A practical synthesis of 2-aroylindoles from N-(2-formylphenyl)trifluoro- acetamides in PEG-400

Article abstract of DOI:10.1055/s-0030-1258445

A one-pot and environmentally benign approach to the synthesis of highly functionalized 3-unsubstituted 2-aroylindoles is described. Moderate to good yields were obtained through the reaction of easily accessible N-(2-formylphenyl)trifluoroacetamides and

Full text of DOI:10.1055/s-0030-1258445

PAPER
873
A Practical Synthesis of 2-Aroylindoles from N-(2-Formylphenyl)trifluoro-
acetamides in PEG-400
S
ynthesis of 2-Aro
u
ylindoles Zhao,a Deyao Li,a Liwen Zhao,a Jiancun Zhang*a,b
a
Guangzhou Institute of Biomedicine and Health, CAS, 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, P. R. of China
Fax +86(20)32015323; E-mail: zhang_jiancun@gibh.ac.cn
b
State Key Laboratory of Respiratory Diseases, Guangzhou Medical College, Guangzhou 510120, P. R. of China
Received 18 November 2010; revised 11 January 2011
formation from o-aminobenzaldehyde and a-bromoaceto-
Abstract: A one-pot and environmentally benign approach to the
synthesis of highly functionalized 3-unsubstituted 2-aroylindoles is
described. Moderate to good yields were obtained through the reac-
tion of easily accessible N-(2-formylphenyl)trifluoroacetamides
and a-bromoacetophenones in the presence of K2CO3. PEG-400
was found to be an efficient and reusable solvent in the process.
phenone.
Herein, we report a convenient and environmentally be-
nign method for the construction of 3-unsubstituted 2-
aroylindoles 3 from N-(2-formylphenyl)trifluoroacet-
amides 1, which can be readily prepared from o-ami-
nobenzaldehydes with trifluoroacetic anhydride, and a-
bromoacetophenones 2 in PEG-400 (Scheme 1).
Key words: 2-aroylindoles, PEG-400, N-(2-formylphenyl)trifluoro-
acetamides, heterocycles, cyclization
CHO
O
The indole skeleton has been referred to as a ‘privileged
structure’ owing to its diverse biological activities.1 Par-
ticularly, free-NH 3-unsubstituted 2-aroylindoles were re-
ported to be highly potent tubulin polymerization
inhibitors,2 histone deacetylase class I/II inhibitors,3 plate-
let-derived growth factor (PDGF) receptor kinase inhibi-
tors,4 peroxisome proliferator-activated receptor (PPAR)
agonists,5 and cyclooxygenase-2 (COX-2) inhibitors.6
Different methods have been developed for their synthe-
ses. Among these transformations, addition of acyl elec-
trophiles to 2-lithioindole species7 and palladium-
catalyzed coupling reactions8 are widely used processes.
In other cases, isatins also lead to 2-aroylindoles.9 Jones
reported the preparation of 2-benzoylindole by reaction of
2-aminobenzaldehyde ethylene acetal with a-bromoace-
tophenone.10a However, these synthetic approaches some-
times suffer from harsh reaction conditions, the need for
transition-metal assistance, poor availability of starting
materials, or long reaction steps. In light of these chal-
lenges, a direct and practical method for the formation of
3-unsubstituted 2-aroylindoles is still in demand.
R
R
+
Ar
Br
NH
N
Ar
H
COCF3
O
3
1
2
Scheme 1 Approach to synthesis of 2-aroylindoles.
N-(2-Formylphenyl)trifluoroacetamide (1a) and a-bro-
moacetophenone (2a) were used as model compounds to
assess the feasibility of the method. A variety of reaction
conditions were examined and the results are shown in
Table 1.
When a mixture of 1a and 2a was heated in the presence
of K2CO3 in DMF and PEG-400, 2-benzoylindole (3a)
was obtained in moderate yields. Moreover, use of PEG-
400 as the solvent gave the highest yield (Table 1, entries
1–5). Cs2CO3 and K3PO4 performed poorly under the re-
action conditions (entries 6 and 7). Upon adjusting the ra-
tio of 1a to 2a to 1:1.2, an improved yield was observed
(entries 5, 8, and 9). Further investigation of reaction time
and temperature showed that three hours and 100 °C of-
fered the best result for this transformation (entries 10–
13). Thus, the optimized reaction conditions for the for-
mation of 3a were established (Table 1, entry 8).
o-Aminoacetophenones reacted readily with a-bromoace-
tophenones to afford 3-methyl-2-aroylindoles.10 Howev-
er, the reaction was limited to o-aminoacetophenones in
substrate scope, and o-aminobenzaldehyde failed to gen-
erate 3-unsubstituted aroylindoles.10a Our preliminary ex-
periments also showed the failure of this reaction.11 In a
recent patent report, pyrrolo[2,3-d]pyrimidines were pre-
pared from 4-(phenylamino)pyrimidine-5-carbaldehydes
and a-bromoactophenones.12 To the best of our knowl-
edge, there is no other report on the analogous indole
PEG-400 is inexpensive and is known to be thermally sta-
ble, non-toxic, and is often used as a recyclable reaction
medium.13 Thus, the reusability of PEG-400 in the reac-
tion was examined. After the initial reaction with 1a and
2a, the reaction mixture was extracted with diethyl ether
and the PEG-400 layer was subjected to a subsequent
reaction run by adding further substrates (1a, 2a, and
K2CO3).14 The results of the initial and the subsequent
three runs of the reaction were consistent in yields (3a; 77,
76, 75, and 75%).
