An efficient synthesis of achiral and chiral cyclic dehydro-α-amino acid derivatives through nucleophilic addition of amines to β,γ- unsaturated α-keto esters

Article abstract of DOI:10.1002/ejoc.200600092

A very simple and efficient synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2- ones is reported. These cyclic dehydro-amino acid derivatives with a stereogenic center at the 5-position were obtained by the addition of two equivalents of amine to β,γ-unsaturate

Full text of DOI:10.1002/ejoc.200600092

FULL PAPER
DOI: 10.1002/ejoc.200600092
An Efficient Synthesis of Achiral and Chiral Cyclic Dehydro-α-Amino Acid
Derivatives Through Nucleophilic Addition of Amines to β,γ-Unsaturated
α-Keto Esters
Francisco Palacios,*[a] Javier Vicario,[a] and Domitila Aparicio[a]
Keywords: Dehydro-amino acids / Unsaturated keto esters / Cyclization / Enamines / Nucleophilic addition / Amines
A very simple and efficient synthesis of 3-amino-1,5-dihydro-
2H-pyrrol-2-ones is reported. These cyclic dehydro-amino
acid derivatives with a stereogenic center at the 5-position
were obtained by the addition of two equivalents of amine
to β,γ-unsaturated keto esters. These cyclic enamines can
also be obtained by the three-component reaction of ethyl
pyruvate, amines and aldehydes.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
1,5-Dihydro-2H-pyrrol-2-ones are an appealing family of the conjugate addition of amines to β,γ-unsaturated α-keto
lactams found as substructures in many natural products esters (Scheme 1).
with interesting pharmacological properties, such as the
lipopeptides microcolin A and B.[1] When an amino substit-
uent is present at the 3-position, these heterocycles are also
enamines, substrates that have attracted a great deal of at-
Results and Discussions
tention in recent years because of their range of applica-
tions.[2,3] In addition, these cyclic enamines are not only
susceptible to being further functionalized,[4] but they are
also an important family of compounds in organic and me-
dicinal chemistry, for example, the cyclic dehydro-α-amino
acid derivatives[5] and, therefore, α-amino acid sources with
an additional stereogenic center at the γ position.
Reaction of β,γ-Unsaturated α-Keto Esters 2 with Amines 3
The required β,γ-unsaturated α-keto esters 2 were pre-
pared by using strategies outlined in Scheme 2. Olefination
with aldehydes 4 was performed either by the Wittig–
Horner reaction starting from the phosphorylated α-keto
ester 5 derived from phosphane oxide[14] (Scheme 2,
route A) or by the Wittig reaction of the conjugated phos-
phorus ylide 6 using Le Corre’s method[15] (Scheme 2,
route B). The acid-catalyzed aldolic condensation of ethyl
pyruvate 7 and aldehydes 4[16] was also used to prepare α-
keto esters 2 (Scheme 2, route C).
The acid-catalyzed aldol reaction (route C, Scheme 2) is
the best choice when an aromatic aldehyde (p-nitrobenzal-
dehyde) is used, since lower yields were obtained with the
other two olefination approaches (Table 1, entry 1). The
yield dropped considerably in the case of a conjugated alde-
hyde (Table 1, entry 5) and dramatically when a heteroaro-
matic aldehyde (Table 1, entry 4) was used. No unsaturated
ketones 2 were observed when aliphatic aldehydes were
used. Attempts to improve the reactivity by addition of tri-
methyl orthoformate as a co-solvent to promote the dehy-
dration process were unsuccessful. Direct use of the conju-
gated phosphorus ylide 6 with aldehydes 4 improved the
yield (Scheme 2, route B) when 2-furylaldehyde was used
(Table 1, entry 4) and good yields were obtained in the Wit-
tig reaction with ethyl glyoxalate or acetaldehyde (Table 1,
entries 2 and 3). Note that by using any of the proposed
approaches only the (E)-alkene was obtained.
In this context, we are interested in the preparation of
three-,[6] five-[7] and six-membered[8] nitrogen heterocycles,
as well as in the synthesis of acyclic enamines or dehydro-
β-amino phosphorus derivatives[9] and their synthetic use in
the preparation of functionalized acyclic compounds[10,11]
and heterocycles.[12] As a continuation of our work on the
synthesis and reactivity of 1-azabutadienes[13] and en-
amines,[11] we report herein a very simple and efficient syn-
thesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones through
Scheme 1. Retrosynthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones
(1).
[a] Departamento de Química Orgánica I, Facultad de Farmacia,
Universidad del País Vasco,
Apartado 450, 01080 Vitoria-Gasteiz, Spain
E-mail: qoppagaf@vc.ehu.es
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F. Palacios, J. Vicario, D. Aparicio
FULL PAPER
Scheme 2. Synthetic strategies used for the synthesis of β,γ-unsaturated α-keto esters 2.
Table 1. Yields of the β,γ-unsaturated α-keto esters 2 prepared by consistent with an (E) configuration of the double bond.
1
the three approaches.
On the other hand, characteristic signals of 1aa in the H
Entry
Compd.
R1
Yield [%][a]
NMR spectrum are the two doublets at δ = 5.75 and
5.96 ppm, with a coupling constant JH,H = 2.4 Hz, corre-
3
1
2
3
4
5
2a
2b
2c
2d
2e
p-NO2-Ph
CO2Et
Me
2-furyl
(E)-CH2=CH–Ph
35,[b] 49,[c] 72[d]
77[c]
sponding to the protons at the stereogenic center and the
double bond, respectively, whereas the 13C NMR spectrum
shows characteristic signals at δ = 63.7 ppm for C-5, 105.5
and 138.6 ppm for the C-4 and C-3 enamine carbon atoms,
respectively, and 167.1 ppm for the amide C=O. The forma-
tion of both products can be explained by an initial amine/
carbonyl condensation to give 1-azadiene 8, which un-
dergoes conjugate addition of a second molecule of amine
to yield a γ-amino α-enamino ester 9. The enamine is ex-
pected to have an (E) configuration if the α,β-unsaturated
imine is in its more stable pseudo-trans conformation dur-
ing the addition of the amine. The 3-amino-1,5-dihydro-2H-
pyrrol-2-one (1aa) is obtained after the loss of ethanol
(Scheme 3). The participation of the functionalized azadi-
ene 8 in the formation of cyclic enamine 1 was also tested.
Reaction of 1-azadiene 8aa with one equivalent of p-tolu-
idine (3a) (R2 = p-Me-Ph) in the presence of Ti(OEt)4 and
H2SO4 also gave cyclic enamine 1aa (R1 = p-NO2-Ph, R2 =
p-Me-Ph) (Table 2, entry 1).
61[c]
55,[c] 10[d]
42[d]
[a] Isolated yield. [b] Method A. [c] Method B. [d] Method C.
