Thesis (Ph. D.)--University of Wisconsin--Madison, 1933. / Typescript. With this is bound: Pyrazolones derived from the carbethoxypiperidones / By S.M. Elizabeth Englert and S.M. McElvain. Reprinted from Journal of the American Chemical Society, vol. 56 (1934), p. 700-702. Includes bibliographical references (leaves 47-49).

Orientador: Fernando Antonio Santos Coelho / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-21T05:18:40Z (GMT). No. of bitstreams: 1 Correia_JoseTiagoMenezes_M.pdf: 8686931 bytes, checksum: bcb49e865e00306bf2105e6bcda93583 (MD5) Previous issue date: 2012 / Resumo: Esse trabalho é composto de dois capítulos. No primeiro relatamos nossos esforços visando descrever a primeira síntese total da (+)-Napalilactona, um nor-sesquiterpeno clorado extraído do coral Lemnalia africana. Essa substância marinha possui quatro centros estereogênicos consecutivos em sua estrutura, dois deles quaternários, sendo que um destes centros quaternários pertence também a um anel espiro. A estratégia sintética utilizou a (S)-Carvona como material de partida, de modo que foi possível, através do centro pré-existente no monoterpeno de partida, gerar o primeiro centro existente no produto natural. A partir deste centro, utilizando metodologias já bem estabelecidas na literatura, foi possível induzir a formação de dois dos três centros restantes, de modo que 78% do esqueleto carbônico do produto natural foi construído em um total de 10 etapas, com um rendimento global de 3%. Na segunda parte desse trabalho relatamos os resultados obtidos em um estudo metodológico envolvendo a reação entre a aminoguanidinina, um bis-nucleófilo polinitrogenado, e adutos de Morita-Baylis-Hillman (MBH) sililados e acetilados. Frente aos adutos de MBH sililados, as reações com a aminoguanidina conduziram, através de um processo tandem, à formação de uma mistura diastereoisomérica de pirazolidinonas sililadas em excelentes rendimentos, sendo que o diastereoisomero syn é o favorecido em todos os casos. A diastereosseletividade dessa reação variou de 2:1 a 7:1 (syn:anti). Quando investigamos o comportamento da aminoguanidina frente aos adutos de MBH acetilados, utilizando como solvente a acetonitrila, as reações com a aminoguanidina conduziram, também através de um processo tandem, à formação exclusiva de pirazolidinonas benzilidênicas, quando um aduto oriundo de um aldeído alifático ou oriundo de um aldeído aromático substituído com grupos doadores de elétrons foram utilizados. No entanto, frente a adutos oriundos de aldeídos aromáticos com grupos retiradores de elétrons, foi observada uma tendência à formação de pirazolonas, que são regioisomeros das pirazolidinonas previamente obtidas. Estes dados indicaram que, sob estas condições, a natureza do grupo substituinte rege a seletividade destas reações. Mais tarde, observou-se que, ao submetermos as pirazolidinonas a uma solução de 2 equivalentes de K2CO3 em metanol, estas poderiam ser completamente convertidas às respectivas pirazolonas. Mostrando a influência da natureza do solvente nestas transformações químicas / Abstract: This work is composed by two chapters. In the first one we disclosed our efforts towards the first total synthesis of (+)-Napalilactone, a chlorinated nor-sesquiterpene isolated from the coral Lemnalia africana. This marine natural compound has four consecutive stereogenic centers in their structure, two of them quaternaries. One of these quaternary centers belonging to a spiro ring. Our synthetic strategy started from commercially available (S)-carvone. The asymmetric center presented in this monoterpene was used to induce the first stereogenic center exhibited by the natural product. This task was accomplished by employing a sequence of well-established synthetic metodologies. This stereogenic center has induced the formation of two of the remaining three estereogenic centers. So that 78% of the carbon skeleton of the natural product has been built in a total of 10 steps with an overall yield of 3%. In the second part of this work we described the results of a methodological study envolving the reaction between aminoguanidinine, a polynitrogenated bis-nucleophile, and silylated and acetylated Morita-Baylis-Hillman adducts (MBH). The reaction of aminoguanidine with silylated MBH adducts gave, through a tandem process, a diastereoisomeric mixture of silylated pyrazolidinones in excellent yields, in which the syn diastereoisomer is favored in all cases. The diastereoselectivity of theses reactions ranged from 2:1 to 7:1 (syn:anti). When we investigated the reaction of aminoguanidine with acetylated aliphatic and eletron rich aromatic MBH adducts, using acetonitrile as solvent, the reaction afforded exclusively benzylidenic pyrazolidinones. However, when we investigated the reaction with acetylated eletron-poor aromatic MBH adducts, we observed the formation almost exclusively of pyrazolones, which are regioisomers of the previously obtained pyrazolidinones. These data indicated that under these conditions, the nature of the substituent group governed the selectivity of these reactions. Later, it was observed that by subjecting the pyrazolidinones to a solution of 2 equivalents of K2CO3 in methanol, they were completely converted to the corresponding pyrazolones, showing the influence of the nature of the solvent in these chemical transformations / Mestrado / Quimica Inorganica / Mestre em Química

Nitrogen-containing heterocyclic compounds are very important to the pharmaceutical and agrochemical industries, among others. Over the past few years, the Beauchemin group has been exploring reactivity of N-substituted isocyanates and as part of this has developed a metal-free alkene aminocarbonylation process relying on imino-isocyanates to form azomethine imines. The azomethine imines formed are interesting since they contain a cyclic β-aminocarbonyl motif. Catalysis of this reaction using basic additives allowed milder reaction conditions with electron-rich C=C bonds such as enol ethers. Efforts have also been made towards the derivatization of these azomethine imines into useful products. It was discovered that upon reduction and aromatization of azomethine imines, pyrazolones could be obtained. This is providing a novel modular approach to these compounds, which have relevance in pharmaceuticals and agrochemicals. This reactivity was extended to include imino-isothiocyanates.

