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Regioselective alkylation of a methylene group via meta-bridging of calix[4]arenes† Petr Slavı´k,a Hana Dvorˇa´kova´,b Va´clav Eignerc and Pavel Lhota´k*a
Received 8th June 2014, Accepted 13th July 2014 DOI: 10.1039/c4cc04356a www.rsc.org/chemcomm
The meta-iodo derivative, fixed in the cone conformation, enables the gram-scale preparation of a meta-bridged calix[4]arene. This intermediate, possessing a fluorene moiety within the macrocyclic skeleton, can be regioselectively alkylated on the corresponding methylene bridge to form a unique substitution pattern in classical calixarene chemistry.
Calix[n]arenes,1 a family of macrocyclic oligophenols, are very popular compounds in supramolecular chemistry due to their simple largescale preparation and isolation. The well-established chemistry of these compounds allows almost limitless derivatization of the basic skeleton. Moreover, as the size and/or the shape of the cavity can be easily tuned, calixarenes represent versatile building blocks in the design of many new receptors.2 In this context, the calix[4]arene is a perfect choice for the role of a molecular scaffold as it can be immobilized in any of its four basic conformations (cone, partial cone, 1,2-alternate, and 1,3-alternate), allowing a deliberate arrangement of selected functions into exactly defined positions. The most straightforward derivatization of a calixarene skeleton usually relies on electrophilic substitution of the upper rim (the aromatic part of the molecule), or on the alkylation/acylation of the lower rim (hydroxyl groups).3 On the other hand, the modification of methylene bridges remains relatively unexplored. Thus, the introduction of an alkyl group into the methylene bridge represents a synthetic challenge and several different approaches were developed. Biali et al. described4 the introduction of two alkyl groups based on the bis(spirodienone) derivative, which was brominated, reacted with the RMgX/CuCN agent and finally reduced using LiAlH4.
Another method5 is based on a ‘‘2+2’’ fragment condensation of alkylidene(2,20 -bisphenols), representing a multistage procedure with very low overall yields. From this point of view, the direct lithiation of methylene bridges6 followed by the reaction with alkyl halides seems to be much more promising. Unfortunately, this procedure (n-BuLi/THF/78 1C) can be performed only with methyl-substituted calixarenes which are conformationally mobile and does not work with immobilized conformations.7 Very recently we have reported the formation of an unprecedented calix[4]arene derivative possessing a bridge (single bond) between the meta positions of the neighbouring phenolic subunits.8 In this communication we report on the application of these compounds in the regioselective alkylation of calix[4]arenes immobilized in the cone conformation. As we have shown recently,9 the reaction of tetrapropoxycalix[4]arene 1 in the cone conformation with one equiv. of Hg(TFA)2 leads to the meta-substituted product 2 in 65% yield. The intramolecular cyclization of the chloromercurio derivative in the presence of Cs2CO3 as a base and Pd(OAc)2/AsPh3 as a catalyst gave the meta-bridged compound 4 in 60% yield (Scheme 1). While this reaction worked well on a 100 mg scale, the attempts to carry out the same procedure on a large-scale led to lower yields and rather complicated reaction mixtures. To overcome these problems
a
Department of Organic Chemistry, Institute of Chemical Technology Prague (ICTP), Technicka 5, 166 28, Prague 6, Czech Republic. E-mail: [email protected]; Fax: +420-220444288; Tel: +420-220445055 b Laboratory of NMR Spectroscopy, ICTP, Czech Republic. E-mail: [email protected] c Department of Solid State Chemistry, ICTP, Czech Republic. E-mail: [email protected] † Electronic supplementary information (ESI) available: Synthetic details, NMR spectra, dynamic NMR measurements and crystallographic details. CCDC 1006510–1006513. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc04356a
10112 | Chem. Commun., 2014, 50, 10112--10114
Scheme 1
Regioselective alkylation of calix[4]arenes.
