Nickel-catalyzed, base-mediated amination/hydroamination reaction sequence for a modular synthesis of indoles

Article abstract of DOI:10.1016/j.jorganchem.2010.08.047

A catalytic system consisting of [Ni(cod)₂] and ligand dppf enabled an efficient synthesis of differently substituted indoles through a modular reaction sequence, which consists of intermolecular aminations and intramolecular hydroaminations with ortho-alkynylhaloarenes.

Full text of DOI:10.1016/j.jorganchem.2010.08.047

Journal of Organometallic Chemistry 696 (2011) 195e201
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Nickel-catalyzed, base-mediated amination/hydroamination reaction sequence
for a modular synthesis of indoles
*
Lutz Ackermann , Weifeng Song, René Sandmann
Institut für Organische und Biomolekulare Chemie, Georg-August-Universitaet, Tammannstrasse 2, 37077 Goettingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalytic system consisting of [Ni(cod)2] and ligand dppf enabled an efficient synthesis of differently
substituted indoles through a modular reaction sequence, which consists of intermolecular aminations
and intramolecular hydroaminations with ortho-alkynylhaloarenes.
Received 31 July 2010
Accepted 26 August 2010
Available online 16 October 2010
Ó 2010 Elsevier B.V. All rights reserved.
Keywords:
Amination
Base
Hydroamination
Indole
Nickel
1. Introduction
2. Results and discussion
The addition of nitrogen nucleophiles onto non-activated,
unsaturated carbonecarbon multiple bonds represents one of the
most attractive approaches to substituted amines and imines,
largely because these hydroamination reactions [1] occur with
ideal atom-economy.[2] Particularly, intramolecular hydro-
aminations set the stage for the preparation of various N-hetero-
cycles.[3,4] Since indoles are omnipresent in biologically active
compounds and natural products, a continued strong demand
exists for broadly applicable syntheses of this structural
motif.[5e11] Specifically, significant progress was accomplished
with intramolecular addition reactions of ortho-alkynylani-
lines.[3,12] Contrarily, we devised transition-metal-catalysts for the
selective conversion of easily accessible ortho-alkynylhaloarenes 1
to indole derivatives 4 through a reaction cascade comprising
intermolecular aminations[13e15] of aryl halides and subsequent
intramolecular hydroamin(d)ations [16] of alkynes (Scheme 1).
Hence, palladium[17e21] and copper[17,22] complexes were found
to enable the formation of indoles bearing inter alia aryl-, alkyl- or
alkoxycarbonyl-substituents on nitrogen.[7] In continuation of our
research program on sustainable catalysis for effective heterocycle
syntheses,[23] we became interested in exploring the unprece-
dented use of inexpensive nickel catalysts[24] for a modular indole
synthesis starting from ortho-alkynylhaloarenes 1, the results of
which we wish to disclose herein.
At the outset of our studies, we probed representative ligands and
nickel compounds for the envisioned amination/hydroamination
sequential synthesis of indole 4a (Table 1). Notably, no conversion of
starting material 1a to desired product 4a occurred in the absence of
a stabilizing ligand, irrespective of the oxidation state of the nickel
precursors (entries 1, and 2). While monodentate phosphine ligands
5e8 provided only unsatisfactory catalysis (entries 3e6), improved
isolated yields were obtained with precursors to N-heterocyclic car-
benes (NHC) 9e11 (entries 7e9). However, nickel complexes derived
from bidentate ligands proved to be superior (entries 10e13), with
dppf (16) being optimal (entry 14). Generally, the use of additional
base KOt-Bu proved beneficial to ensure quantitative cyclization of
intermediate 3a to the desired indole 4a via a base-mediated or
-catalyzed (entry 15)[25] intramolecular hydroamination.
With an optimized catalytic system in hands, we probed its
scope in the amination/hydroamination reaction sequence
employing aniline derivatives (Table 2). Notably, differently
substituted aromatic amines could be employed, bearing either
electron-donating or electron-withdrawing substituents (entries
1e4). Further, the nickel catalyst was not restricted to the use of
tolane derivatives. Indeed, substrates 1 displaying alkyl-substituted
alkynes were converted with an efficacy being comparable to the
one observed when using the corresponding aryl-substituted
analogues (entries 5e7). Moreover, sterically hindered aniline
derivatives 2 provided the desired indoles in high yields (entries 8,
and 9), as did a nucleophile bearing a further Lewis-basic pyridyl
moiety (entry 10).
* Corresponding author. Fax: þ49551 39 6777.
E-mail address: Lutz.Ackermann@chemie.uni-goettingen.de (L. Ackermann).
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.08.047

196
L. Ackermann et al. / Journal of Organometallic Chemistry 696 (2011) 195e201
R2
R2
cat. [Ni]
R1
H2N R3
R1
R1
R2
+
base, solvent
H
N
X
N
R3
R3
1
2
3
4
Scheme 1. Nickel-catalyzed sequential synthesis of substituted indoles 4.
Moreover, the nickel catalyst derived from dppf (16) enabled
also the preparation of indoles 4le4o when using benzyl or even
more challenging n-alkyl amines 2 (Scheme 2).
Table 1
Effect of ligands on the nickel-catalyzed synthesis of indole 4a.a
Notably, the catalytic system was further not limited to aryl
bromides as electrophiles, but also proved amenable to an efficient
amination/hydroamination sequence with aryl iodide 1d as starting
material (Scheme 3). As was observed for the corresponding bro-
moarenes 1ae1c, the intermolecular amination as well as the
intramolecular hydroamination occurred readily with both aniline
derivatives and alkyl amines, thereby yielding the corresponding
indoles 4b and 4n, respectively.
