Syntheses and reactivity of calixarenes functionalized at meso positions

In this paper the syntheses and reactivity of calixarenes functionalized at their meso positions are reviewed. First the calixarenes substituted at one, two and all meso positions are described; they are followed by presentation of ketocalixarenes


Calixarenes Substituted at One meso Position
Selected examples of calix [4]arenes and calix [6]arenes substituted at one meso position are described, showing their syntheses, reactivity and results of conformational analyses.

OMe
OMe OMe The same procedure leading to 2 served for subsequent attachment of chloro or iodo, pyridinium and amino moieties at the end of the alkyl tether of 3-6 carbon atoms at a single meso position of calixarene 1. 24 The reaction of 2 with 1-bromo--chloroalkanes containing 3 It was found that 5 (n = 3-5) treated with NaI afforded iodo derivatives 6 (n = 3-5), while the reaction with pyridine yielded pyridinium salts 7 (n = 3-5).The attachment of aniline or its derivatives required their conversion into their potassium salts.Thus, calixarene 5 (n = 4,5) was treated with previously prepared potassium salts of aniline or its derivatives to give compounds 9 (n = 4,5).It should be noted that the above syntheses of amine-functionalized calixarenes enable their metallation or binding to solid supports.24  In the study of calixarenes, substituted at a single meso position 25,26 compound 3d was reduced to give the alcohol 10, and was esterified to give esters 11a-c. 27However the attempted conversion of 3d to an amide unexpectedly afforded lactone 14.The conformational analysis of calixarene 3d has been performed in solution and in crystalline state.It was found that calixarene 3d in CDCl3 undergoes a fast interconversion of phenyl units.The steric crowding of t-butyl groups on the wide rim exists, therefore the less symmetrical paco conformers prevail, while the more symmetrical cone and 1,2-alt are not favored.The existence of a special monomeric paco-1 conformation of 3d with an intramolecular hydrogen bond in apolar solvents was confirmed by DOSY NMR measurements and MM calculations; it was found that cone, paco-2 and 1,2-alt conformers of 3d form aggregates. 28  The crystal structures of unsolvated 3d as well as of two mixed solvent complexes 15a, i.e.

3d•EtOH•H
2 O (1:1:1) and 15b, i.e.3d•EtOH•THF (1:1:1) are reported.It is of interest that in paco 3d the carbon atom of the CH2 group, bearing the carboxyl group becomes a centre of chirality due to the asymmetric geometry of the calixarene; this is a rare conformational chirality isomerism.The above investigation of 3d is promising for use of similarly substituted calixarenes in design of nanostructures 29  and of immobilized devices.30

2.2.Calix[6]arenes
In order to obtain calix [6]arenes substituted at one meso position, the photochemical reaction of calixarene 16 with NBS was performed.The resulting bromination of a single meso position, followed by hydrolysis afforded the desired calixarene 17 which is hydroxylated at a single meso position.
Calixarene 17 is a starting material for synthesis of a wide range of calixarenes functionalized at a single meso position.Thus the treatment of 17 with thionyl chloride yields calixarene 18 which upon reaction with 2-propanol or with TFE gives calixarenes 19a,b, and upon reaction with m-xylene or with p-t-butylphenol yields 20a,b, respectively. 31he above investigation has shown that easily available hydroxy-and chloro-functionalized calixarenes 17 and 18 are valuable starting materials for a variety of calixarenes substituted at one meso position. 31

Calixarenes Substituted at Two meso Positions
In the first part of this section, calixarenes meso disubstituted by various nucleophiles are shown; then the functionalization of meso positions of calixarenes by ortho-Fries rearrangement is described.

• Sulfur nucleophile
The reaction of 26 with NaSMe was performed using THF as a solvent; it was found that the results depend upon the dryness of THF.The reaction made in "wet" THF yielded the expected disubstituted bis(spirodienone)calixarene 30, while in dry THF the meso trans-disubstituted calixarene 31 was formed.The LiAlH4 reduction of 30 may also afford calixarene 31.

