(4-Acetyl-2,5-dihydro-5,5-dimethyl-2-oxofuran-3yl)
vinyl)styryl)-4-acetyl-5,5-dimethylfuran-2(5H)-one 9d. The general

1550
N. Cheikh et al. / Tetrahedron 67 (2011) 1540e1551
procedure 8, using 3-acetyl-4,5,5-trimethyl-5H-furan-2-one 8d
(0.67 g, 4 mmol), teraphtalaldehyde (0.27 g, 2 mmol) and trie-
thylamine (0.40 g, 4 mmol), gave 9d (0.58 g, 67%) as yellow solid,
Crystal size: 0.47ꢂ0.39ꢂ0.28 mm Formula C19H28N4O4, formula
weight 376.45, crystal system monoclinic, space group C 2/c,
¼90ꢁ,
ꢂ
ꢂ
ꢂ
a¼16.9302(4) A, b¼10.9054(4) A, c¼11.3432(3) A,
a
3
ꢂ
mp 213e214 ꢁC. 1H NMR (CDCl3)
d
8.08 (2H, d, 3J¼17.0 Hz, 2CH]
b
¼103.316(2)ꢁ,
g
¼90ꢁ, V¼2038.00(10) A , Z¼4, calculated
CHPh), 7.65 (4H, s, Harom), 7.26 (2H, d, 3J¼17.0 Hz, 2CH]CHPh),
density¼1.227 g/cm3,
m
¼0.087 mmꢀ1, Rint¼0.042, R[F2>2
s
(F2)]¼
2.66 (6H, s, 2COCH3), 1.76 (12H, s, 4CH3). 13C NMR (CDCl3)
d
196.0,
0.051, wR(F )¼0.151. Selected bond lengths (A), angles (deg) and
dihedral angles (deg): N8eC2 1.2626(13), C6-O7 1.2216(12),
C10eC5eC13 111.67(9) N8eC2-O1 124.23(9). Program(s) used to
solve structure: SHELXSe97. Program(s) used to refine structure:
SHELXLe97. Software used to prepare material for publication:
SHELXTLe97 (G. M. Sheldrick, Bruker ACS Inc.: Madison, WI, 2004).
Crystallographic data for compound 6a have been deposited at the
Cambridge Crystallographic Data Centre, CCDC No 769499. Copies
of this information may be obtained free of charge from The Di-
rector, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (þ44 1223
336408; E-mail:deposit@ccdc.cam.ac.ukor http://www.ccdc.ca-
m.ac.uk). Deposited Data-CCDC 769499.
2
ꢂ
171.3, 162.6, 142.3, 137.6, 128.9, 128.6, 119.8, 85.2, 30.9, 27.3. EIMS m/
z (% relative abundance): 435 (MþH, 100), 417 (84), 399 (16), 375
(37). HRMS (ES-QTOF) Calcd for C26H27O6 MþH 435.1808. Found
435.1803. IR nmax (neat/cmꢀ1): 1742, 1681, 1607, 1564.
4.9.5. Ethyl 4-(3-(2-(4-ethoxycarbonyl-2,5-dihydro-5,5-dimethyl-2-
oxofuran-3-yl)vinyl)styryl)-2,5-dihydro-2,2-dimethyl-5-oxofuran-3-
carboxylate 9e. The general procedure 8, using ethyl 4,5,5-tri-
methyl-2-oxo-2,5-dihydrofuran-3-carboxylate 8a (0.79 g, 4 mmol),
isophtalaldehyde (0.27 g, 2 mmol) and triethylamine (0.40 g,
4 mmol), gave 9e (0.80 g, 81%) as white solid, mp 130e132 ꢁC. 1H
NMR (CDCl3)
d
7.92 (2H, d, 3J¼17.0 Hz, 2CH]CHPh), 7.49e7.85 (4H,
m, Harom), 7.19 (2H, d, 3J¼17.0 Hz, 2CH]CHPh), 4.37 (4H, q,
3J¼7.1 Hz, 2CH2CH3), 1.69 (12H, s, 4CH3), 1.36 (6H, t, 3J¼7.1 Hz,
Acknowledgements
2CH2CH3). 13C NMR (CDCl3)
d 171.4, 166.9, 162.2, 140.7, 137.1, 133.0,
We gratefully acknowledge financial support from the ‘Minis-
131.6, 129.9, 128.9, 119.4, 84.2, 61.7, 27.0, 14.2. EIMS m/z (% relative
abundance): 495 (MþH, 84), 467 (100), 449 (57), 421 (15). HRMS
(ES-QTOF) Calcd for C28H31O8 MþH 495.2019. Found 495.2004. IR
nmax (neat/cmꢀ1): 1747, 1702, 1610, 1574.
