Palladium-Catalyzed Carbonylative Synthesis of N -Benzoylindoles with Mo(CO)6 as the Carbon Monoxide Source

Article abstract of DOI:10.1055/s-0034-1380752

A mild and carbon monoxide gas-free palladium-catalyzed aminocarbonylation of indole has been developed for the synthesis of N-benzoylindoles. This method uses Mo(CO)₆ as a convenient CO-precursor and BuPAd₂ as the ligand. A number o

Full text of DOI:10.1055/s-0034-1380752

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, A–F
paper
A
X.-F. Wu et al.
Paper
Synthesis
Palladium-Catalyzed Carbonylative Synthesis of N-Benzoylindoles
with Mo(CO)6 as the Carbon Monoxide Source
Xiao-Feng Wu*a,b
Stefan Oschatzb,c
Muhammad Sharifb
Peter Langer*b,c
Br
Pd(OAc)2, n-BuPAd2, DMF
N
+
DBU, K3PO4, 120 °C, Mo(CO)6
N
O
H
R
a Department of Chemistry, Zhejiang Sci-Tech University, Xiasha
Campus, Hangzhou Province, P. R. of China
xiao-feng.wu@catalysis.de
b Leibniz-Institut für Katalyse e.V. an der Universität Rostock,
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
c Universität Rostock, Institut für Chemie, Albert-Einstein-Str. 3a,
18059 Rostock, Germany
R
up to 97% yield
17 examples
peter.langer@uni-rostock.de
O
O
Received: 12.02.2015
Accepted after revision: 16.04.2015
Published online: 28.05.2015
DOI: 10.1055/s-0034-1380752; Art ID: ss-2015-z0108-op
H
Me
MeO
OH
H
Me
N
Me
O
N
Abstract A mild and carbon monoxide gas-free palladium-catalyzed
aminocarbonylation of indole has been developed for the synthesis of
N-benzoylindoles. This method uses Mo(CO)6 as a convenient CO-pre-
cursor and BuPAd2 as the ligand. A number of substituents on the aryl
bromide species is tolerated under the presented conditions and gave
the desired products in up to excellent yields.
MeO
N
O
O
Cl
H
H
vobasidine A (2)
indometacin (1)
OMe
MeO
MeO
Key words benzoylindole, aminocarbonylation, palladium catalyst,
molybdenum hexacarbonyl, indole
Me
H
N
O
N
Me
N
As an omnipresent structure, indole plays a superior
role in material science and in the chemistry of pharmaceu-
ticals, agrochemicals, flavoring agents, and dyes.1 One of
the most important pharmacological actions of indole de-
rivatives is their application to CNS disorders, for example,
reserpine (4),2 or their use as anti-inflammatory properties,
for example, indometacin (1, Figure 1).3 Some other indole
containing structures show cytostatic effect, such as voba-
sidin A (2),4 or act as nonpeptide angiotensin II receptor an-
tagonist for the treatment of hypertension, for example, 3.5
Due to the versatile applications of 2,3-benzopyrrole
containing structures, many efforts have been made to-
wards the synthesis or direct functionalization of these
compounds.6 Among the extensive achievements, selected
examples for the direct N-functionalization are mentioned
here. Notably, the NH group is not the most reactive center
for electrophilic reactions, which is C3, and usually has to
be transformed preliminary into the indolyl anion. Due to
the weak NH acidity [pK, e.g., 16.97 (H2O)7 and 21.0
(DMSO)8], the Mitsunobu reaction requires additional elec-
tron-withdrawing substituents on the indole-system to ac-
cess more branched N-alkyl derivatives.9 Many other proto-
O
N
Et
N
H
MeO
N
H
H
OMe
O
OMe
COOH
reserpine (4)
O
AII receptor antagonist (3)
Figure 1 Selected pharmacologically relevant indoles
cols for the N-alkylation and N-arylation have been devel-
oped such as the Morita–Baylis–Hilman reaction10 or
copper-11 and palladium12-catalyzed N-arylations, to name
only a few. Additionally, several procedures for the direct N-
benzoylation of indole have been reported in the literature.
The use of benzoyl chloride13 has been taken as a standard
procedure to obtain N-benzoylindoles. Palladium-catalyzed
carbonylation reaction has been explored in benzoylindoles
synthesis as well. Notably, Quesnel and Arndtsen reported
on the Pd-catalyzed in situ generation of the acid chloride
from iodobenzene under the use of 1 atm of CO gas, leading
to 85% benzoylindole.14 Additionally, the group of Bremner
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–F

B
X.-F. Wu et al.
