ORGANIC LETTERS
Innovative Methodologies for the N-Protection of N-Alkylimidazole Groups: Application to the First Synthesis of a Water-Soluble Calix[6]arene Presenting Three Ammonium Substituents at the Large Rim and Three Neutral N-Donors at the Small Rim
2007 Vol. 9, No. 17 3271-3274
David Coquie`re,† Je´roˆme Marrot,‡ and Olivia Reinaud*,† Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR CNRS 8601, UniVersite´ Paris Descartes, 45 rue des Saints-Pe` res, 75006 Paris, France, and Institut LaVoisier de Versailles, UMR CNRS 8180, UniVersite´ de Versailles St-Quentin en YVelines, 45 aV. des Etats-Unis, 78035 Versailles cedex, France
[email protected] Received May 22, 2007
ABSTRACT
The first synthesis of a cationic amphiphile calixarene ligand, which bears three neutral imidazole donors on one side of the hydrophobic cone and three quaternary ammonium substituents on the other side, is reported. The synthetic strategy relies on two key steps: (i) the “small rim-directed” selective ipso-nitration at the large rim and (ii) a protection−deprotection sequence of the N-alkylimidazole groups, for which two equally efficient novel methods (coordination to Zn(II) or to a cyanoborane) are presented.
Calixarenes are highly versatile scaffolds as they present a hydrophobic core separating two functionalizable rims.1 This allows the introduction of functional groups either in a convergent way (on the same rim) or in a divergent way (opposite rims). Whereas the first case has been widely † ‡
Universite´ Paris Descartes. Universite´ de Versailles St-Quentin en Yvelines.
10.1021/ol071208t CCC: $37.00 Published on Web 07/18/2007
© 2007 American Chemical Society
developed, the second case has been the subject of few reports since it is synthetically more challenging, particularly (1) (a) Gutsche, C. D. Calixarenes ReVisited, Monographs in Supramolecular Chemistry; Stoddart, J. F., Ed.; The Royal Society of Chemistry: Cambridge, U.K., 1998. (b) Calixarenes 2001; Asfari, Z., Bo¨hmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer Academic Publishers: Dordrecht, The Netherlands, 2001. (c) Calixarenes in the Nanoworld; Harrowfield, J., Vicens, J., Eds.; Springer, Dordrecht: The Netherlands, 2006.
with the highly flexible calix[6]arenes. Indeed, selective large rim substitution methods have been only scarcely reported. They are classically based on the higher reactivity of the para position of ArOH units compared to ArOR units toward electrophiles, but most suffer poor yields due to the high sensitivity of the phenol moieties to the experimental conditions.1a Interestingly, we have discovered that directionality of the large rim substitution can be actually monitored by the nature of the OR groups at the small rim.2,3 Indeed, when the R substituent bears an electron-withdrawing protic site in the β-position (Scheme 1), the corresponding
Scheme 1. Selective Functionalization of the Calixarene Large Rim Monitored by the Calixarene Small Rim Substituents and Application for Obtaining Triply Charged Cone Calix[6]arenes Bearing Y Functionalities
phenyl unit is efficiently deactivated toward an electrophilic attack, which is then selectively directed toward the other ArOR units. As a matter of fact, the small rim-directed ipsonitration was revealed to be a highly versatile method for the selective functionalization of the large rim of calix[n]arenes.2 More recently, we have described the first examples of ipso-chlorosulfonylation3 that was revealed to also be very selective. The latter case allowed us to prepare structures that bear three imidazolyl arms in one direction, at the small rim, and three anionic sulfonato groups in the opposite direction, at the large rim (Scheme 1, Y ) N-Me-imidazole). The cone is maintained as the major conformation thanks to the reduced charge-repulsion when the ionic substituents are placed on every second aromatic unit. The resulting trisimidazole ligands are water-soluble and display interesting amphiphilic properties, driving them to self-assemble in water and to coordinate a metal ion.4 We wanted to make use of the selective nitration methodology for the introduction of quaternary ammonium ions in place of the sulfonato groups. One of the goals is to validate the synthetic strategy for obtaining the cationic counterpart of the previously reported trisanionic calix[6]arene ligand (Scheme 1). Indeed, the sequence of selective nitration/reduction applied to the large rim allows the easy introduction of three amino groups. However, as imidazole (2) Redon, S.; Li, Y.; Reinaud, O. J. Org. Chem. 2003, 68, 7004-7008. (3) Coquie`re, D.; Cadeau, H.; Rondelez, Y.; Giorgi, M.; Reinaud, O. J. Org. Chem. 2006, 71, 4059-4065. (4) Houmadi, S.; Coquie`re, D.; Legrand, L.; Faure´, M. C.; Goldmann, M.; Reinaud, O.; Re´mita, S. Langmuir 2007, 23, 4849-4855. 3272
