2-Substituted 3-arylindoles through palladium-catalyzed arylative cyclization of 2-alkynyltrifluoroacetanilides with arylboronic acids under oxidative conditions

Article abstract of DOI:10.1039/c2ob27125g

Free NH 2-substituted 3-arylindoles have been prepared usually in good to high yields through the palladium-catalyzed reaction of readily available 2-alkynyltrifluoroacetanilides with arylboronic acids under oxidative conditions. The reaction tolerates a variety of useful functional groups both in the arylboronic acid and in the alkyne, including chloro, formyl, and ester groups.

Full text of DOI:10.1039/c2ob27125g

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2-Substituted 3-arylindoles through
palladium-catalyzed arylative cyclization of
2-alkynyltrifluoroacetanilides with arylboronic
acids under oxidative conditions†
Cite this: Org. Biomol. Chem., 2013, 11,
545
Received 31st October 2012,
Accepted 21st November 2012
Antonio Arcadi,*a Sandro Cacchi,b Giancarlo Fabrizi,b Antonella Goggiamani,*b
Antonia Iazzettib and Fabio Marinellia
DOI: 10.1039/c2ob27125g
www.rsc.org/obc
Free NH 2-substituted 3-arylindoles have been prepared usually in the palladium-based chemistry of organoboron compounds
good to high yields through the palladium-catalyzed reaction of has been extended to include the oxidative carbonylation to
readily available 2-alkynyltrifluoroacetanilides with arylboronic form esters11 and the reaction with carbon–carbon multiple
acids under oxidative conditions. The reaction tolerates a variety bonds as coupling partners. In the latter context, the arylation
of useful functional groups both in the arylboronic acid and in the of olefins via oxidative Heck reactions has attracted consider-
alkyne, including chloro, formyl, and ester groups.
able interest.12 Less attention has been paid to the palladium-
catalyzed reaction of organoboron compounds with alkynes.
Relatively few papers have shown its potential in the synthesis
of polysubstituted olefins via hydroarylation13 and diaryla-
tion14 reactions.
We hypothesized that the palladium-catalyzed reaction of
alkynes bearing proximate nucleophiles with boronic acids
could provide a new access to functionalized heterocycles via a
heteroarylation process (Scheme 1).
2-Alkynyltrifluoroacetanilides appeared to us to be particu-
larly attractive substrates to probe the feasibility of this chem-
istry as in the case of success a new tool for the construction
of the functionalized free NH pyrrole nucleus incorporated
into the indole system would be available.
We started our study by examining the reaction of 2-phenyl-
ethynyltrifluoroacetanile 1a9 with 4-methoxyphenylboronic
acid 2a (2 equiv.) in the presence of Pd(OAc)2 (0.05 equiv.),
dppp (0.05 equiv.), and K2CO3 (2 equiv.) at 80 °C under a
balloon of oxygen. The effect of solvents, other phosphine
Enormous interest has been devoted to the synthesis of indole
scaffolds. Because of their unique biological and physical
properties, which make these target motifs useful for the prep-
aration of pharmaceutical ingredients and innovative
materials, this research area is continuously active.1 In recent
years, the focus was on transition metal-catalyzed transform-
ations and particularly on the use of palladium catalysis.2
Among them, the palladium-catalyzed reaction of organic
electrophiles with 2-alkynyltrifluoroacetanilides has been
shown to constitute a versatile tool for the synthesis of 3- and
2,3-disubstituted indoles.2c,3 A variety of organic electro-
philes such as aryl/heteroaryl,4 alkyl,5 and alkynyl halides,6
α-iodoenones,7 aryl4d and vinyl triflates,4c,e,g arenediazonium
tetrafluoroborates,8 and allyl esters9 have been successfully
employed.
Organoboron reagents are widely used in carbon–carbon
bond forming reactions.10 Their availability, stability, good
functional group tolerance, nontoxicity, and ease of handling
make them very attractive aryl and vinyl donors. Nowadays,
classical Suzuki cross-coupling reactions of organoboron com-
pounds with aryl or vinyl halides or triflates represent a well
established methodology in organic synthesis. In recent years,
aDipartimento di Scienze Fisiche e Chimiche, Università degli Studi di L’Aquila,
Via Vetoio, 67010 Coppito, L’Aquila, Italy. E-mail: antonio.arcadi@univaq.it
bDipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Università di Roma,
P.le A. Moro 5, 00185 Rome, Italy. E-mail: antonella.goggiamani@uniroma1.it;
Fax: +39 (06) 4991-2789; Tel: +39 (06) 4991-2795
†Electronic supplementary information (ESI) available: A complete descrip-
tion of experimental details and product characterization. See DOI:
10.1039/c2ob27125g
Scheme 1 Our working hypothesis.
