A series of phenanthrene and oxidized phenanthrene derivatives with typical substitution patterns, 1.31, 1.32, 2.30a-f, 3.1a,b and (-)-4.1 have been synthesized as liquid crystal cores by a combined Directed ortho Metalation (DoM), cross coupling and Directed Remote Metalation (DreM) strategy. The synthetic methodology employed allowed variation of the tail and core structures, for the preparation of a new smectic liquid crystal compound (1.32), a homologous series of 9,10-dihydrophenanthrene-9,10-diones (2.30a-f), a diastereomeric trans-9,10-dihydrophenanthrene-9,10-diol (1.31), two enantiomeric 9,10-dihydrophenanthrene-9,10-diones (R)-3.1a-b) and an enantiomeric 9,10-dihydro-9,10-dimethylphenanthrene-9,10-diol ((-)-4.1). Polarized microscopic and differential scanning calorimetric measurements suggest that 1.31 forms a large range of SmC phase, ca. 100 ºC, followed by a small range of nematic phase, ca. 10 ºC; the 2.30a-f series show similar mesogenic properties, but with the extension of the length of a side chain from six carbons to eleven carbons, the nematic phase has disappeared (in the cases of 2.30a-c). Although (R)-3.1a-b and (-)-4.1 are not liquid crystals, they show ferroelectric induction by doping, in the amount of ca. 5 mol%, into unchiral liquid crystal hosts PhB, DFT, PhP1, NCB76 and 2.30f. However, due to the detection limit of the instrument, i.e., ca. 0.5 nC/cm2, the spontaneous polarizations (Ps) induced could not be measured. / Thesis (Ph.D, Chemistry) -- Queen's University, 2009-08-17 15:52:54.612

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N,N-Diethyl-O-sulfamate (OSO2NEt2) has been established as a new directed metalation group (DMG). Its similarity to the established O-carbamate DMG has prompted investigation into its potential as a partner in transition metal-catalyzed cross coupling reactions with aryl organometallics with the intention to develop a new route to contiguously substituted aromatics. Furthermore, aryne formation of ortho-magnesiated O-sulfamates at higher temperatures can be trapped with furan to afford cycloaddition products having substitution patterns difficult to prepare by similar methods. Schumanniophytine is a structurally interesting alkaloid possessing anti-viral activity. Thus far, only a single synthesis has been reported which proceeds in poor yield and offers little opportunity for the synthesis of structurally diverse schumanniophytine derivatives. Herein we report the total synthesis of schumanniophytine by a directed ortho metalation (DoM) – cross coupling strategy using a key directed remote metalation (DreM) step. The synthesis proceeds in 10 steps with 24% overall yield, offering plenty of opportunity for structural variation. Naturally abundant chromone derivatives contain an array of biological activities. The ability to prepare differentially substituted chromones in a rapid manner is of great interest in medicinal chemistry. Reported is a general and divergent synthesis of chromone carboxamides, from easily prepared 2-but-2-ynoyl aryl O-carbamates. The reaction proceeds by carbamoyl translocation and anionic Fries rearrangement followed by Michael addition of the initially generated cumulenolate for which evidence is provided. Further metalation and borylation reactions of the synthesized compounds allow the regioselective construction of polysubstituted chromones. / Thesis (Ph.D, Chemistry) -- Queen's University, 2007-11-30 11:18:51.673

Directed metalation reactions are an interesting area of synthetic chemistry. They provide a powerful regiospecific method for functionalizing complex aromatic rings. Presently, directed ortho metalations are well understood. However, there has been very little progress in the remote metalation of naphthalene derivatives. Presently the peri lithiation of naphthalamides is a reaction that has not been solved to a level that allows for it to be deployed in a vast number of synthetic schemes. The processes by which peri functionalized naphthalamides are present obtained required several steps and give poor yields. Previously attempts directed toward the peri lithiation in the Schwan lab have met with little success. Herein experiments were preformed to understand why the pervious attempts failed and other experiments were performed in an effort to acheive the peri lithiation of a specific naphthalamide. The mechanism of previous chemical observations was understood by trapping experiments and clearly demonstrated how problematic acidic sites can interfere with intended directed metalation. The acidic site was sterically hindered by employing strategic protecting groups. However, the steric demand of the protecting groups considered was not sufficient to eliminate the problematic acidic site. This led to the consideration of an alternative strategy for the peri lithiation by removing the acidic center of the specific substrate. This however, resulted in remote addition of lithiating reagents to the naphthalamide and clearly showed that several naphthalamides are not a suitable directed metalation group for the peri lithiation.