is a stronger nucleophile than aniline, an efficient protectiondeprotection sequence was required before quaternization of the aniline moieties. Surprisingly, whereas several methods for the protection of the secondary NH group of imidazole have been described (Boc, tosyl, Ph3C, dinitrophenyl),5 we have not found any report on groups that are commonly used to protect the imino lone pair of N-alkylimidazole and can be selectively removed.6 Here, we report two efficient routes: protection through the formation of a “Zn(II) funnel complex”,7 a way that is specific to our C3V symmetrical calix[6]N3 system,8 or coordination of each imidazole to a stronger Lewis acid, a cyanoborane. Whereas the first mode requires directionality and convergence of the imidazole donors for the central metal ion binding to be strong enough, the second method is not directional, thus being of a wide scope and applicable to a variety of compounds presenting N-alkylimidazole moieties. Selective O-methylation of tBu-calix[6]arene in an alternate position9 allows the symmetry of the macrocyclic structure to decrease from C6V to C3V. The resulting trisphenolic calix[6]arene, 1, is then peralkylated by chloromethylimidazole to yield ligand 2 in high yield.7a Under strongly acidic conditions, the three imidazole residues of 2 are protonated. As a result, ipso-nitration occurs with a remarkable selectivity on the anisol units, and subsequent reduction of the three nitro substituents led to the trisanilino derivative 3 in high yield10 (Scheme 2). Since the last step consisted of the quaternization of the large rim aniline moieties, a protection-deprotection method for the more nucleophilic N-Me-imidazolyl groups was required. N-Me-Imidazole Protection through Zn2+ Complexation. Protection of the imidazolyl arms has been first planned through their complexation to a metal ion. Indeed, we have previously reported the formation of a tetrahedral mononuclear Zn(II) complex with ligand 3 in which all three imidazole arms are bound to the central metal ion, with a guest ligand L completing the coordination sphere.10 However, direct reaction of this Zn(II) derivative with MeI led to its decomplexation due to the formation of HI. Addition of a base to trap the released equivalents of protons did not allow isolation of the desired product as the complex is not stable enough in basic media, and peralkylation leading to (5) Protecting Groups in Organic Synthesis; Greene, T. W., Wuts, P. G. M., Eds.; Wiley: New York, 1999. (6) A classical strategy consists of first protecting the secondary nitrogen atom of the imidazole, then alkylating the imino nitrogen to finally withdraw the protecting group (see ref 5). This sequence, which often results in poor yields, is not applicable to an imidazole group that is already Nfunctionalized. For an illustrative example, see: Pappo, D.; Shimony, S.; Kashman, Y. J. Org. Chem. 2005, 70, 199-206. (7) (a) Se´ne`que, O.; Rager, M. N.; Giorgi, M.; Reinaud, O. J. Am. Chem. Soc. 2000, 122, 6183-6189. (b) Se´ne`que, O.; Giorgi, M.; Reinaud, O. Chem. Commun. 2001, 984-985. (c) Se´ne`que, O.; Rager, M. N.; Giorgi, M.; Reinaud, O. J. Am. Chem. Soc. 2001, 123, 8442-8443. (d) Seneque, O.; Giorgi, M.; Reinaud, O. Supramol. Chem. 2003, 15, 573-580. (8) Reinaud, O.; Le Mest, Y.; Jabin, I. Supramolecular models of metalloenzyme active sites. In Calixarenes in the Nanoworld; Harrowfield, J., Vicens, J., Eds.; Springer, Dordrecht: The Netherlands, 2006; Chapter 13. (9) Janssen, R. G.; Verboom, W.; Reinhoudt, D. N.; Casnati, A.; Freriks, M.; Pochini, A.; Ugozzoli, F.; Ungaro, R.; Nieto, P. M.; Carramolino, M.; Cuevas, F.; Prados, P.; de Mendoza, J. Synthesis 1993, 380-386. (10) Coquie`re, D.; Marrot, J.; Reinaud, O. Chem. Commun. 2006, 39243926.