SYNTHESIS 2011, No. 6, pp 0873–0880
x
x
.
x
x
.2
0
1
1
Various N-(2-formylphenyl)trifluoroacetamides 1 and a-
bromoacetophenones 2 were then applied to investigate
Advanced online publication: 18.02.2011
DOI: 10.1055/s-0030-1258445; Art ID: F20910SS
© Georg Thieme Verlag Stuttgart · New York

874
Y. Zhao et al.
PAPER
the reaction scope under the optimized reaction condition; electronic influence of the substituents of 1 and/or 2 in the
the results were shown in Table 2. This method was suit- reaction.
able for a variety of substrates, giving the desired func-
The reaction sequence presumably involves three steps:
tionalized 2-aroylindoles in moderate to good yields. No
(1) N-alkylation of the trifluoroacetamide, (2) intramolec-
obvious electronic effects were observed with either 1 or
ular condensation followed by dehydration, and (3) depro-
2. Both electron-donating (1b–d, 2g, and 2h) and elec-
tection of the N-trifluoroacetyl group. Moreover, we
tron-withdrawing (1e, 1f, and 2i–k) substituents on the
explored the reactions 1a with various 2-bromo-1-(2-
aromatic rings in these two components were accommo-
heteroaryl)-ethanones and found that 2-(2-bromo-
dated (Table 2, entries 1–10). The ortho-substitution of a-
acetyl)naphthalene (2o), 2-(2-bromoacetyl)furan (2p),
bromoacetophenones (2m and 2n) provided the corre-
and 2-(2-bromoacetyl)thiophene (2q) were also compati-
sponding products 3m and 3n in good yields (67 and 72%,
ble in the reactions, providing the desired 2-heteroaroyl-
indoles in fair to good yields (entries 14–16).
respectively). Steric hindrance at the ortho-position of 2
was tolerated. In addition, when the aromatic ring of 2 was
substituted with methoxy groups at various positions,
similar yields were observed (Table 2, entries 7, 11, and
12). It was presumed that the acidic nature of the NH
group, caused by the withdrawing effect of the tri-
fluoacetyl group of 1, is strong enough to counteract the
Finally, we applied this procedure to a-bromoacetone (2r)
and 1a. The reaction proceeded smoothly under the above
optimized reaction conditions and provided 2-acetyl-
indole (3r) in satisfactory yield (Schemes 2, 82%). This
result further extends the application of this method to the
preparation of 2-alkoyl-indoles.
Table 1 Screen and Optimization of the Reaction Conditionsa
In conclusion, we have developed a simple and practical
method to synthesize 3-unsubstituted 2-aroylindoles
O
Br
through the reaction of N-(2-formylphenyl)trifluoroacet-
Ph
CHO
amides and a-bromoacetophenones in PEG-400 in moder-
ate to good yields. Our approach is characterized by some
features: (1) free (NH)-aroylindoles were obtained direct-
ly under one-pot, catalyst-free conditions; (2) PEG-400
was used as an efficient and reusable solvent; (3) starting
materials are readily available, and (4) the reaction is tol-
erant of various functional groups. The method provides a
valuable alternative for the preparation of 3-unsubstituted
2-aroylindoles.
2a
Ph
base
N
NH
H
O
COCF3
1a
3a
Entry Solvent
Ratio (1a/2a) Base
1:1.1 K2CO3
acetonitrile 1:1.1
Temp (°C) Yield (%)b
1
2
acetone
reflux
reflux
100
trace
8
K2CO3
K2CO3
K2CO3
K2CO3
3
toluene
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.2
1:1.3
1:1.2
1:1.2
1:1.2
1:1.2
12c
68
O
4
DMF
100
Br
CHO
2r
5
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
100
74
K2CO3, PEG-400
100 °C, 3 h, 82%
N
NH
H
6
Cs2CO3 100
30
O
COCF3
1a
3r
7
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
100
100
100
100
100
80
61
Scheme 2 Synthesis of 2-acetylindole
8
77
9
71
Reagents and solvents were purchased from commercial sources
and were used as received without additional purification unless
mentioned otherwise. Analytical thin-layer chromatography was
performed on silica gel 60 F254 glass plates. Melting points are un-
corrected. NMR spectra were recorded with a Bruker AV400 or a
Bruker AV500 spectrometer. Chemical shifts are given as values in
ppm relative to the residual solvent peak as the internal reference
[CDCl3: d = 7.26 ppm (1H NMR), d = 77.0 ppm (13C NMR);
DMSO-d6: d = 2.50 ppm (1H NMR)], coupling constants are given
in Hertz. Mass spectra were recorded with an Agilent1200/MSD
LC-MS spectrometer. High-resolution mass spectra were per-
formed with Kompact Axima-CFR MALDI mass spectrometers.
Elemental analysis was performed with an Elementar vario EL an-
alyzer. Petroleum ether (PE) refers to the fraction boiling between
60–90 °C.
10
11
12
13
75d
65e
62
110
64
a Reaction conditions: N-(2-formylphen-yl)trifluoroacetamide (100
mg, 0.46 mmol), a-bromoactophenone, base (3.0 equiv), solvent (5
mL), 3 h (unless noted otherwise), under nitrogen.
b Isolated yield.
c 100 °C for 8 h.
d 100 °C for 2 h.
e 100 °C for 10 h.
