The first direct synthesis of β-unsubstituted meso-decamethylcalix[5]pyrrole

The first direct synthesis of β-unsubstituted meso-decamethylcalix[5]pyrrole from pyrrole and acetone, with moderate yield, is described. The results showed that a bismuth salt was necessary to obtain calix[5]pyrrole, with the best results obtained using Bi(NO3)3.


Results and Discussion
Calix [n]pyrroles have attracted attention because of their ability recognize anions [1,2].To date, the calix [4]pyrroles have been studied the most, in part due to the ease with which the macrocycle can be obtained by the condensation of pyrrole with a ketone catalyzed by a Brønsted-Lowry acid such as HCl or methanesulfonic acid, or a Lewis acid such as zeolites with aluminium or cobalt, BF 3 or a bismuth salt [2][3][4][5].The synthesis of calix [n]pyrroles where n > 4 has been reported for n = 5 or 6.The latter compounds have been synthesized via two routes: a) from the sterically hindered diaryldi(pyrrol-2-yl)methane with 25% yield; and b) through the conversion of a calix [6]furan into the corresponding calix [6]pyrrole by an opening process of the six heterocycles, a selective reduction of the double bond and then a Paal-Knorr condensation with ammonium acetate with 40% yield [6,7].On the other hand, β-unsubstituted calix [5]pyrroles have been obtained by two routes: a) from the corresponding meso-decamethylcalix [5]furan, via a method analogous to that reported for calix [6]pyrroles, with 1% yield; and b) directly when the macrocycle is covalently bound to a calix [5]arene, with 10% yield [8,9].However, these approaches afford calix [5]pyrroles in low yield, which has limited the study of these compounds as anion receptors.
One explanation for why it is difficult to obtain calix [5]pyrroles via direct condensation of a pyrrole and the corresponding ketone is that the five heterocycle system is unstable: it opens and loses a pyrrole-isopropyl fragment to give the calix [4]pyrrole [8,10].Bi(NO 3 ) 3 25 100 --a As reported in [5].
Scheme 1: Products obtained by the reaction of pyrrole and acetone with bismuth(III).
In a recent report we described the synthesis of calix [4]pyrroles via the direct condensation of pyrrole with a series of ketones in the presence of a bismuth salt such as Bi(NO 3 ) 3 , BiCl 3 , BiI 3 , and Bi(CF 3 SO 3 ) 3 , in a 1 : 1 : 0.25 (pyrrole : ketone : BiX 3 ) ratio or with the ketone as a solvent at room temperature [5].Here we describe the first direct synthesis of β-unsubstituted mesodecamethylcalix [5]pyrrole (2) with Bi(NO 3 ) 3 in moderate yield (Scheme 1).
While studying the role of bismuth as a Lewis acid in the synthesis of calix [4]pyrroles, we found that at low catalyst concentrations some additional products were formed, as observed by 1 H NMR spectroscopy.These byproducts exhibited 1 H NMR, 13 C NMR and MS data consistent with those reported for calix[n]pyrroles with n = 4, 5 and 6 (compounds 1-3, respectively) and 5,5-dimethyldipyrromethane (4); see Experimental section [5,6,8].The relative proportions of these four products obtained using different catalyst equivalents are listed in Table 1.Compounds 1 and 2 were almost indistinguishable on TLC because of their similar R f values, and recrystallization from ethanol, as reported in other works, was not satisfactory to give the pure compounds.However, it was possible to separate 1 and 2 by HPLC, to obtain 2 in 25% yield (using the conditions specified in Table 1, entry 12).Compound 2 was found to be unstable, which probably decreased the yield.
To determine whether the reaction proceeds with other Lewis acids, we explored the use of MgCl 2 , CuCl 2 , ZnCl 2 , AlCl 3 , BiCl 3 , BiI 3 , BiPO 4 , Bi(OTf) 3 and Bi(NO 3 ) 3 under the conditions described above.Except for MgCl 2 , which gave none of the byproducts, all of these Lewis acids catalyzed the reaction to give 1 and/or 4 in amounts ranging from traces to moderate yields.Bismuth salts also produced 3. The results showed that a bismuth salt was necessary to obtain calix [5]pyrrole 2, with the best results being obtained with Bi(NO 3 ) 3 .The advantages of the method described here-namely that bismuth is relatively non-toxic, the macrocycle is obtained in moderate yield, and the synthesis proceeds without any intermediates-make it the best route to β-unsubstituted meso-decamethylcalix [5]pyrrole reported to date.
Experimental meso-Decamethylcalix [5]pyrrole (2).In a typical reaction, 6 mg of Bi(NO 3 ) 3 , 2 mL of acetone and 0.09 mL of pyrrole were mixed with stirring at room temperature for 6 h.The reaction mixture was filtered and the solvent evaporated without heat.
Reactants were not distilled prior to use and heat was avoided throughout the process.meso-Decamethylcalix [5]pyrrole was purified from the crude reaction mixture using an Agilent Tech-nologies HPLC 1200 system equipped with a multiple wavelength detector (G1365D) operating at 350 nm.Purification was performed on an analytical

Table 1 :
Catalyst conditions and relative proportions of compounds 1

, 2, 3 and 4 detected
in the crude reaction mixture by 1 H NMR spectroscopy.