Hypervalent iodine(III) mediated synthesis of 2-substituted-5-aryloxazoles

Article abstract of DOI:10.1002/jccs.200200147

A direct and efficient method for the preparation of 2-substituted-5- aryloxazoles was realized by reaction of aryl methyl ketones with various nitriles in the presence of phenyliodine(III) triflate.

Full text of DOI:10.1002/jccs.200200147

Journal of the Chinese Chemical Society, 2002, 49, 1031-1034
1031
Hypervalent Iodine(III) Mediated Synthesis of 2-Substituted-5-aryloxazoles
Iou-Jiun Kanga (
Mei-Ling Lina (
), Huey-Min Wangb (
),
) and Ling-Ching Chen*a (
)
aGraduate Institute of Pharmaceutical Sciences, Kaohsiung Medical University,
Kaohsiung, Taiwan 807, R.O.C.
bChung Hwa College of Medical Technology, Tainan, Taiwan 717, R.O.C.
A direct and efficient method for the preparation of 2-substituted-5-aryloxazoles was realized by reaction
of aryl methyl ketones with various nitriles in the presence of phenyliodine(III) triflate.
INTRODUCTION
Oxazoles are important constituents in biologically ac-
the reasons for this is that the triflate group is a good leaving
group, and this accounts for the considerable synthetic utility
associated with these groups in functionalization of carbonyl
compounds. Due to the triflate having better leaving ability
than the corresponding halide, -keto triflate reacts rapidly
with nitrile without assistance of Lewis acid to give oxazoles.
As shown in Table 1, various oxazoles were prepared in
good to high yields. Gratifyingly, the reactions were com-
pleted by heating at reflux for 1.5 h and found to be clean in
all cases. The steric influence of nitriles had little effect on
the oxazole formation. The structures of 3 spectral were iden-
tified by their IR, 1H NMR, and MS spectra data.
tive natural products and serve as versatile starting materials
in synthetic transformations.1 Although many good general
methods are available for the preparation of oxazoles, little is
known about their synthesis from ketones. Oxazole synthesis
is usually accomplished through indirect methods which uti-
lize -halo ketones,2 -diazo ketones,3 or -azido ketones4 as
precursors.
Recently, hypervalent iodine reagents have been exten-
sively used in organic syntheses due to their low toxicity,
ready availability and easy handling.5 As a continuation of
our studies concerning hypervalent iodine(III) chemistry and
its application to the synthesis of heterocycles, we report here
a new and direct method for the conversion of aryl methyl ke-
tones (1) to the corresponding oxazoles (3) by the reaction
with phenyliodine(III) triflate [generated in situ by reaction
of phenyliodine(III) diacetate (PIDA) with trifluoromethane-
sulfonic acid] in refluxing nitriles (Scheme I).
A reasonable pathway of the above transformations
may be explained as follows: The electrophilic addition of
phenyliodine(III) triflate to the enolic form of the ketone (1)
gave intermediate 4. Step 4 to -keto triflate (2) can occur
through displacement of the iodobenzene by 1,2 shift of the
OSO2CF3 group. The reaction of -keto triflates with
nitriles probably proceeded via the formation of nitrilium
salts as proposed by Meyers8 (Scheme II).
The above results can be rationalized by the formation
of phenyliodine(III) triflate in situ by the action of trifluoro-
methanesulfonic acid on PIDA (eq. 1).
RESULTS AND DISCUSSION
The triflate group positioned in the position to a car-
bonyl group represents an increasingly important entity in
both mechanistic6 and synthetic7 organic chemi s t r y. One of
PhI(OAc)2 + 2CF3SO3H
PhI(OSO2CF3)2 + 2AcOH
(1)
Scheme I
R
O
O
PIDA, CF3SO3H
RCN
reflux
OSO2CF3
O
N
Ar
Ar
Ar
1
2
3

