Synthesis of multisubstituted furans, pyrroles, and thiophenes via ynolates

Article abstract of DOI:10.1021/ol0705200

An efficient synthetic method for the preparation of multisubstituted furans, thiophenes, and pyrroles using ynolates was developed. This novel formal [4 + 1] annulation by C2-C3 and C3-C4 bond formations Includes cycloaddition, cyclization, decarboxylati

Full text of DOI:10.1021/ol0705200

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1963-1966
Synthesis of Multisubstituted Furans,
Pyrroles, and Thiophenes via Ynolates
Mitsuru Shindo,*,† Yutaka Yoshimura,‡ Maiko Hayashi,§ Hiroe Soejima,‡
Takashi Yoshikawa,§ Kenji Matsumoto,§ and Kozo Shishido§
Institute for Materials Chemistry and Engineering, Kyushu UniVersity,
Kasuga 816-8580, Japan, Interdisciplinary Graduate School of Engineering Sciences,
Kyushu UniVersity, Kasuga 816-8580, Japan, and Graduate School of Pharmaceutical
Sciences, UniVersity of Tokushima, Sho-machi, Tokushima 770-8505, Japan
shindo@cm.kyushu-u.ac.jp
Received March 1, 2007
ABSTRACT
An efficient synthetic method for the preparation of multisubstituted furans, thiophenes, and pyrroles using ynolates was developed. This
novel formal [4
as key steps.
+ 1] annulation by C2−C3 and C3−C4 bond formations includes cycloaddition, cyclization, decarboxylation, and dehydration
Furans, pyrroles, and thiophenes are frequently encountered
components of natural products and of compounds used in
medicine and material sciences.1 Efficient synthetic methods
for these heterocycles consequently are highly desirable for
the construction of these compounds. Although numerous
methods for syntheses of heterocycles have been reported,
they can generally be categorized as 1-2 and/or 1-5 bond
connections, such as the Paal-Knorr synthesis,2 1-2 and/
or 3-4 bond connections,3 2-3 and 4-5 connections,4 and
so on (Figure 1).5 However, efficient short-step methods for
the construction of unsymmetrical multisubstituted hetero-
Figure 1. Representative category of the synthesis of heterocycles.
† Institute for Materials Chemistry and Engineering, Kyushu University.
‡ Interdisciplinary Graduate School of Engineering Sciences, Kyushu
University.
§ University of Tokushima.
cycles are limited by the preparation of substituted starting
materials and by steric congestion, which the cyclization must
(1) For reviews, see: (a) ComprehensiVe Heterocyclic Chemistry II;
Katrizky, A. R., Rees, C. W., Scriven, E. F., Eds.; Pergamon: Oxford, 1996;
Vol. 2. (b) Walsh, C.; Garneau-Tsodikova, S.; Howard-Jones, A. R. Nat.
Prod. Rep. 2006, 23, 517-531. (c) Hoffmann, H.; Lindel, T. Synthesis 2003,
1753-1783.
(3) For a recent example, see: Kel’in, A. V.; Sromek, A. W.; Gevorgyan,
V. J. Am. Chem. Soc. 2001, 123, 2074-2075.
(4) For a recent example, see: Kamijo, S.; Kanazawa, C.; Yamamoto,
Y. J. Am. Chem. Soc. 2005, 127, 9260-9266.
(2) (a) Knorr, L. Ber. 1884, 17, 1635. (b) Paal, C. Ber. 1885, 18, 367-
371.
10.1021/ol0705200 CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/17/2007

