Oxidative cyclization of thiophenolic and phenolic Schiff's bases promoted by PCC: a new oxidant for 2-substituted benzothiazoles and benzoxazoles

Article abstract of DOI:10.1016/j.tet.2008.01.004

Pyridinium chlorochromate (PCC) supported on silica gel effects the oxidative cyclization of structurally diverse thiophenolic and phenolic Schiff's bases, thereby providing an efficient and convenient method for the synthesis of a library of 2-arylbenzot

Full text of DOI:10.1016/j.tet.2008.01.004

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2369e2374
www.elsevier.com/locate/tet
Oxidative cyclization of thiophenolic and phenolic Schiff’s bases
promoted by PCC: a new oxidant for 2-substituted benzothiazoles
and benzoxazoles
*
C. Praveen, K. Hemanth Kumar, D. Muralidharan, P.T. Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai, Tamil Nadu 600 020, India
Received 24 September 2007; received in revised form 11 December 2007; accepted 3 January 2008
Available online 5 January 2008
Abstract
Pyridinium chlorochromate (PCC) supported on silica gel effects the oxidative cyclization of structurally diverse thiophenolic and phenolic
Schiff’s bases, thereby providing an efficient and convenient method for the synthesis of a library of 2-arylbenzothiazoles and 2-arylbenzox-
azoles.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
All the above methods have limited applications for the syn-
thesis of either benzothiazoles or benzoxazoles. As part of
our current interest in oxidation processes,17 we sought
PCC18 as an effective oxidant for the oxidative cyclization
of both thiophenolic and phenolic Schiff’s bases to the corre-
sponding 2-arylbenzothiazole and benzoxazole.
Benzothiazoles and benzoxazoles are a class of molecules
that possess an array of biological properties.1 In particular,
benzothiazole 1 acts as a Ca2þ channel antagonist,2 and benz-
oxazole 2 acts as a 5HT3 receptor partial agonist,3 (Fig. 1).
Although a wide range of methods are available for synthesiz-
ing benzothiazole4 and benzoxazole,5 a real need exists for
new procedures that support many kinds of structural diversity
and various substitution patterns in the target library.
In general benzothiazoles are synthesized by condensation
of 2-aminobenzenethiol with carboxylic acid derivatives,6 the
base induced cyclization of the corresponding 2-haloanilides,7
or the radical cyclization of thioacylbenzanilides.8,9 On
the other hand the most common synthetic approach to 2-aryl-
benzoxazoles involves (1) coupling of carboxylic acids with
2-aminophenols by dehydration catalyzed by strong acid;10
and (2) the oxidative cyclization of phenolic Schiff’s bases,
derived from the condensation of 2-aminophenols and
aldehydes, using various oxidants such as PhI(OAc)2,11
Mn(OAc)3,12 ThClO4,13 Ba(MnO4)2,14 NiO2,15 and Pb(OAc)4.16
2. Result and discussion
2.1. Efficacy of different oxidants on the oxidative cyclization
Even though PCC has been used for various oxidation
processes,18,19 it was under-utilized for oxidative cyclization
reactions. We have explored the possibility of utilizing PCC
as an oxidant for the oxidative cyclization of Schiff’s base 3.
N
N
S
+
_
N
O
F
I
N
N
N
O
1
2
* Corresponding author. Tel.: þ91 44 24911329; fax: þ91 44 24911539.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
Figure 1.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.004

2370
C. Praveen et al. / Tetrahedron 64 (2008) 2369e2374
Table 2
PCC mediated synthesis of 2-phenylbenzoxa(thia)zoles
Our initial studies on the reaction of Schiff’s base 3 with PCC/
SiO2 in dichloromethane at room temperature afforded the
compound 4 in excellent yield at a short reaction time.
To assess the efficacy of PCC over different oxidants the
oxidative cyclization of Schiff’s base 3 with different oxidants
was performed. Dichloromethane was used as the solvent for
all reactions. The results revealed that FeCl3 led to the forma-
tion of 2-(2-chlorophenyl)-1,3-benzoxa(thia)zole in low
yields. MnO2 led to the formation of benzoxazole in low yield,
but it failed to form benzothiazole. CuCl2 and molecular io-
dine, respectively, led to the formation of the desired products
in moderate yield and IBX in CH2Cl2 completely failed to ox-
idize the substrates. Thus it is obvious from this study that the
oxidizing performance of PCC was superior in this oxidative
cyclization protocol (Scheme 1; Table 1).
Entry
Z
S
R1
R2
R3
R4
R5 Time (min) Producta Yieldb (%)
1
2
3
4
5
6
7
8
9
10
a
Cl
H
H
NO2
H
H
H
H
H
H
H
H
H
H
H
20
15
45
35
30
30
6a
6b
6c
6d
6e
6f
89
82
78
75
74
91
89
91
88
89
H
OMe OBn
H
OMe OBn OMe
H
Br
H
OH OMe
O
Cl
H
H
H
H
H
H
H
H
NO2
H
Me 20
Me 15
Me 15
Cl 25
6g
6h
6i
Cl
NO2
H
H
H
NO2
H
H
6j
All the products were characterized by IR, NMR, and mass spectroscopies.
