Synthesis of trifluoromethyl- A nd ester group-substituted α-carbolines via iron-catalyzed tandem cyclization reaction

Article abstract of DOI:10.1021/acs.joc.0c00048

An efficient approach to prepare trifluoromethyl-α-carbolines and ester group-substituted α-carbolines via the tandem cyclization reaction of 2-(2-aminophenyl)acetonitriles and trifluoromethyl 1,3-diones or ,?-unsaturated α-ketoesters was reported. The tr

Full text of DOI:10.1021/acs.joc.0c00048

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Article
Synthesis of Trifluoromethyl and Ester Group Substituted #-
Carbolines via Iron-Catalyzed Tandem Cyclization Reaction
Yumin Xu, Xiaoqian Chen, Yiqin Gao, Zicong Yan, Changfeng Wan, Jin-Biao Liu, and Zhiyong Wang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Feb 2020
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Synthesis of Trifluoromethyl and Ester Group Substituted α-
Carbolines via Iron-Catalyzed Tandem Cyclization Reaction
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Yumin Xu, a Xiaoqian Chen,a Yiqin Gao,a Zicong Yan,b Changfeng Wan,*a Jin-Biao
Liu*ac and Zhiyong Wangb
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a College of Chemistry and Chemical Engineering and Key Laboratory of Functional
Small Organic Molecule, Ministry of Education, Jiangxi Normal University,
Nanchang 330022, China.E-mail: wanfeng@jxnu.edu.cn (C.W.) b Department of
Chemistry, University of Science and Technology of China, Hefei, 230026, China.
c School of Metallurgy and Chemical Engineering, Jiangxi University of Science and
technology, Ganzhou 341000, China. E-mail: liujinbiao@jxust.edu.cn (J.B.L.)
R3
N
(CF or COOEt)
O
4
R
3
O
O
O
O
R3
R4
R3
R3
N
R4(CF3 or COOEt)
R2
R2
O
R4
R2
N
O
N
NH
R1
N
R1
Fe(OTf)3
FeCl3
R1
Abstract
An efficient approach to prepare trifluoromethyl-α-Carbolines and ester group
substituted α-Carbolines via tandem cyclization reaction of 2-(2-
aminophenyl)acetonitriles and trifluoromethyl 1,3-diones or β,γ-unsaturated α-
ketoesters was reported. The transformation proceeded smoothly in the presence of
catalytic environment-benign iron salts, which prepared the desired products in
moderate to good yields.
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Introduction
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As a core structure, α-carboline (pyrido[2,3-b]indole) can be found in a number of
natural products, such as grossularine-1 and grossularine-2 from Dendrodoa
grossularia,1 N,N-didesmethylgrossularine-1 from Indonesian ascidian Polycarpa
aurata,2 and mescengricin from a culture of Streptomyces griseoflavus.3 Implitapide is
a microsomal triglyceride transfer protein (MTP)-inhibitor (Figure 1). These α-
carbolines exhibited high cytotoxicity, anticancer properties and CNS activities.4
Therefore, synthetic α-carbolines have attracted considerable attention in heterocyclic
synthetic chemistry during the past century.5 As an attractive synthetic target, a series
of useful tandem cyclic methodologies including modified Graebe−Ullman reaction
of triazoles,6 intramolecular hetero Diels-Alder cycloaddition-aromatization,7
transition metal-catalyzed coupling-cyclization,8 as well as annulation of pyridine ring
to indole derivative,9 have been reported. Recently, Swamy group developed a new
method for the synthesis of α-Carbolines under metal-free condition.10
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HO
N
O
N
HO
O
O
NH
N
N
N
O
R
N
OH
N
H
O
HO
N
HO
N
H
H
grossularines
R= 3-indolyl or p-hydroxyphenyl
Mescengricin
Implitapide
Figure 1. Examples of Biologically α-Carbolines.
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In recent decades, the introduction of fluorine or trifluoromethyl group into drug
molecules has sparked tremendous interest in the scientific community.11 Owning to
the α-carbolines’ marked biological activity, study of α-carbolines containing fluorine
or trifluoromethyl group is of great significance. In 2008, Iaroshenko and co-workers
reported an AcOH-promoted condensation/cyclization approach to prepare
trifluoromethyl-α-carbolines from indole-2-amine,12 which was an important method
for the introduction of trifluoromethyl on the α-carbolines structure. However, few
examples were reported for the synthesis of trifluoromethyl-α-carbolines. Therefore,
the development of simple and practical protocols for the preparation of multi-
substituted trifluoromethyl-α-carbolines is highly desirable.
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It is also worth noting that iron is one of the most abundant, inexpensive and
environmentally friendly metals on earth. Over the past years, our group has devoted
great efforts on the studies of iron catalysis13 and the synthesis of N-heterocyclic
compounds.14 Herein, we report an efficient iron-catalyzed synthetic method for the
preparation of trifluoromethyl-α-carbolines. We envisioned that a small library of
trifluoromethyl substituted α-carbolines starting from 2-(2-aminophenyl)acetonitriles
and trifluoromethyl 1,3-dione could be constructed. In the presence of Fe(III) salt,
nitrogenous fused-ring can be efficiently formed through a tandem cyclization
reaction.
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Results and Discussion
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Optimization of Reaction Conditions
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Initially, the model reaction of 2-(2-(methylamino)phenyl)acetonitrile 1a and 4,4,4-
trifluoro-1-phenylbutane-1,3-dione 2a was carried out in the presence of 10 mol%
FeCl3 as catalyst and chlorobenzene (PhCl) as solvent. Under aerobic conditions, the
reaction was stirred at 100 °C for 8 h, regioselective generating the product 3a
(structure confirmed by coupling of CF3) in 75% yield (Table 1, entry 1), while the
3a’ product wasn’t detected by TLC and GC-MS. Encouraged by this result, other
iron salts were investigated [FeCl3·6H2O, FeCl2, Fe(OTf)3 and Fe2(SO4)3] (entries 2-
5). It is pleased to find that Fe(OTf)3 was the best choice, giving rise to the product 3a
with 81% yield (entry 4). When other metal salts [Cu(OTf)2 and Zn(OTf)2] or
protonic acid (TfOH) were used in the reaction, the low efficiency was obtianed
(entries 6-8). Subsequently, the effect of solvents in this transformation was evaluated
(entries 9-15). The result revealed that toluene gave the highest yield (entry 15, 86%),
while ClCH2CH2Cl (DCE), DMF, DMSO, CH3CN, CH3NO2 and 1,4-dioxane offered
relatively lower yields (entry 15 versus entries 9–14). Increasing the amount of
Fe(OTf)3-catalyst to 20 mol% resulted in a comparable yield (entry 16, 85%).
However, reduction of Fe(OTf)3 loading to 5 mol% made a dramatic effect on the
yield of the product, giving 3a in 62% yield (entry 17). Iron catalyst is necessary for
the tandem cycloaddition/condensation, and no product was observed in the absence
of iron catalyst (entry 18). In addition, when the reaction temperature was raised or
lowered, no better results were observed (19 and 20 versus entry 15).
Table 1 Optimization of Reaction Conditions a
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F3C
O
O
CF3
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Iron salts
CN
CF3
N
N
+
+
Solvent, 100 °C
N
N
NHCH3
3a
2a
1a
3a'
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entry
1
catalyst
FeCl3
solvent
PhCl
yieldb [%]
75
2
FeCl3·6H2O
FeCl2
PhCl
58
3
PhCl
42
4
Fe(OTf)3
Fe2(SO4)3
Cu(OTf)2
Zn(OTf)2
TfOH
PhCl
81
5
PhCl
71
6
PhCl
32
7
PhCl
26
8
PhCl
34
9
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
DCE
78
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13
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15
16c
17d
DMF
55
DMSO
CH3CN
CH3NO2
1,4-dioxane
toluene
toluene
toluene
38
63
57
65
86
85
62
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18
-
toluene
0
5
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19e
20f
Fe(OTf)3
Fe(OTf)3
toluene
toluene
65
82
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aReaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), catalyst (10 mol%), solvent (1
b
c
d
mL), 100 °C, 8 h. Isolated yields of 3a. Fe(OTf)3 (20 mol%). Fe(OTf)3 (5 mol%).
e80 °C. f120 °C.