•Carbon nucleophiles
The reaction of 26 with sodium enolates of acetylacetone or diethyl malonate yielded 37 and 38, respectively.The subsequent LiAlH4 reduction of 38 gave calixarene 39.The cone conformation of parent calixarene 22 is stabilized by the existence of the circular array of hydrogen bonds between hydroxyl groups.It was observed that meso diphenyl calixarene 43 also adopts the cone conformation, whereas meso dimesityl calixarene 44 has the 1,2-alt conformation due to the presence of bulky mesityl substituents. 34Calixarenes meso trans disubstituted by alkyl, allyl, p-bromobenzyl and carboxyl groups have been obtained via a simple two-step procedure.36  The first step involves lithiation of one meso position of 51 followed by reaction with bromoderivatives RBr (R=Me, Et, allyl) or with CO2.The obtained monosubstituted products 52-55 adopt a paco conformation in CDCl3 solution, however addition of small amounts of NaI and acetonitrile-d3 leads to their cone conformation, this behavior being due to complexation of the sodium ion with the methoxy group.
All products adopt a cone conformation, even when the starting calixarenes were not in cone conformations (as 65a,b), but were in paco (as 66a,b) or 1,3-alt conformation (as 67a,b).In the case of mono-rearranged products, the remaining O-carbamate group is stable (as in 69a,b) or may undergo hydrolysis to form the hydroxyl group (as in 68a,b).
The rearrangement proceeds via an intermediate five-membered ring.In the case of monorearrangement, the deprotonation by LDA affords a carbanion, which attacks the carbonyl of the ortho (adjacent) O-carbamate group, to form a five-membered ring.The subsequent quenching of the reaction mixture completes the migration, affording compound bearing at one meso position the amide group.For cone 65a, the formation of five-membered ring in the intermediate 74, leading to axial mono-rearranged product 75, is presented.The bis-rearrangement proceeds via two five-membered intermediates.
74 75 It should be pointed out that the above Fries rearrangement proceeds readily and the obtained calixarenes containing amide groups at meso positions undergo further reactions; as examples those of 70a and 73a are shown.
In 70a the existence of two axial amide groups in proximal positions allows the reaction with n-propyl bromide in the presence of K2CO3 affording 76, and the reaction with acetic acid yielding bis-lactone 77.This behavior of 70a results from the close proximity of two axial amide groups, which increases the acidity of the hydroxyl groups.
It is noteworthy that in 73a, bearing two equatorial amide groups in distal positions, the propylation in the presence of K2CO3 would be impossible, instead NaH is required.The propylation of 73a in the presence of NaH affords 78 which by reduction with diborane yields the diamine 79. 37

O
The conformational analysis of trans-disubstituted calixarenes 80a-c has shown that in 80a (R = Me) the cone and 1,2-alt conformations coexist in CDCl3, however in calixarenes 80b and 80c bearing more bulky substituents (R = i-Pr and t-Bu, respectively) the 1,2-alt conformation is preferred. 38or 1 H NMR examination of 81, the model compounds 83 (with both dimethylamino groups nonprotonated) and 84 (with both dimethylamino groups protonated) have been synthesized.The reaction of 81 with Cs 2 CO 3 in acetonitrile afforded 83, and reaction with p-toluenesulfonic acid yielded 84.The measurement of 1 H NMR spectra has confirmed the existence of 81 as a zwitterion 82 in THF. 39

4.Calixarenes substituted at all meso positions
The functionalization reactions of calixarenes proceeding at all meso positions will be described for calix[n]arenes, where n = 4, 5 and 6.Then the direct synthesis of chiral meso substituted calixarenes will be shown.
1][42] Reactions of calixarenes 86a-c with O-, N-and C-nucleophiles involve replacement of bromine atoms by nucleophiles, leading to calixarenes 87a-c functionalized at all meso positions.[42] OMe n The solvolytic Friedel-Crafts reaction of 93 (obtained from the corresponding calixarene by similar bromination with NBS) with 2-methylfuran, performed with the use of 1,2-butylene oxide as a HBr scavenger, afforded 94. 43