Isolated yield.
b
R2
R3
R4
R1
R2
R1
R5
R5
N
PCC/Silica
DCM, rt
N
Z
N
ZH
N
R3
PCC
DCM, rt
Z
Cl
Cl
ZH
R4
5
3
6
4
Z=S,O
Scheme 2.
Scheme 1.
presence of bulky phenyl group at the C3 atom of the pyrazole
ring, which may hinder cyclization (Table 3).
2.2. Synthesis of 2-arylbenzoxa(thia)zole
The generality of the transformation of thiophenolic and
phenolic Schiff’s bases to the corresponding benzothiazole
and benzoxazole was checked by treating PCC with a range
of substituted and structurally diverse Schiff’s bases. Treat-
ment of Schiff’s bases 5 bearing different substituents with sil-
ica gel supported PCC (1.1 equiv) in CH2Cl2 afforded the
oxidized products in good to excellent yields (Scheme 2; Table
2).The results revealed that, the substrates bearing electron re-
leasing functionalities afforded comparitively low yields of
products (Table 2; entries 3e5). This observation was in
good agreement with other oxidative cyclization protocols.
On the basis of the above results, coupled with the fact that
benzoxa(thia)zoles and pyrazoles20 are often associated with
important biological properties, we extended our methodology
for the oxidative cyclization of Schiff’s bases of formyl pyr-
azoles 7.21
R2
N
N
R2
N
N
N
PCC/Silica
DCM; rt
N
Z
ZH
R1
R1
7
8
Scheme 3.
To extend the applicability further, we focussed our atten-
tion on the synthesis of indolyl and pyrrolyl benzoxa(thia)-
zoles (Scheme 4), which had been shown to possess
cytotoxic activity.22 Here too the reaction requires longer reac-
tion time, but the yield of the products were fairly high (Table
4) as compared to pyrazolyl benzoxa(thia)zoles.
However, these substrates toward cyclization had shown
lesser reactivity as indicated by longer reaction times and
lower yields (Scheme 3, Table 3). This may be due to the
Table 3
PCC mediated synthesis of 2-pyrazolyl benzoxa(thia)zoles
Table 1
Effect of different oxidants on the oxidative cyclization of Schiff’s base 3
Entry
Z
S
R1
R2
Time (min)
Producta
Yieldb (%)
1
2
3
4
5
6
7
a
Br
H
50
40
45
40
55
30
30
8a
8b
8c
8d
8e
8f
74
70
68
72
72
81
69
Entry
Oxidant
Equiv
Time (h)
Z¼Sa (%)
15
Z¼Oa (%)
10
15
0
OEt
Cl
H
H
1
2
3
4
5
6
a
FeCl3
MnO2
IBX
1.1
1.0
1.0
1.1
1.0
1.0
2.0
1.0
3.0
0.5
1.0
1.0
OMe
OEt
Cl
H
0
O
H
0
H
Me
PCC
CuCl2
I2
89
50
42
91
39
51
Br
8g
All the products were characterized by IR, NMR, and mass spectroscopies.
Isolated yield.
b
Isolated yield.

C. Praveen et al. / Tetrahedron 64 (2008) 2369e2374
2371
Table 4
PCC mediated synthesis of 2-indolyl and pyrollyl benzoxa(thia)zoles
be rationalized through the intermediacy of 2-aryl-2,3-dihydro-
1,3-benzoxa(thia)zole (11a), which may be formed by an initial
attack of pyridinium ion on the imino nitrogen atom, followed
by deprotonation. The subsequent attack of Cr6þ on the nitro-
gen atom results in dehydrogenation to afford 12.
Entry
1
Z
Ar
Me
Time (min)
Producta
Yieldb (%)
S
45
10a
88
N
3. Conclusion
Me
N
2
O
O
45
40
10b
10c
83
80
In summary, the present procedure involving PCC mediated
oxidative cyclization of a wide range of phenolic and thiophe-
nolic Schiff’s bases provides a convenient and synthetically
useful method for the preparation of 2-arylbenzoxa(thia)zoles.
The oxidative cyclizing performance of PCC is noteworthy,
since it is capable of oxidizing both phenolic and thiophenolic
Schiff’s bases in good to excellent yields. The applications of
this new methodology to the synthesis of other heterocycles
are actively underway.
H
N
3
a
All the products were characterized by IR, NMR, and mass spectroscopies.
Isolated yield.
b
N
Ar
N
Z
PCC/Silica
DCM, rt
Ar
ZH
4. Experimental section
10
9
Scheme 4.
4.1. General
The intramolecular cyclization of phenolic and thiophe-
Melting points are uncorrected. Infrared (IR) spectra were
recorded on a PerkineElmer FTIR spectrophotometer as
KBr pellets. 1H and 13C NMR spectra were recorded in
CDCl3 and DMSO-d6 using TMS as an internal standard on
a JEOL spectrometer at 500 and 125 MHz, respectively.
Mass spectra were recorded on a Thermo Finnigan LCQ Ad-
vantage MAX 6000 ESI mass spectrometer. Elemental analy-
ses were recorded using a Thermo Finnigan FLASH EA 1112
CHN analyzer. Column chromatography was performed on
silica gel (100e200 mesh, SRL, India). Analytical TLC was
performed on precoated plastic sheets of silica gel G/UV-
254 of 0.2 mm thickness (MachereyeNagel, Germany).
nolic Schiff’s bases was characterized by the absence of
CH]N proton signal at d 8.3e8.8 ppm (except, compounds
8ae8g, where a singlet at this region is observed due to the
C5-H proton in the pyrazole ring).
