Synthesis of 5-(sulfamoylmethyl)indoles

Article abstract of DOI:10.1016/S0040-4020(00)01091-7

The synthesis of 5-(sulfamoylmethyl)indoles bearing a two-carbon chain at C-3 (aminoethyl, acetate, hydroxyethyl, ethyl) either by the Grandberg modification of the Fischer indolization or by intramolecular Heck reaction of suitable o-halotrifluoroacetanilides is reported.

Full text of DOI:10.1016/S0040-4020(00)01091-7

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1041±1048
Synthesis of 5-(sulfamoylmethyl)indoles
a,p
Joan Bosch, Tomas Roca, Montserrat Armengol and Dolors Fernandez-Forner
a
a
b
Á
Â
aLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
bDepartment of Medicinal Chemistry, Almirall Prodesfarma S.A., Cardener 68-74, 08024 Barcelona, Spain
Received 14 September 2000; revised 27 October 2000; accepted 17 November 2000
AbstractÐThe synthesis of 5-(sulfamoylmethyl)indoles bearing a two-carbon chain at C-3 (aminoethyl, acetate, hydroxyethyl, ethyl) either
by the Grandberg modi®cation of the Fischer indolization or by intramolecular Heck reaction of suitable o-halotri¯uoroacetanilides is
reported. q 2001 Elsevier Science Ltd. All rights reserved.
The discovery of the anti-migraine drug sumatriptan
(Imigranw)1 has stimulated the search and design of
second-generation 5-HT1D receptor agonists. From the
chemical point of view, many of these tryptamines (suma-
triptan,1 CP-122,288,2 avitriptan,3 almotriptan4) have the
common feature of possessing a sulfamoyl group attached
at the indole 5 position through a methylene spacer (Fig. 1).
conditions), with subsequent reductive alkylation (CH2O,
NaBH4) of the resulting tryptamine. Although it could be
expected that an electron-withdrawing group on the indole
nitrogen would reduce the leaving group tendency of the
benzylic substituent at C-5, the use of the N-(benzenesulfo-
nyl)indole 5 did not prove to be satisfactory either.
For this reason, we turned our attention to an alternative
approach, involving the elaboration of the indole nucleus9
from starting materials already incorporating the sulfamoyl
moiety. Taking into account that the Grandberg indolization
allows the one-pot preparation of tryptamines from readily
accessible hydrazines, we selected this procedure, although
we were aware that the Fischer indolization from hydrazines
bearing a benzylic para substituent able to act as a leaving
group under acidic conditions usually gives low yields or
even fails completely.10 The required p-(sulfamoylmethyl)-
phenylhydrazine 7 was prepared in 82% yield from aniline
In the context of the study of possible almotriptan metabo-
lites it was necessary to synthesize a variety of 5-(sulfa-
moylmethyl)indoles, including tryptamines and other
derivatives bearing a two-carbon chain at the indole 3-posi-
tion. For this purpose, we had initially planned the intro-
duction of the sulfamoyl moiety from 5-(chloromethyl)-
tryptamine 4, by displacement of the chlorine atom with
sodium sul®te, followed by reaction of the resulting sulfo-
nate with thionyl chloride and then with the appropriate
amine. Although similar approaches, i.e. the displacement
of a leaving group from the benzylic C-5 indole position by
a nucleophile, have been employed successfully for the
synthesis of related tryptamines,5 this route proved to be
non-viable due to the rapid decomposition of the required
(chloromethyl)tryptamine 4, probably through a reactive
conjugate imine intermediate formed by elimination of
HCl.6 This process is assisted by the indole nitrogen lone
pair. In fact, attempts to prepare the hydrochloride of tryp-
tamine-methanol 3 also caused complete decomposition.
Alcohol 3 was obtained as shown in Scheme 1, by LiAlH4
reduction of ester 2.7 This ester was easily accessible (30%
overall yield) by reaction of hydrazine 1 with 4-chloro-
butyraldehyde diethyl acetal (following the Grandberg
modi®cation of the Fischer indole synthesis8 whereby the
halogen atom undergoes ammonolysis under the reaction
Keywords: indoles; indolization; Heck reactions; metabolites; drugs.
Corresponding author. Tel.: 134-93-402-4537; fax: 134-93-402-4539;
e-mail: jbosch@farmacia.far.ub.es
p
Figure 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01091-7

1042
J. Bosch et al. / Tetrahedron 57 (2001) 1041±1048
tion.11 Following standard procedures, tryptamine 8 was
methylated to 9a, dimethylated to 9b (almotriptan), and
converted by Pictet±Spengler reaction to tetrahydro-b-
carbolines 11a and 11b. Finally, although the conversion
of tryptamine 9b to oxindole 10 took place in a yield that
was unsatisfactory from the preparative standpoint, it was
suf®cient for the identi®cation of this potential metabolite.
In spite of the success of the above indolization to a
5-[(dialkylsulfamoyl)methyl]indole, the Grandberg method
could not be applied to the synthesis of related N-unsubsti-
tuted sulfonamides. Hydrazine 1312 failed to give the
expected tryptamine under a variety of reaction conditions,
complex mixtures were formed instead.
Scheme 1. Reagents and conditions: (i) 4-chlorobutyraldehyde diethyl
acetal, 2N HCl, then Na2HPO4, pH 5, D, 32%; (ii) HCHO, NaBH4, 93%;
(iii) LiAlH4, THF, D, 58%; (iv) PhSO2Cl, 50% NaOH/toluene, TBAHS,
55%; (v) LiAlH4, THF, D, 53%.
The above results prompted us to use the Pd-catalyzed intra-
molecular Heck reaction as an alternative method for the
construction of the indole ring.13 This approach required the
previous preparation of N-protected 2-halo-4-(sulfamoyl-
methyl)anilines and their allylation with appropriate allyl
halides (Scheme 3). As expected, the Heck cyclization of
N-allyl substituted o-iodotri¯uoroacetanilide 17 took place
in satisfactory yield (60%), with concomitant deprotection
of the indole nitrogen, to give indoleacetic ester 19.14 The
main shortcoming of this route, however, was the low and
erratic yield of the allylation step. Thus, although regio-
selective iodination of 4-(sulfamoylmethyl)aniline 12 with
6, by diazotization followed by reduction of the resulting
diazonium salt with SnCl2 (Scheme 2). Satisfactorily, treat-
ment of hydrazine 7 with 4-chlorobutyraldehyde diethyl
acetal gave the corresponding hydrazone, which underwent
rearrangement to tryptamine 8 in 58% overall yield upon
treatment with HCl in the presence of Na2HPO4 to buffer the
reaction to pH 5. These mild reaction conditions, which
prevent the decomposition of indole, are probably respon-
sible for the success and relatively high yield of the reac-
Scheme 2. Reagents and conditions: (i) NaNO2, conc. HCl, then SnCl2, 82%; (ii) 4-chlorobutyraldehyde diethyl acetal, 2N HCl, then Na2HPO4, pH 5, D, 58%;
(iii) HCOOH/Ac2O, then B2H6´DMS, D, 40% (9a); (iv) HCHO/MeOH, NaBH4, 88% (9b); (v) NBS, t-BuOH, 5%; (vi) CH2(OMe)2, AcOH, D, 72% (11a);
(vii) 35% HCHO, AcOH, D, 87% (11b).
Scheme 3. Reagents and conditions: (i) I(C5H5N)2´BF4, then TFAA, 78% (15); (ii) Br2, MeOH, then TFAA, 33% (16); (iii) LDA, BrCH2CHvCHCO2CH3,
15% (17), 63% (18); (iv) Pd(AcO)2, Et3N, TBABr, DMF, 808C, 60% (19), 57% (20); (v) 2N KOH/MeOH, 97%; (vi) PCl5, 08C, then Me2NH´HCl, TEA, 60%;
(vii) LiAlH4, THF, D, 33%.