Scope of Substrates
With the optimized conditions identified (see entry 15 in Table 1), the substrate
scope for the reactions of 2-(2-aminophenyl)acetonitriles (1) and trifluoromethyl 1,3-
dione (2) was then studied (Table 2). As for the 1,3-dione 2, the electronic effect of
substituent R3 had a slight impact on the outcome, producing the desired products 3a–
f in high yields. Heteroaryl-substituted 1,3-dione 2 were also tolerant in this reaction
and showed good yields (3g-h, 71-77%). When R3 was replaced by CH3 or CF3 group,
the reaction provided α-carbolines 3i and 3k in 82% and 74% yields under standard
conditions, respectively. Moreover, the lower reactive acetylacetone employed as
reactant also provided the corresponding product in 72% yield (3j). Subsequently, we
explored the effect of the R1 substituents, and found that the R1 position could be
occupied by iodine or bromine atoms. The corresponding products 3l and 3m were
obtained in good yields, which enabled further derivation of the trifluoromethyl-α-
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carbolines through various cross-coupling techniques. Not only methyl as the R2
substitute was compatible with the reaction, but also ethyl and benzyl groups could
take part in the reactions smoothly, affording the corresponding products 3n-s in
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satisfying yields.
Table 2 Iron-Catalyzed Synthesis of Trifluoromethyl Substituted α-Carbolinesa
F3C
R1
O
O
R1
R3
Fe(OTf)3
CN
+
R3
CF3
N
toluene, 100°C
NH
R2
N
R2
1
2
3
F3C
F3C
F3C
F3C
Cl
N
N
N
N
N
N
N
N
3a, 86%
3b, 73%
3c, 79%
3d, 92%
H
F3C
F3C
F3C
F3C
S
O
F
N
N
N
N
N
N
N
N
3g, 71%
3e, 85%
3f, 75%
3h, 77%
F3C
F3C
F3C
CF3
I
N
N
N
N
N
N
N
N
3j, 72%b
3i, 82%
3k, 74%
3l, 83%
F3C
F3C
F3C
F3C
N
N
Br
N
N
N
N
N
N
3m, 77%
3n, 82%
3p, 74%
3o, 76%
F
F3C
F3C
F3C
N
N
N
N
N
N
3q, 85%
3r, 72%
3s, 79%
Br
aReaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), Fe(OTf)3 (10 mol%), toluene (1 mL), 100 °C, 8 h, isolated yield.
bAcetylacetone as substrate at 120 °C.
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To illustrate the generality of the tandem cyclization method, we have also tried
the reaction between 1 and ethyl acetopyruvate (Table 3). For instance, the reaction of
ethyl acetopyruvate gave the desired product 3t-v in yields of more than 80%. The
substrate 1 with a benzyl group was less efficient than that with an alkyl group
attached on the R2 position for the above cyclization, affording the product 3w in 75%
yield. It could be attributed to the slightly lower nunucleophilicity of benzyl amine
compared with alkyl amine in the substrate 1.
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Table 3 Synthesis of α-Carbolines from Ethyl Acetopyruvate a
O
O
R1
O
O
R1
Fe(OTf)3
CN
O
+
N
toluene, 100°C
NH
R2
N
R2
O
1
3
O
O
O
O
O
O
O
O
Br
N
N
N
N
N
N
N
N
3w, 75%
3v, 83%
3u, 85%
3t, 86%
aReaction conditions: 1 (0.3 mmol), ethyl acetopyruvate (0.2 mmol), Fe(OTf)3 (10 mol%), toluene (1 mL),
100 °C, 8 h, isolated yield.
To further explore the substrate scope of the reaction, β,γ-unsaturated α-ketoesters
employed as reactants reacted with o-aminophenylacetonitriles to generate the
corresponding desired products. Experiments illustrated that the reaction was carried
out best at 100 °C using 20 mol% of FeCl3 in DCE. Subsequently, the substrate scope
for the reactions of 2-(2-(methylamino)phenyl)acetonitrile 1a with various β,γ-
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unsaturated α-ketoesters 4 was then studied (Table 4). As for the β,γ-unsaturated α-
ketoesters 4, when the phenyl containing Br, Cl, F or CF3 as the R2 substituents, the
reactions proceeded smoothly, producing the α-carbolines 5a-5d in 79-87% yields
under standard conditions. However, once involving the strong electron-withdrawing
group NO2 on R2, the corresponding product 5e was only obtained in 63% yield.
Other benzene or electron-rich benzene rings substituted β,γ-unsaturated α-ketoesters
could also participated in the reaction, forming the products 5f-5h in good yields.
Heteroaryl-substituted substrates were also tolerant in this reaction and provided
moderate yields (5j-5k). In particular, β,γ,δ,ε-unsaturated α-ketoester was also tolerant,
and the same type product 5l could be selectively synthesized in 61% yield. Moreover,
α,β-unsaturated ketones as substrates reacted with 2-(2-aminophenyl)acetonitriles to
generate the corresponding products in moderate to good yields (5o-5r).
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Table 4 The Reaction of 2-(2-Aminophenyl)acetonitriles 1 with Various β,γ-
Unsaturated α-Ketoesters 4a
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R2
N
O
CN
R3
5b
FeCl3
R2
R3
+
N
DCE, 100°C
NH
R1
1
4
R2= aryl, R3 = ester, aryl
R1
9
Cl
Br
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F
O
O
O
O
N
O
O
5a, 81%
N
N
N
N
5c, 79%
N
5b, 85%
F
O2N
F
F
OBn
O
O
O
N
O
N
N
O
N
N
5e, 63%
5f, 71%
5d, 87%
N
O
O
O
O
O
O
N
N
O
N
N
N
S
N
O
5i, 65%
5g, 74%
5h, 69%
O
OBn
OBn
OBn
O
O
O
N
N
N
N
N
N
N
5j, 70%
5k, 65%
5l, 61%
O
O
O
N
O
N
N
N
N
H
5o, 72%
F
5n, 68%
5m, 63%
F
Br
N
N
5q, 83%
N
N
5p,77%
N
N
5r, 81%
aReaction conditions: 1 (0.3 mmol), 4 (0.2 mmol), FeCl3 (20 mol%), DCE (1 mL), 100 °C, 6 h. bIsolated yield.
Owing of the importance of the introduction of fluorine or trifluoromethyl group
into drug molecules, we chosen 4d as reactant to react with various 2-(2-
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aminophenyl)acetonitriles 1 (Table 5). When contained Br atom, the reaction went
smoothly to give 4bd in 76% yield. Then we investigated the effect of the substituent
groups on the amino-group of 1. Ethyl substituted 1 could also take part in the
cyclizations, forming the trifluoromethyl group-containing α-carboline 4cd in high
yield. Furthermore, this method could tolerate several benzyl substituent groups on
the amino-group of 1. For instance, the corresponding trifluoromethyl-α-carbolines
4dd, 4ed and 4fd were obtained in moderate yield. Research is underway to
investigate the biological activities of the above trifluoromethyl-α-carbolines.
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Table 5 The Reaction of Various 2-(2-Aminophenyl)acetonitriles 1 with β,γ-
Unsaturated α-Ketoester 4d.a
F3C
O
R1
FeCl3
O
CN
O
R1
+
DCE, 100°C
O
NH
R2
O
F3C
N
4bd-4fdb
N
R2
1
4d
F3C
F3C
F3C
O
O
O
O
O
Br
N
O
N
N
N
N
4dd, 73%
N
4cd, 82%
4bd, 76%
F3C
F3C
O
O
O
O
N
N
N
N
Br
4ed, 71%
4fd, 62%
aReaction conditions: 1 (0.3 mmol), 4d (0.2 mmol), FeCl3 (20 mol%), DCE (1 mL), 100 °C, 6 h. bIsolated yields .
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To improve the practicality of this synthesis method, a gram-scale reaction of 1a
(15 mmol) and 2a (10 mmol) was carried out, and 2.34 g of the desired product 3a
was obtained in 72% yield.
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Reaction Mechanism
According to the experimental results and similar literature reports, we
speculated that 1a first undergone intramolecular cyclization by iron catalyst to
obtain1-methyl-1H-indol-2-amine, which then reacted with 2a through intermolecular
addition and intramolecular condensation to finally obtain the target product.
Therefore, a control experiment was made (Scheme 1 A), and only 1a was added
under the same conditions. During the experiment, we found that the system was
relatively disordered and difficult to carry out separation, which may be due to the
instability and easy oxidation of 1-methyl-1H-indol-2-amine. But it is found that 1-
methyl-1H-indol-2-amine may be detected by GC-MS. Moreover, we employed
commercially available 2-aminoindole hydrogenchloride as reactant which reacted
with 2a after neutralization under the same conditions (Scheme 1 B), and the
corresponding product was obtained.
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N
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Fe(OTf)3
toluene, 100 °C
mixture
A
NH
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2a, Fe(OTf)3
Et3N
toluene,rt
NH2 HCl
3b
B
N
100 °C
73%
H
Scheme 1 Control Experiments
According to the above results and the research findings from other groups15, we
proposed a possible reaction process (Figure 2). Firstly, 1a generates intermediate A
through intramolecular cyclization under the catalysis of iron salt. Because of the
stronger nucleophilicity C-3 position of intermediate A relative to NH2 group,
intermediate A rapidly reacted with 2a to form intermediate B, which then undergoes
intramolecular condensation, and dehydrates to obtain the target product.