The formation of the product was further supported by the
disappearance of 3360 cmꢀ1 (OeH stretch) and 2250 cmꢀ1
(SeH stretch) peaks in the IR spectra.
2.3. Mechanism
A mechanistic rationale portraying the probable sequence of
events is given in Scheme 5. The formation of 12 from 11 can
4.2. Preparation of silica supported PCC
H
..
..
Z
H
+
Z
..
Ar
H
Z
..
The solid supported PCC was prepared by a procedure re-
ported by Vanden Eynde et al.19 Silica gel 100e200 mesh
(200 g) was added to a solution of PCC (45 g; 200 mmol) in
acetone (200 mL) and stirred well for 3 h. The solvent was
evaporated under reduced pressure and the resulting solid
was dried at 100 ꢁC for 2 h and used.
Ar
H
-H+
-Py
N
N
N
..
Ar
11
H
11a
H
PyH+
Cr6+ -Cr5+
Z = S, O
..
..
4.3. Preparation of phenolic and thiophenolic Schiff’s bases
..
Z
.
Z
+
Ar
H
Cr5+
-Cr4+
Z
Ar
Ar
H
.
-H+
H
N
H
N
+
N
Schiff’s bases were prepared by refluxing a solution of ap-
propriate aldehyde (20.0 mmol) and o-aminophenols/o-amino-
thiophenol (30.0 mmol) in methanol (10 mL) for 4e5 h. The
solid product thus obtained was filtered off and washed with
ice-cold methanol (5 mL) in portions and dried.
-H+
..
Z
4.4. Typical procedure for the preparation of
2-arylbenzoxa(thia)zoles
Ar
N
..
12
Schiff’s base (2.0 mmol) was rapidly added to a stirred sus-
pension of silica supported PCC (2.2 mmol corresponding to
Scheme 5. Proposed mechanism.

2372
C. Praveen et al. / Tetrahedron 64 (2008) 2369e2374
PCC) in dichloromethane. The mixture was stirred at room
temperature for the specified time (see Tables 2e4). After
completion of the reaction as indicated by TLC (petroleum
ether/ethyl acetate), the reaction mixture was filtered on
a thin Celite pad. The filtrate was concentrated, poured into
water, and extracted with ethyl acetate (3ꢂ20 mL). The or-
ganic layer was dried over anhydrous Na2SO4, filtered, con-
centrated, and purified by column chromatography on silica
gel using petroleum ether/ethyl acetate to give product.
7.38 (m, 6H, Ar-H), 7.46e7.50 (m, 3H, Ar-H), 7.86 (d, 1H,
J¼7.6 Hz, Ar-H), 8.04 (d, 1H, J¼8.4 Hz, Ar-H). 13C NMR
(125 MHz, CDCl3) dC 56.2, 76.9, 104.9, 121.7, 123.1, 125.2,
126.4, 128.1, 128.3, 128.6, 129.3, 135.1, 137.6, 139.5. MS
(EI): m/z¼377 [Mþ]. Anal. Calcd for C22H19NSO3: C,
70.00; H, 5.07; N, 3.71. Found: C, 69.89; H, 4.99; N, 3.82.
4.4.5. 4-(1,3-Benzothiazol-2-yl)-2-bromo-6-methoxyphenol
(6e)
Colorless solid; mp 184e186 ꢁC; Rf¼0.46 (AcOEt/petro-
4.4.1. 2-(2-Chlorophenyl)-1,3-benzothiazole (6a)
leum ether 30%). IR (KBr): 3447, 2922, 1510, 1416, 1292,
Colorless solid; mp 71e73 ꢁC; Rf¼0.39 (AcOEt/petroleum
ether 10%). IR (KBr): 3053, 2359, 1559, 1454, 1429, 1316,
1270, 1059, 965, 749, 726 cmꢀ1. 1H NMR (500 MHz, CDCl3)
dH 7.38e7.44 (m, 3H, Ar-H), 7.51e7.54 (m, 2H, Ar-H), 7.93
(d, 1H, J¼7.6 Hz, Ar-H), 8.13 (d, 1H, J¼8.4 Hz, Ar-H), 8.20e
8.21 (m, 1H, Ar-H). 13C NMR (125 MHz, CDCl3) dC 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/z¼245 [Mþ], 247 [Mþ2].
Anal. Calcd for C13H8ClNS: C, 63.54; H, 3.28; N, 5.70.
Found: C, 63.44; H, 3.33; N, 5.67.
1
1183, 1022, 831, 722 cmꢀ1. H NMR (500 MHz, DMSO-d6)
dH 3.93 (s, 3H, ꢀOCH3), 7.39 (d, 1H, J¼7.6 Hz, Ar-H), 7.49e
7.50 (m, 1H, Ar-H), 7.57 (s, 1H, Ar-H), 7.72 (s, 1H, Ar-H),
7.97e8.07 (m, 2H, Ar-H), 10.32 (s, 1H, ꢀOH). 13C NMR
(125 MHz, DMSO-d6) dC 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/z¼335 [Mþ], 337 [Mþ2]. Anal. Calcd for
C14H10BrNO2S: C, 50.01; H, 3.00; N, 4.17. Found: C,
49.89; H, 3.09; N, 4.10.
