The Use of Anhydrous Barium Hydroxide for Selective Alkylation of Dialkyloxy-tert-butyl-calix[4]arenes

A practical method of selective alkylation of the third hydroxyl group of disubstituted tert-butyl-calix[4]arenes using anhydrous barium hydroxide as a base was developed in this study. The use of this method in the synthesis of inherently chiral derivatives is shown herein.


Introduction
Calixarenes are unique macrocyclic compounds that display a lipophilic cup-like structure that can be easily functionalized at different positions. They are widely used as effective and selective receptors of ions and molecules [1]. Inherently chiral calixarenes with an asymmetric placement of achiral substituents on the calixarene platform are of particular interest [2][3][4][5]. The receptors that are based on such compounds can recognize and bind enantiomers of chiral "guest" molecules and are promising for use in chiral technologies. Therefore, the development of convenient, preparative methods for the synthesis of inherently chiral calix [4]arenes is an urgent task in organic and supramolecular chemistry.
The standard method for obtaining inherently chiral derivatives of calix [4]arene consists of the sequential functionalization of the lower or upper rim of the macrocycle. The alkylation of phenolic hydroxyl groups is the most important method of macrocycle modification. The methods of monoalkylation [6,7] and distal [6,8] or proximal [9,10] alkylation of the second phenolic group are well developed and are often used. At the same time, before the publication of our work, the practical methods of the selective substitution of the third phenolic hydrogen group had not been developed.
It is known from the literature that the alkylation of calix [4]arene in anhydrous DMF in the presence of barium hydroxide as a base leads, mainly, to the tri-substituted derivatives in the cone conformation. Despite the fact that this reaction has been known since 1983 [11], and has been used in almost 40 works, in almost all of these cases the alkylation of tetrahydroxy-calix [4]arenes was carried out, and products with three identical alkyl groups on the lower rim were obtained. The alkylation of the third phenolic group in distally substituted calixarenes has been described in only three works [12][13][14], and inherently chiral derivatives were obtained in only one of them [13].
In all cases of alkylation using this method, a mixture of Ba(OH) 2 ·8H 2 O and BaO was used instead of anhydrous barium hydroxide. When the alkylation of bromoacetic acid esters was carried out, which can be hydrolyzed under the action of barium hydroxide, only BaO was used [15,16]. However, the use of such reagents and their mixtures has a number of significant disadvantages for carrying out a selective process. It is clear that BaO was added to bind water, which is released during the interaction of the barium hydroxide with a hydroxyl group, as well as hydrate water. At the same time, an additional amount of Ba(OH) 2 is formed, which can significantly affect the result of the alkylation.
It is also known that, when it is stored, some part of the barium hydroxide goes into carbonate, and the barium oxide also goes into hydroxide and into carbonate. However, to accurately determine the content of the main substance in Ba(OH) 2 ·8H 2 O and BaO is very difficult. Therefore, in the literature, we observed the different ratios of the reagents and the conditions of reaction. In terms of one hydroxyl group, from 0.3 to 1.2 equivalents Ba(OH) 2 ·8H 2 O and from 0.5 to 6.6 equivalents BaO were taken. The temperature of the process varied from room temperature to 70 • C, and the reaction time varied from 0.5 h to 7 days. The yields of the tri-substituted calixarenes ranged from 20 to 80%. In addition, BaO is quite an expensive reagent.
We have noticed that the use of anhydrous barium hydroxide allows the removal of almost all of the disadvantages. This reagent is easily obtained by the dehydration of cheap Ba(OH) 2 ·8H 2 O. The content of the main substance in it is determined very simply, and a small excess of anhydrous hydroxide can serve as a good water-binding agent. In this work, we have investigated the possibility of using anhydrous barium hydroxide for the selective alkylation of 1,2-dialkyloxy-and 1,3-dialkyloxy-tert-butyl-calix [4]arenes in order to obtain inherently chiral derivatives.