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N
N
NH
Fe(OTf)3
NH
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NH
N
Fe(OTf)3
N
N
O
H2N
O
A
H2N
CF3
OH
-H2O
3a
N
B
N
CF3
Fe(OTf)3
HO
O
CF3
Fe
(OTf)3
Figure 2 Proposed Reaction Pathway to α-Carbolines.
In conclusion, we have described a new method for the synthesis of trifluoromethyl
and ester group substituted α-carbolines by an iron-catalyzed tandem cyclization
reaction. In the presence of iron salts, a variety of trifluoromethyl and ester group
substituted α-carbolines were obtained in good to excellent yields under a simple and
mild condition. The synthetic method reported can be classified into general
approaches according to a one-pot construction of three fused heterocyclic ring
system. Research is underway to investigate the biological activities of the above
trifluoromethyl-α-carbolines and ester group substituted α-carbolines.
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Experimental Section
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Materials and Methods: Compounds 1 were prepared using known literature
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16,17,18,19,20
methods,
Compounds 2 and ethyl acetopyruvate were purchased from
commercial suppliers and used without further purification. Compounds 4a-n were
obtained from Zhiyong Wang’ group,21 2-aminoindole hydrogenchloride was
purchased from Bidepharm company, 1H NMR were recorded on a Mercury Plus 400
NMR spectrometer using TMS as internal reference. The chemical shifts (δ) and
coupling constants (J) were expressed in ppm and Hz respectively. The HRMS
measurements were recorded on a ESI-TOF analyzer. Melting points were measured
on a capillary melting point apparatus WRS-2. All reactions were monitored by thin-
layer chromatography (TLC). Column chromatography was performed using silica gel
(200−300 mesh) as the stationary phase.
General procedure synthesis of 2-(2-(methylamino)phenyl)acetonitrile (1a)：16 A
mixture
of
2-(2-aminophenyl)acetonitrile
(20
mmol,
2.64g),
1H-
benzo[d][1,2,3]triazole (20 mmol, 2.38g) was stirred at room temperature in Methanol
50 mL, and formaldehyde solution (37%) (30 mmol, 2.27g) was dropped to the
mixture. Then reaction mixture was stirred overnight. The resulting precipitation was
filtered and dissolved in 30 ml tetrahydrofuran, The mixture was added NaBH4 (20
mmol), After completion of the reaction (indicated by TLC), the mixture quenched
with saturated NaCl solution, extracted with EtOAc, dried over Na2SO4, and
concentrated. The crude material thus obtained was purified by column
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chromatography on silica gel using petroleum ether /ethyl acetate (100:10) to obtain
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the pure product 1a. Yield, 2.13g (73%), white solid, m.p. 62–64°C, H NMR (400
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MHz, CDCl3) δ 7.32 – 7.27 (m, 1H), 7.22 (d, J = 7.4 Hz, 1H), 6.81 – 6.75 (m, 1H),
6.72 (d, J = 8.1 Hz, 1H), 3.54 (s, 2H), 2.91 (s, 3H). 1a is known compound.22
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Synthesis of 2-(2-(benzylamino)phenyl)acetonitriles (1p, 1q, 1r, 1s, 1t, 1g).17A
mixture of 2-(2-aminophenyl)acetonitrile (1 mmol, 132 mg), aldehyde 1 (1 mmol),
was stirred at room temperature in methanol 10 mL overnight. Without further
purification, NaBH4 (1 mmol, 37 mg) was added to the mixture system. After
completion of the reaction (indicated by TLC), solvent was evaporated, and the
mixture was diluted with saturated NaCl solution (15 mL), extracted with EtOAc (10
mL×3). The combined organic part was dried over anhydrous Na2SO4. The solvent
was evaporated, and the residue was purified by column chromatography on silica gel
using petroleum ether /ethyl acetate (16:1 to 8:1) to provide the corresponding product.
Among these, 1p is known;23 compounds 1q, 1r, 1s, 1t, 1g are new.
2-(2-(benzylamino)phenyl)acetonitrile (1p). Yield :151 mg (68%), yellow solid, m.p.
1
75–78°C, H NMR (400 MHz, CDCl3) δ 7.35 (q, J = 7.6 Hz, 4H), 7.31 – 7.25 (m,
1H), 7.20 (t, J = 8.5 Hz, 2H), 6.76 (t, J = 7.4 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 4.37 (s,
2H), 3.80 (s, 1H), 3.52 (s, 2H).
2-(2-(4-fluorobenzylamino)phenyl)acetonitrile (1q). Yield :175 mg (73%), light
yellow solid, m.p. 94–96°C, 1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 8.0, 5.6 Hz,
2H), 7.28 – 7.16 (m, 2H), 7.04 (t, J = 8.6 Hz, 2H), 6.79 (t, J = 7.4 Hz, 1H), 6.68 (d, J
= 8.1 Hz, 1H), 4.36 (s, 2H), 3.80 (s, 1H), 3.57 (s, 2H). 13C{1H} NMR (100 MHz,
CDCl3) δ 163.4, 161.0, 145.2, 134.3 (d, J = 3 Hz), 129.6 (d, J = 12 Hz), 129.1 (d, J =
8 Hz), 118.3, 117.2, 115.7(d, J = 21 Hz), 114.7, 111.9, 47.6, 20.3. HRMS (ESI): calcd
for C15H14FN2 [M+H]+ 241.1141, Found: 241.1137.
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2-(2-(4-methylbenzylamino)phenyl)acetonitrile (1r). Yield : 186 mg (79%) , white
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solid, m.p. 82–84°C, H NMR (400 MHz, CDCl3) δ 7.24 (dt, J = 16.1, 8.0 Hz, 4H),
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7.17 (d, J = 7.8 Hz, 2H), 6.78 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.33 (s,
2H), 3.73 (s, 1H), 3.55 (s, 2H), 2.35 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
145.4, 137.2, 135.6, 129.7, 129.5, 129.4, 129.3, 127.6, 127.1, 118.1, 117.2, 114.5,
111.9, 48.1, 21.1, 20.3. HRMS (ESI): calcd for C16H17N2 [M+H]+ 237.1391, Found:
237.1388.
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2-(2-(4-bromolbenzylamino)phenyl)acetonitrile (1s). Yield: 195 mg (65%), white
1
solid, m.p. 113-116°C, H NMR (400 MHz, CDCl3) δ 7.41 (dd, J = 39.6, 7.8 Hz, 2H),
7.42 – 7.13 (m, 4H), 6.78 (t, J = 7.2 Hz, 1H), 6.63 (d, J = 7.9 Hz, 1H), 4.34 (s, 2H),
3.86 (s, 1H), 3.56 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 145.0, 139.9, 137.8,
131.8, 131.6, 129.7, 129.6, 129.1, 128.6, 121.4, 121.2, 118.4, 117.2, 114.7, 111.9,
47.6, 20.4. HRMS (ESI): calcd for C15H14BrN2 [M+H]+ 301.0340, Found: 301.0336.
2-(2-(3-methy benzylamino)phenyl)acetonitrile (1t). 179 mg (76%), yellow solid,
m.p. 72-74°C, 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.16 (m, 5H), 7.11 (d, J = 7.3 Hz,
1H), 6.78 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.34 (s, 2H), 3.75 (s, 1H), 3.56
(s, 2H), 2.36 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 145.4, 138.5, 129.7, 129.4,
128.7, 128.4, 128.3, 124.6, 118.1, 117.1, 114.5, 111.9, 48.4, 21.4, 20.3. HRMS (ESI):
calcd for C16H17N2 [M+H]+ 237.1391, Found: 237.1389.
2-(2-(3-bromo benzylamino)phenyl)acetonitrile (1g). Yield: 189 mg (63%), white
1
solid, m.p. 108-110°C, H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.41 (d, J = 7.5
Hz, 1H), 7.25 (m, 4H), 6.79 (t, J = 7.2 Hz, 1H), 6.64 (d, J = 7.9 Hz, 1H), 4.37 (s, 2H),
3.81 (d, J = 47.0 Hz, 1H), 3.59 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 144.9,
141.2, 130.6, 130.4, 129.7, 129.6, 125.9, 122.9, 118.5, 117.1, 114.7, 111.9, 47.7, 20.4.
HRMS (ESI): calcd for C15H14BrN2 [M+H]+ 301.0340, Found: 301.0338.
