A simple and efficient synthesis of novel naphthyridine-1-H-pyrazole-4- carboxylic acid esters/carbaldehydes using Vilsmeier-Haack reagent

Article abstract of DOI:10.1515/hc-2012-0097

The reaction of hydrazide 4 with β-keto esters 5 gave hydrazones 6. Cyclization of 6 with Vilsmeier-Haack reagent (DMF-POCl₃ ) for 20 min at room temperature gave 1-(4-oxo-1,4-dihydro-[ 1 ,8]naphthyridine-3-carbonyl)- 1 H -pyrazole-4-carboxylic acid ethyl esters 7. The treatment of 4 with substituted acetophenones 8 yielded the corresponding hydrazones 9 of substituted aceto phenones. The treatment of 9 with Vilsmeier-Haack reagent (DMF-POCl₃) for 30 min at room temperature gave product 10, the reaction of which with (diacetoxyiodo)benzene in ethanol at room temperature for 12 h in the presence of molecular iodine furnished 7.

Full text of DOI:10.1515/hc-2012-0097

ꢁꢁꢁꢂ
DOI 10.1515/hc-2012-0097ꢀ ꢀHeterocycl. Commun. 2013; aop
Muggu V.S.R.K. Chaitanya* and Pramod K. Dubey
A simple and efficient synthesis of novel
naphthyridine-1-H-pyrazole-4-carboxylic acid
esters/carbaldehydes using Vilsmeier-Haack
reagent
Abstract: The reaction of hydrazide 4 with β-keto esters 5
gave hydrazones 6. Cyclization of 6 with Vilsmeier-Haack
Results and discussion
reagent (DMF-POCl3) for 20 min at room temperature
The starting hydrazide 4 was prepared as described pre-
gave 1-(4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
viously [16] as summarized in Scheme 1. Condensation of
1H-pyrazole-4-carboxylic acid ethyl esters 7. The treatment
2-aminopyridine 1 with ethoxymethylenemalonic ester in
of 4 with substituted acetophenones 8 yielded the corre-
ethanol under reflux conditions for 4 h yielded the inter-
sponding hydrazones 9 of substituted acetophenones. The
mediate product 2 [17], the thermal cyclization of which in
treatment of 9 with Vilsmeier-Haack reagent (DMF-POCl3)
polyphosphoric acid for 30 min resulted in the formation
for 30 min at room temperature gave product 10, the reac-
of 1,8-naphthyridine derivative 3 [17]. Treatment of 3 with
tion of which with (diacetoxyiodo)benzene in ethanol at
hydrazine hydrate in ethanol for 3 h yielded 4.
room temperature for 12 h in the presence of molecular
Treatment of 4a with methyl acetoacetate (5a) in
iodine furnished 7.
methanol under reflux conditions for 1 h yielded product
6a. Cyclization of 6a using Vilsmeier-Haack reagent (DMF-
Keywords: (diacetoxyiodo)benzene; hydrazide; β-keto
POCl3) at room temperature for 20 min yielded 3-methyl-
esters; naphthyridine; substituted acetophenone; Vils-
1-(4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
meier-Haack reagent.
1H-pyrazole-4-carboxylic acid methyl ester (7a). The
1H NMR spectrum of 7a shows the disappearance of the
*Corresponding author: Muggu V.S.R.K. Chaitanya, Department of
Chemistry, Jawaharlal Nehru Technological University, Hyderabad
College of Engineering, Kukatpally, 500 085 Hyderabad (A.P.), India,
e-mail: chaitu.mvsrk@yahoo.com
Pramod K. Dubey: Department of Chemistry, Jawaharlal Nehru
Technological University, Hyderabad College of Engineering,
Kukatpally, 500 085 Hyderabad (A.P.), India
methylene proton signal and N-N-H proton signal that are
observed in the spectrum of the substrate 6a. The proton
signal for the newly formed pyrazole ring appears at δ
8.27. This structure is also fully consistent with mass spec-
tral and elemental analysis data.
This series of transformations was successfully
extended on the preparations of the corresponding
analogs 6b–h and 7b–h. All these products were fully
characterized as discussed above for 6a and 7a.
Substrates 4a,b were also allowed to react with sub-
stituted acetophenones 8a–e to give the corresponding
Introduction
Pyrazoles possess a wide range of useful biological activi- hydrazides 9a–j (Scheme 2). The treatment of 9a–j with
ties such as antibacterial [1–5], anti-inflammatory [6–9], Vilsmeier-Haack reagent at room temperature for 30 min
and antiviral [10, 11] properties. They are also useful lumi- caused cyclization to yield the corresponding products
nescent and fluorescent [12] substances and an impor- 10a–j. Further, 10a was treated with (diacetoxyiodo)
tant class of chemicals in the development of cine films. benzene in ethanol in the presence of molecular iodine at
Pyrimidinopyrazoles are being studied as drug candidates room temperature for 12 h. This reaction furnished product
against cancer [13]. In continuation of earlier work on the which was found to be identical with 7e obtained is dis-
synthesis of naphthyridinonoes [14, 15], it was considered cussed above. This interesting transformation involves
worthwhile to prepare naphthyridine derivatives con- oxidation of the aldehyde function of 10a followed by
taining a pyrazolyl group as compounds with potentially esterification of the resultant intermediate carboxylic acid
useful biological properties.
or its derivative.
