Дисертації з теми "Radical rearrangement"

Le squelette indolo[2,3-b]quinoléique est une cible synthétique attrayante car il est présent notamment dans la néocryptolépine, alcaloïde aux propriétés cytotoxiques et antipaludéennes. Nous proposons ici une approche originale pour accéder à ce tétracycle, qui combine dans une réaction radicalaire en cascade une cyclisation à un réarrangement de Smiles. La mise au point des conditions expérimentales et l'étude mécanistique de cette voie ont constitué le premier objectif de ce travail. Outre les produits attendus, les études structurales approfondies ont mis en évidence la formation de composés inédits résultant d'étapes radicalaires supplémentaires. En parallèle, l'application de la méthode à un substrat judicieusement fonctionnalisé a conduit au 3-(2'-aryl-N-alkylacétamido)oxindole, un intermédiaire clé vers le système indolo[2,3-b]quinoléique 6 et 11 disubstitué ciblé
The indolo[2,3-b]quinoline ring system is an attractive synthetic target present in neocryptolepine, an antiplasmodial and cytotoxic alkaloid. We proposed an original pathway toward this squeleton, combining as key step a 5-exo-trig cyclisation to a Smiles rearrangement in a domino radical process. We first focused on scope and limitations studies and mechanistic investigations. Apart from the cyclised-rearranged products we isolated new original structures resulting from supplementary radical reactions. The application of the developed method to a conveniently functionalised substrate led to 3-(2'-aryl-N-alkylacetamido)indolinone, a key intermediate which was further converted to the aimed 6,11-disubstituted indolo[2,3-b]quinoline tetracycle

This thesis describes efforts to develop new methods for the synthesis of bridged azacycles using nitrogen-directed free radical rearrangements. Free radical addition to 7-azanorbornadienes were carried out to give 7-substituted 2- azanorbornenes (Scheme a.l, X-Y = RS-H or PhSe-H). [illustration in text ...] Scheme a. 1 Nitrogen-directed homoallylic radical rearrangement via intermolecular radical addition. A conceptually novel and theoretically interesting nitrogen-directed neophyl rearrangement (Scheme a.2) was developed into a synthesis of 2- azabenzonorbornanes 2. [illustration in text ...] Scheme a.2 Nitrogen-directed neophyl-like rearrangement to 2-azabenzonorbornanes. In this case the radical 1 was generated by Barton deoxygenation of 7- azabenzonorbornanols. The effect on rearrangement of bicyclic core substitution and of aromatic ring electronics was probed in some detail, and the process was synthetically useful for a wide range of substrates. Variation of the protecting group on nitrogen was investigated and the product profiles from neophyl-like rearrangement were consistent with a process driven by the stability of a radical α to nitrogen as a result of SOMO-lone pair orbital interaction. The kinetics and mechanism of these processes are examined where appropriate, leading to estimates of rate constants for the rearrangements.

The ring-opening of cyclopropylcarbinyl radicals has been postulated to proceed via a dipolar transition state. In this thesis it was hoped to delineate some of the factors that influence the rate of ring-opening of some substituted cyclopropylcarbinyl radicals and hence estimate their relative importance. This would allow the involvement of the dipolar transition state in the ring-opening process to be assessed. In order to achieve the above objective it was necessary to synthesise methylcyclopropanes with substituents at both the a-position and the 2-position. Such compounds should readily react with t-butoxyl radicals to give a series of cyclopropylcarbinyl radicals. The bulk of the synthetic work was in two parts, the first involved synthesis of 2,2-difluoro substituted cyclopropanes, to determine the influence of fluorine substituents in the cyclopropane ring. The second section involved cyclopropanations using carboethoxycarbene. Radicals were generated, from successfully synthesised precursors, and their electron spin resonance spectra recorded. The data obtained provided evidence for the involvement of a dipolar transition state in some of the ring-opening rearrangements. However, in several of the radicals other factors are clearly influencing the observed ring-opening. In another section of the work the effect of phenyl and ferrocenyl substituents on the ring-opening of cyclopropylcarbinyl radicals was assessed.

