Sequential Sonogashira and Suzuki cross-coupling reactions in the indole and indazole series

Article abstract of DOI:10.1055/s-2005-861825

3-Iodoindoles, 5-bromo-3-iodoindoles and 5-bromo-3-iodoindazoles have been studied with respect to their reactivity and selectivity in palladium catalyzed Sonogashira and Suzuki cross-coupling reactions. As a result, sequential Sonogashira-Sonogashira, So

Full text of DOI:10.1055/s-2005-861825

PAPER
771
Sequential Sonogashira and Suzuki Cross-Coupling Reactions in the Indole
and Indazole Series
S
equential Sonog
e
ashira and
r
Suzuki
C
n
ross-Coupli
h
ngReactionsard Witulski,*a Javier Ramon Azcon, Carole Alayrac,a Anca Arnautu,b Valérie Collot,b Sylvain Rault*b
a
Westfälische Wilhelms-Universität Münster, Organische Chemie Institut, Correnstr. 40, 48143 Münster, Germany
Fax +49(251)8336501; E-mail: witulski@uni-muenster.de
b
CERMN, UFR des Sciences Pharmaceutiques, 5 rue Vaubénard, 14032 Caen cedex, France
Received 5 August 2004; revised 24 November 2004
or aryl moieties, should have the following consequences:
(i) distinct spacing of significant functional groups, such
as the amino function and the indole nitrogen atom, (ii)
changing their pKa values, and (iii) implementing confor-
Abstract: 3-Iodoindoles, 5-bromo-3-iodoindoles and 5-bromo-3-
iodoindazoles have been studied with respect to their reactivity and
selectivity in palladium catalyzed Sonogashira and Suzuki cross-
coupling reactions. As a result, sequential Sonogashira–Sonoga-
shira, Sonogashira–Suzuki, and Suzuki–Sonogashira reactions with mational restrictions within the molecule. Finally, such
5-bromo-3-iodoindoles or indazoles were used to obtain a large
modifications shall influence affinity, selectivity and ago-
range of new functionalized indoles and indazoles, which are poten-
nist versus antagonist character of these potential 5-HT re-
tial 5-HT receptor ligands.
ceptor ligands.
Key words: palladium, catalysis, alkynes, indoles, indazoles
NR2
NH2
RO
I
The neurotransmitter serotonin (5-hydroxytryptamine)
mediates a wide range of physiological functions by inter-
acting with multiple receptors.1,2 In the past eighteen
years, seven distinct families (5-HT1–5-HT7), compro-
mising a total of at least fourteen structurally and pharma-
cologically distinct mammalian 5-HT receptor subtypes
have been identified. The function of many 5-HT recep-
tors can be unequivocally associated with specific physi-
ological responses, ranging from modulation of neuronal
activities, transmitter releases, to behavioral changes. In
contrast to 5-HT1–5-HT4 receptors, the 5-HT5–5-HT7 re-
ceptors have been less intensively studied and much less
is known about them. The function of the 5-HT5 receptors
remains unidentified and no selective agent of 5-HT5 re-
ceptors has been developed yet.3 Interestingly, most re-
cently disclosed agents which act on 5-HT6 receptors are
sulfonamides or derivatives of tryptamines bearing a N-
arylsulfonyl moiety.4 The design of selective ligands for
the 5-HT5–5-HT7 receptors shall offer much promise for
future drug development.
Br
HO
X
X
N
N
N
H
R
spacer
group
X = CH, N
serotonin
:
R
Figure 1
Starting from 3,5-bis-halogenated indoles or indazoles as
molecular scaffolds, their potential for combinatorial
modifications via sequential palladium-catalyzed cross-
coupling reactions was investigated.10 Palladium cata-
lyzed cross-coupling reactions tend to be more facile with
aryl iodines than with aryl bromides and for aryl chlorides
specific ligands are required.11 Commonly used proce-
dures for cross-coupling reactions with aryl iodines em-
ploy room temperature, whereas elevated reaction
temperatures are necessary for aryl bromides. We there-
fore anticipated, that 3-iodo-5-bromo indoles or indazoles
are suitable building blocks for the purpose of sequential
modifications of indoles or indazoles in the 3- and 5-posi-
tion, because palladium catalyzed cross-couplings should
first proceed at the position where the iodine atom is lo-
cated.
As part of our ongoing program on the synthesis of func-
tionalized indoles5 and carbazoles6 via transition metal
catalyzed reactions we became interested in the develop-
ment of a strategy for the synthesis of alkynyl and/or aryl
analogues of serotonin based on palladium catalyzed
cross-coupling reactions.7 Sonogashira8 as well as
Suzuki9 reactions with 3,5-bis-halogenated indoles or
their 2-azabioisosteres, indazoles, and various alkynyl- or
arylamines should lead to the preparation of conjugated
serotonin derivatives where inherent functional groups
are elongated through a rigid spacer (Figure 1). Further-
more, the introduction of such spacer groups, like alkynyl
Preliminary studies by us have already disclosed that 3-ar-
yl- as well as 3-alkynyl-indazoles are readily accessible
from 3-iodoindazoles by either a Suzuki or Sonogashira
cross-coupling reaction.12,13 Moreover, 3-iodoindoles
have been used in Heck and Stille reactions,14,15 in palla-
dium catalyzed cyanations,16 and a few examples of Sono-
gashira couplings with 1-methylsulfonyl-3-iodoindole
and simple terminal alkynes have been reported.17
In order to test the feasibility of the Sonogashira reaction
in sequential palladium catalyzed reactions in the indole
and indazole series and with the attempt to synthesize a
SYNTHESIS 2005, No. 5, pp 0771–0780
Advanced online publication: 14.02.2005
DOI: 10.1055/s-2005-861825; Art ID: T09204SS
x
x
.
x
x
.2
0
0
5
© Georg Thieme Verlag Stuttgart · New York

772
B. Witulski et al.
PAPER
variety of 3-alkynyl indoles structurally related to seroto- tography on silica gel or on aluminium oxide (Table 1).
nin, cross-couplings with the 3-iodoindoles 1a–h and a se- However, in all cases the protection of the nitrogen atom
ries of alkynylamines and amides were performed at the N-1 position was necessary in order to avoid any
(Scheme 1 and Table 1).
coupling at this position. While the Boc group in the inda-
zole series13 proved to be much more suitable than the to-
syl group, which was partially cleaved under these
reaction conditions, the choice of the protecting group
(Boc, tosyl or phenylsulfonyl group) did not play any sig-
nificant role in the indole series. Moreover, electron-
deficient alkynylamides, such as the 1-propioloylpyrroli-
dine,19 proved to be efficient cross-coupling partners here
(Table 1, entry 5). Electron-deficient alkynes are known
to be poor substrates in Sonogashira reactions.20,21 How-
ever, a few examples of efficient couplings with electron-
deficient propiolic amides have been described by us and
others recently.13,22
The nature of the substituent R1 on the benzene moiety of
either the indole or indazole showed no relevant influence
on the course of the coupling reaction. Importantly, sub-
strates bearing an iodine atom at the 3-position and a bro-
mine atom at the 5-position were exclusively
functionalized at position 3 when the reactions were car-
ried out at room temperature. In these cases no double
ethynylated product was observed (Table 1, entries 10–
15). The selectivity thus achieved was crucial for allowing
further sequential modifications via additional palladium
catalyzed cross-coupling reactions at the remaining 5-po-
sition.
Table 1 Synthesis of the Indoles 4a–m and the Indazoles 5a,b Start-
ing from 3-Iodoindoles 1a–h and 1-Boc-5-bromo-3-indazole 2
Entry 1/2
R
R1
R2
Product Yield
4/5
4a
4b
4c
(%)
69
81
84
97
93
1
2
3
4
5
1a
1a
1b
1c
1c
Boc
Boc
Ts
H
CH2NMe2
CH2NHTs
CH2NHTs
CH2NMe2
H
H
Boc
Boc
OMe
OMe
4d
4e
O
N
6
7
1d
1d
1d
1e
1f
1g
1h
1h
2
SO2Ph
SO2Ph
SO2Ph
Ts
OMe
OMe
OMe
OMe
Br
CH2NMe2
CH2NHTs
CH2OH
4f
94
96
91
76
91
88
90
79
91
98
4g
4h
4i
8
9
Ph
10
11
12
13
14
15
Boc
CH2NHTs
CH2NMe2
CH2NHTs
CH2OH
4j
SO2Ph
Ts
Br
4k
4l
Br
Consequently, Sonogashira–Sonogashira sequential
cross-couplings in both the indole and the indazole series
were examined next (Scheme 2 and Table 2). Aryl bro-
mides are known to be less reactive than the parent iodides
in palladium catalyzed cross-coupling reactions. Indeed,
the conversion of 5-bromoindoles 4 and 5-bromoinda-
zoles 5 into their bis-alkynylated derivatives 7 and 8 did
not proceed at room temperature23 but required heating at
70 °C. In these cases an additional amount of 10 mol%
PPh3 was necessary in order to stabilize the active catalyst
and to keep the overall efficiency of the catalysis.
Ts
Br
4m
5a
5b
Boc
Br
CH2NHTs
CH2NMe2
2
Boc
Br
R2
I
H
R2
R1
R1
3
X
X
(i)
N
N
R
R
R2
R2
1a–h: X = CH
2: X = N
4a–m: X = CH
5a–b: X = N
R3
H
R3
Br
6
X
X
Scheme 1 Reagents and conditions: (i) 3 (1.2 equiv), PdCl2(PPh3)2
(5 mol%), CuI (10 mol%), Et3N–DMF (2:1), 20 °C, 12 h, for details
see Table 1.
