Synthesis of functionalized 2-aryl-4-(indol-3-yl)-4H-chromenes via iodine-catalyzed domino Michael addition-intramolecular cyclization reaction

Article abstract of DOI:10.1039/c2ob26642c

An efficient synthesis of novel functionalized 2-aryl-4-(indol-3-yl)-4H- chromenes has been developed, in the presence of a catalytic amount of iodine, from easily available starting materials, 2-hydroxychalcone derivatives. Indole, substituted indoles and 7-azaindole are suitable for this transformation. The possible domino Michael addition-intramolecular cyclization reaction mechanism is proposed.

Full text of DOI:10.1039/c2ob26642c

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PAPER
Synthesis of functionalized 2-aryl-4-(indol-3-yl)-4H-chromenes via
iodine-catalyzed domino Michael addition–intramolecular cyclization
reaction†
Guodong Yin,*a Ling Fan,a Tianbing Ren,a Chunyang Zheng,a Qing Tao,a Anxin Wub and Nengfang She*b
Received 17th August 2012, Accepted 24th September 2012
DOI: 10.1039/c2ob26642c
An efficient synthesis of novel functionalized 2-aryl-4-(indol-3-yl)-4H-chromenes has been developed, in
the presence of a catalytic amount of iodine, from easily available starting materials, 2-hydroxychalcone
derivatives. Indole, substituted indoles and 7-azaindole are suitable for this transformation. The possible
domino Michael addition–intramolecular cyclization reaction mechanism is proposed.
Introduction
The chromene (or benzopyran) moiety often appears as an
important structural component in both biologically active and
natural compounds. It is widely present in natural alkaloids,
flavonoids, tocopherols, and anthocyanins.1,2 Many chromenes
also exhibit photochromism in the crystalline state.3 The wide
application of these heteroaromatic compounds has made them
popular synthetic targets.4–8 In addition, indole derivatives, such
as indomethacin, tryptophan and melatonin,9 exist in a variety of
natural products and medicinal agents. Generally, the presence of
two or more different heterocyclic moieties in a single molecule
often enhances the biocidal profile remarkably. For example, it
has been reported that 4-aryl-pyrrolo-4H-chromenes (7,8-fused
chromenes bearing an indole moiety) are potent in cell growth
inhibition assays and as inhibitors of tubulin polymerization.10
Scheme 1 Strategy for the synthesis of 4-(indol-3-yl)-4H-chromenes.
This encouraged us to synthesize new heterocyclic systems con-
taining both chromene and indole moieties. A literature survey
revealed that only a few examples of indolyl chromenes have
been reported. In 2007, Perumal11 reported the first example of
the synthesis of 2-amino-4-(indol-3-yl)-4H-chromene via a multi-
component condensation reaction of 2-hydroxy-1-naphthalde-
hyde, malononitrile, and indole (Scheme 1a).12 Some
functionalized 4-(indol-3-yl)-4H-chromenes could be prepared
through the reaction of 2-hydroxy-2-(trifluoromethyl)-2H-chro-
menes with indoles (Scheme 1b).13 As such, the development of
new and more general methods towards 4-(indol-3-yl)-4H-chro-
menes is of significant interest.
Recently, Mayr14 and Sashidhara15 described an efficient
approach to the synthesis of 4-phenacylideneflavenes involved in
the cyclization reaction of 2-hydroxychalcone intermediates.
Moreover, it is well known that iodine has received considerable
attention as a mild, non-toxic and selective reagent in organic
synthesis due to its unique catalytic properties.16 As a continuous
study on the application of iodine in organic synthesis,17 we
herein describe an efficient iodine-catalyzed domino reaction of
2-hydroxychalcone derivatives with indole, substituted indoles,
or 7-azaindole for the synthesis of novel 2-aryl-4-(indol-3-yl)-
4H-chromenes (Scheme 1c).
aHubei Key Laboratory of Pollutant Analysis and Reuse Technology,
College of Chemistry and Environmental Engineering, Hubei Normal
University, Huangshi 435002, China. E-mail: gdyin@hbnu.edu.cn
bKey Laboratory of Pesticides and Chemical Biology of the Ministry of
Education, College of Chemistry, Central China Normal University,
Wuhan 430079, China. E-mail: nfshe@mail.ccnu.edu.cn
Results and discussion
Initially, trans-2-hydroxychalcone derivatives (3a–g) were syn-
thesized in 81–90% yields by the Claisen–Schmidt condensation
of salicylaldehyde (1) with different methyl ketones (2) in the
†Electronic supplementary information (ESI) available: Copies of 1H,
13C NMR, HSQC and HRMS spectra for the products. See DOI:
10.1039/c2ob26642c
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exhibited the characteristic two sets of doublets at 5.67 and
5.16 ppm with the coupling constant of 4.0 Hz, which were
assigned to the 3- and 4-position protons of the chromene ring,
respectively. The NH signal as a broad peak at 7.99 ppm indi-
cated the existence of the indole ring of 5a. In addition, in the
13C NMR spectrum, no carbonyl signal (CvO) was observed
and the distinguishing resonances at 101.0 ppm for C-3 and
32.1 ppm for C-4 proved the formation of the chromene ring.
