Hypervalent lodine(III) sulfonate reagent mediated synthesis of 4-aryl-2-phenyloxazoles in ionic liquid

Article abstract of DOI:10.1002/jccs.200800136

A new and efficient method for the synthesis of 4-aryl-2-phenyloxazoles is described which is based upon the reaction of α-[(2,4-dinitrobenzene) sulfonyl]oxy ketone intermediates with benzamide in ionic liquid.

Full text of DOI:10.1002/jccs.200800136

Journal of the Chinese Chemical Society, 2008, 55, 919-922
919
Hypervalent Iodine(III) Sulfonate Reagent Mediated Synthesis of
4-Aryl-2-phenyloxazoles in Ionic Liquid
Hui-Ting Chenga (
Huey-Min Wangb (
), Rei-Sheu Houb* (
),
) and Ling-Ching Chena* (
)
aGraduate Institute of Pharmaceutical Sciences, College of Pharmacy, Kaohsiung Medical University,
Kaohsiung 807, Taiwan, R.O.C.
bChung Hwa College of Medical Technology, Tainan 717, Taiwan, R.O.C.
A new and efficient method for the synthesis of 4-aryl-2-phenyloxazoles is described which is based
upon the reaction of a-[(2,4-dinitrobenzene)sulfonyl]oxy ketone intermediates with benzamide in ionic
liquid.
Keywords: Hypervalent iodine; Ionic liquid; Oxazoles.
INTRODUCTION
Room temperature ionic liquids (RTIL) are liquids
synthesis,18 we now report a new and direct method for the
synthesis of 4-aryl-2-phenyloxazoles by the cycloconden-
sation of benzamide with a-[(2,4-dinitrobenzene)sulfo-
nyl]oxy carbonyl compounds (2), formed by the reaction of
[hydroxyl(2,4-dinitrobenzenesulfonyloxy)iodo]benzene
(HDNIB) with aryl ketones (1) (Scheme I). The required
HDNIB was prepared in satisfactory yields from the reac-
tion of 2,4-dinitrobenzenesulfonic acid with phenylido-
dine(III) diacetate (PIDA).19 Treatment of aromatic ke-
tones with HDNIB in CH3CN under reflux for 1 h produced
the a-[(2,4-dinitrobenzene)sulfonyl]oxy ketone intermedi-
ates (2). Subsequent cyclocondensation by benzamide in
ionic liquid, 1-n-butyl-3-methylimidazolium hexafluoro-
phosphate, [Bmin][PF6] at 80 °C for 0.5 h gave the corre-
sponding 4-aryl-2-phenyloxazoles (3) in good yields.
that are composed entirely of ions. In fact, ionic liquids can
now be produced which remain liquid at room temperature
and below (even as low as -90 °C) and appear to be unde-
manding and inexpensive to manufacture.1 Ionic liquids
offer an attractive alternative to conventional organic liq-
uids for clean synthesis, as they are easy to recycle, lack
flammability, and possess effectively no vapour pressure.
Compared with classical molecular solvents, ionic liquids
are environmentally benign reaction media.2 To date some
of the more important reactions have been carried out and
investigated in ionic liquids, including Friedel-Crafts re-
action,3 alkoxycarbonylation,4 hydrogenation,5 Diels-Al-
der reaction,6 Wittig reaction,7 Heck reaction,8 Trost-
Tsuji coupling,9 ring-closing metathesis (RCM),10 Suzuki
cross-coupling,11 Fischer indole synthesis,12 1,3-dipolar
cycloaddition reaction,13 Beckmann rearrangement,14 the
Knoevenagel condensation, Robinson annulation reac-
tions,15 etc.
RESULTS AND DISCUSSION
The 2,4-dinitrobenzenesulfonyloxy group located at
the a position to a carbonyl group represents an increas-
ingly important entity in both mechanistic and synthetic or-
ganic chemistry. One reason for this importance is that the
2,4-dinitrobenzenesulfonyloxy group is a good leaving
group, and this accounts for the considerable synthetic util-
ity associated with these groups in the functionalization of
carbonyl compounds.
2,4-Substituted oxazoles is a basic building block of
several biologically interesting compounds.16 The reaction
of a-halo ketones with amides have been widely used for
the preparation of 2,4-substituted oxazoles. However, the
method gave only moderate yields with high reaction tem-
perature.17 Furthermore, it involves the use of a-halo ke-
tones, which are lachrymatory and toxic. Recently, hyper-
valent iodine(III) reagents have been used extensively in
organic synthesis due to their low toxicity, ready availabil-
ity and easy handling. As a part of our ongoing studies to
utilize hypervalent iodine(III) sulfonate reagents in organic
As shown in Scheme I, our experiments involving a
one-pot procedure for the preparation of 4-aryl-2-phenyl-
oxazoles (3) by cyclocondensation of benzamide with a-
[(2,4-dinitrobenzene)sulfonyl]oxy carbonyl compounds
(2) in [Bmin][PF6] at 80 °C were successful. The results are
summarized in Table 1. When the reaction was conducted

