Regioselective synthesis of pyridines and dihydropyridines derived from β-amino acids and aminophosphonates by reaction of N-vinylic phosphazenes with α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tet.2007.03.146

Reaction of N-vinylic phosphazenes with α,β-unsaturated ketones leads to the formation of pyridines derived from β-amino acids in a regioselective fashion. The use of functionalized enones derived from α-acylstyryl-carboxylates or -phosphonates affords biologically active asymmetrical and symmetrical dihydropyridines substituted with carboxylate or phosphonate groups including nitrendipine, felodipine, MRS 1097, and efonidipine analogs.

Full text of DOI:10.1016/j.tet.2007.03.146

Tetrahedron 63 (2007) 5669–5676
Regioselective synthesis of pyridines and dihydropyridines derived
from b-amino acids and aminophosphonates by reaction of
N-vinylic phosphazenes with a,b-unsaturated ketones
*
Francisco Palacios, Esther Herran, Gloria Rubiales and Concepcion Alonso
ꢀ
ꢀ
Departamento de Quꢀımica Orgaꢀnica I, Facultad de Farmacia, Universidad del Paꢀıs Vasco, Apartado 450, 01080 Vitoria, Spain
Received 22 February 2007; revised 20 March 2007; accepted 22 March 2007
Available online 27 March 2007
Abstract—Reaction of N-vinylic phosphazenes with a,b-unsaturated ketones leads to the formation of pyridines derived from b-amino acids
in a regioselective fashion. The use of functionalized enones derived from a-acylstyryl-carboxylates or -phosphonates affords biologically
active asymmetrical and symmetrical dihydropyridines substituted with carboxylate or phosphonate groups including nitrendipine, felodi-
pine, MRS 1097, and efonidipine analogs.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
N-vinylic phosphazenes13 have proved to be useful building
blocks for the synthesis of electronically neutral 2-aza-
dienes,14 3-fluoroalkyl-2-azadienes,15 electron-poor 2-aza-
dienes derived from aminophosphorus derivatives,16 a-17 or
b-amino acids,18 and to be key intermediates in the prepara-
tion of cyclic compounds19 and in the construction of the
framework of pharmacologically active alkaloids.20
1,4-Dihydropyridine derivatives (1,4-DHPs) are versatile
intermediates in organic synthesis.1,2 Moreover, compounds
basedonthisheterocycle playkeyrolesintherapeuticandbio-
organic chemistry3 as calcium channel modulators.4,5 Many
natural products as well as first, second, and third generation
calcium channel blockers such as nifedipine I,6 nitrendipine
IIa,7 felodipine IIb,8 amlodipine IIc,9 and efonidipine III 10
are 1,4-DHPs (see Chart 1). Hantzsch reaction1 as well as the
reduction of N-alkylpyridinium salts11 or the regioselective
addition of nucleophilic reagents to N-acylpyridinium
ions12 is a method for the formation of 1,4-DHP derivatives.
Continuing with our interest in the chemistry of phosph-
azenes,21 we report here the use of N-vinylic phosphazenes
with a,b-unsaturated ketones as key intermediates in the
synthesis of dihydropyridine and pyridine compounds
derived from b-amino acids.
NO2
R2
CO2C2H5
R1
NO2
O
P
O
O
R1O2C
H3C
H3CO2C
H3C
CO2CH3
H3CO2C
H3C
N
H
CH3
N
H
N
H
CH3
IIa. Nitrendipine
I. Nifedipine
R1 = Me, R2 = 3-NO2
III. Efonidipine
R1 = (CH2)2 N(Ph)CH2Ph
IIb. Felodipine
R1= Me; R2 = 2,3-Cl2
IIc. Amlodipine
R
1 = CH2O(CH2)2NH2; R2 = 2-Cl
Chart 1. Some pharmacologically active 1,4-DHPs.
Keywords: N-Vinylic phosphazenes; Dihydropyridines; Pyridines.
* Corresponding author. Tel.: +34 945 013103; fax: +34 945 013049; e-mail: francisco.palacios@ehu.es
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.03.146

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F. Palacios et al. / Tetrahedron 63 (2007) 5669–5676
2. Results and discussion
N-vinylic phosphazenes 1c (R3¼CO2Me) also reacted with
ketone 4a (R5¼Me, R6¼H) in refluxing toluene and 4b
(R5¼Me, R6¼Ph) in refluxing DMF leading to the formation
of pyridines 5b, 5c, and 5d, respectively (Scheme 1; Table 1,
entries 4–6). The presence of an electron-releasing group in
the phosphazene (R3¼Me) allowed the isolation of dihy-
dropyridine 8e, precursor of pyridine 5e. Thus, reaction of
N-vinylic phosphazene 1d (R3¼Me), with chalcone 4c
(R5¼R6¼Ph) performed in refluxing DMF, gave dihydro-
pyridine 8e (entry 7). Oxidation of dihydropyridine 8e
with quinone led to the formation of pyridine 5e derived
from b-amino acids (entry 8).
2.1. Reaction of phosphazenes with a,b-unsaturated
ketones 4
The treatment of ethyl 3-triphenylphosphazenyl-acrylate 1a
(R1¼R2¼Ph, R3¼H, R4¼Et) with methylvinylketone 4a
(R5¼Me, R6¼H) in refluxing toluene gave pyridine 5a
(R3¼H, R4¼Et, R5¼Me, R6¼H) in moderate yield (Scheme
1; Table 1, entry 1). The value of the coupling constant
(8.5 Hz) of the vicinal 4- and 5-hydrogen in this compound
5a is consistent with the literature.22,23
Given these results and in accordance with the litera-
ture,13,25,26 the formation of pyridines 5 could be explained
by an initial Michael addition (1,4-addition) of phosph-
azenes 1–3 to the b-carbon atom of unsaturated ketones 4
followed by intramolecular aza-Wittig reaction of the func-
tionalized phosphazenes 6 to give 4,5-dihydropyridines 7.
