Synthesis of 5-substituted indole derivatives. Part 3: A facile synthesis of 5-chloromethyl-1H-indole-2-carboxylates: Replacement of sulfonic acid functionality by chlorine

Article abstract of DOI:10.1016/S0040-4039(01)00361-6

Valuable new synthetic intermediates, 5-chloromethyl-1H-indole-2-carboxylates, were prepared by the elimination of SO₂ from 2-ethoxycarbonyl-1H-indole-5-methanesulfonic acids, which are easily accessible by Fischer-type indolization.

Full text of DOI:10.1016/S0040-4039(01)00361-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3373–3375
Synthesis of 5-substituted indole derivatives. Part 3: A facile
synthesis of 5-chloromethyl-1H-indole-2-carboxylates:
†
replacement of sulfonic acid functionality by chlorine
B e´ la Pete* and L a´ szl o´ T o3 ke
Organic Chemical Technology Research Group of the Hungarian Academy of Sciences at the Technical University of Budapest,
H-1521 Budapest, Hungary
Received 13 September 2000; revised 15 February 2001; accepted 28 February 2001
Abstract—Valuable new synthetic intermediates, 5-chloromethyl-1H-indole-2-carboxylates, were prepared by the elimination of
SO from 2-ethoxycarbonyl-1H-indole-5-methanesulfonic acids, which are easily accessible by Fischer-type indolization. © 2001
2
Elsevier Science Ltd. All rights reserved.
The synthesis of functionalized indoles has been of
interest to organic chemists for many years due to the
large number of natural products that contain this
structural element. More importantly, indole-contain-
ing compounds have pronounced effects in many phys-
iological processes, and indoles having 5-HT receptor
activity as agonists or antagonists have aroused con-
siderable synthetic interest during the last decade in
many research groups. Although the 5-indolylcarbinyl
unit is a common structural element of these com-
pounds, their synthesis is carried out in a different way:
the latent 5-substituent had been introduced prior to
the indolization step. This approach is impractical;
instead a common advanced intermediate suitable for
facile derivatization to generate a diverse group of
5-substituted indoles is required. An obvious target to
fulfill these requirements would be the 5-halomethyl in-
doles. In this paper we disclose our results on the
3,4
2
3
Scheme 1.
Keywords: Fischer synthesis; 3,5-disubstituted 2-carboxyindoles; desulfination.
*
Corresponding author.
For Part 2, see Ref. 1.
†
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00361-6

