A general and efficient synthesis of substituted furans and dihydrofurans via gold-catalyzed cyclization of (Z)-2-en-4-yn-1-ols

Article abstract of DOI:10.1016/j.tet.2008.11.109

A highly efficient Au-catalyzed cyclization of (Z)-enynols that proceeds under mild reaction conditions has been developed. This methodology provides rapid access to substituted furans and stereodefined (Z)-5-ylidene-2,5-dihydrofurans in a regioselective

Full text of DOI:10.1016/j.tet.2008.11.109

Tetrahedron 65 (2009) 1839–1845
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A general and efficient synthesis of substituted furans and dihydrofurans
via gold-catalyzed cyclization of (Z)-2-en-4-yn-1-ols
,
Xiangwei Du a, Feijie Song a, Yuhua Lu b, Haoyi Chen a, Yuanhong Liu a
*
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032,
People’s Republic of China
b Department of Chemistry, Shanghai University, Shangda Rd. 99, Shanghai 200444, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 June 2008
Received in revised form 12 November 2008
Accepted 13 November 2008
Available online 24 December 2008
A highly efficient Au-catalyzed cyclization of (Z)-enynols that proceeds under mild reaction conditions
has been developed. This methodology provides rapid access to substituted furans and stereodefined (Z)-
5-ylidene-2,5-dihydrofurans in a regioselective manner from suitably substituted (Z)-2-en-4-yn-1-ols.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
reaction. Recently, Hashmi et al. reported a gold-catalyzed8 cycli-
zation of 2-methylpent-2-en-4-yn-1-ol to furan.4g We have also
The furan rings and its analogues widely occur as key structural
subunits in numerous natural products, they also can find a variety
of applications such as pharmaceuticals, flavor and fragrance
compounds.1 Substituted furans are of significant interest since
they are useful and versatile synthetic intermediates for access to
heterocyclic and acyclic compounds.2 As a consequence, much at-
tention has been paid to the synthesis of furan derivatives either by
traditional methods3 or by transition-metal-catalyzed reactions
including cyclization of allenyl ketones4 and 3-alkyn-1-ones,5
cycloisomerizations of (Z)-2-en-4-yn-1-ols,4l,6 Pd-catalyzed cycli-
zation of (Z)-2-iodoalk-2-enyl ketones,7 and so on. A particularly
attractive methodology is based on cycloisomerization of (Z)-2-en-
4-yn-1-ols.6 Although a number of methods have been reported for
the synthesis of furans from this kind of substrate, they have certain
drawbacks. For example, base-promoted cyclization of (Z)-enynols
was achieved under strongly basic conditions, which was not
suitable for the synthesis of base-sensitive furan.6c–e A Ru-catalyzed
cyclization was only suitable for terminal alkynes.6f–h A K2PdI4-
based catalytic system was reported to accomplish the
cycloisomerization of a wide variety of (Z)-enynols under neutral
conditions. However, the reaction was usually carried out in a di-
polar aprotic solvent such as DMA at temperatures of 25–100 ꢀC,
especially, when (Z)-enynols bearing a phenyl substituent at C-3,
a high temperature of 80–100 ꢀC and long reaction time were
required.6a Thus, the catalytic version of enynol-cyclization that
proceeds under mild conditions in combination with the efficient
(Z)-enynol construction would greatly enhance the utility of this
reported that gold could be used as catalyst for the cyclization of
(Z)-enynols9 prepared via zirconium-mediated three-components
coupling of alkyne, aldehyde (or ketone), and alkynyl bromide in
a one-pot procedure, which offers an efficient and straightforward
route to fully substituted furans or dihydrofurans under mild re-
action conditions. However, only fully substituted (Z)-enynols
(substituted at all the C-1 to C-5 positions) were used as the sub-
strates. In this paper, we wish to report the full details of this study
with a wide range of different substituted (Z)-2-en-4-yn-1-ols, in
which a variety of mono- to tetra-substituted furans and its de-
rivatives could be efficiently synthesized (Scheme 1).
R4
R3
R2
R4
R3
R4
R3
R1
R1
R2
cat. AuCl3 or PPh3AuOTf
or
R2
cyclization
O
O
R5
HO
R5
R5
Scheme 1.
2. Results and discussion
2.1. Gold-catalyzed formation of furans from fully substituted
(Z)-2-en-4-yn-1-ols
As shown in Table 1, a wide range of fully substituted (Z)-enynols
with a secondary alcohol group at C-1 participated in the gold-
catalyzed cycloisomerization reactions.9 The reactions can be run
using AuCl3 or cationic gold(I) complex (PPh3)AuCl/AgOTf as cata-
lyst at low catalyst loadings (1 mol %), and the reactions were
usually complete within several hours. Alkyl, alkenyl, and aryl
* Corresponding author.
