Iodobenzene diacetate on alumina: Efficient synthesis of 1,3,4-oxadiazolyl-1,8-naphthyridines in solventless system using microwaves

Article abstract of DOI:10.1002/jhet.5570430235

1-(5-Aryl-[1,3,4]oxadiazol-2-ylmethyl)-3-(p-methoxyphenyl)-1H-[1,8] naphthyridin-2-ones (5) were synthesized by the oxidative cyclization of [2-oxo-3-(p-methoxyphenyl)-2H-[1,8]naphthyridin-1-yl]acetic acid arylidene-hydrazides (4) with alumina-supported i

Full text of DOI:10.1002/jhet.5570430235

Mar-Apr 2006
485
Iodobenzene Diacetate on Alumina: Efficient Synthesis of
1,3,4-Oxadiazolyl-1,8-naphthyridines in Solventless System
Using Microwaves
K. Mogilaiah*, J. Uma Rani, B. Sakram and N. Vasudeva Reddy
Department of Chemistry, Kakatiya University
Warangal – 506 009, India
E-mail : mogilaiah_k@yahoo.co.in
1-(5-Aryl-[1,3,4]oxadiazol-2-ylmethyl)-3-(p-methoxyphenyl)-1H-[1,8]naphthyridin-2-ones (5) were
synthesized by the oxidative cyclization of [2-oxo-3-(p-methoxyphenyl)-2H-[1,8]naphthyridin-1-yl]acetic
acid arylidene-hydrazides (4) with alumina-supported iodobenzene diacetate (IBD) in solvent-free
conditions under microwave irradiation. The products are obtained in good yields and in a state of high
purity.
J. Heterocyclic Chem., 43, 485 (2006).
Introduction.
phenyl)-2H-[1,8]naphthyridin-1-yl]acetic acid aryl-
idenehydrazides (4).
The 1,3,4-oxadiazole [1-3] and 1,8-naphthyridine [4-6]
classes of heterocycles are of current interest due to their
broad spectrum biological activity. In recent years, the
organic reactions on solid supports [7,8] and assisted by
microwaves [9-11] in particular, have gained special
attention because of their enhanced selectivity, milder
reaction conditions and associated ease of manipulation. In
view of this and in continuation of our work on microwave
assisted organic transformation on 1,8-naphthyridine
derivatives [12-15] we now report an efficient and high
yielding protocol for the synthesis of 1,3,4-oxadiazolyl-1,8-
naphthyridines (5) using Al2O3-PhI(OAc)2 under solvent-
free conditions and microwave irradiation.
Oxidative cyclization of hydrazones 4 with alumina-
supported IBD (Al2O3-PhI(OAc)2) [17] under microwave
irradiation afforded the respective 1-(5-aryl-[1,3,4]-
oxadiazol-2-ylmethyl)-3-(p-methoxyphenyl)-1H-[1,8]-
naphthyridin-2-ones (5).
The reaction proceeded
smoothly providing good yield of the corresponding
1,3,4-oxadiazole as shown in the Table 1. The oxidative
transformation is clean and efficient and is devoid of any
by-products. Furthermore, the products obtained are of
high purity by this procedure and no further purification
was needed. The experimental procedure is very simple.
The recyclability of the alumina support renders this
process into truly ecofriendly green protocol.
Results and Discussion.
Interestingly, this reaction proceeds only to a
minor extent (9-15% in 5.0-7.0 minutes) when
conducted under conventional conditions in an oil-
bath preheated to 125 °C (temperature measured at
the end of exposure during microwave experiment),
which confirms the rate increase during microwave
heating.
Alkylation of 1,2-dihydro-3-(p-methoxyphenyl)-1,8-
naphthyridin-2-one (1) [16] with ethyl chloroacetate in
DMF in the presence of anhydrous K2CO3 under
microwave irradiation afforded ethyl [2-oxo-3-(p-
methoxyphenyl)-2H-[1,8]naphthyridin-1-yl]acetate (2).
