Cyclocondensation of 3,3-diamino-1-phenylpropenone with pyridine and quinoline N-oxides containing an electrophilic group in position 3

Article abstract of DOI:10.1007/s10593-008-0062-0

The cyclocondensation of the N-oxide of the methyl ester of nicotinic acid with 3,3-diamino-1-phenylpropenone and the ethyl ester of 3,3-diaminoacrylic acid in the presence of benzenesulfonyl chloride gives the corresponding 2,7-naphthyridines. The cycloc

Full text of DOI:10.1007/s10593-008-0062-0

Chemistry of Heterocyclic Compounds, Vol. 44, No. 4, 2008
CYCLOCONDENSATION OF 3,3-DIAMINO-
1-PHENYLPROPENONE WITH PYRIDINE
AND QUINOLINE N-OXIDES CONTAINING
AN ELECTROPHILIC GROUP IN POSITION 3*
D. V. Dar'in, S. I. Selivanov, P. S. Lobanov, and A. A. Potekhin*2
The cyclocondensation of the N-oxide of the methyl ester of nicotinic acid with
3,3-diamino-1-phenylpropenone and the ethyl ester of 3,3-diaminoacrylic acid in the presence of
benzenesulfonyl chloride gives the corresponding 2,7-naphthyridines. The cyclocondensation of
3,3-diamino-1-phenylpropene with the N-oxides of dimethyl 3,5-pyridinedicarboxylate and quinolines
containing an electrophilic group at in position 3 yields products of the nucleophilic attack of the
carbon nucleophilic site of the enediamine at the 2-pyridine ring position, while the amine group binds
to the exocyclic electrophilic group.
Keywords: benzo[b]-1,6-naphthyridines, enediamines, 2,7-naphthyridines, pyridine N-oxides, quinoline
N-oxides, cyclocondensation.
The N-oxide group permits the facile introduction of substituents into pyridine and quinoline rings [2].
The presence of other reactive substituents in the N-oxide molecule opens a pathway to the construction of
condensed heterocycles [3, 4].
In a continuation of an investigation of the reactivity of α-acylacetamidines [5], we have studied the
synthetic potential and regioselectivity of the reactions of benzoylacetamidine, which exists in solution as
3,3-diamino-1-phenylpropene (1a) with pyridine and quinoline N-oxides containing an electrophilic group in the
β-position to the nitrogen atom. In reactions with aromatic aldehydes and esters containing an active halogen
atom in the ortho position studied in our previous work [5-7], benzoylacetamidine acts as a C,N-dinucleophile.
The reactions with aromatic dielectrophiles are chemoselective: the carbon nucleophilic site replaces the halogen
atom in the ring, while the amino group reacts with the exocyclic electrophilic group. The formation of
regioisomers is also possible in reactions with azine N-oxides having two active positions in the pyridine ring
depending on which ring position undergoes nucleophilic attack.
The reactions were carried out under conditions similar to those described by Iwao and Kuraishi [8].
DMF was used as the solvent and benzenesulfonyl chloride was used as the acylating agent. A two-fold excess
_______
* Previous communication, see [1].
_______
*2 Deceased.
__________________________________________________________________________________________
St. Petersburg State University, 198504 St. Petersburg, Russia; e-mail: pslob@mail.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 578-584, April, 2008. Original article submitted
October 16, 2007.
0009-3122/08/4404-0451©2008 Springer Science+Business Media, Inc.
451

