Gold(I)-catalyzed synthesis of highly substituted furans

Article abstract of DOI:10.1021/ol0514101

(Chemical Equation Presented) Cationic triphenylphosphinegold(I) complexes are excellent catalysts for a cascade reaction of propargyl-Claisen rearrangement and heterocyclization to synthesize tri- and tetrasubstituted furans. Starting from easily accessed propargyl vinyl ethers, the furans are obtained in 72-99% yield.

Full text of DOI:10.1021/ol0514101

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3925-3927
Gold(I)-Catalyzed Synthesis of Highly
Substituted Furans
Michael H. Suhre, Michael Reif, and Stefan F. Kirsch*
Lehrstuhl fu¨r Organische Chemie I, Technische UniVersita¨t Mu¨nchen,
Lichtenbergstr. 4, D-85747 Garching, Germany
stefan.kirsch@ch.tum.de
Received June 17, 2005
ABSTRACT
Cationic triphenylphosphinegold(I) complexes are excellent catalysts for
heterocyclization to synthesize tri- and tetrasubstituted furans. Starting from easily accessed propargyl vinyl ethers, the furans are obtained
in 72 99% yield.
a cascade reaction of propargyl-Claisen rearrangement and
−
Highly substituted furans play an important role as structural
elements of many natural and pharmaceutically important
substances (e.g., ranitidine or zantac).1 Moreover, they are
useful intermediates in synthetic organic chemistry.2 Among
the many different approaches to multiply substituted
furans,3,4 cycloisomerizations of alkynyl ketones catalyzed
by transition metals are particularly attractive.5 An alternative
strategy involves allenyl ketones as starting materials for
furan synthesis mostly using Rh(I), Ag(I), Au(III),5c and Pd-
(0/II) compounds as transition-metal catalysts for 5-endo-
trig cyclizations.6 Transition-metal-catalyzed cyclization has
been typically used to prepare di- and trisubstituted furans,
while tetrasubstituted furans are not readily accessed.3d,6a,7
Herein, we report a flexible synthetic approach to tri- and
tetrasubstituted furans via a gold(I)-catalyzed cascade reac-
tion of a formal [3,3]-sigmatropic rearrangement and a
heterocyclization. Importantly, readily obtained acceptor
substituted propargyl vinyl ethers are used as starting
materials for this protocol.
To obtain highly substituted furans 3 from allenylcarbonyl
compounds of type 2, we planned a transition-metal-
catalyzed 5-exo-dig cyclization (Scheme 1). A catalytic
version of a propargyl-Claisen rearrangement8 of propargyl
vinyl ethers 1 should give access to the required allenylcar-
bonyl compounds 2. We assumed that coordination of
(5) For gold(III) catalysts, see: (a) Yao, T.; Zhang, X.; Larock, R. C. J.
Am. Chem. Soc. 2004, 126, 11164-11165. (b) Hashmi, A. S. K.; Frost, T.
M.; Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553-11554. (c) Hashmi,
A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem., Int. Ed.
2000, 39, 2285-2288. For Pd(II) catalysts, see: (d) Fukuda, Y.; Shiragami,
H.; Utimoto, K.; Nozaki, H. J. Org. Chem. 1991, 56, 5815-5819. For Ag-
(I) catalysts, see: (e) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1995,
60, 5966-5968. For Cu(I) catalysts, see: (f) Sromek, A. W.; Kel’in, A.
V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2004, 43, 2280-2282. (g) Kim,
J. T.; Kel’in, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2003, 42, 98-
101.
(1) (a) Hou, X. L.; Yang, Z.; Wong, H. N. C. In Progress in Heterocyclic
Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon: Oxford, 2003;
Vol. 15, pp 167-205. (b) Keay, B. A.; Dibble, P. W. In ComprehensiVe
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Eds.; Elsevier: Oxford, 1997; Vol. 2, pp 395-436. (c) Donnelly, D.
M. X.; Meegan, M. J. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 4, pp 657-712.
(2) Lipshutz, B. H. Chem. ReV. 1986, 86, 795-819.
(3) For recent reviews, see: (a) Brown, R. C. D. Angew. Chem., Int.
