Efficient synthesis of 1,2,4-triazolo[4,3-a][1,8]naphthyridines under microwave irradiation

Article abstract of DOI:10.1002/jhet.33

A simple and highly efficient procedure has been described for the synthesis of 6-aryl-9-(4-phenox-phenyl)-1,2,4-triazolo [4,3-a] [1,8] napthyridines (4) by the oxidation of 4-phenoxybenzaldehyde 3-aryl-1,8- naphthyridin-2-ylhydrazones (3) with chloramine

Full text of DOI:10.1002/jhet.33

124
Efficient Synthesis of 1,2,4-Triazolo[4,3-a][1,8]naphthyridines
Under Microwave Irradiation
Vol 46
K. Mogilaiah,* T. Kumara Swamy, and K. Shiva Kumar
Department of Chemistry, Kakatiya University, Warangal 506 009, Andhra Pradesh, India
*E-mail: mogilaiah_k@yahoo.co.in
Received January 23, 2008
DOI 10.1002/jhet.33
Published online 11 February 2009 in Wiley InterScience (www.interscience.wiley.com).
A simple and highly efficient procedure has been described for the synthesis of 6-aryl-9-(4-phenox-
phenyl)-1,2,4-triazolo [4,3-a] [1,8] napthyridines (4) by the oxidation of 4-phenoxybenzaldehyde 3-aryl-
1,8-naphthyridin-2-ylhydrazones (3) with chloramines-T in methanol under microwave irradiation. The
products were obtained in very good yields and excellent purities.
J. Heterocyclic Chem., 46, 124 (2009).
Scheme 1
INTRODUCTION
1,8-Naphthyridines constitute an important class of
compounds possessing diverse biological activities [1–3].
Various 1,2,4-triazoles have been extensively explored
for their applications in the field of biological and phar-
macological activities [4–6]. Therefore, it was envisaged
that chemical entities with both 1,8-naphthyridine and
1,2,4-triazole might result in compounds with interesting
biological activity. Microwave-assisted organic synthesis
has attracted considerable attention in recent years [7–
10], due to enhanced reaction rates, high yields, improved
selectivity, and cleaner products. Several methods have
been developed for performing reactions with microwave
irradiation in solution and under solvent-free conditions,
but a homogeneous mixture is preferred to obtain uniform
heating. The solvents with higher dielectric constants are
superheated and the reactions take place rapidly. Chlor-
amine-T (CAT) is a very versatile oxidizing agent and is
of much importance in its synthetic utility [11,12]. In
view of this and in continuation of our interest in micro-
wave-assisted organic transformations on 1,8-napthyridine
derivatives [13–17], we report herein, a convenient, prac-
tical and efficient method for the synthesis of 1,2,4-tria-
zolo[4,3-a][1,8] naphthyridines using CAT in methanol
under microwave irradiation.
C
V
2009 HeteroCorporation

