Pavel S. Silaichev

Heterocyclic compounds containing two exocyclic double bonds are underrepresented in the literature compared with aromatic heterocycles. However, over the past decade, there has been a growing interest among organic chemists, both in Russia and globally, in developing effective methods for the synthesis (or generation) of heterocycles that incorporate two or more exocyclic double bonds. Exocyclic bonds are involved in chemical reactions that yield products of various structural forms, including spirocyclic compounds, condensed heterocycles and indolones featuring a C3 quaternary stereocentre. Among these compounds, compounds with diverse biological activities were identified. Currently available reviews focus on specific types of heterocycles or particular scaffolds, or address catalytic reactions only. This review summarizes and systematizes the literature concerning the synthesis, properties, and biological activities of five-membered heterocycles containing two exocyclic conjugated bonds such as C=C and C=C, C=C and C=N, C=C and C=O, C=O and C=N, and C=C and C=S, with a primary focus on materials published between 2016 and 2025. The bibliography includes 218 references. Keywords: heterocycles, furans, pyrroles, indoles

В настоящей работе представлены результаты продолжения изучения синтетических превращений под действием нуклеофильных реагентов замещенных 3-тиенилимино-3Н-фуран-2-онов, содержащих нитрильный заместитель в третьем положении тиофенового кольца. Данный класс соединений вызывает большой интерес для изучения благодаря содержанию в своей структуре нескольких реакционных центров, что позволяет получать продукты разнообразного строения, сохраняя при этом важные фармакофорные группы (фрагмент 2-аминотиофена и фрагмент 2,4-диоксобутановой кислоты). Нами были синтезированы и изучены на предмет биологической активности эфиры замещенных 4-оксо-2-(3-циано-4,5,6,7-тетрагидробензо[b]тиофен-2-иламино)бут-2-еновых кислот, которые были получены многостадийным синтезом. Предложенный метод обеспечивает высокие выходы целевых продуктов и включает в себя взаимодействие 4-арил-2-гидрокси-4-оксобутановых кислот с нитрилом 2-амино-4,5,6,7-тетрагидробензо[b]тиофен-3-карбоновой кислоты, последующую внутримолекулярную циклизацию полученных продуктов под действием пропионового ангидрида, а также дециклизацию полученных замещенных 3-тиенилимино-3Н-фуран-2-онов под действием первичных спиртов. Подтверждение структуры выделенных итоговых соединений проводилось методами ¹Н и ¹³С ЯМР спектроскопии, а также элементного анализа. Полученные соединения подвергались скринингу in vivo с целью обнаружения и оценки их биологической активности и острой токсичности. Антиноцицептивная активность изучалась на белых беспородных мышах обоих полов посредством термического раздражения «горячая пластинка» при внутрибрюшинном введении. Острая токсичность изучалась по методу Першина, основанном на наблюдении за состоянием мышей в течении 10 сут. после внутрибрюшинного введения тестируемых соединений. Согласно полученным результатам, протестированные соединения обладают выраженной антиноцицептивной активностью, а оценка острой токсичности указывает на их принадлежность к V классу практически нетоксичных препаратов. Высокие значения антиноцицептивной активности в сочетании с низкой токсичностью делают рассмотренные эфиры замещенных 4-оксо-2-(3-циано-4,5,6,7-тетрагидробензо[b]тиофен-2-иламино)бут-2-еновых кислот высоко перспективным классом для дальнейшего изучения с целью поиска и разработки новых биологически активных соединений с обезболивающим действием и низкой токсичностью. Для цитирования: Шаравьева Ю.О., Махмудов Р.Р., Шипиловских Д.А., Силайчев П.С., Горбунова И.А. Синтез и исследование антиноцицептивной активности замещенных эфиров 4-оксо-2-(3-циано-4,5,6,7-тетрагидробензо[b]тиофен-2-иламино)бут-2-еновых кислот. Изв. вузов. Химия и хим. технология. 2024. Т. 67. Вып. 7. С. 19-27. DOI: 10.6060/ivkkt.20246707.7029.

A novel and efficient base-catalyzed, transition-metal-free method for the synthesis of diheterocyclic compounds connected by an amidine linker, including apart from the common 1,2,3-triazole ring, either an additional pyrimidinedione, 4-nitroimidazole, isoxazole, 1,3,4-triazole, 2-oxochromone or thiazole ring, has been developed. The process was facilitated by a strong base and includes the cycloaddition reaction of 3,3-diaminoacrylonitriles (2-cyanoacetamidines) to heterocyclic azides followed by a Cornforth-type rearrangement to the final products. The reaction is tolerant to various N-monosubstituted 3,3-diaminoacrylonitriles and to different heterocyclic azides. The developed method has a broad scope and can be applied to obtain a variety of N-heteroaryl-1,2,3-triazole-4-carbimidamides with alkyl, allyl, propargyl, benzyl, cycloalkyl, and indolyl substituents at the N¹ position .

