The research activity was mainly towards synthesis of various heterocyclic compounds through blocks 1,2- diaza-1,3-butadienes. During the thesis work are developed different methods for the synthesis of mono and polyheterocyclic systems containing nitrogen such as pyrazole, pyridazines, imidazoles, pyrroles, triazoles, triazepines, pyrrolidines and polycyclic heteroarenes. DDs are eterodieniche molecules characterized by the presence of a C = C double bond conjugated with a double bond N = N, a characteristic that makes them both the excellent Michael acceptors and therefore susceptible to nucleophilic attack, that dienes or dienophiles particularly reactive in reactions of cycloaddition. The 1,2-diaza-1,3-dienes, generated in situ by dehydrohalogenation reaction from the corresponding α- halogen-N-EWG hydrazones, have been used in annulation of type [4 + 1] and [4 + 2]. In a first job, In situ derived acyclic and cyclic 1,2-diaza-1,3- dienes (DDs) were engaged in interceptive [4+1] annulation strategy with diazo esters (DEs). The catalytic activity of inexpensive copper(II) chloride allows the direct synthesis of mono-, bi-, and tricyclic 4,5-dihydropyrazole-5-carboxylic acid derivatives in a process that circumvents the use of an anhydrous and inert atmosphere Another study explains the synthesis of 5- Methylene-6-methoxy-1,4,5,6-tetrahydropyridazines derivatives, regioselective inverse-electron-demand hetero-Diels–Alder reaction of in situ generated 1,2- diaza-1,3- dienes with methoxyallene is reported. These Lewis and Brønsted acid free reactions benefit from operational simplicity and allow access to synthetically valuable 5-methylene-6- methoxy-1,4,5,6- tetrahydropyridazines in high yields. Continuing to investigate the reactivity of 1,2-diaza-1,3-dienes we went to test their reactivity for the synthesis of pyrazoles derivatives. The base (NaH)-promoted Michael addition of N-arylhydrazones (AHs) with 1,2-diaza-1,3- dienes (DDs) produces unprecedented β-azohydrazone adducts. Strategically, the use of AHs as acyl anion equivalents and DDs as α-electrophiles of carbonyl compounds open the way to two important classes of pyrazole compounds. Another study focused on Synthesis of indole-imidazoles, indole-pyrroles and idole triazoles derivatives. The rapid and expedient assembly of three new classes of biheterocycles of biological interest, viz. indole– imidazoles, indole–pyrroles and indole–triazoles was accomplished using different combinations of tryptamines, 1,2-diaza-1,3-dienes, aldehydes, and/or alkynes as readily available building blocks. Twenty- six derivatives were thus prepared in excellent yields (up to 100 %). The products were screened for invitro biological studies. Some of these revealed promising anticancer activity against MCF7 and Caco-2 human tumor cell lines. The multicomponent 1,3-dipolar cycloaddition of different 1,2-diaza-1,3-dienes with in-situ-generated azomethine ylides produces 1,2,4-triazepines or pyrrolidines by [3+4] or [3+2] cycloadditions, respectively. The regioselectivity is controlled by the electron-withdrawing group bound to the azomoiety of the 1,2- diaza-1,3-diene, which promotes exclusively the [3+4] cycloaddition. When the electron-withdrawing group is replaced with a phenyl group, only a [3+2] cycloaddition occurs. Finally, A protocol for the direct construction of valuable polycyclic heteroarene scaffolds has been developed by using a palladium catalyst. From a retrosynthetical point of view, the strategic formation of a C-C bond via cross-dehydrogenative coupling (CDC) a cross biheterocyclic precursors may beuseful in de novo syntheses of indole-derived natural products and pharmaceuticals. In conclusion we have been developed of the new methodologies for the synthesis of new and interesting systems mono, bi and poly heterocycles through the use of 1,2-diaza systems, 1-3 diene
1,2-Diaza-1,3-butadienes as useful building blocks for the construction of mono-, bi- and poly-aza heterocyclic architectures
