En aquest treball s'ha desenvolupat una metodologia eficaç envers la síntesi de diferents derivats pirimidínics amb un alt grau de diversitat molecular. Aquesta metodologia es basa en la S-alquilació selectiva dels 2-tiouracils (2) utilitzats com a material de partida. Aquesta reacció es realitza amb bromur de benzil quan es treballa en dissolució, o bé amb la reïna de Merrifield quan la química és sobre suport sòlid. Seguidament, s'alquila selectivament l'àtom d'oxigen de les benzilsulfanilpirimidinones (3) mitjançant la reacció de Mitsunobu, o bé utilitzant diferents halurs d'alquil en presència d'una base. Amb les 4-alcoxipirimidines (4) es realitzen diverses transformacions químiques, per exemple, addicions de Grignard, reducció i posterior metilació del grup carbonil (quan R2 = CH2COPh), etc. Posteriorment, s'oxida el grup sulfanil a sulfona utilitzant m-CPBA. Finalment es desplaça la funció sulfona amb diversos nucleòfils.Gràcies a aquesta metodologia s'han preparat diferents 2-amino-4-alcoxipirimidines (7, Nu = RR'N) en dissolució i sobre suport sòlid. Mitjançant algunes variacions s'han pogut obtenir altres derivats pirimidínics: - 4(3H)-pirimidinones 2,6-disubstituïdes (8, Nu = RR'N, ArO, RR'R''C), preparades a partir de la hidròlisi del grup alcòxid (OR5) dels compostos (7) en medi àcid.- imidazo[1,2-a]pirimidinones (9 o 10, n = 1) i pirimido[1,2-a]pirimidinones (9 o 10, n = 2). Els compostos (9) s'han obtingut selectivament a través d'una ciclació intramolecular de les pirimidines (7, Nu = aminoalcohols) utilitzant àcid sulfúric. Quan s'han ciclat els compostos (8, Nu = aminoalcohols) mitjançant una reacció de Mitsunobu intramolecular, s'han obtingut els regioisòmers (9) i (10) en diferents proporcions en funció dels grups presents en l'anell.- pirimidines funcionalitzades amb restes d'-arilglina (11). La funció arilglicina s'ha preparat mitjançant la condensació d'amines (4, R2 = CH2CHR3NHR4) amb àcid glioxàlic i àcids arilborònics (reacció de Petasis). L'oxidació del grup sulfanil dels compostos (11) a sulfona utilitzant m-CPBA ha provocat també l'oxidació de l'àtom de nitrogen de l'arilglicina.Alguns d'aquests derivats pirimidínics han mostrat ser inhibidors del Mycobacterium tuberculosis. / We have developed an efficient methodology that allows the synthesis of pyrimidine derivatives with a high degree of molecular diversity. We have shown that easily available 2-thiouracils of type (2) can be used as versatile building blocks toward the preparation of substituted 4-alkoxypyrimidine (4) through a simple O-alkylation reaction. The steric effects have a remarkable influence over the regioselectivity of the reaction, both using alkyl halides in basic conditions and with alcohols under Mitsunobu conditions. Optionally, further suitable manipulations over the substituents at the 4-position would enhance the introduction of additional diversity. Finally, oxidation of the thioether moiety to the corresponding sulfone 6 and nucleophilic displacement by different nucleophiles would produce the corresponding highly molecular diverse pyrimidines of type (7).The methodology developed in solution has been, successfully, transferred to the solid support (benzyl bromide replaced by Merrifield resin). A small library of molecularly diverse 4-alkoxypyrimidines has been prepared in parallel on solid support. The final products, 2-amino-4-alkoxypyrimidines (7), have been obtained in good overall yields.The study of the nucleophilic ipso-substitution reaction in 4-isopropoxypyrimidines (5, R5 = (CH3)2CH) has been expanded using a wide variety of nucleophiles (N-, C- and O-). The cleavage of 4-isopropoxy group afforded a collection of 2,6-disubstituted 4(3H)-pyrimidinones (8) (Figure 1).The introduction of several - and -aminoalcohols at the position 2- on the pyrimidine ring and the subsequent intramolecular cyclisation afforded different imidazo- and pyrimido[1,2-a]pyrimidinones (9 and 10). Intramolecular cyclisation of 4(3H)-pyrimidininones (8, Nu = aminoalcohols) under Mitsunobu conditions, afforded a separable mixture of the regioisomeric compounds (9) and (10) (Figure 1). Cyclisation of 4-isopropoxypyrimidines (7, Nu = aminoalcohols) with H2SO4 yielded the regioisomers (9) as the only products.Fynally, a little collection of -arylglycines linked to the pyrimidinone ring (11) (Figure 1) has been prepared using the Petasis reaction.Several pyrimidine derivatives have shown inhibitory activity against Mycobacterium tuberculosis.

