Cycloadditions of chiral carbonyl ylides with imine dipolarophiles as a route to enantiomerically pure alpha-amino-beta-hydroxy acids

The preparation of enantiomerically pure threo-beta-amino-alpha-hydroxy acids via 1,3-dipolar cycloadditions of imine dipolarophiles with the chiral isomunchnone derived from (5R)-5-phenylmorpholin-3-one 1 is described. The cycloadducts were obtained with excellent diastereofacial- and exo-selectivity. Subsequent hydrolysis and chemoselective exocyclic amide cleavage afforded the threo-beta-amino-alpha-hydroxy acids with recovery of the initial chiral auxiliary. (C) 2009 Published by Elsevier Ltd.

Regio and diastereoselective multicomponent 1,3-dipolar cycloadditions between prolinate hydrochlorides, aldehydes and dipolarophiles for the direct synthesis of pyrrolizidines

A general synthesis of highly substituted pyrrolizidines can be performed by a multicomponent 1,3-dipolar cycloaddition using proline ester hydrochlorides, aldehydes and dipolarophiles, at room temperature without catalysts or in the presence of AgOAc (5 mol %). In the case of (2S,4R)-4-hydroxyproline derivatives it is possible to obtain enantioenriched pyrrolizidines with high control of the regio- and diastereoselectivity affording the adducts 2,4-trans-2,5-trans according to an endo-approach and a S-dipole geometry of the in situ generated azomethine ylide. For proline esters a similar regioselectivity and endo-diastereoselectivity are observed when the dipole promotes an α-attack. However, when ethyl glyoxylate is used as aldehyde component the γ-attack of the S-ylide takes place preferentially giving rise the opposite regioselectivity for acrylic dipolarophiles, being crucial the role of silver acetate. In this case, the exo-adducts with a 2,3-cis-2,5-trans relative configuration are diastereoselectively obtained. In addition, computational studies have also been carried out to shed light on the origins of the diastereo- and regioselectivity observed for the described 1,3-dipolar cycloadditions.

Unusual Anisotropic Effects from 1,3-Dipolar Cycloadducts of 4-Azidomethyl Coumarins

4-Bromomethylcoumarins (1) reacted with sodium azide in aqueous acetone to give 4-azidomethyl-coumarins (2), which underwent 1,3-dipolar cycloaddition with acetylenic dipolarophiles to give triazoles (3). These triazoles (3) have been found to exhibit interesting variations in the chemical shifts of C-3-H and C-4-methylene protons. Protonation studies indicate that the shielding effect of the C-3-H of coumarin is due to pi-electrons of the triazole ring, further supported by diffraction and computational studies.

A facile entry into a new class of spiroheterocycles: synthesis of dispiro[oxindolechromanone/flavanone/tetralone]pyrroloisoquinoline ring systems

A series of novel dispiroheterocyclic systems have been synthesized by the cycloaddition of a new azomethine ylide generated by the decarboxylative route from tetrahydroisoquinoline-3-carboxylic acid and isatin with various dipolarophiles containing exocyclic double bond such as 3-arylidene-4-chromanone, 3-arylidene-4-flavanone and 2-arylidenetetrahydro-1-naphthalenone in moderate to good yield. The regio and stereochemistry of the title compounds was established by single crystal X-ray structure and spectroscopic techniques. (C) 2002 Elsevier Science Ltd. All rights reserved.

The application of trimethylsilyl diazomethane to the synthesis of optically active pyrazolines and related studies

The 1,3-dipolar cycloadditions of trimethylsilyl diazomethane with camphorsultam-derived acrylates are reported as a means for the efficient synthesis of optically active pyrazolines. Trimethylsilyl diazomethane is a safe, commercially available diazoalkane which provides Δ¹-pyrazolines 1n good yield and diastereoselectivity when camphorsultam-derived acrylates are used as the reaction dipolarophiles . These initial cycloadducts are subsequently converted to stable, characterizable Δ²-pyrazolines upon desilylation.

