Silver(I)-catalyzed cascade: Direct access to furans from alkynyloxiranes

Article abstract of DOI:10.1021/jo900483m

(Chemical Equation Presented) Functionalized furans are conveniently formed by a new silver(I)-catalyzed reaction of alk-1-ynyl oxiranes in the presence of p-toluenesulfonic acid and methanol. Evidence supported a cascade mechanism.

Full text of DOI:10.1021/jo900483m

Silver(I)-Catalyzed Cascade: Direct Access to
Furans from Alkynyloxiranes
SCHEME 1. Two-Step Ag-Promoted Synthesis of Furans
14
and Dihydrofurans from Epoxyalkynols
Aur e´ lien Blanc, Katharina Tenbrink, Jean-Marc Weibel, and
Patrick Pale*
Laboratoire de Synth e` se et R e´ actiVit e´ Organiques, associ e´
au CNRS, UniVersit e´ de Strasbourg, Institut de Chimie,
4
rue Blaise Pascal, 67000 Strasbourg, France
ppale@chimie.u-strasbg.fr
ReceiVed March 4, 2009
almost never applied to a one-step formation of furans and
only two methods, both reported by Marshall, have been
described. The first one was based on the cyclization of
9
allenones using a catalytic amount of silver nitrate in
1
0
acetone. The second one used the combination of silver
nitrate and silica gel to cyclize ꢀ-methylene alkynols afford-
1
1
ing furans in high yields. Very recently, these conditions
were applied to the synthesis of furans from 3-alkyne-1,2-
12
13
Functionalized furans are conveniently formed by a new
silver(I)-catalyzed reaction of alk-1-ynyl oxiranes in the
presence of p-toluenesulfonic acid and methanol. Evidence
supported a cascade mechanism.
diols orgem-difluorohomopropargylalcohols inacyclization-
1
4
elimination process. Some years ago, our group reported a
two-step approach to furans based on the cyclization of
epoxyalkynols and nucleophilic addition (Scheme 1), and
taking advantage of the mild Lewid acid properties of silver
ion, we wondered if a one-pot procedure could be amenable.
I
Furans are important compounds in organic chemistry as
such motifs occur in many natural products, as well as in
various pharmaceutical products and flavor and fragrance
compounds. Furans also act as key building blocks in the
In the presence of Ag , a nucleophile would open the epoxide
N N
either in a S 2 process or in a S 2′ process, leading to an
I
allenol or an alkynol. Both cyclized in the presence of Ag
and produced dihydrofurans (Scheme 2).
1
Although known with copper, palladium, and gold,8d-f,16
15
4a
synthesis of numerous substances. Due to such wide interest,
1
,2
several furan syntheses have already been developed, but
any new synthetic method able to provide highly substituted
furans under mild conditions would be particularly valuable.
Among the developed methods, the cyclization or rear-
rangement of allene or alkyne derivatives catalyzed by late
transition metals is particularly interesting due to conver-
nucleophilic additions to alkynyloxiranes appeared to be
9
unprecedented with silver. This lack of results incited us to
17
examine the reactivity of readily available R-alkynyl epoxides
(6) (a) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005,
127, 15022–15023. (b) F u¨ rstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005,
127, 15024–15025. (c) F u¨ rstner, A.; Heilmann, E. K.; Davies, P. W. Angew.
Chem., Int. Ed. 2007, 46, 4760–4763.
3
gence. Mercury was originally proposed for such cyclization,
but toxicity and compatibility with functional groups led to
(7) Hashmi, A. S. K.; Pradipta, S. AdV. Synth. Catal. 2004, 346, 432–438.
4
(8) (a) Hashmi, A. S. K.; Schwarz, L.; Choi, J. H.; Frost, T. M. Angew.
the use of palladium as catalyst. Platinum was more recently
5
,6
Chem., Int. Ed. 2000, 39, 2285–2288. (b) Yao, T.; Zhang, X.; Larock, R. C.