With the optimal reaction conditions in hand, we then exam-
ined the reactions of trans-2-hydroxychalcone derivatives (3)
with a variety of substituted indoles (4) to establish the general-
ity of the present transformation. The results are listed in
Table 2. It was observed that substituents on the indole ring had
an obvious effect on the reaction yields. The treatment of 3a
with 4-chloro-, 5-bromo-, 5-fluoro-substituted indoles gave the
desired products 5b–d in 63–70% yields. 2-Methyl indole also
delivered 5e in good yield (71%). However, when N-methyl
indole was employed, the reaction gave a complex mixture and
only a trace of 5f was detected by the mass spectrum.
Scheme 2 Synthesis of trans-2-hydroxychalcone derivatives 3a–g.
presence of 40% potassium hydroxide solution, followed by
treatment with
2 M HCl according to known methods
(Scheme 2).18
Next, trans-2-hydroxychalcone (3a, 1.0 mmol) was used as
the model substrate to react with indole (4a, 1.0 mmol) for the
synthesis of desired product 3-(2-phenyl-4H-chromen-4-yl)-1H-
indole (5a). As shown in Table 1, 5a was obtained in 68% yield
in refluxing toluene for 3 h in the presence of a catalytic amount
(0.1 mmol) of iodine (Table 1, entry 1). Prolonging the reaction
time to 10 h and increasing the ratio of indole to 3a to 2 : 1 did
not efficiently improve the yield (Table 1, entry 2). Decreasing
the reaction temperature resulted in a lower yield of 5a (Table 1,
entries 3, 4). There was no obvious effect on the yield when 0.2
or 0.05 molar equivalent iodine was employed (Table 1, entries
5, 6). It should be noted that even in the absence of iodine, the
reaction could also deliver 5a in 38% yield (Table 1, entry 7).
Also, the reaction occurred in other solvents (THF, MeCN,
EtOH and t-BuOH) and 5a was isolated in 32–50% yield
(Table 1, entries 8–11). It was found that the reactions also gave
5a in moderate yield (45–66%) using a Brønsted acid (AcOH) or
other Lewis acids (ZnBr2, ZnCl2, InCl3, InBr3, AgOTf and
BF3·Et2O) as the catalyst (Table 1, entries 12–18). Accordingly,
the optimal reaction conditions were identified as the reaction of
3a with 1.0 equiv. of indole in the presence of 0.1 equiv. iodine.
On the other hand, the transformation was extended to other
α,β-unsaturated ketones. In the case of substrates bearing an
electron-donating group (–OMe) on the phenyl ring, 5g and 5h
were obtained in slightly lower yields. The substrates bearing
Table 2 Synthesis of 2-aryl-4-(indol-3-yl)-4H-chromenesa,b
1
The structure of compound 5a was confirmed by means of H
NMR, 13C NMR, HRMS, and IR. The 1H NMR spectrum
Table 1 Optimization of reaction conditions for the synthesis of 5aa
Entries
Solvent
Catalyst (mmol)
Temp. (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.2)
I2 (0.05)
I2 (0)
I2 (0.1)
I2 (0.1)
Reflux
Reflux
70
68
69c
53
5
25
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
68
65
38d
45
32
48
50
66
62
60
60
48
45
40
9
MeCN
EtOH
10
11
12
13
14
15
16
17
18
I2 (0.1)
I2 (0.1)
t-BuOH
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
AcOH (0.1)
ZnBr2 (0.1)
ZnCl2 (0.1)
InCl3 (0.1)
InBr3 (0.1)
AgOTf (0.1)
BF3·Et2O (0.1)
a Unless otherwise noted, reactions were performed with 3a (1.0 mmol)
and 4a (1.0 mmol) in solvent (6 mL) for 3 h. b Isolated yield. c The
reaction time was 10 h, with 3a/4a = 1 : 2. d The yield was 40% while
prolonging the reaction time to 10 h, with 3a/4a = 1 : 2.
a Reaction conditions: 3 (1.0 mmol), 4 (1.0 mmol) and iodine
(0.1 mmol) in toluene (6 mL) for 3 h. b Isolated yields. c Complex
mixtures.
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Scheme 3 Synthesis of 4-(3-(7-azaindolyl))-4H-chromenes.
Scheme 5 Proposed mechanism for the domino reaction.
Scheme 4 One-pot reaction.
hydroxyl group (–OH) with indole in the presence of the Lewis
acid (iodine)26,13a or to 5a after loss of water. Obviously, for-
mation of 5a was a more favorable process.
electron-withdrawing groups (–Cl and –F) led to the correspond-
ing 5i–l in 65–75% yields. To our delight, heterocyclic (furan
and thiophene) substrates were also suitable for the reactions
resulting in 5m and 5n in 70% and 69% yields, respectively.
However, when R1 was an alkyl group (CH3), 5o was not
observed even after 8 h.
Furthermore, the reaction of 7-azaindole (6) with 3a, 3c and
3f under the above-mentioned standard conditions furnished the
corresponding 2-aryl-4-(3-(7-azaindolyl))-4H-chromenes (7–9)
in 70–79% yields (Scheme 3). No expected products were
obtained using furan, benzofuran and benzothiophene as sub-
strates probably owing to their weak nucleophilicity.
Conclusions
In summary, this paper describes a novel and efficient method
for the synthesis of functionalized 2-aryl-4-(indol-3-yl)-4H-chro-
menes from easily available starting materials, 2-hydroxychal-
cone and indole derivatives. In this transformation, a broad
substrate scope has been demonstrated and iodine (10 mmol%)
is proven to be an efficient catalyst. The possible domino
Michael addition–intramolecular cyclization reaction mechanism
is also proposed.