Synthesis 2011, No. 6, 873–880 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Aroylindoles
875
Table 2 Substrate Scope of the 2-Aroylindole Synthesisa
CHO
O
K2CO3, PEG-400
100 °C, 3 h
R
+
Br
R
Ar
Ar
NH
N
H
COCF3
O
1
2
3
Entry
1
Substrate 1
Substrates 2
Product
Yield (%)b
BnO
O
BnO
CHO
Br
1b
1c
1d
1e
1f
2a
3b
3c
3d
3e
3f
60
52
71
79
64
57
69
Ph
Ph
N
NHCOCF3
CHO
H
O
O
O
O
O
2
3
4
5
6
7
2a
2a
2a
2a
N
NHCOCF3
CHO
H
O
MeO
MeO
MeO
MeO
Ph
N
NHCOCF3
H
O
CHO
Ph
Cl
N
H
Cl
NHCOCF3
CHO
O
Ph
MeO2C
N
H
MeO2C
NHCOCF3
O
O
O
CHO
Br
Br
1a
1a
2g
2h
2i
3g
3h
N
H
NHCOCF3
O
OMe
Cl
N
H
O
O
O
OMe
Cl
O
O
O
Br
Br
Br
8
9
1a
1a
3i
3j
78
64
N
H
F
2j
N
H
F
NO2
10
11
12
1a
1a
1a
2k
2l
3k
3l
50
70
67
N
H
NO2
O
O
O
O
O
Br
Br
OMe
N
H
OMe
OMe
2m
3m
N
H
OMe
Synthesis 2011, No. 6, 873–880 © Thieme Stuttgart · New York

876
Y. Zhao et al.
PAPER
Table 2 Substrate Scope of the 2-Aroylindole Synthesisa (continued)
CHO
O
K2CO3, PEG-400
100 °C, 3 h
R
+
Br
R
Ar
Ar
NH
N
H
COCF3
O
1
2
3
Entry
13
Substrate 1
Substrates 2
Product
Yield (%)b
72
O
O
Br
Br
1a
2n
3n
3o
3p
3q
N
H
O
O
O
O
Br
Br
14
15
16
1a
1a
1a
2o
64
77
85
N
H
O
O
2p
2q
Br
Br
O
S
N
H
O
S
N
H
a Rection conditions (0.36–0.5 mmol scale): N-(2-formylphenyl)trifluoroacetamide (1.0 equiv), a-bromoacetophenone (1.2 equiv), K2CO3 (3.0
equiv), PEG-400 (5 mL), 100 °C, 3 h, under nitrogen.
b Isolated yield.
Synthesis of N-(2-Formylphenyl)trifluoroacetamides (1a–f);
General Procedure
Yield: 1.55 g (96%); white solid; mp 112–113 °C.
1H NMR (400 MHz, CDCl3): d = 11.91 (br s, 1 H), 9.90 (s, 1 H),
8.62 (d, J = 9.0 Hz, 1 H), 7.45–7.34 (m, 5 H), 7.33 (d, J = 3.0 Hz,
1 H), 7.30 (dd, J = 9.0, 3.0 Hz, 1 H), 5.15 (s, 2 H).
To a cold solution of o-aminobenzaldehyde (5.0 mmol) in anhy-
drous CH2Cl2 (10 mL) was added anhydrous pyridine (0.8 mL, 10
mmol), followed by dropwise addition of TFAA (0.9 mL, 6.4
mmol). After the addition was complete, the reaction mixture was
warmed to r.t. and further stirred at r.t. for 3–4 h. H2O (15 mL) was
added to the reaction mixture, the organic layer was separated, and
the aqueous layer was washed with CH2Cl2 (2 × 15 mL). The com-
bined organic layer was washed with 1 M HCl (20 mL), brine (20
mL), dried over anhydrous Na2SO4, filtered and concentrated. The
residue was purified by flash chromatography to afford N-(2-
formylphenyl)trifluoroacetamide 1.
13C NMR (100 MHz, CDCl3): d = 195.0, 155.9, 155.4 (2JC–F
=
38.0 Hz), 136.0, 131.7, 128.8, 128.4, 127.4, 123.7, 122.6, 122.1,
121.5, 115.7 (1JC–F = 288.5 Hz), 70.8.
MS (ESI): m/z = 322 [M – H]–.
HRMS: m/z [M + H]+ calcd for C16H13F3NO3: 324.0842; found:
324.0843.
2,2,2-Trifluoro-N-(6-formylbenzo[d][1,3]dioxol-5-yl)acetamide
(1c)
Following the general procedure, the reaction was performed with
6-aminobenzo[d][1,3]dioxole-5-carbaldehyde (0.83 g, 5.0 mmol).
Eluent for chromatography: PE–EtOAc (9:1).
2,2,2-Trifluoro-N-(2-formylphenyl)acetamide (1a)
Following the general procedure, the reaction was performed with
o-aminobenzalidehyde (0.6 g, 5.0 mmol). Eluent for chromatogra-
phy: PE–EtOAc (20:1).
Yield: 1.24 g (95%); pale-yellow solid; mp 127–128 °C.
1H NMR (400 MHz, CDCl3): d = 12.52 (br s, 1 H), 9.72 (s, 1 H),
8.23 (s, 1 H), 7.10 (s, 1 H), 6.12 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 193.0, 155.7 (2JC–F = 38.1 Hz),
154.0, 144.9, 136.1, 116.9, 115.5 (1JC–F = 288.2 Hz), 113.2, 102.8,
101.8.
MS (ESI): m/z = 260 [M – H]–.
HRMS: m/z [M + H]+ calcd for C10H7F3NO4: 262.0322; found:
Yield: 1.04 g (95%); white solid; mp 72–73 °C.
