Zinc-gold cooperative catalysis for the direct alkynylation of benzofurans

Article abstract of DOI:10.3762/bjoc.9.204

The direct alkynylation of benzofurans was achieved for the first time using the hypervalent iodine reagent 1-[(triiso-propylsilyl)ethynyl]-1,2- benziodoxol-3(1H)-one (TIPS-EBX) based on the cooperative effect between a gold catalyst and a zinc Lewis acid. High selectivity was observed for C2-alkynylation of benzofurans substituted with alkyl, aryl, halogen and ether groups. The reaction was also successful in the case of the more complex drug 8-methoxypsoralen (8-MOP).

Full text of DOI:10.3762/bjoc.9.204

Zinc–gold cooperative catalysis for the
direct alkynylation of benzofurans
Yifan Li and Jérôme Waser*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1763–1767.
Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique
Fédérale de Lausanne, EPFL SB ISIC LCSO, BCH4306, 1015
Lausanne, Switzerland
doi:10.3762/bjoc.9.204
Received: 25 June 2013
Accepted: 08 August 2013
Published: 29 August 2013
Email:
Jérôme Waser* - jerome.waser@epfl.ch
This article is part of the Thematic Series "Gold catalysis for organic
synthesis II".
* Corresponding author
Keywords:
Guest Editor: F. D. Toste
alkynylation; benzofurans; cooperative catalysis; direct
functionalization; gold catalysis; hypervalent iodine
© 2013 Li and Waser; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The direct alkynylation of benzofurans was achieved for the first time using the hypervalent iodine reagent 1-[(triiso-
propylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS-EBX) based on the cooperative effect between a gold catalyst and a zinc
Lewis acid. High selectivity was observed for C2-alkynylation of benzofurans substituted with alkyl, aryl, halogen and ether
groups. The reaction was also successful in the case of the more complex drug 8-methoxypsoralen (8-MOP).
Introduction
Benzofurans are important heterocycles frequently encountered Due to the importance of benzofurans, the discovery of new
in both bioactive compounds and organic materials (Figure 1). efficient methods for their synthesis and functionalization is an
For example, members of the furocoumarin class of natural intensive field of research [9-11]. Especially interesting would
products including psoralen (1), 8-methoxypsoralen (2) and be methods allowing the direct and regioselective C–H func-
angelicin (3) can cross-link with DNA upon light irradiation. tionalization of benzofurans [12]. In this context, the introduc-
They have consequently been used for the treatment of skin tion of an alkyne would be particularly useful, as acetylenes are
diseases such as cancer or psoriasis [1-4]. The natural product important building blocks in synthetic chemistry, chemical
coumestrol (4) is found especially in soy beans and has estro- biology and materials science [13]. Nevertheless, to the best of
genic activity [5]. Synthetic bioactive compounds containing our knowledge, the direct alkynylation of benzofurans is still an
benzofurans are also important, as exemplified by amiodarone unknown process.
(5), as antiarrythmic drug [6,7]. Finally, benzofurans have also
emerged recently as important structural elements for organic Since 2009, our group has developed a mild gold-catalyzed [14-
materials, such as the organic transistor 6 [8].
17] method for the alkynylation of electron-rich aryls such as
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was also more stable in the presence of acidic additives, and
co-activation became possible, whereas Zn(OTf)2 was superior
to trifluoroacetic acid (TFA) at 60 °C (Table 1, entries 3 and 4)
[19,28]. No product was observed in the absence of AuCl,
demonstrating the cooperative effect of the two metals (Table 1,
entry 5). Lower or higher temperatures did not increase the
yield (Table 1, entries 6 and 7). Finally, using a larger excess of
TIPS-EBX (8) and Zn(OTf)2 gave 75% yield of alkynylation
product 9a (Table 1, entry 8). The use of Zn(OTf)2 in catalytic
amount led to a lower yield (Table 1, entry 9), and a larger
excess resulted in decomposition of the starting material only
(Table 1, entry 10). Although other Lewis acids could also be
used (Table 1, entries 11 and 12) [29], no better results than
with Zn(OTf)2 were obtained (Table 1, entry 7). Importantly, in
contrast to our previous work with benzothiophenes [19], high
selectivity for C2 alkynylation was observed.
Table 1: Optimization of the alkynylation of benzofuran (7a).
Figure 1: Benzofurans in bioactive compounds and materials.
indoles and pyrroles [18], thiophenes [19], anilines [20] and
furans [21]. Key for success was the use of ethynylbenziodox-
olones, which are cyclic hypervalent iodine reagents [22,23].
Nevertheless, the conditions we have used for other hetero-
cycles gave only very low yields in the case of benzofurans.
Herein, we would like to report the first catalytic direct
C2-alkynylation of benzofurans 7 based on a cooperative effect
between a gold catalyst and a zinc Lewis acid using 1-[(triiso-
propylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS-EBX, 8)
as reagent (Scheme 1). The reaction proceeded under mild
conditions (60 °C under air) and could also be used to alkyny-
late the more complex polycyclic natural product 8-methoxy-
psoralen (2).
Entrya
Equiv 8
Additiveb
T [°C]
Yield
1
2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2
–
23
60
60
60
60
40
82
60
60
60
60
60
<5%
<5%
42%
56%
<5%
48%
36%
75%
37%
0%
–
3
TFA
4
Zn(OTf)2
Zn(OTf)2c
