Cycloaddition reaction of 2-azadienes derived from β-amino acids with electron-rich and electron-deficient alkenes and carbonyl compounds. Synthesis of pyridine and 1,3-oxazine derivatives

Article abstract of DOI:10.1021/jo016273+

Functionalized keto-enamines 6 were obtained by nucleophilic addition of enol ethers to the imine moiety of 2-azadienes derived from dehydroaspartic esters 4. Reactions of 2-azadiene 4c containing three electron-withdrawing substituents (CO₂R) with enol ethers 5 in the presence of lithium perchlorate led to the formation of tetrahydropyridine derivatives 7 in a regio- and stereoselective fashion. 2H-[1,3]-oxazines 10 and pyridine derivatives 12 and 13 were obtained by heterocycloaddition reactions of electron-poor azadienes 4d-g containing two electron-withdrawing substituents (4-O₂N-C₆H₄, CO₂R) in positions 1 and 4 with carbonyl derivatives (ethyl glyoxalate 9a and diethyl ketomalonate 9b) and the electron-deficient olefin tetracyanoethylene 11.

Full text of DOI:10.1021/jo016273+

J . Org. Chem. 2002, 67, 2131-2135
2131
Cycloa d d ition Rea ction of 2-Aza d ien es Der ived fr om â-Am in o
Acid s w ith Electr on -Rich a n d Electr on -Deficien t Alk en es a n d
Ca r bon yl Com p ou n d s. Syn th esis of P yr id in e a n d 1,3-Oxa zin e
Der iva tives
Francisco Palacios,*,† Esther Herra´n,† Gloria Rubiales,† and J ose Mar´ıa Ezpeleta‡
Departamento de Quı´mica Orga´nica, Facultad de Farmacia, Universidad del Pa´ıs Vasco, and
Departamento de Fı´sica Aplicada, Facultad de Farmacia, Universidad del Pa´ıs Vasco, Apartado 450,
01080 Vitoria, Spain
qoppagaf@vf.ehu.es
Received November 7, 2001
Functionalized keto-enamines 6 were obtained by nucleophilic addition of enol ethers to the imine
moiety of 2-azadienes derived from dehydroaspartic esters 4. Reactions of 2-azadiene 4c containing
three electron-withdrawing substituents (CO2R) with enol ethers 5 in the presence of lithium
perchlorate led to the formation of tetrahydropyridine derivatives 7 in a regio- and stereoselective
fashion. 2H-[1,3]-oxazines 10 and pyridine derivatives 12 and 13 were obtained by heterocycload-
dition reactions of electron-poor azadienes 4d -g containing two electron-withdrawing substituents
(4-O2N-C6H4, CO2R) in positions 1 and 4 with carbonyl derivatives (ethyl glyoxalate 9a and diethyl
ketomalonate 9b) and the electron-deficient olefin tetracyanoethylene 11.
Sch em e 1
In tr od u ction
2-Azabutadiene systems have proved to be efficient
Diels-Alder partners for dienophiles.1 The great majority
of 2-azadienes studied are substituted with strong electron-
donating groups and are excellent reagents in normal
Diels-Alder reactions with electron-deficient dieno-
philes.1,2 Neutral azadienes have been used as hetero-
dienes, not only in inverse-demand Diels-Alder reactions
with electron-rich dienophiles3 but also in normal Diels-
Alder reactions with electron-poor dienophiles1e and with
heterodienophiles4,5 for the preparation of nitrogen het-
erocyclic compounds. Nevertheless, electron-poor 2-aza-
dienes, despite their potential as heterodienes for Diels-
Alder reactions, have received much less attention.1
Azadienes 1 (Scheme 1) undergo dimerization,6 and
these heterodienes 1 (R ) C6H5, 4-Me2N-C6H4) bearing
one electron-withdrawing substituent (CO2R) take part
in the Diels Alder reaction both with electron-rich di-
enophiles such as enamines as well as with electron-
deficient dienophiles.7 However, azadienes 1 (R ) 4-O2N-
C6H4, 4-pyridyl, COC6H5, CO2Et) containing a second
electron-withdrawing substituent participate only in
inverse cycloaddition reactions with enamines,7 whereas
similar azadienes 2 (Scheme 1) containing a second
substituent in position 1 (R ) C6H5, OEt) are found to
react only with strongly activated dienophiles.8 None of
these azadienes 1 react with enol ethers because the use
of more activated electron-rich dienophiles is necessary,
and in an excellent semiempirical molecular orbital study
of the Diels-Alder reaction of acyclic 2-azadienes 1, it
has been suggested9 that the introduction of a new
electron-withdrawing substituent in azadienes 1 could
favor the reaction of these heterodienes with enol ethers.
Given the above, we have been involved in the syn-
thesis of neutral5 and electron-poor azadienes derived
* Phone: 34-945-013103. Fax: 34-945-013049.
† Departamento de Qu´ımica Orga´nica.
‡ Departamento de F´ısica Aplicada.
(1) For reviews, see: (a) Tietze, L. F.; Kettschau, G. Top. Curr.
