Regioselective cycloaddition of 3-azatrienes with enamines. Synthesis of pyridines derived from β-aminoacids

Article abstract of DOI:10.1016/j.tet.2006.05.073

Aza-Wittig reaction of N-vinylic phosphazenes with α,β-unsaturated aldehydes leads to the formation of 3-azatrienes through a [2+2]-cycloaddition-cycloreversion process. Subsequent, regioselective [4+2]-cycloaddition of 3-azatrienes with pyrrolidinocycloa

Full text of DOI:10.1016/j.tet.2006.05.073

Tetrahedron 62 (2006) 7661–7666
Regioselective cycloaddition of 3-azatrienes with enamines.
Synthesis of pyridines derived from b-aminoacids
*
Francisco Palacios, Esther Herran, Concepcion Alonso and Gloria Rubiales
ꢀ
ꢀ
´
Departamento de Quımica Organica I, Facultad de Farmacia, Universidad del Paıs Vasco, Apartado 450, 01080, Spain
ꢀ
´
Received 2 May 2006; revised 25 May 2006; accepted 29 May 2006
Available online 21 June 2006
Abstract—Aza-Wittig reaction of N-vinylic phosphazenes with a,b-unsaturated aldehydes leads to the formation of 3-azatrienes through
a [2+2]-cycloaddition–cycloreversion process. Subsequent, regioselective [4+2]-cycloaddition of 3-azatrienes with pyrrolidinocycloalkanone
affords bicyclic dihydropyridines and pyridines in a regioselective fashion. 2-Heterodiene moiety of azatriene is involved in the formation of
the six-membered ring skeleton of pyridine derivatives.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
In this context, we have described new methods for the
preparation of nitrogen heterocyclic compounds by the use
of 2-azabutadiene systems.2,5,6 Therefore, we report here
the preparation of 3-azatrienes by aza-Wittig reaction of
N-vinylic phosphazenes with a,b-unsaturated aldehydes.
Moreover, we report that 3-azatrienes can be used as key
intermediates in the synthesis of dihydropyridine and pyri-
dine compounds derived from b-aminoacids (Scheme 1)
through [4+2] cycloaddition processes. It is known that
3-azatriene systems give heterocyclic compounds through
electrocyclic ring closure.16,17 However, as far as we know
no examples of aza-Diels–Alder (ADA) reaction of 3-aza-
trienes have been reported.
Aza-Wittig reaction of N-vinylic phosphazenes with carbonyl
compounds represents an easy method for the preparation
of 2-azadienes. Therefore, N-vinylic phosphazenes1 have
proved to be useful building blocks for the synthesis of
functionalized imine compounds such as electronically
neutral-2-azadienes I (Fig. 1),2 electron-poor 2-azadienes
derived from aminophosphorus derivatives,3 electron-poor
2-azadienes II (Fig. 1) derived from a-4 or b-aminoacids,5
and 3-fluoroalkyl-2-azadienes III (Fig. 1).6 N-vinylic phos-
phazenes have also been used as key intermediates in the
preparation of glycosides7 and cyclic compounds8–11 as well
as in the construction of the framework of pharmacologi-
cally active alkaloids.12
P
N
Heterocyclic
Compounds
N
Functionalized 2-azabutadienes have proved to be efficient
key intermediates in organic synthesis for the preparation
of heterocycles although the great majority of 2-azadienes
studied are substituted with electron-donating groups being
excellent reagents in aza-Diels–Alder (ADA) reactions with
electron-poor dienophiles.13–15
+
O
Scheme 1.
2. Results and discussion
(CO2R1)
(CO2R1)
2.1. Aza-Wittig reaction of phosphazenes 1 with a,b-
unsaturated aldehydes 2. Synthesis of 3-azatrienes
N
N
N
Ar
RF
III
Ar
Reaction of N-vinylic phosphazenes 1a (R¼Ph, R1¼Et,
R2¼H) and 1b (R¼Ph, R1¼Me, R2¼CO2Me) with cinna-
maldehyde 2a (R3¼H, R4¼Ph), crotonaldehyde 2b
(R3¼H, R4¼Me) or methacrolein 2c (R3¼Me, R4¼H) at
room temperature, gave the [2+2]-aza-Wittig18 products
3a–d in excellent yields (Scheme 2, Table 1, entries 1–4).
However, these azatrienes 3 were unstable during distillation
(CO2R1)
(CO2R1)
I
II
Figure 1.
* Corresponding author. Tel.: +34 945 013103; fax: +34 945 013049;
e-mail: francisco.palacios@ehu.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.073

7662
F. Palacios et al. / Tetrahedron 62 (2006) 7661–7666
Table 1. Azatrienes 3 obtained
Entry
Starting materials
Product
R1
R2
R3
R4
Reaction conditions
Yield (%)a
Phosphazene
Aldehyde
T (ꢀC)
Time (h)
1
2
3
4
1a/1c
1a/1c
1a/1c
1b
2a
2b
2c
2a
3a
3b
3c
3d
Et
Et
Et
Me
H
H
H
H
Me
H
Ph
Me
H
rt
rt
rt
70
7/1
75/98
65/90
90/62
85
24/5
30/4
30
H
CO2Me
Ph
Yield calculated by 1H NMR.
a
and/or chromatography and were used without purifica-
tion.19 The use of conjugated phosphazenes 1c derived from
trimethylphosphine (R¼Me, R1¼Et, R2¼H) was more favor-
able because the formation of azatrienes 3 took place in
shorter periods of time and the elimination of trimethylphos-
phine oxide from the reaction mixture was easier (Table 1,
entries 1–3). Next, we explored the synthetic utility of these
3-azatrienes 3 and whether new azatrienes 3 could be used as
versatile tools for the construction of nitrogen-containing
heterocycles through their cycloaddition reaction.
