Synthesis of highly substituted 3-formylfurans by a gold(I)-catalyzed oxidation/1,2-alkynyl migration/cyclization cascade

Article abstract of DOI:10.1002/anie.201310146

3-Formylfuran derivatives are core structures of a variety of bioactive natural products. However, procedures for their preparation are still rare and generally inefficient in terms of atom economy: These methods require multiple steps or harsh reaction c

Full text of DOI:10.1002/anie.201310146

Angewandte
Chemie
DOI: 10.1002/anie.201310146
Gold Catalysis
Synthesis of Highly Substituted 3-Formylfurans by a Gold(I)-Catalyzed
Oxidation/1,2-Alkynyl Migration/Cyclization Cascade**
Tao Wang, Shuai Shi, Max M. Hansmann, Eva Rettenmeier, Matthias Rudolph, and A.
Stephen K. Hashmi*
Abstract: 3-Formylfuran derivatives are core structures of
a variety of bioactive natural products. However, procedures
for their preparation are still rare and generally inefficient in
terms of atom economy: These methods require multiple steps
or harsh reaction conditions and show selectivity problems. An
efficient gold(I)-catalyzed cascade reaction that leads to 3-
formylfurans from easily accessible starting materials is now
described. A wide variety of 3-formylfurans were obtained
from the corresponding symmetric and unsymmetric 1,4-diyn-
Figure 1. Selected examples of natural products with the 3-formylfuran
motif.
3-ols in the presence of an N-oxide in good to excellent yields.
Isotope-labeling experiments as well as DFT calculations
support a mechanism in which, after an initial oxygen transfer,
a 1,2-alkynyl migration is favored over a hydride shift;
a cyclization ensues to afford the desired functionalized
furan core.
efforts directed towards the development of efficient syn-
thetic strategies for this heteroarene. However, methods for
the preparation of 3-formylated furans are still rare, and their
development can be considered as one of the great remaining
challenges of furan chemistry. Commonly used methods are
based either on the direct formylation of furans[3] or on the
reduction of other functional groups, such as carboxylic acids
or carboxylic esters, at the 3-position.[4] Because of the high
intrinsic selectivity for the 2-position of the furan ring, the
direct formylation of the 3-position is only possible if the 2-
and 5-positions are occupied, and harsh conditions are often
required. For the latter method, the use of other functional
groups is limited to those that tolerate the required reducing
agents. Furthermore, both methods start from pre-synthe-
sized furan systems. Cascade reactions for the synthesis of 3-
formylfurans have also been reported;[5] however, these
reactions were usually carried out at high temperatures, and
several steps were required for the preparation of the starting
materials. Therefore, the development of an efficient and
simple method for the synthesis of 3-formylfurans from
readily available starting materials is still highly desired. As
part of our efforts on the synthesis of polysubstituted furans,[6]
we herein report a highly efficient gold(I)-catalyzed cascade
reaction for the preparation of 3-formylfurans from easily
accessible starting materials.
P
olysubstituted furans are not only common motifs in
natural products and pharmaceuticals, but also useful building
blocks for the construction of highly complex target struc-
tures.[1] As important members of the furan family, 3-
formylfuran derivatives are core structures of some bioactive
natural products, such as lophotoxin and its derivatives
pukalide and lophodiol A (Figure 1). Lophotoxin, which can
be isolated from pacific gorgonians of the genus Lophogorgia,
is a potent neurotoxin that leads to paralysis and asphyxia-
tion.[2] The importance of furan motives initiated substantial
[*] M. Sc. T. Wang, M. Sc. S. Shi, M. Sc. M. M. Hansmann,
Dipl.-Chem. E. Rettenmeier, Dr. M. Rudolph,
Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: hashmi@hashmi.de
Homepage: http://www.hashmi.de
Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science
King Abdulaziz University
Jeddah 21589 (Saudi Arabia)
Recently, gold-catalyzed oxygen transfer from sulfox-
ides[7] and nitrogen oxides[8] to alkynes has become an
efficient strategy for the generation of a-oxo gold carbenoids,
which can undergo a variety of valuable transformations. Very
recently, our group developed an efficient approach for the
synthesis of 1,3-diketones from propargyl alcohols and
pyridine N-oxides by gold catalysis (Scheme 1a).[9] 1,2-Aryl
and 1,2-hydride migrations were key steps of the outlined
reaction mechanism. In this specific case, 1,2-aryl migration
was favored over 1,2-hydride migration. We envisioned that
a gold catalyst should activate 1,4-diyn-3-ol 1 in the presence
[**] T.W. and S.S. are grateful for fellowships from the China Scholarship
Council (CSC). M.M.H. is grateful to the Fonds der chemischen
Industrie for a Chemiefonds scholarship and the Studienstiftung
des deutschen Volkes. E.R. is grateful for a scholarship of the state
of Baden-Wꢁrttemberg via the Graduate Academy of Heidelberg
University. We thank Umicore AG & Co. KG for the generous
donation of gold salts. The computational studies were supported
by bwGRiD, member of the German D-Grid initiative, funded by the
Ministry for Education and Research and the Ministry for Science,
Research and Arts Baden-Wꢁrttemberg.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310146.
