Synthesis of 2-acylfurans from 3-(1-alkynyl)-2-alken-1-ones via the oxidation of gold-carbene intermediates by H2O2

Article abstract of DOI:10.1039/c0dt00024h

An efficient approach to 2,4,5-trisubstituted 2-acylfurans is described: treating 3-(1-alkynyl)-2-alken-1-ones with AuCl₃ in DCM at rt in the presence of H₂O₂ afforded good yields of 2-acylfurans.

Full text of DOI:10.1039/c0dt00024h

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Synthesis of 2-acylfurans from 3-(1-alkynyl)-2-alken-1-ones via the oxidation
of gold–carbene intermediates by H2O2†
Tao Wang and Junliang Zhang*
Received 11th December 2009, Accepted 5th March 2010
First published as an Advance Article on the web 8th April 2010
DOI: 10.1039/c0dt00024h
Table 1 Scope of oxidantsa
An efficient approach to 2,4,5-trisubstituted 2-acylfurans is
described: treating 3-(1-alkynyl)-2-alken-1-ones with AuCl3
in DCM at rt in the presence of H2O2 afforded good yields of
2-acylfurans.
Polysubstituted furans play an important role in organic chemistry,
not only as key structural units in many natural products and
important pharmaceuticals, but also as useful building blocks
in synthetic chemistry.1-2 Therefore, the development of new
approaches to polysubstituted multi-functionalized furans from
Yield (%)b
readily available starting materials still represents a continuing
goal in the synthetic community.3 Most recently, metal-catalyzed
Entry
Oxidant
O2
Time/h
2a
3
transformations have been reported among the cyclization of
3-alkyn-1-ones,4-5 allenyl ketones,5 2-(1-alkynyl)-2-alken-1-ones6
and (Z)-2-en-4-yn-1-ols7 or cycloisomerization of alkylidenecyclo-
propyl ketones8/cyclopropenyl ketones.9 Several examples for the
synthesis of 2-acylfurans catalyzed by metals have been reported.10
However, these methods often present low yield or require multi-
step synthetic transformations.
1
2
20
0.5
NDc
86
93
NDc
3
4
0.5
0.5
15
79
74
Very recently, our group focused on developing novel reactions
of 2-(1-alkynyl)-2-alken-1-ones for the synthesis of highly substi-
tuted furans.11 During this course, we have become interested in
the chemistry of 3-(1-alkynyl)-2-alken-1-ones. Herein we report a
novel efficient, general gold-catalyzed oxidative cyclization of 3-
(1-alkynyl)-2-alken-1-ones leading to trisubstituted 2-acylfurans.
As indicated in Table 1, we started our studies by treating 3-
(3-phenylprop-2-ynylidene) pentane-2,4-dione (1a) with various
oxidants in the presence of Ph3PAuCl and AgOTf in DCM. First,
we tested O2 as the oxidant. However, the reaction gave a Z/E
mixture of furyl dimer 3 in 93% yield rather than the expected acyl
furan 2a (entry 1). Fortunately, other oxidants such as sulfoxides
and nitrogen oxides12 gave the expected 2-acylfuran 2a in 15–86%
yield (entries 2–5). For example, when the diphenyl sulfoxide12b
(entry 2) or (Z)-N-(4-nitrobenzylidene)aniline oxide12c (entry 4)
was used as oxidant, the reaction afforded 2a in 86% and 79%
yields, respectively. Further studies showed that environmentally
friendly 30% H2O2 also works well to give 2a in a relatively
lower yield (entry 6). Since the by-product of the H2O2-oxidation
reaction is H2O, it is much greener than other oxidants. Thus, we
next turned our examination on screening different catalysts and
NDc
5
6
10
20
63
69
Trace
Trace
H2O2
a Unless otherwise noted, reactions were performed with 0.5 mmol of 1a,
0.75 mmol of oxidant, and 5 mol% of Ph3PAuCl and 5 mol% of AgOTf in
5.0 mL DCM at rt. b Yield of isolated product. c No product was detected.
the results are summarized in Table 2. The structures of 2a and 3
were confirmed by the X-ray crystallographic analysis (Fig. 1).13
Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
Department of Chemistry, East China Normal University, 3663 N. Zhong-
shan Road, Shanghai, 200062, China. E-mail: jlzhang@chem.ecnu.edu.cn;
Fax: (86)-21-6223-5039
† Electronic supplementary information (ESI) available: Complete ex-
perimental procedures and characterization data for all new com-
pounds. CCDC reference numbers 755496 and 755497. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0dt00024h
Fig. 1 ORTEP representation of 2a and (Z)-isomer of 3.
When three equivalents of H2O2 (30%) were used, the reaction
gave a higher yield when using the same catalyst Ph3PAuCl/AgOTf
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a
Table 2 Screening conditions for the tandem reaction of 1a with H2O2
Entry
Catalyst
Solvent
H2O2 (equiv)
Time/h
Yield (%)b
1
2
3
4
5
6
7
8
Ph3PAuCl/AgOTf
Ph3PAuCl
AgOTf
AgSbF6
Cu(OTf)2
AuCl3
AuCl3
AuCl3
AuCl3
AuCl3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
3
3
3
3
3
3
1.5
3
3
20
24
24
20
6
2
3
24
24
24
76
23c
50c
32c
NR
88 (85)c
83
48d
85
64
9
10
Toluene
DMF
3
a Unless otherwise noted, reactions were performed with 0.5 mmol of 1a, 1.5 mmol of oxidant, and 5 mol% of catalyst in 5.0 mL DCM at rt. b Yield of