The ester 2 on hydrazinolysis with refluxing hydrazine
hydrate furnished [2-oxo-3-(p-methoxyphenyl)-2H-
[1,8]naphthyridin-1-yl]acetic acid hydrazide (3).
Condensation of hydrazide 3 with various aromatic
aldehydes in the presence of a catalytic amount of DMF
under microwave irradiation resulted in the formation of
the corresponding hydrazones, [2-oxo-3-(p-methoxy-
The structural assignments to these compounds 2-5
1
were based on their spectroscopic (IR and H NMR) and
analytical data. To the best of our knowledge this is the
first report on the alumina-supported IBD mediated
synthesis of 1,3,4-oxadiazoles under solvent-free
conditions and microwave irradiation.

486
K. Mogilaiah*, J. Uma Rani, B. Sakram and N. Vasudeva Reddy
Vol 43
Scheme 1
OCH3
OCH3
DMF/K2CO3
ClCH2COOC2H5
+
MW
N
N
H
O
N
N
O
CH2COOC2H5
(1)
(2)
OCH3
OCH3
Ar-CHO
MW
N2H4.H2O
EtOH
N
N
O
N
N
O
CH2CONHN CH Ar
CH2CONHNH2
(4a-h)
(3)
OCH3
PhI(OAc)2-Al2O3
MW
N
N
O
N
N
CH2
O
Ar
(5a - h)
Compounds
4 and 5
Compounds
4 and 5
Ar
Ar
a
b
c
C6H5
p-CH3C6H4
p-CH3OC6H4
o-ClC6H4
e
f
g
h
p-ClC6H4
o-BrC6H4
m-NO2C6H4
3,4-(O-CH2-O)C6H3
d
chloroacetate (0.244 g, 20.0 mmol), anhydrous K2CO3
(0.196 g, 20.0 mmol) and DMF (15 ml) was exposed to
microwave irradiation at 400 watts intermittently at 30 sec
intervals for 4.0 minutes. After completion of the reaction,
as indicated by TLC, the reaction was cooled and treated
In conclusion, we have demonstrated a convenient,
efficient, simple and mild procedure for the synthesis of
1,3,4-oxadiazoles using Al2O3-PhI(OAc)2 in solvent-free
conditions under microwave irradiation. In addition, high
yield, short reaction time, pure products, simpler work-up
and environmental acceptability are worthy advantages of
this method.
with chilled water.
The solid that precipitated was
collected by filtration, washed with water and recrystallized
from ethanol to afford 0.331 g (98%) of pure 2, mp 130-132
°C; ir (potassium bromide): 1736 (C=O), 1644 (C=O), 1607
1
(C=N) cm-1; H nmr (CDCl3): δ 1.30 (t, J=7.0 Hz, 3H, CH3),
EXPERIMENTAL
3.89 (s, 3H, OCH3), 4.22 (q, J=7.0 Hz, 2H, CH2), 5.38 (s,
2H, N-CH2), 8.12 (s, 1H, C4-H), 8.55 (m, 1H, C5-H), 7.89
(m, H, C6-H), 9.13 (m, 1H, C7-H), 6.90-7.72 (m, 4H, Ar-H).
Anal. Calcd. for C19H18N2O4 : C, 67.46; H, 5.33; N, 8.28.
Found: C, 67.62; H, 5.38; N, 8.35.
The melting points were determined on a Cintex melting
point apparatus and are uncorrected. The purity of the
compounds was checked using precoated TLC plates (Merk,
60F-254). IR spectra were recorded as KBr pellets on a
Perkin-Elmer BX series FT-IR spectrophotometer. 1H NMR
were recorded on a Varian Gemini 200 MHz spectrometer
(chemical shifts in δ, ppm) using TMS as internal standard.
Elemental analyses were performed on a Perkin-Elmer 240
CHN elemental analyser. For microwave irradiation a
suitably designed LG MG 556P (2450 MHz) domestic
microwave oven was used [18].
