Thesis advisor: Jason S. Kingsbury / <bold>Chapter 1</bold>: The reaction of diazomethane with simple aldehydes to deliver methyl ketones has a long studied history in the art of organic synthesis. Formyl electrophiles have also been homologated with trimethylsilyldiazomethane, diazoacetates, and aryl-diazomethanes that very rarely proceed with catalytic activation. Due to the stigma of handling non-stabilized diazoalkanes this history is limited to examples utilizing &alpha;diazoesters and entirely missing are examples of tertiary &alpha;substituted ketone synthesis beginning with disubstituted (internal) diazoalkanes. This work describes a general catalytic procedure for convergent ketone production using non-stabilized, mono- and disubstituted diazomethanes. The method involves mild reaction conditions, produces molecular nitrogen as the only byproduct, and includes six examples of chiral ketone synthesis from various aryl, heteroaryl, or aliphatic aldehydes. The latter feature, together with new evidence that the catalytic reaction mechanism invokes a stereospecific, intramolecular C-H migration, sets the stage for an enantioselective synthesis of acyclic ketones by asymmetric carbon insertion. The remarkable tolerance of this transformation to steric crowding in either reaction partner is showcased in a simple, five-step construction of the complete carbon framework in achyrofuran, a complex dibenzofuranoid. <bold>Chapter 2</bold>: Paraformaldehyde is an inexpensive and readily available source of carbon (~30 USD/kg). Upon heating, the polymer thermally depolymerizes to yield gaseous formaldehyde that can be bubbled through reactions or stored in solution at low temperature. In this work, a new and general strategy for complex ketone synthesis is described based on Sc-catalyzed, double diazoalkyl C-H insertion reactions with formaldehyde as a 1-C source. The method forms di-, tri-, and even tetrasubstituted acetones efficiently, and it has streamlined a synthesis of the <underline>Erythroxylon</underline> alkaloid (-)-dihydrocuscohygrine in which absolute stereochemistry in a proline-based starting material is preserved. <bold>Chapter 3</bold>: Use of geminally-substituted diorganometallics often gives new forms of reactivity that are unavailable to their monosubstituted counterparts. With the expanding use of boronic acids in many areas of synthetic organic methodology, an underappreciated research area has been full development of disubstitited <italic>gem</italic> diboronic ester derivatives for use in tandem reactions, olefination methods, metal catalyzed coupling reactions, and transmetallations to mixed <italic>gem</italic> diorganometallics. The nature of molecular boron is routinely engaged through its Lewis acidic vacant <italic>p</italic>-orbital, and, after metalation, this orbital interaction is enlisted to stabilize &alpha;-carbanion or &alpha;-carbanion like species to allow dependable reactivity in various applications. The platinum-catalyzed geminal diboration of diazoalkanes provides reliable and efficient access to a full range of disubstitited <italic>gem</italic> diboronic esters enabling the exploration of novel methodologies. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Boron reagents are known to be valuable in the field of organic chemistry due to their abilities to undergo a variety of transformations, resulting in useful pharmaceuticals and synthetic intermediates. It has also been shown that diboron reagents can act as reaction mediators due to the unique properties of the boron atom. To that end, this dissertation discloses three novel methods of employing boron reagents. Chapter 1 describes a method of utilizing a diboron reagent mediator in the palladium-catalyzed hydrogenation of allenes. In the presence of a palladium catalyst, tetrahydroxydiboron and stoichiometric water, allene semireduction proceeds in good yield. This semireduction is regioselective for the terminal alkene and results in the selective formation of Z-alkenes when used with unsymmetrical allenes (>80:20 Z:E). It is also compatible with more sterically hindered 1,1-diarylallenes, resulting in tri-substituted alkenes in good yields (63-88%). A borylation, defluorination of alpha-trifluoromethyl-alpha,beta-unsaturated esters is described in Chapter 2. The borylation is copper-catalyzed (10 mol %) and proceeds in the presence of stoichiometric bis(pinacolato)diboron and sodium tert-butoxide. The reaction affords compounds that contain two potentially useful functional handles: boronic esters and gem-difluoroalkenes. The products are obtained in moderate to good yield (up to 75%) with