First part is focused on finding suitable reaction conditions for organocatalytic domino Michael/Michael reaction of ethyl (E)-3-(2-thiophenyl)acrylate with α,β-unsaturated aldehydes. Second part deals with the preparation of pyrazolone derivatives from commercially available compounds and describes effects of various substituents in α-position on chemical efficiency and stereoselectivity of amination with azodicarboxylate catalyzed by quinine.

The thesis entitled “Design and Development of Metal-Free Cross Dehydrogenative Coupling Reactions for the construction of C-S, C-O and C-C bonds” is divided into three Chapters. Chapter 1 is presented in five parts, which reveals the cross dehydrogenative coupling (CDC) strategies for the C–S bond forming reactions through C–H functionalization strategy using heterocyclic thiols and thiones. Chapter 2 presents tetrabutyl ammonium iodide (TBAI) catalyzed chemoselective α-aminoxylation of ketones with N-hydroxyimidates using TBHP as oxidant under cross dehydrogenative coupling (CDC) strategy. Chapter 3 describes a transition metal-free Minisci reaction for the acylation of isoquinolines, quinolines, and quinoxaline. Chapter 1 Iodine Promoted C-S Bond Forming Reactions using Dimethyl Sulfoxide as an Oxidant Chapter 1 reveals the utility of cross dehydrogenative coupling (CDC) reactions for the formation of C–S bonds by employing C–H functionalization strategies.1 The direct functionalization of C–H bonds to form C–C and C–X (N, O, S and P) bonds using metal-free reaction conditions is an interesting research topic in recent years.2 Use of dimethyl sulfoxide as an oxidant is emerging as one of the research topics of great interest and utility.3 Heterocyclic thiols and thiones are important precursors for synthesizing a variety of pharmaceuticals and biologically active compounds.4 Therefore it is useful to develop CDC reactions using heterocyclic thiols and thiones as precursors. In this chapter, we describe CDC reactions of heterocyclic thiols and thiones for the sulfenylation of ketones, aldehydes, α, β unsaturated methyl ketone derivatives, pyrazolones, enaminones and imidazoheterocycles using DMSO as an oxidant Chapter 1: Part 1 Iodine Promoted Regioselective α-Sulfenylation of Carbonyl Compounds using Dimethyl Sulfoxide as an Oxidant: In this chapter, a rare regioselective C–H sulfenylation of carbonyl compounds with heterocyclic thiones and thiols have been described using iodine and dimethyl sulfoxide as reagents. Thus, dimethyl sulfoxide (as an oxidant) and stoichiometric amount of iodine have been used for the sulfenylation of ketones using heterocyclic thiones. Whereas the sulfenylation of ketones with heterocyclic thiols required catalytic amount of iodine. This protocol offers a rare regioselective sulfenylation of (i) methyl ketones in the presence of more reactive α-CH2 or α-CH groups, and (ii) aldehydes under CDC method. A few representative examples are highlighted in Scheme 1.5 The application of this methodology has been demonstrated by synthesizing a few precursors for Julia-Kocienski olefination intermediates. Scheme 1. Iodine promoted rare regioselective α-sulfenylation of ketones and aldehydes Siddaraj , Y.; Prabhu, K. R. Org. Lett. 2016, 18, 6090 Chapter 1: Part 2 Regioselective Sulfenylation of α’-CH3 or α’-CH2 Groups of α, β Unsaturated Ketones using Dimethyl Sulfoxide as an Oxidant: In this chapter, an interesting regioselective sulfenylation of α’-CH3 or α’-CH2 groups of α, β unsaturated ketones using dimethyl sulfoxide as an oxidant and catalytic amount of aq. HI (20 mol %) as an additive has been described. This eco-friendly method uses readily available, inexpensive I2 or HI and DMSO. This methodology exhibits a high regioselectivity without forming Michael addition product in the presence of strong acid such as aq. HI or iodine, which is difficult to achieve under cross dehydrogenative coupling (CDC) conditions. Current methodology exhibits a broad substrate scope. A few examples are shown in Scheme 2.6 Scheme 2. HI and DMSO promoted α’-sulfenylation of α, β unsaturated ketones Siddaraju, Y.; Prabhu, K. R. (Manuscript