Rapid access to α-carbolines via a one-pot tandem reaction of α,β-unsaturated ketones with 2-nitrophenylacetonitrile and the anti-proliferative activities of the products

Article abstract of DOI:10.1039/c3ob41921e

An effective and convenient method has been developed for the preparation of 2 or 2,4-substituted α-carbolines via a one-pot tandem reaction of α,β-unsaturated ketones with 2-nitrophenylacetonitrile in the presence of zinc dust, acetic acid and triethylamine. This protocol presents a simple, rapid and pot/step economical strategy for preparing biologically interesting α-carbolines with moderate anti-tumor activities.

Full text of DOI:10.1039/c3ob41921e

Organic &
Biomolecular Chemistry
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PAPER
Rapid access to α-carbolines via a one-pot
tandem reaction of α,β-unsaturated ketones with
2-nitrophenylacetonitrile and the anti-proliferative
activities of the products†
Cite this: Org. Biomol. Chem., 2014,
12, 355
Xiaofei Zhang, Qian He, Haoyue Xiang, Shanshan Song, Zehong Miao* and
Chunhao Yang*
An effective and convenient method has been developed for the preparation of 2 or 2,4-substituted
α-carbolines via a one-pot tandem reaction of α,β-unsaturated ketones with 2-nitrophenylacetonitrile in
the presence of zinc dust, acetic acid and triethylamine. This protocol presents a simple, rapid and
pot/step economical strategy for preparing biologically interesting α-carbolines with moderate anti-
tumor activities.
Received 22nd September 2013,
Accepted 5th November 2013
DOI: 10.1039/c3ob41921e
www.rsc.org/obc
Introduction
α-Carboline derivatives (pyrido[2,3-b]indoles) have gained
much attention in medicinal chemistry recently. α-Carboline
core and derivatives are found in many natural products, such
as grossularine-1/2,1 cryptotackieine,2 mescengricin3 and pero-
phoramidine4 (Fig. 1), and they displayed interesting biological
activities such as anti-viral and anti-tumor activities caused by
the interaction with DNA or the inhibition of topoisomerase
II.5 Furthermore, synthetic α-carbolines have demonstrated an
array of bioproperties, including anxiolytic, anti-inflammatory,
and central nervous system stimulating activities.6 Implitapide
(Fig. 1) was once in the clinical trials as a potential drug for
treating atherosclerosis.7 Interestingly, α-carbolines were also
detected in cigarette smoke and pyrolysis products of protein-
containing food.8
Therefore, several methodologies involving Diels–Alder
reaction,9 Graebe–Ullman and modified type reactions of
triazoles,10 annulation of the indole ring onto pyridine,11
annulation of prepared Baylis–Hillman acetates,12 some multi-
component reactions,13 and more recently, multistep or one-
pot synthesis via Pd-catalyzed aryl amination followed by intra-
molecular arylation14 have been developed. However, in many
Fig. 1 α-Carboline, α-carboline skeleton containing natural products
and implitapide.
cases, these multistep processes required noble metal catalysts
and harsh conditions (usually over 145 °C). In addition, some
of these methods ended with poor overall yields of α-carbo-
lines and often suffered from the limited accessibility of start-
ing materials such as the unstable 2-aminoindole13c,15 and
Baylis–Hillman acetates. In contemporary organic synthesis, it
is an important goal to construct useful molecular skeletons
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203,
P.R. China. E-mail: zhmiao@simm.ac.cn, chyang@simm.ac.cn;
Fax: +86-21-50806820, +86-21-50806770; Tel: +86-21-50806820, +86-21-50806770
†Electronic supplementary information (ESI) available: Experimental section,
characterization data and NMR spectra data. CCDC 955664–955665. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob41921e
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under economical and environmentally benign principles. As of AcOH and TEA was 10 : 1 (v/v) (Table 1, entry 2). Further-
part of our continuing effort at constructing bioactive mole- more, the optimal ratio of acid and base was found (AcOH–
cules including δ-carbolines16 and carbazole derivatives,17 our TEA = 2 : 1 (v/v)) and product 3a was obtained in 68% yield
group was interested in developing a cheap, robust and quick (Table 1, entry 3). Having concern about the pollution and
method to synthesize α-carbolines. It is well known that difficult treatment of iron mud, we replaced iron dust with
tandem reactions can provide an efficient way to generate zinc dust and a higher yield was obtained (Table 1, entry 4). In
complex molecules from readily accessible starting materials. consideration of using more environmentally-friendly solvents,
Herein, we wish to report a one-pot tandem reaction of α,β-un- H2O, EtOH, and the mixture of H2O and EtOH were used as
saturated ketones with 2-nitrophenylacetonitrile in the pres- the solvent. The yield decreased rapidly when the amount of
ence of zinc dust, acetic acid and triethylamine to synthesize AcOH was less than 30 equiv., and this may be the reason that
α-carbolines with moderate to excellent yields. The practical the reaction required the acidic environment and enough
protocol shows a broad substrate scope and good functionality proton source. Different ratios of AcOH and TEA in water–
tolerance. Notably, there are no noble metal catalysts, expens- alcohol were also tested, and only a moderate yield of 3a (55%)
ive ligands or additives in this transformation and it is not was obtained (Table 1, entry 6 vs. entries 5, 7, 8, and 9).
need to exclude air and moisture.