Tautomerization of these heterocycles 7 to the isomeric
1,4-dihydropyridines 8 and subsequent aromatization could
afford pyridines 5.
R5
PR12R2
CO2R4
O
N
N
R5
+
R3
OPR12R2
R3
R6
CO2R4
R6
4
5
1 R1=R2=Ph
2 R1=Ph, R2=Me
3 R1=R2=Me
[O]
R5
R5
O
R5
This process can be applied to the synthesis of pyridines 5
containing two carboxylate groups (R6¼CO2Me) when the
corresponding, commercially available, unsaturated ketone
4d (R5¼Me, R6¼CO2Me) was used (Scheme 1). The reac-
tion of phosphazenes derived from ethyl b-azidoacrylate
1a (R3¼H) and from dehydroaspartic ester 1c (R3¼CO2Me)
with methyl trans-4-oxo-2-pentenoate 4d (R5¼Me,
R6¼CO2Me) in refluxing toluene gave highly functionalized
pyridines 5f and 5g (Scheme 1; Table 1, entries 9 and 10).
Dihydropyridine 8h (R6¼CO2Me) was also isolated when
the reaction of phosphazene 1d (R3¼Me) with ketone 4d
(R5¼Me, R6¼CO2Me) was performed in toluene, leading
to the formation of a mixture of both the dihydropyridine
8h and the corresponding pyridine 5h (Scheme 1; Table 1,
entry 11). Oxidation of dihydropyridine 8h with quinone
led to the formation of pyridine 5h (entry 12).
R2R12P
N
HN
R3
N
-R2R12PO
R6
CO2R4
R3
R6
R3
R6
CO2R4
CO2R4
7
8
6
Scheme 1. Reaction of phosphazenes 1–3 with a,b-unsaturated ketones 4.
The nucleophilic character of the nitrogen atom of N-vinylic
phosphazenes depends on the influence of phosphorus atom
substituents.23 The use of the more reactive phosphazenes 2a
derived from diphenylmethylphosphine (R1¼Ph, R2¼Me,
R3¼H, R4¼Et) with the same ketone 4a led also to the
formation of pyridine 5a at room temperature in low yield
(Table 1, entry 2), and even when the reaction was performed
with very reactive phosphazenes 3a derived from trimethyl-
phosphine24 (R1¼R2¼Me, R3¼H, R4¼Et) at room tempera-
ture, pyridine 5a was obtained in low yield (entry 3) along
with hydrolysis products of the starting phosphazene.24
2.2. Reaction of phosphazenes with functionalized
a,b-unsaturated ketones 9 and 11
The scope of this reaction was not limited to the phosph-
azenes derived from ethyl b-azidoacrylate, given that 3-phenyl-
1b, -3b (R3¼Ph), and 3-methoxycarbonyl-substituted
In order to explore the synthetic usefulness of N-vinylic
phosphazenes 1–3 for the preparation of biologically
active 1,4-DHPs,4–10 we studied the reactions of these
Table 1. Pyridines 5 and dihydropyridines 8 obtained via Scheme 1
Entry
Starting materials
Products
R3
R4
R5
R6
Conditions
T (ꢀC)
Time (h)
Yielda %
1
2
3
4
5
6
7
8
1a
2a
3a
1b
3b
1c
1d
8e
1a
1c
1d
8h
4a
4a
4a
4b
4a
4a
4c
—
4d
4d
4d
—
5a
5a
5a
5b
5c
5d
8e
5e
5f
5g
5h/8h
5h
H
H
H
Ph
Ph
CO2Me
Me
Me
H
CO2Me
Me
Me
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
Ph
H
H
H
Ph
H
H
Ph
Ph
CO2Me
CO2Me
CO2Me
CO2Me
110
25
25
110
120
5
150
96
140
40
48
168
336
168
24
40
8
15
48
67
60
153
110
110
153
101
110
110
110
101
Et
Me
Me
Me
Et
Me
Me
Me
61
Ph
88b
50
9
Me
Me
Me
Me
10
11
12
59
20/36
92b
a
Purified by chromatography.
Obtained by oxidation with p-benzoquinone.
b

F. Palacios et al. / Tetrahedron 63 (2007) 5669–5676
5671
phosphazenes with functionalized a,b-unsaturated ketones
containing an electron-withdrawing group (E¼CO2R5) in
the a-position such as 2-arylmethyleneacetoacetates 9
(Scheme 2). This reaction could afford a new strategy for
the preparation of symmetrical and asymmetrical 4-aryl-
1,4-dihydro-3,5-pyridinedicarboxylates 10 (E¼CO2R) under
mild reaction conditions.
Furthermore, a phosphonate substituent28 could regulate im-
portant biological functions and increase the biological ac-
tivity of this type of compounds in a similar way to that
reported for other pharmaceuticals.29 Therefore, in connec-
tion with our interest in the chemistry of aminophosphonate
derivatives and the design of new cyclic derivatives bearing
a phosphonate group,30 we aimed to extend the process for
the preparation of 1,4-DHPs 12 containing a phosphonate
group as substituent, since compounds with this substructure
are shown hypotensive and selective cerebral vasodilating
activities.10
R6
R6
CO2R4
R3
E
E
CO2R4
R3
+
N
- OPR12R2
Me
O
PR12R2
Me
N
H
Thus, the reaction of N-vinylic phosphazenes derived from
triphenylphosphine 1a, 1d with diethyl a-acetylstyryl-
phosphonate 11a (R6¼2,6-Cl2–C6H3), and 11b (R6¼
3-NO2–C6H4) at room temperature gave compounds 12a
(R3¼H, R6¼2,3-Cl2–C6H3) and the efonidipine10 analog
12b (R3¼H, R6¼3-NO2–C6H4) in good yields and in a regio-
selective fashion (Scheme 2; Table 2, entries 7 and 8).