1H NMR (400 MHz, CDCl3): d = 12.19 (br s, 1 H), 9.98 (s, 1 H),
6.69 (d, J = 8.4 Hz, 1 H), 7.79 (dd, J = 7.6, 1.6 Hz, 1 H), 7.73–7.69
(m, 1 H), 7.41 (td, J = 7.6, 0.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 195.4, 155.8 (2JC–F = 38.2 Hz),
138.2, 136.3, 135.9, 125.2, 122.7, 120.4, 117.0 (1JC–F = 288.7 Hz).
MS (ESI): m/z = 216 (M – H)–.
HRMS: m/z [M + H]+ calcd for C9H7F3NO2: 218.0423; found:
262.0321.
218.0421.
2,2,2-Trifluoro-N-(2-formyl-4,5-dimethoxyphenyl)acetamide
(1d)
Following the general procedure, the reaction was performed with
2-amino-4,5-dimethoxybenzaldehyde (0.9 g, 5.0 mmol). Eluent for
chromatography: PE–EtOAc (5:1).
N-[4-(Benzyloxy)-2-formylphenyl]-2,2,2-trifluoroacetamide
(1b)
Following the general procedure, the reaction was performed with
2-amino-5-(benzyloxy)benzaldehyde (1.13 g, 5.0 mmol). Eluent for
chromatography: PE–EtOAc (9:1).
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Synthesis of 2-Aroylindoles
877
Yield: 1.36 g (98%); white solid; mp 187–188 °C.
1H NMR (400 MHz, CDCl3): d = 12.38 (br s, 1 H), 9.78 (s, 1 H),
8.32 (s, 1 H), 7.12 (s, 1 H), 3.99 (s, 3 H), 3.94 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 187.3, 138.2, 137.8, 134.5, 132.3,
129.2, 128.4, 127.8, 126.5, 123.2, 121.0, 112.8, 112.3.
MS (ESI): m/z = 222 [M + H]+.
13C NMR (100 MHz, CDCl3): d = 193.3, 155.7 (2JC–F = 47.8 Hz),
155.6, 146.2, 134.4, 116.8, 115.7, 115.6 (1JC–F = 288.5 Hz), 103.8,
56.5, 56.4.
HRMS: m/z [M + H]+ calcd for C15H12NO: 222.0913; found:
222.0915.
[5-(Benzyloxy)-1H-indol-2-yl](phenyl)methanone (3b)
Following the general procedure, the reaction was performed with
1b (100 mg, 0.31 mmol) and 2a (74 mg, 0.37 mmol). Eluent for
chromatography: PE–EtOAc (10: 1).
MS (ESI): m/z = 276 [M – H]–.
HRMS: m/z [M + H]+ calcd for C11H11F3NO4: 278.0635; found:
278.0635.
Yield: 61 mg (60%); yellow solid; mp 190–191 °C (Lit.8a 190–
191 °C).
1H NMR (400 MHz, CDCl3): d = 9.26 (br s, 1 H), 7.99–7.97 (m,
2 H), 7.64–7.60 (m, 1 H), 7.55–7.51 (m, 2 H), 7.47 (d, J = 7.2 Hz,
2 H), 7.41–7.38 (m, 3 H), 7.34–7.31 (m, 1 H), 7.16–7.13 (m, 2 H),
7.07 (d, J = 1.2 Hz, 1 H), 5.11 (s, 2 H).
13C NMR (125 MHz, CDCl3): d = 186.9, 154.0, 138.1, 137.2, 134.9,
133.2, 132.3, 129.2, 128.6, 128.4, 128.1, 127.9, 127.5, 119.0, 113.1,
112.3, 104.6, 70.7.
N-(5-Chloro-2-formylphenyl)-2,2,2-trifluoroacetamide (1e)
Following the general procedure, the reaction was performed with
2-amino-4-chlorobenzaldehyde (0.78 g, 5.0 mmol). Eluent for chro-
matography: PE–EtOAc (9:1).
Yield: 1.20 g (96%); white solid; mp 63–64 °C.
1H NMR (400 MHz, CDCl3): d = 12.24 (br s, 1 H), 9.94 (d,
J = 0.4 Hz, 1 H), 8.74 (d, J = 1.6 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H),
7.38 (dd, J = 8.0, 2.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 194.2, 155.8 (2JC–F = 38.3 Hz),
MS (ESI): m/z = 328 [M + H]+.
HRMS: m/z [M + H]+ calcd for C22H18NO2: 328.1332; found:
143.1, 139.0, 136.7, 125.5, 121.0, 120.7, 115.4 (1JC–F = 288.4 Hz).
MS (ESI): m/z = 250 [M – H]–.
HRMS: m/z [M + H]+ calcd for C9H6ClF3NO2: 252.0034; found:
328.1329.
252.0033.
(5H-[1,3]dioxolo[4,5-f]indo-6-yl)(phenyl)methanone (3c)
Following the general procedure, the reaction was performed with
1c (100 mg, 0.38 mmol) and 2a (91 mg, 0.46 mmol). Eluent for
chromatography: PE–EtOAc (10:1).
Yield: 52 mg (52%); yellow solid; mp 198–200 °C (Lit.8a 200–
201 °C).
1H NMR (400 MHz, CDCl3): d = 9.43 (br s, 1 H), 7.96–7.94 (m,
2 H), 7.60 (t, J = 7.2 Hz, 1 H), 7.53–7.50 (m, 2 H), 7.04 (d,
J = 1.2 Hz, 1 H), 7.00 (s, 1 H), 6.89 (s, 1 H), 5.99 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 185.9, 149.0, 144.5, 138.3, 134.1,
133.8, 131.9, 129.0, 128.3, 122.2, 113.1, 101.1, 100.0, 91.8.