Finally, we gave up using extra solvent, and the reaction
afforded the highest yield when being performed in the
mixture of AcOH (30 equiv.) and TEA (3 equiv.) under reflux
for 4 h (Table 1, entry 10–11). Subsequently, KOAc was
screened as the base for this reaction, and it provided a rather
lower yield than TEA did. This means that the base has signifi-
cant effects on the yield of this tandem reaction (Table 1,
entry 12 vs. 10). Other reductive agents such as Na2S and
Na2S2O4 were also considered, while the expected product 3a
could not be detected under these conditions (Table 1, entries
13–14). Therefore, the optimal reaction conditions for the syn-
thesis of α-carbolines from chromone were obtained:
chromone 1a (1 equiv.), 2-nitrophenylacetonitrile 2 (2 equiv.),
Zn dust (8 equiv.) and TEA (3 equiv.) in AcOH (30 equiv.)
under reflux for 4 h. The structures of similar products 3f and
5l were confirmed by X-ray crystallography as shown in Fig. 2.
Results and discussion
Chromones are useful building blocks for constructing various
bioactive heterocycles.18 We initiated our studies by examining
reaction conditions using commercially available α,β-un-
saturated ketone chromone 1a and 2-nitrophenylacetonitrile 2
as model substrates. The initial attempt started with the reac-
tion of 1a (1 equiv.), 2 (2 equiv.) and iron dust (12 equiv.) in
AcOH under reflux for 8 hours. However, the desirable product
3a only gave a trace yield (Table 1, entry 1). We speculated that
the existence of a base might be helpful for the step of
Michael addition. By increasing the amount of TEA, the
expected product was observed with 22% yield when the ratio
Table 1 Optimization of the reaction conditionsa
Reducing agent
(equiv.)
Timeb
(h)
Yieldc
(%)
Entry
Solvent
1
2
3
4
5
6
7
8
Fe (12)
Fe (12)
Fe (12)
Zn (8)
Zn (8)
Zn (8)
Zn (8)
Zn (8)
Zn (8)
Zn (8)
Zn (8)
Zn (8)
Na2S (5)
Na2S2O4 (5)
AcOH
8
8
4
Trace
22
68
78
18
55
35
Trace
38
82
62
40
Nd
Nd
AcOH–TEA (10 : 1 v/v)
AcOH–TEA (2 : 1 v/v)
AcOH–TEA (2 : 1 v/v)
H2Od
4
12
12
12
8
12
4
8
10
8
H2Oe
H2Of
EtOHe
9
H2O–EtOHe (1 : 1 v/v)
AcOHg (30 equiv.)
AcOHg (25 equiv.)
AcOHh (30 equiv.)
H2O–EtOH (1 : 1 v/v)
H2O–EtOH (1 : 1 v/v)
10
11
12
13
14
8
a Reagents and reaction conditions: 1a (0.5 mmol), 2-nitrophenyl-
acetonitrile 2 (1 mmol), solvent (5 mL), heated to reflux. b Determined
by TLC. c Isolated yield. d 3 eq. TEA and 30 eq. AcOH were added.
e 12 eq. TEA and 30 eq. AcOH were added. f 15 eq. TEA and 30 eq.
AcOH were added. g 3 eq. TEA was added. h 3 eq. KOAc was added.
Fig. 2 X-ray crystal structures of 3f and 5l.
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Table 2 Scope of the chromone derivativesa,b
Table 3 Scope of the α,β-unsaturated ketonesa,b
a Reagents and reaction conditions: chromone derivatives
1
(0.5 mmol), 2-nitrophenylacetonitrile 2 (1 mmol), Zn dust (4 mmol)
and TEA (1.5 mmol) in AcOH (15 mmol), heated to reflux for 4 h.
b Isolated yield.
a Reagents and reaction conditions: α,β-unsaturated ketones
4
(0.5 mmol), 2-nitrophenylacetonitrile 2 (1 mmol), Zn dust (4 mmol)
and TEA (1.5 mmol) in AcOH (15 mmol), heated to 80 °C for 2 h.
b Isolated yield.
With optimal reaction conditions in hand, we further exam-
ined the substrate scope of the chromone derivatives as shown
in Table 2. The chromones containing both electron-donating
substituents (Me and OMe) and electron-withdrawing substitu-
ents (F, Cl and Br) on the benzene ring were investigated.
These substrates tolerated the reaction conditions well to
provide α-carbolines with good to excellent yields (Table 2,
3b–3j). These investigations demonstrated that the electronic
properties of the substituents on the benzene ring present a
very limited influence on the reactivity and yield of the reac-
tion. The steric factor also has little influence on the yield
(Table 2, 3i vs. 3a). However, the bulky group may cause a
slight reduction in the yield (Table 2, 3k vs. 3l).
After successfully synthesizing α-carbolines from chromone
derivatives, we turned our attention to typical α,β-unsaturated
ketones. Because of its high reactivity, the yield of the expected
product 5a was only 36% from benzylidene acetone 4a under
previous optimized conditions. By decreasing the temperature
and shortening the time of the reaction, the highest yield of
expected 5a (58%) was obtained when the reaction was carried
out under the conditions of benzylidene acetone 4a (1 equiv.),
2-nitrophenylacetonitrile 2 (2 equiv.), Zn dust (8 equiv.) and
TEA (3 equiv.) in AcOH (30 equiv.) at 80 °C for 2 h. After deter-
mining the optimized conditions, we further examined the
scope of the substrates using a variety of typical and commer-
cially available α,β-unsaturated ketones (Table 3, 4b–4n).
