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A general method for obtaining calix[4]arene derivatives in the 1,2-alternate conformation
Tetrahedron 72 (2016) 6348e6355
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Tetrahedron journal homepage: www.elsevier.com/locate/tet
A general method for obtaining calix[4]arene derivatives in the 1,2-alternate conformation clav Eigner b, Pavel Lhota k a, * Petr Slavík a, Va a b
5, 166 28 Prague 6, Czech Republic Department of Organic Chemistry, University of Chemistry and Technology, Prague (UCT), Technicka 5, 166 28 Prague 6, Czech Republic Department of Solid State Chemistry, University of Chemistry and Technology, Prague (UCT), Technicka
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 May 2016 Received in revised form 28 July 2016 Accepted 9 August 2016 Available online 13 August 2016
The 1,2-alternate conformation, so far the least accessible atropisomer of calix[4]arene, is now easily available on a gram scale. The entire synthetic sequence consists of only two stepsd(a) proximal dialkylation (R1-I, NaH/DMF), and (b) another subsequent dialkylation (R2-I, Me3SiOK/THF). The selection of appropriate base/solvent combinations in both stages was the key prerequisite for the successful preparation of the 1,2-alternate conformers, which are available without the use of any protecting groups. Ó 2016 Elsevier Ltd. All rights reserved.
Keywords: Calixarene Conformation Alkylation 1,2-Alternate Partial cone Conformational mobility
1. Introduction Calix[n]arenes1 represent highly versatile macrocyclic compounds as can be demonstrated by their widespread applications as building blocks and/or molecular scaffolds in supramolecular chemistry. The simple preparation of these compounds, almost limitless freedom in their derivatization and excellent complexation abilities make calixarenes a highly desirable choice in the design of new receptors. Probably, the most attractive feature of these macrocycles is the tuneable 3D shape of their molecules, which is extremely useful in the design and synthesis of novel receptors. Thus, the introduction of bulky substituents (R¼propyl or any higher alkyl group) at the phenolic subunits of calix[4]arene leads to the immobilisation of the macrocyclic skeleton into four basic conformations (atropisomers) called cone, partial cone, 1,2alternate and 1,3-alternate (Scheme 1). The chemistry of the cone, partial cone and 1,3-alternate conformations has recently been well established, and all three atropisomers are accessible on a multigram scale via direct stereoselective alkylation of parent calix[4]arenes. Consequently, the three conformations are frequently used in the design of novel receptors, self-assemblies or more sophisticated calixarene-based
supramolecular systems.2 Unfortunately, until recently, a broader application of the 1,2-alternates has been hindered by our limited knowledge of their chemistry, in particular, by the lack of a general synthetic methodology. Thus, the 1,2-alternate conformation can be prepared using rather unusual alkylation agents, like 2pyridylmethyl chloride (a-picolyl chloride),3 or by the formation of short proximal bridges using oligoethylene glycol ditosylates.4 Another, even rarer approach, is based on the steric
Scheme 1. The four basic conformers (atropisomers) of calix[4]arene. * Corresponding author. Fax: þ420 220 444 288; e-mail address: [email protected] k). (P. Lhota http://dx.doi.org/10.1016/j.tet.2016.08.028 0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
P. Slavík et al. / Tetrahedron 72 (2016) 6348e6355
destabilization of the cone conformation of unsubstituted calix[4] arene by introducing substituents on the methylene bridges.5 In our previous work6 we showed that calix[4]arenes immobilised in the 1,2-alternate conformation can be prepared on a multigram scale using a simple dialkylation/dialkylation procedure.6 Thus, alkylation of starting p-tert-butylcalixarene with propyl bromide/NaOH in a DMSOH2O mixture gave a proximally dipropylated derivative, which could be subsequently alkylated to give the corresponding 1,2-alternate. Surprisingly, this procedure did not work with de-tert-butylated calixarene 1 leaving the corresponding 1,2-alternates unavailable. In this paper we report on a simple and general synthetic procedure that selectively provides the 1,2-alternate derivatives with unsubstituted upper rims, hence, paving the way for their applications in supramolecular chemistry.
2. Results and discussion The synthesis starts with a proximal dialkylation of starting calix [4]arene 1 (Scheme 2). We employed a subtle modification of the reaction conditions7 recently described for the preparation of compound 2. Thus, calixarene 1 was dissolved in dry DMF and reacted with NaH (3.6 equiv), stirred for 15 min at room temperature and then treated with 1-iodopropane (2.15 equiv) as the alkylating agent. The reaction is surprisingly regioselective and proximally disubstituted isomer 2 was obtained in 54% yield using just simple precipitation of the crude reaction product from a MeOHeCH2Cl2 mixture (up to 5.0 g scale). This was highly desired as easy isolation without column chromatography step is an important prerequisite for large scale synthesis. To show the general applicability of these reaction conditions, we carried out a similar alkylation using 1-iodobutane. The corresponding proximal dibutoxy derivative 3 was isolated in 30% yield. We mention that the same compound was already prepared by Lin et al.8 using a very complicated procedure. Thus, the starting calixarene 1 was (i) monoalkylated, (ii) monobenzoylated into the distal position (52% yield), (iii) monoalkylated once again, and (iv) deprotected by hydrolysis of the benzoyl group (11% overall yield for last two steps). Interestingly, similar direct alkylation employing a protected propargyl bromide (3-bromo-1-(trimethylsilyl)-1-
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Fig. 1. X-ray structure of compound 2 showing the interactions of the CH2Cl2 molecule with the cavity, a) side view, b) same from above.
propyne) led to the isolation of compound 4 (44% yield) with free propargyl groups. The structure of the dialkylated compounds was confirmed by 1 H NMR spectra and reflected the expected symmetry of these compounds. Thus, the presence of three well resolved doublets at 4.61 ppm, 4.50 ppm and 4.36 ppm in a 1:2:1 ratio with typical geminal coupling constants (J¼12.5e13.3 Hz) for the axial protons of the methylene bridges clearly supported that compound 4 (400 MHz, CDCl3, 293 K) was proximally alkylated and adopted the cone conformation. Moreover, the structure of dipropoxy derivative 2 was unequivocally assigned using single crystal X-ray analysis. The compound crystalized in the monoclinic system, space group P21/n as a 1:1 complex with CH2Cl2. The cavity of the calixarene is filled with a solvent molecule (Fig. 1) with close contacts between the hydrogen atoms of the CH bonds (CH2Cl2) and the neighbouring aromatic subunits. The distances between the hydrogen atoms and the phenolic planes 2.397 A and 2.567 A indicated the complex is held together by the CeHep interactions. To find the most suitable conditions for the formation of the 1,2alternate conformation, dipropoxy derivative 2 was screened for an optimal base/solvent/temperature combination. Obviously, subsequent propylation of 2 could lead to three different conformers: 1,2-alternate 5a, partial cone 5b and cone 5c. Fortunately, all these isomers possess well resolved signals in the aromatic region of their
Scheme 2. Synthesis of calix[4]arenes in the 1,2-alternate conformation.
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1
H NMR spectra allowing easy assignment of the conformations formed, including their molar ratios in the crude products. Small scale alkylations with 1-iodopropane (30 mg of dipropoxy compound 2) were carried out using various reaction conditions commonly applied in calixarene chemistry (collected in Table 1). As expected, applying standard NaH/DMF conditions (Run 1) led exclusively to the cone conformation 5c, while Cs2CO3/MeCN (Run 2) provided a high percentage of the partial cone 5c. On the other hand, combinations of KH/DMF, K2CO3/DMF, Me3SiOK/DMF and tBuOK/toluene (Runs 3e4, 12) were found to be unsuitable as they yielded complex reaction mixtures containing unreacted 2 together with partly and fully alkylated products. Very promising results were achieved with Me3SiOK/THF leading to a mixture of 5a and 5b with a desirable amount of the 1,2-alternate atropisomer presenting in the crude products (Runs 6 and 7), similar results were also observed for Me3SiOK/THF and t-BuOK/THF. Interestingly, Me3SiOK or t-BuOK in benzene (Runs 10 and 11) gave an even higher molar ratio of 5a. Unfortunately, in both cases a small amount of the cone conformer 5c was also formed which substantially hindered isolation of 5a in a pure form as the Rf values for 5a and 5c were essentially identical on a silica gel column. As a result, large scale preparation of the 1,2-alternate conformer was carried out using Me3SiOK in THF at room temperature. Table 1 Screening of reaction conditions for the alkylation of compound 2 Reaction conditionsa
1 2 3 4 5 6 7 8 9 10 11 12
Conformer distrib.b
Base
Solvent
Temp [ C]
Time [h]
5a
5b
5c
NaH Cs2CO3 KH K2CO3 Me3SiOK Me3SiOK Me3SiOK KHMDS t-BuOK t-BuOK Me3SiOK t-BuOK
DMF MeCN DMF DMF MeCN THF THF THF THF C6H6 C6H6 Toluene
rt Reflux 90 90 90 rt Reflux rt Reflux Reflux Reflux Reflux
24 120 120 100 120 24 24 24 24 24 24 24
0 0
0 90
100 10
49 47 48 46 24 26
0 0 0 0 2 2
c c c
51 53 52 54 74 72 c
dibutyloxy 7a 1,2-alternates (both isolated in 51% yield) together with the partial cone isomers 6b, 7b (both 41%). Applying a longer alkyl group (using 1-hexyl iodide) led to higher selectivity for the 1,2-alternate conformer although in slightly lower overall yieldd8a (44%), 8b (20%). As shown in Table 2, the best selectivity for the 1,2alternate was achieved employing propargyl bromide. This alkylating agent furnished 67% of 11a, while the partial cone conformer 11b was obtained in only 18% yield. In all these examples, the 1,2alternates possessed higher Rf values than the corresponding partial cone isomers and both conformers could be easily separated using column chromatography on silica gel. Treatment with allyl bromide (Run 6) or benzyl bromide (Run 8) gave a corresponding mixtures of conformations with the 1,2-alternate (10a:10b¼58:42, 12a:12b¼63:37) prevailing, but unfortunately, these mixtures could not be efficiently separated using column chromatography on silica gel. The 1H NMR spectra of the resulting 1,2-alternate conformers were fully in agreement with the expected C2h symmetry. Thus, the pair of doublets in the 1H NMR spectrum of 6a (CDCl3) at 3.17 ppm (J¼12.5 Hz) and 4.21 ppm (J¼12.5 Hz) represent the methylene bridge fenced by two syn-oriented phenolic moieties (equatorial and axial protons possessing a geminal coupling constant from the conical fragments of the molecule). On the other hand, the singlet at 3.91 ppm clearly showed the presence of the methylene bridge surrounded by two identical aromatic subunits with an antiorientation (the 1,3-alternate segment of the molecule). Similar structural features can be seen in all the remaining molecules possessing the 1,2-alternate conformationde.g., two pairs of doublets at 3.18, 3.19, 4.20 and 4.23 ppm for 7a indicating lower symmetry due to the presence of two different alkyl groups (npropyl and n-butyl). The structures of several 1,2-alternate products were also unambiguously assigned using single crystal X-ray analysis. Compounds 5a (Fig. 2a) and 7a (Fig. 2b) crystalized in the triclinic system, space group P-1, compounds 10a (Fig. 2c) and 12a (Fig. 2d) crystalized in the monoclinic system, space group P21/n or P21/c, respectively, and in all cases without any solvent molecules in the crystal lattice.
a
Five equivalents of base and propyl iodide were used. H NMR spectrum, 400 MHz, CDCl3. c Incomplete reaction (unreacted starting compound, and/or trialkylated and tetraalkylated products). b 1
The results of the synthesis of 1,2-alternates on a preparative scale are collected in Table 2. In all cases, starting calixarenes 2 or 3 were stirred with the corresponding alkylating agent (5 equiv) and Me3SiOK as a base (5 equiv) in THF at room temperature for 1e3 days. Tetrapropoxy 1,2-alternate 5a was obtained in 51% yield accompanied by the partial cone isomer 5b (44%). Very similar results were shown for tetrabutyloxy 6a and for the mixed dipropoxy Table 2 Synthesis of the 1,2-alternate conformation Run
Starting calix[4]arene
Alkylating agenta
Xa (yield)b
Xb (yield)b
1 2 3 4 5 6 7 8
2 3 2 2 2 2 2 2
n-Pr-I n-Bu-I n-Bu-I n-Hex-I Et-I Allyl-Br Propargyl-Br Benzyl-Br
5a (51) 6a (52) 7a (52) 8a (44) 9a (53) 10a (58)c 11a (67) 12a (63)c
5b (44) 6b (41) 7b (41) 8b (20) 9b (35) 10b (42)c 11b (18) 12b (37)c
a 5 equiv. Me3SiOKþ5 equiv alkylating agent in THF, 1 day stirring at room temperature. b Isolated yields after chromatography. c Separation failed, the ratio of conformers was assigned using the 1H NMR spectra of crude products.
Fig. 2. X-ray structures of several 1,2-alternate conformations: a) 5a, b) 7a, c) 10a, d) 12a.
