Cationic gold(I)-mediated intramolecular cyclization of 3-alkyne-1,2-diols and 1-amino-3-alkyn-2-ols: A practical route to furans and pyrroles

Article abstract of DOI:10.1021/ol901942t

The intramolecular cyclizations of the 3-alkyne-1,2-diols and the 1-amlno-3-alkyn-2-ols with a low catalyst loading (0.05-0.5 mol %) of (Ph ₃P)AuCl - AgNTf₂ or (Ph₃P)AuCl-AgOTf proceeded at room temperature to provide a variety of substituted furans and pyrroles In excellent yields (85-98% yields). This method Is also fully applicable to the conversion of several dozen grams of the substrate using only 0.05 mol % each of the Au and Ag catalysts.

Full text of DOI:10.1021/ol901942t

ORGANIC
LETTERS
2009
Vol. 11, No. 21
5002-5005
Cationic Gold(I)-Mediated Intramolecular
Cyclization of 3-Alkyne-1,2-diols and
1-Amino-3-alkyn-2-ols: A Practical Route
to Furans and Pyrroles
Masahiro Egi, Kenji Azechi, and Shuji Akai*
School of Pharmaceutical Sciences, UniVersity of Shizuoka, 52-1, Yada, Suruga-ku,
Shizuoka, Shizuoka 422-8526, Japan
akai@u-shizuoka-ken.ac.jp
Received August 21, 2009
ABSTRACT
The intramolecular cyclizations of the 3-alkyne-1,2-diols and the 1-amino-3-alkyn-2-ols with a low catalyst loading (0.05-0.5 mol %) of
(Ph3P)AuCl-AgNTf2 or (Ph3P)AuCl-AgOTf proceeded at room temperature to provide a variety of substituted furans and pyrroles in excellent
yields (85-98% yields). This method is also fully applicable to the conversion of several dozen grams of the substrate using only 0.05 mol
% each of the Au and Ag catalysts.
Furans and pyrroles have been found to be key structural
components in abundant naturally occurring products.1 They
are also important intermediates in industrial organic syn-
theses, such as pharmaceuticals, flavors, and material sci-
ences. For these extensive utilities, a huge number of
synthetic methods of furans and pyrroles have been devel-
oped, including classical procedures under either acidic or
basic conditions, such as the Paal-Knorr,2 Hantzsch,3 and
Feist-Be´nary syntheses.4 Recently, from the viewpoint of
atom economy or environmental concern, the transition-
metal-catalyzed intramolecular cyclizations have attracted
increasing attention,5 in which various metal compounds,
including copper,6 zinc,7 palladium,6d,8 and silver,6b,9 have
been utilized. While these reactions are useful, most of the
methods still need improvement in terms of catalyst loadings,
yields, scope limitations, and/or vigorous reaction conditions.
On the other hand, the gold catalysts work under relatively
(5) (a) Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850–852. (b)
Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076–2080. (c) Patil, N. T.;
Yamamoto, Y. ARKIVOC 2007, 121–141.
(6) (a) Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2005, 70,
4531–4534. (b) Schwier, T.; Sromek, A. W.; Yap, D. M. L.; Chernyak, D.;
Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 9868–9878. (c) Kel’in, A. V.;
Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074–2075.
(d) Gabriele, B.; Salerno, G.; Fazio, A. J. Org. Chem. 2003, 68, 7853–
7861.
(1) For selected reviews, see: (a) Keay, B. A.; Hopkins, J. M.; Dibble,
P. W. In ComprehensiVe Heterocyclic Chemistry III; Jones, G., Ramsden,
C. A., Eds.; Elsevier: Amsterdam, 2008; Vol. 3, pp 571-623. (b) d’Ischia,
M.; Napolitano, A.; Pezzella, A. In ComprehensiVe Heterocyclic Chemistry
III; Jones, G., Ramsden, C. A., Eds.; Elsevier: Amsterdam, 2008; Vol.3,
pp 353-388. (c) Lipshutz, B. H. Chem. ReV. 1986, 86, 795–819.
