A facile synthesis of indole-furan conjugates via integration of convergent and linear domino reactions

Article abstract of DOI:10.1016/j.tet.2011.05.058

The convergent and linear domino reactions have been first integrated, for the first time, to provide an efficient synthesis of indole-furan conjugates from indoles, methyl ketones, and 1,3-dicarbonyl compounds.

Full text of DOI:10.1016/j.tet.2011.05.058

Tetrahedron 67 (2011) 5142e5149
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A facile synthesis of indoleefuran conjugates via integration of convergent
and linear domino reactions
*
Yan Yang, Meng Gao, Liu-Ming Wu, Cong Deng, Dong-Xue Zhang, Yang Gao, Yan-Ping Zhu, An-Xin Wu
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The convergent and linear domino reactions have been first integrated, for the first time, to provide an
efficient synthesis of indoleefuran conjugates from indoles, methyl ketones, and 1,3-dicarbonyl
compounds.
Received 24 March 2011
Received in revised form 6 May 2011
Accepted 13 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 19 May 2011
Keywords:
Domino reaction
FriedeleCrafts alkylation
PaaleKnorr cyclization
Furan
Indole
Biheteroaryls
1. Introduction
The indole and furan skeletons are privileged scaffolds in medicinal
chemistry, and they have been widely found in natural products
In modern synthetic chemistry, a growing trend toward green
and sustainable synthesis has been well illustrated by domino
reactions,1 which allow the direct synthesis of complex molecules
in a highly efficient way. However, as many reactions are not
compatable with each other in one domino process, a practical
synthetic strategy usually has to consist of step-wise reactions. In
this context, we envision that a series of coupled domino processes
could be rationally designed for target molecules to minimize
reaction steps and maximize synthetic efficiency.
Up to now, most domino reactions reported in the literature
proceed along a linear route (Fig. 1a).1 Because it would be more
efficient if two or more parallel domino routes could coexist in one-
pot and converge on the final product, we have developed a self-
sorting domino reaction and a focusing domino reaction (Fig. 1b
and c).2 Considering the necessity of step-wise reactions for com-
plex architectures, it would be particularly attractive if convergent
and linear domino reactions could be efficiently integrated in two-
step reactions to afford the desired products (Fig. 1d and e).
Because of the pharmacological importance of heterocycles,
their efficient and elegant synthesis would be an ideal testing
ground for demonstrating the power and potential of this strategy.
and therapeutic agents.3 As the combination of two or more dif-
ferent heterocyclic moieties in a single molecule would enhance
biological activity significantly,4 a series of promising biheteroaryls
containing indole or furan skeletons have been prepared.5 How-
ever, there are only few examples reported in the literature for the
synthesis of 3-(furan-3-yl or 4-yl)indole derivatives,6 partly due to
the difficulty in obtaining the starting materials. Considering the
potential biological activity of this class of biheterocyclic com-
pounds, it is highly desirable to develop an efficient and practical
method for their synthesis.
Integration of Domino Reactions
(a)
Linear Domino Reaction
(d)
(b)
Self-sorting Domino Reaction
(e)
(c)
Focusing Domino Reaction
* Corresponding author. Tel.: þ86 027 6786 7773; e-mail address: chwuax@
mail.ccnu.edu.cn (A.-X. Wu).
Fig. 1. Integration of convergent and linear domino reactions.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.058

Y. Yang et al. / Tetrahedron 67 (2011) 5142e5149
5143
Table 1
Recently, we have established two efficient convergent domino
Optimization of the reaction conditionsa
reactions for the preparation of various substituted 1,4-enediones:
(a) homo-coupling of methyl ketones via self-sorting domino
reaction; (b) hetero-coupling of 1,3-dicarbonyl compounds and
methyl ketones or terminal aryl alkenes via focusing domino re-
action (Scheme 1). Remarkably, both of them start from readily
available, inexpensive substrates with good tolerance of various
functional groups. Inspired by these discoveries, we envisaged that
exposure of indoles to these 1,4-enedione electrophiles would
undergo linear domino FriedeleCrafts alkylation/PaaleKnorr
cyclization to afford the expected 3-(furan-3-yl or 4-yl)indole
derivatives. In combination with the convergent domino synthesis
of 1,4-enediones, this linear domino FriedeleCrafts alkylation/
PaaleKnorr cyclization would enable a two-step synthesis of di-
verse 3-(furan-3-yl or 4-yl)indole derivatives.
Entry
Catalyst (equiv)
Solvent
Temp (ꢀC)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
InCl3 (0.1)
AlCl3 (0.1)
ZnCl2 (0.1)
CuCl2 (0.1)
Cu(CF3SO3)2 (0.1)
FeCl3 (0.1)
CH3SO3H (0.1)
CH3SO3H (0.3)
CH3SO3H (0.5)
H2SO4 (0.5)
CF3SO3H (0.5)
PTSA (0.5)
HCl (0.5 )
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
DCE
40
40
40
40
40
40
81
81
81
81
81
81
81
81
81
110
84
40
62
77
80
78
12
12
12
12
12
12
12
12
8
8
8
8
8
8
8
8
8
8
8
8
8
27
5
9
0
20
16
74
86
99
90
82
91
8
9
2. Results and discussion
10
11
12
13
14
15
16
17
18
19
20
21
22
Our initial investigations were focused on the systematic eval-
uation of different catalysts for the desired domino FriedeleCrafts
alkylation/PaaleKnorr cyclization of indole 1a and 1,4-enedione
2a7 (Table 1). Different Lewis acids were first examined in this re-
action, but the desired product 4a was obtained in very low yields,
such as InCl3, AlCl3, ZnCl2, CuCl2, Cu(CF3SO3)2, and FeCl3 (Table 1,
entries 1e6). We reasoned that the poor catalytic activity of Lewis
acids might be ascribed to their weak acidity and sensitivity of
water. Accordingly, we began searching for the appropriate
Brønsted acids that would readily catalyze the domino reaction.
Gratifyingly, switching the catalyst to CH3SO3H (0.1 equiv) fur-
nished the product 4a in 74% yield after 12 h in MeCN at reflux
(entry 7). Increasing the loading of catalyst to 0.5 equiv, the reaction
could complete in less than 8 h with quantitative yield (entry 9).
Other sulfonic acids tested could also promote this domino re-
action, although lower yields were obtained (entries 10e12). When
the reaction was carried out in the presence of other Brønsted acids,
such as HCl, HOAc, and CF3CO2H, the yields decreased dramatically
HOAc (0.5)
0
CF3COOH (0.5)
CH3SO3H (0.5)
CH3SO3H (0.5)
CH3SO3H (0.5)
CH3SO3H (0.5)
CH3SO3H (0.5)
CH3SO3H (0.5)
CH3SO3H (0.5)
15
49
61
90
59
70
0
CH2Cl2
CHCl3
EtOAc
DMSO
EtOH
8
85
a
Reaction conditions: 1a (1.2 mmol) and 2a (1.0 mmol) in 5 mL of solvent under
an atmosphere of argon.
b
Isolated yields. PTSA¼p-toluenesulfonic acid; DCE¼1,2-dichloroethane.
(entries 13e15). The reaction was also studied in other solvents,
however, the yield of the desired product was decreased (entries
16e22). Thus, the use of CH3SO3H (0.5 equiv) in MeCN at reflux was
found to be the most efficient conditions.
O
O
I-
S
I
R5
R5
O
O O
R5
R5
R5 CH3
O
O
-H2O
S
I
R5
R5 CHO
Self-sorting Domino Reaction
O
O
O
O
O
I
R1 CH3
R1
O O
R1 CHO
R2
R3
R2
R3
R1
O
O
-H2O
R1
O
I
R1
R1 CHO
Focusing Domino Reaction
R2
R3
O O
O
R2
R3
R1
R1
O
O
O O
N
R4
R1
R2
R3
N
N
R4
R4
Friedel-Crafts
Alkylation
Paal-Knorr
Cyclization
R5
O
O
R5
O O
O O
R5
R5
R5
R5
S
S
S
N
R4
N
R4
Intermolecular Domino Reaction
Scheme 1. Two-step synthesis of indoleefuran conjugates.