P. Slavík et al. / Tetrahedron 72 (2016) 6348e6355
It is well documented1 that the presence of four propyl groups on the lower rim of calix[4]arene leads to the immobilization of a given conformation as the propyl groups are sufficiently bulky substituents to hinder rotation of the phenolic subunits through the macrocyclic cavity. To confirm the conformational mobility in the 1,2-alternate series we prepared compounds proximally bearing two propyl and two ethyl groups. Using our general alkylation procedure the corresponding 1,2-alternate 9a was prepared in 53% yield, accompanied again by the partial cone conformer 9b (35%). Both conformations were easily separated using column chromatography indicating the conformations are stable on a laboratory time scale at ambient temperature. Indeed, the 1H NMR spectra of 9a or 9b in CDCl3 at 25 C did not reveal any conformational interconversion of these isomers. On the other hand, heating of 9a to 130 C for 2 days (in CDCl2eCDCl2) led to a mixture of all three theoretically possible isomers (showing that, obviously, only Et groups can rotate through the annulus). In the independent experiment 9b gave the identical mixture of isomers indicating that a thermodynamic equilibrium was achieved (Fig. 3). Integration of the resulting mixture showed the presence of the partial cone (56%), cone (28%), and 1,2-alternate (16%) conformers reflecting the relative thermodynamic stabilities of the corresponding conformations under the given conditions.
Fig. 3. Aromatic region of the 1H NMR spectra of: a) pure 9b, c) pure 9a, b) spectrum obtained after 47 h heating of 9a to 130 C (400 MHz, CDCl2eCDCl2), - partial cone, , 1,2-alternate, : cone.
3. Conclusions In conclusion, the upper rim unsubstituted calix[4]arenes immobilised in the 1,2-alternate conformation are now easily accessible using a proximal dialkylation/dialkylation strategy. Careful selection of the appropriate base/solvent combination in each step enables the synthesis of the 1,2-alternates on a gram scale. This paves the way for potential applications of this least accessible conformation of calix[4]arene in supramolecular chemistry. 4. Experimental 4.1. General All chemicals were purchased from commercial sources and used without further purification. 1,2-Dichloroethane, CH2Cl2 and
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N,N’-dimethylformamide used for the reactions were dried with CaH2 or MgSO4 and stored over molecular sieves. THF was dried using the sodium/benzophenone method. Melting points were measured on Heiztisch Mikroskop-Polytherm A (Wagner & Munz, Germany) and were not corrected. The IR spectra were measured on an FTIR spectrometer Nicolet 740 in KBr transmission mode. NMR spectra were recorded on spectrometers Varian Gemini 300 (1H: 300 MHz, 13C: 75 MHz) and Agilent 400-MR DDR2 (1H: 400 MHz, 13C: 100 MHz). Chemical shifts (d) are expressed in parts per million and are referenced to the residual peak of solvent or TMS as an internal standard, coupling constants (J) are in hertz. The mass analyses were performed using ESI on an FT-MS (LTQ Orbitrap Velos) spectrometer. Purity of the substances and courses of the reactions were monitored by thin layer chromatography (TLC) using silica gel 60 F254 on aluminium-backed sheets (Merck) and analyzed at 254 or 365 nm. Preparative TLC chromatography was carried out on a Chromatotron (Harrison Research) with plates covered by Silica gel 60 GF254 (Merck). 4.2. General procedure for proximal dialkylation Calixarene 1 was dissolved in dry DMF and NaH (3.6 equiv) was carefully added. The solution was stirred at room temperature for 15 min. Then, the alkylating agent (2.15 equiv) was added dropwise and the resulting solution was stirred for 2 h at room temperature. The reaction mixture was carefully quenched by aqueous 1 M HCl and to this mixture dichloromethane was added. The organic layer was separated, washed with water and dried over magnesium sulfate. Solvent was removed under reduced pressure to yield the crude product which was purified by precipitation from a CH2Cl2/ MeOH mixture. Depending on the scale of the reaction, this step can be replaced by column chromatography or by preparative thin layer chromatography on silica gel. 4.2.1. Synthesis of 25,26-dihydroxy-27,28-dipropoxycalix[4]arene (2). Compound 2 was prepared according to the general procedure for proximal alkylation using 1.06 g (2.50 mmol) of calixarene 1, 0.36 g (9.01 mmol) of NaH (60% dispersion in mineral oil) and 0.53 ml (5.38 mmol) of 1-iodopropane. Compound 2 (0.68 g, 54%) was obtained as a white powder by simple precipitation of the crude product from a MeOHeCH2Cl2 mixture. The analytical data was in agreement with previously published data.7 1 H NMR (400 MHz, CDCl3, 293 K) d (ppm): 8.99 (s, 2H, AreOH), 7.06 (dd, 2H, J¼7.8, 1.6 Hz, AreH), 7.01e6.96 (m, 6H, AreH), 6.79 (t, 2H, J¼7.4 Hz, AreH), 6.63 (t, 2H, J¼7.8 Hz, AreH), 4.55 (d, 1H, J¼12.5 Hz, AreCH2eAr), 4.34 (d, 3H, J¼12.9 Hz, AreCH2eAr), 4.13e4.05 (m, 2H, OeCH2), 3.94e3.86 (m, 2H, OeCH2), 3.41 (d, 1H, J¼12.5 Hz, AreCH2eAr), 3.40 (d, 2H, J¼12.9 Hz, AreCH2eAr), 3.36 (d, 1H, J¼13.3 Hz, AreCH2eAr), 2.22e2.06 (m, 4H, OeCH2eCH2), 1.16 (t, 6H, J¼7.4 Hz, OeCH2eCH2eCH3). 4.2.2. Synthesis of 25,26-dihydroxy-27,28-dibutoxycalix[4]arene (3). Compound 3 was prepared according to the general procedure for proximal alkylation by reacting 1.05 g (2.50 mmol) of calixarene 1, 0.36 g (9.01 mmol) of NaH (60% dispersion in mineral oil) and 0.71 ml (5.3 mmol) of 1-iodobutane. Compound 3 (0.38 g, 30%) as a white powder was obtained by simple precipitation of the crude product from a MeOHeCH2Cl2 mixture. Another portion of product (15% yield) can be obtained by column chromatography of the mother liquor remaining after the precipitation. The analytical data was in agreement with previously published data.8 1 H NMR (400 MHz, CDCl3, 293 K) d (ppm): 9.00 (s, 2H, AreOH), 7.15e7.06 (m, 2H, AreH), 7.06e6.98 (m, 6H, AreH), 6.83 (t, 2H, J¼7.4 Hz, AreH), 6.67 (t, 2H, J¼7.4 Hz, AreH), 4.59 (d, 1H, J¼12.1 Hz, AreCH2eAr), 4.45e4.36 (m, 3H, AreCH2eAr), 4.20e4.12 (m, 2H, OeCH2), 4.03e3.94 (m, 2H, OeCH2), 3.49e3.36 (m, 4H, AreCH2eAr),
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2.27e2.02 (m, 4H, OeCH2eCH2), 1.74e1.56 (m, 4H, OeCH2eCH2eCH2), 1.12 (t, 6H, J¼7.4 Hz, OeCH2eCH2eCH2eCH3). 13C NMR (100 MHz, CDCl3, 293 K) d (ppm): 153.5,151.2, 134.7, 134.2, 129.4, 129.1 (2),128.8 (2),128.0,124.8,120.6, 76.7, 32.1, 32.0, 31.8, 30.0,19.3,14.1. 4.2.3. Synthesis of 25,26-dihydroxy-27,28-dipropargyloxycalix[4] arene (4). Compound 4 was prepared according to the general procedure for proximal alkylation using 0.53 g (1.26 mmol) of calixarene 1, 0.18 g (4.52 mmol) of NaH (60% dispersion in mineral oil) and 0.44 ml (2.7 mmol) of 3-bromo-1-(trimethylsilyl)-1-propyne. After the workup, the unprotected title compound was obtained (0.28 g, 44%) as a white powder using preparative TLC on silica gel (hexane:CH2Cl2 1:2, v/v). Mp 166e167 C. 1H NMR (400 MHz, CDCl3, 293 K) d (ppm): 7.08e7.01 (m, 4H, AreH), 6.97 (d, 4H, J¼7.4 Hz, AreH), 6.88e6.82 (m, 2H, AreH), 6.67e6.61 (m, 2H, AreH), 4.96 (dd, 2H, J¼15.7, 2.4 Hz, OeCH2), 4.87 (dd, 2H, J¼15.7, 2.4 Hz, OeCH2), 4.61 (d, 1H, J¼12.5 Hz, AreCH2eAr), 4.50 (d, 2H, J¼13.3 Hz, AreCH2eAr), 4.36 (d, 1H, J¼13.3 Hz, AreCH2eAr), 3.47e3.36 (m, 4H, AreCH2eAr), 2.66 (t, 2H, J¼2.4 Hz, OeCH2eCeCH). 13C NMR (100 MHz, CDCl3, 293 K) d (ppm): 152.7, 151.0, 134.8 (2), 129.4, 129.3, 129.1, 129.0, 128.8, 128.2, 125.6, 120.9, 79.2, 76.5, 62.5, 32.1, 31.9 (2). IR (KBr) n (cm1): 2122.7, 1462.7. HRMS-ESI (C34H28O4) m/z calcd: 501.20604 [MþH]þ, 523.18798 [MþNa]þ, 539.16192 [MþK]þ, found: 501.20611 [MþH]þ, 523.18837 [MþNa]þ, 539.16221 [MþK]þ. 4.3. General procedure for the synthesis of calix[4]arenes in the 1,2-alternate conformation Proximally dialkylated calix[4]arene was dissolved in dry THF and stirred at room temperature. To this solution potassium trimethylsilanolate (5 equiv, 90% purity) was added and stirred for another 30 min. The alkylating agent (5 equiv) was then added and the mixture was stirred at room temperature for 1e3 days. The course of reaction was monitored by TLC. After disappearance of the starting compound aqueous 1 M HCl was added, and the mixture was extracted with CH2Cl2. The organic layer was washed with water and dried over MgSO4. The solvent was removed under reduced pressure to yield the crude product which was purified by preparative chromatography to separate the conformers. 4.3.1. Synthesis of 25,26,27,28-tetrapropoxy-calix[4]arenes-1,2-alt (5a) and paco (5b). Compound 5a was prepared according to the general procedure using 0.31 g (0.62 mmol) of calixarene 2, 0.61 g (3.08 mmol) of potassium trimethylsilanolate (90% purity), and 0.30 ml (3.08 mmol) of 1-iodopropane. The crude reaction mixture was purified by column chromatography on silica gel (hexane: CH2Cl2 5:1, v/v) to give the title compounds 5a (0.19 g, 51%, white powder) and 5b (0.16 g, 44%, white powder). 4.3.1.1. Data for 1,2-alternate 5a. Mp 140.5e142 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.12e7.03 (m, 8H, AreH), 6.84 (t, 4H, J¼7.4 Hz, AreH), 4.21 (d, 2H, J¼12.5 Hz, AreCH2eAr), 3.89 (s, 4H, AreCH2eAr), 3.41e3.32 (m, 8H, OeCH2), 3.18 (d, 2H, J¼12.5 Hz, AreCH2eAr), 1.30e1.15 (m, 4H, OeCH2eCH2), 1.02e0.86 (m, 4H, OeCH2eCH2), 0.63 (t, 12H, J¼7.4 Hz, OeCH2eCH2eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 156.6, 134.6, 132.9, 129.3, 128.3, 121.8, 74.7, 38.1, 29.0, 22.7, 10.3. IR (KBr) n 1456.1 cm1. HRMS-ESIþ (C40H48O4) m/z calcd: 593.36254 [MþH]þ, 610.38909 [MþNH4]þ, 615.34448 [MþNa]þ, 631.31842 [MþK]þ, found: 593.36267 [MþH]þ, 610.38971 [MþNH4]þ, 615.34442 [MþNa]þ, 631.31775 [MþK]þ. 4.3.1.2. Data for partial cone 5b. The analytical data were in agreement with previously published data.9 4.3.2. Synthesis of 25,26,27,28-tetrabutoxy-calix[4]arenes-1,2-alt (6a) and paco (6b). Compound 6a was prepared according to