920 J. Chin. Chem. Soc., Vol. 55, No. 4, 2008
Cheng et al.
Scheme I
Table 1. Synthesis of 4-aryl-2-phenyloxazole 3a-k
ionic liquid.
Entry
Product
Ar
R
Yield (%)
EXPERIMENTAL SECTION
1
3a
3b
3c
3d
3e
3f
C6H5
H
H
82
77
75
81
80
83
76
74
75
84
82
All melting points are uncorrected. The IR spectra
were recorded on a Shimadzu IR-27 G spectrophotometer.
1H NMR and 13C NMR spectra were recorded on a Varian
Unity Plus 400 MHz. Chemical shifts (d) were measured in
ppm with respect to TMS. MS were obtained on a JEOL
JMS D-300 instrument. Elemental analyses were per-
formed on an EA-1110 instrument.
2
4-MeC6H4
4-MeOC6H4
4-FC6H4
3
H
4
H
5
4-ClC6H4
4-BrC6H4
3-Furyl
H
6
H
7
3g
3h
3i
H
8
3-Thienyl
C6H5
H
9
Me
H
10
11
3j
4-NO2C6H4
3,4-Cl2C6H4
Typical procedure for the preparation of 2,4-diphen-
yloxazole (3a)
3k
H
To a solution of acetophenone (1a) (120 mg, 1.0
mmol) in actonitrile (30 mL) was added HDNIB (561 mg,
1.2 mmol) and stirred under refluxing for 1 h. After remov-
ing the solvent, benzamide (0.36 g, 3 mmol) was added to
[Bmin][PF6] (2 mL) at 80 °C for 0.5 h. Subsequently, the
reaction mixture was extracted with AcOEt. The extract
was dried over MgSO4. The solvent was evaporated off and
the residue was purified by chromatography on a silica gel
column eluting with AcOEt-n-hexane (1:5) to give 0.18 g
(82%) of 3a, mp 105-106 °C (lit.20, 105-106 °C). IR (KBr)
n: 1606, 1551, 1444, 1068, 927, 780, 754, 717, 691 cm-1;
1H NMR (CDCl3) d: 7.97 (s, 1H), 7.31-7.36 (m, 1H), 7.41-
7.51 (m, 5H), 7.81-7.84 (m, 2H), 8.10-8.15 (m, 2H); 13C
NMR (CDCl3, 100 MHz) d: 125.6, 126.5, 127.5, 128.1,
128.7, 130.4, 131.1, 133.4, 141.9, 161.9; EI-MS m/z (rela-
in the classical molecular solvent, such as acetoniltrile, the
preparation of 2,4-diphenyloxazole (3a) needs refluxing
for 6 h.
The ionic liquid [Bmin][PF6] can be typically recov-
ered by extracting out the product first and filtering the sus-
pension followed by vacuum drying. The recovered sol-
vent can be reused without any loss of activity.
In summary, our results herein demonstrate that the
use of a-[(2,4-dinitrobenzene)sulfonyl]oxy ketone inter-
mediates and benzamide in ionic liquid [Bmin][PF6] can be
performed rapidly to prepare 4-aryl-2-phenyloxazles by
cyclocondensation. The ionic liquid plays the dual role of
solvent and promoter. Separation of the products from the
ionic liquids is very straightforward, as is recycling of the

