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European	Journal	of	Chemistry	5	(4)	(2014)	668‐670	

	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2014	Eurjchem	Publishing	‐	Printed	in	the	USA	

http://dx.doi.org/10.5155/eurjchem.5.4.668‐670.1085	

	
	

	

	

European	Journal	of	Chemistry	
Journal	homepage:	www.eurjchem.com	

	 	 	

β‐Cyclodextrin	catalyzed	synthesis	of	substituted	indoles	in	aqueous	medium	

Jilla	Shankar,	Gaddam	Satish,	Bandam	Santosh	Pavan	Anil	Kumar		
and	Yadavalli	Venkata	Durga	Nageswar	*	

Council	of	Scientific	Industrial	Research‐Medicinal	Chemistry	and	Pharmacology	Division,	Indian	Institute	of	Chemical	Technology,	Uppal	Road,	Hyderabad	500‐007,	
India	

*Corresponding	author	at:	Council	of	Scientific	Industrial	Research‐Medicinal	Chemistry	and	Pharmacology	Division,	Indian	Institute	of	Chemical	Technology,	Uppal	
Road,	Hyderabad	500‐007,	India.		
Tel.:	+91.040.27191654.	Fax:	+91.040.27193189.	E‐mail	address:	dryvdnageswar@gmail.com	(Y.V.D.	Nageswar).	

	
	

	 	

	 	 	
COMMUNICATION	INFORMATION	 	 ABSTRACT

	
DOI:	10.5155/eurjchem.5.4.668‐670.1085	

Received:	28	April	2014	
Received	in	revised	form:	16	June	2014	
Accepted:	16	June	2014	
Online:	31	December	2014	

KEYWORDS	

	 β‐Cyclodextrin	 catalyzed	 synthesis	 of	 indole	 derivatives	 from	 indole,	 aldehyde	 and	 N‐
methylaniline	is	reported.	The	β‐cyclodextrin	can	be	recovered	and	reused	without	significant
loss	 of	 catalytic	 activity,	 and	 it	 is	 inexpensive,	 readily	 available	 when	 compared	 to	 other
cyclodextrins	(α,	γ).	

Indole	
β‐Cyclodextrin	
N‐Methylaniline	
Aqueous	medium		
N‐Methylbenzamines	
Aldehyde	derivatives	

	
1.	Introduction	
	

Multicomponent	 reactions	 (MCRs)	 are	 of	 increasing	
importance	 in	 organic	 and	 medicinal	 chemistry	 and	 have	
offered	 many	 fascinating	 and	 challenging	 transformations	 in	
organic	 synthesis	 [1‐7].	 These	 multicomponent	 reactions	 are	
emerging	 as	 powerful	 tools	 for	 the	 synthesis	 of	 biologically	
important	compounds	[8‐9].	3‐Substituted	 indole	moieties	are	
important	as	they	are	widely	distributed	in	nature	and	reveal	a	
broad	 range	 of	 biological	 activities	 [10].	 Indoles	 with	 amino	
alkyl/aryl	 substituents	 at	 the	 3‐position	 are	 considered	 as	
potential	pharmacophores	[11]	in	drug	discovery	and	are	found	
in	 various	 natural	 products	 [12],	 useful	 in	 the	 treatment	 of	
migraine,	 breast	 cancer	 [13],	 and	 HIV‐1	 [14].	 The	 immense	
potential	of	indole	nucleus	for	development	of	drug	candidates,	
prompted	 many	 synthetic	 chemists	 to	 explore	 different	
methodologies	 suitable	 for	 the	 synthesis	 of	 3‐substituted	
indoles.	

In	 view	 of	 different	 biological	 activities	 associated	 with	
indole	derivatives	and	in	continuation	of	our	interest	in	the	use	
of	 cyclodextrins	 as	 mild	 and	 efficient	 biomimetic	 catalysts	 in	
promoting	various	organic	transformations	[15‐22],	we	here	in	
report	 the	 synthesis	 of	 indole	 derivatives	 by	 the	 reaction	 of	
indole	 with	 different	 aldehydes	 and	 N‐methylaniline	 under	
neutral	conditions	involving	β‐cyclodextrin	in	water	medium.	