general procedure using 0.10 g (0.19 mmol) of calixarene 3, 0.12 g (0.94 mmol) of potassium trimethylsilanolate (90% purity), and 0.13 ml (0.94 mmol) of 1-iodobutane. The crude reaction mixture was purified by preparative TLC on silica gel (hexane:CH2Cl2 3:2, v/ v) to give the title compounds 6a (0.064 g, 52%, white powder) and 6b (0.050 g, 41%, white powder). 4.3.2.1. Data for 1,2-alternate 6a. Mp 86.5e88 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.14e7.03 (m, 8H, AreH), 6.89e6.82 (m, 4H, AreH), 4.21 (d, 2H, J¼12.5 Hz, AreCH2eAr), 3.91 (s, 4H, AreCH2eAr), 3.47e3.34 (m, 8H, OeCH2), 3.17 (d, 2H, J¼12.5 Hz, AreCH2eAr), 1.27e1.15 (m, 4H, OeCH2eCH2), 1.14e1.01 (m, 8H, OeCH2eCH2eCH2), 0.93e0.78 (m, 16H, OeCH2eCH2þOeCH2eCH2eCH2eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 156.6, 134.6, 132.9, 129.2, 129.8, 121.9, 72.9, 38.2, 31.7, 28.9, 19.1, 14.1. IR (KBr) n 1457.2 cm1. HRMS-ESIþ (C44H56O4) m/z calcd: 649.42514 [MþH]þ, 671.40708 [MþNa]þ, 687.38102 [MþK]þ, found: 649.42631 [MþH]þ, 671.40758 [MþNa]þ, 687.38060 [MþK]þ. 4.3.2.2. Data for partial cone 6b. Mp 116e118 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.23 (d, 2H, J¼7.3 Hz, AreH), 7.09 (d, 2H, J¼7.3 Hz, AreH), 6.97e6.80 (m, 4H, AreH), 6.44 (t, 2H, J¼7.6 Hz, AreH), 6.26 (dd, 2H, J¼7.6, 1.8 Hz, AreH), 4.07 (d, 2H, J¼13.2 Hz, AreCH2eAr), 3.84e3.74 (m, 4H, OeCH2), 3.65 (s, 4H, AreCH2eAr), 3.64e3.52 (m, 2H, OeCH2), 3.40e3.30 (m, 2H, OeCH2), 3.05 (d, 2H, J¼13.5 Hz, AreCH2eAr), 1.97e1.78 (m, 6H, CH2), 1.64e1.36 (m, 6H, CH2), 1.20e1.09 (m, 2H, eCH2), 1.07e0.97 (m, 12H, OeCH2eCH2eCH2eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 157.5, 157.2, 155.6, 137.0, 133.9, 133.4, 132.1, 130.3, 129.3, 128.9, 128.3, 122.0 (2), 121.4, 74.1, 74.0, 72.9, 35.8, 33.0, 32.8, 31.0, 30.5, 19.6, 19.4, 18.9, 14.3, 14.2, 14.0. IR (KBr) n 1454.2 cm1. HRMSESIþ (C44H56O4) m/z calcd: 666.45169 [MþNH4]þ, 671.40708 [MþNa]þ, 687.38102 [MþK]þ, found: 666.45251 [MþNH4]þ, 671.40752 [MþNa]þ, 687.38065 [MþK]þ. 4.3.3. Synthesis of 25,26-dipropoxy-27,28-di-butoxycalix[4]arene1,2-alt (7a) and paco (7b). Compound 7a was prepared according to the general procedure using 0.11 g (0.21 mmol)of calixarene 2, 0.13 g (1.04 mmol) of potassium trimethylsilanolate (90% purity), and 0.14 ml (1.04 mmol) of 1-iodobutane. The crude reaction mixture was purified by preparative TLC on silica gel (hexane: CH2Cl2 2:1, v/v) to give the title compounds 7a (0.067 g, 52%, white powder) and 7b (0.053 g, 41%, white powder). 4.3.3.1. Data for 1,2-alternate 7a. Mp 86e87 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.15e7.03 (m, 8H, AreH), 6.90e6.82 (m, 4H, AreH), 4.23 (d, 1H, J¼12.5 Hz, AreCH2eAr), 4.20 (d, 1H, J¼12.5 Hz, AreCH2eAr), 3.91 (s, 4H, AreCH2eAr), 3.46e3.34 (m, 8H, OeCH2), 3.19 (d, 1H, J¼12.5 Hz, AreCH2eAr), 3.18 (d, 1H, J¼12.5 Hz, AreCH2eAr), 1.31e1.16 (m, 4H), 1.15e1.03 (m, 4H), 1.03e0.93 (m, 2H) 0.89e0.76 (m, 2H), 0.84 (t, 6H, J¼7.4 Hz, eCH3), 0.64 (t, 6H, J¼7.4 Hz, eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 156.6 (2), 134.6, 134.5, 132.9 (2), 129.3, 128.9, 128.8, 122.0, 121.8 (2), 74.7, 73.0, 38.1, 31.6, 28.9, 22.8 (2), 19.1, 14.1, 10.3. IR (KBr) n 1457.2 cm1. HRMS-ESIþ (C42H52O4) m/z calcd: 638.42039 [MþNH4]þ, 643.37578 [MþNa]þ, 659.34972 [MþK]þ, found: 638.42072 [MþNH4]þ, 643.37585 [MþNa]þ, 659.34930 [MþK]þ. 4.3.3.2. Data for partial cone 7b. Mp 135e138 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.28e7.22 (m, 2H, AreH), 7.11 (d, 2H, J¼7.4 Hz, AreH), 6.99e6.87 (m, 4H, AreH), 6.46 (t, 2H, J¼7.4 Hz, AreH), 6.28 (d, 2H, J¼7.8 Hz, AreH), 4.10 (d, 2H, J¼13.3 Hz, AreCH2eAr), 3.86e3.74 (m, 4H, OeCH2), 3.68 (s, 4H, AreCH2eAr), 3.65e3.53 (m, 2H, OeCH2), 3.37e3.29 (m, 2H, OeCH2), 3.07 (d, 2H, J¼13.3 Hz, AreCH2eAr), 1.98e1.80 (m, 6H), 1.66e1.48 (m, 4H), 1.46e1.35 (m, 2H), 1.11 (t, 3H, J¼7.4 Hz, eCH3), 1.09e1.01 (m, 6H,
P. Slavík et al. / Tetrahedron 72 (2016) 6348e6355
eCH3), 0.73 (t, 3H, J¼7.4 Hz, eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 157.6, 157.1, 155.6 (2), 137.1, 134.0, 133.4, 132.1, 130.4 (2), 129.3, 128.9, 128.3, 122.1, 121.6, 121.4, 76.1, 75.5, 74.1, 72.9, 35.8, 33.0, 32.8, 30.5, 23.8, 22.3, 19.6, 19.5, 14.2, 14.1, 10.9, 9.3. IR (KBr) n 1453.8 cm1. HRMS-ESIþ (C42H52O4) m/z calcd: 638.42039 [MþNH4]þ, 643.37578 [MþNa]þ, 659.34972 [MþK]þ, found: 638.42132 [MþNH4]þ, 643.37647 [MþNa]þ, 659.34954 [MþK]þ. 4.3.4. Synthesis of 25,26-dipropoxy-27,28-dihexyloxycalix[4]arene1,2-alt (8a) and paco (8b). Compound 8a was prepared according to the general procedure using 0.077 g (0.15 mmol) of calixarene 2, 0.098 g (0.76 mmol) of potassium trimethylsilanolate (90% purity), and 0.11 ml (0.76 mmol) of 1-iodohexane. The crude reaction mixture was purified by preparative TLC on silica gel (hexane:CH2Cl2 5:1, v/v) to give the title compounds 8a (0.046 g, 44%, white powder) and 8b (0.021 g, 20%, white powder). 4.3.4.1. Data for 1,2-alternate 8a. Mp 58e60 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.11e6.98 (m, 8H, AreH), 6.82 (dt, 4H, J¼7.4, 1.2 Hz, AreH), 4.21e4.13 (m, 2H, AreCH2eAr), 3.87 (s, 4H, AreCH2eAr), 3.41e3.29 (m, 8H, OeCH2), 3.15 (d, 1H, J¼12.5 Hz, AreCH2eAr), 3.14 (d, 1H, J¼12.5 Hz, AreCH2eAr), 1.30e0.91 (m, 16H, CH2), 0.89 (t, 6H, J¼7.0 Hz, CH3), 0.83e0.63 (m, 4H, CH2), 0.59 (t, 6H, J¼7.4 Hz, CH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 156.6, 156.5, 134.6, 134.5, 132.9, 129.2 (2) 128.8 (2), 121.9, 121.8, 74.6, 73.3, 38.1, 31.9, 29.4, 29.0, 28.9, 25.6, 22.8, 22.7, 14.1, 10.3. IR (KBr) n 1457.3 cm1. HRMS-ESIþ (C46H60O4) m/z calcd: 694.48299 [MþNH4]þ, 699.43838 [MþNa]þ, 715.41232 [MþK]þ, found: 694.48354 [MþNH4]þ, 699.43872 [MþNa]þ, 715.41178 [MþK]þ. 4.3.4.2. Data for partial cone 8b. Mp 74e76 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.23 (d, 2H, J¼7.4 Hz, AreH), 7.10 (d, 2H, J¼7.4 Hz, AreH), 6.97e6.84 (m, 4H, AreH), 6.43 (t, 2H, J¼7.4 Hz, AreH), 6.25 (dd, 2H, J¼7.4, 1.2 Hz, AreH), 4.08 (d, 1H, J¼13.3 Hz, AreCH2eAr), 4.07 (d, 1H, J¼13.3 Hz, AreCH2eAr), 3.84e3.72 (m, 4H, OeCH2), 3.65 (s, 4H, AreCH2eAr), 3.62e3.51 (m, 2H, OeCH2), 3.34e3.27 (m, 2H, OeCH2), 3.05 (d, 2H, J¼13.7 Hz, AreCH2eAr), 1.97e1.79 (m, 6H, CH2), 1.60e1.32 (m, 18H, CH2), 1.10 (t, 3H, J¼7.4 Hz, CH3), 0.98e0.92 (m, 6H, CH3), 0.91e0.75 (m, 4H, CH2), 0.71 (t, 3H, J¼7.4 Hz, CH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 157.6, 157.1, 155.6 (2), 137.0, 134.0, 133.4, 132.0, 130.4, 129.3, 128.9, 128.3, 122.0, 121.5, 121.4, 76.1, 75.5, 74.4, 73.1, 35.8, 31.9 (2), 30.9, 30.7, 26.2, 25.9, 23.8, 22.7 (2), 22.3, 14.1 (2), 10.9, 9.3. IR (KBr) n 1454.1 cm1. HRMS-ESIþ (C46H60O4) m/z calcd: 694.48299 [MþNH4]þ, 699.43838 [MþNa]þ, 715.41232 [MþK]þ, found: 694.48394 [MþNH4]þ, 699.43908 [MþNa]þ, 715.41217 [MþK]þ. 4.3.5. Synthesis of 25,26-diethoxy-27,28-propoxycalix[4]arene-1,2alt (9a) and paco (9b). Compound 9a was prepared according to the general procedure using 0.079 g (0.16 mmol) of calixarene 2, 0.10 g (0.78 mmol) of potassium trimethylsilanolate (90% purity), and 0.07 ml (0.78 mmol) of 1-iodoethane. The crude reaction mixture was purified by preparative TLC on silica gel (hexane:CH2Cl2 1:1, v/v) to give the title compounds 9a (0.046 g, 53%, white powder) and 9b (0.031 g, 35%, white powder). 4.3.5.1. Data for 1,2-alternate 9a. Mp 95e97 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.15e7.02 (m, 8H, AreH), 6.85e6.81 (m, 4H, AreH), 4.23 (d, 1H, J¼12.5 Hz, AreCH2eAr), 4.17 (d, 1H, J¼12.5 Hz, AreCH2eAr), 3.90 (s, 4H, AreH), 3.46 (q, 4H, J¼7.04 Hz, OeCH2), 3.42e3.36 (m, 4H, OeCH2), 3.21e3.13 (m, 2H, AreCH2eAr), 1.30e1.16 (m, 2H, OeCH2eCH2), 1.07e0.94 (m, 2H, OeCH2eCH2), 0.67 (t, 6H, J¼7.04 Hz, OeCH2eCH3), 0.61 (t, 6H, J¼7.4 Hz, OeCH2eCH2eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 156.6, 156.3, 134.9, 134.6, 133.0, 132.9, 129.2 (2), 128.8,
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n 1456.6 cm1. HRMS-ESIþ (C38H44O4) m/z calcd: 582.35779
[MþNH4]þ, 587.31318 [MþNa]þ, 603.28712 [MþK]þ, found: 582.35866 [MþNH4]þ, 587.31364 [MþNa]þ, 715.28683 [MþK]þ. 4.3.5.2. Data for partial cone 9b. Mp 230e232 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.22 (d, 2H, J¼7.4 Hz, AreH), 7.09 (d, 2H, J¼7.4 Hz, AreH), 6.96e6.86 (m, 4H, AreH), 6.49e6.41 (m, 2H, AreH), 6.34e6.26 (m, 2H, AreH), 4.08 (d, 1H, J¼12.9 Hz, AreCH2eAr), 4.06 (d, 1H, J¼12.6 Hz, AreCH2eAr), 3.91e3.81 (m, 3H, OeCH2), 3.80e3.71 (m, 1H, OeCH2), 3.70e3.60 (m, 5H, OeCH2þAreCH2eAr), 3.58e3.48 (m, 1H, OeCH2), 3.36e3.27 (m, 2H, OeCH2), 3.05 (dd, 2H, J¼12.9, 2.4 Hz, AreCH2eAr), 1.92e1.82 (hex, 2H, J¼7.4 Hz, OeCH2eCH2), 1.49e1.34 (m, 8H, OeCH2eCH2þCH3), 1.09 (t, 3H, J¼7.4 Hz, CH3), 0.71 (t, 3H, J¼7.4 Hz, CH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 157.3, 157.1, 155.6, 155.4, 137.0 (2), 134.1, 134.0, 133.5, 133.4, 132.2, 132.0, 130.7, 130.5, 129.6, 129.5, 128.9, 128.8, 128.3 (2), 122.1, 121.6, 121.4, 121.3, 76.1, 75.5, 69.3, 67.7, 36.2, 36.0, 30.5, 30.4, 23.8, 22.1, 16.1, 15.9, 10.9, 9.3. IR (KBr) n 1452.8 cm1. HRMS-ESIþ (C38H44O4) m/z calcd: 582.35779 [MþNH4]þ, 587.31318 [MþNa]þ, 603.28712 [MþK]þ, found: 582.35905 [MþNH4]þ, 587.31382 [MþNa]þ, 715.28693 [MþK]þ. 4.3.6. Synthesis of 25,26-diallyloxy-27,28-propoxycalix[4]arene-1,2alt (10a) and paco (10b). A mixture of compounds 10a and 10b was prepared according to the general procedure using 0.035 g (0.069 mmol) of calixarene 2, 0.044 g (0.340 mmol) of potassium trimethylsilanolate (90% purity), and 0.030 ml (0.34 mmol) of allyl bromide. The 1H NMR analysis of the crude product (0.040 g) showed the presence of 10a and 10b conformers in a 58:42 ratio (see Supplementary data). This mixture was purified by repeated preparative thin layer chromatography on silica gel, unfortunately, we were not able to isolate pure desired 1,2-alternate conformer 10a. However, we were able to obtain a single crystal of compound 10a (CH2Cl2/methanol) suitable for X-ray analysis. 