Three-component indole synthesis using ortho-dihaloarenes

Article abstract of DOI:10.1016/j.tet.2005.09.095

A three-component synthesis of substituted indoles is accomplished starting from ortho-dihaloarenes through the use of a multicatalytic system consisting of an N-heterocyclic carbene palladium complex and CuI. The corresponding indole derivatives are obtained as single regioisomers in high yields of isolated product.

Full text of DOI:10.1016/j.tet.2005.09.095

Tetrahedron 61 (2005) 11311–11316
Three-component indole synthesis using ortho-dihaloarenes
Ludwig T. Kaspar and Lutz Ackermann
*
Department Chemie und Biochemie, Ludwig-Maximilians-Universit a¨ t M u¨ nchen, D-81377 M u¨ nchen, Germany
Received 1 July 2005; accepted 21 September 2005
Available online 20 October 2005
Abstract—A three-component synthesis of substituted indoles is accomplished starting from ortho-dihaloarenes through the use of a
multicatalytic system consisting of an N-heterocyclic carbene palladium complex and CuI. The corresponding indole derivatives are obtained
as single regioisomers in high yields of isolated product.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
An important goal of modern synthetic chemistry is the
development of highly efficient and selective processes that
minimize the formation of waste. The design of multi-
On the outset of our studies, we explored a one-pot sequence
consisting of a transition metal-catalyzed amination
reaction of ortho-alkynylhaloarenes 3 and an intramolecular
hydroamination (Scheme 2). While aryl bromides were
converted using a copper catalyst, aryl chlorides required
the use of a palladium complex. Both protocols allowed for
quantitative conversion of starting material 3 within 2 h in
good to excellent yields of isolated product.
1
1
2
component reactions (MCRs), in which three or more
starting materials react in a highly selective sequence of
chemical transformations, constitutes a powerful tool to
2
achieving this goal. Catalytic additions represent ideal
reactions within the sequence, preventing the formation of
1
,3
undesired byproducts.
amines onto unsaturated carbon–carbon multiple bonds
Addition reactions of simple
1
1
In contrast to the previously described method, the
protocol was not only applicable to sterically hindered
amines, but also to simple, less sterically demanding alkyl-
substituted amines. Furthermore, it was not limited to
simple alkyl-substituted alkynes, but could also be used for
the conversion of aryl-substituted derivatives with excellent
4
attracted considerable attention recently. Intramolecular
hydroamination reactions were employed for efficient
syntheses of the indole backbone employing ortho-
5
–10
alkynylaniline derivatives 5.
On the contrary, much
less attention was paid to the use of ortho-alkynylhaloarenes
1
1,12
3
,
and a direct indole synthesis employing easily
accessible ortho-dihaloarenes 1 was not reported. Transition
metal-catalyzed C–N bond forming reactions using aryl
halides proved to be a versatile method for the synthesis of a
1
3,14
variety of amines.
N-heterocyclic carbenes showed high catalytic activity
Inter alia, complexes featuring
1
5
1
6
in the coupling of aryl chlorides. In addition, such
complexes were used as catalysts for Sonogashira coupling
reactions between aryl bromides and phenylacetylene.
Consequently, we wondered if a multicatalytic regiose-
lective three-component indole synthesis could be devised
using easily available ortho-dihaloarenes 1 (Scheme 1).
1
7
1
8
Scheme 1. Indole synthesis using ortho-dihaloarenes.
Herein, we wish to report a full account on an unprece-
dented three-component indole synthesis starting from
ortho-dihaloarenes 1.
1
9
Keywords: Indoles; Multi-component reaction; Multi-catalytic reaction.
Corresponding author. Tel.: C49 89 2180 77675; fax: C49 89 2180
7425; e-mail: lutz.ackermann@cup.uni-muenchen.de
*
7
Scheme 2. Indole synthesis using ortho-alkynylhaloarenes 3 and amines 4.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.095

11312
L. T. Kaspar, L. Ackermann / Tetrahedron 61 (2005) 11311–11316
yields. Accordingly, we focused on the use of aryl-
substituted alkynes throughout our studies on the develop-
ment of a multicatalytic three-component indole synthesis.
respectively). The conversion of silyl-substituted alkyne 2b
2
0
in the Sonogashira coupling was also viable, but less
efficient. This resulted in a longer reaction time and a
significantly reduced yield of indole 6a (entry 7). For the
amination–hydroamination sequence KOt-Bu was used as
2.1. Development and optimization of the three-com-
ponent reaction
2
1
base. The milder base Cs CO could also be used, thereby
2
3
expanding the functional group tolerance (entry 8).