4.4.6. 2-(2-Chlorophenyl)-1,3-benzoxazole (6f)
4.4.2. 2-(3-Nitrophenyl)-1,3-benzothiazole (6b)
Colorless solid; mp 61e64 ꢁC; Rf¼0.53 (AcOEt/petroleum
Colorless solid; mp 181e183 ꢁC; Rf¼0.50 (AcOEt/petro-
ether 30%). IR (KBr): 2953, 1537, 1430, 1253, 1194, 1022,
leum ether 30%). IR (KBr): 3402, 2937, 1529, 1461, 1347,
1
806, 738 cmꢀ1. H NMR (500 MHz, CDCl3) dH 7.36e7.46
1
1107, 1048, 731 cmꢀ1. H NMR (500 MHz, CDCl3) dH 7.42
(m, 4H, Ar-H), 7.56e7.57 (m, 1H, Ar-H), 7.61e7.62 (m,
1H, Ar-H), 7.84e7.86 (m, 1H, Ar-H), 8.13 (dd, 1H, J¼7.6,
2.3 Hz, Ar-H). 13C NMR (125 MHz, CDCl3) dC 110.9,
120.6, 124.8, 125.7, 126.2, 127.1, 131.5, 131.9, 132.0, 133.6,
141.8, 150.6, 161.1. MS (EI): m/z¼229 [Mþ], 231 [Mþ2].
Anal. Calcd for C13H6ClNO: C, 67.99; H, 3.51; N, 6.10.
Found: C, 68.11; H, 3.62; N, 5.99.
(t, 1H, J¼7.6 Hz, Ar-H), 7.51 (t, 1H, J¼7.6 Hz, Ar-H), 7.65 (t,
1H, J¼7.6 Hz, Ar-H), 7.92 (d, 1H, J¼7.6 Hz, Ar-H), 8.09 (d,
1H, J¼7.6 Hz, Ar-H), 8.30 (dd, 1H, J¼6.9, 9.2 Hz, Ar-H),
8.38 (d, 1H, J¼7.6 Hz, Ar-H), 8.90 (s, 1H, Ar-H). 13C
NMR (125 MHz, CDCl3) dC 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/z¼256 [Mþ]. Anal. Calcd for C13H8N2SO2:
C, 60.92; H, 3.15; N, 10.93. Found: C, 60.75; H, 3.22; N,
10.89.
4.4.7. 5-Methyl-2-(4-nitrophenyl)-1,3-benzoxazole (6g)
Pale yellow solid; mp 218e250 ꢁC; Rf¼0.44 (AcOEt/petro-
leum ether 30%). IR (KBr): 3402, 1556, 1521, 1342, 854,
.
706 cmꢀ1 1H NMR (500 MHz, CDCl3) dH 2.50 (s, 3H,
eCH3), 7.22 (d, 1H, J¼8.4 Hz, Ar-H), 7.48 (d, 1H, J¼
8.4 Hz Ar-H), 7.59 (s, 1H, Ar-H), 8.35e8.41 (m, 4H, Ar-H).
13C NMR (125 MHz, CDCl3) dC 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/z¼254 [Mþ]. Anal. Calcd for C14H10N2O3: C, 66.14;
H, 3.96; N, 11.02. Found: C, 66.32; H, 4.10; N, 10.92.
4.4.3. 2-[4-(Benzyloxy)-3-methoxyphenyl]-1,3-
benzothiazole (6c)
Colorless solid; mp 97e99 ꢁC; Rf¼0.63 (AcOEt/petroleum
ether 30%). IR (KBr): 3468, 2937, 1630, 1264, 1141, 997 cmꢀ1
.
1H NMR (500 MHz, CDCl3) dH 3.94 (s, 3H, eOCH3), 5.22 (s,
2H, eOCH2C6H5), 6.93 (d, 1H, J¼8.4 Hz, Ar-H), 7.31e7.39
(m, 4H, Ar-H), 7.42e7.48 (m, 3H, Ar-H), 7.51 (dd, 1H,
J¼2.3, 8.4 Hz, Ar-H), 7.72 (d, 1H, J¼2.3 Hz, Ar-H), 7.85 (d,
1H, J¼7.6 Hz, Ar-H), 8.01 (d, 1H, J¼8.4 Hz, Ar-H). 13C
NMR (125 MHz, CDCl3) dC 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/z¼349 [Mþ].
Anal. Calcd for C20H17NSO: C, 72.60; H, 4.93; N, 4.03. Found:
C, 72.49; H, 4.82; N, 3.99.
4.4.8. 2-(2-Chlorophenyl)-5-methyl-1,3-benzoxazole (6h)
Colorless solid; mp 74e76 ꢁC; Rf¼0.59 (AcOEt/petroleum
ether 25%). IR (KBr): 2921, 1734, 1590, 1548, 1468, 1423,
1
1325, 1263, 1194, 1019, 774, 730 cmꢀ1. H NMR (500 MHz,
CDCl3) dH 2.49 (s, 3H, eCH3), 7.18 (d, 1H, J¼8.4 Hz, Ar-H),
7.38 (m, 2H, Ar-H), 7.47 (d, 1H, J¼8.4 Hz, Ar-H), 7.54 (d,
1H, J¼9.2 Hz, Ar-H), 7.62 (s, 1H, Ar-H), 8.11 (d, 1H,
J¼8.4 Hz, Ar-H). 13C NMR (125 MHz, CDCl3) dC 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/z¼245 [Mþ],
247 [Mþ2]. Anal. Calcd for C14H10ClNO: C, 69.00; H, 4.14;
N, 5.75. Found: C, 69.22; H, 4.25; N, 5.88.
