Palladium-catalyzed regioselective C2-arylation of 5-aminoindole

Article abstract of DOI:10.1002/jhet.3724

Pd(II)-catalyzed C-H arylations of 5-aminoindole using iodobenzenes as aryl source was studied. Despite pivalamide directing group at 5-position of the indole, the direct C2-arylation of the indole observed in high yields and with high regioselectivity.

Full text of DOI:10.1002/jhet.3724

Received: 21 May 2019
DOI: 10.1002/jhet.3724
Revised: 21 August 2019
Accepted: 25 August 2019
A R T I C L E
Palladium‐catalyzed regioselective C2‐arylation of
5‐aminoindole
Yunus Taskesenligil1
| Ferruh Lafzi1
| Haydar Kilic1,2
| Nurullah Saracoglu1
1 Department of Chemistry, Faculty of
Sciences, Atatürk University, Erzurum,
Turkey
2 Oltu Vocational Training School, Atatürk
University, Erzurum, Turkey
Abstract
Pd(II)‐catalyzed C‐H arylations of 5‐aminoindole using iodobenzenes as aryl
source was studied. Despite pivalamide directing group at 5‐position of the
indole, the direct C2‐arylation of the indole observed in high yields and with
high regioselectivity.
Correspondence
Nurullah Saracoglu, Department of
Chemistry, Faculty of Sciences, Atatürk
University, Erzurum 25240, Turkey.
Email: nsarac@atauni.edu.tr
Funding information
Atatürk University, Grant/Award Num-
bers: 2016/161 and FAD‐2017‐6107
1 | INTRODUCTION
examples of transition metal catalyzed ortho‐C─H
functionalization of aromatic compounds have been
The indole framework has paramount importance to
biology and chemistry due to its ubiquitous presence in
numerous natural products, bioactive molecules, and
functional molecules.[1] Amongst the indole class, aryl‐
substituted indole moieties are the constituent of numer-
ous natural products and bioactive compounds (Figure 1).
reported to date.[8] For example, Daugulis and Zaitsev
reported anilide ortho‐arylation by using Pd(OAc)2‐cata-
lyzed sp2 C─H activation methodology via stoichiomet-
ric AgOAc in conjunction with Ar‐I (Scheme 1).[9] This
process has been applied to the arylation of 2‐aryl pyri-
dine, benzoxazoles, and benzoic acid derivatives as well
as substituted anilides.[10] So far, Sames group reported
the synthesis of two 2‐arylindoles (single example) for
N‐(1H‐indol‐5‐yl)pivalamide (7) using Pd(II) and Rh(I)
catalysis.[11,12]
However, arylated‐indoles through benzenoid ring
could not be accessed with the two methods despite
the use of directing groups such as carbamate, and
carboxamide at the C5.[11,12] Furthermore, although the
C2‐ and C3‐arylation mechanisms of the indoles via Pd
(0)/Pd(II) are well established, the mechanism via the high
oxidation state Pd(II)/Pd(IV) are less well known. Clearly,
protocols for the functionalization of indoles are still of
high interest. We, therefore, attempted the arylation using
the reaction conditions of Daugulis and Zaitsev in the hope
of arylation in the benzenoid ring of N‐(1H‐indol‐5‐yl)
pivalamide (7), which unfortunately did not provide the
desired arylation (Scheme 1). We report herein an efficient
strategy for the synthesis of 2‐arylindoles 8 via Pd(II)‐
[2]
Particularly, C2‐ and C3‐arylindoles are ubiquitous
substructures of many natural products as well as drug
components.[3] In this context; installation of various sub-
stituents on the indole ring has served as structural plat-
forms for the search of new synthetic methods and
strategies for many years.[4] At the same time, the search
for methods to functionalize of indole has also been the
topic of many studies to impart a variety of bioactivity
to the heterocyclic molecules.[5]
In recent years, transition metal‐catalyzed C─H
functionalization of indoles has been used as a powerful
tool to access the substituted indoles and has been
examined experimentally and theoretically.[6,7] In com-
parison with the selective direct functionalization at
the pyrrole core of indoles, the regioselective introduc-
tion of a functional group at the benzenoid ring is a
great challenge due to the poor reactivity of the benzene
ring.[7] A survey of the literature reveals that numerous
J Heterocyclic Chem. 2019;1–8.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
TASKESENLIGIL ET AL.
protocol provides 2‐arylindoles under mild reaction condi-
tions in good yields with excellent regioselectivity.