1,2,6,7,8,8a-hexahydroisoquinoline compounds 6 (Table 2,
entries 1 and 2). Spectral data were in agreement with the
enamine structure of a bicyclic heterocycle.
R4
R4
R3
N
R3
N
N
+
( )n
R2
R1O2C
R2
N
( )n
CO2R1
3
4a n = 2
4b n = 1
5 n = 2
8 n = 1
R4
R3
R4
PR2Me
R3
O
N
N
-
HN
+
R2
R4
R4
R2
- OPR2Me
CO2R1
R3
R3
CO2R1
3 R2 = H,
2 = CO2Me, 1Z
1
2
1E
N
HN
R
( )n
( )n
R2
R2
Scheme 2.
CO2R1
CO2R1
6 n = 2
7 n = 2
2.2. Cycloaddition reaction of azatrienes 3 with
enamines
10 n = 1
9 n = 1
Scheme 3.
The presence of a third double bond in 3-azatrienes conju-
gated with 2-azadiene may have influence in the reactivity
of the new systems. As it has been reported previously,
3-azatrienes through a thermal electrocyclic ring closure
afford the corresponding heterocyclic compounds.16,17,20
Therefore, we studied the synthetic usefulness of these new
azatrienes 3 as heterodienes for heterocyclic synthesis.13,20
At this point, it is noteworthy that these substrates would
be an interesting starting material for the preparation of
pipecolic acid derivatives.21
The formation of these hexahydroisoquinolines 6 can be
explained through a [4+2] cycloaddition reaction of 3-aza-
triene 3 with enamine 4a, formation of a cycloadduct 5
followed by the loss of pyrrolidine and prototropic tauto-
merization under the reaction conditions. Oxidation of bi-
cyclic heterocycles 6 with quinone or Mn(AcO)3 led to
the formation of 5,6,7,8-tetrahydroisoquinoline 7 derived
from b-aminoacids (Table 2, entries 3 and 4).
22
Then, we tried to extend the process to other enamine,
pyrrolidinecyclopentanone 4b. Thus, 3-azatriene 3c (R2¼H)
reacted with N-cyclopent-1-enylpyrrolidine 4b (n¼1) at
room temperature until disappearance of starting material,
affording bicyclic compound 9 (Table 2, entry 5). Similarly,
We then turned our attention to study the cycloaddition reac-
tion of electron-deficient 3-azatrienes 3 with enamines
(Scheme 3). Pyrrolidinecyclohexanone 4a(n¼2) reacted with
heterodienes 3a,b (R2¼H) at room temperature affording
Table 2. Bicyclic heterocycles 5–8 obtained
Entry
Starting material
Products
R1
R2
R3
R4
Reaction conditions
Yield (%)a
T (ꢀC)
Time (h)
1
2
3
4
5
6
3a
3b
6a
6b
3c
3d
6a
6b
7a
7b
9
Et
Et
Et
Et
Et
Me
H
H
H
H
H
H
H
H
Me
H
Ph
Me
H
Me
H
rt
rt
100
rt
rt
18
18
24
0.5
14
20
42
42
84b
83c
35
H
CO2Me
10
Ph
rt
40
a
Purified by chromatography.
Obtained by oxidation with p-benzoquinone.
Obtained by oxidation with Mn(AcO)3.
b
c

F. Palacios et al. / Tetrahedron 62 (2006) 7661–7666
7663
3-methoxycarbonyl-substituted azatriene 3d also reacted
with pyrrolidinecyclopentanone 4b (n¼1). However in this
case, completely aromatized bicyclic pyridine 10 (Table 2,
entry 6) was obtained. Formation of compounds 9 and 10
could be explained, as before, by formation of a [4+2]-cyclo-
adduct 8 followed by the loss of pyrrolidine to give dihydro-
pyridine 9 and oxidation to yield bicyclic compound 10
(Scheme 3).
used without purification for the following reactions. It was
obtained as a 85:15 diastereomeric mixture of E/Z isomers of
1
1c. H NMR (300 MHz, CDCl3) of crude reaction mixture
d 1.14–1.22 (m, 6H), 1.61 (d, 2JPH¼12.8 Hz, 9H) for isomer
2
E, 1.81 (d, JPH¼12.8 Hz, 9H) for isomer Z, 3.98–4.09 (m,
3
4
4H), 4.59 (dd, JHH¼7.6 Hz, JPH¼3.1 Hz, 1H) for isomer
3
Z, 4.99 (d, JPH¼12.4 Hz, 1H) for isomer E, 6.97 (dd,
3
3JHH¼7.6 Hz, JPH¼35.5 Hz, 1H) for isomer Z, 7.86 (dd,
3
3JHH¼12.4 Hz, JPH¼33.3 Hz, 1H) for isomer E ppm; 13C
In summary, we conclude that aza-Wittig reaction of
N-vinylic phosphazenes with the carbonyl group of unsatu-
rated aldehydes gives 3-azatrienes 3. Hetero-Diels–Alder
reaction of azatrienes 3 with enamines leads to the formation
of bicyclic pyridine compounds derived from b-aminoacids.
