Alkylation of ketones with 3-bromomethyl-1,2-benzisothiazoles

The synthesis of 3-bromomethyl-1,2-benzisothiazole and its 5- and 7-methoxy derivatives has been accomplished. In alkylation reactions, these bromides were found to behave much like benzylic bromides; and in this respect they have been used successfully to alkylate strongly basic enolates, thus introducing a latent β-phenylethyl moiety in situations where β-phenylethyl bromide and phenacyl bromide give at best poor yields of alkylated product. In several cases, degradative procedures have been devised to remove the heteroatoms from the benzisothiazoyl system to provide the actual β-phenylethyl fragment; however, no generally applicable degradative method has yet been developed.

Selective hydroxylation of small alkanes by the particulate methane monooxygenase

The particulate methane monooxygenase (pMMO) catalyzes the oxidation of methane to methanol under ambient temperatures and pressures. Other small alkanes and alkenes are also substrates of this enzyme. We measured and compared the initial rate constants of oxidation of small alkanes (C1 to C5) catalyzed by pMMO. Both primary and secondary alcohols were formed from oxidation of n-butane and n-pentane. The alcohols produced from alkane oxidation can be further oxidized, probably by pMMO, to aldehydes and ketones. The apparent regioselectivity for n-butane and n-pentane is 100% 2-alcohols because the formation of primary alcohols is slower than further oxidation of these alcohols. The hydroxylation at the secondary carbons is highly stereoselective: (R)-alcohols are preferentially formed. The enantiomeric excess increases slightly with decreasing reaction temperature. The steric course of hydroxylation on primary carbons was also studied by using isotopically substituted ethane: (S)- or (R)-CH_3-CHDT, and (S)- or (R)-CD_3- CHDT and the reactions were found to proceed with 100% retention of configuration. A primary isotopic effect of k_H/k_D=5.0 was observed in these experiments.

Polymerization of functionalized olefins with neutral group ten catalysts

This thesis describes the preparation, characterization, and application of welldefined single-component group ten salicylaldimine complexes for the polymerization of ethylene to high molecular weight materials as well as the copolymerization of ethylene and functionalized olefins. After an initial introduction to the field, Chapter 2 describes the preparation of PPh₃ complexes that contain a series of modified salicylaldimine and naphthaldimine ligands. Such complexes were activated for polymerization by the addition of cocatalysts such as Ni(COD)₂ or B(C₆F₅)₃. As the steric demand of the ligand set increased-the molecular weight, polymerization activity, and lifetime of the catalyst was observed to increase. In fact, complexes containing "bulky" ligands, such as the [^Anthr,HSal] ligand (2.5), were found to be highly-active single component complexes for the polymerization of ethylene. Model hydrido compound were prepared-allowing for a better understanding of both the mechanism of polymerization and one mode of decomposition.

Chapter 3 describes the effect which additives play on neutral Ni^II polymerization catalysts such as 2.5. The addition of excess ethers, esters, ketones, anhydrides, alcohols, and water do not deactivate the catalysts for polymerization. However, the addition of excess acid, thiols, and phosphines was observed to shut-down catalysis. Since excess phosphine was found to inhibit catalysis, "phosphine-free" complexes, such as the acetonittile complex (3.26), were prepared. The acetonitrile complex was found to be the most active neutral polymerization catalyst prepared to date.

Chapter 4 outlines the use of catalyst 2.5 and 3.26 for the preparation of linear functionalized copolymers containing alcohols, esters, anhydrides, and ethers. Copolymers can be prepared with γ-functionalized-α-olefins, functionalized norbornenes, and functionalized tricyclononenes, with up to 30 mol% comonomer incorporation.

Chapter 5 outlines the preparation of a series of Pt^II alkyl/olefin salicylaldimine complexes which serve as models for the active species in the Ni^II-catalyzed polymerization process. Understanding the nature of the M-olefin interaction as a the electronic and steric properties of the salicylaldimine ligand is varied has allowed for a number of predictions about the design of future polymerization systems.

Oxidation of Volatile Organic Compounds in Aqueous Solution and at the Air-water Interface of Aqueous Microdroplets

Isoprene (ISO),the most abundant non-methane VOC, is the major contributor to secondary organic aerosols (SOA) formation. The mechanisms involved in such transformation, however, are not fully understood. Current mechanisms, which are based on the oxidation of ISO in the gas-phase, underestimate SOA yields. The heightened awareness that ISO is only partially processed in the gas-phase has turned attention to heterogeneous processes as alternative pathways toward SOA.