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yield (entries 10–12). Among the tested silver salts,
AgOTf in combination with [IPrAuCl] gave the best
result. A solvent screen (entries 13–15) revealed that
toluene was the most suitable solvent for this trans-
formation (entry 15). Decreasing the catalyst loading to
3 mol% was possible without a drop in yield (entry 16).
Reducing the amount of pyridine N-oxide to 1.2 equiv-
alents led to a slightly lower yield (entry 18).
Under the optimized reaction conditions, a wide
variety of 1,4-diyn-3-ols 1 were examined, and the results
are summarized in Table 2. Substrates with substituents at
the para position of the phenyl group reacted smoothly to
afford 3-formylfurans 4 in good to excellent yields under
standard conditions. Substrates with electron-donating
groups usually gave the corresponding products with
slightly higher yields (entries 2–4) than those with elec-
tron-withdrawing groups (entries 6 and 7). Phenyl sub-
strates with a substituent in meta position also worked
well to give the corresponding furans 4 in good yields
(entries 9 and 10). The furans 4e, 4h, and 4k were
obtained in good yields by using 1.2 equivalents of
pyridine N-oxide (2a; entries 5, 8, and 11). The reduced
amount of N-oxide for these substrates was necessary
because of the low solubility of the products; crystallization
was the preferred purification method, and larger amounts of
the N-oxide led to impure products. A heteroaromatic
Scheme 1. Previous work and our hypothesis.
of pyridine N-oxide to form an a-oxo gold carbenoid
intermediate A, which could undergo a 1,2-hydride migration
to provide 1,3-diketone B. Upon cyclization, this intermediate
should generate 4-pyranone 3 (Scheme 1b). Alternatively, a-
oxo gold carbenoid A could also form intermediate C through
a 1,2-alkynyl migration, but no report of such a 1,2-alkynyl
migration onto a gold carbenoid species can be found in the
literature. Cyclization of intermediate C would afford 3-
formylfuran 4 or 4-acylfuran 5 (Scheme 1c). Considering the
greater nucleophilicity of the ketone, the formation of 3-
formylfuran 4 should be the favoured pathway.
Table 1: Optimization of the reaction conditions.[a]
Diynol 1a was prepared according to a simple one-step
procedure by treating phenylacetylene with n-butyllithium,
which was followed by the one-pot addition of ethyl formate.
1a was then treated with 3,5-dichloropyridine N-oxide
(1.5 equiv) in the presence of [IPrAuCl]/AgNTf2 (IPr= 1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene, Tf = trifluoro-
methylsulfonyl). Pleasingly, a clean reaction took place at
room temperature. To our surprise, 3-formyl furan 4a was
formed within ten minutes as the exclusive product (Table 1,
entry 1). This indicates that an unprecedented 1,2-alkynyl
migration seems to be involved in the reaction cascade.