ꢁ
ꢀ
tere de l’Enseignement Superieur et de la Recherche Scientifique
ꢀ
Algerien’ (MESRS) within the program PNE 2007.
ꢀ
Also the authors would like to thank Dr. Remy Legay and Mr.
ꢀ
Baptiste Rigaud for NMR spectra and Mrs. Karine Jarsale for ESIMS
and HRMS analysis.
4.9.6. Ethyl 4-(3-(2-(4-ethoxycarbonyl-2,5-dihydro-5-methyl-2-ox-
ofuran-3-yl)vinyl)styryl)-2-ethyl-2,5-dihydro-2-methyl-5-oxofuran-
3-carboxylate 9f. The general procedure 8, using ethyl 5-ethyl-4,
5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate 8b (0.85 g,
4 mmol), isophtalaldehyde (0.27 g, 2 mmol) and triethylamine
(0.40 g, 4 mmol), gave 9f (0.76 g, 73%) as white solid, mp
References and notes
1. (a) Rao, Y. S. Chem. Rev. 1964, 64, 353e388; (b) Rao, Y. S. Chem. Rev. 1976, 76,
625e694; (c) Kitajima, H.; Ito, K.; Katsumi, T. Tetrahedron 1997, 53,
17015e17028; (d) Avetisyan, A. A.; Dangyan, M. T. Russ. Chem. Rev. 1977, 46,
643e656; Usp. Khim. 1977, 1250e1278; (e) Knight, D. W. Contemp. Org. Synth.
1994, 1, 287e315; (f) Laduwahetty, T. Contemp. Org. Synth. 1995, 2, 133e149; (g)
Collins, I. Contemp. Org. Synth. 1996, 3, 295e321.
2. (a) Dreux, J. Bull. Soc. Chim. Fr. 1956, 1777e1779; (b) Avetisyan, A. A.;
Dzhandzhapanyan, A. N.; Karagez, S. K.; Dangyan, M. T. Arm. Khim. Zh. 1977, 30,
90e92; Chem. Abstr. 1977, 87, 68049z; (c) Liao, L. Ph.D. thesis, University of
110e112 ꢁC. 1H NMR (CDCl3)
d
7.95 (2H, d, 3J¼16.9 Hz, 2CH]CHPh),
7.45e7.70 (4H, m, Harom), 7.23 (2H, d, 3J¼16.9 Hz, 2CH]CHPh),
4.42 (4H, q, 3J¼7.1 Hz, 2OCH2CH3), 1.98e2.20 (4H, m, 2CH2CH3), 1.71
(6H, s, 2CCH3), 1.44 (6H, t, 3J¼7.1 Hz, 2OCH2CH3), 0.87 (6H, t,
3J¼7.2 Hz, 2CH2CH3). 13C NMR (CDCl3)
d 170.7, 167.3, 162.2, 140.8,
ꢀ
Caen, 1999; (d) Maheut, G.; Liao, L.; Catel, J. M.; Jaffres, P. A.; Villemin, D. J. Chem.
Educ. 2001, 78, 654e657.
136.1, 129.8, 129.5, 128.1, 119.0, 118.6, 86.9, 61.6, 32.6, 26.0, 14.2, 7.6.
EIMS m/z (% relative abundance): 523 (MþH, 72), 495 (100), 477
(54), 431 (17). HRMS (ES-QTOF) Calcd for C30H35O8 MþH 523.2332.
Found 523.2312. IR nmax (neat/cmꢀ1): 1748, 1705, 1608, 1574.
3. (a) Black, D. K. J. Chem. Soc. 1966, 23, 1123e1127; (b) Lattmann, E.; Dunn, S.;
Niamsanit, S.; Sattayasai, N. Bioorg. Med. Chem. Lett. 2005, 15, 919e921.
4. (a) Cochrane, C. G. Am. J. Med. 1991, 91, S23eS30; (b) Gutteridge, J. M. C. Free
Radical Res. Commun.1993,19,141e158; (c) Halliwell, B. Drugs 1991, 42, 569e605.
