Two versatile routes towards Cerpegin and analogues: Applications of a one pot reaction to new analogues of Cerpegin

Article abstract of DOI:10.1016/j.tet.2012.03.057

Simple and efficient routes to the natural alkaloid Cerpegin and new analogues are described herein. In a first approach, we extend the scope of a one pot three steps reaction, which permits the synthesis of new analogues of Cerpegin, substituted in different ways. In a second line of approach, we present an unprecedented synthesis of Cerpegin and analogues where methylfuranones are condensed with dimethylformamide diethylacetal (DMFDEA) to yield enaminolactone esters, which react easily with various primary amines affording Cerpegin and new analogues. We applied this second approach to the synthesis of new bis-Cerpegins and N-amino-Cerpegins. Most of the syntheses are performed under environmental friendly conditions.

Full text of DOI:10.1016/j.tet.2012.03.057

Tetrahedron 68 (2012) 4906e4918
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Two versatile routes towards Cerpegin and analogues: applications of a one pot
reaction to new analogues of Cerpegin
,
a
,
,
Didier Villemin a , Nawel Cheikh b, Liang Liao a, Nathalie Bar a, Jean-Franc¸ ois Lohier a c, Jana Sopkova c,
*
Noureddine Choukchou-Braham b, Bachir Mostefa-Kara b
a
ꢀ
ꢀ
Laboratoire de Chimie Moleculaire et Thioorganique (LCMT), UMR CNRS 6507, INC3M, FR 3038, Labex EMC3, ENSICAEN & Universite de Caen, 14050 Caen, France
b
c
ꢁ
ꢀ
ꢀ
Laboratoire de Catalyse et Synthese en Chimie Organique, Dept de Chimie, Faculte des Sciences, Universite Abou Bekr Belkaid, BP 119, Tlemcen 13000, Algeria
Centre d’Etudes et de Recherche sur le Medicament de Normandie (CERMN), Universite de Caen, 5 rue Vaubenard, 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:
Simple and efficient routes to the natural alkaloid Cerpegin and new analogues are described herein. In
a first approach, we extend the scope of a one pot three steps reaction, which permits the synthesis of
new analogues of Cerpegin, substituted in different ways. In a second line of approach, we present an
unprecedented synthesis of Cerpegin and analogues where methylfuranones are condensed with di-
methylformamide diethylacetal (DMFDEA) to yield enaminolactone esters, which react easily with var-
ious primary amines affording Cerpegin and new analogues. We applied this second approach to the
synthesis of new bis-Cerpegins and N-amino-Cerpegins. Most of the syntheses are performed under
environmental friendly conditions.
Received 13 February 2012
Received in revised form 13 March 2012
Accepted 16 March 2012
Available online 28 March 2012
Keywords:
Cerpegin
Enamines
2-(5H)-Furanones
Bis-butenolides
Solvent-free conditions
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
easy availability of the reactants, use of hot benzene). In addition,
the two methodologies were not versatile enough to permit the
Cerpegin 1 is an alkaloid extracted from Ceropegia juncea in
1990,1 which is a plant used in traditional Indian phamacopeia and
known for its tranquillising, anti-inflammatory, analgesic and anti-
ulcer properties.2 The skeleton of Cerpegin (Fig. 1) is original and is
composed of two fused ring moieties: pyridinone and lactone. The
pyridinone ring system and the corresponding derivatives occur
abundantly in a wide variety of naturally occurring alkaloids and
are also found in synthetic biologically active molecules.3
synthesis of new Cerpegin analogues 2,6, which can be interesting
candidates in the pharmaceutical research.
H3C
R1
CH3
R2
O
O
N
N
H3C
R3
Several syntheses of Cerpegin have been reported in liter-
ature.4e12 Some of them were based on the synthesis of pyridinone
ring followed by the synthesis of lactone4e8 and others were based
on lactone modification.9e12 For instance, most of them were
multistep and permitted the synthesis of Cerpegin in poor overall
O
O
O
O
1
Fig. 1. Cerpegin 1 and analogues of Cerpegin.
yields (15e34%).4,6e10 Only three protocols allowed to attain good
In the course of our ongoing research on Cerpegin, we are in-
terested in performing simple, easy and versatile syntheses, which
permit the preparation of Cerpegin analogues with high purity and
good yields. We report herein two approaches: the first one is based
on our previous work,11 a two or three steps one pot synthesis using
1,3,5-triazine and possibly alkyl halides, affording several Cerpegin
derivatives.13 The second one,14 which constituted an un-
precedented route, permitted the building of the pyridinone ring of
the Cerpegin and analogues, via the reaction between an enami-
none and several primary amines.
5
overall yields: Queguiner (71%), Villemin (75%),11 and more re-
ꢀ
cently Avetysian (89%).12 However, the one-pot protocol described
5
ꢀ
by Queguiner, required sophisticated reaction conditions (low
temperature of ꢀ78 ꢁC and use of lithium reagent) and the one
reported by Avetysian exhibited several drawbacks (multistep, no
* Corresponding author. Fax: þ33 231452877; e-mail addresses: didier.villemin@
ensicaen.fr, villemin@ensicaen.fr (D. Villemin).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.057

D. Villemin et al. / Tetrahedron 68 (2012) 4906e4918
4907
2. Results and discussion
Next, this one pot approach has been extended to the synthesis
of Cerpegin 1 and analogues 6aek, alkylated on nitrogen, by using
alkyl halides as described in Scheme 3.
As previously, we performed the synthesis by a one-pot protocol:
compared to the first procedure, the alkyl halide was simply added
some times after the addition of 1,3,5-triazine and the reaction was
First approach: Initially, we were interested in the synthesis of
analogue of Cerpegin, non alkylated on nitrogen 2 (R3¼H). The
retrosynthetic pathway for synthesis of such derivatives of Cerpe-
gin is shown in Scheme 1.
R1
R1
R2
O
R2
H3C
R1
R2
O
H3C
CO2Et
CO2Et
O
+
HN
OH
EtO2C
O
O
O
5
4
3
2
Scheme 1. Retrosynthetic scheme of the preparation of NH-Cerpegin analogues 2 by the first methodology involving 1,3,5-triazine.
The first step is based on the formation of lactone ring from the
reaction of -hydroxyketone 3a,c with diethyl malonic acid ester 4
in the presence of a base resulting in the formation of 2(5H)-fur-
anone 5. This synthesis involved base-catalyzed trans-
allowed to proceed for an additional time at room temperature or
a
under reflux, depending on the nature of the alkyl halide (Scheme 4).
Initially, we have used methyl iodide 7a permitting the prepa-
ration of Cerpegin 1 and analogues 6a,b, which differ from Cerpegin
only by the substitution of R1 and R2 on the lactone ring (Table 2).
Interestingly, the overall yield of Cerpegin 1 was appreciably im-
proved compared to our previous work.11
Secondly, other alkyl halides 7beg as described in Scheme 4,
have been used, affording several Cerpegin analogues 6cel,
substituted in various ways. As previously, these analogues are
prepared in very good yields (71e98%). The wide range of the alkyl
halides used shows the great versatility and the efficiency of this
methodology in the preparation of new compounds with pyr-
idinone moiety (Table 3).
a
esterification, followed by a Knoevenagel reaction favoured by the
ThorpeeIngold effect.15 Precedently,11 we have shown that Cs2CO3
can be employed for the cascade synthesis of Cerpegin, but we have
chosen to replace it by EtONa/EtOH because it is less expensive and
it improved the reaction yields within shorter reaction times. The
butenolide 5 is an allylic analogue of the malonate and can be easily
deprotonated at methyl group. The carbanion formed is then con-
densed with 1,3,5-triazine16e18 (an aminoformyl equivalent) per-
mitting the formation of the pyridinone ring, affording compounds
2aec (Scheme 2). The results are reported in the Table 1.
R1
R1
R2
O
R2
H3C
H3C
R1
O
CO2Et
CO2Et
1,3,5-triazine
20°C, 3h
EtONa/EtOH
20°C, 30 min
O
+
HN
R2
OH
EtO2C
O
O
O
5
4
3a-c
2a-c
Scheme 2. One pot cascade synthesis of NH-Cerpegin analogues 2aec from hydroxyketones 3aec (3a R1¼R2¼Me; 3b R1, R2¼e(CH2)5e; 3c R1¼Et, R2¼Me), using 1,3,5-triazine.
Second approach: The second approach for the synthesis of
Cerpegin analogues is a multistep one (Scheme 5). The first step is
the same as in the first approach. The second step involved the use
Table 1
Synthesis of NH-Cerpegin analogues 2aec in one pot conditions
of enaminone intermediates 8 instead of 1,3,5-triazine and alkyl
halide. Indeed, enaminones are attractive intermediates that have
been employed in the preparation of various heterocycles.19,20 In
this context, Stanovnik and Svete reported two exhaustive reviews
on the synthesis of enaminone derivatives and their use as syn-
thetic intermediates in heterocyclic chemistry and natural products
synthesis.21 Valla et al. have used them for the synthesis of ‘ter-
penoid-like chalcones.22
Since the discovery of N,N-dimethylformamide diethylacetal
(DMFDEA), synthesized for the first time by Meerwein,23 several
applications of formamide acetals appeared in literature, in par-
ticular as formylating agent for the preparation of enamines.24 In
our present work, DMFDEA is used in the preparation of enami-
nolactones 8aec. These compounds are readily obtained by the
condensation of the 2(5H)-furanone 5aec with DMFDEA. Surpris-
ingly, a simple mixing of the reactants at room temperature, in the
absence of solvent, led to a precipitate corresponding to 8aec after
only 1 h. Thus, new enaminone esters 8aec are prepared in good
yields under solvent-free conditions (Table 4).
Entry
Hydroxyketone
Product
Yield [%]
90
H3C
CH3
H3C
O
2a
2b
3a
3b
O
1.
H3C
H3C
HN
OH
O
O
O
H3C
H3C
2.
3.
90
93
O
OH
HN
HN
O
O
O
O
2c
3c
O
OH
O