5144
Y. Yang et al. / Tetrahedron 67 (2011) 5142e5149
Encouraged by the successful synthesis of 3-furyl-substituted
Next, we extend this domino process to a-methylthio-
indole 4a, a series of unsymmetrical 1,4-enediones 2 were used to
explore the scope of this synthetic strategy under optimal
conditions. In general, this reaction showed broad tolerance for
aromatic R1 substituents (Table 2, entries 1e13). For example,
substrates with electron-neutral (H, CH3), electron-rich (OCH3),
electron-deficient (NO2), and sterically hindered (1-naphthyl,
2-naphthyl) R1 substituents all reacted efficiently to afford the
desired products in excellent yields (Table 2, entries 1e6). Much
to our satisfaction, high yields were also obtained with haolo-
genated and hydroxylated substrates (Table 2, entries 7e11). The
heteroaryl groups for R1 were also investigated, such as 3-thienyl
group, the corresponding product could be obtained in an ex-
cellent yield (Table 2, entry 12). However, only 26% yield was
obtained with 2-benzofuryl group (Table 2, entry 13), while an
intricate mixture of byproducts was formed with 2-furyl or
1-methyl-1H-pyrrol-3-yl group (Table 2, entries 14e15). We have
also examined the effect on the yields by varying the electronic
and steric nature of R2, R3, and R4 substituents, while retaining R1
as a phenyl group. As to the substituents R2, various electron-
donating, electron-withdrawing, and halogen groups on the aryl
ring were compatible with the reaction conditions, and the cor-
responding products were obtained in high yields (Table 2,
entries 16e20). Unfortunately, the yield was much lower with
2-furyl group for R2 (Table 2, entry 21). To our delight, when R2
and R3 both were phenyl or methyl groups, the reaction
proceeded cleanly to give the desired products (Table 2, entries
22e23). Furthermore, an excellent yield was observed when
substituted 1,4-enediones with the aim of introducing methylthio
groups into the biheteroaryls. The methylthio-substituted hetero-
cycles are particularly attractive since they are found as structural
elements in many bioactive compounds as well as electronic,
magnetic, and optical materials.8 In addition, they are also versatile
intermediates for further transformations, such as transition-
metal-catalyzed cross-coupling reaction,9 additioneelimination,10
and electrophilic cyclization.11 Therefore, the development of an
efficient and convenient protocol for their synthesis remains an
area of ongoing interest. Because of the electron-donating property
of methylthio group compared to carbonyl group, the electrophi-
licity of a-methylthio-substituted 1,4-enediones was lower toward
FriedeleCrafts alkylation and a prolonged reaction time was
needed (Table 3, 24 h). In addition, the nature of substituents in the
aromatic ring shows strong influence on the reaction efficiency. For
example, substrates with electron-neutral (He, Mee) and electron-
withdrawing (NO2e) groups gave higher yields (Table 3, entries
1e3) than electron-donating counterpart (MeOe) (Table 3, entry 4).
Significantly, the steric (2-naphthyl) and halogen substituted
(Cle, Bre, Fe) substrates could give their corresponding products in
high yields (Table 3, entries 5e8). Furthermore, heterocyclic sub-
strate for 3-thiophenyl group could also work well under this
condition (Table 3, entry 9). Unfortunately, an intricate mixture of
byproducts was formed with 2-furyl group (Table 3, entry 10).
Table 3
Reaction scope of a
-methylthio-substituted 1,4-enediones 3aa
1-methyl-1H-indole 1b was used as
a substrate (Table 2,
entry 24).
Table 2
Reaction scope of indoles 1 and 1,4-enediones 2a
Entry
3
R5
5
Yieldb(%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
83
86
97
47
91
89
87
92
82
dc
4-MeC6H4
4-NO2C6H4
4-MeOC6H4
2-Naphthyl
4-ClC6H4
4-BrC6H4
4-FC6H4
Entry R1
R2
R3
R4
4
Yieldb(%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4a 99
4b 94
4c 96
4d 92
4e 85
4f 95
4g 84
4h 82
4i 89
4j 90
4k 83
4l 92
4m 26
4n dc
4o dc
4p 85
4q 97
4r 95
4s 92
4t 87
4u 24
4v 94
4w 96
4-MeC6H4
4-MeOC6H4,
4-NO2C6H4
1-Naphthyl
2-Naphthyl
4-ClC6H4
3,4-Cl2C6H3
4-BrC6H4
4-FC6H4
4-OHC6H4
3-Thienyl
2-Benzofuryl
2-Furyl
3-Thienyl
2-Furyl
10
3j
5j
a
Reaction conditions: 1a (1.2 mmol), 3 (1.0 mmol), and CH3SO3H (0.5 mmol) in
MeCN (5 mL) at reflux for 24 h.
b
Isolated yields.
An intricate mixture of byproducts was formed.
c
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Finally, we conducted the synthesis of 4a as a direct two-step
protocol without purification of the 1,4-enedione intermediates,
the desired product was obtained in 85% overall yield on a 5 mmol
scale (Scheme 2), which displayed the high efficiency of this syn-
thetic strategy.
1-Methyl-1H-pyrrol-3-yl Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3,4,5-(MeO)3eC6H2 OEt
4-NO2C6H4
3-NO2C6H4
4-ClC6H4
4-FC6H4
2-Furyl
Ph
OEt
OEt
OMe
OMe
OEt
Ph
Me
Ph
Me
OEt Me 4x 98
a
Reaction conditions: 1 (1.2 mmol), 2 (1.0 mmol), and CH3SO3H (0.5 mmol) in
MeCN (5 mL) at reflux for 8e10 h.
b
Isolated yields.
An intricate mixture of byproducts was formed.
c
Scheme 2. A telescoped two-step synthesis of 4a.

Y. Yang et al. / Tetrahedron 67 (2011) 5142e5149
5145
4.4. General procedure for the preparation of 5 (5a as an
example)
3. Conclusion
In summary, we have developed an efficient methodology for
the synthesis of 3-(furan-3-yl or 4-yl)indole derivatives via the
integration of convergent and linear domino reactions. It should be
noted that this protocol has significant advantages over previous
methods for the simple substrates and operational simplicity.
Therefore, we believe that this protocol would be very useful in
synthetic chemistry, as well as in medicinal chemistry.
CH3SO3H (48.0 mg, 0.5 mmol) was added to a solution of 1H-
indole 1a (140 mg, 1.2 mmol) and 2-(methylthio)-1,4-diphenylbut-
2-ene-1,4-dione 3a (282 mg, 1.0 mmol) in CH3CN (5 mL) under
argon. The reaction mixture was stirred at reflux for 24 h and
monitored to completion by TLC analysis. After cooling to room
temperature, saturated aq NaHCO3 (10 mL) was then added and the
aqueous mixture was extracted with diethyl acetate (3ꢂ20 mL). The
combined organic extracts were washed with brine (20 mL), dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (el-
uent: petroleum ether/EtOAc) to afford the desired product 5a
4. Experimental section
4.1. General methods
All reagents were purchased from commercial suppliers and
used without further purification. Reactions were carried out under
an argon atmosphere unless indicated otherwise. Solvents were
dried according to published methods and distilled before use. IR
spectra were recorded on an infrared spectrometer as KBr pellets
with absorption in cmꢁ1. 1H spectra were recorded in CDCl3 on 400/
(316 mg, 83%) as a white solid. 1H NMR (CDCl3, 600 MHz):
d (ppm)
600 MHz NMR spectrometers and resonances (d) are given in parts
8.33 (br s, 1H), 8.27 (d, J¼7.2 Hz, 2H), 7.56 (d, J¼7.2 Hz, 1H),
7.49e7.45 (m, 3H), 7.39 (s, 1H), 7.35 (t, J¼7.2 Hz, 1H), 7.32 (d,
J¼7.8 Hz, 1H), 7.24e7.14 (m, 5H), 7.05 (t, J¼7.2 Hz, 1H), 1.94 (s, 3H);
per million relative to tetramethylsilane. Data are reported as fol-
lows: chemical shift, multiplicity (s¼singlet, d¼doublet, t¼triplet,
dd¼doublet of doublets, m¼multiplet), coupling constants (Hz),
and integration. 13C spectra were recorded in CDCl3 on 100/
13C NMR (CDCl3, 150 MHz):
d (ppm) 152.0, 148.6, 136.0, 130.8, 130.7,
128.4, 128.2, 127.8, 127.2, 126.8, 126.1, 125.2, 124.2, 122.2, 120.2,
119.9, 117.7, 111.2, 107.4, 18.8; IR (KBr): 3344, 1697, 1501, 1236, 841,
751, 695 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C25H20NOS:
382.1260; found: 382.1255.
