Synthesis of 2-Arylindoles through Pd(II)-Catalyzed Cyclization of Anilines with Vinyl Azides

Article abstract of DOI:10.1021/acs.joc.8b01618

Vinly azides are featured as electrophiles, nucleophiles, and radical acceptors in synthetic chemistry and have emerged as rapid and versatile synthons in the preparation of N-heterocyclic systems. Herein, a novel approach to 2-arylindoles via Pd(II)-catalyzed cyclization reaction of anilines with vinyl azides has been achieved, which furnishes the versatile 2-arylindoles with high efficieny and excellent regioselectivity.

Full text of DOI:10.1021/acs.joc.8b01618

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Article
Synthesis of 2-Arylindoles through Pd (II)-
Catalyzed Cyclization of Anilines with Vinyl Azides
Lianghua Jie, Lianhui Wang, Dan Xiong, Zi Yang, Di Zhao, and Xiuling Cui
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01618 • Publication Date (Web): 13 Aug 2018
Downloaded from http://pubs.acs.org on August 13, 2018
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Synthesis of 2-Arylindoles through Pd (II)-Catalyzed Cyclization of
Anilines with Vinyl Azides
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Lianghua Jie, Lianhui Wang,* Dan Xiong, Zi Yang, Di Zhao, and Xiuling Cui*
Engineering Research Center of Molecular Medicine, Ministry of Education, Key Laboratory of Fujian
Molecular Medicine, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical
Sciences, Huaqiao University, Xiamen, 361021, P. R. China.
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ABSTRACT: Vinly azides feature as electrophile, nucleophile and radical acceptor in synthetic
chemistry, which have emerged as rapid and versatile synthon in the preparation of Nꢀheterocyclic
systems. Herein, a novel approach to 2ꢀarylindoles via Pd(II)ꢀcatalyzed cyclization reaction of
anilines with vinyl azides has been achieved, which furnishs the vesatile 2ꢀarylindoles with high
efficieny and excellent regioselectivity.
INTRODUCTION
Indole is not only widely found in natural products, but also a key structural unit in a large number
of synthetic drugs.1 By this token, indole and its derivatives are one kind of heterocyclic
compounds in the field of skeletal modification.2 Among them, 2ꢀarylindoles are the important
moiety of many natural products as well as drug components.3 Consequently, chemists have thus
far been pursuing the efficient methods for the regioselective synthesis of 2ꢀarylindoles, such as
the Fischer4 and Larock5 indole synthesis (Scheme 1a, b). However, these methods possess poor
chemoselectivity especially with unsymmetrical carbonyl and alkyne substrates. In the past
decades, transitionꢀmetalꢀcatalyzed direct C―H bond activations proves to be powerful protocol
in the preparation of indole derivatives.6 In this context, the easiest way was to decorate the core
indole structure itself through metalꢀcatalyzed direct 2ꢀarylation reactions (Scheme 1c).7
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Alternatively, 2ꢀarylindoles could be obtained through transitionꢀmetalꢀcatalyzed cyclization of
orthoꢀNꢀsubstituted styrene or phenylacetylene derivatives, which would take multiꢀsteps and
therefore increases the synthetic costs (Scheme 1d).8 Palladiumꢀcatalyzed oxidative cyclization of
Nꢀaryl enamines derived from anilines and ketones represents more promising protocol along with
the pioneering contributions from Glorius and Yoshikai (Scheme 1e).9 More recently, alternative
appealing strategy involving the direct intermolecular dehydrogenation coupling of anilines with
C2 fragments, such as alkenes10 and their analogs11 was explored (Scheme 1f). However, some
challenges still remain, such as chemoꢀ or regioselectivity and relatively harsh reaction conditions.
Therefore, it is would be highly desirable to explore more efficiently and regioselectively
synthetic protocols.
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The divergent modes of reactivity of vinyl azides, which occur due to their distinct
azideꢀappended olefin motif, have been explored in various annulation reactions for the
construction of various Nꢀheterocyclies.12,13 With our ongoing efforts to the
transitionꢀmetalꢀcatalyzed C―H bond functionalisations,14 we reported herein an efficient strategy
for the synthesis of 2ꢀarylindoles via Pd(II)ꢀcatalyzed cyclization of anilines with vinyl azides as
the coupling partner (Scheme 1). This protocol features good functional group tolerance and
provides 2ꢀarylindoles under mild reaction conditions. Moreover, the thermal decomposition of
vinyl azides to 2Hꢀazirines ensured an inducing migratory insertion process, which promised the
2ꢀarylindole transformations with excellent chemoꢀ and regioselectivities.
Scheme 1. Strategies for the regioselective 2-arylindole syntheses
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RESULTS AND DISCUSSION
At the outset of our investigation, we chose the readily available Nꢀphenylꢀ2ꢀaminopyridine (1a)
and (1ꢀazidovinyl)ꢀbenzene (2a) as model substrates to screen the reaction conditions (Table 1).
The cyclization product 3aa was obtained in 19% yield when applying Pd(OAc)2 as the catalyst
and 1,4ꢀbenzoquinone(BQ) as the oxidant (entry 1). The structure of 3aa was confirmed by Xꢀray
single crystal diffraction.15 Further studies showed that TFA exhibit positive effect and led to the
target product 3aa in 30% yield (entry 1 vs entry 2). Next, oxidants including BQ, TBHP, K2S2O8
and AgNO3 were explored, and K2S2O8 could efficiently facilitate the cyclization (entry 2 vs
entries 3ꢀ5). Screening various palladium catalysts proved that Pd(TFA)2 was superior to other
palladium salts in this transformation (entry 4 vs entries 6ꢀ8). Besides, supplementary
investigation of the reaction temperature revealed that 75 °C was most suitable, giving 3aa in 58%
yield (entries 9ꢀ10). Notably, addition of a catalytic amount of DABCO could efficiently
accelerate this cyclization process (entries 11ꢀ13).16 With the combination of Pd(TFA)2, K2S2O8
and DABCO, organic solvents such as toluene, DMF, and THF were then screened and toluene
gave the optimal performance (entry 12 vs entries 14ꢀ15). The yield of the target product 3aa
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declined by decreasing the loading of Pd(TFA)2 to 5.0 mol% (entry 16). In addition, control
experiments indicated that the cyclization was completely inefficient in the absence of Pd(TFA)2,
HOAc and/or BQ (entries 17ꢀ20). Finally, several popular transition metal catalysts including
[Cp*RhCl2]2, [Cp*CoI2(CO)], [Cp*IrCl2]2 and [(pꢀCymene)RuCl2]2 were explored as well,
however, failed to promote this reaction. It should be noteworthy that pyrimidine as directing
group had a detrimental effect for the current transformation comparing to the pyridine, probably
due to its appropriate electron effect in the initial coordination with the palladium species and the
following transfer processes (entry 12 vs entry 21).17
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Table 1. Optimization of various reaction parametersa
Entry
Catalyst
Oxidant
(equiv)
Additive
(equiv)
T
Yield%
(10 mol%)
(°C)
1
Pd(OAc)2
BQ (2.0 )
HOAc (1.5)
TFA (1.5 )
TFA (1.5)
90
90
90
90
90
90
90
90
60
75
75
19%
31%
30%
41%
30%
32%
49%
36%
22%
58%
65%
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
BQ (2.0)
3
TBHP (2.0)
K2S2O8(2.0)
AgNO3(2.0)
K2S2O8(2.0)
K2S2O8(2.0)
K2S2O8(2.0)
K2S2O8(2.0)
K2S2O8(2.0)
K2S2O8(2.0)
4
TFA (1.5)
5
TFA (1.5)
6
TFA (1.5)
7
Pd(TFA)2
Pd(CH3CN)2Cl2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
TFA (1.5)
8
TFA (1.5)
9
TFA (1.5)
10
11
TFA (1.5)
TFA (1.5)
DABCO (0.1)
TFA (1.5)
DABCO (0.2)
TFA (1.5)
12
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
K2S2O8(2.0)
K2S2O8(2.0)
K2S2O8(2.0)
K2S2O8(2.0)
75
75
75
75
83%
55%
trace
46%
13
DABCO (0.4)
TFA (1.5)
14b
15c
DABCO (0.2)
TFA (1.5)
DABCO (0.2)
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16d
Pd(TFA)2
K2S2O8(2.0)
TFA (1.5)
75
66%
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5
6
7
8
9
DABCO (0.2)
17
18
19
20
21e
/
BQ (2.0)
/
HOAc (1.5)
90
90
90
NR
NR
NR
Pd(TFA)2
Pd(TFA)2
/
BQ (2.0 )
/
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Pd(TFA)2
Pd(TFA)2
/
HOAc (1.5)
90
75
<5%
35%
K2S2O8(2.0)
TFA (1.5)
DABCO (0.2)
a Reaction conditions: 1a (0.2 mmol) and 2a (0.3 mmol) in PhMe under air for 12h unless
otherwise noted. bDMF as solvent. cTHF as solvent. dPd(TFA)2 (5 mol%).
e(Nꢀphenylꢀ2ꢀaminopyrimidine) (1b) was loaded instead of 1a. BQ=1,4ꢀbenzoquinone;
TBHP= tertꢀbutyl hydroperoxide; DABCO=triethylenediamine. TFA=Trifluoroacetic acid.
