Neste trabalho foram aprofundados nossos estudos para obtenção da (S)-2-terc-butilamida-4-(3-picolil)piperazina, pela abertura da (S)-2-terc-butilcarboxamida-N-p-tosilaziridina seguida de ciclização, em 78% de rendimento, com o triflato de vinildifenilsulfônio. A aziridina foi preparada por um processo de ciclização, em condições de transferência de fase, partindo-se da L-serina, um aminoácido natural de baixo custo. Esta rota sintética rendeu um material que apresenta a mesma estereoquímica S do fragmento piperazínico usado na síntese do Indinavir, podendo vir a constituir uma via alternativa para a obtenção deste fármaco. / In this work we performed a deeper study for obtaining (S)-2-tert-butylamide-4-(3-picolyl)piperazine by opening (S)-2-tert-butylcarboxamide-N-p-tosylaziridine followed by cyclization, in 78% yield, with diphenylvinylsulfonium trifluoromethanesulfonate. The aziridine were prepared by a cyclization process in phase transfer conditions, starting from L-serine, a low cost amino acid. This synthetic route yielded a material which has the same S piperazinic fragment stereochemistry used in the synthesis of Indinavir, and may constitute an alternative route for obtaining this drug.

No description available.

Nucleophilic substitution reactions of alkylamines, cyclic alkylamines, and hydroxyalkylamines with 5-substituted-1,4-naphthoquinones have been studied. It has been found that the nature of the solvent employed in the reaction influences the position of mono-substitution at either the 2- or 3-position. Although both regioisomers were produced in all the reactions, protic polar solvents favoured the formation of the 3-regioisomer, whereas non-protic solvents favoured the formation of the 2-regioisomer. It has also been found that formation of 2,3-diaminoalkyl derivatives is normally unlikely. A series of hydroxyalkylamino-1,4-naphthoquinones were also synthesised. The collision-induced dissociation mass spectra of protonated hydroxyalkylamino-1,4- naphthoquinones showed fragmentation patterns which were dependent on the nature and length of the side chain and the presence and nature of the adjacent group on the 3-position on the 1,4-naphthoquinone ring. A total of 27 novel compounds were synthesised during the course of this research, the structures of which were confirmed via 1D and 2D NMR spectroscopy, mass spectrometry (ESI), IR spectroscopy and high resolution mass spectrometry (HRESIMS and HREIMS).

