Table 1 Acylation and rearrangement of O-phenyloxime ether 5
Entry
(CX3CO)2O (eq.)
Base (eq.)
Temp./ЊC
Time/h
Yield (%) 6
Yield (%) 7
1
2
3
TFAA (1)
TFAA (1)
TCAA (1)
Et3N (1.5)
—
—
0
0
40
4
3
5
—
99
94
8
—
—
Table 2 Acylation and rearrangement of O-phenyloxime ethers 10
Entry
Substrate
Y
Base
Solvent
Temp./ЊC
Time/h
Yield (%) 11
Yield (%) 12
1
2
3
4
5
6
7
8
10a
10a
10b
10b
10c
10c
10d
10d
OCOCF3
OSO2CF3
OCOCF3
OSO2CF3
OCOCF3
OSO2CF3
OCOCF3
OSO2CF3
—
Et3N
—
Et3N
—
Et3N
—
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
MeCN
CH2Cl2
MeCN
CH2Cl2
0
rt
80
rt
80
rt
23
5
5
4
4
1
20
2.5
94
—
64
—
82
—
—
—
—
85
—
80
—
81
—
83
80
rt
DMAP
phenol 7 was protonated by TFA to form the iminium A which
was immediately subjected to cyclization to give the dihydro-
benzofuran 6a. In the acylation of oxime ether 5 with TFAA in
the presence of Et3N (entry 1, Table 1), TFA formed was
immediately trapped as the corresponding salt. Therefore, the
dihydrobenzofuran 6a was not obtained but rearranged
product 7a was formed in low yield. In the presence of only
TFAA, successive reactions involving acylation of oxime ether
5, [3,3]-sigmatropic rearrangement of enehydroxylamine 8, and
intramolecular cyclization of 7 catalysed by TFA proceeded
very smoothly. This result contrasts sharply with that in the
case of the rearrangement of N-trifluoroacetyl enehydrazine 2a
which required higher reaction temperature (above 60 ЊC) for
the successful rearrangement and cyclization.
a solution of oxime ether 5 in CH2Cl2 was placed on the
Celite. After being left for 10 min which is sufficient for the
reaction, the mixture was eluted with n-hexane–AcOEt (10 : 1)
to give dihydrobenzofuran 6a in 99% yield. This method is very
simple and useful for the practical synthesis of dihydrobenzo-
furan.
We have now established a novel synthetic route to dihydro-
benzofurans and benzofurans under the acylating conditions of
oxime ether which cause smoothly [3,3]-sigmatropic rearrange-
ment and subsequent cyclization at below room temperature.
The new methodology provides a synthetic approach to a wide
range of natural products having a benzofuran nucleus.
Representative general procedure
In order to survey the scope and limitations of the present
method, we next investigated the substituent effect on an
enamine part (Scheme 3, Table 2). The reaction of 10a having a
(Table 1, entry 3) To a solution of oxime ether 5 (175 mg, 1
mmol) in CH2Cl2 (10 ml) was added TFAA (0.14 ml, 1 mmol)
at 0 ЊC under nitrogen atmosphere. After being stirred at 0 ЊC
for 3 h, the solvent was evaporated under reduced pressure.
Purification of the residue by medium-pressure column
chromatography (n-hexane–AcOEt 5 : 1) afforded dihydro-
benzofuran. 6a (268 mg, 99%) as a pale yellow oil; νmax/cmϪ1
3422 (NH), 1726 (NHCOCF3); δH (500 MHz; CDCl3) 1.59 (1H,
m, 2-H), 1.85 (2H, m, 1-H, and 2-H), 2.32 (3H, m, 1-H, and
3-H2), 4.00 (1H, br d, J 8.5, 8b-H), 6.78 (1H, br d, J 8, 5-H),
6.89 (1H, br s, NH), 6.94 (1H, br t, J 8, 7-H), 7.15 (1H, br d, J 8,
8-H), 7.16 (1H, br t, J 8, 6-H); HRMS (EI) [Mϩ] calcd for
C13H12F3NO2: 217.0819, found: 217.0820.
NOE was observed between 8b-H (δ 4.00) and NH (δ 6.89) in
NOESY spectroscopy.
Acknowledgements
Scheme 3
We thank a Grant-in Aid for Scientific Research on Priority
Areas (A) from the Ministry of Education, Culture, Sports,
Science and Technology and the Science Research Promotion
Fund of the Japan Private School Promotion Foundation for
research grant.
cyclohexenyl group with TFAA gave dihydrobenzofuran 11a in
94% yield while the treatment of 10a with trifluoroacetyl triflate
and triethylamine5 gave the benzofuran 12a in 85% yield with
no isolation of dihydrobenzofuran 11a (entries 1 and 2). A
similar trend was observed in the reaction of acyclic substrates
10b and 10c (entries 3–6). Treatment of acyclic substrate
10d having the phenyl group with trifluoroacetyl triflate gave
benzofuran 12d6 in 83% yield while the acylation of 10d with
TFAA did not give 11d and the substrate 10d was recovered.
The structure of cyclized products of either dihydrobenzofuran
11 or benzofuran 12 is dependent on the reaction conditions
involving both an acylating agent and base.
References
1 (a) B. Robinson, Chem. Rev., 1969, 69, 227–250; (b) B. Robinson, in
The Fischer Indole Synthesis, John Wiley and Sons, New York, 1982;
(c) D. L. Hughes, Org. Prep. Proced. Int., 1993, 25, 609–632.
2 (a) O. Miyata, Y. Kimura, K. Muroya, H. Hiramatsu and T. Naito,
Tetrahedron Lett., 1999, 40, 3601–3604; (b) O. Miyata, Y. Kimura
and T. Naito, Chem. Commun., 1999, 2429–2430; (c) O. Miyata,
N. Takeda and T. Naito, Heterocycles, 2002, 57, 1101–1107.
3 (a) A. Mooradial and P. E. Dupont, Tetrahedron Lett., 1967,
2867–2870; (b) A. Alemagna, C. Baldoli, P. D. Buttero, E. Licandro
and S. Maiorana, J. Chem. Soc., Chem. Commun., 1985, 417–418; (c)
Next, we examined a more practical method for performing
the preparation and purification of benzofuran simultaneously
in a glass tube for column chromatography. The Celite con-
taining TFAA was added to the top of silica gel column. Then,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 4 – 2 5 6
255