Annulation of internal alkynes through a hydroamination/aza-Heck reaction sequence for the regioselective synthesis of indoles

Article abstract of DOI:10.1016/j.tet.2007.10.117

Highly regioselective annulation reactions of unsymmetrically substituted alkynes by primary 2-bromo or 2-chloroanilines are achieved with an efficient one-pot protocol, which relies on a regioselective TiCl₄-catalyzed intermolecular hydroamination and a subsequent palladium-catalyzed intramolecular aza-Heck reaction. The use of unsymmetrically substituted alkynes in this strategy enables the synthesis of diversely functionalized indoles, with a regioselectivity that is complementary to the one obtained when employing Larock's annulation reaction.

Full text of DOI:10.1016/j.tet.2007.10.117

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 769e777
www.elsevier.com/locate/tet
Annulation of internal alkynes through a hydroamination/aza-Heck
reaction sequence for the regioselective synthesis of indoles
Lutz Ackermann*, Ren e´ Sandmann, Amparo Villar, Ludwig T. Kaspar
Institut fuer Organische und Biomolekulare Chemie, Georg-August-Universitaet Goettingen, Tammannstrasse 2, D-37077 Goettingen, Germany
Received 10 August 2007; received in revised form 22 October 2007; accepted 26 October 2007
Available online 3 December 2007
Abstract
Highly regioselective annulation reactions of unsymmetrically substituted alkynes by primary 2-bromo or 2-chloroanilines are achieved with
an efficient one-pot protocol, which relies on a regioselective TiCl -catalyzed intermolecular hydroamination and a subsequent palladium-
4
catalyzed intramolecular aza-Heck reaction. The use of unsymmetrically substituted alkynes in this strategy enables the synthesis of diversely
functionalized indoles, with a regioselectivity that is complementary to the one obtained when employing Larock’s annulation reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
1
. Introduction
Figure 1, with an emphasis on alkyne functionalization-based
processes. The majority of these methodologies make use of
entropically favorable cyclization reactions, Larock’s elegant
direct annulation of ortho-haloanilides with alkynes being
Indole derivatives are likely to represent one of the most
1
,2
important structural classes in drug discovery. Selected ex-
amples of indoles with activities relevance to biology include
nonsteroidal anti-inflammatory drug indomethacin or 5HT-3
antagonist ondansetron. Due to this prevalence of indoles
in biologically active compounds, as well as natural products,
a continued strong demand for the development of general,
flexible, and regioselective methodologies for the synthesis
of this structural motif exists. Despite the development of
a variety of effective strategies, the synthesis of indole deriv-
atives featuring substituents at positions other than C5 remains
challenging by classical protocols, such as the Fischer indole
6
a valuable exception (method E).
1
,2
R4
X
R6
N
R
3
,4
1
X
N
R3
+
HNR2
A
N
R5
B
1
R
2
(R = NR2)
C
R3
2
synthesis. Consequently, metal-catalyzed reactions for the
construction of the indole backbone were developed, largely
5
relying on palladium-catalysis. These approaches can be cat-
R2
N
R1
D
egorized into (a) the functionalization of existing indoles or
(
F
R2
b) the de novo indole construction from benzenoid precursors
through pyrrole ring assembly. Representative examples for
the latter, inherently more modular, approach are depicted in
E
I
+
+
H
H2NR
R2
+ XR3
R3
1
X
NHR1
Cl
+
NHR1
R2
*
Corresponding author.
E-mail address: lutz.ackermann@chemie.uni-goettingen.de (L. Ackermann).
Figure 1. Retrosynthetic representation of selected alkyne functionalization-
based palladium-catalyzed reactions for the assembly of the pyrrole ring.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.117

770
L. Ackermann et al. / Tetrahedron 64 (2008) 769e777
Examination of the literature revealed considerable room
Consequently, we probed the use of enamines 5 derived
from 2-chloroanilines 1 and unsymmetrically substituted
alkynes 2 in intramolecular palladium-catalyzed aza-Heck
reactions (Scheme 3). Importantly, this strategy should prove
complementary to Larock’s annulation reaction with respect
to its regioselectivity. Herein, we wish to present a full
account on this one-pot indole synthesis, consisting of an in-
termolecular titanium-catalyzed hydroamination and a palla-
dium-catalyzed intramolecular aza-Heck reaction.
for the improvement of the existing procedures. For example,
the ortho-haloaniline starting materials for the Larock annula-
tion reaction, as well as for the initial Sonogashira reaction of
7
e9
method D proved, prior to our investigations,
0
not generally
compatible with the use of chloroarenes, displaying a wide
1
6
,11,12
28
variety of substituents.
Further, the Larock annulation
reaction of unsymmetrically substituted alkynes by aniline
derivatives yielded, with good to excellent selectivities, indole
derivatives with the bulkiest group of the alkyne in the position
6
,8,11
Ar
Ar
2
(for an example, see Scheme 1).
Consequently, the syn-
R
R
R
Cl
Cl
Ar
cat. [Ti]
cat. [Pd]
thesis of indoles with the bulkiest substituent of the alkyne
in position 3 required the use of 1-silyl-1-alkynes, and an
additional subsequent functionalization of the resulting
+
Alk
N
H
NH2
N
H
Alk
Alk
2
1
5
6
6
2
-silylindole.
Scheme 3. Regioselective annulation of internal alkynes 2.
Me
Me
cat. Pd(OAc)2,
LiCl, KOAc
I
2. Results and discussion
+
Ph
DMF, 24h, 100 °C
N
Ac
NH
Ac
At the outset of our studies, we explored the planned regiose-
lective one-pot synthesis of indoles employing 2-chloroaniline
Ph
1a
2a
3a
5%
7
(1c) (Scheme 4). Since the TiCl
hydroamination of 2-haloanilines 1 was well elaborated previ-
-catalyzed intermolecular
4
Scheme 1. Larock’s direct annulation with unsymmetrical internal alkyne 2a.
2
4
ously in our laboratories, we focused on the development of
effective reaction conditions for the subsequent palladium-
catalyzed intramolecular aza-Heck reaction of the resulting
Thus, we became interested in the development of novel
and flexible indole syntheses employing inexpensive and read-
ily available aryl chlorides as electrophilic starting materials.
While we reported previously on modular indole syntheses
2-chlorophenyl-substituted enamine5within a one-potprocedure.
Ph
cat. [Pd],
KOt-Bu
Ph
cat. TiCl4,
t-BuNH2
PhMe,
1
3,14
Cl
Cl
Ph
Et
employing ortho-dihaloarenes (method F in Fig. 1),
we
+
Et
envisioned as well a one-pot indole synthesis starting from
inexpensive 2-chloroanilines. Particularly, a protocol yielding
indoles with the bulkiest substituent of the alkyne in position
PhMe,
105 °C
N
H
NH2
N
H
Et 105 °C
57%
1c
2b
5
6a
3
was highly desirable, as it should prove complementary to
Scheme 4. One-pot synthesis of indole 6a used for the optimization of palla-
dium catalysts.
the regioselectivity observed with Larock’s annulation.
