Efficient synthesis of novel 3-[5-(1H-benzimidazol-2-ylmethanesulfonyl)-4- phenyl-4H-(1,2,4)triazol-3-Yl]-1H-(1,8)naphthyridin-4-one derivatives

Article abstract of DOI:10.1080/10426507.2011.643433

of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbohydrazide (4) with substituted phenyl isothiocyanates (5) in ethanol under reflux for 30 min gave thiosemicarbazide derivatives 6, which on cyclization in 2N NaOH under refluxing conditions for 1 h resulted in 3-(5-mercapto- 4-phenyl-4H-1,2,4-triazol-3-yl)- 1,8-naphthyridin-4(1H)-one (7). Alternatively, 7 could also be prepared from following sequence of reactions, i.e., 4→8→7. In another sequence of reactions, condensation of 7 with chloroacetic acid in dimethylformamide (DMF) and K₂CO₃ as a mild base at 120 °C for 2 h resulted in 2-((5-(1,4-dihydro-4-oxo-1,8-naphthyridin-3-yl)-4-phenyl-4H-1,2,4-triazol-3-yl) sulfanyl)acetic acid (10). The latter, on reaction with substituted o-phenylenediamine (11) in 6N HCl for 4 h yielded 3-(5-((1H-benzo[d]imidazol-2- yl)methylthio)-4-phenyl-4H-1,2,4-triazol-3-yl)-1,8-naphthyridin-4(1H)-one (12). Alternatively, 12 could also be prepared by reacting 7 with 13 in DMF and K ₂CO₃ as a mild base at 120 °C for 2 h, followed by oxidation with H₂O₂ resulting in the corresponding sulfonyl derivatives 14. Copyright

Full text of DOI:10.1080/10426507.2011.643433

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Phosphorus, Sulfur, and Silicon and the
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Efficient Synthesis of Novel 3-[5-(1H-
Benzimidazol-2-Ylmethanesulfonyl)-4-
Phenyl-4H-(1,2,4)Triazol-3-Yl]-1H-
(1,8)Naphthyridin-4-One Derivatives
P. Venkateshwarlu a , M. V. S. R. K. Chaitanya a & P. K. Dubey a
a Department of Chemistry, College of Engineering , Jawaharlal
Nehru Technological University , Kukatpally , Hyderabad , India
Accepted author version posted online: 04 Jan 2012.Published
online: 05 Apr 2012.
To cite this article: P. Venkateshwarlu , M. V. S. R. K. Chaitanya & P. K. Dubey (2012) Efficient
Synthesis of Novel 3-[5-(1H-Benzimidazol-2-Ylmethanesulfonyl)-4-Phenyl-4H-(1,2,4)Triazol-3-Yl]-1H-
(1,8)Naphthyridin-4-One Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 187:6,
711-721, DOI: 10.1080/10426507.2011.643433
To link to this article: http://dx.doi.org/10.1080/10426507.2011.643433
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Phosphorus, Sulfur, and Silicon, 187:711–721, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.643433
EFFICIENT SYNTHESIS OF NOVEL 3-[5-(1H-
BENZIMIDAZOL-2-YLMETHANESULFONYL)-4-PHENYL-
4H-(1,2,4)TRIAZOL-3-YL]-1H-(1,8)NAPHTHYRIDIN-4-ONE
DERIVATIVES
P. Venkateshwarlu, M. V. S. R. K. Chaitanya, and P. K. Dubey
Department of Chemistry, College of Engineering, Jawaharlal Nehru
Technological University, Kukatpally, Hyderabad, India
GRAPHICAL ABSTRACT
H
N
N
O
N
H2
S C
N
N
O
X
SH
X
N
R1
N
N
N
N
N
N
H
(7)
H
(12)
R
R
H
O
S C
O
N
N
O
N
H2
X
N
R1
N
N
N
H
R
(14)
Abstract of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbohydrazide (4) with substituted
phenyl isothiocyanates(5) in ethanol under reflux for30 min gave thiosemicarbazide derivatives
6, which on cyclization in 2N NaOH under refluxing conditionsfor1 h resulted in 3-(5-mercapto-
4-phenyl-4H-1,2,4-triazol-3-yl)-1,8-naphthyridin-4(1H)-one (7). Alternatively, 7 could also
be prepared from following sequence of reactions, i.e., 4 → 8 → 7. In another sequence of
reactions, condensation of 7 with chloroacetic acid in dimethylformamide (DMF) and K2CO3
as a mild base at 120 ◦C for 2 h resulted in 2-((5-(1,4-dihydro-4-oxo-1,8-naphthyridin-
3-yl)-4-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl)acetic acid (10). The latter, on reaction with
substituted o-phenylenediamine (11) in 6N HCl for 4 h yielded 3-(5-((1H-benzo[d]imidazol-
2-yl)methylthio)-4-phenyl-4H-1,2,4-triazol-3-yl)-1,8-naphthyridin-4(1H)-one (12). Alterna-
tively, 12 could also be prepared by reacting 7 with 13 in DMF and K2CO3 as a mild base
Received 2 October 2011; accepted 19 November 2011.
The authors are thankful to the University Grants Commission, Govt. of India, New Delhi, for giving
financial support and to the authorities of Jawaharlal Nehru Technological University Hyderabad for providing
laboratory facilities.
