Anti-Markovnikov Intermolecular Hydroamination of Alkenes and Alkynes : A Mechanistic View

Altres ajuts: acords transformatius de la UABHydroamination, the addition of an N-H bond across a C-C multiple bond, is a reaction with a great synthetic potential. Important advances have been made in the last decades concerning catalysis of these reactions. However, controlling the regioselectivity in the amine addition toward the formation of anti-Markovnikov products (addition to the less substituted carbon) still remains a challenge, particularly in intermolecular hydroaminations of alkenes and alkynes. The goal of this review is to collect the systems in which intermolecular hydroamination of terminal alkynes and alkenes with anti-Markovnikov regioselectivity has been achieved. The focus will be placed on the mechanistic aspects of such reactions, to discern the step at which regioselectivity is decided and to unravel the factors that favor the anti-Markovnikov regioselectivity. In addition to the processes entailing direct addition of the amine to the C-C multiple bond, alternative pathways, involving several reactions to accomplish anti-Markovnikov regioselectivity (formal hydroamination processes), will also be discussed in this review. The catalysts gathered embrace most of the metal groups of the Periodic Table. Finally, a section discussing radical-mediated and metal-free approaches, as well as heterogeneous catalyzed processes, is also included

Syntheses of novel acyclic amino-amido ligands

Bibliography: page 154.Towards the labelling of biological macromolecules in contrast media, a synthesis of the novel bifunctional amido-ligands N,N' -bis[2-(N'',N''-dimethylamino)ethyl]-4-aminobenzylmalondiamide (67) and the 3-aminopropyl derivative (66) from appropriately C-functionalized malonates by amidation with N,N-dimethylethylenediamine (62) followed by reduction of the respective nitro (64) and cyano (63) groups is described. The synthesis of N,N'-bis[2-(N'',N''-dimethylamino)ethyl]iminodiacetamide (73) from diethyl N-benzyliminodiacetate (79) by amidation· with (62) followed by debenzylation is described. Herein is also reported the unsuccessful attempts to prepare a functionalized pentaamine ligand similar to (73) via the intermediacy of N,N'-bis[2-(N'',N''-dimethylamino)ethyl]-N'''-(2,2-diethoxyethyl) iminodiacetamide (112) whose preparation is also detailed. Attempts to this end via the Mitsunobu and Steglich coupling of N,N' -bis[2-(N'',N''- dimethylamino)ethyl]-N'''-(2-hydroxyethyl)iminodiacetamide (100) with N-tertbutyloxycarbonylglycine (105) also met with failure .. Further failed attempts to secure suitably functionalized intermediates by N-alkylation of diethyl iininodiacetate (70) with appropriate electrophiles are described. The successful functionalization of the pentaamine series of ligands by N-alkylation of (73) withpnitrobenzoyl chloride (118) to give N,N' -bis[2-(N'',N''- dimethylamino)ethyl] N''' -(4-nitrobenzamido)iminodiacetamide (119) is presented. The preparation of the non-functionalized novel trioxo heptaamine ligand N,N' ,N''-tris[2-(N'',N''-dimethylamino)ethyl]nitrilotriacetamide hydrochloride (86a) is also described. An investigative study towards the assembly of a novel triamine system for encapsulating NMR or isotopic NMR-active metal ions for possible use in diagnostic medicine is reported. The key facet to this end is the reported preparation of N,N' ,N''-tris(2-aminoethyl)propane-1,2,3-tricarboxamide (89) by controlled amidation of trimethyl propane 1,2,3-tricarboxylate (88) with ethylenediamine. The syntheses of functionalized and non-functionalized novel tetraamine dioxo and trioxo ligands from glycine, ethyl N-benzylglycinate (78), L-valine, and L-lysine via classical peptide synthesis methodology (in part) are described