With the optimized catalytic system in hand, various anilines 1 were employed to examine the
generality of the current methodology with (1ꢀazidovinyl)benzene (2a) (Scheme 2). In general,
incorporation of electronꢀdonating (1cꢀf) or ꢀwithdrawing (1gꢀk) group at the para position on the
benzene ring was well tolerated. Concretely, substrates bearing electronꢀrich substituent afforded
good yields (3ca-3fa), whereas electronꢀdeficient groups, such as halide (1g-1i), trifluoromethyl
(1j) and carbonyl (1k) groups led to the 2ꢀphenylindole products in moderate yields. Moreover,
functional groups at the meta position were investigated. Notably, in the case of anilines with
metaꢀsubstituent (1hꢀn), excellent regioselectivities at the less hindered C―H bond were observed.
The reaction of orthoꢀmethylaniline (1o) smoothly proceeded as well, delivering the target product
(1oa) in 54% yield.
Scheme 2. Pd(II)-catalyzed deamination cyclization of anilines 1 with vinyl azide 2a
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Next, we examined the scope of vinyl azides
2 (Scheme 3). A range of functional groups
including methyl (2b), tertꢀbutyl (2c), halide (2d-2f), nitro (2g) and trifluoromethyl (2h
)
were well tolerated under the standard reaction conditions. In accordance with aniline
substrates, vinyl azides bearing para and meta moieties on the benzene ring reacted
smoothly, and electronꢀrich groups other than electronꢀdeficient ones could accelerate the
conversion more efficiently. In contrast, transformation of substrates (2l
ꢀm) with aniline
(
1a) generated the target products in lower yields perhaps due to the steric hindrance.
Moreover, 1,2ꢀdiaryl vinyl azide 2n proceeded smoothly and the cyclization product 3an
was obtained in 52% yield.
Scheme 3. Pd(II)-catalyzed deamination cyclization of 2-aminopyridine 1a with vinyl
azides 2
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To gain insight into the mechanism of this cyclization reaction, kinetic isotope effect
experiments were first conducted (Scheme 4). A KIE of 1.4 was identified in the
independent experiments of vinyl azide 2a with 1a and [D]5-1a under this palladium
catalytic system, which symbolized the C―H bond cleavage was likely involved in the
rateꢀdetermining step (Scheme 4a). In addition, this deamination cyclization was carried
out in the presence of [D1]ꢀAcOH under the standard reaction conditions. However, no
orthoꢀdeuterium incorporation was observed both in the recycled aniline substrate 1a and
in the indole product 3aa, indicating a probably irreversible C―H activation process
(
Scheme 4b).
Scheme 4. KIE experiments
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Moreover, a series of control experiments was conducted. To this end, a SETꢀtype process could
be ruled out by successfully performing the deamination reaction in the presence of stoichiometric
amounts of TEMPO (Scheme 5a). Besides, 3ꢀphenylꢀ2Hꢀazirine (4) was applied to the
deamination reaction with aniline 1a delivering to the cyclization product 3aa in 39% yield, which
indicated the formation of 2Hꢀazirine from azide 2 by the acceleration of DABCO would involve
in the cyclization process (Scheme 5b).16 Finally, HRMS analysis indicated the final deamination
cyclization process likely underwent an intramolecular nucleophilic addition from intermediate 5
and 6(Scheme 5c).
Scheme 5. Mechanistic investigations
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a)
N3
4
5
6
standard conditions
NH
N
+
N
N
TEMPO (2.0 equiv)
7
8
2a
1a
3aa:
81% yield
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b)
N
N
NH
standard conditions
+
N
N
1a
4
3aa: 39% yield (with DABCO);
3aa: 40% yield (without DABCO)
2-py
c)
2-py
NH
N3
NH2
Ph
N
standard conditions
60min
NH
+
N
Ph
NO2CCF3
1a
2a
5
6
[M + H]+: 288.1495,
Detected: 288.1496
[M + H]+: 400.1267,
Detected: 400.1267
On the basis of the experimental results and previous reports,18 the possible pathway was
proposed (Scheme 6). Initially, a chelationꢀassisted C―H bond activation occurred through a
concertedꢀmetalationꢀdeprotonation process19 to form the sixꢀmembered cyclopalladated
intermediate A. Then, two pathways were perhaps involved in the following transformations: 1)
palladacycle A underwent directly migratory insertion with vinyl azide 2a, and a subsequent
elimination of TFA from E furnish the sixꢀmembered intermediate F. Next, oxidative cyclization
yielded the indoline intermediate 7, which further transferred to the indole product 3aa through
the elimination of HN320. Meanwhile, the catalytically active Pd(II) species was regenerated by
oxidation of the Pd(0) species with K2S2O8; 2) thermal decomposition of vinyl azide 2a afforded
2Hꢀazirine 4 by the acceleration of DABCO, which subsequently underwent migratory insertion
into palladacycle A to give intermediate B. Next, reductive elimination of B generated
intermediate 5 with concurrent formation of Pd(0) species, which could be reoxidized to the active
catalytic Pd(II) species with K2S2O8. Finally, an intramolecular nucleophilic addition of
intermediate 5 led to intermediate 6, which further underwent deamination generating the indole
product 3aa.
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Scheme 6. Proposed reaction mechanism
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Finally, we were pleased to find that the 2ꢀpyridyl directing group could be steadily cleaved.21
Thus, 2ꢀarylindole 3aa was treated with methyl trifluoromethanesulfonate (MeOTf) to form a
pyridinium intermediate. The crude mixture was treated with NaOH/MeOH solution at 60 °C for
12 h to generate the NHꢀfree indole 7aa in 89% yield (Scheme 7).
Scheme 7. Removal of the N-pyridine group
CONCLUSION
In conclusion, we have developed a palladiumꢀcatalyzed highly regioselective cyclization
reaction of anilines with vinyl azides by using pyridine as a directing group, which delivered a
straightforward approach to 2ꢀarylindole derivatives with good functional group tolerance.
Moreover, the pyridyl moiety on the catalytic products could be efficiently removed to furnish the
versatile NHꢀfree indoles.
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EXPERIMENTAL SECTION
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General information. Unless otherwise stated, all commercial materials and solvents were used
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directly without further purification. Melting points were determined in open glass capillaries and
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1
were uncorrected. H NMR spectra were recorded on 400 MHz spectrometers, and 13C NMR
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spectra were recorded on a 100 MHz spectrometer. Chemical shifts (δ in ppm) were referenced to
tetramethylsilane (δ = 0 ppm) in CDCl3 as an internal standard at room temperature. 13C NMR
spectra were obtained by using the same NMR spectrometer and were calibrated with CDCl3 (δ =
77.00 ppm). Highꢀresolution mass spectra (HRMS) were equipped with an ESI source and a TOF
detector. Column chromatography was performed on silica gel (70−230 mesh ASTM) using the
reported eluents. Thinꢀlayer chromatography (TLC) was carried out on 4×15 cm plates with a
layer thickness of 0.2 mm (silica gel 60 F254).
Pyridyl/ pyrimidyl arylamines22ꢀ24, vinyl azides25ꢀ28 and 3ꢀphenylꢀ2Hꢀazirine28 were prepared
according to the reported procedures.
