Palladium-catalyzed amination and sulfonylation of 5-bromo-3-[2- (diethylamino)ethoxy]indoles to potential 5-HT6 receptor ligands

Article abstract of DOI:10.1002/ejoc.200800638

A general and efficient palladium-catalyzed amination of 5-bromo-3-[2-(diethylamino)ethoxy]indoles has been developed. Best results are obtained in the presence of Pd(OAc)₂ and 2-[di(1-adamantyl) phosphanyl]-1-phenylpyrrole as ligand. Subsequent sulfonylation gave novel indole derivatives, which are of interest as potentially biological active 5-HT₆ receptor ligands. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800638

FULL PAPER
DOI: 10.1002/ejoc.200800638
Palladium-Catalyzed Amination and Sulfonylation of 5-Bromo-3-[2-
(diethylamino)ethoxy]indoles to Potential 5-HT6 Receptor Ligands
Nicolle Schwarz,[a] Anahit Pews-Davtyan,[a] Dirk Michalik,[a] Annegret Tillack,[a]
Karolin Krüger,[a] Antoni Torrens,[b] José Luis Diaz,[b] and Matthias Beller*[a]
Keywords: Indole / Sulfonylation / Amination / Palladium
A general and efficient palladium-catalyzed amination of 5-
bromo-3-[2-(diethylamino)ethoxy]indoles has been devel-
oped. Best results are obtained in the presence of Pd(OAc)2
and 2-[di(1-adamantyl)phosphanyl]-1-phenylpyrrole as li-
gand. Subsequent sulfonylation gave novel indole deriva-
tives, which are of interest as potentially biological active 5-
HT6 receptor ligands.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
pholes via titanium-catalyzed hydrohydrazination of chlo-
ro- and silyloxo-substituted alkynes.[9] Based on this work,
more recently we studied the catalytic hydrohydrazination
of propargyl alcohol derivatives to give 3-silyloxy-2-meth-
ylindoles (Scheme 1).[10]
Introduction
Among the known biologically active amines, especially
indoles continue to attract significant synthetic and medici-
nal interest.[1] A variety of substituted indoles bind selec-
tively to different receptors with high affinity and have been
referred as “privileged pharmacological structures”. Thus,
it is not surprising that indoles have become an important
component in many of today’s pharmaceuticals.[2] 5-Hy-
droxytryptamine6 (5-HT6) receptors are an essential sub-
[3]
type of the identified serotonin receptors 5-HT1–7
.
Their
selective attraction for a wide range of drugs used in central
nervous system related diseases (e.g. Alzheimer’s disease,
anxiety, and schizophrenia) has stimulated significant re-
cent work in this field.[4] In addition, 5-HT6 receptor li-
gands are known to facilitate the reduction of food intake,
fat absorption and body weight in genetic and dietary mod-
els of obesity. Interestingly, the 5-HT6 receptor has no
known functional splice variants and it appears to be ex-
pressed almost exclusively in the central nervous system
(CNS).[5]
Figure 1. 5-HT6 receptor ligands containing indoles or indole-like
structures.
Since the discovery of selective ligands for 5-HT6 recep-
tors by high-throughput-screening in 1998, several medici-
nal-chemistry-driven approaches have delivered novel lead
structures. Among the active compounds the majority are
indole derivatives, especially with tryptamine scaffold (Fig-
ure 1).[6] For some time we have been interested in the im-
provement and exploration of methodologies for the syn-
thesis and functionalization of indoles.[7,8] For example, we
developed a one-pot synthesis of tryptamines and trypto-
Scheme 1. Catalytic synthesis of 3-siloxyindoles.
In continuation of these studies, we report here the
synthesis of novel 3-[2-(diethylamino)ethoxy]-2-methyl-
indoles,[11] their palladium-catalyzed amination and sub-
sequent sulfonylation of the corresponding coupled
indoles.
[a] Leibniz-Institut für Katalyse e.V. an der Universität Rostock,
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Fax: +49-381-1281-51113
E-mail: matthias.beller@catalysis.de
[b] ESTEVE,
Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain
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M. Beller et al.
FULL PAPER
benzylamine in presence of different ligands was investi-
gated. Best results are obtained applying Pd(OAc)2/1-
phenyl-2-[di(1-adamantyl)phosphanyl]pyrrole L as in situ
catalyst at 100 °C for 20 h in toluene in the presence of
LiHMDS (or Cs2CO3) as base. This catalyst system has also
been proven successful in several other catalytic coupling
reactions before.[13a,13b] As shown in Scheme 3 and Table 1
aminations with benzylamine as well as aliphatic amines [n-
hexylamine and 2-(4-fluorophenyl)ethylamine] worked well
and led to the corresponding products in good yields (56–
85%). In general, the yields of the Boc-protected indoles are
decreased in comparison with the N-methyl and N-benzyl-
protected ones. All attempts to couple tert-butyl 5-bromo-
3-[2-(diethylamino)ethoxy]-2-methylindole-1-carboxylate (2c)
with secondary amines (imidazole, pyrazole, 2-aminopyr-
imidine) gave the free NH-indole derivative [2-(5-bromo-2-
methyl-1H-indol-3-yloxy)ethyl]diethylamine 2d.
Results and Discussion
As shown in Scheme 2 initially we envisioned two dif-
ferent synthetic strategies (A and B) to obtain the desired
compounds 5 and 6. The synthetic route A starts with 5-
bromo-2-methyl-3-silyloxyindole 1 with in situ deprotection
of the silyl group, followed by nucleophilic substitution with
2-(diethylamino)ethyl chloride to give 2. Palladium-cata-
lyzed Buchwald–Hartwig amination[12] towards 3, subse-
quent hydrogenation to 4 and finally sulfonylation should
lead to the desired products 5 and 6. Route B demonstrates
another access to these structures starting from the same
compound. Here, 5-bromo-2-methyl-3-silyloxyindole
1
should be catalytically aminated to the according indole de-
rivatives 7. Subsequent sulfonylation of the arylamino-
indoles 7 would give the sulfonylated intermediates 8. Then,
the aminoalkyl side chain has to be introduced in the last
step to give the target compounds 5 and 6.
The lower stability of the Boc-derivatives is explained by
partial deprotection under the reaction conditions. In order
to prepare the pharmaceutically more interesting free 5-
aminoindoles, catalytic debenzylation of 3a–c was investi-
gated (Scheme 4, Table 2). For this purpose hydrogenation
reactions 3a–b have been performed in a 20 mL autoclave
at room temperature with a hydrogen pressure of 50 bar for
8 h. In the case of compound 3c lower hydrogen pressure
(5 bar), shorter reaction time and elevated temperatures
(60 °C) were needed, to avoid the formation of 3-indoline
as a by-product. Formation of the free NH2-group in posi-
tion 5 of the indole proceeded smoothly and gave the corre-
sponding 5-amino-3-[2-(diethylamino)ethoxy]indoles 4a–c
in good to high yields (50–91%).
In exploratory experiments the palladium-catalyzed am-
ination of 5-bromo-3-[2-(diethylamino)ethoxy]indole 2 with
Scheme 4. Palladium-catalyzed hydrogenation of 5-benzylamino-3-
[2-(diethylamino)ethoxy]indoles.
Next, we attempted the sulfonylation of 3c, 3e, and 4a–c
with different aryl- and heteroarylsulfonyl chlorides as
shown in Scheme 5. The selection of the sulfonyl groups is
Scheme 2. Synthetic routes of 5-sulfonylamine-3-[2-(diethylamino)-
ethoxy]indoles.
Scheme 3. Palladium-catalyzed amination of 5-bromo-3-[2-(diethylamino)ethoxy]lindoles.
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Synthesis of Potential 5-HT6 Receptor Ligands
Table 1. Pd-catalyzed amination of 5-bromo-3-[2-(diethylamino)-
ethoxy]indoles.
Table 2. Pd-catalyzed hydrogenation.
[a] Isolated yield based on indole derivative. [b] Reaction conditions:
Indole derivative (1 mmol), Pd/C (10%) (200 mg), H2, 50 bar, room
temp., 8 h in 40 mL of ethanol. [c] Reaction conditions: Indole de-
rivative (1 mmol), Pd/C (10%) (200 mg), H2, 5 bar, 60 °C, 3.5 h in
40 mL of ethanol.
[a] Isolated yield based on the indole. [b] Reaction conditions: 5-
bromo-3-[2-(diethylamino)ethoxy]indole
(1 mmol),
amine
Scheme 5. Sulfonylation of 5-amino-3-[2-(diethylamino)ethoxy]-
indoles with different sulfonyl chlorides.
(1.3 mmol), 2 mol-% Pd(OAc)2, 4 mol-% ligand L, LiHMDS
(1.3 mmol), solvent: toluene 3 mL, 100 °C, 20 h. [c] Reaction condi-
tions: 5-bromo-3-[2-(diethylamino)ethoxy]indole (1 mmol), amine
(1.5 mmol), 6 mol-% Pd(OAc)2, 12 mol-% ligand L, Cs2CO3
(1.0 mmol), solvent: toluene 3 mL, 100 °C, 20 h.
the newly prepared compounds in Table 3 possess two
hydrophobic areas and an indole core. Because the recep-
tor-ligand affinity increases additionally with a free NH-
group in position 1, we have deprotected compound 5g and
5h to the biologically more active indole derivatives 6a and
6b. We obtained these indole derivatives in high yields up
to 88% (Table 3, entries 8 and 10).
based on a pharmacophore-framework model for known 5-
HT6 receptor ligands, which was postulated in 2004 by Ho-
lenz et al.[6] based on a medicinal-chemistry-guided analysis
of reference compounds. Favourable sulfonyl motives came
from a modelling study of Pullagurla et al., including naph-
thyl, benzothiophenyl, imidazo[2,1-b]thiazolyl and p-ami-
nophenyl substituents.[14]
Finally, we studied the sulfonylation of the 3-siloxy-pro-
tected 5-aminoindoles 7a–e[13a] to give 8a–i (Scheme 6).
The newly synthesized sulfonylated indoles are listed in
Table 3. Treatment of the respective 5-aminoindole with the
different aryl- and heteroarylsulfonyl chlorides in Et3N at
40 °C or in CH2Cl2 in the presence of Cs2CO3 at room tem-
perature for 2 h gave the corresponding sulfonylated indole
derivatives 5a–h in general in good yields (Table 3, entries
1–4, 6–7 and 9, 50–98%). An exception is the reaction with
6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (Table 3,
entry 5) which gave a lower yield due to the decreased reac-
tivity of this sulfonyl chloride. In accordance with the phar-
Scheme 6. Sulfonylation of 5-amino-3-(silyloxy)indoles with dif-
macophore-framework model for 5-HT6 receptor ligands ferent sulfonyl chlorides.
