2-Alkylindoles via palladium-catalyzed reductive cyclization of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargyl carbonates

Article abstract of DOI:10.1016/j.tetlet.2007.07.213

The reaction of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargyl carbonates with formate anions in the presence of Pd(PPh₃)₄ affords 2-alkylindoles in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2007.07.213

Tetrahedron Letters 48 (2007) 7721–7725
2-Alkylindoles via palladium-catalyzed reductive cyclization
of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargyl carbonates
Ilaria Ambrogio, Sandro Cacchi* and Giancarlo Fabrizi
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive,
`
Universita degli Studi ‘La Sapienza’, P.le A. Moro5, 00185 Roma, Italy
Received 15 June 2007; revised 27 July 2007; accepted 31 July 2007
Available online 3 August 2007
Abstract—The reaction of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargyl carbonates with formate anions in the presence of
Pd(PPh3)4 affords 2-alkylindoles in good to excellent yields.
Ó 2007 Elsevier Ltd. All rights reserved.
The substituted indole nucleus is an ubiquitous motif in
a vast array of biologically active natural and unnatural
compounds. In view of this, the construction of this
structural unit through cyclization of suitable benzenoid
precursors has attracted the interest of many research
groups and palladium catalysis has provided an almost
unique tool to develop a wide range of synthetic strate-
gies.1 Based on our continuing interest in indole chemis-
try,2 we recently developed a new straightforward
approach to the construction of the indole ring system
whereby 2-aminomethylindoles can be prepared through
the palladium-catalyzed reaction of ethyl 3-(o-trifluoro-
acetamidophenyl)-1-propargyl carbonate with amines,
generating two C–N bonds in a single operative step3
(Scheme 1).
3-unsubstituted 2-alkylindoles 2, including 2-benzylin-
doles (Scheme 2). Despite the interest for 3-unsubsti-
tuted 2-alkylindoles as synthetic intermediates,4 the
number of available routes to this class of compounds
is quite limited5 and the development of new straightfor-
ward procedures is desirable.
The starting ethyl 3-(o-trifluoroacetamidophenyl)-1-
propargyl carbonates 1 were prepared, usually in good
to high overall yields, from the corresponding o-iodotri-
fluoroacetanilide through Sonogashira cross-coupling
with propargylic alcohols (obtained, in turn, via reaction
of aldehydes with commercially available ethynylmagne-
sium chloride) followed by the reaction of the resultant
coupling product with ethyl chloroformate.6
We now report that subjecting ethyl 3-(o-trifluoroacet-
amidophenyl)-1-propargyl carbonates 1 to formate
anions as a reducing agents in the presence of a palla-
dium catalyst provides a ready access to NH free
Initial cyclization attempts were directed toward finding
a general set of reaction conditions that could be
applied to a wide range of ethyl 3-(o-trifluoroacetamido-
phenyl)-1-propargyl carbonates. Compound 1a (R1 =
R2 = H) was selected as the model system and the fol-
lowing reaction variables were examined: the source of
Pd(0) species, the nature of the ligands, the source of
OCOOEt
Pd(PPh3)4
NHR2
THF, 80 °C
N
NR2
NHCOCF3
H
OCOOEt
R2
Pd(PPh3)4
HCOOH, Et3N
R1
R1
Scheme 1.
R2
MeCN, 80 °C
N
H
2
NHCOCF3
Keywords: Alkylindoles; Cyclization; Palladium; Alkynes; Propargyl
esters.
1
*
Corresponding author. Tel.: +39 06 4991 2795; fax: + 39 06 4991
2780; e-mail: sandro.cacchi@uniroma1.it
Scheme 2.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.213

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I. Ambrogio et al. / Tetrahedron Letters 48 (2007) 7721–7725
Table 1. Palladium precatalysts, formate anions, solvents, and temperature in the cyclization of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargyl
carbonate 1a to 2-methylindole 2aa
Entry
Palladium precatalyst
Reducing agent
Base
Solvent
t (h)
2a yieldb (%)
3a yieldb (%)
c
1
2
3
4
5
6
7
8
9
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3/dppe
HCOOK
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
—
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
—
7
5
12
10
19
8
d
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
d
5
—
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 Yields are given for isolated products.
c Pd(OAc)2–PPh3 = 1:4.
d Pd(OAc)2–PPh3 = 1:2.
e In the presence of 1 equiv of H2O.
formate anions, solvents, and temperature. Some of
the results of our screening study are summarized in
Table 1.
Me
N
CHO
3a
Utilization of HCOOH in the presence of Et3N proved
to be superior to HCOOK (compare entry 1 with entry
2) and Pd(PPh3)4 gave better results than
Pd(OAc)2(PPh3)2 (compare entry 3 with entry 4). Under
a variety of conditions the main byproduct was N-
formylindole 3a which in some cases was isolated in
significant yields (entries 4–6).
The best result in terms of yield and reaction time was
obtained using Pd(PPh3)4, HCOOH, and Et3N in
MeCN (entry 8). In the presence of dppe-reported to
be the best ligand for the palladium-catalyzed reaction
of propargyl halides7 and carbonates8 with soft nucleo-
philes and to give more stable p-propargylpalladium
Table 2. Palladium-catalyzed reductive cyclization of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargyl carbonates 1 to 2-alkylindoles 2a
Entry
1
t (h)
2-Alkylindole 2
Yieldb (%)
R1
H
R2
H
1
1a
1
2a
91
N
H
2
H
H
Me
Et
1b
1c
1
2
2b
2c
70
70
N
H
3b
N
H
4
5
H
H
n-Pr
1d
1e
1
3
2d
2e
67
75
N
H
Ph
N
H
Ph
6
7
4,6-Me2
4-Me
H
H
1f
1
2f
99
80
N
H
1g
0.5
2g
N
H

