Electrophilic substitution of indoles catalyzed by triphenyl phosphonium perchlorate: Synthesis of 3-acetyl indoles and bis-indolylmethane derivatives

Article abstract of DOI:10.1081/SCC-120001515

Triphenyl phosphonium perchlorate (TPP) is found to catalyze the acetylation of indoles with acetic anhydride to give 3-acetyl indoles. Similarly bis-indolylmethane derivatives were prepared by the electrophilic substitution reaction of indole with substituted benzaldehydes.

Full text of DOI:10.1081/SCC-120001515

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ELECTROPHILIC SUBSTITUTION OF INDOLES
CATALYZED BY TRIPHENYL PHOSPHONIUM
PERCHLORATE: SYNTHESIS OF 3-ACETYL INDOLES
AND BIS-INDOLYLMETHANE DERIVATIVES
a
Rajagopal Nagarajan & Paramasivan T. Perumal
a
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai, 600
020, India
Version of record first published: 21 Aug 2006
To cite this article: Rajagopal Nagarajan & Paramasivan T. Perumal (2002): ELECTROPHILIC SUBSTITUTION OF INDOLES
CATALYZED BY TRIPHENYL PHOSPHONIUM PERCHLORATE: SYNTHESIS OF 3-ACETYL INDOLES AND BIS-INDOLYLMETHANE
DERIVATIVES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 32:1, 105-109
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SYNTHETIC COMMUNICATIONS, 32(1), 105–109 (2002)
ELECTROPHILIC SUBSTITUTION OF
INDOLES CATALYZED BY TRIPHENYL
PHOSPHONIUM PERCHLORATE:
SYNTHESIS OF 3-ACETYL INDOLES AND
BIS-INDOLYLMETHANE DERIVATIVES
Rajagopal Nagarajan andParamasivan T. Perumal *
Organic Chemistry Division, Central Leather
Research Institute, Adyar, Chennai-600 020, India
ABSTRACT
Triphenyl phosphonium perchlorate (TPP) is found to cata-
lyze the acetylation of indoles with acetic anhydride to give 3-
acetyl indoles. Similarly bis-indolylmethane derivatives were
prepared by the electrophilic substitution reaction of indole
with substituted benzaldehydes.
Indole and its derivatives possess a wide range of biological activities
1
and recently the chemistry of indoles was reviewed by Gribble. Acetyl
2
indoles are used as starting material for the synthesis of carbazole, pyrido
3
4
carbazole and carbolines. Several catalysts like Si(O CꢀCH ꢀCH ꢀ
2
2
2
5
COOCH ) /SnCl , HClO , SiCl
6
7
8
and ZnCl have been used for the
2
3
4
2
4
4
9
acetylation of indoles. However the yields are very low. Okauchi et al.
*
Corresponding author. Fax: 91-044-491 1589; E-mail: ptperumal@hotmail.com
05
1
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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1
06
NAGARAJAN AND PERUMAL
reported that the indoles were converted into a metal derivative with
Et AlCl or Me AlCl followed by treatment with acid chlorides to give
acetyl indoles.
2
2
In this paper we wish to report our observation on acetylation of
indoles with triphenyl phosphonium perchlorate (TPP) which is so far not
reported in the literature. Recently we have reported that the TPP effectively
catalyzing the imino Diels-Alder reaction of imines with electron rich die-
1
0
nophiles to give quinoline derivatives in good yields.
To a stirred solution of indole (1a) in excess anhydride, 20 mol%
PPh ꢀHClO was added and stirred for 30 min. After work-up, 3-acetyl
3
4
indole is obtained in 61% yield (Scheme 1). The yields obtained with
other indoles are given in Table 1.
Scheme 1.
The electrophilic substitution of indoles with carbonyl system pro-
duces bis-indolylmethanes. Bis-indolylmethane derivatives affects central
1
1
nervous system and also used as tranquilizers.
12
In the presence of 20 mol% TPP, benzaldehyde 3a was treated with
indole 1a in acetonitrile and stirred at room temperature for 30 min, the
reaction afforded bis-indolylmethane 4a in 66% yield (Scheme 2). The results
obtained with other substituted benzaldehydes are given in Table 2.
Table 1. Synthesis of 3-Acetyl Indoles* Catalyzed by 20 mol% PPh ÁHClO4
3
Substituents
Time in
min
Yield
%
1
2
Sl. No.
R
R
1
2
3
4
H
H
H
CH
H
30
25
25
30
61
50
91
79
3
SO Ph
2
COPh
H
*
The products were characterized by IR, NMR and Mass Spectra.

