A facile synthesis of 3-[(N-alkylanilino)(aryl)methyl]indoles using TCT

Article abstract of DOI:10.1055/s-0029-1218637

Three component reaction of indoles, benzaldehydes, and N-alkylanilines in the presence of 2,4,6-trichloro-1,3,5-triazine (TCT) afforded the corresponding 3-[(N-alkylanilino)(aryl)methyl]indoles at room temperature in high yields (87-95%) within 1 to 2.5 hours. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0029-1218637

914
SHORT PAPER
A Facile Synthesis of 3-[(N-Alkylanilino)(aryl)methyl]indoles Using TCT1
A
F
acile Synthes
i
s
[(
N
-Alkyl
w
anilino)(aryl)meth
a
yl]indole
s
U
n
sing TCT ath Das,* Jayprakash Narayan Kumar, Avula Satya Kumar, Kongara Damodar
Organic Chemistry Division-1, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27193198; E-mail: biswanathdas@yahoo.com
Received 17 November 2009; revised 24 November 2009
Table 1 Synthesis of 3-[(N-Alkylanilino)(aryl)methyl]indoles 1a
Entry R1 R2 R3 R4 Product Time Yieldb
Abstract: Three component reaction of indoles, benzaldehydes,
and N-alkylanilines in the presence of 2,4,6-trichloro-1,3,5-triazine
(TCT) afforded the corresponding 3-[(N-alkylanilino)(aryl)meth-
yl]indoles at room temperature in high yields (87–95%) within 1 to
2.5 hours.
(h)
(%)
87
91
90
94
87
89
90
91
90
95
87
88
1
2
H
H
H
H
H
H
Me 1a
Me 1b
Me 1c
Me 1d
2.5
Key words: 3-[(N-alkylanilino)(aryl)methyl]indoles,
hyde, N-alkylanilines, TCT
benzalde-
4-NO2
3,4-(OMe)2
2.0
3
H
1.75
1.25
1.75
1.75
1.75
2.0
4
H
Me 4-Cl
Indoles possess numerous important biological properties
including antioxidant, antibacterial, and insecticidal activ-
ity;2 they act as colon cancer cell and tumor growth inhib-
itors;3 and they are employed as valuable antibiotics.2a
Some of indole derivatives occur in bioactive metabolites
of terrestrial and marine organisms.4 Among various de-
rivatives of indoles, 3-substituted indoles have been much
studied and several synthetic methods have been devel-
oped for the preparation of these compounds.2a,5 Here we
report a convenient method for the synthesis of 3-[(N-
alkylanilino)(aryl)methyl]indoles starting from indole de-
rivatives using 2,4,6-trichloro-1,3,5-triazine (TCT).
In continuation of our work6 on the development of useful
synthetic methods, we observed that the treatment of in-
doles with benzaldehydes and N-alkylanilines in acetoni-
trile in the presence of TCT afforded the corresponding 3-
[(N-alkylanilino)(aryl)methyl]indoles 1 at room tempera-
ture (Scheme 1).
5
H
H
H
H
H
H
H
H
H
3,4,5-(OMe)3 Me 1e
3,4,5-(OMe)3 Me 1f
6
Br
Br
Br
H
7
3,4-(OMe)2
4-NO2
Me 1g
Me 1h
8
9
3,4-(OMe)2
4-NO2
Et
Et
Pr
Pr
1i
2.0
10
11
12
H
1j
1k
1l
1.0
H
3,4-(OMe)2
3-OH
2.0
H
2.0
a The structures of the products were determined from their spectral
(IR, 1H and 13C NMR, and MS) and analytical data.
b Yields of pure isolated products after column chromatography.
hydes containing both electron-donating and electron-
withdrawing groups were used, and different N-alkyl-
anilines, such as N-methyl-, N-ethyl-, and N-propyl-
anilines, afforded the desired products in high yields. The
N-alkylanilines were used in excess to avoid the formation
of bis(indolyl)alkanes. Various functional groups such as
halogen, hydroxy, ether, and nitro groups remain intact.