In the course of our studies on the preparation of 1-aza-
dienes,[13] the condensation of β,γ-unsaturated α-keto esters
2 with amines 3 was explored. p-Toluidine (3a) (R1 = p-Me-
Ph) did not react with unsaturated carbonyl compounds 2
using Dean–Stark apparatus or with a dehydrating agent or
in the presence of Lewis acids [Yb(OTf)3, BF3, Ti(OEt)4]
and starting compounds were recovered. However, when
β,γ-unsaturated α-keto ester 2a (R1 = p-NO2-Ph) was
treated with one equivalent of p-toluidine (3a) (R2 = p-Me-
Ph) in the presence of an equimolecular amount of
Ti(OEt)4 and a catalytic amount of H2SO4, not only was
the 1-azadiene derived from α-amino ester 8aa (18%, R1 =
p-NO2-Ph, R2 = p-Me-Ph) obtained as an anti/syn mixture
of imines (60:40), but also a cyclic enamine 1aa (36%, R1
= p-NO2-Ph, R2 = p-Me-Ph) containing two amino groups
(Scheme 3).
Table 2. 3-Amino-1,5-dihydro-2H-pyrrol-2-ones 1 obtained in this
work.
Scheme 3. Synthesis of 1-azadiene 8 and cyclic amines 1.
[a] Isolated yield. [b] Yield obtained by the reaction of amines 3
with β,γ-unsaturated α-keto ester 2. [c] Yield obtained by the reac-
tion of amine 3 with 1-azadiene 8. [d] Yield obtained by the three-
component reaction.
Heterodiene 8aa and enamine 1aa were fully charac-
terized by 1H and 13C NMR, MS and IR spectroscopy.
1
Characteristic signals of 8aa in the H NMR spectrum are
Next, we tried to extend this process to the regioselective
the two doublets observed at δ = 7.47 and 6.76 ppm, with preparation of cyclic enamines[17,18] 1 by using an excess of
3
a coupling constant JH,H = 16.2 Hz, corresponding to the amine. Thus, when the reaction of β,γ-unsaturated α-keto
anti isomer, as well as another two doublets at δ = 7.02 and ester 2a (R1 = p-NO2-Ph) was performed with two equiva-
7.29 ppm, with a coupling constant JH,H = 16.3 Hz, which lents of p-toluidine (3a) (R2 = p-Me-Ph) in the presence of
3
correspond to the syn isomer. Both coupling constants are Ti(OEt)4 and H2SO4 and in refluxing CH2Cl2 only cyclic
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Achiral and Chiral Cyclic Dehydro-α-Amino Acid Derivatives
FULL PAPER
enamine 1aa (76%, R1 = p-NO2-Ph, R2 = p-Me-Ph) was zylamine (3d) in toluene at 110 °C and in the presence of
obtained (Scheme 3, Table 2, entry 1). By following a sim- Ti(OEt)4 and H2SO4 gave a 1:1 mixture of the two dia-
ilar procedure, a wide variety of cyclic α-dehydro-amino stereoisomers 13 and 14 with three stereogenic centers
acid derivatives 1 were prepared. Good yields were obtained (Scheme 5, Table 2, entry 8). Separation and isolation of the
when the substituent at the 5-position was an ester (Table 2, two optically pure isomeric cyclic enamines 13 and 14 were
entries 2-4), a methyl (Table 2, entry 5 and 6) or a furyl carried out by simple chromatography (see Expt. Sect.).
group (Table 2, entry 7).
Different behavior was observed when α-keto ester 2e
Taking into account the fact that β,γ-unsaturated α-keto containing two conjugated double bonds was used. The re-
ester 2a was obtained from ethyl pyruvate 7 and p-ni- action of the conjugate α-keto ester 2e with p-toluidine (3a)
trobenzaldehyde (see Scheme 2, vide supra), we next tried (Ar = p-Me-Ph) under the same conditions as described
to explore if dehydro-amino acid derivatives 1 could also above did not give cyclic enamine 1ea (Scheme 6); instead
be prepared by a three-component reaction involving ethyl 1,2-dihydropyridine 15 derived from an α-amino ester was
pyruvate 7, aldehydes 4 and amines 3. Reaction of a mix- obtained (81%). The formation of this heterocycle 15 can
ture of ethyl pyruvate 7, aldehyde 4 and two equivalents of be explained through the generation of the nonisolable 1-
amine 3 in CH2Cl2 at room temperature and with a catalytic azatriene 16 followed by a 6π-azaelectrocyclization.
amount of H2SO4 yielded dehydro-α-amino acid derivatives
1aa, 1ba, 1ca and 1da in excellent yields (Scheme 4, Table 2,
entries 1, 2, 5 and 7). The three-component reaction was
monitored by 1H NMR spectroscopy when p-toluidine (3a)
(R2 = p-Me-Ph) and p-nitrobenzaldehyde (4a) (R2 = p-NO2-
Ph) were used, and enamine 10 and imine 11 were detected
as intermediates. Therefore in this three-component process,
the formation of cyclic enamines 1 can be explained by the
initial formation of enamine 10 by condensation of ethyl
pyruvate 7 and amine 3 and subsequent imine–enamine tau-
tomerization (Scheme 4). The enamines 10 then reacted
with imines 11 generated by condensation of aldehydes 4
and amines 3, followed by intramolecular cyclocondensa-
tion of functionalized enamine 12 and the loss of ethanol.
The formation of enamines 10 and imines 11 is favored by
the presence of a catalytic amount of acid.
Scheme 6. Synthesis of 1,2-dihydropyridine 15.
The thermal cyclization of 1-azatrienes into 1,2-dihy-
dropyridines (6π-azaelectrocyclization) is a well-known
concerted pericyclic reaction.[19] The synthesis of 1,2-dihy-
dropyridines from primary amines and diunsaturated car-
bonyl compounds usually requires high temperatures and
the isolation of 1-azatriene intermediates involved is un-
common. Not many 6π-azaelectrocyclization reactions car-
ried out under mild conditions are described in the litera-
ture and it has been established that the orbital interaction
between the HOMO (C5–C6) and the LUMO (C1–C4) can
be improved if C6-phenyl or -alkenyl and C4- or C3-car-
bonylic substituents are present.[20] In our case the com-
Scheme 4. Proposed mechanism for the three-component reaction.
bined effect of an electron-withdrawing group in the 2-posi-
The process can also be extended to the formation of tion and a phenyl terminal substituent seems to activate the
optically pure dehydro-α-amino acid derivatives when chiral intramolecular 6π-azaelectrocyclization reaction with the
amines are used. The reaction of β,γ-unsaturated α-keto es- process favoring the electrocyclization of 2-azatrienes[21]
ter 2a (R1 = p-NO2-Ph) with enantiopure (R)-α-methylben- and 3-azatrienes.[22]
Scheme 5. Synthesis of the optically pure 1,5-dihydro-2H-pyrrol-2-ones 13 and 14.
Eur. J. Org. Chem. 2006, 2843–2850
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2845

F. Palacios, J. Vicario, D. Aparicio
FULL PAPER
phosphanylidene)propionate 6 (18.8 g, 50 mmol) and the corre-
sponding aldehyde (50 mmol) was refluxed in xylene (150 mL) or
stirred at room temp. in benzene (150 mL) for 3 h. The solvent
was evaporated under reduced pressure and the crude residue was
purified as indicated.
