Synthesis of 2,3-disubstituted benzofurans on solid-support

Article abstract of DOI:10.1016/j.tetlet.2010.10.027

A library of 2,3-disubstituted benzofuran scaffold was developed by using intramolecular Wittig olefination and Friedel-Crafts acylation.

Full text of DOI:10.1016/j.tetlet.2010.10.027

Tetrahedron Letters 51 (2010) 6588–6589
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2,3-disubstituted benzofurans on solid-support
Chun-Won Jung a, Liu-Lan Shen a, , Brian Hyun Choi a,à, Young-Shin Kwak b, Jin-Hyun Jeong a,
⇑
a College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea
b Bio Therapeutic Research Institute, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 685-1 Yangcheong-ri, Ochang-eup, Cheongwon-gun,
ChungBuk 363-883, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A library of 2,3-disubstituted benzofuran scaffold was developed by using intramolecular Wittig olefin-
ation and Friedel–Crafts acylation.
Received 6 August 2010
Revised 6 October 2010
Accepted 7 October 2010
Available online 14 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Aiming at supplying the library of small molecule ligands as the
chemical tools for understanding biological mechanisms, we devel-
oped a solid-phase synthesis of benzofuran derivatives. We se-
lected benzofuran as the key structural motif not only because of
its frequent appearance in numerous natural or unnatural com-
pounds of biological significance,1 but also because it would make
the appropriate next step for our on-going efforts of building bicy-
clic heterocycle libraries in continuation from our previous indole
library synthesis.2
by treating 7 with triphenylphosphine hydrogen bromide in reflux-
ing acetonitrile, as shown in Scheme 2. The progress of the reac-
tions was monitored by FT-IR spectroscopy using KBr plates.
In order to examine the viability of the on-bead phosphonium
salt 8 for the subsequent Wittig olefination, we synthesized a
2,3-disubstituted benzofuran target on solid-support as a model
study as summarized in Scheme 3. O-Alkylation of 8 with propi-
onic anhydride was successfully accompanied by the subsequent
intramolecular Wittig olefination in the presence of triethylamine
in refluxing toluene7 for 24 h to afford the desired 2-ethylbenzofu-
ran 9. Compound 9 was then elaborated on C-3 by a Friedel–Crafts
acylation using p-anisoyl chloride and tin(IV) chloride to produce
the on-bead benzofuran 10. Finally, the benzofuran 11 was re-
Intramolecular Wittig olefination3 protocol is one of the most
widely used methods for constructing benzofurans and, however,
its utility on solid-support has not been validated yet in the previ-
ously reported benzofuran library syntheses.4 We were thus
prompted at developing the synthesis of 2,3-disubstituted benzo-
furans by utilizing intramolecular Wittig olefination on solid-
support.
We designed the general synthetic scheme featuring the intra-
molecular Wittig olefination followed by the Friedel–Crafts acyla-
tion5 and it is depicted in Scheme 1. The synthesis would involve
the acid anydrides for R1 introduction and the acyl chlorides for
R2 variation. We envisioned that the commercial abundance of
both R1 and R2 sources would provide the competitive advantage
of our synthetic strategy over other known methods.
With all these perspectives, we set out our synthesis by treating
the commercially available (4-methoxyphenyl) dimethylsilylpro-
pyl polystyrene 5 (0.83 mmol/g) with BBr3 to liberate phenol 6. A
Zn(NO3)2-catalyzed electrophilic aromatic substitution of 6 with
paraformaldehyde6 gave rise to the formation of the benzyl alcohol
7, and the desired key phosphonium intermediate 8 was obtained
O
O
OH
O
R1
R1
O
R1
Linker
Linker Si
Si
CH2PPh3Br
Base
1
2
O
O
R1
R2
O
Cl
R2
R1
R2
Linker Si
O
O
3
4
Linker Si
Si
⇑
Corresponding author. Tel.: +82 2 961 0368; fax: +82 2 959 0368.
E-mail address: organicjeong@gmail.com (J.-H. Jeong).
Present address: School of Pharmaceutical Engineering, ShenYang Pharmaceutical
University, China.
à
Present address: Department of Chemistry and Chemical Biology, Cornell
Scheme 1. General synthetic strategy for benzofuran library synthesis on solid-
University, New York, USA.
support.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.027