9 E=CO2R5
11 E=PO(OEt)2
10 E=CO2R5
12 E=PO(OEt)2
1 R1=R2=Ph
2 R1=Ph, R2=Me
3 R1=R2=Me
Scheme 2. Synthesis of 1,4-DHPs 10 and 12.
Reaction of N-vinylic phosphazenes derived from triphenyl-
phosphine 1a (R3¼H, R4¼Et, Scheme 2) with methyl 2-(p-
nitrophenyl)methyleneacetoacetate 9a (R6¼p-NO2–C6H4)
was performed at room temperature to give 3-methyl-5-
methyl-1,4-dihydro-6-methyl-4-(p-nitrophenyl)-3,5-pyridine-
dicarboxylate 10a (R3¼H, R6¼p-NO2–C6H4) in excellent
yields and in a regioselective fashion (Table 2, entry 1).
Finally, we extended the process to optically active phos-
phazenes derived from b-amino esters of (1R,2S,5R)-
(ꢁ)menthol, in order to know if the presence of a chiral
auxiliary could afford optically enriched 1,4-DHPs. The
preparation of the required N-vinylic phosphazene 13 was
accomplished through the Staudinger reaction21 involving
chiral vinyl azide18a and triphenylphosphine (Scheme 3).
The reaction of E-vinylic phosphazene 13 with methyl
2-(p-nitrophenyl)methyleneacetoacetate 9a in CH2Cl2 at
room temperature was explored and 1,4-DHP 14 was
obtained as a mixture (64:34) of two diastereoisomers (Table
2, entry 9).
Similar results were obtained when phosphazenes derived
from diphenylmethylphosphine 2a and from trimethylphos-
phine 3a were used. However, in the case of the more reactive
phosphazene 3a lower reaction time was necessary for the
process (Table 2, entries 2 and 3). The formation of dihy-
dropyridine 10a could start with a Michael addition of phos-
phazenes 1a to the enone 9 followed by intramolecular
aza-Wittig reaction in a similar way to that described in
Scheme 1.
NO2
NO2
The scope of this reaction was not limited to the preparation
of this 1,4-DHP 10a given that the strategy can also be used
for the synthesis not only of calcium channel blockers such
as nitrendipine7 10c or felodipine8 10d, but also for the
synthesis of selective A3 adenosine receptor antagonist
MRS 109727 10b when appropriate unsaturated ketones 9b
(R6¼CH]CH–C6H5), 9c (R6¼3-NO2–C6H4), 9d (R6¼2,6-
Cl2–C6H5), and N-vinylic phosphazenes 1b or 1d were
used (Table 2, entries 4–6).
MeO2C
Me
Me
O
Me
Me
O
O
MeO2C
Me
Me
9a
O
O
N
PPh3
N
H
- OPPh3
Me
Me
14 (36:64)
13
Scheme 3. Synthesis of optically enriched 1,4-DHP 14.
Table 2. Dihydropyridines (1,4-DHPs) 10, 12, and 14 obtained
Entry
Starting materials
Products
R3
R4
R5
R6
Conditions
T (ꢀC)
Time (h)
Yielda %
1
2
3
4
5
6
7
8
9
1a
2a
3a
1b
1d
1d
1a
1d
13
9a
9a
9a
9b
9c
9d
11a
11b
9a
10a
10a
10a
10bb
10cc
10dd
12a
12b
14
H
H
H
Ph
Me
Me
H
Et
Et
Et
Et
Me
Me
Et
Me
Me
Me
Et
Et
Et
4-NO2–C6H4
4-NO2–C6H4
4-NO2–C6H4
(E) CH]CH–C6H5
3-NO2–C6H4
2,3-Cl2–C6H3
2,3-Cl2–C6H3
3-NO2–C6H4
—
25
25
25
60
25
40
60
60
25
3
3
0.5
30
0.5
24
36
24
93
95
96
71
77
82
65
87
92
—
—
Me
Me
2.5
a
Purified by chromatography.
MRS 1097.
Nitrendipine.
b
c
d
Felodipine.

5672
F. Palacios et al. / Tetrahedron 63 (2007) 5669–5676
3. Conclusion
4.2.1. Ethyl 6-methyl-3-pyridinecarboxylate (5a). The
general procedure was followed using phosphazene 1a
(1.127 g, 3 mmol), 2a (0.940 g, 3 mmol) or 3a (3 mmol),
prepared ‘in situ’, and methylvinylketone 4a (0.250 mL,
3 mmol). The reaction mixture was stirred at 110 ꢀC for
110 h for phosphazene 1a (toluene), at rt for 120 h for phos-
phazene 2a (chloroform), and at rt for 5 h for phosphazene
3a (chloroform). The crude oil was chromatographed on
silica gel (10:1 hexane/AcOEt) to give the pyridine 5a as a
yellow oil [0.198 g (40%) for phosphazene 1a, 0.039 g
(8%) for phosphazene 2a, and 0.074 g (15%) for phosph-
azene 3a] (Rf ¼0.30, hexane/AcOEt 2:1). 1H NMR
We conclude that N-vinylic phosphazenes 1–3 are interme-
diates in the regioselective preparation of pyridines 5 derived
from b-amino acids, when they react with enones 4.
Enamine type addition (1,4-addition) of N-vinylic phosph-
azenes with the b-carbon atom of unsaturated ketones leads
to a regioselective synthesis of functionalized pyridines 5.
This strategy can be used for an efficient synthesis of sym-
metrical and asymmetrical 1,4-DHPs derived from amino
esters 10 and aminophosphonates 12 including biologically
active nitrendipine,7 felodipine,8 MRS 1097,27 and efoni-
dipine10 analogs, as well as for the preparation of optically
enriched 1,4-DHP 14. It is worth noting that pyridine
compounds derived from b-amino acids are also useful het-
erocycles not only for their biological activities31 but also
because the pyridine nucleus is a structural unit appearing
in many natural products.32
3
(300 MHz, CDCl3): d 1.31 (t, JHH¼7.1 Hz, 3H), 2.56 (s,
3
3
3H), 4.30 (q, JHH¼7.1 Hz, 2H), 7.17 (d, JHH¼8.1 Hz,
3
1H), 8.11 (d, JHH¼8.1 Hz, 1H), 9.04 (s, 1H); 13C NMR
(75 Hz, CDCl3): d 14.1, 24.5, 61.0, 122.7, 123.4, 137.0,
150.2, 162.8, 165.2; IR (NaCl): 1722; MS (EI): m/z 165
(M+, 93). Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71;
N, 8.48. Found: C, 65.50; H, 6.69; N, 8.47.
