Microwave-assisted one-pot synthesis of benzothiazole and benzoxazole libraries as analgesic agents

Article abstract of DOI:10.1007/s12039-012-0251-3

Microwave-assisted synthesis of benzothiazole and benzoxazole libraries via PIFA promoted cyclocondensation of 2-aminothiophenols/2-aminophenols with aldehydes under one-pot condition in good to excellent yields was achieved. Twenty compounds have been investigated for their analgesic activity and showed moderate to good activity. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-012-0251-3

c
J. Chem. Sci. Vol. 124, No. 3, May 2012, pp. 609–624. ꢀ Indian Academy of Sciences.
Microwave-assisted one-pot synthesis of benzothiazole and benzoxazole
libraries as analgesic agents
C PRAVEENa, A NANDAKUMARa, P DHEENKUMARb, D MURALIDHARANa and
P T PERUMALa,∗
aOrganic Chemistry Division, Central Leather Research Institute (CSIR), Adyar, Chennai 600 020, India
bDepartment of Pharmaceutical Chemistry, EGS Pillay College of Pharmacy, Nagapattinam 611 002, India
e-mail: ptperumal@gmail.com
MS received 28 August 2011; revised 19 November 2011; accepted 2 December 2011
Abstract. Microwave-assisted synthesis of benzothiazole and benzoxazole libraries via PIFA promoted
cyclocondensation of 2-aminothiophenols/2-aminophenols with aldehydes under one-pot condition in good
to excellent yields was achieved. Twenty compounds have been investigated for their analgesic activity and
showed moderate to good activity.
Keywords. Microwave; one-pot synthesis; benzothiazoles; benzoxazoles; analgesic activity.
1. Introduction
the radical cyclization of thioacylbenzanilides,30
DMP mediated intramolecular cyclization of thiofor-
manilides.31 Apart from these general methods, there
have been many methodologies disclosed in the liter-
ature for the construction of benzothiazoles.32–40 On
the other hand, the classical approach for the synthesis
of benzoxazoles involves (i) coupling of carboxylic
acids with 2-aminophenols by dehydration catalysed
by strong acid;41 and (ii) the oxidative cyclization of
phenolic Schiff’s bases derived from the condensation
of 2-aminophenols and aldehydes, using various oxi-
dants such as PhI(OAc)2,42 Mn(OAc)3,43 ThClO4,44
Ba(MnO4)2,45 NiO2,46 Pb(OAc)4,47 DDQ,48 NIS,49
Cu-np,50 aerial oxidation in the presence of activated
carbon (Darco KB),51 CuCl52 and Pd/Pt-C.53 Other
synthetic routes for benzoxazole include microwave-
assisted reaction of N-acyl-aminophenol,54 iron catal-
ysed intramolecular O-arylation of 2-haloacetanilides55
and cyclization of phenolic Schiff base under UV irra-
diation.56 Apart from these methodologies, there have
been many precedents for the synthesis of 2-aryl ben-
zothiazoles and benzoxazoles via palladium catalysed
cross-coupling reactions have been disclosed in the
literature.57
The biaryl pharmacophore of benzothiazole and ben-
zoxazole exhibits a wide range of biological properties
and has led to continued interest in medicinal chem-
istry.1 The benzothiazolyl moiety is a component in
various antagonists like Ca2+ channel,2 LTD4 and
3
orexin receptor.4 Benzothiazoles are known to inhibit
several enzymes such as acetyl cholinesterase,5 mon-
amine oxidase,6–9 lipoxygenase,10 lysophosphatidic
acid acyltransferase-β,11 aldose reductase,12 cyclooxy-
genase,13 carbonic anhydrase,14 H+-K+ATPase, 15 HCV
helicase,16 protease17 and stearoyl-coA δ-9 desatu-
rase.18 Other recognized pharmacological activities of
benzothiazoles include antitumour,19 antimicrobial,20
antioxidant21 and antiglutamate.22 On the other hand,
benzoxazole moiety is found in various pharmaceuti-
cals displaying a broad spectrum of biological activity
including antiinflammatory, antitumour, antirheumatic,
antimicrobial and antiviral effects.23 Other signifi-
cant physiological activities associated with benzoxa-
zoles are H37Rv inhibitory,24 elastase inhibitory,25
5HT3 receptor agonist26 and cytotoxicity towards P338
cells.27
The most useful synthesis of benzothiazoles include
condensation of 2-aminobenzenethiol with carboxyl
derivatives,28 cyclization of ortho-haloanilides,29
The synthetic scope of the aforesaid protocols is
limited by two factors: (i) lack of general procedure
that supports the synthesis of both benzothiazoles and
benzoxazoles, (ii) lack of practical synthesis support-
ing structurally diverse spacers and substitution pat-
terns in the target library. Thus, it is clear that an effi-
cient protocol is needed. In the context of heterocycle
∗For correspondence
609

610
C Praveen et al.
synthesis,58 we have already addressed this problem 2.2 General procedure for the synthesis of
by employing PCC as an effective oxidant for the benzothiazoles 2a–2z
synthesis of both benzothiazoles and benzoxazoles
To
a
pyrex reaction vessel were added 2-
via oxidative cyclization of thiophenolic and phenolic
Schiff’s bases, respectively.58a Although the substrate
scope was modestly explored, this procedure is limi-
ted by the powerful oxidizing ability of PCC and the
potential carcinogenicity of Cr6+. In order to circum-
vent this limitation, we envisaged an alternate oxidant
for the synthesis of benz(oxa)thiazoles. In this paper,
we report PIFA [phenyliodonium bis(trifluoroacetate)]
as an effective oxidant for the one-pot synthe-
sis of benz(oxa)thiazoles via cyclocondensation of
2-aminothiophenols/2-aminophenols with aldehydes
under microwave irradiation. Representative com-
pounds were screened for their in vivo analgesic activity
and the results were presented.
aminothiophenol (1.1 mmol), aldehyde (1.0 mmol)
and PIFA (1.05 mmol) in ethanol (3 ml). The reaction
vessel was then placed in the Emrys Optimizer and
exposed to microwave irradiation (80◦C) for 15 min.
The reaction mixture was then allowed to cool at room
temperature and quenched with 15 mL of water. The
crude reaction mixture was extracted with EtOAc (3
× 15 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered, concentrated and
purified by column chromatography on silica gel using
petroleum ether/EtOAc to afford the pure product.
2.2a 2-(4-Methoxyphenyl)benzo[d]thiazole (2a): Yel-
low solid; mp 122–124◦C; Rf = 0.59 (AcOEt/
petroleum ether 10%). IR (KBr): 3023, 2996, 2900,
2836, 1605, 1521, 1485, 1260, 832 cm−1. H NMR
1
(500 MHz, CDCl3) δH 3.91 (s, 3H, -OCH3); 7.00–7.05
(m, 2H, Ar-H); 7.35 (d, 1H, J = 7.6 Hz, Ar-H); 7.50
(d, 1H, J = 7.6 Hz, Ar-H); 7.91–8.04 (m, 4H, Ar-H).
13C NMR (125 MHz, CDCl3) δC 55.5, 114.4, 121.6,
122.9, 124.9, 126.3, 126.5, 129.2, 135.0, 154.3, 162.0,
167.9. MS (EI): m/z = 241 [M+]. Anal. Calcd for
C14H11NOS: C, 69.68; H, 4.59; N, 5.80%. Found: C,
69.89; H, 4.54; N, 5.72%.
2. Experimental
2.1 Materials, methods and instruments
Melting points were determined on Gallenkamp melt-
ing point apparatus and are uncorrected. Infrared (IR)
spectra were recorded on a Perkin-Elmer FTIR spec-
trophotometer as KBr pellets. H and 13C NMR spec-
1
tra were obtained in CDCl3 and DMSO-d6 on a JEOL
spectrometer at 500 and 125 MHz, respectively. Pro-
ton chemical shifts (δ) are relative to tetramethylsilane
(TMS, δ = 0.00) as internal standard and expressed
in parts per million. The number of protons (n) for a
given resonance was indicated as nH. Coupling con-
stants (J) are given in hertz. Spin multiplicities are
given as s (singlet), d (doublet), t (triplet) and m
(multiplet). Mass spectra were recorded on a Thermo
Finnigan LCQ Advantage MAX 6000 ESI mass spec-
trometer and Perkin-Elmer GC-MS. Elemental analy-
ses were recorded using a Thermo Finnigan FLASH
EA 1112CHN analyzer. All the compounds gave C, H
and N analysis within 0.5% of the theoretical val-
ues. All microwave experiments were performed using
an Emrys Optimizer in 2–5 mL pyrex reaction vessels.
Each vessel contained a Teflon stir bar and Teflon-
coated reaction vessel cap. Column chromatography
was performed using a mixture of petroleum ether and
ethyl acetate on silica gel (100–200 mesh, SRL, India).
Analytical TLC was performed on precoated plastic
sheets of silica gel G/UV-254 of 0.2 mm thickness
(Macherey-Nagel, Germany) using analytical grade sol-
vents and visualizing with iodine spray (10% (w/w) I2
in silica gel) or UV light (λ = 254 and 365 nm).
2.2b 2-(4-(Trifluoromethyl)phenyl)benzo[d]thiazole
(2b): Colourless solid; mp 158–160◦C; Rf = 0.35
(AcOEt/petroleum ether 40%). IR (KBr): 3058, 2898,
1658, 1154, 1071, 798 cm−1. 1H NMR (500 MHz,
CDCl3) δH 7.40–7.45 (m, 1H, Ar-H); 7.50–7.54 (m,
1H, Ar-H); 7.77 (d, 2H, J = 8.4 Hz, Ar-H); 7.93 (ddd,
1H, J = 0.8, 0.8, 8.4 Hz, Ar-H); 8.11 (ddd, 1H, J =
1.1, 1.1, 7.1 Hz, Ar-H); 8.20 (dd, 2H, J = 0.7, 8.8 Hz,
Ar-H). 13C NMR (125 MHz, CDCl3) δC 121.8, 123.4,
124.5 (JC-F = 268.0 Hz), 125.5, 126.0 (JC-F = 3.6 Hz),
126.7, 132.4 (JC-F = 32.9 Hz), 135.0, 136.7, 154.2,
159.9. MS (EI): m/z = 280 [M+H]+. Anal. Calcd for
C14H8F3NS: C, 60.21; H, 2.89; N, 5.02%. Found: C,
59.99; H, 2.94; N, 5.11%.
2.2c 4-(Benzo[d]thiazol-2-yl)-N,N-dimethylbvenzenamine
(2c): Brown solid; mp 175–177◦C; Rf = 0.30
(AcOEt/petroleum ether 20%). IR (KBr): 3398, 1598,
1478, 1201, 1012, 981 cm−1. 1H NMR (500 MHz,
CDCl3) δH 3.07 (s, 6H, -N(CH3)2); 6.75 (dd, 2H, J =
7.2, 1.8 Hz, Ar-H); 7.31–7.35 (m, 1H, Ar-H); 7.43–
7.46 (m, 1H, Ar-H); 7.85–7.88 (m, 1H, Ar-H); 8.01
(dd, 3H, J = 7.2, 1.8 Hz, Ar-H). 13C NMR (125 MHz,

