Lewis acid catalyzed electrophilic substitution of indole with aldehydes and Schiff's bases under microwave solvent-free irradiation

Article abstract of DOI:10.1081/SCC-200028611

Bis(indolyl)methane derivatives can be rapidly and smoothly prepared in good yields under solvent-free microwave irradiation, though Lewis acid catalyzed electrophilic substitution of indoles with aldehydes and Schiff's bases of aryldehydes.

Full text of DOI:10.1081/SCC-200028611

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Lewis Acid Catalyzed
Electrophilic Substitution
of Indole with Aldehydes
and Schiff's Bases Under
Microwave Solvent‐Free
Irradiation
Min Xia a , Si‐hai Wang a & Wei‐bo Yuan a
a Department of Applied Chemistry, Zhejiang
Institute of Science and Technology, Hangzhou,
310033, P.R. China
Version of record first published: 10 Jan 2011.
To cite this article: Min Xia , Si‐hai Wang & Wei‐bo Yuan (2004): Lewis Acid
Catalyzed Electrophilic Substitution of Indole with Aldehydes and Schiff's Bases
Under Microwave Solvent‐Free Irradiation, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:17, 3175-3182
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 17, pp. 3175–3182, 2004
Lewis Acid Catalyzed Electrophilic
Substitution of Indole with Aldehydes
and Schiff’s Bases Under Microwave
Solvent-Free Irradiation
*
Min Xia, Si-hai Wang, and Wei-bo Yuan
Department of Applied Chemistry, Zhejiang Institute of Science and
Technology, Hangzhou, P.R. China
ABSTRACT
Bis(indolyl)methane derivatives can be rapidly and smoothly prepared in
good yields under solvent-free microwave irradiation, though Lewis acid
catalyzed electrophilic substitution of indoles with aldehydes and Schiff’s
bases of aryldehydes.
Key Words: bis(Indolyl)methanes; Lewis acid-catalysis; Microwave.
Indoles and their derivatives have long been utilized as antibiotics in the
field of pharmaceuticals. Bis(indolyl)alkanes and their derivatives are more
*
Correspondence: Min Xia, Department of Applied Chemistry, Zhejiang Institute of
Science and Technology, Hangzhou 310033, P.R. China; E-mail: chchxm@21cn.com.
3175
DOI: 10.1081/SCC-200028611
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3176
Xia, Wang, and Yuan
attractive compounds as the bioactive metabolites of terrestrial and marine
origin.[1] The acid catalyzed reaction of electron-rich heterocyclic compounds
with p-dimethylaminobenzaldehyde is known as Ehrlich test[2] for p-electron
excessive heterocycles such as pyrroles and indoles. The analogous reaction of
indoles with other aromatic or aliphatic aldehydes and ketones produces aza-
fulvenium salts, which undergo the further addition with another indole mole-
cule to afford bis(indolyl)methanes. Protic acids[3] and Lewis acids[4] are both
known to promote this reaction. However, more than stoichiometric amounts
of Lewis acids are required due to the capture of acids by nitrogen.[5] Recently,
it was reported that the synthesis of bis(indolyl)methane derivatives could be
catalyzed by LiClO4,[6] Ln(OTf)3,[7] PPh3 HClO4,[8] In(OTf)3,[9] montmoril-
.
lonite clay K-10,[10] etc., but the long reaction time (4–10 hr) and complicated
operation limited their further development.
In recent years, microwave-assisted organic synthesis has been the
focus of considerable attention and is becoming an increasingly popular
technology.[11] The prominent features of the microwave approach are the
rapid reaction rates, clean reaction conditions, and ease of manipulation.
Reactions in “dry media” or under solvent-free conditions are especially
appealing as they provide an opportunity to work with open vessels,
thus avoiding the risk of high pressure development. Currently, we reported
the 1,3-dipolar cycloaddition offering the pyrazoline derivatives on silica
gel under solvent-free microwave irradiation,[12] herein we describe the Lewis
acid catalyzed electrophilic substitution of indole with carbonyl compounds
and Schiff’s bases of arylaldehydes under dry microwave heating.
First, we surveyed the effect of radiation power on the reaction.
para-Chlorobenzaldehyde and FeCl3 (20%) were selected for the investi-
gation (Sch. 1). It was found that the reaction was obviously influenced
by the irradiation power. After parallel experiments, we decided that
235 W irradiation power was the best option. If the irradiation power was
weaker than 235 W, the conversion of the substrates would be low.
However, the Lewis acid tended to be combined with indole to form the
complex with strong fluorescence when the irradiation power was over
Scheme 1.