The structures of the products were confirmed from their
A series of 3-[(N-alkylanilino)(aryl)methyl]indoles 1a–l
were conveniently prepared using different indoles, benz-
aldehydes, and N-alkyl anilines following the above meth-
od (Table 1). The conversion was completed within 1–2.5
hours and the products were formed in high yields (87–
95%). 1H-Indole, 5-bromo-1H-indole, and 2-methyl-1H-
indole were employed as the indole derivative, benzalde-
R3
NHR4
CHO
R1
TCT
MeCN
R1
N
R2
R4
+
+
r. t., 1–2.5 h
87–95%
N
H
R3
R2
N
H
1
Scheme 1
SYNTHESIS 2010, No. 6, pp 0914–0916
x
x
.
x
x
.2
0
1
0
Advanced online publication: 08.01.2010
DOI: 10.1055/s-0029-1218637; Art ID: Z24409SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
A Facile Synthesis of 3-[(N-Alkylanilino)(aryl)methyl]indoles Using TCT
915
1H NMR (200 MHz, CDCl3): d = 7.82 (br s, 1 H), 7.31–7.13 (m, 3
H), 7.11 (t, J = 8.0 Hz, 1 H), 7.01–6.84 (m, 3 H), 6.75–6.60 (m, 3
H), 6.52–6.41 (m, 3 H), 5.42 (s, 1 H), 3.82 (s, 3 H), 3.71 (s, 3 H),
2.82 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 152.9, 151.7, 148.0, 147.4, 137.9,
133.3, 130.1, 130.0, 124.2, 122.1, 121.0, 119.9, 119.2, 112.2, 111.0,
110.9, 56.0, 47.5, 29.8.
spectral (IR, 1H and 13C NMR, and MS) and analytical da-
ta.
TCT is an inexpensive reagent. It reacts7 with ‘incipient
moisture’ and releases HCl which can catalyze the present
conversion. The reagent is easy to handle and is safe com-
pared to concentrated hydrochloric acid. Initially the
benzaldehyde reacts with an N-alkylaniline to form the
corresponding aldimine, which is then attacked by the in-
dole in the presence of HCl to form the 3-[(N-alkylanili-
no)(aryl)methyl]indole (Scheme 2). The conversion did
not proceed under perfectly dry reaction conditions. Thus,
the experimental procedure becomes simple. Cyanuric
acid formed from TCT was washed out with water.
MS (ESI): m/z = 373 [M + H]+.
Anal. Calcd for C24H24N2O2: C, 77.42; H, 6.45; N, 7.53. Found: C,
77.58; H, 6.38; N, 7.61.
3-[(4-Chlorophenyl)(N-methylanilino)methyl]-2-methyl-1H-in-
dole (1d)
Violet solid; yield: 338 mg (94%).
IR (KBr): 3401, 1685, 1613, 1519, 1487 cm–1.
OH
1H NMR (200 MHz, CDCl3): d = 7.69 (br s, 1 H), 7.21–6.80 (m, 11
Cl
H), 6.48 (d, J = 8.0 Hz, 2 H), 5.56 (s, 1 H), 2.81 (s, 3 H), 2.03 (s, 3
N
N
N
N
+
H2O
+
H).
HCl
HO
N
OH
13C NMR (50 MHz, CDCl3): d = 147.5, 144.2, 135.4, 132.2, 132.0,
130.1, 130.0, 129.5, 126.6, 121.0, 120.0, 119.9, 113.4, 111.1, 46.5,
30.8, 29.5.
Cl
N
Cl
MS (ESI): m/z = 361, 363 [M + H]+.
R
••
N
Anal. Calcd for C23H21ClN2: C, 76.56; H, 5.83; N, 7.77. Found: C,
76.68; H, 5.74; N, 7.82.
H
H
Ar1CHO
Ar2N CH
Ar1
1
Ar2NHR
+
3-[(N-Methylanilino)(3,4,5-trimethoxyphenyl)methyl]-1H-in-
dole (1e)
Light red solid; yield: 350 mg (87%).
Scheme 2
IR (KBr): 3407, 1591, 1509, 1457, 1420 cm–1.
In conclusion, we have developed a simple and efficient
method for the high-yielding synthesis of 3-[(N-alkyl-
anilino)(aryl)methyl]indoles by treatment of indoles,
benzaldehydes, and N-alkylanilines in the presence of
TCT at room temperature.
1H NMR (200 MHz, CDCl3): d = 7.87 (br s, 1 H), 7.30–7.09 (m, 4
H), 7.01–6.90 (m, 3 H), 6.51 (br s, 1 H), 6.48 (d, J = 8.0 Hz, 2 H),
6.39 (s, 2 H), 5.44 (s, 1 H), 3.80 (s, 3 H), 3.68 (s, 6 H), 2.81 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 152.8, 148.7, 140.2, 132.1, 129.9,
126.7, 124.3, 121.8, 119.9, 119.8, 119.1, 112.7, 111.1, 106.0, 61.1,
56.0, 48.5, 29.6.
