Gold(III) bromide catalyzed furannulation of 2-alkynylcycloalk-2-enols: An expedient route to fused furans

Article abstract of DOI:10.1055/s-0029-1217517

An efficient synthesis of fused furans from 2-alkynylcycloalk-2-enols via gold(III) bromide catalyzed cycloisomerization was achieved. The reaction condition is moderate and amenable to structurally diverse substrates, leading to good yield of products. G

Full text of DOI:10.1055/s-0029-1217517

1990
LETTER
Gold(III) Bromide Catalyzed Furannulation of 2-Alkynylcycloalk-2-enols:
An Expedient Route to Fused Furans
Route to Fused
F.
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600020, India
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received 15 February 2009
number of natural products and their metabolites possess-
Abstract: An efficient synthesis of fused furans from 2-alkynyl-
cycloalk-2-enols via gold(III) bromide catalyzed cycloisomeriza-
tion was achieved. The reaction condition is moderate and
amenable to structurally diverse substrates, leading to good yield of
products.
ing fused furan rings continues to emerge in the litera-
ture.1e,f Therefore the synthesis of these structural motifs
receives paramount importance in synthetic viewpoint.
Not surprisingly, many synthetic approaches to this skel-
eton have been disclosed in the literature.6 Of particular
value are Pt(II)-catalyzed cyclization of propargyl
oxiranes,6a Au(III)-,6b Pt(II)-,6c and Cu(I)6d-catalyzed
cyclization of 2-(1-alkynyl)-2-alken-1-ones in the pres-
ence of alcohol, Au(I)-catalyzed ring expansion of 1-alkynyl-
bicyclo[4.1.0]heptan-2-ones,6e intramolecular condensation
of triketones promoted by trimethylsilylchloride under
microwave irradiation.6f Apart from these methodologies,
there have been many strategies disclosed in the literature
for the construction of fused furan-containing natural
products.1d,h,2b,4a,5a,7 Despite the conceivable synthetic util-
ity of the above methodologies, a catalytic protocol ac-
complishing the furannulation of 2-alkynylcycloalk-2-
enol remains to be developed. On the other hand, because
of their unique ability to activate carbon–carbon triple
bond, the use of gold catalysts plays an important role in
modern transition-metal catalysis.8 Moreover, gold cata-
lysts have proved to be very efficient in intramolecular
cyclization of acetylenic alcohols to the corresponding
oxygenated heterocycles.9 As part of our ongoing interest
directed towards the synthetic applications of gold cata-
lysts,10 we planned to investigate the catalytic cyclo-
isomerization of 2-alkynylcycloalk-2-enol in the presence
of a gold salt. Although cycloisomerization of 2-alkynyl-
3-alkyl allyl alcohol using AgNO3,11 Pd(MeCN)2Cl2,12 to
furans have been already reported, there have been no pre-
cedents for the cycloisomerization of 2-alkynylcycloalk-
2-enol, leading to fused furans. Therefore a two-step ap-
proach to fused furans has been examined involving (i)
the Sonogashira coupling13 of 2-iodocycloalk-2-enol with
terminal alkynes and (ii) gold-catalyzed cycloisomeriza-
tion (Scheme 1). Herein, we report a more convenient
synthesis of the starting 2-alkynylcycloalk-2-enols and
the successful application of gold(III)-catalyzed cyclo-
isomerization strategy as a convenient and general syn-
thetic method for the synthesis of fused furans.
Key words: 2-alkynylcycloalk-2-enol, gold(III), cycloisomeriza-
tion, fused furans
Fused furans are important heterocyclic target molecules
because of their occurrence as structural units in a variety
of natural products and biologically active compounds1
(Figure 1). These includes tubipofurane (1) an ent-fura-
noeudesmane, isolated from the stolonifier Tubipora
musica, shows ichtiotoxicity toward a killifish Orizias
latipes.2 Pallescensin A (2), obtained from the marine
sponge Disidea Pallescens involves in the defensive
mechanism employed by opisthobranch molluscs, which
concentrate such sponge metabolites in their skin and then
release them when they come under attack.3
O
H
O
H
tubipofuran (1)
pallescensin A (2)
HO
O
O
frondosin B (3)
echinofuran (4)
Figure 1 Examples of naturally occurring fused furans
Frondosin B (3), isolated from a marine sponge Dysidea
frondosa was shown to possess interleukin-8 (IL-8) inhib-
itory activity.4 Echinofuran (4), a kind of furanosesqui-
terpenoid-tetrahydrolinderazulene isolated from the
gorgonian species Echinogorgia praelonga was found to
inhibit the cell division of fertilized sea urchin eggs.5 A
R
OH
OH
O
R
I
R
2
cat. Au
( )n
cat. Pd/Cu
( )
( )n
SYNLETT 2009, No. 12, pp 1990–1996
x
x
.x
x
.2
0
0
9
n
Advanced online publication: 25.06.2009
DOI: 10.1055/s-0029-1217517; Art ID: G04809ST
1
3
4
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Synthetic strategy for fused furans

