Development of diversified methods for chemical modification of the 5,6-double bond of uracil derivatives depending on active methylene compounds

Article abstract of DOI:10.3390/molecules17066547

The reaction of 5-halogenouracil and uridine derivatives 1 and 7 with active methylene compounds under basic conditions produced diverse and selective C-C bond formation products by virtue of the nature of the carbanions. Three different types of reactions such as the regioselective C-C bond formation at the 5-and 6-positions of uracil and uridine derivatives (products 2, 5, 8, 17, 20 and 21), and the formation of fused heterocycle derivatives 2,4-diazabicyclo[4.1.0]heptane (15) and 2,4-diazabicyclo-[4.1.0]nonane (16) via dual C-C bond formations at both the 5-and 6-positions were due to the different active methylene compounds used as reagents.

Full text of DOI:10.3390/molecules17066547

Molecules 2012, 17, 6547-6556; doi:10.3390/molecules17066547
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Condensation Reactions of 3-Oxo-2-arylhydrazonopropanals
with Active Methylene Reagents: Formation of 2-Hydroxy-
and 2-Amino-6-substituted-5-arylazonicotinates and
Pyrido[3,2-c]cinnolines via 6π-Electrocyclization Reactions
Saleh M. Al-Mousawi 1,* and Morsy A. El-Apasery 1,2
1
Chemistry Department, Faculty of Science, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait
2
Dyeing, Printing and Textile Auxiliaries Department, Textile Research Division,
National Research Centre, Dokki, Giza 12622, Egypt
* Author to whom correspondence should be addressed; E-Mail: saleh.almousawi@yahoo.com.
Received: 18 May 2012; in revised form: 25 May 2012 / Accepted: 25 May 2012 /
Published: 30 May 2012
Abstract: 3-Oxo-3-phenyl-2-(p-tolylhydrazono)propanal (1a) undergoes condensation
with ethyl cyanoacetate in acetic acid in the presence of ammonium acetate to yield either
2-hydroxy-6-phenyl-5-p-tolylazonicotinic acid ethyl ester (6a) or 2-amino-6-phenyl-5-p-
tolyl-azonicotinic acid ethyl ester (8), depending on the reaction conditions. Similarly,
other 3-oxo-3-aryl-2-arylhydrazonopropanals 1a,b condense with active methylene nitriles
2c,d to yield arylazonicotinates 6b,c. In contrast, 2-[(4-nitrophenyl)-hydrazono]-3-oxo-3-
phenyl-propanal (1c) reacts with ethyl cyanoacetate to yield ethyl 6-(4-nitrophenyl)-2-oxo-
2,6-dihydropyrido[3,2–c]cinnoline-3-carboxylate (11), via a novel 6π-electrocyclization
pathway. Finally, 3-oxo-2-(phenylhydrazono)-3-p-tolylpropanal (1d) condenses with 2a–c
to yield pyridazinones 13a–c.
Keywords: arylhydrazonopropanals; arylazonicotinates; pyridazinones; cinnolines
1. Introduction
The chemistry of arylhydrazonopropanals 1 has attracted considerable attention [1,2]. These
substances have proven to be valuable precursors of 3-aroylpyrzoles [3], 3-aroylpyridazine-4,6-
dicaboxylic acids [4], 3-aroylcinnolines [5], as well as novel 3-aroyl-1,6-dihydropyridazines [6].

