PIDA-mediated synthesis of oxazoles through oxidative cycloisomerization of propargylamides

Article abstract of DOI:10.1016/j.tetlet.2010.02.096

PIDA [phenyliodine(III) diacetate] in AcOH or AcOH-HFIP (hexafluoroisopropanol) efficiently promotes the formation of 2,5-disubstituted oxazoles via the oxidative cycloisomerization of propargylamide derivatives.

Full text of DOI:10.1016/j.tetlet.2010.02.096

Tetrahedron Letters 51 (2010) 2247–2250
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
PIDA-mediated synthesis of oxazoles through oxidative cycloisomerization
of propargylamides
*
*
Akio Saito , Asami Matsumoto, Yuji Hanzawa
Laboratory of Organic Reaction Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
PIDA [phenyliodine(III) diacetate] in AcOH or AcOH-HFIP (hexafluoroisopropanol) efficiently promotes
the formation of 2,5-disubstituted oxazoles via the oxidative cycloisomerization of propargylamide
derivatives.
Received 26 January 2010
Revised 16 February 2010
Accepted 18 February 2010
Available online 21 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Since oxazole nucleus has found widespread applications in the
fields of medicinal chemistry and synthetic chemistry,1,2 many
strategies have been developed for the construction of oxazole nu-
cleus.3 In the construction of oxazole nucleus, the cycloisomeriza-
we describe the PIDA-mediated formation of the oxazolylmethyl
acetate derivatives from propargylamides.
The evaluation of solvents was conducted for the oxidative cyclo-
isomerization reaction of propargylamide 1a with phenyliodine(III)
diacetate (PIDA, 1.5 equiv) as shown in Table 1. It turned out that
fluorinated alcohols were very important for the smooth formation
of oxazolylmethyl acetate 2a (entries 1–7), and thus, the use of hexa-
fluoroisopropanol (HFIP) gave 2a in 54% yield at room temperature
within 6 h (entry 1). In trifluoroethanol (TFE) or MeOH, ether
compound 4a or 5a was obtained with the formation of 2a (entries
2 and 6). Although the oxidative cycloisomerization of 1a in AcOH
proceeded slowly (90 °C, 22 h), the isolated yield of 2a was improved
up to 86% (entry 9).19 The addition of AcOH (5 equiv) was also effec-
tive for the reaction of 1a in HFIP, and 2a was isolated in 81% yield at
room temperature for 20 h (entry 10).20
tion of propargylamides provides us with
a straightforward
approach to the synthesis of 2,5-disubsituted oxazole compounds
(Scheme 1). Although the cycloisomerization of propargylamides
under basic reaction conditions has been used so far,4 the alterna-
tive procedure catalyzed by AuCl3 has been reported.5 Pd-catalyzed
reaction of propargylamides with aryl iodides, acyl chloride, or al-
lyl reagent leads to the oxazoles with the incorporation of aryl,
acyl, or allyl groups into the side chain at 5-position by the tandem
cycloisomerization-coupling reaction.6,7 Recently, the oxidative
cycloisomerization of propargylamides under Pd-catalyzed condi-
tions was reported for the preparation of 5-oxazole-carbaldehy-
des.8 Thus, a novel and efficient procedure for the construction of
oxazole nucleus has remained an attractive goal.
N
AuCl3
Hypervalent iodine compounds have received much attention as
oxidants due to their low toxicity, mild reactivity, high stability, easy
handling, and so on.9 In particular, phenyliodine(III)diacetate (PIDA)
and phenyliodine(III) bis(trifluoroacetate) (PIFA) are very useful not
only as oxidants in the metal-catalyzed oxidative addition of carbon
or hetero atom nucleophiles to alkyne compounds10 but also as pro-
HN
O
R
R
R
(or Base)
O
N
Pd(0), E-X
E
(E=aryl, acyl, allyl)
O
N
moters in the oxidation of alkynes to carboxylic acids,11
or
-acyloxyketones,12 alkynyliodoniumsalts,13 andsoon.14–16 PIFA
a-hydroxy
Pd(II), Oxidant
R
a
O
CHO
also promotes the intramolecular oxidative amidation or carboxyla-
tion of 4-alkynylamide or 4-alkynyl-carboxylic acid derivatives
(Scheme 2).17 As a part of our study on the synthesis of heterocycles
from propargylamine compounds,7,18 we are prompted to attempt
the oxidative cycloisomerization of propargylamides. In this Letter,
Scheme 1. Synthesis of oxazoles from N-propargylamides.
O
O
O
PIFA
YH
Y
Y
OCOCF3
(Y=O, NR')
I
O
* Corresponding authors. Tel.: +81 (0) 42 721 1571; fax: +81 (0) 42 721 1569.
E-mail addresses: akio-sai@ac.shoyaku.ac.jp (A. Saito), hanzaway@ac.shoya
ku.ac.jp (Y. Hanzawa).
R
R
Ph
R
Scheme 2. Oxidative amidation or carboxylation.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.096