Paper
Synthesis
reported in 2004 on the reaction of carboxylic acids with
indole, with DMAP and DCC as the activating agents.15 In
2010, Ren and Yamane published a protocol using Mo(CO)6
as CO-source and catalyst for the carbonylation of aryl io-
dides, and one example on iodobenzene and indole to give
60% benzoylindole was given.16
Table 2 Palladium-Catalyzed Carbonylative Synthesis of N-Benzoylin-
dolesa
Pd(OAc)2
n-BuPAd2
DMF
Br
N
+
DBU, K3PO4
120 °C, Mo(CO)6
N
O
Transition-metal-catalyzed carbonylation is a powerful
and versatile tool to access a broad variety of carbonyl com-
pounds.17 Since the first reported Pd-catalyzed aminocar-
bonylation in 1974,18 extensive work in the field of carbon-
ylation chemistry led to the development of a wide range of
catalytic systems that allow for the synthesis of various car-
bonyl-containing compounds.19 Many efforts have been
made to replace gaseous carbon monoxide as C1-building
block by easier to handle carbonyl sources. For instance, the
group of Skrydstrup developed COgen (9-methylfluorene-
9-carbonyl chloride) as a convenient organic CO-precursor
that also allows for the introduction of 13C-labeled carbonyl
groups.20 Additionally, transition metal carbonyls such as
Mo(CO)6 have been proven as beneficial CO-source in a va-
riety of carbonylative coupling reactions. The group of
Larhed reported on the broad applicability of the metal car-
bonyls.21 Recently, we showed that the molybdenum CO-
precursor is also appropriate for the tandem dicarbonyla-
tive coupling of o-dibromobenzenes to obtain phthalimid-
es.22 Here, we report our recent results on the palladium-
catalyzed carbonylative synthesis of benzoylindoles with
Mo(CO)6 as the CO source.
H
R
R
Entry
1
Product
Yield (%)b
N
89
53
97
O
N
2
3
4
O
NMe2
N
O
N
98
42
O
OMe
Table 1 Optimization of the Synthesis of N-Benzoylindolea
N
5
6
Br
[Pd], [CO]
O
N
+
N
H
O
Entry
Ligand
CO source
Yield (%)b
N
80
1c
2
n-BuPAd2
n-BuPAd2
Ph3P
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Co2(CO)8
W(CO)6
0
90
0
O
3
4
Cy3P
0
5
dppp
0
N
7
8
94
50
6d
7
n-BuPAd2
n-BuPAd2
n-BuPAd2
n-BuPAd2
0
O
OMe
85
68
95
8
9
Cr(CO)6
N
a Reaction conditions: indole (0.5 mmol), bromobenzene (0.5 mmol), DBU
(0.5 mmol), K3PO4 (0.5 mmol), CO source (0.5 mmol), Pd(OAc)2 (3 mol%),
ligand (6 mol%), DMF (3 mL), argon atmosphere, 120 °C, 16 h.
b GC yields with hexadecane as internal standard.
O
N
c Reaction was carried out without K3PO4.
d Reaction was carried out without DBU.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–F

C
X.-F. Wu et al.
Paper
Synthesis
Table 2 (continued)
Initial experiments for the carbonylative coupling of in-
dole and bromobenzene were carried out using Pd(OAc)2 as
the palladium source and BuPAd2 as the ligand (Table 1, en-
try 1). Our experience in the field of carbonylative C–N cou-
pling showed that the CataCXium® A [di(1-adamantyl)-n-
butylphosphine] ligand, developed by Beller et al., proved to
be excellent for aminocarbonylations.23 DBU was used as
the base of choice due to its ability to coordinate at the mo-
lybdenum to promote the in situ release of CO.24 Unfortu-
nately, no desired product could be detected in the first
testing. To our delight, when performing the reaction with
the addition of one equivalent of K3PO4 as the base, 90%
yield of benzoylindole was formed (Table 1, entry 2). Then,
investigation on the influence of different ligands on this
reaction was carried out. Interestingly, standard ligands
such as Ph3P (Table 1, entry 3) and the bidentate dppp did
not show any conversion of the substrate.
Notably, when performing the reaction only with K3PO4
and without the addition of DBU no reaction took place. Af-
terwards, different metal carbonyls were tested as CO
sources. According to our previous work,22 Cr(CO)6 (Table 1,
entry 9) shows high potential as CO-precursor. Cobalt and
tungsten carbonyls lead to lower yields. Chromium carbon-
yl gave better yield, however, due to the high toxicity of
chromium salts Mo(CO)6 was used for further studies.
With a working procedure in hand, substrate testing
was started. As shown in Table 2, the presented method
shows high yields up to 98% for electron-donating substitu-
ents such as methyl (Table 2, entries 3, 6) or methoxy (Table
2, entries 4, 7, and 10). The lower yields of the reaction with
mesityl bromide (Table 2, entry 5) can be explained by the
steric hindrance due to the two ortho methyl groups. A
methoxy group attached in meta position (Table 2, entry 9)
decreases the yield to 38%. This may cohere with the loss of
the electron donation and the I-effect. The developed pro-
cedure works also for electron-withdrawing substituents.
Heterocyclic bromides such as pyridyl and thiophenyl can
also be applied as substrates for this transformation, al-
though the yields are lower compared to the model reac-
tion.25
Entry
Product
Yield (%)b
OMe
N
9
38
O
OMe
N
10
11
12
13
14
15
16
87
23
23
28
39
25
49
O
N
O
N
O
N
N
O
N
S
O
F
N
O
CF3
In summary, a versatile method to obtain various N-
benzoylindoles via palladium-catalyzed aminocarbonyla-
tion of aryl bromides has been elaborated. Mo(CO)6 was
used as a convenient and easy-to-handle carbonyl source.
The protocol works very well for electron-donating substit-
uents such as methyl and methoxy, and also applicable for
heterocyclic arenes.
