2-Trifluoromethanesulfonyloxyindole-1-carboxylic acid ethyl ester: A practical intermediate for the synthesis of 2-carbosubstituted indoles

Article abstract of DOI:10.1055/s-2005-918509

Ready accessible 2-trifluoromethanesulfonyloxyindole-1-carboxylic acid ethyl ester undergoes palladium-catalyzed coupling reactions with different partners giving rise to 2-aryl, heteroaryl, vinyl, allyl, and alkynyl indoles in good to excellent yields. G

Full text of DOI:10.1055/s-2005-918509

PAPER
299
2-Trifluoromethanesulfonyloxyindole-1-carboxylic Acid Ethyl Ester:
A Practical Intermediate for the Synthesis of 2-Carbosubstituted Indoles
S
ynthesis of 2-C
l
arbosu
i
bstitut
s
ed Indolesabetta Rossi,* Giorgio Abbiati, Valentina Canevari, Giuseppe Celentano, Elsa Magri
Istituto di Chimica Organica ‘Alessandro Marchesini’, Facoltà di Farmacia, Università degli Studi di Milano,
Via Venezian 21, 20133 Milano, Italy
Fax +39(02)50314476; E-mail: elisabetta.rossi@unimi.it
Received 15 July 2005; revised 29 July 2005
alkynyl and 2-aryl substituted indoles following
Sonogashira5, Suzuki,6 or Stille6 protocols. Both precur-
sors were prepared from the corresponding N-protected
indoles by lithiation and subsequent treatment with io-
dine.
Abstract: Ready accessible 2-trifluoromethanesulfonyloxyindole-
1-carboxylic acid ethyl ester undergoes palladium-catalyzed cou-
pling reactions with different partners giving rise to 2-aryl, het-
eroaryl, vinyl, allyl, and alkynyl indoles in good to excellent yields.
Key words: indoles, palladium-catalyzed, boronic acids/esters,
alkynes, heteroarylzinc chlorides
Moreover, only two reports on the synthesis of the
corresponding
2-trifluoromethanesulfonyloxy-indoles
(Figure 1) are reported in the literature. In 1992, Gribble7
described a single-step synthesis of the trifluoromethane-
sulfonic acid 1-trifluoromethanesulfonyl-1H-indol-2-yl
ester 3 starting from 1,3-dihydroindol-2-one and triflic an-
hydride. In 1994, Mérour8 reported a three-step synthesis
of the trifluoromethanesulfonic acid 1-benzenesulfonyl-
1H-indol-2-yl ester 4 starting from 1-benzenesulfonyl-
1H-indole. However, while compound 4 was tested in pal-
ladium-catalyzed coupling reactions with boronic acids
following Suzuki methodology,9 compound 3 has never
been tested as a substrate in palladium-catalyzed reac-
tions.
Simple indole derivatives are versatile building blocks in
the synthesis of naturally occurring indole alkaloids, poly-
cyclic indoles, and therapeutic agents. Practical synthesis
of all these derivatives depends on the existence of avail-
able methods to synthesize the functionalized indole nu-
cleus.
In connection with our ongoing interest in developing new
synthetic strategies for the construction of polycyclic in-
dole rings1 we needed to prepare several 3-unsubstituted
indoles bearing aryl, heteroaryl, vinyl, allyl, or alkynyl
groups at position 2.
As a result of the growth in transition metal catalysis tech-
nologies,2 polycyclic indole rings have been synthesized
by palladium-catalyzed coupling reactions from a previ-
ously assembled indole nucleus, using 2-halo or
pseudohalo-indoles in the oxidative addition step
(Scheme 1, path a) or metallated indoles in the transmet-
allation step (Scheme 1, path b).
I
I
N
N
H
COOt-Bu
1
2
4
OSO2CF3
OSO2CF3
SO2Ph
N
N
SO2CF3
3
RX
Pd(0)
R
R'
Figure 1
X = halogen, OTf
M = H, B, Sn, Zn
Indole 2-boronic acids,10 indol-2-ylzinc halogenides,11
and indol-2-yltributylstannanes11b,12 have been utilized as
organometallic partners in palladium-catalyzed coupling
reactions with aryl, heteroaryl, allyl or vinyl halogenides,
or triflates.
R
Pd X
R
Pd R'
path a R = indol-2-yl
path b R' = indol-2-yl
R'-M
MX
Nevertheless, taking into consideration both availability
and simplicity, the approach to 2-substituted indoles de-
scribed in Scheme 1, path a, is the most suitable for our
purposes although a reinvestigation of the starting 2-halo
or pseudohalo indoles is required.
Scheme 1
In particular, both 2-iodo-1H-indole3 (1) itself, as well as
the corresponding N-protected derivative4 2 (Figure 1),
have been exploited as substrates for the synthesis of 2-
Indeed, several reported starting materials, e.g. 1, 2, and 4,
require multistep and complex synthesis1,2,8 or are
unstable13 (3) and decompose when reacted under palladi-
um-catalyzed conditions.