The thesis entitled “Chemistry of Tetrathiomolybdate and Tetraselenotungstate: Studies on Aziridine and Epoxide Ring Opening Reactions” is divided into five chapters. (For Formulas and Equations Refer PDF File) Chapter 1: Part 1: Synthesis of β-Sulfonamidodisulfides and β-Sulfonamidosulfides using Benzyltriethylammonium Tetrathiomolybdate In this chapter, a comprehensive study of general and effective one step procedure for the synthesis of β-sulfonamidodisulfides directly from optically pure N-tosyl aziridines using benzyltriethylammonium tetrathiomolybdate [BnEt3N]2MoS4 as sulfur transfer reagent in a regio manner under neutral conditions without the use of any Lewis acid or base has been reported. Additionally, we have demonstrated regio- and stereospecific ring opening of di- and trisubstituted aziridines using [BnEt3N]2MoS4 to synthesize substituted β-sulfonamidodisulfides in good yields. This methodology is extended to the synthesis of an optically pure unnatural amino acid with the disulfide bridge and a cyclic seven membered disulfide. Synthesis of a variety of β-sulfonamidosulfides involving cleavage of disulfide bonds assisted by tetrathiomolybdate and the use of masked thiolate for the synthesis of β-sulfonamidosulfides involving multi-step reactions in a one pot is also demonstrated. Chapter 1: Part 2: Synthesis of β-Sulfonamidodiselenides using Tetraethylammonium Tetraselenotungstate In this chapter, we report the results of regio- and stereospecific, nucleophilic ring opening of chirally pure N-tosyl aziridines with tetraethylammonium tetraselenotungstate [Et4N]2WSe4 as selenium transfer reagent to afford a number of β- sulfonamidodiselenides in good yields. Using this methodology, carbohydrate derived β- sulfonamidodiselenides from the corresponding carbohydrate derived aziridines have been synthesized. These enantiopure diselenide derivatives have the potential to be used as chiral ligands in diethyl zinc addition to aldehydes. Chapter 2: Ring Opening of Aziridine/Epoxide, Disulfide Formation, Reduction of Disulfide Bond and Michael Reaction In this chapter, we report a systematic study of tetrathiomolybdate mediated tandem regio- and stereospecific ring opening of aziridines, disulfide formation, in situ reduction of disulfide bond followed by Michael reaction in an one pot operation to give a variety of β-sulfonamidosulfides in good yields. The main advantage of this methodology is that four reactions involving three components take place in a one-pot operation. Chapter 3: Part 1: New Thia-aza Payne type Rearrangement Mediated by Benzyltriethylammonium Tetrathiomolybdate In this chapter, reaction of aziridinemethanol sulfonate esters with tetrathiomolybdate to give thiirane derivatives as the major product and cyclic disulfides as minor product under mild reaction conditions via an unprecedented thia-aza-Payne type rearrangement have been presented. Interestingly, when the reaction of tetrathiomolybdate was carried out with 2-aziridino-cyclohexanol derivatives it resulted in the formation of thia-bicyclo[3.1.1]heptane or dithia-bicyclo[3.2.1]octane derivatives. Chapter 3: Part 2: New selena-aza Payne Type Rearrangement Mediated by Tetraethylammonium Tetraselenotungstate In this chapter, reaction of tetraselenotungstate with simple N-tosyl aziridinemethanol tosylates to give allyl amine derivatives as the only product via an unprecedented selena-aza-Payne type rearrangement is discussed. When the methodology is extended to disubstituted N-tosyl aziridinemethanol tosylates, regio- and stereospecific ring opening of aziridines occurs to afford allyl amine derivatives as the major products and cyclic five membered diselenides as the minor products in good yields. Chapter 3: Part 3: Synthesis of Sulfur and Selenium Heterocycles by Azirdine Ring Opening followed by Cyclization In this chapter, studies on the synthesis of sulfur and selenium-heterocycles by aziridine ring opening followed by cyclization of N-tosyl aziridino-ethanol tosylates using tetrathiomolybdate as a sulfur transfer reagent and tetraselenotungstate as a selenium transfer reagent respectively are presented. Chapter 4: Tetrathiomolybdate Mediated Ring Opening of bis-Aziridines, bis-Epoxides and Aziridino-epoxides In this chapter, studies on the synthesis and ring opening of bis-aziridines, bis-epoxides and aziridino-epoxides with tetrathiomolybdate as the sulfur transfer reagent are presented. This has resulted in the synthesis of optically active sulfur heterocycles ranging from three membered to eight membered ring systems with excellent stereo and regio- control in good yields. Chapter 5: Part 1: Synthesis of Conformationally Locked, Bridged, Bicyclic Mono and Disulfides In this chapter, work related to the synthesis of conformationally locked bridged bicyclic disulfides and sulfides from cis-aziridino-epoxides by ring opening of both aziridines and epoxides in a tandem fashion using tetrathiomolybdate as a sulfur transfer reagent has been discussed. Comparative studies on the behavior of conformationally locked disulfides which has the dihedral angle close to zero (φ = 0) with disulfides having larger dihedral angles (φ>90) have been presented in this chapter. Some correlations have been made on the physicochemical characteristics of the disulfides with change in the dihedral angles. Chapter 5: Part 2: Synthesis of Conformationally Locked, Bridged, Bicyclic Diselenides In this chapter, work related to the development of a general synthetic methodology for the synthesis of conformationally locked, bridged diselena-bicyclo[3.2.1]octane skeleton by regio- and stereospecific, tandem nucleophilic ring opening of cis-1,4-aziridino-epoxides with tetraselenotungstate in one-pot are presented. To compare the behavior of conformationally locked diselenides which has the dihedral angle close to zero (φ = 0) with diselenides having larger dihedral angles (φ > 90), we have synthesized the acyclic diselenide (see chapter 1.2) and cyclic diselenide by regio- and stereospecific ring opening of simple aziridine and bis-aziridine respectively with tetraselenotungstate. Some correlations have been made on the physicochemical characteristics of the diselenides with change in the dihedral angles.