It is worth noting that pyridine compounds derived from
b-aminoacids are useful heterocycles not only for their bio-
logical activities23 but also because the pyridine nucleus is
a structural unit appearing in many natural products.24
NMR (75 MHz, CDCl3) of crude reaction mixture d 13.4
(d, JPC¼66 Hz) for isomer Z, 13.5 (d, JPC¼66 Hz) for
2
2
isomer E, 14.3 for isomer E, 14.5 for isomer Z, 56.7 for
isomer E, 57.2 for isomer Z, 92.2 (d, JPC¼27 Hz) for iso-
3
3
mer E, 95.5 (d, JPC¼29 Hz) for isomer Z, 153.7 (d,
2
2JPC¼5 Hz) for isomer Z, 156.2 (d, JPC¼4 Hz) for isomer
E, 166.1 for isomer E, 169.4 for isomer Z ppm; 31P NMR
(120 MHz, CDCl3) d 27.41 for isomer Z, 28.12 for isomer
E ppm.
3.3. General procedure A for the preparation
of 3-azatrienes 3
3. Experimental
3.1. General
Unsaturated aldehyde 2 (4 mmol) was added to a 0–10 ꢀC
solution of phosphazene 1 (4 mmol) in CHCl3 (10 mL)
under N2, and the mixture was stirred at room temperature
or warmed at 70 ꢀC until 1H NMR indicated the disappear-
ance of phosphazene. 3-Azatrienes 3 are unstable during
distillation and/or chromatography and were used without
purification for the following reactions.
Solvents for extraction and chromatography were of techni-
cal grade. All solvents used in reactions were freshly dis-
tilled from appropriate drying agents before use. All other
reagents were recrystallized or distilled as necessary. All re-
actions were performed under an atmosphere of dry nitro-
gen. Analytical TLC was performed with silica gel 60 F254
and aluminum oxide N/UV254 plates. Visualization was
accomplished by UV light. Flash chromatography was
carried out using silica gel 60 (230–400 mesh ASTM) and
aluminum oxide 90 active neutre (70–230 mesh ASTM).
Melting points were determined with an Electrothermal
IA9100 Digital Melting Point Apparatus and are uncor-
rected. 1H NMR (300 MHz, 250 MHz), 13C NMR (75 MHz),
and 31P NMR (120 MHz) spectra were recorded on a Varian
VXR 300 MHz spectrometer using CDCl3 or CD3OD solu-
tions with TMS as an internal reference (d¼0.00 ppm) for
1H and 13C NMR spectra, and phosphoric acid (85%)
(d¼0.0 ppm) for 31P NMR spectra. Chemical shifts (d) are
reported in parts per million. Coupling constants (J) are
reported in hertz. Low-resolution 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 base ¼ 100).
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 reported in cmꢁ1. Elemental analyses
were performed in a LECO CHNS-932 apparatus. Phospha-
zenes 1a and 1b were prepared according to literature
processes.5
3.4. General procedure B for the preparation
of 3-azatrienes 3
Unsaturated aldehyde 2 (4 mmol) was added to a 0–10 ꢀC
solution of phosphazene 1 (4 mmol), prepared ‘in situ’ in
CHCl3 (10 mL) under N2, and the mixture was stirred at
1
room temperature until H NMR indicated the disappear-
ance of phosphazene. 3-Azatrienes 3 are unstable during
distillation and/or chromatography and were used without
purification for the following reactions.
3.4.1. 1-(Ethoxycarbonyl)-6-phenyl-3-azahexa-1,3,5-
triene (3a). The general procedure A was followed using
phosphazene 1a (1.252 g, 4 mmol) and cinnamaldehyde
2a (0.504 mL, 4 mmol) (room temperature/7 h). H NMR
(300 MHz, CDCl3) of crude reaction mixture (3a+
1
3
Ph2MePO)
d
1.25 (t, JHH¼7.2 Hz, 3H), 1.96 (d,
2JPH¼13.0 Hz, 3H), 4.17 (q, JHH¼7.2 Hz, 2H), 6.08 (d,
3
3JHH¼13.1 Hz, 1H), 6.98 (dd, JHH¼9.0, 16.0 Hz, 1H),
3
3
7.14 (d, JHH¼16.0 Hz, 1H), 7.31–7.70 (m, 15H), 7.77
3
3
(d, JHH¼13.1 Hz, 1H), 8.14 (d, JHH¼9.0 Hz, 1H) ppm;
13C NMR (75 MHz, CDCl3) of crude reaction mixture
1
(3a+Ph2MePO) d 14.2, 16.5 (d, JPC¼74.0 Hz), 60.3,
118.6, 126.3–131.7, 147.1, 152.6, 155.5, 167.5, 169.4 ppm.
