An extremely facile synthesis of furans, pyrroles, and thiophenes by the dehydrative cyclization of propargyl alcohols

Article abstract of DOI:10.1021/ol901901m

Furans, pyrroles, and thiophenes are efficiently prepared by gold-catalyzed dehydrative cyclizations of readily available, heteroatom-substituted propargyllc alcohols. The reactions are rapid, high-yielding, and procedurally simple, giving essentially pure aromatic heterocycles In minutes under open-flask conditions with catalyst loadings as low as 0.05 mol %.

Full text of DOI:10.1021/ol901901m

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4624-4627
An Extremely Facile Synthesis of
Furans, Pyrroles, and Thiophenes by
the Dehydrative Cyclization of Propargyl
Alcohols
Aaron Aponick,* Chuan-Ying Li, Jeremy Malinge, and Emerson Finco Marques
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611
aponick@chem.ufl.edu
Received August 15, 2009
ABSTRACT
Furans, pyrroles, and thiophenes are efficiently prepared by gold-catalyzed dehydrative cyclizations of readily available, heteroatom-substituted
propargylic alcohols. The reactions are rapid, high-yielding, and procedurally simple, giving essentially pure aromatic heterocycles in minutes
under open-flask conditions with catalyst loadings as low as 0.05 mol %.
Furans, pyrroles, and thiophenes are important compounds
found in biologically active natural products, organic materi-
als, pharmaceuticals, and agrochemicals.1 Additionally, they
are synthetically useful building blocks for both heterocyclic
and acyclic compounds.2,3 As such, numerous classical
reactions exist4 and new methods are continually reported
for the preparation of these heterocycles,5 but different
strategies are frequently employed for the synthesis of these
aromatic systems depending on which heteroatom (O, N, S)
is required.6 The development of new strategies that facilitate
rapid access to each of these heterocycles by a single method
and provide highly substituted furans, pyrroles, and thiophenes
would be extremely useful.
As part of a research program aimed at developing new
catalytic reactions, we have been exploring dehydrative
transformations of unsaturated alcohols that are catalyzed
by simple gold(I) salts.7 We recently reported that mono-
(5) For selected examples, see: (a) Zhang, M.; Jiang, H.-F.; Neumann,
H.; Beller, M.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2009, 48, 1681–
1684. (b) Devarie-Baez, N. O.; Kim, W.-S.; SmithI, A. B., III; Xian, M.
Org. Lett. 2009, 11, 1861–1864. (c) Saquib, M.; Husain, I.; Kumar, B.;
Shaw, A. K. Chem.sEur. J. 2009, 15, 6041–6049. (d) Ackermann, L.;
Sandmann, R.; Kaspar, L. T. Org. Lett. 2009, 11, 2031–2034. (e) Dudnik,
A. S.; Sromek, A. W.; Rubina, M.; Kim, J. T.; Kel’in, A. V.; Gevorgyan,
V. J. Am. Chem. Soc. 2008, 130, 1440–1452. (f) Liang, F.; Li, D.; Zhang,
L.; Gao, J.; Liu, Q. Org. Lett. 2007, 9, 4845–4848.
(1) For a detailed list of uses of these heterocycles in a multitude of
applications, see: Yin, G.; Wang, Z.; Chen, A.; Gao, M.; Wu, A.; Pan, Y.
J. Org. Chem. 2008, 73, 3377–3383.
(2) For pyrroles, see: (a) Trofimov, N. A.; Nedolya, N. A. In Compre-
hensiVe Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A.,
Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier Ltd.: Oxford, 2008; Vol.
3, pp 45-268. For furans, see: (b) Wong, H. N. C.; Yeung, K. -S.; Yang,
Z. In ComprehensiVe Heterocyclic Chemistry III; Katritzky, A. R., Ramsden,
C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier Ltd.: Oxford, 2008;
Vol. 3, pp 407-496. For thiophenes, see: (c) Rajappa, S.; Deshmunkh,
A. R. In ComprehensiVe Heterocyclic Chemistry III; Katritzky, A. R.,
Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier Ltd.:
Oxford, 2008; Vol. 3, pp 741-841.
(6) To prepare furans, pyrroles, and thiophenes by the same method, in
addition to the Paal-Knorr synthesis, several methods have been reported,
but these methods generally require specific substrates. For select examples,
see: (a) Yadav, J. S.; Reddy, B. V. S.; Eeshwaraiah, B.; Gupta, M. K.
Tetrahedron Lett. 2004, 45, 5873–5876. (b) Shindo, M.; Yoshimura, Y.;
Hayashi, M.; Soejima, H.; Yoshikawa, T.; Matsumoto, K.; Shishido, K.
Org. Lett. 2007, 9, 1963–1966. (c) Metwally, N. H. Synth. Commun. 2007,
37, 4227–4237. (d) Kaniskan, N.; Elmali, D.; Civcir, P. U. ARKIVOC 2008,
xii, 17–29.
(3) Maier, M. In Organic Synthesis Highlights II; Waldmann, H., Ed.;
VCH: Weinheim, 1995; pp 231-242.
(4) Li J. J. In Name Reactions in Heterocyclic Chemistry; Wiley-VCH:
Weinheim, 2004.
(7) (a) Aponick, A.; Li, C.-Y.; Palmes, J. A. Org. Lett. 2009, 11, 121–
124. (b) Aponick, A.; Biannic, B. Synthesis 2008, 20, 3356–3359. (c)
Aponick, A.; Li, C.-Y.; Biannic, B. Org. Lett. 2008, 10, 669–671.
10.1021/ol901901m CCC: $40.75
Published on Web 09/22/2009
 2009 American Chemical Society

