PhI(OAc)2-Al2O3 mediated synthesis of 1,8-naphthyridinyl-1,3,4-oxadiazoles under microwave irradiation

Article abstract of DOI:10.1002/jhet.34

Alumina-supported iodobenzene diacetate [PhI(OAc)₂-Al ₂O₃] is a highly efficient reagent for the oxidative cyclization of [o-(1,8-naphthyridin-2-yl)phenoxy]acetic acid arylidene hydrazides 4 to 5-aryl-2- [o-(1,8-naphthyrid

Full text of DOI:10.1002/jhet.34

January 2009
PhI(OAc)2-Al2O3 Mediated Synthesis of 1,8-Naphthyridinyl-
1,3,4-Oxadiazoles Under Microwave Irradiation
127
K. Mogilaiah,* E. Anitha, H. Sharath Babu, and T. Kumara Swamy
Department of Chemistry, Kakatiya University, Warangal 506 009, Andhra Pradesh, India
*E-mail: mogilaiah_k@yahoo.co.in
Received January 25, 2008
DOI 10.1002/jhet.34
Published online 11 February 2009 in Wiley InterScience (www.interscience.wiley.com).
Alumina-supported iodobenzene diacetate [PhI(OAc)2-Al2O3] is a highly efficient reagent for the oxi-
dative cyclization of [o-(1,8-naphthyridin-2-yl)phenoxy]acetic acid arylidene hydrazides 4 to 5-aryl-2-
[o-(1,8-naphthyridin-2-yl)phenoxymethyl]-1,3,4-oxadiazoles 5 in solvent-free conditions under micro-
wave irradiation. The products are obtained in good yields and in a state of high purity.
J. Heterocyclic Chem., 46, 127 (2009).
INTRODUCTION
diazoles using alumina-supported IBD [PhI(OAc)2-
Al2O3] in solvent free conditions under MW irradiation.
1,8-Naphthyridine derivatives acquired a special place
in the heterocyclic field because of their diversified
activities such as antibacterial [1], antitumor [2], antihy-
pertensive [3], and anti-inflammatory [4]. 1,3,4-Oxadia-
zoles are biologically active [5,6], synthetically useful
and important heterocyclic compounds. For these rea-
sons the chemistry of 1,3,4-oxa-diazoles have been the
subject of many investigations [7–10]. However, most
of these investigations suffer from serious drawbacks
which include the use of hazardous, highly toxic, long
reaction times, low yields, drastic reaction conditions,
and expensive or commercially unavailable reagents. In
view of the rapidly increasing demands for green chem-
istry, an efficient and convenient method for the synthe-
sis of 1,3,4-oxadiazoles is highly desirable.
RESULTS AND DISCUSSION
Alkylation of 2-(o-hydroxyphenyl)-1,8-naphthyridine 1
[24] with ethyl chloroacetate in DMF in the presence of an-
hydrous K2CO3 under MW irradiation resulted in the for-
mation of ethyl [o-(1,8-naphthyridin-2-yl)phenoxy]
acetate 2, which on hydrazinolysis with refluxing hydrazine
hydrate afforded [o-(1,8-naphthyridin-2-yl)phenoxy]acetic
acid hydrazide 3. Treatment of hydrazide 3 with aromatic
aldehydes in the presence of catalytic amount of DMF
under MW irradiation furnished the corresponding hydra-
zones, [o-(1,8-naphthyridin-2-yl)phenoxy]acetic acid aryli-
denehydrazides 4 in excellent yields.
The versatile synthetic utility of organic hypervalent io-
dine reagents in general and iodobenzene diacetate (IBD)
in particular is of current interest [11–13]. Microwave
(MW) activation has become a very popular and useful
technology in synthetic organic chemistry [14–16].
