2,3-Disubstituted indoles through the palladium-catalyzed reaction of aryl chlorides with o-alkynyltrifluoroacetanilides

Article abstract of DOI:10.1002/adsc.200606060

2,3-Disubstituted indoles can be prepared in moderate to excellent yields by reacting readily available o-alkynyltrifluoroacetanilides with aryl chlorides in MeCN at 120°C in the presence of Pd₂(dba)₃ and Xphos.

Full text of DOI:10.1002/adsc.200606060

UPDATES
DOI: 10.1002/adsc.200606060
2,3-Disubstituted Indoles through the Palladium-Catalyzed
Reaction of Aryl Chlorides with o-Alkynyltrifluoroacetanilides
Sandro Cacchi,a,* Giancarlo Fabrizi,a and Antonella Goggiamania
a
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi “La
Sapienza”, P. le A. Moro 5, 00185 Rome, Italy
Fax : (+39)-06–4991–2780; e-mail: sandro.cacchi@uniroma1.it
Received: February 13, 2006; Accepted: May 25, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: 2,3-Disubstituted indoles can be prepared
in moderate to excellent yields by reacting readily
available o-alkynyltrifluoroacetanilides with aryl
chlorides in MeCN at 1208C in the presence of
as coupling partners.[2] Therefore, as part of our con-
tinuing interest in the construction of the indole ring
from acyclic alkynes, we decided to explore the feasi-
bility of a process in which aryl chlorides could be
used as partners in a cyclization process leading to
Pd2(dba)3 and Xphos.
A
À
N H-free, 2-substituted 3-aryl-/heteroarylindoles 3
from o-alkynyltrifluoroacetanilides
1
(Scheme 1).
Keywords: alkynes; aminopalladation-reductive
elimination; cyclization; indoles; palladium
Herein we report the results of this study.
Introduction
The palladium-catalyzed reaction of o-alkynyltrifluor-
oacetanilides with organopalladium complexes gener-
ated in situ has been proved to be a remarkably effi-
cient and versatile procedure for the de novo con-
Scheme 1.
struction of the substituted pyrrole nucleus incorpo- Results and Discussion
rated into the indole system.[1] A wide variety of pre-
cursors of organopalladium complexes, required to The palladium-catalyzed reaction of o-(phenylethy-
trigger the cyclization of o-alkynyltrifluoroacetani- nyl)trifluoroacetanilide (1a) and p-chloroanisole (2a),
lides through the aminopalladation-reductive elimina- expected to be one of the most reluctant aryl chlor-
tion mechanism, have been successfully employed in ides to enter the catalytic cycle producing the desired
this chemistry, including aryl iodides, bromides, and indole products, was chosen as the model system for
triflates. Obviously, extension of the procedure to aryl our initial investigation of this cyclization process
chlorides would greatly widen its scope and generality (Scheme 2). The preparation of the starting alkyne for
because of the wider diversity of available compounds this chemistry is quite simple and straightforward. In
and their lower cost. Because of their reluctance to
undergo oxidative addition to Pd(0) centers, aryl
chlorides were known to be usually unreactive under
the conditions used for aryl iodides, bromides and tri-
flates. However, in the past seven years or so remark-
able progress has been achieved in their utilization in
À
palladium-catalyzed reactions and a vast array of C
C bond forming reactions (such as Suzuki, Stille, Ne-
gishi, Sonogashira cross-couplings and Heck reac-
À
À
tions) as well as C N and C O bond forming reac-
tions, usually referred to as Buchwald–Hartwig reac-
tions, has been accomplished by using aryl chlorides Scheme 2.
Adv. Synth. Catal. 2006, 348, 1301 – 1305
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1301

Sandro Cacchi et al.
UPDATES
general, the appropriate o-alkynyltrifluoroacetanilides 10% yield and the starting alkyne 1a was recovered
are readily available, usually in high yields, in two in 78% yield. When 1a was subjected to the palladi-
steps from o-iodoaniline via Sonogashira cross-cou- um catalyst in the presence of Cs2CO3, compound 4a
pling with terminal alkynes followed by a trifluorace- was isolated in 70% yield.