January 2009
Efficient Synthesis of 1,2,4-Triazolo[4,3-a][1,8]naphthyridines
Under Microwave Irradiation
125
RESULTS AND DISCUSSION
The structural assignments of compounds 3 and 4
were based on their spectroscopic (IR and 1H NMR;
Table 1) and analytical data (Table 2).
Condensation of 3-aryl-2-hydrazino-1,8-napthyridines
(1) with 4-phenoxybenzaldehyde (2) in the presence of
catalytic amount of DMF under microwave irradiation
afforded the respective 4-phenoxybenzaldehyde 3-aryl-
1,8-napthyridin-2-ylhydrazones (3) in excellent yields.
Oxidative cyclization of hydrazones 3 with CAT in
methanol under microwave irradiation resulted in the for-
mation of 6-aryl-9-(4-phenoxyphenyl)-1,2,4-triazolo-[4,3-
a][1,8]naphthyridines (4). The oxidative transformation is
clean and efficient. The experimental procedure is very
simple. The high yield transformation did not form any
undesirable by-products. Furthermore, the products were
obtained with a higher degree of purity by this procedure
and in most cases no further purification was needed.
Interestingly, this oxidative reaction proceeds only to a
minor extent (5–8% in 3.5–4.5 min) when conducted
under conventional conditions in an oil-bath preheated to
110ꢀC (temperature measured at the end of exposure dur-
ing microwave experiment) which confirms the rate aug-
mentation during microwave heating (Scheme 1).
The significant advantages of this procedure are
operational simplicity, short reaction time, pure
products, inexpensive, and nontoxicity of the reagent
and high yields.
EXPERIMENTAL
Melting points were measured on a Cintex melting point ap-
paratus and are uncorrected. The purity of the compounds was
checked using precoated TLC plates (Merk, 60F-254). IR spec-
tra (KBr) (mmax: cmꢁ1) were recorded on a Perkin-Elmer BX
series FTIR spectrophotometer. 1H NMR spectra were
recorded on a Varian Gemini 200 MHz spectrometer (Chemi-
cal shifts in d, ppm) using TMS as internal standard. Micro-
analyses were performed on a Perkin-Elmer 240 CHN elemen-
tal analyzer. Microwave irradiation was carried out in a
domestic microwave oven (LG MG 556p, 2450 MHz). The
starting compounds 1 were prepared according to our reported
Table 1
IR and 1H NMR spectral data of 4-phenoxybenzaldehyde 3-aryl-1,8-naphthyridin-2-ylhydrazones (3) and
6-aryl-9-(4-phenoxyphenyl)-1,2,4-triazolo-[4,3-a][1,8]naphthyridines (4).
Compd
IR cmꢁ1 (KBr)
1H NMR (d, ppm) (CDCl3)
3a
3377 (NH), 1623 (C¼N)
7.63 (m, 2H, C4AH, C6AH), 7.82 (m, 1H, C5AH), 8.44 (m, 1H, C7AH), 8.59 (s, 1H, N¼CH),
6.92A7.50 (m, 15H, NH, 14ArAH)
3b
3c
3d
3e
3f
3330 (NH), 1622 (C¼N)
3431 (NH), 1627 (C¼N)
3390 (NH), 1625 (C¼N)
3425 (NH), 1623 (C¼N)
3360 (NH), 1628 (C¼N)
3353 (NH), 1625 (C¼N)
3345 (NH), 1626 (C¼N)
3360 (NH), 1626 (C¼N)
3.90 (s, 3H, OCH3), 7.92 (m, 2H, C4AH, C6AH), 8.15 (m, 1H, C5AH), 8.52 (m, 1H, C7AH),
8.85 (s, 1H, N¼CH), 6.95–7.72 (m, 14H, NH, 13ArAH)
7.60 (m, 2H, C4AH, C6AH), 7.78 (m, 1H, C5AH), 8.45 (m, 1H, C7AH), 8.59 (s, 1H, N¼CH),
6.90–7.38 (m, 14H, NH, 13ArAH)
7.65 (m, 2H, C4AH, C6AH), 7.87 (m, 1H, C5AH), 8.53 (m, 1H, C7AH), 8.65 (s, 1H, N¼CH),
6.92–7.45 (m, 14H, NH, 13ArAH)
7.62 (m, 2H, C4AH, C6AH), 7.89 (m, 1H, C5AH), 8.43 (m, 1H, C7AH), 8.62 (s, 1H, N¼CH),
6.91–7.40 (m, 14H, NH, 13ArAH)
7.67 (m, 2H, C4AH, C6AH), 7.80 (m, 1H, C5AH), 8.25 (m, 1H, C7AH), 8.78 (s, 1H, N¼CH),
6.90–7.43 (m, 14H, NH, 13ArAH)
3g
3h
3i
7.65 (m, 2H, C4AH, C6AH), 7.85 (m, 1H, C5AH), 8.47 (m, 1H, C7AH), 8.66 (s, 1H, N¼CH),
6.92–7.45 (m, 14H, NH, 13ArAH)
7.60 (m, 2H, C4AH, C6AH), 7.88 (m, 1H, C5AH), 8.14 (m, 1H, C7AH), 8.63 (s, 1H, N¼CH),
6.88–7.42 (m, 14H, NH, 13ArAH)
7.75 (m, 2H, C4AH, C6AH), 8.00 (m, 1H, C5AH), 8.22 (m, 1H, C7AH), 8.78 (s, 1H, N¼CH),
6.91–7.43 (m, 14H, NH, 13ArAH)
4a
4b
1603 (C¼N)
1608 (C¼N)
8.12 (m, 3H, C3AH, C4AH, C5AH), 8.45 (m, 1H, C2AH), 7.02–7.70 (m, 14H, ArAH)
3.89 (s, 3H, OCH3), 8.10 (m, 3H, C3AH, C4AH, C5AH), 8.40 (m, 1H, C2AH),
7.00–7.65 (m, 13H, ArAH)
4c
4d
4e
4f
1605 (C¼N)
1608 (C¼N)
1604 (C¼N)
1605 (C¼N)
1610 (C¼N)
7.70 (m, 2H, C3AH, C5AH), 8.15 (m, 1H, C4AH), 8.50 (m, 1H, C2AH),
7.02–7.52 (m, 13H, ArAH)
7.82 (m, 2H, C3AH, C5AH), 8.20 (m, 1H, C4AH), 8.48 (m, 1H, C2AH),
7.00–7.54 (m, 13H, ArAH)
7.78 (m, 2H, C3AH, C5AH), 8.18 (m, 1H, C4AH), 8.45 (m, 1H, C2AH),
7.02–7.56 (m, 13H, ArAH)
7.63 (m, 1H, C3AH), 8.05 (m, 1H, C5AH), 8.15 (m, 1H, C4AH), 8.47 (m, 1H, C2AH),
7.00–7.53 (m, 13H, ArAH)
7.80 (m, 2H, C3AH, C5AH), 8.16 (m, 1H, C4AH), 8.45 (m, 1H, C2AH),
7.02–7.66 (m, 13H, ArAH)
4g
4h
4i
1606 (C¼N)
1607 (C¼N)
8.13 (m, 3H, C3AH, C4AH, C5AH), 8.44 (m, 1H, C2AH), 7.00–7.65 (m, 13H, ArAH)
8.20 (m, 3H, C3AH, C4AH, C5AH), 8.48 (m, 1H, C2AH), 7.03A7.82 (m, 13H, ArAH)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