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the organomercurial compound 2 was transformed into the corresponding iodo derivative 3 (86% yield, 5 grams scale) by the reaction with I2 in MeCN/CHCl3 (room temp., overnight). This compound was then successfully transformed into the meta-bridged derivative 4 (52% yield) on a gram scale with the Pd(OAc)2/PCy3HBF4 catalytic system in the presence of K2CO3 and Ag2CO3. Technically speaking, compound 4 contains a fluorene moiety within its molecule. It is well known from the chemistry of fluorene that the acidity of hydrogens in position 9 can be used for derivatization of this hydrocarbon. Deprotonation with a strong base leads to the formation of a stable aromatic carbanion which can react with electrophiles, including various alkylating agents. Although the fluorene fragment in bridged calixarenes is far from planarity, as can be seen in the X-ray structure of compound 4,8 we hoped that the acidity of the corresponding protons (invoked by the bridging) is still much higher than that of normal CH2 moieties (Fig. 1). The deprotonation of 4 was carried out using n-BuLi in 2-Me-THF. Originally colourless solution of calixarenes became yellow upon addition of 4 equiv. of BuLi at 78 1C indicating the formation of carbanions. Finally, the addition of propyl iodide led to smooth alkylation to give compound 5a in 82% yield (after column chromatography). The same reaction with LDA as a base gave slightly lower yield of the alkylated product (72%). To show the general applicability of this strategy several other alkylation agents were used. Thus, benzyl bromide, allyl bromide, and ethyl bromoacetate gave the corresponding monoalkylated products 5b–5d in 64, 72 and 46% yields, respectively. Interestingly, the products of dialkylation have never been identified in the reaction mixtures (Fig. 2 and Table 1). In all cases, the hydroxy derivative 6 was isolated as a minor byproduct (E10% yield). The formation of this compound could be explained by the reaction of radical species with the residual oxygen present in the reaction mixture.10 On the other hand, all our attempts to carry out this reaction by strictly excluding oxygen (glove box) did not lead to disappearance of this byproduct. Interestingly, when only 1 equiv. of BuLi was used for the deprotonation reaction, product 5a was isolated in low yield (11%) together with 6 (20%) and dimeric11 calixarene 7 (13%). The formation of dimer 7 is again indicative of the presence of a radical (formed from the carbanion)12 as the combination of these species seems to be the acceptable mechanism of its formation. Another indirect proof is a dramatic change in the colour when the solution
Fig. 1
Fluorene fragment in derivative 4.
Fig. 2
Byproducts from alkylation reactions.
This journal is © The Royal Society of Chemistry 2014
ChemComm Table 1
Alkylation of bridged calix[4]arenes
Entry
Alkylation agenta
Yield (%)
Byproduct (%)
1 2 3 4 5 6
Propyl iodide Propyl iodideb Propyl iodided Benzyl bromide Allyl bromide Ethyl bromoacetate
5a (82) 5a (11)c 5a (71) 5b (64) 5c (72) 5d (46)
6 (13) 6 (20), 7 (13) No 6 (12) 6 (10) 6 (8)
a
Reaction conditions: (1) 78 1C, 4–6 equiv. of BuLi, (2) alkylation agent, 78 1C to r.t. b Only 1 equiv. of BuLi used. c Unreacted starting compound recovered. d LDA used as a base.