2 | RESULTS AND DISCUSSION
To begin our investigation of Pd(OAc)2/AgOAc catalytic
system‐based amide‐directed C─H arylation method, we
first prepared substrate 7 from 5‐nitroindole (10). Reduc-
tion of the nitro group in compound 10, with Pd and H2
in MeOH, gave compound 11, which on treatment with
pivaloyl chloride, Et3N in THF gave amide compound
11 as the pivaloyl amide (Scheme 2). As a starting
point, we then proceeded to optimize the reaction con-
ditions for the Pd‐catalyzed C─H arylation of 7 with
iodobenzene as model substrates (Table 1). The reaction
between 5‐carboxamide indole 7 and iodobenzene (2a)
with AgOAc as an additive in the presence of Pd(OAc)
FIGURE 1 Chemical structures of the selected aryl substituted
indoles. [Color figure can be viewed at wileyonlinelibrary.com]
in trifluoroacetic acid (TFA) at 120°C for 24 hours
2
gave unexpected C2‐arylated product 8a along with acyl-
ation product 12 as a by‐product (Scheme 2). Structures
of the products 8a and 12 were confirmed from NMR
experiments. On the other hand, when the reaction
was carried out in the presence of 5 mol% of the Pd
(OAc)2 catalyst without TFA or with TFA in aprotic
and protic solvents such as THF; toluene; 1,2‐
dichloroethane
(1,2‐DCE);
N,N‐dimethylformamide
(DMF); 1,4‐dioxane; and AcOH, at 70°C for 24 hours,
any arylated product was not obtained (Table 1, entries
1‐13). We then carried out the C─H arylation in the
presence of 5 mol% of the Pd(OAc)2 catalyst and AgOAc
(2 equiv.) as the additive in TFA at 70°C for 24 hours.
This reaction at the lower temperature in TFA was
remarkably highly regioselective and provided C2
arylated product 8a in 70% yield with a trace amount
acylation product 12 (Table 1, entry 14). Furthermore,
the Pd(II)‐catalyzed arylation reaction of substrate 7
with iodobenzene (5a) at the lower temperature such
as 50 and 30°C resulted in significantly decreased yields
of 8a (53% and 35%) (Table 1, entries 15 and 16). A sig-
nificant improvement was achieved by using 1,1,1,3,3,3‐
hexafluoro‐2‐propanol (HFIP) and a mixture of HFIP:
SCHEME 1 Pd(II)‐catalyzed selective C2 arylation of indole
despite amide directing group [Color figure can be viewed at
wileyonlinelibrary.com]
catalyzed C─H activation of indole pivalamide 7 with aryl
iodides 5a‐5i as the coupling partner (Scheme 1). This
SCHEME 2 Synthesis of substrate 7
from 5‐nitroindole (10) and the Pd‐
catalyzed C─H arylation of 7 with
iodobenzene [Color figure can be viewed
at wileyonlinelibrary.com]

TASKESENLIGIL ET AL.
3
TABLE 1 Optimization of reaction conditions
TFA (1:1, v/v), and the yield was dramatically increased
up to 80% and 95% (Table 1, entries 17 and 18). Accord-
ingly, HFIP:TFA (1:1, v/v) was selected as the optimal
solvent for the rest of our exploration of the reaction
scope. Notably, in the absence of Pd(OAc)2 in TFA or
HFIP for the reaction between 7 and 8, while no
arylation reaction did take place, the reaction using
TFA gave almost completely the acylation product 12.
We next explored the scope of the direct C2 arylation
of the indole under the optimized conditions (Table 2).
Cross‐coupling reactions of indole pivalamide 7 with a
broad range of aryl iodides 5a‐q were also examined.
Iodoarenes 5b‐k containing an alkyl, halogen, ketone,
ester, hydroxide, and methoxy groups on the aryl ring
at ortho, meta, and para positions afforded the desired
products 8b‐k in 75 to 96% yield. The reactions of indole
with 1‐(tert‐butyl)‐4‐iodobenzene (5d) and 4‐iodo‐1,2‐
dimethylbenzene (5b) as the coupling partner afforded
the corresponding 2‐aryl indoles in 80 and 87% yields,
whereas the 1‐iodo‐4‐(trifluoromethyl)benzene (5h) yielded
corresponding coupling product in 96% yield. The other
aryl iodides also delivered the C2‐arylated indoles under
the optimum reaction conditions.