5. Song, Y. S.; Lee, Y.-J.; Kim, B. T.; Heo, J.-N. Tetrahedron Lett. 2006, 47, 7427e7430.
6. (a) Rupprecht, J. K.; Hui, Y.-H.; McLaughlin, J. L. J. Nat. Prod. 1990, 53, 237e278;
(b) Fang, X.-P.; Rieser, M. J.; Gu, Z.-M.; McLaughlin, J. L. Phytochem. Anal. 1993, 4,
27e48; Chem. Abstr. 1993, 119, 24542e; (c) Gu, Z.-M.; Zhao, G. X.; Oberlies, N. H.;
Zeng, L.; McLaughlin, J. L. In Recent Advances in Phytochemistry; Arnason, J. T.,
Mata, R., Romeo, J. R., Eds.; Plenum: New York, NY, 1995; 29, pp 249e310; (d)
Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; McLaughlin, J. L. J. Nat.
Prod. Rep. 1996, 13, 275e306.
7. de Silava, E. D.; Scheuer, P. J. Tetrahedron Lett. 1980, 21, 1611e1614.
8. Potts, B. C. M.; Faulkner, D. J.; de Carvalho, M. S.; Jacobs, R. S. J. Am. Chem. Soc.
1992, 114, 5093e5100.
9. (a) Braun, M.; Hohmann, A.; Rahematpura, J.; Buhne, C.; Grimme, S. Chem.dEur.
J. 2004, 10, 4584e4593; (b) Sorg, A.; Siegel, K.; Bruckner, R. Chem.dEur. J. 2005,
4.9.7. Ethyl 4-(3-(2-(4-(ethoxycarbonyl)-2,5-dihydro-2,2-pentam-
ethylene-5-oxofuran-3yl)vinyl)styryl)-2,5-dihydro-5,5-pentam-
ethylene-2-oxofuran-3-carboxylate 9g. The general procedure 8,
using ethyl 4-methyl-2-oxo-1-oxa-spiro[4,5]dec-3-ene-3-carbox-
ylate 8c (0.95 g, 4 mmol), isophtalaldehyde (0.27 g, 2 mmol) and
triethylamine (0.40 g, 4 mmol), gave 9g (0.80 g, 70%) as white solid,
mp 99e101 ꢁC. 1H NMR (CDCl3)
d
7.90 (2H, d, 3J¼16.9 Hz, 2CH]
CHPh), 7.50e7.86 (4H, m, Harom), 7.33 (2H, d, 3J¼16.9 Hz, 2CH]
CHPh), 4.36 (4H, q, 3J¼7.1 Hz, 2CH2CH3), 1.68e2.04 (20H, m, 10CH2),
€
€
1.35 (6H, t, 3J¼7.1 Hz, 2CH2CH3).13C NMR (CDCl3)
d 171.0,167.3,162.4,
11, 1610e1624; (c) Boukouvalas, J.; Pouliot, M. Synlett 2005, 343e345; (d)
Boukouvalas, J.; Wang, J.-X.; Marion, O.; Ndzi, B. J. Org. Chem. 2006, 71,
6670e6673; (e) Gogoi, S.; Argade, N. P. Tetrahedron 2006, 62, 2715e2720; (f)
140.8,137.1,132.9,130.0,129.8,128.9,119.4, 86.4, 61.7, 35.6, 24.6, 21.9,
14.2. EIMS m/z (% relative abundance): 575 (MþH, 76), 547 (100), 529
(86). HRMS (ES-QTOF) Calcd for C34H39O8 MþH 575.2644. Found
575.2634. IR nmax (neat/cmꢀ1): 1745, 1709, 1612, 1574.
Boukouvalas, J.;ˇ Robichaud, J.; Maltais, F. Synlett 2006, 2480e2482; (g) Bou-
ꢀ
kouvalas, J.; Cote, S.; Ndzi, B. Tetrahedronˇ Lett. 2007, 48, 105e107; (h) Bou-
ꢀ
ꢀ
kouvalas, J.; Beltran, P. P.; Lachance, N.; Cote, S.; Maltais, F.; Pouliot, M. Synlett
2007, 219e222; (i) Boukouvalas, J.; Wang, J.-X.; Marion, O. Tetrahedron Lett.