4.3.7. Synthesis of 25,26-dipropargyloxyoxy-27,28-propoxycalix[4] arene-1,2-alt (11a) and paco (11b). Compound 11a was prepared according to the general procedure using 0.048 g (0.094 mmol) of calixarene 2, 0.070 g (0.47 mmol) of potassium trimethylsilanolate (90% purity), and 0.050 ml (0.47 mmol) of propargyl bromide (80% in toluene). The crude reaction mixture was purified by preparative TLC on silica gel (hexane:CH2Cl2 1:1, v/v) to give the title compounds 11a (0.037 g, 67%, white powder) and 11b (0.010 g, 18%, white powder). 4.3.7.1. Data for 1,2-alternate 11a. Mp 160e162 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.16 (d, 4H, J¼7.8 Hz, AreH), 7.05 (dd, 2H, J¼7.4, 1.6 Hz, AreH), 6.97 (dd, 2H, J¼7.4, 1.6 Hz, AreH), 6.90e6.84 (m, 4H, AreH), 4.48 (d, 1H, J¼12.9 Hz, AreCH2eAr), 4.14 (d, 1H, J¼12.9 Hz, AreCH2eAr), 4.04 (d, 2H, J¼16.0 Hz, AreCH2eAr), 3.95 (m, 4H, OeCH2eCeCH), 3.85 (d, 2H, J¼16.0 Hz, AreCH2eAr), 3.37e3.22 (m, 5H, OeCH2þAreCH2eAr), 3.16 (d, 1H, J¼12.9 Hz, AreCH2eAr), 2.33 (t, 2H, J¼2.4 Hz, OeCH2eCeCH), 1.25e1.12 (m, 2H, OeCH2eCH2), 0.77e0.65 (m, 2H, OeCH2eCH2), 0.62 (t, 6H, J¼7.0 Hz, OeCH2eCH2eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 156.2, 154.7, 135.3, 135.1, 133.8, 132.9, 129.9, 129.4, 128.8, 128.7, 122.8, 122.5, 80.8, 75.4, 74.1, 59.8, 37.4, 30.2, 29.5, 22.3, 10.1. IR (KBr) n 2123.1, 1454.9 cm1. HRMS-ESIþ (C40H40O4) m/z calcd: 602.32649 [MþNH4]þ, 607.28188 [MþNa]þ, 623.25582 [MþK]þ, found: 602.32642 [MþNH4]þ, 607.28134 [MþNa]þ, 623.25429 [MþK]þ. 4.3.7.2. Data for partial cone 11b. Mp 171e172 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.33 (dd, 1H, J¼7.4, 1.6 Hz, AreH), 7.24 (dd, 1H, J¼7.8, 1.6 Hz, AreH), 7.12e7.06 (m, 2H, AreH),
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7.05e7.00 (m, 2H, AreH), 6.95 (t, 1H, J¼7.4 Hz, AreH), 6.90 (t, 1H, J¼7.4 Hz, AreH), 6.54 (t, 1H, J¼7.4 Hz, AreH), 6.47 (t, 1H, J¼7.4 Hz, AreH), 6.37 (dd, 1H, J¼7.8, 1.6 Hz, AreH), 6.31 (dd, 1H, J¼7.4, 1.6 Hz, AreH), 4.49e4.35 (m, 4H, OeCH2eCeCH), 4.10 (d, 1H, J¼13.3 Hz, AreCH2eAr), 4.09 (d, H, J¼13.0 Hz, AreCH2eAr), 3.82e3.64 (m, 5H, OeCH2þAreCH2eAr), 3.59e3.51 (m, 1H, OeCH2), 3.38e3.28 (m, 2H, OeCH2), 3.09 (d, 1H, J¼13,3 Hz, AreCH2eAr), 3.07 (d, 1H, J¼13,3 Hz, AreCH2eAr), 2.51 (t, 1H, J¼2.4 Hz, OeCH2eCeCH), 2.50 (t, 1H, J¼2.4 Hz, OeCH2eCeCH), 1.92e1.80 (m, 2H, OeCH2eCH2), 1.45e1.31 (m, 2H, OeCH2eCH2), 1.08 (t, 3H, J¼7.4 Hz, OeCH2eCH2eCH3), 0.72 (t, 3H, J¼7.4 Hz, OeCH2eCH2eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 157.0, 156.3, 155.5, 154.4, 136.9, 136.7, 134.3, 134.1, 133.6, 133.4, 132.3, 131.8, 130.8, 130.7, 129.5, 129.4, 129.1, 128.7, 128.6, 128.4, 122.7, 122.6, 122.3, 121.6, 76.1, 75.6, 74.6, 74.4, 60.9, 59.3, 36.2, 36.1, 30.8, 30.4, 23.8, 22.1, 10.9, 9.4. IR (KBr) n 2123.1, 1453.6 cm1. HRMS-ESIþ (C40H40O4) m/z calcd: 602.32649 [MþNH4]þ, 607.28188 [MþNa]þ, 623.25582 [MþK]þ,
reduction and absorption correction were done using Apex3 software.10 The structures 5a and 12a were measured using Xcalibur PX with an Onyx CCD detector and graphite monochromated Cu Ka (l¼1.54184 A) radiation. The data reduction and absorption correction were done using CrysAlis PRO software.11 The structures 2$CH2Cl2, 5a, 10a and 12a were solved by direct methods12 and the structure 7a was solved by charge flipping methods.13 The structured were refined by full matrix least squares on F squared value using Crystals software.14 MCE software15 was used for visualization of the electron density maps. The positions of the disordered functional groups were found in difference Fourier maps; the bond lengths and angles were restrained. The overall occupancy of the disordered functional groups was constrained to 1. According to common practice the hydrogen atoms attached to the carbon atoms were placed geometrically with Uiso(H) in the range of 1.2e1.5 Ueq for parent atom (C). For further information on crystal structures and data collection see Table 3.
Table 3 The information on crystal structures and data collection Compound
2$CH2Cl2
5a
7a
10a
12a
Formula Mr Crystal system Space group a ( A) b ( A) c ( A) a ( ) b ( ) g ( ) V ( A3) Z T (K) Dcalcd (g cm3) m (mm1) Reflections used Independent (Rint) Observed [I>2s(I)] Parameters/restrains A3) Drmax/Drmin (e GOF R/wR CCDC number
C34$H36$O4, C$H2$Cl2 593.59 Monoclinic P21/n 11.6864 (3) 14.6226 (3) 18.1551 (4) 90 101.0873 (9) 90 3044.54 (12) 4 180 1.295 2.22 29,831 5518 (0.060) 5279 398/34 0.78/0.54 0.89 0.072/0.180 1478270
C40$H48$O4 592.82 Triclinic P-1 9.5234 (3) 18.5382 (6) 19.0955 (4) 85.559 (2) 85.451 (2) 86.181 (3) 3344.33 (17) 4 180 1.177 0.58 28,112 13,453 (0.042) 10,837 820/58 0.60/0.51 0.91 0.074/0.165 1478271
C42$H52$O4 620.87 Triclinic P-1 9.4668 (11) 10.8903 (14) 18.778 (2) 80.119 (4) 82.721 (3) 70.323 (3) 1790.9 (4) 2 180 1.151 0.56 22,594 6505 (0.049) 6127 452/68 0.64/0.48 1.14 0.092/0.206 1478272
C40$H44$O4 588.79 Monoclinic P21/n 10.8996 (2) 19.7499 (4) 15.3146 (3) 90 95.5843 (9) 90 3281.07 (11) 4 180 1.192 0.59 49,970 6013 (0.053) 5763 425/28 0.56/0.48 1.06 0.067/0.155 1478273
C48$H48$O4 688.91 Monoclinic P21/c 10.5744 (2) 18.5382 (4) 39.8504 (10) 90 93.760 (2) 90 7795.1 (3) 8 180 1.174 0.57 63,509 16,023 (0.042) 11,746 965/28 0.29/0.32 1.01 0.061/0.150 1478274
found: 602.32621 [MþNH4]þ, 607.28114 [MþNa]þ, 623.25442 [MþK]þ. 4.3.8. Synthesis of 25,26-dibenzyloxy-27,28-propoxycalix[4]arene1,2-alt (12a) and paco (12b). A mixture of compounds 12a and 12b was prepared according to the general procedure using 0.072 g (0.14 mmol) of calixarene 2, 0.091 g (0.71 mmol) of potassium trimethylsilanolate (90% purity), and 0.085 ml (0.71 mmol) of benzyl bromide. The 1H NMR analysis of the crude product (0.077 g) showed the presence of 12a and 12b conformers in a 63:37 ratio (see Supplementary data). This mixture was purified by repeated preparative TLC on silica gel, unfortunately, we were not able to isolate pure desired 1,2-alternate conformer 12a. On the other hand, we were able to obtain a single crystal of compound 12a (CH2Cl2/ methanol) suitable for X-ray analysis. 4.4. Single crystal X-ray diffraction measurements The structures 2$CH2Cl2, 7a and 10a were measured using a D8 VENTURE with a Photon 100 CMOS detector and microfocused mirror collimated Cu Ka (l¼1.54178 A) radiation. The data
Acknowledgements The authors wish to thank the Czech Science Foundation (grant Nr. 16-13869S and 16-10035S) and Specific University Research (MSMT No 20-SVV/2016). Supplementary data Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2016.08.028. References and notes 1. For books on calixarenes and their applications see: (a) Gutsche, C. D. Calixarenes an Introduction, 2nd ed.; The Royal Society of Chemistry, Thomas Graham House: Cambridge, 2008, ISBN: 978-0-85404-258-6; (b) Calixarenes in the Nanoworld; Vicens, J., Harrowfield, J., Backlouti, L., Eds.; Springer: Dordrecht, €hmer, V., Har2007, ISBN: 1-4020-5021-6; (c) Calixarenes 2001; Asfari, Z., Bo rowfield, J., Vicens, J., Eds.; Kluwer Academic: Dordrecht, 2001, ISBN: 0-79236960-2; (d) Mandolini, L.; Ungaro, R. Calixarenes in Action; Imperial College Press: London, 2000, ISBN: 1-86094-194-X. 2. For selected reviews on various calixarene-based receptors see: (a) Siddiqui, S.; Cragg, P. J. Mini-Rev Org. Chem. 2009, 6, 283e299; (b) Leray, I.; Valeur, B. Eur. J. Inorg. Chem. 2009, 24, 3525e3535; (c) Matthews, S. E.; Beer, P. D. In Calixarenes
P. Slavík et al. / Tetrahedron 72 (2016) 6348e6355 2001, pp. 421e439 (in Ref. 1b). (d) Lhot ak, P. Top. Curr. Chem. 2005, 255, 65e96; (e) Matthews, S. E.; Beer, P. D. Supramol. Chem. 2005, 17, 411e435; (f) Coquiere, D.; Le Gac, S.; Darbost, U.; Seneque, O.; Jabin, I.; Reinaud, O. Org. Biomol. Chem. 2009, 7, 2485e2500; (g) Lhotak, P.; Kundrat, O. In Artificial Receptors for Chemical Sensors; Mirsky, V., Yatsimirsky, A., Eds.; Wiley-VCH: Weinheim, 2011, ISBN: 978-3-527-32357-9; pp 249e272. 3. (a) Pappalardo, S.; Giunta, J. L.; Foti, M.; Ferguson, G.; Gallagher, J. F.; Kaitner, B. J. Org. Chem. 1992, 57, 2611e2624; (b) Pappalardo, S.; Petringa, A.; Parisi, M. F.; Ferguson, G. Tetrahedron Lett. 1996, 37, 3907e3910; (c) Arnaud-Neu, F.; Ferguson, G.; Fuangswasdi, S.; Notti, A.; Pappalardo, S.; Parisi, M. F.; Petringa, A. J. Org. Chem. 1998, 63, 7770e7779; (d) Ferguson, G.; Lough, A. J.; Notti, A.; Pappalardo, S.; Parisi, M. F.; Petringa, A. J. Org. Chem. 1998, 63, 9703e9710. 4. (a) Arduini, A.; Domiano, L.; Pochini, A.; Secchi, A.; Ungaro, R.; Ugozzoli, F.; Struck, O.; Verboom, W.; Reinhoudt, D. N. Tetrahedron 1997, 53, 3767e3776; (b) Arduini, A.; Bozzoli, M.; Massera, C.; Pochini, A.; Secchi, A.; Ugozzoli, F. Collect. Czech. Chem. Commun. 2004, 69, 1309e1324; (c) Zhang, D.; Cao, X.; Purkiss, D. W.; Bartsch, R. A. Org. Biomol. Chem. 2007, 5, 1251e1259; (d) Boston, A. L.; Lee, E. K.; Crawford, J. D.; Hanes, R. E., Jr.; Bartsch, R. A. Tetrahedron 2012, 68, 10241e10251; (e) Xia, Y.-X.; Zhou, H.-H.; Shi, J.; Li, S.-Z.; Zhang, M.; Luo, J.;
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
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Xiang, G.-Y. J. Inclusion Phenom. Macrocyclic Chem. 2012, 74, 277e284; (f) Lynch, J. A.; Mestayer, J. J.; Blanda, M. T. J. Supramol. Chem. 2001, 1, 139e145. Simaan, S.; Biali, S. E. J. Org. Chem. 2004, 69, 95e98. Lhotak, P.; Bila, A.; Budka, J.; Pojarova, M.; Stibor, I. Chem. Commun. 2008, 1662e1664. Awada, M.; Jeunesse, C.; Matt, D.; Toupet, L.; Welter, R. Dalton Trans. 2011, 40, 10063e10070. Kuo, C.-H.; Huang, J.-R.; Chen, H.-R.; Chen, P.-Y.; Lin, C.-H.; Lin, L.-G. Tetrahedron 2011, 67, 3936e3944. Iki, H.; Kikuchi, T.; Shinkai, S. J. Chem. Soc., Perkin Trans. 1 1993, 205e2010. Bruker (2015). APEX3, SAINT, Bruker AXS: Madison, Wisconsin, USA. Rigaku Oxford Diffraction. CrysAlis PRO; Rigaku Oxford Diffraction: Yarnton, England, 2015. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435. Palatinus, L.; Chapuis, G. J. Appl. Crystallogr. 2007, 40, 786e790. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487. Rohlicek, J.; Husak, M. J. Appl. Crystallogr. 2007, 40, 600e601.