Entry
Solvent
T, °C
TFA, mL
8a, %
12, %
1
TFA
120
70
70
70
70
70
70
70
70
70
70
70
70
70
50
30
60
60
70
2
56
‐
14
2
THF
‐
‐
3
1,2‐DCE
Toluene
DMF
‐
‐
‐
4
‐
‐
‐
5
‐
‐
‐
6
1,4‐Dioxane
AcOH
‐
‐
‐
7
‐
‐
‐
8
THF
0.1
0.1
0.1
0.1
0.1
0.1
2
‐
‐
9
1,2‐DCE
Toluene
DMF
‐
‐
10
11
12
13
14
15
16
17
18
19
‐
‐
‐
‐
1,4‐Dioxane
AcOH
‐
‐
‐
‐
TFA
70
53
35
80
95
80
trace
TFA
2
trace
TFA
2
Trace
Surprisingly, the aryl iodides 5l‐q bearing an electron‐
withdrawing and electron‐donating substituent (such as
ortho‐methyl, para‐methoxy, para‐nitrile, meta‐nitrile,
and para‐formyl) and 3‐iodopyridine (5n) did not partici-
pate in the C─H activation/coupling reaction to yield the
desired arylation product 8l‐q under these conditions. For
the ortho‐methyl‐substituted aryl derivative, this case
HFIP (1 mL)
HFIP (1 mL)
HFIP (1 mL)
‐
‐
‐
‐
1
1
Reaction conditions: Iodobenzene (2 equiv.), Pd(OAc)2 (5 mol%), AgOAc (2 equiv.)
Bold text shows the highest yield condition obtained.
TABLE 2 Reaction scope of aryl iodides
product: yield
(Continues)

4
TASKESENLIGIL ET AL.
TABLE 2 (Continued)
product: yield
SCHEME 3 Plausible mechanistic pathway to C2‐arylation of N‐(1H‐indol‐5‐yl)pivalamide (3) [Color figure can be viewed at
wileyonlinelibrary.com]
might be attributable to the influence of steric hindrance.
These results indicate that the electronic effect is not a
major factor in this reaction.
2‐position of the indole. It should be noted that this reac-
tion did not undergo the arylpalladium intermediates D
and E leading to 4‐ or 6‐arylindoles.
Although more mechanistic pathways on C─H activa-
tion reactions involving Pd(0) for the formation of
C2 arylated indoles have been proposed, the cationic
palladium‐proposed mechanisms have been much less.[13]
In this context, Sames and co‐workers showed a mecha-
nism involving initial palladation at C3 followed by palla-
dium migration to C2 via the Pd(II)/Pd(IV) pathways for
C2 arylations of indoles.[14] Accordingly, this scenario is
progressing to afford an arylpalladium intermediate indole
cations A and B, followed by oxidative addition of palla-
dium(II) to the ArI (Scheme 3). And then, this
arylpalladium intermediate C dictates the selectivity, and
the arene‐Pd(IV) complex C installs the C─C bond at the
3 | CONCLUSIONS
In conclusion, a palladium‐catalyzed reaction between a
wide range of functionalized aryl iodides and indole con-
taining pivalamide as the directing group was performed
based on regioselective C─H activation. The correspond-
ing pivaloylamide group was not served as an effective
directing group. Based on these results, we assume that
the origin of regioselectivity resulted from the natural
electronic properties of the indole substrate. The present
method highlights a simple one‐step transformation from

TASKESENLIGIL ET AL.
5
readily available aryl iodides and free (NH)‐indole to
structurally diverse 2‐aryl‐5‐pivalamide indole deriva-
tives. New C2‐arylated indoles may be candidates for the
development of NorA efflux pump inhibitor.
was purified by silica gel chromatography (eluting 20:80
EtOAc‐hexane, 700 mL) to yield N‐(1H‐indol‐5‐yl)
pivalamide (7) as a light brown solid (758 mg, 93%; m.p.
1
= 208‐209 °C). H NMR (400 MHz, DMSO‐d6): δ 10.96
(bs, NH, 1H), 9.00 (bs, NH, 1H), 7.80 (s, =CH, 1H),
7.33–7.28 (m, =CH, 2H), 7.24 (dd, j = 8.6, 1.3 Hz, B part
of AB system, =CH, 1H), 6.37 (s, =CH, 1H), 1.25 (s,
CH3, 9H). 13C NMR (100 MHz, DMSO‐d6): δ 176.2,
132.9, 131.0, 127.5, 125.8, 116.3, 112.6, 110.7, 101.3, 38.8,
27.6.
