Unusual reactivity of (vinylimino)phosphoranes and their utility in the preparation of pyridine and dihydropyridine derivatives

Article abstract of DOI:10.1021/jo960940v

New reactions of (vinylimino)phosphoranes with aldehydes involving an initial nucleophilic attack of the β-carbon atom of the vinyl side chain on the carbonyl carbon atom are reported. Iminophosphorane 4 derived from ethyl β-azidoacrylate reacts with substituted cinnamyl aldehydes to give a mixture of 2-arylpyridine and 4-styryldihydropyridine derivatives, whereas the reaction with substituted benzaldehydes provides 4-aryldihydropyridine derivatives. However, the iminophosphorane 16 derived from the diethyl azidofumarate reacts with cinnamyl aldehydes through the expected aza-Wittig fashion to give 4-arylpyridine derivatives after dehydrogenation of the resulting dihydropyridine.

Full text of DOI:10.1021/jo960940v

8094
J . Org. Chem. 1996, 61, 8094-8098
Un u su a l Rea ctivity of (Vin ylim in o)p h osp h or a n es a n d Th eir Utility
in th e P r ep a r a tion of P yr id in e a n d Dih yd r op yr id in e Der iva tives
Pedro Molina,* Aurelia Pastor, and Mar´ıa J esu´s Vilaplana
Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad de Murcia Campus de
Espinardo, E-30071 Murcia, Spain
Received May 20, 1996X
New reactions of (vinylimino)phosphoranes with aldehydes involving an initial nucleophilic attack
of the â-carbon atom of the vinyl side chain on the carbonyl carbon atom are reported.
Iminophosphorane 4 derived from ethyl â-azidoacrylate reacts with substituted cinnamyl aldehydes
to give a mixture of 2-arylpyridine and 4-styryldihydropyridine derivatives, whereas the reaction
with substituted benzaldehydes provides 4-aryldihydropyridine derivatives. However, the imino-
phosphorane 16 derived from the diethyl azidofumarate reacts with cinnamyl aldehydes through
the expected aza-Wittig fashion to give 4-arylpyridine derivatives after dehydrogenation of the
resulting dihydropyridine.
The utility of (vinylimino)phosphoranes as useful
building blocks for the synthesis of azaheterocycles has
been demonstrated convincingly.1 (Vinylimino)phospho-
ranes may be considered to be an equivalent of an
enamine and to contain two nucleophilic centers at the
â-carbon atom of the vinyl side chain and the nitrogen
atom of the iminophosphorane portion. Thus (vinylimi-
no)phosphoranes undergo a single-step annulation with
compounds containing two electrophilic centers such as
R,â-unsaturated ketones,2 R,â-unsaturated aldehydes,3
and related Michael acceptors4 to give several types of
nitrogen-containing heterocycles. This kind of conversion
takes place through two pathways: (i) a Michael type
addition followed by proton transfer to generate an
intermediate iminophosphorane which then undergoes
an intramolecular aza-Wittig reaction and (ii) aza-Wittig
reaction leading to an intermediate azahexatriene which
then undergoes a thermal 6π-electrocyclization.5 In this
sense, (vinylimino)phosphoranes of type 1 reacted with
aliphatic, aromatic, and heteroaromatic aldehydes to give
the corresponding 2-azahexatriene, which underwent
electrocyclic ring-closure followed by dehydrogenation to
give pyridines6 or isoquinoline derivatives7 2. However,
the reaction with R,â-unsaturated aldehydes provided
3-arylpyridines 3 in a completely regioselective fashion.8
We wish to report therein that the behavior of the
(vinylimino)phosphorane 4, bearing an ethoxycarbonyl
group at the position â toward aldehydes is completely
different from those previously reported for unsubstituted
(vinylimino)phosphoranes and even for the closely related
(vinylimino)phosphorane 1.
Resu lts a n d Discu ssion
(Vinylimino)phosphorane 4 was readily prepared in
79% yield by Staudinger reaction of ethyl â-azidoacrylate9
with triphenylphosphine at room temperature. In the
1H-NMR spectrum the chemical shifts of the vinylic
protons and the vicinal H-H coupling constant (3J H-H
)
12.6 Hz) suggested that both protons were relatively
trans.10 Compound 4 reacted with R,â-unsaturated al-
dehydes in o-xylene at 160 °C, in the presence of
palladium on charcoal, in a sealed tube to give a mixture
of pyridine 5 and dihydropyridine 6, instead of the
expected pyridine 7 (Scheme 1). From the reaction with
Sch em e 1
X Abstract published in Advance ACS Abstracts, November 1, 1996.
(1) For reviews see: Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron
1992, 48, 1353. Eguchi, S.; Matsushita, Y.; Yamashita, K. Org. Prep.
Proced. Int. 1992, 24, 209. Molina, P.; Vilaplana, M. J . Synthesis, 1994,
1197. Wamhoff, H.; Richardt, G.; Sto¨lben, S. Adv. Heterocycl. Chem.
1995, 64, 159 and references cited therein.
(2) Kobayashi, T.; Nitta, M. Chem. Lett. 1981, 1459. Iino, Y.; Nitta,
M. Bull. Chem. Soc. J pn. 1988, 61, 2235.
(3) Molina, P.; Pastor, A.; Vilaplana, M. J . Tetrahedron Lett. 1993,
3773. Molina, P.; Pastor, A.; Vilaplana, M. J .; Foces-Foces, C. Tetra-
hedron 1995, 51, 1265.
(4) Nitta, M.; Iino, Y.; Hara, E.; Kobayashi, T. J . Chem. Soc, Perkin
Trans. 1 1989, 51.
(5) Katritzky, A. R.; Mazurkiewicz, R.; Stevens, C. V.; Gordeev, M.