E-mail address: yhliu@mail.sioc.ac.cn (Y. Liu).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.109

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X. Du et al. / Tetrahedron 65 (2009) 1839–1845
Table 1
Gold-catalyzed cyclization of enynols: formation of fully substituted furans
Entry
Enynol
R2
R3
R4
R5
Conditiona
A, 4 h
Product
Yieldb (%)
Pr
Pr
Ph
1
1a
p-MeC6H4
Pr
Pr
Ph
92
O
(2a)
Me
Bu
MeO
Bu
2
3
1b
1c
Ph
Bu
Pr
Bu
Pr
p-MeOC6H4
B, 3 h
A, 2 h
85
85
Ph
O
(2b)
Pr
Pr
Bu
p-MeOC6H4
Bu
O
(2c)
OMe
Ph
Ph
MeO
4
5
1d
1e
Pr
Ph
Et
Ph
Et
p-MeOC6H4
p-ClC6H4
A, 3 h
B, 2 h
79
64
Pr
O
Et
(2d)
Cl
Et
p-CF3C6H4
O
(2e)
CF3
CH3
TMS
Ph
CH3
Ph
+
6
1f
Ph
CH3
TMS
Ph
A, 1 h
B, 3 h
92
82
Ph
Ph
O
O
O
(2f) (2:1)
Et
Et
Et
Et
C6H4Cl-p
+
7
1g
p-ClC6H4
Et
Et
Cyc
C6H4Cl-p
(2:1)
O
(2g)
a
All the reactions were carried out at rt using 1 mol % catalyst. Condition A: 1% AuCl3, in CH2Cl2. Condition B: 1% (PPh3)AuCl, 1% AgOTf, in THF. In all cases, R1¼H.
b
c
Isolated yields.
Cy is 1-cyclohexenyl group.
substitution at C1–C5 were all compatible with cyclization condi-
byproduct is ca. 1:1. It was suggested that the byproduct might be
dihydrofuran 5a, since it shows characteristic singlet at
5.42 ppm corresponding to side-chain vinylic proton of 5a, while
the signals of H-2 to H-4 appeared in the range of 5.85–6.01 ppm.
Compound 5a was highly unstable and could isomerize completely
to the corresponding furan 4a upon evaporation of the solvent or
chromatographic purification on Al2O3.11 When the reaction was
carried out at 50 ꢀC, the side product of 5a was mostly converted
into furan 4a during the reaction, and the desired furan 4a was
obtained in 70% yield.
tions, good yields of the corresponding furans were obtained in
each case (64–92%). Substitution at C-1 with an electron-with-
drawing group p-CF3C6H4, as in 1e, led to the corresponding
product 2e in 64% yield (Table 1, entry 5). Enynol substituted at C-3
with a TMS group (E-1f) resulted in partial desilylation during the
separation, the two products were obtained in a ratio of 2:1 with
a combined yield of 92% (Table 1, entry 6). When the alkyne moiety
in 1g terminated with 1-cyclohexenyl group, a double bond isom-
erization to an exocyclic double bond was observed, owing to better
conjugation with furan ring in product 2g (Table 1, entry 7).
a
d
The method has been applied successfully to a variety of (Z)-
enynols, and the results are summarized in Table 3. The cyclization
2.2. Gold-catalyzed formation of furans from various
substituted (Z)-2-en-4-yn-1-ols
Table 2
Optimization study of gold-catalyzed cyclization of (Z)-enynols
2
3
The requisite (Z)-enynols were easily synthesized through
multistep transformations by the modified procedures of the
published reports.10 We chose (Z)-enynol 1,5-diphenyl-pent-2-en-
4-yn-1-ol 3a for the optimization studies (Table 2). Treatment of 3a
with 1 mol % AuCl3 in CH2Cl2 resulted, however, in this case, in
a complicated reaction mixture as observed by 1H NMR. In the
presence of 1 mol % cationic gold(I) complex (PPh)3AuCl/AgOTf, the
desired furan 4a was isolated in 74% yield. Monitoring the reaction
mixture by TLC indicated that the expected furan 4a was accom-
panied by some amounts of a byproduct. The 1H NMR (in C6D6/THF)
of the reaction mixture revealed that the ratio of 4a with the
catalyst
solvent
1
4
Ph
Ph
Ph
Ph
O
O
Ph
HO
3a
Ph
4a
5a
Entry
Conditions
AuCl3 (1 mol %), in CH2Cl2, rt, 1 h
(Ph3P)AuCl/AgOTf (1 mol %), in THF, rt, 1 h
(Ph3P)AuCl/AgOTf (2 mol %), in THF, rt, 3 h
(Ph3P)AuCl/AgOTf (1 mol %), in THF, 50 ꢀC, 1 h
Isolated yield
of 4a (%)
da
1
2
3
4
74
73
70
Complicated reaction mixture was observed by 1H NMR.