	
2.	Experimental	
	
2.1.	Instrumentation	
	

All	the	products	were	characterized	by	their	NMR	and	Mass	
spectra.	1H	NMR	is	recorded	on	Varian	200	spectrometer	(200	
MHz,	 in	CDCl3)	and	 the	chemical	shifts	were	reported	 in	parts	
per	million	(ppm,	δ)	downfield	from	tetramethylsilane.	 IR	was	
recorded	on	a	Thermo	Nicolet	Nexus	670	FT‐IR	spectrometer.	
Mass	spectra	were	obtained	using	a	VG	Autospec	mass	spectro‐
meter.	
	
2.2.	General	procedure	for	the	synthesis	of	N‐((1H‐indol‐3‐yl)	
(phenyl)	methyl)‐N‐methylbenzenamine	
	

All	 chemicals	 were	 purchased	 from	 Fluka	 and	 S.	 D.	 Fine	
Chemicals	 and	directly	 used	 for	 the	 synthesis.	Analytical	Thin	
Layer	Chromatography	(TLC)	was	carried	out	by	using	silica	gel	
60F254	pre‐coated	plates.	Visualization	was	accomplished	with	
UV	lamp	or	I2	stain.	All	reactions	were	carried	out	without	any	
special	precautions	in	an	atmosphere	of	air.	

	

 



Shankar	et	al.	/	European	Journal	of	Chemistry	5	(4)	(2014)	668‐670	 669	
 

	

	
	

Scheme	1
	

	
Table	1.	β‐CD	catalyzed	synthesis	of	3‐substituted	indoles	a.	
Entry	 R	 R1	 Product Time	(h) Yield	(%)	b	
1	 H	 H	 4a	 4.0	 86	
2	 H	 4‐Cl	 4b	 3.5	 84	
3	 H	 4‐CH3	 4c	 4.5	 86	
4	 H	 4‐NO2	 4d 4.5 85	
5	 H	 4‐OCH3	 4e	 4.5	 83	
6	 H	 4‐OH	 4f 4.5 81	
7	 Br	 4‐NO2	 4g 4.5 86	
8	 Br	 4‐OCH3 4h 4.5 85	
9	 Br	 4‐Cl	 4i 3.5 80	
10	 Br	 4‐CH3	 4j 4.5 85	
a	Reaction	conditions:	Aldehyde	(1.0	mmol),	N‐methylaniline	(1.0	mmol),	indole	(1.0	mmol),	β‐cyclodextrin	(10	mol	%),	60	°C.	
b	Isolated	yield.	
	

	
β‐Cyclodextrin	 (1.135	 g,	 1	 mmol)	 was	 dissolved	 in	 water	

(15	 mL)	 by	 warming	 up	 to	 60	 °C	 until	 a	 clear	 solution	 was	
formed.	To	this	clear	solution,	aldehyde	(1.0	mmol)	was	added	
and	 stirred	 for	 10	min,	 and	 then	N‐methylaniline	 (1.0	mmol)	
was	added.	After	stirring	for	half	an	hour	1	equivalent	of	indole	
(1.0	mmol)	was	added.	The	reaction	mixture	was	stirred	until	
completion	 of	 the	 reaction	 as	 indicated	 by	 TLC.	 The	 reaction	
mixture	was	cooled	and	β‐CD	was	filtered.	The	aqueous	phase	
was	extracted	with	ethyl	acetate	 (3	×	10	mL)	and	 the	organic	
layers	were	washed	with	water,	 saturated	brine	 solution,	 and	
dried	 over	 anhydrous	 Na2SO4.	 The	 combined	 organic	 layers	
were	 evaporated	 under	 reduced	 pressure	 and	 the	 resulting	
crude	 product	 was	 purified	 by	 column	 chromatography	 by	
using	 ethyl	 acetate:	 hexane	 (2:8,	 v:	 v)	 as	 eluent	 to	 give	 the	
corresponding	 N‐((1H‐indol‐3‐yl)	 (phenyl)	 methyl)‐N‐methyl	
benzeneamine	as	pure	product	in	good	yield	(Scheme	1).	

