C–Me Bond Formation at All Methylene Bridges of the Calix[4]arene

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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C−Me Bond Formation at All Methylene Bridges of the Calix[4]arene Scaffold Ori Shalev and Silvio E. Biali* Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel S Supporting Information *

ABSTRACT: A reaction of a distal dibromo diketocalix[4]arene with excess MeLi, followed by acid-catalyzed dehydration, yields a derivative with a pair of opposite exocyclic double bonds, and a pair of trans methyl groups at the bridges. A reaction of a tetrabromo calix[4]arene derivative with excess MeLi yields a calix[4]arene derivative with all methylene bridges monomethylated in all-cis fashion.

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bromospirodiene routes afforded the trans isomer of the corresponding dimethyl derivative. Thus far, a simple route for the preparation of a calix[4]arene with all bridges monomethylated (a C-Me-calix[4]arene) has remained an elusive target. We have previously described the preparation, via a multistep route, of a calix[4]arene derivative possessing two exocyclic double bonds at opposite bridges (4).9 The key starting material in this route was the 1,2-alternate atropisomer of p-tertbutylcalix[4]arene tetraacetate, obtained as the minor product in the acetylation of p-tert-butylcalix[4]arene.10 Since the dibromodioxo calix[4]arene 3 is more readily available,11 we examined the reaction of the derivative with 5 equiv of MeLi. ̈ expectation was that both addition to the carbonyl Our naive groups12 and metalation-halogen exchange reactions at the bromomethine bridges will occur, yielding 4 after quenching and acid-catalyzed elimination of water (see Scheme 1). 1H NMR analysis of the product obtained after acid-catalyzed elimination indicated that, indeed, a calix[4]arene derivative possessing two exocyclic double bonds at two distal bridges was obtained. However, unexpectedly, the product also contained a pair of methylated bridges (5, Scheme 1), indicating that, under the reaction conditions, C−Me bond formation occurred at the bridges. There are precedents in the literature on the direct formation of C−alkyl bonds by reaction of C−Br bonds with an alkyllithium reagent; however, generally, the utility is limited by the competing side reactions.13,14 In some cases, the reaction proceeds in a stereoselective fashion.14a It has been proposed that the coupling reaction between a bromoalkane and an organolithium reagent may proceed via a single electron transfer (SET) mechanism involving a caged radical pair, which rapidly undergoes coupling or via an SN2 mechanism, in which the organolithium reagent serves as the nucleophile.13−15 Calixarene 5 displayed in the 1H NMR spectrum (400 MHz, CDCl3, room temperature (rt)) two sets of signals indicating the presence of two conformers in a 9:1 ratio (see Figure 1).

[14]metacyclophane scaffold with all methylene bridges monoalkylated is fairly common in the calix[4]resorcinarene family, since the compounds can be prepared by acid-catalyzed condensation of aliphatic aldehydes and resorcinol. In contrast, such scaffold has been unknown in the calix[4]arene family since the parent compound is prepared via base-catalyzed condensation of a p-tert-butylphenol with formaldehyde, yielding a derivative with unsubstituted bridges.1

The incorporation of substituents at the methylene bridges of the calixarenes is of interest as a means to modify the conformational preferences of the macrocyclic ring and to rigidify it.2 Calix[4]arenes with functionalized bridges have been prepared via cyclocondensation of suitable precursors3 or via direct modification of the methylene groups of a preformed calix scaffold. Using the second approach, calix[4]arenes with all bridges monofunctionalized with a variety of substituents have been obtained via reaction of the bromocalixarenes derivatives4 (e.g., 1a, 1b) with nucleophiles under SN1 reactions conditions.5 Using this route, in a few cases, C−C bond formation has been achieved by a reaction with electron-rich aromatic groups (e.g., 2-methylfuran).5 Methyl groups (or more generally, simple alkyl groups) could not be incorporated by this route since both Grignard and organolithium reagents (which could serve as C-nucleophiles in the reaction with the carbocation intermediates) are incompatible with the acidic ionizing solvent used in the reaction (2,2,2-trifluoroethanol or hexafluoro isopropanol). Incorporation of one methyl group into the calix[4]arene scaffold has been achieved by a lithiation/methylation sequence of 2.6 Repeating the sequence lithiation/alkylation twice afforded a calix[4]arene with a pair of opposite bridges monoalkylated.7 A tetrahydroxy calix[4]arene derivative with two distal bridges monomethylated was prepared via the addition of an organocopper reagent to a bromospirodiene calix[4]arene derivative.8 Both the lithiation/alkylation and the © XXXX American Chemical Society

