Transformations of (1E,3E)-1-(benzoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylates into pyridine and pyrrole derivatives

Article abstract of DOI:10.1016/j.tet.2008.07.109

New, highly functionalised (1E,3E)-1-(benzoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylates proved to be useful and versatile reagents in the formation of highly substituted pyridine, N-aminopyridine, pyrrole and pyrido[3,4-c]pyridazine deri

Full text of DOI:10.1016/j.tet.2008.07.109

Tetrahedron 64 (2008) 9937–9946
Contents lists available at ScienceDirect
Tetrahedron
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Transformations of (1E,3E)-1-(benzoylamino)-4-(dimethylamino)buta-
1,3-diene-1,2,3-tricarboxylates into pyridine and pyrrole derivatives
*
ˇ
ˇ ˇ
Uros Ursic, Jurij Svete, Branko Stanovnik
ˇ
ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, 1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 May 2008
Received in revised form 15 July 2008
Accepted 31 July 2008
Available online 6 August 2008
New, highly functionalised (1E,3E)-1-(benzoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxy-
lates proved to be useful and versatile reagents in the formation of highly substituted pyridine,
N-aminopyridine, pyrrole and pyrido[3,4-c]pyridazine derivatives. The formation of the particular type
heterocyclic system is dependent on the starting (1E,3E)-1-(benzoylamino)-4-(dimethylamino)buta-1,3-
diene-1,2,3-tricarboxylate. By an appropriate choice of different ester groups it is possible to drive the
reactions towards the formation of either pyridine or pyrrole derivatives.
Keywords:
(1E,3E)-1-(Benzoylamino)-4-
Ó 2008 Elsevier Ltd. All rights reserved.
(dimethylamino)buta-1,3-diene-1,2,3-
tricarboxylates
Pyridine
Pyrrole
Aniline
Hydrazine
1. Introduction
So far, it has been shown that 3-dimethylaminopropenoates and
related enaminones are very useful and versatile reagents in the
Pyridines and pyrroles are basic structural elements of many
important metabolites. Among others, pyridine is an integral part of
niacin, while pyrrole is irreversibly connected with haem and
chlorophyll. Many synthetic routes have been developed for the
synthesis of pyridines and pyrroles.1a–g However, literature con-
cerning highly functionalised ring systems, especially those pos-
sessing additional ester and amino groups, is scarce. A widely
recognised way of producing highly substituted pyridines and pyr-
idinones is by the cycloaddition of acetylenes or olefins to 2(1H)-
pyrazinones.2a–d On the other hand, to obtain highly substituted
pyrrole derivatives, a few different approaches have been used.3a–e
Furthermore, 3-dimethylaminopropenoates have been employed in
the synthesis of 3-aminopyrrole-2,4-dicarboxylates,4 3-amino-
pyrrole-2-carboxylates4 and pyrrole-2-carboxylates.5a–c
Wehaverecentlyreportedanew, efficientwayofobtaininghighly
functionalised buta-1,3-dienes by [2þ2] cycloaddition of electron-
poor acetylenes to (Z)-2-acylamino-3-dimethylaminopropenoates.6
Inthisway, weobtainedanewgroupof3-dimethylaminopropenoate
reagents, i.e., (1E,3E)-1-(benzoylamino)-4-(dimethylamino)buta-
1,3-diene-1,2,3-tricarboxylates 1, with several reactive functional
groups, thus enabling a wide range of further transformations.
synthesis of a wide variety of heterocyclic systems,7a,b including
some natural products and their analogues, such as aplysinop-
sins,8a,b meridianines,9a–c dipodazines and tryprostatins.10a–d
In this paper, we present the transformations of (1E,3E)-1-(ben-
zoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylates
1 into highly functionalised pyridinone and pyrrole derivatives.
2. Results and discussion
When
4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylate
1a6 reacted with anilines 2a–f in anhydrous methanol under reflux,
substitution of the dimethylamino group took place yielding a
mixture of (1E,3E) 4-(arylamino)buta-1,3-diene-1,2,3-tricarboxy-
lates 3a–f and (1E,3Z) 4-(arylamino)buta-1,3-diene-1,2,3-tri-
carboxylates 30a–f. In order to achieve cyclisation, the crude
mixtures of 3 and 30 were heated to reflux in a basic solution of KOH
in ethanol producing di-tert-butyl 1-aryl-5-benzamido-6-oxo-1,6-
dihydropyridine-3,4-dicarboxylates 4a–f (Scheme 1). The disap-
pearance of signals for the methyl ester in the 1H NMR spectra of
pyridines 4a–f confirms that the cyclisation took place at the
methyl ester group.
The mixtures of 3 and 30 were not separated and were used in
the following reaction as such. The structures and ratios of 3a–f and
30a–f were confirmed by 1H NMR spectroscopy and HRMS. From
the 1H NMR spectra it was also deduced that we were dealing with
* Corresponding author: Tel.: þ386 1 2419 100; fax: þ386 1 2419 220.
E-mail address: branko.stanovnik@fkkt.uni-lj.si (B. Stanovnik).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.109

ˇ ˇ
U. Ursic et al. / Tetrahedron 64 (2008) 9937–9946
9938
Ar
N
t-Bu-OOC
COO-t-Bu
COOMe
t-Bu-OOC
COO-t-Bu
t-Bu-OOC
COO-t-Bu
COOMe
O
i
ii
+
HN
Ar
COOMe
NHCOPh
PhOCHN
COO-t-Bu
COO-t-Bu
4a-f
HN NHCOPh
Ar
Me2N NHCOPh
1a
3a-f
3'a-f
Ar
3 and 3', Yield (%)
3 : 3'
4, Yield (%),
Ph
98
96
98
91
98
92
63 : 37
50 : 50
60 : 40
59 : 41
54 : 46
40 : 60
68
69
80
66
72
74
a
b
c
d
e
f
4-Methylphenyl
4-Hydroxyphenyl
4-Fluorophenyl
3-Methoxyphenyl
1-Naphthyl
Scheme 1. Reagents and conditions: (i) anilines 2a–f, anhydrous MeOH, reflux; (ii) KOH (w0.15 M), EtOH, reflux.
t-Bu
ROOC
COOR
COOMe
COOMe
i
t-Bu-OOC
COO-t-Bu
O
2
3
O
COO-t-Bu
1
Me2N
NHCOPh
COOMe
4
H
Me2N NHCOPh
N
NHCOPh
N
COOMe
NHCOPh
1b,c
Ar
6
H
Ar
3'a-f
3a-f
Compound
R
Yield (%)
Me
Et
93
94
1b
δΝΗ = 6.8-7.5 ppm
(no hydrogen bonding)
δΝΗ = 10.21-11.17 ppm
(hydrogen bonding)
1c
Scheme 3. Reagents and conditions: (i) acetylenedicarboxylates 7a,b, acetonitrile,
δ (ppm)
Compound
δ (ppm)
Compound
microwave, 80 ꢀC.
NHAr
NHAr
10.35
10.30
10.21
10.34
10.33
11.17
~6.8a
3a
3'a
3'b
3'c
3'd
3'e
3'f
~6.9a
3b
Reactions of anilines 2a–e with trimethyl 4-(dimethylamino)-
buta-1,3-diene-1,2,3-tricarboxylate 1b in anhydrous methanol at
reflux produced mixtures of (1E,3E) 4-(arylamino)buta-1,3-diene-
1,2,3-tricarboxylates 8a–e and (1E,3Z) 4-(arylamino)buta-1,3-di-
ene-1,2,3-tricarboxylates 80a–e, as in the reactions of anilines 2a–f
with compound 1a mentioned above. The yield of exchange
products 8 and 80 can be improved by use of a multiple excess of
aniline 2. When the crude mixtures of 8a–e and 80a–e were stirred
at room temperature in a solution of KOH in ethanol, formation of
(Z)-methyl 4-(1-benzamido-2-methoxy-2-oxoethylidene)-5-oxo-
1-aryl-4,5-dihydro-1H-pyrrole-3-carboxylates 9a–e took place
(Scheme 4).
Mixtures of 8a–e and 80a–e were not separated. The structures
and ratios of components were determined by 1H NMR spectros-
copy and HRMS. Again, 1H NMR spectra revealed that we were
dealing with isomers around the C(3)]C(4) double bond, where
the NHAr signals of isomers 8a–e appear at a higher field than those
of isomers 80a–e, due to the presence of intramolecular hydrogen
bonding in the latter case (Fig. 2).
The determination of the structure of compounds 9a–e was not
as ambiguous as in the case of pyridinones 4a–f. From the 1H NMR
spectra and the substantially different chemical shifts for the NHCO
signals, it was clear that we were not dealing with pyridinone de-
rivatives. In this case, the cyclisation proceeded on the ester group
at position 2, resulting in the formation of pyrrole derivatives,
which can exist as two isomers due to the exocyclic C]C double
bond. The very high chemical shifts for NHCO protons indicate that
(Z)-isomers are formed, where a very favourable six-membered
ring hydrogen bond can be formed (Fig. 3). Additionally, the 13C
6.81
3c
~6.9a
3d
6.89
3e
~7.5a
3f
a Overlapped by other protons.
Figure 1.
isomers around the C(3)]C(4) double bond. The NHAr signals of
isomers 3a–f appear at a higher field because no intramolecular
hydrogen bonding is present, while the NHAr signals of isomers
30a–f appear at much lower field due to intramolecular hydrogen
bonding with one of the ester carbonyl groups (Fig. 1).
When a mixture of (1E,3E) 4-(arylamino)buta-1,3-diene-1,2,3-
tricarboxylate 3a and (1E,3Z) 4-(arylamino)buta-1,3-diene-1,2,3-
tricarboxylate 30a was heated to reflux in a solution of KOH in
methanol instead of ethanol, cyclisation into a pyridinone derivative
was accompanied by removal of the benzoyl group producing di-
tert-butyl 5-amino-6-oxo-1-phenyl-1,6-dihydropyridine-3,4-dicar-
boxylate (5) (Scheme 2).
The formation of pyridinone derivatives 4a–f from 4-(dime-
thylamino)buta-1,3-diene-1,2,3-tricarboxylate 1a is probably due
to a larger steric hindrance of the two tert-butyl esters in com-
parison with the methyl ester where the cyclisation takes place.
This gives rise to a question, how would the cyclisation proceed
with a compound with three methyl ester groups? In this manner,
two new (1E,3E)-1-(benzoylamino)-4-(dimethylamino)buta-1,3-
diene-1,2,3-tricarboxylates 1b,c were prepared analogously to the
literature procedure6 (Scheme 3).
Ph
N
t-Bu-OOC
COO-t-Bu
t-Bu-OOC
COO-t-Bu
O
i
+
COOMe
HN
Ph
COOMe
NHCOPh
H2N
COO-t-Bu
HN NHCOPh
Ph
COO-t-Bu
5
3a
3'a
Scheme 2. Reagents and conditions: (i) KOH (0.13 M), MeOH, reflux.