No description available.

Les travaux menés au laboratoire depuis plusieurs années ont permis d'élaborer une nouvelle méthode de construction de chaînes carbonées. Son principe repose sur des additions radicalaires entre un xanthate et une insaturation. La maîtrise de telles réactions a permis l'émergence de nouvelles stratégies de synthèse. Les travaux présentés dans ce manuscrit ont permis de développer avec succès une série de réactions applicables en synthèse organique. Ces réactions ont pour point commun l'utilisation des xanthates comme source de radicaux carbonés. Ainsi, un nouvel accès radicalaire à des azapyridines bicycliques variées a été développé. Les synthèses basées sur une étape clé de cyclisation radicalaire sur le noyau pyridinique, ont permis d'accéder avec succès à plusieurs membres de la famille des azaoxindoles, des azaindolines, des azaindoles, des tétrahydronaphtyridines, des dihydronaphtyridinones et enfin des tétrahydropyridoazépinones. Par la suite, quelques applications synthétiques du transfert radicalaire de groupement xanthate par un dérivé de l'a-chloroacétone ont permis d'accéder de manière très flexible à des molécules complexes. Une approche à la synthèse totale d'un produit naturel, la perhydrohistrionicotoxine a également été entreprise. Enfin, un nouveau réarrangement de type Smiles radicalaire découvert au cours de ce travail de thèse, faisant intervenir une cyclisation via un cycle à 4 chaînons, a été présenté. Ces études nous ont surtout aidé à mieux comprendre la réactivité des espèces radicalaires engendrées par les xanthates

Philosophiae Doctor - PhD / This d~ssertation concerns the modernisation of Islam-oriented schooling in Cape Town and environs whereby Muslim Mission Primary Schools emerge as a socio-cultural compromise between community needs and State school provision policy. It proceeds from the recognition of the cultural diversity that has since the pioneering days characterised the social order of the Mother City. Two religious and cultural traditions have coexisted here in a superordinate and subordinate relationship; one developed a school system for domestication and cultural assimilation, and the other a covert instructional programme for an"alternative religious system and behaviour code. The thrust of the argument is that the Islamic community, developed on the periphery of society that excluded non-Christians, were in the main concerned with cultural transmission, first in the homes of Free Blacks during the Dutch regime, and later in the mosques that arose when religious freedom was obtained. Traditional schools for Islamic culture transmission were conducted by imams and tended to attract in large numbers the children of slaves and other non-white children causing concern among evangelists In 1863, a political understanding between the governments of Britain and Turkey resulted in Abu Bakr Effendi being assigned by the Sultan to conduct a school in Cape Town to effect some uniformity of Islamic instruction. A latent consequence of this Turkish funded school was the production of the first Afrikaans textbook on Islam, a step in the modernisation of cultural transmission. After Effendi's demise the school was discontinued. State education policy ensured that non-white children generally were educated only at State-funded Christian Mission schools. Most Muslim children received only Islamic instruction at the various madressahs (traditional schools) as a result. An increasingly rigid segregation of public schools oriented towards reproducing the superordinate-subordinate culture relationship resulted in a widening gap of literacy which was increasingly important for the economic and political dispensation. Concerned Muslims organised themselves to address the educational deficiency. The South African Moslem Association urged mOre educational opportunity but floundered before accomplishing anything noteworthy. Their importance lay in their making the Muslims more aware of the need to have a secular education in a changing social order. It was self-evident that education had to be seen in the political context: the weaker community was most likely to suffer the greatest lack of schools. Dr A. Abdurahman, foremost political figure of the first forty years of this century, took the first steps in establishing State-aided primary schools for Muslim children. Whatever success he had in this regard was entirely due to his personali ty and political acumen. In contrast to Abdurahman was the philanthropic effort of Hajee Sullaiman Shah Mohamed to build a school with an Islamic ethos. Why he failed is considered against the social historical background of the Cape Muslims and the communities' manifest needs. Politically, Abdurahman was in a better position and better equipped to address the problem. He served as manager of three Muslim primary schools, the development of which form a substantial part of this study. Abdurahman could harness the creative energies and resources of immigrant and indigenous Muslims in creating these schools. But the Cape Malay Association, disenchanted with Abdurahman's perceived partisanship, politically sought to advance Malay communal interests in the political patronage of the Afrikaner political faction in power. In terms of schooling policy they were to be disillusioned.

