72 J. CHEM.

RESEARCH (S), 2003

SHORT PAPER J. Chem. Research (S),

2003, 72-74

Electrophilic substitution reactions of indoles with

carbonyl compounds using ceric ammonium nitrate:
A novel and efficient method for the synthesis of
di- and tri-indolylmethanes1,†
C. Ramesh, N. Ravindranath and Biswanath Das*
Organic Chemistry Division - I, Indian Institute of Chemical Technology, Hyderabad - 500 007,
India

Ceric ammonium nitrate (CAN) is used to catalyse the electrophilic substitution reactions of indoles with carbonyl
compounds at room temperature to produce di- and tri-indolylmethanes in high yields.

Keywords: indoles, carbonyl compounds, ceric ammonium nitrate, di- and tri-indolylmethanes

Indoles are familiar for their manifold biological activity. In conclusion: we have developed a simple, novel and
They possess cytotoxic, antibacterial, antioxidative and insec- highly efficient method for electrophilic substitution reactions
ticidal properties.2 Some indole compounds are used as anti- of indoles with carbonyl compounds to produce di- and tri-
biotics.2b Different derivatives of indole have been synthesised indolylmethanes by use of CAN as catalyst. The short reaction
to study their bioactivity. Di- and tri-indolylmethanes are well time, high yields, ready availability of the catalyst and mild
known amongst these compounds, and the electrophilic sub- experimental conditions are the main advantages of the pre-
stitution reaction of indoles with carbonyl compounds is an sent procedure. CAN has been used as a versatile reagent in
important method for their preparation. Both protic2a,3 and modern chemical synthesis8. However, to our knowledge, this
Lewis4 acids are known to catalyse these reactions. However, is the first report of its application to electrophilic substitution
low yields, long reaction times and complex reaction mixtures reactions of indoles with carbonyl compounds.
are the drawbacks of using of some of the reported acids.
Protic acids (e.g. HCl, H2SO4) and Lewis acids (e.g. BBr3,
Experimental
BF3) which are generally used are hazardous and difficult to
handle. The Lewis acids are also deactivated by nitrogen-con- Melting points were measured in a Buchi-510 apparatus. 1H-NMR
spectra were recorded on a Varian Gemini 200 MHz spectrometer
taining reagents. Some of the acids may even decompose the using TMS as internal standard, IR spectra on a Nicolet 740 FTIR
starting indoles. Lanthanide triflates5 and lithium perchlorate6 spectrophotometer, and mass spectra (EIMS) on a VG Micromass
have also been used, but these compounds are not common 7070H (70 eV).
bench reagents and not easily available. Reaction of indoles with carbonyl compounds in presence of CAN
The electrophilic substitution of indoles with carbonyl com- To a stirred solution of the carbonyl compound (1 mmol) and indole
pounds in presence of protic and Lewis acids follows a gen- (2 mmol) in acetonitrile (5 ml) under N2 atmosphere CAN (0.3 mmol)
eral mechanism. The catalyst activates the carbonyl group by was added. Stirring was continued at room temperature and the reac-
tion was monitored by TLC. On completion, the solvent was removed
attracting the lone pair of electrons of oxygen so that the bond
and the mixture was extracted with EtOAc (3 × 10 ml). The concen-
formation at C-3 of indoles with the carbonyl group is trated extract was subjected to column chromatography over silica gel
favoured. We have recently discovered that ceric ammonium and the product di/tri–indolylmethane was eluted with hexane -
nitrate (CAN) is a novel and efficient catalyst for the prepara- EtOAc (4 : 1).
tion of di- and tri-indolylmethanes by electrophilic reactions Spectroscopic and analytical data of the novel di- and tri-indolyl-
of indoles with aldehydes and ketones (Scheme 1 and Table methanes:
1). CAN is a mild oxidising agent.7 It is readily available and Compound 4: m.p.122–124 °C. 1H NMR (CDCl3 + DMSO-d6): δ
easy to handle. Indoles when reacted with 3-formylindole in = 5.68 (s, 1H, >CH-) 6.62 (d, 4H, J = 8.2 Hz), 6.83 (t, 2H, J = 8.1
Hz), 7.02 (t, 2H, J = 8.1 Hz), 7.08 (d, 2H, J = 2.4 Hz), 7.28 (d, 4H, J
presence of CAN produced tri-indolylmethanes while other = 8.2Hz), 8.71 (brs, OH), 10.24 (brs, 2H, NH). EIMS: m/z (%): 338
carbonyl compounds yielded di-indolylmethanes. The reac- (100 M+.), 337 (40), 245 (50), 222 (35), 116 (20), 93 (10). IR (KBr):
tions proceed at room temperature to afford the products in νmax 3430, 3150, 2970, 1610, 1560, 1070, 1015, 760 cm-1. Anal.
high yields in short reaction times. The time required for the Calcd for C23H18N2O (338.41): C, 81.63; H, 5.36; N, 8.28. Found: C,
preparation of the tris-indolylmethanes is longer than that 81.53; H, 5.21; N, 8.29.
required for the di-indolylmethanes. The assigned structures Compound 7: m.p. 226–228 °C. 1H NMR (CDCl3 + DMSO-d6): δ
of all the prepared compounds were consistent with their spec- = 5.99 (s, 1H, >CH-), 6.71 (d, 2H, J = 2.3 Hz), 6.92 (t, 2H, J = 8.1
tral data.6 Hz), 7.08 (t, 2H, J = 8.1 Hz), 7.29 (t, 2H, J = 8.2 Hz), 7.41 (t, 2H, J
= 8.1 Hz), 7.57 (d, 2H, J = 8.2 Hz), 8.12 (d, 2H, J = 8.2 Hz), 10.18
(br s, 2H, NH). EIMS: m/z (%): 367 (100, M+.), 366 (20), 245 (60),
251 (25), 204 (12), 160 (8), 122 (15), 116 (10), 97 (20). IR (KBr):
νmax 3440, 3120, 2990, 1620, 1490, 1240, 1015, 760 cm-1. Anal.
Calcd for C23H17N3O2 (367.41): C, 75.19; H, 4.66; N, 11.43. Found:
C, 75.06; H, 4.42; N, 11.21.
Compound 11: m.p. 245-247 °C. 1H NMR (CDCl3 + DMSO-d6):
δ 6.41 (s, 1H, >CH-), 6.69 (d, 3H, J = 2.4 Hz), 6.82 (t, 3H, J = 8.0
Scheme 1
Hz), 6.98 (t, 3H, J = 8.0 Hz), 7.24 (d, 3H, J = 8.0 Hz), 7.39 (d, 3H, J
= 8.0 Hz) ,9.89 (brs, 3H, NH). EIMS m/z (%): 361 (100, M+.), 360
(48), 243 (52), 216 (5), 117 (5). I.R. (KBr): νmax 3430, 3400, 2970,
* To receive any correspondence. E-mail: [email protected] 1620, 1470, 1335, 1030, 740 cm-1. Anal. Calcd for C25H19N3
† This is a Short Paper, there is therefore no corresponding material in (361.44): C, 83.11; H, 5.25; N, 11.63. Found: C, 83.03; H, 5.39; N,
J Chem. Research (M). 11.93.
 J. CHEM. RESEARCH (S), 2003 73