4.2.2. Ethyl 6-methyl-2,4-diphenyl-3-pyridinecarboxy-
late (5b). The general procedure was followed using phos-
phazene 1b (1.355 g, 3 mmol) and benzylideneacetone 4b
(0.438 g, 3 mmol) in DMF. The mixture was stirred at
153 ꢀC for 150 h. The crude oil was chromatographed on sil-
ica gel (40:1 hexane/AcOEt) to give 0.457 g (48%) of 5b
4. Experimental section
4.1. General
Solvents for extraction and chromatography were of techni-
cal 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 an atmosphere of dry nitro-
gen. Analytical TLC was performed with silica gel 60F254
plates. Visualization was accomplished by UV light. Flash
chromatography was carried out using silica gel 60 (230–
400 mesh ASTM). Melting points were determined with
an Electrothermal IA9100 Digital Melting Point Apparatus
and are uncorrected. 1H NMR (300 MHz), 13C NMR
(75 MHz), and 31P NMR (120 MHz) spectra were recorded
on a Varian VXR 300 MHz spectrometer using CDCl3 or
CD3OD solutions 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 con-
stants (J) are reported in Hertz. Low-resolution mass spectra
(MS) were obtained at 50–70 eV by electron impact (EI) on
a Hewlett Packard 5971 or 5973 spectrometer. Data are re-
ported in the form m/z (intensity relative to base¼100). In-
frared 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. Phosph-
azenes 1, 2, and 3 were synthesized according to literature
procedures.18b,23
1
as a yellow oil (Rf ¼0.53, hexane/AcOEt 2:1). H NMR
3
(300 MHz, CDCl3): d 0.78 (t, JHH¼7.2 Hz, 3H), 2.60 (s,
3
3H), 3.86 (q, JHH¼7.2 Hz, 2H), 7.09 (s, 1H), 7.29–7.59
(m, 10H); 13C NMR (75 Hz, CDCl3): d 13.4, 24.6, 61.2,
122.3, 125.9, 127.9–129.3, 138.4, 140.0, 148.8, 156.5,
158.9, 168.7; IR (NaCl): 1731; MS (EI): m/z 317 (M+, 9).
Anal. Calcd for C21H19NO2: C, 79.47; H, 6.03; N, 4.41.
Found: C, 79.51; H, 6.03; N, 4.42.
4.2.3. Ethyl 6-methyl-2-phenyl-3-pyridinecarboxylate
(5c). The general procedure was followed using phosph-
azene 3b (3 mmol), prepared ‘in situ’, and methylvinylketone
4a (0.250 mL, 3 mmol) in toluene. The reaction mixture was
stirred at 110 ꢀC for 96 h. The crude oil was chromato-
graphed on silica gel (10:1 hexane/AcOEt) to give 0.484 g
(67%) of 5c as a yellow oil (Rf ¼0.51, hexane/AcOEt 2:1).
3
1H NMR (300 MHz, CDCl3): d 0.95 (t, JHH¼7.2 Hz, 3H),
3
3
2.57 (s, 3H), 4.05 (q, JHH¼7.2 Hz, 2H), 7.11 (d, JHH
¼
3
7.9 Hz, 1H), 7.19–7.42 (m, 5H), 7.91 (d, JHH¼7.9 Hz,
1H); 13C NMR (75 Hz, CDCl3): d 13.5, 24.7, 61.1, 121.1,
124.3, 127.9, 128.2, 128.5, 138.1, 140.5, 158.6, 160.6,
168.0; IR (NaCl): 1725; MS (EI): m/z 241 (M+, 10). Anal.
Calcd for C15H19NO2: C, 74.67; H, 6.27; N, 5.80. Found:
C, 74.69; H, 6.26; N, 5.81.
4.2.4. Dimethyl 6-methyl-2,3-pyridinedicarboxylate (5d).
The general procedure was followed using phosphazene 1c
(1.257 g, 3 mmol) and methylvinylketone 4a (0.250 mL,
3 mmol) in toluene. The mixture was stirred at 110 ꢀC for
140 h. The crude oil was chromatographed on silica gel
(20:1 hexane/AcOEt) to give 0.376 g (60%) of 5d as a white
solid. Mp 68–69 ꢀC (recrystallized from AcOEt/hexane); 1H
NMR (300 MHz, CDCl3): d 2.58 (s, 3H), 3.85 (s, 3H), 3.93
4.2. General procedure for the preparation of
pyridines 5 and dihydropyridines 8
Unsaturated ketone 4 (3 mmol) was added to a 0–10 ꢀC
solution of phosphazene 1, 2, or 3 (3 mmol) in CHCl3, tolu-
ene or DMF (9 mL) under N2. The mixture was stirred at rt,
110, or 153 ꢀC until TLC indicated the disappearance of
phosphazene. Evaporation of solvent under reduced pressure
afforded an oil that was chromatographed on silica gel to
give the compounds 5 and/or 8.
3
3
(s, 3H), 7.25 (d, JHH¼8.1 Hz, 1H), 8.04 (d, JHH¼8.1 Hz,
1H); 13C NMR (75 Hz, CDCl3): d 24.5, 52.6, 52.9, 122.5,
124.3, 137.9, 151.2, 162.1, 165.4, 167.1; IR (KBr): 1749,
1713; MS (EI): m/z 209 (M+, 2). Anal. Calcd for

F. Palacios et al. / Tetrahedron 63 (2007) 5669–5676
5673
1
C10H11NO4: C, 57.41; H, 5.30; N, 6.70. Found: C, 57.46; H,
5.29; N, 6.71.
