Synthesis of Imidazole Derivatives from β-Lapachone and Related Compounds using Microwave and Supported Reagents

β-Lapachone (1a) is an ortho-naphthoquinone present in small amounts in trees of the Tabebuia species (Bignoniaceae), commonly called “ipê” or “pau d’arco” in Brazil. In addition, it can be obtained by the isomerization of lapachol, a quinone that is more abundant and more readily extracted from the same sources. The biological activities of these compounds and simple derivatives, have been investigated since the 1940’s (anti-malarial) up to the present (anti-tumor, anti-microbial, anti-inflammatory and anti-parasitic) and were recently reviewed. The use of β-lapachone and some semi-synthetic derivatives as chemotherapic agents in the treatment of American trypanosomiasis (Chagas disease) has been investigated, and five imidazole derivatives, prepared from this quinone and aromatic aldehydes, have shown expressive action over the tripamastigote form of Trypanosoma cruzi. These imidazole derivatives were prepared by conventional methods. As part of an ongoing study into the use of microwave activation and the use of supported reagents, in this case ammonium acetate, we investigated the preparation of the previously unknown simple imidazole derivatives of β-lapachone and related ortho-quinones with formaldehyde. Microwave activation has provided significant improvement on heterocyclic synthesis, including imidazoles, with or without support, with reduction/ elimination of solvents, decreased reaction times and equal or improved yields.


Introduction
β-Lapachone (1a) is an ortho-naphthoquinone present in small amounts in trees of the Tabebuia species (Bignoniaceae), commonly called "ipê" or "pau d'arco" in Brazil.In addition, it can be obtained by the isomerization of lapachol, a quinone that is more abundant and more readily extracted from the same sources.The biological activities of these compounds and simple derivatives, have been investigated since the 1940's (anti-malarial 1 ) up to the present (anti-tumor, 2 anti-microbial, 3 anti-inflammatory 4 and anti-parasitic 5 ) and were recently reviewed. 6he use of β-lapachone and some semi-synthetic derivatives as chemotherapic agents in the treatment of American trypanosomiasis (Chagas disease) has been investigated, 7 and five imidazole derivatives, prepared from this quinone and aromatic aldehydes, have shown expressive action over the tripamastigote form of Trypanosoma cruzi. 8,9hese imidazole derivatives were prepared by conventional methods. 9s part of an ongoing study into the use of microwave activation and the use of supported reagents, in this case ammonium acetate, we investigated the preparation of the previously unknown simple imidazole derivatives of β-lapachone and related ortho-quinones with formaldehyde.
Microwave activation has provided significant improvement on heterocyclic synthesis, 10 including imidazoles, with [11][12][13] or without support, 14,15 with reduction/ elimination of solvents, decreased reaction times and equal or improved yields.

Results and Discussion
Imidazole synthesis from α-diketones has a long history 16 and was initially plagued by low yields and by-products (such as oxazoles).Improvements occurred by the use of acidic conditions, e.g., glacial acetic acid reflux. 17The availability of microwave technology for synthetic purposes has allowed the efficient preparation of 2,4,5-trissubstituted and 1,2,4,5-tetrassubstituted imidazoles.Further observed benefits, that were occasionally associated with solid supports such as silica, alumina, clays, amongst others, [11][12][13] included improved yields, and dramatic reductions in reaction time and quantities of solvent used (AcOH). 14,15Interestingly, the best supports found in these studies were always the acidic in nature.
However, when the support was changed to basic alumina, whilst keeping the other conditions as before (Experimental), significant improvement of the yields (81-85%, Table 1) for formation of the products 2a-c was observed.The competitive formation of oxazoles was determined to be less than 5% relative to imidazole in all cases, and these products were practically absent from the isolated product.The oxazoles could be clearly detected in the crude reaction mixture, after initial workup, as GC peaks of smaller t R , relative to the corresponding imidazoles.The oxazoles were identified by GC-MS and the relative amount was determined by FID-GC.
One of the possible reasons for the success of the use of basic alumina (pH 9.5) as support in the studied reactions, may be related to the nature of the o-quinones used, which contain an alkoxy group conjugated with one of the ketone moieties.This feature not only decreases the electrofilicity of this carbonyl, but provides a route for tautomerization in acidic media.Scheme 2 integrates these ideas and Orru's 15 mechanistic proposals on imidazole synthesis.
This synthetic method (using ammonium acetate supported on basic alumina) that was developed to prepare the previously unknown derivatives was applied to the preparation of the known imidazoles by reaction of β-lapachone with piperonal (to give 2d), and 9,10-phenanthrenequinone and benzil with paraformaldehyde (to give 3 and 4 respectively).Yields are given in Table 1 together with yields from previously reported synthesis.3]17 In addition, it was also investigated whether these reactions could occur efficiently without a support or microwave energy (other conditions kept equal).The experiments were carried out for the synthesis of compound 2a.With microwave irradiation but no support, TLC analysis of the crude product revealed the presence of imidazole in much reduced yield, with most of the quinone left unreacted.With alumina as support but no microwave irradiation, no conversion was detected after 24 h at room temperature.

Conclusions
The method described above, with ammonium acetate supported on basic alumina and microwave activation, which does not use solvents at the reaction stage, seems to be an appropriate alternative for synthesis of imidazoles from some 4-alkoxy-substituted 1,2-quinones.But it does not displace previously known methods for other 1,2-dicarbonyl substrates.Preliminary biological tests with compounds 2a-c detected promising activity against T. cruzi, specially for 2a. 24
The montmorillonite k-10 supported reagent was prepared by adding 9.3 g of the solid support to a 100 mL solution of 4.3 g of ammonium acetate in methanol (the solvent was used to alleviate mixing problems due to the montmorillonite being a very fine powder, adhering to the mortar and pestle), and vigorously stirred for 2 h; the solvent was then evaporated under reduced pressure.With basic alumina, the supported reagent was prepared by grinding 9.3 g of solid support and 4.3 g of ammonium acetate in a mortar, until homogeneous.The supported reagents were stored in a dessicator.