2-Substituted 3-aryl- and 3-heteroarylindoles by the palladium-catalyzed reaction of o-trifluoroacetanilides with aryl bromides and triflates

Article abstract of DOI:10.1055/s-2003-38079

The palladium-catalyzed reaction of aryl and heteroaryl bromides and triflates with o-alkynyltrifluoroacetanilides affords 2-substituted 3-aryl- and heteroarylindoles usually in excellent yield. The procedure can be applied to the synthesis of 2-substituted indole-3-carboxaldehydes.

Full text of DOI:10.1055/s-2003-38079

728
PAPER
2-Substituted 3-Aryl- and 3-Heteroarylindoles by the Palladium-Catalyzed
Reaction of o-Trifluoroacetanilides with Aryl Bromides and Triflates.
2
, 3-Disubstitu
a
ted Indoles
n
from
o
-Alky
d
nyltrifluoroa
r
cetanilid
o
es and
A
ryl
BromiC
des or Triflates acchi,*a Giancarlo Fabrizi,a Doriano Lamba,b Fabio Marinelli,c Luca M. Parisia
a
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi ‘La Sapienza’, P.le A.
Moro5, 00185 Roma, Italy.
Fax +39(06)49912780; E-mail: sandro.cacchi@uniroma1.it.
b
c
Institute of Structural Chemistry - CNR Trieste, XRD1 beamline - Elettra Trieste, Italy.
Dipartimento di Chimica Ingegneria Chimica e Materiali della Facoltà di Scienze, Università di L’Aquila, Via Vetoio, Coppito Due,
67100 L’Aquila, Italy.
Received 27 January 2003
Compounds 1 were prepared from o-iodoaniline.4 Our ini-
tial attempts focused on achieving optimal reaction condi-
tions for the reaction of phenyl bromide and o-
(phenylethynyl)trifluoroacetanilide 1a (R = Ph) in
MeCN, selected as the model system. The effect of bases,
phosphine ligands, and temperature on the reaction yield
was explored and some of our results are shown in
Table 1.
Abstract: The palladium-catalyzed reaction of aryl and heteroaryl
bromides and triflates with o-alkynyltrifluoroacetanilides affords 2-
substituted 3-aryl- and heteroarylindoles usually in excellent yield.
The procedure can be applied to the synthesis of 2-substituted in-
dole-3-carboxaldehydes.
Key words: palladium, alkynes, indoles, aryl halides, cyclization
At 60 °C and 80 °C a tendency to produce 2-phenylindole
4a (Figure 1) was observed with a variety of phosphine
ligands and bases (Table 1, entries 1–5, 11, 12). Apparent-
ly, at these temperatures the oxidative addition of phenyl
bromide to Pd(0) is relatively slow and the cyclization of
1a to 4a can be a significant side reaction or even the main
reaction path. This cyclization appears to be a palladium-
catalyzed reaction, as suggested by the observation that no
indole product was observed when the reaction was car-
ried out omitting the palladium catalyst. In a few cases
(Table 1, entries 1 and 5) the dimer 5a was also isolated in
significant yield.
The palladium-catalyzed reaction of o-alkynyltrifluoro-
acetanilides with organopalladium complexes generated
in situ has been shown to be a powerful and extremely ver-
satile procedure for the construction of the substituted
pyrrole nucleus of the indole system.1 This chemistry has
been employed in the preparation of biologically active
compounds.2 It has also been adapted to a solid-supported
synthesis for the preparation of combinatorial libraries of
indoles with three variable components.3 However, while
a variety of indole derivatives could be prepared in good
to excellent yield by using aryl iodides as the aryl donors,
their employment was rather limited. Obviously, exten-
sion of the procedure to include aryl bromides and triflates
would greatly widen its scope and generality and is highly
desirable: reactions that employ the less expensive aryl
bromides have significant practical advantages relative to
those employing aryl iodides; including aryl triflates
among the aryl donors can make it possible to look at phe-
nols, widely diffused among natural products, as precur-
sors of indole derivatives.
H
N
Ph
Ph
Ph
N
N
H
H
4a
5a
Herein we wish to report the successful application of our
reaction to the synthesis of 2-substituted 3-aryl-, het-
eroarylindoles using o-trifluoroacetanilides 1 and aryl and
heteroaryl bromides or triflates 2 (Scheme 1).
Figure 1
The reaction was shifted towards the aminopalladation-
reductive elimination mechanism by increasing the tem-
perature to 100 °C and by using Pd2(dba)3 and Xantphos
[9,9-dimethyl-4,6-bis(diphenylphosphino)xanthene]5 in
the presence of K2CO3 (Table 1, entry 6) or Cs2CO3
(Table 1, entry 7) or even by using Pd(PPh3)4 in the pres-
ence of K2CO3 (Table 1, entry 9). Under these conditions
the desired indole product was isolated in high yield.
However, the best results with regard to reaction time and
yield were obtained with Cs2CO3 and Pd(PPh3)4 (Table 1,
entry 10). The latter conditions proved satisfactory also
for the reaction of 1a with phenyl triflate (Table 1, entry
15) and have been used when the procedure has been ex-
tended to include other aryl and heteroaryl bromides
R
Ar
Pd cat, base
R
ArX
N
NHCOCF3
H
1
2
3
X = Br, OTf
Scheme 1
Synthesis 2003, No. 5, Print: 01 04 2003.