Recently, more interest has been focused on ‘‘dry media’’
synthesis using inorganic solid supports. The coupling of
MW heating mode with the use of mineral solid support
[17–19] such as alumina, silica, and clays have been used
for the synthesis of several organic compounds with
higher selectivity, yield and purity compared to traditional
methods. In continuation of our interest in the MW
assisted organic transformations of 1,8-naphthyrdines
[20–23], we report herein, a practical and highly efficient
method for the synthesis of 1,8-naphthyridinyl-1,3,4-oxa-
The hydrazones 4 on oxidative cyclization with alu-
mina-supported IBD [PhI(OAc)2-Al2O3] [25] in the ab-
sence of solvent under MW irradiation resulted in the for-
mation of 5-aryl-2-[o-(1,8-naphthyridin-2-yl)phenoxy-
methyl]-1,3,4-oxadiazoles 5 (Scheme 1). The reaction
proceeds efficiently in good yields at ambient pressure
within a few minutes. The transformation is very clean
and rapid. The reaction conditions and work-up proce-
dures are mild, simple and convenient. Furthermore, it is
to be noted that highly pure products were obtained using
this simple procedure and in most cases no further purifi-
cation was needed. The recyclability of the alumina sup-
port makes this an environmentally friendly ‘‘green’’ pro-
tocol. On comparing the rate enhancement effect of MW
irradiation on the investigated reaction, the oxidative
C
V
2009 HeteroCorporation

128
K. Mogilaiah, E. Anitha, H. S. Babu, and T. K. Swamy
Vol 46
Scheme 1
Ethyl [o-(1,8-naphthyridin-2-yl)phenoxy]-acetate 2. A mix-
ture of 2-(o-hydroxyphenyl)-1,8-naphthyridine 1 (0.01 mol),
ethyl chloroacetate (0.01 mol), anhydrous K2CO3 (0.01 mol),
and DMF (10 mL) was exposed to MWs at 400 watts intermit-
tently at 30 s intervals for 4.5 min. After completion of reac-
tion, as indicated by TLC, the reaction was cooled and poured
onto crushed ice. The precipitate thus obtained was collected
by filtration, washed with water and re-crystallized from etha-
cyclization of hydrazone 4a was chosen as a model reac-
tion. The reaction gave compound 5a in 10% yield in 5.0
min, when conducted under conventional conditions in an
oil-bath preheated to 120ꢀC (temperature measured at the
end of exposure during MW experiment).
The structural assignments to compounds 2–5 were
1
based on their spectral (IR and H NMR) and analytical
nol to give 2, yield 96%, mp 130ꢀC; IR: 1755, 1610 cmꢁ1
;
data. To the best of our knowledge this is the first report of
the rapid synthesis of 1,3,4-oxadiazoles using PhI(OAc)2-
Al2O3 under solvent-free MW irradiation conditions.
In conclusion, the present procedure with PhI(OAc)2-
Al2O3 provides a very efficient method for the synthesis
of 1,3,4-oxadiazoles under solvent-free conditions using
MW irradiation. The notable advantages of this method
are: operational simplicity, ready availability of reagents
and general applicability, mild reaction conditions, short
reaction times, good yields, and environmentally benign
procedure.
1H NMR (CDCl3): d 1.29 (t, J ¼ 7.0 Hz, 3H, CH3), 4.28 (q,
J ¼ 7.0 Hz, 2H, CH2), 4.71 (s, 2H, OACH2), 8.28 (m, 3H,
C3AH, C4AH, C5AH), 7.98 (m, 1H, C6AH), 9.13 (m, 1H,
C7AH), 6.90–7.59 (m, 4H, ArAH); Anal. Calcd. for
C18H16N2O3: C, 70.13; H, 5.19; N, 9.09. Found : C, 70.29; H,
5.24; N, 9.15%.
[o-(1,8-Naphthyridin-2-yl)-phenoxy]acetic acid hydrazide
3. A mixture of 2 (0.01 mol) and hydrazine hydrate (0.015
mol) in ethanol (20 mL) was refluxed on a water-bath for 6 h.