MS (ESI): m/z = 266 [M + H]+.
HRMS: m/z [M + H]+ calcd for C16H12NO3: 266.0812; found:
Methyl 4-Formyl-3-(2,2,2-trifluoroacetamido)benzoate (1f)
Following the general procedure, the reaction was performed with
methyl 3-amino-4-formylbenzoate (0.9 g, 5.0 mmol). Eluent for
chromatography: PE–EtOAc (5:1).
Yield: 1.36 g (99%); yellow solid; mp 120–121 °C.
1H NMR (400 MHz, CDCl3): d = 12.10 (br s, 1 H), 10.06 (s, 1 H),
9.28 (s, 1 H), 8.06 (dd, J = 8.0, 1.6 Hz), 7.88 (d, J = 8.0 Hz, 1 H),
3.98 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 195.2, 165.2, 155.8 (2JC–F
38.2 Hz), 138.1, 136.8, 135.8, 126.0, 124.8, 121.4, 115.4 (1JC–F
286.2 Hz), 52.9.
MS (ESI): m/z = 274 [M – H]–.
HRMS: m/z [M + H]+ calcd for C11H9F3NO4: 276.0478; found:
=
=
266.0810.
276.0480.
(5,6-Dimethoxy-1H-indol-2-yl)(phenyl)methanone (3d)
Following the general procedure, the reaction was performed with
1d (100 mg, 0.36 mmol) and 2a (86 mg, 0.43 mmol). Eluent for
chromatography: PE–EtOAc (10:1).
Yield: 72 mg (71%); yellow solid; mp 183–184 °C (Lit.8a 181–
182 °C).
1H NMR (400 MHz, CDCl3): d = 9.43 (br s, 1 H), 8.00 (d,
J = 7.4 Hz, 2 H), 7.60 (t, J = 7.3 Hz, 1 H), 7.51 (t, J = 7.4 Hz, 2 H),
7.06–7.04 (m, 2 H), 6.91 (s, 1 H), 3.96 (s, 3 H), 3.92 (s, 3 H).
Synthesis of 2-Aroylindoles (3a–s); General Procedure
To a stirring mixture of N-(2-formylphenyl)trifluoroacetamide 1
(100 mg) and a-bromoacetophenone 2 (1.2 equiv) in PEG-400 (5
mL), was added solid K2CO3 (3.0 equiv). The resulting reaction
mixture was heated to 100 °C in an oil-bath for 3 h under a nitrogen
atmosphere. The reaction was cooled to r.t. and the black mixture
was extracted with Et2O (3 × 20 mL). The organic layer was washed
with H2O (20 mL), brine (20 mL), dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by flash chro-
matography to afford 3.
13C NMR (100 MHz, CDCl3): d = 186.0, 151.4, 146.7, 138.5, 133.6,
133.4, 131.9, 129.0, 128.3, 121.0, 112.9, 103.3, 93.9, 56.3, 56.1.
MS (ESI): m/z = 282 [M + H]+.
HRMS: m/z [M + H]+ calcd for C17H16NO3: 282.1125; found:
(1H-Indol-2-yl)(phenyl)methanone (3a)
Following the general procedure, the reaction was performed with
1a (100 mg, 0.46 mmol) and 2a (109 mg, 0.55 mmol). Eluent for
chromatography: PE–EtOAc (15:1).
282.1121.
(6-Chloro-1H-indol-2-yl)(phenyl)methanone (3e)7e
Following the general procedure, the reaction was performed with
1e (100 mg, 0.40 mmol) and 2a (95 mg, 0.48 mmol). Eluent for
chromatography: PE–EtOAc (15:1).
Yield: 78 mg (77%); yellow solid; mp 150–151 °C (Lit.8a,b 149–
150 °C).
1H NMR (400 MHz, CDCl3): d = 9.29 (br s, 1 H), 8.01–7.98 (m,
2 H), 7.73 (dd, J = 8.0, 0.8 Hz, 1 H), 7.65–7.61 (m, 1 H), 7.56–7.47
(m, 2 H), 7.48 (dd, J = 8.4, 0.8 Hz, 1 H), 7.40–7.36 (m, 1 H), 7.20–
7.16 (m, 2 H).
Yield: 80 mg (79%); off-white solid; mp 205–206 °C.
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Y. Zhao et al.
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1H NMR (400 MHz, CDCl3): d = 9.46 (br s, 1 H), 7.99 (d, J = 7.2
Hz, 2 H), 7.65 (d, J = 6.0 Hz, 1 H), 7.62 (s, 1 H), 7.54 (pseudo-t, J =
7.2 Hz, 2 H), 7.49 (s, 1 H), 7.15–7.14 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 187.0, 137.7, 135.0, 132.5, 132.4,
129.2, 128.5, 126.3, 124.2, 122.2, 112.5, 112.0.
MS (ESI): m/z = 256 [M + H]+.
HRMS: m/z [M + H]+ calcd for C15H11ClNO: 256.0524; found:
chromatography: PE–EtOAc (15:1).
Yield: 92 mg (78%); yellow solid; mp 196–198 °C (Lit.8a 196–
197 °C).
1H NMR (400 MHz, CDCl3): d = 9.38 (br s, 1 H), 7.95 (dt, J = 8.8,
2.0 Hz, 2 H), 7.73 (dd, J = 8.4, 0.8 Hz, 1 H), 7.52 (dt, J = 8.8,
2.4 Hz, 2 H), 7.49 (dd, J = 8.4, 0.8 Hz, 1 H), 7.41–7.37 (m, 1 H),
7.20–7.16 (m, 1 H), 7.14 (dd, J = 2.0, 0.8 Hz, 1 H).