N‐((1H‐Indol‐3‐yl)	(phenyl)	methyl)‐N‐methylbenzenamine	
(Table	 1,	 entry	 1):	 Yield:	 86%.	 1H	 NMR	 (200	 MHz,	 CDCl3,	 δ,	
ppm):	8.00	(s,	1H,	NH,	Pyr),	7.84	(s,	1H,	CH,	Pyr.),	7.15‐7.36	(m,	
8H,	Ar‐H),	7.0‐7.12	(m,	3H,	Ar‐H),	6.47‐6.60	(d,	J	=	9.06	Hz,	3H,	
Ar‐H),	 5.57	 (s,	 1H,	 CH),	 2.82	 (s,	 3H,	 CH3).	MS	 (ESI,	m/z):	 313	
[M+H]	+.	

N‐((4‐Chlorophenyl)	 (1H‐indol‐3‐yl)	 methyl)‐N‐methyl	
benzeneamine	 (Table	 1,	 entry	 2):	 Yield:	 84%.	 1H	 NMR	 (200	
MHz,	CDCl3,	δ,	ppm):	8.01(s,	1H,	NH,	Pyr),	7.96	(s,	1H,	CH,	Pyr.),	
7.04‐7.26	 (m,	 7H,	 Ar‐H),	 6.91‐7.02	 (d,	 J	 =	 8.49	Hz,	 2H,	 Ar‐H),	
6.39‐6.53	(m,	4H,	Ar‐H),	5.48	(s,	1H,	CH),	2.72	(s,	3H,	CH3).	MS	
(ESI,	m/z):	347	[M+H]	+.	

N‐((1H‐Indol‐3‐yl)	(p‐tolyl)	methyl)‐N‐methylbenzenamine	
(Table	 1,	 entry	 3):	 Yield:	 86%.	 1H	 NMR	 (200	 MHz,	 CDCl3,	 δ,	
ppm):	8.00	(s,	1H,	NH,	Pyr),	7.90	(s,	1H,	CH,	Pyr.),	7.36‐7.39	(d,	
2H,	 J	=	8.49	Hz,	 Ar‐H),	 7.19‐7.23	 (m,	 3H,	 Ar‐H),	 6.93‐7.16	 (m,	
5H,	Ar‐H),	6.49‐6.52	(d,	J	=	7.52	Hz,	3H,	Ar‐H),	5.51	(s,	1H,	CH),	
2.77	(s,	3H,	CH3),	2.29	(s,	3H,	CH3).	MS	(ESI,	m/z):	327	[M+H]	+.	

N‐((1H‐Indol‐3‐yl)	 (4‐nitrophenyl)	 methyl)‐N‐methyl	
benzeneamine	 (Table	 1,	 entry	 4):	 Yield:	 85%.	 1H	 NMR	 (200	
MHz,	 CDCl3,	 δ,	 ppm):	 8.30	 (s,	 1H,	 NH,	 Pyr),	 	 8.25	 (s,	 1H,	 CH,	
Pyr.),	 7.23‐7.35	 (m,	 5H,	 Ar‐H)	 7.09‐7.15	 (m,	 2H,	 Ar‐H),	 6.91‐
6.99	(d,	J=8.1	Hz,	3H,	Ar‐H),	6.44‐6.55	(d,	J=6.79	Hz,	3H,	Ar‐H),	
5.58	(s,	1H,	CH),	2.78	(s,	3H,	CH3).	MS	(ESI,	m/z):	380	[M+Na]	+.	

N‐((1H‐Indol‐3‐yl)	 (4‐methoxyphenyl)	 methyl)‐N‐methyl	
benzenamine	(Table	1,	entry	5):	Yield:	83%.	1H	NMR	(200	MHz,	

CDCl3,	δ,	ppm):	8.01	(s,	1H,	NH,	Pyr),	7.89	(s,	1H,	CH,	Pyr.),	7.47‐
7.60	 (m,	 4H,	 Ar‐H),	 6.94‐7.18	 (m,	 5H,	 Ar‐H),	 6.47‐6.52	 (d,	 J	=	
8.30	Hz,	4H,	Ar‐H),	5.54	(s,	1H,	CH),	3.80	(s,	3H,	OCH3),	2.78	(s,	
3H,	CH3).	MS	(ESI,	m/z):	343	[M+H]	+.	