Delightfully, both substrates of α,β-unsaturated ketones with
the electron-donating (Me, OMe, OH and N(CH3)2) groups
and electron-withdrawing substituents (F, Cl, Br and CF3) on
the benzene ring reacted well to give the similar results of the
yields. In these reactions, the main byproducts were the
Michael adducts by the reaction of nucleophilic amino
of 2-aminobenzeneacetonitrile and α,β-unsaturated ketones,
which caused the lower yields of the target products. Notably,
the replacement of Me by CF3 in the α position of the benzyl-
idene acetone had little effect on the yield (5n vs. 5a).
To demonstrate the synthetic utility of this new method,
the reaction was carried out on a gram scale (1a, 8 mmol,
1.17 g; 4a, 8 mmol, 1.17 g). 3a and 5a were obtained in 83%
and 60% yield respectively. Therefore, this synthetic protocol
provided a practical access to bioactive α-carbolines.
Based on our knowledge and previous results, we proposed
a plausible mechanism for the construction of α-carbolines. In
our preliminary work for the verification of the mechanism,
we found that the reaction of chromone with 2-aminobenzene-
acetonitrile under the same conditions as shown in Table 1
to synthesize 3a required longer time and gave a much lower
yield (52%). For this reason, we proposed that Michael
addition occurred before the reduction step for most sub-
strates. As shown in Scheme 1, when Michael adduct 6 was
formed, Zn dust reduced NO2 to NH2 followed by the attack to
the CN group to generate intermediate 8. Then, after the tauto-
merization, condensation, and dehydration, 11 was formed
and finally oxidized to form compound 5a. For the chromone
derivatives, the mechanism was similar. Because the rings of
the chromone derivatives were opened in the Michael addition
step, the process did not need the oxidation step to form the
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various bioactive α-carbolines in medicinal chemistry in the
near future.
Experimental section
General experimental procedures
The reagents were purchased from commercial sources and
used without further purification. Analytical thin layer chromato-
graphy (TLC) was carried out on HSGF 254 (0.15–0.2 mm
thickness, Yantai Huiyou Company, China). Column chromato-
graphy was carried out on silica gel (200–300 mesh). Proton
and carbon magnetic resonance spectra (1H NMR and 13C
NMR) were recorded on Varian Mercury-300/400 and Varian
Mercury-400/500 spectrometers. Tetramethylsilane (TMS) was
used as internal standard (1H NMR: TMS at 0.00 ppm; CHCl3
at 7.26 ppm; DMSO at 2.50 ppm; 13C NMR: CDCl3 at 77.0 ppm;
DMSO-d6 at 39.6 ppm). HRMS spectra were recorded on a
Micromass Ultra Q-TOF spectrometer. Melting points were
measured using a Büchi 510 melting point apparatus and were
uncorrected.
Scheme 1 A proposed mechanism.
Table 4 Anti-tumour activity of selected compoundsa
IC50 b,c [μM]
Compd
BEL-7402
HT-29
SGC-7901
General procedure of biology
3c
3f
5c
5d
5e
5j
5k
5l
—
—
18.46
87.12
>100
—
—
The sulforhodamine B (SRB) assay: cells were seeded into
96-well plates on day 0 and exposed to 2-fold serial drug
dilutions on day 1. On day 4, the cells were fixed by adding
10% pre-cooled trichloroacetic acid. After 1 h at 4 °C, the
plates were washed with distilled water, dried, and then
stained with SRB (Sigma, MO) in 1% acetic acid. SRB in the
cells was dissolved in 10 mM Tris-HCl and was measured at
515 nm using spectra-MAX190 (Molecular Devices, CA). The
cell proliferation inhibition rate was calculated as: prolifer-
ation inhibition (%) = [1 ( (A515treated/A515control)] × 100%.
41.44
28.09
18.10
79.22
29.90
64.20
4.66
15.69
52.55
15.29
86.81
71.97
69.33
9.79
>100
78.70
79.10
75.21
76.65
11.57
VP-16
a The experiments were based on using the SRB assay. b Exposure time:
72 h. c The average IC50 values were determined by at least three
independent tests.
pyridine ring of α-carboline. This also explained the higher
yields of chromone than that of typical α,β-unsaturated
ketones.
General procedure for the synthesis of compounds 3a–3l
Chromone 1a (73 mg, 0.5 mmol), 2-nitrophenylactonitrile 2
(162 mg, 1 mmol), Zn dust (262 mg, 4 mmol), TEA (154 mg,
1.5 mmol) and AcOH (904 mg, 15 mmol) were added to a reac-
tion flask. The reaction mixture was stirred and heated to
reflux for 4 h. After completion of the reaction, the mixture
was diluted with water and extracted by EtOAc. After drying by
anhydrous Na2SO4, EtOAc was removed under reduced
pressure. The residue was purified by column chromatography
on silica gel using petroleum ether–ethyl acetate (8 : 1 v/v) as
the eluent to provide the pure product 3a.