Address correspondence to P. Venkateshwarlu, Department of Chemistry, College of Engineering, Jawa-
harlal Nehru Technological University, Kukatpally, Hyderabad (A.P.)–500 085, India. E-mail: venkychem66@
yahoo.co.in
711

712
P. VENKATESHWARLU ET AL.
at 120 ◦C for 2 h, followed by oxidation with H2O2 resulting in the corresponding sulfonyl
derivatives 14.
Keywords Naphthyridine acid hydrazide; phenyl isothiocyanate; thiosemicarbazide;
chloroacetic acid; o-phenylenediamine; H2O2
INTRODUCTION
Naphthyridine derivatives have a wide spectrum of biological activity.1 Drugs con-
taining naphthyridine nucleus are being widely used for the diagnostics and chemotherapy
of various infectious diseases.2 The 1,2,4-triazole derivatives possess a large number of bi-
ological activities such as antibacterial,3 antifungal,4 diuretic,5 and anticonvulsant.6 These
compounds have a wide range of applications in the area of pharmacology.7 Therefore, a
variety of methods have been reported8 for the synthesis of these type of heterocyclic com-
pounds. New challenging problems have prompted researchers to develop more efficient
molecules, among which 1,2,4-triazoles play a prominent role.9,10 According to literature
reports, compounds having a benzimidazole moiety are reported to possess a number of in-
teresting biological activities, such as antimicrobial,11 anticancer,12 and anthelmentic.13 In
view of these observations, we report herein, the syntheses of novel naphthyridine-appended
1,2,4-triazole derivatives, as new chemical entities that may posses useful biological
activities.
RESULTS AND DISCUSSION
Commercially available 2-aminopyridine (1, i.e., X = H or Br) was condensed
with ethoxymethylenemalonic ester (also commercially available) in ethanol under re-
fluxing conditions for 4 h yielding the previously known14 4-ethoxy-3-oxo-2(pyridine-
2-ylaminomethylene)-butyric acid ethyl ester (2, i.e., X = H or Br), which on thermal
cyclization in freshly prepared hot polyphosphoric acid (PPA) for 30 min resulted in 4-
oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (3, i.e., X = H or Br),
also known earlier.14 Treatment of 3 with hydrazine hydrate in ethanol for 3 h yielded 415
(i.e., X = H or Br) (Scheme 1), the starting material used for further transformations in the
present work.
Scheme 1

SYNTHESIS OF NAPHTHYRIDINE-APPENDED-1,2,4-TRIAZOLE DERIVATIVES
713
Scheme 2
The reaction of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbohydrazide (4) with
phenyl isothiocyanate (5) in refluxing ethanol for 30 min gave the corresponding thiosemi-
carbazide derivatives 6. The structures of the products obtained were assigned on the basis
of their spectral and analytical data (see Experimental Section). 6 on treatment with 2N
NaOH under refluxing conditions for 1 h gave products, which have been characterized as
3-(5-mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)-1,8-naphthyridin-4(1H)-one (7). The latter
could also be prepared by the reaction of 1,8-naphthyridine acid hydrazide (4) with CS2
in ethanolic KOH under refluxing conditions for 12 h giving the previously reported16
3-(5-mercapto-1,3,4-oxadiazol-2-yl)-1,8-naphthyridin-4(1H)-one (8), which on reaction
with substituted anilines (9) in xylene under refluxing conditions for 3 h gave 7. The
structures of the products thus obtained were assigned on the basis of their identity (i.e.,
m.p., m.m.p, Co-TLC, and IR) with those of the same compounds obtained in the earlier
route (i.e., 4 + 5 → 6 → 7) .
The conversion of 6 to 7 might appear to follow the mechanism shown in Scheme
3. The mechanism, probably, involves the reversible formation of the intermediary anion
Scheme 3

714
P. VENKATESHWARLU ET AL.
Scheme 4
6A that undergoes intramolecular electrophilic attack by the carbonyl carbon leading to the
cyclic intermediate 6B. The latter, then, loses a molecule of water giving 7, aromatization
being the driving force for the last step of the reaction (a similar mechanism was reported17
in the literature by Cretu et al. for the synthesis of 1,2,4-triazole-3-thiones).
Once again, the conversion of 8 to 7 by reaction with 9 seems to follow the mech-
anism given in Scheme 4. This mechanism, probably, involves the nucleophilic attack
of aniline (9) on α-carbon atom of the oxadiazole ring of 8 resulting in the formation
of the intermediate 8A that cyclizes intra-molecularly to form the intermediates 8B and
then 8C, which, of course, loses a molecule of water to form 7, aromatization leading
to stability being the driving force for the last step of this mechanism sequence (Simi-
lar mechanism was reported18 in the literature by Padmavathi et al. for the synthesis of
3,5-bis(arylsulfonylmethyl)-4-amino-1,2,4-triazoles).