4‐((1H‐Indol‐3‐yl)	(methyl	(phenyl)	amino)	methyl)	phenol	
(Table	 1,	 entry	 6):	 Yield:	 81%.	 1H	 NMR	 (200	 MHz,	 CDCl3,	 δ,	
ppm):	8.01	(s,	1H,	NH,	Pyr),	7.71	(s,	1H,	CH,	Pyr.),	7.31‐7.36	(d,	J	
=	7.55	Hz,	2H,	Ar‐H),	7.20‐7.26	(d,	J	=	8.30	Hz,	3H,	Ar‐H),	6.91‐
7.15	 (m,	 6H,	Ar‐H),	 6.60‐6.65(d,	 J=9.01	Hz,	 2H,	Ar‐H),	 5.47	 (s,	
1H,	CH),	5.37	(s,	1H,	OH),	2.16	(s,	3H,	CH3).	MS	(ESI,	m/z):	329	
[M+H]	+.	

N‐((5‐Bromo‐1H‐indol‐3‐yl)	 (4‐nitrophenyl)	 methyl)‐N‐
methylbenzenamine	 (Table	 1,	 entry	 7):	 Yield:	 86%.	 1H	 NMR	
(200	MHz,	CDCl3,	δ,	ppm	):	8.92	(s,	1H,	NH,	Pyr),	8.84	(s,	1H,	CH,	
Pyr.),	8.09‐8.23	(m,	6H,	Ar‐H),	7.30‐7.35	(t,	J	=	8.30	Hz,	3H,	Ar‐
H),	6.93(s,	1H,	Ar‐H),	6.49‐6.59(d,	J	=	8.32	Hz,	2H,	Ar‐H),	5.56	(s,	
1H,	CH),	2.83	(s,	3H,	CH3).	MS	(ESI,	m/z):	459	[M+Na]	+.	

N‐((5‐Bromo‐1H‐indol‐3‐yl)	 (4‐methoxyphenyl)methyl)‐N‐
methylbenzenamine	 (Table1,	 entry	 8):	 Yield:	 85%.	 1H	 NMR	
(200	MHz,	CDCl3,	δ,	ppm):	8.00	(s,	1H,	NH,	Pyr),	7.30	(s,	1H,	CH,	
Pyrro	),	7.10‐7.71	(m,	6H,	Ar‐H),	6.98‐7.05	(d,	J=9.16	Hz,	2H,	Ar‐
H),	6.71‐6.75	(d,	J	=	8.25	Hz,	2H,	Ar‐H),	6.44‐6.49	(d,	J	=	8.24	Hz,	
2H,	Ar‐H),	5.40	(s,	1H,	CH),	3.71	(s,	3H,	OCH3),	2.76	(s,	3H,	CH3).	
MS	(ESI,	m/z):	422	[M+H]	+.	

N‐((5‐bromo‐1H‐indol‐3‐yl)	 (4‐chlorophenyl)methyl)‐N‐
methylbenzenamine	 (Table	 1,	 entry	 9):	 Yield:	 80%.	 1H	 NMR	
(200	MHz,	CDCl3,	δ,	ppm):	8.10	(s,	1H,	NH,	Pyr),	8.00	(s,	1H,	CH,	
Pyr.),	7.05‐7.32	(m,	6H,	Ar‐H),	6.92‐6.94	(d,	 J=8.30	Hz,	2H,	Ar‐
H),	6.47‐6.53	(d,	J	=	8.30	Hz,	4H,	Ar‐H),	5.42	(s,	1H,	CH),	2.75	(s,	
3H,	CH3).	MS	(ESI,	m/z):	426	[M+H]	+.	