SYNTHESIS 2006, No. 2, pp 0299–0304
Advanced online publication: 21.12.2005
x
x
.
x
x
.2
0
0
5
DOI: 10.1055/s-2005-918509; Art ID: Z13905SS
© Georg Thieme Verlag Stuttgart · New York

300
E. Rossi et al.
PAPER
1. ClCOOEt
Et3N, THF
(CF3SO2)2O, i-Pr2EtN
CH2Cl2, r.t., 97%
O
O
OSO2CF3
COOEt
2. (NH4)2CO3
DMF
N
N
N
H
COOEt
6 (80%)
5
7
Scheme 2
In particular, we envisaged that 2-oxo-2,3-dihydroindole- tigram quantities, by a straightforward method, starting
1-carboxylic acid ethyl ester (6) obtained, in 80% yield,14 from a commercially available and inexpensive interme-
from commercially available 1,3-dihydroindol-2-one 5, diate. Moreover, we have shown that compound 7 is a re-
could represent a useful building block for the synthesis of active, stable, precursor for 2-carbosubstituted indoles,
the corresponding triflate. Thus, 2-trifluoromethanesulfo- thus providing a valuable alternative to the previously re-
nyloxyindole-1-carboxylic acid ethyl ester (7) was ob- ported synthetic strategies.
tained in multigram quantities by the treatment of 6 with
triflic anhydride at room temperature in anhydrous dichlo-
romethane in the presence of diisopropylethylamine
(Scheme 2).
Pd(PPh3)4,
NaHCO3 soln
Ar(Het)
7
7
+
+
Ar(Het)B(OH)2
EtOH, toluene,
100 °C
N
COOEt
8a–d
The reactivity of compound 7 was then tested in order to
asses the range of 2-substituted indoles which could be
produced. In particular, 2-aryl, 2-heteroaryl, 2-allyl, and
2-vinyl indoles 8a–i were prepared in good to excellent
yield by palladium-catalyzed reactions of 7 with commer-
cially available boronic acids 8a–h or boronic ester 8i
(Suzuki coupling), whereas 2-alkynyl derivatives 8j–o
were synthesized in excellent yields starting from 7 and 1-
alkynes following the Sonogashira protocol (Scheme 3,
Table 1).
Pd(PPh3)4,
NaHCO3 soln
B(OH)2
R
EtOH, toluene,
100 °C
R
N
COOEt
8e–h
(Ph3P)2PdCl2,
Na2CO3 soln
O
7
+
THF, 80 °C
O
B
N
COOEt
8i
Pd(PPh3)4, CuI,
Et3N
However, whereas the reaction between 7 and 3-
thiopheneboronic acid gave the corresponding 2-
thiophen-3-yl-indole-1-carboxylic acid ethyl ester (8d) in
good yield, the related 2-thiophene and 2-furanboronic ac-
ids react with 7, under our standard reaction conditions,
giving rise to the desired products in only 25% yields.
This is probably related to the low nucleophilicity of C-2
with respect to C-3 in the boronic acids. However, the 2-
thiophen(furan)-3-yl-indole-1-carboxylic acid ethyl esters
8p–q were obtained in good yields by treatment of 7 with
the more reactive 2-thienyl and 2-furylzinc chloride15
(Negishi coupling) (Scheme 3, Table 1).
R
7
7
+
+
H
R
DMF, r.t.
N
COOEt
8j–o
Pd(PPh3)4
THF, 50 °C
ZnCl
N
(O)S
S(O)
COOEt
8p–q
Scheme 3
K2CO3, MeOH
r.t., 2–6 h
R
8b,h
N
H
Furthermore, deprotection of the indolic nitrogen by re-
moval of the ethoxycarbonyl group has been easily
achieved by treatment of 8b and 8h with potassium car-
bonate in methanol at room temperature. Under these con-
ditions the corresponding unprotected indoles 9a and 9b
were isolated in almost quantitative yields (Scheme 4,
Table 1).
9a–b
o-i-Pr
R =
Scheme 4
All chemicals and solvents are commercially available and were
distilled or treated with drying agents prior to use. Silica gel F254
thin-layer plates were employed for TLC. Silica gel 40–63 mm/60A
was employed for flash column chromatography. Mps are uncor-
rected. 1H NMR spectra were recorded at r.t. in CDCl3 at 200 MHz,
with residual CHCl3 as the internal reference (7.27 ppm). 13C NMR
spectra were recorded at r.t. in CDCl3 at 50.3 MHz, with the central
peak of CHCl3 as the internal reference (77.3 ppm). The APT se-
quence was used to distinguish the methine and methyl carbon sig-
nals from those due to methylene and quaternary carbons.