During my research project, I investigated the photochemical oxidation of isoprene in bulk water. Below, I will report on the λ > 305 nm photolysis of H₂O₂ in dilute ISO solutions. This process yields C₁₀H₁₅OH species as primary products, whose formation both requires and is inhibited by O₂. Several isomers of C₁₀H₁₅OH were resolved by reverse-phase high-performance liquid chromatography and detected as MH⁺ (m/z = 153) and MH⁺-18 (m/z = 135) signals by electrospray ionization mass spectrometry. This finding is consistent with the addition of ·OH to ISO, followed by HO-ISO· reactions with ISO (in competition with O₂) leading to second generation HO(ISO)₂· radicals that terminate as C₁₀H₁₅OH via β-H abstraction by O₂.

It is not generally realized that chemistry on the surface of water cannot be deduced, extrapolated or translated to those in bulk gas and liquid phases. The water density drops a thousand-fold within a few Angstroms through the gas-liquid interfacial region and therefore hydrophobic VOCs such as ISO will likely remain in these relatively 'dry' interfacial water layers rather than proceed into bulk water. In previous experiments from our laboratory, it was found that gas-phase olefins can be protonated on the surface of pH < 4 water. This phenomenon increases the residence time of gases at the interface, an event that makes them increasingly susceptible to interaction with gaseous atmospheric oxidants such as ozone and hydroxyl radicals.

In order to test this hypothesis, I carried out experiments in which ISO(g) collides with the surface of aqueous microdroplets of various compositions. Herein I report that ISO(g) is oxidized into soluble species via Fenton chemistry on the surface of aqueous Fe(II)Cl₂ solutions simultaneously exposed to H₂O₂(g). Monomer and oligomeric species (ISO)1-8H⁺ were detected via online electrospray ionization mass spectrometry (ESI-MS) on the surface of pH ~ 2 water, and were then oxidized into a suite of products whose combined yields exceed ~ 5% of (ISO)1-8H⁺. MS/MS analysis revealed that products mainly consisted of alcohols, ketones, epoxides and acids. Our experiments demonstrated that olefins in ambient air may be oxidized upon impact on the surface of Fe-containing aqueous acidic media, such as those of typical to tropospheric aerosols.

Related experiments involving the reaction of ISO(g) with ·OH radicals from the photolysis of dissolved H₂O₂ were also carried out to test the surface oxidation of ISO(g) by photolyzing H₂O₂(aq) at 266 nm at various pH. The products were analyzed via online electrospray ionization mass spectrometry. Similar to our Fenton experiments, we detected (ISO)1-7H⁺ at pH < 4, and new m/z⁺ = 271 and m/z^- = 76 products at pH > 5.

Investigations of group IVA transition metal mediated carbon-carbon bond forming reactions

Zirconocene aldehyde and ketone complexes were synthesized in high yield by treatment of zirconocene acyl complexes with trimethylaluminum or diisobutylaluminum hydride. These complexes, which are activated by dialkylaluminum chloride ligands, inserted unsaturated substrates such as alkynes, allenes, ethylene, nitriles, ketenes, aldehydes, ketones, lactones, and acid chlorides with moderate to high conversion. Insertion of aldehyde substrates yielded zirconocene diolate complexes with up to 20:1 (anti:syn) diastereoselectivity. The zirconocene diolates were hydrolyzed to afford unsymmetrical 1,2-diols in 40-80% isolated yield. Unsymmetrical ketones gave similar insertion yields with little or no diastereoselectivity. A high yielding one-pot method was developed that coupled carbonyl substrates with zirconocene aldehyde complexes that were derived from olefins by hydrozirconation and carbonylation. The zirconocene aldehyde complexes also inserted carbon monoxide and gave acyloins in 50% yield after hydrolysis.

The insertion reaction of aryl epoxides with the trimethylphoshine adduct of titanocene methylidene was examined. The resulting oxytitanacyclopentanes were carbonylated and oxidatively cleaved with dioxygen to afford y-lactones in moderate yields. Due to the instability and difficult isolation of titanocene methylidene trimethylphoshine adducts, a one-pot method involving the addition of catalytic amounts of trimethylphosphine to β,β-dimethyltitanacyclobutane was developed. A series of disubstituted aryl epoxides were examined which gave mixtures of diastereomeric insertion products. Based on these results, as well as earlier Hammett studies and labeling experiments, a biradical transition state intermediate is proposed. The method is limited to aryl substituted epoxide substrates with aliphatic examples showing no insertion reactivity.

The third study involved the use of magnesium chloride supported titanium catalysts for the Lewis acid catalyzed silyl group transfer condensation of enol silanes with aldehydes. The reaction resulted in silylated aldol products with as many as 140 catalytic turnovers before catalyst inactivation. Low diastereoselectivities favoring the anti-isomer were consistent with an open transition state involving a titanium atom bound to the catalyst surface. The catalysts were also used for the aldol group transfer polymerization of t-butyldimethylsilyloxy-1-ethene resulting in polymers with molecular weights of 5000-31,000 and molar mass dispersities of 1.5-2.8. Attempts to polymerize methylmethacrylate using GTP proved unsuccessful with these catalysts.