À
tylation step.[3]
The acidity of the N H bond, which plays an im-
One of the major problems in realizing this indole portant role in the aminopalladation-reductive elimi-
synthesis with relatively unreactive precursors of or- nation reaction (vide infra), was found to play an im-
ganopalladium complexes is the competitive forma- portant role in the formation of 4a as well. In fact,
tion of simple 2-substituted indoles 4, the formation whereas 1a was converted in high yield into 4a in the
of which does not involve the aryl halide partner. In presence of Pd
some cases, 2-substituted indoles can even be the (phenylethynyl)aniline containing a less acidic N H
main reaction products. bond was recovered in almost quantitative yield when
Indeed, when the reaction of 1a with 2a was at- it was subjected to the same conditions.
tempted under the reaction conditions that were suc- Since the palladium-catalyzed cyclization of 1a to
cessfully employed with aryl bromides[4] [Pd
(PPh3)4, 4a does not necessarily require the presence of phos-
Cs2CO3, MeCN] for 24 h, but increasing the tempera- phine ligands – as suggested by the isolation of 4a in
ture to 1208C, indole 3a was obtained in trace high yield with Pd2(dba)3 (Scheme 3) – whereas the
2(dba)3 and Cs2CO3 (Scheme 3), o-
À
AHCTREUNG
AHCTREUNG
amounts along with a 20% yield of 4a. The starting formation of s-arylpalladium complexes from aryl
alkyne was recovered in 53% yield and o-(phenyl- halides is strongly dependent on the nature of phos-
ethynyl)aniline, derived from the hydrolysis of 1a, was phine ligands,[1] we decided to explore the role of
isolated in 9% yield. No significantly better results phosphine ligands in controlling the 3 vs. 4 pathway.
were obtained by using Pd2(dba)3 as the Pd(0) source In particular, we turned our attention to the utiliza-
E
in the presence of Cs2CO3 and the air-stable HP- tion of biarylmonophosphines, a class of phosphine li-
(t-Bu)3BF4 (which is converted into the corresponding gands introduced by Buchwald et al.[7] which were
bulky phosphine ligand by simple deprotonation shown to produce catalyst systems with a greater
under the reaction conditions)[5] or 1,3-bis-(2,4,6-tri- degree of activity in the oxidative addition of aryl
methylphenyl)imidazolium chloride (shown to gene- chlorides to Pd(0) species than other commonly used
rate in situ, in the presence of Cs2CO3 as the base, the ligands. For example, they were reported to give ex-
corresponding carbene ligand)[6] in MeCN at 1208C cellent results in palladium-catalyzed C N bond
À
for 24 h. The efficacy of both these ligand precursors forming reactions[7b] and Suzuki–Miyaura cross-cou-
in palladium-catalyzed reactions of aryl chlorides pling reactions[7c] involving aryl chlorides. Some re-
were originally demonstrated via their successful uti- sults from that study are summarized in Table 1.
lization in Suzuki and Stille cross-couplings and Heck
reactions. However, when used with our model the presence of 0.025 equivs. of Pd
Treatment of 1a with 5 equivs. of p-chloroanisole in
AHCTREUNG
system they led to the formation of 3a in 5 and 10% phosphine ligand a–e and 1.5 equivs. of Cs2CO3 in
yield, respectively, with 2-phenylindole (4a) being iso- MeCN at 1208C produced 4a as the main product
lated in 60 and 45% yield.
(Table 1, entries 1–5). Acceptable results were instead
Control experiments revealed that both palladium obtained with monophosphine f, Xphos, under the
catalysis and base are required for the competitive same conditions (Table 1, entry 6). Decreasing the
cyclization of 1a to 4a (Scheme 3). Indeed, compound excess of p-chloroanisole to 3 equivs. gave similar re-
4a was isolated only in 4% yield together with an 8% sults (Table 1, entry 7) and with 1.5 equivs. of p-chloro-
yield of o-(phenylethynyl)aniline upon treatment of anisole 4a was isolated as the main product (Table 1,
1a with Cs2CO3 in MeCN at 1208C for 24 h while entry 8). We examined the effect of different amounts
omitting the palladium catalyst. The starting alkyne of Xphos and found that the best results were ob-
1a was recovered in 82% yield. In the presence of tained when 0.1 equiv. of the phosphine were used.
Pd2(dba)3 and omitting the base, 4a was formed in Increasing the amount of phosphine to 0.2 equivs. did
A
not afford better results (Table 1, entry 9) whereas
lower amounts of phosphine (0.05 equivs.) gave a
lower yield and a lower 3a to 4a ratio (Table 1,
entry 10). A further decrease to 0.025 equivs. led to
the formation of 4a as the main product (Table 1,
entry 11). Even a decrease in the reaction tempera-
ture to 908C favored the formation of 4a (Table 1,
entry 12).
