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

Results and Discussion

Calix[n]pyrroles have attracted attention because of their ability to 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, BF₃ or a bismuth salt [2-5]. 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].

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(NO₃)₃, BiCl₃, BiI₃, and Bi(CF₃SO₃)₃, in a 1 : 1 : 0.25 (pyrrole : ketone : BiX₃) ratio or with the ketone as a solvent at room temperature [5]. Here we describe the first direct synthesis of β-unsubstituted meso-decamethylcalix[5]pyrrole (2) with Bi(NO₃)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 ¹H NMR spectroscopy. These byproducts exhibited ¹H NMR, ¹³C 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 MgCl₂, CuCl₂, ZnCl₂, AlCl₃, BiCl₃, BiI₃, BiPO₄, Bi(OTf)₃ and Bi(NO₃)₃ under the conditions described above. Except for MgCl₂, 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(NO₃)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(NO₃)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 Technologies HPLC 1200 system equipped with a multiple wavelength detector (G1365D) operating at 350 nm. Purification was performed on an analytical Zorbax Eclipse XDB-C18 column (150 × 4.6 mm, Agilent Tech. Santa Clara, CA, USA). The column temperature was maintained at room temperature and the mobile phases consisted of solvent A (80% MeOH/20% H₂O) and solvent B (100% EtOAc). Separations were performed by the following solvent gradient: 0 min 20% B, 2.5 min 22.5% B, 20–22.5 min 50% B, 24–26 min 80% B, 31–34 min 100% B, 42–47 min 20% B. All increases of solvent B were linearly programmed. The flow rate was 1 mL/min and the injection volume 20 µL. Yield ca. 25%; mp 208–210 °C; ¹H NMR (400 MHz, CDCl₃): 1.51 (s, 30H, CH₃), 5.77 (d, J = 2.8 Hz, 10H, CH), 7.54 (bs, 5H, NH); ¹³C NMR: 29.3 (CH₃), 35.3 (C(CH₃)₂), 102.8 (CH), 138.5 (β-C pyrrole); EIMS m/z: 535 (M^•+).