of the carbanion in 2-MeTHF is heated from 78 1C (yellow) to room temp. (dark red). The reaction took place strictly regioselectively as only the CH2 group near the meta-bridge could react under the reaction conditions. The structures of alkylated products 5a–5d were identified by MS and NMR techniques. The HRMS ESI+ analysis (Orbitrap) of 5a showed signals at m/z = 633.39486, 655.37712 and 671.35075 which are in perfect agreement with the [M + H]+ (633.39384), [M + Na]+ (655.37578), and [M + K]+ (671.34972) cations corresponding to the introduction of one propyl group. The splitting pattern and multiplicity of signals in 1H NMR spectra indicated the Cs symmetry (one symmetry plane). Thus, four doublets at 2.93, 3.33, 4.17 and 4.23 ppm in a 1 : 2 : 1 : 2 ratio with typical geminal coupling constants ( J E 13 Hz) exactly correspond to the expected signals of equatorial and axial protons of CH2 bridges in the 1H NMR spectrum of 5a. The final unequivocal structural evidence was obtained by single crystal X-ray crystallography (Fig. 3a). Compound 5a crystallizes in the triclinic system, space group P1% . The presence of an additional single bond within the calixarene skeleton (a bridge between two neighbouring meta positions) results in a significant distortion of the cavity. Thus, the distance between two opposite CH2 groups (short diagonal) is only 5.800 (3) Å, while the length of the longer diagonal is 8.087 (3) Å (compared with appropriate distances 7.0–7.2 Å in common calix[4]arene derivatives). As shown in Fig. 3b the alkylation occurs exclusively in the equatorial position of the CH2 bridging unit. As a consequence, the alkyl group points outside the cavity of calixarenes. The same characteristics can be found in the X-ray structure of 5b, again possessing a significantly distorted cavity (8.080 (3) 5.760 (2) Å) with a benzyl group appended to the equatorial position (see ESI†) (Fig. 4). As expected, the fluorene moiety contained in the bridged products is heavily distorted from planarity. Thus, the interplanar angle between both phenolic subunits of the fluorene moiety in 5a (planes C3–C7, C25 versus C9–C13, C26) is 126.71 (8)1.
Fig. 3 X-ray structure of 5a showing the distances between opposite CH2 bridges (a) and the equatorial position of an additional alkyl group (b).
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Fig. 4 X-ray structure of 5a and 5b with interplanar angles (only the fluorene part of molecules shown for better clarity).
Similar angles can be found in benzylic derivative 5b (124.50 (7)1) and allylic compound 5c (126.94 (8)1). Despite huge differences from the ideal geometry (cca 551 from an interplanar angle of 1801) the presence of a formal fluorene group enables the formation of a stabilized anion as proven by the alkylation itself. In this context, we should stress that no alkylation was achieved using simple nonbridged compound 1 under otherwise identical reaction conditions. This clearly shows the crucial importance of the skeleton rigidification via an additional meta bridge. The structure of dimer 7 was also confirmed by X-ray crystallography (monoclinic system, space group P21/c). As expected, both calixarene units are interconnected via equatorial positions. On the other hand, the anticipated Cs symmetry is broken as the cavities are twisted towards each other by approx. 601 around the C8–C108 single bond (Fig. 5a). Interestingly, the same twisted structure is preferred also in solution. The 1H NMR spectrum of compound 7 in CDCl3 exhibits a double number of signals at room temp. indicating a hindered rotation around the C8–C108 (inter-calixarene) bond (Fig. 5b). Thus, terminal methyl groups (from propyl moieties) can be found at 1.35, 0.96, 0.83 and 0.72 ppm. Heating of the sample in C2D2Cl4 up to 120 1C did not lead to the averaging of signals, which shows a high energy barrier of this type of atropisomerism. The asymmetric nature of dimer 7 in solution is further supported by the addition of
Fig. 5 (a) X-ray structure of dimer 7 (hydrogen atoms were omitted for better clarity). (b) Partial 1H NMR spectrum of 7 (298 K, CDCl3, 600 MHz)-aliphatic part of the spectrum shown, intensive methyl signals (triplets) are cut off for better clarity.
10114 | Chem. Commun., 2014, 50, 10112--10114
Fig. 6 Partial 1H NMR spectra of dimer 7: before (upper part) and after (lower part) the addition of Pirkle’s agent (6 equiv.) (500 MHz, 298 K, CDCl3).
