Gold-catalyzed carbene transfer to alkynes: Access to 2,4-disubstituted furans

Article abstract of DOI:10.1002/anie.201200307

Furans of gold: The first example of a gold-catalyzed intermolecular addition of carbon ylides to terminal alkynes is reported (see scheme; DCE=dichloroethane, Tf=trifluoromethanesulfonyl). Subsequent intramolecular trapping of the generated gold carbene completes a formal [3+2] cycloaddition, which represents a novel synthesis of 2,4-disubstituted furans. Copyright

Full text of DOI:10.1002/anie.201200307

Angewandte
Chemie
DOI: 10.1002/anie.201200307
Gold Catalysis
Gold-Catalyzed Carbene Transfer to Alkynes: Access to 2,4-
Disubstituted Furans**
Søren Kramer and Troels Skrydstrup*
Furans are common motifs in biologically active compounds
and therefore significant efforts have been made to synthesize
this heteroaromatic ring.[1] 2,4-Disubstituted furans possess an
interesting substitution pattern, which is difficult to access
synthetically, and the most common routes to such com-
pounds rely on intramolecular rearrangements of complex
motifs.[2–4] The development of an intermolecular approach
whereby the two substituents originate from different
reagents that can combine in one step to form the aromatic
core with complete regiocontrol would allow for a more direct
route to the assembly of these furans, potentially with higher
diversity.
Homogenous gold catalysis has been a rapidly growing
field in synthetic organic chemistry within the last decade.[5,6]
The discovery of the formation of gold carbenes through
intra- and intermolecular oxygen transfer has led to the
development of a number of new synthetic transformations.[7]
The generation of a-oxo gold carbenes from alkynes is
a promising alternative to the generation of a-oxo metal
carbenes from hazardous a-diazo ketones. Few examples
have been reported on the intramolecular nitrogen ana-
logue,[8] and the use of intermolecular nitrene transfer has
only been recently demonstrated.[9] On the other hand, there
are no examples of the use of intermolecular carbene transfer
to alkynes for the generation of gold carbenes. This reactivity
would represent a considerable extension of this type of
gold(I) chemistry because it would allow for highly valuable
We hypothesized that carbon ylides would represent the
required carbene equivalent, and would be analogous to the
oxygen and nitrogen ylides used for oxygen and nitrene
transfer, respectively. A variety of carbon ylides are available.
We decided to focus on ylides stabilized by a carbonyl group
for two reasons: 1) their relatively high stability would
facilitate the handling and storage of the ylide, and 2) the
carbonyl group could potentially trap the generated gold
carbene intramolecularly.[10] We believed that the addition of
the ylides to the terminal alkynes would be highly regiose-
lective, and thus we envisaged the application of this carbene
transfer/gold carbene formation as an entry to 2,4-disubsti-
tuted furans (Scheme 2).
Scheme 2. Gold carbene formation through carbene transfer for the
synthesis of 2,4-disubstituted furans.
The treatment of a solution of 1-octyne (1a) in DCE with
two equivalents of the sulfur ylide 2a and 5 mol% of Gagoszꢀs
catalyst [(Ph3P)AuNTf2] afforded furan 3a in 63% yield after
stirring at 608C for 22 hours (Table 1, entry 1).[11–14] The
reaction appeared to be unaffected by the concentration of
the reagents because lowering the alkyne concentration from
0.4m to 0.1m had no effect on the product yield (Table 1,
entry 2). When toluene or acetonitrile was used as the solvent,
the yields were lower than that obtained with DCE (Table 1,
entries 3 and 4). When the alkyne/ylide ratio was changed
(Table 1, entries 5 and 6) or the reaction temperature was
decreased or increased (Table 1, entries 7 and 8), the yield
was also lowered. The use of the catalyst with the NTf2
counter anion gave the furan product in better yield than
the use of the catalyst with the OTf counter anion (Table 1,
entries 1 and 9). However, the presence of silver chloride,
which is generated when these catalysts were made in situ,
appeared to be detrimental to the reaction (Table 1, entries 10
and 11). Indeed, the yield dropped significantly when 7 mol%
of AgCl was added together with the otherwise active
[(Ph3P)AuNTf2] (Table 1, entry 13). Other catalysts, including
AgNTf2, PtCl2, [PicAuCl2], [JohnPhosAu(MeCN)]SbF6,
[XPhosAuNTf2], [SPhosAuNTf2], and [IPrAuNTf2] provided
less than 5% yield of the furan 3a.[15] The high sensitivity of
the reaction toward the presence of a silver salt and variation
of the ligand is intriguing.
