Synthesis of 5-substituted indole derivatives. Part 4: Naratriptan from α-anilinoacetaldehyde dimethylacetal by TiCl4-mediated cyclisation

Article abstract of DOI:10.3987/COM-03-9838

N-Methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide (Naratriptan, 2) was prepared from N-methyl-N-phenylmethyl-2-(4-aminophenyl)-ethanesulfonamide (3b) through reductive alkylation with dimethoxyacetaldehyde followed by N-acylation and TiCl₄-mediated indolisation, according to Sundberg procedure. The isopropyl group proved to be a useful protecting group for sulfonate esters in a number of transformations but was cleaved in the presence of TiCl₄.

Full text of DOI:10.3987/COM-03-9838

HETEROCYCLES, Vol. 60, No. 11, 2003, pp. 2441 - 2455
Received, 26th June, 2003, Accepted, 5th September, 2003, Published online, 8th September, 2003
SYNTHESIS OF 5-SUBSTITUTED INDOLE DERIVATIVES. PART 41:
NARATRIPTAN FROM α-ANILINOACETALDEHYDE
DIMETHYLACETAL BY TiCl4-MEDIATED CYCLISATION
Béla Pete,*a Gyula Simig,b László Poszáváczb, and László Tőkea
a) Research Group of the Hungarian Academy of Sciences, Department of
Organic Chemical Technology, Technical University of Budapest, H-1521
Budapest, Hungary
b) Chemical Research Division, EGIS Pharmaceuticals Ltd., P.O. Box 100, H-
1475 Budapest, Hungary
E-mail: bpete@mail.bme.hu
Abstract - N-Methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide
(Naratriptan, 2) was prepared from N-methyl-N-phenylmethyl-2-(4-aminophenyl)-
ethanesulfonamide (3b) through reductive alkylation with dimethoxyacetaldehyde
followed by N-acylation and TiCl4-mediated indolisation, according to Sundberg
procedure. The isopropyl group proved to be a useful protecting group for
sulfonate esters in a number of transformations but was cleaved in the presence of
TiCl4.
Among the serotonin (5-hydroxytriptamine, 5-HT) receptor subtypes, 5-HT1B and 5-HT1D are of particular
interest because of the therapeutic potential of drugs acting at these sites. Sumatriptan (1, Scheme 1), a 5-
HT1B/1D receptor agonist, was the first of a new class of therapeutic agents for the acute treatment of
migraine headaches.2 Its discovery has intensified research in this area and over the past years several
related compounds, the so called ‘triptans,’ have entered the marketplace and late phase clinical trials.
Among those, Naratriptan (2),3 having an excellent overall bioavailability index, has been perharps the
most successful.
The key feature in the synthesis of Naratriptan is the introduction of the ethanesulfonyl moiety at the 5-
position of indole. This is accomplished by the Heck-coupling of N-methylethenesulfonamide and 5-
bromoindole in the industrial synthesis3 of compound (2) in excellent yield. The following step, the
electrophilic substitution at the 3-position of the indole, as the most characteristic feature of the

heterocycle, to attach the piperidine moiety,3 also proceeds in yields over 80%. However, the use of Pd on
industrial scale is a drawback of the synthesis, which might cause alternative synthetic pathways to
emerge in the future.
Scheme 1
N
NMe2
MeHNO2S
SO2NHMe
N
N
H
H
1
2
Synthesis of Naratriptan (2)
In this paper we want to report our results on the practical synthesis of compound (2) starting from 4-
substituted aniline derivatives, according to Scheme 2. As a part of our ongoing research of the chemistry
of indole-5-alkanesulfonic acids we have developed a practical synthesis of 2-(4-amino-
phenyl)ethanesulfonic acid (23). This offered the possibility to synthesize compound (2) by traditional
methods to obtain indoles. The Fischer synthesis did not seem attractive in this case as the Fischer
indolisation of N-methyl-2-(4-hydrazinophenyl)ethanesulfonamide and (N-methyl-4-piperidino)-
acetaldehyde furnished Naratriptan in a disappointingly low 30% yield.3a
The Nordlander4 or Sundberg5 type of indolisation offers an alternative route from anilines to indoles and
is particularly suitable for 5-substituted indoles with electron-donor substituents. Sundberg method
applies methanesulfonamides of (2,2-diethoxyethyl)anilines as starting materials for indoles and TiCl4 to
effect cyclisation, while Nordlander conditions involve heating N-(2,2-diethoxyethyl)trifluoroacetanilides
in TFA-TFAA mixture. Alkylation of methanesulfonanilides or trifluoroacetanilides with
bromoacetaldehyde diethylacetal was used to prepare the substrates for the ring closure.4,5 The same
alkylation of methanesulfonanilides (4a, b) to yield 5a, b failed in our case using either Nordlander
o
o
conditions (NaHCO3 in EtOH, 80 C) or that of Sundberg (NaH in DMF, rt (4a) or 110 C (4b)). The
reductive alkylation, however, was successfully applied to furnish α-anilinoacetaldehyde acetals6 (6a, b).
Sulfonylation of 6a, b with methanesulfonyl chloride failed but the acylation prodeeded smoothly with
TFAA to yield trifluoroacetanilides (7a, b) in good yields. In effecting the ring closure, Sundberg
conditions were superior compared to that of Nordlander: while the former gave pure trifluoracetylindole
(8b) over 50% after recrystallisation, the yield of the latter did not exceeded 25% and the product needed
chromatographic purification. Although the indolisation of 7a furnished 8a, the loss of i-Pr group of the