The general procedure B was followed using phosphazene
1c (4 mmol), prepared ‘in situ’, and 0.504 mL (4 mmol) of
cinnamaldehyde 2a (room temperature/1 h). 1H NMR
(300 MHz, CDCl3) of crude reaction mixture (3a+Me3PO)
3.2. 4-(Ethoxycarbonyl)-1,1,1-trimethyl-2-aza-1-l5-
phosphabuta-1,3-diene (1c)
A solution of 0.705 g (5 mmol) of ethyl 3-azidoacrylate in
anhydrous CH2Cl2 (3 mL) was added dropwise to a 0 ꢀC
solution of 5 mL (5 mmol) of trimethylphosphine (1.0 M
solution in hexane) in anhydrous CH2Cl2 (8 mL), and the
mixture was stirred for 30 min at 0 ꢀC. Phosphazene 1c is
unstable during distillation and/or chromatography and was
3
2
d 1.25 (t, JHH¼7.2 Hz, 3H), 1.47 (d, JPH¼12.8 Hz, 9H),
3
3
4.17 (q, JHH¼7.2 Hz, 2H), 6.08 (d, JHH¼13.1 Hz, 1H),
3
3
6.98 (dd, JHH¼9.0, 16.0 Hz, 1H), 7.14 (d, JHH¼16.0 Hz,
3
1H), 7.30–7.51 (m, 5H), 7.77 (d, JHH¼13.1 Hz, 1H), 8.14
(d, JHH¼9.0 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
3

7664
F. Palacios et al. / Tetrahedron 62 (2006) 7661–7666
of crude reaction mixture (3a+Me3PO) d 14.2, 17.8
(d, JPC¼70.0 Hz), 60.3, 118.6, 126.3–131.7, 147.1, 152.6,
reaction mixture (3d+Ph2MePO) d 16.5 (d, 1JPC¼74.0 Hz),
51.2, 52.7, 108.4, 124.9–134.6, 146.2, 152.3, 163.7,
165.0 ppm.
1
155.5, 167.5, 169.4 ppm.
3.4.2. 1-(Ethoxycarbonyl)-3-azahepta-1,3,5-triene (3b).
The general procedure A was followed using phosphazene
1a (1.252 g, 4 mmol) and crotonaldehyde 2b (0.328 mL,
4 mmol) (room temperature/24 h). 1H NMR (300 MHz,
CDCl3) of crude reaction mixture (3b+Ph2MePO) d 1.23
(t, 3JHH¼7.2 Hz, 3H), 1.92 (dd, 4JHH¼1.2 Hz, 3JHH¼6.7 Hz,
3.5. General procedure for [4D2] cycloaddition reaction
of 3-azatrienes 3 with cyclic enamines 4a,b
Cyclic enamine 4 (4 mmol) was added to a 0–10 ꢀC solution
of 3-azatriene 3 (4 mmol), prepared ‘in situ’, in CHCl3
(10 mL) under N2, and the mixture was stirred at room
2
3
1
3H), 1.96 (d, JPH¼13.0 Hz, 3H), 4.15 (q, JHH¼7.2 Hz,
temperature until H NMR indicated the disappearance of
3
4
2H), 6.00 (d, JHH¼13.1 Hz, 1H), 6.33 (ddd, JHH
¼
3-azatriene. Evaporation of solvent under reduced pressure
afforded an oil that was chromatographed on silica gel to
give the compounds 6, 9, and 10.
3
3
1.2 Hz, JHH¼15.3, 9.0 Hz, 1H), 6.48 (dq, JHH¼6.7,
3
15.3 Hz, 1H), 7.36–7.74 (m, 11H), 7.95 (d, JHH¼9.0 Hz,
1H) ppm; 13C NMR (75 MHz, CDCl3) of crude reaction
1
mixture (3b+Ph2MePO) d 14.0, 16.5 (d, JPC¼74.0 Hz),
3.5.1. Ethyl 1-(2-phenylethenyl)-1,2,6,7,8,8a-hexahydro-
4-isoquinolinecarboxylate (6a). The general procedure was
followed using 3-azatriene 3a and 1-pyrrolidine-1-cyclo-
hexene 4a (0.605 g, 4 mmol) for 18 h at room temperature.
The crude oil was chromatographed on silica gel (10:1
hexane/AcOEt) to give 0.381 g (42%) of 6a as a white solid:
mp 169–170 ꢀC (recrystallized from hexane/AcOEt). 1H
NMR (300 MHz, CDCl3) d 1.02–1.19 (m, 1H), 1.21 (t,
3JHH¼7.2 Hz, 3H), 1.48–2.21 (m, 6H), 3.45–3.51 (m, 1H),
18.8, 60.0, 117.8, 128.3–134.5, 147.4, 153.7, 155.5,
166.8, 169.4 ppm. The general procedure B was followed
using phosphazene 1c (4 mmol), prepared ‘in situ’, and
0.328 mL (4 mmol) of crotonaldehyde 2b (room tempera-
1
ture/5 h). H NMR (300 MHz, CDCl3) of crude reaction
mixture (3b+Me3PO) d 1.23 (t, 3JHH¼7.2 Hz, 3H), 1.47 (d,
2JPH¼12.8 Hz, 9H), 1.92 (dd, JHH¼1.2 Hz, JHH¼6.7 Hz,
4
3
3
3
3H), 4.15 (q, JHH¼7.2 Hz, 2H), 6.00 (d, JHH¼13.1 Hz,
4
3
3
1H), 6.33 (ddd, JHH¼1.2 Hz, JHH¼15.3, 9.0 Hz, 1H),
6.48 (dq, 3JHH¼6.7, 15.3 Hz, 1H), 7.68 (d, 3JHH¼13.1 Hz),
4.04–4.15 (m, 2H), 4.23 (d, JHH¼6.1 Hz, 1H), 6.01 (dd,
3
3JHH¼8.6, 15.7 Hz, 1H), 6.47 (s, 1H), 6.55 (d, JHH
¼
7.95 (d, JHH¼9.0 Hz, 1H) ppm; 13C NMR (75 MHz,
15.7 Hz, 1H), 7.18–7.34 (m, 5H), 7.44 (d, JHH¼6.1 Hz,
1H) ppm; 13C NMR (75 MHz, CDCl3) d 14.6, 21.8, 25.9,
27.2, 38.4, 59.1, 60.4, 99.1, 120.6, 126.5, 128.0, 128.7,
128.8, 134.2, 136.1, 142.0, 142.1, 167.3 ppm; IR (KBr)
3423, 1656; MS (EI) m/z 309 (M+, 14). Anal. Calcd for
C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 77.68;
H, 7.48; N, 4.52.
