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Project titleTransformations of enyne-substituted imidazolidines as a starting point for skeletal diversity

AffiliationPeoples’ Friendship University of Russia named after Patrice Lumumba,

Research area 03 - CHEMISTRY AND MATERIAL SCIENCES, 03-101 - Synthesis, structure and reactivity of organic compounds

Keywordschemical diversity, domino reactions, diversity-oriented synthesis, heterocycles, imidazolidine, rearrangements, photoredox

Annotation
Structural diversity of the compound library is the key success factor in the search for biologically active substances. Difference in structure will give different properties, and the wide coverage of the chemical space by changing the shape, spatial structure, functionality increases the likelihood of identifying a compound that can bind to the biotarget. Diversity-oriented chemical synthesis makes it possible to effectively create libraries of such compounds, and methods which grant access to skeletal diversity are of special value. One of the approaches towards skeletal diversity is the use of polyfunctional compounds capable of undergoing transformations under the action of various reagents and conditions. Often, such substances require a large number of transformations to obtain a high degree of skeletal diversity, which reduces the commercial attractiveness of the compound library. Those systems and methods that make it possible to achieve skeletal diversity in one synthetic step are of greatest interest. In this project, readily available imidazolidines with vinyl and ethynyl moieties will be studied as starting points for creating skeletal diversity. The presence of unsaturated bonds, as well as the aminal fragment, make these substances extremely interesting objects for the incorporation of various transformation channels. Preliminary experiments have shown the possibility of both the thermal rearrangement of the imidazolidine ring to pyrrole and the acid-promoted pyridine formation. It is assumed that no less interesting are the transformations of imidazolidines induced by one-electron transfer. Thus, the project will study the transformations of imidazolidines with a wide variety of substituents under (a) thermal conditions, (b) acid catalyzed conditions, and (c) radical reactions taking place under photoredox-catalytic conditions. This will create a number of new methods for generating biologically relevant compounds. The transformations studied have a high degree of scientific novelty, similar imidazolidine systems have been hitherto unknown.

Expected results
Effective approaches towards potentially useful substances will be developed as a result of the project, including new, original transformations, which will significantly expand knowledge in the domain of domino reactions, making a wide range of new compounds with a high degree of structural diversity accessible to biological screening.

Annotation of the results obtained in 2019
The statistics of registered drugs indicates a linear increase in their number, and the ongoing difficulties in identifying leader compounds indicate the disadvantages of compound libraries consisting of a large number of structurally similar substances. It was believed that for the success of biological screening, it is not so much the size of the library that is important, but its diversity in terms of molecular structure and, accordingly, properties. The main way to overcome this situation is to use diversity-oriented synthesis (DOS) to create compound libraries. The present project is devoted to the study of enyne-substituted imidazolidines as starting points for creating chemical diversity. Chemical diversity can be divided into three types: appendage, stereochemical and skeletal. The most desirable and most elusive is the creation of skeletal diversity. It is the skeleton that sets the basic shape, rigidity or flexibility of the molecule, directs the substituents in space. One of the approaches to obtaining a variety of skeletons is the use of multifunctional molecules that can undergo transformations under the influence of various reagents. Often this diversity is achieved through a series of successive transformations, which complicates the generation of the library and increases its value. Of particular value are the classes of compounds in which, as a result of one-pot or domino transformations, a significant rearrangement of the skeleton can be achieved in one synthetic step. This type of compounds is the scaffold of imidazolidine 1 proposed in this project, which has a double and triple C — C bonds in its structure, as well as a relatively labile aminal fragment, which makes it an excellent object for studying various transformations induced thermally, acidically, or due to electron transfer. At the second stage of the project, mechanistic insight for imidazolidine-to-pyrrole transforamtion has been obtained. The synthetic scope of the reaction has been significantly broaden, especially with respect to 1-alkyl-substituted imidazolidines. A one-pot approach to the synthesis of pyrroles from 2-imidazolines using a sequential pseudo-three-component reaction or a pseudo-four-component reaction with the addition of acylating agents was developed. A preparative approach to the synthesis of imidazopyridines by means of acid-catalyzed domino transformation of imidazolidines has been developed. It was found that the formation of imidazopyridines occurs through pyridinium salts, which can be isolated as final products. It was shown that imidazopyridines and pyridinium salts can be reversibly converted into each other depending on the conditions. A photochemical approach to the conversion of imidazolidines to pyrroles has been developed. The reaction proceeds under the conditions of catalysis by the iridium complex when irradiated with blue light. The photocatalytic interaction of imidazolidines with homophthalonitrile and salicylic aldehyde was detected. A sequential multicomponent reaction of pyrroles with homophthalonitrile and salicylic aldehyde was developed. Thus, approaches to the synthesis of various heterocycles based on one class of compounds — enyne-substituted imidazolidines — have been developed, making them an excellent source of chemical diversity.