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2ꢀ
ꢀM.V.S.R.K. Chaitanya and P.K. Dubey: Naphthyridine-1-H-pyrazole-4-carboxylic acid esters/carbaldehydes
EtOOC
EtO
COOEt
H
OEt
O
O
O
R1
R1
R1
O
PPA
OEt
OEt
Δ
Δ
, 0.5 h
EtOH, , 4 h
N
NH2
N
N
H
N
N
H
1a b
-
3a b
-
2a-b
R2
O
O
R3O
5a-d
O
O
O
O
R1
N
R2
COOR3
R1
NH2
NH2-NH2
N
H
N
H
Δ
Δ
EtOH, , 3 h
MeOH, , 1 h
74-88%
N
N
H
N
N
H
90-95%
4a-b
6a-h
O
O
R1
DMF-POCl3
N
R2
COOR3
N
rt, 20 min
60-72%
N
N
H
7a h
-
,
,
: R1 = H; R2 = R3 = Me
6a 7a
: R1 = Br; R2 = R3 = Me
6b 7b
1a, 2a, 3a, 4a: R1 = H
1b, 2b, 3b, 4b: R1 = Br
6c, 7c: R1 = H; R2 = Me; R3 = Et
6d, 7d: R1 = Br; R2 = Me; R3 = Et
: R2 = Me; R3 = Me
: R1 = H; R2 = Ph; R3 = Et
,
: R1 = Br; R2 = Ph; R3 = Et
6f 7f
5a
5b
5c
6e 7e
,
: R2 = Me; R3 = Et
: R2 = Ph; R3 = Et
: R1 = H; R2 = CH2Cl; R3 = Et
6g 7g
,
5d: R2 = CH2Cl; R3 = Et
6h, 7h: R1 = Br; R2 = CH2Cl; R3 = Et
Scheme 1
Me
C
O
O
O
O
R1
NH2
O
R1
N
N
H
N
H
C
R2
Δ
R2
EtOH, , 1 h
Me
N
N
H
N
N
H
70-84%
4a b
-
8a e
-
9a-j
O
O
DMF-POCl3
R1
I2, PhI(OAc)2
EtOH, rt, 12 h
N
R2
N
10a
7e
rt, 30 min
68-75%
N
N
H
CHO
10a j
-
4a: R1 = H
4b: R1 = Br
8a: R2 = H
9a, 10a: R1 = R2 = H
9f, 10f: R1 = Br; R2 = NO2
9g, 10g: R1 = H; R2 = Me
9h, 10h: R1 = Br; R2 = Me
9b, 10b: R1 = Br; R2 = H
9c, 10c: R1 = H; R2 = Cl
: R2 = Cl
,
: R1 = Br; R2 = Cl
: R1 = H; R2 = NO2
: R1 = H; R2 = OMe
,
: R1 = Br; R2 = OMe
9j 10j
8b
9d 10d
,
9i 10i
,
: R2 = NO2
8c
9e 10e
8d: R2 = Me
8e: R2 = OMe
Scheme 2
-1H-pyrazole-4-carboxylic acid methyl esters
7 and
Conclusion
1-(4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
Simple methods for the preparation of 3-methyl- 3-phenyl-1H-pyrazole-4-carbaldehydes 10 using a Vils-
1-(4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl) meier-Haack reagent are reported.
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M.V.S.R.K. Chaitanya and P.K. Dubey: Naphthyridine-1-H -pyrazole-4-carboxylic acid esters/carbaldehydesꢀ ꢀ3
2H, -CH2), 4.20 (s, 2H, CH2), 7.78–8.16 (m, 2H, Ar-H), 8.74 (s, 1H, CH,
α-proton to the enamine nitrogen), 9.79 (s, 1H, -NH), 11.90 (sharp, s,
1H, -NH, D2O exchangeable); MS: m/z 396 [M+H]+. Anal. Calcd for
C15H15BrN4O4: C, 45.59; H, 3.83; N, 14.18. Found: C, 45.56; H, 3.80; N,
14.16.
Experimental section
All reagents used in this work were obtained from commercial sup-
pliers. Solvents were freshly distilled before use. Melting points are
uncorrected and were determined using open capillary tubes in a sul-
furic acid bath. TLC analyses were done on glass plates coated with
silica gel GF-254 and visualization was done using treatment with
iodine or illumination with a UV lamp. IR spectra were recorded on a
Perkin-Elmer model 1000 instrument in KBr pellets. 1H NMR spectra
were recorded in DMSO-d6 on a 400-MHz Varian Gemini spectrome-
ter. Electrospray ionization mass spectra were recorded on an Agilent
LC-MS instrument. Elemental analyses were performed on a Varian
3LV analyzer series CHN analyzer.
3-[(4-Oxo-1,4-dihydro-[1,8]naphthyridine-3-cabonyl)-
hydrazono]-3-phenyl-propionic acid ethyl ester (6e)ꢀYield
3.34 g (88%); mp 256–258°C; IR: 3400–3100 (sharp, medium, -NH-
stretching), 1690 (strong, sharp, -O-C෇O stretching), 1667 cm-1
(strong, sharp, -CO- stretching); 1H NMR: δ 1.30 (t, 3H, -CH3), 2.70 (q,
2H, -CH2), 4.15 (s, 2H, -CH2), 7.16–8.35 (m, 8H, Ar-H), 8.67 (s, 1H, -CH,
α-proton to the enamine nitrogen), 9.76 (s, 1H, -NH), 12.00 (sharp,
s, 1H, -NH, D2O exchangeable); MS: m/z 379 [M+H]+. Anal. Calcd for
C20H18N4O4: C, 63.48; H, 4.79; N, 14.81. Found: C, 63.45; H, 4.76; N,
14.80.