The hydroamination reaction, i.e., the direct addition of
amines onto carbonecarbon multiple bonds, represents one
of the most efficient and atom-economical approaches to
substituted amines and imines from inexpensive feed-
2.1. Annulation with palladium complexes derived from
imidazolium salts
1
5e21
16,22,23
Initially, we explored palladium complexes derived from in
2
stocks.
Titanium-based
hydroamination methodo-
9e31
situ generated N-heterocyclic carbenes (NHC)
for the
logies are especially attractive, inter alia due to low cost and
low toxicity of the catalysts. During studies on user-friendly
regioselective one-pot strategy. Most effective catalysis was
accomplished with commercially available imidazolium salt
HIPrCl 7 (Fig. 2) as precursor for a sterically hindered
2
4e26
TiCl -catalyzed hydroamination reactions,
we realized
that a variety of valuable aryl halides were tolerated by the cata-
4
2
8
2
lytic system. Furthermore, intermolecular TiCl -catalyzed
4
carbene.
4
hydroamination reactions of unsymmetrically substituted al-
kynes gave rise to the formal anti-Markovnikov addition prod-
ucts with good to excellent regioselectivities, as illustrated for
Me
N
Me
Me
Me
Cl
2
4,27
N
the hydroamination of alkyne 2b in Scheme 2.
Me
Me
Me
Me
HIPrCl 7
Ph 1) 20 mol% TiCl , t-BuNH
4
2
Ph
Et
PhMe, 105 °C, 22h
+
NH2
Figure 2. Imidazolium salt 7.
2
) NaBH3CN, ZnCl2,
N
H
Et
THF/MeOH, 20 °C, 16h
96 : 4 regioselectivity
1
b
2b
4
Consequently, its scope was probed in the hydroamination/
aza-Heck sequence for the annulation of various internal al-
kynes by 2-chloroaniline (1c) (Table 1). Generally, the desired
3-aryl-substituted indoles 6 were obtained with good to
9
2%
Scheme 2. TiCl
4
-catalyzed intermolecular hydroamination of alkyne 2b with
formal anti-Markovnikov selectivity.

L. Ackermann et al. / Tetrahedron 64 (2008) 769e777
Table 1 (continued)
771
Table 1
Scope of indole synthesis with 2-chloroaniline (1c)
a
1
R
2
R
b
6/3
Entry
Product
Yield
(%)
R1
Cl
R1
R2
e
N
H
9
4-Cl
2-Cl
Hex
Hex
6j
67
>99:<1
>99:<1
1
) 10 mol% TiCl4, t-BuNH2,
PhMe, 105 °C, 20h
6
Hex
Cl
N
H
+
+
2
) 10 mol% Pd(OAc)2,
NH2
R2
R2
10 mol% 7, KOt-Bu,
PhMe, 105 °C, 20h
1c
2
Cl
e
46
R1
10
N
H
6k
Hex
N
3
H
1
2
b
a
Entry
R
R
Product
Yield
(
6/3
Isolated yields.
GC-analysis.
b
c
d
e
%)
Isolated with up to 8% of a regioisomer.
Isolated with up to 5% of a regioisomer.
Using 2-bromoaniline.
Ph
1
H
H
Ph
Ph
N
6b
76
d
H
Ph
3
2
excellent regioselectivities.
F- (entry 6), F C- (entries 7 and 8), or Cl-substituents (entries
9
Functional groups, such as
c
c
2
3
Hex
Hex
N
H
6c
81
92:8
3
and 10) were tolerated by the catalytic system. While para-
and meta-substituted aryl alkynes were efficiently converted,
the preparation of the corresponding ortho-substituted analog
k occurred with significantly reduced isolated yield (entry
0). Unfortunately, the application to the synthesis of aza-
Ph
H
Bu
Bu
N
H
6d
81
92:8
92:8
6
1
Me
indoles using the corresponding pyridine derivatives proved
thus far less successful.
c
81
4
4-Me
Hex
6e
Hex
2.2. Optimization of the one-pot annulation
N
H
OMe
The most commonly used ligands for palladium-catalyzed
3
3e35
Heck reactions are phosphorus-based.
Therefore, we ex-
plored a variety of phosphine (pre)ligands for the palladium-
catalyzed intramolecular aza-Heck reaction within our one-
pot annulation of internal alkynes. Additionally, we wished
to expand our approach to the regioselective preparation of
indoles with substituents on the benzenoid backbone. Thus,
we chose as a test reaction the one-pot annulation of alkyne
6f
5
4-MeO
Hex
66
>99:<1
Hex
N
H
F
2
b with aniline 1d (Table 2). Not surprisingly, PPh (8) as
3
d
6
7
4-F
Hex
Hex
6g
74
>99:<1
ligand did not enable an efficient palladium-catalyzed aza-
Heck reaction of the 2-chlorophenyl-substituted enamine de-
rived from aniline 1d at a reaction temperature of 105 C
(entry 1). Monophosphine biaryl ligands 9e12 (Fig. 3)
were probed (entries 2e5), and provided an isolated yield
comparable to the one obtained with the previously used imi-
dazolium salt HIPrCl 7 (entry 6). Interestingly, with air- and
Hex
N
H
ꢀ
CF3
d
82
3-F
3
C
6h
97:3
Hex
N
H
3
6
moisture-stable secondary phosphine oxide (1-Ad) P(O)H
2
3
7
13
an efficient intramolecular aza-Heck-reaction with an
aryl chloride was accomplished (entry 7). However, a com-
CF3
plex derived from PCy (14) proved superior to all other
3
d
84
8
3-CF
3
Bu
6i
97:3
catalytic systems studied in the annulation of alkyne 2b (en-
try 8). Among a variety of bases KO-t-Bu was found superior
(entries 8e11).
Bu
N
H

7
72
L. Ackermann et al. / Tetrahedron 64 (2008) 769e777
Table 3 (continued)
Table 2
Optimization of the palladium catalyst
a
1
R
2
3
R
4
R
Entry
R
Product
Isolated
yield (%)
Ph
Ph
1
) 20 mol% TiCl4, t-BuNH2,
Me
Cl
Me
PhMe, 105 °C, 14h
Ph
Ph
+
Et
2
) 10 mol% Pd(OAc)2,
10 mol% L, base,
PhMe, 105 °C, 19h
N
H
NH2
Et
3
H
H
H
H
Ph
6b
74
N
1d
2b
6l
H
OMe
Entry Ligand (L)
Base
KO-t-Bu
KO-t-Bu 10
Isolated yield (%)
b
1
2
3
4
5
6
7
8
9
1
1
PPh
1
3
(8)
2
c
4
Me
4-MeO Bu
6n
58
2
3
4
b
Me
R ¼i-Pr, R ¼H, R ¼H, R ¼H (9)
1
2
3
4
Bu
R ¼Cy, R ¼NMe , R , R ¼H (10) KO-t-Bu 40
2
4
1
2
3
N
H
R ¼Cy, R , R , R ¼i-Pr (11)
KO-t-Bu 50
KO-t-Bu 55
KO-t-Bu 52
KO-t-Bu 55
KO-t-Bu 71
1
2
3
4
R ¼Cy, R , R ¼OMe, R ¼H (12)
HIPrCl 7
OMe
2
(1-Ad) P(O)H (13)
PCy
PCy
PCy
PCy
3
3
3
3
(14)
(14)
(14)
(14)
K
K
2
CO
PO
CO
3
d
d
d
5
H
H
4-MeO Hex
6f
68
0
1
a
3
4
Hex
Cs
2
3
N
H
Isolated yield of analytically pure product.