Received: April 26, 2018

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DOI: 10.1021/acs.orglett.8b01314 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 1. Expected (Top) and Obtained (Bottom) Product in the Reaction of Dioxodibromocalix[4]arene 3 with Excess MeLi, Followed by Acid-Catalyzed Dehydration

Figure 2. Graphics showing the cis and trans isomers of 5. In the trans form, the C2 axis passes through the two exocyclic double bonds, whereas, in the cis form, the axis is perpendicular to the mean macrocyclic plane. In each form, pairs of vinyl protons of the same color (red or blue) are homotopic, while pairs of protons of different colors are enantiotopic. Red and blue protons are expected to be anisochronous in a chiral nonracemic medium.

Figure 1. 1H NMR (400 MHz, CDCl3) spectrum of the methine region of 5. The two quartets at δ 4.72 and 3.91 ppm indicate the presence of two conformers in a ca. 9:1 ratio. Figure 3. 1H NMR (500 MHz, CDCl3) spectrum of the vinyl region of 5 (major conformer) in the absence (bottom) and presence of the chiral solvating agent.

The major conformer displayed single signals for the OMe and t-Bu groups, while the minor form displayed a pair of signals for those groups. This is reminiscent of the pattern previously observed for the nonmethylated analogue 4.9 Notably, the vinyl protons appeared as a singlet for the major conformer (at δ 5.40 ppm), and as a pair of closely spaced singlets (at δ 5.311 and 5.306 ppm) for the minor form. The pattern of signals observed in the 1H NMR spectrum could be consistent with either the cis or trans isomer of 5. The simple pattern of signals observed for the major conformer could correspond to the cis form (adopting a cone conformation) or the trans form (adopting a 1,2-alternate conformation). For example, both forms should display a single signal for the methylidene protons (see Figure 2). In the cis form, pairs of protons of a given group are enantiotopic, while they are homotopic in the trans isomer. Precluding accidental isochrony, both isomers are expected to display two signals for the four vinyl protons in a chiral medium. However, both isomers may be distinguished based on the presence or absence of a coupling interaction between the two signals in a chiral medium. For the cis form, since the two methylidene protons of a given vinyl group are enantiotopic (shown in red and blue in Figure 2), the two signals are expected to display mutual coupling. In contrast, for the trans isomer, no coupling is expected between the two signals, since pairs of enantiotopic protons are located at different double bonds. The 1H NMR spectrum of 5 (500 MHz, CDCl3) displayed in the presence of (R)-(−)-α-(trifluoromethyl)benzyl alcohol (a chiral solvating agent) two singlets for the vinyl protons of the major conformer (Figure 3). The absence of mutual splitting between the signals indicates that the product obtained is the trans isomer of 5.