Synthesis of [2-Oxo-3-(p-methoxyphenyl)-2H-[1,8]naphthy-
ridin-1-yl]acetic Acid Hydrazide (3).
A mixture of 2 (0.676 g, 20.0 mmol) and hydrazine
hydrate (0.17 g, 30.0 mmol) in ethanol (30 ml) was refluxed
on a water-bath for 5 hours. The reaction mixture was
concentrated to one third of its volume and cooled. The
resulting solid product was filtered and recrystallized from
ethanol to give 0.301 g (93%) of pure 3, mp 110-112 °C; ir
(potassium bromide): 3420, 3305, 3170, (NHNH2), 1648
Synthesis of Ethyl [2-Oxo-3-(p-methoxyphenyl)-2H-[1,8]naph-
thyridin-1-yl]-acetate (2).
1
(C=O), 1608 (C=N) cm-1; H nmr (CDCl3 + DMSO-d6): δ
A mixture of 1,2-dihydro-3-(p-methoxyphenyl)-1,8-
naphthyridin-2-one (1, 0.504 g, 20.0 mmol), ethyl
3.36 (br, 2H, NH2), 3.90 (s, 3H, OCH3), 5.30 (s, 2H, CH2),

Mar-Apr 2006
Efficient Synthesis of 1,3,4-Oxadiazolyl-1,8-naphthyridine
487
Table 1
Physical data of [2-Oxo-3-(p-methoxyphenyl)-2H-[1,8]naphthyridin-1-yl]acetic acid arylidenehydrazides (4) and 1-(5-Aryl-[1,3,4]oxadiazol-2-
ylmethyl)-3-(p-methoxy-phenyl)-1H-[1,8]naphthyridin-2-ones (5)
Compound
Reaction
time
(min)
M.P.
(°C)
Yield
(%)
Molecular
formula
Elemental analysis
Found / (Calcd)
H
C
N
4a
4b
4c
4d
4e
4f
1.5
1.0
1.5
1.5
1.0
1.5
1.0
1.5
5.5
5.0
6.0
6.0
5.5
6.5
7.0
6.0
170-172
140-42
198-200
218-220
161-163
229-231
220-222
200-202
>300
95
98
96
94
97
94
95
96
88
94
90
87
92
88
87
90
C24H20N4O3
C25H22N4O3
C25H22N4O4
C24H19N4O3Cl
C24H19N4O3Cl
C24H19N4O3Br
C24H19N5O5
C25H20N4O5
C24H18N4O3
C25H20N4O3
C25H20N4O4
C24H17N4O3Cl
C24H17N4O3Cl
C24H17N4O3Br
C24H17N5O5
C25H18N4O5
69.72
(69.90)
4.80
(4.85)
13.67
(13.59)
70.62
(70.42)
5.22
(5.16)
13.24
(13.15)
67.70
(67.87)
4.92
(4.98)
12.58
(12.67)
64.71
(64.50)
4.33
(4.26)
12.62
(12.54)
64.70
(64.50)
4.34
(4.26)
12.63
(12.54)
58.87
(58.66)
3.81
(3.87)
11.52
(11.41)
4g
4h
5a
5b
5c
5d
5e
5f
63.24
(63.02)
4.20
(4.16)
15.42
(15.32)
65.98
(65.79)
4.32
(4.39)
12.39
(12.28)
70.44
(70.24)
4.45
(4.39)
13.77
(13.66)
>300
70.96
(70.75)
4.76
(4.72)
13.30
(13.21)
>300
68.43
(68.18)
4.60
(4.55)
12.64
(12.73)
>300
64.98
(64.79)
3.86
(3.82)
12.71
(12.60)
>300
64.97
(64.79)
3.87
(3.82)
12.72
(12.60)
>300
58.74
(58.90)
3.53
(3.47)
11.56
(11.45)
5g
5h
>300
63.51
(63.30)
3.80
(3.74)
15.47
(15.38)
>300
66.29
(66.08)
3.91
(3.96)
12.45
(12.33)
Synthesis of 1-(5-Phenyl-[1,3,4]oxadiazol-2-ylmethyl)-3-(p-
methoxyphenyl) -1H-[1,8]naphthyridin-2-one (5a)
8.30 (m, 2H, C4-H, C5-H), 7.95 (m, 1H, C6-H), 9.10 (m, 1H,
C7-H), 6.92-7.78 (m, 4H, Ar-H), 9.40 (s, 1H, CONH).
