Base-Promoted Tandem Cyclization for the Synthesis of Polyfunctional 2-Hydroxy-2,3-dihydrofurans from Arylglyoxal Monohydrates and 3-(1 H -Indol-3-yl)-3-oxopropanenitrile

Article abstract of DOI:10.1055/s-0037-1609555

An efficient base-promoted tandem cyclization for the synthesis of polyfunctional 2-hydroxy-2,3-dihydrofurans from arylglyoxal monohydrates and 3-(1 H -indol-3-yl)-3-oxopropanenitrile has been established. The investigation of the mechanism suggested that this reaction proceeds through a Knoevenagel condensation-Michael addition-oxidation-cyclization sequence. This method demonstrates the compatibility with a wide range of functional groups to produce the 2-hydroxy-2,3-dihydrofuran scaffolds in good to excellent yields in one pot.

Full text of DOI:10.1055/s-0037-1609555

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2018, 29, A–G
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Synlett
Q. Cai et al.
Letter
Base-Promoted Tandem Cyclization for the Synthesis of
Polyfunctional 2-Hydroxy-2,3-dihydrofurans from Arylglyoxal
Monohydrates and 3-(1H-Indol-3-yl)-3-oxopropanenitrile
Qun Caia
Hui-Yang Shenga
Deng-Kui Lib
Yi Liu*a
An-Xin Wu*b
R1
R2
CN
O
N
O
CN
O
K2CO3
OH
OH
Ar
+
R1
N
R1
R2
DMSO, 80 °C
O
N
CN
R2
OH
Ar
a
1
2
Coal Conversion and New Carbon Materials Key
R
R
= 5-Br, 6-Me
= H, Me
Laboratory of Hubei Province, School of Chemistry and
Chemical Engineering, Wuhan University of Science
and Technology, Wuhan 430081, P. R. of China
yiliuchem@whu.edu.cn
gram-scale reaction
2
2 examples, up to 93% yield
b
readily available materials
one-pot one-step operation
Key Laboratory of Pesticide & Chemical Biology,
Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan 430079, P. R. of China
chwuax@mail.ccnu.edu.cn
Received: 01.05.2018
Accepted after revision: 12.06.2018
Published online: 09.08.2018
them, 2-hydroxy-2,3-dihydrofuran derivatives, serving as
an important class of O-heterocyclic scaffolds, can be found
in numerous natural products such as auranfuron A, auran-
DOI: 10.1055/s-0037-1609555; Art ID: st-2018-w0281-l
furon B, siphonarienfuranone, drimanes, alphitonin, and
Abstract An efficient base-promoted tandem cyclization for the syn-
thesis of polyfunctional 2-hydroxy-2,3-dihydrofurans from arylglyoxal
monohydrates and 3-(1H-indol-3-yl)-3-oxopropanenitrile has been es-
tablished. The investigation of the mechanism suggested that this reac-
tion proceeds through a Knoevenagel condensation–Michael addition–
oxidation–cyclization sequence. This method demonstrates the com-
patibility with a wide range of functional groups to produce the 2-hy-
droxy-2,3-dihydrofuran scaffolds in good to excellent yields in one pot.
marsupsin (Figure 1).2 Thus they have been reported to
possess a wide spectrum of biological activities like anti-
fungal, antitumor, antibiotic, bacteriostatic, and cytotoxic
properties.3 Besides, 2-hydroxy-2,3-dihydrofurans have
also been used as unique synthetic intermediates for the
preparation of more complex functional material mole-
cules.8
–7
Due to their great value, various approaches for 2-hy-
droxy-2,3-dihydrofuran derivatives have been developed.
The main and classical synthetic methods focused on the
reaction of aldehydes and/or ketones. For example, Kalesse
and co-workers reported a three-step procedure to synthe-
size 2-hydroxy-2,3-dihydrofurans from aldehyde and di-
ethyl ketone through intramolecular cyclization and meth-
Key words 2-hydroxy-2,3-dihydrofurans, tandem cyclization, arylgly-
oxal monohydrates, 3-(1H-indol-3-yl)-3-oxopropanenitrile, one pot
The synthesis of O-heterocyclic compounds is a long-
standing and continuing research topic due to their physi-
cochemical and pharmacological properties with potential
1
applications in the field of medicinal chemistry. Among
OH
OH
OH
O
OH
O
O
O
HO
Auranfuron A
Auranfuron B
OH
OMe
O
O
HO
O
O
OH
HO
OH
OH
O
O
H
HO
HO
O
OH
OH
Siphonarienfuranone
Drimanes
Alphitonin
Marsupsin
Figure 1 Selected natural products and pharmaceutical compounds containing a 2-hydroxy-2,3-dihydrofuran skeleton
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