Cyclopropyl-containing substrates have been frequently utilized as "probes" for the detection of SET pathways in organic and biorganic systems. These reactions are based on the cyclorpropylcarbinyl - homoallyl rearrangement, which is fast and essentially irreversible. The implicit assumption in such studies is that if a "radical" species is produced, it will undergo ring opening. We have found that there are two important factors to consider in the design of SET probes: 1) ring strain, the thermodynamic driving force for the rearrangement, and 2) resonance energy, which may help or hinder rearrangement, depending on the specific system. Delocalization of spin and charge were found to be important factors pertaining to substituent effects on the rates of radical anion rearrangements. Previous studies from our lab have centered on highly conjugated phenyl cyclopropyl ketones. This work considers a series of compounds varying in their conjugative components from a highly conjugated spiro[2.5]octa-4,7-dien-6-one and derivatives to simple aliphatic ketones. Utilizing cyclic, linear sweep voltammetry, and preparative electrolysis techniques, it was discovered that all substrates yielded ring opened products with rates and selectivities that will prove useful and informative in the design of mechanistic probes based on the cyclorpropylcarbinyl - homoallyl rearrangement. Rates of homogeneous electron transfer from a series of hydrocarbon mediators to substrates were measured using homogeneous catalysis techniques. Standard reduction potentials and reorganization energies of substrates were derived using Marcus theory. Conjugative interactions with the cyclopropyl group are discussed.
Ph. D.

The dissociative electron transfer reactions of a series of α-epoxyketones and tetra-n-butylammonium acetate have been examined by electrochemical and computational techniques. Results for both the direct electrochemical (linear sweep voltammetry and convolution voltammetry) and indirect electrochemical (homogeneous redox catalysis) reductions of the epoxyketones are presented. In cases where the ring-closed radical anion generated by reduction of the epoxyketones is resonance stabilized (aromatic epoxyketones) the mechanism proceeds in a stepwise fashion, where the electron transfer and bond breaking reactions occur in sequential, discrete steps. On the other hand, where there is no additional resonance stabilization afforded to the ring-closed epoxide radical anion (aliphatic epoxyketones) the reaction proceeds in a concerted fashion, where electron transfer and ring cleavage occur simultaneously. The presence (or absence) of resonance stabilization in the ring-opened distonic radical anion plays little role in the kinetics of these dissociative electron transfers. Computations with the Density Functional Theory (B3-LYP and BHandH-LYP) on α-epoxyketones are also presented, and are in good agreement with the electrochemical results. The oxidative dissociative electron transfers of the acetate anion in "dry" and "wet" (0.5 M H2O) acetonitrile were also characterized with direct and indirect electrochemical experiments, again utilizing linear sweep voltammetry, convolution voltammetry, and homogeneous redox catalysis. There is a significant change in the observed oxidation potential of the anion upon addition of water, as well as an apparent decrease in the intrinsic barrier to the electron transfer. The possible transition from a concerted to stepwise mechanism for the dissociative electron transfer of acetate upon addition of water is examined - the electrochemical data is compared to theoretical models for both the concerted and stepwise processes. It is determined that the indirect electrochemical experiments do not proceed through an outer sphere electron transfer. Additionally, it is shown that the difference between the direct oxidation of acetate in anhydrous and wet acetonitrile is unlikely to be the result of transition from a purely concerted mechanism to a purely stepwise mechanism based on thermodynamic considerations.
Ph. D.