4 | EXPERIMENTAL SECTION
4.1 | General Information
All reactions were monitored by thin‐layer chromatogra-
phy (silica gel 60 F254, Sigma) using ultraviolet light
1
1
and/or H NMR spectroscopy. H and 13C NMR spectra
were recorded with tetramethylsilane as an internal stan-
dard at ambient temperature with Bruker and Varian 400
5 | THE REACTION OF 7 AND
IODOBENZENE (5a) AT 120 OC
1
MHz instruments at 400 MHz for H NMR and 100 MHz
Pd(OAc)2 (5.19 mg, 0.023 mmol), AgOAc (154 mg,
0.92 mmol), and iodobenzene (5a; 0.10 mL, 0.92 mmol)
was added to the solution of 7 (100 mg, 0.46 mmol) in
TFA (2 mL) in pyrex thermolysis tube. After the tube was
sealed, the reaction mixture was stirred at 120 °C for 1
hour. The mixture was cooled to room temperature, diluted
with toluene (40 mL) filtered, and concentrated. The crys-
tallization from chloroform‐hexane of the resulting mate-
rial gave N‐(2‐phenyl‐1H‐indol‐5‐yl)pivalamide (8a) as
white solid (74 mg, 56%; m.p. = 286‐287 °C). The recrystal-
lization of the liquid fraction from chloroform‐hexane
for 13C NMR spectroscopy. Coupling constants (J) are
given in hertz, and splitting patterns are reported as sin-
glet (s), doublet (d), triplet (t), and multiplet (m). The
high‐resolution mass spectrometry (HRMS) analysis was
carried out using an atmospheric pressure chemical
ionization‐time of flight (APCI‐TOF) mass spectrometer.
The solvents were dried and distilled according to the lit-
erature methods. All the chemical reagents were obtained
from commercial sources unless otherwise indicated. Col-
umn chromatography was performed on silica gel (60
mesh, Merck). Melting points are uncorrected.
yielded
N‐(3‐(2,2,2‐trifluoroacetyl)‐1H‐indol‐5‐yl)
pivalamide (12) as yellow solid (21 mg, 14%; m.p. = 257‐
258 °C). For N‐(2‐phenyl‐1H‐indol‐5‐yl)pivalamide
(8a): H NMR(400 MHz, DMSO‐d6): δ 11.44 (bs, NH,
4.2 | 1H‐Indol‐5‐amine (11)
1
1H), 9.05 (bs, NH, 1H), 7.98–7.74 (m, =CH, 3H), 7.45 (t, J
= 7.4 Hz, =CH, 2H), 7.36–7.21 (m, =CH, 3H), 6.86 (m,
=CH, 1H), 1.26 (s, CH3, 9H). 13C NMR (100 MHz, DMSO‐
d6): δ 176.0, 138.0, 134.0, 132.2, 131.6, 128.8, 128.3, 127.3,
About 10% Pd/C (130 mg) was added to a solution of the
5‐nitro‐1H‐indole 10 (1 g, 6.17 mmol) in MeOH (30 mL).
The system was degassed 3 times (vacuum/H2), then
reacted under H2 atmosphere (1 atm) for 12 hours at
room temperature. The mixture was filtered over a filter
paper, and the filtrate was concentrated on rotary evapo-
rator to provide the product 11 as a brown solid (800 mg,
1
124.9, 117.0, 112.2, 110.7, 98.7, 38.9, 27.4. H NMR (400
MHz, Acetone‐d6): δ 10.41 (bs, NH, 1H), 8.26 (bs, NH,
1H), 7.81 (s, =CH, 1H), 7.71 (d, J = 7.8 Hz, =CH, 2H),
7.30 (t, J = 7.7 Hz, =CH, 2H), 7.24–7.10 (m, =CH, 3H),
6.71 (d, J = 2.1 Hz, =CH, 1H), 1.18 (s, CH3, 9H). 1H NMR
(400 MHz, Methanol‐d4): δ 9.01 (bs, NH, 1H), 7.79 (d, J =
8.3 Hz, =CH, 2H), 7.66 (d, J = 1.7 Hz, =CH, 1H), 7.43 (t, J
= 7.7 Hz, =CH, 2H), 7.36 (d, J = 8.6 Hz, A part of AB sys-
tem, =CH, 1H), 7.30 (t, J = 7.3 Hz, =CH, 1H), 7.16 (dd, J
= 8.6, 1.9 Hz, B part of AB system, =CH, 1H), 6.79 (s,
=CH, 1H), 1.35 (s, CH3, 9H). HRMS (APCI‐TOF) (m/z):
[M + H]+ calcd for C19H21N2O 293.1609; found, 293.1636.