General procedure for the preparation of 6
3-[(6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-cabonyl)-
hydrazono]-3-phenyl-propionic acid ethyl ester (6f)ꢀYield 3.89 g
(85%); mp 262–264°C; IR: 3300–3000 (sharp, medium, -NH- stretch-
ing), 1710 (strong, sharp, -O-C෇O stretching), 1678 cm-1 (strong, sharp,
-CO- stretching); 1H NMR: δ 1.36 (t, 3H, -CH3), 2.73 (q, 2H, -CH2), 4.18
(s, 2H, -CH2), 7.25–8.18 (m, 7H, Ar-H), 8.59 (s, 1H, -CH, α-proton to
the enamine nitrogen), 9.62 (s, 1H, -NH), 11.45 (sharp, s, 1H, -NH, D2O
exchangeable); MS: m/z 458 [M+H]+. Anal. Calcd for C20H17BrN4O4: C,
52.53; H, 3.75; N, 12.25. Found: C, 52.51; H, 3.70; N, 12.23.
A mixture of 4 (10 mmol), β-ketoester (5a–d) (10 mmol) and metha-
nol (20 mL) was heated under reflux for 1 h and then poured into
ice-cold water (25 mL). The separated solid was filtered, washed with
water (2×20 mL) and dried, and crystallized from ethanol to give ana-
lytically pure product 6a–h.
3-[(4-Oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
hydrazono]-butyric acid methyl ester (6a)ꢀYield 2.23 g (74%);
mp 164–166°C; IR: 3100–2800 (broad, medium, -NH- stretching),
1735 (strong, sharp, O-C෇O stretching), 1678 cm-1 (strong, sharp, -CO-
4-Chloro-3-[(4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
hydrazono]-butyric acid ethyl ester (6g)ꢀYield 2.73 g (78%); mp
221–223°C; IR: 3400–3100 (sharp, medium, -NH- stretching), 1738
(strong, sharp, -O-C෇O stretching), 1676 cm-1 (strong, sharp, -CO-
1
stretching); H NMR: δ 1.25 (s, 3H, -CH3), 2.00 (s, 3H, -CH3), 4.20 (s,
2H, CH2), 7.62–8.26 (m, 3H, Ar-H), 9.11 (s, 1H, -CH, α-proton to the
enamine nitrogen), 9.25 (s, 1H, -NH), 11.85 (sharp, s, 1H, -NH, D2O ex-
changeable); MS: m/z 303 [M+H]+. Anal. Calcd for C14H14N4O4: C, 55.63;
H, 4.67; N, 18.53. Found: C, 55.60; H, 4.64; N, 18.51.
1
stretching); H NMR: δ 1.28 (t, 3H, -CH3), 2.59 (q, 2H, -CH2), 3.42 (s,
2H, -CH2), 4.15 (s, 2H, -CH2), 7.84–8.43 (m, 3H, Ar-H), 8.80 (s, 1H, -CH,
α-proton to the enamine nitrogen), 9.56 (s, 1H, -NH), 12.10 (sharp,
s, 1H, -NH, D2O exchangeable); MS: m/z 351 [M+H]+. Anal. Calcd for
C15H15ClN4O4: C, 51.36; H, 4.31; N, 15.97. Found: C, 51.34; H, 4.30; N,
15.96.
3-[(6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
hydrazono]-butyric acid methyl ester (6b)ꢀYield 3.0 g (80%); mp
172–174°C; IR: 3400–3000 (broad, medium, -NH- stretching), 1710
(strong, sharp, -O-C෇O stretching), 1677 (strong, sharp, -C෇O) cm-
3-[(6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
hydrazono]-4-chloro-butyric acid ethyl ester (6h)ꢀYield 3.23 g
(75%); mp 230–232°C; IR: 3400–3100 (sharp, medium, -NH- stretch-
ing), 1738 (strong, sharp, -O-C෇O stretching), 1676 cm-1 (strong,
sharp, -CO- stretching); 1H NMR: δ 1.30 (t, 3H, -CH3), 2.78 (q, 2H,
-CH2), 3.60 (s, 2H, -CH2), 4.27 (s, 2H, -CH2), 7.94–8.27 (m, 2H, Ar-H),
8.87 (s, 1H, -CH, α-proton to the enamine nitrogen), 9.66 (s, 1H, -NH),
11.25 (sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 431 [M+H]+.
Anal. Calcd for C15H14ClBrN4O4: C, 41.93; H, 3.28; N, 13.04. Found: C,
41.90; H, 3.26; N, 13.00.
1
1; H NMR: δ 1.25 (s, 3H, -CH3), 2.10 (s, 3H, -CH3), 4.32 (s, 2H, CH2),
7.84–8.29 (m, 2H, Ar-H), 9.17 (s, 1H, -CH, α-proton to the enamine ni-
trogen), 9.50 (s, 1H, CH), 11.90 (sharp, s, 1H, -NH, D2O exchangeable);
MS: m/z 382 [M+H]+. Anal. Calcd for C14H13BrN4O4: C, 44.11; H, 3.44; N,
14.70. Found: C, 44.10; H, 3.42; N, 14.68.
3-[(4-Oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
hydrazono]-butyric acid ethyl ester (6c)ꢀYield 2.6 g (82%); mp
178–180°C; IR: 3400–3100 (broad, medium, -NH- stretching), 1725
(strong, sharp, -O-C෇O stretching), 1689 cm-1 (strong, sharp, -CO-
1
stretching); H NMR: δ 1.20 (s, 3H, -CH3), 2.20 (t, 3H, -CH3), 3.32 (q,
2H, -CH2), 4.17 (s, 2H, CH2), 7.42–8.26 (m, 3H, Ar-H), 8.65 (s, 1H, CH,
α-proton to the enamine nitrogen), 9.89 (s, 1H, -NH), 11.85 (sharp,
s, 1H, -NH, D2O exchangeable); MS: m/z 317 [M+H]+. Anal. Calcd for
C15H16N4O4: C, 56.96; H, 5.10; N, 17.71. Found: C, 56.94; H, 5.07; N,
17.68.