Anal. Calcd. for C17H16N4O3 : C, 62.96; H, 4.94; N, 17.28.
Found: C, 62.81; H, 4.98; N, 17.36.
Compound 4a (0.824 g, 20.0 mmol) and IBD (0.71 g, 20.0
mmol) doped on neutral alumina (2 g) and mixed thoroughly and
subjected to microwave irradiation at 800 watts intermittently at 30
sec intervals for 5.5 minutes. After complete conversion as
indicated by TLC, the reaction mixture was cooled and extracted
into dichloromethane and is neutralized with aqueous sodium
bicarbonate solution. The dichloromethane layer is separated, dried
over magnesium sulfate, filtered, and the crude product was
recrystallized from methanol to give 0.36 g (88%) of pure 5a, mp
>300. Physical and spectral data of 5a are given in Table 1 and 2.
Other members of 5 are prepared by the same procedure.
Synthesis of [2-Oxo-3-(p-methoxyphenyl)-2H-[1,8]naphthy-
ridin-1-yl]acetic Acid Benzylidenehydrazide (4a).
A mixture of 3 (0.648 g, 20.0 mmol), benzaldehyde (0.212 g,
20.0 mmol) and DMF (5 drops) was subjected to microwave
irradiation at 200 watts intermittently at 30 sec intervals for 1.5
minutes. On completion of reaction, as monitored by TLC, the
reaction mixture was digested with cold water. The precipitate
thus obtained was collected by filtration, washed with water and
recrystallized from ethanol to furnish 0.392 g (95%) of pure 4a,
mp 170-172. Physical and spectral data of 4a are given in Tables
1 and 2. Other members of 4 are prepared by the same procedure.
Acknowledgements.
We are grateful to the Directors, IICT, Hyderabad and IIT,
Madras for providing spectral and analytical data.

488
K. Mogilaiah*, J. Uma Rani, B. Sakram and N. Vasudeva Reddy
Vol 43
Table 2
IR and 1H NMR spectral data of [2-Oxo-3-(p-methoxyphenyl)-2H-[1,8]naphthyridin-1-yl]acetic acid arylidenehydrazides (4) and 1-(5-Aryl-
[1,3,4]oxadiazol-2-ylmethyl)-3-(p-methoxyphenyl)-1H-[1,8]naphthyridin-2-ones (5)
Compound
IR cm-1
(KBr)
1H NMR (δ, ppm)
(CDCl3 / CDCl3 + DMSO-d6)
4a
4b
3438 (NH), 1692 (C=O), 3.92 (s, 3H, OCH3), 5.85 (s, 2H, CH2), 8.12 (m, 2H, C4-H, C5-H), 7.85 (m, 1H, C6-H), 8.20
1657 (C=O), 1609 (C=N) (m, 1H, C7-H), 8.63 (s, 1H, N=CH), 6.98-7.80 (m, 9H, Ar-H), 11.02 (s, 1H, CONH)
3436 (NH), 1694 (C=O), 2.40 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 5.80 (s, 2H, CH2), 8.15 (m, 2H, C4-H, C5-H), 7.84 (m,