IR (Acetone, cm−1): 3271, 2964, 1618, 1543, 1479, 1219,
763. For N‐(3‐(2,2,2‐trifluoroacetyl)‐1H‐indol‐5‐yl)
pivalamide (12): 1H NMR(400 MHz, Acetone‐d6): δ
11.45 (bs, NH, 1H), 8.63 (bs, NH, 1H), 8.33 (d, J = 1.8 Hz,
=CH, 1H), 8.17 (dd, J = 3.1, 1.6 Hz, =CH, 1H), 7.68 (dd, J
= 8.8, 2.0 Hz, =CH, 1H), 7.37 (d, J = 8.8 Hz, =CH, 1H),
1.20 (s, CH3, 9H). 13C NMR (100 MHz, Acetone‐d6): δ
1
97%; m.p. = 131‐132 °C). H NMR (400 MHz, DMSO‐d6):
δ 10.57 (bs, NH, 1H), 7.13‐7.09 (m, =CH, 2H), 6.71 (s,
=CH, 1H), 6.50 (dd, J = 8.4, 1.6Hz, =CH, 1H) 6.14 (s,
=CH, 1H), 4.40 (bs, NH2, 2H). 13C NMR (100 MHz,
DMSO‐d6): δ 141.2, 130.1, 128.4, 124.9, 111.8, 11.4, 103.2,
99.6.
4.3 | N‐(1H‐indol‐5‐yl)pivalamide (7)
Pivaloyl chloride (0.51 mL, 4.16 mmol) and triethylamine
(0.58 mL, 4.16 mmol) was added to a stirred solution of
compound 11 (500 mg, 3.78 mmol) in THF (30 mL)
dropwise at 0 °C, and the reaction mixture was stirred
at room temperature for 3 hours. The solvent was
removed under reduced pressure, and the compound

6
TASKESENLIGIL ET AL.
177.2, 175.0, 137.5 (q, J = 4.9 Hz), 136.8, 134.3, 127.3, 119.7,
116.7, 114.0, 113.1, 110.7, 40.2, 27.9. HRMS (APCI‐TOF)
(m/z): [M + H]+ calcd for C15H16F3O2 313.1199; found
313.1143. IR (Acetone, cm−1): 3434, 2103, 1647, 564.
CH3, 3H), 1.29 (s, CH3, 9H). 13C NMR (100 MHz,
DMSO‐d6): δ 175.9, 138.3, 136.6, 135.4, 133.9, 131.4,
129.9, 129.8, 128.4, 126.0, 122.3, 116.6, 112.0, 110.5, 97.9,
38.9, 27.4, 19.5, 19.1. HRMS (APCI‐TOF) (m/z): [M +
H]+ calcd for C21H25N2O 321.1922; found 371.1948. IR
(Acetone, cm−1): 3429, 2087, 1642, 1481, 1219, 551.
6 | THE REACTION OF 7 AND
IODOBENZENE (5a) AT 70 OC
WITHOUT Pd(OAc)2
7.3 | N‐(2‐(p‐Tolyl)‐1H‐indol‐5‐yl)
pivalamide (8c)
AgOAc (154 mg, 0.92 mmol) and iodobenzene (5a; 0.10
mL, 0.92 mmol) was added to the solution of 7 (100 mg,
0.46 mmol) in TFA (2 mL) in pyrex thermolysis tube.
After the tube was sealed, the reaction mixture was
stirred at 70 °C for 2 hours. The mixture was cooled to
room temperature, diluted with toluene (40 mL) filtered,
and concentrated. The crude product was purified by sil-
ica gel chromatography (eluting 30:70 EtOAc‐hexane,
200 mL) to yield N‐(3‐(2,2,2‐trifluoroacetyl)‐1H‐indol‐5‐
yl)pivalamide (12) (122 mg, 85%).
The product 8c was prepared according to general
procedure using 1‐iodo‐4‐methylbenzene (5c; 402 mg,
1.84 mmol), as a white solid (154 mg, 90%; m.p. = 285‐
286 °C). 1H NMR (400 MHz, DMSO‐d6): δ 11.35 (bs,
NH, 1H), 9.02 (bs, NH, 1H), 7.79 (s, =CH, 1H), 7.74
(d, J = 8.0 Hz, =CH, 2H), 7.45–6.98 (m, =CH, 4H), 6.79
(s, =CH, 1H), 2.33 (s, CH3, 3H), 1.25 (s, CH3, 9H). 13C
NMR (100 MHz, DMSO‐d6): δ 175.9, 138.2, 136.6,
133.9,131.5, 129.5, 129.4, 128.4, 124.8, 116.7, 112.0, 110.6,
98.1, 38.9, 27.4, 20.8. HRMS (APCI‐TOF) (m/z): [M +
H]+ calcd for C20H23N2O 307.1766; found 307.1789. IR
(Acetone, cm−1): 3422, 3292, 2093, 1618, 791.
