Nucleophilic addition of potassium organotrifluoroborates to chiral cyclic N-acyliminium ions: stereoselective synthesis of functionalized N-heterocycles

The stereoselective nucleophilic addition of potassium aryl- and alkynyltrifluoroborates to cyclic N-acyliminium ion derivatives from N-benzyl-3,4,5-triacetoxy-2-pyrrolidinone, affording the respective 5-substituted 2-pyrrolidinone is described. The products were obtained in moderate to good yields and with preference for the syn diastereomer. (C) 2008 Elsevier Ltd. All rights reserved.

Direct Zincation of Functionalized Aromatics and Heterocycles by Using a Magnesium Base in the Presence of ZnCl(2)

A wide range of polyfunctional aryl and heteroaryl zinc reagents were efficiently prepared in THF by using (TMP)(2)Mg center dot 2LiCl (TMP = 2,2,6,6-tetramethylpiperamidyl) in the presence of ZnCl(2). The possible pathways of this metalation procedure as well as possible reactive intermediates are discussed. This experimental protocol expands the tolerance of functional groups and allows an efficient zincation of sensitive heterocycles such as quinoxaline or pyrazine. The zincated arenes and heteroarenes react with various electrophiles providing the expected products in 60-95 % yield.

Formation of cumulenes, triple-bonded, and related compounds by flash vacuum thermolysis of five-membered heterocycles

Flash vacuum thermolysis of a large variety of heterocyclic compounds is a useful means of production of ketenes, ketenimines, thioketenes, allenes, iminopropadienones, bis(imino)propadienes, iminopropadienethiones, carbodiimides, isothiocyanates, acetylenes, fulminic acid, nitrile imines and nitrile ylides, nitriles, cyanamides, cyanates, and other compounds, often in preparatively useful yields.

Synthesis of five-membered heterocycles by indirect electrochemical approach in "Green" media

Radical cyclization continues to be a central methodology for the preparation of natural products containing heterocyclic rings. Hence, some electrochemical results obtained by cyclic voltammetry and controlled-potential electrolysis in the study of electroreductive intramolecular cyclization of ethyl (2S, 3R)-2-bromo-3-propargyloxy-3-(2’,3’,4’,6’-tetra-O-acetyl-beta-D-glucopyranosyloxy) propanoate (1a), 2-bromo-3-allyloxy-3-(2’,3’,4’,6’-tetra-O-acetyl-beta-D-glucopyranosyloxy)propanoate (1b), 2-bromo-[1-(prop-2-yn-1-yloxy)propyl]benzene (1c) and [1-bromo-2-methoxy-2-(prop-2’-yn-1-yloxy)ethyl]benzene (1d) promoted by (1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane)nickel(I), [Ni(tmc)]+, electrogenerated at glassy carbon cathodes in ethanol and ethanol:water mixtures containing tetraalkylammonium salts, are presented. During controlled-potential electrolyses of solutions containing [Ni(tmc)]2+ and bromoalkoxylated compounds (1) catalytic reduction of the latter proceeds via one-electron cleavage of the carbon–bromine bond to form a radical intermediate that undergoes cyclization to afford the substituted tetrahydrofurans.

Understanding the Origin of Selectivity in the Asymmetric Lithiation Reaction of N-Heterocycles: A Theoretical Study

The natural abundance of the N-heterocycle containing compounds has pushed the synthetic community toward the invention of new synthetic methods that result in the structural diversity of N-heterocycles. Among this, is the efficient and highly selective diamine mediated asymmetric lithiation process. Amongst the diamine chiral ligands, (-)-sparterine, which is a naturally occurring alkaloid proved to be an efficient one. Many successful, good yielding and highly selective lithiation reactions have been accomplished with the mediation by this chiral diamine base. Although, there are some examples of experimental and theoretical mechanistic studies in the literature, there is a lack of detailed understanding as to how it exactly induces the chirality. In this thesis is described a systematic investigation of how (-)-sparteine influences the stereoselectivity in the course of asymmetric lithiation reaction. This led us to the establishment of the function of A-ring’s β-CH2 effect and D-ring effect. Consequently, the importance of the A-ring and D-ring portions of (-)-sparteine in the stereoselectivity is unraveled. Another part of this thesis deals with the asymmetric lithiation of BF3-activated N,N- dimethylaminoferrocene in the presence of (1R, 2R)-N1,N2-bis(3,3-dimethylbutyl)-N1,N2-dimethylcyclohexane-1,2-diamine ( a (R,R)-TMCDA surrogate) with i-PrLi. Computational findings were in full accord with the experimental observations. Subsequently, the theoretically provided insights into the mechanism of the reaction were exploited in computational design of a new ligand. Unfortunately, the outcome of this design was not experimentally robust and an updated approach towards a successful design was explained.