150 MHz spectrometers and resonances (d) are given in ppm rela-
tive to the center line of a triplet at 77.0 ppm of chloroform-d. HRMS
were obtained on an FT-ICR MS equipped with an electrospray
source. Column chromatography was performed on silica gel
(200e300 mesh).
4.5. A telescoped two-step synthesis of 4a (5 mmol scale)
4.2. Synthesis of 1,4-enediones 2 and 3
The preparation and characterization of the 1,4-enediones 2 and
3 have been previously reported.2
4.3. General procedure for the preparation of 4 (4a as an
example)
A mixture of acetophenone (0.60 g, 5.0 mmol), ethyl benzoyla-
cetate (0.99 g, 5.0 mmol), iodine (1.40 g, 5.5 mmol), and CuO (0.44 g,
5.5 mmol) in 20 mL of DMSO was stirred at 70 ꢀC for 12 h. After the
reaction completed (monitored by TLC), the reaction mixture was
cooled to room temperature, then filtered through a layer of silica
gel and eluted with EtOAc. The filtrate was diluted with water and
the aqueous phase was extracted with additional EtOAc (3ꢂ50 mL),
then the combined organic layers were washed with Na2S2O3 (5%
w/w, aq) and brine successively. After drying over Na2SO4 and
evaporation, the crude product was dissolved in CH3CN (20 mL)
under argon, then 1H-indole 1a (0.70 g, 6.0 mmol) and CH3SO3H
(0.24 g, 2.5 mmol) were added. The reaction mixture was stirred at
reflux for 8 h and monitored to completion by TLC analysis. After
cooling to room temperature, saturated aq NaHCO3 (40 mL) was
added and the aqueous mixture was extracted with diethyl acetate
(3ꢂ50 mL). The combined organic extracts were washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (eluent: petroleum ether/EtOAc) to afford the desired
product 4a (1.73 g, 85%) as a yellow solid.
CH3SO3H (48.0 mg, 0.5 mmol) was added to a solution of
1H-indole 1a (140 mg, 1.2 mmol) and ethyl 2-benzoyl-4-oxo-4-
phenylbut-2-enoate 2a (308 mg, 1.0 mmol) in CH3CN (5 mL) un-
der argon. The reaction mixture was stirred at reflux for 8 h and
monitored to completion by TLC analysis. After cooling to room
temperature, saturated aq NaHCO3 (10 mL) was then added and the
aqueous mixture was extracted with diethyl acetate (3ꢂ20 mL). The
combined organic extracts were washed with brine (20 mL), dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (el-
uent: petroleum ether/EtOAc) to afford the desired product 4a
(403 mg, 99%) as a yellow solid. 1H NMR (CDCl3, 600 MHz):
d (ppm)
8.29 (br s, 1H), 7.93 (d, J¼7.2 Hz, 2H), 7.54 (d, J¼7.2 Hz, 2H), 7.47 (t,
J¼7.2 Hz, 2H), 7.42e7.39 (m, 3H), 7.26e7.17 (m, 5H), 7.06 (t,
J¼7.2 Hz, 1H), 3.99 (q, J¼7.2 Hz, 2H), 0.78 (t, J¼7.2 Hz, 3H); 13C NMR
(CDCl3, 150 MHz):
d
(ppm) 164.8, 153.8, 149.2, 136.0, 130.4, 129.9,
4.6. Spectroscopic data
128.9, 128.3, 128.2, 127.5, 127.3, 125.5, 124.0, 122.0, 120.0, 119.7,
117.9, 115.9, 111.1, 107.4, 60.6, 13.2; IR (KBr): 3339, 1699, 1486, 1235,
1067, 767, 747, 691 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C27H22NO3: 408.1594; found: 408.1599.
4.6.1. Ethyl 4-(1H-indol-3-yl)-2,5-diphenylfuran-3-carboxylate
(4a). Yield 99%; yellow solid; 1H NMR (CDCl3, 600 MHz):
d
(ppm)
8.29 (br s, 1H), 7.93 (d, J¼7.2 Hz, 2H), 7.54 (d, J¼7.2 Hz, 2H), 7.47 (t,

5146
Y. Yang et al. / Tetrahedron 67 (2011) 5142e5149
J¼7.2 Hz, 2H), 7.42e7.39 (m, 3H), 7.26e7.17 (m, 5H), 7.06 (t,
J¼7.2 Hz, 1H), 3.99 (q, J¼7.2 Hz, 2H), 0.78 (t, J¼7.2 Hz, 3H); 13C NMR
HRMS (ESI): m/z [MþH]þ calcd for C31H24NO3: 458.1751; found:
458.1757.
(CDCl3, 150 MHz):
d (ppm) 164.8, 153.8, 149.2, 136.0, 130.4, 129.9,
128.9, 128.3, 128.2, 127.5, 127.3, 125.5, 124.0, 122.0, 120.0, 119.7,
117.9, 115.9, 111.1, 107.4, 60.6, 13.2; IR (KBr): 3339, 1699, 1486, 1235,
1067, 767, 747, 691 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C27H22NO3: 408.1594; found: 408.1599.
4.6.7. Ethyl 5-(4-chlorophenyl)-4-(1H-indol-3-yl)-2-phenylfuran-3-
carboxylate (4g). Yield 84%; yellow solid; 1H NMR (CDCl3,
600 MHz):
d
(ppm) 8.34 (br s, 1H), 7.91 (d, J¼7.8 Hz, 2H), 7.47e7.46
(m, 4H), 7.42e7.40 (m, 2H), 7.36 (d, J¼7.8 Hz,1H), 7.25e7.21 (m, 2H),
7.16e7.15 (m, 2H), 7.07 (t, J¼7.8 Hz, 1H), 4.00 (q, J¼7.2 Hz, 2H), 0.80
4.6.2. Ethyl 4-(1H-indol-3-yl)-2-phenyl-5-p-tolylfuran-3-
(t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 164.5, 154.1,
carboxylate (4b). Yield 94%; yellow solid; 1H NMR (CDCl3,
148.2, 136.0, 133.2, 129.8, 129.1, 128.9, 128.5, 128.3, 127.5, 127.2,
126.7, 123.9, 122.3, 120.1, 118.0, 116.3, 111.2, 107.4, 60.6, 13.3; IR
600 MHz):
d
(ppm) 8.27 (br s, 1H), 7,93 (d, J¼7.8 Hz, 2H), 7.47e7.39
(m, 7H), 7.21 (t, J¼7.2 Hz, 2H), 7.06 (t, J¼7.2 Hz,1H), 7.00 (d, J¼7.8 Hz,
(KBr): 3360, 1698, 1483, 1241, 1091, 1069, 1012, 829, 745, 690 cmꢁ1
;
2H), 3.98 (q, J¼7.2 Hz, 2H), 2.27 (s, 3H), 0.78 (t, J¼7.2 Hz, 3H); 13C
HRMS (ESI): m/z [MþH]þ calcd for C27H21ClNO3: 442.1204; found:
NMR (CDCl3, 150 MHz):
d
(ppm) 164.8, 153.6, 149.6, 137.4, 136.0,
442.1213.
130.0, 129.0, 128.8, 128.3, 127.7, 127.6, 127.5, 125.5, 123.8, 122.1,
120.2, 119.9, 117.9, 115.1, 111.0, 108.0, 60.5, 21.2, 13.3; IR (KBr): 3380,
1702, 1488, 1231,1135, 762 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C28H24NO3: 422.1751; found: 422.1745.