4908
D. Villemin et al. / Tetrahedron 68 (2012) 4906e4918
R1
R1
R2
R1
R2
O
R2
H3C
O
O
N
HN
R3
EtO2C
O
O
O
O
O
5
1, 6a-k
2
Scheme 3. Retrosynthetic scheme of the preparation of Cerpegin 1 (R1¼R2¼R3¼Me) and N-alkyl analogues 6aek by the first methodology involving 1,3,5-triazine and alkyl halides.
R1
R1
R2
R2
1°) EtONa/EtOH
20°C, 30 min
3
H3C
R1
O
7a-g
R CH2X
CO2Et
CO2Et
O
O
R3
N
+
HN
2°) 1,3,5-triazine
20°C, 3h
4-20h
R2
OH
O
O
O
20°C or reflux
O
4
2
3a,c
1, 6a-k
Scheme 4. One pot cascade synthesis of Cerpegin 1 and N-alkyl analogues 6 from hydroxyketones 3aec (3a R1¼R2¼Me; 3b R1, R2¼e(CH2)5e; 3c R1¼Et, R2¼Me), using 1,3,5-triazine
and alkyl halide 7aeg.
Table 2
Synthesis of Cerpegin analogues in one pot conditions in the presence of methyl iodide 7a
Entry
Hydroxyketone
Alkyl halide
Product
Yield [%]
91
H3C
CH3
H3C
O
1
3a
3b
O
1.
H3C
H3C
H3CeI 7a
N
H3C
OH
O
O
H3C
H3C
O
6a
6b
2.
3.
H3CeI 7a
84
85
O
OH
N
H3C
H3C
O
O
O
3c
H3CeI 7a
O
N
OH
O
O
The structure of ethyl 4-(E)-2-(dimethylaminovinyl)-2,5-
dihydro-5,5-dimethyl-2-oxofuran-3-carboxylate 8a is confirmed
by X-ray crystallography. The ORTEP diagram is shown in Fig. 2. The
X-ray structure of the compound 8a showed that the molecule is
flat and that the double bond of the enamine exhibited a s-trans
conformation with ‘E’ stereochemistry. A weak electrostatic in-
teraction is observed between C7eH7 and O3, the observed dis-
tance between O3 and H7 in the structure is smaller than their sum
In fact, Cerpegin is easily prepared by a cyclisation reaction
between the ethyl 4-((E)-2-(dimethylamino)vinyl)-2,5-dihydro-
5,5-dialkyl-2-oxofuran-3-carboxylate 8a and methylamine as nu-
cleophilic agent under solvent-free conditions. Interestingly, simple
heating of the reactants with a heat-gun for a few minutes per-
mitted the preparation of Cerpegin in excellent yield (94%). These
reaction conditions are applied to several primary amines pro-
viding new analogues of Cerpegin in excellent yields as summa-
rized in Table 5. A wide variety of primary amines (aliphatic,
aromatic and heterocyclic as tryptamine 9e and histamine 9f) are
tested in the aim of investigating the versatility of this methodol-
ogy and for synthesizing new structures, which could exhibit pro-
nounced biological activities.
ꢂ
of van der Waals radii minus 0.4 A. The observed length of the
ꢂ
C2eC11 single bond [1.4083(10) A] is shorter than the theoretical
25
ꢂ
length for a CaromeC bond of 1.46 A, which indicates the for-
mation of a conjugated-electron system along this bond.
The enaminolactone esters are known to react as ‘pushepull’
dienes with either nucleophilic or electrophilic reagents, and
thus, they can be good candidates for cycloadditions.21,22 In our
case, these enaminolactones are used as electrophilic reagents for
the preparation of the Cerpegin and its analogues in the third
step.
Reaction mechanism: The mechanism proposed for this reaction
involved the addition of the amine on the double bond of the
enaminone 8 accompanied with the departure of dimethylamine
(CH3)2NH, followed by an intramolecular cyclization reaction be-
tween the nitrogen of the formed secondary amine A and the

Table 3
Synthesis of Cerpegin analogues in one pot conditions in the presence of alkyl halide 7aeg
Entry
Hydroxyketone
Alkyl halide
Product
Yield [%]
H3C
H3C
H3C
O
H3C
CH3
I
O
1.
84
7b
N
OH
6c
O
O
3a
H3C
CH3
Br
O
2.
87
7c
N
6d
O
O
H3C
CH3
O
3.
4.
94
86
N
Cl
6e
7d
O
O
N
H3C
H3C
CH3
O
Cl 7e
6f
Cl
Cl
Cl
Cl
O
O
O
CH3
O
5.
6.
98
91
N
6g
Cl
7f
O
H3C
O
Br
OH
7c
O
N
6h
O
O
3b
Cl
Cl
7.
71
84
84
91
O
Cl
7g
N
6i
O
O
8.
O
7d
Cl
6j
N
O
O
N
9.
O
Cl 7e
6k
6l
Cl
Cl
Cl
Cl
O
O
O
10.
O
N
Cl 7f
O

4910
D. Villemin et al. / Tetrahedron 68 (2012) 4906e4918
N
R1
R1
R2
R1
R2
O
R2
H3C
O
O
N
R3
EtO2C
EtO2C
O
O
O
O
1,6
8
5
Scheme 5. General retrosynthetic scheme of Cerpegin and analogues by the second approach.
Table 4
Preparation of enaminolactones 8aec with dimethylformamide diethylacetal (DMFDEA)
EtO
N
CO2Et
O
N
CO2Et
O
R1
R2
EtO
R1
R2
without solvent, rt
O
O
5a: R1 = R2 = Me
8a: R1 = R2 = Me
5b:R1 = R2 = -(CH2)5-
5c: R1 = Me, R2 = Et
8b:R1 = R2 = -(CH2)5-
8c: R1 = Me, R2 = Et
Entry
1.
Lactone
Enaminolactone
Yield [%]
N
CO2Et
CO2Et
73
5a
O
O
8a
8b
8c
O
O
N
N
CO2Et
CO2Et
2.
3.
70
62
5b
O
O
O
O
O
CO2Et
O
CO2Et
5c
O
O
carbonyl of the ester group to give B. Finally, the reaction ends up
with the elimination of ethanol forming Cerpegin 1 or analogues 6
(Scheme 6).
The structure of the Cerpegin 1 is already described in liter-
ature2a but we confirm our synthesis by the first example of X-ray
crystal structure of a synthetic Cerpegin. The ORTEP diagram is
shown in Fig. 3.
The structure is flat; the root mean square deviation (rms) of
ꢂ
a least-squares plane through these atoms is about 0.0169 A.
In view of these encouraging results, we have decided to de-
velop this procedure for the preparation of dimers of Cerpegin. For
instance, Porthogese has shown that bivalency is often an efficient
way for increasing potency of a substance,26 which could be con-
ferred by bridging two neighbouring recognition sites. In the aim of
obtaining new original polycyclic heterocycles, an equivalent of
Fig. 2. ORTEP diagram of the X-ray crystal structure of compound 8a with thermal
ellipsoids at 50% probability.

D. Villemin et al. / Tetrahedron 68 (2012) 4906e4918
4911
Table 5
Preparation of Cerpegin 1 and derivatives 6 from enaminolactones 8
R1
R2
O
R2
O
R1
N
RNH2
N
without solvent
R
EtO2C
O
O
O
8a : R1 = R2 = Me
1, 6d,e, j,m-p
8b : R1 = R2 = -(CH2)5-
8c : R1 = Me, R2 = Et
Entry
1.
Enaminolactone
RNH2
Product
Yield [%]
H3C
CH3
8a
8a
O
94
89
NH2
9a
1
N
H3C
O
O
H3C
CH3
O
2.
3.
6e
N
9b
9b
NH2
O
O
8b
8c
88
80
6j
O
NH2
NH2
N
O
O
9b
6m
4.
O
N
O
O
H3C
CH3
O
5.
6.
7.
8a
8a
8a
91
92
84
NH2
9c
6d
N
O
O
H3C
CH3
O
9d
NH2
6n
N
N
N
O
O
N
H3C
CH3
NH2
9e
O
6o
HN
N
O
O
HN
H3C
CH3
NH2
9f
O
8.
8a
87
6p
N
N
HN
O
O
HN