1032 J. Chin. Chem. Soc., Vol. 49, No. 6, 2002
Kang et al.
Scheme II
OH
O
Ph
I
O
PhI(OSO2CF3)2
Ar
CH2
Ar
OSO2CF3
Ar
PhI
4
1
R
O
RCN
O
N
OSO2CF3
Ar
Ar
3
2
reflux for 1.5 h. The residue obtained after removing the sol-
vent was extracted with CH2Cl2, and the organic layer was
washed with saturated aqueous NaHCO3 solution, dried over
MgSO4, and concentrated under reduced pressure. The resi -
due was purified by chromatography on a silica gel colu m n
with hexane-ethyl acetate (2:1) as eluent to give the products
3a-h.
Table 1. Yields of Oxazoles Prepared
Oxazole
R
Ar
Yield (%)a
3a
3b
3c
3d
3e
3f
CH3
CH3
CH3
CH3
Ph
80
84
81
82
80
84
80
75
p-MeOC6H4
p-ClC6H4
p-BrC6H4
p-MeOC6H4
Ph
CH2CH3
CH2CH2CH3
(CH3)2CH
CH2 = CH
3g
3h
Ph
2-Methyl-5-phenyloxazole (3a)
p-MeOC6H4
Colorless needles; mp 57-58 C (lit.,9 58-59 C). IR
(neat) 1620, 1557, 1450, 1214, 1060 cm-1; 1H NMR (CDCl3,
400 MHz): 2.52 (s, 3H), 7.17 (s, 1H), 7.36-7.39 (m, 3H),
7.57-7.62 (m, 2H); EI-MS m/z (relative intensity) 159 (M+,
100), 130 (54), 104 (54), 89 (22), 77 (26), 63 (8), 51 (14).
a All compounds gave satisfactory spectral data.
In summary, the method described herein provides a
good approach for the direct transformation of 2-subs t i -
tuted-5-aryloxazoles by usi n g the reaction of aryl methyl ke-
tones with phenyliodine(III) triflate in refluxing nitriles.
5-p-Methoxyphenyl-2-methyloxazole (3b)
Colorless needles; mp 104-105 C (lit.,10 105-106 C).
1
IR (neat) 1620, 1577, 1504, 1250, 1023 cm-1; H NMR
(CDCl3, 200 MHz): 2.17 (s, 3H), 3.84 (s, 3H), 6.95 (d, J =
8.9 Hz, 2H), 7.18 (s, 1H), 7.54 (d, J = 8.9 Hz, 2H); EI-MS m/z
(relative intensity) 189 (M+, 100), 174 (31), 146 (34), 134
(49), 119 (28), 91 (11), 77 (22).
EXPERIMENTAL SECTION
All melting points are uncorrected. The IR spectra were
1
recorded on a Shimadzu IR-27 G spectrophotometer. H
NMR and 13C spectra were recorded on a Varian Unity Plus
200 and 400 MHz. Chemical shifts ( ) were measured in ppm
with respect to TMS. MS were obtained on a JEOL JMS
D-300 instrument.
5-p-Chlorophenyl-2-methyloxazole (3c)
Pale yellow needles; mp 54-56 C (lit.,10 57-59 C). IR
1
(neat) 1620, 1573, 1483, 1284, 939 cm-1; H NMR (CDCl3,
400 MHz): 2.51 (s, 3H), 7.19 (s, 1H), 7.36 (d, J = 8.8 Hz,
2H), 7.52 (d, J = 8.8 Hz, 2H); EI-MS m/z (relative intensity)
193 (M+, 100), 164 (38), 140 (26), 138 (76), 111 (26), 103
(39), 89 (45), 75 (24), 54 (24).
General procedure for the preparation of oxazoles 3a-h
To a stirred solution of the phenyliodine diacetate (242
mg, 0.75 mmol) in CH3CN (20 mL) was added CF3SO3H (225
mg, 1.50 mmol), and the mixture was stirred at room temper-
ature for 10 min. To the reaction mixture, ketone (0.5 mmol)
in CH3CN (10 mL) was added and stirring was continued at
5-p-Bromophenyl-2-methyloxazole (3d)
Colorless needles; mp 82-84 C (lit.,10 83-85 C). IR