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Scheme 2. Synthetic Strategies for the Selective Introduction of Three Cationic Substituents at the Large Rim of a Calix[6]arene Bearing a Trisimidazole Coordination Core at the Small Rim and XRD Structure of Complex 5 (guest ligand, L ) EtOH in green)
the hexacationic derivative was observed. Therefore, calixarene 3 was first transformed into its tertiary amino derivative 4 by reductive N-methylation of its aniline groups with formaldehyde in the presence of formic acid. Crude ligand 4 was then complexed to 1 equiv of zinc perchlorate to yield mononuclear complex 5 (L ) H2O). This step actually was revealed to be the most efficient method for the purification of 4 that can easily be released after treatment of 5 with sodium hydroxide. The related EtOH adduct (5, L ) EtOH) was characterized by XRD analysis, and its molecular structure, displayed in Scheme 2, confirmed the expected formation of a C3V symmetrical dicationic complex, thereby showing that the replacement of tBu or NH2 substituents by dimethylamino groups at the large rim does not affect the binding properties of the trisimidazole core at the small rim. Our first attempts of selective quaternization of the NMe2 groups of complex 5 under classical conditions (i.e., in MeCN with MeI) were unsuccessful and invariably led to the alkylation of the imidazole arms. Reasoning that competitive coordination of Zn(II) by the solvent was the problem, we carefully studied the course of the reaction in dry CH2Cl2. Progress of the reaction could not be directly monitored at the level of the Zn complex by 1H NMR spectroscopy due to the broadness of the peaks (owing to the released I- interacting with the complex). However, in DMSO, sharp resonances characteristic of the free calixarenes were obtained, as in this solvent, decoordination of zinc occurs, allowing the interpretation of the spectroscopic data. This allowed us to find the optimal conditions, and after 5 days of reaction at rt, the desired compound 6 was formed almost exclusively (96%). Attempts with other metal ions Org. Lett., Vol. 9, No. 17, 2007
such as Cu(II) (which is five-coordinated in our system)11 or Co(II) (which is a weaker Lewis acid than Zn(II)) gave lower yields.12 Thanks to this procedure, the amphiphilic triscationic ligand 6 was obtained within six steps from synthon 1, with an overall yield of 46% (77% for the transformation of 3 into 6). N-Me-Imidazole Protection through Cyanoboration. Reasoning that amines can form stable complexes with borane derivatives,13 we designed a new method for an efficient protection-deprotection sequence of the N-alkylimidazole groups. In situ generation of BH2CN by successive introduction of NaBH3CN and the corresponding molar equivalent of acetic acid into a THF solution containing ligand 3 led to the corresponding triscyanoborane derivative 7 almost quantitatively. The comparative 1H NMR spectra of 3 and 7 (displayed in Figure 1) show that, whereas the NMe2 resonance remains almost unaffected, the imidazole protons are low-field shifted, thus confirming their selective cyanoboration. Compound 7 was revealed to be very stable and resistant to strong bases and acids at room temperature. Heating it overnight in the presence of excess MeI quantitatively yielded compound 8. This trisammonium derivative (11) Le Clainche, L.; Giorgi, M.; Reinaud, O. Inorg. Chem. 2000, 39, 3436-3437. (12) Se´ne`que, O.; Campion, M.; Giorgi, M.; Le Mest, Y.; Reinaud, O. Eur. J. Inorg. Chem. 2004, 1817-1826. (13) A few articles have reported the formation of boron derivatives, but not as a protective group. See: (a) Wacker, A.; Pritzkow, H.; Siebert, W. Eur. J. Inorg. Chem. 1999, 789-793 and refs cited therein. (b) Bhaumik, J.; Yao, Z.; Borbas, K. E.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2006, 71, 8807-8817. The synthesis of cyanoborane adducts of 2′deoxynucleosides has also been reported: (c) Sood, A.; Spielvogel, B. F.; Shaw, B. R. J. Am. Chem. Soc. 1989, 111, 9234-9235. 3273