Subsequently, some of these products have been evaluated
for their anti-tumor activities against human hepatic cancer
cell line BEL-7402, colon cancer cell line HT-29 and stomach
cancer cell line SGC-7901. Some results are summarized in
Table 4. As shown in Table 4, several compounds such as 5c,
5d, 5e, 5k displayed moderate antitumor activities. Although
they are less potent than VP-16, they provide a useful clue of a
novel scaffold to develop new anti-tumour drugs.
General procedure for the synthesis of compounds 5a–5n
Conclusions
Benzylidene acetone 4a (73 mg, 0.5 mmol), 2-nitrophenyl-
In summary, we have developed a direct, rapid and practical actonitrile 2 (162 mg, 1 mmol), Zn dust (262 mg, 4 mmol),
one-pot tandem reaction for the synthesis of 2 or 2,4-substi- TEA (154 mg, 1.5 mmol) and AcOH (904 mg, 15 mmol) were
tuted α-carbolines. Under the conditions of zinc dust, acetic added to a reaction flask. The reaction mixture was stirred and
acid and triethylamine, two series of α-carbolines could be heated to 80 °C for 2 h. After completion of the reaction, the
obtained with moderate to excellent yields. Some compounds mixture was diluted with water and extracted by EtOAc. After
showed moderate anti-tumour activities in vitro. We believe drying by anhydrous Na2SO4, EtOAc was removed under
that this method should have wide application in constructing reduced pressure. The residue was purified by column
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chromatography on silica gel using petroleum ether–ethyl (m, 2H), 7.36–7.23 (m, 2H), 6.99 (d, J = 8.8 Hz, 1H); 13C NMR
acetate (4 : 1 v/v) as the eluent to provide the product 5a. (125 MHz, DMSO-d6) δ = 157.78, 151.55, 148.88, 139.22,
2-(9H-Pyrido[2,3-b]indol-2-yl)phenol (3a). Grey solid, m.p. 133.17, 130.70, 129.66, 127.16, 122.45, 121.38, 120.29, 120.19,
1
>300 °C; H NMR (300 MHz, DMSO-d6) δ = 13.89 (s, 8H), 12.13 115.00, 111.73, 111.61, 110.40; HRMS (ESI): m/z [M + H]+ calcd
(s, 1H), 8.69 (d, J = 8.3 Hz, 2H), 8.19 (d, J = 7.4 Hz, 1H), 8.10 for C17H12N2OBr: 339.0133, found: 339.0139.
(dd, J = 8.2, 1.3 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.57–7.44 (m,
5-Methoxy-2-(9H-pyrido[2,3-b]indol-2-yl)phenol (3g). Yellow
2H), 7.34–7.23 (m, 2H), 6.99–6.90 (m, 1H); 13C NMR (125 MHz, solid, m.p. >300 °C; 1H NMR (400 MHz, DMSO-d6) δ = 14.29 (s,
DMSO-d6) δ = 158.67, 153.22, 148.74, 138.98, 130.82, 130.60, 1H), 12.10 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 7.7 Hz,
127.34, 126.83, 121.11, 120.31, 120.04, 119.97, 119.02, 117.90, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.53 (d, J =
114.30, 111.49, 110.99; HRMS (ESI): m/z [M + H]+ calcd for 8.1 Hz, 1H), 7.49–7.43 (m, 1H), 7.26 (t, J = 7.5 Hz, 1H),
C17H13N2O: 261.1028, found: 261.1025.
6.57–6.50 (m, 2H), 3.80 (s, 3H); 13C NMR (125 MHz, DMSO-d6)
4-Methyl-2-(9H-pyrido[2,3-b]indol-2-yl)phenol (3b). Yellow δ = 153.14, 152.74, 152.09, 149.01, 139.16, 130.65, 126.99,
solid, m.p. >300 °C; 1H NMR (300 MHz, DMSO-d6) δ = 13.64 (s, 121.30, 120.43, 120.20, 120.15, 118.70, 117.71, 114.48, 111.61,
1H), 12.12 (s, 1H), 8.68 (d, J = 8.3 Hz, 1H), 8.19 (d, J = 7.8 Hz, 111.55, 111.48, 55.74; HRMS (ESI): m/z [M + H]+ calcd for
1H), 8.00 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.56–7.44 (m, 2H), C18H15N2O2: 291.1134, found: 291.1136.
7.27 (t, J = 7.3 Hz, 1H), 7.14–7.08 (m, 2H), 6.86 (d, J = 8.3 Hz,
5-Fluoro-2-(9H-pyrido[2,3-b]indol-2-yl)phenol
(3h). Brown
1H), 2.32 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 156.44, solid, m.p. >300 °C; 1H NMR (300 MHz, DMSO-d6) δ = 13.89 (s,
153.34, 148.82, 138.96, 131.51, 130.51, 127.44, 127.39, 126.76, 1H), 12.17 (s, 1H), 8.70 (d, J = 8.3 Hz, 1H), 8.27 (d, J = 2.5 Hz,
121.06, 120.33, 120.01, 119.57, 117.70, 114.15, 111.46, 110.98, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.57–7.46
20.30; HRMS (ESI): m/z [M + H]+ calcd for C18H15N2O: (m, 2H), 7.44 (dd, J = 8.7, 2.4 Hz, 1H), 7.31–7.25 (m, 1H), 6.94
275.1184, found: 275.1181.