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U. Ursic et al. / Tetrahedron 64 (2008) 9937–9946
9939
Ar
N
MeOOC
COOMe
MeOOC
COOMe
MeOOC
COOMe
COOMe
O
i
ii
+
COOMe
HN NHCOPh
Ar
HN
Ar
COOMe
NHCOPh
PhOCHN
COOMe
Me2N NHCOPh
COOMe
1b
8a-e
8'a-e
9a-e
Ar
8 and 8', Yield (%)
8 : 8'
9, Yield (%)
Ph
51
77
73
58
58
67 : 33
70 : 30
73 : 27
73 : 27
68 : 32
68
71
63
61
62
a
b
c
d
e
4-Methylphenyl
4-Hydroxyphenyl
4-Fluorophenyl
3-Methoxyphenyl
Scheme 4. Reagents and conditions: (i) anilines 2a–e, anhydrous MeOH, reflux; (ii) KOH (w0.05 M), EtOH, rt.
NMR spectra of compounds 9a–e exhibit four characteristic car-
bonyl signals, which confirm that compounds 9a–e exist in the
5-oxo form. Furthermore, spectral data for compounds 9a–e are
in agreement with those of similar compound found in the
literature.3d,e
MeOOC
3
COOMe
OMe
2
O
COOMe
1
COOMe
NHCOPh
4
H
N
N
COOMe
NHCOPh
8'a-e
Ar
H
Ar
8a-e
Similar to the cyclisation of the mixture of 3a and 30a in
methanol, when a mixture of (1E,3E) 4-(arylamino)buta-1,3-diene-
1,2,3-tricarboxylate 8b and (1E,3Z) 4-(arylamino)buta-1,3-diene-
1,2,3-tricarboxylate 80b was stirred in a solution of KOH in methanol
instead of ethanol, removal of the benzoyl group also took place
forming (Z)-methyl 4-(1-amino-2-methoxy-2-oxoethylidene)-
5-oxo-1-p-tolyl-4,5-dihydro-1H-pyrrole-3-carboxylate (10) and
(E)-methyl 4-(1-amino-2-methoxy-2-oxoethylidene)-5-oxo-1-p-
tolyl-4,5-dihydro-1H-pyrrole-3-carboxylate (100) as an equimolar
mixture (Scheme 5). The mixture of 10 and 100 is unstable, therefore
the structures were determined by1H NMR spectroscopyand HRMS.
In reactions of 4-(dimethylamino)buta-1,3-diene-1,2,3-tri-
carboxylates 1a,c with hydrazines 11a,b, cyclisation products
were formed in one step. In all cases, 1-arylamino-5-benzamido-
6-oxo-1,6-dihydropyridine-3,4-dicarboxylates 12a,d were formed
(Scheme 6). While the cyclisation of 1a with hydrazines 11a,b
proceeded on the methyl ester at position 1, the similarity of the 1H
NMR spectra of products obtained from 1b with hydrazines 11a,b
confirms the same reaction pathway. Furthermore, the formation of
diazepine derivative 13a was ruled out by closer examination of the
1H NMR spectra, where the NHR2 protons appear at quite high
chemical shifts due to intramolecular hydrogen bonding, which in
diazepine derivatives would not be possible (Fig. 4). Additionally,
the NMR signals for 2-H of the pyridinones 11a–d appear as sin-
glets, while signals for 3-H of the diazepine derivative 13a would
appear as doublets. The formation of 13b is excluded due to easier
exchange of the dimethylamino group in comparison to the re-
action with the ester group.
δΝΗ = 6.97-7.11 ppm
δΝΗ = 10.29-10.40 ppm
(no hydrogen bonding)
(hydrogen bonding)
δ (ppm)
Compound
δ (ppm)
Compound
NHAr
NHAr
~7.0a
10.40
8a
8'a
~7.0a
10.36
8b
8'b
6.99
10.40
8c
8'c
7.11
10.39
8d
8'd
6.97
10.29
8e
8'e
a Overlapped by other protons.
Figure 2.
δΝΗ = 13.08-13.09 ppm
(hydrogen bonding)
δΝΗ = 8.14-8.34 ppm
(hydrogen bonding)
Ar
Ar
N
O
N
N
O
H
H
COO-t-Bu
COO-t-Bu
N
COOMe
COOMe
O
O
Ph
4a-f
Ph
9a-e
δ (ppm)
NHCO
δ (ppm)
NHCO
Compound
Compound
13.09
13.09
13.08
13.09
13.09
-
8.25
8.25
8.14
8.22
8.24
8.34
9a
9b
9c
9d
9e
-
6a
6b
6c
6d
6e
6f
When N-aminopyridinone 12a was heated to reflux in hydrazine
monohydrate (11c), a derivative of pyrido[3,4-c]pyridazine 14 was
formed (Scheme 7). Elemental analysis for C, H and N showed that
compound 14 exists as a salt with hydrazine, which also explains its
very high melting point.
Figure 3.
Me
Me
MeOOC
COOMe
COOMe
MeOOC
HN
COOMe
i
COOMe
NHCOPh
+
HN NHCOPh
N
N
O
O
+
H2N
MeOOC
COOMe
COOMe
COOMe
Me
Me
NH2
10'
8b
8'b
10
Scheme 5. Reagents and conditions: (i) KOH (0.06 M), MeOH, rt.

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U. Ursic et al. / Tetrahedron 64 (2008) 9937–9946
9940
R2
later separately prepared by intramolecular cyclisation of 4-
(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylate 1b in DMF by
microwave irradiation (Scheme 8).
HN
N
R1OOC
COOR1
COOMe
O
i
PhOCHN
COOR1
COOR1
12a-d
Me2N NHCOPh
MeOOC
COOMe
COOMe
MeOOC
COOMe
COOMe
i
1a,b
N
H
Me2N NHCOPh
Compound R1
R2
Yield (%)
76
1b
15
Scheme 8. Reagents and conditions: DMF, microwave, 160 ꢀC.
N
N
Me
12a
3. Conclusion
N
N
N
Me
84
82
86
12b
N
N
N
N
N
The reactivity of two highly functionalised (1E,3E)-1-(benzoyl-
amino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylates 1a,b
towardsvariousanilines2a–f andhydrazines 11a,bwasinvestigated.
Ithasbeenshownthatthisnew typeof3-dimethylaminopropenoate
reagent 1 can easily be transformed into various highly substituted
pyridinones 4 and 5, N-aminopyridinones 12 and pyrroles 9, 10 and
15. Although, 4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxy-
lates 1 possess many reaction sites, it has been shown that reactions
can be directed by selecting the appropriate starting compound to
yield either pyridinone 4 or pyrrole 9 derivatives. Namely, different
ester groups in the starting 4-(dimethylamino)buta-1,3-diene-1,2,3-
tricarboxylates 1 exhibit different steric hindrance. Due to their
highlyfunctionalisednatureallnewlyformedcompoundsofferwide
possibilities for further transformations.
N
N
t-Bu
12c
N
N
t-Bu
12d
Scheme 6. Reagents and conditions: (i) hydrazines 11a,b, anhydrous MeOH, reflux.
δΝΗ = 11.60-12.34 ppm
(hydrogen bonding)
higher field
no hydrogen bonding
H
R2
R2
1
N
N
1
O
H
7
6
N
O
2
3
COOR1
N
2
6
5
4. Experimental
4.1. General
3
PhOCHN
R1OOC
PhOCHN
COOR1
4
5
4
COOR1
12a-d
13a
Melting points were determined on a Kofler micro hot stage.
NMR spectra were obtained on a Bruker Avance DPX 300 at
300 MHz for 1H, and 75.5 MHz for 13C, using DMSO-d6 and CDCl3 as
solvents and TMS as the internal standard. Microwave irradiations
were performed on CEM Corporation Discover microwave unit.
Mass spectra were recorded on an AutoSpecQ and Qtof-premier
spectrometers, IR spectra on a Perkin–Elmer Spectrum BX FTIR
spectrophotometer. Microanalyses were performed on a Perkin–
Elmer CHN Analyser 2400 II. Column chromatography was per-
formed on silica gel (Fluka, silica gel 60, 0.04–0.06 mm).
Anilines 2a–g, acetylenes 7a,b, hydrazines 11a–c and KOH (85%)
are commercially available (Sigma–Aldrich). (Z)-Methyl 2-benza-
mido-3-(dimethylamino)propenoate12 (6) and 2,3-di-tert-butyl
1-methyl (1E,3E)-1-(benzoylamino)-4-(dimethylamino)buta-1,3-
diene-1,2,3-tricarboxylate6 (1a) were prepared according to the
literature procedures.
H
O
R2
N
N
PhOCHN
R1OOC
COOR1
13b
δ (ppm)
NHCO
9.64
9.97
9.61
Compound
NHR2
12.34
11.65
12.25
11.60
2-H
8.24
8.66
8.13
8.48
12a
12b
12c
12d
9.91
Figure 4.
N
N
N
N
4.2. General procedure for the synthesis of di-tert-butyl
1-aryl-5-benzamido-6-oxo-1,6-dihydropyridine-3,4-
dicarboxylates 4a–f through (1E,3E)-2,3-di-tert-butyl
1-methyl 4-(arylamino)-1-(benzamido)buta-1,3-diene-
1,2,3-tricarboxylates 3a–f and (1E,3Z)-2,3-di-tert-
butyl 1-methyl 4-(arylamino)-1-(benzamido)buta-1,3-
diene-1,2,3-tricarboxylates 30a–f
HN
N
NH
N
i
O
O
O
PhOCHN
COOMe
COOMe
12a
NH2
HN
N
O
H3N
2
14
Scheme 7. Reagents and conditions: (i) hydrazine monohydrate (11c), reflux.
Amine hydrochlorides 2a–f (0.6–0.91 mmol, 1–1.2 equiv) were
added to a solution of 2,3-di-tert-butyl 1-methyl (1E,3E)-1-(ben-
zoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylate
(1a) (0.5–0.7 mmol) in dry methanol (2–3.5 ml). The reaction
mixture was heated to reflux. Volatile components were evaporated
in vacuo and the residue was purified by column chromatography
on silica gel. Fractions containing the product were combined and
evaporated in vacuo, which gave a yellow oily product. No further
In the reactions of 4-(dimethylamino)buta-1,3-diene-1,2,3-tri-
carboxylate 1b with anilines we noticed when following the re-
actions by TLC that trimethyl 1H-pyrrole-2,3,4-tricarboxylate (15)11
was always formed as a side product. The amount of this side
product can be lowered by using anilines in excess. Pyrrole 15 was

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U. Ursic et al. / Tetrahedron 64 (2008) 9937–9946
9941
purification of thus obtained mixture of (1E,3E)-2,3-di-tert-butyl
1-methyl 4-(arylamino)-1-(benzamido)buta-1,3-diene-1,2,3-tri-
carboxylates 3a–f and (1E,3Z)-2,3-di-tert-butyl 1-methyl 4-(aryl-
amino)-1-(benzamido)buta-1,3-diene-1,2,3-tricarboxylates 30a–f
was undertaken. Potassium hydroxide (0.015–0.037 g) was
added to a solution of crude mixture of 3a–f and 30a–f (0.27–
0.62 mmol) in ethanol (2–4 ml). The reaction mixture was heated
to reflux and at the end neutralised with concentrated hydrochloric
acid. Volatile components were evaporated in vacuo and the
residue was purified by column chromatography on silica gel.