a

X. Du et al. / Tetrahedron 65 (2009) 1839–1845
1841
Table 3
Formation of various substituted furans catalyzed by gold
Entry
1
Enynol
R2
R3
R4
R5
Product
Yielda (%)
70
Ph
3a
Ph
H
H
H
H
H
H
H
H
Ph
4a
Ph
O
Ar
Ar
2
3
4
5
6
7
3b
3c
3d
3e
3f
p-ClC6H4
H
H
H
H
H
Et
p-MeOC6H4
p-ClC6H4
Bu
4b Ar¼p-MeOC6H4
71b
85b
76
O
O
Cl
Cl
p-ClC6H4
4c Ar¼p-ClC6H4
Bu
Ph
Ph
Et
H
4d
Ph
Et
O
O
Ph
4e
67
Ar
p-MeOC6H4
Ph
4f Ar¼p-MeOC6H4
69
O
Et
3g
Ph
4g
99
Ph
Ph
O
Et
Ph
8
9
3h
3i
p-ClC6H4
Et
Et
H
H
Ph
Ph
4h
4i
92
86
O
Cl
Et
Ph
p-MeOC6H4
O
OMe
Et
10
11
12
13
14
3j
Ph
H
Et
H
H
H
H
H
Bu
Ph
H
4j
91b
93
Bu
Ph
O
Ph
3k
3l
Ph
Ph
Ph
Ph
4k
4l
Ph
Ph
O
Ph
H
57
Ph
O
Ph
3m
3n
H
4m
4n
67b
O
O
Ph
Ph
Ph
11b,c
Ph
Bu
Ph
15
3o
Ph
–(CH2)4–
Bu
4o
56d
Ph
O
a
Isolated yields. Unless noted, all the reactions were carried out using 1 mol % (Ph3P)AuCl/AgOTf as catalyst at 50 ꢀC for 1 h. In all cases, R1¼H.
b
c
Catalyst (5 mol %) was used.
In this case, some unidentified side products were formed.
The reaction was carried out at rt in dichloromethane for 30 min using 2 mol % (Ph3P)AuCl/AgOTf as catalyst.
d
of enynols 3a–3f unsubstituted both at C-2 and C-3 was in-
respectively (Table 3, entries 2 and 3). C-5 or C-1-Alkyl substituted
3d and 3e afforded the corresponding furans 4d and 4e in good
yields of 76% and 67%, respectively (Table 3, entries 4 and 5). C-1-
Unsubstituted 3f also afforded 4f in a satisfactory yield of 69% at
50 ꢀC (Table 3, entry 6). When the reaction was carried out at room
vestigated firstly. The aromatic rings of R2 and/or R5 bearing an
electron-withdrawing group (–Cl) or an electron-donating group
(–OMe) had no significant influence on the product yields, and the
desired furans 4b and 4c were isolated in 71% and 85% yields,

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X. Du et al. / Tetrahedron 65 (2009) 1839–1845
Table 4
Gold-catalyzed cyclization of (Z)-enynols: formation of (Z)-5-ylidene-2,5-dihydrofurans
Entry
Enynol
R1
R2
R3
R4
R5
Conditiona
A, 3 h
Product
Ph Ph
Yieldb (%)
Cl
1
6a
Me
o-ClC6H4
Ph
Ph
Ph
97
O
Ph
(7a)
Ph
Ph
2
3
4
6b
6c
6d
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Cyc
Bu
Ph
A, 1 h
A, 1 h
A, 3 h
92
89
91
O
Ph
(7b)
Ph
Ph
p-FC6H4
O
Bu
(7c)
F
Ph
Ph
Ph
O
Ph
(7d)
C3H7
C3H7
5
6
6e
Me
Me
p-FC6H4
C3H7
C3H7
Ph
B, 3 h
84
O
Ph
(7e)
F
S
Ph
Ph
O
6f
2-Thienyl
Ph
Ph
Ph
Ph
p-MeC6H4
B, 3 h
87
83
(7f)
Me
Ph
Ph
Cl
7
8
6g
Me
Ph
o-ClC6H4
Bu
A, 1 h
O
Bu
(7g)
H
NOE
H
Ph
Ph
6h
6i
Ph
H
H
H
Ph
Ph
B, 30 min
B, 50 min
85
87
O
Ph
(7h)
Ph
9
–(CH2)5–
Ph
O
(7i)
Ph
a
All the reactions were carried out at rt using 1 mol % catalyst. Condition A: 1% AuCl3, in CH2Cl2. Condition B: 1% (PPh3)AuCl, 1% AgOTf, in THF.
Isolated yields.
