Iodoarene-mediated one-pot preparation of 2,4,5-trisubstituted oxazoles from ketones

Article abstract of DOI:10.1055/s-2007-1000871

2-Methyl-5-aryloxazole and 2-ethyl-5-aryloxazole derivatives were smoothly and efficiently obtained in one-pot manner from alkyl aryl ketones with iodoarene, m-chloroperbenzoic acid, and trifluoromethanesulfonic acid in acetonitrile and propionitrile, res

Full text of DOI:10.1055/s-2007-1000871

LETTER
217
Iodoarene-Mediated One-Pot Preparation of 2,4,5-Trisubstituted Oxazoles
from Ketones
I
Y
odoarene-Mediate
u
dOne-Pot
P
h
reparationof
t
2,4,5-T
a
risubstitutedOxa
K
z
oles awano, Hideo Togo*
Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku Chiba 263-8522, Japan
E-mail: togo@faculty.chiba-u.jp
Received 24 October 2007
syloxyketones with MCPBA and p-toluenesulfonic acid
in the presence of a catalytic amount of IL (ionic liquid)-
supported PhI in [emim]OTs (1-ethyl-3-methylimidazoli-
Abstract: 2-Methyl-5-aryloxazole and 2-ethyl-5-aryloxazole de-
rivatives were smoothly and efficiently obtained in one-pot manner
from alkyl aryl ketones with iodoarene, m-chloroperbenzoic acid,
and trifluoromethanesulfonic acid in acetonitrile and propionitrile, um tosylate).10
respectively. In these reactions, iodoarene works as a catalyst.
Herein, as part of our study on organic synthesis using
Key words: 2,4,5-trisubstituted oxazoles, one-pot reaction, PhI-catalyzed system with MCPBA, we report the PhI-
MCPBA, iodoarene
mediated direct preparation of 2,5-disubstituted and 2,4,5-
trisubstituted oxazoles from alkyl aryl ketones with TfOH
in acetonitrile or propionitrile.
The synthetic study of oxazole units is very important be-
cause of the potent biological activity of these moeities
and their utility as versatile starting materials in organic
11
The reaction was carried out as follows: To an acetoni-
trile solution were added iodoarene (1.1 equiv), MCPBA
(
1.1 equiv), and TfOH (2.0 equiv), and the mixture was
1
synthesis. One of the most reliable and direct methods for
stirred for 0.5–2 hours, depending on the substrate, to gen-
erate the corresponding arene iodonium species. Then, a
solution of alkyl aryl ketone (1.0 equiv) in acetonitrile (2
mL) was added, and the obtained mixture was refluxed for
the construction of oxazole ring is the cyclodehydration of
a-acylamino ketones using dehydrating reagents, such as
sulfuric acid, phosphorus pentachloride, and polyphos-
1
phoric acid. To our knowledge, there are two methods for
2
–4 hours to provide the corresponding 2-methyl-5-aryl-
the direct preparation of oxazoles from ketones with ni-
oxazole. First, the effect of iodoarenes with MCPBA, ac-
2
triles, which use copper(II) triflate and thallium(III) tri-
etophenone, and TfOH was studied, using iodobenzene,
3
flate. As less toxic and efficient methods, the preparation
4
-iodotoluene, 4-chloroiodobenzene, 4-iodoanisole, 1-io-
of 2,5-disubstituted oxazoles from aryl methyl ketones us-
ing (diacetoxyiodo)benzene with trifluoromethanesulfon-
donaphthalene, 4,4¢-diiodobiphenyl, 1,4-bis(4¢-iodophen-
yl)benzene, and poly(4-iodostyrene) as shown in Table 1
4
ic acid (TfOH) in acetonitrile, and the preparation of
(
entries 2–9). In the absence of iodoarene, 2-methyl-5-
2
,4,5-trisubstituted oxazoles from carbonyl compounds
phenyloxazole was not formed at all, and acetophenone
was recovered in ca. 70% yield (entry 1). However, in the
presence of iodoarene, 2-methyl-5-phenyloxazole was
formed in moderate yields (54–60%) in a one-pot manner,