À
C C bond formation (Scheme 1).
Scheme 1. General scheme for gold-catalyzed addition of ylides to
alkynes. LG=leaving group.
[*] S. Kramer, Prof. Dr. T. Skrydstrup
Center for Insoluble Protein Structures, Department of Chemistry
Interdisciplinary Nanoscience Center, Aarhus University
Langelandsgade 140, 8000 Aarhus C (Denmark)
E-mail: ts@chem.au.dk
[**] We appreciate the generous financial support from the Danish
National Research Foundation, H. Lundbeck A/S, the Carlsberg
Foundation, the OChem Graduate School, and Aarhus University.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200307.
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Table 1: Optimization of the catalytic system.
column chromatography and they were significantly more
stable than the dimethyl ylide 2b.[17]
A variety of substituents on the aryl moiety of the ylide
were tolerated in this formal [3+2] cycloaddition (Table 3).
The presence of a halide (Table 3, entries 2–4), a nitrile
(Table 3, entry 5), a nitro (Table 3, entry 6), and an ester
Entry
Modification
Yield [%][a]
1
2
3
4
5
6
7
8
none
0.1m
toluene
MeCN
1.5 equiv ylide
2.5 equiv ylide
508C
808C
63
62
33
39
47
56
35
49
39
11
15
6
Table 3: Furan synthesis with different sulfur ylides.
Entry
Ylide
Product
Yield
[%][a]
9
[(Ph3P)AuOTf]
10
11
12
13
14
[(Ph3P)AuCl]/AgOTf
[(Ph3P)AuCl]/AgNTf2
[(Ph3P)AuCl]
[(Ph3P)AuNTf2] (5 mol%)/AgCl (7 mol%)
no catalyst
1
2
3
4
5
6
63
73
65
54
64
57
4
0[b]
[a] Yield of product after column chromatography. [b] Observed by
1H NMR analysis of the crude reaction mixture. DCE=1,2-dichloro-
ethane, Hex=hexyl, Tf=trifluoromethylsulfonyl.
Table 2: Optimization of the sulfur ylide.
Entry
R
Yield [%][a]
1
2
3
4
5
Me (2b)
4-MeOC6H4 (2c)
C6H5 (2a)
4-ClC6H4 (2d)
4-FC6H4 (2e)
24
50
63
64
67
7
73
[a] Yield of product after column chromatography.
With the optimized reaction conditions established, we
turned our attention toward fine-tuning the sulfur ylide
(Table 2). Reactions using aryl ylides (Table 2, entries 2–5)
gave significantly better yields than those of the dimethyl
ylide (Table 2, entry 1). Within the methyl aryl ylide series, the
use of an ylide bearing an electron-donating group on the aryl
substituent of the sulfur atom (Table 2, entry 2) led to a lower
yield than the use of ylides bearing electron-withdrawing
groups (Table 2, entries 4 and 5). Attempts to prepare the
more electron poor pentafluorophenyl sulfur ylide derivative,
the more sterically hindered 2,6-dimethylphenyl derivative,
and the diphenyl sulfur ylide derivative were unsuccessful.
Furthermore, the use of the corresponding pyridinium ylide,
under the same reaction conditions, did not provide any of the
furan. Although the use of p-fluorophenyl derivative 2e gave
slightly higher yields than the use of the simple phenyl
derivative 2a, variation of the latter was chosen as a means for
investigating the substrate scope because of its significantly
lower price (approximately 40 times cheaper).[16]
8
36
9
59
10
51[b]
[a] Yield of product after column chromatography. [b] The reaction was
performed at 848C.
group (Table 3, entry 7) were tolerated. Whereas the furan
with a methyl substituent on the aryl moiety (Table 3, entry 8)
was synthesized in relatively low yield, the naphthyl substi-
tuted furan was synthesized in good yield (Table 3, entry 9).
Furthermore, the ylide derived from a t-butyl ketone, 2n, was
also tolerated, however, a higher temperature was required
for the reaction to occur (Table 3, entry 10).
The methyl phenyl ylides 2 f–n were easily prepared from
the corresponding a-bromo ketones without the use of
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The tolerance of the reaction toward variation of the
substituent on the alkyne was then examined (Table 4).