B
Synlett
Q. Cai et al.
Letter
9
ylation (Scheme 1, a). The Jiang group developed an AgOTf-
catalyzed intramolecular ring closing of ynedione to fur-
nish 2-hydroxy-2,3-dihydrofuran derivatives under nitro-
DMSO was shown to be the most effective in this reaction
(Table 1, entries 2–8). Then, several bases were screened for
this domino reaction, such as Cs CO , NaHCO , NaOH, K PO ,
2
3
3
3
4
10
gen conditions (Scheme 1, b). In addition, the Yan group
reported a Michael addition and cyclization to achieve 2-
hydroxy-2,3-dihydrofuran derivatives from pre-prepared
pyridinium salts and 3-phenacylideneoxindoles (Scheme 1,
c). Despite these significant advances made to date, the
development of simple and practical synthetic strategies to
access polyfunctional 2-hydroxy-2,3-dihydrofurans is still
highly desirable. We herein report a base-promoted tan-
dem cyclization to construct diversely substituted 2-hy-
droxy-2,3-dihydrofurans from arylglyoxal monohydrates
and 3-(1H-indol-3-yl)-3-oxopropanenitrile in one pot
TEA, piperidine, and K CO . Still, K CO showed the highest
2 3 2 3
activity for this reaction (Table 1, entries 9–15). Improving
or decreasing the reaction temperature would not increase
the yield of target product (Table 1, entries 16–18), as well
as the equivalent of K CO (Table 1, entries 19 and 20). Based
11
12
2
3
on the experiments described above, the optimal reaction
conditions were determined as follows: 1a (0.5 mmol), 2a
(1.0 mmol), and K CO (1.0 mmol) in 3 mL of DMSO at 80 °C
2
3
in a sealed vessel for 2 hours.
Table 1 Optimization of the Reaction Conditions for the Synthesis of
a
3
a
(
Scheme 1, d). The advantages of this method include the
use of readily available starting materials, metal-free cata-
lysts, mild reaction conditions, one-step operation, and
easy workup.
O
H
N
OH
CN
O
OH
NH
1
a
conditions
O
previous work
+
CN
CN
OH
O
O
O
O
O
LiHMDS
DMP
MeI
S
(
a)
+
S
R
R
O
3a
CaCO3
OH
N
H
R2
O
2a
AgOTf, H2O
toluene, N2
R1
b) R1
(
R2
Yield (%)b
O
Entry
Solvent
Base
Amount of
base (equiv)
Temp (°C)
OH
O
Ar'
Ar
O
1
2
EtOH
K2CO3
2
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
rt
30
22
<10
11
92
<10
0
Ar'
O
R
Et N
HO
i-PrOH
t-BuOH
K
K
K
K
K
K
K
–
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
2
3
O
+
(
c)
N+
3
2
O
CH3CN
Ar
O
Br–
N
N
H
4
CH
3
CN
2
H
5
DMSO
DMF
2
this work
6
2
O
R
7
DCE
2
OH
OH
H
N
Ar
8
THF
2
0
CN
O
K2CO3
DMSO
(
d)
+
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
–
0
CN
NH
O
R
O
10
11
Cs CO
2
22
33
45
47
16
0
2
3
CN
OH
Ar
NaHCO3
NaOH
2
R
12
13
14
15
2
N
H
K
3
PO
TEA
piperidine
CO
K2CO3
4
2
Scheme 1 Protocols for the synthesis of 2-hydroxy-2,3-dihydrofurans
2
2
Our study commenced with the tandem cyclization
reaction of phenylglyoxal monohydrate (1a) and 3-(1H-
indol-3-yl)-3-oxopropanenitrile (2a) in the presence of dif-
ferent bases and solvents to optimize the reaction condi-
tions (Table 1). Initially, we treated the substrate 1a (0.5
mmol) and 2a (1.0 mmol) with K CO (1.0 mmol) in EtOH at
0 °C (Table 1, entry 1), the desired product 3a was
obtained in 30% yield. A range of different solvent (i-PrOH,
t-BuOH, CH CN, DMSO, DMF, DCE, THF) were screened, and
16
17
K
2
3
2
21
80
70
82
90
2
60
100
80
80
18
19
20
K
K
K
2
2
2
CO
CO
CO
3
3
3
2
1.5
2.5
2
3
aReaction conditions: 1a (0.5 mmol, 1.0 equiv), 2a (1.0 mmol, 2 equiv),
and base (x equiv) were heated in 3 mL of solvent in a sealed vessel for 2
hours.
8
b
Isolated yields.