isolated product. c 3 mol% of AuCl3 was used. d Furyl dimer were formed determined by TLC analysis.
(entry 1 in Table 2, comparing with entry 6 in Table 1). Interest-
ingly, a silver(I) complex can also catalyze this reaction, but gives
lower yields (entries 3–4). Cu(OTf)2 is not effective for this reaction
(entry 5). Finally, AuCl3 was found to be the most effective catalyst
providing 2a in 88% yield within 2 h in DCM (entry 6). When H2O2
was reduced to 1.5 equivalents, the yield decreased slightly to 83%
(entry 7). Other solvents failed to improve the yield (entries 8–10).
Under the optimal conditions, a wide variety of 3-(1-alkynyl)-
2-alken-1-ones were examined and the results are summarized
in Table 3. The substitute (R1) on the alkynes can be aromatic
or aliphatic groups. For example, the reaction of 1f afforded 2-
acylfuran 2f in 63% yield (entry 5), in this case, 10 equivalents
of H2O2 were used due to the potential b-hydride migration of
the metal–carbene intermediate.14 R2, R3 could also be aryl or
alkyl groups. When they were the same groups, excellent yields
of the single product were obtained (entries 6–7). But if R2 and
R3 are alkyl and phenyl groups respectively, the Z-isomer of 1i
afforded a single product 2i (entry 8) and the E-isomer gave a
mixture of products 2i and 2i¢ (entry 9), indicating that the E-
isomer could be converted into the Z-isomer in the presence of the
gold catalyst.15 Moreover, when the reaction of (E)-1i with H2O2
was carried out at 0 ◦C, the yield of 2i increased to 37%. When one
of R2 and R3 is an alkoxy group, both the E-isomer and Z-isomer
of the substrates could be converted into 2-acylfurans 2 under
the reaction conditions. For example, both the reactions of (E)-1j
and (Z)-1j gave the same product 2j (entry 11, 2j¢ = entry 10, 2j),
albeit the latter one gave a relatively lower yield (entries 10–11).
The phenylsulfonyl-substituted substrate 1l could also afford 2-
acylfuran 21 in 79% yield under the reaction conditions (eqn (1)).
Table 3 Au(III)-catalyzed oxidative cyclization of 1a
(1)
Enyne 1
R1, R2/R3
Entry
Time/h
Isolated yield (%)
A proposed mechanistic pathway is shown in Scheme 1.
The AuCl3 coordination of the triple bond of 1 enhances the
electrophilicity of the alkyne. Subsequent nucleophilic attack of
the carbonyl oxygen to the gold-activated alkyne would form
intermediate B, which was then converted into the gold–carbene
intermediate C. In the presence of H2O2, the gold–carbene C would
produce the 2-acylfuran and regenerate the catalyst to finish the
catalytic cycle.16 If R3 is an alkoxy group, the reaction still could
give the product but structured as 2¢ due to the isomerization of
the substrate in the presence of the gold catalyst.15
To further confirm the formation of gold–carbene intermediate
C in the reaction, styrene was added instead of H2O2 (eqn (2)).17
The reaction afforded the expected cyclopropane 4 via gold–
carbene cyclopropanation in 56% yield as a mixture of two
diastereomers (1/1.2).
1
2
3
4
5
6
7
8
4-MeOPh/Me/Me (1b)
4-MePh/Me/Me (1c)
4-NO2Ph/Me/Me (1d)
1-naphthyl/Me/Me (1e)
n-Bu/Me/Me (1f)b
Ph/Et/Et (1g)
17
11
10
14.5
8
3.5
10
12
12
36
53
16
2b (74)
2c (84)
2d (82)
2e (64)
2f (63)
2g (83)
2h (87)
2i (89)
Ph/Ph/Ph (1h)
Ph/Me/Ph ((Z)-1i)
Ph/Ph/Me ((E)-1i)
Ph/MeO/Me ((E)-1j)
Ph/Me/MeO ((Z)-1j)
Ph/EtO/Ph (1k)
9
2i (23), 2i¢(57)c
2j (80)
10
11
12
2j¢ (66)
2k (73)
a Unless otherwise noted, reactions were performed with 0.5 mmol of 1,
1.5 mmol of H2O2 (30%) and 5 mol% of AuCl3 in 5.0 mL DCM at rt.
b 10 equivalents of H2O2 were used. c When the reaction was carried out at
0 ◦C, the yield of 2i and 2i¢ was 37% and 44%, respectively.
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Table 4 Oxidative rearrangement of propargyl estersa
Entry
Catalyst
Solvent
Time/h
Yield (%)b
Z/E
1
AuCl3
AuCl3
AuCl3
AuCl3
DCM
DCE
DCE
Toluene
DCM
21
10
10
10
0.5
65
90/10
78/22
90/10
38/62
86/14
2
77(65c)
79
3d
4
60
50
5
AuCl3/AgOTf
a Unless otherwise noted, reactions were performed with 0.5 mmol of 1a, 1.5 mmol of H2O2, and 5 mol% of catalysts in 5.0 mL DCM at rt. b NMR yield.
c Isolated yield. d 0.75 mmol H2O2 was used.
program (2009CB825300) and Shanghai Shuguang Program
(07SG27).
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(2)
Pleasingly, this H2O2–AuCl3 system could be applied in other
gold–carbene involved reactions. For example the oxidative re-
arrangement of propargyl ester 5 could give aldehyde 6 in a
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cyclization of 3-(1-alkynyl)-2-alken-1-ones, in which H2O2 acts as
an efficient and green oxidant for gold–carbene intermediate. This
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Acknowledgements
This research was supported by the National Natural Science
Foundation of China (20702015, 20972054), Shanghai Munici-
pal Committee of Science and Technology (08dj1400-101), 973
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