Infrared spectra were recorded using a Perkin-Elmer RX1 FT-IR
spectrophotometer. 1H and 13C NMR spectra were obtained at 200
MHz and 50 MHz, respectively, using a Varian Gemini 200 MHz
spectrometer and CDCl3 as the solvent. Mass spectra (ESI-MS)
were recorded using an LC-MSD Trap SL spectrometer. Elemental
analyses were performed with an Elementar Vario EL instrument.
Column chromatography was carried out over silica gel (BDH 100–
200 mesh) and TLC was performed using silica gel GF254 (Merck)
plates. The spectral and analytical data of unknown compounds 1c–
l are given. All known compounds had spectroscopic data identical
to the literature values, 1a,5e 1b.5e
MS (ESI): m/z = 403 [M + H]+.
Anal. Calcd for C25H26N2O3: C, 74.63; H, 6.47; N, 6.97. Found: C,
74.52; H, 6.51; N, 6.94.
5-Bromo-3-[(N-methylanilino)(3,4,5-trimethoxyphenyl)meth-
yl]-1H-indole (1f)
Violet solid; yield: 428 mg (89%).
IR (KBr): 3415, 1590, 1513, 1457, 1221 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.81 (br s, 1 H), 7.37–7.12 (m, 4
H), 6.92 (d, J = 8.0 Hz, 2 H), 6.58 (br s, 1 H), 6.51 (d, J = 8.0 Hz, 2
H), 6.37 (s, 2 H), 5.39 (s, 1 H), 3.81 (s, 3 H), 3.70 (s, 6 H), 2.81 (s,
3 H).
13C NMR (50 MHz, CDCl3): d = 153.1, 149.2, 140.0, 136.9, 129.9,
127.0, 125.2, 125.0, 122.6, 120.4, 120.0, 112.5, 110.0, 105.9, 61.0,
56.3, 48.1, 29.8.
3-[(N-Alkylanilino)(aryl)methyl]indoles 1a–f; General Proce-
dure
To a mixture of a benzaldehyde (1 mmol) and N-alkylaniline (2
mmol) in MeCN (5 mL) was added TCT (10 mol%). The mixture
was stirred at r.t. for 30 min. Indole (1 mmol) was subsequently add-
ed and the mixture was allowed to stir (TLC monitoring) for the
time indicated in Table 1. After completion, H2O (10 mL) was add-
ed. The mixture was extracted with EtOAc (3 × 10 mL). The com-
bined extracts were concentrated and the residue was subjected to
column chromatography (silica gel, hexane–EtOAc) to obtain pure
1.
MS (ESI): m/z = 481, 483 [M + H]+.
Anal. Calcd for C25H25BrN2O3: C, 62.37; H, 5.20; N, 5.82. Found:
C, 62.45; H, 5.26; N, 5.74.
5-Bromo-3-[(3,4-dimethoxyphenyl)(N-methylanilino)methyl]-
1H-indole (1g)
Light red solid; yield: 406 mg (90%).
IR (KBr): 3410, 1607, 1514, 1434 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.82 (br s, 1 H), 7.32 (s, 1 H),
7.18–7.11 (m, 3 H), 6.95 (d, J = 8.0 Hz, 2 H), 6.76 (d, J = 8.0 Hz, 1
3-[(3,4-Dimethoxyphenyl)(N-methylanilino)methyl]-1H-indole
(1c)
Violet solid; yield: 335 mg (90%).
IR (KBr): 3401, 1609, 1513, 1459 cm–1.
Synthesis 2010, No. 6, 914–916 © Thieme Stuttgart · New York

916
B. Das et al.
SHORT PAPER
H), 6.64 (dd, J = 8.0, 2.0 Hz, 1 H), 6.57–6.42 (m, 4 H), 5.82 (s, 1 H),
MS (ESI): m/z = 401 [M + H]+.
3.69 (s, 3 H), 3.61 (s, 3 H), 2.81 (s, 3 H).
MS (ESI): m/z = 453, 451 [M + H]+.
Anal. Calcd For C26H28N2O2: C, 78.00; H, 7.00; N, 7.00. Found: C,
78.18; H, 7.08; N, 7.10.