GC-conversion.
b
OMe
OMe
c
Me
6
7
8
Me
Me
H
H
H
H
3-MeO Hex
3-MeO Bu
3-MeO Hex
6o 51
Hex
1
P(R )
R
2
N
H
R2
3
R4
Figure 3. General structure of monophosphine biaryl ligands.
c
Me
6p 55
Bu
N
H
2
.3. Scope of the annulation protocol
With an optimized catalyst in hand, we probed its scope in
OMe
6q
71
Hex
the annulation of various aryl-substituted alkynes 2 by
substituted primary 2-chloroanilines 1 (Table 3). Both sym-
metrically as well as unsymmetrically substituted aryl alkynes
could be employed providing comparable isolated yields
N
H
CF3
c
Me
9
Me
Me
H
H
3-F
3
C
Hex
Hex
6r 71
Hex
Table 3
Regioselective synthesis of indoles 6
a
N
H
R3
R3
F
R1
1) 20 mol% TiCl4, t-BuNH2,
R1
Cl
PhMe, 105 °C, 14h
c
R4
10
4-F
6s 54
+
Me
F
2
) 10 mol% Pd(OAc)2,
10 mol% 14, KOt-Bu,
PhMe, 105 °C, 22h
N
NH2
R4
Hex
R2
R2
H
N
1
2
6
H
Ph
1
R
2
3
R
4
R
Entry
R
Product
Isolated
yield (%)
b
1
1
F
F
H
H
Et
Et
Et
6t
52
53
N
H
Ph
F
Me
Ph
1
Me
Me
H
H
H
H
Et
Et
6l
71
Cl
N
H
Ph
b
2
1
Cl
H
Et
6u
N
H
Me
a
b
c
71
Isolated yield of analytically pure product.
Starting from the corresponding 2-bromoaniline.
Isolated with up to 4% of a regioisomer.
2
Ph
Ph
6m
N
H

L. Ackermann et al. / Tetrahedron 64 (2008) 769e777
773
(
entries 1e3). When using unsymmetrically substituted al-
Et O 20:1/10:1/4:1) yielded 2,3-diphenylindole (6b)
2
1
(974 mg, 76%) as an off-white solid. H NMR (CDCl3,
kynes the corresponding 3-aryl indoles 6 could be isolated
with good regioselectivities. Additionally, functionalities,
such as ethers (entries 4e8), alkyl fluorides (entry 9), as
well as aryl fluorides (entries 10, and 11) and chlorides (entry
300 MHz): d 8.22 (br s, 1H), 7.67 (d, J¼7.8 Hz, 1H), 7.45e
1
7.12 (m, 13H). C NMR (CDCl , 75 MHz): d 135.9, 135.1,
3
3
134.1, 132.7, 130.2, 128.8, 128.7, 128.5, 128.2, 127.7,
126.2, 122.7, 120.4, 119.7, 115.2, 110.9. MS (EI) m/z (relative
1
2) were tolerated by the two catalytic systems.
þ
intensity) 269 (100) [M ], 254 (4), 239 (5), 165 (11), 134 (6),
127 (4). HRMS (EI) m/z calcd for C H N 269.1204, found
3
. Conclusions
2
0 15
269.1198.
In summary, we described the development of a one-pot
3
9
annulation strategy of internal alkynes with primary 2-bromo-
or 2-chloroanilines, yielding regioselectively various indole
derivatives. The reaction sequence commences with a user-
4.2.2. 2-Ethyl-3-phenylindole (6a)
Following the general procedure using 2-chloroaniline (1c)
(191 mg, 1.50 mmol), 1-phenyl-1-butyne (2b) (195 mg,
2.00 mmol), HIPrCl (7) (64 mg, 0.15 mmol), and Pd(OAc)2
(34 mg, 0.15 mmol), 6a (192 mg, 57%) was obtained after
purification by column chromatography (SiO , n-pentane/
Et O 50:1/30:1/20:1/10:1) as a yellow oil. H NMR
friendly TiCl -catalyzed intramolecular hydroamination. This
4
sets the stage for an intramolecular palladium-catalyzed aza-
Heck reaction, which was most effectively accomplished
with PCy as ligand. For unsymmetrically substituted aryl
2
1
3
2
alkynes our one-pot annulation approach yields selectively
-aryl-substituted indoles. With respect to its regioselectivity,
our approach to substituted indoles proved to be complemen-
tary to Larock’s frequently employed direct annulation.
(300 MHz, CDCl ): d 7.87 (br s, 1H), 7.61 (d, J¼7.5 Hz, 1H),
3
3
7.47e7.37 (m, 4H), 7.27e7.23 (m, 2H), 7.15e7.06 (m, 2H),
1
3
2.81 (q, J¼7.6 Hz, 2H), 1.24 (t, J¼7.6 Hz, 3H). C NMR
(75 MHz, CDCl ): d 137.2, 135.5, 135.1, 129.6, 128.5,
3
127.9, 125.9, 121.6, 119.9, 118.9, 113.9, 110.4, 19.7, 14.3.
IR (KBr): 3404, 3055, 2970, 2931, 1601, 1459, 1460, 772,
7
4
. Experimental
ꢂ1 þ
52, 703 cm . MS m/z (relative intensity) 221 (100) [M ],
206 (98), 179 (15), 102 (5). HRMS (EI) m/z calcd for
4
.1. General
C H N 221.1204, found 221.1182.
16 15
All catalytic reactions were carried out on a 1.00e4.76 mmol
scale under N using pre-dried glassware. Chemicals were ob-
4.2.3. 2-n-Hexyl-3-phenylindole (6c)
2
tained from commercial sources, and were used without further
purification. PhMe was distilled from sodium-benzophenone
˚
under nitrogen and stored over molecular sieves (4 A). Yields
refer to isolated compounds, estimated to be >95% pure as
1
determined by H NMR and GC, unless otherwise stated. Flash
Following the general procedure using 2-chloroaniline
(1c) (191 mg, 1.50 mmol), 1-phenyl-1-octyne (244 mg,
1.31 mmol), HIPrCl (7) (57 mg, 0.13 mmol), and Pd(OAc)2
(29 mg, 0.13 mmol), 6c (295 mg, 81%) was obtained after pu-
rification by column chromatography (SiO , n-pentane/Et O
2
2
chromatography: Merck silica gel 60 (230e400 mesh). NMR:
1
H was recorded on a Varian Unity 300, Bruker AC 300, or
50:1/30:1/20:1) as a yellow oil. Ratio of regioisomers:
1
7:86:7 (GC). H NMR (CDCl , 300 MHz): d 7.92 (br s, 1H),
3
1
AMX 600, C was recorded on a Varian Mercury 300, Unity
3
7.66e7.63 (m, 1H), 7.51e7.43 (m, 4H), 7.33e7.28 (m, 2H),
7.21e7.08 (m, 2H), 2.83 (t, J¼7.8 Hz, 2H), 1.67 (tt, J¼7.8,
1
00, Bruker AC 300, AMX 600, or Inova 500, F was recorded
9
3
1
3
on a Mercury 300 in the solvent indicated; chemical shifts (d)
are given in parts per million, coupling constants (J ) in hertz.