N
O
Br
N
17
18
O
Distilled H2O was used as solvent. All commercially available chemi-
cals were used without further purification. NMR spectra were re-
corded on Bruker ARX 300 and Bruker ARX 400 spectrometers. 1H
and 13C spectra were referenced to the residual solvent signals in the
deuterated solvent. Standard abbreviations were used to denote the
multiplicity of the signals. Gas chromatography/mass analysis was
a Reaction conditions: indole (0.5 mmol), aryl bromide (0.5 mmol), DBU
(0.5 mmol), K3PO4 (0.5 mmol), Mo(CO)6 (0.5 mmol), Pd(OAc)2 (3 mol%),
n-BuPAd2 (6 mol%), DMF (3 mL), argon atmosphere, 120 °C, 16 h.
b Isolated yields.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–F

D
X.-F. Wu et al.
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Synthesis
carried out using an Agilent HP-5890 with Agilent HP-5973 Mass Se-
lective Detector (EI) and an HP-5 capillary column using He as carrier
gas. Column chromatography was performed using Merck silica Gel
60 (0.043–0.06 mm) and distilled solvents were used.
1H NMR (300 MHz, CDCl3): δ = 8.33 (1 H, dd, 3J = 8.2 Hz, 4J = 1.1 Hz,
CH-7), 7.60 (1 H, ddd, 3J = 7.4 Hz, 4J = 1.6 Hz, 5J = 0.7 Hz, CH-4), 7.43–
7.27 (2 H, m, CH-5 + 6), 7.13 (1 H, d, 3J = 3.8 Hz, CH-2), 6.88–6.77 (3 H,
m, CH-11 + 13 + 14), 6.59 (1 H, dd, 3J = 3.8 Hz, 5J = 0.8 Hz, CH-3), 3.87
(3 H, s, OCH3), 2.36 (3 H, s, CH3).
13C NMR (75 MHz, CDCl3): δ = 169.1 (C=O), 161.3 (COMe), 138.9 (CH-
14), 135.8 (Cq-7a), 132.9 (Cq-9), 131.1 (Cq-3a), 130.0 (CH-11), 127.4
(CH-4), 125.0 (CH-2), 124.0 (CH-5), 121.0 (CH-6), 116.5 (CH-7), 113.0
(CH-13), 111.1 (Cq-10), 108.7 (CH-3), 55.5 (OCH3), 19.9 (CH3).
GC/MS (EI 70 eV): m/z (%) = 265 ([M]+, 17), 150 (14), 149 (100), 121
(13), 91 (12).
N-Benzoylindole; Typical Procedure
An argon flushed pressure tube was charged with indole (59 mg, 0.5
mmol), bromobenzene (62 μL, 0.5 mmol), Mo(CO)6 (132 mg, 0.5
mmol), DBU (75 μL, 0.5 mmol), K3PO4 (106 mg, 0.5 mmol), Pd(OAc)2
(3.4 mg, 3 mol%), BuPAd2 (10.8 mg, 6 mol%), and DMF (3 mL). The tube
was subsequently sealed and the mixture was stirred at 120 °C for 16
h. Afterwards, the reaction mixture was diluted with CH2Cl2 (3 × 5
mL) and washed with H2O (3 × 5 mL). The aqueous layer was extracted
with CH2Cl2 (2 × 5 mL), the combined organic phases were dried
(Na2SO4), and the solvent was evaporated. The crude product was pu-
rified by column chromatography (pentane–EtOAc (8:2) with addi-
tion of 0.5% Et3N) to give benzoylindole as a viscous oil that solidified
on standing; yield: 98 mg (89%); mp 64–65 °C.
1H NMR (300 MHz, CDCl3): δ = 8.42 (1 H, d, J = 8.0 Hz, CH-7), 7.80–
7.69 (2 H, m, CH-10 + 14), 7.66–7.58 (2 H, m, CH-12 + 4), 7.53 (2 H, dd,
3J = 8.1 Hz, 4J = 6.3 Hz, CH-11 + 13), 7.45–7.28 (3 H, m, CH-2 + 5 + 6),
6.62 (1 H, d, 3J = 3.7 Hz, CH-3).
13C NMR (63 MHz, CDCl3): δ = 168.8 (C=O), 136.2 (Cq-7a), 134.7 (Cq-9),
132.0 (CH-12), 130.9 (Cq-3a), 129.3 (CH-10 + 14), 128.7 (CH-11 + 13),
127.7 (CH-4), 125.0 (CH-2), 124.1 (CH-5), 121.0 (CH-6), 116.5 (CH-7),
108.7 (CH-3).
N-(2,4,6-Trimethylbenzoyl)indole
Yield: 55 mg (42%); viscous liquid.
1H NMR (300 MHz, CDCl3): δ = 8.69 (1 H, dd, 3J = 8.2 Hz, 4J = 1.0 Hz,
CH-7), 7.59 (1 H, ddd, 3J = 7.7 Hz, 4J = 1.4 Hz, 5J = 0.7 Hz, CH-4), 7.43 (1
H, ddd, 3J = 8.4 Hz, 3J = 7.3 Hz, 4J = 1.4 Hz, CH-6), 7.38–7.30 (1 H, m,
4
4
CH-5), 6.93 (2 H, d, J = 1.3 Hz, J = 0.8 Hz, CH-11 + 13), 6.81 (1 H, d,
3J = 3.8 Hz, CH-2), 6.54 (1 H, d, 3J = 3.8 Hz, CH-3), 2.35 (3 H, s, CH3),
2.19 (6 H, d, 4J = 0.7 Hz, CH3).