A manifold of reactions that can be applied to these Δ²-pyrazolines has been developed which includes pyrazoline reduction, N-N bond reduction, addition to the pyrazoline C=N by mild carbon nucleophiles, and both solvolytic and reductive chiral auxiliary removal. Additionally, it has been demonstrated that the pyrazoline reduction products can take part in peptide coupling reactions that allow for the pyrazolidines to serve as proline-like molecules. The development of this methodology is a general solution to the problem of highly substituted, functionalized pyrazoline synthesis. Importantly, the pyrazolines thus provided have been demonstrated to be amenable to reactions that add to their value as synthetic intermediates.

An investigation into reactivity and selectivity in cycloadditions of 1,3-dipoles with formamidines

The objective of this research was to investigate the synthesis of nitrile oxides and to study their reactivity in 1,3-dipolar cycloadditions with formamidines. Chapter one looks at the literature surrounding the 1,3-dipolar cycloaddition reaction. It explores the generation of 1,3-dipoles (mainly nitrile oxides) and dipolarophiles (predominantly amidines). It discusses the potential synthetic uses of the 1,3-dipolar cycloadducts. It examines both and inter- and intra-molecular cycloaddition reactions. It recognises the use of the 1,3-dipolar cycloadditions as a successful method in building natural products and oxadiazolines. The decomposition of oxadiazolines as a route to nitriles is also outlined in this chapter. Chapter two discusses the results of this research candidate. The preparation of nitrile oxide precursors - hydroximoyl halides - is outlined at first. The generation of nitrile oxides is then demonstrated, followed by the preparation of furoxans. Methods for preparing the reference materials (nitriles and ureas), which result from decomposition of oxadiazolines, then follow. The preparation of series of Δ2-1,2,4- oxadiazolines via the 1,3-dipolar cycloaddition reaction is illustrated in this chapter. The selectivity of the addition of nitrile oxides to dipolarophiles was tested by competition reactions, which are also described in this chapter. NMR techniques were used in the study of the kinetics of the 1,3-dipolar cycloadditions used for the preparation of a series of Δ2-1,2,4-oxadiazolines, which is addressed in this chapter. Chapter three charts the experimental procedures followed to gain results which are discussed in chapter two. It also outlines all analytical data produced during the course of this research.