submitted) Chapter 1: Part 3 Iodine Catalyzed Sulfenylation of Pyrazolones using Dimethyl Sulfoxide as an Oxidant: In this chapter, a sustainable and efficient strategy for the sulfenylation of pyrazolones has been described using metal-free conditions by employing DMSO as an oxidant and iodine as a catalyst. A variety of heterocyclic thiols, heterocyclic thiones and disulfides undergo C–H functionalization reaction with pyrazolone derivatives furnishing the corresponding sulfenylated products in short time. Most of the products are isolated in pure form without column purification. A few examples are presented in Scheme 3.7 Scheme 3. Iodine promoted sulfenylation of pyrazolones Siddaraju, Y.; Prabhu, K. R. Org. Biomol. Chem. 2017, 15, 5191 Chapter 1: Part 4 Iodine-Catalyzed Cross Dehydrogenative Coupling Reaction: Sulfenylation of Enaminones using Dimethyl Sulfoxide as an Oxidant: In this chapter, synthesis of poly functionalized aminothioalkenes has been described using substoichiometric amount of iodine and DMSO as an oxidant. This metal-free methodology enables a facile sulfenylation of enaminones with heterocyclic thiols and thiones. This methodology is one of the simple approaches for the sulfenylation of enaminones under cross dehydrogenative coupling method. A few examples are highlighted in Scheme 4.8 Scheme 4. Cross-dehydrogenative coupling approach for sulfenylation of enaminones Siddaraju, Y.; Prabhu, K. R. J. Org. Chem. 2017, 82, 3084 Chapter 1: Part 5 Iodine-Catalyzed Cross Dehydrogenative Coupling Reaction: A Regioselective Sulfenylation of Imidazoheterocycles using DMSO as an Oxidant: In this chapter, a simple synthetic approach for the regioselective sulfenylation of imidazoheterocycles using iodine as a catalyst and DMSO as an oxidant under cross dehydrogenative coupling (CDC) reaction conditions has been demonstrated. This protocol provides an efficient, mild and inexpensive method for coupling heterocyclic thiols and heterocyclic thiones with imidazoheterocycles. This is the first report on sulfenylation of imidazoheterocycles with heterocyclic thiols and heterocyclic thiones under metal-free conditions. A few examples are shown in Scheme 5.9 Scheme 5. Cross-dehydrogenative coupling approach for sulfenylation of imidazoheterocycles Siddaraju, Y.; Prabhu, K. R. J. Org. Chem. 2016, 81, 7838 Chapter 2 Chemoselective α-Aminoxylation of Aryl Ketones: Cross Dehydrogenative Coupling Reactions Catalyzed by Tetrabutyl Ammonium Iodide: In this chapter, chemoselective α-aminoxylation of ketones with N-hydroxyimidates catalyzed by tetrabutyl ammonium iodide (TBAI) has been presented. The coupling reaction of a variety of ketones with N-hydroxysuccinimide (NHSI), N-hydroxyphthalimide (NHPI), N-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) using TBHP as oxidant has been investigated. This α-aminoxylation of ketones is chemoselective as aryl methyl ketones, aliphatic ketones as well as benzylic position are inactive under the reaction condition. A few examples are highlighted in Scheme 6.10 The application of this method has been demonstrated by transforming a few coupled products into synthetically useful vinyl phosphates. Scheme 6. Chemoselective α-aminoxylation of ketones with N-hydroxyimidates Siddaraju, Y.; Prabhu, K. R. Org. Biomol. Chem. 2015, 13, 11651 Chapter 3 A Transition Metal-Free Minisci Reaction: Acylation of Isoquinolines, Quinolines, and Quinoxaline: In this chapter, transition metal-free acylation of isoquinoline, quinoline and quinoxaline derivatives with aldehydes has been described by employing TBAB (tetrabutyl ammonium bromide, 30 mol %) and K2S2O8 as an oxidant under cross dehydrogenative coupling (CDC) reaction. This intermolecular acylation of electron-deficient heteroarenes provides an easy access and a novel acylation method of heterocyclic compounds. The application of this CDC strategy has been illustrated by synthesizing isoquinoline-derived natural products. A few representative examples are shown in Scheme 7.11 Scheme 7. CDC reactions of heteroarenes with aldehydes Siddaraju, Y.; Lamani, M.; Prabhu, K. R. J. Org. Chem. 2014, 79, 3856