I. Ambrogio et al. / Tetrahedron Letters 48 (2007) 7721–7725
7723
Table 2 (continued)
Entry
1
t (h)
2-Alkylindole 2
Yieldb (%)
R1
R2
8
4-Me, 6-NO2
H
1h
2
2h
78
N
H
NO2
Cl
9
4-Me, 6-Cl
4,6-Me2
H
1i
1j
2
1
2i
2j
51
50
N
H
10
Ph
N
H
Ph
Cl
F
11
12
4-Cl
H
H
1k
1l
0.5
1
2k
2l
60
65
N
H
4-F, 6-Me
N
H
Cl
13
14
4-Cl, 6-CF3
H
1m
1n
1
1
2m
2n
86
75
c
N
H
CF3
H
3-MeO–C6H4
N
H
OMe
N
H
15
H
4-MeO–C6H4
1o
24
2o
—
OMe
N
H
16
17
H
4-F–C6H4
1p
1q
1
2
2p
2q
85
72
F
4,6-Me2
3-MeO–C6H4
N
H
OMe
Cl
18
4-Cl,6-CF3
3-MeO–C6H4
1r
0.5
2r
85
N
H
OMe
CF3
O
19
20
4-MeCO
H
H
1s
1t
0.66
1
2s
2t
73
70
N
H
O
MeO
4-MeOCO
N
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.
b Yields are given for isolated products.
c The starting material was recovered in 11% yield and the reduction product 4o was isolated in 38% yield.

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I. Ambrogio et al. / Tetrahedron Letters 48 (2007) 7721–7725
complexes,9 likely intermediates in this type of chemistry
(vide infra)—the reaction gave a slightly lower yield
(entry 9). Consequently, Pd(PPh3)4, HCOOH, and
Et3N in MeCN were used when this cyclization to in-
doles was extended to other ethyl 3-(o-trifluoroacet-
amidophenyl)-1-propargyl carbonates10 (Table 2).
Acknowledgments
Work carried out in the framework of the National Pro-
ject ‘Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni’, supported by the Ministero dell’Univer-
`
sita e della Ricerca Scientifica e Tecnologica and by
the University ‘La Sapienza’.
2-Alkylindoles 2 were isolated in good to high yields
with a wide range of ethyl 3-(o-trifluoroacetamidophe-
nyl)-1-propargyl carbonates. The only exception among
the substrates that we have investigated is propargyl
derivative 1o (Table 2, entry 15). In this case, no evi-
dence of the desired indole product was attained. The
reason of this behavior was not further investigated.
References and notes
1. (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873–
2920; (b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
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2. Cacchi, S.; Fabrizi, G.; Goggiamani, A. Adv. Synth. Catal.
2006, 348, 1301–1305, and references cited therein.
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Taber, D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058–
1059; (k) Sanz, R.; Escribano, J.; Pedrosa, M. R.; Aguado,
As to the mechanism of this cyclization to indoles, we
believe that the reaction proceeds through the basic
steps shown in Scheme 3 for 1a: (a) formation of r-alle-
nylpalladium complex 4, in equilibrium with p-propar-
gylpalladium intermediate 5,11 via an SN20reaction of
the palladium complex with 1a, which releases CO2
and the ethoxide anion (this anion formally deproto-
nates the NH group), (b) intramolecular nucleophilic at-
tack of the nitrogen at the central carbon of the allenyl/
propargylpalladium complex,9,12,13 (c) conversion of the
resultant carbene 6 into p-allylpalladium complex 7, (d)
formation of 2 by concerted decarboxylation and
hydride transfer to one of the allylic termini of p-allyl-
palladium complex 8.14
To sum up, we have developed a useful new approach to
2-alkylindoles, usually isolated in good to high yields.
The procedure is simple and straightforward, and
provides a valuable alternative to the preparation of this
class of compounds through the Pd(II)-catalyzed cycli-
zation of o-alkynylanilides.5a o-Alkynylanilides are
prepared from o-haloanilides and terminal alkynes,
and the latter are not always readily available. The
required alkyne component for the present cyclization
can be readily prepared from ethynylmagnesium chlo-
ride and aldehydes.
´
R.; Arnaiz, F. J. Adv. Synth. Catal. 2007, 349, 713–718;
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Caselli, A.; Fantauzzi, S. Curr. Org. Chem. 2006, 10, 1479–
1510.
6. Typical procedure for the preparation of (1). Sonogashira
cross-coupling: o-Iodotrifluoroacetanilide (1.50 g, 4.76
mmol), PdCl2(PPh3)2 (0.067 g, 0.09 mmol) and CuI
(0.018 g, 0.09 mmol) were dissolved in 1.5 mL of DMF,
6.0 mL of Et(i-Pr)2N and 3.0 mL of (i-Pr)2NH. The
mixture was stirred under argon for 30 min. Then, a
solution of 1-(3-methoxyphenyl)-2-propyn-1-ol (0.925 g,
5.71 mmol) in 3.0 mL of (i-Pr)2NH was added dropwise in
5 min. The resulting reaction mixture was stirred at room
temperature for 12 h. After this time the reaction mixture
was diluted with Et2O, washed twice with a saturated
NH4Cl solution, dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by
chromatography (SiO2, 140 g; n-hexane/AcOEt 70/30 v/v)
to give 1.492 g (90% yield) of 1-(3-methoxyphenyl)-3-(2-
trifluoroacetamido)-2-propyn-1-ol. Acylation of the cross
coupling product: 1-(3-methoxyphenyl)-3-(2-trifluoroace-
tamido)-2-propyn-1-ol (1.00 g, 2.86 mmol) and 4-dimeth-
ylaminopyridine (0.524 g, 4.3 mmol) were dissolved in
5.0 mL of CH2Cl2 and stirred at ꢀ20 °C for 10 min. Then,
a solution of ClCOOEt (0.367 g, 3.4 mmol) in 1.0 mL of
CH2Cl2 was added at the same temperature dropwise in
5 min. The resulting reaction mixture was stirred at
ꢀ20 °C for 3 h. After this time, the reaction mixture was
diluted with AcOEt, washed twice with a HCl 2 N solution
OCO2Et
1a
NHCOCF3
CO2
N
CF3COOEt
H
2
CO2
Pd(0)
(a)
(d)
N
EtOH
EtOH
Pd
N
Pd
OCOH
Pd
N
4
5
COCF3
COCF3
7
COCF3
Pd
Et3N
(c)
(b)
N
Et3NH
HCOO
6
COCF3
Scheme 3.