256.0521.
13C NMR (125 MHz, CDCl3): d = 185.8, 138.8, 137.6, 136.3, 134.0,
130.6, 128.8, 127.7, 126.8, 123.3, 121.2, 112.7, 112.2.
Methyl 2-(Phenylcarbonyl)-1H-indole-6-carboxylate (3f)
Following the general procedure, the reaction was performed with
1f (100 mg, 0.36 mmol) and 2a (87 mg, 0.44 mmol). Eluent for
chromatography: PE–EtOAc (10:1).
MS (ESI): m/z = 256 [M + H]+.
HRMS: m/z [M + H]+ calcd for C15H11ClNO: 256.0524; found:
256.0523.
Yield: 65 mg (64%); pale-yellow solid; mp 208–209 °C.
(4-Fluorophenyl)(1H-indol-2-yl)methanone (3j)
Following the general procedure, the reaction was performed with
1a (100 mg, 0.46 mmol) and 2j (119 mg, 0.55 mmol). Eluent for
chromatography: PE–EtOAc (15:1).
Yield: 70 mg (64%); white solid; mp 185–186 °C (Lit.8b 185.2–
185.6 °C).
1H NMR (400 MHz, CDCl3): d = 9.63 (br s, 1 H), 8.08–8.03 (m,
2 H), 7.73 (dd, J = 8.0, 0.8 Hz, 1 H), 7.50 (dd, J = 8.0, 0.8 Hz, 1 H),
7.41–7.37 (m, 1 H), 7.25–7.16 (m, 3 H), 7.15 (dd, J = 2.0, 0.8 Hz,
1 H).
13C NMR (125 MHz, CDCl3): d = 185.7, 165.4 (1JC–F = 253.6 Hz),
137.7, 134.2 (4JC–F = 3.3 Hz), 134.1, 131.7 (3JC–F = 8.9 Hz), 127.7,
126.6, 123.2, 121.1, 115.6 (2JC–F = 22.0 Hz), 112.7, 112.2.
1H NMR (400 MHz, CDCl3): d = 9.62 (br s, 1 H), 8.26 (s, 1 H), 8.01
(d, J = 7.2 Hz, 2 H), 7.85 (dd, J = 8.4, 0.8 Hz, 1 H), 7.76 (d,
J = 8.4 Hz, 1 H), 7.67–7.63 (m, 1 H), 7.55 (t, J = 7.6, 7.2 Hz, 2 H),
7.18 (d, J = 0.8 Hz, 1 H), 3.97 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 187.1, 167.4, 137.6, 136.6, 136.5,
132.7, 130.9, 129.3, 128.6, 127.8, 122.9, 121.6, 114.6, 111.9, 52.2.
MS (ESI): m/z = 280 [M + H]+.
HRMS: m/z [M + H]+ calcd for C17H14NO3: 280.0968; found:
280.0968.
Anal. Calcd for C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found: C,
72.92; H, 4.80; N, 5.07.
(1H-Indol-2-yl)(4-methyphenyl)methanone (3g)
Following the general procedure, the reaction was performed with
1a (100 mg, 0.46 mmol) and 2g (117 mg, 0.55 mmol). Eluent for
chromatography: PE–EtOAc (15:1).
MS (ESI): m/z = 240 [M + H]+.
HRMS: m/z [M + H]+ calcd for C15H11FNO: 240.0819; found:
240.0815.
Yield: 62 mg (57%); off-white solid; mp 189–190 °C (Lit.8a 184–
186 °C).
1H NMR (400 MHz, CDCl3): d = 9.34 (br s, 1 H), 7.92 (d,
J = 8.0 Hz, 2 H), 7.72 (dd, J = 8.0, 0.6 Hz, 1 H), 7.48 (dd, J = 8.0,
0.6 Hz, 1 H), 7.39–7.33 (m, 3 H), 7.19–7.15 (m, 2 H), 2.47 (s, 3 H).
(1H-Indol-2-yl)(4-nitrophenyl)methanone (3k)7c
Following the general procedure, the reaction was performed with
1a (100 mg, 0.46 mmol) and 2k (134 mg, 0.55 mmol). Eluent for
chromatography: PE–EtOAc (10:1).
Yield: 61 mg (50%); yellow solid; mp 205–206 °C.
13C NMR (100 MHz, CDCl3): d = 186.7, 143.0, 137.4, 135.4, 134.6,
1H NMR (400 MHz, CDCl3): d = 9.34 (br s, 1 H), 8.39 (dt, J = 8.6,
2.0 Hz, 2 H), 8.12 (dt, J = 8.6, 2.0 Hz, 2 H), 7.73 (d, J = 8.0 Hz,
1 H), 7.50 (d, J = 8.4 Hz, 1 H), 7.43 (t, J = 7.4 Hz, 1 H), 7.2 (t, J =
7.4 Hz, 1 H), 7.14 (d, J = 1.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 185.0, 149.9, 143.2, 138.0, 133.6,
130.0, 127.6, 127.4, 123.7, 123.5, 121.5, 113.7, 112.3.
129.3, 129.1, 127.9, 126.3, 123.1, 121.0, 112.1, 112.0, 21.5.
MS (ESI): m/z = 236 [M + H]+.
HRMS: m/z [M + H]+ calcd for C16H14NO: 236.1070; found:
236.1069.