A more polar solvent such as DMF (Table 1,
entry 15) afforded a higher 3a to 4a ratio, although
the yield of 3a was almost the same. The use of a less
Scheme 3.
1302
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Adv. Synth. Catal. 2006, 348, 1301 – 1305

Pd-Catalyzed Reaction of Aryl Chlorides with o-Alkynyltrifluoroacetanilides
UPDATES
Table 1. Biarylmonophosphine ligands in the palladium-catalyzed reaction of o-(phenylethynyl)trifluoroacetanilide (1a) with
p-chloroanisole.[a]
Entry Phosphine ligand
Equivs. of phosphine Equivs. of p-chloroanisole t [h] Yield of 3a [%][b] Yield of 4a [%][b]
1
a
0.1
0.1
5
5
7
4
94
59
2
b
24
15
3
4
c
0.1
0.1
5
5
24
8
27
36
48
42
d
5
e
0.1
5
7
23
75
6
7
8
9
10
11
12
13
14
15
f
f
f
f
f
f
f
f
f
f
0.1
0.1
0.1
5
3
1.5
3
3
3
3
3
3
8
8
24
8
11
9
6
2
1
2
57
55
33
58
50
37
10
50
58
58
26
25
41
26
38
40
0.2
0.05
0.025
0.1
0.1
0.1
58[c]
30[d]
13[e]
5[f]
0.1
3
[a]
Unless otherwise stated, reactions were run in MeCN under an argon atmosphere in the presence of 0.025 equivs. of Pd2
A
[b] Yields are given for isolated products.
[c]
At 908C.
[d] In toluene.
[e]
In toluene at 1408C.
[f] In DMF.
polar solvent such as toluene gave a slightly lower tuted indoles. No indole derivative was observed
yield at 1208C (Table 1, entry 13), but 4a was isolated when o-(phenylethynyl)aniline was subjected to p-
in 58% yield at 1408C (Table 1, entry 14).
chloroanisole in the presence of Pd2(dba)3, Cs2CO3,
A
The influence of the nature of the ortho nitrogen in Xphos in MeCN at 1208C after 24 h, the starting
this chemistry was also briefly investigated. Apparent- alkyne being recovered in 94% yield. Switching to o-
À
ly, the acidity of the N H bond plays a key role for (phenylethynyl)acetanilide as the starting alkyne af-
the success of the cyclization leading to 2,3-disubsti- forded a 12% yield of 3a and a 52% yield of 4a
Adv. Synth. Catal. 2006, 348, 1301 – 1305
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Sandro Cacchi et al.
UPDATES
Table 2. Synthesis of 2,3-disubstituted indoles 3 via the palla-
dium-catalyzed reaction of o-(phenylethynyl)trifluoroacet-
anilide (1a) with aryl chlorides 2.[a]
We next extended the procedure to o-alkynyltri-
fluoroacetanilides bearing electron-donating, elec-
tron-withdrawing, and alkyl substituents on one of the
acetylenic carbons. Their reaction with a variety of
aryl chlorides produced the corresponding 2,3-disub-
stituted indoles in moderate to high yields. The results
obtained are summarized in Table 3 and confirm the
tendency of electron-poor and almost neutral aryl
chlorides to give better results than electron-rich aryl
chlorides. o-Alkynyltrifluoroacetanilide 1c, bearing an
alkyl substituent, gave lower yields than o-alkynyltri-
fluoroacetanilides bearing aryl substituents (compare
entry 4 with entries 3 and 8).
