Syntheses of Calix [ 4 ] Pyrroles by Amberlyst-15 Catalyzed Cyclocondensations of Pyrrole with Selected Ketones

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 reaction of dialkyl or cycloalkyl ketones with pyrrole catalyzed by reusable AmberlystTM-15 under eco-friendly conditions.


Introduction
The design and synthesis of receptors to recognize, sense and bind the anions is an important area of supramolecular chemistry [1][2][3][4][5].Calix [4]pyrroles are conformationally flexible macrocycles [6,7] of significant importance due to their binding under different conditions with anions [8], neutral substrates [9] and metal ions [10].The complexation behavior of calix [4]pyrroles with anions and cations has been widely studied using fluorescent [11], colorimetric [12] and electrochemical signaling [13] devices.They find interesting applications as raw materials for transformation into novel calix [4]pyridines and calix [4]pyridinopyrroles [14], as new solid supports capable of separating anion mixtures [15], in optical recognition of organic vapors [16] and as biologically active species [17].Porphyrinogens, bearing hydrogen atoms at meso positions, are key intermediates in biological and chemical synthesis of porphyrins [18,19].Various attempts have been made for the development of milder methods for the synthesis of porphyrins [20][21][22], N-C isomerization [23,24] and higher homologues of porphyrins [25].The meso-octamethylcalix [4]pyrrole 3a has been prepared by condensation of pyrrole with acetone in the presence of aqueous hydrochloric acid or methanesulfonic acid in methanol [26,27].The reaction of pyrrole and acetone in the presence of trifluoroacetic acid in ethanol gave meso-octamethylcalix [4]pyrrole (3a) and the N-confused octamethylcalix [4]pyrrole (4b) [28].The reactions of pyrrole with dialkyl ketones in the presence of protic acids (HCl, H 2 SO 4 ), organic acids (CH 3 SO 3 H) and Lewis acids (BBr 3 and BF 3 ) have also been used in the synthesis of calix [4]pyrroles [29][30][31][32][33].The reaction of excess of pyrrole with dialkylketones in the presence of acid gave 5,5-dialkyldipyrromethanes which on subsequent reaction with dialkylketones in the presence of borontrifluoride-etherate formed strapped calix [4]pyrroles [34,35].These acids are considered hazardous and corrosive and their removal from the reaction mixtures is difficult.Recently, condensations in dichloromethane of pyrrole with dialkyl ketones in the presence of the molecular sieve Al-MCM-41 and the zeolite HY afforded dipyrromethane, calix [4]pyrroles and other linear products, but not the N-confused calix [4]pyrroles [36,37].Amberlyst™-15 is an inexpensive and non-hazardous solid acid, useful as a catalyst.It can be easily handled and is removed from reaction mixtures by simple filtration.In recent years Amberlyst™-15 has been explored as a powerful catalyst for various organic transformations [38].The reaction of pyrrole with different aldehydes in dichloromethane in the presence of Amberlyst TM -15 gave dipyrromethanes, which in the presence of excess aldehydes followed by oxidation with chloronil [39] or DDQ [40] gave 5,10,15,20-tetraaryl porphyrins, whereas the reaction of pyrrole with aldehydes in the absence of solvent followed by oxidation with DDQ gave 5,10,15-triarylcorroles [40].Herein we report an eco-friendly synthesis of calix [4]pyrroles and related products under mild reaction conditions by the reaction between ketones and pyrrole catalyzed by Amberlyst™-15.

Results and Discussion
The reaction in dichoromethane of pyrrole (1) with acetone for 8 hrs in the presence of Amberlyst™-15 (10 %, w/w) gave the calix [4]pyrrole 3a and the N-confused calix [4]pyrrole 4a in 83 and 14 % yield, respectively (Scheme 1, Table 1).On the other hand, an Amberlite™ IR-120 catalyzed reaction of pyrrole with acetone afforded 3a and 4a in poorer yields (61.3 and 3.7 %).The same reaction was examined using different solvents and the best yields were obtained in dichloromethane (Table 1).This high yield formation of 3a and 4a in the presence of Amberlyst™-15 prompted us to examine the reaction in dichloromethane of other ketones 3b-3g with pyrrole.The reaction products, yields and physical data are given in Table 2.