J. Bosch et al. / Tetrahedron 57 (2001) 1041±1048
1043
1. Experimental
1.1. General
Melting points were determined in a capillary tube and are
uncorrected. NMR spectra were recorded at 200 or 300 (1H)
and 50.3 or 75 MHz (13C). Coupling constants are expressed
in hertz and signals are quoted as follows: s, singlet; d,
doublet; dd, doublet of doublets; t, triplet; dt, doublet of
triplets; ddd, doublet of doublet of doublets; q, quadruplet;
dq, doublet of quadruplets; m, multiplet; br s, broad signal.
Analytical thin layer chromatography was carried out on
Merck silica gel 60 F254 plates, and the spots were located
with UV light. Flash chromatography was carried out on
SiO2 (silica gel 60, SDS, 0.04±0.06 mm). Drying of organic
extracts during the work-up of reactions was performed over
anhydrous Na2SO4. Evaporation of the solvents was accom-
plished under reduced pressure with a rotatory evaporator.
Microanalyses were performed on a Carlo Erba 1106
Scheme 4. Reagents and conditions: (i) Br2, MeOH, then TFAA, 26%
(23a); (ii) I(C5H5N)2´BF4, then TFAA, 81% (23b); (iii) LDA,
BrCH2CHvCHCO2CH3, 73% (24a), 52% (24b); (iv) LDA,
BrCH2CHvCHCH3, 49% (25); (v) Pd(AcO)2, Et3N, TBABr, DMF,
808C, 52% (from 24a) and 60% (from 24b) for 26, 57% (from 25) for
27; (vi) 2N KOH/MeOH, 83%; vii) LiBH4, THF, D, 71%.
Â
analyzer by Centre d'Investigacio i Desenvolupament
(CSIC), Barcelona.
15
IPy2BF4 followed by protection of the aniline nitrogen
with TFAA gave tri¯uoroacetanilide 15 in 78% overall
yield, the subsequent introduction of the crotonate moiety
by sequential treatment with LDA and methyl 4-bromo-
crotonate afforded the desired product 17 in only 15%
yield, which was not reproducible when operating on a
scale higher than 100 mg. This problem could be circum-
vented starting from the protected sulfonamide 14, which
was converted to the N-protected bromoaniline 16 and then
satisfactorily allylated (63% yield) to 18. In this case, the
crucial Heck ring forming reaction took place in 57% yield.
The resulting indoleacetic ester 20 was converted to trypta-
mine 22 via the amide 21.
1.1.1. Ethyl 3-[2-(dimethylamino)ethyl]-5-indolecarboxyl-
ate (2). A solution of 4-chlorobutyraldehyde diethyl acetal17
(20.62 g, 114 mmol) in 35% aqueous HCl (4.5 mL) and
H2O (240 mL) was stirred at rt for 1 h and then added to a
solution of 1 hydrochloride7 (22.6 g,104 mmol) in H2O
(50 mL) and MeOH (265 mL). The mixture was stirred at
rt for 1 h and cooled at 08C. The precipitated yellow solid
was collected by ®ltration and successively washed with 9:1
H2O±MeOH (100 mL) and cool H2O (200 mL) to afford the
intermediate hydrazone hydrochloride as an orange solid. A
solution of this hydrazone and Na2HPO4 (13.1 g,
73.6 mmol) in H2O (150 mL), MeOH (600 mL), and 35%
aqueous HCl (6.1 mL) was re¯uxed overnight. MeOH was
evaporated, H2O (400 mL) was added, and the resulting
mixture was saturated with Na2CO3 and extracted with
CH2Cl2 (3£200 mL). The extracts were dried, ®ltered, and
concentrated to give ethyl 3-(2-aminoethyl)-5-indole-
carboxylate7 (7.43 g, 32%) as a brown solid. 1H NMR
(300 MHz, CDCl3) d 1.42 (t, 3H, Jˆ7.1 Hz), 2.94 (t, 2H,
Jˆ6.4 Hz), 3.04 (t, 2H, Jˆ6.4 Hz), 4.40 (q, 2H, Jˆ7.1 Hz),
7.07 (s, 1H), 7.35 (d, 1H, Jˆ8.6 Hz), 7.90 (d, 1H, Jˆ
8.6 Hz), 8.38 (s, 1H), 8.80 (br s, 1H). A solution of 35%
HCHO (43 mL, 512 mmol) in MeOH (43 mL) and a solu-
tion of NaBH4 (6 g, 160 mmol) in H2O (85 mL) were added
dropwise (2 h), simultaneously, to a well-stirred solution of
the above tryptamine (7.43 g, 32 mmol) in MeOH (190 mL)
cooled at 2158C. The mixture was stirred at 2158C for
0.5 h, 4N aqueous HCl was cautiously added to bring the
pH to 3, and the resulting mixture was stirred for 10 min.
Then, the pH was adjusted to 6.5±7 with saturated aqueous
NaHCO3, MeOH was evaporated, and H2O (50 mL) was
added. The mixture was washed with EtOAc (2£100 mL),
basi®ed with Na2CO3, and extracted with CH2Cl2 (3£
100 mL). The organic extracts were dried, ®ltered, and
concentrated to give 2 as a brown solid: 7.75 g; 93%
yield. 1H NMR (200 MHz, CDCl3) d 1.42 (t, 3H, Jˆ
7 Hz), 2.35 (s, 6H), 2.65 (t, 2H, Jˆ6.5 Hz), 2.98 (t, 2H, Jˆ
6.5 Hz), 4.40 (q, 2H, Jˆ7 Hz), 7.06 (s, 1H), 7.35 (d, 1H,
Jˆ8.4 Hz), 7.88 (d, 1H, Jˆ8.5 Hz), 8.38 (s, 1H), 8.50 (br s,
1H). 13C NMR (50 MHz, CDCl3) d 14.4, 23.3, 45.2, 59.9, 60.5,
110.7, 115.2, 121.1, 121.5, 122.9, 123.0, 126.9, 138.9, 168.0.
The Heck approach also proved to be satisfactory for the
preparation of a variety of 3,5-disubstituted indoles bearing
the pyrrolidinylsulfonyl moiety of almotriptan and a two-
carbon chain at carbon 3. Thus, aniline 6 was converted to
the brominated tri¯uoroacetanilide 23a (26% overall yield)
and, more satisfactorily, to the iodo analogue 23b (81%
overall yield) (Scheme 4). Treatment of either 23a or 23b
with LDA and then methyl 4-bromocrotonate afforded the
respective allylated derivatives 24a and 24b, which under-
went the Pd-catalyzed Heck cyclization leading to the same
indole-3-acetic ester 26. By simple functional group inter-
conversions ester 26 was converted to indoleacetic acid 2816
and tryptophol 29. Similarly, allylation of o-iodotri¯uoro-
acetanilide 23b with crotyl bromide, followed by Heck
cyclization (57% yield) led to 3-ethylindole 27. In
contrast with the above satisfactory results, the Fischer
indolization failed to give 3-indoleacetic esters when
starting either from hydrazine 7 and ethyl 4-oxobutano-
ate or from the hydrazone formed by Japp±Klingemann
reaction of diethyl 2-acetylglutarate with the diazonium
salt derived from 6.