Results and Discussion
Anhydrous barium hydroxide is easily obtained by the dehydration of commercial and cheap barium hydroxide octahydrate. In order to remove the hydrate water, it was heated up to 140-150 • C under vacuum conditions to a constant weight. During storage, barium hydroxide slowly reacts with carbon dioxide and moist air and turns into barium carbonate BaCO 3 . The amount of carbonate in the anhydrous reagent is easy to determine. In order to perform this, a sample of the substance must be dissolved in warm water; the barium hydroxide quickly and completely dissolves in the water, while the carbonate remains as a precipitate. The precipitate is filtered, dried, and weighed, then the amount of barium hydroxide is calculated (see Section 3). Dry anhydrous barium hydroxide should be stored in conditions without access to moisture and carbon dioxide from the air.
It is known that carbonates of alkaline metals are used as bases in the alkylation of calixarenes and lead to di-or tetra-substituted products [6]. In order to determine whether the presence of barium carbonate will affect the alkylation processes, we investigated the interaction of dipropyloxy-calixarenes 1a and 2a with propyl bromide in the presence of BaCO 3 . The experiments have shown that, with a such base, alkylation does not occur either at room temperature or when it is heated to 60-70 • C. That means that barium carbonate impurities do not interfere with this reaction and will not affect the composition of the products.
Next, we studied the possibility of selective alkylation of the third hydroxyl group on 1,2-dipropyloxy [9] 1a and 1,3-dipropyloxy [6] 2a derivatives of tert-butyl-calix [4]arene in the presence of anhydrous barium hydroxide. The alkylation was carried out in dry DMF with a different ratio of reagents. The qualitative and quantitative composition of the reaction mixture was determined using 1 H NMR spectra in a CDCl 3 solution. The following characteristic, separately placed 1 H signals were used for integration and comparison: The alkylation of the third hydroxyl group of calix [4]arenes 1a and 2a with propyl bromide proceeded very easily in 18-20 h at room temperature, and tripropyloxy-calix [4]arene 3a was formed with a yield of 95-96% (Scheme 1). In both cases, the formation of 3-4% of the tetrasubstituted derivative 4a was also recorded. The alkylation of 1,2-dioctyloxy-1b and 1,3-dioctyloxy-2b calix [4]arenes with octyl bromide was similar, but slightly more (up to 5-6%) of the corresponding tetrasubstituted product of 4b was formed.
In order to check whether complete substitution to tetrapropyloxy-calix [4]arene 4a can occur under these reaction conditions, we investigated the alkylation of tripropyloxycalixarene 3a. It was found that further alkylation of the compound 3a at room temperature practically does not occur. Even in the presence of a 1.5-fold excess of Ba(OH)2 after long-term mixing, no more than 9% of tetrapropiloxy-calix [4]arene 4a was formed. When it is heated, the amount of product 4a increases, but does not exceed 30%. Tetrasubstituted calixarene 4a can be separated by crystallization from DMF (4a is precipitated) or by column chromatography.
We have also shown that there is no hydrolysis of ester groups in these conditions. Alkylation with the ethyl ester of the bromoacetic acid of calixarene 2c with two distally placed ester groups led to the formation of corresponding trisubstituted product 3c, which was isolated in 95% yield after column chromatography. Therefore, anhydrous barium hydroxide can be used for alkylation with esters of bromoacetic acid.
Thus, the anhydrous barium hydroxide is a convenient reagent for the selective alkylation of calix [4]arenes. The amount of base should be slightly larger than the equimolar and sufficient to bind the water. An excess of barium hydroxide of 20-30% is the best option. The reaction should be carried out at room temperature (20-25°C) while stirring the mixture for at least 20 hours. However, before adding an alkylating reagent, the mixture of calixarene with barium hydroxide should be mixed for 30-40 minutes at 40-50°C for complete salt formation (except for calixarenes containing an ester group).