The representative procedure for the preparation of compounds 3. A flameꢀdried Schlenk tube
was cooled to ambient temperature. To this tube were added Nꢀphenylpyridinꢀ2ꢀamine (1a, 34.0
mg, 0.2 mmol, 1.0 equiv), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1 mg, 0.4 mmol),
DABCO (4.4 mg, 0.04 mmol), toluene (1.0 mL) and TFA (34.2 mg, 0.3 mmol), and then were
added (1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol). After that, the tube was heated at 75 °C for
12 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted
with EtOAc (3 x 50 mL). The organic layer was washed by brine (50 mL), then separated, dried
over Na2SO4 and filtered. The solvents were removed under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc/PE = 1:100→1:20, v/v) to afford the
desired product 3aa (44. 9mg, 83%) as a white solid.
Synthesis of 2-phenyl-1-(pyridin-2-yl)-1H-indole (3aa): The representative procedure was
followed using Nꢀphenylpyridinꢀ2ꢀamine (1a, 34.1 mg, 0.2 mmol), (1ꢀazidovinyl)benzene (2a,
43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1 mg, 0.4 mmol), TFA (34.2
mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h, purification by column
chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the desired product 3aa
(44.9 mg, 83%) as a white solid. M. p. = 130−131 °C. 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J =
4.8 Hz, 1H), 7.68 (dd, J = 10.0, 4.4 Hz, 2H), 7.60 (td, J = 7.8, 1.9 Hz, 1H), 7.31 – 7.18 (m, 8H),
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6.88 (d, J = 8.0 Hz, 1H), 6.81 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 152.1 (Cq), 149.2 (CH),
140.0 (Cq), 138.6 (Cq), 137.8 (CH), 132.8 (Cq), 128.8 (CH), 128.4 (CH), 127.5 (CH), 123.1 (CH),
122.1 (CH), 121.7 (CH), 121.4 (CH), 120.6 (CH), 111.6 (CH), 105.7 (CH). One Cq is invisible.
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HRMS (ESI) m/z calcd for C19H15N2 [M + H]+: 271.1230, Found 271.1230. The spectroscopic
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data were in accordance with those reported in Ref. 19.
Synthesis of 2-phenyl-1-(pyrimidin-2-yl)-1H-indole (3ba): The representative procedure was
followed using Nꢀphenylpyrimidinꢀ2ꢀamine (1b, 34.3 mg, 0.2 mmol), (1ꢀazidovinyl)benzene (2a,
43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1 mg, 0.4 mmol) , TFA (34.2
mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h, purification by column
chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the desired product 3ba
(19.1 mg, 35%) as a white solid. M. p. = 139−140 °C. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J =
4.8 Hz, 2H), 8.13 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.33 – 7.19 (m, 7H), 7.07 (dd, J =
4.8 Hz, 4.8 Hz, 1H), 6.80 (s, 1H).13C NMR (100 MHz, CDCl3) δ 158.2 (CH), 158.2 (CH), 158.2
(Cq), 140.5 (Cq), 138.2 (Cq), 134.0 (Cq), 129.4 (Cq), 128.2 (CH), 128.1 (CH), 127.1 (CH), 123.6
(CH), 122.2 (CH), 120.7 (CH), 117.6 (CH), 112.9 (CH), 108.2 (CH). HRMS (ESI) m/z calcd for
C18H14N3+ [M + H]+: 272.1182, Found 272.1186. The spectroscopic data were in accordance with
those reported in Ref. 7a.
Synthesis of 5-methyl-2-phenyl-1-(pyridin-2-yl)-1H-indole (3ca): The representative procedure
was followed using Nꢀ(pꢀtolyl)pyridinꢀ2ꢀamine (1c, 36.7 mg, 0.2 mmol), (1ꢀazidovinyl)benzene
(2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1 mg, 0.4 mmol) , TFA
(34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h, purification by column
chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the desired product 3ca
(47.1mg, 83%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 4.0 Hz, 1H), 7.68
(d, J = 8.4 Hz, 1H), 7.65 – 7.59 (m, 1H), 7.53 (s, 1H), 7.38 – 7.30 (m, 5H), 7.23 (dd, J = 7.4, 4.9
Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.81 (s, 1H), 2.55 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 152.3 (Cq), 149.2 (CH), 140.1 (Cq), 137.7 (CH), 137.1 (Cq), 133.0 (Cq),
130.7 (Cq), 129.1 (Cq), 128.8 (CH), 128.4 (CH), 127.4 (CH), 124.7 (CH), 121.9 (CH), 121.5 (CH),
120.4 (CH), 111.4 (CH), 105.5 (CH), 21.5 (CH3). HRMS (ESI) m/z calcd for C20H17N2+ [M + H]+:
285.1386, Found 285.1389.
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Synthesis of 5-methoxy-2-phenyl-1-(pyridin-2-yl)-1H-indole (3da): The representative procedure
was followed using Nꢀ(4ꢀmethoxyphenyl)pyridinꢀ2ꢀamine (1d, 40.0 mg, 0.2 mmol),
(1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1
mg, 0.4 mmol) , TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h,
purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the
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desired product 3da (50.3 mg, 84%) as a white solid. M. p. = 91−92 °C. H NMR (400 MHz,
CDCl3) δ 8.61 (d, J = 3.6 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.57 (ddd, J = 7.8, 7.8, 1.9 Hz, 1H),
7.28 – 7.23 (m, 5H), 7.18 (dd, J = 8.2, 4.9 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 9.0, 2.5
Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.73 (s, 1H), 3.87 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 155.2
(Cq), 152.2 (Cq), 149.2 (CH), 140.4 (Cq), 137.7 (CH), 133.8 (Cq), 132.8 (Cq), 129.3 (Cq), 128.7
(CH), 128.4 (CH), 127.5 (CH), 121.8 (CH), 121.5 (CH), 112.9 (CH), 112.6 (CH), 105.6 (CH),
102.3 (CH), 55.8 (CH3). HRMS (ESI) m/z calcd for C20H17N2O+ [M + H]+: 301.1335, Found
301.1335. The spectroscopic data were in accordance with those reported in Ref. 19.
Synthesis of 5-isopropyl-2-phenyl-1-(pyridin-2-yl)-1H-indole (3ea): The representative procedure
was followed using Nꢀ(4ꢀisopropylphenyl)pyridinꢀ2ꢀamine (1e, 42.1 mg, 0.2 mmol),
(1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1
mg, 0.4 mmol) , TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h,
purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the
desired product 3ea (49.9mg, 80%) as a yellowish liquid.1H NMR (400 MHz, CDCl3) δ 8.59 (dd,
J = 4.9, 1.2 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.56 – 7.51 (m, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.27 –
7.19 (m, 5H), 7.16 – 7.09 (m, 2H), 6.83 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H), 3.07 – 2.96 (m, 1H),
1.31 (d, J = 6.9 Hz, 6H).13C NMR (100 MHz, CDCl3) δ 152.3 (Cq), 149.2 (CH), 142.2 (Cq), 140.1
(Cq), 137.7 (CH), 137.2 (Cq), 133.0 (Cq), 128.9 (Cq), 128.8 (CH), 128.4 (CH), 127.4 (CH), 122.4
(CH), 121.9 (CH), 121.5 (CH), 117.6 (CH), 111.5 (CH), 105.7 (CH), 34.2 (CH), 24.7
(CH3).HRMS (ESI) m/z calcd for C22H21N2+ [M + H]+: 313.1699, Found 313.1700.
Synthesis of 5-(tert-butyl)-2-phenyl-1-(pyridin-2-yl)-1H-indole (3fa): The representative
procedure was followed using Nꢀ(4ꢀ(tertꢀbutyl)phenyl)pyridinꢀ2ꢀamine (1f, 45.2 mg, 0.2 mmol),
(1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1
mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h,
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purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the
desired product 3fa (52.7 mg, 81%) as a yellowish liquid. 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J
= 3.5 Hz, 1H), 7.78 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.64 (ddd, J = 7.8, 7.8, 1.9 Hz, 1H), 7.43 (dd,
J = 8.8, 1.9 Hz, 1H), 7.39 – 7.31 (m, 5H), 7.24 (dd, J = 7.1, 5.1 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H),
6.88 (s, 1H), 1.51 (s, 9H).13C NMR (100 MHz, CDCl3) δ 152.3 (Cq), 149.2 (CH), 144.4 (Cq),
140.1 (Cq), 137.7 (CH), 136.8 (Cq), 133.0 (Cq), 128.8 (CH), 128.6 (Cq), 128.4 (CH), 127.4 (CH),
121.8 (CH), 121.5 (CH), 121.4 (CH), 116.6 (CH), 111.2 (CH), 106.0 (CH), 34.7 (Cq), 32.0
(CH3).HRMS (ESI) m/z calcd for C23H23N2+ [M + H]+: 327.1856, Found 327.1854.
