Three-step synthesis of an array of substituted benzofurans using polymer-supported reagents

Article abstract of DOI:10.1039/a904384e

An efficient combinatorial route to substituted 3-phenyl-benzofurans, is achieved by the bromination of acetophenones to α-bromoacetophenones by polymer-supported pyridinium bromide perbromide (PSPBP). The subsequent clean substitution of the obtained bromides by phenols using 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD-P) and cyclodehydration of the resulting α-phenoxyacetophenones using Amberlyst 15, affords pure products without the need for any chromatographic purification step.

Full text of DOI:10.1039/a904384e

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Three-step synthesis of an array of substituted benzofurans using
polymer-supported reagents
Jörg Habermann, Steven V. Ley* and René Smits
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW
Received (in Cambridge, UK) 2nd June 1999, Accepted 27th July 1999
An efficient combinatorial route to substituted 3-phenyl-
benzofurans, is achieved by the bromination of aceto-
phenones to ꢀ-bromoacetophenones by polymer-
supported pyridinium bromide perbromide (PSPBP). The
subsequent clean substitution of the obtained bromides by
phenols using 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD-P)
and cyclodehydration of the resulting ꢀ-phenoxyaceto-
phenones using Amberlyst 15, affords pure products with-
out the need for any chromatographic purification step.
The continuous identification of new pharmacological targets
by biological screening has led to the synthesis of a large
number of substances using combinatorial techniques. In
general, chemical libraries containing large numbers of
compounds may be prepared either on polymeric supports or in
solution.1a The use of supported reagents combines the advan-
tages of solution (e.g. the ease of monitoring the progress of the
reactions by applying LC-MS, TLC or NMR techniques) and
solid phase chemistry (e.g. allowing the employment of an
excess of reagent without the need for additional purification
steps). Solid supported reagents have been heavily investigated
since 1970. Despite the fact that an overwhelming number of
reagents and sequestering agents have been developed on solid
phase1 only a few of these have found an application in com-
binatorial chemistry.2 Recent work in our group has focussed on
the application of polymer-supported reagents in the multi-step
synthesis of chemical libraries and natural products.3 In this
communication we wish to report a further example using
various supported reagents for the efficient construction of
heterocyclic derivatives.
Fig. 1 Acetophenones brominated to α-bromoacetophenones by
PSPBP.
Benzofuran derivatives are an important class of heterocyclic
compounds that are known to possess important biological
properties. Substituted benzofurans find application as antioxid-
ants, brightening agents, a variety of drugs and in other fields
of chemistry and agriculture.4 Therefore, the development of
a simple, fast and flexible method to generate libraries of such
compounds was desirable. 3-Substituted benzofurans, which
are difficult to obtain as the aryl group easily rearranges from
the 3- to 2-position,5 could be synthesised conveniently from
α-phenoxyacetophenones in the presence of zeolites, although
the yields were quite low and a tedious cleaning procedure was
required.6 Toluene-p-sulfonic acid has also been used to cyclise
an aryloxyketone to yield a substituted benzofuran in the
synthesis of benzopsoralenquinone derivatives.7 We have
designed a route to 3-phenylbenzofurans using an orchestrated
sequence of polymer-supported reagents. In the key step, the
cyclodehydration, the polymer-bound equivalent of toluene-
p-sulfonic acid, Amberlyst 15 is used.
Starting from a range of commercially available acetophe-
nones 1a–h (Fig. 1) an α-bromination was carried out, using
polymer-supported pyridinium bromide perbromide (PSPBP)8
in toluene at 5 ЊC (1a–e), Ϫ10 ЊC (1f, g) and Ϫ15 ЊC (1h).9 The
major problem was the formation of the undesired dibromin-
ation product. Therefore, the process needed careful control
of the reaction temperature, especially when using activ-
ated acetophenones. When using deactivated ketones the reac-
tion could not be driven to completion (see Table 1). Similar
Scheme 1
brominations using Amberlyst resins have also been des-
cribed.10a–d The α-bromoacetophenones 2a–h (Scheme 1) were
then reacted with a range of commercially available phenols
J. Chem. Soc., Perkin Trans. 1, 1999, 2421–2423
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Table 1 Summary of polymer-supported reactions
Yield (%)16
Purity (%)17
ES-MS18
Yield (%)16
Purity (%)17
ES-MS18
2a
87
60
84
92
93
80
quant.