LETTER
Route to Fused Furans
1991
Table 1 Synthesis of 2-Alkynylcycloalk-2-enol under Sonogashira Conditionsa
OH
OH
I
R
Pd(Ph3)2Cl2 (5 mol%)
+
R
( )
n
CuI (5 mol%), Et3N, N2, r.t.
(
)
n
1
2
3
a n = 3, b n = 2, c n = 1
Entry
1
2-Iodocycloalk-2-enol (1) Alkyne (2)
2-Alkynyl-1-cycloalk-2-enol (3)b
Yield (%)c
90
I
OH
OH
OH
OH
OH
2a
2b
1a
1a
1a
1a
1a
3a
I
2
3
4
5
92
88
89
77
OH
3b
S
S
I
OH
2c
3c
I
2d
OH
3d
OH
I
OH
OH
OH
2e
2a
3e
OH
OH
I
6
7
8
91
94
79
1b
1b
1b
3f
OH
OH
I
2b
2f
3g
OH
OH
N
I
N
3h
Synlett 2009, No. 12, 1990–1996 © Thieme Stuttgart · New York

1992
C. Praveen et al.
LETTER
Table 1 Synthesis of 2-Alkynylcycloalk-2-enol under Sonogashira Conditionsa (continued)
OH
OH
I
R
Pd(Ph3)2Cl2 (5 mol%)
+
R
( )
n
CuI (5 mol%), Et3N, N2, r.t.
(
)
n
1
2
3
a n = 3, b n = 2, c n = 1
Entry
2-Iodocycloalk-2-enol (1) Alkyne (2)
2-Alkynyl-1-cycloalk-2-enol (3)b
Yield (%)c
OH
I
OH
9
89
2d
1b
3i
OH
OH
OH
I
I
10
11
12
79
80
81
OH
2e
2a
2b
1b
1c
3j
OH
OH
3k
I
OH
OH
1c
3l
a All reactions were carried out at r.t. for 6 h using of 2-iodocycloalk-2-enol (1.0 mmol), terminal alkyne (1.2 mmol), Pd(PPh3)2Cl2 (5 mol%)
and CuI (5 mol%), respectively, in dry Et3N (5 mL) under a nitrogen atmosphere.
b All products were characterized by IR, 1H NMR, 13 C NMR, and MS.
c Isolated yield.
To assess the generality of this approach, the scope of the Initial studies were conducted using 2-(phenylethynyl)-
Sonogashira coupling of 2-iodocycloalk-2-enols and ter- cyclohex-2-enol (3f) as a prototype reaction in dichloro-
minal alkynes were first studied. Treatment of 2-iodo- ethane at room temperature for 12 hours (Scheme 2). The
cycloalk-2-enols 1 with a variety of terminal alkynes use of AuCl led to a very low conversion of the starting
under standard Sonogashira conditions [1.0 mmol of 2-iodo- material (Table 2, entry 1). Whereas, the use of gold (I)
cycloalk-2-enol, 1.2 mmol of terminal alkyne, 5 mol% of complexes, such as Ph3PAuCl, Me3PAuCl, and Et3PAuCl
Pd(Ph3)2Cl2, 5 mol% of CuI and 5 mL of Et3N at r.t. for 6 did not lead to any desired product at all (Table 2, entries
h] affords good to excellent yields of the coupling prod- 2–4). However, the combination of gold(I) complex and
ucts (Table 1 and Table 2).14
AgOTf led to afford the product 4f with increased yield
(Table 2, entries 5 and 6). The use of AgOTf or AuCl3
alone afforded the product in 25% yield only (Table 2, en-
tries 7 and 8). Finally, the use of AuBr3 gave the product
in 55% yield (Table 2, entry 9). As 5 mol% of AuBr3 gave
the best result in terms of conversion and yield, it was
used as the catalyst for our further studies. When the same
reaction was carried out at elevated temperature (70 °C)
using 5 mol% of AuBr3, the reaction went into completion
within 30 minutes and higher yield of the product (86%)
was observed (Table 2, entry 10). So we followed the
OH
catalyst
DCE, N2, r.t., 12 h
O
4f
3f
Scheme 2
Synlett 2009, No. 12, 1990–1996 © Thieme Stuttgart · New York