Zr(IV)-Assisted Peptide Hydrolysis

The development of new reagents to efficiently cleave peptides and proteins has become increasingly important for protein structural studies and other applications. However, this has proved to be a very challenging task due to the extreme stability of the peptide amide bond. Transition metal complexes cleave proteins and peptides through either oxidative or hydrolytic pathways. However, hydrolytic cleavage is preferred over oxidative cleavage, because the latter process produces irreversibly modified peptide fragments. Metal-assisted peptide hydrolysis is introduced in Chapter I. The metals Ce(IV), Co(II), Co(III), Cu(II), Fe(III), Mo(IV), Ni(II), Pd(II), Pt(II), Zn(II), and Zr(IV) are described as promising non-enzymatic hydrolysis reagents. In Chapter II, Zr(IV)-assisted hydrolysis of the dipeptide Gly-Gly and of its N- and C- blocked analogs is described. The highest levels of cleavage were observed at pH values ranging from 4.4 to 4.7. When the pH was raised to ~ 7.0, hydrolysis yields were decreased and amounts of zirconium precipitation were increased proportionately. Zirconium(IV)-assisted peptide hydrolysis in the presence of 4,13-diaza-18-crown-6 is reported in Chapter III. The goal of this work was to use an azacrown ether to reduce Zr(IV) precipitation and enhance levels of hydrolysis at neutral pH. An experiment in which 16 glycine containing dipeptides were hydrolyzed by Zr(IV) and by Zr(IV)/4,13-diaza-18-crown-6 indicated that 4,13-diaza-18-crown-6 markedly enhanced the reactivity of Zr(IV) under near physiological conditions. Because Zr(IV) precipitation was not reduced in these reactions, we proposed that hydrolysis of peptides by Zr(IV)/4,13-diaza-18-crown-6 might be heterogeneous in nature. In Chapter IV, seventeen macrocyclic and open-chain Zr(IV) ligands were compared in order to gain mechanistic insights that would enable hydrolysis yields at neutral pH to be further improved. While the macrocyclic ligands 4,13-diaza-18-crown-6 and 4,10-trioxa-7,13-diazacyclopentadecane tended to produce higher levels of Zr(IV)-assisted dipeptide cleavage, it was not necessary to have a ring structure to enhance Zr(IV) reactivity. With respect to the open-chain ligands, the potential ability to form multiple chelate rings appeared to coincide with reduced levels of Zr(IV) precipitation as well as with reduced levels of dipeptide hydrolysis. In Chapter V, a summary of our results and conclusions is presented

Synthesis of novel heterocyclic systems as potential inhibitors of HIV-1 enzymes

This study has focussed on the application of Baylis-Hillman methodology in the development of efficient synthetic pathways to libraries of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones and indolizine-2-carboxamides and on an exploration of their medicinal potential. The approach to 3-[(N-cycloalkylbenzamido)methyl]-2(1H)-quinolones involved a six-step pathway comprising: Baylis-Hillman reaction of 2-nitrobenzaldehyde derivatives and methyl acrylate to afford nitro-Baylis-Hillman adducts; thermal cyclisation of the adducts to give a range of 3-(acetoxymethyl)-2(1H)-quinolones in good to excellent yields; hydrolysis of the acetates; conversion of the resulting alcohols to the 3-chloromethyl analogues; amination; and, finally, acylation to afford the target amides. Variable temperature NMR methods were used to facilitate analysis of the ¹H and ¹³C NMR spectra which were complicated by internal rotation and cycloalkyl ring-flipping effects. On the other hand, the indolizine-2-carboxamides were obtained in several steps commencing with the Baylis-Hillman reaction of pyridine-2-carboxaldehyde and methyl acrylate. Thermal cyclisation of the Baylis-Hillman adduct afforded indolizine esters, hydrolysis of which gave the corresponding acids which served as precursors to the target indolizine-2-carboxamides. The final amidation step, however, proved to be particularly challenging. Various coupling strategies were explored to access indolizine-2-carboxamides. These included the use of 2,2,2-trifluoroethyl borate which showed limited promise, but propylphosphonic acid anhydride (T3P) proved to be the most effective coupling agent, permitting the formation of 24 novel indolizine-2-carboxamides from hydrazines, aliphatic amines and a range of heterocyclic amines. A high-field NMR-based kinetic study of the mechanism of the Baylis-Hillman reaction of pyridine-4-carboxaldehyde and methyl acrylate in the presence of 3-hydroxyquinuclidine in deuterated chloroform was initiated, reaction progress being followed by the automated collection of ¹H and DEPT 135 NMR spectra over ca. 24 hours using a high-field (600 MHz) NMR instrument. The results have provided critical new insights into the mechanism. NMR analysis has also been used to elucidate the multiplicity of signals associated with rotameric equilibria observed at ambient probe temperature. Variable temperature 1D- and 2D-NMR spectra were used to facilitate the unambiguous characterisation of the 2-quinolone benzamides and some of the indolizine-2-carboxamides. The 3-[(N-cycloalkylbenzamido)methyl]-2(1H)-quinolones, together with selected precursors, and a number of the indolizine-2-carboxamides have been screened in vitro as potential HIV-1 enzyme inhibitors. A survey of the activity of the 2-quinolones against HIV-1 integrase, protease and reverse transcriptase revealed selective inhibition of HIV-1 integrase with the most active IN inhibitor, 3-[(cyclopentylamino)methyl-6-methoxy-2(1H)-quinolone 115e, producing residual enzyme activity of 40% at a concentration of 20 μM. Many of the 2-quinolones exhibited no significant cytotoxicity against HEK 293 cells at 20 μM concentrations. 3-[(N-Cyclohexylamino)methyl]-6-methoxy-2(1H)-quinolone 114e was the only compound to exhibit ant-plasmodial activity (55% pfLDH activity). The survey of indolizine-2-carboxamides also revealed encouraging inhibition against HIV-1 integrase. None of these compounds exhibited cytotoxicity at 20 μM against HEK 293 cells, while a number of them exhibited some activity against Plasmodium falciparum (3D7 strain) and Trypanosoma brucei. Selected indolizine-2-carboxamides exhibited significant anti-tubercular activity in the 7H9 CAS GLU Tx and 7H9 ADC GLU Tw media. In view of the inherent fluorescent character and biological potential of the synthesised indolizine-2-carboxamides, their photophysical properties were explored to establish their possible dual use as bio-imaging and therapeutic agents. The major absorption and corresponding emission bands, and the associated molar absorption coefficients (Ɛ) expressed in the form of log Ɛ were determined. Their high extinction coefficients, large Stokes shift and red-shifted emissions in the visible region indicate their potential for use as fluorophores