Molecules 2012, 17
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Although condensation reactions of arylhydrazonopropanals with active methylene nitriles were
originally reported to afford pyridazin-6-imines [3], more recent studies in our laboratories have
demonstrated that arylazonicotinates are also formed in some of these processes [7–9].
Because arylazonicotinates are a valuable class of arylazopyridine dyes whose chemistry has
attracted some interest as new disperse dyes [10,11], it seemed of value to undertake an investigation
aimed at exploring the potential utility of arylhydrazonopropanals as precursors for the preparation
of these targets. A recent investigation, described below, has led to the synthesis of two different types
of substances, including 2-hydroxyarylazonicotinic acid ethyl esters and 2-aminoarylazonicotinic
acid ethyl esters, along with ethyl 6-(4-nitrophenyl)-2-oxo-2,6-dihydropyrido[3,2–c]cinnoline-3-
carboxylate, which forms via a pathway involving a novel 6-electrocyclization reaction.
2. Results and Discussion
In the first phase of the current effort, we observed that reaction of the 3-oxo-3-phenyl-2-(p-
tolylhydrazono)propanal (1a) with ethyl cyanoacetate in acetic acid for 30 min in the presence of a
catalytic amount of ammonium acetate leads to formation of the ethyl 2-hydroxy-6-phenyl-5-p-
tolylazonicotinate (6a; Scheme 1) whose structure was established by X-ray crystallographic analysis
(Figure 1) [12].
In contrast, when the condensation reaction of 1a with ethyl cyanoacetate is conducted in the
presence of excess of ammonium acetate, ethyl 2-amino-6-phenyl-5-p-tolylazonicotinate (8) is produced.
The structure of 8 was also assigned by using X-ray crystallographic methods (Figure 2) [12].
It is believed that these processes involve initial reaction of 1a with ethyl cyanoacetate to yield the
hydrazono-enone 3 that then cyclizes to generate the pyran-imine 4. In the absence of ammonium ion,
4 undergoes a Dimroth type rearrangement to yield 6a. However, in the presence of a high
concentration of ammonium acetate, pyran-imine 4 participates in a ring opening to yield amidine 7
that then cyclizes followed by water elimination to yield 8.
In a similar manner, the 3-oxo-3-aryl-2-arylhydrazonopropanals 1a,b undergo condensation
reactions with other active methylene nitriles 2c,d (Scheme 1) to yield the corresponding
arylazonicotinates 6b,c (catalytic ammonium acetate).
In contrast to the reactivity profiles displayed by its analogs, the 2-[(4-nitrophenyl)-hydrazono]-3-
oxo-3-phenylpropanal (1c) reacts with ethyl cyanoacetate (90 min) to afford the novel ethyl 6-(4-
nitrophenyl)-2-oxo-2,6-dihydropyrido[3,2-c]cinnoline-3-carboxylate (11; Scheme 2). This substance is
believed to be formed via a 6π-electrocyclization reaction of the initially formed arylazonicotinate 9
(analogous to 5 in Scheme 1) that generates the tricyclic intermediate product 10, which then
aromatizes to produce the pyrido[3,2–c]cinnoline 11. The high electrocyclization reactivity of 9
appears to be a consequence of the presence of the electron-withdrawing nitro substituent that
apparently alters in a favorable way the frontier orbital interactions involved in the pericyclic process.
In the final phase of the current effort, we observed that reactions of the 3-oxo-2-
(phenylhydrazono)-3-p-tolylpropanal (1d) with active methylene nitriles 2a–c in the presence of
catalytic amounts of ammonium acetate in acetic acid for 30 min lead to the respective pyridazinones
13a–c, which are likely formed via the intermediacy of the readily hydrolyzed imine analogs 12
(Scheme 3). The structure of 13a was established by X-ray crystallography (Figure 3) [12].

Molecules 2012, 17
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The differences in the reactivity profiles of 1a–c vs. 1d may be a result of the decreased
nucleophilicity of the aroyl carbon in the later substance, enabling cyclization of the hydrazone moiety
to predominate.
Scheme 1. Synthesis of 2-hydroxy-6-substituted-5-arylazonicotinates derivatives 6a–c
and 2-amino-6-phenyl-5-p-tolylazo-nicotinate 8.
O
O
CN
X
CHO
NH
CN
R
R
N
X
N
2a, X= CO2Et
b, X= CONH2
c, X= CN
NH
Ar
Ar
1
d, X=CSNH2
Compound
R
Ar
C6H4CH3(p)
3
a
C6H5
1
b
C6H4NO2(p ) C6H5
NH
O
OH
H
R
X
X
X
O
N
N
R
R
N
N
N
N
N
N
Ar
Ar
Ar
6
5
4
Compound
R
Ar
X
6 a C6H5
C6H4CH3(p) CO2Et
C6H4NO2(p) C6H5 CN
b
c
C6H5
C6H4CH3(p) CSNH2
NH3
NH2
CO2Et
N
OH
NH2
NH
Ph
N
R
H O
2
-
N
N
X
N
Ar
7
CH3
8

Molecules 2012, 17
6550
Figure 1. Ball and stick drawing of 6a.
Figure 2. Ball and stick drawing of 8a.