Calix[4]pirróis: síntese e aplicação como sensores de aniões

A presente dissertação descreve, essencialmente, o desenvolvimento de novos métodos de funcionalização de calix[4]pirróis. O uso desses calix[4]pirróis, bem como o de porfirinas e ftalocianinas, como sensores de aniões, incluindo a determinação das suas constantes de afinidade é igualmente discutido. Esta dissertação encontra-se dividida em três partes distintas. Na primeira é feita uma revisão bibliográfica acerca das metodologias de síntese dos calix[4]pirróis, bem como das suas características e aplicações. A segunda parte encontra-se subdividida em diversos pontos de acordo com o tipo de funcionalização realizada nos calix[4]pirróis. No primeiro ponto desta parte encontram-se discutidos a síntese e a caracterização do mesooctametilcalix[ 4]pirrol-2-carbaldeído e do 3-(meso-octametilcalix[4]pirrol-2- il)propenal bem como os resultados obtidos da funcionalização destes aldeídos por reacções de cicloadição 1,3-dipolar. Esses aldeídos foram usados para gerar iletos de azometino, os quais foram “apanhados” com diversos dipolarófilos, tais como o fumaronitrilo, o fumarato de dimetilo, a N-(4- metoxifenil)maleimida, a 1,4-benzoquinona e a 1,4-naftoquinona. Ambos os calixpirróis com grupo formilo deram origem a aductos de cicloadição 1,3- dipolar com rendimentos moderados ou bons, principalmente quando se utilizou fumaronitrilo, fumarato de dimetilo ou N-(4-metoxifenil)maleimida como dipolarófilos. Neste estudo verificou-se que quando as quinonas eram utilizadas como dipolarófilos apenas eram obtidos os cicloaductos do 3-(mesooctametilcalix[ 4]pirrol-2-il)propenal. No segundo ponto descrevem-se as reacções de condensação aldólica e de Knoevenagel do mesooctametilcalix[ 4]pirrol-2-carbaldeído e do 3-(meso-octametilcalix[4]pirrol-2- il)propenal. Verificou-se a ausência de resultados para as reacções de condensação aldólica mas resultados muito satisfatórios para as reacções de Knoevenagel. Foram utilizados como compostos metilénicos activados a indano-1,3-diona, o 1,3-bis(dicianometilideno)indeno, o malononitrilo, o cianoacetato de etilo, o malonato de dietilo e o ácido de Meldrum. No penúltimo ponto encontram-se discutidas as reacções dos dois aldeídos com aminas bem como a sua redução e posterior tentativa de funcionalização dos calixpirróis com grupo hidroxilo. Em ambas as tentativas os resultados foram pouco satisfatórios. No último ponto da segunda parte descrevem-se, pormenorizadamente, os métodos de síntese, purificação e caracterização estrutural dos diversos compostos sintetizados. Na terceira parte são descritos os testes dos novos calix[4]pirróis sintetizados e também de outros derivados tetrapirrólicos, nomeadamente porfirinas e ftalocianinas, com aniões. Os calix[4]pirróis sintetizados demonstraram capacidade de interagir com diferentes aniões, e a sua capacidade de interacção é dependente dos grupos funcionais introduzidos. Verificou-se que os compostos com grupos ciano conjugados com um anel pirrólico do macrociclo apresentam constantes de afinidade mais elevadas para os aniões. A concluir esta dissertação encontra-se uma revisão da literatura sobre a utilização de porfirinas como sensores de aniões. Apresentam-se também os resultados obtidos com duas porfirinas e uma ftalocianina em tal aplicação. As porfirinas testadas apresentam elevadas constantes de afinidade com os iões fluoreto e di-hidrogenofosfato. No caso da ftalocianina verificou-se que esta interage com vários aniões, bem como com metanol e sulfóxido dimetílico, originando soluções de cores muito diferentes.

Novel Strategies for Heterocyclic Constructions via 1, 4-Dipolar Intermediates

In the thesis entitled " Novel Strategies for Heterocyclic Constructions via 1 ,4-Dipolar Intermediates"Synthesis of a complex organic molecules essentially involves the formation of carbon-carbon and carbon-heteroatom bonds. Various synthetic methods are available for these processes involving ionic, pericyclic and radical reactions. Among the pericyclic reactions, dipolar cycloaddition reactions, introduced by Huisgen, have emerged as a very powerful tool for heterocyclic construction. Heterocyclic compounds remain an important class of organic molecules due to their natural abundance and remarkable biological activity, thus constituting an intergral part of pharmaceutical industry. In this respect, developing newer synthetic methodology for heterocyclic construction has been an area of immense interest. In recent years, 1,3-dipolar cycloaddition reactions proved to be efficient routes to a wide variety of five membered heterocycles, as attested by their application in the total synthesis of various complex organic molecules. However, the potential application of similar 1,4- dipolar cycloaddition reactions for the construction of six memebered heterocycles remained underexploited. In this context, a systematic investigation of the reactivity of 1,4-dipoles generated from nitrogen heterocycles (pyridine and its analogues) and dimethyl acetylenedicarboxy!ate (DMAD) towards various dipolarophiles has been carried out and the results are embodied.

