Reaction of N-vinylic phosphazenes derived from β-amino acids with aldehydes. Azadiene-mediated synthesis of dihydropyridines, pyridines, and polycyclic nitrogen derivatives

Article abstract of DOI:10.1021/jo9902650

Enamino phosphonium salts 2 are obtained by 1,2-addition of hydrogen chloride to N-vinylic phosphazenes 1 derived from triphenylphosphine. Aza- Wittig reaction of phosphazenes 1 derived from triphenylphosphine and 6 derived from diphenylmethylphosphine with aldehydes 3 leads to the formation of 2-azadienes 7. Reaction of azadienes 7 with enamines affords dihydropyridines 9 and 11, pyridines 12, and bicyclic nitrogen heterocycles 15-18 in a regioselective fashion, while heterodiene 20 reacts in the same way with pyrrolidinocyclohexanone giving 1-azaphenanthrene compound 21. Reaction of enamino phosphonium salts 2 with aldehydes 3 gives symmetrical dihydropyridines 5.

Full text of DOI:10.1021/jo9902650

J . Org. Chem. 1999, 64, 6239-6246
6239
Rea ction of N-Vin ylic P h osp h a zen es Der ived fr om â-Am in o Acid s
w ith Ald eh yd es. Aza d ien e-Med ia ted Syn th esis of
Dih yd r op yr id in es, P yr id in es, a n d P olycyclic Nitr ogen Der iva tives
Francisco Palacios,*,† Esther Herra´n, and Gloria Rubiales
Departamento de Quı´mica Orga´nica, Facultad de Farmacia, Universidad del Pais Vasco,
Apartado 450, 01080 Vitoria, Spain
Received February 11, 1999
Enamino phosphonium salts 2 are obtained by 1,2-addition of hydrogen chloride to N-vinylic
phosphazenes 1 derived from triphenylphosphine. Aza-Wittig reaction of phosphazenes 1 derived
from triphenylphosphine and 6 derived from diphenylmethylphosphine with aldehydes 3 leads to
the formation of 2-azadienes 7. Reaction of azadienes 7 with enamines affords dihydropyridines 9
and 11, pyridines 12, and bicyclic nitrogen heterocycles 15-18 in a regioselective fashion, while
heterodiene 20 reacts in the same way with pyrrolidinocyclohexanone giving 1-azaphenanthrene
compound 21. Reaction of enamino phosphonium salts 2 with aldehydes 3 gives symmetrical
dihydropyridines 5.
In tr od u ction
pounds.6,8,12 In some cases the reaction involves the
phosphazene group,3,4,11b,12d while in other examples it
remains unaffected.4b,11a,12a In the case of N-vinylic phos-
phazenes, an adjacent double bond in conjugation with
the phosphazene moiety introduces the interesting prob-
lem of site selectivity: reaction at the nitrogen (1,2-
addition) of the phosphazene group1 versus reactions at
the γ-C atom (1,4-addition).2,4b,7a,13 We have reported that
the influence of substituents of the phosphorus atom in
N-vinylic phosphazenes I can play an important role in
the reactivity pattern observed with carbonyl compounds,4b
since reaction of phosphazenes derived from triphen-
ylphosphine (I, R1 ) Ph) with carbonyl compounds gives
the monoadduct II (1,4-addition), while phosphazene
derived from diphenylmethylphosphine (I, R1 ) Me)
undergoes aza-Wittig reaction with carbonyl compounds
and leads to the formation of 2-azadienes III (Scheme
1).
Phosphazenes1 represent an important class of com-
pounds and have attracted a great deal of attention in
recent years because of their broad range of applications.
The utility of N-vinylic phosphazenes2 has been demon-
strated in the synthesis of functionalized imine com-
pounds, such as electronically neutral3 and electron-poor
2-azadienes,4 and as key intermediates in the preparation
of heterocycles, such as 1,3-oxazines,3 pyridine deriva-
tives,4a,b-7 and bicyclic8 and polycyclic compounds,2,9 as
well as in elegant routes toward both the preparation of
biologically active natural products and the construction
of the framework of pharmacologically active alkaloids.10
We have been involved in the study of simple and
functionalized phosphazenes1b as well as in their use in
the preparation of acyclic3,4,11 and heterocyclic com-
† Telephone: 34-945-013103. Fax: 34-945-130756. E-mail:
qoppagaf@vf.ehu.es.
(1) For reviews see: (a) Wamhoff, H.; Richardt, G.; Stoelben, S. Adv.
Heterocycl. Chem. 1995, 64, 159. (b) Barluenga, J .; Palacios F. Org.
Prep. Proced. Int. 1991, 23, 1.
(2) For a review see: Nitta, M. in Reviews on Heteroatom Chemistry;
Oae, S., Ed.; MYU: Tokyo, 1993; Vol. 9, p 87.
(3) Palacios, F.; Alonso, C.; Rubiales, G. J . Org. Chem. 1997, 62,
1146.
(4) (a) Palacios, F.; Pe´rez de Heredia, I.; Rubiales, G. J . Org. Chem.
1995, 60, 2384. (b) Palacios, F.; Aparicio, D.; de los Santos, J . M.
Tetrahedron 1996, 52, 4857. (c) Barluenga, J .; Ferrero, M.; Palacios,
F. Tetrahedron Lett. 1990, 31, 3497. (d) Barluenga, J .; Ferrero, M.;
Palacios, F. Tetrahedron Lett. 1988, 29, 4863.
(5) Barluenga, J .; Ferrero, M.; Palacios, F. Tetrahedron 1997, 53,
4521.
A recent publication14 has reported that N-vinylic
phosphazenes IV (R1 ) Ph, R3 ) H), with an ethoxycar-
bonyl group at the â-position and prepared by Staudinger
reaction of â-azido carboxylate15 with phosphines in a
similar way to that described4a for IV (R1 ) Ph, R3 ) Me),
reacted with aldehydes. This reaction was reported as
involving an initial nucleophilic attack of the γ-C atom
(1,4-addition) of the phosphazene on the aldehyde, in
contrast to the behavior of conjugated phosphazenes with
carbonyl compounds to give 2-azadienes.4a These results
have prompted us to report our own study on the
ambident reactivity (1,2- and 1,4-addition) of phos-
(6) Barluenga, J .; Ferrero, M.; Lopez, F.; Palacios, F. J . Chem Soc.,
Perkin Trans 1 1990, 2193.
(7) (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.
(8) Palacios, F.; Alonso, C.; Rubiales, G. Tetrahedron 1995, 51, 3683.
(9) (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.
(11) (a) Lopez, F.; Pelaez, E.; Palacios, F.; Barluenga, J .; Garc´ıa, S.;
Tejerina, B.; Garc´ıa, A. J . Org. Chem., 1994, 59, 1984. (b) Barluenga,
J .; Merino, I.; Palacios, F. Tetrahedron Lett. 1989, 30, 5493.
(12) (a) Barluenga, J .; Lo´pez, F.; Palacios, F. Tetrahedon Lett. 1987,
28, 4327. (b) Barluenga, J .; Lo´pez, F.; Palacios, F. Tetrahedon Lett.
1987, 28, 2875. (c) Barluenga, J .; Lo´pez, F.; Palacios, F. Chem.