Scheme 2. Asymmetric alkylation of 1,2-dipropyloxy-calix[4]arene 1a.
The presence of two enantiomer structures in a 1:1 ratio was clearly visible in the 1 H NMR spectra with the addition of the Pirkle reagent [(S)-2,2,2-thrifluoro-1-(9-anthryl)ethanol]. Splitting of the 1 H signals of the methyl and hydroxyl groups, as well as bridging protons, was also observed ( Figure 1). In order to check whether complete substitution to tetrapropyloxy-calix [4]arene 4a can occur under these reaction conditions, we investigated the alkylation of tripropyloxycalixarene 3a. It was found that further alkylation of the compound 3a at room temperature practically does not occur. Even in the presence of a 1.5-fold excess of Ba(OH) 2 after longterm mixing, no more than 9% of tetrapropiloxy-calix [4]arene 4a was formed. When it is heated, the amount of product 4a increases, but does not exceed 30%. Tetrasubstituted calixarene 4a can be separated by crystallization from DMF (4a is precipitated) or by column chromatography.
We have also shown that there is no hydrolysis of ester groups in these conditions. Alkylation with the ethyl ester of the bromoacetic acid of calixarene 2c with two distally placed ester groups led to the formation of corresponding trisubstituted product 3c, which was isolated in 95% yield after column chromatography. Therefore, anhydrous barium hydroxide can be used for alkylation with esters of bromoacetic acid.
Thus, the anhydrous barium hydroxide is a convenient reagent for the selective alkylation of calix [4]arenes. The amount of base should be slightly larger than the equimolar and sufficient to bind the water. An excess of barium hydroxide of 20-30% is the best option. The reaction should be carried out at room temperature (20-25 • C) while stirring the mixture for at least 20 h. However, before adding an alkylating reagent, the mixture of calixarene with barium hydroxide should be mixed for 30-40 min at 40-50 • C for complete salt formation (except for calixarenes containing an ester group).
In order to check whether complete substitution to tetrapropyloxy-calix [4]arene 4a can occur under these reaction conditions, we investigated the alkylation of tripropyloxycalixarene 3a. It was found that further alkylation of the compound 3a at room temperature practically does not occur. Even in the presence of a 1.5-fold excess of Ba(OH)2 after long-term mixing, no more than 9% of tetrapropiloxy-calix [4]arene 4a was formed. When it is heated, the amount of product 4a increases, but does not exceed 30%. Tetrasubstituted calixarene 4a can be separated by crystallization from DMF (4a is precipitated) or by column chromatography.
We have also shown that there is no hydrolysis of ester groups in these conditions. Alkylation with the ethyl ester of the bromoacetic acid of calixarene 2c with two distally placed ester groups led to the formation of corresponding trisubstituted product 3c, which was isolated in 95% yield after column chromatography. Therefore, anhydrous barium hydroxide can be used for alkylation with esters of bromoacetic acid.
Thus, the anhydrous barium hydroxide is a convenient reagent for the selective alkylation of calix [4]arenes. The amount of base should be slightly larger than the equimolar and sufficient to bind the water. An excess of barium hydroxide of 20-30% is the best option. The reaction should be carried out at room temperature (20-25°C) while stirring the mixture for at least 20 hours. However, before adding an alkylating reagent, the mixture of calixarene with barium hydroxide should be mixed for 30-40 minutes at 40-50°C for complete salt formation (except for calixarenes containing an ester group).