Philosophiae Doctor - PhD / There is confusion in literature concerning the early beginnings of sport in South Africa. Indications are that it was informal in nature and only took on organised form with the arrival of the British in 1795. Black spoLt similarly had obscure beginning, the dearth of literature in this respect being even more pronounced. There were occasional instances of Whites and Blacks playing together, but this was not a typical characteristic of early South African sport. South Africa's Black people developed their own sports teams and played mainly amongst their own race groups. This was a result of the prevailing class consciousness of the British, which excluded all except the most talented Boers from British clubs, and the incompatibility the Boer felt with the Black people. The result was development of 'racial' clubs that tended to cater exclusively for one particular group, with some sports clubs using religion as a means of demarcation. While there tended to be a racial exclusiveness about the early clubs, informal inter-racial contact was present. This tended to disappear when the belief was encouraged through legislation that the Black people were to develop as a separate nation. The introduction of an official colour bar in the Mines and Amendment Act of 1911 began the crystalisation of this idea. White sports clubs in South Africa had in some cases become founder members of international sports associations, and because these associations recognised only one organisation per country, Black sportsmen were denied access to international competition. By tho 1930s racial demarcation had fully permeated South African sport, effectively denying the Black sportsmen equal opportunity and equal facilities. Reaction by Black sportsmen led to, several non-racial spcrts organisations being Founded in South Africa. Already in 1946 a request for affiliation was made to the British Amateur Weightlifters by the Non-White South African Association, but this was turned down. This demarcation was· carried further with the election to power in 1948 of a Nationalist government which brought with it an apartheid ideology that manifested itself indirectly in sport through legislation such as the Group ·Areas Act, the Black Urban Areas Consolidation Act and the Reservation of Separate Amenities Act. In the fifties the dissatisfaction of Non-White sports organisations with sports oppression increased in intensity, and in 1958 a non-racial South African Sports Association was formed to further the interests of the non-racial sportsmen. There was considerable opposition from White sports organisations and the government. In 1963 the South African Non-Racial Olympic Committee was formed to further the Olympic aspirations of South African sportsmen. exile in London in 1965. This organisation went into self Operating from this base, it set about creating a worldwide awareness of the plight of the Non- White sportsman in South Africa, co-ordinating and organising prot~st movements against South African teams and persuading sports associations and governments not to have sporting contact with South Africa.