SOUSA, Alexandre Carreira da Cruz. 5,10,15,20-meso-tetrapiridilporfirina de európio: síntese, caracterização e investigações espectroscópicas. 2015. 62. Dissertação (Mestrado em química)- Universidade Federal do Ceará, Fortaleza-CE, 2015. / Submitted by Elineudson Ribeiro (elineudsonr@gmail.com) on 2016-10-04T14:55:21Z No. of bitstreams: 1 2015_dis_accsousa.pdf: 1629715 bytes, checksum: 264276171b2e35ae1514203c752b6856 (MD5) / Approved for entry into archive by Jairo Viana (jairo@ufc.br) on 2016-10-10T19:42:17Z (GMT) No. of bitstreams: 1 2015_dis_accsousa.pdf: 1629715 bytes, checksum: 264276171b2e35ae1514203c752b6856 (MD5) / Made available in DSpace on 2016-10-10T19:42:17Z (GMT). No. of bitstreams: 1 2015_dis_accsousa.pdf: 1629715 bytes, checksum: 264276171b2e35ae1514203c752b6856 (MD5) Previous issue date: 2015 / Increasingly, porphyrins have gained a position of detached interest in scientific circles. Its high biological compatibility, being a molecule found naturally in plants and many red blood animals, coupled with the possibility of forming complexes with lanthanide atoms, makes these compounds are particularly attractive in a branch of medicine quite promising in terms respect to combat cancer, called photodynamic therapy. The lanthanide-porphyrin complex act as photosensitizers in the production of singlet oxygen, a cytotoxic species, may be soaked in organic tissue of interest, promoting the cancer cell death. The synthesis of some Ln-porphyrin complexes [Ln (Ln = Gd, Er, Yb)] are already reported in the literature. However, with increasing ionic radius of metal that is intended to complex in the porphyrin, the energy barrier which prevails opposite the occurrence of this synthesis also increases, hindering the occurrence of the metalation process. Thus, this study seeks to promote metalation with europium, in 5,10,15,20 - meso - tetrapyridilporphyrin (H2TPyP). Was used the europium acetylacetonate salt [Eu(acac)3] in the synthesis as a source of Eu3+ ion. The obtained compound was purified by column chromatography on elution of alumina (Al2O3) and further characterized by absorption spectroscopy in the ultraviolet-visible region (UV-VIS) and infrared region (IR), luminescence and termogravimetric analysis (TG). The results obtained for the UV-vis spectra show for complex synthesized 3 Q bands, a lower number compared to the spectrum of the free base porphyrin, which has 4 Q bands, which discloses the formation of a compound with higher symmetry, which rose from D2h to D4h due to insertion of the metal ion in the porphyrin ring. It was observed also a bathochromic shift of the Soret band in the complex shifted from 417 to 429nm, consistent with the fact that the metallation occurred. The IR results and suggest the occurrence of metalation of the suppression band 3304cm-1, indicating deprotonation of the central atoms of Nytrogen, also suggested maintaining the acetylacetonate ion in stabilizing the structure of the complex. The luminescence showed that there was enhancement of emission bands, which is consistent with the formation of a metal complex. In the TG results, it was found that the compound formed to the amount of residue obtained was much higher than that for H2TPyP, suggesting the formation of metal oxide in the first case, consistent with the fact that formation of europium metalloporphyrin. / Cada vez mais, as porfirinas vêm conquistando uma posição de destacado interesse no meio científico. Sua elevada compatibilidade biológica, sendo uma molécula encontrada naturalmente em plantas e em diversos animais de sangue vermelho, aliada a possibilidade da formação de complexos com átomos de