of amidine was taken. Attempts to carry out the reaction with an equimolar amount of the amidine using other
bases such as potassium carbonate, 1,4-diazabicyclo[5.4.0]undec-7-ene, triethylamine, and triethylamine acetate
led to considerable tar formation and a low product yield.
The reaction of N-oxide 2 with 1a yielded only 2,7-naphthyridine 3a. The reaction of N-oxide 2 with
enediamine 1b gave a 10:1 mixture of two products in 45% yield. The structures of the major products,
1
2,7-naphthyridines 3a and 3b, were established using H and 13C NMR spectroscopy as well as NOESY
correlation spectra, in which cross peaks are observed between the signals of the protons of the substituent at the
exocyclic carbonyl group (R) and H-5 of the naphthyridine system. The structure of the minor product of the
1
reaction with enediamine 1b could not be unequivocally established but the H NMR spectrum suggested the
isomeric 1,6-naphthyridine 4b.
The only product of the reaction of N-oxide 5 with enediamine 1a was 1,6-napthyridine 6, which was
1
isolated in 28% yield. The structure of this product was established by H and 13C NMR spectroscopy. The
major indication for nucleophilic attack at C-2 was found in the values of the direct coupling constants
1
1JC-H = 182 Hz for C-2 and JC-H = 167 Hz for C-4, which depend strongly on the arrangement of the nitrogen
atom and C-H fragment and are 178 and 162 Hz for C-2 and C-4, respectively, in quinoline [9].
COR
COR
MeO2C
H2N
H2N
N
RCO
H2N
PhSO2Cl
+
N
+
NH2
HN
HN
N
O
O
O
1a,b
3a,b
4b
2
a R = Ph
b R = OEt
49%
41%
0%
(4%)*
O
MeO2C
CO2Me
CO2Me
HN
H2N
PhSO2Cl
1a
+
N
N
COPh
O
6 28%
5
This finding indicates that the protons remaining in the pyridine ring are in the α- and γ-positions
relative to the nitrogen atom. The chemical shift of the carbon atom of the ring carbonyl group (161.6 ppm)
indicates that this group is bound to the nitrogen atom. In the case of the isomeric product, the signal for the
carbonyl carbon atom would have been shifted toward higher field by ~10 ppm.
Thus, the literature data indicate that the chemical shifts of the carbonyl group carbon atom in 2- and
4-pyridones are 162.3 and 175.7 ppm, respectively [10].
The reaction of N-oxide 7 with enediamine 1a gives an 8:1 mixture of benzonaphthyridines 8 and 9. The
major product 8 was isolated in 41% yield. The minor product could not be isolated as a pure compound and its
structure was suggested from the 1H NMR spectrum of the reaction mixture.
_______
1
* Here and subsequently, the yields of the products observed in the reation mixture by H NMR spectroscopy
and not isolated as individual substances are indicated in the brackets.
452

NH2
NH
PhOC
O
CO2Me
MeO
MeO
MeO
MeO
MeO
MeO
O
NH
NH2
1a
+
PhSO2Cl
N
O
N
N
COPh
9 (5%)
7
8 (41%)
It is known [1] that the presence of electron-donor substituents in the ring of the N-oxide, especially,
alkoxy groups in pyridines, markedly enhances the yields of the substitution products in comparison with the
analogous substrates lacking electron-donor substituents. This effect may be related to the increased
nucleophilicity of the N-oxide oxygen atom and increased rate of the acylation step. In order to check this
tendency, we carried out the reaction of enediamine 1a with N-oxide 10, which has a methoxy group directly
attached to the pyridine ring. This reaction gave benzonaphthyridine 11 in a yield indeed somewhat higher.
OMe
OMe O
CO2Me
NH
PhSO2Cl
+
1a
Cl
N
NH2
Cl
N
COPh
O
10
65%
11
Considerable interest is found in the N-oxides of 3-azinecarbaldehydes. At present, we have obtained
only one such compound, N-oxide 12. The reaction of N-oxide 12, which has the synthetic equivalent of the
formyl group at C-3, with enediamine 1a gives a mixture of two products, one of which is
1
benzonaphthyridine 14. H NMR spectroscopy was used to ascribe the structure of the intermediate product of
substitution in the quinoline system with an unaffected dioxolane group (13) to the second compound, which
could not be isolated in pure form. In order to check the conversion of intermediate 13 into cyclization
product 14, the reaction mixture was treated with picric acid in ethanol. Product 14 was isolated
chromatographically after completion of the cyclization reaction and treatment with potassium carbonate.
Thus, in all cases, the cyclocondensation proceeds with the same selectivity as the reaction with
ortho-halocarbonyl dielectrophiles. Specifically, the carbon nucleophilic site participates in the nucleophilic
attack of the aromatic ring, while the enediamine nitrogen atom forms a bond with the exocyclic electrophilic
group. In regard to the direction of the reaction relative to the activated positions of the pyridine ring, we should
note that the cyclocondensation proceeds selectively with the participation of C-4 only in the case of methyl
nicotinate N-oxide 2. On the other hand, attack of the carbon nucleophilic site of the enediamine at C-2 is
preferred for dimethyl pyridinedicarboxylate N-oxide 5, methyl 6,7-dimethoxy-3-quinolinecarboxylate
N-oxide (7), and 7-methoxy-3-(1,3-dioxolan-3-yl)quinoline N-oxide (12).
O
O
O
+
O
1a
N
H
COPh
PhSO2Cl
MeO
N
MeO
N
NH2
MeO
N
COPh
O
H2N
NH2
12
13
14 42%
453

