Gold-catalyzed regioselective synthesis of 2- and 3-alkynyl furans

Article abstract of DOI:10.1002/anie.201302210

Chemical Matching: C2- or C3-alkynylated furans were selectively synthesized by using gold catalysis. Direct C-H alkynylation of furans was achieved with C2 selectivity, and a domino cyclization/alkynylation process starting from allenes gave C3-alkynylat

Full text of DOI:10.1002/anie.201302210

Angewandte
Chemie
Communications
Gold Catalysis
Y. Li, J. P. Brand,
J. Waser*
&&&& — &&&&
Gold-Catalyzed Regioselective Synthesis
of 2- and 3-Alkynyl Furans
Chemical Matching: C2- or C3-alkyny-
lated furans were selectively synthesized
by using gold catalysis. Direct C–H
alkynylation of furans was achieved with
C2 selectivity, and a domino cyclization/
alkynylation process starting from allenes
gave C3-alkynylated products. The exact
matching of the structure of the gold
catalyst and an electrophilic hypervalent
iodine reagent was essential for success.
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DOI: 10.1002/anie.201302210
Gold Catalysis
Gold-Catalyzed Regioselective Synthesis of 2- and 3-Alkynyl Furans**
Yifan Li, Jonathan P. Brand, and Jꢀrꢁme Waser*
Furans are omnipresent in synthetic bioactive compounds,
natural products, and innovative organic materials
(Scheme 1).[1] They also give access to equally important
of halogenated precursors being the most frequently used.
New catalytic methods giving a more direct and regioselective
access to alkynylated furans need consequently to be
developed.
The exceptional properties of gold for the activation of p
À
systems and the functionalization of C H bonds have been
investigated intensively in the last 15 years.[6] Nevertheless,
most gold-catalyzed processes were terminated by protona-
tion or halogenation until very recently. In the last five years,
important breakthroughs towards more efficient domino
processes have been realized by using two approaches: the
transmetalation of the gold intermediate to another metal[7]
and the in situ oxidation to a AuIII intermediate by using
a strong oxidant, followed by reductive elimination.[8] Despite
this progress, there are currently only two examples of Au-
catalyzed alkynylation through in situ oxidation: the C–H
functionalization of arenes developed by Nevado and
de Haro[5g] and a domino cyclization/alkynylation of alle-
noates to give butenolides introduced by Gouverneur and co-
workers.[8d]
Scheme 1. Examples of furans and alkynyl furans in synthetic bioactive
compounds, natural products, and organic materials.
To develop more general oxidative electrophilic alkyny-
lation methods, we have turned towards well-defined hyper-
valent ethynylbenziodoxolone (EBX) reagents.[9] The unique
possibility to tightly modulate the electrophilicity and oxida-
tion potential of these reagents allowed us to develop the Au-
catalyzed C–H alkynylation of electron-rich arenes,[9a–e] the
metal-free a-alkynylation of carbonyl compounds[9f] and the
Pd-catalyzed oxy- and amino-alkynylation of olefins.[9g–h]
Herein, we report the first example of direct alkynylation of
furans by using a AuI catalyst and 1-[(triisopropylsilyl)-
ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS-EBX, 7). This
reaction proceeds at low temperature (23 to 608C) and is
highly selective for the most electron-rich C2 position of
furans (Scheme 2a). To access C3-alkynylated furans, we
envisaged a domino process based on the well-established Au-
catalyzed cyclization of allenic ketones.[6f,10] However, we had
shown before that TIPS-EBX (7) is not able to intercept Au–
Csp2 intermediates in domino processes.[9c] Herein, we dem-
tetrahydrofurans through reduction or dihydropyrans
through oxidation. It is consequently not surprising that the
development of new methods to synthesize and functionalize
furans is an area of intense research in modern organic
chemistry.[2] In particular, direct metal-catalyzed methods
based on C–H functionalization or domino cyclization
reactions constitute promising efficient approaches.[3]
The efficient synthesis of alkyne-substituted furans would
be highly desirable, because these compounds are present in
bioactive molecules and natural products (Scheme 1). They
also constitute ideal building blocks for the elaboration of
more complex scaffolds, owing to the versatile chemistry of
the triple bond.[4] Recently, efficient direct C–H alkynylation
reactions have emerged for the functionalization of a broad
range of (hetero)aromatic compounds.[5] In the case of furans,
only two examples of direct alkynylation occurring in 45–53%
yield have been reported very recently by Su and co-
workers.[5m] Alkynylated furans are usually accessed from
prefunctionalized heterocycles, with the Sonogashira reaction
[*] Y. Li, Dr. J. P. Brand, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (Switzerland)
E-mail: jerome.waser@epfl.ch
Homepage: http://lcso.epfl.ch/
[**] EPFL and F. Hoffmann-La Roche Ltd are acknowledged for financial
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302210.