(2) Minetto, G.; Raveglia, L. F.; Taddei, M. Org. Lett. 2004, 6, 389–
392, and references cited therein.
(7) Sniady, A.; Durham, A.; Morreale, M. S.; Marcinek, A.; Szafert,
S.; Lis, T.; Brzezinska, K. R.; Iwasaki, T.; Ohshima, T.; Mashima, K.;
Dembinski, R. J. Org. Chem. 2008, 73, 5881–5889.
(8) (a) Ma, S.; Lu, L.; Zhang, J. J. Am. Chem. Soc. 2004, 126, 9645–
9660. (b) Xiao, Y.; Zhang, J. Angew. Chem., Int. Ed. 2008, 47, 1903–1906.
(c) Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64, 7687–
(3) Trautwein, A. W.; Su¨ssmuth, R. D.; Jung, G. Bioorg. Med. Chem.
Lett. 1998, 8, 2381–2384, and references cited therein.
7692. (d) Ma, S.; Li, L. Org. Lett. 2000, 2, 941–944
.
(4) For recent example of the Feist-Be´nary synthesis, see: Tamaso, K.;
Hatamoto, Y.; Obora, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2007, 72,
8820–8823.
(9) (a) Marshall, J. A.; Wang, X.-j. J. Org. Chem. 1991, 56, 960–969.
(b) Robinson, R. S.; Dovey, M. C.; Gravestock, D. Tetrahedron Lett. 2004,
45, 6787–6789
.
10.1021/ol901942t CCC: $40.75
Published on Web 09/25/2009
 2009 American Chemical Society

mild conditions for the synthesis of furans from allenyl
ketones,10 2-(1-alkynyl)-2-alken-1-ones,11 1-(1-alkynyl)cy-
clopropyl ketones,12 or alkynyl epoxides13,14 and of pyrroles
from homopropargyl azides.15 In these approaches, however,
expensive gold catalysts usually require high loadings (1-5
mol %). We now describe that the combinations of
(Ph3P)AuCl with either AgNTf2 or AgOTf (each as low as
0.05-0.5 mol %) present a highly powerful catalyst for the
intramolecular cyclizations of the 3-alkyne-1,2-diols 1 and
the 1-amino-3-alkyn-2-ols 3. This method offers advantages
over the known methods for the production of a wider range
of substituted furans 2 and pyrroles 4 in excellent yields and
the ready availability of the substrates (1 and 3).
mol %), generated in situ from an equimolar mixture of
(Ph3P)AuCl and AgOTf, converted the propargyl alcohol 1a
having another hydroxyl group into the furan 2a in 90%
yields (entry 3, Table 1)20,21 and the Meyer-Schuster
Table 1. Preliminary Survey for the Cyclization of
3-Alkyne-1,2-diol 1a into 2a
The use of gold catalysts for organic synthesis has been
an ever growing research area for the past decade, and a
variety of reactions have already been developed.16 For
instance, propargyl alcohols are known to cause Meyer-
Schuster rearrangements,17 nucleophilic substitutions,18 and
the addition of alcohols.19 During the course of our studies
on the gold-mediated Meyer-Schuster rearrangement,17a we
happened to disclose that the cationic Au(I) complex (0.5
entry
Au cat.
Ag cat. mol %
time
yield of 2a (%)
1
2
3
4
5
6
7
(Ph3P)AuCl none
none
1.0
1.0
0.5
0.5
0.5
0.1
0.1
30 min
30 min
20 min
20 min
15 min
2.5 h
no reactiona
AgOTf
tracea
90
(Ph3P)AuCl AgOTf
(Me2S)AuCl AgOTf
(Ph3P)AuCl AgNTf2
(Ph3P)AuCl AgOTf
(Ph3P)AuCl AgNTf2
87
96
94
97
1 h
a NMR yield using p-dimethoxybenzene as the internal standard.