7.8 Hz, 2H), 1.36e1.23 (m, 6H), 0.86 (t, J¼6.8 Hz, 3H).
C
NMR (CDCl , 75 MHz): d 136.1, 135.5, 135.2, 129.6, 128.4,
3
127.9, 125.8, 121.5, 119.8, 118.9, 114.4, 110.3, 31.5, 29.5,
29.1, 26.3, 22.5, 14.0. IR (KBr): 3409, 3057, 2955, 2927,
4
.2. Representative procedure for annulation of alkynes
ꢂ1
with imidazolium salt 7 as preligand
2856, 1496, 1460, 772, 744, 702 cm . MS (EI) m/z (relative
þ
intensity) 277 (48) [M ], 206 (100), 179 (9). HRMS (EI) m/z
calcd for C H N 277.1830, found 277.1839.
3
8
4
.2.1. 2,3-Diphenylindole (6b)
-Chloroaniline (1c) (610 mg, 4.76 mmol) and tolan
1.02 g, 5.70 mmol) were added to a solution of TiCl4
2
0 23
2
(
(
4.2.4. 2-n-Butyl-3-phenylindole (6d)
0.05 mL, 0.47 mmol) and t-BuNH (0.30 mL, 2.86 mmol) in
2
Following the general procedure using 2-chloroaniline (1c)
(191 mg, 1.50 mmol), 1-phenyl-1-hexyne (237 mg, 1.5 mmol),
HIPrCl (7) (64 mg, 0.15 mmol), and Pd(OAc)2 (34 mg,
0.15 mmol), 6d (303 mg, 81%) was obtained after purification
by column chromatography (SiO , n-pentane/Et O 50:1/
PhMe (5 mL) and the resulting mixture was stirred for 20 h
ꢀ
at 105 C. The solvent was partially removed and KO-t-Bu
(1.60 g, 14.0 mmol), HIPrCl (7) (202 mg, 0.48 mmol), and
Pd(OAc)2 (106 mg, 0.48 mmol) were added. The mixture
was stirred at 105 C for 24 h. CH Cl (75 mL) and aq HCl
2
2
2
ꢀ
30:1/20:1/10:1) as a yellow oil. Ratio of regioisomers:
2
1
8:85:7 (GC). H NMR (CDCl , 300 MHz): d 7.95 (br s, 1H),
(
2 M, 50 mL) were added to the cold suspension. The sepa-
3
rated aqueous phase was washed with CH Cl (2ꢁ75 mL).
7.73e7.69 (m, 1H), 7.59e7.49 (m, 4H), 7.39e7.35 (m,
2H), 7.26e7.15 (m, 2H), 2.89 (t, J¼7.8 Hz, 2H), 1.71 (tt,
J¼7.8, 7.8 Hz, 2H), 1.49e1.36 (m, 2H), 0.96 (t, J¼7.3 Hz,
2
2
The combined organic phases were washed with satd aq
NaHCO (50 mL) and brine (50 mL). Drying with MgSO
and purification by column chromatography (SiO , n-pentane/
3
4
13
3H). C NMR (CDCl , 75 MHz): d 136.0, 135.5, 135.2, 129.6,
3
2

774
L. Ackermann et al. / Tetrahedron 64 (2008) 769e777
1
2
1
2
28.4, 127.9, 125.8, 121.5, 119.8, 118.9, 114.4, 110.3, 32.0,
6.1, 22.5, 13.8. IR (KBr): 3409, 3057, 2957, 2928, 1496,
J¼8 Hz), 128.0, 121.6, 120.0, 118.6, 115.3 (d, J¼21 Hz),
1
9
113.5, 110.4, 31.5, 29.8, 29.0, 26.3, 22.5, 14.0. F NMR
(CDCl , 375 MHz): d ꢂ115.9 (tt, J¼9.2, 5.7 Hz). IR (KBr):
ꢂ1
460, 771, 744, 702 cm . MS (EI) m/z (relative intensity)
3
þ
49 (43) [M ], 206 (100), 23 (10). HRMS (EI) m/z calcd
3956, 3404, 3056, 3956, 2928, 2857, 1507, 1460, 1222,
ꢂ1
for C H N 249.1517, found 249.1525.
8 19
1156, 835, 745 cm . MS (EI) m/z (relative intensity) 295
1
þ
(
50) [M ], 238 (9), 224 (100), 197 (11), 177 (2). HRMS
4
.2.5. 2-n-Hexyl-3-(4-methylphenyl)indole (6e)
Following the general procedure using 2-chloroaniline (1c)
(EI) m/z calcd for C H FN 295.1736, found 295.1732.
20 22
(
1
(
191 mg, 1.50 mmol), 1-(4-methylphenyl)-1-octyne (300 mg,
.50 mmol), HIPrCl (7) (64 mg, 0.15 mmol), and Pd(OAc)2
34 mg, 0.15 mmol), 6e (354 mg, 81%) was obtained after pu-
rification by column chromatography (SiO , n-pentane/Et O
4.2.8. 3-(3-Trifluoromethylphenyl)-2-n-hexylindole (6h)
Following the general procedure using 2-chloroaniline (1c)
(191 mg, 1.50 mmol), 1-(3-trifluoromethylphenyl)-1-octyne
(382 mg, 1.50 mmol), HIPrCl (7) (64 mg, 0.15 mmol), and
Pd(OAc)2 (34 mg, 0.15 mmol), 6h (422 mg, 82%) was
obtained after purification by column chromatography (SiO2,
2
2
5
(
0:1/30:1) as a yellow oil. Ratio of regioisomers: 9:81:10
1
GC). H NMR (CDCl , 300 MHz): d 7.95 (br s, 1H), 7.65e
3
7
2
.62 (m, 1H), 7.42e7.09 (m, 7H), 2.85 (t, J¼7.8 Hz, 2H),
n-pentane/Et O 50:1/20:1/10:1) as a yellow oil. Ratio of
2
1
regioisomers: 4:93:3 (GC). H NMR (CDCl , 300 MHz):
.44 (s, 3H), 1.70 (tt, J¼7.8, 7.8 Hz, 2H), 1.39e1.41
3
1
3
(
m, 6H), 0.88 (t, J¼6.8 Hz, 3H).
