Microwave-assisted synthesis of novel 2-naphthol bis -Mannich Bases

Mannich bases of 2-naphthol have the ability to chelate strongly to metal ions. Hence, they have great potential to be used as chiral catalysts, metallo-enzyme inhibitors and/or scavenger of heavy metal poisons. This paper deals with an efficient and expeditious microwave assisted-synthesis of novel bis-Mannich bases of 2-naphthols derived from aromatic aldehydes and diamines namely piperazine and N,N’ -dialkylethylenediamines under solvent-free conditions. These compounds were also prepared under conventional reflux in ethanol. The compounds of this series displayed interesting NMR behaviour.


Introduction
Mannich bases find variety of commercial applications.It was estimated that at least 35% of Mannich bases related articles are published in pharmaceutical journals.They are known for their use in polymers, resins, surface active agents, 1 detergent additives, 2 and antioxidants. 3They have a broad range of biological activities including diuretic, 4 antipsychotic, 5 oxytocic, 6 anticonvulsant, 7 centrally acting muscle relaxant, 8 antimalarial, 9,10 antiviral 11 and anticancer. 12lso, Mannich bases of various bioactive compounds have been prepared as prodrugs as a means of overcoming some of their limitations. 124][15][16][17][18][19] Many of these reactions involve the use of organozinc compounds as alkylating agents which are relatively unreactive if uncoordinated. 13These ligands may be used in catalytic amounts.The first synthesis of racemic Mannich-bases of 2-naphthol was achieved by Betti at the turn of the twentieth century. 209][30][31] Also, these compounds have the potential to be used as scavengers in cases of heavy metal poisoning. 32,33ence, it is paramount to develop synthetic strategies around the naphthalene nucleus to gain easy access to variety of naphthalene derivatives.Previously, a novel and convenient procedure for the formation of Mannich bases of 2-naphthol under solvent free conditions was reported by our group. 26,27As part of the extension of this project, we herein report a microwave-assisted convenient and expeditious method for synthesizing N,N'-bis-[aryl-(2-hydroxynaphthalen-1-yl)methyl]piperazines (1) and N,N'-bis(arylmethyl)-N,N'-bis(2-hydroxynaphthalen-1-yl-methyl)ethylenediamines (2).