F. J . Org. Chem. 1994, 59, 2740.
(6) Barluenga, J .; Ferrero, M.; Palacios, F. J . Chem. Soc., Perkin
Trans. 1 1990, 2193.
(7) Molina, P.; Fresneda, P. M.; Ca´novas, M. Tetrahedron Lett. 1992,
2891. Molina, P.; Murcia, F.; Fresneda, P. M. Tetrahedron Lett. 1994,
1453. Molina, P.; Garc´ıa-Zafra, S.; Fresneda, P. M. Synlett 1995, 43.
Molina, P.; Fresneda, P. M.; Garc´ıa-Zafra, S. Tetrahedron Lett. 1995,
3581.
acrolein, only the pyridine 5e (R ) H) was isolated in
moderate yield. In the 1H NMR spectra, the observed
H-3/H-4 coupling constant (3J H-H ) 8.1-8.4 Hz) clearly
(9) Hassner, A.; Fowler, F. W. J . Org. Chem. 1968, 33, 2686.
(10) Palacios, F.; Aparicio, S.; de los Santos, J . M.; Pe´rez de Heredia,
I.; Rubiales. G. Org. Prep. Proced. Int. 1995, 27, 145.
(8) Molina, P.; Vilaplana, M. J .; Pastor, A. Synlett. 1992, 873. Molina,
P.; Pastor, A.; Vilaplana, M. J . Tetrahedron 1993, 49, 7769.
S0022-3263(96)00940-1 CCC: $12.00 © 1996 American Chemical Society

Unusual Reactivity of Vinyliminophosphoranes
J . Org. Chem., Vol. 61, No. 23, 1996 8095
Sch em e 2
Ta ble 1. P yr id in es 5 a n d Dih yd r op yr id in e Der iva tives 6
Sch em e 3
compound
R
yield (%)
5a
5b
5c
5d
5e
6a
6b
6c
6d
C6H5
33
30
30
31
42
44
40
46
38
4-ClC6H4
2-O2NC6H4
2-H3COC6H4
H
C6H5
4-ClC6H4
2-O2NC6H4
2-H3COC6H4
confirms the proposed 2-aryl-substituted pyridine 5 and
rule out the isomeric 4-substituted pyridine 7.
These findings are in clear contrast with the recently
reported behavior of this kind of (vinylimino)phospho-
ranes toward carbonyl compounds, such as ethyl glyox-
alate, diethyl ketomalonate, and pyruvonitrile, to give
2-azadienes.11
Ta ble 2. 4-Ar yld ih yd r op yr id in e Der iva tives 12 a n d 14
compound
R
yield (%)
12a
12b
12c
12d
14a
14b
14c
14d
4-H3CC6H4
4-ClC6H4
4-H3COC6H4
3-H3COC6H4
4-H3CC6H4
4-ClC6H4
43
40
40
41
44
43
38
36
Formation of compounds 5 and 6 could be rationalized
in terms of an initial addition of the â-carbon atom of
the iminophosphorane 4 to the carbonyl carbon atom of
the R,â-unsaturated aldehyde to give the betaine 8, which
cyclized to give the isomeric 1,2,5-oxaazaphosphane 9
(Scheme 2). The endo isomer 9a underwent intra-
molecular cyclization with concomitant elimination of
triphenylphosphine oxide to give the dihydropyridine 10,
which was dehydrogenated under reaction conditions to
give 5. Regiospecific attack of a second molecule of the
iminophosphorane 4 on the exo isomer 9b with loss of
triphenylphosphine oxide provided the tetrahydropyri-
dine 11. Subsequent elimination of triphenylphosphin-
imine afforded the dihydropyridine 6, which was sur-
prisingly stable under the reaction conditions.
4-H3COC6H4
3-H3COC6H4
aldehydes for a longer period of time afforded the fused
dihydropyridines 14 (36-44%).
Formation of dihydropyridines 12 and 14 (Scheme 3)
could follow a pathway similar to the conversion 9 f 6.
As it has been mentioned before, dihydropyridines 6 and
12 are stable under thermal conditions; however, when
they were exposed to sunlight for 324 h, the correspond-
ing pyridines were obtained in almost quantitative yields.
Dihydropyridines were also formed from the reaction
of iminophosphorane 4 with the aromatic aldehydes. In
this case, dihydropyridines 12 were prepared in moderate
yields (40-43%), as the only reaction product, under the
above-mentioned conditions. Likewise, the closely re-
lated (vinylimino)phosphorane 13 reacted with aromatic
Keeping in mind, that the reactivity of (vinylimino)-
phosphoranes bearing an ethoxycarbonyl group as sub-
stituent strongly depends on the relative position of the
substituents on the vinylic chain, we have turned our
attention to the preparation and synthetic applications
of this type of (vinylimino)phosphorane bearing two
ethoxycarbonyl groups at the two different positions of
the vinylic chain. Diethyl fumarate was treated sequen-
(11) Palacios, F.; Perez de Heredia, I.; Rubiales, G. J . Org. Chem.
1995, 60, 2384.

8096 J . Org. Chem., Vol. 61, No. 23, 1996
Molina et al.
Sch em e 4
been utilized as key intermediates in the synthesis of the
marine alkaloid amphimedine,13 have been prepared
recently by Pd-catalyzed Suzuki14 or Stille15 cross-
coupling reaction followed by cyclization.
These results show a detailed picture of the reactivity
of (vinylimino)phosphoranes bearing ethoxycarbonyl
groups as substituents toward several kind of aldehydes.
Several trends have surfaced from this study. First,
when both functionalities are placed at the same carbon
atom, the reaction takes place via an aza-Wittig process.
Second, when they are placed on different carbon atoms,
the reaction is initiated by nucleophilic attack of the
â-carbon atom of the vinylic side chain on the carbonyl
group (charge-controlled reaction). And third, when the
two ethoxycarbonyl groups are placed on different carbon
atoms, the reaction takes place via an aza-Wittig process
to give a 3-azahexatriene moiety, which undergoes elec-
trocyclic ring-closure to give the pyridine ring after
dehydrogenation.