1) [Ni] (5.0 mol%),
Ph
ligand (5.0 mol%),
NaOt-Bu, PhMe,
105 °C, 16h
NH2
+
Ph
p-Tol
2) KOt-Bu, 120 °C, 6h
N
Br
Me
1a
2a
4a
Finally, we exploited the excellent chemoselectivity of the dppf
(16) derived catalyst for the synthesis of indoles 4pe4r highlighting
6-chloro-substituents, a valuable asset for further catalyzed func-
tionalizations (Scheme 4).
Entry
[Ni]
Ligand
Yield
1
2
3
4
5
NiCl2
e
<2%
<5%
<2%
<2%
10%
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
e
PPh3
PCy3
(1-Ad)2P(O)H
5b
6b
7b
3. Conclusion
We have devised a nickel catalyst for a sequential indole
synthesis consisting of intermolecular aminations of aryl halides
and subsequent intramolecular hydroaminations. Thus, an in-situ
generated complex derived from ligand dppf allowed for efficient
transformations of ortho-alkynylhaloarenes with aryl as well as
alkyl-substituted amines, and enabled the chemoselective
synthesis of chloro-substituted indoles.
PCy2
i-Pr
i-Pr
6
7
[Ni(cod)2]
[Ni(cod)2]
8b
<5%
i-Pr
9b
12%
Me
Cl
Me
Me
Me
4. Experimental section
N
N
Me
Me
Me
4.1. General remarks
8
9
[Ni(cod)2]
10b
51%
47%
Me
N
Me
Me
Catalytic reactions were carried out under a N2 atmosphere
using pre-dried glassware. ortho-Alkynylbromoarenes
1 were
Cl
Cl
prepared as previously described [17e22]. Other starting materials
were obtained from commercial sources, and were used without
further purification. Yields refer to isolated compounds, estimated
to be > 95% pure as determined by 1H NMR and GC. Flash chro-
matography: MachereyeNagel silica gel 60 (70e230 mesh). NMR:
Spectra were recorded on Varian Mercury 300, Unity 300 or Inova
N
Me
Me
Me
Me
[Ni(cod)2]
11b
Me
N
Me
Me
Me
500 instruments in the solvent indicated; chemical shifts (
given in ppm.
d) are
N
Me
Me
Me
Me
4.1.1. Representative procedure: nickel-catalyzed synthesis of 4a
(Table 1, entry 14)
N
N
To a solution of [Ni(cod)2] (6.9 mg, 0.025 mmol, 5.0 mol%), dppf
(13.9 mg, 0.025 mmol, 5.0 mol%) and NaOt-Bu (96 mg, 0.750 mmol)
in PhMe (2.0 mL) were added 1a (129 mg, 0.500 mmol) and 2a
(80 mg, 0.750 mmol) at ambient temperature. The resulting
mixture was stirred for 16 h at 105 ꢀC. At ambient temperature,
KOt-Bu (168 mg, 1.500 mmol) was added, and the resulting mixture
was stirred for 6 h at 120 ꢀC. EtOAc (5 mL) and H2O (5 mL) were
added to the cold suspension. The separated aqueous phase was
extracted with EtOAc (3 ꢁ 10 mL), the combined organic phases
were washed with H2O (10 mL) and brine (10 mL). Drying with
Na2SO4 and purification by column chromatography on silica gel
(n-hexane/EtOAc, 500/1) yielded 4a (125 mg, 88%) as a white solid
10
[Ni(cod)2]
12
49%
11
12
13
14
15
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
BINAP
dppp
dppe
dppf
13
14
15
16
16
31%
46%
71%
88%
92%c
dppf
a
Reaction conditions: 1a (1.0 equiv.), 2a (1.5 equiv.), [Ni] (5.0 mol%), ligand
(5.0 mol%), NaOt-Bu (1.5 equiv), PhMe (2.0 mL), 105 ꢀC, 16 h; b) KOt-Bu (3.0 equiv.),
120 ꢀC, 6 h; isolated yields.
b
Ligand (10 mol%).
b) KOt-Bu (0.6 equiv.).
c

L. Ackermann et al. / Journal of Organometallic Chemistry 696 (2011) 195e201
197
Table 2
Scope of nickel-catalyzed hydroamination-based indole synthesis with aniline derivatives 2.a
1) [Ni(cod)2] (5.0 mol%),
R1
NH2
16
dppf ( ) (5.0 mol%),
NaOt-Bu, PhMe,
105 °C, 16h
+
R1
2) KOt-Bu, 120 °C, 6h
N
R2
Br
R2
1
2
4
Entry
R1
1
R2
4
Isolated Yield
Ph
N
1
Ph
1a
H
4b
86%
Ph
N
2
Ph
1a
4-MeO
4c
98%
OMe
OMe
N
3
4-MeOC6H4
1b
4-MeO
4d
89%
OMe
N
Ph
4
5
Ph
1a
1c
3-CF3
4e
72%
78%
CF3
n-Hex
N
N
n-Hex
H
4f
n-Hex
6
n-Hex
1c
4-Me
4g
81%
Me
n-Hex
N
7
n-Hex
1c
4-MeO
4h
75%
OMe
(continued on next page)

198
L. Ackermann et al. / Journal of Organometallic Chemistry 696 (2011) 195e201
Table 2 (continued )
Entry
R1
1
R2
4
Isolated Yield
Ph
N
8
Ph
1a
1-Naphthyl
4i
78%
Ph
Me
N
Me
9
Ph
1a
Mes
4j
81%
Me
Ph
N
10
Ph
1a
3-py
4k
74%
N
a
Reaction conditions: 1 (1.0 equiv.), 2 (1.5 equiv.), [Ni(cod)2] (5.0 mol%), 16 (5.0 mol%), NaOt-Bu (1.5 equiv), PhMe (2.0 mL), 105 ꢀC, 16 h; b) KOt-Bu (3.0 equiv.), 120 ꢀC, 6 h;
isolated yields.
