J. Org. Chem. 1999, 64, 6135-6146
6135
Synthesis and Protonation Behavior of 26-Membered Oxaaza and Polyaza Macrocycles Containing Two Heteroaromatic Units of 3,5-Disubstituted Pyrazole or 1-Benzylpyrazole. A Potentiometric and 1H and 13C NMR Study Vicente J. Ara´n,† Manoj Kumar,† Jose´ Molina,† Laurent Lamarque,† Pilar Navarro,*,† Enrique Garcı´a-Espan˜a,*,‡ Jose´ A. Ramı´rez,‡ Santiago V. Luis,§ and Beatriz Escuder§ Instituto de Quı´mica Me´ dica, Centro de Quı´mica Orga´ nica “Manuel Lora Tamayo”, CSIC. c/ Juan de la Cierva 3, 28006 Madrid, Spain, Departamento de Quı´mica Inorga´ nica, Facultad de Quı´mica, Universidad de Valencia. c/ Dr Moliner 50, 46100 Burjassot, Valencia, Spain, and Laboratorio de Quı´mica Orga´ nica, Departamento de Ciencias Experimentales, Universidad Jaime I, 12080 Castello´ n, Spain Received August 20, 1998
The synthesis and acid-base behavior of two series of 26-membered dioxatetraamine and hexaamine heterocyclophanes containing two nuclei of either pyrazole (4a and 6a) or 1-benzylpyrazole (4b and 6b), respectively, are reported. Dipodal (2 + 2) condensations of 3,5-pyrazoledicarbaldehyde 2a or its 1-benzyl derivative 2b with 1,5-diamino-3-oxapentane afford in both cases the stable Schiff bases 3a,b in 90% yield, which after reduction with NaBH4 gave 4a,b in 75% and 84% yield, respectively. Condensation of 2a with diethylenetriamine leads to a complex mixture containing imidazolidine isomers, which was reduced in situ to afford 6a in 30% yield. Condensation of 2b with the same amine gave the stable diimidazolidine derivative 5b, which after crystallization was isolated as a pure compound in 80% yield and fully identified from analytical and 1H and 13C NMR data as a constitutional isomer with both imidazolidine rings located at the side of the pyrazole closer to the benzylic substituents. Reduction of 5b with NaBH4 afforded the polyamine 6b in 86% yield. Protonation constants of 4a,b and 6a,b have been determined by potentiometric methods in the pH 2-11 range, and their protonation sequences were established by a 1H and 13C NMR study in D2O at variable pH. For each compound, the number of protonation constants equals the number of nitrogens in the side chains. In the pH range studied, the pyrazole rings are not involved in protonation or deprotonation processes. Introduction Dopamine and norepinephrine are neurotransmitter catecholamines involved in the normal emotional and autonomic control of humans, the physiological levels of which are altered in neurodegenerative and mental illnesses,1 as well as in toxic syndromes induced by cocaine and psychotropic drugs of hallucinogen effects.2 Consequently, the development of synthetic receptors able to diminish or increase the level of some of these neurotransmitters by selective complexation and/or transport mechanisms is of great interest. It is well-known that neutral polyoxa, oxaaza, and polyaza macrocycles containing a trigonal arrangement of binding sites are able to selectively bind the primary ammonium cation of dopamine and norepinephrine.3 Also, the catechol groups of dopamine and its derivatives,4 as well as anionic substrates of biological impor* Address correspondence to Pilar Navarro. Tel: 34 1-5622900. Fax: 34 1-5644853. † Instituto de Quı´mica Me ´ dica de Madrid. ‡ Universidad de Valencia. § Universidad Jaime I de Castello ´ n. (1) Hoffman, B. B.; Lefkowitz, R. J. In Goodman & Gilman′s The Pharmacological Basis of Therapeutics; Hardman, J. G., Limbird, L. E., Eds.; McGraw-Hill: New York, 1996; Chapter 10. (2) (a) Nestler, E. J. J. Neurosci. 1992, 12, 2439-2450. (b) Giros, B.; Jaber, M.; Jones, R. S.; Wightman, R. M.; Caron, M. G. Nature 1996, 379, 606-612. (3) (a) Lehn, J. M. Angew. Chem., Int. Ed. Engl. 1988, 27, 89-112. (b) Shutherland, I. O. Chem. Soc. Rev. 1986, 15, 63-91.