In conclusion, we have described herein an easy and ef-
ficient synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones
either through double nucleophilic addition of amines to
β,γ-unsaturated α-keto esters or by the three-component re-
action of ethyl pyruvate, aldehydes and amines. We have
shown that in the addition of amines to conjugated α-keto
esters, a 1-azadiene could be involved in the reaction and
that the mechanism of the reaction could involve sequential
1,2 addition of the amine to β,γ-unsaturated α-keto esters
and conjugate addition of the amine to the 1-azadiene fol-
lowed by spontaneous intramolecular cyclization. An exam-
ple of a 6π-azaelectrocyclization reaction of a function-
alized 1-azatriene under mild conditions has also been re-
ported. Note that pyridine compounds derived from α-
amino acids are useful heterocycles not only for their bio-
logical activity[23] but also because the pyridine nucleus is a
structural unit that appears in many natural products.[24]
Procedure C: Acid-catalyzed aldol condensation of ethyl pyruvate
7. Following a literature procedure,[16] a solution of ethyl pyruvate
7 (8.33 mL, 75 mmol), aldehyde (50 mmol) and Cu(OTf)2 (1.81 g,
5 mmol) in CHCl3 (150 mL) was stirred and refluxed for 7 d. The
resulting mixture was cooled to room temp. and filtered through
basic alumina and the homogeneous solution was evaporated under
reduced pressure. The crude residue was purified by crystallization
from EtOH.
Ethyl (E)-4-(p-Nitrophenyl)-2-oxobut-3-enoate (2a): Synthesized ac-
cording to general procedure A with p-nitrobenzaldehyde (7.56 g,
50 mmol), affording 4.35 g (35%) of 2a as a yellow solid. Synthe-
sized according to general procedure B with p-nitrobenzaldehyde
(7.56 g, 50 mmol) in xylene at 140 °C. The crude residue was puri-
fied by crystallization from EtOH, affording 6.10 g (49%) of 2a as
a yellow solid. Synthesized according to general procedure C with
p-nitrobenzaldehyde (7.56 g, 50 mmol), affording 8.96 g (72%) of
2a as a yellow solid. Physical and spectroscopic data are in agree-
ment with published data.[15]
Experimental Section
General: Chemicals were purchased from Aldrich or Acros. Sol-
vents for extraction and chromatography were technical grade. All
solvents used in reactions were freshly distilled from appropriate
drying agents before use. All other reagents were recrystallized or
distilled as necessary. All reactions were performed under dry nitro-
gen. Analytical TLC was performed with Merck silica gel 60 F254
plates. Visualization was accomplished using UV light. Flash
chromatography was carried out using Merck silica gel 60 (230–
400 mesh ASTM). Melting points were determined with an Elec-
trothermal IA9100 Digital Melting Point Apparatus and are uncor-
rected. NMR spectra were obtained using a Varian VXR 300 MHz
Ethyl (E)-4-Oxo-pent-2-enedioate (2b): Synthesized according to
general procedure B with ethyl glyoxalate (5.10 g, 50 mmol) in ben-
zene at room temp. The crude residue was purified by distillation
(86–88 °C, 10–3 Torr), affording 7.74 g (77%) of 2b as a yellow oil.
3
1H NMR (300 MHz, CDCl3, 30 °C): δ = 7.56 (d, JH,H = 6.0 Hz,
3
3
1 H, CH=), 6.92 (d, JH,H = 6.0 Hz, 1 H, CH=), 4.36 (d, JH,H
=
3
7.2 Hz, 2 H, CH2–O), 4.26 (d, JH,H = 7.2 Hz, 2 H, CH2–O), 1.37
3
3
(t, JH,H = 7.2 Hz, 3 H, CH3), 1.30 (t, JH,H = 7.2 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3, 30 °C): δ = 182.2 (C=O),
164.2 (C=O), 160.3 (C=O), 135.0 (CH), 133.7 (CH), 62.4 (CH2–
1
spectrometer operating at 300 and 80 MHz for H and 13C nuclei,
respectively. Chemical shifts are reported in δ units (ppm) relative
to the residual deuteriated solvent signals of CDCl3 (1H NMR: δ
= 7.26 ppm; 13C NMR: δ = 77.0 ppm) and coupling constants (J)
are reported in Hertz. Low-resolution mass spectra (MS) were ob-
tained at 50–70 eV by electron impact (EI-MS) with a Hewlett–
Packard 5971 or 5973 spectrometer and by chemical ionization (CI)
(N2) on a Hewlett-Packard 1100MSD instrument. Data are re-
ported in the form m/z (intensity relative to base×100). Infrared
spectra (IR) were recorded with a Nicolet IRFT Magna 550 spec-
trometer as solids in KBr or as neat oils. Peaks are reported in
cm–1. Elemental analyses were performed with a LECO CHNS-932
apparatus.
O), 61.2 (CH –O), 13.5 (CH ), 13.4 (CH ) ppm. IR (KBr): ν =
˜
max
2
3
3
1738 (br s, C=O ester + ketone) cm–1. EI-MS: m/z = 200 (10)
[M]+, 127 (100) [M – CO2Et]+. C9H12O5 (200.1): calcd. C 54.00, H
6.04; found: C 53.95, H 6.08.
Ethyl (E)-2-Oxopent-3-enoate (2c): Synthesized according to gene-
ral procedure B with acetaldehyde (2.81 mL, 50 mmol) in xylene at
140 °C. The crude residue was purified by distillation (42–45 °C,
10–3 Torr), affording 5.34 g (61%) of 2c as a pale yellow oil. Physi-
cal and spectroscopic data are in agreement with published data.[25]
Ethyl (E)-4-(Furan-2-yl)-2-oxobut-3-enoate (2d): Synthesized ac-
cording to general procedure B with 2-furfural (4.14 mL, 50 mmol)
in xylene at 140 °C. The crude residue was purified by crystalli-
zation from EtOH, affording 5.34 g (55%) of 2d as a pale brown
solid. Synthesized according to general procedure C with 2-furfural
(4.14 mL, 50 mmol), affording 0.91 g (10%) of 2d as a yellow solid.
Physical and spectroscopic data are in agreement with published
data.[26]
General Procedure for the Synthesis of β,γ-Unsaturated α-Keto Es-
ters 2
Procedure A: Wittig–Horner reaction of β-ketophosphane oxide 5.
Following a literature procedure,[14] a solution of ethyl 3-(diphenyl-
phosphinoyl)-2-oxopropionate (5, 15.8 g, 50 mmol) in THF
(100 mL) was added to a suspension of NaH (1.24 g, 50 mmol) in
THF (100 mL) at 0 °C. The mixture was stirred at this temperature
for 1 h and then a solution of the corresponding aldehyde
(50 mmol) in THF (50 mL) was added. After allowing the mixture
to warm to room temp., the reaction was stirred overnight. The
mixture was then diluted with water (200 mL) and extracted with
CH2Cl2 (3×100 mL). The combined organic layers were washed
with water, dried with MgSO4 and concentrated under reduced
pressure. The crude residue was purified by chromatography (SiO2,
AcOEt/hexanes, 1:4).
