3-(o-Trifluoroacetamidoaryl)-1-propargylic esters: common intermediates for the palladium-catalyzed synthesis of 2-aminomethyl-, 2-vinylic, and 2-alkylindoles

Article abstract of DOI:10.1016/j.tet.2009.06.113

3-(o-Trifluoroacetamidoaryl)-1-propargylic esters have been used as common synthetic intermediates for the preparation of a variety of 3-unsubstituted 2-substituted indoles. Treating ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates unsubstituted or containing an aryl substituent at the propargylic carbon with piperazines and Pd(PPh₃)₄ in THF at 80 °C affords 2-(piperazin-1-ylmethyl)indoles in excellent yields. Good to excellent yields of 2-aminomethylindoles are also obtained with other secondary amines. Ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates bearing an alkyl substituent at the propargylic carbon and ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic acetates disubstituted at the propargylic carbon give 2-vinylic indoles with the Pd(OAc)₂/PPh₃ combination and Et₃N in THF at 80 °C. Formation of 2-vinylic indoles is quite stereoselective, generating trans vinylic derivatives, at least with the substrates that we have investigated. In the presence of formic acid, Et₃N, and Pd(PPh₃)₄ in MeCN at 80 °C, ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates afford 2-alkylindoles in good to excellent yields.

Full text of DOI:10.1016/j.tet.2009.06.113

Tetrahedron 65 (2009) 8916–8929
Contents lists available at ScienceDirect
Tetrahedron
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3-(o-Trifluoroacetamidoaryl)-1-propargylic esters: common intermediates for the
palladium-catalyzed synthesis of 2-aminomethyl-, 2-vinylic, and 2-alkylindoles
*
Ilaria Ambrogio, Sandro Cacchi , Giancarlo Fabrizi, Alessandro Prastaro
`
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Universita di Roma, P.le A. Moro 5, 00185 Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
3-(o-Trifluoroacetamidoaryl)-1-propargylic esters have been used as common synthetic intermediates
for the preparation of a variety of 3-unsubstituted 2-substituted indoles. Treating ethyl 3-(o-tri-
fluoroacetamidoaryl)-1-propargylic carbonates unsubstituted or containing an aryl substituent at the
propargylic carbon with piperazines and Pd(PPh3)4 in THF at 80 ꢀC affords 2-(piperazin-1-ylmethyl)-
indoles in excellent yields. Good to excellent yields of 2-aminomethylindoles are also obtained with
other secondary amines. Ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates bearing an alkyl
substituent at the propargylic carbon and ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic acetates di-
substituted at the propargylic carbon give 2-vinylic indoles with the Pd(OAc)2/PPh3 combination and
Et3N in THF at 80 ꢀC. Formation of 2-vinylic indoles is quite stereoselective, generating trans vinylic
derivatives, at least with the substrates that we have investigated. In the presence of formic acid, Et3N,
and Pd(PPh3)4 in MeCN at 80 ꢀC, ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates afford
2-alkylindoles in good to excellent yields.
Received 27 April 2009
Received in revised form 11 June 2009
Accepted 26 June 2009
Available online 2 July 2009
Ó 2009 Published by Elsevier Ltd.
1. Introduction
or electron-rich o-(iodo)trifluoroacetanilides. Alternatively, partic-
ularly when the preparation of ethyl 3-(o-trifluoroacetamidoaryl)-
The indole nucleus is prevalent in a vast array of biologically
active natural and unnatural compounds. In view of this, the de-
velopment of efficient and versatile methods for the construction of
this structural unit is a subject of great interest in drug discoveryand
palladium catalysis has provided an almost unique tool to develop
a wide range of synthetic strategies.1 In attempting to further extend
our palladium-catalyzed alkyne-based synthesis of indoles,2 we
observed and previously communicated that ethyl 3-(o-tri-
fluoroacetamidoaryl)-1-propargylic carbonates 13 could be used as
precursors of 2-aminomethyl-4 and 2-alkylindoles5 via trapping of
1-propargylic carbonates containing electron-poor aromatic rings
was required, they were synthesized from o-iodoanilines via
Sonogashira cross-coupling with the THP derivatives of propargylic
alcohols followed by treatment of the resultant cross-coupling
products with trifluoroacetic anhydride and deprotection and
esterification steps (Scheme 2).
R2
R3
R1
PdCl2(PPh3)2, CuI
R1
OH
R2
I
(i-Pr)2NH
R3
p-allylic palladium intermediates generated in situ with amines and
+
DMF, r.t.
NHCOCF3
formate anions, respectively. We wish at this time to report full
details on this very useful new synthetic approach to indoles, in-
cluding its extension to the preparation of 2-vinylic indoles.
OH
NHCOCF3
R2
R3
R1
OCO2Et
2. Results and discussion
ClCO2Et, DMAP
CH2Cl2
-30 °C to 0 °C
NHCOCF3
Ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates 1
were prepared from o-(iodo)trifluoroacetanilides via Sonogashira
cross-coupling with propargylic alcohols followed by an esterifica-
tion step (Scheme 1). This protocol was typically used with neutral
Scheme 1.
2.1. Synthesis of 2-aminomethylindoles
Initial studies were directed toward finding a general set of re-
action conditions that could be applied to the conversion of a wide
* Corresponding author. Tel.: þ39 06 4991 2795; fax: þ39 06 4991 2780.
E-mail address: sandro.cacchi@uniroma1.it (S. Cacchi).
0040-4020/$ – see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.06.113

I. Ambrogio et al. / Tetrahedron 65 (2009) 8916–8929
8917
was obtained at 100 ꢀC after 9 h, but still significantly lower than
with 1a.
R2
R3
PdCl2(PPh3)2, CuI
R1
OTHP
R1
R2
As observed in our previous studies on the aminopalladation/
reductive elimination route to indoles,6 the acidity of the nitrogen–
hydrogen bond was found to play a crucial role. Treatment of ethyl
3-(o-acetamidophenyl)-1-propargyl carbonate 4, containing a less
acidic nitrogen–hydrogen bond, with 4-ethylpiperazine under the
conditions shown in Table 1, entry 6 afforded a complex reaction
mixture and the indole product was formed only in trace amounts,
if any.
(i-Pr)2NH
I
R3
OTHP
+
DMF, r.t.
NH2
R2
NH2
R2
R3
OH
R3
R1
R1
(CF3CO)2O
Et3N
OTHP
p-TsOH
THF, r.t.
H2O/Me2CO
NHCOCF3
NHCOCF3
r.t.
R2
R3
OCO2Et
R1
OCO2Et
ClCO2Et, DMAP
NHCOMe
CH2Cl2
-30 °C to 0 °C
4
NHCOCF3
Scheme 2.
Interestingly, the reaction gives excellent results using a mono-
dentate phosphine ligand such as PPh3, although it has been
reported that p-propargylic palladium complexes (which are likely
range of ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbon-
ates into the corresponding 2-aminomethylindoles. Compound 1a
and N-ethylpiperazine 2a were selected as the model system. Re-
actions were carried out at 80 ꢀC and the following reaction vari-
ables were closely examined: the source of Pd(0) species, the nature
of the ligands, and solvents. Some results of our screening study are
summarized in Table 1.
intermediates in this chemistry, vide infra) are formed in a more
stable manner in the presence of bidentate ligands, particularly
with dppe,7 and that the best ligands for the palladium-catalyzed
reaction of propargylic halides8 and carbonates9 with soft nucleo-
philes are the bidentate ligands.
Using the optimized conditions [Pd(PPh3)4, THF, 80 ꢀC], we
next explored the scope and generality of the reaction. As in-
dicated in Table 2, a large number of 2-(piperazin-1-ylmethyl)-
indoles were prepared in excellent yields. Piperazines were
selected as nitrogen nucleophiles because they are (as indoles
themselves) privileged structures10 and 2-(piperazin-1-ylmethyl)-
indoles, which exhibit important biological activities, have attrac-
ted considerable attention in organic, medical, and pharmaceutical
chemistry.11 Only with 2j (Table 2, entry 10) the corresponding
indole product was isolated in moderate yield, very likely because
of the low nucleophilicity of the nitrogen derivative due to steric
effects.
Table 1
Optimization of reaction conditionsa
OCO2Et
Et
N
N
H
N
NHCOCF3
N
H
NEt
1a
2a
3a
Entry
Precatalyst
Solvent
Time (h)
Yield % of 3ab
The reaction can be applied to other secondary amines and
yields are usually good to high (Table 3, entries 1–3). The mod-
erate yield obtained with diisopropylamine (Table 3, entry 4) was
attributed again to the involvement of steric effects. With pri-
mary amines the efficiency of the reaction is flawed by the oc-
currence of side reactions. For example, with benzylamine and
butylamine complex reaction mixtures of unidentified products
were obtained, presumably containing indole derivatives gener-
ated via N-allylation of the initially formed 2-amino-
methylindoles.
The extension of the reaction to propargylic carbonates
substituted at the propargylic carbon was next examined. The
phenyl-containing propargylic carbonate 1b was initially used and
its treatment with a variety of secondary amines under standard
conditions afforded the desired products in moderate to excellent
yields (Table 4). Interestingly, moderate to high yields were in this
case obtained with primary amines as well (Table 4, entries 7 and
8). Very likely, steric effects due to the presence of the phenyl group
may play a role in preventing 2-aminomethylindoles from un-
dergoing a subsequent N-allylation reaction.
1
2
3
4
5
6
7
8
Pd(OAc)2/PPh3
Pd2(dba)3/PPh3
PdCl2(2-furyl)2
Pd2(dba)3/dppe
Pd2(dba)3/dppf
Pd(PPh3)4
THF
THF
THF
THF
THF
THF
MeCN
DMF
6
6
24
24
6
1.5
6
6
52c
58d
33
50e
85e
91
Pd(PPh3)4
Pd(PPh3)4
57
54
a
Unless otherwise stated, reactions were carried out on a 0.159 mmol scale in
1 mL of solvent under argon at 80 ꢀC by using 1 equiv of 1a, 3 equiv of 2a, 0.05 equiv
of [Pd].
b
Yields are given for isolated products.
0.2 equiv of PPh3.
0.1 of PPh3.
0.05 equiv of bidentate phosphine ligand.
c
d
e
The desired indole derivative was isolated in low to moderate
yields using Pd(OAc)2 and Pd2(dba)3 with PPh3 as ligand (Table 1,
entries 1 and 2) or PdCl2(2-furyl)2 (Table 1, entries 3) in THF. The
Pd2(dba)3/dppe [1,3-bis(diphenylphosphino)ethane] combination
gave a similar yield (Table 1, entry 4). Switching to Pd2(dba)3 and
dppf [1,10-bis(diphenylphoshino)ferrocene] allowed for the iso-
lation of 3a in high yield (Table 1, entry 5) but the best result in
terms of yield and reaction time was obtained with Pd(PPh3)4 in
THF (Table 1, entry 6). Lower yields and longer reaction times were
observed when the same precatalyst system was used in MeCN or
DMF (Table 1, entries 7 and 8) as well as when the corresponding
less reactive propargylic acetate was used as the starting alkyne
[50% yield; Pd(PPh3)4, THF, 80 ꢀC, 24 h]. A slightly higher yield (67%)
However, when the reaction was extended to the ethyl de-
rivative 1c no formation of the corresponding 2-amino-
methylindole was observed upon treatment with 2a, the main
product being 2-(propen-1-yl)indole 5a, isolated in 70% yield as an
approximately 80:20 E/Z mixture (Scheme 3). Apparently, the cor-
responding
p-allylic palladium intermediate (vide infra), contain-
ing an adjacent carbon–hydrogen bond, is more prone to undergo
an elimination reaction12 than a nucleophilic attack.

