The hydrobromide of 3-carbomethoxy-trans-3, 5-dimethyl-Δ¹-pyrazoline, C₇H₁₃N₂O₂Br, crystallises in the monoclinic system with a = 8.28, b = 10.31, c = 13.92Å and β = 122.4°. The space group is P2₁/c and there are four molecules per unit cell, thus each molecule forms an asymmetric unit in the cell. The intensities of 580 reflections were estimated from films exposed to CuK α radiation. The structure determination was based on the heavy atom Patterson and Fourier methods and least squares refinement. The final discrepancy, R, for the 409 observed reflections is 0.116. The compound was found to contain a bromide ion and a cation with no double bond, with a trigonal C(5) atom, and a positive charge distributed between N(1) and C(5). The five-membered ring is non-planar with N(2) displaced 0.32 Å from the plane of the remaining four atoms, or N(1) and N(2) displaced above and below the plane of the three carbon atoms and the methyl group on C(5) lying almost on these planes. All other molecular dimensions are normal. The shortest intermolecular approach is a C(5)...O(3) distance of 2.76 Å, which results from the attraction between the positively-charged carbon and the relatively negative oxygen. The shortest approach involving a bromide ion is a Br⁻•••H-N(2) hydrogen bond of 3.22 Å; the next shortest approach is a Br⁻•••N(2) distance of 3.31 Å. The other intermolecular distances are normal. / Science, Faculty of / Chemistry, Department of / Graduate

A series of pyrazolines having a carbomethoxy group on C-3 and a bridge (number of the carbon atoms = 3, 4, 5) connecting C-3 and C-4 was synthesized and studied. l-Carbomethoxy-2,3-diazabicyclo (3.3.0)oct-2-ene-5d₁ was also prepared and the overall deuterium kinetic isotope effect determined. The calculations concerning the specific deuterium kinetic isotope effects for the different processes involved in the thermolysis led to values similar to those obtained from other experiments with the exception of that for cyclopropane formation which was found to have a "inverse" isotope effect (kH/kD = 0.71). 3-tert-Butyl-3-carbomethoxy-1-pyrazoline was synthesized and its thermal and photo decomposition studied. The effect of the size of the ester group on product distribution was also examined by undertaking a product study on 3-methyl-3-carbethoxy-1-pyrazoline and 3-methyl-3-carbo-tert-butoxy-1-pyrazoline. cis- and trans-3-Methyl-3-carbomethoxy-l-pyrazoline-4d₁ and trans-3-methyl-carbethoxy-1-pyrazoline-4d₁ were prepared. Kinetic studies were done on the trans isomers and the specific deuterium kinetic isotope effects were calculated from the measured overall kinetic isotope effects. The n.m.r. studies of 1-methyl-l-carbomethoxy-cyclopropane-2d₁ obtained by both the thermal and sensitized photo-decomposition of cis- and trans-3-methyl-3-carbomethoxy-l-pyrazoline-4d₁ revealed that each of the samples isolated (collected from the gas chromatograph) from the four decomposition products contained equal amounts of cis- and trans-1-methyl-1-carbomethoxycyclopropane- 2- d₁. Especially these results, but also the thermal and photo-decomposition of cis- and trans-3-methyl-4-tert-butyl-3-carbomethoxy-l-pyrazolines, suggested that the cyclopropane formation occurred via a diradical intermediate in which the free rotation about the carbon-carbon bond would be reduced or prevented by bulky substituents. The formation of deuterated β,ƴ -olefinic esters and ethyl and methyl angelate-4d₁ as well as ethyl and methyl tiglate-3d₁ from the trans-isomers corroborated McGreer's suggestion for stereospecific olefin formation. Kinetic and product studies done on a series of cis- and trans- 3- methyl-4-alkyl-3-carbomethoxy-l-pyrazolines (alkyl = isopropyl, isobutyl and tert-butyl) provided additional proof for stereospecific olefin formation and also substantiated the idea of restricted or prevented rotation about the carbon-carbon bond in the 1,3-diradical intermediate. Since both cis- and trans-3-methyl-4-tert-butyl-3-carbomethoxy-l-pyrazolines gave only cyclopropane product upon thermolyses in contrast to most pyrazolines it became possible to undertake a direct measurement of the secondary g deuterium kinetic isotope effect for cyclopropan formation. / Science, Faculty of / Chemistry, Department of / Graduate