1652 (C=O), 1609 (C=N) 1H, C6-H), 8.40 (m, 1H, C7-H), 8.60 (s, 1H, N=CH), 6.89-7.78 (m, 8H, Ar-H), 11.05 (s, 1H,
CONH)
4c
4d
4e
4f
3434 (NH), 1690 (C=O), 3.88 (s, 6H, 2xOCH3), 5.81 (s, 2H, CH2), 8.02 (m, 2H, C4-H, C5-H), 7.82 (m, 1H, C6-H),
1660 (C=O), 1605 (C=N) 8.32 (m, 1H, C7-H), 8.63 (s, 1H, N=CH), 6.82-7.78 (m, 8H, Ar-H), 11.06 (s, 1H, CONH)
3440 (NH), 1693 (C=O), 3.93 (s, 3H, OCH3), 5.76 (s, 2H, CH2), 8.22 (m, 2H, C4-H, C5-H), 8.01 (m, 1H, C6-H), 8.50
1658 (C=O), 1616 (C=N) (m, 1H, C7-H), 9.02 (s, 1H, N=CH), 6.92-7.83 (m, 8H, Ar-H), 11.70 (s, 1H, CONH)
3450 (NH), 1692 (C=O), 3.95 (s, 3H, OCH3), 5.78 (s, 2H, CH2), 8.00 (m, 2H, C4-H, C5-H), 7.81 (m, 1H, C6-H), 8.56
1659 (C=O), 1609 (C=N). (m, 1H, C7-H), 8.62 (s, 1H, N=CH), 6.87-7.73 (m, 8H, Ar-H), 11.52 (s, 1H, CONH)
3435 (NH), 1703 (C=O), 3.92 (s, 3H, OCH3), 5.93 (s, 2H, CH2), 8.26 (m, 2H, C4-H, C5-H), 8.00 (m, 1H, C6-H), 8.60
1652 (C=O), 1608 (C=N) (m, 1H, C7-H), 9.08 (s, 1H, N=CH), 6.98-7.82 (m, 8H, Ar-H), 11.08 (s, 1H, CONH)
3439 (NH), 1692 (C=O), 3.93 (s, 3H, OCH3), 5.82 (s, 2H, CH2), 8.21 (m, 2H, C4-H, C5-H), 7.99 (m, 1H, C6-H), 8.56
1652 (C=O), 1608 (C=N) (m, 1H, C7-H), 8.78 (s, 1H, N=CH), 6.92-7.83 (m, 8H, Ar-H), 11.62 (s, 1H, CONH)
3435 (NH), 1690 (C=O), 3.90 (s, 3H, OCH3), 5.86 (s, 2H, CH2), 6.02 (s, 2H, O-CH2-O), 8.26 (m, 2H, C4-H, C5-H),
1658 (C=O), 1609 (C=N) 7.86 (m, 1H, C6-H), 8.48 (m, 1H, C7-H), 8.67 (s, 1H, N=CH), 6.89-7.78 (m, 7H, Ar-H),
11.53 (s, 1H, CONH)
4g
4h
5a
5b
5c
5d
5e
5f
1658 (C=O), 1609 (C=N) 3.90 (s, 3H, OCH3), 6.10 (s, 2H, CH2), 8.18 (m, 2H, C4-H, C5-H), 7.90 (m, 1H, C6-H), 8.42
(m, 1H, C7-H), 6.90-7.69 (m, 9H, Ar-H)
1656 (C=O), 1605 (C=N) 2.42 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 6.02 (s, 2H, CH2), 8.23 (m, 2H, C4-H, C5-H), 8.02 (m,
1H, C6-H), 8.42 (m, 1H, C7-H), 6.92-7.86 (m, 8H, Ar-H)
1660 (C=O), 1604 (C=N) 3.90 (s, 6H, 2xOCH3), 6.00 (s, 2H, CH2), 8.20 (m, 2H, C4-H, C5-H), 7.98 (m, 1H, C6-H),
8.40 (m, 1H, C7-H), 6.90-7.85 (m, 8H, Ar-H)
1658 (C=O), 1607 (C=N) 3.92 (s, 3H, OCH3), 6.03 (s, 2H, CH2), 8.36 (m, 2H, C4-H, C5-H), 7.96 (m, 1H, C6-H), 8.48
(m, 1H, C7-H), 6.96-7.82 (m, 8H, Ar-H)
1665 (C=O), 1612 (C=N) 3.90 (s, 3H, OCH3), 5.98 (s, 2H, CH2), 8.32 (m, 2H, C4-H, C5-H), 7.95 (m, 1H, C6-H), 8.58