Cy is 1-cyclohexenyl group.
b
c
temperature, enynol 3f could not be completely consumed even
enynols with a phenyl substituent at C-1 (3l) or without any sub-
stituent at C-1 (3m) led to moderate to good yields of 4l–4m (Table
3, entries 12 and 13). However, for 1,3,5-triphenyl-pent-2-en-4-yn-
1-ol 3n substituted at C-1 with a phenyl group and with an internal
triple bond, only low yield (11%) of 4n was observed (Table 3, entry
14). In this case, the main products were isolated as a mixture of
two compounds, the structure of which has not been identified yet
(they could not be separated from each other through column
chromatography). A furan derivative fused with a six-membered
ring 4o could also be synthesized in 56% yield by this method
prolonged the reaction time to 48 h. Introducing one more sub-
stituent at C-2, that means for enynols 3g–3j, resulted in an in-
crease in reactivity as shown in entries 7–10, the corresponding
products 4g–4j were formed in high yields of 86–99%. This may due
to the steric effect between a C-1 and C-2 group, which makes the
hydroxyl group much closer to the triple bond. The results of
enynols bearing a phenyl group at C-3 are highly dependent on the
substituents at C-1 and C-5. C-1-Unsubstituted 3k afforded furan
4k smoothly in a high yield of 93% (Table 3, entry 11). Terminal

X. Du et al. / Tetrahedron 65 (2009) 1839–1845
1843
R4
R3
R4
R3
R1
R4
R3
R1
R4
R3
H
+ H+
R1
R2
Au
R5
+
_
+
Au+
H
+
+
R2
R2 when R1=H
path a
R2
O
O
R5
5
O
HO
1, 3 or 6
R
Au+
R5
H
8
7
9
when R1=H
path b
-H+
R4
R3
R4
Au
R3
H
Au
R5
-H+
+ H+
Au+
R2
2 or 4
+
R2
O
O
10
R5
11
Scheme 2.
(Table 3, entry 15). It is interesting to note that this strategy
offers the additional flexibility to the existing methodology in the
creation of regiochemical patterns around the furan nucleus.
3. Experimental section
3.1. General
All reactions were carried out under nitrogen or argon. THF
was distilled from sodium and benzophenone. All commercially
available materials were used without further purification.
AuCl(PPh3) was prepared according to the published method.12
AuCl3 was used as a 0.05 M solution in MeCN AuCl(PPh3) was used
as a 0.05 M solution in THF and AgOTf was used as a 0.05 M or
0.1 M solution in THF. 1H and 13C NMR spectra were recorded at
300 and 75.4 MHz, respectively, on Varian XL-300 MHz spectro-
meter at room temperature, and in CDCl3 (containing 0.03% TMS)
solutions.
2.3. Gold-catalyzed formation of dihydrofurans from (Z)-2-
en-4-yn-1-ols bearing a tertiary alcoholic group
We have also investigated the cyclization of (Z)-enynols 6
bearing a tertiary alcoholic group for the synthesis of dihydrofur-
ans. To our delight, it has been proved that the cyclization pro-
ceeded quite smoothly using these substrates to afford the high
yields of fully or non-fully substituted dihydrofurans 7 (Table 4).
The alkyne moiety in enynols 6 bearing an aromatic ring as well as
alkyl substrate, all reacted very well to provide the 5-exo-dig cy-
clization products in high yields (83–97%). The appearance of a vi-
nylic group at C-5 in 6b did not influence the efficiency of this
reaction, in which the corresponding product 7b was formed in 92%
yield (Table 4, entry 2). C-1-Substituted with two phenyl groups 6h
afforded the desired 5-benzylidene-2,2-diphenyl-2,5-dihydrofuran
7h in 85% yield, while a spirocyclic dihydrofuran 7i was formed in
87% yield for 50 min (Table 4, entries 8 and 9). A high reactivity of
enynols 6 may also due to the steric effect between two groups on
tertiary alcoholic carbon, which makes the hydroxyl group closer to
the triple bond. It is interesting to note that only stereoisomerically
pure compounds (Z)-7 derived from 5-exo-dig cyclization were
obtained. The stereochemistry of the products was unambiguously
established by 2D NMR spectroscopy of several products and the
single-crystal analysis of 7a.9 The results suggested that the acti-
vation of the alkyne and the subsequent addition of the oxygen
nucleophile were highly stereoselective.
The spectroscopic data of 2a–2g, 7a–7g have been reported.9
The spectroscopic data of 4a,13 4d,14 4f,15 4l,16 4m,17 and 4n18 are
in agreement with those previously reported.
3.2. A typical procedure for the gold-catalyzed synthesis of
furans and dihydrofurans from (Z)-enynols
To a solution of (Z)-enynols (0.35 mmol) in 3.5 mL THF was
added 1 mol % (PPh3)AuCl followed by AgOTf (1 mol %). The
resulting solution was stirred at 50 ꢀC or at room temperature until
the reaction was complete as monitored by thin-layer chromato-
graphy. The solvent was removed in vacuo and the residue was
purified by flash chromatography on neutral Al2O3 or silica gel to
afford the furan and dihydrofuran derivatives 2, 4 or 7.
