Synthesis of substituted 2,3-dihydrobenzofuran in a process involving a facile acyl migration

Article abstract of DOI:10.1016/S0040-4039(02)00157-0

Reduction of 2,6-diacetoxy-2′-bromoacetophenone (10) with NaBH₄ led to 3,4-diacetoxydihydrobenzofuran (12) in a process involving acyl migration followed by cyclization. Subsequent hydrogenolysis gave 4-acetoxydihydrobenzofuran which, upon saponification, afforded 4-hydroxydihydrobenzofuran (8) in good yield. This approach is shown to be a general method for preparation of substituted dihydrobenzofurans.

Full text of DOI:10.1016/S0040-4039(02)00157-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1923–1925
Synthesis of substituted 2,3-dihydrobenzofuran in a process
involving a facile acyl migration
Wen-Sen Li,* Zhenrong Guo, John Thornton, Kishta Katipally, Richard Polniaszek,
John Thottathil, Truc Vu and Michael Wong
Process Research and Development, Bristol-Myers Squibb Pharmaceutical Research Institute, One Squibb Drive,
New Brunswick, NJ 08903, USA
Received 31 May 2001; accepted 17 January 2002
Abstract—Reduction of 2,6-diacetoxy-2%-bromoacetophenone (10) with NaBH4 led to 3,4-diacetoxydihydrobenzofuran (12) in a
process involving acyl migration followed by cyclization. Subsequent hydrogenolysis gave 4-acetoxydihydrobenzofuran which,
upon saponification, afforded 4-hydroxydihydrobenzofuran (8) in good yield. This approach is shown to be a general method for
preparation of substituted dihydrobenzofurans. © 2002 Elsevier Science Ltd. All rights reserved.
We demonstrated previously that 4-hydroxydihy-
drobenzofuran (8) could be attained by Parham
cycloalkylation1 of the appropriate brominated resor-
cinol derivative. While simple and practical for prepar-
ing small amounts of material, this synthesis was not
amenable for large scale preparation due to the need
for excess n-butyl lithium under cryogenic conditions.
As a potentially more efficient synthesis of phenol 8, we
chose to investigate deoxygenation of 4-hydroxybenzo-
furan-3-one (3).2
steps (Scheme 1). Persilylation, followed by treatment
with N-bromosuccinimide and then NaOH, afforded
the desired compound in 93% overall yield. Unfortu-
nately, when this material was subjected to hydrogenoly-
sis in the presence of PdꢀC, over-reduction to 6 and 7
was a major problem with little or no formation of the
desired 8 being observed. Alternatively, reduction of 3
with NaBH4 gave a mixture of 4 and 5, with the latter
as the major product.
It was felt that diacetate 12 might be an alternative
substrate for hydrogenolysis. To explore this possibility,
diacetylation of 2%,6%-dihydroxyacetophenone (1) (2.2
Synthesis of 4-hydroxybenzofuran-3-one (3) from 2%,6%-
dihydroxyacetophenone (1) was accomplished in two
OR OR
OH
O
OH
O
NBS
TMSCl
NaOH
O
OR
LiHMDS
OH
3
2
93% yield
1
R = TMS
NaBH4
Pd-C/[H]
OH
OH
OH
OH
OH
OH
OH
OH
+
+
+
+
O
O
O
O
O
O
5
8
7
4
5
6
Scheme 1.
* Corresponding author. Tel.: 732-519-3899; fax: 732-519 1922; e-mail: wensen.li@bms.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00157-0