Art Id.1437-210X,E;2003,0,05,0728,0734,ftx,en;Z01403SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
2,3-Distributed Indoles from o-Trifluoroacetanilides and Aryl Bromides or Triflates
729
Table 1 Ligands, Bases, and Temperature Dependence of the Reaction of o-(Phenylethynyl)trifluoroacetanilide (1a) with Phenyl Bromide
and Triflatea
Entry
X
Base
[Pd]
T (°C)
Time (h)
Yield%b
3a
22
-
4a
45
80
80
27
60
6
5a
30
-
1
2
Br
K2CO3
K2CO3
t-BuONa
K2CO3
Cs2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Pd2(dba)3/PPh3
Pd2(dba)3/P(But)3
Pd2(dba)3/Xantphos
Pd2(dba)3/Xantphos
Pd2(dba)3/PPh3
Pd2(dba)3/Xantphos
Pd2(dba)3/Xantphos
Pd2(dba)3/Xantphos
Pd(PPh3)4
80
80
8
5
Br
3
Br
80
10
20
4
-
-
4
Br
80
46
-
-
5
Br
80
18
-
6
Br
100
100
100
100
100
80
8
84
88
-
7
Br
4
5
-
8
Br
20
1
72c
-
-
9
Br
79
93
60
-
-
10
11
12
13
14
15
Br
Pd(PPh3)4
0.5
0.5
20
5
-
-
Br
Pd(PPh3)4
18
63
27
80
-
-
Br
Pd(PPh3)4
60
-
OTf
OTf
OTf
Pd2(dba)3/Xantphos
Pd(PPh3)4
100
80
73
-
-
8
-
Pd(PPh3)4
100
0.25
97
-
a Reactions were conducted under argon, in MeCN, using 1 equiv of 1a, 1.5 equiv of PhBr or 1 equiv of PhOTf, 0.05 equiv of [Pd], 0.1 equiv
of monodentate ligands or 0.05 equiv of Xantphos, 1.5 equiv of base (5 equiv when K2CO3 was used).
b Yields are given for isolated products.
c In toluene.
Table 2 Synthesis of 2-Substituted 3-Aryl- and 3-Heteroarylindoles
(Table 2, entries 1–22), triflates (Table 2, entries 23–31)
and o-alkynyltrifluoroacetanilides (Table 3).
from o-(Phenylethynyl)trifluoroacetanilide 1a and Aryl or Heteroaryl
Bromides and Triflates 2a
As seen in Table 2, the reaction allows easy access to a
Entry Aryl or Heteroaryl Bromide and
Time
(h)
Yield %b of 3
wide variety of indole derivatives and tolerates, in the
Csp2 donor, various functional groups amenable of further
functionalization. Aryl bromides and triflates containing
aldehyde, ketone, ester, nitro, nitrile functionality all af-
forded the desired indole product usually in excellent
yields. Substituents close to the oxidative addition site do
not hamper the reaction (Table 2, entries 4 and 22). As for
the alkyne component (Table 3), indole derivatives have
been obtained in high yield with alkynes containing both
electron-withdrawing and electron-donating substituents.
Triflate 2
1
2
2a
2b
2c
2d
2e
2f
PhBr
0.5
1
3a
3b
3c
3d
3e
3f
93
98
98
96
91
98
88
98
86
98
98
99
p-Me-C6H4-Br
m-Me-C6H4-Br
o-Me-C6H4-Br
p-t-BuC6H4-Br
3,5-Me2-C6H3-Br
p-MeO-C6H4-Br
p-Ph-C6H4-Br
m-MeO-C6H4-Br
m-F-C6H4-Br
m-CF3-C6H4-Br
m-CN-C6H4-Br
3
1
4
1
5
0.5
0.5
0.25
1
6
In conclusion, we have developed an efficient synthesis of
various 2-substituted 3-aryl- and 3-heteroarylindoles by
the palladium-catalyzed reaction of o-alkynyltrifluoro-
acetanilides with aryl and heteroaryl bromides or triflates.
Present results widen significantly the scope of our ami-
nopalladation-reductive elimination domino procedure
for the construction of the substituted pyrrole nucleus of
the indole system.
7
2g
2h
2i
3g
3h
3i
8
9
0.5
0.5
0.5
0.5
10
11
12
2j
3j
2k
2l
3k
3l
Synthesis 2003, No. 5, 728–734 ISSN 0039-7881 © Thieme Stuttgart · New York

730
S. Cacchi et al.
PAPER
Table 3 The Reaction of o-Alkynyltrifluoroacetanilides with Aryl
Table 2 Synthesis of 2-Substituted 3-Aryl- and 3-Heteroarylindoles
from o-(Phenylethynyl)trifluoroacetanilide 1a and Aryl or Heteroaryl
Bromides and Triflates 2a (continued)
and Heteroaryl Bromidesa
en- o-Alkynyl Trifluoro- Aryl and Heteroaryl
try acetanilide 1 R Bromide 2
Time Yield%b
(h) of 3
Entry Aryl or Heteroaryl Bromide and
Time
(h)
Yield %b of 3
Triflate 2
1
2
1b p-MeO-C6H4- 2zf p-t-Bu-C6H4-Br 1
3zb 87
3zc 80
13
14
15
16
17
18
2m
2n
2o
2p
2q
2r
p-CN-C6H4-Br
0.5
0.5
1
3m
3n
3o
3p
3q
3r
90
84
94
98
97
70
1b p-MeO-C6H4- 2zg
2
S
Br
m-CHO-C6H4-Br
p-CHO-C6H4-Br
p-MeCO-C6H4-Br
p-NO2-C6H4-Br
N
3
4
1c p-MeCO-C6H4- 2zf p-t-Bu-C6H4-Br 1
3zd 98
0.5
1
1c p-MeCO-C6H4- 2zg
2
3ze
74
S
Br
N
S
2
5
1d p-NO2-C6H4-
2zg
2
3zf
40
S
Br
Br
N
N
19
20
2s
2t
2
5
3s
3t
94
56
6
7
1e C5H11
1e C5H11
2zh m-CN-C6H4-Br 0.5 3zg 88
N
Br
2zf
3
3zh 75
S
Br
Br
N
a Reactions were conducted at 100 °C under argon, in MeCN, using 1
equiv of 1, 1.5 equiv of 2, 0.05 equiv of Pd(PPh3)4, 1.5 equiv of
Cs2CO3.