Scheme 2
R
S
R
S
R
O
O
S
O
O
O
O
OEt
EtO
(EtO)2CHCH2Br
MeSO Cl
2
HN
S
pyridine
N
S
H2N
O
O
3a
3b
a: R= O- i-Pr
Me
O
Me
4a, b
5a, b
O
b: R=N(Bn)Me
H2/Pd
(MeO)2CHCH=O
R
S
R
R
S
O
S
O
O
O
O
O
OMe
OMe
MeO
MeO
TiCl4
TFAA
Et 3N
C6H5Cl
N
N
N
H
O
6a, b
7a, b
CF3
O
F3C
8a, b
8a R=OH
Me
Me
O
Me
O
NMe
NMe
NCH2Ph
S
NCH2Ph
S
NCH2Ph
S
O
O
O
O
KOH
KOH
H2/10%Pd/C
N
MeOH
N
N
H
MeN
O
H
H
11
10
9
Na/NH3
2
sulfonic ester occurred during the ring closure and neither the free sulfonic acid nor its salts could be
isolated from the hydrolysed reaction mixture. The introduction of the (1,2,3,6-tetrahydro-1-methyl-4-
pyridinyl)-substituent at the 3 position of the indole is effected by methanolic KOH and N-methyl-4-
piperidone.. The trifluoroacetyl indole (8b) can either directly be applied in this reaction or hydrolysed by
KOH-EtOH at rt previously to indole (9). The yield of the two-step procedure is about 15% higher than
that of the one-step procedure.
The reported condensation of N-methyl-1H-indole-5-ethanesulfonamide and N-methyl-4-piperidone gave
the 3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)indole in 30% yield.3a The replacement of the sulfonamide

N-H to N-benzyl in this reaction improved the yield considerably as 9 furnished 10 in 85% yield. We
envisaged the hydrogenation of the exocyclic double bond and the hydrogenolysis of the N-benzyl group
as a one-pot reaction by catalytic hydrogenation. While the reduction of the exocyclic double-bond was
very facile, the forcing-conditions (5 bar, 50-60 oC) necessary to remove an amide-benzyl group resulted
in the hydrogenation of the endocyclic double bond at the indole-2,3 position without the hydrogenolysis
of the benzyl group. The deprotection of the sulfonamide-N atom, finally carried out by dissolving-metal
reduction of the sulfonamide (11), completed the synthesis of Naratriptan in 16% overall yield. from 3b.
Synthesis of vinyl sulfonic acid derivatives
Screening the literature for a practical, low-cost procedure to prepare 2-(4-nitrophenyl)ethene-
sulfonamides as precursors for 3b revealed that base-mediated condensation of 4-nitrobenzaldehyde and
methanesulfonamides offers a facile way for these compounds. The Knoevenagel-type condensation7 of
phenylaminosulfonylacetic acid with 4-nitrobenzaldehyde has been effected by piperidinium acetate in
refluxing toluene but the product contains methanesulfonanilide owing to the concomitant
decarboxylation. The one-pot synthesis of vinylsulfonamides8 through the addition of N-Boc-N-alkyl-
methanesulfonamides on 4-nitrobenzaldehyde followed by elimination in the presence of t-BuOK seemed
attractive. In our case, however, the reaction of N-Boc-N-methyl-methanesulfonamide with 4-
nitrobenzaldehyde in THF at -78 oC with t-BuOK resulted in the formation of several major components
which failed to give a single elimination product so this reaction was not further investigated. While N-
benzyl-N-methylmethanesulfonamide (13) and 4-nitrobenzaldehyde failed to react under the same
conditions, a smooth addition occured to give the hydroxysulfonamide (14) when using n-BuLi instead of
t-BuOK (Scheme 3). The elimination proceeded quantitatively in the presence of mesyl chloride and
triethylamine to give 15. As none of these processes seemed satisfactory from industrial point of view, we
decided to prepare the vinylsulfonamides by the classical method from amines and sulfonylchlorides. We
have developed a facile synthesis of 2- (4-nitrophenyl)ethenesulfonic acid (19), the immediate precursor
of 2-(4-aminophenyl)ethanesulfonic acid (23), in which the yields are almost quantitative and none of the
products needs purification (Scheme 4). This acid (19) have been prepared by the nitration9 of 2-phenyl-1-
ethenesulfonic acid, by the sulfonylation of 4-nitrostyrene with SO3,10 and in the Wittig-Horner reaction
of triethyl α-phosphorylmethanesulfonate11 and 4-nitrobenzaldehyde with n-BuLi. The ethyl ester of 19 is
formed in the latter case, NaI is used to dealkylate the ester. Alkyl mesylates undergo α-deprotonation
easier than mesyl amides, and isopropyl12 and isobutyl methanesulfonates13 are reported to form stable α-
carbanions capable of undergoing alkylation with alkyl iodides or even adding on formyl group.14
Surprisingly, however, the alkyl mesylates have seldom been applied for the preparation of

Scheme 3
OH
O
O
CHO
O
O
S
n-BuLi
NCH2Ph
Me
S
Me
NCH2Ph
Me
+
THF
O2N
O2N
13
14
12
H
O
S
O
MeSO Cl
2
NCH2Ph
Me
TEA
O2N
CH Cl2
2
15
vinylsulfonates15 yet The carbanion derived from isopropyl mesylate was used to prepare the acid (19) in
our procedure according to Scheme 4. The sulfonyl chloride (20) was prepared in good yield from the acid
(19). The sulfonylation of methylamine, however, was accompanied by addition of the amine on the
double bond and the ratio of the two product (21, 22) could not be affected by altering the reaction
conditions indicating that the vinylsulfonamide and the vinylsulfonyl chloride have similar reactivity in
conjugate addition. The Michael-type addition of vinyl sulfonamides is well-documented.11 When N-
methyl-N-benzylamine was sulfonylated, no nucleophilic addition occurred probably because of steric
reasons, and the sulfonamide (15) was formed exclusively. Catalytic reduction of the nitro group and the
double bond can be accomplished simultaneously yielding the aniline (3a, b). It is worth mentioning that
dioxane is the solvent of choice for this reduction while other solvents, either protic or aprotic, decrease
the yield considerably in case of 3b or gave no aniline at all as in case of 3a.
ACKNOWLEDGEMENT
The authors would like to thank the National Fund for Science and Research (OTKA Project No.
T038329) and EGIS Pharmaceuticals Ltd for finacial support.
EXPERIMENTAL
13
1H NMR and C NMR spectra were recorded at 250 MHz or 62.5 MHz, respectively, on a Bruker AC
250 spectrometer. All δ values are given in ppm, TMS was used as an internal standard. HRMS spectra
were measured on a VG ZAB-2SEQ instrument (direct inlet at 200 oC, EI). Column chromatography was
performed on Merck silica gel (0.63-0.20 mm). IR spectra were measured on Perkin-Elmer 1600 series
FTIR spectrophotometer. All chemicals were reagent grade and used without further purification. N-

