A facile synthesis of 4- and 6-chloromethyl-1H-indole-2-carboxylates: Replacement of a sulfonic acid functionality by chlorine

Article abstract of DOI:10.1016/S0040-4039(03)00327-7

Valuable new synthetic intermediates, 4- or 6-chloromethyl-1H-indole-2-carboxylates, were prepared by the elimination of SO₂ from 2-ethoxycarbonyl-1H-indole-4- or 6-methanesulfonic acids, respectively, which are easily accessible by Fischer-typ

Full text of DOI:10.1016/S0040-4039(03)00327-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2537–2539
A facile synthesis of 4- and
6
-chloromethyl-1H-indole-2-carboxylates: replacement of a
sulfonic acid functionality by chlorine
a,
b
B e´ la Pete * and Gyula Parlagh
a
Research Group of the Hungarian Academy of Sciences, Department of Organic Chemical Technology, Technical University of
Budapest, H-1521 Budapest, Hungary
b
Department of Physical Chemistry, Technical University of Budapest, H-1521 Budapest, Hungary
Received 29 November 2002; revised 21 January 2003; accepted 31 January 2003
Abstract—Valuable new synthetic intermediates, 4- or 6-chloromethyl-1H-indole-2-carboxylates, were prepared by the elimination
of SO from 2-ethoxycarbonyl-1H-indole-4- or 6-methanesulfonic acids, respectively, which are easily accessible by Fischer-type
2
indolization. © 2003 Elsevier Science Ltd. All rights reserved.
The synthesis of highly substituted indoles has been a
goal of organic chemists for many years. The direct
required during the indolization step it is necessary to
utilize fairly robust benzenoid precursors compatible
with the required conditions. Elaboration to the more
reactive functionalities actually found in the targeted
indoles is then often a multistep procedure and ineffi-
cient in yield.
1
introduction of substituents onto the benzene part of an
already constructed indole always raises the question of
appropriate regioselectivity. This is well known from
works dealing with the Friedel–Crafts-type acylation of
2
indoles. In most cases it seems more useful to intro-
duce the desired functionalities prior to the elaboration
of the indole ring. Due to the rather harsh conditions
In this paper we demonstrate that the sulfomethyl
group while being extremely stable as a benzenoid or
Scheme 1.
Keywords: Fischer synthesis; 4-(chloromethyl)indoles; 6-(chloromethyl)indoles; desulfination.
*
Corresponding author.
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00327-7

2
538
B. Pete, G. Parlagh / Tetrahedron Letters 44 (2003) 2537–2539
6
,7
indole substituent, can easily be transformed into a 4-
or 6-chloromethyl group in 2-ethoxycarbonyl-1H-
indole-4- or 6-methanesulfonic acids, respectively. Ear-
NaOAc/AcOH or Me NH/H O
to give 6 and 7,
2
2
respectively (Scheme 1). Compared to ethyl 3-[3-
(chlorocarbonyl)propyl]-5-(chloromethyl)-1H-indole-2-
carboxylate, however, they appear to be less reactive.
With this compound, the stepwise methanolysis of
3
lier we reported that the 2-ethoxycarbonyl-1H-
indole-5-methanesulfonic acids were easily transformed
into 5-chloromethyl-1H-indole-2-carboxylates using
typical conditions for the formation of sulfonyl chlo-
COCl and 5-CH Cl, according to the process 2 to 3,
2
then 4 cannot be carried out as the two groups react
3
rides. It was suggested that a ‘gramine type’ resonance
simultaneously. Although we have only investigated the
8
interaction must facilitate the elimination of SO from
3-carboxypropyl-indoles 1a,b until now, it is apparent
from our previous work on indole-5-methanesulfonic
2
3
the 5-indolylcarbinyl carbon in 2-ethoxycarbonyl-1H-
indole-5-methanesulfonic acids. This was by analogy
acids, that this peculiar behavior of the sulfo group is
not affected by the indole-3-substituent.
with the facile loss of SO from 2-(phenylthio)ethane-
2
4
5
sulfonates or aryloxymethanesulfonates explained by
the intermediacy of episulfonium-, or [ArO ꢀCH ] ions,
+
The regioselective synthesis of 4- or 6-substituted
indoles as reactive synthetic intermediates is an impor-
tant aspect in the chemistry of this heterocycle. Due to
the enormous interest in ergot alkaloids a significant
amount of work has appeared dealing with 3,4-disubsti-
2
respectively. According to this explanation the pre-
ferred compounds that undergo this type of elimination
would be indole-5- and indole-7-methanesulfonic acids.
To prove this mechanism we have synthesized indole-4-
and indole-6-methanesulfonic acids 1a,b with the expec-
tation that they will behave like normal sulfonic acids
yielding sulfonyl chlorides with SOCl2.
9
tuted indoles also present in the antibiotic nosihep-
10
tide. The 4-vinyl-6,7-(dihydroxy)indole-2-carboxylates
are key intermediates for the synthesis of the antitumor
agent CC-1065 and of the inhibitors of cyclic
Suprisingly, we found that 1a,b underwent the same
adenosine-3%,5%-monophosphate
phosphodiesterase
11
type of elimination under the influence of SOCl more
PDE-I and PDE-II. Indoles substituted at the 6-posi-
tion are also important intermediates for the synthesis
of a wide range of indolic alkaloids, such as members
2
readily than the indole-5-methanesulfonic acids, with
concomitant formation of 4- and 6-(chloromethyl)-
indoles (Scheme 1).
12
13
of the neoechinulin and teleocidine families.
The elimination and replacement of the SO group by
The synthesis of indoles 1a,b was accomplished through
Fischer-type indolization of the hydrazone 10 obtained
by the Japp–Klingemann procedure from diazotized
(3-aminophenyl)methanesulfonic acid 8 and ethyl 2-
cyclohexanonecarboxylate 9 (Scheme 2). The Fischer
synthesis starting from meta-substituted phenylhydra-
zones usually leads to the formation of 4- and 6-substi-
tuted indoles. The formation of mixtures of
regioisomers can be avoided by blocking the appropri-
3
chlorine in 1a,b is actually so facile that the SO group
3
may be regarded as a kind of latent chlorine atom.
During chlorination (Scheme 1), the 3-carboxypropyl
groups of 1a,b are transformed to acid chlorides 2a,b
and undergo methanolysis much faster than the
chloromethyl group. The chloromethyl indoles 3a,b are
reactive compounds that easily react with alcohols at rt
even in the absence of base to give 4 and 5; and with
14
Scheme 2.