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M. Beller et al.
Table 4. Sulfonylation of 5-amino-3-(silyloxy)indoles.[a]
FULL PAPER
Table 3. Sulfonylation of 5-amino-3-[2-(diethylamino)ethoxy]in-
doles with different sulfonyl chlorides.
[a] Isolated yield based on the indole. [b] Reaction conditions: In-
dole derivative (1 mmol), arylsulfonyl chloride (1 mmol), triethyl-
amine (5 mL), 40 °C, 24 h. [c] Reaction conditions: Indole derivative
(1 mmol), arylsulfonyl chloride (3 mmol), Cs2CO3 (2 mmol), sol-
vent: CH2Cl2 (10 mL), 40 °C, 24 h. [d] Reaction conditions: Indole
derivative (0.1 mmol), methylamine in 10 mL of ethanol (33%),
room temp., 24 h. [e] Reaction conditions: indole derivative
(0.5 mmol), sulfonyl chloride (0.5 mmol), NaHCO3 (2 equiv.), sol-
vent: acetonitrile (5 mL), room temp., 15 h. [f] Reaction conditions:
indole derivative (0.5 mmol), 140 °C, 3 h.
[a] Reaction conditions: Indole derivative (1 mmol), arylsulfonyl
chloride (1 mmol), triethylamine (5 mL), 40 °C, 2 h. [b] Isolated
yield based on the indole.
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Synthesis of Potential 5-HT6 Receptor Ligands
bonate (12 mmol) and DMAP (0.35 mmol) were dissolved in dry
THF and stirred overnight at room temperature. After complete
conversion (TLC control) the solvent was removed and the residue
was cleaned by column chromatography (eluent: ethyl acetate gra-
dient 0–25% in heptane). The isolated product gave a light-yellow
The sulfonylation proceeded similar compared to the sul-
fonylations shown in Scheme 3. Again, most sulfonylated
indoles 8a–i were isolated in good yields (Table 4, entries 1–
5, 7–9; 51–90%). Despite several attempts, the in situ depro-
tection with TBAF and nucleophilic substitution of 2-(di-
ethylamino)ethyl chloride to compounds 5 and 6 according
to route B could not be achieved.
1
solid material in a yield of 90%. H NMR (300.13 MHz, CDCl3):
δ = 7.99 (d, J = 8.9 Hz, 1 H), 7.49 (d, J = 2.0 Hz, 1 H), 7.29 (dd,
J = 8.9, J = 2.0 Hz, 1 H), 2.44 (s, 3 H), 1.66 (s, 9 H), 1.08 (s, 9 H),
0.17 (s, 6 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 150.5 (Cq),
134.7 (Cq), 132.2, 127.0 (Cq), 126.3, 123.6, 119.6 (Cq), 116.9 (Cq),
115.6 (Cq), 83.7 (Cq), 28.3, 25.8, 18.2 (Cq), 12.9, –4.1 ppm. MS
(EI, 70 eV): m/z (%) = 441 (11), 440 (3), 439 (11) [M+], 386 (24),
385 (100), 384 (23), 383 (97), 341 (58), 340 (13), 339 (57), 284 (12),
283 (14), 282 (12), 204 (12), 203 (64), 145 (4), 144 (26), 75 (15), 74
(6), 73 (83), 59 (12), 58 (7), 57 (91). HRMS: calcd. for
Conclusions
In summary, a series of new potential 5-HT6 receptor
ligands has been synthesized. For the first time palladium-
catalyzed coupling reactions of 3-[2-(diethylamino)ethoxy]-
indoles have been performed. Catalytic amination applying
Pd(OAc)2/1-phenyl-2-[di(1-adamantyl)phosphanyl]pyrrole
as catalyst system gave the corresponding 5-aminoindoles
in good yields. Straightforward sulfonylation with different
aryl- and heteroarylsulfonyl chlorides proceeded smoothly
and led to the targeted products.
C H BrNO Si: 439.11728; found 439.116436. FTIR (ATR): ν =
˜
20 30
3
3077, 3004, 2976, 2958, 2930, 2896, 2858, 1724, 1454, 1360, 1320,
1267, 1251, 1217, 1150, 1129, 1068, 1010, 887, 835, 820, 799, 783,
764, 729 cm–1.
Step 3. tert-Butyl 5-Bromo-3-[2-(diethylamino)ethoxy]-2-methyl-1H-
indole-1-carboxylate (2c): In a round-bottomed flask carboxylate
1b (3.4 mmol) and tetrabutylammonium fluoride (TBAF)
(4.1 mmol) were dissolved in dry THF and stirred for 10 min at
room temperature. After Na2CO3 (6.8 mmol) was added, the reac-
tion mixture was stirred for further 10 min at room temperature.
Finally (2-chloroethyl)diethylamine (6.8 mmol) was added and the
solution was heated up to 45 °C for 4 h. After removal of the sol-
vent the residue was cleaned by column chromatography (eluent
CH2 Cl2/ethanol, 20:1). The isolated product obtained as pale yel-
Experimental Section
General: All reactions were carried out under argon atmosphere.
Chemicals were purchased from Aldrich, Fluka, Acros and Strem
and unless otherwise noted were used without further purification.
All compounds were characterized by 1H NMR, 13C NMR, MS,
HRMS and IR spectroscopy. 1H and 13C NMR spectra were re-
corded on Bruker AV 300, AV 400 and AV 500 spectrometers. The
1H and 13C NMR chemical shifts are referenced to trimethylsilane
(TMS) [δ(TMS) = 0 (1H)], and to the solvent resonance [δ(CDCl3)
= 77.0 (13C)]. EI mass spectra were recorded on an AMD 402 spec-
trometer (70 eV, AMD Intectra GmbH). IR spectra were recorded
on a FT-IR Nicolet 6700 (Thermo ELECTRON CORPORA-
TION). The synthesis of compounds 2a–b and 7a–d have been al-
ready described in earlier publications.[11,13a]
1
low oil with a yield of 68%. H NMR (300.13 MHz, CDCl3): δ =
8.00 (d, J = 8.9 Hz, 1 H), 7.64 (d, J = 2.0 Hz, 1 H), 7.29 (dd, J =
8.9, J = 2.0 Hz, 1 H), 4.05 (t, J = 6.3 Hz, 2 H), 2.84 (t, J = 6.3 Hz,
2 H), 2.63 (q, J = 7.2 Hz, 4 H), 2.49 (s, 3 H), 1.65 (s, 9 H), 1.06 (t,
J = 7.2 Hz, 6 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 150.4
(Cq), 138.9 (Cq), 132.4 (Cq), 126.6 (Cq), 126.4, 126.0 (Cq), 119.5,
117.1, 115.8 (Cq), 84.0 (Cq), 72.7 (CH2), 52.8 (CH2), 47.5 (CH2),
28.2, 12.5, 11.7 ppm. MS (EI, 70 eV): m/z (%) = 426 (1), 425 (1)
[M+], 424 (1), 385 (7), 384 (1), 383 (6), 341 (3), 279 (4), 225 (6),
197 (4), 167 (11), 149 (31), 101 (25), 100 (100), 72 (17), 57 (76).
HRMS: calcd. for C20H29BrN2O: 425.14362; found 425.14343.
Three-Step Synthesis of the Starting Material tert-Butyl 5-Bromo-
3-[2-(diethylamino)ethoxy]-2-methyl-1H-indole-1-carboxylate (2c)
FTIR (ATR): ν = 3052, 2969, 2930, 2873, 2805, 1728, 1453, 1369,
˜
Step 1. 5-Bromo-3-(tert-butyldimethylsilanyloxy)-2-methyl-1H-in-
dole (1a): In a round-bottomed flask under argon atmosphere (4-
bromophenyl)hydrazine (0.09 mol), tert-butyldimethylsilyloxy-2-
propyne (0.07 mol) and ZnCl2 (0.09 mmol) were dissolved in 50 mL
of THF. The reaction mixture was heated to 100 °C under reflux
for 24 h. After removal of the solvent the mixture was purified by
column chromatography (eluent: ethyl acetate gradient 0–25% in
heptane with 1–2% triethylamine). The isolated product gave a
light-brown solid in a yield of 50% 1H NMR (300.13 MHz,
CDCl3): δ = 7.53 (d, J = 1.9 Hz, 1 H), 7.37 (br., 1 H, NH), 7.14
(dd, J = 8.5, J = 1.9 Hz, 1 H), 7.04 (d, J = 8.5 Hz, 1 H), 2.30 (s, 3
H), 1.07 (s, 9 H), 0.15 (s, 6 H) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 131.3 (Cq), 130.4 (Cq), 124.5 (Cq), 123.8, 121.6 (Cq), 119.7,
112.1 (Cq), 111.8, 25.7, 18.1 (Cq), 10.6, –4.2 ppm. MS (EI, 70 eV):
m/z (%) = 340 (22), 339 [M+, 93], 285 (17), 284 (10), 283 (16), 205
(5), 204 (19), 203 (100), 188 (19), 145 (9), 144 (47), 73 (41). HRMS:
calcd. for C15H22BrNOSi: 339.06485; found 339.064659. FTIR
1348, 1319, 1221, 1172, 1148, 1130, 1116, 1061, 1015, 765, 745
cm–1.
[2-(5-Bromo-2-methyl-1H-indol-3-yloxy)ethyl]diethylamine (2d): 1H
NMR (300.13 MHz, CDCl3): δ = 7.67 (d, J = 2.0 Hz, 1 H), 7.60
(br., 1 H, NH), 7.16 (dd, J = 8.5, J = 2.0 Hz, 1 H), 7.06 (d, J =
8.5 Hz, 1 H), 4.09 (t, J = 6.3 Hz, 2 H), 2.86 (t, J = 6.3 Hz, 2 H),
2.65 (q, J = 7.2 Hz, 4 H), 2.35 (s, 3 H), 1.07 (t, J = 7.2 Hz, 6 H)
ppm. 13C NMR (75.5 MHz, CDCl3): δ = 134.7 (Cq), 131.3 (Cq),
124.1 (Cq), 123.9, 123.7 (Cq), 119.6, 112.4 (Cq), 112.1, 72.7 (CH2),
52.7 (CH2), 47.4 (CH2), 11.7, 10.3 ppm. MS (EI, 70 eV): m/z (%)
= 324 (0.3) [M+], 226 (3), 225 (1), 224 (3), 145 (3), 117 (5), 101
(8), 100 (100), 87 (3), 86 (47). HRMS: calcd. for C15H21BrN2OSi:
324.08318; found 324.081805. FTIR (ATR): ν = 3410, 3300, 2964,
˜
2919, 2850, 1453, 1284, 1234, 1154, 1122, 1034, 862, 791, 732, 668
cm–1.