Commun. 1986, 1574. (d) Barluenga, J .; Lo´pez, F.; Palacios, F. J .
Organomet. Chem. 1990, 382, 61.
(13) Molina, P.; Aller, E.; Lo´pez-La´zaro, A.; Alajarin, M.; Lorenzo,
A. Tetrahedron Lett. 1994, 35, 3817.
(10) (a) Chavignon, O.; Teulade, J . C.; Roche, D.; Madesclaire, M.;
Blache, Y.; Gueiffier, A.; Chabard, J . L.; Dauphin, G. J . Org. Chem.
1994, 59, 6413. (b) Rodrigues, J .; Augusto, R.; Leiva, G. C.; de Sousa,
D. F. Tetrahedron Lett. 1995, 36, 59.
(14) Molina, P.; Pastor, A,; Vilaplana, M. J . J . Org. Chem. 1996,
61, 8094.
(15) Palacios, F.; Aparicio, D.; de los Santos, J .; Pe´rez de Heredia,
I.; Rubiales, G. Org. Prep. Proc. Int. 1995, 27, 145.
10.1021/jo9902650 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/30/1999

6240 J . Org. Chem., Vol. 64, No. 17, 1999
Palacios et al.
Sch em e 2. P h osp h on iu m Sa lts 2 F or m a tion
Sch em e 1. 1,2-Ad d ition ver su s 1,4-Ad d ition of
N-Vin ylic P h osp h a zen es I w ith Ald eh yd es
Sch em e 3. 1,4-Dih yd r op yr id in es 5 F or m a tion
th r ou gh Rea ction of N-Vin ylic P h osp h a zen es 1
a n d Ald eh yd es 3
phazenes IV (R1 ) Ph) derived from triphenylphosphine
with hydrogen chloride. The regioselective aza-Wittig
reaction (1,2-addition) of phosphazenes IV (R1 ) Me)
derived from diphenylmethylphosphine with aldehydes
and the isolation of the corresponding 2-azadiene deriva-
tive were also studied. This is consistent with the
reported behavior not only of these kinds of phospha-
zenes4a derived from â-amino acids but also that of
N-vinylic phosphazenes derived from R-amino acids4c,d
and that of other N-vinylic phosphazenes.3,4b Moreover,
we report here that 2-azadienes can be used as key
intermediates in the synthesis of heterocyclic compounds
derived from â-amino acids and of polycyclic nitrogen
derivatives.
moderate yields.14 The authors suggest that these het-
erocycles 5 could be formed by an initial addition of
aldehydes 3 on the â-carbon atom of the N-vinylic
phosphazene 1a (1,4-addition) to give 1,2,5-oxaazaphos-
phorane 4 followed by regioselective attack of a second
molecule of the phosphorane 1a with loss of tri-
phenylphosphine oxide (Scheme 3).
Resu lts a n d Discu ssion
R egioselect ive 1,2-Ad d it ion of H Cl t o P h os-
p h a zen es 1 Der ived fr om Tr ip h en ylp h osp h in e. Hy-
drogen chloride was bubbled through a solution of N-
vinylic phosphazenes 1a (R1 ) H) in CH2Cl2/Et2O to yield
hygroscopic enamino phosphonium salt 2a in a regio-
selective fashion. The hygroscopic compound 2a was not
isolated but characterized by its spectroscopic properties.
The 31P NMR spectrum of 2a showed an absorption at
δP 37.99 ppm. The signal for the 2a vinylic protons
appeared at δH 7.02 and 6.40 ppm, respectively, with a
We found that the room-temperature reaction of N-
vinylic phosphazene 6a (containing an ethoxycarbonyl
group as substituent in the 4 position) with p-nitrobenz-
aldehyde at room temperature gave the aza-Wittig
product (1,2-addition) 7a a in excellent yield (Scheme 4,
Table 1, entry 1). Spectroscopic data and mass spectrom-
etry of compound 7a a indicate that only the E,Z-isomer
was obtained. The olefinic protons of 7a a showed absorp-
tions at δ 7.88 and 6.23 ppm (3J HH ) 13.0 Hz) as doublets,
and the iminic proton appeared at δ 8.44 ppm as a
singlet. The selective saturation of the singlet at 8.44 ppm
afforded positive NOE over the adjacent vinylic proton
without interaction with the olefinic proton in the 4
position (Scheme 4). This NOE observation was consis-
tent with the E stereochemistry of azadiene 7a a . Het-
erodienes 7a b-a e (Table 1, entries 2-5) are unstable
during distillation and/or chromatography and were used
without purification.17
3
coupling constant of J HH ) 13.6 Hz. This is consistent
with the E-configuration of the carbon-carbon double
bond.4a,16 The olefinic carbons gave a singlet at δC 139.5
and a doublet at 105.1 ppm (3J PC ) 11.1 Hz). The crude
2a was used without purification. In the case of 3-methyl-
substituted N-vinylic phosphazenes 1b (R1 ) Me) the
reaction with HCl gave a mixture of both Z- and E-
enamines 2b in a 1:1 ratio (Scheme 2).
Aza -Wittig Rea ction of P h osp h a zen es 6 Der ived
fr om Dip h en ylm eth ylp h osp h in e w ith Ald eh yd es 3
(1,2-Ad d ition ver su s 1,4-Ad d ition ). A recent report
describes the reaction of N-vinylic phosphazene 1a with
aromatic aldehydes 3, in o-xylene at 160 °C, in the
presence of palladium on charcoal and in a sealed tube,
giving 4-aryl-3,5-(diethoxycarbonyl)dihydropyridines 5 in
The scope of this aza-Wittig reaction was not limited
to the phosphazenes derived from ethyl â-azidoacrylate,
given that 3-methyl- 6b (R1 ) Me) and 3-phenyl-
substituted N-vinylic phosphazenes 6c (R1 ) Ph) also
reacted with aldehydes leading to the formation of
(17) The reaction was monitored by 31P and 1H NMR showing the
disapperance of phosphazene 6 or 19 and the formation of azadiene 7
or 20.
(16) Palacios, F.; Aparicio, D.; Garcia, J . Tetrahedron 1996, 52, 9609.

Azadiene-Mediated Syntheses
J . Org. Chem., Vol. 64, No. 17, 1999 6241
Ta ble 1. Com p ou n d s 7 Obta in ed
reactn conditions
entry
starting material
products
R1
R2
R3
T (°C)
time (h)
yield (%)
E/Z ratiob
1
2
3
4
5
6
7
8
9
10
11
12
13
14
6a
6a
6a
6a
6a
6b
1b
6b
1b
6b
6c
1c
6c
1c
7a a
7a b
7a c
7a d
7a e
7ba
7ba
7bb
7bb
7bc
7ca
7ca
7cb
7cb
H
H
H
H
Et
Et
Et
Et
p-NO2-Ph
o-NO2-Ph
Ph
rt
rt
rt
rt
45
rt
2
2
3
82a
75d
88d
67d
68d
80a
61a
80d
45d
75d
71a
52a
75d
47d
100/0
100/0
100/0
100/0
100/0
100/0
100/0
80/20
80/20
80/20
100/0
100/0
90/10
90/10
3-Pyr
2
H
Et
p-OMe-Ph
p-NO2-Ph
p-NO2-Ph
Ph
24
24
3
200
24
24
2
3
30
30
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Et
Et
Et
Et
100c
45
100c
rt
Ph
o-NO2-Ph
p-NO2-Ph
p-NO2-Ph
p-Me-Ph
p-Me-Ph
rt
100c
60
100c
a
b
1
Purified by chromatography. E/Z ratio (iminic bond) by GC and H NMR assignment. c The reaction was performed without solvent.