Lewis Acid Catalyzed Electrophilic Substitution of Indole with Aldehydes 3177
235 W. As the power was raised to more than 530 W, the Lewis acid would be
deactivated totally without the yield of 3,30-bis(indolyl)-4-chlorophenyl-
methane.
Encouraged by the above survey, we then examined the catalytic activity
of different Lewis acids in the reaction of indole with 4-chlorobenzaldehyde
under 235 W irradiation power. As shown in Table 1, all catalysts tested
were effective in the dry microwave-assisted reaction. Among them, FeCl3
and BiCl3 displayed the best catalytic activity; the reactions involving them
could be rapidly completed in good yields within 2.0 min and 2.5 min, respect-
ively. Also, InCl3 was efficient in 4.0 min to fulfill the reaction in good yield.
The ZnCl2, and even CoCl2, which was not usually used as a Lewis acid in
organic synthesis, showed enough good catalytic activity, providing the
target products in moderate to good yields. Owing to their weaker catalytic
activity, they always required longer irradiation time and increased amount
of catalysts.
We extended the dry microwave-induced reaction to other aldehydes
(Sch. 2). It is indicated in Table 2 (entry 3a ꢀ e) that arylaldehydes could
be efficiently carried out in the electrophilic substitution with indole under
our conditions to offer the bis(indolyl)methane derivatives in good yields.
Unfortunately, aliphatic carbonyl compounds could not provide the satis-
factory results under our conditions.[13] The products system was quite
complicated for them.
Traditionally, carbonyl compounds such as aldehydes and ketones were
involved in the electrophilic substitution with indoles to form the bis(indolyl)-
methane derivatives. In the literature, there have been reports that imines
could also be applied as alternatives to the presence of acids, such as
InCl3,[14] acetic acid,[15] BF3Et2O,[16] etc. However, the long reaction time
(generally several hours) and complicated products system in some cases[15]
hindered their development for building the bis(indolyl)methane scaffold.
Table 1. Catalytic activity of Lewis acids in the solvent-free
microwave-promoted electrophilic substitution with indole.
Lewis acid
(mol%)
Time
(min)
Yield
(%)a
Entry
1
2
3
4
5
FeCl3 (20%)
BiCl3 (20%)
InCl3 (20%)
ZnCl2 (30%)
CoCl2 (30%)
2.0
2.5
4.0
5.5
8.5
93
88
87
74
62
aIsolation yields.

3178
Xia, Wang, and Yuan
Scheme 2.
Microwave-assisted solvent-free reaction of imines with indole afforded
the efficient routine to extend the capacity of imines in synthesis of
bis(indolyl)methane derivatives. It was reported that FeCl3 was an effective
Lewis acid to catalyze Biginelli condensation,[17] since it could favor the for-
mation of iminium ions, which were the key intermediates to the Biginelli
reaction.[18] The situation was analogues to our case in which activation of
imine groups by Lewis acids was the key step (Sch. 3). It was found that
FeCl3 (20 mol%) was effective for the Schiff’s bases of arylaldehydes to
carry out the electrophilic substitution with indole under microwave
heating, giving good yields rapidly and readily (Table 3, entry 3a–e). Gener-
ally, it took longer for imines to fulfill the reaction under microwave
irradiation, but the simple products system resulted in easy separation and
purification. Indeed, imines were helpful alternatives to the classical alde-
hydes or ketones for the synthesis of bis(indolyl)methane derivatives in the
microwave-assisted substitution reaction.
In conclusion, we have developed a rapid and efficient routine to the
Lewis acids catalyzed electrophilic substitution of indole with aryldehydes
and imines under solvent-free microwave irradiation. Efforts to select a
more active catalytic system are in due course.
Table 2. FeCl3 catalyzed synthesis of bis(iodolyl)methane
derivatives with aldehydes.
Time
(min)
Yield
(%)a,b
Entry
R
3a
3b
3c
3d
3e
H
Cl
2.5
2.0
2.5
2.0
2.5
86
93
81
72
74
HO
CH3
CH3O
aAll products were determined by 1H NMR, FT-IR, and EA.
bIsolation yields.