B. Pete, G. Parlagh / Tetrahedron Letters 44 (2003) 2537–2539
2539
ate ortho-position of the phenylhydrazone with Cl or
5. Barber, H. J.; Fuller, R. F.; Green, M. B.; Zwartouw, H.
T. J. Appl. Chem. 1953, 3, 266.
6. General procedure for 7a or 7b: the appropriate sulfonate
Br which is then removed from the indole by
1
5
hydrogenolysis. In our case the two regioisomeric
indoles 1a,b were produced in a 1:1 ratio and were
easily separated by fractional crystallization from water
in good overall yield (70%) as 1a has much less solubil-
ity in polar solvents than 1b. As the sulfonic acids or
their salts possess very good crystallization properties
the easy separation of the regioisomers is an important
feature of the above process.
salt (1a or 1b, 0.407 g, 0.1 mmol) was stirred in CH
Cl
2
2
(25 ml) containing SOCl (1 ml, 14 mmol) and DMF
2
(0.06 ml) at rt for 4 h and then the solution was evapo-
rated to dryness. The solid residue (2a or 2b) was dis-
solved in MeOH, left for 10 min at rt then rotary
evaporated to give 3a (95%) or 3b (92%) as white crys-
talline solids. The solution of 3a or 3b (0.34 g, 0.1 mmol,
in CH Cl2 (12 ml)) was added dropwise to Me NH
2
2
solution (1 ml, 35% in H O) at 0°C while stirring. After
Another advantage related to our process is that the
sulfo group of 1a,b, as one of the chemically most
stable functional groups, allows for a broad range of
transformations of the indole nucleus. The
chloromethyl functionality can then be introduced
under mild conditions.
2
1
0 min at 0°C the organic phase was separated and
evaporated to dryness to give 7a (88%, mp: 82–83°C) or
b (95%, mp: 92–93°C).
7
1
7
. H NMR data (250 MHz, in CDCl ) for 7a and 7b: 7a: l
3
1
(
(
.40 (3H, t, J=7 Hz), 1.98 (2H, m), 2.24 (6H, s), 2.45
2H, m), 3.36 (2H, m), 3.65 (3H, s), 3.68 (2H, s), 4.39
2H, q, J=7 Hz), 6.96 (1H, d, J=8 Hz), 7.21 (1H, t, J=8
In summary,
chloromethyl)indoles featuring the transformation of
the CH SO H group to CH Cl has been developed. The
a
new synthesis of 4- and 6-
Hz), 7.26 (1H, d, J=8 Hz), 8.78 (1H, s). 7b: l 1.41 (3H,
t, J=7 Hz), 2.01 (2H, m), 2.30 (6H, s), 2.36 (2H, m), 3.14
(
2
3
2
(
2H, m), 3.57 (2H, s), 3.63 (3H, s), 4.39 (2H, q, J=7 Hz),
.09 (1H, d, J=8.3 Hz), 7.35 (1H, s), 7.61 (1H, d, J=8.3
Hz), 8.83 (1H, s).
fact that the position of the sulfomethyl group does not
7
play an important role in the loss of SO suggests that
2
the resonance interaction may not be the governing
factor in this process. To reveal the exact nature, this
desulfination process needs further investigation.
1
13
8
. All compounds were characterized by H, C NMR and
IR spectroscopy. Compounds 3–7 were also identified by
FAB-MS.
9. (a) P e´ rez-Serrano, L.; Casarrubios, L.; Dom ´ı nguez, G.;
Freire, G.; P e´ rez-Castells, J. Tetrahedron 2002, 58, 5407;
(
b) Kozikowski, A. P. Heterocycles 1981, 16, 267.
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