Yield calculated by 1H NMR.
d
Sch em e 4. 1,2-Dih yd r op yr id in es 9 F or m a tion
th r ou gh [4 + 2] Cycloa d d ition Rea ction of
Aza d ien es 7 a n d P h osp h a zen es 1 a n d 6
elimination of the iminophosphorane from the cyclo-
adduct 8 could give dihydropyridines 9 (Scheme 4).
Cycloa d d it ion R ea ct ion of Aza d ien es 7 w it h
En a m in es. To test the synthetic usefulness of the new
azadienes 7 as reagents for heterocyclic synthesis18 we
explore cycloaddition reactions of electron deficient 2-aza-
dienes 7 (Scheme 4). At first, the reaction of azadienes 7
with conjugated phosphazenes 6 was studied. Treatment
of azadienes 7a a ,a e with a second molecule of phos-
phazene 6a also led to dihydropyridines 9a f,a g (Scheme
4, route b, Table 2, entries 6 and 7). This behavior
suggests that, in the reaction of 2 equiv of phosphazenes
6 and 1 with aldehydes to obtain dihydropyridines 9
(Scheme 4, route a), azadienes 7 are involved. Dihydro-
pyridines 9 (R1 ) H, R2 ) R4) may alternatively be
obtained through reaction of azadienes 7 with â-enamino
esters 10 (Scheme 5). Reaction of azadienes 7 with
enamines 10 led to the formation of dihydropyridines 9
(R1 ) H, R2 ) R4 ) Et) (Table 2, entries 8 and 9).
Likewise, dihydropyridines 11 (R2 * R4) can be obtained
when azadienes 7 react with enamines 10 derived from
other carboxylic esters (R2 * R4, Table 2, entries 10-
15). Calcium channel antagonist action of 1,2-dihydro-
pyridines derived from â-amino acids has been reported.19
Dihydropyridines 11 underwent aromatization to give
functionalized pyridines 12 by means of oxidation with
quinone (Table 2, entries 16 and 17). Nevertheless
pyridines 12a c,bd were directly obtained when azadienes
7a b,bc were used (Table 2, entries 18 and 19). The
reduction of 2-o-nitrophenyl-substituted pyridines 12a c,-
bd with Fe/HOAc affords benzonaphthyridinones 13a ,b
(Scheme 6).
azadienes 7ba ,bc and 7ca ,cb, obtained mainly as E-
imine isomers (Table 1, entries 6 and 11). In the case of
7bb, 7bc, and 7cb a mixture of E- and Z-imine isomers
(Table 1, entries 8, 10, and 13) was obtained. Azadienes
7ba , 7bb, 7ca , and 7cb (Table 1, entries 7, 9, 12, and
14) were obtained in moderate yields from N-vinylic
phosphazenes derived from triphenylphosphine 1b,c
when the reaction of 1b,c with aldehydes 3 was per-
formed at 100 °C without solvent. Treatment of 2 equiv
of phosphazenes 6b and 1b,c derived from both diphen-
ylmethylphosphine and triphenylphosphine respectively
with 1 equiv of aromatic aldehydes 3 gave 2-aryl-3,4-
(dialkoxycarbonyl)dihydropyridines 9 (Scheme 4, route
a) in good yields and in a regioselective fashion (Table 2,
entries 1-5). The process could start with an aza-Wittig
reaction of the phosphazenes 1 or 6 and aldehydes 3 to
give azadienes 7, which then undergo a regioselective [4
+ 2] cycloaddition reaction with a second molecule of
phosphazenes 1 or 6, which act as dienophile. Thermal
The reaction of heterodienes 7 with more reactive
enamines was also performed. Pyrrolidinecyclohexanone
14a (n ) 2) reacts with azadienes 7a a ,a d (R1 ) H) at
(18) For reviews, see: (a) Boger, D. L. In Comprehensive Organic
Synthesis; Trost, B. M., Paquete, L. A., Eds.; Pergamon Press: Oxford,
U.K., 1991; Vol. 5, p 451. (b) Barluenga, J .; J oglar, J .; Gonza´lez, F. J .;
Fustero, S. Synlett 1990, 129. (c) Fringuelli, F.; Tatichi, A. In Dienes
in the Diels-Alder Reaction; Wiley: New York, 1990. (d) Boger, D. L.;
Weinreb, S. M. In Hetero Diels-Alder Methodology in Organic Chem-
istry; Academic Press: San Diego, CA, 1987; p 239. (e) Ghosez, L.;
Serckx-Poncin, B.; Rivero, M.; Bayard, Ph. Sainte, F.; Dermoulin, A.;
Hesbain-Frisque, A. M.; Mockel, A.; Mun˜oz, L.; Bernard-Henriet, C.
Lect. Heterocycl. Chem. 1985, 8, 69. (f) Barluenga, J .; Toma`s, M. Adv.
Heterocycl. Chem. 1993, 57, 1. (g) Ghosez, L. In Stereocontrolled
Organic Synthesis; Blackwell: Oxford, U.K., 1994; p 193. (h) Boger,
D. L. Chemtracts: Org. Chem. 1996, 9, 149.
(19) Soboleski, D. A.; Li-Kwong-Ken, M. C.; Wynn, H.; Triggle, C.
R.; Wolowyk, M. W.; Knaus, E. E. Drug Des. Delivery 1988, 2, 177.

6242 J . Org. Chem., Vol. 64, No. 17, 1999
Ta ble 2. Com p ou n d s 9, 11, a n d 12 Obta in ed
Palacios et al.
yield (%)a
reactn conditions
entry
products
R1
R2
R3
R4
T (°C)
time (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
9ba b
9bbb
9bcb
Me
Me
Me
Me
Ph
H
H
H
H
H
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Et
Et
Et
p-NO2-Ph
Ph
60
100c
60
72
165
280
300
48
4
48
112
70
160
17
68
15
120
48
24
90
48
48
44
43
65
44
55
39
72
55
45
62
43
42
61
44
51
95
87
52
50
p-OMe-Ph
p -Me2N-Ph
p-Me-Ph
p-NO2-Ph
p-OMe-Ph
p-NO2-Ph
p-OMe-Ph
p-NO2-Ph
Ph
p-OMe-Ph
p-NO2-Ph
Ph
p-NO2-Ph
p-OMe-Ph
p-NO2-Ph
o-NO2-Ph
o-NO2-Ph
9bd b
9ceb
60
100c
60
9a fd
9a gd
60
rt
75
rt
60
60
100
60
100
100
100
60
9a fe
Et
Et
Me
Me
Me
Et
9a ge
11a a e
11a be
11a ce
11bd e
11bee
11cfe
12a a f
12cbf
12a ce
12bd e
H
H
Me
Me
Ph
H
Ph
H
Et
Me
Me
Me
Me
Me
Et
Me
Me
60
a
b
Purified by chromatography. Obtained by reaction of 2 equiv of phosphazenes 6 or 1 and 1 equiv of aldehydes. c The reaction was
performed without solvent. Obtained from 1 equiv of phosphazenes 6 and azadienes 7. e Obtained from azadienes 7 and enamines 10.
d
f Obtained by oxidation of dihydropyridines 11.