lantanídeos, faz com que esses compostos sejam particularmente atrativos em um ramo bastante promissor da medicina no que diz respeito ao combate ao câncer, denominado de terapia fotodinâmica. Isso porque os complexos lantanídeos-porfirina atuam como fotossensibilizadores na produção de oxigênio singlete, uma espécie citotóxica, podendo esses complexos serem saturados em tecidos orgânicos de interesse, promovendo a morte de células cancerígenas. A síntese de alguns complexos Ln-porfirina (Ln= Gd, Er, Yb) já são reportadas na literatura. Entretanto, com o aumento do raio iônico do metal que se pretende complexar a porfirina, a barreira energética que se impera frente a ocorrência desta síntese também aumenta, dificultando a ocorrência do processo de metalação. Dessa forma, o presente estudo busca promover a metalação de európio na 5,10,15,20 – meso – tetrapiridilporfirina (H2TPyP). Utilizou-se o sal acetilacetonato de európio [Eu(acac)3] na síntese como fonte do íon Eu3+. O composto obtido foi purificado por eluição em coluna cromatográfica de alumina (Al2O3) e posteriormente caracterizado por espectroscopia de absorção na região do ultravioleta-visível (UV-Vis) e infravermelho (IR), luminescência e análise termogravimética (TG). Os resultados obtidos por UV-Vis para o complexo sintetizado mostraram espectros com 3 bandas Q, um menor número comparado ao espectro da porfirina base livre que apresenta 4 bandas Q, o que sugere a formação de um composto com maior simetria, que passou de D2h para D4h, devido a inserção do íon metálico no anel porfirínico. Observou-se também um deslocamento batocrômico da banda Soret no complexo que deslocou de 417 para 429nm, fato condizente com a ocorrência da metalação. Os resultados de IR, além de sugerirem a ocorrência da metalação pela supressão da banda em 3304cm-1, indicando a desprotonação dos nitrogênios centrais, também sugeriram a manutenção do íon acetilacetonato na estabilização da estrutura do complexo. A luminescência mostrou que houve intensificação das bandas de emissão, o que condiz com a formação de um complexo metálico. Nos resultados de TG constatou-se que para o composto formado a quantidade de resíduo obtido foi bastante superior de que para a H2TPyP, sugerindo a formação de óxido metálico no primeiro caso, fato condizente com a formação da metaloporfirina de európio.

New Carbanion Rearrangement of Sulfur Compounds and Its Application Abstract This thesis reports the investigation of an unusual reversal in the metalation selectivity of alkyl aryl sulfones and sulfoxides and its application. Such compounds undergo initial directed ortho-metalation at −78 řC despite having an acidic α-hydrogen atom and the resulting aryllithiums rearrange subsequently completely to the initially expected α-sulfonyllithiums on warming. The scope and the limitations for this process were identified. Both carbanion types of sulfones were applied in reactions with various electrophiles. α-Lithiated sulfones generated upon the transmetalation process were used in Julia olefinations. A mechanistic study of the course of the transmetalation reaction is presented. The kinetics of the transmetalation were determined. Investigations concerning the concentration dependence, proton transfer equilibria between the different ortho-sulfonyllithium intermediates and crossover experiments provided the evidence that a concerted intermolecular pathway prevails. On this basis a new integrated synthetic approach to naturally occurring iridoids was developed. It is based on a tandem alkoxycarbonylation/oxidative radical cyclization of the olefins synthesized by the Julia reaction after the investigated...