N
H
21
22
2u
2v
5
5
3u
3v
85
70
N
b Yields are given for isolated products.
Br
N
Cl
The positive results obtained in the preparation of 2-sub-
stituted 3-thiazolylindoles (Table 2, entry 18; Table 3, en-
tries 2, 4, 5, 7) prompted us to explore briefly the
combination of our indole synthesis with the conversion
of the thiazolyl group into the formyl group6 to develop a
route to 2-substituted indole-3-carboxaldehydes from o-
alkynyltrifluoroacetanilides. As an example, 2-phenylin-
dole-3-carboxaldehyde was prepared in 33% overall yield
according to the sequence shown in Scheme 2.
N
Cl
Br
N
23
24
25
26
27
28
29
2w
2x
PhOTf
0.5
1
3a
3g
3w
3h
3x
3q
3y
97
98
98
89
99
94
35
p-MeO-C6H4-OTf
3,4,5-(MeO)3-C6H2-OTf
p-Ph-C6H4-ONf
2y
1
2z
1
2za
2zb
2zc
p-PhCO-C6H4-OTf
p-NO2-C6H4-OTf
1
N
S
1
Pd(PPh3)4
Cs2CO3
2
1a
Ph
N
S
MeCN
N
H
100 °C, 2 h
N
Br
70%
OTf
MeCN, 90 °C MeI
12 h
30
31
2zd
2ze
1
1
3z
91
80
100%
N
OTf
Me
N
Me
N
S
S
3za
I
NaBH4
Ph
Ph
O
O
OTf
MeOH
- 10 °C
N
N
H
a Reactions were conducted at 100 °C under argon, in MeCN, using 1
equiv of 1a, 1.5 equiv of ArBr or 1 equiv of ArOTf, 0.05 equiv of
Pd(PPh3)4, 1.5 equiv of Cs2CO3.
H
78%
MeCN:H2O CuO
10:1
CuCl2 2H2O
b Yields are given for isolated products.
CHO
61%
Ph
N
H
Scheme 2
Synthesis 2003, No. 5, 728–734 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
2,3-Distributed Indoles from o-Trifluoroacetanilides and Aryl Bromides or Triflates
731
Melting points are uncorrected. Aryl and heteroayl bromides,
MeCN, palladium precatalysts, and phosphine ligands are commer-
cially available and were used as purchased, without further purifi-
cation. Aryl triflates were prepared according to known methods.7
o-Alkynyltrifluoroacetanilides 1a–e were prepared as described in
the literature.4 Reaction products were purified on axially com-
pressed columns, packed with SiO2 25–40 µm, connected to a sol-
vent delivery system and to a refractive index detector, and eluting
Anal. Calcd for C21H17N: C, 89.01; H, 6.05; N, 4.94. Found: C,
88.95; H, 6.03; N, 4.93.
3e
Mp 140–141 °C.
IR (KBr): 3400, 2960, 1455 cm–1.
1H NMR (CDCl3): δ = 1.34 (s, 9 H), 7.08–7.42 (m, 11 H), 7.69 (d,
J = 7.5 Hz, 1 H), 8.10 (s, 1 H).
13C NMR (CDCl3): δ = 31.5, 34.6, 110.9, 114.9, 119.9, 120.3,
122.6, 125.4, 127.6, 128.3, 128.6, 128.9, 129.7, 132.0, 132.9, 134.0,
136.0, 149.0.
with hexane–EtOAc. 1H NMR were recorded at 200 MHz and 13
NMR were recorded at 50.3 MHz).
C
Preparation of 2-Substituted 3-Aryl- and 3-Heteroarylindoles
(3); Typical Procedure
Anal. Calcd for C24H23N: C, 88.57; H, 7.12; N, 4.30. Found: C,
88.51; H, 7.10; N, 4.29.
To a 50 mL carousel reaction tube (Radely Discovery Technology)
containing a magnetic stir bar was added MeCN (2.0 mL), 1a (0.100
g, 0.346 mmol), phenyl bromide (0.055 mL, 0.519 mmol), Cs2CO3
(0.169 g, 0.519 mmol), and Pd(Ph3P)4 (0.020 g, 0.0173 mmol). The
mixture was stirred for 0.5 h at 100 °C under argon. After this time,
the reaction mixture was cooled to r.t., diluted with EtOAc (100
mL), and washed with H2O (3 × 15 mL). The organic extract was
dried over Na2SO4 and concentrated under reduced pressure. The
residue was purified by chromatography (silica gel, hexane–EtOAc,
85:15) to give 0.087 g of 3a (93% yield); mp 120–121 °C.
3f
Oil.
IR (neat): 3407, 2917, 1601, 1328 cm–1.
1H NMR (CDCl3): δ = 2.28 (s, 6 H), 6.92 (br s, 1 H), 7.05 (br s, 2
H), 7.11–7.42 (m, 8 H), 7.67 (d, J = 7.5 Hz, 1 H), 8.05 (s, 1 H).
13C NMR (CDCl3): δ = 21.4, 110.3, 115.2, 119.9, 120.3, 122.6,
127.6, 127.9, 128.0, 128.1, 128.6, 129.0, 132.8, 133.9, 134.9, 135.9,
137.9.
IR (KBr): 3387, 1454 cm–1.