Sch em e 5. Rea ction of Aza d ien es 7 w ith
En a m in es 10 a n d 14
Sch em e 6. F or m a tion of
Ben zo[h ][1,6]n a p h th yr id in -5-on es 13
(n ) 1) reacted similarly with azadienes 7a a ,a d (R1 )
H) to give bicyclic compounds 17a a ,a b (Table 3, entries
8 and 9). Aromatization of these nitrogen heterocycles
17 provided bicyclic pyridine compounds 18a a ,a b in
excellent yields (Table 3, entries 10 and 11). 3-Methyl-
7ba ,bb (R1 ) Me) and 3-phenyl-substituted azadienes
7ca (R1 ) Ph) also reacted with pyrrolidinecyclohexanone
14a (n ) 2) to yield 5,6,7,8-tetrahydroisoquinoline com-
pounds 16 (see Table 2, entries 5-7).
Aza -Wittig Rea ction of P h osp h a zen es 19 w ith
Ald eh yd es (1,2-Ad d ition ) a n d P r ep a r a tion of P h en -
a n tr id in -1-on e Der iva tive 21. Aza-Wittig reaction of
phosphazenes 6 and aldehydes 3 was extended to con-
jugated phosphazenes 19. N-vinylic phosphazene derived
from cyclic ketones 19a (R1 ) Me) was prepared by
Staudinger reaction1b of diphenylmethylphosphine and
3-azidocyclohex-2-enone.20 Compound 19a reacts with
p-nitrobenzaldehyde at 45 °C and gave the aza-Wittig
reaction (1,2-addition). Azadiene 20 was not isolated and
was used “in situ” without isolation in a [4 + 2] cyclo-
addition reaction with pyrrolidinecyclohexanone enamine
14a leading to the formation of the tricyclic phenantridin-
1-one derivative 21. These findings are in contrast with
the reported reaction of phosphazenes derived from
triphenylphosphine 19b (R1 ) Ph) with aldehydes in
o-xylene at 160 °C in a sealed tube, to afford 9-azaantra-
cene compounds 2214 (Scheme 7).
room temperature affording 1,2,6,7,8,8a-hexahydroiso-
quinoline compounds derived from â-amino acids 15aa,ab
(Table 3, entries 1 and 2). Spectral data were in agree-
ment with the enamine structure of a bicyclic heterocycle.
1
In the H NMR spectrum of 15a a (R1 ) H) the signal for
3-H appeared at δH 7.59 as a doublet with a coupling
constant of 6.3 Hz, while 1-H and 5-H showed absorptions
at δH 3.95 (3J HH ) 10.8 Hz) and 6.62 ppm (3J HH ) 1.8
Hz) as doublets. Oxidation of bicyclic heterocycles 15a a ,-
a b with quinone led to the formation of 5,6,7,8-tetra-
hydroisoquinoline 16a a ,a b derived from â-amino acids
(Table 3, entries 3 and 4). Pyrrolidinecyclopentanone 14b
(20) (a) Fowler, F. W.; Hassner, A.; Levy, I. A. J . Am. Chem. Soc.
1967, 89, 2077. (b) Fowler, F. W. J . Org. Chem. 1968, 33, 2686.

Azadiene-Mediated Syntheses
J . Org. Chem., Vol. 64, No. 17, 1999 6243
Ta ble 3. Com p ou n d s 15-18 Obta in ed
reactn conditions
entry
starting material
products
R1
R2
R3
T (°C)
time (h)
yield (%)a
1
2
3
4
5
6
7
8
9
7a a
7a d
15a a
15a b
7ba
7bb
7ca
7a a
7a d
15a a
15a b
16a a
16a b
16bc
16bd
16ce
17a a
17a b
18a a
18a b
H
H
H
H
Me
Me
Ph
H
H
H
Et
Et
Et
Et
Me
Me
Et
Et
Et
Et
Et
p-NO2-Ph
3-Pyr
p-NO2-Ph
3-Pyr
p-NO2-Ph
Ph
p-NO2-Ph
p-NO2-Ph
3-Pyr
rt
rt
100
100
rt
rt
rt
rt
rt
1
24
14
24
14
24
14
1
95
96
90
90
76
44
46
98
97
93
95
24
12
120
10
11
17a a
17a b
p-NO2-Ph
3-Pyr
100
100
H
a
Purified by chromatography.
Sch em e 7. Aza -Wittig Rea ction of P h osp h a zen e
Sch em e 8. P r ep a r a tion of Sym m etr ica l
1,4-Dih yd r op yr id in es 5
19 w ith p-Nitr oben za ld eh yd e
attack2,14 of a second molecule of the phosphonium salt
2a (Scheme 8). Dihydropyridines 5a a ,a b were character-
ized and their structures were consistent with reported
symmetrical heterocycles.14 This reaction can also be
extended to 3-methyl-substituted phosphonium salt 2b
(R1 ) CH3), to give 3-methyl-substituted symmetrical
dihydropyridines 5ba -bd (Table 4, entries 3-6). This
methodology has been also used in the preparation (Table
4, entry 6) of the biologically active nifedipine 5bd used
for the treatment of coronary diseases.21 The synthesis
of dihydropyridines 5 does not require the isolation and
purification of phosphonium salts 2, and they can also
be obtained when phosphazenes 1 are directly treated
with acid with subsequent addition of aldehydes. There-
fore, this strategy offers a new approach to the synthesis
of symmetrical dihydropyridines 5 under mild reaction
conditions. 1,4-Dihydropyridines are compounds with
interesting therapeutic22 and biorganic23 applications.
We conclude that N-vinylic phosphazenes 1 derived
from triphenylphosphine are ambident nucleophilic re-
agents. They are suitable for 1,2-addition with hydrogen
chloride. The nucleophilic character of the nitrogen atom
of N-vinylic phosphazenes can be increased when they
are derived from diphenylmethylphosphine 6, and these
undergo aza-Wittig reaction (1,2-addition) with aldehydes
Ta ble 4. Com p ou n d s 5 Obta in ed
starting
time yield
(h)
entry material products R1 R2
R3
(%)a
1
2
3
4
5
6
1a
1a
1b
1b
1b
1b
5a a
5a b
5bc
5bd
5be
5bf
H
H
Et 3-Pyr
Et p-OMe-Ph
24
24
5
5
5
52
66
61
71
71
65
Me Me Ph
Me Me p-OMe-Ph
Me Me p-Me-Ph
Me Me o-NO2-Ph
5
a
Purified by chromatography.
Rea ction of En a m in o P h osp h on iu m Sa lts 2 De-
r ived fr om P h osp h a zen es 1 w ith Ald eh yd es 3.