Strategies for the Stereoselective Synthesis of Carbon Quaternary Centers via Transition Metal-Catalyzed Alkylation of Enolate Compounds

Notwithstanding advances in modern chemical methods, the selective installation of sterically encumbered carbon stereocenters, in particular all-carbon quaternary centers, remains an unsolved problem in organic chemistry. The prevalence of all-carbon quaternary centers in biologically active natural products and pharmaceutical compounds provides a strong impetus to address current limitations in the state of the art of their generation. This thesis presents four related projects, all of which share in the goal of constructing highly-congested carbon centers in a stereoselective manner, and in the use of transition-metal catalyzed alkylation as a means to address that goal.

The first research described is an extension of allylic alkylation methodology previously developed in the Stoltz group to small, strained rings. This research constitutes the first transition metal-catalyzed enantioselective α-alkylation of cyclobutanones. Under Pd-catalysis, this chemistry affords all–carbon α-quaternary cyclobutanones in good to excellent yields and enantioselectivities.

Next is described our development of a (trimethylsilyl)ethyl β-ketoester class of enolate precursors, and their application in palladium–catalyzed asymmetric allylic alkylation to yield a variety of α-quaternary ketones and lactams. Independent coupling partner synthesis engenders enhanced allyl substrate scope relative to allyl β-ketoester substrates; highly functionalized α-quaternary ketones generated by the union of our fluoride-triggered β-ketoesters and sensitive allylic alkylation coupling partners serve to demonstrate the utility of this method for complex fragment coupling.

Lastly, our development of an Ir-catalyzed asymmetric allylic alkylation of cyclic β-ketoesters to afford highly congested, vicinal stereocenters comprised of tertiary and all-carbon quaternary centers with outstanding regio-, diastereo-, and enantiocontrol is detailed. Implementation of a subsequent Pd-catalyzed alkylation affords dialkylated products with pinpoint stereochemical control of both chiral centers. The chemistry is then extended to include acyclic β-ketoesters and similar levels of selective and functional group tolerance are observed. Critical to the successful development of this method was the employment of iridium catalysis in concert with N-aryl-phosphoramidite ligands.

Palladium-Catalyzed Decarboxylative and Decarbonylative Transformations in the Synthesis of Fine and Commodity Chemicals

Decarboxylation and decarbonylation are important reactions in synthetic organic chemistry, transforming readily available carboxylic acids and their derivatives into various products through loss of carbon dioxide or carbon monoxide. In the past few decades, palladium-catalyzed decarboxylative and decarbonylative reactions experienced tremendous growth due to the excellent catalytic activity of palladium. Development of new reactions in this category for fine and commodity chemical synthesis continues to draw attention from the chemistry community.

The Stoltz laboratory has established a palladium-catalyzed enantioselective decarboxylative allylic alkylation of β-keto esters for the synthesis of α-quaternary ketones since 2005. Recently, we extended this chemistry to lactams due to the ubiquity and importance of nitrogen-containing heterocycles. A wide variety of α-quaternary and tetrasubstituted α-tertiary lactams were obtained in excellent yields and exceptional enantioselectivities using our palladium-catalyzed decarboxylative allylic alkylation chemistry. Enantioenriched α-quaternary carbonyl compounds are versatile building blocks that can be further elaborated to intercept synthetic intermediates en route to many classical natural products. Thus our chemistry enables catalytic asymmetric formal synthesis of these complex molecules.

In addition to fine chemicals, we became interested in commodity chemical synthesis using renewable feedstocks. In collaboration with the Grubbs group, we developed a palladium-catalyzed decarbonylative dehydration reaction that converts abundant and inexpensive fatty acids into value-added linear alpha olefins. The chemistry proceeds under relatively mild conditions, requires very low catalyst loading, tolerates a variety of functional groups, and is easily performed on a large scale. An additional advantage of this chemistry is that it provides access to expensive odd-numbered alpha olefins.

Finally, combining features of both projects, we applied a small-scale decarbonylative dehydration reaction to the synthesis of α-vinyl carbonyl compounds. Direct α-vinylation is challenging, and asymmetric vinylations are rare. Taking advantage of our decarbonylative dehydration chemistry, we were able to transform enantioenriched δ-oxocarboxylic acids into quaternary α-vinyl carbonyl compounds in good yields with complete retention of stereochemistry. Our explorations culminated in the catalytic enantioselective total synthesis of (–)-aspewentin B, a terpenoid natural product featuring a quaternary α-vinyl ketone. Both decarboxylative and decarbonylative chemistries found application in the late stage of the total synthesis.