Regioselective synthesis of pyrrolin-3-ones and 2,3,4,5-tetrahydro[1,3]-oxazines from N-vinylic amidines

Article abstract of DOI:10.1016/j.tet.2008.12.014

Achiral and optically active N-vinylic amidines are obtained by simple addition of amidines to acetylenic esters. Thermal intramolecular cyclization of these substrates containing a carboxylate group in position 3 gives pyrrolin-3-ones. The enaminone char

Full text of DOI:10.1016/j.tet.2008.12.014

Tetrahedron 65 (2009) 1119–1124
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Tetrahedron
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Regioselective synthesis of pyrrolin-3-ones and 2,3,4,5-tetrahydro[1,3]-oxazines
from N-vinylic amidines
*
´
Francisco Palacios , Concepcion Alonso, Gloria Rubiales, Maite Villegas
´
´
Departamento de Qu´ımica Organica I, Facultad de Farmacia, Universidad del Paıs Vasco, Apartado 450, 01080 Vitoria, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Achiral and optically active N-vinylic amidines are obtained by simple addition of amidines to acetylenic
esters. Thermal intramolecular cyclization of these substrates containing a carboxylate group in position
3 gives pyrrolin-3-ones. The enaminone character of these compounds towards propargyl bromide, di-
ethyl azodicarboxylate, diethyl acetylenedicarboxylate, ethyl propiolate and phenyl isocyanate is studied
and functionalized pyrrolin-3-one derivatives are obtained. The reaction of the pyrrolinones prepared
with diethyl ketomalonate leads to new 1,3-oxazine derivatives.
Received 7 November 2008
Received in revised form 2 December 2008
Accepted 3 December 2008
Available online 10 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
enamines IV (Fig. 1) and in a previous communication13 we
reported that these substrates could be used in the preparation of
Pyrrolinone derivatives are important five-membered hetero-
cycles1,2 because these compounds constitute the skeleton of cyclic
substrates for the preparation of biologically active tetramic acid
derivatives3 I (Fig. 1) and antibiotics.4 Moreover, functionalized
2-azabutadiene systems II (Fig. 1) represent versatile intermediates
mainly for the synthesis of five- and six-membered heterocycles.5,6
Furthermore, the presence of electron-donating groups in these
substrates III (Fig. 1), for example, an amine group, could even fa-
vour their reactivity as enamine IV (Fig. 1), due to the imine–en-
amine prototropic rearrangement and enamines being excellent
synthons for carbon–carbon bond formation.7
5-dialkylamino-4-pyrrolin-3-one derivatives, which are starting
materials for biologically active tetramic acid derivatives.3,4 Herein,
we extend the preparative scope of our methodology and report,
for example, the synthesis of a variety of six- and five-membered
heterocycles.
2. Results and discussion
2.1. Synthesis of N-vinylic amidines
Conjugated amidines 3 were prepared through a conjugated
addition of amidines 114 to acetylenic esters 2 (Scheme 1). Initially
the addition (R1¼H, R2¼Et) in CHCl3 at 20 ꢀC was performed and
mixtures of E,E and E,Z-N-vinylic amidines 3a (20:80) and 3b
(35:65) were obtained (Scheme 1, Table 1, entries 1 and 3). The
isomerization of E,Z towards E,E isomer was observed when a so-
lution of E,Z isomer of 3a or 3b was heated at 60 ꢀC in CHCl3.
We have been involved in the chemistry of enamines8 and in the
design of new strategies for the preparation of three,9 five10 and
six11 nitrogen heterocyclic compounds as well as in the study of
functionalized 2-azadiene systems II (Fig. 1) and their use in the
preparation of heterocyclic compounds.12 In this context, little is
known about the reactivity of 1-amino-2-aza-1,3-butadienes as
NR2
R1
(R1= CO2Me)
CO2R2
NR2
NH
NR2
N
+
O
NH
2
N
1
NR
CO2H
(R1 = H)
NR2
O
CO2R1
CO2R1
NR2
II
I
IV
III
Δ
N
N
(R1 = H)
CO2R2
R1
R1
Figure 1.
CO2R2
(1E,3E)-3a-e
(1E,3Z)-3a,b
* Corresponding author. Tel.: þ34 945 013103; fax: þ34 945 013049.
E-mail address: francisco.palacios@ehu.es (F. Palacios).
Scheme 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.014

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F. Palacios et al. / Tetrahedron 65 (2009) 1119–1124
Table 1
1-Amino-2-azadienes 3 produced via Scheme 1
Entry
Compound
R2
R1
R2
Conditions
3E/3Z (%)
Yielda (%)
1
2
3
4
5
6
3a
3a
3b
3b
3c
3d
Et2
Et2
–(CH2)5–
–(CH2)5–
Et2
H
H
H
H
Et
Et
Et
Et
Me
Me
CHCl3, 20 ꢀC, 24 h
CHCl3, 60 ꢀC, 24 h
CHCl3, 20 ꢀC, 24 h
CHCl3, 60 ꢀC, 4 h
CHCl3, ꢁ15 ꢀC, 4 h
CHCl3, ꢁ15 ꢀC, 2 h
20/80b
100/0
35/65b
100/0
100/0
100/0
98
95
95
90
97
95
CO2Me
CO2Me
–(CH2)5–
CHCl3, ꢁ15 ꢀC, 4 h
100/0
90
OCH3
7
3e
CO2Me
Me
a
Percent (%) of consumption of the starting material by NMR analysis of crude reaction mixture.