Pirkle’s reagent. The triplet at 6.73 ppm (aromatic para-H) and a doublet at 3.20 ppm (the equatorial proton of the CH2 bridge) became visibly split into two sets of signals in the presence of 6 equiv. of the chiral agent (Fig. 6). This indicates that the dimeric compound 7 exists as a racemic mixture in solution. In conclusion, the meta-bridged calix[4]arene that is available on a gram-scale from the corresponding meta-iodo compound can serve as the starting point for subsequent derivatization of the calixarene skeleton. The presence of a fluorene moiety possessing acidic CH2 protons enables the regio and stereoselective alkylation of calixarenes at a specific position. These compounds, fixed in the cone conformation, represent a unique substitution pattern of classical calixarenes with possible applications in supramolecular chemistry. This research was supported by the Czech Science Foundation (P207/12/2027) and by specific University research (MSMT No. 20/2014).
Notes and references 1 C. D. Gutsche, Calixarenes An introduction 2nd Edition, The Royal Society of Chemistry, Thomas Graham House, Cambridge, 2008. 2 (a) Calixarenes in the Nanoworld, ed. J. Vicens, J. Harrowfield and L. Backlouti, Springer, Dordrecht, 2007; (b) L. Mandolini and R. Ungaro, Calixarenes in Action, Imperial College Press, London, 2000. ¨hmer, Angew. Chem., Int. Ed. Engl., 1995, 34, 713. 3 V. Bo 4 This approach needs the lower rim unsubstituted starting calixarenes: S. Simaan and S. E. Biali, J. Org. Chem., 2003, 68, 3634. ¨hmer, W. Vogt, I. Thondorf, S. E. Biali and ¨ttner, V. Bo 5 C. Gru F. Grynszpan, Tetrahedron Lett., 1994, 35, 6267. 6 For some recent examples, see: (a) P. A. Scully, T. M. Hamilton and J. L. Bennett, Org. Lett., 2001, 3, 2741; (b) C. Fischer, G. Lin, W. Seichter and E. Weber, Tetrahedron, 2011, 67, 5656; (c) C. Fischer, F. Katz and E. Weber, Tetrahedron Lett., 2013, 35, 2874. 7 According to the literature, all attempts to deprotonate calix[4]arenes immobilized in the cone conformation failed. The starting compound must be conformationally mobile (i.e. tetramethoxy derivative): (a) C. Fischer, W. Seichter and E. Weber, Beilstein J. Org. Chem., 2011, 7, 1602; (b) M. J. Hardman, A. M. Thomas, L. T. Carroll, L. C. Williams, S. Parkin and J. F. Fantini, Tetrahedron, 2011, 67, 7027. ´ and P. Lhota ´k, Chem. 8 (a) J. Holub, V. Eigner, L. Vrzal, H. Dvorˇ´ akova ´, P. Slavı´k, V. Eigner, Commun., 2013, 49, 2798; (b) K. Flı´drova ´ and P. Lhota ´k, Chem. Commun., 2013, 49, 6749. H. Dvorˇ´ akova ¨hm and 9 P. Slavik, M. Dudic, K. Flidrova, J. Sykora, I. Cisarova, S. Bo ´k, Org. Lett., 2012, 14, 3628. P. Lhota 10 The overnight stirring of deprotonated compound 4 in air without the presence of an alkylating agent gave product 6 in 76% yield. 11 The formation of a similar dimer containing conformationally mobile methoxycalixarene moieties was reported: L. T. Caroll, P. A. Hill, C. Q. Ngo, K. P. Klatt and J. L. Fantini, Tetrahedron, 2013, 69, 5002. 12 (a) W. Huber, Tetrahedron Lett., 1985, 26, 181; (b) M. H. Al-Afyouni, T. A. Huang, F. Hung-Low and C. A. Bradley, Tetrahedron Lett., 2011, 52, 3261.