The Directed ortho Metalation reaction is described in Chapter 1 of this thesis with particular emphasis on its mechanism and synthetic potential. Chapter 2 contains a review of the DoM (Directed ortho Metalation) of pyridine systems and describes the conditions that allow the one-pot DoM (Directed ortho-Metalation)-Boronation-Suzuki-Miyaura cross coupling of pyridines 2.263a-c, 2.351-2.53 (Table 2.9) bearing several DMGs (Directed Metalation Groups) including the synthetically versatile diethyl amide functionality without incurring into commonly observed self-condensation processes. The method avoids the tedious and uncertain isolation of the intermediate boronic acids while offering rapid access to synthetically valuable arylpyridines (2.354a-s, Table 2.9). Selected aryl pyridine carboxamides were used to demonstrate the DoM-DreM (Directed remote Metalation) nexus that furnishes substituted and isomerically diverse azafluorenones 2.380a-d (Table 2.11) with high regioselectivity. The previous discovery of the anionic O→C -vinyl carbamoyl migration of carbamoyl stilbenes stimulated its application in the total synthesis of natural product isoprekinamycin, bearing the unusual diazo group. Chapter 3 of this thesis describes the efficient synthesis of the key stilbene derivative 3.113 and its structural variations whose conversion to the desired naphthols 3.143, 3.144, 3.153 and 3.169 (Table 3.3) is accompanied by extensive decomposition, thus terminating this approach to isoprekinamycin. A modified approach via Z-3.271 (Scheme 3.54) gave the desired naphthyl carbamate intermediates 3.274 and 3.278 (Schemes 3.55 and 3.56, respectively) whose complex DreM reactions prevented the completion of the synthesis but remain under active investigation in our laboratories. Previous studies of the DoM reaction of aryl tetramethyl phosphorodiamidate have shown that unpractical experimental conditions are necessary, thus limiting synthetic application. Chapter 4 of this thesis describes the results concerning the performance of the tetraethyl phosphorodiamidate DMG under standard DoM and DreM conditions, anionic phospha-Fries rearrangement, 1,4 lateral migration, and Suzuki cross coupling which demonstrate synthetic utility and application in synthetic aromatic chemistry. / Thesis (Ph.D, Chemistry) -- Queen's University, 2008-12-16 14:15:09.695

The electron rich and aromatic character of the indole group allows for a wide range of oxidative and substitution reactions, creating a versatile platform for generating structurally diverse molecules. This thesis explores enzyme and synthetic chemistries that act upon indoles and related molecules. Chapter 1 describes the results of in vivo studies of RebC, an enzyme that plays a pivotal role in the biosynthesis of the indolocarbazole alkaloid rebeccamycin. A homologous enzyme, StaC, exists in the biosynthetic pathway for staurosporine, a related indolocarbazole. Structural differences between the RebC and StaC active sites were hypothesized to play a pivotal role in determining the oxidation state in the corresponding natural products. Sequence alignment of RebC and StaC with homologous enzymes from related indolocarbazole biosynthetic pathways revealed six non-conserved residues in the active site. Three RebC variants were generated by replacement of all six, four, or two specific residues with their StaC counterparts. It was demonstrated that only two substitutions, F216V and R239N, are required to convert the specificity of RebC to that of StaC. Analysis of the structure of the RebC bound to a putative reaction intermediate supports the importance of F216 and R239 in catalysis. Based on these results, contrasting mechanisms for RebC and StaC are proposed to account for their differing specificities. Chapter 2 describes a synthetic approach to primarily heterocyclic analogues of lycogarubin C. Suzuki coupling of appropriately functionalized 3,4-dibromopyrrole or 3,4-bis(trifluoromethanesulfonyl)pyrrole was effective for numerous π-excessive five-membered heterocyclic-3-boronic acids. The optimized conditions were less effective for cross-couplings involving heteroaromatic-2-boronic acids, π-deficient heteroaromatic boronic acids, and heteroaromatic boropinacolate esters. Oxidative cyclization of the 3,4-bis(thiophen-3-yl)pyrrole and 3,4-bis(benzothiophen-3-yl)pyrrole to give analogues of the corresponding indolocarbazoles was demonstrated. Chapter 3 describes preliminary results on the development of regioselective C-5 and C-7 indole metalation tactics of indole-6-carboxamides, in order to provide new functionalized indoles. The use of an indole C-2 silicon protection strategy in combination with a sterically bulky C-6 N,N-di-isopropyl carboxamide directed metalation group overcame undesired side reactions observed with the analogous N,N-diethyl indole-6-carboxamide, affording the C-5 and C-7 substituted products in 40% and 13% yields, respectively. / Thesis (Ph.D, Chemistry) -- Queen's University, 2013-02-13 11:14:49.599