Thesis (Ph.D.)--Boston University / [delta]'-Pyrazolines were prepared in which one or more of the groups R, Rl, R2, R3 are alkyl or phenyl and the other groups are hydrogen. In addition, the molecule was modified by the use of four other activating groups in the place of the carboxyl group, i.e. -CN, -CONH2 , -COCH3, and -No2. The compounds were decomposed thermally and the kinetics of the decomposition was followed by measuring the volume of nitrogen evolved as a function of time. From the data obtained, the rate constants and energies of activation were calculated. The purpose of the investigation was to determine the effects upon the rate constants and energies of activation produced by the alteration of the molecule at the above-indicated positions. The pyrazolines were prepared by the addition of diazomethane to the appropriate olefin, or by the addition of the appropriate diazoalkane to ethyl methacrylate. [TRUNCATED]

The kinetics for the liquid-phase thermal decomposition of a number of 1-pyrazolines have been determined. Factors determining the relative rates of decomposition were: i) the nature of the polar substituent at the C-3 position; ii) the position and stereochemistry of alkyl substitution on positions C-4 and C-5; and iii) the polarity of the solvent employed. The pyrolysis rates were found to increase with the increasing electron-withdrawing ability of the C-3 substituent. Alkyl substitution at C-4 decreased the rate of pyrolysis relative to hydrogen at C-4 but this decrease also depended on the stereochemistry of the C-4 substituted pyrazoline. Alkyl substitution at C-5 increased the rate of pyrolysis relative to hydrogen at C-5 but the stereochemistry of substitution at C-5 had little effect on the rates. A drastic polarity increase upon going from n-butyl phthalate to formamide solvent decreased the rate of pyrolysis of 3-cyano and 3-carbomethoxy substituted 1-pyrazolones by a factor of about two. However, the rate of pyrolysis of 3-acetyl substituted 1-pyrazolines was increased by a factor of about two upon going from n-butyl phthalate to formamide solvent. These results are discussed in relation to the current views on pyrazoline pyrolysis. Deuterium substitution at the C-5 position was found to decrease the pyrolysis rate due to a secondary deuterium kinetic isotope effect. A comparison of the magnitudes of these effects with those found for similar systems indicated that there is considerable breakage of the C (5)-N bond in the transition states for pyrolysis in both n-butyl phthalate and formamide solvents. Deuterium substitution at C-5 had very little effect on the product distribution. A pyrazoline with deuterium at the C-4 position was prepared, 3-mothyl-: 3-carbomethoxy- 1-pyrazolone-4, 4-d₂, The product distribution, compared to the natural compound, showed that olefin formation was decreased due to the deuterium substitution. The kinetic isotope effect on the rate of pyrolysis was found to be 1. 36 in n-butylphthalate solvent. It has been previously suggested that there may be separate transition states for olefin and cyclopropane formation. Calculations using the above isotope effect and the product distributions for the deuterated and natural pyrazoline gave a value of 1. 94 for the deuterium isotope effect on the olefin-forming reaction. This supports a mechanism for olefin formation where the migration of a C-4 hydrogen to the C-5 position is concerted with breakage of the carbon-nitrogen bond. In formamide solvent, however, the kinetic isotope effect was found to be only 1. 06. This was taken as an indication that C (4)-H bond breakage was not advanced in the transition state for pyrazoline pyrolysis in this polar solvent. However, the effect of deuterium substitution on the product distribution suggests that a nitrogen-free intermediate is formed in the rate-determining step. The deuterium isotope effect on the olefin forming step, largely primary, was estimated to be 2.2. The synthesis and decomposition products of a new pyrazoline, 3, 5, 5, -trimethyl-3-acetyl-1-pyrazoline, are described. The preparations of the deuterated pyrazolones are described and their nuclear magnetic resonance spectra arc discussed in detail. / Science, Faculty of / Chemistry, Department of / Graduate