J. Am. Chem. Soc. 2004, 126, 11164–11165. (c) Yao, T.; Zhang, X.; Larock,
R. C. J. Org. Chem. 2005, 70, 7679–7685. (d) Shu, X.-Z.; Liu, X.-Y.; Xiao,
H.-Q.; Ji, K.-G.; Guo, L.-N.; Qi, C.-Z.; Liang, Y.-M. AdV. Synth. Catal. 2007,
explored as catalyst for such reactions, but gold exhibited
7
,8
higher flexibility due to its mildness. Surprisingly, silver
salts, inexpensive compared to gold or platinum salts, were
3
49, 2493–2498. (e) Ji, K.-G.; Shen, Y.-M.; Shu, X.-Z.; Xiao, H.-Q.; Bian, Y.-
J.; Liang, Y.-M. AdV. Synth. Catal. 2008, 350, 1275–1280. (f) Dai, L.-Z.; Shi,
(
1) (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795–819. (b) Hou, X. L.;
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Trans. 1 2001, 2491–2515.
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A. P.; Pale, Chem. ReV. 2008, 108, 3149–3173. (b) Alvarez-Corral, M.; Munoz-
Dorado, M.; Rodriguez-Garcia, I. Chem. ReV. 2008, 108, 3174–3198. (c)
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V.; Pale, P. Tetrahedron Lett. 1996, 37, 2781–2784. (c) Chuche, J.; Pale, P.
Eur. J. Org. Chem. 2000, 1019–1025.
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Lett. 1989, 30, 2387–2390. (b) Alexakis, A.; Marek, I.; Mangeney, P.; Normant,
J. F. Tetrahedron 1991, 47, 1677–1686.
(
2) (a) Eicher, T.; Hauptmann S. The Chemistry of Heterocycles, 2nd ed.;
Wiley-VCH: Weinheim, 2003. (b) Bird, C. W. In ComprehensiVe Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven E. F. V., Eds.; Elsevier
Science Ltd.; Oxford, 1996; Vol. 2.
(
(
3) Miller, D. J. Chem. Soc. C 1969, 12–15.
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1
987, 334, 225–242. (b) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. J.
Org. Chem. 1991, 56, 5816–5819. (c) Hashmi, A. S. K. Angew. Chem., Int. Ed.
995, 34, 1581–1583. (d) Seiller, B.; Bruneau, C.; Dixneuf, P. H. Tetrahedron
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Lu, L. H. Chem.sEur. J. 2003, 9, 2447–2456.
1
1
(
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5
021–5023.
4
360 J. Org. Chem. 2009, 74, 4360–4363
10.1021/jo900483m CCC: $40.75  2009 American Chemical Society
Published on Web 04/28/2009

SCHEME 2. Proposed Ag-Catalyzed Transformations of
Alkynyloxiranes to Dihydrofurans and/or Furans
SCHEME 3. Ag-Promoted Formation of Furan from
ꢀ-Methoxy-ꢀ-alkynol
and the presence of an aromatic moiety, suggesting a
tetrahydrobenzofuran structure for 2a. As expected, methanol
acted as nucleophile in this reaction, but it seemed that the
expected dihydrofuran was not stable under these conditions
and aromatization occurred leading to the observed furan (cf.
Schemes 2 and 3).
TABLE 1. Screening of Reaction Conditions for the
Transformation of the Alkynyl Oxirane 1a
The more electrophilic and soluble silver triflate alone
surprisingly proved effective enough in dichloromethane to
cleanly convert 1a into the furan 2a, although in modest and
19
variable yields (entry 4). As expected, the addition of methanol
as nucleophile dramatically increased the conversion, and 2a
was isolated in good yield (entry 5). Running the reaction in
pure methanol did not improve yield (entry 6).
Switching to the even more electrophilic silver hexafluoro-
antimonate and triflimido salt led to complete conversion in
dichloromethane in the presence of methanol, providing the
same compound 2a but in moderate yields due to some
degradation (entries 7 and 8).