(m, 1H, C7-H), 6.93-7.84 (m, 8H, Ar-H)
1659 (C=O), 1610 (C=N) 3.88 (s, 3H, OCH3), 6.03 (s, 2H, CH2), 8.37 (m, 2H, C4-H, C5-H), 8.06 (m, 1H, C6-H), 8.48
(m, 1H, C7-H), 6.96-7.79 (m, 8H, Ar-H)
5g
5h
1658 (C=O), 1610 (C=N) 3.92 (s, 3H, OCH3), 6.08 (s, 2H, CH2), 8.40 (m, 2H, C4-H, C5-H), 8.21 (m, 1H, C6-H), 8.80
(m, 1H, C7-H), 6.98-7.80 (m, 8H, Ar-H)
1659 (C=O), 1609 (C=N) 3.90 (s, 3H, OCH3), 6.02 (s, 2H, O-CH2-O), 6.10 (s, 2H, CH2), 8.37 (m, 2H, C4-H, C5-H),
8.02 (m, 1H, C6-H), 8.56 (m, 1H, C7-H), 6.95-7.80 (m, 7H, Ar-H)
REFERENCES AND NOTES
[1] C. H. Adelstein, G. W. Yen, E. Z. Dajani and R. G.
[11] P. Lidstrom, J. Tierney, B. Wathey and J. Westman,
Tetrahedron., 57, 9225 (2001).
[12] K. Mogilaiah and N.V. Reddy, Synth Commun., 33, 1067
(2003).
Bianchi, J. Med. Chem., 19, 1221 (1976).
[2] R. Kalsi, K. Pande and J. P. Bathwal, Indian J. Chem.,
27B, 197 (1988).
[13] K. Mogilaiah and G.R. Reddy, J. Chem. Res(S)., 145
(2004).
[3] A. K. Dubey and N. K. Sangwan, Indian J. Chem., 33B,
1043 (1994).
[14] K. Mogilaiah and Ch.S. Reddy, Heterocyclic Commun., 10,
363 (2004).
[4] T. Kuroda, F. Suzuki, T. Tamura, K. Ohmori and H.
Hosoe, J. Med. Chem., 35, 1130 (1992).
[15] K. Mogilaiah, G.R. Reddy and Ch. S. Reddy, J. Chem.
Res(S), 832 (2004).
[5] G. Roma, M. D. Braccio, G. Grossi, F. Mattioli and M.
Ghia, Eur. J. Med. Chem., 35, 1021 (2000).
[16] K. Mogilaiah, H. R. Babu and N. V. Reddy, Synth. Commun.,
32, 2377 (2002).
[6] M. Badawneh, P.L. Ferrarini, V. Calderone, C. Manera,
E. Martinotti, C. Mori, G. Saccomanni and L. Testai, J. Med. Chem.,
36, 925 (2001).
[7] A. Cornelis and P. Laszlo, Synthesis, 849 (1980).
[8] R. S. Verma and R. K. Saini, Tetrahedron Lett., 38 2623 (1997).
[9] S. Caddick, Tetrahedron., 51, 10403 (1995)
[10] A. Loupy, A. Petit, J. Hamelin, F. Texier-Boullet, P Jacquault
and D. Mathe, Synthesis., 1213 (1998).
[17] IBD (0.355 g, 10.0 mmol) per gram of neutral
alumina is ground using a pestle and mortar; the recovered
alumina after removal of the products is reused without any
loss of activity.
[18] The design involves piercing the roof of a domestic
microwave oven and as such, proper sealing must be done in order
to avoid the hazards of direct microwave exposure to the
investigator.