Ind. Eng. Chem. Res. 2000, 39, 3465-3470
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Synthesis of Armed and Double-Armed Macrocyclic Ligands by the Mannich Reaction: A Short Review Yoichi Habata* and Sadatoshi Akabori Department of Chemistry, Faculty of Science, Toho University, Funabashi, Chiba 274-8510, Japan
Jerald S. Bradshaw and Reed M. Izatt Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602
The Mannich reaction is useful in the chemical industry because of its wide applicability to organic synthesis. This short review summarizes some recent work (1996-2000) on the synthesis of new armed and double-armed macrocyclic ligands using the Mannich reaction, presents a study concerning side reaction products, and discusses reaction mechanisms. Introduction The Mannich reaction has wide applicability in organic synthesis, and many reviews have been reported.1-9 Advantages of the Mannich reaction in organic synthesis are as follows: (i) the synthesis operation is simple, and (ii) the desired compounds are generally obtained in high yields. Since Bogatsky and co-workers reported that the Mannich reaction is a convenient method to introduce chelating sidearms to monoaza- and diazacrown ethers,10 many functionalized macrocyclic ligands have been synthesized using the Mannich and modified Mannich reactions. A review on the application of the Mannich reaction in the synthesis of azamacroheterocycles was published in 1996.11 Since that time, the synthesis of many interesting macrocyclic ligands using the Mannich reaction has been reported. This short review summarizes some recent work (1996-2000) on the synthesis of new armed-macrocyclic ligands using the Mannich reaction, presents a study concerning side reaction products, and discusses reaction mechanisms.
Figure 1. Phenol-containing benzoaza-15-crown-5 ligands.
Scheme 1
Synthesis of Armed Macrocyclic Ligands Containing Phenol and Hydroxyquinoline Units The Mannich reaction is suitable for the synthesis of armed macrocyclic ligands containing phenol and hydroxyquinoline as sidearms because aminomethylation occurs at positions ortho to the hydroxy group. The o-OH group of the resulting armed macrocycle can bind guest cations incorporated into the macrocyclic cavity. The selectivity and complexing ability toward guest cations in these armed ligands are enhanced over that for the parent macrocyclic ligands. Using Bogatsky’s aminomethylation method,10 Wang reported the synthesis of armed-benzoazacrown ethers 1-7 (Figure 1).12 These ligands were used for solvent extraction of the alkali metal cations. Lagow and co-workers reported13 a convenient synthesis of double-armed macrocyclic ligands using a onepot Mannich reaction (Scheme 1). When para-substituted phenols were used for the Mannich reaction with diaza-18-crown-6 in the presence of paraformaldehyde, double-armed macrocyclic ligands 8-15 were obtained * To whom correspondence should be addressed. Tel./fax: +81-47-472-4322. E-mail:
[email protected].
in relatively high yields without isolating the N,N′dimethoxymethyldiaza-18-crown-6 intermediate. Solidstate structures of ligands 11 and 12 were reported. As shown in Scheme 2, Bradshaw and co-workers reported14 a wide variety of new double-armed diaza18-crown-6 ligands containing phenols for possible use as sensor molecules (16-22). Ligands 20 and 21 containing both phenolic OH and amino groups in the sidearms act as heterobinuclear metal ion receptors for Na+ and Cu2+ ions. They also reported the preparation of symmetrical and asymmetrical double-armed diaza18-crown-6 ligands having 8-hydroxyquinoline groups
10.1021/ie0002327 CCC: $19.00 © 2000 American Chemical Society Published on Web 08/31/2000