However, the cyclization reaction of the generated ortho-
alkynylanilines 3 was found incomplete with Cs CO when
The catalytic efficiency of palladium complexes derived
from in situ generated N-heterocyclic carbenes (NHC) was
evaluated in the three-component reaction, employing
chloroiodobenzene 1a, phenylacetylene (2a) and para-
toluidine (4a) (Table 1). Mesityl-substituted carbene ligand
precursors 7a and 7b failed to give any desired product due
to a significantly reduced activity in the Sonogashira
coupling of alkyne 2a (entries 1 and 2). Contrarily, sterically
congested preligands 7c (entry 3) and 7d (entry 4) gave rise
to the corresponding indole 6a. The catalytic activity of the
complex derived from imidazolium salt 7d was generally
superior to the one observed for the corresponding
imidazolinium salt 7c (entries 3 and 5 vs entries 4 and 6,
2
3
using alkyl-substituted amines (vide infra). Therefore, we
employed throughout the subsequent studies KOt-Bu.
2
.2. Scope of the three-component indole synthesis
With an optimized catalyst in hand, we studied the scope
of the three-component indole synthesis employing
Table 2. Three-component indole synthesis starting from chloroiodoarene
1
a
Table 1. Influence of the carbene precursor on the one-pot indole synthesis
Entry
1
R
Product
Isolated
yield (%)
a
4-MeC
6
H
4
6a
65
2
3
4
5
2,4,6-Me
3
C
6
H
2
6b
6c
6d
6e
58
52
66
67
1
2
Entry
1
Ligand 7
R
R
Isolated
a
yield
Ph
H 2a
H 2a
H 2a
H 4a
H 4a
H 4a
—
6 4
3-MeC H
7
7
a
2
3
—
2 6 3
3,5-Me C H
b
22% 6a
6
7
4-FC
6
H
4
6f
54
61
7c
4
H 2a
H 4a
65% 6a
2-FC
6
H
4
6g
b
7
d
8
9
n-Oct
6h
6i
58
5
6
7
8
7c
7d
7d
7d
H 2a
H 2a
TMS 2b
H 2a
Me 4b
Me 4b
H 4a
18% 6b
58% 6b
b
50
b,c
PhCH2
42% 6a
68% 6a
b
H 4a
a
Isolated yield of analytically pure product.
Using Cs CO instead of KOt-Bu for the amination.
Sonogashira coupling: 14 h, 105 8C.
b
c
a
2
3
Isolated yield of analytically pure product.
KOt-Bu (2.5 equiv).
b

L. T. Kaspar, L. Ackermann / Tetrahedron 61 (2005) 11311–11316
11313
Table 3. Three-component synthesis of substituted indole derivatives 6
transformation and leads to the indole derivatives in good
yields of isolated product.
4. Experimental
4.1. General
Entry
1
R
Product
Isolated
yield (%)
a
All three-component reactions were carried out on a 1 mmol
scale under N using pre-dried glassware. Chemicals were
4-MeC
6
H
4
6j
63
2
obtained from commercial sources, and were used without
further purification. Toluene was freshly distilled from
sodium under nitrogen. Yields refer to isolated compounds,
b
2
3
2,4,6-Me
3
C
6
H
2
6k
6l
68
1
estimated to be O95% pure as determined by H NMR and
GC. Flash chromatography: Merck silica gel 60 (230–400
1
13
mesh). NMR: H and C were recorded on a Bruker AC
4-MeOC
6
H
H
4
65
1
00 or AMX 600, F was recorded on a Varian VXR 400 in
9
3
the solvent indicated; chemical shifts (d) are given in ppm,
coupling constants (J) in Hz.
4.1.1. Representative procedure for three-component
indole synthesis: 2-phenyl-1-p-tolyl-1H-indole (6a).