89
71
59
95
89
67
76
62
75
76
92
87
76
54
42
82
85
30
57
55
83
73
56
64
52
>95
95
87
93
95
>95
70
93
95
95
90
95
95
95
>95
>95
>95
95
>95
>95
87
201.10 (ϩ)
215.10 (ϩ)
243.81 (Ϫ)
266.91 (Ϫ)
218.00 (ϩ)
227.1219
4hc
4hd
4he
5aa
5ab
5ac
5ad
5ae
5ba
5bb
5bc
5bd
5be
5da
5db
5dc
5dd
5de
5fa
5fb
5fc
5fd
5fe
5ha
5hb
5hc
5hd
5he
6a
86
83
61
96
97
95
99
quant.
quant.
91
98
94
89
61
58
85
quant.
77
86
81
92
quant.
89
79
95
95
>95
95
95
90
95
95
95
>95
>95
>95
95
>95
>95
87
87
75
90
95
90
95
95
95
95
95
95
>95
>95
93
>95
95
293.19 (ϩ)
323.09 (ϩ)
273.23 (ϩ)
194.1019
209.22 (ϩ)
245.12 (ϩ)
292.29 (ϩ)
224.1019
209.23 (ϩ)
223.20 (ϩ)
259.26 (ϩ)
288.50 (ϩ)
239.15 (ϩ)
262.1019
276.98 (ϩ)
353.12 (ϩ)
360.45 (ϩ)
292.1019
2b
2c
2d
2e
2f
2g
218.00 (ϩ)
231.05 (ϩ)
213.01 (ϩ)
227.19 (ϩ)
263.13 (ϩ)
293.10 (ϩ)
243.23 (ϩ)
281.02 (ϩ)
258.30 (ϩ)
227.25 (ϩ)
241.17 (ϩ)
227.20 (ϩ)
305.07 (Ϫ)
257.16 (ϩ)
281.17 (ϩ)
295.21 (ϩ)
352.12 (ϩ)
359.01 (Ϫ)
311.13 (ϩ)
231.23 (ϩ)
244.99 (ϩ)
281.10 (ϩ)
311.00 (ϩ)
261.20 (ϩ)
243.23 (ϩ)
257.18 (ϩ)
2h
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ba
4bb
4bc
4bd
4be
4da
4db
4dc
4dd
4de
4fa
4fb
4fc
4fd
4fe
4ha
4hb
235.18 (ϩ)
227.20 (ϩ)
262.1019
93
87
93
75
90
95
90
95
292.0019
243.23 (ϩ)
223.66 (Ϫ)
239.25 (ϩ)
275.10 (ϩ)
302.0019
255.27 (ϩ)
238.22 (ϩ)
306.13 (ϩ)
256.19 (ϩ)
268.19 (ϩ)
80
quant.
quant.
57
66
89
73
65
95
95
95
6d
6f
6h
phenoxy)acetophenones 4(a–h)e, mixtures of 2- and 3-phenyl
isomers were obtained. The presence of the methoxy group on
the acyl ring lowers the reaction temperature for the cyclo-
dehydration and facilitates the acid catalysed migration of the
phenyl group. The reaction could be controlled by reducing the
temperature to 80 ЊC and in one case (5hd) to 100 ЊC;12 only the
desired 3-phenyl isomers were formed. The reaction works well
with unsubstituted α-phenoxyacetophenones and with com-
pounds containing activating substituents in the phenoxy ring.
The cyclisation of aryloxyketones that carry electron deficient
phenoxy groups was not possible under these conditions.