2248
A. Saito et al. / Tetrahedron Letters 51 (2010) 2247–2250
Table 1
Table 2
Optimization for the oxidative cycloisomerization of 1a
The oxidative cycloisomerization of various propargylamides 1
HN
HN
N
PIDA (1.5 equiv)
Method A or B
N
O
Oxidant (1.5 equiv)
Ph
R1
R1
Ph
OAc
OR
O
O
O
Solvent, rt
1
2
1a
2a: R = Ac
4a: R = CF3CH2
3a: R = CF3CO 5a: R = Me
Entry
R1
1
Conditionsa/(h)
2b (%)
Entry
Oxidant
Solvent
(h)
2aa (%)
1aa (%)
1
2
A
B
22
20
2a
2a
86
81
1a
1
2b
3
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIFA
PIFA
PIFA
HFIP
TFE
6
6
6
54
19
12
0
0
8
5
25
91 (86)
78 (81)
3a 35
3a 36
3a 76
0
63
44
50
87
65
58
74
0
0
0
0
0
3
4
A
B
22
23
2b
2b
92
88
1b
1c
1d
1e
O2N
Cl
CH2Cl2
THF
MeCN
MeOH
H2O
AcOH
AcOH
HFIP
4
23
23
23
23
23
22
20
3
5
6
A
B
22
24
2c
2c
81
80
5
6c
7
7
8
A
B
22
24
2d
2d
84
86
8
Me
9d
10e
11
12
13
9
10
A
B
22
24
2e
2e
83
66
MeO
O
HFIP
TFE
CH2Cl2
22
18
11
12
A
B
45
47
2f
2f
71
53
1f
a
Yields were determined by 1H NMR analysis. Yield in the parenthesis is the
13
14
A
B
21
12
2g
2g
73
78
1g
1h
1i
isolated yield.
Ph
b
4a was detected in 7% yield.
15
16
A
B
22
24
2h
2h
86
88
c
d
e
5a was detected in 21% yield.
t-Bu
Ph
Temp: 90 °C.
17
18
A
B
34
24
2i
2i
67
25
Additive: 5 equiv AcOH.
a
Conditions A: solvent; AcOH, temp; 90 °C. Conditions B: solvent; HFIP, additive;
Next, the scope of substrates 1 having the various acyl groups
AcOH (5 equiv), temp; rt.
under the PIDA (1.5 equiv)-mediated conditions A (solvent: AcOH,
temp: 90 °C) or B (solvent: HFIP, additive: 5 equiv AcOH, temp: rt)
is shown in Table 2. Both the conditions could be applied to the
oxidative cycloisomerization of not only aromatic amides 1a–g
but also aliphatic amides 1h–i, and the corresponding oxazoles
2a–i were obtained. In some cases, the conditions A brought about
the superior results to the conditions B (entries 9, 11, and 17). Fur-
thermore, the conditions A could be applied to the reaction of
internal alkynes 6a (R2 = Ph) and 6b (R2 = Et) (Scheme 3). It should
b
Isolated yield.
be mentioned that phenyliodine(III) bis(trifluoroacetate) (PIFA,
1.5 equiv) in CH2Cl2, which worked well for the formation of 3a
(Table 1, entry 13), did not yield good results in reactions of other
substrates.
On the basis of these observations and the previous report
about the PIFA-mediated cyclization of 4-alkynylamides,17b,21 the
present formation of oxazole would consist of (i) the cyclization
of Int-A through the activation of the triple bond by PIDA, (ii)
the formation of Int-D12e by the proton transfer of Int-B and the
subsequent isomerization of Int-C, and (iii) the substitution of phe-
nyliodonium group in Int-D by AcOH (Scheme 4). This is supported
by the reaction of internal alkynes (Scheme 3) or the reaction of the
deuterated d-1a (Scheme 5). Thus, the treatment of d-1a with PIDA
(1.5 equiv) in AcOH brought about the mono-deuterated oxazole
d1-2a with the undeuterated 2a in 80% yield (d1-2a/2a = 62:38,
N
O
HN
O
PIDA (1.5 equiv)
Ph
Ph
OAc
AcOH, 90 °C, 22 h
(Conditions A)
R2
R2
6a: R2=Ph
6b: R2=Et
7a: 37%
7b: 26%
Scheme 3. The oxidative cycloisomerization of internal alkynes 6.
H
N
AcO
AcO
OAc
HN
O
OAc
R1
R1
I
Ph
I
O
Ph
R2
R2
Int-A
Int-B
AcOH
(
route a: R2 = H, D, Ph, Et)
H
HN
O
N
O
N
O
N
O
AcOH
OAc
R1
R1
R1
2, 7
R1
PIDA
I
OAc
H R2
I
Ph
Ph
route b: R2 = H, D)
R2
(
PhI
R2
1, 6
AcOH
R2
Int-D
Int-C
AcOH
(R2 = H or D)
H
N
HN
R1
OAc
R1
O
I
O
Ph
I
OAc
Int-E
Int-F
Ph
Scheme 4. A possible mechanism.