Product Characterization
A strong N-H stretching peak appeared at 3450 cm -1 in the IR spectra of calix [4]pyrrole 3a in both CHCl 3 solution and KBr pellets.In the 1 H-NMR spectrum of 3a a sharp singlet at δ 1.50 is assigned to the eight bridge methyl groups, a doublet at δ 5.89 (J = 2.5 Hz) to the eight pyrrole ring β-protons and a broad peak at δ 7.01 was assigned to the four N-H protons.The ratio of the integrated peak areas are 6:2:1, in agreement with the empirical formula and D 4 symmetry of 3a.In the 1 H-NMR spectrum of 4a the appearance of a multiplet at δ 1.56-1.48for the eight bridge methyl groups, signals at δ 6.30 and δ 5.50 corresponding to the αand β-pyrrole hydrogens (1H each) of the 2,4-disubstituted pyrrole, respectively, well apart from those of the 2,5-disubstituted pyrrole β-hydrogen atoms (δ 5.93-6.04,6H) and three broad peaks at δ 7.75 (1H), 7.41 (1H) and 7.26 (2H) for four N-H protons indicate the reduction of symmetry as compared to 3a.Indeed, the higher polarity and non-zero dipole moment of N-confused calix [4]pyrrole than calix [4]pyrrole have been attributed to this lower symmetry [50].Calix [4]pyrrole 3a and N-confused calix [4]pyrrole 4a each gave a [M-H] -ion peak at 427.2860 and 427.2868, respectively, along with a peaks at 462.7863 and 462.7859 for the [M+Cl] -ion at 65V (cone voltage) in negative ion ESI-MS.A detailed ESI-MS study of these macrocycles has been reported recently [44].The structures of calix [4]pyrroles 3a-3g and N-confused calix [4]pyrroles 4a, 4b, 4d and 4e were all confirmed by their physical and spectroscopic data (Tables 2, 3 and 4).
In the reactions of 2a, 2d and 2e with pyrrole, a third isomer (1-4 %) was also observed, but due to small sample availability and poor solubility in organic solvents a detailed structural characterization was not possible [28].The reactions of cycloheptanone (2f) and cyclooctanone (2g) with pyrrole gave the corresponding calix [4]pyrroles 3f and 3g in 30.2% and 19.7% yield at ambient temperature, but the time required for the conversions was considered too long.By refluxing the reaction mixtures, improved yields of 46.0 % (3f) and 40.0 % (3g) were obtained after shorter reaction times.In the reactions of pyrrole with 2c, 2f and 2g, the corresponding N-confused calix [4]pyrroles could not be isolated.This could be attributed to the steric hindrance encountered with these higher acyclic and cyclic ketones.The C-2 and C-5 atoms are more reactive than the C-3 and C-4 positions in pyrrole, hence the electrophilic reaction at C-2 and C-5 position of pyrrole with acetone in the presence of acid gave calix [4]pyrrole in preference to N-confused calix [4]pyrrole [28,43].The data presented in Tables 1 and 2 indicates that Amberlyst™-15 is a more efficient and superior catalyst than other solid catalysts for the formation of calix [4]pyrroles in DCM [36].The recovered catalyst was recycled twice with modest product yield loss being noted (Table 1).The catalytic activity of Amberlyst™-15 is remarkable and it is environmentally benign.The ready commercial availability of this catalyst and its superiority over the existing methods should make the present protocol an attractive addition to the many conventional procedures.

Conclusions
A facile and efficient method has been developed for preparing a variety of calix [4]pyrroles and Nconfused calix [4]pyrroles in high yields by the reactions of various ketones with pyrrole in dichloromethane in the presence of a catalytic amount of Amberlyst™-15.  a 1 H-NMR spectra of N-confused calix [4]pyrroles 4a and 4e are comparable to those reported in [43] and [28] respectively.

General
The infrared spectra (IR) were recorded on Perkin Elmer FT-1710 spectrophotometer. 1 H-NMR spectra were recorded in CDCl 3 with TMS as internal standard on a Bruker Avance 300 MHz spectrophotometer.ESI-MS spectra were recorded on KC ESI 455-TOF mass spectrometer (Micromass, Manchester, UK).The starting materials such as pyrrole, ketones, Amberlyst™-15 and Amberlite™ IR-120 were obtained from Acros USA.Pyrrole and ketones were distilled immediately prior to use.The experimental operations were performed under ambient conditions.Neutral alumina was used for all the chromatographic purifications.

Table 1 :
Amberlyst™-15 catalyzed condensation of pyrrole and acetone in different solvents a .
bCatalyst was reused over three runs.