4
5
2-MeOC
6
4
6m
6n
76
79
2
2
A
solution of Cs CO (489 mg, 1.50 mmol), HIPrCl (7d)
2
3
(43 mg, 0.10 mmol) and Pd(OAc) (22 mg, 0.10 mmol) in
2
toluene (3 mL) was stirred at ambient temperature for
0 min. Chloroiodobenzene 1a (239 mg, 1.00 mmol), CuI
19 mg, 0.10 mmol) and phenylacetylene (2a) (153 mg,
6
4-FC H
4
3
(
1
1
.50 mmol) were added. The reaction mixture was stirred at
05 8C for 2 h and was thereafter allowed to cool to room
temperature. KOt-Bu (168 mg, 1.50 mmol) and p-toluidine
(4a) (129 mg, 1.20 mmol) were added and the reaction
was heated at 105 8C for 21 h. Et O (60 mL), aq NH (1 N,
6
6
2-FC H
4
6o
74
2
3
1
suspension. The separated aq phase was washed with Et O
5 mL) and brine (50 mL) were added to the cold
2
(2!60 mL). The combined organic phases were dried over
MgSO and concentrated in vacuo. Purification by column
chromatography (silica gel, n-pentane/Et O 500:1) yielded
2
a
Isolated yield of analytically pure product.
KOt-Bu (2.5 equiv).
4
b
2
6
2
2
1
1
3
7
-phenyl-1-p-tolyl-1H-indole (6a) as a yellow oil (185 mg,
chloroiodobenzene 1a, phenylacetylene (2a) and a variety
of different amines 4 (Table 2).
1
5%). H NMR (300 MHz, CDCl ): d 7.59 (dd, JZ6.2,
3
.9 Hz, 1H), 7.22–7.00 (m, 12H), 6.70 (d, JZ0.7 Hz, 1H),
1
3
.31 (s, 3H). C NMR (75 MHz, CDCl ): d 140.8, 139.1,
3
Electron-rich (entries 1–5) and electron-poor (entries 6 and
7
37.0, 135.9, 132.6, 129.9, 128.9, 128.2, 128.1, 127.8,
27.2, 122.2, 120.5, 120.4, 110.7, 103.4, 21.1. IR (KBr):
029, 1511, 1456, 1440, 1351, 1320, 1209, 1109, 793, 761,
) aniline derivatives were converted with a comparable
efficacy. Importantly, less sterically hindered alkyl-sub-
stituted amines could be employed as well (entry 8). This
allows for the installation of a benzyl-group on nitrogen of
the indole moiety (entry 9). The conversion of chloro-
iodoarene 1b, bearing an electron-withdrawing substituent,
proceeded also well (Table 3). Accordingly, the correspond-
ing indoles 6 were obtained with good yields of isolated
product. It is worthy to note that the indole derivatives were
generated as single regioisomers.
K1
47, 697 cm . MS (EI) m/z (relative intensity) 283 (100)
C
[M ], 282 (12), 267 (10), 165 (6). HR-MS (EI) m/z calcd for
C H N 283.1361, found 283.1375.
2
1 17
4
(
5
.1.2. 1-(2,4,6-Trimethylphenyl)-2-phenyl-1H-indole
6b). Following the general procedure, indole 6b (180 mg,
8%) was obtained as a yellow oil after purification by
column chromatography on silica gel (n-pentane/Et O
2
1
3
7
00:1). H NMR (300 MHz, CDCl ): d 7.59 (m, 1H),
3
.20–7.00 (m, 7H), 6.87 (s, 2H), 6.76 (s, 1H), 6.71 (m, 1H),
1
3
3. Conclusion
2.23 (s, 3H), 1.72 (s, 6H). C NMR (75 MHz, CDCl ): d
3
140.5, 138.0, 138.0, 137.9, 136.9, 133.9, 132.8, 129.2,
In summary, we reported the development of an efficient
three-component indole synthesis, which makes use of
easily accessible ortho-dihaloarenes, terminal alkynes and
differently substituted amines. A single catalytic system
consisting of an in situ generated palladium carbene
complex and CuI gives rise to a highly regioselective
128.3, 127.5, 127.2, 122.1, 120.4, 120.2, 110.5, 102.0, 21.1,
17.7. IR (KBr): 3057, 3027, 2919, 1603, 1472, 1375, 1210,
1029, 855, 791, 738, 695 cm . MS (EI) m/z (relative
K1
C
intensity) 311 (100) [M ], 296 (19), 234 (13), 140 (12).
HR-MS (EI) m/z calcd for C H N 311.1674, found
311.1698.