Chem. 1997, 189, 1. (b) Ghosez, L. In Stereocontrolled Organic
Synthesis; Backwell: Oxford, 1994; p 193. (c) Barluenga, J .; Toma´s,
M. Adv. Heterocycl. Chem. 1993, 57, 1. (d) Boger, D. L. In Compre-
hensive Organic Synthesis; Trost, M. B., Paquete, L. A., Eds.; Pergamon
Press: Oxford, 1991; Vol. 5, p 451. (e) Barluenga, J .; J oglar, J .;
Gonza´lez, F. J .; Fustero, S. Synlett 1990, 129. (f) Fringuelli, F.; Tatichi,
A. In Dienes in the Diels-Alder Reaction; Wiley: New York, 1990. (g)
Boger, D. L.; Weinreb, S. M. In Hetero Diels-Alder Methodology in
Organic Chemistry; Academic Press: San Diego, 1987; p 239.
(2) For recent contributions, see: (a) J noff, E.; Ghosez, L. J . Am.
Chem. Soc. 1999, 121, 2617. (b) Ntirampebura, D.; Ghosez, L.
Tetrahedron Lett. 1999, 40, 7079. (c) Mathieu, B.; Ghosez, L. Tetra-
hedron Lett. 1997, 38, 5497. (d) Ghosez, L. Pure Appl. Chem. 1996,
68, 15. (e) Gouverneur, V.; Ghosez, L. Tetrahedron 1996, 52, 7585. (f)
Marchand, A.; Pradere, J . P.; Guingant, A. Tetrahedron Lett. 1997,
38, 1033. (g) Beres, M.; Hajos, G.; Riedl, Z.; Timari, G.; Messmer, A.;
Holly, S.; Schantl, J . G. Tetrahedron 1997, 53, 9393.
(6) (a) Wulff, G.; Klinken, H. T. Tetrahedron 1992, 48, 5985. (b)
Wulff, G.; Lindner, H. G.; Bo¨hnke, H.; Steigel, A.; Klinken, H. T. Liebigs
Ann. Chem. 1989, 527. (c) Wulff, G.; Bo¨hnke, H. Angew. Chem., Int.
Ed. Engl. 1986, 25, 90.
(7) (a) Gilchrist, T. L.; d’A Rocha Gonsalves, A. M.; Pinho e Melo,
T. M. V. D. Pure Appl. Chem. 1996, 68, 859. (b) d’A Rocha Gonsalves,
A. M.; Pinho e Melo, T. M. V. D.; Gilchrist, T. L. Tetrahedron 1994,
50, 13709. (c) Gilchrist, T. L.; d’A Rocha Gonsalves, A. M.; Pinho e
Melo, T. M. V. D. Tetrahedron Lett. 1993, 34, 4097.
(3) Cheng, Y.; Ho, E.; Mariano, P. S.; Ammon, H. L. J . Org. Chem.
1985, 50, 5678.
(4) Venturini, A.; J oglar, J .; Fustero, S.; Gonzalez, J . J . Org. Chem.
1997, 62, 3919.
(5) Palacios, F.; Alonso, C.; Rubiales, G. J . Org. Chem. 1997, 62,
1146.
(8) Balsamini, C.; Bedini, A.; Galarini, R.; Spadni, G.; Tarzia, G.;
Hamdam, M. Tetrahedron 1994, 50, 12375.
(9) Pinho e Melo, T. M. V. D.; Fausto, R.; d’A Rocha Gonsalves, A.
M.; Gilchrist T. L. J . Org. Chem. 1998, 63, 5350.
10.1021/jo016273+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/09/2002

2132 J . Org. Chem., Vol. 67, No. 7, 2002
Palacios et al.
from aminophosphorus derivatives10 and â-amino esters11
3 (Scheme 1) and in the preparation of nitrogen hetero-
cyclic compounds.12As a continuation of our work on the
[4 + 2] cycloaddition chemistry of 2-azadienes, here we
aim to explore whether azadienes 3 could react not only
with electron-deficient dienophiles such as tetracyano-
ethylene or carbonyl derivatives but also with electron-
rich enol ethers, as well as study their use as key
intermediates in the synthesis of pyridine and oxazine
compounds.
Sch em e 2
Resu lts a n d Discu ssion
Sch em e 3
Rea ction of 2-Aza d ien es 4a -c w ith En ol Eth er s
5. “Ab initio” molecular orbital calculations (HF/3-21G*
level)13 of 2-aza-1,3-butadiene and vinyl alcohol have been
reported before. But azadienes 1 (Scheme 1) have not
reacted with enol ethers,7,9 although molecular orbital
calculations (AM1) of the energies of frontier orbitals
(HOMO and LUMO) suggested9 that with the introduc-
tion of new electron-withdrawing substituents in aza-
dienes 1, these heterodienes should then be reactive
enough to participate in the Diels-Alder reaction with
enol ethers. In addition, a recent report describes the
cycloaddition reaction in the gas phase of N-protonated
2-azadienes with ethyl vinyl ether.14 We thought that the
complementary substitution of electron-withdrawing
groups to azadienes 3 could accelerate its 4π-participation
in LUMO-diene-controlled Diels-Alder Reactions.
First, we explored the reaction of 2-azadienes derived
from dehydroaspartic esters 4a (R1 ) H) and 4b (R1 )
NO2) containing three electron-withdrawing groups (one
nitro-aryl group and two carboxylic esters) with methoxy
propene 5a (R2 ) R3 ) Me), but no reaction took place.
Taking into account that Lewis acids such as lithium
perchlorate can activate5,11c,15 Diels-Alder reactions, we
attempted the activation of the process with this catalyst.