Ed. 2005, 44, 850-852. (b) Cacchi, S. J. Organomet. Chem. 1999, 576,
42-64. (c) Keay, B. A. Chem. Soc. ReV. 1999, 28, 209-215. (d) Hou, X.
L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong,
H. N. C. Tetrahedron 1998, 54, 1955-2020.
(6) For Pd(II) and Pd(0) catalysts, see: (a) Ma, S.; Zhang, J.; Lu, L.
Chem. Eur. J. 2003, 9, 2447-2456. (b) Hashmi, A. S. K.; Ruppert, T. L.;
Kno¨fel, T.; Bats, J. W. J. Org. Chem. 1997, 62, 7295-7304. (c) Hashmi,
A. S. K. Angew. Chem., Int. Ed. Engl. 1995, 34, 1581-1583; For Ag(I)
and Rh(I) catalysts, see: (d) Marshall, J. A.; Bartley, G. S. J. Org. Chem.
1994, 59, 7169-7171. (e) Marshall, J. A.; Wang, X.-j. J. Org. Chem. 1991,
56, 960-969.
(4) For selected examples, see: (a) Sniady, A.; Wheeler, K. A.;
Dembinski, R. Org. Lett. 2005, 7, 1769-1772. (b) Bellur, E.; Freifeld, I.;
Langer, P. Tetrahedron Lett. 2005, 46, 2185-2187. (c) Jung, C.-K.; Wang,
J.-C.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4118-4119.
(7) Ma, S.; Lu, L.; Zhang, J. J. Am. Chem. Soc. 2004, 126, 9645-9660.
10.1021/ol0514101 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/06/2005

Scheme 1. Synthesis of Furan 3 from Propargyl Vinyl Ether 1
Table 1. Efficiency of Transition-Metal Catalysts for the
Transformation of 1a into 3aa
entry
catalyst (mol %)
time
yield of 3ab (%)
1
2
3
4
5
6
7
8
9
CuI (5)
PdCl2(MeCN)2 (5)
PtCl2 (2)
AgBF4 (10)
K[AuCl4] (5)
AuCl3 (2)
(PPh3)AuCl (2)
(PPh3)AuCl (2)/AgBF4 (2)
(PPh3)AuCl (2)/AgSbF6 (2) 40 min
(PPh3)AuCl (2)/AgOTf (2) 40 min
24 h
0
0c
52
0d
0
24 h
24 h
24 h
24 h
24 h
24 h
40 min
transition metals to π-bonds9 would allow for a catalyzed
process related to the thermal rearrangement10 through alkyne
activation. In the ideal case, the catalyst system used for
rearrangement should also promote the cycloisomerization
to the furan in a cascade reaction that proceeds at ambient
temperature and under neutral conditions.
7e
0
97
83
60
10
a Conditions: 0.2 mmol of 1a, 23 °C, CH2Cl2 (0.2 M). b Yield of pure
3a after column chromatography. c No starting material 1a remained.
d Complete conversion after 6 h under formation of allene 2a. e Formation
of allene 2a with in 47% yield.
On the basis of these considerations, we initially examined
the conversion of proparyl vinyl ether 1a (R1 ) Me, R2 )
Me, R3 ) H, Y ) OEt) to furan 3a (Table 1). The desired
transformation was examined using a variety of transition-
metal complexes in CH2Cl2 at room temperature. In the
presence of CuI or PdCl2(MeCN)2, the formation of furan
3a was not observed under these conditions (Table 1, entries
1-2). Treatment of proparyl vinyl ether 1a with 2 mol % of
presence of 2 mol % (PPh3)AuCl/AgBF4 at room temperature
followed the order CH2Cl2 (97%, 40 min) ≈ C6H6 (95%, 40
min) > C6H12 (99%, 48 h) > MeCN (30%, 48 h) > THF
(3%, 28 h).
