Oxygenation Approach to Calix[6]arenes Selectively

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

pubs.acs.org/OrgLett

The Lithiation/Oxygenation Approach to Calix[6]arenes Selectively Functionalized at a Pair of Opposite Methylene Bridges Ori Shalev and Silvio E. Biali* Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel S Supporting Information *

ABSTRACT: Lithiation of the calix[6]arene methyl ether 2 followed by reaction with O2 yields derivatives with two opposite methylene groups hydroxylated. Calix[6]arenes with two opposite bridges functionalized with alkoxy, azido, and m-xylyl groups were prepared via reaction of a dichlorocalix[6]arene derivative with nucleophiles.

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easily derivatized (e.g., to ethers, esters), replaced by halogens, and oxidized to carbonyl groups. Calix[6]- and calix[8]arene derivatives possessing a single hydroxymethylene bridge have been previously obtained in low yield via photochemical bromination of 2 or 3 with NBS in a mixture of THF/water/CaCO3.7 A calix[4]arene derivative with a single hydroxymethylene bridge was prepared by Fantini and co-workers via lithiation of 1, reaction with CCl4, and hydrolysis of the resulting chloromethylene derivative.1d The key step involving reaction with CCl4 resulted in a polarity reversal (umpolung) of the modified bridge: from nucleophilic in the lithiated form to electrophilic in its chloromethylene form. In some cases, the reaction of organolithium derivatives with oxygen gas can be synthetically useful for the preparation of alcohols.8 The reaction may proceed via a lithium hydroperoxide intermediate that is cleaved in the presence of excess organolithium reagent.9 In principle, the selective introduction of hydroxyl group(s) into a calixarene could be conducted in a single step via oxygenation of the organolithium intermediate obtained after reaction of n-BuLi with the calixarene methyl ether. Since the lithiation is conducted with a large excess of n-BuLi, the lithiated hydroperoxide intermediate should be readily cleaved under the reaction conditions, yielding the desired alcohol functionality. As shown by Singh and co-workers,6 2 undergoes selective lithiation at a pair of opposite bridges; hence, it could be expected that the lithiation/oxygenation sequence should provide a facile synthetic entry into a calix[6]arene derivative with two opposite bridges monohydroxylated.

ne of the most challenging structural modifications of the calixarene scaffold is the selective introduction of substituents on the methylene groups of the macrocycle. Fantini and co-workers developed a very useful methodology for the preparation of calix[4]arene derivatives monosubstituted at a single methylene bridge.1−5 The method involves lithiation (n-BuLi/ TMEDA) of a methylene group of the tetramethyl ether of calix[4]arene (1) followed by reaction of the metalated calixarene with an alkyl halide (eq 1) or, more generally, with an

electrophile. Although a large excess of n-BuLi is used in the metalation step, the reaction affords calix[4]arene derivatives with only a single bridge monosubstituted (4). Recently, Singh and co-workers showed that, for calix[6]arene 2, the reaction affords derivatives with a pair of opposite bridges monosubstituted.6 The selective introduction of OH functionalities into the methylene bridges of the calixarenes is of interest since these groups (in conjunction to the lower rim groups) can serve as binding groups of cations. From a synthetic point of view, aliphatic OH functionalities are of interest since they can be © XXXX American Chemical Society

Received: February 26, 2018

A

DOI: 10.1021/acs.orglett.8b00671 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters To determine the workability of the oxygenation reaction on the calix scaffold, we initially examined the reaction of calix[4]arene 1. The compound was reacted with excess n-BuLi (in the absence of TMEDA) at rt, and after 5 min, the reaction was quenched with oxygen gas (eq 2). Examination of the crude product by 1 H NMR spectroscopy (CDCl3/CD3CN, excess NaI)1d indicated the nearly complete conversion of 1 into its corresponding monohydroxy derivative 5.