Synthesis and Transformations of a Few Nitrogen and Oxygen Heterocycles

Department of Applied Chemistry, Cochin University of Science and Technology

Synthesis of chiral 3,4,5,6-tetrahydro-1,4-thiazin-2-ones (thiamorpholin-2-ones)-novel heterocycles possessing enhanced carbonyl electrophilicity over their oxygen counterparts

We report herein the first synthesis of chiral derivatives possessing the 1,4-thiazinone core. As predicted, the thiolactone is more susceptible to nucleophilic attack than the equivalent lactone system.

Solvent extraction of Am(III) and Eu(III) from nitrate solution using synergistic mixtures of n-tridentate heterocycles and chlorinated cobalt dicarbollide

The separation by solvent extraction of Am-241(III) from Eu-152(III), in 1 M NaNO3 weakly acidic (pH 4) aqueous solutions, into dilute (ca. 10(-2) M) solutions of triazinylbipyridine derivatives (diethylhemi-BTP or di(benzyloxyphenyl) hemi-BTP) and chlorinated cobalt dicarbollide (COSAN) in 1-octanol or nitrobenzene has been studied. The N-tridentate heterocyclic ligands, which are selective for Am(III) over Eu(III), secured efficient separation of the two metal ions, while COSAN, strongly hydrophobic and fully dissociated in polar diluents, enhanced the extraction of the metal ions by ion-pair formation. Molecular interactions between the two co-extractants, observed at higher concentrations, led to the precipitation of their 1: 1 molecular adduct. In spite of that, efficient separations of Am and Eu ions were attained, with high separation factors, SFAm/Eu of 40 and even 60, provided the concentration of hemi-BTP was significantly greater than that of COSAN. Excess COSAN concentrations caused an antagonistic effect, decreasing both the distribution ratio of the metal ions and their separation factor.

Synthesis of linked heterocycles via use of bis-acetylenic compounds

Linked bis-pyrazoles, a pyrazolyl-isoxazole, a pyrazolyl-pyrimidine and a pyrazolyl-triazole were synthesized starting with commercially available 1,4-bis(trimethylsilyl)-1,3-butadiyne 1 or readily available bis-acetylenic diketone 22. A stepwise approach based on the use of 1 allowed the synthesis of nonsymmetrically substituted bis-pyrazoles and linked heterocycles with two different cores whereas a symmetric approach based on the use of 22 allowed a very short synthesis of symmetric bis-pyrazoles.

Physico-chemical parameter correlations in the [RuCl2(CO)(L)(PPh3)2] complexes (L = N-heterocycles)

Fourteen complexes in the series [RuCl2(CO)(L)(PPh3)2] (where L = N-heterocycles) have been prepared and characterized by IR and NMR spectroscopies, and cyclic voltammetry. A good correlation is found between observed and calculated electrochemical potentials; E1/2 vs pKa or (Gp, σm for a series of similar ligands. It is now reported that the carbonyl stretching frequency, νCO, and the 13C and 31P NMR signals do not correlate well with any of the physico-chemical parameters used (E1/2, Taft's and Hammett's parameters). This behaviour is probably due to the characteristics of the Ru(II) species, which does not transmit the steric and electron donor/acceptor properties of the ligands to the carbonyl group, or because the measurements are not able to detect the effect induced by the changes in the ligand L. Indeed, good correlations are obtained when the measurements directly involve the metal centre, as is the case in the E1/2 measurements. Crystals of o[RuCl2(CO)(4-pic)(PPh3)2] are monoclinic, space group P21/n, a = 12.019(2), b = 13.825(3) and c = 22.253(3) . The structure was solved by the Patterson method and was refined by full-matrix least-squares procedure to R = 0.054 and Rw = 0.055, for 2114 reflections with I > 3σ(I). For L = 2-acetylpyridine and 2-methylimidazole, complexes with formulae [RuCl2(CO)(L)(PPh3)] · L and [RuCl2(CO)(L)2 (PPh3)], respectively, were obtained. © 1998 Elsevier Science Ltd. All rights reserved.

Stereoselective synthesis of heterocycles as intermediates of biologically active compounds

The aim of this thesis was to investigate the synthesis of enantiomerically enriched heterocycles and dehydro-β-amino acid derivatives which can be used as scaffolds or intermediates of biologically active compounds, in particular as novel αvβ3 and α5β1 integrin ligands. The starting materials of all the compounds here synthesized are alkylideneacetoacetates. Alkylidene derivates are very usefull compounds, they are usually used as unsaturated electrophiles and they have the advantage of introducing different kind of functionality that may be further elaborated. In chapter 1, regio- and stereoselective allylic amination of pure carbonates is presented. The reaction proceeds via uncatalyzed or palladium-catalyzed conditions and affords enantiopure dehydro-β-amino esters that are useful precursor of biologically active compounds. Chapter 2 illustrates the synthesis of substituted isoxazolidines and isoxazolines via Michael addition followed by intramolecular hemiketalisation. The investigation on the effect of the Lewis acid catalysis on the regioselectivity of the addition it also reported. Isoxazolidines and isoxazolines are interesting heterocyclic compounds that may be regarded as unusual constrained -amino acids or as furanose mimetics. The synthesis of unusual cyclic amino acids precursors, that may be envisaged as proline analogues, as scaffolds for the design of bioactive peptidomimetics is presented in chapter 3. The synthesis of 2-substituted-3,4-dehydropyrrole derivatives starting from allylic carbonates via a two step allylic amination/ring closing metathesis (RCM) protocol is carried out. The reaction was optimized by testing different Grubbs’ catalysts and carbamate nitrogen protecting groups. Moreover, in view of a future application of these dehydro-β-amino acids as central core of peptidomimetics , the malonate chain was also used to protect nitrogen prior to RCM. Finally, chapter 4 presents the synthesis of two novel different classes of integrin antagonists, one derived from dehydro-β-amino acid prepared as described in chapter 1 and the other one has isoxazolidines synthesized in chapter 2 as rigid constrained core. Since that these compounds are promising RGD mimetics for αvβ3 and α5β1 integrins, they have been submitted to biological assay. and to interpret on a molecular basis their different affinities for the αvβ3 receptor, docking studies were performed using Glide program.