Molecules 2012, 17
Scheme 2. Synthesis of ethyl 6-(4-nitrophenyl)-2-oxo-2,6-dihydropyrido[3,2-c]cinnoline-
6551
3-carboxylate (11).
O
O
H
O
N
N
OEt
CHO
NH
Ph
N
CNCH2CO2Et
N
2a
NO2
NO2
1c
9
O
O
O
N
O
N
OEt
H
N
N
OEt
N
H
-
2
N
NO2
NO2
10
11
Scheme 3. Synthesis of 6-(4-methylbenzoyl)-3-oxo-2-phenyl-2,3-dihydropyridazine
derivatives 13a–c.
O
CN
X
O
CHO
X
N
N
H3C
NH
Ph
2a, X= CO2Et
b, X= CONH2
c, X= CN
H3C
N
NH
Ph
1d
12
O
X
N
H3C
N
O
Ph
13a, X= CO2Et
b, X= CONH2
c, X= CN

Molecules 2012, 17
6552
Figure 3. ORTEP drawing of 13a.
Currently, we are utilizing the 2-hydroxy-and 2-aminoazonicotinates dyes as disperse dyes and
applying them to polyester fabrics by using high temperature dyeing method. We are also inspecting
the biological activity of these disperse dyes against Gram positive bacteria, Gram negative bacteria
and yeast.
3. Experimental
3.1. General
Melting points were recorded on a Gallenkamp apparatus. IR spectra were recorded using KBr
1
13
pellets on a Jasco FTIR-6300 FT-IR spectrophotometer. H- and C-NMR spectra were recorded on
Bruker DPX 400 MHz or AvanceII 600 MHz super-conducting NMR spectrometers (proton spectra
measured at 400, 600 MHz and carbon spectra at 100 and 150 MHz, respectively). Mass spectra were
measured on a high resolution GC/MS DFS-Thermo. Microanalyses were performed on Elementar-
Vario Micro cube Analyzer. X-Ray analyses were performed using a Rigaku Rapid II diffractometer.
3.2. General Procedure for the Preparation of Compounds 6a–c
Independent mixtures of 1a,b (0.01 mol), active methylenenitrile derivatives 2a or 2c or 2d
(0.01 mol), and ammonium acetate (0.5 g) in acetic acid (10 mL) were stirred at reflux for 30 min
(progress of the reactions was monitored by using TLC using 1:1 ethyl acetate-petroleum ether as
eluent). The mixtures were cooled and then poured into ice-water. The solids that formed were
collected by using filtration and crystallized from proper solvents to give 6a–c.
2-Hydroxy-6-phenyl-5-p-tolylazonicotinic acid ethyl ester (6a). This compound was obtained as dark
brown crystals (83%); mp 180–182 °C; IR (KBr): = 3401 (OH), 1692 (CO) cm−1; 1H-NMR (DMSO-d6):