(i)
N
N
R
R
4j–l: X = CH
5a–b: X = N
7a–d: X = CH
8a–d: X = N
The 3-iodoindoles 1 were obtained from the correspond-
ing indoles by direct iodination followed by N-protection
of the indole nitrogen as described by us earlier.18 Palladi-
um-promoted cross-coupling reactions of 3-iodo-indoles
1a–h or the indazole 2 with a set of terminal alkynes 3
proceeded under very mild conditions. The reaction could
be carried out already at room temperature in the presence
of 5 mol% PdCl2(PPh3)2 and 10 mol% CuI as catalysts.
The new 3-alkynyl indoles 4a–m, as well as the 3-alkynyl
indazoles 5a and 5b were obtained in good to excellent
yields after isolation and purification by column chroma-
Scheme 2 Reagents and conditions: (i) 6 (2–3 equiv), PdCl2(PPh3)2
(10 mol%), CuI (20 mol%), PPh3 (10 mol%), Et3N–DMF (2:1), 70 °C,
48 h for X = CH, 24 h for X = N; for details see Table 2.
Still, the coupling reactions proved to be relatively slow
(up to 3 d) and therefore a higher catalyst loading [10
mol% PdCl2(PPh3)2, 20 mol% CuI] and 2–3 equivalents of
monoalkynes 6 were used. Under these modified condi-
tions, the coupling reactions advanced in one day (inda-
zole) or two days (indole) to give the indoles 7 and the
Synthesis 2005, No. 5, 771–780 © Thieme Stuttgart · New York

PAPER
Sequential Sonogashira and Suzuki Cross-Coupling Reactions
773
Table 2 Sonogashira Cross-Coupling Reactions of 3-Alkynyl-5-
bromo-indoles 4j–l and Indazoles 5a and 5b
NMe2
Me2N
Entry 4/5
R
R2
R3
Products Yield
MeO
7/8
7a
7b
7c
(%)
55
83
74
77
54
76
80
78
B(OH)2
1d
N
1
2
3
4
5
6
7
8
4j
Boc
CH2NHTs
CH2NHTs
CH2NHTs
CH2OH
(i)
SO2Ph
4k
4k
4l
SO2Ph CH2NMe2
SO2Ph CH2NMe2
10 (79%)
Ts
CH2NHTs
CH2NHTs
CH2NMe2
CH2NMe2
CH2NMe2
CH2NMe2
CH2NMe2
CH2NHTs
CH2OH
7d
8a
8b
8c
R5
B(OH)2
5a
5b
5b
5b
Boc
Boc
Boc
Boc
I
(1.1 equiv)
Br
N
R
(i)
Ph
8d
1g: R = SO2Ph
1h: R = Ts
indazoles 8 in up to 83% yield (Table 2). N-Boc substrates
bearing a tosylamide group on the alkynyl moiety were
transformed in lower yields (Table 2, entries 1 and 5)
probably because of their lower thermal stability.
R5
R5
R5
Br
+
Next our efforts focused on the synthesis of the 3-alkynyl-
5-aryl substitution pattern via sequential Sonogashira–Su-
zuki cross-couplings. For this purpose the 3-alkynyl-5-
bromoindoles 4k–l were subjected to Suzuki cross-cou-
pling reactions with 3- or 4-methoxybenzeneboronic ac-
ids leading to the new substituted indoles 9a–c in good to
excellent yields (Scheme 3).
N
R
N
R
11a: R = SO2Ph,
R5 = 4-NMe2 (93%)
11b: R = Ts,
12a: R = SO2Ph,
R5 = 4-NMe2 (<3%)
12b: R = Ts,
R5 = 3-OMe (<3%)
R5 = 3-OMe (94%)
Scheme 4 Reagents and conditions: (i) Pd(PPh3)4 (2 mol%),
Na2CO3 (1.5 equiv), DME–H2O (2:1), 70–80 °C, 12–24 h.
R2
R4
R4
B(OH)2
(1.1 equiv)
We then attempted the opposite substitution pattern, i.e.
the synthesis of 5-alkynyl-3-aryl indoles, by means of se-
quential Suzuki–Sonogashira cross-coupling reactions
starting from the same 3-iodo-5-bromoindoles 1g–h.
4k–l
N
R
(i)
9a: R = SO2Ph, R2 = CH2NMe2, R4 = 4-OMe
9b: R = SO2Ph, R2 = CH2NMe2, R4 = 3-OMe
9c: R = Ts, R2 = CH2NHTs, R4 = 3-OMe
The Suzuki reaction between 5-bromo-3-iodoindole 1h
(R = Ts) and 3-methoxybenzeneboronic acid under the
previously described conditions was low-yielding and
less selective (53% mono-coupling and 4% bis-coupling
products) than the above investigated Sonogashira cou-
pling. However, by performing the reaction at 70 °C in-
stead of 80 °C a significant improvement concerning
reactivity and selectivity was observed. Under these con-
ditions the indole 11b was obtained in 94% yield
(Scheme 4).
Scheme 3 Reagents and conditions: (i) Pd(PPh3)4 (2 mol%),
Na2CO3 (1.5.equiv), DME–H2O (2:1), 80 °C, 1–6 h, 9a (89%), 9b
(98%), 9c (75%).
The choice of base proved to be crucial here. Indeed,
while a significant amount of cleavage of the sulfonyl
group occurred with Ba(OH)2, a clean reaction was ob-
tained with Na2CO3. Under optimized reaction conditions,
i.e. 1.1 equivalents of areneboronic acids, 2 mol% of
Pd(PPh3)4, 1.5 equivalents of base, and a solvent mixture
of DME and water (2:1), a full conversion was achieved
after 1–6 hours at 80 °C. This protocol was also applied to
the cross-coupling reaction of 5-methoxy-3-iodoindole 1d
with 4-dimethylaminobenzeneboronic acid and afforded
the corresponding 5-methoxy-3-aryl indole 10 in 79%
yield (Scheme 4).
This cross-coupling reaction was also attempted at 60 °C
but was too slow at this temperature to go to completion
in a reasonable time scale. Under optimized conditions,
the Suzuki reaction of 5-bromo-3-iodoindole 1g (R =
SO2Ph) with 4-dimethylaminobenzeneboronic acid yield-
ed the 5-bromoindole 11a in 93% yield after 24 hours of
heating. Thus compared to the Sonogashira reaction, the
Suzuki cross-coupling reactions seem to be less selective
in the 5-bromo-3-iodoindole series since some bis-cou-
pling product 12 (3%) was also isolated. However, this
Synthesis 2005, No. 5, 771–780 © Thieme Stuttgart · New York

774
B. Witulski et al.
PAPER
3-Alkynyl-Indoles 4a–m and Indazoles 5a,b; General Proce-
minor side product could be easily separated from indole
11 by simple column chromatography.
dure
In a Schlenk tube with screw cap were introduced under Ar indole
1a–h or indazole 2 (1.0 mmol), alkyne 3 (1.2 mmol, 1.2 equiv),
PdCl2(PPh3)2 (35 mg, 5 mol%), CuI (19 mg, 10 mol%), then anhyd
Et3N (10 mL) and anhyd DMF (5 mL). The reaction mixture was
stirred at r.t. for 12 h and then poured into water and extracted with
CH2Cl2 (2 × 15 mL). The combined organic layers were washed
with brine (2 × 15 mL), dried over MgSO4, filtered through celite
and evaporated to dryness. The residue was purified by flash chro-
matography (petroleum ether–Et2O or petroleum ether–EtOAc) on
silica gel (4b–c, 4e, 4h–j, 4l,m and 5a) or alumina (4a, 4d, 4k, 4f,g
and 5b).
Having the 5-bromoindole 11b in hand, the complemen-
tary substitution pattern to indole 9b via sequential Suzu-
ki–Sonogashira reactions was facile. The coupling
reaction of the 5-bromoindole 11b with the terminal
alkynes 6 at an elevated temperature of 70 °C and in the
presence of 10 mol% PdCl2(PPh3)2 and 20 mol% CuI re-
sulted in the indoles 13a,b in high yields (Scheme 5).
OMe
R3
(3 equiv)
H
R3
3-[3-(Dimethylamino)-prop-1-ynyl]-indole-1-carboxylic Acid
tert-Butyl Ester (4a)
6
11b
Yield: 69%; white crystals; mp 68–69 °C (CHCl3–pentane).
(i)
N
Ts
IR (KBr): 2977, 2944, 2779, 1730, 1612, 1455, 1371, 1276, 1232,
1154, 1098, 1031, 762 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.67 (s, 9 H), 2.41 (s, 6 H), 3.56
(s, 2 H), 7.27–7.37 (m, 2 H), 7.68–7.66 (m, 1 H), 7.74 (s, 1 H), 8.13
(d, J = 8.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 28.1 (q), 44.2 (q), 48.8 (t), 76.9
(s), 84.1 (s), 87.8 (s), 103.3 (s), 115.2 (d), 120.0 (d), 123.1 (d), 125.0
(d), 128.6 (d), 130.7 (s), 134.6 (s), 149.1 (s).
MS (EI, 70 eV): m/z (%) = 298 (51) [M+], 242 (74), 197 (100), 154
(85), 82 (9).
HRMS (ESI): m/z [MH+] calcd for C18H23N2O2: 299.1754; found:
299.1752.