3
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

C
Synlett
Q. Cai et al.
Letter
With the optimized conditions in hand, we then ex-
tended the scope of this reaction, and the results are illus-
trated in Scheme 2. It is worth mentioning that the reaction
demonstrated wide tolerance for diverse substituents of
arylglyoxals. Arylglyoxals bearing electron-neutral (e.g., 4-
H, 4-Me) and electron-rich (e.g., 3-OMe, 4-OMe) groups
proceeded smoothly to give the corresponding products in
excellent yields (88–93%, 3a–d). Electron-deficient (e.g., 4-
hydrofuran (Scheme 3). For example, 2b could react
smoothly with arylglyoxals containing electron-neutral
(4-H, 4-Me) and electron-donating (4-OMe) groups to
furnish the target products (88–91%; 3k–m). Much to our
satisfaction, electron-deficient (e.g., 4-NO ) and halo-sub-
2
stituted (e.g., 4-Br, 3-Br, 4-Cl) arylglyoxals could also afford
the desired products in excellent yields (80–83%, 3n–q),
which provided the possibility for further functionalization.
Meanwhile, the optimized conditions could be applied to 2-
naphthyl and 2-thienyl arylglyoxals to offer the corre-
sponding products (3r,s, 78–88%). Furthermore, a variety of
3-(1H-indol-3-yl)-3-oxopropanenitriles with different sub-
stituents, such as 6-methyl and 5-bromo groups, were also
explored. Gratifyingly, all proved to be compatible under
NO ) and halogenated (e.g., 3-Br, 4-Br, 4-Cl) substituents
2
were converted into the corresponding products in good
yields (80–88%; 3e–h). In addition, 2-naphthyl and hetero-
aryl (e.g., 3-thienyl) substituents could afford the products
3i and 3j in 90% and 75% yields, respectively.
Notably, 3-(1-methyl-1H-indol-3-yl)-3-oxopropane-
nitrile (2b) could also be successfully applied in the conve-
nient synthesis of the polyfunctional 2-hydroxy-2,3-di-
H
N
CN
O
O
O
NC
CN
OH
K2CO3
DMSO, 80 °C
OH
Ar
+
OH
N
O
Ar
H
HN
1
2a
3
H
H
H
N
N
N
H
N
O
O
O
O
CN
OH
CN
OH
CN
OH
NC
NC
NC
CN
OH
NC
O
O
O
O
O
HN
HN
HN
HN
O
3a
92%
3b
93%
3c 90%
3d 88%
H
H
N
H
N
N
H
N
O
O
O
O
CN
OH
NC
CN
OH
NC
CN
OH
NC
CN
OH
NC
O
O
O
O
Br
HN
HN
HN
HN
NO2
Br
Cl
3e
85%
3f
87%
3g
88%
3h
80%
H
N
H
N
O
O
NC
CN
OH
CN
OH
NC
O
O
HN
HN
3i
90%
3j 75%
S
Scheme 2 Scope of arylglyoxals. Reagents and conditions: 1 (0.5 mmol), 2a (1.0 mmol), K CO (1.0 mmol) in DMSO (3 mL) at 80 °C for 2 hours.
2
3
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

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Synlett
Q. Cai et al.
Letter
R2
N
R1
CN
O
O
CN
O
NC
R1
K2CO3
OH
R1
OH
Ar
Ar
+
DMSO, 80 °C
O
OH
N
R2
N
R2
1
2
3
N
N
N
N
O
O
O
O
CN
OH
CN
OH
CN
OH
NC
CN
OH
NC
NC
NC
O
O
O
O
N
N
N
N
O
3m
88%
3n
83%
N
NO2
3
k
91%
3l
90%
N
N
N
O
O
O
O
CN
OH
CN
OH
CN
NC
NC
CN
OH
NC
NC
OH
O
O
O
O
Br
N
N
N
N
3q
80%
Cl
3r
88%
Br
3p
80%
3o
82%
N
H
N
H
N
H
N
O
O
Br
O
O
Br
CN
OH
Br
Br
NC
CN
OH
CN
OH
CN
OH
NC
NC
NC
O
O
O
O
N
S
HN
HN
HN
3s
78%
3u
84%
3v
82%
O
3t
75%
Scheme 3 Scope of arylglyoxals and 3-(1H-indol-3-yl)-3-oxopropanenitriles. Reagents and conditions: 1 (0.5 mmol), 2 (1.0 mmol), K CO (1.0 mmol) in
2
3
DMSO (3 mL) at 80 °C for 2 hours.
the optimal conditions (75–84%; 3t–v). The structure of 3q
was unambiguously confirmed by X-ray diffraction analysis
tion. Furthermore, when this reaction was conducted under
an argon condition, the desired product 3k was still isolated
in 81% yield (Scheme 4, c), which indicated that DMSO
might serve as double rules of solvent and oxidant for the
synthesis of 2-hydroxy-2,3-dihydrofurans.
On the basis of experimental results above and the
precedent literature,13 a tandem process was proposed for
the formation of 2-hydroxy-2,3-dihydrofuran 3 (3a as an
example) in Scheme 5. Initially, intermediate A′ was formed
by means of a Knoevenagel condensation between phenyl-
glyoxal monohydrate (1a) and 3-(1H-indol-3-yl)-3-oxopro-
panenitrile (2a). Subsequently, another amount of 2a react-
ed with A′ to form intermediate B via a Michael addition.