Thus the effectiveness and synthetic application, in palla-
dium-catalyzed reactions, of indol-2-yl triflate has been
reported. We have achieved our goal which was to pro-
vide a clean, high yielding, general synthesis of 2-carbo-
substituted 3-unsubstituted 1H-indoles starting from an
easy accessible and unique building block. In particular,
starting indol-2-yl triflate 7 has been synthesized in mul-
Synthesis 2006, No. 2, 299–304 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Carbosubstituted Indoles
301
Table 1 Analytical Data for Indoles 8a–q and 9a–d
Indole Structure
Yield (%)a Mp (°C) MS
1H NMR (200 MHz), CDCl3 [d, J (Hz)] 13C NMR (50.3 MHz), CDCl3 (d)
8a
84
98
80
61
280b 1.16 (t, 3 H, CH3, J = 7.3), 2.41 (s, 3
14.2 (CH3), 21.7 (CH3), 63.3
H, CH3), 4.28 (q, 2 H, OCH2, J = 7.3), (CH2), 70.2 (CH), 110.7 (ArCH),
6.57 (s, 1 H, ArH), 7.19–7.35 (m, 6 H, 115.8 (ArCH), 120.8 (ArCH),
ArH), 7.57 (m, 1 H, ArH), 8.17 (d, 1
H, ArH, J = 8.4)
N
123.5 (ArCH), 124.7 (ArCH),
129.1 (ArCH), 129.9 (ArC),
129.9 (ArCH), 131.9 (ArC),
137.5 (ArC), 138.0 (ArC), 141.2
(ArC), 152.2 (C=O)
COOEt
8b
oil
324c 1.15 (t, 3 H, CH3, J = 7.3), 1.38 (d, 6 14.1 (CH3), 22.3 (CH3), 63.1
H, CH3, J = 6.2), 4.27 (q, 2 H, OCH2, (CH2), 70.2 (CH), 110.2 (ArCH),
O-i-Pr
J = 7.3), 4.60 [st,f 1 H, (CH3)2CH,
J = 6.2], 6.54 (s, 1 H, ArH), 6.90
115.2 (ArCH), 115.7 (ArCH),
120.6 (ArCH), 123.3 (ArCH),
N
COOEt
(AA¢BB¢ system, 4 H, ArH, J = 8.8), 124.4 (ArCH), 126.8 (ArC),
7.33 (AA¢BB¢ system, 4 H, ArH, 129.7 (ArC), 130.3 (ArCH),
J = 8.8), 7.28 (m, 2 H, ArH), 7.53 (m, 137.3 (ArC), 140.8 (ArC), 152.0
1 H, ArH), 8.18 (d, 1 H, ArH, J = 8.4) (ArC), 157.9 (C=O)
8c
101
308, 1.13 (t, 3 H, CH3, J = 7.3), 2.64 (s, 3
14.0 (CH3), 26.9 (CH3), 63.3
COCH3k
330b,e H, CH3), 4.27 (q, 2 H, OCH2, J = 7.3), (CH2), 111.6 (ArCH), 115.9
6.65 (s, 1 H, ArH), 7.28–7.67 (m, 5 H, (ArCH), 121.0 (ArCH), 123.6
ArH), 7.97 (dt, 1 H, ArH, J = 1.5, 7.7), (ArCH), 125.1 (ArCH), 127.9
8.04 (t, 1 H, ArH, J = 1.5), 8.20 (d, 1 (ArCH), 128.2 (ArCH), 128.9
N
COOEt
H, ArH, J = 8.1)
(ArCH), 129.5 (ArC), 133.7
(ArCH), 135.2 (ArC), 136.9
(ArC), 137.5 (ArC), 139.6 (ArC),
152.6 (C=O), 197.9 (C=O)
8d
8e
84
93
45
79
272b 1.22 (t, 3 H, CH3, J = 7.3), 4.32 (q, 2 13.9 (CH3), 63.0 (CH2), 110.8
H, OCH2, J = 7.3), 6.62 (s, 1 H, ArH), (ArCH), 115.6 (ArCH), 120.5
7.15–7.57 (m, 6 H, ArH), 8.18 (d, 1 H, (ArCH), 123.2 (ArCH), 123.5
S
N
ArH, J = 8.4)
(ArCH), 124.3 (ArCH), 124.6
(ArCH), 129.0 (ArCH), 129.3
(ArC), 134.5 (ArC), 135.4 (ArC),
137.0 (ArC), 151.7 (C=O)
COOEt
306c 1.52 (t, 3 H, CH3, J = 7.3), 2.37 (s, 3