Publications

1. Golantsov N.E., Golubenkova A.S., Festa A.A., Varlamov A.V., Voskressensky L.G. A Domino Route toward Polysubstituted Pyrroles from 2-Imidazolines and Electron-Deficient Alkynes Organic Letters, - (year - 2020)

2. Golubenkova A.S., Golantsov N.E., Festa A.A., Voskressensky L.G. 1-Benzyl-2-(thien-2-yl)-4,5-dihydro-1H-imidazole MolBank, - (year - 2020)

3. Yue X, Festa A.A., Storozhenko O.A., Varlamov A.V., Subramani K., Boccarelli A., Purgatorio R., Altomare C.D., Voskressensky L.G. Reductive Domino Reaction to Access Chromeno[2,3-c]isoquinoline-5-amines with Antiproliferative Activities Against Human Tumor Cells Bioorganic Chemistry, - (year - 2020)

4. Yue X., Storozhenko O.A., Festa A.A., Sorokina E.A., Varlamov A.V., Voskressensky L.G. Microwave-assisted sequential three-component synthesis of pyrrolyl-substituted chromeno[2,3-c]isoquinolin-5-amines Chemistry of Heterocyclic Compounds, том 56, номер 4, стр. 495-498 (year - 2020)

5. Golubenkova A.S., Golantsov N.E. Синтез 1,2,3,4-тетрагидолпирроло[1,2-a]пиразинов из 2-имидазолинов и электронодефицитных алкинов Сборник тезисов конференции «Марковниковские чтения: Органическая химия от Марковникова до наших дней» (МО, Красновидово, 18-21 января 2019 года), стр. 41 (year - 2019)

6. Golubenkova A.S., Golantsov N.E., Festa A.A., Voskressensky L.G. A domino route from imidazolines and electron-deficient alkynes to polysubstituted pyrroles сборник тезисов международной научной конференции The Fifth International Conference "Advances in Synthesis and Complexing", том 1, стр. 143 (year - 2019)

Annotation of the results obtained in 2018
A series of 2-phenyl-2-imidazoline adducts containing in the 1 position alkyl, aryl or alkoxycarbonyl groups with two methyl propiolate or butin-2-one molecules was obtained. It is established that in all cases the adducts are 1,2,2,3-tetrasubstituted imidazolidines containing fragments of acrylic and propiolic acids. It was found that when heated, the obtained 3-arylimidazolidines undergo [3,3] -sigmatropic rearrangement, which, as a result of the subsequent transannular nucleophilic attack and oxidation by air oxygen, leads to the formation of 1-(2-(arylamino)ethyl)-2-aroylpyrrole-3,4-dicarboxylic acids esters. This made it possible to develop a convenient aerobic domino-method for the synthesis of 1-(2-(arylamino)ethyl)-2-aroylpyrrole-3,4-dicarboxylic acid esters from the corresponding 3-arylimidazolidines, with the final oxidative step. The use of 3-alkylimidazolidines made it possible to synthesize esters of 1-(2-(alkylamino)ethyl)-2-aroylpyrrole-3,4-dicarboxylic acids containing acyl, carbamate, carbamoyl or thiocarbamoyl groups at the nitrogen atom of the side chain. Under microwave irradiation and in the presence of bases, 1,2,2,3-tetrasubstituted imidazolidines are converted to esters of 1,2-disubstituted 1,2,3,4-tetrahydropyrrolo [1,2-a]pyrazine-7,8-dicarboxylates. A one-pot method was developed for the synthesis of 1,2-disubstituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7,8-dicarboxylates starting with imidazolines 1. Thus, it was shown that imidazolines are valuable substrates for creating chemical diversity, including skeletal diversity.

Publications

1. Golubenkova A.S., Golantsov N.E. Синтез 1,2,3,4-пирроло[1,2-a]пиразинов из 2-имидазолинов и электронодефицитных алкинов Сборник тезисов конференции «Марковниковские чтения: Органическая химия от Марковникова до наших дней» (МО, Красновидово, 18-21 января 2019 года), c. 41 (year - 2019)

2. Golubenkova A.S., Golantsov N.E., Festa A.A., Voskressensky L.G. A domino route from imidazolines and electron-deficient alkynes to polysubstituted pyrroles Сборник тезисов международной научной конференции The Fifth International Conference "Advances in Synthesis and Complexing" (Москва, 22-26 апреля 2019 года), том 1, стр. 143 (year - 2019)