(d, J = 8.7 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ = 163.53
1
3
4-Methoxy-2-(9H-pyrido[2,3-b]indol-2-yl)phenol (3c). Yellow (d, JCF = 246.58 Hz), 160.71 (d, JCF = 12.46 Hz), 152.55,
solid, m.p. 246–248 °C; 1H NMR (300 MHz, DMSO-d6) δ = 148.64, 139.06, 130.91, 129.37 (d, JCF = 10.38 Hz), 127.01,
3
4
13.33 (s, 1H), 12.13 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 121.26, 120.42, 120.24, 117.00 (d, JCF = 2.48 Hz), 114.50,
2
2
8.0 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 111.66, 111.01, 106.41 (d, JCF = 22.00 Hz), 104.51 (d, JCF
=
7.57–7.44 (m, 2H), 7.27 (t, J = 7.7 Hz, 1H), 6.97–6.88 (m, 2H), 23.24 Hz); HRMS (ESI): m/z [M + H]+ calcd for C17H12N2OF:
3.81 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 153.14, 152.74, 279.0934, found: 279.0921.
152.09, 149.01, 139.16, 130.65, 126.99, 121.30, 120.43, 120.20,
3-Methoxy-2-(9H-pyrido[2,3-b]indol-2-yl)phenol (3i). Yellow
120.15, 118.70, 117.72, 114.48, 111.61, 111.55, 111.48, 55.74; solid, m.p. 228–230 °C; 1H NMR (300 MHz, DMSO-d6) δ =
HRMS (ESI): m/z [M + H]+ calcd for C18H15N2O2: 291.1134, 12.49 (s, 1H), 11.94 (s, 1H), 8.57 (d, J = 8.2 Hz, 1H), 8.16 (d, J =
found: 291.1129.
4-Fluoro-2-(9H-pyrido[2,3-b]indol-2-yl)phenol
7.7 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.55–7.43 (m, 2H),
(3d). Yellow 7.28–7.18 (m, 2H), 6.65–6.57 (m, 2H), 3.82 (s, 3H); 13C NMR
solid, m.p. >300 °C; 1H NMR (300 MHz, DMSO-d6) δ = 13.66 (s, (100 MHz, DMSO-d6) δ = 158.61, 151.50, 149.75, 139.23,
1H), 12.15 (s, 1H), 8.69 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 8.1 Hz, 130.33, 129.62, 126.92, 121.34, 120.66, 120.04, 117.23, 113.99,
1H), 8.04 (d, J = 8.5 Hz, 1H), 7.96 (dd, J = 10.7, 2.8 Hz, 1H), 113.11, 111.66, 110.24, 102.78, 56.05; HRMS (ESI): m/z
7.57–7.43 (m, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.14 (td, J = 8.5, [M + H]+ calcd for C18H15N2O2: 291.1134, found: 291.1125.
2.9 Hz, 1H), 6.95 (dd, J = 9.1, 5.1 Hz, 1H); 13C NMR (125 MHz,
4-Chloro-5-methyl-2-(9H-pyrido[2,3-b]indol-2-yl)phenol (3j).
1
1
DMSO-d6) δ = 155.40 (d, JCF = 233.14 Hz), 154.93, 152.05 (d, Brown solid, m.p. >300 °C; H NMR (300 MHz, DMSO-d6) δ =
4JCF = 2.74 Hz), 148.85, 139.23, 130.72, 127.14, 121.36, 120.71 13.86 (s, 1H), 12.13 (s, 1H), 8.68 (d, J = 8.3 Hz, 1H), 8.20 (d, J =
3
3
(d, JCF = 7.22 Hz), 120.32, 120.19, 119.04 (d, JCF = 7.97 Hz), 8.7 Hz, 1H), 8.13 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.57–7.44 (m,
117.55 (d, JCF = 23.41 Hz), 114.92, 113.19 (d, JCF = 23.91 Hz), 2H), 7.31–7.23 (m, 2H), 6.97 (s, 1H), 2.31 (s, 3H); 13C NMR
2
2
111.63 (d, JCF = 2.23 Hz); HRMS (ESI): m/z [M + H]+ calcd for (125 MHz, DMSO-d6) δ = 157.36, 151.94, 148.84, 139.15,
4
C17H12N2OF: 279.0934, found: 279.0927.
138.13, 130.77, 127.06, 127.02, 123.43, 121.34, 120.39, 120.34,
4-Chloro-2-(9H-pyrido[2,3-b]indol-2-yl)phenol
(3e). Grey 120.20, 119.55, 114.70, 111.63, 111.28, 39.10; HRMS (ESI): m/z
solid, m.p. >300 °C; 1H NMR (300 MHz, DMSO-d6) δ = 13.89 (s, [M + H]+ calcd for C18H14N2OCl: 309.0795, found: 309.0781.