(see Supplementary Information).
To gain some insight into the mechanism of this reac-
tion, a series of control experiments were performed as
shown in Scheme 4. Initially, the reaction of phenylglyoxal
monohydrate 1a and 3-(1-methyl-1H-indol-3-yl)-3-oxo-
propanenitrile (2b) in 1:1 ratio was performed under the
standard conditions. When the reaction stopped at 5 min-
utes, compound A was obtained in 13% yield (Scheme 4, a).
Moreover, treatment of A with 2b in 1:1 ratio under the
standard conditions directly generated the target product
3k in good yield (Scheme 4, b). These results clearly con-
firmed that A was the key intermediate in this transforma-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

E
Synlett
Q. Cai et al.
Letter
Finally, the intermediate B underwent oxidation, tautomer-
ization, and intramolecular cyclization to form the final
product 3a.
O
OH
OH
CN
O
To further make this reaction more attractive in terms
of synthetic practicality, a gram-scale synthesis of 2-hy-
droxy-2,3-dihydrofuran (3a) was carried out. To our great
pleasure, the reaction proceeded well and the desired prod-
uct 3a was isolated in 80% yield after 4 hours in DMSO at 80
1
a
K2CO3
O
H
N
+
CN
N
O
H
H2O
A'
NC
O
2a
°
C (Scheme 6).
N
H
In conclusion, a convenient and efficient tandem-
2a
cyclization reaction has been established for the synthesis
of 2-hydroxy-2, 3-dihydrofuran derivatives under mild con-
14
ditions. Initial studies of the mechanism suggest that this
reaction occurred via a Knoevenagel condensation–Michael
addition–oxidation–cyclization protocol. Moreover, the re-
action is compatible with a variety of functionalities and is
amenable to be scaled up to a gram scale. This practical
synthetic strategy also demonstrates potential for the con-
struction of complex heterocyclic compounds.
HN
HN
O
O
[
O]
O
O
NC
NC
O
O
DMSO
CN
CN
N
N
H
H
B
C
O
OH
OH
CN
O
O
1
a
K2CO3
(
a)
+
HN
HN
CN
DMSO, 80 °C
N
O
5
min
OH
O
A
O
NC
NC
yield: 13%
O
O
N
OH
2b
CN
CN
N
N
CN
H
H
O
O
3a
D
N
Scheme 5 Possible mechanism
N
O
A
standard conditions
2 h
(
b)
+
NC
CN
OH
CN
O
HN
O
CN
O
O
N
3k
OH
K CO
NC
N
2
3
O
yield: 88%
+
O
OH
DMSO, 80 °C
4 h
2
b
N
OH
H
CN
3a
80%, 2.5 g
1
a
2a
2.4 g
O
N
N
H
OH
1.0 g
OH
Scheme 6 Gram-scale experiment of product 3a
O
1a
K2CO3 Ar
DMSO, 80 °C
CN
OH
(
c)
+
NC
CN
O
2
h
O
N
Funding Information
3k
N
yield: 81%
21673166We would like to thank the National Natural Science Foun-
2b
dation of China (Grant 21272085, 21673166) for their generous
Scheme 4 Control experiments to prove the mechanism
financial support.
N
oaitn
a
l
N
a
ut ra
l
Secince
F
o
u
n
d
oaitn
of
C
h
n
i
a
2(
1
2
7
2
0
8
5
N) oaitn
a
l
N
a
ut arl
Secince
F
o
u
n
d
oaitn
of
C
h
n
i
a
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

F
Synlett
Q. Cai et al.
Letter
Supporting Information
Ed. 2010, 49, 129. (e) Gao, Q. H.; Wu, X.; Liu, S.; Wu, A. X. Org.
Lett. 2014, 16, 1732. (f) Uchida, R.; Lee, D.; Suwa, I.; Ohtawa, M.;
Watanabe, N.; Demachi, A.; Ohte, S.; Katagiri, T.; Nagamitsu, T.;
Tomoda, H. Org. Lett. 2017, 19, 5980.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609555.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(
13) (a) Mase, N.; Horibe, T. Org. Lett. 2013, 15, 1854. (b) Su, C.; Chen,
Z.-C.; Zhen, Q.-G. Synthesis 2003, 555. (c) Ogiwara, Y.;
Takahashi, K.; Kitazawa, T.; Sakai, N. J. Org. Chem. 2015, 80,
References and Notes
3
101. (d) Yadav, J. S.; Reddy, B. S. S.; Basak, A. K.; Visali, B.;
(
1) (a) Santos, E. A.; Quintela, A. L.; Ferreira, E. G.; Sousa, T. S.; Pinto,
Narsaiah, A. V.; Nagaiah, K. Eur. J. Org. Chem. 2004, 546.