C NMR (CDCl ,
3
d 8.04 (br s, 1H), 7.78e7.77 (m, 1H), 7.71e7.67 (m, 1H),
7.63e7.57 (m, 3H), 7.39e7.36 (m, 1H), 7.22 (ddd, J¼7.4,
7.4, 1.3 Hz, 1H), 7.16 (ddd, J¼7.4, 7.4, 1.3 Hz, 1H), 2.86 (t,
7
1
2
1
5 MHz): d 135.9, 135.4, 135.2, 132.4, 129.5, 129.2, 128.1,
21.4, 119.8, 118.9, 114.3, 110.3, 31.6, 29.9, 29.1, 26.4,
2.6, 21.2, 14.0. IR (KBr): 3408, 3052, 2926, 2955, 2857,
J¼7.8 Hz, 2H), 1.72 (tt, J¼7.8, 7.8 Hz, 2H), 1.39e1.24
ꢂ1
13
511, 1460, 1330, 819, 744 cm . MS (EI) m/z (relative inten-
(m, 6H), 0.88 (t, J¼6.8 Hz, 3H).
C NMR (CDCl ,
3
þ
sity) 291 (55) [M ], 234 (11), 220 (100), 205 (36), 178 (7).
HRMS (EI) m/z calcd for C H N 291.1987, found 291.1975.
75 MHz): d 136.6, 136.4, 135.2, 132.7, 130.4 (q, J¼32 Hz),
128.9, 127.6, 126.2 (q, J¼4 Hz), 124.3 (q, J¼272 Hz), 122.5
2
1 25
(
q, J¼4 Hz), 121.9, 120.3, 118.5, 113.2, 110.5, 31.5, 29.8,
1
9
4
.2.6. 2-n-Hexyl-3-(4-methoxyphenyl)indole (6f)
Following the general procedure using 2-chloroaniline
29.0, 26.3, 22.5, 14.0.
d ꢂ61.4. IR (KBr): 3405, 3060, 2958, 2929, 2858, 1461,
F NMR (CDCl , 375 MHz):
3
ꢂ1
(
1c) (191 mg, 1.50 mmol), 1-(4-methoxyphenyl)-1-octyne
324 mg, 1.50 mmol), HIPrCl (7) (64 mg, 0.15 mmol), and
1323, 1306, 1166, 1127, 1073, 804 cm . MS (EI) m/z (rela-
þ
(
Pd(OAc)2 (34 mg, 0.15 mmol), 6f (306 mg, 66%) was
tive intensity) 345 (50) [M ], 288 (15), 274 (100), 254 (6),
204 (17). HRMS (EI) m/z calcd for C H F N 345.1704,
found 345.1695.
21
22 3
obtained after purification by column chromatography (SiO2,
n-pentane/Et O 50:1/30:1/20:1/10:1) as a yellow oil.
2
1
H NMR (CDCl , 300 MHz): d 7.97 (br s, 1H), 7.63 (d,
3
4.2.9. 2-n-Butyl-3-(3-trifluoromethylphenyl)indole (6i)
J¼7.6 Hz, 1H), 7.45e7.42 (m, 2H), 7.36e7.33 (m, 1H),
Following the general procedure using 2-chloroaniline (1c)
(191 mg, 1.50 mmol), 1-(3-trifluoromethylphenyl)-1-hexyne
(339 mg, 1.50 mmol), HIPrCl (7) (64 mg, 0.15 mmol), and
Pd(OAc)2 (34 mg, 0.15 mmol), 6i (398 mg, 84%) was
obtained after purification by column chromatography (SiO2,
7
.22e7.10 (m, 2H), 7.07e7.02 (m, 2H), 3.90 (s, 3H), 2.84
(
(
7
1
2
1
t, J¼7.8 Hz, 2H), 1.70 (tt, J¼7.8, 7.8 Hz, 2H), 1.39e1.26
3
1
3
m, 6H), 0.90 (t, J¼6.8 Hz, 3H).
C NMR (CDCl ,
5 MHz): d 157.9, 135.8, 135.8, 135.1, 130.7, 128.2, 127.8,
21.4, 119.7, 118.8, 113.9, 110.3, 55.3, 31.5, 29.9, 29.1,
6.3, 22.5, 14.0. IR (KBr): 3406, 3056, 2955, 2928, 2856,
n-pentane/Et O 50:1/30:1/15:1) as a yellow solid. Ratio
2
1
of regioisomers: 3:96:3 (GC). H NMR (CDCl , 300 MHz):
3
ꢂ1
510, 1460, 1243, 1175, 831, 745 cm . MS (EI) m/z (relative
d 8.03 (br s, 1H), 7.79 (m, 1H), 7.72e7.69 (m, 1H), 7.65e
7.58 (m, 3H), 7.38 (d, J¼6.3 Hz, 1H), 7.26e7.15 (m, 2H),
2.86 (t, J¼7.6 Hz, 2H), 1.71 (tt, J¼7.6, 7.6 Hz, 2H), 1.41
þ
intensity) 307 (90) [M ], 250 (5), 236 (100), 220 (9), 205 (25),
192 (12). HRMS (EI) m/z calcd for C H NO 307.1936,
21 25
found 307.1939.
13
(tq, J¼7.6, 7.6 Hz, 2H), 0.93 (t, J¼7.6 Hz, 3H). C NMR
3
(CDCl , 75 MHz): d 136.6, 136.4, 135.2, 132.7, 130.4
4
.2.7. 3-(4-Fluorophenyl)-2-n-hexylindole (6g)
Following the general procedure using 2-chloroaniline (1c)
191 mg, 1.50 mmol), 1-(4-fluorophenyl)-1-octyne (306 mg,
.50 mmol), HIPrCl (7) (64 mg, 0.15 mmol), and Pd(OAc)2
34 mg, 0.15 mmol), 6g (329 mg, 74%) was obtained after
(q, J¼32 Hz), 128.9, 127.6, 126.1 (q, J¼4 Hz), 124.3
(q, J¼272 Hz), 122.5 (q, J¼4 Hz), 121.9, 120.3, 118.4,
1
113.2, 110.5, 31.9, 26.0, 22.4, 13.7. F NMR (CDCl ,
9
(
1
(
3
375 MHz): d ꢂ61.4. IR (KBr): 3411, 3366, 3060, 2955,
2928, 2863, 1460, 1326, 1308, 1163, 1124, 1073, 802, 747,
ꢂ1
þ
purification by column chromatography (SiO , n-pentane/
702 cm . MS (EI) m/z (relative intensity) 317 (46) [M ],
274 (100), 254 (6), 204 (22), 178 (6). HRMS (EI) m/z calcd
for C H F N 317.1391, found 317.1411.