7 | GENERAL PROCEDURE FOR
ARYLATION REACTION
Pd(OAc)2 (5.19 mg, 0.023 mmol), AgOAc (154 mg,
0.92 mmol), and aryl iodide (2 equiv) was added to the
solution of 7 (100 mg, 0.46 mmol) in HFIP:TFA (1:1
mL) in pyrex thermolysis tube. After the tube was sealed,
the reaction mixture was stirred at 60 °C for 2 hours. The
mixture was cooled to room temperature, diluted with tol-
uene (40 mL) filtered, and concentrated. The resulting
material was purified by silica gel column chromatogra-
phy (20% Acetone/hexane) to yield a residue that was
recrystallized from Acetone/hexane.
7.4 | N‐(2‐(4‐(tert‐Butyl)phenyl)‐1H‐indol‐
5‐yl)pivalamide (8d)
The product 8d was prepared according to general proce-
dure using 1‐(tert‐butyl)‐4‐iodobenzene (5d; 481 mg, 1.84
mmol), as a white solid (256 mg, 80%; m.p. = ≫300 °C).
1H NMR (400 MHz, DMSO‐d6): δ 11.37 (bs, NH, 1H),
9.03 (bs, NH, 1H), 8.07–7.57 (m, =CH, 3H), 7.46 (d, J =
8.4 Hz, =CH, 2H), 7.27 (dt, J = 8.7, 5.2 Hz, =CH, 2H),
6.79 (s, =CH, 1H), 1.32 (s, CH3, 9H), 1.25 (s, CH3, 9H).
13C NMR (100 MHz, DMSO‐d6): δ 175.9, 149.8, 138.1,
133.9, 131.5, 129.5, 128.4, 125.6, 124.6, 116.7, 112.0,
110.6, 98.2, 38.9, 34.3, 31.0, 27.4. HRMS (APCI‐TOF) (m/
z): [M + H]+ calcd for C23H29N2O 349.2235; found
349.2259. IR (Acetone, cm−1): 3344, 3288, 2955, 1619, 794.
7.1 | N‐(2‐Phenyl‐1H‐indol‐5‐yl)pivalamide
(8a)
The product 8a was prepared according to general proce-
dure using iodobenzene (5a; 0.206 mL, 1.84 mmol), as a
white solid (256 mg, 95%; m.p. = 286‐287 °C).
7.5 | N‐(2‐(3‐Hydroxyphenyl)‐1H‐indol‐5‐
yl)pivalamide (8e)
7.2 | N‐(2‐(3,4‐Dimethylphenyl)‐1H‐indol‐
5‐yl)pivalamide (8b)
The product 8e was prepared according to general proce-
dure using 3‐iodophenol (5e; 406 mg, 1.84 mmol), as a
white solid (232 mg, 82%; m.p. = 254‐255 °C). H NMR
(400 MHz, DMSO‐d6): δ 11.36 (bs, NH, 1H), 9.55 (bs,
OH, 1H), 9.03 (bs, NH, 1H), 7.81 (s, =CH, 1H), 7.48–
6.96 (m, =CH, 4H), 6.85‐6.65 (m, =CH, 2H), 1.25 (s,
CH3, 9H). 13C NMR (100 MHz, DMSO‐d6): δ 176.0,
157.7, 138.3, 133.9, 133.5, 131.5, 129.8, 128.3, 116.9,
115.9, 114.5, 112.2, 111.8, 110.7, 98.6, 38.9, 27.4 HRMS
1
The product 8b was prepared according to general proce-
dure using 4‐iodo‐1,2‐dimethylbenzene (5b; 0.262 mL,
1.84 mmol), as a white solid (254 mg, 87%; m.p. = 268‐
269 °C). 1H NMR (400 MHz, DMSO‐d6): δ 11.37 (bs,
NH, 1H), 9.06 (bs, NH, 1H), 7.82 (s, =CH, 1H), 7.69 (s,
=CH, 1H), 7.60 (d, J = 7.8 Hz, =CH, 1H), 7.37–7.18 (m,
=CH, 3H), 6.81 (s, =CH, 1H), 2.34 (s, CH3, 3H), 2.29 (s,

TASKESENLIGIL ET AL.