1924
W.-S. Li et al. / Tetrahedron Letters 43 (2002) 1923–1925
equiv. Ac2O, 2.3 equiv. Et3N, ambient temperature)
gave an 80% yield of diacetate 9, which was treated
with bromine (1.0 equiv. Br2, CH2Cl2, 0°C) to give an
ꢀ85:15 mixture of mono- and dibromide 10 and 11
(Scheme 2). The reaction product was crystallized from
isopropanol to afford a 90% recovery of a 93:7 mixture,
Scheme 2.
Table 1. Conversion of bromoacetophenones to acetates by NaBH4
Bromoacetophenonea
Conditions
Yieldb
84%c
Entry
Product
AcO
O
OAc
OAc
NaBH4
Br
Br
1
2
anhydrous EtOH
-15oC, 45 minutes
O
OAc
10
12
OAc
AcO
O
Cl
Cl
NaBH4
98%
81%
90%
O
anhydrous EtOH
-15oC, 40 minutes
Cl
14
Cl
15
AcO
O
OAc
OAc
F
Br
3
4
NaBH4
O
anhydrous EtOH
0oC, 30 minutes
16
17
F
AcO
O
Br
Br
NaBH4
Br
anhydrous EtOH
0oC, 30 minutes
O
Br
Br
18
19
AcO
O
OAc
Br
NaBH,
MeO
5
6
87%
93%
anhydrous EtOH
0oC, 30 minutes
O
OMe
20
21
AcO
O
OAc
Br
NaBH4
Cl
anhydrous EtOH
0oC, 30 minutes
O
Cl
22
23
a) Preparation by bromination of corresponding acetophenones followed by column
chromatographic purification (bromination is not selective; better conditions are being developed); b) Purified
by column chromatography; c) Isolated by crystallization from EtOAc/heptane.