In recent years, much attention has been paid to one-pot
syntheses.19 It has been reported that chalcone derivatives can be
synthesized in situ by condensation of aromatic aldehyde with
acetophenone in the presence of iodine20 or without any cata-
lyst.21 Therefore, we attempted to synthesize 5a from salicylalde-
hyde (1), acetophenone (2a) and indole (4a) in a one-pot
procedure under the standard conditions. However, 5a was not
formed and the reaction only occurred between 1 and 4a to give
the unexpected product 6,12-bis(2-hydroxylphenyl)-6,12-dihy-
droindolo-[3,2-b]carbazole (10)22 in 70% yield with recovery of
unreacted starting material 2a (Scheme 4).
Next, the plausible mechanism was further investigated using
α,β-unsaturated ketone (3a) as an example (Scheme 5). First,
indole reacts with 3a via a Michael-type addition reaction to
deliver intermediate A and this process could take place without
any catalyst (Table 1, entry 7).23 In the presence of a catalytic
amount of iodine, the reaction efficiency could be improved.24
Subsequently, A could easily undergo an intramolecular cycliza-
tion to give intermediate B, which is converted to the expected
product 5a after loss of water. Attempts to isolate the intermedi-
ate A (observed in the reaction mixture after 10 min using ESI-
mass spectrometry, see ESI†), were unsuccessful, probably due
to the fast transformation to B.25 In addition, the unexpected
Experimental
General remarks
All chemicals were commercial and used without further purifi-
cation. All organic solvents were dried and freshly distilled
1
before use. H and 13C NMR spectra were recorded on Bruker
AV 300 MHz spectrometers using CDCl3 or DMSO-d6 as the
solvent. Chemical shifts are reported relative to TMS (internal
standard). HSQC NMR spectrum was recorded on Varian
600 MHz spectrometers (CDCl3). Mass spectra were measured
on a LCQ Advantage MAX (ESI). HRMS were obtained on a
Bruker 7-T FT-ICR MS and apex-Ultra MS equipped with an
ACPI source. IR spectra were obtained as KBr pellet samples on
a Nicolet 5700 FTIR spectrometer. Flash column chromato-
graphy was performed on silica gel (200–300 mesh).
General experimental procedure for the synthesis of 318
To a solution of aromatic methyl ketones (40 mmol) and salicyl-
aldehyde (6.10 g, 50 mmol) in EtOH (50 mL) was added 40%
KOH (10 mL) aqueous solution dropwise and the reaction was
carried out at 60 °C (or room temperature) for 2–4 h until the
disappearance of starting material (monitored by thin layer
chromatography). The solution/suspension was poured into cold
H2O and the mixture neutralized with 2 M HCl to a pH in the
3,3′-(2-phenylchroman-2,4-diyl)bis(1H-indole)
(5ab)
was
obtained in 4% yield when increasing the amounts of substrates.
These results indicate that intermediate B is formed during the
reaction, which can be converted to 5ab after substitution of the
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(E)-4-(2-Hydroxyphenyl)but-3-en-2-one (3g).31 Yellow solid,
5.83 g, yield 90%; mp 138–139 °C. IR (KBr) v 3356, 2358,
range of 2–3. The resulting precipitate was collected, washed
with H2O and recrystallized from EtOH to give 3a–f. Compound
3g was synthesized according to the analogous method using
acetone as the solvent.
1
1635, 1611, 1461, 1357, 1255, 759 cm−1; H NMR (300 MHz,
CDCl3) δ 7.87 (d, J = 16.4 Hz, 1H), 7.63 (s, 1H, OH), 7.47 (dd,
J1 = 7.8, J2 = 1.5 Hz, 1H), 7.29–7.23 (m, 1H), 7.05 (d, J =
16.4 Hz, 1H), 6.95–6.89 (m, 2H), 2.44 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3) δ 201.4, 156.1, 141.0, 131.9, 129.7, 127.7,
121.5, 120.6, 116.6, 26.8; ESI-MS: m/z 162.88 [M + H]+.
(E)-3-(2-Hydroxyphenyl)-1-phenyl-2-propen-1-one (3a).27 Yellow
solid, 7.80 g, yield 87%; mp 154–155 °C. IR (KBr) v 3209,
1639, 1592, 1567, 1451, 1345, 1228 cm−1; 1H NMR (300 MHz,
CDCl3) δ 8.16 (d, J = 15.9 Hz, 1H), 8.03 (d, J = 7.1 Hz, 2H),
7.72 (d, J = 15.9 Hz, 1H), 7.62–7.48 (m, 4H), 7.30–7.25 (m,
1H), 7.00–6.91 (m, 2H), 6.52 (br, 1H, OH); ESI-MS: m/z 224.76
[M + H]+.
General experimental procedure for the synthesis of compounds
5 and 7–9
(E)-3-(2-Hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one
(3b).28 Yellow solid, 8.57 g, yield 84%; mp 148–149 °C. IR
A mixture of 3 (1.0 mmol), indole (substituted indoles or
7-azaindole) (1.0 mmol) and iodine (25 mg, 0.1 mmol) was
heated at 110 °C in anhydrous toluene (6 mL). After the reactant
disappeared (2–4 h, monitored by thin layer chromatography),
the mixture was cooled to room temperature. The reaction
mixture was directly added to the column chromatography using
petroleum ether as the eluent to remove toluene, then eluted with
petroleum ether/EtOAc to give the expected compounds 5 and
7–9.