The above results make evident that the intramolecular
Pd-catalyzed Heck reaction of N-protected N-allyl o-halo-
anilines constitutes a convergent general method for the
synthesis of 3-substituted indoles bearing labile sub-
stituents, such as sulfamoylmethyl, at the indole 5-position,
thus allowing the straightforward preparation of indoles
inaccessible by the classical Fischer reaction.

1044
J. Bosch et al. / Tetrahedron 57 (2001) 1041±1048
1.1.2. 3-[2-(Dimethylamino)ethyl]-5-indolemethanol (3).
A solution of 2 (7.75 g, 29.8 mmol) in anhydrous THF
(150 mL) was added dropwise under N2 to a suspension of
LiAlH4 (2.27 g, 59.6 mmol) in anhydrous THF (70 mL).
The mixture was re¯uxed for 2 h and cooled to 0±58C.
Then H2O (2.3 mL), 10% aqueous NaOH (2.3 mL), and
H2O (9.2 mL) were added successively. The resulting
suspension was ®ltered through Celite, and the cake was
washed with CH2Cl2. H2O (40 mL) was added to the ®ltrate,
and the mixture was extracted with CH2Cl2 (2£100 mL).
The combined organic phases were dried, ®ltered, and
concentrated to give alcohol 3, which was chromatographed
(99:1:0.1 CH2Cl2±MeOH±NH4OH): colorless oil, 3.8 g,
and then was added at 2208C to a solution of SnCl2´2H2O
(16.46 g, 73 mmol) in 35% aqueous HCl (12 mL). After
stirring at 2208C for 25 min and at 258C for another
25 min period, the precipitated hydrazine 7 hydrochloride
was collected by ®ltration and successively washed with
cool H2O and Et2O (3.06 g, 82%). A solution of 4-chloro-
butyraldehyde diethyl acetal17 (21.8 g, 120.5 mmol) in 35%
aqueous HCl (5.3 mL) and H2O (270 mL) was stirred at rt
for 1 h and added to a solution of hydrazine 7 (28.0 g,
109.6 mmol) in 35% aqueous HCl (9.8 mL), H2O
(65 mL), and MeOH (300 mL). The mixture was stirred at
rt for 1 h and cooled to 08C. The precipitated yellow solid
was collected by ®ltration and successively washed with 9:1
H2O±MeOH (150 mL) and cool H2O (300 mL) to afford the
intermediate hydrazone hydrochloride as an orange solid.
A solution of this hydrazone and Na2HPO4 (12.4 g,
69.6 mmol) in H2O (70 mL), MeOH (450 mL), and 35%
aqueous HCl (9.8 mL) was re¯uxed overnight. MeOH was
evaporated, H2O (300 mL) was added to the mixture, and
the pH was adjusted to 6.5±7 with solid Na2CO3. The
aqueous solution was washed with CH2Cl2 (2£300 mL)
and then saturated with Na2CO3, extracted with CH2Cl2
(3£200 mL), dried, ®ltered, and concentrated to give 8
1
58% yield. H NMR (300 MHz, CDCl3) d 2.21 (s, 6H),
2.55 (t, 2H, Jˆ6.6 Hz), 2.85 (t, 2H, Jˆ6.6 Hz), 4.30 (br s,
1H), 4.69 (s, 2H), 6.79 (s, 1H), 7.12 (d, 1H, Jˆ8.4 Hz), 7.19
(d, 1H, Jˆ8.5 Hz), 7.48 (s, 1H), 9.17 (br s, 1H). The oxalate
precipitated on treating a solution of the base in EtOH with
oxalic acid in EtOH; white solid, mp 125±1278C. 1H NMR
(300 MHz, D2O) d 2.71 (s, 6H), 3.06 (t, 2H, Jˆ7.4 Hz), 3.27
(t, 2H, Jˆ7.4 Hz), 4.54 (s, 2H), 7.10 (d, 1H, Jˆ8.4 Hz), 7.15
(s, 1H), 7.34 (d, 1H, Jˆ8.4 Hz), 7.46 (s, 1H). 13C NMR
(75 MHz, D2O) d 21.0, 43.6, 58.5, 65.6, 109.4, 113.1,
118.5, 123.4, 125.5, 127.3, 132.2, 136.9, 166.6. Anal.
calcd for C13H18N2O´C2H2O4: C, 58.43; H, 6.54; N, 9.09.
Found: C, 58.34; H, 6.57; N, 8.94.
1
(19.6 g, 58%) as a brown solid. H NMR (200 MHz, CDCl3)
d 1.45 (br s, 2H), 1.79 (m, 4H), 2.90 (m, 2H), 3.01 (m, 2H),
3.17 (m, 4H), 4.38 (s, 2H), 7.06 (s, 1H), 7.24 (d, 1H, Jˆ8.4 Hz),
7.33 (d, 1H, Jˆ8.4 Hz), 7.60 (s, 1H), 8.30 (br s, 1H).
1.1.3. 3-[2-(Dimethylamino)ethyl]-1-(phenylsulfonyl)-5-
indolemethanol (5). A solution of tetrabutylammonium
hydrogen sulfate (0.24 g, 0.72 mmol) in 50% aqueous
NaOH (12 mL) and a solution of benzenesulfonyl chloride
(1.3 mL, 10.1 mmol) in toluene (20 mL) were successively
added to a solution of 2 (2.5 g, 9.6 mmol) in toluene
(20 mL). After stirring at rt for 2 h, the organic phase was
washed with H2O, dried, ®ltered and concentrated. Flash
chromatography (97:3:0.1 CH2Cl2±MeOH±NH4OH) gave
the corresponding N-(phenylsulfonyl)indole as a yellow
1.1.5. 3-[(2-Methylamino)ethyl]-5-(1-pyrrolidinylsulfonyl-
methyl)indole (9a). A mixture of 98% HCO2H (5.6 mL,
150 mmol) and Ac2O (14.1 mL, 150 mmol) was stirred at
608C for 1 h. After cooling to rt, a solution of tryptamine 8
(9.2 g, 30 mmol) in anhydrous CH2Cl2 (50 mL) was added.