Ethyl (E,E)-2-Oxo-6-phenylhexa-3,5-dienoate (2e): Synthesized ac-
cording to general procedure
C with trans-cinnamaldehyde
(6.29 mL, 50 mmol), affording 4.83 g (42%) of 2e as a pale yellow
solid. M.p. 81–82 °C (EtOH). 1H NMR (300 MHz, CDCl3, 30 °C):
3
3
δ = 7.64 (dd, JH,H = 13.9, JH,H = 15.4 Hz, 1 H, CH=), 7.51–7.47
(m, 2 H, 2 CH Ph), 7.39–7.35 (m, 3 H, 3 CH Ph), 7.11–6.95 (m, 2
3
3
H, 2 CH=), 6.87 (d, JH,H = 15.4 Hz, 1 H, CH=), 4.38 (q, JH,H
=
7.2 Hz, 2 H, CH2O), 1.37 (t, JH,H = 7.2 Hz, 3 H, CH3) ppm. 13C
NMR (75 MHz, CDCl3, 30 °C): δ = 182.6 (C=O), 162.0 (C=O),
148.1 (CH), 144.3 (CH), 135.4 (Cquat), 129.7 (CH), 128.7 (2 CH),
127.5 (2 CH), 126.4 (CH), 123.9 (CH), 62.2 (CH2O), 13.9
3
Procedure B: Wittig reaction of phosphorus ylide 6. Following a
literature procedure,[15] a solution of ethyl 2-oxo-3-(triphenyl-λ5-
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Achiral and Chiral Cyclic Dehydro-α-Amino Acid Derivatives
(CH ) ppm. IR (KBr): ν = 729 (s, C=O ester), 1679 (s, C=O (71%) of 1ba as a white solid. Synthesized according to general
FULL PAPER
˜
3
max
ketone) cm–1. EI-MS: m/z = 230 (10) [M]+, 157 (100) [M – CO2- procedure C with ethyl glyoxalate (0.51 g, 5 mmol) and p-toluidine
Et]+. C14H14O3 (230.1): C 73.03, H 6.13; found: C 72.95, H 6.17.
(3a) (1.07 g, 10 mmol), affording 1.35 g (77%) of 1ba as a white
solid. M.p. 159–160 °C (Et2O). 1H NMR (300 MHz, CDCl3,
General Procedure for the Synthesis of 3-Amino-1,5-dihydro-2H-pyr-
rol-2-ones 1
3
3
30 °C): δ = 7.49 (d, JH,H = 8.4 Hz, 2 H, 2 CH tol), 7.21 (d, JH,H
3
= 8.6 Hz, 2 H, 2 CH tol), 7.14 (d, JH,H = 8.4 Hz, 2 H, 2 CH tol),
3
Procedure A: Reaction of amines with β,γ-unsaturated α-keto esters
2. A solution of β,γ-unsaturated α-keto ester 2 (5 mmol), the corre-
sponding amine (10 mmol), Ti(OEt)4 (2.10 mL, 10 mmol) and a
drop of H2SO4 in CH2Cl2 (15 mL) was stirred and refluxed for 2 h.
The reaction was warmed to room temp. and a solution of aqueous
saturated NaHCO3 (20 mL) was then added. The mixture was fil-
tered through Celite, washed with H2O (50 mL) and extracted with
CH2Cl2 (3×25 mL). The organic layer was dried with MgSO4 and
concentrated under reduced pressure and the crude residue purified
by crystallization from Et2O.
7.00 (d, JH,H = 8.6 Hz, 2 H, 2CH tol), 6.66 (s, 1 H, NH), 5.93 (d,
3JH,H = 2.9 Hz, 1 H, CH=), 5.26 (d, JH,H = 2.9 Hz, 1 H, CH–N),
3
4.20–4.08 (m, 2 H, CH2–O diastereotopic), 2.35 (s, 3 H, CH3 tol),
2.32 (s, 3 H, CH3 tol), 1.17 (t, 3JH,H = 7.6 Hz, 3 H, CH3) ppm. 13
C
NMR (75 MHz, CDCl3, 30 °C): δ = 168.7 (C=O), 166.5 (C=O),
138.3 (Cquat), 135.1 (Cquat), 134.9 (Cquat), 134.7 (Cquat), 130.9
(Cquat), 129.7 (2 CH), 129.5 (2 CH), 120.4 (2 CH), 117.0 (2 CH),
97.9 (CH=), 62.5 (CH–N), 61.7 (CH2–O), 20.7 (CH3), 20.5 (CH3),
13.8 (CH ) ppm. IR (KBr): ν
= 3350 (s, N–H enamine), 1759
˜
3
max
(s, C=O ester), 1666 (s, C=O amide) cm–1. EI-MS: m/z = 350 (41)
[M]+, 277 (100) [M – CO2Et)+. C21H22N2O3 (350.2): C 71.98, H
6.33, N 7.99; found: C 72.01, H 6.33, N 7.96.
Procedure B: Reaction of amines 3 with 1-azadiene 8. A solution
of 1-azadiene 8 (1 mmol), the corresponding amine (1 mmol), Ti-
(OEt)4 (0.42 mL, 2 mmol) and a drop of H2SO4 in CH2Cl2 (5 mL)
was stirred and refluxed for 2 h. The reaction was warmed to room
temp. and a solution of aqueous saturated NaHCO3 (10 mL) was
then added. The mixture was filtered through Celite, washed with
H2O (20 mL) and extracted with CH2Cl2 (3×15 mL). The organic
layers were dried with MgSO4 and concentrated under reduced
pressure and the crude residue purified by crystallization from
Et2O.
5-(Ethoxycarbonyl)-1-(p-methoxyphenyl)-3-(p-methoxyphenyl-
amino)-1,5-dihydro-2H-pyrrol-2-one (1bb): Synthesized according to
general procedure A with ethyl 4-(ethoxycarbonyl)-2-oxobut-3-eno-
ate (2b) (1.00 g, 5 mmol) and p-anisidine (3b) (1.23 g, 10 mmol),
affording 1.62 g (85%) of 1bb as a white solid. M.p. 170–171 °C
1
3
(Et2O). H NMR (300 MHz, CDCl3, 30 °C): δ = 7.47 (d, JH,H
=
8.7 Hz, 2 H, 2 CH ar), 7.05 (d, 3JH,H = 8.7 Hz, 2 H, 2 CH ar), 6.93
(d, JH,H = 9.2 Hz, 2 H, 2 CH ar), 6.89 (d, JH,H = 9.2 Hz, 2 H, 2
3
3
3
CH ar), 6.51 (s, 1 H, NH), 5.83 (d, JH,H = 2.7 Hz, 1 H, CH=),
Procedure C: The three-component reaction. A solution of ethyl
pyruvate 7 (0.55 mL, 5 mmol), aldehyde 4 (5 mmol) and amine 3
(10 mmol) in CH2Cl2 was stirred for 48 h at room temp. The solu-
tion was then dried with MgSO4 and concentrated under reduced
pressure and the crude residue purified by crystallization from
Et2O.