1H NMR (CHCl3): δ = 7.11–7.58 (m, 13 H), 7.62–7.78 (m, 1 H),
Anal. Calcd for C22H19N: C, 88.85; H, 6.44; N, 4.71. Found: C,
88.78; H, 6.41; N, 4.68.
8.25 (s, 1 H).
13C NMR (CHCl3): δ = 111.0, 115.1, 119.8, 120.5, 122.8, 126.3,
3g
127.8, 128.3, 128.6, 128.7, 128.9, 130.3, 132,8, 134.2, 135.2, 136.0.
Mp 184–185 °C.
IR (KBr): 3418, 1602, 1510 cm–1.
Anal. Calcd for C20H15N: C, 89.19; H, 5.61; N, 5,20. Found: C,
89.10; H, 5.59; N, 5.15.
1H NMR (CDCl3): δ = 3.78 (s, 3 H), 6.91–7.55 (m, 13 H), 11.49 (s,
1 H).
13C NMR (CDCl3): δ = 55.4, 111.8, 113.5, 114.6, 119.0, 120.0,
122.3, 127.8, 128.4, 128.6, 128.7, 128.9, 131.3, 133.0, 134.0, 136.5,
158.2.
3b
Mp 123–124 °C.
IR (KBr): 3401, 1446, 1327 cm–1.
1H NMR (CDCl3): δ = 2.38 (s, 3 H), 7.05–7.46 (m, 12 H), 7.68 (d,
J = 7.9 Hz, 1 H), 8.19 (s, 1 H).
13C NMR (CDCl3): δ = 21.4, 111.1, 115.1, 119.9, 120.5, 122.8,
127.7, 128.3, 128.8, 129.0, 129.4, 130.1, 132.2, 133.0, 134.0, 135.9,
136.0.
Anal. Calcd for C21H17NO: C, 84.25; H, 5.72; N, 4.68. Found: C,
84.20; H, 5.71; N, 4.66.
3h
Mp 155–156 °C.
IR (KBr): 3417, 3056, 769, 743, 692 cm–1.
Anal. Calcd for C21H17N: C, 89.01; H, 6.05; N, 4.94. found: C,
88.96; H, 6.04; N, 4.93.
1H NMR (DMSO-d6): δ = 7.08–7.77 (m, 18 H), 8.12 (s, 1 H).
3c
Oil.
13C NMR (DMSO-d6): δ = 111.0, 114.6, 119.8, 120.6, 122.8, 127.0,
127.18, 127.23, 127.8, 128.3, 128.74, 128.77, 128.84, 130.5, 132.7,
134.2, 134.3, 136.0, 138.8, 141.0.
IR (neat): 3408, 1455, 1328 cm–1.
1H NMR (CDCl3): δ = 2.32 (s, 3 H), 7.02–7.45 (m, 12 H), 7.66 (d,
J = 6.8 Hz, 1 H), 8.15 (s, 1 H).
13C NMR (CDCl3): δ = 21.6, 111.0, 115.3, 119.9, 120.5, 122.8,
127.2, 127.4, 127.7, 128.2, 128.5, 128.8, 129.0, 130.9, 132.9, 134.1,
135.1, 136.0, 138.1.
Anal. Calcd for C26H19N: C, 90.40; H, 5.54; N, 4.05. Found: C,
90.37, H, 5.53; N, 4.01.
3i
Mp 122–123 °C.
IR (KBr): 3373, 2998, 2832, 1600 cm–1.
Anal. Calcd for C21H17N: C, 89.01; H, 6.05; N, 4.94: found: C,
88.87, H, 6,01; N, 4.89.
1H NMR (CDCl3): δ = 3.79 (s, 3 H), 6.88–6.97 (m, 1 H), 7.07–7.72
(m, 2 H), 7.18–7.72 (m, 9 H), 7.80 (dd, J1 = 7.8 Hz, J2 = 1.1 Hz, 1
H), 8.29 (br s, 1 H).
13C NMR (CDCl3): δ = 55.2, 111.0, 112.2, 114.9, 115.5, 119.8,
120.5, 122.7, 122.8, 127.8, 128.3, 128.69, 128.71, 129.6, 132.7,
134.3, 135.9, 136.6, 159.7.
3d
Mp 170–171 °C.
IR (KBr): 3400, 1455, 1328 cm–1.
1H NMR (DMSO-d6): δ = 1.95 (s, 3 H), 6.90–7.58 (m, 13 H), 11.57
(s, 1 H).
Anal. Calcd for C21H17NO: C, 84.25; H, 5.72; N, 4.68. Found: C,
84.18; H 5.71; N 4.68.
13C NMR (DMSO-d6): δ = 20.3, 111.9, 113.5, 119.3, 120.0, 122.4,
126.6, 129.2, 127.6, 127.7, 129.1, 129.3, 130.8, 131.7, 133.3, 134.2,
135.5, 136.6, 137.5.
Synthesis 2003, No. 5, 728–734 ISSN 0039-7881 © Thieme Stuttgart · New York

732
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S. Cacchi et al.
PAPER
Anal. Calcd for C21H15NO: C, 84.82; H, 5.08; N, 4.71. Found: C,
84.75; H, 5.07; N, 4.69.
Mp 148–149 °C.
IR (KBr): 3409, 1605, 1570 cm–1.
1H NMR (CDCl3): δ = 6.96–7.11 (m, 1 H), 7.11–7.35 (m, 11 H),
7.75 (d, J = 7.6 Hz, 1 H), 8.25 (s, 1 H).