Isomerization of 3Z towards 3E by heating in CHCl3 at 60 ꢀC.
b
In addition only E,E isomers were observed when the reaction of
amidines 1 to acetylenic ester 2 was performed in CHCl3 at the
same temperature (Table 1, entries 2 and 4). Similar isomerizations
Moreover the IR spectra of compound 4a showed a signal corre-
sponding to a frequency associated with an amino group at
3409 cmꢁ1 that does not change with sample dilution (0.5 M,
0.25 M, 0.12 M in CHCl3). This result is consistent with the presence
of the hydrogen bridge bonding between the hydrogen atom of the
amino group and the oxygen atom of carboxylic group, which in-
dicates the Z configuration of an exocyclic double bond.
of 2-azadienes derived from
b-amino esters had been observed
previously.15 However, the addition of amidines 1 to dimethyl
acetylendicarboxylate (DMAD) 2 (R1¼CO2Me, R2¼Me) in CHCl3 at
ꢁ15 ꢀC gave only E,E-azadiene isomers 3c,d in excellent yields
(Scheme 2, Table 1, entries 5 and 6). The higher reactivity of acet-
ylenic diesters seems to favour the formation of the more stable E,E
isomers 3c,d. Compounds 3a–c were unstable to distillation
or chromatography and therefore were not isolated and used in
situ for the subsequent reactions. The presence of the non-isolable
compounds was established on the basis of the spectroscopic data
of their crude reaction mixtures. The scope of this process is not
restricted to the use of achiral amidines 1a (R2¼Et2), 1b (R2¼
(CH2)5–) (Scheme 1, Table 1, entries 1–6), given that optically active
amidine 1c derived from (S)-2-methoxymethylpyrrolidine gave
exclusively optically active 1E,3E conjugated amidine 3e (Scheme 1,
Table 1, entry 7).
2.3. Reactivity of 5-amino-4-pyrrolin-3-ones with
electrophilic reagents
Taking into account both, the potential interest of these sub-
strates for the preparation of functionalized pyrrolinones and that
these amino-4-pyrrolin-3-ones 4 are multifunctional compounds
containing two enamines, an enaminone and a secondary enamino
ester, the regioselective enaminone character (reaction through the
C-4) versus the enamino ester reactivity (reaction through the
exocyclic carbon) was explored by the reaction of compounds 4
with electrophilic reagents such as propargyl bromide, diethyl
azodicarboxylate, acetylenic esters and phenyl isocyanate.
Initially, compound 4a reacted with propargyl bromide in
refluxing CHCl3 to give compound 5 (Scheme 3, Table 3, entry 1).
Similarly, in the reaction of 4a with diethyl azodicarboxylate at
room temperature in CHCl3, only adduct 6 (Scheme 3, Table 3, entry
2) was obtained in a regioselective fashion.
NR2
NH
NR2
Δ / xylene
N
CH3
or toluene
-MeOH
O
O
MeO
O
CO2Me
OMe
4a-c
Formation of compounds 5 and 6 can be explained by nucleo-
philic addition of C-4 (enaminone moiety) of 5-amino-1,2-dihy-
dropyrrol-3-one ring of 4a to electrophilic methylenic carbon of
propargyl bromide or to nitrogen of diethyl azodicarboxylate.
Compounds 5 and 6 were characterized by their spectroscopic data.
Thus, in 1H NMR spectroscopic data showed the disappearance of
a signal at around 4.7 ppm corresponding to the cyclic enaminic
proton, while signal at around 5.8 ppm corresponding to exocyclic
enaminic proton remained.
3c-e
NR2
NH
Δ
-MeOH
MeO
O
CO2Me
3'
Scheme 2.
The use of acetylenic esters as electrophiles gave similar results.
Thus, the reaction of 4a with DMAD in CHCl3 at room temperature
led to compound 7 (Scheme 3, Table 3, entry 3) as a mixture of Z/E
isomers (57:43) in relation to the newly formed exocyclic double
bond. On the other hand, the reaction of 4a,b (R2¼Et2, –(CH2)5–)
with methyl propiolate were inefficient even on prolonged heating
and at a higher temperature. However, the metalation of the en-
amine by treatment of compound 4a with MeLi increased its re-
activity and thus the reaction with methyl propiolate in THF
2.2. Intramolecular cyclization of N-vinylic amidines:
synthesis of 4-pyrrolin-3-ones
The enamine character of N-vinylic amidines 3 (IV, Fig. 1, vide
supra) was observed when these substrates were heated. Thermal
treatment of conjugated amidine 3c (R2¼Et2) in xylene at 140 ꢀC in
a sealed tube led directly to cyclic derivative 4a (Scheme 2, Table 2,
entry 1). The process was extended to 1-piperidino derivative 3d
(R2¼–(CH2)5–) and optically active amidine 3e and 2-alkyliden-
pyrrolin-3-ones 4b,c were obtained (Scheme 2, Table 2, entries 2
and 3). Formation of compounds 4 could be explained by intra-
molecular cyclization of the enaminic tautomer 30 of amidines 3
with the loss of methanol.
The structure of compounds 4 was assigned on the basis of 1D
and 2D spectroscopic data. HOESY 1H–13C experiment for com-
pound 4a showed a cross signal between the hydrogen atom of the
amino group and the carboxylate carbon atom, which suggests
a hydrogen bridge bonding between amino and carboxylate groups.
Table 2
2-Alkyliden-pyrrolin-3-ones 4 obtained (Scheme 2)
Entry
Compound
R2
Conditions
Yielda (%)
1
2
4a
4b
Et2
–(CH2)5–
Xylene, 140 ꢀC, 48 h
Toluene, 110 ꢀC, 168 h
76
66
OCH3
3
4c
Toluene, 110 ꢀC, 144 h
49
a
Yield of isolated compound by column chromatography.

F. Palacios et al. / Tetrahedron 65 (2009) 1119–1124
1121
compound 10a showed two doublets at 2.55 and 2.95 ppm with
Et2N
O
Br
2
, CHCl3, Δ
a coupling constant of JHH¼15.8 Hz corresponding to methylenic
NH
protons of C-5 of new formed oxazine ring, two double doublets at
CO2Me
2
2.62 and 2.81 ppm with coupling constants of JHH¼14.3 Hz and
3JHH¼5.3 Hz corresponding to exocyclic methylenic protons and
5
EtO2C
3
a triplet at 5.48 ppm with coupling constant of JHH¼5.3 Hz corre-
N
N
Et2N
, CHCl3
CO2Et
sponding to methynic proton of C-2 of oxazine ring. HMBC exper-
iment for compound 10a showed cross signals between the
exocyclic methylenic protons and the C-2 of oxazine ring. Moreover,
cross signals were observed between the methylenic protons of C-5
with the iminic carbon and the quaternary carbon C-6 of the oxa-
zine ring.
EtO2C
NH
N
HN
EtO2C
CO2Me
O
6
MeO2C
NEt2
NH
NEt2
NH
, CHCl3
DMAD
MeO2C
NR2
O
O
CO2Me
7
CO2Me
NEt2
NH
CO2Me
N
O
4a
CO2Et
CO2Et
MeO2C
CO2Et
1. MeLi, THF
11
NR2
NR2
O
2.