Methyl-N-benzylamine16 (13) and isopropyl methanesulfonate17 (16) were prepared by standard
procedures.
Scheme 4
OH
O
O
MeSO Cl
2
CHO
S
O
O
t-BuOK
Oi-Pr
S
+
Et 3N
Me
Oi-Pr
THF
O2N
O2N
17
16
12
O
O
O
O
S
S
H2/10%Pd/C
dioxane
Oi-Pr
Oi-Pr
O2N
H2N
3a
18
Na I
acetone
O
O
O
O
Me
S
S
SOCl2
HNCH2Ph
Cl
O
Na+
C6H6
O2N
Et N
3
O2N
19
20
O
O
S
O
O
S
H2/10%Pd/C
dioxane
NCH2Ph
NCH2Ph
Me
Me
O2N
H2N
3b
15
O
O
O
O
MeNH
S
S
MeNH2
NHMe
NHMe
20
+
O2N
O2N
22
21
2-(4-Aminophenyl)ethanesulfonic acid isopropyl ester (3a).
2-(4-Nitrophenyl)ethenesulfonic acid isopropyl ester (18) (10 g, 36.9 mmol) was hydrogenated in dioxane
(170 mL) with 10% Pd/C (1 g) at rt and 1 bar for 24 h. The reaction mixture was filtered, the dioxane

solution was rotary evaporated while keeping the bath temperature under 25 oC to give 7.2 g (80 %) of 3a
as a colorless oil. The product slowly polimerizes at rt but stable at -20 oC for weeks. 1H NMR (CDCl3) δ:
1.40 (d, 6H, J=6.5 Hz), 3.00 (m, 2H), 3.25 (m, 2H), 3.55 (br s, 2H), 4.92 (m, 1H, J=6.5 Hz), 6.62 (d, 2H,
13
J=8.5 Hz), 6.95 (d, 2H, J=8.5 Hz). C NMR (CDCl3) δ: 23.11; 28.96; 52.93; 76.72; 115.4; 126.91;
129.20, 145.60. Analysis was carried out on the N,N-dimesylate: Anal. Calcd for C13H21NO7S3: C, 39.08;
H, 5.30; N, 3.51; S, 24.08. Found: C, 38.49; H, 5.48; N, 3.41; S, 23.86. IR of dimesylate (KBr): 1361,
1160, 911 cm-1.
2-(4-Aminophenyl)ethanesulfonic acid benzylmethylamide (3b)
2-(4-Nitrophenyl)ethenesulfonic acid benzylmethylamide (15) (10 g, 0.301 mol) was hydrogenated in
dioxane (170 mL) with 10% Pd/C (1 g) at rt and 1 bar for 24 h. The reaction mixture was filtered, the
o
dioxane solution was rotary evaporated to give 8 g (88 %) of 3b as yellow crystals, mp 85-87 C (ethyl
acetate). 1H NMR (CDCl3) δ: 2.75 (s, 3H), 2.95-3.08 (m, 2H), 3.12-3.22 (m, 2H), 3.64 (br s, 2H), 4.33 (s,
13
2H), 6.62 (d, 2H, J=8.6 Hz), 6.98 (d, 2H, J=8.6 Hz), 7.35 (s, 5H). C NMR (CDCl3) δ: 28.66; 34.25;
52.10; 53.80; 115.44; 127.75; 127.98; 128.29; 128.73; 129.21; 135.87; 145.23. IR (KBr): 3462, 3426,
3372, 3352, 1337, 1151 cm-1. Anal. Calcd for C16H20N2O2S: C, 63.13; H, 6.62; N, 9.20; S, 10.53. Found:
C, 62.84; H, 6.48; N, 9.10; S, 10. 36.
2-(4-Methanesulfonylaminophenyl)ethanesulfonic acid isopropyl ester (4a)
To the stirring solution of 2-(4-aminophenyl)ethanesulfonic acid isopropyl ester (3a) (3.70 g, 15.2 mmol)
in CH2Cl2 (100 mL) and pyridine (5.2 mL, 65 mmol) was added dropwise methanesulfonyl chloride (1.75
mL, 21.8 mmol) in CH2Cl2 (70 mL) at 3 oC over a period of 1 h. The reaction mixture was stirred at 3 oC
for an additional 3 h then poured onto ice (200 g). The organic phase was separated, washed with water
(2x50 mL), dried (MgSO4), and evaporated in vacuum to give 3.13 g (64%) of 4a as an oil which was
sufficiently pure for spectral analysis. 1H NMR (CDCl3) δ: 1.40 (d, 6H, J=6.3 Hz), 2.95 (s, 3H), 3.10 (m,
2H), 3.30 (m, 2H), 4.96 (m, 1H, J=6.3 Hz), 7.20 (s, 4H). IR (film): 3182, 1352, 1155 cm-1.
2-(4-Methanesulfonylaminophenyl)ethanesulfonic acid benzylmethylamide (4b)
To the stirring solution of 2-(4-aminophenyl)ethanesulfonic acid benzylmethylamide (3b) (3.04 g, 10
mmol) in CH2Cl2 (100 mL) and pyridine (2.6 mL, 33 mmol) was added dropwise methanesulfonyl chloride
(1 mL, 13 mmol) in CH2Cl2 (30 mL) at 3 oC over a period of 1 h. The reaction mixture was stirred at 3 oC
for an additional 3 h then poured onto ice (200 g). The organic phase was separated, washed with water
o
1
(2x50 mL) then evaporated in vacuum to give 2.07 g (54%) of 4b, mp 71-73 C (ethanol). H NMR

