Efficient ZnCl2 assisted synthesis of calix[4]pyrroles catalysed by Br?nsted acidic ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2014.10.020

A facile and efficient protocol is reported for the synthesis of calix[4]pyrroles and N-confused calix[4]pyrroles in moderate to excellent yields by one-pot condensation of ketones and pyrrole in the presence of catalytic amount of nontoxic acidic ionic liquids. In this reaction the products were obtained in short reaction time with selectivity of regular calix[4]pyrroles.

Full text of DOI:10.1016/j.tetlet.2014.10.020

Accepted Manuscript
Efficient ZnCl assisted synthesis of calix[4]pyrroles catalyzed by Brønsted
2
acidic ionic liquids
Amit Kumar Rawat, S.M.S. Chauhan
PII:
S0040-4039(14)01691-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.020
TETL 45249
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
14 May 2014
3 October 2014
5 October 2014
Please cite this article as: Rawat, A.K., Chauhan, S.M.S., Efficient ZnCl assisted synthesis of calix[4]pyrroles
2
catalyzed by Brønsted acidic ionic liquids, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2
014.10.020
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Graphical Abstract
Efficient ZnCl
2
assisted synthesis of calix[4]pyrroles
Leave this area blank for abstract info.
catalyzed by Brønsted acidic ionic liquids
Amit Kumar Rawat and S.M.S. Chauhan*
H
3
C
CH3
CH3
3
H C
H
N
O
NH HN
NH HN
NH
NH
H
3
C
C
CH3
H
+
ZnCl
2
/ AILs
3
C
CH3
CH
+
H C
3
CH3
DCM, rt
H
3
CH
3
N
H
H C
3
3
HN
CH
H
3
C
CH
3
3
H C
3
Tetrahedron Letters
j o u r n a l h o m e p a g e : w w w . e l s e v i er .c o m
Efficient ZnCl
2
assisted synthesis of calix[4]pyrroles catalyzed by Brønsted acidic ionic liquids
*
Amit Kumar Rawat and S.M.S. Chauhan
Bio-organic Research Laboratory, Department of Chemistry, University of Delhi, Delhi-110007, India;
ARTICLE INFO ABSTRACT
———
*
correspondence Author Tel.: +; Fax : +91-11-27666845
E-Mail: smschauhan@chemistry.du.ac.in

2
Article history:
Received
A facile and efficient protocol is reported for the synthesis of
calix[4]pyrroles and N-confused calix[4]pyrroles in moderate to
excellent yields by one-pot condensation of ketones and pyrrole in
the presence of catalytic amount of non-toxic acidic ionic liquids. In
this reaction the products were obtained in short reaction time with
selectivity of regular calix[4]pyrroles.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Acidic
ionic
liquids,
Calix[4]pyrrole;
N-confused
calix[4]pyrrole; catalysis;
Calix[4] pyrroles or meso-substituted
chlorinated solvents makes such processes
porphyrinogens are an important class of neutral environmentally questionable.
1
macrocycles receptor capable of binding anions,
It is therefore of considerable interest to
2
transition metals and neutral molecules in both
3
search for alternative methods for the synthesis of
calix[4]pyrroles in high yields along with trace
amount of N-confused calix[4]pyrroles. The
product distribution in the synthesis of
porphyrinogens and related compounds can be
4
solution and solid states. Although calix[4]pyrroles
have been synthesized 100 years ago by the acid
5
catalyzed condensation of ketones and pyrrole,
after that a number of strategies have been
employed to synthesize and characterize various switched from one to another, depending on the
functionalized calix[4]pyrroles by using a wide type of acid catalysts and their way of
6
,7
varieties of catalyst including HCl,
Lewis
implementation in the reaction. In this context, the
8
,9
10
13 14
p-toluenesulfonic acid or literature reports by Dehaen, Radha Kishan, and
acids,
chlorzinc,
1
1,12
15
to improve the yield of specific Chavasiri are particularly attractive. Although all
organic acid
calix[4]pyrroles. However, the use of excess and
even stoichiometric amount of acids with
the reported methods for the synthesis of
calix[4]pyrroles have been examined in the
.
presence of strong acids such as BF
3
O(Et)
2
, TFA,