13C NMR (CDCl3): δ = 111.0, 113.1 (d, J = 21.1 Hz), 113.8 (d,
J = 2.3 Hz), 116.7 (d, J = 21.3 Hz), 119.4, 120.7, 122.9, 125.8 (d,
J = 2.8 Hz), 128.0, 128.2, 128.4, 128.8, 129.9 (d, J = 8.6 Hz), 132.3,
134.6, 135.8, 137.4 (d, J = 8.3 Hz), 163.0 (d, J = 245.0 Hz).
3o
Mp 207–208 °C.
IR (KBr): 3257, 2832, 2744, 1681 cm–1.
1H NMR (DMSO-d6): δ = 7.08 (dt, J1 = 6.7 Hz, J2 = 0.9 Hz, 1 H),
7.20 (dt, J1 = 7.2 Hz, J2 = 1.1 Hz, 1 H), 7.27–7.64 (m, 9 H), 7.88 (d,
J = 8.2 Hz, 2 H), 9.97 (s, 1 H), 11.78 (s, 1 H).
13C NMR (DMSO-d6): δ = 112.3, 112.6, 118.9, 120.7, 122.8, 127.8,
128.5, 129.1, 129.2, 130.4, 130.5, 132.5, 134.2, 136.1, 136.8, 142.6,
192.9.
19F NMR {1H} (CDCl3): δ = –113.81.
Anal. Calcd for C20H14FN: C, 83.60; H, 4.91; N, 4.87. Found: C,
83.54; H, 4.90; N, 4.85.
Anal. Calcd for C21H15NO: C, 84.82; H, 5.08; N, 4.71. Found: C,
84.77; H, 5.09; N, 4.70.
3k
Mp 70–71 °C.
IR (KBr): 3383, 1456, 1324 cm–1.
1H NMR (CDCl3): δ = 7.25-7.90 (m, 13 H), 8.27 (s, 1 H).
3p
Mp 203–204 °C.
IR (KBr): 3264, 2923, 1658, 1599 cm–1.
13C NMR (CDCl3): δ = 111.2, 113.5, 119.2, 120.9, 122.9 (q, J = 3.9
Hz), 123.0, 124.3 (q, J = 272.5 Hz), 126.7 (q, J = 3.9 Hz), 128.2,
128.3, 128.9, 129.0, 130.9 (q, J = 31.9 Hz), 132.1, 133.4 (q, J = 1.2
Hz), 134.9, 135.9, 136.1.
1H NMR (CDCl3): δ = 2.61 (s, 3 H), 7.00–7.68 (m, 11 H), 7.99 (d,
J = 8.3 Hz, 2 H), 11.77 (s, 1 H).
13C NMR (CDCl3): δ = 26.6, 111.7, 112.1, 118.5, 120.2, 122.3,
127.4, 128.0, 128.5, 128.6, 128.7, 129.6, 132.2, 134.3, 135.3, 136.3,
140.6, 197.4.
19F NMR {1H} (CDCl3): δ = –62.9.
Anal. Calcd for C21H14F3N: C, 74.77; H, 4.18; N, 4.15. Found: C,
74.73; H, 4.17; N, 4.13.
Anal. Calcd for C22H17NO: C, 84.86; H, 5.50; N, 4.50. Found: C,
84.61; H, 5.50; N, 4.48.
3l
3q
Mp 179–180 °C.
IR (KBr): 3400, 2223, 746, 698 cm–1.
1H NMR (DMSO-d6): δ = 7.09 (t, J = 7.3 Hz, 1 H), 7.21 (t, J = 7.5
Hz, 1 H), 7.27–7.78 (m, 11 H), 11.76 (s, 1 H).
13C NMR (DMSO-d6): δ = 111.1, 111.7, 111.8, 118.2, 118.9, 120.2,
122.3, 127.4, 128.0, 128.4, 128.7, 129.7, 129.9, 131.9, 132.8, 134.6,
135.2, 136.1, 136.8.
Mp 228–229 °C.
IR (KBr): 3374, 1591, 1500, 1336 cm–1.
1H NMR (DMSO-d6): δ = 7.11 (dt, J1 = 7.5 Hz, J2 = 1.1 Hz, 1 H),
7.23 (dt, J1 = 7.5 Hz, J2 = 1.2 Hz, 1 H), 7.35–7.68 (m, 9 H), 8.22 (d,
J = 8.8 Hz, 2 H), 11.88 (s, 1 H).
13C NMR (DMSO-d6): δ = 111.1, 111.9, 118.3, 120.5, 122.5, 123.9,
127.0, 128.3, 128.7, 128.8, 130.2, 131.7, 136.1, 136.3, 143.0, 145.0.
Anal. Calcd for C21H14N2: C, 85.69; H 4.79; N, 9.52. Found: C,
85.60; H, 4.78; N, 9.50.
Anal. Calcd for C20H14N2O2: C, 76.42; H, 4.49; N, 8.91. Found: C,
76.35; H, 4.48; N, 8.90.
3m
3r
Mp 212–213 °C.
IR (KBr): 3325, 2227 cm–1.
1H NMR (DMSO-d6): δ = 7.09 (t, J = 6.4 Hz, 1 H), 7.21 (t, J = 7.4
Hz, 1 H), 7.28–7.67 (m, 9 H), 7.80 (d, J = 8.2 Hz, 2 H), 11.81 (s, 1
Mp 163–164 °C.
IR (KBr): 3400, 3052, 1499, 1545 cm–1.
1H NMR (CDCl3): δ = 7.16 (d, J = 3.3 Hz, 1 H), 7.20–7.47 (m, 6 H),
7.47–7.58 (m, 2 H), 7.80 (d, J = 3.3 Hz, 1 H), 8.22–8.30 (m, 1 H),
8.69 (s, 1 H).
H).
13C NMR (DMSO-d6): δ = 108.1, 111.5, 111.8, 118.3, 119.1, 120.3,
122.4, 127.1, 128.1, 128.6, 128.8, 130.3, 131.9, 132.5, 135.7, 136.2,
140.7.