<div>The first chapter reports a study of aryl nitrene intermediates. Although extensively studied over the past 30 years, phenyl nitrenes have a propensity to undergo rearrangement reactions and form polymeric tars. This is in stark contrast to the phenyl carbenes which are known to undergo several important reactions to produce a library of useful organic compounds. One such reaction is the insertion of phenyl carbenes into a double bond to produce a cyclopropane moiety. If aryl nitrenes can be exploited to conjure a similar reactivity, they would be an excellent synthetic route to produce aziridine rings which are a crucial component of many natural products. This review chapter is a collection of all the efforts that have been made in this regard.</div><div><br></div><div>In the next chapter, the electronic effect of the azide functional group on an aromatic system has been investigated by using Hammett-Taft parameters obtained from the effect of azide-substitution on the gas-phase acidity of phenol. Gas-phase acidities of 3- and 4-azidophenol have been measured by using mass spectrometry and the kinetic method and found to be 340.8 ± 2.2 and 340.3 ± 2.0 kcal/mol respectively. The relative electronic effects of the azide substituent on an aromatic system have been measured by using Hammett-Taft parameters. The σF and σR values are determined to be 0.38 and 0.02 respectively, consistent with predictions based on electronic structure calculations. The values of σF and σR demonstrate that azide acts an inductively withdrawing group but has negligible resonance contribution on the phenol. In contrast, acidity values calculated for substituted benzoic acids gives values of σF = 0.69 and σR = -0.39, indicating that the azide is a strong  donor, comparable to that of a hydroxyl group. The difference is explained as being the result of “chimeric” electronic behavior of the azide, similar to that observed previously for the n-oxide moiety, which can be more or less resonance donating depending on the electronic effects of other groups in the system.</div><div><br></div><div>Phenyl nitrenes undergo bimolecular chemistry under very specific circumstances. For example, having an oxide substituent at the para position of the phenyl ring enables the formation of an indophenol product from a photocatalyzed reaction of the nitrene. Although, this reaction has been reported before, the mechanism involved in this reaction has not been fully understood. A two-electron mechanism involving electrophilic aromatic substitution reaction has been proposed in the literature, however we found evidence that did not support this theory. Instead, we find this reaction analogous to the popular Gibbs’ reaction whose single electron transfer mechanism has been extensively studied. The following chapter encompasses a study of the mechanism of the photolysis reaction to look for evidence of a single electron transfer similar to the Gibbs’ reaction.</div><div><br></div><div>As mentioned earlier, phenyl nitrenes have a proclivity to undergo rearrangement reactions instead of exhibiting bimolecular reactivity that can lead to useful products. One of the strategies to overcome this challenge is to spatially separate the two electrons of an open-shell singlet nitrene so as to minimize electron-electron repulsion. This separation can be achieved by delocalizing the individual electrons over multiple aromatic rings and heteroatoms which can act as radical stabilizers. In this chapter, a short review of literature that sets precedence for developing a unique heteroatom containing aromatic backbone to achieve the necessary stabilization is presented. Our efforts in synthesizing the model azide precursor compound have also been discussed.</div>

This thesis deals with the development of new reaction methodology as well as stereochemical investigations. The first part concerns the investigation of 1,2- and merged 1,2- and 1,3- asymmetric induction in Mukaiyama aldol additions to α-heteroatom and α,β- heteroatom substituted aldehydes respectively. In particular, the unexpected 1,2-syn selectivity obtained in the addition of sterically hindered nucleophiles to α-chloroaldehydes is examined, and an explanation for the observed stereochemical trends is proposed. The second part describes the development of a novel entry to α-amino-β- hydroxy esters by a 1,3-dipolar cycloaddition reaction of aldehydes and azomethine ylides, generated by thermolysis of aziridines. The third part deals with our efforts to develop a novel entry to vicinal all- carbon quaternary centers, based on an intramolecular domino Heck- carbonylation reaction using tetrasubstituted olefins. / QC 20120611