36%) (Rf ¼0.41, hexane/AcOEt 2:1). H NMR (300 MHz,
CDCl3): d 1.67 (s, 3H), 2.21 (s, 3H), 3.57 (s, 3H), 3.61 (s,
3
3
3H), 4.16 (d, JHH¼4.7 Hz, 1H), 4.50 (d, JHH¼4.7 Hz,
1H), 5.45 (s, 1H); 13C NMR (75 Hz, CDCl3): d 18.7, 20.1,
42.1, 50.8, 51.9, 93.6, 97.1, 148.6, 153.0, 168.4, 175.0; IR
(NaCl): 3349, 1745; MS (EI): m/z 225 (M+, 4). Anal. Calcd
for C11H15NO4: C, 58.66; H, 6.71; N, 6.22. Found: C, 58.70;
H, 6.72; N, 6.21.
4.2.5. Methyl 2-methyl-4,6-diphenyl-1,4-dihydro-3-pyr-
idinecarboxylate (8e). The general procedure was followed
using phosphazene 1d (1.127 g, 3 mmol) and benzylidene-
acetophenone 4c (0.626 g, 3 mmol) in DMF. The mixture
was stirred at 153 ꢀC for 40 h. The crude oil was chromato-
graphed on silica gel (hexane) to give 0.558 g (61%) of 8e
1
as a yellow oil (Rf ¼0.50, hexane/AcOEt 2:1). H NMR
4.3. General procedure for the oxidation of
1,4-dihydropyridines 8
(300 MHz, CDCl3): d 2.34 (s, 3H), 3.51 (s, 3H), 4.62 (d,
3
3JHH¼5.5 Hz, 1H), 5.13 (d, JHH¼5.5 Hz, 1H), 5.56 (s,
1H), 7.06–7.45 (10H); 13C NMR (75 Hz, CDCl3): d 20.7,
40.8, 50.6, 98.9, 105.1, 125.0–130.9, 144.1, 146.9, 148.6,
168.8; IR (NaCl): 3376, 1692; MS (EI): m/z 209 (M+, 2).
Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59.
Found: C, 78.70; H, 6.26; N, 4.60.
To a solution of dihydropyridine 8 (2 mmol) in dioxane
(8 mL) was added 0.212 g (2 mmol) of p-benzoquinone
and the mixture was stirred at 101 ꢀC under N2. The solvent
was evaporated under reduced pressure and the resulting oil
was purified by silica gel column chromatography.
4.2.6. 3-Ethyl 4-methyl 6-methyl-3,4-pyridinedicarboxyl-
ate (5f). The general procedure was followed using phosph-
azene 1a (1.126 g, 3 mmol) and ketone 4d (0.384 g, 3 mmol)
in toluene. The mixture was stirred at 110 ꢀC for 168 h. The
crude oil was chromatographed on silica gel (10:1 hexane/
AcOEt) to give 0.335 g (50%) of 5f as a yellow oil
(Rf ¼0.31, hexane/AcOEt 2:1). 1H NMR (300 MHz,
CDCl3): d 1.32 (t, 3JHH¼7.2 Hz, 3H), 2.58 (s, 3H), 3.87 (s,
3H), 4.32 (q, 3JHH¼7.2 Hz, 2H), 7.25 (s, 1H), 8.92 (s, 1H);
13C NMR (75 Hz, CDCl3): d 14.0, 24.6, 52.9, 61.8, 121.2,
122.1, 141.0, 150.3, 162.8, 165.0, 167.2; IR (NaCl): 1752;
MS (EI): m/z 223 (M+, 9). Anal. Calcd for C11H13NO4: C,
59.19; H, 5.87; N, 6.27. Found: C, 59.15; H, 5.86; N, 6.28.
4.3.1. Methyl 2-methyl-4,6-diphenyl-3-pyridinecarboxyl-
ate (5e). The general procedure was followed using dihydro-
pyridine 8e (0.610 g, 2 mmol) and stirred for 48 h.
Evaporation of solvent under reduced pressure afforded an
oil, which was chromatographed on silica gel (7:1 hexane/
AcOEt) to give 0.533 g (88%) of 5e as a brown oil
(Rf ¼0.44, hexane/AcOEt 2:1). 1H NMR (300 MHz,
CDCl3): d 2.54 (s, 3H), 3.50 (s, 3H), 7.32–7.87 (m, 11H);
13C NMR (75 Hz, CDCl3): d 22.3, 52.1, 126.9, 127.7–
130.9, 132.8, 134.7, 136.8, 144.4, 146.1, 146.8, 168.3; IR
(NaCl): 1725; MS (EI): m/z 303 (M+, 62). Anal. Calcd for
C20H17NO2: C, 79.19; H, 5.65; N, 4.62. Found: C, 79.26;
H, 5.64; N, 4.61.
4.2.7. Trimethyl 6-methyl-2,4,5-pyridinetricarboxylate
(5g). The general procedure was followed using phosph-
azene 1c (1.257 g, 3 mmol) and ketone 4d (0.384 g,
3 mmol) in toluene. The mixture was stirred at 110 ꢀC for
336 h. The crude oil was chromatographed on silica gel
(4:1 hexane/AcOEt) to give 0.473 g (59%) of 5g as an
orange oil (Rf ¼0.20, hexane/AcOEt 2:1). 1H NMR
(300 MHz, CDCl3): d 2.66 (s, 3H), 3.88 (s, 3H), 3.92 (s,
3H), 3.93 (s, 3H), 7.79 (s, 1H); 13C NMR (75 Hz, CDCl3):
d 24.4, 52.9, 53.1, 53.3, 125.7, 126.8, 137.1, 145.8, 160.5,
164.0, 164.5, 167.0; IR (NaCl): 1736; MS (EI): m/z 267
(M+, 3). Anal. Calcd for C12H13NO6: C, 53.93; H, 4.90; N,
5.24. Found: C, 53.96; H, 4.91; N, 5.23.
4.3.2. Dimethyl 2,6-dimethyl-3,4-pyridinedicarboxylate
(5h). The general procedure was followed using dihydropyr-
idine 8d (0.450 g, 2 mmol) and stirred for 24 h. The crude oil
was chromatographed on silica gel (4:1 hexane/AcOEt) to
give 0.410 g (92%) of 5h as a yellow oil (Rf ¼0.45, hex-
ane/AcOEt 2:1). See spectroscopy data of compound 5h.