4912
D. Villemin et al. / Tetrahedron 68 (2012) 4906e4918
RNH2
H
R
N
H
N
H2N
R
R
R
N
HN
NHR
OEt
O
N
OEt
O
N
O
OEt
OEt
O
O
O
OEt
R1
R2
R1
R2
R1
R2
R1
R1
O
R1
- EtOH
R2
O
O
O
R2
1,6
R2
O
O
8
O
O
B
O
O
O
O
A
Scheme 6. Proposed mechanism for the Cerpegin and analogues from enaminolactones 8.
different diamines (10aec) is added to 2 equiv of enaminone 4-((E)-
2-(dimethylamino)vinyl)-2,5-dihydro-5,5-dimethyl-2-oxofuran-3-
carboxylate 8a (Table 6). Contrary to the previous synthesis, where
no solvent is used, refluxed DMF is employed in order to render the
reaction to completion, because a double addition is necessary
resulting in the formation of new original bis-Cerpegins not de-
scribed in the literature in moderate to good yields according to
reaction times (Table 6).
Furthermore, we are interested in synthesizing heterocyclic
compounds exhibiting seven-membered rings, such as dia-
zepinones 12. For this reason, the diamines are replaced with hy-
drazines: the hydrazine monohydrate and the methylhydrazine
(Scheme 7).
Surprisingly, the X-ray structure of the compound (Fig. 4)
obtained from the addition of hydrazine on the enaminolactone 8a
was not in accordance with our proposed compound 12. The X-ray
Fig. 3. ORTEP diagram of the X-ray crystal structure of Cerpegin 1 with thermal el-
lipsoids at 50% probability.
structure did not show
a
seven-membered cycle, instead,
Table 6
Preparation of bis-Cerpegins from diamines 10aec
N
O
X
O
O
O
O
O
H2N
NH2
OEt
X
N
N
10a-c
O
O
DMF, reflux
O
8a
11a : X = -(CH2)3-
11b : X = -(CH2)6-
11c : X = -CH2PhCH2-
Entry
1.
NH2eXeNH2
Product
Yield [%]
54
O
O
O
O
O
O
10a
N
N
N
N
H2N
NH2
11a
11b
O
O
O
O
NH2
10b
2.
3.
36
80
4
H2N
O
O
O
O
O
O
H2N
NH2
10c
N
N
11c
O
O

D. Villemin et al. / Tetrahedron 68 (2012) 4906e4918
4913
In a second part, we have presented a new unprecedented three
steps procedure, which involved the preparation of enamino-
lactones. This protocol has been applied to the synthesis of N-
substituted Cerpegins, bis-Cerpegins and N-amino-Cerpegins. Ex-
cept for the synthesis of bis-Cerpegins, all the reactions are per-
formed without solvent, often at room temperature, following the
precepts of green chemistry.
NH2NH2
without solvent,
HN
HN
O
O
O
12
N
O
4. Experimental section
4.1. General methods
EtO2C
O
8a
NH2NH2
without solvent,
All commercial reagents were purchased from Acros, Aldrich
and Sigma and were used as received without further purification.
Reaction times were monitored by TLC until no starting material
remained. TLC was performed using Silica gel 60 F254 precoated
aluminium sheets. 1H and 13C NMR spectra are recorded on
a Bruker AC 250 or Bruker AC 400 spectrometers. Chemical shifts
O
N
H2N
O
O
13a
Scheme 7. Reaction of enaminolactone 8a in the presence of hydrazine under solvent-
(d) are expressed in parts per million [ppm] and are referenced to
free condition.
the internal deuterated solvents with tetramethylsilane as the in-
ternal standard. Mass spectra were recorded on a QTOF Micro
(Waters) spectrometer with electrospray ionization (ESI, positive
mode), lockspray orthophosphoric acid, infusion introduction at
10 m
L/min, a source temperature of 80 ꢁC and desolvation temper-
ature of 120 ꢁC.
4.2. General procedure 1: one pot synthesis of the NH-
Cerpegin 2aec
In a round-bottomed flask equipped with a condenser, a mixture
of
a-hydroxyketone 3 (3 mmol), diethyl malonate (480 mg,
3 mmol) and a solution of sodium ethoxide (6 mmol) in ethanol
(3.9 mL) was stirred at 20 ꢁC for 30 min; then 1,3,5-triazine
(240 mg, 3 mmol) was added and stirred for 3 h. The mixture was
then concentrated in vacuum and neutralized with HCl solution
(18%). The mixture was extracted by chloroform (3ꢂ10 mL). The
combined organic layers were dried on MgSO4, filtered and evap-
orated and the residue was purified on a silica column (EtOH/
CH2Cl2: 5/95) to afford the corresponding NH-Cerpegin 2.
Fig. 4. X-ray of N-amino-1,1-dimethylfuro [3,4-c] pyridine-3,4(1H,5H)-dione 13a.
a compound 13a with a six-membered ring and a N-amino-
pyridinone moiety is formed. Interestingly, the same nitrogen of
the hydrazine attacked the enaminolactone in the first step and it is
then involved in the cyclization step.
4.2.1. 1,1-Dimethylfuro[3,4-c]pyridine-3,4(1H,5H)-dione (2a). The
general procedure 1 using 3-hydroxy-3-methylbutan-2-one 3a
(306 mg, 3 mmol) gave 2a (0.48 g, 90%) as a pale yellow solid, mp
248e249 ꢁC. 1H NMR (CDCl3)
d
8.00 (d, J¼6.5 Hz, 1H, NeCH]), 6.41
The conformation of compound 13a is close to the Cerpegin (see
Fig. 4), the compound 13a is also flat (the rms deviation of a least-
(d, J¼6.5 Hz, 1H, NeCH]CH), 1.63 (s, 6H, 2CH3). 13C NMR (CDCl3)
d
173.3, 167.2, 160.3, 143.5, 112.1, 99.8, 83.4, 25.9. IR nmax (neat/
ꢂ
squares plane through these atoms is about 0.0088 A). Further-
cmꢀ1): 3406, 1758, 1702, 1652, 1606, 1560, 1478. EIMS m/z (% rela-
tive abundance): 180 (Mþ1, 90), 162 (100), 134 (10). HRMS (ES-
QTOF) calcd for C9H10NO3 MþH 180.0661. Found 180.0665.
more, the change of the substituent on N1 affected neither the bond
lengths nor bond angles in the cycle. Each hydrogen of the amino
group is involved in a hydrogen bond, one with oxygen of the amide
function of a separate molecule and one with oxygen of the lactone
group of another molecule leading to infinite chain of Cerpegin
derivatives along b axis (see Fig. 5).
4.2.2. 1,1-Pentamethylenefuro[3,4-c]pyridine-3,4(1H,5H)-dione
(2b). The general procedure
ethanone 3b (426 mg, 3 mmol) gave 2b (0.59 g, 90%) as a yellow
solid, mp 267e269 ꢁC. 1H NMR (CDCl3)
7.96 (d, J¼5.0 Hz, 1H,
NeCH]), 6.13 (d, J¼5.0 Hz, 1H, NeCH]CH), 1.80e1.25 (m, 10H,
1 using 1-(1-hydroxycyclohexyl)
The results about the amino-Cerpegins 13aed are reported in
Table 7.
d
5CH2). 13C NMR (CDCl3)
d 172.4, 168.4, 163.5, 152.6, 106.8, 100.2,
3. Conclusion
85.1, 35.2, 24.6, 21.9. IR nmax (neat/cmꢀ1): 2934, 1734, 1680, 1606,
1564, 1516. EIMS m/z (% relative abundance): 220 (Mþ1, 85), 202
(100). HRMS (ES-QTOF) calcd for C12H15NO3 MþH 220.0974. Found
220.0966.
In this work, Cerpegin and many analogues are prepared via two
routes in good yields using easily accessible reagents under con-
venient and environmentally friendly conditions. Firstly, we have
extended the scope of a three steps one pot synthesis using 1,3,5-
triazine and alkyl halides in order to prepare new N-alkyl ana-
logues of Cerpegin. The same reaction without the use of alkyl
halide permitted to obtain NH-Cerpegin derivatives in excellent
yields.
4.2.3. 1-Ethyl-1-methylfuro[3,4-c]pyridine-3,4(1H,5H)-dione
(2c). The general procedure 1 using 3-hydroxy-3-methylpentan-
2-one 3c (348 mg, 3 mmol) gave 2c (0.54 g, 93%) as a yellow solid,
mp 215e216 ꢁC. 1H NMR (CDCl3)
6.37 (d, J¼6.4 Hz, 1H, NeCH]CH), 2.04 (dq, J¼7.3, 14.6 Hz,
d
8.02 (d, J¼6.4 Hz, 1H, NeCH]),

4914
D. Villemin et al. / Tetrahedron 68 (2012) 4906e4918
Fig. 5. Infinite chain of Cerpegin derivatives in crystal packing.
Table 7
Synthesis of amino-Cerpegins 13aed in solvent-free condition
N
RNHNH2
O
O
N
without solvent,
HN
R
EtO2C
O
O
O
8a-c
13a-d
Entry
1.
Enaminolactone
RNHNH2
N-Amino-Cerpegin
Yield [%]
80
H3C
CH3
O
8a
NH2NH2
13a
N
H2N
O
O
13b
13c
2.
3.
8b
8c
NH2NH2
71
81
O
N
N
H2N
H2N
O
O
O
NH2NH2
O
O
H3C
CH3
13d
O
4.
8a
CH3NHNH2
46
N
N
H
O
O