Adducts 6a ,b (R2 ) Me) were obtained in low yield (30-
31%) when the reaction of azadienes 4a ,b with enol ether
5a was performed in the presence of lithium perchlorate
in nitromethane or ether (Scheme 2). Similarly, azadiene
4b reacted with 1-trimethylsilyloxy-1-phenylethene 5b
(Scheme 2) to give functionalized enamine 6c (61%). The
formation of adducts 6 could be explained by nucleophilic
addition of enol ethers 5 to the imine carbon of azadienes
4 in a manner similar to that observed for simple
aldimines in the presence of Lewis acids.16
Substitution of azadienes 1 with electron-withdrawing
groups makes these substrates more electron-deficient,
lowering both HOMO and LUMO energies and favoring
the cycloaddition reaction with electron-rich dienophiles.9
For this reason, we thought that the addition of two
electron-withdrawing groups (CO2Et) to position 1 of
azadienes 3 could accelerate its 4π-participation in
LUMO-diene-controlled Diels-Alder reactions so that the
corresponding azadiene 4c could be sufficiently reactive
to participate in hetero Diels-Alder reactions with enol
ethers.
The treatment of 2-azadiene 4c containing three
electron-withdrawing groups with methoxy propene 5a
in the presence of lithium perchlorate in ether led to the
formation of cycloadduct 7a in a regio- and stereoselective
fashion (Scheme 3) in good yield (70%). A similar result
was obtained when azadiene 4c reacted with 1-trimeth-
ylsilyloxy-1-phenylethene 5b to give substituted tetrahy-
dropyridine derivative 7b (R ) SiMe3). NOE difference
experiments were combined with spectral data to confirm
the structures of tetrahydropyridine derivatives 7a ,b.
The selective saturation of the singlet of the methyl group
at 1.55 ppm in compound 7a afforded positive NOE over
the adjacent H-3 proton (see Scheme 3), suggesting a syn
configuration between the methyl group and the position
3 proton and, therefore, the endo stereoselectivity of the
cycloaddition with controlled stereochemistry of two
stereocenters. A concerted reaction mechanism could
explain these results in a manner similar to that observed
(10) (a) Palacios, F.; Gil, M. J .; Mart´ınez, E.; Rodr´ıguez, M.
Tetrahedron Lett. 1999, 40, 2411. (b) Palacios, F.; Aparicio, D.; de los
Santos, J . M. Tetrahedron 1996, 52, 4857.
(11) (a) Palacios, F.; Herra´n, E.; Rubiales, G. J . Org. Chem. 1999,
64, 6239. (b) Palacios, F.; Rubiales, G. Tetrahedron Lett. 1996, 37, 6379.
(c) Palacios, F.; Pe´rez de Heredia, I.; Rubiales, G. J . Org. Chem. 1995,
60, 2384.
(12) For recent contributions: (a) Palacios, F.; Ochoa de Retana, A.
M.; Gil, J . I.; Ezpeleta, J . M. J . Org. Chem. 2000, 65, 3213. (b) Palacios,
F.; Ochoa de Retana, A. M.; Gil, J . I. Tetrahedron Lett. 2000, 41, 5363.
(c) Palacios, F.; Ochoa de Retana, A. M.; Pagalday, J . Tetrahedron 1999,
55, 14451. (d) Palacios, F.; Aparicio, D.; de los Santos, J . M. Tetrahe-
dron 1999, 55, 13767. (e) Palacios, F.; Ochoa de Retana, A. M.;
Oyarzabal, J . Tetrahedron 1999, 55, 5947. (f) Palacios, F.; Aparicio,
D.; Ochoa de Retana, A. M.; de los Santos, J . M.; Oyarzabal, J .
Tetrahedron 1999, 55, 3105.
(13) Gonza´lez, J .; Houk, K. N. J . Org. Chem. 1992, 58, 3031.
(14) Augusti, R.; Gozzo, F. C.; Moraes, A. B.; Sparrapan, R.; Eberlin,
N. E. J . Org. Chem. 1998, 63, 4889.
(15) (a) Kumar, A. J . Org. Chem. 1994, 59, 4612. (b) Grieco, P. A.;
Beck. J . P.; Handy, S. T.; Saito, N.; Daenble, J . F. Tetrahedron Lett.
1994, 35, 6783. (c) Waldmann, H. Angew. Chem., Int. Ed. Engl. 1991,
30, 1306.
(16) (a) Enders, D.; Oberborsch, S.; Adam, J . Synlett 2000, 644. (b)
Hagiwara, E.; Fujii, A.; Sodeoka, M. J . Am. Chem. Soc. 1998, 120, 2474.
(c) Oyamada, H.; Kobayashi, S. Synlett 1998, 249. (d) Kobayashi, S.;
Nagayama, S. J . Am. Chem. Soc. 1997, 119, 10049. (e) Kobayashi, S.;
Iwamoto, S.; Nagayama, S. Synlett 1997, 1099. (f) Kobayashi, S.;
Baraki, M.; Ishitani, H.; Nagayama, S.; Hachiya, I. Synlett 1995, 233.

Synthesis of Pyridine and 1,3-Oxazine Derivatives
J . Org. Chem., Vol. 67, No. 7, 2002 2133
Sch em e 4
appropriate atom numbering is available in Supporting
Information. Given that only the trans stereoisomers
(C2-C6) were obtained, formation of 1,3-oxazines 10 can
be explained by [4 + 2] cycloaddition reaction of hetero-
dienes 4d ,e with ethyl glyoxalate with exo selectivity.