W.-S. Li et al. / Tetrahedron Letters 43 (2002) 1923–1925
1925
which was adequate for the subsequent transformation.
Treatment of this mixture with NaBH4 in anhydrous
EtOH at −15°C afforded a 94:6 mixture of diacetate 12
and the enol acetate 13. Crystallization from EtOAc/
hexane gave an 85% yield of the desired diacetate 12.
We postulate that acyl migration3 of the phenolacetate
to the sodium alkoxide moiety of 10a provides the
phenoxide 10b. Ring closure by nucleophilic displace-
ment then leads to the observed diacetate 12.
Hydrogenolysis (10 wt% load of 5% PdꢀC, MeOH, ꢀ3
psi, ambient temperature) and subsequent saponifica-
tion of the resulting phenolic acetate furnished the
desired 4-hydroxy-2,3-dihydrobenzofuran (8) in 90%
yield.
3. (a) Taub, D.; Hoffsommer, R. D.; Wendler, N. L. J. Am.
Chem. Soc. 1959, 81, 3291; (b) Wei-Shan, Z.; Hui-Quiang,
Z.; Zhi-Qin, W. J. Chem. Soc., Perkin Trans. 1 1990, 2281;
(c) Quazzani, J.; Buisson, D.; Azerad, R. Tetrahedron Lett.
1987, 28, 1109.
4. Compound 12, colorless solid, mp 64–65°C; 1H NMR
(CDCl3) l 7.32 (t, 1H, J=6.2 Hz), 6.85 (d, 1H, J=6.2 Hz),
6.65 (d, 1H, J=6.2 Hz), 6.40 (dd, 1H, J=6.4 and 2.4 Hz),
4.66 (dd, 1H, J=11.2 and 6.4 Hz), 4.50 (dd, 1H, J=11.2
and 2.4 Hz), 2.32 (s, 3H), 2.08 (s, 3H) ppm; 13C NMR
(CDCl3) l 170.2, 168.1, 162.5, 147.9, 132.2, 117.1, 114.3,
108.3, 76.6, 71.5, 20.8 ppm.
Compound 15: Slightly yellow solid, mp 75.5–77°C; 1H
NMR (CDCl3) l 7.33 (d, 1H, J=2.2 Hz), 7.30 (d, 1H,
J=2.2 Hz), 6.22 (dd, 1H, J=6.9, 2.5 Hz), 4.72 (dd, 1H,
J=6.9 and 12.1 Hz), 4.63 (dd, 1H, J=2.7 and 12.1 Hz),
2.23 (s, 3H) ppm; 13C NMR (CDCl3) l 170.0, 155.4, 130.8,
127.2, 131.7, 125.9, 125.8, 116.4, 77.2, 74.2, 21.6 ppm.
Compound 17: Oil; 1H NMR (CDCl3) l 7.15 (dd, 1H,
J=7.9, 2.5 Hz), 6.98 (ddd, 1H, J=8.8, 2.4, and 2.5 Hz),
6.81 (dd, 1H, J=8.8, 3.9 Hz), 6.20 (dd, 1H, J=6.8, 2.4
Hz), 4.64 (dd, 1H, J=11.2, 6.8 Hz), 4.53 (dd, 1H, J=11.2,
2.4 Hz), 2.07 (s, 3H) ppm; 13C NMR (CDCl3) l 170.2,
158.1 (d, J=149.1 Hz), 155.8, 125.3 (d, J=8.5 Hz), 117.8
(d, J=24.6 Hz), 113.5 (d, J=24.6 Hz), 110.8 (d, J=8.5
Hz), 76.8, 74.4, 21.7 ppm.
To demonstrate the scope and limitations of this
method, a number of bromoacetophenones were pre-
pared and subjected to the NaBH4 reduction (Table 1).4
Efficient acyl migration was found to be general,
affording 3-acetoxydihydrobenzofurans in high yields.
This methodology is applicable for those acetophe-
nones with both electron-donating and electron-with-
drawing substituents.
Compound 19: off-white solid, mp 87.5–89°C; 1H NMR
(CDCl3) l 7.58 (d, 1H, J=2.0 Hz), 7.50 (d, 1H, J=2.0
Hz), 4.72 (dd, 1H, J=11.2, 6.8 Hz), 4.61 (dd, 1H, J=11.7,
2.4 Hz), 2.08 (s, 3H) ppm; 13C NMR (CDCl3) l 170.0,
157.3, 136.1, 128.7, 127.3, 113.0, 104.2, 77.0, 74.3, 21.6
ppm.
Acknowledgements
The authors thank Mr. John Venesky for spectroscopic
assistance.
Compound 21: Oil; 1H NMR (CDCl3) l 6.98 (d, 1H,
J=2.4 Hz), 6.86 (dd, 1H, J=2.4 and 8.8 Hz), 6.80 (d, 1H,
J=8.8 Hz), 6.20 (dd, J=2.4 and 6.3 Hz), 4.59 (dd, 1H,
J=6.3 and 11.7 Hz), 4.48 (dd, 1H, J=2.4 and 11.7 Hz),
3.76 (s, 3H), 2.07 (s, 3H) ppm; 13C NMR (CDCl3) l 170.4,
154.8, 154.0, 124.7, 117.7, 111.2, 110.7, 76.5, 75.0, 56.5,
21.8 ppm.
References
1. Details of this work will be published elsewhere. (a) Brad-
sher, C. K.; Parham, W. E. Acc. Chem. Res. 1982, 15, 300;
(b) Bradsher, C. K.; Reames, D. C. J. Org. Chem. 1981,
46, 1384; (c) Alabaster, R. J.; Cottrell, I. F.; Marley, H.;
Wright, S. H. B. Synthesis, 1988, 950; (d) Plotkin, M.;
Chen, S.; Spoors, P. G. Tetrahedron Lett. 2000, 41, 2269.
2. (a) Horton, W. J.; Paul, E. G. J. Org. Chem. 1959, 24,
2000; (b) Lin, Y.-Y.; Thom, E.; Liebman, A. A. J. Hetero-
cyclic Chem. 1979, 16, 799.
Compound 23: Oil; 1H NMR (CDCl3) l 7.41 (d, 1H,
J=2.4 Hz), 7.23 (dd, 1H, J=2.4 and 8.8 Hz), 6.81 (d, 1H,
J=8.8 Hz), 6.19 (dd, 1H, J=2.5 and 6.4 Hz), 4.63 (dd,
1H, J=6.4 and 11.7 Hz), 4.52 (dd, 1H, J=2.5 and 11.7
Hz), 2.07 (s, 3H) ppm; 13C NMR (CDCl3) l 170.2, 159.3,
131.1, 126.6, 126.0, 125.6, 111.5, 76.8, 74.0, 21.7 ppm.