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Synthesis of 5-fluoro-2-phenyl-1-(pyridin-2-yl)-1H-indole (3ga): The representative procedure
was followed using Nꢀ(4ꢀfluorophenyl)pyridinꢀ2ꢀamine (1g, 37.6 mg, 0.2 mmol),
(1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1
mg, 0.4 mmol) , TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h,
purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the
desired product 3ga (38.2 mg, 66%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J
= 4.9, 1H), 7.62 (dd, J = 9.0, 4.5 Hz, 1H), 7.57 (ddd, J = 7.8, 7.8, 1.9 Hz, 1H), 7.29 (dd, J = 9.2,
2.5 Hz, 1H), 7.27 – 7.22 (m, 5H), 7.20 (ddd, J = 7.4, 4.9, 0.8 Hz, 1H), 6.95 (ddd, J = 9.1, 9.1, 2.5
1
Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.74 (s, 1H).13C NMR (100 MHz, CDCl3) δ 158.8 (d, JC‒F
=
237 Hz, Cq), 151.9 (Cq), 149.2 (CH), 141.5 (Cq), 137.9 (CH), 135.1 (Cq), 132.4 (Cq), 129.2 (d, 3JC‒
F = 10 Hz, Cq), 128.8 (CH), 128.4 (CH), 127.8 (CH), 122.0 (CH), 121.8 (CH), 112.6 (d, 3JC‒F = 10
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Hz, CH), 111.2 (d, JC‒F = 21 Hz, CH), 105.5 (d, JC‒F = 24 Hz, CH), 105.4 (d, JC‒F = 4 Hz,
CH).19F NMR (376 MHz, CDCl3) δ ꢀ122.9 (s).HRMS (ESI) m/z calcd for C19H14FN2+ [M + H]+:
289.1136, Found 289.1138.
Synthesis of 5-chloro-2-phenyl-1-(pyridin-2-yl)-1H-indole (3ha): The representative procedure
was followed using Nꢀ(4ꢀchlorophenyl)pyridinꢀ2ꢀamine (1h, 40.8 mg, 0.2 mmol),
(1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1
mg, 0.4 mmol) , TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h,
purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the
desired product 3ha (38.4 mg, 63%) as a yellowish liquid. 1H NMR (400 MHz, CDCl3) δ 8.63 (d,
J = 3.7 Hz, 1H), 7.63 (m, 2H), 7.59 (s, 1H), 7.29 – 7.22 (m, 6H), 7.16 (dd, J = 8.8, 2.1 Hz, 1H),
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6.84 (d, J = 8.0 Hz, 1H), 6.73 (s, 1H).13C NMR (101 MHz, CDCl3) δ 151.7 (Cq), 149.3 (CH),
141.2 (Cq), 137.9 (CH), 136.8 (Cq), 132.2 (Cq), 129.8 (Cq), 128.8 (CH), 128.5 (CH), 127.8 (CH),
126.9 (Cq), 123.2 (CH), 122.0 (CH), 122.0 (CH), 119.9 (CH), 112.8 (CH), 104.9 (CH).HRMS
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(ESI) m/z calcd for C19H14ClN2 [M + H]+: 305.0840, Found 305.0845. The spectroscopic data
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were in accordance with those reported in Ref. 7c.
Synthesis of 5-bromo-2-phenyl-1-(pyridin-2-yl)-1H-indole (3ia): The representative procedure
was followed using Nꢀ(4ꢀbromophenyl)pyridinꢀ2ꢀamine (1i, 49.6 mg, 0.2 mmol),
(1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1
mg, 0.4 mmol) , TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h,
purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the
desired product 3ia (39.0 mg, 56%) as a yellowish liquid. 1H NMR (400 MHz, CDCl3) δ 8.62 (d,
J = 3.7 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.59 (dd, J = 7.8, 1.9 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H),
7.30 – 7.19 (m, 7H), 6.82 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H).13C NMR (100 MHz, CDCl3) δ 151.7
(Cq), 149.3 (CH), 141.1 (Cq), 137.9 (CH), 137.2 (Cq), 132.2 (Cq), 130.4 (Cq), 128.8 (CH), 128.5
(CH), 127.9 (CH), 125.8 (CH), 123.0 (CH), 122.0 (CH), 122.0 (CH), 114.5 (Cq), 113.2 (CH),
104.8 (CH).HRMS (ESI) m/z calcd for C19H14BrN2 [M + H]+: 349.0335, Found 349.0336.The
+
spectroscopic data were in accordance with those reported in Ref. 19.
Synthesis of 2-phenyl-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-indole (3ja): The representative
procedure was followed using Nꢀ(4ꢀ(trifluoromethyl)phenyl)pyridinꢀ2ꢀamine (1j, 47.6 mg, 0.2
mmol), (1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8
(108.1 mg, 0.4 mmol) , TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h,
purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:10, v/v) yielded the
desired product 3ja (39.2 mg, 58%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 8.62 (dd,
J = 4.9, 1.2 Hz, 1H), 7.94 (s, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.59 (dd, J = 7.8, 1.9 Hz, 1H), 7.43 (d,
J = 8.7 Hz, 1H), 7.29 – 7.19 (m, 6H), 6.85 (d, J = 8.0 Hz, 1H), 6.83 (s, 1H).13C NMR (100 MHz,
CDCl3) δ 151.5 (Cq), 149.4 (CH), 141.9 (Cq), 139.7 (Cq), 138.1 (CH), 132.0 (Cq), 128.9 (CH),
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128.5 (CH), 128.1 (Cq), 128.0 (CH), 125.3 (q, JC‒F = 271 Hz, Cq), 123.7 (q, JC‒F = 31 Hz, Cq),
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122.3 (CH), 122.1 (CH), 119.6 (q, JC‒F = 4 Hz, CH), 118.2 (q, JC‒F = 4 Hz, CH), 112.0 (CH),
105.7 (CH).19F NMR (376 MHz, CDCl3) δ ꢀ60.45 (s).HRMS (ESI) m/z calcd for C20H14F3N2+ [M
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Synthesis of 1-(2-phenyl-1-(pyridin-2-yl)-1H-indol-5-yl)ethan-1-one (3ka): The representative
procedure was followed using 1ꢀ(4ꢀ(pyridinꢀ2ꢀylamino)phenyl)ethanꢀ1ꢀone (1k, 42.2 mg, 0.2
mmol), (1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8
(108.1 mg, 0.4 mmol) , TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h,
purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:4, v/v) yielded the
desired product 3ka (25.1 mg, 40%) as a yellowish liquid. 1H NMR (400 MHz, CDCl3) δ 8.65 (d,
J = 3.6 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 7.88 (dd, J = 8.8, 1.7 Hz, 1H), 7.70 – 7.61 (m, 2H), 7.32
– 7.21 (m, 6H), 6.90 (d, J = 8.0 Hz, 1H), 6.88 (s, 1H), 2.68 (s, 3H).13C NMR (100 MHz, CDCl3) δ
198.2 (Cq), 151.4 (Cq), 149.4 (CH), 141.7 (Cq), 140.9 (Cq), 138.1 (CH), 132.0 (Cq), 131.2 (Cq),
128.8 (CH), 128.5 (CH), 128.3 (Cq), 128.0 (CH), 123.3 (CH), 122.6 (CH), 122.3 (CH), 122.1
(CH), 111.5 (CH), 106.4 (CH), 26.7 (CH3).HRMS (ESI) m/z calcd for C21H17N2O+ [M + H]+:
313.1335, Found 313.1336.