4.4.4. 2-[4-(Benzyloxy)-3,5-dimethoxyphenyl]-1,3-
benzothiazole (6d)
Brown solid; mp 77e79 ꢁC; Rf¼0.58 (AcOEt/petroleum
ether 30%). IR (KBr): 3432, 2915, 2369, 1623, 1590, 1406,
1
1329, 1240, 1118, 1019 cmꢀ1. H NMR (500 MHz, CDCl3)
dH 3.93 (s, 6H, eOCH3), 5.09 (s, 2H, eOCH2C6H5), 7.29e

C. Praveen et al. / Tetrahedron 64 (2008) 2369e2374
2373
4.4.9. 5-Methyl-2-(2-nitrophenyl)-1,3-benzoxazole (6i)
4.4.13. 2-[3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-
1,3-benzothiazole (8c)
Pink solid; mp 134e136 ꢁC; Rf¼0.49 (AcOEt/petroleum
ether 30%). IR (KBr): 3431, 2915, 1542, 1480, 1374, 1196,
Colorless solid; mp 173e175 ꢁC; Rf¼0.45 (AcOEt/petro-
1
1044, 800, 772 cmꢀ1. H NMR (500 MHz, CDCl3) dH 2.48
leum ether 25%). IR (KBr): 3421, 1599, 1502, 1388, 1203,
1
(s, 3H, eCH3), 7.19 (d, 1H, J¼8.4 Hz, Ar-H), 7.42 (d, 1H,
J¼8.4 Hz, Ar-H), 7.58 (s, 1H, Ar-H), 7.65 (t, 1H, J¼7.6 Hz,
Ar-H), 7.71 (t, 1H, J¼7.6 Hz, Ar-H), 7.86 (d, 1H, J¼7.6 Hz,
Ar-H), 8.11 (d, 1H, J¼7.6 Hz, Ar-H). 13C NMR (125 MHz,
CDCl3) dC 21.61, 110.40, 120.57, 121.69, 124.26, 127.30,
131.81, 132.43, 134.97, 141.78, 149.22, 149.37, 158.92. MS
(EI): m/z¼254 [Mþ]. Anal. Calcd for C14H10N2O3: C, 66.14;
H, 3.96; N, 11.02. Found: C, 66.00; H, 4.02; N, 10.89.
1067, 932, 823 cmꢀ1. H NMR (500 MHz, CDCl3) dH 7.33e
7.37 (m, 2H, Ar-H), 7.43e7.51 (m, 5H, Ar-H), 7.72 (d, 2H,
J¼8.4 Hz, Ar-H), 7.79e7.82 (m, 3H, Ar-H), 8.00 (d, 1H,
J¼8.4 Hz, Ar-H), 8.59 (s, 1H, pyrazolyl-H). 13C NMR
(125 MHz, CDCl3) dC 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/z¼388 [Mþ], 390
[Mþ2]. Anal. Calcd for C22H14ClN3S: C, 68.12; H, 3.64; N,
10.83. Found: C, 67.99; H, 3.76; N, 10.90.
4.4.10. 5-Chloro-2-(3-nitrophenyl)-1,3-benzoxazole (6j)
Colorless solid; mp 184e186 ꢁC; Rf¼0.52 (AcOEt/petro-
leum ether 30%). IR (KBr): 3424, 2361, 1526, 1449, 1351,
4.4.14. 2-[3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl]-
1,3-benzothiazole (8d)
1100, 821 cmꢀ1
.
1H NMR (500 MHz, CDCl3) dH 7.38 (q,
Colorless solid; mp 167e169 ꢁC; Rf¼0.44 (AcOEt/petro-
1H, J¼8.4 Hz, Ar-H), 7.54 (d, 1H, J¼9.1 Hz, Ar-H), 7.72
(d, 1H, J¼8.4 Hz, Ar-H), 7.78 (s, 1H, Ar-H), 8.39 (d, 1H,
J¼8.8 Hz, Ar-H), 8.55 (d, 1H, J¼7.6 Hz, Ar-H), 9.07 (s, 1H,
Ar-H). 13C NMR (125 MHz, CDCl3) dC 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/z¼274 [Mþ], 276 [Mþ2]. Anal. Calcd for
C13H7ClN2O3: C, 56.85; H, 2.57; N, 10.20. Found: C, 56.75;
H, 2.49; N, 10.15.
leum ether 30%). IR (KBr): 3402, 2346, 1609, 1558, 1505,
.
1406, 1248, 1034, 833, 755 cmꢀ1 1H NMR (500 MHz,
CDCl3) dH 3.87 (s, 3H, eOCH3), 6.99 (d, 2H, J¼8.4 Hz,
Ar-H), 7.32 (q, 2H, J¼7.6 Hz, Ar-H), 7.44e7.48 (m, 3H,
Ar-H), 7.66 (d, 2H, J¼8.4 Hz, Ar-H), 7.76 (d, 1H, J¼
7.6 Hz, Ar-H), 7.81 (d, 2H, J¼7.6 Hz, Ar-H), 7.99 (d, 1H,
J¼8.4 Hz, Ar-H), 8.63 (s, 1H, pyrazolyl-H). 13C NMR
(125 MHz, CDCl3) dC 55.4, 114.0, 117.4, 119.4, 121.5,
122.6, 124.3, 124.9, 126.2, 127.3, 128.2, 129.7, 131.1, 135.1,
139.5, 152.1, 153.2, 160.4, 160.5. MS (EI): m/z¼383 [Mþ].