(m.p. 97e98 ꢀC). 1H NMR (300 MHz, CDCl3):
3.3 Hz, 1H), 7.44e7.03 (m, 12H), 6.81 (s, 1H), 2.41 (s, 3H). 13C NMR
(75 MHz, CDCl3): 140.8, 139.1, 137.0, 135.9, 132.6, 129.9, 128.9,
d
7.70 (dd, J ¼ 5.7,
(35), 165 (26), 133 (27), 127 (12). HR-MS (ESI) m/z calcd for
[C20H15N þ H]þ 270.1277, found 270.1275.
d
128.2, 128.1, 127.8, 127.2, 122.2, 120.5, 120.4, 110.7, 103.4, 21.1. IR
(KBr): 3054, 3033, 2920, 1514, 1451, 1356, 1322, 1208, 1108, 1022,
741, 696 cmꢂ1. MS (EI) m/z (relative intensity) 283 (100) [Mþ], 267
(14), 165 (13), 133 (9). HR-MS (EI) m/z calcd for C21H17N 283.1361,
found 283.1359. The spectral data are in accordance with those
reported in literature[17].
4.1.3. 1-(p-Anisyl)-2-phenyl-1H-indole (4c).[17]
Following the general procedure, indole 4c (146 mg, 98%) was
obtained as a white solid (m.p. 143e144 ꢀC) after purification by
column chromatography (n-hexane/EtOAc 500:1). 1H NMR
(300 MHz, CDCl3):
d 7.74 (m, 1H), 7.42e7.12 (m, 10H), 6.97 (d,
J ¼ 8.9 Hz, 2H), 6.85 (s, 1H), 3.86 (s, 3H). 13C NMR (75 MHz, CDCl3):
d
158.5, 140.8, 139.3, 132.6, 131.3, 129.1, 128.8, 128.1, 128.1, 127.2,
4.1.2. 1,2-Diphenyl-1H-indole (4b).[17]
122.1, 120.5, 120.4, 114.4, 110.6, 103.1, 55.4. IR (KBr): 3054, 2956,
2835, 1612, 1512, 1460, 1294, 1175, 1031, 842, 754, 694 cmꢂ1. MS (EI)
m/z (relative intensity) 299 (100) [Mþ], 284 (26), 256 (10), 254 (16).
HR-MS (EI) m/z calcd for C21H17NO 299.1310, found 299.1313.
Following the general procedure, indole 4b (115 mg, 86%) was
obtained as a white solid (m.p. 83e84 ꢀC) after purification by
column chromatography (n-hexane/EtOAc 500:1). 1H NMR
(300 MHz, CDCl3):
d 7.73 (m, 1H), 7.48e7.14 (m, 13H), 6.85 (d,
J ¼ 0.8 Hz,1H). 13C NMR (75 MHz, CDCl3):
d
140.7,139.0,138.5,132.5,
4.1.4. 1,2-Di-p-anisyl-1H-indole (4d)
129.2, 129.0, 128.3, 128.1, 128.0, 127.3, 127.2, 122.3, 120.7, 120.5,
110.6, 103.7. IR (KBr): 3056, 1597, 1495, 1451, 1377, 1352, 1321, 795,
755, 697 cmꢂ1. MS (EI) m/z (relative intensity) 269 (100) [Mþ], 268
Following the general procedure, indole 4d (147 mg, 89%) was
obtained as a yellow solid (m.p. 136e137 ꢀC) after purification by
column chromatography (n-hexane/EtOAc, 100/1). 1H NMR
1) [Ni(cod)2] (5.0 mol%),
16
R1
dppf ( ) (5.0 mol%),
NaOt-Bu, PhMe,
105 °C, 16h
+
H2N R2
R1
2) KOt-Bu, 120 °C, 6h
N
Br
N
R2
1
2
4
Ph
n-Hex
Ph
Ph
N
N
N
Bn
Bn
n-Hex
n-Oct
4n
4o
4l: 85%
4m: 67%
: 74%
: 80%
Scheme 2. Nickel-catalyzed indole synthesis with alkyl amines 2.

L. Ackermann et al. / Journal of Organometallic Chemistry 696 (2011) 195e201
199
1) [Ni(cod)2] (5.0 mol%),
16
dppf ( ) (5.0 mol%),
NaOt-Bu, PhMe,
105 °C, 16h
Ph
+
H2N R
Ph
2) KOt-Bu, 120 °C, 6h
N
I
R
1d
2
R = Ph (4b):
R = n-Hex (4n):
88%
74%
Scheme 3. Nickel-catalyzed indole synthesis with aryl iodide 1d.
(300 MHz, CDCl3):
3.4 Hz, 2H), 6.80 (dt, J ¼ 9.8, 3.1 Hz, 2H), 6.73 (d, J ¼ 0.7 Hz, 1H), 3.86
(s, 3H), 3.79 (s, 3H). 13C NMR (75 MHz, CDCl3):
140.8,139.2,131.4,130.1,129.2,128.2,125.1,121.8,120.4,120.2,114.4,
113.6, 110.5, 102.2, 55.4, 55.2. IR (KBr): 3000, 2933, 2838, 1608, 1541,
1513, 1456, 1361, 1249, 1116, 1031, 834, 740, 646 cmꢂ1. MS (EI) m/z
(relative intensity) 329 (100) [Mþ], 314 (36), 298 (2), 283 (5), 271
(5), 254 (15), 242 (16), 215 (3), 190 (2). HR-MS (ESI) m/z calcd for
[C22H19NO2þH]þ 330.1489, found 330.1489.
d
7.68 (m, 1H), 7.23e7.13 (m, 7H), 6.93 (dt, J ¼ 9.8,
(3), 152 (2), 128 (6). HR-MS (EI) m/z calcd for C20H23N 277.1830,
found 277.1831.