This behavior seems to be consistent with previous
results of our group5 and of others4 when neutral 2-aza-
dienes were used. Diethyl ketomalonate 9b also reacted
with azadiene 4d to give the corresponding substituted
1,3-oxazine 10c in very good yield (Table 1, entry 3).
Next, we extended the process to the optically active
azadiene containing the (1R,2S,5R)-(-)-menthyl group.
Electron-deficient 2-azadiene derived from (1R,2S,5R)-
(-)-menthyl ester 4f could be obtained by means of an
Aza-Wittig reaction of the correspondent functionalized
phosphazene with p-nitrobenzaldehyde in a manner
similar to that reported for simple azadienes.11c,17 The
reaction of optically active azadiene 4f with ethyl glyox-
alate 9a in refluxing THF was studied, and 2H-[1,3]-
oxazine 10d (R ) menthyl) (Scheme 4, Table 1, entry 4)
was obtained with an enantiomeric excess of 30%.
However, when diethyl ketomalonate 9b was treated
with azadiene 4f, 2H-[1,3]-oxazine 10e (R ) menthyl)
(Scheme 4, Table 1, entry 5) was obtained in a regiose-
lective fashion but without enantiomeric excess. Hetero
Diels-Alder reactions have a great potential for the
efficient construction of heterocycles1a,22 and natural
products,23a,b as well as for asymmetric synthesis.23b-e In
our case, the reaction led to a new approach to the
formation of dihydro-2H-[1,3]-oxazines 10 with controlled
stereochemistry of two stereocenters. In this context, it
is notewortly that 2H-[1,3]-oxazines are known interme-
diates in organic synthesis.24
Ta ble 1. Com p ou n d s Obta in ed by Rea ction of
2-Aza d ien es 4d -g w ith Dien op h iles 9 a n d 11
entry
compound
R1
R
time (h)
yield (%)a
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
12
H
Ph
H
H
H
H
Ph
Me
Et
Et
Et
menthyl
menthyl
Et
20b
16b
20c
20b
20c
30d
16d
13d
92
70
86
43
52
30
25
33
13a
13b
Et
Me
a
b
Purified by chromatography. At 60 °C in THF. c In refluxing
d
CHCl3. In THF at room temperature.
Rea ction of 2-Aza d ien es 4d ,e,g w ith Tetr a cya n o-
eth ylen e 11. Finally, the Diels-Alder reaction of 2-aza-
dienes 4d ,e,g with some electron-deficient alkenes and
alkynes was explored. No cycloaddition was observed
when azadiene 4d reacted with N-phenyl maleinimide,
maleic anhydride, or dimethyl acetylendicarboxylate.
for neutral azadienes with enol ethers in the presence of
boron trifluoride,3 although a stepwise process cannot be
excluded. The treatment of silyloxy-tetrahydropyridine
derivative 7b with tetrabutylammonium fluoride did not
give the deprotected cycloadduct 7c (R ) H), and the
aromatic pyridine 8 was obtained instead, which could
be explained by desilylation of compound 7b and subse-
quent decarboxylation and loss of water from tetrahy-
dropyridine 7c.
Heter o Diels-Ald er Rea ction of 2-Aza d ien es 4d -f
w ith Ca r bon yl Com p ou n d s 9. Some examples of
Diels-Alder reaction of azadienes derived from R-amino
acids 1 (R ) C6H5, 4-Me2N-C6H4)7 and 2 (R ) C6H5,
OC2H5)8 with very activated dienophiles such as electron-
deficient alkenes or alkynes have been described. How-
ever, as far as we know, examples either of hetero Diels-
Alder reaction of electron-poor 2-azadienes 1-3 with
carbonyl compounds or of the normal Diels-Alder reac-
tion of azadienes 3 with heterodienophiles and electron-
deficient dienophiles have not been reported.
(17) Required N-vinylic phosphazene was prepared as follows:
optically active (1R,2S,5R)-(-)-menthyl propiolate was prepared by
titanium-catalyzed transesterification of ethyl propiolate with
(1R,2S,5R)-(-)-menthol in the presence of titanium(IV) ethoxide.18 The
addition of tetramethylguanidinium azide (TMGA) to (1R,2S,5R)-(-
)-menthyl propiolate in chloroform at room temperature led to the
formation of the corresponding vinyl azide, which was isolated as a
mixture of the E/ Z isomers (40:60). The preparation of phosphazene
was accomplished very easily through the classic Staudinger reaction19
of the former vinyl azide and methyldiphenylphosphine to give only
the trans isomer of the N-vinylic phosphazene (see Supporting
Information).20
(18) (a) Bella, M.; Margarita, R.; Orland, C.; Orsini, M.; Parlanti,
L.; Piancatelli, G. Tetrahedron Lett. 2000, 41, 561. (b) Krasik, P.
Tetrahedron Lett. 1998, 39, 4223.
(19) For reviews, see: (a) Eguchi, S.; Matsushita, Y.; Yamoshita,
K. Org. Prep. Proced. Int. 1992, 24, 209. (b) Barluenga, J .; Palacios, F.
Org. Prep. Proced. Int. 1991, 23, 1.
(20) Synthesis of the trans isomer of conjugated phosphazenes from
a mixture of E/ Z vinyl azide and phosphines has been previously
observed by our group11c and by others.21
(21) Molina, P.; Pastor, A.; Vilaplana, M. J . J . Org. Chem. 1996,
61, 8094.