(CDCl3) δ: 2.78 (s, 3H), 2.93 (s, 3H), 3.12 (m, 2H), 3.19 (m, 2H), 4.32 (s, 2H), 7.18 (d, 2H, J=7.5 Hz),
7.37 (m, 7H). IR (KBr): 3212, 1348, 1153 cm-1. Anal. Calcd for C17H22N2O4S2: C, 53.38; H, 5.80; N,
7.32; S, 16.77. Found: C, 53.20; H, 5.91; N, 7.22; S, 16. 42.
2-[4-(2,2-Dimethoxyethylamino)phenyl]ethanesulfonic acid isopropyl ester (6a).
To the mixture of 2-(4-aminophenyl)ethanesulfonic acid isopropyl ester (3a) (3.0 g, 12.3 mmol) and 10%
Pd/C (0.4 g) in ethanol (100 mL) was added a solution of dimethoxyacetaldehyde (3.3 mL, 21.8 mmol,
60% in H2O) and the whole was stirred under hydrogen atmosphere at rt for 8 h. The catalyst was filtered
off, the ethanolic solution was rotary evaporated and the oily residue was purified by flash-cromatography
1
with hexane:ethyl acetate (4:1) to give 2.9 g (71%) of 6a, as colorless oil. H NMR (CDCl3) δ: 1.40 (d,
6H, J=6.3 Hz), 3.03 (m, 2H), 3.25 (m, 2H), 3.3-3.55 (m, 2H), 3.45 (s, 6H), 4.56 (t, 1H, J=5.7 Hz), 4.98
13
(m, 1H, J=6.3 Hz), 6.58 (d, 2H, J=8 Hz), 7.03 (d, 2H, J=8 Hz). C NMR (CDCl3) δ: 23.00 ; 28.87;
45.38; 52.77; 53.72; 76.47; 102.48; 113.20; 126.07; 129.14; 146.96. IR (film): 3391, 1336, 1142 cm-1.
HRMS ( M+) calcd for C15H25NO5S 331.1453; found: 331.1448.
2-[4-(2,2-Dimethoxyethylamino)phenyl]ethanesulfonic acid benzylmethylamide (6b)
To the mixture of 2-(4-aminophenyl)ethanesulfonic acid benzylmethylamide (3b) (8.0 g, 26.3 mmol) and
10% Pd/C (1.4 g) in ethanol (200 mL) was added a solution of dimethoxyacetaldehyde (6.7 mL, 44.4
mmol, 60% in H2O) and the whole was stirred under hydrogen atmosphere at rt for 8 h. The catalyst was
filtered off, the ethanolic solution was rotary evaporated and the crystalline residue was washed with
o
1
isopropanol to give 8.6 g (84%) of 6b, mp 65-67 C (ethyl acetate). H NMR (CDCl3) δ: 2.72 (s, 3H),
2.96-3.05 (m, 2H), 3.12-3.20 (m, 2H), 3.22 (d, 2H, J=5.5 Hz), 3.40 (s, 6H), 4.32 (s, 2H), 4.56 (t, 1H,
13
J=5.5 Hz), 6.58 (d, 2H, J=8.3 Hz), 7.00 (d, 2H, J=8.3 Hz), 7.33 (s, 5H). C NMR (CDCl3) δ: 28.58;
34.22; 45.41; 52.07; 53.77; 53.86; 102.48; 113.33; 126.82; 127.93; 128.26; 128.69; 129.18; 135.87;
146.79. IR (KBr): 3408, 1524, 1332, 1144, 1063 cm-1. Anal. Calcd for C20H28N2O4S: C, 61.20; H, 7.19; N,
7.14; S, 8.17. Found: C, 61.25; H, 7.18; N, 7.09; S, 8.06.
2-{4-[(2,2-Dimethoxyethyl)-(2,2,2-trifluoroacetyl)amino]phenyl}ethanesulfonic acid isopropyl ester
(7a)
To the solution of 2-[4-(2,2-dimethoxyethylamino)phenyl]ethanesulfonic acid isopropyl ester (6a) (9.0 g,
27.3 mmol) and triethylamine (4.5 mL, 32 mmol) in dry toluene (120 mL) was added TFAA (4.23 mL, 30
mmol) over a period of 15 min at 0 oC. The reaction mixture was kept at rt for 16 h, then cooled again to 0
oC and triethylamine (4.0 mL, 29 mmol) and TFAA (3.0 mL, 21.3 mmol) were added as before. After 16

h at rt, the solution was rotary evaporated, the oily residue dissolved in CH2Cl2 (100 mL) and washed with
cold H2O (3x50 mL). The CH2Cl2 solution was dried (MgSO4), and rotary evaporated to give an oil (10 g)
which was purified by flash-cromatography with hexane:ethyl acetate (5:1) to give 8.0 g (69%) of 7a as a
1
colorless oil. H NMR (CDCl3) δ: 1.40 (d, 6H, J=6.8 Hz), 3.1-3.25 (m, 2H), 3.25-3.40 (m, 2H), 3.30 (s,
6H), 3.78 (d, 2H, J=5.4 Hz), 4.60 (t, 1H, J=5.4 Hz), 4.98 (m, 1H, J=6.8 Hz), 7,22 (s, 4H). IR (film):
1708, 1201, 1148 cm-1. HRMS (M+) calcd for C17H24NO6F3S 427.1277; found: 427.1273.
N-{4-[2-(Benzylmethylsulfamoyl)ethyl]phenyl}-N-(2,2-dimethoxyethyl)-2,2,2-trifluoroacetamide (7b)
To the solution of 2-[4-(2,2-dimethoxyethylamino)phenyl]ethanesulfonic acid benzylmethylamide (6b)
(20.0 g, 51 mmol) and triethylamine (38.0 mL, 271 mol) in dry CH2Cl2 (600 mL) was added TFAA (37.0
mL, 262 mmol) in dry CH2Cl2 (60 mL) over a period of 3 h at 0 oC. The reaction mixture was kept at rt for
16 h, then poured onto ice (200 g) and stirred for 1 h. The organic phase was separated, washed with H2O
(3x100 mL) and dried (MgSO4). The dry solution was rotary evaporated and the oily residue (25 g) was
purified by flash-cromatography with hexane:ethyl acetate (5:1) to give 21.6 g (87%) of pure 7b as a pale
yellow oil. 1H NMR (CDCl3) δ: 2.75 (s, 3H), 3.1-3.30 (m, 4H), 3.33 (s, 6H), 3.70 (d, 2H, J=5.6 Hz), 4.33
13
(s, 2H), 4.63 (t, 1H, J=5.6 Hz), 7,24 (s, 5H), 7.35 (s, 4H). C NMR (CDCl3) δ: 29.07; 34.24; 51.31;
52.60; 53.75; 53.76; 100.31; 116.24 (q, J=287 Hz); 128.05; 128.28; 128.76; 128.83; 129.21; 135.67;
138.25; 139.26; 157.28 (q, J=7.5 Hz). IR (film): 1698, 1332, 1205, 1153 cm-1. HRMS (M+) calcd for
C22H27N2O5F3S 488.1593; found: 488.1597.
2-(1H-Indol-5-yl)ethanesulfonic acid (8a)
o
To dry chlorobenzene (50 mL), well stirred and kept at 115-120 C, were added 2-{4-[(2,2-
dimethoxyethyl)-(2,2,2-trifluoroacetyl)amino]phenyl}ethanesulfonic acid isopropyl ester (7a) (0.8 g, 1.87
mmol) in chlorobenzene (8 mL) and TiCl4 (0.6 mL, 5.5 mmol) in chlorobenzene (4 mL) simultaneously
over a period of 10 min. The reaction mixture was stirred at 125-130 oC for additional 25 min then cooled
fast to rt with icy water and poured into the mixture of ice (25 g) and NaHCO3 (6 g). The aqueous phase
was separated, evaporated to dryeness and extracted with MeOH (2x40 mL). Evaporation of MeOH gave
1
2.2 g brown solid the H NMR spectrum of which showed that of 8a. Attempts to separate 8a from
inorganic materials were unsuccessful. 1H NMR (D2O) δ : 3.15-3.65 (m, 4H), 6.55 (d, 1H, J=3 Hz), 7.21 (d,
1H, J=8.7 Hz), 7,40 (d, 1H, J=3 Hz), 7.52 (d, 1H, J=8.7 Hz), 7.60 (s, 1H).
2-[1-(2,2,2-Trifluoroacetyl)-1H-indol-5-yl]ethanesulfonic acid benzylmethylamide (8b)
o
To dry chlorobenzene (150 mL), well stirred and kept at 100-105 C, were added N-{4-[2-
(benzylmethylsulfamoyl)ethyl]phenyl}-N-(2,2-dimethoxyethyl)-2,2,2-trifluoroacetamide (7b) (14 g, 28.6

