Synthesis of furans through silver-catalyzed propargyl-claisen rearrangement followed by cyclocondensation

Article abstract of DOI:10.1002/ejoc.201402983

The generation of highly substituted furans from propargyl vinyl ethers bearing a free hydroxy group was investigated. In the presence of catalytic amounts of AgBF₄, a formal [3,3] sigmatropic rearrangement takes place in the first stage of the

Full text of DOI:10.1002/ejoc.201402983

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402983
Synthesis of Furans through Silver-Catalyzed Propargyl–Claisen
Rearrangement Followed by Cyclocondensation
Adeline Palisse[a,b] and Stefan F. Kirsch*[a]
Keywords: Homogeneous catalysis / Silver / Rearrangement / Domino reactions / Oxygen heterocycles
The generation of highly substituted furans from propargyl
vinyl ethers bearing a free hydroxy group was investigated.
In the presence of catalytic amounts of AgBF4, a formal [3,3]
sigmatropic rearrangement takes place in the first stage of
the sequence. The resulting allenyl carbonyl intermediates
then undergo cyclocondensation, which upon double-bond
isomerization leads directly to the five-membered hetero-
cyclic products. This domino reaction allows the synthesis of
various tri- and tetrasubstituted furan products; an example
leading to pyrroles in an analogous way is also described.
Introduction
The development of methods for the synthesis of substi-
tuted furans is a major playground in contemporary chem-
istry: Furans can be found as structural units in many natu-
rally occurring and biologically active compounds, and they
have been recognized as important building blocks in or-
ganic synthesis and materials sciences.[1,2] In consequence,
it comes as no surprise that a plethora of highly efficient
methods for the synthesis of furans and their derivatives
have been reported in the past,[3,4] and the development of
novel methodologies is still in constant demand. A particu-
lar focus was recently put on the use of transition-metal
catalysts for a range of furan-forming cycloadditions and
cycloisomerizations.[5]
Over the last decade, noble-metal catalysts, and in par-
ticular gold catalysts, have, as a result of their carbophilic
character, become the most prominent tools for the synthe-
sis of furans through cyclization onto unsaturated C–C
bonds;[6] various types of substrates including allenyl
ketones,[7] alkynyl ketones,[8] and alkynyl alcohols[9] have
been successfully cyclized. In this context, we[10] and
others[11] studied the capability of propargyl vinyl ethers for
the flexible synthesis of furans and related heterocycles
(Scheme 1, a).[12] The domino reaction begins with a silver-
or gold-catalyzed Claisen-type rearrangement[13] that
rapidly leads to a skipped allenyl carbonyl intermediate;
subsequent 5-exo cyclization followed by isomerization then
provides the furan core.
Scheme 1. Synthesis of furans from propargyl vinyl ethers.
Herein, we show that propargyl vinyl ethers 1 having an
additional hydroxy group are also great precursor com-
pounds for the synthesis of furans (Scheme 1, b). In the
presence of silver catalysts, a propargyl–Claisen rearrange-
ment takes place first to provide allene 3;[13] then, a classical
cyclocondensation[14] followed by double-bond isomeriza-
tion is believed to produce furans 2.[15]
[a] Organic Chemistry, Bergische Universität Wuppertal,
Gaußstrasse 20, 42119 Wuppertal, Germany
E-mail: sfkirsch@uni-wuppertal.de
http://www.oc.uni-wuppertal.de/prof-dr-stefan-f-kirsch.html
[b] Galapagos NV,
Results and Discussion
Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402983.
We began our studies by investigating the conversion of
propargyl vinyl ether 1a in the presence of several noble-
Eur. J. Org. Chem. 2014, 7095–7098
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Palisse, S. F. Kirsch
SHORT COMMUNICATION
metal catalysts as summarized in Table 1. Regarding the which the Z isomer was the major isomer. To simplify the
formation of desired furan 2a, soluble silver catalysts were purification and the analysis of the furan products, several
in general superior to gold catalysts in terms of yield if furans 2 were, without purification, directly submitted to