Figure 2. X-ray structure of 6a (trans isomer).

are nonadjacent to the functionalized bridges (in blue in Figure 3). In the 1,2,3-alternate conformation, the axial methylene protons (“a”) should resonate at a lower field than the equatorial ones (“e”), as usually observed in calixarenes,11 due to the proximity of the former to the ether oxygens. Pairs of geminal isoclinal protons (located on a methylene bridges connecting a ring pointing “up” with a ring pointing “down”) are diastereotopic (denoted i and i′ in Figure 3). However, since they are located at comparable environments, they are expected to display similar chemical shifts (in-between those of the axial and equatorial methylene protons). Under fast exchange conditions, two average signals result: a lower field doublet arising from the exchange between an axial with an isoclinal proton and a higher field doublet arising from the exchange between an equatorial and an isoclinal proton. As a result of these exchanges, the Δδ value between the two doublets is relatively small. The 1H NMR signal pattern of the minor isomer displaying a well-resolved pair of doublets for the methylene protons is consistent with a cis isomer adopting a distorted cone conformation, as found by Singh and co-workers.6 The methylene pattern can therefore be used as a diagnostic tool for assigning the configuration of the calix[6]arene monofunctionalized at two opposite bridges: two relatively closely spaced doublets suggest a trans configuration, while a well-separated pair of doublets suggests that the configuration is cis. The conformational preferences of the trans and cis isomers for the 1,2,3-alternate and cone conformations, respectively, can be rationalized on the basis of the preference of the OH groups at the bridges for the equatorial positions. In the cis form, a cone conformation allows a diequatorial arrangement of the groups; in the trans isomer, a cone conformation would result in a axial disposition of one of the OH groups. To avoid the repulsive interactions present in an axial group, the macrocycle adopts the 1,2,3-alternate conformation where the two trans substituents can both be located at equatorial positions. To increase the reactivity of the derivative under SN1 conditions, trans 6a was reacted with SOCl2/Et3N to yield the corresponding dichloro derivative.12 The reaction proceeded in the presence of Et3N in stereoselective fashion yielding exclusively the trans isomer 7. Heating the dichloro derivative 7 with alcohols yielded the corresponding dialkoxy derivatives (eq 4).13 Examination of the crude product indicated that in all cases a mixture of the trans and cis isomers was obtained. According to the 1H NMR spectrum, the trans/cis ratio was 9:1(8), 8:2 (9), and 7:3 (10), suggesting that this ratio is affected by the bulk of the alcohol nucleophile (MeOH < EtOH < i-PrOH). The major trans product in all cases was separated by crystallization. A single crystal of 8-trans was grown from CHCl3 and submitted to

Reaction of the larger calixarene 2 with 10 equiv of n-BuLi at rt, followed by reaction with oxygen gas, resulted in a 2:1 mixture (as judged by the 1H NMR spectrum of the crude product) of dihydroxylated derivatives (eq 3). The major product displayed a

pair of relatively closely spaced doublets for the methylene protons (Δδ = 0.29 ppm), while in the minor product, these signals were well separated (Δδ = 0.8 ppm, Figure 1). These patterns

Figure 1. 1H NMR spectrum of the methylene region of the crude mixture of dihydroxycalix[6]arenes derivatives 6a and 6b.

resemble the ones reported for the dialkylated derivatives of 2.6 The major isomer was separated in pure form by trituration of the mixture with hexane and was characterized by X-ray crystallography as the trans isomer 6a (Figure 2). The molecule adopts in the crystal a 1,2,3-alternate conformation where the two hydroxy groups are located at equatorial positions in a mutually trans disposition.10 The OH groups are intermolecularly hydrogen-bonded to the methoxy groups of a neighboring molecule (O···O distances of 2.85 and 2.98 Å). The presence of a closely spaced pair of doublets for the methylene protons of the trans isomer 6a can be rationalized, assuming that the molecule adopts in solution a 1,2,3-alternate conformation, which undergoes a rapid topomerization process. This process involves “flipping” of the two opposite rings, which B

DOI: 10.1021/acs.orglett.8b00671 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Figure 3. Topomerization of 7a.