The mixture was stirred at rt for 1.5 h and then concentrated
to dryness. The residue was basi®ed with saturated aqueous
Na2CO3 and extracted with CH2Cl2 (3£200 mL). The
organic extracts were dried, ®ltered, and concentrated to
give the corresponding N-formyltryptamine, which was
chromatographed (96:4:1 CH2Cl2±MeOH±NH4OH): 6.63 g,
66% yield. A solution of 95% B2H6±DMS (13 mL,
136 mmol) was added dropwise at rt under N2 to a solution
of the above N-formyltryptamine (5.7 g, 17 mmol) in
anhydrous THF (25 mL). The mixture was stirred at re¯ux
for 2 h. After cooling to 0±58C, MeOH (45 mL) was added,
and the solution was re¯uxed for 8 h. The mixture was
concentrated, and the resulting residue was chromato-
graphed (90:10:1 CH2Cl2±MeOH±NH4OH): 3.23 g, 60%
1
oil (2.1 g, 55%). H NMR (200 MHz, CDCl3) d 1.40 (t,
3H, Jˆ7 Hz), 2.35 (s, 6H), 2.62 (t, 2H, Jˆ6.5 Hz), 2.95 (t,
2H, Jˆ6.5 Hz), 4.39 (q, 2H, Jˆ7 Hz), 7.2±7.5 (m, 6H), 7.85
(d, 1H, Jˆ8.4 Hz), 8.09 (s, 1H), 8.22 (s, 1H). A solution of
the above ester (2.1 g, 5.25 mmol) in anhydrous THF
(50 mL) was added dropwise under N2 to a suspension of
LiAlH4 (0.4 g, 10.5 mmol) in anhydrous THF (20 mL). The
mixture was re¯uxed for 2 h and cooled to 0±58C. Then,
H2O (0.4 mL), 10% aqueous NaOH (0.4 mL), and H2O (1.7
mL) were successively added. The resulting suspension was
®ltered through Celite, and the cake was washed with
CH2Cl2. H2O (20 mL) was added to the ®ltrate, and the
mixture was extracted with CH2Cl2 (2£50 mL). The
combined organic phases were dried, ®ltered, and concen-
trated to give alcohol 5, which was chromatographed
(95:5:0.1 CH2Cl2±MeOH±NH4OH): colorless oil, 1.5 g,
1
yield. H NMR (200 MHz, CDCl3) d 1.79 (m, 4H), 1.95
(br s, 1H), 2.44 (s, 3H), 2.93 (m, 4H), 3.15 (m, 4H), 4.36
(s, 2H), 7.03 (s, 1H), 7.20 (d, 1H, Jˆ8.5 Hz), 7.31 (d, 1H,
Jˆ8.5 Hz), 7.60 (s, 1H), 8.65 (br s, 1H). 13C NMR (50 MHz,
CDCl3) d 25.1, 25.7, 35.9, 48.0, 51.8, 56.4, 111.5, 113.0,
119.3, 120.9, 123.3, 124.0, 127.4, 136.4. The oxalate pre-
cipitated on treating a solution of the base in EtOH with
1
53% yield. H NMR (200 MHz, CDCl3) d 2.22 (s, 6H),
1
2.55 (t, 2H, Jˆ6.6 Hz), 2.76 (t, 2H, Jˆ6.6 Hz), 4.70 (s,
2H), 7.3±7.5 (m, 6H), 7.79 (s, 1H), 7.84 (s, 1H), 7.93 (d,
1H, Jˆ8.4 Hz).
oxalic acid in EtOH; mp 194±1958C. H NMR (300 MHz,
(CD3)2SO) d 1.74 (m, 4H), 2.59 (s, 3H), 3.10 (m, 8H), 4.43
(s, 2H), 7.12 (dd, 1H, Jˆ8.4, 1.5 Hz), 7.25 (d, 1H,
Jˆ2.0 Hz), 7.35 (d, 1H, Jˆ8.4 Hz), 7.59 (s, 1H), 11.10 (br
s, 1H). 13C NMR (75 MHz, (CD3)2SO) d 21.8, 25.6, 32.6,
47.9, 48.7, 54.4, 109.6, 111.6, 119.8, 120.9, 124.2, 124.3,
126.9, 136.2, 165.1. Anal. calcd for C16H25N3O2S´C2H2O4:
C, 52.55; H, 6.57; N, 10.20. Found: C, 52.54; H, 6.37; N,
9.92.
1.1.4. 3-(2-Aminoethyl)-5-(1-pyrrolidinylsulfonylmethyl)-
indole (8). A solution of NaNO2 (1.36 g, 19.7 mmol) in
H2O (8 mL) was added dropwise at 2208C to a suspension
of aniline 618 (3.5 g, 14.6 mmol) in 35% aqueous HCl
(30 mL). The mixture was stirred at 2208C for 15 min

J. Bosch et al. / Tetrahedron 57 (2001) 1041±1048
1045
1.1.6. 3-[(2-Dimethylamino)ethyl]-5-(1-pyrrolidinylsul-
fonylmethyl)indole (9b). A solution of 35% formaldehyde
(35 mL, 416 mmol) in MeOH (35 mL) and a solution of
NaBH4 (5 g, 132 mmol) in H2O (70 mL) were added drop-
wise, simultaneously, at 158C to a well-stirred solution of
tryptamine 8 (8.1 g, 26 mmol) in MeOH (150 mL). The
mixture was stirred at 158C for 0.5 h, 2N aqueous HCl
was cautiously added to bring the pH to 3, and the resulting
mixture was stirred for 10 min. Then, the pH was adjusted to
6.5±7 with saturated aqueous NaHCO3, MeOH was evapo-
rated, and H2O (50 mL) was added. The mixture was
washed with EtOAc (2£150 mL), basi®ed with K2CO3,
and extracted with EtOAc (2£130 mL). The organic
extracts were dried, ®ltered, and concentrated to give 9b4
(7.70 g, 88%) as a brown solid. 1H NMR (300 MHz, CDCl3) d
1.76 (m, 4H), 2.35 (s, 6H), 2.63 (t, 2H, Jˆ7.8 Hz), 2.93 (t, 2H,
Jˆ7.8 Hz), 3.14 (m, 4H), 4.37 (s, 2H), 6.99 (s, 1H), 7.19 (d,
1H, Jˆ8.4 Hz), 7.27 (d, 1H, Jˆ8.4 Hz), 7.56 (s, 1H), 8.60 (br s,
1H). 13C NMR (75 MHz, CDCl3) d 23.5, 25.7, 45.3, 48.0, 56.6,
60.1, 111.4, 113.7, 119.3, 120.8, 122.6, 123.9, 127.4, 136.2.
(4 g, 13 mmol) in 35% HCHO (5 mL) and AcOH (18 mL)
was re¯uxed for 6 h. After cooling to rt, saturated aqueous
Na2CO3 was added, and the mixture was extracted with 95:5
CH2Cl2±MeOH. The residue was dissolved in THF (20 mL)
and saturated aqueous Na2CO3 (20 mL). After stirring at rt
overnight, the mixture was extracted with CH2Cl2
(2£30 mL). The organic extracts were washed with H2O
(2£20 mL), dried, ®ltered, and concentrated to give b-
carboline 11b as a yellow oil (3.60 g, 87%). The oxalate
precipitated on treating a solution of the base in EtOH
with oxalic acid in EtOH; mp decomposed above 1458C.
1H NMR (300 MHz, (CD3)2SO) d 1.75 (m, 4H), 2.88 (s,
3H), 2.93 (m, 2H), 3.09 (m, 4H), 3.42 (m, 2H), 4.31 (s,
2H), 4.44 (s, 2H), 7.15 (d, 1H, Jˆ8.5 Hz), 7.34 (d, 1H,
Jˆ8.5 Hz), 7.48 (s, 1H), 11.15 (s, 1H). 13C NMR (75 MHz,
(CD3)2SO) d 18.4, 25.2, 42.2, 47.6, 50.1, 51.3, 54.6, 105.0,
111.1, 120.1, 120.2, 124.2, 125.9, 128.1, 136.1, 164.1.
1.1.10. [3-Iodo-4-(tri¯uoroacetamido)phenyl]methane-
sulfonamide (15). Bis(pyridine)iodonium(I) tetra¯uorobor-
ate19 (2.37 g, 6.4 mmol) was added at rt to a suspension of
aniline 1418 (1.19 g, 6.4 mmol) in CH2Cl2 (15 mL). After
stirring at rt for 2 h, the mixture was ®ltered, and the ®ltrate
was concentrated to dryness. TFAA (0.9 mL, 6.8 mmol)
was added under Ar to a solution of the resulting crude
o-iodoaniline in anhydrous THF (40 mL). The mixture
was stirred at rt for 4 h, and then concentrated approxi-
mately to 2 mL. A 1:1 mixture of Et2O±hexane was
added, and the precipitated crude product was collected by
1.1.7. 3-[(2-Dimethylamino)ethyl]-2-oxo-5-(1-pyrrolidinyl-
sulfonylmethyl)-2,3-dihydroindole (10). NBS (0.53 g,
3 mmol) was added in small portions under Ar during a
15 min period to a solution of 9b (0.5 g, 1.50 mmol) in
95% t-BuOH (10 mL). After stirring at rt for 18 h, the
mixture was concentrated to dryness. The residue was
dissolved in CH2Cl2, and the organic phase was washed
with saturated aqueous Na2CO3, dried, ®ltered, and concen-
trated to give crude oxindole 10, which was puri®ed twice
by ¯ash chromatography (98:2:0.1 CH2Cl2±MeOH±
1
®ltration (2.04 g, 78%); white solid, mp 126±1288C. H
NMR (200 MHz, (CD3)2SO) d 4.32 (s, 2H), 7.02 (s, 2H),
7.38 (d, 1H, Jˆ 8.2 Hz), 7.46 (d, 1H, Jˆ8.2 Hz), 7.95 (s,
1H). 13C NMR (75 MHz, (CD3)2SO) d 58.9, 98.3, 116.5 (q,
Jˆ296 Hz), 128.4, 131.8, 132.8, 136.9, 141.3, 155.8 (q,
Jˆ36 Hz). Anal. calcd for C9H8F3IN2O3S: C, 26.49; H,
1.97; N, 6.86. Found: C, 26.61; H, 1.93; N, 6.76.