d
¼ 158.9, 158.5,
4.1.7. 2-n-Hexyl-1-p-tolyl-1H-indole (4g).[17]
Following the general procedure, indole 4g (117 mg, 81%) was
obtained as a yellow oil after purification by column chromatog-
raphy (n-hexane/EtOAc 500:1). 1H NMR (300 MHz, CDCl3):
d 7.66
(m,1H), 7.38 (d, J ¼ 8.5 Hz, 2H), 7.29 (m, 2H), 7.20e7.10 (m, 3H), 6.48
(s, 1H), 2.70 (t, J ¼ 7.8 Hz, 2H), 2.52 (s, 3H), 1.71e1.60 (m, 2H), 1.32
(m, 6H), 0.94 (t, J ¼ 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d 142.1,
4.1.5. 2-Phenyl-1-{m-(trifluoromethyl)phenyl}-1H-indole (4e)
Following the general procedure, indole 4e (115 mg, 72%) was
obtained as a white solid (m.p. 91e92 ꢀC) after purification by
column chromatography (n-hexane/EtOAc 500:1). 1H NMR
138.4, 137.6, 135.4, 130.0, 128.1, 128.0, 120.8, 119.8, 119.5, 110.0, 99.8,
31.5, 28.9, 28.6, 27.0, 22.5, 21.2, 14.0. IR (KBr): 3054, 2954, 2926,
2858, 1608, 1514, 1459, 1394, 1211, 1017, 817, 741 cmꢂ1. MS (EI) m/z
(relative intensity) 291 (46) [Mþ], 234 (29), 221 (100), 220 (66), 205
(34), 204 (44). HR-MS (EI) m/z calcd for C21H25N 291.1987, found
291.1978.
(300 MHz, CDCl3):
d 7.71 (m, 1H), 7.67e7.47 (m, 3H), 7.39 (d,
J ¼ 7.9 Hz, 1H), 7.34e7.16 (m, 8H), 6.83 (s, 1H). 13C NMR (75 MHz,
CDCl3):
d
140.6, 139.1, 138.6, 132.0, 131.8 (2JC,F ¼ 34 Hz), 131.2, 129.8,
129.0, 128.5, 128.3, 127.6, 124.7 (3JC,F ¼ 4 Hz), 123.7 (3JC,F ¼ 4 Hz),
122.8, 121.5 (1JC,F ¼ 251 Hz), 121.2, 120.8, 110.2, 104.6. IR (KBr): 3059,
1597, 1496, 1456, 1375, 1326, 1129, 799, 752, 698 cmꢂ1. MS (EI) m/z
(relative intensity) 337 (100) [Mþ], 336 (19), 267 (14), 165 (26), 133
(23). HR-MS (ESI) m/z calcd for [C21H14NF3þH]þ 338.1151, found
338.1152.
4.1.8. 1-(p-Anisyl)-2-n-hexyl-1H-indole (4h).[22]
Following the general procedure, indole 4h (113 mg, 75%) was
obtained as a yellow oil after purification by column chromatog-
raphy (n-hexane/EtOAc 500:1). 1H NMR (300 MHz, CDCl3):
d 7.61
(m, 1H), 7.33e7.23 (m, 2H), 7.19e6.99 (m, 5H), 6.43 (s, 1H), 3.91 (s,
3H), 2.67e2.57 (t, J ¼ 7.4 Hz, 2H), 1.69e1.55 (m, 2H), 1.28 (s, 6H),
0.90 (t, J ¼ 5.9 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d 159.0, 142.3,
4.1.6. 2-n-Hexyl-1-phenyl-1H-indole (4f).[17]
138.6, 130.7, 129.4, 128.0, 120.8, 119.7, 119.5, 114.5, 109.9, 99.6, 55.5,
31.5, 28.9, 28.6, 27.0, 22.5, 14.1. IR (KBr): 3050, 2928, 2857, 1580,
1547, 1460, 1294, 1211, 1036, 831, 778, 742 cmꢂ1. MS (EI) m/z
(relative intensity) 307 (51) [Mþ], 250 (31), 237 (100), 205 (29), 192
(11), 43 (15). HR-MS (EI) m/z calcd for C21H25NO 307.1936, found
307.1936.
Following the general procedure, indole 4f (108 mg, 78%) was
obtained as a yellow oil after purification by column chromatog-
raphy (n-hexane/EtOAc 500:1). 1H NMR (300 MHz, CDCl3):
d
7.71e7.47 (m, 4H), 7.42 (t, J ¼ 4.2 Hz, 2H), 7.23e7.11 (m, 3H), 6.50
(s,1H), 2.76e2.58 (t, J ¼ 7.6 Hz, 2H),1.71e1.58 (m, 2H),1.40e1.20 (m,
6H), 0.93 (t, J ¼ 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d 142.0,138.3,
138.1, 129.4, 128.3, 128.1, 127.8, 121.0, 119.9, 119.6, 109.9, 100.1, 31.5,
28.9, 28.6, 27.1, 22.5, 14.0. IR (KBr): 3056, 2927, 2857, 1596, 1498,
1459, 1392, 1211, 1016, 778, 762, 699 cmꢂ1. MS (EI) m/z (relative
intensity) 277 (44) [Mþ], 220 (46), 207 (100), 191 (6), 178 (7), 165
4.1.9. 1-Naphthyl-2-phenyl-1H-indole (4i)
Following the general procedure, indole 4i (124 mg, 78%) was
obtained as a yellow solid (m.p. 73e74 ꢀC) after purification by
column chromatography (n-hexane/EtOAc 500:1). 1H NMR
1) [Ni(cod)2] (5.0 mol%),
16
dppf ( ) (5.0 mol%),
Ph
NaOt-Bu, PhMe,
105 °C, 16h
+
H2N
R
Ph
2) KOt-Bu, 120 °C, 6h
N
Cl
Cl
Br
N
Cl
Cl
R
1e
2
4
Ph
Ph
N
Ph
N
n-Oct
Cl
Ph
Me
4p: 72%
4q: 73%
4r: 53%
Scheme 4. Nickel-catalyzed sequential synthesis of chloro-substituted indoles 4pe4r.