A series of tetrasubstituted 1-pyrazolines uniquely substituted at all three carbon centers has been prepared and decomposed thermally. The 1-pyrazolines in which three of the substituents occupy a pseudo equatorial position and the remaining substituent occupies a pseudo axial position give as the major product the cyclopropane with retention of configuration. On the other hand,the 1-pyrazolines in which two substituents are pseudo equatorial and two are pseudo axial give a random distribution of cyclopropanes. Evidence is presented that the former set of pyrazolines have a larger degree of folding between the two planes defined by C-3, C-4, C-5 and C-5, N-1, N-2, C-3. This suggests that the larger the degree of folding in the pyrazoline molecule the more stereospecificity there is. Two mechanisms are proposed to account for the cyclopropane formed with retention of configuration - one involving a concerted mechanism and the other involving an intermediate resembling a pyramidal diradical. In the case of one pair of C-5 isomeric pyrazolines, the pyrazoline in which three substituents are pseudo equatorial and one is pseudo axial gave 99% cyclopropane products whereas the C-5 isomer in which there are two substituents both equatorial and axial gave 67% olefin products. This supports the mechanism involving concerted migration of the hydrogen at C-4 that is trans to the leaving nitrogen. / Science, Faculty of / Chemistry, Department of / Graduate

The thermal and photolytic decomposition of cis and trans_-3,5-dimethyl-3-acetyl-Δ¹-pyrazoline have been found to give six products. They have been separated and identified as 2,3,5-trimethyl-Δ²-dihydrofuran, cis and trans-1,2-dimethyl-1- acetyleyclopropane, cis and trans-3-methyl-3-hexen-2-one and 3-methyl-4-hexen-2-one. The formation of cyclopropanes by photolysis showed some degree of stereospecifIcity. Both pyrolysis and photolysis yielded olefins with high degree of stereospecificity. 2,3,5-TrImethyl-Δ²-dihydrofuran was a major product from the decomposition of cis-3,5-dimethyl-3-acetyl-Δ¹ -pyrazoline only. Pyrolysis gave a higher ratio of olefins to cyclopropanes than photolysis. These decomposition reactions gave results analogous to those of cis and trans-3,5-dimethyl-3-carbomethoxy-Δ¹-pyrazoline. The product compositions from both the pyrolysis and photolysis of cis and trans_-3,5-dimethyl-3-carbomethoxy-Δ¹-pyrazoline have been found to show a small and regular influence of the solvent and this has been related to the dielectric constant of the solvent. Pyrolysis and photolysis gave an olefin to cyclopropane ratio of 57:43 and 21:79, respectively, in formamide, and 7:93 and 5:95, respectively, in cyclohexane. A small kinetic solvent effect has been observed for the pyrolysis of 3,5-dimethyl-3-carboraethoxy-Δ¹-pyrazoline. The rate of pyrolysis as followed by the rate of nitrogen evolution has been found to decrease for the following series of solvents: dl-n-butyl ether, tetralin, nitrobenzene and form-amide. These rates were all within a factor of three. The absence of rate enhancement in a solvent of high dielectric constant has been used as an argument against an ionic Intermediate in these reactions. Liquid phase photolysis of trans-3,5-dimethyl-3-carbo- methoxy-Δ¹-pyrazolIne at various temperatures ranging from -55ᵒ to 58ᵒ did not show appreciable change in the product compositions attributable to the influence of temperature. The solvent temperature therefore does not affect the amount of quenching of any "hot" intermediate. Photolysis and pyrolysis of cis and trans-3,5-dimethy1-3-carbomethoxy-Δ¹ -pyrazoline under identical conditions did not give the same product composition. This suggested the two reactions do not have a common Intermediate. No isomerization between the cis and trans-3,5-dimethyl-3-carbomethoxy-Δ¹-pyrazolines has been observed as shown by the partial pyrolysis and photolysis of the trans-pyrazoline. These results are discussed In view of current mechanistlc proposals for the pyrolysis and photolysis of Δ¹-pyrazolines. / Science, Faculty of / Chemistry, Department of / Graduate