Compounds 3a–f, General Procedure for the Coupling Synthesis of
5-Amino-3-[2-(diethylamino)ethoxy]-1H-indole Derivatives 2a–c: In
an Ace-pressure tube under argon atmosphere, a 5-bromo-3-[2-(di-
(KBr): ν = 3399, 2954, 2929, 2856, 1724, 1471, 1314, 1285, 1255,
˜
1238, 1156, 888, 861, 838, 791, 780, 583 cm–1.
Step 2. tert-Butyl 5-Bromo-3-(tert-butyldimethylsilanyloxy)-2- ethylamino)ethoxy]indole derivative of type 2a–c (1 mmol), amine
methyl-1H-indole-1-carboxylate (1b): In a round-bottomed flask
under argon atmosphere indole 1a (10 mmol), di-tert-butyl dicar-
(1.3 mmol), Pd(OAc)2 (2 mol-%, 6 mol-% for 3c and 3e), 1-phenyl-
2-[di(1-adamantyl)phosphanyl]pyrrole L (4 mol-%; 12 mol-% for 3c
Eur. J. Org. Chem. 2008, 5425–5435
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M. Beller et al.
FULL PAPER
and 3e) and lithium hexamethyldisilazane (LiHMDS) (1.3 mmol or
1.5 mmol Cs2CO3 for 3c and 3e) were dissolved in toluene (3 mL).
The pressure tube was fitted with a Teflon cap and heated up to
100 °C for 20 h. After removal of the solvent in vacuo, the corre-
sponding indole product was isolated as oil by column chromatog-
raphy (eluent: ethyl acetate gradient 0–20% in heptane with 1–2%
triethylamine).
(CH2), 29.7 (CH2), 29.3, 27.0 (CH2), 22.6 (CH2), 14.0, 11.0,
9.0 ppm. MS (EI, 70 eV): m/z (%) = 359 (5) [M+], 259 (6), 244 (1),
187 (3), 173 (4), 100 (100), 86 (6), 44 (5). HRMS: calcd. for
C H N O: 359.29311; found 359.292382. FTIR (ATR): ν = 3313,
˜
22 37
3
2959, 2932, 2856, 2808, 2590, 2461, 1626, 1475, 1460, 1367, 1253,
1176, 1024, 781, 732 cm–1.
tert-Butyl 3-[2-(Diethylamino)ethoxy]-5-hexylamino-2-methyl-1H-
indole-1-carboxylate (3e): 1H NMR (400.13 MHz, CDCl3): δ = 7.89
(d, J = 8.8 Hz, 1 H), 6.66 (d, J = 2.3 Hz, 1 H), 6.55 (dd, J = 8.8,
J = 2.3 Hz, 1 H), 4.06 (t, J = 6.4 Hz, 2 H), 3.13 (t, J = 7.2 Hz, 2
H), 2.86 (t, J = 6.4 Hz, 2 H), 2.64 (q, J = 7.2 Hz, 4 H), 2.46 (s, 3
H), 1.63 (s, 9 H), 1.50–1.25 (m, 8 H), 1.06 (t, J = 7.2 Hz, 6 H), 0.89
(t, J = 6.7 Hz, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
150.9 (Cq), 144.5 (Cq), 139.7 (Cq), 127.0 (Cq), 125.4 (Cq), 125.3
(Cq), 116.4, 111.6, 98.9, 82.9 (Cq), 72.2 (CH2), 52.8 (CH2), 47.6
(CH2), 44.9 (CH2), 31.7 (CH2), 29.7 (CH2), 28.4, 26.9 (CH2), 22.7
(CH2), 14.1, 12.4, 11.8 ppm. MS (EI, 70 eV): m/z (%) = 446 (1),
445 (5) [M+], 346 (2), 345 (9), 290 (3), 246 (16), 245 (7), 244 (3),
176 (3), 175 (23), 174 (5), 147 (4), 146 (3), 145 (7), 100 (100), 99
(8), 98 (8), 97 (17), 86 (42), 85 (10), 84 (12), 83 (21), 58 (8), 57 (45),
44 (58). HRMS: calcd. for C26H43N3O3: 445.32989; found
Benzyl{3-[2-(diethylamino)ethoxy]-1,2-dimethyl-1H-indol-5-
1
yl}amine (3a): H NMR (300.13 MHz, CDCl3): δ = 7.44–7.26 (m,
5 H), 7.05 (d, J = 8.4 Hz, 1 H), 6.77 (d, J = 2.4 Hz, 1 H), 6.59 (dd,
J = 8.4, J = 2.4 Hz, 1 H), 4.37 (s, 2 H), 4.08 (t, J = 6.5 Hz, 2 H),
3.54 (s, 3 H), 3.30 (br., 1 H, NH), 2.90 (t, J = 6.5 Hz, 2 H), 2.69
(q, J = 7.2 Hz, 4 H), 2.31 (s, 3 H), 1.09 (t, J = 7.2 Hz, 6 H) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 141.6 (Cq), 140.1 (Cq), 134.2
(Cq), 128.6 (Cq), 128.5, 127.7, 127.0, 125.3 (Cq), 121.4 (Cq), 110.5,
109.4, 99.0, 72.0 (CH2), 52.5 (CH2), 49.8 (CH2), 47.5 (CH2), 29.4,
11.5, 8.9 ppm. MS (EI, 70 eV): m/z (%) = 366 (2), 365 (1) [M+],
288 (1), 262 (19), 261 (6), 250 (3), 249 (2), 175 (4), 174 (9), 173
(26), 118 (1), 101 (7), 100 (100), 99 (2), 86 (9), 44 (7). HRMS: calcd.
for C H N O: 365.24616; found 365.245156. FTIR (ATR): ν =
˜
23 31
3
3392, 3060, 3027, 2966, 2630, 2871, 2820, 1774, 1451, 1370, 1256,
1169, 1069, 1028, 787, 737, 670 cm–1.
445.330462. FTIR (ATR): ν = 3400, 2964, 2927, 2856, 1721, 1367,
˜
1329, 1314, 1221, 1168, 1127, 1061, 1018, 846, 764, 678 cm–1.
Benzyl{1-benzyl-3-[2-(diethylamino)ethoxy]-2-methyl-1H-indol-5-
1
yl}amine (3b): H NMR (300.13 MHz, CDCl3): δ = 7.44–7.19 (m,
{3-[2-(Diethylamino)ethoxy]-1,2-dimethyl-1H-indol-5-yl}[2-(4-fluo-
rophenyl)ethyl]amine (3f): 1H NMR (500.13 MHz, CDCl3): δ = 7.19
(m, 2 H), 7.05 (d, J = 8.6 Hz, 1 H), 7.00 (m, 2 H), 6.78 (d, J =
2.0 Hz, 1 H), 6.51 (dd, J = 8.6, J = 2.0 Hz, 1 H), 4.13 (t, J = 6.3 Hz,
2 H), 4.01 (br., 1 H, NH), 3.54 (s, 3 H), 3.43 (t, J = 6.9 Hz, 2 H),
2.95–2.91 (m, 4 H), 2.72 (q, J = 7.1 Hz, 4 H), 2.32 (s, 3 H), 1.10
(t, J = 7.1 Hz, 6 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ =
161.5 (d, J = 244 Hz, Cq), 141.1 (Cq), 135.3 (d, J = 3.0 Hz, Cq),
134.2 (Cq), 130.2 (d, J = 7.5 Hz), 128.7 (Cq), 125.2 (Cq), 121.5
(Cq), 115.3 (d, J = 21.0 Hz), 110.8, 109.4, 99.4, 72.3, 52.7, 47.5,
46.7, 34.8, 29.3, 11.5, 8.9 ppm. MS (EI, 70 eV): m/z (%) = 397 (4)
[M+], 297 (3), 281 (1), 188 (6), 173 (7), 159 (4), 130 (1), 100 (100),
86 (8), 44 (7). HRMS: calcd. for C24H32FN3O: 397.25239; found
8 H), 6.97 (d, J = 8.7 Hz, 1 H), 6.92 (dd, J = 7.7, J = 1.7 Hz, 2
H), 6.82 (d, J = 2.1 Hz, 1 H), 6.53 (dd, J = 8.7, J = 2.1 Hz, 1 H),
5.17 (s, 2 H), 4.35 (s, 2 H), 4.09 (t, J = 6.6 Hz, 2 H), 2.86 (t, J =
6.6 Hz, 2 H), 2.63 (q, J = 7.1 Hz, 4 H), 2.24 (s, 3 H), 1.05 (t, J =
7.1 Hz, 6 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 141.8 (Cq),
140.0 (Cq), 138.4 (Cq), 134.8 (Cq), 128.7, 128.5, 128.4 (Cq), 127.7,
127.1, 125.9, 125.1 (Cq), 121.9 (Cq), 110.7, 110.0, 99.0, 72.5 (CH2),
52.7 (CH2), 49.7 (CH2), 47.6 (CH2), 46.4 (CH2), 11.8, 8.9 ppm. MS
(EI, 70 eV): m/z (%) = 441 (1) [M+], 252 (3), 251 (4), 181 (2), 161
(3), 145 (2), 100 (100), 91 (54). HRMS: calcd. for C29H35N3O:
441.27746; found 441.277177. FTIR (KBr): ν = 3061, 3028, 2968,
˜
2930, 2871, 2813, 1625, 1494, 1452, 1373, 1354, 1269, 1168, 1028,
733, 697 cm–1.