2
3 21

11314
L. T. Kaspar, L. Ackermann / Tetrahedron 61 (2005) 11311–11316
2
.1.3. 1,2-Diphenyl-1H-indole (6c). Following the
3
1
4
general procedure, indole 6c (139 mg, 52%) was obtained
H NMR (300 MHz, CDCl ): d 7.75–7.72 (m, 1H),
3
1
3
7.44–7.15 (m, 12H), 6.87 (d, JZ0.6 Hz, 1H). C NMR
as a yellow solid after purification by column chromato-
graphy on silica gel (n-pentane/Et O 500:1). H NMR
(75 MHz, CDCl ): d 158.1 (d, JZ251.7 Hz), 141.3, 139.0,
3
1
132.3, 130.5, 129.5 (d, JZ7.6 Hz), 128.5, 128.4, 128.2,
127.5, 126.5 (d, JZ12.6 Hz), 124.6 (d, JZ4.1 Hz), 122.5,
2
(
300 MHz, CDCl ): d 7.73 (ddd, JZ6.0, 3.1, 0.7 Hz, 1H),
3
1
9
7
.48–7.25 (m, 11H), 7.23 (d, JZ3.1 Hz, 1H), 7.21 (d, JZ
.1 Hz, 1H), 6.85 (d, JZ0.8 Hz, 1H). C NMR (75 MHz,
120.9, 120.6, 116.8 (d, JZ19.7 Hz), 110.5, 103.8. F NMR
1
3
3
CDCl ): d 140.7, 139.0, 138.5, 132.5, 129.2, 128.9, 128.3,
(375 MHz, CDCl ): K118.9 (m). IR (KBr): 3060, 1604,
1504, 1455, 1380, 1326, 1268, 1229, 816, 797, 759,
696 cm . MS (EI) m/z (relative intensity) 287 (100)
3
3
K1
1
1
7
2
28.1, 128.0, 127.3, 127.2, 122.3, 120.7, 120.5, 110.6,
03.7. IR (KBr): 3054, 1596, 1499, 1456, 1381, 1352, 1324,
47, 762, 736, 698 cm . MS (EI) m/z (relative intensity)
C
[M ], 267 (11), 165 (9). HR-MS (EI) m/z calcd for
K1
C H NF 287.1110, found 287.1076.
20 14
C
69 (100) [M ], 165 (14), 134 (7). HR-MS (EI) m/z calcd
for C H N 269.1204, found 269.1166.
0 15
4.1.8. 1-(n-Octyl)-2-phenyl-1H-indole (6h). Following the
general procedure, indole 6h (178 mg, 58%) was obtained
as a yellow oil after purification by column chromatography
2
4.1.4. 2-Phenyl-1-m-tolyl-1H-indole (6d). Following the
general procedure, indole 6d (188 mg, 66%) was obtained
1
on silica gel (n-pentane/Et O 400:1). H NMR (300 MHz,
2
as a yellow oil after purification by column chromatography
on silica gel (n-pentane/Et O 500:1). H NMR (300 MHz,
CDCl ): d 7.75–7.71 (m, 1H), 7.36–7.15 (m, 11H),
3
CDCl ): d 7.54 (d, JZ7.9 Hz, 1H), 7.43–7.20 (m, 6H), 7.14
(dt, JZ7.6, 1.3 Hz, 1H), 7.04 (dt, JZ7.4, 1.0 Hz, 1H), 6.43
(d, JZ0.7 Hz, 1H), 4.05 (t, JZ7.6 Hz, 2H), 1.60 (t, JZ
3
1
2
7
.09–7.05 (m, 1H), 6.85 (d, JZ0.8 Hz, 1H), 2.40 (s, 3H).
7.4 Hz, 2H), 1.20–1.05 (m, 10H), 0.77 (t, JZ7.0 Hz, 3H).
1
3
13
C NMR (75 MHz, CDCl ): d 140.7, 139.2, 139.1, 138.4,
C NMR (75 MHz, CDCl ): d 141.3, 137.3, 133.3, 129.4,
3
3
1
1
3
7
32.6, 129.0, 128.8, 128.5, 128.2, 128.1, 128.0, 127.2,
25.2, 122.2, 120.6, 120.5, 110.7, 103.5, 21.3. IR (KBr):
057, 2920, 1603, 1590, 1490, 1457, 1442, 1351, 1322, 784,
128.4, 128.2, 127.9, 121.4, 120.5, 119.7, 110.0, 102.0, 43.9,
31.7, 29.9, 29.1, 29.0, 26.7, 22.6, 14.1. IR (KBr): 3030,
2927, 2854, 1605, 1460, 1348, 1161, 1013, 786, 748,
K1
K1
C
61, 747, 700 cm . MS (EI) m/z (relative intensity) 283
699 cm . MS (EI) m/z (relative intensity) 305 (70) [M ],
207 (18), 206 (100), 204 (12). HR-MS (EI) m/z calcd for
C H N 305.2143, found 305.2129.