4.6.8. Ethyl 5-(3,4-dichlorophenyl)-4-(1H-indol-3-yl)-2-
phenylfuran-3-carboxylate (4h). Yield 82%; yellow solid; 1H NMR
(CDCl3, 600 MHz):
d
(ppm) 8.48 (br s, 1H), 7.90 (d, J¼7.8 Hz, 2H),
7.71 (d, J¼1.8 Hz, 1H), 7.47 (t, J¼7.8 Hz, 2H), 7.41 (t, J¼7.8 Hz, 1H),
7.36e7.32 (m, 2H), 7.24e7.14 (m, 4H), 7.06 (t, J¼7.8 Hz, 1H), 4.01 (q,
J¼7.2 Hz, 2H), 0.81 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
4.6.3. Ethyl 4-(1H-indol-3-yl)-5-(4-methoxyphenyl)-2-phenylfuran-
3-carboxylate (4c). Yield 96%; yellow solid; 1H NMR (CDCl3,
600 MHz):
d
(ppm) 8.40 (br s, 1H), 7.91 (d, J¼7.8 Hz, 2H), 7.47e7.43
d (ppm) 164.5, 154.5, 146.7, 136.0, 132.4, 131.1, 130.3, 130.2, 129.5,
(m, 4H), 7.39e7.34 (m, 3H), 7.18e7.17 (m, 2H), 7.04 (t, J¼7.2 Hz, 1H),
129.3, 128.3, 127.6, 126.9, 124.5, 124.1, 122.3, 120.1, 119.8, 118.0, 117.5,
111.3, 106.7, 60.8, 13.3; IR (KBr): 3366, 1701, 1465, 1338, 1134, 1104,
766 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C27H20Cl2NO3:
476.0815; found: 476.0814.
6.70 (d, J¼8.4 Hz, 2H), 3.99 (q, J¼7.2 Hz, 2H), 3.70 (s, 3H), 0.78 (t,
J¼7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 164.9, 158.9,
153.3, 149.4, 136.0, 130.0, 128.7, 128.2, 127.5, 127.4, 127.0, 124.0,
123.3, 122.0, 120.0, 119.8, 117.8, 114.3, 113.7, 111.1, 107.7, 60.6, 55.1,
13.3; IR (KBr): 3374, 1703, 1606, 1493, 1251, 833, 747, 689 cmꢁ1
;
4.6.9. Ethyl 5-(4-bromophenyl)-4-(1H-indol-3-yl)-2-phenylfuran-3-
HRMS (ESI): m/z [MþH]þ calcd for C28H24NO4: 438.1700; found:
carboxylate (4i). Yield 89%; yellow solid; 1H NMR (CDCl3,
438.1706.
600 MHz):
d
(ppm) 8.43 (br s, 1H), 7.90 (d, J¼7.8 Hz, 2H), 7.45 (t,
J¼7.2 Hz, 2H), 7.41e7.34 (m, 5H), 7.28 (t, J¼9.0 Hz, 2H), 7.20e7.17 (m,
4.6.4. Ethyl 4-(1H-indol-3-yl)-5-(4-nitrophenyl)-2-phenylfuran-3-
2H), 7.05 (t, J¼7.2 Hz, 1H), 4.00 (q, J¼7.2 Hz, 2H), 0.80 (t, J¼7.2 Hz,
carboxylate (4d). Yield 92%; yellow solid; 1H NMR (CDCl3,
3H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 164.6, 154.1, 148.2, 137.3,
600 MHz):
d
(ppm) 8.41 (br s, 1H), 8.05 (d, J¼9.0 Hz, 2H), 7.93 (d,
136.0,131.4,129.7,129.3,129.1,128.3,127.5,127.1,126.9,124.0,122.2,
121.4, 120.0, 117.9, 116.5, 111.2, 107.1, 60.7, 13.3; IR (KBr): 3387, 1715,
1589, 1246, 1068, 1009, 748 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd
for C27H21BrNO3: 486.0699; found: 486.0706.
J¼7.8 Hz, 2H), 7.68 (d, J¼7.2 Hz, 2H), 7.51e7.46 (m, 4H), 7.36 (s, 1H),
7.32 (d, J¼7.8 Hz, 1H), 7.26e7.24 (m, 1H), 7.08 (t, J¼7.2 Hz, 1H), 4.02
(q, J¼7.2 Hz, 2H), 0.83 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d
(ppm) 164.3, 155.4, 146.7, 146.0, 136.2, 136.0, 129.5, 129.3, 128.4,
127.6,126.6,125.4,124.3,123.7,122.4,120.2,120.0,119.7,118.5,111.4,
106.4, 60.9, 13.3; IR (KBr): 3363, 1694, 1595, 1511, 1338, 1237, 1110,
855, 747, 693 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C27H21N2O5:
453.1445; found: 453.1450.
4.6.10. Ethyl 5-(4-fluorophenyl)-4-(1H-indol-3-yl)-2-phenylfuran-3-
carboxylate (4j). Yield 90%; yellow solid; 1H NMR (CDCl3,
600 MHz):
d
(ppm) 8.35 (br s, 1H), 7.92 (d, J¼7.2 Hz, 2H), 7.52e7.39
(m, 6H), 7.36 (d, J¼7.8 Hz, 1H), 7.25e7.20 (m, 2H), 7.06 (t, J¼7.2 Hz,
1H), 6.88 (t, J¼8.4 Hz, 2H), 4.00 (q, J¼7.2 Hz, 2H), 0.80 (t, J¼7.2 Hz,
4.6.5. Ethyl 4-(1H-indol-3-yl)-5-(naphthalen-1-yl)-2-phenylfuran-3-
3H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 164.6, 162.0 (d,
carboxylate (4e). Yield 85%; brown oil; 1H NMR (CDCl3, 400 MHz):
JCF¼248.0 Hz), 153.9, 148.5, 136.0, 129.9, 129.0, 128.3, 127.51, 127.4
(d, JCF¼8.9 Hz),127.30,126.7,123.9,122.2,120.05,119.97,117.9,115.5,
115.3 (d, JCF¼20.9 Hz), 111.1, 107.5, 60.6, 13.3; IR (KBr): 3378, 1709,
1493, 1233, 1069, 836, 763 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C27H21FNO3: 426.1500; found: 426.1505.
d
(ppm) 8.09 (d, J¼8.4 Hz, 1H), 7.95e7.94 (m, 3H), 7.81 (d, J¼8.4 Hz,
1H), 7.76 (d, J¼8.4 Hz, 1H), 7.47e7.35 (m, 7H), 7.24e7.18 (m, 2H),
7.09 (t, J¼7.2 Hz, 1H), 6.97 (t, J¼7.2 Hz, 1H), 6.87 (s, 1H), 4.05 (q,
J¼7.2 Hz, 2H), 0.80 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d
(ppm) 165.2, 154.8, 149.5, 135.7, 133.6, 131.7, 129.9, 129.1, 128.9,
128.8, 128.3, 128.2, 127.7, 127.4, 127.3, 126.4, 125.9, 125.0, 123.8,
121.7, 119.5, 118.5, 116.5, 111.0, 107.2, 60.9, 13.3; IR (KBr): 3413, 1708,
1233, 1110, 765, 743, 692 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C31H24NO3: 458.1751; found: 458.1759.
4.6.11. Ethyl 5-(4-hydroxyphenyl)-4-(1H-indol-3-yl)-2-phenylfuran-
3-carboxylate (4k). Yield 83%; yellow solid; 1H NMR (CDCl3,
600 MHz):
d
(ppm) 8.22 (br s, 1H), 7.90 (d, J¼7.8 Hz, 2H), 7.45 (t,
J¼7.8 Hz, 2H), 7.41e7.38 (m, 5H), 7.23 (d, J¼1.8 Hz, 1H), 7.20 (t,
J¼7.8 Hz, 1H), 7.06 (t, J¼7.8 Hz, 1H), 6.61 (d, J¼8.4 Hz, 2H), 5.01 (br s,
1H), 3.99 (q, J¼7.2 Hz, 2H), 0.79 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
4.6.6. Ethyl 4-(1H-indol-3-yl)-5-(naphthalen-2-yl)-2-phenylfuran-3-
carboxylate (4f). Yield 95%; yellow solid; 1H NMR (CDCl3,
150 MHz): d (ppm) 165.1, 155.3, 153.5, 149.5, 136.0, 130.0, 128.8,
600 MHz):
d
(ppm) 8.30 (br s, 1H), 8.11 (s, 1H), 7.98 (d, J¼7.2 Hz, 2H),
128.5, 128.2, 127.5, 127.3, 123.9, 123.3, 122.1, 120.1, 119.9, 117.6, 115.2,
114.1, 111.1, 107.8, 60.7, 13.3; IR (KBr): 3476, 3402, 1730, 1608, 1492,
1333, 1200, 1121, 1068, 835, 749, 690 cmꢁ1; HRMS (ESI): m/z
[MþH]þ calcd for C27H22NO4: 424.1543; found: 424.1534.