1
(KBr) v 3433, 3235, 1642, 1595, 1254, 1166 cm−1; H NMR
(300 MHz, CDCl3) δ 8.18 (d, J = 15.8 Hz, 1H), 8.06 (d, J =
6.9 Hz), 7.69 (d, J = 15.8 Hz, 1H), 7.60 (dd, J1 = 8.1 Hz, J2 =
1.7 Hz, 1H), 7.29–7.25 (m, 1H), 7.00–6.92 (m, 4H), 6.82 (br,
1H, OH), 3.89 (s, 3H, OCH3); ESI-MS: m/z 254.82 [M + H]+.
(E)-1-(4-Chlorophenyl)-3-(2-hydroxyphenyl)prop-2-en-1-one
(3c).29 Yellow solid, 9.21 g, yield 89%; mp 151–152 °C. IR
1
(KBr) v 3438, 1643, 1592, 1392, 1342, 1215 cm−1; H NMR
3-(2-Phenyl-4H-chromen-4-yl)-1H-indole (5a). Pale red solid,
220 mg, yield 68%; mp 100–102 °C. IR (KBr) v 3424, 2922,
(300 MHz, CDCl3) δ 8.16 (d, J = 15.8 Hz, 1H), 8.06 (d, J =
8.7 Hz, 2H), 7.65 (d, J = 15.8 Hz, 1H), 7.60 (dd, J1 = 7.8 Hz,
J2 = 1.6 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.31–7.25 (m, 1H),
6.99–6.89 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 190.5, 155.8,
141.4, 139.1, 136.6, 131.9, 130.0, 129.6, 128.8, 122.2, 122.0,
120.9, 116.5; ESI-MS: m/z 258.70 [M + H]+.
2855, 1632, 1454, 1227, 747 cm−1 1H NMR (300 MHz,
;
CDCl3) δ 7.99 (s, 1H, NH), 7.74–7.70 (m, 2H), 8.62 (d, J =
7.8 Hz, 1H), 7.38–7.31 (m, 4H), 7.19–7.02 (m, 6H), 6.94–6.89
(m, 1H), 5.67 (d, J = 4.0 Hz, 1H, chromene H-3), 5.16 (d, J =
4.0 Hz, 1H, chromene H-4); 13C NMR (75 MHz, CDCl3) δ
151.1, 147.7 (chromene C-2), 136.6, 134.4, 129.5, 128.3, 128.2,
127.5, 126.3, 124.7, 123.3, 122.1, 122.0, 121.5, 119.6, 119.4,
116.5, 111.2, 101.0 (chromene C-3), 32.1 (chromene C-4);
HRMS (ACPI): m/z [M + H]+ calcd for C23H18NO: 324.1383,
found: 324.1387.
(E)-1-(4-Fluorophenyl)-3-(2-hydroxyphenyl)prop-2-en-1-one
(3d).29 Yellow solid, 8.74 g, yield 90%; mp 164–165 °C. IR
1
(KBr) v 3307, 1646, 1600, 1568, 1334, 1229, 1150 cm−1; H
NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H, OH), 8.26–8.21
(m, 2H), 8.15 (d, J = 15.8 Hz, 1H), 7.93–7.88 (m, 2H),
7.43–7.30 (m, 3H), 7.01–6.90 (m, 2H); 13C NMR (75 MHz,
4-Chloro-3-(2-phenyl-4H-chromen-4-yl)-1H-indole (5b). Pale
red solid, 250 mg, yield 70%; mp 83–85 °C. IR (KBr) v 3419,
1
DMSO-d6) δ 188.0, 164.9 (d, JC–F = 250.3 Hz), 157.4, 139.7,
4
3
134.6 (d, JC–F = 2.8 Hz), 132.1, 131.2 (d, JC–F = 9.3 Hz),
2921, 2357, 1721, 1666, 1587, 1486, 1333, 1231, 1183 cm−1
;
2
128.7, 121.4, 120.6, 119.4, 116.3, 115.7 (d, JC–F = 21.6 Hz);
1H NMR (300 MHz, CDCl3) δ 7.97 (s, 1H, NH), 7.68 (d, J =
8.0 Hz, 2H), 7.36–6.93 (m, 10H), 6.64 (d, J = 2.4 Hz, 1H), 5.86
(d, J = 4.2 Hz, 1H, chromene H-3), 5.78 (d, J = 4.2 Hz, 1H,
chromene H-4); 13C NMR (75 MHz, CDCl3) δ 151.3, 146.9
(chromene C-2), 137.5, 134.4, 130.0, 128.2, 127.4, 125.9,
124.6, 124.0, 123.3, 123.1, 123.0, 122.5, 120.9, 116.4, 110.0,
102.1 (chromene C-3), 31.2 (chromene C-4); HRMS (ACPI):
m/z [M + H]+ calcd for C23H17ClNO: 358.0993, found:
358.1000.
ESI-MS: m/z 242.77 [M + H]+.