mmol) in chlorobenzene (105 mL) and TiCl4 (8.4 mL, 76.6 mmol) in chlorobenzene (55 mL)
o
simultaneously over a period of 8 min. The reaction mixture was stirred at 105-110 C for additional 9
min then cooled fast to 60 oC with icy water and poured onto the mixture of ice (150 g) and NaHCO3 (60 g).
The organic phase was separated, the aqueous phase extracted with CH2Cl2 (2x60 mL), and the combined
organic phases dried (MgSO4). The solvents were evaporated (high vacuum) to give a brown crystalline
o
1
mass recrystallised from CH2Cl2 to give 6.2 g (51%) of pure 8b, mp 106-110 C. H NMR: (CDCl3) δ:
2.78 (s, 3H), 3.25 (s, 4H), 4.35 (s, 2H), 6.73 (d, 1H, J=4 Hz), 7.25 (m, 1H), 7.32 (s, 5H), 7.43 (s, 1H),
7.51 (m, 1H), 8.38 (d,1H, J=8.8 Hz). 13C NMR (CDCl3) δ: 29.48; 34.32; 52.00; 53.83; 112.27; 119.20 (q,
J=274 Hz); 117.13; 121.06; 124.52; 124.59; 126.44; 128.06; 128.30; 128.46; 130.89; 134.73; 135.70,
153.00 (q, J=8.5 Hz). IR (KBr): 1723, 1166, 1147 cm-1. Anal. Calcd for C20H19N2O3F3S: C, 56.60; H,
4.51; N, 6.60; S, 7.55. Found: C, 56.44; H, 4.37; N, 6.65; S, 7.43.
2-(1H-Indol-5-yl)ethanesulfonic acid benzylmethylamide (9)
To the solution of KOH (4.0g, 71 mmol) in MeOH (200 mL) was added 2-[1-(2,2,2-trifluoroacetyl)-1H-
indol-5-yl]ethanesulfonic acid benzylmethylamide (8b) (4.5 g, 10.6 mmol) at rt. After standing for 2 h the
pH was adjusted to 7 (10% aq. HCl solution), the inorganic salt separated was filtered off, and the filtrate
was evaporated to dryeness. The product was extracted with CH2Cl2 (80 mL) and isolated by evaporation
o
1
of the solvent to give 2.9 g (84%) of 9, mp 70-72 C (ethyl acetate). H NMR: (CDCl3) δ: 2.78 (s, 3H),
3.25 (m, 4H), 4.33 (s, 2H), 6.51 (s, 1H), 7.02 (d, 1H, J=8.3 Hz), 7.21 (m, 1H), 7.38 (s, 6H), 7.49 (s, 1H),
8.22 (br s, 1H). 13C NMR (CDCl3) δ: 29.00; 34.31; 51.57; 53.82; 120.94; 127.95; 128.08; 128.31; 128.78;
129.19; 129.34; 129.53; 133.50, 135.71, 136.36. IR (KBr): 3320, 1732, 1329, 1145 cm-1. Anal. Calcd for
C18H20N2O2S: C, 65.83; H, 6.14; N, 8.53; S, 9.76. Found: C, 65.76; H, 6.12; N, 8.37; S, 9.66.
2-[3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]ethanesulfonic acid benzylmethylamide
(10)
To the solution of 2-(1H-indol-5-yl)ethanesulfonic acid benzylmethylamide (9) (2.0 g, 6.09 mmol) in
MeOH (70 mL) was added KOH (6.7 g, 120 mmol) followed by N-methyl-4-piperidone (2.3 mL, 19.7
o
mmol). The reaction mixture was refluxed under argon for 8 h, then cooled to 0 C. After standing for a
o
few hours at 0 C, the product was filtered, washed with cold MeOH to give 2.13 (83%) of pure 10, mp
o
1
188-190 C (ethanol). H NMR: (CDCl3) δ: 1.65 (s, 2H), 2.43 (s, 3H), 2.60 (m, 1H), 2.70 (m, 1H), 2.78
(s, 3H), 3.19 (m, 2H); 3.24 (m, 4H), 4.33 (s, 2H), 6.15 (s, 1H), 7.02 (d, 1H, J=8.8 Hz), 7.14 (s, 1H),
13
7.35 (m, 6H), 7.71 (s, 1H), 8.23 (s, 1H). C NMR (CDCl3) δ: 28.54; 29.79; 34.16; 45.44; 52.09; 52.61;
53.74; 54.57; 111.85; 116.71; 117.84; 119.88; 122.28; 122.42; 125.33; 127.92; 128.19; 128.66; 129.09;