CO2Et, Δ
8
N
N
CO2Et
CO2Et
O
Ph
O
+
NH
O
NEt2
NH
CO2Et
EtO2C
CO2Et
CO2Et
10
1. Pyr, CCl4
3a,b
O
2. Ph-NCO, Δ
CO2Me
9
Scheme 3.
NR2
O
afforded adduct 8 in a regioselective fashion (Scheme 3, Table 3,
entry 4). A similar behaviour was observed when compound 4a
reacted with phenyl isocyanate, since no transformation was ob-
served through thermal treatment. However, the corresponding
pyrrolinone derivative 9 (Scheme 3, Table 3, entry 5) was obtained
when the reaction was performed in refluxing CCl4 and in the
presence of 1 equiv of pyridine.
NR2
HN
CO2Et
CO2Et
CO2Et
HN
EtO2C
O
O
OEt
12
CO2Et
3'
Scheme 4.
2.4. Reactivity of N-vinylic amidines 3 with diethyl
ketomalonate: synthesis of 1,3-oxazine derivatives
Formation of compounds 10 could be explained by the nucleo-
philic addition of methylenic carbon of compound 30 to carbon-
ylic group of diethyl ketomalonate to give intermediate 12, which
cyclizes intramolecularly to lead to compound 10. As far as we
know, this strategy represents the first example of the preparation
of the previously unknown, 2,3,4,5-tetrahydro[1,3]oxazine de-
rivatives 10.
Previously, we had described the reaction of 2-azadienes with
ethyl glyoxalate and diethyl ketomalonate for the synthesis of
oxazine type derivatives.12d,16 Now, we explored whether N-vinylic
amidines 3 showed either a reactivity pattern as heterodienes (III,
Fig. 1, vide supra) or as enamines (IV, Fig. 1, vide supra) with some
carbonyl derivatives. In this case the reaction of azadienes 3 with
ethyl glyoxalate was inefficient. Indeed, even on prolonged heating
and at higher temperature no significant cycloaddition was
observed.
3. Conclusion
In conclusion, N-vinylic amidines derived from b-amino esters 3
can be readily prepared with very high yields by conjugated addi-
However, reaction of conjugated amidines 3a,b with ethyl
ketomalonate at room temperature in CHCl3 gave 1,3-oxazine de-
rivatives 10a,b, respectively (Scheme 4), in moderate yields (37%
and 42%, respectively), instead of the corresponding [4þ2] cyclo-
adducts 11. The structure of compounds 10 was assigned on the
basis of the 1D and 2D spectroscopy, including HMQC and HMBC
experiments and mass spectral data. The 1H NMR spectrum of
tion of N-unsubstituted amidines to acetylenic compounds. The
new family of conjugated amidines derived from b-amino esters
may be important synthons in organic synthesis in the preparation
of heterocycles. N-Vinylic amidines 3 containing a carboxylate
group in position 3 cyclize to 5-amino-4-pyrrolin-3-ones 4. These
compounds (4) present an enaminone character reacting with
electrophilic reactivities through the C-4 to give a wide range of
functionalized pyrrolinone derivatives 5–9. The reaction of conju-
gated amidines 3 with ethyl ketomalonate gives new oxazine de-
rivatives 10.
Table 3
Compounds 5–9 produced via Scheme 3
Entry
Compound
Conditions
Yielda (%)
38
1
2
3
4
5
5
6
7
8
9
CHCl3, 60 ꢀC, 24 h
CHCl3, 20 ꢀC, 24 h
CHCl3, 20 ꢀC, 144 h
THF, 65 ꢀC, 24 h
CCl4, 75 ꢀC, 72 h
4. Experimental
4.1. General
42
b
40
42
a
Chemicals were purchased from Aldrich, Lancaster and Acros
Chemical Companies. Solvents for extraction and chromatography
Yield of isolated compound by column chromatography.
A mixture of Z isomer (21%) and E isomer (16%) was obtained.
b

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F. Palacios et al. / Tetrahedron 65 (2009) 1119–1124
3
were technical grade. All solvents used in reactions were freshly
distilled from appropriate drying agents before use. All other re-
agents were recrystallized or distilled as necessary. All reactions
were performed under an atmosphere of dry nitrogen. Analytical
TLC was performed with Merck silica gel 60 F254 and aluminium
oxide N/UV254 plates. Visualization was accomplished by UV light.
Flash chromatography was carried out using Merck silica gel 60
(230–400 mesh ASTM). Melting points were determined with an
Electrothermal IA9100 Digital Melting Point Apparatus and are
uncorrected. 1H (400 MHz, 300 MHz, 250 MHz) and 13C (100 MHz,
75 MHz), spectra were recorded on a Bruker Avance 400 MHz and
a Varian VXR 300 MHz spectrometer using CDCl3 or CD3OD solu-
NMR (300 MHz, CDCl3)
d
:
1.17 (t, JHH¼7.2 Hz, 6H), 1.27 (t,
3JHH¼7.2 Hz, 3H), 2.12 (s, 3H), 3.44–3.50 (m, 4H), 4.16 (q,
3JHH¼7.2 Hz, 2H), 5.50 (d, JHH¼12.6 Hz, 1H), 8.11 (d, JHH¼12.6 Hz,
3
3
1H). 13C NMR (75 MHz, CDCl3)
152.8, 162.6, 169.8.
d: 13.3, 13.7, 14.5, 42.8, 59.1, 105.2,
4.3.2. (1E,3E/1E,3Z)-4-Ethoxycarbonyl-1-methyl-N-piperidyl-
2-azabuta-1,3-diene (3b)
The general procedure was followed using acetamidine 1b
(0.63 g) and ethyl propiolate (0.51 mL) at 20 ꢀC for 24 h. Evapora-
tion of solvent to reduced pressure gave 3b as a mixture of isomers
1E,3E/1E,3Z (35/65, 95% of consumption of the starting material by
NMR analysis of crude reaction mixture). Spectroscopic data of
crude reaction mixture [(1E,3E and 1E,3Z) 3b]: 1H NMR (300 MHz,
tions with TMS as an internal reference (
d
¼0.00 ppm) for 1H and
13C NMR spectra. Chemical shifts (
d) are reported in parts per
3
3
million. Coupling constants (J) are reported in hertz. Low-resolu-
tion mass spectra (MS) were obtained at 50–70 eV by electron
impact (EIMS) on a Hewlett Packard 5971 or 5973 spectrometer.