C
(100) [M ], 267 (16), 165 (11), 134 (7). HR-MS (EI) m/z
calcd for C H N 283.1361, found 283.1337.
2
1
17
22 27
2
4
25
4.1.9. 1-Benzyl-2-phenyl-1H-indole (6i). Following the
4
Following the general procedure, indole 6e (197 mg, 67%)
.1.5. 1-(3,5-Dimethylphenyl)-2-phenyl-1H-indole (6e).
general procedure, indole 6i (140 mg, 50%) was obtained as
yellow solid after purification by column chromatography
was obtained as a yellow solid after purification by column
chromatography on silica gel (n-pentane/Et O 500:1). H
1
1
on silica gel (n-pentane/Et O 400:1). H NMR (300 MHz,
2
2
NMR (300 MHz, CDCl ): d 7.75–7.71 (m, 1H), 7.38–7.20
3
CDCl ): d 7.58 (dd, JZ5.9, 0.8 Hz, 1H), 7.36–7.00 (m, 11H),
6.92 (dd, JZ8.2, 1.8 Hz, 2H), 6.56 (s, 1H), 5.26 (s, 2H). C
3
1
3
(
1
m, 8H), 7.03 (m, 1H), 6.93 (m, 2H), 6.85 (d, JZ0.8 Hz,
1
H), 2.34 (s, 3H), 2.34 (s, 3H). C NMR (75 MHz, CDCl3):
3
NMR (75 MHz, CDCl ): d 141.8, 138.2, 138.0, 132.7,
129.2, 128.7, 128.5, 128.3, 128.0, 127.1, 125.9, 121.9,
120.5, 120.1, 110.5, 102.3, 47.7. IR (KBr): 3026, 1494,
3
d 140.7, 139.1, 138.9, 138.3, 132.7, 128.9, 128.8, 128.2,
28.1, 127.2, 125.7, 122.1, 120.5, 120.4, 110.8, 103.3, 21.2.
IR (KBr): 3044, 2918, 1610, 1594, 1487, 1459, 1354, 1328,
1
K1
1462, 1344, 1306, 1175, 1158, 1026, 772, 749, 697 cm
.
K1
C
1
310, 854, 763, 749, 702 cm . MS (EI) m/z (relative
intensity) 297 (100) [M ], 281 (10), 267 (6), 165 (6), 134
MS (EI) m/z (relative intensity) 283 (100) [M ], 193 (10),
165 (11), 91 (77). HR-MS (EI) m/z calcd for C H N
283.1361, found 283.1376.
C
2
1 17
(
5). HR-MS (EI) m/z calcd for C H N 297.1517, found
2
2 19
2
97.1500.
4
.1.10. 5-Trifluoromethyl-2-phenyl-1-p-tolyl-1H-indole
(6j). Following the general procedure, indole 6j (222 mg,
4.1.6. 1-(4-Fluorophenyl)-2-phenyl-1H-indole (6f).
Following the general procedure, indole 6f (155 mg, 54%)
63%) was obtained as a yellow solid after purification by
column chromatography on silica gel (n-pentane/Et O
was obtained as a yellow solid after purification by column
chromatography on silica gel (n-pentane/Et O 400:1). H
2
1
1
200:1). H NMR (300 MHz, CDCl ): d 8.01 (s, 1H), 7.43
2
3
NMR (300 MHz, CDCl ): d 7.73–7.72 (m, 1H), 7.33–7.21
3
(dd, JZ8.7, 1.2 Hz, 1H), 7.34 (d, JZ8.7 Hz, 1H), 7.32–7.29
(m, 5H), 7.27 (d, JZ8.2 Hz, 2H), 7.16 (d, JZ8.2 Hz, 2H),
1
3
(
m, 10H), 7.19–7.21 (m, 2H), 6.85 (d, JZ0.6 Hz, 1H).