Fractions containing the product were combined and evaporated
in vacuo.
1.51 (9H, s, C(Me)3), 3.88 (3H, s, COOMe), 5.54 (1H, s, OH), 6.66–6.76
(4H, m, 4H of Ph), 6.81 (1H, br d, J¼15.6 Hz, NH), 7.33–7.56 (3H, m, 3H
of Ph), 7.60 (1H, br s, NHCO), 7,64–7.69 (2H, m, 2H of Ph), 7.91 (1H, d,
J¼14.4 Hz, 4-H); Z-isomer:
d
1.50 (18H, s, 2ꢂC(Me)3), 3.91 (3H, s,
COOMe), 5.53 (1H, s, OH), 6.66–6.76 (4H, m, 4H of Ph), 7.23 (1H, d,
J¼13.2 Hz, 4-H),7.33–7.56(3H,m,3HofPh), 7.72(1H, brs, NHCO), 7.72–
7.76 (2H, m, 2H of Ph),10.21 (1H, br d, J¼13.3 Hz, NH). Ratio of isomers:
60:40. (Found:C, 64.99; H, 6.75;N, 4.89. C29H34N2O8 requires:C, 64.67;
H, 6.36; N, 5.20.) nmax (KBr) 3375, 3303, 2979, 1717, 1658, 1622, 1597,
1518, 1476, 1368, 1301, 1269, 1251, 1155, 1130, 829, 713 cmꢁ1
.
4.2.1.4. (1E,3E)-2,3-Di-tert-butyl 1-methyl 1-benzamido-4-(4-fluo-
rophenylamino)buta-1,3-diene-1,2,3-tricarboxylate (3d) and (1E,3Z)-
2,3-di-tert-butyl 1-methyl 1-benzamido-4-(4-fluorophenylamino)buta-
1,3-diene-1,2,3-tricarboxylate (30d). Prepared from 1a (0.237 g,
0.5 mmol) and 4-fluoroaniline hydrochloride (2d) (0.096 g,
0.65 mmol) in methanol (2.5 ml), 7.5 h, chromatography (ethyl ace-
tate/petroleum ether¼1:4). Yield: 0.245 g (91%) of yellow oil.
ESI-MS: m/z¼541.2 (MHþ), FABMS m/z¼541 (MHþ). 1H NMR (CDCl3):
4.2.1. (1E,3E)-2,3-Di-tert-butyl 1-methyl 4-(arylamino)-1-
(benzamido)buta-1,3-diene-1,2,3-tricarboxylates 3a–f and (1E,3Z)-
2,3-di-tert-butyl 1-methyl 4-(arylamino)-1-(benzamido)buta-1,3-
diene-1,2,3-tricarboxylates 30a–f
4.2.1.1. (1E,3E)-2,3-Di-tert-butyl 1-methyl 1-benzamido-4-(phenyl-
amino)buta-1,3-diene-1,2,3-tricarboxylate (3a) and (1E,3Z)-2,3-di-
tert-butyl 1-methyl 1-benzamido-4-(phenylamino)buta-1,3-diene-
1,2,3-tricarboxylate (30a). Prepared from 1a (0.237 g, 0.5 mmol) and
aniline hydrochloride (2a) (0.077 g, 0.6 mmol) in methanol (2 ml),
5.5 h, chromatography (ethyl acetate/petroleum ether¼1:4). Yield:
0.255 g (98%) of yellow oil. ESI-MS: m/z¼523.2 (MHþ), FABMS
E-isomer:
d 1.50 (9H, s, C(Me)3), 1.51 (9H, s, C(Me)3), 3.88 (3H, s,
COOMe), 6.82–6.98 (5H, m, 4H of Ph and NH), 7.30–7.56 (3H, m, 3H of
Ph), 7.60 (1H, br s, NHCO), 7.64–7.69 (2H, m, 2H of Ph), 7.96 (1H, d,
J¼14.2 Hz, 4-H); Z-isomer:
d 1.50 (9H, s, C(Me)3), 1.51 (9H, s, C(Me)3),
3.91 (3H, s, COOMe), 6.82–6.98 (4H, m, 4H of Ph), 7.30–7.56 (4H, m,
3H of Ph and 4-H), 7.69 (1H, br s, NHCO), 7.73–7.77 (2H, m, 2H of Ph),
10.34 (1H, br d, J¼13.0 Hz, NH). Ratio of isomers: 59:41. ESI-HRMS:
m/z¼541.2360 (MHþ); C29H34FN2O7 requires: m/z¼541.2350 (MHþ);
nmax (KBr) 3384, 2979, 1733, 1717, 1663, 1624, 1599, 1514, 1475, 1367,
m/z¼523 (MHþ). 1H NMR (CDCl3): E-isomer:
d 1.51 (9H, s, C(Me)3),
1.52 (9H, s, C(Me)3), 3.90 (3H, s, COOMe), 6.87–7.03 (4H, m, 3H of Ph
and NH), 7.21–7.27 (2H, m, 2H of Ph), 7.32–7.55 (3H, m, 3H of Ph),
7.59 (1H, br s, NHCO), 7.63–7.68 (2H, m, 2H of Ph), 8.07 (1H, d,
1298, 1273, 1251, 1226, 1155, 1128, 830, 713 cmꢁ1
.
J¼14.3 Hz, 4-H); Z-isomer:
d 1.50 (9H, s, C(Me)3),1.51 (9H, s, C(Me)3),
3.92 (3H, s, COOMe), 6.87–7.03 (3H, m, 3H of Ph), 7.21–7.27 (2H, m,
2H of Ph), 7.32–7.55 (4H, m, 3H of Ph and 4-H), 7.71 (1H, br s, NHCO),
7.72–7.77 (2H, m, 2H of Ph), 10.35 (1H, br d, J¼12.7 Hz, NH). Ratio
of isomers: 63:37. ESI-HRMS: m/z¼523.2450 (MHþ); C29H35N2O7
requires: m/z¼523.2444 (MHþ); nmax (KBr) 3377, 3292, 2979, 1737,
1718, 1661, 1624,1601, 1587, 1505, 1476, 1367, 1299, 1272,1250, 1156,
4.2.1.5. (1E,3E)-2,3-Di-tert-butyl 1-methyl 1-benzamido-4-(3-methoxy-
phenylamino)buta-1,3-diene-1,2,3-tricarboxylate (3e) and (1E,3Z)-2,3-
di-tert-butyl 1-methyl 1-benzamido-4-(3-methoxyphenylamino)buta-
1,3-diene-1,2,3-tricarboxylate (30e). Prepared from 1a (0.332 g,
0.7 mmol) and 2-methoxyaniline hydrochloride (2e) (0.145 g,
0.91 mmol) in methanol (3.5 ml), 6.5 h, chromatography (ethyl ace-
tate/petroleum ether¼1:4 and 1:3). Yield: 0.378 g (98%) of yellow oil.
1127, 752, 714, 691 cmꢁ1
.
EIMS: m/z¼552 (Mþ). 1H NMR (CDCl3): E-isomer:
d 1.51 (9H, s,
4.2.1.2. (1E,3E)-2,3-Di-tert-butyl 1-methyl 1-benzamido-4-(p-tolyl-
amino)buta-1,3-diene-1,2,3-tricarboxylate (3b) and (1E,3Z)-2,3-di-
tert-butyl 1-methyl 1-benzamido-4-(p-tolylamino)buta-1,3-diene-
1,2,3-tricarboxylate (30b). Prepared from 1a (0.316 g, 0.67 mmol)
and p-toluidine hydrochloride (2b) (0.114 g, 0.67 mmol) in metha-
nol (3 ml), 7 h, chromatography (ethyl acetate/petroleum
ether¼1:5). Yield: 0.342 g (96%) of yellow oil. 1H NMR (CDCl3):
C(Me)3), 1.51 (9H, s, C(Me)3), 3.76 (3H, s, COOMe), 3.89 (3H, s, OMe),
6.23–6.58 (3H, m, 3H of Ph), 6.89 (1H, br d, J¼13.9 Hz, NH), 7.13 (1H, t,
J¼8.1 Hz,1H of Ph), 7.33–7.54 (3H, m, 3H of Ph), 7.59 (1H, br s, NHCO),
7.64–7.69 (2H, m, 2H of Ph), 8.04 (1H, d, J¼14.2 Hz, 4-H); Z-isomer:
d
1.50 (9H, s, C(Me)3), 1.50 (9H, s, C(Me)3), 3.72 (3H, s, COOMe), 3.92
(3H, s, OMe), 6.23–6.58 (3H, m, 3H of Ph), 7.06 (1H, t, J¼8.0 Hz, 1H of
Ph), 7.33–7.54 (4H, m, 3H of Ph and 4-H), 7.71 (1H, br s, NHCO), 7.72–
7.77 (2H, m, 2H of Ph), 10.33 (1H, br d, J¼14.2 Hz, NH). Ratio of iso-
mers: 54:46. EI-HRMS: m/z¼522.2488 (Mþ); C30H36N2O8 requires:
m/z¼522.2472 (Mþ); nmax (KBr) 3375, 3289, 2979, 1737, 1717, 1661,
1621, 1600, 1591, 1503, 1476, 1367, 1274, 1255, 1153, 1128, 1048, 842,
E-isomer: d 1.50 (9H, s, C(Me)3), 1.51 (9H, s, C(Me)3), 2.26 (3H, s, Ph–
Me), 3.91 (3H, s, COOMe), 6.77–6.87 (3H, m, 2H of Ph and NH), 7.00–
7.07 (2H, m, 2H of Ph), 7.32–7.55 (3H, m, 3H of Ph), 7.59 (1H, br s,
NHCO), 7.65–7.70 (2H, m, 2H of Ph), 8.04 (1H, d, J¼14.4 Hz, 4-H);
Z-isomer:
d
1.50 (9H, s, C(Me)3), 1.51 (9H, s, C(Me)3), 2.26 (3H, s, Ph–
713, 688 cmꢁ1
.
Me), 3.88 (3H, s, COOMe), 6.77–6.87 (2H, m, 2H of Ph), 7.00–7.07
(2H, m, 2H of Ph), 7.32–7.55 (4H, m, 3H of Ph and 4-H), 7.71 (1H, br s,
NHCO), 7.72–7.77 (2H, m, 2H of Ph), 10.30 (1H, br d, J¼13.2 Hz, NH).
Ratio of isomers: 50:50. (Found: C, 66.90; H, 7.04; N, 5.27.
4.2.1.6. (1E,3E)-2,3-Di-tert-butyl 1-methyl 1-benzamido-4-(naph-
thalen-1-ylamino)buta-1,3-diene-1,2,3-tricarboxylate (3f) and (1E,3Z)-
2,3-di-tert-butyl 1-methyl 1-benzamido-4-(naphthalen-1-ylamino)-
buta-1,3-diene-1,2,3-tricarboxylate (30f). Prepared from 1a (0.332 g,
0.7 mmol) and 1-naphthylamine hydrochloride (2f) (0.177 g,
0.91 mmol) in methanol (3.5 ml), 8 h, chromatography (ethyl ace-
tate/petroleum ether¼1:4). Yield: 0.367 g (92%) of yellow oil. EIMS:
C
30H36N2O7 requires: C, 67.15; H, 6.76; N, 5.22.) nmax (KBr) 3383,
3288,1736,1717,1662,1612,1583,1519,1474,1367,1296,1273,1248,
1155, 1126, 713 cmꢁ1
.