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Table 1 Optimization studiesa
Table 2 Synthesis of 2,3-diarylindoles 3a
Equiv. Time Yieldb %
Entry R1
R2
R3
of 2
(h)
of 3
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-OMe
H
2
2
2
3
2
2
2
3
3
3
2
2
2
2
3
2
2
2
1.5
2
9
3
1
1.5
2
4
24
2
3
4
2
2
3
3
24
4
76 3a
65 3b
43 3c
83 3c
73 3d
65 3e
58 3f
75 3g
31 3h
66 3i
54 3j
55 3k
59 3l
59 3m
47 3n
—
4-CO2Me
4-CO2Me
4-Me
2-Me
1-Naph
4-Cl
Yieldb (%)
Entry Ligand
Base
Solvent
MeCN
Dioxane 80/24
MeOH
T (°C)/t (h) 3a 4a 5a
1
2
3
4
5
6
7
8
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dpppO
dppe
K2CO3
K2CO3
K2CO3
80/24
5
—
—
3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
41
—
—
—
68
60
40
9
H
H
Cl
4-COMe
4-OMe
4-OMe
4-OMe
H
4-Br
80/2
80/2
10
11
12
13
14
15
16
17
18
3-CHO
4-OMe
H
Cs2CO3 MeOH
K3CO4
NaOAc
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
80/1.1
80/21
60/2
60/1.5
60/1.5
60/2.5
60/1.5
60/1.5
80/5
19 71
H
68
76
51
69
23 15
69
38
—
—
—
—
4-Me
4-CO2Me
H
H
4-SMe
9c
10d
11
12
13
14
15
16
17
18
19
20
21
4-CO2Me
4,6-Me2
H
H
34c 3o
71 3p
3-CO2Me
—
7
a Reactions were carried out at 60 °C under a balloon of oxygen on a
0.345 mmol scale in 2 mL of MeOH using 1 equiv. of 3, 0.05 equiv. of
Pd(OAc)2, 0.05 equiv. of dppp, 2 or 3 equiv. of 2, and 2 equiv. of K3PO4.
b Yields are given for isolated products. c Calculated by NMR analysis.
Xantphos K2CO3
dppb
dppm
dppf
PPh3
P(o-tol)3
Xphos
—
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
K3PO4
80/3
80/3
17 53
25 41
80/6
80/2
80/2
80/5
60/8
60/7
11 46 14
—
52
—
—
—
—
—
10 66
32 40
12 25
—
4
90
(entry 6). Lowering temperature to 60 °C gave the same result
with K2CO3 (entry 7) while K3PO4 afforded 3a in higher yield
(entry 8).
Interestingly, when 2-(phenylethynyl)aniline was treated
with 2a under the same conditions the starting material was
recovered in 55% yield after 7 h and only traces of 3a were
detected showing that the protecting/activating trifluoroacetyl
group plays a key role in the success of the reaction, possibly
generating an anionic nucleophile.
a Unless otherwise stated, reactions were carried out on a 0.345 mmol
scale in 2 mL of solvent under a balloon of oxygen using 1 equiv. of 3a,
0.05 equiv. of Pd(OAc)2, 0.05 equiv. of ligand, 2 equiv. of 2a, and 2
equiv. of base. b Yields are given for isolated products. c With 1.2 equiv.
of 2a. d Under an atmosphere of air.
ligands, bases, and temperature on the yield of 3a was explored
and some of our results are shown in Table 1.
Decreasing the excess of boronic acid to 1.2 equiv. (entry 9)
or changing oxygen with air as the final oxidant (entry 10) led
to lower yields. As to the ligands, poor yields were obtained
omitting them (entries 20, 21) or in the presence of monophos-
phines (entries 17–19). Bidentate phosphines such as Xant-
phos, dppb, dppm, dppf, and dppO15 were also ineffective
(entries 11, 13–16).
Under a variety of conditions, the competitive cyclization of
1a to 4a revealed to be a significant side reaction (entries 11,
13) or even the main reaction path (entries 6, 14–21). In a
few cases the dimer 5a was also isolated in significant
yield (entries 13, 16). Formation of variable amounts of
4,4′-dimethoxybiphenyl, possibly derived from the palladium-
catalyzed coupling of 2a, was also observed.
Thus, the optimized conditions described in entry 8 of
Table 1 were chosen for exploring the scope of this chemistry.