D. Villemin et al. / Tetrahedron 68 (2012) 4906e4918
4915
CHaHbCH3), 1.87 (dq, J¼7.3, 14.6 Hz, CHaHbCH3)1.60 (s, 3H, CH3),
6c (0.52 g, 84%) as an orange solid, mp 125e126 ꢁC. 1H NMR (CDCl3)
7.96 (d, J¼6.7 Hz, 1H, NeCH]), 6.43 (d, J¼6.7 Hz, 1H, NeCH]CH),
4.11 (q, J¼6.9 Hz, 2H, CH2CH3), 1.59 (s, 6H, 2CH3), 1.35 (t, J¼6.9 Hz,
0.84 (t, J¼7.3 Hz, CH2CH3). 13C NMR (CDCl3)
d
172.3, 167.5, 160.4,
d
143.3, 113.1, 99.9, 86.0, 31.6, 24.4, 7.6. IR nmax (neat/cmꢀ1): 3196,
2974, 2938, 2884, 1751, 1670, 1604, 1556, 1450, 1348, 1210, 1158.
EIMS m/z (% relative abundance): 194 (Mþ1, 60), 176 (100), 148
(30). HRMS (ES-QTOF) calcd for C10H12NO3 MþH 194.0817. Found
194.0820.
3H, CH3CH2). 13C NMR (CDCl3)
d 171.3,167.5,163.2,157.4,145.6, 99.0,
83.0, 44.6, 25.4, 14.4. IR nmax (neat/cmꢀ1): 1754, 1720, 1662, 1552,
1306,1090, 948. EIMS m/z (% relative abundance): 208 (8), 207 (Mþ,
76), 203 (49), 192 (50), 188 (63), 163 (100), 43 (56).
4.3. General procedure 2: one pot synthesis of the substituted
4.3.5. 5-Allyl-1,1-dimethylfuro[3,4-c]pyridine-3,4(1H,5H)-dione
N-alkylCerpegin 1, 6ael
(6d). The general procedure 2 using 3-hydroxy-3-methyl-2-
butanone 3a (306 mg, 3 mmol) and H2C]CHCH2Br (363 mg,
3 mmol) with a third step performed under reflux during 3 h gave
6d (0.57 g, 87%) as a yellow solid, mp 174e175 ꢁC. 1H NMR (CDCl3)
In a round-bottomed flask equipped with a condenser, a mixture
a-hydroxyketone 3 (3 mmol), diethyl malonate (480 mg,
of
3 mmol) and a solution of sodium ethoxide (6 mmol) in ethanol
(3.9 mL) was stirred at 20 ꢁC for 30 min; then 1,3,5-triazine
(240 mg, 3 mmol) was added and stirred for 3 h. After addition of
alkyl halide (3 mmol), the reaction was then allowed to proceed
under stirring under different conditions proper to every com-
pound. The mixture was then concentrated in vacuum and the
residue was extracted by dichloromethane (2ꢂ15 mL). The com-
bined organic layers were dried on MgSO4, filtered and evaporated
and the residue was crystallised from ethanolechloroform to afford
the corresponding N-alkylCerpegin 1,6.
d
7.65 (d, J¼6.7 Hz, 1H, NeCH]), 6.24 (d, J¼6.7 Hz, 1H, NeCH]CH),
6.03e5.87 (m, 1H, CH]CH2), 5.35e5.25 (2H, m, CH]CH2),
4.65e4.62 (2H, m, CH2eCH]CH2), 1.58 (6H, s, 2CH3). 13C NMR
(CDCl3) d 171.7,166.6,157.1,144.5,131.8,120.0,112.5, 98.4, 82.3, 50.9,
25.9. IR nmax (neat/cmꢀ1): 1768, 1660, 1594, 1556, 1428. EIMS m/z (%
relative abundance): 220 (MþH, 32), 202 (100), 174 (2). HRMS (ES-
QTOF) calcd for C12H14NO3 MþH 220.0974. Found 220.0969.
4.3.6. 5-Benzyl-1,1-dimethylfuro[3,4-c]pyridine-3,4(1H,5H)
(6e). The general procedure using 3-hydroxy-3-methyl-2-
dione
2
butanone 3a (306 mg, 3 mmol) and benzyl chloride ArCH2Cl
(380 mg, 3 mmol) with a third step performed under reflux during
3 h gave 6e (0.76 g, 94%) as a yellow solid, mp 202e203 ꢁC. 1H NMR
4.3.1. 1,1,5-Trimethylfuro[3,4-c]pyridine-3,4(1H,5H)-dione or Cerpe-
gin (1). The general procedure 2 using 3-hydroxy-3-methylbutan-
2-one 3a (306 mg, 3 mmol) and methyl iodide (3 mL, 48 mmol)
with a third step performed at room temperature during 20 h gave
1 (0.53 g, 91%) as a white solid, mp 267e270 ꢁC. 1H NMR (CDCl3)
(CDCl3)
d
7.63 (d, J¼6.8 Hz, 1H, NeCH]), 7.39e7.35 (m, 5H, Harom),
6.19 (d, J¼6.8 Hz, 1H, NeCH]CH), 5.20 (s, 2H, CH2), 1.57 (s, 6H,
2CH3). 13C NMR (CDCl3)
d 171.8, 167.0, 157.6, 144.8, 135.7, 129.2,
d
7.68 (d, J¼6.7 Hz, 1H, NeCH]), 6.27 (d, J¼6.7 Hz, 1H, NeCH]CH),
128.8, 128.6, 112.9, 98.9, 82.6, 52.0, 26.0. IR nmax (neat/cmꢀ1): 1756,
1668, 1548. EIMS m/z (% relative abundance): 270 (MþH, 41), 252
(10), 91 (100). HRMS (ES-QTOF) calcd for C16H16NO3 MþH 270.1130.
Found 270.1136.
3.64 (s, 3H, NCH3), 1.59 (s, 6H, 2CH3). 13C NMR (CDCl3)
d 171.9, 166.9,
157.9, 146.0, 112.2, 98.4, 82.5, 37.8, 26.1. IR nmax (neat/cmꢀ1): 1752,
1720, 1666, 1636, 1598, 1552. EIMS m/z (% relative abundance): 194
(MþH, 81), 176 (100). HRMS (ES-QTOF) calcd for C10H12NO3 MþH
194.0816. Found 194.0817.
4.3.7. 5-(3-Chlorobenzyl)-1,1-dimethylfuro[3,4-c]pyridine-
3,4(1H,5H)-dione (6f). The general procedure 2 using 3-hydroxy-3-
methyl-2-butanone 3a (306 mg, 3 mmol) and m-CleArCH2Cl
(483 mg, 3 mmol) with a third step performed under reflux during
3 h gave 6f (0.78 g, 86%) as an orange solid, mp 213e214 ꢁC. 1H NMR
4.3.2. 5-Methyl-1,1-pentamethylenefuro[3,4-c]pyridine-3,4(1H,5H)-
dione (6a). The general procedure 2 using 1-(1-hydroxycyclohexyl)
ethanone 3b (426 mg, 3 mmol) and MeI (2.27 g, 16 mmol) with
a third step performed at room temperature during 20 h gave 6a
(0.58 g, 84%) as a white solid, mp 247e248 ꢁC. 1H NMR (CDCl3)
(CDCl3)
6.48 (d, J¼6.8 Hz, 1H, NeCH]CH), 5.30 (s, 2H, CH2), 1.61 (s, 6H,
2CH3). 13C NMR (CDCl3)
171.8, 166.4, 157.0, 145.9, 132.9, 132.7,
d
8.00 (d, J¼6.8 Hz,1H, NeCH]), 7.40e7.22 (m, 4H, Harom),
d
7.64 (d, J¼6.7 Hz, 1H, NeCH]), 6.21 (d, J¼6.7 Hz, 1H, NCH]CH),
d
3.61 (s, 3H, NCH3), 1.90e1.67 (m, 8H, 4CH2), 1.39e1.24 (m, 2H, CH2).
130.0, 129.4, 129.3, 127.1, 111.4, 98.7, 82.3, 49.5, 25.5. IR nmax (neat/
cmꢀ1): 1752, 1670, 1598, 1552. EIMS m/z (% relative abundance):
304 (MþH, 38), 286 (35), 125 (100). HRMS (ES-QTOF) calcd for
C16H15NO3Cl MþH 304.0740. Found 304.0728.
13C NMR (CDCl3)
d 171.8, 167.3, 158.0, 145.8, 112.3, 98.7, 84.2, 37.7,
34.9, 24.6, 21.9. IR nmax (neat/cmꢀ1): 2940, 1748, 1670, 1548. EIMS
m/z (% relative abundance): 234 (MþH, 52), 216 (100). HRMS (ES-
QTOF) calcd for C13H16NO3 MþH 234.1130. Found 234.1129.
4.3.8. 5-(4-Chlorobenzyl)-1,1-dimethylfuro[3,4-c]pyridine-
3,4(1H,5H)-dione (6g). The general procedure 2 using 3-hydroxy-3-
methyl-2-butanone 3a (306 mg, 3 mmol) and p-CleArCH2Cl
(483 mg, 3 mmol) with a third step performed under reflux during
3 h gave 6g (0.89 g, 98%) as an orange solid, mp 243e244 ꢁC. 1H
4.3.3. 1-Ethyl-1,5-dimethylfuro[3,4-c]pyridine-3,4(1H,5H)-dione
(6b). The general procedure 2 using 3-hydroxy-3-methylpentan-2-
one 3c (348 mg, 3 mmol) and MeI (3 mL, 48 mmol) with a third
step performed at room temperature during 20 h gave 6b (0.53 g,
85%) as a yellow solid, mp 201e202 ꢁC. 1H NMR (CDCl3)
d
7.65 (d,
NMR (CDCl3)
d
8.11 (d, J¼6.7 Hz, 1H, NeCH]), 7.40 (d, J¼8.5 Hz, 2H,
J¼6.5 Hz, 1H, NeCH]), 6.18 (d, J¼6.5 Hz, 1H, NCH]CH), 3.63 (s, 3H,
NCH3), 2.00 (dq, J¼7.5, 15.0 Hz, CHaHbCH3), 1.82 (dq, J¼7.5, 15.0 Hz,
CHaHbCH3),1.56 (s, 3H, CCH3), 0.81 (t, J¼7.5 Hz, 3H, CH2CH3). 13C
Harom), 7.31 (d, J¼8.5 Hz, 2H, Harom), 6.44 (d, J¼6.7 Hz, 1H,
NeCH]CH), 5.20 (s, 2H, CH2), 1.59 (s, 6H, 2CH3). 13C NMR (CDCl3)
d
171.7, 166.3, 156.9, 145.8, 134.4, 133.4, 129.8, 128.5, 111.4, 98.7, 82.2,
NMR (CDCl3)
d
171.0, 167.3, 158.0, 145.6, 113.6, 98.6, 85.3, 38.0, 32.0,
50.9, 25.5. IR nmax (neat/cmꢀ1): 1756, 1668, 1598, 1550. EIMS m/z (%
relative abundance): 304 (MþH, 60), 125 (100). HRMS (ES-QTOF)
calcd for C16H15NO3Cl MþH 304.0740. Found 304.0744.
24.9, 8.0. IR nmax (neat/cmꢀ1): 2966, 2936, 1748, 1670, 1594, 1554,
1456. EIMS m/z (% relative abundance): 207 (Mþ, 24), 192 (5), 179
(15), 178 (100), 42 (25). HRMS (ES-QTOF) calcd for C11H13NO3Na
MþNa 230.0793. Found 230.0800.
4.3.9. 5-Allyl-1,1-pentamethylenefuro[3,4-c]pyridine-3,4(1H,5H)-di-
one (6h). The general procedure 2 using 1-(1-hydroxycyclohexyl)
ethanone 3b (426 mg, 3 mmol) and H2C]CHCH2Br (363 mg,
3 mmol) with a third step performed under reflux during 3 h gave
6h (0.71 g, 91%) as a brown solid, mp 149e151 ꢁC. 1H NMR (CDCl3)
4.3.4. 5-Ethyl-1,1-dimethylfuro[3,4-c]pyridine-3,4(1H,5H)-dione
(6c). The general procedure
2 using 3-hydroxy-3-methyl-2-
butanone 3a (306 mg, 3 mmol) and ethyl iodide (4.67 g,
30 mmol) with a third step performed at 70e80 ꢁC during 3 h gave
d
7.77 (d, J¼6.7 Hz, 1H, NeCH]), 6.35 (d, J¼6.7 Hz, 1H, NCH]CH),

