Isothiazoles. Part 11: 3-Azahexatrienes from 2-arylpropenamidines: Electrocyclization to 6-aminonicotinic acid derivatives

Article abstract of DOI:10.1016/S0040-4020(00)00399-9

A new synthesis of 6-aminonicotinic acid derivatives was developed starting from the readily available 3-substituted acrylamidines 1 and electron-poor alkynes 2. By nucleophilic addition of the basic amidinic NH to the electron-poor triple bond, the intermediate azatrienes 4 were obtained. Through thermally induced electrocyclization compounds 4 afforded the pyridines 3 by alcohol elimination or oxidation. Another approach was the direct cyclization of acrylamidines with the dienyne system as a backbone. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00399-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4817±4821
Isothiazoles. Part 11: 3-Azahexatrienes from
2-Arylpropenamidines: Electrocyclization to 6-Aminonicotinic
Acid Derivatives
*
Egle M. Beccalli, Francesca Clerici and Maria Luisa Gelmi
Á
Istituto di Chimica Organica, Facolta di Farmacia e Centro Interuniversitario di Ricerca sulle Reazioni Pericicliche e Sintesi di Sistemi
Á
Etero e Carbociclici, Universita di Milano, Via Venezian 21, 20133 Milan, Italy
Received 14 February 2000; revised 25 April 2000; accepted 11 May 2000
AbstractÐA new synthesis of 6-aminonicotinic acid derivatives was developed starting from the readily available 3-substituted
acrylamidines 1 and electron-poor alkynes 2. By nucleophilic addition of the basic amidinic NH to the electron-poor triple bond, the
intermediate azatrienes 4 were obtained. Through thermally induced electrocyclization compounds 4 afforded the pyridines 3 by alcohol
elimination or oxidation. Another approach was the direct cyclization of acrylamidines with the dienyne system as a backbone. q 2000
Elsevier Science Ltd. All rights reserved.
Introduction
electrocyclic ring closure to the intermediates 5a,b followed
by alcohol elimination.
It is well known that 1-azabutadienes are excellent starting
materials for the synthesis of ®ve- and six-membered
heterocycles.1,2 Recently, we reported the base-catalyzed
ring opening of 3-amino-4-aryl-isothiazole 1,1-dioxides to
2-arylpropenamidines incorporating the 1-azadiene system
in their structure. By this method a large number of
compounds with different substituents on C-3 can easily
be obtained in good yields.3 In this paper we report on the
suitability of these compounds as starting materials for the
synthesis of highly substituted pyridines. 2-Arylpropena-
midines react easily with various acetylenic compounds
allowing the preparation of derivatives of 6-aminonicotinic
acid in good yields.
This result is in agreement with the literature data, since
1-azabutadiene derivatives show, in general, little aptitude
to give Diels±Alder cycloaddition reactions.4±7
The structures of compounds 3 and 4 were con®rmed by
analytical and spectroscopic data showing for 3a,b the
characteristic signals associated with the alkoxy groups
and the singlet in the range of 8.60±8.70 ppm clearly asso-
ciated with the pyridine hydrogen H-2. The spectra of
compounds 4a,b were mainly characterized by the methoxy
groups and an AX system clearly associated with the H-2
and H-3 protons. The con®guration of the azatriene system
was assigned by performing NOESY and NOE difference
experiments demonstrating the Z con®guration of the
amidinic double bond due to a clear relationship between
the H-3 (8.1 ppm) and the signals of the diethylamino group.
The E-con®guration of the C-2 C-3 double bond was
con®rmed by a clear NOE effect between the methoxy-
carbonyl group and both H-2 and H-3 which, in turn, did
not show any effect on each other.
Results and Discussion
3,3-Dialkoxy-N,N-diethylamino-2-(4-methoxyphenyl)pro-
penamidines 1a,b were reacted with methyl propiolate (2a)
at re¯ux in anisole to give compounds 3a,b in 50% yield.