14) Typical Procedure for the Synthesis of 3a
F.; Hajdu, E.; Carvalho, M. S.; Salani, S.; Rocha, D. D.; Wilke, D.
V.; Torres Mda, C.; Jimenez, P. C.; Silveira, E. R.; La Clair, J. J.;
Pessoa, O. D.; Costa-Lotufo, L. V. J. Nat. Prod. 2015, 78, 996. (b) Li,
H.; Zhao, M.; Su, G.; Lin, L.; Wang, Y. J. Agric. Food Chem. 2016, 64,
(
A mixture of phenylglyoxal monohydrate (1a, 0.5 mmol), 3-(1H-
indol-3-yl)-3-oxopropanenitrile (2a, 1.0 mmol), and K CO (1.0
mmol) in DMSO (3 mL) was stirred at 80 °C for 2 h till almost
completed conversion of the substrates by TLC analysis, then
2
3
4725. (c) Wegener, S.; Bornik, M. A.; Kroh, L. W. J. Agric. Food
Chem. 2015, 63, 6457. (d) Mahidol, C.; Prawat, H.;
Sangpetsiripan, S.; Ruchirawat, S. J. Nat. Prod. 2009, 72, 1870.
30% NaCl solution (50 mL) was added to the mixture, which was
then extracted with EtOAc three times (3 × 50 mL). The extract
was dried over anhydrous Na SO and concentrated in vacuo.
The crude product was purified by column chromatography on
silica gel (eluent: petroleum ether/EtOAc) to afford the product
(e) Tsukamoto, S.; Miura, S.; van Soest, R. W. M.; Ohta, T. J. Nat.
2
4
Prod. 2003, 66, 438. (f) Ueda, A.; Yamamoto, A.; Kato, D.; Kishi,
Y. J. Am. Chem. Soc. 2014, 136, 5171. (g) Oblak, E. Z.; VanHeyst,
M. D.; Li, J.; Wiemer, A. J.; Wright, D. L. J. Am. Chem. Soc. 2014,
3
a (221.7 mg, 92%) as a yellow solid.
136, 4309. (h) Cafieri, F.; Fattorusso, E.; Taglialatela-Scafati, O.;
(E)-4-[2-(1H-Indol-3-yl)-2-oxoethylidene]-5-hydroxy-2-(1H-
Ianaro, A. Tetrahedron 1999, 55, 7045.
indol-3-yl)-5-phenyl-4,5-dihydrofuran-3-carbonitrile (3a)
Yield 92%, 221.7 mg; yellow solid; mp 255.5–257.3 °C. H NMR
(
2) For representative references, see: (a) Cho, J. Y.; Kwon, H. C.;
Williams, P. G.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. J. Nat.
Prod. 2006, 69, 425. (b) Bromley, C. L.; Popplewell, W. L.;
Pinchuck, S. C.; Hodgson, A. N.; Davies-Coleman, M. T. J. Nat.
Prod. 2012, 75, 497. (c) Montagnac, A.; Martin, M. T.; Debitus,
C.; Païs, M. J. Nat. Prod. 1996, 59, 866. (d) Barrero, A. F.; Cortés,
M.; Manzaneda, E. A.; Cabrera, E.; Chahboun, R.; Lara, M.; Rivas,
A. R. J. Nat. Prod. 1999, 62, 1488. (e) Elsinghorst, P. W.; Cavlar, T.;
Müller, A.; Braune, A.; Blaut, M.; Gütschow, M. J. Nat. Prod.
1
(600 MHz, DMSO-d ): δ = 12.75 (s, 1 H), 12.21 (s, 1 H), 9.65 (s, 1
6
H), 8.68 (s, 1 H), 8.22 (s, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 7.87 (d, J =
.8 Hz, 1 H), 7.72–7.64 (m, 2 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.54 (d,
7
13
J = 7.8 Hz, 1 H), 7.54–7.44 (m, 3 H), 7.33–7.23 (m, 4 H). C NMR
100 MHz, DMSO-d ): δ = 180.1, 173.8, 159.6, 137.0, 136.7,
(
6
1
1
1
1
36.1, 136.0, 135.2, 129.6, 128.3, 125.6, 125.0, 124.7, 123.9,
23.3, 123.0, 122.2, 121.3, 121.2, 116.8, 115.7, 114.5, 113.2,
13.0, 112.4, 103.4, 96.6, 79.4. IR (KBr): 3424, 3265, 2208, 1610,
2011, 74, 2243. (f) Jahromi, M. A. F.; Ray, A. B.; Chansouria, J. P.
–1
523, 1483, 1430, 1307, 1235, 745 cm . HRMS (ESI): m/z [M +
N. J. Nat. Prod. 1993, 56, 989. (g) Manickam, M.; Ramanathan, M.;
Farboodniay Jahromi, M. A.; Chansouria, J. P. N.; Ray, A. B. J. Nat.