P r ep a r a tion of Sym m etr ica l Dih yd r op yr id in es 5. To
test the 1,4 addition versus the 1,2-addition reaction of
conjugated phosphazenes derived from triphenylphos-
phine 1, we explored the reactivity of phosphazene 1 and
their derivatives 2 with aldehydes 3. Neither symmetric
1,4-dihydropyridines 5 nor asymmetric 1,4-dihydro-
pyridines 9 were obtained by the reaction of phosphazene
1a (R1 ) H) with aromatic aldehydes at 60 °C, and the
starting phosphazene 1a was recovered. However, the
reaction of enamino phosphonium salts 2a , prepared by
acid treatment of N-vinylic phosphazene 1a (R1 ) H),
with aromatic and heteroaromatic aldehydes in refluxing
CH2Cl2 led to the formation of 4-aryl-3,5-diethoxy-
carbonyl-1,4-dihydropyridines 5a a ,a b (Table 4, entries
1 and 2). The formation of dihydropyridines 5a a ,a b could
be explained by an initial 1,4-addition of the aldehyde to
the γ-carbon atom of the phosphonium salt 2a to give
1,2,5-oxaazaphosphorane 4 followed by regioselective
(21) Bossert, F.; Vater, W. Med. Res. Rev. 1989, 9, 291.
(22) For reviews see: Triggle, D. J . In Comprehensive Medicinal
Chemistry; Hansch, C., Ed.; Pergamon: Oxford, U.K., 1990; Vol. 3, p
1070.
(23) (a) Bennasar, M. L.; J uan, C.; Bosch, J . Tetrahedron Lett. 1998,
39, 9275. (b) Almarsson, O.; Bruice, T. C. J . Am. Chem. Soc. 1993,
115, 2125. (c) Wu, Y. D.; Haunk, K. N. J . Org. Chem. 1993, 58, 2043.

6244 J . Org. Chem., Vol. 64, No. 17, 1999
Palacios et al.
Gen er a l P r oced u r e A for th e P r ep a r a tion of 2-Aza -
d ien es 7. Aldehyde 3 (4 mmol) was added to a 0-10 °C
solution of phosphazene 6 (4 mmol) in CHCl3 (15 mL) under
N2, and the mixture was stirred at room temperature or
warmed at 45 °C or 60 °C until TLC indicated the disappear-
ance of phosphazene.
in a regioselective fashion. Isolated azadienes 7 are
intermediates in the preparation not only of monocyclic
1,2-dihydropyridines 9 and pyridines 12 but also of
bicyclic nitrogen heterocycles 15-18 derived from â-ami-
no acids, as well as of phenanthridin-1-one 21 and
benzonaphthyridinone derivatives 13. The efficient syn-
thesis of symmetrical dihydropyridines 5 here described
provides an easy approach to the preparation of these
kinds of compounds, avoiding the use of high tempera-
tures (160 °C).14 It is worth noting that pyridine com-
pounds derived from â-amino acids are useful hetero-
cycles not only for their biological activities24 but also
because the pyridine nucleus is a structural unit appear-
ing in many natural products.25
Gen er a l P r oced u r e B for th e P r ep a r a tion of 2-Aza -
d ien es 7. Aldehyde 3 (4 mmol) was added to phosphazene 1
(4 mmol) under N2, and the mixture was warmed at 100 °C
until TLC indicated the disappearance of phosphazene.
4-(Eth oxyca r bon yl)-1-(4-n itr op h en yl)-3-p h en yl-2-a za -
bu ta -1,3-d ien e (7ca ). The general procedure A was followed
using phosphazene 6c (1.558 g, 4 mmol) and 0.604 g (4 mmol)
of p-nitrobenzaldehyde (room temperature/2 h). Evaporation
of solvent under reduced pressure afforded an oil which was
chromatographed on silica gel (1/10 AcOEt/hexane) to give 0.92
g (71%) of 7ca as a brown oil. Following the general procedure
B 1.806 g (4 mmol) of phosphazene 1c and 0.604 g (4 mmol) of
p-nitrobenzaldehyde were used for 3 h, and the crude oil was
chromatographed on silica gel (1/10 AcOEt/hexane) to give
0.674 g (52%) of 7ca as a brown oil (Rf ) 0.52, AcOEt): 1H
NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.23 (d, 3J HH ) 8.7 Hz,
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried under nitro-
gen. Dioxane and diethyl ether were distilled from benzo-
phenone ketyl and sodium, while CHCl3 and CH2Cl2 were
distilled from P2O5. Phosphazenes 1 and 6 were synthesized
according to literature procedures.4a,15 For new phosphazenes
1a ,c and 6c, see the Supporting Information.
Gen er a l P r oced u r e for th e P r ep a r a tion of P h osp h o-
n iu m Sa lts 2. Hydrogen chloride was bubbled through a 0-10
°C solution of phosphazene 1 (1.13 g, 3 mmol) in CH2Cl2 (10
mL)/Et2O (20 mL), and the mixture was stirred at 0-10 °C
for 30 min. Evaporation of solvent under reduced pressure
afforded to the enamino phosphonium salt 2.
3
2H), 8.02 (d, J HH ) 8.7 Hz, 2H), 7.55-7.28 (m, 5H), 5.76 (s,
3
3
1H), 4.02 (q, J HH ) 7.2 Hz, 2H), 1.27 (t, J HH ) 7.2 Hz, 3H).
Anal. Calcd for C18H16N2O4: C, 66.66; H, 4.97; N, 8.64.
Found: C, 66.99; H, 4.91; N, 8.67.
Gen er a l P r oced u r e A for th e P r ep a r a tion of Dih yd r o-
p yr id in es 9. Aldehyde 3 (3 mmol) was added to a 0-10 °C
solution of phosphazene (6 mmol) in CHCl3 (8 mL) under N2,
and the mixture was stirred at 60 °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 commpounds 9.
Dim eth yl 4,6-Dim eth yl-2-(4-n itr op h en yl)-1,2-d ih yd r o-
3,5-p yr id in ed ica r boxyla te (9ba ). The general procedure A
was followed using phosphazene 6b (1.88 g, 6 mmol) and 0.453
g (3 mmol) of p-nitrobenzaldehyde for 72 h. The crude oil was
chromatographed on silica gel (5/1 hexane/AcOEt) to give 0.455
g (44%) of 9ba as an orange oil (Rf ) 0.25, AcOEt): 1H NMR
((2-(Eth oxyca r bon yl)-1-eth en yl)a m in o)tr ip h en ylp h os-
p h on iu m Ch lor id e (2a ). The general procedure was followed
using phosphazene 1a to give 2a (E). The reaction product is
unstable to recrystalation or chromatography and therefore
was not isolated and used for the following reactions: 1H NMR
(300 MHz, CDCl3) δ 12.51 (s, 1H), 7.89-7.47 (m, 15H), 7.02
3
3
3
(dd, J HH ) 13.6 Hz, J PH ) 24.1 Hz, 1H), 6.40 (d, J HH ) 13.6
3
3
Hz, 1H), 4.04 (q, J HH ) 7.2 Hz, 2H), 1.17 (t, J HH ) 7.2 Hz,
3
3
3H); 13C NMR (75 MHz, CDCl3) δ 166.3, 139.5, 135.0-128.0
(300 MHz, CDCl3) δ 8.04 (d, J HH ) 8.7 Hz, 2H), 7.36 (d, J HH
3
1
3
) 8.7 Hz, 2H), 5.99 (s, 1H), 5.64 (d, J HH ) 4.5 Hz, 1H), 3.63
(m), 118.5 (d, J PC ) 100 Hz), 105.1 (d, J PC ) 11.1 Hz), 59.1,
(s, 3H), 3.62 (s, 3H), 2.32 (s, 3H), 2.19 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 167.9, 166.9, 154.7, 149.7, 147.7, 145.2, 127.0,
123.8, 108.5, 104.3, 53.9, 51.3, 50.8, 20.9, 19.3; IR (film) 3326,
3081, 2952, 2930, 2853, 1696, 1595, 1518, 1345, 1214; M/S (EI)
m/z 346 (M+, 3). Anal. Calcd for C17H18N2O6: C, 59.93; H, 5.24;
N, 8.12. Found: C, 59.00; H, 5.29; N, 8.10.