14.8 (CH3), 21.7 (CH3), 63.7
H, CH3), 4.54 (q, 2 H, OCH2, J = 7.3), (CH2), 107.2 (CH), 116.2 (CH),
7.06 (d, 1 H, =CH, J = 16.1), 7.74 (d, 119.7 (CH), 120.7 (CH), 123.6
N
1 H, =CH, J = 16.1), 6.87 (s, 1 H,
(CH), 124.6 (CH), 127.0 (CH),
ArH), 7.16–7.55 (m, 7 H, ArH), 8.11 129.9 (CH), 130.0 (ArC), 131.4
COOEt
(m, 1 H, ArH)
(CH), 134.8 (ArC), 137.1 (ArC),
138.2 (ArC), 140.1 (ArC), 152.6
(C=O)
8f
93
98
51
230b 1.50 (t, 3 H, CH3, J = 7.3), 1.92 (dd, 3 14.6 (CH3), 18.9 (CH3), 63.4
H, CH3, J = 1.8, 6.7), 4.51 (q, 2 H,
OCH2, J = 7.3), 6.20 (dq, 1 H, =CH,
(CH2), 106.6 (CH), 115.9 (CH),
120.3 (CH), 123.3 (CH), 123.4
N
J = 6.7, 15.4), 6.63 (s, 1 H, ArH), 6.97 (CH), 124.1 (CH), 129.0 (CH),
COOEt
(m, 1 H, =CH), 7.24 (m, 2 H, ArH),
7.48 (m, 1 H, ArH), 8.07 (m, 1 H,
ArH)
129.8 (ArC), 136.5 (ArC), 140.1
(ArC), 152.3 (C=O)
8g
oil
272c 0.94 (t, 3 H, CH3, J = 7.3), 1.26–1.56 14.2 (CH3), 14.6 (CH3), 22.5
(m, 7 H, CH3, CH2), 2.25 (m, 2 H, (CH2), 31.5 (CH2), 32.9 (CH2),
CH2C=), 4.51 (q, 2 H, OCH2, J = 7.3), 63.3 (CH2), 106.6 (CH), 115.9
6.39 (dt, 1 H, =CH, J = 6.6, 15.7), (CH), 120.3 (CH), 122.1 (CH),
n-C4H9
N
COOEt
6.64 (d, 1 H, ArH, J = 0.7), 6.95 (dd, 1 123.2 (CH), 124.0 (CH), 129.9
H, =CH, J = 0.7, 15.7), 7.23 (m, 2 H, (ArC), 136.7 (ArC), 140.2 (ArC),
ArH), 7.48 (m, 1 H, ArH), 8.08 (m, 1 134.4 (CH), 152.3 (C=O)
H, ArH)
Synthesis 2006, No. 2, 299–304 © Thieme Stuttgart · New York

302
E. Rossi et al.
PAPER
Table 1 Analytical Data for Indoles 8a–q and 9a–d (continued)
Indole Structure
Yield (%)a Mp (°C) MS
1H NMR (200 MHz), CDCl3 [d, J (Hz)] 13C NMR (50.3 MHz), CDCl3 (d)
8h
75
oil
298b 1.10–1.38 (m, 6 H, CH2), 1.50 (t, 3 H, 14.8 (CH3), 26.4 (CH3), 26.6
CH3, J = 7.3), 1.7–1.92 (m, 4 H, CH2), (CH2), 33.1 (CH2), 41.3
2.16 (m, 1 H, CH), 4.50 (q, 2 H,
OCH2, J = 7.3), 6.16 (dd, 1 H, =CH,
(CH2CH), 63.8 (CH2), 106.6
(CH), 116.1 (CH), 120.0 (CH),
N
J = 6.7, 15.8), 6.64 (s, 1 H, ArH), 6.97 120.4 (CH), 123.6 (CH), 124.2
(d, 1 H, =CH, J = 15.8), 7.23 (m, 2 H, (CH), 130.0 (ArC), 136.8 (ArC),
ArH), 7.46 (m, 1 H, ArH), 8.08 (m, 1 140.0 (CH), 140.6 (ArC), 152.5
COOEt
H, ArH)
(C=O)
8i
8j
77
98
oil
oil
230c 1.44 (t, 3 H, CH3, J = 7.3), 3.79 (dd, 2 14.7 (CH3), 34.7 (CH2), 63.4
H, CH2, J = 1.1, 6.2), 4.48 (q, 2 H, (CH2), 108.8 (CH), 116.0 (CH),
OCH2, J = 7.3), 5.14 (m, 2 H, =CH2), 117.1 (=CH2), 120.3 (CH), 123.3
6.10 (m, 1 H, =CH), 6.41 (d, 1 H, ArH, (CH), 124.0 (CH), 129.8 (ArC),
J = 1.1), 7.20 (m, 2 H, ArH), 7.43 (m, 135.5 (CH), 137.0 (ArC), 140.3
N
COOEt
1 H, ArH), 8.08 (m, 1 H, ArH)
(ArC), 152.3 (C=O)