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B. Pete, L. T o3 ke / Tetrahedron Letters 42 (2001) 3373–3375
Scheme 2.
facile synthesis of ethyl 5-chloromethyl-1H-indole-2-
carboxylates 3a–d. The preparation of compounds 3a–d
SO and formation of halides, we recall the thermal
2
12
desulfination of allylic sulfonyl halides. Whether the
displacement of the chlorosulfonyl group of 2a–d by
chloride follows a nucleophilic path or occurs simulta-
neously is not yet clear and needs further investigation.
is based on our observation that the SO H group of the
3
indole-5-methanesulfonic acids 1a–d is easily replaced
by chlorine under the circumstances of the formation of
sulfonyl chlorides (Scheme 1). Such a type of ‘func-
tional group chemistry’ is rare in the literature, and
unprecedented in the chemistry of the indoles. To the
best of our knowledge, only two examples exist where
this type of transformation has been used for prepara-
tive purposes: Barber and co-workers developed a gen-
eral method for the preparation of aryloxymethyl
References
1. Pete, B.; Bitter, I.; Hars a´ nyi, K.; To
3 ke, L. Heterocycles
2000, 53, 665.
2. Xu, Y.-C.; Schaus, J. M.; Walker, C.; Krushinski, J.;
Adham, N.; Zgombick, J. M.; Liang, S. X.; Kohlman, D.
T.; Audia, J. E. J. Med. Chem. 1999, 42, 526.
chlorides from aryloxymethanesulfonates and PCl at
5
5
rt. Moreover, a number of 2-benzimidazolyl chlorides
were prepared in good yields from the corresponding
3. (a) Moloney, G. P.; Robertson, A. D.; Martin, G. R.;
MacLennan, S.; Mathews, N.; Dodsworth, S.; Sang, P.
Y.; Knight, C.; Glen, R. C. J. Med. Chem. 1997, 40,
2
-benzimidazolyl sulfonic acids by treatment with PCl5
6
and POCl3.
2347; (b) Moloney, G. P.; Martin, G. R.; Mathews, N.;
The formation of alkyl chlorides and even alkyl amines
Milne, A.; Hobbs, H.; Dodsworth, S.; Sang, P. Y.;
Knight, C.; Williams, M.; Maxwell, M.; Glen, R. C. J.
Med. Chem. 1999, 42, 2504.
has been observed by the elimination of SO from alkyl
2
7
8
sulfonyl chlorides or sulfonamides, respectively, but
the reactions have not been shown to have any syn-
thetic utility.
4. Chen, C.-yi; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1994, 59,
3738.
The advantages related to our process are obvious: the
sulfo group of 1a–d, as one of the most chemically
5. Barber, H. J.; Fuller, R. F.; Green, M. B.; Zwartouw, H.
9
T. J. Appl. Chem. 1953, 3, 266.
stable, allows for a broad range of transformations of
the indole nucleus. The chloromethyl functionality can
then be introduced under mild conditions.
6. Hinkley, J. M.; Porcari, A. R.; Walker, II, J. A.; Swayze,
E. E.; Townsend, L. B. Synth. Commun. 1998, 28, 1703.
7. (a) McManus, S. P.; Smith, M. R.; Herrmann, F. T.;
Abramovitch, R. A. J. Org. Chem. 1978, 43, 647; (b)
King, J. M.; Khemani, K. C. Can. J. Chem. 1985, 63,
619.
The chloromethyl indoles 3a–d are very reactive com-
10
pounds that easily undergo hydrolysis or alcoholysis
at rt even in the absence of bases (Scheme 2).
8. Takahashi, M.; Muta, S. Synthesis 1997, 866.
9
. General
methanesulfonic acid
procedure
for
1a–d:
(4-Nitrophenyl)-
11
13
Castro and Matassa have already proved that the
-indolylcarbinyl carbon has a high reactivity, similar
was prepared from (4-nitro-
5
phenyl)methyl chloride and Na SO3 and was then
2
to that of the 3-indolylcarbinyl carbon (e.g. in gramine)
by synthesizing the tryptamine 4. This high reactivity
toward nucleophilic substitution is the result of reso-
nance interaction, quite similar to that operating in the
case of the 3-indolylcarbinyl carbon. This type of reso-
reduced using catalytic hydrogenation (Pd/C) to afford
(4-aminophenyl)methanesulfonic acid (62% overall from
(4-nitrophenyl)methyl chloride). The sulfonic acids 1a–
14,15
d
were prepared as sodium salts as follows: first
hydrazones were prepared in the Japp–Klingemann reac-
tion of diazotized (4-aminophenyl)methanesulfonic acid
with the appropriate C–H acids: 1a: ethyl 2-(3-dimethyl-
aminopropyl)oxobutanoate; 1b: ethyl 2-oxo-cyclopen-
tanecarboxylate; 1c: ethyl 2-oxo-cyclohexanecarboxylate;
1d: butylmalonic acid monoethylester. The hydrazones
were then subjected to Fischer-type indolization in
nance stabilization must facilitate the loss of SO from
2
sulfonyl chlorides 2a–d, if elimination proceeds through
an ionic intermediate. Evidence has already been pre-
sented for the intermediacy of an episulfonium ion in
the thermal desulfination of 2-(phenylthio)ethane-
7
a
sulfonyl chloride by McManus et al. The probable
driving force for the loss of SO on attempted chlorina-
AcOH–HCl at rt (1a) or in 80% HCO H (1b–d) at reflux.
2
2
5
tion of aryloxymethanesulfonates is the formation of
Overall yields: 1a: 61%; 1b: 80%; 1c: 76%; 1d: 73%.
+
14,15
14,15
the resonance-stabilized intermediate [ArO ꢀCH ]. On
10. General procedure for 5a–d,
and 6, 7:
The sulfo-
2
the other hand, as a precedent for the concerted loss of
nate salt (1a–d, 1 mmol) was stirred in CHCl3 (30 ml)