Lewis Acid Catalyzed Electrophilic Substitution of Indole with Aldehydes 3179
Scheme 3.
TYPICAL EXPERIMENTAL PROCEDURE
In a flask, the mixture of well-ground Lewis acid (20 mol%) and silica gel
(3 g) was combined with the solution of indole (1 mmol) and corresponding
aldehyde or Schiff’s base (0.5 mmol) in CH2Cl2 (20 mL). Under reduce press-
ure, the mixture was dried to powder on a rotating evaporator and transferred
into an open vessel. The vessel was put in the microwave oven under
irradiation for needed time and the mixture gradually turned pink to red.
After cooling to room temperature, the mixture was extracted with Et2O by
three times (3 ꢀ 15 mL) and the ether layer was dried with anhydrous
MgSO4. After removal of ether, the residue was isollated by column chrom-
atography to afford the pure product.
3,30-bis(Indolyl)-phenylmethane 3a
mp 1258C–1278C (Lit.[16] 1248C–1258C): 1H NMR (500 MHz, CDCl3):
d 5.91 (s, 1H, Ar-CH), 6.51 (s, 2H), 7.45–7.16 (m, 13H), 7.58 (s, 2H, NH);
FT-IR (KBr) n 3414, 3056, 2981, 2853, 1600, 1495, 1455, 1413, 800, 744, 701.
Table 3. FeCl3 catalyzed synthesis of bis(indolyl)methane
derivatives with imines.
Time
(min)
Yield
(%)a,b
Entry
R
R0
3a
3b
3c
3d
3e
H
H
HO
4.5
78
Cl
H
4.5
4.0
4.5
4.0
74
85
83
73
Cl
CH3O
CH3
H
CI
aAll products were determined by 1H NMR, FT-IR, and EA.
bIsolation yields.

3180
Xia, Wang, and Yuan
Anal. Calcd. for C23H18N2: C, 85.68; H, 5.63; N, 8.69; Found C, 85.77; H,
5.69; N, 8.55.
3,30-bis(Indolyl)-4-chlorophenylmethane 3b
Mp 988C–1018C; 1H NMR (500MHz, CDCl3): d 5.88 (s, 1H, Ar-CH), 6.65
(s, 2H), 7.03 (t, 2H, J ¼ 8.0 Hz), 7.17 (d, 2H, J ¼ 8.0 Hz), 7.24–7.40 (m, 6H),
7.47 (d, 2H, J ¼ 8.0 Hz), 7.88 (s, 2H, NH); FT-IR (KBr) n 3414, 3056, 2869,
1493, 1452, 1420, 1339, 1216, 1086, 1013, 744 cm21. Anal. calcd. for
C23H17ClN2: C, 77.53; H, 4.77; N, 7.86; Found C, 77.81; H, 4.82; N, 7.79.
3,30-bis(Indolyl)-4-hydrophenylmethane 3c
1
Mp 1308C–1328C; H NMR (500 MHz, CDCl3): d 4.67 (brs, 1H), 5.82
(s, 1H), 6.64 (s, 2H), 6.74 (d, J ¼ 8.0 Hz, 2H), 6.99 (t, J ¼ 8.0 Hz, 2H),
7.14–7.20 (m, 4H), 7.36 (t, J ¼ 9.2 Hz, 4H), 7.90 (s, 2H); FT-IR (KBr) n
3445, 3405, 3053, 1613, 1512, 1455, 1419, 1338, 1257, 1167, 1090, 795,
742; Anal. Calcd. for C23H18N2O: C, 81.65; H, 5.32; N, 8.28; Found C,
81.78; H, 5.41; N, 8.18.
3,30-bis(Indolyl)-4-methylphenylmethane 3d
1
Mp 958C–968C (Lit.[19] 968C–978C); H NMR (500 MHz, CDCl3): d
2.36 (s, 3H, Ar-CH3), 5.85 (s, 1H, Ar-CH), 6.71 (d, 2H, J ¼ 2.3 Hz), 7.02
(t, 2H, J ¼ 8.0 Hz), 7.1 (d, 2H, J ¼ 8.0 Hz), 7.2–7.34 (m, 6H), 7.44 (d, 2H,
J ¼ 8.0 Hz), 7.88 (s, 2H, NH); FT-IR (KBr) n 3443, 3065, 2967, 1600,
1520, 1420, 1210, 1050, 761; Anal. Calcd for C24H20N2: C, 85.68; H, 5.99;
N, 8.33; Found C, 85.81; H, 6.08; N, 8.24.
3,30-bis(Indolyl)-4-methoxylphenylmethane 3e
1
Mp 1918C–1938C; H NMR (500 MHz, CDCl3): d 3.77 (s, 3H), 5.83
(s, 1H), 6.63 (d, J ¼ 1.0 Hz, 2H), 6.82 (d, J ¼ 8.8 Hz, 2H), 6.99
(t, J ¼ 7.2 Hz, 2H), 7.15 (t, J ¼ 7.2 Hz, 2H), 7.23, (D, J ¼ 1.2 Hz, 2H), 7.32
(d, J ¼ 8.4 Hz, 2H), 7.39 (d, J ¼ 8.0 Hz, 2H), 7.86 (s, 2H); FT-IR (KBr) n
3395, 3054, 2947, 2831, 1610, 1509, 1455, 1419, 1336, 1243, 1171, 1096,
1024, 784, 740; Anal. calcd. for C24H20N2O: C, 81.82; H, 5.68; N, 7.95;
Found C, 81.93; H, 5.74; N, 8.08.

Lewis Acid Catalyzed Electrophilic Substitution of Indole with Aldehydes 3181
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Received in Japan March 31, 2004