3.2.1. 2-(4-Chlorophenyl)-5-(4-methoxybenzyl)furan (4b)
Column chromatography on neutral Al2O3 (eluent: petroleum
ether/ethyl acetate¼40:1) afforded the title product in 71% isolated
2.4. Mechanistic aspects
yield as a white solid. Mp 77–79 ꢀC. 1H NMR (CDCl3, Me4Si)
d 3.77
(s, 3H), 3.94 (s, 2H), 6.02 (s, 1H), 6.51 (d, J¼3.0 Hz, 1H), 6.85 (d,
We propose the following mechanism for this reaction, which is
analogous to what has been previously reported on Pd-catalyzed
cycloisomerization of (Z)-enynols6a (Scheme 2). In the first step, the
coordination of the triple bond of enynol 1, 3 or 6 to PPh3AuOTf
enhances the electrophilicity of alkyne, and the subsequent anti-5-
exo-dig nucleophilic attack of the hydroxyl group on a Au(I)–alkyne
J¼8.4 Hz, 2H), 7.18 (d, J¼8.1 Hz, 2H), 7.28 (d, J¼8.1 Hz, 2H), 7.51 (d,
J¼8.4 Hz, 2H); 13C NMR (CDCl3, Me4Si)
d 33.71, 55.17, 106.22, 108.31,
113.86, 124.56, 128.70, 129.5, 129.47, 129.78, 132.32, 151.66, 155.17,
158.23; IR (neat) 3007, 2937, 1515, 1253, 1031, 824, 683 cmꢁ1. Anal.
Calcd for C18H15O2Cl: C, 72.36; H, 5.06; Cl, 11.87. Found C, 71.96; H,
5.12; Cl, 12.24.
complex would form complex 8. Protonolysis of
8 affords
dihydrofuran 7 and regenerate Auþ. Furans 2 or 4 were formed
either by isomerization of 7 (path a) or through isomerization/
protonolysis pathway (path b). The above results also indicated that
the oxyauration from (Z)-enynols is highly stereoselective.
3.2.2. 2-(4-Chlorobenzyl)-5-(4-chlorophenyl)furan (4c)
Column chromatography on neutral Al2O3 (eluent: petroleum
ether/ethyl acetate¼40:1) afforded the title product in 85% isolated
yield as a white solid. Mp 91–93 ꢀC. 1H NMR (CDCl3, Me4Si)
d 3.95 (s,
In summary, we have developed a highly efficient Au(I)-cata-
lyzed cyclization of (Z)-enynols that proceeds under neutral con-
ditions at room temperature or 50 ꢀC. This methodology provides
rapid access to substituted furans and stereodefined (Z)-5-ylidene-
2H), 6.03 (d, J¼2.7 Hz, 1H), 6.50 (d, J¼3.0 Hz, 1H), 7.16 (d, J¼8.4 Hz,
2H), 7.24–7.29 (m, 4H), 7.47–7.51 (m, 2H); 13C NMR (CDCl3, Me4Si)
d
33.89,106.21,108.73,124.58,128.61,128.73,129.29,130.02,132.34,
132.50, 136.22, 151.94, 153.93; IR (neat) 1540, 1481, 1093, 829,
796 cmꢁ1. Anal. Calcd for C17H12OCl2: C, 67.35; H, 3.99; Cl, 23.39.
Found C, 67.11; H, 4.14; Cl, 23.24.
2,5-dihydrofurans in
a regioselective manner from suitably
substituted (Z)-2-en-4-yn-1-ols.

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X. Du et al. / Tetrahedron 65 (2009) 1839–1845
3.2.3. 2-Benzyl-5-ethylfuran (4e)
a pale yellow oil. 1H NMR (CDCl3, Me4Si)
d
0.90 (t, J¼6.6 Hz, 3H),
Column chromatography on neutral Al2O3 (eluent: petroleum
1.31–1.38 (m, 4H), 1.61–1.77 (m, 6H), 2.45 (t, J¼5.7 Hz, 2H), 2.57 (t,
ether/ethyl acetate¼60:1) afforded the title product in 67% isolated
J¼7.5 Hz, 2H), 2.75 (t, J¼6.0 Hz, 2H), 7.12–7.20 (m, 1H), 7.32–7.37 (m,
yield as a colorless oil. 1H NMR (CDCl3, Me4Si)
d
1.19 (t, J¼7.2 Hz,
2H), 7.58 (d, J¼7.2 Hz, 2H); 13C NMR (CDCl3, Me4Si)
d 14.05, 20.65,
3H), 2.59 (q, J¼7.5 Hz, 2H), 3.91 (s, 2H), 5.85 (s, 2H), 7.18–7.31 (m,
22.46, 22.99, 23.04, 23.49, 26.36, 28.04, 31.48, 117.95, 119.09, 123.79,
125.46, 128.39, 132.40, 144.35, 149.17; IR (neat) 3056, 2932, 1768,
1671, 1492, 762 cmꢁ1; HRMS (EI) calcd for C19H24O: 268.1827, found
268.1839.
5H); 13C NMR (CDCl3, Me4Si)
d
12.12, 21.33, 34.51, 104.31, 106.62,
126.30, 128.38, 128.67, 138.45, 152.55, 156.74; IR (neat) 3029, 2973,
1564, 1496, 1454, 1012, 706 cmꢁ1; HRMS (EI) calcd for C13H14O:
186.1045, found 186.1049.