General procedure for the preparation of 7
POCl3 (4.5 mL, 30 mmol) was added dropwise to an ice-cold, stirred
DMF (4 mL) and the mixture was stirred for 30 min before portion-
wise treatment with hydrazone 6a–h (10 mmol) for approximately
15 min. The mixture was stirred for an additional 20 min at room tem-
perature and then poured onto crushed ice (25 mL) and neutralized
with aqueous solution of NaOH (5%, 10 mL). The separated solid of
7a–h was filtered, washed with water (2×10 mL) and dried, and crys-
tallized from hot ethanol.
3-[(6-Bromo - 4- oxo -1,4- dihydro -[1,8]naphthyridine-
3-carbonyl)-hydrazono]-butyric acid methyl ester (6d)ꢀYield
3.0 g (78%); mp 186°C; IR: 3458–3026 (broad, medium, -NH-), 1716
(strong, sharp, -O-C෇O stretching), 1697 cm-1 (strong, sharp, -CO-
1
stretching); H NMR: δ 1.23 (s, 3H, -CH3), 2.27 (t, 3H, -CH3), 3.35 (q,
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4ꢀ ꢀM.V.S.R.K. Chaitanya and P.K. Dubey: Naphthyridine-1-H-pyrazole-4-carboxylic acid esters/carbaldehydes
3-Methyl-1-(4- oxo -1,4- dihydro -[ 1, 8]naphthyridine- 1H, -NH, D2O exchangeable); MS: m/z 468 [M+H]+. Anal. Calcd for
3-carbonyl)-1H-pyrazole-4-carboxylic acid methyl ester (7a) C21H15BrN4O4: C, 53.98; H, 3.24; N, 11.99. Found: C, 53.95; H, 3.21; N, 11.97.
Yield 1.86 g (60%); mp 174–176°C; IR: 3431–2800 (broad, medium,
-NH- stretching), 1710 (strong, sharp, -O-C෇O stretching), 1685 and 3-Chloromethyl-1-(4-oxo-1,4-dihydro-[1,8]naphthyridine-
1660 cm-1 (sharp, strong, -CO- stretching); 1H NMR: δ 1.34 (s, 3H, 3-carbonyl)-1H-pyrazole-4-carboxylic acid ethyl ester (7g)ꢀYield
-CH3), 4.26 (s, 3H, -CH3), 7.42–7.97 (m, 3H, Ar-H), 8.15 (s, 1H, pyrazole- 2.08 g (58%); mp 192–194°C; IR: 3300–3100 (broad, medium, due to
CH), 9.26 (s, 1H, CH, α-proton to the enamine nitrogen), 12.27 (sharp, -NH- stretching), 1705 (sharp, strong, due to -O-C෇O stretching), 1694
s, 1H, -NH, D2O exchangeable); MS: m/z 313 [M+H]+. Anal. Calcd for and 1676 cm-1 (strong, sharp, due to -CO- stretching); 1H NMR: δ 1.12 (t,
C15H12N4O4: C, 57.69; H, 3.87; N, 17.94. Found: C, 57.66; H, 3.86; N, 17.90. 3H, -CH3), 4.12 (s, 2H, -CH2), 4.18 (q, 2H, -CH2), 7.74–8.23 (m, 3H, Ar-
H), 8.21 (s, 1H, pyrazole-CH), 8.94 (s, 1H, CH, α-proton to the enamine
1-(6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)- nitrogen), 12.13 (sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 361
3-methyl-1H-pyrazole-4-carboxylic acid methyl ester (7b)ꢀYield [M+H]+. Anal. Calcd for C16H13ClN4O4: C, 53.27; H, 3.63; N, 15.53. Found:
2.43 g (62%); mp 190–192°C; IR: 3400–2800 (broad, medium, -NH- C, 53.25; H, 3.62; N, 15.51.
stretching), 1710 (sharp, strong, -O-C෇O stretching), 1698 and 1665
1
cm-1 (strong, sharp, -CO- stretching); H NMR: δ 1.20 (s, 3H, -CH3), 1-(6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
3.35 (s, 3H, -CH3), 7.78–8.29 (m, 2H, Ar-H), 8.24 (s, 1H, pyrazole -CH), 3-chloromethyl-1H-pyrazole-4-carboxylic acid ethyl ester
9.10 (s, 1H, CH, α-proton to the enamine nitrogen), 11.90 (sharp, s, (7h) ꢀYield 2.64 g (60%); mp 149–151°C; IR: 3400–3100 (broad, me-
1H, -NH, D2O exchangeable); MS: m/z 392 [M+H]+. Anal. Calcd for dium, -NH- stretching), 1726 (sharp, strong, -O-C෇O stretching), 1698
C15H11BrN4O4: C, 46.06; H, 2.83; N, 14.32. Found: C, 46.04; H, 2.82; N, and 1686 cm-1 (strong, sharp, -CO- stretching); 1H NMR: δ 1.19 (t, 3H,
14.30.
-CH3), 4.16 (s, 2H, -CH2), 4.25 (q, 2H, -CH2), 7.90–8.13 (m, 2H, Ar-H),
8.35 (s, 1H, pyrazole-CH), 9.10 (s, 1H, CH, α-proton to the enamine
3-Methyl-1-(4- oxo -1,4- dihydro -[ 1, 8]naphthyridine- nitrogen), 11.55 (sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 440
3-carbonyl)-1H-pyrazole-4-carboxylic acid ethyl ester (7c)ꢀYield [M+H]+. Anal. Calcd for C16H12BrClN4O4: C, 43.71; H, 2.75; N, 12.74.