X-ray crystallography. As in the case of 6a, the molecule adopts a 1,2,3-alternate conformation with the substituents at the bridges located at equatorial positions. The crystal structure (Figure 4)

Figure 5. X-ray structure of 11 (trans form).

As an example of the formation of C(sp3)−C(Ar) bonds, we examined the reaction of the dichlorocalix[6]arene 7 with m-xylene/CF3COOH (eq 6).14 Examination of the 1H NMR spectrum of the crude product indicated that a 2:1 mixture of the cis and trans dixylyl derivatives (12b and 12a) was obtained. The reaction with the bulky m-xylene affords the cis isomer as the major product in agreement with the trend observed with the O-nucleophiles: the larger the nucleophile, the smaller the

Figure 4. X-ray structure of 8 (trans isomer).

corroborated the trans disposition of the substituents at the bridges assigned on the basis of Δδ value of the methylene protons in 1H NMR spectrum. Reaction of the dichloro derivative 7 with NaN3 was conducted in 2,2,2-trifluoroethanol in the presence of 18-crown-6 (eq 5). NMR analysis of the crude product showed that a 9:1 mixture of the trans and cis isomers was obtained. The major form was purified by crystallization and characterized by X-ray crystallography (Figure 5). The molecule adopts a 1,2,3-alternate conformation with the azido groups located at equatorial positions (i.e., a trans configuration). An attempt to conduct the reaction under SN2 conditions by replacing the ionizing solvent by THF resulted only in unchanged starting material.

trans/cis ratio. The major isomer 12b was purified by crystallization from CHCl3/hexane. X-ray diffraction of a single crystal corroborated the cis disposition of the xylyl groups (Figure 6). The molecule adopts a pinched-cone conformation with both xylyl groups located at equatorial positions. In this pinched-cone conformation, the two substituted bridges are symmetry equivalent, but the rings at positions 1, 3, and 5 are less twisted than the rings at the 2, 4, and 6 positions. The 1 H NMR spectrum of 12b displayed extensive broadening of the signals at rt, indicating restricted rotation at the NMR time scale. C

DOI: 10.1021/acs.orglett.8b00671 Org. Lett. XXXX, XXX, XXX−XXX

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However, the signals sharpened at higher temperatures, and at 110 °C (tetrachloroethane-d2) the t-Bu, Me, and aromatic protons displayed sharp signals and a signal pattern consistent with a structure of averaged C2v symmetry. In summary, the reaction of lithiated calix[6]arenes with oxygen gas proceeds cleanly, affording calixarenes derivatives with two bridges hydroxylated. The hydroxyl groups can be converted to chloro functionalities, which readily react with nucleophiles. Since the hydroxylation results in the polarity reversal of the lithiated bridges, the present approach complements the method introduced by Fantini1 involving lithiation followed by reaction with an electrophile.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00671. General experimental procedures; NMR spectra of 5, 6a, 7−11, and 12b (PDF) Accession Codes

CCDC 1825067−1825070 contain 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 [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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REFERENCES