In another sequence of reactions, 7 on treatment with chloroacetic acid in dimethyl-
formamide (DMF) containing K2CO3 as a mild base at 120 ◦C for 2 h followed by simple
processing gave a product that has been characterized as 2-((5-(1,4-dihydro-4-oxo-1,8-
naphthyridin-3-yl)-4-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl)acetic acid (10). The structure
of 10 was assigned on the basis of their spectral and analytical data (see Experimental Sec-
tion). The compound 10 on reaction with substituted o-phenylenediamines (11) in 6N HCl
under refluxing conditions for 4h resulted in 3-(5-((1H-benzo[d]imidazol-2-yl)methylthio)-
4-phenyl-4H-1,2,4-triazol-3-yl)-1,8-naphthyridin-4(1H)-one (12). Alternatively, 12 could
also be synthesized by reacting 7 with 2-chloromethylbenzimidazole (13) in DMF con-
◦
taining K2CO3 as a mild base at 120 C for 2h. The structures of the products obtained
in this route were assigned based on their identity (i.e., m.p., m.m.p., Co-TLC, and IR) with
those of the same compounds obtained in the earlier route (7 → 10 → 12). the compound
13 required in this work were obtained from 11 and chloroacetic acid using a previously
reported method.19
Oxidation of 12 with H2O2 (30%) in acetic acid at 100 ◦C for 6 h gave
3-(5-((1H-benzo[d]imidazol-2-yl)methylsulfonyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-1,8-
naphthyridin-4(1H)-one (14). The structures of 14 were assigned on the basis of their
spectral and analytical data (see Experimental Section) .

SYNTHESIS OF NAPHTHYRIDINE-APPENDED-1,2,4-TRIAZOLE DERIVATIVES
715
Scheme 5
EXPERIMENTAL SECTION
All the reagents used in this work were obtained from commercial suppliers. Sol-
vents were freshly distilled before being used. Melting points are uncorrected and were
determined using open capillary tubes in a sulfuric acid bath. TLC analyses were done
on silica gel G and spotting was done using Iodine/UV lamp. IR spectra were recorded
1
on a Perkin–Elmer model 1000 instrument in KBr phase. H NMR were recorded in
CDCl3/DMSO using 400 MHz Varian Gemini spectrometer and mass spectra were recorded
on Agilent – LC-MS instrument giving only M+.+ 1 or M+.− 1. Elemental analyses were
performed by Varian 3LV analyzer series CHN analyzer and are reported in terms of
percentage for C, H, and N only.
Preparation of 6 from 4 and 5
A mixture of 4 (10 mM), 5 (10 mM), and ethanol (25 mL) was refluxed for 1 h. At
the end of this period, the reaction mixture was poured into ice-cold water (25 mL) and
stirred for 10 min. The separated solid was filtered, washed with water (25 mL) and dried.
The crude product was recrystallized from hot ethanol to obtain pure 6.
◦
6a (i.e., 6, X = H, R = H): Yield: 2.40 g (70%); m.p. 184–186 C; IR (KBr):
3520–2810 cm−1 (broad, medium, –NH), 1724 cm−1 and 1700 cm−1(strong, sharp, twin
peaks due to symmetric and asymmetric stretchings of –CO–); 1H NMR (DMSO d6/TMS):
δ 7.09–8.30 (m, 8H, Ar–H, five protons of the phenyl ring and three protons of the pyridine
ring), 8.74 (s, 1H, –CH, α-proton to the enamine nitrogen), 9.05 (s, 1H, –NH), 9.68 (s,

716
P. VENKATESHWARLU ET AL.
1H, –NH), 9.80 (s, 1H, –NH), 10.55 (s, 1H, pyridine –NH, D2O exchangeable); 13C NMR
(DMSO d6/TMS): δ 94.90, 108.31, 117.69, 125.95, 126.30, 126.45, 126.55, 128.50, 128.63,
134.63, 140.26, 140. 91, 144.92, 163.19, 166.34, 177. 75; MS: m/z 340 [M+H]+. Anal.
Calcd for C16H13N5O2S: C, 56.63; H, 3.86; N, 20.64, Found: C, 56.59; H, 3.84; N, 20.60.
◦
6b (i.e., 6, X = Br, R = H): Yield: 2.90 g (69%); m.p. 191–193 C; IR (KBr):
3550–3005 cm−1 (broad, medium, –NH–), 1736 and 1724 cm−1 (strong, sharp, twin peaks
1
due to symmetric and asymmetric stretchings of –CO–); H NMR (DMSO d6/TMS): δ
7.19–8.34 (m, 7H, Ar–H), 8.72 (s, 1H, –CH, α-proton to the enamine nitrogen), 9.15
(s, 1H, –NH), 9.70 (s, 1H, –NH), 9.82 (s, 1H, –NH), 10.25 (s, 1H, pyridine –NH, D2O
exchangeable); MS: m/z 419 [M+H]+. Anal. Calcd for C16H12 BrN5O2S: C, 45.94; H,
2.89; N, 16.74. Found: C, 45.90; H, 2.84; N, 16.70.
◦
6c (i.e., 6, X = H, R = CH3): Yield: 2.48 g (70%); m.p. 200–202 C; IR (KBr):
3492–3210 cm−1 (broad, medium, –NH–), 1720 and 1702 cm−1 (strong, sharp, twin peaks
1
due to symmetric and asymmetric stretchings of –CO–); H NMR (DMSO d6/TMS): δ
2.70 (s, 3H, –CH3), 7.29–8.45 (m, 8H, Ar–H), 8.66 (s, 1H, –CH, α-proton to the enamine
nitrogen), 9.20 (s, 1H, –NH), 9.65 (s, 1H, –NH), 9.89 (s, 1H, –NH), 10.40 (s, 1H, pyridine
–NH, D2O exchangeable); MS: m/z 354 [M+H]+. Anal. Calcd for C17H15N5O2S: C, 57.78;
H, 4.28; N, 19.82. Found: C, 57.72; H, 4.23; N, 19.80.