7.72e7.67 (m, 2H), 7.60e7.55 (m, 2H), 7.50 (t, J¼7.2 Hz, 2H),
7.46e7.40 (m, 5H), 7.31 (d, J¼1.8 Hz, 1H), 7.23 (t, J¼7.2 Hz, 1H), 7.05
(t, J¼7.2 Hz, 1H), 4.01 (q, J¼7.2 Hz, 2H), 0.80 (t, J¼7.2 Hz, 3H); 13C
NMR (CDCl3, 150 MHz):
d (ppm) 164.8, 154.1, 149.3, 136.0, 133.1,
132.5, 129.9, 129.0, 128.3, 128.2, 127.9, 127.7, 127.6, 127.5, 127.4,
126.2, 126.0, 124.5, 124.1, 123.5, 122.1, 120.1, 119.9, 118.0, 116.4, 111.1,
4.6.12. Ethyl 4-(1H-indol-3-yl)-2-phenyl-5-(thiophen-3-yl)furan-3-
carboxylate (4l). Yield 92%; brown solid; 1H NMR (CDCl3,
107.5, 60.7, 13.3; IR (KBr): 3472, 1727, 1197, 1117, 1063, 747 cmꢁ1
;
600 MHz):
d
(ppm) 8.43 (br s, 1H), 7.92 (d, J¼7.8 Hz, 2H), 7.46e7.36

Y. Yang et al. / Tetrahedron 67 (2011) 5142e5149
5147
(m, 4H), 7.32e7.30 (m, 2H), 7.18e7.16 (m, 2H), 7.10e7.04 (m, 3H),
4.00 (q, J¼7.2 Hz, 2H), 0.79 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
3342, 1702, 1485, 1237, 1092, 832, 746, 694 cmꢁ1; HRMS (ESI): m/z
[MꢁH]ꢁ calcd for C26H17ClNO3: 426.0902; found: 426.0897.
150 MHz):
d (ppm) 164.7, 153.6, 147.1, 135.9, 131.3, 129.9, 128.9,
128.2, 127.5, 127.4, 125.3, 124.2, 122.0, 121.0, 119.9, 119.8, 117.4, 114.9,
111.1, 107.1, 60.6, 13.2; IR (KBr): 3340, 1690, 1487, 1242, 1118, 1070,
769, 743 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C25H20NO3S:
414.1158; found: 414.1148.
4.6.18. Methyl 2-(4-fluorophenyl)-4-(1H-indol-3-yl)-5-phenylfuran-
3-carboxylate (4t). Yield 87%; yellow solid; 1H NMR (CDCl3,
600 MHz):
d
(ppm) 8.31 (br s, 1H), 7.90 (dd, J1¼8.4 Hz, J2¼5.4 Hz,
2H), 7.51e7.50 (m, 2H), 7.40 (d, J¼8.4 Hz, 1H), 7.35 (d, J¼7.8 Hz, 1H),
7.24 (d, J¼2.4 Hz, 1H), 7.21e7.14 (m, 6H), 7.05 (t, J¼7.2 Hz, 1H), 3.51
4.6.13. Ethyl 5-(benzofuran-2-yl)-4-(1H-indol-3-yl)-2-phenylfuran-
(s, 3H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 165.0, 163.0 (d,
3-carboxylate (4m). Yield 26%; yellow oil; 1H NMR (CDCl3,
JCF¼248.3 Hz), 153.3, 149.4, 136.0, 130.3, 129.6 (d, JCF¼9.2 Hz), 128.3,
127.6, 127.1, 126.3, 125.6, 124.0, 122.2, 119.99, 119.96 117.2, 115.8,
115.5 (d, JCF¼20.8 Hz), 111.2, 107.4, 51.6; IR (KBr): 3400, 1482, 1098,
925, 767, 748, 690 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C26H19FNO3: 412.1343; found: 412.1333.
600 MHz):
d
(ppm) 8.22 (d, J¼8.4 Hz, 1H), 8.15 (s, 1H), 8.13 (br s,
1H), 7.73 (d, J¼7.8 Hz, 1H), 7.67 (d, J¼7.8 Hz, 1H), 7.56 (t, J¼7.2 Hz,
2H), 7.51e7.33 (m, 7H), 7.25e7.23 (m, 1H), 7.17 (t, J¼7.2 Hz, 1H),
4.14 (q, J¼7.2 Hz, 2H), 1.03 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
150 MHz):
d (ppm) 167.7, 155.5, 155.0, 140.9, 139.1, 137.2, 129.0,
128.8, 127.9, 127.3, 126.8, 126.7, 124.5, 124.3, 123.9, 123.1, 122.8,
122.7, 122.0, 121.1, 120.0, 111.4, 110.8, 105.3, 60.9, 13.7; IR (KBr):
4.6.19. Ethyl 4-(1H-indol-3-yl)-5-phenyl-2,20-bifuran-3-carboxylate
(4u). Yield 24%; brown oil; 1H NMR (CDCl3, 600 MHz):
d (ppm)
3587, 3419, 3267, 1701, 1453, 1319, 1252, 1210, 1157, 751, 739 cmꢁ1
;
8.30 (br s, 1H), 7.59 (s, 1H), 7.55e7.54 (m, 2H), 7.42 (d, J¼8.4 Hz, 1H),
7.37 (d, J¼8.4 Hz, 1H), 7.33 (d, J¼3.0 Hz, 1H), 7.22e7.18 (m, 5H), 7.06
(t, J¼7.2 Hz, 1H), 6.57 (s, 1H), 3.99 (q, J¼7.2 Hz, 2H), 0.74 (q, J¼7.2 Hz,
HRMS (ESI): m/z [MþH]þ calcd for C29H22NO4: 448.1543; found:
448.1551.
3H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 163.7, 149.2, 146.8, 144.7,
4.6.14. Ethyl 4-(1H-indol-3-yl)-5-phenyl-2-(3,4,5-trimethoxyphenyl)
143.32, 143.26, 135.9, 130.2, 128.2, 127.7, 125.7, 123.7, 122.0, 120.1,
116.5, 115.4, 112.1, 111.9, 111.8, 111.1, 107.8, 60.4, 13.3; IR (KBr): 3403,
1707, 1614, 1458, 1239, 1076, 1017, 743, 693 cmꢁ1; HRMS (ESI): m/z
[MþH]þ calcd for C25H20NO4: 398.1387; found: 398.1385.
furan-3-carboxylate (4p). Yield 85%; yellow solid; 1H NMR (CDCl3,
600 MHz):
d (ppm) 8.44 (br s, 1H), 7.55e7.54 (m, 2H), 7.41 (d,
J¼7.8 Hz, 2H), 7.28 (s, 2H), 7.22e7.18 (m, 5H), 7.07 (t, J¼7.2 Hz, 1H),
3.95e3.93 (m, 11H), 0.71 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
150 MHz):
d
(ppm) 164.9, 153.6, 153.0, 148.9, 138.8, 136.0, 130.4,
4.6.20. (4-(1H-Indol-3-yl)-2,5-diphenylfuran-3-yl)(phenyl)meth-
128.3, 127.5, 125.6, 125.4, 123.7, 122.1, 120.0, 119.9, 117.8, 115.9, 111.1,
107.8, 105.0, 60.9, 60.6, 56.2, 13.3; IR (KBr): 3370, 1722, 1503, 1225,
1127, 1072, 762, 747, 689 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C30H28NO6: 498.1911; found: 498.1912.