3.2.10. (Z)-5-Benzylidene-2,2-diphenyl-2,5-dihydrofuran (7h)
Column chromatography on silica gel (eluent: petroleum ether)
afforded title product in 85% isolated yield as a pale yellow oil. 1H
3.2.4. 5-Benzyl-3-ethyl-2-phenylfuran (4g)
Column chromatography on neutral Al2O3 (eluent: petroleum
ether/ethyl acetate¼60:1) afforded the title product in 99% isolated
NMR (CDCl3, Me4Si)
d
5.44 (s, 1H), 6.28 (d, J¼5.4 Hz, 1H), 6.69 (d,
yield as a yellow oil. 1H NMR (CDCl3, Me4Si)
d
1.18 (d, J¼7.5 Hz, 3H),
J¼5.4 Hz, 1H), 7.09–7.13 (m, 1H), 7.22–7.37 (m, 12H), 7.73 (d,
2.61 (q, J¼7.5 Hz, 2H), 3.95 (s, 2H), 5.95 (s, 1H), 7.15–7.34 (m, 8H),
J¼7.8 Hz, 2H); 13C NMR (CDCl3, Me4Si)
d 98.54, 99.65, 125.29,
7.56 (d, J¼7.8 Hz, 2H); 13C NMR (CDCl3, Me4Si)
d
14.37, 19.17, 34.59,
126.04, 126.50, 127.72, 127.88, 128.35, 128.37, 136.58, 137.50, 142.60,
109.80, 123.85, 125.21, 126.34, 126.40, 128.39, 128.44, 128.76, 131.91,
138.06, 146.85, 153.11; IR (neat) 3085, 2967, 1599, 1493, 982,
695 cmꢁ1; HRMS (EI) calcd for C19H18O: 262.1358, found 262.1353.
158.60; IR (neat) 3084, 1953, 1765, 1649, 1490, 937, 694 cmꢁ1
HRMS (EI) calcd for C23H18O: 310.1358, found 310.1349.
;
3.2.11. (Z)-2-Benzylidene-3-phenyl-1-oxa-spiro[4.5]dec-3-ene (7i)
3.2.5. 5-Benzyl-2-(4-chlorophenyl)-3-ethylfuran (4h)
Column chromatography on silica gel (eluent: petroleum ether)
afforded the title product as a brown solid in 87% isolated yield. Mp
Column chromatography on neutral Al2O3 (eluent: petroleum
ether/ethyl acetate¼60:1) afforded the title product in 92% isolated
112–114 ꢀC.1H NMR (CDCl3, Me4Si)
d 1.37–1.48 (m,1H),1.56–1.73 (m,
yield as a pale yellow oil. 1H NMR (CDCl3, Me4Si)
d
1.17 (t, J¼7.5 Hz,
5H),1.79–1.93 (m, 4H), 5.42 (s,1H), 6.31 (s,1H), 7.09 (tt, J¼7.5,1.2 Hz,
3H), 2.57 (q, J¼7.5 Hz, 2H), 3.95 (s, 2H), 5.96 (s, 1H), 7.19–7.32 (m,
1H), 7.26–7.32 (m, 2H), 7.34–7.46 (m, 5H), 7.67 (d, J¼7.8 Hz, 2H); 13C
7H), 7.44–7.48 (m, 2H); 13C NMR (CDCl3, Me4Si)
d
14.24,19.20, 34.57,
NMR (CDCl3, Me4Si) d 22.94, 25.11, 36.02, 91.95, 97.60,124.81,127.56,
109.95, 124.40, 126.28, 126.48, 128.48,128.57, 128.75, 130.35,131.89,
137.88, 145.80, 153.43; IR (neat) 3085, 2968, 1487, 1094, 982,
128.14, 128.21, 128.43, 128.48, 133.32, 136.99, 137.44, 138.73, 158.46.
Anal. Calcd for C22H22O: C, 87.38; H, 7.33. Found C, 87.16; H, 7.14.
830 cmꢁ1
296.0979.
; HRMS (EI) calcd for C19H17OCl: 296.0968, found
Acknowledgements
3.2.6. 5-Benzyl-3-ethyl-2-(4-methoxyphenyl)furan (4i)
We thank the National Natural Science Foundation of China
(Grant Nos. 20732008, 20872163), Chinese Academy of Science,
Science and Technology Commission of Shanghai Municipality
(Grant Nos. 08QH14030, 07JC14063) and the Major State Basic
Research Development Program (Grant No. 2006CB806105) for fi-
nancial support.