◦
6d (i.e., 6, X = Br, R = CH3): Yield: 3.11 g (72%); m.p. 208–210 C; IR (KBr):
3360–2912 cm−1 (broad, medium, –NH–), 1710 and 1699 cm−1 (strong, sharp, twin peaks
due to symmetric and asymmetric stretchings of –CO–); δ 2.74 (s, 3H, –CH3), 7.10–8.18
(m, 7H, Ar–H), 8.54 (s, 1H, –CH, α-proton to the enamine nitrogen), 9.18 (s, 1H, –NH),
9.78 (s, 1H, –NH), 9.90 (s, 1H, –NH), 11.20 (s, 1H, pyridine –NH, D2O exchangeable);
MS: m/z 432 [M+H]+. Anal. Calcd for C17H14 BrN5O2S: C, 47.23; H, 3.26; N, 16.26.
Found: C, 47.18; H, 3.21; N, 16.21.
Preparation of 7 from 6
A solution of 6 (10 mM) in 2N NaOH (25 mL) was refluxed at 100 ◦C for 1 h. At the
end of this period, the reaction mixture was cooled to RT and neutralized with conc. HCl
(5 mL). The separated solid was filtered, washed with water (20 mL) and dried. The crude
product was recrystallized with ethanol to obtain pure 7.
◦
7a (i.e., 7, X = H, R = H): Yield: 2.20 g (69%); m.p. 174–176 C; IR (KBr):
3420–3205 cm−1 (broad, medium, –NH and –SH) and at 1663 cm−1(strong, sharp, –CO–);
1H– NMR spectrum (DMSO/d6/TMS) δ 5.40 (s,1H, –SH), 7.40–8.30 (m, 8, Ar–H, five aryl
protons of the phenyl ring and three aryl protons of the pyridine ring), 8.85 (s, 1H, –CH,
α-proton to the enamine nitrogen), 11.50 (s, 1H, –NH, D2O exchangeable); MS: m/z 322
[M+H]+. Anal. Calcd for C16H11N5OS: C, 59.80; H, 3.45; N, 21.79. Found: C, 59.72; H,
3.41; N, 21.75.
◦
7b (i.e., 7, X = Br, R = H): Yield: 2.28 g (71%); m.p. 191–193 C; IR (KBr):
3444–3120 cm−1 (broad, medium, –NH– and –SH), 1710 cm−1 (strong, sharp, –CO–); 1H
NMR (DMSO d6/TMS): δ 5.48 (s, 1H, –SH), 7.10–8.30 (m, 7H, two aryl protons of the
pyridine ring + five aryl protons of the benzene ring), 8.70 (s, 1H, –CH, α-proton to the
enamine nitrogen), 12.58 (s, 1H, –NH, D2O exchangeable); MS: m/z 400 [M+H]+. Anal.
Calcd for C16H10 BrN5OS: C, 48.01; H, 2.52; N, 17.50. Found: C, 47.98; H, 2.45; N, 17.46.
◦
7c (i.e., 7, X = H, R = CH3): Yield: 2.35 g (72%); m.p. 180–182 C; IR (KBr):
3460–3218 cm−1 (broad, medium, –NH– and –SH), 1725cm−1 (strong, sharp, –CO–); 1H

SYNTHESIS OF NAPHTHYRIDINE-APPENDED-1,2,4-TRIAZOLE DERIVATIVES
717
NMR (DMSO d6/TMS): δ 2.43 (s, 3H, –CH3), 5. 46 (s, 1H, –SH), 7.06–8.29 (m, 7H, three
aryl protons of the pyridine ring + four aryl protons of the benzene ring), 8.88 (s, 1H, –CH,
α-proton to the enamine nitrogen), 12.15 (s, 1H, –NH, D2O exchangeable); MS: m/z 336
[M+H]+. Anal. Calcd for C17H13 N5OS: C, 60.88; H, 3.91; N, 20.88. Found: C, 60.81; H,
3.88; N, 20.83.
◦
7d (i.e., 7, X = Br, R = CH3): Yield: 3.15 g (70%); m.p. 196–198 C; IR (KBr):
3340–2910 cm−1 (broad, medium, –NH– and –SH), 1690 cm−1 (strong, sharp, –CO–); 1H
NMR (DMSO d6/TMS): δ 2.47 (s, 3H, –CH3), 5. 50 (s, 1H, –SH), 7.06–8.38 (m, 6H, two
aryl protons of the pyridine ring + four aryl protons of the benzene ring), 8.54 (s, 1H, –CH,
α-proton to the enamine nitrogen), 12.15 (s, 1H, –NH, D2O exchangeable); MS: m/z 415
[M+H]+. Anal. Calcd for C17H12 BrN5OS: C, 49.29; H, 2.92; N, 16.90. Found: C, 49.22;
H, 2.90; N, 16.86.
Alternate Preparation of 7 from 8 and 9
A mixture of 8 (10 mM), 9 (10 mM) and xylene (25 mL) was refluxed for 3 h.
At the end of this period, the excess of xylene was distilled off under reduced pressure.
The separated solid was filtered, washed with hexane and dried. The crude product was
recrystallized from ethanol to obtain pure 7.
Preparation of 10 from 7
A mixture of 7 (10 mM), chloroacetic acid (10 mM), DMF (20 mL), and K2CO3 (5
◦
mM) was refluxed at 120 C for 2 h. At the end of this period, the reaction mixture was
cooled to RT and diluted with water (20 mL). The separated solid was filtered, washed with
water (20 mL) and dried. The crude product was recrystallized from ethanol (20 mL) to
obtain pure 10.