7
(APCI‐TOF) (m/z): [M + H]+ calcd for C19H21N2O2
309.1558; found 309.1329. IR (Acetone, cm−1): 3434,
2963, 2102, 1646.
361.1483; found 361.1503. IR (Acetone, cm−1): 3434,
2986, 2096, 1619.
7.9 | Methyl 4‐(5‐pivalamido‐1H‐indol‐2‐
yl)benzoate (8i)
7.6 | N‐(2‐(4‐Acetylphenyl)‐1H‐indol‐5‐yl)
pivalamide (8f)
The product 8i was prepared according to general proce-
dure using methyl 4‐iodobenzoate (5i; 484 mg, 1.84
mmol), as a light yellow solid (242 mg, 75%; m.p. = 288‐
289 °C). 1H NMR (400 MHz, DMSO‐d6): δ 11.63 (bs,
NH, 1H), 9.07 (bs, NH, 1H), 8.10‐7.95 (m, =CH, 4H),
7.87 (s, =CH, 1H), 7.33 (s, =CH 2H), 7.04 (s, =CH, 1H),
3.87 (s, CH3, 3H), 1.25 (s, CH3, 9H). 13C NMR (100
MHz, DMSO‐d6): δ 176.0, 165.9, 136.63, 136.61, 134.5,
131.9, 129.8, 128.2, 127.8, 124.9, 117.9, 112.4, 111.0,
100.8, 52.1, 38.9, 27.4. HRMS (APCI‐TOF) (m/z): [M +
H]+ calcd for C21H23N2O3 351.1664; found 351.1686. IR
(Acetone, cm−1): 2916, 2845, 2397, 2291, 1608, 1541.
The product 8f was prepared according to general proce-
dure using 1‐(4‐iodophenyl)ethan‐1‐one (5f; 454 mg,
1.84 mmol), as a light green solid (264 mg, 86%; m.p. =
1
291‐292 °C). H NMR (400 MHz, DMSO‐d6): δ 11.62 (bs,
NH, 1H), 9.07 (bs, NH, 1H), 8.07‐7.95 (m, =CH, 4H),
7.87 (s, =CH, 1H), 7.39–7.17 (m, =CH, 2H), 7.05 (s,
=CH, 1H), 2.61 (s, CH3, 3H), 1.25 (s, CH3, 9H). 13C
NMR (100 MHz, DMSO‐d6): δ 197.1, 176.0, 136.7, 136.5,
135.1, 134.5, 131.9, 128.9, 128.2, 124.7, 117.9, 112.3,
111.0, 100.9, 38.9, 27.4, 26.7. HRMS (APCI‐TOF) (m/z):
[M + H]+ calcd for C21H23N2O2 335.1715; found
335.1739. IR (Acetone, cm−1): 3344, 3254, 2969, 2313,
1678, 1617.
7.10 | N‐(2‐(3‐Methoxyphenyl)‐1H‐indol‐5‐
yl)pivalamide (8j)
7.7 | N‐(2‐(4‐Bromophenyl)‐1H‐indol‐5‐yl)
pivalamide (8g)
The product 8j was prepared according to general proce-
dure using methyl 4‐iodobenzoate (5j; 0.220 mL, 1.84
mmol), as a white solid (247 mg, 83%; m.p. = 237.4‐
238.4 °C). 1H NMR (400 MHz, Acetone‐d6): δ 10.56
(bs, NH, 1H), 8.42 (bs, NH, 1H), 7.94 (s, =CH, 1H),
7.46–7.26 (m, =CH, 5H), 6.91–6.83 (m, =CH, 2H), 3.86
(s, CH3, 3H), 1.32 (s, CH3, 9H). 13C NMR (100 MHz,
Acetone‐d6): δ 166.5, 161.2, 139.4, 135.3, 135.0, 133.1,
130.8, 130.0, 118.3, 117.6, 113.9, 112.9, 111.6, 111.2,
100.3, 55.6, 40.0, 28.0. HRMS (APCI‐TOF) (m/z): [M +
H]+ calcd for C20H23N2O2 323.1760; found 323.1775.