C.-W. Jung et al. / Tetrahedron Letters 51 (2010) 6588–6589
6589
Table 1
OH
OMe
BBr3, CH2Cl2, -78 oC->RT;
MeOH, 0oC
Benzofuran scaffolds synthesized using solid-support
Linker
Si
Yielda (%)
Linker
Si
Scaffold
Entry
R1
R2
O
5
6
R1
R2
1a
Me
4-MeO–Ph–
5
O
C
OH
OH
O
PPh3 HBr
H
H
1b
1c
1d
1e
1f
1g
1h
1i
Me
Me
Et
Et
Et
Bu
Bu
Bu
PhCH2CH2À
Propyl
4-MeO–Ph–
PhCH2CH2À
Propyl
4-MeO–Ph–
PhCH2CH2À
Propyl
4
3
7
5
3
4
4
3
Linker
Si
MeCN,reflux
Zn(NO3) 6H2O
DMF, 100 oC
7
OH
Linker
Si
CH2PPh3Br
O
R1
R2
8
1j
Et
4-MeO–Ph–
3
Scheme 2. Synthesis of the phosphonium intermediate on solid-support.
a
Six-step overall yields from the (4-methoxyphenyl) dimethylsilylpropyl poly-
styrene resin.
OH
O
O
O
O
Linker
Si
CH2PPh3Br
Linker
Si
Pd-assisted
coupling reaction
O
O
Et3N, toluene, reflux
R1
R1
8
9
Br
R2
12
O
O
OMe
R-4
Cl
Scheme 4. Pd-assisted C–C coupling strategy for C-3 variation on the benzofuran
Linker
Si
scaffold.
tin(IV)chloride, CS2
0 oC - rt
O
OMe
10
egy aiming at expanding the diversity of the benzofuran compound
library, as shown in Scheme 4 and it will be reported in due course.
O
TFA/CH2Cl2 (1/1)
rt
Acknowledgment
O
OMe
11
This work was supported by the Kyung Hee University Research
Fund in 2007 (KHU-20080379).
Scheme 3. Synthesis of
support.
a 2-ethyl-3-(4-methoxybenzoyl)benzofuran on solid-
References and notes
1. (a) Engler, T. A.; LaTessa, K. O.; Lyengar, R.; Chai, W.; Agrios, K. Bioorg. Med. Chem.
1996, 4, 1755–1769; (b) Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.;
Vlietinck, A.; Lemiere, G. J. Med. Chem. 1999, 42, 5473–5481; (c) Vishnu, V. R. K.;
Ashok, D. In Book of Abstracts, Proceedings of the 219th ACS National Meeting,
San Francisco, CA, Mar 26–30, 2000.
leased from the solid-support by TFA-assisted cleavage during
10 h. The overall yield during six-steps was 7% and the structure
of 11 was fully confirmed by 1H NMR and HRMS.
Encouraged by the success in the model experiment, we applied
the developed protocol to the synthesis of a benzofuran library
with variations on C-2 and C-3. Totally, nine additional compounds
of the benzofuran scaffold were prepared in the same manner and
they are shown below in Table 1.
In conclusion, we developed a solid-supported synthetic proto-
col featuring intramolecular Wittig reaction and Friedel–Crafts
acylation for the benzofuran library synthesis. We believe this pro-
tocol provides an easy access to the synthesis of benzofuran scaf-
folds by using commercially abundant acid anhydrides and acid
chlorides. We are currently examining halogenation on C-3 of the
on-bead benzofurans such as 12 for Pd-assisted C–C coupling strat-
2. Mun, H. S.; Ham, W. H.; Jeong, J. H. J. Comb. Chem. 2005, 7, 130.
3. Hercouet, A.; Corre, L. Tetrahedron Lett. 1979, 23, 2145.
4. (a) Boehm, T. L.; Showalter, H. D. H. J. Org. Chem. 1996, 61, 6498; (b) Fancelli, D.;
Fagnola, M. C.; Severino, D.; Bedeschi, A. Tetrahedron Lett. 1997, 38, 2311; (c)
Arcadi, A.; Marinelli, F.; Cacchi, S. Synthesis 1986, 749; (d) Kundu, N. G.; Pal, M.;
Mahanty, J. S.; Dasgupta, S. K. Chem. Commun. 1992, 41; (e) Larock, R. C.; Yum, E.
K.; Doty, M. J.; Sham, K. K. C. J. Org. Chem. 1995, 60, 3270; (f) Du, X.; Armstrong,
R. W. Tetrahedron Lett. 1998, 39, 2281; (g) Liao, Y.; Fathi, R.; Yang, Z. J. Comb.
Chem. 2003, 5, 79.
5. Datil, M. L.; Borate, H. B.; Donde, D. E.; Bhawal, B. H.; Deshpande, V. H.
Tetrahedron Lett. 1999, 40, 4437.
6. Saimoto, H.; Yoshida, K.; Murakami, T.; Morimoto, M.; Sashiwa, H.; Shigemasa,
Y. J. Org. Chem. 1996, 61, 6768.
7. Marion, F.; Williams, D. E.; Patrick, B. O.; Hollander, I.; Mallon, R.; Kim, S. C.; Roll,
D. M.; Feldberg, L.; Soest, R. V.; Andwesen, R. J. Org. Lett. 2006, 8, 321.