The pattern of signals of trans-5 in CDCl3 in a achiral medium is consistent with a mixture of the 1,2-alternate (of C2h symmetry, major conformer) and 1,3-alternate (of C2 symmetry, minor conformer) forms (see Scheme 2). In the 1,3-alternate Scheme 2. Conformational Equilibrium between the 1,2Alternate (Major Form) and 1,3-Alternate (Minor Form) Conformers of 5

conformation of trans-5, the C2 axis bisects the two exocyclic double bonds. Since this is the only symmetry present, the two groups are diastereotopic, while a pair of geminal methylidene protons are homotopic, resulting in the two singlets observed for these protons in the 1H NMR spectrum. In both conformations, the two exocyclic double bonds are located between pairs of geminal rings oriented anti. The interconversion rates between the conformers of 5 were determined in tetrachloroethane-d2 by means of an EXSY spectrum at 338 K. Under these conditions, the equilibrium constant between the two conformers was 4.3:1. From the rates B

DOI: 10.1021/acs.orglett.8b01314 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters for the forward (major → minor isomer: 0.17 s−1) and reverse (minor → major isomer: 0.73 s−1) processes, barriers of 21.1 and 20.1 kcal mol−1 were calculated for the two processes. These barriers are similar to those determined for the nonmethylated analogue 4 (21.0 and 20.5 kcal mol−1).9 The similar rotational barriers for the 1,2-alternate → 1,3-alternate process in both systems, may be due to the disposition of the methyl groups of 5 in the relatively unencumbered equatorial positions in the 1,2-alternate conformation. Since 3 underwent methylation at the bromomethine bridges, we asked ourselves whether the method might work also on a derivative possessing four monobrominated bridges as a possible pathway to obtain a calix[4]arene monomethylated at the four methylene bridges. Accordingly, we examined the reaction of the tetrabromocalix[4]arene 1b (all-cis)5a,b with MeLi. Calixarene 1b was reacted with 12 equiv of MeLi (1.6 M in ether, dry THF, −15 °C) and after 5 min, the reaction was quenched with methanol. 1H NMR analysis indicated that the major product obtained was the desired tetramethylated derivative 6, indicating that 4-fold C−Me bond formation occurred (see eq 1).

Figure 4. Crystal structure of 6 (top and side view).

(CDCl3, 263 K, 1:1 ratio of 6 and 2) was conducted using 0.5 equiv NaI. The ratio between the (Na, 6)+ and (Na, 2)+ complexes, determined from the integration of the four methine protons of (Na, 6)+ and 12 protons of the OMe groups of (Na, 2)+), is 3.5:1 (Figure 5). Calixarene 6 is indeed a better ligand for Na+ than 2.

Four different configurational isomers are possible for a calix[4]arene with four identically monosubstituted methylene bridges. The 1H NMR spectrum of the major product displayed a single signal each for the t-Bu, aromatic, and methoxy groups and a quartet and a doublet for the CHMe units at the bridges. The simplicity of the pattern observed is consistent with a highly symmetrical structure, where all aromatic protons are equivalent, i.e., with either the all-cis or all-trans isomer. X-ray analysis of a single crystal of 6 indicated that the product obtained is the all-cis form (Figure 4). Generally, the conformation is reminiscent of that observed in the crystal for the tetrabromo derivative 1b.5a The molecule adopts a somewhat distorted cone conformation (a “pinched cone” conformation) of approximate C2v symmetry, where two opposite rings have a larger twist angle (relative to the mean macrocyclic plane), than the other pair of opposite rings. The methoxy groups are all oriented in an “out” fashion. All methyls are located at equatorial positions. Lowering the temperature of an NMR sample of 6 in CD2Cl2 to 213 K did not result in any decoalescence of the aromatic signals, and even at the lowest temperature examined, a single signal was observed for these protons. This indicates that a pinched-cone/pinched cone topomerization process (involving a mutual exchange between rings possessing different twist angles) is fast on the NMR times scale, even at 213 K. The cone conformation adopted by 6 should allow all four methoxy oxygens to ligate a cation in a cooperative fashion. The 1H NMR spectrum in CDCl3 after addition of a small amount of NaI displayed separate signals for the free and complexed forms (see Figure S8 in the Supporting Information). This is in agreement with the observation that the cone conformation of the parent 2 (with unsubstituted methylene bridges) undergoes slow cation exchange on the NMR time scale.16 A competition experiment between 6 and 2