4.2.1.3. (1E,3E)-2,3-Di-tert-butyl 1-methyl 1-benzamido-4-(4-hydroxy-
phenylamino)buta-1,3-diene-1,2,3-tricarboxylate (3c) and (1E,3Z)-2,3-
di-tert-butyl 1-methyl 1-benzamido-4-(4-hydroxyphenylamino)buta-
1,3-diene-1,2,3-tricarboxylate (30c). Prepared from 1a (0.237 g,
0.5 mmol) and 4-hydroxyaniline hydrochloride (2c) (0.087 g,
0.6 mmol) in methanol (2 ml), 9 h, chromatography (ethyl acetate/
petroleum ether¼1:4). Yield: 0.255 g (98%) of yellow oil. FABMS
m/z¼572 (Mþ). 1H NMR (CDCl3): E-isomer:
d 1.53 (9H, s, C(Me)3),1.54
(9H, s, C(Me)3), 3.93 (3H, s, COOMe), 7.11 (1H, d, J¼7.5 Hz, 1H of Ar),
7.28–7.90 (12H, m,11H of Ar and NH), 8.09 (1H, br s, NHCO), 8.17 (1H,
d, J¼13.6 Hz, 4-H); Z-isomer:
d 1.52 (9H, s, C(Me)3), 1.55 (9H, s,
C(Me)3), 3.93 (3H, s, COOMe), 6.95 (1H, d, J¼7.5 Hz, 1H of Ar), 7.28–
7.90 (12H, m, 10H of Ar, NHCO and 4-H), 8.02–8.07 (1H, m, 1H of Ar),
11.17 (1H, br d, J¼12.4 Hz, NH). Ratio of isomers: 40:60. EI-HRMS:
m/z¼572.2511 (Mþ); C33H36N2O7 requires: m/z¼572.2523 (Mþ); nmax
m/z¼539 (MHþ). 1H NMR (CDCl3): E-isomer:
d 1.50 (9H, s, C(Me)3),

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U. Ursic et al. / Tetrahedron 64 (2008) 9937–9946
9942
(KBr) 3397, 2978, 1739, 1716, 1660, 1634, 1612, 1596,1579, 1473,1367,
1298, 1251, 1152, 792, 771 cmꢁ1
162.2, 162.5 (d, J¼250 Hz), 163.4, 165.8. (Found: C, 66.39; H, 5.98; N,
5.34. C28H29FN2O6 requires: C, 66.13; H, 5.75; N, 5.51.) nmax (KBr)
3447, 3280, 2980, 1718, 1676, 1654, 1508, 1478, 1369, 1330, 1287,
.
4.2.2. Di-tert-butyl 1-aryl-5-benzamido-6-oxo-1,6-dihydro-
1252, 1155, 846, 706 cmꢁ1
.
pyridine-3,4-dicarboxylates 4a–f
4.2.2.5. Di-tert-butyl 5-benzamido-1-(3-methoxyphenyl)-6-oxo-1,6-
dihydropyridine-3,4-dicarboxylate (4e). Prepared from a mixture of
3e and 30e (0.230 g, 0.416 mmol) and KOH (0.023 g, 0.35 mmol) in
ethanol (2 ml), 65 min, HCl(concd) (one drop), chromatography
(ethyl acetate/petroleum ether¼1:3), recrystallised from toluene/
n-heptane (5:1). Yield: 0.157 g (72%) of white crystals; mp 120–
4.2.2.1. Di-tert-butyl 5-benzamido-6-oxo-1-phenyl-1,6-dihydropyr-
idine-3,4-dicarboxylate (4a). Prepared from a mixture of 3a and 30a
(0.139 g, 0.266 mmol) and KOH (0.015 g, 0.23 mmol) in ethanol
(2 ml), 40 min, HCl(concd) (one drop), chromatography (ethyl ace-
tate/petroleum ether¼1:3 and 1:2), recrystallised from toluene/
n-heptane (4:1). Yield: 0.089 g (68%) of white crystals; mp
124 ꢀC. ESI-MS: m/z¼521.2 (MHþ). 1H NMR (CDCl3):
d 1.55 (9H, s,
179–181 ꢀC. 1H NMR (CDCl3):
C(Me)3), 7.36–7.57 (8H, m, 8H of Ph), 7.79 (1H, s, 2-H), 7.87–7.93 (2H,
m, 2H of Ph), 8.25 (1H, s, NH). 13C NMR (CDCl3)
27.8, 28.0, 82.0,
d
1.55 (9H, s, C(Me)3), 1.57 (9H, s,
C(Me)3),1.56 (9H, s, C(Me)3), 3.84 (3H, s, OMe), 6.89–6.96 (2H, m, 2H
of Ph), 7.00–7.05 (1H, m,1H of Ph), 7.40–7.48 (3H, m, 3H of Ph), 7.50–
7.57 (1H, m, 1H of Ph), 7.77 (1H, s, 2-H), 7.88–7.93 (2H, m, 2H of Ph),
d
83.3, 111.1, 125.5, 126.3, 127.5, 128.4, 129.1, 129.4, 131.9, 133.4, 135.5,
137.4, 139.6, 159.2, 162.4, 163.4, 165.8. (Found: C, 68.56; H, 6.37; N,
5.95. C28H30N2O6 requires: C, 68.56; H, 6.16; N, 5.71.) nmax (KBr)
3434, 3269, 2980, 1727, 1718, 1702, 1676, 1646, 1506, 1475, 1368,
8.24 (1H, s, NH). 13C NMR (CDCl3):
d 27.8, 28.1, 55.5, 82.1, 83.3, 111.2,
112.1, 115.1, 118.4, 125.5, 127.5, 128.5, 130.3, 132.0, 133.4, 135.3, 137.4,
140.7, 159.1, 160.2, 162.4, 163.4, 165.8. EI-HRMS: m/z¼521.2305
(MHþ); C29H33N2O7 requires: m/z¼521.2288 (MHþ); nmax (KBr)
3325, 2979, 1720, 1683, 1661, 1605, 1507, 1489, 1425, 1368, 1343,
1327, 1287, 1255, 1153, 1123, 1028, 846, 707, 699 cmꢁ1
.
1305, 1286, 1242, 1158, 1132, 1030, 847, 707 cmꢁ1
.
4.2.2.2. Di-tert-butyl 5-benzamido-6-oxo-1-p-tolyl-1,6-dihydropyr-
idine-3,4-dicarboxylate (4b). Prepared from a mixture of 3b and 30b
(0.330 g, 0.615 mmol) and KOH (0.037 g, 0.56 mmol) in ethanol
(4 ml), 35 min, HCl(concd) (two drops), chromatography (ethyl ace-
tate/petroleum ether¼1:3), recrystallised from toluene/n-heptane
(3:1). Yield: 0.213 g (69%) of white crystals; mp 172–176 ꢀC. 1H NMR
4.2.2.6. Di-tert-butyl 5-benzamido-1-(naphthalen-1-yl)-6-oxo-1,6-
dihydropyridine-3,4-dicarboxylate (4f). Prepared from a mixture of
3f and 30f (0.260 g, 0.454 mmol) and KOH (0.025 g, 0.38 mmol) in
ethanol (2 ml),15 min, HCl(concd) (one drop), chromatography (ethyl
acetate/petroleum ether¼1:2), recrystallised from toluene/n-hep-
tane (3:1). Yield: 0.182 g (74%) of white crystals; mp 196–198 ꢀC. 1H
(CDCl3):
d 1.54 (9H, s, C(Me)3), 1.56 (9H, s, C(Me)3), 2.43 (3H, s, Me),
7.23–7.35 (4H, m, 4H of Ph), 7.41–7.49 (2H, m, 2H of Ph), 7.50–7.57
(1H, m, 1H of Ph), 7.77 (1H, s, 2-H), 7.88–7.93 (2H, m, 2H of Ph), 8.25
NMR (CDCl3): d 1.52 (9H, s, C(Me)3), 1.61 (9H, s, C(Me)3), 7.40–7.63
(8H, m, 8H of Ar), 7.76 (1H, s, 2-H), 7.87–7.93 (2H, m, 2H of Ar), 7.94–
7.99 (1H, m, 1H of Ar), 8.00–8.05 (1H, m, 1H of Ar), 8.34 (1H, br s,
(1H, s, NH). 13C NMR (CDCl3)
d 21.1, 27.9, 28.1, 82.1, 83.2, 111.3, 125.6,
126.0, 127.6, 128.5, 130.1, 132.0, 133.6, 134.8, 137.2, 137.3, 139.4,
159.3, 162.6, 163.5, 165.8. (Found: C, 69.12; H, 6.58; N, 5.44.
NH). 13C NMR (CDCl3)
d 27.9, 28.0, 82.1, 83.4, 111.6, 122.0, 125.0,
125.4,125.7,126.9,127.5,127.8, 128.4,128.6,130.1, 131.9, 133.4,134.1,
135.0, 136.3, 137.7, 159.4, 162.5, 163.5, 165.8. (Found: C, 71.20; H,
6.00; N, 5.32. C32H32N2O6 requires: C, 71.09; H, 5.97; N, 5.18.) nmax
(KBr) 3309, 2978, 1713, 1686, 1507, 1478, 1433, 1394, 1369, 1333,
C
29H32N2O7 requires: C, 69.03; H, 6.39; N, 5.55.) nmax (KBr) 3309,
2979, 2931, 1721, 1686, 1659, 1510, 1479, 1426, 1369, 1330, 1298,
1250, 1159, 1097, 1028, 847, 708 cmꢁ1
.
1300, 1248, 1157, 844, 784, 712 cmꢁ1
.
4.2.2.3. Di-tert-butyl 5-benzamido-1-(4-hydroxyphenyl)-6-oxo-1,6-
dihydropyridine-3,4-dicarboxylate (4c). Prepared from a mixture of
3c and 30c (0.240 g, 0.474 mmol) and KOH (0.027 g, 0.41 mmol) in
ethanol (3 ml), 40 min, HCl(concd) (two drops), chromatography
(ethyl acetate/petroleum ether¼1:1 and ethyl acetate), recrystal-
lised from toluene/n-heptane (8:1). Yield: 0.192 g (80%) of white
4.3. Di-tert-butyl 5-amino-6-oxo-1-phenyl-1,6-dihydro-
pyridine-3,4-dicarboxylate (5)
Potassium hydroxide (0.026 g, 0.39 mmol) was added to a solu-
tion of crude mixture of (1E,3E)-2,3-di-tert-butyl 1-methyl 1-benz-
amido-4-(phenylamino)buta-1,3-diene-1,2,3-tricarboxylate (3a) and
(1E,3Z)-2,3-di-tert-butyl 1-methyl 1-benzamido-4-(phenylamino)-
buta-1,3-diene-1,2,3-tricarboxylate (30a) (0.242 g, 0.463 mmol) in
methanol (3 ml). The reaction mixture was heated to reflux for 4 h.