Synthesis and anti-inflammatory evaluation of benz(oxa)thiazoles
611
CDCl3) δC 39.9, 111.5, 121.2, 122.3, 124.0, 126.0, J = 9.1 Hz, Ar-H); 8.01–8.10 (m, 2H, Ar-H). 13C NMR
128.9, 134.6, 152.0, 154.5, 168.9. MS (EI): m/z = (125 MHz, CDCl3) δC 55.9, 106.0, 115.4, 122.1, 127.3,
255 [M+H]+. Anal. Calcd for C15H14N2S: C, 70.83; H, 127.7, 129.3, 131.1, 134.1, 156.0, 159.5, 169.4. MS
5.55; N, 11.01%. Found: C, 71.01; H, 5.51; N, 10.92%. (EI): m/z = 241 [M+]. Anal. Calcd for C14H11NOS: C,
69.68; H, 4.59; N, 5.80%. Found: C, 69.48; H, 4.61; N,
5.87%.
2.2d 2-(4-Chlorophenyl)benzo[d]thiazole (2d): Yel-
low solid; mp 114–116◦C; Rf = 0.50 (AcOEt/
petroleum ether 10%). IR (KBr): 3055, 2360, 1560,
1455, 1430, 1317, 1275, 1060, 966, 750, 725 cm−1. 1H
NMR (500 MHz, CDCl3) δH 7.39–7.43 (m, 2H, Ar-H);
7.45–7.52 (m, 2H, Ar-H); 7.85–8.01 (m, 4H, Ar-H).
13C NMR (125 MHz, CDCl3) δC 121.9, 123.6, 125.5,
126.8, 129.0, 129.6, 132.4, 135.4, 137.1, 154.4, 166.9.
MS (EI): m/z = 245 [M+], 247 [M+2]. Anal. Calcd for
C13H8ClNS: C, 63.54; H, 3.28; N, 5.70%. Found: C,
63.75; H, 3.24; N, 5.63%.
2.2h
2-(3-Nitrophenyl)benzo[d]thiazole (2h): Col-
0.50
ourless solid; mp 181–183◦C; Rf
=
(AcOEt/petroleum ether 30%). IR (KBr): 3402, 2937,
1529, 1461, 1347, 1107, 1048, 731 cm−1. H NMR
1
(500 MHz, CDCl3) δH 7.42 (t, 1H, J = 7.6 Hz, Ar-H);
7.51 (t, 1H, J = 7.6 Hz, Ar-H); 7.65 (t, 1H, J = 7.6 Hz,
Ar-H); 7.92 (d, 1H, J = 7.6 Hz, Ar-H); 8.09 (d, 1H, J
= 7.6 Hz, Ar-H); 8.30 (dd, 1H, J = 6.9, 9.2 Hz, Ar-H);
8.38 (d, 1H, J = 7.6 Hz, Ar-H); 8.90 (s, 1H, Ar-H).
13C NMR (125 MHz, CDCl3) δC 121.9, 122.4, 123.8,
125.2, 126.1, 126.9, 130.2, 133.1, 135.3, 135.4, 148.8,
154.0, 164.9. MS (EI): m/z = 256 [M+]. Anal. Calcd
for C13H8N2SO2: C, 60.92; H, 3.15; N, 10.93%. Found:
C, 60.75; H, 3.22; N, 10.89%.
2.2e 2-(Naphthalen-2-yl)benzo[d]thiazole (2e): Brown
solid; mp 123–125◦C; Rf = 0.64 (AcOEt/petroleum
ether 20%). IR (KBr): 3049, 2920, 2855, 1597, 1499,
1452, 1430, 1362, 1306, 1270, 1174, 1123, 982, 937,
1
880 cm−1. H NMR (500 MHz, CDCl3) δH 7.30–7.37
2.2i 2-(2-Methoxyphenyl)benzo[d]thiazole (2i):
(m, 1H, Ar-H); 7.44–7.50 (m, 3H, Ar-H); 7.80–7.91 (m,
4H, Ar-H); 8.09 (d, 1H, J = 8.0 Hz, Ar-H); 8.15 (d, 1H,
J = 8.4 Hz); 8.50 (s, 1H, Ar-H). 13C NMR (125 MHz,
CDCl3) δC 121.6, 123.2, 124.4, 125.2, 126.7, 127.4,
127.5, 127.9, 128.8, 130.9, 133.1, 134.6, 135.1, 154.2,
168.1. MS (EI): m/z = 261 [M+]. Anal. Calcd for
C17H11NS: C, 78.13; H, 4.24; N, 5.36%. Found: C,
78.30; H, 4.17; N, 5.29%.
Colourless solid; mp 123–125◦C; Rf
=
0.55
(AcOEt/petroleum ether 10%). IR (KBr): 3024, 2999,
2900, 2837, 1604, 1521, 1485, 1260, 831 cm−1. H
1
NMR (500 MHz, CDCl3) δH 3.99 (s, 3H, -OCH3);
7.10–7.55 (m, 4H, Ar-H); 7.92–8.49 (m, 4H, Ar-H).
13C NMR (125 MHz, CDCl3) δC 55.5, 111.5, 120.9,
121.0, 122.6, 124.4, 125.7, 129.3, 131.5, 135.9, 152.0,
157.0, 162.9. MS (EI): m/z = 242 [M+H]+. Anal.
Calcd for C14H11NOS: C, 69.68; H, 4.59; N, 5.80%.
Found: C, 69.91; H, 4.53; N, 5.70%.
2.2f Methyl 4-(benzo[d]thiazol-2-yl)benzoate (2f):
Colourless solid; mp 148–151◦C; Rf
=
0.25
(AcOEt/petroleum ether 30%). IR (KBr): 3360, 3270,
2.2j 2-(2-Chlorophenyl)benzo[d]thiazole (2j):
2933, 2853, 1724, 1679, 751, 724 cm−1; H NMR
1
Colourless solid; mp 71–73◦C; Rf
=
0.39
(500 MHz, CDCl3) δH 3.99 (s, 3H, -COOCH3); 6.94–
6.99 (td, 1H, J = 7.6, 1.3 Hz, Ar-H); 7.26–7.29 (m,
1H, Ar-H); 7.45–7.49 (dd, 1H, J = 7.6, 1.3 Hz, Ar-H);
7.70–7.73 (d, 2H, J = 8.3 Hz, Ar-H); 8.09–8.12 (d, 2H,
J = 8.3 Hz, Ar-H); 8.42–8.46 (d, 1H, J = 8.3 Hz, 1H).
13C NMR (125 MHz, CDCl3) δC 52.5, 120.7, 124.0,
124.7, 127.1, 130.0, 132.4, 133.2, 136.7, 138.0, 139.7,
164.0, 166.2. MS (EI): m/z = 270 [M+H]+. Anal.
Calcd for C15H11NO2S: C, 66.89; H, 4.12; N, 5.20%.
Found: C, 67.10; H, 4.06; N, 5.11%.
(AcOEt/petroleum ether 10%). IR (KBr): 3053,
2359, 1559, 1454, 1429, 1316, 1270, 1059, 965, 749,
726 cm−1. H NMR (500 MHz, CDCl3) δH 7.38–7.44
1
(m, 3H, Ar-H); 7.51–7.54 (m, 2H, Ar-H); 7.93 (d,
1H, J = 7.6 Hz, Ar-H); 8.13 (d, 1H, J = 8.4 Hz, Ar-
H); 8.20–8.21 (m, 1H, Ar-H). 13C NMR (125 MHz,
CDCl3) δC 121.5, 123.6, 125.6, 126.4, 127.2, 130.9,
131.3, 131.9, 132.4, 132.8, 136.2, 152.6, 164.3. MS
(EI): m/z = 245 [M+], 247 [M+2]. Anal. Calcd for
C13H8ClNS: C, 63.54; H, 3.28; N, 5.70%. Found: C,
63.44; H, 3.33; N, 5.67%.
2.2g
5-Methoxy-2-phenylbenzo[d]thiazole (2g):
Colourless solid; mp 74–76◦C; Rf = 0.62 (AcOEt/
petroleum ether 15%). IR (KBr): 2955, 2940, 2840, 2.2k 2-(3,4-Dimethoxyphenyl)benzo[d]thiazole (2k):
1597, 1462, 1429, 1256, 1167, 1150, 1077 cm−1. H Colourless solid; mp 133–135◦C; Rf
=
0.54
1
NMR (500 MHz, CDCl3) δH 3.86 (s, 3H, -OCH3); 7.05 (AcOEt/petroleum ether 20%). IR (KBr): 2955, 2940,
(dd, 1H, J1 = 2.6 Hz, J2 = 9.1 Hz, Ar-H); 7.39–7.47 (m, 2840, 1600, 1521, 1483, 1431, 1336, 1312, 1260, 1167,
3H, Ar-H); 7.56 (d, 1H, J = 2.6 Hz, Ar-H); 7.70 (d, 1H, 1145, 1075 cm−1. 1H NMR (500 MHz, CDCl3) δH 3.96