tance such as polycarboxylate anions, carbonate, and phosphates,5 are selectively recognized by macrocyclic polyamines as polyprotonated species in neutral pH solutions. In such receptors the ammonium groups are separated from each other by hydrocarbon chains and aromatic or heteroaromatic rings.6 Indeed, these compounds may act as ambivalent receptors; in their fully or partly protonated forms, they may interact with the catechol group or with anionic species, whereas when disposing of free lone pairs they can act as Lewis bases toward metal ions. Hence, their ability to interact with catechol groups, anions, or metal cations can be simply switched by changing the pH of the medium. Previously, we have reported on a series of heteroaromatic crowns containing two or more units of 3,5- or (4) (a) Kimura, E.; Watanabe, A.; Kodama, M. J. Am. Chem. Soc. 1983, 105, 2063-2066. (b) Kimura, E. Top. Curr. Chem. 1985, 128, 113. (c) Kimura, E.; Fujioka, H.; Kodama, M. J. Chem. Soc., Chem. Commun. 1986, 1158-1159. (5) (a) Kimura, E.; Kuramoto, Y.; Koike, T.; Fijioka, H.; Kodama, M. J. Org. Chem. 1990, 55, 42-46 and references contained therein. (b) Llobet, A.; Reibenspies, J.; Martell, A. E. Inorg. Chem. 1994, 33, 5946-5951. (c) Aguilar, J. A.; Garcı´a-Espan˜a, E.; Guerrero, J. A.; Luis, S. V.; Llinares, J. M.; Miravet, J. F.; Ramirez, J. A.; Soriano, C. J. Chem. Soc., Chem. Commun. 1995, 2237-2239. (6) (a) Supramolecular Chemistry of Anions; Bianchi, A., BowmanJames, K., Garcı´a-Espan˜a, E., Eds.; John Wiley & Sons: New York, 1997; Chapters 5 and 9. (b) Martell, A. E. In Crown Compounds: Toward Future Applications; Copper, S. R., Ed.; VHS: New York, 1992. (c) Mertes, K. B.; Lehn, J. M. In Comprehensive Coordination Chemistry; Wilkinson, G., Ed.; Pergamon Press: New York, 1987.
10.1021/jo981699i CCC: $18.00 © 1999 American Chemical Society Published on Web 07/27/1999
6136 J. Org. Chem., Vol. 64, No. 17, 1999
1,3,5-substituted pyrazole linked to the side chains by ester or ether bonds, which are able to either irreversibly complex or transport NH4+ ions7 and/or RNH3+ ions of dopamine and norepinephrine.8 We have also reported a different series of polyaza macrocycles and macrobicycles containing two or three 3,5-disubstituted pyrazole units linked to the polyamine side chains by imine or amine bonds.9,10 In basic medium, these ligands formed di- or tripyrazolate sodium salts from which di- and/or tetranuclear Zn(II) and Cu(II) complexes were formed.10,11 Now, we are interested in the study of the basicity of the last mentioned polyamine macrocycles of pyrazole to subsequently evaluate their potential ability as complexing receptors of dopamine and norepinephrine by selective interaction with their catechol groups. The influence of different aromatic and heteroaromatic rings on the basicity of dinuclear polyamine cyclophanes12 and heterocyclophanes13 in relation to [18]aneN6 (1,4,7,10,13,16-hexaazacyclooctadecane) has been previously reported. In this paper we have studied the influence of both the 3,5-disubstituted pyrazole and the 1-benzylpyrazole rings on the basicity of two different series of 26membered dioxatetraamine and hexaamine heterocyclophanes of general structures I and II, respectively (Scheme 1). Herewith, we present the 1H and 13C NMR spectra in D2O at different pH values of polyaza macrocycles of 3,5disubstituted pyrazole of general structure I (R ) H) and II (R ) H) previously mentioned in a short communication,9 as well as the synthesis and spectroscopic properties of a new series of 1-benzyl analogue receptors of structures I (R ) Bn) and II (R ) Bn). All of them were obtained by reduction of tetraimine or diimine derivatives of general structures III (X ) O, NH; R ) H, Bn) or IV (R ) H, Bn), respectively. Although several groups have detected the formation of imidazolidine derivatives related to IV in equilibrium with Schiff bases similar to III (X ) NH), as far as we know there are few examples