1
NH4OH): 25 mg, 5% yield. H NMR (200 MHz, CDCl3) d
1.83 (m, 4H), 2.05 (m, 2H), 2.21 (s, 6H), 2.42 (m, 2H), 3.21
(m, 4H), 3.57 (t, 1H) 4.21 (s, 2H), 6.93 (d, 1H, Jˆ8.4 Hz),
7.22 (d, 1H, Jˆ8.4 Hz), 7.30 (s, 1H), 9.0 (br s, 1H). 13C
NMR (50 MHz, CDCl3) d 25.8, 28.2, 43.8, 45.1, 48.0,
55.4, 55.8, 109.6, 122.9, 126.5, 130.0, 130.3, 142.2, 180.1.
The oxalate precipitated on treating a solution of the base in
1:1 EtOH±Et2O with oxalic acid in 1:1 EtOH±Et2O;
mp decomposed above 1258C. Anal. calcd for
C17H25N3O3S´C2H2O4: C, 51.70; H, 6.10; N, 9.52. Found:
C, 51.67; H, 6.33; N, 9.79.
1.1.11. [3-Bromo-4-(tri¯uoroacetamido)phenyl]-N-tert-
butyl-methanesulfonamide (16).
A solution of Br2
(0.15 mL, 2.2 mmol) in MeOH (3 mL) was added dropwise
to an ice-cooled suspension of aniline 1418 (0.48 g, 2 mmol)
in MeOH (5 mL). The mixture was stirred at rt for 1 h, and
then Na2CO3 (0.5 g) was added. Solvent was evaporated,
and the resulting residue was digested with CH2Cl2. The
organic extracts were dried, ®ltered, and evaporated. Flash
chromatography (9:1 CH2Cl2±Et2O) gave pure o-bromo-
1.1.8. 6-(1-Pyrrolidinylsulfonylmethyl)-1,2,3,4-tetrahydro-
b-carboline (11a). A solution of tryptamine 8 (3.1 g,
10 mmol) and CH2(OMe)2 (3.5 mL, 40 mmol) in AcOH
(amount suf®cient to dissolve) was stirred at 1008C for
96 h. The mixture was basi®ed with saturated aqueous
Na2CO3 and extracted with CH2Cl2 (2£70 mL). The organic
extracts were dried, ®ltered, and concentrated to give
b-carboline 11a as a yellow oil (2.30 g, 72%). The oxalate
precipitated on treating a solution of the base in EtOH with
1
aniline (0.27 g, 43%). H NMR (200 MHz, (CD3)2SO) d
1.23 (s, 9H), 4.07 (s, 2H), 6.73 (br s, 1H), 6.78 (d, 1H, Jˆ
8.8 Hz), 7.04 (d, 1H, Jˆ8.8 Hz), 7.34 (s, 1H). TFAA
(0.94 mL, 0.67 mmol) was added under Ar to a solution of
the above bromoaniline (0.2 g, 0.62 mmol) in anhydrous
THF (4 mL), and the mixture was stirred at rt for 2 h.
Solid Na2CO3 (60 mg) was added, and the mixture was
concentrated to dryness. The resulting residue was digested
with EtOAc, and the organic extracts were dried, ®ltered
and concentrated. Flash chromatography (CH2Cl2) gave
pure 16 (0.2 g, 77%); white solid, mp 118±1208C. 1H
NMR (200 MHz, CDCl3) d 1.37 (s, 9H), 4.15 (br s, 1H),
4.21 (s, 2H), 7.42 (d, 1H, Jˆ8.2 Hz), 7.68 (s, 1H), 8.36 (d,
1H, Jˆ8.2 Hz), 8.55 (br s, 1H).
1
oxalic acid in EtOH; mp 250±2528C. H NMR (300 MHz,
(CD3)2SO) d 1.74 (m, 4H), 2.91 (m, 2H), 3.08 (m, 4H), 3.42
(m, 2H), 4.34 (s, 2H), 4.44 (s, 2H), 7.13 (d, 1H, Jˆ8.5 Hz),
7.35 (d, 1H, Jˆ8.5 Hz), 7.48 (s, 1H), 11.23 (s, 1H). 13C
NMR (75 MHz, DMSO-d6) d 18.4, 25.6, 39.9, 41.6, 47.8,
54.2, 105.7, 111.3, 120.3, 120.5, 124.7, 126.1, 127.9, 135.9,
164.8. Anal. calcd for C16H21N3O2S´C2H2O4´1/2H2O: C,
51.55; H, 5.73; N, 10.03. Found: C, 51.16; H, 5.57; N, 9.80.
1.1.9. 2-Methyl-6-(1-pyrrolidinylsulfonylmethyl)-1,2,3,4-
tetrahydro-b-carboline (11b). A solution of tryptamine 8
1.1.12. {4-[N-(3-Methoxycarbonyl-2-propenyl)tri¯uoro-
acetamido]-3-iodophenyl}methanesulfonamide (17). A

1046
J. Bosch et al. / Tetrahedron 57 (2001) 1041±1048
solution of 1.5N LDA in cyclohexane (0.16 mL, 0.24 mmol)
and methyl 4-bromocrotonate (0.03 mL, 0.29 mmol) were
added successively at 2788C under N2 to a solution of
tri¯uoroacetanilide 15 (90 mg, 0.22 mmol) in anhydrous
THF (5 mL), and the resulting solution was allowed to
rise to rt. After being stirred at re¯ux for 20 h, the mixture
was poured into saturated aqueous NH4Cl and extracted
with CH2Cl2. Concentration of the dried extracts gave a
residue, which was chromatographed (99:1 CH2Cl2±
(2 mL). After stirring at 08C for 3 h, a suspension of
Me2NH´HCl (0.5 g, 6.2 mmol) and Et3N (1.7 mL,
12.4 mmol) in CH2Cl2 (10 mL) was added, and the resulting
mixture was stirred at rt for 4 h. The mixture was succes-
sively washed with 1N aqueous HCl (3£20 mL), 2N
aqueous Na2CO3 (3£20 mL), and H2O (7£20 mL). The
organic extracts were dried, ®ltered, and concentrated to
1
give amide 21 (0.65 g, 60%) as a yellow oil. H NMR
(200 MHz, CDCl3) d 1.38 (s, 9H), 2.98 (s, 3H), 3.06 (s,
3H), 3.80 (s, 2H), 4.33 (s, 2H), 7.10 (s, 1H), 7.21 (d, 1H,
Jˆ8.4 Hz), 7.31 (d, 1H, Jˆ8.4 Hz), 7.62 (s, 1H), 8.42 (br s,
1H).