N‐((5‐bromo‐1H‐indol‐3‐yl)	 (p‐tolyl)	 methyl)‐N‐methyl	
aniline	 (Table	 1,	 entry	 10):	 Yield:	 85%.	 1H	 NMR	 (200	 MHz,	
CDCl3,	δ,	ppm):	8.00	(s,	1H,	NH,	Pyr),	7.95	(s,	1H,	CH,	Pyr.),	7.36	
(s,	1H,	Ar‐H),	7.17‐7.25	(m,	2H,	Ar‐H),	7.05	(s,	3H,	Ar‐H),	6.95‐
6.99	(d,	J	=	8.30	Hz,	3H,	Ar‐H),	6.49‐6.53	(d,	J	=	8.30	Hz,	3H,	Ar‐
H),	5.44	(s,	1H,	CH),	2.81	(s,	3H,	CH3),	2.31	(s,	3H,	CH3).	MS	(ESI,	
m/z):	406	[M+H]	+.	
	
3.	Results	and	discussion		

	
Cyclodextrins	are	cyclic	oligosaccharides	with	hydrophobic	

cavities,	 and	 can	 bind	 substrates	 selectively	 and	 catalyze	



670	 Shankar	et	al.	/	European	Journal	of	Chemistry	5	(4)	(2014)	668‐670	
	
chemical	 reactions	 by	 supramolecular	 catalysis	 involving	
reversible	 host‐guest	 complexation.	 We	 describe	 herein,	 the	
aqueous	 phase	 synthesis	 of	 indole	 derivatives	 demonstrating	
the	remarkable	catalytic	activity	of	β‐cyclodextrin	(Scheme	1).	
In	general,	the	reaction	was	carried	out	by	the	in	situ	formation	
of	 the	 β‐CD	 complex	 of	 aldehyde	 in	 water	 followed	 by	 the	
addition	of	1	equivalent	of	N‐methylaniline	and	1	equivalent	of	
indole	 followed	 by	 subsequent	 stirring	 at	 60	 °C	 to	 give	 the	
corresponding	 N‐((1H‐indol‐3‐yl)(phenyl)methyl)‐N‐methyl	
benzenamine	in	high	yields.		

The	reaction	goes	to	the	completion	in	a	short	time	(3.5‐4.5	
h).	 Several	 examples	 illustrating	 this	 simple	 and	 practical	
methodology	are	summarized	in	Table	1.	No	byproduct	forma‐
tion	was	observed.	β‐Cyclodextrin	can	be	easily	recovered	and	
reused.	All	the	compounds	were	characterized	by	1H	NMR,	and	
mass	 spectrometry.	 The	 catalytic	 activity	 of	 cyclodextrin	 in	
these	reactions	was	established	by	the	fact	that	no	reaction	was	
observed	 in	 the	 absence	 of	 cyclodextrin.	 Evidence	 for	 the	
complexation	between	aldehyde	and	cyclodextrin	is	supported	
by	 1H	 NMR	 spectroscopy.	 The	 complexation	 with	 β‐CD	
increases	the	reactivity	of	aldehyde	functional	group	due	to	the	
intermolecular	hydrogen	bonding	with	the	CD‐hydroxyl	groups	
facilitating	the	addition	of	N‐methylaniline.	Here,	β‐CD	not	only	
forms	the	inclusion	complex	with	aldehyde	but	is	also	involved	
in	 the	 intermolecular	 hydrogen	 bonding	 with	 the	 guest	 to	
promote	the	reaction.	
	
4.	Conclusion	
	

A	 neutral	 aqueous	 phase	 synthesis	 of	 substituted	 indoles	
was	developed	by	 the	 reaction	of	 the	corresponding	aldehyde	
with	N‐methylaniline	 and	 indole	 promoted	 by	 β‐cyclodextrin.	
These	cyclodextrin‐mediated	aqueous	phase	reactions	are	very	
useful	 both	 from	 economical	 and	 environmental	 perspective.	
This	straightforward	and	environmentally	benign	methodology	
may	 find	 wide	 spread	 application	 in	 organic	 and	 medicinal	
chemistry.	
	
Acknowledgement	
	

We	thank	Council	of	Scientific	and	Industrial	Research,	New	
Delhi,	 India,	 for	 fellowship	 to	 JillaShankar,	Gaddam	Satish	and	
Bandam	Santosh	Pavan	Anil	Kumar.	
	
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