In order to improve the efficiency of the reaction, we screened
several cocatalysts, which could facilitate the oxirane opening
without altering the silver catalyzed cyclization. We eventually
found that p-toluenesulfonic acid was the best compromise. In
the presence of 5 mol % of this acid and 5 mol % of silver
triflate, 1a was efficiently converted to the furan 2a in a mixture
of dichloromethane and methanol (entry 9). Control experiments
with p-toluenesulfonic acid alone revealed that almost no
reaction occurred without silver salt or methanol (entry 12).
However, and as expected, p-toluenesulfonic acid alone in pure
methanol or in mixtures of dichloromethane and methanol led
to the epoxide opening product (entry 13; see below). Under
the best conditions (entry 9), increasing or lowering the
temperature did not further improve the reaction and proved
even deleterious, the yield of furan being lowered (entries 10
and 11).
b
yield
time (h) (%)
a
entry catalyst (mol %)
conditions
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
AgCl (5)
CH
CH
2
Cl
Cl
2
2
(dry), rt
(dry), rt
MeOH, rt
24
24
24
24
24
24
24
24
24
24
24
24
0.5
24
24
0
0
AgNO
AgNO
3
(5)
(5)
2
d
c
3
40
20
73
72
55
41
80
55
AgOTf (5)
AgOTf (5)
AgOTf (5)
CH
CH
2
Cl
Cl
2
(dry),rt
/MeOH (9/1), rt
2
2
MeOH, rt
d
d
AgSbF
AgNTf
6
(5)
(5)
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
2
/MeOH (9/1), rt
/MeOH (9/1), rt
/MeOH (9/1), rt
/MeOH (9/1), -78 °C
/MeOH (9/1), 40 °C
(dry), rt
2
AgOTf/p-TsOH (5/5) CH
AgOTf/p-TsOH (5/5) CH
AgOTf/p-TsOH (5/5) CH
p-TsOH (5)
p-TsOH (5)
0
1
2
3
4
5
d
Traces
0
CH
e
MeOH, rt
0
23
35
AgOTf/p-TsOH (5/5) CH
AgOTf/TsOH (5/5) CH
2
Cl
Cl
2
/EtOH (9/1), rt
/t-BuOH (9/1), rt
2
2
a
b
Reactions run under argon, c ) 0.1 mol/L. Yields of 2a were
calculated from H NMR spectra relative to an internal standard
hexamethylbenzene). Depending on AgOTf source, variations in yield
were noticed, see ref 19. Degradation occurred leading to unidentified
1
c
(
d
e
byproduct. Product resulting from epoxide opening (see Scheme 3) was
obtained.
in the presence of silver salts. We report here that highly
substituted furans were easily obtained by silver-catalyzed
transformation of alkynyloxiranes in the presence of alcohols.
In order to find more appropriate conditions for the reaction,
we applied various conditions and silver catalysts to the readily
Other hydroxy nucleophiles did not give satisfactory results
under the same conditions. A rapid screening confirmed that
18
available 1-(hex-1-ynyl)-1,2-epoxycyclohexane 1a in the pres-
ence or absence of alcohol (Table 1).
20
bulkier alcohols are less efficient (entries 14 and 15).
With these conditions in hand, we briefly investigated the
scope of this new formation of furans. Various representative
alkynyl oxiranes 1b-k, easily prepared by m-CPBA epoxidation
of the corresponding enynes, were then submitted to the above
conditions (Table 2).
The six-membered hexynyl epoxide 1a was used as reference
for comparison purposes (entry 1), and the ring size as well as
the alkyne side chain were varied. With the strained five-
membered derivative 1b, we expected an easier reaction.
However, degradation mostly occurred, and the expected product
could be barely detected (entry 2). The seven-membered
derivative 1c behaved as the six-membered 1a, but the furan
formation was slightly less effective (entry 3 vs 1). With the
eight-membered derivative 1d, the expected furan 2d was
isolated in excellent yield (entry 4 vs 1).