612
C Praveen et al.
(s, 3H, -OCH3); 4.03 (s, 3H, -OCH3); 6.97 (d, 1H, J = 137.6, 139.5. MS (EI): m/z = 377 [M+]. Anal. Calcd
8.4 Hz, Ar-H); 7.35 (t, 1H, J = 7.6 Hz, Ar-H); 7.49 for C22H19NSO3: C, 70.00; H, 5.07; N, 3.71%. Found:
(t, 1H, J = 7.4 Hz, Ar-H); 7.65 (d, 1H J = 8.4 Hz, C, 69.89; H, 4.99; N, 3.82%.
Ar-H); 7.76 (s, 1 H, Ar-H); 7.89 (d, 1H J = 7.6 Hz,
Ar-H); 8.00 (d, 1H, J = 8.0 Hz, Ar-H). 13C NMR
2.2o 4-(1,3-Benzo[d]thiazol-2-yl)-2-bromo-6-metho-
xyphenol (2o): Colourless solid; mp 184–186◦C; Rf
= 0.46 (AcOEt/petroleum ether 30%). IR (KBr): 3447,
2922, 1510, 1416, 1292, 1183, 1022, 831, 722 cm−1. 1H
NMR (500 MHz, DMSO-d6) δH 3.93 (s, 3H, -OCH3);
7.39 (d, 1H, J = 7.6 Hz, Ar-H); 7.49–7.50 (m, 1H,
Ar-H); 7.57 (s, 1H, Ar-H); 7.72 (s, 1H, Ar-H); 7.97–
8.07 (m, 2H, Ar-H); 10.32 (s, 1H, -OH). 13C NMR
(125 MHz, DMSO-d6) δC 56.9, 109.7, 110.2, 122.8,
123.1, 124.1, 125.5, 125.8, 127.2, 134.9, 147.4, 149.2,
153.9, 166.5. MS (EI): m/z = 335 [M+], 337 [M+2].
Anal. Calcd for C14H10BrNO2S: C, 50.01; H, 3.00; N,
4.17%. Found: C, 49.89; H, 3.09; N, 4.10%.
(125 MHz, CDCl3) δC 55.9, 109.7, 111.0, 121.1, 121.5,
122.8, 124.9, 126.2, 126.6, 134.9, 149.2, 151.5, 154.0,
168.1. MS (EI): m/z = 271 [M+]. Anal. Calcd for
C15H13NO2S: C, 66.40; H, 4.83; N, 5.16%. Found: C,
66.61; H, 4.79; N, 5.04%.
2.2l 2-[4-(Benzyloxy)-3-methoxyphenyl]benzo[d]
thiazole (2l): Colourless solid; mp 97–99◦C; Rf
=
0.63 (AcOEt/petroleum ether 30%). IR (KBr):
1
3468, 2937, 1630, 1264, 1141, 997 cm−1. H NMR
(500 MHz, CDCl3) δH 3.94 (s, 3H, -OCH3); 5.22 (s,
2H, -OCH2C6H5); 6.93 (d, 1H, J = 8.4 Hz, Ar-H);
7.31–7.39 (m, 4H, Ar-H); 7.42–7.48 (m, 3H, Ar-H);
7.51 (dd, 1H, J = 2.3, 8.4 Hz, Ar-H); 7.72 (d, 1H, J =
2.3 Hz, Ar-H); 7.85 (d, 1H, J = 7.6 Hz, Ar-H); 8.01 (d,
1H, J = 8.4 Hz, Ar-H). 13C NMR (125 MHz, CDCl3)
δC 56.3, 71.0, 110.3, 113.5, 121.1, 121.6, 122.9, 124.9,
126.3, 127.1, 127.3, 128.1, 128.8, 134.9, 136.6, 149.9,
150.7, 154.2, 168.1. MS (EI): m/z = 349 [M+]. Anal.
Calcd for C20H17NSO: C, 72.60; H, 4.93; N, 4.03%.
Found: C, 72.49; H, 4.82; N, 3.99%.
2.2p 2-(Benzo[d][1,3]dioxol-5-yl)benzo[d]thiazole
(2p): Yellow solid; mp 128–130◦C; Rf = 0.60
(AcOEt/petroleum ether 15%). IR (KBr): 1602, 1492,
1454, 1377, 1305, 1274, 1149, 744, 699 cm−1. 1H NMR
(500 MHz, CDCl3) δH 6.07 (s, 2H, -OCH2O-); 6.99
(d, 1H, J = 7.6 Hz, Ar-H); 7.35–7.40 (m, 1H, Ar-H);
7.45–7.50 (m, 1H, Ar-H); 7.61–7.65 (m, 2H, Ar-H);
7.91 (d, 1H, J = 8.4 Hz, Ar-H); 8.05 (d, 1H, J =
8.4 Hz, Ar-H). 13C NMR (125 MHz, CDCl3) δC 101.5,
107.4, 108.5, 121.4, 122.4, 123.0, 125.0, 126.3, 128.0,
135.0, 148.5, 150.2, 154.2, 167.5. MS (EI): m/z = 256
[M+H]+. Anal. Calcd for C14H9NO2S: C, 65.87; H,
3.55; N, 5.49%. Found: C, 66.01; H, 3.51; N, 5.42%.
2.2m 4-(Benzo[d]thiazol-2-yl)-2,6-methoxyphenol (2m):
Colourless solid; mp 140–142◦C; Rf = 0.59 (AcOEt/
petroleum ether 25%). IR (KBr): 3480, 2939, 1615,
1530, 1480, 1450, 1427, 1366, 1334, 1284, 1211,
1
1200 cm−1. H NMR (500 MHz, CDCl3) δH 3.99 (s,
6H, -OCH3); 5.98 (s, 1H, -OH); 7.33–7.39 (m, 3H,
Ar-H); 7.50 (t, 1H J = 7.6 Hz, Ar-H); 7.89 (d, 1H, J
= 7.6 Hz, Ar-H); 8.03 (d, 1H, J = 8.1 Hz, Ar-H). 13C
NMR (125 MHz, CDCl3) δC 56.6, 106.6, 121.5 (2C),
122.8, 124.9, 125.1, 126.2, 134.8, 137.7, 147.3, 154.0,
168.1. MS (EI): m/z = 287 [M+]. Anal. Calcd for
C15H13NO3S: C, 62.70; H, 4.56; N, 4.87%. Found: C,
62.88; H, 4.51; N, 4.81%.
2.2q 2-(Phenylbenzo[d]thiazole
(2q): Colourless
solid; mp 114–116◦C; Rf = 0.60 (AcOEt/petroleum
ether 10%). IR (KBr): 3064, 1588, 1555, 1509, 1478,
1433, 1244, 962, 766 cm−1. 1H NMR (500 MHz,
CDCl3) δH 7.38 (d, 2H, J = 7.6 Hz, Ar-H); 7.50–755
(m, 4H, Ar-H); 7.92 (d, 1H, J = 7.6 Hz, Ar-H); 8.07–
8.15 (m, 3H, Ar-H). 13C NMR (125 MHz, CDCl3) δC
121.5, 123.1, 125.1, 126.2, 127.5, 129.0, 130.8, 133.6,
135.1, 154.2, 167.9. MS (EI): m/z = 211 [M+]. Anal.
Calcd for C13H9NS: C, 73.90; H, 4.29; N, 6.63%.
Found: C, 74.05; H, 4.24; N, 6.55%.
2.2n 2-[4-(Benzyloxy)-3,5-dimethoxyphenyl]benzo
[d]thiazole (2n): Brown solid; mp 77–79◦C; Rf
=
0.58 (AcOEt/petroleum ether 30%). IR (KBr): 3432,
2915, 2369, 1623, 1590, 1406, 1329, 1240, 1118,
1
1019 cm−1. H NMR (500 MHz, CDCl3) δH 3.93 (s,
2.2r 2-(Pyridin-2-yl)benzo[d]thiazole (2r): Yellow
solid; mp 130–131◦C; Rf = 0.15 (AcOEt/petroleum
ether 40%). IR (KBr): 3322, 3079, 2901, 1655, 989,
6H, -OCH3); 5.09 (s, 2H, -OCH2C6H5); 7.29–7.38 (m,
6H, Ar-H); 7.46–7.50 (m, 3H, Ar-H); 7.86 (d, 1H, J =
7.6 Hz, Ar-H); 8.04 (d, 1H, J = 8.4 Hz, Ar-H). 13C
NMR (125 MHz, CDCl3) δC 56.2, 76.9, 104.9, 121.7,
123.1, 125.2, 126.4, 128.1, 128.3, 128.6, 129.3, 135.1,
1
874 cm−1. H NMR (500 MHz, CDCl3) δH 7.35–7.41
(m, 2H, Ar-H); 7.50–7.54 (m, 1H, Ar-H); 7.81 (ddd,
1H, J = 1.6, 7.6, 7.6 Hz, Ar-H); 7.95 (dd, 1H, J =