Scheme 2. Selective Au-catalyzed synthesis of 2- and 3-ethynylated
furans through C–H alkynylation and domino cyclization/alkynylation.
2
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onstrate that the modified ethynylbenziodoxole reagent 10 is
exceptionally efficient in this domino process, leading to C3-
alkynylated furans in high yields at room temperature
(Scheme 2b). The availability of a well-defined reagent for
alkynylation in gold-catalyzed domino processes represents
a major breakthrough and is expected to find broad applica-
tion beyond the synthesis of alkynyl furans.
the 3-substituted regioisomers based on a domino cyclization/
alkynylation process (Table 2). The first results were not
promising: a AuI catalyst (AuCl) did not promote the
cyclization of allene 9a[12] (Table 2, entry 1), whereas a AuIII
Table 2: Optimization of the domino cyclization/alkynylation.
We started our investigations with the C2-alkynylation of
2-hexylfuran (6a) as substrate. When this substrate was
treated under the standard conditions for thiophene alkyny-
lation (TIPS-EBX (7, 1.2 equiv),[11] trifluoroacetic acid (TFA,
1.2 equiv) in acetonitrile),[9b] only decomposition of the
starting material was observed. This was probably due to
the acid sensitivity of furans. In fact, the C2-alkynylation
product was isolated in 90% yield in the absence of TFA,
thereby allowing us to proceed directly with the examination
of the scope of the reaction (Table 1).
The reaction worked well for 2-alkyl-substituted furans
(Table 1, entries 1–5) and furan (6 f) itself (entry 6). For
volatile substrates, it was more convenient to run the reaction
in the furan itself as solvent. The alkynylation of 2-aryl furans
was slower, but the products could be obtained in 56–71%
yield by running the reaction at 608C (Table 1, entries 7–10).
Finally, disubstituted furans could also be used in the reaction
(Table 1, entries 11 and 12). In case of 2,5-disubstituted furan
6l, 3-alkynylation product 8l was obtained in 45% yield
(Table 1, entry 12).
Entry
Catalyst
Equivalents
(reagent)
Base
Solvent
Yield [%]
11a/8g[a]
1
2
3
4
5
6
7
8
AuCl
AuCl3
12
12
12
12
12
12
12
12
12
12
12
12
12
12
1.2 (7)
1.2 (7)
1.2 (7)
1.2 (7)
1.2 (7)
1.2 (7)
1.2 (10)
1.2 (13)
1.2 (14)
1.2 (15)
1.2 (10)
2.0 (10)
2.0 (10)
2.0 (10)
2.0 (10)
2.0 (10)
–
–
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
<5
<5[b]
24:7
<5
NEt3
K2CO3
Na2CO3
–
–
–
10:0
31:0
50:0[c]
<5
9
<5
<5
10
11
12
13
14
15
16
–
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
33:0[d]
73:0[d]
11:0[d]
6:0[d]
23:0[d]
93:0[d]
EtOH
iPrOH
After having developed a C–H functionalization method
for the 2-alkynylation of furans, we turned to the synthesis of
[a] Reaction conditions: 9a (0.1 mmol), Au catalyst (5 mol%), 0.02m,
RT, 72 h, yield of isolated product. [b] Formation of cyclization product
6g was observed. [c] Furan 6g was isolated in 14% yield. [d] Yield was
determined by GC.
Table 1: Scope of the ethynylation of furans.