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2d
Zn(OTf)2e
Zn(NTf)2
Yb(OTf)3
5
6
7
8
9
2
Findings
10
11
12
2
2
57%
62%
Benzofuran (7a) is less reactive then furans and indeed no prod-
uct was observed under the conditions optimized for the latter
[21] at room temperature or at 60 °C using the commercially
available electrophilic alkynylation reagent TIPS-EBX (8)
(Table 1, entries 1 and 2) [24-27]. Fortunately, benzofuran (7a)
2
aReaction conditions: 7a (0.20 mmol) and AuCl (0.01 mmol) in acetoni-
trile (0.8 mL) under air for 26 h, isolated yield; bsame amount as 8;
cwithout gold catalyst; d0.2 equiv; e4.0 equiv.
Scheme 1: Zinc–gold catalyzed C2-alkynylation of benzofurans.
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Beilstein J. Org. Chem. 2013, 9, 1763–1767.
The scope of the reaction was then investigated (Scheme 2). Finally, we wondered if the alkynylation method could also be
Substitution by diverse functional groups was first examined on successful in the case of more complex benzofuran-containing
the C5 position. An electron-rich methoxy group was well toler- natural products and drugs. We were pleased to see that the
ated, giving the desired alkynylation product 9b in 73% yield. alkynylation of 8-methoxypsoralen (2) was indeed possible. The
The reaction was also successful with a bromide substituent major product 10 bearing the acetylene group at the C5’ pos-
(product 9c), making the method orthogonal to classical cross- ition was obtained in 37% yield (Scheme 4) [32]. Although the
coupling chemistry [30]. In presence of an aryl or an alkyl yield was still moderate, this was one of the first examples of
substituent, alkynylation was also obtained in 72% and 50% direct alkynylation of a marketed drug. It also gave access in a
respectively (products 9d and 9e). Benzofurans substituted at single step to an interesting furocoumarin derivative with an
the C7 position could also be used, as demonstrated by the effi- extended chromophore, which could be important for
cient formation of alkynes 9f and 9g. In contrast, when phototherapy.
7-methoxybenzofuran (7j) was used, no C2 alkynylation prod-
uct could be isolated. Instead, a mixture of C4 and C6 alkyny- Mechanistically, the reaction could proceed either via π-acti-
lated benzofurans 9j and 9j’ was obtained (Scheme 3) [31]. vation of the triple bond by the gold catalyst followed by conju-
Substitution on the furan ring was also possible at the C3 pos- gate addition of the benzofuran, α-elimination and 1,2-shift, or
ition (product 9h), but the use of 2-methylbenzofuran (7i) led to oxidative addition of TIPS-EBX (8) onto the gold catalyst
very a low yield in the alkynylation reaction.
(either at the Au(I) or Au(0) oxidation level) followed by elec-
Scheme 2: Scope of the reaction.
Scheme 3: Alkynylation of 7-methoxybenzofuran (7j) [31].
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Beilstein J. Org. Chem. 2013, 9, 1763–1767.
Scheme 4: Alkynylation of 8-methoxypsoralen (2).
2. Gasparro, F. P.; Dallamico, R.; Goldminz, D.; Simmons, E.;
trophilic auration and reductive elimination [33]. The role of the
zinc Lewis acid is not completely clear at this stage, but it may
act by complexing the carboxylate group of the hypervalent
iodine reagent, enhancing its electrophilic reactivity [19,34]. In
fact, a complete shift of the 1H NMR signals of TIPS-EBX (8)
was observed when Zn(OTf)2 was added, whereas no signal
shift was observed when mixing the Lewis acid and benzofuran
(7a) [35].
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In conclusion, the first direct alkynylation method of benzofu-
rans has been developed. Key for success was a cooperative
effect between a gold catalyst and a zinc Lewis acid, together
with the use of the hypervalent iodine reagent TIPS-EBX (8).
Preliminary results obtained with 8-methoxypsoralen (2)
demonstrated that the reaction could also be applied to more
complex furocoumarin natural products.
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General procedure for the alkynylation of benzofurans:
TIPS-EBX (8, 342 mg, 0.800 mmol, 2.0 equiv), AuCl (4.6 mg,
0.020 mmol, 0.050 equiv), Zn(OTf)2 (289 mg, 0.800 mmol,
2.0 equiv) and benzofuran 7 (0.40 mmol, 1.0 equiv) were added
into CH3CN (2.0 mL) under air. The mixture was stirred for
26 hours at 60 °C. Then the mixture was concentrated in pres-
ence of silica gel and purified directly by column chromatog-
raphy.
14.Fürstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
doi:10.1002/anie.200604335
15.Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. doi:10.1021/cr000436x
16.Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351.
doi:10.1021/cr068430g
Supporting Information
17.Arcadi, A. Chem. Rev. 2008, 108, 3266. doi:10.1021/cr068435d
18.Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int. Ed. 2009,
48, 9346. doi:10.1002/anie.200905419
Supporting Information File 1
Experimental part.
19.Brand, J. P.; Waser, J. Angew. Chem., Int. Ed. 2010, 49, 7304.
doi:10.1002/anie.201003179
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-204-S1.pdf]
20.Brand, J. P.; Waser, J. Org. Lett. 2012, 14, 744. doi:10.1021/ol203289v
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Acknowledgements
The EPFL and F. Hoffmann-La Roche Ltd are acknowledged
23.Brand, J. P.; Fernández González, D.; Nicolai, S.; Waser, J.
Chem. Commun. 2011, 47, 102. doi:10.1039/c0cc02265a
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doi:10.1055/s-0031-1290589
for financial support.
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