8918
I. Ambrogio et al. / Tetrahedron 65 (2009) 8916–8929
Table 2
Table 2 (continued)
Palladium-catalyzed synthesis of 2-(piperazin-1-ylmethyl)indoles 3 from ethyl 3-
Entry
15
Piperazine 2
Time (h)
Yield % of 2b
3o (92)
(o-trifluoroacetamidophenyl)-1-propargyl carbonate 1a and piperazines 2a
Ph
Entry
1
Piperazine 2
Time (h)
1.5
Yield % of 2b
3a (91)
HN
N
2o
2p
8
2a
2b
HN
N
Et
Cl
Cl
CO2Et
2
3
2
3b (96)
3c (80)
16
20
3p (88)
HN
N
HN
HN
N
N
Cl
Cl
a
Reactions were carried out on a 0.159 mmol scale in 1 mL of THF under argon at
80 ꢀC by using 1 equiv of 1a, 3 equiv of 2, 0.05 equiv of Pd(PPh3)4.
b
Yields are given for isolated products.
2c
24
Cl
Table 3
NC
The palladium-catalyzed reaction of ethyl 3-(o-trifluoroacetamidophenyl)-1-prop-
argyl carbonate 1a with secondary aminesa
4
5
2d
2e
3
6
3d (98)
3e (96)
HN
N
Entry
1
Amine
HN
Time (h)
1
Yield % of 3b
3q (94)c
HN
N
F
2
1
3r (98)
HN
O
HN
N
F
6
7
2f
6
3f (98)
3g (97)
3
4
Et2NH
(i-Pr)2NH
2
4
3s (60)d
3t (45)
a
Unless otherwise stated, reactions were carried out on a 0.159 mmol scale in
1 mL of THF under argon at 80 ꢀC by using 1 equiv of 1a, 3 equiv of secondary amine,
0.05 equiv of Pd(PPh3)4.
F
2g
2.5
HN
HN
N
b
Yields are given for isolated products.
c
The indole product 3q was isolated in 84% yield in the presence of 0.0125 equiv
of Pd2(dba)3 and 0.05 equiv of PPh3 after 6 h and in 73% yield with 0.025 equiv of
Pd2(dba)3, omitting PPh3, after 24 h.
N
N
d
With 5 equiv of amine.
8
2h
3
3h (92)
Cl
Br
Table 4
The palladium-catalyzed synthesis of 2-aminomethylindoles from of 1ba
HN
9
2i
2j
3
6
3i (94)
3j (58)
Ph
OCO2Et
Ph
HNR1R2
Ph
HN
NR1R2
N
H
NHCOCF3
10
N Me
1b
2
3
Entry
1
Amine
Time (h)
1
Yield % of 3b
3u (92)
HN
N
11
12
2k
2l
4
3k (85)
3l (78)
HN
NEt
Me
Cl
2
3
4
2
1
1
3v (90)
3w (94)
3x (98)
HN
NCO2Et
HN
N
F
12
HN
HN
N
HN
O
13
14
2m
4
4
3m (81)
OMe
Me
5
6
7
8
Et2NH
2
4
4
5
3y (60)
3z (45)
3za (54)
3zb (80)
(i-Pr)2NH
NH2CH2Ph
n-NH2Bu
HN
N
Me
2n
3n (80)
a
Reactions were carried out on a 0.159 mmol scale in 2 mL of THF under argon at
80 ꢀC by using 1 equiv of 1b, 3 equiv of 2, 0.05 equiv of Pd(PPh3)4.
Me
b
Yields are given for isolated products.

I. Ambrogio et al. / Tetrahedron 65 (2009) 8916–8929
8919
The results obtained in the synthesis of 2-vinylic indoles from
ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates and
acetates are summarized in Table 6. The process is quite general and
a variety of substituents can be accommodated both on the aniline
fragment and on the propargylic carbon. Interestingly, high yields of
2-vinylic indoles were obtained even with propargylic esters bear-
ing electron-withdrawing substituents on the anilide fragment
(Table 6, entries 16–18), although electron-withdrawing sub-
stituents might be expected to decrease the nucleophilicity of the
nitrogen atom and consequently hamper the cyclization step. Most
noteworthy from the synthetic viewpoint is the essentially 100%
stereoselective formation of trans vinylic derivatives under the
‘optimal’ conditions used, at least with the substrates that we have
investigated (Table 6, entries 1, 3, 7).
OCO2Et
HN
Pd(PPh3)4
NEt
THF, 80 °C
1 h
N
H
NHCOCF3
1c
5a (70%)
E/Z = 80:20
Scheme 3.
2.2. Synthesis of 2-vinylic indoles
Although we did not obtain the desired indole derivative, we were
attracted by the possibility to develop this reaction into a general
method for the synthesis of 2-vinylic indoles (Scheme 4). These
compounds are useful synthetic intermediates.13 The 2-vinylic indole
motif is also diffused among molecules exhibiting interesting bio-
logical activities.14 Therefore, we decided to optimize the conditions
of this type of reaction.
2.3. Synthesis of 2-alkylindoles
During our early studies on this chemistry,4 we had the occasion
to observe that subjecting ethyl 3-(o-trifluoroacetamidoaryl)-1-
propargylic carbonates to formate anions in the presence of a pal-
ladium catalyst could form 2-alkylindoles. Consequently, we
became interested even in the utilization of these substrates as
precursors of free NH 3-unsubstituted 2-alkylindoles 6 (Scheme 5).
Despite the interest for 3-unsubstituted 2-alkylindoles as synthetic
intermediates,15 the number of available routes to this class of
compounds is indeed quite limited16 and the development of new
straightforward procedures is desirable.
R2
R3
R1
R1
R2
R3
OCO2Et
Pd cat
N
H
NHCOCF3
1
5
Scheme 4.
Some of the results of our screening study using 1a as the model
system are summarized in Table 7. Utilization of HCOOH in the
presence of Et3N proved to be superior to HCOOK (Table 7, compare
entry 1 with entry 2) and, as found in the synthesis of 2-amino-
methylindoles, Pd(PPh3)4 gave better results than the Pd(OAc)2/
(PPh3)2 combination (Table 7, compare entry 3 with entry 4). Under
a variety of conditions the main byproduct was the N-formylindole
7a, which in some cases was isolated in significant yields (Table 7,
entries 4–6).
Using the methyl derivative 1d as the model system, a few rep-
resentative bases and palladium precatalysts were tested (Table 5).
The best result was obtained with Et3N in the presence of 0.05 equiv
of Pd(OAc)2 and 0.2 equiv of PPh3 (Table 5, entry). Interestingly, the
Pd(OAc)2/PPh3 combination gave excellent results in this reaction
whereas Pd(PPh3)4 was found to be superior in the reaction of ethyl
3-(o-trifluoroacetamidophenyl)-1-propargyicl carbonate 1a with
N-ethylpiperazine 2a.
Table 5
Optimization of reaction conditionsa
Me
N
CHO
OCO2Et
Pd cat, base
7a
THF, 80 °C
N
NHCOCF3
H
1d
5b
The highest yield of 6a was obtained using Pd(PPh3)4, HCOOH,
and Et3N in MeCN (Table 8, entry 8) and these conditions were
applied when the synthetic scope of the reaction was examined. As
shown by the results listed inTable 8, 2-alkylindoles were isolated in
Entry
Precatalyst
Base
Time (h)
Yield % of 5bb
1
2
3
4
5
6
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2/(PPh3)2
Pd(OAc)2/(PPh3)2
Pd(OAc)2/(PPh3)2
d
24
1
4
2
0.5
12
d
K2CO3
Et3N
K2CO3
Et3N
40
53
70
90
80
good to high yields with
a wide range of ethyl 3-(o-tri-
fluoroacetamidophenyl)-1-propargylic carbonates. The presence of
one alkyl or aryl substituent on the propargylic carbon is tolerated
(Table 8, entries 2–5, 14–18).
Styrene oxide
a
With propargylic esters containing two alkyl groups on the
propargylic carbon, however, a competition between the reduction
to 2-alkylindoles and the elimination to 2-vinylic indoles is observed.
The reaction of the model compound 1r under standard con-
ditions gave a 91% yield of an approximately 88:12 mixture of 6u
and 5p (Scheme 6). Changing some reaction parameters in the at-
tempt to suppress the formation of the vinylic product (mixtures of
these indole derivatives are difficult to separate) met with failure.
Worse results were usually obtained both in terms of yields and
selectivity. For example, using n-Bu4NO2CH as reducing agent in the
absence of tertiary amines (they might favor the formation of the
vinylic product through a base promoted elimination of the ele-
ments HPdX17) gave a complex mixture of products that we have
not identified. With the Pd2(dba)3/dppb precatalyst system,
Reactions were carried out on a 0.32 mmol scale in 2 mL of THF under argon at
80 ꢀC by using 1 equiv of 1d, 0.05 equiv of [Pd], 0.2 equiv of PPh3 (when added), and
3 equiv of base.
b
Yields are given for isolated products.
The conditions shown in Table 5, entry 5 were then used when
the procedure was extended to include other propargylic substrates
containing one and two alkyl groups on the propargylic carbon.
With the latter, propargylic acetates were needed as the starting
material. Indeed, the preparation of carbonates via esterification of
tertiary propargylic alcohols with ethyl chlorocarbonate and a va-
riety of amine bases in CH2Cl2 failed to give the desired products.
Good results were instead obtained by using acetic anhydride and
4-dimethylaminopyridine (DMAP).

8920
I. Ambrogio et al. / Tetrahedron 65 (2009) 8916–8929
Table 6
Palladium-catalyzed heterocyclization of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargylic esters 1 to 2-vinylic indoles 5a
Entry
Ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic esters 1
Time (h)
2-Vinylic indole 5b
Yieldc
95
%
OCO2Et
1
1c
1
5a
5b
5c
N
H
NHCOCF3
OCO2Et
2
1d
0.5
90
83
63
82
N
H
NHCOCF3
3b
1e
1
OCO2Et
N
H
NHCOCF3
OCO2Et
Me
F
Me
F
4
1f
2
5d
5e
N
H
NHCOCF3
OCO2Et
5
1g
2
N
H
F
NHCOCF3
F
OCO2Et
6
7
1h
1
5f
76
85
N
H
N
H
NHCOCF3
50:50
Ph
Me
Ph
OCO2Et
1i
0.5
5g
Me
Me
N
H
NHCOCF3
Me
OCO2Et
8
1j
1
8
7
5h
5i
87
77
75
N
H
NHCOCF3
Me
Me
9
1k
1l
OAc
N
H
NHCOCF3
Me
10
5j
OAc
Me
N
H
NHCOCF3
Cl
11
1m
7
5k
85
OAc
Cl
N
H
NHCOCF3

I. Ambrogio et al. / Tetrahedron 65 (2009) 8916–8929
8921
Table 6 (continued )
Entry
Ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic esters 1
Time (h)
6
2-Vinylic indole 5b
Yieldc
%
Ph
OAc
12
1n
5l
78
N
H
Ph
NHCOCF3
Cl
OAc
Cl
13
14
15
16
17
1o
1p
1q
1r
1s
2
3
1
1
1
5m
5n
5o
5p
5q
85
84
80
91
83
N
H
NHCOCF3
Me
OAc
Me
c
N
H
NHCOCF3
OAc
N
H
NHCOCF3
MeCO
NC
OAc
MeCO
NC
N
H
NHCOCF3
OAc
N
H
NHCOCF3
MeO2C
OAc
MeO2C
18
19
1t
2
1
5r
5s
87
68
N
H
NHCOCF3
Ph
F
OAc
F
1u
N
Ph
H
NHCOCF3
a
b
c
Reactions were carried out on a 0.32 mmol scale in 2 mL of THF under argon at 80 ꢀC by using 1 equiv of 1, 3 equiv of Et3N, 0.05 equiv of Pd(OAc)2, and 0.2 equiv of PPh3.
Single E-isomers were obtained when not otherwise stated.
Yields are given for isolated products.
OCOOEt
R2
a quantitative conversion of 1r was observed: 6u and 5p were
isolated in 99% yield. However, a dramatic worsening of the se-
lectivity led to an approximately 55:45 mixture.
R1
R1
Pd cat, HCOO BH
R2
A possible solution to the reduction/elimination competition
observed with this type of propargylic esters is converting them into
2-vinylic indoles, a reaction that usually occurs in high to excellent
yields (Table 6), and reducing the carbon–carbon double bond by
N
H
NHCOCF3
1
6
Scheme 5.
Table 7
Palladium precatalysts, formate anions, solvents, and temperature in the cyclization of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargyl carbonate 1a to 2-methylindole 6aa
Entry
Palladium precatalyst
Reducing agent
Base
Solvent
Time (h)
6a yieldb
%
7a yieldb
%
c
1
2
3
4
5
6
7
8
9
Pd(OAc)2/PPh3
HCOOK
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
d
DMF
DMF
THF
THF
Dioxane
Toluene
Dioxanee
MeCN
MeCN
4
4
3
1.5
1
3
1
1
1
24
38
48
62
56
48
69
91
84
d
7
5
12
10
19
8
5
d
d
Pd(OAc)2/PPh3
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
d
Pd(OAc)2/PPh3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3/dppe
a
Reactions were conducted under argon at 80 ꢀC on a 0.317 mmol scale using 1 equiv of 1a, 2 equiv of HCOOH, 3 equiv of Et3N in 2 mL of solvent.
b
c
Yields are given for isolated products.
Pd(OAc)2:PPh3¼1:4.
d
e
Pd(OAc)2:PPh3¼1:2.
In the presence of 1 equiv of H2O.