Data are reported in the form m/z (intensity relative to base¼100).
HRMS were recorded on a MAT95S mass spectrometer. Infrared
spectra (IR) were taken on a Nicolet IRFT Magna 550 spectrometer,
and were obtained as solids in KBr or as neat oils. Peaks are
CDCl3)
d
: 1.23 (t, JHH¼7.2 Hz, 6H), 1.26 (t, JHH¼7.2 Hz, 6H), 1.42–
1.73 (m, 12H), 2.03 (s, 3H), 2.11 (s, 3H), 3.43–3.68 (m, 8H), 4.08–4.17
3
3
(m, 4H), 4.98 (d, JHH¼8.4 Hz, 1H), 5.50 (d, JHH¼12.7 Hz, 1H), 7.22
(d, 3JHH¼8.4 Hz, 1H), 8.10 (d, 3JHH¼12.7 Hz, 1H).
When the general procedure was followed at 60 ꢀC for 4 h,
isomer 1E,3E of 3b was obtained (90% of consumption of the
starting material by NMR analysis of crude reaction mixture). 1H
reported in cmꢁ1
.
NMR (300 MHz, CDCl3)
d
: 1.26 (t, JHH¼7.2 Hz, 6H), 1.42–1.63 (m,
3
3
6H), 2.11 (s, 3H), 3.43–3.62 (m, 4H), 4.15 (q, JHH¼7.2 Hz, 2H), 5.50
3
3
4.2. Preparation of N-[2-(S)-methoxymethylpyrrolidinyl]-
acetamidine (1c)
(d, JHH¼12.7 Hz, 1H), 8.10 (d, JHH¼12.7 Hz, 1H). 13C NMR
(75 MHz, CDCl3)
162.3, 169.4.
d: 14.3, 14.5, 24.4, 25.7, 46.1, 58.9, 105.3, 152.6,
Compound 1c was synthesized according to the literature pro-
cedure14 using 15 mmol (1.48 g) of CuCl, 90.0 mmol (7.89 mL) of
acetonitrile and (1.73 mL) of (S)-(þ)-2-methoxymethylpirrolidine.
The mixture was refluxed during 20 h. Yield: 0.93 g (40%) as brown
4.3.3. (1E,3E)-1-Diethylamino-1-methyl-3,4-dimethoxycarbonyl-
2-azabuta-1,3-diene (3c)
The general procedure was followed using acetamidine 1a (0.
57 g) and DMAD (0.61 mL) at ꢁ15 ꢀC for 4 h. Evaporation of solvent
to reduced pressure gave 3c (97% of consumption of the starting
material by NMR analysis of crude reaction mixture). Spectroscopic
oil. IR (KBr)
n . d:
3386, 1620, 15 cmꢁ1 1H NMR (300 MHz, CDCl3)
1.89–2.03 (m, 4H), 2.11 (s, 3H), 3.24–3.32 (m, 2H), 3.35 (s, 3H), 3.37–
3.44 (m, 2H), 3.98–4.05 (m, 1H), 4.90 (s, 1H). 13C NMR (100 MHz,
20
CDCl3)
d
: 23.3, 23.7, 28.3, 47.5, 57.1, 58.9, 73.2, 163.2. [
a
]
ꢁ36.5 (c
data of crude reaction mixture: 1H NMR (300 MHz, CDCl3)
d: 1.21 (t,
D
5.5 mg/mL, CH2Cl2). MS (EI) m/z (%) 156 (Mþ, 7).
3JHH¼7.2 Hz, 6H), 1.89 (s, 3H), 3.35–346 (m, 4H), 3.65 (s, 3H), 3.78 (s,
3H), 6.04 (s, 1H). 13C NMR (75 MHz, CDCl3)
50.7, 52.4, 103.1, 151.0, 157.3, 166.4, 166.9.
d: 13.3 (m), 15.5, 42.7,
4.3. General procedure for the preparation of N-vinylic
amidines 3
4.3.4. (1E,3E)-1-Methyl-3,4-dimethoxycarbonyl-1-N-piperidyl-2-
azabuta-1,3-diene (3d)
A solution of acetylenic ester (5 mmol) in CHCl3 (5 mL) was
added drop wise to a solution of amidine 1 (5 mmol) in CHCl3
(10 mL) under N2 and was stirred to adequate temperature until
TLC indicated the disappearance of amidine. Evaporation of solvent
to reduced pressure afforded N-vinylic amidines 3. The reaction
product is unstable during distillation and/or chromatography and
was used without purification for the following reactions.
The general procedure was followed using acetamidine 1b
(0.63 g) and DMAD (0.61 mL) at ꢁ15 ꢀC for 2 h. Evaporation of
solvent to reduced pressure gave 3d (95% of consumption of the
starting material by NMR analysis of crude reaction mixture).
Spectroscopic data of crude reaction mixture: 1H NMR (300 MHz,
CDCl3) d: 1.55–1.67 (m, 6H), 1.87 (s, 3H), 3.56–3.68 (m, 4H), 3.65 (s,
3H), 3.78 (s, 3H), 6.05 (s, 1H). 13C NMR (75 MHz, CDCl3)
25.6, 46.2, 50.8, 52.6, 103.0, 151.1, 158.2, 166.5, 166.8.