The product 8f was prepared according to general proce-
dure using 1‐bromo‐4‐iodobenzene (5f; 523 mg, 1.84
mmol), as a yellow solid (290 mg, 85%; m.p. = 300‐301 °
C). 1H NMR (400 MHz, DMSO‐d6): δ 11.49 (bs, NH,
1H), 9.05 (bs, NH, 1H), 8.07–7.70 (m, =CH, 3H), 7.64 (d,
J = 7.6 Hz, =CH, 2H), 7.30 (s, =CH, 2H), 6.90 (s, =CH,
1H), 1.25 (s, CH3, 9H). 13C NMR (100 MHz, DMSO‐d6):
δ 176.0, 136.8, 134.1, 131.7, 131.6, 131.5, 128.2, 126.8,
120.2, 117.3, 112.2, 110.8, 99.4, 38.9, 27.4. HRMS (APCI‐
TOF) (m/z): [M + H]+ calcd for C19H20BrN2O 371.0714;
found 371.0733. IR (Acetone, cm−1): 3355, 3263, 2952,
1615, 1542, 1433, 1213, 792.
7.11 | N‐(2‐(m‐Tolyl)‐1H‐indol‐5‐yl)
pivalamide (8k)
7.8 | N‐(2‐(4‐(Trifluoromethyl)phenyl)‐1H‐
indol‐5‐yl)pivalamide (8h)
The product 8k was prepared according to general
procedure using methyl 4‐iodobenzoate (5k; 0.237 mL,
1.84 mmol), as a white solid (252 mg, 89%; m.
The product 8h was prepared according to general proce-
dure using 1‐iodo‐4‐(trifluoromethyl)benzene (5h; 0.270
mL, 1.84 mmol), as a white solid (318 mg, 96%; m.p. =
1
p. = 255.8‐256.8 °C). H NMR (400 MHz, Acetone‐d6): δ
10.56 (bs, NH, 1H), 8.43 (bs, NH, 1H), 7.94 (s, =CH,
1H), 7.67 (s, =CH, 1H), 7.63 (d, J = 7.9 Hz, =CH, 1H),
7.36–7.28 (m, =CH, 3H), 7.12 (d, J = 7.5 Hz, =CH, 1H),
6.82 (d, J = 2.1 Hz, =CH, 1H), 2.38 (s, CH3, 3H), 1.31
(s, CH3, 9H). 13C NMR (100 MHz, Acetone): δ 176.7,
139.6, 139.2, 135.3, 133.6, 133.0, 130.1, 129.7, 128.9,
126.5, 123.0, 117.5, 112.9, 111.5, 99.9, 40.0, 28.0, 21.5.
1
≫300 °C). H NMR (400 MHz, DMSO‐d6): δ 11.64 (bs,
NH, 1H), 9.07 (bs, NH, 1H), 8.06 (d, J = 8.1 Hz, =CH,
2H), 7.87 (s, =CH, 1H), 7.80 (d, J = 8.1 Hz, =CH, 2H),
7.38‐7.28 (m, =CH, 2H), 7.04 (s, =CH, 1H), 1.25 (s, CH3,
9H). 13C NMR (100 MHz, DMSO‐d6): δ 176.0, 136.2,
136.1, 134.4. 131.9, 128.1, 127.3, 127.0, 125.7 (q, J=4.9
Hz), 125.2, 117.9, 112.3, 111.0, 100.8, 38.9, 27.4. HRMS
(APCI‐TOF) (m/z): [M + H]+ calcd for C20H20F3N2O
HRMS (APCI‐TOF) (m/z): [M
C20H23N2O 307.1810; found 307.1816.
+
H]+ calcd for

8
TASKESENLIGIL ET AL.
J. Park, S. Han, Y. Shin, S. Sharma, Y. Lee, E. Lee, J. H. Kwak,
I. S. Kim, Chem. Commun. 2014, 50, 14249. (e) X. F. Yang, X. H.
Hu, T. P. Loh, Org. Lett. 2015, 17, 1481.
ACKNOWLEDGMENTS
This study is supported by the coordination of scientific
research projects of Atatürk University (project numbers:
2016/161 and FAD‐2017‐6107). We want to thank Atatürk
University for its support.
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ORCID
Yunus Taskesenligil
https://orcid.org/0000-0002-5399-
2520
Ferruh Lafzi https://orcid.org/0000-0002-3371-0899
Haydar Kilic https://orcid.org/0000-0002-7009-9953
Nurullah Saracoglu
https://orcid.org/0000-0002-1504-
7480
[7] J. A. Leitch, Y. Bhonoah, C. G. Frost, ACS Catal. 2017, 7, 5618.
[8] Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu, Y. Zhang, Org.
Chem. Front. 2015, 2, 1107.
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
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How to cite this article: Taskesenligil Y, Lafzi F,
Kilic H, Saracoglu N. Palladium‐catalyzed
regioselective C2‐arylation of 5‐aminoindole. J
Heterocyclic Chem. 2019;1–8. https://doi.org/
10.1002/jhet.3724
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