Esters of cyclohexa-2,5-diene-l-carboxylic acid were investigated to study the transfer of the labile bisallylic hydrogens (C-4) to give the cyclohexadienyl radical and then the subsequent decarboxylative stage to give R •, the driving force being the rearomatisation of the benzene ring. The undesirable reaction, whereby hydrogen is abstracted from C-1, was prevented by the introduction of a methyl group into this position. The cyclohexa-2,5-diene-l-carboxylic acids are readily prepared by a Birch type reduction of benzoic acid. All the esters derived from cyclohexa-2,5-diene-l-carboxylic acid, were examined by EPR spectroscopy and showed the cyclohexadienyl radical. No decarboxylation was evident by this technique. Also investigated, by EPR spectroscopy, were the acids with different substituents at C-1, showing that for acids with highly stabilised alkyl substituents, decomposition occurs. Esters reacted with N- bromosuccinimide showed some of the desired bromides, formed after CO2 loss from the cyclohexadienyl radical. Esters forming non-stabilised radicals on decarboxylation have given the intended products in lower yields. The esters have also been examined in reactions with acrylonitrile, addition being observed to varying degrees. The radicals generated from 9-hydroxy- and 9-bromo-pentacyclo-[4.4.0.0 2·5.0 3⋅8.0 4·7]nonane (homocubane) and for the same derivatives of pentacyclo- [4.4.0.0 2·5.0 3⋅8.0 4·7]]decane (basketane) were observed by EPR spectroscopy. In spite of their very large strain energies both radicals rearranged extremely slowly and unrearranged products were obtained from homolytic reactions in solution at temperatures below 150°C. At higher temperatures the 9-basketyl radical rearranged by a cascade of three beta-scissions, the ultimate product being l-(4-cyclobut-2-enyl)cyclohexa-2,4-diene. The 9-homocubyl radical did not rearrange even at 220°C. Several reasons why these cage radicals rearrange at least six orders of magnitude more slowly than the related cubylcarbinyl radical are discussed. Photobromination of basketane yielded a mixture of four tetrabromides which were formed by bimolecular homolytic substitution at every bridgehead. Norcubylcarbinyl radicals, that were generated by bromine abstraction from norcubylcarbinyl bromide, rearranged so rapidly that only the product of β-scission, 6-methylenebicyclo[3.1.1]hept-3-yl, could be observed by EPR spectroscopy. The rate constant for β-scission was estimated from the EPR experiments, and from reductions of norcubylcarbinyl bromide with tributyltin hydride, to be > 5x109s-l at 298K. A series of 3-substituted bicyclo[l.l.l]pent-l-yl radicals, including the 3-fluoro-derivative, was generated by bromine atom abstraction from l-bromo-3-substituted- bicyclo[l.l.l]pentanes and examined by EPR spectroscopy. The exceptionally large hyperfine splittings obtained from magnetic nuclei of the 3-substituents indicated that crosscage electronic interactions were substantial in these species. Bromine atom abstraction by triethylsilyl radicals from l-bromo-3-fluorobicyclo[l.l.l]pentane was found to take place more rapidly than bromine abstraction from the unsubstituted parent, i.e. the fluorine substituent mediated a significant polar effect. Evidence was found of a novel disproportionation process in which the γ-fluorine atom was transferred from the 3-fluoro-radical to a triethylsilyl or to a second bicyclo[l.l.l]pent-l-yl radical; an analogous chlorine atom transfer process was found for the 3-chloro-radical. 4-Substituted bicyclo[2.2.2]oct-l-yl radicals were generated by bromine atom abstraction from the corresponding l-bromobicyclo[2.2.2]octanes and observed in solution by EPR spectroscopy. The EPR data indicated that 4-substituents exercised a significant effect at the radical centre, mainly by a through bond mechanism. 10-Substituted triptycyl radicals were generated in a similar way but showed no hfs from magnetic nuclei of the substituents. Bicyclo[2.2.2]oct-l-yl radicals were added to benzene, tert-butylbenzene and 1,3-di-tert-butylbenzene to give cyclohexadienyl radicals which were characterised by EPR spectroscopy. The bicyclo[2.2.2]oct-l-yl radical generated in rerr-butylbenzene showed exclusive meta addition with formation of the corresponding l-polycyclo-3-tert-butylcyclohexadienyl radical.

Verdazyl radicals, discovered in 1963, are a family of exceptionally stable radicals defined by their 6-membered ring containing four nitrogen atoms. Verdazyl radicals are highly modular compounds with a large assortment of substitution patterns reported. Their stability and high degree of structural variability has been exploited in the fields of materials, inorganic, polymer and physical chemistry; however their deliberate use as starting materials towards organic synthesis had only been reported in recent years by the Georges lab. In 2008, the Georges group reported a disproportionation reaction that was observed to a occur with 6-oxoverdazyl radicals resulting in azomethine imines capable of undergoing 1,3-dipolar cycloaddition reactions. With this discovery, the door to using verdazyl radicals as substrates towards organic synthesis had been opened. Their utility in synthesis was soon discovered not to be limited to just the cycloadducts their azomethine imine derivatives could generate but also the increasing number of N-heterocycles that could be generated from these cycloadducts via unique rearrangement reactions, a major theme of this thesis. In addition, triphenyl verdazyl radicals, a distinct class of verdazyl radicals, has been shown to react with alkynes by direct radical addition and rearrangement to afford isoquinolines. As part of this thesis, a new synthetic methodology of generating 6-oxoverdazyl radicals is reported that does not rely on the use of phosgene or hydrazines. This new synthesis allows for the expansion of available alkyl substituents possible on N1 and N5 positions of 6-oxoverdazyl radicals, as well as, generation of unsymmetrical examples of 6-oxoverdazyl radicals with non-identical N1 and N5 alkyl substituents. Employing the new 6-oxoverdazyl radicals synthesized via this method, a study on the effects of different alkyl substituents on the disproportionation reaction of 6-oxoverdazyls was undertaken. Lastly, given the assortment of N-heterocyclic molecular scaffolds capable of being synthesised starting from verdazyl radicals as precursors, the applicability of verdazyl radicals in making a diversity oriented synthesis (DOS) based library was explored. In a group effort with other Georges lab members, a small library composed of various classes of verdazyl radical derived compounds was synthesized and non-specifically tested for cytotoxicity against acute myeloid leukemia and multiple myeloma cell lines in collaboration with The Princess Margaret Hospital. One example was shown to effectively kill cancer cells in both these lines in 250 μM concentration pointing out the potential of using verdazyl radical based chemistry in drug discovery.