4916
D. Villemin et al. / Tetrahedron 68 (2012) 4906e4918
6.04e5.91 (m, 1H, CH]CH2), 5.34e5.30 (m, 2H, CH]CH2), 4.67 (d,
J¼6.1 Hz, 2H, NCH2), 1.90e1.60 (m, 8H, 4CH2), 1.45e1.20 (m, 2H,
stirred at room temperature without solvent for 1 or 2 h. A purple
colouration more pronounced overtime occurred. The purple solid
obtained was washed several times with diethylether and some
drops of ethanol. Recrystallisation in absolute ethanol afforded yel-
low crystals of enaminolactone 8aec.
CH2). 13C NMR (CDCl3)
d 171.8, 167.5, 157.6, 144.9, 131.8, 120.0, 112.4,
99.4, 84.6, 51.1, 34.8, 24.5, 21.9. IR nmax (neat/cmꢀ1): 1770, 1700,
1662, 1594, 1552, 1438, 1386, 1148. EIMS m/z (% relative abun-
dance): 259 (Mþ, 74), 254 (96), 253 (46), 241 (100), 236 (71), 213
(45), 212 (49), 207 (46), 202 (82), 198 (60), 184 (86).
4.4.1. Ethyl 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-dimethyl-
2-oxofuran-3-carboxylate (8a). The general procedure 3 using ethyl
4,5,5-trimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate 5a (3.96 g,
20 mmol) and DMF acetal (2.94 g, 20 mmol) gave 8a (3.69 g, 73%) as
4.3.10. 5-(2-Chloroprop-1-ene)-1,1-pentamethylenefuro[3,4-c]pyri-
dine-3,4(1H,5H)-dione (6i). The general procedure 2 using 1-(1-
hydroxycyclohexyl)ethanone 3b (426 mg, 3 mmol) and H2C]
CClCH2Cl (330 mg, 3 mmol) with a third step performed under
reflux during 3 h gave 6i (0.62 g, 71%) as a brown solid, mp
yellow crystals, mp 159e160 ꢁC. 1H NMR (CDCl3)
d 7.64 (1H, d,
3J¼13.2 Hz, ]CHeN), 6.05 (1H, d, 3J¼13.2 Hz, CH]CHeN), 4.32
(2H, q, 3J¼7.0 Hz, CH2), 3.10 (6H, d large, N(CH3)2),1.56 (6H, s, 2CH3),
170e171 ꢁC. 1H NMR (DMSO-d6)
d
8.14 (d, J¼6.8 Hz, 1H, NeCH), 6.72
(d, J¼6.8 Hz, 1H, NCHeCH), 5.54 (dd, J¼2.1, 11.0 Hz, 2H, CCH2), 4.88
(s, 1H, CH2CCl), 2.00e1.16 (m, 10H, 5CH2). 13C NMR (CDCl3)
172.1,
1.37 (3H, t, 3J¼7.0 Hz, CH2CH3). 13C NMR (CDCl3)
d 176.8, 169.2,
164.9, 153.4, 100.5, 90.1, 82.2, 60.1, 36.9, 28.1, 14.5. IR nmax (neat/
cmꢀ1): 1716, 1681, 1604, 1540, 1188. EIMS m/z (% relative abun-
dance): 254 (MþH, 24), 226 (100), 208 (26). HRMS (ES-QTOF) calcd
for C13H19NO4Na MþNa 276.1212. Found 276.1194.
d
167.1, 157.2, 144.8, 134.7, 118.4, 112.8, 99.1, 84.5, 54.1, 34.8, 24.6, 21.8.
IR nmax (neat/cmꢀ1): 2934, 1750, 1673, 1596, 1545. EIMS m/z (%
relative abundance): 294 (MþH, 47), 276 (100). HRMS (ES-QTOF)
calcd for C15H17NO3Cl MþH 294.0897. Found 294.0902.
4.4.2. Ethyl 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-
pentamethylene-2-oxofuran-3-carboxylate (8b). The general pro-
cedure 3 using ethyl 4-methyl-2,5-dihydro-5,5-pentamethylene-2-
oxofuran-3-carboxylate 5b (4.76 g, 20 mmol) and DMF acetal
(2.94 g, 20 mmol) gave 8b (4.10 g, 70%) as yellow crystals, mp
4.3.11. 5-Benzyl-1,1-pentamethylenefuro[3,4-c]pyridine-3,4(1H,5H)-
dione (6j). The general procedure 2 using 1-(1-hydroxycyclohexyl)
ethanone 3b (426 mg, 3 mmol) and ArCH2Cl (380 mg, 3 mmol)
with a third step performed under reflux during 3 h gave 6j (0.78 g,
163e164 ꢁC. 1H NMR (CDCl3)
d
8.00 (1H, d, 3J¼13.2 Hz, ]CHeN),
84%) as a yellow solid, mp 215e216 ꢁC. 1H NMR (CDCl3)
d
7.59 (1H,
5.81 (1H, d, 3J¼13.2 Hz, CH]CHeN), 4.32 (2H, q, 3J¼7.0 Hz, CH2),
3.04 (6H, d large, N(CH3)2), 1.90e1.59 (10H, m, 5CH2), 1.37 (3H, t,
d, 3J¼6.8 Hz, ]CHeN), 7.37e7.26 (5H, m, Harom), 6.17 (1H, d,
3J¼6.8 Hz, CH]CHeN), 5.18 (2H, s, CH2Ph), 1.70e1.23 (10H, m,
3J¼7.0 Hz, CH2CH3). 13C NMR (CDCl3)
d 176.4, 169.7, 165.2, 153.9,
5CH2). 13C NMR (CD2Cl2)
d
175.9, 160.8, 151.0, 140.7, 134.5, 132.7,
100.4, 89.9, 84.4, 60.1, 45.2, 36.7, 24.9, 22.0, 14.5. IR nmax (neat/
cmꢀ1): 1720, 1674, 1614, 1540, 1181. EIMS m/z (% relative abun-
dance): 294 (MþH, 36), 266 (100), 248 (17). HRMS (ES-QTOF) calcd
for C16H23NO4Na MþNa 316.1525. Found 316.1506.
132.0, 131.9, 114.7, 103.3, 87.6, 55.3, 37.7, 27.9, 25.7. IR nmax (neat/
cmꢀ1): 1754, 1664, 1542. EIMS m/z (% relative abundance): 310
(MþH, 19), 292 (100), 91 (33). HRMS (ES-QTOF) calcd for C19H20NO3
MþH 310.1443. Found 310.1452.
4.4.3. Ethyl 4-(E)-2-(dimethylaminovinyl)-5-ethyl-2,5-dihydro-5-
4.3.12. 5-(3-Chlorobenzyl)-1,1-pentamethylenelfuro[3,4-c]pyridine-
methyl-2-oxofuran-3-carboxylate (8c). The general procedure 3
3,4(1H,5H)-dione (6k). The general procedure
2
using 1-(1-
using
ethyl
5-ethyl-2,5-dihydro-4,5-dimethyl-2-oxofuran-3-
hydroxycyclohexyl)ethanone 3b (426 mg, 3 mmol) and m-
CleArCH2Cl (483 mg, 3 mmol) with a third step performed under
carboxylate 5c (4.24 g, 20 mmol) and DMF acetal (2.94 g,
20 mmol) gave 8c (3.31 g, 62%) as yellow crystals, mp 138e140 ꢁC.
reflux during 3 h gave 6k (0.86 g, 84%) as
230e231 ꢁC. 1H NMR (DMSO-d6)
8.24 (d, J¼6.8 Hz, 1H, NeCH]),
7.57e7.34 (m, 4H, Harom), 6.76 (d, J¼6.8 Hz, 1H, NCH]CH), 5.27 (s,
2H, CH2), 1.98e1.23 (m, 10H, 5CH2). 13C NMR (CDCl3)
171.4, 166.6,
a
yellow solid,
1H NMR (CDCl3)
d
7.64 (1H, d, 3J¼13.0 Hz, ]CHeN), 6.08 (1H, d,
d
3J¼13.0 Hz, CH]CHeN), 4.31 (2H, m, CO2CH2CH3), 2,90 (6H, s large,
N(CH3)2), 1.98 (1H, dq J¼7.5, 15.0 Hz, CHAHBCH3), 1.73 (1H, dq J¼7.5,
15.0 Hz, CHAHBCH3), 2.06e1.65 (2H, m, CH2CH3), 1.52 (3H, s, CCH3),
1.37 (3H, t, 3J¼7.0 Hz, CO2CH2CH3), 0.81 (3H, t, CH2CH3). 13C NMR
d
157.2, 145.0, 133.1, 132.5, 130.7, 129.5, 129.3, 127.1, 111.8, 98.7, 83.8,
49.3, 34.2, 24.0, 21.4. IR nmax (neat/cmꢀ1): 1749, 1667, 1543. EIMS m/
z (% relative abundance): 344 (MþH, 70), 326 (100). HRMS (ES-
QTOF) calcd for C19H19NO3Cl MþH 344.1053. Found 344.1050.
(CDCl3) d 175.3, 169.7, 164.8, 152.9, 101.7, 90.3, 84.9, 60.0, 36.8, 33.6,
27.1, 14.5, 7.5. IR nmax (neat/cmꢀ1): 1725, 1677, 1605, 1538, 1195.
EIMS m/z (% relative abundance): 268 (MþH, 16), 240 (100), 222
(08). HRMS (ES-QTOF) calcd for C14H22NO4Na MþH 268.1549.
Found 268.1559.
4.3.13. 5-(4-Chlorobenzyl)-1,1-pentamethylenefuro[3,4-c]pyridine-
3,4(1H,5H)-dione (6l). The general procedure
2 using 1-(1-
hydroxycyclohexyl)ethanone 3b (426 mg, 3 mmol) and p-
CleArCH2Cl (483 mg, 3 mmol) with a third step performed under
reflux during 3 h gave 6l (0.93 g, 91%) as a yellow solid, mp
4.5. General procedure 4: Cerpegin 1 and analogues
6d,e,j,mep synthesis via the enaminolactones 8
247e248 ꢁC. 1H NMR (DMSO-d6)
d
8.37 (d, J¼6.7 Hz, 1H, NeCH]),
7.48e7.39 (m, 4H, Harom), 6.73 (d, J¼6.7 Hz, 1H, NCH]CH), 5.18 (s,
2H, CH2), 1.98e1.25 (m, 10H, 5CH2). 13C NMR (CDCl3)
171.8, 167.2,
A mixture of enaminolactone 8 (2 mmol) and primary amine
(2 mmol) was heated with a hot gun. After cooling, the solid obtained
was washed several times with diethylether. Recrystallisation in
absolute ethanol afforded crystals of Cerpegin and analogues.
d
157.7, 144.8, 134.6, 134.2, 130.2, 129.3, 112.7, 99.5, 84.4, 51.6, 34.8,
24.6, 21.2. IR nmax (neat/cmꢀ1): 2941, 1755, 1664, 1551. EIMS m/z (%
relative abundance): 344 (MþH, 93), 326 (100). HRMS (ES-QTOF)
calcd for C19H19NO3Cl MþH 344.1053. Found 344.1055.
4.5.1. 1,1,5-Trimethylfuro[3,4-c]pyridine-3,4(1H,5H)-dione: Cerpegin
(1). The general procedure 4 using enaminolactone 8a (0.50 g,
2 mmol) and methylamine (0.15 g, 3 mmol) gave Cerpegin 1 (0.36 g,
4.4. General procedure 3: synthesis of 4-(2-
dimethylaminovinyl)-2-oxo-2,5-dihydrofuran-3-ethyl
carboxylate (8aec)
94%) as white crystals, mp 267e269 ꢁC (lit. 268e270 ꢁC).1b 1H and13
C
NMR, IR and HRMS are conformed to those reported inSection4.3.1.
4.5.2. 5-Benzyl-1,1-dimethylfuro[3,4-c]pyridine-3,4(1H,5H)-dione
(6e). The general procedure 4 using enaminolactone 8a (0.50 g,
2 mmol) and benzylamine 9b (0.21 g, 2 mmol) with a 5 min hot gun
A mixture of ethyl 5,5-dialkyl-4-methyl-2-oxo-2,5-dihydrofuran-
3-carboxylate 5aec (20 mmol) and DMF acetal (20 mmol) was