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Ind. Eng. Chem. Res., Vol. 39, No. 10, 2000
Scheme 2
as sidearms (23-31) by the reactions of diaza-18crown-6 with 2-iodomethyl-8-hydroxyquinoline derivatives in the presence of diisopropylethylamine (Scheme 3), reductive amination by 8-hydroxyquinoline-2-carboxaldehyde and sodium triacetoxyborohydride, and the Mannich reaction (Schemes 4 and 5).15 Mono- and disubstituted diaza-18-crown-6 ligands (23 and 24, Scheme 3) were prepared by changing the diaza-18crown-6 ether/CHQ ratio. When 10-hydroxybenzoquinoline (HBQ) was used for the Mannich reaction, only the mono-armed diaza-18-crown-6 ether was obtained (32, Scheme 6) presumably because of the steric hindrance of the large HBQ substituent or intramolecular hydrogen bonding between the nitrogen atom of HBQ and the NH of the crown ether. Double-armed diaza-18-crown-6 ligands containing the pyrazol ring in the sidearms (33) were also prepared by the Mannich reaction of N,N′(bismethoxymethyl)diaza-18-crown-6 with chloropyrazolylphenol (Scheme 7). Yang et al. also reported16 double-armed diaza-18-crown-6 ligands having pyrazolyl and triazolyl groups (34 and 35) by the one-pot aminomethylation method.13 Double-armed diaza-18-crown-6 ligands containing phenols with various alkyl substituents on the aromatic sidearms (36-51, Figure 2) were also prepared for a study of the aggregation of metal ion chelates.17
Scheme 3
Scheme 4
Tetra- and hexa-armed macrocyclic ligands containing phenols as sidearms (52-55) were prepared from hexaaza- and octaazamacrocycles, respectively, by the onepot Mannich reaction (Figure 3).18 In these syntheses, formalin (37% aqueous formaldehyde) was used instead
Ind. Eng. Chem. Res., Vol. 39, No. 10, 2000 3467 Scheme 5
Figure 2. Alkylphenol-containing diaza-18-crown-6 ligands.
Scheme 6
of paraformaldehyde. The structures of ligands 52 and 53 were confirmed by X-ray crystallography. Synthesis of Armed Macrocyclic Ligands Containing Phenol Derivatives for Intermolecular Interactions As described above, armed macrocyclic ligands usually contain o-phenolic units so that the sidearm may bind with guest cations incorporated into the macrocyclic cavity. When other groups are substituted at both ortho positions of the reacting phenol, aminomethylation takes place on the para position of the phenol. Thus, the sidearm of the armed macrocyclic ligand can only bind guest cations incorporated into another macrocyclic ligand. This new class of armed-macrocyclic ligands was prepared to form “polymer-like complexes” with alkali metal cations. Habata and Akabori have prepared19
Scheme 7
armed-macrocyclic ligands (56-71) containing various p-phenolic groups by the reaction of N-methoxymethylsubstituted monoaza-15-crown-5 or monoaza-12-crown-4 with 2,6-disubstituted phenols in methanol (Figure 4). Using similar conditions, double-armed macrocyclic ligands 72-86 were also obtained from the appropriate diazacrown ethers.20-23 The authors reported the formation of polymer-like complexes of the ligands with alkali metal cations.19,20,23 Byproducts and Reaction Mechanisms in the Synthesis of Armed Macrocyclic Ligands Using the Mannich Reaction It is important to use phenols that can be aminomethylated by the Mannich reaction. Unexpected side reaction products were reported in the reaction of
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Ind. Eng. Chem. Res., Vol. 39, No. 10, 2000 Scheme 8
Figure 3. Tetra- and hexa-armed polyazamacrocycles.
Table 1. pH Values for 2,6-Disubstituted Phenols and 2-Methyl-1-naphthol in Methanol (1.0 mol/L, 25 °C) and Electrostatic Charges at the Position 4 Carbon (AM1 Level)
Figure 4. Mono- and diazacrown ethers containing one and two p-phenol arms.