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Synthesis of 2-(5-iodo-2-(methylamino)phenyl)acetonitrile (1l): 18To CH3CN (10
mL) solution of 2-(2-(methylamino)phenyl)acetonitrile (1 mmol, 146 mg) was added
iodine (1.05 mmol, 267 mg), A mixture was stirred at room temperature for 5 hours,
Then the mixture was diluted with saturated NaCl solution (15 mL), extracted with
EtOAc (10 mL×3). The combined organic part was dried over anhydrous Na2SO4. The
solvent was evaporated, and the residue was purified by flash column chromatography
on silica gel using petroleum ether /ethyl acetate (100:5 to 100: 10) to obtain to the
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corresponding product. Yield :138 mg (51%) , yellow solid, m.p. 64-66°C, H NMR
(400 MHz, CDCl3) δ 7.54 (dd, J = 8.6, 1.5 Hz, 1H), 7.47 (s, 1H), 6.47 (d, J = 8.6 Hz,
1H), 3.57 (s, 1H), 3.48 (s, 2H), 2.88 (d, J = 2.3 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 146.2, 138.4, 137.4, 116.5, 116.5, 113.0, 78.0, 30.7, 19.8. HRMS (ESI):
calcd for C9H10IN2 [M+H]+ 272.9888, Found: 272.9881. 1l is new compound.
Synthesis of 2-(5-bromo-2-(methylamino)phenyl)acetonitrile (1m):19 To CH2Cl2
(15 mL) solution of 2-(2-(methylamino)phenyl)acetonitrile (1 mmol, 146 mg ) was
dropped CH2Cl2 (5mL) solution of NBS (1 mmol, 178 mg ) at 0 °C, then mixture was
stirred at room temperature for 3 hours. After completion of the reaction detected
by TLC, the solvent was evaporated. Then the mixture was diluted with saturated
NaCl solution (15 mL), extracted with EtOAc (10 mL×3). The combined organic part
was dried over anhydrous Na2SO4. The solvent was evaporated, and the residue
was purified by flash column chromatography on silica gel using petroleum ether
/ethyl acetate (100:5 to 100:10) to provide the corresponding product. Yield : 192 mg
(86%) , light yellow solid, m.p. 73-75°C, 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J =
8.7, 2.0 Hz, 1H), 7.32 (d, J = 1.7 Hz, 1H), 6.58 (d, J = 8.6 Hz, 1H), 3.52 (d, J = 10.3
Hz, 1H), 3.50 (s, 2H), 2.89 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 145.6, 132.4,
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131.7, 116.6, 116.9, 112.4, 109.1, 30.8, 19.9. HRMS (ESI): calcd for C9H10BrN2
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[M+H]+ 225.0027, Found: 225.0026. 1m is new compound.
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Synthesis of 2-(2-(ethylamino)phenyl)acetonitrile (1n):20 A mixture of 2-(2-
aminophenyl)acetonitrile (1 mmol, 146 mg), bromoethane (1.5 mmol, 162 mg),
K2CO3 (1.5 mmol, 207 mg) was stirred at 80 °C in DMF 5 mL in high pressure test
tube for 6 hours. Then the mixture was diluted with saturated NaCl solution (15 mL),
extracted with EtOAc (10 mL×3). The combined organic part was dried over
anhydrous Na2SO4. The solvent was evaporated, and the residue was purified by flash
column chromatography on silica gel using petroleum ether /ethyl acetate (100:5) to
provide the corresponding product. Yield : 67mg (42%) , yellow solid, m.p. 53-55°C,
1H NMR (400 MHz, CDCl3) δ 7.28 – 7.18 (m, 2H), 6.74 (dd, J = 12.6, 5.1 Hz, 1H),
6.70 (d, J = 8.1 Hz, 1H), 3.51 (s, 2H), 3.31 (s, 1H), 3.20 (q, J = 7.1 Hz, 2H), 1.39 –
1.26 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 145.7, 129.6, 129.3, 117.7, 117.3,
114.3, 111.5, 38.6, 20.2, 14.8. HRMS (ESI): calcd for C10H13N2 [M+H]+ 161.1078,
Found: 161.1075. 1n is new compound.
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General procedure for the reaction of 2-(2-aminophenyl)acetonitriles with
trifluoromethyl 1,3-diones or acetopyruvate: A mixture of trifluoromethyl 1,3-
diones 2 or ethyl acetopyruvate (0.2 mmol), 2-(2-aminophenyl)acetonitriles 1 (0.3
mmol), Fe(OTf)3 (10 mol %), was stirred at 100 °C in toluene 1 mL for 8 h. After
completion of the reaction (indicated by TLC), Then the mixture was diluted with
saturated NaCl solution (10 mL), extracted with EtOAc (10 mL×3). The combined
organic part was dried over anhydrous Na2SO4. The solvent was evaporated, and the
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residue was purified by flash column chromatography on silica gel using petroleum
ether /ethyl acetate (40:1 to 20:1) to provide the corresponding product.
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General procedure for the reaction of 2-(2-aminophenyl)acetonitriles with β,γ-
unsaturated α-ketoesters: A mixture of β,γ-unsaturated α-ketoesters or α,β-
unsaturated ketones (0.2 mmol, 4), 2-(2-aminophenyl)acetonitriles 1 (0.3 mmol),
FeCl3 (20 mol %), was stirred at 100 °C in DCE 1 mL for 6 h. After completion of the
reaction (indicated by TLC), Then the mixture was diluted with saturated NaCl
solution (10 mL), extracted with EtOAc (10 mL×3). The combined organic part was
dried over anhydrous Na2SO4. The solvent was evaporated, and the residue
was purified by flash column chromatography to on silica gel using petroleum ether
/ethyl acetate (12:1 to 8:1) provide the corresponding product.
A large scale experiment: A mixture of 1a (15 mmol, 2.19 g), 2a (10 mmol, 2.16 g),
Fe(OTf)3 (10 mol %, 503 mg), was stirred at 100 °C in toluene 30 mL for 16 h. After
completion of the reaction (indicated by TLC), the solvent was evaporated, Then the
mixture was diluted with saturated NaCl solution (30 mL), extracted with EtOAc (40
mL×3). The combined organic part was dried over anhydrous Na2SO4. The solvent
was evaporated, and the residue was purified by flash column chromatography on
silica gel using petroleum ether/ethyl acetate (40:1 to 20:1) to provide the
corresponding product 3a (2.34 g, 72%).
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Control experiment A : 1a (0.5 mmol, 29.2 mg) and Fe(OTf)3 (10 mol %, 26.5 mg),
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Control experiment B: A mixture of 2-aminoindole hydrogenchloride (0.3 mmol, 51
mg) and Et3N (0.3 mmol, 30.3 mg) was stirred at rt in toluene 1 mL for 0.5 h. Then 2a
(0.2 mmol, 43.2 mg) and Fe(OTf)3 (10 mol %, 10 mg) were added, and temperature
rised to 100 °C. After completion of the reaction (indicated by TLC), Then the
mixture was diluted with saturated NaCl solution (10 mL), extracted with EtOAc (10
mL×3). The combined organic part was dried over anhydrous Na2SO4. The solvent
was evaporated, and the residue was purified by flash column chromatography on
silica gel using petroleum ether/ethyl acetate (10:1 to 6:1) to provide the
corresponding product for 73% yield (45.6 mg).
9-methyl-2-phenyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3a)12
Yield: 56 mg (86%), white solid, m.p. 105–106 °C, 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.0 Hz,
1H), 8.22 (d, J = 7.6 Hz, 2H), 7.88 (s, 1H), 7.63 – 7.44 (m, 5H), 7.36 (t, J = 7.6 Hz, 1H), 4.07 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 152.9, 151.5, 140.2, 137.9, 130.2 (q, J = 34 Hz,), 128.3, 127.8,
126.6, 126.1, 122.7 (q, J = 4 Hz,), 121.5 (q, J = 271 Hz,), 119.7, 116.9, 109.0, 108.2, 106.9 (q, J = 5
Hz), 26.9. HRMS (ESI): calcd for C19H14F3N2 [M+H]+ 327.1109, Found: 327.1107.
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Yield: 45 mg (73%) light yellow solid, m.p. 279-283 °C, H NMR (400 MHz, DMSO-d6) δ 12.54 (s,
1H), 8.26 (d, J = 7.7 Hz, 2H), 8.11 (d, J = 7.9 Hz, 1H), 8.05 (s, 1H), 7.59 (dt, J = 21.7, 7.5 Hz, 4H),
7.54 – 7.47 (m, 1H), 7.34 (t, J = 7.5 Hz, 1H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 154.1, 153.2,
140.6, 138.6, 130.3 (q, J = 34 Hz), 129.9, 129.4, 128.4, 127.5, 123.1 (q, J = 4 Hz), 122.9 (q, J = 271
Hz), 121.1, 117.8, 112.4, 109.5, 108.0 (q, J = 5 Hz). HRMS (ESI): calcd for C18H12F3N2[M+H]+
313.0952, Found: 313.0955.
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9-methyl-2-p-tolyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3c)
Yield: 54 mg (79%), colourless solid, m.p.130–133 °C, 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 9.0
Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 9.0 Hz, 1H), 7.35 (t,
J = 7.6 Hz, 1H), 4.07 (s, 3H), 2.45 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.1, 152.5, 141.2,
139.5, 136.2, 130.9 (q, J = 40 Hz), 129.6, 127.5, 127.1, 123.7 (q, J = 4 Hz), 122.9 (q, J = 271 Hz),
120.7, 118.0, 110.9, 109.2, 107.7 (q, J = 4 Hz), 27.9, 21.4. HRMS (ESI): calcd for C20H16F3N2 [M+H]+
341.1265, Found: 341.1265.
