Generation Of Electron Deficient Carbodiimides And Their Application In The Guanidine Forming, Zwitterionic 1,3-Diaza-Claisen Rearrangement

The 1,3-diaza Claisen rearrangement was initially discovered by the Madalengoitia group in the early 2000s. Tertiary, allylic, amines nucleophilically add to the carbon of a heterocumulene (isocyanate, isothiocyanate, or carbodiimide) to generate a zwitterion which then undergoes [3,3]-sigmatropic rearrangement. The rearrangements conducted with a carbodiimide generate guanidine-containing skeletons. The guanidine functional group is found in many biologically active products, making it a worthwhile chemical target. To this end, strained, tertiary, allylic, amine 2-benzyl-2-azabicyclo[2.2.1]hept-5-ene reacts with in-situ generated carbodiimides in the 1,3-diaza-Claisen rearrangement to afford structurally interesting bicyclic guanidines. Use of more electron deficient carbodiimides makes these rearrangements more facile; however, there are not sufficient methods for the synthesis of highly electron deficient carbodiimides. The synthesis of such carbodiimides was explored through new synthetic methodologies for the dehydration of ureas and desulfurization of isothioureas and the carbodiimides were used in a series of intermolecular rearrangements with the strained, tertiary, allylic, amine. The new methodologies for the synthesis of electron deficient carbodiimides were then applied to a series of intramolecular substrates, further expanding the 1,3-diaza Claisen rearrangement methodologies. To date series of bicyclic, tricyclic, and monocyclic guanidines of varying structures have been synthesized. The synthetic efforts towards these products are herein described

Pd0-Catalyzed Formal 1,3-Diaza-Claisen Rearrangement. Design And Development Of Cationic 1,3-Diaza-Claisen Rearrangement.

The dissertation describes Pd0-catalyzed formal 1,3-diaza-Claisen rearrangement and the design and development of cationic 1,3-diaza-Claisen rearrangement. Our previous work has shown that isocyanates react with azanorbornenes and azabicyclo[2.2.2]octenes under thermal conditions to afford zwitterionic intermediates that undergo a thermal 1,3-diaza-Claisen rearrangement to give both ureas and isoureas. However, some azanorbornenes and azabicyclooctenes failed to rearrange or proceeded in low yields. To address these challenging substrates for the thermal 1,3-diaza-Claisen rearrangement, we have developed a Pd0-catalyzed formal 1,3-diaza-Claisen rearrangement. Interestingly, under Pd0-catalyzed condition, both isocyanates with electron-withdrawing groups and isocyanates without electron-withdrawing groups react with azanorbornenes and azabicyclo[2.2.2]octenes to provide ureas as the only products in high yields. More importantly, the reactions that failed under thermal conditions were all successful under Pd0-catalysis. In addition to azanorbornenes and azabicyclo[2.2.2]octenes, other ring systems were also investigated. Pd0 catalysis has broadened the scope of tertiary allylic amines that react with isocyanates to afford 1,3-diaza-Claisen rearrangement products. In the presence of p-TsCl and NEt3, allylaminopropyl benzyl ureas were initially dehydrated to form protonated carbodiimides whose presence was confirmed by the infrared absorption frequency at 2100 cm-1 which is the characteristic band of -N=C=N-; then the in situ generated protonated carbodiimides were poised for further cationic 1,3-diaza-Claisen rearrangement to afford synthetically challenging guanidines. The effect of acid on the rearrangement was ascertained by the fact that no rearrangement product was observed by simply heating free base carbodiimide 3.10 in benzene at reflux. Other dehydration reagents, such as Tf2O, Ts2O, MsCl were also investigated, and none of them provide satisfactory results. A selection of allyamino benzyl ureas with different tether length, substituents, or in varied ring systems, were synthesized to explore the scope of this methodology. This methodology works best at allylaminopropyl benzyl ureas, and the substituents on the benzyl group does not seem to affect the reaction rate in a significant way

Expansion Of The Intramolecular Zwitterionic-1,3-Diaza-Claisen Rearrangement Beyond Bridged-Bicyclic Electron-Deficient Isothioureas To Generate Substituted Cyclic Guanidines