1
MeOH) to give 17 (17 mg, 15%) as an orange oil. H
NMR (200 MHz, CDCl3) d 3.75 (s, 3H), 3.77 (m, 1H),
4.31 (s, 2H), 4.95 (br s, 2H), 5.02 (ddd, 1H, Jˆ15.8, 5.6,
1.8 Hz), 5.92 (dt, 1H, Jˆ15.8, 1.4 Hz), 6.85 (m, 1H), 7.25
(d, 1H, Jˆ8.2 Hz), 7.47 (d, 1H, Jˆ8.2 Hz), 8.03 (s, 1H).
1.1.17. N-tert-Butyl-{3-[2-(dimethylamino)ethyl]-5-in-
dolyl}methanesulfonamide (22). Operating as in the
above preparation of alcohol 3, from amide 21 (0.66 g;
1.8 mmol) was obtained crude tryptamine 22. Flash chro-
matography (9:1 CH2Cl2±MeOH) afforded pure 22 as a
1.1.13. {3-Bromo-4-[N-(3-methoxycarbonyl-2-propenyl)-
tri¯uoroacetamido]phenyl}-N-tert-butyl-methanesulfona-
mide (18). Operating as above, from methyl 4-
bromocrotonate (2 mL, 16.8 mmol) and tri¯uoroacetanilide
16 (5 g, 12 mmol) was obtained 18 (3.9 g, 63%) as orange
oil. 1H NMR (200 MHz, CDCl3) d 1.36 (s, 9H), 3.74 (s, 3H),
3.85 (dd, 1H, Jˆ15.8, 7.6 Hz), 4.25 (s, 2H), 5.01 (ddd, 1H,
Jˆ15.8, 5.6, 1.8 Hz), 5.92 (dt, 1H, Jˆ15.8, 1.4 Hz), 6.88 (m,
1H), 7.25 (d, 1H, Jˆ8.2 Hz), 7.41 (d, 1H, Jˆ8.2 Hz), 7.78
(s, 1H).
1
white foam (0.2 g, 33%). H NMR (200 MHz, CDCl3) d
1.37 (s, 9H), 2.35 (s, 6H), 2.64 (t, 2H, Jˆ9.2 Hz), 2.93 (t,
2H, Jˆ9.2 Hz), 4.36 (s, 2H), 7.05 (s, 1H), 7.23 (d, 1H,
Jˆ8.4 Hz), 7.34 (d, 1H, Jˆ8.4 Hz), 7.61 (s, 1H), 8.10 (br
s, 1H).
1.1.18. 1-{[3-Bromo-4-(tri¯uoroacetamido)phenyl]methyl-
sulfonyl}pyrrolidine (23a). A solution of Br2 (2.3 mL,
45.8 mmol) in MeOH (30 mL) was added dropwise
(40 min) to a suspension of aniline 618 (10 g, 41.6 mmol)
in MeOH (100 mL). The mixture was stirred at rt for 1 h,
and then concentrated to dryness. The residue triturated with
CH2Cl2 to give a white solid (12.7 g) as a 1:1:2 mixture of
starting material, dibromoaniline, and o-bromoaniline.
TFAA (5.8 mL, 41.2 mmol) was added under Ar to a
suspension of the above mixture in anhydrous THF
(275 mL). The mixture was stirred at rt for 0.5 h and then
concentrated to dryness. The resulting residue was triturated
with 1:1 hexane±Et2O (200 mL) to give a white solid. Flash
chromatography (97:3 CH2Cl2±hexane) afforded pure 23a
(4.5 g, 26%); mp 175±1778C. 1H NMR (300 MHz, CDCl3)
d 1.88 (m, 4H), 3.23 (m, 4H), 4.19 (s, 2H), 7.42 (d, 1H,
Jˆ8.2 Hz), 7.70 (s, 1H), 8.32 (d, 1H, Jˆ8.2 Hz), 8.52
(br s, 1H). 13C NMR (75 MHz, CDCl3) d 25.8, 48.2,
54.8, 114.0, 115.9 (q, Jˆ290 Hz), 121.7, 128.7, 130.9,
133.3, 134.4, 155.1 (q, Jˆ35 Hz). Anal. calcd for
C13H14BrF3N2O3S´1H2O: C, 36.06; H, 3.72; N, 6.46.
Found: C, 36.03; H, 3.33; N, 6.24.
1.1.14. Methyl 5-(sulfamoylmethyl)-3-indoleacetate (19).
Bu4NBr (16 mg, 0.05 mmol), freshly distilled Et3N
(0.02 mL, 0.125 mmol), and Pd(OAc)2 (2 mg) were added
under Ar to a solution of 17 (24 mg, 0.05 mmol) in
anhydrous DMF (0.5 mL). After stirring at 808C for 3 h,
EtOAc (5 mL) was added, and the mixture was successively
washed with brine (5£5 mL) and 1N aqueous HCl (2£5 mL).
Evaporation of the dried organic extracts gave a residue, which
was chromatographed (95:5 CH2Cl2±MeOH) to give indole 19
(14 mg, 60%) as a yellow oil. 1H NMR (200 MHz, CDCl3) d
3.71 (s, 3H), 3.79 (s, 2H), 4.42 (s, 2H), 7.20 (s, 1H), 7.23 (d, 1H,
Jˆ8.4 Hz), 7.38 (d, 1H, Jˆ8.4 Hz), 7.62 (s, 1H), 8.8 (br s, 1H).
1.1.15. Methyl 5-(tert-butylsulfamoylmethyl)-3-indole-
acetate (20). Operating as above, from Bu4NBr (2.4 g,
7.5 mmol), Pd(OAc)2 (35 mg), Et3N (2.6 mL, 18.75
mmol), and 18 (3.9 g, 7.5 mmol) was obtained indole 20
1
(1.45 g, 57%) as a white solid. mp 94±968C. H NMR
(200 MHz, CDCl3) d 1.37 (s, 9H), 3.71 (s, 3H), 3.79 (s,
2H), 3.87 (br s, 1H), 4.36 (s, 2H), 7.20 (s, 1H), 7.24 (d,
1H, Jˆ8.4 Hz), 7.35 (d, 1H, Jˆ8.4 Hz), 7.63 (s, 1H), 8.2
(br s, 1H). Anal. calcd for C16H22N2O4S´1/4 H2O: C, 56.03;
H, 6.56; N, 8.16. Found: C, 56.01; H, 6.54; N, 7.84.
1.1.19. 1-{[3-Iodo-4-(tri¯uoroacetamido)phenyl]methyl-
sulfonyl}pyrrolidine (23b). Bis(pyridine)iodonium(I)
tetra¯uoroborate19 (4.6 g, 12.36 mmol) was added at rt to
a solution of aniline 618 (2.9 g, 12.1 mmol) in CH2Cl2
(30 mL). After stirring at rt for 5 h, the mixture was washed
with H2O (30 mL) and 0.1N aqueous Na2S2O3 (2£30 mL).