8922
I. Ambrogio et al. / Tetrahedron 65 (2009) 8916–8929
Table 8
Palladium-catalyzed reductive heterocyclization of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargylic carbonates 1 to 2-alkylindoles 6a
Entry
1
Ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonate 1
Time (h)
2-Alkylindole 6
Yieldb
91
%
OCO2Et
Me
1a
1
6a
6b
N
H
NHCOCF3
Ph
OCO2Et
2
3
4
5
1b
3
2
1
1
75
70
70
67
N
H
Ph
NHCOCF3
Et
OCO2Et
n-Pr
1c
6c
6d
6e
N
H
NHCOCF3
Me
OCO2Et
Et
1d
N
H
NHCOCF3
n-Pr
OCO2Et
n-Bu
1e
N
H
NHCOCF3
OCO2Et
Me
Me
Me
6
7
1w
1
6f
99
80
N
H
NHCOCF3
Me
Me
OCO2Et
Me
Me
Me
Me
Me
1x
0.5
6g
N
H
NHCOCF3
OCO2Et
Me
8
9
1y
2
2
6h
6i
78
51
N
H
NHCOCF3
NO2
NO2
OCO2Et
Me
Me
Me
Me
1z
N
H
NHCOCF3
Cl
Cl
Ph
OCO2Et
Me
10
1aa
1
6j
50
N
Ph
H
Me
NHCOCF3
Me
Cl
F
OCO2Et
Cl
F
Me
Me
11
12
1ab
1ac
0.5
6k
6l
60
65
N
H
NHCOCF3
OCO2Et
1
N
H
NHCOCF3
Me
Me

I. Ambrogio et al. / Tetrahedron 65 (2009) 8916–8929
8923
Table 8 (continued )
Entry
Ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonate 1
Time (h)
2-Alkylindole 6
Yieldb
%
OCO2Et
Cl
Cl
Me
13
1ad
1
6m
86
N
H
NHCOCF3
CF3
CF3
MeO
OCO2Et
14
1ae
1
6n
75
N
H
OMe
NHCOCF3
OMe
N
H
15
1af
1
6o
70
OCO2Et
OMe
NHCOCF3
F
N
H
16
1ag
1
6p
85
OCO2Et
F
NHCOCF3
OMe
Me
OCO2Et
17
1ah
2
6q
72
N
Me
H
OMe
Me
NHCOCF3
Me
MeO
Cl
OCO2Et
Cl
18
1ai
0.5
6r
85
N
H
OMe
CF3
O
NHCOCF3
CF3
O
OCO2Et
Me
19
Me
1aj
0.66
6s
6t
73
70
Me
N
H
NHCOCF3
O
O
OCO2Et
MeO
20
MeO
1ak
1
Me
N
NHCOCF3
H
a
Reactions were conducted under argon at 80 ꢀC on a 0.2–0.3 mmol scale using 1 equiv of 1, 2 equiv of HCOOH, 3 equiv of Et3N in 2 mL of MeCN.
Yields are given for isolated products.
b

8924
I. Ambrogio et al. / Tetrahedron 65 (2009) 8916–8929
a SN20 reaction), affords the
would be in equilibrium with the
s
-allenylic palladium complex 8 which
AcO
Me
Me
p-propargylic palladium in-
Pd(PPh3)4
termediate 9.18 The intramolecular nucleophilic attack of the nitrogen
at the central carbon of the allenylic/propargylic palladium com-
plex3,19,20 generates the carbene 10, which is subsequently pro-
HCOOH, Et3N
MeCN, 80 °C, 10 min
NHCOCF3
1r
tonated to give the p-allylic palladium complex 11. In the presence of
Me
Me
formic acid and triethylamine, this intermediate is converted into the
formate derivative 12 from which the 2-alkylindole product 6 is
formed by concerted decarboxylation and hydride transfer to one of
N
H
N
H
Me
5p
6u
88:12
(91%)
the allylic termini.21 With primaryand secondaryamines the
p-allylic
palladium complex 11 undergoes a regioselective intermolecular
nucleophilic attack of the nitrogen nucleophile at the exocyclic allylic
Scheme 6.
terminus to afford the 2-aminomethylindole 3. If the p-allylic palla-
palladium-catalyzed hydrogenation. To make this overall approach
more attractive from a synthetic standpoint, we explored a process
that would omit the isolation of 2-vinylic indole intermediates.
After some experimentation, we were pleased to find that excellent
results could be obtained treating 1r with palladium on charcoal in
the presence of PPh3, evaporating the volatile material after com-
pletion of the indole formation process (no 2-alkylindole formation
was observed when the evaporation step was omitted), and adding
ethanol and a hydrogen atmosphere (balloon). Under these condi-
tions, 6u was prepared in 99% overall isolated yield (Scheme 7).
dium complex 11 is unable to undergo a nucleophilic attack by the
nitrogen nucleophile, an elimination reaction can take place and
a 2-vinylic indole 5 is formed.
3. Conclusions
In summary, we have developed a convenient straightforward
approach for the construction of the functionalized pyrrole ring in-
corporated into the indole system from 3-(o-trifluoroacetamidoaryl)-
1-propargylicesters.Inparticular, thesecompoundshavebeenshown
to be useful common synthetic intermediates for the preparation of
a variety of 3-unsubstituted 2-substituted indoles. Depending on re-
action conditions and the substitution pattern, they can be converted
into 2-aminomethylindoles, 2-vinylic indoles, and 2-alkylindoles
usually in good to excellent yields.
AcO
Me
1. Pd/C, PPh3, THF, 110 °C, overnight
Me
Me
Me
2. EtOH, H2, room temperature, 2 h
N
H
NHCOCF3
6r (99%)
1r
4. Experimental
4.1. General
Scheme 7.
Although the mechanistic details of this new approach to the
construction of the indole skeleton are not clear, a possible rationale
considers the basic steps described in Scheme 8. The initial reaction of
the palladium complex with the starting propargylic derivative (via
Melting points were determined with a Bu¨chi apparatus and are
uncorrected. All of the reagents and solvents are commercially
available and were used as purchased, without further purification.
R1 R2
R3
OCO2Et
N R4
R1
1
R2
N
H
NHCOCF3
3
EtOCOCF3
CO2
R3
Pd(0)
N R4
EtO
EtOH
H
Pd
Pd
R1
Pd
R1
H
R1
R2
R1
R2
COCF3
N
R2
N
R2
COCF3
N
H
N
COCF3
8
9
11
5
Pd
R1
R2
OCOH
Pd
R1
EtO
N
EtOH
10
COCF3
([H+] with HCO2H)
R2
N
12
EtOH
COCF3
CF3COOEt, CO2
R1
R2
N
H
6
Scheme 8.