(10) (a) 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. (b) Zhou,
C.-Y.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2006, 8, 325–328. (c) Hashmi,
A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem., Int. Ed.
2000, 39, 2285–2288.
rearrangement product was not obtained at all. In search of
more effective conditions, we screened the combinations of
gold and silver catalysts. Among a variety of gold com-
pounds, (Ph3P)AuCl and (Me2S)AuCl gave comparably good
results, which produced 2a in 90 and 87% yields, respectively
(entries 3 and 4). Additionally, AgOTf and AgNTf2 proved
to be good choices as silver catalysts. These combined
catalysts could reduce the catalyst loading to 0.1 mol %
giving 2a almost quantitatively within 1-2.5 h (entries 6
and 7). On the contrary, when the gold or silver compound
alone was used, the intramolecular cyclization did not take
place at all (entries 1 and 2). Because the substrate 1a is
readily available by the reaction of hydroxyacetone with a
lithium acetylide in 80% yield, the developed method offers
a convenient and high-yielding means for the preparation of
the substituted furan 2a.
The optimized conditions were applicable to various
alkynyldiols bearing a proton 1b-d, aromatic 1e,f, and
heteroaromatic ring 1g at the end of the acetylene functional-
ity, which were readily prepared via the alkynylation of
R-hydroxy carbonyl compounds in 52-84% yields,22 to give
the furans 2b-g in excellent yields (Table 2). The combina-
tion of (Ph3P)AuCl and AgNTf2 generally provided better
results for 2 with lower catalyst loading compared to the
(Ph3P)AuCl-AgOTf catalyst (entries 3 vs 4 and 5 vs 6). It
is worth noting that the intramolecular cyclization of the less
reactive terminal alkynes 1b-d was achieved to give the
corresponding furans 2b-d in 85-91% yields (entries 1-3),
while the known transformations of a similar 3-alkyne-1,2-
diol required the higher catalyst loadings (5-100 mol %)
with scope limitations or did not proceed at all.21 The reaction
of 1g having the unstable thienyl moiety was also ac-
(11) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126,
11164–11165.
(12) (a) Zhang, J.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2006, 45,
6704–6707. (b) Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc.
2008, 130, 1814–1815.
(13) Blanc et al. reported the intramolecular cyclization of alkynyl
epoxides in CH2Cl2/MeOH, which was expected to proceed via 3-alkyne-
1,2-diol derivatives to afford the corresponding furans; see: Blanc, A.;
Tenbrink, K.; Weibel, J.-M.; Pale, P. J. Org. Chem. 2009, 74, 5342–5348
.
(14) Hashmi, A. S. K.; Sinha, P. AdV. Synth. Catal. 2004, 346, 432–
438
.
(15) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 11260–11261.
(16) (a) Muzart, J. Tetrahedron 2008, 64, 5815–5849. (b) Gorin, D. J.;
Toste, F. D. Nature 2007, 446, 395–403. (c) Hashmi, A. S. K. Chem. ReV.
2007, 107, 3180–3211.
(17) (a) Egi, M.; Yamaguchi, Y.; Fujiwara, N.; Akai, S. Org. Lett. 2008,
10, 1867–1870. (b) Ramo´n, R. S.; Marion, N.; Nolan, S. P. Tetrahedron
2009, 65, 1767–1773.
(18) Georgy, M.; Boucard, V.; Campagne, J.-M. J. Am. Chem. Soc. 2005,
127, 14180–14181.
(19) Teles, J. H.; Brode, S.; Chabanas, M. Angew. Chem., Int. Ed. 1998,
37, 1415–1418.
(20) The epoxide 5 reacted with (Ph3P)AuCl-AgNTf2 within 1 h to
give 2a albeit in low yield. A similar reaction of the alcohol 6 resulted in
the formation of complex mixtures of products which included no furan
compound. Hence, it was found that the hydroxyl group at the propargyl
position of 1 plays an important role in this intramolecular cyclization.