Table 1. Synthesis of Furans and Thiophenes
yield
(%)
entry
1
R1
5
R2
R3
R4
X
methoda
products
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1a
1a
1a
1a
1b
1a
1a
1a
1a
1a
1a
1a
Me
Me
Me
Me
Me
Bu
Me
Me
Me
Me
Me
Me
Me
5b
5c
5c
5d
5e
5b
5f
5g
5h
5i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Me
Me
Me
Me
Ph
Me
Me
Me
H
Me
Me
Me
Me
Me
Ph
Ph
4-pentenyl
Ph
Me
Me
Ph
Me
O
O
O
O
O
O
S
S
S
S
S
A
A
B
A
A
A
C
C
C
C
D
C
b
10
11
11
12
13
14
15
16
17
18
19
20
21
70
84
77
66
42
83
90
85
84
66
90
93
71
2-thienyl
(E)-styryl
Ph
5j
5k
5l
S
S
2-thienyl
Ph
a Decarboxylation, A: TsOH (0.1 equiv) in benzene under reflux; B: one-pot reaction (see text); C: TsOH (1 equiv) in toluene under reflux; D: reflux
in xylene without acid. b Direct formation of thiophene (see text).
overcome.6 A new category of synthesis that addresses these
concerns is therefore needed.
8,11 which was considered to form via cycloaddition of 1a
and 5a, followed by cyclization of the resulting enolate 6.
This intermediate 8 was treated with TsOH in benzene under
reflux to afford the tetrasubstituted furan 9 via decarboxyl-
ation and dehydration. Using this protocol, we then synthe-
sized several types of tetrasubstituted furans. The initial
cycloaddition was complete within 1 h at -78 °C, and the
resulting fused â-lactones, without purification, were decar-
boxylated under reflux in benzene in the presence of TsOH
(0.1 equiv) to provide the furans. As shown in Table 1
(entries 1-6), aliphatic and aromatic groups can be used as
R2-R4. This reaction can be carried out in one pot by
addition of an excess of TsOH into the reaction mixture after
the formation of the fused â-lactone (entry 3). R-Acyl-
thioketones also afforded multisubstituted thiophenes via the
Ynolates 1 are ketene anion equivalents, which initiate
sequential one-pot reactions.7 Since ynolates are compact
linear-shape carbanions, they can react with even sterically
hindered substrates, leading to multisubstituted products.8
Herein, we describe a novel methodology for the efficient
synthesis of multisubstituted furans, pyrroles, and thiophenes
3 using ynolates 1 with R-acyloxy-, R-acylamino-, and
R-acylthioketones 2 via a method of the category of the 2-3
and 3-4 bond connection (Scheme 1).9
Scheme 1
Scheme 2
In the torquoselective olefination of R-acyloxyketone 5
via the ynolate 1a,10 we discovered a small amount of a less
polar side product, the tetrasubstituted furan 9. In order to
elucidate the mechanism, we tried to isolate the reaction
intermediates. When the reaction of the acyloxyketone 5a
with the ynolate 1a, prepared from R,R-dibromo ester 4 with
t-BuLi, was carried out at -78 °C and quenched for 30 min,
an intermediate was obtained in good yield as a single isomer
(Scheme 2). Its structure was found to be the fused â-lactone
(5) For recent examples, see: (a) Dhawan, R.; Arndtsen, B. A. J. Am.
Chem. Soc. 2004, 126, 468-469. (b) Jung, C-K.; Wang, J-C.; Krische, M.
J. J. Am. Chem. Soc. 2004, 126, 4118-4119.
1964
Org. Lett., Vol. 9, No. 10, 2007