Anal. Calcd for C24H23BrN2O2: C, 63.86; H, 5.10; N, 6.21. Found:
C, 63.72; H, 5.15; N, 6.28.
3-[(4-Hydroxyphenyl)(N-propylanilino)methyl]-1H-indole (1l)
Violet solid; yield: 313 mg (88%).
5-Bromo-3-[(N-methylanilino)(4-nitrophenyl)methyl]-1H-in-
dole (1h)
Light green solid; yield: 397 mg (91%).
IR (KBr): 3410, 1609, 1517, 1442 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.52 (br s, 1 H), 8.13 (d, J = 8.0
Hz, 2 H), 7.32–7.15 (m, 6 H), 6.88 (d, J = 8.0 Hz, 2 H), 6.51–6.42
(m, 3 H), 5.53 (s, 1 H), 2.82 (s, 3 H).
IR (KBr): 3414, 1607, 1513, 1457 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.90 (br s, 1 H), 7.34–7.20 (m, 4
H), 7.19–7.04 (m, 2 H), 7.01–6.94 (m, 3 H), 6.80 (d, J = 8.0 Hz, 1
H), 6.62 (d, J = 8.0 Hz, 1 H), 6.60 (br s, 1 H), 6.57–6.46 (m, 3 H),
5.46 (s, 1 H), 3.01 (t, J = 7.0 Hz, 2 H), 1.62–1.50 (m, 2 H), 0.98 (t,
J = 7.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 155.6, 146.8, 146.0, 136.5, 132.8,
129.7, 129.0, 128.1, 126.4, 124.1, 121.9, 121.3, 119.8, 119.6, 119.1,
115.2, 115.1, 110.4, 48.3, 46.1, 22.5, 11.2.
MS (ESI): m/z = 438, 436 [M + H]+.
Anal. Calcd for C22H18BrN3O2: C, 60.55; H, 4.13; N, 9.63. Found:
C, 60.68; H, 4.08; N, 9.76.
MS (ESI): m/z = 357 [M + H]+.
Anal. Calcd for C24H24N2O: C, 80.90; H, 6.74; N, 7.87. Found: C,
80.82; H, 6.70; N, 7.93.
3-[(3,4-Dimethoxyphenyl)(N-ethylanilino)methyl]-1H-indole
(1i)
Violet solid; yield: 347 mg (90%).
IR (KBr): 3412, 1606, 1512, 1342 cm–1.
Acknowledgment
The authors thank CSIR and UGC, New Delhi for financial assi-
stance.
1H NMR (200 MHz, CDCl3): d = 7.90 (br s, 1 H), 7.32–7.22 (m, 3
H), 7.14 (t, J = 8.0 Hz, 1 H), 7.08–6.92 (m, 3 H), 6.81 (d, J = 8.0
Hz, 1 H), 6.71–6.50 (m, 5 H), 5.94 (s, 1 H), 3.71 (s, 3 H), 3.61 (s, 3
H), 3.11 (q, J = 7.0 Hz, 2 H), 1.2 (t, J = 7.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 154.0, 151.6, 146.5, 137.1, 135.2,
132.8, 129.9, 127.1, 124.2, 121.4, 120.1, 120.0, 119.1, 117.0, 112.5,
111.8, 111.0, 110.9, 56.3, 55.9, 40.8, 38.9, 15.2.
References
(1) Part 196 in the series Studies on Novel Synthetic
Methodologies.
(2) (a) Sundberg, R. J. The Chemistry of Indoles; Academic
Press: New York, 1970. (b) Lounasman, M.; Tolvanen, A.
Nat. Prod. Rep. 2000, 17, 175. (c) Jiang, B.; Yang, C.-G.;
Wang, J. J. Org. Chem. 2001, 66, 4865. (d) Hibino, S.;
Chozi, T. Nat. Prod. Rep. 2001, 18, 66.
MS (ESI): m/z = 387 [M + H]+.
Anal. Calcd for C25H26N2O2: C, 77.72; H, 6.74; N, 7.25. Found: C,
77.68; H, 6.82; N, 7.21.
(3) Zhang, H.-C.; Bonaga, L. V. R.; Ye, H.; Derian, C. K.;
Damiano, B. P.; Maryanoff, B. E. Bioorg. Med. Chem. Lett.
2007, 17, 2863.
3-[(N-Ethylanilino)(4-nitrophenyl)methyl]-1H-indole (1j)
Light yellow solid; yield: 352 mg (95%).
IR (KBr): 3411, 1606, 1516, 1343 cm–1.