Prod. 1997, 60, 609. (h) Krenn, L.; Presser, A.; Pradhan, R.; Bahr,
B.; Paper, D. H.; Mayer, K. K.; Kopp, B. J. Nat. Prod. 2003, 66,
+
H] calcd for C30H19N O : 483.1452; found: 483.1449.
4
3
(E)-4-[2-(1H-Indol-3-yl)-2-oxoethylidene]-5-hydroxy-2-(1H-
indol-3-yl)-5-(4-nitrophenyl)-4,5-dihydrofuran-3-carboni-
trile (3e)
Yield 85%, 224.0 mg; yellow solid; mp 249.3–250.1 °C. H NMR
1107.
1
(3) Schreiber, S. L.; Kelly, S. E.; Porco, J. A. Jr.; Sammakia, T.; Suh, E.
M. J. Am. Chem. Soc. 1988, 110, 6210.
(600 MHz, DMSO-d ): δ = 12.84 (s, 1 H), 12.25 (s, 1 H), 10.07 (s,
6
1
H), 8.74 (s, 1 H), 8.44–8.34 (m, 2 H), 8.26 (s, 1 H), 8.20–8.13
(
(
4) Capon, R. J.; Faulkner, D. J. J. Org. Chem. 1984, 49, 2506.
5) Okanya, P. W.; Mohr, K. I.; Gerth, K.; Kessler, W.; Jansen, R.;
Stadler, M.; Müller, R. J. Nat. Prod. 2014, 77, 1420.
(
(
m, 1 H), 8.03–7.93 (m, 2 H), 7.86 (d, J = 6.0 Hz, 1 H), 7.68–7.61
m, 1 H), 7.58–7.53 (m, 1 H), 7.35–7.22 (m, 4 H). C NMR (150
13
MHz, DMSO-d ): δ = 180.1, 174.1, 159.1, 148.4, 143.4, 137.0,
6
(
(
6) Das, S.; Koley, P.; Pramanik, A. Tetrahedron Lett. 2011, 52, 3243.
7) Bergeron, R. I.; Cavanaugh, P. F. Jr.; Kline, S. J.; Hughes, R. G. Jr.;
Elliott, G. T.; Porter, C. W. Biochem. Biophys. Res. Commun. 1984,
1
1
1
1
36.3, 135.8, 127.6, 125.3, 124.8, 124.3, 123.9, 123.6, 123.4,
22.5, 122.3, 121.5, 121.4, 116.9, 115.8, 114.4, 113.5, 112.6,
11.7, 103.5, 96.9, 79.8. IR (KBr): 3387, 3256, 2205, 1607, 1563,
121, 848.
–1
525, 1427, 1348, 1304, 1235, 1206, 1143, 979, 744 cm . HRMS
(
8) (a) Barjau, J.; Schnakenburg, G.; Waldvogel, S. R. Angew. Chem.
Int. Ed. 2011, 50, 1415. (b) Mukaiyama, T.; Ishikawa, H.;
Koshino, H.; Hayashi, Y. Chem. Eur. J. 2013, 19, 17789. (c) Tyurin,
R. V.; Kosygina, O. V.; Mezheritskii, V. V. Russ. J. Org. Chem. 2009,
+
(ESI): m/z [M + H] calcd for C30H18N O : 528.1302; found:
5
5
528.1296.
(E)-4-[2-(1H-Indol-3-yl)-2-oxoethylidene]-5-(4-chlorophe-
nyl)-5-hydroxy-2-(1H-indol-3-yl)-4,5-dihydrofuran-3-carbo-
nitrile (3h)
Yield 80%, 206.4 mg; yellow solid; mp 245.0–246.3 °C. H NMR
45, 848. (d) Debnath, K.; Pathak, S.; Pramanik, A. Tetrahedron
Lett. 2014, 55, 1743. (e) Hirose, S.; Tomatsu, K.; Yanase, E. Tetra-
hedron Lett. 2013, 54, 7040. (f) Suzuki, M.; Imai, K.;
Wakabayashi, H.; Arita, A.; Johmoto, K.; Uekusa, H.; Kobayashi,
K. Tetrahedron 2011, 67, 5500.
1
(600 MHz, DMSO-d ): δ = 12.77 (s, 1 H), 12.20 (s, 1 H), 9.78 (s, 1
6
H), 8.68 (s, 1 H), 8.21 (s, 1 H), 8.14 (d, J = 5.4 Hz, 1 H), 7.85 (d, J =
8
7
1
1
1
1
.4 Hz, 1 H), 7.67 (d, J = 7.2 Hz, 2 H), 7.63–7.49 (m, 4 H), 7.34–
(9) Hartmann, O.; Kalesse, M. Org. Lett. 2012, 14, 3064.