The products arising from the liquid-phase pyrolyses of 3,5-dimethyl-3-carbomethoxy-1-pyrazoline and 4,5-dimethyl-3-carbomethoxy-2- pyrazoline have been isolated and identified. The pyrolysis of 3,5-dimethyl-3-carbomethoxy-1-pyrazoline has been found to yield a mixture of 5 isomers consisting of 15% methyl trans-2-methyl-2-pentenoate, 10% methyl cis-2-methyl-2-pentenoate, 3% methyl trans-2-methyl-3-pentenoate. 45% methyl cis-1,2-dimethylcyclopropane-1-carboxylate and 27% methyl trans-1,2-dimethylcyclopropane-1-carboxylate. The pyrolysis of 4,5-dimethyl-3-carbomethoxy-2-pyrazoline yielded a mixture of 7 isomers consisting of 25.5% methyl trans-3-methy1-2-pentenoate, 26% methyl cis-3-methyl-2-pentenoate, 3% methyl trans-3-methyl-3-pentenoate, 2% methyl cis-3-methyl-3-pentenoate, 26% methyl trans-1,2-dimethylcyclo-propane-3-carboxylate, 16% methyl cis-1,2-dimethylcyclopropane-3-trans-carboxylate and 0.8% methyl 3-ethyl-3-butenoate. Pyrolysis of both pyrazolines has also been obtained in the vapour-phase and under these conditions a higher proportion of cyclopropanecarboxylic esters was formed than that obtained in the liquid-phase pyrolysis: 3,5-dimethyl-3-carbo-methoxy-1-pyrazoline yielded a mixture containing 94.5% cyclopropane carboxylic esters and 4,5-dimethyl-3-carbomethoxy-2-pyrazoline yields a mixture containing 67% of cyclopropane carboxylic esters. The vapour-phase pyrolysis of the 1-pyrazoline occurred readily at 200° whereas the vapour-phase pyrolysis of the 2-pyrazoline was found to require a catalyst. This catalyst is believed to facilitate the transformation of the 2-pyrazoline to the readily pyrolisable 1-pyrazoline form. Studies have been made of the equilibration of the unsaturated, esters arising from the pyrolysis of the pyrazolines and have shown that the composition of the olefin portion of the pyrolysis mixture in general is not an equilibrium mixture. A mechanism for the pyrolysis is suggested. The unsaturated esters arising from the pyrolysis of 4,5-dimethyl-3-carbomethoxy-2-pyrazoline have been synthesised and identified and structural assignments have been made. / Science, Faculty of / Chemistry, Department of / Graduate

The present thesis will be largely focused on identifying and understanding the scope and mechanistic details associated with the tetrabutylammonium fluoride (TBAF) mediated cyclization of alkynyl hydrazines and (O)-hydroxylamines. Also, the synthesis of 2-(2-carboxyethyl)-4-methyl-5-propylfuran-3-carboxylic acid (CMPF) and its analogs will be discussed along with an analysis of their effects on insulin secretion. Chapter 1 will present the importance of developing isoxazoline and pyrazoline type heterocycles given that they are continually demonstrated to possess a variety of biological activities. Further, the scope of the reaction in terms of functional group tolerability, scalability and mild conditions will be shown. To expand the importance of this work, a route to access non-racemic heterocycles is also noted. With the heterocycles in hand, new methods were developed to generate more complex frameworks in the form of a novel one pot deprotection/functionalization reaction. Chapter 2 will focus on mechanistic investigations of the cyclization. From the initial discovery of the reaction, its actual mechanism was unknown and a main point of interest. What appeared unusual is that a nucleophilic attack occurs on an unactivated triple bond. Given the identity of the products, a reasonable proposal was a 5-endo-dig type cyclization. However, such a pathway would result in the generation of a vinyl anion intermediate which is well known to be of very high energy and it would seem unlikely to occur under mild conditions. Various trapping experiments were used to demonstrate that the vinyl anion forms and a 5-endo-dig-cyclization is the operative mechanism. Chapter 3 analyzes the importance of the tetrabutylammonium fluoride reagent. During optimization studies, it became clear that this base is the ideal reagent to facilitate the cyclization although other bases can also enable the transformation at much slower rates. Addition of non-basic ammonium salt additives to bases such as KF and CsF had a dramatic effect on the rate of the reaction. To determine whether the observed rate differences were merely a phase transfer effect or something more, both empirical and Raman spectroscopy data were collected. Based on this, the first evidence for an ammonium-alkyne cation-pi type interaction was shown. Chapter 4 will summarize the work on the synthesis of 2-(2-carboxyethyl)-4-methyl-5-propylfuran-3-carboxylic acid (CMPF) and its analogs in order to be used in various biological assays. The main goals were to determine a possible structure activity relationship between the substrates and insulin secretion in beta cells and also determine the fate of CMPF in vivo. Several 13C labeled analogs of CMPF were synthesized and successfully used to show for the first time that CMPF in metabolized in vivo in mice. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2017. / FAU Electronic Theses and Dissertations Collection