The organic extract was dried, ®ltered, and concentrated to
give the corresponding o-iodoanaline. TFAA (1.8 mL,
12.84 mmol) was added under Ar to a solution of this iodo-
aniline (4.1 g) in anhydrous THF (85 mL). The mixture was
stirred at rt for 1 h and then concentrated to dryness. The
resulting residue was redissolved in CH2Cl2 and succes-
sively washed with 1N aqueous HCl and saturated aqueous
Na2CO3. The organic phase was dried, ®ltered, and concen-
trated to give 23b (4.6 g, 81%) as a white solid; mp 149±
1.1.16. 5-(tert-Butylsulfamoylmethyl)-N,N-dimethyl-3-
indoleacetamide (21). A solution of ester 20 (1.45 g,
4.3 mmol) in a 1:1 mixture of 2N aqueous KOH±MeOH
(60 mL) was stirred at rt for 1 h. The MeOH was evapo-
rated, and the mixture was acidi®ed with 1N aqueous HCl
and extracted with EtOAc (3£30 mL). The organic extracts
were dried, ®ltered, and concentrated to give the correspond-
ing 3-indoleacetic acid (1.35 g, 97%) as a yellow solid;
1
190±1928C. H NMR (200 MHz, CD3OD) d 1.41 (s, 9H),
3.84 (s, 2H), 4.45 (s, 2H), 7.26 (d, 1H, Jˆ8.4 Hz), 7.29 (s,
1H), 7.44 (d, 1H, Jˆ8.4 Hz), 7.69 (s, 1H). PCl5 (0.7 g,
3.3 mmol) was added to an ice-cooled suspension of the
above acid (1 g, 3.1 mmol) in CH2Cl2 (20 mL) and DMF
1
1518C. H NMR (200 MHz, CDCl3) d 1.88 (m, 4H), 3.23

J. Bosch et al. / Tetrahedron 57 (2001) 1041±1048
1047
(m, 4H), 4.17 (s, 2H), 7.45 (d, 1H, Jˆ8.2 Hz), 7.92 (s, 1H),
8.25 (d, 1H, Jˆ8.2 Hz), 8.35 (br s, 1H).
organic extracts were dried, ®ltered, and concentrated to
give indoleacetic acid 28 (0.51 g, 83%) as an orange solid.
An analytical sample was obtained by ¯ash chromatography
1
1.1.20.
1-{[3-Bromo-4-[N-(3-methoxycarbonyl-2-pro-
(99:1 CH2Cl2±MeOH); mp 95±978C. H NMR (300 MHz,
penyl)tri¯uoroacetamido]phenyl]methylsulfonyl}pyrro-
lidine (24a). Operating as in the above preparation of 17,
from 23a (1 g, 2.4 mmol) and methyl 4-bromocrotonate
(0.4 mL, 3.36 mmol) was obtained 24a (0.9 g, 73%) as a
(CD3)2SO) d 1.74 (m, 4H), 3.09 (m, 4H), 3.63 (s, 2H), 4.44
(s, 2H), 7.13 (d, 1H, Jˆ8.5 Hz), 7.26 (s, 1H), 7.33 (d, 1H,
Jˆ8.5 Hz), 7.52 (s, 1H), 10.99 (s, 1H), 12.18 (br s, 1H). 13C
NMR (75 MHz, (CD3)2SO) d 25.5, 31.1, 47.8, 54.4, 107.9,
111.4, 119.8, 121.2, 124.2, 124.9, 127.3, 135.9, 173.2. Anal.
calcd for C15H18N2O4S´H2O: C, 52.98; H, 5.92; N, 8.24.
Found: C, 52.95; H, 5.90; N, 8.16.
1
yellow oil. H NMR (200 MHz, CDCl3) d 1.86 (m, 4H),
3.19 (m, 4H), 3.74 (s, 3H), 3.85 (dd, 1H, Jˆ15.8, 7.6 Hz),
4.23 (s, 2H), 5.01 (ddd, 1H, Jˆ15.8, 5.6, 1.8 Hz), 5.90 (dt,
1H, Jˆ15.8, 1.4 Hz), 6.88 (dq, 1H, Jˆ15.7, 7.5, 5.6 Hz),
7.25 (d, 1H, Jˆ8.2 Hz), 7.45 (d, 1H, Jˆ8.2 Hz), 7.78 (s,
1H).
1.1.26. 5-(1-Pyrrolidinylsulfonylmethyl)-3-indolemetha-
nol (29). LiBH4 (8 mg, 0.37 mmol) was added under N2 to
a solution of ester 26 (0.22 g, 0.65 mmol) in anhydrous THF
(3 mL) and toluene (0.5 mL). After being stirred at 1008C
for 2 h, the mixture was poured into saturated aqueous
NH4Cl (10 mL) and extracted with CH2Cl2 (2£10 mL).
Concentration of the dried extracts gave a residue, which
was chromatographed (99:1 CH2Cl2±MeOH). Crystalliza-
tion from 8:2 H2O±MeOH gave alcohol 29 (0.14 g, 71%) as
a white solid; mp 103±1058C. 1H NMR (300 MHz, CDCl3)
d 1.74 (s, 1H), 1.79 (m, 4H), 3.02 (t, 2H, Jˆ7.2 Hz), 3.17
(m, 4H), 3.88 (m, 2H), 4.36 (s, 2H), 7.08 (s, 1H), 7.21 (d,
1H, Jˆ8.5 Hz), 7.32 (d, 1H, Jˆ8.5 Hz), 7.60 (s, 1H), 8.37
(s, 1H). 13C NMR (75 MHz, CDCl3) d 26.0, 28.8, 48.3, 56.7,
62.8, 111.7, 112.5, 120.1, 121.3, 123.6, 124.7, 127.8, 136.5.
Anal. calcd for C15H20N2O3S´H2O: C, 55.26; H, 6.80; N,
8.59. Found: C, 55.20; H, 6.74; N, 8.56.
1.1.21. 1-{[4-[N-(3-methoxycarbonyl-2-propenyl)tri¯uoro-
acetamido]-3-iodophenyl]methylsulfonyl}pyrrolidine
(24b). Operating as in the above preparation of 17, from 23b
(4.5 g, 9.7 mmol) and methyl 4-bromocrotonate (1.6 mL,
13.5 mmol) was obtained 24b (2.8 g, 52%) as a yellow
1
oil. H NMR (200 MHz, CDCl3) d 1.86 (m, 4H), 3.19 (m,
4H), 3.74 (s, 3H), 3.75 (m, 1H), 4.21 (s, 2H), 5.02 (ddd, 1H,
Jˆ15.8, 5.6, 1.8 Hz), 5.91 (dt, 1H, Jˆ15.8, 1.4 Hz), 6.88
(dq, 1H, Jˆ15.8, 7.5, 5.6 Hz), 7.24 (d, 1H, Jˆ8.2 Hz), 7.45
(d, 1H, Jˆ8.2 Hz), 8.0 (s, 1H).
1.1.22.
1-{[4-(N-2-Butenyltri¯uoroacetamido)-3-iodo-
phenyl]methylsulfonyl}pyrrolidine (25). Operating as in
the above preparation of 17, from 23b (1.34 g, 2.9 mmol)
and crotyl bromide (0.69 g, 4.3 mmol) was obtained 25
(0.74 g, 49%) as a yellow oil. 1H NMR (200 MHz,
CDCl3) d 1.0 (d, 3H, Jˆ6.6 Hz), 1.85 (m, 4H), 3.17 (m,
4H), 3.57 (dd, 1H, Jˆ15.7, 7.5 Hz), 4.22 (s, 2H), 4.85 (dd,
1H, Jˆ15.7, 5.6 Hz), 5.5 (m, 1H), 7.17 (d, 1H, Jˆ8.2 Hz),
7.45 (d, 1H, Jˆ8.2 Hz), 7.98 (s, 1H).
Acknowledgements
This work was supported by the CICYT (Spain)-European
Comission (project 2FD97-1086). Thanks are also due to the
Comissionat per Universitats i Recerca (Generalitat de
Catalunya) for Grant 1999SGR-00079.