93
• Functionalization of calix [5]arenes at all meso positions Replacement of bromine atoms in 86b by nucleophiles affords calixarenes 87b.It was found that the reactions with TFE and 2-propanol proceed by refluxing 86b with these alcohols, however in the case of propargyl alcohol, m-and p-xylenes and p-t-butylphenol, the use of HFIP is necessary. 41ne should point out the importance of calix [5]arene derivatives functionalized at meso positions; their cavity is larger than that of functionalized calix [4]arenes, but in contrast to larger calixarenes they still adopt nearly symmetric cone conformations.• Functionalization of calix [6]arenes at all meso positions Calixarene 86c was refluxed in alcohols MeOH, EtOH, n-PrOH, i-PrOH, n-BuOH to give products 87c substituted at all meso positions by alkoxy groups.Refluxing of 86c in TFE yielded 86c (Nu = OCH2CF3), and refluxing of 86c with ethylene glycol in TFE afforded 87c (Nu= OCH2CH2OH). 42Reactions of 86c with m-and p-xylenes and with mesitylene leading to products 87c substituted at all meso positions by aryl groups were carried out in HFIP.Reactions of 86c with sodium azide and with aniline performed in TFE, lead to calixarenes 87c (Nu = N3) and 87c (Nu = HNPh), respectively.Acetolysis of 86c afforded 87c (Nu = OAc) which upon LiAlH 4 reduction yielded 87c (Nu= OH).It is worth noting that the presence of substituents at meso positions of 87c rigidifies the calixarene structure.

MeO
Calixarene 88 with all four meso positions monosubstituted by phenyl groups has been obtained from tetraketocalixarene 89b. 44The synthesis begins with the reaction of 89b with PhLi.The starting tetraketocalixarene 1,3-alt 89b was obtained by methylation of 89a; this protection of the hydroxyl groups of 89a was necessary to avoid the acid-base reactions of these hydroxyl groups with PhLi.
The reaction of 89b with PhLi in THF afforded trans di-addition product 90; with the excess of PhLi, the tetra-addition product 91 was obtained as a mixture of four isomers rccc, rcct, rctt and rtct, which upon recrystalization gave one product, 91 (rccc).The next step was the reduction of the four hydroxyl groups in 91, performed with Et3SiH/CF3COOH to give 88. 44

Y = OMe
It was found that 88 has all cis, i.e. the rccc form; 88 in the crystal adopts the 1,3-alt conformation.Calixarene 92 which is an isomer of 88 has the rcct form; 92 in the crystal also adopts the 1,3-alt conformation.Examination of the X-ray structures of 88 and 92 shows that in the 1,3-alt conformation their methoxy groups, intramolecularly hydrogen bonded to neighboring hydroxyl groups are pointing toward the cavity (orientation "in"). 44

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© ARKAT-USA, Inc.When 88 is dissolved in acetone-d6, the hydroxyl protons exchange with the deuterium atoms present in residual water of the solvent.The analysis of the 1 H NMR (400 MHz) spectrum of 88 in acetone-d6 differs from that in CDCl3.This behavior results from isotopic perturbation of the conformational equilibrium in 88.Several species (isotopomers) of a different number and positions of the OD groups are possible for 88. 45   An attention should be paid also to the method allowing a direct construction of mesosubstituted chiral calixarenes in which the chirality results from the substitution of meso positions.46 This method is highly valuable, having in mind that among syntheses of calixarenes substituted at meso positions, the approach to chiral species is rare.

(rccc)
The synthetic procedure is similar to the shown below annulation of the biscarbene complex 93 with diyne 94, leading to calixarene 95; in this reaction new rings of the product were built.The formed calixarene 95 is meso-unsubstituted, however the substitution of one or both methylene groups in 93 and/or 94 allows to obtain the desired meso-functionalized calixarenes. 46iscarbene complexes: unsubstituted 96a, (X=H) and disubstituted 96b (X=OMe) and diynes: (R,R)-97 (X=OMe), (S,S)-97 (X=OMe) and (R,R)-98 (X=OTBS) served as starting compounds.Synthesis of calixarenes, substituted at two meso positions: The reaction of 96a with diyne (R,R) 97 (X=OMe) afforded the mixture of cone and paco conformers of calixarene 99, substituted at two meso positions, the major species being cone 99.Similarly the reaction of 96a with diyne (R,R) 98 (X=OTBS) afforded the mixture of cone and paco conformers of calixarene 100, the major product being cone 100.Upon removal of the TBS group from 100, the calixarene (S,S) 101, substituted at two meso positions, existing exclusively as cone conformer was obtained.