Synthesis of 2-Substituted-5-aryloxazoles
J. Chin. Chem. Soc., Vol. 49, No. 6, 2002 1033
(neat) 1620, 1573, 1480, 1220, 1009 cm-1; 1H NMR (CDCl3,
400 MHz): 2.52 (s, 3H), 7.21 (s, 1H), 7.47 (d, J = 8.8 Hz,
2H), 7.53 (d, J = 8.8 Hz, 2H); EI-MS m/z (relative intensity)
238 (M+, 8), 239 (99), 184 (46), 182 (57), 157 (22), 130 (100),
103 (85), 75 (17), 54 (24).
cil of the Republic of China for the financial support of this
work (Grant No. 90-2113-M-037-016).
Received March 14, 2002.
Key Words
2-Ethyl-5-p-methoxyphenyloxazole (3e)
Pale yellow needles; mp 60-61 C (lit.,9 61-62 C). IR
Phenyliodine(III) diacetate; Trifluoromethane-
sulfonic acid; -Keto triflate.
(neat) 1620, 1560, 1504, 1462, 1304, 1248 cm-1; H NMR
1
(CDCl3, 400 MHz): 1.38 (t, J = 7.6 Hz, 3H), 2.84 (q, J = 7.6
Hz, 2H), 3.84 (s, 3H), 6.94 (d, J = 8.8 Hz, 2H), 7.09 (s, 1H),
7.54 (d, J = 8.8 Hz, 2H); EI-MS m/z (relative intensity) 203
(M+, 100), 188 (50), 147 (28), 133 (80), 77 (27).
REFERENCES
1. (a) Pattenden, G. J. Heterocyclic Chem. 1992, 29, 607. (b)
Michael, J. P.; Pattenden, G. Angew. Chem., Int. Ed. Engl.
1993, 32, 1. (c) Wipf, P. Chem. Rev. 1995, 95, 2115. (d)
Lewis, J. R. Nat. Prod. Rep. 1995, 12, 135. (e) Vedejs, E.;
Monahan, S. D. J. Org. Chem. 1996, 61, 5192.
2. (a) Bredereck, H.; Gompper, R. Chem. Ber. 1954, 87, 700.
(b) Bredereck, H.; Gompper, R.; Reich, F. Chem. Ber. 1960,
93, 1389. (c) Lora-Tamayo, M.; Madronero, R.; Leipprand,
H. Chem. Ber. 1964, 97, 2230.
3. (a) Kitatani, K.; Hiyama, T.; Nozaki, H. Bull. Chem. Soc.
Jpn. 1977, 50, 1647. (b) Doyle, M. P.; Buhro, W. E.;
Davidson, J. G.; Elliot, R. C.; Hoekstra, J. W.; Oppenhuizen,
M. J. Org. Chem. 1980, 45, 3657. (c) Ibata, T.; Fukushima,
K. Chem. Lett. 1992, 2197.
4. (a) Takeuchi, H.; Yanagida, S.; Ozaki, T.; Hagiwara, S.;
Eguchi, S. J. Org. Chem. 1989, 54, 431. (b) Molina, P.;
Fresneda, P. M.; Almendros, P. Synthesis 1993, 54.
2-Propyl-5-phenyloxazole (3f)
Colorless oil; IR (neat) 1620, 1556, 1449, 1133, 1077
cm-1; 1H NMR (CDCl3, 400 MHz): 1.04 (t, J = 7.6 Hz, 3H),
1.85 (sex, J = 7.6 Hz, 2H), 2.82 (t, J = 7.6 Hz, 2H), 7.24 (s,
1H), 7.31-7.62 (m, 5H); 13C NMR (CDCl3, 100 MHz): 13.5,
20.3, 29.9, 121.5, 123.7, 127.8, 128.1, 128.6, 150.6, 164.3;
EI-MS m/z (relative intensity) 187 (M+, 35), 172 (13), 159
(100), 103 (72), 77 (28). HRMS m/z Calcd for C12H13NO:
187.0998. Found: 187.0998.
2-Isopropyl-5-phenyloxazole (3g)
Pale yellow oil; IR (neat) 1620, 1553, 1449, 1139, 1060
cm-1; 1H NMR (CDCl3, 200 MHz): 1.41 (t, J = 7.0 Hz, 6H),