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Cite this: Chem. Commun., 2014, 50, 10112
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Regioselective alkylation of a methylene group via meta-bridging of calix[4]arenes† Petr Slavı´k,a Hana Dvorˇa´kova´,b Va´clav Eignerc and Pavel Lhota´k*a
Received 8th June 2014, Accepted 13th July 2014 DOI: 10.1039/c4cc04356a www.rsc.org/chemcomm
The meta-iodo derivative, fixed in the cone conformation, enables the gram-scale preparation of a meta-bridged calix[4]arene. This intermediate, possessing a fluorene moiety within the macrocyclic skeleton, can be regioselectively alkylated on the corresponding methylene bridge to form a unique substitution pattern in classical calixarene chemistry.
Calix[n]arenes,1 a family of macrocyclic oligophenols, are very popular compounds in supramolecular chemistry due to their simple largescale preparation and isolation. The well-established chemistry of these compounds allows almost limitless derivatization of the basic skeleton. Moreover, as the size and/or the shape of the cavity can be easily tuned, calixarenes represent versatile building blocks in the design of many new receptors.2 In this context, the calix[4]arene is a perfect choice for the role of a molecular scaffold as it can be immobilized in any of its four basic conformations (cone, partial cone, 1,2-alternate, and 1,3-alternate), allowing a deliberate arrangement of selected functions into exactly defined positions. The most straightforward derivatization of a calixarene skeleton usually relies on electrophilic substitution of the upper rim (the aromatic part of the molecule), or on the alkylation/acylation of the lower rim (hydroxyl groups).3 On the other hand, the modification of methylene bridges remains relatively unexplored. Thus, the introduction of an alkyl group into the methylene bridge represents a synthetic challenge and several different approaches were developed. Biali et al. described4 the introduction of two alkyl groups based on the bis(spirodienone) derivative, which was brominated, reacted with the RMgX/CuCN agent and finally reduced using LiAlH4.
Another method5 is based on a ‘‘2+2’’ fragment condensation of alkylidene(2,20 -bisphenols), representing a multistage procedure with very low overall yields. From this point of view, the direct lithiation of methylene bridges6 followed by the reaction with alkyl halides seems to be much more promising. Unfortunately, this procedure (n-BuLi/THF/78 1C) can be performed only with methyl-substituted calixarenes which are conformationally mobile and does not work with immobilized conformations.7 Very recently we have reported the formation of an unprecedented calix[4]arene derivative possessing a bridge (single bond) between the meta positions of the neighbouring phenolic subunits.8 In this communication we report on the application of these compounds in the regioselective alkylation of calix[4]arenes immobilized in the cone conformation. As we have shown recently,9 the reaction of tetrapropoxycalix[4]arene 1 in the cone conformation with one equiv. of Hg(TFA)2 leads to the meta-substituted product 2 in 65% yield. The intramolecular cyclization of the chloromercurio derivative in the presence of Cs2CO3 as a base and Pd(OAc)2/AsPh3 as a catalyst gave the meta-bridged compound 4 in 60% yield (Scheme 1). While this reaction worked well on a 100 mg scale, the attempts to carry out the same procedure on a large-scale led to lower yields and rather complicated reaction mixtures. To overcome these problems
a
Department of Organic Chemistry, Institute of Chemical Technology Prague (ICTP), Technicka 5, 166 28, Prague 6, Czech Republic. E-mail: [email protected]; Fax: +420-220444288; Tel: +420-220445055 b Laboratory of NMR Spectroscopy, ICTP, Czech Republic. E-mail: [email protected] c Department of Solid State Chemistry, ICTP, Czech Republic. E-mail: [email protected] † Electronic supplementary information (ESI) available: Synthetic details, NMR spectra, dynamic NMR measurements and crystallographic details. CCDC 1006510–1006513. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc04356a
10112 | Chem. Commun., 2014, 50, 10112--10114
Scheme 1
Regioselective alkylation of calix[4]arenes.