As shown in Table 2, electron-neutral and electron-rich aryl-
boronic acids, even bearing a methyl substituent in the ortho
position, work quite well when 2-(phenylethynyl)trifluoroacet-
anilide (R1 = R2 = H) is used as the alkyne (entries 1, 2, 5, 6).
Solvents were found to play a key role. MeOH was by far the
most effective (entry 3) while MeCN and dioxane gave dis-
appointing results (entries 1, 2). Among the bases that we
tested, moderate to good yields were obtained with K2CO3,
Cs2CO3, and K3PO4 (entries 3–5) whereas using NaOAc
afforded 3a in low yield, the main reaction product being 4a
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The lower yield obtained when 1-naphthylboronic acid was
employed possibly arises from a less facile transmetalation
due to steric effects (entry 7). The relatively electron-poor
4-chlorophenylboronic acid also gave the desired indole deriva-
tive in high yield (entry 8). It is interesting that the remaining
halide functionality may serve as a valuable handle for increas-
ing molecular complexity through transition metal-catalyzed
cross-coupling reactions. However, only a 31% yield of the cor-
responding indole was obtained with 4-bromophenylboronic
acid (entry 9). 2-(Phenylethynyl)aniline, derived from the
hydrolysis of the trifluoroacetamido group, and 4a, derived
from the intramolecular cyclization of 1a, were isolated in 20
and 34% yield, respectively. Very likely, competitive oxidative
addition of the carbon–bromo bond to Pd(0) species generated
under the reaction conditions may take place. This decreases
the excess of the arylboronic acid, thus favoring the forma-
tion of by-products. Electron-poor arylboronic acids proved
to be less effective, probably because of their lower nucleophi-
licity (entry 3), and an excess of 3 equiv. was required to
afford the indole derivative in good to high yields (entries 4
and 10).
Scheme 2 The palladium-catalyzed synthesis of 2-alkyl- and 2-alkenyl-3-
arylindoles.
Further investigations of the substrate scope showed that
substituents on the anilide ring have a strong influence on the
reaction outcome, at least with the substituents that we tested.
None of the indole product was observed with the 4-COOMe
group (entry 16). Apparently, the presence of a strongly elec-
tron-withdrawing substituent decreases the nucleophilicity of
the (anionic) trifluoroacetamide fragment favoring instead the
hydrolysis of the amide bond. The corresponding alkynylani-
line, derived from the hydrolysis of the amide bond, was iso-
lated in 85% yield. Only a 34% yield of the corresponding
indole was obtained when the 4,6-dimethyl derivative
(entry 17) was employed, most probably because of the ortho
effect of the 6-methyl group decreasing the acidity of the NH
bond and, consequently, the concentration of the anionic
nucleophile.
Both electron-donating and -withdrawing substituents are
tolerated on the other aromatic ring (entries 11–15, 18),
although yields are in some cases slightly lower than those
observed with the parent phenyl ring.
Scheme 3 Proposed reaction mechanism.
Finally, the cyclization of 2-(heptyn-1-yl)- and 2-(4-phe-
nylcyclohex1-en-1-yl)trifluoroacetanilide with 4-methyl- and
3-methoxyphenylboronic acid, respectively, afforded the corres-
ponding indole derivatives 3q and 3r in moderate yields
(Scheme 2).
As to the mechanism, we believe that the reaction proceeds
through a process (Scheme 3) that starts with the formation of
the π-alkynepalladium complex A. A subsequent intramolecu-
lar nucleophilic attack of the anionic nitrogen across the acti-
vated carbon–carbon triple bond gives the σ-indolylpalladium
complex B. Its reaction with arylboronic acid affords the inter-
mediate C from which the indole derivative 3 is obtained by
reductive elimination. An oxidation step then regenerates the
active palladium catalyst. However, the formation of 3, at least
arising from the reaction of palladium with the arylboronic
acid16 cannot be ruled out.
In conclusion, an efficient alternative approach to free N–H
2,3-disubstituted indoles from 2-alkynyltrifluoroacetanilides
and arylboronic acids under oxidative conditions has been
developed. The new method affords indole derivatives usually
in good to high yields and tolerates a variety of useful func-
tional groups both in the arylboronic acid and in the alkyne,
including chloro, formyl, and ester groups, as well as ortho
substituents in the arylboronic acid.
Acknowledgements
in part, through the alternative aminopalladation/reductive We gratefully acknowledge MURST and the University
elimination pathway that involves an arylpalladium complex “La Sapienza”, Rome, for financial support.
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