Verdazyl radicals are a family of multicoloured stable free radicals. Aside from the defining backbone of four nitrogen atoms, these radicals contain multiple highly modifiable sites that grant them a high degree of derivatization. Despite having been discovered more than half a century ago, limited applications have been found for the verdazyl radicals and little is known about their chemistry. This thesis begins with an investigation to determine whether verdazyl radicals have a future as mediating agents in living radical polymerizations and progresses to their application as substrates for organic synthesis, an application that to date has not been pursued either with verdazyl or nitroxide stable radicals. The first part of this thesis describes the successful use of the 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical as a mediating agent for styrene and n-butyl acrylate stable free radical polymerizations. The study of other verdazyl derivatives demonstrated the impact of steric and electronic properties of the verdazyl radicals on their ability to mediate polymerizations. The second part of this thesis outlines the initial discovery and the mechanistic elucidation of the transformation of the 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical into an azomethine imine, which in the presence of dipolarophiles, undergoes a [3+2] 1,3-dipolar cycloaddition reaction to yield unique pyrazolotetrazinone structures. The reactivity of the azomethine imine and the scope of the reaction were also examined. The third part of this thesis describes the discovery and mechanistic determination of a base-induced rearrangement reaction that transforms the verdazyl-derived pyrazolotetrazinone cycloadducts into corresponding pyrazolotriazinones or triazole structures. The nucleophilicity, or the lack thereof, of the base employed leading to various rearrangement products was examined in detail. The final part of this thesis demonstrates the compatibility of the verdazyl-initiated cycloaddition and rearrangement reactions with the philosophy of diversity-oriented synthesis in generating libraries of heterocycles. A library of verdazyl-derived heterocycles was generated in a short amount of time and was tested non-specifically for biological activity against acute myeloid leukemia and multiple myeloma cell lines. One particular compound showed cell-killing activity at the 250 mM range, indicating future potential for this chemistry in the field of drug discovery.

The β-acyloxyalkyl radical rearrangement has been known since 1967 but its mechanism is still not fully understood, despite considerable investigation. Since the migration of a β-trifluoroacetoxy group generally proceeds more rapidly and with more varied regiochemistry than its less electronegative counterparts, this reaction was studied in the hope of understanding more about the subtleties of the mechanism of the β- acyloxyalkyl radical rearrangement. The mechanism of the catalysed rearrangement of Nalkoxy- 2(1H)-pyridinethiones was also explored because preliminary studies indicated that the transition state (TS) for this process was isoelectronic with TSs postulated for the β-acyloxyalkyl radical and other novel rearrangements. ¶ ...