13a: R3 = CH2NMe2 (78%)
13b: R3 = Ph (85%)
Scheme 5 Reagents and conditions: [PdCl2(PPh3)2] (10 mol%), CuI
(20 mol%), PPh3 (10 mol%), Et3N–DMF (2:1), 70 °C, 48 h.
In conclusion, with the aim of developing a flexible strat-
egy for the design of a new indole and indazole library
closely related to the structural motif of serotonin, we
have studied the reactivity and the selectivity of 3-iodo- as
well as 5-bromo-3-iodo-indoles and indazoles in palladi-
um catalyzed cross-coupling reactions. Sonogashira reac-
tions proceeded smoothly affording a large range of new
alkynylated indoles or indazoles. Furthermore, sequential
Sonogashira–Sonogashira, Sonogashira–Suzuki, as well
as Suzuki–Sonogashira couplings were possible starting
3-[3-(Toluene-4-sulfonylamino)-prop-1-ynyl]-indole-1-carbox-
ylic Acid tert-Butyl Ester (4b)
Yield: 81%; yellow crystals; mp 119–120 °C (CHCl3–pentane).
IR (KBr): 3266, 3056, 2979, 2245, 1715, 1600, 1454, 1421, 1383,
from 5-bromo-3-iodo-indoles and indazoles by using the 1343, 1284, 1235, 1164, 1102, 1062, 892, 811, 766, 736, 670, 585,
550 cm–1.
remaining bromine group as a synthetic handle. Prelimi-
1H NMR (400 MHz, CDCl3): d = 1.66 (s, 9 H), 2.29 (s, 3 H), 4.15
(d, J = 6.0 Hz, 2 H), 4.84 (t, J = 6.0 Hz, 1 H), 7.22–7.26 (m, 3 H),
7.31–7.37 (m, 2 H), 7.53 (s, 1 H), 7.83 (d, J = 8.2 Hz, 2 H), 8.08 (d,
J = 8.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.3 (q), 28.0 (q), 33.9 (t), 76.9
(s), 84.5 (s), 86.6 (s), 102.2 (s), 115.2 (d), 119.8 (d), 123.0 (d), 125.1
(d), 127.4 (d), 129.2 (s), 129.6 (d), 130.0 (d), 134.4 (s), 136.9 (s),
143.8 (s), 149.0 (s).
nary results of binding properties of these new (aza) ana-
logues of serotonin towards the 5-HT4 to 5-HT7 receptors
are promising in view of the result of compound 4c (IC50
ca 1 mM versus 5-HT5 receptor). Additional experiments
are on the way.
All reagents used were analytical grades and all solvents were puri-
fied by standard methods and distilled prior to use. All reactions
were run under Ar using vacuum lines in Schlenk tubes in oven-
dried glassware. Reaction mixtures were stirred magnetically and
were monitored by TLC using Polygram Sil G/UV254 silica plates
from Macherey–Nagel & Co. (Düren, Germany). Flash column
chromatography (FCC) was performed with Merck silica gel 60
(40–60 mm). Microanalysis was performed using a Perkin-Elmer
Elementaranalyzer EA 240 and a Perkin-Elmer Elementaranalyzer
MS (EI, 70 eV): m/z (%) = 423 (10) [M+], 367 (28), 323 (27), 258
(32), 245 (18), 231 (18), 185 (41), 168 (100), 155 (34), 143 (66),
115 (31), 91 (70), 84 (47).
Anal. Calcd for C23H24N2O4S (423.60): C, 65.16; H, 5.67; N, 6.61.
Found: C, 64.84; H, 5.68; N, 6.52.
4-Methyl-N-{3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-prop-2-
ynyl}-benzenesulfonamide (4c)
1
2400 CHN. H and 13C NMR spectra were recorded on Bruker
Yield: 84%; white crystals; mp 165–166 °C (CHCl3–pentane).
AC200 and Bruker AMX400 spectrometers using TMS (d = 0.00
ppm for 1H) and CDCl3 (d = 77.0 ppm, 13C) as internal standards.
13C NMR assignments were made on the basis of DEPT experi-
ments. Mass spectra were obtained on a Finnigan MAT 90 spec-
trometer (EI, 70 eV) and on a Quattro-LCZ from Waters-
Micromass (ESI). IR spectra were recorded as solids in KBr pellets
or as film on NaCl plates on a Perkin-Elmer FT-IR spectrometer.
Melting points were recorded on a Büchi apparatus, and are uncor-
rected. Compounds 1a–h18 and 212 were prepared according to the
literature.
IR (KBr): 3268, 1597, 1447, 1381, 1325, 1281, 1233, 1187, 1173,
1159, 1127, 1104, 1089, 993, 817, 746, 664, 568 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.20 (s, 3 H), 2.33 (s, 3 H), 4.12
(d, J = 6.1 Hz, 2 H), 4.97 (t, J = 6.1 Hz, 1 H), 7.18–7.24 (m, 4 H),
7.30–7.34 (m, 3 H), 7.47 (s, 1 H), 7.73 (d, J = 8.5 Hz, 2 H), 7.80 (d,
J = 8.3 Hz, 2 H), 7.90–7.93 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.2 (q), 21.5 (q), 33.8 (t), 76.0
(s), 87.5 (s), 104.0 (s), 113.4 (d), 120.4 (d), 123.6 (d), 125.4 (d),
Synthesis 2005, No. 5, 771–780 © Thieme Stuttgart · New York

PAPER
Sequential Sonogashira and Suzuki Cross-Coupling Reactions
775
126.8 (d), 127.4 (d), 129.2 (s), 129.6 (d), 130.0 (d), 130.3 (d), 133.9
(s), 134.7 (s), 136.8 (s), 143.8 (s), 145.4 (s).
N-[3-(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-prop-2-
ynyl]-4-methyl-benzenesulfonamide (4g)
Yield: 96%; yellow crystals; mp 153 °C (CHCl3–pentane).
MS (EI, 70 eV): m/z (%) = 477 (5) [M+], 423 (8), 367 (24), 323 (27),
258 (36), 231 (18), 168 (100), 141 (57), 91 (86).
IR (KBr): 3251, 1612, 1475, 1445, 1377, 1327, 1291, 1249, 1215,
1163, 1124, 1094, 1029, 988, 942, 846, 816, 723, 684, 601 cm–1.
1H NMR (200 MHz; CDCl3): d = 2.27 (s, 3 H), 3.85 (s, 3 H), 4.15
(d, J = 6.0 Hz, 2 H), 4.92 (t, J = 6.0 Hz, 1 H), 6.84 (d, J = 2.4 Hz, 1
H), 6.98 (dd, J = 2.2, 9.1 Hz, 1 H), 7.24 (d, J = 8.5 Hz, 2 H), 7.43–
7.64 (m, 4 H), 7.82–7.90 (m, 5 H).
Anal. Calcd for C25H22N2O4S2 (477.6): C, 62.81; H, 4.61; N, 5.86.
Found: C, 62.45; H, 4.57; N, 5.78.
3-(3-Dimethylamino-prop-1-ynyl)-5-methoxy-indole-1-carbox-
ylic Acid tert-Butyl Ester (4d)
Yield: 97%; yellow crystals; mp 69–70 °C (CHCl3–pentane).
13C NMR (50 MHz, CDCl3): d = 21.7 (q), 34.4 (t), 56.2 (q), 76.5 (s),
88.2 (s), 102.9 (d), 104.7 (s), 114.9 (d), 115.4 (d), 127.2 (d), 127.9
(d), 129.0 (s), 129.8 (d), 130.1 (d), 130.2 (d), 131.9 (s), 134.6 (d),
137.2 (s), 138.2 (s), 144.4 (s), 157.3 (s).
MS (EI, 70 eV): m/z (%) = 494 (56) [M+], 429 (7), 401 (7), 338 (38),
311 (21), 289 (33), 260 (31), 214 (30), 197 (51), 183 (33), 170 (89),
155 (54), 91 (100), 78 (31).
IR (KBr): 2937, 2781, 1728, 1615, 1479, 1451, 1378, 1330, 1289,
1245, 1156, 1090, 1036, 1017, 853, 807, 764 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.65 (s, 9 H), 2.40 (s, 6 H), 3.55
(s, 2 H), 3.87 (s, 3 H), 6.95 (dd, J = 9.0, 2.6 Hz, 1 H), 7.10 (d, J =
2.6 Hz, 1 H), 7.70 (s, 1 H), 7.99 (d, J = 9.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 28.1 (q), 44.2 (q), 48.8 (t), 55.7
(q), 76.9 (s), 84.0 (s), 87.9 (s), 102.3 (d), 103.1 (s), 114.0 (d), 116.0
(d), 129.2 (d), 131.5 (s), 149.0 (s), 156.3 (s).
Anal. Calcd for C25H22N2O5S2 (494.58): C, 60.71; H, 4.48; N, 5.66.
Found: C, 60.48; H, 4.48; N, 5.66.
MS (EI, 70 eV): m/z (%) = 328 (63) [M+], 272 (74), 227 (100), 213
(52), 184 (96), 113 (7).
3-(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-prop-2-yn-1-ol
(4h)
Yield: 91%; yellow crystals; mp 179–180 °C (CHCl3–pentane).
Anal. Calcd for C19H24N2O3 (327.7): C, 69.58; H, 7.32; N, 8.54.
Found: C, 69.43; H, 7.40; N, 8.47.