Molecules 2012, 17
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δ = 1.35 (t, 3H, J = 7.2 CH3), 2.50 (s, 3H, CH3), 4.36 (q, 2H, J = 7.2 CH2), 7.32 (d, 2H, J = 8.0 Hz
arom-H), 7.48–7.50 (m, 3H, arom-H), 7.60 (d, 2H, J = 8.0 Hz arom-H), 7.78–7.79 (m, 2H, arom-H),
13
7.98 (s, 1H, OH, D2O exchangeable). 8.54 (s, 1H, arom-H); C-NMR (DMSO-d6): δ = 166.5, 161.0,
158.5, 154.5, 150.6, 142.9, 138.3, 136.5, 131.0, 130.8, 129.8, 127.4, 122.3, 105.2, 61.0, 20.9, 14.1;
MS, m/z (%), 359 ([M-2]+, 100), 331 (7), 241 (10), 213 (23), 196 (12), 168 (8), 148.1 (17), 115 (14),
91 (35). HRMS: m/z (EI) for C21H19N3O3; calcd. 361.1417; found: 361.1417.
2-Hydroxy-6-(4-nitrophenyl)-5-phenylazonicotinonitrile (6b). This compound was obtained as a dark
brown powder (91%); mp 276–278 °C; IR (KBr): = 3446 (OH), 2201 (CN) cm−1; 1H-NMR (DMSO-d6):
7.25–7.62 (m, 6H, arom-H, OH), δ = 7.27 (d, 1H, J = 8.8 Hz arom-H), 8.01–8.08 (m, 1H, arom-H),
8.20 (d, 1H, J = 8.8 Hz arom-H), 8.27–8.36 (m, 2H, arom-H), 13C-NMR (DMSO-d6): δ = 159.8, 152.2,
151.1, 147.6, 141.7, 139.6, 139.0, 131.1, 129.7, 129.2, 126.3, 123.4, 123.1, 114.0, MS, m/z (%),
343 ([M-2]+, 10), 313 (8), 284 (16), 207 (36), 193 (12), 150 (26), 93 (100), 77 (54). Anal. Calcd for
C18H11N5O3: C, 62.61; H, 3.21; N, 20.28. Found: C, 62.78; H, 3.28; N, 20.20
2-Hydroxy-6-phenyl-5-p-tolylazothionicotinamide (6c). This compound was obtained as a dark brown
powder (77%); mp 276–278 °C; IR (KBr): = 3441 (OH), 3385, 3291 (NH2), 1660 (CO) cm−1;
1H- NMR (DMSO-d6): δ = 2.26 (s, 3H, CH3), 7.02–8.01 (m, 9H, arom-H), 8.57 (s, 1H, OH), 8.76 (s,
13
1H, arom-H), 12.38 (s, 2H, NH2, D2O exchangeable). C-NMR (DMSO-d6): δ = 190.3, 162.2, 158.0,
152.7, 141.7, 138.8, 137.3, 135.8, 131.7, 130.6, 129.4, 129.0, 124.5, 94.0, 20.8; MS, m/z (%), 348
([M]+, 6), 333 (7), 315 (42), 257 (4), 183 (6), 119 (100), 91 (50), 77 (20). Anal. Calcd for C19H16N4OS:
C, 65.50; H, 4.63; N, 16.08; S, 9.20. Found: C, 65.60; H, 4.30; N, 16.43; S, 8.73.
3.3. 2-Amino-6-phenyl-5-p-tolylazonicotinic Acid Ethyl Ester (8)
Independent mixtures of 1a (0.01 mol), ethyl cyanoacetate 2a (0.01 mol), and ammonium acetate
(3 g) in acetic acid (10 mL) were stirred at reflux for 30 min (progress of the reactions was monitored
by using TLC using 1:1 ethyl acetate-petroleum ether as eluent). The mixtures were cooled and then
poured into ice-water. The solids that formed were collected by using filtration and crystallized from
proper solvents to give 8 as wine red crystals (83%) (mp 210–212 °C); IR (KBr): = 3402, 3275 (NH2)
1693 (CO) cm−1; 1H-NMR (DMSO-d6): δ = 1.37 (t, 3H, J = 7.2 CH3), 2.50 (s, 3H, CH3), 4.39 (q, 2H,
J = 7.2 CH2), 7.31 (d, 2H, J = 8.4 Hz arom-H), 7.47–7.48 (m, 3H, arom-H), 7.98 (s, 2H, NH2, D2O
exchangeable). 7.59 (d, 2H, J = 8.4 Hz arom-H), 7.80–7.82 (m, 2H, arom-H), 8.54 (s, 1H, arom-H);
13C-NMR (DMSO-d6): δ = 166.2, 161.3, 159.5, 150.4, 140.6, 137.2, 136.5, 130.8, 129.8, 129.2, 127.4,
127.2, 122.3, 104.9, 61.0, 20.9, 14.1; MS, m/z (%), 359 ([M-1]+, 100), 315 (9), 290 (12), 241 (6), 213
(20), 196 (9), 168 (5), 140 (9), 105 (26), 91 (36), 77 (16). Anal. Calcd for C21H20N4O2: C, 69.98; H,
5.59; N, 15.55. Found: C, 69.99; H, 5.50; N, 15.25.
3.4. Synthesis of Ethyl 6-(4-nitrophenyl)-2-oxo-2,6-dihydropyrido[3,2-c]cinnoline-3-carboxylate (11)
A mixture of 1c (0.01 mol), ethyl cyanoacetate (0.01 mol), and ammonium acetate (0.5 g) in acetic
acid (10 mL) was stirred at reflux for 90 min (progress of the reaction was monitored by using TLC
using 1:1 ethyl acetate: petroleum ether). The mixture was cooled and then poured into ice-water. The