Efficient access to molecular complexity and diversity is important for the development of small-molecule screening libraries designed to identify highly specific modulators of disease relevant macromolecular interactions. We envisioned the use of iteratively synthesized bis-vinyl ether substrates for cascade-type transformations to gain rapid access to several different classes of stereochemically rich, linear or polycyclic scaffolds. To evaluate their utility in this context, mechanistic investigations were undertaken to understand the chemical reactivity of bis-vinyl ethers in radical cyclization reactions and [3,3]-sigmatropic rearrangements. Radical cyclization across bis-vinyl ethers proceeded through an apparent 6-endo-trig/5-exo-trig ring closure to afford functionalized hexahydro-2H-furo[3,4-b]pyrans in good yield, with high diastereoselectivity and excellent regiocontrol. Combination of two electron-withdrawing substituents on the bis-vinyl ether backbone resulted in the trapping of a 5-exo-trig/β-scission product, prompting us to investigate the mechanism for cyclization. Formation of the hexahydrofuropyrans was found to be the result of a 5-exo-trig/3-exo-trig/retro-3-exo-trig pathway to afford a “formal” 6-endo pyranosyl radical that could participate in a second 5-exo-trig cyclization to secure the two ring system. From this earlier study, we found certain combinations of substituents on the bis-vinyl ether backbone increased the propensity for these substrates to undergo Claisen rearrangement at remarkably low temperatures. Kinetic investigations of the substituent effects influencing bis-vinyl ether stability found that electron-releasing substituents on the γ-allyloxy fragment increased the rate of rearrangement as a result of stabilization of a cationic allyl fragment in the transition state. Thermochemical data derived from the earlier kinetic investigations also indicated that the Claisen rearrangement of bis-vinyl ether substrates occured through a dissociative mechanism, characterised by an ΔS‡ of +2.3 cal K-1 mol-1. A palladium-catalyzed auxiliary-controlled diastereoselective Claisen rearrangement of bis-vinyl ethers to access aldol-type products is currently under development. Preliminary results indicate that a modest degree of diastereoselectivity can be achieved in this reaction, provided that the steric burden at the stereogenic element is close enough to the pericyclic framework to exert an influence on facial selectivity.
Graduate

碩士
義守大學
化學工程學系暨生物技術與化學工程研究所
103
To investigate the photo rearrangement reactions of the substituted propargyl derivatives and allenyl derivatives in matrix isolation by the substituent and halogen effects. The mechanism of the photorearrangement reactions was discussed. To use the TEMPO trapping method to capture the radical generated from the photorearrangement reaction of the propargyl derivative and allenyl derivative. The results show that the rate of TEMPO traps C3H3 radical generated from the photorearrangement reaction of the propargyl derivative and allenyl is faster than the rate of resonance for C3H3 radical. The results of photolytic reactions of propargyl bromide in toluene solution with different concentrations might be ascribed to the kinetic control reactions. However, the results of photolytic reactions of the substituted propargyl derivatives and allenyl derivatives in matrix isolation might be ascribed to thermodynamically control reactions partly.

碩士
國立交通大學
應用化學系碩博士班
107
The first part: Compounds containing heteroatoms are the most prominent entities in commercially available drugs that are sold in large quantities.Among all heteroatom molecules, benzimidazole,benzoselenazole, guanidine and pyrrole are considered to be the privileged core of drug and drug discovery.In particular, these biologically important heterocyclic fused/linked heterocyclic molecules are considered to be well known scaffolds in medical and drug discovery research. Therefore, the synthesis of fused and linked heterocyclic molecules must be taken care of this paper deals with the design and synthesis of biologically interesting fused and linked heterocycles.A catalyst-controlled chemical reaction cyclization strategy was reported to obtain diazepam [1,7-a] fluorene and hydrazine from the reaction of the readily available ortho-anisidine and diazonium ester as coupling partners.And [1,2-a] quinoxaline.Under Rh(III) catalyst, the reaction is carried out by amine-assisted C2-H activation followed by amidation to obtain diazepam [1,7-a]pyrene in a highly selective manner.Under the Ru(II) catalyst, the reaction involves the formation of a Ru-carbene complex, followed by a metal-olefin reaction and a β-hydrogen removal reaction, and finally the insertion of the -NH2 group and the cascade cyclization to obtain a ruthenium. Indole [1,2-a] quinoxaline.This newly developed catalyst control strategy is broadly applicable to the construction of a series of very high yields of ruthenium diazide/quinoxaline and pyrrole fused diazapest/quinoxaline scaffolds.We believe this approach opens up new avenues in the fields of catalysis and organic synthesis. The second part: We have successfully developed a regioselective method for the synthesis of isoquinoline [1,2-a]isoquinolines.First of all, the tetrahydroisoquinoline skeleton is synthesized by a Pictet-Spengler reaction, and then reacted with allyl bromide to carry out cyclization and rearrangement of a six-membered ring in the presence of a monovalent gold catalyst.The process of this cascade involves a metal catalyzed cyclization reaction and a process in which the allyl group migrates from the nitrogen atom to ethylene. The third part: In order to obtain the biologically active 2-thiohydantoin ring (B), we perform the Pictet-Spengler reaction by radical to form a tetrahydroisoquinoline skeleton compound having antibacterial and antitumor activity, and then it will react with isothiocyanate, a biologically active heterocyclic small molecule structure is obtained.