especially with iodobenzene, 4-iodotoluene, and 4-
chloroiodobenzene (entries 2–4). When 4-iodoanisole or
using [(hydroxy)(2,4-dinitrobenzenesulfonyloxy)io-
do]benzene with amides under solvent-free microwave ir-
5
radiation conditions were reported recently. Especially,
the former method is readily available for the direct prep-
aration of 2-methyl-5-aryloxazoles, and a variety of 2,4,5-
trisubstituted oxazoles can be obtained using different
types of aryl alkyl ketones in acetonitrile and other nitrile
solvents. On the other hand, recently, PhI-catalyzed a-ac-
etoxylation of ketones with m-chloroperbenzoic acid
1
-iodonaphthalene was used, the reaction provided black
tar species, without formation of 2-methyl-5-phenylox-
azole, whereas, when 1,4-bis(4¢-iodophenyl)benzene or
poly(4-iodostyrene) was used, the yield of 2-methyl-5-
phenyloxazole was poor due to the low solubility in ace-
tonitrile. Based on these results, 2-methyl-5-(4¢-meth-
ylphenyl)oxazole (entries 10–12), 2-methyl-5-(4¢-
chlorophenyl)oxazole (entries 13–15), and 2-methyl-5-
(
MCPBA) in AcOH in the presence of BF ·OEt and wa-
3
2
ter was reported to provide the corresponding a-acet-
oxyketones in moderate yields, and hypervalent
6
iodine(III)-catalyzed oxidative cyclization of b-(4-hy-
droxyaryl)propanoic acids with MCPBA was reported to
(
4¢-nitrophenyl)oxazole (entries 16–18) were obtained in
7
give the corresponding spirolactones. We also reported
moderate yields from 4-methylacetophenone, 4-
chloroacetophenone, and 4-nitroacetophenone, respec-
tively. When propiophenone and nonanophenone were
used under the same conditions, 2,4-dimethyl-5-phenyl-
oxazole (entries 19–21) and 2-methyl-4-heptyl-5-phenyl-
oxazole (entries 22–24) were obtained in moderate yields.
Here, iodoarene worked as a catalyst, and in the reaction
of 4-chloroiodobenzene, MCPBA, and TfOH with 4-ni-
troacetophenone in acetonitrile, 4-chloroiodobenzene was
direct one-pot preparation of various [(hydroxy)(sulfony-
loxy)iodo]arenes from iodoarenes with MCPBA and sul-
8
fonic acids at room temperature, PhI-catalyzed a-
tosyloxylation of ketones with MCPBA and p-toluene-
9
sulfonic acid, and efficient conversion of ketones to a-to-
SYNLETT 2008, No. 2, pp 0217–0220
x
x.
x
x.
2
0
0
8
Advanced online publication: 21.12.2007
DOI: 10.1055/s-2007-1000871; Art ID: U10307ST
©
Georg Thieme Verlag Stuttgart · New York

2
18
Y. Kawano, H. Togo
LETTER
Table 1 Iodoarene-Mediated Preparation of 2-Methyloxazoles with Ketones, MCPBA, and TfOH in MeCN
O
1
Ar I (1.1 equiv)
R2
MCPBA (1.1 equiv)
Ar2
R2
N
O
TfOH (2.0 equiv)
(1.0 equiv)
MeCN
Me
MeCN (2 mL)
reflux, time y
(
8 mL)
r.t., time x
Ar2
Entry
Ar1I
Ar2
R2
H
H
H
H
H
H
Time x (h)
Time y (h)
Yield (%)a
1
2
3
4
5
6
–
Ph
Ph
Ph
Ph
Ph
Ph
0.5
0.5
2
2
2
2
2
2
2
0
PhI
56
60
54
0
4-MeC H I
6
4
4-ClC H I
1
6
4
4-MeOC H I
2
6
4
C H I
2
0
10
7
7
Ph
H
2
2
17
I
I
I
I
2
8
9
Ph
Ph
H
H
2
2
2
2
14
35
3
PS
I
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
PhI
4-MeC H I
4-MeC H
H
0.5
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
64
58
63
61
54
57
77
47
68b
66
58
55
50
44
45
6
4
4
4
4-MeC H
H
6
4
6
4-ClC H I
4-MeC H
H
1
6
4
6
PhI
4-MeC H I
4-ClC H
H
0.5
2
6
4
4
4
4-ClC H
H
6
4
6
4-ClC H I
4-ClC H
H
1
6
4
6
PhI
4-MeC H I
4-O NC H
H
0.5
2
2
6
4
4
4
4-O NC H
H
6
4
2
6
4-ClC H I
4-O NC H
H
1
6
4
2
6
PhI
4-MeC H I
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
0.5
2
6
4
4-ClC H I
1
6
4
PhI
4-MeC H I
C H
0.5
2
7
15
15
15
C H
6
4
7
4-ClC H I
C H
1
6
4
7
a
Isolated yield.