3
13C NMR (75 MHz, CDCl3): δ = 162.1 (C=O), 139.7 (Cq-9), 134.7 (Cq-7a),
131.2 (Cq-10 + 14), 129.7 (Cq-3a), 128.5 (CH-13 + 11), 126.6 (CH-4),
125.3 (CH-2), 124.3 (CH-5), 123.8 (Cq-12), 121.0 (CH-6), 116.9 (CH-7),
109.4 (CH-3), 21.4 (CH3), 19.3 (CH3).
GC/MS (EI 70 eV): m/z (%) = 263 ([M]+, 12), 148 (11), 147 (100), 119
(18), 91 (10).
GC/MS (EI 70 eV): m/z (%) = 221 ([M]+, 37), 116 (11), 105 (100), 89
(18), 77 (68), 63 (15), 51 (24), 50 (11).
N-(3,5-Dimethylbenzoyl)indole
Yield: 100 mg (80%); light yellow solid; mp 79–81 °C.
N-(4-Dimethylaminobenzoyl)indole
1H NMR (300 MHz, CDCl3): δ = 8.43–8.37 (1 H, m, CH-7), 7.61 (1 H,
ddd, 3J = 7.6 Hz, 4J = 1.5 Hz, 5J = 0.8 Hz, CH-4), 7.42–7.27 (5 H, m, CH-2
+ 5 + 6 + 10 + 14), 7.27–7.20 (1 H, m, CH-12), 6.60 (1 H, dd, 3J = 3.8 Hz,
5J = 0.8 Hz, CH-3), 2.44–2.36 (6 H, m, CH3).
13C NMR (75 MHz, CDCl3): δ = 169.3 (C=O), 138.5 (Cq-10 + 14), 136.2
(Cq-7a), 134.7 (Cq-9), 133.6 (CH-12), 130.9 (Cq-3a), 127.9 (CH-4),
126.9 (CH-11 + 13), 125.0 (CH-2), 124.0 (CH-5), 121.0 (CH-6), 116.6
(CH-7), 108.4 (CH-3), 21.4 (CH3).
Yield: 70 mg (53%); viscous liquid.
1H NMR (300 MHz, CDCl3): δ = 8.31 (1 H, ddd, 3J = 8.1 Hz, 4J = 1.2 Hz,
5J = 0.6 Hz, CH-7), 7.76–7.69 (2 H, m, CH-10 + 14), 7.64–7.59 (1 H, m,
CH-4), 7.47 (1 H, d, 3J = 3.7 Hz, CH-6), 7.40–7.25 (2 H, m, CH-2 + 5),
6.77–6.69 (2 H, m, CH-11 + 13), 6.61 (1 H, d, 3J = 3.7 Hz, CH-3), 3.08 (6
H, s, CH3).
13C NMR (75 MHz, CDCl3): δ = 168.7 (C=O), 153.0 (Cq-12), 136.3 (Cq-
7a), 132.2 (CH-10 + 14), 130.7 (Cq-3a), 128.2 (CH-4), 124.4 (CH-2),
123.2 (CH-5), 120.8 (CH-6), 120.6 (Cq-9), 116.1 (CH-7), 111.0 (CH-11 +
13), 107.2 (CH-3), 40.2 (CH3).
GC/MS (EI 70 eV): m/z (%) = 249 ([M]+, 26), 134 (10), 133 (100), 105
(28), 79 (11), 77 (12).
GC/MS (EI 70 eV): m/z (%) = 264 ([M]+, 17), 149 (13), 148 (100), 116
(13), 104 (10), 89 (18), 77 (14).
N-(4-Methoxybenzoyl)indole
Yield: 118 mg (94%); light yellow solid; mp 137–138 °C.
1H NMR (300 MHz, CDCl3): δ = 8.39–8.31 (1 H, m, CH-7), 7.79–7.71 (2
H, m, CH-10 + 14), 7.61 (1 H, ddd, J = 7.5 Hz, J = 1.5 Hz, J = 0.7 Hz,
CH-4), 7.43–7.27 (3 H, m, CH-2 + 5 + 6), 7.06–6.98 (2 H, m, CH-11 +
13), 6.62 (1 H, dd, 3J = 3.8 Hz, 5J = 0.8 Hz, CH-3), 3.91 (3 H, s, OCH3).
13C NMR (75 MHz, CDCl3): δ = 168.4 (C=O), 162.8 (COMe), 136.2 (Cq-
7a), 131.8 (CH-10 + 14), 130.8 (Cq-3a), 127.9 (CH-4), 126.7 (Cq-9),
124.8 (CH-2), 123.8 (CH-5), 121.0 (CH-6), 116.3 (CH-7), 114.0 (CH-11
+ 13), 108.1 (CH-3), 55.7 (OCH3).
N-(4-Methylbenzoyl)indole
3
4
5
Yield: 114 mg (97%); white solid; mp 87–89 °C.