Silver chloride alone did not promote any transformation,
and the starting material 1a was recovered even after
prolonged contact time (entry 1). The same observations were
gained with silver nitrate (entry 2). However, in pure
methanol, a new compound 2a was produced in reasonable
yield (entry 3). Spectroscopic data of this new compound
revealed the disappearance of the epoxide and acetylenic units
(
16) (a) Dai, L.-Z.; Qi, M.-J.; Shi, Y.-L.; Liu, X.-G.; Shi, M. Org. Lett. 2007,
, 3191–3194. (b) Shu, X.-Z.; Liu, X.-Y.; Ji, K.-G.; Xiao, H.-Q.; Liang, Y.-M.
9
Chem.sEur. J. 2008, 14, 5282–5289. (c) Hashmi, A. S. K.; B u¨ hrle, M.; Salath e´ ,
R.; Bats, J. W. AdV. Synth. Catal. 2008, 350, 2059–2064. (d) Lin, G.-Y.; Li,
C.-W.; Hung, S.-H.; Liu, R.-S. Org. Lett. 2008, 10, 5059–5062. (e) Dai, L.-Z.;
Shi, M. Chem.sEur. J. 2008, 14, 7011–7018.
17) For a review of alkynyloxirane preparations, see: Chemla, F.; Ferreira,
F. Curr. Org. Chem. 2002, 6, 539–570.
18) Compound 1a was obtained following Carlson’s procedure: Carlson,
R. G.; Cox, W. W. J. Org. Chem. 1977, 42, 2382–2386.
19) Traces of water or alcohols contained in the solvent or the reagents
(
(
(
were probably responsible for catalysis of this reaction (see Scheme 4), and
carefully dried solvent and reagents have to be used to miminize it.
(20) Nucleophiles based on other heteroatoms probably poisoned the catalyst,
while carbon nucleophiles are currently explored.
J. Org. Chem. Vol. 74, No. 11, 2009 4361

TABLE 2. Scope of the Ag- and Acid-Catalyzed Rearrangement
of Alkynyloxiranes to Furans
SCHEME 4. Proposed Mechanism for the Ag- and
Acid-Catalyzed Rearrangement of Alkynyloxiranes to
Furans
Finally, the simplest ethynyl derivate 1k only led to decom-
position, probably due to the formation of alkynylsilver under
these conditions (entry 11).
As the present Ag- and acid-catalyzed rearrangement of
alkynyloxiranes to furans probably involved the intermediate
opening of the starting alkynyloxiranes (cf. Scheme 2), we
prepared such products and checked whether they indeed can
be cyclized into furans by catalytic amounts of silver triflate.
The 1,2-epoxyhex-1-ynylcyclohexane 1a was again used as
substrate. The corresponding opening product 3a was easily
obtained in high yield upon treatment by methanol in the
presence of acids, including para-toluenesulfonic acid. As
expected, p-TsOH was not able to promote cyclization (see
Table 1, entry 12), whereas catalytic amounts of silver triflate
in dichloromethane smoothly converted 3a to the corresponding
furan 2a (Scheme 3).
These results thus validated our proposed pathway involv-
ing a cascade of events (Scheme 4), in contrast to the direct
cyclization usually proposed for Au- and Pt-catalyzed furan
5
,7
formations. The starting alkynyloxirane probably is first
opened by an alcohol in a nucleophilic substitution promoted
by the catalytic amounts of p-toluenesulfonic acid. It is worth
noting that electrophilic silver salts can nevertheless promote
this reaction opening (see Table 1, entries 3 and 5-7). The
so formed ꢀ-alkoxy-ꢀ-alkynol A would then cyclize upon
coordination with silver ion, leading to heterocyclic vinyl
silver species B. Protodemetalation then regenerates the
catalyst and gives 4-alkoxy-4,5-dihydrofuran C. Upon elimi-
nation of alcohol, the latter would be converted to a furan
derivative. This elimination could be facilitated either by the
acid present or by the mild Lewis acid silver ion.