propargylic triols undergo a dehydrative spiroketalization
with concomitant loss of the propargylic hydroxyl group to
form unsaturated spiroketals (1 f 2, Scheme 1).7a Since four
atoms in the B-ring of 2 are in the correct oxidation state,
we reasoned that the desired aromatic heterocycles 4 should
be produced when truncated substrates such as 3 are
employed. Additionally, since gold complexes are known
to perform well in the presence of a variety of different
functional groups,8 it seemed likely that the requisite
heteroatoms and functionalized substituents would be toler-
ated. Oxidative reactions employing iodine to produce
3-iodofurans9 and metal-catalyzed reactions have been re-
ported,10 but these methods suffer from having specific
substitution requirements and the necessity for high catalyst
loadings, elevated temperatures, and prolonged reaction
times. Herein we report an extremely facile catalytic dehy-
drative cyclization reaction that proceeds rapidly under mild
conditions and provides furans, pyrroles, and thiophenes in
high yields with exceedingly low catalyst loadings.
7 was subjected to reaction conditions employing 2 mol %
of Au[P(t-Bu)2(o-biphenyl)]Cl 5 and AgOTf 6 at 0 °C in
the presence of molecular sieves, the furan 8 was obtained
in 96% yield (Table 1, entry 1). Using Ph3PAuCl 9 in place
of 5, the product was also easily produced; however, a
slightly longer reaction time was required and a lower yield
was obtained (entry 3). No reaction was observed with
catalyst 11 (entry 2), and control experiments (entries 4, 5)
indicated that the cationic gold complex generated in situ
was the catalytically active species.
Table 1. Catalyst Optimization
Scheme 1. Initial Hypothesis
entry catalyst system loading (mol %) time (min) yielda (%)
1
2
3
4
5
6
5 + 6
11
9 + 6
6
TfOH
10
10
2
0.75
2
2
2
2
2
2
2
10
60
15
30
30
10
10
15
30
96
0
80
0
0
88
87
83
0
7b
8c
9d
10
10
a Isolated yield of pure product. b Reaction conducted without molecular
sieves. c Reaction conducted without molecular sieves in an open vessel
that had not been dried. d Solvent ) water.
The synthesis of heterocycles is an active area for
developing new Au-catalyzed reactions.11 Although pioneer-
ing work in this area has focused on the cycloisomerization
epoxyalkynes,12-14 no such methods have been reported for
the cyclodehydration of substituted propargyl alcohols such
as 3. If successful, a broad range of substrates would be
readily accessible by numerous staightforward synthetic
strategies.
Further experimentation demonstrated that similar results
could be obtained using AuCl 10 (entry 6), which was
advantageous for both economic reasons and procedural
simplicity. Using this salt, the nonpolar reaction products
To test the feasibility of this idea, the diol 7 was prepared
and treated with gold salts (Table 1). To our delight, when
(12) For leading references on isomerization of epoxyalkynes using Hg,
Au, Pt, and Ag salts, see the following. Hg: (a) Miller, D. Chem. Soc. C
1969, 12–15. Au: (b) Hashmi, A. S. K.; Sinha, P. AdV. Synth. Catal. 2004,
346, 432–438. (c) 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, 349, 2493–2498. (d)
Dai, L.-Z.; Shi, M. Tetrahedron Lett. 2008, 49, 6437–6439. (e) Ji, K.-G.;
Shen, Y.-W.; Shu, X.-Z.; Xiao, H.-Q.; Bian, Y.-J.; Liang, Y-M AdV. Synth.
Catal. 2008, 350, 1275–1280. (f) Hashmi, A. S. K.; Buhrle, M.; Salathe,
R.; Bats, J. W. AdV. Synth. Catal. 2008, 350, 2059–2064. Pt: (g) Yoshida,
M.; Al-Amin, M.; Matsuda, K. S. Tetrahedron Lett. 2008, 49, 5021–5023.
(h) Yoshida, M.; Al-Amin, M.; Shishido, K. Synthesis 2009, 2454–2466.
Ag: (i) Blanc, A.; Tenbrink, K.; Weibel, J. -M.; Pale, P. J. Org. Chem.
2009, 74, 4360–4363.
(8) For reviews on Au-catalyzed reactions, see: (a) Hashmi, A. S. K.;
Rudolph, M. Chem. Soc. ReV. 2008, 37, 1766–1775. (b) Li, Z.; Brouwer,
C.; He, C. Chem. ReV. 2008, 108, 3239–3265. (c) Arcadi, A. Chem. ReV.
2008, 108, 3366–3325. (d) Jimenez-Nunez, E.; Echavarren, A. M. Chem.
ReV. 2008, 108, 3326–3350. (e) Gorin, D. J.; Sherry, B. D.; Toste, F. D.
Chem. ReV. 2008, 108, 3351–3378.
(9) Bew, S. P.; El-Taeb, G. M. M.; Jones, S.; Knight, D. W.; Tan, W.-
F. Eur. J. Org. Chem. 2007, 5759–5770.
(10) (a) Hayes, S. J.; Knight, D. W.; Menzies, M. D.; O’Halloran, M.;
Tan, W.-F. Tetrahedron Lett. 2007, 48, 7709–7712. (b) McDonald, F. E.;
Connolly, C. B.; Gleason, M. M.; Towne, T. B.; Treiber, K. D. J. Org.
Chem. 1993, 58, 6952–6953. (c) Yada, Y.; Miyake, Y.; Nishibayashi, Y.
Organometallics 2008, 27, 3614–3617. (d) Wakabayashi, Y.; Fukuda, Y.;
Shiragami, H.; Utimoto, K.; Nozaki, H. Tetrahedron 1985, 41, 3655–3661.
(11) For leading references on Au-catalyzed reactions in heterocycle
synthesis, see: (a) Shen, H. C. Tetrahedron 2008, 64, 3885–3903. (b) Shen,
H. C. Tetrahedron 2008, 64, 7847–7870. (c) Patil, N. T.; Yamamoto, Y.
Chem. ReV. 2008, 108, 3395–3442.
(13) For isomerization of alkynylaziridines to form pyrroles, see: Davies,
P. W.; Martin, N. Org. Lett. 2009, 11, 2293–2296.
(14) For other seminal reports on Au-catalyzed furan synthesis, see: (a)
Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. J. Angew. 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) Sromek, A. W.; Rubina, M.;
Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500–10501.
Org. Lett., Vol. 11, No. 20, 2009
4625