Anal. Calcd for C23H17N3SO: C, 72.02; H, 4.47; N, 10.96.
Found: C, 71.89; H, 4.45; N, 11.01.
4.4.11. 2-[3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl]-
1,3-benzothiazole (8a)
Colorless solid; mp 200e202 ꢁC; Rf¼0.47 (AcOEt/petro-
leum ether 25%). IR (KBr): 3359, 1637, 1554, 1506, 1406,
.
1222, 1085, 829, 754, 684 cmꢀ1
1H NMR (500 MHz,
4.4.15. 2-[3-(4-Ethoxyphenyl)-1-phenyl-1H-pyrazole-4-yl]-
1,3-benzoxazole (8e)
CDCl3) dH 7.35e7.37 (m, 2H, Ar-H), 7.46e7.51 (m, 3H,
Ar-H), 7.58 (d, 2H, J¼8.4 Hz, Ar-H), 7.66 (d, 2H, J¼
8.4 Hz, Ar-H), 7.80 (d, 3H, J¼8.4 Hz, Ar-H), 8.00 (d, 1H,
J¼8.4 Hz, Ar-H), 8.59 (s, 1H, pyrazolyl-H). 13C NMR
(125 MHz, CDCl3) dC 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/z¼431 [Mþ],
433 [Mþ2]. Anal. Calcd for C22H13N3SBr: C, 61.12; H,
3.26; N, 9.72. Found: C, 61.00; H, 3.33; N, 9.77.
Orange solid; mp 189e191 ꢁC; Rf¼0.44 (AcOEt/petroleum
ether 50%). IR (KBr): 3430, 2930, 1631, 1583, 1450, 1240,
1045, 750 cmꢀ1 1H NMR (500 MHz, CDCl3) dH 1.43 (t,
.
3H, J¼6.9 Hz, eOCH2CH3), 4.09 (q, 2H, J¼6.9 Hz,
eOCH2CH3), 6.98 (d, 2H, J¼9.1 Hz, Ar-H), 7.26e7.29 (m,
2H, Ar-H), 7.34 (t, 1H, J¼7.6 Hz, Ar-H), 7.46e7.54 (m, 3H,
Ar-H), 7.69 (d, 1H, J¼6.9 Hz, Ar-H), 7.80 (d, 2H, J¼
7.6 Hz, Ar-H), 7.94 (d, 2H, J¼8.4 Hz, Ar-H), 8.68 (s, 1H, pyr-
azolyl-H). 13C NMR (125 MHz, CDCl3) dC 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/z¼381 [Mþ]. Anal. Calcd for C24H19N3O2: C, 75.57;
H, 5.02; N, 11.02. Found: C, 75.44; H, 5.11; N, 11.09.
4.4.12. 2-[3-(4-Ethoxyphenyl)-1-phenyl-1H-pyrazole-4-yl]-
1,3-benzothiazole (8b)
Pale yellow solid; mp 152e154 ꢁC; Rf¼0.50 (AcOEt/petro-
leum ether 30%). IR (KBr): 3434, 2965, 1613, 1558, 1503,
1
1247, 1106, 1043, 812 cmꢀ1. H NMR (500 MHz, CDCl3)
dH 1.46 (t, 3H J¼7.5 Hz, eOCH2CH3), 4.10 (q, 2H
J¼6.8 Hz, eOCH2CH3), 6.98 (d, 2H, J¼8.6 Hz, Ar-H), 7.31
(q, 2H, J¼8.0 Hz, Ar-H), 7.44e7.50 (m, 3H, Ar-H), 7.62e
7.66 (m, 2H, Ar-H), 7.76 (d, 1H, J¼8.0 Hz, Ar-H), 7.81 (d,
2H, J¼8.6 Hz, Ar-H), 7.99 (d, 1H, J¼8.0 Hz, Ar-H), 8.64 (s,
1H, pyrazolyl-H). 13C NMR (125 MHz, CDCl3) dC 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/z¼397 [Mþ]. Anal. Calcd for C24H19N3OS:
C, 72.52; H, 4.82; N, 10.57. Found: C, 72.67; H, 4.75; N,
10.22.
4.4.16. 2-[3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-
1,3-benzoxazole (8f)
Colorless solid; mp 205e207 ꢁC; Rf¼0.44 (AcOEt/petro-
leum ether 25%). IR (KBr): 3411, 1627, 1590, 1502, 1454,
1
1391, 1244, 1093, 989 cmꢀ1. H NMR (500 MHz, CDCl3)
dH 7.32e7.33 (m, 2H, Ar-H), 7.37e7.39 (m, 1H, Ar-H),
7.45e7.53 (m, 5H, Ar-H), 7.71 (d, 1H, J¼9.1 Hz, Ar-H),
7.81 (d, 2H, J¼8.4 Hz, Ar-H), 7.99 (d, 2H, J¼8.4 Hz, Ar-
H), 8.71 (s, 1H, pyrazolyl-H). 13C NMR (125 MHz, CDCl3)
dC 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

2374
C. Praveen et al. / Tetrahedron 64 (2008) 2369e2374
(EI): m/z¼372 [Mþ], 374 [Mþ2]. Anal. Calcd for
C22H14ClN3O: C, 71.07; H, 3.80; N, 11.30. Found: C, 71.25;
H, 3.75; N, 11.25.