EXPERIMENTAL
The 1H and 13C NMR spectra were obtained on a Bruker DPX 300 spectrometer at 300 and 75 MHz with
1
DMSO-d6 as the solvent. The residual signals of the solvent δ 2.50 (for the H nuclei) and δ 39.7 ppm (for the
13C nuclei) were used as the internal standards. The coupling constants in the 1H NMR spectra were measured to
a first order approximation. The elemental analysis was carried out on a Hewlett-Packard HP-185B
CHN analyzer. The purity of the products and the reaction course were monitored by thin-layer chromatography
on Silufol UV-254 plates.
3-Amino-4-benzoyl-2,7-naphthyridin-1(2H)-one (3a). A solution of benzenesulfonyl chloride
(0.36 g, 2 mmol) in DMF (2 ml) was added dropwise over 20 min with stirring and ice cooling to a mixture of
methyl nicotinate N-oxide (2) (0.3 g, 2 mmol), enediamine 1a [12] (0.65 g, 4 mmol), and DMF (2 ml). The
mixture was then left for 24 h at -10°C. The precipitate of benzoylacetamidine hydrochloride was filtered off.
The filtrate was poured into water (30 ml) and potassium carbonate (0.2 g) was added. The crystalline
precipitate was filtered off and recrystallized from acetonitrile to give compound 3a (0.26 g, 49%);
1
mp 321-324°C (dec.). H NMR spectrum, δ, ppm (J, Hz): 6.44 (1H, d, J = 5.6, H-5); 7.39-7.58 (5H, m, C6H5);
7.88 (2H, s, NH2); 8.07 (1H, d, J = 5.6, H-6); 9.01 (1H, s, H-8); 11.38 (1H, s, NH). Found, %: C 67.59; H 4.23;
N 15.78. C15H11N3O2. Calculated, %: C 67.92; H 4.18; N 15.84.
Ethyl Ester of 3-Amino-1-oxo-1,2-dihydro-2,7-naphthyridine-4-carboxylic Acid (3b). A solution of
benzenesulfonyl chloride (0.44 g, 2.5 mmol) in DMF (2 ml) was added dropwise over 20 min with stirring and
ice cooling to a solution of enediamine 1b [6] (0.65 g, 5 mmol) and compound 2 ( 0.38 g, 2.5 mmol) in DMF
(3 ml). The mixture was maintained for 25 h at room temperature and then poured into water (25 ml). Potassium
hydroxide (0.16 g, 2.8 mmol) was added. The crystalline precipitate was filtered off and dried to give
2,7-naphthyridine 3b with a 9% impurity of the ethyl ester of 7-amino-5-oxo-5,6-dihydro-1,6-naphthyridine-
8-carboxylic acid (4b). The yield of 3b was 0.26 g (45%); mp 271-274°C (dec.). An analytical sample of 3b was
1
obtained by recrystallization from 1:1 ethanol–acetonitrile. H NMR spectrum, δ, ppm (J, Hz): 1.38 (3H, t,
J = 8.2, CH3); 4.33 (2H, q, J = 7.3, CH2); 7.72 (2H, s, NH2); 8.25 (1H, d, J = 5.9, H-5); 8.49 (1H, d, J = 5.9,
H-6); 9.06 (1H, s, H-8); 11.28 (1H, s, NH). Found, %: C 56.46; H 4.72; N 18.05. C11H11N3O3. Calculated, %:
1
C 56.65; N 4.75; N 18.02. The signals for 1,6-naphthyridine 4b were observed in the H NMR spectrum of the
mixture, δ, ppm (J, Hz): 1.31 (3H, t, J = 8.2, CH3); 7.12 (1H, dd, J = 4.5 and J = 7.8, H-3); 7.25 (2H, s, NH2);
8.71 (1H, d, J = 4.5, H-2).
Methyl Ester of 7-Amino-8-benzoyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic Acid (6). A
solution of benzenesulfonyl chloride (0.3 g, 1.7 mmol) in DMF (2 ml) was added dropwise over 30 min with
stirring and ice cooling to a mixture of dimethyl 3,5-pyridinedicarboxylate N-oxide (5) [13] (0.315 g,
1.5 mmol), enediamine 1a (0.5 g, 3.1 mmol), and DMF (2 ml). The mixture was stirred for 23 h at room
temperature and then poured into a solution of NaOH (0.08 g) in water (25 ml). The oil formed crystallized
after 24 h. The crystals were filtered off, heated at reflux in 10 ml methanol, cooled, filtered off, and dried to
give compound 6 (0.135 g, 28%); mp 250-260°C (dec.). An analytical sample was obtained by recrystallization
1
from 1:1 methanol–acetonitrile. H NMR spectrum, δ, ppm (J, Hz): 3.84 (3H, s, OCH3); 7.32 (2H, t, J = 8.2,
m-C6H5); 7.41-7.52 (3H, m, o-C6H5, p-C6H5); 7.67 (2H, s, NH2); 8.62 (2H, s, H-2, H-4); 11.48 (1H, s, NH).
13C NMR spectrum, δ, ppm: 52.5 (OCH3); 95.2 (C-8); 114.8 (C-4a); 118.9 (C-3); 128.1 (m-C6H5); 129.7
(o-C6H5); 131.2 (p-C6H5); 136.2 (C-4); 142.6 (ipso-C6H5); 152.9 (C-2); 155.2 (C-7); 157.4 (C-8a); 161.6 (C-5);
165.0 (CO2CH3); 194.5 (COC6H5). Found, %: C 63.24; H 4.13; N 12.94. C17H13N3O4. Calculated %: C 63.16;
H 4.05; N 13.00.
3-Amino-4-benzoyl-7,8-dimethoxybenzo[b]-1,6-naphthyridin-1(2H)-one (8).
A
solution of
benzenesulfonyl chloride (0.23 g, 1.3 mmol) in DMF (2 ml) was added dropwise over 20 min with stirring and
ice cooling to a mixture of methyl 6,7-dimethoxy-3-quinolinecarboxylate N-oxide (7) (0.32 g, 1.2 mmol),
454