Sch em e 5
This unprecedented behavior of (vinylimino)phospho-
ranes toward aldehydes opens a new way to the prepara-
tion of a wide variety of functionalized pyridines and
dihydropyridines.
Exp er im en ta l Section
All melting points were determined on a Kofler hot-plate
melting point apparatus and are uncorrected. IR spectra were
obtained as Nujol emulsions or films on a Nicolet Impact 400
spectrophotometer. NMR spectra were recorded on a Bruker
AC200 (200 MHz) or a Varian Unity 300 (300 MHz). Mass
spectra were recorded on a Hewlett-Packard 5993C spectrom-
eter. Microanalyses were performed on a Perkin Elmer 240C
instrument.
Ta ble 3. 4-Ar ylp yr id in es 18
P r ep a r a tion of (E)-3-[(Tr ip h en ylp h osp h or a n ylid en e)-
a m in o]p r op en oic Acid Eth yl Ester (4). To a solution of
ethyl â-azidoacrylate (1.0 g, 7.1 mmol) in dry Et2O (20 mL)
cooled at 0 °C was added Ph3P (1.86 g, 7.1 mmol). The mixture
was stirred at room temperature for 6 h, and the separated
solid was collected by filtration and recrystallized from dichlo-
romethane/Et2O/n-hexane (1:1:3) to give 4 in 79% yield; mp
118-124 °C, colorless prisms; 1H-NMR (CDCl3) δ 1.20 (t, 3H,
J ) 7.1 Hz), 4.07 (q, 2H, J ) 7.1 Hz), 5.42 (dd, 1H, J ) 12.6,1.1
Hz), 7.46-7.66 (m, 15H), 7.95 (dd, 1H, J ) 27.5, 12.3 Hz); 13C-
NMR (CDCl3) δ 14.6, 58.5, 99.4 (J ) 29.2 Hz), 127.7 (J ) 99.2
Hz), 128.9 (J ) 12.1 Hz), 132.6 (J ) 2.6 Hz), 132.7 (J ) 9.6
Hz), 157.5 (J ) 2.6 Hz), 170.8; EI MS m/ z (%): 375 (M+, 25),
183 (100). Anal Calcd for C23H22NO2P: C, 73.59; H, 5.91; N,
3.73. Found: C, 73.71; H, 5.75; N, 3.92.
Gen er a l P r oced u r e for th e P r ep a r a tion of P yr id in es
5 a n d Dih yd r op yr id in es 6. A mixture of vinyliminopho-
phorane 4 (0.75 g, 2 mmol), the appropiate R,â-unsaturated
aldehyde (2 mmol), and palladium on charcoal (0.053 g) in dry
o-xylene (35 mL) was treated at 160 °C in a sealed tube for 24
h. After cooling, the mixture was filtered and the filtrate
concentrated to dryness. The crude product was chromato-
graphed on a silica gel column using ethyl acetate/dichlo-
romethane (1:7) as eluent to give the pyridine 5 and the
dihydropyridine 6, which were recrystallized from dichlo-
romethane/Et2O/n-hexane (1:2:1).
compound
R
yield (%)
18a
18b
18c
18d
C6H5
38
40
36
37
2-H3COC6H4
4-ClC6H4
2-O2NC6H4
tially with iodine monochloride/sodium azide12 and tri-
ethylamine to give a mixture of vinyl azides 15 in 60%
yield, which were converted into the corresponding
iminophosphoranes 16 and 17 by reaction with tri-
phenylphosphine (Scheme 4).
All attempts to separate the iminophosphoranes by
columm chromatography were unsuccessful, and only the
corresponding amines were obtained. However, (vin-
ylimino)phosphorane 16 was obtained from the mixture
in pure state (70%) by crystallization. The E configura-
tion of compound 16 was assigned by means of a NOE
difference experiment. Thus, irradiation of the o-phenyl
proton signals of the iminophosphorane portion induced
a 36% enhancement of the vinylic proton signal.
Reaction of (vinylimino)phosphorane 16 with R,â-
unsaturated aldehydes in nitrobenzene at reflux tem-
perature for 8 h gives directly 4-arylpyridines 18 (Scheme
5) in moderate yields (36-40%). The conversion 16 f
18 can be rationalized in terms of an initial aza-Wittig
reaction to give an azahexatriene as an intermediate,
which undergoes ring-closure and further dehydrogena-
tion under the reaction conditions.
2-P h en yl-5-(eth oxyca r bon yl)p yr id in e (5a ): 33% yield;
mp 51-53 °C, colorless prisms; 1H-NMR (CDCl3) δ 1.42 (t, 3H,
J ) 7.1 Hz), 4.43 (q, 2H, J ) 7.1 Hz), 7.47-7.51 (m, 3H), 7.80
(d, 1H, J ) 8.3 Hz), 8.03-8.08 (m, 2H), 8.34 (dd, 1H, J ) 8.4,
2.1 Hz), 9.29 (d, 1H, J ) 1.9 Hz); 13C-NMR (CDCl3) δ 14.3,
61.4, 119.8, 124.5, 127.4, 128.9, 129.9, 137.9, 138.4, 151.0,
Reduction of compound 18d with Fe/HOAc directly
gave the benzo[c][2,7]naphthyridinone 19 in 74% yield.
Some related derivatives of this ring system, which have
(13) Prager, R. H.; Tsopelas, C.; Heisler, T. Aust. J . Chem. 1991,
44, 277.
(14) Guillier, F.; Nivoliers, F.; Godard, A.; Marsais, F.; Que´guiner,
G.; Siddiqui, M. A.; Snieckus, V. J . Org. Chem. 1995, 60, 292.