3
5.20 (d, JH,H = 2.7 Hz, 1 H, CH–N), 4.21–4.03 (m, 2 H, CH2–O
diastereotopic), 3.81 (s, 3 H, CH3), 3.79 (s, 3 H, CH3), 1.16 (t, 3JH,H
= 7.0 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, 30 °C): δ
= 168.8 (C=O), 166.6 (C=O), 157.2 (Cquat), 154.6 (Cquat), 135.5
(Cquat), 134.3(Cquat), 130.6 (Cquat), 122.8 (2 CH), 118.7 (2 CH),
114.5 (2 CH), 114.2 (2 CH), 96.9 (CH=), 62.9 (CH–N), 61.7 (CH2–
5-(p-Nitrophenyl)-1-(p-tolyl)-3-(p-tolylamino)-1,5-dihydro-2H-
pyrrol-2-one (1aa): Synthesized according to general procedure A
with ethyl (E)-4-(p-nitrophenyl)-2-oxobut-3-enoate (2a) (1.25 g,
5 mmol) and p-toluidine (3a) (1.07 g, 10 mmol), affording 1.52 g
(76%) of 1aa as a yellow solid. Synthesized according to general
procedure B with ethyl (E)-4-(p-nitrophenyl)-2-(p-tolylimino)but-3-
enoate (8aa) (0.34 g, 1 mmol) and p-toluidine (3a) (0.11 g, 1 mmol),
affording 0.32 g (79%) of 1aa as a yellow solid. Synthesized accord-
ing to general procedure C with ethyl glyoxalate (0.51 g, 5 mmol)
and p-toluidine (3a) (1.07 g, 10 mmol), affording 1.59 g (80%) of
1aa as a yellow solid. M.p. 142–145 °C (decomp.) (Et2O). 1H NMR
O), 55.4 (CH O), 55.3 (CH O), 13.8 (CH ) ppm. IR (KBr): ν =
˜
max
3
3
3
3303 (s, N–H enamine), 1739 (s, C=O ester), 1686 (s, C=O
amide) cm–1. EI-MS: m/z (%) = 382 (16) [M]+, 309 (100) [M –
CO2Et]+. C21H22N2O5 (382.2): C 65.96, H 5.80, N 7.33; found: C
65.90, H 5.77, N 7.35.
1,3-Bis(p-Chlorophenyl)-5-(ethoxycarbonyl)-1,5-dihydro-2H-pyrrol-
2-one (1bc): Synthesized according to general procedure A with
ethyl 4-(ethoxycarbonyl)-2-oxobut-3-enoate (2b) (1.00 g, 5 mmol)
and p-chlorophenylamine (3c) (1.28 g, 10 mmol), affording 1.71 g
1
(88%) of 1bc as a white solid. M.p. 200–201 °C (Et2O). H NMR
3
3
(300 MHz, CDCl3, 30 °C): δ = 7.56 (d, JH,H = 8.1 Hz, 2 H, 2 CH
(300 MHz, CDCl3, 30 °C): δ = 8.13 (d, JH,H = 8.6 Hz, 2 H, 2 CH
ar), 7.36 (d, 3JH,H = 8.6 Hz, 2 H, 2 CH ar), 7.25 (d, 3JH,H = 8.1 Hz,
ar), 7.38 (d, 3JH,H = 8.6 Hz, 2 H, 2 CH ar), 7.35 (d, 3JH,H = 8.1 Hz,
3
3
2 H, 2 CH ar), 7.01 (d, JH,H = 8.6 Hz, 2 H, 2 CH ar), 6.70 (s, 1
2 H, 2 CH ar), 7.12 (d, JH,H = 7.6 Hz, 2 H, 2 CH ar), 7.09 (d,
3
3
3
3JH,H = 7.6 Hz, 2 H, 2 CH ar), 6.98 (d, JH,H = 8.1 Hz, 2 H, 2 CH
H, NH), 5.96 (d, JH,H = 2.9 Hz, 1 H, CH=), 5.26 (d, JH,H
=
3
2.9 Hz, 1 H, CH–N), 4.22–4.10 (m, 2 H, CH2O diastereotopic),
ar), 6.61 (s, 1 H, NH), 5.96 (d, JH,H = 2.4 Hz, 1 H, CH=), 5.75
3
1.18 (t, JH,H = 7.2 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
3
(d, JH,H = 2.4 Hz, 1 H, CH–N), 2.30 (s, 3 H, CH3 tol), 2.27 (s, 3
H, CH3 tol) ppm. 13C NMR (75 MHz, CDCl3, 30 °C): δ = 167.1
(C=O), 147.9 (Cquat), 145.8 (Cquat), 138.6 (Cquat), 135.5 (Cquat),
134.4 (Cquat), 133.5 (Cquat), 131.5 (Cquat), 130.2 (2 CH), 130.0 (2
CH), 127.9 (2 CH), 124.5 (2 CH), 121.8 (2 CH), 117.3 (2 CH),
105.5 (CH=), 63.7 (CH–N), 21.1 (CH3), 20.9 (CH3) ppm. IR
CDCl3, 30 °C): δ = 168.3 (C=O), 166.3 (C=O), 139.2 (Cquat), 136.2
(Cquat), 134.5 (Cquat), 130.7 (Cquat), 129.4 (Cquat), 129.3 (2 CH),
126.8 (2 CH), 121.4 (2 CH), 118.2 (2 CH), 99.4 (CH=), 62.5 (CH–
N), 62.3 (CH O), 14.0 (CH ) ppm. IR (KBr): νmax = 3317 (s, N–H
˜
2
3
enamine), 1739 (s, C=O ester), 1692 (s, C=O amide) cm–1. EI-MS:
m/z (%) = 390 (39) [M]+, 287 (100) [M – CO2Et]+. C19H16Cl2N2O3
(390.1): C 58.33, H 4.12, N 7.16; found: C 58.26, H 4.09, N 7.14.
(KBr): ν
= 3307 (s, N–H enamine), 1684 (s, C=O amide) cm–1.
˜
max
EI-MS: m/z = 399 (100) [M]+, 277 (55) [M – p-NO2-Ph]+.
C24H21N3O3 (399.2): C 72.16, H 5.30, N 10.52; found: C 72.16, H
5.30, N 10.52.
5-Methyl-1-(p-tolyl)-3-(p-tolylamino)-1,5-dihydro-2H-pyrrol-2-one
(1ca): Synthesized according to general procedure A with ethyl (E)-
2-oxopent-3-enoate (2c) (1.24 g, 5 mmol) and p-toluidine (3a)
(1.07 g, 10 mmol), affording 1.17 g (80%) of 1ca as a white solid.