Synthesis and anti-inflammatory evaluation of benz(oxa)thiazoles
613
0.8, 8.4 Hz, Ar-H); 8.10 (dd, 1H, J = 0.8, 8.4 Hz, Ar- 200–202◦C; Rf = 0.47 (AcOEt/petroleum ether 25%).
H); 8.35–8.38 (m, 1H, Ar-H); 8.69 (d, 1H, J = 4.7 Hz, IR (KBr): 3359, 1637, 1554, 1506, 1406, 1222, 1085,
Ar-H). 13C NMR (125 MHz, CDCl3) δC 120.6, 121.9, 829, 754, 684 cm−1. 1H NMR (500 MHz, CDCl3) δH
123.5, 125.2, 125.5, 126.4, 137.1, 149.5, 151.3, 154.1, 7.35–7.37 (m, 2H, Ar-H); 7.46–7.51 (m, 3H, Ar-H);
159.0, 169.1. MS (EI): m/z = 213 [M+H]+. Anal. 7.58 (d, 2H, J = 8.4 Hz, Ar-H); 7.66 (d, 2H, J =
Calcd for C12H8N2S: C, 67.90; H, 3.80; N, 13.20%. 8.4 Hz, Ar–H); 7.80 (d, 3H, J = 8.4 Hz, Ar-H); 8.00
Found: C, 68.10; H, 3.76; N, 13.11%.
(d, 1H, J = 8.4 Hz, Ar-H); 8.59 (s, 1H, pyrazolyl-H).
13C NMR (125 MHz, CDCl3) δC 117.2, 119.5, 121.5,
122.8, 123.6, 125.1, 126.4, 127.5, 128.7, 129.7, 131.0,
131.2, 131.28, 131.7, 139.3, 151.0, 153.4, 154.2, 154.9.
MS (EI): m/z = 431 [M+], 433 [M+2]. Anal. Calcd for
C22H13N3SBr: C, 61.12; H, 3.26; N, 9.72%. Found: C,
61.00; H, 3.33; N, 9.77%.
2.2s 2-(Thiophen-2-yl)benzo[d]thiazole (2s): Col-
ourless solid; mp 98–100◦C; Rf = 0.65 (AcOEt/
petroleum ether 15%). IR (KBr): 3083, 3043, 1628,
1
1064, 829 cm−1. H NMR (500 MHz, CDCl3) δH 7.30
(t, 1H, J = 3.9 Hz, Ar-H); 7.52–7.63 (m, 2H, Ar-H);
7.65 (d, 1H, J = 3.9 Hz, Ar-H); 7.72 (d, 1H, J =
3.9 Hz); 8.10 (d, 1H, J = 7.6 Hz, Ar-H); 8.20 (d, 1H,
J = 7.6 Hz, Ar-H). 13C NMR (125 MHz, CDCl3) δC
121.3, 123.0, 125.1, 126.3, 127.9, 128.5, 129.2, 134.5,
137.2, 153.5, 161.2. MS (EI): m/z = 217 [M+]. Anal.
Calcd for C11H7NS2: C, 60.80; H, 3.25; N, 6.45%.
Found: C, 60.99; H, 3.21; N, 6.39%.
2.2w 2-[3-(4-Ethoxyphenyl)-1-phenyl-1H-pyrazole-
4-yl]benzo[d]thiazole (2w): Pale yellow solid; mp
152–154◦C; Rf = 0.50 (AcOEt/petroleum ether 30%).
IR (KBr): 3434, 2965, 1613, 1558, 1503, 1247, 1106,
1
1043, 812 cm−1. H NMR (500 MHz, CDCl3) δH 1.46
(t, 3H J = 7.5 Hz, -OCH2CH3); 4.10 (q, 2H J =
6.8 Hz, -OCH2CH3); 6.98 (d, 2H, J = 8.6 Hz, Ar-H);
7.31 (q, 2H, J = 8.0 Hz, Ar-H); 7.44–7.50 (m, 3H,
Ar-H); 7.62–7.66 (m, 2H, Ar-H); 7.76 (d, 1H, J =
8.0 Hz, Ar-H); 7.81 (d, 2H, J = 8.6 Hz, Ar-H); 7.99
(d, 1H, J = 8.0 Hz, Ar-H); 8.64 (s, 1H, pyrazolyl-H).
13C NMR (125 MHz, CDCl3) δC 14.9, 63.6, 114.5,
117.4, 119.4, 121.5, 122.6, 124.1, 124.9, 126.2, 127.3,
128.1, 129.7, 131.1, 135.1, 139.5, 152.2, 153.2, 159.9,
163.2. MS (EI): m/z = 397 [M+]. Anal. Calcd for
C24H19N3OS: C, 72.52; H, 4.82; N, 10.57%. Found: C,
72.67; H, 4.75; N, 10.22%.
2.2t 2-(Furan-2-yl)benzo[d]thiazole (2t): Yellow
solid; mp 100–102◦C; Rf = 0.25 (AcOEt/petroleum
ether 30%). IR (KBr): 2929, 1602, 1475, 1103,
1
885 cm−1. H NMR (500 MHz, CDCl3) δH 6.60–6.62
(m, 1H); 7.20–7.22 (m, 1H, Ar-H); 7.36–7.42 (m, 1H,
Ar-H); 7.45–7.50 (m, 1H, Ar-H); 7.61 (s, 1H, Ar-
H); 7.93 (d, 1H, J = 8.3 Hz, Ar-H); 8.06 (d, 1H,
J = 8.3 Hz). 13C NMR (125 MHz, CDCl3) δC 111.5,
112.8, 121.8, 123.5, 125.4, 126.7, 134.6, 141.0, 154.0,
157.8. MS (EI): m/z = 202 [M+H]+. Anal. Calcd for
C11H7NOS: C, 65.65; H, 3.51; N, 6.96%. Found: C,
65.41; H, 3.56; N, 7.02%.
2.2x 2-[3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-
yl]benzo[d]thiazole (2x): Colourless solid; mp 173–
175◦C; Rf = 0.45 (AcOEt/petroleum ether 25%).
IR (KBr): 3421, 1599, 1502, 1388, 1203, 1067, 932,
2.2u 2-(1-Methyl-1H-indol-2-yl)benzo[d]thiazole
(2u): Colourless solid; mp 147–149◦C; Rf = 0.66
(AcOEt/petroleum ether 30%). IR (KBr): 3419,
3051, 1542, 1450, 1345, 1310, 1191, 1150, 975, 787,
1
823 cm−1. H NMR (500 MHz, CDCl3) δH 7.33–7.37
(m, 2H, Ar-H); 7.43–7.51 (m, 5H, Ar-H); 7.72 (d, 2H,
J = 8.4 Hz, Ar-H); 7.79 = 7.82 (m, 3H, Ar-H); 8.00
(d, 1H, J = 8.4 Hz, Ar-H); 8.59 (s, 1H, pyrazolyl-H).
13C NMR (125 MHz, CDCl3) δC 117.3, 119.4, 121.5,
122.8, 125.1, 126.4, 127.5, 128.7, 128.8, 129.7, 130.6,
131.0, 135.0, 135.2, 139.3, 150.9, 153.4, 159.8. MS
(EI): m/z = 388 [M+], 390 [M+2]. Anal. Calcd for
C22H14ClN3S: C, 68.12; H, 3.64; N, 10.83%. Found: C,
67.99; H, 3.76; N, 10.90%.
1
751 cm−1. H NMR (500 MHz, CDCl3) δH 4.31 (s,
3H, -NCH3); 7.17–7.20 (m, 2H, Ar-H); 7.33–7.44 (m,
3H, Ar-H); 7.48–7.51 (m, 1H, Ar-H); 7.67 (d, 1H,
J = 8.4 Hz, Ar-H); 7.88 (d, 1H, J = 7.6 Hz, Ar-H);
8.06 (d, 1H, J = 8.4 Hz, Ar-H). 13C NMR (125 MHz,
CDCl3) δC 32.4, 107.3, 110.2, 120.6, 121.4, 121.6,
123.3, 124.2, 125.4, 126.4, 127.3, 132.3, 134.5, 139.8,
154.3. 160.7. MS (EI): m/z = 264 [M+]. Anal. Calcd
for C16H12N2S: C, 72.70; H, 4.58; N, 10.60%. Found:
C, 72.81; H, 4.62; N, 10.53%.
2.2y 2-[3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-
yl]benzo[d]thiazole (2y): Colourless solid; mp 167–
169◦C; Rf = 0.44 (AcOEt/petroleum ether 30%). IR
(KBr): 3402, 2346, 1609, 1558, 1505, 1406, 1248,
2.2v 2-[3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-
4-yl]benzo[d]thiazole (2v): Colourless solid; mp

614
C Praveen et al.
1
1034, 833, 755 cm−1. H NMR (500 MHz, CDCl3) δH 124.2, 127.3, 131.8, 132.4, 134.9, 141.7, 149.2, 149.3,
3.87 (s, 3H, -OCH3); 6.99 (d, 2H, J = 8.4 Hz, Ar-H); 158.9. MS (EI): m/z = 254 [M+]. Anal. Calcd for
7.32 (q, 2H, J = 7.6 Hz, Ar-H); 7.44–7.48 (m, 3H, Ar- C14H10N2O3: C, 66.14; H, 3.96; N, 11.02%. Found: C,
H); 7.66 (d, 2H, J = 8.4 Hz, Ar-H); 7.76 (d, 1H, J = 66.00; H, 4.02; N, 10.89%.
7.6 Hz, Ar-H); 7.81 (d, 2H, J = 7.6 Hz, Ar-H); 7.99 (d,
1H, J = 8.4 Hz, Ar-H); 8.63 (s, 1H, pyrazolyl-H). 13C
2.3b Methyl 4-(benzo[d]oxazol-2-yl)benzoate (2bꢀ):
NMR (125 MHz, CDCl3) δC 55.4, 114.0, 117.4, 119.4,
Colourless solid; mp: 194–196◦C; Rf = 0.25
121.5, 122.6, 124.3, 124.9, 126.2, 127.3, 128.2, 129.7,
(AcOEt/petroleum ether 50%). IR (KBr): 3091, 2925,
131.1, 135.1, 139.5, 152.1, 153.2, 160.4, 160.5. MS
2852, 1725, 1606, 740, 707 cm−1. 1H NMR (500 MHz,
(EI): m/z = 383 [M+]. Anal. Calcd for C23H17N3SO:
CDCl3) δH 3.97 (s, 3H, -COOCH3); 7.35–7.43 (m, 2H,
C, 72.02; H, 4.47; N, 10.96%. Found: C, 71.89; H,
Ar-H); 7.60–7.63 (m, 1H, Ar-H); 7.79–7.81 (m, 1H,
4.45; N, 11.01%.
Ar-H); 8.20 (d, 2H, J = 8.4 Hz, Ar-H); 8.35 (d, 2H,
J = 8.4 Hz, Ar-H). 13C NMR (125 MHz, CDCl3) δC
2.2z 5,6-Dimethoxy-2-phenylbenzo[d]thiazole (2z):
Colourless solid; mp 143–145◦C; Rf
0.45
52.4, 120.3, 124.9, 125.7, 127.5, 129.5, 130.1, 131.0,
132.6, 141.9, 150.8, 161.9, 166.3. MS (EI): m/z = 253
[M+]. Anal. Calcd for C15H11NO3: C, 71.14; H, 4.38;
N, 5.53%. Found: C, 70.36; H, 4.33; N, 5.44%.
=
(AcOEt/petroleum ether 10%). IR (KBr): 3025, 2997,
1
2837, 1606, 1525, 1491, 1260, 840 cm−1. H NMR
(500 MHz, CDCl3) δH 3.91 (s, 3H, -OCH3); 3.93 (s,
3H, -OCH3); 7.55–7.59 (m, 3H, Ar-H); 7.65 (s, 1H,
Ar-H); 7.72 (s, 1H, Ar-H); 8.06–8.09 (m, 2H, Ar-H).
13C NMR (125 MHz, CDCl3) δC 56.1, 56.3, 103.6,
105.9, 126.6, 127.0, 129.8, 131.1, 133.5, 148.1, 149.0,
165.1. MS (EI): m/z = 271 [M+]. Anal. Calcd for
C15H13NO2S: C, 66.40; H, 4.83; N, 5.16%. Found: C,
66.19; H, 4.85; N, 6.20%.
2.3c 2-(2-Chlorophenyl)-5-methylbenzo[d]oxazole
(2cꢀ): Colourless solid; mp 74–76◦C; Rf = 0.59
(AcOEt/petroleum ether 25%). IR (KBr): 2921, 1734,
1590, 1548, 1468, 1423, 1325, 1263, 1194, 1019, 774,
1
730 cm−1. H NMR (500 MHz, CDCl3) δH 2.49 (s,
3H, -CH3); 7.18 (d, 1H, J = 8.4 Hz, Ar-H); 7.38 (m,
2H, Ar-H); 7.47 (d, 1H, J = 8.4 Hz, Ar-H); 7.54 (d,
1H, J = 9.2 Hz, Ar-H); 7.62 (s, 1H, Ar-H); 8.11 (d,
1H, J = 8.4 Hz, Ar-H). 13C NMR (125 MHz, CDCl3)
δC 21.6, 110.2, 120.4, 123.5, 126.5, 126.8, 126.9,
131.4, 131.9, 133.5, 134.6, 141.9, 148.9, 161.1. MS
(EI): m/z = 245 [M+], 247 [M+2]. Anal. Calcd for
C14H10ClNO: C, 69.00; H, 4.14; N, 5.75%. Found: C,
69.22; H, 4.25; N, 5.88%.
2.3 General procedure for the synthesis
of benzoxazoles 2aꢀ–2zꢀ
To a pyrex reaction vessel were added 2-aminophenol
(1.1 mmol), aldehyde (1.0 mmol), PIFA (1.05 mmol) in
ethanol (3 ml). The reaction vessel was then placed in
the Emrys Optimizer and exposed to microwave irra-
diation (80◦C) for 15 min. The reaction mixture was
then allowed to cool at room temperature and quenched
with 15 mL of water. The crude reaction mixture was
extracted with EtOAc (3 × 15 mL). The combined
organic layers were dried over anhydrous Na2SO4, fil-
tered, concentrated and purified by column chromato-
graphy on silica gel using petroleum ether/EtOAc to
afford the pure product.
2.3d 2-(4-Chlorophenyl)benzo[d]oxazole (2dꢀ):
Colourless solid; mp: 143–145◦C; Rf = 0.50
(AcOEt/petroleum ether 10%). IR (KBr): 2961, 1621,
1439, 1245, 1092, 740 cm−1. 1H NMR (500 MHz,
CDCl3) δH 7.28–7.32 (m, 2H, Ar-H); 7.40–7.45 (m, 2H,
Ar-H); 7.49–7.53 (m, 1H, Ar-H); 7.66–7.70 (m, 1H,
Ar-H); 8.10–8.13 (m, 2H, Ar-H). 13C NMR (125 MHz,
CDCl3) δC 110.5, 120.0, 124.9, 125.1, 125.8, 128.6,
130.0, 129.1, 129.2, 137.9, 141.9, 150.9, 161.8. MS
(EI): m/z = 229 [M+], 231 [M+2]. Anal. Calcd for
C13H6ClNO: C, 67.99; H, 3.51; N, 6.10%. Found: C,
67.81; H, 3.56; N, 6.18%.
2.3a 5-Methyl-2-(2-nitrophenyl)benzo[d]oxazole
(2aꢀ): Pink solid; mp 134–136◦C; Rf = 0.49
(AcOEt/petroleum ether 30%). IR (KBr): 3431, 2915,
1
1542, 1480, 1374, 1196, 1044, 800, 772 cm−1. H
NMR (500 MHz, CDCl3) δH 2.48 (s, 3H, -CH3); 7.19
(d, 1H, J = 8.4 Hz, Ar-H); 7.42 (d, 1H, J = 8.4 Hz, 2.3e 2-p-Tolylbenzo[d]oxazole
(2eꢀ): Colourless
Ar-H); 7.58 (s, 1H, Ar-H); 7.65 (t, 1H, J = 7.6 Hz, solid; mp: 115–117◦C; Rf = 0.50 (AcOEt/petroleum
Ar-H); 7.71 (t, 1H, J = 7.6 Hz, Ar-H); 7.86 (d, 1H, J ether 10%). IR (KBr): 3088, 1628, 1244, 1055 cm−1.
= 7.6 Hz, Ar-H); 8.11 (d, 1H, J = 7.6 Hz, Ar-H). 13C 1H NMR (500 MHz, CDCl3) δH 2.41 (s, 3H, -CH3);
NMR (125 MHz, CDCl3) δC 21.6, 110.4, 120.5, 121.6, 6.83–7.16 (4H, m, Ar-H); 7.35–7.81 (m, 4H, Ar-H).