a large substrate scope including compounds with electron-donating, electron-withdrawing, heteroatom, and aryl substituents. In addition, the utility of the products in further transformation is demonstrated. A proposed reaction mechanism that provides rationale for the formation of products is described along with experimental evidence. Finally, Chapter 3 describes a transition-metal-free trans hydroboration of alkynoate esters and amides. The reaction is phosphine-catalyzed and proceeds with pinacolborane to afford (E)-beta-borylacrylates and (E)-beta-borylacrylamides in good to excellent yields. The reaction products are converted into novel oxaboroles through reduction with sodium borohydride. Theoretical calculations provide mechanistic insight for the transformation. The formation of a key phosphonocyclobutene intermediate is responsible for the observed stereoselectivity. / Doctor of Philosophy / Boron reagents are valuable in the field of organic chemistry due to their abilities to undergo and to facilitate a wide variety of chemical transformations. In some of these reactions, boron is transferred onto the final molecules. Compounds containing boron are valued both as pharmaceuticals and as intermediates toward the synthesis of other products. In other transformations, the diboron reagents act as reaction mediators. Often, incorporating diboron reagent mediators allows for replacement of less favorable reactants. This dissertation describes three novel uses for diboron reagents in the field of organic chemistry. The first method employs a diboron reagent mediator—replacing flammable hydrogen gas—in the hydrogenation of allenes. The second two methods are novel borylation reactions where boron is incorporated in the final molecules. These compounds are potentially useful in pharmaceuticals and organic synthesis.

The first successful synthesis and isolation of a boronic acid was reported in 1860 by Frankland in the pursuit of novel organometallic compounds. For more than a century, further studies of boronic acids were sparsely published. Suzuki and Miyaura jumpstarted the field in 1979 with an innovative carbon-carbon bond forming reaction employing an organoboronic acid and a carbon halide under palladium catalysis. Indeed, the Nobel Prize in Chemistry was awarded to Professor Akira Suzuki, along with Professors Richard Heck and Ei-ichi Negishi, in 2010 for their important contributions in palladium-catalyzed cross-coupling chemistry. Over the last 30 years, reports on organoboron compounds have increased exponentially. This dissertation describes the author's contributions to the development of preparative methods for organoboronic acid derivatives using transition metal-catalyzed reactions of diboron reagents. A unique "mixed" diboron reagent was developed (PDIPA diboron) that contains sp2- and sp3-hybridized boron atoms, unambiguously confirmed by X-ray crystallography. PDIPA diboron is sufficiently activated internally through a dative-bonding amine to selectively transfer the sp2-hybridized boron regioselectively, in the presence of copper, to electron deficient alkenes including α,β-unsaturated ketones, esters, amides, aldehydes, and nitriles to provide the corresponding boratohomoenolates. A unique β,β-diboration of an α,β-acetylenic ketone was also discovered. The scope of PDIPA diboron reactions was then expanded to a set of substrates with a more complex structural backbone. Allenoates are α,β,γ-unsaturated esters with orthogonal pi systems, which pose several possible difficulties with the regioselectivity of addition, not to mention known isomerizations catalyzed by copper. However, we successfully installed the boron moiety regioselectively on the β-carbon of a variety of allenoates, providing a vinyl boronic ester, and also observed exclusive formation of the (Z)-isomer from racemic starting materials. The resulting vinyl boronic ester was then shown to be an excellent Suzuki-Miyaura cross-coupling partner, affording a diastereopure, trisubstituted alkene in quantitative yield. Commercially available bis(pinacolato)diboron has shown remarkable stability towards hydrolysis and autoxidation. Using this reagent, we developed a copper- and amine-catalyzed boration protocol performed entirely in water and open to air. Using only 1 mol% copper, extraordinary activity was observed. UV-Vis, 11B NMR, and solvent kinetic isotope experiments were employed to gain insight into the mechanism, which showed the possibility of autocatalysis. Attempts to control stereoselectivity were not successful, although these results were rationalized by a dynamic catalyst structure. / Ph. D.