Synthesized according to general procedure C with acetaldehyde
(0.21 mL, 5 mmol) and p-toluidine (3a) (1.07 g, 10 mmol), afford-
5-(Ethoxycarbonyl)-1-(p-tolyl)-3-(p-tolylamino)-1,5-dihydro-2H-
pyrrol-2-one (1ba): Synthesized according to general procedure A
with ethyl (E)-4-(ethoxycarbonyl)-2-oxobut-3-enoate (2b) (1.00 g,
5 mmol) and p-toluidine (3a) (1.07 g, 10 mmol), affording 1.24 g
Eur. J. Org. Chem. 2006, 2843–2850
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2847

F. Palacios, J. Vicario, D. Aparicio
FULL PAPER
ing 1.14 g (78 %) of 1ca as a white solid. M.p. 121–122 °C
0.88 g of the diastereoisomer 14 (41%) as pale yellow solids. M.p.
13: 137–138 °C (Et2O); 14: 143–144 °C (Et2O). 13: [α]2D0 = +81.2 (c
3
(Et2O).1H NMR (300 MHz, CDCl3, 30 °C): δ = 7.40 (d, JH,H
=
3
1
7.8 Hz, 2 H, 2 CH tol), 7.23 (d, JH,H = 8.2 Hz, 2 H, 2 CH tol),
7.13 (d, JH,H = 8.2 Hz, 2 H, 2 CH tol), 7.00 (d, JH,H = 7.8 Hz, 2 (300 MHz, CDCl3, 30 °C): 13: δ = 8.10 (d, JH,H = 8.9 Hz, 2 H, 2
H, 2 CH tol), 6.49 (s, 1 H, NH), 6.00 (d, JH,H = 2.4 Hz, 1 H,
=CH), 4.73 (dq, JH,H = 2.4, JH,H = 6.6 Hz, 1 H, CH–N), 2.37 (s,
3 H, CH3 tol), 2.31 (s, 3 H, CH3 tol), 1.27 (d, 3JH,H = 6.6 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3, 30 °C): δ = 166.0 (C=O),
= 1.01, CH2Cl2). 14: [α]2D0 = +71.2 (c = 0.91, CH2Cl2). H NMR
3
3
3
3
3
CH ar), 7.28–7.23 (m, 8 H, 8 CH Ph), 7.12 (d, JH,H = 8.9 Hz, 2
3
3
H, 2 CH ar), 7.08–7.02 (m, 2 H, 2 CH Ph), 5.56 (q, 3JH,H = 7.3 Hz,
3
1 H, CH–N), 4.70 (d, JH,H = 2.3 Hz, 1 H, CH=), 4.65 (s, 1 H,
NH), 4.54 (d, 3JH,H = 2.3 Hz, 1 H, CH–N), 4.22 (q, 3JH,H = 6.7 Hz,
3
3
139.1 (Cquat), 134.9 (Cquat), 134.1 (Cquat), 132.9 (Cquat), 130.3 1 H, CH–N), 1.50 (d, JH,H = 6.7 Hz, 3 H, CH3), 1.20 (d, JH,H
=
(Cquat), 129.8 (2 CH), 129.6 (2 CH), 122.5 (2 CH), 116.6 (2 CH), 7.3 Hz, 3 H, CH3) ppm; 14: δ = 7.80 (d, 3JH,H = 8.9 Hz, 2 H, 2 CH
3
107.3 (CH), 55.6 (CH–N), 20.8 (CH3), 20.6 (CH3), 18.7 (CH3) ppm. ar), 7.26 (s, 5 H, 5 CH Ph), 7.06 (s, 5 H, 5 CH Ph), 6.83 (d, JH,H
3
IR (KBr): ν
= 3312 (s, N–H enamine), 1676 (s, C=O = 8.9 Hz, 2 H, 2 CH ar), 5.01 (q, JH,H = 7.2 Hz, 1 H, CH–N),
˜
ma x
amide) cm–1. EI-MS: m/z (%) = 292 (100) [M]+, 277 (51) [M – CH3].
C19H20N2O (292.2): C 78.05, H 6.89, N 9.58; found C 77.98, H
6.93, N 9.63.
4.88 (d, JH,H = 2.4 Hz, 1 H, CH=), 4.72 (d, JH,H = 2.4 Hz, 1 H,
3
3
3
CH–N), 4.65 (s, 1 H, NH), 4.24 (q, JH,H = 6.7 Hz, 1 H, CH–N),
3
3
1.68 (d, JH,H = 7.3 Hz, 3 H, CH3), 1.52 (d, JH,H = 6.7 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3, 30 °C): 13: δ = 168.6
(C=O), 147.5 (Cquat), 147.2 (Cquat), 143.5 (Cquat), 139.9 (Cquat),
137.6 (Cquat), 128.5 (2 CH), 128.4 (2 CH), 128.2 (2 CH), 127.6
(CH), 127.3 (2 CH), 127.0 (CH), 125.8 (2 CH), 123.6 (2 CH), 104.8,
61.2 (CH–N), 54.3 (CH–N), 51.7 (CH–N), 24.1 (CH3), 18.1
(CH3) ppm; 14: δ = 168.4 (C=O), 147.0 (Cquat), 145.8 (Cquat), 143.4
(Cquat), 140.4 (Cquat), 138.3 (Cquat), 128.4 (CH), 128.1 (2 CH), 128.0
(CH), 127.2 (2 CH), 127.1 (2 CH), 127.0 (2 CH), 125.7 (2 CH),
123.1 (2 CH), 104.6 (CH=), 61.6 (CH–N), 54.3 (CH–N), 51.9 (CH–
1-(p-Methoxyphenyl)-3-(p-methoxyphenylamino)-5-methyl-1,5-dihy-
dro-2H-pyrrol-2-one (1cb): Synthesized according to general pro-
cedure A with ethyl (E)-2-oxopent-3-enoate (2c) (1.24 g, 5 mmol)
and p-anisidine (3b) (1.23 g, 10 mmol), affording 1.35 g (83%) of
1cb as a white solid. M.p. 151–152 °C (Et2O). 1H NMR (300 MHz,
3
CDCl3, 30 °C): δ = 7.38 (d, JH,H = 9.1 Hz, 2 H, 2 CH ar), 7.05
3
3
(d, JH,H = 9.0 Hz, 2 H, 2 CH ar), 6.96 (d, JH,H = 9.1 Hz, 2 H, 2
3
CH ar), 6.89 (d, JH,H = 9.0 Hz, 2 H, 2 CH ar), 6.40 (s, 1 H, NH),
3
3
3
5.92 (d, JH,H = 2.4 Hz, 1 H, CH–N), 4.65 (dq, JH,H = 2.4, JH,H
= 6.6 Hz, 1 H, CH–N), 3.82 (s, 3 H, CH3), 3.89 (m, 3 H, CH3),
N), 23.9 (CH ), 17.9 (CH ) ppm. IR (KBr): 13: νmax = 3329 (s, N–
˜
3
3
H enamine), 1692 (s, C=O amide) cm–1; 14: ν
= 3329 (s, N–H
˜
max
1.23 (d, JH,H = 6.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
3
enamine), 1679 (s, C=O amide) cm–1. CI-MS: 13: m/z (%) = 428
(100) [M + 1]+, 306 (64) [M – p-NO2-Ph]+; 14: m/z (%) = 429 (100)
[M + 1]+, 306 (92) [M – p-NO2-Ph]+. C26H25N3O3 (427.2): C 73.05,
H 5.89, N 9.83; found: 13: C 73.01, H 5.93, N 9.80; 14: C 73.09,
H 5.84, N 9.79.