Nucleophilic substitution reactions of alkylamines, cyclic alkylamines, and hydroxyalkylamines with 5-substituted-1,4-naphthoquinones have been studied. It has been found that the nature of the solvent employed in the reaction influences the position of mono-substitution at either the 2- or 3-position. Although both regioisomers were produced in all the reactions, protic polar solvents favoured the formation of the 3-regioisomer, whereas non-protic solvents favoured the formation of the 2-regioisomer. It has also been found that formation of 2,3-diaminoalkyl derivatives is normally unlikely. A series of hydroxyalkylamino-1,4-naphthoquinones were also synthesised. The collision-induced dissociation mass spectra of protonated hydroxyalkylamino-1,4- naphthoquinones showed fragmentation patterns which were dependent on the nature and length of the side chain and the presence and nature of the adjacent group on the 3-position on the 1,4-naphthoquinone ring. A total of 27 novel compounds were synthesised during the course of this research, the structures of which were confirmed via 1D and 2D NMR spectroscopy, mass spectrometry (ESI), IR spectroscopy and high resolution mass spectrometry (HRESIMS and HREIMS).

Le développement de nouvelles méthodologies de synthèse toujours plus efficaces, sélectives et éco-compatibles apparaît comme un défi permanent tant l’intérêt suscité pour les composés hétérocycliques est important. Ce projet de thèse s’articule autour de plusieurs axes dans ce domaine.Tout d’abord, nous avons exploité la réactivité des N-(sulfonyl) et N-(sulfamoyl)aziridines en tant que précurseurs de dipôles 1,3 en vue de préparer divers 1-azaspiro[5.n]alcanes. L’étude mécanistique de cette réaction de cycloaddition [3+2] réalisée par calculs DFT permet de montrer que l’étape cinétiquement déterminante de la réaction est la formation du dipôle 1,3 ; la force motrice étant la fermeture du cycle à cinq chaînons.Nous nous sommes également attachés à valoriser le savoir-faire du laboratoire dans le domaine des transferts catalytiques de nitrènes (aziridination et amination C-H) dans le cadre du projet de synthèse totale de la pactamycine, aminocyclopentitol hautement fonctionnalisé.Par ailleurs, la mise au point d’une cascade Passerini-Smiles/Réduction/Cyclisation et d’une séquence monotope Passerini-Double-Smiles/SNAr permet un accès rapide et efficace à des motifs hétérocycliques de type 1,4-benzoxazin-3-ones. Conduisant à des familles régioisomères de produits, ces deux voies de synthèse se sont avérées complémentaires.Parallèlement, une nouvelle méthodologie basée sur l’ouverture pallado-catalysée de thiocyclopropanes a permis d’obtenir de nouveaux hétérocycles de type thiochromènes. Compte tenu des nombreuses fonctionnalisations envisageables, ces composés semblent très prometteurs dans le domaine de la chimie hétérocyclique.Enfin, des études électrochimiques et RMN couplées à des calculs DFT ont été entreprises afin d’élucider le mécanisme mis en jeu lors des couplages pallado-catalysés entre un halogénure d’aryle, un isonitrile et un nucléophile. / The development of new and more efficient synthetic methodologies, selective and eco-friendly seems to be an ongoing challenge as the interest in the heterocyclic compounds is important. All the studies performed during the last three years are divided in several axes in this field.First, the reactivity of N-(sulfonyl) and N-(sulfamoyl) aziridines as precursors of 1,3-zwitterionic species was explorated in order to obtain various 1-azaspiro[5.n]alkanes. The mechanism of the reaction has been studied by DFT calculations. The initial formation of the zwitterionic 1,3-dipole has been found to be the rate-determining step whereas the five-membered ring closure appeared to be the driving force.We tried to apply our expertise in the field of catalytic nitrene transfers (aziridination and C-H amination) to the total synthesis of pactamycin, highly functionalized aminocyclopentitol compound.Furthermore, the developments of a Passerini-Smiles/reduction/cyclization cascade and of a one-pot Passerini-Double-Smiles/SNAr sequence provide straightforward and efficient accesses to 1,4-benzoxazin-3-ones. These paths are complementary as they lead to regioisomers.Meanwhile, a new methodology based on Pd-catalyzed thiocyclopropanes ring opening gave thiochromenes. Due to their high synthetic potential, these compounds appear to be very promising scaffolds in heterocyclic chemistry.Finally, electrochemical and NMR studies coupled with DFT calculations have been done in order to elucidate the mechanism involved in the Pd-catalyzed couplings between an aryl halide, an isocyanide and a nucleophile.