IR (KBr): 3565, 3117, 1610, 1482, 1447, 1364, 1313, 1290, 1251,
1212, 1175, 1147, 1127, 1097, 1025, 991, 970, 841, 812, 759, 725,
690, 610, 582 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.80 (br s, 1 H), 3.84 (s, 3 H), 4.56
(s, 2 H), 6.96 (dd, J = 9.0, 2.6 Hz, 1 H), 7.02 (d, J = 2.4 Hz, 1 H),
7.42–7.45 (m, 2 H), 7.54 (tt, J = 7.5, 1.2 Hz, 1 H), 7.69 (s, 1 H) 7.84–
7.87 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 51.8 (t), 55.7 (q), 76.9 (s), 91.7
(s), 102.3 (d), 104.7 (s), 114.5 (d), 115.1 (d), 126.8 (d), 128.8 (s),
129.4 (d), 129.9 (d), 131.7 (s), 134.1 (d), 137.8 (s), 157.0 (s).
3-(2-Pyrrolidinocarboxy-prop-1-ynyl)-5-methoxy-indole-1-car-
boxylic Acid tert-Butyl Ester (4e)
Yield: 93%; white crystals; mp 166–167 °C (petroleum ether–
Et2O).
IR (KBr): 2975, 2932, 2875, 1750, 1628, 1482, 1450, 1394, 1332,
1249, 1155, 1091, 1035, 1020, 853, 798, 762 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.66 (s, 9 H), 1.96–2.04 (m, 4 H),
3.56 (t, J = 6.3 Hz, 2 H), 3.80 (t, J = 6.4 Hz, 2 H), 3.88 (s, 3 H), 6.98
(dd, J = 9.0, 2.3 Hz, 1 H), 7.11 (d, J = 2.3 Hz, 1 H), 7.89 (s, 1 H),
8.02 (d, J = 8.6 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 341 (100) [M+], 200 (57), 185 (51), 170
(54), 157 (60), 134 (15), 78 (25).
13C NMR (100 MHz, CDCl3): d = 24.9, 25.6, 28.3, 45.6, 48.4, 55.9,
82.1, 84.9, 86.8, 100.8, 102.6, 114.7, 116.4, 129.4, 131.1, 132.2,
153.1, 156.8.
Anal. Calcd for C18H15NO4S (341.38): C, 63.32; H, 4.42; N, 4.10.
Found: C, 63.22; H, 4.55; N, 4.13.
MS (EI, 70 eV): m/z (%) = 368 (42) [M+], 312 (100), 268 (70), 239
(30), 198 (55), 170 (14).
5-Methoxy-3-phenylethynyl-1-(toluene-4-sulfonyl)-1H-indole
(4i)
Yield: 76%; brown crystals; mp 127–128 °C (CHCl3–pentane).
Anal. Calcd for C21H24N2O4 (368.44): C, 68.46; H, 6.57; N, 7.90.
Found: C, 68.29; H, 6.68; N, 7.81.
IR (KBr): 3124, 1611, 1476, 1445, 1371, 1301, 1214, 1164, 1118,
1093, 1028, 976, 892, 818, 758, 679, 589 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.29 (s, 3 H), 3,80 (s, 3 H), 6,92
(dd, J = 9.0, 2.4 Hz, 1 H), 7.05 (d, J = 2.4 Hz, 1 H), 7.18 (d, J = 8.6
Hz, 2 H), 7.30–7.32 (m, 3 H), 7.49–7.52 (m, 2 H), 7.70–7.72 (m, 3
H), 7.82 (d, J = 9.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.5 (q), 55.7 (q), 80.4 (s), 93.6
(s), 102.6 (d), 105.2 (s), 114.6 (d), 114.8 (d), 123.0 (s), 126.8 (d),
128.38 (s), 128.40 (d), 128.9 (d), 129.4 (d), 129.9 (d), 131.5 (d)
131.8 (s), 134.9 (s), 145.2 (s), 156.9 (s).
[3-(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-prop-2-ynyl]-
dimethyl-amine (4f)
Yield: 94%; pale yellow crystals; mp 84–85 °C (CHCl3–pentane).
IR (KBr): 3198, 3187, 2768, 1610, 1482, 1445, 1378, 1294, 1248,
1215, 1176, 1128, 1085, 1032, 994, 856, 818, 726, 685, 612, 582
cm–1.
1H NMR (400 MHz, CDCl3): d = 2.32 (s, 6 H), 3.47 (s, 2 H), 3.76
(s, 3 H), 6.89 (dd, J = 2.6, 9.0 Hz, 1 H), 6.97 (d, J = 2.1 Hz, 1 H),
7.31–7.51 (m, 3 H), 7.60 (s, 1 H), 7.77–7.81 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 44.7 (q), 49.2 (t), 56.1 (q), 76.5
(s), 89.5 (s), 103.0 (d), 105.8 (s), 114.9 (d), 115.2 (d), 127.2 (d),
129.3 (s), 129.77 (d), 129.79 (d), 132.5 (s), 134.4 (d), 138.3 (s),
157.3 (s).
MS (EI, 70 eV): m/z (%) = 401 (57) [M+], 246 (100), 231 (25), 203
(18), 176 (9), 82 (11).
Anal. Calcd for C24H19NO3S (401.48): C, 71.74; H, 4.76; N, 3.48.
Found: C, 71.41; H, 4.74; N, 3.43.
MS (EI, 70 eV): m/z (%) = 368 (53) [M+], 324 (37), 227 (100), 212
(34), 183 (93), 168 (25), 146 (15), 78 (13).
5-Bromo-3-[3-(toluene-4-sulfonylamino)-prop-1-ynyl]-indole-
1-carboxylic Acid tert-Butyl Ester (4j)
Yield: 91%; pale yellow crystals; mp 147–148 °C (CHCl3–pen-
tane).
Anal. Calcd for C20H20N2O3S (368.45): C, 65.19; H, 5.47; N, 7.60.
Found: C, 65.10; H, 5.51; N, 7.59.
IR (KBr): 3280, 2970, 1721, 1600, 1453, 1426, 1383, 1343, 1285,
1270, 1228, 1165, 1116, 1094, 1055, 892, 862, 814, 798, 670 cm–1.
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1H NMR (400 MHz, CDCl3): d = 1.66 (s, 9 H), 2.25 (s, 3 H), 4.15
(d, J = 6.0 Hz, 2 H), 4.89 (t, J = 6.0 Hz, 1 H), 7.25–7.27 (m, 2 H),
7.40–7.44 (m, 2 H), 7.52 (s, 1 H), 7.82 (d, J = 8.5 Hz, 2 H), 7.95 (d,
J = 8.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.3 (q), 28.1 (q), 33.9 (t), 76.0
(s), 85.0 (s), 87.2 (s), 101.6 (s), 116.62 (s), 116.64 (d), 122.6 (d),
127.4 (d), 128.1 (d), 129.7 (d), 130.1 (d), 131.7 (s), 133.1 (s), 136.8
(s), 143.8 (s), 148.5 (s).
MS (EI, 70 eV): m/z (%) = 404 (48) [M+], 402 (47) [M+], 249 (7),
247 (7), 232 (15), 230 (15), 169 (44), 155 (61), 91 (100), 84 (41).
Anal. Calcd for C18H14BrNO3S (403.90): C, 53.48; H, 3.47; N, 3.47.
Found: C, 53.32; H, 3.37; N, 3.46.
5-Bromo-3-[3-(toluene-4-sulfonylamino)-prop-1-ynyl]-inda-
zole-1-carboxylic Acid tert-Butyl Ester (5a)
Yield: 91%; white crystals; mp 151–152 °C (CHCl3–pentane).
MS (EI, 70 eV): m/z (%) = 404, 402 [M+ – Boc] (7), 249 (8), 248
(20), 247 (10), 246 (20), 184 (9), 171 (87), 155 (89), 107 (32), 91
(100).
IR (KBr): 3279, 2986, 1741, 1596, 1494, 1386, 1326, 1158, 810
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.60 (s, 9 H), 2.14 (s, 3 H), 4.13
(d, J = 6.0 Hz, 2 H), 4.86 (t, J = 6.0 Hz, 1 H), 7.17 (s, 1 H), 7.19 (s,
1 H), 7.47–7.48 (m, 1 H), 7.54 (dd, J = 8.8, 1.8 Hz, 1 H), 7.75 (dt,
J = 8.4 Hz, J = 1.8 Hz, 2 H), 7.95 (d, J = 8.8 Hz, 1 H).
Anal. Calcd for C23H23BrN2O4S (503.41): C, 54.87; H, 4.61; N,
5.56. Found: C, 55.08; H, 4.69; N, 5.45.
[3-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-prop-2-ynyl]-
dimethyl-amine (4k)
Yield: 88%; yellow crystals; mp 125 °C (CHCl3–pentane).
13C NMR (100 MHz, CDCl3): d = 21.3 (q), 28.0 (q), 33.6 (t), 74.6
(s), 86.0 (s), 90.2 (s), 116.1 (d), 117.4 (s), 122.9 (d), 127.4 (d), 127.8
(s), 129.7 (d), 132.4 (d), 132.6 (s), 136.6 (s), 138.4 (s), 143.9 (s),
148.2 (s).
MS (EI, 70 eV): m/z (%) = 405, 403 (11) [M+ – Boc], 404 (4), 250
(92), 249 (43), 248 (100), 247 (35), 223 (9), 222 (28), 221 (10), 220
(26), 199 (5), 155 (33), 139 (28), 91 (90).