(15) Malm, J .; Bjo¨rk, P.; Gronowitz, S.; Ho¨rnfeldt. A.-B. Tetrahedron
Lett. 1994, 3195.
(12) Fowler, F. W.; Hassner, A.; Levy, L. A. J . Am. Chem. Soc. 1967,
89, 2077.

Unusual Reactivity of Vinyliminophosphoranes
J . Org. Chem., Vol. 61, No. 23, 1996 8097
160.8, 165.4; EI MS m/ z (%): 227 (M+, 25), 182 (100). Anal.
Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C,
74.20; H, 5.96; N, 6.02.
Hz), 7.28 (d, 2H, J ) 5.4 Hz), 7.39 (dd, 1H, J ) 7.6, 1.5 Hz);
13C-NMR (CDCl3) δ 14.4, 34.4, 55.5, 60.1, 106.7, 110.9, 120.6,
124.5, 126.6, 126.7, 128.1, 132.7, 134.3, 156.6, 167.3; EI MS
m/ z (%): 357 (M+, 22), 168 (100). Anal. Calcd for C20H23
-
2-(4-Ch lor op h en yl)-5-(et h oxyca r bon yl)p yr id in e (5b):
30% yield; mp 122-124 °C, colorless prisms; 1H-NMR (CDCl3)
δ 1.43 (t, 3H, J ) 7.1 Hz), 4.43 (q, 2H, J ) 7.2 Hz), 7.47 (d,
2H, J ) 8.4 Hz), 7.77 (dd, 1H, J ) 8.4, 0.6 Hz), 8.01 (d, 2H, J
) 8.7 Hz), 8.34 (dd, 1H, J ) 8.3, 2.3 Hz), 9.27 (dd, 1H, J )
1.8, 0.6 Hz); 13C-NMR (CDCl3) δ 14.4, 61.5, 119.6, 124.8, 128.6,
129.2, 136.2, 136.8, 138.0, 151.0, 159.5, 165.3; EI MS m/ z
(%): 263 (M+ + 2, 6), 261 (M+, 17), 216 (100). Anal. Calcd
for C14H12ClNO2: C, 64.25; H, 4.62; N, 5.35. Found: C, 64.11;
H, 4.73; N, 5.11.
2-(2-Nitr oph en yl)-5-(eth oxycar bon yl)pyr idin e (5c): 30%
yield; mp 113-115 °C, colorless prisms; 1H-NMR (CDCl3) δ
1.42 (t, 3H, J ) 7.1 Hz), 4.43 (q, 2H, J ) 7.2 Hz), 7.55-7.71
(m, 4H), 7.92 (d, 1H, J ) 7.8 Hz), 8.39 (dd, 1H, J ) 8.1, 2.1
Hz), 9.23 (dd, 1H, J ) 1.5, 0.9 Hz); 13C-NMR (CDCl3) δ 14.2,
61.5, 122.2, 124.5, 125.3, 129.8, 131.1, 132.6, 134.5, 137.9,
149.1, 150.7, 159.1, 164.9; EI MS m/ z (%): 272 (M+, 18), 170
(100). Anal. Calcd for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29.
Found: C, 61.59; H, 4.63; N, 10.53.
2-(2-Me t h o x y p h e n y l)-5-(e t h o x y c a r b o n y l)p y r id in e
(5d ): 31% yield; mp 51-52 °C, colorless prisms; 1H-NMR
(CDCl3) δ 1.41 (t, 3H, J ) 7.1 Hz), 3.86 (s, 3H), 4.42 (q, 2H, J
) 7.2 Hz), 7.01 (d, 1H, J ) 8.3 Hz), 7.09 (td, 1H, J ) 7.5, 0.9
Hz), 7.41 (td, 1H, J ) 8.3, 1.3 Hz), 7.86 (dd, 1H, J ) 7.7, 1.8
Hz), 7.95 (dd, 1H, J ) 8.4, 0.7 Hz), 8.29 (dd, 1H, J ) 8.3, 2.1
Hz), 9.29 (dd, 1H, J ) 1.9, 0.5 Hz); 13C-NMR (CDCl3) δ 14.3,
55.6, 61.2, 111.5, 121.1, 124.0, 124.5, 128.1, 130.8, 131.3, 136.6,
150.5, 157.2, 159.7, 165.5; EI MS m/ z (%): 257 (M+, 33), 152
(100). Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44.
Found: C, 70.26; H, 5.75; N, 5.22.
NO5: C, 67.21; H, 6.49; N, 3.92. Found: C, 67.33; H, 6.64; N,
3.69.
Gen er a l P r oced u r e for th e P r ep a r a tion of Dih yd r o-
p yr id in es 12 a n d 14. A mixture of the appropriate (vinylimi-
no)phosphorane 4 or 13 (2 mmol), the corresponding aromatic
aldehyde (2 mmol), and palladium on charcoal (0.056 g) in dry
o-xylene (35 mL) was treated at 160 °C in a sealed tube for 24
h (for compounds 12) or 48 h (for compounds 14). After cooling,
the mixture was filtered and from the filtrate the solvent was
removed under reduced pressure. The residual material was
chromatographed on a silica gel columm using ethyl acetate/
n-hexane (1:2) as eluent to give the dihydropyridine 12 or 14,
respectively.
1,4-Dih yd r o-4-(4-m eth ylp h en yl)-3,5-bis(eth oxyca r bon -
yl)p yr id in e (12a ): 43% yield; oil; 1H-NMR (CDCl3) δ 1.11 (t,
6H, J ) 7.1 Hz), 2.19 (s, 3H), 3.90-4.07 (m, 4H), 4.76 (s, 1H),
6.97 (d, 2H, J ) 8.0 Hz), 6.99-7.05 (m, 1H), 7.14 (d, 2H, J )
7.5 Hz), 7.17 (d, 2H, J ) 5.1 Hz); 13C-NMR (CDCl3) δ 14.2,
21.0, 37.1, 60.0, 106.1, 128.1, 128.7, 133.9, 135.6, 144.2, 167.4;
EI MS m/ z (%): 315 (M+, 6), 224 (100). Anal. Calcd for
C18H21NO4: C, 68.55; H, 6.71; N, 4.44. Found: C, 68.68; H,
6.54; N, 4.68.