Synthesis and anti-inflammatory evaluation of benz(oxa)thiazoles
615
13C NMR (125 MHz, CDCl3) δC 22.4, 110.6, 120.8, 2.1 Hz, Ar-H); 8.65 (d, 2H, J = 2.1 Hz, Ar-H). 13C
123.5, 125.5, 126.8, 127.9, 131.1, 142.2, 150.9, 164.7. NMR (125 MHz, CDCl3) δC 110.8, 116.1, 121.0, 125.8,
MS (EI): m/z = 209 [M+]. Anal. Calcd for C14H11NO: 127.9, 129.0, 132.5, 142.5, 154.0. MS (EI): m/z = 240
C, 80.36; H, 5.30; N, 6.69%. Found: C, 80.12; H, 5.35; [M+]. Anal. Calcd for C13H8N2O3: C, 65.00; H, 3.36;
N, 6.77%.
N, 11.66%. Found: C, 64.81; H, 3.41; N, 11.75%.
2.3f 2-(3,4,5-Trimethoxyphenyl)benzo[d]oxazole 2.3j 2-(4-Bromophenyl)benzo[d]oxazole (2jꢀ):
(2fꢀ): Colourless solid; mp 111–113◦C; Rf = 0.25 Pale yellow solid; mp: 142–144◦C; Rf = 0.40
(AcOEt/petroleum ether 10%). IR (KBr): 2935, 1632, (AcOEt/petroleum ether 25%). IR (KBr): 1581, 1501,
1246, 1145, 1058 cm−1. H NMR (500 MHz, CDCl3) 1269, 1052, 944, 830, 799 cm−1. H NMR (500 MHz,
δH 3.89 (s, 3H, -OCH3); 3.91 (s, 3H, -OCH3); 3.96 (s, CDCl3) δH 7.30–7.37 (m, 2H, Ar-H); 7.50–7.55 (m, 1H,
3H, -OCH3); 7.35–7.69 (m, 4H, Ar-H) 7.99–8.18 (m, Ar-H); 7.60–7.65 (m, 2H, Ar-H); 7.70–7.75 (m, 1H,
2H, Ar-H). 13C NMR (125 MHz, CDCl3) δC 57.0, 57.5, Ar-H); 8.05–8.10 (m, 2H, Ar-H). 13C NMR (125 MHz,
58.7, 112.8, 122.7, 124.4, 127.5, 131.0, 132.5, 143.4, CDCl3) δC 110.5, 120.0, 124.6, 125.5, 126.1, 126.3,
149.5, 150.1, 151.1. MS (EI): m/z = 285 [M+]. Anal. 128.9, 132.3, 142.0, 150.5, 161.9. MS (EI): m/z =
Calcd for C16H15NO4: C, 67.36; H, 5.30; N, 4.91%. 273 [M+], 275 [M+2]. Anal. Calcd for C13H8BrNO: C,
1
1
Found: C, 67.51; H, 5.26; N, 4.85%.
56.96; H, 2.94; N, 5.11%. Found: C, 57.16; H, 2.90; N,
5.05%.
2.3g Methyl 3-(benzo[d]oxazol-2-yl)benzoate (2gꢀ):
Yellow solid; mp: 128–130◦C; Rf
=
0.30 2.3k
2-(4-Nitrophenyl)benzo[d]oxazole (2kꢀ):
(AcOEt/petroleum ether 50%). IR (KBr): 3083, 2950, Yellow solid; mp: 262–264◦C; Rf
=
0.25
2922, 1720, 1606, 745 cm−1. 1H NMR (500 MHz, (AcOEt/petroleum ether 50%). IR (KBr): 1640, 1524,
CDCl3) δH 3.96 (s, 3H, -COOCH3); 7.40–7.43 (m, 1346, 1242, 1058 cm−1. H NMR (500 MHz, CDCl3)
1
2H, Ar-H); 7.60–7.65 (m, 2H, Ar-H); 7.80–7.83 (m, δH 7.75–8.11 (m, 4H, Ar-H); 8.22–8.5 (4H, m, Ar-
1H, Ar-H); 8.25 (d, 1H, J = 7.6 Hz, Ar-H); 8.48 (d, H). 13C NMR (125 MHz, CDCl3) δC 112.4, 120.8,
1H, J = 7.6 Hz, Ar-H); 8.95 (s, 1H, Ar-H). 13C NMR 124.8, 126.0, 127.0, 129.1, 130.7, 141.0, 148.9, 150.5,
(125 MHz, CDCl3) δC 110.7, 120.1, 124.9, 125.5, 161.0. MS (EI): m/z = 240 [M+]. Anal. Calcd for
127.4, 128.7, 129.2, 131.1, 131.7, 132.5, 141.7, 150.7, C13H8N2O3: C, 65.00; H, 3.36; N, 11.66%. Found: C,
162.0, 166.2. MS (EI): m/z = 253 [M+]. Anal. Calcd 65.13; H, 3.31; N, 11.58%.
for C15H11NO3: C, 71.14; H, 4.38; N, 5.53%. Found:
C, 70.99; H, 4.41; N, 5.60%.
2.3l 2-(Benzo[d][1,3]dioxol-5-yl)benzo[d]oxazole
(2lꢀ): Yellow solid; mp 147–149◦C; Rf = 0.30
(AcOEt/petroleum ether 20%). IR (KBr): 2931, 1639,
1245, 1042, 1115, 761 cm−1. 1H NMR (500 MHz,
CDCl3) δH 4.39 (s, 2H, -OCH2O-); 6.86–7.02 (m, 3H,
Ar-H); 7.37–7.78 (m, 4H, Ar-H). 13C NMR (125 MHz,
CDCl3) δC 91.1, 113.0, 114.5, 119.0, 124.8, 125.5,
131.0, 138.4, 145.2, 146.7. MS (EI): m/z = 239 [M+].
Anal. Calcd for C14H9NO3: C, 70.29; H, 3.79; N,
5.86%. Found: C, 70.51; H, 3.66; N, 5.79%.
2.3h 5-Methyl-2-(4-nitrophenyl)benzo[d]oxazole
(2hꢀ): Pale yellow solid; mp 218–250◦C; Rf = 0.44
(AcOEt/petroleum ether 30%). IR (KBr): 3402, 1556,
1521, 1342, 854, 706 cm−1. 1H NMR (500 MHz,
CDCl3) δH 2.50 (s, 3H, -CH3); 7.22 (d, 1H, J = 8.4 Hz,
Ar-H); 7.48 (d, 1H, J = 8.4 Hz Ar-H); 7.59 (s, 1H,
Ar-H); 8.35–8.41 (m, 4H, Ar-H). 13C NMR (125 MHz,
CDCl3) δC 21.6, 110.4, 120.5, 124.3, 127.6, 128.4,
133.0, 135.3, 142.2, 149.4, 160.8, 162.7. MS (EI):
m/z = 254 [M+]. Anal. Calcd for C14H10N2O3: C,
66.14; H, 3.96; N, 11.02%. Found: C, 66.32; H, 4.10;
N, 10.92%.
2.3m 2-(4-Methoxyphenyl)benzo[d]oxazole (2mꢀ):
Colourless solid; mp: 97–99◦C; Rf
=
0.55
(AcOEt/petroleum ether 10%). IR (KBr): 3052, 1618,
1255, 1248, 1037, 1025, 802 cm−1. 1H NMR (500 MHz,
CDCl3) δH 3.88 (s, 3H, -OCH3); 7.00 (d, 2H, J =
8.4 Hz, Ar-H); 7.29–7.36 (m, 2H, Ar-H); 7.48–7.52 (m,
1H, Ar-H); 7.65–7.73 (m, 1H, Ar-H); 8.21 (d, 2H, J =
8.7 Hz, Ar-H). 13C NMR (125 MHz, CDCl3) δC 55.5,
110.5, 114.5, 119.5, 119.9, 124.5, 124.8, 129.4, 142.3,
150.8, 162.3, 162.8. MS (EI): m/z = 225 [M+]. Anal.
2.3i 5-Nitro-2-phenylbenzo[d]oxazole (2iꢀ): Yellow
solid; mp: 241–243◦C; Rf = 0.20 (AcOEt/petroleum
ether 30%). IR (KBr): 1641, 1525, 1350, 1247,
1
1051 cm−1. H NMR (500 MHz, CDCl3) δH 7.51–7.58
(m, 3H, Ar-H); 7.70 (d, 1H, J = 9.2 Hz, Ar-H);
8.22–8.27 (m, 2H, Ar-H); 8.29 (dd, 1H, J = 9.2,