d: 15.7, 24.2,
4.3.1. (1E,3E/1E,3Z)-4-Ethoxycarbonyl-1-dietylamino-1-methyl-
2-azabuta-1,3-diene (3a)
The general procedure was followed using acetamidine 1a
(0.57 g) and ethyl propiolate (0.51 mL) at 20 ꢀC for 24 h. Evapora-
tion of solvent to reduced pressure gave 3a as a mixture of isomers
1E,3E/1E,3Z (20/80, 98% of consumption of the starting material by
NMR analysis of crude reaction mixture). Spectroscopic data of
4.3.5. (1E,3E)-1-Methyl-1-[2-(S)-methoxymethylpirrolidyl]-3,4-
dimetoxycarbonyl-2-azabuta-1,3-diene (3e)
The general procedure was followed using N-[2-(S)-methoxy-
methylpyrrolidinyl]-acetamidine 1c (0.78 g) and DMAD (0.61 mL)
at ꢁ15 ꢀC for 4 h. Evaporation of solvent to reduced pressure gave
3e (90% of consumption of the starting material by NMR analysis of
crude reaction mixture). Spectroscopic data of crude reaction
crude reaction mixture [(1E,3E and 1E,3Z) 3a]: 1H NMR (300 MHz,
3
CDCl3)
d
: 1.17 (t, JHH¼7.2 Hz, 6H) for isomer 3E, 1.19–1.25 (m, 9H)
for isomer 3Z, 1.27 (t, 3JHH¼7.2 Hz, 3H) for isomer 3E, 2.05 (s, 3H) for
isomer 3Z, 2.12 (s, 3H) for isomer 3E, 3.43–3.50 (m, 8H), 4.10–4.21
mixture: 1H NMR (300 MHz, CDCl3)
3H), 3.24–3.39 (m, 2H), 3.40–3.59 (m, 2H), 3.66 (s, 3H), 3.79 (s, 3H),
4.12 (s, 1H), 6.07 (s, 1H). 13C NMR (75 MHz, CDCl3)
: 16.8, 23.6, 27.7,
d: 1.89–2.15 (m, 4H), 2.05 (s,
3
(m, 4H), 4.97 (d, JHH¼8.3 Hz, 1H) for isomer Z, 5.50 (d,
d
3JHH¼12.6 Hz, 1H) for isomer E, 7.19 (d, 3JHH¼8.3 Hz, 1H) for isomer
47.9, 50.6, 52.4, 57.2, 58.8, 76.0, 103.3, 150.7, 156.8, 166.1, 166.6.
Z, 8.11 (d, 3JHH¼12.6 Hz, 1H) for isomer E. 13C NMR (75 MHz, CDCl3)
d
: 13.3, 13.5, 13.7, 14.4, 14.5, 42.6, 42.8, 58.9, 59.1, 105.1, 105.2, 150.2,
4.4. General procedure for preparation of 5-amino-4-
pyrrolin-3-ones 4
152.7, 152.8, 162.6, 167.0, 169.8.
When the general procedure was followed at 60 ꢀC for 24 h,
isomer 1E,3E of 3a was obtained (95% of consumption of the
starting material by NMR analysis of crude reaction mixture). 1H
A solution of compound 3 (5 mmol) in toluene or xylene (15 mL)
under N2, was refluxed until TLC indicated the disappearance of

F. Palacios et al. / Tetrahedron 65 (2009) 1119–1124
1123
compound 3. Evaporation of solvent and chromatographic sepa-
ration (silica gel, ethyl acetate) gave compounds 4.
1730, 1663 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
: 1.26 (t, 3JHH¼7.2 Hz,
6H), 1.30–1.34 (m, 6H), 3.42–3.63 (m, 4H), 3.77 (s, 3H), 4.20 (q,
3JHH¼7.2 Hz, 4H), 5.80 (s, 1H), 7.67 (s, 1H), 8.68 (s, 1H). 13C NMR
4.4.1. (2Z)-5-Diethylamino-2-(1-methoxycarbonylmethylene)-
1,2-dihydropyrrol-3-one (4a)
The general procedure was followed using 3c (1.28 g) in xylene
for 48 h. Compound 4a (0.85 g, 76%) was obtained as a brown solid;
(75 MHz, CDCl3) d: 13.7, 14.4, 44.1, 51.8, 61.7, 63.3, 92.5, 101.2, 145.6,
156.1,157.1,158.9,169.5,176.9. EM (CI, 90 V): 399 (Mþþ1,100). Calcd
for C17H26N4O7 [Mþ] 398.1802, found [Mþ] 398.1805.
mp 167–168 ꢀC (hexane/CH2Cl2). IR (KBr)
n
3393,1661,1594 cmꢁ1.1H
4.5.3. (2Z)-5-Diethylamino-4-(1,2-dimethoxycarbonyl-ethenyl)-2-
(1-methoxycarbonylmethylene)-1,2-dihydropyrrol-3-one (7)
3
NMR (300 MHz, CDCl3)
d
: 1.31 (t, JHH¼7.1 Hz, 6H), 3.41 (q,
3JHH¼7.1 Hz, 4H), 3.77 (s, 3H), 4.64 (s,1H), 5.80 (s,1H), 8.61 (s,1H).13
C
The general procedure was followed using DMAD (0.27 mL) at
room temperature for 144 h. Chromatographic separation (silica
gel, 1:1, pentane/ethyl acetate) gave 0.15 g (21%) of Z isomer of 7 as
a brown oil. Rf¼0.50 (ethyl acetate) and 0.12 g (16%) of E isomer of
7 as a brown oil. Rf¼0.43 (ethyl acetate). Spectroscopic data for Z
NMR (75 MHz, CDCl3) d: 13.0, 14.1, 43.5, 45.9, 51.7, 80.6, 91.4, 149.5,
166.0,169.8,180.9. MS (EI) m/z (%) 224 (Mþ,10). Calcd for C11H16N2O3
[Mþ] 224.1161, found [MþꢁMeOH] 192.0889.
4.4.2. (2Z)-2-(1-Methoxycarbonylmethylene)-5-(N-piperidyl)-1,2-
dihydropyrrol-3-one (4b)
isomer: IR (KBr)
n
3383, 1730, 1578 cmꢁ1. 1H NMR (300MHz, CDCl3)
3
3
d
: 1.30 (t, JHH¼7.2 Hz, 6H), 3.55 (q, JHH¼7.2 Hz, 4H), 3.74 (s, 3H),
The general procedure was followed using 3d (1.34 g) in toluene
for 168 h. Compound 4b (0.78 g, 66%) was obtained as a brown
3.78 (s, 3H), 3.83 (s, 3H), 5.85 (s, 1H), 6.01 (s, 1H), 8.86 (s, 1H). 13C
NMR (75 MHz, CDCl3) : 13.4, 44.8, 51.8, 51.9, 52.6, 93.1, 121.5,
d
solid; mp 164–165 ꢀC (hexane/ethyl acetate). IR (KBr)
n
3387, 1672,
: 1.67–1.80 (m, 6H), 3.43–
3.45 (m, 4H), 3.77 (s, 3H), 4.71 (s, 1H), 5.80 (s, 1H), 8.61 (s, 1H). 13C
138.5, 146.5, 163.5, 165.9, 168.1, 169.6, 179.3. EM (CI, 90 V): 367
(Mþþ1, 95). Calcd for C17H22N2O7 [Mþ] 366.1427, found [Mþ]
366.1443.
