Nickel-Catalyzed Sulfonylation of Aryl Bromides Enabled by Potassium Metabisulfite as a Uniquely Effective SO2 Surrogate.

The development and mechanistic investigation of a nickel-catalyzed sulfonylation of aryl bromides is disclosed. The reaction proceeds in good yields for a variety of substrates and utilizes an inexpensive, stench-free, inorganic sulfur salt (K2 S2 O5 ) as a uniquely effective SO2 surrogate. The active oxidative addition complex was synthesized, isolated, and fully characterized by a combination of NMR spectroscopy and X-ray crystallography analysis. The use of the isolated oxidative addition complex in both stoichiometric and catalytic reactions revealed that SO2 insertion occurs via dissolved SO2 , likely released upon thermal decomposition of K2 S2 O5 . Key to the success of the reaction is the role of K2 S2 O5 as a reservoir of SO2 that is slowly released, thus preventing catalyst poisoning.

Nickel-Catalyzed Cyanation of (Hetero)aryl Bromides Using DABAL-Me3 as a Soluble Reductant.

A nickel-catalyzed cyanation of (hetero)aryl halides using air-stable bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane (DABAL-Me3) as a soluble reductant has been developed. The reaction uses readily available and inexpensive Ni(dppf)Cl2 as a precatalyst, a substoichiometric amount of Zn(CN)2, and DABAL-Me3 as an alternative to commonly prescribed insoluble reductants. We found the addition of catalytic tetrabutylammonium bromide (TBABr) to be beneficial, due to facilitating dissolution of low levels of the cyanide salt (confirmed via a control study). Similarly, slow addition of a tetrabutylammonium cyanide (TBACN) solution is effective and results in a completely homogeneous reaction mixture.

Air-Tolerant Nickel-Catalyzed Cyanation of (Hetero)aryl Halides Enabled by Polymethylhydrosiloxane, a Green Reductant.

An air-tolerant nickel-catalyzed cyanation of aryl bromides is reported. The reaction uses a NiCl2/Xantphos catalyst in combination with substoichiometric quantities of zinc cyanide and polymethylhydrosiloxane. This silane is a green, homogeneous alternative to the traditional, insoluble solid reductant zinc and renders the reaction tolerant to air. The reaction can be performed under an air atmosphere, obviating the need for degassing, a glovebox, or Schlenk techniques. The reaction scope is broad, proceeding in good yields with a variety of (hetero)arenes.

Intramolecular Hydrogen Shift Chemistry of Hydroperoxy-Substituted Peroxy Radicals.

Gas-phase autoxidation - the sequential regeneration of peroxy radicals (RO2) via intramolecular hydrogen shifts (H-shifts) followed by oxygen addition - leads to the formation of organic hydroperoxides. The atmospheric fate of these peroxides remains unclear, including the potential for further H-shift chemistry. Here, we report H-shift rate coefficients for a system of RO2 with hydroperoxide functionality produced in the OH-initiated oxidation of 2-hydroperoxy-2-methylpentane. The initial RO2 formed in this chemistry are unable to undergo α-OOH H-shift (HOOC-H) reactions. However, these RO2 rapidly isomerize (>100 s-1 at 296 K) by H-shift of the hydroperoxy hydrogen (ROO-H) to produce a hydroperoxy-substituted RO2 with an accessible α-OOH hydrogen. First order rate coefficients for the 1,5 H-shift of the α-OOH hydrogen are measured to be ∼0.04 s-1 (296 K) and ∼0.1 s-1 (318 K), within 50% of the rate coefficients calculated using multiconformer transition state theory. Reaction of the RO2 with NO produces alkoxy radicals which also undergo rapid isomerization via 1,6 and 1,5 H-shift of the hydroperoxy hydrogen (ROO-H) to produce RO2 with alcohol functionality. One of these hydroxy-substituted RO2 exhibits a 1,5 α-OH (HOC-H) H-shift, measured to be ∼0.2 s-1 (296 K) and ∼0.6 s-1 (318 K), again in agreement with the calculated rates. Thus, the rapid shift of hydroperoxy hydrogens in alkoxy and peroxy radicals enables intramolecular reactions that would otherwise be inaccessible.

Synergistic O3 + OH oxidation pathway to extremely low-volatility dimers revealed in ß-pinene secondary organic aerosol.