3
3
CDCl3) of crude reaction mixture (3b+Me3PO) d 14.0,
17.8 (d, JPC¼70.0 Hz), 18.8, 60.0, 117.8, 147.4, 153.7,
1
155.5, 166.8, 169.4 ppm.
3.4.3. 1-(Ethoxycarbonyl)-5-methyl-3-azahexa-1,3,5-
triene (3c). The general procedure A was followed using
phosphazene 1a (1.252 g, 4 mmol) and methacrolein 2c
(0.238 mL, 4 mmol) (room temperature/30 h). 1H NMR
(300 MHz, CDCl3) of crude reaction mixture (3c+
3.5.2. Ethyl 1-(1-propenyl)-1,2,6,7,8,8a-hexahydro-4-iso-
quinolinecarboxylate (6b). The general procedure was fol-
lowed using 3-azatriene 3b and 1-pyrrolidine-1-cyclohexene
4a (0.605 g, 4 mmol) for 18 h at room temperature. The
crude oil was chromatographed on silica gel (10:1 hexane/
AcOEt) to give 0.594 g (42%) of 6b as a white solid: mp
3
Ph2MePO) d 1.23 (t, JHH¼7.2 Hz, 3H), 1.91 (s, 3H), 1.96
2
3
(d, JPH¼13.0 Hz, 3H), 4.15 (q, JHH¼7.2 Hz, 2H), 5.58
3
(s, 1H), 5.77 (s, 1H), 6.03 (d, JHH¼13.3 Hz, 1H), 7.27–
3
7.09 (m, 10H), 7.76 (d, JHH¼13.3 Hz, 1H), 7.99 (s, 1H)
ppm; 13C NMR (75 MHz, CDCl3) of crude reaction mixture
134–135 ꢀC (recrystallized from hexane/AcOEt). H NMR
1
1
3
(3c+Ph2MePO) d 14.1, 16.4, 16.5 (d, JPC¼74.0 Hz), 60.1,
(300 MHz, CDCl3) d 0.89–1.00 (m, 1H), 1.20 (t, JHH
7.1 Hz, 3H), 1.26–2.21 (m, 9H), 3.23–3.29 (m, 1H), 4.02–
¼
118.1, 128.4–132.4, 133.2, 155.1, 166.8, 170.1 ppm. The
general procedure B was followed using phosphazene 1c
(4 mmol), prepared ‘in situ’, and 0.238 mL (4 mmol) of
methacrolein 2c (room temperature/4 h). 1H NMR
(300 MHz, CDCl3) of crude reaction mixture (3c+Me3PO)
3
4.17 (m, 2H), 4.35 (s, 1H), 5.28 (dd, JHH¼8.7, 15.3 Hz,
1H), 5.61–5.72 (m, 1H), 6.43 (s, 1H), 7.40 (d, 3JHH¼6.6 Hz,
1H) ppm; 13C NMR (75 MHz, CDCl3) d 14.6, 17.7, 21.8,
25.9, 27.1, 38.1, 59.0, 60.2, 98.5, 120.1, 130.5, 130.7,
142.2, 142.3, 167.4 ppm; IR (KBr) 3320, 1690; MS (EI)
m/z 247 (M+, 31). Anal. Calcd for C15H21NO2: C, 72.84;
H, 8.56; N, 5.66. Found: C, 72.87; H, 8.57; N, 5.65.
3
2
d 1.23 (t, JHH¼7.2 Hz, 3H), 1.47 (d, JPH¼12.8 Hz, 9H),
3
1.91 (s, 3H), 4.15 (q, JHH¼7.2 Hz, 2H), 5.58 (s, 1H),
3
3
5.77 (s, 1H), 6.03 (d, JHH¼13.3 Hz, 1H), 7.76 (d, JHH
¼
13.3 Hz, 1H), 7.99 (s, 1H) ppm; 13C NMR (75 MHz,
CDCl3) of crude reaction mixture (3c+Me3PO) d 14.1, 16.4,
3.5.3. Ethyl 6-(1-methylethenyl)-5,4-(1-propanyl-3-
yliden)-1,4,5,6-tetrahydro-3-pyridinecarboxylate (9).