◦
10a (i.e., 10, X = H, R = H): Yield: 2.46 g (65%); m.p. 112–114 C; IR (KBr):
3605–2821 cm−1 (broad, medium, –NH), 1730 cm−1 (strong, sharp, –O–C O–), 1698
cm−1 (strong, sharp, –CO–); 1H NMR (DMSO/d6/TMS) δ 4.13 (s, 2H, –CH2), 7.16–7.95
(m, 8H, Ar–H, five aryl protons of the phenyl ring and three aryl protons of the pyridine
ring), 8.77 (s, 1H, –CH, α-proton to the enamine nitrogen), 10.25 (s, 1H, –OH, D2O
exchangeable), 11.30 (s,1H, –NH, D2O exchangeable); MS: m/z 380 [M+H]+. Anal. Calcd
for C18H13N5O3S: C, 56.98; H, 3.45; N, 18.46. Found: C, 56.93; H, 3.40; N, 18.40.
◦
10b (i.e., 10, X = Br, R = H): Yield: 3.00 g (67%); m.p. 136–138 C; IR (KBr):
3412–3060 cm−1 (broad, medium, –NH– and –OH), 1712cm−1 (strong, sharp, –O–C O),
1
1697 cm−1 (strong, sharp, –CO–); H NMR (DMSO d6/TMS): δ 4.15 (s, 3H, –CH3),
7.16–8.39 (m, 7H, two aryl protons of the pyridine ring + five aryl protons of the benzene
ring), 8.56 (s, 1H, –CH, α-proton to the enamine nitrogen), 10.15 (s, 1H, –OH, D2O
exchangeable), 11.55 (s, 1H, –NH, D2O exchangeable); MS: m/z 459 [M+H]+. Anal.
Calcd for C18H12 BrN5O3S: C, 47.17; H, 2.64; N, 15.28. Found: C, 47.10; H, 2.60; N,
15.22.
10c (i.e., 10, X = H, R = CH3): Yield: 2.48 g (63%); m.p. 156–158 ◦C; IR (KBr):
3320–2817 cm−1 (broad, medium, –NH– and –OH), 1716 cm−1 (strong, sharp, –O–C =
O), 1680 cm−1 (strong, sharp, –CO–); 1H NMR (DMSO d6/TMS): δ 2.43 (s, 3H, –CH3),
4.20 (s, 2H, –CH2), 7.06–8.29 (m, 7H, three aryl protons of the pyridine ring + four aryl
protons of the benzene ring), 8.48 (s, 1H, –CH, α-proton to the enamine nitrogen), 10.20
(s, 1H, –OH, D2O exchangeable), 11.99 (s, 1H, –NH, D2O exchangeable); MS: m/z 394

718
P. VENKATESHWARLU ET AL.
[M+H]+. Anal. Calcd for C19H15N5O3S: C, 58.01; H, 3.84; N, 17.80. Found: C, 57.97; H,
3.79; N, 17.73.
10d (i.e., 10, X = Br, R = CH3): Yield: 3.31 g (70%); m.p. 167–169 ◦C; IR (KBr):
3330–2922 cm−1 (broad, medium, –NH– and –OH), 1710 cm−1 (strong, sharp, –O–C O),
1697 cm−1 (strong, sharp, –CO–); 1H NMR (DMSO d6/TMS): δ 2.55 (s, 3H, –CH3), 4.46
(s, 2H, –CH2), 7.12–8.38 (m, 6H, two aryl protons of the pyridine ring + four aryl protons
of the benzene ring), 8.50 (s, 1H, –CH, α-proton to the enamine nitrogen), 11.00 (s, 1H,
–OH, D2O exchangeable), 12.15 (s, 1H, –NH, D2O exchangeable); MS: m/z 473 [M+H]+.
Anal. Calcd for C19H14 BrN5O3S: C, 48.32; H, 2.99; N, 14.83. Found: C, 48.29; H, 2.95;
N, 14.80.
Preparation of 12 from 10 and 11
A mixture of 10 (10 mM), 11 (10 mM), and 6N HCl (25 mL) was refluxed at 100 ◦C
for 4 h. At the end of this period, the reaction mixture was cooled to RT and neutralized
with aq. NH3 (10 mL). The separated solid was filtered, washed with water (25 mL) and
dried. The crude product was recrystallized from hot ethanol to obtain 12.
◦
12a (i.e., 12, X = H, R = H, R1 = H): Yield: 3.38 g (75%); m.p. 236–238 C;
IR (KBr) 3100–3000 cm−1 (broad, medium, –NH), 1692 cm−1 (strong, sharp, –CO–); 1H
NMR (DMSO/d6/TMS) δ 4.50 (s, 2H, –CH2), 7.05–8.39 (m, 12H, Ar–H), 8.62 (s, 1H,
–CH, α-proton to enamine nitrogen), 12.20 (s, 1H, pyridine –NH, D2O exchangeable),
14.10 (s, 1H, benzimidazole – NH, D2O exchangeable); 13C NMR (DMSO d6/TMS): δ
37.29, 111.71, 112.06, 114.91, 124.76, 126.08, 126.42, 126.80, 127.41, 128.02, 128.23,
128.47, 128.56, 132.59, 139.53, 142.94, 144.23, 150.08, 150. 42, 162.66, 164.10, 176.24,
176.54; MS: m/z 452 [M+H]+. Anal. Calcd for C24H17N7OS: C, 63.84; H, 3.80; N, 21.72.