NOVEL APPROACHES FOR CATALYTIC DIRECT AMIDE FORMATION

Abstract The significance of amides as a component of biomolecules and synthetic products has triggered the development of catalytic direct amidation methods which involve reaction of a carboxylic acid and amine to form an amide with water as the only by-product. These methods evade the need for stoichiometric activation or coupling reagents and hence, are important green chemical processes. Investigations into direct amide formation began with the development a mild reaction conditions for the direct amidation reaction with known arylboronic acid catalysts in two different model reactions and compared with both reported and potential organometallic catalysts (Zr and Fe based). After a systematic evaluation of solvent, temperature and catalyst, ambient reaction conditions were applied in the direct amidation of amino-acid derivatives in order to exploit these more economical reagents for peptide synthesis which is both little used and little explored. Protected amino acid derivatives showed slow reactivity compared to simple amine-carboxylic acid combinations and hence high catalyst loadings were required, though did proceed at 65~68 °C generally avoiding racemisation. However, an interesting synergistic catalytic effect was observed during dipeptide formation using mixture of two arylboronic acid catalysts (1:1) in the direct amidation reaction at lower temperatures, although the process was particularly slow. This impressive result led to explore more about the effect of ‘Cooperative Catalysts’, particularly, on the less reactive acid-amine combination. As a consequence, some commercially important synthesis has been reviewed through this novel cooperative catalysis to ensure their real applicability in industries. Acceptance of the practicability and general applicability of this new approach depends upon the understanding of the mechanism of the cooperative catalysis. In order to reveal the mechanism of the cooperative catalysis the direct amide formation reactions were followed by the real time monitoring technology (React-IR) and HPLC. However, further investigations are required to understand the mechanistic intricacies of this cooperative catalysis. Further, the role of H-bonding in the amide bond formation with significantly inert acid (pivalic acid) towards the amine to form amide has been attempted. In order to accelerate the catalytic activity the use of a potential catalyst promoter, ‘ANB 209’ in the direct amidation reactions was also examined. Improvements in catalysts activity or alterations in catalyst would need further study so that the direct amide formation becomes a common tool for a wide range of carboxylic acid and amine partners. The effect of different substituents on the α-position of carboxylic acid with various amine substrates was investigated to understand the exceptional direct amide formation of the synthesis of mandipropamid, a well known fungicide. Both uncatalysed and catalysed direct amidations of mandelic acid was done with different amine substrates at different temperatures, resulting different rate of amide formation. Finally, the application of two novel borinic acid (R1RBOH) compounds in the direct amide formation reactions has been assessed for the first time, which displayed in some cases the potential to act as catalysts for direct amide formation. Further research will likely to accelerate the developments of this type of catalysts in direct amidations