D. Villemin et al. / Tetrahedron 68 (2012) 4906e4918
4917
heating gave 6e (0.48 g, 89%) as a white solid, mp 202e203 ꢁC. 1H
and 13C NMR, IR and HRMS are conformed to those reported
inSection4.3.6.
3J¼5.0 Hz, CH]CHeN), 4.21 (2H, t, 3J¼6.6 Hz, NCH2), 2.74 (2H, t,
3J¼6.6 Hz, CH2CH2N),1.55(6H, s,2CH3).13CNMR(CDCl3)
d171.9,166.3,
156.5,147.1,135.5,135.0,113.0,110.1, 98.1, 82.1, 48.8, 26.8, 25.4. IR nmax
(neat/cmꢀ1):3296,1730,1668,1556. EIMS m/z(%relative abundance):
274 (MþH, 12), 256 (100), 212 (17), 180 (27), 95 (100). HRMS (ES-
QTOF) calcd for C14H16N3O3 MþH 274.1192. Found 274.1187.
4.5.3. 5-Benzyl-1-cyclohexylfuro[3,4-c]pyridine-3,4(1H,5H)-dione
(6j). The general procedure 4 using enaminolactone 8b (0.58 g,
2 mmol) and benzylamine 9b (0.21 g, 2 mmol) with a 5 min hot gun
heating gave 6j (0.54 g, 88%) as a white solid, mp 216 ꢁC. 1H and 13C
NMR, IR and HRMS are conformed to those reported inSection4.3.11.
4.6. General procedure 5: synthesis of bis-Cerpegins 11aec
Ethyl 4-((E)-2-(dimethylamino)vinyl)-2,5-dihydro-5,5-dimethyl-
2-oxofuran-3-carboxylate 8a (2 mmol) and diamine 10 (1 mmol)
were stirred in DMF (5 mL). After dissolution, the mixture was
refluxed during 3 h. After cooling and evaporation of the solvent, the
residue was washed several times with diethylether to give the bis-
Cerpegins 11.
4.5.4. 5-Benzyl-1-ethyl-1-methylfuro[3,4-c]pyridine-3,4(1H,5H)-di-
one (6m). The general procedure 4 using enaminolactone 8c (0.53 g,
2 mmol) and benzylamine 9b (0.21 g, 2 mmol with a 5 min hot gun
heating gave 6m (0.45 g, 80%) as a white solid, mp 165e166 ꢁC. 1H
NMR (CDCl3)
d
7.66 (1H, d, 3J¼6.7 Hz, ]CHeN), 7.43e7.36 (5H, m,
Harom), 6.15 (1H, d, 3J¼6.7 Hz, CH]CHeN), 5.26 (1H, d, J¼14.5 Hz,
CHaPh), 5.13 (1H, d, J¼14.5 Hz, CHbPh), 1.98 (1H, dq J¼7.5, 15 Hz,
CHaCH3), 1.81 (1H, dq J¼7.5, 15 Hz, CHbCH3),1.54 (3H, s, CH3), 0.81
4.6.1. 1,1-Dimethyl-5-(3-(1,1-dimethyl-3,4-dioxofuro[3,4-c]pyridin-
5(1H,3H,4H)-yl)propyl)furo[3,4-c]pyridine-3,4(1H,5H)-dione
(11a). The general procedure 5 using ethyl 4-(E)-2-(dimethyla-
mino)vinyl)-2,5-dihydro-5,5-dimethyl-2-oxofuran-3-carboxylate
8a (0.50 g, 2 mmol) and 1,3-propyldiamine 10a (0.074 g, 1 mmol)
gave the compound 11a (0.21 g, 54%) as a white solid, mp >260 ꢁC.
(3H, t, 3J¼7.5 Hz, CH2CH3). 13C NMR (CDCl3)
d 170.6, 167.0, 157.3,
144.3, 135.5, 129.1, 128.7, 128.6, 113.6, 98.7, 85.0, 51.9, 31.6, 24.4, 7.7.
IR nmax (neat/cmꢀ1): 1753, 1664, 1547, 1065. EIMS m/z (% relative
abundance): 284 (MþH, 67), 266 (100), 91 (73). HRMS (ES-QTOF)
calcd for C17H18NO3 MþH 284.1287. Found 284.1298.
1H NMR (CDCl3)
d
7.98 (2H, d, 3J¼6.7 Hz, 2CH]CHeN), 6.31 (2H, d,
3J¼6.7 Hz, 2CH]CHeN), 4.11 (4H, t, 3J¼6.2 Hz, CH2CH2CH2), 2.32
4.5.5. 5-Allyl-1-ethyl-1-methylfuro[3,4-c]pyridine-3,4(1H,5H)-dione
(6d). The general procedure 4 using enaminolactone 8a (0.50 g,
2 mmol) and allylamine 9c (0.11 g, 2 mmol) with a 2 min hot gun
heating gave 6d (0.40 g, 91%) as a white solid, mp 174e175 ꢁC. 1H
and 13C NMR, IR and HRMS are conformed to those reported in
Section4.3.5.
(2H, t, 3J¼6.2 Hz, CH2CH2CH2), 1.60 (12H, s, 4CH3). 13C NMR (CDCl3)
d
172.0, 166.9, 147.5, 135.4, 112.2, 99.1, 82.3, 46.8, 30.0, 25.9. IR nmax
(neat/cmꢀ1): 1752, 1664, 1594, 1542, 1149, 1082. EIMS m/z (% rela-
tive abundance): 399 (MþH, 40), 220 (100). HRMS (ES-QTOF) calcd
for C21H23N2O6 MþH 399.1556. Found 399.1573.
4.6.2. 1,1-Dimethyl-3,4-dioxofuro[3,4-c]pyridine-5(1H,3H,4H)-hexyl)
4.5.6. 1,1-Dimethyl-5-((pyridine-2-yl)methyl)furo[3,4-c]pyridine-
3,4(1H,5H)-dione (6n). The general procedure 4 using enamino-
lactone 8a (0.50 g, 2 mmol) and pyridin-2-ylmethanamine 9d
(0.21 g, 2 mmol) with a 2 min hot gun heating gave 6n (0.49 g, 92%)
furo[3,4-c]pyridine-3,4(1H,5H)-dione (11b). Thegeneral procedure5
using
ethyl
4-(E)-2-(dimethylamino)vinyl)-2,5-dihydro-5,5-