4.4. General procedure for the preparation of
1,4-dihydropyridines 10
Acetoacetate33 9 (3 mmol) was added to a 0–10 ꢀC solution
of phosphazene 1 or 2 (3 mmol) in CHCl3 (9 mL) under N2
and the mixture was stirred at rt, 40, or 60 ꢀC until TLC in-
dicated the disappearance of phosphazene. Evaporation of
solvent under reduced pressure afforded an oil that was chro-
matographed on silica gel to give compounds 11.
4.2.8. Dimethyl 2,6-dimethyl-3,4-pyridinedicarboxylate
(5h). The general procedure was followed using phosph-
azene 1d (1.127 g, 3 mmol) and methyl trans-4-oxo-2-pent-
enoate 4d (0.384 g, 3 mmol) in toluene. The mixture was
stirred at 110 ꢀC for 168 h. The crude oil was chromato-
graphed on silica gel (4:1 hexane/AcOEt) to give 0.134 g
(20%) of 5h as a yellow oil (Rf ¼0.45, hexane/AcOEt 2:1)
and dihydropyridine 8h. 1H NMR (300 MHz, CDCl3):
d 2.51 (s, 3H), 2.53 (s, 3H), 3.84 (s, 3H), 3.87 (s, 3H), 7.40
(s, 1H); 13C NMR (75 Hz, CDCl3): d 22.5, 24.4, 52.7,
52.9, 119.6, 126.0, 136.3, 155.8, 159.8, 165.8, 168.5; IR
(NaCl): 1739; MS (EI): m/z 223 (M+, 12). Anal. Calcd for
C11H13NO4: C, 59.19; H, 5.87; N, 6.27. Found: C, 59.25;
H, 5.85; N, 6.26.
4.4.1. 3-Ethyl 5-methyl 6-methyl-4-(4-nitrophenyl)-1,4-
dihydro-3,5-pyridinedicarboxylate (10a). The general
procedure was followed using phosphazene 1a (1.126 g),
2a (0.939 g) or 3a (3 mmol, prepared ‘in situ’), and
0.747 g of methyl 2-(4-nitrophenylmethylene)acetoacetate
9a, the mixture was stirred at rt for 3/3/0.5 h, respectively.
The crude oil was chromatographed on silica gel (10:1 hex-
ane/AcOEt) to give 10a as a yellow solid (0.966 g (93%) for
the phosphazene 1a, 0.986 g (95%) for the phosphazene 2a,
and 0.996 g (96%) for the phosphazene 3a. Mp 48–49 ꢀC
1
(recrystallized from AcOEt/hexane); H NMR (300 MHz,
CDCl3): d 1.14 (t, 3JHH¼7.2 Hz, 3H), 2.31 (s, 3H), 3.55 (s,
4.2.9. Dimethyl 2,6-dimethyl-1,4-dihydro-3,4-pyridinedi-
carboxylate (8h). It was obtained as a yellow oil (0.243 g,
3H), 3.98–4.12 (m, 2H), 5.00 (s, 1H), 6.19 (s, 1H), 7.24 (d,
3
3JHH¼5.5 Hz, 1H), 7.41 (d, JHH¼8.7 Hz, 2H), 8.04 (d,

5674
F. Palacios et al. / Tetrahedron 63 (2007) 5669–5676
3
3JHH¼8.7 Hz, 2H); 13C NMR (75 Hz, CDCl3): d 14.2, 19.7,
39.0, 51.1, 60.2, 102.9, 107.7, 123.4, 128.9, 133.9, 144.9,
146.4, 154.4, 166.4, 167.5; IR (KBr): 3327, 1698, 1514;
MS (EI): m/z 346 (M+, 19). Anal. Calcd for C17H18N2O6:
C, 58.96; H, 5.24; N, 8.09. Found: C, 58.90; H, 5.25; N, 8.08.
2.25 (s, 3H), 1.25 (t, JHH¼7.0 Hz, 3H), 2.24 (s, 3H),
3.27–3.38 (m, 1H), 3.63–3.73 (m, 1H), 3.87–4.10 (m, 4H),
5.16 (d, JPH¼8.4 Hz, 1H), 6.87 (s, 1H), 7.03 (t, JHH
3
3
¼
7.8 Hz, 1H), 7.18–7.28 (m, 3H); 13C NMR (75 Hz,
6
CDCl3): d 14.1, 15.5 (d, JPC¼7.6 Hz), 16.2, 18.5, 37.2 (d,
2JPC¼9.1 Hz), 59.9, 60.7, 61.2, 96.3 (d, JPC¼200.9 Hz),
1
3
4.4.2. Diethyl 6-methyl-2-phenyl-4-(2-phenylethenyl)-
1,4-dihydro-3,5-pyridinedicarboxylate (10b). The general
procedure was followed using phosphazene 1b (1.624 g,
3 mmol) and ethyl 2-(3-phenylpropylene)acetoacetate 9b
(0.732 g, 3 mmol). The mixture was stirred at 60 ꢀC for
30 h. The crude oil was chromatographed on silica gel
(20:1 hexane/AcOEt) to give 0.889 g (71%) of 10b as a yel-
low solid. Mp 123–124 ꢀC (recrystallized from AcOEt/hex-
ane); 1H NMR (300 MHz, CDCl3): d 0.84 (t, 3JHH¼7.2 Hz,
3H), 1.24 (t, 3JHH¼7.2 Hz, 3H), 2.29 (s, 3H), 3.81–3.92 (m,
2H), 4.08–4.22 (m, 2H), 4.68 (d, 3JHH¼6.1 Hz, 1H), 5.75 (s,
1H), 6.21 (dd, 3JHH¼6.1, 15.9 Hz, 1H), 7.08–7.34 (m, 10H);
13C NMR (75 Hz, CDCl3): d 13.7, 14.4, 19.4, 36.8, 59.7,
59.8, 101.4, 102.3, 126.3–131.6, 136.9, 137.8, 146.2,
144.9, 166.8, 167.4; IR (KBr): 3444, 1694, 1646; MS (EI):
m/z 417 (M+, 13); Anal. Calcd for C26H27NO4: C, 74.80;
H, 6.52; N, 3.35. Found: C, 74.85; H, 6.51; N, 3.36.