2
Et O 50:1/30:1/20:1/10:1) as a yellow oil. Ratio of
2
1
regioisomers: 5:95:0 (GC). H NMR (CDCl , 300 MHz):
3
19 18 3
d 7.98 (br s, 1H), 7.60e7.57 (m, 1H), 7.47e7.42 (m, 2H),
7
.37e7.34 (m, 1H), 7.22e7.10 (m, 4H), 2.83 (t, J¼7.7 Hz,
4.2.10. 3-(4-Chlorophenyl)-2-n-hexylindole (6j)
2
H), 1.69 (tt, J¼7.7, 7.7 Hz, 2H), 1.41e1.24 (m, 6H), 0.88
Following the general procedure using 2-bromoaniline
(258 mg, 1.50 mmol), 1-(4-chlorophenyl)-1-octyne (331 mg,
1.50 mmol), HIPrCl (7) (64 mg, 0.15 mmol), and Pd(OAc)2
1
3
(
t, J¼6.8 Hz, 3H). C NMR (CDCl , 75 MHz): d 161.4 (d,
3
J¼244 Hz), 136.1, 135.1, 131.4 (d, J¼3 Hz), 131.1 (d,

L. Ackermann et al. / Tetrahedron 64 (2008) 769e777
775
(
34 mg, 0.15 mmol), 6j (312 mg, 67%) was obtained after
d 137.3, 135.6, 133.4, 129.6, 129.2, 128.4, 128.1, 125.8,
123.0, 118.6, 113.4, 110.0, 21.5, 19.7, 14.3. IR (film): 3401,
3051, 2970, 2931, 2872, 2361, 2339, 1603, 1312, 1265,
purification by column chromatography (SiO , n-pentane/
Et O 50:1/30:1/15:1) as a yellow oil. H NMR (CDCl ,
2
1
2
3
ꢂ1
3
(
00 MHz): d 8.00 (br s, 1H), 7.60e7.57 (m, 1H), 7.43
m, 4H), 7.37e7.34 (m, 1H), 7.22e7.10 (m, 2H), 2.83 (t,
J¼7.8 Hz, 2H), 1.69 (tt, J¼7.8, 7.8 Hz, 2H), 1.40e1.23 (m,
1012, 876 cm . MS (EI) m/z (relative intensity) 235 (100)
þ
[M ], 220 (56), 204 (23), 178 (6), 103 (6). HRMS (ESI) m/z
calcd for C H N 236.1434, found 236.1434.
1
7 18
1
3
6
H), 0.88 (t, J¼6.8 Hz, 3H). C NMR (CDCl , 75 MHz):
3
d 136.6, 135.6, 134.4, 132.0, 131.2, 129.0, 128.1, 122.1,
20.5, 119.0, 113.7, 110.8, 31.9, 30.2, 29.4, 26.7, 22.9, 14.4.
IR (KBr): 3403, 3055, 2955, 2927, 2856, 1493, 1460, 1090,
8
1
4.3.2. 5-Methyl-2,3-diphenylindole (6m)
Following the general procedure, indole 6m (208 mg, 71%)
ꢂ1
1
014, 820, 744 cm . MS (EI) m/z (relative intensity) 311
was obtained after purification by column chromatography
(SiO , n-hexane/EtOAc, 30:1/25:1/15:1/5:1) as an off-
þ
(61) [M ], 254 (10), 240 (48), 205 (100), 130 (4). HRMS
(EI) m/z calcd for C H NCl 311.1441, found 311.1417.
2
1
white solid. H NMR (300 MHz, CDCl ): d 8,14 (br s, 1H),
20
22
3
7
.45e7.26 (m, 12H), 7.09 (d, J¼8.1 Hz, 1H), 2.45 (s, 3H).
1
3
4
.2.11. 3-(2-Chlorophenyl)-2-n-hexylindole (6k)
Following the general procedure using 2-bromoaniline
C NMR (125 MHz, CDCl ): d 135.2, 134.2, 134.2, 132.8,
3
130.2, 129.7, 129.0, 128.6, 128.5, 128.1, 127.6, 126.1,
124.3, 119.2, 114.7, 110.5, 21.5. IR (KBr): 3369, 3058,
2361, 2338, 1617, 1506, 1316, 1306, 1295, 1255, 1030,
(
1
(
258 mg, 1.50 mmol), 1-(2-chlorophenyl)-1-octyne (331 mg,
.50 mmol), HIPrCl (7) (64 mg, 0.15 mmol), and Pd(OAc)2
34 mg, 0.15 mmol), 6h (214 mg, 46%) was obtained after
ꢂ1
þ
914 cm . MS (EI) m/z (relative intensity) 283 (100) [M ],
267 (12), 133 (7). HRMS (ESI) m/z calcd for C H N
284.1434, found 284.1434.
purification by column chromatography (SiO , n-pentane/
Et O 50:1/20:1/10:1) as a yellow oil. H NMR (CDCl ,
2
21 18
1
2
3
3
00 MHz): d 8.01 (br s, 1H), 7.57e7.54 (m, 1H), 7.44e7.41
(
m, 1H), 7.38e7.32 (m, 4H), 7.20 (ddd, J¼7.5, 7.5, 1.3 Hz,
1
1
3
1
1
H), 7.12 (ddd, J¼7.5, 7.5, 1.0 Hz, 1H), 2.76e2.66 (m, 2H),
4.3.3. 2-n-Butyl-3-(4-methoxyphenyl)-5-methylindole (6n)
Following the general procedure, indole 6n (168 mg, 58%)
was obtained after purification by column chromatography
.71e1.59 (m, 2H), 1.33e1.21 (m, 6H), 0.87 (t, J¼6.9 Hz,
1
H). C NMR (CDCl , 75 MHz): d 137.0, 135.0, 135.0,
3
3
34.2, 133.1, 129.7, 128.2, 128.1, 126.4, 121.4, 119.7,
19.2, 112.1, 110.4, 31.5, 29.2, 28.8, 26.7, 22.5, 14.0. IR
(SiO , n-hexane/EtOAc, 30:1/25:1/15:1) as a yellow oil.
2
1
Ratio of regioisomers: 97:3 (GC). H NMR (300 MHz,
(
1
3
(
3
KBr): 3409, 3058, 2928, 2857, 1479, 1462, 1434, 1332,
CDCl ): d 7.88 (br s, 1H), 7.43e7.37 (m, 3H), 7.22
3
ꢂ1
066, 1036, 820, 741 cm . MS (EI) m/z (relative intensity)
(d, J¼8.2 Hz, 1H), 7.04e6.97 (m, 3H), 3.88 (s, 3H), 2.81
(t, J¼7.7 Hz, 2H), 2.43 (s, 3H), 1.71e1.60 (m, 2H), 1.44e
þ
11 (52) [M ], 254 (12), 240 (49), 217 (14), 205 (100), 130
1
3
4). HRMS (EI) m/z calcd for C H NCl 311.1441, found
2
1.31 (m, 2H), 0.90 (t, J¼7.3 Hz, 3H). C NMR (125 MHz,
0 22
11.1444.