using dichloromethane at room temperature. In complete hydrogenation [H2 (101.3 kPa), Pd/C, r.t., MeOH/EtOAc
accordance with our previous results that silver salts are (2:1)]. Table 3 shows a range of furans 5 that were easily
ideal catalysts for the propargyl–Claisen rearrangement, obtained through this two-step procedure consisting of
whereas simple Brønsted acids are less effective,[10d] hidden furan formation and hydrogenation. Reactions of starting
Brønsted acids[16] can be ruled out to trigger the overall substrates containing methyl, phenyl, or hydrogen at R3
furan-forming sequence (Table 1, entries 6 and 7): The ini- were possible; sterically demanding substituents at R2 were
tial propargyl–Claisen rearrangement appears to be cata- found to have no influence on the course of the reaction.
lyzed best by silver, but the final cyclocondensation might
be possible through the action of either the silver salts or
Table 2. Scope of the silver-catalyzed furan formation.
trace amounts of protons. The highest yields were obtained
by using AgBF4 (10 mol-%) in dichloromethane at 35 °C
(Table 1, entry 9); higher temperatures led to slightly dimin-
ished yields owing to decomposition. Although product for-
mation was observed in low yields under simple heating
conditions (Table 1, entry 8),[11e–11g] only decomposition
was found upon adding Brønsted acids at elevated tempera-
tures. Of note, we never found a dihydrofuran product
formed through a sequence in which activated allene 3 was
attacked by the secondary hydroxy upon propargyl–Claisen
rearrangement.[17] Instead, trace amounts of lactone 4 were
observed in some cases by analysis of the crude mixtures
by GC, albeit in negligible yields (Ͻ5%).
Entry
R1
R2
Product
Yield [%][a]
1
2
3
4
5
6
7
8
Ph
Et
Ph
Et
Ph
H
H
H
Me
Me
Et
Et
Ph
Ph
2b
2c
2d
2e
2f
2g
2h
2i
36
43
31[b]
56[b]
34[b]
45[c]
70
H
iBu
75[d]
Table 1. Screening of the catalysts and the conditions.
[a] Yield of isolated product after column chromatography. [b] Z/E
= 3:1. [c] Z/E = 6:1. [d] Z/E = 2:1.
Table 3. Scope of silver-catalyzed furan formation including subse-
quent hydrogenation.
Entry Catalyst (10 mol-%) Conditions
Yield [%][a]
1
2
3
4
AuCl
CH2Cl2, 3 h, r.t.
CH2Cl2, 24 h, r.t.
CH2Cl2, 24 h, r.t.
CH2Cl2, 24 h, r.t.
CH2Cl2, 24 h, r.t.
CH2Cl2, 24 h, r.t.
tBuCl, CH2Cl2, 24 h, r.t.
ClCH2CH2Cl, 24 h, 90 °C
CH2Cl2, 1 h, 35 °C
ClCH2CH2Cl, 30 min, 70 °C
CH2Cl2, 24 h, 35 °C
23
32
76
74
88
trace
9
12
91
83
87
[b]
(Ph3P)AuNTf2
AgOTf[c]
AgSbF6
AgBF4
pTsOH[d]
AgOTf
–
AgBF4
AgBF4
AgBF4
5
6
7[e]
8
Entry
R1
R2
R3
Product
Yield [%][a]
9
1
2
3
4
5
6
7
8
Me
Me
Me
Me
iBu
iBu
Ph
Et
Me
Me
Me
Me
Me
Me
Me
Me
H
5a
5j
5k
5l
5m
5i
5f
5n
5o
5p
5g
5h
72
68
66
78
64
60
30
65
33
68
53
60
10
nPr
tBu
Ph
Et
Ph
Et
Ph
Et
Et
11[f]
[a] Yield of isolated product after column chromatography. Com-
pound 2a was isolated as a mixture of E/Z isomers (entries 1 and
4, Z/E = 7:2; entry 2, Z/E = 5:1; entry 3, Z/E = 4:1; entries 5 and
9–11, Z/E = 3:1; entries 6–8, Z/E not determined). [b] (Ph3P)-
Ph
AuNTf2
phine)gold(I). [c] AgOTf
=
[bis(trifluoromethanesulfonyl)imidate](triphenylphos-
silver trifluoromethanesulfonate.
9
Me
Me
H
=
10
11
12
Ph
Me
Me
[d] pTsOH = p-toluenesulfonic acid. [e] Conditions for hidden
Brønsted acids as introduced by Hintermann et al.[16] [f] Catalyst
(2 mol-%).
Et
Ph
H
[a] Yield of isolated product after column chromatography. The re-
action time for the silver-catalyzed step was 12 h in all cases.
With the optimized conditions [AgBF4 (2 mol-%),
CH2Cl2 (0.1 m), 35 °C], we then investigated the scope of
the reaction. Table 2 demonstrates that R1 and R2 can be
To further explore how to synthesize furans with dif-
aryl, alkyl, or hydrogen if R3 = Me. Products 2 were formed ferent substitution patterns, we briefly studied the oxidative
in varying yields ranging from 31 to 75%. Typically, the cleavage of the olefinic moiety generated in the course of
furans were obtained as mixtures of diastereoisomers, for this domino strategy. As exemplified for furan 2a, the alde-
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Eur. J. Org. Chem. 2014, 7095–7098