Table 2. One-Pot Synthesis of Pyrroles
yield
(%)
entry
1
R4
22
R1
R2
R3
Ph
i-Pr
CF3
t-Bu
Ph
Ph
Ph
Ph
CO2Et
Ph
X
methoda
product
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1c
1d
1a
1a
1a
1a
1a
Me
Me
Me
Me
i-Pr
Ph
Me
Me
Me
Me
Me
22b
22c
22d
22e
22a
22a
22f
22g
22h
22i
Ph
Ph
Ph
Ph
Ph
Ph
Pr
Me
Me
Me
Me
Me
Me
Et
Bn
Bn
Bn
C
A
B
A
C
C
C
D
C
A
Ab
27
28
29
30
31
32
33
34
35
36
37
67
65
71
49
75
59
67
71
36
83
70
allyl
PMP
PMP
PMP
Bn
allyl
OMPc
PMP
-(CH2)4-
Ph
Ph
Ph
Me
Me
H
10
11
22k
Ph
a A: at -20 °C for 2-3 h; B: after method A, the â-lactone was treated with TsOH (0.1 equiv) under reflux in toluene; C: at 0 °C for 1-3 h; D: after
method C, the â-lactone was treated with TsOH (0.1 equiv). b Phenyl dibromopropionate was used as the precursor of the ynolate. BuLi (1 equiv) was added
after the formation of the â-lactone. c o-Methoxyphenyl.
reaction with ynolates in excellent yield (entries 7-13). In
the decarboxylation step, the conditions using 1 equiv of
TsOH under reflux in toluene gave better yields. In the case
of acid-sensitive products, the decarboxylation was carried
out only by heating without use of an acid (entry 11). In the
case of entry 13, the thiophene 21 was directly generated
without heating or acid treatment. The in situ decarboxylation
by base would proceed, as can be seen in the synthesis of
pyrroles, which will be described next, probably due to the
electron-donating thienyl substituent.
This successful result prompted us to examine the synthesis
of pyrroles using R-acylaminoketones (e.g., 22) as a substrate.
Since it was sluggish at -78 °C, we carried out the reaction
at -20 °C. Within 3 min, we obtained the fused â-lactone
24 in 68% yield along with the pyrrole in 15% yield. After
optimization of the reaction conditions, we succeeded in
obtaining the desired pyrrole in good yield in one pot at -20
°C in 3 h without treatment with acid. This result suggests
a different decarboxylation pathway from that of the synthesis
of furans. In situ reaction monitoring with IR spectroscopy
indicated that initially the â-lactone (1821 cm-1) appeared
and then gradually disappeared. Also a carboxylate absorp-
tion (1678 cm-1) appeared and did not decrease until
quenching. These facts indicated that â-syn-elimination from
the intermediate 23 by the LiOEt base generated in the step
producing the ynolates leads to the ring opening of the
â-lactone. Actually, the isolated â-lactone 24 was treated
with BuLi to afford the pyrrole 26 in 75% yield. We
speculate that, on quenching with water, the pyrrole was
finally generated via decarboxylation and dehydration from
the carboxylate 25. This one-pot process was unsuccessful
for the synthesis of furans and thiophenes due to decomposi-
tion of 6 and/or 7 at -20 °C, except for the case of 21.
The synthesis of multisubstituted pyrroles is summarized
in Table 2. Aromatic, aliphatic, and cyclic ketones (R1 and
R2) gave the penta- and tetrasubstituted pyrroles. Sterically
hindered (entries 2 and 4), electron-withdrawing (entry 3),
and functionalized (entry 9) acyl groups (R3) also provided
the pyrroles. When less reactive substrates (entries 5-10)
or ynolates (entry 6) were used, the reactions were carried
out at 0 °C, although the electrocyclic ring opening of the
â-lactone enolates should have proceeded at that tempera-
ture.12 When the ring opening of 23 to 25 did not occur, the
isolated â-lactones were decarboxylated under acidic condi-
(6) For recent examples for synthesis of multisubstituted heterocycles,
see: (a) Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151-2153. (b)
Mathew, P.; Asokan, C. V. Tetrahedron 2006, 62, 1708-1716. (c) Dhawan,
R.; Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126, 468-469. (d) Bharadwaj,
A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465-2468. (e) Yao, T.; Zhang,
X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164-11165. (f) Wang,
Y.; Zhu, S. Org. Lett. 2003, 5, 745-748. (g) Mortensen, D, S.; Rodriguez,
A. L.; Carlson, K. E.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen,
J. A. J. Med. Chem. 2001, 44, 3838-3848. (h) Wills, M. S. B.; Danheiser,
R. L. J. Am. Chem. Soc. 1998, 120, 9378-9379. For reviews on furans
and pyrroles, see: (i) 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. (j) Balm, G. Angew. Chem., Int. Ed. 2004, 43, 6238-6241. (k) Kirsch,
S. Org. Biomol. Chem. 2006, 4, 2076-2080.
(7) For reviews, see: (a) Shindo, M. Tetrahedron 2007, 63, 10-36. (b)
Shindo, M. Synthesis 2003, 2275-2288. (c) Shindo, M. J. Synth. Org. Chem.
Jpn. 2000, 58, 1155-1166. (d) Shindo, M. Yakugaku Zasshi 2000, 120,
1233-1246. (e) Shindo, M. Chem. Soc. ReV. 1998, 27, 367-374.
(8) (a) Shindo, M.; Sato, Y.; Shishido, K. J. Am. Chem. Soc. 1999, 121,
6507. (b) Shindo, M.; Sato, Y.; Shishido, K. J. Org. Chem. 2001, 66, 7818.
(c) Shindo, M.; Matsumoto, K.; Sato, Y.; Shishido, K. Org. Lett. 2001, 3,
2029.
(9) Only a few examples of this category have been reported. For
pyrroles, see: (a) Suzuki, M.; Miyoshi, M.; Matsumoto, K. J. Org. Chem.
1974, 39, 1980. (b) van Leusen, D.; van Echten, E.; van Leusen, A. M. J.
Org. Chem. 1992, 57, 2245-2249. For thiophenes, see: (c) Liebscher, J.;
Feist, K. Synthesis 1985, 412-414.
(10) Shindo, M.; Yoshikawa, T.; Itou, Y.; Mori, S.; Nishii, T.; Shishido,
K. Chem.sEur. J. 2006, 12, 524-536.
(11) In the case of entry 8 (Table 1), the structure of the â-lactone
intermediate was determined by X-ray crystal structure analysis. See
Supporting Information.
Org. Lett., Vol. 9, No. 10, 2007
1965