Entry Substrate
Product
Method Yield [%][d]
catalyst (AuCl3) led to cyclization as reported,[10a] but no
alkynylation was observed (entry 2). We consequently
extended our search to a broad range of other AuI and AuIII
catalysts, and a promising result was obtained with pyridine-2-
carboxylato-gold(III) dichloride (12), which gave 24% of the
desired 3-alkynylation product 11a together with 7% of 2-
alkynylation product (Table 2, entry 3).[13] In principle, 2-
alkynylation could have occurred after premature protona-
tion of the formed gold intermediate. Indeed, furan 8g was
obtained exclusively in 23% yield when catalyst 12 was used
with 2-phenyl-furan (6g) under the conditions of Table 1. We
speculated that a base could prevent protonation of the
1
2
3
4
5
6
7
8
9
10
R=hexyl 6a
R=methyl 6b
R=ethyl 6c
R=tBu 6d
R=CH2OBn 6e
R=H 6 f
R=phenyl 6g
R=tolyl 6h
R=4-MeOC6H4 6i 8i
R=thiophenyl 6j 8j
8a
8b
8c
8d
8e
8 f
A
B
B
A
C
B
C
C
C
C
90
78
79
56
55
61
68
66
71
56
8g
8h
11
A
65
À
intermediate Au C bond and avoid 2-alkynylation. In fact, 3-
alkynylation was observed exclusively in presence of bases,
with the best result (31%) obtained with sodium carbonate
(Table 2, entries 4–6). However, when using TIPS-EBX (7),
we were not able to further increase the yield of 11a, despite
extensive optimization of the reaction conditions.
12
B
45
[a] Reaction conditions: 6 (0.40 mmol), 7 (0.48 mmol), AuCl (5 mol%),
0.2m, RT, 26 h. [b] Furan 6 (1 mL), 7 (0.40 mmol), RT, 26 h. [c] As [a] but
at 608C. [d] Yields of isolated products after column chromatography.
For the domino process to be successful, fine-tuning of the
reactivity of the alkynylation reagent is expected to be an
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essential factor. We therefore decided to examine other
hypervalent iodine reagents for the reaction. Indeed, the
domino process was more efficient when using bistrifluoro-
methyl benziodoxole reagent 10,[11a] which gave 50% of 11a
together with 14% of 2-phenyl furan (6g), resulting probably
from protonation of the putative organogold intermediate
(Table 2, entry 7). The fact that no 2-alkynylation product was
obtained in this case is probably due to the lower efficiency of
reagent 10 in direct C–H alkynylation.[9d,14] In contrast, no
product was observed with the dimethyl-substituted reagent
13 or alkynyl iodonium salt 14, with a more or less basic
oxygen atom bound to the iodine, respectively (Table 2,
entries 8 and 9). On the other hand, no product was observed
when alkynyl iodide 15 was used (Table 2, entry 10). These
results further demonstrated that success in this challenging
domino process can be achieved only for a very narrow
window of electronic density at the iodine atom. In presence
of sodium carbonate, the formation of 2-phenyl furan (6g)
was suppressed, albeit at the cost of the yield of 11a (Table 2,
entry 11). Fortunately in this case, a larger excess of hyper-
valent iodine reagent 10 allowed increasing the yield sub-
stantially to 73% (Table 2, entry 12). Finally, reinvestigation
of the solvent led to the use of isopropanol, for which the 3-
alkynylated product 11a was obtained in 93% yield deter-
mined by using GC (Table 2, entries 13–16). On a 0.3 mmol
scale, furan 11a could finally be isolated in 68% yield
(Table 3, entry 1).
nearly quantitative yields (94–95%), independently of its
position (Table 3, entries 2–4). A para-methoxy or a phenyl
group were also well-tolerated in the reaction (Table 3,
entries 5 and 6), as well as a furyl substituent (entry 7). A
current limitation of the method is that electron-withdrawing
groups were not tolerated, because in this case Michael
addition of the solvent on the allene was observed in
isopropanol and decomposition was obtained in other sol-
vents. The reaction was not limited to aromatic substituents,
and excellent yields were obtained with both primary
(Table 3, entries 8–9) and a secondary (entry 10) aliphatic
substituent. A more sensitive benzyl group was also well
tolerated, giving the alkynylation product 11k in 77% yield
(Table 3, entry 11). Finally, an important preliminary result
was obtained for the synthesis of polysubstituted furans:
Starting from allene ketone 16, trisubstituted furan 17 was
obtained in 94% yield (Table 3, entry 12). The synthesis of
such a product would be very challenging through C–H
functionalization, owing to serious issues of reactivity and
regioselectivity.
The obtained silylated alkynyl furan 8a was easily
deprotected to give the corresponding free acetylene. By
using a methodology developed previously in our group,[9b]
one-pot dimerization and thiophene formation then resulted
in the formation of alternating heterocyclic oligomer 18
(Scheme 3, (1)). Heterocyclic oligomers are important in
Investigation of the scope of the reaction showed that
substitution of the benzene ring by a methyl group led to
Table 3: Scope of the domino cyclization/alkynylation.