Synthesis of Furans through Rearrangement and Cyclocondensation
AgBF4 (0.6 mg, 3.32 μmol) was added to a solution of propargyl
vinyl ether 1a (40 mg, 0.166 mmol) in dry CH2Cl2 (1.6 mL, 0.1 m).
The mixture was heated to 35 °C for 12 h. After filtration through
Celite and concentration, the residue was dissolved in dry MeOH/
EtOAc (2:1, 1.1 mL, 0.15 m), and Pd/C (10.6 mg, 4.98 μmol, 5 mol-
%) was added. The mixture was stirred at room temperature for
1 h under a H2 atmosphere. After filtration through Celite and con-
centration, the crude product was purified by flash chromatography
(cyclohexane/EtOAc = 95:5) to obtain the product (26.8 mg,
0.120 mmol, 72%). Rf = 0.74 (cyclohexane/EtOAc = 4:1) [UV/
CAM]. 1H NMR (600 MHz, CDCl3): δ = 4.27 (q, J = 7.1 Hz, 2
H), 2.53–2.45 (m, 5 H), 2.16 (s, 3 H), 1.48–1.41 (m, 2 H), 1.34 (t,
J = 7.1 Hz, 3 H), 1.33–1.28 (m, 2 H), 0.91 (t, J = 7.3 Hz, 3 H)
ppm. 13C NMR (151 MHz, CDCl3): δ = 165.0, 157.6, 146.0, 119.6,
hyde functionality was smoothly introduced in 63% yield
by using conditions developed by Nicolaou and co-workers
[Equation (1), NMO = N-methylmorpholine N-oxide].[18]
(1)
We finally envisioned to access pyrroles (rather than
furans) through the same process consisting of propargyl– 113.3, 59.7, 33.0, 24.2, 22.7, 14.4, 14.3, 14.1, 11.2 ppm. MS (EI):
m/z (%) = 224.1 (53) [M+], 195.1 (16) [M+ – Et], 182.0 (100) [M+
–
Claisen rearrangement and subsequent cyclocondensation.
To this end, amine 7 was subjected to various noble-metal
catalysts: In the presence of silver salts only trace amounts
of desired pyrrole 8 were obtained, but the use of gold(I)
chloride in 1,2-dichloroethane at 50 °C was found to be
highly efficient to produce the pyrrole core in 80% yield
[Equation (2)].
nPr], 167.0 (18) [M+ – nBu], 153.0 (88), 137.0 (58). HRMS (ESI):
calcd. for C13H21O3 [M + H+] 225.1485; found 225.1485.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, analytical data, and copies of the
1H NMR and 13C NMR spectra.
Acknowledgments
Support of this research by the Deutsche Forschungsgemeinschaft
(DFG) through grant KI 1289/1-3 is gratefully acknowledged. The
authors thank RockwoodLithium for the kind donation of chemi-
cals. A. P. thanks the Deutscher Akademischer Austausdienst
(DAAD) for a Ph.D. fellowship.
(2)
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Conclusions
In conclusion, we reported a silver-catalyzed route to
highly substituted furans through a domino sequence in-
volving Claisen-type rearrangement and cyclocondensation.
We also showed that this strategy is applicable for the syn-
thesis of pyrroles. Further work is currently underway to
expand this strategy to the synthesis of thiophenes.
Experimental Section
Synthesis of Ethyl 4-(But-1-en-1-yl)-2,5-dimethylfuran-3-carboxyl-
ate (2a) as a Representation of General Procedure A: Under a N2
atmosphere, AgBF4 (0.8 mg, 4.16 μmol) was added to a solution
of propargyl vinyl ether 1a (50.5 mg, 0.208 mmol) in dry CH2Cl2
(2.1 mL, 0.1 m). The mixture was heated to 35 °C for 12 h. After
filtration through Celite and concentration, the crude product was
purified by flash chromatography (cyclohexane/EtOAc = 95:5) to
obtain the product (40.9 mg, 0.184 mmol, 87%) as a mixture of
E/Z isomers.
Synthesis of Ethyl 4-Butyl-2,5-dimethylfuran-3-carboxylate (5a) as
a Representation of General Procedure B: Under a N2 atmosphere,
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A. Palisse, S. F. Kirsch
SHORT COMMUNICATION
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Received: July 23, 2014
Published Online: September 26, 2014
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