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the organomercurial compound 2 was transformed into the corresponding iodo derivative 3 (86% yield, 5 grams scale) by the reaction with I2 in MeCN/CHCl3 (room temp., overnight). This compound was then successfully transformed into the meta-bridged derivative 4 (52% yield) on a gram scale with the Pd(OAc)2/PCy3HBF4 catalytic system in the presence of K2CO3 and Ag2CO3. Technically speaking, compound 4 contains a fluorene moiety within its molecule. It is well known from the chemistry of fluorene that the acidity of hydrogens in position 9 can be used for derivatization of this hydrocarbon. Deprotonation with a strong base leads to the formation of a stable aromatic carbanion which can react with electrophiles, including various alkylating agents. Although the fluorene fragment in bridged calixarenes is far from planarity, as can be seen in the X-ray structure of compound 4,8 we hoped that the acidity of the corresponding protons (invoked by the bridging) is still much higher than that of normal CH2 moieties (Fig. 1). The deprotonation of 4 was carried out using n-BuLi in 2-Me-THF. Originally colourless solution of calixarenes became yellow upon addition of 4 equiv. of BuLi at 78 1C indicating the formation of carbanions. Finally, the addition of propyl iodide led to smooth alkylation to give compound 5a in 82% yield (after column chromatography). The same reaction with LDA as a base gave slightly lower yield of the alkylated product (72%). To show the general applicability of this strategy several other alkylation agents were used. Thus, benzyl bromide, allyl bromide, and ethyl bromoacetate gave the corresponding monoalkylated products 5b–5d in 64, 72 and 46% yields, respectively. Interestingly, the products of dialkylation have never been identified in the reaction mixtures (Fig. 2 and Table 1). In all cases, the hydroxy derivative 6 was isolated as a minor byproduct (E10% yield). The formation of this compound could be explained by the reaction of radical species with the residual oxygen present in the reaction mixture.10 On the other hand, all our attempts to carry out this reaction by strictly excluding oxygen (glove box) did not lead to disappearance of this byproduct. Interestingly, when only 1 equiv. of BuLi was used for the deprotonation reaction, product 5a was isolated in low yield (11%) together with 6 (20%) and dimeric11 calixarene 7 (13%). The formation of dimer 7 is again indicative of the presence of a radical (formed from the carbanion)12 as the combination of these species seems to be the acceptable mechanism of its formation. Another indirect proof is a dramatic change in the colour when the solution
Fig. 1
Fluorene fragment in derivative 4.
Fig. 2
Byproducts from alkylation reactions.
This journal is © The Royal Society of Chemistry 2014
ChemComm Table 1
Alkylation of bridged calix[4]arenes
Entry
Alkylation agenta
Yield (%)
Byproduct (%)
1 2 3 4 5 6
Propyl iodide Propyl iodideb Propyl iodided Benzyl bromide Allyl bromide Ethyl bromoacetate
5a (82) 5a (11)c 5a (71) 5b (64) 5c (72) 5d (46)
6 (13) 6 (20), 7 (13) No 6 (12) 6 (10) 6 (8)
a
Reaction conditions: (1) 78 1C, 4–6 equiv. of BuLi, (2) alkylation agent, 78 1C to r.t. b Only 1 equiv. of BuLi used. c Unreacted starting compound recovered. d LDA used as a base.