1,4-Dih yd r o-4-(4-ch lor op h en yl)-3,5-bis(eth oxyca r bon -
yl)p yr id in e (12b): 40% yield; oil; 1H-NMR (CDCl3) δ 1.19 (t,
6H, J ) 6.9 Hz), 3.99-4.16 (m, 4H), 4.87 (s, 1H), 7.05-7.19
(m, 1H), 7.21 (d, 2H, J ) 8.4 Hz), 7.27 (d, 2H, J ) 8.4 Hz),
7.30 (d, 2H, J ) 5.4 Hz); 13C-NMR (CDCl3) δ 14.2, 37.2, 60.2,
107.8, 128.1, 129.7, 132.1, 134.0, 145.5, 167.1; EI MS m/ z
(%): 337 (M+ + 2, 14), 335 (M+, 48), 224 (100). Anal. Calcd
for C17H18ClNO4: C, 60.81; H, 5.40; N, 4.17. Found: C, 60.99;
H, 5.45; N, 4.04.
3-(Eth oxyca r bon yl)p yr id in e (5e): 42% yield; oil; 1H-
NMR (CDCl3) δ 1.42 (t, 3H, J ) 7.1 Hz), 4.42 (q, 2H, J ) 7.2
Hz), 7.40 (ddd, 1H, J ) 8.2, 4.9, 0.7 Hz), 8.31 (dt, 1H, J ) 8.0,
2.0 Hz), 8.78 (dd, 1H, J ) 4.9, 1.7 Hz), 9.24 (d, 1H, J ) 2.0
Hz); 13C-NMR (CDCl3) δ 14.3, 61.5, 123.3, 126.4, 137.1, 151.0,
153.4, 165.4; EI MS m/ z (%): 151 (M+, 28), 122 (100). Anal.
Calcd for C8H9NO2: C, 63.57; H, 6.00; N, 9.27. Found: C,
63.34; H, 6.15; N, 9.15.
1,4-D ih y d r o -4-(4-m e t h o x y p h e n y l)-3,5-b is (e t h o x y -
ca r bon yl)p yr id in e (12c): 40% yield; mp 125-128 °C, yellow
1
prisms; H-NMR (CDCl3) δ 1.12 (t, 6H, J ) 7.1 Hz), 3.66 (s,
3H), 3.88-4.12 (m, 4H), 4.75 (s, 1H), 6.71 (d, 2H, J ) 8.7 Hz),
6.80-6.91 (m, 1H), 7.17 (d, 2H, J ) 8.3 Hz), 7.20 (d, 2H, J )
5.1 Hz); 13C-NMR (CDCl3) δ 14.2, 36.7, 55.1, 60.0, 108.4, 113.3,
129.2, 133.7, 139.6, 158.1, 167.4; EI MS m/ z (%): 331 (M+,
5), 224 (100). Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39;
N, 4.23. Found: C, 65.15; H, 6.57; N, 4.31.
1,4-Dih yd r o-4-[(E)-2-p h en yleth en yl]-3,5-bis(eth oxyca r -
bon yl)p yr id in e (6a ): 44% yield; mp 132-135 °C, colorless
1
prisms; H-NMR (CDCl3) δ 1.26 (t, 6H, J ) 7.1 Hz), 4.18 (m,
4H), 4.54 (m, 1H), 6.28-6.30 (m, 2H), 6.74-6.89 (m, 1H), 7.15-
7.35 (m, 7H); 13C-NMR (CDCl3) δ 14.4, 34.0, 60.1, 106.2, 126.3,
127.1, 128.4, 129.7, 132.2, 134.6, 137.5, 167.3; EI MS m/ z
(%): 327 (M+, 4), 224 (100). Anal. Calcd for C19H21NO4: C,
69.71; H, 6.47; N, 4.28. Found: C, 69.49; H, 6.71; N, 4.19.
1,4-Dih yd r o-4-[(E)-2-(4-ch lor op h en yl)eth en yl]-3,5-bis-
(eth oxyca r bon yl)p yr id in e (6b): 40% yield, oil; 1H-NMR
(CDCl3) δ 1.19 (t, 6H, J ) 7.1 Hz), 4.03-4.19 (m, 4H), 4.46-
4.49 (m, 1H), 6.10-6.28 (m, 2H), 6.60-6.71 (m, 1H), 7.10-
7.19 (m, 4H), 7.21 (2H, d, J ) 5.3 Hz); 13C-NMR (CDCl3) δ
14.4, 34.0, 60.2, 106.0, 127.5, 128.4, 128.5, 132.6, 132.8, 134.6,
136.0, 167.2; EI MS m/ z (%): 363 (M+ + 2, 16), 361 (M+, 46),
332 (100). Anal. Calcd for C19H20ClNO4: C, 63.07; H, 5.29;
N, 3.87. Found: C, 62.95; H, 5.42; N, 4.08.
1,4-D ih y d r o -4-(3-m e t h o x y p h e n y l)-3,5-b is (e t h o x y -
ca r bon yl)p yr id in e (12d ): 40% yield; mp 135-138 °C, color-
1
less prisms; H-NMR (CDCl3) δ 1.08 (t, 6H, J ) 7.1 Hz), 3.76
(s, 3H), 3.83-4.07 (m, 4H), 5.14 (s, 1H), 6.72-6.81 (m, 3H),
7.05 (td, 1H, J ) 7.8, 1.7 Hz), 7.18-7.23 (m, 3H); 13C-NMR
(CDCl3) δ 14.2, 32.4, 55.6, 59.8, 107.9, 110.8, 120.3, 127.6,
131.1, 134.4, 135.6, 157.1, 167.6; EI MS m/ z (%): 331 (M+,
13), 302 (100). Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39;
N, 4.23. Found: C, 65.15; H, 6.62; N, 4.12.
