CARBON-CARBON AND CARBON-HETEROATOM CONJUGATE ADDITION OF N-SUBSTITUTED MALEIMIDES TO 4 H -1,2,4-TRIAZOL-3-THIOLES, 2-AMINO-1,3-THIAZOLES, 1 H -IMIDAZOLE AND 2-PHENYLINDOLIZINE CATALYZED BY LEWIS ACIDS

In the paper the cheap and effective method of the synthesis of 3-heteryl substituted succinimides via catalytic Michael addition are presented. Lewis acids have been found to be effective catalysts for conjugate addition of N-aryl substituted maleimides to the heterocycles with donor-heteroatoms or CH-active function. Catalytic reactions proceed in mild conditions without formation of by-products that are often present in the classical Michael reaction. The compounds synthesized are promising and interesting substrates for biological evaluation since numerous natural products, drugs and drug candidates bear the succinimide core. Moreover, regioselectivity of addition of ambident heterocyclic nucleophiles such as 4H-1,2,4-triazole-3-thiole, 1H-imidazole and 2-ami-no-1,3-thiazole to maleimides have been investigated. Lewis acids such as aluminium chloride, zinc chloride and lithium perchlorate have been tested on different heterocyclic substrates as catalysts. Interestingly, depending on nucleophilicity of the substrate different Lewis acids have shown significantly varying efficacy. In this respect aluminium chloride was identified as the most effective catalyst for C–C addition among the Lewis acids tested. Lithium perchlorate appears to be the most efficient in the case of C–N addition with the endocyclic nitrogen atom of the hererocycle. Zinc chloride shows a good catalytic efficacy in addition of maleimides to the exocyclic amino group of 2-aminothiazole. Finally, the advantages of the catalytic approach developed such as mild reaction con- ditions, easy handling, low toxicity of the catalysts and their low cost make this method useful for the synthesis of new 3-heteryl substituted succinimides, which, in turn, are interesting substrates in medicinal chemistry. за Міхаелем; каталізатор; малеїнімід; кислоти Льюїса; сукцинімід; регіосе-лективністьВ

In the paper the cheap and effective method of the synthesis of 3-heteryl substituted succinimides via catalytic Michael addition are presented. Lewis acids have been found to be effective catalysts for conjugate addition of N-aryl substituted maleimides to the heterocycles with donor-heteroatoms or CH-active function. Catalytic reactions proceed in mild conditions without formation of by-products that are often present in the classical Michael reaction. The compounds synthesized are promising and interesting substrates for biological evaluation since numerous natural products, drugs and drug candidates bear the succinimide core. Moreover, regioselectivity of addition of ambident heterocyclic nucleophiles such as 4H-1,2,4-triazole-3-thiole, 1H-imidazole and 2-amino-1,3-thiazole to maleimides have been investigated. Lewis acids such as aluminium chloride, zinc chloride and lithium perchlorate have been tested on different heterocyclic substrates as catalysts. Interestingly, depending on nucleophilicity of the substrate different Lewis acids have shown significantly varying efficacy. In this respect aluminium chloride was identified as the most effective catalyst for C-C addition among the Lewis acids tested. Lithium perchlorate appears to be the most efficient in the case of C-N addition with the endocyclic nitrogen atom of the hererocycle. Zinc chloride shows a good catalytic efficacy in addition of maleimides to the exocyclic amino group of 2-aminothiazole. Finally, the advantages of the catalytic approach developed such as mild reaction conditions, easy handling, low toxicity of the catalysts and their low cost make this method useful for the synthesis of new 3-heteryl substituted succinimides, which, in turn, are interesting substrates in medicinal chemistry. Michael and conjugated addition reactions are well known as efficient methods for the construction of carbon-carbon and carbon-heteroatom bonds with wide applications in organic synthesis [1,2]. These reactions have been widely used in the synthesis of pharmaceutical intermediates, peptide analogues, antibiotics, and other drugs [3][4][5]. On the other hand, maleimides are an important class of substrates, which have been successfully used in the wide range of organic transformations. They have emerged as excellent dienophiles/dipolarophiles in cycloaddition reactions, as well as Michael acceptors. Traditionally, conjugate additions are performed under the influence of strong bases, but basic conditions often lead to formation of undesirable side products by polymerization, self-condensation, and other reactions.