1H), 12.17 (s, 1H), 8.71 (d, J = 8.3 Hz, 1H), 8.21 (d, J = 7.4 Hz,
1-(9H-Pyrido[2,3-b]indol-2-yl)naphthalen-2-ol
(3k). Yellow
1H), 8.17 (d, J = 2.5 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.58–7.45 solid, m.p. >300 °C; 1H NMR (300 MHz, DMSO-d6) δ = 11.81 (s,
(m, 2H), 7.36–7.24 (m, 2H), 6.99 (d, J = 8.8 Hz, 1H); 13C NMR 1H), 9.92 (s, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.20 (d, J = 7.7 Hz,
(125 MHz, DMSO-d6) δ = 157.41, 151.68, 148.87, 139.24, 1H), 7.88–7.82 (m, 2H), 7.55–7.44 (m, 3H), 7.36–7.22 (m, 5H);
130.74, 130.36, 127.17, 126.82, 122.86, 121.79, 121.39, 120.30, 13C NMR (125 MHz, DMSO-d6) δ = 152.64, 152.49, 151.78,
120.21, 119.75, 115.01, 111.68, 111.62; HRMS (ESI): m/z 139.07, 133.33, 129.58, 128.66, 128.00, 126.51, 126.34, 124.38,
[M + H]+ calcd for C17H12N2OCl: 295.0638, found: 295.0645.
122.70, 121.15, 120.59, 120.57, 119.55, 118.64, 118.05, 113.59,
4-Bromo-2-(9H-pyrido[2,3-b]indol-2-yl)phenol (3f). Orange 111.33; HRMS (ESI): m/z [M + H]+ calcd for C21H15N2O:
solid, m.p. >300 °C; 1H NMR (300 MHz, DMSO-d6) δ = 13.89 (s, 311.1184, found: 311.1181.
1H), 12.17 (s, 1H), 8.71 (d, J = 8.3 Hz, 1H), 8.21 (d, J = 7.9 Hz,
2-(9H-Pyrido[2,3-b]indol-2-yl)naphthalen-1-ol
(3l). Yellow
1H), 8.17 (d, J = 2.5 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.59–7.45 solid, m.p. 262–263 °C; 1H NMR (400 MHz, DMSO-d6) δ =
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15.64 (s, 1H), 12.22 (s, 1H), 8.75 (d, J = 8.3 Hz, 1H), 8.40–8.36 (100 MHz, DMSO-d6) δ = 162.40 (d, JCF = 245.48 Hz), 155.06,
4
(m, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 152.39, 143.45, 138.89, 135.09 (d, JCF = 2.82 Hz), 130.69 (d,
7.91–7.86 (m, 1H), 7.62–7.44 (m, 5H), 7.30 (t, J = 7.5 Hz, 1H); 3JCF = 8.80 Hz), 126.02, 121.42, 119.96, 119.17, 115.84 (d, 2JCF
=
13C NMR (125 MHz, DMSO-d6) δ = 155.84, 153.60, 148.54, 25.34 Hz), 115.70, 111.41, 109.84, 24.29; HRMS (ESI): m/z [M +
139.05, 134.57, 130.92, 127.57, 127.41, 126.91, 125.72, 125.46, H]+ calcd for C18H14N2F: 277.1141, found: 277.1142.
124.04, 123.00, 121.13, 120.51, 120.22, 118.25, 114.31, 112.57,
111.62, 110.82; HRMS (ESI): m/z [M + H]+ calcd for C21H15N2O: White solid, m.p. 275–277 °C; 1H NMR (300 MHz, DMSO-d6)
311.1184, found: 311.1173. δ = 11.82 (s, 1H), 7.72–7.63 (m, 4H), 7.47 (t, J = 8.0 Hz, 2H),
4-(4-Chlorophenyl)-2-methyl-9H-pyrido[2,3-b]indole
(5g).
2-Methyl-4-phenyl-9H-pyrido[2,3-b]indole (5a). White solid, 7.40–7.33 (m, 1H), 7.05–6.99 (m, 1H), 6.98 (s, 1H), 2.62 (s, 3H);
1
m.p. 232–233 °C; H NMR (300 MHz, DMSO-d6) δ = 11.80 (s, 13C NMR (125 MHz, DMSO-d6) δ = 155.08, 152.37, 143.10,
1H), 7.69–7.54 (m, 5H), 7.48 (d, J = 4.2 Hz, 1H), 7.46 (d, J = 138.88, 137.53, 133.47, 130.39, 128.92, 126.04, 121.41, 119.82,
3.9 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.02–6.95 (m, 2H), 2.62 (s, 119.19, 115.49, 111.40, 109.65, 24.25; HRMS (ESI): m/z
3H); 13C NMR (100 MHz, DMSO-d6) δ = 154.93, 152.30, 144.43, [M + H]+ calcd for C18H14N2Cl: 293.0846, found: 293.0835.
138.76, 138.65, 128.76, 128.60, 128.41, 125.85, 121.37, 119.95,
118.96, 115.54, 111.25, 109.69, 24.20; HRMS (ESI): m/z Pink solid, m.p. >300 °C; 1H NMR (300 MHz, DMSO-d6) δ =
[M + H]+ calcd for C18H15N2: 259.1235, found: 259.1234.
11.83 (s, 1H), 7.83–7.77 (m, 2H), 7.65–7.59 (m, 2H), 7.47 (t, J =
4-(4-Bromophenyl)-2-methyl-9H-pyrido[2,3-b]indole
(5h).