200
L. Ackermann et al. / Journal of Organometallic Chemistry 696 (2011) 195e201
(300 MHz, CDCl3):
d
7.98e7.88 (m, 2H), 7.74 (m, 1H), 7.55e7.42 (m,
J ¼ 7.6 Hz, 1H), 7.62e7.43 (m, 6H), 7.32 (m, 1H), 7.26e7.19 (m, 1H),
6.62 (s, 1H), 4.29e4.15 (m, 2H), 1.86e1.70 (m, 2H), 1.30e1.22 (m,
3H), 7.42e7.30 (m, 2H), 7.26e7.04 (m, 7H), 6.94 (d, J ¼ 0.8 Hz, 1H),
6.82 (dd, J ¼ 8.2, 0.9 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d
142.1,
6H), 0.91 (t, J ¼ 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d 141.3, 137.3,
140.2, 135.3, 134.3, 132.5, 131.3, 128.6, 128.3, 128.2, 128.2, 128.1,
127.3,127.2,127.1,126.5,125.5,123.6,122.2,120.6,120.5,111.2,103.2.
IR (KBr): 3053, 1599, 1509, 1460, 1403, 1317, 1215, 1017, 796, 747,
695 cmꢂ1. MS (EI) m/z (relative intensity) 319 (100) [Mþ], 302 (4),
133.3, 129.4, 128.4, 128.2, 127.8, 121.4, 120.5, 119.7, 110.0, 102.0, 43.9,
31.2, 29.9, 26.4, 22.4, 13.9. IR (KBr): 3056, 2954, 2859, 1646, 1462,
1350, 1313, 1166, 744, 699 cmꢂ1. MS (EI) m/z (relative intensity) 277
(44) [Mþ], 221 (11), 206 (100), 204 (15), 178 (12), 165 (19). HR-MS
(ESI) m/z calcd for [C20H23N þ H]þ 278.1903, found 278.1900.
289 (3), 241 (8), 215 (5), 190 (2). HR-MS (EI) m/z calcd for C24H17
319.1361, found 319.1364.
N
4.1.15. 1-n-Octyl-2-phenyl-1H-indole (4o).[17]
4.1.10. 1-Mesityl-2-phenyl-1H-indole (4j).[17]
Following the general procedure, indole 4o (120 mg, 80%) was
obtained as a yellow solid after purification by column chroma-
tography (n-hexane/EtOAc 500:1). 1H NMR (300 MHz, CDCl3):
Following the general procedure, indole 4j (124 mg, 81%) was
obtained as a yellow oil after purification by column chromatog-
raphy (n-hexane/EtOAc 500:1). 1H NMR (300 MHz, CDCl3):
d
7.80
(dd, J ¼ 6.2, 2.8 Hz, 1H), 7.43e7.18 (m, 7H), 7.03 (s, 2H), 7.00e6.90
(m, 2H), 2.42 (s, 3H), 1.93 (s, 6H). 13C NMR (75 MHz, CDCl3):
140.5,
d
7.67 (d, J ¼ 7.8 Hz, 1H), 7.59e7.36 (m, 6H), 7.26 (m, 1H), 7.15 (m,
1H), 6.55 (s, 1H), 4.16 (t, J ¼ 7.7 Hz, 2H), 1.77e1.65 (m, 2H), 1.34e1.09
d
(m, 10H), 0.89 (t, J ¼ 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d 141.3,
138.0, 137.9, 136.9, 133.9, 132.8, 129.2, 128.2, 128.2, 127.4, 127.2,
122.1, 120.4, 120.2, 110.5, 102.0, 21.1, 17.7. IR (KBr): 3054, 3027, 2919,
1604, 1486, 1371, 1209, 1030, 854, 793, 741, 696 cmꢂ1. MS (EI) m/z
(relative intensity) 311 (100) [Mþ], 310 (17), 296 (20), 237 (13). HR-
MS (ESI) m/z calcd for [C23H21N þ H]þ 312.1747, found 312.1741.
137.3,133.3,129.4,128.4,128.2,127.9,121.4,120.5,119.7,110.0,102.0,
43.9, 31.7, 29.9, 29.1, 29.0, 26.7, 22.6,14.1. IR (KBr): 3030, 2926, 2855,
1606, 1462, 1350, 1163, 1016, 786, 743, 700 cmꢂ1. MS (EI) m/z
(relative intensity) 305 (43) [Mþ], 207 (16), 206 (100), 193 (13), 178
(12), 165 (9). HR-MS (ESI) m/z calcd for [C22H27N þ H]þ 306.2216,
found 306.2218.
4.1.11. 2-Phenyl-1-(3-pyridyl)- 1H-indole (4k)
Following the general procedure, indole 4k (98 mg, 74%) was
obtained as a white oil after purification by column chromatog-
raphy (n-hexane/EtOAc 500:1). 1H NMR (300 MHz, CDCl3):
4.1.16. 6-Chloro-2-phenyl-1-p-tolyl-1H-indole (4p)
Following the general procedure, indole 4p (113 mg, 72%) was
obtained as a white solid (m.p. 112e113 ꢀC) after purification by
column chromatography (n-hexane/EtOAc 500:1). 1H NMR
d
8.70e8.55 (m, 2H), 7.73 (m, 1H), 7.55 (m, 1H), 7.41e7.18 (m, 9H),
6.87 (s, 1H). 13C NMR (75 MHz, CDCl3):
d
148.9, 148.0, 140.6, 138.7,
(300 MHz, CDCl3):
7.16e7.05 (m, 3H), 6.75 (s,1H), 2.41 (s, 3H).13C NMR (75 MHz, CDCl3):
141.5,139.5,137.5,135.3,132.1,130.1,128.8,128.2,128.0,127.6,127.5,
d
7.57 (d, J ¼ 8.4 Hz, 1H), 7.30e7.19 (m, 8H),
135.2,135.1,131.8,129.0,128.5,128.4,127.6,123.7,122.8,121.2,120.7,
110.0, 104.7. IR (KBr): 3053, 1482, 1426, 1326, 1208, 1024, 798, 749,
703 cmꢂ1. MS (EI) m/z (relative intensity) 270 (100) [Mþ], 241 (8),
216 (3),190 (4),165 (12),134 (11). HR-MS (EI) m/z calcd for C19H14N2
270.1157, found 270.1161.
d
126.7, 121.2, 121.2, 110.7, 103.2, 21.2. IR (KBr): 3057, 3034, 1604, 1514,
1457, 1378, 1071, 927, 759, 732, 695 cmꢂ1. MS (EI) m/z (relative
intensity) 317 (100) [Mþ], 281 (23), 267 (14), 239 (3),179 (6),165 (8).