105.4 (d, JPC¼9.6 Hz), 126.9, 128.2, 129.6, 130.9, 132.5,
135.3, 146.6 (d, JPC¼24.7 Hz), 147.9, 166.9; 31P NMR
2
(CDCl3, 120 MHz): d 20.81; IR (KBr): 3250, 3184, 1692,
1222, 1029; MS (EI): m/z 448 (M+, 5). Anal. Calcd for
C19H24NCl2O5P: C, 50.91; H, 5.40; N, 3.12. Found: C,
50.98; H, 5.42; N, 3.13.
4.5.2. Methyl 5-(diethoxyphosphonoyl)-2,6-dimethyl-
4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate
(12b). The general procedure was followed using phosph-
azene 1d (1.126 g, 3 mmol) and diethyl a-acetyl-3-nitro-
styrylphosphonate 11b (0.982 g, 3 mmol) for 24 h. It was
obtained as a yellow solid (1.107 g, 87%). Mp 159–160 ꢀC
1
(recrystallized from AcOEt/hexane); H NMR (300 MHz,
CDCl3): d 0.97 (t, 3JHH¼7.2 Hz, 3H), 1.17 (t, 3JHH¼7.2 Hz,
3H), 2.25 (s, 3H), 2.29 (s, 3H), 3.59 (s, 3H), 3.73–3.89 (m,
3
4H), 4.79 (d, JPH¼10.1 Hz, 1H), 6.07 (s, 1H), 7.29–7.34
(m, 1H), 7.61 (d, 3JHH¼7.6 Hz, 1H), 7.95 (d, 3JHH¼8.2 Hz,
1H), 8.06 (s, 1H); 13C NMR (75 Hz, CDCl3): d 16.0, 16.1,
18.2, 19.2, 40.0 (d, 2JPC¼9.6 Hz), 50.9, 61.1, 61.3, 96.7 (d,
4.4.3. 3-Ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-
1,4-dihydro-3,5-pyridinedicarboxylate (10c). The general
procedure was followed using phosphazene 1d (1.126 g,
3 mmol) and ethyl 2-(3-nitrophenylmethylene)acetoacetate
9c (1.185 g, 3 mmol). The mixture was stirred at rt for
30 min. The crude oil was chromatographed on silica gel
(7:1 hexane/AcOEt) to give 0.832 g (77%) of 10c as a yellow
solid. Mp 157–158 ꢀC (recrystallized from AcOEt/
hexane).34
1JPC¼201.4 Hz), 100.9 (d, JPC¼9.6 Hz), 121.3, 122.7,
3
128.6, 134.2, 146.1, 146.4, 148.1, 149.6, 167.5; 31P NMR
(CDCl3, 120 MHz): d 20.67; IR (KBr): 3283, 3224, 1705,
1530, 1241, 1023; MS (EI): m/z 424 (M+, 5); Anal. Calcd
for C19H25N2O7P: C, 53.77; H, 5.94; N, 6.60. Found: C,
53.82; H, 5.95; N, 6.59.
4.5.3. 4-[(1R,2S,5R)-(L)-menthyl]-1,1,1-triphenyl-2-aza-
1l5-phosphabuta-1,3-diene (13). A solution of (1R,2S,5R)-
(ꢁ)menthyl 3-azidoacrylate18a (1.257 g, 5 mmol) in
anhydrous CH2Cl2 (3 mL) was added dropwise to a solution
of triphenylphosphine (5 mmol) for 1 h in anhydrous CH2Cl2
(8 mL) under N2 and the mixture was stirred at room temper-
ature. Evaporation of solvent under reduced pressure af-
forded an oil, which was recrystallized from hexane/
CH2Cl2 to give 2.088 g (86%) of 13 as a white solid (mp
4.4.4. 3-Ethyl 5-methyl 2,6-dimethyl-4-(2,3-dichloro-
phenyl)-1,4-dihydro-3,5-pyridinedicarboxylate (10d).
The general procedure was followed using phosphazene 1d
(1.126 g, 3 mmol) and ethyl 2-(2,3-dichlorophenylmethyl-
ene)acetoacetate 9d (0.862 g, 3 mmol). The mixture was
stirred at 40 ꢀC for 24 h. The crude oil was chromatographed
on silica gel (15:1 hexane/AcOEt) to give 0.945 g (82%) of
10d as a yellow solid. Mp 143–144 ꢀC (recrystallized from
AcOEt/hexane).34
1
86–87 ꢀC). H NMR (300 MHz, CDCl3): d 0.64–1.97 (m,
3
3
18H), 4.55 (dt, JHH¼4.4, 10.8 Hz, 1H), 5.33 (d, JHH
¼
4.5. General procedure for the preparation of
1,4-dihydropyridines 12
12.4 Hz, 1H), 7.39–7.60 (m, 15H), 7.78 (dd, 3JHH¼12.4 Hz,
3JPH¼27.0 Hz, 1H); 13C NMR (75 Hz, CDCl3): d 16.5, 20.5,
21.9, 23.6, 26.1, 31.2, 34.3, 41.3, 47.1, 71.6, 99.7 (d,
3JPC¼29.2 Hz), 127.6 (d, 1JPC¼99.2 Hz), 128.6–132.6 (m),
a-Acetylstyrylphosphonate35 11 (3 mmol) was added to a
0–10 ꢀC solution of phosphazene 1 (3 mmol) in CHCl3
(9 mL) under N2 and the mixture was stirred at 60 ꢀC until
TLC indicated the disappearance of phosphazene. Evapora-
tion of solvent under reduced pressure afforded an oil that
was chromatographed on silica gel (AcOEt) to give the
compounds 12.