13
.22 (m, 4 H). C NMR (150 MHz, DMSO-d ): δ = 180.4, 174.2,
6
(
(
(
10) Zhang, Z. G.; Dai, Z. H.; Jiang, X. F. Asian J. Org. Chem. 2016, 5, 52.
11) Fu, Q.; Yan, C.-G. Tetrahedron 2013, 69, 5841.
12) (a) Smith, L. I.; Holum, J. R. J. Am. Chem. Soc. 1956, 78, 3417.
59.6, 136.4, 136.2, 135.6, 134.7, 128.7, 128.0, 125.4, 124.9,
24.3, 123.6, 123.3, 122.5, 121.5, 117.0, 115.9, 114.6, 113.5,
13.3, 112.6, 103.6, 96.8, 79.7, 56.2. IR (KBr): 3427, 2208, 1610,
(b) Hwu, J. R.; Sambaiah, T.; Chakraborty, S. K. Tetrahedron Lett.
–1
570, 1525, 1486, 1427, 1308, 1235, 1140, 745 cm . HRMS
2003, 44, 3167. (c) Peter, M.; Gleiter, R.; Rominger, F.; Oeser, T.
+
(ESI): m/z [M + Na] calcd for C30H17ClN NaO : 539.0881; found:
4
3
Eur. J. Org. Chem. 2004, 3212. (d) Jensen, K. L.; Franke, P. T.;
Nielsen, L. T.; Daasbjerg, K.; Jørgensen, K. A. Angew. Chem. Int.
539.0885.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

G
Synlett
Q. Cai et al.
Letter
(E)-4-[2-(1H-Indol-3-yl)-2-oxoethylidene]-5-hydroxy-2-(1H-
(150 MHz, DMSO-d ): δ = 179.7, 173.6, 159.8, 139.5, 139.1,
6
indol-3-yl)-5-(thiophen-3-yl)-4,5-dihydrofuran-3-carboni-
trile (3j)
Yield 75%, 183.0 mg; yellow solid; mp 267.9–269.3 °C. H NMR
138.6, 138.5, 137.6, 137.5, 137.1, 132.9, 131.0, 128.7, 125.7,
125.2, 125.0, 124.3, 123.7, 123.6,122.6, 121.6, 116.9, 114.7,
114.3, 111.9, 111.1, 102.5, 96.5, 79.8, 34.2, 33.6. IR (KBr): 3443,
1
–1
(
600 MHz, DMSO-d ): δ = 12.77 (s, 1 H), 12.26 (s, 1 H), 9.63 (s, 1
2197, 1522, 1462, 1363, 1321, 1226, 1087, 748 cm . HRMS
6
+
H), 8.73 (s, 1 H), 8.31 (s, 1 H), 8.25–8.18 (m, 1 H), 7.97 (d, J = 6.0
Hz, 1 H), 7.90 (s, 1 H), 7.67–7.61 (m, 2 H), 7.58 (d, J = 5.4 Hz, 1
(ESI): m/z [M + H] calcd for C32H22BrN O : 589.0870; found:
4
3
589.0877.
13
H), 7.34–7.26 (m, 5 H). C NMR (150 MHz, DMSO-d ): δ = 180.6,
(E)-5-Hydroxy-2-(1-methyl-1H-indol-3-yl)-4-[2-(1-methyl-
1H-indol-3-yl)-2-oxoethylidene]-5-(naphthalen-2-yl)-4,5-
dihydrofuran-3-carbonitrile (3r)
6
1
1
1
3
1
73.8, 159.4, 138.8, 137.1, 136.4, 135.5, 135.4, 127.5, 125.8,
25.5, 125.0, 124.2, 123.6, 123.3, 122.6, 121.5, 117.1, 116.1,
16.0, 114.8, 113.5, 112.6, 111.7, 103.8, 96.8, 79.3. IR (KBr):
260, 2204, 1613, 1568, 1509, 1481, 1434, 1304, 1237, 1207,
1
Yield 88%, 246.4 mg; yellow solid; mp 228.8–230.0 °C. H NMR
(600 MHz, DMSO-d ): δ = 9.84 (s, 1 H), 8.68 (s, 1 H), 8.18 (s, 1 H),
6
–1
+
146, 1023, 742 cm . HRMS (ESI): m/z [M + H] calcd for
8.14 (d, J = 7.2 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 2 H), 7.73–7.68 (m, 2
H), 7.60 (t, J = 8.4 Hz, 3 H), 7.48 (t, J = 7.2 Hz, 1 H), 7.44–7.25 (m,
C28H18N O S: 489.1016; found: 489.1015.