including X-ray structures14,15 and a detailed NMR characterization of such compounds has not previously been reported. (7) Elguero, J. Pyrazoles. In Comprehensive Heterocyclic Chemistry II, A Review of the Literature 1982-1995; Katritzky, A. R., Rees C. V., Scriven, E. F. V., Eds.; Pergamon: New York, 1997; Vol. 3, pp 68-70 and references contained therein. (8) (a) Gonza´lez, B.; Jimeno, M. L.; Navarro, P.; Ochoa, C.; Rodrı´guez-Franco, M. I.; Sanz, A.; Trevin˜o, M. A. An. R. Acad. Cienc. Exact. Fı´s. Nat. Madrid 1993, 87, 105-110. (b) Fierros, M.; Conde, S.; Martinez, A.; Navarro, P.; Rodriguez-Franco, M. I. Tetrahedron 1995, 51, 2417-2426. (c) Rodriguez-Franco, M. I.; Fierros, M.; Martinez, A.; Navarro, P.; Conde. S. Bioorg. Med. Chem. 1997, 5, 363-367. (d) Bueno, J. M.; Campayo, L.; Navarro, P.; Ochoa, C.; Jimenez-Barbero, J.; Samat, A.; Pe`pe. G. J. Org. Chem. 1997, 62, 2684-2693. (e) Sanz, A. M.; Navarro, P.; Gomez-Contreras, F.; Pardo, M.; Pe`pe, G.; Samat, A. Can. J. Chem. 1998, 76, 1-6. (9) Kumar, M.; Ara´n, V. J.; Navarro, P. Tetrahedron Lett. 1993, 34, 3159-3162. (10) Kumar, M.; Ara´n, V. J.; Navarro, P. Tetrahedron Lett. 1995, 36, 2161-2164. (11) Kumar, M.; Ara´n, V. J.; Navarro, P.; Ramos-Gallardo, A.; Vega, A. Tetrahedron Lett. 1994, 35, 5723-5726. (12) Nation, D. A.; Reinbenspies, J.; Martell, A. E. Inorg. Chem. 1996, 35, 4597-4603. (13) Lu, Q.; Motekaitis, R. J.; Reibenspies, J. J.; Martell, A. E. Inorg. Chem. 1995, 34, 4958-4964. (14) Bailey, N. A.; Eddy, M. M.; Fenton, D. E.; Moss, S.; Mukhopadhyay, A.; Jones, G. J. Chem. Soc., Dalton Trans. 1984, 2281-2288. (15) (a) Menif, R.; Martell, A. E.; Squattrito, P. J.; Clearfield, A. Inorg. Chem. 1990, 29, 4723-4729. (b) Adams, H.; Bailey, N. A.; Fenton, D. E.; Hempstead, P. D.; Westwood, G. P. J. Inclusion Phenom. Mol. Recognit. Chem. 1991, 11, 63-69.
Ara´n et al. Scheme 1
In this paper we also report on the preparation of the pure imidazolidine derivative IV (R ) Bn) and its characterization by 1H and 13C NMR spectroscopy. Results and Discussion Synthesis. Heteroaromatic polyazamacrocycles containing pyridine, pyrrole, furan, and thiophene rings have been obtained following a two-step synthetic method that includes a first dipodal (2 + 2) condensation of R,ωdiamines with the corresponding dialdehydes, followed by hydrogenation of the Schiff base imine bonds.14,16,17 However, several authors have pointed out that when such R,ω-diamines have additional NH or OH groups in the middle of the chain, the first condensation step affords a mixture of two isomers. Thus, Fenton and coworkers reported that, in the absence of metal ions, the condensation of 2,5-thiophenedicarbaldehyde with diethylenetriamine affords a solid product whose 1H NMR spectrum corresponds to a mixture of the desired tetraimine Schiff base together with an imidazolidine isomer formed by nucleophilic addition of the two secondary amine groups of the tetraimine macrocycle across the adjacent imine bonds.14 Similar processes have also been reported in the synthesis of tetraimine Schiff base macrocycles in which Ba(II)18 and Pb(II)19 were used as metal templating agents. In fact, tetraimine dicopper(II) complexes have been prepared from ring-contracted oxazolidine lead complexes by transmetalation with concomitant expansion of the macrocycle.20 Furthermore, as mentioned above, Martell et al. have characterized by X-ray diffrac(16) Chen, D.; Martell, A. E. Tetrahedron 1991, 47, 6895-6902. (17) Dhont, K. I.; Lippens, W.; Herman, G.; Goeminne A. M. Bull. Soc. Chim. Belg. 1992, 101, 1061-1064. (18) Drew, M. G. B.; Nelson, J.; Nelson, S. M. J. Chem. Soc., Dalton Trans. 1981, 1678-1684. (19) Bailey, N. A.; Fenton, D. E.; Jackson, I. T.; Moody, R.; de Barbarin, C. R. J. Chem. Soc., Chem. Commun. 1983, 1463-1465. (20) Bailey, N. A.; Fenton, D. E.; Moody, R.; Rodriguez de Barbarin, C. O.; Sciambarella, I. N.; Latour, J. M.; Limosin, D.; McKee, V. J. Chem. Soc., Dalton Trans. 1987, 2519-2529.