Synthesis of 4-Aryl-2-phenyloxazoles
J. Chin. Chem. Soc., Vol. 55, No. 4, 2008 921
tive intensity) 221 (M+), 193, 164, 166, 90.
4-(3-Furyl)-2-phenyloxazole (3g)
4-(4-Methylphenyl)-2-phenyloxazole (3b)
mp 64-66 °C. IR (KBr) n: 1647, 1555, 1533, 1481,
1212, 1085, 1001 cm-1; 1H NMR (CDCl3) d: 7.90 (s, 1H),
6.49-6.50 (m, 1H), 6.80 (d, J = 3.2 Hz, 1H), 7.45-7.49 (m,
4H), 8.09-8.12 (m, 2H); 13C NMR (CDCl3, 100 MHz) d:
107.4, 111.6, 126.8, 127.4, 129.0, 130.9, 133.4, 134.7,
142.4, 147.1, 162.3; EI-MS m/z (relative intensity) 211
(M+), 183, 155, 154, 52; Anal. Calcd for C13H9NO2: C,
73.92; H, 4.29; N, 6.63. Found: C, 73.83; H, 4.38; N, 6.57.
2-Phenyl-4-(3-thienyl)oxazole (3h)
mp 110-112 °C. IR (KBr) n: 3140, 1604, 1482, 1066,
822, 781, 722, 693 cm-1; 1H NMR (CDCl3) d: 2.39 (s, 3H),
7.93 (s, 1H), 7.23-7.26 (m, 2H), 7.46-7.49 (m, 3H), 7.72 (d,
J = 8.4 Hz, 2H), 8.11-8.13 (m, 2H); 13C NMR (CDCl3, 100
MHz) d: 21.3, 125.5, 126.5, 127.6, 128.3, 128.7, 129.4,
130.3, 133.0, 137.9, 142.0, 161.8.; EI-MS m/z (relative in-
tensity) 235 (M+), 208, 207, 206, 192, 165, 78; Anal. Calcd
for C16H13NO: C, 81.68; H, 5.57; N, 5.95. Found: C, 81.74;
H, 5.62; N, 5.83.
mp 77-79 °C. IR (KBr) n: 1653, 1552, 1481, 1445,
1268, 1113, 1060, 906 cm-1; 1H NMR (CDCl3) d: 7.88 (s,
1H), 7.09-7.11 (m, 1H), 7.31-7.32 (m, 1H), 7.42-7.43 (m,
1H), 7.46-7.49 (m, 3H), 8.10-8.13 (m, 2H); 13C NMR
(CDCl3, 100 MHz) d: 124.2, 125.0, 126.6, 127.1, 127.6,
128.7, 130.5, 132.6, 133.8, 137.0, 161.8; EI-MS m/z (rela-
tive intensity) 227 (M+), 199, 198, 171, 96, 70; Anal. Calcd
for C13H9NOS: C, 68.70; H, 3.99; N, 6.16. Found: C,
68.62; H, 3.81; N, 6.28.
4-(4-Methoxyphenyl)-2-phenyloxazole (3c)
mp 106-108 °C. IR (KBr) n: 3129, 1617, 1503, 1068,
834, 762, 712, 690 cm-1; 1H NMR (CDCl3) d: 3.85 (s, 3H),
7.88 (s, 1H), 6.95-6.99 (m, 2H), 7.45-7.51 (m, 3H), 7.76
(td, J = 3.2, 8.4 Hz, 2H), 8.10-8.13 (m, 2H); 13C NMR
(CDCl3, 100 MHz) d: 55.3, 114.1, 114.2, 123.8, 126.4,
126.9, 127.5, 128.7, 130.3, 132.4, 141.7, 159.5, 161.8; EI-
MS m/z (relative intensity) 251 (M+), 223, 208, 180, 91;
Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21; N, 5.57.
Found: C, 76.51; H, 5.38; N, 5.63.
5-Methyl-2,4-diphenyloxazole (3i)
Oily compound. IR (neat) n: 1620, 1597, 1557, 1495,
1
4-(4-Fluorophenyl)-2-phenyloxazole (3d)
1447, 1206, 1069, 1014, 964 cm-1; H NMR (CDCl3) d:
mp 103-104 °C. IR (KBr) n: 3129, 1608, 1496, 1064,
843, 777, 727, 693 cm-1; 1H NMR (CDCl3) d: 7.92 (s, 1H),
7.10-7.16 (m, 2H), 7.47-7.51 (m, 3H), 7.78-7.83 (m, 2H),
8.09-8.14 (m, 2H); 13C NMR (CDCl3, 100 MHz) d: 115.6,
115.8, 126.5, 127.3, 127.4, 128.8, 130.5, 133.0, 141.1,
161.4, 163.8; EI-MS m/z (relative intensity) 239 (M+), 212,
184, 183, 107, 89; Anal. Calcd for C15H10FNO: C, 75.30;
H, 4.21; N, 5.85. Found: C, 75.48; H, 4.35; N, 5.97.