397.251869. FTIR (ATR): ν = 2966, 2930, 2871, 2821, 1508, 1476,
˜
1446, 1371, 1256, 1220, 1169, 1157, 1067, 1014, 824, 786 cm–1.
tert-Butyl 5-Benzylamino-3-[2-(diethylamino)ethoxy]-2-methyl-1H-
indole-1-carboxylate (3c): 1H NMR (300.13 MHz, CDCl3): δ = 7.91
(d, J = 8.9 Hz, 1 H), 7.41–7.25 (m, 5 H), 6.70 (d, J = 2.4 Hz, 1 H),
6.60 (dd, J = 8.9, J = 2.4 Hz, 1 H), 4.37 (s, 2 H), 4.01 (t, J = 6.5 Hz,
2 H), 2.82 (t, J = 6.5 Hz, 2 H), 2.61 (q, J = 7.1 Hz, 4 H), 2.47 (s,
3 H), 1.64 (s, 9 H), 1.04 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 150.8 (Cq), 144.0 (Cq), 139.6 (Cq), 139.6
(Cq), 128.5, 127.5, 127.1 (Cq), 125.5 (Cq), 125.2 (Cq), 116.4, 111.5,
99.1, 82.9 (Cq), 72.1 (CH2), 52.7 (CH2), 49.0 (CH2), 47.5 (CH2),
28.3, 12.4, 11.8 ppm. MS (EI, 70 eV): m/z (%) = 451 (1) [M+], 351
(3), 252 (18), 251 (5), 250 (6), 161 (22), 160 (4), 159 (5), 134 (3),
133 (9), 101 (11), 100 (100), 92 (5), 91 (27), 86 (40), 85 (5), 72 (18),
71 (10), 57 (16), 56 (23), 44 (51), 43 (9), 42 (11), 40 (32). HRMS:
calcd. for C27H37N3O3: 451.28294; found 451.283100. FTIR
Compounds 4a–c. General Procedure for the Hydrogenation of 5-
Benzylamino-3-[2-(diethylamino)ethoxy]-1H-indole Derivatives 3a–c:
In a 20-mL autoclave 5-benzylamino-3-[2-(diethylamino)ethoxy]in-
dole derivative (1 mmol) was dissolved in 40 mL of ethanol, before
Pd/C (10%) (200 mg) was added. Under a pressure of 50 bar (5 bar
for 4c) H2, the reaction mixture was stirred for 8 h (3.5 h for 4c) at
room temperature (60 °C for 4c). After removal of the solvent in
vacuo, the hydrogenated indole derivative was isolated as an oil by
column chromatography [eluent heptane/ethyl acetate (5:1) with
5% triethylamine].
{3-[2-(Diethylamino)ethoxy]-1,2-dimethyl-1H-indol-5-yl}amine (4a):
1H NMR (300.13 MHz, CDCl3): δ = 6.95 (d, J = 8.6 Hz, 1 H),
6.78 (d, J = 2.1 Hz, 1 H), 6.51 (dd, J = 8.6, J = 2.1 Hz, 1 H), 3.99
(t, J = 6.5 Hz, 2 H), 3.45 (s, 3 H), 3.21 (br., 2 H, NH2), 2.79 (t, J
= 6.5 Hz, 2 H), 2.56 (q, J = 7.1 Hz, 4 H), 2.23 (s, 3 H), 0.99 (t, J
= 7.1 Hz, 6 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 138.6 (Cq),
134.0 (Cq), 129.1 (Cq), 125.4 (Cq), 121.5 (Cq), 111.4, 109.2, 102.2,
72.6 (CH2), 52.7 (CH2), 47.5 (CH2), 29.3, 11.8, 8.8 ppm. MS (EI,
(ATR): ν = 3416, 3062, 3028, 2969, 2927, 2872, 2810, 1720, 1470,
˜
1452, 1367, 1330, 1275, 1221, 1168, 1129, 1062, 734, 697 cm–1.
{3-[2-(Diethylamino)ethoxy]-1,2-dimethyl-1H-indol-5-yl}hexylamine
(3d): 1H NMR (300.13 MHz, CDCl3): δ = 7.03 (d, J = 8.6 Hz, 1
H), 6.73 (d, J = 2.1 Hz, 1 H), 6.56 (dd, J = 8.6, J = 2.1 Hz, 1 H),
4.17 (t, J = 6.2 Hz, 2 H), 3.53 (s, 3 H), 3.14 (t, J = 7.1 Hz, 2 H),
3.01 (t, J = 6.2 Hz, 2 H), 2.82 (q, J = 7.1 Hz, 4 H), 2.31 (s, 3 H), 70 eV): m/z (%) = 275 (4) [M+], 176 (3), 175 (12), 160 (4), 159 (2),
1.71–1.58 (m, 2 H), 1.50–1.26 (m, 6 H), 1.17 (t, J = 7.1 Hz, 6 H),
0.90 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
142.0 (Cq), 134.0 (Cq), 128.5 (Cq), 125.1 (Cq), 121.3 (Cq), 110.7,
101 (7), 100 (100), 91 (4), 86 (13), 72 (8), 44 (9). HRMS: calcd. for
C H N O: 275.19921; found 275.199332. FTIR (KBr): ν = 3420,
˜
16 25
3
3342, 3219, 2966, 2933, 2872, 2819, 1628, 1495, 1470, 1372, 1322,
109.4, 98.8, 71.6 (CH2), 52.4 (CH2), 47.6 (CH2), 45.6 (CH2), 31.7 1257, 1165, 1068, 793 cm–1.
5430
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5425–5435

Synthesis of Potential 5-HT6 Receptor Ligands
{1-Benzyl-3-[2-(diethylamino)ethoxy]-2-methyl-1H-indol-5-yl}- J = 1.2 Hz, 1 H), 7.56 (dd, J = 8.8, J = 7.0 Hz, 1 H), 7.24–7.17 (m,
amine (4b): 1H NMR (300.13 MHz, CDCl3): δ = 7.23–7.20 (m, 3
3 H), 7.13 (d, J = 2.0 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 1 H), 6.86–
H), 6.97 (d, J = 8.6 Hz, 1 H), 6.93–6.90 (m, 3 H), 6.53 (dd, J = 6.80 (m, 2 H), 6.66 (dd, J = 8.7, J = 2.0 Hz, 1 H), 5.11 (s, 2 H),
8.6, J = 2.2 Hz, 1 H), 5.18 (s, 2 H), 4.11 (t, J = 6.6 Hz, 2 H), 3.10
(br., 2 H, NH2), 2.88 (t, J = 6.6 Hz, 2 H), 2.65 (q, J = 7.1 Hz, 4
H), 2.25 (s, 3 H), 1.07 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR
3.93 (t, J = 6.4 Hz, 2 H), 2.77 (t, J = 6.4 Hz, 2 H), 2.61 (q, J =
7.1 Hz, 4 H), 2.20 (s, 3 H), 1.05 (t, J = 7.1 Hz, 6 H) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 155.2 (Cq), 149.3 (Cq), 137.4 (Cq),
(75.5 MHz, CDCl3): δ = 138.9 (Cq), 138.3 (Cq), 134.5 (Cq), 129.0 135.1 (Cq), 132.1 (Cq), 132.0, 131.0 (Cq), 128.7, 128.3, 127.4, 127.2
(Cq), 128.7, 127.1, 125.9, 125.4 (Cq), 121.9 (Cq), 111.7, 109.8, (Cq), 126.3 (Cq), 126.3, 125.8, 121.2 (Cq), 117.4, 112.1, 109.6, 72.8
102.3, 72.6 (CH2), 52.7 (CH2), 47.5 (CH2), 46.4 (CH2), 11.8, (CH2), 52.6 (CH2), 47.5 (CH2), 46.5 (CH2), 11.8, 9.0 ppm. MS (EI,
8.9 ppm. MS (EI, 70 eV): m/z (%) = 351 (3) [M+], 251 (2), 236 (1),
159 (1), 132 (2), 100 (100), 91 (26). HRMS: calcd. for C22H29N3O:
70 eV): m/z (%) = 550 (1), 549 (1) [M+], 351 (1), 252 (4), 251 (7),
250 (2), 236 (1), 235 (2), 162 (1), 161 (3), 160 (2), 137 (1), 136 (7),
135 (1), 101 (9), 100 (100), 99 (2), 92 (4), 91 (44), 86 (15), 85 (2),
58 (3), 57 (5), 56 (5), 44 (12). HRMS: calcd. for C28H31N5O3S2:
351.23051; found 351.230802. FTIR (KBr): ν = 3035, 2970, 2921,
˜
1626, 1490, 1456, 1437, 1371, 1356, 1329, 1268, 1165, 732 cm–1.
549.18628; found 549.187203. FTIR (KBr): ν = 3452, 2970, 2929,
˜
tert-Butyl 5-Amino-3-[2-(diethylamino)ethoxy]-2-methyl-1H-indole-
1-carboxylate (4c): H NMR (300.13 MHz, CDCl3): δ = 7.91 (d, J
2872, 1626, 1495, 1474, 1454, 1375, 1353, 1289, 1210, 1155, 1142,
1
967, 754, 731, 608 cm–1.
= 8.9 Hz, 1 H), 6.79 (d, J = 2.2 Hz, 1 H), 6.62 (dd, J = 8.9, J =
2.2 Hz, 1 H), 4.06 (t, J = 6.4 Hz, 2 H), 3.59 (br., 2 H, NH2), 2.86
(t, J = 6.4 Hz, 2 H), 2.64 (q, J = 7.1 Hz, 4 H), 2.47 (s, 3 H), 1.65
(s, 9 H), 1.07 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 150.8 (Cq), 141.7 (Cq), 139.4 (Cq), 127.8 (Cq), 125.7
(Cq), 125.3 (Cq), 116.4, 112.8, 102.1, 83.1 (Cq), 72.2 (CH2), 52.8
(CH2), 47.5 (CH2), 28.5, 12.4, 11.8 ppm. MS (EI, 70 eV): m/z (%)
= 362 (2), 361 (8) [M+], 261 (3), 162 (9), 161 (8), 147 (2), 146, (5),
145 (5), 101 (19), 100 (100), 86 (67), 72 (17), 57 (40). HRMS: calcd.
tert-Butyl 5-[(2,1,3-Benzothiadiazol-4-ylsulfonyl)(hexyl)amino]-3-[2-
1
(diethylamino)ethoxy]-2-methyl-1H-indole-1-carboxylate (5c): H
NMR (400.13 MHz, CDCl3): δ = 8.15 (dd, J = 8.8, J = 1.3 Hz, 1
H), 7.94 (d, J = 9.0 Hz, 1 H), 7.91 (dd, J = 7.1, J = 1.3 Hz, 1 H),
7.51 (dd, J = 8.8, J = 7.1 Hz, 1 H), 7.06 (d, J = 2.0 Hz, 1 H), 6.78
(dd, J = 9.0, J = 2.0 Hz, 1 H), 4.02 (t, J = 7.1 Hz, 2 H), 3.83 (t, J
= 6.2 Hz, 2 H), 2.72 (t, J = 6.2 Hz, 2 H), 2.57 (q, J = 7.2 Hz, 4 H),
2.45 (s, 3 H), 1.62 (s, 9 H), 1.50–1.25 (m, 8 H), 1.01 (t, J = 7.2 Hz,
6 H), 0.84 (m, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 155.5
(Cq), 150.4 (Cq), 149.7 (Cq), 139.4 (Cq), 133.0 (Cq), 132.7 (Cq),
132.6, 131.7 (Cq), 128.1, 126.5 (Cq), 126.0, 124.6 (Cq), 124.5,
117.6, 116.1, 84.0 (Cq), 72.5 (CH2), 52.9 (CH2), 52.6 (CH2), 47.4
(CH2), 31.4 (CH2), 28.9 (CH2), 28.2, 26.1 (CH2), 22.5 (CH2), 14.0,
12.4, 11.7 ppm. MS (EI, 70 eV): m/z (%) = 643 (1) [M+], 346 (1),
345 (2), 246 (5), 245 (3), 244 (2), 187 (2), 186 (1), 169 (3), 168 (10),
167 (2), 147 (2), 146 (1), 145 (3), 101 (7), 100 (100), 99 (6), 86 (27),
85 (7), 84 (10), 71 (15), 70 (15), 69 (24), 57 (30), 56 (39), 45 (9), 44
(99), 43 (36). HRMS: calcd. for C32H45N5O5S2: 643.28566; found
for C H N O : 361.23599; found 361.235080. FTIR (ATR): ν =
˜
20 31
3
3
3443, 3369, 3211, 3027, 2969, 2929, 2873, 2810, 1720, 1365, 1327,
1254, 1218, 1166, 1129, 1060, 1033 cm–1.