The scope of the triphenylphosphinegold(I)-catalyzed
conversion of propargyl vinyl ethers to a variety of substi-
tuted furans is summarized in Table 2. With optimized
reaction conditions17 in hand, tetrasubstituted furans 3 were
formed in high yields with R1 being alkyl and phenyl
substituents (Table 2, entries 1-3). Moreover, the corre-
sponding trisubstituted furan 3d (R1 ) H) was easily obtained
in 75% yield (Table 2, entry 4). The acceptor substituents
11
PtCl2 gave the desired tetrasubstituted furan 3a in 52%
yield, but the reaction did not proceed to completion even
after 24 h at room temperature (Table 1, entry 3); in the
absence of a transition-metal salt, furan formation did not
take place. With 10 mol % of AgBF4 as a catalyst, the starting
alkyne 1a was rapidly consumed, but capillary gas chroma-
tography did not indicate traces of furan 3a to be formed
after 24 h (Table 1, entry 4).12 Indeed, the starting material
was completely and cleanly converted into an isomeric
mixture of allene 2a after 6 h. Among the gold catalysts13,14
used (Table 1, nos. 5-7), only AuCl3 gave furan 3a (7%
yield) with concomitant generation of allene 2a (47%
yield).15 While (PPh3)AuCl was unreactive, changing of the
counterion to hexafluoroantimonate by addition of AgSbF6
led to a clean and rapid formation of furan 3a in 83% yield.
By far, the best catalyst system was a combination of (PPh3)-
AuCl and AgBF4, which provided furan 3a in 97% yield
after 40 min [2 mol % (PPh3)AuCl/AgBF4, 23 °C, 40 min,
CH2Cl2 (0.2 M)]. Activation of (PPh3)AuCl with other silver
salts such as AgOTf was less effective (Table 1, nos.
8-10).16 Solvent had a marked influence on catalytic
efficiency. Reactions of propargyl vinyl ether 1a in the
(14) Representative examples for gold-catalyzed activation of alkynes:
(a) Hashmi, A. S. K.; Rudolph, M.; Weyrauch, J. P.; Wo¨lfle, M.; Frey, W.;
Bats, J. W. Angew. Chem., Int. Ed. 2005, 44, 2798-2801. (b) Shi, X.; Gorin,
D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 5802-5803. (c) Mamane,
V.; Hannen, P.; Fu¨rstner, A. Chem. Eur. J. 2004, 10, 4556-4575. (d)
Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner, A. J. Am. Chem. Soc. 2004,
126, 8654-8655. (e) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J.
W. Org. Lett. 2004, 6, 4391-4394. (f) Staben, S. T.; Kennedy-Smith, J. J.;
Toste, F. D. Angew. Chem., Int. Ed. 2004, 43, 5350-5352. (g) Nieto-
Oberhuber, C.; Mun˜oz, M. P.; Bun˜uel, E.; Nevado, C.; Ca´rdenas, D. J.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402-2406. (h)
Fu¨rstner, A.; Hannen, P. Chem. Commun. 2004, 2546-2547. (i) Kennedy-
Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526-
4527. (j) Hashmi, A. S. K.; Weyrauch, J. P.; Rudolph, M.; Kurpejoviæ, E.
Angew. Chem., Int. Ed. 2004, 43, 6545-6547. (k) Casado, R.; Contel, M.;
Laguna, M.; Romero, P.; Sanz, S. J. Am. Chem. Soc. 2003, 125, 11925-
11935.
(15) Addition of AgBF4 (6 mol %) or AgOTf (6 mol %) to AuCl3 (2
mol %) did not lead to an increase in the formation of furan 3a.
(16) Addition of AgOAc or AgCOOCF3 to (PPh3)AuCl did not give a
catalytically active gold(I) species.
(8) (a) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978-
15979. (b) Grissom, J. W.; Kilingberg, D.; Huang, D.; Slattery, B. J. J.
Org. Chem. 1997, 62, 603-626. For a review, see: (c) Hashmi, A. S. K.
In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-
VCH: Weinheim, 2004; pp 3-50.
(9) Reviews: (a) Me´ndez, M.; Mamane, V.; Fu¨rstner, A. Chemtracts-
Org. Chem. 2003, 16, 397-425. (b) Nevado, C.; Ca´rdenas, D. J.;
Echavarren, A. M. Chem. Eur. J. 2003, 9, 2627-2635.
(10) (a) Bhat, L.; Ila, H.; Junjappa, H. J. Chem. Soc., Perkin Trans. 1
1994, 1749-1752. (b) Black, D. K.; Landor, S. R. J. Chem. Soc. 1965,
6784-6788.
(11) Harrison, T. J.; Dake, G. R. Org. Lett. 2004, 6, 5023-5026.