The versatility of organoboron compounds has been demonstrated by their use as synthetic intermediates and more recently in therapeutic applications since the FDA approval of Velcade©. As a result, transition metal-catalyzed protocols to incorporate boron reagents into unsaturated compounds have been extensively researched. While an abundance of literature protocols have been reported, the majority utilize harsh reaction conditions in combination with expensive reagents. This dissertation discloses the author’s contributions to the development of efficient, cost-effective, and operationally simple transition metal-catalyzed borylation protocols with alkynes and diboron reagents. An open-to-air copper(II)-catalyzed aqueous borylation protocol of alkynoates and a symmetrical diboron reagent is reported. Conjugate addition of the boryl-copper species to the electrophilic β-carbon provided β-boryl-α,β-unsaturated esters in moderate to excellent yields. Exclusive (Z)-stereochemistry was confirmed by nOe experiments. The resulting vinyl boronate esters are useful cross-coupling partners. The scope of the aqueous β-borylation protocol was extended to the unsymmetrical diboron reagent, pinB-Bdan. This alternative protecting group has emerged as an orthogonal protecting group and alters the reactivity of the boron moiety. Activation of the pinacol moiety to form the Lewis acid-base adduct allowed for the chemoselective transfer of the 1,8- diaminonapthalene moiety to the β-carbon. An alternative novel synthesis of vinyl, allyl diboronate esters from propargylic alcohols has also been described. Formation of a leaving group in-situ with a palladium- and coppercatalyzed protocol can lead to several competing reaction pathways and the formation of multiple products. Fortunately, the resulting vinyl, allyl diboronate esters were stereoselectively synthesized in moderate GC yields despite significate decomposition during purification, as confirmed by stability studies. The terminal diboration of allenes was previously the only reported method for the synthesis of vinyl, allyl diboronate esters. / Ph. D.

Organoboron compounds have shown a wide variety of applications in both organic synthesis and the pharmaceutical field in the past decades. Transition metal-catalyzed boration of unsaturated compounds has been studied extensively as an efficient method to install C-B bonds. Most of the previous examples employed symmetrical diboron reagents such as B₂(pin)₂ (pin = pinacolate) and B₂(cat)₂ (cat = catecholate). There are, however, limited examples of boration using unsymmetrical diboron reagents. This dissertation discloses two transition metal-catalyzed borations of unsaturated compounds with unsymmetrical diboron compounds. A Cu-catalyzed β-boration of electrophilic allenoates with a novel sp²-sp³ hybridized diboron reagent (PDIPA) is described. This unsymmetrical diboron reagent is preactivated and allows the boration to go smoothly under mild reaction conditions. The reaction provides β-borylated β,γ- unsaturated esters with exclusive (Z)-double bond geometry. These borylated products are useful intermediates for subsequent Suzuki-Miyaura cross-coupling reaction. In order to install two C-B bonds in one reaction, a Pt-catalyzed diboration of allenes with a differentially protected diboron reagent (PDAN) is presented. This unsymmetrical diboron reagent is prepared from the sp²-sp³ hybridized diboron compound, and it reacts with a series of 1,1- disubstituted allenes chemo- and regioselectively. Steric control ensures that both boryl moieties add to the terminal double bond, and the pinacol boronate preferentially attaches to the sp-hybridized carbon. The bis-boronyl products can be further converted to other functional groups as well as cross-coupling reactions. A collaborative project with Department of Physics and Department of Chemical Engineering is also discussed. In this project, a series of 𝑜-nitrobenzyl ligands containing a disulfide group as the anchor to gold surfaces are synthesized. The 𝑜-nitrobenzyl group uncages an amine upon photoexcitation. Attempts to make a water soluble analog failed, however, the mixture of methanol and water as the solvent was sufficient to attach them on gold surfaces. / Ph. D.