LETTER
Route to Fused Furans
1993
at a short reaction time even at room temperature
(Table 3, entries 1–5). Substrates owing cyclohexyl ring
resulted in good yields of products only, when the reaction
was carried out for 30 min at 70 °C (Table 3, entries 6–
10). However, substrates having cyclopentyl rings gave
the desired product, albeit in low yield even when the
reaction was carried out for 45 minutes. These observa-
tions can be rationalized due to the greater strain associat-
ed with the formed cyclopenta[b]furan than cyclo-
hexa[b]furan and cyclohept[b]furan. In contrast, the sub-
stituents on the triple bond of the 2-alkynylcycloalk-2-
enol does not play a significant role in the cyclization,
since groups like aliphatic, aromatic, and heteroaromatic
gave almost the same yield of the product.
Table 2 Effect of Different Gold Catalysts on the Cycloisomeriza-
tion of 2-(Phenylethynyl)cyclohex-2-enol (3f)
Entry
Catalyst
Yield (%)a
1
2
AuCl (5 mol%)
12
Ph3PAuCl (5 mol%)
Me3PAuCl (5 mol%)
Et3PAuCl (5 mol%)
Ph3PAuCl (5 mol%)/AgOTf (5 mol%)
Et3PAuCl (5 mol%)/AgOTf (5 mol%)
AgOTf (5 mol%)
trace
–
3
4
trace
41
5
6
38
7
25
The formation of the products was ascertained by the
appearance of a singlet peak at dH = 6.20–6.30 ppm in
CDCl3, which corresponds to the C3–H of the furan ring.
Moreover all the products exhibited a 13C peak at dC =
104–109 ppm, confirmed the presence of C3 carbon of the
furan ring. On the basis of the above result, a mechanistic
manifold for the formation of the fused furans is presented
in Scheme 3. Thus, coordination of the carbophilic AuBr3
to the alkyne 3 would lead to the formation of a p-complex
5. As a consequence of the increased electrophilicity, a
nucleophilic attack of the tethered hydroxyl group would
lead to the cyclized intermediate 6. Protodemetallation of
6, followed by rearrangement would produce the fused
furan 3.
8
AuCl3 (5 mol%)
25
9
AuBr3 (5 mol%)
55
10
AuBr3 (5 mol%)
86b
a Isolated yield.
b The reaction was carried out at 70 °C for 30 min.
same reaction procedure for subsequent studies, which
utilizes 5 mol% of AuBr3 in dichloroethane at 70 °C.15
Under this conditions, a wide variety of substrates bearing
rings of different size, aromatic, aliphatic, and heteroaro-
matic groups have been successfully employed in this
furan synthesis (Table 3). The results indicated that the ef-
ficiency of the cyclization depends on the nature of the
size of the ring attached on the substrates (3a–3l). Sub-
strates possessing cycloheptyl ring underwent the reaction
Table 3 Gold(III)-Catalyzed Synthesis of Fused Furansa
Entry
2-Alkynylcycloalk-2-enol (3)
Fused furan (4)b
Time (min) Yield (%)c
1
2.0
1.0
1.0
4.0
90
91
89
95
O
O
OH
4a
4b
3a
2
3
4
OH
3b
S
S
O
O
OH
4c
3c
OH
4d
3d
Synlett 2009, No. 12, 1990–1996 © Thieme Stuttgart · New York

1994
C. Praveen et al.
LETTER
Table 3 Gold(III)-Catalyzed Synthesis of Fused Furansa (continued)
Entry
5
2-Alkynylcycloalk-2-enol (3)
Fused furan (4)b
Time (min) Yield (%)c
HO
OH
5.0
79
86
O
OH
4e
3e
OH
6
7
8
30.0
O
4f
3f
OH
30.0
30.0
88
70
O
4g
3g
OH
N
O
N
4h
4i
3h
OH
9
30.0
92
O
3i
OH
OH
OH
10
11
12
30.0
45.0
45.0
83
60
66
O
4j
3j
O
OH
4k
4l
3k
O
OH
3l
a All reactions were carried out using AuBr3 (5 mol%) in DCE. Reaction conditions: For substrates 3a–3e, the reaction went to completion with
in 5 min at 25 °C; for substrates 3f–j the reactions were carried out at 70 °C for 30 min; for substrates 3k–l, the reactions were carried out at
70 °C for 45 min.
b All products were characterized by IR, 1H NMR, 13C NMR, and MS.
c The yields were calculated after isolation from column chromatography.
Synlett 2009, No. 12, 1990–1996 © Thieme Stuttgart · New York