(21) The related intramolecular cyclizations of 3-alkyne-1,2-diols to the
substituted furans using Ag, Pd, Ru, and Mo catalysts have been reported;
see: (a) Knight, D. W. Patent Application No. PCT/GB2006/001048. (b)
Hayes, S. J.; Knight, D. W.; Menzies, M. D.; O’Halloran, M.; Tan, W.-F.
Tetrahedron Lett. 2007, 48, 7709–7712. (c) Wakabayashi, Y.; Fukuda, Y.;
Shiragami, H.; Utimoto, K.; Nozaki, H. Tetrahedron 1985, 41, 3655–3661.
(d) Yada, Y.; Miyake, Y.; Nishibayashi, Y. Organometallics 2008, 27, 3614–
3617. (e) McDonald, F. E.; Connolly, C. B.; Gleason, M. M.; Towne, T. B.;
Treiber, K. D. J. Org. Chem. 1993, 58, 6952–6953.
(22) For synthesis of starting materials, see the Supporting Informa-
tion.
Org. Lett., Vol. 11, No. 21, 2009
5003

2-ols 3a-c to form the synthetically useful N-Boc or N-Ts
pyrroles 4a-c in excellent yields (Table 3).21a Only a few
Table 2. Au-Ag-Catalyzed Intramolecular Cyclization of 1b-g
into Furans 2b-ga
Table 3. Conversion of 3a-c into Pyrroles 4a-c Using the
Combination of Au and Ag Catalysts
substrate 1
product 2
entry
R1
H
R2
R3
time (h)
isolated yield (%)
1
1b
Ph
H
8
10
1.5
0.25 2d
5 2e
0.67 2e
2b
2c
2d
85
91
90
73
90
83
97
90
2
1c Ph Ph
H
3b
1d H Ph(CH2)2
H
H
Ph
Ph
4b,c 1d H Ph(CH2)2
5
1e
1e
1f
H
H
H
H
6c
7
-(CH2)4- Ph
Me 2-thienyl
3
5
2f
2g
8
1g
H
a Standard condition: substrates (2.5 mmol) were employed. b Run at
60 °C. c Using 0.5 mol % each of (Ph3P)AuCl and AgOTf.
a All reactions were conducted in toluene (0.4 M) at room temperature.
MethodA:Using(Ph3P)AuCl-AgOTf.MethodB:Using(Ph3P)AuCl-AgNTf2.
b Each loading of the Au and Ag catalysts.
complished to afford 2g in 90% yield (entry 8).21b Due to
the poor solubility of 1d in toluene, its reaction was
conducted at 60 °C without inducing any side reactions (entry
3). The reactions of the alkynyldiols 1e-g having internal
acetylene groups were completed in a shorter time (entries
5, 7, and 8).23
gold-catalyzed preparations of pyrroles by inter- and in-
tramolecular cyclizations have been previously reported.15,24
Our protocol features the production of various pyrroles
having substituents at the 2-, 3-, or 5-positions and the use
of readily available substrates.22 Generally, AgOTf as a silver
catalyst more effectively facilitated the reaction than AgNTf2
in this pyrrole synthesis. For example, in the case of 3b
having a bulky tert-butyl group at the acetylenic terminus,
the reaction employing (Ph3P)AuCl and AgOTf smoothly
proceeded at room temperature to give the corresponding
pyrrole 4b in 88% yield (entry 3), while a similar reaction
catalyzed by (Ph3P)AuCl-AgNTf2 for the same time pro-
vided 4b in 64% yield, accompanied by the recovery of 3b
(entry 4).
Interestingly, the diastereomers (anti- and syn-1h)22 were
found to have different reactivities (Scheme 1), while the
Scheme 1. Influence of Diastereomeric Conformations
Worthy of note was the fact that this method was
applicable for a larger scale reaction (Scheme 2). Only 0.05
Scheme 2
.