1584 cmꢁ1 1H NMR (300 MHz, CDCl3)
. d
NMR (75 MHz, CDCl3)
d
: 23.6, 25.4, 48.7, 51.6, 80.9, 91.9,149.6,165.7,
Spectroscopic data for E isomer: IR (KBr) n 3384, 1722, 1663,
169.7, 181.1. MS (EI) m/z (%) 236 (Mþ, 8). Calcd for C12H16N2O3 [Mþ]
236.1161, found [MþꢁMeOH] 204.0897.
1596 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
: 1.30 (t, JHH¼7.2 Hz, 6H),
3
3.43 (q, 3JHH¼7.2 Hz, 4H), 3.73 (s, 3H), 3.77 (s, 3H), 3.79 (s, 3H), 5.83
(s, 1H), 6.92 (s, 1H), 8.80 (s, 1H). 13C NMR (75MHz, CDCl3)
d: 13.5,
4.4.3. (2Z)-2-(1-Methoxycarbonylmethylene)5-[N-(2-(S)-
methoxymethyl)pyrrolidinyl]-1,2-dihydropyrrol-3-one (4c)
The general procedure was followed using 3e (1.49 g) in toluene
for 144 h. Compound 4c (0.65 g, 49%) was obtained as a brown oil.
44.8, 51.7, 51.8, 52.8, 92.6, 128.3, 136.0, 147.4, 163.2, 165.6, 167.2,
169.7, 178.2. EM (CI, 90 V): 367 (Mþþ1, 100). Calcd for C17H22N2O7
[Mþ] 366.1427, found [Mþ] 366.1427.
Rf¼0.23 (10:1, ethyl acetate/methanol). IR (KBr)
n
3399, 1702, 1666,
4.6. Procedure for preparation of (2Z)-5-diethylamino-4-[(E)-
2-methoxycarbonylethenyl)-2-(1-methoxycarbonyl-
methylene)-1,2-dihydropyrrol-3-one] (8)
1578 cmꢁ1 1H NMR (300 MHz, CDCl3)
.
d
: 1.77–1.83 (m, 1H), 1.99–
2.07 (m, 2H), 2.13–2.20 (m, 1H), 3.41–3.45 (m, 2H), 3.47 (s, 3H),
3
3.50–3.56 (m, 2H), 3.76 (s, 3H), 4.20 (t, JHH¼8.8 Hz, 1H), 4.58 (s,
1H), 5.74 (s, 1H), 9.70 (s, 1H). 13C NMR (75 MHz, CDCl3)
d
: 23.6, 28.7,
To a solution of compound 4a (0.45 g, 2 mmol) in THF (10 mL)
at ꢁ78 ꢀC under N2, MeLi (2.75 mL, 4.4 mmol) was added and the
mixture was stirred for 1 h. The reaction was warmed to 0 ꢀC and
a solution of methyl propiolate (0.18 mL, 2 mmol) in THF (5 mL) was
added. The mixture was stirred to 65 ꢀC for 24 h. The crude reaction
mixture was washed with water, extracted with CH2Cl2 and dried
over MgSO4. Evaporation of solvent and chromatographic separa-
tion (silica gel, 1:2 pentane/ethyl acetate) gave compound 8 (0.25 g,
20
50.1, 51.2, 58.8, 60.0, 75.9, 81.3, 92.3, 149.0, 167.1, 168.3, 181.5. [a]
D
ꢁ153.3 (c 0.3 mg/mL, CH2Cl2). MS (EI) m/z (%) 266 (Mþ, 8). Calcd for
C13H18N2O4 [Mþ] 266.1267, found [MþꢁMeOH] 234.1011.
4.5. General procedure for preparation of 4-substituted
pyrrolinones 5–7
To a solution of compound 4a (0.45 g, 2 mmol) in CHCl3 (15 mL)
to 0 ꢀC under N2, electrophilic reactive (2 mmol) was added and the
mixture was stirred to adequate temperature until TLC indicated
the disappearance of compound 4a. Evaporation of solvent and
chromatographic separation (silica gel, ethyl acetate) gave com-
pound 5, 6 or 7.
40%) as a red oil. Rf¼0.30 (2:1, ethyl acetate/pentane). IR (KBr)
n
3367, 1695, 1664, 1583 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d: 1.44 (t,
3JHH¼7.2 Hz, 6H), 3.63 (q, 3JHH¼7.2 Hz, 4H), 3.73 (s, 3H), 3.79 (s, 3H),
3
3
5.85 (s, 1H), 7.03 (d, JHH¼15.0 Hz, 1H), 7.53 (d, JHH¼15.0 Hz, 1H),
9.00 (s, 1H). 13C NMR (75 MHz, CDCl3)
d: 13.6, 46.1, 51.1, 51.9, 92.5,
93.2, 111.6, 134.1, 146.3, 162.8, 169.7, 170.1, 180.4. EM (CI, 90 V) m/z:
308 (Mþþ1, 100). Calcd for C15H20N2O5 [Mþ] 308.1372, found [Mþ]
308.1389.
4.5.1. (2Z)-5-Diethylamino-2-(1-methoxycarbonylmethylene)-4-
(2-propinyl)-1,2-dihydropyrrol-3-one (5)
The general procedure was followed using propargyl bromide
(2.72 mL) and the reaction was warmed to 60 ꢀC for 24 h. Com-
pound 5 (0.20 g, 38%) was obtained as a brown oil. Rf¼0.43 (ethyl
4.7. Procedure for preparation of (2Z)-5-diethylamino-
2-(1-methoxycarbonylmethylene)-4-(phenylcarbamoyl)-
1,2-dihydropyrrol-3-one (9)
acetate). IR (KBr)
(300 MHz, CDCl3)
n .