Manufacturing companies have begun developing Product Service Systems to provide customers with enhanced product-service offerings. Transitioning to a service-oriented development process allows companies to restructure risks, responsibilities, and costs normally associated with owning products. They potentially allow companies to sell products through different channels and offer additional elements of differentiation to their competitors. However, PSS comes with a lot of challenges that manufacturing companies have struggled to overcome. Some of these challenges include switching away from traditional hardware-focused mindset and the service manufacturing paradox. This thesis focused on challenges regarding integrating services within product development processes. A Swedish manufacturing company was considered as the primary case study for investigation. 14 people from different functions were interviewed. The investigation revealed 17 challenges categorized into five main themes. These themes were lack of clear company messaging regarding services, immature service development process, sub-optimal division of tasks and responsibilities, resources issues, and lack of integration in processes. Additionally, three external companies were interviewed to investigate their service maturity level and how they were able to overcome common challenges in service integration. Based on the insights gained from both internal and external interviews three solutions were created. These solutions are new roles and updated responsibilities, a new integrated service process, and a Product-Service Readiness Level chart. Future considerations for the investigated company were also submitted to provide a guide for further development of these solutions. / Tillverkningsföretag har börjat utveckla produktservicesystem för att ge kunderna förbättrade produkttjänster. Övergången till en tjänsteorienterad utvecklingsprocess tillåter företag att omstrukturera risker, ansvar och kostnader som normalt är förknippade med att äga produkter. De tillåter potentiellt företag att sälja produkter genom olika kanaler och erbjuder ytterligare inslag av differentiering till sina konkurrenter. Men PSS kommer med många utmaningar som tillverkande företag har kämpat för att övervinna. Några av dessa utmaningar inkluderar att byta bort från traditionella hårdvarufokuserade tänkesätt och tjänstetillverkningsparadoxen. Detta examensarbete fokuserade på utmaningar när det gäller att integrera tjänster i produktutvecklingsprocesser. Ett svenskt tillverkningsföretag ansågs vara den primära fallstudien för utredning. 14 personer från olika funktioner intervjuades. Undersökningen avslöjade 17 utmaningar kategoriserade i fem huvudteman. Dessa teman var brist på tydliga företagsmeddelanden om tjänster, omogen tjänsteutvecklingsprocess, suboptimal fördelning av uppgifter och ansvar, resursfrågor och bristande integration i processer. Dessutom intervjuades tre externa företag för att undersöka deras mognadsnivå för tjänster och hur de kunde övervinna vanliga utmaningar inom tjänsteintegration. Baserat på insikterna från både interna och externa intervjuer skapades tre lösningar. Dessa lösningar är nya roller och uppdaterade ansvarsområden, en ny integrerad serviceprocess och ett diagram för produkt-tjänstberedskapsnivå. Framtida överväganden för det undersökta företaget lämnades också in för att ge vägledning för vidareutveckling av dessa lösningar.

The first part of the thesis presents the KMnO4/ carboxylic acid/ organic solvent which is a powerful reagent for C-C bond formation, aryl coupling reactions and enone oxidation. The a&cent / -acetoxylation of enones and the a-acetoxylation of aromatic ketones were carried out with potassium permanganate and acetic acid, in which acetoxylation products were obtained in 74-96% yields. The same reaction was carried out with carboxylic acids other than acetic acid, which furnished corresponding acyloxy ketones with the same regioselectivity. For the first time, formyloxylation products were synthesized in a 61-85% yield by using formic acid. The potassium permanganate and acetic acid method was also used for aryl coupling reactions. The reaction of arylboronic acids and aryl hydrazines in benzene with potassium permanganate and acetic acid in turn furnished biaryls in a 85-96% yield. We showed that potassium permanganate/carboxylic acid/organic solvent behaves as manganese(III) acetate. In the second part of the thesis, ipso-nitration of arylboronic acids with AgNO2/ TMSCl was performed. Nitration of aromatic compounds is one of the most extensively studied reactions, and nitroaryl moieties play key roles in the physical and chemical properties of many target molecules in organic synthesis. For electrophilic nitration of aromatic compounds, a wide variety of reagents are available to date. Most of them are very strong nitrating agents and often lead to further nitration and mixture of isomers. Since most nitrating agents are oxidants, oxidation of other functional groups can also occur, giving a mixture of products. Thus, a search for milder and selective nitrating agents is a good research goal. In this work, we aimed to apply AgNO2/ TMSCl system to ipso nitration of arylboronic acids.