of the carbanion in 2-MeTHF is heated from 78 1C (yellow) to room temp. (dark red). The reaction took place strictly regioselectively as only the CH2 group near the meta-bridge could react under the reaction conditions. The structures of alkylated products 5a–5d were identified by MS and NMR techniques. The HRMS ESI+ analysis (Orbitrap) of 5a showed signals at m/z = 633.39486, 655.37712 and 671.35075 which are in perfect agreement with the [M + H]+ (633.39384), [M + Na]+ (655.37578), and [M + K]+ (671.34972) cations corresponding to the introduction of one propyl group. The splitting pattern and multiplicity of signals in 1H NMR spectra indicated the Cs symmetry (one symmetry plane). Thus, four doublets at 2.93, 3.33, 4.17 and 4.23 ppm in a 1 : 2 : 1 : 2 ratio with typical geminal coupling constants ( J E 13 Hz) exactly correspond to the expected signals of equatorial and axial protons of CH2 bridges in the 1H NMR spectrum of 5a. The final unequivocal structural evidence was obtained by single crystal X-ray crystallography (Fig. 3a). Compound 5a crystallizes in the triclinic system, space group P1% . The presence of an additional single bond within the calixarene skeleton (a bridge between two neighbouring meta positions) results in a significant distortion of the cavity. Thus, the distance between two opposite CH2 groups (short diagonal) is only 5.800 (3) Å, while the length of the longer diagonal is 8.087 (3) Å (compared with appropriate distances 7.0–7.2 Å in common calix[4]arene derivatives). As shown in Fig. 3b the alkylation occurs exclusively in the equatorial position of the CH2 bridging unit. As a consequence, the alkyl group points outside the cavity of calixarenes. The same characteristics can be found in the X-ray structure of 5b, again possessing a significantly distorted cavity (8.080 (3) 5.760 (2) Å) with a benzyl group appended to the equatorial position (see ESI†) (Fig. 4). As expected, the fluorene moiety contained in the bridged products is heavily distorted from planarity. Thus, the interplanar angle between both phenolic subunits of the fluorene moiety in 5a (planes C3–C7, C25 versus C9–C13, C26) is 126.71 (8)1.
Fig. 3 X-ray structure of 5a showing the distances between opposite CH2 bridges (a) and the equatorial position of an additional alkyl group (b).
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Fig. 4 X-ray structure of 5a and 5b with interplanar angles (only the fluorene part of molecules shown for better clarity).
Similar angles can be found in benzylic derivative 5b (124.50 (7)1) and allylic compound 5c (126.94 (8)1). Despite huge differences from the ideal geometry (cca 551 from an interplanar angle of 1801) the presence of a formal fluorene group enables the formation of a stabilized anion as proven by the alkylation itself. In this context, we should stress that no alkylation was achieved using simple nonbridged compound 1 under otherwise identical reaction conditions. This clearly shows the crucial importance of the skeleton rigidification via an additional meta bridge. The structure of dimer 7 was also confirmed by X-ray crystallography (monoclinic system, space group P21/c). As expected, both calixarene units are interconnected via equatorial positions. On the other hand, the anticipated Cs symmetry is broken as the cavities are twisted towards each other by approx. 601 around the C8–C108 single bond (Fig. 5a). Interestingly, the same twisted structure is preferred also in solution. The 1H NMR spectrum of compound 7 in CDCl3 exhibits a double number of signals at room temp. indicating a hindered rotation around the C8–C108 (inter-calixarene) bond (Fig. 5b). Thus, terminal methyl groups (from propyl moieties) can be found at 1.35, 0.96, 0.83 and 0.72 ppm. Heating of the sample in C2D2Cl4 up to 120 1C did not lead to the averaging of signals, which shows a high energy barrier of this type of atropisomerism. The asymmetric nature of dimer 7 in solution is further supported by the addition of
Fig. 5 (a) X-ray structure of dimer 7 (hydrogen atoms were omitted for better clarity). (b) Partial 1H NMR spectrum of 7 (298 K, CDCl3, 600 MHz)-aliphatic part of the spectrum shown, intensive methyl signals (triplets) are cut off for better clarity.
10114 | Chem. Commun., 2014, 50, 10112--10114
Fig. 6 Partial 1H NMR spectra of dimer 7: before (upper part) and after (lower part) the addition of Pirkle’s agent (6 equiv.) (500 MHz, 298 K, CDCl3).