Entry Aryl chloride 2
t [h]
3
Yield
[%][b]
1
2
3
4
5
6
7
8
p-MeO-C6H4-Cl
m-MeO-C6H4-Cl
p-Me-C6H4-Cl
o-Me-C6H4-Cl
PhCl
p-Me-CO-C6H4-Cl
m-MeO-CO-C6H4-Cl 2g
2a overnight 3a
55
88
48
40
90
94
84
85
2b
2c
2d
2e
2f
3
3b
3c
3d
3e
3f
3g
3h
5.5
5.5
3.5
2
3
m-CF3-C6H4Cl
2h
1.5
As to the mechanism, we believe that the forma-
tion of 2,3-disubstituted indoles proceeds through
the aminopalladation-reductive elimination path[1]
which involves the following basic steps: (a) forma-
tion of a p-alkyne-s-arylpalladium complex via coor-
dination of 1 to a s-arylpalladium intermediate gen-
erated in situ via oxidative addition of the aryl chlo-
ride to Pd(0), (b) intramolecular nucleophilic attack
of the nitrogen across the activated carbon-carbon
triple bond, (c) reductive elimination of the resultant
s-pyrrolyl-s-arylpalladium intermediate which af-
fords the indole product 3 and regenerates the active
9
2i
3
2
3i
3j
83
80
10
2j
[a]
Reactions were run in MeCN under an argon atmosphere
in the presence of 0.025 equivs. of Pd2(dba)3 , 0.1 equiv. of
Xphos, and 1.5 equivs. of Cs2CO3 at 1208C.
[b] Yields are given for isolated products.
AHCTREUNG
(24 h) and using o-(phenylethynyl)trifluoroacetanilide palladium catalyst.
(1a) gave 3a and 4a in 55 and 25% yields, respectively
(Table 1, entry 7).
Formation of 2,3-disubstituted indoles 3 via direct
palladium-catalyzed C-3 arylation of 2-substituted in-
On the basis of our screening study, we decided to doles 4 – derived from the cyclization of 1 (Scheme 3)
choose MeCN as the most convenient solvent when – was ruled out by the following experiment. 2-Phe-
the reaction was extended to other o-alkynyltrifluoro- nylindole was subjected to the reaction conditions
acetanilides and aryl chlorides. As shown in Table 2, producing 2,3-disubstituted indoles in the presence of
under the conditions used in Table 1, entry 7 [Pd2 p-chloroacetophenone (2f), one of the aryl chlorides
(dba)3, Cs2CO3, Xphos, MeCN, 1208C] excellent re- which gave the highest yields (Table 2, entry 6;
sults were obtained with neutral (entry 5), electron- Table 3, entries 2 and 7). 2-Phenylindole was recov-
poor (entries 2, 6–8) aryl chlorides and heteroaryl ered in 73% yield and no evidence was attained for
chlorides (entries 9 and 10) whereas moderate to the formation of 2-phenyl-3-(p-acetylphenyl)indole
good yields were observed with electron-rich aryl (Scheme 4).
chlorides (entries 1, 3, and 4).
Table 3. Synthesis of 2,3-disubstituted indoles 3 via the palladium-catalyzed reaction of o-alkynyltrifluoroacetanilides 1 with
aryl chlorides 2.[a]
Entry
o-Alkynyltrifluoroacetanilide R (1)
Aryl chloride (2)
t [h]
3
Yield [%][b]
1
2
3
4
5
6
7
8
p-MeO-C6H4
p-MeO-C6H4
p-MeO-C6H4
n-C5H11
1b
1b
1b
1c
1c
1d
1d
1d
p-MeO-C6H4-Cl
p-Me-CO-C6H4-Cl
PhCl
2a
2f
2e
2e
2g
2b
2f
2e
5
5
3
1.5
1.5
2.5
1
3k
3l
40
73
60
40
54
56
87
50
3m
3n
3o
3p
3q
3r
PhCl
n-C5H11
m-MeO-CO-C6H4-Cl
m-MeO-C6H4-Cl
p-Me-CO-C6H4-Cl
PhCl
p-Me-CO-C6H4
p-Me-CO-C6H4
p-Me-CO-C6H4
5.5
[a]
Reactions were run in MeCN in the presence of 0.025 equivs. of Pd2(dba)3, 0.1 equiv of Xphos, and 1.5 equivs. of Cs2CO3
A
at 1208C.
[b] Yields are given for isolated products.
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Adv. Synth. Catal. 2006, 348, 1301 – 1305

Pd-Catalyzed Reaction of Aryl Chlorides with o-Alkynyltrifluoroacetanilides
UPDATES
(16.5 mg, 0.0346 mmol), and Cs2CO3 (169 mg, 0.519 mmol).