MANTENUTO, SERENA
2017
Abstract
The research activity was mainly towards synthesis of various heterocyclic compounds through blocks 1,2- diaza-1,3-butadienes. During the thesis work are developed different methods for the synthesis of mono and polyheterocyclic systems containing nitrogen such as pyrazole, pyridazines, imidazoles, pyrroles, triazoles, triazepines, pyrrolidines and polycyclic heteroarenes. DDs are eterodieniche molecules characterized by the presence of a C = C double bond conjugated with a double bond N = N, a characteristic that makes them both the excellent Michael acceptors and therefore susceptible to nucleophilic attack, that dienes or dienophiles particularly reactive in reactions of cycloaddition. The 1,2-diaza-1,3-dienes, generated in situ by dehydrohalogenation reaction from the corresponding α- halogen-N-EWG hydrazones, have been used in annulation of type [4 + 1] and [4 + 2]. In a first job, In situ derived acyclic and cyclic 1,2-diaza-1,3- dienes (DDs) were engaged in interceptive [4+1] annulation strategy with diazo esters (DEs). The catalytic activity of inexpensive copper(II) chloride allows the direct synthesis of mono-, bi-, and tricyclic 4,5-dihydropyrazole-5-carboxylic acid derivatives in a process that circumvents the use of an anhydrous and inert atmosphere Another study explains the synthesis of 5- Methylene-6-methoxy-1,4,5,6-tetrahydropyridazines derivatives, regioselective inverse-electron-demand hetero-Diels–Alder reaction of in situ generated 1,2- diaza-1,3- dienes with methoxyallene is reported. These Lewis and Brønsted acid free reactions benefit from operational simplicity and allow access to synthetically valuable 5-methylene-6- methoxy-1,4,5,6- tetrahydropyridazines in high yields. Continuing to investigate the reactivity of 1,2-diaza-1,3-dienes we went to test their reactivity for the synthesis of pyrazoles derivatives. The base (NaH)-promoted Michael addition of N-arylhydrazones (AHs) with 1,2-diaza-1,3- dienes (DDs) produces unprecedented β-azohydrazone adducts. Strategically, the use of AHs as acyl anion equivalents and DDs as α-electrophiles of carbonyl compounds open the way to two important classes of pyrazole compounds. Another study focused on Synthesis of indole-imidazoles, indole-pyrroles and idole triazoles derivatives. The rapid and expedient assembly of three new classes of biheterocycles of biological interest, viz. indole– imidazoles, indole–pyrroles and indole–triazoles was accomplished using different combinations of tryptamines, 1,2-diaza-1,3-dienes, aldehydes, and/or alkynes as readily available building blocks. Twenty- six derivatives were thus prepared in excellent yields (up to 100 %). The products were screened for invitro biological studies. Some of these revealed promising anticancer activity against MCF7 and Caco-2 human tumor cell lines. The multicomponent 1,3-dipolar cycloaddition of different 1,2-diaza-1,3-dienes with in-situ-generated azomethine ylides produces 1,2,4-triazepines or pyrrolidines by [3+4] or [3+2] cycloadditions, respectively. The regioselectivity is controlled by the electron-withdrawing group bound to the azomoiety of the 1,2- diaza-1,3-diene, which promotes exclusively the [3+4] cycloaddition. When the electron-withdrawing group is replaced with a phenyl group, only a [3+2] cycloaddition occurs. Finally, A protocol for the direct construction of valuable polycyclic heteroarene scaffolds has been developed by using a palladium catalyst. From a retrosynthetical point of view, the strategic formation of a C-C bond via cross-dehydrogenative coupling (CDC) a cross biheterocyclic precursors may beuseful in de novo syntheses of indole-derived natural products and pharmaceuticals. In conclusion we have been developed of the new methodologies for the synthesis of new and interesting systems mono, bi and poly heterocycles through the use of 1,2-diaza systems, 1-3 dieneI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