HR-MS (EI) m/z calcd for C21H16ClN 317.0971, found 317.0968.
4.1.12. 1-Benzyl-2-phenyl-1H-indole (4l).[17]
Following the general procedure, indole 4l (120 mg, 85%) was
obtained as a white solid (m.p. 95e96 ꢀC) after purification by
column chromatography (n-hexane/EtOAc 500:1). 1H NMR
4.1.17. 1-Benzyl-6-chloro-2-phenyl-1H-indole (4q)
Following the general procedure, indole 4q (115 mg, 73%) was
obtained as a white solid (m.p. 130e131 ꢀC) after purification by
column chromatography (n-hexane/EtOAc 500:1). 1H NMR
(300 MHz, CDCl3):
7.07e7.02 (m, 2H), 6.66 (s, 1H), 5.37 (s, 2H). 13C NMR (75 MHz,
CDCl3): 141.8, 138.2, 138.0, 132.7, 129.2, 128.7, 128.5, 128.3, 128.0,
127.1, 126.0, 121.9, 120.5, 120.1, 110.5, 102.3, 47.7. IR (KBr): 3056,
d
7.68 (dd, J ¼ 5.9, 0.8 Hz,1H), 7.36e7.14 (m, 11H),
(300 MHz, CDCl3):
d
7.56 (d, J ¼ 8.4 Hz, 1H), 7.44e7.35 (m, 12H), 6.61
d
(s, 1H), 5.31 (s, 2H). 13C NMR (75 MHz, CDCl3):
d
142.6, 138.4, 137.6,
132.2, 129.2, 128.9, 128.6, 128.3, 127.7, 127.3, 126.9, 125.9, 121.4,
120.9,110.5,102.4, 47.8. IR (KBr): 3060, 3030,1605,1460,1384,1073,
916, 760, 732, 698 cmꢂ1. MS (EI) m/z (relative intensity) 317 (80)
[Mþ], 226 (8), 199 (12), 91 (100), 65 (15), 43 (13). HR-MS (EI) m/z
calcd for C21H16ClN 317.0971, found 317.0971.
3029, 2917, 1603, 1488, 1454, 1348, 1312, 1163, 730, 698, 670 cmꢂ1
.
MS (EI) m/z (relative intensity) 283 (50) [Mþ], 165 (12), 91 (100), 65
(9). HR-MS (ESI) m/z calcd for [C21H17N þ H]þ 284.1434, found
284.1434.
4.1.13. 1-Benzyl-2-n-hexyl-1H-indole (4m).[21c]
4.1.18. 6-Chloro-1-n-octyl-2-phenyl-1H-indole (4r)
Following the general procedure, indole 4m (95 mg, 67%) was
obtained as a white solid (m.p. 68e69 ꢀC) after purification by
column chromatography (n-hexane/EtOAc 500:1). 1H NMR
Following the general procedure, indole 4r (91 mg, 53%) was
obtained as a yellow oil after purification by column chromatography
(n-hexane/EtOAc 500:1). 1H NMR (300 MHz, CDCl3):
d 7.60e7.34 (m,
(300 MHz, CDCl3):
d
7.61 (m, 1H), 7.36e7.06 (m, 6H), 6.98 (d,
7H), 7.10 (d, J ¼ 8.4 Hz, 1H), 6.48 (s, 1H), 4.09 (t, J ¼ 7.5 Hz, 2H),
J ¼ 8.1 Hz, 2H), 6.38 (s, 1H), 5.34 (s, 2H), 2.69 (t, J ¼ 7.8 Hz, 2H),
1.69e1.63 (m, 2H),1.32e1.10 (m,10H), 0.87 (t, J ¼ 6.9 Hz, 3H).13C NMR
1.82e1.61 (m, 2H), 1.48e1.19 (m, 6H), 1.02e0.81 (m, 3H). 13C NMR
(75 MHz, CDCl3): d 142.1, 137.8, 132.8, 129.4, 128.5, 128.1, 127.3, 126.7,
(75 MHz, CDCl3):
d
141.4,138.0,137.1,128.7,128.2,127.2,125.9,120.7,
121.3, 120.3, 110.0, 102.1, 44.1, 31.7, 29.8, 29.0, 28.9, 26.6, 22.6, 14.1. IR
(KBr): 3062, 2926, 2856, 1607, 1463, 1341, 1302, 1068, 919, 810, 759,
699 cmꢂ1. MS (EI) m/z (relative intensity) 339 (81) [Mþ], 254 (11), 242
(38), 240 (100), 227 (23), 205 (88). HR-MS (ESI) m/z calcd for
[C22H26ClN þ H]þ 340.1827, found 340.1814.
120.0, 119.4, 109.3, 99.3, 46.3, 31.6, 29.0, 28.4, 26.7, 22.5, 14.1. IR
(KBr): 3031, 2953, 2921, 2851, 1650, 1541, 1453, 1352, 1309, 1250,
773, 733, 697 cmꢂ1. MS (EI) m/z (relative intensity) 291 (70) [Mþ],
234 (32), 221 (94), 130 (23), 91 (100), 65 (14). HR-MS (EI) m/z calcd
for C21H25N 291.1987, found 291.1978.