Acknowledgements
We thank the Council of Scientific and Industrial Research,
New Delhi, for the financial support.
4.4.17. 2-[3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl]-5-
methyl-1,3-benzoxazole (8g)
References and notes
Colorless solid; mp 210e214 ꢁC; Rf¼0.52 (AcOEt/petro-
leum ether 30%). IR (KBr): 2920, 1589, 1500, 1262, 1223,
1. (a) Nagel, A. A.; Liston, D. R.; Jung, S.; Maher, M.; Vincent, L. A.;
Chapin, D.; Chen, Y. L.; Hubbard, S.; Ives, J. L.; Jones, S. B. J. Med.
Chem. 1995, 38, 1084; (b) Deluca, M. R.; Kerwin, S. M. Tetrahedron
Lett. 1997, 38, 199; (c) Temiz, O.; Oren, I.; Sener, E.; Yalcin, I.; Ucarturk,
N. Farmaco 1998, 53, 337; (d) Sato, S.; Kajiura, T.; Noguchi, M.; Take-
hana, K.; Kobayashi, T.; Tsuji, T. J. Antibiot. 2001, 54, 102.
2. Kashiyama, E.; Hutchinson, I.; Chua, M. S.; Stinson, S. F.; Phillips, L. R.;
Kaur, G.; Sausville, E. A.; Bradshaw, T. D.; Westwell, A. D.; Stevens,
M. F. G. J. Med. Chem. 1999, 42, 4172.
1
1057, 944, 830, 799 cmꢀ1. H NMR (500 MHz, CDCl3) dH
2.46 (s, 3H, eCH3), 7.11 (d, 1H, J¼8.4 Hz, Ar-H), 7.34e7.39
(m, 2H, Ar-H), 7.49e7.52 (m, 3H, Ar-H), 7.60 (d, 2H,
J¼8.4 Hz, Ar-H), 7.80 (d, 2H, J¼7.6 Hz, Ar-H), 7.91 (d,
2H, J¼8.4 Hz, Ar-H), 8.68 (s, 1H, pyrazolyl-H). 13C NMR
(125 MHz, CDCl3) dC 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/z¼430
[Mþ], 432 [Mþ2]. Anal. Calcd for C23H15BrN3O: C, 64.20;
H, 3.75; N, 9.77. Found: C, 64.25; H, 3.69; N, 10.02.
3. Sato, Y.; Yamada, M.; Yoshida, S.; Soneda, T.; Ishikawa, M.; Nizato, T.;
Suzuki, K.; Konno, F. J. Med. Chem. 1998, 41, 3015.
4. (a) Chua, M.-S.; Shi, D.-F.; Wrigley, S.; Bradshaw, T. D.; Hutchinson, I.;
Shaw, P. N.; Barrett, D. A.; Stanley, L. A.; Stevens, M. F. G. J. Med.
Chem. 1999, 42, 381; (b) Hutchinson, I.; Chua, M.-S.; Browne, H. L.; Tra-
pani, V.; Bradshaw, T. D.; Westwell, A. D.; Stevens, M. F. G. J. Med.
Chem. 2001, 44, 1446; (c) Leng, W.; Zhou, Y.; Xu, Q.; Liu, J. Macromol-
ecules 2001, 34, 4774; (d) Hutchinson, I.; Jennings, S. A.; Vishnuvajjala,
B. R.; Westwell, A. D.; Stevens, M. F. G. J. Med. Chem. 2002, 45, 744.
5. (a) Shi, D.-F.; Bradshaw, T. D.; Wrigley, S.; McCall, C. J.; Lelieveld, P.;
Fichtner, I.; Stevens, M. F. G. J. Med. Chem. 1996, 39, 3375; (b) Beebe,
X.; Wodka, D.; Sowin, T. J. J. Comb. Chem. 2001, 3, 360; (c) Hari, A.;
Karan, C.; Rodrigues, W. C.; Miller, B. L. J. Org. Chem. 2001, 66, 991;
(d) Pottorf, R. S.; Chadha, N. K.; Katkevics, M.; Ozola, V.; Suna, E.;
Ghane, H.; Regberg, T.; Player, M. R. Tetrahedron Lett. 2003, 44, 175.
6. Ben-Alloum, A.; Bakkas, S.; Soufiaoui, M. Tetrahedron Lett. 1997, 38,
6395.