1H NMR (300 MHz, CDCl3): δ = 8.44–8.33 (1 H, m, CH-7), 7.65 (2 H, d,
3J = 8.1 Hz, CH-10 + 14), 7.43–7.28 (5 H, m, CH-2 + 5 + 6 + 11 + 13),
7.13 (1 H, dd, 3J = 8.6 Hz, 4J = 2.5 Hz, CH-4), 6.61 (1 H, dd, 3J = 3.7 Hz,
5J = 0.8 Hz, CH-3), 1.43 (3 H, s, CH3).
13C NMR (75 MHz, CDCl3): δ = 168.9 (C=O), 142.7 (Cq-9), 136.2 (Cq-7a),
131.8 (Cq-12), 130.9 (Cq-3a), 129.5 (CH-10 + 14), 129.4 (CH-11 + 13),
127.8 (CH-4), 124.9 (CH-2), 123.9 (CH-5), 121.0 (CH-6), 116.5 (CH-7),
108.4 (CH-3), 21.8.
GC/MS (EI 70 eV): m/z (%) = 251 ([M]+, 17), 135 (100), 116 (23), 107
(11), 92 (27), 89 (25), 77 (27), 64 (16), 63 (25).
GC/MS (EI 70 eV): m/z (%) = 235 ([M]+, 28), 119 (100), 116 (15), 91
(49), 90 (10), 89 (31), 65 (26), 63 (24), 39 (12).
(1H-Indol-1-yl)(pyridin-3-yl)methanone
Yield: 55.5 mg (50%); viscous liquid.
N-(4-Methoxy-2-methylbenzoyl)indole
Yield: 135 mg (98%); viscous liquid.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–F

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X.-F. Wu et al.
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3
1H NMR (300 MHz, CDCl3): δ = 9.00–8.96 (1 H, m, CH-10), 8.84 (1 H,
dd, 4J = 4.9 Hz, 5J = 1.7 Hz, CH-12), 8.41 (1 H, d, 3J = 8.1 Hz, CH-7), 8.06
(1 H, ddd, 3J = 7.9 Hz, 4J = 2.3 Hz, 4J = 1.7 Hz, CH-14), 7.61 (1 H, ddd, 3J =
7.5 Hz, 4J = 1.5 Hz, 5J = 0.7 Hz, CH-4), 7.49 (1 H, ddd, 3J = 7.9 Hz, 3J = 4.9
Hz, 4J = 0.9 Hz, CH-13), 7.45–7.30 (2 H, m, CH-6 + 5), 7.22 (1 H, d, 3J =
3.8 Hz, CH-2), 6.67 (1 H, dd, 3J = 3.8 Hz, 5J = 0.8 Hz, CH-3).
13C NMR (75 MHz, CDCl3): δ = 166.4 (C=O), 152.5 (Cq-9), 149.7 (CH-
10), 136.8 (CH-12), 136.0 (Cq-7a), 130.9 (Cq-3a), 130.8 (CH-14), 126.9
(CH-4), 125.4 (CH-2), 124.5 (CH-5), 123.6 (CH-13), 121.2 (CH-6),
116.5 (CH-7), 109.8 (CH-3).
1H NMR (250 MHz, CDCl3): δ = 8.39 (1 H, d, J = 7.3 Hz, CH-7), 7.70–
7.58 (3 H, m, CH-4 + 10 + 14), 7.45–7.27 (5 H, m, CH-2 + 5 + 6 + 11 +
13), 6.61 (1 H, dd, 3J = 3.7 Hz, 5J = 0.8 Hz, CH-3), 2.47 (3 H, s, CH3).
13C NMR (63 MHz, CDCl3): δ = 168.9 (C=O), 142.7 (Cq-12), 136.2 (Cq-
7a), 131.8 (Cq-9), 130.9 (Cq-3a), 129.5 (CH-10 + 14), 129.4 (CH-11 +
13), 127.8 (CH-4), 124.9 (CH-2), 123.9 (CH-5), 121.0 (CH-6), 116.5
(CH-7), 108.4 (CH-3), 21.8 (CH3).
GC/MS (EI 70 eV): m/z (%) = 235 ([M]+, 29), 119 (100), 116 (13), 91
(58), 90 (10), 89 (29), 65 (29), 63 (24), 39 (15).
GC/MS (EI 70 eV): m/z (%) = 222 ([M]+, 54), 116 (25), 106 (100), 89
(37), 78 (84), 63 (24), 62 (10), 51 (47), 50 (25), 39 (13).
(1H-Indol-1-yl)(pyridin-2-yl)methanone
Yield: 31 mg (28%); light yellow solid; mp 65–67 °C.
1H NMR (300 MHz, CDCl3): δ = 8.75 (1 H, ddd, 3J = 4.8 Hz, 4J = 1.7 Hz,
5J = 0.9 Hz, CH-11), 8.59–8.49 (1 H, m, CH-7), 8.09 (1 H, ddd, 3J = 7.9
Hz, 4J = 1.1 Hz, 5J = 1 Hz, CH-14), 8.04–7.89 (2 H, m, CH-12 + 13), 7.60
(1 H, ddd, 3J = 7.4 Hz, 4J = 1.6 Hz, 5J = 0.7 Hz, CH-4), 7.52 (1 H, ddd, 3J =
7.6 Hz, 4J = 4.8 Hz, 5J = 1.3 Hz, CH-6), 7.45–7.27 (3 H, m, CH-2 + 5), 6.64
(1 H, dd, 3J = 3.8 Hz, 5J = 0.8 Hz, CH-3).