3
and methylsulfuric acid. In order to avoid the use of there is decrease in hydrophobicity and +I effect
corrosive acid and to minimize the amount of of ionic liquid leading to an increase in acidic
harmful organic solvents, the development of a new character. Primarily 1a was screened under a
method for the synthesis of calix[4]pyrroles
catalyzed by Brønsted acidic ionic liquids assist by product distribution at room temperature.
zinc chloride would be highly desirable. Initially, equimolar amounts of pyrrole (14
In recent years, Brønsted acidic ionic liquids mmol) and acetone (14 mmol) were taken up in
variety of experimental conditions to optimize the
(
AILs) have emerged as revolutionary candidates in
dichloromethane (10 mL). A catalytic amount of 1a
(0.14 mmol) was added to this stirred solution.
After 40 min, the TLC of crude reaction mixture
indicated the complete consumption of starting
the replacement of conventional homogeneous and
heterogeneous acid catalysts because of their
outstanding flexibility, heat resistance, non-
volatility, noncorrosiveness, negligible vapour material with the formation of compound 3+4.
pressure and tunable polarity with common organic
Prolonging the reaction time did not offer any
1
6-20
solvents.
In addition, these advantages turn out noteworthy advantages. The yields of products
to be more attractive using ILs in dichloromethane. were calculated by HPLC using methanol and water
Inspired by the early report and the critical role of (v/v 1:1) as eluent. The HPLC yield of
2
1
AILs in organic synthesis encouraged us to
examine the catalytic scope of AILs in the synthesis
of calix[4]pyrroles and N-confused calix[4]pyrroles
assist by zinc chloride (Scheme 1, Figure 1).
calix[4]pyrrole and N-confused calix[4]pyrrole was
reported 80 and 20 % respectively with retention
time 3.4 and 3.8 minute (See Supplementary
material, Figure S1). Nonetheless, equimolar
amounts of pyrrole (14 mmol) and acetone (14
mmol) were taken up in dichloromethane (10 mL)
For this study various Brønsted acidic ionic
liquids (1a-1h) were prepared by known literature
22
procedure with minor modification. The different containing a catalytic amount of zinc chloride. A
acidic ionic liquids were used for the synthesis of catalytic amount of 1a (0.14 mmol) was added to
calix[4]pyrroles and better yields were obtained in
this stirred solution and observed the formation of
products in 94.67 and 5.33 % HPLC yield of
the presence of acidic ionic liquid 1a with respect to
longer alkyl chains in dichloromethane (Table 1). calix[4]pyrrole and N-confused calix[4]pyrrole
Due to the short chain length of methylene groups, with retention time 3.4 and 3.8 minute Scheme 1

Tetrahedron Letters
See Supplementary material, Figure S2 ). and 10 % yields along with the side products e.g.
4
(
Moreover, the same reaction was performed in the dipyrromethane and tripyromethane. Apart from
presence of (1d) ionic liquid in dichloromethane. this, a black tarry product was also observed, but
After 40 min, the TLC of crude reaction mixture due to less sample availability and poor solubility
indicated the complete consumption of starting
in organic solvents
a
detailed structural
material with the formation of compound 3+4 in 60
characterization was not possible.
R1 R2
R1 R2H
N
O
R1
R2
NHHN
NHHN
NH
AILs-ZnCl2
DCM, rt
R1
R2
R1
R2
1
R
+
R2
+
R1
2
N
H
R
NHHN
R1 R2
3
R1 R2
4
2
1
2
1
2
1
2
2
2
2
2
2
2
a. R =R = CH
3a. R =R = CH
4a. R =R = CH
3
3
3
1
2
1
2
b. R =R = C H
2
3b. R =R = C H
2 5
5
1
2
1
2
1
2
c. R = CH , R = C H 3c. R = CH , R = C H
3
4c. R = CH , R = C H
3 2 5
2
5
3
2
5
1
2
1
2
1
2
d. R -R = (CH )
2
3d. R -R = (CH )
4d. R -R = (CH )
5 4
4
2 4
1
2
1
2
1
2
e.R -R = (CH )
2
3e. R -R = (CH )
4e. R -R = (CH )
2 5
5
2 5
1
2
1
2
f. R -R = (CH )
2
3f. R -R = (CH )
2 6
6
Scheme 1: Synthesis of calix[4]pyrroles and N-confused calix[4]pyrroles
X
R
N
N
1
a. R = -(CH ) SO H, X = CF COO
e. R = -(CH ) SO H, X = CF COO
2 4 3 3
f. R = -(CH ) SO H, X = CF SO
2
b. R = -(CH ) SO H, X = CF SO
3
3
3
2
c. R = -(CH ) SO H, X = CH SO
3
3
3
3
2 4 3 3 3
g. R = -(CH ) SO H, X = CH SO
2 4 3 3 3
h. R = -(CH ) SO H, X = HSO
2
d. R = -(CH ) SO H, X = HSO
3
3
3
3
2
3
3
4
2 4 3 4
Figure 1: Structures of Brønsted acidic ionic liquids
-
COO ]) (1a) as a ZnCl
The use of ([HSO
3
-pmim][CF
3
2
was added (Table 1, Entry 3). The reaction
catalyst showed a higher catalytic activity as
performed without acid catalyst with prolonged
-
compared to [HSO
3
-pmim][ HSO
4
]) (1d) and the reaction time gave calix[4]pyrrole along with other
yields improved further, when catalytic amount of linear products. This type of conversion has been

