Iridium(III)-Catalyzed Tandem Annulation of Pyridine-Substituted Anilines and α-Cl Ketones for Obtaining 2-Arylindoles

Article abstract of DOI:10.1021/acs.joc.0c01619

A facile and expeditious protocol for the synthesis of 2-arylindole compounds from readily available N-(2-pyridyl)anilines and commercially available α-Cl ketones through iridium-catalyzed C-H activation and cyclization is reported here. As a complementary approach to the conventional strategies for indole synthesis, the transformation exhibits powerful reactivity, tolerates a large number of functional groups, and proceeds with good to excellent yields under mild conditions, providing a straightforward method to obtain structurally diverse and valuable indole scaffolds. Furthermore, the reaction could be easily scaled up to gram scale.

Full text of DOI:10.1021/acs.joc.0c01619

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Article
Iridium(III)-Catalyzed Tandem Annulation of Pyridine-Substituted
Anilines and #-Cl Ketones for Accessing to 2-arylindoles
Xinfeng Cui, Xin Qiao, He-Song Wang, and Guosheng Huang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01619 • Publication Date (Web): 28 Sep 2020
Downloaded from pubs.acs.org on October 4, 2020
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The Journal of Organic Chemistry
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Iridium(III)-Catalyzed Tandem Annulation of Pyridine-Substituted
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Anilines and α‑Cl Ketones for Accessing to 2-arylindoles
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Xin-Feng Cui, § Xin Qiao, § He-Song Wang and Guo-Sheng Huang*
State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal
Chemistry and Resources Utilization of Gansu Province, Department of Chemistry, Lanzhou
University, Lanzhou 730000, China.
E-mail: hgs@lzu.edu.cn
R2
O
H
N
N
5 mol% [Cp*IrCl2]2
150 mol% NaF
Cl
R2
R1
R3
N
+
R1
N
MeOH, 90°C, 24h
H
R3
versatile 2-arylindoles synthesis
[3+2] annulation assisted by one sp3 carbon
high regioselectivity & broad substrate scope
36
examples
98%
Up to
yield
ABSTRACT: A facile and expeditious protocol for the synthesis of 2-arylindoles compounds
from readily available N-(2-pyridyl)anilines and commercially available α-Cl ketones through
iridium-catalyzed C-H activation and cyclization is reported here. As a complementary approach to
the conventional strategies for indole synthesis, the transformation exhibits powerful reactivity,
tolerates a large number of functional groups and proceeds in good to excellent yields under mild
conditions, providing a straightforward method to access structurally diverse and valuable indole
scaffolds. Further, the reaction could be easily scaled up to gram scale.
INTRODUCTION
Indole derivatives represent one of long-standing target for synthetic chemists because they are
prevalent in a variety of engrossing compounds, such as functional materials, pharmaceuticals and
diverse bioactive natural products 1. Consequently, a variety of synthetic methodologies have been
developed for the synthesis of such scaffolds. In particular, the Fischer indole synthesis2 and
Larock’s indole synthesis3 represent valuable synthetic protocols. Other effective synthetic methods
including Bischler synthesis4, Sundberg synthesis5, Bartoli synthesis6, Fukuyama synthesis7, etc.
have been versatile tools for the construction of indole framework. Despite these great developments,
these typical synthetic methods still face some disadvantages, such as poor selectivity towards
reaction substrates, low functional group compatibility, and harsh conditions. Hence, designing
simpler and more practical procedures for realizing indoles synthesis from general available
substrates is highly desirable. Recently, directly synthesizing indoles based on transition-metal
catalytic C-H bond activation has attracted much attention owing to its remarkable potential for
receiving high regioselective and atom-economy8. This proposal takes advantage of the ubiquitous
C-H bond in unactivated arenes as the direct source. For example, transition-metal-catalyzed C-H
activation starting from aniline derivatives with alkynes9 or diazo compounds10 has been
demonstrated (Scheme 1, eq I). In 2019, our group reported the Ru(II)-catalyzed construction of 2-
arylindole from tandem C-H activation/annulation of N-(2-pyridyl)anilines with sulfoxonium
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ylides11 (Scheme 1, eq II). Subsequently, Wu and Cui group reported the similar work by using
different catalysts, respectively12. Cui’s group reported an efficient strategy for the synthesis of 2-
arylindoles via palladium-catalyzed cyclization of anilines with vinyl azides as the coupling
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partner13. Liu’s group described a Rh(III)-catalyzed C-H activation/annulation of hydrazines with
sulfoxonium ylides as carbene precursors affording 1-aminoindole derivatives14. Besides, the
construction of indole scaffolds based on transition-metal catalyzed C-H activation-annulation
cascade has many reports15. Among them, sp-carbons, sp2-carbons or metal carbenes precursors
were critical coupling partners in these annulation reactions. To the best of our knowledge, sp3-
carbon synthons have been rarely reported for the construction of 2-arylindoles derivatives.
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I. reported work:
O
N2
O
O
OR2
OR2
R1
R2
H
R1
R2
N
R1
[M]
M = Rh, Ru, Ir
R
R1
[M]
M = Rh, Ru, Ni
N
N
R
R
II. our previous work:
H
N
R
O
O
S
cat. [Ru]
R1
R2
R1
R2
+
N
H
R
R2=Alkyl, Aryl
R=2-Pyridyl
R2
This work:
O
H
N
N
Ir(III) cat.
90°C
Cl
R3
R2
R1
N
+
N
R1
R3
Scheme 1. Transition-Metal-Catalyzed Strategies for the Synthesis of Indoles from Anilines
derivatives.
Very recently, α-Cl ketones have clearly emerged as versatile synthetic reagents in synthetic
chemistry, among them, transformations involving transition-metal-catalyzed inert C-H
activation/annulation with α-Cl ketones are especially appealing. In 2014, Glorius and co-workers
developed a Rh(III)-catalyzed redox-neutral annulations to synthesize diverse N-heterocycles
molecules using α-MsO/TsO/Cl substituted ketones as oxidized alkyne equivalents16. After that time,
Li’s group reported a similar synthetic strategy for isoquinolines via a Rh(III)-catalyzed C-H/N-H
functionalization with α-Cl/MsO/TsO ketones17. In 2018, Liu’s group developed a synthetic strategy
to directly access to 3-acylindoles via Rh(III)-catalyzed C-H activation and [4+1] annulation of N-
phenylamidines with readily accessible α-Cl ketones18. Thereafter, Wang and co-workers have
developed a ruthenium(II)-catalyzed acylmethylation of (hetero)arenes coupling with α-Cl
ketones/sulfoxonium ylides via C-H activation19. Despite these α-halo or pseudohaloketones
functioned as the key synthons to construct these privileged scaffolds, achieving Ir(III)-catalyzed
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C-H activation/annulation between anilines derivatives and α-Cl ketones is still an unexplored
subject. Inspired by those pioneering studies and as continous interest on developing novel and
efficient methods for synthesizing of heterocycles via CHA reactions(C-H bond activation)20, herein
we report sequential C-H activation of N-(2-pyridyl)anilines and coupling with α-Cl ketones, for
highly efficient access to 2-arylindoles derivatives (Scheme 1, eq III), in which the α-Cl ketones
function as the surrogates of alkynes, diazo compounds or sulfoxonium ylides compoounds.
RESULTS AND DISCUSSION
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Table 1. Optimization of Reaction Conditionsa
O
N
cat.
additive
N
X
+
NH
N
solvent, temp
2a
2b
2c
2d
, X=Cl
, X=Br
, X=OTs
, X=OMs
H
1a
3aa
Temp (℃) yieldb
X
entry
1
catalyst
additive
NaOAc
NaOAc
NaOAc
NaOAc
solvent
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Cl
X=Br
[IrCp*Cl2]2
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
100
80
90
90
90
24
15
0
2
[RhCp*Cl2]2
[Ru(p-cymene)Cl2]2
Cp*Co(CO)I2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
3
4
0
5
AgSbF6/NaOAc
AgBF4/NaOAc
AgNTf2/NaOAc
AgOTf/NaOAc
KOAc
8
6
6
7
13
trace
10
67
17
48
91
69
33
28
15
37
0
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Zn(OAc)2
NaHCO3
KH2PO4
NaF
KF
Et3N
NaF
NaF
CF3CH2OH
HFIP
NaF
NaF
DCE
NaF
PhCF3
MeOH
MeOH
MeOH
MeOH
MeOH
0
NaF
89
82
6
NaF
NaF
X=OTs
X=OMs
79
81
NaF
NaF
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.26 mmol), catalyst (5 mol%), Ag salts (20 mol%),
additive (1.5 equiv.) and a solvent (2.0 mL) at 90 ℃ in a pressure tube for 24 h, the vial was capped
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prior to heating. [b] Isolated yields after column chromatography.
To establish the optimal conditions for this C-H activation/annulation protocol, the reaction of
N-(2-pyridyl)anilines (1a) and α-Cl acetophenone(2a) was performed with different catalysts and
solvents. As shown in Table 1, the treatment of 1a (0.2 mmol) with 2a (0.26 mmol, 1.3 equiv.) in
the presence of [IrCp*Cl2]2 (5 mol%) and NaOAc (1.5 equiv) in MeOH at 90 ℃ for 24 h gave the
desired product 2-phenyl-1-(pyridin-2-yl)-1H-indole 3aa in 24% yield (entry 1). The structure of
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1
3aa was confirmed by H and 13C NMR spectroscopy and high-resolution mass spectrometry.
Subsequently, screening of transition-metal catalysts including [RhCp*Cl2]2, [Ru(p-cymene)Cl2]2
and [Cp*Co(CO)I2] revealed that [IrCp*Cl2]2 was the optimal choice (entries 1-4). The yield of the
target product 3aa decreased by using different silver salt as co-catalyst (entries 5-8). Based on these
results, we further replaced NaOAc with other additives, including KOAc, Zn(OAc)2, NaHCO3,
KH2PO4, NaF, KF and Et3N (entries 9-15). Surprisingly, a better yield for this transformation was
achieved in the presence of NaF. A further screening of the solvent revealed that MeOH was the
optimized choice (entries 16-20). Moreover, we further screened the effect of the temperature, lower
and raising the temperature led to inferior results (entries 21-22). Further exploration using different
α-substituted acetophenones, such as α-Br ,α-OTs and α-OMs acetophenones (2b-2d), indicated that
the new group was detrimental to the formation of the 2-arylindole scaffold (entries 23-25). Thus,
the conditions in entry 13 were adopted for subsequent studies.
Table 2. Scope of N-(2-pyridyl)anilines [a,b]
R2
N
H
N
O
5 mol% [Cp*IrCl2]2
150 mol% NaF
Cl
N
+
MeOH, 90°C, 24h
N
R2
R1
R1
2a
1
N
Me
N
N
N
R1
Me
N
N
N
N
R1
Br
Me
1
3va
, 91%
3aa
3ba
R =H,
, 91%
3ua
, 79%
1
3ja
R =F,
, 94%
1
R =F,
, 92%
1
3ka
R =Cl,
, 96%
1
3ca
R =Cl,
, 91%
1
3la
R =CF3,
, 95%
1
3da
, 93%
3ea
R =Br,
1
3ma
R =Me,
, 88%
1
R =Me,
, 97%
N
N
1
i
3fa
Cl
R = Pr,
, 95%
R2
N
N
1
3ga
R =OMe,
, 85%
1
3ha
R =CN,
, 86%
N
Me
1
3ia
R =CO2Et,
, 90%
N
3xa
, 97%
3wa
, 90%
R1
N
N
N
2
N
3pa
, 96%
R =5-Me,
Cl
Cl
N
N
2
3qa
R =5-F,
, 75%
2
3ra
R =5-Cl,
, 84%
3sa
1
2
3na
R =F,
, 88%
R =5-Br,
, 70%
3ta
1
2
3za,
70%
3oa
R =Me,
, 87%
R =4-Me,
, 95%
3ya,
80%
[a] Reaction conditions: 1a-1z (0.2 mmol), 2a (0.26 mmol), [IrCp*Cl2]2 (5 mol%), NaF(1.5 equiv.)
and MeOH (2.0 mL) at 90 ℃ for 24 h. [b] Isolated yields after column chromatography.
We next carried out the reactions of α-Cl ketone 2a with various N-(2-pyridyl)anilines (1a-1z)
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to explore the generality of the current methodology (Table 2). Notably, the chelation-assisted C-
H/N-H bond functionalization proved to be broadly applicable. Anilines substrates bearing electron-
donating or electron-withdrawing substituents at the para-, meta- and ortho- positions of the phenyl
ring all participated well, providing the corresponding annulated products (3ba–3oa) in good to
excellent yields. To our delight, this transformation showed excellent regioselectivities. The
completely regioselective coupling occurred at the less hindered position for meta-substituted
substrates (3ja-3ma). The substituent on the pyridines ring of N-(substituted phenyl)-2-pyridin-
amines showed minor steric effect on reaction activity, affording the products 3pa-3ta in moderate
to outstanding yields (70-96%). It is noteworthy that the halo-substituted (e.g., F, Cl, and Br)
substrates performed well to afford the corresponding products in sensational yields, thus offering
the opportunity for further transformations. Notably, several N-(2-pyridyl)anilines bearing two
substitutes (1u−1y) in the phenyl ring have also been examined, affording the corresponding indoles
(3ua-3ya) in moderate to good yields and high regioselectivity. When N-(naphthalen-2-yl)pyridine-
2-amine (1z) was used in the reaction, the 3-position C-H bond with less steric hindrance was
selectively functionalized to afford the corresponding product (3za) in 70% yield. When pyrimidine
was used as a directing functional group, we couldn’t get the desired product.
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Table 3. Scope of α-Cl Ketonesa,b
H
N
5mol% [Cp*IrCl2]2
150 mol% NaF
O
N
N
Cl
+
R3
R3
N
MeOH, 90°C, 24h
2b-2k
1a
3
N
F
3
N
3ab
Cl
R = p-MePh,
, 95%
N
3
N
N
3ac
R = p-OMePh,
, 92%
N
3
3ad
R = p-ClPh,
, 97%
, 97%
R3
3
3ae
R = p-BrPh,
F
, 98%
Cl
3af
3ag
, 97%
N
N
N
Cl
Cl
N
N
X
N
3aj
X=O,
X=S,
, 85%
3ak
3ai
, 78%
3ah
, 97%
, 82%
[a] Reaction conditions: 1a (0.2 mmol), 2b-2k (0.26 mmol), [IrCp*Cl2]2 (5 mol%), NaF(1.5 equiv.)
and MeOH (2.0 mL) at 90 ℃ for 24 h. [b] Isolated yields after column chromatography.
To further explore the scope of this transformation, more α-Cl ketones were investigated under
the optimized conditions (Table 3). First, diverse monosubstituted α-Cl acetophenones (2b−2e) and
disubstituted α-Cl acetophenones (2f−2h) were selected as the substrates for this reaction, furnishing
the desired products 3ab-3ah in good to excellent yields, in which electronic effects have no
significant effect in this transformation. The reaction also showed good tolerance toward other
ketones containing a naphthyl (3ai) with good yields. we were also pleased to find that
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heteroaromatic ketone derivatives 2j-k could also be employed in the transformation, affording the
corresponding products 3aj-3ak in moderate yields.
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9
To better understand the reaction mechanism, several control experiments were carried out
(Scheme 2). Initially, related H/D scrambling experiments with 1a were implemented in the absence
of α-Cl acetophenone 2a or not, in which a slight H/D exchange took place and the deuterated
product was observed (Scheme 2a). These outcomes clearly disclosed the fact that the ortho-
metalation step process was reversible in this transformation. Subsequently, the kinetic isotope
effect (KIE) experiment was implemented, and a deuterium competition experiment between
substrate 1a and 1a-d5 illustrated a KIE of kH/kD = 1.1 (Scheme 2b, top). Moreover, the kinetic
isotope effect of this reaction was measured on the basis of parallel experiments, and a KIE value
of 1.06 was obtained (Scheme 2b, bottom). The results suggested that the cleavage of the C-H bond
may not be included in the rate-determining step. An intermolecular competition reaction between
N-(4-methylphenyl)pyridin-2-amine 1e and N-(4-fluorophenyl)pyridin-2-amine 1b with 2a was
performed in a one-pot fashion. The NMR yield of 3ba was higher than that of 3ea, indicating a
higher reactivity for the electron-deficient substrate (Scheme 2c).
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To evaluate the synthetic utility of this transformation, a gram-scale preparation of product 3aa
was carried out with a remarkable yield of 93% (Scheme 3).
(a)
H/D exchange experiments
17%
H
H(D)
5 mol% [Cp*IrCl2]2
150 mol% NaF
H
N
H
N
Py
Py
MeOH, 90°C, 12h
CD3COOD (10 eq.)
H
H(D)
17%
1a
1a
d2- (92% recoved)
17% D
H(D)
H
N
H(D)
17%
N
5 mol% [Cp*IrCl2]2
150 mol% NaF
O
H
N
N
N
Cl
+
N
+
Ph
MeOH, 90°C, 12h
CD3COOD (10 eq.)
1a
0.2 mmol
2a
0.1 mmol
H(D)
17%
3aa+3aa-d1
1a
70%
60% recoved
competition and parallel KIE
(b)
standard conditions
competition KIE =1.1
1a
3aa+3aa-d4
+
-d5
1a
2a (1.0equiv), 2 h,21%
standard conditions
3aa
yield:18%
2a
+
1a
2 h
parallel KIE = 1.06
standard conditions
2 h
3aa-d4
2a
+
d5-1a
yield: 17%
(c) competition experiment
H
N
O
N
Py
+
Cl
standard conditions
12h
R
R
1b/1e
(R=F);
= 1:1
1e
2a
3ba
3ea
. R=Me
= 1.33
(1.0 equiv)
, R=F;
3ba/3ea
1b
(R=Me)
Scheme 2. mechanism studies.
H
N
O
N
5 mol% [Cp*IrCl2]2
150 mol% NaF
Cl
+
N
N
MeOH, 90°C, 36h
3aa
93% (isolated yield)
1a
(5mmol)
2a
(1.3 equiv)
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Scheme 3. Large-scale synthesis
[Cp*IrCl2]2
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H
N
3aa
Cp*IrCl2
N
H
1a
H2O+X-
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(X=Cl or F)
base (NaF)
HCl
NaCl+HF
N
H
N
HO IrCp*Cl2
N
Ph
N
Ir
H
D)
(
*Cp
Cl
A)
(
X
O
Ph
2a
Cl
N
NH IrCp*Cl2
O
H
N
Ph
Cl
(C)
N
Ir
Cp*
B)
O
Cl
(
Ph
Scheme 4. Proposed Reaction Mechanism.
According to these mechanistic investigations and the results of previous studies15-17, a
plausible reaction mechanism for the formation of 2-arylindoles was hypothesized (Scheme 4).
Initially, the dimeric precursor [Cp*IrCl2]2 was converted into [Cp*IrCl2] as an active catalyst. Then,
cyclometalation of the N-(2-pyridyl)anilines (1a) affords a six-membered iridacycle A via CMD
(concerted metalation-deprotonation) process. Coordination of oxygen atom of α-Cl acetophenone
(2a) gives a Ir(III) alkyl intermediate B, in which the nucleophilic C(aryl)-Ir species further attacks
the methylene group of α-Cl acetophenone to produce α-aryl ketone species C. Intramolecular
nucleophilic attack at the acyl group under the assistance of Cp*Ir(III) affords D, and subsequent
dehydration eventually furnishes the final product 3aa.
CONCLUSION
In summary, we have developed an unprecedented synthetic strategy to directly access practical 2-
arylindoles via Ir(III)-catalyzed C-H activation and [3+2] annulation of N-(2-pyridyl)anilines
with readily accessible α-Cl ketones. Also, the generality and practicability of this cyclization
reaction was reflected by a broad scope of substrates with diverse functional groups, large-scale
synthesis and good to excellent yields. Meanwhile, the discovery of α-Cl ketones as a coupling
partner may promote the development of indole skeleton construction. We believe that this strategy
will find its wide application in organic synthesis.
EXPERIMENTAL SECTION
General information.
Unless otherwise mentioned, all materials were commercially available and used without further
purification. N-(2-pyridyl)anilines 1a-1z21 are known compounds and synthesized according to
previous reported methods. The α-Cl ketones 2a-2k were commercially available. The solvent used
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in the experiment is commercially available without further purification or drying. The reaction set
up under air and performed in a pressure tube (capacity: 15.0 mL) with oil bath. Flash
Chromatography was performed with silica gel (200-300 mesh). Proton-1 nuclear magnetic
resonance (1H NMR) data were acquired at 400 MHz on a Bruker Ascend 400(400 MHz)
spectrometer, and chemical shifts are reported in delta (δ) units, in parts per million (ppm) downfield
from tetramethylsilane. Resonance patterns are reported with the notations s (singlet), d (doublet), t
(triplet), q (quartet), and m (multiplet). In addition, the notation br is used to indicate a broad signal.
Coupling constants (J) are reported in hertz (Hz). Carbon-13 nuclear magnetic resonance (13C NMR)
data were acquired at 100 MHz on a Bruker Ascend 400 spectrometer, chemical shifts are reported
in ppm relative to the center line of a triplet at 77.0 ppm for CDCl3. HRMS data obtained using a
Q-TOF instrument equipped with an ESI source.
General procedure for the synthesis of starting materials N-(2-pyridyl)anilines [21]
To an oven-dried flask charged with aniline (977.8 mg, 10.5 mmol, 150 mol %), 2-chloropyrimidine
(801.7 mg, 7.0 mmol, 100 mol %) and acetic acid (7 mL) in 1,4-dioxane (19 mL) was added. The
reaction mixture was stirred at 110 ℃ for 24 h and monitored by TLC. Upon completion, the mixture
was extracted with CH2Cl2 (3 × 20 mL) and washed with brine. The organic layer was dried over
Mg2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (n-
hexanes/EtOAc; silica gel) to give N-phenylpyrimidin-2-amine 1a (990.6 mg) in 82% yield.
General procedure for the synthesis of pyridinyl arylamines 1a-1z[21]
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To an oven-dried flask charged with aniline (1.4 g, 15 mmol, 100 mol %), 2-bromopyridine (2.4 g,
15 mmol, 100 mol %) was added. The reaction mixture was stirred at 160℃ for 7 h and monitored
by TLC. Upon completion, saturated NaHCO3 was added and the mixture was extracted with EtOAc
(3 × 15 mL). The combined organic phase was washed with brine and dried over Mg2SO4. The solid
was filtered off and the filtrate was evaporated in vacuum. The crude product was purified by flash
column chromatography (n-hexanes/EtOAc; silica gel) to give N-phenylpyridin-2-amine 1a (2.44
g) in 95% yield.
General procedure for the synthesis of d5-1a22
To an oven-dried flask charged with 2-bromopyridine (79 mg, 0.5 mmol), aniline-d5 (60 mg, 0.6
mmol) and potassium tert-butoxide (112 mg, 1 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol) and (±)-
BINAP (15.55 mg, 0.025 mmol) were added and the reaction vessel was flushed with N2 . Dry
toluene (2 mL) was added to the mixture through the septum. The reaction mixture was stirred at
120℃ for 6 h and monitored by TLC. Upon completion, water was added and the mixture was
extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine and dried
over Na2SO4. The organic layer was evaporated in vacuum and the crude product was purified by
flash column chromatography (Petroleum ether /EtOAc = 6:1; silica gel) to give d5-1a.
General procedure for the synthesis of products 3.
A pressure tube was charged with [IrCp*Cl2]2 (8mg, 5mol%), NaF(13mg, 1.5equiv), N-(2-pyridyl)
anilines (1, 0.2 mmol), and α-Cl acetophenone (2, 0.26 mmol), MeOH (2 mL) was then added and
the mixture was stirred at 90℃ for 24h. Then the solvent was evaporated and the crude product was
purified by column chromatography (silica gel) using PE/EA as the eluent to afford the desired
compound 3.
Representative procedure for synthesis of α-tosyloxyacetophenones/α-OMs acetophenone 23
To a solution of iodosobenzene (660 mg, 3.0 mmol) and p-toluenesulfonic acid monohydrate (567
mg, 3.0 mmol) or methanesulfonic acid (289mg, 3.0 mmol) in acetonitrile (15 ml), was added the
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acetophenone (2.0 mmol) and the reaction mixture was refluxed for 5 h. After the solution had
cooled to ambient temperature, the solvent was removed under vacuum, the unpurified product was
dissolved in CH2Cl2 (50 ml) and washed with NaHCO3(50 ml), water (50 ml), and then brine (50
ml). The product was purified by recrystallization from a toluene-hexane mixture.
9
Characterization data for the all products.
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2-phenyl-1-(pyridin-2-yl)-1H-indole(3aa)
White solid (49.1 mg, 91%), M.p. 132-134 ℃. 1H NMR (400 MHz, CDCl3) δ=
N
8.64 – 8.58 (m, 1H), 7.66 (dd, J = 11.5, 4.6 Hz, 2H), 7.57 (td, J = 7.7, 1.7 Hz,
1H), 7.29 –7.16 (m, 8H), 6.87 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H). 13C{1H}NMR
N
(101 MHz, CDCl3) δ= 152.0 (s), 149.1 (s), 139.9 (s), 138.4 (s), 137.6 (s), 132.6
3aa
(s), 128.6 (s), 128.2 (s), 127.3 (s), 122.9 (s), 121.9 (s), 121.5 (s), 121.3 (s),
120.5 (s), 111.4(s), 105.5 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C19H15N2 271.1230; Found: 271.1231.
5-fluoro-2-phenyl-1-(pyridin-2-yl)-1H-indole(3ba)
Coloress liquid (53.0 mg, 92%). 1H NMR (400 MHz, CDCl3) δ =8.63 (dd,
N
J = 4.9, 1.2 Hz, 1H), 7.66 – 7.56 (m, 2H), 7.33 – 7.19 (m, 7H), 6.95 (td, J
= 9.1, 2.5 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.75 (s, 1H). 13C{1H}NMR
N
(101 MHz, CDCl3) δ =159.9 (s), 157.5 (s), 151.8 (s), 149.1 (s), 141.4 (s),
F
3ba
137.8 (s), 134.9 (s), 132.3 (s), 129.1 (d, JCF = 10.3 Hz), 128.7 (s), 128.3 (s),
127.7 (s), 121.8 (d, JCF = 16.9 Hz), 112.4 (d, JCF = 9.4 Hz), 111.0 (d, JCF = 25.8 Hz), 105.4 (d, JCF = 11.2
Hz), 105.3 (d, JCF = 8.0 Hz).
HRMS (ESI) m/z: (M + H)+ Calcd for C19H14FN2 289.1136; Found: 289.1137.
5-chloro-2-phenyl-1-(pyridin-2-yl)-1H-indole(3ca)
Yellowish liquid (55.3 mg, 91%). 1H NMR (400 MHz, CDCl3) δ= 8.62
N
(dd, J = 4.8, 1.2 Hz, 1H), 7.63 – 7.56 (m, 3H), 7.29 – 7.20 (m, 6H), 7.16
N
(dd, J = 8.7, 2.1 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.72 (s, 1H).
13C{1H}NMR (101 MHz, CDCl3) δ= 151.6 (s), 149.2 (s), 141.2 (s), 137.8
Cl
3ca
(s), 136.8 (s), 132.1 (s), 129.7 (s), 128.7 (s), 128.3 (s), 127.7(s), 126.7 (s),
123.1 (s), 121.9 (s), 121.8 (s), 119.8 (s), 112.7 (s), 104.8 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C19H14ClN2 305.0840; Found: 305.0842.
5-bromo-2-phenyl-1-(pyridin-2-yl)-1H-indole(3da)
Yellowish liquid (64.7 mg, 93%). 1H NMR (400 MHz, CDCl3) δ =8.62
N
(dd, J = 4.6, 1.4 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.58 (ddd, J = 14.8,
N
10.3, 5.3 Hz, 2H), 7.30 – 7.22 (m, 7H), 6.83 (d, J = 8.0 Hz, 1H), 6.71 (s,
1H). 13C{1H}NMR (101 MHz, CDCl3) δ =151.6 (s), 149.2 (s), 141.0 (s),
Br
3da
137.8 (s), 137.1 (s), 132.0 (s), 130.3 (s), 128.7 (s), 128.3 (s), 127.7 (s),
125.6 (s), 122.9 (s), 121.9 (s), 121.9 (s), 114.4 (s), 113.1 (s), 104.7 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C19H14BrN2 349.0335; Found: 349.0336.
5-methyl-2-phenyl-1-(pyridin-2-yl)-1H-indole(3ea)
Colorless liquid (55.0 mg, 97%). 1H NMR (400 MHz, CDCl3) δ= 8.64 –
N
8.59 (m, 1H), 7.58 (ddd, J = 7.9, 4.5, 2.0 Hz, 2H), 7.44 (s, 1H), 7.30 –
N
7.22 (m, 5H), 7.18 (ddd, J = 7.4, 4.9, 0.9 Hz, 1H), 7.04 (dd, J = 8.5, 1.4
Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.72 (s, 1H), 2.45 (s, 3H).
Me
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13C{1H}NMR (101 MHz, CDCl3) δ =152.2 (s), 149.1 (s), 139.9 (s), 137.6 (s), 136.9 (s), 132.8 (s), 130.6
(s), 128.9 (s), 128.6 (s), 128.2 (s), 127.2 (s), 124.5 (s), 121.8 (s), 121.3 (s), 120.2 (s), 111.2 (s), 105.3 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C20H17N2 285.1386; Found: 285.1387.
7
8
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5-isopropyl-2-phenyl-1-(pyridin-2-yl)-1H-indole(3fa)
Yellowish liquid (59.2 mg, 95%). 1H NMR (400 MHz, CDCl3) δ= 8.60
N
(dd, J = 4.7, 1.4 Hz, 1H), 7.57 (ddd, J = 10.9, 9.7, 5.2 Hz, 2H), 7.49 (s,
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N
1H), 7.27 – 7.20 (m, 5H), 7.16 (ddd, J = 7.4, 4.9, 0.7 Hz, 1H), 7.10 (d, J
iPr
= 8.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.74 (s, 1H), 3.01 (dt, J = 13.8,
6.9 Hz, 1H), 1.30 (d, J = 6.9 Hz, 6H). 13C{1H}NMR (101 MHz, CDCl3)
3fa
δ= 152.2 (s), 149.1 (s), 142.1 (s), 140.0 (s), 137.6 (s), 137.1 (s), 132.8 (s), 128.7 (s), 128.6 (s), 128.2 (s),
127.2 (s), 122.2 (s), 121.7 (s), 121.3 (s), 117.4 (s), 111.3 (s), 105.5 (s), 34.1 (s), 24.5 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C22H21N2 313.1699; Found: 313.1697.
5-methoxy-2-phenyl-1-(pyridin-2-yl)-1H-indole(3ga)
White solid (51.0 mg, 85%), M.p. 91-92℃. 1H NMR (400 MHz, CDCl3)
N
δ =8.61 (d, J = 4.5 Hz, 1H), 7.65 – 7.54 (m, 2H), 7.25 (d, J = 7.2 Hz,
N
5H), 7.21 – 7.16 (m, 1H), 7.12 (d, J = 1.6 Hz, 1H), 6.91 – 6.80 (m, 2H),
6.73 (s, 1H), 3.87 (s, 3H). 13C{1H}NMR (101 MHz, CDCl3) δ= 155.2
MeO
3ga
(s), 152.1 (s), 149.0 (s), 140.3 (s), 137.6 (s), 133.7 (s), 132.7 (s), 129.2
(s), 128.6 (s), 128.2 (s), 127.3 (s), 121.7 (s), 121.3 (s), 112.8 (s), 112.4 (s), 105.5 (s), 102.2 (s), 55.7 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C20H17N2O 301.1336; Found: 301.1337.
2-phenyl-1-(pyridin-2-yl)-1H-indole-5-carbonitrile（3ha）
N
1
White solid (44.5 mg, 86%), M.p. 185-187 ℃. H NMR (400 MHz,
N
CDCl3) δ= 8.69 – 8.64 (m, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.72 – 7.61 (m,
2H), 7.48 – 7.42 (m, 1H), 7.33 – 7.28 (m, 4H), 7.28 – 7.23 (m, 2H), 6.88
(d, J = 7.9 Hz, 1H), 6.83 (s, 1H). 13C{1H}NMR (101 MHz, CDCl3) δ=
NC
3ha
151.0 (s), 149.4 (s), 142.3 (s), 139.8 (s), 138.1 (s), 131.5 (s), 128.8 (s), 128.5 (s), 128.4 (s), 128.2 (s),
125.8 (s), 125.7 (s), 122.5 (s), 122.1 (s), 120.4 (s), 112.5 (s), 105.2 (s), 104.4 (s). HRMS (ESI) m/z: (M
+ H)+ Calcd for C20H14N3 260.1182; Found: 260.1185.
ethyl 2-phenyl-1-(pyridin-2-yl)-1H-indole-5-carboxylate （ 3ia）
N
1
Colorless liquid (61.3 mg, 90%). H NMR (400 MHz, CDCl3) δ=
N
8.67 – 8.62 (m, 1H), 8.43 (d, J = 1.5 Hz, 1H), 7.93 (dd, J = 8.7, 1.7
Hz, 1H), 7.63 (dd, J = 12.3, 5.1 Hz, 2H), 7.29 – 7.23 (m, 6H), 6.90
EtOOC
3ia
(d, J = 7.9 Hz, 1H), 6.86 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 1.43 (t, J
= 7.1 Hz, 3H). 13C{1H}NMR (101 MHz, CDCl3) δ= 167.4 (s), 151.5 (s), 149.3 (s), 141.3 (s), 140.8 (s),
137.9 (s), 132.1 (s), 128.7 (s), 128.3 (s), 128.2 (s), 127.7 (s), 124.2 (s), 123.6 (s), 123.2 (s), 122.1 (s),
122.0 (s), 111.1 (s), 106.1 (s), 60.6 (s), 14.4 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C22H19N2O2 342.1368; Found: 342.1370.
6-fluoro-2-phenyl-1-(pyridin-2-yl)-1H-indole(3ja)
Colorless liquid (54.1 mg, 94%). 1H NMR (400 MHz, CDCl3) δ =8.63 (ddd,
N
J = 4.9, 1.9, 0.7 Hz, 1H), 7.61 (td, J = 7.8, 2.0 Hz, 1H), 7.43 (d, J = 8.3 Hz,
F
N
1H), 7.29 – 7.21 (m, 6H), 7.12 (td, J = 8.1, 5.3 Hz, 1H), 6.90 – 6.83 (m,
3H). 13C{1H}NMR (101 MHz, CDCl3) δ= 157.3 (s), 154.8 (s), 151.7 (s),
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149.2 (s), 140.7 (d, JCF = 10.6 Hz), 139.9 (s), 137.8 (s), 132.1 (s), 128.7 (s), 128.3 (s), 127.7 (s), 123.3
(d, JCF = 7.6 Hz), 122.0 (d, JCF = 2.6 Hz), 117.7 (d, JCF = 22.6 Hz), 107.6 (d, JCF = 3.6 Hz), 106.1 (d, JCF
= 18.7 Hz), 100.9 (s).
7
8
9
HRMS (ESI) m/z: (M + H)+ Calcd for C19H14FN2 289.1136; Found: 289.1139.
6-chloro-2-phenyl-1-(pyridin-2-yl)-1H-indole(3ka)
Yellowish liquid (58.3 mg, 96%). 1H NMR (400 MHz, CDCl3) δ= 8.64
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N
(ddd, J = 5.0, 1.8, 0.7 Hz, 1H), 7.70 (s, 1H), 7.60 (td, J = 7.7, 1.9 Hz, 1H),
Cl
N
7.55 (d, J = 8.4 Hz, 1H), 7.27 – 7.21 (m, 6H), 7.18 – 7.14 (m, 1H), 6.85
– 6.82 (m, 1H), 6.75 (s, 1H). 13C{1H}NMR (101 MHz, CDCl3) δ= 151.6
(s), 149.2 (s), 140.6 (s), 138.7 (s), 137.8 (s), 132.2 (s), 128.8 (s), 128.6
3ka
(s), 128.3 (s), 127.6 (s), 127.2 (s), 121.9 (s), 121.9 (s), 121.8 (s), 121.3 (s), 111.7 (s), 105.3 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C19H14ClN2 305.0840; Found: 305.0843.
2-phenyl-1-(pyridin-2-yl)-6-(trifluoromethyl)-1H-indole(3la)
Yellowish liquid (64.2 mg, 95%). 1H NMR (400 MHz, CDCl3) δ= 8.63
N
(ddd, J = 4.9, 1.8, 0.7 Hz, 1H), 7.92 (d, J = 0.6 Hz, 1H), 7.69 (d, J = 8.3
F3C
N
Hz, 1H), 7.59 (td, J = 7.8, 1.9 Hz, 1H), 7.40 (dd, J = 8.3, 1.1 Hz, 1H),
7.27 – 7.19 (m, 6H), 6.82 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 0.4 Hz, 1H).
13C{1H}NMR (101 MHz, CDCl3) δ= 151.3 (s), 149.4 (s), 142.5 (s),
3la
138.0 (s), 137.3 (s), 131.9 (s), 131.0 (s), 128.8 (s), 128.4 (s), 128.0 (s), 126.4 (s), 124.7 (q, J = 31.8 Hz),
123.7 (s), 122.1 (d, J = 19.7 Hz), 120.8 (s), 117.9 (q, J = 3.5 Hz), 109.2 (q, J = 4.5 Hz), 105.2 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C20H14F3N2 339.1104; Found: 339.1106.
6-methyl-2-phenyl-1-(pyridin-2-yl)-1H-indole(3ma)
1
White solid (50.0 mg, 88%), M.p. 147-149 ℃. H NMR (400 MHz,
N
CDCl3) δ= 8.64 (ddd, J = 4.9, 1.9, 0.7 Hz, 1H), 7.61-7.52 (m, 2H), 7.48
Me
N
(d, J = 0.6 Hz, 1H), 7.26-7.18 (m, 6H), 7.03 (dd, J = 8.0, 0.9 Hz, 1H),
6.87-6.83 (m, 1H), 6.75 (d, J = 0.6 Hz, 1H), 2.44 (s, 3H).
3ma
13C{1H}NMR (101 MHz, CDCl3) δ =152.2 (s), 149.1 (s), 139.3 (s),
138.9 (s), 137.6 (s), 132.9 (s), 132.8 (s), 128.5 (s), 128.2 (s), 127.1 (s), 126.5 (s), 123.0 (s), 122.0 (s),
121.4 (s), 120.1 (s), 111.3 (s), 105.5 (s), 21.9 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C20H17N2 285.1386; Found: 285.1388.
7-fluoro-2-phenyl-1-(pyridin-2-yl)-1H-indole(3na)
Colorless liquid (50.6 mg, 88%). 1H NMR (400 MHz, CDCl3) δ= 8.52 (dd, J
F
N
= 4.6, 1.9 Hz, 1H), 7.66 (td, J = 7.7, 2.0 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.27-
7.19 (m, 7H), 7.06 (ddd, J = 9.8, 6.9, 4.4 Hz, 1H), 6.91-6.84 (m, 1H), 6.78 (d,
J = 2.3 Hz, 1H). 13C{1H}NMR (101 MHz, CDCl3) δ= 151.6 (d, J = 118.8 Hz),
148.7 (s), 148.5 (s), 141.9 (s), 137.5 (s), 132.1 (d, J = 4.5 Hz), 132.0 (s), 128.8
N
3na
(s), 128.1 (s), 127.6 (s), 126.1 (d, J = 9.0 Hz), 123.2 (d, J = 2.9 Hz), 122.8 (s), 120.9 (d, J = 6.6 Hz),
116.3 (d, J = 3.4 Hz), 108.5 (d, J = 18.2 Hz), 104.8 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C19H14FN2 289.1136; Found: 289.1141.
7-methyl-2-phenyl-1-(pyridin-2-yl)-1H-indole（3oa）
Me
N
Colorless liquid (49.4 mg, 87%). 1H NMR (400 MHz, CDCl3) δ= 8.67 – 8.61
(m, 1H), 7.60 (td, J = 7.7, 2.0 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.30 (ddd, J =
7.5, 4.9, 0.9 Hz, 1H), 7.25 (dd, J = 6.5, 3.2 Hz, 2H), 7.22-7.18 (m, 3H), 7.10-
N
3oa
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7.04 (m, 2H), 6.94 (d, J = 7.2 Hz, 1H), 6.74 (s, 1H). 13C{1H}NMR (101 MHz, CDCl3) δ= 153.6 (s),
148.6 (s), 141.6 (s), 137.5 (s), 137.3 (s), 132.7 (s), 129.2 (s), 129.0 (s), 128.0 (s), 127.3 (s), 125.3 (s),
125.1 (s), 123.3 (s), 121.8 (s), 120.8 (s), 118.6 (s), 104.2 (s), 19.4 (s). HRMS (ESI) m/z: (M + H)+
Calcd for C20H17N2 285.1386; Found: 285.1389.
1-(5-methylpyridin-2-yl)-2-phenyl-1H-indole(3pa)
Me
Yellowish liquid (54.5 mg, 96%). 1H NMR (400 MHz, CDCl3) δ= 8.44 (dd, J
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= 1.7, 0.7 Hz, 1H), 7.67 – 7.58 (m, 2H), 7.41 (ddd, J = 8.1, 2.4, 0.5 Hz, 1H),
N
7.29 – 7.22 (m, 5H), 7.21 – 7.15 (m, 2H), 6.79 (dd, J = 4.3, 3.7 Hz, 2H), 2.35
(s, 3H). 13C{1H}NMR (101 MHz, CDCl3) δ =149.7 (s), 149.3 (s), 140.0 (s),
N
138.6 (s), 138.3 (s), 132.7 (s), 131.3 (s), 128.7 (s), 128.6 (s), 128.2 (s), 127.3
3pa
(s), 122.8 (s), 121.4 (s), 121.1 (s), 120.4 (s), 111.4 (s), 105.0 (s), 17.9 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C20H17N2 285.1386; Found: 285.1385.
1-(5-fluoropyridin-2-yl)-2-phenyl-1H-indole(3qa)
Yellowish liquid (43.2 mg, 75%). 1H NMR (400 MHz, CDCl3) δ= 8.48 (d, J =
F
3.0 Hz, 1H), 7.69 – 7.64 (m, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.34 (ddd, J = 8.7,
N
7.6, 3.0 Hz, 1H), 7.28 – 7.24 (m, 5H), 7.24 – 7.19 (m, 2H), 6.88 (dd, J = 8.8,
3.9 Hz, 1H), 6.80 (s, 1H). 13C{1H}NMR (101 MHz, CDCl3) δ= 157.7 (d, J =
N
255.8 Hz), 148.1 (s), 140.0 (s), 138.5 (s), 137.0 (d, J = 25.3 Hz), 132.4 (s),
3qa
128.7 (s), 128.6 (s), 128.4 (s), 127.5 (s), 124.8 (d, J = 20.0 Hz), 123.1 (s), 122.9
(d, J = 4.8 Hz), 121.4 (s), 120.6 (s), 111.2 (s), 105.5 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C19H14FN2 289.1136; Found: 289.1138.
1-(5-chloropyridin-2-yl)-2-phenyl-1H-indole(3ra)
Colorless liquid (51.0 mg, 84%). 1H NMR (400 MHz, CDCl3) δ= 8.57 (d, J =
Cl
2.6 Hz, 1H), 7.70 – 7.63 (m, 2H), 7.57 – 7.52 (m, 1H), 7.31 – 7.25 (m, 5H),
N
7.24 – 7.20 (m, 2H), 6.78 (d, J = 9.1 Hz, 2H).
13C{1H}NMR (101 MHz, CDCl3) δ= 150.3 (s), 147.8 (s), 139.8 (s), 138.3 (s),
N
137.4 (s), 132.4 (s), 129.4 (s), 128.7 (s), 128.7 (s), 128.4 (s), 127.6 (s), 123.2
3ra
(s), 122.4 (s), 121.6 (s), 120.6 (s), 111.5 (s), 106.1 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C19H14ClN2 305.0840; Found: 305.0843.
1-(5-bromopyridin-2-yl)-2-phenyl-1H-indole(3sa)
Yellowish liquid (48.7 mg, 70%). 1H NMR (400 MHz, CDCl3) δ= 8.68 (d, J =
Br
2.5 Hz, 1H), 7.67 (ddd, J = 12.8, 7.4, 2.7 Hz, 3H), 7.32 – 7.25 (m, 5H), 7.24 –
7.19 (m, 2H), 6.80 (s, 1H), 6.73 (d, J = 8.6 Hz, 1H). 13C{1H}NMR (101 MHz,
N
N
CDCl3) δ= 150.7 (s), 150.1 (s), 140.2 (s), 139.7 (s), 138.2 (s), 132.4 (s), 128.8
(s), 128.7 (s), 128.4 (s), 127.6 (s), 123.2 (s), 122.9 (s), 121.6 (s), 120.6 (s),
3sa
117.7 (s), 111.5 (s), 106.3 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C19H14BrN2 349.0335; Found: 349.0334.
1-(4-methylpyridin-2-yl)-2-phenyl-1H-indole(3ta)
Yellowish liquid (54.0 mg, 95%). 1H NMR (400 MHz, CDCl3) δ =8.45 (d, J =
Me
5.1 Hz, 1H), 7.68 – 7.60 (m, 2H), 7.26 (dtd, J = 9.5, 7.1, 5.0 Hz, 5H), 7.22 –
N
7.17 (m, 2H), 7.03 (d, J = 4.5 Hz, 1H), 6.77 (d, J = 17.9 Hz, 2H), 2.22 (s, 3H).
13C{1H}NMR (101 MHz, CDCl3) δ =152.0 (s), 149.2 (s), 148.7 (s), 140.0 (s),
N
138.5 (s), 132.7 (s), 128.6 (s), 128.2 (s), 127.3 (s), 126.1 (s), 122.8 (s), 122.8
3ta
(s), 122.6 (s), 121.1 (s), 120.5 (s), 111.4 (s), 105.2 (s), 20.8 (s).
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HRMS (ESI) m/z: (M + H)+ Calcd for C20H17N2 285.1386; Found: 285.1389.
5
6
7
8
5-bromo-7-methyl-2-phenyl-1-(pyridin-2-yl)-1H-indole（3ua）
Me
N
Yellowish liquid (57.1 mg, 79%). 1H NMR (400 MHz, CDCl3) δ= 8.63
(dd, J = 4.7, 1.0 Hz, 1H), 7.67 – 7.58 (m, 2H), 7.31 (dd, J = 6.9, 5.4 Hz,
1H), 7.25 – 7.18 (m, 5H), 7.04 (d, J = 7.7 Hz, 2H), 6.66 (s, 1H), 1.85 (s,
3H). 13C{1H}NMR (101 MHz, CDCl3) δ= 152.9 (s), 148.7 (s), 142.7 (s),
N
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Br
3ua
137.5 (s), 136.2 (s), 132.1 (s), 130.5 (s), 129.1 (s), 128.0 (s), 127.6 (s), 127.6 (s), 124.9 (s), 123.7 (s),
123.6 (s), 120.9 (s), 113.7 (s), 103.4 (s), 19.1 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C20H16BrN2 363.0492; Found: 363.0496.
5,6-dimethyl-2-phenyl-1-(pyridin-2-yl)-1H-indole（3va）
N
White solid (54.2 mg, 91%), m.p.160-163℃. 1H NMR (400 MHz, CDCl3)
Me
Me
N
δ= 8.65 – 8.59 (m, 1H), 7.60 – 7.54 (m, 1H), 7.47 (s, 1H), 7.41 (s, 1H),
7.26 – 7.23 (m, 4H), 7.22 (dd, J = 5.2, 3.4 Hz, 1H), 7.17 (ddd, J = 7.4,
4.9, 1.0 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 6.69 (s, 1H), 2.35 (s, 3H), 2.34
3va
(s, 3H). 13C{1H}NMR (101 MHz, CDCl3) δ= 152.4 (s), 149.0 (s), 139.1 (s), 137.6 (s), 132.9 (s), 132.1
(s), 129.9 (s), 128.5 (s), 128.2 (s), 127.0 (s), 127.0 (s), 121.8 (s), 121.2 (s), 120.6 (s), 111.8 (s), 105.3 (s),
20.6 (s), 20.0 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C21H19N2 299.1543; Found: 299.1544.
N
N
3wa
2-phenyl-1-(pyridin-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indole（3wa）
Colorless liquid (55.8 mg, 90%). 1H NMR (400 MHz, CDCl3) δ= 8.65 – 8.61 (m, 1H), 7.58 (td, J = 7.8,
2.0 Hz, 1H), 7.53 (s, 1H), 7.46 (s, 1H), 7.25 (dt, J = 5.6, 3.1 Hz, 4H), 7.23 – 7.16 (m, 2H), 6.85 (d, J =
7.9 Hz, 1H), 6.72 (s, 1H), 2.97 (q, J = 7.4 Hz, 4H), 2.10 (dq, J = 14.6, 7.3 Hz, 2H). 13C{1H}NMR (101
MHz, CDCl3) δ= 152.4 (s), 149.0 (s), 140.2 (s), 139.2 (s), 138.2 (s), 137.8 (s), 137.6 (s), 133.0 (s), 128.5
(s), 128.2 (s), 127.8 (s), 127.0 (s), 121.9 (s), 121.3 (s), 115.3 (s), 106.9 (s), 105.5 (s), 33.0 (s), 32.4 (s),
26.5 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C22H19N2 311.1543; Found: 311.1549.
6-chloro-5-methyl-2-phenyl-1-(pyridin-2-yl)-1H-indole(3xa)
Yellowish liquid (61.6 mg, 97%). 1H NMR (400 MHz, CDCl3) δ= 8.64
N
(dd, J = 4.8, 1.1 Hz, 1H), 7.74 (s, 1H), 7.61 (td, J = 7.8, 1.9 Hz, 1H), 7.49
Cl
N
(d, J = 4.7 Hz, 1H), 7.28 – 7.21 (m, 6H), 6.83 (d, J = 8.1 Hz, 1H), 6.70 (s,
1H), 2.47 (s, 3H). 13C{1H}NMR (101 MHz, CDCl3) δ= 151.8 (s), 149.2
(s), 140.5 (s), 137.8 (s), 137.4 (s), 132.4 (s), 129.6 (s), 128.8 (s), 128.7
Me
3xa
(s), 128.6 (s), 128.3 (s), 127.6 (s), 127.5 (s), 121.6 (s), 121.6 (s), 112.0 (s), 105.0 (s), 20.3 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C20H16ClN2 319.0997; Found: 319.0999.
5,6-dichloro-2-phenyl-1-(pyridin-2-yl)-1H-indole(3ya)
Yellowish liquid (54.0 mg, 80%). 1H NMR (400 MHz, CDCl3) δ= 8.68-
N
Cl
Cl
N
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8.61 (m, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.61 (td, J = 7.8, 1.9 Hz, 1H), 7.31-7.22 (m, 6H), 6.81 (d, J =
8.1 Hz, 1H), 6.69 (s, 1H).
13C{1H}NMR (101 MHz, CDCl3) δ =151.3 (s), 149.3 (s), 141.7 (s), 137.9 (s), 137.1 (s), 131.7 (s), 128.7
(s), 128.4 (s), 128.2 (s), 128.0 (s), 126.6 (s), 125.1 (s), 122.1 (s), 121.7 (s), 121.3 (s), 113.3 (s), 104.6 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C19H13Cl2N2 339.0451; Found: 339.0450.
2-phenyl-1-(pyridin-2-yl)-1H-benzo[f]indole(3za)
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1
Yellow solid (44.8 mg, 70%), M.p. 167-169℃. H NMR (400 MHz,
N
CDCl3) δ = 8.68 (dt, J = 5.6, 2.8 Hz, 1H), 8.14 (d, J = 22.4 Hz, 2H),
N
7.96 – 7.84 (m, 2H), 7.64 – 7.59 (m, 1H), 7.37 – 7.32 (m, 4H), 7.29 (dd,
J = 5.1, 1.9 Hz, 3H), 7.23 – 7.20 (m, 1H), 6.96 – 6.89 (m, 2H).
13C{1H}NMR (101 MHz, CDCl3) δ = 152.3 (s), 149.1 (s), 143.5 (s),
3za
138.9 (s), 137.8 (s), 132.4 (s), 131.0 (s), 130.0 (s), 129.8 (s), 128.6 (s), 128.3 (s), 128.3 (s), 127.9 (s),
127.8 (s), 123.9 (s), 123.2 (s), 121.8 (s), 121.3 (s), 118.0 (s), 107.2 (s), 105.5 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C23H17N2 321.1386; Found: 321.1387.
1-(pyridin-2-yl)-2-(p-tolyl)-1H-indole(3ab)
Yellowish liquid (54.0 mg, 95%). 1H NMR (400 MHz, CDCl3) δ= 8.66-
N
8.61 (m, 1H), 7.69-7.58 (m, 3H), 7.19 (ddd, J = 12.2, 9.7, 6.6 Hz, 5H),
N
7.07 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 8.0 Hz, 1H), 6.77 (s, 1H), 2.32 (s,
3H). 13C{1H}NMR (101 MHz, CDCl3) δ =152.1 (s), 149.1 (s), 140.0 (s),
Me
3ab
138.4 (s), 137.7 (s), 137.2 (s), 129.7 (s), 129.0 (s), 128.7 (s), 128.6 (s),
122.8 (s), 122.0 (s), 121.5 (s), 121.2 (s), 120.4 (s), 111.4 (s), 105.1 (s), 21.1 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C20H17N2 285.1386; Found: 285.1387.
2-(4-methoxyphenyl)-1-(pyridin-2-yl)-1H-indole（3ac）
N
1
Colorless liquid (55.2 mg, 92%). H NMR (400 MHz, CDCl3) δ =
N
8.64-8.58 (m, 1H), 7.69-7.61 (m, 2H), 7.58 (td, J = 7.8, 1.9 Hz, 1H),
OMe
7.22-7.13 (m, 5H), 6.86 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.6 Hz, 2H),
6.72 (s, 1H), 3.75 (s, 3H). 13C{1H}NMR (101 MHz, CDCl3) δ = 159.0
3ac
(s), 152.0 (s), 149.0 (s), 139.8 (s), 138.2 (s), 137.7 (s), 129.9 (s), 128.7 (s), 125.1 (s), 122.6 (s), 122.0 (s),
121.5 (s), 121.2 (s), 120.2 (s), 113.7 (s), 111.3 (s), 104.6 (s), 55.1 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C20H17N2O 301.1336; Found: 301.1340.
2-(4-chlorophenyl)-1-(pyridin-2-yl)-1H-indole(3ad)
White solid (59.0 mg, 97%), m.p. 110-113℃. 1H NMR (400 MHz, CDCl3)
N
δ =8.64-8.59 (m, 1H), 7.64 (dd, J = 10.8, 4.8 Hz, 3H), 7.21 (dt, J = 16.4,
N
7.3 Hz, 7H), 6.92 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H).
Cl
13C{1H}NMR (101 MHz, CDCl3) δ =151.7 (s), 149.3 (s), 138.7 (s), 138.5
3ad
(s), 137.9 (s), 133.3 (s), 131.1 (s), 129.8 (s), 128.5 (s), 123.2 (s), 121.9
(s), 121.8 (s), 121.4 (s), 120.6 (s), 111.4 (s), 105.8 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C19H14ClN2 305.0740; Found: 305.0743.
2-(4-bromophenyl)-1-(pyridin-2-yl)-1H-indole(3ae)
White solid (67.5 mg, 97%), m.p.125-127℃. 1H NMR (400 MHz, CDCl3)
N
δ= 8.61 (dd, J = 4.8, 1.4 Hz, 1H), 7.65 (td, J = 7.8, 1.6 Hz, 3H), 7.42-7.36
N
(m, 2H), 7.25-7.17 (m, 3H), 7.14-7.08 (m, 2H), 6.92 (d, J = 8.0 Hz, 1H),
6.79 (s, 1H). 13C{1H}NMR (101 MHz, CDCl3) δ= 151.7 (s), 149.3 (s),
Br
3ae
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138.6 (s), 138.5 (s), 137.9 (s), 131.6 (s), 131.4 (s), 130.0 (s), 128.5 (s), 123.2 (s), 121.8 (s), 121.8 (s),
121.5 (s), 121.4 (s), 120.6 (s), 111.4 (s), 105.9 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C19H14BrN2 349.0335; Found: 349.0336.