Volatile components were evaporated in vacuo and the residue
was purified by column chromatography on silica gel (ethyl acetate/
petroleum ether¼1:4). Fractions containing the product were com-
bined and evaporated in vacuo. The product was recrystallised from a
mixture of toluene and n-heptane (5:1). Yield: 0.116 g (65%) of white
crystals; mp 189–191 ꢀC. 1H NMR (CDCl3):
d 1.53 (9H, s, C(Me)3),
1.54 (9H, s, C(Me)3), 6.79–6.85 (2H, m, 2H of Ph–OH), 7.05–7.11 (2H,
m, 2H of Ph-OH), 7.43–7.50 (2H, m, 2H of Ph), 7.51–7.58 (1H, m, 1H
of Ph), 7.82 (1H, s, 2-H), 7.88–7.94 (2H, m, 2H of Ph), 8.14 (1H, br s,
NH), OH exchanged. 13C NMR (DMSO-d6):
d 27.4, 27.6, 81.5, 82.0,
107.3, 115.5, 125.0, 127.5, 127.7, 128.2, 131.1, 131.6, 133.5, 141.1, 142.1,
157.7, 159.3, 162.1, 162.6, 165.9. (Found: C, 66.14; H, 6.17; N, 5.55.
C
28H30N2O7 requires: C, 66.39; H, 5.97; N, 5.53.) nmax (KBr) 3194,
2974, 1720, 1664, 1644, 1612, 1513, 1487, 1458, 1371, 1330, 1308,
1287, 1156, 1124, 1020, 845 cmꢁ1
.
crystals; mp 146–149 ꢀC. 1H NMR (CDCl3):
(9H, s, C(Me)3), 5.85 (2H, br s, NH2), 7.17 (1H, s, 2-H), 7.35–7.40 (2H, m,
2H of Ph), 7.42–7.55 (3H, m, 3H of Ph). 13C NMR (CDCl3):
28.3, 28.4,
d 1.54 (9H, s, C(Me)3), 1.59
4.2.2.4. Di-tert-butyl 5-benzamido-1-(4-fluorophenyl)-6-oxo-1,6-di-
hydropyridine-3,4-dicarboxylate (4d). Prepared from a mixture of
3d and 30d (0.181 g, 0.335 mmol) and KOH (0.019 g, 0.29 mmol) in
ethanol (2 ml), 45 min, HCl(concd) (one drop), chromatography
(ethyl acetate/petroleum ether¼1:2), recrystallised from toluene/
n-heptane (4:1). Yield: 0.113 g (66%) of white crystals; mp 185–
d
81.8, 82.8, 109.7, 113.7, 126.6, 127.2, 129.1, 129.7, 139.7, 140.6, 158.0,
164.6,166.4. (Found: C, 65.23; H, 7.00; N, 7.37. C21H26N2O5 requires: C,
65.27; H, 6.78; N, 7.25.) nmax (KBr) 3478, 3351, 2981, 1719, 1704, 1656,
1586,1438,1368,1339,1277,1258,1172,1112,1022, 847, 790, 692 cmꢁ1
.
187 ꢀC. 1H NMR (CDCl3):
d
1.55 (9H, s, C(Me)3), 1.56 (9H, s, C(Me)3),
4.4. General procedure for the synthesis of (1E,3E)-1-amino-
7.17–7.24 (2H, m, 2H of Ph), 7.34–7.40 (2H, m, 2H of Ph), 7.41–7.48
(2H, m, 2H of Ph), 7.50–7.57 (1H, m,1H of Ph), 7.75 (1H, s, 2-H), 7.87–
4-(dimethylamino)buta-1,3-dienes 1b,c
7.92 (2H, m, 2H of Ph), 8.22 (1H, br s, NH). 13C NMR (CDCl3):
d
27.8,
Acetylenes 7a,b (2 mmol) were added to a solution of (Z)-methyl
2-benzamido-3-(dimethylamino)propenoate (6) (0.248 g, 1 mmol)
in acetonitrile (4 mL) and the mixture was stirred in a closed vessel
28.0, 82.1, 83.4, 111.0, 116.4 (d, J¼23.1 Hz), 125.4, 127.6, 128.3 (d,
J¼8.6 Hz), 128.4, 131.9, 133.2, 135.5 (d, J¼3.1 Hz), 136.4, 137.8, 159.3,

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U. Ursic et al. / Tetrahedron 64 (2008) 9937–9946
9943
under microwave irradiation at automatically controlled constant
temperature. The reaction mixture was cooled. Volatile compo-
nents were evaporated in vacuo and the residue was purified by
column chromatography on silica gel. Fractions containing the
product were combined and evaporated in vacuo.
4-(1-benzamido-2-methoxy-2-oxoethylidene)-5-oxo-1-aryl-4,5-
dihydro-1H-pyrrole-3-carboxylates 9a–e.
4.5.1. (1E,3E)-Trimethyl 1-benzamido-4-(arylamino)buta-1,3-
diene-1,2,3-tricarboxylates 8a–e and (1E,3Z)-trimethyl 1-
benzamido-4-(arylamino)buta-1,3-diene-1,2,3-tricarboxylates 80a–e
4.4.1. Trimethyl (1E,3E)-1-(benzoylamino)-4-(dimethyl-
amino)buta-1,3-diene-1,2,3-tricarboxylate (1b)
4.5.1.1. (1E,3E)-Trimethyl 1-benzamido-4-(phenylamino)buta-1,3-di-
Prepared from (Z)-methyl 2-benzamido-3-(dimethylamino)pro-
penoate (6) (0.248 g, 1 mmol) and dimethyl acetylenedicarboxylate
(7a) (0.250 mL, 2 mmol), 80 ꢀC, 100 min, chromatography (ethyl
acetate/petroleum ether¼1:1), crystallisation from ethyl acetate/
petroleum ether (3:2). Yielþd:0.364 g (93%)of yellowcrystals; mp 92–
ene-1,2,3-tricarboxylate (8a) and (1E,3Z)-trimethyl 1-benzamido-4-
(phenylamino)buta-1,3-diene-1,2,3-tricarboxylate
(80a). Prepared
from 1b (0.390 g, 1 mmol) and aniline hydrochloride (2a) (0.389 g,
3 mmol) in methanol (2 ml), 8 h, chromatography (ethyl acetate/
petroleum ether¼2:3). Yield: 0.224 g (51%) of yellow oil. EIMS:
94 ꢀC. EIMS: m/z¼390 (M ). 1H NMR (CDCl3):
d
2.87 (6H, s, NMe2),
m/z¼438 (Mþ). 1H NMR (CDCl3): E-isomer:
d 3.74 (3H, s, COOMe),
3.67 (3H, s, COOMe), 3.75 (3H, s, COOMe), 3.90 (3H, 3, COOMe), 7.38
(1H, br s, NH), 7.44–7.50 (2H, m, 2H of Ph), 7.54–7.61 (1H, m,1H of Ph),
3.75 (3H, s, COOMe), 3.91 (3H, s, COOMe), 6.90–7.08 (4H, m, 3H of Ph
and NH), 7.20–7.30 (2H, m, 2H of Ph), 7.32–7.55 (3H, m, 3H of Ph),
7.65–7.70 (2H, m, 2H of Ph), 7.79 (1H, br s, NHCO), 8.15 (1H, d, J¼
7.61 (1H, s, 4-H), 7.72–7.76 (2H, m, 2H of Ph). 13C NMR (CDCl3):
d 51.4,
52.4, 52.8, 89.2, 118.6, 127.3, 128.9, 132.2, 132.7, 133.3, 151.1, 164.4,
164.4, 167.2, 168.8. EI-HRMS: m/z¼390.1439 (Mþ); C19H22N2O7 re-
quires: m/z¼390.1427 (Mþ); nmax (KBr) 3279, 2950, 2924,1725,1666,
14.4 Hz, 4-H); Z-isomer: d 3.74 (3H, s, COOMe), 3.75 (3H, s, COOMe),
3.94 (3H, s, COOMe), 6.90–7.08 (3H, m, 3H of Ph), 7.20–7.30 (2H, m,
2H of Ph), 7.32–7.55 (4H, m, 3H of Ph and 4-H), 7.71–7.76 (2H, m, 2H
of Ph), 7.83 (1H, br s, NHCO), 10.4 (1H, br d, J¼13.4 Hz, NH). Ratio
of isomers: 67:33. EI-HRMS: m/z¼438.1438 (Mþ); C23H22N2O7 re-
quires: m/z¼438.1427 (Mþ); nmax (KBr) 3283, 2951,1728,1660,1624,
1609, 1508, 1478, 1434, 1297, 1258, 1219, 1096, 775, 712 cmꢁ1
.
4.4.2. 2,3-Diethyl 1-methyl (1E,3E)-1-(benzoylamino)-4-
(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylate (1c)
1601, 1585, 1505, 1478, 1436, 1266, 1219, 1158, 1127, 754, 691 cmꢁ1
.
Prepared from (Z)-methyl 2-benzamido-3-(dimethylamino)pro-
penoate (6) (0.248 g, 1 mmol) and diethyl acetylenedicarboxylate
(7b) (0.325 mL, 2 mmol), 80 ꢀC, 120 min, chromatography (ethyl ac-
etate/petroleum ether¼1:1). Yield: 0.395 g (94%) of yellow oil. EIMS:
4.5.1.2. (1E,3E)-Trimethyl 1-benzamido-4-(p-tolylamino)buta-1,3-di-
ene-1,2,3-tricarboxylate (8b) and (1E,3Z)-trimethyl 1-benzamido-4-
(p-tolylamino)buta-1,3-diene-1,2,3-tricarboxylate
(80b). Prepared
m/z¼418 (Mþ). 1H NMR (CDCl3):
d
1.22 (3H, t, J¼7.1 Hz, CH2CH3),1.28
from 1b (0.390 g, 1 mmol) and 4-methylaniline hydrochloride (2b)
(0.574 g, 4 mmol) in methanol (3 ml), 5 h, chromatography (ethyl
acetate/petroleum ether¼1:2). Yield: 0.349 g (77%) of yellow oil.
(3H, t, J¼7.1 Hz, CH2CH3), 2.85 (6H, s, NMe2), 3.89 (3H, s, COOMe),
4.04–4.26 (4H, m, 2ꢂCH2CH3), 7.31 (1H, br s, NH), 7.44–7.50 (2H, m,
2H of Ph), 7.54–7.76 (1H, m,1H of Ph), 7.60 (1H, s, 4-H), 7.72–7.76 (2H,
ESI-MS: m/z¼453.2 (MHþ). 1H NMR (CDCl3): E-isomer:
d 2.26 (3H, s,
m, 2H of Ph).13C NMR (CDCl3):
d
14.4,14.7, 53.1, 60.5, 61.6, 90.2,120.3,
Ph–Me), 3.73 (3H, s, COOMe), 3.74 (3H, s, COOMe), 3.90 (3H, s,
COOMe), 6.78–6.86 (2H, m, 2H of Ph), 6.95–7.08 (3H, m, 2H of Ph
and NH), 7.33–7.56 (3H, m, 3H of Ph), 7.66–7.71 (2H, m, 2H of Ph),
127.7, 129.3, 132.6, 132.8, 133.0, 151.5, 164.9, 165.0, 167.3, 168.9. EI-
HRMS: m/z¼418.1751 (Mþ); C21H26N2O7 requires: m/z¼418.1740
(Mþ); nmax (NaCl) 3279, 2982, 2948,1736,1721,1666,1599,1509,1477,
7.83 (1H, br s, NHCO), 8.11 (1H, d, J¼14.5 Hz, 4-H); Z-isomer:
d 2.28
1434, 1365, 1293, 1254, 1219, 1095, 1048, 774, 710 cmꢁ1
.