4.4.18. 2-(1-Methyl-1H-indol-2-yl)-1,3-benzothiazole (10a)
Colorless solid; mp 147e149 ꢁC; Rf¼0.66 (AcOEt/petro-
leum ether 30%). IR (KBr): 3419, 3051, 1542, 1450, 1345,
1
1310, 1191, 1150, 975, 787, 751 cmꢀ1. H NMR (500 MHz,
CDCl3) dH 4.31 (s, 3H, eNCH3), 7.17e7.20 (m, 2H, Ar-H),
7.33e7.44 (m, 3H, Ar-H), 7.48e7.51 (m, 1H, Ar-H), 7.67 (d,
1H, J¼8.4 Hz, Ar-H), 7.88 (d, 1H, J¼7.6 Hz, Ar-H), 8.06 (d,
1H, J¼8.4 Hz, Ar-H). 13C NMR (125 MHz, CDCl3) dC 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/z¼
264 [Mþ]. Anal. Calcd for C16H12N2S: C, 72.70; H, 4.58; N,
10.60. Found: C, 72.81; H, 4.62; N, 10.53.
7. Roe, A.; Tucker, W. P. J. Heterocycl. Chem. 1965, 2, 148.
8. Hutchinson, I.; Stevens, M. F. G.; Westwell, A. D. Tetrahedron Lett. 2000,
41, 425.
4.4.19. 2-(1-Methyl-1H-indol-2-yl)-1,3-benzoxazole (10b)
Colorless solid; mp 161e163 ꢁC; Rf¼0.55 (AcOEt/petro-
leum ether 25%). IR (KBr): 2332, 1579, 1450, 1340, 1240,
9. Spitulnik, M. J. Synthesis 1976, 730.
10. Terashima, M.; Ishii, M. Synthesis 1982, 1484 and references cited
therein.
1
1141, 753 cmꢀ1. H NMR (500 MHz, CDCl3) dH 4.31 (s, 3H,
11. Varma, R. S.; Saini, R. K.; Prakash, O. Tetrahedron Lett. 1997, 38, 2621.
12. Varma, R. S.; Kumar, D. J. Heterocycl. Chem. 1998, 35, 1539.
13. Park, K. H.; Jun, K.; Shin, S. R.; Oh, S. W. Tetrahedron Lett. 1996, 37,
8869.
eNCH3), 7.18 (t, 1H, J¼7.6 Hz, Ar-H), 7.35e7.38 (m, 3H,
Ar-H), 7.42 (d, 2H, J¼10.7 Hz, Ar-H), 7.57 (d, 1H, J¼
7.6 Hz, Ar-H), 7.72 (d, 1H, J¼7.6 Hz, Ar-H), 7.80e780 (m,
1H, Ar-H). 13C NMR (125 MHz, CDCl3) dC 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/z¼248 [Mþ].
Anal. Calcd for C16H12N2O: C, 77.40; H, 4.87; N, 11.28.
Found: C, 77.55; H, 4.75; N, 11.39.
14. Srivastava, R. G.; Venkataramani, P. S. Synth. Commun. 1988, 18, 1537.
15. Nakagawa, K.; Onoue, H.; Sugita, J. Chem. Pharm. Bull. 1964, 12, 1135.
16. Stephens, F. F.; Bower, J. D. J. Chem. Soc. 1949, 2971.
17. Kumar, K. H.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett. 2004,
45, 7903.
18. (a) Cainelli, G.; Cardillo, G. Chromium Oxidations in Organic Chemistry;
Springer: Berlin, 1984; (b) Haines, A. H. Methods for the Oxidation of
Organic Compounds. Alcohols, Alcohol derivatives, Alkyl halides, Nitro-
alkanes, Alkyl azides, Carbonyl Compounds, Hydroxyarenes and
Aminoarenes; Academic: London, 1988; (c) Corey, E. J.; Suggs, J. W. Tet-
rahedron Lett. 1975, 16, 2647; (d) Piancatelli, G.; Scettri, A.; D’Auria, M.
Synthesis 1980, 223; (e) Piancatelli, G.; Scettri, A.; D’Auria, M. Synthesis
1982, 245.
4.4.20. 2-(1H-Pyrrol-2-yl)-1,3-benzoxazole (10c)
Pink solid; mp 144e146 ꢁC; Rf¼0.51 (AcOEt/petroleum
ether 30%). IR (KBr): 3401, 1629, 1585, 1455, 1403, 1243,
1
1117, 741 cmꢀ1. H NMR (500 MHz, CDCl3) dH 6.36e6.38
(m, 1H, Ar-H), 7.04e7.05 (m, 1H, Ar-H), 7.28e7.33 (m, 2H,
Ar-H), 7.52 (d, 1H, J¼7.6 Hz, Ar-H), 7.64 (d, 1H, J¼7.6 Hz,
Ar-H), 10.25 (s, 1H, eNH). 13C NMR (125 MHz, CDCl3) dC
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/z¼184 [Mþ]. Anal. Calcd for
C11H8N2O: C, 71.73; H, 4.38; N, 15.21. Found: C, 71.81; H,
4.25; N, 15.25.
19. Vanden Eynde, J. J.; Mayence, A.; Maquestiau, A. Tetrahedron 1992, 48,
463.
20. (a) Goodman, L. S.; Gillman, A. The Pharmacological Basics of Thera-
peutics; MacMillan: New York, NY, 1980; (b) Watcher, M.; Ferro, M.
U.S. Patent. 4,826,868, 1989; Chem. Abstr. 1988, 108, 186735w.
21. Prakash, O.; Pannu, K.; Kumar, A. Molecules 2006, 11, 43.
22. Moody, C. J.; Roffey, J. R.; Stephens, M. A.; Stratford, I. J. Anticancer
Drugs 1997, 8, 489.