I. Ambrogio et al. / Tetrahedron 65 (2009) 8916–8929
8925
Compounds 1a and 1b, 2-vinylic indoles 5, and 2-alkylindoles 6
were purified on axially compressed columns, packed with SiO2
25–40 mm (Macherey Nagel), connected to a Gilson solvent delivery
washed twice with a saturated NaHCO3 solution, dried over Na2SO4
and concentrated under reduced pressure. The final crude mixture
was dissolved in 7 mL of CH2Cl2, Et3N (10.3 mmol, 1.427 mL) was
added and, subsequenty, ethyl chloroformate (8.22 mmol, 0.78 mL)
was added dropwise at 0 ꢀC. The resulting solution was stirred at
room temperature for 2 h. Then, the reaction mixture was diluted
with diethyl ether, washed twice with a saturated NaCl solution,
dried over Na2SO4 and concentrated under reduced pressure. The
residue was purified by chromatography (SiO2, 140 g; n-hexane/
ethyl acetate 90/10 v/v) to give 1.44 g (78% yield) of 1b: mp: 89–
system and to a Gilson refractive index detector, and eluting with
n-hexane/AcOEt mixtures. 2-Aminomethylindoles were purified by
flash chromatography, using basic Al2O3 Brockmann activity II
(Fluka) as stationary phase, eluting with n-hexane/AcOEt mixtures.
1H NMR (400.13 MHz) and 13C NMR (100.6 MHz) and 19F NMR
(376.5 MHz) spectra were recorded with a Bru¨ker Avance 400
spectrometer. Infrared (IR) spectra were recorded on a JASCO FT/IR-
430 spectrophotometer. Mass spectra were determined with
a QP2010 Gas Chromatograph Mass spectrometer (EI ion source).
91 ꢀC; 1H NMR (CDCl3)
d
8.69 (br s, 1H), 8.35 (d, J¼8.3 Hz, 1H), 7.50–
7.40 (m, 2H), 7.19 (t, J¼7.6 Hz, 1H), 4.96 (s, 2H), 2.15 (s, 3H); 13C NMR
(CDCl3)
d
170.1, 154.6 (q, J¼37.7 Hz), 136.7, 132.1, 130.4, 125.5, 119.9,
4.2. Preparation of (1a)
113.3 (q, J¼288.8 Hz), 112.4, 91.9, 80.5, 52.3, 20.6; 19F NMR (CDCl3)
d
ꢁ75.8; IR (KBr): 3319, 2987, 1748, 1713, 1379 cmꢁ1. Anal. Calcd for
o-Iodoaniline (1.50 g, 6.85 mmol), PdCl2(PPh3)2 (0.072 g,
0.103 mmol), and CuI (0.020 g, 0.103 mmol) were added to 2.5 mL
of DMF and 5.0 mL of Et2NH and the mixture was stirred under
argon for 15 min. Then, tetrahydro-2-(2-propynyloxy)-2H-pyran
(1.15 g, 1.15 mL, 8.22 mmol) was added dropwise in 5 min and the
resulting reaction mixture was stirred at 60 ꢀC for 12 h. After
cooling, the reaction mixture was diluted with diethyl ether,
washed twice with NH4Cl solution, dried over Na2SO4 and con-
centrated under reduced pressure. The crude mixture was dis-
solved in 10 mL of THF containing Et3N (6.85 mmol, 0.95 mL) and
cooled at 0 ꢀC. Then, trifluoroacetic anhydride (13.7 mmol, 1.93 mL)
was added dropwise in 10 min and the resultant solution was
stirred at room temperature for 2 h. After this time, the solution
was diluted with diethyl ether, washed twice with a saturated
NaHCO3 solution, dried over Na2SO4 and concentrated under re-
duced pressure. The residue was dissolved in 12 mL of an acetone/
water 1:1 solution and p-toluensulfonic acid hydrate (1.30 g,
6.85 mmol) was added. The resulting solution was heated at 40 ꢀC
and stirred for 6 h. After cooling, the reaction mixture was diluted
with diethyl ether, washed twice with NaHCO3 solution, dried over
Na2SO4 and concentrated under reduced pressure. The final crude
mixture was dissolved in 7 mL of CH2Cl2, Et3N (10.3 mmol,
1.427 mL) was added and, subsequently, ethyl chloroformate
(8.22 mmol, 0.78 mL) was added dropwise at 0 ꢀC. The resulting
solution was stirred at room temperature for 2 h. Then, the reaction
mixture was diluted with diethyl ether, washed twice with a satu-
rated NaCl solution, dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by chromatography
(SiO2, 140 g; n-hexane/ethyl acetate 90/10 v/v) to give 1.73 g (80%
C13H10F3NO3: C, 54.74; H, 3.53; N, 4.91. Found: C, 54.59; H, 3.51; N,
4.88.
4.4. Typical procedure for the preparation of 2-
(aminomethyl)indoles
A Carousel Tube Reactor (Radley Discovery), equipped with
a magnetic stirrer, was charged with 1a (0.050 g, 0.159 mmol),
N-ethylpiperazine (0.055 g, 0.477 mmol), and Pd(PPh3)4 (0.009 g,
0.00795 mmol) in 1.0 mL of dry THF under argon. The mixture was
warmed at 80 ꢀC and stirred for 1.5 h. After cooling, the reaction
mixture was dried under reduced pressure and the residue was
purified by flash chromatography (Al2O3, 50 g; n-hexane/ethyl ac-
etate 70/30 v/v) to give 0.035 g of 3a: 90% yield; oil; 1H NMR (CDCl3)
d
8.64 (br s, 1H), 7.56 (d, J¼8.3 Hz, 1H), 7.33 (d, J¼8.3 Hz, 1H), 7.16–
7.07 (m, 2H), 6.37 (s, 1H), 3.67 (s, 2H), 2.54–2.41 (m, 10H), 1.09 (t,
J¼8.3 Hz, 3H); 13C NMR (CDCl3)
d 136.2, 135.8, 128.4, 121.6, 120.2,
119.6, 110.7, 101.7, 55.9, 53.3, 52.8, 52.3, 12.0; IR (neat): 3404, 2935,
2816, 1454 cmꢁ1. Anal. Calcd for C15H21N3: C, 74.03; H, 8.70; N,
17.27. Found: C, 74.01; H, 8.68; N, 17.25.
4.4.1. 2-[(4-Ethylpiperazin-1-yl)(phenyl)methyl]-1H-indole (3u)
92% yield; mp: 107.3–10.8.6 ꢀC; 1H NMR (CDCl3)
d 8.53 (br s, 1H),
7.56 (d, J¼8.0 Hz, 1H), 7.48 (d, J¼8.0 Hz, 2H), 7.36 (m, 3H), 7.28 (m,
1H), 7.17 (m, 1H), 7.09 (m, 1H), 6.41 (s, 1H), 4.66 (s, 1H), 2.48 (m,
10H), 1.13 (s, 3H); 13C NMR (CDCl3)
d 139.1, 139.0, 136.0, 128.5, 128.5,
128.4, 127.6, 121.6, 120.4, 119.7, 110.8, 101.6, 69.2, 53.2, 52.3, 51.2,
12.0; IR (KBr): 3405, 3058, 2967, 2811, 1683, 1600, 1454 cmꢁ1. Anal.
Calcd for C21H25N3: C, 78.96; H, 7.89; N, 13.15. Found: C, 78.92; H,
7.83; N, 13.10.
overall yield) of 1a: mp: 69–70 ꢀC; 1H NMR (CDCl3)
d 8.73 (br s, 1H),
8.36 (d, J¼8.3 Hz, 1H), 7.51–7.44 (m, 2H), 7.20 (t, J¼7.6 Hz, 1H), 5.01
(s, 2H), 4.27 (q, J¼7.1 Hz, 2H),1.35 (t, J¼7.1 Hz, 3H); 13C NMR (CDCl3)
4.4.2. 2-[(4-Ethoxycarbonylpiperazin-1-yl)(phenyl)methyl]-
d
154.7 (q, J¼37.6 Hz),154.6,136.8,132.3,130.5,125.5,119.9,115.6 (q,
1H-indole (3v)
J¼288.8 Hz), 112.2, 91.3, 81.1, 64.8, 55.4, 14.3; 19F NMR (CDCl3)
90% yield; mp: 159.0–160.3 ꢀC; 1H NMR (CDCl3)
d 8.56 (br s, 1H),
d
ꢁ75.8; IR (KBr): 3319, 2987, 1748, 1713, 1379 cmꢁ1; Anal. Calcd for
7.56 (d, J¼8.0 Hz, 1H), 7.48 (d, J¼8.0 Hz, 2H), 7.38 (m, 4H), 7.28 (m,
C14H12F3NO4: C, 53.34; H, 3.84; N, 4.44. Found: C, 53.21; H, 3.85; N,
4.40.
1H), 7.18 (m, 1H), 7.11 (m, 1H), 6.42 (s, 1H), 4.68 (s, 1H), 4.13 (s, 2H),
3.35 (m, 4H), 2.42 (m, 4H), 1.33 (s, 3H); 13C NMR (CDCl3)
d 155.5,
138.7, 138.4, 136.2, 128.7, 128.5, 128.3, 127.8, 121.8, 120.4, 119.8,
110.9, 101.9, 69.2, 61.4, 51.0, 43.9, 51.2, 12.0; IR (KBr): 3413, 2919,
2362, 1683, 1600, 1455 cmꢁ1. Anal. Calcd for C22H25N3O3: C, 72.70;
H, 6.93; N, 11.56. Found: C, 72.64; H, 6.87; N, 11.50.
4.3. Preparation of (1b)
o-Iodoaniline (1.50 g, 6.85 mmol), PdCl2(PPh3)2 (0.072 g,
0.103 mmol), and CuI (0.020 g, 0.103 mmol) were added to 2.5 mL of
DMF and 5.0 mL of Et2NH and the mixture was stirred under argon
for 15 min. Then, 1-phenylprop-2-yn-1-ol (1.08 g, 8.22 mmol) was
added dropwise and the resulting reaction mixture was stirred at
room temperature for 6 h. After this time, the reaction mixture was
diluted with diethyl ether, washed twice with NH4Cl solution, dried
over Na2SO4 and concentrated under reduced pressure. Then, tri-
fluoroacetic anhydride (13.7 mmol,1.93 mL) was added dropwise in
10 min and the resultant solution was stirred at room temperature
for 2 h. After this time, the solution was diluted with diethyl ether,
4.4.3. 2-[(Butylamino)(phenyl)methyl]-1H-indole (3zb)
80% yield; oil; 1H NMR (CDCl3)
d
8.62 (br s, 1H), 7.56 (d, J¼8.0 Hz,
1H), 7.46 (d, J¼8.0 Hz, 2H), 7.34 (m, 4H), 7.18 (m, 1H), 7.10 (m, 1H),
6.33 (s, 1H), 5.06 (s, 1H), 3.38 (m, 1H), 2.65 (m, 2H), 1.55 (m, 4H),
0.93 (s, 3H); 13C NMR (CDCl3)
d 142.3, 135.7, 128.6, 128.5, 127.6,
127.3, 121.5, 120.3, 119.6, 110.8, 100.2, 61.5, 47.7, 32.3, 20.4, 13.6; IR
(neat): 3399, 3058, 2958, 2929, 2362, 1712, 1681, 1455 cmꢁ1. Anal.
Calcd for C19H22N2: C, 81.97; H, 7.97; N, 10.06. Found: C, 81.93; H,
7.94; N, 10.00.

