Gold-catalyzed tandem cyclization/Friedel-Crafts type reactions toward furan derivatives

Article abstract of DOI:10.1039/b905332h

A simple and convenient synthetic approach to furan derivatives 4 has been developed via gold-catalyzed tandem cyclization/Friedel-Crafts type reactions. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b905332h

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Gold-catalyzed tandem cyclization/Friedel–Crafts type reactions toward
furan derivatives†
Ke-Gong Ji,a Xing-Zhong Shu,a Jin Chen,a Shu-Chun Zhao,a Zhao-Jing Zheng,a Xue-Yuan Liua and
Yong-Min Liang*a,b
Received 17th March 2009, Accepted 20th April 2009
First published as an Advance Article on the web 28th April 2009
DOI: 10.1039/b905332h
A simple and convenient synthetic approach to furan
derivatives 4 has been developed via gold-catalyzed tandem
cyclization/Friedel–Crafts type reactions.
Furan rings occur widely as key structural subunits in numerous
natural products, which exhibit interesting biological activities
and also in substances of relevance for industry.1 For this
reason, the field of furan synthesis is continuously and rapidly
developing.2 Among many different approaches to multiply sub-
stituted furans,2b,3,4 cycloisomerizations of alkynyloxiranes cat-
alyzed by transition metals are particularly attractive. In general,
traditional methods for furan synthesis from alkynyloxiranes
mostly using Hg(II),5 Mo,6 Ru7 and SmI2/Pd(0/II)8 compounds
as transition-metal catalysts have some limitations. Thus, a new
method for the synthesis of furans is needed.
Recently, it was reported that carbon-carbon and carbon-
Fig. 1 Representative gold-catalyzed cycloisomerizations leading to
furans.
heteroatom bonds can be formed under mild conditions using
gold catalysts.9 Their ability to activate alkynes and promote the
addition of nucleophiles has spurred growing investigations for
the discovery of selective reactions.10
Fig.
1 schematically illustrates representative examples
of gold-catalyzed cycloisomerizations of oxoalkynyl com-
pounds: alkynyloxiranes,10a alk-3-yn-1-ones,10b alka-2,3-dien-1-
ones,10c alk-4-yn-1-ones,10d (Z)-alk-2-en-4-yn-1-ols,10e,f propar-
gyl vinyl ethers,10g alk-3-yn-1-one-2-yl acetates10h,i,j and alkynyl
enones10k,l,m,n that lead to substituted furans. However, most of
them are intramolecular cycloisomerization reactions, examples
of the corresponding highly selective intermolecular reactions
by adding nucleophiles for furan synthesis are limited in gold
chemistry.10k,l,m,n Recently, we have described the gold-catalyzed
tandem cyclization of 1-oxiranyl-2-alkynyl esters 1 with nucle-
ophiles to give 2,5-disubstituted furans 5 (Scheme 1(a)).11 It was
found that the oxonium ion 2 was an important intermediate.
Thus, we envision that if water was exited in the reaction system,
water may play an important role in the cyclization to give
the 2-(a-hydroxyalkyl)-furans 3. Then, under gold catalysis, the
latter may afford furan derivatives 4 through an intermolecular
Friedel–Crafts type reaction,9g,12 which is an efficient approach to
Scheme 1 Design of a gold-catalyzed formation of furan derivatives
through tandem cyclization/Friedel–Crafts type reactions.
the formation of a carbon-carbon or carbon-heteroatom bond.
(Scheme 1(b)).
Herein, we wish to report the gold-catalyzed tandem
cyclization/Friedel–Crafts type reactions toward furan derivatives
under very mild conditions. During this reaction, water as a
nucleophile was the key step.
Initially, we started by treating 1-oxiranyl-2-alkynyl ester 1a
(0.5 mmol) and furan (5 equivs) with 2 mol% of HAuCl4·4H2O in
wet 1,4-dioxane (2 mL) and, gratifyingly, the desired product 4a
was formed in 50% yield after 20 min, along with difurylmethane
6a (5% yield; Table 1, entry 1). To our delight, on increasing the
amount of furan to 10 equivs, a good yield (71%) of 4a was
obtained and no difurylmethane 6a could be isolated (Table 1,
entry 3). With other gold catalysts, such as NaAuCl4·2H2O, AuCl3,
AuCl and Au(I) systems generated from silver salts, no superior
results were obtained (Table 1, entries 4–7). AgBF4 and PtCl2 gave
aState Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, 730000, P.R. China
bState Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical
Physics, Chinese Academy of Science, Lanzhou, 730000, P.R. China.