When the reaction was performed at room temperature in
toluene, besides compounds 3a,b, compounds 4a,b were
obtained as the major products (Scheme 1). Therefore,
pyridines 3 are not generated through a Diels±Alder
cycloaddition reaction but through an addition reaction
affording the azatriene intermediates 4 which undergo
As an extension of this synthetic scheme the reaction was
generalized to dimethyl acetylenedicarboxylate (Scheme 2).
Also in this case, it is possible to perform the reaction
between 1a,b and 2b in one step, operating at re¯ux in
anisole, affording directly the pyridine compounds 3c,d or
in two steps, at room temperature in toluene, isolating the
intermediate triene derivatives which were always obtained
as a mixture of two stereoisomers. In fact, from the reaction
between 1b and 2b the mixture of isomeric azatrienes 4d
Keywords: isothiazoles; amidines; pyridines; electrocyclic reactions.
* Corresponding author. Tel.: 139-2-706-303-48; fax: 139-2-706-384-
73; e-mail: fclerici@mailserver.unimi.it
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00399-9

4818
E. M. Beccalli et al. / Tetrahedron 56 (2000) 4817±4821
Scheme 1.
Scheme 2.
Scheme 3.

E. M. Beccalli et al. / Tetrahedron 56 (2000) 4817±4821
4819
Scheme 4.
was isolated and analyzed: the main features in the 1H NMR
spectra are a singlet associated with H-2 (A isomer:
5.22 ppm, B isomer 5.72 ppm) and the signals associated
with the COOMe groups shifted by 0.1±0.2 ppm in each
isomer with respect to the other (A isomer: 3.55,
3.65 ppm; B isomer: 3.48, 3.60 ppm). NOE difference and
NOESY experiments showed, for each isomer, NOE effect
between H-2 and the two COOMe groups, con®rming the Z
con®guration of the C-2 C-3 double bond in both isomers. In
consequence, we can conclude that the difference between
isomer A and isomer B must consist in the con®guration of
the amidinic double bond.
Indeed, intermediate dihydronicotinic derivative 5i are
formed which spontaneously oxidized to 3f. Con®rmation
was given from the reaction of 1g and 2b in toluene at room
temperature, by isolating compound 4i which, in anisole at
re¯ux, afforded 5i besides its aromatic counterpart 3f.
As shown, the electrocyclization of the azatriene systems 4
appears a good method to synthesize the pyridine ring
but suffers from the fact that only electron-poor alkynes
reacted quite easily with compounds 1. Reaction with
phenylacetylene, 2-butyn-1,4-diol and other electron-rich
alkynes gave only intractable tars. This limitation could
be overcome starting from amidines like 1h incorporating
in their backbone the 1-aza 1,3-hexadien-5-yne system,
which could be obtained according to a known procedure
from 3-amino-4-aryl-isothiazole 1,1-dioxides 6a.3 Pyridine
3i was obtained heating 1h in polyphosphoric acid at 1008C
for 3 h (Scheme 5), according to a literature method.8
As shown, the use of 3,3-dialkoxypropenamidines 1a,b
allowed the synthesis of 4-alkoxy-6-amino-nicotinic acid
derivatives. With the aim to obtain nicotinic derivatives
with different substituents on C-4 we have considered the
synthetic scheme described above utilizing as key starting
material dimethyl acetylenedicarboxylate and propenami-
dines 1c±f substituted on C-3 both with an alkoxy group,
as leaving group, and a different group (Scheme 3).
Conclusion
In this case the reaction pathway is the same as described
above. The azatrienes 4e±h were electrocyclized, giving the
intermediates 5e±h which aromatized with alcohol
elimination affording pyridines 3e±h.
By this method a large number of nicotinic acid derivatives
can be easily synthesized. The synthetic usefulness of this
new method rests upon the possibility of synthesizing tri-,
tetra- or penta-substituted pyridines by the opportune choice
of the C-3 substituent on the propenamidines and of the
acetylenic substrate used as the reactive partner. Further-
more, the simplicity of this procedure and the easy
availability of the material used is also noteworthy.