4-(4-Chlorophenyl)-2-phenyloxazole (3e)
2.61 (s, 3H), 7.33-7.38 (m, 1H), 7.43-7.51 (m, 5H), 7.78-
7.80 (m, 2H), 8.11-8.14 (m, 2H); 13C NMR (CDCl3, 100
MHz) d: 11.9, 125.9, 126.7, 127.2, 128.5, 128.6, 129.8,
132.3, 135.8, 137.3, 143.8, 159.2; EI-MS m/z (relative in-
tensity) 235 (M+), 220, 191, 165, 78; HRMS m/z Calcd for
C16H13NO: 235.0997. Found 235.0995.
4-(4-Nitrophenyl)-2-phenyloxazole (3j)
mp 175-176 °C. IR (KBr) n: 3149, 1516, 1334, 854,
1
747, 715, 689 cm-1; H NMR (CDCl3) d: 8.13 (s, 1H),
mp 126-128 °C (lit.21, 126-128 °C). IR (KBr) n: 3123,
7.50-7.52 (m, 3H), 8.00 (d, J = 8.8 Hz, 2H), 8.12-8.14 (m,
2H), 8.29-8.31 (m, 2H); 13C NMR (CDCl3, 100 MHz) d:
124.2, 126.1, 126.6, 126.9, 128.9, 130.9, 135.4, 137.4,
140.2, 147.3, 162.6; EI-MS m/z (relative intensity) 266
(M+), 238, 192, 165, 89, 63; Anal. Calcd for C15H10N2O3:
C, 67.67; H, 3.79; N, 10.52. Found: C, 67.75; H, 3.62; N,
10.43.
1
1607, 1482, 1065, 841, 778, 722, 693 cm-1; H NMR
(CDCl3) d: 7.96 (s, 1H), 7.39-7.42 (m, 2H), 7.47-7.50 (m,
3H), 7.77 (td, J = 2.4, 8.8 Hz, 2H), 8.10-8.12 (m, 2H); 13
C
NMR (CDCl3, 100 MHz) d: 126.8, 126.9, 127.3, 128.8,
128.9, 130.5, 133.5, 133.8; EI-MS m/z (relative intensity)
257 (M++2), 255 (M+), 228, 227, 192, 165, 89.
4-(4-Bromophenyl)-2-phenyloxazole (3f)
4-(3,4-Dichlorophenyl)-2-phenyloxazole (3k)
mp 134-136 °C. IR (KBr) n: 3166, 1607, 1479, 1068,
841, 777, 721, 693 cm-1; 1H NMR (CDCl3) d: 7.97 (s, 1H),
7.47-7.57 (m, 5H), 7.70 (td, J = 2.4, 8.4 Hz, 2H), 8.09-8.12
(m, 2H); 13C NMR (CDCl3, 100 MHz) d: 121.9, 123.3,
126.5, 127.2, 128.8, 130.1, 130.6, 131.9, 133.6, 141.0,
160.1; EI-MS m/z (relative intensity) 301 (M++2), 299 (M+),
273, 271, 192, 165, 89; Anal. Calcd for C15H1079BrNO: C,
60.02; H, 3.36; N, 4.67. Found: C, 60.18; H, 3.16; N, 4.52.
mp 117-118 °C. IR (KBr) n: 1608, 1557, 1446, 1286,
1061, 1024, 927 cm-1; 1H NMR (CDCl3) d: 7.97 (s, 1H),
7.47-7.50 (m, 4H), 7.63 (dd, J = 2.0, 8.0 Hz, 1H), 7.94 (d, J
= 2.0 Hz, 1H), 8.10-8.12 (m, 2H); 13C NMR (CDCl3, 100
MHz) d: 124.7, 126.5, 127.1, 127.4, 128.8, 130.7, 131.2,
131.8, 132.9, 134.0, 140.0, 162.2; EI-MS m/z (relative in-
tensity) 293 (M++4), 291 (M++2), 289 (M+), 263, 261, 226,
191, 123, 89; Anal. Calcd for C15H9Cl2NO: C, 62.09; H,

922 J. Chin. Chem. Soc., Vol. 55, No. 4, 2008
Cheng et al.
G.; Willauer, H. D.; Swatloski, R. P.; Visser, A. E.; Rogers, R.
D. Chem. Commun. 1998, 1765. (d) Song, C. E.; Shim, W.
H.; Roh, E. J.; Lee, S.; Choi, J. H. Chem. Commun. 2001,
1122.
3.13; N, 4.83. Found: C, 62.23; H, 3.26; N, 4.71.
ACKNOWLEDGEMENT
We gratefully acknowledge the National Science
Council of the Republic of China for financial support of
this work (Grant No. NSC 95-2113-M-037-009).
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Received February 21, 2008.
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