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Synthesis of 6-methyl-2-phenyl-1-(pyridin-2-yl)-1H-indole (3la): The representative procedure
was followed using Nꢀ(mꢀtolyl)pyridinꢀ2ꢀamine (1l, 36.6 mg, 0.2 mmol), (1ꢀazidovinyl)benzene
(2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1 mg, 0.4 mmol) , TFA
(34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h, purification by column
chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the desired product 3la
(44.6 mg, 79%) as a white solid. M. p. = 144−145 °C. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J =
4.7 Hz, 1H), 7.61 (ddd, J = 7.8, 7.8, 1.9 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.27 –
7.19 (m, 6H), 7.03 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.76 (s, 1H), 2.45 (s, 3H).13C
NMR (100 MHz, CDCl3) δ 152.3 (Cq), 149.2 (CH), 139.4 (Cq), 139.0 (Cq), 137.8 (CH), 133.1 (Cq),
132.9 (Cq), 128.7 (CH), 128.3 (CH), 127.3 (CH), 126.6 (Cq), 123.1 (CH), 122.1 (CH), 121.5 (CH),
120.2 (CH), 111.4 (CH), 105.6 (CH), 22.0 (CH3).HRMS (ESI) m/z calcd for C20H17N2+ [M + H]+:
285.1386, Found 285.1387.
Synthesis of 6-fluoro-2-phenyl-1-(pyridin-2-yl)-1H-indole (3ma): The representative procedure
was followed using Nꢀ(4ꢀfluorophenyl)pyridinꢀ2ꢀamine (1m, 37.6 mg, 0.2 mmol),
(1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1
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mg, 0.4 mmol) , TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h,
purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the
desired product 3ma (38.1 mg, 66%) as a colorless liquid.1H NMR (400 MHz, CDCl3) δ 8.62 (d, J
= 4.0 Hz, 1H), 7.60 – 7.50 (m, 2H), 7.43 (d, J = 8.6 Hz, 1H), 7.27 – 7.13 (m, 6H), 6.95 (dd, J = 9.2,
2.1 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.74 (s, 1H).13C NMR (100 MHz, CDCl3) δ 161.5 (d, 1JC‒F
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= 238 Hz, Cq), 151.8 (Cq), 149.3 (CH), 140.4 (d, JC‒F = 4 Hz, Cq), 138.6 (d, JC‒F = 12 Hz, Cq),
137.9 (CH), 132.5 (Cq), 128.7 (CH), 128.4 (CH), 127.6 (CH), 125.2 (Cq), 121.8 (CH), 121.8 (CH),
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2
121.3 (d, JC‒F = 10 Hz, CH), 110.0 (d, JC‒F = 24 Hz, CH), 105.5 (CH), 98.6 (d, JC‒F = 27 Hz,
CH).19F NMR (376 MHz, CDCl3) δ – (118.99 – 119.13) (m).HRMS (ESI) m/z calcd for
C19H14FN2+ [M + H]+: 289.1136, Found 289.1136.The spectroscopic data were in accordance with
those reported in Ref. 7c.
Synthesis of 6-chloro-2-phenyl-1-(pyridin-2-yl)-1H-indole (3na): The representative procedure
was followed using Nꢀ(3ꢀchlorophenyl)pyridinꢀ2ꢀamine (1n, 40.8 mg, 0.2 mmol),
(1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1
mg, 0.4 mmol) , TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h,
purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the
desired product 3na (48.7 mg, 80%) as a yellowish liquid. 1H NMR (400 MHz, CDCl3) δ 8.64 (d,
J = 3.7 Hz, 1H), 7.85 (s, 1H), 7.61 (dd, J = 7.8, 1.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.34 – 7.20
(m, 7H), 6.83 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H).13C NMR (100 MHz, CDCl3) δ 151.6 (Cq), 149.4
(CH), 140.6 (Cq), 139.1 (Cq), 138.0 (CH), 132.2 (Cq), 128.8 (CH), 128.5 (CH), 127.8 (CH), 127.6
(Cq), 124.6 (CH), 122.0 (CH), 122.0 (CH), 121.76 (CH), 116.6 (Cq), 114.7 (CH), 105.4
(CH).HRMS (ESI) m/z calcd for C19H14ClN2+ [M + H]+: 305.0840, Found 305.0838.
Synthesis of 7-methyl-2-phenyl-1-(pyridin-2-yl)-1H-indole (3oa): The representative procedure
was followed using Nꢀ(oꢀtolyl)pyridinꢀ2ꢀamine (1o, 36.8 mg, 0.2 mmol), (1ꢀazidovinyl)benzene
(2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1 mg, 0.4 mmol) , TFA
(34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h, purification by column
chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the desired product 3oa
(30.6 mg, 54%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 3.1 Hz, 1H), 7.58
(td, J = 7.7, 1.9 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.30 – 7.16 (m, 6H), 7.06 (dd, J = 14.1, 7.6 Hz,
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2H), 6.93 (d, J = 7.2 Hz, 1H), 6.73 (s, 1H), 1.90 (s, 3H).13C NMR (100 MHz, CDCl3) δ 153.6 (Cq),
148.7 (CH), 141.7 (Cq), 137.6 (Cq), 137.4 (CH), 132.8 (Cq), 129.2 (CH), 129.1 (Cq), 128.1 (CH),
127.4 (CH), 125.4 (CH), 125.2 (CH), 123.4 (CH), 121.9 (Cq), 120.9 (CH), 118.7 (CH), 104.3 (CH),
19.6 (CH3).HRMS (ESI) m/z calcd for C20H17N2+ [M + H]+: 285.1386, Found 285.1386.
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Synthesis of 1-(pyridin-2-yl)-2-(p-tolyl)-1H-indole (3ab): The representative procedure was
followed
using
Nꢀphenylpyridinꢀ2ꢀamine
(1a,
34.0
mg,
0.2
mmol),
1ꢀ(1ꢀazidovinyl)ꢀ4ꢀmethylbenzene (2b, 48.0 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol),
K2S2O8 (108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After
12 h, purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded
the desired product 3ab (48.5 mg, 85%) as a yellowish liquid. 1H NMR (400 MHz, CDCl3) δ 8.72
(d, J = 6.1 Hz, 1H), 7.80 (d, J = 6.9 Hz, 1H), 7.78 – 7.73 (m, 1H), 7.64 (ddd, J = 7.8, 7.8, 1.9 Hz,
1H), 7.37 – 7.22 (m, 5H), 7.18 (s, 1H), 7.16 (s, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.88 (s, 1H), 2.41 (s,
3H).13C NMR (100 MHz, CDCl3) δ 152.3 (Cq), 149.2 (CH), 140.2 (Cq), 138.6 (Cq), 137.9 (CH),
137.4 (Cq), 129.9 (Cq), 129.2 (CH), 128.9 (Cq), 128.7 (CH), 123.0 (CH), 122.2 (CH), 121.7 (CH),
121.4 (CH), 120.6 (CH), 111.6 (CH), 105.3 (CH), 21.3 (CH3).HRMS (ESI) m/z calcd for
C20H17N2+ [M + H]+: 285.1386, Found 285.1387.
Synthesis of 2-{4-(tert-butyl)phenyl}-1-(pyridin-2-yl)-1H-indole (3ac): The representative
procedure was followed using Nꢀphenylpyridinꢀ2ꢀamine (1a, 34.0 mg, 0.2 mmol),
1ꢀ(1ꢀazidovinyl)ꢀ4ꢀ(tertꢀbutyl)benzene (2c, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol),
K2S2O8 (108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After
12 h, purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded
the desired product 3ac (51.5 mg, 79%) as a yellowish liquid. 1H NMR (400 MHz, CDCl3) δ 8.58
(dd, J = 4.9, 1.2 Hz, 1H), 7.72 – 7.58 (m, 2H), 7.50 (dd, J = 7.8, 2.0 Hz, 1H), 7.25 (d, J = 8.5 Hz,
2H), 7.21 – 7.08 (m, 5H), 6.84 (d, J = 8.0 Hz, 1H), 6.76 (s, 1H) , 1.27 (s, 9H).13C NMR (100 MHz,
CDCl3) δ 152.3 (Cq), 150.6 (Cq), 149.2 (CH), 140.2 (Cq), 138.7 (Cq), 137.8 (CH), 129.8 (Cq),
128.9 (Cq), 128.5 (CH), 125.4 (CH), 122.9 (CH), 122.2 (CH), 121.7 (CH), 121.4 (CH), 120.6
(CH), 111.6 (CH), 105.4 (CH), 34.6 (Cq), 31.4 (CH3).HRMS (ESI) m/z calcd for C23H23N2+ [M +
H]+: 327.1856, Found 327.1857.The spectroscopic data were in accordance with those reported in
Ref. 19.