Servitization is a popular term referring to the innovation of an organization’s capabilities and processes to better create mutual value through a shift from selling products to selling Product-Service Systems. It is generally regarded as an innovative business model with great potential for smoother revenue streams, higher profit margins and longer, more closely-knit customer relationships. It is seldom easy to reengineer the business model of an entire organization and the servitization concept does not come without risks and uncertainties. One of the biggest changes when servitizing is the ownership of products; it is no longer necessarily the customer who owns the product, but the producer. This entails new uncertainties surrounding the use and care of the product, leaving the provider with a risk because of a lack of information about how the product is being used. The technology Internet of Things (IoT) can potentially solve this problem by enabling a constant remote data flow from the products in use back to the provider. IFS, the company at which the research of this study took place, develops and supplies enterprise systems (ES) such as enterprise resource planning systems (ERP) and can be described as forward-thinking and innovative. The ERP is a central point for any manufacturing firm, governing data and enabling an organization to automate and integrate a comprehensive part of their business processes, and to produce and access information in real time. In order to build functionality which can be referred to as the “best practice”, and to make a profit doing it, ES providers, such as IFS, need to stay in touch with the market and develop attractive applications in line with the general demand. One way to do this is to collaboratively develop functionality together with customers. In recent years, IFS has developed the product IFS IoT Business Connector in such a collaborative way with a number of pioneer customers. The product enables the collection and analysis of IoT data as well as seamless integration into IFS’ other products. This has opened up possibilities to utilize IoT functionality to support a more efficient provision of services, but the continued successful development of the Business Connector in this direction entails several more collaborative ventures into many different industries. To assist in this, we have concretized how IoT can be used to support a servitization process, as well as how the market has realized and adopted this. This has rendered a conceptual model for judging the suitability of a company, based on the readiness to utilize IoT and servitization respectively. We have then presented which types of customers an ES provider should aim to collaborate with for joint development of functionality in the enterprise system, to enable IoT solutions which can support servitization. This is followed by a presentation of a short market review, and the visualization of the market in the model. From this we draw conclusions about the fit and usefulness of the model, and the market maturity in general. Finally, we present a number of suggestions on how ES providers can work to develop such support in a more efficient manner.

Dans le cadre d’un projet général concernant l’étude de la réactivité des acidesbenzoïques non protégés avec les organométalliques, la synthèse totale d’analoguesstructuraux de l’apogossypol mettant en jeu des réactions de métallation aromatique a étéétudiée ainsi que la réaction de substitution nucléophile aromatique des acides benzoïquesortho-fluorés et ortho-méthoxylés.Le gossypol, (1,1’,6,6’,7,7’-hexahydroxy-5,5’-di-iso-propyl-3,3’-diméthyl-2,2’-binaphtalène-8,8’-dicarboxaldéhyde), pigment principal des graines du cotonnier, existe sousla forme de deux atropoisomères et possède de multiples applications pharmaceutiques. Il estnotamment un inhibiteur efficace des protéines anti-apoptotiques de la famille Bcl-2. Legossypol déformylé ou apogossypol présente des propriétés similaires mais est plus stable,plus sélectif et moins toxique. Une méthode permettant de remplacer les groupes iso-propylesdu gossypol par des groupes structurellement proches a été mise au point. La stratégie retenuemet à profit les compétences du laboratoire dans le domaine des réactions de métallation etrepose sur la lithiation latérale de l’acide 4-hydroxy-6,7-diméthoxy-8-méthyl-2-naphtoïquepar le tétraméthylpipéridure de lithium. Divers dérivés 5,5’-didés-iso-propyl-5,5’-dialkylapogossypol racémiques ont été préparés selon cette méthode. La synthèse asymétriqued’analogues de l’apogossypol a également été étudiée et la voie de synthèse sélectionnéerepose sur le « concept lactone ». Un intermédiaire avancé de la synthèse, une lactonefonctionnalisée potentiellement réductible de façon asymétrique, a été préparée.La deuxième partie est consacrée à l’étude de la réaction de substitution nucléophilearomatique des acides benzoïques ortho-fluorés et ortho-méthoxylés (réaction