E-mail: liangym@lzu.edu.cn; Fax: +86-931-8912582; Tel: +86-931-
8912593
† Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/b905332h
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Table 1 Optimization of reaction conditions for the synthesis of 4a
substituents on the alkyne moiety like 1i, only a moderate yield
(41%) of 4i was obtained (entry 9). Substrates with an aliphatic R3
group like 1j gave the corresponding products in good yield (entry
10). And we have also investigated the reactions of 1-oxiranyl-2-
alkyn-1-ols with different protective groups. While substrates like
1k and 1l gave the furan derivatives 4a in good yields.
Furthermore, we also investigated the scope of nucleophiles
in this cyclization/Friedel–Crafts type reaction, as depicted in
Table 3. It was found that, in addition to furan, 2-methylfuran,
pyrrole derivatives, 1H-indole, pentane-2,4-dione and NaN3 could
be used as effective nucleophiles for this reaction (up to 81%)
(entries 1–7).
Yield(%)b
Furan (equivs) Time (min) 6a 4a
Entry Catalyst
1
2
3
4
5
6
HAuCl4·4H2O
5
8
10
10
10
10
20
20
20
30
25
5
<5
0
<5
0
50
64
71
68
70
HAuCl4·4H2O
HAuCl4·4H2O
NaAuCl4·2H2O
AuCl3
It is very interesting that when substrate 1h and a pyrrole
derivative were then submitted to the above conditions, the corre-
sponding product 4ah, which contains O, S and N heteroatoms at
the same time, was obtained in 63% yield (Scheme 2).
AuCl
30
trace 71
7
Au(PPh3)Cl/AgBF4 10
30
120
120
0
0
0
35
0
0
8c
9d
AgBF4
PtCl2
10
10
a Conditions: 0.5 mmol of 1a and 10 equivs of furan with 2 mol% of
catalyst in wet 1,4-dioxane (2.0 mL) at room temperature (23–25 ◦C).
b Isolated yield. c 91% of 1a was recovered. d 93% of 1a was recovered.
no reaction. Thus, the use of 10 equivs of furan and HAuCl4·4H2O
(2 mol%) in wet 1,4-dioxane at room temperature was found to be
the most efficient and was utilized as the standard conditions.
To study the scope of this formation of furan derivatives, various
1-oxiranyl-2-alkynyl esters13 were then submitted to the above con-
ditions, as depicted in Table 2. Thus, a tandem cyclization/Friedel–
Crafts type reactions of 1-oxiranyl-2-alkynyl esters 1a-1l pro-
ceeded smoothly to provide the corresponding furan derivatives in
moderate to good yields. The reaction works well with aromatic R2
groups (entries 1–3). While substrates with aliphatic or H R2 group
like 1d and 1e gave the corresponding products in lower yields
(entries 4 and 5). Various aryl substituents on the alkyne moiety,
were compatible with this reaction and generally gave good yields
of the corresponding furan derivatives (entries 6–8). With aliphatic
Scheme 2
In order to uncover the mechanism for the reaction, we started
out our investigation by using 2-(a-hydroxyalkyl)furan 3a and
furan (5 equivs) under 2 mol% of HAuCl4·4H2O and the desired
product 4a was formed in excellent yield. From the above, it was
found that it was a Friedel–Crafts type reaction (Scheme 3).