3.16 (sep, J = 7.0 Hz, 1H), 7.22 (s, 1H), 7.30-7.64 (m, 5H);
13C NMR (CDCl3, 100 MHz): 20.3, 28.4, 121.5, 123.9,
127.9, 128.2, 128.7, 150.6, 168.5; EI-MS m/z (relative inten-
sity) 187 (M+, 60), 172 (100), 117 (88), 82 (37), 55 (12).
HRMS m/z Calcd for C12H13NO: 187.0998. Found: 187.0999.
5. Reviews, see: (a) Banks, D. F. Chem. Rev. 1966, 66, 243. (b)
Varvoglis, A. Chem. Soc. Rev. 1981, 10, 377. (c) Koser, G. F.
in The Chemistry of Functional Groups, Supplement D,
Patai, S.; Rappoport, Z., Ed. Wiley, New York, 1983, Ch. 18
and 25. (d) Varvoglis, A. Synthesis 1984, 709. (e) Moriaty,
R. M.; Prakash, O. Acc. Chem. Res. 1986, 19, 244. (f) Ochiai,
M.; Nagao, Y. Yuki Gosei Kagaku Kyokaishi 1986, 44, 660.
(g) Moriarty, R. M.; Vaid, R. K.; Koser, G. F. Synlett 1990,
365. (h) Varvoglis, A. The Organic Chemistry of Poly-
coordinated Iodine VCH, New York, 1992. (i) Kita, Y.;
Tohma, H.; Yakura, T. Trends Org. Chem. 1992, 3, 113. (j)
Kita, Y.; Tohma, H. Farumashia 1992, 28, 984. (k) Stang, P.
J. Angew. Chem., Int. Ed. Engl. 1992, 31, 274. (l) Kitamura,
T. Yuki Gosei Kagaku Kyokaishi 1995, 53, 893. (m) Stang, P.
J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123. (n) Kitamura,
T.; Fujiwara, Y. Org. Prep. Proc. Int. 1997, 29, 411.
6. Creary, X. Acc. Chem. Res. 1985, 18, 3.
5-p-Methoxyphenyl-2-vinyloxazole (3h)
Colorless oil; IR (neat) 1615, 1498, 1252, 1177, 1029
cm-1; 1H NMR (CDCl3, 400 MHz): 3.85 (s, 3H), 5.62 (d, J =
11.2 Hz, 1H), 6.21 (d, J = 17.6 Hz, 1H), 6.62 (dd, J = 17.6 and
11.2 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 7.24 (s, 1H), 7.60 (d, J
= 8.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz): 55.3, 114.3,
120.7, 120.8, 121.7, 123.4, 125.8, 151.0, 159.9, 160.0;
EI-MS m/z (relative intensity) 201 (M+, 100), 186 (25), 158
(31), 131 (19), 103 (15), 77 (14). HRMS m/z Calcd for
C12H11NO2: 201.0789. Found: 201.0789.
7. (a) Kemp, J. E. G.; Closier, M. D.; Narayanaswami, S.;
Stefaniak, M. H. Tetradedron Lett. 1980, 21, 2991. (b)
Effenberger, F.; Burkard, U.; Willfahrt, J. Angew. Chem. Int.
Ed. Engl. 1983, 22, 65.
ACKNOWLEDGEMENT
We gratefully acknowledge the National Science Coun-

1034 J. Chin. Chem. Soc., Vol. 49, No. 6, 2002
Kang et al.
8. Meyers, A. I.; Sircar, J. C. in The Chemistry of the Cyano
Group, Rappoport, Z., Ed., Interscience, New York, 1970,
341.
9. Ibata, T.; Sato, R. Bull. Chem. Soc. Jpn. 1979, 52, 3597.
10. Takeuchi, H.; Yanagida, S.; Ozaki, T.; Hagiwara, S. Eguchi,
S. J. Org. Chem. 1989, 54, 431.