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I. Ambrogio et al. / Tetrahedron 65 (2009) 8916–8929
4.5. Typical procedure for the cyclization of ethyl
3-(o-trifluoroacetamidoaryl)-1-propargylic
carbonates (1) to 2-vinylic indoles (5)
4.5.5. (E)-2-(Cyclohex-3-enylidenemethyl)-1H-indole and
(Z)-2-(cyclohex-3-enylidenemethyl)-1H-indole (5f)
76% yield; oil; 1H NMR (CDCl3)
1H), 7.34 (d, J¼8.0 Hz, 1H), 7.17 (m, 2H), 6.50 (d, J¼8.0 Hz, 1H), 6.27
(s, 1H), 5.79 (m, 2H), 3.26 (s, 1H), 2.98 (s, 1H), 2.80 (m, 1H), 2.53 (m,
1H), 2.29 (m, 2H).
d
7.98 (br s, 1H), 7.62 (d, J¼8.0 Hz,
A Carousel Tube Reaction (Radley Discovery), equipped with
a magnetic stirrer, was charged with THF (2.0 mL), 1c (0.100 g,
0.291 mmol), Pd(OAc)2 (0.003 g, 0.014 mmol), PPh3 (0015 g,
0.0584 mmol) Et3N (0.088 g, 0.873 mmol), under argon. The
mixture was stirred at 80 ꢀC for 1 h. After cooling, the reaction
mixture was concentrated under reduced pressure and the crude
was purified by chromatography (SiO2, 35 g; n-hexane/AcOEt 92/
8 v/v) to give 0.044 g of 5a: 95% yield; mp: 316.0–317.3 ꢀC; 1H
4.5.6. (E)-5-Methyl-2-styryl-1H-indole (5g)
85% yield; mp: 210.9–212.2 ꢀC; 1H NMR (DMSO-d6)
d 11.2 (br s,
1H), 7.56 (d, J¼8.0 Hz, 2H), 7.39 (t, J1¼8.0 Hz, J2¼8.0 Hz, 2H), 7.24
(m, 5H), 6.93 (d, J1¼8.0 Hz, 1H), 6.49 (s, 1H), 2.36 (s, 3H); 13C NMR
(CDCl3)
d 137.5, 137.2, 136.2, 129.3, 129.2, 128.1, 127.9, 127.3, 126.6,
NMR (CDCl3)
J¼8.0 Hz, 1H), 7.23 (m, 1H), 7.10 (m, 1H), 6.44 (d, J¼16.0 Hz, 1H),
6.08 (m, 1H), 2.76 (m, 2H), 1.95 (s, 3H); 13C NMR (CDCl3)
136.5,
129.0, 124.9, 122.2, 122.1, 120.4, 120.0, 110.5, 101.3, 18.5; IR (KBr):
3409, 2956, 2923, 1685, 1455 cmꢁ1; MS m/z (relative intensity)
157 (Mþ, 4), 130 (29), 117 (13), 87 (6), 74 (36), 63 (100). Anal.
Calcd for C11H11N: C, 84.04; H, 7.05; N, 8.91. Found: C, 84.10; H,
7.00; N, 8.86.
d
8.05 (br s, 1H), 7.63 (d, J¼8.0 Hz, 1H), 7.37 (d,
124.2, 120.2, 120.1, 111.1, 103.0, 21.7; IR (KBr): 3407, 2921, 2360,
1442, 1417 cmꢁ1; MS m/z (relative intensity) 233 (Mþ, 2), 204 (7),
152 (3), 128 (7), 115 (8), 102 (22), 89 (19), 77 (61), 63 (45), 51 (100).
Anal. Calcd for C17H15N: C, 87.52; H, 6.48; N, 6.00. Found: C, 87.48;
H, 6.42; N, 5.96.
d
4.5.7. 5,7-Dimethyl-2-vinyl-1H-indole (5h)
85% yield; oil; 1H NMR (CDCl3)
d
7.96 (br s, 1H), 7.25 (s, 1H), 6.88
(s, 1H), 6.48 (s, 1H), 5.61 (d, J¼16.0 Hz, 1H), 5.30 (d, J¼16.0 Hz, 1H),
2.53 (s, 3H), 2.34 (s, 3H); 13C NMR (CDCl3)
136.1, 134.6, 129.6,
4.5.1. 2-Vinyl-1H-indole (5b)
d
90% yield; mp: 80.1–81.3 ꢀC, lit.22 mp: 83–85 ꢀC; 1H NMR
128.6, 127.9, 125.3, 119.5, 118.1, 111.6, 103.4, 21.4, 16.7; IR (neat):
3417, 2917, 1633, 1598, 1444 cmꢁ1; MS m/z (relative intensity) 171
(Mþ, 7), 156 (4), 144 (26), 130 (11), 115 (7), 89 (24), 77(25), 63 (67),
52 (100). Anal. Calcd for C12H13N: C, 84.17; H, 7.65; N, 8.18. Found: C,
84.10; H, 7.60; N, 8.12.
(CDCl3)
d
8.19 (br s, 1H), 7.61 (d, J¼8.0 Hz, 1H), 7.36 (d, J¼8.0 Hz, 1H),
7.23 (m, 1H), 7.13 (m, 1H), 6.76 (m, 1H), 6.53 (s, 1H), 5.59 (d,
J¼16.0 Hz, 1H), 5.31 (d, J¼16.0 Hz, 1H), 4.19 (m, 1H), 2.75 (m, 2H),
2.45 (m, 2H), 1.96 (d, 2H); 13C NMR (CDCl3)
d 134.6, 131.2, 128.2,
122.3, 121.7, 120.9, 120.6, 119.8, 111.6, 101.0; IR (KBr): 3429, 2948,
2837,1454 cmꢁ1; MS m/z (relative intensity) 143 (Mþ,100),115 (57),
89 (44), 63 (49). Anal. Calcd for C10H9N: C, 83.88; H, 6.34; N, 9.78.
Found: C, 83.86; H, 6.30; N, 9.72.
4.5.8. 2-Cyclopentenyl-1H-indole (5i)
77% yield; mp: 129.3–130.6 ꢀC; 1H NMR (CDCl3)
d
8.49 (br s, 1H),
7.43 (d, J¼7.9 Hz, 1H), 7.30 (m, 4H), 6.06 (s, 1H), 5.95 (s, 1H), 2.75 (m,
2H), 2.45 (m, 2H), 1.96 (d, 2H); 13C NMR (CDCl3)
142.1, 136.2, 130.7,
d
4.5.2. (E)-2-(But-1-enyl)-1H-indole (5c)
128.0,124.3,122.4,120.1,118.6,110.8,100.9, 34.5, 34.2, 23.8; IR (KBr):
3421, 2948, 2835, 1727, 1454 cmꢁ1; MS m/z (relative intensity) 183
(Mþ, 17), 154 (8), 130 (6), 117 (40), 89 (12), 66 (100). Anal. Calcd for
C13H13N: C, 85.21; H, 7.15; N, 7.64. Found: C, 85.15; H, 7.09; N, 85.10.
83% yield; mp: 342.2–343.5 ꢀC; 1H NMR (CDCl3)
d 8.08 (br s,
1H), 7.56 (d, J¼8.0 Hz, 1H), 7.33 (d, J¼8.0 Hz, 1H), 7.18 (t, J¼8.0 Hz,
1H), 7.07 (t, J¼8.0 Hz, 1H), 6.46 (s, 1H), 6.13 (m, 1H), 2.32 (m, 2H),
1.15 (m, 3H); 13C NMR (CDCl3)
d 136.5, 131.7, 122.2, 120.4, 119.9,
119.94, 110.5, 101.3, 26.1, 13.6; IR (KBr): 3421, 2962, 2927,
1454 cmꢁ1; MS m/z (relative intensity) 171 (Mþ, 5), 130 (26), 117
(22), 89 (33), 77 (26), 63 (57), 51 (61), 41 (100). Anal. Calcd for
C12H13N: C, 84.17; H, 7.65; N, 8.18. Found: C, 84.11; H, 7.60; N,
8.14.
4.5.9. 2-Cyclopentenyl-5-methyl-1H-indole (5j)
75% yield; oil; 1H NMR (CDCl3)
d 8.07 (br s, 1H), 7.39 (s, 1H), 7.24
(m, 1H), 7.04 (d, J¼8 Hz, 1H), 6.39 (s, 1H), 6.01 (s, 1H), 2.79 (m, 2H),
2.61 (m, 2 h), 2.48 (s, 3H), 2.39 (s,1H), 2.10 (m, 2H); 13C NMR (CDCl3)
d
142.1,136.2,130.7,128.0,124.3,122.4,120.1,118.6,110.8,100.9, 34.5,
34.2, 24.9, 23.8; IR (neat): 3421, 2948, 2835, 1727 cmꢁ1; MS m/z
(relative intensity) 197 (Mþ, 20),154 (8),130 (6),117 (40), 89 (12), 66
(100). Anal. Calcd for C14H15N: C, 85.24; H, 7.65; N, 7.10. Found: C,
85.20; H, 7.60; N, 7.00.
4.5.3. 5-Methyl-2-vinyl-1H-indole (5d)
63% yield; mp: 153.5–154.7 ꢀC; 1H NMR (CDCl3)
d 8.12 (br s, 1H),
7.63 (d, J¼8.0 Hz, 1H), 7.37 (d, J¼8.0 Hz, 1H), 7.24 (m, 1H), 7.15 (m,
1H), 6.77 (m, 1H), 6.55 (s, 1H), 5.60 (d, J¼16.0 Hz, 1H), 5.33(d,
J¼16.0 Hz, 1H), 4.20 (m, 1H), 2.75 (m, 2H), 2.46 (m, 2H), 2.55 (s, 3H);
4.5.10. 5-Chloro-2-cyclopentenyl-1H-indole (5k)
13C NMR (CDCl3)
d
136.4, 135.0, 129.3, 129.0, 127.8, 124.5, 120.5,
85% yield; mp: 164.6–166.2 ꢀC; 1H NMR (CDCl3)
d 8.13 (br s, 1H),
111.8, 110.4, 102.8, 21.5; IR (KBr): 3392, 3010, 2917, 1454 cmꢁ1; MS
m/z (relative intensity) 157 (Mþ, 6), 130 (8), 104 (12), 89 (17), 78(8),
63 (62). Anal. Calcd for C10H9N: C, 83.88; H, 6.34; N, 9.78. Found: C,
83.86; H, 6.30; N, 9.72.
7.54 (s, 1H), 7.22 (d, J¼8.0 Hz, 1H), 7.11 (d, J¼8.0 Hz, 1H), 6.38 (s, 1H),
6.05 (s, 1H), 2.76 (m, 2H), 2.60 (m, 2H), 2.20 (s, 3H), 2.10 (m, 2H); 13C
NMR (CDCl3)
d 136.8, 134.8, 134.6, 130.0, 125.7, 125.4, 122.4, 119.8,
111.4, 100.3, 33.4, 33.05, 23.3; IR (KBr): 3426, 2919, 1571, 1444,
1062 cmꢁ1; MS m/z (relative intensity) 218 (Mþ, 5), 181 (4), 151 (17),
113 (4), 87 (12), 66 (100). Anal. Calcd for C13H12ClN: C, 71.72; H,
5.56; N, 6.43. Found: C, 71.68; H, 5.50; N, 6.36.
4.5.4. 5,7-Difluoro-2-vinyl-1H-indole (5e)
82% yield; wax; 1H NMR (CDCl3)
d 8.28 (br s, 1H), 7.04 (dd,
J1¼4.0 Hz, J2¼8.0 Hz, 1H), 6.74 (dd, J1¼4.0 Hz, J2¼8.0 Hz, 1H), 6.55
(m, 1H), 5.66 (d, J¼16.0 Hz, 1H), 5.36 (d, J¼16.0 Hz, 1H); 13C NMR
4.5.11. 2-(1-Phenylvinyl)-1H-indole (5l)
(CDCl3)
d
158.4 (d, J¼9.0 Hz), 155.9 (d, J¼10.0 Hz), 149.5 (d,
78% yield; oil; 1H NMR (CDCl3)
d
8.14 (br s, 1H), 7.64 (d, J¼8.0 Hz,
J¼14.0 Hz), 147.12 (d, J¼14.1 Hz), 142.4, 131.2 (dd, J1¼6.4 Hz,
J2¼6.3 Hz), 126.9, 121.4 (d, J¼21.0 Hz), 114.03, 103.6 (d, J¼5.0 Hz),
102.4 (d, J¼29.0 Hz), 97.8 (dd J1¼20 Hz, J2¼10.0 Hz); IR (neat): 3473,
2921, 1654, 1454 cmꢁ1; MS m/z (relative intensity) 179 (Mþ, 2), 166
(5), 149 (3), 135 (2), 120 (6), 99 (11), 86 (15), 75 (38), 63 (44), 51
(100). Anal. Calcd for C10H7F2N: C, 67.06; H, 3.96; N, 7.84. Found: C,
67.11; H, 3.99; N, 7.80.
1H), 7.55 (d, J¼8.0 Hz, 2H), 7.46 (m, 3H), 7.26 (d, J¼8.0 Hz, 1H), 7.24
(m, 1H), 7.16 (m, 1H), 6.58 (s, 1H), 5.65 (s, 1H), 5.43 (s, 1H); 13C NMR
(CDCl3)
d 148.8, 140.3, 135.6, 128.7, 128.2, 128.0, 126.4, 122.2, 120.3,
120.1, 119.0, 111.4, 100.6; IR (neat): 3378, 2923, 1598, 1492,
1454 cmꢁ1; MS m/z (relative intensity) 219 (Mþ, 24), 204 (15), 140
(5), 89 (23), 77 (61), 51 (100). Anal. Calcd for C16H13N: C, 87.64; H,
5.98; N, 6.39. Found: C, 87.56; H, 5.90; N, 6.32.