616
C Praveen et al.
Calcd for C14H11NO2: C, 74.65; H, 4.92; N, 6.22%. (m, 2H, Ar-H). 13C NMR (125 MHz, CDCl3) δC 110.5,
Found: C, 74.81; H, 4.89; N, 6.15%.
120.0, 124.5, 125.0, 127.0, 127.8, 129.0, 131.6, 142.0,
150.8, 162.9. MS (EI): m/z = 195 [M+]. Anal. Calcd
for C13H9NO: C, 79.98; H, 4.65; N, 7.17%. Found: C,
80.11; H, 4.61; N, 7.08%.
2.3n 2-(3,4-Dichlorophenyl)benzo[d]oxazole (2nꢀ):
Colourless solid; mp: 139–141◦C; Rf = 0.50
(AcOEt/petroleum ether 30%). IR (KBr): 2963, 1620,
1440, 1241, 1099, 747 cm−1. 1H NMR (500 MHz, 2.3r 2-(2-Chlorophenyl)benzo[d]oxazole (2rꢀ):
CDCl3) δH 7.20–7.24 (m, 2H, Ar-H); 7.31–7.39 (m, Colourless solid; mp 61–64◦C; Rf
=
0.53
2H, Ar-H); 7.55–7.63 (m, 1H, Ar-H); 7.75–7.80 (m, (AcOEt/petroleum ether 30%). IR (KBr): 2953, 1537,
1H, Ar-H); 8.05 (dt, 1H, J = 8.1, 2.1 Hz, Ar-H); 1430, 1253, 1194, 1022, 806, 738 cm−1. H NMR
1
8.34 (t, 1H, J = 2.1 Hz, Ar-H). 13C NMR (125 MHz, (500 MHz, CDCl3) δH 7.36–7.46 (m, 4H, Ar-H);
CDCl3) δC 110.5, 120.0, 125.0, 125.6, 126.3, 127.0, 7.56–7.57 (m, 1H, Ar-H); 7.61–7.62 (m, 1H, Ar-H);
129.2, 131.0, 133.3, 141.6, 150.5, 160.9. MS (EI): 7.84–7.86 (m, 1H, Ar-H); 8.13 (dd, 1H, J = 7.6,
m/z = 263 [M+], 265 [M+2], 267 [M+4]. Anal. Calcd 2.3 Hz, Ar-H). 13C NMR (125 MHz, CDCl3) δC 110.9,
for C13H7Cl2NO: C, 59.12; H, 2.67; N, 5.30%. Found: 120.6, 124.8, 125.7, 126.2, 127.1, 131.5, 131.9, 132.0,
C, 58.96; H, 2.71; N, 5.37%.
133.6, 141.8, 150.6, 161.1. MS (EI): m/z = 229 [M+],
231 [M+2]. Anal. Calcd for C13H6ClNO: C, 67.99; H,
3.51; N, 6.10%. Found: C, 68.11; H, 3.62; N, 5.99%.
2.3o 2-(3-Methoxyphenyl)benzo[d]oxazole (2oꢀ):
Yellow solid; mp: 107–109◦C; Rf
=
0.50
(AcOEt/petroleum ether 10%). IR (KBr): 3055, 1620, 2.3s 2-(Furan-2-yl)benzo[d]oxazole (2sꢀ): Colour-
1250, 1241, 1030, 1021 cm−1. H NMR (500 MHz, less solid; mp 90–92◦C; Rf = 0.45 (AcOEt/petroleum
1
CDCl3) δH 3.95 (s, 3H, -OCH3); 7.10–7.15 (m, 1H, ether 15%). IR (KBr): 2926, 1620, 1245, 1141, 1046,
Ar-H); 7.35–7.41 (m, 2H, Ar-H); 7.47 (dd, 1H, J = 751 cm−1. H NMR (500 MHz, CDCl3) δH 6.51–6.98
1
8.1, 8.1 Hz, Ar-H); 7.60–7.65 (m, 1H, Ar-H); 7.75– (m, 3H, Ar-H); 7.02–7.56 (m, 4H, Ar-H). 13C NMR
7.82 (m, 2H, Ar-H); 7.85–7.90 (m, 1H, Ar-H). 13C (125 MHz, CDCl3) δC 103.9, 115.0, 116.2, 124.5,
NMR (125 MHz, CDCl3) δC 55.5, 110.7, 112.1, 118.5, 125.6, 126.2, 145.0, 146.3, 150.5, 153.1, 156.5. MS
119.9, 124.4, 125.0, 128.2, 128.9, 141.9, 151.0, 159.9, (EI): m/z = 185 [M+]. Anal. Calcd for C11H7NO2: C,
162.8. MS (EI): m/z = 225 [M+]. Anal. Calcd for 71.35; H, 3.81; N, 7.56%. Found: C, 71.05; H, 3.86; N,
C14H11NO2: C, 74.65; H, 4.92; N, 6.22%. Found: C, 7.65%.
74.52; H, 4.95; N, 6.29%.
2.3t
2-(Thiophen-2-yl)benzo[d]oxazole (2tꢀ):
Yellow solid; mp 104–106◦C; Rf = 0.50 (AcOEt/
petroleum ether 10%). IR (KBr): 2930, 1638, 1252,
1135, 1043, 749 cm−1. 1H NMR (500 MHz, CDCl3) δH
6.66–6.98 (m, 3H, Ar-H); 7.52–7.72 (m, 4H, Ar-H).
13C NMR (125 MHz, CDCl3) δC 112.5, 120.8, 124.5,
125.0, 126.5, 127.0, 127.2, 138.0, 140.6, 149.1, 154.6.
MS (EI): m/z = 201 [M+]. Anal. Calcd for C11H7NOS:
C, 65.65; H, 3.51; N, 6.96%. Found: C, 65.83; H, 3.46;
N, 6.88%.
2.3p 5-Chloro-2-(3-nitrophenyl)benzo[d]oxazole
(2pꢀ): Colourless solid; mp 184–186◦C; Rf = 0.52
(AcOEt/petroleum ether 30%). IR (KBr): 3424, 2361,
1526, 1449, 1351, 1100, 821 cm−1. 1H NMR (500 MHz,
CDCl3) δH 7.38 (q, 1H, J = 8.4 Hz, Ar-H); 7.54 (d, 1H,
J = 9.1 Hz, Ar-H); 7.72 (d, 1H, J = 8.4 Hz, Ar-H);
7.78 (s, 1H, Ar-H); 8.39 (d, 1H, J = 8.8 Hz, Ar-H);
8.55 (d, 1H, J = 7.6 Hz, Ar-H); 9.07 (s, 1H, Ar-H).
13C NMR (125 MHz, CDCl3) δC 111.8, 120.5, 122.7,
126.3, 126.5, 130.4, 130.7, 133.3, 142.9, 149.5, 157.5,
161.9. MS (EI): m/z = 274 [M+], 276 [M+2]. Anal.
Calcd for C13H7ClN2O3: C, 56.85; H, 2.57; N, 10.20%.
Found: C, 56.75; H, 2.49; N, 10.15%.
2.3u 2-(1H-Pyrrol-2-yl)benzo[d]oxazole (2uꢀ): Pink
solid; mp 144–146◦C; Rf = 0.51 (AcOEt/petroleum
ether 30%). IR (KBr): 3401, 1629, 1585, 1455, 1403,
1243, 1117, 741 cm−1. 1H NMR (500 MHz, CDCl3) δH
6.36–6.38 (m, 1H, Ar-H); 7.04–7.05 (m, 1H, Ar-H);
7.28–7.33 (m, 2H, Ar-H); 7.52 (d, 1H, J = 7.6 Hz, Ar-
H); 7.64 (d, 1H, J = 7.6 Hz, Ar-H); 10.25 (s, 1H, -NH).
13C NMR (125 MHz, CDCl3) δC 110.5, 110.9, 113.3,
118.9, 119.9, 123.1, 124.4, 124.7, 150.2, 158.2, 163.7.
MS (EI): m/z = 184 [M+]. Anal. Calcd for C11H8N2O:
2.3q 2-Phenylbenzo[d]oxazole (2qꢀ): Colourless
solid; mp: 100–102◦C; Rf = 0.60 (AcOEt/petroleum
ether 10%). IR (KBr): 2975, 1614, 1248, 1040,
1
803 cm−1. H NMR (500 MHz, CDCl3) δH 7.35–7.40
(m, 2H, Ar-H); 7.50–7.55 (m, 2H, Ar-H); 7.60–7.63
(m, 1H, Ar-H); 7.75–7.85 (m, 1H, Ar-H); 8.25–8.31