O objetivo principal deste trabalho foi a investigação da viabilidade de uma nova rota sintética para a obtenção do fármaco Baclofen em sua forma enantiopura. A etapa principal da rota sintética por nós proposta consiste na síntese de uma aziridina de estereoquímica cis, utilizando uma nova metodologia, desenvolvida em nosso laboratório pelo emprego da catálise de transferência de fase (CTF). Para a obtenção da aziridina apropriada, tornou-se necessário preparar de maneira estereosseletiva, a (2S, 3R)-(4-clorofenil)-serina. Este precursor seria adequado, uma vez que, em estudos preliminares, verificamos que o fechamento do aziridínico ocorre sem racemização dos estereocentros presentes na molécula. Inicialmente, tentamos obter o &#946;-hidróxi-&#945;-aminoácido desejado pela reação de adição aldólica de uma imina do éster terc-butílico da glicina com o 4-clorobenzaldeído, em condições de catálise de transferência de fase assimétrica. Tais reações não apresentaram estereosseletividade. Porém, apesar de gerarem dois produtos diastereoméricos racêmicos, estes são de interesse, uma vez que um deles é uma oxazolidina cis inédita. Para a obtenção da (2S, 3R)-(4-clorofenil)-serina, optamos pelo emprego de uma metodologia alternativa, que consistiu em efetuar a reação aldólica do p-clorobenzaldeído com a glicina, sob a forma de um complexo de quiral de níquel (II). Uma vez obtido o ß-hidróxi-&#945;-aminoácido, efetuamos a reação de aziridinização, seguida da abertura do anel heterocíclico com malonato de dietila, o que resultou na obtenção da (2S,3R) 4-carboetóxi-3-(4-clorofenil)-1-tosil-piroglutamato de metila, que consiste em uma mistura de diastereoisômeros, mas de estereoquímica definida nos carbonos 2 e 3. A hidrólise dos grupos ésteres deste composto, seguida de mono-descarboxilação do diácido resultante, conduziu ao ácido 3-(4-clorofenil)-1-tosil-piroglutâmico opticamente ativo, em 17% a partir da aziridina. As etapas finais de transformação de transformação deste intermediário no fármaco Baclofen não foram efetuadas. No entanto, consistem em reações bem descritas na literatura e freqüentemente utilizadas em outras rotas visando a síntese do mesmo fármaco. / In this work, the feasibility of a new synthetic route to Baclofen was investigated. The starting material, a cis-aziridine, was prepared by ring closure of (2S,3R)-(4-clorophenyl)- serine, under phase transfer conditions (PTC). As for the preparation of the required ß- hydroxy-&#945;-aminoacid, two alternative synthetic strategies were investigated. (i) the PTC aldol addition of 4-chlorobenzaldehyde to the benzophenone imine of the tert-butyl ester of glycine, using chiral catalysts, or (ii) the aldol addition of the same aldehyde to a chiral nickel (II) complex of glycine. The first mentioned reaction failed to yield enantiomerically pure aldol adducts, although a cis oxazolidina, not yet described in the literature, could be isolated and fully characterized. Using a newly prepared nickel complex, bearing (R)-proline as ligand, (2S,3R)-(4-chlorophenyl)-serine could be prepared and subsequentely transformed into the corresponding aziridina. Ring opening of heterocycle, using diethylmalonate as nucleophile, afforded N-tosyl-4-carbethoxy-3-(4-chlorophenyl)-methyl pyroglutamate as a mixture of diastereomers but with defined stereochemistry at C-2 and C-3. Hydrolysis and mono- decarboxalation led to the corresponding N-tosyl-3-(4-chlorophenyl)-pyroglutamic acid, exhibiting optical activity. This valuable intermediate could be prepared in 17% from the starting aziridina and can be further transformed into the &#947;-aminoacid Baclofen using fully investigated and well described procedures.

No description available.