13C NMR (75 MHz, CDCl3): δ = 165.8 (C=O), 152.5 (Cq-9), 148.7 (CH-
11), 137.5 (CH-11), 136.6 (Cq-7a), 130.9 (Cq-3a), 128.6 (CH-4), 126.3
(CH-12), 125.9 (CH-14), 125.1 (CH-2), 124.3 (CH-5), 121.0 (CH-6),
117.0 (CH-7), 109.3 (CH-3).
N-(3-Methoxybenzoyl)indole
Yield: 48 mg (38%); viscous liquid.
1H NMR (300 MHz, CDCl3): δ = 8.46 (1 H, d, 3J = 8.6 Hz, CH-7), 7.58 (1
H, ddd, 3J = 7.5 Hz, 4J = 1.5 Hz, 5J = 0.7 Hz, CH-11), 7.51 (1 H, ddd, 3J =
8.4 Hz, 4J = 7.4 Hz, 5J = 1.8 Hz, CH-6), 7.45 (1 H, ddd, 3J = 7.5 Hz, 4J = 1.8
Hz, 5J = 0.4 Hz, CH-4), 7.42–7.35 (1 H, m, CH-2), 7.31 (1 H, ddd, 3J = 7.4
Hz, 3J = 7.4 Hz, 4J = 1.3 Hz, CH-5), 7.13–7.05 (2 H, m, CH-12 + 13), 7.03
(1 H, dd, 3J = 8.4 Hz, 4J = 0.9 Hz, CH-14), 6.56 (1 H, dd, 3J = 3.8 Hz, 4J =
0.8 Hz, CH-3), 3.78 (3 H, s, OCH3).
13C NMR (63 MHz, CDCl3): δ = 168.6 (C=O), 159.8 (COMe), 136.1 (Cq-
7a), 136.0 (Cq-9), 130.9 (Cq-3a), 129.8 (CH-13), 127.7 (CH-4), 125.1
(CH-2), 124.1 (CH-5), 121.5 (CH-14), 121.0 (CH-6), 118.16 (CH-12),
116.6 (CH-7), 114.2 (CH-10), 108.7 (CH-3), 55.65 (OCH3).
GC/MS (EI 70 eV): m/z (%) = 251 ([M]+, 20), 135 (100), 116 (19), 92
(27), 89 (23), 77 (33), 64 (12), 63 (22).
GC/MS (EI 70 eV): m/z (%) = 222 ([M]+, 55), 221 (23), 106 (44), 89 (13),
78 (100), 51 (13).
(1H-Indol-1-yl)(thiophen-2-yl)methanone
Yield: 44 mg (39%); viscous liquid.
3
1H NMR (250 MHz, CDCl3): δ = 8.41 (1 H, d, J = 8.1 Hz, CH-7), 7.74–
7.66 (3 H, m, CH-2 + 11 + 13), 7.62 (1 H, ddd, 3J = 7.5 Hz, 4J = 1.5 Hz, 5J =
0.8 Hz, CH-4), 7.45–7.27 (2 H, m, CH-5 + 6), 7.20 (1 H, dd, 3J = 4.9 Hz,
3J = 3.9 Hz, CH-12), 6.68 (1 H, dd, 3J = 3.8 Hz, 5J = 0.8 Hz, CH-3).
N-(2-Methoxybenzoyl)indole
Yield: 109 mg (87%); viscous liquid.
1H NMR (300 MHz, CDCl3): δ = 8.46 (1 H, d, 3J = 8.6 Hz, CH-7), 7.58 (1
H, ddd, 3J = 7.5 Hz, 4J = 1.5 Hz, 5J = 0.7 Hz, CH-11), 7.51 (1 H, ddd, 3J =
8.4 Hz, 3J = 7.4 Hz, 4J = 1.8 Hz, CH-12), 7.45 (1 H, ddd, 3J = 7.5 Hz, 4J =
1.8 Hz, 5J = 0.4 Hz, CH-4), 7.42–7.35 (1 H, m, CH-6), 7.31–7.05 (3 H, m,
CH-2 + 5 +13), 7.03 (1 H, dd, 3J = 8.4 Hz, 5J = 0.9 Hz, CH-14), 6.56 (1 H,
dd, 3J = 3.8 Hz, 5J = 0.8 Hz, CH-3), 3.78 (3 H, s, CH3).
13C NMR (63 MHz, CDCl3): δ = 161.8 (C=O), 137.3 (Cq-9), 136.3 (Cq-7a),
133.46 (CH-13), 132.78 (CH-11), 130.8 (Cq-3a), 127.7 (CH-4), 127.17
(CH-12), 125.1 (CH-2), 124.1 (CH-5), 121.1 (CH-6), 116.4 (CH-7),
108.9 (CH-3).
GC/MS (EI 70 eV): m/z (%) = 227 ([M]+, 32), 111 (100), 39 (10).
13C NMR (75 MHz, CDCl3): δ = 167.3 (C=O), 156.4 (C-OMe), 135.7 (Cq-
7a), 132.2 (CH-12), 131.1 (Cq-3a), 129.1 (CH-13), 127.5 (CH-4), 124.9
(CH-2), 124.9 (Cq-9), 124.0 (CH-5), 120.9 (CH-14), 120.8 (CH-6), 116.6
(CH-7), 111.5 (CH-11), 108.7 (CH-3), 55.7 (OCH3).