289d 1.50 (t, 3 H, CH3, J = 7.3), 4.56 (q, 2 14.6 (CH3), 63.3 (CH2), 82.2
H, OCH2, J = 7.3), 6.99 (s, 1 H, ArH), (C≡C), 95.5 (C≡C), 115.9
Ph
N
7.22–7.59 (m, 8 H, ArH), 8.19 (m, 1
H, ArH)
(ArCH), 116.7 (ArCH), 120.7
(ArCH), 120.8 (ArC), 123.2
(ArC), 123.7 (ArCH), 125.9
(ArCH), 128.7 (ArCH), 128.8
(ArCH), 129.1 (ArC), 131.6
(ArCH), 136.4 (ArC), 151.3
(C=O)
COOEt
8k
92
oil
284b 0.93 (t, 3 H, CH3, J = 7.3), 1.25–1.75 14.2 (CH3), 14.5 (CH3), 20.1
(m, 9 H, CH3, CH2), 2.49 (t, 2 H, CH2, (CH2), 22.5 (CH2), 28.5 (CH2),
J = 7.0), 4.51 (q, 2 H, OCH2, J = 7.3), 31.4 (CH2), 63.4 (CH2), 73.1
6.81 (s, 1 H, ArH), 7.17–7.36 (m, 2 H, (C≡C), 97.0 (C≡C), 115.7
n-C5H11
N
COOEt
ArH), 7.48 (m, 1 H, ArH), 8.13 (d, 1
(ArCH), 115.8 (ArCH), 120.6
(ArCH), 121.5 (ArC), 123.5
(ArCH), 125.4 (ArCH), 129.1
(ArC), 136.0 (ArC), 151.4 (C=O)
H, ArH, J = 8.1)
8l
78
87
92
oil
oil
72
254, 1.50 (t, 3 H, CH3, J = 7.3), 2.02 (m, 3 14.6 (CH3), 23.3 (CH3), 63.5
276b,e H, CH3), 4.52 (q, 2 H, OCH2, J = 7.3), (CH2), 79.3 (C≡C), 94.0 (C≡C),
N
5.36 (m, 1 H, =CHH), 5.44 (m, 1
H, =CHH), 6.90 (s, 1 H, ArH), 7.31
(m, 2 H, ArH), 7.49 (m, 1 H, ArH),
8.16 (m, 1 H, ArH)
115.8 (ArCH), 116.7 (ArCH),
119.7 (C), 120.9 (ArCH), 122.8
(=CH2), 123.6 (ArCH), 125.8
(ArCH), 126.8 (C), 128.7 (C),
136.2 (C), 150.9 (C=O)
COOEt
8m
8n
266b,e 1.50 (t, 3 H, CH3, J = 7.3), 1.90 (br s, 14.5 (CH3), 51.9 (CH2), 63.8
1 H, OH, D2O exchange), 4.52 (q, 2 H, (CH2), 78.1 (C≡C), 93.7 (C≡C),
N
OCH2, J = 7.3), 4.57 (s, 2 H, CH2),
115.8 (ArCH), 117.1 (ArCH),
OH
6.91 (s, 1 H, ArH), 7.25 (m, 2 H, ArH), 120.2 (ArC), 121.6 (ArCH),
COOEt
7.46 (m, 1 H, ArH), 8.10 (m, 1 H,
ArH)
123.7 (ArCH), 126.0 (ArCH),
128.9 (ArC), 136.1 (ArC), 151.3
(C=O)
271d 1.38 (t, 3 H, CH3, J = 7.3), 1.65 (s, 6
14.6 (CH3), 31.4 (CH3), 64.5
H, CH3), 2.28 (br s, 1 H, OH, D2O ex- (CH2), 65.9 (COH), 74.8 (C≡C),
change), 4.52 (q, 2 H, OCH2, J = 7.3), 99.8 (C≡C), 115.9 (ArCH), 116.7
6.87 (s, 1 H, ArH), 7.40 (m, 2 H, ArH), (ArCH), 120.3 (ArC), 120.9
7.50 (d, 1 H, ArH, J = 7.3), 8.13 (d, 1 (ArCH), 123.6 (ArCH), 125.8
N
OH
COOEt
H, ArH, J = 8.4)
(ArCH), 128.9 (ArC), 136.2,
(ArC), 151.3 (C=O)
Synthesis 2006, No. 2, 299–304 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Carbosubstituted Indoles
303
Table 1 Analytical Data for Indoles 8a–q and 9a–d (continued)
Indole Structure
Yield (%)a Mp (°C) MS
1H NMR (200 MHz), CDCl3 [d, J (Hz)] 13C NMR (50.3 MHz), CDCl3 (d)
8o
97
oil
334b,e 1.49 (t, 3 H, CH3, J = 7.3), 1.55–2.08 14.7 (CH3), 23.5 (CH2), 25.4
HO
(m, 10 H, CH2), 2.31 (br s, 1 H, OH,
D2O exchange), 4.52 (q, 2 H, OCH2,