129.54; 135.74; 135.89. IR (KBr): 1338, 1147 cm-1. Anal. Calcd for C24H29N3O2S: C, 68.05, H, 6.90, N,
9.92, S, 7.57. Found: C, 67.96; H, 6.82; N, 9.73; S, 7.51.
2-[3-(1-Methylpiperidin-4-yl)-1H-indol-5-yl]ethanesulfonic acid benzylmethylamide (11)
2-[3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]ethanesulfonic acid benzylmethylamide (10)
(0.635 g, 1.5 mmol) was hydrogenated in MeOH (15 mL) with 10% Pd/C (0.13 g) at rt and 5 bar for 6 h.
The reaction mixture was filtered and the catalyst washed with CH2Cl2 (10 mL).The combined solutions
were rotary evaporated to give 0.54 g (85 %) of 11 as a white powder, mp 66-67 oC (ethanol). 1H NMR:
(CDCl3) δ: 1.92 (m, 2H); 2.05 (d, 2H, J=9.3 Hz); 2.24 (t, 2H, J=10.9 Hz); 2.40 (s, 3H); 2.78 (s, 3H); 2.78
(m, 1H); 3.06 (d, 2H, J=9.8 Hz); 3.26 (d, 4H, J=11.4 Hz); 4.33 (s, 2H); 6.96 (m, 2H); 7.34 (m, 6H); 7.44
13
(s, 1H); 8.73 (s, 1H). C NMR (CDCl3) δ: 29.70; 32.58; 34.21; 46.10; 52.66; 53.74; 56.08; 111.66;
118.38; 120.39; 120.65; 122.15; 126.85; 127.85; 128.17; 128.37; 128.62; 135.41; 135.83. IR (KBr): 3397,
1332, 1150 cm-1. Anal. Calcd for C24H31N3O2S: C, 67.73; H, 7.34; N, 9.87; S 7.53. Found: C, 67.35; H,
7.24; N, 9.61; S, 7.42.
2-[3-(1-Methylpiperidin-4-yl)-1H-indol-5-yl]ethanesulfonic acid methylamide (2, Naratriptan)
To the stirring solution of 2-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]ethanesulfonic acid
benzylmethylamide (11) (0.426 g, 1 mmol) in liquid NH3 (50 mL) and THF (9 mL) was added sodium
(0.14 g, 6.1 mmol) at -78 oC over a period of 15 min and stirred for additional 0.5 h. Aqueous NH4Cl (3 g,
o
in 10 mL of H2O) was added at -78 C and the reaction mixture was allowed to reach rt. The aqueous
phase was extracted with CH2Cl2 (3x15 mL) the combined organic phases were dried and evaporated to
give a solid which, when treated with ethyl acetate, yielded 0.27 g (80%) of 2, indentical with naratriptan3
in all respect.
2-Hydroxy-2-(4-nitrophenyl)ethanesulfonic acid benzylmethylamide (14)
To the solution of N-benzyl-N-methylmethanesulfonamide (13, 1.7 g, 8.5 mmol) in dry THF (60 mL) was
o
added n-BuLi solution (7.0 mL, 11.6 mmol, 1.6 M in hexanes) at -78 C and the reaction mixture was
stirred at this temperature for 0.5 h. 4-Nitrobenzaldehyde (1.4 g, 9.3 mmol) was added to the solution over
a period of 2-3 min and stirred for an additional 4 h at -78 oC. The reaction mixture, while kept at the same
temperature, was poured into aqueous NH4Cl solution (5 g in 30 mL of H2O). The dark-red mixture was
allowed to warm to rt, the organic phase was separated, and the aqueous phase was extracted with CHCl3
(30 mL). The combined organic phases were dried (MgSO4) and evaporated to give a red oil (3.0 g,
100%) which slowly crystallises, mp 73-75 oC (hexane-ethyl acetate). 1H NMR (CDCl3) δ: 2.84 (s, 3 H),
3.18 (m, 2H), 3.84 (d, 1H, J=2 Hz); 4.38 (s, 2H); 5.43 (m, 1H), 7.35 (s, 5H), 7.56 (d, 2H, J=8.7 Hz), 8.22