3,4,6,7,9,10-Hexa h yd r o-9-(4-m eth ylp h en yl)-1,8(2H,5H)-
a cr id in ed ion e (14a ): 44% yield; mp 280 °C, decomposed,
colorless prisms; 1H-NMR (DMSO-d6) δ 1.72-1.99 (m, 4H),
2.11-2.25 (m, 4H), 2.43-2.58 (m, 4H) 4.86 (s, 1H), 6.94 (d,
2H, J ) 8.1 Hz), 7.02 (d, 2H, J ) 8.1 Hz), 9.40 (s, 1H); 13C-
NMR (DMSO-d6) δ 20.5, 20.8, 26.3, 31.6, 36.8, 112.6, 127.3,
128.2, 134.2, 144.2, 151.0, 194.6; EI MS m/ z (%): 307 (M+,
24), 216 (100). Anal. Calcd for C20H21NO2: C, 78.15; H, 6.89;
N, 4.56. Found: C, 78.28; H, 7.04; N, 4.35.
3,4,6,7,9,10-Hexa h yd r o-9-(4-ch lor op h en yl)-1,8(2H,5H)-
a cr id in ed ion e (14b): 43% yield; mp 280 °C, decomposed,
colorless prisms; 1H-NMR (DMSO-d6) δ 1.74-1.97 (m, 4H),
2.17-2.20 (m, 4H), 2.51-2.54 (m, 4H) 4.89 (s, 1H), 7.16 (d,
2H, J ) 7.5 Hz), 7.22 (d, 2H, J ) 7.5 Hz), 9.49 (s, 1H); 13C-
NMR (DMSO-d6) δ 20.7, 26.3, 31.9, 36.7, 112.0, 127.6, 129.3,
129.9, 146.2, 151.4, 194.7; EI MS m/ z (%): 329 (M+ + 2, 8),
327 (M+, 22), 216 (100). Anal. Calcd for C19H17ClNO2: C,
69.83; H, 5.24; N, 4.29. Found: C, 69.68; H, 5.42; N, 4.11.
3,4,6,7,9,10-Hexah ydr o-9-(4-m eth oxyph en yl)-1,8(2H,5H)-
a cr id in ed ion e (14c): 38% yield; mp 280 °C, decomposed,
colorless prisms; 1H-NMR (DMSO-d6) δ 1.70-1.84 (m, 2H),
1.85-1.97 (m, 2H), 2.17-2.22 (m, 4H), 2.49-2.51 (m, 4H), 3.66
(s, 3H), 4.84 (s, 1H), 6.71 (d, 2H, J ) 8.7 Hz), 7.04 (d, 2H, J )
1,4-Dih yd r o-4-[(E)-2-(2-n it r op h en yl)et h en yl]-3,5-b is-
(eth oxyca r bon yl)p yr id in e (6c): 46% yield; mp 131-134 °C,
1
colorless prisms; H-NMR (CDCl3) δ 1.29 (t, 6H, J ) 7.1 Hz),
4.22 (q, 4H), 4.61 (d, 1H, J ) 5.9 Hz), 6.36 (dd, 1H, J ) 16.4,
5.9 Hz), 6.75 (d, 1H, J ) 15.9 Hz), 7.00 (t, 1H, J ) 5.0 Hz),
7.32 (tt, 1H, J ) 8.9, 1.5 Hz), 7.37 (d, 2H, J ) 5.4 Hz), 7.50
(td, 1H, J ) 7.9, 1.2 Hz), 7.56 (dd, 1H, J ) 7.9, 2.0 Hz), 7.88
(dd, 1H, J ) 8.6, 0.9 Hz); 13C-NMR (CDCl3) δ 14.4, 34.1, 60.3,
105.8, 124.4, 125.6, 127.6, 128.8, 133.0, 133.6, 135.0, 137.8,
147.6, 167.1; EI MS m/ z (%): 372 (M+, 2), 168 (100). Anal.
Calcd for C19H20N2O6: C, 61.29; H, 5.41; N, 7.52. Found: C,
61.14; H, 5.54; N, 7.64.
1,4-Dih yd r o-4-[(E)-2-(2-m et h oxyp h en yl)et h en yl]-3,5-
bis(eth oxyca r bon yl)p yr id in e (6d ): 38% yield; mp 116-121
1
°C, colorless prisms; H-NMR (CDCl3) δ 1.27 (t, 6H, J ) 7.1
Hz), 3.78 (s, 1H), 4.18 (m, 4H), 4.55 (d, 1H, J ) 6.5 Hz), 6.27
(dd, 1H, J ) 16.1, 6.5 Hz), 6.55 (t, 1H, J ) 5.0 Hz), 6.66 (d,
1H, J ) 16.1 Hz), 6.79-6.90 (m, 2H), 7.15 (td, 1H, J ) 7.7, 1.5

8098 J . Org. Chem., Vol. 61, No. 23, 1996
Molina et al.
8.7 Hz), 9.40 (s, 1H); 13C-NMR (DMSO-d6) δ 21.0, 26.5, 31.4,
7.2 Hz), 4.48 (q, 2H, J ) 7.1 Hz), 7.38-7.46 (m, 5H), 7.48 (d,
1H, J ) 5.1 Hz), 8.78 (d, 1H, J ) 4.8 Hz); 13C-NMR (CDCl3) δ
13.7, 14.2, 61.8, 62.5, 127.0, 128.2, 128.6, 129.1, 131.0, 137.0,
146.0, 149.2, 149.8, 164.8, 167.0; EI MS m/ z (%): 299 (M+,
3), 155 (100). Anal Calcd for C17H17NO4: C, 68.22; H, 5.73;
N, 4.68. Found: C, 68.01; H, 5.87; N, 4.89.