Found: C, 63.80; H, 3.77; N, 21.70.
◦
12b (i.e., 12, X = Br, R = H, R1 = H): Yield: 4.00 g (76%); m.p. >250 C; IR
(KBr): 3415–3100 cm−1 (broad, medium, –NH–), 1675 cm−1 (strong, sharp, –CO–); H
1
NMR (DMSO d6/TMS): δ 4.62 (s, 2H, –CH2), 7.06–8.39 (m, 11H, Ar–H), 8.55 (s, 1H,
–CH, α-proton to enamine nitrogen), 11.95 (s,1H, pyridine –NH, D2O exchangeable), 12.20
(s, 1H, benzimidazole –NH, D2O exchangeable); MS: m/z 531 [M+H]+. Anal. Calcd for
C24H16 BrN7OS: C, 54.35; H, 3.04; N, 18.49. Found: C, 54.30; H, 2.98; N, 18.46.
12c (i.e., 12, X = H, R = CH3, R1 = H): Yield: 3.35 g (72%); m.p. 242–244
◦C; IR (KBr): 3490–3050 cm−1 (broad, medium, –NH–), 1666 cm−1 (strong, sharp, –CO–
stretching); 1H NMR (DMSO d6/TMS): δ 1.23 (s, 3H, –CH3), 4.68 (s, 2H, –CH2), 7.16–8.39
(m, 11H, Ar–H), 8.57 (s, 1H, –CH, α-proton to enamine nitrogen), 11.55 (s, 1H, pyridine
–NH, D2O exchangeable), 12.99 (s, 1H, benzimidazole – NH, D2O exchangeable); MS:
m/z 466 [M+H]+. Anal. Calcd for C25H19N7OS: C, 64.50; H, 4.11; N, 21.06. Found: C,
64.47; H, 4.02; N, 21.00.
12d (i.e., 12, X = Br, R = CH3, R1 = H): Yield: 3.70 g (69%); m.p. 246–248 ◦C;
IR (KBr): 3410–3218 cm−1 (broad, medium, –NH–), 1690 cm−1 (strong, sharp, –CO–);
1H NMR (DMSO d6/TMS): δ 1.14 (s, 3H, –CH3), 4.54 (s, 2H, –CH2), 7.16–8.23 (m, 10H,
Ar–H), 8.59 (s, 1H, –CH, α-proton to enamine nitrogen), 11.25 (s, 1H, pyridine –NH,
D2O exchangeable), 12.45 (s, 1H, benzimidazole –NH, D2O exchangeable); MS: m/z 545
[M+H]+. Anal. Calcd for C25H18 BrN7OS: C, 55.15; H, 3.33; N, 18.01. Found: C, 55.12;
H, 3.29; N, 17.96.
12e (i.e., 12, X = H, R = H, R1 = Cl): Yield: 3.88 g (80%); m.p. >250 ◦C; IR (KBr)
1
3455–3110 cm−1 (broad, medium, –NH), 1690 cm−1 (strong, sharp, –CO–); H NMR

SYNTHESIS OF NAPHTHYRIDINE-APPENDED-1,2,4-TRIAZOLE DERIVATIVES
719
(DMSO/d6/TMS) δ 4.56 (s, 2H, –CH2), 7.15–8.40 (m, 11H, Ar–H), 8.60 (s, 1H, –CH,
α-proton to enamine nitrogen), 12.00 (s, 1H, pyridine –NH, D2O exchangeable), 13.20
(s, 1H, benzimidazole –NH, D2O exchangeable); MS: m/z 486 [M+H]+. Anal. Calcd for
C24H16 ClN7OS: C, 59.32; H, 3.32; N, 20.18. Found: C, 59.30; H, 3.31; N, 20.15.
◦
12f (i.e., 12, X = Br, R = H, R1 = Cl): Yield: 4.62 g (82%); m.p. >250 C; IR
(KBr): 3315–3087 cm−1 (broad, medium, –NH–), 1680 cm−1 (strong, sharp, –CO–); H
1
NMR (DMSO d6/TMS): δ 4.58 (s, 2H, –CH2), 7.25–8.35 (m, 10H, Ar–H), 8.50 (s, 1H,
–CH, α-proton to enamine nitrogen), 11.90 (s,1H, pyridine –NH, D2O exchangeable), 12.65
(s, 1H, benzimidazole –NH, D2O exchangeable); MS: m/z 565 [M+H]+. Anal. Calcd for
C24H15 BrClN7OS: C, 51.03; H, 2.68; N, 17.36. Found: C, 51.00; H, 2.66; N, 17.33.
12g (i.e., 12, X = H, R = CH3, R1 = Cl): Yield: 3.60 g (72%); m.p. 239–240
◦C; IR (KBr): 3410–3034 cm−1 (broad, medium, –NH–), 1696 cm−1 (strong, sharp, –CO–
stretching); 1H NMR (DMSO d6/TMS): δ 1.21 (s, 3H, –CH3), 4.63 (s, 2H, –CH2), 7.10–8.45
(m, 10H, Ar–H), 8.55 (s, 1H, –CH, α-proton to enamine nitrogen), 11.00 (s, 1H, pyridine
–NH, D2O exchangeable), 13.15 (s, 1H, benzimidazole –NH, D2O exchangeable); MS:
m/z 500 [M+H]+. Anal. Calcd for C25H18 ClN7OS: C, 60.06; H, 3.63; N, 19.61. Found: C,
60.04; H, 4.00; N, 18.98.