4
156.9, 170.1 (d, JPC¼3.5 Hz); 31P NMR (CDCl3): d19.4;
IR (KBr): 1686, 1580; [a]2D0 ꢁ47.4 (c, 1.00, CH2Cl2); MS
(EI): m/z 485 (M+, 5); Anal. Calcd for C31H36NO2P: C,
76.68; H, 7.42; N, 2.88. Found: C, 76.72; H, 7.43; N, 2.88.
4.5.4. 5-[(1R,2S,5R)-(L)-menthyl] 3-methyl-2-methyl-4-
(4-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxyl-
ate (14). Methyl 2-(4-nitrophenyl)acetoacetate (0.748 g,
3 mmol) was added to a solution of phosphazene 13
(1.456 g, 3 mmol) in CH2Cl2 (5 mL) at 0 ꢀC under N2. The
mixture was stirred for 2.5 h. Evaporation of solvent under
reduced pressure afforded a solid that was chromatographed
on silica gel (10:1 hexane/AcOEt) to give a diastereomeric
mixture (36:64, a/b) of compound 14 (1.261 g, 92%) as a
yellow solid. 1H NMR (300 MHz, CDCl3): d 0.49–1.98
4.5.1. Ethyl 4-(2,3-dichlorophenyl)-5-(diethoxyphospho-
noyl)-6-methyl-1,4-dihydro-3-pyridinecarboxylate (12a).
The general procedure was followed using phosphazene 1a
(1.126 g, 3 mmol) and diethyl a-acetyl-2,3-dichlorostyryl-
phosphonate 11a (1.053 g, 3 mmol) for 36 h. It was obtained
as a white solid (0.814 g, 65%). Mp 134–135 ꢀC (recrystal-
1
lized from AcOEt/hexane); H NMR (300 MHz, CDCl3):
d 0.87 (t, JHH¼7.0 Hz, 3H), 1.13 (t, JHH¼7.0 Hz, 3H),
3
3

F. Palacios et al. / Tetrahedron 63 (2007) 5669–5676
5675
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(m, 36H), 2.28 (s, 3H) for b, 2.30 (s, 3H) for a, 3.55 (s, 3H)
for a, 3.57 (s, 3H) for b, 4.53–4.66 (m, 2H), 4.98 (s, 1H) for
3
b, 4.99 (s, 1H) for a, 6.06 (s, 2H), 7.21 (d, JHH¼3.1 Hz,
3
1H) for a, 7.28 (d, JHH¼5.5 Hz, 1H) for b, 7.39 (d,
3
3JHH¼8.8 Hz, 2H) for a, 7.40 (d, JHH¼8.8 Hz, 2H) for b,
3
8.03 (d, JHH¼8.7 Hz, 4H); 13C NMR (75 Hz, CDCl3):
d 15.8 for b, 16.6 for a, 19.8 for a, 19.9 for b, 20.7 for a,
20.8 for b, 21.9, 23.0 for b, 23.7 for a, 25.7 for b, 26.6 for
a, 31.3 for a, 31.4 for b, 34.1 for b, 34.2 for a, 39.1, 40.9
for a, 41.2 for b, 47.3 for b, 47.4 for a, 51.1, 73.8 for b,
74.3 for a, 102.8 for a, 103.1 for b, 108.0 for b, 108.3 for
a, 123.2 for a, 123.3 for b, 128.9 for a, 129.0 for b, 133.5
for a, 134.0 for b, 144.7 for b, 144.9 for a, 146.4, 154.4
for b, 154.5 for a, 166.0 for b, 166.1 for a, 167.5; IR
(KBr): 3337, 1692, 1520; MS (EI): m/z 456 (M+, 8). Anal.
Calcd for C25H32N2O6: C, 65.85; H, 7.07; N, 6.14. Found:
C, 65.88; H, 7.06; N, 6.15.
ꢀ
ꢀ
11. (a) Gomez, E.; Miguel, M.; Jimenez, O.; De la Rosa, G.;
Lavilla, R. Tetrahedron Lett. 2005, 46, 3513; (b) Brewster,
M. E.; Simay, A.; Czako, C.; Windwood, D.; Farag, H.;
Bodor, N. J. Org. Chem. 1989, 54, 3721.
Acknowledgements
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Org. Chem. 2003, 4586; (b) Bennasar, M.-L.; Zulaica, E.;
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13. For reviews see: (a) Palacios, F.; Aparicio, D.; Alonso, C.;
Rubiales, G.; de los Santos, J. M. Curr. Org. Chem. 2006,
10, 2371; (b) Nitta, M. Reviews on Heteroatom Chemistry;
Oae, S., Ed.; MYU: Tokyo, 1993; Vol. 9, p 87.
The present work has been supported by the Direccioꢀn Gen-
eral de Investigacioꢀn del Ministerio de Ciencia y Tecnologꢀıa
(MCYT, Madrid DGI, CTQ2006-09323) and by the Univer-
sidad del Paꢀıs Vasco (GIU 06/51). E.H. thanks the Departa-
mento de Educacioꢀn, Universidades e Investigacioꢀn del
Gobierno Vasco for a Predoctoral Fellowship.
References and notes
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Tetrahedron 2005, 61, 2779; (b) Palacios, F.; Alonso, C.;
Rubiales, G.; Villegas, M. Tetrahedron Lett. 2004, 45,
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16. Palacios, F.; Ochoa de Retana, A. M.; Martınez de Marigorta,
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