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A general method for obtaining calix[4]arene derivatives in the 1,2-alternate conformation clav Eigner b, Pavel Lhota k a, * Petr Slavík a, Va a b
5, 166 28 Prague 6, Czech Republic Department of Organic Chemistry, University of Chemistry and Technology, Prague (UCT), Technicka 5, 166 28 Prague 6, Czech Republic Department of Solid State Chemistry, University of Chemistry and Technology, Prague (UCT), Technicka
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 May 2016 Received in revised form 28 July 2016 Accepted 9 August 2016 Available online 13 August 2016
The 1,2-alternate conformation, so far the least accessible atropisomer of calix[4]arene, is now easily available on a gram scale. The entire synthetic sequence consists of only two stepsd(a) proximal dialkylation (R1-I, NaH/DMF), and (b) another subsequent dialkylation (R2-I, Me3SiOK/THF). The selection of appropriate base/solvent combinations in both stages was the key prerequisite for the successful preparation of the 1,2-alternate conformers, which are available without the use of any protecting groups. Ó 2016 Elsevier Ltd. All rights reserved.
Keywords: Calixarene Conformation Alkylation 1,2-Alternate Partial cone Conformational mobility
1. Introduction Calix[n]arenes1 represent highly versatile macrocyclic compounds as can be demonstrated by their widespread applications as building blocks and/or molecular scaffolds in supramolecular chemistry. The simple preparation of these compounds, almost limitless freedom in their derivatization and excellent complexation abilities make calixarenes a highly desirable choice in the design of new receptors. Probably, the most attractive feature of these macrocycles is the tuneable 3D shape of their molecules, which is extremely useful in the design and synthesis of novel receptors. Thus, the introduction of bulky substituents (R¼propyl or any higher alkyl group) at the phenolic subunits of calix[4]arene leads to the immobilisation of the macrocyclic skeleton into four basic conformations (atropisomers) called cone, partial cone, 1,2alternate and 1,3-alternate (Scheme 1). The chemistry of the cone, partial cone and 1,3-alternate conformations has recently been well established, and all three atropisomers are accessible on a multigram scale via direct stereoselective alkylation of parent calix[4]arenes. Consequently, the three conformations are frequently used in the design of novel receptors, self-assemblies or more sophisticated calixarene-based
supramolecular systems.2 Unfortunately, until recently, a broader application of the 1,2-alternates has been hindered by our limited knowledge of their chemistry, in particular, by the lack of a general synthetic methodology. Thus, the 1,2-alternate conformation can be prepared using rather unusual alkylation agents, like 2pyridylmethyl chloride (a-picolyl chloride),3 or by the formation of short proximal bridges using oligoethylene glycol ditosylates.4 Another, even rarer approach, is based on the steric
Scheme 1. The four basic conformers (atropisomers) of calix[4]arene. * Corresponding author. Fax: þ420 220 444 288; e-mail address: [email protected] k). (P. Lhota http://dx.doi.org/10.1016/j.tet.2016.08.028 0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
P. Slavík et al. / Tetrahedron 72 (2016) 6348e6355
destabilization of the cone conformation of unsubstituted calix[4] arene by introducing substituents on the methylene bridges.5 In our previous work6 we showed that calix[4]arenes immobilised in the 1,2-alternate conformation can be prepared on a multigram scale using a simple dialkylation/dialkylation procedure.6 Thus, alkylation of starting p-tert-butylcalixarene with propyl bromide/NaOH in a DMSOH2O mixture gave a proximally dipropylated derivative, which could be subsequently alkylated to give the corresponding 1,2-alternate. Surprisingly, this procedure did not work with de-tert-butylated calixarene 1 leaving the corresponding 1,2-alternates unavailable. In this paper we report on a simple and general synthetic procedure that selectively provides the 1,2-alternate derivatives with unsubstituted upper rims, hence, paving the way for their applications in supramolecular chemistry.
2. Results and discussion The synthesis starts with a proximal dialkylation of starting calix [4]arene 1 (Scheme 2). We employed a subtle modification of the reaction conditions7 recently described for the preparation of compound 2. Thus, calixarene 1 was dissolved in dry DMF and reacted with NaH (3.6 equiv), stirred for 15 min at room temperature and then treated with 1-iodopropane (2.15 equiv) as the alkylating agent. The reaction is surprisingly regioselective and proximally disubstituted isomer 2 was obtained in 54% yield using just simple precipitation of the crude reaction product from a MeOHeCH2Cl2 mixture (up to 5.0 g scale). This was highly desired as easy isolation without column chromatography step is an important prerequisite for large scale synthesis. To show the general applicability of these reaction conditions, we carried out a similar alkylation using 1-iodobutane. The corresponding proximal dibutoxy derivative 3 was isolated in 30% yield. We mention that the same compound was already prepared by Lin et al.8 using a very complicated procedure. Thus, the starting calixarene 1 was (i) monoalkylated, (ii) monobenzoylated into the distal position (52% yield), (iii) monoalkylated once again, and (iv) deprotected by hydrolysis of the benzoyl group (11% overall yield for last two steps). Interestingly, similar direct alkylation employing a protected propargyl bromide (3-bromo-1-(trimethylsilyl)-1-
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Fig. 1. X-ray structure of compound 2 showing the interactions of the CH2Cl2 molecule with the cavity, a) side view, b) same from above.
propyne) led to the isolation of compound 4 (44% yield) with free propargyl groups. The structure of the dialkylated compounds was confirmed by 1 H NMR spectra and reflected the expected symmetry of these compounds. Thus, the presence of three well resolved doublets at 4.61 ppm, 4.50 ppm and 4.36 ppm in a 1:2:1 ratio with typical geminal coupling constants (J¼12.5e13.3 Hz) for the axial protons of the methylene bridges clearly supported that compound 4 (400 MHz, CDCl3, 293 K) was proximally alkylated and adopted the cone conformation. Moreover, the structure of dipropoxy derivative 2 was unequivocally assigned using single crystal X-ray analysis. The compound crystalized in the monoclinic system, space group P21/n as a 1:1 complex with CH2Cl2. The cavity of the calixarene is filled with a solvent molecule (Fig. 1) with close contacts between the hydrogen atoms of the CH bonds (CH2Cl2) and the neighbouring aromatic subunits. The distances between the hydrogen atoms and the phenolic planes 2.397 A and 2.567 A indicated the complex is held together by the CeHep interactions. To find the most suitable conditions for the formation of the 1,2alternate conformation, dipropoxy derivative 2 was screened for an optimal base/solvent/temperature combination. Obviously, subsequent propylation of 2 could lead to three different conformers: 1,2-alternate 5a, partial cone 5b and cone 5c. Fortunately, all these isomers possess well resolved signals in the aromatic region of their
Scheme 2. Synthesis of calix[4]arenes in the 1,2-alternate conformation.
6350
P. Slavík et al. / Tetrahedron 72 (2016) 6348e6355
1
H NMR spectra allowing easy assignment of the conformations formed, including their molar ratios in the crude products. Small scale alkylations with 1-iodopropane (30 mg of dipropoxy compound 2) were carried out using various reaction conditions commonly applied in calixarene chemistry (collected in Table 1). As expected, applying standard NaH/DMF conditions (Run 1) led exclusively to the cone conformation 5c, while Cs2CO3/MeCN (Run 2) provided a high percentage of the partial cone 5c. On the other hand, combinations of KH/DMF, K2CO3/DMF, Me3SiOK/DMF and tBuOK/toluene (Runs 3e4, 12) were found to be unsuitable as they yielded complex reaction mixtures containing unreacted 2 together with partly and fully alkylated products. Very promising results were achieved with Me3SiOK/THF leading to a mixture of 5a and 5b with a desirable amount of the 1,2-alternate atropisomer presenting in the crude products (Runs 6 and 7), similar results were also observed for Me3SiOK/THF and t-BuOK/THF. Interestingly, Me3SiOK or t-BuOK in benzene (Runs 10 and 11) gave an even higher molar ratio of 5a. Unfortunately, in both cases a small amount of the cone conformer 5c was also formed which substantially hindered isolation of 5a in a pure form as the Rf values for 5a and 5c were essentially identical on a silica gel column. As a result, large scale preparation of the 1,2-alternate conformer was carried out using Me3SiOK in THF at room temperature. Table 1 Screening of reaction conditions for the alkylation of compound 2 Reaction conditionsa
1 2 3 4 5 6 7 8 9 10 11 12
Conformer distrib.b
Base
Solvent
Temp [ C]
Time [h]
5a
5b
5c
NaH Cs2CO3 KH K2CO3 Me3SiOK Me3SiOK Me3SiOK KHMDS t-BuOK t-BuOK Me3SiOK t-BuOK
DMF MeCN DMF DMF MeCN THF THF THF THF C6H6 C6H6 Toluene
rt Reflux 90 90 90 rt Reflux rt Reflux Reflux Reflux Reflux
24 120 120 100 120 24 24 24 24 24 24 24
0 0
0 90
100 10
49 47 48 46 24 26
0 0 0 0 2 2
c c c
51 53 52 54 74 72 c
dibutyloxy 7a 1,2-alternates (both isolated in 51% yield) together with the partial cone isomers 6b, 7b (both 41%). Applying a longer alkyl group (using 1-hexyl iodide) led to higher selectivity for the 1,2-alternate conformer although in slightly lower overall yieldd8a (44%), 8b (20%). As shown in Table 2, the best selectivity for the 1,2alternate was achieved employing propargyl bromide. This alkylating agent furnished 67% of 11a, while the partial cone conformer 11b was obtained in only 18% yield. In all these examples, the 1,2alternates possessed higher Rf values than the corresponding partial cone isomers and both conformers could be easily separated using column chromatography on silica gel. Treatment with allyl bromide (Run 6) or benzyl bromide (Run 8) gave a corresponding mixtures of conformations with the 1,2-alternate (10a:10b¼58:42, 12a:12b¼63:37) prevailing, but unfortunately, these mixtures could not be efficiently separated using column chromatography on silica gel. The 1H NMR spectra of the resulting 1,2-alternate conformers were fully in agreement with the expected C2h symmetry. Thus, the pair of doublets in the 1H NMR spectrum of 6a (CDCl3) at 3.17 ppm (J¼12.5 Hz) and 4.21 ppm (J¼12.5 Hz) represent the methylene bridge fenced by two syn-oriented phenolic moieties (equatorial and axial protons possessing a geminal coupling constant from the conical fragments of the molecule). On the other hand, the singlet at 3.91 ppm clearly showed the presence of the methylene bridge surrounded by two identical aromatic subunits with an antiorientation (the 1,3-alternate segment of the molecule). Similar structural features can be seen in all the remaining molecules possessing the 1,2-alternate conformationde.g., two pairs of doublets at 3.18, 3.19, 4.20 and 4.23 ppm for 7a indicating lower symmetry due to the presence of two different alkyl groups (npropyl and n-butyl). The structures of several 1,2-alternate products were also unambiguously assigned using single crystal X-ray analysis. Compounds 5a (Fig. 2a) and 7a (Fig. 2b) crystalized in the triclinic system, space group P-1, compounds 10a (Fig. 2c) and 12a (Fig. 2d) crystalized in the monoclinic system, space group P21/n or P21/c, respectively, and in all cases without any solvent molecules in the crystal lattice.
a
Five equivalents of base and propyl iodide were used. H NMR spectrum, 400 MHz, CDCl3. c Incomplete reaction (unreacted starting compound, and/or trialkylated and tetraalkylated products). b 1
The results of the synthesis of 1,2-alternates on a preparative scale are collected in Table 2. In all cases, starting calixarenes 2 or 3 were stirred with the corresponding alkylating agent (5 equiv) and Me3SiOK as a base (5 equiv) in THF at room temperature for 1e3 days. Tetrapropoxy 1,2-alternate 5a was obtained in 51% yield accompanied by the partial cone isomer 5b (44%). Very similar results were shown for tetrabutyloxy 6a and for the mixed dipropoxy Table 2 Synthesis of the 1,2-alternate conformation Run
Starting calix[4]arene
Alkylating agenta
Xa (yield)b
Xb (yield)b
1 2 3 4 5 6 7 8
2 3 2 2 2 2 2 2
n-Pr-I n-Bu-I n-Bu-I n-Hex-I Et-I Allyl-Br Propargyl-Br Benzyl-Br
5a (51) 6a (52) 7a (52) 8a (44) 9a (53) 10a (58)c 11a (67) 12a (63)c
5b (44) 6b (41) 7b (41) 8b (20) 9b (35) 10b (42)c 11b (18) 12b (37)c
a 5 equiv. Me3SiOKþ5 equiv alkylating agent in THF, 1 day stirring at room temperature. b Isolated yields after chromatography. c Separation failed, the ratio of conformers was assigned using the 1H NMR spectra of crude products.