Table 1 CAN catalysed synthesis of di-and tri-indolylmethanes

Entry Indole Carbonyl Time Isolated M.p./°C
compound /h yields /% (reported)

1 0.5 89 90–91
(88–906)

2 0.5 91 96–97
(95–976)

3 0.5 90 197–198
(198–2006)

4 0.5 92 122–124

5 0.5 91 97–98
(97–996)

6 0.5 84 99–101
(98–1006)

7 0.5 81 222–228

8 0.5 94 167–168
(164–1659)

9 0.75 81 120–121
(118–1206)

10 0.5 85 190–192
(191–1939)

11 1.5 82 245–247

12 1.5 86 273–275
74 J. CHEM. RESEARCH (S), 2003

Compound 12: m.p:273–275 °C. 1H NMR (200 MHz, CDCl3 + Rep. 2000, 17, 175; (c) S. Hibino, and T. Choshi; Nat. Prod. Rep.,
DMSO-d6): δ 2.12 (s, 6H, 2 × Me), 6.09 (s, 1H, >CH-), 6.68 (t, 3H, J 2001, 18, 66.
= 8.1 Hz), 6.87 (t, 3H, J = 8.1 Hz), 6.98-7.32 (m, 7H), 9.86 (br s, 2H, 3 (a) B. Gregorovich, K. Liang, D. Chegston and S. MacDonald;
-NH-), 9.98 (brs,1H, NH). EIMS: m/z (%): 389 (100 M+.), 388 (35), Can. J. Chem., 1968, 46, 3291; (b) M. Roomi and S. MacDonald;
374 (70), 257 (80), 130 (50), 117 (20), 77 (25), 43(90). I.R. (KBr): Can. J. Chem., 1970, 48, 139.
νmax 3430, 3400, 3050, 2930, 2850, 1450, 1415, 1330, 760 cm-1. 4 (a) W. Wolaned, M. Venkiteswaren and C. Richards; J. Org.
Anal. Calcd for C27H23N3 (389.49): C, 83.26; H, 5.95; N, 10.78. Chem. 1961, 26, 4241; (b) A. Chatterjee, S. Manna, J. Banerji, C.
Found: C, 83.01; H, 5.85; N, 10.93. Pascard, T. Prange and J.N. Shoolery; J. Chem. Soc., Perkin Trans
1, 1980, 553; (c) J. Banerji, A. Chatterjee, S. Manna, C. Pascard,
T. Prange and J.N. Shoolery; Heterocycles 1981, 15, 325. (d) R.
The authors thank UGC, New Delhi for financial assistance. Chakrabarti, B. Das, M. Saha and Banerji J.; Ind. J. Chem., 1990,
29B, 737; (e) A. Chatterjee, R. Chakrabarti, B. Das, S. Kanrar, J.
Received 23 February 2002; accepted 2 July 2002 Banerji, H. Budzikiewicz, A. Newman and T. Prange;
Paper 02/1259 Heterocycles, 1992, 34, 259; (f) G. Babu, N. Sridhar and P.T.
Perumal; Synth. Commun. 2000, 30, 1609.
5 D. Chen, L. Yu and P.G. Wang; Tetrahedron Lett. 1996, 37, 4467.
References 6 J.S. Yadav, B.V. Subba Reddy, C.V.S.R. Murthy, G. Mahesh
1 Part 11 in the series ‘Studies on Novel Synthetic Methodologies’, Kumar and C. Madan ; Synthesis 2001, 783.
for Part 10 see N. Ravindranath, C. Ramesh and B. Das; Synlett, 7 K. Pachamuthu and Y.D. Vankar; J. Org. Chem. 2001, 66, 7511.
2001 1777. IICT Communication No. 4667. 8 R.H. Jih and K.V. King,; Curr. Sci. 2001, 81, 1043.
2 (a) R.J. Sundberg The Chemistry of Indoles, Academic Press: 9 W. Wolaned, M. Venkiteswaren and C. Richards; J. Org. Chem.
New York, 1970; (b) M. Lounasmaa and A. Tolvanen; Nat. Prod. 1961, 26, 4263.