Synthesis of dendritic gadolinium complexes with enhanced relaxivities

This thesis deals with the synthesis of dendritic gadolinium complexes based on DOTA, with a view to obtaining enhanced relaxivities. Li addition to the inherently long electronic relaxation time and high paramagnetic moment of the gadolinium (III) ion, the speed of rotation of its complexes in solution is a decisive parameter in the determination of the relaxivity. This parameter is dependent on the molecular mass of the complex. Initially, the enantioselective synthesis of novel a-substituted analogues of DOTA was attempted but was not successful due to difficulties encountered in attaining the tetraalkylation of cyclen and the purification of the products obtained. Therefore, further studies were carried out based on the known [Gd(gDOTA)]" system. The synthesis of three medium M(_W) dendrons, each with a focal primary amino group was carried out. Their structures may be described as dendrimeric analogues of poly(ethylene glycol). Two of these structures were successfully coupled to the gadolinium (III) chelate, [Gd.gDOTA]. The acid-catalysed epimerisation of the statistical distribution of stereoisomers yielded solely the (RRRR)/(SSSS) isomeric pair. This system had previously been shown to undergo fast water exchange. The coupling and deprotection procedure yielded paramagnetic dendritic complexes with molecular weights of 2013 and 3535.Relaxivity measurements were carried out on these systems and the results showed significantly higher relaxivities of 18 and 21 mM(^-1) s(^-1) respectively, compared with a value of 7.8 mM(^-1) s(^-1) for the parent compound. Examination of NMRD profiles for the larger system showed a decrease in the rotational correlation time to 310 ps at 298 K, as expected. However, this was accompanied by an increase in the inner-sphere water exchange lifetime to 570 ns at 298 K. Therefore, although an improvement in relaxivity was obtained through a coupling to the slower rotation of the system in solution, this enhancement was limited by the accompanying decrease in the rate of water exchange. The best fitting procedure of the NMRD profiling procedure revealed the presence of 8 second-sphere water molecules at an average distance of 4Å. The second sphere contribution was shown to be the dominant contributor to the overall relaxivity. This accounted for >50% of the increased relaxivity

Development of hydrogen isotope exchange methodologies for the deuteration of aromatic substrates

This thesis entails the development of practical and cost-efficient deuteration methodologies. The first C–H activation and deuteration of aromatic substrates using an earth-abundant manganese catalyst and transient directing groups was reported. Secondly, the transient directing group strategy was transferred to a ruthenium-catalyzed hydrogen isotope exchange reaction. Lastly, the electronic characteristics of pyridine derivatives were harnessed for a transition metal-free deuteration protocol. The results are expected to inspire future developments in sustainable hydrogen isotope exchange.In dieser Dissertation wurden praktische und kosteneffiziente Deuterierungsreaktionen entwickelt. Die erste C-H-Aktivierung und Deuterierung von aromatischen Substraten mittels eines häufig vorkommenden Mangankatalysators und transienter dirigierender Gruppen (TDG) wird beschrieben. Weiterhin wurde die TDG-Strategie auf eine rutheniumkatalysierte Isotopenaustauschreaktion übertragen. Schließlich wurden die elektronischen Eigenschaften von Pyridinderivaten für eine übergangsmetallfreie Deuterierung genutzt. Es wird erwartet, dass die Ergebnisse weitere nachhaltige Deuterierungen inspirieren

Synthesis and complexation chemistry of new n-functionalised tetra-arzamacrocycles

Tetraazamacrocycles occupy a unique position in coordination chemistry, owing to their ability to form very stable complexes with a large range of metal ions. The inclusion of additional pendent coordinating groups is of particular interest, due to the effect on the properties of these compounds as ligands. The regioselective synthesis of N,N’-dialkylated-1,4,8,11-tetraazacyclotetradecane in positions 1,5-, 1,8- and 1,11- has been accomplished using different substituents, including the potentially coordinating 2-pyridylmethyl group. A number of synthetic strategies have been investigated. The functionalisation of the related, cyclic dioxotetramines, 1,4,8,11-tetraazacyclotetradecane-a,b-diones (a,b = 2,3, 5,7 and 5,12) at the amino nitrogens has also been carried out. The nickel, copper and chromium complexes of some of these ligands have been prepared and characterised. In several cases, solid state structures have been elucidated by X-ray crystallography, and have revealed a number of distinct and intriguing structural types and macro cyclecon formations. UV-Visible absorption spectroscopy, cyclic voltammetry and (forchromium) luminescence spectroscopy have been used to investigate the properties insolution. New octadentate ligands based on the 1,4,7,10-tetraazacyclododecane ring, tris-N-functionalised with acetate groups, have been synthesised, for preparation of water soluble lanthanide complexes of high thermodynamic and kinetic stability. In one class of ligand, the eighth donor atom is the carbonyl oxygen of a covalently-linked para-substituted acetophenone {-CH2C(0)C6H4-X, where X = H, OMe, NMe 2 }. Efficient sensitisation of europium(III) luminescence is observed following excitation of the acetophenone, with the para-substituent exerting a significant effect on the photophysical properties. In the second class, the macrocycle is connected through a three- or four-atom linker, containing a coordinating amide group, to a benzophenone moiety, found to act asan efficient sensitiser of both europium(ffl) and terbium(M) bound to the macrocycle. In both classes, lifetime measurements in H 20 and D20 reveal the presence of a water molecule occupying the ninth coordination site of the metal ion. In the third class, 8-benzyloxyquinoline has been linked to the macrocycle, through a single 2-methylene unit. In this system, the nitrogen of the aromatic group is appropriately positioned to bind to the coordinated metal ion. No additional water molecule is observed in this case, and it is proposed that this is due to the benzyloxy group successfully occupying the site normally taken by the water molecule