Novel1, 3-Dipolar Cycloaddition Reactions of Acyclic Carbonyl Ylides and Related Chemistry

The thesis entitled novel 1,3-dipolar cycloaddition reactions of acyclic carbonyl ylides and related chemistry embodies the results of the investigations carried out to explore the reactivity of acyclic carbonyl ylides,generated by the reaction of dicarbomethoxy carbine and aldehydes towards dipolarophiles such as activated styrenes,1,2-and 1,4-quinones. In conclusion ,we have explored the reactivity pattern of acyclic carbonyl ylides derived from dicarbomethoxycarbene and aldehyde towards activated styrenes with a view to develop a stereoselective synthesis of highly substituted tetrahydrofuran derivatives. It was also found that the ylide could be trapped by various 1,2-and 1,4-diones to form dioxolane derivatives. It is noteworthy that the cycloaddition is highly region- and stereoselective. With isatins the ylide preferentially adds to the more electrone deficient carbonyl group making it regiospecific. Hetrocyclic compounds are of pivotal importance in organic chemistry, and enormous efforts have been devoted to develop new methodologies for their synthesis. It is noteworthy in this context that, 1,3-dipolar cycloaddition reaction,otherwise called Huisgen reaction, constitutes one of the most efficient methods for the synthesis of five membered heterocycles. Among the various dipoles, carbonyl ylides have received substiancial attention in recent years largely due to their utility in the synthesis of a wide range of oxygen hetrocycles, which are often found as structural subunits of many bioactive natural products.

Synthesis of enantiopure prolines via exo-stereoselective 1,3-dipolar cycloadditions to acetone-derived chiral stabilised azomethine ylides

The chiral stabilised azomethine ylide formed from condensation of the dimethyl acetal of acetone with (5S)-5-phenylmorpholinone undergoes stereoselective exo-cycloaddition reactions with a range of doubly and singly activated dipolarophiles when generated in the presence of excess (MgBr2OEt2)-O-.. The cycloadducts can be degraded to yield enantiomerically pure proline derivatives.

Regiocontrolled Synthesis of Pyrazole Derivatives Through 1,3-Dipolar Cycloaddition Reaction And Synthesis of Helicene-Thiourea based and Polymer Supported Soos's Catalyst for Asymmetric Synthesis

In first part we have developed a simple regiocontrolled protocol of 1,3-DC to get ring fused pyrazole derivatives. These pyrazole derivatives were synthesized using 1,3-DC between nitrile imine and various dipolarophiles such as alkynes, cyclic α,β-ketones, lactones, thiocatones and lactums. The reactions were found to be highly regiospecific. In second part we have discussed about helicene, its properties, synthesis and applications as asymmetric catalyst.Due to inherent chirality, herein we have made an attempt to synthesize the helicene-thiourea based catalyst for asymmetric catalysis. The synthesis involved formation of two key intermediates viz, bromo-phenanthrene 5 and a vinyl-naphthalene 10. The coupling of these two intermediates leads to formation of hexahelicene.