(E)-1-(Furan-2-yl)-3-(2-hydroxyphenyl)prop-2-en-1-one (3e).30
Yellow solid, 6.97 g, yield 81%; mp 149–150 °C. IR (KBr) v
3440, 1640, 1580, 1456, 1390, 1249, 1047 cm−1 1H NMR
;
(300 MHz, CDCl3) δ 8.27 (d, J = 16.0 Hz, 1H), 7.66–7.55 (m,
3H), 7.35 (dd, J1 = 3.6 Hz, J2 = 0.7 Hz, 1H), 7.30–7.24 (m, 1H),
6.98–6.91 (m, 2H), 6.59 (dd, J1 = 3.6 Hz, J2 = 1.7 Hz, 1H), 6.50
(br, 1H, OH); 13C NMR (75 MHz, CDCl3) δ 179.0 (CvO),
155.9, 153.8, 146.6, 139.9, 131.9, 129.3, 122.0, 121.6, 120.8,
117.8, 116.7, 112.5; ESI-MS: m/z 215.16 [M + H]+.
5-Bromo-3-(2-phenyl-4H-chromen-4-yl)-1H-indole (5c). Pale
red solid, 260 mg, yield 65%; mp 100–101 °C. IR (KBr) v 3423,
(E)-3-(2-Hydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one (3f).30
Yellow solid, 8.12 g, yield 88%; mp 158–159 °C. IR (KBr) v
1663, 1451, 1227, 1101 cm−1 1H NMR (300 MHz, CDCl3)
;
δ 8.03 (s, 1H, NH), 7.75–7.70 (m, 3H), 7.42–7.06 (m, 8H),
7.01–6.94 (m, 2H), 5.63 (d, J = 4.0 Hz, 1H, chromene H-3),
5.11 (d, J = 4.0 Hz, 1H, chromene H-4); 13C NMR (75 MHz,
CDCl3) δ 151.1, 148.0 (chromene C-2), 135.2, 134.3, 129.3,
128.5, 128.3, 128.0, 127.7, 125.1, 124.7, 123.5, 123.4, 123.0,
121.8, 121.4, 116.7, 113.0, 112.7, 100.5 (chromene C-3), 31.8
(chromene C-4); HRMS (ACPI): m/z [M + H]+ calcd for
C23H17BrNO: 402.0488, found: 402.0487.
3439, 1636, 1567, 1403, 1230 cm−1 1H NMR (300 MHz,
;
DMSO-d6) δ 10.31 (s, 1H, OH), 8.24 (dd, J1 = 3.8 Hz, J2 =
1.0 Hz, 1H), 8.10–8.03 (m, 2H), 7.90 (dd, J1 = 7.8 Hz, J2 =
1.5 Hz, 1H), 7.80 (d, J = 16.0 Hz, 1H), 7.33–7.26 (m, 2H),
6.98–6.87 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 181.8,
157.3, 145.7, 138.6, 135.1, 133.1, 132.2, 128.9, 128.6, 121.2,
120.7, 119.4, 116.3; ESI-MS: m/z 230.82 [M + H]+.
8880 | Org. Biomol. Chem., 2012, 10, 8877–8883
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13C NMR (75 MHz, CDCl3) δ 150.9, 146.7 (chromene C-2),
136.5, 134.0, 132.7, 129.5, 128.4, 127.6, 126.2, 125.9, 123.5,
123.1, 122.1, 122.0, 121.2, 119.6, 119.2, 116.4, 111.2, 101.4
(chromene C-3), 32.0 (chromene C-4); HRMS (ACPI): m/z
[M + H]+ calcd for C23H17ClNO: 358.0993, found: 358.0992.
5-Fluoro-3-(2-phenyl-4H-chromen-4-yl)-1H-indole (5d). Pale
red solid, 215 mg, yield 63%; mp 98–100 °C. IR (KBr) v 3422,
3064, 2358, 1724, 1587, 1484, 1452, 1266, 1228, 1175,
1
1056 cm−1; H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H, NH),
7.73–7.69 (m, 2H), 7.39–7.02 (m, 9H), 6.94–6.84 (m, 2H), 5.62
(d, J = 4.2 Hz, 1H, chromene H-3), 5.08 (d, J = 4.0 Hz, 1H,
chromene H-4); 13C NMR (75 MHz, CDCl3) δ 157.6 (d, 1JC–F
=
5-Bromo-3-(2-(4-chlorophenyl)-4H-chromen-4-yl)-1H-indole
(5j). Pale red solid, 296 mg, yield 68%; mp 75–77 °C. IR (KBr)
233.1 Hz), 151.1, 147.9 (chromene C-2), 134.2, 133.1, 129.3,
1
v 3428, 1656, 1488, 1451, 1399, 1225, 1096 cm−1; H NMR
3
128.4, 128.3, 127.6, 126.5 (d, JC–F = 9.8 Hz), 124.7, 123.8,
3
123.4, 123.0, 121.5 (d, 4JC–F = 4.8 Hz), 116.6, 111.9 (d, JC–F
=
(300 MHz, CDCl3) δ 7.91 (s, 1H, NH), 7.70 (s, 1H), 7.70 (d, J =
8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.22–7.01 (m, 5H),
6.93–6.87 (m, 2H), 5.55 (d, J = 4.0 Hz, 1H, chromene H-3),
5.02 (d, J = 4.0 Hz, 1H, chromene H-4); 13C NMR (75 MHz,
CDCl3) δ 150.8, 147.0 (chromene C-2), 135.1, 134.2, 132.6,
129.3, 128.4, 127.9, 127.8, 125.9, 125.0, 123.6, 123.5, 122.7,
121.6, 121.0, 116.6, 112.9, 112.7, 101.9 (chromene C-3), 31.8
(chromene C-4); HRMS (ACPI): m/z [M + H]+ calcd for
C23H16BrClNO: 436.0098, found: 436.0097.