Using propenamidine 1g, lacking the alkoxy leaving group
on C-3, a different aromatization process has to be con-
sidered in the formation of the pyridine 3f (Scheme 4).
Scheme 5.

4820
E. M. Beccalli et al. / Tetrahedron 56 (2000) 4817±4821
Experimental
aryl-H, Jˆ9 Hz). Calcd for C21H26N2O6 (402.45) C, 62.67,
H, 6.51, N, 6.96; found C, 62.30, H, 6.80, N, 6.73.
1H NMR spectra were obtained in CDCl3 as the solvent with
Bruker AC 200, Bruker Avance 300 and Varian Gemini 200
instruments. Melting points were determined using a Buchi
510 (capillary) or an Electrothermal 9100 apparatus. IR
spectra were recorded on a Jasco IR Report 100 spectro-
photometer. Compounds 1a±h have already been
described.3 Reagents 2a,b are commercially available
(Aldrich).
6-Diethylamino-4-ethoxy-5-(4-methoxyphenyl)pyridine-
2,3-dicarboxylic acid dimethyl ester 3d. Yield 41%. Pale
yellow oil. IR (nujol) 1700 cm21 (CvO), 1720 cm21
1
(CvO); H NMR 0.88±0.97 (m, 9H, CH3); 3.14 (q, 4H,
CH2, Jˆ7 Hz); 3.46 (q, 2H, OCH2, Jˆ7 Hz); 3.85 (s, 3H,
OCH3); 3.89 (s, 3H, OCH3); 3.92 (s, 3H, OCH3); 6.93 (d,
2H, aryl-H, Jˆ9 Hz); 7.29 (d, 2H, aryl-H, Jˆ9 Hz). Calcd
for C22H28N2O6 (416.47) C, 63.45, H, 6.78, N, 6.73; found
C, 63.10, H, 6.58, N, 6.50.
Synthesis of nicotinic derivatives 3a±h. General
procedure
4-Cyano-6-diethylamino-5-(4-methoxyphenyl)pyridine-
2,3-dicarboxylic acid dimethyl ester 3e. Yield 46%. Mp
110±1118C (white crystals from CH2Cl2/Et2O). IR (nujol)
1700 cm21 (CvO), 1720 cm21 (CvO), 2240 cm21 (CN);
1H NMR 0.94 (t, 6H, CH3, Jˆ7 Hz); 3.23 (q, 4H, CH2,
Jˆ7 Hz); 3.86 (s, 3H, OCH3); 3.92 (s, 3H, OCH3); 3.96
(s, 3H, OCH3); 7.00 (d, 2H, aryl-H, Jˆ9 Hz); 7.28 (d, 2H,
aryl-H, Jˆ9 Hz). Calcd for C21H23N3O5 (397.43), C, 63.47,
H, 5.83, N, 10.57; found C, 63.17, H, 5.77, N, 10.66.
Compound 1 (1 mmol) was dissoved in anisole (4 mL) and a
solution of 2 (1 mmol) in anisole (1 mL) was added drop-
wise under stirring at room temperature. The reaction
mixture was then re¯uxed and the end of the reaction
checked by TLC (AcOEt/cyclohexane 1:1 or CH2Cl2/
MeOH 10:1). The solvent was evaporated at reduced
pressure affording an oil which was puri®ed by column
chromatography on silica gel (eluent: AcOEt/cyclohexane
0:100 to 100:0) and crystallized with the solvent indicated
affording compound 3.