IR (KBr): 3132, 2936, 2800, 1445, 1372, 1291, 1258, 1189, 1148,
1108, 986, 873, 838, 799, 753 721, 686, 626, 599, 575, 556 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.38 (s, 6 H), 3.52 (s, 2 H), 7.43–
7.49 (m, 3 H), 7.57 (t, J = 7.6 Hz, 1 H), 7.69 (s, 1 H), 7.75 (d, J =
1.9 Hz, 1 H), 7.84–7.88 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 44.3 (q), 48.7 (t), 75.2 (s), 89.6
(s), 104.7 (s), 115.0 (d), 117.5 (s), 123.3 (d), 126.8 (d), 128.4 (d),
129.5 (d), 129.6 (d), 132.6 (s), 132.9 (s), 134.3 (d), 137.6 (s).
MS (EI, 70 eV): m/z (%) = 419 (5), 418 (20) [M+], 417 (15), 416
(19) [M+], 374 (17), 372 (17), 337 (12), 335 (12), 277 (92), 275 (90),
234 (16), 232 (15),196 (83), 141 (58), 83 (100).
Anal. Calcd for C22H22BrN3O4S (504.40): C, 52.39; H, 4.40; N,
8.33. Found: C, 52.32; H, 4.38; N, 8.35.
5-Bromo-3-(3-dimethylamino-prop-1-ynyl)-indazole-1-carbox-
ylic Acid tert-Butyl Ester (5b)
Yield: 98%; yellow solid; mp 66–68 °C.
1H NMR (200 MHz, CDCl3): d = 1.64 (s, 9 H), 2.37 (s, 6 H), 3.56
(s, 2 H), 7.55 (dd, J = 8.9, 1.8 Hz, 1 H), 7.84 (dd, J = 7.9, 0.7 Hz, 1
H), 7.99 (dd, J = 9.0, 0.7 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 28.1 (q), 44.2 (q), 48.5 (t), 75.4 (s),
85.8 (s), 91.7 (s), 116.2 (d), 117.4 (s), 123.2 (d), 128.4 (s), 132.4 (d),
133.7 (s), 138.6 (s), 148.4 (s).
Anal. Calcd for C19H17BrN2O2S (417.32): C, 54.68; H, 4.10; N,
6.71. Found: C, 54.41; H, 4.11; N, 6.59.
N-{3[5-Bromo-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-prop-2-
ynyl}-4-methyl-benzenesulfonamide (4l)
Yield: 90%; white crystals; mp 183–184 °C (CHCl3–pentane).
MS (EI, 70 eV): m/z (%) = 379, 377 (0.6) [M+], 364 (0.6), 362 (0.6),
336 (12), 334 (13), 278 (30), 262 (5), 235 (13), 168 (3), 126 (9), 57
(100).
IR (KBr): 3261, 1596, 1440, 1372, 1328, 1288, 1258, 1225, 1190,
1158, 1106, 986, 916, 870, 808, 752, 668, 580, 537 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.19 (s, 3 H), 2.35 (s, 3 H), 4.12
(d, J = 6.0 Hz, 2 H), 4.68 (t, J = 6.0 Hz, 1 H), 7.20–7.25 (m, 4 H),
7.39–7.42 (m, 2 H), 7.47 (s, 1 H), 7.71 (d, J = 8.3 Hz, 2 H), 7.77–
7.80 (m, 3 H).
13C NMR (100 MHz, DMSO): d = 21.0 (q), 21.5 (q), 33.2 (t), 74.3
(s), 90.6 (s), 103.7 (d), 115.8 (d), 117.2 (s), 123.0 (d), 127.4 (d),
128.9 (d), 129.7 (d), 130.8 (d), 130.9 (s), 132.2 (s), 133.8 (s), 138.3
(s), 143.1 (s), 146.7 (s).
HRMS (ESI): m/z [MH+] calcd for C17H21BrN3O2: 378.0812; found:
378.0825.
3,5-Bis-Alkynyl-Indoles 7a–d and Indazoles 8a–d; General Pro-
cedure
In a Schlenk tube with screw cap were introduced under Ar indole
4i–k or indazole 5a,b (0.5 mmol), alkyne 6 (1–1.5 mmol, 2–3
equiv), PdCl2(PPh3)2 (35 mg, 10 mol%), CuI (19 mg, 20 mol%),
PPh3 (13 mg, 10 mol%), then anhyd Et3N (6 mL) and anhyd DMF
(3 mL). Then the reaction mixture was stirred at 70 °C. The reaction
was monitored by TLC. After 24 h (indazole series) or 48 h (indole
series) of heating, the reaction mixture was poured into water and
extracted with CH2Cl2 (2 × 10 mL). The combined organic layers
were washed with brine (2 × 10 mL), dried over MgSO4, filtered
through celite and evaporated to dryness. The residue was purified
by flash chromatography (alumina, petroleum ether–Et2O or petro-
leum ether–EtOAc) with the exception of 7a (silica gel, petroleum
ether–Et2O, 1:1).
MS (EI, 70 eV): m/z (%) = 557, 555 (3) [M+], 402 (7), 400 (7), 220
(5), 218 (5), 171 (30), 155 (82), 139 (18), 107 (13), 91 (100).
Anal. Calcd for C25H21BrN2O4S2 (557.48): C, 53.86; H, 3.79; N,
5.02. Found: C, 53.60; H, 3.62; N, 4.98.
3-[5-Bromo-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-prop-2-yn-1-
ol (4m)
Yield: 79%; white crystals; mp 129–130 °C (CHCl3–pentane).
IR (KBr): 3363, 3137, 2231, 1597, 1574, 1494, 1447, 1378, 1335,
1301, 1263, 1231, 1189, 1172, 1152, 1112, 1090, 1034, 983, 802,
869, 751, 670, 585, 569, 539 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.90 (s, 1 H), 2.34 (s, 3 H), 4.54
(s, 2 H), 7.21–7.24 (m, 2 H), 7.43 (dd, J = 8.9, 1.4 Hz, 1 H), 7.70–
7.44 (m, 4 H), 7.82 (d, J = 8.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.6 (q), 51.6 (t), 76.1 (s), 92.0
(s), 103.9 (s), 115.0 (d), 117.5 (s), 123.2 (d), 126.9 (d), 128.4 (d),
130.1 (d), 130.2 (d), 132.3 (s), 132.8 (s), 134.5 (s), 145.7 (s).
3,5-Bis-[3-(Toluene-4-sulfonylamino)-prop-1-ynyl]-indole-1-
carboxylic Acid tert-Butyl Ester (7a)
Yield: 55%; white solid; mp 138–140 °C.
IR (KBr): 3358, 3283, 2981, 2234, 1737, 1597, 1438, 1371, 1156,
812 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.66 (s, 9 H), 2.25 (s, 3 H), 2.33
(s, 3 H), 4.09 (d, J = 5.9 Hz, 2 H), 4.13 (d, J = 5.9 Hz, 2 H), 4.96 (t,
J = 6.0 Hz, 1 H), 5.01 (t, J = 6.0 Hz, 1 H), 7.09 (dd, J = 8.7, 1.6 Hz,
Synthesis 2005, No. 5, 771–780 © Thieme Stuttgart · New York

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Sequential Sonogashira and Suzuki Cross-Coupling Reactions
777
1 H), 7.22–7.31 (m, 5 H), 7.53 (s, 1 H), 7.81–7.84 (m, 4 H), 7.96 (d,
J = 8.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.3 (q), 21.7 (q), 33.8 (t), 44.3
(q), 48.6 (t), 75.1 (s), 84.5 (s), 85.1 (s), 88.9 (s), 104.3 (s), 113.6 (d),
118.8 (s), 124.0 (d), 127.0 (d), 127.5 (d), 128.7 (d), 129.6 (d), 130.2
(d), 130.5 (s), 132.1 (d), 133.4 (s), 134.6 (s), 137.6 (s), 143.5 (s)
145.8 (s).
13C NMR (100 MHz, CDCl3): d = 21.5 (q), 21.6 (q), 28.2 (q), 34.0
(t), 34.1 (t), 76.4 (s), 77.4 (s) 82.7 (s), 85.1 (s), 87.3 (s), 102.3 (s),
115.2 (d), 117.0 (s), 123.7 (d), 126.0 (d), 127.6 (d), 127.62 (d),
128.6 (d), 129.8 (d), 129.9 (d), 130.06 (d), 130.1 (s), 136.9 (s), 137.0
(s), 139.3 (s), 143.7 (s), 143.9(s), 144.0 (s), 148.7 (s).
MS (EI, 70 eV): m/z (%) = 559 (5) [M+], 477 (11), 404 (15), 333 (5),
322 (24), 295 (5), 221 (10), 205 (13), 178 (18), 139 (14), 126 (12),
91 (100), 80 (33).
MS (EI, 70 eV): m/z (%) = 262 (14), 183 (14), 171 (9), 155 (10), 107
(10), 91 (27), 56 (100).
HRMS (ESI): m/z [MH+] calcd for C30H30N3O4S2: 560.1672; found:
560.1662.
HRMS (ESI): m/z [MNa+] calcd for C33H33N3O6S2Na: 654.1703;
found: 654.1654.
5-(3-Dimethylamino-prop-1-ynyl)-3-[3-(toluene-4-sulfonylami-
no)-prop-1-ynyl]-indazole-1-carboxylic Acid tert-Butyl Ester
(8a)
N-{3-[1-Benzenesulfonyl-3-(3-dimethylamino-prop-1-ynyl)-
1H-indol-5-yl]-prop-2-ynyl}-4-methyl-benzenesulfonamide
(7b)
Yield: 54%; pale yellow solid; mp 138–139 °C (CH3Cl3–pentane).