1.1.23. Methyl 5-(1-pyrrolidinylsulfonylmethyl)-3-indole-
acetate (26). Operating as in the above preparation of 19,
from 24a (0.15 g, 0.29 mmol) was obtained indole 26
(51 mg, 52%) as a yellow oil. From 24b the yield arose to
57%. 1H NMR (300 MHz, CDCl3) d 1.77 (m, 4H), 3.14 (m,
4H), 3.70 (s, 3H), 3.76 (s, 2H), 4.37 (s, 2H), 7.16 (s, 1H),
7.21 (d, 1H, Jˆ8.4 Hz), 7.31 (d, 1H, Jˆ8.4 Hz), 7.59 (s,
1H), 8.35 (br s, 1H). 13C NMR (75 MHz, CDCl3) d 25.8,
31.0, 48.1, 51.9, 56.7, 108.4, 111.5, 120.3, 121.2, 124.0,
124.6, 127.3, 136.0, 172.3.
References
1. Hopkins, S. J. Drugs Today 1992, 28, 155±159.
2. Macor, J. E.; Blank, D. H.; Post, R. J.; Ryan, K. Tetrahedron
Lett. 1992, 33, 8011±8014.
3. Brodfuehrer, P. R.; Chen, B.-C.; Sattelberg, T. R.; Smith, Sr.,
P. R.; Reddy, J. P.; Stark, D. R.; Quinlan, S. L.; Reid, J. G.;
Thottathil, J. K.; Wang, S. J. J. Org. Chem. 1997, 62, 9192±
9202.
1.1.24. 3-Ethyl-5-(1-pyrrolidinylsulfonylmethyl)indole (27).
Operating as in the above preparation of 19, from 25 (0.74 g,
1.4 mmol) was obtained the indole 27 (0.24 g, 57%) as a
Â
4. Fernandez, M.-D.; Puig, C.; Crespo, M.-I.; Moragues, J. ES
Patent 2,084,560, 1994; Chem Abstr. 1996, 125, 221573.
5. (a) Castro, J. L.; Matassa, V. G. Tetrahedron Lett. 1993, 34,
4705±4708. (b) Castro, J. L.; Baker, R.; Guiblin, A. R.;
Hobbs, S. C.; Jenkins, M. R.; Russell, M. G. N.; Beer, M. S.;
Stanton, J. A.; Scholey, K.; Hargreaves, R. J.; Graham, M. I.;
Matassa, V. G. J. Med. Chem. 1994, 37, 3023±3032.
6. (a) Remuzon, P.; Dussy, C.; Jacquet, J. P.; Soumeillant, M.;
Bouzard, D. Tetrahedron Lett. 1995, 36, 6227±6230 (for
related eliminations). (b) See also Refs. 3 and 5a.
1
yellow oil. H NMR (200 MHz, CDCl3) d 1.31 (t, 3H,
Jˆ7.2 Hz), 1.76 (m, 4H), 2.75 (q, 2H, Jˆ7.2 Hz), 3.14
(m, 4H), 4.38 (s, 2H), 6.98 (s, 1H), 7.21 (d, 1H,
Jˆ8.4 Hz), 7.30 (d, 1H, Jˆ8.4 Hz), 7.59 (s, 1H), 8.30 (br
s, 1H). 13C NMR (50 MHz, CDCl3) d 14.4, 18.2, 25.8, 48.1,
56.7, 111.3, 118.5, 119.4, 121.1, 121.5, 124.1, 127.8, 136.6.
1.1.25. 5-(1-Pyrrolidinylsulfonylmethyl)-3-indoleacetic
acid (28). A suspension of ester 26 (0.63 g, 1.87 mmol) in
a 1:1 mixture of 2N aqueous KOH±MeOH (20 mL) was
stirred at rt for 1 h. The mixture was ®ltered, MeOH was
evaporated, and the aqueous residue was acidi®ed with 1N
aqueous HCl and extracted with EtOAc (3£15 mL). The
7. Street, L. J.; Baker, R.; Castro, J. L.; Chambers, M. S.;
Guiblin, A. R.; Hobbs, S. C.; Matassa, V. G.; Reeve, A. J.;
Beer, M. S.; Middlemiss, D. N.; Noble, A. J.; Stanton, J. A.;
Scholey, K.; Hargreaves, R. J. J. Med. Chem. 1993, 36, 1529±
1538.

1048
J. Bosch et al. / Tetrahedron 57 (2001) 1041±1048
tization followed by reduction of the resulting diazonium salt
8. (a) Robinson, B. The Fischer Indole Synthesis; Wiley: New
with SnCl2 (78% overall yield). (b) Wyrick, S. D.; Hall, I. H.;
Dubey, A. J. Pharm. Sci. 1984, 73, 374±377.
York, 1982, pp 487±495. (b) Grandberg, I. I. Zh. Org. Khim.
1983, 19, 2439±2452; Chem Abstr. 1984, 100, 156436.
(c) Chen, C.; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1994, 59, 3738±
3741 (for recent examples). (d) See also Refs. 5 and 7.
9. Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1, 1045±
1075 (for a recent review).
13. (a) Odle, R.; Blevins, B.; Ratcliff, M.; Hegedus, L. S. J. Org.
Chem. 1980, 45, 2709±2710. (b) Hegedus, L. S. Angew.
Chem., Int. Ed. Engl. 1988, 27, 1113±1126. (c) See also
Ref. 2.
14. (a) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977, 12,
1037±1040. (b) Wensbo, D.; Annby, U.; Gronowitz, S.
Tetrahedron 1995, 51, 10323±10342 (for previous synthesis
of indole-3-acetic acid derivatives via a Heck cyclization).
10. (a) Chen, C.; Lieberman, D. R.; Larsen, R. D.; Reamer, R. A.;
Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1994, 35,
6981±6984. (b) Street, L. J.; Baker, R.; Davey, W. B.; Guiblin,
A. R.; Jelley, R. A.; Reeve, A. J.; Routledge, H.; Sternfeld, F.;
Watt, A. P.; Beer, M. S.; Middlemiss, D. N.; Noble, A. J.;
Stanton, J. A.; Scholey, K.; Hargreaves, R. J.; Sohal, B.;
Graham, M. I.; Matassa, V. G. J. Med. Chem. 1995, 38,
1799±1810. (c) Chen, C.; Lieberman, D. R.; Street, L. J.;
Guiblin, A. R.; Larsen, R. D.; Verhoeven, T. R. Synth.
Commun. 1996, 26, 1977±1984. (d) See also Refs. 2, 3 and 5b.
11. (a) Albinson, F. D.; MacKinnon, J. W. M.; Crookes, D. L. Eur.
Pat. Appl. EP, 462,837, 1991; Chem. Abstr. 1992, 116,
106088. (b) For an ef®cient two-phase Fischer indole synthesis
of avitriptan, see Ref. 3.
Â
15. Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; Perez,
Â
 Â
M.; Garcõa-Martõn, M. A.; Gonzalez, J. M. J. Org. Chem.
1996, 61, 5804±5812.
16. For the isolation of an indole-3-acetic acid as a major metabo-
lite of the antimigraine drug MK-0462, see Ref. 10c.
17. Loft®eld, R. B. J. Am. Chem. Soc. 1951, 73, 1365±1366.
18. Sulfonamides 6 and 14 were prepared from (p-nitrophenyl)-
methanesulfonyl chloride, following the procedure reported12b
for the preparation of 12, but using pyrrolidine or tert-butyl-
amine instead of NH3.
Â
19. Barluenga, J.; Rodrõguez, M. A.; Campos, P. J. J. Org. Chem.
1990, 55, 3104±3106.
12. (a) Hydrazine 13 was prepared from aniline 1212b by diazo-