An efficient base-catalyzed, metal-free method for thesynthesisof 5-amino-1,2,3-triazole-4-N-sulfonyl- and arylimidamides,directed by the structure of the amidine group, has been developed.It is based on a previously unknown tandem process involving cycloadditionreaction to 3,3-diaminoacrylonitriles (2-cyanoacetamidines) with aryl(alkyl)sulfonylor aryl azides and Cornforth-type rearrangement. During the reactionoptimization, different factors were found to facilitate the titlereaction, which include the use of a strong base and N-mono- or N,N & PRIME;-disubstituted3,3-diaminoacrylonitriles. The reaction is tolerant to variously N-monosubstituted and N,N & PRIME;-disubstituted 3,3-diaminoacrylonitriles and to various aryl-and aryl/alkyl sulfonyl azides. The developed method has a broad scopeand can be applied to obtain a variety of 5-amino-1,2,3-triazole-4-carbimidamidesbearing at the N-1 position alkyl, allyl, propargyl, benzyl,cycloalkyl, and heteroaryl substituents and sulfonyl and aryl substituentsat the amidine group. Post-cyclization reactions of prepared 5-amino-1,2,3-triazoleswith DMF-DMA DMA-DMF leads to 1,2,3-triazolo[4,5-d]pyrimidines, 8-aza purine analogues demonstrating the applicabilityof the prepared compounds in organic synthesis.

The reaction of 3,3-diaminoacrylonitriles with DMAD and 1,2-dibenzoylacetylene was studied. It is shown that the direction of the reaction depends on the structure both of acetylene and of diaminoacrylonitrile. In the reaction of DMAD with acrylonitriles bearing a monosubstituted amidine group, 1-substituted 5-amino-2-oxo-pyrrole-3(2H)ylidenes are formed. On the other hand, a similar reaction of acrylonitriles containing the N,N-dialkylamidine group affords 1-NH-5-aminopyrroles. In both cases, pyrroles containing two exocyclic double bonds are formed in high yields. A radically different type of pyrroles containing one exocyclic C=C bond and sp³ hybrid carbon in the cycle is formed in reactions of 3,3-diaminoacrylonitriles with 1,2-diaroylacetylenes. As in reactions with DMAD, the interaction of 3,3-diaminoacrylonitriles with 1,2-dibenzoylacetylene can lead, depending on the structure of the amidine fragment, both to NH- and 1-substituted pyrroles. The formation of the obtained pyrrole derivatives is explained by the proposed mechanisms of the studied reactions.

A method was proposed for the synthesis of substituted 2-(2-(furan-2-carbonyl)hydrazono)-4-oxobutanoic acids by the reaction of substituted 2,4-dioxobut-2-enoic acids with furan-2-carbohydrazide. It was found that substituted 2-(2-(furan-2-carbonyl)hydrazono)-4-oxobutanoic acids undergo intramolecular cyclization in the presence of propionic anhydride to form the corresponding N'-(2-oxofuran-3(2H)-ylidene)furan-2-carbohydrazides. The anti-inflammatory activity of the obtained compounds was studied. It was found that the obtained compounds have pronounced anti-inflammatory activity.

New methyl 5-aryl-1-(furan-2-carbonyl)-1H-pyrazole-3-carboxylates were obtained via decyclization reaction of N'-(5-aryl-2-oxofuran-3(2H)-ylidene)furan-2-carbohydrazides under the action of methanol. Starting N'-(5-aryl-2-oxofuran-3(2H)-ylidene)furan-2-carbohydrazides were obtained by intramolecular cyclization of substituted 4-aryl-2-[2-(furan-2-ylcarbonyl)hydrazinylidene]-4-oxobutanoic acids in propionic anhydride. The structure of the compounds obtained was confirmed by the 1H NMR spectroscopy, IR spectrometry and elemental analysis methods. Analgesic activity of some obtained compounds was studied by the “hot plate” method on outbred white mice of both sexes with intraperitoneal injection.

Substituted alkyl 4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with urea to give alkyl 2-(carbamoylamino)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylates which underwent intramolecular cyclization to 8-hydroxy-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-triones by the action of sodium methoxide.

Organozinc compounds formed from 1-aryl-2,2-dibromoalkanes, α,α-dibromopinacoline, and dialkyl dibromomalonates and zinc react with (3-phenylprop-2-enylidene)malonodinitriles and primary amides of 2-cyano-5-phenylpenta-2,4-dienoic acid to form 2-alkyl-2-aroyl-3-(phenylvinyl)cyclopropan-1,1-dicarboxylic acid dinitriles, N-substituted amides of 3-(phenylvinyl)-2-(2,2-dimethylpropanoyl)-1-cyanocyclopropan-1-carboxylic acids, and alkyl 3-R-6-(phenylvinyl)-2,4-dioxo-5-cyano-3-azabicyclo[3.1.0]-hexan-1-carboxylates as a single stereoisomer.