LETTER
Route to Fused Furans
1995
OH
R
3
R
(
)
R
n
O
O
AuBr3
(
)
(
)
n
n
H
+
4
7
OH
R
R
O
_
5
6
AuBr3
(
)
n
AuBr3
(
)
n
Scheme 3 Proposed mechanism for the Au(III)-catalyzed cyloisomerization of 2-alkynylcycloalk-2-enol
1994, 26, 1. (c) Foot, J. S.; Phillis, A. T.; Sharp, P. P.; Willis,
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In summary, we have developed an efficient synthesis of
structurally diverse fused furans via Au(III)-catalyzed
furannulation of 2-alkynylcycloalk-2-enols. The reaction
conditions are simple, and the catalyst employed is very
safe to use. Broad substrate scope and no additional sol-
vent extraction steps are the other advantages of this
method. Further studies to utilize this methodology for the
synthesis of naturally occurring fused furans are actively
under way.
Acknowledgment
The authors thank the Council of Scientific and Industrial Research,
New Delhi, India for the research fellowship.
References and Notes
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LETTER
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phenylacetylene 2a (1.2 mmol), the mixture was stirred at r.t.
until TLC showed the disappearance of the starting 2-iodo-
cyclohex-2-enol (ca. 6 h). H2O (50 mL) was added to the
reaction mixture, and the residue was extracted into EtOAc
(4 × 15 mL), and the extract was dried over anhyd Na2SO4.
Removal of the solvent under reduced pressure gave the
crude product, which was further purified by column
chromatography on silica gel using EtOAc–PE (1:9) as
eluent to afford pure product 3f (91%) as a brown oil. IR
(CH2Cl2): 3383, 2928, 1592, 1053, 755 cm–1. 1H NMR (500
MHz, CDCl3): d = 1.60–1.62 (m, 1 H), 1.75–1.78 (m, 3 H),
1.87–1.90 (m, 1 H), 2.12–2.21 (m, 2 H), 4.26 (br s, 1 H), 6.30
(t, J = 4.6 Hz, 1 H), 7.28–7.29 (m, 3 H), 7.43–7.44 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 18.1, 26.0, 30.6, 66.9,
88.4, 89.3, 123.2, 124.2, 128.2, 128.3, 131.6, 137.8. MS
(EI): m/z = 198 [M+]. Anal. Calcd for C14H14O: C, 84.81; H,
7.12. Found: C, 84.91; H, 7.09.
(15) General Procedure for the Synthesis of Fused Furans 4a–l
Representative Procedure for 2-Phenyl-4,5,6,7-
tetrahydrobenzofuran (4f, Table 3, Entry 6)
(10) Praveen, C.; Sagayaraj, Y. W.; Perumal, P. T. Tetrahedron
To a soln of 2-(phenylethynyl)cyclohex-2-enol (3f, 1.0
mmol) in DCE (1 mL) under N2 was added AuBr3 (5 mol%)
and heated the reaction mixture at 70 °C for 30 min. After
completion of the reaction as indicated by TLC, the reaction
mixture was concentrated under reduced pressure and
purified by column chromatography over silica gel (100–
200 mesh) to afford pure product 4f (86%) as a colourless
liquid. Rf = 0.82 (EtOAc–PE, 1:9). IR (CH2Cl2): 2934, 2815,
2354, 1669, 1600, 1247, 760 cm–1. 1H NMR (500 MHz,
CDCl3): d = 1.75–1.78 (m, 2 H), 1.84–1.89 (m, 2 H), 2.46 (t,
J = 6.1 Hz, 2 H), 6.47 (s, 1 H), 7.20 (t, J = 7.6 Hz, 1 H), 7.35
(t, J = 7.6 Hz, 2 H), 7.62 (d, J = 6.9 Hz, 2 H). 13C NMR (125
MHz, CDCl3): d = 22.2, 23.1, 23.2, 23.4, 106.1, 119.0,
123.3, 126.6, 128.6, 131.5, 150.9. MS (EI): m/z = 221 [M+ +
Na+]. Anal. Calcd for C14H14O: C, 84.81; H, 7.12. Found: C,
84.75; H, 7.15.
Lett. 2009, 50, 644.
(11) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1995, 60, 5966.
(12) Qing, F.-L.; Gao, W.-Z.; Ying, J. J. Org. Chem. 2000, 65,
2003.
(13) (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998, Chap. 5, 203–229. (b) Sonogashira, K.;
Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467.
(14) General Procedure for the Synthesis of 2-Alkynyl
cyclo-alk-2-enol 3a–l
Representative Procedure for 2-(Phenylethynyl)cyclohex-
2-enol (3f, Table 1, Entry 6)
2-Iodocyclohex-2-enol (1b, 1.0 mmol), Pd(PPh3)Cl2 (5
mol%), and CuI (5 mol%) were placed in an oven-dried flask
under N2. Dry Et3N was added, and the resulting suspension
was magnetically stirred. Upon dropwise addition of
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