2-Methyl-4-(p-tolyl)-9H-pyrido[2,3-b]indole (5b). Pink solid, 7.2 Hz, 2H), 7.40–7.33 (m, 1H), 7.05–6.99 (m, 1H), 6.98 (s, 1H),
1
m.p. 256–258 °C; H NMR (300 MHz, CDCl3) δ = 10.46 (s, 1H), 2.62 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 155.08, 152.37,
7.69 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 7.9 Hz, 2H), 7.53 (d, J = 8.1 143.10, 138.88, 137.53, 133.47, 130.39, 128.92, 126.04, 121.41,
Hz, 1H), 7.44–7.34 (m, 3H), 7.05 (t, J = 7.6 Hz, 1H), 6.99 (s, 1H), 119.82, 119.19, 115.49, 111.40, 109.65, 24.25; HRMS (ESI): m/z
2.81 (s, 3H), 2.50 (s, 3H); 13C NMR (125 MHz, CDCl3) δ = [M + H]+ calcd for C18H14N2Br: 337.0340, found: 337.0330.
154.72, 152.79, 145.90, 138.65, 138.40, 136.14, 129.33, 128.54,
2-Methyl-4-(4-(trifluoromethyl)phenyl)-9H-pyrido[2,3-b]indole
126.01, 122.39, 121.10, 119.45, 116.47, 111.41, 110.95, 24.49, (5i). White solid, m.p. 270–271 °C; 1H NMR (300 MHz, DMSO-
21.40; HRMS (ESI): m/z [M + H]+ calcd for C19H17N2: 273.1392, d6) δ = 11.88 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.1 Hz,
found: 273.1391.
4-(4-Methoxyphenyl)-2-methyl-9H-pyrido[2,3-b]indole
White solid, m.p. 240–242 °C; H NMR (300 MHz, CDCl3) δ = 152.35, 142.90, 142.76, 138.94, 129.46, 129.08 (q, JCF
10.13 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.67–7.61 (m, 2H), 7.52 31.72 Hz), 126.18, 125.79 (q, JCF = 3.68 Hz), 124.33 (q, JCF
2H), 7.50 (d, J = 7.9 Hz, 1H), 7.43–7.35 (m, 2H), 7.05–6.99 (m,
(5c). 2H), 2.64 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 155.18,
1
2
=
=
3
1
(d, J = 8.1 Hz, 1H), 7.43–7.36 (m, 1H), 7.13–7.03 (m, 3H), 6.98 275.79 Hz), 121.35, 119.66, 119.28, 115.51, 111.47, 109.55,
(s, 1H), 3.94 (s, 3H), 2.79 (s, 3H); 13C NMR (125 MHz, DMSO- 24.25; HRMS (ESI): m/z [M + H]+ calcd for C19H14N2F3:
d6) δ = 159.64, 154.89, 152.47, 144.35, 138.79, 130.84, 129.82, 327.1109, found: 327.1106.
125.79, 121.49, 120.19, 118.98, 115.61, 114.23, 111.26, 109.79,
55.32, 24.26; HRMS (ESI): m/z [M + H]+ calcd for C19H17ON2: m.p. 212–214 °C; H NMR (300 MHz, CDCl3) δ = 10.90 (s, 1H),
289.1341, found: 289.1343. 7.55 (d, J = 8.1 Hz, 1H), 7.47–7.29 (m, 5H), 7.08–6.97 (m, 2H),
2-Methyl-4-(o-tolyl)-9H-pyrido[2,3-b]indole (5j). White solid,
1
N,N-Dimethyl-4-(2-methyl-9H-pyrido[2,3-b]indol-4-yl)aniline 6.94 (s, 1H), 2.85 (s, 3H), 2.15 (s, 3H); 13C NMR (125 MHz,
(5d). White solid, m.p. 279–280 °C; 1H NMR (300 MHz, CDCl3) δ = 154.70, 152.47, 145.34, 138.64, 138.58, 135.67,
DMSO-d6) δ = 11.71 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 130.20, 128.68, 128.33, 126.02, 121.85, 121.26, 119.82, 116.23,
8.5 Hz, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 112.37, 110.90, 24.60, 19.68; HRMS (ESI): m/z [M + H]+ calcd
7.01 (t, J = 7.4 Hz, 1H), 6.91 (d, J = 7.6 Hz, 3H), 3.02 (s, 6H), for C19H17N2: 273.1392, found: 273.1394.
2.59 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ = 154.76, 152.64,
2-(2-Methyl-9H-pyrido[2,3-b]indol-4-yl)phenol
(5k). Pink
150.59, 145.13, 138.73, 129.40, 125.72, 125.61, 121.61, 120.47, solid, m.p. 174–176 °C; 1H NMR (300 MHz, DMSO-d6) δ =
118.87, 115.41, 112.08, 111.17, 109.62, 24.31; HRMS (ESI): m/z 11.63 (s, 1H), 9.53 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.38–7.30
[M + H]+ calcd for C20H20N3: 302.1657, found: 302.1657.
4-(2-Methyl-9H-pyrido[2,3-b]indol-4-yl)phenol
(m, 2H), 7.27 (dd, J = 7.8, 1.3 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H),
(5e). White 7.05 (d, J = 8.1 Hz, 1H), 7.00–6.92 (m, 2H), 6.92 (s, 1H), 2.60 (s,
solid, m.p. 235–237 °C; 1H NMR (300 MHz, DMSO-d6) δ = 3H); 13C NMR (125 MHz, DMSO-d6) δ = 154.67, 154.36, 152.07,
11.72 (s, 1H), 9.78 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.53–7.43 141.87, 138.66, 130.30, 129.79, 125.78, 125.58, 121.90, 120.82,
(m, 3H), 7.35 (t, J = 7.6 Hz, 1H), 7.04–6.94 (m, 3H), 6.92 (s, 1H), 119.24, 118.93, 116.31, 115.86, 111.31, 110.93, 24.35; HRMS
2.60 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 170.45, 158.01, (ESI): m/z [M + H]+ calcd for C18H15N2O: 275.1184, found:
154.87, 152.53, 144.86, 138.79, 129.89, 129.23, 125.75, 121.60, 275.1183.