4.1.14. 1-n-Hexyl-2-phenyl-1H-indole (4n).[17]
Acknowledgements
Following the general procedure, indole 4n (102 mg, 74%) was
obtained as a yellow oil after purification by column chromatog-
Support by the DFG, and the Chinese Scholarship Council
(fellowship to WS) is gratefully acknowledged.
raphy (n-hexane/EtOAc 500:1). 1H NMR (300 MHz, CDCl3):
d 7.73 (d,

L. Ackermann et al. / Journal of Organometallic Chemistry 696 (2011) 195e201
201
[12] For early examples, see: (a) K. Utimoto, H. Miwa, H. Nozaki, Tetrahedron Lett.
22 (1981) 4277e4278;
Appendix. Supplementary material
(b) K. Irtani, S. Matsubara, K. Utimoto, Tetrahedron Lett. 29 (1988)
1799e1802;
(c) A. Arcadi, S. Cacchi, F. Marinelli, Tetrahedron Lett. 30 (1989) 2581e2584;
(d) S. Cacchi, V. Carnicelli, F. Marinelli, J. Organomet. Chem. 475 (1994)
289e296.
Supplementary data related to this article can be found online at
doi:10.1016/j.jorganchem.2010.08.047.
References
[13] B. Schlummer, U. Scholz, Adv. Synth. Catal. 346 (2004) 1599e1626.
[14] B. Schlummer, U. Scholz, in: L. Ackermann (Ed.), Modern Arylation Methods
(2009), pp. 69e120 Weinheim.
[15] M. Kienle, S.R. Dubbaka, K. Brade, P. Knochel, Eur. J. Org. Chem. (2007)
4166e4176.
[16] For select examples of hydroamination reactions from our laboratories, see:
(a) L. Ackermann, R. Sandmann, L.T. Kaspar, Org. Lett. 11 (2009) 2031e2034;
(b) D. Facoetti, G. Abbiati, L. d’Avolio, L. Ackermann, E. Rossi, Synlett (2009)
2273e2276;
[1] Selected reviews on hydroamination reactions: (a) T.E. Müller, K.C. Hultzsch,
M. Yus, F. Foubelo, M. Tada, Chem. Rev. 108 (2008) 3795e3892;
(b) R.A. Widenhoefer, Chem. Eur. J. 14 (2008) 5382e5391;
(c) K.C. Hultzsch, Adv. Synth. Catal. 347 (2005) 367e391;
(d) M. Beller, J. Seayad, A. Tillack, H. Jiao, Angew. Chem. Int. Ed. 43 (2004)
3368e3398;
(e) A.P. Duncan, R.G. Bergman, Chem. Rec. 2 (2002) 431e445.
[2] (a) B.M. Trost, Science 254 (1991) 1471e1477;
(c) L. Ackermann, A. Althammer, Synlett (2008) 995e998;
(d) L. Ackermann, L.T. Kaspar, J. Org. Chem. 72 (2007) 6149e6153;
(e) L. Ackermann, L.T. Kaspar, A. Althammer, Org. Biomol. Chem. 5 (2007)
1975e1978;
(f) L. Ackermann, A. Althammer, Synlett (2006) 3125e3129;
(g) L.T. Kaspar, B. Fingerhut, L. Ackermann, Angew. Chem. Int. Ed. 44 (2005)
5972e5974;
(b) B.M. Trost, Acc. Chem. Res. 35 (2002) 695e705.
[3] G. Zeni, R.C. Larock, Chem. Rev. 104 (2004) 2285e2309.
[4] F. Alonso, I.P. Beletskaya, M. Yus, Chem. Rev. 104 (2004) 3079e3159.
[5] D.A. Horton, G.T. Bourne, M.L. Smythe, Chem. Rev. 103 (2003) 893e930.
[6] G.R. Humphrey, J.T. Kuethe, Chem. Rev. 106 (2006) 2875e2911.
[7] L. Ackermann, Synlett (2007) 507e526.
(h) L. Ackermann, L.T. Kaspar, C.J. Gschrei, Chem. Commun. (2004) 2824e2825;
(i) L. Ackermann, R. Born, Tetrahderon Lett. 45 (2004) 9541e9544;
(j) L. Ackermann, Organometallics 22 (2003) 4367e4368.
[17] L. Ackermann, Org. Lett. 7 (2005) 439e442.
[18] L.T. Kaspar, L. Ackermann, Tetrahedron 61 (2005) 11311e11316.
[19] L. Ackermann, R. Sandmann, M.V. Kondrashov, Synlett (2009) 1219e1222.
[20] L. Ackermann, R. Sandmann, M. Schinkel, M.V. Kondrashov, Tetrahderon 65
(2009) 8930e8939.
[8] S. Cacchi, G. Fabrizi, Chem. Rev. 105 (2005) 2873e2920.
[9] K. Krüger, A. Tillack, M. Beller, Adv. Synth. Catal. 350 (2008) 2153e2167.
[10] I. Nakamura, Y. Yamamoto, Chem. Rev. 104 (2004) 2127e2198.
[11] For selected recent examples, see: (a) L.C. Henderson, M.J. Lindon, M.C. Willis,
Tetrahedron 66 (2010) 6632e6638;
(b) A. Boyer, N. Isono, S. Lackner, M. Lautens, Tetrahedron 66(2010) 6468e6482;
(c) S. Cacchi, G. Fabrizi, A. Goggiamani, A. Perboni, A. Sferrazza, P. Stabile, Org.