. .
In conclusion, the above syntheses are an interesting approach to chiral calixarenes substituted at two and at all meso positions.46

Ketocalixarenes
Ketocalixarenes are a class of compounds which may be regarded as calixarenes functionalized by carbonyl groups situated at their meso positions; they are interesting as synthons for various target products, among them meso-substituted calixarenes.Selected examples of syntheses and reactivity of ketocalixarenes are described below.The synthesis of ketocalixarenes may be achieved by oxidation of calixarene 104b at the meso positions using CrO3.In contrast to 104a, the starting calixarene 104b containing four acetate groups is conformationally rigid, because the rotation of the rings through the annulus is blocked by the bulky acetate substituents.Therefore 104b exists as different atropoisomers rather than the usual types of conformers.
The acetylation of 104a afforded the starting calixarene 104b as a mixture of paco 104b and 1,3-alt 104b.This atropoisomeric mixture upon treatment with CrO3 in boiling Ac2O/AcOH yielded a mixture of paco 105 (from paco 104b) and 1,3-alt 106 (from 1,3-alt 104b), which could be separated by fractional crystallization.The basic hydrolysis of paco 105 afforded paco diketocalixarene 107 with the carbonyl groups in cis positions.During CrO3 oxidation it was found that the rotation of the aryl rings through the annulus does not occur, and that only meso positions connected to geminal rings anti, i.e. rings pointing to opposite directions can be oxidized; the meso positions which are between rings syn, i.e. rings pointing out to the same direction, cannot be oxidized.

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© ARKAT-USA, Inc.In the above process the formation of xanthone groups under methylation conditions is facilitated by the activating influence of the carbonyl groups which enables the intramolecular SNAr reaction between a methylated benzene ring and a neighboring phenolate serving as a nucleophile (A→B→C).It should be pointed out that 111b is able to form such xanthone derivatives, whereas for lower calixarenes it would be impossible, since the large calixarene can better accomodate the increased strain resulting from the presence of the rigid xanthone group.Using a large excess of MeI, dimethylacetamide as a solvent, and Cs2CO3 as a base, 111b could be converted into desired 111c. 52udying the reactivity of ketocalixarenes it was found that tetraketocalixarene 115 upon treatment with excess t-BuLi yielded a complex mixture, with 116 as a major product.Recrystalization of the crude product from CHCl3/acetone afforded a mixture of 116, di-tbutylated at two bridges, and 117, tri-t-butylated at three bridges.It should be emphasized that 116 and 117 are rare examples of calixarenes containing two different functionalities at the meso bridges.In the above reaction, one of the four methoxy groups of 115 was cleaved; compounds 116 and 117 bear only three methoxy groups at the narrow rim.Rotation of the t-butyl groups situated at the meso bridges in calixarenes 116 and 117 is restricted due to steric hindrance.53  By way of contrast, the rotation of t-butyl groups is not restricted in the cone calixarene 118 in which two opposite bridges are substituted by t-butyl groups.

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© ARKAT-USA, Inc. Investigation of the dimethylation and dibenzylation reactions of tetraketocalixarene 119a has shown that they afford proximal (i.e.disubstituted in neighboring rings) products 119c and 119f. 54he result of these processes is other than in the case of the parent 22 which upon the same reactions affords distal, (i.e.disubstituted in opposite rings) products.The methylation products were mono-and di-substituted tetraketocalixarenes 119b and 119c, respectively; the increased amount of a base gave rise to formation of tri-and tetramethylated compounds 119d and 119e.The benzylation afforded di-and tetrasubstituted products 119f and 119g, respectively.
In contrast to parent calixarene 22 which has the cone conformation, the tetraketocalixarene 119a, along with its substituted products 119b-g adopts the 1,3-alt conformation.54

Conclusion
Calixarenes functionalized at their meso positions have been studied in order to achieve new products having desired properties.Since the investigation of calixarenes dealing with their syntheses, reactivity and a large variety of applications is very intense, 55-70   only selected examples of considered compounds are described in this review.
There are relatively few reports concerning functionalization of calixarenes at meso positions, compared to reports on modification of their wide and narrow rims, therefore it seemed of interest to review works on substitution of their meso positions, and to pay attention to the usefulness of obtained species for further reactions, which are often difficult to perform using other methods.