Column chromatography on neutral Al2O3 (eluent: petroleum
ether/ethyl acetate¼60:1) afforded the title product in 86% isolated
yield as a yellow oil. 1H NMR (CDCl3, Me4Si)
d
1.18 (t, J¼7.5 Hz, 3H),
2.58 (q, J¼7.5 Hz, 2H), 3.75 (s, 3H), 3.95 (s, 2H), 5.94 (s, 1H), 6.89 (d,
J¼9.0 Hz, 2H), 7.20–7.32 (s, 5H), 7.48 (d, J¼9.0 Hz, 2H); 13C NMR
(CDCl3, Me4Si)
d 14.46, 19.05, 34.57, 55.13, 109.54, 113.84, 122.22,
124.86,126.35,126.70,128.41,128.75,138.19,146.90,152.45, 158.20;
IR (neat) 3029, 2965, 1604, 1505, 1251, 1177, 832 cmꢁ1; HRMS (EI)
calcd for C20H20O2: 292.1463, found 292.1468.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.11.109.
3.2.7. 3-Ethyl-5-pentyl-2-phenylfuran (4j)
Column chromatography on neutral Al2O3 (eluent: petroleum
ether/ethyl acetate¼100:1) afforded the title product in 91% iso-
References and notes
lated yield as a pale yellow oil. 1H NMR (CDCl3, Me4Si)
d 0.91 (t,
1. (a) Heaney, H.; Ahn, J. S. In Comprehensive Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 2, pp 297–
436; (b) Ko¨nig, B. In Science of Synthesis, Houben-Weyl Methods of Molecular
Transformations; Maas, G., Ed.; Georg, Thieme: Stuttgart, New York, NY, 2001;
Vol. 9, pp 183–285; (c) The Chemistry of Heterocycles: Structure, Reactions,
Syntheses, and Applications; Eicher, T., Hauptmann, S., Eds.; Wiley-VCH: Wein-
heim, 2003; (d) Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
2. (a) Maier, M. In Organic Synthesis Highlights II; Waldmann, H., Ed.; VCH:
Weinheim, 1995; pp 231–242; (b) Benassi, R. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Ox-
ford, 1996; Vol. 2, pp 259–295; (c) Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991.
J¼6.9 Hz, 3H), 1.23 (t, J¼7.5 Hz, 3H), 1.34–1.39 (m, 4H), 1.63–1.72 (m,
2H), 2.60–2.69 (m, 4H), 5.99 (s, 1H), 7.18–7.22 (m, 1H), 7.37 (t,
J¼7.8 Hz, 2H), 7.58 (d, J¼7.2 Hz, 2H); 13C NMR (CDCl3, Me4Si)
d
14.02, 14.44, 19.23, 22.44, 27.75, 28.09, 31.46, 108.25, 123.73,
125.10, 126.14, 128.41, 132.13, 146.04, 155.17; IR (neat) 3085, 2931,
1600, 1492, 1070, 763, 694 cmꢁ1; HRMS (EI) calcd for C17H22O:
242.1671, found 242.1665.
3.2.8. 2-Benzyl-3-phenylfuran (4k)
Column chromatography on neutral Al2O3 (eluent: petroleum
ether/ethyl acetate¼60:1) afforded title product in 93% isolated
3. For recent reviews, see: (a) 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; (b) Keay, B. A. Chem.
Soc. Rev. 1999, 28, 209.
yield as a paleyellowoil.1H NMR (CDCl3, Me4Si)
d 4.12 (s, 2H), 6.53 (d,
4. (a) Marshall, J. A.; Robinson, E. D. J. Org. Chem. 1990, 55, 3450; (b) Marshall, J. A.;
Wang, X.-J. J. Org. Chem. 1991, 56, 960; (c) Marshall, J. A.; Bartley, G. S. J. Org.
Chem. 1994, 59, 7169; (d) Marshall, J. A.; Wallace1, E. M. J. Org. Chem. 1995, 60,
796; (e) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1995, 60, 5966; (f) Hashmi,
A. S. K.; Ruppert, T. L.; Kno¨fel, T.; Bats, J. W. J. Org. Chem. 1997, 62, 7295; (g)
Hashmi, A. S. K.; Schwarz, L.; Choi, J.; Frost, T. M. Angew. Chem., Int. Ed. 2000,
112, 2285; (h) Ma, S.; Zhang, J. Chem. Commun. 2000, 117; (i) Ma, S.; Zhang, J.;
Lu, L. Chem.dEur. J. 2003, 9, 2447; (j) Sromek, A. W.; Rubina, M.; Gevorgyan, V.
J. Am. Chem. Soc. 2005, 127, 10500; (k) Zhou, C.-Y.; Chan, P. W. H.; Che, C.-M. Org.
Lett. 2006, 8, 325; For a recent review, see: (l) Brown, R. C. D. Angew. Chem., Int.
Ed. 2005, 44, 850.
J¼1.5 Hz, 1H), 7.18–7.40 (m, 11H); 13C NMR (CDCl3, Me4Si)
d 32.78,
111.31, 122.33, 126.38, 126.65, 127.70, 128.28, 128.51, 128.55, 128.61,
133.83,138.45,141.26,149.23; IR (neat) 3029,1603,1494,1140,1057,
697 cmꢁ1; HRMS (EI) calcd for C17H14O: 234.1045, found 234.1041.