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Synthesis of 2-(4-fluorophenyl)-1-(pyridin-2-yl)-1H-indole (3ad): The representative procedure
5
was
followed
using
Nꢀphenylpyridinꢀ2ꢀamine
(1a,
34.0
mg,
0.2
mmol),
6
7
8
9
1ꢀ(1ꢀazidovinyl)ꢀ4ꢀfluorobenzene (2d, 49.2 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol),
K2S2O8 (108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After
12 h, purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded
the desired product 3ad (43.1 mg, 76%) as a white solid. M. p. = 146−147 °C. 1H NMR (400 MHz,
CDCl3) δ 8.62 (d, J = 4.9 Hz, 1H), 7.67 – 7.60 (m, 3H), 7.27 – 7.18 (m, 5H), 7.00 – 6.92 (m, 2H),
6.90 (d, J = 8.0 Hz, 1H), 6.76 (s, 1H).13C NMR (100 MHz, CDCl3) δ 162.3 (d, 1JC‒F = 247 Hz, Cq),
151.9 (Cq), 149.4 (CH), 139.0 (Cq), 138.5 (Cq), 137.9 (CH), 130.5 (d, 3JC‒F = 8 Hz, CH), 128.9 (d,
4JC‒F = 3 Hz, Cq), 128.6 (Cq), 123.1 (CH), 122.0 (CH), 121.8 (CH), 121.5 (CH), 120.6 (CH), 115.5
(d, 2JC‒F = 21 Hz, CH), 111.5 (CH), 105.5 (CH). 19F NMR (376 MHz, CDCl3) δ ꢀ114.1 (s).HRMS
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(ESI) m/z calcd for C19H14FN2 [M + H]+: 289.1136, Found 289.1135.The spectroscopic data
+
were in accordance with those reported in Ref. 19.
Synthesis of 2-(4-chlorophenyl)-1-(pyridin-2-yl)-1H-indole (3ae): The representative procedure
was
followed
using
Nꢀphenylpyridinꢀ2ꢀamine
(1a,
34.0
mg,
0.2
mmol),
1ꢀ(1ꢀazidovinyl)ꢀ4ꢀchlorobenzene (2e, 52.7 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol),
K2S2O8 (108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After
12 h, purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded
the desired product 3ae (46.4 mg, 76%) as a white solid. M. p. =108−109 °C. 1H NMR (400 MHz,
CDCl3) δ 8.62 (d, J = 6.1 Hz, 1H), 7.69 – 7.62 (m, 3H), 7.26 – 7.17 (m, 7H), 6.92 (d, J = 8.0 Hz,
1H), 6.79 (s, 1H).13C NMR (100 MHz, CDCl3) δ 151.9 (Cq), 149.4 (CH), 138.8 (Cq), 138.6 (Cq),
138.0 (CH), 133.5 (Cq), 131.3 (Cq), 129.9 (CH), 128.6 (CH), 123.3 (CH), 122.0 (CH), 121.9 (CH),
121.5 (CH), 120.7 (CH), 111.5 (CH), 105.9 (CH). One Cq is invisible.HRMS (ESI) m/z calcd for
C19H14ClN2+ [M + H]+: 305.0840, Found 305.0845.
Synthesis of 2-(4-bromophenyl)-1-(pyridin-2-yl)-1H-indole (3af): The representative procedure
was
followed
using
Nꢀphenylpyridinꢀ2ꢀamine
(1a,
34.0
mg,
0.2
mmol),
1ꢀ(1ꢀazidovinyl)ꢀ4ꢀbromobenzene (2f, 66.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol),
K2S2O8 (108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After
12 h, purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded
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the desired product 3af (52.6mg, 77%) as a yellowish solid. M. p. = 126−127 °C. H NMR (400
MHz, CDCl3) δ 8.62 (d, J = 3.7 Hz, 1H), 7.71 – 7.60 (m, 3H), 7.40 (s, 1H), 7.38 (s, 1H), 7.28 –
7.16 (m, 3H), 7.13 (s, 1H), 7.11 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H).13C NMR (100 MHz,
CDCl3) δ 151.8 (Cq), 149.4 (CH), 138.8 (Cq), 138.6 (Cq), 138.0 (CH), 131.7 (Cq), 131.6 (CH),
130.2 (CH), 128.6 (Cq), 123.4 (CH), 122.0 (CH), 121.9 (CH), 121.7 (Cq), 121.6 (CH), 120.7 (CH),
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+
111.5 (CH), 106.0 (CH). HRMS (ESI) m/z calcd for C19H14BrN2 [M + H]+: 349.0035, Found
349.0037.The spectroscopic data were in accordance with those reported in Ref. 19.
Synthesis of 2-(4-nitrophenyl)-1-(pyridin-2-yl)-1H-indole (3ag): The representative procedure
was
followed
using
Nꢀphenylpyridinꢀ2ꢀamine
(1a,
34.0
mg,
0.2
mmol),
1ꢀ(1ꢀazidovinyl)ꢀ4ꢀnitrobenzene (2g, 57.1 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8
(108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h,
purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:3, v/v) yielded the
desired product 3ag (34.8 mg, 55%) as a yellow solid. M. p. = 145−146 °C. 1H NMR (400 MHz,
CDCl3) δ 8.60 (d, J = 3.5 Hz, 1H), 8.10 (d, J = 8.8 Hz, 2H), 7.74 (dd, J = 7.8, 1.9 Hz, 1H), 7.70 (d,
J = 7.5 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.32 – 7.18 (m, 3H), 7.06 (d, J
= 8.0 Hz, 1H), 6.96 (s, 1H).13C NMR (100 MHz, CDCl3) δ 151.5 (Cq), 149.7 (CH), 146.6 (Cq),
139.3 (Cq), 139.2 (Cq), 138.4 (CH), 137.5 (Cq), 128.8 (CH), 128.4 (Cq), 124.3 (CH), 123.7 (CH),
122.3 (CH), 121.9 (CH), 121.8 (CH), 121.3 (CH), 111.4 (CH), 108.2 (CH). HRMS (ESI) m/z
calcd for C19H14N3O2+ [M + H]+: 316.1081, Found 316.1083.
Synthesis of 1-(pyridin-2-yl)-2-{4-(trifluoromethyl)phenyl}-1H-indole (3ah): The representative
procedure was followed using Nꢀphenylpyridinꢀ2ꢀamine (1a, 34.0 mg, 0.2 mmol),
1ꢀ(1ꢀazidovinyl)ꢀ4ꢀ(trifluoromethyl)benzene (2h, 63.9 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02
mmol), K2S2O8 (108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04
mmol). After 12 h, purification by column chromatography on silica gel (EtOAc/PE =
1:100→1:10, v/v) yielded the desired product 3ah (46.5 mg, 69%) as a white solid. M. p. =
1
135−136 °C. H NMR (400 MHz, CDCl3) δ 8.59 (dd, J = 4.9, 1.2 Hz, 1H), 7.70 – 7.58 (m, 3H),
7.49 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.29 – 7.15 (m, 3H), 6.94 (d, J = 8.0 Hz, 1H),
6.86 (s, 1H).13C NMR (100 MHz, CDCl3) δ 151.7 (Cq), 149.5 (CH), 139.0 (Cq), 138.4 (Cq), 138.2
2
3
(CH), 136.4 (Cq), 129.2 (q, JC‒F = 32 Hz, Cq), 128.7 (CH), 128.6 (Cq) , 125.3 (q, JC‒F = 4 Hz,
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CH),124.2 (q, 1JC‒F = 273 Hz, Cq), 123.8 (CH), 122.1 (CH), 121.9 (CH), 121.7 (CH), 121.0 (CH),
111.6 (CH), 107.0 (CH).19F NMR (376 MHz, CDCl3) δ ꢀ62.4 (s). HRMS (ESI) m/z calcd for
6
7
+
C20H14F3N2 [M + H]+: 339.1104, Found 339.1105.The spectroscopic data were in accordance
8
9
with those reported in Ref. 19.