Synthesis and anti-inflammatory evaluation of benz(oxa)thiazoles
617
C, 71.73; H, 4.38; N, 15.21%. Found: C, 71.81; H, 4.25; 750 cm−1. 1H NMR (500 MHz, CDCl3) δH 1.43 (t, 3H,
N, 15.25%.
J = 6.9 Hz, -OCH2CH3); 4.09 (q, 2H, J = 6.9 Hz,
-OCH2CH3); 6.98 (d, 2H, J = 9.1 Hz, Ar-H); 7.26–
7.29 (m, 2H, Ar-H); 7.34 (t, 1H, J = 7.6 Hz, Ar-H);
7.46–7.54 (m, 3H, Ar-H); 7.69 (d, 1H, J = 6.9 Hz, Ar-
H); 7.80 (d, 2H, J = 7.6 Hz, Ar-H); 7.94 (d, 2H, J =
8.4 Hz, Ar-H); 8.68 (s, 1H, pyrazolyl-H). 13C NMR
(125 MHz, CDCl3) δC 14.9, 63.6, 109.9, 110.4, 114.3,
119.4, 119.8, 124.5, 124.7, 127.4, 129.7, 130.2, 130.6,
139.4, 142.0, 147.0, 150.2, 152.1, 158.6, 159.7. MS
(EI): m/z = 381 [M+]. Anal. Calcd for C24H19N3O2:
C, 75.57; H, 5.02; N, 11.02%. Found: C, 75.44; H,
5.11; N, 11.09%.
2.3v 2-(1-Methyl-1H-indol-2-yl)benzo[d]oxazole
(2vꢀ): Colourless solid; mp 161–163◦C; Rf = 0.55
(AcOEt/petroleum ether 25%). IR (KBr): 2332, 1579,
1450, 1340, 1240, 1141, 753 cm−1. 1H NMR (500 MHz,
CDCl3) δH 4.31 (s, 3H, -NCH3); 7.18 (t, 1H, J =
7.6 Hz, Ar-H); 7.35–7.38 (m, 3H, Ar-H); 7.42 (d, 2H, J
= 10.7 Hz, Ar-H); 7.57 (d, 1H, J = 7.6 Hz, Ar-H); 7.72
(d, 1H, J = 7.6 Hz, Ar-H); 7.80–780 (m, 1H, Ar-H).
13C NMR (125 MHz, CDCl3) δC 32.2, 107.6, 110.2,
110.5, 119.9, 120.7, 122.1, 124.5, 124.6, 125.2, 126.3,
126.9, 139.9, 142.2, 149.9, 157.8. MS (EI): m/z = 248
[M+]. Anal. Calcd for C16H12N2O: C, 77.40; H, 4.87;
N, 11.28%. Found: C, 77.55; H, 4.75; N, 11.39%.
2.3z 5-Chloro-2-phenylethylbenzo[d]oxazole (2zꢀ):
Yellow solid; mp 114–116◦C; Rf
=
0.50
(AcOEt/petroleumether 40%). IR (KBr): 3402, 1621,
1585, 1488, 1391, 1239, 1088, 985 cm−1. H NMR
1
2.3w 2-[3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-
yl]benzo[d]oxazole (2wꢀ): Colourless solid; mp 205–
207◦C; Rf = 0.44 (AcOEt/petroleum ether 25%). IR
(KBr): 3411, 1627, 1590, 1502, 1454, 1391, 1244,
1093, 989 cm−1. 1H NMR (500 MHz, CDCl3) δH
7.32–7.33 (m, 2H, Ar-H); 7.37–7.39 (m, 1H, Ar-H);
7.45–7.53 (m, 5H, Ar-H); 7.71 (d, 1H, J = 9.1 Hz, Ar-
H); 7.81 (d, 2H, J = 8.4 Hz, Ar-H); 7.99 (d, 2H, J =
8.4 Hz, Ar-H); 8.71 (s, 1H, pyrazolyl-H). 13C NMR
(125 MHz, CDCl3) δC 110.3, 110.4, 119.5, 124.6,
124.9, 127.7, 128.5, 129.8, 130.3, 130.6, 134.9, 139.3,
141.9, 150.2, 151.1, 158.1. MS (EI): m/z = 372 [M+],
374 [M+2]. Anal. Calcd for C22H14ClN3O: C, 71.07; H,
3.80; N, 11.30%. Found: C, 71.25; H, 3.75; N, 11.25%.
(500 MHz, CDCl3) δH 3.14 (t, 2H, J = 7.6 Hz); 3.29 (t,
2H, J = 7.6 Hz); 7.15–7.20 (m, 1H, Ar-H); 7.24–7.28
(m, 4H, Ar-H); 7.38 (dd, 1H, J = 2.1, 8.6 Hz, Ar-H);
7.71 (d, 1H, J = 8.6 Hz, Ar-H); 7.75–7.77 (m, 1H,
Ar-H). 13C NMR (125 MHz, CDCl3) δC 29.4, 31.6,
111.7, 119.0, 124.6, 126.2, 128.2, 128.3, 128.4, 140.0,
142.1, 148.9, 167.9. MS (EI): m/z = 257 [M+], 259
[M+2]. Anal. Calcd for C24H19N3O2: C, 69.91; H, 4.69;
N, 5.43%. Found: C, 70.07; H, 4.65; N, 5.47%.
2.4 Animals and drug dosage
2.4a Animals: The selection of animals, caring and
handling was done as per the guidelines set by the
Indian National Science Academy, New Delhi, India.
Inbred albino mice (Swiss strain) of adult gender
weighing 120–150 g were used for the study. The mice
were housed individually in clean polypropylene cages
containing sterile paddy husk (procured locally) as bed-
ding throughout the experiment. All animals were fed
with sterile commercial pelleted rat chow supplied by
Hindustan Lever Ltd. (Mumbai, India) with free access
to water (ad libitum) under standardized housing con-
ditions (natural light-dark cycle, temperature 23 1◦C,
2.3x 2-[3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-
yl]-5-methylbenzo[d]oxazole (2xꢀ): Colourless solid;
mp 210–214◦C; Rf = 0.52 (AcOEt/petroleum ether
30%). IR (KBr): 2920, 1589, 1500, 1262, 1223, 1057,
1
944, 830, 799 cm−1. H NMR (500 MHz, CDCl3) δH
2.46 (s, 3H, -CH3); 7.11 (d, 1H, J = 8.4 Hz, Ar-H);
7.34–7.39 (m, 2H, Ar-H); 7.49–7.52 (m, 3H, Ar-H);
7.60 (d, 2H, J = 8.4 Hz, Ar-H); 7.80 (d, 2H, J =
7.6 Hz, Ar-H); 7.91 (d, 2H, J = 8.4 Hz, Ar-H); 8.68
(s, 1H, pyrazolyl-H). 13C NMR (125 MHz, CDCl3) δC
21.6, 109.7, 110.4, 119.8, 123.3, 126.1, 127.7, 129.7,
130.9, 131.1, 131.4. MS (EI): m/z = 430 [M+], 432
[M+2]. Anal. Calcd for C23H15BrN3O: C, 64.20; H,
3.75; N, 9.77%. Found: C, 64.25; H, 3.69; N, 10.02%.
relative humidity 55
5%). After 7 days of adap-
tation to laboratory conditions, the animals were ran-
domly assigned to 12 experimental groups of 5 mice
each. Each mouse was used only once. All tests were
performed between 08:00 and 16:00 h. All efforts were
2.3y 2-[3-(4-Ethoxyphenyl)-1-phenyl-1H-pyrazole-4- made to minimize animal suffering and to use only the
yl]benzo[d]oxazole (2yꢀ): Orange solid; mp 189– number of animals necessary to produce reliable scien-
191◦C; Rf = 0.44 (AcOEt/petroleumether 50%). IR tific data. The experimental protocols and procedures
(KBr): 3430, 2930, 1631, 1583, 1450, 1240, 1045, listed below conformed to the Guide for the Care and

618
C Praveen et al.
Use of Laboratory Animals and approved by the Insti- corresponding phenolic imines was particularly attrac-
tutional Ethics Committee. Mice equivalent doses in tive, since this reaction utilizes a mild oxidant.42 How-
mg/kg body weight of clinical doses were calculated ever, this protocol was amenable to the synthesis of only
as mg/kg body weight with the help of standard tables benzoxazoles and no synthesis of benzothiazoles was
(Karber’s method).59
reported. It was anticipated that similar oxidant, PIFA
[Phenyliodonium bis(trifluoroacetate)] could promote
the oxidative cyclization of phenolic and thiopheno-
lic imines. The oxidizing capability of PIFA in organic
synthesis is well-documented but recent developments
have seen a host of further applications.60
2.4b Dose and administration of compounds: The
synthesized compounds (50 mg/kg), pentazocine as a
reference opiod analgesic drug (50 mg/kg) and 2% gum
acacia as control were administered orally by intragas-
tric tube.
To begin our studies, we proceeded to explore the
PIFA (1.05 mmol) promoted oxidative cyclization
reaction of 2-aminothiophenol (1.1 mmol) with p-
anisaldehyde (1.0 mmol) in ethanol61 at 80◦C under
microwave irradiation. To our delight, the reaction was
complete after 5 min and showed a good conversion
towards benzothiazole 2a, which was isolated in 60%
yield after aqueous work-up followed by column chro-
matography. This positive initial result prompted us to
further investigate the conditions suitable for this reac-
tion under microwave irradiation. Extension of the irra-
diation time from to 15 min resulted in the complete
conversion and 2a was isolated in 80% yield. Further
irradiation up to 30 min did not lead to the increase in
product yield. Attempts to decrease the reaction tem-
perature were unsuccessful. Starting from these obser-
vations, we chose microwave irradiation of the sub-
strates with PIFA (1.05 mmol) in ethanol at 80◦C for
15 min as the standard reaction conditions for the syn-
thesis of a wide range of benzothiazoles (scheme 2) (see
supporting information). The versatility of this method-
ology was demonstrated with respect to variation in the
aldehyde and amine by synthesis of a small family of
benzothiazoles 2a–2z (figure 1). As shown in figure 1,
our microwave-assisted oxidative cyclization worked
well for a variety of aldehydes and 2-aminothiophenols,
giving good to excellent yields of the corresponding
benzothiazoles 2a–2z. However, compounds (2r, 2s and
2t) containing heterocyclic cores like pyridine, thio-
phene and furan, respectively were obtained only in
moderate yields. These results can be attributed to the
cleavage of these heterocycles under microwave con-
dition. However, other microwave-assisted protocols
resulted in excellent yield of similar products.28e
2.5 Statistical analysis
The obtained data were analysed using one-way anal-
ysis of variance (ANOVA) followed by Dunnet’s mul-
tiple comparison test using computerized Graph Pad
Instat version 3.05 (Graph Pad software, USA). The
results are presented as mean Standard error of means
(SEM). Differences between data sets were considered
as significant when P < 0.001.
3. Results and discussion
3.1 Chemistry
It is pertinent to note that in our earlier study, a two-
step approach for the synthesis of a series of ben-
zoxazoles and benzothiazoles have been described via
PCC promoted oxidative cyclization of phenolic and
thiophenolic imines, respectively (scheme 1).58a
Given the significance of this methodology, we were
interested in a one-pot process by combining the reac-
tions such as condensation and oxidation with particu-
lar emphasis on performing this transformation under
microwave condition using an alternate oxidant. The
choice of the oxidant plays a crucial role, since we
wished a particular oxidant to be capable of promot-
ing the oxidative cyclization of both thiophenolic and
phenolic schiff bases. The IBD (iodobenzene diace-
tate) promoted synthesis of substituted benzoxazoles
through oxidative intramolecular cyclization of the
ZH
ZH
PCC / Silica
CH2Cl2, rt
Z
PIFA (1.05 equiv), EtOH
w, 80 oC, 15 min
Z
R
ArCHO
R
R
Ar
R
Ar
µ
N
NH2
(1.1 equiv)
N
N
Ar
(1.0 equiv)
2a-2y: Z = S
2
1
2a'-2y': Z = O
Z = S, O
Scheme 2. PIFA promoted synthesis of benz(oxa)thiazoles
Scheme 1. PCC promoted synthesis of benz(oxa)thiazoles. under microwave irradiation.