Scheme 3. Functionalization of alkynyl furans 8a and 8b. Reaction
conditions: a) tetrabutylammonium fluoride, THF, 08C, 1 h, 78%;
b) Cu(OAc)2, CH3CN, 808C, 12 h; then Na2S·3H2O, 808C, 24 h, 65%;
c) 10 wt% Pd/C, H2, pentane/EtOH, 12 h, 74%, 5:1 d.r.
Entry
Substrate
Product
Yield [%][a]
organic materials, but are usually composed of a single class of
heterocycles. New properties can be expected to emerge with
an easier access to more-complex oligomers. Furthermore,
hydrogenation gave access to tetrahydrofurans, which are
important building blocks for the synthesis of bioactive
synthetic and natural products (Scheme 3, (2)).
The results obtained for the C2-alkynylation of furans are
in line with our previous work on the alkynylation of
heterocycles.[9a–d] In particular, we had shown that AuCl
reacts instantaneously with TIPS-EBX (7) to form bis(triiso-
propylsilyl)diyne as major product. This led us to propose
a catalytic cycle involving first oxidative addition of a AuI
species on the reagent, followed by C–H auration and
reductive elimination as one of the most probable mecha-
nisms for this transformation. In this context, the fact that the
new domino cyclization/alkynylation process is catalyzed by
a AuIII catalyst is mechanistically intriguing. In fact, the only
domino cyclization/alkynylation process reported to date has
been proposed to proceed through a AuI–AuIII catalytic
cycle.[8d] To explain our results, an unprecedented electro-
1
2
3
4
5
6
7
8
R1 =Phenyl 9a
R1 =4-MeC6H4 9b
R1 =3-MeC6H4 9c
R1 =2-MeC6H4 9d
R1 =4-MeOC6H4 9e
R1 =4-PhC6H4 9 f
R1 =2-furyl 9g
11a
11b
11c
11d
11e
11 f
11g
11h
11i
68
94
95
94
83
53
75
93
96
97
77
R1 =hexyl 9h
9
10
11
R1 =ethyl 9i
R1 =cyclohexyl 9j
R1 =benzyl 9k
11j
11k
12
94
[a] Reaction conditions: 9a (0.3 mmol), Au catalyst 12 (5 mol%),
isopropanol (15 mL), RT, 5–72 h, yields of isolated products after column
chromatography are given.
4
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philic alkynylation of a AuIII intermediate has to be postu-
lated. To better understand the unique properties of catalyst
12 in the domino process, several control experiments were
done:
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1) Product 11a was obtained in 81% yield (determined by
using GC) when the catalyst was formed in situ from
AuCl3 and picolinic acid.
2) No product was obtained with AuCl3/pyridine, AuCl3/
benzoic acid, or AuCl3(pyridine)/benzoic acid as catalyst.
3) The use of AuCl3 together with 4-carboxy-pyridine (iso-
nicotinic acid) did also not lead to product formation.
4) Stoichiometric reaction of 12 with 9a led to the immediate
formation of furan 6g. In contrast to what had been
observed with AuCl, no reaction was observed when
mixing 12 with benziodoxole 10.
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These experiments demonstrated that a gold(III) picolinic
acid complex was required for the domino process, and that
the first step in the reaction most probably involved cycliza-
tion of the allene. Obviously, further work will be required to
better understand the mechanism of the reaction and the
exact role of the picolinic acid ligand.
In summary, we have reported the first selective synthesis
of 2- and 3-alkynylated furans based on gold catalysis. An
unprecedented Au-catalyzed C–H functionalization with the
hypervalent iodine reagent TIPS-EBX (7) was first applied to
access 2-ethynylated furans. By using a conceptually different
domino cyclization/alkynylation approach, we were able to
develop the first Au-catalyzed synthesis of 3-alkynylated
furans. Key for success was a unique combination of a AuIII
catalyst and a modified benziodoxole reagent 10. The clean
interception of an Au–C intermediate with a well-defined
alkynylation reagent constitute an important breakthrough in
the field, and future work will be focused on further
applications in Au-catalyzed C–H functionalization and
domino processes, as well as to the investigation of the
mechanism of the reaction.
Received: March 15, 2013
Revised: April 4, 2013
Published online: && &&, &&&&
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Keywords: C–H functionalization · domino reactions · furans ·
gold · hypervalent iodine
.
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[14] Under the optimized reaction conditions (Table 2, entry 16), no
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13, or 14.
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