2.15 g (66%); mp 202–204°C; IR: 3300–2900 (broad, medium, -NH- Found: C, 43.69; H, 2.73; N, 12.72.
stretching), 1718 (sharp, strong, -O-C෇O stretching), 1695 and 1676
cm-1 (strong, sharp, -CO- stretching); 1H NMR: δ 1.22 (t, 3H, -CH3), 3.27
(s, 2H, -CH3), 4.12 (q, 2H, -CH2), 7.48–8.37 (m, 3H, Ar-H), 8.55 (s, 1H,
General procedure for the preparation of 9
pyrazole -CH, α-proton to the enamine nitrogen), 8.90 (s, 1H, -CH),
12.50 (sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 327 [M+H]+.
Anal. Calcd for C16H14N4O4: C, 58.89; H, 4.32; N, 17.17. Found: C, 58.87;
H, 4.30; N, 17.15.
A mixture of 4 (10 mmol), substituted acetophenone 8a–j (10 mmol)
and ethanol (20 mL) was heated under reflux for 1 h, then cooled and
poured onto crushed ice (25 mL). The separated solid of 9a–j was
filtered, washed with water (2×10 mL), dried and crystallized from
ethanol.
1-(6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (7d)ꢀYield
2.91 g (72%); mp 212–214°C; IR: 3500–3200 (broad, medium, -NH-
stretching), 1728 (sharp, strong, -O-C෇O stretching), 1699 and 1665
cm-1 (strong, sharp, -CO- stretching); 1H NMR: δ 1.27 (t, 3H, -CH3), 3.40
(s, 2H, -CH3), 4.16 (q, 2H, -CH2), 7.88–8.24 (m, 3H, Ar-H), 8.47 (s, 1H,
pyrazole -CH), 9.00 (s, 1H, -CH, α-proton to the enamine nitrogen),
12.15 (sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 406 [M+H]+.
Anal. Calcd for C16H13BrN4O4: C, 47.43; H, 3.23; N, 13.83. Found: C,
47.42; H, 3.20; N, 13.81.
4-Oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (1-phe-
nyl-ethylidene)-hydrazide (9a)ꢀYield 2.23 g (73%); mp 135–137°C;
IR: 3400–3100 (broad, medium, -NH- stretching), 1684 (strong, sharp,
-CO- stretching), 1665 cm-1 (strong, sharp, -CO- stretching); 1H NMR: δ
1.22 (s, 3H, -CH3), 7.29–8.30 (m, 8H, Ar-H), 9.24 (s, 1H, -CH, α-proton
of the enamino nitrogen), 12.27 (s, 1H, -NH), 13.04 (sharp, s, 1H, -NH,
D2O exchangeable); MS: m/z 307 [M+H]+. Anal. Calcd for C17H14N4O2:
C, 66.66; H, 4.61; N, 18.29. Found: C, 66.64; H, 4.59; N, 18.26.
1-(4-Oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-3-phe-
nyl-1H-pyrazole-4-carboxylic acid ethyl ester (7e)ꢀYield 2.32 g
(60%); mp 233–235°C; IR: 3400–3100 (broad, medium, -NH- stretch-
ing), 1746 (sharp, strong, -O-C෇O stretching), 1690 and 1669 cm-1
(strong, sharp, -CO- stretching); 1H NMR: δ 1.17 (t, 3H, -CH3), 4.19 (q,
2H, -CH2), 7.37–8.25 (m, 8H, Ar-H), 8.45 (s, 1H, pyrazole -CH), 9.10 (s,
1H, -CH, α-proton to the enamine nitrogen), 12.15 (sharp, s, 1H, -NH,
D2O exchangeable); MS: m/z 389 [M+H]+. Anal. Calcd for C21H16N4O4:
C, 64.94; H, 4.15; N, 14.43. Found: C, 64.90; H, 4.12; N, 14.40.
6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic
acid (1-phenyl-ethylidene)-hydrazide (9b)ꢀYield 2.88 g (75%); mp
142–144°C; IR: 3400–3100 (broad, medium, -NH- stretching), 1688
(strong, sharp, -CO- stretching), 1675 cm-1 (strong, sharp, -CO- stretch-
1
ing); H NMR: δ 1.27 (s, 3H, -CH3), 7.29–8.32 (m, 7H, Ar-H), 9.24 (s,
1H, -CH, α-proton to the enamine nitrogen), 10.24 (s, 1H, -NH), 12.10
(sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 386 [M+H]+. Anal.
Calcd for C17H13BrN4O2: C, 53.00; H, 3.40; N, 14.54. Found: C, 52.98; H,
3.36; N, 14.5.
1-(6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
3-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (7f)ꢀYield
3.12 g (67%); mp 237–239°C; IR: 3400–3000 (broad, medium, -NH-
stretching), 1716 (sharp, strong, -O-C෇O stretching), 1686 and 1660
cm-1 (strong, sharp, -CO- stretching); 1H NMR: δ 1.18 (t, 3H, -CH3),
4.25 (q, 2H, -CH2), 7.45–8.16 (m, 7H, Ar-H), 8.34 (s, 1H, pyrazole -CH),
8.95 (s, 1H, -CH, α-proton to the enamine nitrogen), 12.20 (sharp, s,
4-Oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicꢁacid
[1-(4-chloro-phenyl)-ethylidene]-hydrazide
(9c)ꢀYield
2.65
g (78%); mp 136–138°C; IR: 3400–3100 (broad, medium, -NH-
stretching), 1684 (strong, sharp, -CO- stretching), 1669 cm-1 (strong,
sharp, -O- stretching); 1H NMR: δ 1.20 (s, 3H, -CH3), 7.25–8.39 (m, 7H,
Ar-H), 8.91 (s, 1H, -CH, α-proton to the enamine nitrogen), 10.16 (s,
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1H, -NH), 11.12 (sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 341 1H, -NH), 12.55 (sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 337
[M+H]+. Anal. Calcd for C17H13ClN4O2: C, 59.92; H, 3.85; N, 16.44. Found: [M+H]+. Anal. Calcd for C18H16N4O3: C, 64.28; H, 4.79; N, 16.66. Found:
C, 59.90; H, 3.80; N, 16.40.