J = 7.3), 6.89 (d, 1 H, ArH, J = 0.7),
7.20–7.51 (m, 3 H, ArH), 8.13 (m, 1
H, ArH)
(CH2), 40.0 (CH2), 63.6 (OCH2),
69.5 (COH), 76.8 (C≡C), 99.1
(C≡C), 115.9 (ArCH), 116.9
(ArCH), 120.5 (ArC), 120.9
(ArCH), 123.6 (ArCH), 125.8
(ArCH), 129.0 (ArC), 136.2
(ArC), 151.3 (C=O)
N
COOEt
8p
8q
84
81
oil
oil
272b 1.21 (t, 3 H, CH3, J = 7.3), 4.32 (q, 2 14.1 (CH3), 63.3 (CH2), 129.2
H, OCH2, J = 7.3), 6.72 (s, 1 H, ArH), (ArC), 112.7 (ArCH), 115.8
7.04–7.57 (m, 6 H, ArH), 8.17 (d, 1 H, (ArCH), 120.8 (ArCH), 123.5
N
S
ArH, J = 8.4)
(ArCH), 125.1 (ArCH), 126.5
(ArCH), 126.7 (ArCH), 128.2
(ArCH), 133.0 (ArC), 135.1
(ArC), 137.4 (ArC), 151.7 (C=O)
COOEt
256b 1.28 (t, 3 H, CH3, J = 7.3), 4.37 (q, 2 14.3 (CH3), 63.4 (CH2), 129.1
H, OCH2, J = 7.3), 6.46 (m, 1 H, (ArC), 110.2 (ArCH), 111.1
ArH), 6.57 (m, 1 H, ArH), 6.80 (s, 1 H, (ArCH), 112.1 (ArCH), 115.8
ArH), 7.22–7.59 (m, 4 H, ArH), 8.21 (ArCH), 121.1 (ArCH), 123.5
N
O
COOEt
(m, 1 H, ArH)
(ArCH), 125.4 (ArCH), 130.1
(ArC), 137.3 (ArC), 142.8
(ArCH), 146.9 (ArC), 151.5
(C=O)
9a
9b
98
92
144
252b 1.37 (d, 6 H, CH3, J = 6.2), 4.59 [st,f
22.3 (2 × CH3), 70.3 (CH), 98.9
1 H, (CH3)2CH, J = 6.2], 6.71 (s, 1 H, (CH), 110.9 (ArCH), 116.6
O-i-Pr
ArH), 6.85 (AA¢BB¢ system, 2 H,
(ArCH), 120.4 (ArCH), 120.6
N
H
ArH, J = 8.8), 7.57 (AA¢BB¢ system, 2 (ArCH), 122.1 (ArCH), 125.2
H, ArH, J = 8.8), 7.14 (m, 2 H, ArH), (ArC), 126.7 (ArCH), 129.7
7.36 (m, 1 H, ArH), 7.57 (m, 1 H,
ArH), 8.22 (s, 1 H, NH)
(ArC), 136.9 (ArC), 138.3 (ArC),
157.9 (ArC)
oil
226c 1.08–1.37 (m, 6 H, CH2), 1.57–1.86
25.3 (CH2), 25.4 (CH2), 33.2
(m, 4 H, CH2), 2.16 (m, 1 H, CH), 6.01 (CH2), 40.3 (CH), 100.8 (CH),
(dd, 1 H, =CH, J = 6.7, 15.8), 6.38 (d, 109.7 (CH), 115.5 (CH), 117.6
N
H
1 H, =CH, J = 15.8), 6.38 (s, 1 H,
(CH), 119.1 (CH), 121.4 (CH),
ArH), 7.09 (m, 2 H, ArH), 7.28 (m, 1 128.0 (ArC), 132.9 (ArC), 135.4
H, ArH),7.52 (d, 1 H, ArH, J = 7.3),
(CH), 135.7 (ArC)
8.07 (s, 1 H, NH)
a Yields are of pure isolated products after chromatography.
b ESI-MS.
c APCI-MS.
d EI-MS.
e [M + Na]+.
f st = septet.
2-Trifluoromethanesulfonyloxyindole-1-carboxylic Acid Ethyl
Ester (7)
1H NMR: d = 1.50 (t, 3 H, CH3, J = 7.3 Hz), 4.58 (q, 2 H, OCH2
J = 7.3 Hz), 6.47 (s, 1 H, ArH), 7.45–7.26 (m, 2 H, ArH), 7.50 (dd,
1 H, ArH, J = 1.3, 6.0 Hz), 7.55 (dd, 1 H, ArH, J = 0.7, 7.7 Hz), 8.17
(d, 1 H, ArH, J = 8.4 Hz).
13C NMR: d = 14.4 (CH3). 64.5 (CH2), 99.0 (ArCH), 115.7 (ArCH),
119.0 (CF3, JC-F = 160 Hz), 121.5 (ArCH), 124.3 (ArCH), 125.4
(ArC), 126.1 (ArCH), 133.1 (ArC), 138.2 (ArC), 149.8 (C=O).