CDCl3, 30 °C): δ = 166.1 (C=O), 157.3 (Cquat), 154.3 (Cquat), 135.1
(Cquat), 133.5 (Cquat), 129.6 (Cquat), 124.6 (2 CH), 118.3 (2 CH),
114.7 (2 CH), 114.3 (2 CH), 106.2 (CH=), 56.1 (CH2O), 55.6 (CH–
N), 55.5 (CH O), 18.8 (CH ) ppm. IR (KBr): νmax = 3330 (s, N–H
˜
2
3
enamine), 1679 (s, C=O amide) cm–1. EI-MS: m/z (%) = 324 (100)
[M]+, 309 (25) [M – CH3]+. C19H20N2O3 (292.2): C 70.35, H 6.21,
N 8.64; found: C 70.29, H 6.18, N 8.63.
Procedure for the Synthesis and Isolation of syn and anti Ethyl (E)-
4-(p-Nitrophenyl)-2-(p-tolylimino)but-3-enoate (8aa): A solution of
β,γ-unsaturated α-keto ester 2a (1.25 g, 5 mmol), p-toluidine (3a)
(0.54 g, 5 mmol), Ti(OEt)4 (2.10 mL, 10 mmol) and a drop of
H2SO4 in CH2Cl2 (15 mL) was stirred and refluxed for 2 h. The
reaction mixture was warmed to room temp. and a solution of
aqueous saturated NaHCO3 (20 mL) was then added. The mixture
was filtered through Celite, washed with H2O (50 mL) and ex-
tracted with CH2Cl2 (3×25 mL). The organic layers were dried
with MgSO4 and concentrated under reduced pressure. The crude
residue was purified by chromatography (SiO2, AcOEt/hexanes,
1:4), affording 0.30 g (18%) of 8aa as a yellow solid (syn/anti =
40:60). M.p. 98–99 °C (Et2O). 1H NMR (300 MHz, CDCl3, 30 °C):
5-(Furan-2-yl)-1-(p-tolyl)-3-(p-tolylamino)-1,5-dihydro-2H-pyrrol-2-
one (1da): Synthesized according to general procedure A with ethyl
(E)-4-furan-2-yl-2-oxobut-3-enoate (2d) (0.97 g, 5 mmol) and p-to-
luidine (3a) (1.07 g, 10 mmol), affording 1.19 g (69%) of 1da as a
white solid. Synthesized according to general procedure C with 2-
furfural (0.47 mL, 5 mmol) and p-toluidine (3a) (1.07 g, 10 mmol),
affording 1.26 g (73%) of 1ca as a white solid. M.p. 151–152 °C
1
3
(Et2O). H NMR (300 MHz, CDCl3, 30 °C): δ = 7.36 (d, JH,H
=
8.5 Hz, 2 H, 2 CH tol), 7.33 (d, 3JH,H = 1.8 Hz, 1 H, CH fur), 7.17
3
3
(d, JH,H = 8.1 Hz, 2 H, 2 CH tol), 7.14 (d, JH,H = 8.1 Hz, 2 H, 2
CH tol), 7.03 (d, 3JH,H = 8.5 Hz, 2 H, 2 CH tol), 6.61 (s, 1 H, NH),
3
3
δ = 8.19 and 8.12 (d, JH,H = 8.8 Hz and d, JH,H = 8.7 Hz, 2 H,
6.28 (dd, 3JH,H = 1.8, JH,H = 3.1 Hz, 1 H, CH fur), 6.19 (d, JH,H
3
3
3
2 CH ar anti and 2 CH ar syn), 7.61 and 7.41 (d, JH,H = 8.8 Hz
and d, JH,H = 8.7 Hz, 2 H, 2 CH ar anti and 2 CH ar syn), 7.47
3
= 3.1 Hz, 1 H, CH fur), 6.03 (d, JH,H = 2.6 Hz, 1 H, =CH), 5.76
3
(d, JH,H = 2.6 Hz, 1 H, CH–N), 2.34 (s, 6 H, 2 CH3 tol) ppm. 13C
3
3
3
and 7.02 (d, JH,H = 16.2 Hz and d JH,H = 16.3 Hz, 1 H, CH =
NMR (75 MHz, CDCl3, 30 °C): δ = 166.6 (C=O), 150.1 (Cquat),
142.5 (CH), 138.8 (Cquat), 135.3 (Cquat), 134.4 (Cquat), 133.5 (Cquat),
130.7 (Cquat), 129.8 (2 CH), 129.4 (2 CH), 122.5 (2 CH), 116.9 (2
CH), 110.4 (CH), 108.3 (CH), 102.8 (CH), 58.8 (CH–N), 20.9
anti and CH = syn), 7.29 and 6.76 (d, 3JH,H = 16.3 Hz and d JH,H
3
= 16.2 Hz, 1 H, CH = syn and CH = anti), 7.17 (d, 3JH,H = 8.1 Hz,
3
2 H, CH ar syn + anti), 6.74 (d, JH,H = 8.1 Hz, 2 H, CH ar syn +
anti), 4.43 and 4.09 (q, JH,H = 7.1 Hz and q, JH,H = 7.2 Hz, 2 H,
CH2O anti and CH2O syn), 2.33 and 2.28 (s, 3 H, CH3 syn and
3
3
(CH ), 20.6 (CH ) ppm. IR (KBr): νmax = 3321 (s, N–H enamine),
˜
3
3
1674 (C=O amide) cm–1. EI-MS: m/z (%) = 344 (36) [M]+, 277
(100) [M – fur]+. C22H20N2O2 (344.2): C 76.72, H 5.85, N 8.13;
found: C 76.67, H 5.81, N 8.09.