13
(d, 2H, J=8.7 Hz). C NMR (CDCl3) δ: 34.32; 53.85; 57.70; 68.20; 123.94; 126.63; 128.26; 128.34;
128.87; 135.22; 147.62; 148.26. IR (KBr): 3464, 1520, 1349, 1147 cm-1. Anal. Calcd for C16H18N2O5S: C,
54.85; H, 5.18; N, 7.99; S, 9.15. Found: C, 54.78; H, 5.22; N, 7.99; S, 9.06.
2-(4-Nitrophenyl)ethenesulfonic acid benzylmethylamide (15).
a.) To the solution of 2-hydroxy-2-(4-nitrophenyl)ethanesulfonic acid benzylmethylamide (14) (3.0 g, 8.5
mmol) in CH2Cl2 (30 mL)) was added triethylamine (1.5 mL, 10.7 mmol) at 0 oC in one portion followed
by methanesulfonyl chloride (0.84 mL, 10.5 mmol) in CH2Cl2 (6 mL) over a period of 10 min at 0 oC. The
o
reaction mixture was kept at 5 C for 24 h then rotary evaporated to dryeness. The oily residue was
dissolved in CH2Cl2 (30 mL) and stirred with 10% aqueous K2CO3 solution (10 mL) for 15 min. The
o
organic layer was separated and evaporated to dryeness to give 2.4 g (85%) of 15, mp 120-122 C
1
(ethanol). H NMR (CDCl3) δ: 2.78 (s, 3H), 4.32 (s, 2H), 6.79 (d, 1H, J=15.2 Hz), 7.32 (s, 5H), 7.49 (d,
13
1H, J=15.2 Hz), 6.60 (d, 2H, J=8.7 Hz), 8.23 (d, 2H, J=8.7 Hz). C NMR (CDCl3) δ: 34.31; 53.92;
124.29; 127.07; 128.17; 128.45; 128.79; 128.89; 135.38; 138.76; 139.20; 148.70. IR (KBr):1518, 1350,
1146 cm-1. Anal. Calcd for C16H16N2O4S: C, 57.82; H, 4.85; N, 8.43; S, 9.65. Found: C, 57.35; H, 4.86;
N, 8.36; S, 9.52.
b.) To the suspension of 2-(4-nitrophenyl)ethenesulfonyl chloride (20) (4.8 g, 19.4 mmol) in benzene (40
mL)
was added the mixture of N-methyl-N-benzylamine (3 mL, 23.5 mmol) and triethylamine (4.2 mL, 30
mmol) at 0 oC over a period of 2 h. The reaction mixture was allowed to reach rt then stirred for additional
3 h. The precipitated material was filtered off, washed with H2O to give 3.5 g (54%) of 15 identical with
the compound described previously. Additional 1.70 g product can be obtained by evaporation of the
benzene filtrate to dryeness and washing the solid residue with H2O and cold MeOH. The combined yield
is 80%.
2-Hydroxy-2-(4-nitrophenyl)ethanesulfonic acid isopropyl ester (17).
To the solution of t-BuOK (35 g, 312 mmol) in dry THF (650 mL) was added isopropyl methanesulfonate
(16) (26 g, 188 mmol) at -78 oC in one portion and stirred for 0.5 h at -78 oC. 4-Nitrobenzaldehyde (26 g,
172 mmol) was added to the solution over a period of 2-3 min and stirred for an additional 4 h at -78 oC.
The reaction mixture, while kept at the same temperature, was poured into aqueous NH4Cl solution (120 g
in 300 mL of H2O). The dark-red mixture was warmed to rt, the organic phase separated and rotary
evaporated to give an oil which was dissolved in CHCl3 (300 mL), dried (MgSO4) and evaporated to give
a pale yellow oil which slowly crystallises to give 47 g (86%) of 17, mp 49-51 oC (hexane-ethyl acetate).

1H NMR (CDCl3-DMSO-d6) δ: 0.94 (d, 3 H, J=6 Hz), 1.10 (d, 3H, J=6 Hz), 3.00 (dd, 1 H, J=13.7 Hz,
J=5.4 Hz), 3.22 (dd, 1 H, J=13.4 Hz, J=4.5 Hz), 3.48 (m, 1H, J=6 Hz), 4.92 (m, 1H), 7.52 (d, 2H, J=8.4
13
Hz), 8.06 (d, 2H, J=6 Hz). C NMR (CDCl3) δ: 21.17; 22.83; 58.59; 70.88; 74.73; 123.59; 127.51;
147.36; 149.89. IR (KBr): 3374, 1519, 1352, 1196 cm-1. Anal. Calcd for C11H15NO6S: C, 45.67; H, 5.23;
N, 4.84; S, 11.08. Found: C, 45.21; H, 5.48; N, 4.49; S, 10.70.
2-(4-Nitrophenyl)ethenesulfonic acid isopropyl ester (18).
To the 2-hydroxy-2-(4-nitrophenyl)ethanesulfonic acid isopropyl ester (17) (47.0 g, 162 mmol) in CHCl3
(300 mL) was added triethylamine (29 mL, 207 mmol) during 15 min at 0 oC, followed by methanesulfonyl
o
chloride (16.4 mL, 204 mmol) in CHCl3 (60 mL) over a period of 1 h at 0 C. The reaction mixture was
kept at 5 oC for 24 h then poured onto ice (200 g). The organic phase was washed with H2O (2x100 mL),
then dried (MgSO4) and rotary evaporated. The crystalline residue was washed with cold methanol to give
36.4 g (82%) of 18, mp 68-70 oC (ethyl acetate). 1H NMR (CDCl3) δ: 1.40 (d, 3H, J=6.3 Hz), J=6.3 Hz),
4.90 (m, 1H, J=6.3 Hz), 6.90 (d, 1H, J=16 Hz ), 7.60 (d, 1H, J=16 Hz), 7.65 (d, 2H, J=8.5 Hz), 8.25 (d,
13
2H, J=8.5 Hz). C NMR (CDCl3 ) δ: 22.80; 78.01; 124.15; 126.90; 129.10; 138.05; 140.08, 149.20. IR
(KBr): 1520, 1343, 1171 cm-1. Anal. Calcd for C11H13NO5S: C, 48.70; H, 4.83; N, 5.16; S, 11.82. Found:
C, 47.77; H, 4.88; N, 5.09; S, 11.60.
Sodium 2-(4-nitrophenyl)ethenesulfonate (19)
The solution of 2-(4-nitrophenyl)ethenesulfonic acid isopropyl ester (18), (19 g, 69 mmol) and NaI.2 H2O
(12.8 g, 69 mmol) in acetone (280 mL) was refluxed for 6 h, then allowed to cool to rt. The product
precipitated was filtered off, and washed with acetone (20 mL) to give 16.6 g of raw 19 used without
further purification. This raw material (1 g) was crystallised from saturated NaCl solution (3.5 mL) to give
pure 19 (0.7 g) identical in all respect with the compound already described.18 1H NMR (D2O) δ: 7.04 (d,
1H, J=15.6 Hz), 7.21 (d, 1H, J=15.6 Hz), 7.55 (d, 2H, J=8 Hz), 8.07 (d, 2H, J=8 Hz).
2-(4-Nitrophenyl)ethenesulfonyl chloride (20)
To the suspension of sodium 2-(4-nitrophenyl)ethenesulfonate (19) (5.0 g, 19.7 mmol) in benzene (140
mL) containing dimethylformamide (0.1 mL) was added SOCl2 (6 mL, 82 mmol) and the reaction mixture
was refluxed for 5 h. The solution was evaporated and the crystalline residue (4.5 g) was recrystallised
from diethyl ether to give 20 (3.1 g, 64%) being identical in all respect with the compound already
described.10
2-(4-Nitrophenyl)ethenesulfonic acid methylamide (21) and 2-Methylamino-2-(4-nitrophenyl)ethane-
sulfonic acid methylamide (22)