To a N2-flushed solution of 614 (500 mg, 2.44 mmol) and i-Pr2EtN
(0.66 mL, 3.66 mmol) in anhyd CH2Cl2 (12.5 mL), Tf2O (0.52 mL,
3.17 mmol) was added dropwise at 0–5 °C. The reaction was stirred
for 3 h at r.t. and then was quenched with H2O (12.5 mL). The pH
of the solution was adjusted to 7 by the addition of an aq solution of
Na2CO3 (1 N) and extracted with CH2Cl2 (2 × 12.5 mL). The com-
bined organic layers were dried (MgSO4), filtered, and the solvent
evaporated under reduced pressure. The crude was purified by flash
chromatography (hexane–EtOAc, 99:1) to give pure 7 (895 mg,
97%) as a white solid; mp 50 °C.
EI-MS: m/z (%) = 337.2 [M+] (30), 204.2 (77), 132.1 (100), 104.1
(69).
2-Substituted Indoles 8a–h; General Procedure
To a N2-flushed solution of 7 (300 mg, 0.89 mmol) in anhyd toluene
(15 mL), Pd(PPh3)4 (51 mg, 0.045 mmol, 5%) was added. The reac-
tion was stirred for 30 min at r.t., then a solution of the appropriate
IR (KBr): 3006, 1758, 1741, 1382 cm–1.
Synthesis 2006, No. 2, 299–304 © Thieme Stuttgart · New York

304
E. Rossi et al.
PAPER
boronic acid (0.89 mmol) in EtOH–sat. Na2HCO3 (3:2, 15 mL) was
added dropwise at r.t. The mixture was then heated at reflux for 2 h,
cooled to r.t., and washed with brine. The organic layer was dried
(MgSO4), filtered, and the solvent evaporated under reduced pres-
sure. The crude was purified by flash chromatography (hexane–
EtOAc, 98:2) to furnish pure 8a–h (Table 1).
Acknowledgment
Financial support from MURST (Ministero dell’Università e della
Ricerca Scientifica) is gratefully acknowledged.
References
2-Allylindole-1-carboxylic Acid Ethyl Ester (8i)
(1) (a) Abbiati, G.; Beccalli, E.; Marchesini, A.; Rossi, E.
Synthesis 2001, 2477. (b) Beccalli, E.; Broggini, G.;
Marchesini, A.; Rossi, E. Tetrahedron 2002, 58, 6673.
(c) Abbiati, G.; Arcadi, A.; Beccalli, E.; Rossi, E.
Tetrahedron Lett. 2003, 44, 5331. (d) Abbiati, G.; Arcadi,
A.; Bellinazzi, A.; Beccalli, E.; Rossi, E.; Zanzola, S. J. Org.
Chem. 2005, 70, 4088. (e) Abbiati, G.; Canevari, V.; Rossi,
E.; Ruggeri, A. Synth. Commun. 2005, 35, 1845.
(2) Tsuji, J. Palladium Reagents and Catalysts Innovation in
Organic Synthesis; Wiley: Chichester, 1995.
To a N2-flushed solution of 7 (100 mg, 0.30 mmol) in anhyd THF
(4 mL), (Ph3P)2PdCl2 (10 mg, 0.015 mmol), allylboronate (75 mg,
0.45 mmol) and an aq solution of Na2CO3 (2 M; 1 mL) were added
at r.t. The reaction was stirred at reflux for 6 h, then poured into H2O
(10 mL), and extracted with Et2O (2 × 10 mL). The combined or-
ganic layers were dried (Na2SO4), filtered, and the solvent evaporat-
ed under reduced pressure. The crude was purified by flash
chromatography (hexane–EtOAc, 97:3) to furnish pure 8i (Table 1).
2-Alkynylindole-1-carboxylic Acid Ethyl Esters (8j–o)
To a N2-flushed solution of 7 (100 mg, 0.30 mmol) in anhyd DMF
(2 mL) the appropriate 1-alkyne (0.30 mmol), Et3N (0.8 mL, 6
mmol), CuI (12 mg, 0.006 mmol), and Pd(PPh3)4 (28 mg, 0.024
mmol) were added at r.t. The mixture was then stirred for 1 h at r.t.,
poured into HCl (0.1 M; 150 mL), and extracted with EtOAc
(2 × 70 mL). The combined organic layers were dried (Na2SO4), fil-
tered, and the solvent evaporated under reduced pressure. The crude
was purified by flash chromatography (hexane–EtOAc, 9:1) to fur-
nish pure 8j–o (Table 1).
(3) Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57, 2495.
(4) (a) Kline, T. J. Heterocycl. Chem. 1985, 505. (b) Vazquez,
E.; Davies, I. W.; Payack, J. F. J. Org. Chem. 2002, 67, 7551.
(5) (a) Perez-Serrano, L.; Casarrubios, L.; Dominguez, G.;
Gonzalez-Perez, P.; Perez-Castells, J. Synthesis 2002, 1810.