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Synthesis of 1-(pyridin-2-yl)-2-(m-tolyl)-1H-indole (3ai): The representative procedure was
followed
using
Nꢀphenylpyridinꢀ2ꢀamine
(1a,
34.0
mg,
0.2
mmol),
1ꢀ(1ꢀazidovinyl)ꢀ3ꢀmethylbenzene (2i, 47.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol),
K2S2O8 (108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After
12 h, purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded
the desired product 3ai (47.1 mg, 83%) as a white solid. M. p. = 106−107 °C. 1H NMR (400 MHz,
CDCl3) δ 8.61 (d, J = 3.6 Hz, 1H), 7.71 – 7.62 (m, 2H), 7.57 (dd, J = 7.7 Hz, 7.7 Hz, 1H), 7.23 –
7.14 (m, 4H), 7.10 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.87 (d,
J = 8.0 Hz, 1H), 6.78 (s, 1H), 2.26 (s, 3H).13C NMR (100 MHz, CDCl3) δ 152.2 (Cq), 149.2 (CH),
140.2 (Cq), 138.6 (Cq), 138.1 (Cq), 137.8 (CH), 132.6 (Cq), 129.5 (CH), 128.8 (Cq), 128.3 (CH),
128.2 (CH), 126.0 (CH), 123.0 (CH), 122.1 (CH), 121.6 (CH), 121.4 (CH), 120.6 (CH), 111.6
(CH), 105.6 (CH), 21.5 (CH3).HRMS (ESI) m/z calcd for C20H17N2 [M + H]+: 285.1386, Found
+
285.1388.The spectroscopic data were in accordance with those reported in Ref. 19.
Synthesis of 2-(3-fluorophenyl)-1-(pyridin-2-yl)-1H-indole (3aj): The representative procedure
was
followed
using
Nꢀphenylpyridinꢀ2ꢀamine
(1a,
34.0
mg,
0.2
mmol),
1ꢀ(1ꢀazidovinyl)ꢀ3ꢀfluorobenzene (2j, 49.3 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol),
K2S2O8 (108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After
12 h, purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded
the desired product 3aj (45.4 mg, 79%) as a white solid. M. p. = 133−134 °C. 1H NMR (400 MHz,
CDCl3) δ 8.62 (d, J = 3.7 Hz, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.63 (s, 1H), 7.27 – 7.17 (m, 4H),
7.02 (d, J = 7.8 Hz, 1H), 6.99 (s, 1H), 6.96 (s, 1H), 6.94 (s, 1H), 6.83 (s, 1H).13C NMR (100 MHz,
1
4
CDCl3) δ 162.6 (d, JC‒F = 246 Hz, Cq), 151.80 (Cq), 149.4 (CH), 138.7 (Cq), 138.6 (d, JC‒F = 3
Hz, Cq), 138.0 (CH), 134.9 (d, 3JC‒F = 8 Hz, Cq), 129.9 (d, 3JC‒F = 8 Hz, CH), 128.5 (Cq), 124.4 (d,
4JC‒F = 3 Hz, CH), 123.4 (CH), 121.9 (CH), 121.8 (CH), 121.6 (CH), 120.8 (CH), 115.5 (d, 2JC‒F
=
23 Hz, CH), 114.3 (d, 2JC‒F = 21 Hz, CH), 111.5 (CH), 106.3 (CH).19F NMR (376 MHz, CDCl3) δ
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ꢀ112.78 (td, J = 9.3, 6.1 Hz).HRMS (ESI) m/z calcd for C19H14FN2 [M + H]+: 289.1136, Found
5
289.1138.
6
7
8
Synthesis of 2-(3-chlorophenyl)-1-(pyridin-2-yl)-1H-indole (3ak): The representative procedure
9
was
followed
using
Nꢀphenylpyridinꢀ2ꢀamine
(1a,
34.0
mg,
0.2
mmol),
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1ꢀ(1ꢀazidovinyl)ꢀ3ꢀchlorobenzene (2k, 53.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol),
K2S2O8 (108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After
12 h, purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded
the desired product 3ak (48.2 mg, 79%) as a white solid. M. p. = 127−128 °C. 1H NMR (400 MHz,
CDCl3) δ 8.62 (d, J = 6.1 Hz, 1H), 7.71 – 7.61 (m, 3H), 7.40 (s, 1H), 7.38 (s, 1H), 7.25 – 7.17 (m,
3H), 7.13 (s, 1H), 7.11 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H).13C NMR (100 MHz, CDCl3)
δ 151.8 (Cq), 149.4 (CH), 138.8 (Cq), 138.6 (Cq), 138.1 (CH), 131.7 (Cq), 131.6 (CH), 131.6 (CH),
130.2 (CH), 130.2 (CH), 128.6 (Cq), 123.4 (CH), 122.0 (CH), 121.9 (CH), 121.7 (Cq), 121.6 (CH),
120.7 (CH), 111.5 (CH), 106.0 (CH).HRMS (ESI) m/z calcd for C19H14ClN2+ [M + H]+: 305.0840,
Found 305.0840.The spectroscopic data were in accordance with those reported in Ref. 19.
Synthesis of 1-(pyridin-2-yl)-2-(o-tolyl)-1H-indole (3al): The representative procedure was
followed
using
Nꢀphenylpyridinꢀ2ꢀamine
(1a,
34.0
mg,
0.2
mmol),
1ꢀ(1ꢀazidovinyl)ꢀ2ꢀmethylbenzene (2l, 47.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol),
K2S2O8 (108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After
12 h, purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded
the desired product 3al (26.2 mg, 46%) as a white solid. M. p. = 149−150 °C. 1H NMR (400 MHz,
CDCl3) δ 8.61 (d, J = 3.6 Hz, 1H), 7.71 – 7.62 (m, 2H), 7.57 (dd, J = 7.7 Hz, 7.7 Hz, 1H), 7.23 –
7.14 (m, 4H), 7.10 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.87 (d,
J = 8.0 Hz, 1H), 6.78 (s, 1H), 2.26 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 152.2 (Cq), 149.2 (CH),
140.2 (Cq), 138.6 (Cq), 138.1 (Cq), 137.8 (CH), 132.6 (Cq), 129.5 (CH), 128.8 (Cq), 128.3 (CH),
128.2 (CH), 126.0 (CH), 123.0 (CH), 122.1 (CH), 121.6 (CH), 121.4 (CH), 120.6 (CH), 111.6
(CH), 105.6 (CH), 21.5 (CH3). HRMS (ESI) m/z calcd for C20H17N2+ [M + H]+: 285.1386, Found
285.1388. The spectroscopic data were in accordance with those reported in Ref. 19.
Synthesis of 2-(2-chlorophenyl)-1-(pyridin-2-yl)-1H-indole (3am): The representative procedure
was
followed
using
Nꢀphenylpyridinꢀ2ꢀamine
(1a,
34.0
mg,
0.2
mmol),
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1ꢀ(1ꢀazidovinyl)ꢀ2ꢀchlorobenzene (2m, 53.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol),
K2S2O8 (108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After
12 h, purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded
the desired product 3am (40.9 mg, 67%) as a white solid. M. p. =132−133 °C. 1H NMR (400 MHz,
CDCl3) δ 8.52 (d, J = 4.8 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.55 (dd, J =
7.8, 1.9 Hz, 1H), 7.40 – 7.31 (m, 2H), 7.29 – 7.18 (m, 4H), 7.12 (dd, J = 7.4, 4.9 Hz, 1H), 6.88 (d,
J = 8.1 Hz, 1H), 6.79 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 151.8 (Cq), 149.0 (CH), 137.7 (CH),
137.3 (Cq), 136.5 (Cq), 134.0 (Cq), 132.7 (CH), 132.4 (Cq), 129.8 (CH), 129.4 (CH), 128.4 (Cq),
126.6 (CH), 123.3 (CH), 121.4 (CH), 121.2 (CH), 120.8 (CH), 120.4 (CH), 111.9 (CH), 107.4
(CH). HRMS (ESI) m/z calcd for C19H14ClN2+ [M + H]+: 305.0840, Found 305.0840.