126
K. Mogilaiah, T. K. Swamy, and K. S. Kumar
Vol 46
Table 2
Physical and analytical data of 4-phenoxybenzaldehyde 3-aryl-1,8-naphthyridin-2-ylhydrazones (3) and
6-aryl-9-(4-phenoxyphenyl)-1,2,4-triazolo-[4,3-a][1,8]naphthyridines (4).
Elemental analysis Found/(Calcd)
Compd
Reaction time (min)
MP (ꢀC)
Yield (%)
Mol. formula
C
H
N
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
4h
4i
1.0
1.5
1.0
1.5
1.0
1.0
1.5
1.5
1.5
3.5
4.5
4.0
4.0
3.5
3.5
4.0
3.5
4.5
170–172
156–158
152–153
145–147
159–160
172–174
148–150
162–163
140–142
208–210
200–202
228–230
214–216
230–232
206–208
210–212
238–240
218–220
95
94
93
92
96
93
94
95
94
90
87
86
85
92
87
86
90
89
C27H20N4O
77.75 (77.89)
75.50 (75.34)
71.77 (71.92)
71.78 (71.92)
71.76 (71.92)
74.81 (74.65)
74.79 (74.65)
74.80 (74.65
69.58 (69.42)
78.41 (78.26)
75.83 (75.68)
72.40 (72.24)
72.38 (72.24)
72.39 (72.24)
75.15 (75.00)
75.16 (75.00)
75.14 (75.00)
69.86 (69.71)
4.86 (4.81)
4.97 (4.93)
4.26 (4.22)
4.28 (4.22)
4.27 (4.22)
4.43 (4.38)
4.44 (4.38)
4.42 (4.38)
3.98 (3.93)
4.40 (4.35)
4.60 (4.50)
3.84 (3.79)
3.85 (3.79)
3.84 (3.79)
3.99 (3.94)
3.98 (3.94)
3.99 (3.94)
3.57 (3.53)
13.53 (13.46)
12.64 (12.56)
12.50 (12.43)
12.49 (12.43)
12.51 (12.43)
12.98 (12.90)
12.97 (12.90)
12.96 (12.90)
11.66 (11.57)
13.61 (13.53)
12.70 (12.61)
12.56 (12.49)
12.58 (12.49)
12.57 (12.49)
13.05 (12.96)
13.04 (12.96)
13.03 (12.96)
11.69 (11.62)
C28H22N4O2
C27H19ClN4O
C27H19ClN4O
C27H19ClN4O
C27H19FN4O
C27H19FN4O
C27H19FN4O
C28H19F3N4O
C27H18N4O
C28H20N4O2
C27H17ClN4O
C27H17ClN4O
C27H17ClN4O
C27H17FN4O
C27H17FN4O
C27H17FN4O
C28H17F3N4O
[2] Ferrarini, P. L.; Badawneh, M.; Franconi, F.; Manera, C.;
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procedures [16–20]. The 4-phenoxylbenzaldehyde (2) was pur-
chased from Aldrich Chemical Company.
General procedure for the synthesis of 4-phenoxybenzal-
dehyde 3-aryl-1,8-naphthyridin-2-ylhydrazones (3). A mix-
ture of 1 (20.0 mmol), 4-phenoxy-benzaldehyde (2, 20.0 mmol)
and DMF (5 drops) was subjected to microwave irradiation at
400 watts intermittently at 30 s intervals for the specified time
(Table 2). On completion of reaction, as monitored by TLC, the
reaction mixture was cooled and treated with cold water. The
resulting solid product was collected by filtration, washed with
water and re-crystallized from ethanol to give 3 (Table 2).
General procedure for the synthesis of 6-aryl-9-(4-phen-
oxyphenyl)-1,2,4-triazolo[4,3-a][1,8]napthyridines (4). To a
solution of appropriate hydrazone 4 (20.0 mmol) in methanol
(15 mL), CAT (20.0 mmol) was added. The reaction mixture
was exposed to microwaves at 400 watts intermittently at 30 s
intervals for specified time (Table 2). After complete conver-
sion as indicated by TLC, the reaction mixture was cooled and
digested with cold water. The solid then obtained was col-
lected by filtration, washed with water and re-crystallized from
ethanol to afford 4 (Table 2).
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Acknowledgments. The authors thank the Directors, IICT,
Hyderabad and IITM, Chennai, India for providing spectral and
analytical data.
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1996, 35B, 106.
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2002, 32, 2377.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet