Palladium-catalyzed tandem oxidative annulation of α-amino ketones leading to 2-aroylindoles

Article abstract of DOI:10.1016/j.tet.2019.130917

A simple synthesis of 2-aroylindoles via palladium-catalyzed tandem oxidative annulation directly from α-amino ketones has been developed. In this transformation, two-step reaction including oxidation of α-amino aetones to generate imine intermediates and

Full text of DOI:10.1016/j.tet.2019.130917

Journal Pre-proof
Palladium-catalyzed tandem oxidative annulation of α-amino ketones leading to 2-
aroylindoles
Tao-Shan Jiang, Long Dai, Yuhui Zhou, Xiuli Zhang
PII:
S0040-4020(19)31336-5
https://doi.org/10.1016/j.tet.2019.130917
TET 130917
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 October 2019
Revised Date: 24 December 2019
Accepted Date: 27 December 2019
Please cite this article as: Jiang T-S, Dai L, Zhou Y, Zhang X, Palladium-catalyzed tandem
oxidative annulation of α-amino ketones leading to 2-aroylindoles, Tetrahedron (2020), doi: https://
doi.org/10.1016/j.tet.2019.130917.
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Palladium-Catalyzed Tandem Oxidative Annulation of α-Amino Ketones
Leading to 2-aroylindoles
Tao-Shan Jiang†,b *, Long Dai†, a, Yuhui Zhoua ,Xiuli Zhanga,c *
Ar
Pd(OAc)2, O2
R
R
Ar
one pot
N
O
N
H
H
O
oxidative
cyclization
Oxidation
R
Ar
N
26 examples
up to 90% yield
O
imine intermediates

Palladium-Catalyzed Tandem Oxidative Annulation of α-Amino
Ketones Leading to 2-aroylindoles
Tao-Shan Jiang†,b *, Long Dai†, a, Yuhui Zhoua , Xiuli Zhanga,c *
a
Department of Applied Chemistry, Anhui Agricultural University, Hefei, Anhui
230036, PR China
e-mail: zhxiuli@163.com.
School of Life Sciences, Anhui Agricultural University, Hefei, 230036, PR China.
b
e-mail: jts2015@ahau.edu.cn.
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
c
Chemistry, Shanghai 200032, P.R. China
These authors contributed equally to this work.
†
Abstract
A simple synthesis of 2-aroylindoles via palladium-catalyzed tandem oxidative
annulation directly from α-amino ketones has been developed. In this transformation,
two-step reaction including oxidation of α-amino aetones to generate imine
intermediates and subsequent palladium-catalyzed aerobic annulation to give
2-aroylindoles was compatible in one pot.
Keywords: 2-aroylindoles, α-amino ketones, palladium-catalyzed, oxidative
annulations
1

1. Introduction
The indole nucleus is prevalent in many chemical substrates which exhibit a
broad spectrum of biological activities, and is recognized as privileged motif in
medicinal chemistry.1 It is also used as a useful building block for the synthesis of
extensive functional molecules in different fields.2 Among them, 2-aroylindoles
constitute a particularly important class of indole derivatives that widely existed in
many
biologically
active
molecules
(Figure
1).3
For
examples,
2-aroyltrimethoxyindoles have been studied as analogues of the naturally occurring
drug Combretastatin A4 and showed well inhibitory activity against the tubulin
polymerization.3a 2-(4-Phenoxybenzoyl)indole derivatives have been identified as a
novel structural class of calmodulin-dependent protein kinases (CaMKII)
inhibitors.3b Therefore, the synthesis of 2-aroylindoles has aroused considerable
interest from organic chemists and many successful cases by
transition-metal-catalyzed reaction and other metal-free conditions were developed
over the past decades.4-6 Although the efforts have greatly enriched the development
of indole synthesis, the direct and efficient procedure for 2-aroylindoles synthesis
has been rarely reported.
Figure 1. Examples of molecules which are of medicinal interest.
Recently palladium-catalyzed oxidative cross-coupling strategy has been one of
the most fascinating strategies in organic synthesis.7-8 Eespecially the successful
methodologies have been applied to the synthesis of indoles from enamine or imine
intermediates under Pd(OAc)2/O2 conditions (Scheme 1a and 1b).9-10 However, for the
2

synthesis of 2-aroylindoles there was only one example in the work of Xiao group.10b
Inspired by previous pioneering achievements,10 we envisaged that 2-aroylindoles
could be synthesized from α-amino ketones through palladium-catalyzed tandam
oxidative annulation reaction (Scheme 1c). This idea is theoretically feasible and the
key problem is how to accomplish the compatibility between the oxidation of α-amino
ketones and subsequent oxidative annulation in one pot. Meanwhile, α-amino ketones
can be readily obtained via a two-step procedure from widely existed anilines and
phenylpropones (see SI). Herein, we report the direct and easy synthesis of
2-aroylindoles via palladium-catalyzed tandem oxidative annulation of α-amino
ketones in one pot.
Indoles Synthesis through Palladium-Catalyzed Oxidative
Annulation from Imines
Yoshikai's work: ref. 9
Pd(OAc)2/O2
R
R
Ar
(a)
TBAB, DMSO,
N
H
N
Ar
Xiao's work: ref. 10
OEt
O
CO2Et
Pd(OAc)2/O2
R
R
(b)
HOAc, DMSO,
N
O
NH2
H
Design of this work:
Ar
O
R
[O]
R
Pd(II)
[O]
R
Ar
N
Ar
N
(c)
N
H
H
O
O
imines
-amino ketones
2-aroylindoles
Key problem of this design: How to solve the compatibility
between the oxidation of amines and subsequent oxidative
cyclizations of in situ formed imine in one pot?
Scheme 1. Indoles Synthesis via Palladium-Catalyzed Oxidative Annulation
Strategy.
2. Results and Discussion
At the outset of our design, we chosen the α-amino ketone 1a to screen the
feasibility using Pd(OAc)2 (10 mol%), Cu(OAc)2 (3.0 equiv.), 4 Å MS (60 mg) and
TBAB (2.0 equiv.) in anhydrous DMSO at 60 oC for 12 h (Table 1).10a To our delight,
1a could be converted into the desired indole product 2a in 49% yield (Entry 1). Then
different conditions were explored. First, considering two kinds of different oxidation
processes in one pot, the conditions using different oxidants (1.0 equiv.) and
molecular oxygen (O2) as the co-oxidant were investigated (Entries 2-7). The best
3

result was obtained under 1.0 equiv. of Cu(OAc)2 and O2 atmosphere, other oxidative
systems were inferior. Much to our pleasure, using O2 as the sole oxidant also could
gave the target product in 73% yield, very similar to the condition employing
Cu(OAc)2 (1.0 equiv.) and O2 (Entry 8 versus entry 2). The addition of TBAB was
important and improved the reaction efficiency (Entry 8 versus entry 9). Further
optimization of the temperature showed the yield could be increased to 88% at 80 oC
(Entry 11 versus entries 10, 12). It should be pointed that an elevated reaction
o
temperature (100 C) caused dramaticly decreased yield (Entry 12). At last, we also
examined the conditions for indole synthesis using a carboxylic acid-promoted
Pd(II)-catalytic system reported by Xiao group.10b Replacing the additive TBAB with
4 equiv of AcOH or PivOH, the reaction also proceeded and the desired product was
isolated in moderate yield (Entries 13-14).
Table 1. Optimization of Reaction Conditions on Palladium(II)-catalyzed Oxidative
Annulation. a
Entry
1
Oxidant (equiv.)
Additive
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
-
Temp
60 oC
60 oC
60 oC
60 oC
60 oC
60 oC
60 oC
60 oC
60 oC
40 oC
80 oC
100 oC
80 oC
80 oC
Yield 2a (%)
Cu(OAc)2 (3.0 )
49
2
Cu(OAc)2 (1.0)/O2
75
3
CuCl2 (1.0)/O2
trace
28
4
AgOAc (1.0)/O2
5
TBHP (1.0)/O2
t-BuONO (1.0)/O2
19
6
trace
22
7
BQ(1.0) / O2
8
O2
O2
O2
O2
O2
O2
O2
73
9
36
10
11
12
13b
14c
TBAB
TBAB
TBAB
HOAc
PivOH
49
88
13
72
56
a Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (10 mol%), Oxidant, TBAB (2.0
b
equiv.) and 4 Å MS (60 mg) in 1.0 mL of anhydrous DMSO for 12 h. HOAc (4.0
equiv.). c PivOH (4.0 equiv.).
4

With the optimal conditions (Table 1, entry 11), the scope about the
palladium-catalyzed tandem oxdative annulation of α-amino ketones is shown in
Scheme 2. First, a series of substitutents on the phenyl rings of aniline motif were
tested and the results showed electron-donating groups and weak
electron-withdrawing groups were suitable for the reaction, giving the corresponding
2-aroylindoles in good to excellent yields (2a-i, 2k-r). However, for the substrates
with the weak electron-withdrawing group on aniline ring (2f-i, 2m-n) longer reaction
time was required. In this condition, strong electron-withdrawing acetyl group (2j) did
not give the desired product. These phenomena were different from those already
reported results about N-aryl imine intermediates for the synthesis of indoles.10a The
possible reason may be the difficulty of the first step oxidation of α-amino ketones.
This oxidative annulation reaction also had good region-selectivity. α-Amino ketones
derived from m-methyl, -methoxy and –chloro could afford the relevant indole
products at the less-hindered position in good yields (2k, 2l, 2n), while the reaction of
m-chloro substitute on aniline motif was accompanied by a minor amount (8%) of the
regioisomer (2m and 2m’). Substituents at the ortho positions of the aniline-derived
moieties were tolerated and the desired products were obtained in good yields (2p-2r).
Then substitutents on the phenyl rings of ketone motif were screened. As expected,
different aryl ketone motifs were suitable for constructing corresponding indoles with
satisfactory yield (2s-2aa). However, the current catalytic system was inapplicable to
non-aromatic ketone substrates (2ab, 2ac, 2ad)
5

Scheme 2. Substrate scope. a Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (10 mol%),
TBAB (2.0 equiv.), O2 (1 atm ) and 4 Å MS (60 mg) in 1.0 mL of anhydrous DMSO
b
c
for 12 h. Reaction time was 24 h. Trace of regioisomeric product was detected by
1HNMR. N.D. = Not Detected.
Although current reaction conditions were similar to previous reports and
detailed mechanisms were discussed,10 other further mechanistic insights
should be known in this catalytic cycle. First, to elucidate the oxidation process
of α-amino ketone and the key intermediate, 1b was performed in the absence
of Pd(OAc)2 condition and imine intermediate 1b’ could be generated (eq 1).
6

This indicated the palladium catalyst was not imperative for the first oxidation
step, but it may be used as a promoter in oxidation process can’t be excluded.
When the imine intermediate 1b’ was conducted in standard conditions for 8 h,
the target product was isolated in 89% yield (eq 2). To further verify the
intermediate 1b’, a time−yield profile of α-amino ketone 1b under the optimal
conditions was depicted in Figure 2. The substrate 1b was consumed to form
imine 1b’ which was then transferred to the product 2b. Meanwhile, 1b’ was
accumulated to a maximum yield in about 3 h and then gradually converted into
product 2b in 12 h. These results indicate that 1b’ was the key intermediate for
indole synthesis.
O2
(eq 1)
TBAB, DMSO, 80 oC
N
N
4 Å MS, 12 h
H
O
O
1b
1b was recovered in 72% yield
1b', 21%
Pd(OAc)2, O2
(eq 2)
TBAB, DMSO, 80 o
4 Å MS, 8 h
C
N
N
O
H
O
2b, 89%
1b'
Figure 2. Selective time course of the reaction.
Based on the above results and previous studies,9-10 a plausible reaction
mechanism was proposed in scheme 3. First, α-amino ketone 1b was oxidized to
imine intermediate 1b’, followed by tautomerization to generate corresponding
enamine which electrophilically attacked by Pd(OAc)2. Then similar catalytic cycle
occured to afford the indole product as depicted in the work of Yoshikai group
7

including intramolecular C-H palladation, reductive elimination of palladacycle and
tautomerization. 10a
Scheme 3. Proposed mechanism.
3. Conclusion
In conclusion, we have developed an efficient and simple protocol for direct
2-aroylindoles synthesis from α-amino ketones. This reaction includes an oxidation of
amine to afford imine intermediates in situ and then palladium-catalyzed oxidative
annulation process to give the 2-aroylindoles in one pot. Further synthetic applications
are currently underway in our laboratory.
4. Experimental section
4.1. General information
All reactions were carried out under O2 atmosphere in dry conditions. Flash
1
Column chromatography was performed using 200-300 mesh silica gel, SiO2. H
13
NMR and C NMR spectra were measured on a 600 MHz spectrometer (Agilent
1
DD2 600Hz, H: 600 MHz, 13C: 150 MHz) using CDCl3 as the solvent at room
temperature. Multiplicities are recorded as: s = singlet, d = doublet, t = triplet, q =
quartet, dd = doublet of doublets, m = multiplet, br = broad. High-resolution mass
spectra (HRMS) were recorded on a BRUKER VPEXII spectrometer with ESI mode.
8

Melting point was measured with melting point instrument.
4.2. Synthesis of α-amino ketones (1)
To a solution of acetone (10.0 mL) was added aniline (1.0 mmol), α-bromo ketone
(1.2 mmol), K2CO3 (2.0 mmol), KI (0.1 mmol), then the reaction was stirred at room
temperature for 18 h under air condition. After the reaction was complete, the solvent
was evaporated in vacuo, and the residue was directly separated by flash column
chromatography on a silica gel to give the α-amino ketone (1).
4.3. Synthesis of 2-aroylindoles (2)
A mixture of α-amino ketone (0.2 mmol), Pd(OAc)2 (0.02 mmol), TBAB(0.4
mmol), O2 (1 atm), 4 Å MS (60 mg) in anhydrous DMSO (1.0 mL) were stirred at 80
oC for 12 h or 24 h. After the reaction was finished, the mixture was diluted with ethyl
acetate (100 mL) and then washed with saturated brine (20 mL*3 times), the organic
phase was concentrated under reduced pressure. The residue was purified by flash
column chromatography on a silica gel using petroleum ether/ethyl acetate as the
eluent to give the desired product 2.
4.3.1. (5-Methyl-1H-indol-2-yl)(phenyl)methanone (2a)11a
1
White solid (41.4 mg, 88% yield). H NMR (600 MHz, CDCl3): δ 9.56 (br, 1H),
8.01 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.2 Hz, 2H), 7.49 (s, 1H),
7.40 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H), 2.46 (s, 3H); 13C NMR
(150 MHz, CDCl3): δ 187.2, 138.1, 136.1, 134.4, 132.2, 130.3, 129.2, 128.6, 128.4,
128.0, 122.3, 112.4, 111.9, 21.4.
4.3.2. (1H-Indol-2-yl)(phenyl)methanone (2b)11a
1
Yellowish solid (39.8 mg, 90% yield). H NMR (600 MHz, CDCl3): δ 9.52 (br,
1H), 8.01 (d, J = 7.8 Hz, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.54
(t, J = 7.2 Hz, 2H), 7.50 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.18 (t, J = 7.2
13
Hz, 2H); C NMR (150 MHz, CDCl3): δ 187.2, 138.0, 137.6, 134.4, 132.3, 129.2,
128.5, 127.8, 126.5, 123.2, 121.0, 112.8, 112.2 ;
4.3.3. (5-Methoxy-1H-indol-2-yl)(phenyl)methanone (2c)11a
Yellow solid (40.7 mg, 81% yield). 1H NMR (600 MHz, CDCl3): δ 9.42 (br, 1H),
7.99 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 2H), 7.39 (d, J =
9

9.0 Hz, 1H), 7.09 (t, J = 2.4 Hz, 2H), 7.06 (dd, J = 9.0, 2.4 Hz, 1H), 3.86 (s, 3H); 13C
NMR (150 MHz, CDCl3): δ 187.0, 154.8, 138.1, 134.8, 133.1, 132.3, 129.2, 128.4,
128.1, 118.4, 113.1, 112.3, 102.8, 55.7;
4.3.4. (5-iso-Propyl-1H-indol-2-yl)(phenyl)methanone (2d)
o
1
Yellow solid (43.7 mg, 83% yield), mp 142.3-143.6 C. H NMR (600 MHz,
CDCl3): δ 9.37 (br, 1H), 7.99 (dd, J = 8.4, 1.2 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H),
7.54-7.52 (m, 3H), 7.41 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 8.4, 1.2 Hz, 1H), 7.11 (d, J
13
= 1.2 Hz, 1H), 3.01 (sep, J = 7.2 Hz, 1H), 1.31 (d, J = 7.2 Hz, 6H); C NMR (150
MHz, CDCl3): δ 187.1, 141.8, 138.1, 136.3, 134.5, 132.2, 129.2, 128.4, 127.9, 126.4,
119.6, 112.7, 112.0, 34.1, 24.4. HRMS (ESI) m/z [M+H+] calcd for C18H18NO
264.1388, found 264.1382.
4.3.5. (5-(tert-Butyl)-1H-indol-2-yl)(phenyl)methanone (2e)
o
1
Yellow solid (43.8 mg, 79% yield), mp 139.0-140.2 C. H NMR (600 MHz,
CDCl3): δ 9.44 (br, 1H), 8.00 (d, J = 7.2 Hz, 2H), 7.69 (s, 1H), 7.62 (t, J = 7.8 Hz,
1H), 7.54 (t, J = 7.8 Hz, 2H), 7.49 (dd, J = 9.0, 1.8 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H),
13
7.15 (d, J = 1.8 Hz, 1H), 1.40 (s, 9H); C NMR (150 MHz, CDCl3): δ 187.1, 144.0,
138.1, 135.9, 134.5, 132.2, 129.2, 128.4, 127.6, 125.4, 118.4, 113.0, 111.8, 34.6, 31.6.
HRMS (ESI) m/z [M+H+] calcd for C19H20NO 278.1545, found 278.1541.
4.3.6. Phenyl(5-phenyl-1H-indol-2-yl)methanone (2f)
o
1
Yellow solid (36.3 mg, 61% yield), mp 161.4-162.5 C. HNMR (600 MHz,
CDCl3): δ 9.45 (br, 1H), 8.02 (dd, J = 8.4, 1.2 Hz, 2H), 7.92 (s, 1H), 7.66-7.63 (m,
4H), 7.57-7.55 (m, 3H), 7.46 (t, J = 7.2Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.22 (d, J =
0.6 Hz, 1H); 13C NMR (150 MHz, CDCl3): δ 187.1, 141.7, 138.0, 137.0, 135.0, 134.6,
132.4, 129.2, 128.8, 128.5, 128.3, 127.3, 126.8, 126.6, 121.3, 113.0, 112.4. HRMS
(ESI) m/z [M+H+] calcd for C21H16NO 298.1232, found 298.1237.
4.3.7. (5-Fluoro-1H-indol-2-yl)(phenyl)methanone (2g)
o
1
Yellowish solid (31.1 mg, 65% yield), mp 181.1-182.3 C. HNMR (600 MHz,
CDCl3): δ 9.67 (br, 1H), 8.00 (d, J = 7.8 Hz, 2H), 7.64 (t, J = 7.2 Hz, 1H), 7.55 (t, J =
7.2 Hz, 2H), 7.45 (dd, J = 9.0, 4.2 Hz, 1H), 7.35 (dd, J = 9.0, 1.2 Hz, 1H), 7.16-7.13
(m, 2H); 13C NMR (150 MHz, CDCl3): δ 187.1, 158.2 (d, J = 235.5 Hz), 137.8, 135.7,
10

134.2, 132.5, 129.2, 128.5, 127.8 (d, J = 10.5 Hz), 115.7 (d, J = 27.0 Hz), 113.2 (d, J
= 9.0 Hz), 112.4 (d, J = 6.0 Hz), 107.2 (d, J = 22.5 Hz). HRMS (ESI) m/z [M+H+]
calcd for C15H11FNO 240.0825, found 240.0822.
4.3.8. (5-Chloro-1H-indol-2-yl)(phenyl)methanone (2h)11a
1
White solid (36.3 mg, 71% yield). H NMR (600 MHz, CDCl3): δ 9.61 (br, 1H),
7.99 (d, J = 7.2 Hz, 2H), 7.69 (s, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H),
7.43 (d, J = 9.0 Hz, 1H), 7.33 (dd, J = 9.0, 1.2 Hz, 1H), 7.09 (d, J = 1.2 Hz, 1H); 13C
NMR (150 MHz, CDCl3): δ 187.1, 137.7, 135.8, 135.4, 132.6, 129.2, 128.6, 128.55,
127.0, 126.7, 122.3, 113.4, 111.8.
4.3.9. (5-Bromo-1H-indol-2-yl)(phenyl)methanone (2i)11a
1
White solid (45.6 mg, 76% yield). H NMR (600 MHz, CDCl3): δ 9.57 (br, 1H),
7.99 (d, J = 8.4 Hz, 2H), 7.85 (s, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.2 Hz, 2H),
7.45 (dd, J = 9.0, 1.8 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.09 (d, J = 1.8 Hz, 1H); 13C
NMR (150 MHz, CDCl3): δ 187.1, 137.6, 136.0, 135.2, 132.6, 129.4, 129.3, 129.2,
128.6, 125.5, 114.1, 113.7, 111.6.
4.3.10. (6-Methyl-1H-indol-2-yl)(phenyl)methanone (2k)
o
1
Yellow solid (40.0 mg, 85% yield), mp 136.0-137.0 C. H NMR (600 MHz,
CDCl3): δ 9.36 (br, 1H), 7.99 (dd, J = 8.4, 1.2 Hz, 2H), 7.63-7.58 (m, 2H), 7.53 (t, J =
7.8 Hz, 2H), 7.26 (s, 1H), 7.12 (dd, J = 1.8, 0.6 Hz, 1H), 7.00 (dd, J = 8.4, 1.2 Hz,
13
1H), 2.49 (s, 3H); C NMR (150 MHz, CDCl3): δ 187.0, 138.2, 138.1, 137.0, 134.0,
132.2, 129.2, 128.4, 125.7, 123.3, 122.8, 113.0, 111.7, 22.1. HRMS (ESI) m/z [M+H+]
calcd for C16H14NO 236.1075, found 236.1080.
4.3.11. (6-Methoxy-1H-indol-2-yl)(phenyl)methanone (2l)
o
1
Yellow solid (39.7 mg, 79% yield), mp 161.5-162.7 C. H NMR (600 MHz,
CDCl3): δ 9.54 (br, 1H), 7.98 (dd, J = 7.8, 1.2 Hz, 2H), 7.61 (tt, J = 7.2, 1.2 Hz, 1H),
7.57 (d, J = 9.0 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.11 (dd, J = 2.4, 1.2 Hz, 1H), 6.89
(d, J = 1.8 Hz, 1H), 6.83 (dd, J = 9.0, 2.4 Hz, 1H), 3.87 (s, 3H); 13C NMR (150 MHz,
CDCl3): δ 186.5, 159.8, 139.0, 138.3, 133.7, 132.1, 129.1, 128.4, 124.1, 122.2, 113.6,
113.0, 93.5, 55.5. HRMS (ESI) m/z [M+H+] calcd for C16H14NO2 252.1025, found
252.1032.
11

4.3.12. (6-Chloro-1H-indol-2-yl)(phenyl)methanone (2m)11a
1
White solid (34.8 mg, 68% yield). H NMR (600 MHz, CDCl3): δ 9.53 (br, 1H),
7.99 (d, J = 7.2 Hz, 2H), 7.64 (t, J = 7.2 Hz, 2H), 7.55 (t, J = 7.8 Hz, 2H), 7.49 (s, 1H),
13
7.15-7.13 (m, 2H); C NMR (150 MHz, CDCl3): δ 187.0, 137.72, 137.71, 135.0,
132.5, 132.4, 129.2, 128.5, 126.3, 124.2, 122.2, 112.6, 112.0.
4.3.13. (4-Methyl-1H-indol-2-yl)(phenyl)methanone (2m’)11a
White solid (4.1 mg, 8% yield); 1H NMR (600 MHz, CDCl3): δ 9.47 (br, 1H), 8.02
(d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.57 (t, J = 7.8 Hz, 2H), 7.39 (d, J = 8.4
Hz, 1H), 7.29 (t, J = 7.2 Hz, 1H), 7.25 (t, J = 1.2 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H).
4.3.14. (5-Chloro-6-methyl-1H-indol-2-yl)(phenyl)methanone (2n)
o
1
Yellow solid (38.3 mg, 71% yield), mp 207.2-208.2 C. H NMR (600 MHz,
CDCl3): δ 9.43 (br, 1H), 7.98 (dd, J = 8.4, 1.2 Hz, 2H), 7.69 (s, 1H), 7.63 (t, J = 7.2
Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.34 (s, 1H), 7.05 (d, J = 1.2 Hz, 1H), 2.50 (s, 3H);
13C NMR (150 MHz, CDCl3): δ 187.0, 137.9, 136.5, 134.9, 134.7, 132.4, 129.2, 128.5,
128.0, 126.9, 122.6, 113.4, 111.9, 21.2. HRMS (ESI) m/z [M+H+] calcd for
C16H13ClNO 270.0686, found 270.0690.
4.3.15. Phenyl(4,5,6-trimethoxy-1H-indol-2-yl)methanone (2o)11b
Yellow solid (48.6 mg, 78% yield). 1H NMR (600 MHz, CDCl3): δ 9.58 (br, 1H),
7.98 (d, J = 7.8 Hz, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.2 Hz, 2H), 7.19 (d, J =
13
1.2 Hz, 1H), 6.65 (s, 1H), 4.10 (s, 3H), 3.91 (s, 3H) , 3.87 (s, 3H); C NMR (150
MHz, CDCl3): δ 186.2, 155.2, 147.1, 138.2, 136.3, 135.4, 133.1, 132.1, 129.1, 128.4,
116.3, 111.3, 89.0, 61.5, 61.0, 56.1.
4.3.16. (7-Methyl-1H-indol-2-yl)(phenyl)methanone (2p)11a
White solid (33.9 mg, 72% yield). 1H NMR (600 MHz, CDCl3): δ 9.31 (br, 1H),
8.00 (dd, J = 7.8, 1.2 Hz, 2H), 7.63 (tt, J = 7.8, 1.2 Hz, 1H), 7.58-7.53 (m, 3H),
7.18-7.17 (m, 2H), 7.09 (t, J = 7.2 Hz, 1H), 2.57 (s, 3H); 13C NMR (150 MHz,
CDCl3): δ 187.3, 138.1, 137.4, 134.1, 132.3, 129.2, 128.4, 127.4, 126.7, 121.5, 121.3,
120.8, 113.4, 16.7.
4.3.17. (7-Methoxy-1H-indol-2-yl)(phenyl)methanone (2q)
o
1
White solid (34.2 mg, 68% yield), mp 158.3-159.5 C. H NMR (600 MHz,
12

CDCl3): δ 9.40 (br, 1H), 7.99 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.53 (t, J =
7.8 Hz, 2H), 7.30 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.08 (t, J = 7.8 Hz,
1H), 6.77 (d, J = 7.2 Hz, 1H), 4.00 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 186.9,
146.7, 138.1, 134.1, 132.3, 129.2, 129.0, 128.9, 128.4, 121.5, 115.3, 112.7, 105.1,
55.5. HRMS (ESI) m/z [M+H+] calcd for C16H14NO2 252.1025, found 252.1025.
4.3.18. (1H-Benzo[g]indol-2-yl)(phenyl)methanone (2r)
o
1
Yellow solid (38.0 mg, 70% yield), mp 181.1-182.0 C. H NMR (600 MHz,
CDCl3): δ 10.38 (br, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.8 Hz, 2H), 7.92 (d, J
= 7.8 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.60- 7.52 (m, 5H),
7.29 (s, 1H); 13C NMR (150 MHz, CDCl3): δ 186.5, 138.2, 134.1, 133.2, 132.6, 132.2,
131.6, 129.2, 129.0, 128.5, 126.2, 124.2, 122.5, 121.8, 121.4, 121.0, 114.2. HRMS
(ESI) m/z [M+H+] calcd for C19H14NO 272.1075, found 272.1073.
4.3.19. (5-Methyl-1H-indol-2-yl)(p-tolyl)methanone (2s)
o
1
White solid (42.9 mg, 86% yield), mp 164.1-165.2 C. H NMR (600 MHz,
CDCl3): δ 9.49 (br, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7.48 (s, 1H), 7.38 (d, J = 8.4 Hz,
1H), 7.34 (d, J = 7.8 Hz, 2H), 7.20 (dd, J = 8.4, 1.2 Hz, 1H), 7.08 (d, J = 1.2 Hz, 1H),
2.47 (s, 3H), 2.46 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 186.9, 143.0, 136.0, 135.5,
134.6, 130.2, 129.4, 129.1, 128.4, 128.0, 122.3, 112.0, 111.8, 21.6, 21.4. HRMS (ESI)
m/z [M+H+] calcd for C17H16NO 250.1232, found 250.1229.
4.3.20. (4-Methoxyphenyl)(5-methyl-1H-indol-2-yl)methanone (2t)
o
1
Grayish-white solid (43.5 mg, 82% yield), mp 191.3-192.8 C. H NMR (600
MHz, CDCl3): δ 9.38 (br, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.48 (s, 1H), 7.37 (d, J = 8.4
Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 1.2 Hz, 1H), 7.02 (d, J = 9.0 Hz, 2H),
3.91 (s, 3H), 2.45 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 185.8, 163.1, 135.8, 134.6,
131.5, 130.8, 130.2, 128.2, 128.1, 122.2, 113.8, 111.8, 111.3, 55.5, 21.4. HRMS (ESI)
m/z [M+H+] calcd for C17H16NO2 266.1181, found 266.1179.
4.3.21. (4-Chlorophenyl)(5-methyl-1H-indol-2-yl)methanone (2u)
o
1
Yellow solid (44.8 mg, 83% yield), mp 210.4-211.3 C. H NMR (600 MHz,
CDCl3): δ 9.35 (br, 1H), 7.94 (d, J = 7.8 Hz, 2H), 7.51 (d, J = 7.8 Hz, 2H), 7.48 (s,
1H), 7.37 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 2.45 (s, 3H); 13C
13

NMR (150 MHz, CDCl3): δ 185.7, 138.7, 136.4, 136.2, 134.1, 130.6, 128.9, 128.8,
128.0, 122.38, 122.35, 112.3, 111.9, 21.4. HRMS (ESI) m/z [M+H+] calcd for
C16H13ClNO 270.0686, found 270.0681.
4.3.22. (5-Methyl-1H-indol-2-yl)(3-(trifluoromethyl)phenyl)methanone (2v)
o
1
Yellow solid (49.1 mg, 81% yield), mp 198.2-199.4 C. H NMR (600 MHz,
CDCl3): δ 9.34 (br, 1H), 8.24 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz,
1H), 7.68 (t, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4
13
Hz, 1H), 7.05 (s, 1H), 2.46 (s, 3H); C NMR (150 MHz, CDCl3): δ 185.5, 138.7,
136.3, 133.8, 132.3 (q, J = 1.0 Hz), 131.1(q, J = 32.7 Hz), 130.8, 129.2, 129.1, 128.7
(q, J = 3.6 Hz), 128.0, 126.0 (q, J = 3.6 Hz), 123.7 (q, J = 271.0 Hz), 122.5, 112.7,
111.9, 21.4. HRMS (ESI) m/z [M+H+] calcd for C17H13F3NO 304.0949, found
304.0950.
4.3.23. (5-iso-propyl-1H-indol-2-yl)(3-(trifluoromethyl)phenyl)methanone (2w)
o
1
Yellow solid (52.3 mg, 79% yield), mp 202.1-203.3 C. HNMR (600 MHz,
CDCl3): δ 9.49 (br, 1H), 8.26 (s, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 7.8 Hz,
1H), 7.68 (t, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4
Hz, 1H), 7.10 (s, 1H), 3.03 (sep, J = 7.2 Hz, 1H) , 1.32 (d, J = 7.2 Hz, 6H); 13C NMR
(150 MHz, CDCl3): δ 185.5, 142.1, 138.8, 136.7, 133.9, 132.3, 131.1 (q, J = 33.0 Hz),
129.1, 128.6, 127.9, 127.0, 126.0, 123.7 (q, J = 271.5 Hz), 119.7, 113.1, 112.1, 34.1,
24.3. HRMS (ESI) m/z [M+H+] calcd for C19H17F3NO 332.1262, found 332.1265.
4.3.24. (5-Bromo-1H-indol-2-yl)(3-(trifluoromethyl)phenyl)methanone (2x)
o
1
Yellow solid (51.5 mg, 70% yield), mp 231.0-232.2 C. HNMR(600 MHz,
CDCl3): δ 9.62 (br, 1H), 8.24 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 7.2 Hz,
1H), 7.88 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.47 (dd, J =1.2, 9.0 Hz, 1H), 7.39 (d, J =
8.4 Hz, 1H), 7.07 (s, 1H); 13C NMR (150 MHz, CDCl3): δ 185.5, 138.2, 136.3, 134.6,
132.3, 131.3 (q, J = 33.0 Hz), 130.0, 129.2, 129.1, 129.0, 126.0, 125.6, 123.7 (q, J =
270.0 Hz), 114.4, 113.8, 112.0. HRMS (ESI) m/z [M+H+] calcd for C16H10BrF3NO
367.9898, found 367.9896.
4.3.25. (5-Methyl-1H-indol-2-yl)(thiophen-2-yl)methanone (2y)
o
1
Yellow solid (42.0 mg, 87% yield), mp 129.4-130.6 C. HNMR (600 MHz,
14

CDCl3): δ 9.37 (br, 1H), 8.03 (dd, J = 3.6, 0.6 Hz, 1H), 7.70 (dd, J = 5.4, 1.2 Hz, 1H),
7.51 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.23-7.20 (m, 2H),
2.46 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 177.8, 142.6, 135.9, 134.2, 133.0, 132.8,
130.4, 128.5, 128.1, 128.0, 122.3, 111.8, 110.2, 21.4. HRMS (ESI) m/z [M+H+] calcd
for C14H12NOS 242.0640, found 242.0643.
4.3.26. (5-iso-propyl-1H-indol-2-yl)(thiophen-2-yl)methanone (2z)
o
1
Yellow solid (41.2 mg, 82% yield), mp 134.3-135.4 C. HNMR (600 MHz,
CDCl3): δ 9.57 (br, 1H), 8.05 (dd, J = 3.6, 1.2 Hz, 1H), 7.71 (dd, J = 4.8, 0.6 Hz, 1H),
7.57 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 1.2 Hz, 1H), 7.29 (dd, J = 8.4, 1.2
Hz, 1H), 7.23 (dd, J = 3.6, 4.2 Hz, 1H) , 3.03 (sep, J = 7.2 Hz, 1H) , 1.33 (d, J = 7.2
13
Hz, 6H); C NMR (150 MHz, CDCl3): δ 177.8, 142.6, 141.8, 136.2, 134.3, 133.0,
132.8, 128.0, 127.9, 126.3, 119.5, 112.0, 110.5, 34.1, 24.4. HRMS (ESI) m/z [M+H+]
calcd for C16H16NOS 270.0953, found 270.0949.
4.3.27. (5-Bromo-1H-indol-2-yl)(thiophen-2-yl)methanone (2aa)
o
1
Yellow solid (45.9 mg, 75% yield), mp 207.1-208.2 C. HNMR (600 MHz,
CDCl3): δ 9.58 (br, 1H), 8.04 (d, J = 3.6 Hz, 1H), 7.88 (s, 1H), 7.74 (d, J = 4.8 Hz,
1H), 7.45 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.35 (s, 1H) , 7.24 (t, J = 4.2
13
Hz, 1H); C NMR (150 MHz, CDCl3): δ 177.6, 142.2, 135.8, 135.0, 133.6, 133.2,
129.4, 129.3, 128.2, 125.4, 114.2, 113.7, 109.4. HRMS (ESI) m/z [M+H+] calcd for
C13H9BrNOS 305.9588, found 305.9584.
Acknowledgments
We are grateful to the National Natural Science Foundation of China (21702002)
and Natural Science Foundation of Anhui Province (1608085MB26, 1808085QC79)
for financial support.
A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
15

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16

Highlights:
efficient synthesis of 2-aroylindoles from α-amino ketones
palladium-catalyzed tandam oxidative reactions in one pot
imines are the key intermediates

Declaration of interests
ꢀ☐ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐ The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
No