(3H, s, Ph–Me), 3.73 (3H, s, COOMe), 3.75 (3H, s, COOMe), 3.94 (3H,
s, COOMe), 6.78–6.86 (2H, m, 2H of Ph), 6.95–7.08 (2H, m, 2H of Ph),
7.33–7.56 (4H, m, 3H of Ph in 4-H), 7.71–7.76 (2H, m, 2H of Ph), 7.85
(1H, br s, NHCO), 10.36 (1H, br d, J¼13.1 Hz, NH). Ratio of isomers:
70:30. ESI-HRMS: m/z¼453.1648 (MHþ); C24H24N2O7 requires:
m/z¼453.1662 (MHþ); nmax (KBr) 3284, 2951, 1731, 1686, 1662, 1610,
4.5. General procedure for the synthesis of (Z)-methyl 4-
(1-benzamido-2-methoxy-2-oxoethylidene)-5-oxo-1-aryl-4,5-
dihydro-1H-pyrrole-3-carboxylates 9a–e through (1E,3E)-
trimethyl 1-benzamido-4-(arylamino)buta-1,3-diene-1,2,3-
tricarboxylates 8a–e and (1E,3Z)-trimethyl 1-benzamido-4-
(arylamino)buta-1,3-diene-1,2,3-tricarboxylates 80a–e
1582, 1519, 1475, 1436, 1293, 1263, 1218, 1125, 715 cmꢁ1
.
4.5.1.3. (1E,3E)-Trimethyl 1-benzamido-4-(4-hydroxyphenylamino)-
buta-1,3-diene-1,2,3-tricarboxylate (8c) and (1E,3Z)-trimethyl 1-ben-
zamido-4-(4-hydroxyphenylamino)buta-1,3-diene-1,2,3-tricarboxylate
(80c). Prepared from 1b (0.390 g, 1 mmol) and 4-hydroxyaniline
hydrochloride (2c) (0.437 g, 3 mmol) in methanol (2 ml), 8 h, chro-
matography (ethyl acetate/petroleum ether¼3:2). Yield: 0.330 g
(73%) of yellow oil. EIMS: m/z¼454 (Mþ). 1H NMR (CDCl3): E-isomer:
Amine hydrochlorides 2a–e (1.8–4.0 mmol, 2.6–4 equiv) were
added to a solution of (1E,3E)-trimethyl 1-benzamido-4-(dime-
thylamino)buta-1,3-diene-1,2,3-tricarboxylate (1b) (0.7–1.0 mmol)
in dry methanol (2.5–3 ml). The reaction mixture was heated to
reflux. After cooling to room temperature, the residual amine hy-
drochloride was filtered off and washed with CH2Cl2. Volatile
components from the filtrate were evaporated in vacuo and the
residue was purified by column chromatography on silica gel.
Fractions containing the product were combined and evaporated
in vacuo, which gave a yellow oily product. No further purifica-
tion of thus obtained mixture of (1E,3E)-trimethyl 1-benz-
amido-4-(arylamino)buta-1,3-diene-1,2,3-tricarboxylates 8a–e and
(1E,3Z)-trimethyl 1-benzamido-4-(arylamino)buta-1,3-diene-1,2,3-
tricarboxylates 80a–e was undertaken. Additionally, in some cases
trimethyl 1H-pyrrole-2,3,4-tricarboxylate (15)11 was isolated by
column chromatography as a side product. Potassium hydroxide
(0.005–0.009 g) was added to a solution of crude mixture of 8a–e
and 80a–e (0.36–0.70 mmol) in ethanol (1.5–2.5 ml). The reaction
mixture was stirred at room temperature. The formed precipitate
was filtered off under reduced pressure to give pure methyl
d
3.73 (3H, s, COOMe), 3.76 (3H, s, COOMe), 3.90 (3H, s, COOMe), 5.56
(1H, br s, OH), 6.66–6.78 (4H, m, 4H of Ph), 6.97 (1H, br d, J¼14.6 Hz,
NH), 7.30–7.54 (3H, m, 3H of Ph), 7.66–7.71 (2H, m, 2H of Ph), 7.82
(1H, br s, NHCO), 7.99 (1H, d, J¼14.5 Hz, 4-H); Z-isomer:
d 3.73 (3H, s,
COOMe), 3.76 (3H, s, COOMe), 3.93 (3H, s, COOMe), 5.56 (1H, br s,
OH), 6.66–6.78 (4H, m, 4H of Ph), 7.30–7.54 (4H, m, 3H of Ph and
4-H), 7.72–7.77 (2H, m, 2H of Ph), 7.85 (1H, br s, NHCO), 10.29 (1H, br
d, J¼13.3 Hz, NH). Ratio of isomers: 73:27. EI-HRMS: m/z¼454.1386
(Mþ); C23H22N2O8 requires: m/z¼454.1376 (Mþ); nmax (KBr) 3280,
2950, 1732, 1717, 1684, 1645, 1599, 1518, 1478, 1436, 1377, 1325, 1300,
1264, 1221, 1175, 1128, 987, 694 cmꢁ1
.
4.5.1.4. (1E,3E)-Trimethyl 1-benzamido-4-(4-fluorophenylamino)-
buta-1,3-diene-1,2,3-tricarboxylate (8d) and (1E,3Z)-trimethyl 1-ben-
zamido-4-(4-fluorophenylamino)buta-1,3-diene-1,2,3-tricarboxylate

ˇ ˇ
U. Ursic et al. / Tetrahedron 64 (2008) 9937–9946
9944
(80d). Prepared from 1b (0.390 g, 1 mmol) and 4-fluoroaniline
hydrochloride (2d) (0.443 g, 3 mmol) in methanol (2.5 ml), 8 h,
chromatography (ethyl acetate/petroleum ether¼2:3). Yield:
0.266 g (58%) of yellow oil. EIMS: m/z¼456 (Mþ). 1H NMR (CDCl3):
nmax (KBr) 3447, 1749, 1719, 1693, 1664, 1606, 1513, 1489, 1395, 1336,
1238, 1196, 1085, 990, 707 cmꢁ1
.
4.5.2.3. (Z)-Methyl 4-(1-benzamido-2-methoxy-2-oxoethylidene)-
1-(4-hydroxyphenyl)-5-oxo-4,5-dihydro-1H-pyrrole-3-carboxylate
(9c). Prepared from a mixture of 8c and 80c (0.300 g, 0.660 mmol)
and KOH (0.009 g, 0.14 mmol) in ethanol (2.5 ml), 65 min. Yield:
0.176 g (63%) of fluorescent yellow crystals; mp 258–260 ꢀC. 1H
E-isomer:
d 3.74 (3H, s, COOMe), 3.76 (3H, s, COOMe), 3.90 (3H, s,
COOMe), 6.85–7.00 (4H, m, 4H of Ph), 7.11 (1H, br d, J¼14.2 Hz, NH),
7.35–7.55 (3H, m, 3H of Ph), 7.66–7.71 (2H, m, 2H of Ph), 7.79 (1H, br
s, NHCO), 8.05 (1H, d, J¼14.3 Hz, 4-H); Z-isomer:
d 3.74 (3H, s,
COOMe), 3.75 (3H, s, COOMe), 3.94 (3H, s, COOMe), 6.85–7.00 (4H,
m, 4H of Ph), 7.35–7.55 (4H, m, 3H of Ph and 4-H), 7.71–7.76 (2H, m,
2H of Ph), 7.81 (1H, br s, NHCO), 10.39 (1H, br d, J¼13.0 Hz, NH).
Ratio of isomers: 73:27. EI-HRMS: m/z¼456.1322 (Mþ);
NMR (CDCl3): d 3.83 (3H, s, COOMe), 3.85 (3H, s, COOMe), 6.79–6.86
(2H, m, 2H of Ph–OH), 7.26–7.32 (2H, m, 2H of Ph–OH), 7.53–7.65
(2H, m, 2H of Ph), 7.68–7.75 (1H, m, 1H of Ph), 7.96–8.04 (2H, m, 2H
of Ph), 8.23 (1H, s, 2-H), 9.69 (1H, s, Ph–OH), 13.09 (1H, s, NH). 13
C
C
23H21FN2O7 requires: m/z¼456.1333 (Mþ); nmax (KBr) 3294, 2952,
NMR (DMSO-d6): d 52.4, 52.5, 103.9, 106.6, 115.4, 125.1, 126.6, 127.7,
1731, 1693, 1661, 1624, 1599, 1514, 1476, 1436, 1296, 1266, 1209,
129.0, 131.6, 133.3, 138.0, 143.7, 156.5, 163.2, 163.8, 165.1, 165.8.
(Found: C, 62.37; H, 4.51; N, 6.50. C22H18N2O7 requires: C, 62.56; H,
4.30; N, 6.63.) nmax (KBr) 3363, 2964, 1750, 1702, 1687, 1662, 1608,
1159, 1126, 830, 779, 716 cmꢁ1
.
4.5.1.5. (1E,3E)-Trimethyl 1-benzamido-4-(3-methoxyphenylamino)
buta-1,3-diene-1,2,3-tricarboxylate (8e) and (1E,3Z)-trimethyl 1-ben-
zamido-4-(3-methoxyphenylamino)buta-1,3-diene-1,2,3-tricarboxylate
(80e). Prepared from 1b (0.273 g, 0.7 mmol) and 3-methoxyaniline
hydrochloride (2e) (0.293 g, 1.8 mmol) in methanol (2 ml), 8 h,
chromatography (ethyl acetate/petroleum ether¼2:3). Yield: 0.190 g
(58%) of yellow oil. EIMS: m/z¼468 (Mþ). 1H NMR (CDCl3): E-isomer:
1519, 1448, 1395, 1348, 1269, 1240, 1193, 1090, 996, 834, 709 cmꢁ1
.