b
4
-Chloroiodobenzene was recovered in 100% yield.
Synlett 2008, No. 2, 217–220 © Thieme Stuttgart · New York

LETTER
Iodoarene-Mediated One-Pot Preparation of 2,4,5-Trisubstituted Oxazoles
219
Table 2 Iodoarene-Mediated Preparation of 2-Ethyloxazoles with Ketones, MCPBA, and TfOH in EtCN
O
1
Ar I (1.1 equiv)
R2
Ar2
MCPBA (1.1 equiv)
TfOH (2.0 equiv)
R2
N
O
(1.0 equiv)
EtCN
8 mL)
Et
r.t., time x
MeCN (2 mL)
reflux, time y
(
Ar2
Entry
Ar1I
Ar2
Ph
Ph
Ph
R2
H
Time x (h)
Time y (h)
Yield (%)a
51
1
2
3
4
5
6
7
8
9
PhI
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
4
4
4
4-MeC H I
H
68
6
4
4-ClC H I
H
61
6
4
PhI
4-MeC H I
4-MeC H
H
33
6
4
4
4
4-MeC H
H
45
6
4
6
4-ClC H I
4-MeC H
H
39
6
4
6
PhI
4-MeC H I
4-ClC H
H
48
6
4
4
4
4-ClC H
H
42
6
4
6
4-ClC H I
4-ClC H
H
63
6
4
6
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
PhI
4-MeC H I
4-O NC H
H
40
2
6
4
4
4
4-O NC H
H
55
6
4
2
6
4-ClC H I
4-O NC H
H
78b
59
6
4
2
6
PhI
4-MeC H I
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
55
6
4
4-ClC H I
52
6
4
PhI
4-MeC H I
C H
22
7
15
15
15
C H
36
6
4
7
1
4-ClC H I
C H
30
6
4
7
a
Isolated yield.
b
4
-Chloroiodobenzene was recovered in 97% yield.
recovered in 100% yield, together with 2-methyl-5-(4¢-ni- action pathway is shown in Scheme 1. Iodoarene is oxi-
trophenyl)oxazole (entry 18). Other iodoarenes such as io- dized to aryl iodonium species A by MCPBA and TfOH,
dobenzene and 4-iodotoluene could also be recovered in and it reacts with the enolate form of ketone to form the
high yields. Under the present conditions, dialkyl ketones corresponding a-keto iodonium species B. Finally, a-keto
gave the corresponding oxazoles in poor yields (~10%).
iodonium species B reacts with nitrile to provide the ox-
azole through the intermediate C.
When the same reaction was carried out in propionitrile
instead of acetonitrile, 2-ethyl-5-phenyloxazole, 2-ethyl- In conclusion, 2-methyl-5-aryloxazole and 2-ethyl-5-aryl-
-(4¢-methylphenyl)oxazole, 2-ethyl-5-(4¢-chlorophen- oxazole derivatives were smoothly and efficiently ob-
5
yl)oxazole, and 2-ethyl-5-(4¢-nitrophenyl)oxazole were tained in one-pot manner from alkyl aryl ketones with
obtained in moderate yields from acetophenone, 4- iodoarene, MCPBA, and TfOH in acetonitrile and propi-
methylacetophenone, 4-chloroacetophenone, and 4-ni- onitrile, respectively. Here, iodoarene worked as a cata-
troacetophenone, respectively, as shown in Table 2 (en- lyst.