anone (4v). Yield 94%; brown solid; 1H NMR (CDCl3, 600 MHz):
d
(ppm) 8.17 (br s, 1H), 7.79 (d, J¼7.2 Hz, 2H), 7.68 (d, J¼7.2 Hz, 2H),
7.61 (d, J¼7.2 Hz, 2H), 7.31e7.29 (m, 3H), 7.26e7.19 (m, 6H), 7.15 (t,
J¼7.2 Hz, 2H), 7.11e7.09 (m, 2H), 6.94 (t, J¼7.2 Hz, 1H); 13C NMR
(CDCl3, 150 MHz):
d (ppm) 194.0, 150.6, 148.8, 137.2, 135.8, 133.1,
4.6.15. Ethyl 4-(1H-indol-3-yl)-2-(4-nitrophenyl)-5-phenylfuran-3-
130.5, 129.7, 129.6, 128.5, 128.3, 128.1, 127.5, 126.3, 126.2, 125.5,
124.7, 124.3, 122.1, 120.3, 119.8, 116.5, 111.0, 107.1; IR (KBr): 3359,
1661, 1598, 1485, 1447, 1346, 1235, 906, 765, 742, 690 cmꢁ1; HRMS
(ESI): m/z [MþH]þ calcd for C31H22NO2: 440.1645; found: 440.1649.
carboxylate (4q). Yield 97%; orange solid; 1H NMR (CDCl3,
600 MHz):
d
(ppm) 8.33e8.31 (m, 3H), 8.15 (d, J¼8.4 Hz, 2H),
7.57e7.56 (m, 2H), 7.52 (d, J¼8.4 Hz, 1H), 7.38 (d, J¼7.8 Hz, 1H),
7.24e7.23 (m, 5H), 7.08 (t, J¼7.2 Hz, 1H), 4.01 (q, J¼7.2 Hz, 2H),
0.77 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d
(ppm) 164.3,
4.6.21. 1-(4-(1H-Indol-3-yl)-2-methyl-5-phenylfuran-3-yl)ethanone
151.0, 150.5, 147.2, 136.0, 135.7, 129.8, 128.4, 128.2, 127.6, 127.3,
125.8, 123.9, 123.8, 122.4, 121.0, 120.1, 120.0, 116.6, 111.2, 107.2,
(4w). Yield 96%; yellow solid; 1H NMR (CDCl3, 600 MHz):
d (ppm)
8.65 (br s, 1H), 7.42e7.39 (m, 4H), 7.23 (t, J¼7.2 Hz, 1H), 7.12e7.08
61.1, 13.2; IR (KBr): 3455, 1720, 1596, 1517, 1341, 747, 693 cmꢁ1
;
(m, 5H), 2.69 (s, 3H), 1.85 (s, 3H); 13C NMR (CDCl3, 150 MHz):
HRMS (ESI): m/z [MþNa]þ calcd for C27H20N2NaO5: 475.1264;
d (ppm) 196.9, 157.6, 148.5, 136.2, 130.4, 128.2, 127.7, 127.1, 125.3,
found: 475.1265.
125.1, 123.7, 122.5, 120.3, 119.6, 113.2, 111.4, 108.3, 29.9, 14.7; IR
(KBr): 3413, 1660, 1558, 1419, 1392, 1241, 770, 693 cmꢁ1; HRMS
(ESI): m/z [MþH]þ calcd for C21H18NO2: 316.1332; found: 316.1329.
4.6.16. Ethyl 4-(1H-indol-3-yl)-2-(3-nitrophenyl)-5-phenylfuran-3-
carboxylate (4r). Yield 95%; yellow solid; 1H NMR (CDCl3,
600 MHz):
d
(ppm) 8.86 (s, 1H), 8.33e8.31 (m, 2H), 8.25 (d,
4.6.22. Ethyl 4-(1-methyl-1H-indol-3-yl)-2,5-diphenylfuran-3-
J¼7.8 Hz, 1H), 7.65 (t, J¼7.8 Hz, 1H), 7.57e7.56 (m, 2H), 7.45 (d,
J¼8.4 Hz, 1H), 7.38 (d, J¼7.8 Hz, 1H), 7.28 (d, J¼2.4 Hz, 1H),
7.25e7.22 (m, 4H), 7.08 (t, J¼7.2 Hz, 1H), 4.02 (q, J¼7.2 Hz, 2H),
carboxylate (4x). Yield 98%; white solid; 1H NMR (CDCl3,
600 MHz):
d
(ppm) 7.91 (d, J¼7.8 Hz, 2H), 7.56 (d, J¼7.8 Hz, 2H),
7.47e7.45 (m, 2H), 7.41e7.35 (m, 3H), 7.25e7.16 (m, 5H), 7.04 (t,
J¼7.8 Hz, 1H), 4.01 (q, J¼7.2 Hz, 2H), 3.85 (s, 3H), 0.82 (t, J¼7.2 Hz,
0.79 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 164.2,
151.0, 150.5, 148.3, 136.1, 133.2, 131.5, 129.9, 129.4, 128.5, 128.1,
127.4, 125.8, 124.1, 123.3, 122.4, 122.3, 120.1, 119.9, 119.7, 116.4,
111.3, 107.1, 61.1, 13.3; IR (KBr): 3391, 1697, 1527, 1346, 1096, 763,
3H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 164.7, 153.5, 149.0, 136.8,
130.5, 130.0, 128.8, 128.5, 128.24, 128.20, 127.8, 127.4, 125.5, 121.6,
120.3, 119.4, 118.0, 115.9, 109.1, 105.9, 60.5, 32.8, 13.3; IR (KBr): 1724,
1487, 1372, 1214, 1188, 1129, 1070, 913, 744, 689 cmꢁ1; HRMS (ESI):
m/z [MþNa]þ calcd for C28H23NNaO3: 444.1570; found: 444.1559.
690 cmꢁ1
;
HRMS (ESI): m/z [MþH]þ calcd for C27H21N2O5:
453.1445; found: 453.1451.
4.6.17. Methyl 2-(4-chlorophenyl)-4-(1H-indol-3-yl)-5-phenylfuran-
4.6.23. 3-(4-(Methylthio)-2,5-diphenylfuran-3-yl)-1H-indole
3-carboxylate (4s). Yield 92%; yellow solid; 1H NMR (CDCl3,
(5a). Yield 83%; white solid; 1H NMR (CDCl3, 600 MHz):
d (ppm)
600 MHz):
d
(ppm) 8.30 (br s, 1H), 7.85 (d, J¼8.4 Hz, 2H), 7.52e7.50
8.33 (br s, 1H), 8.27 (d, J¼7.2 Hz, 2H), 7.56 (d, J¼7.2 Hz, 1H),
7.49e7.45 (m, 3H), 7.39 (s, 1H), 7.35 (t, J¼7.2 Hz, 1H), 7.32 (d,
J¼7.8 Hz, 1H), 7.24e7.14 (m, 5H), 7.05 (t, J¼7.2 Hz, 1H), 1.94 (s, 3H);
(m, 2H), 7.44 (d, J¼8.4 Hz, 2H), 7.41 (d, J¼7.8 Hz, 1H), 7.34 (d,
J¼7.8 Hz,1H), 7.26e7.25 (m,1H), 7.22e7.18 (m, 4H), 7.05 (t, J¼7.8 Hz,
1H), 3.52 (s, 3H); 13C NMR (CDCl3, 150 MHz):
d
(ppm) 165.0, 152.8,
13C NMR (CDCl3, 150 MHz):
d (ppm) 152.0, 148.6, 136.0, 130.8, 130.7,
149.6, 136.0, 134.9, 130.2, 128.7, 128.6, 128.4, 128.3, 127.7, 127.1,
125.7, 124.0, 122.2, 120.0, 117.8, 115.9, 111.2, 107.3, 51.7; IR (KBr):
128.4, 128.2, 127.8, 127.2, 126.8, 126.1, 125.2, 124.2, 122.2, 120.2,
119.9, 117.7, 111.2, 107.4, 18.8; IR (KBr): 3344, 1697, 1501, 1236, 841,

5148
Y. Yang et al. / Tetrahedron 67 (2011) 5142e5149
751, 695 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C25H20NOS:
147.8, 136.0, 131.6, 131.4, 129.4, 129.3, 127.5, 126.7, 126.3, 124.2,
122.4, 121.9, 121.3, 120.6, 120.2, 120.1, 118.5, 111.3, 107.0, 18.7; IR
(KBr): 3439, 1628, 1480, 826, 746, 490 cmꢁ1; HRMS (ESI): m/z
[MþH]þ calcd for C25H18Br2NOS: 539.9460; found: 539.9458.