Dotierte Nanographenstreifen mit definierten Randstrukturen

Die in der vorliegenden Dissertation entwickelten organochemischen Protokolle und Konzepte erweitern die Bottom-Up-Synthese von atompräzisen Nanographenstreifen (GNR) um zwei fundamentale Bereiche. Zum einen die Dotierung der halbleitenden GNR mit Schwefel oder Stickstoffatomen und zum anderen ein Protokoll für eine lösungsbasierte Synthese von stickstoffdotierten Zickzack-Streifen.rnDie Dotierung von GNR beinhaltet die Synthese von monomeren Bausteinen bei denen, im Gegensatz zu ihren reinen Kohlenstoffhomologen, definierte Positionen am Rand mit zwei oder vier Stickstoff- beziehungsweise zwei Schwefelatomen ersetzt wurden. Die Synthese atompräziser GNR konnte mit verschiedenen experimentellen Methoden analysiert und anschaulich über STM visualisiert werden. Neben einer n-Dotierung gelang so auch erstmals eine Bottom-Up-Synthese von schwefeldotierten GNR. Eine mögliche Anwendung in der Nanoelektronik aufbauend auf dotierten GNR wurde bestätigt, indem durch Co-Polymerisation von stickstoffhaltigen mit reinen Kohlenstoffmonomeren Heteroschnittstellen zwischen dotierten und undotierten Bereichen hergestellt werden konnten. Solche Heteroschnittstellen sind fundamentale Grundlage von Dioden und damit Basis einer Vielzahl elektronischer Elemente wie Solarzellen oder Leuchtdioden.rnWährend für halbleitende GNR mit einer Armlehnen-Form ein breites Spektrum an organischen Syntheseprotokollen zur Verfügung stand, existierte zu Beginn dieser Arbeit keines für GNR mit Zickzack-Struktur. Innerhalb dieser Arbeit konnte eine Bottom-Up-Synthese zur Erschließung stickstoffdotierter GNR mit Zickzack-Randstruktur erarbeitet werden. Durch die Verwendung eines (2-Hydroxymethyl)phenylboronsäureesters werden Hydroxymethylsubsituenten entlang eines Polyphenylenrückgrats eingebaut, die nach Kondensation mit dem Stickstoffatom eine Zickzack-Kante ergeben. Innerhalb der synthetisierten Zielstrukturen kann das 9a-Azaphenalen als letztes, bislang nicht erschlossenes Isomer der Azaphenalene, als wiederkehrende Struktur, gefunden werden. Die Reaktivität der Zickzackkante konnte zudem zum Aufbau einer Vielzahl bislang unzugänglicher, polycyclischer Heteroaromaten über 1,3-dipolare Addition dieses polycyclischen Azomethin Ylides (PAMY) genutzt werden.rn

Binap-gold (I) versus Binap-silver trifluoroacetate complexes as catalysts in 1,3-dipolar cycloadditions of axomethine ylides

The 1,3-dipolar cycloaddition between azomethine ylides and alkenes is efficiently catalysed by [{(Sa)-Binap-Au(tfa)}2] (Binap=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; tfa=trifluoroacetyl). Maleimides, 1,2-bis(phenylsulfonyl)ethylene, chalcone and nitrostyrene were suitable dipolarophiles even when using sterically hindered 1,3-dipole precursors. The results obtained in these transformations improve the analogous ones obtained in the same reactions catalysed by [Binap–Ag(tfa)]. In addition, computational studies have also been carried out to demonstrate both the high enantioselectivity exhibited by the chiral gold(I) complex, and the non-linear effect observed in this transformation.

Binap-silver salts as chiral-catalysts for the enantioselective 1,3-dipolar cycloaddition of azomethine ylides and alkenes

Binap-AgSbF6 catalyzed 1,3-dipolar cycloadditions between azomethine ylides and electrophilic alkenes are described and compared with analogous transformations mediated by other Binap-silver(I) salt complexes. Maleimides and 1,2-bis(phenylsulfonyl)ethylene are suitable dipolarophiles for obtaining very good enantioselectivities, even better values are generated by a multicomponent version. There are some very interesting applications of the disulfonylated cycloadducts in the total synthesis of cis-2,5-disubstituted pyrrolidines, precursors of natural products, or valuable intermediates in the synthesis of antiviral compounds.

Coinage Metal Complexes as Chiral Catalysts for 1,3-Dipolar Cycloadditions

In this account, we describe the experience of our research group in the implementation of chiral coinage metal complexes into the efficient enantioselective 1,3-DC of azomethine ylides derived from α-amino acids and azlactones with different dipolarophiles. The corresponding chiral metallodipoles were generated in situ and next focused on the synthesis of highly substituted prolines. For this purpose, privileged ligands such as phosphoramidites and binap with silver(I), gold(I) and copper(II) salts are described. Depending from the ligand and mainly from the metal salt it can be possible to control the facial endo/exo-diasteroselectivity and the enantioselectivity of these types of processes. The synthetic processes are also supported by DFT calculations in order to elucidate the most plausible mechanism and the stereochemical results.