(1) (a) Scully, P. A.; Hamilton, T. M.; Bennett, J. L. Org. Lett. 2001, 3, 2741. See also: (b) Hertel, M. P.; Behrle, A. C.; Williams, S. A.; Schmidt, J. A. R.; Fantini, J. L. Tetrahedron 2009, 65, 8657. (c) Hardman, M. J.; Thomas, A. M.; Carroll, L. T.; Williams, L. C.; Parkin, S.; Fantini, J. L. Tetrahedron 2011, 67, 7027. (d) Carroll, L. T.; Hill, P. A.; Ngo, C. Q.; Klatt, K. P.; Fantini, J. L. Tetrahedron 2013, 69, 5002. (2) For reviews on calixarenes, see: (a) Gutsche, C. D. Calixarenes, an Introduction, 2nd ed.; The Royal Society of Chemistry: Cambridge, 2008. (b) Böhmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713. (c) Böhmer, V. In The Chemistry of Phenols; Rappoport, Z., Ed.; Wiley: Chichester, 2003; Chapter19. (d) Calixarenes and Beyond; Neri, P., Sessler, J. L., Wang, M. X., Eds.; Springer Int Publishing, 2016. (3) 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, 173. (c) Deska, M.; Dondela, B.; Sliwa, W. ARKIVOC 2015, 29. (d) Biali, S. E. In Calixarenes and Beyond; Neri, P., Sessler, J. L., Wang, M. X., Eds.; Springer Int Publishing, 2016; Chapter 4. (4) For additional applications of this route, see: (a) Fischer, C.; Katzsch, F.; Weber, E. Tetrahedron Lett. 2013, 54, 2874. (b) Varaksin, M. V.; Utepova, I. A.; Chupakhin, O. N.; Charushin, V. N. Macroheterocycles 2013, 6, 308. (c) Coletta, M.; McLellan, R.; Cols, J.-M.; Gagnon, K. J.; Teat, S. J.; Brechin, E. K.; Dalgarno, S. J. Supramol. Chem. 2016, 28, 557. (5) For an example of a regioselective alkylation of a meta-bridged calixarene, see: Slavık, P.; Dvorakova, H.; Eigner, V.; Lhotak, P. Chem. Commun. 2014, 50, 10112. (6) Arora, S.; Sharma, S.; Mithu, V. S.; Hee-Lee, C.; Singh, K. Chem. Commun. 2015, 51, 4227. (7) (a) Itzhak, N.; Biali, S. E. J. Org. Chem. 2010, 75, 3437. (b) Itzhak, N.; Kogan, K.; Biali, S. E. Eur. J. Org. Chem. 2011, 6581. (8) For a recent review on the oxidation of organometallic compounds, see: Minko, Y.; Marek, I. Org. Biomol. Chem. 2014, 12, 1535. (9) Warner, P.; Lu, S.-L. J. Org. Chem. 1976, 41, 1459. (10) In the cone conformation, a pair of equatorial substituents at opposite bridges is in a cis relationship. However, in the 1,2,3-alternate conformation, a diequatorial arrangement implies a trans relationship. The cis and trans forms are not different (stable) conformations but different configurational isomers which cannot be interconverted by a rotational process but only via bond cleavage. (11) (a) Alfieri, C.; Dradi, E.; Pochini, A.; Ungaro, R. Gazz. Chim. Ital. 1989, 119, 335. (b) See also: Biali, S. E.; Böhmer, V.; Brenn, J.; Frings, M.; Thondorf, I.; Vogt, W.; Wöhnert, J. J. Org. Chem. 1997, 62, 8350. (12) For the preparation of calix[n]arenes with all bridges monobrominated, see: (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. (c) For a recent example of a pillar[5]arene with all bridges monobrominated, see: Fu, S.; An, G.; Sun, H.; Luo, Q.; Hou, C.; Xu, J.; Dong, Z.; Liu, J. Chem. Commun. 2017, 53, 9024. (13) For reactions of bromocalixarenes under SN1 conditions, see: (a) Columbus, I.; Biali, S. E. Org. Lett. 2007, 9, 2927. (b) Columbus, I.; Biali, S. E. J. Org. Chem. 2008, 73, 2598. (c) Kogan, K.; Columbus, I.; Biali, S. E. J. Org. Chem. 2008, 73, 7327. (14) Kuno, L.; Biali, S. E. J. Org. Chem. 2011, 76, 3664.

Figure 6. X-ray structure of 12b (cis isomer).

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Letter

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 the Israel Science Foundation (ISF) (Grant No. 223/14). We thank Dr. Benny Bogoslavsky (Hebrew University of Jerusalem) for the crystal structure determinations and the Israel Ministry of Science, Technology and Space for a “Levi Eshkol” fellowship to O.S. D

DOI: 10.1021/acs.orglett.8b00671 Org. Lett. XXXX, XXX, XXX−XXX