Yield: 83%; white crystals; mp 147–148 °C (CHCl3–pentane).
IR (KBr): 3453, 2954, 2829, 1737, 1598, 1498, 1461, 1383, 1328,
1256, 1162, 1096, 1067, 754 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.70 (s, 9 H), 2.20 (s, 3 H), 2.45
(s, 6 H), 3.56 (s, 2 H), 4.19 (s, 2 H), 5.25 (s, 1 H), 7.23 (d, J = 8.2
Hz, 2 H), 7.54 (s, 1 H), 7.57 (dd, J = 8.7, 1.6 Hz, 1 H), 7.82 (d, J =
8.2 Hz, 2 H), 8.06 (d, J = 9.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.3 (q), 28.1 (q), 33.7 (t), 44.3
(q), 48.5 (t), 74.9 (s), 84.67 (s), 84.74 (s), 85.9 (s), 90.2 (s), 114.7
(d), 119.1 (s), 123.8 (d), 126.3 (s), 127.4 (d), 129.8 (d), 132.8 (d),
133.4 (s), 136.7 (s), 138.9 (s), 143.9 (s), 148.3 (s).
IR (KBr): 3010, 1462, 1362, 1327, 1158, 1128, 1095, 988, 809, 752,
584 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.26 (s, 3 H), 2.39 (s, 6 H), 3.53
(s, 2 H), 4.06 (s, 2 H), 5.04 (s, 1 H), 7.10 (dd, J = 8.7, 1.6 Hz, 1 H),
7.23 (d, J = 7.9 Hz, 2 H), 7.43–7.48 (m, 3 H), 7.56–7.59 (m, 1 H),
7.70 (s, 1 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.83–7.88 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 21.4 (q), 33.8 (t), 44.3 (q), 48.7
(t), 75.4 (s), 83.0 (s), 84.5 (s), 89.6 (s), 105.1 (s), 113.4 (d), 117.7
(s), 124.0 (d), 126.9 (d), 127.4 (d), 128.8 (d), 129.50 (d), 129.53 (d),
129.7 (d), 130.8 (s), 133.6 (s), 134.3 (d), 136.9 (s), 137.7 (s), 143.7
(s).
MS (EI, 70 eV): m/z (%) = 280 (5), 250 (3), 249 (2), 206 (2), 192
(1), 171 (49), 139 (2), 107 (24), 91 (100).
MS (EI, 70 eV): m/z (%) = 545 (0.9) [M+], 400 (1), 279 (41), 228
(21), 215 (27), 167 (59), 149 (100), 113 (14), 112 (9), 83 (6), 57
(17).
HRMS (ESI): m/z [MH+] calcd for C27H31N4O4S: 507.2061; found:
507.2075.
3-(3-Dimethylamino-prop-1-ynyl)-5-[3-(toluene-4-sulfonylami-
no)-prop-1-ynyl]-indazole-1-carboxylic Acid tert-Butyl Ester
(8b)
Anal. Calcd for C29H27N3O4S2 (545.67): C, 63.23; H, 4.99; N, 7.70.
Found: C, 63.25; H, 5.12; N, 7.47.
Yield: 76%; beige solid; mp 120–121 °C (CH3Cl3–pentane).
3-[1-Benzenesulfonyl-3-(3-dimethylamino-prop-1-ynyl)-1H-in-
dol-5-yl]-prop-2-yn-1-ol (7c)
Yield: 74%; yellow crystals; mp 142–143 °C (CHCl3–pentane).
IR (KBr): 3271, 2926, 2858, 1740, 1599, 1498, 1463, 1384, 1343,
1278, 1257, 1159, 1093, 813 cm–1.
IR (film): 3340, 3133, 2933, 2856, 1468, 1377, 1294, 1175, 1139,
1099, 1033, 801, 721, 685, 603 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.30 (s, 6 H), 3.45 (s, 2 H), 4.39
(s, 2 H), 7.29–7.37 (m, 4 H), 7.45 (m, 1 H), 7.61–7.63 (m, 2 H),
7.77–7.82 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 44.1 (q), 48.5 (t), 51.1 (t), 75.7
(s), 84.6 (s), 87.9 (s), 89.1 (s), 105.1 (s), 113.5 (d), 118.5 (s), 123.9
(d), 126.8 (d), 128.4 (d), 128.6 (d), 128.9 (d), 129.4 (d), 129.5 (s),
130.9 (s), 132.0 (d), 132.1 (s), 133.6 (s), 134.3 (d), 137.6 (s).
1H NMR (400 MHz, CDCl3): d = 1.71 (s, 9 H), 2.33 (s, 3 H), 2.43
(s, 6 H), 3.63 (s, 2 H), 4.09 (s, 2 H), 5.36 (s, 1 H), 7.24–7.28 (m, 3
H), 7.61 (s, 1 H), 7.83 (d, J = 8.3 Hz, 2 H), 8.03 (d, J = 8.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.4 (q), 28.0 (q), 33.7 (t), 44.2
(q), 48.5 (t), 75.5 (s), 83.6 (s), 83.9 (s), 85.8 (s), 91.8 (s), 114.6 (d),
118.1 (s), 124.0 (d), 126.7 (s), 127.4 (d), 129.6 (d), 132.4 (d), 134.4
(s), 136.9 (s), 139.1 (s), 143.6 (s), 148.4 (s).
MS (EI, 70 eV): m/z (%) = 462 (7), 405 (5), 363 (3), 277 (10), 206
(6), 171 (52), 107 (21), 91 (100).
MS (EI, 70 eV): m/z (%) = 392 (3) [M+], 362 (13), 318 (4), 277 (13),
251 (17), 221 (43), 208 (4), 178 (14), 128 (13), 77 (51), 57 (100), 32
(81).
HRMS (ESI): m/z [MH+] calcd for C27H31N4O4S: 507.2061; found:
507.2094.
3-(3-Dimethylamino-prop-1-ynyl)-5-(3-hydroxy-prop-1-ynyl)-
indazole-1-carboxylic Acid tert-Butyl Ester (8c)
Yield: 80%; beige solid; mp 115–116 °C (CH3Cl3–pentane).
Anal. Calcd for C22H20N2O3S (392.45): C, 67.33; H, 5.14; N, 7.14.
Found: C, 67.37; H, 5.15; N, 7.12.
N-{3-[5-(3-Dimethylamino-prop-1-ynyl)-1-(toluene-4-sulfonyl)-
1H-indol-3-yl]-prop-2-ynyl}-4-methyl-benzenesulfonamide
(7d)
IR (KBr): 3094, 2984, 2826, 2229, 1923, 1732, 1614, 1497, 1461,
1386, 1347, 1256, 1159, 1095, 830 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.64 (s, 9 H), 2.36 (s, 6 H + OH),
3.56 (s, 2 H), 4.44 (s, 2 H), 7.48 (d, J = 8.7 Hz, 1 H), 7.76 (s, 1 H),
8.01 (d, J = 8.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 28.0 (q), 44.0 (q), 48.4 (t), 51.3
(t), 75.6 (s), 84.5 (s), 87.9 (s), 89.5 (s), 91.5 (s), 114.8 (d), 118.7 (s),
124.0 (d), 126.8 (s), 132.6 (d), 134.4 (s), 139.1 (s), 148.4 (s).
Yield: 77%; white crystals; mp 162–163 °C (CHCl3–pentane).
IR (KBr): 3059, 2946, 2861, 1596, 1462, 1376, 1332, 1295, 1176,
1158, 1131, 1097, 1065, 1019, 996, 913, 798, 763, 675, 582 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.14 (s, 3 H), 2.32 (s, 3 H), 2.37
(s, 6 H), 3.48 (s, 2 H), 4.10 (s, 2 H), 7.16 (d, J = 8.0 Hz, 2 H), 7.22
(d, J = 8.1 Hz, 2 H), 7.37–7.46 (m, 4 H), 7.72 (d, J = 8.5 Hz, 2 H),
7.80 (d, J = 8.3 Hz, 2 H), 7.84 (d, J = 8.7 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 353 (2) [M+], 338 (2), 310 (52), 254 (80),
252 (61), 210 (51), 192 (6), 152 (9), 127 (3), 82 (7), 57 (100).
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B. Witulski et al.
PAPER
HRMS (ESI): m/z [MH+] calcd for C20H24N3O3: 354.1812; found:
7.34–7.38 (m, 1 H), 7.45–7.49 (m, 2 H), 7.57–7.59 (m, 2 H), 7.74
354.1819.
(s, 1 H), 7.80 (m, 1 H), 7.91–7.93 (m, 2 H), 8.02 (d, J = 8.6 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 44.2 (q), 48.7 (t), 55.3 (q), 76.0 (s),
89.1 (s), 105.6 (s), 112.5 (d), 113.2 (d), 113.7 (d), 118.9 (d), 119.9
(d), 125.1 (d), 126.9 (d), 129.4 (d), 129.5 (d), 129.8 (d), 131.4 (s),
133.6 (s), 134.1 (d), 137.2 (s), 137.9 (s), 142.5 (s), 159.9 (s).
MS (EI, 70 eV): m/z (%) = 444 (0.2) [M+], 390 (0.2), 338 (0.2), 303
(0.9), 279 (18), 223 (0.3), 214 (23), 183 (10), 167 (38), 149 (100),
113 (11), 83 (8), 71 (19), 57 (30), 43 (51).