Lett. 12 (2010) 3279e3281;
(d) S. Mehta, R.C. Larock, J. Org. Chem. 75 (2010) 1652e1658;
(e) L. Ackermann, A. Althammer, P. Mayer, Synthesis (2009) 3493e3503;
(f) R. Bernini, G. Fabrizi, A. Sferrazza, S. Cacchi, Angew. Chem. Int. Ed. 48 (2009)
8078e8081;
[21] For applications of this method, see: (a) P.-Y. Yao, Y. Zhang, R.P. Hsung,
K. Zhao, Org. Lett. 10 (2008) 4275e4278;
(b) R. Sanz, M.P. Castroviejo, V. Guilarte, A. Perez, F.J. Fananas, J. Org. Chem. 72
(2007) 5113e5118;
(c) Z.-Y. Tang, Q.-S. Hu, Adv. Synth. Catal. 348 (2006) 846e850.
[22] L. Ackermann, S. Barfüßer, H.K. Potukuchi, Adv. Synth. Catal. 351 (2009)
1064e1072.
(g) Y. Ohta, H. Chiba,S. Oishi, N.Fujii, H. Ohno, J. Org. Chem. 74 (2009)7052e7058;
(h) J. Barluenga, A. Jimenez-Aquino, F. Aznar, C. Valdes, J. Am. Chem. Soc. 131
(2009) 4031e4041;
[23] For recent representative examples, see: (a) L. Ackermann, R. Jeyachandran,
H.K. Potukuchi, P. Novák, L. Büttner, Org. Lett. 12 (2010) 2056e2059;
(b) L. Ackermann, H.K. Potukuchi, A.R. Kapdi, C. Schulzke, Chem. Eur. J. 16
(2010) 3300e3303;
(i) K. Alex, A. Tillack, N. Schwarz, M. Beller, Angew. Chem. Int. Ed. 47 (2008)
2304e2307;
(j) D.R. Stuart, M. Bertrand-Laperle, K.M.N. Burgess, K. Fagnou, J. Am. Chem. Soc.
130 (2008) 16474e16475;
(c) L. Ackermann, R. Vicente, N. Hofmann, Org. Lett. 11 (2009) 4274e4276;
(d) L. Ackermann, P. Novák, R. Vicente, N. Hofmann, Angew. Chem. Int. Ed. 48
(2009) 6045e6048.
(k) Y.-Q. Fang, M. Lautens, J. Org. Chem. 73 (2008) 538e549;
(l) T. Jensen, H. Pedersen, B. Bang-Andersen, R. Madsen, M. Jørgensen, Angew.
Chem. Int. Ed. 47 (2008) 888e890;
[24] For representative examples of nickel-catalyzed aminations of aryl (pseudo)
halides, see: (a) T. Shimasaki, M. Tobisu, N. Chatani, Angew. Chem. Int. Ed. 49
(2010) 2929e2932;
(m) H. Ohno, Y. Ohta, S. Oishi, N. Fujii, Angew. Chem. Int. Ed. 46 (2007)
2295e2298;
(n) B.M. Trost, A. McClory, Angew. Chem. Int. Ed. 46 (2007) 2074e2077;
(o) M. McLaughlin, M. Palucki, I.W. Davies, Org. Lett. 8 (2006) 3307e3310;
(p) A. Fürstner, P.W. Davies, J. Am. Chem. Soc. 127 (2005) 15024e15025;
(q) A.L. Odom, Dalton Trans. (2005) 225e233;
(r) M.C. Willis, G.N. Brace, I.P. Holmes, Angew. Chem. Int. Ed. 44 (2005) 403e406;
(s) T. Shimada, I. Nakamura, Y. Yamamoto, J. Am. Chem. Soc. 126 (2004)
10546e10547;
(t) H. Siebeneicher, I. Bytschkov, S. Doye, Angew. Chem. Int. Ed. 42 (2003)
3042e3044;
(b) M. Tobisu, T. Shimasaki, N. Chatani, Chem. Lett. 38 (2009) 710e711;
(c) C.-Y. Gao, L.-M. Yang, J. Org. Chem. 73 (2008) 1624e1627;
(d) G. Manolikakes, A. Gavryushin, P. Knochel, J. Org. Chem. 73 (2008)
1429e1434;
(e) C. Chen, L.-M. Yang, J. Org. Chem. 72 (2007) 6324e6327;
(f) J.A. Miller, J.W. Dankwardt, J.M. Penney, Synthesis (2003) 1643e1648;
(g) S. Tasler, B.H. Lipshutz, J. Org. Chem. 68 (2003) 1190e1199;
(h) C. Desmarets, R. Schneider, Y. Fort, Tetrahedron 57 (2001) 7657e7664;
(i) B. Gradel, E. Brenner, R. Schneider, Y. Fort, Tetrahedron Lett. 42 (2001)
5689e5692;
(u) C. Koradin, W. Dohle, A.L. Rodriguez, B. Schmid, P. Knochel, Tetrahedron 59
(2003) 1571e1587;
(j) B.H. Lipshutz, H. Ueda, Angew. Chem. Int. Ed. 39 (2000) 4492e4494;
(k) C. Desmarets, R. Schneider, Y. Fort, Tetrahedron Lett. 41 (2000)
2875e2879;
(v) M.A. Campo, Y. Huang, T. Yao, Q. Tian, R.C. Larock, Direct CeH bond arylations
on indoles, reviews, J. Am. Chem. Soc. 125 (2003) 11506e11507;
(w) L. Ackermann, R. Vicente, A. Kapdi, Angew. Chem. Int. Ed. 48 (2009)
9792e9826;
(x) L. Joucla, L. Djakovitch, an example from our laboratories, Adv. Synth. Catal.
351 (2009) 673e714;
(l) E. Brenner, R. Schneider, Y. Fort, Tetrahedron 55 (1999) 12829e12842;
(m) J.P. Wolfe, S.L. Buchwald, J. Am. Chem. Soc. 119 (1997) 6054e6058;
(n) R. Cramer, D.R. Coulson, J. Org. Chem. 40 (1975) 2267e2273.
[25] J. Seayad, A. Tillack, C.G. Hartung, M. Beller, Adv. Synth. Catal. 344 (2002)
795e813.
(y) L. Ackermann, S. Barfüßer, Synlett (2009) 808e812 (and references cited
therein).