37.0, 55.0, 112.9, 113.3, 128.5, 139.9, 151.2, 157.3, 194.9; EI
MS m/ z (%): 323 (M+, 17), 216 (100). Anal. Calcd for C20H21
-
NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 74.33; H, 6.64; N,
4.44.
3,4,6,7,9,10-Hexah ydr o-9-(3-m eth oxyph en yl)-1,8(2H,5H)-
a cr id in ed ion e (14d ): 36% yield; mp 280 °C, decomposed,
yellow prisms; 1H-NMR (DMSO-d6) δ 1.70-1.99 (m, 4H), 2.18-
2.24 (m, 4H), 2.50-2.51 (m, 4H), 3.66 (s, 3H), 4.90 (s, 1H),
6.60-6.74 (m, 3H), 7.08 (t, 1H, J ) 7.6 Hz), 9.46 (s, 1H); 13C-
NMR (DMSO-d6) δ 20.8, 26.3, 31.9, 36.8, 54.7, 110.2, 112.3,
113.8, 119.7, 128.7, 148.8, 151.3, 158.8, 194.8; EI MS m/ z
(%): 323 (M+, 100), 216 (82). Anal. Calcd for C20H21NO3: C,
74.28; H, 6.55; N, 4.33. Found: C, 74.11; H, 6.46; N, 4.53.
P r ep a r a tion of (E)-[(Tr ip h en ylp h osp h or a n ylid en e)-
a m in o]bu ten ed ioic Acid Dieth yl Ester (16). To a stirred
slurry of sodium azide (15.0 g, 0.25 mol) in dry acetonitrile
(100 mL) at -10 °C under nitrogen was added iodine mono-
chloride (18.3 g, 0.113 mmol) over a period of 20 min. The
reaction mixture was stirred for an additional 10 min, and
diethyl fumarate (17.218 g, 0.1 mol) was added, allowed to
warm to room temperature, and stirred for 20 h. The resultant
solution was poured into water (250 mL) and extracted with
Et2O (3 × 50 mL). The combined organic layers were washed
with 5% sodium thiosulfate (150 mL) and brine (4 × 225 mL)
and dried over anhydrous magnesium sulfate. The solvent was
removed under reduced pressure at room temperature, the
residual material was dissolved in acetone (200 mL), and
triethylamine (10.117 g, 0.1 mol) was added. The resultant
mixture was stirred at room temperature for 24 h and then
poured into water (20 mL) and extracted with Et2O (3 × 100
mL). The combined organic layers were washed with brine
(2 × 100 mL) and dried over anhydrous magnesium sulfate.
The solvent was removed under reduced pressure at room
temperature, and the residual material was chromatographed
on a silica gel column with dichloromethane/n-hexane (1:1) as
eluent to give a mixture of vinyl azides 15a and 15b.
To a solution of Ph3P (3.075g, 11.7 mmol) in dry dichlo-
romethane (20 mL) was added a solution of the vinyl azide 15
(2.5 g, 11.7 mmol) in the same solvent (10 mL) dropwise at
room temperature under nitrogen. The reaction mixture was
stirred at room temperature for 2 h. The solvent was removed
under reduced pressure, and the crude product was found to
be a mixture of (vinylimino)phosphoranes 16 and 17 from
which iminophosphorane 16 was isolated in 69% yield in pure
state by recrystallization from dichloromethane/Et2O (1:1): mp
132-134 °C, colorless prisms; 1H-NMR (CDCl3) δ 1.15 (t, 3H,
J ) 7.2 Hz), 1.25 (t, 3H, J ) 7.2 Hz), 4.01 (q, 2H, J ) 7.1 Hz),
4.03 (q, 2H, J ) 7.1 Hz), 4.82 (d, 1H, J ) 0.6 Hz), 7.43-7.49
(m, 6H), 7.52-7.58 (m, 3H), 7.68-7.75 (m, 6H); 13C-NMR
(CDCl3) δ 13.8, 14.4, 58.8, 60.8, 95.6 (J ) 16.1 Hz), 128.4 (J )
100.7 Hz), 128.7 (J ) 12.5 Hz), 132.6 (J ) 2.5 Hz), 132.6 (J )
10.1 Hz), 159.2 (J ) 4.0 Hz), 167.8 (J ) 1.1 Hz), 168.6 (J )
23.7 Hz); EI MS m/ z (%): 447 (M+, 2), 201 (100). Anal. Calcd
for C26H26NO4P: C, 69.79; H, 5.86; N, 3.13. Found: C, 69.65;
H, 6.05; N, 3.30.
4-(2-Me t h oxyp h e n yl)-2,3-b is(e t h oxyca r b on yl)p yr i-
d in e (18b): 36% yield; mp 75-79 °C, colorless prisms; 1H-
NMR (CDCl3) δ 1.03 (t, 3H, J ) 6.9 Hz), 1.41 (t, 3H, J ) 7.2
Hz), 3.72 (s, 3H), 4.10 (q, 2H, J ) 7.1 Hz), 4.44 (q, 2H, J ) 7.2
Hz), 6.93 (d, 1H, J ) 8.1 Hz), 6.99 (td, 1H, J ) 7.5, 0.9 Hz),
7.18 (dd, 1H, J ) 7.5, 2.1 Hz), 7.38 (td, 1H, J ) 7.5, 1.8 Hz),
7.42 (d, 1H, J ) 5.1 Hz), 8.72 (d, 1H, J ) 4.8 Hz); 13C-NMR
(CDCl3) δ 13.6, 14.2, 55.4, 61.4, 62.3, 110.8, 120.6, 125.8, 128.0,
130.1, 130.5, 130.9, 146.7, 147.1, 149.5, 156.1, 165.3, 166.6;
EI MS m/ z (%): 329 (M+, 15), 256 (100). Anal. Calcd for
C18H19NO5: C, 65.64; H, 5.82; N, 4.25. Found: C, 65.73; H,
5.95; N, 4.11.