3-(3-Dimethylamino-prop-1-ynyl)-5-phenylethynyl-indazole-1-
carboxylic Acid tert-Butyl Ester (8d)
Yield: 78%; pale yellow crystals; mp 117–118 °C (CHCl3–pen-
tane).
IR (KBr): 3432, 2935, 2825, 2781, 1728, 1595, 1501, 1387, 1243,
1154, 1079, 1041, 882, 753 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.64 (s, 9 H), 2.35 (s, 6 H), 3.55
(s, 2 H), 7.26–7.28 (m, 3 H), 7.46–7.49 (m, 2 H), 7.60 (dd, J = 8.8,
2.0 Hz, 1 H), 7.87 (s, 1 H), 8.06 (d, J = 8.7 Hz, 1 H).
HRMS (ESI): m/z [MH+] calcd for C26H25N2O3S: 445.1580; found:
445.1605.
13C NMR (100 MHz, CDCl3): d = 28.0 (q), 44.2 (q), 48.5 (t), 75.5
(s), 85.6 (s), 88.7 (s), 89.5 (s), 91.8 (s), 114.8 (d), 119.2 (s), 122.9
(s), 123.8 (d), 126.9 (s), 128.32 (d), 128.37 (d), 131.5 (d), 132.6 (d),
134.6 (s), 139.0 (s), 148.5 (s).
N-{3-[5-(3-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-indol-3-
yl]-prop-2-ynyl}-4-methyl-benzenesulfonamide (9c)
Yield: 75%; white solid; mp 103–105 °C (CHCl3–pentane).
IR (film): 3285, 2919, 1728, 1598, 1463, 1376, 1161, 1091, 812,
757, 667, 583 cm–1.
MS (EI, 70 eV): m/z (%) = 399 (1) [M+], 356 (13), 298 (79), 284
(12), 268 (38), 256 (100), 226 (28), 149 (19), 127 (15), 82 (7).
1H NMR (400 MHz, CDCl3): d = 2.10 (s, 3 H), 2.34 (s, 3 H), 3.86
(s, 3 H), 4.14 (d, J = 6.1 Hz, 2 H), 4.96 (t, J = 6.1 Hz, 1 H), 6.90 (dd,
J = 8.1, 2.6 Hz, 1 H), 7.10–7.17 (m, 4 H), 7.24 (d, J = 8.5 Hz, 2 H),
7.36 (t, J = 7.8 Hz, 1 H), 7.49–7.51 (m, 2 H), 7.55 (dd, J = 8.6, 1.8
Hz, 1 H), 7.77 (t, J = 8.5 Hz, 4 H), 7.95 (d, J = 8.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.1 (q), 21.5 (q), 33.9 (t), 55.3
(q), 75.9 (s), 87.8 (s), 104.3 (s), 112.4 (d), 113.3 (d), 113.7 (d), 118.7
(d), 119.8 (d), 125.0 (d), 126.9 (d), 127.3 (d), 129.5 (s), 129.6 (d),
129.7 (d), 129.8 (d), 130.0 (d), 130.8 (s), 133.4 (s), 136.8 (s), 137.1
(s), 142.2 (s), 143.8 (s), 145.5 (s), 159.9 (s).
Anal. Calcd for C25H25N3O2 (399.49): C, 75.16; H, 6.31; N, 10.51.
Found: C, 75.11; H, 6.31; N, 10.12.
3-Alkynyl-5-aryl Indoles 9a–c and 3-Aryl Indoles 10 and 11a,b;
General Procedure
In a Schlenk tube with screw cap were introduced under Ar indole
4j,k or 1d or 1g,h (0.3 mmol), 3-methoxy- or 4-methoxy- or 4-di-
methylamino-boronic acid (1.1 equiv), and [Pd(PPh3)4] (7 mg, 2
mol%), then DME (4 mL) was added followed by the addition of
Na2CO3 (48 mg, 1.5 equiv) in H2O (2 mL). The reaction mixture
was vigorously stirred and heated at 80 °C or 70 °C. The progress
of the reaction was monitored by TLC. After completion of the re-
action, the mixture was diluted with CH2Cl2 (10 mL) and the organ-
ic layer was washed with brine (2 × 10 mL). The combined organic
extracts were dried (MgSO4) and evaporated to dryness under re-
duced pressure. The residue was purified by flash chromatography
on alumina (9a,b) or silica gel (9c, 10 and 11a,b).
MS (EI, 70 eV): m/z (%) = 584 (0.9) [M+], 429 (0.2), 336 (0.5), 300
(0.2), 246 (1), 203 (0.6), 155 (2), 149 (5), 117 (2), 91 (11), 61 (12),
43 (100).
Anal. Calcd for C32H28N2O5S2 (584.71): C, 65.73; H, 4.83; N, 4.79.
Found: C, 65.49; H, 4.92; N, 4.82.
[4-(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-phenyl]-di-
methylamine (10)
Yield: 79%; white crystals; mp 126–127 °C (CHCl3–pentane).
{3-[1-Benzenesulfonyl-5-(4-methoxy-phenyl)-1H-indol-3-yl]-
prop-2-ynyl}-dimethylamine (9a)
Yield: 89%; white crystals; mp 130–131 °C (CHCl3–pentane).
IR (film): 2935, 2897, 1615, 1516, 1448, 1367, 1132, 1034, 851,
724, 686, 605 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.95 (s, 6 H), 3.77 (s, 3 H), 6.79
(d, J = 8.8 Hz, 2 H), 6.95 (dd, J = 9.0, 2.5 Hz, 1 H), 7.19 (d, J = 2.5
Hz, 1 H), 7.33–7.45 (m, 5 H), 7.55 (s, 1 H), 7.85 (d, J = 7.3 Hz, 2
H), 7.95 (d, J = 9.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 40.5 (q), 55.7 (q), 103.3 (d), 112.8
(d), 113.7 (d), 114.8 (d), 120.8 (s), 122.6 (d), 124.7 (s), 126.7 (d),
128.6 (d), 129.2 (d), 130.4 (s), 131.0 (s), 133.7 (d), 138.2 (s), 150.1
(s), 156.8 (s).
IR (film): 2938, 2777, 1732, 1608, 1519, 1463, 1372, 1248, 1173,
1038, 993, 814, 752, 722, 685 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.39 (s, 6 H), 3.54 (s, 2 H), 3.85
(s, 3 H), 6.97–6.99 (m, 2 H), 7.44–7.48 (m, 2 H), 7.51–7.56 (m, 4
H), 7.72 (s, 1 H), 7.75 (d, J = 1.2 Hz, 1 H), 7.90–7.93 (m, 2 H), 8.00
(d, J = 8.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 44.3 (q), 48.8 (t), 55.4 (q), 76.0
(s), 89.2 (s), 105.6 (s), 113.7 (d), 114.3 (d), 118.4 (d), 124.8 (d),
126.9 (d), 128.4 (d), 129.2 (d), 129.4 (d), 131.5 (s), 133.2 (s), 133.5
(s), 134.1 (d), 137.1 (s), 137.9 (s), 159.2 (s).
MS (EI, 70 eV): m/z (%) = 444 (32) [M+], 400 (10), 303 (100), 288
(9), 260 (27), 259 (50), 222 (23), 216 (18), 207 (4), 149 (2), 83 (3),
69 (6), 57 (15), 32 (26).
MS (EI, 70 eV): m/z (%) = 406 (10) [M+], 265 (100), 250 (14), 222
(30), 178 (5).
Anal. Calcd for C23H22N2O3S (406.50): C, 67.96; H, 5.46; N, 6.89.
Found: C, 67.97; H, 5.48; N, 6.89.
Anal. Calcd for C26H24N2O3S (444.55): C, 70.25; H, 5.44; N, 6.30.
Found: C, 70.25; H, 5.44; N, 6.28.
[4-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-phenyl]-di-
methylamine (11a)
Yield: 93%; yellow crystals; mp 130–131 °C (CHCl3–pentane).
{3-[1-Benzenesulfonyl-5-(3-methoxy-phenyl)-1H-indol-3-yl]-
prop-2-ynyl}-dimethylamine (9b)
Yield: 98%; yellow oil.
IR (film): 2890, 2800, 1615, 1515, 1441, 1176, 1142, 1113, 1090,
787, 734, 685, 600 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.99 (s, 6 H), 6.80 (d, J = 8.8 Hz,
2 H), 7.41–7.44 (m, 5 H), 7.50–7.54 (m, 1 H), 7.58 (s, 1 H), 7.86–
7.88 (m, 3 H), 7.92 (d, J = 8.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 40.5 (q), 112.8 (d), 115.3 (d),
117.2 (s), 119.9 (s), 122.7 (d), 123.5 (d), 124.0 (s), 126.8 (d), 127.6
IR (film): 2936, 2777, 1728, 1599, 1463, 1090, 1032, 995, 758, 685,
603 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.39 (s, 6 H), 3.54 (s, 2 H), 3.86
(s, 3 H), 6.88–6.91 (m, 1 H), 7.13 (m, 1 H), 7.17–7.20 (m, 1 H),
Synthesis 2005, No. 5, 771–780 © Thieme Stuttgart · New York

PAPER
Sequential Sonogashira and Suzuki Cross-Coupling Reactions
779
(d), 128.6 (d), 129.4 (d), 131.7 (s), 134.0 (d), 134.3 (s), 138.0 (s),
150.3 (s).