C, 64.24; H, 4.73; N, 16.64.
6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic
acid [1-(4-methoxy-phenyl)-ethylidene]-hydrazide (9j)ꢀYield
2.98 g (72%); mp 158–160°C; IR: 3400–3150 (broad, medium, -NH-
stretching), 1710 (strong, sharp, -CO- stretching), 1676 cm-1 (strong,
sharp, -CO- stretching); 1H NMR: δ 1.20 (s, 3H, -CH3), 2.31 (s, 3H, -CH3),
7.27–8.40 (m, 6H, Ar-H), 8.90 (s, 1H, -CH, α-proton to the enamine
nitrogen), 10.50 (s, 1H, -NH), 12.99 (sharp, s, 1H, -NH, D2O exchange-
able); MS: m/z 416 [M+H]+. Anal. Calcd for C18H15BrN4O3: C, 52.06; H,
3.64; N, 13.49. Found: C, 52.02; H, 3.62; N, 13.46.
6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic
acid [1-(4-chloro-phenyl)-ethylidene]-hydrazide (9d)ꢀYield
2.98 g (71%); mp 148–150°C; IR: 3400–3000 (broad, medium, -NH-
stretching), 1684 (strong, sharp, -CO- stretching), 1670 cm-1 (strong,
1
sharp, -CO- stretching); H NMR: δ 1.26 (s, 3H, -CH3), 7.48–8.30 (m,
6H, Ar-H), 8.88 (s, 1H, -CH, α-proton to the enamine nitrogen), 10.26
(s, 1H, -NH), 11.79 (sharp, s, 1H, -NH, D2O exchangeable); MS: m/z
420 [M+H]+. Anal. Calcd for C17H12BrClN4O2: C, 48.65; H, 2.88; N, 13.35.
Found: C, 48.64; H, 2.86; N, 13.30.
4-Oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid [1-(4-ni-
tro-phenyl)-ethylidene]-hydrazide (9e)ꢀYield 2.94
g (84%);
mp162–164°C; IR: 3400–2900 (broad, medium, -NH- stretching),
General procedure for the preparation of 10
Products 10 were obtained from 9 by using the procedure described
above for the preparation of 7.
(strong, sharp, -CO- stretching), 1668 cm-1 (strong, sharp, -CO- stretch-
1
ing); H NMR: δ 1.26 (s, 3H, -CH3), 7.28–8.40 (m, 7H, Ar-H), 8.90 (s,
1H, -CH, α-proton to the enamine nitrogen), 10.25 (s, 1H, -NH), 12.10
(sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 352 [M+H]+. Anal.
Calcd for C17H13N5O4: C, 58.12; H, 3.73; N, 19.93. Found: C, 58.10; H, 3.71;
N, 19.90.
1-(4-Oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-3-phe-
nyl-1H-pyrazole-4-carbaldehyde (10a)ꢀYield 2.33 g (68%); mp
182–184°C; IR: 3400–3100 (broad, medium, -NH- stretching), 1695
(strong, sharp, -CO- stretching), 1684 cm-1 (strong, sharp, -CO- stretch-
ing); 1H NMR: δ 7.10–8.32 (m, 8H, Ar-H), 8.60 (s, 1H, -CH, α-proton to
the enamino nitrogen), 9.10 (s, 1H, -CHO), 9.30 (s, 1H, pyrazole-CH),
10.20 (sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 345 [M+H]+.
Anal. Calcd for C19H12N4O3: C, 66.28; H, 3.50; N, 16.27. Found: C, 66.26;
H, 3.46; N, 16.24.
6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic
acid [1-(4-nitro-phenyl)-ethylidene]-hydrazide (9f)ꢀYield 3.50 g
(81%); mp 177–179°C; IR: 3300–3000 (broad, medium, -NH- stretch-
ing), 1694 (strong, sharp, -CO- stretching), 1678 cm-1 (strong, sharp,
-CO- stretching); 1H NMR: δ 1.30 (s, 3H, -CH3), 7.18–8.35 (m, 6H, Ar-H),
8.11 (s, 1H, -CH, α-proton to the enamine nitrogen), 9.98 (s, 1H, -NH),
11.45 (sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 431 [5+H]+. Anal.
Calcd for C17H12BrN5O4: C, 47.46; H, 2.81; N, 16.28. Found: C, 47.43; H,
2.80; N, 16.26.
1-(6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
3-phenyl-1H-pyrazole-4-carbaldehyde (10b)ꢀYield 3.00 g (71%);
mp 190–192°C; IR: 3400–3100 (broad, medium, -NH- stretching), 1693
(strong, sharp, -CO- stretching), 1659 cm-1 (strong, sharp, -CO- stretch-
ing); 1H NMR: δ 7.11–8.32 (m, 7H, Ar-H), 8.62 (s, 1H, -CH, α-proton to
the enamine nitrogen), 9.12 (s, 1H, -CHO), 9.30 (s, 1H, pyrazole -CH),
11.10 (sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 424 [M+H]+.