In conclusion, we have reported for the first time a one-
step catalytic approach to functionalized furans through an
Ag-catalyzed cascade reaction of R-alkynyl oxiranes. The
reaction proceeds efficiently under mild conditions. Further
work is now underway in our laboratory to broaden the scope
of this reaction and to better understand its mechanism.
a
b
Isolated yields. Degradation occurred leading to unidentified
byproduct.
When not embedded in a cycle, alkynyloxiranes behave in
the same way, giving the corresponding furans in good yields,
similar to those achieved with the six-membered epoxide 1a
entries 5-7 vs 1). It is interesting to note that the functionalized
side chain did not interfere in the reaction. Interestingly, the
corresponding nonprotected epoxyalkynol 1h did give the
expected furan 2h, despite obvious competition with the added
nucleophile (methanol) present in the reaction mixture (entry
). Protection as ester or silyl ether proved nevertheless
beneficial, the corresponding furans being isolated in higher
yields (entries 6 and 7 vs 8).
(
8
Epoxyalkynes in which the alkyne was conjugated with
unsaturated group did not react well under these conditions. For
example, the phenylethynyl epoxide 1i led to a mixture of
products from which the expected furan 2i could only be isolated
in low yield (entry 9).
Experimental Section
General Procedure for Silver(I)-Catalyzed Formation of
Furans from Alkynyloxiranes. To a solution of alkynyloxirane
(1 mmol) in CH Cl /MeOH (5 mL, 9/1 v/v) were added
Interestingly, (3-acetyloxyprop-1-ynyl)oxirane derivative, which
has been described to rearrange to divinyl ketones in the
2
2
successively p-toluenesulfonic acid (p-TsOH, 0.05 mmol) and
AgOTf (0.05 mmol) at room temperature. The reaction was
monitored by thin-layer chromatography until completion. The
reaction mixture was filtered throughout a pad of silica gel with
2
1
presence on Ag or Au salts, afford the furan 2j in modest
yield but with incorporation of methanol in place of acetyl group
(
entry 10).
CH
2 2
Cl . Solvents were removed in vacuo, and the crude residue
(
21) Cordonnier, M.-C.; Blanc, A.; Pale, P. Org. Lett. 2008, 10, 1569–1572.
was purified by flash chromatography (cyclohexane/EtOAc).
4
362 J. Org. Chem. Vol. 74, No. 11, 2009

2
-Butyl-4,5,6,7-tetrahydrobenzofuran (2a). Following the gen-
eral procedure, alkynyloxirane 1a (100 mg, 0.56 mmol) gave 2a
80 mg, 80%) as a colorless oil: R ) 0.64 (cyclohexane/EtOAc
0%); IR (neat) νmax 2935, 2870, 1738, 1674, 1520, 1446, 1379,
Acknowledgment. We thank the CNRS and the French
Ministry of Research for financial support. K.T. thanks the
Friedrich-Alexander-Universit a¨ t Erlagen-N u¨ rnberg and ULP
for their exchange program and support.
(
f
2
1
0
-
1 1
220, 1165, 1120, 1095, 982 cm ; H NMR (300 MHz, CDCl
3
) δ
.94 (t, J ) 7.3 Hz, 3 H), 1.39 (sext, 7.4 Hz, 2 H), 1.58 (quint,
Supporting Information Available: Selected experimental
procedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
J ) 5.7 Hz, 2 H), 1.66-1.75 (m, 2 H), 1.78-1.85 (m, 2 H),
1
3
2
.37-2.40 (m, 2 H), 2.54-2.60 (m, 4 H), 5.79 (s, 1 H); C NMR
(
75 MHz, CDCl ) δ 13.8, 22.1, 22.3, 23.1, 23.2, 23.3, 27.8, 30.4,
3
+
•
1
1
1
05.4, 117.1, 148.6, 154.2; MS (ESI) m/z 357 (100, 2M + 2H),
79 (95, M+ + H); HR-MS 179.1438 (C12
•
H
18O + H calcd
79.1430).
JO900483M
J. Org. Chem. Vol. 74, No. 11, 2009 4363