2
2
9.7 Hz), 110.5 (d, JC–F = 26.3 Hz), 104.2 (d, JC–F = 23.5 Hz),
100.1 (chromene C-3), 32.1 (chromene C-4); HRMS (ACPI):
m/z [M + H]+ calcd for C23H17FNO: 342.1289, found:
342.1292.
2-Methyl-3-(2-phenyl-4H-chromen-4-yl)-1H-indole (5e). Pale
red solid, 240 mg, yield 71%; mp 97–98 °C. IR (KBr) v 3409,
3053, 2920, 1586, 1488, 1453, 1328, 1229 cm−1 1H NMR
;
(300 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz, 2H), 7.62 (s, 1H, NH),
7.43 (d, J = 7.8 Hz, 1H), 7.36–7.28 (m, 3H), 7.19–6.84 (m, 7H),
5.53 (d, J = 4.2 Hz, 1H, chromene H-3), 5.14 (d, J = 4.0 Hz,
1H, chromene H-4), 2.30 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3) δ 151.2, 147.6 (chromene C-4), 135.1, 134.3, 131.4,
129.4, 128.3, 127.8, 127.4, 124.6, 123.4, 123.3, 121.0, 119.4,
118.5, 116.3, 115.9, 110.2, 100.9 (chromene C-3), 30.9 (chro-
mene C-4), 11.8 (CH3); HRMS (ACPI): m/z [M + H]+ calcd for
C24H20NO: 338.1539, found: 338.1542.
3-(2-(4-Fluorophenyl)-4H-chromen-4-yl)-1H-indole (5k). Pale
red solid, 256 mg, yield 75%; mp 69–70 °C. IR (KBr) v 3414,
1
1611, 1500, 1326, 1225, 1100, 820 cm−1; H NMR (300 MHz,
CDCl3) δ 7.95 (s, 1H, NH), 7.68–7.64 (m, 2H), 7.59 (d, J =
7.9 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.18–6.98 (m, 8H),
6.93–6.88 (m, 1H), 5.59 (d, J = 4.0 Hz, 1H, chromene H-3),
5.12 (d, J = 4.0 Hz, 1H, chromene H-4); 13C NMR (75 MHz,
1
CDCl3) δ 162.8 (d, JC-F = 246.1 Hz), 151.0, 146.9 (chromene
4
C-2), 136.6, 130.4 (d, JC–F = 3.3 Hz), 129.5, 127.5, 126.5 (d,
3JC–F = 8.1 Hz), 126.2, 123.5, 122.1, 122.0, 121.4, 119.6, 119.3,
116.4, 115.2 (d, 2JC–F = 21.5 Hz), 111.2, 101.7 (d, 5JC–F = 1.7 Hz,
chromene C-3), 32.0 (chromene C-4); HRMS (ACPI): m/z
[M + H]+ calcd for C23H17FNO: 342.1289, found: 342.1292.
3-(2-(4-Methoxyphenyl)-4H-chromen-4-yl)-1H-indole
Pale red solid, 216 mg, yield 61%; mp 96–97 °C. IR (KBr)
v 3423, 2924, 1639, 1501, 1238, 1172 cm−1 1H NMR
(5g).
;
(300 MHz, CDCl3) δ 7.76 (s, 1H, NH), 7.63–7.58 (m, 3H),
7.24–6.98 (m, 6H), 6.89–6.86 (m, 4H), 5.50 (d, J = 4.0 Hz, 1H,
chromene H-3), 5.08 (d, J = 4.0 Hz, 1H, chromene H-4), 3.75 (s,
3H, OCH3); 13C NMR (75 MHz, CDCl3) δ 159.7, 151.1, 147.4
(chromene C-2), 136.5, 129.4, 127.4, 127.0, 126.2, 126.0,
123.5, 123.2, 122.0, 121.9, 121.5, 119.5, 119.3, 116.4, 113.6,
111.2, 99.3 (chromene C-3), 55.5 (OCH3), 32.0 (chromene C-4);
HRMS (ACPI): m/z [M + H]+ calcd for C24H20NO2: 354.1487,
found: 354.1491.
4-Chloro-3-(2-(4-fluorophenyl)-4H-chromen-4-yl)-1H-indole
(5l). Pale red solid, 244 mg, yield 65%; mp 70–71 °C. IR (KBr)
1
v 3422, 2358, 1598, 1499, 1333, 1228, 1154, 1056 cm−1; H
NMR (300 MHz, CDCl3) δ 8.01 (s, 1H, NH), 7.67–7.62 (m,
2H), 7.24–6.94 (m, 10H), 6.68 (d, J = 2.5 Hz, 1H), 5.80 (d, J =
4.3 Hz, 1H, chromene H-3), 5.78 (d, J = 4.3 Hz, 1H, chromene
1
H-4); 13C NMR (75 MHz, CDCl3) δ 162.7 (d, JC–F
=
4
246.0 Hz), 151.2, 146.1 (chromene C-2), 137.5, 130.6 (d, JC–F
= 3.2 Hz), 130.0, 127.5, 126.4 (d, 3JC–F = 8.1 Hz), 125.9, 125.0,
5-Bromo-3-(2-(4-methoxyphenyl)-4H-chromen-4-yl)-1H-indole
(5h). Pale red solid, 260 mg, yield 60%; mp 92–93 °C. IR
(KBr) v 3421, 2923, 1719, 1602, 1505, 1452, 1242, 1173,
123.9, 123.4, 123.0, 122.6, 121.0, 119.5, 116.4, 115.2 (d, 2JC–F
=
5
21.5 Hz), 110.2, 101.8 (d, JC–F = 1.7 Hz, chromene C-3), 31.3
(chromene C-4); HRMS (ACPI): m/z [M + H]+ calcd for
C23H16ClFNO: 376.0899, found: 376.0899.