(12) Other silver salts such as AgOTf, AgOAc, and AgNO3 catalyzed
the formation of allene 2a less effectively. Generation of furan 3a was not
catalyzed.
(13) Reviews: (a) Hashmi, A. S. K. Gold Bull. 2004, 37, 51-65. (b)
Hashmi, A. S. K. Gold Bull. 2003, 36, 3-9. (c) Dyker, G. Angew. Chem.,
Int. Ed. 2000, 39, 4237-4239.
(17) General Procedure. Synthesis of 3k: (PPh3)AuCl (2 mol %, 2.3
mg) and AgBF4 (2 mol %, 1.0 mg) were added subsequently to a solution
of 1k (70 mg, 0.26 mmol) in CH2Cl2 (1.3 mL), and the reaction vial was
sealed, protected from light, and stirred at room temperature. The dark
reaction mixture was stirred at room temperature for 3 h (until TLC analysis
indicated complete conversion). The mixture was concentrated under reduced
pressure. Purification of the residue by flash chromatography on silica gel
(P/Et2O ) 90/10) gave furan 3k as a colorless oil (69 mg, 0.25 mmol,
99%). Rf ) 0.39 (P/EA ) 80/20). 1H NMR (360 MHz, CDCl3): δ ) 1.03
(t, J ) 7.2 Hz, 3 H), 2.17 (s, 3 H), 2.55 (s, 3 H), 3.77 (s, 3 H), 4.06 (q, J
) 7.2 Hz, 2 H), 6.89 (d, J ) 8.2, 0.8 Hz, 1 H), 6.96 (dt, J ) 0.8, 7.5 Hz,
1 H), 7.13 (dd, J ) 7.5, 1.8 Hz, 1 H), 7.28 (dt, J ) 8.2, 1.8 Hz, 1 H). 13C
NMR (90.6 MHz, CDCl3): δ ) 11.8, 13.8, 13.9, 55.3, 59.5, 110.3, 114.5,
117.3, 120.1, 122.5, 128.5, 131.1, 147.1, 156.6, 157.4, 164.5. MS (70 eV):
m/z 274 (100) [M+], 213 (92), 43 (68). HRMS: calcd for C16H18O4
274.1205, found 274.1206.
3926
Org. Lett., Vol. 7, No. 18, 2005

not necessary to take special precautions to exclude air and
moisture from the reaction mixture.20,21 Reaction of the
Z-stereoisomer of propargyl vinyl ether 1b was marginally
slower compared to the analogous E-isomer and led to the
formation of furan 3b in 92% yield. It was also possible to
conduct the triphenylphosphinegold(I)-catalyzed furan for-
mation with a mixture of E/Z-stereoisomers. For example,
the E/Z-mixture of substrate 1e was transferred into furan
3e (70% yield).
Table 2. Gold(I)-Catalyzed Formation of 3 from 1a
1
time yield 3b
entry
R1
Me
Y
R2
R3 isomer (h)
(%)
1
2
3
4c
5
6
7
8
9
OEt Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
4
15
2
95
97
90
75
72
82
77
87
90
84
99
89
82
73
72
83
45
nPent OMe Me
Ph
H
Ph
Me
OEt Me
OEt Me
Ph
4
8
The use of propargyl vinyl ethers as starting materials is
particularly convenient as these intermediates can easily be
prepared in high yields. Propargyl vinyl ethers 1a-q were
obtained from the corresponding proparyl alcohols and
2-propynoic acid derivatives in the presence of catalytic
amounts of trimethylphosphine22 in high yields (61-98%).23
A plausible mechanism for the furan formation reported
herein is based on a cyclization-induced rearrangement (CIR)
mechanism.8a,24 A 6-endo-dig addition of the enol ether onto
a gold(I)-alkyne complex leads to the formation of a six-
membered intermediate, which collapses into the â-allenic
ketone (or its tautomeric enol forms).25,26 Gold(I)-catalyzed
5-exo-dig cyclization finally delivers furan 3. We assume
that cationic triphenylphosphinegold(I) is the catalytically
active species in both steps of the reaction cascade. Indeed,
we cannot rule out that silver(I) catalyzes the rearrangement
step with the heterocyclization being catalyzed by gold(I).