Compounds 5a–h. General Procedure for the Sulfonylation of 5-
Amino-3-[2-(diethylamino)ethoxy]-1H-indole Derivatives 3c, 3e, 4a–
c: In an Ace-pressure tube under argon atmosphere the correspond-
ing 5-amino-substituted 3-[2-(diethylamino)ethoxy]indole deriva-
tive (1 mmol) and the arylsulfonyl chloride (1 mmol) (see Table 3)
were dissolved in 5 mL of triethylamine (for the synthesis of 5a–b,
5e–f) and heated at 40 °C for 2 h. In the case of 5c and 5g 10 mL
of CH2Cl2 as solvent and 2 equiv. Cs2CO3 as base at room temp.
were used. The pressure tube was fitted with a Teflon® cap. After
removal of the solvent in vacuo the corresponding indole product
was isolated by column chromatography as oil or solid material
with heptane/ethyl acetate (5:1) and 1% triethylamine.
643.284226. FTIR (neat): ν = 3442, 3093, 3060, 2965, 2929, 2871,
˜
2809, 2725, 1732, 1471, 1353, 1272, 1256, 1225, 1208, 1162, 1070,
1021, 970, 853, 831, 754, 730, 622, 604, 593 cm–1.
5-Chloro-N-{3-[2-(diethylamino)ethoxy]-1,2-dimethyl-1H-indol-5-
yl}-3-methyl-1-benzothiophene-2-sulfonamide (5d): 1H NMR
(300.13 MHz, CDCl3): δ = 7.64 (d, J = 8.6 Hz, 1 H), 7.60 (d, J =
2.0 Hz, 1 H), 7.34 (dd, J = 8.6, J = 2.0 Hz, 1 H), 7.25 (d, J =
2.0 Hz, 1 H), 7.05 (d, J = 8.7 Hz, 1 H), 6.91 (dd, J = 8.7, J =
2.0 Hz, 1 H), 5.56 (br. s, 1 H, NH), 3.97 (t, J = 6.2 Hz, 2 H), 3.54
(s, 3 H), 2.87 (t, J = 6.2 Hz, 2 H), 2.74 (q, J = 7.2 Hz, 4 H), 2.30
(s, 3 H), 2.21 (s, 3 H), 1.09 (t, J = 7.2 Hz, 6 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 140.5 (Cq), 137.7 (Cq), 136.9 (Cq), 136.1
(Cq), 134.5 (Cq), 132.5 (Cq), 131.1 (Cq), 127.5, 126.7 (Cq), 126.4
(Cq), 123.6, 123.2, 120.6 (Cq), 118.6, 113.5, 109.1, 71.8 (CH2), 52.4
(CH2), 47.4 (CH2), 29.5, 12.1, 10.9, 8.9 ppm. MS (EI, 70 eV): m/z
(%) = 520 (1), 519 (2) [M+], 421 (5), 420 (9), 419 (8), 275 (1), 274
(1), 184 (7), 183 (10), 182 (20), 181 (24), 176 (15), 175 (69), 174
(51), 173 (27), 101 (49), 100 (100), 99 (6), 98 (8), 87 (5), 86 (97), 85
(2), 73 (7), 72 (44), 71 (7), 70 (7), 57 (4), 56 (16), 55 (1). HRMS:
calcd. for C25H30ClN3O3S2: 519.14116; found 519.139652. FTIR
N-{3-[2-(Diethylamino)ethoxy]-1,2-dimethyl-1H-indol-5-yl}-2,1,3-
benzothiadiazole-5-sulfonamide (5a): 1H NMR (300.13 MHz,
CDCl3): δ = 8.11 (dd, J = 8.9, J = 1.0 Hz, 1 H), 8.08 (dd, J = 7.0,
J = 1.0 Hz, 1 H), 7.53 (dd, J = 8.9, J = 7.0 Hz, 1 H), 7.11 (d, J =
2.0 Hz, 1 H), 6.93 (d, J = 8.8 Hz, 1 H), 6.69 (dd, J = 8.8, J =
2.0 Hz, 1 H), 3.97 (t, J = 6.1 Hz, 2 H), 3.47 (s, 3 H), 2.89 (t, J =
6.1 Hz, 2 H), 2.76 (q, J = 7.2 Hz, 4 H), 2.25 (s, 3 H), 1.13 (t, J =
7.2 Hz, 6 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 155.1 (Cq),
149.2 (Cq), 134.4 (Cq), 133.0 (Cq), 132.0, 130.8 (Cq), 123.2, 127.0
(Cq), 126.4 (Cq), 126.2, 120.6 (Cq), 116.9, 111.7, 109.1, 72.0 (CH2),
52.4 (CH2), 47.5 (CH2), 29.3, 11.1, 8.8 ppm. MS (EI, 70 eV): m/z
(%) = 474 (1), 473 (2) [M+], 472 (1), 374 (6), 373 (9), 372 (2), 176
(12), 175 (52), 174 (38), 173 (22), 161 (4), 160 (11), 159 (11), 148
(5), 147 (11), 146 (3), 145 (5), 137 (3), 136 (12), 135 (2), 101 (37),
100 (100), 99 (5), 98 (7), 86 (72), 85 (3), 84 (6), 73 (5), 72 (30),
71 (8), 70 (7), 69 (6), 57 (9), 56 (15), 55 (5). HRMS: calcd. for
(KBr): ν = 3448, 2966, 2921, 2856, 2668, 1857, 1128, 1486, 1373,
˜
1335, 1326, 1277, 1244, 1156, 1117, 1080, 987, 862, 799, 647, 575,
C22H27N O S : 473.15498; found 473.154213. FTIR (KBr): ν =
˜
5
3 2
563, 547 cm–1.
3448, 3203, 3085, 2962, 2925, 2835, 1521, 1488, 1374, 1347, 1332,
1271, 1252, 1213, 1162, 1143, 966, 834, 819, 764, 733, 669, 612,
594, 482 cm–1.
tert-Butyl 5-{[(6-Chloroimidazo[2,1-b][1,3]thiazol-5-yl)-
sulfonyl](hexyl)amino}-3-[2-(diethylamino)ethoxy]-2-methyl-1H-
indole-1-carboxylate (5e): 1H NMR (300.13 MHz, CDCl3): δ = 8.02
(d, J = 8.9 Hz, 1 H), 7.19 (d, J = 2.1 Hz, 1 H), 7.06 (d, J = 4.5 Hz,
1 H), 6.94 (d, J = 8.9, J = 2.1 Hz, 1 H), 6.70 (d, J = 4.5 Hz, 1 H),
N-{1-Benzyl-3-[2-(diethylamino)ethoxy]-2-methyl-1H-indol-5-yl}-
2,1,3-benzothiadiazole-5-sulfonamide (5b): 1H NMR (300.13 MHz,
CDCl3): δ = 8.14 (dd, J = 8.8, J = 1.1 Hz, 1 H), 8.10 (dd, J = 7.0,
Eur. J. Org. Chem. 2008, 5425–5435
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5431

M. Beller et al.
FULL PAPER
3.89 (t, J = 6.1 Hz, 2 H), 3.76 (t, J = 7.0 Hz, 2 H), 2.81 (t, J =
6.1 Hz, 2 H), 2.63 (q, J = 7.1 Hz, 4 H), 2.47 (s, 3 H), 1.64 (s, 9 H),
= 2.3 Hz, 1 H), 7.01 (dd, J = 8.8, J = 2.3 Hz, 1 H), 6.86 (d, J =
4.5 Hz, 1 H), 5.24 (br., 1 H, NH), 4.01 (t, J = 6.1 Hz, 2 H), 2.88
1.46–1.18 (m, 8 H), 1.65 (t, J = 7.1 Hz, 6 H), 0.83 (t, J = 7.0 Hz, (t, J = 6.1 Hz, 2 H), 2.74 (q, J = 7.1 Hz, 4 H), 2.45 (s, 3 H), 1.63
3 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 150.4 (Cq), 149.3 (s, 9 H), 1.09 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR (75.5 MHz,
(Cq), 139.4 (Cq), 137.6 (Cq), 133.0 (Cq), 132.5 (Cq), 126.8 (Cq),
124.7 (Cq), 124.1, 120.5, 119.0 (Cq), 117.0, 116.2, 113.4, 84.2 (Cq),
CDCl3): δ = 150.4 (Cq), 149.5 (Cq), 139.1 (Cq), 137.3 (Cq), 132.0
(Cq), 130.1 (Cq), 126.7 (Cq), 124.6 (Cq), 120.3, 119.8, 118.6 (Cq),
72.5 (CH2), 52.7 (CH2), 51.7 (CH2), 47.4 (CH2), 31.3 (CH2), 28.2 116.4, 114.0, 112.1, 84.0 (Cq), 72.0 (CH2), 52.5 (CH2), 47.3 (CH2),
(CH2), 28.2, 26.0 (CH2), 22.5 (CH2), 14.0, 12.5, 11.6 ppm. MS (EI,
28.2, 12.4, 11.2 ppm. MS (EI, 70 eV): m/z (%) = 581 (1) [M+], 382
70 eV): m/z (%) = 667 (3), 666 (8) [M+], 568 (2), 567 (3), 566 (4), (1), 381 (1), 158 (12), 101 (18), 100 (100), 86 (83), 72 (16), 57 (15),
447 (5), 446 (15), 445 (7), 444 (4), 347 (13), 346 (16), 345 (11), 344
56 (24). HRMS (ESI+, [M + H]+) Calcd. for C25H32ClN5O5S5:
(7), 300 (2), 299 (8), 161 (37), 160 (11), 159 (100), 158 (10), 101 (6), 582.16061; found 582.16052. FTIR (Nujol): ν = 3436, 3109, 2924,
˜
100 (39), 99 (11), 86 (5), 85 (24), 84 (4), 83 (14). HRMS: calcd. for 2854, 2716, 1728, 1612, 1542, 1460, 1376, 1323, 1271, 1249, 1179,
C H ClN O S : 666.25452; found 666.25510. FTIR (ATR): ν =
1129, 1067, 1022, 933, 725, 622 cm–1.