dimethyl-2-oxofuran-3-carboxylate 8a (0.50 g, 2 mmol) and 1,6-
hexyldiamine 10b (0.116 g, 1 mmol) gave the compound 11b
as a white solid, mp 175 ꢁC. 1H NMR (CDCl3)
d
8.52e8.51 (1H, m,
(0.16 g, 36%)as awhite solid, mp >260 ꢁC.1HNMR (CDCl3)
d 8.22 (2H,
Hpyr), 8.00 (1H, d, 3J¼6.7 Hz, ]CHeN), 7.73e7.66 (1H, m, Hpyr),
7.58e7.55 (1H, m, Hpyr), 7.25e7.21 (1H, m, Hpyr), 6.24 (1H, d,
3J¼6.7 Hz, CH]CHeN), 5.25 (2H, s, CH2),1.59 (6H, s, 2CH3). 13C NMR
d, 3J¼6.7 Hz, 2CH]CHeN), 6.68 (2H, d, 3J¼6.7 Hz, 2CH]CHeN),
3.97 (4H, t, 3J¼6.9 Hz, 2CH2), 1.67e1.65 (4H, m, 2CH2), 1.57 (12H, s,
4CH3),1.41e1.34 (4H, m, 2CH2). 13C NMR (CDCl3)
d 172.1,166.8,147.5,
(CDCl3)
d
171.8, 157.2, 154.4, 149.5, 145.8, 137.2, 124.3, 123.4, 120.3,
135.9, 112.4, 99.2, 85.3, 46.8, 28.00, 26.9, 25.9. IR nmax (neat/cmꢀ1):
1754, 1673, 1594, 1555, 1155, 1112. EIMS m/z (% relative abundance):
463 (MþNa, 100), 441 (MþH, 28), 329 (23), 307 (10). HRMS (ES-
QTOF) calcd for C24H29N2O6 MþH 441.2026. Found 441.2025.
98.4, 82.4, 53.8, 25.9. IR nmax (cmꢀ1): 1746, 1672, 1590, 1546, 1142,
1063. EIMS m/z (% relative abundance): 271 (MþH, 12), 253 (100),
225 (17), 209 (27), 194 (12), 110 (52), 92 (14). HRMS (ES-QTOF) calcd
for C15H15N2O3 MþH 271.1083. Found 271.1087.
4.6.3. 1,1-Dimethyl-5-(3-(1,1-dimethyl-3,4-dioxofuro[3,4-c]pyridin-
5(1H,3H,4H)-yl)methyl)benzyl)-1,1-dimethylfuro[3,4-c]pyridine-
3,4(1H,5H)-dione (11c). The general procedure 5 using ethyl 4-(E)-
2-(dimethylamino)vinyl)-2,5-dihydro-5,5-dimethyl-2-oxofuran-3-
carboxylate 8a (0.50 g, 2 mmol) and m-xylyldiamine 10c (0.136 g,
1 mmol) gave the compound 11c (0.37 g, 80%) as a white solid, mp
4.5.7. 5-(2-(1H-Indol-3-yl)ethyl)-1,1-dimethylfuro[3,4-c]pyridine-
3,4(1H,5H)-dione (6o). The general procedure 4 using enamino-
lactone 8a (0.50 g, 2 mmol) and 2-(1H-indol-3-yl)ethanamine 9e
(0.32 g, 2 mmol) with 5 min hot gun heating gave 6o (0.54 g, 84%)
as a white solid, mp 245e246 ꢁC. 1H NMR (CDCl3)
d 8.10 (1H, s, NH),
7.59 (1H, d, 3J¼6.5 Hz, CH]CHeN), 7.30e7.09 (4H, m, Harom), 6.99
(1H, s, C]CHeNH), 5.89 (1H, d, 3J¼6.5 Hz, ]CHeN), 4.26 (2H, t,
3J¼6.7 Hz, CH2CH2eN), 3.28 (2H, t, 3J¼6.7 Hz, CH2CH2eN), 1.56 (6H,
>260 ꢁC. 1H NMR (CDCl3)
d
7.73 (2H, d, 3J¼6.7 Hz, 2CH]CHeN),
7.49 (1H, s, Harom), 7.34 (3H, s, 3Harom), 6.24 (2H, d, 3J¼6.7 Hz,
2CH]CHeN), 5.15 (4H, s, 2CH2), 1.57 (12H, s, 4CH3). 13C NMR
s, 2CH3). 13C NMR (CDCl3)
d
172.3, 166.7, 157.1, 147.4, 136.5, 127.4,
(CDCl3) d 171.9, 166.8, 157.5, 145.3, 136.4, 128.5e129.6, 112.4, 99.1,
123.6, 121.4, 118.7, 118.5, 111.8, 110.5, 98.6, 82.5, 50.1, 25.8, 24.8. IR
nmax (neat/cmꢀ1): 3269, 1760, 1669, 1596, 1552, 1075, 1057. EIMS m/
z (% relative abundance): 323 (MþH, 09), 144 (100). HRMS (ES-
QTOF) calcd for C19H19N2O3 MþH 323.1396. Found 323.1404.
82.6, 52.1, 25.9. IR nmax (neat/cmꢀ1): 1759, 1667, 1603, 1549, 1155.
EIMS m/z (% relative abundance): 461 (MþH, 46), 443 (100), 425
(14), 282 (60), 264 (25). HRMS (ES-QTOF) calcd for C26H25N2O6
MþH 461.1713. Found 461.1707.
4.5.8. 5-(2-(1H-Imidazol-4-yl)ethyl)-1,1-dimethylfuro[3,4-c]pyri-
dine-3,4(1H,5H)-dione (6p). The general procedure 4 using enami-
nolactone 8a (0.50 g, 2 mmol) and 2-(1H-imidazol-4-yl)ethanamine
9f (0.22 g, 2 mmol) with 5 min hot gun heating gave 6p (0.47 g, 87%)
4.7. General procedure 6: synthesis of amino-Cerpegins 13aed
Ethyl 4-((E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-dialkyl-2-
oxofuran-3-carboxylate 8 (2 mmol) and hydrazine (3 mmol) were
heated with a hot gun during a few minutes. After cooling, the solid
obtained was washed several times with diethylether then recrys-
tallised in absolute ethanol to provide amino-Cerpergins 13aed.
as a white solid, mp 245e246 ꢁC. 1H NMR (CDCl3)
d 12.03 (1H, t,
3J¼2.9 Hz,NH), 7.96 (1H, d, 3J¼5.0 Hz, ]CHeN), 7.67(1H, d,3J¼2.9 Hz,
C]CHeNH), 6.77 (1H, d, 3J¼2.9 Hz, N]CHeNH), 6.58 (1H, d,