SNArAB). Unerevue de la littérature des réactions de substitution nucléophile aromatique activée par lesesters est présentée. L’influence de substituants méthoxylés et halogénés (F, Cl, Br) sur lasélectivité SNAr/addition 1,2 a été évaluée. Il est montré que les acides 2-fluoro-6-halogénobenzoïques conduisent, par réaction avec les aryllithiens et les arylmagnésiens, auxproduits d’ipso-C2-substitution avec un excellent rendement et la réaction SNArAB permet unaccès efficace aux acides 3-halogéno-[1,1’-biphényl]-2-carboxyliques. Dans le cas de l’acide2,3-diméthoxybenzoïque, il a été découvert que la présence d’un substituant méthoxy enposition 3 permet de limiter la formation de cétone et le produit d’ipso-substitution est isoléavec un rendement correct. / As part of a program directed toward the study of the reactivity of unprotected benzoicacids with polar organometallics, the total racemic synthesis of apogossypol analogues bymetalation reactions was studied as well as the aromatic nucleophilic substitution reaction ofortho-fluoro- and ortho-methoxybenzoic acids (SNArAB reaction).Gossypol (1,1’,6,6’,7,7’-hexahydroxy-5,5’-di-iso-propyl-3,3’-diméthyl-2,2’-binaphtalène-8,8’-dicarboxaldéhyde) which is the main pigment of cotton seed, displaysmultiple pharmacological applications. It is a potent anti-apoptotic Bcl-2 protein inhibitor.The racemic route developed herein allows the replacement of the iso-propyl groups byvirtually any alkyl groups, providing a series of 5,5’-dides-iso-propyl-5,5’-dialkylapogossypolderivatives. Lateral metalation of 4-hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic acid withLTMP is the key step of the synthesis. Atroposelective synthesis of apogossypol analoguewas also examined. The strategy relies on the “lactone concept” and involves a functionalizedlactone as a key intermediateThe influence of halogen atoms (F, Cl, Br) and methoxy groups on the 1,2-addition/SNArAB selectivity was examined. Treatment of 2-fluoro-6-halobenzoic acids withorganolithiums or Grignard reagents gives ipso-substituted products in excellent yields. Themethod allows the efficient preparation of 3-halo-[1,1’-biphenyl]-2-carboxylic acids and doesnot require protection of the carboxylate. Interestingly, the presence of an additional methoxyin C3 reduces the nucleophilic addition of the organometallic species to the carboxylate and2,3-dimethoxybenzoic acid affords ipso-substituted products in good yields.

Dans le cadre d'un projet général concernant l'étude de la réactivité des acidesbenzoïques non protégés avec les organométalliques, la synthèse totale d'analoguesstructuraux de l'apogossypol mettant en jeu des réactions de métallation aromatique a étéétudiée ainsi que la réaction de substitution nucléophile aromatique des acides benzoïquesortho-fluorés et ortho-méthoxylés.Le gossypol, (1,1',6,6',7,7'-hexahydroxy-5,5'-di-iso-propyl-3,3'-diméthyl-2,2'-binaphtalène-8,8'-dicarboxaldéhyde), pigment principal des graines du cotonnier, existe sousla forme de deux atropoisomères et possède de multiples applications pharmaceutiques. Il estnotamment un inhibiteur efficace des protéines anti-apoptotiques de la famille Bcl-2. Legossypol déformylé ou apogossypol présente des propriétés similaires mais est plus stable,plus sélectif et moins toxique. Une méthode permettant de remplacer les groupes iso-propylesdu gossypol par des groupes structurellement proches a été mise au point. La stratégie retenuemet à profit les compétences du laboratoire dans le domaine des réactions de métallation etrepose sur la lithiation latérale de l'acide 4-hydroxy-6,7-diméthoxy-8-méthyl-2-naphtoïquepar le tétraméthylpipéridure de lithium. Divers dérivés 5,5'-didés-iso-propyl-5,5'-dialkylapogossypol racémiques ont été préparés selon cette méthode. La synthèse asymétriqued'analogues de l'apogossypol a également été étudiée et la voie de synthèse sélectionnéerepose sur le " concept lactone ". Un intermédiaire avancé de la synthèse, une lactonefonctionnalisée potentiellement réductible de façon asymétrique, a été préparée.La deuxième partie est consacrée à l'étude de la réaction de substitution nucléophilearomatique des acides benzoïques ortho-fluorés et ortho-méthoxylés (réaction SNArAB). Unerevue de la littérature des réactions de substitution nucléophile aromatique activée par lesesters est présentée. L'influence de substituants méthoxylés et halogénés (F, Cl, Br) sur lasélectivité SNAr/addition 1,2 a été évaluée. Il est montré que les acides 2-fluoro-6-halogénobenzoïques conduisent, par réaction avec les aryllithiens et les arylmagnésiens, auxproduits d'ipso-C2-substitution avec un excellent rendement et la réaction SNArAB permet unaccès efficace aux acides 3-halogéno-[1,1'-biphényl]-2-carboxyliques. Dans le cas de l'acide2,3-diméthoxybenzoïque, il a été découvert que la présence d'un substituant méthoxy enposition 3 permet de limiter la formation de cétone et le produit d'ipso-substitution est isoléavec un rendement correct.