N-(2-Fluorobenzoyl)indole
Yield: 35 mg (25%); viscous liquid.
1H NMR (300 MHz, CDCl3): δ = 8.48 (1 H, d, J = 8.1 Hz, CH-7), 7.64–
3
7.52 (3 H, m, CH-4 + 12 + 13), 7.45–7.37 (1 H, m, CH-6), 7.37–7.29 (2
H, m, CH-5 + 14), 7.24–7.19 (1 H, m, CH-11), 7.13 (1 H, dd, 3J = 3.8 Hz,
4J = 2.5 Hz, CH-2), 6.62 (1 H, dd, 3J = 3.8 Hz, 5J = 0.8 Hz, CH-3).
13C NMR (75 MHz, CDCl3): δ = 164.5 (C=O), 159.1 (d, 1J = 252.0 Hz, CF),
135.8 (Cq-7a), 133.2 (d, 3J = 8.1 Hz, CH-12), 131.1 (Cq-3a), 130.09 (d,
3J = 2.7 Hz, CH-14), 126.9 (CH-4), 125.3 (CH-2), 124.74 (d, 4J = 3.6 Hz,
CH-13), 124.4 (CH-5), 123.52 (d, 2J = 16.0 Hz, Cq-9), 121.1 (CH-6),
116.6 (CH-7), 116.5 (d, 2J = 21.0 Hz, CH-11), 109.6 (CH-3).
GC/MS (EI 70 eV): m/z (%) = 251 ([M]+, 41), 135 (100), 116 (23), 107
(31), 92 (38), 89 (33), 77 (43), 76 (11), 64 (21), 63 (38), 50 (10).
N-(3-Methylbenzoyl)indole
Yield: 27 mg (23%); viscous liquid.
1H NMR (300 MHz, CDCl3): δ = 8.45–8.35 (1 H, m, CH-7), 7.64–7.49 (5
H, m, CH-4 + 10 + 12 + 13 + 14), 7.46–7.28 (3 H, m, CH-2 + 5 + 6), 6.61
(1 H, dd, 3J = 3.8 Hz, 5J = 0.8 Hz, CH-3), 2.45 (3 H, s, CH3).
19F NMR (282 MHz, CDCl3): δ = –112.72.
13C NMR (75 MHz, CDCl3): δ = 169.1 (C=O), 138.7 (Cq-11), 136.2 (Cq-
7a), 134.7 (Cq-9), 132.8 (CH-12), 130.9 (Cq-3a), 129.8 (CH-10), 128.5
(CH-13), 127.8 (CH-4), 126.4 (CH-14), 125.0 (CH-2), 124.0 (CH-5),
121.0 (CH-6), 116.6 (CH-7), 108.6 (CH-3), 21.52 (CH3).
GC/MS (EI 70 eV): m/z (%) = 235 ([M]+, 31), 119 (100), 91 (45), 89 (10),
65 (13).
GC/MS (EI 70 eV): m/z (%) = 239 ([M]+, 34), 123 (100), 95 (28).
N-(3-Trifluorobenzoyl)indole
Yield: 71 mg (49%); light yellow solid; mp 83–86 °C.
3
1H NMR (300 MHz, CDCl3): δ = 8.32 (1 H, d, J = 8.1 Hz, CH-7), 7.94–
7.92 (1 H, m, CH-11), 7.86–7.76 (2 H, m, CH-13 + 14), 7.63–7.56 (1 H,
m, CH-4), 7.53 (1 H, ddd, 3J = 7.5 Hz, 4J = 1.5 Hz, 5J = 0.7 Hz, CH-12),
N-(2-Methylbenzoyl)indole
Yield: 27 mg (23%); viscous liquid.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–F

F
X.-F. Wu et al.
Paper
Synthesis
7.32 (1 H, ddd, 3J = 8.3 Hz, 4J = 7.8 Hz, 5J = 1.4 Hz, CH-6), 7.28–7.22 (1
H, m, CH-5), 7.11 (1 H, d, 3J = 3.8 Hz, CH-2), 6.57 (1 H, dd, 3J = 3.8 Hz,
5J = 0.8 Hz, CH-3).
References
(1) (a) Sharma, V.; Kumar, P.; Pathak, D. J. Heterocycl. Chem. 2010,
47, 491. (b) Bandini, M.; Eichholzer, A. Angew. Chem. Int. Ed.
2009, 48, 9608.
(2) Chen, F.-E.; Huang, J. Chem. Rev. 2005, 105, 4671.
(3) Hart, F. D.; Boardman, P. L. Br. Med. J. 1963, 2, 965.
(4) Sim, D. S.-Y.; Chong, K.-W.; Nge, C.-E.; Low, Y.-Y.; Sim, K.-S.;
Kam, T.-S. J. Nat. Prod. 2014, 77, 2504.
(5) Dhanoa, D. S.; Bagley, S. W.; Chang, R. S. L.; Lotti, V. J.; Chen, T.
B.; Kivlighn, S. D.; Zingaro, G. J.; Siegl, P. K. S.; Patchett, A. A.;
Greenlee, W. J. J. Med. Chem. 1993, 36, 4230.