13C NMR (CDCl3): δ = 108.7, 110.9, 117.4, 121.1, 121.5, 123.3,
127.4, 128.8, 129.1, 129.5, 131.9, 135.6, 138.1, 142.5, 162.7.
Anal. Calcd for C17H12N2S: C, 73.88; H, 4.38; N, 10.14. Found: C,
73.81; H, 4.37;N, 10.12.
Anal. Calcd for C21H14N2 C, 85.69; H, 4.79; N, 9.52. Found: C,
85.61; H, 4.77; N, 9.51.
3s
3n
Mp 198–199 °C.
IR (KBr): 3366, 1594 cm–1.
Mp 203–204 °C.
IR (KBr): 3348, 1676 cm–1.
1H NMR (DMSO-d6): δ = 7.02–7.27 (m, 4 H), 7.27–7.58 (m, 6 H),
7.58–7.70 (m, 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 8.58–8.71 (m, 1 H),
11.66 (s, 1 H).
13C NMR (DMSO-d6): δ = 111.4, 112.9, 120.0, 120.2, 120.6, 122.1,
123.9, 127.7, 128.1, 128.6, 128.7, 132.6, 136.0, 136.1, 136.4, 149.4,
155.0.
1H NMR (DMSO-d6): δ = 7.08 (t, J = 7.4 Hz, 1 H), 7.20 (t, J = 7.1
Hz, 1 H), 7.13–7.68 (m, 9 H), 7.78–7.86 (m, 1 H), 7.93 (s, 1 H),
10.01 (s, 1 H), 11.71 (s, 1 H).
13C NMR (DMSO-d6): δ = 111.7, 111.9, 118.3, 120.0, 122.2, 127.1,
127.7, 127.8, 128.3, 128.7, 129.5, 130.5, 132.1, 134.8, 135.8, 136.2,
136.4, 136.7, 193.2.
Anal. Calcd for C19H14N2: C, 84.42; H, 5.22; N, 10.36. Found: C,
84.35; H, 5.21; N, 10.33.
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2,3-Distributed Indoles from o-Trifluoroacetanilides and Aryl Bromides or Triflates
733
3t
Oil.
13C NMR (DMSO-d6): δ = 111.5, 113.0, 120.4, 120.9, 122.5, 122.7,
125.7, 125.9, 127.7, 127.9, 128.5, 128.6, 128.8, 129.1, 129.5, 132.6,
135.3, 136.3, 137.9, 148.0, 155.5.
IR (neat): 3257, 1735 cm–1.
Anal Calcd for C23H16N2: C, 86.22; H, 5.03; N, 8.74. Found: C,
86.15; H, 5.01; N, 8.73.
1H NMR (CDCl3): δ = 6.55–6.65 (m, 1 H), 7.11–7.57 (m, 11 H),
7.69–7.88 (m, 2 H), 8.16 (s, 1 H), 8.25 (s, 1 H).
13C NMR (CDCl3): δ = 102.9, 110.9, 111.2, 116.3, 120.1, 120.3,
122.2, 122.6, 124.4, 125.1, 126.5, 127.4, 128.1, 128.6, 129.6, 133.2,
133.6, 134.8, 136.0.
3z
Mp 232–233 °C.
IR (KBr): 3255, 1736 cm–1.
Anal. Calcd for C22H16N2: C, 85.69; H, 5.23; N, 9.08. Found: C,
85.61; H, 5.20; N, 9.04.
1H NMR (DMSO-d6): δ 6.83–7.01 (m, 2 H), 7.07–7.19 (m, 4 H),
7.19–7.35 (m, 2 H), 7.42–7.55 (m, 2 H), 7.55–7.69 (m, 2 H), 7.93–
8.04 (m, 1 H), 8.41 (dd, J1 = 8.3 Hz, J2 = 1.7 Hz, 1 H), 8.67 (dd,
J1 = 4.1 Hz, J2 = 1.8 Hz, 1 H), 11.60 (s, 1 H).
13C NMR (DMSO-d6): δ = 111.2, 111.9, 119.1, 119.5, 121.3, 121.6,
126.5, 126.9, 127.1, 127.5, 128.3, 128.5, 130.0, 132.0, 132.9, 134.8,
135.0, 136.0, 136.4, 146.9, 149.8.
3u
Mp 224–225 °C.
IR (KBr): 3170, 1554, 1451 cm–1.
1H NMR (DMSO-d6): δ = 7.05–7.31 (m, 2 H), 7.31–7.68 (m, 7 H),
8.76 (s, 2 H), 9.10 (s, 1 H), 11.91 (s, 1 H).
13C NMR (DMSO-d6): δ = 105.9, 112.1, 118.1, 120.5, 122.6, 127.2,
127.3, 128.2, 128.6, 128.9, 129.7, 131.6, 136.1, 136.3, 155.8, 156.9.
Anal. Calcd for C23H16N2: C, 86.22; H, 5.03; N, 8.74. Found: C,
86.16; H, 5.02; N, 8.72.
3za
Anal. Calcd for C18H13N3: C, 79.68; H, 4.83; N, 15.49. Found: C,
79.62; H, 4.81; N, 15.48.
Mp 226–227 °C.
IR (KBr): 3305, 1702, 1610 cm–1.
1H NMR (DMSO-d6): δ = 6.44 (d, J = 9.5 Hz, 1 H), 7.02–7.56 (m,
10 H), 7.56–7.73 (m, 2 H), 8.05 (d, J = 9.5 Hz, 1 H), 11.80 (s, 1 H).
13C NMR (DMSO-d6): δ = 111.6, 111.8, 115.1, 116.4, 116.7, 118.5,
120.3, 122.4, 126.0, 127.3, 128.1, 128.6, 128.7, 128.8, 132.0, 135.7,
136.2, 139.7, 144.2, 153.9, 160.2.