tions to afford the pyrroles (entry 3). The fact that, in the
absence of EtOLi, addition of BuLi was required (entry 11)
supports the mechanism as shown in Scheme 3. As N-
Scheme 4
Scheme 3
In conclusion, we have developed a short-step synthetic
method for multisubstituted furans, thiophenes, and pyrroles
using ynolates. This novel [4 + 1] annulation by C2-C3
and C3-C4 bond formation should be useful for the efficient
synthesis of multisubstituted heterocycles.
Acknowledgment. We thank Professor S. Kanemasa
(Kyushu University) for valuable discussions, and Dr. J.
Tanaka for X-ray crystal structure analysis. This research
was supported by a Grant in Aid for Scientific Research on
Priority Areas “Advanced Molecular Transformations of
Carbon Resources” from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
substituents (X), aryl, benzyl, and allyl groups could be used,
but carbamates (X ) CO2Bn, CO2Et) did not give the
pyrroles.
The N-benzyl group could be removed by the Birch
reduction13 to furnish the tetrasubstituted pyrrole 38 (Scheme
4).
Supporting Information Available: General procedures
and characterization data of new compounds, synthetic
method of starting materials, CIF for the â-lactone (entry 8,
1
Table 1) (CCDC 635505), and H and 13C NMR spectra of
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) (a) Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron Lett. 1998, 39,
4857-4860. (b) Shindo, M.; Sato, Y.; Shishido, K. J. Org. Chem. 2000,
65, 5443-5445. (c) Shindo, M.; Matsumoto, K.; Mori, S.; Shishido, K. J.
Am. Chem. Soc. 2002, 124, 6840-6841. (d) Shindo, M.; Sato, Y.;
Yoshikawa, T.; Koretsune, R.; Shishido, K. J. Org. Chem. 2004, 69, 3912-
3916. (e) Mori, S.; Shindo, M. Org. Lett. 2004, 6, 3945-3948.
OL0705200
(13) Pandey, P. S.; Rao, T. S. Bioorg. Med. Chem. Lett. 2004, 14, 129-
131.
1966
Org. Lett., Vol. 9, No. 10, 2007