˜
31 44
5
5 2
3148, 3121, 2959, 2929, 2870, 2858, 1737, 1619, 1453, 1355, 1324,
N-Benzyl-N-{3-[2-(diethylamino)ethoxy]-2-methyl-1H-indol-5-yl}-1-
benzothiophene-3-sulfonamide (6a): Ester 5g was solved in a 33%
1269, 1248, 1118, 1133, 1069, 1020, 728, 670 cm–1.
N-{3-[2-(Diethylamino)ethoxy]-1,2-dimethyl-1H-indol-5-yl}-1-benzo- methylamine/ethanol solution (10 mL) and stirred at room tem-
1
thiophene-3-sulfonamide (5f): H NMR (300.13 MHz, CDCl3): δ =
8.21–8.14 (m, 1 H), 7.93 (s, 1 H), 7.87–7.79 (m, 1 H), 7.47–7.37 (m,
perature for 24 h. After removal of the solvent in vacuo the corre-
sponding indole product was isolated by column chromatography
2 H), 7.05 (d, J = 2.0 Hz, 1 H), 7.00 (d, J = 8.7 Hz, 1 H), 6.76 (dd, (eluent: ethanol gradient 5–20% in CH2Cl2) as solid material in a
J = 8.7, J = 2.0 Hz, 1 H), 3.87 (t, J = 6.2 Hz, 2 H), 3.52 (s, 3 H),
yield of 78%. 1H NMR (300.13 MHz, CDCl3): δ = 7.98 (m, J =
2.76 (t, J = 6.2 Hz, 2 H), 2.60 (q, J = 7.1 Hz, 4 H), 2.28 (s, 3 H), 7.3 Hz, 1 H), 7.97 (s, 1 H), 7.88 (m, J = 7.3 Hz, 1 H), 7.50 (br. s,
1.03 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
140.1 (Cq), 135.1, 134.7 (Cq), 133.7 (Cq), 132.6 (Cq), 132.5 (Cq),
1 H, NH), 7.44–7.31 (m, 2 H), 7.25–7.14 (m, 5 H), 6.97 (d, J =
1.9 Hz, 1 H), 6.94 (d, J = 8.6 Hz, 1 H), 6.66 (dd, J = 8.6, J =
126.7 (Cq), 126.3 (Cq), 125.6, 125.5, 123.2, 122.8, 120.7 (Cq), 1.9 Hz, 1 H), 4.89 (s, 2 H), 3.77 (t, J = 6.2 Hz, 2 H), 2.71 (t, J =
118.8, 113.8, 109.0, 72.5 (CH2), 52.5 (CH2), 47.3 (CH2), 29.4, 11.5, 6.2 Hz, 2 H), 2.59 (q, J = 7.1 Hz, 4 H), 2.29 (s, 3 H), 1.04 (t, J =
8.9 ppm. MS (EI, 70 eV): m/z (%) = 471 (2) [M+], 470 (1), 373 (3),
7.1 Hz, 6 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 140.1 (Cq),
372 (10), 371 (9), 370 (2), 176 (10), 175 (47), 174 (36), 173 (21), 161
136.4 (Cq), 135.4 (Cq), 134.8, 134.3 (Cq), 133.3 (Cq), 131.9 (Cq),
(3), 160 (7), 159 (14), 134 (25), 133 (4), 132 (7), 131 (5), 101 (36), 130.0 (Cq), 128.7, 128.3, 127.5, 125.4, 125.4, 124.2, 123.7 (Cq),
100 (100), 99 (5), 86 (67), 85 (3), 84 (5), 72 (26), 71 (8), 70 (7), 69 (7), 123.2, 122.6, 121.8 (Cq), 118.0, 110.8, 72.3 (CH2), 55.8 (CH2), 52.5
58 (8), 57 (10), 56 (16), 55 (5). HRMS: calcd. for C24H29N3O3S2:
(CH2), 47.3 (CH2), 11.6, 10.3 ppm. MS (EI, 70 eV): m/z (%) = 547
471.16448; found 471.164566. FTIR (ATR): ν = 3257, 3104, 2965, (1) [M+], 448 (1), 447 (1), 351 (1), 350 (1), 252 (5), 251 (5), 250 (4),
˜
2927, 2872, 2853, 1372, 1276, 1250, 1142, 1064, 076, 797, 756, 731,
161 (4), 134 (16), 133 (3), 101 (8), 100 (100), 99 (8), 71 (25), 70
(15), 57 (41), 56 (16), 55 (29). HRMS: calcd. for C30H33N3O3S2:
706, 668 cm–1.
547.19578; found 547.197375. FTIR (ATR): ν = 3308, 3106, 2966,
˜
tert-Butyl 5-{[(1-Benzothiophen-3-yl)sulfonyl](benzyl)amino}-3-[2-
(diethylamino)ethoxy]-2-methyl-1H-indole-1-carboxylate (5g): H
NMR (300.13 MHz, CDCl3): δ = 7.98 (m, 1 H), 7.97 (s, 1 H), 7.92
2928, 2851, 1492, 1454, 1346, 1291, 1259, 1233, 1146, 1086, 1063,
1
1024, 969, 844, 803, 757, 732, 699 cm–1.
(d, J = 8.8 Hz, 1 H), 7.88 (m, 1 H), 7.46–7.33 (m, 2 H), 7.24–7.14 6-Chloro-N-{3-[2-(diethylamino)ethoxy]-2-methyl-1H-indol-5-
(m, 5 H), 6.96 (d, J = 2.1 Hz, 1 H), 6.85 (dd, J = 8.8, J = 2.1 Hz,
1 H), 4.89 (s, 2 H), 3.70 (t, J = 6.3 Hz, 2 H), 2.68 (t, J = 6.3 Hz, 2
H), 2.55 (q, J = 7.1 Hz, 4 H), 2.44 (s, 3 H), 1.62 (s, 9 H), 1.02 (t,
J = 7.1 Hz, 6 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 150.4
(Cq), 140.1 (Cq), 139.4 (Cq), 136.0 (Cq), 135.0, 134.1 (Cq), 133.0
(Cq), 132.8 (Cq), 132.8 (Cq), 128.7, 128.3, 127.6, 126.2 (Cq), 125.5,
125.5, 125.2, 124.3 (Cq), 124.0, 122.7, 117.6, 115.9, 83.9 (Cq), 72.2
yl}imidazo[2,1-b]thiazole-5-sulfonamide (6b): In a round-bottomed
flask under argon atmosphere 5h was heated up to 140 °C for 3 h.
After column chromatography (eluent: ethanol gradient 10–30% in
CH2Cl2) a light-cream powder was obtained in 88 % yield. 1H
NMR (300.13 MHz, [D6]acetone, referenced to solvent signal δ =
2.05 ): δ = 9.67 (br., 1 H, NH), 7.71 (d, J = 4.5 Hz, 1 H), 7.35 (d,
J = 4.5 Hz, 1 H), 7.30 (d, J = 2.1 Hz, 1 H), 7.12 (dd, J = 8.5, J =
(CH2), 55.4 (CH2), 52.6 (CH2), 47.3 (CH2), 28.2, 12.4, 11.7 ppm. 0.5 Hz, 1 H), 6.87 (dd, J = 8.5, J = 2.1 Hz, 1 H), 3.96 (t, J = 6.3 Hz,
MS (EI, 70 eV): m/z (%) = 647 (1) [M+], 341 (2), 151 (4), 150 (3),
149 (15), 135 (4), 134 (13), 133 (5), 101 (6), 100 (81), 99 (14), 71
2 H), 2.78 (t, J = 6.3 Hz, 2 H), 2.61 (q, J = 7.1 Hz, 4 H), 2.30 (s,
3 H), 1.02 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR (75.5 MHz, [D6]-
(49), 70 (27), 69 (52), 57 (78), 56 (55), 55 (62), 44 (100), 43 (71). acetone, referenced to solvent signal δ = 29.9 ): δ = 150.4 (Cq),
HRMS: calcd. for C35H41N3O5S2: 647.24821; found 647.249346.
138.1 (Cq), 135.8 (Cq), 132.5 (Cq), 128.0 (Cq), 125.4 (Cq), 122.8
(Cq), 121.2, 119.7 (Cq), 118.6, 115.9, 113.2, 112.2, 73.6 (CH2), 53.7
(CH2), 47.4 (CH2), 12.6, 10.3 ppm. MS (EI, 70 eV): m/z (%) = 481
(0.3) [M+], 382 (1), 174 (1), 173 (1), 161 (5) (5) 160, 145 (2), 101
(7), 100 (100), 86 (48), 72 (7), 58 (4). HRMS (ESI+, [M + H]+)
Calcd. for C20H24ClN5O3S2: 482.10819; found 482.10949. FTIR
FTIR (neet): ν = 3109, 3064, 3035, 2970, 2925, 2868, 2811, 2255,
˜
1731, 1471, 1455, 1355, 1325, 1259, 1225, 1160, 1139, 1066, 911,
757, 733, 590 cm–1.
tert-Butyl 5-{[(6-Chloroimidazo[2,1-b][1,3]thiazol-5-yl)-
sulfonyl]amino}-3-[2-(diethylamino)ethoxy]-2-methyl-1H-indole-1-
carboxylate (5h): In a round-bottomed flask under argon atmo-
sphere to a solution of 4c (0.5 mmol), NaHCO3 (2 equiv.) and 6-
chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (0.5 mmol) were
added in 5 mL of acetonitrile. The reaction mixture was stirred at
room temperature for 15 h. The product was isolated by column
chromatography (eluent: ethanol gradient 5–50% in CH2Cl2) in a
(ATR): ν = 3308, 3129, 3059, 2964, 2923, 2853, 1459, 1435, 1269,
˜
1240, 1211, 1177, 1139, 1122, 1103, 1042, 1022, 926, 882, 814, 791,
727, 671 cm–1.