CDCl ): d 157.8, 135.9, 133.4, 130.7, 129.0, 128.4, 128.0,
3
122.8, 118.5, 113.9, 113.6, 109.9, 55.3, 32.0, 26.1, 22.5,
21.5, 13.8. IR (film, CH Cl ): 3399, 2956, 2930, 2859, 2361,
4
(
.3. Representative procedure for annulation with PCy3
14) as ligand
2
2
ꢂ1
2338, 1510, 1464, 1243, 1174, 1036, 833 cm . MS (EI) m/z
þ
(relative intensity) 293 (18) [M ], 250 (8), 206 (18), 150
(35), 135 (71), 121 (100). HRMS (ESI) m/z calcd for
4
.3.1. 2-Ethyl-5-methyl-3-phenylindole (6l)
To a well-stirred solution of t-BuNH (88 mg, 1.2 mmol) in
C H NO 294.1852, found 294.1852.
20 24
2
PhMe (2 mL) was added dropwise TiCl (38 mg, 0.2 mmol).
4
After stirring for 10 min 2-chloro-4-methylaniline (142 mg,
1
The reaction mixture was stirred at 105 C for 20 h and was
thereafter allowed to cool to ambient temperature. Pd(OAc)2
.00 mmol) and alkyne 2b (130 mg, 1.00 mmol) were added.
ꢀ
4.3.4. 2-n-Hexyl-3-(3-methoxyphenyl)-5-methylindole (6o)
Following the general procedure, indole 6o (164 mg, 51%)
was obtained after purification by column chromatography
(
Bu (337 mg, 3.00 mmol), and PhMe (2 mL) were added and
22 mg, 0.10 mmol), PCy (14) (28 mg, 0.10 mmol), KO-t-
(SiO , n-hexane/EtOAc, 30:1/25:1) as a yellow oil. Ratio
3
2
1
of regioisomers: 96:4 (GC). H NMR (300 MHz, CDCl ):
3
ꢀ
the reaction was heated at 105 C for 21 h. CH Cl (10 mL)
2
d 7.90 (br s, 1H), 7.43e7.35 (m, 2H), 7.24 (d, J¼8.1 Hz,
1H), 7.09e6.98 (m, 3H), 6.89e6.86 (m, 1H), 3.86 (s, 3H),
2.84 (t, J¼6.0 Hz, 2H), 2.42 (s, 3H), 1.73e1.63 (m, 2H),
2
and aq HCl (2 M, 5 mL) were added to the cold suspension.
The separated aqueous layer was extracted with CH Cl
2
2
1
3
(
with satd aq NaHCO (10 mL) and brine (10 mL). Drying
3ꢁ10 mL), and the combined organic layers were washed
1.39e1.19 (m, 6H), 0.86 (t, J¼6.9 Hz, 3H). C NMR
(125 MHz, CDCl ): d 159.7, 137.1, 136.3, 133.4, 129.3,
3
3
with MgSO4 and purification by column chromatography
129.2, 128.1, 123.0, 122.2, 118.6, 115.2, 113.9, 111.3,
110.0, 55.2, 31.6, 29.8, 29.1, 26.4, 22.5, 21.5, 14.0. IR
(film): 3402, 2956, 2929, 2589, 2361, 1844, 1608, 1486,
(
(
n-hexane/EtOAc, 20:1/15:1) yielded 6l as a yellow oil
1
166 mg, 71%). H NMR (300 MHz, CDCl ): d 7.84 (br s,
3
ꢂ1
1
H), 7.43e7.34 (m, 5H), 7.26e7.16 (m, 2H), 6.92
1464, 1281, 1265, 1048, 871 cm . MS (EI) m/z (relative in-
þ
(
1
d, J¼8.5 Hz, 1H), 2.81 (q, J¼7.6 Hz, 2H), 2.35 (s, 3H),
tensity) 321 (100) [M ], 250 (54), 234 (6). HRMS (ESI) m/z
calcd for C H NO 322.2165, found 322.2167.
1
3
.24 (t, J¼7.6 Hz, 3H).
C NMR (75 MHz, CDCl ):
3
22 28

776
L. Ackermann et al. / Tetrahedron 64 (2008) 769e777
4
.3.5. 2-n-Butyl-3-(3-methoxyphenyl)-5-methylindole (6p)
Following the general procedure, indole 6p (163 mg, 55%)
was obtained after purification by column chromatography
SiO , n-hexane/EtOAc, 30:1/25:1/20:1) as a yellow oil.
(SiO , n-hexane/EtOAc, 50:1/30:1) as a yellow oil. Ratio
2
1
of regioisomers: 98:2 (GC). H NMR (300 MHz, CDCl ):
3
d 7.97 (br s, 1H), 7.75e7.25 (m, 6H), 7.06e7.03 (m, 1H),
2.38 (t, J¼6.6 Hz, 2H), 2.45 (s, 3H), 1.75e1.65 (m, 2H),
(
2
1
13
1.37e1.24 (m, 6H), 0.87 (t, J¼6.8 Hz, 3H). C NMR
Ratio of regioisomers: 97:3 (GC). H NMR (300 MHz,
CDCl ): d 7.90 (br s, 1H), 7.43e7.35 (m, 2H), 7.24 (d,
(125 MHz, CDCl ): d 161.4 (d, J¼244 Hz), 136.3, 133.5,
3
3
J¼8.2 Hz, 1H), 7.09e6.98 (m, 3H), 6.89e6.86 (m, 1H),
131.6, 131.6, 131.2 (d, J¼8 Hz), 129.3, 128.3, 123.2, 118.4,
115.4 (d, J¼20 Hz), 110.2, 31.6, 29.9, 29.1, 26.4, 22.6, 21.6,
3
1
.87 (s, 3H), 2.85 (t, J¼7.4 Hz, 2H), 2.43 (s, 3H), 1.72e
.63 (m, 2H), 1.44e1.34 (m, 2H), 0.90 (t, J¼7.3 Hz, 3H).
1
9
14.1. F NMR (282 MHz, CDCl ): ꢂ117.3 (tt, J¼9.0,
3
1
3
C NMR (125 MHz, CDCl ): d 159.7, 137.0, 136.2, 133.4,
3
5.0 Hz). IR (KBr): 3400, 2957, 2929, 2859, 2361, 2339,
2247, 1331, 1166, 1128, 1073, 908 cm . MS (EI) m/z (rela-
tive intensity) 309 (4) [M ], 238 (9), 113 (98), 43 (100).
HRMS (ESI) m/z calcd for C H NF 310.1966, found
310.1969.
ꢂ1
1
1
3
1
29.3, 129.2, 128.1, 123.0, 122.2, 118.6, 115.2, 113.9,
11.3, 110.0, 55.2, 32.0, 26.2, 22.5, 21.5, 13.8. IR (film):
456, 3053, 2959, 2361, 1601, 1490, 1458, 1265, 1048,
þ
2
1 25
ꢂ1
023, 896 cm . MS (EI) m/z (relative intensity) 293 (100)
þ
[M ], 250 (79), 235 (9). HRMS (ESI) m/z calcd for
C H NO 294.1852, found 294.1853.