enediamine 1a (0.39 g, 2.4 mmol), and DMF (2 ml). The mixture was left for 20 h at room temperature and then
poured into a solution of NaOH (0.06 g) in water (30 ml). The crystalline precipitate was filtered off, heated at
reflux in 1:1 methanol–acetonitrile (10 ml), cooled and filtered off to give benzonaphthyridine 8 (80 mg).
Crystals precipitated overnight from the aqueous filtrate, which were filtered off, heated at reflux in acetonitrile
(10 ml), cooled, and filtered off to give an additional benzonaphthyridine 8 (0.105 g). The total yield of 8 was
1
0.185 g (41%); mp 285-290°C (dec.). H NMR spectrum, δ, ppm (J, Hz): 3.68 (3H, s, 7-OCH3); 3.83 (3H, s,
8-OCH3); 6.22 (1H, s, H-6); 7.25-7.41 (6H, m, C6H5, H-9); 7.85 (2H, s, NH2); 8.69 (1H, s, H-10); 11.12 (1H, s,
NH). 13C NMR spectrum, δ, ppm (J, Hz): 55.8 (7-OCH3); 56.0 (8-OCH3); 93.9 (C-4); 106.0 (C-9); 106.6 (C-6);
1
113.7 (C-10a); 119.9 (C-9a); 127.6 (m-C6H5); 127.9 (o-C6H5); 129.4 (p-C6H5); 134.4 (C-10, JC-H = 164.4);
144.2 (ipso-C6H5); 147.2 (C-5a); 148.8 (C-8); 151.4 (C-4a); 154.6 (C-3); 154.8 (C-7); 162.2 (C-1); 194.9
(CO2C6H5). Found, %: C 67.15; H 4.57; N 11.13. C21H17N3O4. Calculated %: C 67.13; H 4.56; N 11.19. A
crystalline precipitate settled from the aqueous mother liquor after several days, which was filtered off, heated to
reflux in acetonitrile (5 ml), cooled, and filtered off to give a 2:1 mixture of benzonaphthyridine 8 (0.07 g, 16%)
and
2-amino-1-benzoyl-8,9-dimethoxybenzo[c]-2,7-naphthyridin-4(3H)-one
(9).
The
signals
for
1
benzonaphthyridine 9 were found in the H NMR spectrum, δ, ppm: 3.54 (3H, s, 9-OCH3); 3.84 (3H, s,
8-OCH3); 6.79 (1H, s, H-7 or H-10); 9.12 (1H, s, H-5); 11.43 (1H, s, NH).
3-Amino-4-benzoyl-7-chloro-10-methoxybenzo[b]-1,6-naphthyridin-1(2H)-one (11). A solution of
benzenesulfonyl chloride (0.23 g, 1.3 mmol) in DMF (2 ml) was added dropwise with stirring and ice cooling
over 30 min to a mixture of enediamine 1a (0.4 g, 2.5 mmol), methyl 7-chloro-4-methoxy-3-quinoline-
carboxylate N-oxide (10) (0.32 g, 1.2 mmol), and DMF (3 ml). The mixture was stirred for 48 h at room
temperature and mixed with water (30 ml). Sodium hydroxide (0.06 g, 1.5 mmol) was added. The crystals
formed were filtered off, heated to reflux in 2:1 methanol–acetonitrile (20 ml), cooled, filtered off, and dried to