N-methoxymethyl-substituted monoaza-12-crown-4 with the certain 2,6-disubstituted phenols (Scheme 8).21 Reactions using 2,6-dichloro- and 2,6-dibromophenols gave salts of dihydroxydiphenylmethane with the monoaza-12-crown-4 ether 87 and 88, respectively. Structures of these salts were confirmed by X-ray crystallography. Oxidized product 90 of 4,4′-bis(2-methyl-1-hydroxynaphthyl)methane 89 was obtained when 2-methyl-1-naphthol was used. These unexpected compounds were also confirmed by X-ray analysis. Using 2,6-dinitrophenol gave a salt of the phenol with monoaza-12-crown-4 ether. From the results of pH measurements in methanol and calculations of the electrostatic charge on the
substituents at phenol positions 2 and 6
pH
electrostatic charge (electrons)
(X ) Y ) Me) (X ) Y ) i-Pr) (X ) Me, Y ) t-Bu) (X ) Y ) t-Bu) (X ) Y ) OMe) (X ) OMe, Y ) -CH2CHdCH2) (X ) Y ) Ph) (X ) Y ) F) (X ) Y ) Cl) (X ) Y ) Br) 2-methyl-1-naphthol (X ) Y ) NO2)
7.3 6.7 6.8 6.9 6.6 6.7 7.3a 5.2 4.5 4.6 4.3 1.8
-0.11 -0.15 -0.13 -0.10 -0.15 -0.12 -0.13 -0.10 -0.22 -0.26 -0.22 -0.23
a A pH value of 7 was measured in a mixed solution of methanol and benzene (1:1) because 63 did not dissolve in methanol.
phenol (Table 1), a reaction mechanism for the Mannich reaction and side reaction product formation has been proposed (Scheme 9).21 When 2,6-disubstituted phenols that have low acidity (phenols that exhibit pH values in methanol greater than 5.2) are used, the phenols readily react with the iminium ion derived from N-methoxymethylmonoaza-12-crown-4 to give the Mannich products. In the case of using the more acidic 2,6disubstituted phenols (phenols that exhibit pH values less than 5), the N-methoxymethylmonoaza-12-crown-4 ether dissociates into formaldehyde and monoaza-12crown-4, and the formaldehyde reacts with the phenols having lower electrostatic charge (higher reactivity toward formaldehyde) at the position 4 carbon atom to
Ind. Eng. Chem. Res., Vol. 39, No. 10, 2000 3469 Scheme 9
give hydroxymethylphenol and/or hydroxymethylquinone intermediates, leading to the dihydroxydiphenylmethane derivatives. A very strong phenolic acid such as 2,6-dinitrophenol does not form either the Mannich aminomethylation products or the side reaction products. To confirm the proposed reaction mechanism, onepot Mannich reactions of monoaza-12-crown-4 with 2,6-dimethyphenol (a weak phenolic acid) and 2,6-dibromophenol (a stronger phenolic acid) were carried out. As expected, Mannich product 56 and cleavage-dimerization product 88, respectively, were obtained in these one-pot reactions. Thus, the acidity and electrostatic charge of the phenols, which one wants to attach to an azacrown ether, are a guideline to predicting the suitability of using the Mannich reaction for the attachment process. Acknowledgment This work was supported by the Japan Securities Scholarship Foundation (Heisei 10 nendo) for Y.H. and by the U.S. Office of Naval Research for J.S.B. and R.M.I. Literature Cited (1) Bricke, F. F. The Mannich Reaction. Org. React. 1949, 5, 301. (2) Reichert, B. Die Mannich-Reaction. Springer-Verlag: Berlin, Hellmann, 1959. (3) Tramontini, M. Advances in the Chemistry of Mannich Bases. Synthesis 1973, 703. (4) Thomson, B. B. The Mannich Reaction. J. Pharm. Sci. 1968, 57, 715. (5) Layer, R. W. The Chemistry of Imines. Chem. Rev. 1963, 63, 489. (6) Harada, K. In The Chemistry of the Carbon-Nitrogen Double Bond; Patai, S., Ed.; Interscience: New York, 1970; Chapter 6.