6-Diethylamino-5-(4-methoxyphenyl)-4-methylpyridine-
2,3-dicarboxylic acid dimethyl ester 3f. Yield 36%. Mp
121±1228C (yellow crystals from CH2Cl2/Et2O). IR (nujol)
1
1700 cm21 (CvO), 1720 cm21 (CvO); H NMR 0.85 (t,
Synthesis of 4a,b,d,e,g. General procedure
6H, CH3, Jˆ7 Hz); 2.02 (s, 3H, CH3); 3.10 (q, 4H, CH2,
Jˆ7 Hz); 3.86 (s, 3H, OCH3); 3.90 (s, 3H, OCH3); 3.94 (s,
3H, OCH3); 6.96 (d, 2H, aryl-H, Jˆ9 Hz); 7.10 (d, 2H, aryl-
H, Jˆ9 Hz). Calcd for C21H26N2O5 (386.40) C, 65.27, H,
6.78, N, 7.25; found C, 65.00, H, 6.56, N, 7.47.
Compounds 1 and 2 (1 mmol each) were dissolved in
toluene (5 mL) and stirred at room temperature. The end
of the reaction was checked by TLC (AcOEt/cyclohexane
1:1 or CH2Cl2/MeOH 10:1). The solvent was evaporated at
reduced pressure affording a yellow oil which was puri®ed
by column chromatography on silica gel (eluent: AcOEt/
cyclohexane 0:100 to 100:0) affording compound 4 besides
a minor amount of 3.
60-Diethylamino-50-(4-methoxyphenyl)-[2,40]bipyridinyl-
20,30-dicarboxylic acid dimethyl ester 3g. Yield 51%. Mp
176±1788C (yellow crystals from CH2Cl2/Et2O). IR (nujol)
1
1700 cm21 (CvO), 1720 cm21 (CvO); H NMR 0.94 (t,
6H, CH3, J7 Hz); 3.26 (q, 4H, CH2, J7 Hz); 3.57 (s, 3H,
OCH3); 3.70 (s, 3H, OCH3); 3.90 (s, 3H, OCH3); 6.70 (d,
2H, aryl-H, J9 Hz); 7.00±7.15 (m, 3H, pyridyl-H); 7.52±
7.58 (m, 1H, pyridyl-H); 7.90±8.00 (m, 1H, pyridyl-H);
8.55±8.65 (m, 1H, pyridyl-H). Calcd for C25H27N3O5
(449.51) C, 66.80, H, 6.05, N, 9.35; found C, 66.98, H,
6.25, N, 9.57.
6-Diethylamino-4-methoxy-5-(4-methoxyphenyl)nicotinic
acid methyl ester 3a. Yield 36%. Mp 88±898C (white
crystals from CH2Cl2/pentane). IR (nujol) 1700 cm21
1
(CvO); H NMR 0.92 (t, 6H, CH3, Jˆ7 Hz); 3.18 (q, 4H,
CH2, Jˆ7 Hz); 3.39 (s, 3H, OCH3); 3.85 (s, 3H, OCH3);
3.88 (s, 3H, OCH3); 6.93 (d, 2H, aryl-H, Jˆ9 Hz); 7.76
(d, 2H, aryl-H, Jˆ9 Hz); 8.72 (s, 1H, H-2). Calcd for
C19H24N2O4 (344.41) C, 66.26, H, 7.02, N, 8.13; found C,
66.52, H, 6.94, N, 8.35.
6-Diethylamino-5-(4-methoxyphenyl)pyridine-2,3-dicar-
boxylic acid dimethyl ester 3h. Yield 53%. Mp 108±1108C
(white crystals from CH2Cl2/Et2O). IR (nujol) 1700 cm21
6-Diethylamino-4-ethoxy-5-(4-methoxyphenyl)nicotinic
acid methyl ester 3b. Yield 56%. Mp 948C (white crystals
from CH2Cl2/Et2O). IR (nujol) 1700 cm21 (CvO); 1H NMR
0.88±0.97 (m, 9H, CH3); 3.19 (q, 4H, CH2, Jˆ7 Hz); 3.55
(q, 2H, OCH2, Jˆ7 Hz); 3.84 (s, 3H, OCH3); 3.86 (s, 3H,
OCH3); 6.92 (d, 2H, aryl-H, Jˆ9 Hz); 7.26 (d, 2H, aryl-H,
Jˆ9 Hz); 8.72 (s, 1H, H-2). Calcd for C20H26N2O4 (358.44)
C, 67.02, H, 7.31, N, 7.82; found C, 67.27, H, 7.35, N, 7.99.