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8
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2-(2,5-difluorophenyl)-1-(pyridin-2-yl)-1H-indole(3af)
White solid (60.0 mg, 98%), m.p. 140-143℃. 1H NMR (400 MHz, CDCl3) δ=
N
F
8.56-8.51 (m, 1H), 7.73-7.65 (m, 3H), 7.28-7.24 (m, 1H), 7.23-7.18 (m, 2H),
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N
7.08 (d, J = 8.0 Hz, 1H), 7.06-7.01 (m, 1H), 6.95-6.90 (m, 2H), 6.87 (s, 1H).
13C{1H}NMR (101 MHz, CDCl3) δ = 159.5 (s), 156.8 (d, J = 48.2 Hz), 154.2
F
3af
(s), 151.6 (s), 149.2 (s), 137.9 (d, JCF = 1.9 Hz), 132.6 (s), 128.3 (s), 123.6 (s),
122.4 (dd, JCF = 17.1, 8.8 Hz), 121.6 (s), 121.4 (s), 120.9 (s), 120.3 (s), 117.5
(dd, JCF = 24.8, 3.5 Hz), 116.7 (dd, JCF = 25.1, 8.9 Hz), 115.8 (dd, JCF = 24.0, 8.5 Hz), 111.3 (s), 107.9
(d, JCF = 2.4 Hz). HRMS (ESI) m/z: (M + H)+ Calcd for C19H13F2N2 307.1042; Found: 307.1045.
2-(2,5-dichlorophenyl)-1-(pyridin-2-yl)-1H-indole(3ag)
Colorless liquid (65.5 mg, 97%). 1H NMR (400 MHz, CDCl3) δ= 8.52 – 8.47
N
Cl
(m, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.60 (td, J = 7.8,
N
1.9 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.30 – 7.26 (m, 1H), 7.26 – 7.22 (m,
1H), 7.22 – 7.16 (m, 2H), 7.16 – 7.11 (m, 1H). 13C{1H}NMR (101 MHz,
Cl
3ag
CDCl3) δ= 151.4 (s), 149.0 (s), 137.7 (s), 137.2 (s), 135.2 (s), 134.5 (s), 134.4
(s), 133.2 (s), 130.9 (s), 129.5 (s), 128.2 (s), 126.9 (s), 123.4 (s), 121.4 (s),
121.3 (s), 120.8 (s), 120.2 (s), 111.6 (s), 107.6 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C19H13Cl2N2 339.0451; Found: 339.0456.
2-(3,4-dichlorophenyl)-1-(pyridin-2-yl)-1H-indole(3ah)
Yellowish liquid (65.5 mg, 97%). 1H NMR (400 MHz, CDCl3) δ= 8.61
N
Cl
(dd, J = 4.8, 1.7 Hz, 1H), 7.74 – 7.64 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H),
N
7.42 (d, J = 2.0 Hz, 1H), 7.31 – 7.18 (m, 4H), 7.02 – 6.96 (m, 2H), 6.82
(s, 1H). 13C{1H}NMR (101 MHz, CDCl3) δ= 151.4 (s), 149.5 (s), 138.6
(s), 138.1 (s), 137.3 (s), 132.7 (s), 132.4 (s), 131.4 (s), 130.1 (s), 130.1
Cl
3ah
(s), 128.3 (s), 127.6 (s), 123.6 (s), 122.0 (s), 121.7 (s), 121.6 (s), 120.8 (s), 111.3 (s), 106.4 (s). HRMS
(ESI) m/z: (M + H)+ Calcd for C19H13Cl2N2 339.0451; Found: 339.0454.
2-(naphthalen-1-yl)-1-(pyridin-2-yl)-1H-indole(3ai)
Colourless oil (49.9 mg, 78%). 1H NMR (400 MHz, CDCl3) δ= 8.51 (dd, J =
N
4.9, 1.2 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.81 (d, J
N
= 7.9 Hz, 2H), 7.72 (dd, J = 7.0, 1.2 Hz, 1H), 7.46 – 7.38 (m, 3H), 7.37 – 7.31
(m, 1H), 7.31 – 7.26 (m, 2H), 7.24 (dd, J = 6.6, 1.6 Hz, 1H), 6.99 (ddd, J = 7.4,
3ai
4.9, 0.8 Hz, 1H), 6.86 (s, 1H), 6.64 (d, J = 8.1 Hz, 1H).
13C{1H}NMR (101 MHz, CDCl3) δ= 151.8 (s), 148.7 (s), 137.6 (s), 137.5 (s),
137.4 (s), 133.4 (s), 132.1 (s), 130.6 (s), 128.9 (s), 128.6 (s), 128.5 (s), 128.0 (s), 126.4 (s), 125.9 (s),
125.9 (s), 125.0 (s), 123.0 (s), 121.3 (s), 121.0 (s), 120.5 (s), 120.5 (s), 111.9 (s), 107.5 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C23H17N2 321.1386; Found: 321.1389.
2-(furan-2-yl)-1-(pyridin-2-yl)-1H-indole(3aj)
Brown solid (44.2 mg, 85%), m.p. 123-125℃. 1H NMR (400 MHz, CDCl3) δ=
N
8.66 (dd, J = 4.9, 1.2 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.65 (dd, J = 6.1,
N
O
2.6 Hz, 1H), 7.43-7.39 (m, 1H), 7.37-7.31 (m, 2H), 7.25-7.22 (m, 1H), 7.21-7.15
(m, 2H), 6.96 (s, 1H), 6.32 (dd, J = 3.3, 1.8 Hz, 1H), 5.95 (d, J = 3.4 Hz, 1H).
3aj
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13C{1H}NMR (101 MHz, CDCl3) δ= 151.7 (s), 149.3 (s), 146.8 (s), 142.1 (s), 138.4 (s), 138.1 (s), 130.5
(s), 128.3 (s), 123.1 (s), 122.5 (s), 121.9 (s), 121.2 (s), 120.7 (s), 111.1 (s), 110.9 (s), 108.1 (s), 104.0 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C17H13N2O 261.1023; Found: 261.1025.
1-(pyridin-2-yl)-2-(thiophen-2-yl)-1H-indole(3ak)
1
White solid (45.2 mg, 82%), m.p. 133-136℃. H NMR (400 MHz, CDCl3) δ
=8.66 (dd, J = 4.9, 1.2 Hz, 1H), 7.72 (td, J = 7.8, 1.9 Hz, 1H), 7.63 (dd, J = 6.3,
N
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N
S
2.3 Hz, 1H), 7.49 – 7.45 (m, 1H), 7.29 (ddd, J = 7.4, 4.9, 0.8 Hz, 1H), 7.23 –
7.15 (m, 3H), 7.11 (d, J = 8.0 Hz, 1H), 6.91 (dd, J = 5.1, 3.6 Hz, 1H), 6.85 (s,
1H), 6.74 (dd, J = 3.6, 1.0 Hz, 1H). 13C{1H}NMR (101 MHz, CDCl3) δ =151.5
3ak
(s), 149.3 (s), 138.5 (s), 137.9 (s), 134.2 (s), 133.2 (s), 128.3 (s), 127.2 (s), 126.5 (s), 125.7 (s), 123.1 (s),
122.4 (s), 122.3 (s), 121.3 (s), 120.5 (s), 111.1 (s), 105.5 (s).
HRMS (ESI) m/z: (M + H)+ Calcd for C17H13N2S 277.0794; Found: 277.0795.
Gram-Scale Reaction Experiment.
A mixture of N-(2-pyridyl)anilines 1a (0.85g, 5.0mmol, 1.0equiv), α-Cl acetophenone 2a (1.001 g,
6.5 mmol, 1.3equiv), [Cp*IrCl2]2 (0.199g, 0.25 mmol, 5mol%), NaF (0.315g, 7.5 mmol, 1.5equiv)
was taken in a dry round-bottomed flask under air atmosphere. To the mixture, MeOH (40 mL) was
added via a syringe and the closed reaction mixture was allowed to stir at 90℃ for 36 h monitored
with TLC. After completion of the reaction, the solvent was removed under reduced pressure and
then the crude reaction mixture was purified by flash silica gel column chromatography (petroleum
ether/EtOAc = 10:1) to afford the desired product 3aa (1.26g, 93%).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Control Experiments
1H and 13C NMR spectra for all products (PDF).
AUTHOR INFORMATION
Author Contributions
§These authors contributed equally to this work.
Corresponding Author
Email: hgs@lzu.edu.cn
Notes
The authors declare no competing financial interest.
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