КАТАЛІТИЧНЕ КАРБОН-КАРБОН ТА КАРБОН-ГЕТЕРОАТОМ СПРЯЖЕНЕ ПРИЄДНАННЯ N-ЗАМІЩЕ-НИХ МАЛЕЇНІМІДІВ ДО 4Н-1,2,4-ТРИАЗОЛ-3-ТІОЛІВ, 2-АМІНО-1,3-ТІАЗОЛІВ, 1Н-ІМІДАЗОЛУ ТА 2-ФЕ-
Due to the presence of two carbonyl groups conjugated with a double bond and nitrogen imide atom maleimides have excellent opportunity to formation of complexes with heavy Lewis acids. In this context the search of new and efficient catalysts for various organic transformations is a relevant area of research nowadays. Various alternative catalysts, such as phase-transfer catalysts, transition-metal complexes, lanthanides, alumina [6], have been proposed [1,7]. Despite the broad research and scientific attention to this field only a few catalysts can be used for a preparative synthesis due to high costs, difficulties related to their recovery and reuse, and often a complicated procedure of synthesis. Thus, development of new methods using cheap, commercially available, nontoxic catalysts capable of generating products in good yields is of paramount importance.
In the course of our previous study of Michael reaction on heterocyclic substrates with maleimides as electron-deficient dienophiles [8][9][10][11] we were trying to expand the boundaries of this reaction and find the optimal experimental conditions. Herein we report results of our research on conjugate addition of maleimides to nucleophilic heterocyclic substrates under the mild catalytic conditions. In this respect, we used Lewis acids because of their efficacy, low cost, ease of handling and low toxicity. Only a few examples of using aluminum chloride, as well as other Lewis acids were reported for the activation of maleimides [12] and the potency of those catalysts in the field of Michael addition has not been developed yet. Our interest on maleimides as Michael acceptors is also specified because of a large number of reported pharmaceutical substances bearing the pyrrolidine-2,5-dione fragment. For example, Phensuximide and Suclophenide are already more than 40 years in use as effective anticonvulsant and antiepileptogenic drugs [13,14] and they are still actual nowadays (Fig. 1). Moreover, succinimide is the core structural unit found in natural products. [15,16]. Since Komura and coworkers in 1987 reported isolation of Andrimid as a new and highly specific antibiotic, 1,3-substituted and 3,4-disubstituted succinimides emerged as a new class of natural products with the important biological activity [17]. Andrimid and Moiramide B (Fig.) exhibit a potent antibacterial activity against methicillin-resistant Staphylococcus aureus and a number of other antibiotic-resistant human pathogens. Those natural antibiotics have been described in the target fatty acid biosynthesis system (FAS) that is the primary target for antitubercular drugs [18]. Futhermore, Hirsutellone A, a natural product bearing the succinimide ring (Fig. 1) displayed a significant growth inhibitory activity against Mycobacterium tuberculosis [19]. Due to the wide spectrum of bioactivity of pyrrolidine-2,5-dione derivatives we have synthesized a number of new 3-heteryl substituted succinimides using the optimized catalytic conditions.

Results and Discussion
In our research we have used N-aryl maleimides as electron-deficient reactants in conjugate addition with 4H-1,2,4-triazole-3-thioles, 2-amino-1,3-thiazoles, 1H-imidazole and 2-phenylindolizine. The reactions, in general, proceed smoothly at the room temperature, and the products are in good yields. C-C, C-N and C-S adducts have been synthesized using aluminum chloride, lithium perchlorate and zinc chloride as catalysts. Regioselectivity of maleimide addition in the presence of two alternative nucleophilic centres in a heterocyclic substrate has been investigated. For example, addition of 4H-1,2,4-triazole-ISSN 2308-8303 3-thiol (1) with maleimides gives the conjugated products via a highly nucleophilic mercapto group as a single type of products (Scheme 1) in good yields (Table 1). In the case of the blocked mercapto function (compound 3) the reaction proceeds via the 4-NH-position of the heterocycle forming only one product 4a,b, respectively.
Regioselectivity of Michael addition of maleimides to 2-amino-1,3-thiazoles has been also investigated. Recently we have reported the double conjugate addition of maleimides to 2-amino-1,3-thiazole and 3substituted-2-aminopyridines in the presence of the catalytic amount of lithium perchlorate [19]. In contrast, the presence of the catalytic amount of zinc chloride leads to formation of C-N mono Michael adducts (6a,b) via the exocyclic nitrogen atom of the heterocycle (Scheme 2, Table 2). Aluminum chloride appears to be not effective catalyst in this reaction. Only the trace amounts of mono addition products were isolated. In this case regioselectivity of the reaction depends on the catalyst used. N-Acylated deriva-tive of 2-amino-1,3-thiazole (7) reacts with maleimide via C-5 ring position forming C-C adduct 8. The reaction proceeds in the presence of aluminum chloride. After refluxing of the reaction mixture for 5 hours, compound 8 was isolated as a single product in 76% yield.
Subsequently imidazole has been selected as a substrate for our further investigation of catalytic conjugate addition since it combines the imido group and a CH-active fragment as alternative reactive positions in one ring. The addition occurs on the nitrogen atom of the heterocycle forming carbon-heteroatom adducts 10a-c in good yields (Scheme 3, Table 3). The reaction proceeds at the room temperature in the presence of the catalytic amount of lithium perchlorate with full conversion of the starting products in 2 hours. Aluminum and zinc chlorides appear to be not appropriate catalysts, mixtures of hardly identified products were isolated in both cases.
Thereafter 2-phenylindolizine (11) was selected as a less reactive substrate that contains only CH-active fragment. Unlike previously used conditions, this  reaction requires refluxing of the reaction mixture for 6 hours. The products 12a,b were isolated in good yields only when aluminum chloride was used as a catalyst (Scheme 4, Table 4).