3v
Mp 218–219 °C.
IR (KBr): 3222, 1538 cm–1.
1H NMR (DMSO-d6): δ = 6.93–7.60 (m, 9 H), 8.96 (s, 1 H), 12.12
(s, 1 H).
13C NMR (DMSO-d6): δ = 108.6, 111.9, 119.4, 119.9, 120.6, 122.8,
127.3, 127.6, 128.7, 129.1, 132.0, 136.1, 138.8, 158.5, 162.5, 165.0.
Anal Calcd for C23H15NO2: C, 81.88; H, 4.48; N, 4.15. Found: C,
81.81; H, 4.47; N, 4.13.
Anal. Calcd for C18H11Cl2N3: C, 63.55; H, 3.26; N, 12.35. Found:
C, 63.49; H, 3.25; N, 12.33.
3zb
Mp 145–146 °C.
IR (KBr): 3402, 2959, 1456, 1249 cm–1.
3w
Mp 140–141 °C.
IR (KBr): 3357, 2962, 2934, 1375 cm–1.
1H NMR (CDCl3): δ = 3.77 (s, 6 H), 3.97 (s, 3 H), 6.70 (s, 2 H),
1H NMR (DMSO-d6): δ = 1.41 (s, 9 H), 3.87 (s, 3 H), 6.87–6.95 (m,
2 H), 7.12–7.35 (m, 3 H), 7.38–7.52 (m, 6 H), 7.75 (d, J = 7.5 Hz, 1
H), 8.19 (s, 1 H).
13C NMR (DMSO-d6): δ = 31.0, 34.0, 54.8, 110.2, 113.6, 119.2,
119.7, 121.8, 124.9, 128.0, 128.5, 129.0, 129.1, 129.7, 131.6, 133.5,
135.3, 148.3, 158.7.
7.15–7.52 (m, 8 H), 7.20–7.87 (m, 1 H), 7.43 (s, 1 H).
13C NMR (CDCl3): δ = 56.0, 61.0, 107.1, 111.0, 119.6, 120.5,
122.7, 127.8, 128.3, 128.6, 130.6, 132.6, 134.1, 135.8, 153.2.
Anal. Calcd for C25H25NO: C, 84.47; H, 7.09; N, 3.94. Found: C,
84.41; H, 7.07; N, 3.93.
Anal. Calcd for C23H21NO3: C, 76.86; H, 5.89; N, 3.90. Found: C,
76.81; H, 5.87; N, 3.89.
3zc
3x
Mp 180–181 °C.
Mp 131–132 °C.
IR (KBr): 3155, 1608, 1453 cm–1.
IR (KBr): 3329, 1641, 1598 cm–1.
1H NMR (DMSO-d6): δ = 3.29 (s, 3 H), 7.05–7.30 (m, 2 H), 7.11 (d,
J = 8.8 Hz, 2 H), 7.38–7.52 (m, 1 H), 7.49 (d, J = 3.4 Hz, 1 H), 7.59
(d, J = 8.8 Hz, 2 H), 7.84 (d, J = 3.4 Hz, 1 H), 8.23 (d, J = 7.8 Hz, 1
H), 11.81 (s, 1 H).
13C NMR (DMSO-d6): δ = 55.3, 107.0, 111.4, 114.2, 117.5, 120.4,
120.6, 122.4, 123.8, 126.5, 131.1, 135.6, 138.6, 142.1, 160.0, 162.3.
1H NMR (DMSO-d6): δ = 7.04–7.27 (m, 2 H), 7.30–7.83 (m, 16 H),
11.76 (s, 1 H).
13C NMR (DMSO-d6): δ = 111.7, 112.1, 118.5, 120.2, 122.3, 127.5,
128.0, 128.6, 128.6, 128.7, 129.5, 129.6, 130.3, 132.1, 132.4, 134.1,
135.4, 136.3, 137.4, 140.4, 195.2.
Anal. Calcd for C27H19NO: C, 86.84; H, 5.13; N, 3.75. Found: C,
86.78; H, 5.12; N, 3.74.
Anal. Calcd for C18H14N2OS: C, 70.56; H, 4.61; N, 9.14. Found: C,
70.51; H, 4.59; N, 9.12.
3y
3zd
Mp 271–272 °C.
Mp 202–203 °C.
IR (KBr): 3330, 2957, 1360 cm–1.
1H NMR (DMSO-d6): δ = 1.34 (s, 9 H), 2.59 (s, 3 H), 7.00–7.53 (m,
9 H), 7.63 (d, J = 8.5 Hz, 2 H), 7.94 (d, J = 8.5 Hz, 2 H), 11.72 (s, 1
IR (KBr): 3169, 1600, 1504 cm–1.
1H NMR (DMSO-d6): δ = 7.08–7.32 (m, 3 H), 7.35–7.63 (m, 7 H),
7.73 (t, J = 7.5 Hz, 1 H), 7.87 (d, J = 8.1 Hz, 1 H), 8.06 (dd, J1 = 8.7,
J2 = 8.4 Hz, 2 H), 8.25 (d, J = 7.8 Hz, 1 H), 11.80 (s, 1 H).
H).
Synthesis 2003, No. 5, 728–734 ISSN 0039-7881 © Thieme Stuttgart · New York

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S. Cacchi et al.
PAPER
13C NMR (DMSO-d6): δ = 26.7, 31.2, 34.3, 111.6, 114.9, 119.1,
119.9, 122.6, 125.5, 127.9, 128.1, 128.4, 129.4, 131.9, 132.5, 135.2,
136.5, 137.1, 148.7, 197.3.