13.5; 31P NMR (CDCl3, 120 MHz) δ 37.99.
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 5. Aldehyde 3 (1.5 mmol) was added to a 0-10 °C
solution of phosphonium salt 2 (1.234 g, 3 mmol) in CH2Cl2 (8
mL) under N2, and the mixture was stirred and warmed at 40
°C until TLC indicated the disappearance of aldehyde 3.
Evaporation of solvent under reduced pressure afforded an oil
that was chromatographed on silica gel to give the compounds
5.
Gen er a l P r oced u r e B for th e P r ep a r a tion of Dih yd r o-
p yr id in es 9. Aldehyde 3 (3 mmol) was added to phosphazene
(6 mmol) under N2, and the mixture was warmed at 100 °C
until TLC indicated the disappearance of phosphazene. Evapo-
ration of solvent under reduced pressure afforded an oil that
was chromatographed on silica gel to give the commpounds 9.
Gen er a l P r oced u r e C for th e P r ep a r a tion of Dih yd r o-
p yr id in es 9. Phosphazene 6 (3 mmol) was added to a 0-10
°C solution of 2-azadiene 7 (3 mmol) in CHCl3 (10 mL) under
N2, and the mixture was warmed to 60 °C until TLC indicated
the disappearance of phosphazene. Evaporation of solvent
under reduced pressure afforded an oil that was chromato-
graphed on silica gel to give the commpounds 9.
Gen er a l P r oced u r e D for th e P r ep a r a tion of Dih yd r o-
p yr id in es 9 a n d 11. To a solution of 2-azadiene 7 (3 mmol)
in CHCl3 or toluene (10 mL) was added enamine 10 (3 mmol),
and the mixture was stirred to adequate temperature 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 commpounds 9 or
11.
Diet h yl 4-(3-P yr id yl)-1,4-d ih yd r o-3,5-p yr id in ed ica r -
boxyla te (5a a ). The general procedure was followed using
phosphonium salt 2a and 0.142 mL (1.5 mmol) of 3-pyridin-
ecarboxaldehyde (24 h). Evaporation of solvent under reduced
pressure afforded a oil which was chromatographed on silica
gel (1/2 hexane/AcOEt) to give 0.236 g (52%) of 5a a as a yellow
oil (Rf ) 0.21 in AcOEt): 1H NMR (300 MHz, CDCl3) δ 8.53
3
3
(d, J HH ) 8.7 Hz, 1H), 8.35 (d, J HH ) 4.8 Hz, 1H), 7.68 (d,
3J HH ) 10.5 Hz, 1H), 7.44 (s, 1H), 7.37 (d, J HH ) 5.1 Hz, 2H),
3
7.20-7.16 (m, 1H), 4.91 (s, 1H), 4.10-4.00 (m, 4H), 1.19-1.14
(m, 6H); 13C NMR (75 MHz, CDCl3) δ 166.7, 149.7, 147.3, 142.5,
136.1, 134.2, 123.1, 107.5, 60.2, 35.7, 14.2; IR (film) 3216, 3153,
3088, 2982, 2937, 1697, 1497, 1289, 1176; M/S (EI) m/z 302
(M+, 8). Anal. Calcd for C16H18N2O4: C, 63.56; H, 6.00; N, 9.27.
Found: C, 63.89; H, 6.05; N, 9.29.
(24) For reviews see: (a) Plunkett, A. O. Nat. Prod. Rep. 1994, 11,
581. (b) Numata, A.; Ibuka, T. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1987; Vol. 31. (c) Gould, S. J .; Weinreb,
S. M. Fortsch. Chem. Org. Naturst. 1982, 4177. (d) Daly, J , L.; Spande,
T. F. In Alkaloids. Chemical and Biological Perspectives; Pelletier, S.
W., Ed.; Wiley: New York, 1986; Vol. 4, pp 1-274.
(25) For recent reviews, see: (a) Schneider, M. J . In Alkaloids.
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Perga-
mon: Oxford, U.K., 1996; Vol. 10, pp 155-299. (b) Shipman, M.
Contemp. Org. Synth. 1995, 2, 1.
Dieth yl 2-(4-Nitr op h en yl)-1,2-d ih yd r o-3,5-p yr id in ed i-
ca r boxyla te (9a f). The general procedure C was followed
using azadiene 7a a (0.74 g, 3 mmol) and 0.939 g (3 mmol) of
phosphazene 6a for 4 h. The crude oil was chromatographed
on silica gel (5/1 hexane/AcOEt) to give 0.41 g (39%) of 9a f as
an orange oil. Following the general procedure D azadiene 7a a
(0.74 g, 3 mmol) and 0.51 g (3 mmol) of ethyl trans-2-

Azadiene-Mediated Syntheses
J . Org. Chem., Vol. 64, No. 17, 1999 6245
pyrrolydineacrylate in CHCl3 were used (room temperature/
112 h), and the crude oil was chromatographed on silica gel
(5/1 hexane/AcOEt) to give 0.578 g (55%) of 9a f as an orange
oil (Rf ) 0.54 in AcOEt): 1H NMR (300 MHz, CDCl3) δ 8.07
Eth yl 6-(4-Nitr oph en yl)-4,5-(1-pr opan yl-3-yliden )-1,4,5,6-
t et r a h yd r o-3-p yr id in eca r b oxyla t e (17a a ). The general
procedure was following using azadiene 7a a (0.992 g, 4 mmol)
and 1-pyrrolidine-1-cyclopentene 14b (0.496 g, 4 mmol) for 1
h. The crude oil was chromatographed on silica gel (10/1
hexane/AcOEt) to give 1.232 g (98%) of 17a a as a yellow
solid: mp 118-119 °C (recrystallized from AcOEt/hexane); 1H
NMR (300 MHz, CDCl3) δ 8.24 (d, 3J HH ) 8.7 Hz, 2H), 7.59 (d,
3
3
(d, J HH ) 8.7 Hz, 2H), 7.68 (s, 1H), 7.67 (s, 1H), 7.51 (d, J HH
3
3
) 8.7 Hz, 2H), 6.80 (d, J HH ) 3.0 Hz, 1H), 5.74 (d, J HH ) 2.4
Hz, 1H), 4.16-4.00 (m, 4H), 1.26-1.15 (m, 6H); 13C NMR (75
MHz, CDCl3) δ 165.8, 165.6, 149.7, 147.4, 146.8, 133.4, 127.6,
123.9, 111.7, 97.5, 60.5, 59.9, 54.5, 14.4, 14.1; IR (film) 3302,
3075, 2982, 2928, 2850, 1677, 1620, 1524, 1347, 1223; M/S (EI)
m/z 346 (M+, 2). Anal. Calcd for C17H18N2O6: C, 58.96; H, 5.24;
N, 8.09. Found: C, 59.00; H, 5.27; N, 8.10.