The reaction mixture was cooled, the separated solid was col-
lected by filtration and re-crystallized from ethanol to furnish
3, yield 92%, mp 150ꢀC; IR: 3450, 3275, 3082, 1675, 1605
cmꢁ1 1H NMR (CDCl3): d 1.92 (br, 2H, NH2), 4.83 (s, 2H,
;
CH2), 8.22 (m, 3H, C3AH, C4AH, C5AH), 7.95 (m, 1H,
C6AH), 9.12 (m, 1H, C7AH), 6.97–7.54 (m, 4H, ArAH), 9.56
(s, 1H, CONH); Anal. Calcd. for C16H14N4O2: C, 65.31; H,
4.76; N, 19.05. Found: C, 65.49; H, 4.80; N, 19.12%.
General procedure for the synthesis of [o-(1,8-naphthyri-
din-2-yl)phenoxy]acetic acid arylidene hydrazides 4. A mix-
ture of 3 (0.01 mol), aromatic aldehyde (0.01 mol), and DMF
(five drops) was subjected to MW irradiation at 400 watts
intermittently at 30 s intervals for the specified time (Table 1).
On completion of the reaction, as monitored by TLC, the reac-
tion mixture was digested with cold water. The resulting solid
EXPERIMENTAL
Melting points were measured on a Cintex melting point ap-
paratus and are uncorrected. The purity of the compounds was
checked by TLC. IR spectra in KBr were recorded on a Perkin-
Elmer BX series FTIR spectrophotometer. 1H NMR spectra
were recorded on a Varian Gemini 200 MHz spectrometer
(chemical shifts in d, ppm) using TMS as internal standard.
Elemental analyses (CHN) were performed on a Perkin-
Elmer 240 CHN analyzer. Irradiation was carried out in a
domestic MW oven (LG MG-556P, 2450 MHz).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009
PhI(OAc)2-Al2O3 Mediated Synthesis of 1,8-Naphthyridinyl-1,3,4-oxadiazoles
Under Microwave Irradiation
129
Table 1
Physical and analytical data of [o-(1,8-naphthyridin-2-yl)phenoxy]acetic acid arylidenehydrazides 4 and
5-aryl-2-[o-(1,8-naphthyridin-2-yl)phenoxymethyl]-1,3,4-oxadiazoles 5.
Found % (Calcd)
Reaction period
(min)
Entry
Ar
M.p. (ꢀC)
Yield (%)
Mol. formula
C
H
N
4a
4b
4c
4d
4e
4f
4g
4h
5a
5b
5c
5d
5e
5f
C6H5
1.0
0.5
1.5
1.0
1.5
0.5
1.0
1.5
5.0
4.5
5.5
5.0
6.0
6.5
5.5
6.5
184
176
234
180
200
210
96
98
94
97
94
92
93
92
90
95
92
93
90
88
89
87
C23H18N4O2
C24H20N4O2
C24H20N4O3
72.43 (72.25)
72.91 (72.73)
69.72 (69.90)
66.45 (66.27)
59.71 (59.87)
64.80 (64.64)
61.38 (61.20)
61.36 (61.20)
72.76 (72.63)
73.27 (73.10)
70.42 (70.24)
66.75 (66.59)
60.30 (60.13)
64.78 (64.94)
61.63 (61.47)
61.62 (61.47)
4.76 (4.71)
4.08 (5.05)
4.49 (4.85)
4.02 (4.08)
3.74 (3.69)
3.94 (3.98)
3.40 (3.55)
3.41 (3.55)
4.26 (4.21)
4.61 (4.57)
4.43 (4.39)
3.66 (3.62)
3.32 (3.27)
3.58 (3.53)
3.16 (3.12)
3.17 (3.12)
14.74 (14.66)
14.21 (14.14)
13.66 (13.59)
13.49 (13.45)
12.22 (12.15)
16.46 (16.39)
12.47 (12.42)
12.49 (12.42)
14.80 (14.74)
14.29 (14.21)
13.72 (13.66)
13.58 (13.51)
12.29 (12.20)
16.41 (16.47)
12.55 (12.47)
12.56 (12.47)
p-CH3C6H4
p-CH3OC6H4
p-ClC6H4
C23H17ClN4O2
C23H17BrN4O2
C23H17N5O4
o-BrC6H4
m-NO2C6H4
2,4-Cl2C6H3
2,6-Cl2C6H3
C6H5
p-CH3C6H4
p-CH3OC6H4
p-ClC6H4
185
223
C23H16Cl2N4O2
C23H16Cl2N4O2
C23H16N4O2
C24H18N4O2
C24H18N4O3
C23H15ClN4O2
C23H15BrN4O2
C23H15N5O4
C23H14Cl2N4O2
C23H14Cl2N4O2
>300
>300
>300
>300
>300
>300
>300
>300
o-BrC6H4
m-NO2C6H4
2,4-Cl2C6H3
2,6-Cl2C6H3
5g
5h
product was collected by filtration, washed with water, and re-
crystallized from ethanol to afford 4.