2007, 48, 7747e7750; (j) Gogoi, S.; Argade, N. P. Synthesis 2008, 1455e1459; (k)
Bourdreux, Y.; Bodio, E.; Willis, C.; Billaud, C.; Le Gall, T.; Mioskowski, C. Tet-
rahedron 2008, 64, 8930e8937; (l) Boukouvalas, J.; Loach, R. P. J. Org. Chem.
2008, 73, 8109e8112; (m) Miyazaki, H.; Ogiku, T.; Sai, H.; Moritani, Y.; Ohtani,
A.; Ohmizu, H. Chem. Pharm. Bull. 2009, 57, 979e985; (n) Teixeira, R. R.; Pin-
heiro, P.; Barbosa, L. C. A.; Carneiro, J. W. M.; Forlani, G. Pest Manage. Sci. 2010,
66, 196e202; (o) Boukouvalas, J.; McCann, L. C. Tetrahedron Lett. 2010, 51,
4636e4639.
Supplementary data
Data for crystal structure analysis were collected at 293 K with
a BrukereNonius Kappa CCD area detector diffractometer with
ꢂ
graphiteemonochromatized Mo K
a
radiation (
l
¼0.71073 A). The
10. For contributions from our laboratory: (a) Villemin, D.; Liao, L. J. Chem. Res.,
Synop. 2000, 179e181; (b) Villemin, D.; Mostefa-Kara, B.; Bar, N.; Choukchou-
Braham, N.; Cheikh, N.; Benmeddah, A.; Hazimeh, H.; Ziani-Cherif, C. Lett. Org.
Chem. 2006, 3, 558e559; (c) Villemin, D.; Cheikh, N.; Mostefa-Kara, B.; Bar, N.;
Choukchou-Braham, N.; Didi, M. A. Tetrahedron Lett. 2006, 47, 5519e5521.
structure was solved using direct methods and refined by full-
matrix least-squares analysis on F2. Single crystals of bis-imino-
lactone 6a suitable for X-ray crystallographic analysis were
obtained by slow evaporation of methanol. Crystallographic data:

N. Cheikh et al. / Tetrahedron 67 (2011) 1540e1551
1551
11. Oliaruso, M. A.; Wolf, J. F. In Synthesis of Lactones and Lactams; Wiley: New York,
NY, 1993.
20. Ammar, H.; Fakhfakh, M.; Le Bigot, Y.; El Gharbi, R. Synth. Commun. 2003, 33,
1821e1828.
12. Bernay, E. Ber. 1912, 45, 3682e3686.
21. 8a was formed by the reaction of diethyle malonate and 1. The replacement of
1 by 3-methoxy-3-methyl-2-butanone in the same conditions gave no bute-
nolide or Knoevenagel product (L. Liao, Ph.D. thesis, University of Caen 1999).
From this result we think the transesterification of 1 by malonate takes place
before the cyclisation by Knoevenagel reaction favoured by ThorpeeIngold
effect.
22. Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915, 107, 1080e1106.
23. (a) Ingold, C. K. J. Chem. Soc. 1921, 119, 305e328; (b) Jung, M. E.; Pizzi, G. Chem.
Rev. 2005, 105, 1735e1766.
13. Ukhov, S. V.; Kon’shin, M. E.; Odegova, T. F. Pharm. Chem. J. 2001, 35, 364e365.
14. Mhiri, C.; El Gharbi, R.; Le Bigot, Y. Synth. Commun. 1999, 29, 3385e3399.
15. Borisov, A. V.; Dzhavakhishvili, S. G.; Zhuravel, I. O.; Kovalenko, S. M.; Ni-
kitchenko, V. M. J. Comb. Chem. 2007, 9, 5e8.
16. Tang, Y.; Li, C. Tetrahedron Lett. 2006, 47, 3823e3825.
17. Villemin, D.; Liao, L. Synth. Commun. 2003, 33, 1575e1585.
18. Villemin, D.; Liao, L. Synth. Commun. 2001, 31, 1771e1780.
19. Hakimelahi, G. H.; Moosavi-Movahedi, A. A.; Sambaiah, T.; Zhu, J. L.; Ethiraj, K.
S.; Pasdar, M.; Hakimelahi, S. Eur. J. Med. Chem. 2002, 37, 207e217.
24. Fuson, R. C. Chem. Rev. 1935, 16, 1e27.