382.1260; found: 382.1255.
4.6.24. 3-(4-(Methylthio)-2,5-di-p-tolylfuran-3-yl)-1H-indole
(5b). Yield 86%; yellow solid; 1H NMR (CDCl3, 600 MHz):
d (ppm)
8.25 (br s, 1H), 8.15 (d, J¼7.8 Hz, 2H), 7.43 (d, J¼7.8 Hz, 2H), 7.39 (d,
J¼8.4 Hz, 1H), 7.32e7.31 (m, 2H), 7.27 (d, J¼7.8 Hz, 2H), 7.20 (t,
J¼7.8 Hz, 1H), 7.03 (t, J¼7.8 Hz, 1H), 6.97 (d, J¼7.8 Hz, 2H), 2.40 (s,
4.6.30. 3-(2,5-Bis(4-fluorophenyl)-4-(methylthio)furan-3-yl)-1H-in-
dole (5h). Yield 92%; yellow solid; 1H NMR (CDCl3, 600 MHz):
d
(ppm) 8.36 (br s, 1H), 8.24e8.22 (m, 2H), 7.51e7.48 (m, 2H), 7.45
3H), 2.24 (s, 3H), 1.91 (s, 3H); 13C NMR (CDCl3, 150 MHz):
d
(ppm)
(d, J¼7.8 Hz, 1H), 7.39 (s, 1H), 7.27 (d, J¼8.4 Hz, 1H), 7.24e7.22 (m,
152.0, 148.6, 137.7, 136.9, 136.0, 129.1, 128.9, 128.14, 128.05, 126.9,
126.1, 125.1, 124.1, 122.1, 120.4, 119.8, 119.0, 116.8, 111.2, 107.8, 21.4,
1H), 7.16 (t, J¼8.4 Hz, 2H), 7.05 (t, J¼7.8 Hz, 1H), 6.87 (t, J¼8.4 Hz,
2H), 1.91 (s, 3H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 162.3 (d,
21.2, 18.8; IR (KBr): 3417, 1499, 1454, 1419, 1093, 925, 821, 744 cmꢁ1
;
JCF¼246.2 Hz), 161.9 (d, JCF¼246.2 Hz), 151.3, 147.8, 136.1, 128.0 (d,
JCF¼6.3 Hz), 127.0 (d, JCF¼12.6 Hz), 126.6, 124.2, 124.1, 122.4, 120.2,
120.1, 119.4, 117.2, 115.5 (d, JCF¼21.5 Hz), 115.2 (d, JCF¼13.2 Hz), 111.3,
107.3, 18.7; IR (KBr): 3409, 1669, 1599, 1498, 1233, 1157, 837,
744 cmꢁ1; HRMS (ESI): m/z [MꢁH]ꢁ calcd for C25H16F2NOS:
416.0926; found: 416.0927.
HRMS (ESI): m/z [MþH]þ calcd for C27H24NOS: 410.1573; found:
410.1572.
4.6.25. 3-(4-(Methylthio)-2,5-bis(4-nitrophenyl)furan-3-yl)-1H-in-
dole (5c). Yield 97%; orange solid; 1H NMR (CDCl3, 600 MHz):
d
(ppm) 8.71 (br s, 1H), 8.49 (d, J¼8.4 Hz, 2H), 8.34 (d, J¼8.4 Hz, 2H),
8.05 (d, J¼8.4 Hz, 2H), 7.69 (d, J¼8.4 Hz, 2H), 7.54e7.52 (m, 2H), 7.28
(t, J¼7.8 Hz, 1H), 7.21 (d, J¼7.8 Hz, 1H), 7.07 (t, J¼7.8 Hz, 1H), 1.95 (s,
4.6.31. 3-(4-(Methylthio)-2,5-di(thiophen-3-yl)furan-3-yl)-1H-in-
dole (5i). Yield 82%; brown oil; 1H NMR (CDCl3, 600 MHz):
d (ppm)
3H); 13C NMR (CDCl3, 150 MHz):
d
(ppm) 151.0, 147.9, 146.7, 146.3,
8.33 (br s, 1H), 8.08 (d, J¼2.4 Hz, 1H), 7.92 (d, J¼4.8 Hz, 1H), 7.42 (d,
J¼8.4 Hz, 1H), 7.38 (dd, J1¼4.8 Hz, J2¼3.0 Hz, 1H), 7.34e7.33 (m, 2H),
7.25e7.22 (m, 2H), 7.09e7.06 (m, 3H), 1.93 (s, 3H); 13C NMR (CDCl3,
136.1, 135.8, 126.5, 125.8, 125.6, 124.5, 124.0, 123.8, 122.8, 122.7,
120.5, 119.7, 111.7, 105.8, 18.5; IR (KBr): 3423, 1594, 1512, 1337, 1109,
855, 747, 697 cmꢁ1
;
HRMS (ESI): m/z [MꢁH]ꢁ calcd for
150 MHz): d (ppm) 149.3, 146.0, 136.0, 131.9, 131.7, 126.9, 125.8,
C25H16N3O5S: 470.0816; found: 470.0814.
125.5, 125.33, 125.25, 124.2, 122.3, 121.7, 120.4, 120.3, 120.0, 118.3,
116.1, 111.3, 107.2, 18.7; IR (KBr): 3383, 1697, 1488, 1238, 1119, 745,
4.6.26. 3-(2,5-Bis(4-methoxyphenyl)-4-(methylthio)furan-3-yl)-1H-
696 cmꢁ1
394.0389; found: 394.0383.
;
HRMS (ESI): m/z [MþH]þ calcd for C21H16NOS3:
indole (5d). Yield 47%; brown solid; 1H NMR (CDCl3, 600 MHz):
d
(ppm) 8.33 (br s, 1H), 8.19 (d, J¼9.0 Hz, 2H), 7.46 (d, J¼9.0 Hz, 2H),
7.43 (d, J¼7.8 Hz, 1H), 7.36 (d, J¼1.8 Hz, 1H), 7.31 (d, J¼7.8 Hz, 1H),
7.21 (t, J¼7.8 Hz, 1H), 7.04 (t, J¼7.8 Hz, 1H), 7.01 (d, J¼9.0 Hz, 2H),
6.71 (d, J¼9.0 Hz, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 1.92 (s, 3H); 13C NMR
Acknowledgements
We thank the National Natural Science Foundation of China
(Grant 20872042 and 21032001) and the Doctor Independent
Foundation of Central China Normal University (No. 2009007). We
also thank Prof. Yuanjiang Pan and Dr. Cheng Guo, Zhejiang Uni-
versity, for analytical support.
(CDCl3, 150 MHz):
d (ppm) 159.1, 158.6, 151.7, 148.2, 136.0, 127.6,
126.9, 126.6, 124.1, 123.9, 123.8, 122.2, 120.4, 119.9, 118.0, 115.8,
113.8, 113.7, 111.2, 107.9, 55.3, 55.1, 18.9; IR (KBr): 3419, 1611, 1500,
1250, 1178, 1030, 834, 746 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C27H24NO3S: 442.1471; found: 442.1458.
Supplementary data
4.6.27. 3-(4-(Methylthio)-2,5-di(naphthalen-2-yl)furan-3-yl)-1H-in-
dole (5e). Yield 91%; brown solid; 1H NMR (CDCl3, 600 MHz):
The general experimental methods and the characterizing data
including 1H NMR, 13C NMR, IR, and HRMS for compounds 4 and 5
are available. Supplementary data associated with this article can
be found in online version, at doi:10.1016/j.tet.2011.05.058
d
(ppm) 8.78 (s, 1H), 8.49 (d, J¼8.4 Hz, 1H), 8.40 (br s, 1H), 8.16 (s,
1H), 7.99 (d, J¼7.8 Hz, 1H), 7.96 (d, J¼8.4 Hz, 1H), 7.88 (d, J¼7.8 Hz,
1H), 7.72e7.68 (m, 2H), 7.63e7.59 (m, 2H), 7.54e7.47 (m, 4H),
7.41e7.36 (m, 3H), 7.25e7.23 (m, 1H), 7.03 (t, J¼7.8 Hz, 1H), 2.00 (s,
3H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 152.3, 148.9, 136.1, 133.3,
References and notes
133.2, 132.8, 132.4, 128.6, 128.3, 128.2, 128.1, 128.0, 127.8, 127.6,
126.9, 126.3, 126.1, 125.9, 125.4, 124.3, 124.1, 124.0, 123.5, 122.3,
120.6, 120.4, 120.1, 118.4, 111.2, 107.7, 18.9; IR (KBr): 3451, 1626, 1597,
1090, 859, 820, 747 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C33H24NOS: 482.1573; found: 482.1574.