exposed to MWs at 800 watts intermittently at 30 s intervals
for the specific time (Table 1). After complete conversion as
indicated by TLC, the reaction mixture was cooled and treated
with methanol (30 mL). The methanol solution was poured
into ice-cold water (50 mL), the precipitated solid was col-
lected by filtration and re-crystallized from ethanol to furnish
5 (Table 1).
4a. IR: 3432, 1690, 1615 cmꢁ1 1H NMR (CDCl3): d 4.90
;
(s, 2H, CH2), 8.18 (m, 3H, C3AH, C4AH, C5AH), 7.92 (m,
1H, C6AH), 9.10 (m, 1H, C7AH), 6.92–7.55 (m, 10H, N¼¼CH,
9ArAH), 12.53 (s, 1H, CONH).
4b. IR: 3440, 1685, 1612 cmꢁ1 1H NMR (CDCl3): d 2.22
;
1
(s, 3H, CH3), 4.92 (s, 2H, CH2), 8.27 (m, 3H, C3AH, C4AH,
C5AH), 7.94 (m, 1H, C6AH), 9.12 (m, 1H, C7AH), 6.90–7.58
(m, 9H, N¼¼CH, 8ArAH), 12.36 (s, 1H, CONH).
5a. IR: 1605 cmꢁ1; H NMR (CDCl3 þ DMSO-d6): d 5.46
(s, 2H, CH2), 8.20 (m, 3H, C3AH, C4AH, C5AH), 8.00 (m,
1H, C6AH), 9.15 (m, 1H, C7AH), 7.04–7.60 (m, 9H, ArAH).
4c. IR: 3448, 1696, 1604 cmꢁ1
;
1H NMR (CDCl3): d 3.82
5b. IR: 1602 cmꢁ1; H NMR (CDCl3 þ DMSO-d6): d 2.30
1
s, 3H, OCH3), 4.91 (s, 2H, CH2), 8.28 (m, 3H, C3AH, C4AH,
C5AH), 7.98 (m, 1H, C6AH), 9.13 (m, 1H, C7AH), 6.83–7.80
(m, 9H, N¼¼CH, 8ArAH), 12.42 (s, 1H, CONH).
(s, 3H, CH3), 5.42 (s, 2H, CH2), 8.18 (m, 3H, C3AH, C4AH,
C5AH), 7.98 (m, 1H, C6AH), 9.14 (m, 1H, C7AH), 7.00–7.56
(m, 8H, ArAH).
4d. IR: 3420, 1702, 1609 cmꢁ1
;
1H NMR (CDCl3): d 4.94
5c. IR: 1604 cmꢁ1; H NMR (CDCl3 þ DMSO-d6): d 3.87
1
(s, 2H, CH2), 8.25 (m, 3H, C3AH, C4AH, C5AH), 8.00 (m,
1H, C6AH), 9.13 (m, 1H, C7AH), 7.03–7.80 (m, 9H, N¼¼CH,
8ArAH), 12.89 (s, 1H, CONH).
(s, 3H, OCH3), 5.41 (s, 2H, CH2), 8.17 (m, 3H, C3AH, C4AH,
C5AH), 7.92 (m, 1H, C6AH), 9.12 (m, 1H, C7AH), 6.92–7.60
(m, 8H, ArAH).