are readily obtained in high purity after filtration of the crude
reaction mixture over silica gel to remove the catalyst residue.
Table 2. Optimization Studies
Since only a minimal effect was observed after changing
the catalyst to AuCl, additional experiments focused on
further simplifying the procedure. Omission of molecular
sieves (entry 7) afforded 8 in 87% yield, demonstrating that
the water produced in the reaction could be tolerated by the
catalyst system. Furthermore, conducting the reaction in an
open Vessel that had not been dried and without molecular
sieVes also rapidly proVided 8, albeit in slightly lower yield
(entry 8, 83%). When water was used as the solvent, no
reaction was observed, likely due to solubility issues (entry
9). From these data, it is apparent that the best yield is
obtained using Au[P(t-Bu)2(o-biphenyl)]Cl 5 and AgOTf 6
(entry 1), while the simplest procedure employs AuCl 10
with no precautions taken to exclude water (entry 8).15
The reaction scope was next explored using substituted
diols to produce furans with substituents at the 2-, 3-, and
5-positions (Table 2). Employing reaction conditions A
(complexes 5/6, MS 4 Å, N2 atmosphere) and B (“open flask
conditions” using AuCl with no precautions taken to exclude
air or moisture), the target furans were obtained in excellent
yield after 10-25 min. Using substrates 14 and 16, com-
parison between the conditions demonstrated that the pro-
cedurally simple “open flask” conditions B could function
as well as (entries 1 vs 2), if not better than the more rigorous
conditions A (entries 3 vs 4). In addition to acetals and cyano
groups, additional alcohol moieties were also tolerated (entry
6) and tertiary alcohols (entry 7) were readily dehydrated to
form the products in excellent yield. Using diol 24, the 2,3,5-
trisubstituted furan was easily prepared in 95% yield. Further
substitution is limited by the nature of the propargyl alcohol
substrates, but electrophilic substitution should provide the
2,3,4,5-tetrasubstituted furans if desired.16
a Conditions A: Au[P(t-Bu)2(o-biphenyl)]Cl (2 mol %), AgOTf (2 mol
%), MS4 Å, THF, 0 °C. Conditions B: AuCl (2 mol %), THF, 0 °C, open
flask.15 b Isolated yield of pure product.
We next focused our attention on the preparation of
pyrroles and thiophenes. For comparison, 2-phenylfuran 29
was first prepared from the requisite diol in 93% using
conditions A and 75% using conditions B (Table 3, entries
1,2). Since introducing potentially coordinating heteroatoms
into the substrates may be detrimental to the reaction, the
more rigorous conditions A were employed with the nitrogen
and sulfur analogues. In the event, when the N-tosylamino
alcohol 30 was subjected to the reaction conditions, the
pyrrole 31 was obtained in 89% yield after 10 min (entry
3), and cyclization of the alkyne 32 demonstrated that the
phenyl group is not required for the reaction to proceed (entry
4). Basic amines also perform well in the reaction (entries
5,6), but increased reaction times (50 and 40 min, respec-
tively) were required.
The preparation of thiophene 39 necessitated further
modification to the standard procedure. When the standard
conditions were employed, 39 was only isolated in 19%
yield. Raising the temperature to room temperature and using
5 mol % catalyst, the yield increased to 63%. Finally,
carrying out the reaction at 40 °C (Table 3, entry 7) afforded
the thiophene in 90% yield.
It was also important to determine the lower limit of
catalyst loading. To study this, the sterically demanding diol
24 was employed using AuCl as catalyst. When the loading
was reduced to 0.5 mol % (Table 4, entry 1), the furan 25
was isolated in 82% yield. This reduced yield (cf. 95%, Table
2, entry 8) seemed to indicate that catalyst loadings lower
than 2 mol % could be problematic. We reasoned that by
increasing the temperature to shorten the reaction time and
by excluding water lower loadings may be successful.
Inclusion of activated molecular sieves and conducting the
reaction in refluxing THF, with 0.1 mol % of AuCl, a nearly
quantitative yield of 25 was isolated (Table 4, entry 2).
Decreasing the catalyst loading to 0.05 mol % also resulted
in high yield (91%, entry 3), but this was significantly
diminished (entries 4 and 5) after further reduction in the
(15) General Procedure for Dehydrative Cyclization under “Open
Flask” Conditions. THF (1 M relative to substrate) was added to an
unstoppered, open test tube containing AuCl (2 mol %), and the mixture
was cooled to 0°C. A solution of substrate (0.13 M in THF; overall
concentration of substrate: 0.1 M) was added. After TLC analysis showed
the reaction to be complete, the mixture was filtered through a short plug
of silica with hexanes, and the solvents were removed in vacuo to afford
the desired product in high purity.
(16) (a) Baily, P. S.; Nowlin, G. J. Am. Chem. Soc. 1949, 71, 732–735.
(b) Dominguez, C.; Csaky, A. G.; Plumet, J. Tetrahedron 1992, 48, 149–
158.
4626
Org. Lett., Vol. 11, No. 20, 2009