Organocatalytic tandem reactions of polyfunctional compounds for the synthesis of enantioenriched heterocycles. Reazioni tandem organocatalitiche di composti polifunzionali per la sintesi di eterocicli enantioarricchiti.

In questo lavoro di tesi sono state sviluppate reazioni domino, tandem e procedure one-pot per ottenere eterocicli enatioarricchiti. Lo sviluppo di queste metodologie sintetiche è molto importante perché permettono di ottenere molecole complesse partendo da prodotti semplici, senza effettuare ripetuti passaggi di purificazione (stop-and-go or step-by-step synthesis). Lo scopo di questo lavoro è di ottenere derivati tetraidrofuranici modificati e derivati ossoazzolinici enantioarrichiti tramite reazioni SN2-Michael o tramite reazioni aldolica-ciclizzazione-Michael usando la catalisi asimmetrica a trasferimento di fase (PTC). Come catalizzatori PTC per imprimere enantioselezione sono stati utilizzati sali di ammonio quaternario derivati dagli alcaloidi della Cinchona. Sono state ottimizzate le condizioni di reazione (base inorganica, temperatura, solvente, tempo di reazione) per i diversi substrati presi in considerazione. I prodotti target sono stati ottenuti con buone rese, ottime diastereoselezioni ma con bassa enantioselezione. I risultati ottenuti richiedono un’ulteriore ottimizzazione e dovranno essere valutate variazioni strutturali dei nucleofili utilizzati. In this thesis were developed domino, tandem reactions and one-pot procedures to obtained enantioenriched heterocycles. The development of these methodologies is very fundamental because they allow to obtain complex molecules starting from raw materials, without carrying out repeated purification steps (stop-and-go or step-by-step synthesis). The purpose of this work is to obtain enantioenriched tetrahydrofuran and oxazoline derivatives through a SN2-Michael reaction or a aldol- cyclization-Michael reaction using the phase-transfer asymmetric catalysis (PTC). For imprint enantioselection we used Cinchona alkaloids quaternary ammonium salts derivatives. The reaction conditions (inorganic base, temperature, solvent, reaction time) were optimised for the different substrates taken into account. The target products were obtained with good yields, excellent diastereoselections but with low enantioselections. The obtained results require further optimization and structural changes in the nucleophiles used must be evaluated.

Synthesis of Nitrogenated Heterocycles by Asymmetric Transfer Hydrogenation of N-(tert-Butylsulfinyl)haloimines

Highly optically enriched, protected, nitrogenated heterocycles with different ring sizes have been synthesized by a very efficient methodology consisting of the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)haloimines followed by treatment with a base to promote an intramolecular nucleophilic substitution process. N-Protected aziridines, pyrrolidines, piperidines, and azepanes bearing aromatic, heteroaromatic, and aliphatic substituents have been obtained in very high yields and diastereomeric ratios up to >99:1. The free heterocycles can be easily obtained by a simple and mild desulfinylation procedure. Both enantiomers of the free heterocycles can be prepared with the same good results by changing the absolute configuration of the sulfur atom of the sulfinyl group.

Intramolecular Bromoamination of Conjugated N-Tosylaminodienes Using N-Bromosuccinimide. Synthesis of Bromoallyl-Substituted N-Heterocycles and Their Applications as Building Blocks

The bromonium-promoted cyclization of conjugated aminodienes is described. The reaction proceeds smoothly in the presence of N-bromosuccinimide as halonium promoter, and using N-tosyl-protected aminodienes as substrates, to give the corresponding halocyclization products in high yields and with high diastereoselectivities. It can be envisaged that the formation of these products is the result of an SN2′-type ring-opening of a terminal bromonium intermediate in a 5-exo-trig or 6-exo-trig cyclization mode. The presence of an allyl bromide moiety in the haloamination products makes these molecules highly attractive from a synthetic point of view, as it opens the way for further transformations. Thus, allylic substitution reactions with different nucleophiles (acetate, azide, cyanide, and malonate), palladium-catalysed Suzuki coupling, and silver-mediated bromine displacement reactions were carried out successfully.