Figure 5. Competition experiment between 6 and 2. 1H NMR spectrum of part of the methoxy and methine regions (500 MHz, CDCl3, 263 K). (a) 1:1 mixture of 6 and 2 (1.37 × 10−5 mol); (b) after addition of 0.5 equiv NaI; and (c) after addition of excess NaI. “PC” denotes signals of the methylene protons of the (uncomplexed) partial cone form of 2.17 These signals partially overlap with the methoxy signals of the complex (Na, 6)+.

Notably, whereas in 6 all the methyls are located at equatorial positions, all the alkyl groups are located at axial positions in the all-cis calix[4]resorcinarenes, adopting a cone (“bowl”) conformation.18 Assuming that these arrangements represent the lower energy conformations of each compound, these conformational preferences are consistent with the proposal that the axial/equatorial preferences of an alkyl group are, in large part, determined by the need to avoid repulsive interactions with the oxygens.19 In the calixarene family, the C

DOI: 10.1021/acs.orglett.8b01314 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

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OR are located in the lower rim, and thus in the cone conformation the equatorial positions are preferred, whereas alkyl groups in the calix[4]resorcinarenes favor the axial positions since the OR groups are located at the upper rim (Scheme 3).

In summary, we have disclosed a practical route for the methylation of the methylene bridges of the calix[4]arene scaffold via reaction of bromocalix[4]arene derivatives with MeLi.20

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01314. Experimental procedures and NMR spectra of 5 and 6 (PDF) Accession Codes