On the basis of the above observations, a possible reaction
mechanism is proposed as shown in Scheme 4, which may involve
the following steps. (i) coordination of the alkynyl moiety of A to
the Au catalyst gives the complex B. (ii) The subsequent domino
nucleophilic attack/anti-endo-dig cyclization affords organogold
intermediate E through path a during which trace amounts of
Table 2 Gold(III)-catalyzed reaction of 1-oxiranyl-2-alkynyl ester 1 with furan a
Entry
1b
R1
R2
R3
R4
Time (min)
4
Yields (%)c
1
2
3
4
5
6
7
8
9
1a (7:5)
1b (10:7)
1c (2:1)
1d (2:1)
1e (9:7)
1f (16:7)
1g (2:1)
1h (2:1)
1i (5:3)
1j (1:0)
1k (2:1)
1l (1:1)
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
20
10
10
20
20
10
50
10
60
10
20
10
4a
4b
4c
4d
4e
4f
4g
4h
4i
71
73
70
50d
43d
68
58
60
41
72
68
70
p-CH3-C6H4
p-Cl-C6H4
CH3
H
Ph
p-CH3-C6H4
p-CH3CO-C6H4
2-thienyl
C5H11
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
CH3
H
Ac
Ac
10
11
12
4j
4a
4a
COOCH3
COOC(CH3)3
H
◦
a Conditions: 0.5 mmol of 1 and 10 equivs of furan with 2 mol% of catalysts in wet 1,4-dioxane (2.0 mL) at room temperature (23–25 C). b Syn/anti
mixtures of the substrate were used; syn:anti ratio determined by 1H NMR. c Isolated yield. d Reaction run with furan (15 equivs) and 5 mol% catalyst
loading.
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Table 3 Gold(III)-catalyzed reaction of 1-oxiranyl-2-alkynyl ester 1 with nucleophilesa
Entry
Substrates
Nucleophiles
Products
Time
Yields (%)b
1
20 min
4a
71
2
3
15 min
10 h
4aa
4ab
73
77c
30 min
60 min
10 h
81d
57e
51f
38g
4
5
6
4ac
4ad
4ae
8 h
7
8
NaN3
8 h
4af
46h
79
20 min
4ag
◦
a Conditions: 0.5 mmol of 1a, nucleophile (10 equivs) with 2 mol% of catalyst in wet 1,4-dioxane (2.0 mL) at room temperature (23–25 C). b Isolated
yield. c 0.5 mmol of 1a, 1.0 mmol of 2-methylfuran with 5 mol% of catalysts in water (1.0 mL) at 80 ◦C for 10 h. d 7.5 equivs of 1-benzyl-1H-pyrrole was
recovered. e 7.0 equivs of phenyl(1H-pyrrol-1-yl)methanone was recovered. f 0.5 mmol of 1a, 0.6 mmol of 1H-indole with 5 mol% of catalysts in water
(0.8 mL) at 80 ◦C for 10 h. g 0.5 mmol of 1a, 1.5 mmol of pentane-2,4-dione with 5 mol% of catalysts in water (0.8 mL) at 80 ◦C for 8 h and 38% of
desired product 4ae was obtained, along with 20% 6a was isolated. h 0.5 mmol of 1a, 1.0 mmol of NaN3 with 5 mol% of catalysts in water (0.8 mL) at
80 ◦C for 8 h.
Scheme 3
water act as the nucleophile. Alternatively, the complex B may
form an oxonium ion C14 through path b which is formed by the
nucleophilic attack of epoxide oxygen to the gold-coordinated
alkynes,11a,c,15 then trace amounts of water as the nucleophile
attack oxonium ion C and afford organogold intermediate E
(iii) Protonation of E yields 2,3-dihydrofuran F and regenerates
the catalyst Au. (iv) F undergoes direct reductive elimination of
acetic acid to afford the 2-(a-hydroxyalkyl)furans G. (v) Under
the gold catalysis, G eliminates one molecule water to afford ion
intermediate H. (vi) Then nucleophilic attack on ion intermediate
H affords the furan derivatives I, which is an intermolecular
Friedel–Crafts-type reaction.
In summary, a novel and flexible method for the syn-
thesis of furan derivatives has been developed through the
cyclization/Friedel–Crafts type reactions of esters of 1-oxiranyl-
2-alkyn-1-ols at room temperature under gold catalysis. During
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Scheme 4 Proposed reaction mechanism for Au-catalyzed cyclization/Friedel–Crafts type reactions.
this reaction, water as a nucleophile was the key step. Further
studies, including detailed investigations into the mechanism and
the scope of this reaction, are in progress in our laboratory.
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Acknowledgements
We thank the NSF (NSF-20621091, NSF-20732002) for financial
support.
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