An electron withdrawing group attached to the acetophenone
moiety causes the yields/purities to decrease.
It was also possible to synthesise 3-aminobenzofurans (6a–d)
from α-bromoacetophenones in one step. The bromides were
refluxed with 2-cyanophenol and TBD-P in acetone (Scheme 2).
3-Aminobenzofurans are important precursors of tricyclic
Fig. 2 Phenols used in the substitution reaction to α-phenoxyaceto-
phenones using TBD-P.
3a–g (Fig. 2) in refluxing acetone using 1,5,7-triazabicyclo-
[4.4.0]dec-5-ene (TBD-P)11 as a base to effect the substitution
reaction. Excellent yields and purities of the corresponding
α-phenoxyacetophenones were obtained with electron-rich and
electron-deficient bromides and phenols. When using α-bromo-
3,4-dichloroacetophenone 2e some by-products were formed
and the purity was found to be below 50%. No reaction could
be observed using α-bromo-4-nitroacetophenone 2c, although
the polymer went black after the addition of the bromide.
The heterocyclic benzofuran ring system was then con-
structed by a clean cyclodehydration of the α-phenoxyaceto-
phenones in toluene under reflux for seven hours, using
Amberlyst 15 as a cyclising agent. When α-(1-bromophenoxy)-
acetophenones 4(a–h)d were cyclised, longer reaction times
were observed. It is assumed that this is due to increased steric
hindrance of the reactive center. When using α-(4-methoxy-
Scheme 2
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A.-G. Gervois and B. J. Hall, J. Chem. Soc., Perkin Trans. 1, 1998,
compounds that are of interest in many pharmaceutical
products.13
2239; (d) M. H. Bolli and S. V. Ley, J. Chem. Soc., Perkin Trans. 1,
1998, 2243; (e) J. Habermann, S. V. Ley and J. S. Scott, J. Chem. Soc.,
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S. V. Ley and J. S. Scott, J. Chem. Soc., Perkin Trans. 1, 1999, 1253;
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4 See for example: N. P. Ph. Buu-Hoï, E. Bisagni, R. Royer and
C. Routier, J. Chem. Soc., 1957, 625.
5 W. Davies and S. Middleton, J. Chem. Soc., 1959, 3544.
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In conclusion, we have generated an array of 3-phenylbenzo-
furans 5 and 3-aminobenzofurans 6 without any chromato-
graphic purification step to demonstrate the versatility of
sequentially applying polymer-supported reagents in synthetic
sequences. Many further analogues could, in principle, be
generated by this route. All reactions produced essentially clean
products, as determined by LC-MS and NMR spectroscopy.
All intermediates could also be isolated by intercepting part of
the reaction streams and used in other synthetic programmes,
e.g. α-bromoacetophenones may be used in the synthesis of
2-hydroxy-2-aryl-1,4-benzodioxanes, which exhibit
a wide
range of biological activity,14 or in the synthesis of 4-phenyl-
thiazoles, some of which are Interleukin inhibitors.15
8 M. Fréchet, M. J. Farrel and L. J. Nuyens, J. Macromol. Sci. Chem.,
1977, 11, 507.
Acknowledgements
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We gratefully acknowledge financial support from the Erasmus
Fellowship (to R. S.), the Stiftung Stipendien-Fonds des
Verbandes der Chemischen Industrie (Germany, Post Doctoral
Fellowship to J. H.), Cambridge Combinatorial, the BP endow-
ment and the Novartis Research Fellowship (to S. V. L.).
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16 Yield determined by weight for reaction from precursor compound.
17 Purity as estimated from 1H NMR spectroscopy.
18 Masses given are obtained in the mode denoted in brackets. Mass
ions are generally [M ϩ H] or [M Ϫ H], in some case [MϩNH4] or
[MϩNa].
19 No mass ion could be observed under ES-MS conditions; EI-MS
conditions were applied.
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Communication 9/04384E
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