4-(4-Ch lor op h en yl)-2,3-b is(et h oxyca r b on yl)p yr id in e
(18c): 36% yield; mp 80-82 °C, colorless prisms; 1H-NMR
(CDCl3) δ 1.14 (t, 3H, J ) 7.1 Hz), 1.44 (t, 3H, J ) 6.9 Hz),
4.22 (q, 2H, J ) 7.2 Hz), 4.48 (q, 2H, J ) 7.1 Hz), 7.34 (d, 2H,
J ) 9.0 Hz), 7.43 (d, 2H, J ) 8.7 Hz), 7.45 (d, 1H, J ) 5.1 Hz),
8.79 (d, 1H, J ) 5.1 Hz); 13C-NMR (CDCl3) δ 13.7, 14.2, 61.9,
62.5, 126.7, 128.9, 129.6, 130.8, 135.3, 135.4, 146.1, 147.8,
149.8, 164.6, 166.8; EI MS m/ z (%): 335 (M+ + 2, 4), 333 (M+,
11), 189 (100). Anal. Calcd for C17H16ClNO4: C, 61.18; H,
4.83; N, 4.20. Found: C, 60.95; H, 5.01; N, 4.33.
4-(2-Nit r op h e n yl)-2,3-b is(e t h oxyca r b on yl)p yr id in e
(18d ): 37% yield; mp 116-118 °C, colorless prisms; 1H-NMR
(CDCl3) δ 1.03 (t, 3H, J ) 7.2 Hz), 1.43 (t, 3H, J ) 7.2 Hz),
4.07 (dq, 2H, J ) 7.2 Hz, 4.5 Hz), 4.47 (q, 2H, J ) 7.2 Hz),
7.34 (dd, 1H, J ) 7.2Hz, 1.5 Hz), 7.42 (d, 1H, J ) 5.1 Hz),
7.64 (td, 1H, J ) 7.7 Hz, 1.8 Hz), 7.71 (td, 1H, J ) 7.5 Hz, 1.5
Hz), 8.19 (dd, 1H, J ) 7.5 Hz, 1.4 Hz), 8.83 (d, 1H, J ) 4.8
Hz); 13C-NMR (CDCl3) δ 13.6, 14.2, 62.0, 62.6, 124.8, 126.0,
129.5, 130.1, 131.5, 132.0, 133.2, 146.7, 146.8, 147.7, 149.9,
164.7, 165.9; EI MS m/ z (%):271 (22), 224 (100), 192 (81), 182
(41). Anal. Calcd for C17H16N2O6: C, 59.30; H, 4.68; N, 8.14.
Found: C, 59.09; H, 4.86; N, 8.30.
4-(Eth oxycar bon yl)ben zo[c][2,7]n aph th yr idin -5-on e (5):
A mixture of 18d (0.193 g, 0.56 mmol), acetone (10 mL), acetic
acid (1 mL), water (1 mL), and powdered iron (0.36 g) was
refluxed for 1 h and then dichloromethane (10 mL) was added.
The resultant suspension was filtered, and a saturated solution
of sodium carbonate (5 mL) was added to the filtrate. The
organic layer was separated and dried over anhydrous mag-
nesium sulfate. The solvent was removed under reduced
pressure, and the crude product was recrystallized acetonitrile
1
to give 5 in 74% yield: mp 280-283 °C, colorless prisms; H-
NMR (DMSO-d6) δ 1.33 (t, 3H, J ) 7.1 Hz), 4.24 (q, 2H, J )
7.1 Hz), 7.35 (t, 1H, J ) 8.1Hz), 7.42 (d, 1H, J ) 8.7 Hz), 7.66
(d, 1H, J ) 7.6 Hz), 8.50 (d, 1H, J ) 8.1 Hz), 8.56 (d, 1H, J )
5.6 Hz), 8.78 (d, 1H, J ) 5.5 Hz), 12.01 (s, 1H); 13C-NMR
(DMSO-d6) δ 13.9, 61.1, 115.3, 116.5, 117.0, 117.3, 122.8, 124.6,
132.4, 138.2, 142.0, 150.9, 153.6, 158.9, 167.1; EI MS m/ z
Gen er a l P r oced u r e for t h e P r ep a r a t ion of 4-Ar yl-
p yr id in es 18. A solution of the (vinylimino)phosphorane 16
(0.5 g, 1.12 mmol) and the appropriate R,â-unsaturated alde-
hyde (1.12 mmol) in nitrobenzene (5 mL) was heated at reflux
temperature for 8 h. After cooling, the solvent was removed
under reduced pressure and the residual material was chro-
matographed on a silica gel column with ethyl acetate/n-
hexane (1:3) as eluent to give 18 which was purified by
recrystallization from ethyl acetate/Et2O/n-hexane (1:1:1).
4-P h en yl-2,3-bis(eth oxyca r bon yl)p yr id in e (18a ): 38%
yield; mp 82-83 °C, colorless prisms; 1H-NMR (CDCl3) δ 1.08
(t, 3H, J ) 7.2 Hz), 1.44 (t, 3H, J ) 6.9 Hz), 4.19 (q, 2H, J )
(%): 268 (23), 223 (46), 196 (100). Anal. Calcd for C15H12
N2O3: C, 67.16; H, 4.51; N, 10.44. Found: C, 67.40; H, 4.35;
N, 10.67.
-
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the Direccio´n General de Investi-
gacio´n Cient´ıfica y Te´cnica (project number PB92-0984).
One of us (A.P.) also thanks to the MEC for a
studentship.
J O960940V