I. Ambrogio et al. / Tetrahedron Letters 48 (2007) 7721–7725
7725
and once with a saturated NaCl solution, dried over
Na2SO4 and concentrated under reduced pressure. The
residue was purified by preparative chromatography
(SiO2, 140 g; n-hexane/AcOEt 85/15 v/v) to give 1.107 g
(92% yield) of 1n; mp: 66–68 °C; IR (KBr): 3319, 2987,
AcOEt 92/8 v/v) to give 0.038 g of 2a (91% yield): mp: 57–
59 °C; lit. mp (Aldrich catalogue) 57–59 °C, ; IR (KBr):
3404, 2935, 2816, 1454; 1H NMR (CDCl3) d 7.76 (br s,
1H), 7.59 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H),
7.25–7.10 (m, 2H), 6.29 (s, 1H), 2.46 (s, 3H); 13C NMR
(CDCl3) d 136.1, 135.1, 129.1, 120.9, 119.6, 110.3, 100.4,
13.7; Anal. Calcd for C9H9N: C, 82.41; H, 6.92; N, 10.68.
Found: C, 82.50; H, 6.91; N, 10.70. MS m/z (relative
intensity) 131 (M+, 94%), 130 (100%), 77 (20%).
1748, 1713, 1379 cmꢀ1 1H NMR (CDCl3) d 8.70 (br s,
;
1H), 8.35 (d, J = 8.2 Hz, 1H), 7.51 (dd, J1 = 9.1 Hz,
J2 = 1.4 Hz, 1H), 7.43 (t, J = 8.2 Hz, 1H), 7.36 (t,
J = 7.9 Hz 1H), 7.25–7.10 (m, 3H), 6.95 (dd, J1 =
8.2 Hz, J2 = 1.8 Hz, 1H), 6.49 (s, 1H) 4.27 (q, J =
7.1 Hz, 2H), 3.84 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C
NMR (CDCl3) d 160.1, 154.7 (q, J = 37.6 Hz), 154.2,
137.2, 136.9, 132.3, 130.6, 130.1, 125.5, 119.9, 119.7, 117.1
(q, J = 288.8 Hz), 115.1, 113.1, 112.2, 93.9, 81.8, 69.5,
64.8, 55.4, 14.2; 19F NMR (CDCl3) d ꢀ74.3; Anal. Calcd
for C21H18F3NO5: C,59.86; H, 4.31; N, 3.32. Found: C,
59.80; H, 4.31; N, 3.31. MS m/z (relative intensity) 377
(M+ꢀ15, 10%), 332 (78%), 280 (100%).
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10. Typical procedure for the cyclization of (1) to (2): A
Carousel Tube Reaction (Radley Discovery), equip-
ped 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/