Figure 1. Comparative 1H NMR spectra (300 K, 250 MHz, DMSO-d6) of calix[6]arenes 4, 7, 8, and 6 (from top to bottom). 1 tBu, O OCH3, 2 NCH3 and HIm, ] CH2Ar, 3 NMeAr, b CH2Im, 0 HArN, 9 HArtBu; S ) solvent; W ) water.
presents two characteristic downfield shifted resonances: the one corresponding to the N(CH3)3+ groups and the protons of the aromatic units to which they are connected. Final deprotection was successfully conducted by heating 8 in aqueous triflic acid for 1 h to provide 6 with an overall yield of 78% starting from 3. This excellent yield emphasizes the efficiency of the protection/deprotection methodology for the N-alkylimidazole arms and its selectivity toward the dimethylanilino moieties. When directly applied to the primary anilino derivative 3, cyanoboration led to the formation of a mixture of tri-, tetra-, quinta-, and hexaborane derivative 9, as detected by mass and 1H NMR spectroscopies. However, the cyanoborane groups linked to the aniline substituents could be selectively removed through a mild ethanolysis procedure after which the tris-protected compound 10 was isolated with an equally high yield. Reaction of 10 with excess MeI directly led to 8 with an overall high yield of 92% from 3.
3274
All three routes described herein for the selective quaternization of the aniline moieties were efficient. We have first shown a nice example of the efficient protection of good N-donors (imidazole) by a tetrahedral Zn2+ center that allows the selective alkylation of poor N-donors (aniline). Equally interesting, we have discovered a novel way to protect and deprotect the imino lone pair of N-alkylimidazoles with a cyanoborane. It is noteworthy that the method is simple, efficient, of wide scope, and was absent from the organic chemist’s synthetic toolbox. N-Alkylimidazoles are actually widely utilized as biomimetic ligands as they do not suffer possible deprotonation and their binding to metal ions is easier to control. This novel method may thus find a wide range of applications such as for the synthesis of other biomimetic ligands. Finally, this work nicely illustrates the efficiency of our methodologies based on the small rimdirected ipso-functionalization of the calixarene large rim. Indeed, the sequence of selective ipso-nitration-reductionalkylation at the large rim applied to a tBu-calix[6]arene presenting nitrogen donors at the small rim allows the efficient transformation of a hydrophobic calixarene ligand 2 into its triscationic derivative 6, which is now watersoluble14 and presents an amphiphilic character. Studies of self-assemblies into vesicles and micelles together with their metal ion binding properties in water are currently underway. Acknowledgment. This research was supported by CNRS and Agence National pour la Recherche (Calixzyme Project ANR-05-BLAN-0003). MENESR is acknowledged for a Ph.D. fellowship for D.C. Supporting Information Available: Experimental procedures, spectral data for compounds 4-8 and 10, and XRD data for compound 5. This material is available free of charge via the Internet at http://pubs.acs.org. OL071208T (14) Its 1H NMR recorded in D2O displays a profile similar to the one in DMSO. See the Supporting Information.
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