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ELECTROPHILIC SUBSTITUTION OF INDOLES
107
Scheme 2.
Table 2. Synthesis of bis-Indolylmethanes* Catalyzed by 20 mol% PPh ÁHClO4
3
Substituents
Time in
min
Yield
%
1
2
R
3
R
SL. No.
R
1
2
3
4
H
NO
H
H
H
H
H
H
Cl
30
25
25
30
61
50
91
79
2
H
OH
OCH
3
*
The products were characterized by IR, NMR and Mass Spectra.
In conclusion, we have shown that TPP effectively catalyzes the acet-
ylation of indoles to 3-acetyl indoles as well as catalyzes the reaction of
indole with aromatic aldehydes, leads to bis-indolylmethane derivatives.
The catalyst is mild and cheapwhich has an advantage that only
20 mol% required for the reactions.
TYPICAL EXPERIMENTAL PROCEDURE
Synthesis of 3-Acetyl Indoles
To a stirred solution of indoles 1a–e (2.5 mmol) in acetic anhydride
(
and stirred for appropriate time. After the reaction was over, water (50 mL)
5 mL) protected by guard tube, PPh ꢀHClO (0.181 g, 20 mol%) was added
3
4
was added and stirred for 15–25 min. To this solid NaHCO was added in
3
portions to aid faster precipitation of acetyl indoles and extracted with
CH Cl (3 ꢁ 20 mL). The organic layer was washed with saturated
2
2

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1
08
NAGARAJAN AND PERUMAL
NaHCO (10 mL), brine (10 mL) and dried over anhydrous Na SO , then
3
2
4
concentrated under reduced pressure. The residue was purified by column
chromatography using silica gel (60–120 mesh) and eluted with petroleum
ether–ethyl acetate to afford 3-acetyl indoles. Spectral data for the com-
1
pound 2c: H NMR (CDCl , 300 MHz): d 8.32–7.24 (m, 10H), 2.55 (s, 3H);
3
1
3
C NMR (CDCl , 75 MHz): d 193.4, 137.4, 134.9, 132.7, 131.5, 129.2,
3
1
2
27.9, 126.5, 125.4, 124.3, 123.7, 122.6, 121.8, 113.5, 112.6, 27.9; MS m/z
þ
À1
99 (M ); IR (KBr): 1671, 1378, 1170 cm
.
Synthesis of bis-Indolylmethanes
To a stirred solution of benzaldehyde (1 mmol) and indole 1a (0.234 g,
.0 mmol) in acetonitrile (10 mL) protected by guard tube TPP (0.091 g,
0 mol%) was added and stirred for appropriate time. To the reaction mix-
2
2
ture water (10 mL) was added and extracted with chloroform (3 ꢁ 10 mL).
The combined organic layer was dried over anhydrous Na SO , and then
2
4
concentrated under reduced pressure. The crude product was purified by
column chromatography using silica gel (60–120 mesh) and eluted with pet-
0
roleum ether–ethyl acetate to afford 3,3 -bis-indolylphenylmethane 4a in
1
6
2
1
3
6% yield. H NMR (CDCl , 300 MHz): d 7.59–7.02 (m, 15H), 6.50 (s,
H), 5.90 (s, 1H); C NMR (CDCl , 75 MHz): d 143.9, 136.4, 128.6,
3
1
3
3
28.1, 126.9, 126.0, 123.5, 121.7, 119.8, 119.4, 119.1, 111.0, 40.0; MS m/z
þ
À1
22 (M ); IR (KBr): 3394, 3051, 455, 747 cm
.
REFERENCES
1
2
. Gribble, G.W. J. Chem. Soc., Perkin Trans 1 2000, 1045.
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3
. (a) Gribble, G.W.; Keavy, D.J.; Davis, D.A.; Saulnier, M.G.;
Pelcman, B.; Barden, T.C.; Sibi, M.P.; Olson, E.R.; Belbruno, J.J.
J. Org. Chem. 1992, 57, 5878. (b) Gribble, G.W.; Saulnier, M.G.;
Sibi, M.P.; Obaza-Nutiatits, J.A. J. Org. Chem. 1984, 49, 4518.
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5
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. Markgraf, J.H.; Synder, S.A.; Vosburg, D.A. Tetrahedron 2000, 56,
5329.
. Kost, A.N.; Mitropal’skaya, V.N.; Pornova, S.L.; Krasnova, V.A.
J. Gen. Chem. USSR (English Transl) 1964, 34, 3025.
. Dorofeenko, G.N. Zh. Veses, Khim. Obshehestva im. D.I. Mendeleeva,
1960, 5, 354. Chem. Abstr. 1960, 54, 22563.

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ELECTROPHILIC SUBSTITUTION OF INDOLES
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8
9
. Yur’er, Y.K.; Elyakov, G.B. Zh. Obshch. Kim. 1956, 26, 2350. Chem.
Abstr. 1957, 51, 5042.
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Org. Lett. 2000, 1485.
1
1
1
0. Nagarajan, R.; Chitra, S.; Perumal, P.T. Tetrahedron 2001 (Accepted
for publication).
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Phys. Chem. 1965, 11, 115.
2. Porszasz, J.; Katalin, G.P.; Foleak, S.; Malkovics, B. Acta. Physical.
Acad. Sci. Hunt, 1996, 29, 299.
Received in the Netherlands February 28, 2001

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