I. Ambrogio et al. / Tetrahedron 65 (2009) 8916–8929
8927
4.5.12. 5-Chloro-2-(prop-1-en-2-yl)-1H-indole (5m)
85% yield; mp: 91.6–92.3 ꢀC; 1H NMR (CDCl3)
7.56 (s, 1H), 7.26 (m, 2H), 7.16 (d, J¼8.0 Hz, 3H), 6.50 (s, 1H), 5.14 (s,
1H), 2.10 (s, 3H); 13C NMR (CDCl3)
135.2, 133.3, 130.1, 126.7, 124.2,
4.6. Typical procedure for the cyclization of ethyl
3-(o-trifluoroacetamidoaryl)-1-propargylic
carbonates (1) to 2-alkylindoles (6)
d
8.23 (br s, 1H),
d
122.0, 119.4, 119.2, 112.5, 101.3, 22.7; IR (KBr): 3438, 1704, 1654,
1450, 1380 cmꢁ1; MS m/z (relative intensity) 191 (Mþ, 21), 176 (6),
151 (11),128 (7),113 (9), 87 (29), 52 (100). Anal. Calcd for C11H10ClN:
C, 68.93; H, 5.26; N, 7.31. Found: C, 68.88; H, 5.20; N, 7.26.
A Carousel Tube Reaction (Radley Discovery), equipped with
a magnetic stirrer, was charged with MeCN (2.0 mL), 1a (0.100 g,
0.317 mmol), Pd(PPh3)4 (0.018 g, 0.016 mmol), Et3N (0.096 g,
0.951 mmol), and HCOOH (0.029 g, 0.634 mmol) under argon. The
mixture was stirred at 80 ꢀC for 1 h. After cooling, the reaction
mixture was concentrated under reduced pressure and the crude
was purified by chromatography (SiO2, 35 g; n-hexane/AcOEt 92/8
v/v) to give 0.038 g of 6a: 91% yield; mp: 57–59 ꢀC; lit. mp (Aldrich
4.5.13. 5-Methyl-2-(prop-1-en-2-yl)-1H-indole (5n)
84% yield; mp: 140.0–141.2 ꢀC; 1H NMR (CDCl3)
d
8.08 (br s, 1H),
7.38 (s, 1H), 7.25 (m, 1H), 7.04 (m, 1H), 6.50 (s, 1H), 5.30 (s, 1H), 5.08
(s,1H), 2.45 (s, 3H), 2.20 (s 3H); 13C NMR (CDCl3)
138.6,135.4,134.9,
d
catalogue) 57–59 ꢀC; 1H NMR (CDCl3)
J¼7.5 Hz, 1H), 7.30 (d, J¼7.6 Hz, 1H), 7.25–7.10 (m, 2H), 6.29 (s, 1H),
2.46 (s, 3H); 13C NMR (CDCl3)
136.1, 135.1, 129.1, 120.9, 119.6, 110.3,
d 7.76 (br s, 1H), 7.59 (d,
129.2, 124.3, 120.4, 110.3, 109.2, 100.8, 21.5, 20.6; IR (KBr): 3424,
2919, 1627, 1457, 1396 cmꢁ1; MS m/z (relative intensity) 171 (Mþ,
37),156 (11),144 (12),130 (20),104 (9), 87 (15), 52 (100). Anal. Calcd
for C12H13N: C, 84.17; H, 7.65; N, 8.18. Found: C, 84.11; H, 7.59; N, 8.14.
d
100.4, 13.7 IR (KBr): 3404, 2935, 2816, 1454; MS m/z (relative in-
tensity) 131 (Mþ, 94%), 130 (100%), 77 (20%). Anal. Calcd for C9H9N:
C, 82.41; H, 6.92; N, 10.68. Found: C, 82.50; H, 6.91; N, 10.70.
4.5.14. 2-(Prop-1-en-2-yl)-1H-indole (5o)
80% yield; mp: 116.0–118.5 ꢀC; 1H NMR (CDCl3)
d
8.17 (br s, 1H),
4.6.1. 2-Benzyl-1H-indole (6b)
7.63 (d, J¼8.0 Hz, 1H), 7.37 (d, J¼8.0 Hz, 1H), 7.22 (m, 1H), 7.12 (m,
75% yield; oil; 1H NMR (CDCl3)
d
7.78 (br s, 1H), 7.62 (d, J¼8.0 Hz,
1H), 6.59 (s, 1H), 5.34 (s, 1H), 5.11 (s, 1H), 2.20 (s 3H); 13C NMR
1H), 7.30 (m, 7H), 6.38 (s, 1H), 4.16 (s, 3H); 13C NMR (CDCl3)
d
136.2,
(CDCl3)
d
138.6, 135.4, 134.9, 129.2, 124.3, 120.4, 110.3, 109.2, 100.8,
135.6, 135.3, 129.0, 128.7, 128.0,125.8, 122.2, 120.9, 118.6, 111.2, 101.3,
41.0; IR (neat): 3255, 2964, 1654, 1602 cmꢁ1; MS m/z (relative in-
tensity) 207 (Mþ, 100), 178 (9), 130 (91), 77 (21), 63 (10), 44 (15).
Anal. Calcd for C15H13N: C, 86.92; H, 6.32; N, 6.76. Found: C, 86.98;
H, 6.72; N, 6.70.
21.5, 20.6; IR (KBr): 3428, 2923, 1617, 1523, 1457 cmꢁ1; MS m/z
(relative intensity) 158 (Mþ, 9),141 (8),130 (26),113 (16), 76 (26), 52
(100). Anal. Calcd for C11H11N: C, 84.04; H, 7.05; N, 8.91. Found: C,
84.00; H, 6.98; N, 8.87.
4.5.15. 2-(Prop-1-en-2-yl)-5-acetyl-1H-indole (5p)
4.6.2. 2-Propyl-1H-indole (6c)
90% yield; mp: 134.2–135.7 ꢀC; 1H NMR (CDCl3)
d
8.78 (br s, 1H),
70% yield; mp: 72.1–73.6 ꢀC; 1H NMR (CDCl3)
d
7.83 (br s, 1H),
7.60 (d, J¼8.0 Hz, 1H), 7.33 (d, J¼8.0 Hz, 1H), 7.16 (m, 2H), 6.30 (s,
1H), 2.76 (t, 2H), 1.76 (q, 2H) (t, 3H); 13C NMR (CDCl3)
136.2, 135.3,
8.27 (s,1H), 7.88 (d, J¼8.0 Hz,1H), 7.35 (d, J¼8.0 Hz,1H), 6.65 (s,1H),
5.41 (s, 1H), 5.16 (s, 1H), 2.68 (s, 3H), 2.22 (s 3H); 13C NMR (CDCl3)
d
d
198.5, 140.3, 139.4, 134.8, 130.0, 128.4, 123.1, 122.9, 110.7, 110.6,
129.3, 120.7, 119.5, 110.1, 100.2, 35.9, 24.8, 13.7; IR (KBr): 3367, 3118,
2941,1699, 1655 cmꢁ1; MS m/z (relative intensity) 159 (Mþ, 36),130
(100), 77 (13), 50 (8). Anal. Calcd for C11H13N: C, 82.97; H, 8.23; N,
8.80. Found: C, 82.90; H, 8.23; N, 8.76.
102.4, 26.6, 20.5; IR (KBr): 3322, 1656, 1602, 1428 cmꢁ1; MS m/z
(relative intensity) 199 (Mþ, 26), 184 (33), 156 (34), 144 (12), 129
(20), 100 (22), 52 (100). Anal. Calcd for C13H13NO: C, 78.36; H, 6.58;
N, 7.03. Found: C, 78.30; H, 6.50; N, 7.00.
4.6.3. 2-Ethyl-1H-indole (6d)
4.5.16. 2-(Prop-1-en-2-yl)-5-cyano-1H-indole (5q)
70% yield; wax; 1H NMR (CDCl3)
d
7.82 (br s, 1H), 7.59 (d,
J¼8.0 Hz, 1H), 7.30 (d, J¼8.0 Hz, 1H), 7.15 (m, 2H), 6.43 (s, 1H), 2.81
(m, 2H), 1.38 (t, 3H); 13C NMR (CDCl3)
141.4, 135.8, 128.8, 120.9,
83% yield; mp: 122.3–123.8 ꢀC; 1H NMR (CDCl3)
d
8.76 (br s, 1H),
7.92 (s, 1H), 7.42 (s, 1H), 6.60 (s, 1H), 5.43 (s, 1H), 5.21 (s, 1H), 2.21 (s
3H); 13C NMR (CDCl3)
140.9, 138.3, 134.5, 128.6, 126.1, 125.5, 120.9,
d
d
119.8, 119.6, 110.3, 98.7, 21.4, 13.3; IR (neat): 3366, 3018, 2996, 1699,
1555 cmꢁ1; MS m/z (relative intensity) 145 (Mþ, 54), 130 (100), 77
(13), 50 (3). Anal. Calcd for C10H11N: C, 82.72; H, 7.64; N, 9.65.
Found: C, 82.80; H, 7.70; N, 9.60.
111.6, 111.5, 102.7, 101.4, 20.5; IR (KBr): 3370, 2211, 1610, 1321 cmꢁ1
;
MS m/z (relative intensity) 182 (Mþ, 15), 154 (10), 142 (9), 127 (9),
114 (7), 100 (6), 52 (100). Anal. Calcd for C12H10N2: C, 79.10; H, 5.53;
N, 15.37. Found: C, 79.04; H, 5.47; N, 15.30.
4.6.4. 2-Butyl-1H-indole (6e)
4.5.17. Methyl 2-(prop-1-en-2-yl)-1H-indole-5-carboxylate (5r)
67% yield; oil; 1H NMR (CDCl3)
d
7.89 (br s, 1H), 7.56 (d, J¼8.0 Hz,
1H), 7.29 (d, J¼8.0 Hz, 1H), 7.14 (m, 2H), 6.28 (s, 1H), 2.78 (m, 2H),
1.60 (m, 2H), 1.47 (m, 2H), 1.03 (t, 3H); 13C NMR (CDCl3)
139.9,
87% yield; mp: 143.4–144.7 ꢀC; 1H NMR (CDCl3)
d 8.66 (br s, 1H),
8.37 (s,1H), 7.92 (d, J¼8.0 Hz,1H), 7.33 (d, J¼8.0 Hz,1H), 6.63 (s,1H),
d
5.38 (s, 1H), 5.14 (s, 1H), 3.95 (s, 3H), 2.21 (s 3H); 13C NMR (CDCl3)
135.7, 128.7, 120.8, 119.6, 119.5, 110.1, 99.3, 31.2, 27.8, 22.3, 13.7; IR
(neat): 3369, 3120, 2950, 1690, 1650 cmꢁ1; MS m/z (relative in-
tensity) 174 (Mþ, 5),144 (5),130 (100), 77 (11), 50 (4). Anal. Calcd for
C12H15N: C, 83.19; H, 8.73; N, 8.08. Found: C, 83.13; H, 8.67; N, 8.67.
d
168.3, 140.0, 139.3, 134.8, 128.4, 124.1, 123.7, 121.9, 110.5, 110.3,
102.2, 51.9, 20.5; IR (KBr): 3345, 2923, 1689, 1610, 1430 cmꢁ1; MS
m/z (relative intensity) 215 (Mþ, 29), 184 (19), 174 (19), 144 (19), 129
(11), 101 (12), 59 (100). Anal. Calcd for C13H13NO2: C, 72.54; H, 6.09;
N, 6.51. Found: C, 72.46; H, 6.00; N, 6.48.
4.6.5. 2,5,7-Trimethyl-1H-indole (6f)
90% yield; oil; 1H NMR (CDCl3)
d
7.91 (br s,1H), 7.19 (s,1H), 6.79 (s,
4.5.18. 5-Fluoro-2-(1-phenylvinyl)-1H-indole (5s)
1H), 6.17 (s,1H), 2.47 (s, 3H), 2.46 (s, 3H), 2.43 (s, 3H); 13C NMR (CDCl3)
68% yield; wax; 1H NMR (CDCl3)
d
8.11 (br s, 1H), 8.37 (s, 1H),
7.92 (d, J¼8.0 Hz, 1H), 7.51 (m, 6H), 6.99 (m, 1H), 6.52 (s, 1H), 5.65 (s,
1H), 5.43 (s, 1H); 13C NMR (CDCl3)
159.3, 156.9, 141.5, 139.8, 139.6,
d 134.8,133.9,129.0,128.9,123.3,119.0,117.18,100.5, 21.4,16.7,13.9; IR
(neat): 3382, 2917, 1677, 1498 cmꢁ1; MS m/z (relative intensity) 131
(Mþ, 94),130 (100), 77 (20), 65 (13), 50 (8). Anal. Calcd for C11H13N: C,
82.97; H, 8.23; N, 8.80. Found: C, 82.90; H, 8.18; N, 8.73.
d
133.0, 129.1, 128.9, 128.5, 128.4 113.5, 111.5, 111.4, 111.2, 110.9, 105.6,
105.4, 103.3, 103.3, 29.8; IR (neat): 3442, 3058, 2925, 1484,
1450 cmꢁ1; MS m/z (relative intensity) 237 (Mþ, 24), 222 (16), 132
(5), 107 (14), 129, 50 (100). Anal. Calcd for C16H12FN: C, 80.99; H,
5.10; N, 6.90. Found: C, 80.90; H, 5.04; N, 6.84.
4.6.6. 2,5-Dimethyl-1H-indole (6g)
80% yield; mp: 110.2–11.9 ꢀC; 1H NMR (CDCl3)
d
7.66 (br s, 1H),
7.37 (s, 1H), 7.20 (d, J¼8.0 Hz, 1H), 7.01 (d, J¼8.0 Hz, 1H), 6.19 (s, 1H),