Scheme 2. Asymmetric alkylation of 1,2-dipropyloxy-calix[4]arene 1a.
The presence of two enantiomer structures in a 1:1 ratio was clearly visible in the 1 H NMR spectra with the addition of the Pirkle reagent [(S)-2,2,2-thrifluoro-1-(9-anthryl)ethanol]. Splitting of the 1 H signals of the methyl and hydroxyl groups, as well as bridging protons, was also observed (Figure 1). The presence of two enantiomer structures in a 1:1 ratio was clearly visible in the 1 H NMR spectra with the addition of the Pirkle reagent [(S)-2,2,2-thrifluoro-1-(9-anthryl)ethanol]. Splitting of the 1 H signals of the methyl and hydroxyl groups, as well as bridging protons, was also observed (Figure 1).
The alkylation of compound 1a with optically pure chiral N-(1-phenylethyl)amide of bromoacetic acid led to the formation of a pair of diastereomers, 5c + 6c, with a de of 33% and a total yield of 96%. The stereoisomers were separated using column chromatography or crystallization [17]. The alkylation of compound 1a with optically pure chiral N-(1-phenylethyl)amide of bromoacetic acid led to the formation of a pair of diastereomers, 5c + 6c, with a de of 33% and a total yield of 96%. The stereoisomers were separated using column chromatography or crystallization [17].
We also used this method to obtain inherently chiral calixarenes with three different substituents on the lower rim. For this purpose, we selectively alkylated the calixarene derivatives with two different alkyl groups in the proximal 7a,b or distal 10a-d position [18,19] (Scheme 3). In the case of the alkylation of the proximally substituted derivative 7b with octyl bromide, the reaction took place at 100°C. Depending on the nature of the substituents in the starting compounds and the order of their placement on the macrocyclic platform, the ratio of iteromeric products 8/9 and 11/12 was observed from 1:1 to 9:1, with a total yield of 92-98%. The side tetrasubstituted product was formed in an amount of up to 3-4% and was easily removed by column chromatography.
All of the trisubstituted compounds that were obtained with this method had the cone conformation, which was confirmed by NMR spectra. Thus, in the 1 H NMR spectra, the signals of the axial and equatorial protons of the methylene bridges appeared as four pairs of doublets with the spin-spin coupling constant 12.5-13.9 Hz, and the distance between the signals of the Ar-CH-eq and Ar-CH-ax protons was greater than 0.5 ppm [20,21]. We also used this method to obtain inherently chiral calixarenes with three different substituents on the lower rim. For this purpose, we selectively alkylated the calixarene derivatives with two different alkyl groups in the proximal 7a,b or distal 10a-d position [18,19] (Scheme 3). In the case of the alkylation of the proximally substituted derivative 7b with octyl bromide, the reaction took place at 100 • C. Depending on the nature of the substituents in the starting compounds and the order of their placement on the macrocyclic platform, the ratio of iteromeric products 8/9 and 11/12 was observed from 1:1 to 9:1, with a total yield of 92-98%. The side tetrasubstituted product was formed in an amount of up to 3-4% and was easily removed by column chromatography.

Materials and Methods
The NMR spectra were registered on a Varian VXR-400 spectrometer operating a 400 MHz ( 1 Н) using TMS as a reference. The melting points were measured on a Boёtius heating block and are uncorrected. The reactions were carried out in anhydrous solvents. DMF All of the trisubstituted compounds that were obtained with this method had the cone conformation, which was confirmed by NMR spectra. Thus, in the 1 H NMR spectra, the signals of the axial and equatorial protons of the methylene bridges appeared as four pairs of doublets with the spin-spin coupling constant 12.5-13. 9 Hz, and the distance between the signals of the Ar-CH-eq and Ar-CH-ax protons was greater than 0.5 ppm [20,21].

Materials and Methods
The NMR spectra were registered on a Varian VXR-400 spectrometer operating a 400 MHz ( 1 H) using TMS as a reference. The melting points were measured on a Boёtius heating block and are uncorrected. The reactions were carried out in anhydrous solvents. DMF was purified by the azeotropic drying method with benzene. The column chromatography was performed on silica gel that was purchased from Acros Organics (0.040-0.063 mm, pore diameter 6 nm).

Preparation of Anhydrous Barium Hydroxide
The flask with commercial barium hydroxide octahydrate was heated at 140-150 • C in a vacuum (1-5 mm Hg) until the complete removal of hydrated water (to constant weight). The flask was required to be periodically stirred so that the substance remained in the form of a powder.

Determination of the Content of the Main Substance in Anhydrous Barium Hydroxide
A sample of barium hydroxide with a precisely determined mass m (about 1 g was taken) was dissolved in warm (60-70 • C) boiled (to remove soluble CO 2 ) water. The solution was protected from access to CO 2 from the air. The precipitate of water-insoluble barium carbonate was filtered off, dried, and accurately weighed m