1
1035 cm−1; H NMR (300 MHz, CDCl3) δ 8.08 (s, 1H, NH),
7.74 (s, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.25–6.88 (m, 9H), 5.50
(d, J = 4.0 Hz, 1H, chromene H-3), 5.08 (d, J = 4.0 Hz, 1H,
chromene H-4), 3.82 (s, 3H, OCH3); 13C NMR (75 MHz,
CDCl3) δ 159.9, 151.2, 147.8 (chromene C-2), 135.2, 129.3,
128.1, 127.6, 127.0, 126.1, 125.0, 123.5, 123.4, 123.1, 121.8,
121.6, 116.6, 113.7. 112.9, 112.7, 98.9 (chromene C-3), 55.3
(OCH3), 31.8 (chromene C-4); HRMS (ACPI): m/z [M + H]+
calcd for C24H19BrNO2: 432.0594, found: 432.0594.
3-(2-(Furan-2-yl)-4H-chromen-4-yl)-1H-indole (5m). Pale red
solid, 220 mg, yield 70%; mp 97–99 °C. IR (KBr) v 3415, 1627,
1453, 1228, 1056, 744 cm−1 1H NMR (300 MHz, CDCl3)
;
δ 7.89 (s, 1H, NH), 7.59 (d, J = 7.9 Hz, 1H), 7.34–7.29 (m, 2H),
7.22–7.02 (m, 5H), 6.97 (d, J = 2.4 Hz, 1H), 6.93–6.87 (m, 1H),
6.64 (d, J = 3.3 Hz, 1H), 6.42 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz,
1H), 5.68 (d, J = 4.1 Hz, 1H, chromene H-3), 5.11 (d, J =
4.1 Hz, 1H, chromene H-4); 13C NMR (75 MHz, CDCl3)
δ 150.7, 148.7 (chromene C-2), 142.2, 141.0, 136.6, 129.6,
127.5, 126.2, 123.5, 123.3, 122.12, 122.09, 121.2, 119.6, 119.3,
116.4, 111.2, 111.1, 106.4, 100.0 (chromene C-3), 31.4 (chro-
mene C-4); HRMS (ACPI): m/z [M + H]+ calcd for C21H16NO2:
314.1176, found: 314.1178.
3-(2-(4-Chlorophenyl)-4H-chromen-4-yl)-1H-indole (5i). Pale
red solid, 261 mg, yield 73%; mp 85–86 °C. IR (KBr) v 3426,
1636, 1486, 1394, 1225, 1085 cm−1 1H NMR (300 MHz,
;
CDCl3) δ 7.85 (s, 1H, NH), 7.61–7.55 (m, 3H), 7.31–7.27 (m,
3H), 7.14–7.00 (m, 5H), 6.93–6.86 (m, 2H), 5.62 (d, J = 4.0 Hz,
1H, chromene H-3), 5.11 (d, J = 4.0 Hz, 1H, chromene H-4);
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3-(2-(Thiophen-2-yl)-4H-chromen-4-yl)-1H-indole (5n). Pale
red solid, 228 mg, yield 69%; mp 74–75 °C. IR (KBr) v 3417,
3.6 Hz, 1H), 7.26–6.91 (m, 8H), 5.57 (d, J = 4.1 Hz, 1H, chro-
mene H-3), 5.08 (d, J = 4.1 Hz, 1H, chromene H-4); 13C NMR
(75 MHz, CDCl3) δ 150.8, 149.2 (chromene C-2), 144.1, 142.8,
138.0, 129.4, 128.0, 127.8, 127.3, 124.9, 123.7, 123.6, 122.7,
122.2, 119.4, 119.0, 116.6, 115.7, 99.9 (chromene C-3), 32.4
(chromene C-4); HRMS (ACPI): m/z [M + H]+ calcd for
C20H15N2OS: 331.0900, found: 331.0903.
1634, 1397, 1229, 1101 cm−1 1H NMR (300 MHz, CDCl3)
;
δ 8.00 (s, 1H, NH), 7.61 (d, J = 7.8 Hz, 1H), 7.37–7.34
(m, 2H), 7.25–7.00 (m, 8H), 6.95–6.91 (m, 1H), 5.59 (d, J = 4.1
Hz, 1H, chromene H-3), 5.14 (d, J = 4.1 Hz, 1H, chromene
H-4); 13C NMR (75 MHz, CDCl3) δ 150.8, 143.9 (chromene
C-2), 138.2, 136.6, 129.5, 127.5, 127.2, 126.3, 124.7, 123.5,
123.4, 123.2, 122.2, 122.1, 121.3, 119.6, 119.4, 116.4, 111.2,
100.4 (chromene C-3), 32.0 (chromene C-4); HRMS (ACPI):
m/z [M + H]+ calcd for C21H16NOS: 330.0947, found:
330.0951.