Fig. 2. X-ray structures of several 1,2-alternate conformations: a) 5a, b) 7a, c) 10a, d) 12a.
P. Slavík et al. / Tetrahedron 72 (2016) 6348e6355
It is well documented1 that the presence of four propyl groups on the lower rim of calix[4]arene leads to the immobilization of a given conformation as the propyl groups are sufficiently bulky substituents to hinder rotation of the phenolic subunits through the macrocyclic cavity. To confirm the conformational mobility in the 1,2-alternate series we prepared compounds proximally bearing two propyl and two ethyl groups. Using our general alkylation procedure the corresponding 1,2-alternate 9a was prepared in 53% yield, accompanied again by the partial cone conformer 9b (35%). Both conformations were easily separated using column chromatography indicating the conformations are stable on a laboratory time scale at ambient temperature. Indeed, the 1H NMR spectra of 9a or 9b in CDCl3 at 25 C did not reveal any conformational interconversion of these isomers. On the other hand, heating of 9a to 130 C for 2 days (in CDCl2eCDCl2) led to a mixture of all three theoretically possible isomers (showing that, obviously, only Et groups can rotate through the annulus). In the independent experiment 9b gave the identical mixture of isomers indicating that a thermodynamic equilibrium was achieved (Fig. 3). Integration of the resulting mixture showed the presence of the partial cone (56%), cone (28%), and 1,2-alternate (16%) conformers reflecting the relative thermodynamic stabilities of the corresponding conformations under the given conditions.
Fig. 3. Aromatic region of the 1H NMR spectra of: a) pure 9b, c) pure 9a, b) spectrum obtained after 47 h heating of 9a to 130 C (400 MHz, CDCl2eCDCl2), - partial cone, , 1,2-alternate, : cone.
3. Conclusions In conclusion, the upper rim unsubstituted calix[4]arenes immobilised in the 1,2-alternate conformation are now easily accessible using a proximal dialkylation/dialkylation strategy. Careful selection of the appropriate base/solvent combination in each step enables the synthesis of the 1,2-alternates on a gram scale. This paves the way for potential applications of this least accessible conformation of calix[4]arene in supramolecular chemistry. 4. Experimental 4.1. General All chemicals were purchased from commercial sources and used without further purification. 1,2-Dichloroethane, CH2Cl2 and
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N,N’-dimethylformamide used for the reactions were dried with CaH2 or MgSO4 and stored over molecular sieves. THF was dried using the sodium/benzophenone method. Melting points were measured on Heiztisch Mikroskop-Polytherm A (Wagner & Munz, Germany) and were not corrected. The IR spectra were measured on an FTIR spectrometer Nicolet 740 in KBr transmission mode. NMR spectra were recorded on spectrometers Varian Gemini 300 (1H: 300 MHz, 13C: 75 MHz) and Agilent 400-MR DDR2 (1H: 400 MHz, 13C: 100 MHz). Chemical shifts (d) are expressed in parts per million and are referenced to the residual peak of solvent or TMS as an internal standard, coupling constants (J) are in hertz. The mass analyses were performed using ESI on an FT-MS (LTQ Orbitrap Velos) spectrometer. Purity of the substances and courses of the reactions were monitored by thin layer chromatography (TLC) using silica gel 60 F254 on aluminium-backed sheets (Merck) and analyzed at 254 or 365 nm. Preparative TLC chromatography was carried out on a Chromatotron (Harrison Research) with plates covered by Silica gel 60 GF254 (Merck). 4.2. General procedure for proximal dialkylation Calixarene 1 was dissolved in dry DMF and NaH (3.6 equiv) was carefully added. The solution was stirred at room temperature for 15 min. Then, the alkylating agent (2.15 equiv) was added dropwise and the resulting solution was stirred for 2 h at room temperature. The reaction mixture was carefully quenched by aqueous 1 M HCl and to this mixture dichloromethane was added. The organic layer was separated, washed with water and dried over magnesium sulfate. Solvent was removed under reduced pressure to yield the crude product which was purified by precipitation from a CH2Cl2/ MeOH mixture. Depending on the scale of the reaction, this step can be replaced by column chromatography or by preparative thin layer chromatography on silica gel. 4.2.1. Synthesis of 25,26-dihydroxy-27,28-dipropoxycalix[4]arene (2). Compound 2 was prepared according to the general procedure for proximal alkylation using 1.06 g (2.50 mmol) of calixarene 1, 0.36 g (9.01 mmol) of NaH (60% dispersion in mineral oil) and 0.53 ml (5.38 mmol) of 1-iodopropane. Compound 2 (0.68 g, 54%) was obtained as a white powder by simple precipitation of the crude product from a MeOHeCH2Cl2 mixture. The analytical data was in agreement with previously published data.7 1 H NMR (400 MHz, CDCl3, 293 K) d (ppm): 8.99 (s, 2H, AreOH), 7.06 (dd, 2H, J¼7.8, 1.6 Hz, AreH), 7.01e6.96 (m, 6H, AreH), 6.79 (t, 2H, J¼7.4 Hz, AreH), 6.63 (t, 2H, J¼7.8 Hz, AreH), 4.55 (d, 1H, J¼12.5 Hz, AreCH2eAr), 4.34 (d, 3H, J¼12.9 Hz, AreCH2eAr), 4.13e4.05 (m, 2H, OeCH2), 3.94e3.86 (m, 2H, OeCH2), 3.41 (d, 1H, J¼12.5 Hz, AreCH2eAr), 3.40 (d, 2H, J¼12.9 Hz, AreCH2eAr), 3.36 (d, 1H, J¼13.3 Hz, AreCH2eAr), 2.22e2.06 (m, 4H, OeCH2eCH2), 1.16 (t, 6H, J¼7.4 Hz, OeCH2eCH2eCH3). 4.2.2. Synthesis of 25,26-dihydroxy-27,28-dibutoxycalix[4]arene (3). Compound 3 was prepared according to the general procedure for proximal alkylation by reacting 1.05 g (2.50 mmol) of calixarene 1, 0.36 g (9.01 mmol) of NaH (60% dispersion in mineral oil) and 0.71 ml (5.3 mmol) of 1-iodobutane. Compound 3 (0.38 g, 30%) as a white powder was obtained by simple precipitation of the crude product from a MeOHeCH2Cl2 mixture. Another portion of product (15% yield) can be obtained by column chromatography of the mother liquor remaining after the precipitation. The analytical data was in agreement with previously published data.8 1 H NMR (400 MHz, CDCl3, 293 K) d (ppm): 9.00 (s, 2H, AreOH), 7.15e7.06 (m, 2H, AreH), 7.06e6.98 (m, 6H, AreH), 6.83 (t, 2H, J¼7.4 Hz, AreH), 6.67 (t, 2H, J¼7.4 Hz, AreH), 4.59 (d, 1H, J¼12.1 Hz, AreCH2eAr), 4.45e4.36 (m, 3H, AreCH2eAr), 4.20e4.12 (m, 2H, OeCH2), 4.03e3.94 (m, 2H, OeCH2), 3.49e3.36 (m, 4H, AreCH2eAr),
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2.27e2.02 (m, 4H, OeCH2eCH2), 1.74e1.56 (m, 4H, OeCH2eCH2eCH2), 1.12 (t, 6H, J¼7.4 Hz, OeCH2eCH2eCH2eCH3). 13C NMR (100 MHz, CDCl3, 293 K) d (ppm): 153.5,151.2, 134.7, 134.2, 129.4, 129.1 (2),128.8 (2),128.0,124.8,120.6, 76.7, 32.1, 32.0, 31.8, 30.0,19.3,14.1. 4.2.3. Synthesis of 25,26-dihydroxy-27,28-dipropargyloxycalix[4] arene (4). Compound 4 was prepared according to the general procedure for proximal alkylation using 0.53 g (1.26 mmol) of calixarene 1, 0.18 g (4.52 mmol) of NaH (60% dispersion in mineral oil) and 0.44 ml (2.7 mmol) of 3-bromo-1-(trimethylsilyl)-1-propyne. After the workup, the unprotected title compound was obtained (0.28 g, 44%) as a white powder using preparative TLC on silica gel (hexane:CH2Cl2 1:2, v/v). Mp 166e167 C. 1H NMR (400 MHz, CDCl3, 293 K) d (ppm): 7.08e7.01 (m, 4H, AreH), 6.97 (d, 4H, J¼7.4 Hz, AreH), 6.88e6.82 (m, 2H, AreH), 6.67e6.61 (m, 2H, AreH), 4.96 (dd, 2H, J¼15.7, 2.4 Hz, OeCH2), 4.87 (dd, 2H, J¼15.7, 2.4 Hz, OeCH2), 4.61 (d, 1H, J¼12.5 Hz, AreCH2eAr), 4.50 (d, 2H, J¼13.3 Hz, AreCH2eAr), 4.36 (d, 1H, J¼13.3 Hz, AreCH2eAr), 3.47e3.36 (m, 4H, AreCH2eAr), 2.66 (t, 2H, J¼2.4 Hz, OeCH2eCeCH). 13C NMR (100 MHz, CDCl3, 293 K) d (ppm): 152.7, 151.0, 134.8 (2), 129.4, 129.3, 129.1, 129.0, 128.8, 128.2, 125.6, 120.9, 79.2, 76.5, 62.5, 32.1, 31.9 (2). IR (KBr) n (cm1): 2122.7, 1462.7. HRMS-ESI (C34H28O4) m/z calcd: 501.20604 [MþH]þ, 523.18798 [MþNa]þ, 539.16192 [MþK]þ, found: 501.20611 [MþH]þ, 523.18837 [MþNa]þ, 539.16221 [MþK]þ. 4.3. General procedure for the synthesis of calix[4]arenes in the 1,2-alternate conformation Proximally dialkylated calix[4]arene was dissolved in dry THF and stirred at room temperature. To this solution potassium trimethylsilanolate (5 equiv, 90% purity) was added and stirred for another 30 min. The alkylating agent (5 equiv) was then added and the mixture was stirred at room temperature for 1e3 days. The course of reaction was monitored by TLC. After disappearance of the starting compound aqueous 1 M HCl was added, and the mixture was extracted with CH2Cl2. The organic layer was washed with water and dried over MgSO4. The solvent was removed under reduced pressure to yield the crude product which was purified by preparative chromatography to separate the conformers. 4.3.1. Synthesis of 25,26,27,28-tetrapropoxy-calix[4]arenes-1,2-alt (5a) and paco (5b). Compound 5a was prepared according to the general procedure using 0.31 g (0.62 mmol) of calixarene 2, 0.61 g (3.08 mmol) of potassium trimethylsilanolate (90% purity), and 0.30 ml (3.08 mmol) of 1-iodopropane. The crude reaction mixture was purified by column chromatography on silica gel (hexane: CH2Cl2 5:1, v/v) to give the title compounds 5a (0.19 g, 51%, white powder) and 5b (0.16 g, 44%, white powder). 4.3.1.1. Data for 1,2-alternate 5a. Mp 140.5e142 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.12e7.03 (m, 8H, AreH), 6.84 (t, 4H, J¼7.4 Hz, AreH), 4.21 (d, 2H, J¼12.5 Hz, AreCH2eAr), 3.89 (s, 4H, AreCH2eAr), 3.41e3.32 (m, 8H, OeCH2), 3.18 (d, 2H, J¼12.5 Hz, AreCH2eAr), 1.30e1.15 (m, 4H, OeCH2eCH2), 1.02e0.86 (m, 4H, OeCH2eCH2), 0.63 (t, 12H, J¼7.4 Hz, OeCH2eCH2eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 156.6, 134.6, 132.9, 129.3, 128.3, 121.8, 74.7, 38.1, 29.0, 22.7, 10.3. IR (KBr) n 1456.1 cm1. HRMS-ESIþ (C40H48O4) m/z calcd: 593.36254 [MþH]þ, 610.38909 [MþNH4]þ, 615.34448 [MþNa]þ, 631.31842 [MþK]þ, found: 593.36267 [MþH]þ, 610.38971 [MþNH4]þ, 615.34442 [MþNa]þ, 631.31775 [MþK]þ. 4.3.1.2. Data for partial cone 5b. The analytical data were in agreement with previously published data.9 4.3.2. Synthesis of 25,26,27,28-tetrabutoxy-calix[4]arenes-1,2-alt (6a) and paco (6b). Compound 6a was prepared according to