C
1
6.89 (s, 1H), 2.44 (s, 3H). C NMR (75 MHz, CDCl ): d
3
NMR (75 MHz, CDCl ): d 161.4 (d, JZ247.4 Hz), 140.8,
3
3
1
1
39.1, 134.5 (d, JZ2.9 Hz), 132.3, 129.6 (d, JZ8.5 Hz),
28.9, 128.2, 128.2, 127.4, 122.4, 120.8, 120.6, 116.2 (d,
142.6, 140.3, 137.7, 135.2, 131.9, 130.1, 129.0, 128.2,
127.7, 127.7, 127.5, 125.3 (q, JZ271.7 Hz), 122.9 (q, JZ
31.7 Hz), 118.8 (q, JZ2.9 Hz), 118.1 (q, JZ3.5 Hz), 110.9,
1
9
JZ22.6 Hz), 110.4, 103.7. F NMR (375 MHz, CDCl3):
K113.0 (tt, JZ8.4, 5.0 Hz). IR (KBr): 3070, 1600, 1510,
1
9
103.8, 21.2. F NMR (375 MHz, CDCl ): K59.3 (s). IR
(KBr): 3032, 1516, 1343, 1326, 1271, 1168, 1162, 1131,
1114, 1056, 898, 812, 765, 750, 700 cm . MS (EI) m/z
3
K1
459, 1221, 1210, 850, 767, 749, 699 cm . MS (EI) m/z
1
C
relative intensity) 287 (100) [M ], 183 (5), 165 (5).
K1
(
HR-MS (EI) m/z calcd for C H NF 287.1110, found
C
(relative intensity) 351 (100) [M ], 335 (7). HR-MS (EI)
2
0 14
2
87.1102.
m/z calcd for C H NF 351.1235, found 351.1257.
2
2
16
3
4.1.7. 1-(2-Fluorophenyl)-2-phenyl-1H-indole (6g).
Following the general procedure, indole 6g (174 mg, 61%)
4.1.11. 5-Trifluoromethyl-1-(2,4,6-trimethylphenyl)-2-
phenyl-1H-indole (6k). Following the general procedure,
indole 6k (256 mg, 68%) was obtained as a yellow oil
after purification by column chromatography on silica gel
was obtained as a yellow oil after purification by column
chromatography on silica gel (n-pentane/Et O 300:1).
2

L. T. Kaspar, L. Ackermann / Tetrahedron 61 (2005) 11311–11316
11315
1
n-pentane/Et O 200:1). H NMR (300 MHz, CDCl ): d
(
1227, 1168, 1131, 1111, 1056, 862, 821, 808, 764, 746,
2
3
K1
C
7
7
6
1
.99 (dd, JZ0.8, 0.8 Hz, 1H), 7.35 (dd, JZ8.6, 1.3 Hz, 1H),
.28–7.16 (m, 6H), 6.96–6.87 (m, 3H), 2.35 (s, 3H), 1.81 (s,
699 cm . MS (EI) m/z (relative intensity) 355 (100) [M ],
285 (16), 183 (8), 165 (8). HR-MS (EI) m/z calcd for
C H NF 355.0984, found 355.1004.
1
H). C NMR (75 MHz, CDCl ): d 142.4, 139.2, 138.6,
3
3
21 13
4
36.8, 133.2, 132.1, 129.4, 128.4, 127.8, 127.6, 127.5, 127.2
(
q, JZ271.4 Hz), 122.7 (q, JZ31.4 Hz), 118.8 (q, JZ
4
1
.1.15. 5-Trifluoromethyl-1-(2-fluorophenyl)-2-phenyl-
H-indole (6o). Following the general procedure, indole
1
9
3
NMR (375 MHz, CDCl ): K59.2 (s). IR (KBr): 3029, 2973,
2
1
.5 Hz), 118.2 (q, JZ4.4 Hz), 110.7, 102.7, 21.1, 17.6.