Pirkle’s reagent. The triplet at 6.73 ppm (aromatic para-H) and a doublet at 3.20 ppm (the equatorial proton of the CH2 bridge) became visibly split into two sets of signals in the presence of 6 equiv. of the chiral agent (Fig. 6). This indicates that the dimeric compound 7 exists as a racemic mixture in solution. In conclusion, the meta-bridged calix[4]arene that is available on a gram-scale from the corresponding meta-iodo compound can serve as the starting point for subsequent derivatization of the calixarene skeleton. The presence of a fluorene moiety possessing acidic CH2 protons enables the regio and stereoselective alkylation of calixarenes at a specific position. These compounds, fixed in the cone conformation, represent a unique substitution pattern of classical calixarenes with possible applications in supramolecular chemistry. This research was supported by the Czech Science Foundation (P207/12/2027) and by specific University research (MSMT No. 20/2014).
Notes and references 1 C. D. Gutsche, Calixarenes An introduction 2nd Edition, The Royal Society of Chemistry, Thomas Graham House, Cambridge, 2008. 2 (a) Calixarenes in the Nanoworld, ed. J. Vicens, J. Harrowfield and L. Backlouti, Springer, Dordrecht, 2007; (b) L. Mandolini and R. Ungaro, Calixarenes in Action, Imperial College Press, London, 2000. ¨hmer, Angew. Chem., Int. Ed. Engl., 1995, 34, 713. 3 V. Bo 4 This approach needs the lower rim unsubstituted starting calixarenes: S. Simaan and S. E. Biali, J. Org. Chem., 2003, 68, 3634. ¨hmer, W. Vogt, I. Thondorf, S. E. Biali and ¨ttner, V. Bo 5 C. Gru F. Grynszpan, Tetrahedron Lett., 1994, 35, 6267. 6 For some recent examples, see: (a) P. A. Scully, T. M. Hamilton and J. L. Bennett, Org. Lett., 2001, 3, 2741; (b) C. Fischer, G. Lin, W. Seichter and E. Weber, Tetrahedron, 2011, 67, 5656; (c) C. Fischer, F. Katz and E. Weber, Tetrahedron Lett., 2013, 35, 2874. 7 According to the literature, all attempts to deprotonate calix[4]arenes immobilized in the cone conformation failed. The starting compound must be conformationally mobile (i.e. tetramethoxy derivative): (a) C. Fischer, W. Seichter and E. Weber, Beilstein J. Org. Chem., 2011, 7, 1602; (b) M. J. Hardman, A. M. Thomas, L. T. Carroll, L. C. Williams, S. Parkin and J. F. Fantini, Tetrahedron, 2011, 67, 7027. ´ and P. Lhota ´k, Chem. 8 (a) J. Holub, V. Eigner, L. Vrzal, H. Dvorˇ´ akova ´, P. Slavı´k, V. Eigner, Commun., 2013, 49, 2798; (b) K. Flı´drova ´ and P. Lhota ´k, Chem. Commun., 2013, 49, 6749. H. Dvorˇ´ akova ¨hm and 9 P. Slavik, M. Dudic, K. Flidrova, J. Sykora, I. Cisarova, S. Bo ´k, Org. Lett., 2012, 14, 3628. P. Lhota 10 The overnight stirring of deprotonated compound 4 in air without the presence of an alkylating agent gave product 6 in 76% yield. 11 The formation of a similar dimer containing conformationally mobile methoxycalixarene moieties was reported: L. T. Caroll, P. A. Hill, C. Q. Ngo, K. P. Klatt and J. L. Fantini, Tetrahedron, 2013, 69, 5002. 12 (a) W. Huber, Tetrahedron Lett., 1985, 26, 181; (b) M. H. Al-Afyouni, T. A. Huang, F. Hung-Low and C. A. Bradley, Tetrahedron Lett., 2011, 52, 3261.
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