4.5.2.4. (Z)-Methyl 4-(1-benzamido-2-methoxy-2-oxoethylidene)-
1-(4-fluorophenyl)-5-oxo-4,5-dihydro-1H-pyrrole-3-carboxylate
(9d). Prepared from a mixture of 8d and 80d (0.250 g, 0.548 mmol)
and KOH (0.006 g, 0.09 mmol) in ethanol (2 ml), 45 min. Yield:
0.142 g (61%) of fluorescent yellow crystals; mp 202–205 ꢀC. 1H
d
3.75 (3H, s, COOMe), 3.76 (3H, s, OMe), 3.76 (3H, s, COOMe), 3.91
NMR (CDCl3): d 3.93 (3H, s, COOMe), 4.06 (3H, s, COOMe), 7.08–7.17
(3H, s, COOMe), 6.44–6.62 (2H, m, 2H of Ph), 6.99 (1H, br d, J¼14.4 Hz,
NH), 7.11–7.20 (1H, m, 1H of Ph), 7.33–7.55 (3H, m, 3H of Ph), 7.65–
7.70 (2H, m, 2H of Ph), 7.75 (1H, br s, NHCO), 7.92–7.98 (1H, m, 1H of
(2H, m, 2H of Ph–F), 7.39–7.46 (2H, m, 2H of Ph–F), 7.49–7.56 (2H, m,
2H of Ph), 7.58–7.65 (1H, m, 1H of Ph), 7.82 (1H, s, 2-H), 8.08–8.13
(2H, m, 2H of Ph), 13.09 (1H, s, NH). 13C NMR (CDCl3):
d 52.6, 53.3,
Ph), 8.14 (1H, d, J¼14.3 Hz, 4-H); Z-isomer:
d
3.73 (3H, s, COOMe), 3.74
105.8, 106.3, 116.2 (d, J¼22.9 Hz), 124.9 (d, J¼8.5 Hz), 128.2, 128.8,
131.5, (d, J¼2.9 Hz), 131.8, 133.1, 140.2, 140.9, 161.3 (d, J¼248 Hz),
164.1, 164.6, 165.5, 165.9. (Found: C, 62.47; H, 4.23; N, 4.44.
(3H, s, OMe), 3.75 (3H, s, COOMe), 3.95 (3H, s, COOMe), 6.23–6.33 (1H,
m, 1H of Ph), 6.44–6.62 (2H, m, 2H of Ph), 7.11–7.20 (1H, m, 1H of Ph),
7.33–7.55 (4H, m, 3H of Ph and 4-H), 7.70–7.74 (2H, m, 2H of Ph), 7.83
(1H, br s, NHCO), 10.40 (1H, br d, J¼13.0 Hz, NH). Ratio of isomers:
68:32. EI-HRMS: m/z¼468.1544 (Mþ); C24H24N2O8 requires:
m/z¼468.1533 (Mþ); nmax (KBr) 3285, 2950, 1732, 1717, 1681, 1646,
C
22H17FN2O6 requires: C, 62.26; H, 4.04; N, 4.48.) nmax (KBr) 3447,
3143, 2951, 1745,1715,1677,1610,1512,1488,1396,1340,1264, 1241,
1222, 1085, 709 cmꢁ1
.
1601, 1590, 1505, 1474, 1435, 1267, 1199, 1156, 1124, 778, 689 cmꢁ1
.
4.5.2.5. (Z)-Methyl 4-(1-benzamido-2-methoxy-2-oxoethylidene)-
1-(3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-pyrrole-3-carboxylate
(9e). Prepared from a mixture of 8e and 80e (0.170 g, 0.363 mmol)
and KOH (0.005 g, 0.08 mmol) in ethanol (2 ml), 120 min. Yield:
0.099 g (62%) of fluorescent yellow crystals; mp 173–175 ꢀC. 1H
4.5.2. (Z)-Methyl 4-(1-benzamido-2-methoxy-2-oxoethylidene)-5-
oxo-1-aryl-4,5-dihydro-1H-pyrrole-3-carboxylates 9a–e
4.5.2.1. (Z)-Methyl 4-(1-benzamido-2-methoxy-2-oxoethylidene)-5-
oxo-1-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylate (9a). Prepared
from a mixture of 8a and 80a (0.215 g, 0.49 mmol) and KOH
(0.007 g, 0.11 mmol) in ethanol (1.5 ml), 120 min. Yield: 0.135 g
(68%) of fluorescent yellow crystals; mp 241–242 ꢀC. 1H NMR
NMR (CDCl3): d 3.83 (3H, s, OMe), 3.93 (3H, s, COOMe), 4.07 (3H, s,
COOMe), 6.86 (1H, ddd, J¼0.8, 2.4, 8.4 Hz, 1H of Ph–OMe), 7.00 (1H,
ddd, J¼0.8, 1.9, 7.9 Hz,1H of Ph–OMe), 7.06 (1H, dd, J¼1.9, 2.3 Hz,1H
of Ph–OMe), 7.33 (1H, dd, J¼7.9, 8.3 Hz, 1H of Ph–OMe), 7.49–7.56
(2H, m, 2H of Ph), 7.57–7.64 (1H, m,1H of Ph), 7.86 (1H, s, 2-H), 8.08–
(CDCl3):
d
3.93 (3H, s, COOMe), 4.07 (3H, s, COOMe), 7.28–7.36 (1H,
8.14 (2H, m, 2H of Ph), 13.08 (1H, s, NH). 13C NMR (CDCl3)
d 52.6,
m, 1H of Ph), 7.40–7.48 (4H, m, 4H of Ph), 7.49–7.56 (2H, m, 2H of
Ph), 7.57–7.64 (1H, m, 1H of Ph), 7.88 (1H, s, 2-H), 8.03–8.14 (2H, m,
d 52.6, 53.4, 105.8,
106.6, 123.0, 127.4, 128.3, 128.8, 129.4, 132.0, 133.1, 135.5, 140.0,
141.3, 164.3, 164.6, 165.6, 166.0. (Found: C, 65.20; H, 4.64; N, 6.84.
53.3, 55.5, 105.7, 106.7, 108.8, 113.1, 114.8, 128.3, 128.8, 130.0, 131.9,
133.1, 136.6, 139.8, 141.3, 160.2, 164.3, 164.6, 165.5, 166.0. (Found: C,
63.50; H, 4.85; N, 6.60. C23H20N2O7 requires: C, 63.30; H, 4.62; N,
6.42.) nmax (KBr) 3447, 2953, 1747, 1717, 1695, 1671, 1607, 1514, 1490,
2H of Ph), 13.09 (1H, s, NH). 13C NMR (CDCl3)
1397, 1335, 1260, 1227, 1219, 1087, 1001, 713 cmꢁ1
.
C
22H18N2O6 requires: C, 65.02; H, 4.46; N, 6.89.) nmax (KBr) 3479,
2958,1752,1713,1692,1667,1609,1516,1488,1397,1338,1267,1237,
1225, 1198, 1087, 993, 747, 717, 708 cmꢁ1
4.6. (Z)-Methyl 4-(1-amino-2-methoxy-2-oxoethylidene)-5-
oxo-1-p-tolyl-4,5-dihydro-1H-pyrrole-3-carboxylate (10) and
(E)-methyl 4-(1-amino-2-methoxy-2-oxoethylidene)-5-oxo-1-
p-tolyl-4,5-dihydro-1H-pyrrole-3-carboxylate (100)
.
4.5.2.2. (Z)-Methyl 4-(1-benzamido-2-methoxy-2-oxoethylidene)-5-
oxo-1-p-tolyl-4,5-dihydro-1H-pyrrole-3-carboxylate (9b). Prepared
from a mixture of 8b and 80b (0.317 g, 0.7 mmol) and KOH (0.008 g,
0.12 mmol) in ethanol (2 ml), 150 min. Yield: 0.300 g (71%) of
Potassium hydroxide (0.020 g, 0.30 mmol) was added to a solu-
tion of crude mixture of 8b and 80b (0.150 g, 0.33 mmol) in meth-
anol (2 ml). The reaction mixture was stirred at room temperature
for 6 h. Volatile components were evaporated in vacuo and the
residue was purified by column chromatography on silica gel (ethyl
acetate/petroleum ether¼1:2). Fractions containing the product
were combined and evaporated in vacuo. Yield: 0.046 g (44%) of
yellow oil; mp 60–72 ꢀC. EIMS: m/z¼316 (Mþ). 1H NMR (CDCl3):
fluorescent yellow crystals; mp 202–203 ꢀC. 1H NMR (CDCl3):
d .36
(3H, s, Ph–Me), 3.92 (3H, s, COOMe), 4.06 (3H, s, COOMe), 7.21–7.25
(2H, m, 2H of Ph–Me), 7.30–7.34 (2H, m, 2H of Ph–Me), 7.49–7.55
(2H, m, 2H of Ph), 7.57–7.64 (1H, m, 1H of Ph), 7.84 (1H, s, 2-H),
8.04–8.13 (2H, m, 2H of Ph), 13.09 (1H, s, NH). 13C NMR (CDCl3):
d
20.9, 52.5, 53.2, 105.3, 106.6, 122.6, 128.1, 128.7, 129.7, 131.8, 132.9,
133.0, 137.1, 139.5, 141.5, 164.2, 164.4, 165.5, 165.9. (Found: C, 65.80;
H, 4.94; N, 6.63. C23H20N2O6 requires: C, 65.71; H, 4.79; N, 6.66.)
d
2.34 (3H, s, Ph–Me), 2.37 (3H, s, Ph–Me), 3.76 (3H, s, COOMe), 3.82
(3H, s, COOMe), 3.89 (3H, s, COOMe), 3.94 (3H, s, COOMe), 5.53 (1H,

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U. Ursic et al. / Tetrahedron 64 (2008) 9937–9946
9945
br s, Ha–NH), 5.92 (1H, br, s, Ha–NH), 7.16–7.27 (4H, m, 4H of Ph),
7.31–7.40 (4H, m, 4H of Ph), 7.35 (1H, s, 2-H), 7.57 (1H, s, 2-H), 9.31
(1H, br, s, Hb-NH), 9.58 (1H, br, s, Hb-NH). Ratio of isomers: 50:50.
EI-HRMS: m/z¼316.1066 (Mþ); C16H16N2O5 requires: m/z¼316.1059
(Mþ); nmax (KBr) 3385, 3150, 2953, 1745, 1713, 1684, 1624, 1570,
9.61 (1H, s, NH), 12.25 (1H, s, NH). 13C NMR (DMSO-d6):
d
27.5, 27.6,
81.0, 81.4, 107.6, 124.0, 124.4, 124.9, 126.6, 126.7, 127.6, 128.1, 131.5,
132.1, 133.1, 133.8, 138.4, 139.1, 139.9, 150.7, 156.2, 162.4, 163.1, 165.8.
ESI-HRMS: m/z¼558.2358 (MHþ); C30H32N5O6 requires: m/z¼
558.2353 (MHþ); nmax (KBr) 3419, 3262, 2978, 1717, 1707, 1671, 1654,
1516, 1441, 1391, 1232, 1202, 1181, 1077, 942, 820, 768 cmꢁ1
.
1602, 1515, 1485, 1329, 1286, 1156, 1029, 848 cmꢁ1
.
4.7. Reactions of (1E,3E)-1-(benzoylamino)-4-(dimethyl-
amino)buta-1,3-diene-1,2,3-tricarboxylates 1a,b with
hydrazines 11a,b
4.7.4. Di-tert-butyl 5-benzamido-6-oxo-1-(tetrazolo[1,5-
b]pyridazin-6-ylamino)-1,6-dihydropyridine-3,4-di-
carboxylate (12d)
6-Hydrazinotetrazolo[1,5-b]pyridazine hydrochloride (11b)
(0.063 g, 0.33 mmol) was added to a solution of 2,3-di-tert-butyl
1-methyl (1E,3E)-1-(benzoylamino)-4-(dimethylamino)buta-1,3-
diene-1,2,3-tricarboxylate (1a) (0.158 g, 0.33 mmol) in methanol
(1.5 ml). The reaction mixture was heated to reflux for 6 h. Volatile
components were evaporated in vacuo and the residue was purified
by column chromatography on silica gel (ethyl acetate). Fractions
containing the product were combined and evaporated in vacuo.