The general procedure was followed using 3-azatriene 3c
(4 mmol), prepared ‘in situ’, and 1-pyrrolidine-1-cyclopen-
tene 4b (0.496 g, 4 mmol) for 14 h at room temperature.
The crude oil was chromatographed on silica gel (7:1 hex-
ane/AcOEt) to give 0.594 g (35%) of 9 as a white solid:
mp 120–121 ꢀC (recrystallized from hexane/AcOEt). 1H
NMR (300 MHz, CDCl3) d 1.17–1.31 (m, 4H), 1.72 (s,
3H), 1.90–1.99 (m, 1H), 2.36–2.38 (m, 2H), 2.66–2.72 (m,
1
17.8 (d, JPC¼70.0 Hz), 60.1, 118.1, 129.4, 133.2, 155.1,
166.8, 170.1 ppm.
3.4.4. 1,2-(Dimethoxycarbonyl)-6-phenyl-3-azahexa-
1,3,5-triene (3d). The general procedure A was followed
using phosphazene 1b (1.428 g, 4 mmol) and cinnamalde-
hyde 2a (0.504 mL, 4 mmol) (70 ꢀC/30 h). 1H NMR
(300 MHz, CDCl3) of crude reaction mixture (3d+
Ph2MePO) d 1.96 (d, 2JPH¼13.0 Hz, 3H), 3.59 (s, 3H), 3.73
3
3
(s, 3H), 6.22 (s, 1H), 6.91–7.87 (m, 17H), 7.95 (d, JHH
¼
1H), 3.39 (d, JHH¼10.5 Hz, 1H), 4.09–4.18 (m, 2H), 4.50
8.7 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) of crude
(s, 1H), 4.91 (s, 1H), 4.95 (s, 1H), 5.97 (s, 1H), 7.46

F. Palacios et al. / Tetrahedron 62 (2006) 7661–7666
7665
3
3
4
(d, JHH¼6.4 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3)
1.90 (dd, JHH¼6.9 Hz, JHH¼1.7 Hz, 3H), 2.68 (t,
3
d 14.6, 17.7, 28.4, 31.8, 46.3, 59.2, 65.2, 97.3, 115.0,
120.5, 133.7, 143.2, 144.1, 167.3 ppm; IR (KBr) 3325,
1700; MS (EI) m/z 233 (M+, 100). Anal. Calcd for
C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 72.03;
H, 8.19; N, 6.01.
3JHH¼6.1 Hz, 2H), 3.01 (t, JHH¼6.1 Hz, 2H), 4.28 (q,
3JHH¼7.2 Hz, 2H), 6.59 (dd, JHH¼15.1 Hz, JHH¼1.7 Hz,
3
4
3
1H), 6.91 (dd, JHH¼15.1, 6.9 Hz, 1H), 8.73 (s, 1H) ppm;
13C NMR (75 MHz, CDCl3) d 14.1, 18.7, 21.6, 22.0, 25.9,
27.9, 60.6, 123.5, 126.8, 128.9, 134.6, 147.9, 148.2, 156.2,
166.5 ppm; IR (KBr) 1725; MS (EI) m/z 245 (M+, 99).
Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71.
Found: C, 73.48; H, 7.79; N, 5.70.
3.5.4. Dimethyl 6-(phenylethenyl)-4,5-trimethylene-2,3-
pyridinedicarboxylate (10). The general procedure was
followed using 3-azatriene 3d (4 mmol), prepared ‘in situ’,
and 1-pyrrolidine-1-cyclopentene 4b (0.496 g, 4 mmol) for
20 h at room temperature. The crude oil was chromato-
graphed on silica gel (10:1 hexane/AcOEt) to give 0.540 g
(40%) of 10 as a white solid: mp 145–146 ꢀC (recrystallized
from hexane/AcOEt). 1H NMR (300 MHz, CDCl3) d 2.09–
2.19 (m, 2H), 3.03–3.13 (m, 4H), 3.85 (s, 3H), 3.93 (s,
Acknowledgements
The present work has been supported by the Direccioꢀn Gen-
eral de Investigacioꢀn del Ministerio de Ciencia y Tecnologıa
(MCYT, Madrid DGI, PPQ2003-0910) and by the Universi-
dad del Paıs Vasco (UPV, GC/2002). E.H. thanks the Depar-
tamento de Educacioꢀn, Universidades e Investigacioꢀn del
Gobierno Vasco for a Predoctoral Fellowship.
´
3
´
3H), 7.11 (d, JHH¼15.8 Hz, 1H), 7.23–7.56 (m, 5H), 7.82
3
(d, JHH¼15.8 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 24.1, 30.7, 33.0, 52.5, 52.9, 122.2, 123.7, 127.5, 128.7,
128.9, 136.4, 136.6, 140.0, 147.9, 152.1, 155.6, 166.8,
167.3 ppm; IR (KBr) 1751, 1707; MS (EI) m/z 337 (M+,
100). Anal. Calcd for C20H19NO4: C, 71.20; H, 5.68; N,
4.15. Found: C, 71.18; H, 5.70; N, 4.14.
References and notes
1. Fora review see:(a) Wamhoff, H.;Richard, G.;Stoelben, S. Adv.
Heterocycl. Chem. 1995, 64, 159; (b) Molina, P.; Vilaplana,
M. J. Synthesis1994, 1197;(c) Nitta, M. Reviews onHeteroatom
Chemistry; Oae, S., Ed.; MYU: Tokyo, 1993; Vol. 9, p 87.