Larger Scale Preparation of Furan 2a with Low
Ru-catalyzed cyclizations of a pair of similar diastereomers
were reported to give the same yields of the product for the
same reaction time.21d Using 0.1 mol % each of the Au and
Ag catalysts, the anti-1h was completely converted into 2h
within 10 h, while the cyclization of syn-1h was slightly
slower to obtain a 67% yield of 2h with the recovery of
syn-1h after 15 h. We found, however, using 0.5 mol % each
of the same reagents, both diastereomers were almost
quantitatively converted into 2h, albeit at different reaction
rates.
Catalyst Loadings
mol % each of (Ph3P)AuCl and AgNTf2 were enough to
convert 1a (26.0 g, 0.127 mol) into 2a at room temperature
in 98% yield.
Moreover, the developed method was found to be effective
for the intramolecular cyclization of the 1-amino-3-alkyn-
In conclusion, we have found that the combination of
(Ph3P)AuCl with either AgNTf2 or AgOTf provides a
highly powerful catalyst for the intramolecular cyclization
(23) The terminal alkynes 1b-d have low solubilities in toluene at room
temperature, which then required longer reaction times.
5004
Org. Lett., Vol. 11, No. 21, 2009

of readily available 3-alkyne-1,2-diols 1 and 1-amino-3-
alkyn-2-ols 3.25 The advantages of this method include
the extremely low catalyst loadings (0.05-0.5 mol %),
rapid and clean reactions at room temperature, and
production of a variety of substituted furans and pyrroles
in excellent yields (85-98% yields). Although we have
not yet conducted detailed mechanistic studies, we con-
sider the following mechanism. Coordination of the
acetylene bond of 1 or 3 to a cationic Au species,
generated from Au and Ag compounds, enhances its
electrophilicity and facilitates the 5-endo cyclization of
homopropargylic hydroxyl or amino group to afford the
cyclic intermediates. After dehydration, the furans 2 and
pyrroles 4 were obtained. Further investigation of a
practical extension of this method is now in progress.
Acknowledgment. This work was supported by a Grant-
in-Aid for Young Scientists (B) from MEXT and The Uehara
Memorial Foundation (for M.E.).
Supporting Information Available: Experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL901942T
(25) Typical Experimental Procedure. To a solution of the 2-methyl-6-
phenyl-3-hexyne-1,2-diol 1a (528 mg, 2.6 mmol) in toluene (6.5 mL, 0.4 M)
were added (Ph3P)AuCl (1.3 mg, 0.0026 mmol) and AgNTf2 (1.0 mg, 0.0026
mmol) in this order at room temperature. The reaction mixture was stirred at
room temperature for 1 h and then quenched with saturated aqueous NH4Cl.
The organic materials were extracted with Et2O, and the combined organic
extracts were washed with brine, dried over MgSO4, and evaporated in vacuo.
The residue was purified by column chromatography (silica gel, hexanes) to
give 4-methyl-2-(2-phenylethyl)furan 2a (469 mg, 97%).
(24) (a) Harrison, T. J.; Kozak, J. A.; Corbella-Pane´, M.; Dake, G. R.
J. Org. Chem. 2006, 71, 4525–4529. (b) Binder, J. T.; Kirsch, S. F. Org.
Lett. 2006, 8, 2151–2153. (c) Shu, X.-Z.; Liu, X.-Y.; Xiao, H.-Q.; Ji, K.-
G.; Guo, L.-N.; Liang, Y.-M. AdV. Synth. Catal. 2008, 350, 243–248. (d)
Arcadi, A.; Giuseppe, S. D.; Marinelli, F.; Rossi, E. AdV. Synth. Catal.
2001, 343, 443–446.
Org. Lett., Vol. 11, No. 21, 2009
5005