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Increasingly, porphyrins have gained a position of detached interest in scientific circles. Its high biological compatibility, being a molecule found naturally in plants and many red blood animals, coupled with the possibility of forming complexes with lanthanide atoms, makes these compounds are particularly attractive in a branch of medicine quite promising in terms respect to combat cancer, called photodynamic therapy. The lanthanide-porphyrin complex act as photosensitizers in the production of singlet oxygen, a cytotoxic species, may be soaked in organic tissue of interest, promoting the cancer cell death. The synthesis of some Ln-porphyrin complexes [Ln (Ln = Gd, Er, Yb)] are already reported in the literature. However, with increasing ionic radius of metal that is intended to complex in the porphyrin, the energy barrier which prevails opposite the occurrence of this synthesis also increases, hindering the occurrence of the metalation process. Thus, this study seeks to promote metalation with europium, in 5,10,15,20 - meso - tetrapyridilporphyrin (H2TPyP). Was used the europium acetylacetonate salt [Eu(acac)3] in the synthesis as a source of Eu3+ ion. The obtained compound was purified by column chromatography on elution of alumina (Al2O3) and further characterized by absorption spectroscopy in the ultraviolet-visible region (UV-VIS) and infrared region (IR), luminescence and termogravimetric analysis (TG). The results obtained for the UV-vis spectra show for complex synthesized 3 Q bands, a lower number compared to the spectrum of the free base porphyrin, which has 4 Q bands, which discloses the formation of a compound with higher symmetry, which rose from D2h to D4h due to insertion of the metal ion in the porphyrin ring. It was observed also a bathochromic shift of the Soret band in the complex shifted from 417 to 429nm, consistent with the fact that the metallation occurred. The IR results and suggest the occurrence of metalation of the suppression band 3304cm-1, indicating deprotonation of the central atoms of Nytrogen, also suggested maintaining the acetylacetonate ion in stabilizing the structure of the complex. The luminescence showed that there was enhancement of emission bands, which is consistent with the formation of a metal complex. In the TG results, it was found that the compound formed to the amount of residue obtained was much higher than that for H2TPyP, suggesting the formation of metal oxide in the first case, consistent with the fact that formation of europium metalloporphyrin. / Cada vez mais, as porfirinas vÃm conquistando uma posiÃÃo de destacado interesse no meio cientÃfico. Sua elevada compatibilidade biolÃgica, sendo uma molÃcula encontrada naturalmente em plantas e em diversos animais de sangue vermelho, aliada a possibilidade da formaÃÃo de complexos com Ãtomos de lantanÃdeos, faz com que esses compostos sejam particularmente atrativos em um ramo bastante promissor da medicina no que diz respeito ao combate ao cÃncer, denominado de terapia fotodinÃmica. Isso porque os complexos lantanÃdeos-porfirina atuam como fotossensibilizadores na produÃÃo de oxigÃnio singlete, uma espÃcie citotÃxica, podendo esses complexos serem saturados em tecidos orgÃnicos de interesse, promovendo a morte de cÃlulas cancerÃgenas. A sÃntese de alguns complexos Ln-porfirina (Ln= Gd, Er, Yb) jà sÃo reportadas na literatura. Entretanto, com o aumento do raio iÃnico do metal que se pretende complexar a porfirina, a barreira energÃtica que se impera frente a ocorrÃncia desta sÃntese tambÃm aumenta, dificultando a ocorrÃncia do processo de metalaÃÃo. Dessa forma, o presente estudo busca promover a metalaÃÃo de eurÃpio na 5,10,15,20 â meso â tetrapiridilporfirina (H2TPyP). Utilizou-se o sal acetilacetonato de eurÃpio [Eu(acac)3] na sÃntese como fonte do Ãon Eu3+. O composto obtido foi purificado por eluiÃÃo em coluna cromatogrÃfica de alumina (Al2O3) e posteriormente caracterizado por espectroscopia de absorÃÃo na regiÃo do ultravioleta-visÃvel (UV-Vis) e infravermelho (IR), luminescÃncia e anÃlise termogravimÃtica (TG). Os resultados obtidos por UV-Vis para o complexo sintetizado mostraram espectros com 3 bandas Q, um menor nÃmero comparado ao espectro da porfirina base livre que apresenta 4 bandas Q, o que sugere a formaÃÃo de um composto com maior simetria, que passou de D2h para D4h, devido a inserÃÃo do Ãon metÃlico no anel porfirÃnico. Observou-se tambÃm um deslocamento batocrÃmico da banda Soret no complexo que deslocou de 417 para 429nm, fato condizente com a ocorrÃncia da metalaÃÃo. Os resultados de IR, alÃm de sugerirem a ocorrÃncia da metalaÃÃo pela supressÃo da banda em 3304cm-1, indicando a desprotonaÃÃo dos nitrogÃnios centrais, tambÃm sugeriram a manutenÃÃo do Ãon acetilacetonato na estabilizaÃÃo da estrutura do complexo. A luminescÃncia mostrou que houve intensificaÃÃo das bandas de emissÃo, o que condiz com a formaÃÃo de um complexo metÃlico. Nos resultados de TG constatou-se que para o composto formado a quantidade de resÃduo obtido foi bastante superior de que para a H2TPyP, sugerindo a formaÃÃo de Ãxido metÃlico no primeiro caso, fato condizente com a formaÃÃo da metaloporfirina de eurÃpio.