13C NMR (75 MHz, CDCl3): δ = 167.2 (C=O), 136.1 (Cq-7a), 135.6 (CH-
2
14), 132.4 (q, 4J = 1.4 Hz, Cq-9), 131.49 (q, J = 33.1 Hz, CH-11), 130.9
(Cq-3a), 129.4 (CH-13), 128.45 (q, 3J = 3.6 Hz, CH-12), 127.0 (CH-4),
126.04 (q, 3J = 3.8 Hz, CH-10), 125.4 (CH-2), 124.5 (CH-5), 121.2 (CH-
6), 120.0 (q, 1J = 272.7 Hz, CF3), 116.6 (CH-7), 109.6 (CH-3).
19F NMR (282 MHz, CDCl3): δ = –62.81.
GC/MS (EI 70 eV): m/z (%) = 290 (15), 289 ([M]+, 80), 174 (18), 173
(100), 145 (96), 95 (11), 89 (11).
(6) Dalpozzo, R. Chem. Soc. Rev. 2015, 44, 742.
(7) Yagil, G. Tetrahedron 1967, 23, 2855.
(8) Bordwell, F. G.; Drucker, G. E.; Fried, H. E. J. Org. Chem. 1981, 46,
632.
(9) Laha, J. K.; Cuny, G. D. J. Org. Chem. 2011, 76, 8477.
(10) Cui, H.-L.; Feng, X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y.-C. Angew.
Chem. Int. Ed. 2009, 48, 5737.
(11) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 11684.
(12) Old, D. W.; Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403.
(13) Weißgerber, R. Ber. Dtsch. Chem. Ges. 1910, 43, 3520.
(14) Quesnel, J. S.; Arndtsen, B. A. J. Am. Chem. Soc. 2013, 135, 16841.
(15) Bremner, J. B.; Samosorn, S.; Ambrus, J. I. Synthesis 2004, 2653.
(16) Ren, W.; Yamane, M. J. Org. Chem. 2010, 75, 8410.
(17) (a) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1.
(b) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Soc. Rev. 2011, 40,
4986.
(18) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327.
(19) (a) Fang, W.; Zhu, H.; Deng, Q.; Liu, S.; Liu, X.; Shen, Y.; Tu, T.
Synthesis 2014, 46, 1689. (b) Barnard, C. F. J. Organometallics
2008, 27, 5402.
(20) Gøgsig, T. M.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T.
Angew. Chem. Int. Ed. 2012, 51, 798.
(21) Odell, L. R.; Russo, F.; Larhed, M. Synlett 2012, 23, 685.
(22) Wu, X.-F.; Oschatz, S.; Sharif, M.; Flader, A.; Krey, L.; Beller, M.;
Langer, P. Adv. Synth. Catal. 2013, 355, 3581.
(2-Bromo-4,5-dimethylphenyl)(1H-indol-1-yl)methanone
Yield: 30 mg (18%); light yellow solid; mp 64–67 °C.
3
1H NMR (300 MHz, CDCl3): δ = 8.38 (1 H, d, J = 8.1 Hz, CH-7), 7.65–
7.50 (3 H, m, CH-4 + 11 + 14), 7.51–7.27 (2 H, m, CH-5 + 6), 7.01 (1 H,
d, 3J = 3.8 Hz, CH-2), 6.63–6.57 (1 H, m, CH-3), 2.33 (3 H, s, CH3), 2.27
(3 H, s, CH3).
13C NMR (63 MHz, CDCl3): δ = 167.1 (C=O), 141.3 (Cq-10), 136.7 (Cq-7),
134.5 (Cq-9), 133.9, 130.0 (Cq-3a), 127.1 (CH-4), 125.3 (CH-2), 124.9,
124.3 (CH-5), 121.0 (CH-6), 120.9, 116.6 (CH-7), 116.49, 109.5 (CH-3),
19.8 (CH3), 19.40 (CH3).
GC/MS (EI 70 eV): m/z (%) = 329 ([M (81Br)]+, 20), 327 ([M (79Br)]+, 20),
213 (98), 211 (100), 104 (22), 103 (16), 77 (10).
Acknowledgment
The authors thank the state of Mecklenburg-Vorpommern and the
Bundesministerium für Bildung und Forschung (BMBF) for financial
support. We also thank Drs. W. Baumann, C. Fischer, D. Michalik, Ms.
S. Schareina, and Ms. S. Buchholz (LIKAT) for analytical support. X. F.
Wu thanks the financial support from NSFC (21472174) and Zhejiang
Sci-Tech University (1206838-Y).
(23) (a) Zapf, A.; Beller, M. Chem. Commun. 2005, 431. (b) Klaus, S.;
Neumann, H.; Zapf, A.; Strübing, D.; Hübner, S.; Almena, J.;
Riermeier, T.; Groß, P.; Sarich, M.; Krahnert, W.-R.; Rossen, K.;
Beller, M. Angew. Chem. Int. Ed. 2006, 45, 154.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380752.
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(24) Wannberg, J.; Larhed, M. J. Org. Chem. 2003, 68, 5750.
(25) Wu, X.-F.; Oschatz, S.; Sharif, M.; Beller, M.; Langer, P. Tetrahe-
dron 2014, 70, 23.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–F