4
3
13
(
1
E)-5-Hydroxy-2-(1-methyl-1H-indol-3-yl)-4-[2-(1-methyl-
H-indol-3-yl)-2-oxoethylidene]-5-phenyl-4,5-dihydro-
furan-3-carbonitrile (3k)
Yield 91%, 232.1 mg; yellow solid; mp 244.1–245.2 °C. H NMR
600 MHz, DMSO-d ): δ = 9.65 (s, 1 H), 8.67 (s, 1 H), 8.20 (s, 1 H),
6 H), 3.99 (s, 3 H), 3.91 (s, 3 H). C NMR (150 MHz, DMSO-d ):
6
δ = 179.7, 173.6, 159.8, 139.6, 139.0, 138.6, 137.6, 137.1, 132.8,
130.9, 128.8, 125.8, 125.2, 125.0, 124.2, 123.7, 123.6, 122.8,
121.7, 121.6, 116.9, 114.7, 114.3, 111.9, 111.0 , 102.5, 96.6, 79.8,
79.2, 59.8, 34.1, 33.6, 20.8, 14.1. IR (KBr): 3235, 2188, 1650,
1
(
6
–1
+
8.15 (d, J = 5.4 Hz, 1 H), 7.89 (d, J = 7.8 Hz, 1 H), 7.75–7.63 (m, 3
1387, 1232, 1125, 1085, 748 cm . HRMS (ESI): m/z [M + H]
H), 7.60 (d, J = 7.2 Hz, 1 H), 7.55–7.46 (m, 3 H), 7.39–7.33 (m, 2
H), 7.32–7.27 (m, 2 H), 3.98 (s, 3 H), 3.91 (s, 3 H). C NMR (150
calcd for C36H25N O : 561.1921; found: 561.1915.
(E)-5-Hydroxy-2-(6-methyl-1H-indol-3-yl)-4-[2-(6-methyl-
1H-indol-3-yl)-2-oxoethylidene]-5-phenyl-4,5-dihydro-
4
3
13
MHz, DMSO-d ): δ = 179.9, 173.6, 160.2, 139.0, 138.3, 137.6,
6
1
1
1
1
37.2, 137.0, 129.8, 128.5, 125.8, 125.7, 125.3, 124.2, 123.6,
23.5, 122.7, 121.6, 116.9, 114.7, 114.4, 113.1, 111.9, 111.0,
02.5, 96.5, 79.6, 34.1, 33.6. IR (KBr): 3437, 3226, 2189, 1580,
furan-3-carbonitrile (3u)
Yield 84%, 214.2 mg; yellow solid; mp 230.1–232.1 °C. H NMR
1
(600 MHz, DMSO-d ): δ = 12.64 (s, 1 H), 12.08 (s, 1 H), 9.63 (s, 1
6
-1
+
535, 1471, 1365, 1244, 746 cm . HRMS (ESI): m/z [M + Na]
H), 8.62 (s, 1 H), 8.15 (s, 1 H), 8.02 (d, J = 7.8 Hz, 1 H), 7.75 (d, J =
8.4 Hz, 1 H), 7.66 (d, J = 6.0 Hz, 2 H), 7.53–7.48 (m, 3 H), 7.41 (s,
1 H), 7.33 (s, 1 H), 7.08 (d, J = 8.4 Hz, 2 H), 2.44 (s, 3 H), 2.41 (s, 3
calcd for C32H22N NaO : 533.1584; found: 533.1576.
4
3
(E)-5-(3-Bromophenyl)-5-hydroxy-2-(1-methyl-1H-indol-3-
13
yl)-4-[2-(1-methyl-1H-indol-3-yl)-2-oxoethylidene]-4,5-
H). C NMR (100 MHz, DMSO-d ): δ = 180.1, 173.7, 159.6, 139.1,
6
dihydrofuran-3-carbonitrile (3p)
Yield 80%, 235.6 mg; yellow solid; mp 235.4–237.1 °C. H NMR
136.7, 136.0, 135.9, 134.1, 128.7, 125.5, 125.1, 124.6, 123.8,
123.2, 122.9, 122.1, 121.2, 116.7, 115.6, 114.4, 113.1, 112.3,
103.4, 96.5, 79.3, 56.0, 21.0, 18.7. IR (KBr): 3265, 2205, 1571,
1
(
600 MHz, DMSO-d ): δ = 9.85 (s, 1 H), 8.68 (s, 1 H), 8.19 (s, 1 H),
6
–1
8
.15 (d, J = 6.6 Hz, 1 H), 7.89 (d, J = 7.8 Hz, 1 H), 7.72 (d, J = 5.4
Hz, 1 H), 7.69 (d, J = 6.6 Hz, 1 H), 7.62–7.57 (m, 2 H), 7.50–7.45
m, 1 H), 7.43–7.24 (m, 5 H), 3.99 (s, 3 H), 3.91 (s, 3 H).13C NMR
1536, 1503, 1440, 1237, 1018, 765 cm . HRMS (ESI): m/z [M +
+
Na] calcd for C32H22N NaO : 533.1584; found: 533.1580.
4
3
(
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G