Variation of the alkyl length or the presence of cycloalkyl
substituents did not adversely affect the yields (Table 4,
entries 1–3). However, a small amount of the 2,5-substituted
regioisomer was observed in the case of the cyclohexyl
substituted alkyne 1d, presumably because of the increased
steric bulk (Table 4, entry 3). The presence of silyl and alkyl
ethers was also tolerated (Table 4, entries 4 and 5). Surpris-
ingly, a slight decrease in yield was observed when using an
alkyne bearing an ester substituent (Table 4, entry 6); this
result is in contrast to the relatively good yields that were
obtained when ester substituents were part of the ylide
(Table 4, entries 2, 7, and 8, and Table 3, entry 7). The use of
alkynes bearing a sulfonamide (Table 4, entry 7) or a carba-
mate (Table 4, entry 8) also provided the corresponding furan
in high yields. Interestingly, for the sulfonamide derivative,
when the standard 2.0 equivalents of ylide was used, the furan
3q was obtained in 53% yield, however, 26% of alkyne 1h
was recovered. This amounts to a 72% yield based on
recovered starting material. Increasing the amount of the
ylide to 2.5 equivalents only increased the yield slightly to
57% (Table 4, entry 7).
The use of an alkyne bearing a primary chloride also
afforded the desired furan, albeit in moderate yield (Table 4,
entry 9). Under the same reaction conditions, however, the
use of phenylacetylene or the internal alkynes, 2-octyne, and
ethyl 3-phenylpropiolate, did not lead to any of the corre-
sponding furans. It would therefore appear that this trans-
formation is selective for terminal alkynes over internal
alkynes.
Table 4: Furan synthesis with different alkynes.
A mechanistic proposal for this furan synthesis is depicted
in Scheme 3. Activation of the alkyne by gold(I) would be
followed by a highly regioselective nucleophilic attack by the
ylide, thus leading to the vinyl gold intermediate 4. Back
donation from the gold center would lead to the liberation of
Entry
1
Alkyne
Product
Yield
[%][a]
62
82
2
3
61[b]
Scheme 3. Mechanistic proposal for the 2,4-disubstituted furan syn-
thesis.
4
5
6
67
78
48
the leaving group with concurrent generation of an allylic
gold carbene. This carbene would then be trapped intra-
molecularly by the carbonyl oxygen and a subsequent elim-
ination of the gold catalyst would furnish the 2,4-disubstituted
furan. A 5-endo-trig SN2’ cyclization of 4, can also account for
product formation, however, because it is a disfavored ring
formation according to Baldwinꢀs rules, we believe that this
pathway is less likely.[18]
7
57[c]
In summary, we have developed a reaction involving the
first example where a gold carbene is formed through carbene
transfer to an alkyne. An ensuing intramolecular trapping of
the gold carbene affords the nontrivial 2,4-disubstituted
furans in good to high yields; the entire transformation
represents a formal [3+2] cycloaddition. The use of carbon
ylides as nucleophiles in this work represents a significant
expansion of the intermolecular gold carbene formation
chemistry, which previously included the use of oxygen and
nitrogen ylides. Further studies on the addition of carbon
ylides to alkynes using gold catalysis are underway.
8
9
69
30
[a] Yield of product after column chromatography. [b] Isolated as 96:4
mixture of regioisomers (2,4-substituted/2,5-substituted). [c] 2.5 equiv-
alents of ylide. Bn=benzyl, Piv=pivaloyl, TIPS=triisopropylsilyl.
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Experimental Section
In an argon-filled glove box [(Ph3P)AuNTf2]·1= toluene (5 mol%,
2
5 mmol, 7.9 mg), sulfur ylide 2a (2.0 equiv, 0.400 mmol, 96.9 mg),
DCE (0.5 mL), and 1-octyne (1a; 1.0 equiv, 0.200 mmol, 29.8 mL)
were added to a vial. The vial was sealed and the reaction mixture was
stirred for 22 h at 608C. The reaction mixture was then cooled to room
temperature and was directly purified by flash chromatography on
silica gel using 100% pentane as the eluent, thus affording the desired
furan (3a) in 63% yield (29 mg) as a colorless solid.
Received: January 12, 2012
Keywords: alkynes · cycloaddition · furans · gold · sulfur ylides
.
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Equivalent results were obtained using the [(Ph3P)AuNTf2]·1=
2
toluene complex purchased from Sigma – Aldrich and a toluene-
free [(Ph3P)AuNTf2] complex made by our research group.
[15] These catalysts were added as the active complex, not made
in situ with silver salts. Additional inactive catalytic systems are
provided in the Supporting Information.
[16] Prices of thiophenol and 4-fluorothiophenol from Sigma-
Aldrich.
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