2-(4-chlorophenyl)-9-methyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3d)
Yield: 66 mg (92%) light yellow solid, m.p.140–142 °C, 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.0
Hz, 1H), 8.09 (d, J = 8.6 Hz, 2H), 7.76 (s, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.43 (m, 3H), 7.30 (t, J = 7.6
Hz, 1H), 3.99 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ152.6, 152.5, 141.3, 137.3, 135.5, 130.9 (q,
J = 34 Hz), 129.0, 128.4, 127.8, 123.8 (q, J = 4 Hz), 122.4(q, J = 272 Hz), 120.8, 117.8, 110.3, 109.3,
107.6 (q, J = 4 Hz), 27.9.. HRMS (ESI): calcd for C19HlF3N2 [M+H]+ 361.0719, Found: 361.0716.
2-(4-fluorophenyl)-9-methyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3e)
Yield: 59 mg (85%) light yellow solid, m.p.132–134 °C, 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.0
Hz, 1H), 8.24 – 8.14 (m, 2H), 7.80 (s, 1H), 7.61-7.50 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.42 – 7.31 (m,
1H), 7.21 (t, J = 8.7 Hz, 2H), 4.03 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.0, 162.5, 152.5 (d,
J = 40 Hz), 141.3, 135.1(d, J = 3 Hz), 130.9 (q, J = 34 Hz), 129.0 (d, J = 6 Hz), 127.7, 123.8 (q, J = 4
Hz), 122.5 (q, J = 271 Hz), 120.8, 117.9, 115.7(d, J = 21 Hz), 110.0, 109.2, 107.5 (q, J = 6 Hz), 27.83.
HRMS (ESI): calcd for C19H13F4N2 [M+H]+ 345.1005, Found: 345.1023.
9-methyl-2-(naphthalen-1-yl)-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3f)
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Yield: 56 mg (75%) light yellow solid, m.p.112–114 °C, H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H),
8.45 – 8.24 (m, 2H), 8.07 – 7.92 (m, 3H), 7.87 (s, 1H), 7.65 – 7.51 (m, 3H), 7.46 (d, J = 6.8 Hz, 1H),
7.37 (d, J = 6.8 Hz, 1H), 4.04 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.7, 152.5, 141.3, 136.2,
133.8, 133.5, 130.8 (q, J = 34 Hz), 128.8, 128.5, 127.7, 127.6, 126.7, 126.6, 126.4, 124.6, 123.8(q, J =
4 Hz), 122.6 (q, J = 271 Hz), 120.7, 117.9, 110.1, 109.2, 108.1 (q, J = 6 Hz), 27.8. HRMS (ESI): calcd
for C23H16F3N2 [M+H]+ 377.1265, Found: 377.1269.
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Yield: 47 mg (71%) yellow solid, m.p.152–155 °C, 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.6 Hz,
1H), 7.67 – 7.58 (m, 2H), 7.50 – 7.40 (m, 1H), 7.36-7.27 (m, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.12 – 7.00
(m, 1H), 3.98 (s, 3H). 13C{1H} δ 152.2, 149.3, 144.8, 141.1, 130.8 (q, J = 34 Hz), 128.2, 127.9, 127.5,
125.4, 123.5 (q, J = 4 Hz), 122.3 (q, J = 272 Hz), 120.8, 118.1, 109.8, 109.2, 106.7, 106.7 (q, J =5 Hz),
27.8. HRMS (ESI): calcd for C17H12F3N2S [M+H]+ 333.0673, Found: 333.0675.
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2-(furan-2-yl)-9-methyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3h)
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Yield: 48 mg (77%) yellow solid, m.p.98–100 °C, H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.2 Hz,
1H), 7.87 (s, 1H), 7.61-7.54 (m, 2H), 7.50 (d, J = 8.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 3.4
Hz, 1H), 6.62 (d, J = 3.4, 1H), 4.04 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.8, 152.3, 145.9,
143.7, 141.2, 130.8 (q, J = 34 Hz), 128.8, 127.6, 123.6 (q, J = 4 Hz), 122.3 (q, J = 271 Hz), 120.8,
118.1, 112.3, 110.0, 109.3, 109.2, 106.5 (q, J = 6 Hz), 27.8. HRMS (ESI): calcd for
C17H12F3N2O[M+H]+ 317.0901, Found: 317.0902.
2,9-dimethyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3i)
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Yield: 43 mg (82%) yellow solid, m.p.102–104°C, H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.0 Hz,
1H), 7.57 (t, J = 7.6 Hz, 1H), 7.51 – 7.44 (m, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.28 (s, 1H), 3.98 (s, 3H),
2.77 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 155.7, 152.4, 140.6, 130.4 (q, J = 34 Hz), 127.2,
123.5 (q, J = 4 Hz), 122.5 (q, J = 271 Hz), 120.5, 117.9, 110.6 (q, J =5 Hz), 109.1, 108.8, 27.83 24.8.
HRMS (ESI): calcd for C14H12F3N2 [M+H]+ 265.0952, Found: 265.0961.
2,4,9-trimethyl-9H-pyrido[2,3-b]indole (3j)
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Yield: 30 mg (72%), yellow solid, m.p.90-92°C, H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.8 Hz,
1H), 7.52 – 7.41 (m, 2H), 7.27 (dd, J = 10.7, 3.7 Hz, 1H), 6.83 (s, 1H), 3.94 (s, 3H), 2.80 (s, 3H), 2.67
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 155.0, 151.8, 142.2, 139.8, 125.3, 122.3, 121.2, 119.6,
116.8, 112.2, 108.7, 27.6, 24.7, 19.8. HRMS (ESI): calcd for C14H15N2[M+H]+ 211.1235, Found:
211.1239..
9-methyl-2,4-bis(trifluoromethyl)-9H-pyrido[2,3-b]indole (3k)12
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Yield: 47 mg (74%) white solid, m.p.185-187 °C, H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.1 Hz,
1H), 7.70 (s, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 3.97 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.7, 144.0 (q, J = 35 Hz), 142.1, 130.9 (q, J = 35 Hz),
129.4, 124.6(q, J = 4 Hz), 121.8(q, J = 272 Hz), 121.5, 120.3 (q, J = 272 Hz), 117.1, 112.3, 109.7,
107.4 (q, J = 4 Hz), 28.12. HRMS (ESI): calcd for C14H9F6N2 [M+H]+ 319.0670, Found: 319.0671.
6-iodo-9-methyl-4-phenyl-2-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3l)
Yield: 75 mg (75%), white solid, m.p. 232-233 °C, 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.20 (d,
J = 7.2 Hz, 2H), 7.89 (s, 1H), 7.85-7.74 (m, 1H), 7.6 (t, J = 7.4 Hz, 2H), 7.48 (t, J = 7.2 Hz, 1H), 7.29
(d, J = 8.6 Hz, 1H), 4.05 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.9, 152.3, 140.3, 138.6, 135.9,
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132.3 (q, J = 4 Hz), 131.3 (q, J = 32 Hz), 129.6, 128.9, 127.2, 122.3 (q, J = 272 Hz), 120.3, 111.2,
108.6, 108.5, 83.4, 27.9. HRMS (ESI): calcd for C19H13F3IN2 [M+H]+ 453.0075, Found: 453.0075.
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6-bromo-9-methyl-2-phenyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3m)
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Yield: 62 mg (77%) yellow solid, m.p.173-175 °C, 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.23 –
8.16 (m, 2H), 7.87 (s, 1H), 7.65-7.59 (m, 1H), 7.53 (t, J = 7.2 Hz, 2H), 7.47 (t, J = 7.2 Hz, 1H), 7.35 (d,
J = 8.6 Hz, 1H), 4.02 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.8, 152.5, 139.8, 138.6, 131.3
(q, J = 34 Hz), 130.4, 129.6, 128.9, 127.2, 126.2 (q, J = 5 Hz), 122.3 (q, J = 271 Hz), 119.5, 113.6,
110.7, 108.8, 108.5, 108.4 (q, J = 5 Hz), 27.9. HRMS (ESI): calcd for C19H13BrF3N2 [M+H]+ 405.0214,
Found: 405.0216.