To the stirring suspension of 2-(4-nitrophenyl)ethenesulfonyl chloride (20) (16.6 g, 67 mmol) in benzene
(200 mL) cooled to 0 oC was added the solution of MeNH2 (23.0 mL, 268 mmol, 36% in H2O) at the same
temperature over a period of 20 min. The reaction mixture was allowed to reach rt and stirred for 3 h. The
reaction mixture was rotary evaporated to dryeness and the residue was washed with H2O (2x100 mL) to
give 13.4 g solid as a 1:1 mixture of 21 and 22 . Recrystallisation of the solid from CHCl3 gave 3.2 g of
o
1
pure 22, and flash chromatography of the mother liquor furnished 1.6 g of pure 21, mp 148-150 C, H
NMR (CDCl3+DMSO-d6) δ: 2.58 (d, 3H, J=4.9 Hz), 7.16 (q, 1H, J=4.9 Hz), 7.21 (d, 1H, J=15.6 Hz),
13
7.40 (d, 1H, J=15.6 Hz), 7.87 (d, 2H, J=8.8 Hz), 8.19 (d, 2H, J=8.8 Hz). C NMR (CDCl3) δ: 28.06,
123.38, 128.86, 129.33, 136.20, 138.22, 148.70. IR (KBr): 3289, 1519, 1348, 1148 cm-1. Anal. Calcd for
C9H10N2O4S: C, 44.62; H, 4.16; N, 11.56; S, 13.24. Found: C, 44.76; H, 4.19; N, 11.54; S, 13.20. 22: mp:
o
128-130 C, 1H NMR (CDCl3+DMSO-d6) δ: 2.17 (s, 3H), 2.68 (s, 3H), 3.13 (dd, 1 H, J=14 Hz, J=3 Hz),
3.33 (dd, 1 H, J=14 Hz, J=10 Hz), 4.27 (dd, 1H, J=3 Hz, J=10 Hz), 7.56 (d, 2H, J=8 Hz), 8.27 (d, 2H,
13
J=8 Hz). C NMR (CDCl3) δ: 28.78; 33.83; 56.47; 59.90; 124.07; 128.15; 147.56; 148.15. IR (KBr):
3307, 1521,1349, 1292. Anal. Calcd for C10H15N3O4S: C, 43.95; H, 5.53; N 15.37; S, 11.73. Found: C,
43.84; H, 5.53; N, 15.17; S, 11.53.
2-(4-Aminophenyl)ethanesulfonic acid (23)
The solution of sodium 2-(4-nitrophenyl)ethenesulfonate (19) (5 g, 19.9 mmol) and KOH (1.2 g, 21.4
mmol) in H2O (150 mL) was hydrogenated with 10% Pd/C (0.6 g) at rt and 1 bar for 48 h. The reaction
mixture was filtered, the solution rotary evaporated to 40 mL of volume and the pH adjusted to 3-4 (10%
aq. HCl). The solid precipitate was filtered off and washed with H2O (10 mL) to give 2.95 g (73.6%) of 23
as inner salt. 1H NMR (D2O) δ: 3.20 (m, 2H), 3.29 (m, 2H), 7.00 (d, 2H, J=8 Hz), 7.32 (d, 2H, J=8 Hz).
13C NMR (D2O) δ: 27.49, 50.63, 114.76, 127.30, 128.29, 142.28. IR (KBr): 3300, 1220, 1130 cm-1. Anal.
Calcd for C8H11NO3S: C, 47.75; H, 5.51; N, 6.96; S, 15.93. Found: C, 47.21; H, 5.53; N, 6.65; S, 15.53.
REFERENCES
1. B. Pete and L. Tőke, Tetrahedron Lett., 2001, 42, 3373.
2. W. Feniuk and P. P. A. Humphrey, Drug Development Research, 1992, 26, 235; S. J. Hopkins, Drug
of Today, 1992, 28, 155.
3. (a) EP 0303507 A2 (Glaxo Group Ltd. GB) [Chem. Abstr., 1989, 111, 57535], (b) WO 95/09166
(Glaxo Group Ltd. GB) [Chem. Abstr., 1995, 123, 143646].
4. J. E. Nordlander, D. B. Catalane, K. D. Kotian, R. M. Stevens, and J. E. Haky, J. Org. Chem., 1981,
46, 778.

5. R. J. Sundberg and J. P. Laurino, J. Org. Chem., 1984, 49, 249.
6. S. M. Bromidge, S. Dabbs, D. T. Davies, D. M. Duckworth, I. T. Forbes, P. Ham, G. E. Jones, F. D.
King, D. V. Saunders, S. Starr, K. M. Thewlis, P. A. Wyman, F. E. Blaney, C. B. Naylor, F. Bailey, T.
P. Blackburn, V. Holland, G. A. Kennett, G. J. Riley, and M. D. Wood, J. Med. Chem., 1998, 41,
1598.
7. J. E. Oliver and A. B. DeMilo, Synthesis, 1975, 321.
8. M. J. Tozer, A. J. A. Woolford, and I. D. Linney, Synlett, 1998, 186.
9. F. G. Bordwell, A. B. Colbert, and B. Alan, J. Am. Chem. Soc., 1946, 68, 1778.
10. W. E. Truce and P. F. Gunberg, J. Am. Chem. Soc., 1950, 72, 2400.
11. P. Wipf, D. C. Aslan, E. C. Southwick, and J. S. Lazo, Bioorganic & Medicinal Chemistry Letters,
2001, 11, 313.
12. B. Musicki and T. S. Widlanski, J. Org. Chem., 1990, 55, 4231.
13. M. Xie and T. S. Widlanski,Tetrahedron Lett., 1996, 37, 4443.
14. Z. Zhong, J. A. Bibbs, W. Yuan, and Chi-H. Wong, J. Am. Chem. Soc., 1991, 113, 2259.
15. M. Hohmann and N. Krause, Chem. Ber., 1995, 128, 851.
16. E. Alonso, D. J. Ramón, and M. Yus, Tetrahedron, 1997, 53, 14355.
17. R. Laughton, Can. J. Chem., 1957, 35, 1319.
18. C. S. Rondestvedt and J. C. Wygant, J. Am. Chem. Soc., 1954, 76, 509.