[3-(tert-Butyldimethylsilanyloxy)-1,2-dimethyl-1H-indol-5-yl]amine
(7e): Ammonia (gaseous) was liquified in a flask at –80 °C. After
addition of sodium (10 equiv.) to liquid ammonia a solution of
benzyl[3-(tert-butyldimethylsilanyloxy)-1,2-dimethyl-1H-indol-5-
1
yield of 81% as a white powder. H NMR (300.13 MHz, CDCl3):
δ = 7.98 (d, J = 8.8 Hz, 1 H), 7.70 (d, J = 4.5 Hz, 1 H), 7.31 (d, J yl]amine (0.9 mmol) in THF (4 mL) was added carefully over sy-
5432 Eur. J. Org. Chem. 2008, 5425–5435
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of Potential 5-HT6 Receptor Ligands
ringe. The reaction mixture was stirred for 2 h at –30 °C. The dark
violet solution was charged with NH4Cl carefully until all sodium
was destroyed. After 1 h water was added to the reaction mixture,
extracted with dichloromethane and dried with Mg2SO4. The sol-
vent was removed and the crude product was cleaned by column
chromatography (eluent: ethyl acetate gradient 5–20% in hexane).
1.9 Hz, 1 H), 7.61–7.57 (m, 1 H), 7.55–7.51 (m, 1 H), 7.04–7.01 (m,
2 H), 6.85 (dd, J = 8.8, J = 2.0 Hz, 1 H), 6.49 (br. s, 1 H, NH),
3.53 (s, 3 H), 2.22 (s, 3 H), 0.93 (s, 9 H), –0.12 (s, 6 H) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 136.2 (Cq), 134.9 (Cq), 132.3 (Cq),
132.1 (Cq), 130.3 (Cq), 129.3, 129.1, 128.8, 128.6, 127.8, 127.2,
126.6 (Cq), 123.9 (Cq), 122.7, 121.6 (Cq), 118.6, 113.6, 108.9, 29.5,
25.7, 18.0 (Cq), 9.2, –4.5 ppm. MS (EI, 70 eV): m/z (%) = 481 (23),
The product was obtained as brown oil with a yield of 130 mg
1
(20%). H NMR (500.13 MHz, CDCl3): δ = 7.00 (d, J = 8.5 Hz, 1 480 (70) [M+], 291 (6), 290 (23), 289 (100), 232 (5), 231 (5), 161 (2),
H), 6.78 (d, J = 2.2 Hz, 1 H), 6.60 (dd, J = 8.5, J = 2.2 Hz, 1 H),
160 (7), 159 (5), 129 (2), 128 (7), 127 (8), 79 (3), 78 (5), 77 (11), 57
3.54 (s, 3 H), 2.93 (br., 2 H, NH2), 2.25 (s, 3 H), 1.07 (s, 9 H), 0.15 (5), 56 (4). HRMS: calcd. for C26H32N2O3SSi: 480.18974; found
(s, 6 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 137.7 (Cq), 129.5 480.189326. FTIR (ATR): ν = 3237, 3056, 2930, 2857, 1376, 1331,
˜
(Cq), 129.4 (Cq), 123.2 (Cq), 122.2 (Cq), 111.5, 108.9, 102.8, 29.4,
25.9, 18.2 (Cq), 9.2, –4.2 ppm. MS (EI, 70 eV): m/z (%) = 292 (19),
290 (100) [M+], 233 (25), 218 (6), 192 (7), 175 (5), 160 (14), 159
(13), 73 (5).. HRMS: calcd. for C16H26N2OSi: 290.18089; found
1273, 1247, 1161, 1153, 1130, 1074, 895, 836, 816, 795, 777, 743,
675 cm–1.
Naphthalene-2-sulfonamide 8d: 1H NMR (300.13 MHz, CDCl3): δ
= 8.19 (d, J = 1.5 Hz, 1 H), 7.89–7.83 (m, 3 H), 7.64–7.51 (m, 3
H), 7.30–7.12 (m, 4 H), 7.02 (d, J = 2.1 Hz, 1 H), 6.90 (dd, J =
8.7, J = 2.1 Hz, 1 H), 3.93 (m, 2 H), 3.62 (s, 3 H), 2.80 (m, 2 H),
2.28 (s, 3 H), 0.89 (s, 9 H), –0.11 (s, 6 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 138.5 (Cq), 136.1 (Cq), 134.7 (Cq), 133.0
(Cq), 132.1 (Cq), 130.4 (Cq), 129.6 (Cq), 129.3, 128.9, 128.8, 128.7,
128.4 (2ϫ), 127.7, 127.2, 126.4, 123.9 (Cq), 123.3, 122.3, 121.6
(Cq), 117.5, 108.8, 53.2 (CH2), 35.2 (CH2), 29.6, 25.6, 18.0 (Cq),
9.2, –4.5 ppm. MS (EI, 70 eV): m/z (%) = 585 (15), 584 (35) [M+],
394 (12), 393 (28), 392 (2), 303 (34), 302 (100), 246 (7), 245 (17),
218 (4), 217 (12), 216 (3), 188 (4), 187 (10), 128 (13), 127 (13), 73
(16). HRMS: calcd. for C34H40N2O3SSi: 584.25234; found
290.180559. FTIR (Nujol): ν = 3446, 2952, 2923, 2854, 1844, 1648,
˜
1559, 1506, 1457, 1419, 1376, 1318, 1251, 1160, 1066, 891, 778
cm–1.
Compounds 8a–i. General Procedure for the Sulfonylation of 5-
Amino-3-(silanyloxy)indole Derivatives: Under argon atmosphere
the indole derivative (1 mmol) and the arylsulfonyl chloride
(2 mmol) were dissolved in triethylamine (5 mL) and heated to
40 °C for 2 h. After the reaction was complete by TLC control, the
solvent was removed in vacuo. The product was isolated by column
chromatography with hexane/ethyl acetate (10:1) as a solid mate-
rial.
584.25293. FTIR (ATR): ν = 3083, 3061, 3026, 2958, 2930, 2855,
˜
N-Benzyl-N-[3-(tert-butyldimethylsilanyloxy)-1,2-dimethyl-1H-
indol-5-yl]naphthalene-2-sulfonamide (8a): 1H NMR (500.13 MHz,
CDCl3): δ = 8.27 (d, J = 1.7 Hz, 1 H), 7.91 (d, J = 8.7 Hz, 1 H),
7.91–7.87 (m, 2 H), 7.71 (dd, J = 8.7, J = 1.7 Hz, 1 H), 7.63, 7.57
(2 ddd, 2 H), 7.27–7.24 (m, 2 H), 7.21–7.14 (m, 3 H), 7.01 (d, J =
8.8 Hz, 1 H), 6.95 (d, J = 2.0 Hz, 1 H), 6.71 (dd, J = 8.8, J =
2.0 Hz, 1 H), 4.87 (s, 2 H), 3.51 (s, 3 H), 2.22 (s, 3 H), 0.88 (s, 9
H), –0.16 (s, 6 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 136.6
(Cq), 136.6 (Cq), 134.8 (Cq), 132.8 (Cq), 132.2 (Cq), 130.4 (Cq),
129.6 (Cq), 129.3, 128.9, 128.8, 128.7, 128.5, 128.2, 127.8, 127.4,
127.2, 123.5 (Cq), 123.3, 122.2, 121.4 (Cq), 118.0, 108.5, 56.2
(CH2), 29.5, 25.7, 18.0 (Cq), 9.1, –4.5 ppm. MS (EI, 70 eV): m/z
(%) = 571 (16), 570 (38) [M+], 380 (46), 379 (99), 378 (15), 277 (6),
276 (5), 205 (28), 204 (5), 203 (31), 191 (5), 93 (9), 92 (13), 91
(100), 78 (10), 77 (21), 74 (11), 73 (96), 57 (38). HRMS: calcd. for
1331, 1249, 1152, 1129, 1072, 937, 890, 833, 817, 783, 750, 692, 665
cm–1.
Naphthalene-2-sulfonamide 8e: 1H NMR (300.13 MHz, CDCl3): δ
= 8.17 (d, J = 1.7 Hz, 1 H), 7.87–7.82 (m, 3 H), 7.61–7.52 (m, 3
H), 7.11 (d, J = 8.6 Hz, 1 H), 7.10–7.05 (m, 2 H), 7.00 (d, J =
2.0 Hz, 1 H), 6.95–6.90 (m, 2 H), 6.84 (dd, J = 8.5, J = 2.0 Hz, 1
H), 3.90 (m, 2 H), 3.59 (s, 3 H), 2.76 (m, 2 H), 2.26 (s, 3 H), 0.88
(s, 9 H), –0.11 (s, 6 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
161.6 (d, J = 244 Hz, Cq), 136.0 (Cq), 134.7 (Cq), 134.1 (d, J =
3.2 Hz, Cq), 132.9 (Cq), 132.1 (Cq), 130.4 (Cq), 130.3 (d, J =
7.8 Hz), 129.5 (Cq), 129.2, 128.8, 128.8, 128.4, 127.8, 127.2, 123.9
(Cq), 123.2, 122.1, 121.6 (Cq), 117.6, 115.2 (d, J = 21.5 Hz), 108.8,
53.1 (CH2), 34.3 (CH2), 29.6, 25.6, 17.9 (Cq), 9.1, –4.5 ppm. MS
(EI. 70 eV): m/z (%) = 603 (14), 602 (34) [M+], 413 (2), 412 (8), 411
(18), 304 (8), 303 (32), 302 (100), 246 (5), 245 (13), 217 (7), 216 (2),
187 (7), 186 (2), 185 (5), 128 (7), 127 (7), 109 (5), 73 (9). HRMS:
calcd. for C34H39FN2O3SSi: 602.24292; found 602.243034. FTIR
C H N O SSi: 570.236511; found 570.23669. FTIR (ATR): ν =
˜
33 38
2
3
3057, 3301, 2956, 2929, 2854, 1337, 1321, 1247, 1156, 1131, 1077,
820, 807, 786, 754, 699, 666 cm–1.
(ATR): ν = 3064, 3042, 2959, 2932, 2855, 1509, 1337, 1248, 1219,
˜
Naphthalene-2-sulfonamide 8b: 1H NMR (500.13 MHz, CDCl3): δ
= 8.21 (d, J = 1.8 Hz, 1 H), 7.89–7.85 (m, 3 H), 7.65 (dd, J = 8.8,
J = 1.8 Hz, 1 H), 7.61, 7.55 (2m, 2 H), 7.09 (d, J = 8.8 Hz, 1 H),
7.01 (d, J = 2.2 Hz, 1 H), 6.84 (dd, J = 8.8, J = 2.2 Hz, 1 H), 3.66
(t, J = 7.0 Hz, 2 H), 3.58 (s, 3 H), 2.26 (s, 3 H), 1.45–1.18 (m, 8
1152, 1130, 1106, 1075, 938, 891, 855, 835, 815, 781, 749, 665 cm–1.