4918
D. Villemin et al. / Tetrahedron 68 (2012) 4906e4918
ꢀ
4.7.1. N-Amino-1,1-dimethylfuro[3,4-c]pyridine-3,4(1H,5H)-dione
(13a). The general procedure 6 using ethyl 4-((E)-2-(dimethyla-
minovinyl)-2,5-dihydro-5,5-dialkyl-2-oxofuran-3-carboxylate 8a
(0.50 g, 2 mmol) and monohydrate hydrazine (0.15 g, 3 mmol) gave
the compound 13a (0.31 g, 80%) as a white solid, mp 245e246 ꢁC.
(Centre National de la Recherche Scientifique), the ‘Region
Basse-Normandie’ and the European Union (FEDER funding) for
financial support. Also the authors thank Remy Legay and
Baptiste Rigaud for NMR spectra, Mrs. Karine Jarsale for EIMS
and HRMS analysis and Dr. Saada Dakdouki for English
corrections.
ꢀ
ꢀ
1H NMR (DMSO-d6)
d
8.17 (1H, d, 3J¼6.7 Hz, CH]CHeNH), 6.56 (1H,
d, 3J¼6.7 Hz, CH]CHeNH), 6.23 (2H, s, NH2), 1.55 (6H, s, 2CH3). 13
C
NMR (DMSO-d6)
d 169.6, 166.2, 155.3, 145.0, 109.0, 97.4, 82.3, 25.6.
IR nmax (neat/cmꢀ1): 3303, 3203,1743, 1587, 1639, 1545. EIMS m/z (%
relative abundance): 195 (MþH, 32), 177 (100). HRMS (ES-QTOF)
calcd for C9H11N2O3 MþH 195.0770. Found 195.0779.
References and notes
1. (a) Sivakumar, K.; Eswaramurthy, K. S.; Sabramanian, K.; Natarajan, S. Acta
Crystallogr. 1990, c46, 839e841; (b) Adibatti, N. A.; Thirugnanasambantham, P.;
Kuilothungan, C.; Viswanathan, S.; Kameswean, L.; Balakrishna, K.; Sukumar, E.
Phytochemistry 1991, 30, 2449e2450.
2. (a) Usman, A. S.; Narayanaswamy, V. J. Res. Indian Med. 1970, 5, 10e15; (b)
Sukumar, E.; Gopal, R. H.; Rao, R. B.; Viswanathan, S.; Thirugnanasambantham, P.;
Vijayasekaran, V. Fitoterapia 1995, 66, 403e406; (c) Jong, Y. J.; Snell, E. E. J. Biol.
Chem. 1986, 261, 15112e15114.
4.7.2. N-Amino-1-cyclohexylfuro[3,4-c]pyridine-3,4(1H,5H)-dione
(13b). The general procedure 6 using ethyl 4-((E)-2-(dimethylami-
novinyl)-2,5-dihydro-5,5-pentamethylene-2-oxofuran-3-carboxylate
8b (0.58 g, 2 mmol)andmonohydratehydrazine(0.15 g, 3 mmol)gave
the compound 13b (0.33 g, 71%) as a white solid, mp 238e239 ꢁC. 1H
3. (a) Jessen, H. J.; Gademann, K. Nat. Prod. Rep. 2010, 27, 1168e1185; (b) Groutas,
W. C.; Stanga, M. A.; Brubaker, M. J.; Huang, T. L.; Moi, M. K.; Carroll, R. T. J. Med.
Chem. 1985, 28, 1106e1109.
NMR (DMSO-d6)
d
8.14 (1H, d, 3J¼6.7 Hz, CH]CHeNH), 6.54 (1H, d,
3J¼6.7 Hz, CH]CHeNH), 6.22 (2H, s, NH2), 1.91e1.32 (10H, m, 5CH2).
4. Guillier, F.; Nivoliers, F.; Bourguignon, J.; Dupas, G.; Marsais, F.; Godard, A.;
ꢀ
13C NMR (DMSO-d6)
d 169.2, 166.3, 155.4, 144.8, 109.1, 97.7, 83.6, 33.9,
Queguiner, G. Tetrahedron Lett. 1992, 33, 7355e7356.
ꢀ
ꢀ
5. Lazaar, J.; Hoarau, C.; Mongin, F.; Trecourt, F.; Godard, A.; Queguiner, G.; Mar-
23.7, 21.6. IR nmax (neat/cmꢀ1):3310,3190,1748,1669,1582,1545.EIMS
m/z (% relative abundance): 235 (MþH, 19), 217 (100). HRMS (ES-
QTOF) calcd for C12H15N2O3 MþH 235.1083. Found 235.1102.
sais, F. Tetrahedron Lett. 2005, 46, 3811e3813.
6. (a) Kelly, T. R.; Walsh, J. J. Org. Chem. 1992, 57, 6657e6658; (b) Kelly, T. R.; Kim,
M. H. J. Org. Chem. 1992, 57, 1593e1597.
7. Hong, H.; Comins, D. L. J. Org. Chem. 1996, 61, 391e392.
8. Tarasov, E. V.; Henckens, A.; Ceulemans, E.; Dehaen, W. Synlett 2000, 625e626.
9. Sarkar, T. K.; Basak, S. Org. Lett. 2004, 6, 2925e2927.
10. (a) Matsuo, K.; Arase, T. Chem. Pharm. Bull. 1994, 42, 715e717; (b) Matsuo, K.;
Arase, T. Chem. Pharm. Bull. 1995, 43, 2091e2094; (c) Matsuo, K.; Kobayashi, M.;
Sugimoto, K. I. Heterocycles 1997, 44, 1191e1195.
11. Villemin, D.; Liao, L. Tetrahedron Lett. 1996, 37, 8733e8734.
12. Avetisyan, A. A.; Karapetyan, L. V.; Tadevosyan, M. D. Russ. J. Org Chem. 2010, 46,
1259e1261.
13. This work was a part of the PhD thesis of Liang Liao, University of Caen, 1999.
14. This work was a part of the PhD thesis of Nawel Cheikh, University of Tlemcen
2008.
15. (a) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735e1766; (b) Cheikh, N.; Bar, N.;
Choukchou-Braham, N.; Mostefa-Kara, B.; Lohier, J.-F.; Sopkova, J.; Villemin, D.
Tetrahedron 2011, 67, 1540e1551.
16. (a) Balogh, M.; Hermecz, I.; Nabor-Szabo, G.; Simon, K.; Meszaros, Z. J. Chem.
Soc., Perkin Trans. 1 1986, 53e57; (b) Balogh, M.; Hermecz, I.; Simon, K.; Pusztay,
L. J. Heterocycl. Chem. 1989, 26, 1755e1769; (c) Balogh, M.; Hermecz, I.;
4.7.3. N-Amino-1-methyl-1-ethylfuro[3,4-c]pyridine-3,4(1H,5H)-di-
one (13c). The general procedure 6 using ethyl 4-((E)-2-(dimethyla-
minovinyl)-5-ethyl-2,5-dihydro-5-methyl-2-oxofuran-3-carboxylate
8c(0.53 g, 2 mmol)and monohydratehydrazine(0.15 g, 3 mmol)gave
the compound 13c (0.33 g, 81%) as a white solid, mp 206 ꢁC. 1H NMR
(DMSO-d6)
d
8.24 (1H, d, 3J¼6.7 Hz, CH]CHeNH), 6.57 (1H, d,
3J¼6.7 Hz, CH]CHeNH), 6.25 (2H, s, NH2), 1.91 (2H, m, CH2CH3), 1.55
(3H, s, CH3), 0.69 (3H, t, 3J¼7.3 Hz, CH2CH3). 13C NMR (DMSO-d6)
d
168.27, 166.5, 155.3, 144.9, 110.0, 97.6, 84.9, 30.6, 24.2, 7.4. IR nmax
(neat/cmꢀ1): 3303, 3199, 1746, 1664, 1585, 1546. EIMS m/z (% relative
abundance): 209 (MþH, 26), 191 (100), 163 (22). HRMS (ES-QTOF)
calcd for C10H13N2O3 MþH 209.0926. Found 209.0930.
ꢁ
ꢀ ꢁ
ꢀ
ꢁ
ꢁ
ꢁ
Meszaros, Z.; Simon, K.; Pusztay, L.; Horvath, G.; Dvortsak, P. J. Heterocycl. Chem.
4.7.4. 1,1-Dimethyl-5-(methylamino)furo[3,4-c]pyridine-3,4(1H,5H)-
dione (13d). The general procedure 6 using ethyl 4-((E)-2-(dime-
thylaminovinyl)-2,5-dihydro-5,5-dimethyl-2-oxofuran-3-carbox-
ylate 8a (0.50 g, 2 mmol) and methylhydrazine (0.14 g, 3 mmol)
gave the compound 13d (0.19 g, 46%) as a white solid, mp 218 ꢁC.
1980, 17, 359e368.
17. Katritzky, A. R.; Barcock, R. A.; Long, Q. H.; Balasubramanian, M.; Malhotra, N.;
Greenhill, J. V. Synthesis 1993, 233e236.
18. Bartoli, G.; Cimarelli, C.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Synthesis 1990,
895e897.
€
19. Kucklander, U., Chapter 10 Enaminones as Synthons InThe Chemistry of Enamines
Part 1; Rappoport, Z., Ed.; John Wiley: Chichester, UK, 1994.
20. Al-Omran, F.; Khalik Mervat, M. A.; Abou-Elkhair, A.; Elnagdi, M. H. Synthesis
1997, 91e94.
21. (a) Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433e2480; (b) Stanovnik, B.;
Svete, J. Synlett 2000, 1077e1091.
1H NMR (DMSO-d6)
d
8.24 (1H, d, 3J¼6.7 Hz, CH]CHeN), 6.78 (1H,
q, 3J¼5.7 Hz, NHMe), 6.62 (1H, d, 3J¼6.7 Hz, CH]CHeN), 2.65 (3H,
d, 3J¼5.7 Hz, CH3), 1.52 (6H, s, 2CH3). 13C NMR (DMSO-d6)
d 177.3,
170.7, 155.5, 146.1, 110.2, 98.3, 82.4, 38.5, 25.4. IR nmax (neat/cmꢀ1):
3310, 3190, 1748, 1669, 1582, 1545. EIMS m/z (% relative abun-
dance): 439 (2MþNa, 20), 231 (59), 209 (100), 191 (58). HRMS (ES-
QTOF) calcd for C20H24N4O6Na 2MþNa 439.1594. Found 439.1591.
22. Valla, A.; Valla, B.; Cartier, D.; Guillou, R.; Labia, R.; Potier, P. Tetrahedron Lett.
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We gratefully acknowledge financial support from the
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‘Ministere de la Recherche et des Nouvelles Technologies’, CNRS