Acknowledgement
The financial support of this work provided by Polish Science Foundation (Grant NN 209441539) is gratefully acknowledged.
amines to the meso position of calixarenes, as an example, the reaction of 5 (n = 3 or 5) with cyclohexylamine leading to derivatives 8 is shown: also that 17 reacts with Et2NSF3 (deoxofluorinating agent DAST) via replacement of the hydroxyl group by fluorine, affording 21; one should mention that 21 is the first example of a calixarene functionalized by fluorine atom at the single meso position.

reaction of 26 with sodium azide affords 32 . 36
obtained trans 31 undergoes a thermal isomerization to give more stable cis 31.One may confirm this result by using Huisgen click reaction with an alkyne, however in order to avoid the concomitant Diels-Alder reaction of alkyne with the two diene systems of 32, the NaBH4 reduction of 32, leading to 33, was made.Treatment of 33 with dimethyl acetylenedicarboxylate yielded the desired 34 bearing two 1,2,3-triazole units.reaction of 26 with aniline afforded 35 which was reduced with LiAlH4 to give calixarene

Compound 26
It was observed that 26 reacts with tetrabutylammonium fluoride (TBAF) to give difluorinated bis(spirodienone)calixarene 40 which upon reduction afforded trans-difluorinated compound 41.In order to substitute meso positions with alkyl groups, the reactions of 26 with RMgX/ CuCN (for R = Me or Et, X = Br; for R = i-Pr, X= Cl) were carried out to give transdisubstituted calixarenes 42a-c. is also the starting material for synthesis of calixarenes meso trans-disubstituted by phenyl and mesityl groups, 43 and 44, respectively; the reaction of 26 with PhMgBr/CuCN affords 43, while the reaction of 26 with MesMgBr/CuCN leads to formation of bis(spirodienone)calixarene 45 which upon reduction with LiAlH4 yields 44.
obtain compounds related to spirodienonecalix[6]arenes, the mild oxidation of the macrocycle 46, joining structural features of calixarenes and spherands, was performed with 23 in a similar way as for calix[4]arene 22.It was found that the reaction result depends on the amount of used 23: the oxidation with one or two 23 equivalents leads to products 47 and 48 containing one or two spirodienone units, respectively, whereas the use of three 23 equivalents affords two isomeric compounds 49 and 50 containing three spirodienone units.It was observed that the oxidation of 48 with iodine in aqueous KOH solution also yields 49 and 50.49 and 50 isomerize upon heating in the solid state and in benzene solution; in equlibrium mixture 49 is the major component.35 and 1,3-alt calixarenes 65a,b-67a,b were reacted with LDA in THF to give products 68-77.The rearrangement was made from starting materials substituted by O-C(O)NEt2 groups; for synthesis of 68b, 69b, 72b and 73b the starting materials substituted by O-C(O)NMe2 groups were used

c 6 Nu•86a
Functionalization of calix[4]arenes at all meso positions The solvolysis of 86a with TFE (=2,2,2-trifluoroethanol), performed in the absence of an additional nucleophile or a Lewis acid, yielded 88, and when carried out with EtOH/TFE 1:1 mixture, gave 89.The reaction of 86a with NaN3 in the presence of TFE or HFIP yielded 90.In a similar procedure 86a reacted with n-PrOH, i-PrOH and ethylene glycol.Solvolysis of 86a in AcOH yielded 91 which upon reduction of acetoxy groups gave calixarene 92 bearing hydroxyl groups at all meso positions.
of 111b with MeI in MeCN in the presence of K2CO3 as a base did not give the expected 111c, instead the monoxanthone calixarene 112 and three calixarenes 113a,b and 114 containing two xanthone moieties were obtained.

arene 24, which by a bromination/debromination sequence, via compound 25 yields dibromoderivative 26. Reaction of 26 with nucleophiles leads to trans-disubstituted bis(spirodienone)calixarenes 27 which upon reduction with LiAlH4 give trans-disubstituted calixarenes 28. 32 22
that the calixarene 55 bearing carboxyl group may be converted into its methyl ester 56 by esterification with methanol; this compound may be also obtained from calixarene 51 by lithiation and subsequent treatment with methyl chloroformate.
grown from acetonitrile was investigated by X-ray diffraction.Calixarene 81 crystallizes with two MeCN molecules, one of them being situated inside the cavity.It was found that 81 adopts a cone conformation and exists in the crystal and in polar solvents as a zwitterion 82, with the axial dimethylamino group protonated and one hydroxyl group deprotonated.