◦
12h (i.e., 12, X = Br, R = CH3, R1 = Cl): Yield: 4.68 g (81%); m.p. >250 C;
IR (KBr): 3210–2987 cm−1 (broad, medium, –NH–), 1691 cm−1 (strong, sharp, –CO–);
1H NMR (DMSO d6/TMS): δ 1.16 (s, 3H, –CH3), 4.50 (s, 2H, –CH2), 7.16–8.26 (m,
9H, Ar–H), 8.52 (s, 1H, –CH, α-proton to enamine nitrogen), 11.55 (s,1H, pyridine –NH,
D2O exchangeable), 12.50 (s,1H, benzimidazole –NH, D2O exchangeable); MS: m/z 579
[M+H]+. Anal. Calcd for C25H17BrClN7OS: C, 51.87; H, 2.96; N, 16.94. Found: C, 51.85;
H, 2.93; N, 16.91.
Alternate Synthesis of 12 from 7 and 13
A mixture of 7 (10 mM), 13 (10 ◦mM), DMF (20 mL), and K2CO3 was heated in a
temperature controlled oil-bath at 120 C for 2 h. At the end of this period, the reaction
mixture was cooled to RT and diluted with water (20 mL). The separated solid was filtered,
washed with water (20 mL) and dried. The crude product was recrystallized from ethanol
to obtain pure 12.
Preparation of 14 from 13
To a suspens◦ion of 13 (10 mM) in acetic acid (20 mL) was added H2O2 (30%)
drop-wise at 5–10 C. After completion of addition, the reaction mixture was heated on
water-bath at 100 ◦C for 6 h. At the end of this period, the reaction mixture was poured into
ice-cold water (25 mL). The separated solid was filtered, washed with water (50 mL) and
dried. The crude product was recrystallized from hot ethanol to obtain pure 14.
14a (i.e., 14, X = H, R = H, R1 = H): Yield: 2.95 g (61%); m.p. 162–164 ◦C; IR (KBr)
3470–2999 cm−1 (broad, medium, –NH), 1662 cm−1 (strong, sharp, –CO–), 1332 and 1127
cm−1 (strong, sharp, twin peaks due to symmetric and asymmetric stretching vibrations
of –SO2 grouping); 1H NMR (DMSO/d6/TMS) δ 4.40 (s, 2H, –CH2), 7.00–8.40 (m, 12H,
Ar–H), 9.15 (s, 1H, –CH, α-proton to enamine nitrogen), 10.40 (s, 1H, pyridine –NH, D2O
exchangeable), 11.00 (s, 1H, benzimidazole –NH, D2O exchangeable); 13C NMR (DMSO
d6/TMS): δ 55.38, 111.87, 118.18, 121.00, 121.71, 123.79, 125.90, 126.72, 126.84, 127.36,
127.51, 130.65, 133.74, 137.67, 139.41, 145.45, 148.19, 148.93, 150.08, 150.42, 162.66,

720
P. VENKATESHWARLU ET AL.
172.22, 176.54, 176.82; MS: m/z 484 [M+H]+. Anal. Calcd for C24H17N7O3S: C, 59.62;
H, 3.54; N, 20.28. Found: C, 59.58; H, 3.49; N, 20.20.
14b (i.e., 14, X = Br, R = H, R1 = H): Yield: 3.60 g (65%); m.p. 210–212 ◦C; IR
(KBr): 3443–3150 cm−1 (broad, medium, –NH–), 1675 cm−1 (strong, sharp, –CO–), 1334
and 1128 cm−1 (strong, sharp, due to symmetric and asymmetric stretching vibrations of
–SO2– grouping); 1H NMR (DMSO d6/TMS): δ 4.68 (s, 2H, –CH2), 7.12–8.43 (m, 11H,
Ar–H), 8.54 (s, 1H, –CH), 11.55 (s, 1H, pyridine –NH, D2O exchangeable), 12.55 (s, 1H,
benzimidazole –NH, D2O exchangeable); MS: m/z 563 [M+H]+. Anal. Calcd for C24H16
BrN7O3S: C, 51.25; H, 2.87; N, 17.43. Found: C, 51.20; H, 2.81; N, 17.38.
◦
14c (i.e., 14, X = H, R = CH3, R1 = H): Yield: 3.28 g (66%); m.p. 194–196 C;
IR (KBr): 3450–3100 cm−1 (broad, medium, –NH–), 1696 cm−1 (strong, sharp, –CO–),
1345 and 1129 cm−1 (strong, sharp, due to symmetric and asymmetric stretching vibrations
1
of –SO2– grouping); H NMR (DMSO d6/TMS): δ 1.46 (s, 3H, –CH3), 4.62 (s, 2H,
–CH2), 7.10–8.25 (m, 11H, Ar–H), 8.61 (s, 1H, –CH), 11.25 (s, 1H, pyridine –NH, D2O
exchangeable), 13.15 (s, 1H, benzimidazole – NH, D2O exchangeable); MS: m/z 498
[M+H]+. Anal. Calcd for C25H19N7O3S: C, 60.35; H, 3.85; N, 19.71. Found: C, 60.30; H,
3.81; N, 19.67.