Dimeric compounds contribute significantly to the formation and growth of atmospheric secondary organic aerosol (SOA) derived from monoterpene oxidation. However, the mechanisms of dimer production, in particular the relevance of gas- vs. particle-phase chemistry, remain unclear. Here, through a combination of mass spectrometric, chromatographic, and synthetic techniques, we identify a suite of dimeric compounds (C15-19H24-32O5-11) formed from concerted O3 and OH oxidation of ß-pinene (i.e., accretion of O3- and OH-derived products/intermediates). These dimers account for an appreciable fraction (5.9-25.4%) of the ß-pinene SOA mass and are designated as extremely low-volatility organic compounds. Certain dimers, characterized as covalent dimer esters, are conclusively shown to form through heterogeneous chemistry, while evidence of dimer production via gas-phase reactions is also presented. The formation of dimers through synergistic O3 + OH oxidation represents a potentially significant, heretofore-unidentified source of low-volatility monoterpene SOA. This reactivity also suggests that the current treatment of SOA formation as a sum of products originating from the isolated oxidation of individual precursors fails to accurately reflect the complexity of oxidation pathways at play in the real atmosphere. Accounting for the role of synergistic oxidation in ambient SOA formation could help to resolve the discrepancy between the measured atmospheric burden of SOA and that predicted by regional air quality and global climate models.

Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation.

The development of the first enantioselective transition-metal-catalyzed allylic alkylation providing access to acyclic products bearing vicinal all-carbon quaternary centers is disclosed. The iridium-catalyzed allylic alkylation reaction proceeds with excellent yields and selectivities for a range of malononitrile-derived nucleophiles and trisubstituted allylic electrophiles. The utility of these sterically congested products is explored through a series of diverse chemo- and diastereoselective product transformations to afford a number of highly valuable, densely functionalized building blocks, including those containing vicinal all-carbon quaternary stereocenters.

Enantioselective Halolactonization Reactions using BINOL-Derived Bifunctional Catalysts: Methodology, Diversification, and Applications.

A general protocol is described for inducing enantioselective halolactonizations of unsaturated carboxylic acids using novel bifunctional organic catalysts derived from a chiral binaphthalene scaffold. Bromo- and iodolactonization reactions of diversely substituted, unsaturated carboxylic acids proceed with high degrees of enantioselectivity, regioselectivity, and diastereoselectivity. Notably, these BINOL-derived catalysts are the first to induce the bromo- and iodolactonizations of 5-alkyl-4( Z)-olefinic acids via 5- exo mode cyclizations to give lactones in which new carbon-halogen bonds are created at a stereogenic center with high diastereo- and enantioselectivities. Iodolactonizations of 6-substituted-5( Z)-olefinic acids also occur via 6- exo cyclizations to provide δ-lactones with excellent enantioselectivities. Several notable applications of this halolactonization methodology were developed for desymmetrization, kinetic resolution, and epoxidation of Z-alkenes. The utility of these reactions is demonstrated by their application to a synthesis of precursors of the F-ring subunit of kibdelone C and to the shortest catalytic, enantioselective synthesis of (+)-disparlure reported to date.

Intermolecular Stereoselective Iridium-Catalyzed Allylic Alkylation: An Evolutionary Account.

Our lab has long been interested in the development of methods for the creation of enantioenriched all-carbon quaternary stereocenters. Historically, our interest has centered on palladium-catalyzed allylic alkylation, though recent efforts have moved to include the study of iridium catalysts. Whereas palladium catalysts enable the preparation of isolated stereocenters, the use of iridium catalysts allows for the direct construction of vicinal stereocenters via an enantio-, diastereo-, and regioselective allylic alkylation. This account details the evolution of our research program from inception, which focused on the first iridium-catalyzed allylic alkylation to prepare stereodyads containing a single quaternary center, to our most recent discovery that allows for the synthesis of vicinal quaternary centers.

Atmospheric autoxidation is increasingly important in urban and suburban North America.