Ce travail s'inscrit dans le cadre d'un programme de collaboration entre l'Université Libanaise et l'université de Rennes 1. La thèse est divisée en deux parties :Chimie du fluor : synthèse de nouveaux hétérocycles portant des chaînes latérales fluorées ; chimie médicinale : recherche de nouvelles molécules à visées anticancéreuses. La première partie se compose de trois chapitres : dans le premier chapitre, des intermédiaires de synthèse de type énones fluorées ont été synthétisés par une voie originale, et leur réactivité en cyclocondensation a été étudiée pour obtenir de pyrazolines et de pyrrolines avec des chaînes latérales fluorés. Dans le deuxième chapitre, nous nous sommes intéressés à la préparation d'hétérocycles de type chroman-4-one, en utilisant les intermédiaires difluorés précédents. Dans le dernier chapitre, la réaction de Kinugasa a été appliquée pour la première fois sur des dérivés propargyliques gem-difluorés. Cette réaction nous a permis de découvrir une voie de synthèse originale à une famille de composés nouveaux, à savoir des exoalkylidène b-lactames portant un fluor en position vinylique. Dans la seconde partie, notre objectif était de restaurer les propriétés apoptotiques au sein des cellules cancéreuses afin d'obtenir de nouveaux composés à activité antitumorale. A partir de données obtenues par modélisation moléculaire, nous avons fait le design de plusieurs séries d'analogues d'un inhibiteur connu (MIM-1) de la protéine anti-apoptotique Mcl-1. Plus de 40 analogues ont été préparés et testés sur trois variétés de cellules cancéreuses (sein, ovaire et mélanome). Un certain nombre de ces composés ont présenté des activités prometteuses dans ces différents domaines. / This work is a part of a collaboration program between Lebanese University and University of Rennes 1. The thesis is divided into two parts: fluorine chemistryv : synthesis of new heterocycles bearing fluorine-containing side chains ; medicinal chemistry : research towards new anticancer molecules. The first part consists of three chapters: in the first chapter, gem-difluoro enone-type intermediates were synthesized through a new route and their cyclocondensation reactions were studied to get pyrazolines and pyrrolines with fluorinated side chains. In the second chapter, type-chroman-4-one heterocycles were prepared using the previous difluorinated intermediates. In the third chapter, the Kinugasa reaction was applied for the first time on gem-difluoro propargylic derivatives. This reaction has allowed us to discover a pathway to a new family of molecules, the fluorine-containing exoalkylidene β-lactames. In the second part, our goal was to reinduce the proapoptotic properties in cancer cells in order to obtain new antitumor compounds. Starting from data obtained through molecular modeling studies, we designed and prepared several series of analogs for a known inhibitor (MIM-1) of the anti-apoptotic protein Mcl-1. Over 40 analogs have been synthetized and screened towards three types of cancer cells (breast, ovarian and melanoma). Some of these derivatives have demonstrated promising data in these areas.

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