(22) For reviews, see: (a) J orgensen, K. A. Angew. Chem., Int. Ed.
2000, 39, 3559. (b)Waldmann, H. Synlett 1995, 133.
(23) (a) Kaufman, M. D.; Grieco, P. A. J . Org. Chem. 1994, 59, 7197.
(b) Mulzer, J .; Meyer, F.; Buchmann, J .; Luger, P. Tetrahedron Lett.
1995, 36, 3503. (c) Mikami, K.; Motoyama, Y.; Terada, M. J . Am. Chem.
Soc. 1994, 116, 2812. (d) J ohannsen, M.; J orgensen, K. A. J . Org. Chem.
1995, 60, 5757. (e) Mikami, K.; Kotero, O.; Motoyama, Y.; Sakaguchi,
H. Synlett 1995, 975.
(24) (a) Cherkauskas, J . P.; Klos, A. M.; Borzilleri, R. M.; Sisko, J .;
Weinreb, S. M. Tetrahedron 1996, 52, 3135. (b) Barluenga, J .; Tomas,
M.; Ballesteros, A.; Kong, J . S. Tetrahedron 1996, 52, 3095.
For this reason, the reaction of heterodienes 4d ,e with
a reactive aldehyde such as ethyl glyoxalate 9a was
studied. Cycloaddition of azadienes 4d ,e (R1 ) H, Ph)
with ethyl glyoxalate in refluxing CHCl3 gave 2H-[1,3]-
oxazines 10a ,b (Scheme 4, Table 1, entries 1 and 2)
obtained as single isomers in a regio- and stereoselective
fashion. 2H-[1,3]-Oxazines 10a ,b, in which two new
stereogenic centers are created, proved to be single
stereoisomers and were characterized on the basis of
their spectroscopic data and X-ray diffraction analysis
of 10a , showing the trans configuration between H-6 and
H-2 protons. The corresponding ORTEP drawing with the

2134 J . Org. Chem., Vol. 67, No. 7, 2002
Palacios et al.
Sch em e 5
Exp er im en ta l Section
Gen er a l. All reactions were carried out under nitrogen.
Ethyl ether and tetrahydrofuran were distilled from benzophe-
none ketyl and sodium, while CHCl3 was distilled from P2O5.
2-Azadienes 4c-e,g were synthesized according to literature
procedures.11
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Aza d ien es
4a ,b. Aldehyde (4 mmol) was added to a 0-10 °C solution of
phosphazene 3,4-bis(methoxycarbonyl)-1-methyl-1,1-diphenyl-
2-aza-1λ5-phosphabuta-1,3-diene11c (1.430 g, 4 mmol) in CHCl3
(15 mL) under N2, and the mixture was stirred at room
temperature or warmed at 60 °C until TLC indicated the
disappearance of phosphazene.
(1E,3Z)-3,4-Dim et h oxyca r b on yl-1-(4-n it r op h en yl)-2-
a za bu ta -1,3-d ien e (4a ). The general procedure was followed
using 4-nitrobenzaldehyde (0.604 g, 4 mmol) and warming for
15 h. Evaporation of solvent under reduced pressure and
chromatography on silica gel (5:1 hexane/AcOEt) gave 0.584
g (50%) of 4a as a yellow solid: mp 83-84 °C (recrystallized
from AcOEt/hexane); 1H NMR (300 MHz, CDCl3) δ 3.62 (s, 3H),
3
3.80 (s, 3H), 6.28 (s, 1H), 7.99 (d, J HH ) 9.0 Hz, 2H), 8.26 (d,
3J HH ) 9.0 Hz, 2H), 8.29 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
51.7, 53.2, 109.6, 123.9, 129.9, 140.1, 149.9, 151.1, 162.2, 163.4,
165.1; IR (KBr) 1720, 1712, 1526; EIMS m/z 292 (M+, 2). Anal.
Calcd for C13H12N2O6: C, 53.43; H, 4.14; N, 9.59. Found: C,
53.47; H, 4.13; N, 9.60.
(1E,3E)-4-[(1R,2S,5R)-(-)-Men t h yl]-1-(4-n it r op h en yl)-
2-a za bu ta -1,3-d ien e (4f). 4-Nitrobenzaldehyde (0.604 g, 4
mmol) was added to a solution of 1.964 g (4 mmol) of phos-
phazene (see Supporting Information) in CHCl3 (10 mL) at 0
°C under N2. The mixture was stirred for 2 h, and the crude
oil was chromatographed on silica gel (20:1 hexane/AcOEt) to
give 1.200 g (67%) of 4f as a yellow solid: mp 100-101 °C
(recrystallized from AcOEt/hexane); 1H NMR (300 MHz,
However, azadiene 4d (R1 ) H) underwent a hetero
Diels-Alder reaction with tetracyanoethylene 11, leading
to the formation of the polysubstituted tetrahydropyri-
dine 12 (Scheme 5, Table 1, entry 6). 3-Substituted
azadienes 4e (R1 ) Ph) and 4g (R1 ) Me) also reacted
with this dienophile 11, but in this case, polysubstituted
dihydropyridines 13a ,b were obtained (Scheme 5, Table
1, entries 7 and 8). The formation of pyridine derivatives
12 and 13 could be explained through a [4 + 2] hetero
cyclization of the azadienes and the alkene to give the
cycloadduct 14. Subsequent tautomerization of azadiene
4d (R1 ) H) could afford the tetrahydropyridine 12, while
the loss of cyanide acid from cycloadduct 14 could give
the dihydropyridines 13 when substituted azadienes 4e
(R1 ) Ph) and 4g (R1 ) Me) are used.