(7) Bohme, H.; Haake, M. Methyleniminium Salts. Adv. Org. Chem. 1976, 9, 107. (8) Tramontini, M.; Angiolini, L. Further Advances in the Chemistry of Mannich Basis. Tetrahedron 1990, 46, 1791. (9) Trost, B. M.; Fleming, I.; Heathcock, C. H. Comprehensive Organic Synthesis; Pergamon Press: Oxford, 1991; Chapter 4, p 1893. (10) Bogatsky, A. V.; Lukyanenko, N. G.; Pastushok, V. N.; Kostyanovsky, R. G. Macroheterocycles, LVII. Improved Synthesis of Aza Crown Ethers with Phenolic Sidearms. Synthesis 1983, 992. (11) Bordunov, A. V.; Bradshaw, J. S.; Pastushok, V. N.; Izatt, R. M. Application of the Mannich Reaction for the Synthesis of Azamacroheterocycles. Synlett 1996, 933. (12) Wang, J. Synthesis of New Mannich Bases of Azacrown Ethers and Extraction of Alkali Metal Ions. Yingyong Huaxue 1996, 13, 69. (13) Chi, K.; Wei, H.; Kottke, T.; Lagow, R. A New One-Pot Synthesis of Double Armed Ionizable Crown Ethers Using the Mannich Reaction. J. Org. Chem. 1996, 61, 5684. (14) Su, N.; Bradshaw, J. S.; Zhang, X. X.; Savage, P. B.; Krakoviak, K. E.; Izatt, R. M. Diaza-18-crown-6 Ligands Containing Two Aminophenol Sidearms: New Heterobinuclear Metal Ion Receptors. J. Org. Chem. 1999, 64, 3825. (15) Su, N.; Bradshaw, J. S.; Zhang, X. X.; Song, H.; Savage, P. B.; Xue, G.; Krakowiak, K. E.; Izatt, R. M. Syntheses and Metal Ion Complexation of Novel 8-Hydroxyquinoline-Containing Diaza18-Crown-6 Ligands and Analogs. J. Org. Chem. 1999, 64, 8855. (16) Yang, M. M.; Zhang, J. Q.; Shen, Z. A New One-Pot Synthesis of Macroheterocycles Using the Mannich Reaction. Chin. Chem. Lett. 1997, 8, 845. (17) Su, N.; Bradshaw, J. S.; Savage, P. B.; Krakowiak, K. E.; Izatt, R. M.; De Wall, S. L.; Gokel, G. W. Syntheses and Aggregate Study of Bisphenol-Containing Diaza-18-crown-6 Ligands. Tetrahedron 1999, 55, 9737. (18) Bligh, S. W. A.; Evagoras, N. C.; McPartlin, M. Hexaaza and Octaaza Macrocycles with 2-Hydroxy-3,5-dimethylbenzyl Pendent Arms. J. Chem. Soc., Perkin Trans. 1 1997, 3151. (19) Habata, Y.; Akabori, S. Molecular Structure of Novel Polymer-like Complexes of Armed Azacrown Ethers with Alkali Metal Cations. J. Chem. Soc., Dalton Trans. 1996, 3871.
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(20) Habata, Y.; Watanabe, A.; Akabori, S. Molecular Structure of RbCN Complex with N-(4′-Hydroxy-3′,5′-diisopropylbenzyl)monoaza-15-Crown-5 Ether: Two Structures in a Unit Cell. Supramolecular Chem. submitted. (21) Habata, Y. Saeki, T.; Akabori, S.; Bradshaw, J. S. Syntheses of Armed-Azacrown Ethers by the Mannich Reaction: Molecular Structures and Reaction Mechanism for the Side Reaction Products. J. Heterocyclic Chem. 1999, 36, 355. (22) Habata, Y.; Saeki. T.; Akabori, S. Synthesis and Complexing Properties of Double Armed Diaza-15-Crown-5 and Diaza-18Crown-6 Ethers Having 4′-Hydroxy-3′,5′-Disubstituted Benzyl Groups. J. Heterocyclic Chem., submitted.
(23) Habata, Y.; Saeki, T.; Akabori, S.; Zhang, X. X.; Bradshaw, J. S. Polymer-like Complexes Bridged by a Fluorine Substituent of the Side Arm in the 3′,5′-Difluoro-4′-Hydroxybenzyl-Armed Monoaza-15-Crown-5 Ether. Chem. Comm. 2000, 1469.
Received for review February 14, 2000 Revised manuscript received May 25, 2000 Accepted May 26, 2000 IE0002327