A. Saito et al. / Tetrahedron Letters 51 (2010) 2247–2250
2249
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HN
O
N
O
PIDA (1.5 equiv)
Ph
R
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OAc
AcOH, 90 °C, 22 h
80%
D
H D(H)
d-1a
d1-2a
(d1-2a:2a = 62:38)
Scheme 5. The oxidative cycloisomerization of 1a–D.
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K.; Hanzawa, Y. Tetrahedron Lett. 2010, 51, 1471.
HN
O
N
O
PIDA (1.5 equiv)
Ph
R
OAc
AcOD, 90 °C, 22 h
81%
(H)D D(H)
1a
d2-2a
(d2-2a:d1-2a:2a = 40:39:21)
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Scheme 6. The oxidative cycloisomerization of 1a in AcOD.
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Scheme 5). It is suggested that the oxazole d1-2a was derived from
the route a shown in Scheme 4. The formation of the undeuterated
2a shown in Scheme 5 would be a result of an intervention of the
route b shown in Scheme 4.
The reaction of 1a with PIDA (1.5 equiv) in AcOD afforded a
mixture of di-deuterated, mono-deuterated, and undeuterated
oxazoles (d2-2a/d1-2a/2a = 40:39:21, Scheme 6).22 On the other
hand, regardless of the addition of PIDA, the treatment of undeu-
terated 2a in AcOD did not yield deuterated 2a. A similar observa-
tion has been reported in the PIDA-mediated oxidation of terminal
alkyne compounds to
a
-acetoxy ketones.12e It has been proposed
that the incorporation of acetoxy groups into the ketones proceeds
via the alkynyliodonium intermediate like the Int-E shown in
Scheme 4.12 Thus, the di-deuterated compound shown in Scheme
6 was derived from the deuteration of Int-F and Int-D by AcOD.12e
In conclusion, we have demonstrated the facile preparation of
the oxazolylmethyl acetate derivatives through the oxidative
cycloisomerization of propargylamides with PIDA. A plausible
mechanism for the present formation of oxazole was proposed.
Particularly, in reactions of terminal alkyne substrates, we sug-
gested that the two routes (routes a and b shown in Scheme 4)
were involved in deuterium labeling experiments. The present pro-
cedure would shed new light on the convenient approach for the
preparation of oxazole compounds. Synthetic applications and de-
tailed mechanistic studies of the present reaction are underway.
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Acknowledgments
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This work was supported by Grant-in-Aid for Young Scientists
(B), MEXT Japan (No. 21790024). A generous donation of HFIP by
Central Glass Co., Ltd is gratefully acknowledged.
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2250
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C
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19. Representative procedure for the preparation of oxazolylmethyl acetate derivatives
in AcOH (conditions A): PhI(OAc)2 (193 mg, 0.6 mmol) was added to a solution
of propargylamide 1a (63.6 mg, 0.4 mmol) in AcOH (2.0 mL), and the reaction
mixture was stirred at 90 °C for 22 h. The mixture was diluted with ether and
satd NaHCO3 aq was added. The aqueous solution was extracted with ether and
the combined organic layer was dried with MgSO4. After concentration of the
filtrate to dryness and purification of the residue by silica gel column
chromatography (hexane/AcOEt = 80:20) gave oxazolylmethyl acetate 2a
20. Representative procedure for the preparation of oxazolylmethyl acetate derivatives
in HFIP (conditions B): PhI(OAc)2 (193 mg, 0.6 mmol) and AcOH (114 lL,
2.0 mmol) were added to a solution of propargylamide 1a (63.6 mg, 0.4 mmol)
in HFIP (2.0 mL), and the reaction mixture was stirred at room temperature for
20 h. The mixture was diluted with ether and filtered through a short alumina
column. After concentration of the filtrate to dryness, purification of the
residue by silica gel column chromatography (hexane/AcOEt = 80:20) gave
oxazolylmethyl acetate 2a (70.1 mg, 81%) as a white solid.
(74.5 mg, 86%) as a white solid. Mp 143 °C. IR (KBr)
m
cmÀ1; 1735. 1H NMR
21. See, oxidative cyclization of cis-2-en-4-yn-1-ones mediated by 2-
iodoxybenzoic acid (IBX): Du, X.; Chen, H.; Liu, Y. Chem. Eur. J. 2008, 14, 9495.
22. In the absence of PIDA, the treatment of 1a in AcOD did not bring about H–D
exchange reaction of terminal alkyne moiety of 1a.
(300 MHz, CDCl3) d; 2.08 (s, 3H), 5.14 (s, 2H), 7.19 (s, 1H), 7.42–7.44 (m, 3H),
8.01–8.04 (m, 2H). 13C NMR (75 MHz, CDCl3) d; 20.7, 55.6, 126.4, 127.1, 128.6,
128.7, 130.5, 146.5, 162.4, 170.3. FAB-LM m/z: 218 (M++1). FAB-HM Calcd for