6-Chloroimidazo[2,1-b]thiazole-5-sulfonamide 8f: 1H NMR
(300.13 MHz, CDCl3): δ = 7.07 (d, J = 2.0 Hz, 1 H), 6.91 (d, J =
4.5 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 1 H), 6.60 (dd, J = 8.6, J =
2.0 Hz, 1 H), 6.51 (d, J = 4.5 Hz, 1 H), 3.66 (t, J = 7.0 Hz, 2 H),
3.44 (s, 3 H), 2.24 (s, 3 H), 1.36–1.01 (m, 8 H), 0.90 (s, 9 H), 0.70
(t, J = 7.0 Hz, 3 H), –0.09 (s, 6 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 149.1 (Cq), 137.2 (Cq), 132.9 (Cq), 130.4 (Cq), 128.4
(Cq), 124.1 (Cq), 121.6 (Cq), 120.7, 120.6, 119.4 (Cq), 118.2, 113.0,
108.8, 52.1 (CH2), 31.4 (CH2), 29.6, 28.2 (CH2), 26.1 (CH2), 25.8,
22.5 (CH2), 18.1 (Cq), 14.0, 9.2, –4.3 ppm. MS (EI, 70 eV): m/z (%)
= 595 (12), 594 (34) [M+], 531 (4), 530 (11), 495 (10), 494 (12), 424
(19), 423 (8), 422 (38), 375 (18), 374 (76), 373 (100), 304 (12), 303
(52), 302 (9), 290 (13), 262 (15), 158 (14), 73 (31). HRMS: calcd.
for C27H39ClN4O3S2Si: 594.19159; found 594.192313. FTIR (KBr):
H), 0.89 (s, 9 H), 0.84 (t, J = 7.3 Hz, 3 H), –0.10 (s, 6 H) ppm. 13
C
NMR (125.8 MHz, CDCl3): δ = 138.2 (Cq), 136.3 (Cq), 134.6 (Cq),
132.8 (Cq), 130.4 (Cq), 129.7 (Cq), 129.3, 128.7, 127.8, 128.7,
128.3, 127.1, 123.7 (Cq), 123.3, 122.1, 121.5 (Cq), 117.5, 108.6, 51.7
(CH2), 31.4 (CH2), 28.3 (CH2), 26.1 (CH2), 22.5 (CH2), 29.5, 25.6,
17.9 (Cq), 13.9, 9.1, –4.5 ppm. MS (EI, 70 eV): m/z (%) = 565 (18),
373 (100), 304 (4), 303 (15), 302 (4), 243 (6), 185 (5), 160 (8), 128
(10), 127 (8), 83 (11), 82 (6), 73 (12), 57 (17), 55 (18). HRMS: calcd.
for C H N O SSi: 564.28364; found 564.283310. FTIR (KBr): ν
˜
32 44
2
3
= 3444, 3060, 2958, 2929, 2852, 1732, 1487, 1464, 1377, 1337, 1249,
1163, 1129, 1074, 891, 839, 813, 782, 749, 666, 616, 544 cm–1.
ν = 3150, 3117, 2954, 2925, 2852, 2709, 2479, 1842, 1736, 1486,
˜
Naphthalene-2-sulfonamide 8c: 1H NMR (300.13 MHz, CDCl3): δ
= 8.27 (d, J = 1.5 Hz, 1 H), 7.83 (m, 3 H), 7.69 (dd, J = 8.6, J =
1455, 1360, 1324, 1269, 1248, 1178, 1133, 1084, 1068, 946, 890,
839, 807, 781, 727, 668, 619 cm–1.
Eur. J. Org. Chem. 2008, 5425–5435
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5433

M. Beller et al.
FULL PAPER
1
5-Chloro-3-methylbenzo[b]thiophene-2-sulfonamide 8g: H NMR
(300.13 MHz, CDCl3): δ = 7.72 (d, J = 8.6 Hz, 1 H), 7.65 (d, J =
2.0 Hz, 1 H), 7.41 (dd, J = 8.6, J = 2.0 Hz, 1 H), 7.11 (d, J =
2.0 Hz, 1 H), 7.09 (d, J = 8.7 Hz, 1 H), 6.85 (dd, J = 8.7, J =
2.0 Hz, 1 H), 3.73 (t, J = 6.6 Hz, 2 H), 3.59 (s, 3 H), 2.27 (s, 3 H),
2.04 (s, 3 H), 1.50–1.15 (m, 8 H), 0.91 (s, 9 H), 0.83 (t, J = 6.6 Hz,
3 H), –0.06 (s, 6 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 140.8
(Cq), 137.6 (Cq), 136.4 (Cq), 135.8 (Cq), 132.9 (Cq), 131.2 (Cq),
130.5 (Cq), 128.9 (Cq), 127.4, 123.9 (Cq), 123.6, 123.4, 121.8, 121.6
(Cq), 117.7, 108.6, 52.2 (CH2), 31.4 (CH2), 29.6, 28.3 (CH2), 26.1
(CH2), 25.6, 22.5 (CH2), 18.0 (Cq), 14.0, 12.1, 9.2, –4.4 ppm. MS
(EI, 70 eV): m/z (%) = (rel, intensity): 619 (23), 618 (61) [M+], 555
(4), 554 (10), 375 (13), 374 (54), 373 (100), 304 (6), 303 (24), 302
(7), 290 (8), 258 (4), 257 (11), 218 (4), 217 (7), 183 (6), 182 (11), 181
(14), 73 (19), 57 (9), 43 (12). HRMS: calcd. for C31H43ClN2O3S2Si:
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618.216211; found 618.21674. FTIR (KBr): ν = 3448, 2954, 2921,
˜
2860, 1486, 1464, 1378, 1341, 1250, 1158, 1145, 1081, 894, 864,
839, 810, 783, 662, 573, 558 cm–1.
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1
2,1,3-Benzothiadiazole-4-sulfonamide 8h: H NMR (300.13 MHz,
CDCl3): δ = 8.15 (dd, J = 8.8, J = 1.1 Hz, 1 H), 7.93 (dd, J = 7.1,
J = 1.1 Hz, 1 H), 7.50 (dd, J = 8.8, J = 7.1 Hz, 1 H), 7.05 (d, J =
9.2 Hz), 6.84–6.80 (m, 2 H), 4.10 (t, J = 7.0 Hz, 2 H), 3.55 (s, 3 H),
2.23 (s, 3 H), 1.55–1.20 (m, 8 H), 0.91 (s, 9 H), 0.87 (t, J = 7.0 Hz,
3 H), –0.16 (s, 6 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 155.6
(Cq), 149.8 (Cq), 132.8 (Cq), 132.6, 132.2 (Cq), 130.2 (Cq), 129.1
(Cq), 128.2, 125.8, 123.8 (Cq), 122.4, 121.4 (Cq), 117.6, 108.7, 53.7
(CH2), 31.5 (CH2), 29.6, 29.0 (CH2), 26.2 (CH2), 25.6, 22.6 (CH2),
18.0 (Cq), 14.0, 9.1, –4.5 ppm. MS (EI, 70 eV): m/z (%) = 573 (13),
572 (36) [M+], 374 (72), 373 (100), 372 (8), 304 (13), 303 (55), 302
(6), 290 (10), 289 (4), 217 (11), 216 (5), 188 (6), 187 (11), 168 (9),
136 (15), 109 (9), 75 (12), 74 (5), 73 (65), 57 (12), 56 (8), 44 (15).
HRMS: calcd. for C28H40N4O3S2Si: 572.23056; found 572.229155.
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FTIR (ATR): ν = 3058, 2952, 2927, 2856, 1344, 1247, 1158, 1137,
˜
1068, 963, 892, 834, 826, 778, 750, 665 cm–1.
Naphthalene-1-sulfonamide 8i: 1H NMR (300.13 MHz, CDCl3): δ
= 8.66–8.61 (m, 1 H), 8.03 (dd, J = 7.5, J = 1.2 Hz, 1 H), 7.95 (d,
J = 8.2 Hz, 1 H), 7.90–7.84 (m, 1 H), 7.56–7.50 (m, 2 H), 7.35 (dd,
J = 8.2, J = 7.5 Hz, 1 H), 7.01 (d, J = 2.0 Hz, 1 H), 7.00 (d, 1 H,
J = 8.8 Hz), 6.83 (dd, 1 H, J = 8.8 Hz, J = 2.0 Hz), 3.72 (t, 2 H, J
= 7.0 Hz), 3.54 (s, 3 H), 2.24 (s, 3 H), 1.45–1.10 (m, 8 H), 0.96 (s,
9 H), 0.80 (t, 3 H, J = 7.0 Hz), –0.08 (s, 6 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 134.6 (Cq), 134.2 (Cq), 133.8 (Cq), 132.7
(Cq), 130.9, 130.3 (Cq), 129.1, 129.0 (Cq), 128.6, 127.6, 126.5,
125.6, 124.0, 123.6 (Cq), 122.0, 121.4 (Cq), 118.5, 108.5, 51.4
(CH2), 31.4 (CH2), 29.5, 28.3 (CH2), 26.1 (CH2), 25.7, 22.5 (CH2),
18.0 (Cq), 14.0, 9.1, –4.0 ppm. MS (EI, 70 eV): m/z (%) = 565 (18),
564 (48) [M+], 374 (35), 373 (100), 304 (4), 303 (15), 302 (4), 243
(6), 185 (5), 161 (2), 160 (8), 128 (10), 127 (8), 83 (11), 73 (12), 57
(17), 56 (10), 55 (18). HRMS: calcd. for C32H44N2O3SSi:
[6]
[7]
[8]
[9]
564.28364; found 564.285035. FTIR (KBr): ν = 3452, 3060, 2950,
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˜
2921, 2856, 1488, 1377, 1321, 1249, 1159, 1128, 1082, 893, 838,
797, 772, 672, 612, 503 cm–1.
Acknowledgments
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This work has been supported by the State of Mecklenburg-Vor-
pommern, the Bundesministerium für Bildung und Forschung
(BMBF), the Deutsche Forschungsgemeinschaft (DFG) (Leibniz
price, GRK 1213), and the Fonds der Chemischen Industrie
(FCI). We also thank Dr. C. Fischer, S. Schareina, S. Bucholz, A.
Lehmann, K. Mevius, and K. Reincke for their excellent technical
and analytical support.
K. Alex, N. Schwarz, V. Khedkar, I. A. Sayyed, A. Tillack, D.
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Received: June 25, 2008
Published Online: October 1, 2008
Eur. J. Org. Chem. 2008, 5425–5435
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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