Gas-phase autoxidation-regenerative peroxy radical formation following intramolecular hydrogen shifts-is known to be important in the combustion of organic materials. The relevance of this chemistry in the oxidation of organics in the atmosphere has received less attention due, in part, to the lack of kinetic data at relevant temperatures. Here, we combine computational and experimental approaches to investigate the rate of autoxidation for organic peroxy radicals (RO2) produced in the oxidation of a prototypical atmospheric pollutant, n-hexane. We find that the reaction rate depends critically on the molecular configuration of the RO2 radical undergoing hydrogen transfer (H-shift). RO2 H-shift rate coefficients via transition states involving six- and seven-membered rings (1,5 and 1,6 H-shifts, respectively) of α-OH hydrogens (HOC-H) formed in this system are of order 0.1 s-1 at 296 K, while the 1,4 H-shift is calculated to be orders of magnitude slower. Consistent with H-shift reactions over a substantial energetic barrier, we find that the rate coefficients of these reactions increase rapidly with temperature and exhibit a large, primary, kinetic isotope effect. The observed H-shift rate coefficients are sufficiently fast that, as a result of ongoing NO x emission reductions, autoxidation is now competing with bimolecular chemistry even in the most polluted North American cities, particularly during summer afternoons when NO levels are low and temperatures are elevated.

Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via a Catalytic Enantioselective Allylic Alkylation Strategy.

Rapid access to enantioenriched spirocycles possessing a 1,4-dicarbonyl moiety spanning an all-carbon quaternary stereogenic spirocenter was achieved using a masked bromomethyl vinyl ketone reagent. The developed protocol entails an enantioselective palladium-catalyzed allylic alkylation reaction followed by a one-pot unmasking/RCM sequence that provides access to the spirocyclic compounds in good yields and selectivities.

Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives through Iridium-Catalyzed Allylic Alkylation.

The first highly enantioselective iridium-catalyzed allylic alkylation that provides access to products bearing an allylic all-carbon quaternary stereogenic center has been developed. The reaction utilizes a masked acyl cyanide (MAC) reagent, which enables the one-pot preparation of α-quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. The utility of these products is further explored through a series of diverse product transformations.

Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents.

The first enantioselective iridium-catalyzed allylic alkylation reaction of a masked acyl cyanide (MAC) reagent has been developed. The transformation allows for the use of an umpoled synthon, which serves as a carbon monoxide equivalent. The reaction proceeds with good yield and excellent selectivity up to gram scale for a wide range of substituted allylic electrophiles, delivering products amenable to the synthesis of highly desirable, enantioenriched vinylated α-aryl carbonyl derivatives.

Iridium-Catalyzed Stereoselective Allylic Alkylation Reactions with Crotyl Chloride.

The development of the first enantio-, diastereo-, and regioselective iridium-catalyzed allylic alkylation reaction of prochiral enolates to form an all-carbon quaternary stereogenic center with an aliphatic-substituted allylic electrophile is disclosed. The reaction proceeds with good to excellent selectivity with a range of substituted tetralone-derived nucleophiles furnishing products bearing a newly formed vicinal tertiary and all-carbon quaternary stereodyad. The utility of this protocol is further demonstrated via a number of synthetically diverse product transformations.

Diastereoselective addition of monoorganocuprates to a chiral fumarate: reaction development and synthesis of (-)-dihydroprotolichesterinic acid.

Recent studies of diastereoselective conjugate additions of monoorganocuprates, Li[RCuI], to chiral γ-alkoxycrotonates and fumarates are disclosed. This methodology was applied to the shortest total synthesis of (-)-dihydroprotolichesterinic acid to date, but several attempts to prepare other succinate-derived natural products, such as pilocarpine and antrodin E, were unsuccessful.

Total synthesis of (-)-dihydroprotolichesterenic acid via diastereoselective conjugate addition to chiral fumarates.

A diastereoselective conjugate addition of a variety of monoorganocuprates, Li[RCuI], to chiral fumarates to provide funtionalized succinates has been developed. The utility of this reaction is demonstrated in a concise total synthesis of (-)-dihydroprotolichesterenic acid that required only four steps and proceeded in an overall 31% yield.

Enantioselective iodolactonization of disubstituted olefinic acids using a bifunctional catalyst.

The enantioselective iodolactonizations of a series of diversely substituted olefinic carboxylic acids are promoted by a BINOL-derived, bifunctional catalyst. Reactions involving 5-alkyl- and 5-aryl-4(Z)-pentenoic acids and 6-alkyl- and 6-aryl-5(Z)-hexenoic acids provide the corresponding γ- and δ-lactones having stereogenic C-I bonds in excellent yields and >97:3 er. Significantly, this represents the first organocatalyst that promotes both bromo- and iodolactonization with high enantioselectivities. The potential of this catalyst to induce kinetic resolutions of racemic unsaturated acids is also demonstrated.