3405, 3280, 1689, 1664 cmꢁ1 1H NMR
3
4
d
: 1.37 (t, JHH¼7.2 Hz, 6H), 1.99 (t, JHH¼2.6Hz,
To a solution of compound 4a (0.45 g, 2 mmol) in CCl4 (10 mL) at
0 ꢀC under N2, pyridine (0.18 mL, 2.2 mmol) and a solution of
phenylisocyanate (0.24 mL, 2.2 mmol) in CCl4 (5 mL) were added
and the mixture was refluxed for 72 h. The crude reaction mixture
was washed with HCl 1 M, water, extracted with CH2Cl2 and dried
over MgSO4. Evaporation of solvent and chromatographic separa-
tion (silica gel, 1:1 pentane/ethyl acetate) gave compound 9 (0.29 g,
42%) as a yellow solid. Mp 170–171 ꢀC (pentane/ethyl acetate). IR
4
3
1H), 3.30 (d, JHH¼2.6Hz, 2H), 3.64 (q, JHH¼7.2 Hz, 4H), 3.77 (s,
3H), 5.81 (s, 1H), 8.55 (s, 1H). 13C NMR (75 MHz, CDCl3)
d
: 12.5, 14.7,
45.1, 51.9, 68.3, 83.7, 89.3, 92.1, 147.8, 163.5, 170.1, 180.6. EM (CI,
90 V): 263 (Mþþ1, 100). Calcd for C14H18N2O3 [Mþ] 262.1317, found
[Mþ] 262.1314.
4.5.2. (2Z)-5-Diethylamino-4-(N,N0-diethoxycarbonyl-hidrazino)-
2-(1-methoxycarbonylmethylene)-1,2-dihydropyrrol-3-one (6)
The general procedure was followed using DEAD (0.34 mL) at
room temperature for 24 h. Compound 6 (0.33 g, 42%) was obtained
(KBr)
n d: 1.41 (t,
3361, 1670, 1576 cmꢁ1. 1H NMR (300 MHz, CDCl3)
3JHH¼7.2 Hz, 6H), 3.81 (s, 3H), 3.79–3.87 (m, 4H), 5.91 (s,1H), 7.05 (t,
3JHH¼7.5 Hz, 1H), 7.29 (dd, JHH¼8.5 Hz, JHH¼7.5 Hz, 2H), 7.61 (d,
3
3
as a yellow oil. Rf¼0.26 (1:1, ethyl acetate/pentane). IR (KBr)
n 3383,
3JHH¼8.5 Hz, 2H), 9.14 (s, 1H), 10.85 (s, 1H). 13C NMR (75 MHz,

1124
F. Palacios et al. / Tetrahedron 65 (2009) 1119–1124
CDCl3)
d
: 13.5, 47.2, 52.0, 93.4, 120.3, 123.1, 128.7, 129.0, 139.1, 146.0,
References and notes
161.3, 164.4, 169.4, 181.0. EM (CI, 90 V): 344 (Mþþ1, 27). Calcd for
C15H20N2O5 [Mþ] 343.1532, found [Mþ] 343.1525.
1. For an excellent review of pyrroline derivatives, see: Bellina, F.; Rossi, R.
Tetrahedron 2006, 62, 7213–7256.
2. For recent contributions of pyrrolinones, see: (a) Sultan, M. Z.; Park, K.; Lee, S. Y.;
Park, J. K.; Varughese, T.; Moon, S. S. J. Antibiot. 2008, 61, 420–425; (b) Erden, I.;
Ozer, G.; Hoarau, C.; Cao, W.; Song, J.; Gartner, C.; Baumgardt, I.; Butenschon, H.
J. Org. Chem. 2008, 73, 6943–6945; (c) Gein, V. L.; Kasinova, N. N.; Moissev, A. L.;
Sheptukha, M. A.; Syropyatov, B. Y.; Ismailova, N. G.; Voronina, E. V.; Ivanenko, O. I.
Pharm. Chem. J. 2007, 41, 476–479; (d) Huang, J.; Liang, Y.; Pan, W.; Yang, Y.; Dong,
D. Org. Lett. 2007, 9, 5345–5348; (e) Gein, V. L.; Yushkov, V. V.; Voronina, E. V.;
Rakshina, N. S.; Vasil’eva, M. Y. Pharm. Chem. J. 2007, 41, 256–263.
3. For reviews about bioactive tetramic acid derivatives, see: (a) Schobert, R.;
Schlenk, A. Bioorg. Med. Chem. 2008, 16, 4203–4221; (b) Huang, P.-Q. Synlett
2006, 1133–1149; (c) Ghisalberti, E. L. Bioactive Natural Products (Part I). In
Studies in Natural Products Chemistry; Rahman, A.-u., Ed.; Elsevier: Amsterdam,
2003; Vol. 28, pp 109–163; (d) Royles, B. J. L. Chem. Rev. 1995, 95, 1981–2001.
4. For recent contributions about tetramic acid antibiotics, see: (a) Iwata, Y.;
Maekawara, N.; Tanino, K.; Miyashita, M. Angew. Chem., Int. Ed. 2005, 44, 1532–
1536; (b) Segeth, M. P.; Bonnefoy, A.; Bronstrup, M.; Knauf, M.; Schummer, D.;
Toti, L.; Vetrtesy, L.; Wetzel-Raynal, M. C.; Wink, J.; Seibert, G. J. Antibiot. 2003,
56, 114–122; (c) Michael, A. P.; Grace, E. J.; Kotiw, M.; Barrow, R. A. J. Nat. Prod.
2002, 65, 1360–1362; (d) Holtzel, A.; Ganzle, M. G.; Nicholson, G. J.; Hammes,
W. P.; Jung, G. Angew. Chem., Int. Ed. 2000, 39, 2766–2768.
5. For reviews, see: (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassiliko-
giannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698; (b) Jayakumar, S.;
Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379–471; (c) Buonora, P.;
Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099–6138.
6. (a) Jnoff, E.; Ghosez, L. J. Am. Chem. Soc. 1999, 121, 2617–2618; (b) Bandini, E.;
Martelli, G.; Spunta, G.; Bongini, A.; Panunzio, M. Synlett 1999, 1735–1738; (c)
Ntirampebura, D.; Ghosez, L. Tetrahedron Lett.1999, 40, 7079–7082; (d) Ghosez, L.
Pure Appl. Chem. 1996, 68, 15–22.