The product was recrystallised from a mixture of ethyl acetate and
n-heptane (3:1). Yield: 0.158 g (86%) of white crystals; mp de-
4.7.1. Dimethyl 5-benzamido-6-oxo-1-(phthalazin-1-ylamino)-1,6-
dihydropyridine-3,4-dicarboxylate (12a)
1-Hydrazinophthalazine hydrochloride (11a) (0.196 g, 1 mmol)
was added to a solution of trimethyl (1E,3E)-1-(benzoylamino)-4-
(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylate (1b) (0.390 g,
1 mmol) in methanol (5 ml). The reaction mixture was heated to
reflux for 17 h and then allowed to cool to room temperature. The
precipitated product was filtered under reduced pressure. Yield:
0.358 g (76%) of white crystals; mp 245–248 ꢀC. EIMS: m/z¼473
(Mþ). 1H NMR (DMSO-d6):
d
3.73 (3H, s, COOMe), 3.75 (3H, s,
composes above 158 ꢀC. 1H NMR (DMSO-d6):
d 1.41 (9H, s, C(Me)3),
COOMe), 7.46–7.52 (2H, m, 2H of Ar), 7.54–7.62 (1H, m, 1H of Ar),
7.82–7.94 (5H, m, 5H of Ph), 8.24 (1H, s, 2-H), 8.33 (1H, s, 1H of Ar),
8.39 (1H, d, J¼7.6 Hz, 1H of Ar), 9.65 (1H, s, NH), 12.34 (1H, s, NH). 1H
1.52 (9H, s, C(Me)3), 7.45–7.52 (2H, m, 2H of Ph), 7.49 (1H, d,
J¼9.6 Hz,1H of Ar), 7.53–7.60 (1H, m,1H of Ph), 7.90–7.95 (2H, m, 2H
of Ph), 8.48 (1H, s, 2-H), 8.62 (1H, d, J¼9.7 Hz, 1H of Ar), 9.91 (1H, s,
NMR (DMSO-d6/D2O),
d
3.78 (3H, s, COOMe), 3.79 (3H, s, COOMe),
NH), 11.60 (1H, br s, NH). 1H NMR (DMSO-d6/D2O):
d 1.43 (9H, s,
7.51–7.60 (2H, m, 2H of Ar), 7.60–7.68 (1H, m, 1H of Ar), 8.84–8.97
(5H, m, 5H of Ph), 8.34 (1H, s, 2-H), 8.38 (1H, s, 1H of Ar), 8.42 (1H, d,
J¼7.8 Hz, 1H of Ar). (Found: C, 60.92; H, 4.17; N, 14.73. C24H19N5O6
requires: C, 60.89; H, 4.05; N, 14.79.) EI-HRMS: m/z¼473.1349 (Mþ);
C(Me)3), 1.52 (9H, s, C(Me)3), 7.46–7.56 (3H, m, 3H of Ar), 7.58–7.65
(1H, m, 1H of Ar), 7.88–7.94 (2H, m, 2H of Ar), 8.50 (1H, s, 2-H), 8.53
(1H, d, J¼9.6 Hz, 1H of Ar). 13C NMR (DMSO-d6):
d 102.9, 107.5, 120.1,
124.2, 124.5, 126.7, 126.8, 132.2, 133.1, 139.2, 141.3, 150.1, 153.0,
153.3, 160.2. (Found: C, 56.61; H, 5.35; N, 20.50. C26H28N8O6 re-
quires: C, 56.93; H, 5.14; N, 20.43.) nmax (KBr) 3447, 3232, 2980,
1721, 1683, 1676, 1506, 1482, 1370, 1331, 1290, 1249, 1155, 836,
C
24H19N5O6 requires: m/z¼475.1349 (Mþ); nmax (KBr) 3431, 3237,
2952, 1724, 1646, 1600, 1542, 1511, 1485, 1449, 1307, 1281, 1225,
1131, 1112, 1038, 781, 713 cmꢁ1
.
711 cmꢁ1
.
4.7.2. Dimethyl 5-benzamido-6-oxo-1-(tetrazolo[1,5-b]pyridazin-
6-ylamino)-1,6-dihydropyridine-3,4-dicarboxylate (12b)
4.8. Hydrazine-1,2-diium di(8-amino-4,7-dioxo-
6-(phthalazin-1-ylamino)-3,4,6,7-tetrahydropyrido[3,4-d]-
pyridazin-1-olate) (14)
6-Hydrazinotetrazolo[1,5-b]pyridazine hydrochloride (11b)
(0.188 g, 1 mmol) was added to a solution of trimethyl (1E,3E)-1-
(benzoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxy-
late (1b) (0.390 g,1 mmol) in methanol (5 ml). The reaction mixture
was heated to reflux for 14 h and then allowed to cool to room
temperature. The precipitated product was filtered under reduced
pressure. Yield: 0.388 g (84%) of white crystals; mp 228–230 ꢀC.
FABMS: m/z¼465 (MHþ). ESI-MS: m/z¼465.1 (MHþ). 1H NMR
Dimethyl 5-benzamido-6-oxo-1-(phthalazin-1-ylamino)-1,6-
dihydropyridine-3,4-dicarboxylate (12a) (0.473 g, 1 mmol) was
dissolved in hydrazine monohydrate (11c) (2 ml). The reaction
mixture was heated to reflux for 1.5 h and then allowed to cool to
room temperature before adding water (5 ml). The precipitated
product was filtered under reduced pressure and washed with
water (2 ml). Yield: 0.274 g (76%) of yellow crystals; mp de-
composes above 323 ꢀC. EIMS: m/z¼337 (MHþ of the anionic part).
(DMSO-d6):
d 3.78 (3H, s, COOMe), 3.81 (3H, s, COOMe), 7.46–7.53
(2H, m, 2H of Ph), 7.50 (1H, d, J¼9.6 Hz, 1H of Ar), 7.54–7.61 (1H, m,
1H of Ph), 7.88–7.92 (2H, m, 2H of Ph), 8.62 (1H, d, J¼9.7 Hz, 1H of
Ar), 8.66 (1H, s, 2-H), 9.97 (1H, s, NH), 11.65 (1H, br s, NH). 13C NMR
1H NMR (DMSO-d6):
d
3.60 (5H, br s, 5HꢂNH), 7.24 (2H, br s,
(DMSO-d6):
d
52.5, 52.6,105.6,118.4,125.8,126.6,127.6, 128.3,131.8,
2HꢂNH), 7.28 (1H, s, 5-H), 7.81–7.94 (3H, m, 3H of Ar), 8.31 (1H, s,
1H of Ar), 8.40 (1H, d, J¼7.5 Hz, 1H of Ar). (Found: C, 50.67; H, 3.89;
N, 31.63. C30H26N16O6 requires: C, 50.99; H, 3.71; N, 31.71.) nmax
(KBr) 3463, 3319, 3136, 1639, 1606, 1559, 1540, 1484, 1470, 1430,
133.1, 140.3, 141.1, 145.2, 155.2, 157.3, 162.7, 164.1, 166.1. ESI-HRMS:
m/z¼465.1267 (MHþ); C20H17N8O6 requires: m/z¼465.1271 (MHþ);
nmax (KBr) 3447, 3226, 2956, 1725, 1698, 1668, 1627, 1506, 1484,
1448, 1313, 1284, 1244, 782, 714 cmꢁ1
.
1358, 1274, 1255, 1189, 1154, 1094, 1076, 808, 773 cmꢁ1
.
4.7.3. Di-tert-butyl 5-benzamido-6-oxo-1-(phthalazin-1-ylamino)-
1,6-dihydropyridine-3,4-dicarboxylate (12c)
4.9. Trimethyl 1H-pyrrole-2,3,4-tricarboxylate (15)11
1-Hydrazinophthalazine hydrochloride (11a) (0.066 g,
0.33 mmol) was added to a solution of 2,3-di-tert-butyl 1-methyl
(1E,3E)-1-(benzoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-
tricarboxylate (1a) (0.158 g, 0.33 mmol) in methanol (1.5 ml). The
reaction mixture was refluxed for 7.5 h and then allowed to cool to
room temperature. The precipitated product was filtered under re-
duced pressure. Yield: 0.152þg (82%) of white crystals; mp 167–
170 ꢀC. FABMS: m/z¼558 (MH ). ESI-MS: m/z¼558.2 (MHþ).1H NMR
A solution of (1E,3E)-trimethyl 1-benzamido-4-(dimethylami-
no)buta-1,3-diene-1,2,3-tricarboxylate (1b) (0.130 g, 0.33 mmol) in
DMF (3 ml) was stirred in a closed vessel under microwave irradi-
ation (160 ꢀC, 30 min). The reaction mixture was cooled. Volatile
components were evaporated in vacuo and the residue was purified
by column chromatography on silica gel (ethyl acetate/petroleum
ether¼1:1). Fractions containing the product were combined and
evaporated in vacuo. Yield: 0.079 g (99%) of white crystals; mp 96–
98 ꢀC (literature mp 97–98 ꢀC11). EIMS: m/z¼241 (Mþ). 1H NMR
(DMSO-d6): d 1.41 (9H, s, C(Me)3), 1.51 (9H, s, C(Me)3), 7.45–7.52 (2H,
m, 2H of Ar), 7.53–7.60 (1H, m, 1H of Ar), 7.81–7.97 (5H, m, 5H of Ar),
8.13 (1H, s, 2-H), 8.32 (1H, s,1H of Ar), 8.40 (1H, d, J¼7.5 Hz,1H of Ar),
(CDCl3):
d 3.82 (3H, s, COOMe), 3.87 (3H, s, COOMe), 3.95 (3H, s,
COOMe), 7.48 (1H, d, J¼3.3 Hz, 5-H), 9.43 (1H, br s, NH). EI-HRMS:

ˇ ˇ
U. Ursic et al. / Tetrahedron 64 (2008) 9937–9946
9946
m/z¼241.0590 (Mþ); C10H11NO6 requires: m/z¼241.0586 (Mþ); nmax
Comprehensive Heterocyclic Chemistry; McKillop, A., Ed.; Pergamon: Oxford,
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Pergamon: Oxford, 1996; Vol. 2, pp 119–206.
(KBr) 3297, 3123, 1739, 1708, 1520, 1443, 1291, 1198, 1173, 1070,
1016, 787 cmꢁ1
.
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Acknowledgements
The financial support from the Slovenian Research Agency
through grants P1-0179 and J1-6689-0103-04 is gratefully ac-
knowledged. We thank the pharmaceutical companies Krka d.d.
(Novo mesto, Slovenia) and Lek d.d., a Sandoz company (Ljubljana,
Slovenia) for the financial support. Crystallographic data were
collected on a Kappa CCD Nonius diffractometer in the Laboratory
of Inorganic Chemistry, Faculty of Chemistry and Chemical Tech-
nology, University of Ljubljana, Slovenia. We acknowledge with
thanks the financial contribution of the Ministry of Science and
Technology, Republic of Slovenia through grant Packet X-2000 and
PS-511-102, which made the purchase of the apparatus possible.
ˇ
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