3
3
CDCl3) δ 0.70-2.01 (m, 18H), 4.75 (dt, J HH ) 4.4 MHz, J HH
3
3
) 10.8 Hz, 1H), 6.22 (d, J HH ) 13.1 Hz, 1H), 7.87 (d, J HH
)
3
3
13.1 Hz, 1H), 7.97 (d, J HH ) 8.9 Hz, 2H), 8.24 (d, J HH ) 8.9
Hz, 2H), 8.45 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 16.5, 20.7,
21.9, 23.6, 26.4, 31.4, 34.2, 40.9, 47.1, 74.0, 121.6, 124.0, 129.9,
20
140.5, 149.8, 153.8, 164.4, 166.1; IR (KBr) 1679, 1527; [R]D
-48.0° (c 1.02, CH2Cl2); M/S (EI) m/z 358 (M+, 5). Anal. Calcd
for C20H26N2O4: C, 67.05; H, 7.32; N, 7.82. Found: C, 67.02;
H, 7.31; N, 7.81.
Dim eth yl 2-[1-(4-Nitr op h en yl)-3-oxo-bu tyla m in o]-fu -
m a r a te (6a ). LiClO4 (1.28 g, 3 mmol) and 2-methoxypropene
(0.14 mL, 1.5 mmol) were added to a solution of 2-azadiene
4a (0.877 g, 3 mmol) in nitromethane (3 mL) under N2. The
mixture was stirred at room temperature for 19 h. The reaction
mixture was poured onto CH2Cl2 (20 mL), washed with a
saturated solution of NaHCO3, and dried (MgSO4). Evapora-
tion of the solvent under reduced pressure afforded an oil that
was chromatographed on silica gel (5:1 hexane/AcOEt) to give
0.158 g (30%) of 6a as a yellow oil (Rf ) 0.21, 2:1 hexane/
AcOEt): 1H NMR (300 MHz, CDCl3) δ 2.08 (s, 3H), 2.87 (dd,
Con clu sion
We conclude that electron-poor azadienes derived from
â-amino acids 4c containing three electron-withdrawing
substituents (CO2R) are suitable 4π systems in inverse-
demand Diels-Alder reactions with enol ethers 5 in the
presence of lithium perchlorate. However, azadienes
4d -g containing two electron-withdrawing substituents
(4-O2N-C6H4, CO2R) in positions 1 and 4 can be used as
heterodienes in normal Diels-Alder reactions with car-
bonyl derivatives (ethyl glyoxalate 9a and ethyl ketoma-
lonate 9b) and with the electron-deficient olefin tetracy-
anoethylene 11. These processes provide a useful route
to new oxazine and pyridine compounds derived from
â-amino acids. It is worth noting that pyridine com-
pounds derived from â-amino acids are useful hetero-
cycles not only for their biological activities25 but also
because the pyridine nucleus is a structural unit appear-
ing in many natural products.26
3
3
3J HH ) 5.6 Hz, J HH ) 17.2 Hz, 1H), 3.00 (dd, J HH ) 7.2 Hz,
3J HH ) 17.2 Hz, 1H), 3.64 (s, 3H), 3.66 (s, 3H), 5.23 (s, 1H),
5.50 (td, J HH ) 5.6 Hz, J HH ) 7.2 Hz, J HH ) 8.9 Hz, 1H),
7.41 (d, J HH ) 8.7 Hz, 2H), 8.11 (d, J HH ) 8.7 Hz, 2H), 8.55
(d, 3J HH ) 8.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 30.6, 50.8,
51.0, 52.7, 53.4, 91.0, 123.9, 127.3, 147.2, 149.7, 149.8, 163.6,
170.5, 204.6; IR (NaCl disks) 3325, 2930, 1732, 1600, 1527;
M/S (EI) m/z 350 (M+, 2). Anal. Calcd for C16H18N2O7: C, 54.86;
H, 5.18; N, 8.00. Found: C, 54.90; H, 5.19; N, 7.99.
3
3
3
3
3
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
7a ,b. To a solution of 2-azadiene 4c11c (0.406 g, 1.5 mmol) in
Et2O (5 mL) were added 1.5 mmol of enol ether and 2.66 g (25
mmol) of LiClO4, and the mixture was stirred at room
temperature under N2. The reaction mixture was poured onto
CH2Cl2 (20 mL), washed with a saturated solution of NaHCO3,
(25) 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. Forsch. Chem. Org. Naturist 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.
(26) For recent reviews, see: (a) Schneider, M. J . In Alkaloids.
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Perga-
mon: Oxford, 1996; Vol. 10, pp 155-299. (b) Shipman, M. Contemp.
Org. Synth. 1995, 2, 1.

Synthesis of Pyridine and 1,3-Oxazine Derivatives
J . Org. Chem., Vol. 67, No. 7, 2002 2135
and dried (MgSO4). The solvent was evaporated under reduced
pressure, and the resulting oil was purified by silica gel column
chromatography.