Anal. Calcd for C19H11BrN4O3: C, 53.92; H, 2.62; N, 13.24. Found: C,
53.90; H, 2.60; N, 13.22.
4-Oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid [1-(4-
methyl-phenyl)-ethylidene]-hydrazide (9g)ꢀYield 2.30 g (72%);
mp 134–136°C; IR: 3400–3200 (broad, medium, -NH- stretching), 1692
(strong, sharp, -CO- stretching), 1665 cm-1 (strong, sharp, -CO- stretch-
ing); 1H NMR: δ 1.25 (s, 3H, -CH3), 2.30 (s, 3H, -CH3), 7.28–8.19 (m, 7H,
Ar-H), 8.90 (s, 1H, -CH, α-proton to the enamine nitrogen), 10.16 (s,
1H, -NH), 12.55 (sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 321
[M+H]+. Anal. Calcd for C18H16N4O2: C, 67.49; H, 5.03; N, 17.49. Found:
C, 67.46; H, 5.00; N, 17.46.
3-(Chloro-phenyl)-1-(4-oxo-1,4-dihydro-[1,8]naphthyridine-
3-carbonyl)-3-phenyl-1H-pyrazole-4-carbaldehyde (10c)ꢀYield
2.64 g (70%); mp 198–200°C; IR: 3300–3200 (broad, medium, -NH-
stretching), 1695 (strong, sharp, -CO- stretching), 1665 cm-1 (strong,
6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic
acid [1-(4-methyl-phenyl)-ethylidene]-hydrazide (9h)ꢀYield
3.15 g (79%); mp 138–140°C; IR: 3400–3000 (broad, medium, -NH-
stretching), 1699 (strong, sharp, -CO- stretching), 1670 cm-1 (strong,
sharp, -CO- stretching); 1H NMR: δ 1.32 (s, 3H, -CH3), 2.29 (s, 3H, -CH3),
7.19–8.40 (m, 6H, Ar-H), 8.86 (s, 1H, -CH, α-proton to the enamine
nitrogen), 10.05 (s, 1H, -NH), 12.65 (sharp, s, 1H, -NH, D2O exchange-
able); MS: m/z 400 [M+H]+. Anal. Calcd for C18H15BrN4O2: C, 54.15; H,
3.79; N, 14.03. Found: C, 54.12; H, 3.76; N, 14.00.
1
sharp, due to -CO- stretching); H NMR: δ 7.20–8.45 (m, 7H, Ar-H),
8.72 (s, 1H, -CH, α-proton to the enamine nitrogen), 9.10 (s, 1H, -CHO),
9.25 (s, 1H, pyrazole -CH), 11.25 (sharp, s, 1H, -NH, D2O exchangea-
ble); MS: m/z 379 [M+H]+. Anal. Calcd for C19H11ClN4O3: C, 60.25; H,
2.93; N, 14.79. Found: C, 60.21; H, 2.90; N, 14.76.
1-(6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
3-(4-chloro-phenyl)-1H-pyrazole-4-carbaldehyde
(10d)ꢀYield
3.29 g (72%); mp 204–206°C; IR: 3400–2900 (broad, medium, -NH-
4-Oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid [1-(4- stretching), 1692 (strong, sharp, -CO- stretching), 1670 cm-1 (strong,
methoxy-phenyl)-ethylidene]-hydrazide (9i)ꢀYield 2.35 g (70%); sharp, -CO- stretching); H NMR: δ 7.26–8.30 (m, 6H, Ar-H), 8.72 (s,
1
mp 152–154°C; IR: 3400–3150 (broad, medium, -NH- stretching) 1690 1H, -CH, α-proton to the enamine nitrogen), 9.15 (s, 1H, -CHO), 9.27 (s,
(strong, sharp, -CO- stretching), 1674 cm-1 (strong, sharp, -CO- stretch- 1H, pyrazole -CH), 11.55 (sharp, s, 1H, -NH, D2O exchangeable); MS:
ing); 1H NMR: δ 1.25 (s, 3H, -CH3), 2.56 (s, 3H, -CH3), 7.10–8.20 (m, 7H, m/z 458 [M+H]+. Anal. Calcd for C19H10ClBrN4O3: C, 49.86; H, 2.20; N,
Ar-H), 8.80 (s, 1H, -CH, α-proton to the enamine nitrogen), 10.15 (s, 12.24. Found: C, 49.84; H, 2.18; N, 12. 22.
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6ꢀ ꢀM.V.S.R.K. Chaitanya and P.K. Dubey: Naphthyridine-1-H-pyrazole-4-carboxylic acid esters/carbaldehydes
3-(Nitro-phenyl)-1-(4-oxo-1,4-dihydro-[1,8]naphthyridine- 3-(Methoxy-phenyl)-1-(4-oxo-1,4-dihydro-[1,8]naphthyridine-
3-carbonyl)-3-phenyl-1H-pyrazole-4-carbaldehyde (10e)ꢀYield 3-carbonyl)-3-phenyl-1H-pyrazole-4-carbaldehyde (10i)ꢀYield
2.91 g (75%); mp 212–214°C; IR: 3400–3000 (broad, medium, -NH- 2. 61 g (70%); mp 166–168°C; IR: 3430–3100 (broad, medium, -NH-
stretching), 1698 (strong, sharp, -CO- stretching), 1669 cm-1 (strong, stretching), 1697 (strong, sharp, -CO- stretching), 1655 cm-1 (strong,
1
1
sharp, -CO- stretching); H NMR: δ 7.23–8.40 (m, 7H, Ar-H), 8.68 (s, sharp, -CO-); H NMR (DMSO d6/TMS): δ 3.15 (s, 3H, -OCH3), 7.27–
1H, -CH, α-proton to the enamine nitrogen), 9.10 (s, 1H, -CHO), 9.25 (s, 8.11 (m, 7H, Ar-H), 8.54 (s, 1H, -CH, α-proton to the enamine ni-
1H, pyrazole-CH), 10.50 (sharp, s, 1H, -NH, D2O exchangeable); MS: trogen), 9.26 (s, 1H, -CHO), 9.28 (s, 1H, pyrazole-CH), 11.55 (sharp,
m/z 390 [M+H]+. Anal. Calcd for C19H11N5O5: C, 58.62; H, 2.85; N, 17.99. s, 1H, -NH, D2O exchangeable); MS: m/z 375 [M+H]+. Anal. Calcd
Found: C, 58.60; H, 2.81; N, 17.96.