3zh
Mp 86–87 °C.
IR (KBr): 3147, 2950, 2849, 1377 cm–1.
Anal. Calcd for C26H25NO: C, 84.98; H, 6.86; N, 3.81. Found: C,
84.91; H, 6.85; N, 3.80.
1H NMR (CDCl3): δ = 0.88–0.93 (m, 3 H), 1.28–1.41 (m, 4 H),
1.64–1.77 (m, 2 H), 3.12 (t, J = 7.6 Hz, 2 H), 7.20–7.37 (m, 4 H),
7.95 (d, J = 3.4 Hz, 1 H), 8.23 (d, J = 7.8 Hz, 1 H), 8.86 (s, 1 H).
13C NMR (CDCl3): δ = 14.0, 22.4, 27.5, 28.8, 31.6, 107.6, 110.8,
116.0, 119.9, 121.1, 122.2, 126.5, 135.0, 141.0, 142.1, 163.4.
3ze
Mp 207–208 °C.
IR (KBr): 3089, 1678 cm–1.
Anal. Calcd for C16H18N2S: C, 71.07; H, 6.71; N, 10.36. Found: C,
70.99; H, 6.70, N, 10.33.
1H NMR (DMSO-d6): δ = 2.66 (s, 3 H), 7.15–7.35 (m, 2 H), 7.52 (d,
J = 7.3 Hz, 1 H), 7.63 (d, J = 3.3 Hz, 1 H), 7.82 (d, J = 8.3 Hz, 2 H),
7.89 (d, J = 3.3 Hz, 1 H), 8.05–8.20 (m, 3 H), 12.07 (s, 1 H).
13C NMR (DMSO-d6): δ = 26.8, 107.9, 111.8, 118.5, 120.3, 120.9,
123.1, 126.7, 128.4, 129.7, 136.0, 136.2, 136.6, 136.8, 142.5, 161.5,
197.5.
2-Phenylindole-3-carboxaldehyde
Mp 248–250 °C (Lit.8 249–253 °C)
Acknowledgment
Anal. Calcd for C19H14N2OS: C, 71.67; H, 4.43; N, 8.80. Found: C,
71.61; H, 4.42; N, 8.77.
Work carried out in the framework of the National Project ‘Stereo-
selezione in Sintesi Organica. Metodologie ed Applicazioni’ sup-
ported by the Ministero dell’Università e della Ricerca Scientifica e
Tecnologica. Financial support of this research by the University
‘La Sapienza’ is also gratefully acknowledged
3zf
Mp 240–241 °C.
IR (KBr): 3351, 1509, 1597 cm–1.
1H NMR (DMSO-d6): δ = 11.1 (s, 1 H), 8.34–8.30 (m, 2 H), 7.77 (d,
J = 3.1 Hz, 1 H), 7.64–7.60 (m, 2 H), 7.59–7.55 (m, 2 H), 7.34–7.30
(m, 2 H), 7.22–7.17 (m, 1 H).
13C NMR (DMSO-d6): δ = 163.9, 148.2, 147.6, 146.1, 142.2, 135.2,
126.5, 124.3, 121.4, 121.3, 121.0, 120.4, 110.4, 102.5.
References
(1) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem.
2002, 2671.
(2) (a) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F.
Tetrahedron 1994, 50, 437. (b) Saulnier, M. G.; Frennesson,
D. B.; Deshpande, M. S.; Vyas, D. M. Tetrahedron Lett.
1995, 36, 7841. (c) Carangio, A.; McGuigan, C.; Andrei, G.;
Snoeck, R.; De Clercq, E.; Balzarini, J. Antiviral Chem.
Chemother 2001, 12, 187. (d) Flynn, B. L.; Hamel, E.; Jung,
M. K. J. Med. Chem. 2002, 45, 2670.
(3) Collini, M. D.; Ellingboe, J. W. Tetrahedron Lett. 1997, 38,
7963.
(4) Cacchi, S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63,
1001.
Anal. Calcd for C17H11N3O2S: C, 63.54; H, 3.45; N, 13.08. Found:
C, 63.49; H, 3.43; N, 13.01.
3zg
Mp 124–125 °C.
IR (KBr): 3157, 2948, 2854, 2237, 1460, 1320 cm–1.
1H NMR (CDCl3): δ = 0.82–0.96 (m, 3 H), 1.24–1.47 (m, 4 H),
1.63–1.79 (m, 2 H), 2.84 (t, J = 8.3 Hz, 2 H), 7.09–7.33 (m, 2 H),
7.33–7.53 (m, 1 H), 7.53–7.72 (m, 3 H), 7.72–7.80 (m, 2 H), 8.24
(s, 1 H). 13C NMR (CDCl3): δ = 14.0, 22.4, 26.3, 29.5, 31.5, 110.8,
112.3, 112.6, 118.2, 119.3, 120.4, 122.0, 127.3, 129.4, 132.8, 134.0,
135.2, 136.0, 137.1.
(5) Kranenburg, M.; van der Burgt, Y. E. M.; Kramer, P. C. J.;
van Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J.
Organometallics 1995, 14, 3081.
(6) Dondoni, A.; Marra, A.; Perrone, D. J. Org. Chem. 1993, 58,
275.
(7) Stang, J. P.; Hanak, M.; Subramanian, L. R. Synthesis 1982,
85.
Anal. Calcd for C20H20N2: C, 83.30; H, 6.99; N, 9.71. Found: C,
83.25, H, 6.98; N, 9.69.
(8) Aldrich Catalog.
Synthesis 2003, No. 5, 728–734 ISSN 0039-7881 © Thieme Stuttgart · New York