(1H-Indol-2-yl)(4-methoxyphenyl)methanone (3h)
Following the general procedure, the reaction was performed with
1a (100 mg, 0.46 mmol) and 2h (126 mg, 0.55 mmol). Eluent for
chromatography: PE–EtOAc (15:1).
MS (ESI): m/z = 265 [M – H)–.
HRMS: m/z [M + H]+ calcd for C15H11N2O3: 267.0764; found:
267.0766.
Yield: 80 mg (69%); off-white solid; mp 190–191 °C (Lit.8a 189–
190 °C).
1H NMR (400 MHz, CDCl3): d = 9.42 (br s, 1 H), 8.04 (dt, J = 8.8,
1.9 Hz, 2 H), 7.73 (dd, J = 8.0, 0.3 Hz, 1 H), 7.48 (dd, J = 8.3,
0.6 Hz, 1 H), 7.37 (td, J = 7.0, 0.9 Hz, 1 H), 7.19–7.15 (m, 2 H),
7.03 (dt, J = 8.8, 1.9 Hz, 2 H), 3.92 (s, 3 H).
(1H-Indol-2-yl)(3-methoxyphenyl)methanone (3l)
Following the general procedure, the reaction was performed with
1a (100 mg, 0.46 mmol) and 2l (126 mg, 0.55 mmol). Eluent for
chromatography: PE–EtOAc (15:1).
Yield: 81 mg (70%); yellow solid; mp 128–129 °C (Lit.7e 124–
126 °C).
13C NMR (125 MHz, CDCl3): d = 185.8, 163.2, 137.3, 134.5, 131.5,
1H NMR (400 MHz, CDCl3): d = 9.90 (br s, 1 H), 7.73 (d,
J = 8.0 Hz, 1 H), 7.64 (d, J = 7.6 Hz, 1 H), 7.55 (dd, J = 2.4, 1.6 Hz,
1 H), 7.52 (dd, J = 8.4, 0.4 Hz, 1 H), 7.46 (t, J = 8.0 Hz, 1 H), 7.40–
7.36 (m, 1 H), 7.21 (d, J = 1.2 Hz, 1 H), 7.20–7.16 (m, 2 H), 3.90 (s,
3 H).
13C NMR (125 MHz, CDCl3): d = 187.0, 159.6, 139.3, 137.7, 134.3,
129.4, 127.6, 126.5, 123.2, 121.8, 120.9, 118.6, 113.8, 112.9, 112.3,
55.4.
130.7, 127.8, 126.2, 123.1, 120.9, 113.8, 112.1, 111.8, 55.5.
MS (ESI): m/z = 252 [M + H]+.
HRMS: m/z [M + H]+ calcd for C16H14NO2: 252.1019; found:
252.1022.
(4-Chlorophenyl)(1H-indol-2-yl)methanone (3i)
Following the general procedure, the reaction was performed with
1a (100 mg, 0.46 mmol) and 2i (128 mg, 0.55 mmol). Eluent for
MS (ESI): m/z = 252 [M + H]+.
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Synthesis of 2-Aroylindoles
879
HRMS: m/z [M + H]+ calcd for C16H14NO2: 252.1019; found:
252.1020.
13C NMR (100 MHz, CDCl3): d = 172.6, 152.9, 146.4, 137.4, 133.6,
128.1, 126.4, 123.3, 121.0, 118.4, 112.4, 112.1, 111.4.
MS (ESI): m/z = 212 [M + H]+.
HRMS: m/z [M + H]+ calcd for C13H10NO2: 212.0706; found:
(1H-Indol-2-yl)(2-methoxyphenyl)methanone (3m)
Following the general procedure, the reaction was performed with
1a (100 mg, 0.46 mmol) and 2m (126 mg, 0.55 mmol). Eluent for
chromatography: PE–EtOAc (15:1).
Yield: 77 mg (67%); pale-yellow solid; mp 133–134 °C (Lit.8a 129–
130 °C).
1H NMR (400 MHz, CDCl3): d = 9.56 (br s, 1 H), 7.66 (dd, J = 8.0,
0.8 Hz, 1 H), 7.55–7.47 (m, 3 H), 7.37–7.33 (m, 1 H), 7.16–7.12
(m, 1 H), 7.08–7.04 (m, 2 H), 6.93 (dd, J = 2.0, 0.8 Hz, 1 H), 3.84
(s, 3 H).
212.0703.
(1H-Indol-2-yl)(thiophen-2-yl)methanone (3q)
Following the general procedure, the reaction was performed with
1a (100 mg, 0.46 mmol) and 2q (104 mg, 0.55 mmol). Eluent for
chromatography: PE–EtOAc (15:1).
Yield: 89 mg (85%); yellow solid; mp 162–163 °C (Lit.8b 161–
163 °C).
1H NMR (400 MHz, CDCl3): d = 9.85 (br s, 1 H), 8.07 (dd, J = 3.6,
0.9 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.73 (dd, J = 4.8, 0.8 Hz,
1 H), 7.53 (dd, J = 8.0, 0.3 Hz, 1 H), 7.46 (d, J = 1.2 Hz, 1 H), 7.40–
7.36 (m, 1 H), 7.23 (dd, J = 4.8, 3.9 Hz, 1 H), 7.20–7.17 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 187.2, 157.4, 137.8, 135.8, 132.0,
129.7, 128.2, 127.6, 126.4, 123.2, 120.8, 120.0, 113.2, 112.3, 111.6.
MS (ESI) m/z = 252 [M + H]+.
HRMS: m/z [M + H]+ calcd for C16H14NO2: 252.1019; found:
252.1017.