1
(CvO), 1730 cm21 (CvO); H NMR 0.97 (t, 6H, CH3,
J7 Hz); 3.27 (q, 4H, CH2, J7 Hz); 3.83 (s, 3H, COOCH3);
3.84 (s, 3H, COOCH3); 3.98 (s, 3H, OCH3); 6.93 (d, 2H,
aryl-H, J9 Hz); 7.29 (d, 2H, aryl-H, J9 Hz); 7.82 (s, 1H, H-
4). Calcd for C20H24N2O5 (372.42) C, 64.50, H, 6.50, N,
7.52; found C, 64.23, H, 6.65, N, 7.40.
3-[1-Diethylamino-3,3-dimethoxy-2-(4-methoxyphenyl)-
allylideneamino]acrylic acid methyl ester 4a. Yield 54%.
IR (nujol) 1600±1620 cm21 (CvN), (CvC); 1690 cm21
(CvO); Mp 137±1398C (white crystals from CH2Cl2/
6-Diethylamino-4-methoxy-5-(4-methoxyphenyl)pyridine-
2,3-dicarboxylic acid dimethyl ester 3c. Yield 51%. Mp
1208C (white crystals from CH2Cl2/Et2O). IR (nujol)
1
1
1700 cm21 (CvO), 1720 cm21 (CvO); H NMR 0.92 (t,
Et2O). H NMR 0.87 (t, 3H, CH3, J7 Hz); 1.16 (t, 3H,
CH3, J7 Hz); 3.10±3.35, 3.35±3.50, 3.80±3.95 (3m, 4H,
CH2); 3.60 (s, 3H, OCH3); 3.63 (s, 3H, OCH3); 3.74 (s,
3H, OCH3); 3.79 (s, 3H, OCH3); 5.63 (d, 1H, H-2, Jˆ13);
6H, CH3, Jˆ7 Hz); 3.15 (q, 4H, CH2, Jˆ7 Hz); 3.31 (s, 3H,
OCH3); 3.85 (s, 3H, COOCH3); 3.91 (s, 3H, COOCH3); 3.93
(s, 3H, OCH3); 6.94 (d, 2H, aryl-H, Jˆ9 Hz); 7.29 (d, 2H,

E. M. Beccalli et al. / Tetrahedron 56 (2000) 4817±4821
4821
6.84 (d, 2H, aryl-H, J9 Hz); 7.18 (d, 2H, aryl-H, J9 Hz);
8.09 (d, 1H, H-3, Jˆ13). Calcd for C20H28N2O5 (376.45)
C, 63.81, H, 7.50, N, 7.44; found C, 63.60, H, 7.60, N, 7.29.
6-Diethylamino-5-(4-methoxyphenyl)-4-methylpyridine-
2,3-dicarboxylic acid dimethyl ester 3f. Yield 38%.
2-[1-Diethylamino-3-methyl-2-(4-methoxyphenyl)but-2-
enylideneamino]but-2-enedioic acid dimethyl ester 4i
(mixture of two isomers). Yield 30%. Yellow oil. IR
(nujol) 1600±1620 cm21 (CvN), (CvC); 1690 cm21
3-[1-Diethylamino-3,3-diethoxy-2-(4-methoxyphenyl)-
allylideneamino]acrylic acid methyl ester 4b. Yield 87%.
Pale yellow oil. IR (nujol) 1600±1620 cm21 (CvN),
1
1
(CvC); 1690 cm21 (CvO); H NMR 0.84 (t, 3H, CH3,
(CvO); 1710 cm21 (CvO); H NMR 0.60±1.50 (m, 12H,
J7 Hz); 1.10±1.13 (m, 9H, CH3); 3.25 (q, 2H, CH2,
J7 Hz); 3.50±4.10 (m, 6H, CH2); 3.61 (s, 3H, OCH3);
3.67 (s, 3H, OCH3); 5.60 (d, 1H, H-2, Jˆ13); 6.81 (d, 2H,
aryl-H, J9 Hz); 7.22 (d, 2H, aryl-H, J9 Hz); 8.07 (d, 1H, H-
3, Jˆ13). Calcd for C22H32N2O5 (404.51) C, 65.32, H, 7.97,
N, 6.93; found C, 65.10, H, 7.69, N, 6.85.