3J HH ) 6.6 Hz, 1H), 7.50 (d, J HH ) 8.7 Hz, 2H), 6.12 (d, J HH
) 2.4 Hz, 1H), 4.76 (d, 3J HH ) 6.6 Hz, 1H), 4.24-4.19 (m, 2H),
4.08 (d, 3J HH ) 9.9 Hz, 1H), 2.87-2.84 (m, 1H), 2.42-2.40 (m,
2H), 1.79-1.70 (m, 1H), 1.44-1.21 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 167.1, 147.9, 147.7, 143.6, 133.1, 128.0, 124.1, 121.8,
98.5, 63.0, 59.4, 50.7, 31.5, 28.3, 14.5; IR (KBr) 3296, 3070,
2975, 2929, 2848, 1657, 1578, 1514, 1346, 1232; M/S (EI) m/z
314 (M+, 2). Anal. Calcd for C17H18N2O4: C, 64.96; H, 5.77; N,
8.91. Found: C, 64.75; H, 5.80; N, 8.86.
Gen er a l P r oced u r e for Ar om a tiza tion of Com p ou n d s
15 and 17. To a solution of bicyclic compound (2 mmol) in
dioxane (5 mL) was added 0.212 g (2 mmol) of p-benzoquinone,
and the mixture was stirred at 100 °C under N2. The solvent
was evaporated under reduced pressure, and the resulting oil
was purified by silica gel column chromatography.
3
3
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zo[h ]-
[1,6]n a p h th yr id in -5-on e 13. A mixture of pyridine 12 (1.5
mmol), acetone (10 mL), acetic acid (1 mL), water (1 mL), and
powdered iron (0.36 g) was refluxed for 5 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 magnesium sulfate. The solvent was
removed under reduced pressure, and the crude product was
recrystallized from acetonitrile to give 13.
3-(E t h o x y c a r b o n y l)-b e n zo [h ][1,6]n a p h t h y r id in -5-
on e (13a ). It was prepared according to the general procedure
using pyridine 12a c (0.494 g) to give 0.285 g (71%) of 13a as
Eth yl 6-(4-Nitr op h en yl)-4,5-tr im eth ylen e-3-p yr id in e-
ca r boxyla te (18a a ). The general procedure was following
using 0.63 g (2 mmol) of compound 17a a for 12 h. The crude
oil was chromatographed on silica gel (10/1 hexane/AcOEt) to
give 0.58 g (93%) of 18a a as a brown solid: mp 110-111 °C
(recrystallized from AcOEt/hexane); 1H NMR (300 MHz,
1
a white solid: mp 291-292 °C; H NMR (300 MHz, DMSO-
3
d6) δ 12.04 (s, 1H), 9.45 (s, 1H), 8.98 (s, 1H), 8.63 (d, J HH
)
3
3
7.8 Hz, 1H), 7.66 (t, J HH ) 7.5 Hz, 1H), 7.41 (d, J HH ) 8.1
3
3
Hz, 1H), 7.34 (t, J HH ) 7.5 Hz, 1H), 4.41 (q, J HH ) 7.0 Hz,
3
CDCl3) δ 9.08 (s, 1H), 8.31 (d, J HH ) 9.0 Hz, 2H), 7.59 (d,
2H), 1.38 (t, J HH ) 7.0 Hz, 3H); 13C NMR (75 MHz, DMSO-
3
3
3
3J HH ) 9.0 Hz, 2H), 4.40 (q, J HH ) 7.2 Hz, 2H), 3.36 (t, J HH
d6) δ 164.0, 160.4, 153.7, 153.5, 138.8, 136.7, 132.5, 124.8,
124.7, 122.8, 120.7, 118.2, 116.2, 61.5, 14.1; IR (KBr) 3433,
3177, 3033, 2962, 2905, 1708, 1666, 1275, 1250; M/S (EI) m/z
268 (M+, 100). Anal. Calcd for C15H12N2O3: C, 67.05; H, 4.50;
N, 10.42. Found: C, 67.11; H, 4.55; N, 10.40.
3
) 7.5 Hz, 2H), 3.11 (t, J HH ) 7.5 Hz, 2H), 2.15-2.13 (m, 2H),
1.41 (t, 3J HH ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.6,
158.0, 154.3, 149.5, 145.5, 138.9, 129.6, 123.5, 122.5, 61.2, 33.9,
32.5, 25.2, 14.3; IR (KBr) 3423, 2980, 2925, 2851, 1706, 1516,
1346, 1281; M/S (EI) m/z 312 (M+, 100). Anal. Calcd for
Gen er a l P r oced u r e for [4 + 2] Cycloa d d ition Rea ction
of 2-Aza d ien es 7 w ith Cyclic En a m in es 14. Cyclic enamine
(4 mmol) was added to a 0-10 °C solution of 2-azadiene 7 (4
mmol) in CHCl3 (15 mL) under N2, and the mixture was stirred
at room temperature until TLC indicated the disappearance
of 2-azadiene. Evaporation of solvent under reduced pressure
afforded an oil that was chromatographed on silica gel to give
the compounds 15, 16, or 17.
Eth yl 1,2,6,7,8,8a -Hexa h yd r o-1-(4-n itr op h en yl)-4-iso-
qu in olin eca r boxyla te (15a a ). The general procedure was
following using azadiene 7a a (0.992 g, 4 mmol) and 1-pyrro-
lidine-1-cyclohexene 14a (0.605 g, 4 mmol) for 1 h. The crude
oil was chromatographed on silica gel (10/1 hexane/AcOEt) to
give 1.25 g (95%) of 15a a as an orange solid: mp 110-111 °C
(recrystallized from Et2O/hexane); 1H NMR (300 MHz, CDCl3)
δ 8.25 (d, 3J HH ) 8.7 Hz, 2H), 7.59 (d, 3J HH ) 6.3 Hz, 1H), 7.51
C
17H16N2O4: C, 65.37; H, 5.16; N, 8.97. Found: C, 65.29; H,
5.14; N, 8.98.