Guanidines are ubiquitous in nature and have important applications in biological chemistry and industry, presenting themselves in biomacromolecules and organic materials respectively. The zwitterionic-1,3-diaza-Claisen rearrangement has allowed facile access to a variety of highly-substituted, complex guanidines, which would otherwise require a significant amount of time or resources to synthesize. Previously, the intramolecular version of the 1,3-diaza-Claisen rearrangement has been used to generate tricyclic guanidines from bridged, bicyclic electron-deficient isothioureas. Extension of this methodology to simpler electron-deficient isothioureas has afforded stable zwitterionic intermediates, which have been isolated via silica gel column chromatography with common organic solvents. Heating the zwitterionic intermediates in an aromatic solvent gives the desired guanidines in good yields. A substrate scope examining isothiourea sterics and electronics has shown that the rearrangement can be accelerated by increasing the strength of the electron withdrawing group, stabilizing the alkene fragment, and employing additional substitution patterns. Mechanistic studies employing deuterium-labeled isothioureas have shown that a sigmatropic rearrangement mechanism and ionic rearrangement mechanisms are both possible. The mechanism is dependent on the substrate structure, and the presence of trace thiophilic metal or weak acid. Diastereoselective rearrangements employing remote stereocontrol of an existing stereocenter are also possible. DFT-calculations are being examined to predict rearrangement activation energies based on the possible transition states. Finally, altering the electronics of the isothiourea has resulted in an unexpected Sommelet-Hauser [2,3]-sigmatropic rearrangement. This new result has expanded the scope of guanidines, producing guanidine scaffolds represented in various natural products

Sigmatropic Rearrangements of Polymer Backbones: Vinyl Polymers from Polyesters in One Step

Polymer modification is a fundamental scientific challenge, as a means of both upcycling plastics and extracting a stimulus response from them. To date, the overwhelming majority of polymer modifications has focused on the polymer periphery. Herein, we demonstrate nearly quantitative, scission-free modification of polymer backbones, namely, a metamorphosis of polyesters into vinyl polymers resembling commodity materials via the Ireland-Claisen sigmatropic rearrangement. The glass transition temperature (Tg) and thermal stability of the polyesters undergo dramatic changes post-transformation. Beyond polymer modification, our work advances the application of retrosynthetic analysis in polymer synthesis; the nontraditional production of vinyl polymers from lactones opens the door to a slew of previously inaccessible materials

Diazaphospholene and diazaarsolene derived homogeneous catalysis

The past 20 years has seen significant advances in main group chemistry and their use in catalysis. This minireview showcases the recent emergence of phosphorus and arsenic containing heterocycles as catalysts. With that, we discuss how the Group 15 compounds diazaphospholenes, diazaarsolenes, and their cationic counterparts have proven to be highly effective catalysts for a wide range of reduction transformations. This minireview highlights how the initial discovery by Gudat of the hydridic nature of the P–H bond in these systems led to these compounds being used as catalysts, and discusses the wide range of examples currently present in the literature

Significance and Implications of Vitamin B-12 Reaction Shema- ETH ZURICH VARIANT: Mechanisms and Insights

This is an undergraduate chemistry thesis document. This involves a discussion of the mechanisms and overall reactions involved in the total synthesis of vitamin B-12

Part I: Nitroalkane Transformations: Synthesis of Vicinal Diamines and Arylnitromethanes Part II: Quantification of Electrophile Lumo-Lowering via Colorimetric Probes

Part I of this dissertation focuses on the synthetic chemistry of arylnitromethanes as both products and reactants. Use of these compounds as key building blocks in the synthesis of vicinal diamines was explored via a catalytic aza-Henry strategy. These studies resulted in the identification of simple cinchonidinium acetate as an effective catalyst for the asymmetric synthesis of syn-1,2-diarylethylenediamines with excellent diastereocontrol. Difficulties in synthesizing arylnitromethanes from existing techniques provided impetus for the development of an improved method of greater generality. Ultimately, successful conditions were identified for the palladium-catalyzed cross coupling of nitromethane with readily available aryl halide partners, providing facile access to an array of functionalized arylnitromethanes. A tandem reductive Nef process was incorporated to provide a one-pot transformation directly to aryl aldehyde or oxime, thereby exploiting the use of nitromethane as a formylation equivalent. Application of the nitromethylation conditions to vinyl halides resulted in the discovery of a unique tandem cross-coupling/π-allylation nitroethylation reaction. Part II of this dissertation focuses on the use of colorimetric sensors for the quantitative measurement of catalyst strength via LUMO-lowering of electrophiles. Despite rampant growth in catalyst synthesis and application, understanding of controlling factors of catalyst activity, particularly for those functioning through hydrogen-bonding, remains limited. A simple pyrazinone chromophore was found to exhibit hypsochromic shifts upon binding to an array of known hydrogen-bond catalysts. These wavelength shifts showed high correlation to relative rate enhancement of the catalysts in Diels Alder and Friedel Crafts reactions. Acidity values, often used to estimate hydrogen-bond strength, were illustrated to be poor indicators of catalytic activity, in contrast to that of the wavelength shifts. The results establish the catalyst-sensor wavelength is a useful tool with which to gauge catalyst strength and also reveal catalyst structure-activity relationships. Current efforts for measuring stronger Brønsted and Lewis Acid catalysts with an alternate colorimetric sensor are also described