7. For reviews, see: (a) Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433–2480; (b)
Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42, 975–978; (c) Elassar, A. Z. A.; El-
Khair, A. A. Tetrahedron 2003, 59, 8463–8480; (d) Rappoport, Z. The Chemistry
of Enamines. In The Chemistry of Functional Groups; Patai, S., Rappoport, Z., Eds.;
J. Wiley: Chichester, UK, 1994.
8. (a) Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J.; Pascual, S.; Fernandez de
Troconiz, G. J. Org. Chem. 2008, 73, 4568–4574; (b) Palacios, F.; Ochoa de Retana,
A. M.; Pascual, S.; Oyarzabal, J. J. Org. Chem. 2004, 69, 8767–8774.
4.8. General procedure for the reaction of N-vinylic amidines
3 with diethyl ketomalonate
To a solution of compound 3 (2 mmol) in CHCl3 (10 mL) under
N2 was added diethyl ketomalonate (0.30 mL, 2 mmol) and the
mixture was stirred at room temperature for 24 h. Evaporation of
solvent and chromatographic separation (silica gel, 2:1, pentane/
ethyl acetate) gave compounds 10.
4.8.1. Diethyl 4-diethylamino-2-ethoxycarbonylmethyl-2,5-
dihydro-[1,3]oxazine-6,6-dicarboxylate (10a)
The general procedure was followed using 3a (0.42 g) and
compound 10a (0.28 g, 37%) was obtained as a yellow oil. Rf¼0.31
(2:1, hexane/ethyl acetate). IR (KBr)
n .
1739, 1627 cmꢁ1 1H NMR
3
(300 MHz, CDCl3)
d
: 1.09 (t, JHH¼7.0 Hz, 6H), 1.29–1.30 (m, 9H),
2.55 (d, 2JHH¼15.8 Hz, 1H), 2.62 (dd, 2JHH¼14.3 Hz, 3JHH¼5.3 Hz, 1H),
2.81 (dd, 2JHH¼14.3 Hz, 3JHH¼5.3 Hz, 1H), 2.95 (d, 2JHH¼15.8 Hz, 1H),
3
3
3.18 (q, JHH¼7.0 Hz, 2H), 3.38 (q, JHH¼7.0 Hz, 2H), 4.12–4.18 (m,
2H), 4.25–4.31 (m, 4H), 5.48 (t, 3JHH¼5.3 Hz, 1H). 13C NMR (75MHz,
CDCl3) d: 13.8, 13.9, 14.0, 14.2, 27.9, 41.1, 43.6, 60.1, 62.3, 62.4, 78.8,
83.9, 152.2, 167.9, 168.2, 170.4. MS (EI) m/z (%) 386 (Mþ, 6). Calcd for
C18H30N2O7 [Mþ] 386.2053, found [Mþ] 386.2049.
4.8.2. Diethyl 2-ethoxycarbonylmethyl-4-(N-piperidyl)-2,5-
dihydro-[1,3]oxazine-6,6-dicarboxylate (10b)
The general procedure was followed using 3b (0.45 g) and
compound 10b (0.33 g, 42%) was obtained as a yellow oil. Rf¼0.28
(2:1, hexane/ethyl acetate). IR (KBr)
n .
1739, 1633 cmꢁ1 1H NMR
9. (a) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org. Chem. 2005, 70,
8895–8901; (b) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Alonso, J. M.
Tetrahedron 2004, 60, 8937–8947.
10. (a) Palacios, F.; Vicario, J.; Aparicio, D. Eur. J. Org. Chem. 2006, 2843–2850; (b)
Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Alonso, J. M. Tetrahedron: Asym-
metry 2002, 13, 2541–2552.
11. (a) Palacios, F.; Aparicio, D.; Lopez, Y.; de los Santos, J. M.; Alonso, C. Eur. J. Org.
Chem. 2005, 1142–1147; (b) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.;
Lopez de Munain, R.; Oyarzabal, J.; Ezpeleta, J. M. Tetrahedron 2005, 61, 1087–
(300 MHz, CDCl3) d: 1.25–1.30 (m, 9H), 1.48–1.61 (m, 6H), 2.49 (d,
2JHH¼15.9 Hz, 1H), 2.62 (q, 2JHH¼14.3 Hz, 3JHH¼5.8 Hz, 1H), 2.79 (q,
3
2
2JHH¼14.3 Hz, JHH¼5.8 Hz, 1H), 2.95 (d, JHH¼15.9 Hz, 1H), 3.32–
3.40 (m, 4H), 4.22–4.35 (m, 6H), 5.44 (t, 3JHH¼5.8 Hz, 1H). 13C NMR
(75 MHz, CDCl3) d: 13.8, 13.9, 14.1, 24.7, 25.4, 27.7, 43.4, 44.9, 60.1,
62.2, 78.7, 83.6, 153.2, 167.8, 168.0, 170.2. MS (EI) m/z (%) 398 (Mþ,
´
1094; (c) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Lopez de Munain, R. Org.
8). Calcd for C19H30N2O7 [Mþ] 398.2053, found [Mþ] 398.2057.
Lett. 2002, 4, 2405–2408.
12. (a) Palacios, F.; Herra´n, E.; Rubiales, G.; Alonso, C. Tetrahedron 2007, 63, 5669–
5676; (b) Palacios, F.; Herra´n, E.; Rubiales, G.; Ezpeleta, J. M. J. Org. Chem. 2002,
67, 2131–2135; (c) Palacios, F.; Alonso, C.; Amezua, P.; Rubiales, G. J. Org. Chem.
2002, 67, 1941–1946; (d) Palacios, F.; Alonso, C.; Rubiales, G. J. Org. Chem. 1997,
62, 1146–1154.
Acknowledgements
´
The present work has been supported by the Direccion General de
13. Palacios, F.; Alonso, C.; Legido, M.; Rubiales, G.; Villegas, M. Tetrahedron Lett.
2006, 47, 7815–7818.
14. Rousselet, G.; Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1993, 34, 6395–6398.
15. Palacios, F.; Alonso, C.; Rubiales, G.; Villegas, M. Tetrahedron 2005, 61, 2779–2794.
16. Palacios, F.; Alonso, C.; Rubiales, G. Heterocycles 2003, 61, 493–503.
´
´
Investigacion del Ministerio de Ciencia y Tecnologıa (MCYT, Madrid
´
DGI, CTQ2006-09323) and by the Departamento de Educacion,
Universidades e Investigacion del Gobierno Vasco (IT-277-07). M.V.
thanks the Universidad del Paıs Vasco for a Predoctoral Fellowship.
´
´