Results and Discussion
Reactions between 2-naphthol, aromatic aldehydes and piperazine resulted in the synthesis of N,N'-bis-[aryl-(2-hydroxynaphthalen-1-yl)-methyl]piperazines (Scheme 1).These reactions were studied under two conditions, as follows: A) Solvent-free microwave irradiation using CEM Discover S Class microwave oven at 125 o C for five minutes in absence of any catalyst; B) Reflux in ethanol for 72 h in presence of catalytic amount of pTSA.Two N,N'-bis(arylmethyl)ethylenediamines were also prepared utilizing non-cyclic secondary diamines in place of piperazine under microwave-assisted reactions (Scheme 2).All final compounds reported in this paper are new to the chemical literature and were completely characterized by spectroscopic means.To determine the actual spatial arrangement of atoms in the 3-D space, x-ray crystallography of compound 3b was performed (Figure 1).The resolved structure shows the molecule in its most relaxed form with 2-naphthol and tolyl rings projecting in opposite directions.The H-bonding between phenolic H and N is clearly indicated at the two sites.5][36] Our previous endeavour which led to formation of simple Mannich bases of 2naphthol under solvent-free conditions involved the use of a conventional kitchen microwave and pTSA as catalyst. 26,27As evident from data presented in Table 1, we were able to obtain bis-Mannich bases 1a-l in good to excellent yields in absence of any catalyst using neat conditions under microwave irradiation; conventional reflux reactions in ethanol benefitted from the use of pTSA (Table 1, entry 1a).The comparison of isolated yields, reaction time and material requirements of the two conditions employed showed microwave-assisted solvent-free reactions as the most efficient synthetic method in terms of energy and time consumption.It should be noted that none of the conditions herein presented were optimized, and the products obtained were not subjected to extensive purification.The products obtained through the reflux reaction protocol had the inherent advantage of digestion of insoluble product precipitates and therefore the purity of the obtained product were consistently better as evidenced by the sharper and higher melting point as compared to same products obtained by employing other conditions.
The final products in Scheme 1 (1a-l) contained two chiral centers meaning that three diastereomeric forms were possible.More specifically, the final product may include a pair of enantiomers and a meso stereoisomer.This was clearly observed in 1 H NMR spectra of a number of analogs where the H at the stereogenic centre appeared as two discrete peaks (Figure 3; speactra at 300 and 323K).In addition, we observed some difficulty with solubility for all compounds while trying to obtain NMR spectra.Interestingly, the isolated products were fairly soluble in CDCl 3 but precipitated after prolonged standing (~5 h).The precipitated compounds had poor solubility in CDCl 3 although the NMR spectra of dilute sample remained unchanged.This led us to speculate that the compounds were crystallizing in a new crystal lattice, exhibiting polymorphism.The precipitation of the compounds after prolonged standing also caused difficulty in recording 13 C NMR spectra where molecular dynamics 27 was already causing disappearance of some peaks at room temperature (vide infra); the problem was compounded by frequent appearance of two peaks for some of the carbons since the products were diastereomeric mixtures.
In 1 H-NMR, all compounds clearly showed strong hydrogen-bonding between phenolic H and neighboring N.However, peak broadening was causing ambiguity in the peak assignment.Both 1 H and 13 C NMR spectra of compounds suffered from peak broadening owing to molecular dynamics characteristic of cyclic amines. 27To improve the resolution of the NMR spectra, variable temperature NMR experiments were conducted on compound 1b (Figures 2-4).Recording of NMR spectra at lower temperature (253K) did improve the resolution but the peaks were still relatively broad.From the Figure 2, the H-bonds (12.8-13.6 ppm) were shown to be weakened by an increase in temperature.The protons and carbons on the piperzine ring displayed molecular dynamics presumably because of the possibility of restricted N-inversion at the two centers.The diastereotopic protons of piperazine appeared as broad peaks in the range 2.3-3.3 ppm at room temperature (~300 K) and above.These peaks were better resolved at lower temperatures (Figure 3).Interestingly with temperature increase, the 2 benzylic protons of enantiomeric pair and the meso diastereomer appeared to resolve better (5.0-5.2 ppm; Figure 3).The carbons on the piperazine ring did not display on 13 C NMR spectrum which was recorded at 300K or above (presumably because of peak broadening).At lower temperatures, not only did the 13 C NMR spectrum display the well resolved peaks, but also it showed discrete peaks in the range 50-55 ppm for each of the four carbons on the heterocyclic rings (Figure 4).This implied the magnetic non-equivalence of these carbons at experimental temperature due to distortion and loss of symmetry of the molecule.
In conclusion, fourteen bis-Mannich bases of 2-naphthol were successfully synthesized and purified.Although reflux conditions provided products with higher purity, the use of microwaveassisted conditions was shown to be the most efficient method of synthesizing compounds of this type in terms of atom economy, energy consumption and time required.Compounds displayed interesting molecular dynamic as evident by variable temperature NMR and peaks were found to be better resolved at sub-zero temperatures.These compounds may find use as catalysts or pharmaceuticals owing to their potential for metal chelation.

Experimental Section
General Procedures.All chemicals were obtained from Aldrich Chemical Co.Column chromatographic purifications were undertaken using silica gel (230-400 mesh) obtained from Silicycle. 1 H and 13 C NMR were recorded on Bruker AV500 and AV300 NMR spectrometers.ESI-HRMS spectra were obtained on Bruker microTOF instrument with an ESI source.Melting points were recorded on an electro-thermal apparatus and are uncorrected.UV-Vis and IR spectra were recorded on LKB Biochrom Ultraspec Plus 4054 and Nicolet Avatar 330 FT-IR spectrophotometers respectively.CEM Discover S-Class microwave reactor was used for the microwave-assisted reactions.
Solvent-free microwave irradiation using CEM Discover S Class microwave oven at 125 o C for five minutes in absence of any catalyst.B.
In the reflux conditions, reaction mixtures in ethanol (40 ml) were refluxed for 72 hours.Catalytic amount of pTSA was added.
After the reaction proceeded for a stated period of time, respective of the reaction conditions, the insoluble products were sonicated in cold ethanol, filtered and air dried.Appearance, yield and melting points of products obtained under condition B are reported with experimental data.

Figure 1 .
Figure 1.The ORTEP diagram of compound 3b as obtained by X-ray crystallography.