CCDC 1839250 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

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REFERENCES

(1) For recent reviews on calixarenes and resorcinarenes, see: Calixarenes and Beyond; Neri, P., Sessler, J. L., Wang, M. X., Eds.; Springer International Publishing: Chaz, Switzerland, 2016. (2) For reviews on methylene-functionalized calixarenes, see: (a) Simaan, S.; Biali, S. E. J. Phys. Org. Chem. 2004, 17, 752. (b) Sliwa, W.; Deska, M. ARKIVOC 2012, 1, 173. (c) Biali, S. E. Preparation of Methylene-Substituted Calixarenes. In Calixarenes and Beyond; Neri, P., Sessler, J. L., Wang, M. X., Eds.; Springer International Publishing: Chaz, Switzerland, 2016; Ch. 4, pp 75−93. (3) For a review on the synthesis of calixarenes via stepwise and fragment condensation methods, see: (a) Böhmer, V. Liebigs Ann./ Recueil 1997, 1997, 2019. See also: (b) Gopalsamuthiram, V.; Predeus, A. V.; Huang, R. H.; Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 18018. (c) Gopalsamuthiram, V.; Huang, R. H.; Wulff, W. D. Chem. Commun. 2010, 46, 8213. (4) (a) Klenke, B.; Näther, C.; Friedrichsen, W. Tetrahedron Lett. 1998, 39, 8967. (b) Kumar, S. K.; Chawla, H. M.; Varadarajan, R. Tetrahedron Lett. 2002, 43, 7073. The only tetrabromomethine calix[4]arene derivatives known to date are those where the lower rim groups are OMe. In our experience, attempted demethylation of 1b yields decomposition products and, therefore, a demethylation/ alkylation route cannot be applied. (5) (a) Columbus, I.; Biali, S. E. Org. Lett. 2007, 9, 2927. (b) Columbus, I.; Biali, S. E. J. Org. Chem. 2008, 73, 2598. (c) Fong, A.; McCormick, L.; Teat, S. J.; Brechin, E. K.; Dalgarno, S. J. Supramol. Chem. 2018, 30, 504. (6) Scully, P. A.; Hamilton, T. M.; Bennett, J. L. Org. Lett. 2001, 3, 2741. (7) Fischer, C.; Katzsch, F.; Weber, E. Tetrahedron Lett. 2013, 54, 2874. (8) Simaan, S.; Biali, S. E. J. Org. Chem. 2003, 68, 3634. (9) Shalev, O.; Biali, S. E. J. Org. Chem. 2014, 79, 8584. (10) Jaime, C.; de Mendoza, J.; Prados, P.; Nieto, P. M.; Sanchez, C. J. Org. Chem. 1991, 56, 3372. (11) Kuno, L.; Biali, S. E. J. Org. Chem. 2011, 76, 3664. (12) The reaction of the carbonyl groups of ketocalixarenes with organolithium ragents proceeds in non-stereoselective fashion, and mixture of isomers are obtained. See, for example: Poms, D.; Itzhak, N.; Kuno, L.; Biali, S. E. J. Org. Chem. 2014, 79, 538. (13) For a review, see: Reich, H. Chem. Rev. 2013, 113, 7130. (14) See, for example: (a) Sommer, L. H.; Korte, W. D. J. Org. Chem. 1970, 35, 22. (b) Bailey, W. F.; Gagnier, R. P.; Patricia, J. J. J. Org. Chem. 1984, 49, 2098. (c) Eccles, W.; Jasinski, M.; Kaszynski, P.; Zienkiewicz, K.; Stulgies, B.; Jankowiak, A. J. Org. Chem. 2008, 73, 5732. (d) Averina, E. B.; Sedenkova, K. N.; Borisov, I. S.; Grishin, Y. K.; Kuznetsova, T. S.; Zefirov, N. S. Tetrahedron 2009, 65, 5693. (15) Alternatively, the reaction may proceed via a SN2 mechanism after a transmetalation step (the nascent MeBr serving as the electrophile). In our case, this route seems unlikely, because of the high efficiency of the reaction. (16) Blixt, J.; Detellier, C. J. Am. Chem. Soc. 1995, 117, 8536. (17) Only the cone conformation of 2 forms a complex (1:1) with Na+ (see ref 16). (18) For a review on resorcinarenes, see: Timmerman, P.; Verboom, W.; Reinhoudt, D. N. Tetrahedron 1996, 52, 2663. (19) Biali, S. E.; Böhmer, V.; Brenn, J.; Frings, M.; Thondorf, I.; Vogt, W.; Wöhnert, J. J. Org. Chem. 1997, 62, 8350. (20) Following suggestions by the reviewers, several preliminary reactions were conducted: (i) Reaction of 3 with MeMgI followed by dehydration: 5 is obtained, but the reaction is less clean than with the organolithium reagent. (ii) Reaction of 1a with MeLi: the 1H NMR spectrum of the crude product displays signals consistent with the presence of CHMe units (i.e., methylated methylene bridges) but the reaction is not clean, and seems to be accompanied by O−Me cleavage. (iii) Reaction of 1b with EtLi or BuLi: the 1H NMR spectra shows decomposition products. These negative results notwithstanding, we believe that the reaction of bromocalixarenes with these and additional organometallic reagents merits further examination.

Scheme 3. Conformational Preference of the Methyl Groups of the All-cis C-Me-calix[4]arene 6 (Y = OMe) vis-à-vis a Allcis C-Me-calix[4]resorcinarene (Y = OH) Adopting a Cone Conformation

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Ori Shalev: 0000-0002-1628-834X Silvio E. Biali: 0000-0001-6683-9704 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Israel Science Foundation (ISF) Grant No. 223/14). We thank Dr. Benny Bogoslavsky (Hebrew University of Jerusalem) for the crystal structure determination, Dr. Roy Hoffman (Hebrew University of Jerusalem) for assistance with the EXSY experiment and the Israel Ministry of Science, Technology and Space for a “Levi Eshkol” fellowship to O.S. D

DOI: 10.1021/acs.orglett.8b01314 Org. Lett. XXXX, XXX, XXX−XXX