4e. IR: 3450, 1705, 1604 cmꢁ1
;
1H NMR (CDCl3): d 4.92
5d. IR: 1605 cmꢁ1; H NMR (CDCl3 þ DMSO-d6): d 5.43
1
(s, 2H, CH2), 8.20 (m, 3H, C3AH, C4AH, C5AH), 7.93 (m,
1H, C6AH), 9.14 (m, 1H, C7AH), 7.00–7.73 (m, 9H, N¼¼CH,
8ArAH), 12.89 (s, 1H, CONH).
(s, 2H, CH2), 8.20 (m, 3H, C3AH, C4AH, C5AH), 7.81 (m,
1H, C6AH), 9.09 (m, 1H, C7AH), 7.10–7.32 (m, 8H, ArAH).
1
5e. IR: 1602 cmꢁ1; H NMR (CDCl3 þ DMSO-d6): d 5.46
4f. IR: 3435, 1697, 1604 cmꢁ1
;
1H NMR (CDCl3): d 4.95
(s, 2H, CH2), 8.23 (m, 3H, C3AH, C4AH, C5AH), 7.92 (m,
1H, C6AH), 9.03 (m, 1H, C7AH), 7.20–7.74 (m, 8H, ArAH).
(s, 2H, CH2), 8.17 (m, 3H, C3AH, C4AH, C5AH), 7.91 (m,
1H, C6AH), 9.08 (m, 1H, C7AH), 6.90–7.49 (m, 9H, N¼¼CH,
8ArAH), 12.42 (s, 1H, CONH).
1
5f. IR: 1603 cmꢁ1; H NMR (CDCl3 þ DMSO-d6): d 5.42
(s, 2H, CH2), 8.21 (m, 3H, C3AH, C4AH, C5AH), 7.97 (m,
1H, C6AH), 9.11 (m, 1H, C7AH), 7.05–7.52 (m, 8H, ArAH).
4g. IR: 3425, 1702, 1607 cmꢁ1 1H NMR (CDCl3): d 4.92
;
1
(s, 2H, CH2), 8.24 (m, 3H, C3AH, C4AH, C5AH), 7.95 (m,
1H, C6AH), 9.10 (m, 1H, C7AH), 6.98–7.62 (m, 8H, N¼¼CH,
7ArAH), 12.52 (s, 1H, CONH).
5g. IR: 1600 cmꢁ1; H NMR (CDCl3 þ DMSO-d6): d 5.45
(s, 2H, CH2), 8.19 (m, 3H, C3AH, C4AH, C5AH), 7.92 (m,
1H, C6AH), 9.13 (m, 1H, C7AH), 6.94–7.56 (m, 7H, ArAH).
4h. IR: 3422, 1707, 1604 cmꢁ1
;
1H NMR (CDCl3): d 4.90
5h. IR: 1601 cmꢁ1
5.43 (s, 2H, CH2), 8.21 (m, 3H, C3AH, C4AH, C5AH),
7.98 (m, 1H, C6AH), 9.10 (m, 1H, C7AH), 7.01–7.52 (m,
7H, ArAH).
;
1H NMR (CDCl3 þ DMSO-d6): d
(s, 2H, CH2), 8.19 (m, 3H, C3AH, C4AH, C5AH), 7.90 (m,
1H, C6AH), 9.12 (m, 1H, C7AH), 6.96–7.58 (m, 8H, N¼¼CH,
7ArAH), 12.73 (s, 1H, CONH).
General procedure for the synthesis of 5-aryl-2-
[o-(1,8-naphthyridin-2-yl)-phenoxymethyl]-1,3,4-oxadiazoles
5. Compound 4 (0.01 mol) and PhI(OAc)2 (0.01 mol)
doped on neutral alumina (1 g) are mixed thoroughly and
Acknowledgment. The authors thank the Directors, IICT,
Hyderabad and IITM, Chennai for providing spectroscopic and
analytical data.
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130
K. Mogilaiah, E. Anitha, H. S. Babu, and T. K. Swamy
Vol 46
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