1,1-Diph en yl-1-m eth yl-3,4-(tetr am eth ylen -4-on e)-2-aza-
1λ5-p h osp h a bu ta -1,3-d ien e (19a ). A solution of 0.686 g (5
mmol) of 3-azidocyclohex-2-enone21 in anhydrous CH2Cl2 (3
mL) was added dropwise to a 0-10 °C solution of 1.001 g (5
mmol) of methyldiphenylphospine in anhydrous CH2Cl2 (8 mL)
under N2, and the mixture was stirred for 30 min at room
temperature. The reaction product is unstable to distillation
or chromatography and therefore was not isolated and used
for the following reactions: 1H NMR (300 MHz, CDCl3) of
crude reaction mixture (19a + Ph2CH3PO) δ 7.66-7.40 (m,
3
10H), 4.87 (s, 1H), 2.45 (t, J HH ) 6.0 Hz, 2H), 2.21-2.16 (m,
2H), 2.09 (d, 2J PH ) 13.0 Hz, 3H), 1.90-1.88 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 198.0, 176.0 (d, 2J PC ) 6.3 Hz), 132.4-128.1
3
3
(m), 108.5 (d, J PC ) 15.5 Hz), 36.3, 35.7 (d, J PC ) 24.7 Hz),
3
3
22.2, 13.3 (d, J PC ) 67.9 Hz); 31P NMR (CDCl3, 120 MHz) δ
1
(d, J HH ) 8.7 Hz, 2H), 6.62 (d, J HH ) 1.8 Hz, 1H), 4.61 (d,
3J HH ) 6.3 Hz, 1H), 4.26-4.15 (m, 2H), 4.05 (d, J HH ) 10.8
3
5.91.
Hz, 1H), 2.54-1.42 (m, 6H), 1.30 (t, 3J HH ) 7.2 Hz, 3H), 1.09-
1.01 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 167.1, 148.0, 147.9,
142.0, 128.7, 127.6, 124.0, 121.6, 98.5, 62.1, 59.3, 40.2, 26.7,
25.9, 21.6, 14.5; IR (KBr) 3283, 2931, 2866, 1655, 1592, 1519,
1342; M/S (EI) m/z 328 (M+, 24). Anal. Calcd for C18H20N2O4:
C, 65.84; H, 6.14; N, 8.53. Found: C, 65.65; H, 6.18; N, 8.50.
1-(4-Nitr oph en yl)-3,4-(tetr a m eth ylen -4-on e)-2-a za bu ta -
1,3-d ien e (20). p-Nitrobenzaldehyde (0.604 g, 4 mmol) was
added to a 0-10 °C solution of phosphazene 19a (4 mmol) in
CHCl3 (15 mL) under N2, and the mixture was stirred at 45
°C until TLC indicated the disappearance of phosphazene. The
reaction product is unstable to distillation or chomatography
and therefore was not isolated and used for the following
reactions: 1H NMR (300 MHz, CDCl3) of crude reaction
Meth yl 3-Meth yl-1-(4-n itr op h en yl)-5,6,7,8-tetr a h yd r o-
4-isoqu in olin eca r boxyla te (16bc). The general procedure
was following using azadiene 7ba (0.996 g, 4 mmol) and
1-pyrrolidine-1-cyclohexene 14a (0.605 g, 4 mmol) for 14 h. The
crude oil was chromatographed on silica gel (10/1 hexane/
AcOEt) to give 0.996 g (76%) of 16bc as an orange solid: mp
114-115 °C (recrystallized from AcOEt/hexane); 1H NMR (300
MHz, CDCl3) δ 8.30 (d, 3J HH ) 8.7 Hz, 2H), 7.63 (d, 3J HH ) 8.7
3
mixture (20 + Ph2CH3PO) δ 8.23 (d, J HH ) 8.7 Hz, 2H), 7.96
(s, 1H), 7.94 (d, J HH ) 8.7 Hz, 2H), 7.61-7.30 (m, 10H), 5.53
3
3
3
(s, 1H), 2.53 (t, J HH ) 6.1 Hz, 2H), 2.36 (t, J HH ) 6.6 Hz,
2H), 1.98-2.06 (m, 2H), 1.83 (d, 2J PH ) 13.0 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 199.6, 170.8, 155.9, 150.9, 139.9, 134.3-
1
122.9 (m), 113.0, 36.8, 28.4, 21.7, 16.1 (d, J PC ) 74.0 Hz).
3
3
Hz, 2H), 3.97 (s, 3H), 2.80 (t, J HH ) 6.3 Hz, 2H), 2.60 (t, J HH
) 6.3 Hz, 2H), 2.52 (s, 3H), 1.84-1.78 (m, 2H), 1.73-1.70 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 169.2, 156.5, 151.3 147.0,
146.7, 144.6, 129.9, 128.8, 128.1, 123.4, 52.4, 27.4, 26.8, 22.4,
22.3, 21.7; IR (KBr) 3433, 3077, 2923, 2854, 1727, 1521, 1348,
1255; M/S (EI) m/z 326 (M+, 41). Anal. Calcd for C18H18N2O4:
C, 66.25; H, 5.56; N, 8.58. Found: C, 66.11; H, 5.60; N, 8.59.
6-(4-Nitr op h en yl)-2,3,4,6,7,8,9-h ep ta h yd r op h en a n th r i-
d in -1(5H)-on e (21). 1-Pyrrolidine-1-cyclohexene 14a (0.605
g, 4 mmol) was added to a 0-10 °C solution of 2-azadiene 20
(4 mmol) in CHCl3 (15 mL) under N2, and the mixture was
stirred at room temperature for 17 h. Evaporation of solvent
under reduced pressure afforded an oil that was chromato-
graphed on silica gel (1/2 hexane/AcOEt) to give 0.675 g (52%)

6246 J . Org. Chem., Vol. 64, No. 17, 1999
Palacios et al.
of 21 as an orange solid: mp 109-110 °C; 1H NMR (300 MHz,
gacio´n del Gobierno Vasco (PI 96-36). E.H. thanks the
Departamento de Educacio´n, Universidades e Investi-
gacio´n del Gobierno Vasco, for a Predoctoral Fellowship.
3
3
CDCl3) δ 8.18 (d, J HH ) 8.4 Hz, 2H), 7.45 (d, J HH ) 8.4 Hz,
3
3
2H), 6.97 (d, J HH ) 2.4 Hz, 1H), 4.71 (s, 1H), 4.03 (d, J HH
)
10.5 Hz, 1H), 2.56-0.77 (m, 13H); 13C NMR (75 MHz, CDCl3)
δ 194.5, 157.9, 148.0, 147.8, 128.7, 126.9, 124.0, 123.6, 106.4,
62.4, 39.9, 38.7, 30.0, 29.7, 26.9, 26.0, 21.2; IR (film) 3350, 3215,
2926, 2858, 1513, 1345; M/S (EI) m/z 324 (M+, 2). Anal. Calcd
for C19H20N2O3: C, 70.36; H, 6.22; N, 8.64. Found: C, 70.56;
H, 6.20; N, 8.65.
Su ppor tin g In for m ation Available: Text providing prepa-
ration, elemental analysis, and spectral data (1H NMR, 13C
NMR, 31P NMR, IR, and MS) for compounds 1a ,c, 6c, 2b, 5a b-
5bf, 7a a -7bc, 7cb, 9bb-9ce, 9a g, 11a a -11cf, 12a a -12bd ,
13b, 15a b, 16bd -16ce, 17a b, 16a a -16a b, and 18a b. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Ack n ow led gm en t. The present work has been
supported by the Direccio´n General de Investigacio´n
Cient´ıfica y Te´cnica (DGICYT PB-96-0252) and by the
Departamento de Educacio´n, Universidades e Investi-
J O9902650