3
3
CH3 anti), 1.42 and 0.98 (t, JH,H = 7.1 Hz and t, JH,H = 7.2 Hz,
3 H, CH3 syn and CH3 anti) ppm. 13C NMR (75 MHz, CDCl3,
30 °C): δ = 164.3 and 164.0 (C=O syn and anti), 159.5 and 157.4
(C=N anti and syn), 147.7 (Cquat syn + anti), 146.5 and 145.0 (Cquat
anti and syn), 141.3 and 141.1 (Cquat syn and anti), 139.0 and 137.9
(CH syn and anti), 135.4 and 135.3 (Cquat syn and anti), 129.4 and
129.1 (2 CH syn and anti), 128.0 and 127.9 (2 CH syn and anti),
123.8 and 123.7 (2 CH anti and syn), 121.6 and 120.6 (2 CH anti
and syn), 120.2 and 119.4 (CH syn and anti), 62.2 and 61.5 (CH2O
1-[(R)-α-Methylbenzyl]-3-[(R)-α-methylbenzylamino]-5-(p-nitro-
phenyl)-1,5-dihydro-2H-pyrrol-2-one (13/14): Synthesized according
to general procedure A with ethyl (E)-4-(p-nitrophenyl)-2-oxobut-
3-enoate (2a) (1.25 g, 5 mmol) and (R)-α-methylbenzylamine
(1.10 mL, 10 mmol) using xylene as solvent at 140 °C. The mixture
of diastereoisomers was purified by chromatography (SiO2, AcOEt/
hexanes, 1:4), affording 0.87 g (41%) of the diastereoisomer 13 and syn and anti), 20.5 and 20.4 (CH3 syn and anti), 13.7 and 13.4 (CH3
2848
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2843–2850

Achiral and Chiral Cyclic Dehydro-α-Amino Acid Derivatives
FULL PAPER
Org. Proc. Res. Develop. 2003, 7, 355–361; c) H. Brunner, Curr.
Org. Chem. 2002, 6, 441–451.
syn and anti) ppm. IR (KBr): ν
= 1732 (s, C=O ester), 1599 (s,
˜
max
C=N imine) cm–1. EI-MS: m/z (%) = 338 (20) [M]+, 265 (100) [M –
CO2Et]+, 216 (92) [M – p-NO2-Ph]+. C19H18N2O4 (338.1): C 67.44,
H 5.36, N 8.28; found: C 67.51, H 5.40, N 8.23.
[6]
a) F. Palacios, A. M. Ochoa de Retana, J. M. Alonso, J. Org.
Chem. 2005, 70, 8895–8901; b) F. Palacios, A. M. Ochoa de Re-
tana, J. Pagalday, Eur. J. Org. Chem. 2003, 68, 913–919; c) F.
Palacios, D. Aparicio, A. M. Ochoa de Retana, J. M.
de los Santos, J. I. Gil, R. López de Munain, J. Org. Chem.
2002, 67, 7283–7288; d) F. Palacios, A. M. Ochoa de Retana,
J. I. Gil, J. M. Ezpeleta, J. Org. Chem. 2000, 65, 3213–3217.
a) F. Palacios, A. M. Ochoa de Retana, J. I. Gil, J. M. Alonso,
Tetrahedron 2004, 60, 8937–8947; b) F. Palacios, A. M.
Ochoa de Retana, J. I. Gil, J. M. Alonso, Tetrahedron: Asym-
metry 2002, 13, 2541–2552; c) F. Palacios, D. Aparicio, J. M.
de los Santos, Tetrahedron 1999, 55, 13767–13778.
a) F. Palacios, C. Alonso, M. Rodríguez, E. Martínez de Mari-
gorta, G. Rubiales, Eur. J. Org. Chem. 2005, 1795–1804; b) F.
Palacios, D. Aparicio, Y. López, J. M. de los Santos, C. Alonso,
Eur. J. Org. Chem. 2005, 1142–1147; c) F. Palacios, C. Alonso,
G. Rubiales, M. Villegas, Tetrahedron 2005, 61, 2779–2794; d)
F. Palacios, E. Herran, G. Rubiales, J. M. Ezpeleta, J. Org.
Chem. 2002, 67, 2131–2135; e) F. Palacios, A. M. Ochoa de Re-
tana, J. I. Gil, R. López de Munain, Org. Lett. 2002, 4, 2405–
2408.
Procedure for the Synthesis of 6-(Ethoxycarbonyl)-2-phenyl-1-(p-
tolyl)-1,2-dihydropyridine (15): A solution of ethyl (E,E)-2-oxo-6-
phenylhexa-3,5-dienoate (2e) (0.32 g, 1 mmol), p-toluidine (3a)
(0.11 g, 1 mmol), Ti(OEt)4 (0.32 g, 1.5 mmol) and a drop of H2SO4
in CH2Cl2 (6 mL) was stirred and refluxed for 3 h. The reaction
was warmed to room temp. and an aqueous saturated solution of
NaHCO3 was then added. The mixture was filtered through Celite
and the organic layer was washed with H2O, dried with MgSO4
and concentrated under reduced pressure. The crude residue was
purified by flash column chromatography eluting with AcOEt/hex-
anes (1:2), affording 0.26 g (81%) of 15 as a white solid. M.p. 197–
[7]
[8]
1
199 °C (decomp.) (Et2O). H NMR (300 MHz, CDCl3, 30 °C): δ =
7.47–7.51 (m, 2 H, 2 CH Ph), 7.37–7.21 (m, 3 H, 3 CH Ph), 7.04
3
3
(d, JH,H = 8.1 Hz, 2 H, 2 CH tol), 6.86 (d, JH,H = 8.1 Hz, 2 H, 2
CH tol), 6.43 (d, 3JH,H = 4.9 Hz, 1 H, CH=), 6.17 (dd, 3JH,H = 4.9,
3JH,H = 8.7 Hz, 1 H, CH=), 5.96 (dd, JH,H = 6.6, JH,H = 8.7 Hz,
3
3
1 H, CH=), 5.41 (d, 3JH,H = 6.6 Hz, 1 H, CH–N), 4.12 (q, JH,H
=
3
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7.2 Hz, 2 H, CH2O), 2.29 (s, 3 H, CH3 tol), 1.10 (t, 3JH,H = 7.2 Hz,
3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, 30 °C): δ = 164.4
(C=O), 145.3 (Cquat), 142.7 (Cquat), 131.8 (Cquat), 131.5 (Cquat),
129.0 (2 CH), 128.3 (2 CH), 126.7 (CH), 124.8 (2 CH), 122.6 (CH),
120.9 (CH), 119.5 (2 CH), 115.4 (CH), 62.0 (CH–N), 62.3 (CH2O),
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20.3 (CH ), 13.5 (CH ) ppm. IR (KBr): ν = 1753 (s, C=O es-
˜
max
3
3
ter) cm–1. EI-MS: m/z (%) = 319 (36) [M]+, 246 (100) [M – CO2-
Et]+, 214 (44) [M – p-Me-Ph-N]+. C19H18N2O4 (319.2): C 67.44, H
5.36, N 8.28; found: C 67.51, H 5.40, N 8.23.
Acknowledgments
The present work was supported by the Dirección General de In-
vestigación del Ministerio de Ciencia y Tecnología (MCYT, Mad-
rid DGI, PPQ2003-0910) and by the Universidad del País Vasco
(UPV, G2002). J.V. thanks the Departamento de Educación, Uni-
versidades e Investigación del Gobierno Vasco, for a postdoctoral
fellowship.
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Received: February 2, 2006
Published Online: April 11, 2006
2850
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2843–2850