The mixture was stirred for 3 h at 1208C under argon. After
this time, the reaction mixture was cooled to room tempera-
ture, diluted with ethyl acetate, and washed with water. The
organic extract was dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by chro-
matography (silica gel, n-hexane/EtOAc, 85/15 v/v) to give
3g; yield: 94.9 mg (84%); mp: 187–1888C; IR (KBr): n=
1
3326, 1702, 1455 cmÀ1; H NMR (CDCl3): d=8.46 (bs, 1H),
8.28–8.25 (m, 1H), 8.03–7.99 (m, 1H), 7.70 (d, J=7.6 Hz,
1H), 7.60–7.56 (m, 1H), 7.49–7.27 (m, 8H), 7.21 (t, J=
7.21 Hz, 1H), 3.93 (s, 3H); 13C NMR (CDCl3): d=167.4,
135.9, 134.9, 132.4, 131.2, 130.6, 128.8, 128.7, 128.6, 128.2,
127.9, 127.5, 122.9, 120.7, 119.4, 114.0, 111.1, 52.1; MS: m/z
(relative intensity)=327 (M+, 95), 133 (100); calcd. for
C22H17NO2: 327.38.
Scheme 4.
Conclusions
In conclusion, we have developed a convenient
straightforward approach for the construction of the
functionalized pyrrole ring incorporated into the
indole system from readily available o-alkynyltrifluoro-
acetanilides and aryl chlorides, thus widening signifi-
cantly the scope of our indole synthesis. 2,3-Disubsti-
tuted indoles are isolated in moderate to excellent
yields. The reaction tolerates a variety of important
functional groups.
Acknowledgements
Work carried out in the framework of the National Project
“Stereoselezione in Sintesi Organica. Metodologie ed Appli-
cazioni” was supported by the Ministero dell’Università e
della Ricerca Scientifica e Tecnologica and by the University
“La Sapienza”
Experimental Section
References
Melting points were determined with a Büchi B-545 appara-
tus and are uncorrected. o-Alkynyltrifluoroacetanilides 1
were prepared according to the procedure described in the
literature.[8] All of the reagents and the catalysts are com-
mercially available and were used as purchased, without fur-
ther purification. Reaction products were purified on axially
compressed columns, packed with SiO2 25–40 mm (Macher-
ey&Nagel), connected to a Gilson solvent delivery system
and to a Gilson refractive index detector, and eluting with
n-hexane/ethyl acetate mixtures. 1H NMR (400 MHz) and
13C NMR (100.6 MHz) spectra were recorded with a Bruker
Avance 400 spectrometer. IR spectra were recorded with a
Jasco FT-IR 430 spectrometer.
[1] a) For reviews, see: G. Battistuzzi, S. Cacchi, G. Fabrizi,
Eur. J. Org. Chem. 2002, 2671; b) S. Cacchi, F. Fabrizi,
Chem. Rev. 2005, 105, 2873; see also: c) A. Arcadi, S.
Cacchi, G. Fabrizi, F. Marinelli, L. M. Parisi, J. Org.
Chem. 2005, 70, 6213.
[2] For a recent review on palladium-catalyzed reactions of
aryl chlorides, see: A. F. Littke, G. C. Fu, Angew. Chem.
Int. Ed. 2002, 41, 4176.
[3] S. Cacchi, G. Fabrizi, P. Pace, J. Org. Chem. 1998, 63,
1001.
[4] S. Cacchi, G. Fabrizi, D. Lamba, F. Marinelli, L. M.
Parisi, Synthesis 2003, 728.
[5] M. Netherton, G. C. Fu, Org. Lett. 2001, 3, 4295.
[6] C. Zhang, J. Huang, M. L. Trudell, S. P. Nolan, J. Org.
Chem. 1999, 64, 3804.
[7] a) D. W. Old, J. P. Wolfe, S. L. Buchwald, J. Am. Chem.
Soc. 1998, 120, 9722; see also: b) X. Huang, K. W. An-
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Walker, J. R. Martinelli, S. L. Buchwald, J. Am. Chem.
Soc. 2005, 127, 4685.
Typical Procedure for the Preparation of 2,3-Disub-
stituted Indoles (3) from o-Alkynyltrifluoro-
acetanilides (1) and Aryl/Heteroaryl Chlorides (2)
To a 50 mL Carousel Tube Reactor (Radleys Discovery
Technology) containing a magnetic stirring bar were added
2.0 mL of MeCN, 1a (100 mg, 0.346 mmol), 2g (144 mL,
[8] S. Cacchi, G. Fabrizi, P. Pace, J. Org. Chem. 1998, 63,
1001.
1.039 mmol), Pd2(dba)3 (7.9 mg, 0.0087 mmol), Xphos
A
Adv. Synth. Catal. 2006, 348, 1301 – 1305
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