8928
I. Ambrogio et al. / Tetrahedron 65 (2009) 8916–8929
2.50 (s, 3H), 2.44 (s, 3H); 13C NMR (CDCl3)
d
135.2, 134.4, 129.4,
167 (6), 130 (100), 102 (12), 77 (26), 63 (15). Anal. Calcd for
C16H15NO: C, 80.93; H, 6.37; N, 5.92. Found: C, 80.90; H, 6.33; N, 5.90.
128.8, 122.4, 119.4, 109.9, 99.9, 21.5, 13.7; IR (KBr): 3399, 2917, 1685,
1405, 775.2 cmꢁ1; MS m/z (relative intensity) 145 (Mþ, 100), 130
(16), 115 (7), 71 (9), 51 (6). Anal. Calcd for C10H11N: C, 82.72; H, 7.64;
N, 9.65. Found: C, 82.75; H, 7.69; N, 9.70.
4.6.14. 2-(4-Methoxybenzyl)-1H-indole (6o)
70% yield; mp: 71.6–72.8 ꢀC; 1H NMR (CDCl3)
d 7.86 (br s, 1H),
7.61 (d, J¼8.0 Hz, 1H), 7.31 (m, 2H), 7.28 (m, 2H), 7.17 (m, 3H), 6.88
4.6.7. 2,5-Dimethyl-7-nitro-1H-indole (6h)
(m, 3H), 6.38 (s, 1H), 3.82 (s, 3H); 13C NMR (CDCl3)
d
160.2, 140.1,
78% yield; mp: 161.4–162.8 ꢀC; 1H NMR (CDCl3)
d
9.56 (br s, 1H),
137.7, 136.4, 130.1, 128.7, 124.4, 121.3, 120.3, 120.0, 119.7, 114.6, 112.3,
110.5, 101.0, 55.2, 34.8; IR (KBr): 3401, 2921, 2834, 1704, 1604,
1581 cmꢁ1; MS m/z (relative intensity) 237 (Mþ, 2), 222 (4),130 (63),
117 (10), 103 (20), 92 (38), 77 (100), 63 (92), 51 (60). Anal. Calcd for
C16H15NO: C, 80.93; H, 6.37; N, 5.92. Found: C, 80.91; H, 6.33; N, 5.93.
7.87 (s,1H), 7.61 (s 1H), 6.28 (s,1H), 2.52 (s, 3H), 2.49 (s, 3H); 13C NMR
(CDCl3) d 138.0,133.0,131.7, 128.8,128.2,127.9,118.6, 101.1, 21.0,13.7;
IR (KBr): 3421, 2923,1680,1457 cmꢁ1; MS m/z (relative intensity) 145
(Mþ, 100), 130 (16), 115 (7), 71 (9), 51 (6). Anal. Calcd for C10H10N2O2:
C, 63.15; H, 5.30; N, 14.73. Found: C, 63.10; H, 5.24; N, 14.64.
4.6.15. 2-(4-Fluorobenzyl)-1H-indole (6p)
4.6.8. 7-Chloro-2,5-dimethyl-1H-indole (6i)
85% yield; mp: 80.3–81.9 ꢀC; 1H NMR (CDCl3)
d
7.78 (br s, 1H),
7.60 (d, J¼8.0 Hz, 1H), 7.18 (m, 5H), 7.07 (m, 2H), 6.35 (m, 1H), 4.12
(s, 3H); 13C NMR (CDCl3)
163.0, 137.7, 136.4, 134.3, 134.2, 130.4,
51% yield; oil; 1H NMR (CDCl3)
d
7.99 (br s, 1H), 7.28 (s, 1H), 6.98
(s,1H), 6.20 (s,1H), 2.47 (s, 3H), 2.44 (s, 3H); 13C NMR (CDCl3)
d
136.0,
d
131.0, 130.7, 130.1,121.7,118.1,115.2,101.0, 21.3, 13.7; IR (neat): 3326,
2919, 1668, 1619, 1577, 1498 cmꢁ1; MS m/z (relative intensity) 179
(Mþ, 100), 144 (57), 115 (21), 89 (10), 51 (1). Anal. Calcd for
C10H10ClN: C, 66.86; H, 5.61; N, 7.80. Found: C, 66.80; H, 5.57; N, 7.76.
130.3, 128.7, 121.5, 120.1, 119.9, 115.7, 115.5, 110.8, 110.6, 101.3, 33.9;
IR (KBr): 3396, 3045, 2890, 1600, 1544, 1508 cmꢁ1; MS m/z (relative
intensity) 225 (Mþ, 87), 196 (5), 177 (2), 130 (65), 77 (14), 44 (84).
Anal. Calcd for C15H12FN: C, 79.98; H, 5.37; N, 6.22. Found: C, 79.93;
H, 5.33; N, 6.18.
4.6.9. 2-Benzyl-5,7-dimethyl-1H-indole (6j)
50% yield; wax; 1H NMR (CDCl3)
d
7.64 (br s, 1H), 7.38 (d,
J¼8.0 Hz,1H), 7.33 (m, 4H), 7.23 (s, 1H), 6.80 (s, 1H), 6.28 (s, 1H), 4.16
(s, 2H), 2.43 (s, 3H), 2.36 (s, 3H); 13C NMR (CDCl3)
136.4, 135.8,
4.6.16. 2-(3-Methoxybenzyl)-5,7-dimethyl-1H-indole (6q)
72% yield; oil; 1H NMR (CDCl3)
d
7.78 (br s, 1H), 7.27 (m, 2H), 6.84
(m, 4H), 6.30 (s, 1H), 3.81 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H); 13C NMR
(CDCl3) 159.9, 140.4, 137.3, 134.2, 129.7, 129.1, 128.5, 123.7, 121.2,
d
133.3, 129.0, 128.7, 128.0,127.8, 120.5, 120.4, 117.1, 101.5, 41.4, 25.3,
20.1; IR (neat): 3436, 2917, 1679, 1621, 1494, 1280 cmꢁ1; MS m/z
(relative intensity) 235 (Mþ, 100), 178 (9), 130 (91), 77 (21), 63 (10),
44 (15). Anal. Calcd for C17H17N: C, 86.77; H, 7.28; N, 6.76. Found: C,
86.70; H, 7.22; N, 6.70.
d
119.3, 117.5, 114.5, 112.0, 101.4, 55.2, 34.8, 21.4, 16.7; IR (neat): 3849,
2917, 2358, 1598, 1454, 1384 cmꢁ1; MS m/z (relative intensity) 265
(Mþ, 44), 158 (100), 143 (16), 115 (25), 92 (21), 77 (56), 51 (27). Anal.
Calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C, 81.51; H, 7.28;
N, 5.20.
4.6.10. 5-Chloro-2-methyl-1H-indole (6k)
60% yield; wax; 1H NMR (CDCl3)
d
7.91 (br s,1H), 7.50 (s,1H), 7.19
4.6.17. 5-Chloro-2-(3-methoxybenzyl)-7-(trifluoromethyl)-
(d, J¼8.0 Hz, 1H), 7.07 (d, J¼8.0 Hz, 2H), 6.19 (s, 1H), 2.44 (s, 3H); 13C
1H-indole (6r)
NMR (CDCl3)
d
136.7, 134.4, 125.2, 121.1, 119.0, 111.2, 100.2, 13.8; IR
85% yield; wax; 1H NMR (CDCl3)
d
8.26 (br s, 1H), 7.67 (s, 1H),
7.37 (s, 1H), 7.29 (m, 2H), 6.86 (m, 3H), 6.34 (m, 1H), 3.8 (s, 3H), 2.44
(s, 3H); 13C NMR (CDCl3)
160.5, 137.4, 135.6, 130.6, 129.9, 127.4,
(neat): 3399, 2942,1700,1457 cmꢁ1; MS m/z (relative intensity) 131
(Mþ, 94), 130 (100), 77 (20), 65 (13), 50 (8). Anal. Calcd for C9H8ClN:
C, 65.24; H, 4.87; N, 8.46. Found: C, 65.28; H, 4.80; N, 8.40.
d
124.9, 121.3, 116.8, 114.9, 113.3, 111.3, 101.5, 55.9, 41.3; IR (neat):
3399, 2942, 1700, 1457 cmꢁ1; MS m/z (relative intensity) 304 (Mþ,
94), 275 (10), 207 (34), 77 (20), 50 (8). Anal. Calcd for C17H13F3NO: C,
67.10; H, 4.31; N, 4.60. Found: C, 67.04; H, 4.24; N, 4.56.
4.6.11. 5-Fluoro-2,7-dimethyl-1H-indole (6l)
65% yield; wax; 1H NMR (CDCl3)
d
7.78 (br s, 1H), 7.07 (d,
J¼8.0 Hz, 1H), 6.74 (d, J¼8.0 Hz, 1H), 6.23 (s, 1H), 6.17 (s, 1H), 2.47 (s,
6H); 13C NMR (CDCl3)
d
138.2 (J¼233.1 Hz), 136.5, 132.0, 128.7
4.6.18. 2-Methyl-5-acetyl-1H-indole (6s)
(J¼10.7 Hz), 120.5 (J¼9.6 Hz), 109.7 (J¼25.7 Hz), 102.1 (J¼23.4 Hz),
101.2 (J¼4.6 Hz), 16.6, 13.8; IR (neat): 3372, 3072, 2933, 1685,
1492 cmꢁ1; MS m/z (relative intensity) 131 (Mþ, 94), 130 (100), 77
(20), 65 (13), 50 (8). Anal. Calcd for C10H10FN: C, 73.60; H, 6.18; N,
8.58. Found: C, 73.64; H, 6.22; N, 8.53.
73% yield; mp: 129.7–130.2 ꢀC; 1H NMR (CDCl3)
d
8.65 (br s, 1H),
8.21 (s, 1H), 7.96 (s, 1H), 7.35 (s, 1H), 6.34 (s, 1H), 2.68 (s, 3H), 2.47 (s,
3H); 13C NMR (CDCl3)
198.8, 139.0, 137.0, 135.6, 129.7, 128.7, 121.8,
d
121.5, 110.3, 101.8, 26.7, 13.8; IR (KBr): 3380, 2997, 1700, 1587 cmꢁ1
;
MS m/z (relative intensity) 173 (Mþ, 6), 158 (16), 130 (24), 103 (16),
77 (16), 43 (100). Anal. Calcd for C11H11NO: C, 76.28; H, 6.40; N,
8.09. Found: C, 76.24; H, 6.36; N, 8.03.
4.6.12. 5-Chloro-2-methyl-7-(trifluoromethyl)-1H-indole (6m)
86% yield; mp: 57.2–58.9 ꢀC; 1H NMR (CDCl3)
d
8.29 (br s, 1H),
7.64 (s, 1H), 7.36 (s, 1H), 6.27 (s, 1H), 2.50 (s, 3H); 13C NMR (CDCl3)
138.2, 133.6, 131.9, 130.0, 129.8, 127.8, 125.7, 124.7, 122.9, 118.5,
4.6.19. Methyl 2-methyl-1H-indole-5-carboxylate (6t)
d
70% yield; mp: 157.1–158.0 ꢀC; 1H NMR (CDCl3)
d
8.45 (br s, 1H),
8.30 (s, 2H), 7.89 (d, J¼8.0 Hz, 1H), 7.28 (d, J¼8.0 Hz, 1H), 7.29 (m,
2H), 6.86 (m, 3H), 3.95 (s, 3H), 2.46 (s, 3H); 13C NMR (CDCl3)
168.5,
118.4, 113.9, 113.5, 113.2, 100.7, 13.7; IR (KBr): 3372, 3072, 2933,
1685, 1492 cmꢁ1; MS m/z (relative intensity) 131 (Mþ, 94), 130
(100), 77 (20), 65 (13), 50 (8). Anal. Calcd for C10H7ClF3N: C, 51.41; H,
3.02; N, 6.00. Found: C, 51.36; H, 3.07; N, 6.04.
d
138.8,136.7,128.7,122.5,121.6,109.9,101.6, 51.8,13.7; IR (KBr): 3328,
2950, 1698, 1436 cmꢁ1; MS m/z (relative intensity) 189 (Mþ, 19), 158
(65),130 (94),103 (94), 77 (99), 51 (100). Anal. Calcd for C11H11NO: C,
69.83; H, 5.86; N, 7.40. Found: C, 69.79; H, 5.80; N, 7.36.
4.6.13. 2-(3-Methoxybenzyl)-1H-indole (6n)
75% yield; wax; 1H NMR (CDCl3)
d
7.86 (br s, 1H), 7.60 (d,
J¼8.0 Hz, 1H), 7.28 (m, 2H), 7.13 (m, 2H), 6.85 (m, 4H), 6.37 (s, 1H),
3.81 (s, 3H); 13C NMR (CDCl3)
140.2,137.7,136.4,130.1,129.8,129.7,
d
Acknowledgements
128.7, 121.4, 121.3, 120.0, 119.7, 114.7, 112.3, 112.1, 110.7, 110.6, 101.1,
55.2, 34.8; IR (neat): 3390, 2913, 2360, 1698, 1596, 1600, 1490,
1455 cmꢁ1; MS m/z (relative intensity) 237 (Mþ, 46), 204 (6),192 (7),
Work carried out in the framework of the National Projects
‘Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni’