MS (EI, 70 eV): m/z (%) = 456, 454 (15) [M+], 315 (100), 313 (94),
299 (10), 297 (6), 234 (9), 197 (19), 190 (17), 110 (15), 77 (22), 43
(92).
1H NMR (200 MHz, CDCl3): d = 2.30 (s, 3 H), 2.35 (s, 6 H), 3.44
(s, 2 H), 3.85 (s, 3 H), 6.91 (dd, J = 8.2, 2.5 Hz, 1 H), 7.08–7.45 (m,
6 H), 7.70 (s, 1 H), 7.78 (d, J = 8.4 Hz, 2 H), 7.87 (s, 1 H), 7.98 (d,
J = 8.4 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.5 (q), 44.3 (q), 48.6 (t), 55.3 (q),
84.0 (s), 85.1 (s), 112.9 (d), 113.6 (d), 113.7 (d), 118.5 (s), 120.3 (d),
123.6 (s), 123.7 (d), 123.9 (d), 126.8 (d), 128.4 (d), 129.2 (s), 129.9
(d) (2 peaks), 133.8 (s), 134.7 (s), 134.9 (s), 145.2 (s), 159.9 (s).
Anal. Calcd for C22H19BrN2O2S (455.37): C, 58.03; H, 4.21; N,
6.15. Found: C, 57.98; H, 4.20; N, 6.15.
5-Bromo-3-(3-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-in-
dole (11b)
MS (EI, 70 eV): m/z (%) = 458 (22) [M+], 414 (9), 303 (43), 260
(40), 216 (9), 190 (3), 149 (5), 124 (13), 91 (28), 32 (100).
Yield: 94%; yellow oil.
HRMS: m/z [M+] calcd for C27H26N2O3S: 458.1664; found:
IR (film): 2934, 2963, 1732, 1596, 1439, 1372, 1248, 1175, 1023,
739, 697, 657, 584, 537 cm–1.
458.1651.
3-(3-Methoxy-phenyl)-5-phenylethynyl-1-(toluene-4-sulfonyl)-
1H-indole (13b)
Yield: 85%; yellow crystals; mp 139–140 °C (CHCl3–pentane).
1H NMR (400 MHz, CDCl3): d = 2.34 (s, 3 H), 3.86 (s, 3 H), 6.92
(dd, J = 8.3, 2.4 Hz, 1 H), 7.07 (s, 1 H), 7.12 (d, J = 7.5 Hz, 1 H),
7.23 (d, J = 8.3 Hz, 2 H), 7.38 (t, J = 7.5 Hz, 1 H), 7.44 (dd, J = 8.8,
1.6 Hz, 1 H), 7.68 (s, 1 H), 7.77 (d, J = 8.3 Hz, 2 H), 7.88 (s, 1 H),
7.92 (d, J = 8.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.6 (q), 55.3 (q), 113.1(d), 113.6
(d), 115.2 (d), 117.2 (s), 120.2 (d), 123.19 (d), 123.25 (s), 124.1 (d),
126.8 (d), 127.8 (d), 130.0 (d), 130.1 (d), 131.0 (s), 133.6 (s), 134.1
(s), 134,9 (s), 145.3 (s), 160.0 (s).
IR (film): 2931, 1732, 1595, 1493, 1456, 1373, 1299, 1275, 1248,
1189, 1146, 1128, 1090, 1023, 969, 891, 812, 755, 738, 672, 589
cm–1.
1H NMR (200 MHz, CDCl3): d = 2.29 (s, 3 H), 3.83 (s, 3 H), 6.95
(dd, J = 8.3, 2.5 Hz, 1 H), 7.17–7.24 (m, 3 H), 7.33–7.42 (m, 5 H),
7.54–7.60 (m, 3 H), 7.77 (s, 1 H), 7.84 (d, J = 8.4 Hz, 2 H), 8.01 (d,
J = 0.8 Hz, 1 H), 8.07 (d, J = 8.3 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.5 (q), 55.3 (q), 88.8 (s), 89.6 (s),
113.0 (d), 113.7 (d), 113.9 (d), 118.7 (s), 120.4 (d), 123.2 (s), 123.7
(s), 123.89 (d), 123.94 (d), 126.8 (d), 128.2 (d), 128.3 (d), 128.4 (d),
129.3 (s), 130.01 (d), 130.02 (d), 131.5 (d), 133.9 (s), 134.9 (s),
135.0 (s), 145.3 (s), 160.0 (s).
MS (EI, 70 eV): m/z (%) = 457 (35) [M+], 455 (38) [M+], 377 (39),
302 (61), 300 (63), 257 (3), 222 (100), 178 (21), 151 (22), 91 (43).
3,5-bis-(4-Dimethylamino-phenyl)-1-benzenesulfonyl-1H-in-
dole (12a)
Yield: 3%; oil.
1H NMR (400 MHz, CDCl3): d = 2.99 (s, 6 H), 3.02 (s, 6 H), 6.79–
6.84 (m, 4 H), 7.42–7.56 (m, 8 H), 7.59 (s, 1 H), 7.90–7.95 (m, 3 H),
8.06 (d, J = 8.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 40.5 (q), 40.6 (q), 112.77 (d),
112.81 (d), 113.9 (d), 118.1 (d), 120.9 (s), 122.0 (d), 123.8 (d),
124.8 (s), 126.8 (d), 128.0 (d), 128.7 (d), 129.2 (d), 129.5 (s), 130.4
(s), 133.7 (d), 134.3 (s), 137.2 (s), 138.3 (s), 149.8 (s), 150.1 (s).
MS (EI, 70 eV): m/z (%) = 477 (54) [M+], 323 (77), 322 (100), 292
(3), 277 (7), 252 (13), 139 (9), 91 (24).
HRMS (ESI): m/z [MNa+] calcd for C30H23NNaO3S: 500.1291;
found: 500.1300.
Acknowledgment
Financial support from the Fonds der Chemischen Industrie is gra-
tefully acknowledged.
3,5-bis-(3-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-indole
(12b)
Yield: 4% (when the Suzuki reaction was performed at 80 °C); pale
yellow crystals; mp 164–166 °C.
References
1H NMR (400 MHz, CDCl3): d = 2.36 (s, 3 H), 3.86 (s, 3 H), 3.87
(s, 3 H), 6.89 (dd, J = 8.2, 2.6 Hz, 1 H), 6.93 (dd, J = 8.2, 2.6 Hz, 1
H), 7.10–7.24 (m, 6 H), 7.33–7.41 (m, 2 H), 7.58 (dd, J = 8.7, 1.8
Hz, 1 H), 7.72 (s, 1 H), 7.84 (d, J = 8.4 Hz, 2 H), 7.94 (d, J = 1.8 Hz,
1 H), 8.10 (d, J = 8.5 Hz, 1 H).
(1) (a) Hoyer, D.; Hannon, J. P.; Martin, G. R. Pharmacol.
Biochem. Behav. 2002, 71, 533. (b) Barnes, N. M.; Sharp, T.
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Neurotransmitters and Neuromodulators; Wiley-VCH:
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(3) For a recent review about 5-HT5, 5-HT6 and 5-HT7
receptors, see: Glennon, R. A. J. Med. Chem. 2003, 46,
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(4) (a) Tsai, Y.; Dukat, M.; Slassi, A.; MacLean, N.;
Demchyshyn, L.; Savage, J. E.; Roth, B. L.; Hufesein, S.;
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2295. (b) Glennon, R. A.; Lee, M.; Rangisetty, J. B.; Dukat,
M.; Roth, B. L.; Savage, J. E.; McBride, A.; Rauser, L.;
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(c) Bromidge, S. M.; Brown, A. M.; Clark, S. E.; Dodgson,
K.; Gager, T.; Grassam, H. L.; Jeffrey, P. M.; Joiner, G. F.;
King, F. D.; Middlemiss, D. N.; Moss, S. F.; Newman, H.;
Riley, G.; Routledge, C.; Wyman, P. J. Med. Chem. 1999,
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Trafit, B.; Riemer, C.; Bourson, A. Br. J. Pharmacol. 1998,
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5-Alkynyl-3-aryl Indoles (13a,b); General Procedure
In a Schlenk tube with screw cap were introduced under Ar indole
11b (0.2 mmol), alkyne 6 (0.6 mmol, 3 equiv), PdCl2(PPh3)2 (14
mg, 10 mol%), CuI (8 mg, 20 mol%), PPh3 (5 mg, 10 mol%), then
anhyd Et3N (4 mL) and anhyd DMF (2 mL). Then the reaction mix-
ture was stirred at 70 °C for 48 h. The reaction mixture was poured
into water and extracted with CH2Cl2 (2 × 8 mL). The combined or-
ganic layers were washed with brine (2 × 8 mL), dried over MgSO4,
filtered through celite and evaporated to dryness. The residue was
purified by flash chromatography (petroleum ether–EtOAc) on alu-
mina (13a) or silica gel (13b).
{3-[3-(3-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-indol-5-
yl]-prop-2-ynyl}-dimethylamine (13a)
Yield: 78%; yellow oil.
IR (film): 2939, 1732, 1596, 1557, 1455, 1373, 1267, 1173, 1137,
1024, 812, 667, 590, 538 cm–1.
Synthesis 2005, No. 5, 771–780 © Thieme Stuttgart · New York

780
B. Witulski et al.
PAPER
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protocol to our substrates has not been satisfactory so far.
Synthesis 2005, No. 5, 771–780 © Thieme Stuttgart · New York