general procedure using 0.10 g (0.19 mmol) of calixarene 3, 0.12 g (0.94 mmol) of potassium trimethylsilanolate (90% purity), and 0.13 ml (0.94 mmol) of 1-iodobutane. The crude reaction mixture was purified by preparative TLC on silica gel (hexane:CH2Cl2 3:2, v/ v) to give the title compounds 6a (0.064 g, 52%, white powder) and 6b (0.050 g, 41%, white powder). 4.3.2.1. Data for 1,2-alternate 6a. Mp 86.5e88 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.14e7.03 (m, 8H, AreH), 6.89e6.82 (m, 4H, AreH), 4.21 (d, 2H, J¼12.5 Hz, AreCH2eAr), 3.91 (s, 4H, AreCH2eAr), 3.47e3.34 (m, 8H, OeCH2), 3.17 (d, 2H, J¼12.5 Hz, AreCH2eAr), 1.27e1.15 (m, 4H, OeCH2eCH2), 1.14e1.01 (m, 8H, OeCH2eCH2eCH2), 0.93e0.78 (m, 16H, OeCH2eCH2þOeCH2eCH2eCH2eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 156.6, 134.6, 132.9, 129.2, 129.8, 121.9, 72.9, 38.2, 31.7, 28.9, 19.1, 14.1. IR (KBr) n 1457.2 cm1. HRMS-ESIþ (C44H56O4) m/z calcd: 649.42514 [MþH]þ, 671.40708 [MþNa]þ, 687.38102 [MþK]þ, found: 649.42631 [MþH]þ, 671.40758 [MþNa]þ, 687.38060 [MþK]þ. 4.3.2.2. Data for partial cone 6b. Mp 116e118 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.23 (d, 2H, J¼7.3 Hz, AreH), 7.09 (d, 2H, J¼7.3 Hz, AreH), 6.97e6.80 (m, 4H, AreH), 6.44 (t, 2H, J¼7.6 Hz, AreH), 6.26 (dd, 2H, J¼7.6, 1.8 Hz, AreH), 4.07 (d, 2H, J¼13.2 Hz, AreCH2eAr), 3.84e3.74 (m, 4H, OeCH2), 3.65 (s, 4H, AreCH2eAr), 3.64e3.52 (m, 2H, OeCH2), 3.40e3.30 (m, 2H, OeCH2), 3.05 (d, 2H, J¼13.5 Hz, AreCH2eAr), 1.97e1.78 (m, 6H, CH2), 1.64e1.36 (m, 6H, CH2), 1.20e1.09 (m, 2H, eCH2), 1.07e0.97 (m, 12H, OeCH2eCH2eCH2eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 157.5, 157.2, 155.6, 137.0, 133.9, 133.4, 132.1, 130.3, 129.3, 128.9, 128.3, 122.0 (2), 121.4, 74.1, 74.0, 72.9, 35.8, 33.0, 32.8, 31.0, 30.5, 19.6, 19.4, 18.9, 14.3, 14.2, 14.0. IR (KBr) n 1454.2 cm1. HRMSESIþ (C44H56O4) m/z calcd: 666.45169 [MþNH4]þ, 671.40708 [MþNa]þ, 687.38102 [MþK]þ, found: 666.45251 [MþNH4]þ, 671.40752 [MþNa]þ, 687.38065 [MþK]þ. 4.3.3. Synthesis of 25,26-dipropoxy-27,28-di-butoxycalix[4]arene1,2-alt (7a) and paco (7b). Compound 7a was prepared according to the general procedure using 0.11 g (0.21 mmol)of calixarene 2, 0.13 g (1.04 mmol) of potassium trimethylsilanolate (90% purity), and 0.14 ml (1.04 mmol) of 1-iodobutane. The crude reaction mixture was purified by preparative TLC on silica gel (hexane: CH2Cl2 2:1, v/v) to give the title compounds 7a (0.067 g, 52%, white powder) and 7b (0.053 g, 41%, white powder). 4.3.3.1. Data for 1,2-alternate 7a. Mp 86e87 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.15e7.03 (m, 8H, AreH), 6.90e6.82 (m, 4H, AreH), 4.23 (d, 1H, J¼12.5 Hz, AreCH2eAr), 4.20 (d, 1H, J¼12.5 Hz, AreCH2eAr), 3.91 (s, 4H, AreCH2eAr), 3.46e3.34 (m, 8H, OeCH2), 3.19 (d, 1H, J¼12.5 Hz, AreCH2eAr), 3.18 (d, 1H, J¼12.5 Hz, AreCH2eAr), 1.31e1.16 (m, 4H), 1.15e1.03 (m, 4H), 1.03e0.93 (m, 2H) 0.89e0.76 (m, 2H), 0.84 (t, 6H, J¼7.4 Hz, eCH3), 0.64 (t, 6H, J¼7.4 Hz, eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 156.6 (2), 134.6, 134.5, 132.9 (2), 129.3, 128.9, 128.8, 122.0, 121.8 (2), 74.7, 73.0, 38.1, 31.6, 28.9, 22.8 (2), 19.1, 14.1, 10.3. IR (KBr) n 1457.2 cm1. HRMS-ESIþ (C42H52O4) m/z calcd: 638.42039 [MþNH4]þ, 643.37578 [MþNa]þ, 659.34972 [MþK]þ, found: 638.42072 [MþNH4]þ, 643.37585 [MþNa]þ, 659.34930 [MþK]þ. 4.3.3.2. Data for partial cone 7b. Mp 135e138 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.28e7.22 (m, 2H, AreH), 7.11 (d, 2H, J¼7.4 Hz, AreH), 6.99e6.87 (m, 4H, AreH), 6.46 (t, 2H, J¼7.4 Hz, AreH), 6.28 (d, 2H, J¼7.8 Hz, AreH), 4.10 (d, 2H, J¼13.3 Hz, AreCH2eAr), 3.86e3.74 (m, 4H, OeCH2), 3.68 (s, 4H, AreCH2eAr), 3.65e3.53 (m, 2H, OeCH2), 3.37e3.29 (m, 2H, OeCH2), 3.07 (d, 2H, J¼13.3 Hz, AreCH2eAr), 1.98e1.80 (m, 6H), 1.66e1.48 (m, 4H), 1.46e1.35 (m, 2H), 1.11 (t, 3H, J¼7.4 Hz, eCH3), 1.09e1.01 (m, 6H,
P. Slavík et al. / Tetrahedron 72 (2016) 6348e6355
eCH3), 0.73 (t, 3H, J¼7.4 Hz, eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 157.6, 157.1, 155.6 (2), 137.1, 134.0, 133.4, 132.1, 130.4 (2), 129.3, 128.9, 128.3, 122.1, 121.6, 121.4, 76.1, 75.5, 74.1, 72.9, 35.8, 33.0, 32.8, 30.5, 23.8, 22.3, 19.6, 19.5, 14.2, 14.1, 10.9, 9.3. IR (KBr) n 1453.8 cm1. HRMS-ESIþ (C42H52O4) m/z calcd: 638.42039 [MþNH4]þ, 643.37578 [MþNa]þ, 659.34972 [MþK]þ, found: 638.42132 [MþNH4]þ, 643.37647 [MþNa]þ, 659.34954 [MþK]þ. 4.3.4. Synthesis of 25,26-dipropoxy-27,28-dihexyloxycalix[4]arene1,2-alt (8a) and paco (8b). Compound 8a was prepared according to the general procedure using 0.077 g (0.15 mmol) of calixarene 2, 0.098 g (0.76 mmol) of potassium trimethylsilanolate (90% purity), and 0.11 ml (0.76 mmol) of 1-iodohexane. The crude reaction mixture was purified by preparative TLC on silica gel (hexane:CH2Cl2 5:1, v/v) to give the title compounds 8a (0.046 g, 44%, white powder) and 8b (0.021 g, 20%, white powder). 4.3.4.1. Data for 1,2-alternate 8a. Mp 58e60 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.11e6.98 (m, 8H, AreH), 6.82 (dt, 4H, J¼7.4, 1.2 Hz, AreH), 4.21e4.13 (m, 2H, AreCH2eAr), 3.87 (s, 4H, AreCH2eAr), 3.41e3.29 (m, 8H, OeCH2), 3.15 (d, 1H, J¼12.5 Hz, AreCH2eAr), 3.14 (d, 1H, J¼12.5 Hz, AreCH2eAr), 1.30e0.91 (m, 16H, CH2), 0.89 (t, 6H, J¼7.0 Hz, CH3), 0.83e0.63 (m, 4H, CH2), 0.59 (t, 6H, J¼7.4 Hz, CH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 156.6, 156.5, 134.6, 134.5, 132.9, 129.2 (2) 128.8 (2), 121.9, 121.8, 74.6, 73.3, 38.1, 31.9, 29.4, 29.0, 28.9, 25.6, 22.8, 22.7, 14.1, 10.3. IR (KBr) n 1457.3 cm1. HRMS-ESIþ (C46H60O4) m/z calcd: 694.48299 [MþNH4]þ, 699.43838 [MþNa]þ, 715.41232 [MþK]þ, found: 694.48354 [MþNH4]þ, 699.43872 [MþNa]þ, 715.41178 [MþK]þ. 4.3.4.2. Data for partial cone 8b. Mp 74e76 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.23 (d, 2H, J¼7.4 Hz, AreH), 7.10 (d, 2H, J¼7.4 Hz, AreH), 6.97e6.84 (m, 4H, AreH), 6.43 (t, 2H, J¼7.4 Hz, AreH), 6.25 (dd, 2H, J¼7.4, 1.2 Hz, AreH), 4.08 (d, 1H, J¼13.3 Hz, AreCH2eAr), 4.07 (d, 1H, J¼13.3 Hz, AreCH2eAr), 3.84e3.72 (m, 4H, OeCH2), 3.65 (s, 4H, AreCH2eAr), 3.62e3.51 (m, 2H, OeCH2), 3.34e3.27 (m, 2H, OeCH2), 3.05 (d, 2H, J¼13.7 Hz, AreCH2eAr), 1.97e1.79 (m, 6H, CH2), 1.60e1.32 (m, 18H, CH2), 1.10 (t, 3H, J¼7.4 Hz, CH3), 0.98e0.92 (m, 6H, CH3), 0.91e0.75 (m, 4H, CH2), 0.71 (t, 3H, J¼7.4 Hz, CH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 157.6, 157.1, 155.6 (2), 137.0, 134.0, 133.4, 132.0, 130.4, 129.3, 128.9, 128.3, 122.0, 121.5, 121.4, 76.1, 75.5, 74.4, 73.1, 35.8, 31.9 (2), 30.9, 30.7, 26.2, 25.9, 23.8, 22.7 (2), 22.3, 14.1 (2), 10.9, 9.3. IR (KBr) n 1454.1 cm1. HRMS-ESIþ (C46H60O4) m/z calcd: 694.48299 [MþNH4]þ, 699.43838 [MþNa]þ, 715.41232 [MþK]þ, found: 694.48394 [MþNH4]þ, 699.43908 [MþNa]þ, 715.41217 [MþK]þ. 4.3.5. Synthesis of 25,26-diethoxy-27,28-propoxycalix[4]arene-1,2alt (9a) and paco (9b). Compound 9a was prepared according to the general procedure using 0.079 g (0.16 mmol) of calixarene 2, 0.10 g (0.78 mmol) of potassium trimethylsilanolate (90% purity), and 0.07 ml (0.78 mmol) of 1-iodoethane. The crude reaction mixture was purified by preparative TLC on silica gel (hexane:CH2Cl2 1:1, v/v) to give the title compounds 9a (0.046 g, 53%, white powder) and 9b (0.031 g, 35%, white powder). 4.3.5.1. Data for 1,2-alternate 9a. Mp 95e97 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.15e7.02 (m, 8H, AreH), 6.85e6.81 (m, 4H, AreH), 4.23 (d, 1H, J¼12.5 Hz, AreCH2eAr), 4.17 (d, 1H, J¼12.5 Hz, AreCH2eAr), 3.90 (s, 4H, AreH), 3.46 (q, 4H, J¼7.04 Hz, OeCH2), 3.42e3.36 (m, 4H, OeCH2), 3.21e3.13 (m, 2H, AreCH2eAr), 1.30e1.16 (m, 2H, OeCH2eCH2), 1.07e0.94 (m, 2H, OeCH2eCH2), 0.67 (t, 6H, J¼7.04 Hz, OeCH2eCH3), 0.61 (t, 6H, J¼7.4 Hz, OeCH2eCH2eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 156.6, 156.3, 134.9, 134.6, 133.0, 132.9, 129.2 (2), 128.8,
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128.7, 122.0, 121.8, 74.6, 68.0, 38.1, 29.1, 28.9, 22.8, 14.9, 10.3. IR (KBr)
n 1456.6 cm1. HRMS-ESIþ (C38H44O4) m/z calcd: 582.35779