Table 3. Heteroatom Studies
Table 4. Catalyst Loading
entry
catalyst loading (mol %)
time (min)
yielda (%)
1b
2c
3c
4c
5c
0.5
0.1
0.05
0.02
0.01
35
10
15
20
20
82
99
91
34
4
a Isolated yield. b 0 °C. c 65 °C, MS4 Å.
In conclusion, we have developed an extremely mild and
efficient method for the preparation of furans, pyrroles, and
thiophenes. The reaction employs very simple and readily
available substrates, tolerates a range of functional groups
to produce highly substituted heteroaromatics, and is typically
complete in minutes with high yield. Although care must be
taken to exclude water when loadings below 0.5 mol % are
utilized, the use of AuCl as a catalyst under “open-flask
conditions” in combination with facile purification makes
this method highly practical.
Acknowledgment. We gratefully acknowledge the Uni-
versity of Florida, the Herman Frasch Foundation (647-
HF07), and the donors of the Petroleum Research Fund
(47539-G1) for their generous support of our programs.
E.F.M. thanks the NSF/FAPESP US/South America REU
program for summer support. We thank Petra Research, Inc.,
for their gift of alkynes.
a Au[P(t-Bu)2(o-biphenyl)]Cl (2 mol %), AgOTf (2 mol %), THF, MS4
Å, 0 °C. b AuCl (2 mol %), THF, 0 °C, open flask.15 c 5 (5 mol %), 6 (5
mol %), THF, MS4 Å, 40 °C.
Supporting Information Available: Experimental pro-
cedures and data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
loadings. It is likely that this is due to trace amounts of
impurity below NMR detection limits in diol 24 as a reaction
with 0.01 mol % requires an extremely small amount of
AuCl.
OL901901M
Org. Lett., Vol. 11, No. 20, 2009
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