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9-ethyl-2-phenyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3n)
Yield: 56 mg (82%), yellow solid, m.p.100-103 °C, 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.0 Hz,
1H), 8.27 – 8.20 (m, 2H), 7.90 (s, 1H), 7.58-7.48 (m, 4H), 7.47-7.40 (m, 1H), 7.39 – 7.32 (m, 1H), 4.75
– 4.63 (m, 2H), 1.54 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.9, 152.1, 140.2,
139.0, 130.9(q, J = 33 Hz), 129.3, 128.8, 127.6, 127.2, 123.9 (q, J = 4 Hz), 122.6(q, J = 272 Hz), 120.6,
118.1, 110.0, 109.3, 107.9 (q, J = 5 Hz), 36.5, 14.0. HRMS (ESI): calcd for C20H16F3N2 [M+H]+
341.1265, Found: 341.1265.
9-benzyl-2-phenyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3o)
Yield: 61 mg (76%) light yellow solid, m.p.131-132 °C, 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.0
Hz, 1H), 8.12 (d, J = 7.2 Hz, 2H), 7.84 (s, 1H), 7.47 – 7.32 (m, 5H), 7.27 – 7.14 (m, 6H), 5.73 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3) δ 154.1, 152.5, 140.5, 138.8, 137.1, 131.1(q, J = 34 Hz), 129.4,
128.9, 128.7, 127.7, 127.6, 127.5, 127.3, 127.2, 123.9 (q, J = 4 Hz), 122.6 (q, J = 272 Hz), 120.9, 118.3,
110.1, 108.4 (q, J = 5 Hz), 45.3.HRMS (ESI): calcd for C25H18F3N2 [M+H]+ 403.1422, Found:
403.1422.
9-(4-fluorobenzyl)-2-phenyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3p)
Yield: 62 mg (74%), yellow solid, m.p.145–148 °C, 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.0 Hz,
1H), 8.19 (d, J = 7.5 Hz, 2H), 7.92 (s, 1H), 7.56 – 7.38 (m, 5H), 7.36 – 7.26 (m, 3H), 6.95 (t, J = 8.6
Hz, 2H), 5.76 (s, 2H).13C{1H} NMR (100 MHz, CDCl3) δ 163.5, 161.0, 154.2, 152.4, 140.4, 138.8,
132.8 (d, J = 3 Hz), 131.2(q, J = 33 Hz), , 129.1(d, J = 41 Hz), 128.9 (d, J = 8 Hz), 127.8, 127.2, 123.9
(q, J = 4 Hz), 122.5 (q, J = 271 Hz), 121.1, 118.3, 115.7(d, J = 21 Hz), 110.1, 109.9, 108.5(q, J = 5 Hz),
108.5, 44.6. HRMS (ESI): calcd for C25H17F4N2 [M+H]+ 421.1328, Found: 421.1327.
9-(4-methylbenzyl)-2-phenyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3q)
Yield: 71 mg (85%) yellow solid, m.p.127–129 °C, 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.0 Hz,
1H), 8.21 (d, J = 8.2 Hz, 2H), 7.92 (s, 1H), 7.54 – 7.41 (m, 5H), 7.31-7.24 (m, 1H), 7.22 (d, J = 7.2 Hz,
2H), 7.07 (d, J = 8.0 Hz, 2H), 5.77 (s, 2H), 2.27 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.1,
152.5, 140.6, 138.9, 137.3, 134.1, 131.1(q, J = 34 Hz), 129.4, 129.4, 128.9, 127.7, 127.3, 127.2,
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123.9(q, J = 4 Hz), 122.6(q, J = 271 Hz), 120.9, 118.3, 110.1, 108.4 (q, J = 5 Hz), 45.1, 21.1. HRMS
(ESI): calcd for C26H20F3N2 [M+H]+ 417.1578, Found: 417.1579.
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9-(4-methylbenzyl)-2-phenyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3r)
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Yield: 69mg (72%) Yellow solid, m.p.165–166 °C, 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.0 Hz,
1H), 8.21 (d, J = 7.4 Hz, 2H), 7.95 (s, 1H), 7.57 – 7.33 (m, 8H), 7.20 (d, J = 8.0 Hz, 2H), 5.76 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3) δ 154.3, 152.4, 140.3, 138.7, 136.1, 131.9, 131.2(q, J = 34 Hz),
129.5, 128.9, 128.9, 127.8, 127.2, 124.0 (q, J = 4 Hz), 122.5 (q, J = 271 Hz), 121.6, 121.2, 118.3, 110.2,
109.9, 108.6 (q, J = 5 Hz), 44.7. HRMS (ESI): calcd for C25H17BrF3N2 [M+H]+ 481.0527, Found:
481.0528.
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9-(3-methylbenzyl)-2-phenyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (3s)
Yield: 66 mg (79%) yellow solid, m.p.132–134 °C, 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.0 Hz,
1H), 8.12 (d, J = 8.0 Hz, 2H), 7.84 (s, 1H), 7.45 – 7.29 (m, 5H), 7.23-7.12 (m, 1H), 7.09 – 6.93 (m,
4H), 5.67 (s, 2H), 2.18 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) 154.1, 152.6, 140.6, 138.87, 138.5,
137.0, 131.1(q, J = 34 Hz), 129.4, 128.9, 128.7, 128.4, 127.9, 127.7, 127.2, 126.8, 124.4, 123.9 (q, J =
4 Hz), 122.6(q, J = 272 Hz), 120.9, 118.3, 110.2, 108.4 (q, J = 5 Hz), 45.3, 21.4. HRMS (ESI): calcd
for C26H20F3N2 [M+H]+ 417.1578, Found: 417.1578.
ethyl 2,9-dimethyl-9H-pyrido[2,3-b]indole-4-carboxylate (3t)
Yield: 46 mg (86%) yellow solid, m.p.58–60 °C, 1H NMR (400 MHz, CDCl3) δ 8.71
(d, J = 8.2 Hz, 1H), 7.51 – 7.43 (m, 2H), 7.36 (d, J = 8.2 Hz, 1H), 7.21-7.12 (m, 1H),
4.48 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.67 (s, 3H), 1.43 (t, J = 7.2 Hz, 4H). 13C{1H}
NMR (100 MHz, CDCl3) δ 166.9, 154.9, 152.7, 140.9, 132.4, 127.1, 125.8, 120.1,
119.4, 115.2, 111.5, 108.7, 61.7, 27.9, 24.6, 14.4.C16H17N2 O2[M+H]+ 269.1290,
Found: 269.1289.
ethyl 9-ethyl-2-methyl-9H-pyrido[2,3-b]indole-4-carboxylate (3u)
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Yield: 48 mg (85%), white solid, m.p.66–69 °C, H NMR (400 MHz, CDCl3) δ 8.79
(d, J = 8.0 Hz, 1H), 7.59 – 7.51 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.29-7.25 (m, 1H),
4.57-4.23 (m, 4H), 2.74 (s, 3H), 1.51 (t, J = 7.1 Hz, 3H), 1.45 (t, J = 7.2 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 167.0, 155.0, 152.2, 139.9, 132.4, 126.9, 125.8,
119.8, 119.6, 115.1, 111.3, 108.8, 61.6, 36.2, 24.7, 14.4, 13.9. HRMS (ESI): calcd for
C17H19N2O2[M+H]+ 283.1446, Found: 283.1448.
ethyl 6-bromo-2,9-dimethyl-9H-pyrido[2,3-b]indole-4-carboxylate (3v)
Yield: 57 mg (83%), yellow solid, m.p.112–114 °C, 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 7.64 –
7.58 (m, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 4.56 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H),
2.73 (s, 3H), 1.53 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.5, 155.9, 152.7, 139.4,
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for C16H16BrN2O2[M+H]+ 347.0395, Found: 347.0395.
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Yield: 52 mg (75%), yellow solid, m.p.86–88 °C, H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 8.1 Hz,
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1H), 7.57 (s, 1H), 7.49 – 7.40 (m, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.29 – 7.20 (m, 6H), 5.74 (s, 2H), 4.57
(q, J = 7.2 Hz, 2H), 2.74 (s, 3H), 1.51 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.9,
155.3, 152.7, 140.2, 137.3, 132.5, 128.6, 127.3, 127.1, 126.9, 125.7, 120.2, 119.7, 115.6, 111.3, 109.6,
61.6, 44.9, 24.7, 14.4. HRMS (ESI): calcd for C22H21N2O2[M+H]+ 345.1603, Found: 345.1605.
isopropyl 4-(4-bromophenyl)-9-methyl-9H-pyrido[2,3-b]indole-2-carboxylate (5a)
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Yield: 68 mg (81%), yellow solid, m.p.135–137 °C, H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.70
(dd, J = 14.8, 8.2 Hz, 3H), 7.56 (dd, J = 13.6, 7.8 Hz, 3H), 7.48 (d, J = 8.2 Hz, 1H), 7.12 (t, J = 7.5 Hz,
1H), 5.44 – 5.31 (m, 1H), 4.07 (s, 3H), 1.47 (t, J = 10.1 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ
165.3, 151.9, 144.2, 143.7, 141.9, 137.5, 132.1, 130.4, 128.0, 123.2, 123.1, 120.0, 119.2, 117.5, 115.8,
109.4, 69.4, 28.2, 21.9. HRMS (ESI): calcd for C22H20BrN2O2[M+H]+423.0708, Found:423.0709.