tries 1–12). 2-Ethyl-4-methyl-5-phenyloxazole and 2-
ethyl-4-heptyl-5-phenyloxazole were obtained in moder-
ate yields, when propiophenone and nonanophenone were
used instead of aryl methyl ketones under the same condi- Financial support in the form of a Grant-in-Aid for Scientific Rese-
tions (entries 13–18). In entry 12, 4-chloroiodobenzene
Acknowledgment
arch on Priority Area (18045008) from the Ministry of Education,
Science, Sports, and Culture is gratefully acknowledged.
was recovered in 97% yield as a catalyst. The proposed re-
Synlett 2008, No. 2, 217–220 © Thieme Stuttgart · New York

2
20
Y. Kawano, H. Togo
LETTER
R2
(9) (a) Yamamoto, Y.; Togo, H. Synlett 2006, 798.
N
R1
(b) Yamamoto, Y.; Kawano, Y.; Toy, P. H.; Togo, H.
Tetrahedron 2007, 63, 4680.
10) Akiike, J.; Yamamoto, Y.; Togo, H. Synlett 2007, 2168.
–
TfOH
O
Ar2
(
+
N
R2
(11) Typical Experimental Procedure: To a mixture of
iodobenzene (purity 98%, 1.1 mmol, 228 mg) and MCPBA
(purity 65%, 292 mg) in MeCN (8 mL) was added TfOH (2.0
mmol, 0.17 mL). The obtained mixture was stirred for 0.5 h
at r.t. under an argon atmosphere. Then, a solution of
acetophenone (purity 98.5%, 1.0 mmol, 122 mg) in MeCN
C
R1
Ar2
–
O
H
C
TfO
OH
O
C
Ar2
C
C
H
R2
Ar2
CH2R2
(
2 mL) was added, and the mixture was stirred for 2 h under
R1 CN
O
refluxing conditions. After the reaction, the reaction mixture
was poured into sat. aq NaHCO solution and extracted with
CHCl (3 × 30 mL). The organic layer was dried over
Na SO . After filtration and removal of the solvent under
+
H
C
R2
1
Ar2
Ar I
C
3
–
3
TfO
B
– H2O
2
4
reduced pressure, the residue was purified by preparative
TLC on silica gel (eluent: hexane–EtOAc, 5:1) to give 2-
methyl-5-phenyloxazole in 56% yield.
–
+
1
TfO Ar I OH
12
Ar1I
2-Methyl-5-phenyloxazole: mp 57–58.5 °C (lit. mp 57–
A
–1 1
5
8 °C). IR (KBr): 1580, 1560, 1480 cm . H NMR (400
MHz, CDCl ): d = 2.53 (s, 3 H), 7.20 (s, 1 H), 7.30 (tt, J =
3
1
7
.5, 7.8 Hz, 1 H), 7.40 (t, J = 7.8 Hz, 2 H), 7.60 (dd, J = 1.5,
.8 Hz, 2 H). MS (FAB): m/z = 160 [M + H].
Analytical data for selected oxazoles are as follows:
-Methyl-5-(4¢-chlorophenyl)oxazole: mp 71–72 °C (lit.
mp 74–75.5 °C). IR (KBr): 3060, 1580, 1560, 1480, 1090,
1
3
2
–
1 1
8
20 cm . H NMR (400 MHz, CDCl ): d = 2.53 (s, 3 H, s),
3
MCPBA
TfOH
4-ClC H CO H
6
4
2
7.20 (s, 1 H), 7.38 (d, J = 8.9 Hz, 2 H), 7.54 (d, J = 8.9 Hz,
2
H).
1
4
Scheme 1 Reaction pathway
2-Methyl-5-(4¢-nitrophenyl)oxazole: mp 161–162 °C (lit.
mp 167–168 °C). IR (KBr): 3020, 1610, 1560, 1500, 1350,
330, 1130, 1110, 1060, 940, 850, 760 cm . H NMR (400
–
1 1
1
MHz, CDCl ): d = 2.58 (s, 3 H), 7.42 (s, 1 H), 7.76 (d, J =
3
9.0 Hz, 2 H), 8.28 (d, J = 9.0 Hz, 2 H). MS (FAB): m/z = 205
References and Notes
[M + H].