for C20H14N4O4: C, 64.14; H, 3.77; N, 14.97. Found: C, 64.10; H, 3.75;
N, 14.94.
1-(6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
3-(4-nitro-phenyl)-1H-pyrazole-4-carbaldehyde (10f)ꢀYield 3.65 1-(6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
g (78%); mp 218–220°C; IR: 3200–3100 (broad, medium, -NH- stretch- 3-(4-methoxy-phenyl)-1H-pyrazole-4-carbaldehyde (10j)ꢀYield
ing), 1698 (strong, sharp, -CO- stretching), 1676 cm-1 (strong, sharp, 3.34 g (75%); mp 175–177°C; IR: 3430–3100 (broad, medium, -NH-
-CO- stretching); 1H NMR: δ 7.13–8.30 (m, 6H, Ar-H) 8.79 (s, 1H, -CH, stretching), 1698 (strong, sharp, due to -CO- stretching), 1666 cm-1
α-proton to the enamine nitrogen), 9.10 (s, 1H, -CHO), 9.28 (s, 1H, (strong, sharp, due to -CO- stretching); 1H NMR: δ 3.20 (s, 3H, -OCH3),
pyrazole-CH), 11.95 (sharp, s, 1H, -NH, D2O exchangeable); MS: m/z 7.45–8.24 (m, 6H, Ar-H), 8.58 (s, 1H, -CH, α-proton to the enamine ni-
469 [M+H]+. Anal. Calcd for C19H10BrN5O5: C, 48.74; H, 2.15; N, 14.96. trogen), 9.21 (s, 1H, -CHO), 9.30 (s, 1H, pyrazole-CH), 11.35 (sharp, s, 1H,
Found: C, 48.73; H, 2.13; N, 14.95.
-NH, D2O exchangeable); MS: m/z 454 [M+H]+. Anal. Calcd for C20H13Br-
N4O4: C, 53.00; H, 2.89; N, 12.36. Found: C, 52.97; H, 2.86; N, 12.31.
3-(Methyl-phenyl)-1-(4-oxo-1,4-dihydro-[1,8]naphthyridine-
3-carbonyl)-3-phenyl-1H-pyrazole-4-carbaldehyde (10g)ꢀYield
2.68 g (75%); mp 186–188°C; IR: 3400–3100 (broad, medium, -NH-
stretching), 1698 (strong, sharp, -CO- stretching), 1675 cm-1 (strong, Preparation of 7 from 10
sharp, -CO- stretching); 1H NMR: δ 2.45 (s, 3H, -CH3), 7.25–8.35 (m, 7H,
A mixture of 10a (10 mmol), iodine (5 mmol), (diacetoxyiodo)ben-
Ar-H), 8.54 (s, 1H, -CH, α-proton to the enamine nitrogen), 9.16 (s,
1H, -CHO), 9.42 (s, 1H, pyrazole-CH), 12.00 (sharp, s, 1H, -NH, D2O ex-
changeable); M: m/z 359 [M+H]+. Anal. Calcd for C20H14N4O3: C, 67.03;
H, 3.94; N, 15. 63. Found: C, 67.00; H, 3.90, N, 15.60.
zene (15 mmol), and ethanol (25 mL) was stirred for 12 h, then poured
onto crushed ice (25 mL) and extracted with CHCl3 (2×10 mL). The
organic extract was dried over anhydrous Na2SO4, concentrated, and
the residue of 7e crystallized from ethanol.
1-(6-Bromo-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-
3-(4-methyl-phenyl)-1H-pyrazole-4-carbaldehyde (10h)ꢀYield
3.05 g (70%); mp 194–196°C; IR: 3100–2900 (broad, medium, -NH-
stretching), 1710 (strong, sharp, -CO- stretching), 1686 cm-1 (strong,
Acknowledgments: The authors are thankful to the Uni-
versity Grants Commission, Government of India, New
Delhi, for giving financial support and to the authorities
of Jawaharlal Nehru Technological University Hyderabad
for providing laboratory facilities.
1
sharp, -CO- stretching); H NMR: δ 2.70 (s, 3H, -CH3), 7.30–8.14 (m,
6H, Ar-H), 8.60 (s, 1H, -CH, α-proton to the enamine nitrogen), 9.20
(s, 1H, -CHO), 9.35 (s, 1H, pyrazole-CH), 11.20 (sharp, s, 1H, -NH, D2O
exchangeable); MS: m/z 438 [M+H]+. Anal. Calcd for C20H13BrN4O3: C,
54.94; H, 3.00; N, 12.81. Found: C, 54.90; H, 2.97; N, 12.80.
Received June 19, 2012; accepted August 7, 2012
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M.V.S.R.K. Chaitanya and P.K. Dubey: Naphthyridine-1-H -pyrazole-4-carboxylic acid esters/carbaldehydesꢀ ꢀ7
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