B. Pete, L. To
3
ke / Tetrahedron Letters 42 (2001) 3373–3375
3375
containing SOCl (1 ml, 14 mmol) and DMF (0.03 ml), at
J=7 Hz), 4.63 (2H, s), 7.28 (2H, s), 7.60 (1H, s), 8.83
(1H, s). Compound 3c: l 1.30 (3H, t, J=7 Hz), 1.98 (2H,
m), 2.85 (2H, m), 3.05 (2H, m), 4.35 (2H, q, J=7 Hz),
4.62 (2H, s), 7.28 (2H, s), 7.53 (1H, s), 8.88 (1H, s).
Compound 3d: l 0.89 (3H, t, J=5 Hz), 1.33 (3H, t, J=7
Hz), 1.60 (2H, m), 2.97 (2H, m), 4.30 (2H, q, J=7 Hz),
4.65 (2H, s), 7.27 (2H, s), 7.58 (1H, s), 8.90 (1H, s).
Compound 5a: l 1.44 (3H, t, J=7 Hz), 2.95 (6H, s), 3.22
(2H, m), 3.41 (3H, s), 3.66 (2H, m), 4.41 (2H, q, J=7
Hz), 4.55 (2H, s), 7.40 (2H, s), 7.78 (1H, s), 8.92 (1H, s);
mp: 158–160°C (EtOH). Compound 5b: l 1.40 (3H, t,
J=7 Hz), 2.65 (2H, m), 3.38 (3H, s), 3.40 (2H, m), 3.63
(3H, s), 4.40 (2H, q, J=7 Hz), 4.57 (2H, s), 7.32 (2H, m),
7.66 (1H, s), 8.88 (1H, s); mp: 70–72°C (hexane). Com-
pound 5c: l 1.35 (3H, t, J=7 Hz), 2.00 (2H, m), 2.30
(2H, m), 3.09 (2H, m), 3.34 (3H, s), 3.59 (3H, s), 4.34
(2H, q, J=7 Hz), 4.40 (2H, s), 7.25 (2H, m), 7.57 (1H, s),
9.08 (1H, s); mp: 48–50°C (hexane). Compound 5d: l
0.98 (3H, t, J=5 Hz), 1.42 (3H, t, J=7 Hz), 1.69 (2H,
m), 3.07 (2H, m), 3.40 (3H, s), 4.37 (2H, q, J=7 Hz), 4.55
(2H, s), 7.27 (2H, m), 7.64 (1H, s), 9.09 (1H, s); mp:
74–76°C (hexane). Compound 6: l 1.40 (3H, t, J=7 Hz),
2.37 (6H, s), 2.58 (2H, m), 3.30 (2H, m), 4.40 (2H, q,
J=7 Hz), 4.77 (2H, s), 7.35 (2H, s), 7.68 (1H, s), 8.82
(1H, s); mp: 128–130°C (EtOH). Compound 7: l 1.25
(3H, t, J=7 Hz), 1.44 (3H, t, J=7 Hz), 2.89 (3H, s), 2.91
(3H, s), 3.24 (2H, m), 3.54 (2H, q, J=7 Hz), 3.64 (2H,
m), 4.40 (2H, q, J=7 Hz), 4.58 (2H, s), 7.39 (2H, s), 7.77
(1H, s), 9.00 (1H, s); mp: 188–190°C (EtOH).
2
rt for 24 h (3b–d), or at reflux for 4 h (3a) and the
14
solution was evaporated to dryness to give 3a–d. The
solid residue was dissolved in MeOH (5a–d) or aqueous
dioxane (1:1, 6) or EtOH (7). After standing for 3 h at rt,
the solvent was rotary evaporated to give the products.
Overall yields from 1a–d, respectively: 5a (88%), 5b
(
72%), 5c (80%), 5d (66%), 6 (82%), 7 (94%).
1. Castro, J. L.; Matassa, V. G. Tetrahedron Lett. 1993, 34,
705.
1
1
1
1
4
2. King, M. D.; Sue, R. E.; White, R. H.; Young, D. J.
Tetrahedron Lett. 1997, 38, 4493.
3. Macor, J. E.; Blank, D. H.; Post, R. J.; Ryan, K.
Tetrahedron Lett. 1992, 33, 8011.
1
4. Melting points and H NMR data (500 MHz, in D O for
2
compounds 1a–d and CDCl for compounds 3a–d, 5a–d,
3
6
and 7): Compound 1a: l 1.29 (3H, t, J=7 Hz), 2.69
6H, s), 2.8–3.2 (4H, m), 3.96 (2H, s), 4.25 (2H, q, J=7
Hz), 7.22 (1H, d, J=8.5 Hz), 7.33 (1H, d, J=8.5 Hz),
(
7
.62 (1H, s); mp: 280–284°C (H O). Compound 1b: l
2
1
.48 (3H, t, J=7 Hz), 2.66 (2H, m), 3.32 (2H, m), 4.37
(2H, q, J=7 Hz), 4.40 (2H, s), 7.42 (2H, s), 7.73 (1H, s);
mp: 272–276°C (H O). Compound 1c: l 1.53 (3H, t, J=7
2
Hz), 2.04 (2H, m), 2.58 (2H, m), 3.04 (2H, m), 4.43 (2H,
q, J=7 Hz), 4.50 (2H, s), 7.53 (2H, s), 7.78 (1H, s); mp:
2
37–240°C (H O). Compound 1d: l 1.22 (3H, t, J=5
2
Hz), 1.65 (3H, t, J=7 Hz), 1.83 (2H, m), 3.18 (2H, m),
.50 (2H, s), 4.56 (2H, q, J=7 Hz), 7.60 (2H, s), 7.92
4
(
1H, s); mp: 238–242°C (H O). Compound 3a: l 1.40
2
13
(3H, t, J=7 Hz), 2.92 (3H, s), 2.95 (3H, s), 3.20 (2H, m),
15. C NMR was used for the structure elucidation of
compounds 1a–d, and 5a–d, 6 and 7, and low-resolution
MS for compounds 5a–d, 6 and 7. IR also confirmed the
3
.65 (2H, m), 4.42 (2H, q, J=7 Hz), 4.72 (2H, s), 7.40
(
(
2H, s), 7.88 (1H, s), 9.18 (1H, s). Compound 3b: l 1.32
3H, t, J=7 Hz), 3.16 (2H, m), 3.35 (2H, m), 4.32 (2H, q,
loss of the SO group in all cases.
3
.
.