isopropyl 4-(4-chlorophenyl)-9-methyl-9H-pyrido[2,3-b]indole-2-carboxylate (5b)
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Yield: 64 mg (85%), yellow solid, m.p.96–98 °C, H NMR (400 MHz, CDCl3) H NMR (400 MHz,
CDCl3) δ 7.79 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.52 – 7.45 (m, 3H), 7.40 (d,
J = 8.2 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 5.30 (hept, J = 6.2 Hz, 1H), 3.99 (s, 3H), 1.38 (d, J = 6.3 Hz,
6H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.4, 151.9, 144.2, 143.7, 141.9, 136.9, 134.9, 130.2,
129.1, 128.04, 123.1, 120.0, 119.2, 117.6, 115.9, 109.4, 69.4, 29.7, 22.0. HRMS (ESI): calcd for
C22H20ClN2O2[M+H]+ 379.1213, Found:379.1218.
isopropyl 4-(3-fluorophenyl)-9-methyl-9H-pyrido[2,3-b]indole-2-carboxylate (5c)
Yield: 57 mg (79%), yellow solid, m.p.85–88 °C, 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.60 (d, J
= 8.0 Hz, 1H), 7.53 – 7.43 (m, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 9.3 Hz, 1H), 7.24 – 7.09 (m,
1H), 7.04 (t, J = 7.5 Hz, 1H), 5.42 – 5.19 (m, 1H), 4.00 (s, 3H), 1.38 (d, J = 6.3 Hz, 6H). 13C{1H}
NMR (100 MHz, CDCl3) δ 165.3, 164.2, 161.7, 151.9, 144.2, 143.6, 141.9, 140.6 (,d, J = 8 Hz)
130.4(,d, J = 9 Hz), 128.0, 124.5(,d, J = 3 Hz), 123.2, 120.0, 119.2, 117.5, 115.9, 115.8, 115.7(,d, J =
24 Hz), 115.6, 109.4, 69.4, 28.2, 21.9. HRMS (ESI): calcd for C22H20FN2O2[M+H]+ 363.1509,
Found:363.1511.
isopropyl 9-methyl-4-(4-(trifluoromethyl)phenyl)-9H-pyrido[2,3-b]indole-2-carboxylate (5d)
Yield: 71 mg (87%), yellow solid, m.p.166–168 °C, 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 5.7 Hz,
3H), 7.80 (d, J = 8.0 Hz, 2H), 7.72 (s, 1H), 7.65 (dd, J = 8.7, 1.4 Hz, 1H), 7.36 (t, J = 11.8 Hz, 1H),
5.38 (dp, J = 12.5, 6.2 Hz, 1H), 4.07 (s, 3H), 1.46 (d, J = 6.2 Hz, 6H).13C{1H} NMR (100 MHz,
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CDCl3) δ 165.2, 151.9, 144.3, 143.3, 142.2, 141.9, 130.8 (q, J = 33 Hz), 129.2, 128.2, 125.8(q, J = 3
Hz), 123.0, 122.7(q, J = 271Hz), 120.2, 119.1, 117.5, 115.8, 109.5, 69.5, 28.2, 21.9. HRMS (ESI):
calcd for C23H20F3N2O2[M+H]+ 413.1477, Found:413.1478.
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isopropyl 9-methyl-4-(4-nitrophenyl)-9H-pyrido[2,3-b]indole-2-carboxylate (5e)
8
9
1
Yield: 49 mg (63%), yellow solid, m.p.211–213 °C, H NMR (400 MHz, CDCl3) δ 8.46 – 8.28 (m,
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2H), 7.80 (d, J = 6.8 Hz, 3H), 7.48 (ddd, J = 29.0, 16.7, 6.0 Hz, 3H), 7.13 – 6.99 (m, 1H), 5.31 (dp, J =
12.3, 6.2 Hz, 1H), 4.00 (s, 3H), 1.37 (t, J = 9.5 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.1,
151.8, 148.2, 145.2, 144.4, 142.3, 142.1, 129.9, 128.4, 124.1, 122.9, 120.3, 118.8, 117.1, 115.6, 109.6,
69.6, 28.2, 21.9. HRMS (ESI): calcd for C22H20N3O4[M+H]+ 390.1454, Found:390.1457.
benzyl 9-methyl-4-phenyl-9H-pyrido[2,3-b]indole-2-carboxylate (5f)
1
Yield: 55 mg (71%), yellow solid, m.p.102–105 °C, H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.61
(dd, J = 12.9, 7.2 Hz, 3H), 7.53 – 7.37 (m, 7H), 7.37 – 7.25 (m, 3H), 7.01 (t, J = 7.3 Hz, 1H), 5.42 (s,
2H), 4.00 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) 13C{1H} NMR (100 MHz, CDCl3) δ 165.9, 151.9,
145.3, 143.4, 141.9, 138.4, 136.0, 128.9, 128.8, 128.8, 128.6, 128.5, 128.3, 128.0, 123.4, 119.9, 119.5,
118.1, 116.4, 109.3, 67.3, 28.2. HRMS (ESI): calcd for C26H21N2O2[M+H]+ 393.1603, Found:
393.1608.
methyl 9-methyl-4-p-tolyl-9H-pyrido[2,3-b]indole-2-carboxylate (5g)
1
Yield: 49 mg (74%), yellow solid, m.p.108–110 °C, H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.79
(d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.56 – 7.50 (m, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.38 (d, J =
7.8 Hz, 2H), 7.10 (dt, J = 11.1, 2.0 Hz, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 2.50 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 166.6, 151.9, 145.5, 143.4, 141.9, 138.8, 135.4, 129.5, 128.7, 127.9, 123.4, 119.9,
119.6, 118.2, 116.4, 109.2, 52.8, 28.1, 21.4. HRMS (ESI): calcd for C21H19N2O2[M+H]+ 331.1446,
Found:331.1447.
isopropyl 4-(4-methoxyphenyl)-9-methyl-9H-pyrido[2,3-b]indole-2-carboxylate (5h)
1
Yield:52 mg (69%), yellow solid, m.p.143–146 °C, H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.77
(d, J = 8.0 Hz, 1H), 7.63 (t, J = 10.0 Hz, 2H), 7.50 (dd, J = 11.2, 4.0 Hz, 1H), 7.48 – 7.40 (m, 1H), 7.08
(dd, J = 7.3, 5.1 Hz, 3H), 5.41 – 5.27 (m, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 1.43 (d, J = 6.3 Hz, 6H).
13C{1H} NMR (100 MHz, CDCl3) δ 165.6, 160.2, 152.1, 145.0, 144.1, 141.8, 130.8, 130.1, 127.7,
123.3, 119.8, 119.7, 117.9, 116.1, 114.2, 109.2, 69.2, 55.4, 28.1, 22.0. HRMS (ESI): calcd for
C23H23N2O3[M+H]+ 375.1702, Found:375.1706.
isobutyl 9-methyl-4-(naphthalen-2-yl)-9H-pyrido[2,3-b]indole-2-carboxylate (5i)
1
Yield:51 mg (65%), yellow solid, m.p.177–179 °C, H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 8.07
(d, J = 8.4 Hz, 1H), 8.02 (d, J = 5.9 Hz, 1H), 8.02 – 7.94 (m, 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.72 (t, J =
12.2 Hz, 1H), 7.61 (dd, J = 9.1, 5.3 Hz, 2H), 7.51 (dd, J = 14.6, 7.6 Hz, 2H), 7.06 (t, J = 7.3 Hz, 1H),
5.47 – 5.33 (m, 1H), 4.11 (s, 3H), 1.47 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.5,
150.9, 144.0, 143.1, 140.9, 134.9, 132.3, 132.3, 127.5, 127.3, 126.9, 126.9, 125.8, 125.7, 125.5, 122.3,
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118.9, 118.5, 116.9, 115.2, 108.2, 76.3, 76.0, 75.7, 68.3, 27.2, 20.9. HRMS (ESI): calcd for
C26H23N2O2[M+H]+ 395.1759, Found:395.1768.