Synthesis and anti-inflammatory evaluation of benz(oxa)thiazoles
619
N
S
N
S
N
S
N
S
Cl
OMe
CF3
NMe2
2b
2d
90%
2c
71%
N
2a
2e
80%
70%
88%
86%
MeO
CO2Me
N
S
N
N
S
S
S
NO2
2f
2g
2h
81%
92%
MeO
N
S
N
S
N
S
N
S
OMe
OMe
OBn
OMe
Cl
2i
2j
2l
79 %
82 %
2k
79%
77%
OMe
OH
OMe
O
OMe
OH
OMe
OBn
OMe
N
S
N
N
N
S
O
S
S
Br
2p
2u
2m
2q
2n
2o
75%
87%
76%
74%
84%
N
S
N
S
N
S
N
N
S
N
S
O
N
S
Me
2r
2s
2t
59%
63%
61%
74%
Ph
Ph
Ph
N
N
S
N
S
N
S
N
N
MeO
MeO
N
N
Ph
N
S
N
N
Ph
N
N
S
2z
80%
MeO
Br
EtO
2w
Cl
2v
2x
77%
79%
81%
2y
80%
Figure 1. Library of benzothiazoles 2a–2z and their isolated yield (%).
To study the scope of this reaction, a range of 2- makes the adjacent carbon more electrophilic, thus it
aminophenols and aldehydes carrying different func- makes way for the facile attack of nucleophilic Z (S
tional groups were subjected under the same reaction or O) atom leading to the benzoxa(thia)zoline interme-
condition. The results obtained are summarized in fig- diate 1a. Subsequent dehydrogenation affords the ben-
ure 2. As shown in figure 2, the substrates possessing zoxa(thia)zole product 2 along with iodobenzene and
both electron releasing and electron donating groups trifluoroacetic acid as by-product. From the mechanism
were compatible with this microwave-assisted protocol it was evident that PIFA serves both as a Lewis acid as
giving good to excellent yields of the corresponding well as an oxidant.
benzoxazole derivatives 2aꢀ–2zꢀ (see supporting infor-
mation). Similar to the benzothiazole series, benzoxa-
4. Pharmacology
zoles possessing furan, thiophene and pyrrolle (2sꢀ, 2tꢀ
and 2uꢀ) were obtained in moderate yields. The struc-
4.1 Evaluation of in vivo analgesic activity
ture of all the synthesized compounds was confirmed by
1
spectral data (IR, H NMR 13C NMR and EI-MS) and Ten compounds of benzothiazoles (2h, 2j, 2l, 2n, 2o
elemental analyses (see supplementary information).
and 2u–2y) and benzoxazoles (2aꢀ, 2cꢀ, 2hꢀ, 2pꢀ, 2rꢀ
The formation of benzoxa(thia)zole derivatives can and 2uꢀ–2yꢀ), respectively were selected to evaluate the
be explained by scheme 3. Reaction of aldehyde with analgesic activity. To begin with the oral toxicity of
2-aminothiophenol/2-aminophenol produces the imine the synthesized compounds was performed by acute
intermediate 1. The attack of the imino nitrogen of toxic class method.59 The selected adult albino rats
intermediate 1 on the Lewis acidic trivalent iodine were used to determine the dose. The animals were

620
C Praveen et al.
Me
Me
N
O
N
O
N
O
N
O
Cl
CO2Me
O2N
2a' 89%
Cl
90%
2b'
88%
2c'
2d'
91%
OMe
OMe
OMe
Me
N
O
N
O
N
O
N
Me
NO2
O
CO2Me
2g'
2e'
86%
2f' 80%
87%
2h'
93%
O
O2N
N
O
N
O
N
O
N
O
O
Br
NO2
2j'
2i'
85%
89%
2k' 90%
2l' 80%
N
O
N
O
N
O
N
O
OMe
Cl
NO2
OMe
Cl
2p'
2u'
2m'
2q'
82%
87%
2n' 85%
2o'
80%
83%
N
O
N
O
N
O
N
O
N
N
H
S
O
O
Cl
50%
2r'
88%
2s' 55%
2t'
64%
Ph
Ph
N
O
Ph
N
O
N
N
O
N
N
N
N
N
N
O
N
Me
2y'
75%
2v'
80%
2w'
2x' 81%
79%
EtO
Cl
Br
Cl
N
O
2z' 69%
Figure 2. Library of benzoxazoles 2aꢀ–2zꢀ and their isolated yield (%).
fasted overnight prior to the acute experimental proce- tively. As no mortality was observed with the above
dure. Following the period of fasting, the animals were dose even after 96 h, the LD50 value of the compounds
weighed and the synthesized compounds were orally expected to exceed 50 mg/kg body weight. Toxi-
administered at a dose of 50 mg/kg body weight. Imme- city assays showed that all the compounds proved to
diately after dosing, the animals were observed continu- be non-toxic at tested dose levels and well-tolerated by
osly for the first 30 min for behavioural changes and for the experimental animals as their LD50 cut-off values
mortality at the end of 24 h, 48 h, 72 h and 96 h, respec- > 50 mg/kg body weight.
H
Z
Z
Z
Ar
Ar
-CF3COOH
N
I
H
N
-PhI
-CF3COOH
N
Ar
O
2
1
Ph
O
F3C
1a
O
F3C
O
O
CF3
I
O
Ph
Scheme 3. Plausible mechanism for the formation of benz(oxa)thiazoles 2.

Synthesis and anti-inflammatory evaluation of benz(oxa)thiazoles
Table 1. Analgesic activity of selected compounds by tail immersion test.
621
Dose
levels
Tail immersion response in seconds (mean SEM)
15 min 30 min 60 min 90 min
Entry
Treatments
0 min
% potency
1
2
3
4
5
6
7
8
2h
2j
2l
2n
2o
2u
2v
2w
2x
2y
50 mg/kg 1.31 0.01 2.46 0.02 2.52 0.02 2.56 0.02 2.61 0.01*
50 mg/kg 1.30 0.01 2.46 0.02 2.50 0.02 2.55 0.02 2.61 0.02*
50 mg/kg 1.30 0.01 2.50 0.01 2.54 0.04 2.60 0.02 2.67 0.01*
50 mg/kg 1.32 0.01 2.66 0.02 2.69 0.02 2.73 0.03 2.78 0.03*
50 mg/kg 1.31 0.01 2.33 0.02 2.38 0.01 2.62 0.09 2.78 0.08*
50 mg/kg 1.30 0.01 2.63 0.01 2.66 0.03 2.83 0.01 3.09 0.08*
50 mg/kg 1.30 0.01 2.68 0.02 3.52 0.01 4.10 0.03 4.98 0.02*
50 mg/kg 1.31 0.01 2.69 0.01 3.62 0.01 4.37 0.04 5.00 0.01*
50 mg/kg 1.30 0.01 2.55 0.02 3.49 0.01 3.99 0.03 4.70 0.02*
50 mg/kg 1.31 0.01 2.59 0.02 3.59 0.02 4.00 0.02 4.64 0.03*
50 mg/kg 1.30 0.01 2.45 0.02 2.56 0.03 2.60 0.02 2.63 0.01*
50 mg/kg 1.30 0.01 2.46 0.01 2.50 0.02 2.59 0.01 2.65 0.01*
50 mg/kg 1.30 0.01 2.47 0.01 2.60 0.01 2.64 0.01 2.67 0.01*
50 mg/kg 1.31 0.01 2.49 0.03 2.59 0.2 2.64 0.01 2.69 0.02*
50 mg/kg 1.30 0.01 2.38 0.02 2.44 0.01 2.51 0.01 2.60 0.01*
50 mg/kg 1.30 0.01 2.37 0.02 2.43 0.03 2.70 0.09 2.86 0.08*
50 mg/kg 1.30 0.01 2.69 0.01 3.01 0.01 3.13 0.01 3.22 0.08*
50 mg/kg 1.32 0.01 2.60 0.02 3.37 0.03 4.12 0.01 4.99 0.01*
50 mg/kg 1.31 0.01 2.78 0.01 3.57 0.03 4.31 0.01 5.02 0.01*
50 mg/kg 1.30 0.01 2.67 0.02 3.45 0.01 4.25 0.03 5.00 0.02*
50.0
50.0
51.3
52.5
52.8
58.0
73.9
73.8
72.3
71.7
50.6
50.9
51.3
51.3
50.0
54.5
59.6
73.5
76.4
74.0
-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
2aꢀ
2cꢀ
2hꢀ
2pꢀ
2rꢀ
2uꢀ
2vꢀ
2wꢀ
2xꢀ
2yꢀ
Gum acaciaa 2 mL/kg 1.30 0.01 1.24 0.01 1.12 0.01 1.15 0.01 1.30 0.01*
Pentazocine 50 mg/kg 1.30 0.01 6.31 0.03 6.39 0.04 6.54 0.03 6.72 0.02*
80.6
Data were analysed by one way ANOVA followed by Dunnet’s test; *indicates p < 0.001; SEM: Standard error of means.
a2% (w/v) of gum acacia was used as control.
Analgesic activity of the synthesized compounds was percentage analgesic activity was calculated using the
determined using tail immersion method.62 Healthy formula:
Swiss mice (n = 6) of either sex was selected by
ꢀ
ꢁ
% potency = (T2 − T1) /T2 × 100,
random sampling technique and placed into individual
restraining cages leaving the tail hanging out freely. The
animals were then allowed to adapt in the cages for 30
min before testing. The lower 5 cm portion of the tail
was marked and immersed in a beaker of freshly filled
warm water of at 55 5◦C. Within a few seconds the
rat reacted by withdrawing the tail. The reaction time
was recorded by a stop watch. After each determination
the tail was carefully dried. This reaction was deter-
mined before oral feeding of the drug and synthesized
compounds which were recorded as zero minutes read-
ing. The test compounds, control (2% gum acacia) and
standard (pentazocine) at a dose level of 50 mg/kg body
weight were administered orally by intragastric tube.
The time (in seconds) to withdraw the tail clearly out
of water was taken as the reaction time. The first read-
ing (0 min) was taken immediately after the administra-
tion of the test compound and subsequent reaction time
was recorded at 15, 30, 60 and 90 min, respectively. The
cut-off time of the immersion is 15 s. The mean reac-
tion time was recorded for each group and compared
with the value of the standard drug pentazocine. The
where, T1 is the reaction time (in sec) before treatment
and T2 is the reaction time (in seconds) after treatment.
The results of analgesic activity are pre-
sented in table 1, which demonstrate that 2-aryl
benz(oxa)thiazole analogues (2h–2o) were generally
found to be less potent than their corresponding hete-
roaryl analogues (2u–2y and 2uꢀ–2yꢀ). Among the
heteroaryl analogues, pyrazolyl groups (2v–2y and
2wꢀ–2yꢀ) exhibited good analgesic activity and their
values are comparable to the standard pentazocine.
Compounds adjoined with indolyl (2u and 2vꢀ) and
pyrollyl motifs (2uꢀ) showed moderate potency with
activities greater than 2-aryl analogues but lesser than
2-pyrazolyl analogues.
5. Conclusion
In summary, we have explored a useful and practical
approach to benzoxazoles and benzothiazoles by PIFA

622
C Praveen et al.
promoted cyclocondensation of 2-aminothiophenol/2-
aminophenol with aldehydes. The current protocol is
noteworthy; since it has advantages like wide sub-
strate scope, short reaction time, microwave condition
and satisfactory yields. Evaluation of analgesic acti-
vity of twenty compounds was performed by tail
immersion test. All the tested compounds displayed
varying degrees of analgesic activity. Benz(oxa)thiazole
derivatives bearing pyrazolyl system exhibited compa-
rable to or slightly less potent activity than the standard
pentazocine.
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Supplementary information
For supplementary information see www.ias.ac.in/
chemsci.
Acknowledgements
The author CP thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi, India, for the
research fellowship. PD thanks Dr. K Karthikeyan,
Organic Chemistry Division, Central Leather Research
Institute, Chennai for recording NMR spectrum.
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