Encouraged by this result, we started to optimize the reaction
conditions (Table 1). First, a variety of pyridine N-oxides were
tested, but no improvement was achieved. Using relatively
electron-rich pyridine N-oxide (2b) or 4-picoline N-oxide
(2c) resulted in an incomplete conversion of 1a (entries 2 and
3), whereas 3-bromopyridine N-oxide (2d) and 2,6-dibromo-
pyridine N-oxide (2e) afforded 4a in a slightly lower yield
(entries 4 and 5). A further screen revealed that both AuCl3
and AuCl can catalyze the reaction, but 4a was only obtained
in moderate yield even after prolonged reaction times
(entries 7 and 8). With AgNTf2 as the catalyst, product 4a
was not observed (entry 9). Replacing AgNTf2 with different
silver salts, such as AgOTf, AgClO4, and AgSbF6, as the
activator for [IPrAuCl] did not have a substantial effect on the
Entry Catalyst
N-oxide Solvent
t
Yield[b] [%]
1
[IPrAuCl]/AgNTf2
2a
2b
2c
2d
2e
(CH2Cl)2 10 min 85
2
3
4
5
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
(CH2Cl)2 2 h
(CH2Cl)2 2 h
(CH2Cl)2 2 h
(CH2Cl)2 1 h
66 (30)
59 (33)
83
80
6
[Ph3PAuCl]/AgNTf2 2a
(CH2Cl)2 10 min 30[c]
7
AuCl3
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a[g]
(CH2Cl)2 24 h
(CH2Cl)2 24 h
(CH2Cl)2 24 h
(CH2Cl)2 10 min 88
(CH2Cl)2 10 min 85
(CH2Cl)2 10 min 83
CH3CN
CH2Cl2
toluene
toluene
toluene
toluene
75
71
8
AuCl
[d]
9
AgNTf2
–
10
11
12
13
14
15
16
17
18
[IPrAuCl]/AgOTf
[IPrAuCl]/AgClO4
[IPrAuCl]/AgSbF6
[IPrAuCl]/AgOTf
[IPrAuCl]/AgOTf
[IPrAuCl]/AgOTf
[IPrAuCl]/AgOTf[e]
[IPrAuCl]/AgOTf[f]
[IPrAuCl]/AgOTf[e]
5 h
50 (45)
10 min 85
10 min 91
30 min 90
2 h
30 min 85
78 (20)
[a] All reactions were carried out on a 0.4 mmol scale in 2 mL of solvent
with the catalyst (5 mol%) and the N-oxide (1.5 equiv) at room
temperature. [b] Yields of isolated products; the number in parentheses
represents the amount of 1a that was recovered after column
chromatography. [c] Decomposition of 1a was observed. [d] No reaction
was observed. [e] 3 mol%. [f] 1 mol%. [g] 1.2 equiv.
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Table 2: Scope of the reaction for symmetric starting materials.
Next, we evaluated unsymmetric starting materials
(Table 3). 4o and 4o’ were obtained with poor selectivity
and in 50% and 29% yield, respectively (entry 1). This result
may be explained in terms of the competing electronic effects
of the halogen substituent at the para position. A significantly
higher selectivity was observed with compounds 4p and 4p’,
which were obtained in a 1:10 ratio (entry 2). It was found that
the electron-rich phenyl group ends up at the 2-position of the
3-formylfuran. This regioselectivity can be explained by the
preference of the cationic gold fragment to coordinate to the
more electron-rich alkyne system (based on the donating
ability of the methoxy group at the para position), which
facilitates the nucleophilic attack by pyridine N-oxide to the
activated alkyne. 4q was obtained as a single regioisomer,
which further supports this hypothesis (entry 3). Substrate 1r,
which contains a sterically hindered aromatic group, was also
tested and afforded 4r as the sole product (entry 4). The
unsymmetric combination of a phenyl and a thiophenyl group
led to 4s and 4s’ in a 1:5 ratio (entry 5). As for entry 4, 1,4-
diyn-3-ols that comprise bulky groups, such as TMS (trime-
thylsilyl), TIPS (triisopropylsilyl), or tBu (tert-butyl) substitu-
ents, all afforded single regioisomers (entries 6–8). The
regioselectivity substantially decreased when the sterically
hindered group (tBu; 100% selectivity) was replaced for
a less bulky group, such as a cyclohexyl (6:1) or an n-butyl
(3:1) moiety (entries 8–10). Vinyl groups were also tolerated
in this reaction (entry 11). Furthermore, a terminal alkyne
generated 4-formylfuran 4z’ in moderate yield (entry 12).
Substrates with two different aliphatic groups (nBu and tBu)
led to a single regioisomer with the formyl group positioned
next to the less bulky group (entry 13). An ether group was
also tolerated in this furan synthesis (entry 14).
Entry
1
4
Yield[a] [%]
1
2
3
4
R=Ph (1a)
4a
4b
4c
4d
4e
4 f
4g
4h
4i
90
88
95
90
85
86
85
85
86
82
R=4-CH3C6H4 (1b)
R=4-MeOC6H4 (1c)
R=4-Me2NC6H4 (1d)
R=3,4,5-(MeO)3C6H2 (1e)
R=4-ClC6H4 (1 f)
R=4-FC6H4 (1g)
R=4-PhC6H4 (1h)
R=3-MeC6H4 (1i)
R=3-FC6H4 (1j)
5[b]
6
7
8[b]
9
10
4j
11[b]
12
4k
80
4l
86
63
13
14
R=nBu (1m)
R=H (1n)
4m
4n
[c]
–
[a] Yields of isolated products. [b] 2a (1.2 equiv) was used. [c] The
expected product was not obtained.