CH3); 1.74 (d, 3H, CH3); 1.85 (d, 3H, CH3); 3.26±3.40,
3.66±3.80 (2m, 8H, CH2); 3.30, 3.34, 3.55, 3.58, 3.78
3.80 (6s, 18H, OCH3); 5.81, 5.90 (2s, 2H, H-2); 6.05, 6.25
(2q, 2H, H-30, J7 Hz); 6.70±6.85 (m, 4H, aryl-H); 7.15±
7.30 (m, 4H, aryl-H). Calcd for C21H28N2O5 (388.46) C,
64.93, H, 7.27, N, 7.21; found C, 64.65, H, 7.32, N, 7.00.
2-[1-Diethylamino-3,3-diethoxy-2-(4-methoxyphenyl)-
allylideneamino]but-2-enedioic acid dimethyl ester 4d
(mixture of two inseparable isomers, 1:1 ratio). Yield
70%. Pale yellow oil. IR (nujol) 1600±1620 cm21
(CvN), (CvC); 1690 cm21 (CvO); 1710 cm21 (CvO);
1H NMR 0.80±0.95 (m, 6H, CH3); 1.12-1.34 (m, 18H,
CH3); 3.18±3.35 (m, 4H, CH2); 3.51±3.65 (m, 4H, CH2);
3.48, 3.55, 3.60, 3.65, 3.77, 3.78 (6s, 18H, OCH3); 5.22 (s,
1H, H-2); 5.72 (s, 1H, H-2); 6.77 (d, 2H, aryl-H, J9 Hz);
6.82 (d, 2H, aryl-H, J9 Hz); 7.31 (d, 4H, aryl-H). Calcd for
C24H34N2O7 (462.54) C, 62.32, H, 7.41, N, 6.06; found C,
62.54, H, 7.20, N, 6.25.
6-Diethylamino-5-(4-methoxyphenyl)-4-methyl-3,4-di-
hydropyridine-2,3-dicarboxylic acid dimethyl ester 5i.
Yield 30%. Mp 1488C (white crystals from CH2Cl2/Et2O).
IR (nujol) 1700 cm21 (CvO); 1720 cm21 (CvO); 1H NMR
1.00±1.20 (m, 6H, CH3); 1.25 (s, 3H, CH3); 2.80±2.95 (m,
1H); 2.96±3.20 (m, 1H) 3.25±3.55 (m, 2H); 3.57 (s, 1H,
H-3); 3.60, 3.76, 3.88 (3s, 9H, OCH3); 3.70±3.85 (m, 1H,
H-4); 6.82 (d, 2H, aryl-H, J9 Hz); 7.06 (d, 2H, aryl-H,
J9 Hz). Calcd for C21H28N2O5 (388.46) C, 64.93, H, 7.27,
N, 7.21; found C, 65.15, H, 7.30, N, 7.35.
Diethyl-[3-(4-methoxyphenyl)-6-phenylpyridin-2-yl]amine
3i. Compound 1h (107 mg, 0.32 mmol) and polyphosphoric
acid (1 mL) were heated at 1008C for 3 h. The reaction
mixture was cooled at room temperature and neutralized
with a 2N NaOH solution. The crude mixture was extracted
with Et2O, dried with Na2SO4 and the solvent evaporated
under reduced pressure, yielding an oil which was crystal-
lized with CH2Cl2/Et2O. Mp 134±1368C. Yield 20% (white
2-[3-Cyano-1-diethylamino-3-methoxy-2-(4-methoxy-
phenyl)allylideneamino]but-2-enedioic acid dimethyl
ester 4e (mixture of two inseparable isomers, 4:1 ratio).