One-pot reaction procedure
The mixture of salicylaldehyde (1, 305 mg, 2.5 mmol), aceto-
phenone (2a, 300 mg, 2.5 mmol) and indole (4a, 295 mg,
2.5 mmol) and iodine (63 mg, 0.25 mmol) was heated at 110 °C
in anhydrous toluene (8 mL) for 3 h. The mixture was cooled to
room temperature. The precipitate was filtered off, washed with
EtOH and carefully dried to give 6,12-bis(2-hydroxylphenyl)-
6,12-dihydroindolo[3,2-b]carbazole (10)22 in 70% yield
(388 mg) as a white solid. mp > 300 °C. IR (KBr) v 3450, 3400,
3,3′-(2-Phenylchroman-2,4-diyl)bis(1H-indole)
(5ab). Mp
230–232 °C. IR (KBr) v 3460, 3458, 1459, 1318, 1256, 1180,
1
1052, 823 cm−1; H NMR (300 MHz, CDCl3) δ 7.88 (s, 1H,
NH), 7.85 (s, 1H, NH), 7.73 (d, J = 8.0 Hz, 1H), 7.49 (d, J =
7.2 Hz, 2H), 7.27–6.89 (m, 12H), 6.79–6.58 (m, 3H), 4.05–3.99
(m, 1H), 3.24–3.15 (m, 1H), 2.94–2.85 (m, 1H); 1H NMR
(300 MHz, DMSO-d6) δ 11.04 (s, 1H, NH), 10.97 (s, 1H, NH),
7.70 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 2H), 7.39–7.04
(m, 12H), 6.96–6.83 (m, 2H), 6.72–6.63 (m, 2H), 3.97–3.91 (m,
1H), 3.17–3.14 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ
153.7, 144.2, 136.8, 136.7, 128.9, 128.2, 127.6, 126.6, 126.0,
125.8, 125.7, 125.0, 123.7, 122.4, 121.1, 120.9, 120.6, 120.5,
119.9, 118.7, 118.6, 118.3, 116.4, 116.0, 111.7, 111.6, 80.4,
30.3; ESI-MS: m/z 440.03 [M + H]+.
1
1454, 1323, 1267, 1184, 1082, 753 cm−1; H NMR (300 MHz,
DMSO-d6) δ 10.42 (s, 2H, NH), 9.87 (s, 2H, OH), 7.28–7.23
(m, 4H), 6.99–6.95 (m, 6H), 6.93–6.90 (m, 2H), 6.81–6.54 (m,
4H), 6.10 (s, 2H); ESI-MS: m/z 443.14 [M + H]+.
Acknowledgements
We gratefully acknowledge support from the National Natural
Science Foundation of China (Grant 20902035 and 21102042).
3-(2-Phenyl-4H-chromen-4-yl)-1H-pyrrolo[2,3-b]pyridine (7).
White solid, 228 mg, yield 70%; mp 155–156 °C. IR (KBr) v
3437, 3140, 2357, 1663, 1582, 1490, 1329, 1116, 1064 cm−1
;
1H NMR (300 MHz, CDCl3) δ 10.68 (s, 1H, NH), 8.27 (d, J =
4.2 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.2 Hz, 2H),
7.39–6.93 (m, 9H), 5.65 (d, J = 4.0 Hz, 1H, chromene H-3),
5.10 (d, J = 4.0 Hz, 1H, chromene H-4); 13C NMR (75 MHz,
CDCl3) δ 151.0, 149.2 (chromene C-2), 148.0, 142.5, 134.2,
129.4, 128.5, 128.3, 128.1, 127.7, 124.7, 123.5, 122.9, 122.3,
119.6, 119.1, 116.6, 115.6, 100.6 (chromene C-3), 32.6 (chro-
mene C-4); HRMS (ACPI): m/z [M + H]+ calcd for C22H17N2O:
325.1335, found: 325.1338.
Notes and references
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pyridine (8). Pale red solid, 284 mg, yield 79%; mp
178–180 °C. IR (KBr) v 3440, 3412, 2891, 1491, 1328, 1229,
1
1118 cm−1; H NMR (300 MHz, CDCl3) δ 9.77 (s, 1H, NH),
8.27 (d, J = 3.5 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.65 (d, J =
8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.19–6.92 (m, 6H), 5.63
(d, J = 4.0 Hz, 1H, chromene H-3), 5.10 (d, J = 4.0 Hz, 1H,
chromene H-4); 13C NMR (75 MHz, CDCl3) δ 150.9, 149.2
(chromene C-2), 147.1, 143.1, 134.3, 132.6, 129.5, 128.5,
127.9, 127.8, 126.0, 123.7, 122.6, 122.0, 119.6, 118.8, 116.6,
115.8, 101.0 (chromene C-3), 32.6 (chromene C-4); HRMS
(ACPI): m/z [M + H]+ calcd for C22H16ClN2O: 359.0946, found:
359.0948.
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1
1065 cm−1; H NMR (300 MHz, CDCl3) δ 10.16 (s, 1H, NH),
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Org. Biomol. Chem., 2012, 10, 8877–8883 | 8883