Table 3: Scope of the reaction for unsymmetric starting materials.
R1
R2
4, Yield[a] [%] 4’, Yield[a] [%]
Product 4e displays anti-proliferation effects against two
cancer cell lines, including a solid tumor (UACC-62, mela-
noma) and a human lymphoma (JURKAT) line.[10a] However,
based on literature precedents, this compound could only be
obtained in very low yield under harsh reaction conditions;
for example, the procedures involve a Stille coupling with
toxic tin compounds and a Vilsmeier–Haack formylation
reaction that requires high temperatures (Scheme 2a).[10] In
contrast to the literature procedures (4.4% overall yield), our
simple approach delivered this useful product in good overall
efficiency (68% overall yield; Scheme 2b).
1[b] 4-ClC6H4
Ph (1o)
Ph (1p)
4-OMeC6H4 (1q) 4q, 85
4o, 50
4p, 8
4o’, 29
4p’, 78
2
3
4
4-MeOC6H4
4-CF3C6H4
2,4,6-(CH3)3C6H2 Ph (1r)
–
–
4r, 83
5
Ph (1s)
4s, 14
4s’, 71
6
7
8
9
TMS
TIPS
tBu
Cy
Ph (1t)
Ph (1u)
Ph (1v)
Ph (1w)
Ph (1x)
4t, 60
4u, 62
4v, 90
4w, 75
4x, 63
–
–
–
4w’, 12
4x’, 20
To investigate the mechanism of this transformation, 18O-
and 13C-labeled starting materials were prepared and sub-
jected to the standard conditions of this gold-catalyzed
process. Both of the 18O and 13C labels were transferred
from the former propargylic position to the formyl group
(Scheme 3a,b). Compound 6 was independently prepared
and treated with HCl (aq) to generate the assumed inter-
mediate 1,3-diketone 7. However, 6 was rapidly converted
into 4a in the presence of HCl. 7 exists in the enol form, which
10[b] nBu
11
Ph (1y)
4y, 13
4y’, 69
12
H
Ph (1z)
nBu (1a)
–
4z’, 50
13 tBu
14 2,4,6-(CH3)3C6H2
4a, 78
4b, 83
–
–
[a] Yields of isolated products. [b] 2e (1.5 equiv) was used instead of 2a
as the oxygen donor.
1
was observed by in situ H NMR spectroscopy of a quickly
substrate was also examined and led to the corresponding 3-
formylfuran in good yield (entry 12). An aliphatic diyne
starting material such as 1m afforded the corresponding 2,5-
dibutylfuran-3-carbaldehyde (4m) under standard conditions
(entry 13). A substrate with two terminal alkynes did not give
the desired product (entry 14).
prepared sample.
Based on the labeling experiments in combination with
literature reports,[8,9] a plausible mechanism that accounts for
the novel furan synthesis is depicted in Scheme 4. In an
established process, an a-oxo gold carbenoid is generated
from 1 and pyridine N-oxide. As we propose an unprece-
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molÀ1), which indicates an irreversible and
kinetically controlled reaction. In accord-
ance with the outlined mechanism, the
transition state for the 1,2-alkyne shift
(+ 1.2 kcalmolÀ1) is lower in free energy
than that for the corresponding 1,2-hy-
dride shift process (+ 6.6 kcalmolÀ1) by
DDG* = 5.4 kcalmolÀ1 (Scheme 4). After
the 1,2-alkyne shift, intermediate C under-
goes cyclization with the ketone oxygen
atom to afford the observed 3-formylfur-
ans 4.[11]
Scheme 2. A comparison of synthetic approaches to the bioactive product 4e.
TMEDA=N,N,N’,N’-tetramethylethylenediamine.
In conclusion, we have developed an
efficient and mild gold(I)-catalyzed cas-
cade reaction that leads to 3-formylfurans
from simple starting materials. This
approach represents a significant improvement compared to
literature procedures. 18O- and 13C-labeled starting materials
were prepared to investigate the reaction mechanism.
According to isotope-labeling experiments and in agreement
with DFT calculations, a 1,2-alkynyl migration pathway was
proposed as the key step for the transformation of an a-oxo
gold carbenoid intermediate into the final product 4. To the
best of our knowledge, this is the first example of a 1,2-alkynyl
migration onto a gold carbenoid intermediate.[12]
Received: November 22, 2013
Published online: February 24, 2014
Scheme 3. Mechanistic investigations. The 18O content was deter-
mined by mass spectrometry; the 13C content was determined by mass
Keywords: alkynyl migration · cyclization · furans · gold ·
N-oxides
spectrometry and NMR analysis.
.
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