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benzyl 9-methyl-4-(thiophen-2-yl)-9H-pyrido[2,3-b]indole-2-carboxylate (5j)
1
Yield: 55 mg (70%), yellow solid, m.p.75–77 °C, H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.0 Hz,
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1H), 8.03 (s, 1H), 7.61 – 7.46 (m, 6H), 7.44 – 7.33 (m, 3H), 7.29 – 7.25 (m, 1H), 7.17 (t, J = 7.2 Hz,
1H), 5.50 (s, 2H), 4.06 (s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ165.7, 152.1, 143.3, 141.9, 139.3,
137.9, 136.0, 129.3, 128.6, 128.4, 128.3, 128.2, 127.9, 127.7, 127.4, 123.3, 120.1, 119.4, 118.7, 116.5,
109.3, 67.3, 29.7. HRMS (ESI): calcd for C24H19N2O2S[M+H]+ 399.1167, Found:399.1169.
benzyl 4-(furan-2-yl)-9-methyl-9H-pyrido[2,3-b]indole-2-carboxylate (5k)
1
Yield: 49 mg (65%), yellow solid, m.p.49–51, °C H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 8.1 Hz,
1H), 8.18 (s, 1H), 7.77 (s, 1H), 7.57 (dd, J = 17.3, 8.0 Hz, 3H), 7.49 – 7.34 (m, 4H), 7.33 – 7.23 (m,
1H), 7.10 (d, J = 3.3 Hz, 1H), 6.67 (s, 1H), 5.50 (d, J = 6.4 Hz, 2H), 4.02 (d, J = 7.1 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 165.8, 152.6, 151.8, 143.7, 143.3, 142.1, 136.1, 132.6, 128.6, 128.4, 128.3,
128.1, 124.7, 120.2, 119.4, 115.0, 114.0, 112.2, 111.4, 109.01, 67.3, 28.1. HRMS (ESI): calcd for
C24H19N2O3[M+H]+ 383.1395, Found:383.1395.
(E)-benzyl 4-(2-(furan-2-yl)vinyl)-9-methyl-9H-pyrido[2,3-b]indole-2-carboxylate (5l)
1
Yield: 50 mg (61%), yellow solid, m.p.72–75 °C, H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 8.1 Hz,
1H), 8.18 (s, 1H), 7.77 (s, 1H), 7.62 – 7.51 (m, 4H), 7.47 (d, J = 7.1 Hz, 1H), 7.41 (t, J = 7.3 Hz, 2H),
7.38 – 7.33 (m, 1H), 7.33 – 7.21 (m, 2H), 7.10 (d, J = 3.3 Hz, 1H), 6.67 (s, 1H), 5.51 (s, 2H), 4.04 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.7, 152.6, 151.8, 143.7, 143.3, 142.1, 136.1, 132.7,
128.6, 128.4, 128.3, 128.1, 124.7, 120.2, 119.4, 115.1, 114.0, 112.3, 111.4, 109.1, 67.3, 28.1. HRMS
(ESI): calcd for C26H21N2O3[M+H]+ 409.1552, Found:409.1552.
methyl 9-(4-fluorobenzyl)-4-p-tolyl-9H-pyrido[2,3-b]indole-2-carboxylate (5m)
1
Yield:53 mg (63%), yellow solid, m.p.201–203 °C, H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.72
(d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.6 Hz, 2H), 7.40 – 7.15 (m, 6H), 7.00 (t, J = 7.5 Hz, 1H), 6.88 (t, J =
8.4 Hz, 2H), 5.71 (s, 2H), 3.95 (s, 3H), 2.42 (s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ 165.52,
162.35, 159.91, 150.70, 144.61, 142.55, 139.85, 137.90, 134.27, 131.8(d, J = 3 Hz), 128.5, 128.0(d, J =
8 Hz), 127.6, 126.9, 122.5, 118.9(d, J = 13 Hz), 117.6, 115.2, 114.4(d, J = 13 Hz), 109.0, 51.7, 43.6,
20.40. HRMS (ESI): calcd for C27H22FN2O2[M+H]+ 425.1665, Found:425.1669.
methyl 9-(3-bromobenzyl)-4-p-tolyl-9H-pyrido[2,3-b]indole-2-carboxylate (5n)
1
Yield:66 mg (68%), yellow solid, m.p.255–258 °C, H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.81
(d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.5 Hz, 2H), 7.50 – 7.35 (m, 5H), 7.32 (d, J = 8.2 Hz, 1H), 7.21 (d, J =
7.7 Hz, 1H), 7.17 – 7.07 (m, 2H), 5.79 (s, 2H), 4.03 (s, 3H), 2.51 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 165.5, 150.7, 144.7, 142.6, 139.8, 138.4, 137.9, 134.2, 129.7, 129.3, 129.2, 128.5, 127.6,
126.9, 124.9, 122.5, 121.7, 119.3, 118.9, 117.8, 115.3, 108.9, 51.7, 43.7, 20.4. HRMS (ESI): calcd for
C27H22BrN2O2[M+H]+ 485.0864, Found:485.0867.
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Yield: 46 mg (72%), yellow solid, m.p. 218–220 °C, 1H NMR (400 MHz, CDCl3) δ 11.22 (s, 1H), 8.21
(d, J = 7.2 Hz, 2H), 7.80 – 7.73 (m, 2H), 7.66 – 7.46 (m, 8H), 7.23 (t, J = 7.7 Hz, 1H), 7.00 (t, J = 7.6
Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.3, 153.1, 146.1, 140.1,
139.7, 139.3, 129.1, 128.8, 128.7, 128.7, 127.7, 126.4, 122.4, 120.7, 119.9, 119.6, 114.5, 112.8, 111.3.
. HRMS (ESI): calcd for C23H17N2[M+H]+ 321.1391, Found:321.1396.
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9-methyl-2,4-diphenyl-9H-pyrido[2,3-b]indole (5p)8
Yield:52 mg (77%), yellow solid, m.p. 145–148 °C, 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 7.6 Hz,
2H), 7.76 (d, J = 6.7 Hz, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.65 – 7.41 (m, 9H), 7.14 – 7.06 (m, 1H), 4.09
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.7, 152.5, 145.6, 140.9, 140.1, 139.4, 128.8, 128.7,
128.6, 127.3, 126.4, 122.5, 120.2, 119.5, 113.6, 112.1, 108.9, 27.8. HRMS (ESI): calcd for
C24H19N2[M+H]+ 335.1548, Found:335.1549.
9-methyl-2-phenyl-4-p-tolyl-9H-pyrido[2,3-b]indole (5q)
Yield: 58 mg (83%), yellow solid, m.p.189–192 °C, 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 7.7 Hz,
2H), 7.78 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.59 (s, 1H), 7.48 (ddd, J = 27.6, 15.6, 7.6 Hz,
7H), 7.11 (t, J = 7.2 Hz, 1H), 4.09 (s, 3H), 2.54 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.7,
152.6, 145.7, 140.9, 140.1, 138.5, 136.5, 129.4, 128.7, 128.7, 127.3, 126.3, 122.6, 120.3, 119.4, 113.6,
112.1, 108.9, 27.8, 21.5. HRMS (ESI): calcd for C25H21N2[M+H]+ 349.1704, Found:349.1709.
4-(4-fluorophenyl)-9-methyl-2-phenyl-9H-pyrido[2,3-b]indole (5r)
Yield: 57 mg (81%), yellow solid, m.p.172–175 °C, 1H NMR (400 MHz, CDCl3) δ 8.13 (t, J = 9.0 Hz,
2H), 7.62 (dd, J = 8.2, 5.6 Hz, 2H), 7.56 (d, J = 7.9 Hz, 1H), 7.48 – 7.34 (m, 6H), 7.19 (t, J = 8.7 Hz,
2H), 7.01 (t, J = 7.1 Hz, 1H), 3.99 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.3, 153.8, 152.5,
144.5, 140.9, 139.9, 135.3 (d, J = 4 Hz), 130.5(d, J =8 Hz), 128.7, 127.2, 126.5, 122.3, 120.1, 119.6,
115.7(d, J = 21 Hz), 113.5, 112.1, 109.0, 27.8. HRMS (ESI): calcd for C24H18FN2[M+H]+ 353.1454,
Found:353.1457.
isopropyl 6-bromo-9-methyl-4-(4-(trifluoromethyl)phenyl)-9H-pyrido[2,3-b]indole-2-carboxylate
(4bd)
Yield:75 mg (76%), yellow solid, m.p.210–213 °C, 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 5.7 Hz,
3H), 7.80 (d, J = 8.0 Hz, 2H), 7.72 (s, 1H), 7.65 (dd, J = 8.7, 1.4 Hz, 1H), 7.36 (t, J = 11.8 Hz, 1H),
5.38 (dp, J = 12.5, 6.2 Hz, 1H), 4.07 (s, 3H), 1.46 (d, J = 6.2 Hz, 6H). 13C{1H} NMR (100 MHz,
CDCl3) δ 164.9, 151.9, 145.1, 143.9, 141.7, 140.5, 131.2(q, J =31 Hz), 130.9, 129.1, 126.0 (q, J =4 Hz),
125.5, 122.7 (q, J =270 Hz), 120.7, 117.8, 114.7, 112.9, 110.9, 69.6, 28.3, 21.9. HRMS (ESI): calcd
for C23H19BrF3N2O2[M+H]+ 491.0582, Found:491.0583.
isopropyl 9-ethyl-4-(4-(trifluoromethyl)phenyl)-9H-pyrido[2,3-b]indole-2-carboxylate (4cd)
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