1H NMR (400 MHz, DMSO-d6 and D2O): d = 8.10 (d, J = 0.4 Hz,
1 H), 7.99 (d, J = 4.8 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.50 (t,
J = 4.0 Hz, 2 H), 7.33–7.30 (m, 2 H), 7.12–7.09 (m, 1 H). The ex-
istence of active H-atom of indole was proved by the disappearance
of H (no H shown from d = 9 to 11 ppm) in the 1H NMR spectra (the
mixture of DMSO-d6 and D2O as the solvent).
(2-Bromophenyl)(1H-indol-2-yl)methanone (3n)15
Following the general procedure, the reaction was performed with
1a (100 mg, 0.46 mmol) and 2n (152 mg, 0.55 mmol). Eluent for
chromatography: PE–EtOAc (15:1).
13C NMR (125 MHz, CDCl3): d = 177.9, 142.5, 137.5, 134.1, 133.2,
133.0, 128.1, 127.7, 126.4, 123.1, 121.0, 112.3, 110.7.
Yield: 99 mg (72%); yellow solid; mp 139–140 °C.
1H NMR (400 MHz, CDCl3): d = 9.95 (br s, 1 H), 7.92 (dd, J = 8.0,
1.2 Hz, 1 H), 7.66 (dd, J = 8.0, 0.8 Hz, 1 H), 7.57–7.54 (m, 2 H),
7.47–7.42 (m, 1 H), 7.41–7.37 (m, 2 H), 7.18–7.14 (m, 1 H), 6.90
(dd, J = 2.0, 0.8 Hz, 1 H).
MS (ESI): m/z = 228 [M + H]+.
HRMS: m/z [M + H]+ calcd for C13H10NOS: 228.0478; found:
228.0482.
13C NMR (125 MHz, CDCl3): d = 187.1, 139.7, 138.4, 134.5, 133.5,
2-Acetylindole (3r)
131.4, 129.3, 127.4, 127.1, 126.8, 123.3, 121.1, 120.0, 114.6, 112.6.
Following the general procedure, the reaction was performed with
1a (100 mg, 0.46 mmol) and 2r (75 mg, 0.55 mmol). Eluent for
chromatography: PE–EtOAc (10:1).
Yield: 60 mg (82%); white solid; mp 154–155 °C (Lit.16 157–
158 °C).
MS (ESI): m/z = 300 [M + H]+.
HRMS: m/z [M + H]+ calcd for C15H11BrNO: 300.0019; found:
300.0022.
(1H-Indol-2-yl)(naphthalene-2-yl)methanone (3o)
Following the general procedure, the reaction was performed with
1a (100 mg, 0.46 mmol) and 2o (137 mg, 0.55 mmol). Eluent for
chromatography: PE–EtOAc (15:1).
Yield: 80 mg (64%); pale-yellow solid; mp 176–177 °C (Lit.8a 174–
175 °C).
1H NMR (400 MHz, CDCl3): d = 9.39 (br s, 1 H), 8.56 (s, 1 H), 8.05
(dd, J = 8.4, 1.5 Hz, 1 H), 8.01 (t, J = 9.0 Hz, 2 H), 7.94 (d,
J = 8.0 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.66–7.58 (m, 2 H), 7.51
(d, J = 8.3 Hz, 1 H), 7.40 (t, J = 7.3 Hz, 1 H), 7.25 (s, 1 H), 7.19 (t,
J = 7.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 187.0, 137.5, 135.3, 134.5, 132.5,
130.6, 129.4, 128.4, 128.2, 127.9, 127.8, 126.9, 126.5, 125.3, 123.3,
121.1, 112.8, 112.2.
1H NMR (400 MHz, CDCl3): d = 9.40 (s, 1 H), 7.72 (d, J = 8.0 Hz,
1 H), 7.45 (dd, J = 8.4, 0.4 Hz, 1 H), 7.38–7.36 (m, 1 H), 7.21 (d,
J = 1.2 Hz, 1 H), 7.18–7.14 (m, 1 H), 2.61 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 190.4, 137.5, 135.5, 127.7, 126.3,
123.0, 120.9, 112.2, 109.8, 25.7.
MS (ESI): m/z = 160 [M + H]+.
HRMS: m/z [M + H]+ calcd for C10H10NO: 160.0757; found:
160.0756.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
MS (ESI): m/z = 272 [M + H]+.
This work was supported by a Grant-in-Aid for Scientific Research
from the Chinese Academy of Science Innovation Grant (KSCX1-
YW-10) and the Guangdong Natural Science Foundation (Grant
No. 06200872).
HRMS: m/z [M + H]+ calcd for C19H14NO: 272.1070; found:
272.1072.
(Furan-2-yl)(1H-indol-2-yl)methanone (3p)
Following the general procedure, the reaction was performed with
1a (100 mg, 0.46 mmol) and 2p (113 mg, 0.55 mmol). Eluent for
chromatography: PE–EtOAc (20:1).
Yield: 75 mg (77%); pale-yellow solid; mp 130–132 °C (Lit.8b 128–
131 °C).
1H NMR (400 MHz, CDCl3): d = 9.71 (br s, 1 H), 7.77 (d, J =
8.0 Hz, 1 H), 7.72 (s, 2 H), 7.50–7.48 (m, 2 H), 7.39–7.35 (m, 1 H),
7.19–7.15 (m, 1 H), 6.64 (dd, J = 3.6, 1.6 Hz, 1 H).
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Synthesis 2011, No. 6, 873–880 © Thieme Stuttgart · New York