(4) (a) Garbe, T. R.; Kobayashi, M.; Shimizu, N.; Takesure, N.;
Ozawa, M.; Yukawa, H. J. Nat. Prod. 2000, 63, 596.
(b) Bao, B.; Sun, Q.; Yao, X.; Hong, J.; Lee, C. O.; Sim, C.
J.; Im, K. S.; Jung, J.-H. J. Nat. Prod. 2005, 68, 711.
(5) (a) Wynne, J. H.; Stalick, W. M. J. Org. Chem. 2002, 67,
5850. (b) Hogan, I.; Jenkins, P. D.; Sainsbury, N.
Tetrahedron 1990, 46, 2943. (c) Ramesh, C.; Banerjee, J.;
Pal, R.; Das, B. Adv. Synth. Catal. 2003, 345, 557. (d) Ji,
S.-J.; Wang, S.-Y.; Zhang, Y.; Loh, T.-P. Tetrahedron 2004,
60, 2051. (e) Srihari, P.; Sing, V. K.; Bhunia, D. C.; Yadav,
J. S. Tetrahedron Lett. 2009, 50, 3763. (f) Jia, Y.-X.; Xia,
J.-H.; Duan, H.-F.; Wang, L.-X.; Zhou, Q. L. Org. Lett.
2006, 8, 1621. (g) Renzetti, A.; Dardennes, E.; Fontana, A.;
De Maria, P.; Sapi, J.; Gerand, S. J. Org. Chem. 2008, 73,
6824. (h) Kobayashi, K.; Shirai, Y.; Konishi, H.
Heterocycles 2009, 78, 2033. (i) Fridkin, G.; Boutard, N.;
Lubell, W. D. J. Org. Chem. 2009, 74, 5603.
1H NMR (200 MHz, CDCl3): d = 8.12 (d, J = 8.0 Hz, 2 H), 8.04 (br
s, 1 H), 7.42–7.33 (m, 4 H), 7.20–7.13 (m, 2 H), 7.03–6.95 (m, 3 H),
6.61–6.52 (m, 3 H), 5.62 (s, 1 H), 3.11 (q, J = 7.0 Hz, 2 H), 1.22 (t,
J = 7.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 152.1, 147.3, 140.1, 136.4, 130.8,
130.0, 129.1, 126.4, 124.6, 124.5, 123.7, 122.2, 119.5, 112.4, 111.0,
47.5, 38.3, 14.6.
MS (ESI): m/z = 372 [M + H]+.
Anal. Calcd for C23H21N3O2: C, 74.39; H, 5.66; N, 11.32. Found: C,
74.46; H, 5.72; N, 11.38.
3-[(3,4-Dimethoxyphenyl)(N-propylanilino)methyl]-1H-indole
(1k)
Violet solid; yield: 348 mg (87%).
IR (KBr): 3408, 1606, 1512, 1422 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.89 (br s, 1 H), 7.32–7.23 (m, 3
H), 7.14 (t, J = 8.0 Hz, 1 H), 7.06–6.91 (m, 3 H), 6.81 (d, J = 8.0
Hz, 1 H), 6.71–6.50 (m, 5 H), 5.92 (s, 1 H), 3.72 (s, 3 H), 3.61 (s, 3
H), 3.02 (t, J = 7.0 Hz, 2 H), 1.65–1.57 (m, 2 H), 0.99 (t, J = 7.0 Hz,
3 H).
(6) (a) Das, B.; Damodar, K.; Bhunia, N. J. Org. Chem. 2009,
74, 5607. (b) Das, B.; Satyalakshmi, G.; Suneel, K.
Tetrahedron Lett 2009, 50, 2770. (c) Das, B.; Krishnaiah,
M.; Laxminarayana, K.; Suneel, K.; Kumar, D. N. Chem.
Lett. 2009, 38, 42.
(7) Bigdeli, M. A.; Mahdavinia, G. H.; Jafari, S.; Hazarkhani, H.
13C NMR (50 MHz, CDCl3): d = 153.8, 152.2, 148.3, 146.2, 138.4,
134.6, 132.2, 129.5, 124.0, 122.0, 119.9, 119.1, 117.2, 112.5, 111.4,
110.1, 110.0, 56.5, 55.2, 46.2, 40.5, 22.2, 11.1.
Catal. Commun. 2007, 8, 2229.
Synthesis 2010, No. 6, 914–916 © Thieme Stuttgart · New York