1
4
2
-Methyl-5-(4¢-methylphenyl)oxazole: mp 54–55 °C (lit.
(
1) (a) Comprehensive Heterocyclic Chemistry, Vol. 6; Boyd,
G. V.; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon:
Oxford, 1984, Chap. 4.18. (b) Comprehensive Heterocyclic
Chemistry II, Vol. 3; Hartner, F. W. J. r.; Katritzky, A. R.;
Rees, C. W.; Scriven, E. F. V., Eds.; Elsevier Science:
Oxford, 1996, Chap. 3.04. (c) Pattenden, G. J. Heterocycl.
Chem. 1992, 29, 607. (d) Michael, J. P.; Pattenden, G.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1. (e) Wipf, P.
Chem. Rev. 1995, 95, 2115. (f) Vedejs, E.; Monahan, S. D.
J. Org. Chem. 1996, 61, 5192.
–1
mp 56–57 °C). IR (KBr): 1580, 1560, 1500, 1460, 1380 cm .
1
H NMR (400 MHz, CDCl ): d = 2.37 (s, 3 H), 2.52 (s, 3 H),
3
7
2
2
1
.15 (s, 1 H), 7.21 (d, J = 8.1 Hz, 2 H), 7.49 (d, J = 8.1 Hz,
H).
-Ethyl-5-phenyloxazole: oil. IR (neat): 3060, 2980, 2940,
580, 1560, 1490, 1450, 760, 690 cm . H NMR (400 MHz,
–1
1
CDCl ): d = 1.40 (t, J = 7.6 Hz, 3 H), 2.86 (q, J = 7.6 Hz, 2
3
H), 7.22 (s, 1 H), 7.30 (tt, J = 1.4, 7.6 Hz, 1 H), 7.40 (dd, J =
7.6, 8.0 Hz, 2 H), 7.61 (dd, J = 1.4, 8.0 Hz, 2 H). HRMS:
m/z [M + H] calcd for C H NO: 174.0919; found:
1
1
12
(2) Nagayoshi, K.; Sato, T. Chem. Lett. 1983, 12, 1355.
(3) Lee, J. C.; Hong, T. Tetrahedron Lett. 1997, 38, 8959.
(4) Varma, R. S.; Kumar, D. J. Heterocycl. Chem. 1998, 35,
1
2
8
7
74.0922.
12
-Ethyl-5-(4¢-nitrophenyl)oxazole: mp 81–82 °C (lit. mp
5–86 °C). IR (KBr): 3120, 2990, 1620, 1560, 1500, 1330,
1
533.
5) Lee, J. C.; Choi, H. J.; Lee, Y. C. Tetrahedron Lett. 2003, 44,
23.
6) Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.;
Miyamoto, K. J. Am. Chem. Soc. 2005, 127, 12244.
7) Dohi, T.; Maruyama, A.; Yoshimura, M.; Morimoto, K.;
Tohma, H.; Kita, Y. Angew. Chem. Int. Ed. 2005, 44, 6193.
8) Yamamoto, Y.; Togo, H. Synlett 2005, 2486.
–1 1
50 cm . H NMR (400 MHz, CDCl ): d = 1.42 (t, J = 7.6
3
(
(
(
(
Hz, 3 H), 2.90 (q, J = 7.6 Hz, 2 H), 7.44 (s, 1 H), 7.76 (d,
J = 9.0 Hz, 2 H), 8.28 (d, J = 9.0 Hz, 2 H).
1
(
(
12) Lamattina, J. L. J. Org. Chem. 1980, 45, 2261.
13) Houwing, H. A.; Wildeman, J.; Leusen, A. M. Tetrahedron
Lett. 1976, 17, 143.
(
14) Ibata, T.; Sato, R. Bull. Chem. Soc. Jpn. 1979, 52, 3597.
Synlett 2008, No. 2, 217–220 © Thieme Stuttgart · New York

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