(b) Prikhod’ko, T. A.; Kurilenko, V. M.; Khlienko, Z. h. N.;
Vasilevskii, S. F.; Shvartsberg, M. S. Bull. Acad. Sci. USSR,
Div. Chem. Sci. (Engl. Transl.) 1990, 120. (c) Passarella,
D.; Lesma, G.; Deleo, M.; Martinelli, M.; Silvani, A. J.
Chem. Soc., Perkin Trans. 1 1999, 2669. (d) Sakamoto, T.;
Numata, A.; Saitoh, H.; Kondo, Y. Chem. Pharm. Bull.
1999, 1740. (e) Passarella, D.; Giardini, A.; Martinelli, M.;
Silvani, A. J. Chem. Soc., Perkin Trans. 1 2001, 127.
(6) (a) Merlic, C. A.; McInnes, D. M. Tetrahedron Lett. 1997,
38, 7661. (b) Merlic, C. A.; You, Y.; McInnes, D. M.;
Zechman, A. L.; Miller, M. M.; Deng, Q. Tetrahedron 2001,
57, 5199.
(7) Conway, S. C.; Gribble, G. W. Synth. Commun. 1992, 2987.
(8) Bourlot, A. S.; Desarbe, E.; Mérour, J. Y. Synthesis 1994,
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(9) Benoît, J.; Malapel, B.; Mérour, J. Y. Synth. Commun. 1996,
3289.
(10) Johnson, C. N.; Stemp, G.; Anand, N.; Stephen, S. C.;
Gallagher, T. Synlett 1998, 1025.
(11) (a) Sakamoto, T.; Kondo, Y.; Takazawa, N.; Yamanaka, H.
J. Chem. Soc., Perkin Trans. 1 1996, 1927. (b) Danieli, B.;
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2-Thiophen-2-ylindole-1-carboxylic Acid Ethyl Ester (8p) and
2-Furan-2-ylindole-1-carboxylic Acid Ethyl Ester (8q)
To a N2-flushed solution of thiophene (0.06 mL, 0.74 mmol) or fu-
ran (0.05 mL, 0.74 mmol) in THF (0.5 mL), n-BuLi (2.5 M solution
in hexanes; 0.3 mL) was added dropwise at 0 °C. After stirring for
3 h at 0 °C a solution of ZnCl2 (162 mg, 0.012 mmol) in THF (1 mL)
was added. The mixture was stirred for an additional 30 min and
then added to a second flask containing 7 (100 mg, 0.3 mmol), and
Pd(PPh3)4 (14 mg, 0.02 mmol) in THF (0.7 mL). The reaction mix-
ture was then heated at 50 °C for 3 h, cooled to r.t., quenched by the
addition of a sat. aq solution of NH4Cl (5 mL), and extracted with
EtOAc (2 × 10 mL). The combined organic layers were washed
with H2O (10 mL), and brine (10 mL), dried (MgSO4), and the sol-
vent evaporated under reduced pressure. The crude was purified by
flash chromatography (hexane–EtOAc, 98:2) to furnish pure 8p or
8q (Table 1).
2-(4-Isopropoxyphenyl)-1H-indole (9a) and 2-[(E)-2-cyclohexyl-
vinyl]-1H-indole (9b)
(12) (a) Labadie, S. S.; Teng, E. J. Org. Chem. 1994, 59, 4250.
(b) Palmisano, G.; Santagostino, M. Helv. Chim. Acta 1993,
76, 2356.
To a solution of the appropriate indole 8b or 8h (0.3 mmol) in anhyd
MeOH (3 mL), K2CO3 (41.5 mg, 0.3 mmol) was added and the mix-
ture was stirred at r.t. for 6 h. The solvent was then removed under
reduced pressure and the crude taken up in H2O–EtOAc (1:1, 20
mL). The organic layer was dried (Na2SO4), filtered, and the solvent
evaporated under reduced pressure. The crude was purified by flash
chromatography (hexane–EtOAc, 8:2) to furnish pure 9a or 9b
(Table 1).
(13) We synthesized the trifluoromethanesulfonic acid 1-
trifluoromethanesulfonyl-1H-indol-2-yl ester 3 from 1,3-
dihydroindol-2-one(5) in 70% yield following the procedure
described by Gribble.7 However, 3 is stable only at low
temperatures and after reaction with phenylacetylene or with
2-methyl-3-butyn-2-ol under Sonogashira conditions at
60 °C, the corresponding coupled products were isolated in
poor yields (31% and 32%, respectively).
(14) Porcs-Makkay, M.; Argay, G.; Kálmán, A.; Simig, G.
Tetrahedron 2000, 56, 5893.
(15) Johnson, A. T.; Klein, E. S.; Wang, L.; Pino, M. E.;
Chandraratna, R. A. S. J. Med. Chem. 1996, 39, 5027.
Synthesis 2006, No. 2, 299–304 © Thieme Stuttgart · New York