Molecules 2012, 17
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solid that formed was collected by using filtration and crystallized from dioxane to give 11. This
compound was obtained as a dark brown powder (62%); mp 148–150 °C; IR (KBr): = 1694 (CO) cm−1;
1H-NMR (DMSO-d6): δ = 1.35 (t, 3H, J = 7.2 CH3), 4.37 (q, 2H, J = 7.8 CH2), 7.51–7.55 (m, 3H,
13
arom-H), 7.78–8.04 (m, 3H, arom-H), 8.28-8.38 (m, 2H, arom-H), 8.62 (s, 1H, arom-H); C-NMR
(DMSO-d6): δ = 189.4, 166.0, 163.8, 160.2, 155.7, 147.6, 142.2, 136.9, 131.0, 130.2, 129.8, 128.2,
127.4, 125.1, 123.2, 105.3, 61.2, 14.1; MS, m/z (%), 390 ([M]+, 100), 361 (9), 321 (7), 257 (5), 241
(8), 213 (24), 196 (14), 168 (11), 140 (22), 105 (31), 77 (16). Anal. Calcd for C20H14N4O5: C, 61.54;
H, 3.62; N, 14.35. Found: 61.61; H, 3.57; N, 14.58.
3.5. General Procedure for the Preparation of Compounds 13a–c
Independent mixtures of 1d (0.01 mol), active methylenenitrile derivatives 2a–c (0.01 mol), and
ammonium acetate (0.5 g) in acetic acid (10 mL) were stirred at reflux for 30 min (progress of the
reactions was monitored by using TLC using 1:1 ethyl acetate-petroleum ether as eluent). The mixtures
were cooled and then poured into ice-water. The solids that formed were collected by using filtration
and crystallized from proper solvents to give 13a–c.
6-(4-Methylbenzoyl)-3-oxo-2-phenyl-2,3-dihydropyridazine-4-carboxylic acid ethyl ester (13a). This
compound was obtained as buff crystals (55%); mp 108–110 °C; IR (KBr): = 1746 (CO) cm−1;
1H-NMR (DMSO-d6): δ = 1.32 (t, 3H, J = 7.2 CH3), 2.37 (s, 3H, CH3), 4.34 (q, 2H, J = 7.2 CH2), 7.33
(d, 2H, J = 8.0 Hz arom-H), 7.45–7.49 (m, 1H, arom-H), 7.51–7.55 (m, 2H, arom-H), 7.59–7.63
(m, 2H, arom-H), 7.93 (d, 2H, J = 8.4 Hz arom-H), 8.31 (s, 1H, arom-H); 13C-NMR (DMSO-d6):
δ = 188.3, 162.6, 155.9, 144.4, 141.6, 141.1, 132.3, 132.1, 131.0, 130.7, 129.2, 128.8, 126.0, 115.2,
61.8, 21.2, 13.9; MS, m/z (%), 362 ([M]+, 48), 315 (18), 290 (16), 261 (6), 182 (12), 119 (100),
91 (46), 77 (26). HRMS: m/z (EI) for C21H18N2O4; calcd. 362.1261; found: 362.1261.
6-(4-Methylbenzoyl)-3-oxo-2-phenyl-2,3-dihydropyridazine-4-carboxylic acid amide (13b). This
compound was obtained as a brown powder (52%); mp 243–245 °C; IR (KBr): = 3343, 3156 (NH2),
1
1698 (CO) cm−1; H-NMR (DMSO-d6): δ = 1.37 (s, 3H, CH3), 7.33 (d, 2H, J = 8.0 Hz arom-H),
7.47–7.56 (m, 3H, arom-H), 7.63 (d, 2H, J = 7.8 Hz arom-H), 7.93 (d, 2H, J = 8.0 Hz arom-H), 8.27