2. (a) Palacios, F.; Alonso, C.; Amezua, P.; Rubiales, G. J. Org.
Chem. 2002, 67, 1941; (b) Palacios, F.; Alonso, C.; Rubiales,
G. J. Org. Chem. 1997, 62, 1146.
3.6. Oxidation with p-benzoquinone. Synthesis of ethyl
1-(2-phenylethenyl)-5,6,7,8-tetrahydro-4-isoquinoline-
carboxylate (7a)
To a solution of bicyclic compound 6a (0.619 g, 2 mmol) in
dioxane (8 mL) was added 0.212 g (2 mmol) of p-benzo-
quinone, and the mixture was stirred for 24 h at 100 ꢀC under
N2. The solvent was evaporated under reduced pressure, and
the resulting oil was purified by silica gel column chromato-
graphy (10:1 hexane/AcOEt) to give 0.515 g (84%) of 7a as
´
3. Palacios, F.; Ochoa de Retana, A. M.; Martınez de Marigorta,
E.; Rodrıguez, M.; Pagalday, J. Tetrahedron 2003, 59, 2617.
´
4. (a) Barluenga, J.; Ferrero, M.; Palacios, F. Tetrahedron Lett.
1990, 31, 3497; (b) Barluenga, J.; Ferrero, M.; Palacios, F.
J. Chem. Soc., Perkin Trans. 1 1990, 2193; (c) Barluenga, J.;
Ferrero, M.; Palacios, F. Tetrahedron Lett. 1988, 29, 4863.
a white solid: mp 126–127 ꢀC (recrystallized from hexane/
3
AcOEt). 1H NMR (300 MHz, CDCl3) d 1.34 (t, JHH
¼
ꢀ
5. (a) Palacios, F.; Herran, E.; Rubiales, G.; Ezpeleta, J. M. J. Org.
Chem. 2002, 67, 2131; (b) Palacios, F.; Herran, E.; Rubiales, G.
7.0 Hz, 3H), 1.74–1.81 (m, 4H), 2.82–2.86 (m, 2H), 3.03–
3.07 (m, 2H), 4.30 (q, JHH¼7.0 Hz, 2H), 7.22–7.56 (m,
3
ꢀ
6H), 7.81 (d, JHH¼15.4 Hz, 1H), 8.82 (s, 1H) ppm; 13C
J. Org. Chem. 1999, 64, 6239; (c) Palacios, F.; Perez de
3
ꢀ
NMR (75 MHz, CDCl3) d 14.3, 21.8, 22.1, 28.1, 29.7,
60.9, 123.3–128.7, 130.2, 136.2, 136.9, 148.2, 148.6,
150.1, 166.3 ppm; IR (KBr) 1705; MS (EI) m/z 307 (M+,
100). Anal. Calcd for C20H21NO2: C, 78.15; H, 6.89; N,
4.56. Found: C, 78.18; H, 6.90; N, 4.57.
Heredia, I.; Rubiales, G. J. Org. Chem. 1995, 60, 2384.
6. (a) Palacios, F.; Alonso, C.; Rubiales, G.; Villegas, M.
Tetrahedron 2005, 61, 2779; (b) Palacios, F.; Alonso, C.;
Rubiales, G.; Villegas, M. Tetrahedron Lett. 2004, 45, 4031.
ꢀ
7. Wamhoff, H.; Warnecke, H.; Sohar, P.; Csampai, A. Synlett
1998, 1193.
3.7. Oxidation with manganese triacetate. Ethyl
1-(1-propenyl)-5,6,7,8-tetrahydro-4-isoquinoline-
carboxylate (7b)22
8. (a) Barluenga, J.; Ferrero, M.; Palacios, F. Tetrahedron 1997,
53, 4521; (b) Barluenga, J.; Ferrero, M.; Lopez, F.; Palacios,
F. J. Chem. Soc., Perkin Trans. 1 1989, 615.
9. (a) Katritzky, A. R.; Mazurkiewicz, R.; Stevens, C. V.; Gordeev,
M. F. J. Org. Chem. 1994, 59, 2740; (b) Molina, P.; Pastor, A.;
Vilaplana, M. J. Tetrahedron Lett. 1993, 34, 3773; (c) Oikawa,
T.; Kanomata, N.; Tada, M. J. J. Org. Chem. 1993, 58, 2046;
(d) Krutosikova, A.; Dandarova, M.; Chylova, J.; Vegh, D.
Monatsh. Chem. 1992, 123, 807.
10. Palacios, F.; Alonso, C.; Rubiales, G. Tetrahedron 1995, 51,
3683.
11. (a) Wamhoff, H.; Schmidt, A. J. Org. Chem. 1993, 58, 6976;
(b) Nitta, M.; Iino, Y.; Mori, S.; Takayasu, T. J. Chem. Soc.,
Perkin Trans. 1 1995, 1001.