Meth yl 3,3,4-Tr icya n o-6-m eth yl-2-(4-n itr op h en yl)-2,3-
d ih yd r o-5-p yr id in eca r boxyla te (13b). The general proce-
dure was followed using 2-azadiene 4g11a (0.496 g, 2 mmol)
for 13 h. The crude oil was chromatographed on silica gel (5:1
hexane/AcOEt) to give 0.230 g (33%) of 13b as a brown solid:
mp 193-194 °C (recrystallized from AcOEt/hexane); 1H NMR
(300 MHz, CDCl3) δ 2.39 (s, 3H), 3.73 (s, 3H), 5.91 (s, 1H),
Tr iet h yl 4-Tr im et h ylsila n yloxy-4-p h en yl-2,3,4,5-t et -
r a h yd r op yr id in eca r boxyla te (7b). The general procedure
was followed using 0.285 g (1.5 mmol) of 1-trimethylsilyloxy-
1-phenylethene for 5 h. The crude oil was chromatographed
on silica gel (hexane) to give 0.486 g (70%) of 7b as a colorless
oil (Rf ) 0.7, 1:2 AcOEt/hexane): 1H NMR (300 MHz, CDCl3)
3
3
7.67 (d, J HH ) 8.4 Hz, 2H), 8.22 (d, J HH ) 8.4 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 14.3, 51.6, 55.9, 81.7, 99.9, 108.4,
110.2, 110.3, 123.9, 128.3, 140.6, 148.7, 161.4, 166.4, 167.5;
IR (KBr) 2370, 2350, 1699, 1527; M/S (EI) m/z 349 (M+, 5).
Anal. Calcd for C17H11N5O4: C, 58.45; H, 3.17; N, 20.05.
Found: C, 58.50; H, 3.19; N, 20.08.
2
δ 0.2 (s, 9H), 1.29-1.35 (m, 4H), 3.08 (d, J HH ) 12.0 Hz, 1H),
2
3.23 (d, J HH ) 12 Hz, 1H), 4.08 (m, 2H), 4.26-4.39 (m, 4H),
3
3
4.80 (d, J HH ) 14 Hz, 1H), 7.26-7.34 (m, 3H), 7.38 (d, J HH
)14 Hz, 1H), 7.48-7.52 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
1.5, 13.9, 14.4, 45.9, 59.0, 59.1, 62.5, 67.9, 92.5, 93.8, 125.8,
128.4, 141.5, 142.6, 167.5, 167.7, 168.9; IR (NaCl disks) 1755,
X-r a y Cr yst a llogr a p h y. Single-crystal X-ray diffraction
experiments were carried out on a STOE IPDS diffractometer
using graphite-monochromated Mo KR radiation (λ ) 0.7173
Å). A prismatic crystal of dimensions 0.26 × 0.18 × 0.12 mm
was used for data collection. Crystal data: orthorhombic (space
group P212121), a ) 4.6620(10), b ) 12.888(5), c ) 28.008(14)
Å, V ) 1682.8(11) Å3, Fcal ) 1.383 g/cm3. Data collection was
performed at 293 K, with 2θmax ) 52°. Intensities were
measured on an image plate with oscillating crystal geometry.
The total number of measured reflections was 9095, of which
2973 were independent. The criterion for observed reflections
was I > 2σ(I). Lorentzian polarization correction was applied
using STOE software,27 but no absorption correction (µ ) 0.110
mm-1) was made. The structure was solved by direct methods
using the SIR97 program.28 The structure was refined by full-
1709, 1624; M/S (EI) m/z 463 (M+, 5). Anal. Calcd for C23H33
-
NO7Si: C, 59.59; H, 7.17; N, 3.02. Found: C, 59.64; H, 7.12;
N, 3.01.
Dieth yl 4-P h en yl-2,5-p yr id in ed ica r boxyla te (8). Tet-
rabutylammonium fluoride (1.4 mL, 11 M in THF) was added
to a solution of 7b (0.710 g, 1.54 mmol) in THF (5 mL) under
N2. The reaction mixture was stirred for 30 min. Evaporation
of the solvent under reduced pressure afforded an oil that was
chromatographed on silica gel (1:1 CH2Cl2/hexane) to give
0.451 g (98%) of 8 as a pale yellow solid: mp 98-99 °C
(recrystallized from AcOEt/hexane); 1H NMR (300 MHz,
3
3
CDCl3) δ 1.04 (t, J HH ) 7 Hz, 3H), 1.43 (t, J HH ) 7 Hz, 3H),
3
3
4.16 (q, J HH ) 7 Hz, 2H), 4.48 (q, J HH ) 7 Hz, 2H), 7.26-
7.45 (m, 5H), 8.13 (s, 1H), 9.07 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 13.6, 14.2, 61.6, 62.2, 126.1, 127.9, 128.5, 128.8, 129.4,
137.7, 149.7, 150.6, 150.9, 164.4, 166.3; IR (KBr) 1749, 1723;
M/S (EI) m/z 299 (M+, 5). Anal. Calcd for C17H17NO4: C, 68.20;
H, 5.73; N, 4.68. Found: C, 68.15; H, 5.71; N, 4.66.
2
matrix least-squares against |F| , and all reflections were
considered (SHELXL-97 software).29 The total number of
parameters was 229, and all H atoms were generated using
geometrical criteria and refined isotropically. Final values for
R-indices: Rw(all) ) 0.1269, Rw(obs) ) 0.0972, R(all) ) 0.1030,
and R(obs) ) 0.0405. Residual electron density: min ) -0.140
and max ) 0.163. Crystallographic data (excluding structure
factors) for the structure reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC-173076. Copies of the
data can be obtained free of charge upon application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax, (+44) 1223-
336-033; e-mail, deposit@ccdc.cam.ac.uk).