120.32, 118.99, 115.61, 111.26, 109.83, 24.31; HRMS (ESI): m/z
2-Methyl-4-(m-tolyl)-9H-pyrido[2,3-b]indole (5l). Pink solid,
m.p. 204–206 °C; H NMR (300 MHz, CDCl3) δ = 11.07 (s, 1H),
1
[M + H]+ calcd for C18H15N2O: 275.1184, found: 275.1182.
4-(4-Fluorophenyl)-2-methyl-9H-pyrido[2,3-b]indole
(5f). 7.66 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.53–7.44 (m,
1
White solid, m.p. 254–255 °C; H NMR (400 MHz, CDCl3) δ = 3H), 7.41 (d, J = 7.1 Hz, 1H), 7.35 (s, 1H), 7.05 (s, 1H), 7.00 (s,
10.74 (s, 1H), 7.70–7.63 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.56 1H), 2.84 (s, 3H), 2.48 (s, 3H); 13C NMR (125 MHz, CDCl3) δ =
(d, J = 8.1 Hz, 1H), 7.45–7.39 (m, 1H), 7.30–7.23 (m, 2H), 154.55, 152.91, 146.02, 139.01, 138.85, 138.31, 129.27, 129.19,
7.10–7.04 (m, 1H), 6.97 (s, 1H), 2.82 (s, 3H); 13C NMR 128.49, 126.00, 125.71, 122.34, 121.00, 119.40, 116.31, 111.48,
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111.03, 24.47, 21.49; HRMS (ESI): m/z [M + H]+ calcd for
C19H17N2: 273.1392, found: 273.1396.
E. V. Van der Eycken, D. M. Vandenberghe and
G. J. Hoornaert, Tetrahedron, 1998, 54, 13211–13226;
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8, 829–840.
2-Methoxy-5-(2-methyl-9H-pyrido[2,3-b]indol-4-yl)phenol (5m).
1
Brown solid, m.p. 186–188 °C; H NMR (400 MHz, DMSO-d6)
δ = 11.74 (s, 1H), 9.30 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.47 (d,
J = 8.0 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 10 (a) L. u. Kaczmarek, W. Peczyńska-Czoch, J. Osiadacz,
7.11–7.05 (m, 2H), 7.02 (t, J = 7.5 Hz, 1H), 6.92 (s, 1H), 3.88 (s,
3H), 2.60 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ = 154.84,
152.46, 148.13, 146.65, 144.68, 138.78, 131.27, 125.75, 121.70,
120.22, 119.42, 118.94, 115.72, 115.49, 112.37, 111.21, 109.74,
55.74, 24.26; HRMS (ESI): m/z [M + H]+ calcd for C19H17N2O2:
305.1290, found: 305.1286.
M. Mordarski, W. A. Sokalski, J. Boratyński,
E. Marcinkowska, H. Glazman-Kuśnierczyk and
C. Radzikowski, Bioorg. Med. Chem., 1999, 7, 2457–2464;
(b) P. Vera-Luque, R. Alajarín, J. Alvarez-Builla and
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4-Phenyl-2-(trifluoromethyl)-9H-pyrido[2,3-b]indole (5n).
White solid, m.p. 219–221 °C; 1H NMR (500 MHz, DMSO-d6) 11 (a) E. Erba, M. Luisa Gelmi and D. Pocar, Tetrahedron,
δ = 12.49 (s, 1H), 7.78–7.74 (m, 2H), 7.69–7.62 (m, 3H), 7.60 (t,
J = 8.7 Hz, 2H), 7.56–7.51 (m, 2H), 7.12 (t, J = 7.1 Hz, 1H);
13C NMR (125 MHz, DMSO-d6) δ = 151.55, 145.42, 142.25 (q,
2JCF = 34.02 Hz), 140.33, 137.29, 129.27, 128.97, 128.52, 128.13,
2000, 56, 9991–9997; (b) E. M. Beccalli, F. Clerici and
A. Marchesini, Tetrahedron, 2001, 57, 4787–4792; (c) A. Ono
and K. Narasaka, Chem. Lett., 2001, 146–147;
(d) M. Funicello, C. Bonini and P. Spagnolo, Synlett, 2006,
1574–1576; (e) F. Liger, F. Popowycz, T. Besson, L. Picot,
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1
122.26 (q, JCF = 272.71 Hz), 122.40, 119.96, 118.95, 115.27,
3
111.95 (q, JCF = 2.81 Hz), 111.82; HRMS (ESI): m/z [M + H]+
calcd for C18H12N2F3: 313.0953, found: 313.0941.
12 D. Basavaiah and D. Mallikarjuna Reddy, Org. Biomol.
Chem., 2012, 10, 8774–8777.
Acknowledgements
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This work was supported by the “Interdisciplinary Cooperation
Team” Program for Science and Technology Innovation of the
Chinese Academy of Sciences, and the National Natural
Science Foundation of China (21072205, 81025020) and
SIMM1203ZZ-0103.
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