2
0 24
4.3.9. 2-Ethyl-5,7-difluoro-3-phenylindole (6t)
Following the general procedure, indole 6t (134 mg, 52%)
was obtained after purification by column chromatography
4
.3.6. 2-n-Hexyl-3-(3-methoxyphenyl)indole (6q)
Following the general procedure, indole 6q (224 mg, 71%)
1
(SiO , n-pentane/Et O 30:1) as a yellow oil. H NMR
2 2
was obtained after purification by column chromatography
SiO2, n-hexane/EtOAc, 50:1/30:1/20:1/10:1) as
(300 MHz, CDCl ): d 8.13 (br s, 1H), 7.50e7.42 (m, 4H),
3
(
a yellow oil. H NMR (300 MHz, CDCl ): d 7.99 (br s, 1H),
1
7.37e7.32 (m, 1H), 7.11e7.07 (dd, J¼9.5, 2.2 Hz, 1H),
3
6
.76e6.68 (ddd, J¼11.7, 9.5, 2.2 Hz, 1H), 2.90 (q,
7
6
.69e7.66 (m, 1H), 7.41e7.33 (m, 2H), 7.21e7.07 (m, 4H),
.90e6.87 (m, 1H), 3.87 (s, 3H), 2.87 (t, J¼8.7 Hz, 2H), 1.75
1
3
J¼7.7 Hz, 2H), 1.35 (t, J¼7.6 Hz, 3H). C NMR (75 MHz,
CDCl ): d 157.2 (dd, J¼237, 10 Hz), 148.1 (dd, J¼237,
3
e1.65 (m, 2H), 1.41e1.25 (m, 6H), 0.87 (t, J¼6.9 Hz, 3H).
1
3
14 Hz), 139.5 (d, J¼1 Hz), 134.4 (d, J¼1 Hz), 130.5 (dd,
J¼11, 7 Hz), 129.3, 128.6, 126.4, 119.8, 115.1 (dd, J¼5,
C NMR (75 MHz, CDCl ): d 159.6, 136.8, 136.2, 135.1,
3
1
1
29.4, 127.8, 122.1, 121.5, 119.9, 118.9, 115.0, 114.2,
11.5, 110.3, 55.2, 31.6, 29.9, 29.1, 26.4, 22.5, 14.0. IR
3
1
Hz), 100.0 (dd, J¼24, 4 Hz), 96.6 (dd, J¼30, 21 Hz), 19.8,
4.0. IR (ATR): 3462, 2972, 1653, 1587, 1494, 1438, 1294,
(
1
KBr): 3465, 2956, 2928, 2856, 2361, 2336, 2252, 1601,
ꢂ1
ꢂ1
1113, 978, 701 cm . MS (EI) m/z (relative intensity) 257
(100) [M ], 242 (67), 240 (17), 222 (17), 214 (8), 200 (4).
HRMS (EI) m/z calcd for C H F N 257.1016, found
457, 1329, 1163, 1049 cm . MS (EI) m/z (relative intensity)
þ
þ
3
07 (28) [M ], 236 (24), 204 (5), 113 (75), 85 (29), 43 (100).
HRMS (ESI) m/z calcd for C H NO 308.2009, found
1
6 13 2
2
1 26
257.0994.
3
08.2010.
4
.3.7. 3-(3-Trifluoromethylphenyl)-2-n-hexyl-5-
methylindole (6r)
4
.3.10. 5-Chloro-2-ethyl-3-phenylindole (6u)
Following the general procedure, indole 6u (136 mg, 53%)
was obtained after purification by column chromatography
SiO , n-hexane/EtOAc, 30:1/20:1/5:1) as a brown oil.
Following the general procedure, indole 6r (256 mg, 71%)
was obtained after purification by column chromatography
(SiO , n-hexane/EtOAc, 50:1/30:1/25:1) as a yellow oil.
Ratio of regioisomers: 99:1 (GC). H NMR (300 MHz,
(
2
1
2
H NMR (300 MHz, CDCl ): d 8.04 (br s, 1H), 7.60 (d,
3
1
J¼1.7 Hz, 1H), 7.51e7.44 (m, 4H), 7.36e7.30 (m, 1H),
13
CDCl ): d 7.90 (br s, 1H), 7.47e7.38 (m, 3H), 7.26e7.15
3
7
.27e7.24 (m, 1H), 7.12 (dd, J¼2.0, 8.6 Hz, 1H), 2.89 (q,
(
(
(
1
1
1
2
m, 3H), 7.05e7.02 (m, 1H), 2.81 (t, J¼7.6 Hz, 2H), 2.46
J¼7.6 Hz, 2H), 1.32 (t, J¼7.5 Hz, 3H). C NMR (75 MHz,
s, 3H), 1.73e1.63 (m, 2H), 1.39e1.25 (m, 6H), 0.89
CDCl ): d 138.6, 134.7, 133.5, 129.5, 129.1, 128.6, 126.2,
3
1
3
t, J¼6.8 Hz, 3H). C NMR (125 MHz, CDCl ): d 136.8,
3
1
3
1
25.7, 121.7, 118.4, 113.8, 111.3, 19.7, 14.2. IR (KBr):
417, 3055, 2971, 2931, 2873, 2361, 2338, 1496, 1466,
311, 1065, 870 cm . MS (EI) m/z (relative intensity) 255
36.6, 133.5, 132.8, 130.4 (q, J¼31.4 Hz), 129.6, 128.9,
27.8, 126.2 (q, J¼3.7 Hz), 124.3 (q, J¼272.8 Hz), 123.4,
22.5 (q, J¼3.7 Hz), 118.1, 112.8, 110.2, 31.5, 29.8, 29.0,
ꢂ1
þ
(89) [M ], 240 (32), 205 (48), 84 (39), 56 (65), 43 (100).
HRMS (ESI) m/z calcd for C H ClN 256.0888, found
2
1
9
6.3, 22.5, 21.5, 14.0.
F NMR (282 MHz, CDCl ):
3
1
6 15
d ꢂ62.5 (s). IR (film): 3460, 3401, 3049, 2927, 2857, 2361,
56.0888.
ꢂ1
1
tive intensity) 359 (26) [M ], 288 (21), 253 (4), 159 (25).
507, 1265, 1221, 1156, 1093, 874 cm . MS (EI) m/z (rela-
þ
HRMS (ESI) m/z calcd for C H NF 360.1934, found
2
Acknowledgements
2
25
3
3
60.1933.
Support by the DFG, the Fonds der Chemischen Industrie
(Dozentenstipendium), the Dr. Otto R o¨ hm Ged a¨ chtnisstiftung,
the R o¨ mer Foundation, and the Georg-August-Universitaet
Goettingen is gratefully acknowledged.
4
.3.8. 3-(4-Fluorophenyl)-2-n-hexyl-5-methylindole (6s)
Following the general procedure, indole 6s (168 mg, 54%)
was obtained after purification by column chromatography

L. Ackermann et al. / Tetrahedron 64 (2008) 769e777
20. Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673e686.
777
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3