[MþNH4]þ, 587.31318 [MþNa]þ, 603.28712 [MþK]þ, found: 582.35866 [MþNH4]þ, 587.31364 [MþNa]þ, 715.28683 [MþK]þ. 4.3.5.2. Data for partial cone 9b. Mp 230e232 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.22 (d, 2H, J¼7.4 Hz, AreH), 7.09 (d, 2H, J¼7.4 Hz, AreH), 6.96e6.86 (m, 4H, AreH), 6.49e6.41 (m, 2H, AreH), 6.34e6.26 (m, 2H, AreH), 4.08 (d, 1H, J¼12.9 Hz, AreCH2eAr), 4.06 (d, 1H, J¼12.6 Hz, AreCH2eAr), 3.91e3.81 (m, 3H, OeCH2), 3.80e3.71 (m, 1H, OeCH2), 3.70e3.60 (m, 5H, OeCH2þAreCH2eAr), 3.58e3.48 (m, 1H, OeCH2), 3.36e3.27 (m, 2H, OeCH2), 3.05 (dd, 2H, J¼12.9, 2.4 Hz, AreCH2eAr), 1.92e1.82 (hex, 2H, J¼7.4 Hz, OeCH2eCH2), 1.49e1.34 (m, 8H, OeCH2eCH2þCH3), 1.09 (t, 3H, J¼7.4 Hz, CH3), 0.71 (t, 3H, J¼7.4 Hz, CH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 157.3, 157.1, 155.6, 155.4, 137.0 (2), 134.1, 134.0, 133.5, 133.4, 132.2, 132.0, 130.7, 130.5, 129.6, 129.5, 128.9, 128.8, 128.3 (2), 122.1, 121.6, 121.4, 121.3, 76.1, 75.5, 69.3, 67.7, 36.2, 36.0, 30.5, 30.4, 23.8, 22.1, 16.1, 15.9, 10.9, 9.3. IR (KBr) n 1452.8 cm1. HRMS-ESIþ (C38H44O4) m/z calcd: 582.35779 [MþNH4]þ, 587.31318 [MþNa]þ, 603.28712 [MþK]þ, found: 582.35905 [MþNH4]þ, 587.31382 [MþNa]þ, 715.28693 [MþK]þ. 4.3.6. Synthesis of 25,26-diallyloxy-27,28-propoxycalix[4]arene-1,2alt (10a) and paco (10b). A mixture of compounds 10a and 10b was prepared according to the general procedure using 0.035 g (0.069 mmol) of calixarene 2, 0.044 g (0.340 mmol) of potassium trimethylsilanolate (90% purity), and 0.030 ml (0.34 mmol) of allyl bromide. The 1H NMR analysis of the crude product (0.040 g) showed the presence of 10a and 10b conformers in a 58:42 ratio (see Supplementary data). This mixture was purified by repeated preparative thin layer chromatography on silica gel, unfortunately, we were not able to isolate pure desired 1,2-alternate conformer 10a. However, we were able to obtain a single crystal of compound 10a (CH2Cl2/methanol) suitable for X-ray analysis. 4.3.7. Synthesis of 25,26-dipropargyloxyoxy-27,28-propoxycalix[4] arene-1,2-alt (11a) and paco (11b). Compound 11a was prepared according to the general procedure using 0.048 g (0.094 mmol) of calixarene 2, 0.070 g (0.47 mmol) of potassium trimethylsilanolate (90% purity), and 0.050 ml (0.47 mmol) of propargyl bromide (80% in toluene). The crude reaction mixture was purified by preparative TLC on silica gel (hexane:CH2Cl2 1:1, v/v) to give the title compounds 11a (0.037 g, 67%, white powder) and 11b (0.010 g, 18%, white powder). 4.3.7.1. Data for 1,2-alternate 11a. Mp 160e162 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.16 (d, 4H, J¼7.8 Hz, AreH), 7.05 (dd, 2H, J¼7.4, 1.6 Hz, AreH), 6.97 (dd, 2H, J¼7.4, 1.6 Hz, AreH), 6.90e6.84 (m, 4H, AreH), 4.48 (d, 1H, J¼12.9 Hz, AreCH2eAr), 4.14 (d, 1H, J¼12.9 Hz, AreCH2eAr), 4.04 (d, 2H, J¼16.0 Hz, AreCH2eAr), 3.95 (m, 4H, OeCH2eCeCH), 3.85 (d, 2H, J¼16.0 Hz, AreCH2eAr), 3.37e3.22 (m, 5H, OeCH2þAreCH2eAr), 3.16 (d, 1H, J¼12.9 Hz, AreCH2eAr), 2.33 (t, 2H, J¼2.4 Hz, OeCH2eCeCH), 1.25e1.12 (m, 2H, OeCH2eCH2), 0.77e0.65 (m, 2H, OeCH2eCH2), 0.62 (t, 6H, J¼7.0 Hz, OeCH2eCH2eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 156.2, 154.7, 135.3, 135.1, 133.8, 132.9, 129.9, 129.4, 128.8, 128.7, 122.8, 122.5, 80.8, 75.4, 74.1, 59.8, 37.4, 30.2, 29.5, 22.3, 10.1. IR (KBr) n 2123.1, 1454.9 cm1. HRMS-ESIþ (C40H40O4) m/z calcd: 602.32649 [MþNH4]þ, 607.28188 [MþNa]þ, 623.25582 [MþK]þ, found: 602.32642 [MþNH4]þ, 607.28134 [MþNa]þ, 623.25429 [MþK]þ. 4.3.7.2. Data for partial cone 11b. Mp 171e172 C. 1H NMR (CDCl3, 400 MHz, 293 K) d (ppm): 7.33 (dd, 1H, J¼7.4, 1.6 Hz, AreH), 7.24 (dd, 1H, J¼7.8, 1.6 Hz, AreH), 7.12e7.06 (m, 2H, AreH),
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7.05e7.00 (m, 2H, AreH), 6.95 (t, 1H, J¼7.4 Hz, AreH), 6.90 (t, 1H, J¼7.4 Hz, AreH), 6.54 (t, 1H, J¼7.4 Hz, AreH), 6.47 (t, 1H, J¼7.4 Hz, AreH), 6.37 (dd, 1H, J¼7.8, 1.6 Hz, AreH), 6.31 (dd, 1H, J¼7.4, 1.6 Hz, AreH), 4.49e4.35 (m, 4H, OeCH2eCeCH), 4.10 (d, 1H, J¼13.3 Hz, AreCH2eAr), 4.09 (d, H, J¼13.0 Hz, AreCH2eAr), 3.82e3.64 (m, 5H, OeCH2þAreCH2eAr), 3.59e3.51 (m, 1H, OeCH2), 3.38e3.28 (m, 2H, OeCH2), 3.09 (d, 1H, J¼13,3 Hz, AreCH2eAr), 3.07 (d, 1H, J¼13,3 Hz, AreCH2eAr), 2.51 (t, 1H, J¼2.4 Hz, OeCH2eCeCH), 2.50 (t, 1H, J¼2.4 Hz, OeCH2eCeCH), 1.92e1.80 (m, 2H, OeCH2eCH2), 1.45e1.31 (m, 2H, OeCH2eCH2), 1.08 (t, 3H, J¼7.4 Hz, OeCH2eCH2eCH3), 0.72 (t, 3H, J¼7.4 Hz, OeCH2eCH2eCH3). 13C NMR (CDCl3, 100 MHz, 293 K) d (ppm): 157.0, 156.3, 155.5, 154.4, 136.9, 136.7, 134.3, 134.1, 133.6, 133.4, 132.3, 131.8, 130.8, 130.7, 129.5, 129.4, 129.1, 128.7, 128.6, 128.4, 122.7, 122.6, 122.3, 121.6, 76.1, 75.6, 74.6, 74.4, 60.9, 59.3, 36.2, 36.1, 30.8, 30.4, 23.8, 22.1, 10.9, 9.4. IR (KBr) n 2123.1, 1453.6 cm1. HRMS-ESIþ (C40H40O4) m/z calcd: 602.32649 [MþNH4]þ, 607.28188 [MþNa]þ, 623.25582 [MþK]þ,
reduction and absorption correction were done using Apex3 software.10 The structures 5a and 12a were measured using Xcalibur PX with an Onyx CCD detector and graphite monochromated Cu Ka (l¼1.54184 A) radiation. The data reduction and absorption correction were done using CrysAlis PRO software.11 The structures 2$CH2Cl2, 5a, 10a and 12a were solved by direct methods12 and the structure 7a was solved by charge flipping methods.13 The structured were refined by full matrix least squares on F squared value using Crystals software.14 MCE software15 was used for visualization of the electron density maps. The positions of the disordered functional groups were found in difference Fourier maps; the bond lengths and angles were restrained. The overall occupancy of the disordered functional groups was constrained to 1. According to common practice the hydrogen atoms attached to the carbon atoms were placed geometrically with Uiso(H) in the range of 1.2e1.5 Ueq for parent atom (C). For further information on crystal structures and data collection see Table 3.
Table 3 The information on crystal structures and data collection Compound
2$CH2Cl2
5a
7a
10a
12a
Formula Mr Crystal system Space group a ( A) b ( A) c ( A) a ( ) b ( ) g ( ) V ( A3) Z T (K) Dcalcd (g cm3) m (mm1) Reflections used Independent (Rint) Observed [I>2s(I)] Parameters/restrains A3) Drmax/Drmin (e GOF R/wR CCDC number
C34$H36$O4, C$H2$Cl2 593.59 Monoclinic P21/n 11.6864 (3) 14.6226 (3) 18.1551 (4) 90 101.0873 (9) 90 3044.54 (12) 4 180 1.295 2.22 29,831 5518 (0.060) 5279 398/34 0.78/0.54 0.89 0.072/0.180 1478270
C40$H48$O4 592.82 Triclinic P-1 9.5234 (3) 18.5382 (6) 19.0955 (4) 85.559 (2) 85.451 (2) 86.181 (3) 3344.33 (17) 4 180 1.177 0.58 28,112 13,453 (0.042) 10,837 820/58 0.60/0.51 0.91 0.074/0.165 1478271
C42$H52$O4 620.87 Triclinic P-1 9.4668 (11) 10.8903 (14) 18.778 (2) 80.119 (4) 82.721 (3) 70.323 (3) 1790.9 (4) 2 180 1.151 0.56 22,594 6505 (0.049) 6127 452/68 0.64/0.48 1.14 0.092/0.206 1478272
C40$H44$O4 588.79 Monoclinic P21/n 10.8996 (2) 19.7499 (4) 15.3146 (3) 90 95.5843 (9) 90 3281.07 (11) 4 180 1.192 0.59 49,970 6013 (0.053) 5763 425/28 0.56/0.48 1.06 0.067/0.155 1478273
C48$H48$O4 688.91 Monoclinic P21/c 10.5744 (2) 18.5382 (4) 39.8504 (10) 90 93.760 (2) 90 7795.1 (3) 8 180 1.174 0.57 63,509 16,023 (0.042) 11,746 965/28 0.29/0.32 1.01 0.061/0.150 1478274
found: 602.32621 [MþNH4]þ, 607.28114 [MþNa]þ, 623.25442 [MþK]þ. 4.3.8. Synthesis of 25,26-dibenzyloxy-27,28-propoxycalix[4]arene1,2-alt (12a) and paco (12b). A mixture of compounds 12a and 12b was prepared according to the general procedure using 0.072 g (0.14 mmol) of calixarene 2, 0.091 g (0.71 mmol) of potassium trimethylsilanolate (90% purity), and 0.085 ml (0.71 mmol) of benzyl bromide. The 1H NMR analysis of the crude product (0.077 g) showed the presence of 12a and 12b conformers in a 63:37 ratio (see Supplementary data). This mixture was purified by repeated preparative TLC on silica gel, unfortunately, we were not able to isolate pure desired 1,2-alternate conformer 12a. On the other hand, we were able to obtain a single crystal of compound 12a (CH2Cl2/ methanol) suitable for X-ray analysis. 4.4. Single crystal X-ray diffraction measurements The structures 2$CH2Cl2, 7a and 10a were measured using a D8 VENTURE with a Photon 100 CMOS detector and microfocused mirror collimated Cu Ka (l¼1.54178 A) radiation. The data
Acknowledgements The authors wish to thank the Czech Science Foundation (grant Nr. 16-13869S and 16-10035S) and Specific University Research (MSMT No 20-SVV/2016). Supplementary data Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2016.08.028. References and notes 1. For books on calixarenes and their applications see: (a) Gutsche, C. D. Calixarenes an Introduction, 2nd ed.; The Royal Society of Chemistry, Thomas Graham House: Cambridge, 2008, ISBN: 978-0-85404-258-6; (b) Calixarenes in the Nanoworld; Vicens, J., Harrowfield, J., Backlouti, L., Eds.; Springer: Dordrecht, €hmer, V., Har2007, ISBN: 1-4020-5021-6; (c) Calixarenes 2001; Asfari, Z., Bo rowfield, J., Vicens, J., Eds.; Kluwer Academic: Dordrecht, 2001, ISBN: 0-79236960-2; (d) Mandolini, L.; Ungaro, R. Calixarenes in Action; Imperial College Press: London, 2000, ISBN: 1-86094-194-X. 2. For selected reviews on various calixarene-based receptors see: (a) Siddiqui, S.; Cragg, P. J. Mini-Rev Org. Chem. 2009, 6, 283e299; (b) Leray, I.; Valeur, B. Eur. J. Inorg. Chem. 2009, 24, 3525e3535; (c) Matthews, S. E.; Beer, P. D. In Calixarenes
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