I. Ambrogio et al. / Tetrahedron 65 (2009) 8916–8929
8929
2007, 517; (c) Nicolaou, K. C.; Dalby, S. M.; Majumder, U. J. Am. Chem. Soc. 2008,
130, 14942.
14. Wang, M.; Gao, M.; Miller, K. D.; Sledge, G. W.; Hutchin, G. D.; Zheng, Q.-H. Eur.
J. Med. Chem. 2009, 44, 2300.
`
and supported by the Ministero dell’Universita e della Ricerca and
by the University ‘La Sapienza’.
15. (a) Katritzky, A. R.; Akutagawa, K. J. Am. Chem. Soc. 1986, 108, 6808; (b) Inagaki, S.;
Nishizawa, Y.; Sugiura, T.; Ishihara, H. J. Chem. Soc., Perkin Trans. 1 1990, 179;
(c) Naruse, Y.; Ito, Y.; Inagaki, S. J. Org. Chem. 1991, 56, 2256; (d) Rajeswaran, W.
G.; Srinivasan, P. C. Indian J. Chem. 1994, 33B, 368.
References and notes
1. For some selected recent reviews, see: (a) Zeni, G.; Larock, R. C. Chem. Rev. 2004,
104, 2285; (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079;
(c) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127; (d) Cacchi, S.;
Fabrizi, G. Chem. Rev. 2005, 105, 2873; (e) Humphrey, G. R.; Kuethe, J. T. Chem.
Rev. 2006, 106, 2875; (f) Ackermann, L. Synlett 2007, 5607; (g) Kru¨ ger, K.;
Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2153.
2. Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671.
3. For a review on the palladium-catalyzed reactions of propargylic esters, see:
Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed. Engl. 1995, 34, 2589.
16. For some selected examples, see: (a) Cadogan, J. I. G.; Cameron-Wood, M.;
Mackie, R. K.; Searle, R. J. G. J. Chem. Soc. 1965, 4831; (b) Sundberg, R. J. J. Org.
Chem. 1965, 30, 3604; (c) Sundberg, R. J.; Yamazaki, T. J. Org. Chem. 1967, 32,
290; (d) Levy, A. B. J. Org. Chem. 1978, 43, 4684; (e) Taylor, E. C.; Katz, A. H.;
Salgado-Zamora, H.; McKillop, A. Tetrahedron Lett. 1985, 26, 5963; (f) Gharpure,
M.; Stoller, A.; Bellamy, F.; Firnau, G.; Snieckus, V. Synthesis 1991, 1079;
(g) Sadanandan, E. V.; Srinivasan, P. C. Synthesis 1992, 648; (h) Mali, R. S.;
Babu, K. N.; Jagtap, P. J. Chem. Res., Synop. 1995, 114; (i) Wiedenau, P.; Blechert,
S. Synth. Commun. 1997, 27, 2033; (j) Taber, D. F.; Tian, W. J. Am. Chem. Soc.
2006, 128, 1058; (k) Sanz, R.; Escribano, J.; Pedrosa, M. R.; Aguado, R.; Arna´iz,
F. J. Adv. Synth. Catal. 2007, 349, 713; For a review, see: (l) Ragaini, F.; Cenini,
S.; Gallo, E.; Caselli, A.; Fantauzzi, S. Curr. Org. Chem. 2006, 10, 1479.
17. (a) Andersson, P. G.; Schab, S. Organometallics 1995, 14, 1; (b) Takacs, J.; Lawson,
E. C.; Clement, F. J. Am. Chem. Soc. 1997, 119, 5956.
4. Ambrogio, I.; Cacchi, S.; Fabrizi, G. Org. Lett. 2006, 10, 2083.
5. Ambrogio, I.; Cacchi, S.; Fabrizi, G. Tetrahedron Lett. 2007, 48, 7721.
6. Cacchi, S.; Fabrizi, G.; Goggiamani, A. Adv. Synth. Catal. 2006, 348, 1301 and the
references cited therein.
7. Tsutsumi, K.; Kawase, T.; Kakiuchi, K.; Ogoshi, S.; Okada, Y.; Kurosawa, H. Bull.
Chem. Soc. Jpn. 1999, 72, 2687.
8. Tsutsumi, K.; Yabukami, T.; Fujimoto, K.; Kawase, T.; Morimoto, T.; Kakiuchi, K.
Organometallics 2003, 22, 2996.
9. Korawa, Y.; Mori, M. J. Org. Chem. 2003, 68, 8068.
10. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
11. For some recent selected references, see: (a) Hu¨bner, H.; Gmeiner, P.; Kraxner, J.
J. Med. Chem. 2000, 43, 4563; (b) Clifford, J. J.; Waddington, J. L. Neuro-
psychopharmacol. 2000, 22, 538; Ortner, B.; Waibel, R.; Gmeiner, P. Angew. Chem.,
Int. Ed. 2001, 40, 1283; (c) Moll, A.; Hu¨bner, H.; Gmeiner, P.; Troschutz, R. Bioorg.
Med. Chem. 2002,10,1671; (d) Brioni, J.D.;Kolasa,T.;Hsieh,G. C.; Donnelly-Roberts,
D. L. WO2002041894, 2002; Chem.Abstr. 2002,136, 395987; (e)Fliri, A. F. J.; Sanner,
M. A.; Seymour, P. A.; Zorn, S. H. Eur. Patent 1177792, 2002; Chem. Abstr. 2002, 136,
145264;(f)Fliri, A. F. J.; Majchrzak, M. J.; Seymour, P. A.; Zorn, S. H.; Rollema, H.
U.S. Patent 842,569, 2003; Chem.Abstr. 2003, 138, 401610; (g) Cowart, M.;
Latshaw, S. P.; Bhatia, P.; Daanen, J. F.; Rohde, J.; Nelson, S. L.; Patel, M.; Kolasa, T.;
Nakane, M.; Uchic, M. E.; Miller, L. N.; Terranova, M. A.; Chang, R.; Donnelly-
Roberts, D. L.; Namovic, M. T.; Hollingsworth, P. R.; Martino, B. R.; Lynch, J. J., III;
Sullivan, J. P.; Hsieh, G. C.; Moreland, R. B.; Brioni, J. D. S.; Andrew, O. J. Med. Chem.
2004, 47, 3853; (h) Stewart, A. O.; Cowart, M. D.; Moreland, R. B.; Latshaw, S. P.;
Matulenko, M. A.; Bhatia, P. A.; Wang, X.; Daanen, J. F.; Nelson, S. L.; Terranova,
M. A.; Namovic, M. T.; Donnelly-Roberts, D. L.; Miller, L. N.; Nakane, M.; Sullivan,
J. P.; Brioni, J. D. J. Med. Chem. 2004, 47, 2348.
18. Tsutsumi, K.; Ogoshi, S.; Nishiguchi, S.; Kurosawa, H. J. Am. Chem. Soc. 1998, 120,
1938.
19. Baize, M. W.; Blosser, P. W.; Plantevin, V.; Schimpff, D. G.; Gallucci, J. C.; Wojcicki,
A. Organometallics 1996, 15, 164.
20. For some examples of reactions involving a nucleophilic attack at the central sp
carbon of a
s-propargylpalladium complex to give a p-allylpalladium complex
which is further attacked by a second nucleophile, see: (a) Fournier-Nguefack,
C.; Lhoste, P.; Sinou, D. Synlett 1996, 553; (b) Labrosse, J.-R.; Lhoste, P.; Sinou, D.
Tetrahedron Lett. 1999, 40, 9025; (c) Labrosse, J.-R.; Lhoste, P.; Sinou, D. Org. Lett.
2000, 2, 527; (d) Yoshida, M.; Fujita, M.; Ishii, T.; Ihara, M. J. Am. Chem. Soc.
2003, 125, 4874; (e) Yoshida, M.; Morishita, Y.; Fujita, M.; Ihara, M. Tetrahedron
Lett. 2004, 45, 1861; (f) Yoshida, M.; Morishita, Y.; Fujita, M.; Ihara, M. Tetra-
hedron 2005, 61, 4381; (g) Duan, X.-H.; Guo, L.-N.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M.
Org. Lett. 2006, 8, 5777; (h) Guo, L.-Na.; Duan, X.-H.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M.
J. Org. Chem. 2007, 72,1538; (i) Bi, H.-P.; Liu, X.-Y.; Gou, F.-R.; Guo, L.-N.; Duan, X.-H.;
Liang, Y.-M. Org. Lett. 2007, 9, 3527; (j) Bi, H.-P.; Guo, L.-N.; Gou, F.-R.; Duan, X.-H.;
Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2008, 73, 4713; (k) Yoshida, M.; Higuchi, M.;
Shishido, K. Tetrahedron Lett. 2008, 49, 1678.
21. (a) Tsuji, J.; Yamakawa, T. Tetrahedron Lett. 1979, 613; (b) Tsuji, J.; Shimizu, I.;
Minami, I. Chem. Lett. 1984, 1017; (c) Tsuji, J.; Minami, I.; Shimizu, I. Synthesis
1986, 623; (d) Hutchins, R. O.; Learn, K. J. Org. Chem. 1982, 47, 4380; See also: (e)
Inomata, K.; Kinoshita, H. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; John Wiley & Sons: New York, NY, 2002; Vol. 2,
p 1887.
12. (a) Tsuji, J.; Yamanaka, T.; Mitsumasa, K.; Mandai, T. Tetrahedron Lett. 1978, 2075;
(b) Trost, B. M.; Verhoeven, T. R.; Fortunak, J. M. Tetrahedron Lett. 1979, 2301.
13. (a) Laronze, M.; Boisbrun, M.; Leonce, S.; Pfeiffer, B.; Renard, P.; Lozach, O.;
Meijer, L.; Lansiaux, A.; Bailly, C.; Sapi, J.; Laronze, J.-Y. Bioorg. Med. Chem. 2005,
13, 2263; (b) Abbiati, G.; Canevari, V.; Facoetti, D.; Rossi, E. Eur. J. Org. Chem.
22. Eitel, M.; Pindur, U. Synthesis 1989, 364.