F
3
6o (264 mg, 74%) was obtained as a yellow solid after
purification by column chromatography on silica gel
921, 1706, 1611, 1489, 1451, 1366, 1340, 1322, 1268,
158, 1116, 1054, 810, 762, 752, 694 cm . MS (EI) m/z
K1
1
n-pentane/Et O 200:1). H NMR (300 MHz, CDCl ): d
(
2
3
C
(
(
relative intensity) 379 (100) [M ], 364 (22), 349 (5), 302
10), 286 (6). HR-MS (EI) m/z calcd for C H NF
7
.98 (dd, JZ0.8, 0.8 Hz, 1H), 7.44–7.36 (m, 2H), 7.30–7.15
13
2
4
20
3
(m, 9H), 6.88 (d, JZ0.8 Hz, 1H). C NMR (75 MHz,
CDCl ): d 158.0 (d, JZ252.1 Hz), 143.1, 140.2, 131.6,
3
79.1548, found 379.1537.
3
130.1 (d, JZ7.6 Hz), 128.5, 128.4, 128.1, 127.9, 127.0,
4
1
.1.12. 5-Trifluoromethyl-1-(4-methoxyphenyl)-2-phenyl-
H-indole (6l). Following the general procedure, indole 6l
125.7 (d, JZ12.6 Hz), 125.2 (q, JZ271.4 Hz), 124.8 (d, JZ
3.8 Hz), 123.3 (q, JZ31.7 Hz), 119.2 (q, JZ3.5 Hz), 118.3
1
9
(240 mg, 65%) was obtained as a yellow solid after puri-
fication by column chromatography on silica gel (n-pentane/
(q, JZ4.1 Hz), 117.0 (d, JZ20.0 Hz), 110.8, 104.1.
F
NMR (375 MHz, CDCl ): K59.4 (s), K119.0 (m). IR
3
1
Et O 300:1). H NMR (300 MHz, CDCl ): d 7.98 (dd, JZ
0
(KBr): 1507, 1343, 1326, 1232, 1166, 1133, 1113, 1055,
812, 762, 697 cm . MS (EI) m/z (relative intensity) 355
2
3
K1
.8, 0.8 Hz, 1H), 7.40 (dd, JZ8.7, 1.8 Hz, 1H), 7.30–7.27
C
(100) [M ], 336 (10), 285 (8), 165 (4). HR-MS (EI) m/z
(
m, 6H), 7.17 (dm, JZ9.0 Hz, 2H), 6.95 (dm, JZ9.0 Hz,
1
3
2
H), 6.86 (d, JZ0.7 Hz, 1H), 3.81 (s, 3H). C NMR
calcd for C H NF 355.0984, found 355.1002.
2
1
13
4
(
75 MHz, CDCl ): d 159.0, 142.7, 140.5, 131.9, 130.6,
3
1
1
4
29.1, 129.0, 128.3, 127.8, 127.4, 125.3 (q, JZ271.7 Hz),
23.3 (q, JZ31.7 Hz), 118.8 (q, JZ3.5 Hz), 118.1 (q, JZ
.4 Hz), 114.7, 110.9, 103.5, 55.5. F NMR (375 MHz,
Acknowledgements
1
9
CDCl ): K59.3 (s). IR (KBr): 3057, 2966, 1516, 1341,
3
Support by Professor Paul Knochel, the DFG (Emmy
Noether-Programm), the Fonds der Chemischen Industrie
and the Ludwig-Maximilians-Universit a¨ t is gratefully
acknowledged.
1
7
3
3
326, 1272, 1256, 1170, 1116, 1054, 1029, 813, 767, 751,
K1
C
01 cm . MS (EI) m/z (relative intensity) 367 (100) [M ],
52 (12), 322 (6). HR-MS (EI) m/z calcd for C H NOF
3
2
2
16
67.1184, found 367.1199.
4.1.13. 5-Trifluoromethyl-1-(2-methoxyphenyl)-2-phenyl-
1H-indole (6m). Following the general procedure, indole
6m (277 mg, 76%) was obtained as a yellow solid after
References and notes
purification by column chromatography on silica gel (n-
pentane/Et O 200:1). H NMR (600 MHz, CDCl ): d 7.96
1
2
3
1. Trost, B. M. Acc. Chem. Res. 2002, 35, 695–705.
2. D o¨ mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168–3210.
(
8
s, 1H), 7.40–7.36 (m, 2H), 7.28–7.22 (m, 6H), 7.11 (d, JZ
.6 Hz, 1H), 7.02 (ddd, JZ7.6, 7.6, 1.2 Hz, 1H), 6.97 (d,
1
3
JZ7.6 Hz, 1H), 6.85 (s, 1H), 3.51 (s, 3H). C NMR
150 MHz, CDCl ): d 155.4, 143.4, 140.4, 132.4, 129.9,
3. Catalytic Heterofunctionalization; Togni, A., Gr u¨ tzmacher,
H., Eds.; Wiley-VCH: Weinheim, 2001.
4. Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int.
Ed. 2004, 43, 3368–3398.
(
3
1
2
2
29.8, 128.3, 128.1, 127.7, 127.7, 126.7, 125.4 (q, JZ
71.1 Hz), 122.7 (q, JZ31.7 Hz), 121.0, 118.6 (q, JZ
1
9
.9 Hz), 118.1 (q, JZ3.5 Hz), 112.4, 111.0, 103.0, 55.4.
F
5. Utimoto, K.; Miwa, H.; Nozaki, H. Tetrahedron Lett. 1981, 22,
4277–4278.
NMR (375 MHz, CDCl ): K59.2 (s). IR (KBr): 3067, 1506,
3
1
6
3
3
339, 1323, 1282, 1269, 1167, 1112, 1053, 1025, 766, 754,
6. Irtani, K.; Matsubara, S.; Utimoto, K. Tetrahedron Lett. 1988,
29, 1799–1802.
K1
C
98 cm . MS (EI) m/z (relative intensity) 367 (100) [M ],
36 (9), 290 (5). HR-MS (EI) m/z calcd for C H NOF
67.1184, found 367.1135.
2
2
16
3
7. Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1989,
30, 2581–2584.
8
. Cacchi, S.; Carnicelli, V.; Marinelli, F. J. Organomet. Chem.
1994, 475, 289–296.
4
1
6
.1.14. 5-Trifluoromethyl-1-(4-fluorophenyl)-2-phenyl-
H-indole (6n). Following the general procedure, indole
n (281 mg, 79%) was obtained as a yellow solid after
9. Tsuji, J. Palladium Reagents and Catalysts, 2nd ed.; Wiley:
Chichester, 2004.
purification by column chromatography on silica gel
(
10. Leni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285–2309.
11. For a two-step, one-pot approach, see: Siebenreicher, H.;
Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. 2003, 42,
3042–3044.
1
n-pentane/Et O 200:1). H NMR (600 MHz, CDCl ): d
2 3
7
8
.97 (s, 1H), 7.41 (dd, JZ8.7, 1.1 Hz, 1H), 7.28–7.20 (m,
H), 7.14–7.11 (m, 2H), 6.85 (s, 1H). C NMR (150 MHz,
13
CDCl ): d 161.8 (d, JZ248.3 Hz), 142.6, 140.3, 133.9,
12. Ackermann, L. Org. Lett. 2005, 7, 439–442.
13. Jiang, L.; Buchwald, S. L. In Metal-catalyzed Cross-coupling
Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004; pp 699–760.
3
1
1
2
1
31.6, 129.6 (d, JZ8.2 Hz), 129.0, 128.4, 128.0, 127.6,
25.2 (q, JZ271.7 Hz), 123.2 (q, JZ31.7 Hz), 119.1 (q, JZ
.9 Hz), 118.3 (q, JZ3.5 Hz), 116.5 (d, JZ21.9 Hz), 110.7,
1
9
04.1. F NMR (375 MHz, CDCl ): K59.4 (s), K112.0 (tt,
14. Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.;
Wiley-VCH: Weinheim, 2000; pp 195–262.
3
JZ8.4, 4.6 Hz). IR (KBr): 3081, 1513, 1341, 1325, 1268,

11316
L. T. Kaspar, L. Ackermann / Tetrahedron 61 (2005) 11311–11316
1
5. Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290–1309.
6. Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
176–4211.
21. Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38,
6359–6362.
1
4
22. Old, D. W.; Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2,
1403–1406.
1
7. Herrmann, W. A.; Reisinger, C.-P.; Spiegler, M.
J. Organomet. Chem. 1998, 557, 93–96.
8. Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. Rev. 2004,
23. Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S. P. J. Org.
Chem. 2001, 66, 7729–7737.
1
3
3, 302–312.
24. Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727–7729.
25. Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897–2900.
1
2
9. For a single example, see Ref. 12.
0. Yang, C.; Nolan, S. P. Organometallics 2002, 21, 1020–1022.