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Synthesis of 2,3-diphenyl-1-(pyridin-2-yl)-1H-indole (3an): The representative procedure was
followed
using
Nꢀphenylpyridinꢀ2ꢀamine
(1a,
34.0
mg,
0.2
mmol),
(1ꢀazidoetheneꢀ1,2ꢀdiyl)dibenzene (2m, 66.6 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol),
K2S2O8 (108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After
12 h, purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) the
1
desired product 3an was yielded (36.1 mg, 52%) as a white solid. M. p. =162−163 °C. H NMR
(400 MHz, CDCl3) δ 8.60 (dd, J = 4.9, 1.2 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 8.0 Hz,
1H), 7.53 (dd, J = 7.7, 5.8 Hz, 1H), 7.38 – 7.33 (m, 2H), 7.33 – 7.28 (m, 2H), 7.27 – 7.22 (m, 2H),
7.22 – 7.09 (m, 7H), 6.81 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 151.9 (Cq), 149.2
(CH), 137.6 (CH), 137.5 (Cq), 136.0 (Cq), 134.7 (Cq), 131.8 (Cq), 131.0 (CH), 130.4 (CH), 128.3
(Cq), 128.3 (CH), 128.1 (CH), 127.5 (CH), 126.2 (CH), 123.5 (CH), 122.3 (CH), 121.7 (CH),
121.6 (CH), 119.7 (CH), 118.3 (Cq), 111.6 (CH). HRMS (ESI) m/z calcd for C25H19N2+ [M + H]+:
347.1543, Found 347.1544. The spectroscopic data were in accordance with those reported in Ref.
29.
Kinetic isotope effect experiments (Scheme 4): A flameꢀdried tube was cooled to ambient
temperature. To this tube were added Nꢀphenylpyridinꢀ2ꢀamine (1a, 34.0 mg, 0.2 mmol, 1.0 equiv)
or [D5]ꢀ1a (35.0 mg, 0.2 mmol, , 1.0 equiv), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1 mg,
0.4 mmol), DABCO (4.4 mg, 0.04 mmol), toluene (1.0 mL) and TFA (34.2 mg, 0.3 mmol), and
then were added (1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol). After that, the tube was heated at
75 °C for 90 min. The reaction mixture was cooled to ambient temperature, diluted with water and
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extracted with EtOAc (3 x 50 mL). The organic layer was washed by brine (50 mL), then
separated, dried over Na2SO4 and filtered. The solvents were removed under reduced pressure.
The residue was purified by silica gel column chromatography (EtOAc/PE = 1:100→1:20, v/v) to
afford the desired product 3aa (22.1 mg, 41%) as a white solid and [D4]ꢀ3aa (16.4 mg, 30%) as a
white solid, respectively (Scheme 4a).
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A flameꢀdried Schlenk tube was cooled to ambient temperature. To this tube were added 1a (17.0
mg, 0.2 mmol) , Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8 (108.1 mg, 0.4 mmol), DABCO (4.4 mg,
0.04 mmol), toluene (1.0 mL), TFA (34.2mg, 0.3 mmol) and[D1]ꢀHOAc (36.5mg, 0.6mmol), and
then were added (1ꢀazidovinyl)benzene (2b, 43.5 mg, 0.3 mmol). After that, the tube was heated at
75 °C for 90 min. The reaction mixture was cooled to ambient temperature, diluted with water and
extracted with EtOAc (3 x 50 mL). The organic layer was washed by brine (50 mL), then
separated, dried over Na2SO4 and filtered. The solvents were removed under reduced pressure.
The residue was purified by silica gel column chromatography (EtOAc/PE = 1:100→1:20, v/v) to
afford the desired product 3aa (21.5 mg, 40%) as a white solid, and the recycled substrate 1a (15.9
mg, 47%) as a white solid. The deuterium incorporation was estimated by 1HꢀNMR spectroscopy
(Scheme 4b).
Mechanistic investigations (Scheme 5): A flameꢀdried tube was cooled to ambient temperature.
To this tube were added Nꢀphenylpyridinꢀ2ꢀamine (1a, 34.0 mg, 0.2 mmol, 1.0 equiv), Pd(TFA)2
(6.6 mg, 0.02 mmol), K2S2O8 (108.1 mg, 0.4 mmol), DABCO (4.4 mg, 0.04 mmol), TEMPO (62.4
mg, 0.4 mmol), toluene (1.0 mL) and TFA (34.2 mg, 0.3 mmol), and then were added
(1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol). After that, the tube was heated at 75 °C for 12 h.
The reaction mixture was cooled to ambient temperature, diluted with water and extracted with
EtOAc (3 x 50 mL). The organic layer was washed by brine (50 mL), then separated, dried over
Na2SO4 and filtered. The solvents were removed under reduced pressure. The residue was purified
by silica gel column chromatography (EtOAc/PE = 1:100→1:20, v/v) to afford the desired product
3aa (43. 8mg, 81%) as a white solid (Scheme 5a).
The representative procedure was followed using Nꢀphenylpyridinꢀ2ꢀamine (1a, 34.2 mg, 0.2
mmol), 3ꢀphenylꢀ2Hꢀazirine (4, 35.2 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8
(108.1 mg, 0.4 mmol), TFA (34.1 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 12 h,
purification by column chromatography on silica gel (EtOAc/PE = 1:100→1:20, v/v) yielded the
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desired product 3aa (20.9 mg, 39%) as a white solid (Scheme 5b).
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8
The representative procedure was followed using Nꢀphenylpyridinꢀ2ꢀamine (1a, 34.1 mg, 0.2
mmol), (1ꢀazidovinyl)benzene (2a, 43.5 mg, 0.3 mmol), Pd(TFA)2 (6.6 mg, 0.02 mmol), K2S2O8
(108.1 mg, 0.4 mmol), TFA (34.2 mg, 0.3 mmol) and DABCO (4.4 mg, 0.04 mmol). After 60 min,
the reaction solution was detected by HRMS analysis (Scheme 5c).
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Removal of the N-pyridyl directing group (Scheme 7):8 Methyl trifluoromethanesulfonate (58.7
mg, 0.36 mmol) was added dropwise to a solution of 3aa (81.0 mg, 0.3 mmol) in CH2Cl2 (10 mL)
o
at 0 C, and the resulting solution was stirred at ambient temporature for 12 h. Then the solvent
was removed under vacuum, and the residue was dissolved in MeOH (2 mL). aq. NaOH solution
o
(2 M, 1.7 mL) was added, and stirring was continued at 60 C for 12 h. After cooling to ambient
temporature, the solvents were removed under reduced pressure, and the resulting residue was
extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4,
and concentrated in vacuo. The residue was purified by silica gel column chromatography
(EtOAc/PE = 1:0→1:20, v/v) to afford the desired product 2ꢀphenyl indole (7aa, 51.4 mg, 89%)
as a brown solid. M. p. = 192−193 °C. 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.63 (s, 1H),
7.62 (d, J = 7.4 Hz, 1H), 7.61 (s, 1H), 7.41 (dd, J = 7.7 Hz, 7.7 Hz, 2H), 7.36 (d, J = 8.1 Hz, 1H),
7.30 (dd, J = 7.4 Hz, 7.4 Hz, 1H), 7.22 – 7.15 (m, 1H), 7.11 (dd, J = 7.4 Hz, 7.4 Hz, 1H), 6.81 (d,
J = 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 137.9 (Cq), 136.9 (Cq), 132.4 (Cq), 129.3 (Cq),
129.1 (CH), 127.8 (CH), 125.2 (CH), 122.4 (CH), 120.7 (CH), 120.3 (CH), 111.0 (CH), 100.0
(CH). HRMS (ESI) m/z calcd for C14H12N+ [M + H]+: 194.0964, Found 194.0968. The
spectroscopic data were in accordance with those reported in Ref. 19.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
1H and 13C NMR spectra for the indole compounds and CIF file for compound 3aa.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: lianhui.wang@hqu.edu.cn
* Eꢀmail: cuixl@hqu.edu.cn
ORCDs
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Lianhui Wang: 0000ꢀ0002ꢀ9899ꢀ3148
5
Xiuling Cui: 0000ꢀ0001ꢀ5759ꢀ766X
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7
Notes
8
9
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
This research was supported by NSF of China (Nos. 21602064 and 21572072), Huaqiao
University (ZQNꢀPY317), and Postgraduates’ Innovative Fund in Scientific Research of Huaqiao
University.
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15 CCDC 1836805 (3aa) contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre.
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