14d (i.e., 14, X = Br, R = CH3, R1 = H): Yield: 3.90 g (68%); m.p. 206–208 ◦C; IR
(KBr): 3505–3150 cm−1 (broad, medium, –NH–), 1690 cm−1 (strong, sharp, –CO–), 1332
and 1124 cm−1 (strong, sharp, due to symmetric and asymmetric stretching vibrations of
–SO2– grouping); 1H NMR (DMSO d6/TMS): δ 1.26 (s, 3H, –CH3), 4.54 (s, 2H, –CH2),
7.16–8.23 (m, 10H, Ar–H), 8.54 (s, 1H, –CH), 11.55 (s,1H, pyridine –NH, D2O exchange-
able), 12.99 (s, 1H, benzimidazole –NH, D2O exchangeable); MS: m/z 577 [M+H]+. Anal.
Calcd for C25H18BrN7O3S: C, 52.09; H, 3.15; N, 17.01. Found: C, 52.06; H, 3.10; N, 16.97.
14e (i.e., 14, X = H, R = H, R1 = Cl): Yield: 3.60 g (70%); m.p. 189–191 ◦C; IR
(KBr) 3460–3114 cm−1 (broad, medium, –NH), 1670 cm−1 (strong, sharp, –CO–), 1330
and 1125 cm−1 (strong, sharp, twin peaks due to symmetric and asymmetric stretching
vibrations of –SO2 grouping); 1H NMR (DMSO/d6/TMS) δ 4.36 (s, 2H, –CH2), 7.10–8.41
(m, 11H, Ar–H), 9.11 (s, 1H, –CH, α-proton to enamine nitrogen), 10.55 (s, 1H, pyridine
–NH, D2O exchangeable), 11.10 (s, 1H, benzimidazole –NH, D2O exchangeable); MS:
m/z 518 [M+H]+. Anal. Calcd for C24H16 ClN7O3S: C, 55.65; H, 3.11; N, 18.93. Found:
C, 55.62; H, 3.10; N, 18.90.
14f (i.e., 14, X = Br, R = H, R1 = Cl): Yield: 4.35 g (73%); m.p. 210–212 ◦C; IR
(KBr): 3323–3125 cm−1 (broad, medium, –NH–), 1685 cm−1 (strong, sharp, –CO–), 1332
and 1130 cm−1 (strong, sharp, due to symmetric and asymmetric stretching vibrations of
–SO2– grouping); 1H NMR (DMSO d6/TMS): δ 4.63 (s, 2H, –CH2), 7.10–8.40 (m, 10H,
Ar–H), 8.55 (s, 1H, –CH, α-proton to enamine nitrogen), 11.33 (s, 1H, pyridine –NH,
D2O exchangeable), 12.55 (s, 1H, benzimidazole –NH, D2O exchangeable); MS: m/z 597
[M+H]+. Anal. Calcd for C24H15 BrClN7O3S: C, 48.30; H, 2.53; N, 16.43. Found: C,
48.28; H, 2.50; N, 16.41.
14g (i.e., 14, X = H, R = CH3, R1 = Cl): Yield: 3.66 g (69%); m.p. 196–198 ◦C; IR
(KBr): 3430–3120 cm−1 (broad, medium, –NH–), 1699 cm−1 (strong, sharp, –CO–), 1340
and 1127 cm−1 (strong, sharp, due to symmetric and asymmetric stretching vibrations of
–SO2– grouping); 1H NMR (DMSO d6/TMS): δ 1.43 (s, 3H, –CH3), 4.60 (s, 2H, –CH2),
7.15–8.20 (m, 10H, Ar–H), 8.60 (s, 1H, –CH, α-proton to enamine nitrogen), 11.21 (s, 1H,
pyridine –NH, D2O exchangeable), 13.55 (s, 1H, benzimidazole –NH, D2O exchangeable);
MS: m/z 532 [M+H]+. Anal. Calcd for C25H18ClN7O3S: C, 56.44; H, 3.41; N, 18.43. Found:
C, 56.41; H, 3.40; N, 18.42.

SYNTHESIS OF NAPHTHYRIDINE-APPENDED-1,2,4-TRIAZOLE DERIVATIVES
721
14h (i.e., 14, X = Br, R = CH3, R1 = Cl): Yield: 4.57 g (75%); m.p. 221–223 ◦C; IR
(KBr): 3420–3105 cm−1 (broad, medium, –NH–), 1695 cm−1 (strong, sharp, –CO–), 1343
and 1128 cm−1 (strong, sharp, due to symmetric and asymmetric stretching vibrations of
–SO2– grouping); 1H NMR (DMSO d6/TMS): δ 1.24 (s, 3H, –CH3), 4.51 (s, 2H, –CH2),
7.18–8.29 (m, 9H, Ar–H), 8.75 (s, 1H, –CH, α-proton to enamine nitrogen), 11.10 (s,1H,
pyridine –NH, D2O exchangeable), 13.10 (s,1H, benzimidazole –NH, D2O exchangeable);
MS: m/z 611 [M+H]+. Anal. Calcd for C25H17BrClN7O3S: C, 49.15; H, 2.81; N, 16.05.
Found: C, 49.11; H, 2.78; N, 16.03.
CONCLUSION
In conclusion, herein this communication, we report, a simple, efficient, and alternate
methods for the synthesis of naphthyridinoyl-[1,2,4] triazoles and their subsequent products
using different conditions and their oxidation studies in good yields.
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