Protonation Behavior of Oxaaza and Polyaza Macrocycles
J. Org. Chem., Vol. 64, No. 17, 1999 6137
Scheme 2
tion the structure of a crystalline imidazolidine isomer obtained by (2 + 2) Schiff base condensation of diethylenetriamine and m-phthalaldehyde.15 In a previous communication9 we have reported briefly the synthesis of 3,5-pyrazoledicarbaldehyde 2a from 3,5bis(hydroxymethyl)pyrazole 1a21 by oxidation with MnO2 in 1,2-dimethoxyethane (DME) (Scheme 2). The dioxatetraimine 3a was obtained as a crystalline solid, which precipitated in almost quantitative yield from the solution by dipodal (2 + 2) condensation of 2a with 1,5diamino-3-oxapentane. Further reduction of 3a with NaBH4 in absolute ethanol gave the expected dioxatetraazamacrocycle 4a, which after crystallization from toluene was also isolated as a pure compound. In contrast with the above behavior, in the (2 + 2) dipodal condensation of 2a with diethylenetriamine in
methanol at room temperature there was not precipitation of the expected Schiff base. The 1H and 13C NMR spectra of the solution indicated the presence of more than one species, which could correspond to a mixture of tetraimine and imidazolidine isomers of structures III (X ) NH, R ) H) and IV (R ) H) (Scheme 1). Consequently, the mixture was directly reduced in situ with NaBH4 to obtain the hexaamine macrocycle 6a, which after being carefully purified by chromatography and later crystallized from toluene was obtained as a pure compound in moderate yield (Scheme 2). Starting from 1-benzyl-3,5-bis(hydroxymethyl)pyrazole 1b22 and following similar procedures, we have now obtained the 1-benzyl-3,5-pyrazoledicarbaldehyde 2b in high yield. With acetonitrile as solvent, the (2 + 2) dipodal condensation of 2b with 1,5-diamino-3-oxapen-
(21) Schenck, T. G.; Downes, J. M.; Milne, C. R. C.; Mackenzie, P. B.; Boucher, H.; Whelan, J.; Bosnich, B. Inor. Chem. 1985, 24, 23342337.
(22) Iturrino, L.; Navarro, P.; Rodriguez-Franco, M. I.; Contreras, M.; Escario, J. A.; Martinez, A.; Pardo, M. R. Eur. J. Med. Chem. 1987, 22, 445-451.
6138 J. Org. Chem., Vol. 64, No. 17, 1999 Table 1.
Ara´n et al.
13C
NMR (δ, ppm) Spectra of 2a [(CD3)2So], 2a′ [(CD3)2SO], and 2b (CDCl3)
Table 2.
13C
NMR (δ, ppm) Spectra of 3a [(CD3)2SO], 3b (CDCl3), and 5b (CDCl3)
compound C3 C5 C4 OC2 OC6 N-HCOH-C5 C7 Cgem Co Cm Cp
compound
2aa
2a′
2b
n.o. n.o. 110.97 184.85b 184.85b
151.47 140.06 (139.78)c 104.54 (104.22)c 186.68
150.50 135.17 114.55 185.46 179.50
75.48 (74.97)c 56.14 139.98 127.97 128.74 128.40
a
Registered from a diluted solution (