To a solution of manganese triacetate (0.536 g, 2 mmol) in
acetic acid (5 mL) was added the bicyclic compound 6b
(0.247 g, 1 mmol). The reaction mixture was stirred at room
temperature for 30 min. After completion of the reaction, as
indicated by TLC examination, manganese diacetate was
filtered off and the reaction mixture poured into water. The
contents were then neutralized by NaHCO3, extracted with
dichloromethane (2ꢂ10 mL) of 7b and dried over anhydrous
sodium sulfate. The solvent was removed under reduced
pressure and the resulting crude product was purified by
silica gel column chromatography (20:1 hexane/AcOEt) to
give 0.204 g (83%) of 7b as a white solid: mp 51–52 ꢀC
12. (a) Eguchi, S. Arkivoc 2005, ii, 98; (b) Fresneda, P. M.;
Molina, P. Synlett 2004, 1; (c) Rodrigues, J.; Augusto, R.; Leiva,
G. C.; de Sousa, D. F. Tetrahedron Lett. 1995, 36, 59; (d)
Chavignon, O.; Teulade, J. C.; Roche, D.; Madesclaire, M.;
1
(recrystallized from hexane/AcOEt). H NMR (300 MHz,
CDCl3) d 1.32 (t, JHH¼7.2 Hz, 3H), 1.63–1.83 (m, 4H),
3

7666
F. Palacios et al. / Tetrahedron 62 (2006) 7661–7666
Blache, Y.; Gueiffier, A.; Chabard, J. L.; Dauphin, G. J. Org.
Chem. 1994, 59, 6413.
17. (a) Bonini, C.; D’Auria, M.; Funicello, M.; Romaniello, G.
Tetrahedron 2002, 58, 3507; (b) Rossi, E.; Abbianti, G.; Pini,
E. Synlett 1999, 1265; (c) Molina, P.; Pastor, A.; Vilaplana,
M. J. J. Org. Chem. 1996, 61, 8094.
18. Cossio, F.; Alonso, C.; Lecea, B.; Ayerbe, M.; Rubiales, G.;
Palacios, F. J. Org. Chem. 2006, 71, 2839.
19. The reaction was monitored by 31P and 1H NMR showing the
disappearance of phosphazene 1 and the formation of aza-
trienes 3.
20. For a review, see: Marvell, E. N. Thermal Electrocyclic
Reactions; Academic: New York, NY, 1980.
13. For reviews see: (a) Stocking, E. M.; Williams, R. M. Angew.
Chem., Int. Ed. 2003, 42, 3078; (b) Nicolaou, K. C.; Snyder,
S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem.,
Int. Ed. 2002, 41, 1668; (c) Jayakumar, S.; Ishar, M. P. S.;
Mahajan, M. P. Tetrahedron 2002, 58, 379; (d) Buonora, P.;
Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099; (e) Tietze,
L. F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1; (f) Stereo-
controlled Organic Synthesis; Ghosez, L., Ed.; Blackwell:
Oxford, 1994; pp 193–233.
14. For recent contributions, see: (a) Nicolau, K. C.; Safina, B. S.;
Zak, M.; Lee, S. H.; Nevalainen, M.; Bella, M.; Estrada, A. A.;
Funke, C.; Zecri, F. J.; Bulat, S. J. Am. Chem. Soc. 2005, 127,
11159; (b) Altuna-Urquijo, M.; Stanforth, S. P.; Tarbit, B.
Tetrahedron Lett. 2005, 46, 6111; (c) Bongini, A.; Panunzio,
M.; Tamanini, E.; Martelli, G.; Vicennati, P.; Moneri, M.
Tetrahedron: Asymmetry 2003, 14, 993; (d) Nicolaou, K. C.;
Nevalainen, M.; Safina, B. S.; Zak, M.; Bulat, S. Angew.
Chem., Int. Ed. 2002, 41, 1941; (e) Ntirampebura, D.;
Ghosez, L. Synthesis 2002, 2043.
15. (a) Jnoff, E.; Ghosez, L. J. Am. Chem. Soc. 1999, 121, 2617; (b)
Bandini, E.; Martelli, G.; Spunta, G.; Bongini, A.; Panunzio,
M. Synlett 1999, 1735; (c) Ntirampebura, D.; Ghosez, L.
Tetrahedron Lett. 1999, 40, 7079.
16. Palacios, F.; Gil, M. J.; Martinez de Marigorta, E.; Rodriguez,
M. Tetrahedron 2000, 56, 6319.
21. (a) Hofle, G.; Glaser, N.; Leibold, T.; Karama, U.; Sasse, F.;
Steinmetz, H. Pure Appl. Chem. 2003, 75, 167; (b) Cativiela,
C.; Diaz de Villegas, M. D. Tetrahedron: Asymmetry 2000,
11, 645; (c) Couty, F. Amino Acids 1999, 16, 197.
22. Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 21.
23. For reviews see: (a) Plunkett, A. O. Nat. Prod. Rep. 1994, 11,
581; (b) Numata, A.; Ibuka, T. The Alkaloids; Brossi, A.,
Ed.; Academic: New York, NY, 1987; Vol. 31; (c) Gould,
S. J.; Weinreb, S. M. Fortschr. Chem. Org. Naturst. 1982, 41,
77; (d) Daly, J. L.; Spande, T. F. Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, NY, 1986; Vol. 4, pp 1–274.
24. For recent reviews see: (a) Schneider, M. J. Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Pergamon: Oxford, 1996; Vol. 10, pp 155–299; (b) Shipman,
M. Contemp. Org. Synth. 1995, 2, 1.