give compound 11 (0.295 g, 65%); mp 238-245°C. 1H NMR spectrum, δ, ppm (J, Hz): 4.12 (3H, s, OCH3); 6.81
(1H, s, H-6); 7.25-7.46 (6H, m, C6H5, H-8); 7.80 (2H, s, NH2); 8.08 (1H, d, J = 8.4, H-9); 11.09 (1H, s, NH).
13C NMR spectrum, δ, ppm: 63.9 (OCH3); 94.1 (C-4); 107.5 (C-10a); 119.1 (C-9a); 124.9, 125.77, 125.80, (C-6,
C-8, C-9); 127.7 (m-C6H5); 127.8 (o-C6H5); 129.7 (p-C6H5); 137.3 (C-7); 144.1 (ipso-C6H5);150.6 (C-5a); 154.8
(C-3); 156.8 (C-4a); 159.9 (C-1); 166.9 (C-10); 195.2 (CO2C6H5). Found, %: C 61.52; H 3.60; N 10.78.
C20H14N3O3. Calculated, %: C 63.25; H 3.72; N 11.06.
3-Amino-4-benzoyl-7-methoxybenzo[b]-1,6-naphthyridine (14). A solution of benzenesulfonyl
chloride (0.23 g, 1.3 mmol) in DMF (1.5 ml) was added dropwise with stirring and ice cooling over 1 h to a
mixture of 7-methoxy-3-(1,3-dioxolan-2-yl)quinoline N-oxide (12) (0.296 g, 1.2 mmol), enediamine 1a (0.39 g,
2.4 mmol), and DMF (2 ml). The mixture was stirred at room temperature for 24 h. The solvent was distilled off
in vacuum at 55-60°C over 2.5 h. The residue was added to water (30 ml) and thoroughly triturated. Then,
potassium carbonate (0.4 g, 3 mmol) was added and the mixture was left for 72 h at 6°C. The crystalline
precipitate was filtered off and dissolved in ethanol (20 ml). Then, picric acid (0.8 g, 3.5 mmol) was added and
the mixture was stirred at room temperature for 20 h. The solvent was evaporated off. The residue was added to
aqueous potassium carbonate (30 ml, 5%) and thoroughly extracted with methylene chloride. The organic layer
was dried over sodium sulfate. The solvent was evaporated off. The residue was subjected to column
chromatography using chloroform as the eluent to give compound 14 (0.164 g, 42%); mp 213-216°C. An
1
analytical sample was obtained by recrystallization from acetonitrile. H NMR spectrum, δ, ppm (J, Hz): 3.79
(3H, s, OCH3); 6.67 (1H, d, J = 2.3, H-6); 7.04 (2H, s, NH2); 7.07 (1H, dd, J = 2.3 and J = 9.4, H-8); 7.40 (2H, t,
J = 8.4, m-C6H5); 7.54 (1H, t, J = 8.4, p-C6H5); 7.64 (2H, d, J = 8.4, o-C6H5); 7.93 (1H, d, J = 9.4, H-9); 8.91
1
(1H, s, JC-H = 163.2, H-10); 9.28 (1H, s, 1JC-H = 180.7, H-1). Found %: C 73.06; H 4.63; N 12.96. C19H15N3O2.
Calculated %: C 72.94; H 4.59; N 12.76.
455

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