5
2
reported in the litrature (Table 1, Entry 2). neutral alumina under virtually identical
3
Typically, equimolar amounts of pyrrole and
acetone (14 mmol) were taken up in stirred solution
of dichloromethane (10 ml). Ia (0.14 mmol) and
catalytic amount of zinc chloride was added to this
stirred solution and allowed to reflux. The progress
of the reaction was monitored after each 10 min. To
our delight, after 40min, an excellent concentration
of 3 was recognized on TLC. The reaction was
worked-up to this point. Importantly, no dimer
formation was observed at refluxing conditions. On
the other hand reaction at refluxing temperature did
not offer any noteworthy advantages in the yield of
N-confused calix[4]pyrrole.
conditions. This yield enhancement in the presence
of Ia–Ih assisted by zinc chloride may be attributed
to be template effect of chloride anion between
pyrrole rings, forcing the reacting groups to the
correct position, for regular calix[4]pyrrole
formation (Figure 2).
X
H
N
H H
N N
H
N
Figure 2: Plausible geometry of calix[4]pyrrole
with chloride anion
Interestingly, when the reaction was performed
with various organic solvents the best results were
obtained in dichloromethane; where chloride ion
act as a template to assist the formation and
selectivity of regular calix[4]pyrroles. This finding
was in sharp contrast to the report, where a
declining trend favouring the formation of cyclic
tetramer is reported using a high stoichiometric
Prompted by above reports and in
continuation of our interest in synthesis of various
meso substituted calix[4]pyrroles and N-confused
calix[4]pyrroles, we report herein a high yielding
and time efficient synthesis of calix[4]pyrroles,
which would be a new practical alternative to the
existing procedures for this useful ring system. The
results are summarized in Table 1. The results
indicate that the use of AILs catalysts directs the
reaction process towards the efficient formation of
2
4
ratio of pyrrole and acetone with Al-MCM-41 .
Presumably, it is due to the strong acidity of 1a
over Al-MCM-41 which may significantly affect
the formation of porphyrinogens.
3
. Compound 3 was isolated typically in between
8
0-93 % yields by column chromatography over

Tetrahedron
6
b
Table 1: Synthesis of calix[4]pyrrole and N-
Entry ZnCl /AILs ketone Time Yield (%)
2
confused calix[4]pyrrole in presence of different
(min)
40
3
4
a
Brønsted acidic ionic liquids Ia-1h
1
2
3
4
5
6
ZnCl /1a
2
2a
2b
2c
2d
2e
2f
92% 3%
80%
c
Yield (%)
Entry ZnCl
AILs
-/1a
2
ketone Time
(min)
ZnCl /1a
2
60
-
/
3
4
ZnCl /1a
2
40
80% 2%
85% 3%
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
120
360
40
45
45
45
50
50
50
50
79.60 20.40
ZnCl /1a
2
45
b
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
2
/-
60
-
ZnCl /1a
2
40
93
90
6
-
2
/1a
/1b
/1c
/1d
/1e
/1f
/1g
/1h
94.76 5.33
ZnCl /1a
2
60
a
2
80
80
5%
Reaction conditions: reaction temperature 25 °C,
2
-
6.13
4
pyrrole (14.4 mmol), ketones (14.4 mmol); solvent
b
b
(10 mL) dichloromethane; Isolated yields.
2
49.49
80
2
The structures of 3a-3f and 4a, 4c, 4d and 4e
1 13
were confirmed by IR, H-NMR, C-NMR and
2
80
5
75
-
HRMS spectroscopic data and compared with
2
b
25
10
2
50
7
reported literature.
a
The rapid development in the synthesis of
Reaction conditions: reaction temperature 25 °C,
calix[4]pyrroles and N-confused calix[4]pyrroles
pyrrole (14.4 mmol), acetone (14.4 mmol); solvent
b
10 mL) dichloromethane; other linear products
building blocks used in the
supramolecular
(
c
were observed; HPLC yields
chemistry, stimulate continued investigation of
methods for one-flask synthesis.
Thus high yield of compound 3a in the
presence of Brønsted acidic ionic liquids prompted
us to examine the reaction in dichloromethane of
other ketones 2b-2f with pyrrole. The reaction
products and yields are summarized in Table 2.
Table 2: Reaction of different ketones 2a-2f with
pyrrole in presence of (1a)
Acknowledgments
The authors are thankful to the University Grant
Commission (UGC), and the Department of
Science and Technology (DST), New Delhi, for the
financial assistance.

7
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