In summary, a convenient and flexible method for the
synthesis of tri- and tetrasubstituted furans is described. The
reaction is accomplished at room temperature using low
catalyst loadings, and allows for the introduction of highly
functional groups by a novel cascade reaction. The starting
propargyl vinyl ethers are easily accessible. Further studies,
including detailed investigations into mechanism and cata-
lytic active species, and applications in total synthesis, are
currently underway in our labaratories.
Me
H
H
OEt
12
12
2
nPent OMe
Me
Ph
H
Me
Ph
OEt Ph
OEt Ph
OEt Ph
OEt 2-MeO-phenyl
OEt 3-thienyl
OEt 2-pyridyl
OEt CH2c-C6H11
OEt CH2CH2OTBS
OEt TBS
4
4
3
4
10c
11
12
13c Ph
14
15d Ph
16d Me
17e Ph
48
5
Ph
3
4
OEt Me
24
a Conditions: 0.2 mmol 1, 2 mol % of [(PPh3)AuCl/AgBF4], 23 °C,
CH2Cl2 (0.2 M). b Yield of pure product after column chromatography.
c Solvent ) benzene. d TBS ) tert-butyldimethylsilyl. e 38 °C.
in the 3-position do not necessarily have to be esters (Y )
OMe or OEt). The reaction of E-olefin 1e with Y ) Ph also
took place in good yield (Table 2, entry 5). Reactions of
terminal alkynes 1f,g with R2 ) H provided the correspond-
ing trisubstituted furans 3f,g in 77-82% yield (Table 2,
entries 6 and 7). A broad variety of propargyl vinyl ethers 1
with different substituents R2 at the alkyne terminus was
effectively converted into the substituted furans (Table 2,
entries 8-16). Notably, the reaction of aromatic and het-
eroaromatic substrates was as clean as the reaction of the
sterically demanding substrate 1n (R2 ) CH2-c-C6H11). The
presence of heteroatom substituents in the propargyl vinyl
ether was well tolerated. Propargyl vinyl ether 1o containing
a silyl ether gave furan 3o in 72% yield,18 as did substrates
containing esters, ethers, and silanes. Although substrate 1q
derived from a secondary propargyl alcohol reacted to furan
3q (R3 ) Me) in 45% yield, flexibility at this position
remains limited. Preliminary experiments indicated that
heterocyclization with R3 * H was slow under the influence
of [(PPh3)AuCl/AgBF4] as catalyst system.
Acknowledgment. This project was supported by the
“Bundesministerium fu¨r Bildung und Forschung” and the
“Fonds der Chemischen Industrie”. S.F.K. thanks Professor
T. Bach and Professor L. E. Overman for persistent
encouragement.
Supporting Information Available: Representative ex-
perimental procedures, copies of 1H NMR spectra of 3a-q,
and 13C NMR spectra of 3a-q. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0514101
Several additional observations merit note. To our surprise,
the conversion of propargyl vinyl ethers 1d and 1j (R1 )
H) in dichloromethane as a solvent led to a mixture of
unidentified decomposition products. Nevertheless, perform-
ing the reaction in benzene allowed for the clean formation
of the desired furans 3d and 3j.19 The reactions reported in
Table 2 were remarkably clean, taking place without the
formation of significant amounts of any byproducts. It was
(20) Dichloromethane was purchased from Fluka and contained less than
0.005% of water.
(21) In the presence of higher amounts of water (10% v/v), furan
formation was not observed.
(22) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241-244.
(23) Propargyl vinyl ethers 1b and 1e were obtained as a mixture of E-
and Z-isomers. The Z-isomers of 1b and 1e were isolated in 15% and 38%
yield, respectively.
(24) Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579-586.
(25) Allene 2a was isolated as a mixture of isomers and was not converted
into furan 3a by addition of AgBF4 or (PPh3)AuCl. Addition of 2 mol %
of [(PPh3)AuCl/AgBF4] led to a quantitative furan formation.
(26) Allene 2a was detected as intermediary occurring species in the
catalyzed transformation 1a f 3a by capillary gas chromatography.
(18) With reaction times >3 h, decomposition of product 3n was
observed.
(19) The origin of this effect remains unclear.
Org. Lett., Vol. 7, No. 18, 2005
3927