1. (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, Germany, 2006; (b) Zhu, J. P.; Bienayme, H. Multicom-
ꢀ
ponent Reactions; Wiley-VCH: Weinheim, 2005; (c) Tietze, L. F. Chem. Rev. 1996,
96, 115e136; (d) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun.
2003, 551e564; (e) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341e5378; (f)
Shindoh, N.; Takemoto, Y.; Takasu, K. Chem.dEur. J. 2009, 15, 12168e12179.
2. (a) Yin, G.-D.; Zhou, B.-H.; Meng, X.-G.; Wu, A.-X.; Pan, Y.-J. Org. Lett. 2006, 8,
2245e2248; (b) Yin, G.-D.; Wang, Z.-H.; Chen, A.-H.; Gao, M.; Wu, A.-X.; Pan,
Y. -J. J. Org. Chem. 2008, 73, 3377e3383; (c) Gao, M.; Yang, Y.; Wu, Y.-D.; Deng,
C.; Cao, L.-P.; Meng, X.-G.; Wu, A.-X. Org. Lett. 2010, 12, 1856e1859; (d) Gao, M.;
Yang, Y.; Wu, Y.-D.; Deng, C.; Shu, W.-M.; Zhang, D.-X.; Cao, L.-P.; She, N.-F.; Wu,
A.-X. Org. Lett. 2010, 12, 4026e4029 For more details, see the Supporting
information.
4.6.28. 3-(2,5-Bis(4-chlorophenyl)-4-(methylthio)furan-3-yl)-1H-in-
dole (5f). Yield 89%; red solid; 1H NMR (CDCl3, 600 MHz):
d (ppm)
8.37 (br s, 1H), 8.20 (d, J¼8.4 Hz, 2H), 7.47e7.40 (m, 6H), 7.27e7.23
(m, 2H), 7.15 (d, J¼8.4 Hz, 2H), 7.06 (t, J¼7.2 Hz, 1H), 1.92 (s, 3H); 13C
NMR (CDCl3, 150 MHz):
d (ppm) 151.2, 147.8, 136.0, 133.7, 133.0,
3. For reviews, see: (a) Sundberg, R. J. The Chemistry of Indoles; Academic: New
129.04, 128.96, 128.7, 128.5, 127.3, 126.4, 124.2, 122.4, 120.4, 120.2,
118.3, 111.3, 107.0, 18.6; IR (KBr): 3421, 1481, 1090, 1011, 831, 743,
497 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C25H18Cl2NOS:
450.0481; found: 450.0482.
ꢀ
York, NY, 1970; (b) de Sa Alves, F. R.; Barreiro, E. J.; Fraga, C. A. M. Mini-Rev. Med.
Chem. 2009, 9, 782e793; (c) Eicher, T.; Hauptmann, S. The Chemistry of Het-
erocycles, 2nd ed.; Wiley-VCH: Weinheim, 2003, pp 52e62 and 99e110; (d)
Joule, J.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell: 2010;
pp 347e431.
4. For reviews, see: (a) Steel, P. J. Adv. Heterocycl. Chem. 1996, 67, 1e117; (b) Horton,
D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893e930.
5. For selected examples, see: (a) Thirumurugan, P.; Nandakumar, A. D.; Mur-
alidharan; Perumal, P. T. J. Comb. Chem. 2010, 12, 161e167; (b) Lachia, M.;
Moody, C. J. Nat. Prod. Rep. 2008, 25, 227e253; (c) Oakdale, J. S.; Boger, D. L. Org.
Lett. 2010, 12, 1132e1134; (d) Reddy, B. V. S.; Reddy, A. M.; Somashekar, D.;
Yadav, J. S.; Sridhar, B. Synthesis 2010, 2571e2576.
4.6.29. 3-(2,5-Bis(4-bromophenyl)-4-(methylthio)furan-3-yl)-1H-in-
dole (5g). Yield 87%; red solid; 1H NMR (CDCl3, 600 MHz):
d (ppm)
8.34 (br s, 1H), 8.13 (d, J¼8.4 Hz, 2H), 7.58 (d, J¼8.4 Hz, 2H), 7.43 (d,
J¼7.8 Hz, 1H), 7.38e7.36 (m, 3H), 7.28e7.22 (m, 4H), 7.05 (t,
J¼7.2 Hz,1H),1.89 (s, 3H); 13C NMR (CDCl3,150 MHz):
d (ppm) 151.2,

Y. Yang et al. / Tetrahedron 67 (2011) 5142e5149
5149
ꢀ
ꢀ
6. (a) Blay, G.; Fernandez, I.; Monleon, A.; Pedro, J. R.; Vila, C. Tetrahedron 2009, 65,
9264e9270; (b) Amat, M.; Hadida, S.; Pshenichnyi, G.; Bosch, J. J. Org. Chem.
1997, 62, 3158e3175; (c) Chou, S. Y.; Chen, S. S. T.; Tsai, H. J. PCT Int. Appl. WO
US 2006/0122232 A1, 2006. (d) Hiremath, S. P.; Jivanagi, A. S.; Purohit, M. G.
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1993, 32B, 662e667.
7. The 1,4-enediones 2 and 3 were used as a mixture of isomers. Due to the re-
action mechanism, they lead solely to the 3-furyl-substituted indoles.
Kobayashi, K.; Masu, H.; Shuto, A.; Yamaguchi, K. Chem. Mater. 2005, 17,
6666e6673; (h) Enoki, T.; Miyazaki, A. Chem. Rev. 2004, 104, 5449e5478; (i)
Forgie, J. C.; Kanibolotsky, A. L.; Skabara, P. J.; Coles, S. J.; Hursthouse, M. B.;
Harrington, R. W.; Clegg, W. Macromolecules 2009, 42, 2570e2580; (j) Ar-
royo, I. J.; Hu, R. R.; Merino, G.; Tang, B. Z.; Pena-Cabrera, E. J. Org. Chem.
2009, 74, 5719e5722.
9. (a) Takei, H.; Miura, M.; Sugimura, H.; Okamura, H. Chem. Lett. 1979, 8,
1447e1450; (b) Mehta, V. P.; Sharma, A.; Van der Eycken, E. Org. Lett. 2008, 10,
1147e1150; (c) Begouin, J. M.; Rivard, M.; Gosmini, C. Chem. Commun. 2010,
5972e5974; (d) Pellegatti, L.; Vedrenne, E.; Leger, J. M.; Jarry, C.; Routier, S.
Synlett 2009, 2137e2142.
8. For selected examples, see: (a) Capon, R. J.; Stewart, M.; Ratnayake, R.;
Lacey, E.; Gill, J. H. J. Nat. Prod. 2007, 70, 1746e1752; (b) Carroll, A. R.; Avery,
V. M. J. Nat. Prod. 2009, 72, 696e699; (c) El-Gamal, A. A.; Wang, W. L.; Duh,
C. Y. J. Nat. Prod. 2005, 68, 815e817; (d) Li, G. Y.; Li, B. G.; Yang, T.; Yan, J. F.;
Liu, G. Y.; Zhang, G. L. J. Nat. Prod. 2006, 69, 1374e1376; (e) Blanchard, P.;
10. Misra, N. C.; Ila, H. J. Org. Chem. 2010, 75, 5195e5202.
ꢁ
ꢀ
Jousselme, B.; Frere, P.; Roncali, J. J. Org. Chem. 2002, 67, 3961e3964; (f)
11. Sanz, R.; Guilarte, V.; Hernando, E.; Sanjuacn, A. M. J. Org. Chem. 2010, 75,
Reddinger, J. L.; Reynolds, J. R. J. Org. Chem. 1996, 61, 4833e4834; (g)
7443e7446.