A funcionalização régiosseletiva e quimiosseletiva de arenos utilizando reagentes organometálicos têm sido uma ferramenta importante na síntese de novas moléculas de interesse científico e tecnológico, principalmente para a Química Medicinal. Neste contexto, o objetivo deste trabalho foi investigar a reatividade de amidetos metálicos na funcionalização de benzonitrilas, uma vez que o grupo ciano é um importante intermediário sintético e pode ser transformado em diversos grupos funcionais. Para tanto, inicialmente, cianofenóis foram convertidos aos respectivos pivalatos, carboxilatos e fosforodiamidetos, sendo estes grupos estudados como grupos orto-dirigentes de metalação. Com o objetivo de desenvolver metodologias para funcionalização dos substratos, diferentes amidetos de lítio e mistos de magnésio e lítio foram estudados sob diferentes condições reacionais, sendo iodo o eletrófilo padrão para monitoramento das reações. De maneira geral, observou-se pouca reatividade das bases mistas TMPMgCl?LiCl e TMP2MgCl?2LiCl frente aos substratos estudados. Por outro lado, a base TMPLi se mostrou efetiva na funcionalização dos substratos, sendo que os produtos de rearranjo de Fries foram sempre majoritários em detrimento aos produtos de iodólise. Com isso, diferentes benzonitrilas funcionalizadas de estrutura inédita na literatura puderam ser sintetizadas de maneira regiosseletiva, sendo os produtos caracterizados por meio de análises de RMN bidimensionais. Similarmente, na etapa final do projeto, a reatividade das mesmas bases foi investigada em reações com metóxi-benzonitrilas, sendo que neste caso os iodetos esperados foram obtidos em bons rendimentos pelo uso das bases mistas de magnésio e litio. Adicionalmente, os intermediários organometálicos demostraram boa reatividade frente a diversos eletrófilos, proporcionando o isolamento de benzonitrilas substituídas com diferentes grupos funcionais, sendo estas de grande interesse sintético e medicinal. / The regioselective and chemoselective functionalization of arenes using organometallic reagents has been an important tool for the synthesis of new molecules of scientific and technologic interest, especially for the Medicinal Chemistry. In this context, the objective of this work was to investigate the reactivity of metallic amides in the functionalization of benzonitriles once the cyano group is an important synthetic intermediate and can be transformed in several different functional groups. Thus, initially, cyanophenols were converted to the respective pivalates, carboxylates and phosphodiamides which were studied as ortho directing metalation groups. With the goal of developing methodologies for the functionalization of the cited substrates, different lithium amides and mixed lithium-magnesium amides were studied under different reaction conditions being iodide the standard electrophile for reaction monitoring. In general, it was observed little reactivity of the mixed bases TMPMgCl?LiCl and TMP2MgCl?2LiCl against the studied substrates. On the other hand, the TMPLi base has proved to be effective in the functionalization of the substrates though the Fries\' rearrangement products were always observed in majority compared to the iodolysis products. By using this strategy, several novel functionalized benzonitriles could be synthetized in a regioselective way with the products being characterized by bidimensional NMR techniques. Similarly, in the final stage of the project the reactivity of the same bases was investigated in reactions employing methoxi-benzonitriles where the mixed lithium-magnesium afforded the expected iodides in good yields. Additionally, the organometallic intermediates demonstrated good reactivity against several electrophiles providing the isolation of substituted benzonitriles of great synthetic and medicinal interest.