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
10. Ethyl glyoxalate 9a or diethyl ketomalonate 9b (2 mmol)
was added to a solution of 2-azadiene 4d -f (2 mmol) in THF
or CHCl3 under N2. The mixture was refluxed until TLC
indicated the disappearance of azadiene. Evaporation of
solvent under reduced pressure afforded an oil that was
chromatographed on silica gel to give the compounds 10.
5,6-Diet h oxyca r b on yl-2-(4-n it r op h en yl)-3,6-d ih yd r o-
2H-[1,3]-oxa zin e (10a ). The general procedure was followed
using 9a (0.204 g) and 2-azadiene 4d 11b (0.496 g, 2 mmol) in
THF (5 mL) for 20 h. The crude oil was chromatographed on
silica gel (5:1 hexane/AcOEt) to give 0.644 g (92%) of 10a as a
white solid: mp 110-111 °C (recrystallized from AcOEt/
hexane); 1H NMR (300 MHz, CDCl3) δ 1.18-1.26 (m, 6H),
4.08-4.21 (m, 4H), 4.99 (s, 1H), 5.13 (s, 1H), 5.92 (s, 1H), 7.56
Ack n ow led gm en t. The present work has been
supported by The University of the Basque Country
(UPV-170.123-G11/99) and by the Direccio´n General de
Investigacio´n of the Ministerio de Ciencia y Tecnolog´ıa
(Madrid, DGI-MCYT, BQU2000-0217). E.H. thanks the
Departamento de Educacio´n, Universidades e Investi-
gacio´n del Gobierno Vasco for a Predoctoral Fellowship.
3
3
(d, J HH ) 5.8 Hz, 1H), 7.63 (d, J HH ) 8.7 Hz, 2H), 8.20 (d,
3J HH ) 8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 14.1, 14.4,
59.8, 61.5, 71.8, 78.4, 97.8, 123.9, 127.9, 140.6, 143.6, 148.7,
165.5, 171.0; IR (KBr) 3283, 1732, 1659, 1527; M/S (EI) m/z
350 (M+, 8). Anal. Calcd for C16H18N2O7: C, 54.86; H, 5.18; N,
8.00. Found: C, 54.89; H, 5.19; N, 7.99.
Su p p or tin g In for m a tion Ava ila ble: Preparation, el-
emental analysis, and spectral data (1H NMR, 13C NMR, IR,
and MS) for compounds 4b, 6b, 6c, 7a , 10b-e, and 13a ;
preparation, elemental analysis, and spectral data (1H NMR,
13C NMR, IR, and MS) for (1R,2S,5R)-(-)-menthylpropiolate
and (1R,2S,5R)-(-)-menthyl 3-azidoacrylate; preparation, el-
emental analysis, and spectral data (1H NMR, 13C NMR, 31P,
IR, and MS) for (3E)-4-[(1R,2S,5R)-(-)-menthyl]-1-methyl-1,1-
diphenyl-2-aza-1λ5-phosphabuta-1,3-diene required for prepa-
ration of 4f; and supplementary tables, an ORTEP drawing,
and X-ray crystallography data for 10a . This material is
available free of charge via the Internet at http://pubs.acs.org.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
12 a n d 13. Tetracyanoethylene (0.256 g, 2 mmol) was added
to a solution of 2-azadiene 4d ,e or 4g in THF (6 mL) at 0 °C
under N2. The mixture was stirred 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 12 or 13.
Eth yl 3,3,4,4-Tetr a cya n o-2-(4-n itr op h en yl)-1,2,3,4-tet-
r a h yd r o-4-p yr id in eca r boxyla te (12). The general procedure
was followed using 2-azadiene 4d 11b (0.496 g, 2 mmol) for 30
h. The crude oil was chromatographed on silica gel (6:1 hexane/
AcOEt) to give 0.226 g (30%) of 23 as a brown oil (Rf ) 0.37,
1:2 AcOEt/hexane): 1H NMR (300 MHz, CDCl3) δ 1.30 (t, 3J HH
J O016273+
3
) 7.2 Hz, 3H), 4.26 (q, J HH ) 7.2 Hz, 2H), 5.02 (s, 1H), 7.30
3
3
(s, 1H), 7.79 (d, J HH ) 8.7 Hz, 2H), 7.85 (d, J HH ) 4.1 Hz,
(27) STOE; STOE IPDS Software: Darmstadt, Germany, 1998.
(28) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.;
Molitemi, A. G. G.; Burla, M. C.; Polidori, G.; Camalli, M.; Spagna, R.
SIR97, A Package for Crystal Structure Solution by Direct Methods
and Refinement; Universities of Bari, Perugia, and Roma, Italy, 1997.
(29) Sheldrick, G. M. SHELXL-97, Program for the Refinement of
Crystal Structures; University of Gottingen: Gottingen, Germany,
1997.
1H), 8.31 (d, J HH ) 8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
3
14.1, 40.2, 45.6, 58.1, 62.0, 88.6, 107.7, 108.9, 109.9, 111.0,
124.7, 129.7, 136.3, 145.1, 149.9, 162.7; IR (NaCl) 3356, 2919,
1692, 1520; M/S (EI) m/z 376 (M+, 5). Anal. Calcd For
C
18H12N6O4: C, 57.45; H, 3.21; N, 22.33. Found: C, 57.50; H,
3.20; N, 22.30.