Experimental Part
All chemicals were obtained from Aldrich or Acros Organics and used without further purification. All solvents were distilled before use. Compounds 3, 7 and 11 have been synthesized according to the literature procedures and completely characterized using 1 H and 13 C NMR, MS and C,H,N analysis with all the results obtained fitting the previously reported literature data (details are not reported here) [22,23,24]. Nuclear magnetic resonance spectra were recorded on a 'Mercury 400' Varian spectrometer ( 1 H and 13 C NMR), TMS signal was used as an inter-nal standard for calibration of spectral data. Melting points were measured on a Mettler Toledo MP50 melting point system and are uncorrected.
General procedure for the synthesis of derivatives 2a-f, 4a,b and 8: 100 mg (0,99 mmol) of 4H-1,2,4triazole-3-thiole (1) or 143 mg (0,1 mmol) of S-(4H-1,2,4-triazol-3-yl)ethanethioate (3) and 1 mmol of N-substituted maleimide were dispersed in a dry dioxane. The mixture was stirred for 15 minutes for dissolving of maleimide. Thereafter 2,0 mg of anhydrous aluminum chloride (0,015 mmol) was quickly added. The reaction mixture was stirred at the room temperature for 10 hours. The progress of the reaction was monitored by TLC. After its completion the solvent was evaporated. Then the residue was washed two times with distilled water and the crude product was purified by crystallization.    ISSN 2308-8303

1-Benzyl-3-(4H-1,2,4-triazol-3-ylsulfanyl)-2,5-pyrrolidinedione (2f)
A crude product was crystallized from isopropyl alcohol to give a white powder. Yield 62%; m.p.: 154-155 о С. 1  General procedure for the synthesis of derivatives 10a-c: 80 mg (1,18 mmol) of imidazole was dissolved in 7 mL of dry dioxane. After that N-substituted maleimide (1,18 mmol) was added. The resulting mixture was stirred for complete dissolution of the reagents. Then the catalytic amount of lithium perchlorate 2,0 mg (0,019 mmol) was added and the reaction mixture was stirred for 2h at the room temperature. Then 18 mL of distilled water was added. The precipitate obtained was filtered and washed with isopropyl alcohol and diethyl ether to give a white powder.
3-(1H-Imidazol-1-yl)- General procedure for the synthesis of derivatives 12a,b: 2-Phenylindolizine 100 mg (0,52 mmol) was dispersed in dry dioxane. Then 0,53 mmol of N-substituted maleimide was added. The mixture was stirred for 15 minutes. After that the catalytic amount of aluminum chloride 1.5 mg (0,011 mmol) was added. The reaction mixture was refluxed for 6 hours. The reaction progress was monitored by TLC. After completion, the solvent was evaporated and the crude product was purified by crystallization.

Conclusions
We have demonstrated that Lewis acids can be effective catalysts for carbon-carbon and carbon-heteroatom Michael addition. The advantages of this method such as mild reaction conditions, simple experimental procedure, low toxicity of the catalysts and their low cost can make this method synthetically useful. Moreover, it is an easy way to synthesize 3-heteryl substituted pyrrolidine-2,5-diones, which are attractive synthetic compounds in the field of medicinal chemistry.