3.2.9. 1-Pentyl-3-phenyl-4,5,6,7-tetrahydro-isobenzofuran (4o)
Column chromatography on silica gel (eluent: petroleum ether/
ethyl acetate¼60:1) afforded title product in 56% isolated yield as

X. Du et al. / Tetrahedron 65 (2009) 1839–1845
1845
5. (a) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. J. Org. Chem. 1991, 56,
5816; (b) Arcadi, A.; Cacchi, S.; Larock, R. C.; Marinelli, F. Tetrahedron Lett. 1993,
34, 2813.
Nue´n˜ez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326; (n) Gorin, D. J.; Sherry,
B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351; (o) Patil, N. T.; Yamamoto, Y. Chem.
Rev. 2008, 108, 3395.
6. (a) Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64, 7687 and ref-
9. Liu, Y.; Song, F.; Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7, 5409.
10. (a) Takeuchi, R.; Tanabe, K.; Tanaka, S. J. Org. Chem. 2000, 65, 1558; (b) Marshall,
J. A.; DeHoff, B. S. J. Org. Chem.1986, 51, 863; (c) Tang, J.; Bhunia, S.; Abu Sohel, S. M.;
Lin, M.-Y.; Liao, H.-Y.; Datta, S.; Das, A.; Liu, R.-S. J. Am. Chem. Soc. 2007, 129, 15677;
(d) Zhang, Y.; Herndon, J. W. Org. Lett. 2003, 5, 2043; (e) Kim, K. D.; Magriotis, P. A.
Tetrahedron Lett. 1990, 43, 6137; (f) Romero, D. L.; Fritzen, E. L. Tetrahedron Lett.
1997, 38, 8659.
11. Similar isomerization has been observed in Pd-catalyzed coupling of butatrienyl
carbinols with aryl halides and triflates to furans: Aurrecoechea, J. M.; Pe´rez, E.
Tetrahedron 2004, 60, 4139.
12. Braunstein, P.; Lehner, H.; Matt, D. Inorg. Synth. 1990, 27, 218.
13. Imagawa, H.; Kurisaki, T.; Nishizawa, M. Org. Lett. 2004, 6, 3679.
14. Jeevanandam, A.; Narkunan, K.; Ling, Y. J. Org. Chem. 2001, 66, 6014.
15. Hashmi, A. S. K.; Schwarz, L.; Bats, J. W. J. Prakt. Chem. 2000, 342, 40.
16. Zhan, Zh.; Cai, X.; Wang, Sh.; Yu, J.; Liu, H.; Cui, Y. J. Org. Chem. 2007, 72, 9838.
17. Shu, H.; Shiu, L.; Wang, Sh.; Wang, S.; Lee, G.; Peng, Sh.; Liu, R. J. Am. Chem. Soc.
1996, 118, 530.
ˇ
erences therein; (b) Ve´gh, D.; Zalupsky, P.; Kova´c, J. Synth. Commun. 1990, 20,
1113; (c) Marshall, J. A.; Dubay, W. J. J. Org. Chem. 1993, 58, 3435; (d)
Marshall, J. A.; Bennett, C. E. J. Org. Chem. 1994, 59, 6110; (e) Marshall, J. A.;
Dubay, W. J. J. Org. Chem. 1994, 59, 1703; (f) Seiller, B.; Bruneau, C.; Dixneuf,
P. H. J. Chem. Soc., Chem. Commun. 1994, 493; (g) Ku¨cu¨kbay, H.; Cetinkaya, B.;
Guesmi, S.; Dixneuf, P. H. Organometallics 1996, 15, 2434; (h) Seiller, B.;
Bruneau, C.; Dixneuf, P. H. Tetrahedron 1995, 51, 13089; (i) See Ref. 4e.
7. Lou, F.-T.; Bajji, A. C.; Jeevanandam, A. J. Org. Chem. 1999, 64, 1738.
8. For reviews on gold-catalyzed reactions, see: (a) Dyker, G. Angew. Chem., Int. Ed.
2000, 39, 4237; (b) Bond, G. C. Catal. Today 2002, 72, 5; (c) Hashmi, A. S. K. Gold
Bull. 2003, 36, 3; (d) Hashmi, A. S. K. Gold Bull. 2004, 37, 51; (e) Arcadi, A.;
Giuseppe, S. D. Curr. Org. Chem. 2004, 8, 795; (f) Hoffmann-Ro¨der, A.; Krause, N.
Org. Biomol. Chem. 2005, 3, 387; (g) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2005,
44, 6990; (h) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45,
7896; (i) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180; (j) Ma, S.; Yu, S.; Gu, Z.
Angew. Chem., Int. Ed. 2006, 45, 200; (k) Li, Z.; Brouwer, C.; He, C. Chem. Rev.
´
2008, 108, 3239; (l) Arcadi, A. Chem. Rev. 2008, 108, 3266; (m) Jimeenez-
18. Brown, C. D.; Chong, J. M.; Shen, L. Tetrahedron Lett. 1999, 55, 14233.