Yield 70%. Pale yellow oil. IR (nujol) 1600±1620 cm21
(CvN), (CvC); 1690 cm21 (CvO); 1710 cm21 (CvO);
2240 cm21(CN); 1H NMR 0.80±0.90, 1.10±1.40 (2m,
12H, CH3); 3.25±3.88 (2m, 8H, CH2); 3.44, 3.56, 3.60,
3.65, 3.79, 3.80, 3.85, 3.90 (8s, 24H, OCH3); 5.80, 5.90
(2s, 2H, H-2); 6.85 (d, 2H, aryl-H, J9 Hz); 6.90 (d, 2H,
aryl-H, J9 Hz); 7.33 (d, 2H, aryl-H, J9 Hz); 7.45 (d, 2H,
aryl-H, J9 Hz). Calcd for C22H27N3O6 (429.47) C, 61.53,
H, 6.34, N, 9.78; found C, 61.77, H, 6.13, N, 9.56.
1
powder). H NMR 1.03 (t, 6H, CH3, J7 Hz); 3.24 (q, 4H,
CH2, J7 Hz); 3.86 (s, 3H, OCH3); 6.96 (d, 2H, aryl-H,
J9 Hz); 7.28±7.50 (m, 5H, aryl-H); 7.48 (d, 2H, aryl-H,
J9 Hz); 8.06±8.12 (m, 2H, aryl-H). Calcd for C21H24N2O
(332.45) C 79.48 H 7.28 N 8.43 found C 79.32 H 7.19 N
8.30.
2-[1-Diethylamino-3-methoxy-2-(4-methoxyphenyl)-3-
pyridin-2-ylallylideneamino]but-2-enedioic acid dimethyl
ester 4g (mixture of two isomers, 1:1 ratio). Yield 61%.
Yellow oil. IR (nujol) 1600±1620 cm21 (CvN), (CvC);
References
1
1700 cm21 (CvO); 1710 cm21 (CvO); H NMR 0.76±
1. Barluenga, J. Synthesis 1975, 191±192.
2. Barluenga, J.; Tomas, M. Adv. Heterocycl. Chem. 1993, 57, 1±
71.
1.59 (m, 12H, CH3); 3.20±3.89 (m, 8H, CH2); 3.42, 3.50,
3.58, 3.62, 3.65, 3.68, 3.70, 3.83 (8s, 24H, OCH3); 5.46 (s,
1H, H-2); 5.86 (s, 1H, H-2); 6.52±6.65, 6.70±6.83, 7.10±
7.26, 7.47±7.87 (4m, 12H, pyridyl-H1aryl-H); 8.55±8.65
(m, 1H); 8.70±8.80 (m, 1H). Calcd for C26H31N3O6 (481.55)
C, 64.85, H, 6.49, N, 8.73; found C, 64.98, H, 6.40, N, 8.61.
3. Beccalli, E. M.; Clerici, F.; Gelmi, M. L. Tetrahedron 1999, 55,
14975±14984.
4. Cheng, Y. S.; Fowler, F. W.; Lupo Jr., A. T. J. Am. Chem Soc.
1981, 103, 2090±2091.
5. Cheng, Y. S.; Fowler, F. W.; Lupo Jr., A. T. J. Am. Chem Soc.
1983, 105, 7696±7703.
Isolation of dihydronicotinic derivative 5i. 1g and 2b
were reacted in anisole at re¯ux and the reaction stopped
after 2 h. A mixture of 3f, 5i and 4i were obtained and
puri®ed by column chromatography on silica gel (eluent:
AcOEt/cyclohexane 0:100 to 100:0).
6. Boger, D. L. Tetrahedron 1983, 39, 2869±2939.
7. Barluenga, J.; Rubio, V.; Gotor, V. J. Org. Chem. 1980, 45,
2592±2596.
8. Ried, W.; Erle, H.-E. Chem. Ber. 1979, 112, 640±647.