(s, 2H, NH2, D2O exchangeable). 8.56 (s, 1H, arom-H); 13C-NMR (DMSO-d6): δ = 188.4, 162.1,
159.5, 144.1, 142.6, 141.1, 132.5, 132.3, 130.9, 130.7, 129.0, 128.9, 128.8, 126.1, 21.2; MS, m/z (%),
333 ([M]+, 100), 318 (15), 261 (5), 214 (5), 182 (9), 119 (100), 91 (36), 77 (20). Anal. Calcd for
C19H15N3O3: C, 68.46; H, 4.54; N, 12.61. Found: 68.93; H, 4.56; N, 13.02.
6-(4-Methylbenzoyl)-3-oxo-2-phenyl-2,3-dihydropyridazine-4-carbonitrile (13c). This compound was
obtained as brown powder crystals (64%); mp 186–188 °C; IR (KBr): 2209 (CN), 1656 (CO) cm−1;
1H-NMR (DMSO-d6): δ = 2.32 (s, 3H, CH3), 7.25 (d, 2H, J = 8.0 Hz arom-H), 7.46–7.58 (m, 5H,
13
arom-H), 7.85 (d, 2H, J = 8.0 Hz arom-H), 8.60 (s, 1H, arom-H); C-NMR (DMSO-d6): δ = 187.6,
162.0, 156.1, 144.4, 141.6, 140.5, 138.6, 132.0, 130.7, 130.2, 126.1, 125.6, 115.2, 113.7, 21.0, MS, m/z
(%), 315 ([M]+, 60), 257 (6), 211 (8), 183 (14), 119 (100), 91 (42), 77 (20). HRMS: m/z (EI) for
C19H13N3O2; calcd. 315.1001; found: 315.1001.

Molecules 2012, 17
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4. Conclusions
In conclusion, in the investigation described above, we have observed that 3-oxo-2-
arylhydrazonopropanals that do not possess strongly electron-withdrawing aryl substituents react with
active methylene nitriles to afford 2-arylhydroxyazonicotinates and 2-arylaminoazonicotinates, in a
manner that depends on the concentrations of ammonium acetate. In the case of the p-nitro-substituted
members of this family, a facile 6π-electrocyclization reaction takes place on the hydrazono-pyridone
intermediate to yield the corresponding ethyl 6-(4-nitrophenyl)-2-oxo-2,6-dihydropyrido[3,2-
c]cinnoline-3-carboxylate, a likely result of a substituent effect on frontier orbital interactions that
favor the pericyclic process.
Acknowledgments
The authors are grateful to M. H. Elnagdi for his help and valuable advice. Support of this work
provided by Kuwait University through a research grant (SC 05/09) and the facilities of Analab/SAF,
supported by research grants (GS03/08), (GS01/01), (GS01/03) and (GS01/05) are highly appreciated.
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Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk.
Sample Availability: Samples of compounds 6a–c, 8, 11 and 13a–c are available from the authors.
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