Nickel-Catalyzed Reductive Conjugate Addition of Primary Alkyl Bromides to Enones To Form Silyl Enol Ethers.

Conjugate addition of organometallic reagents to enones to form silyl enol ether products is a versatile method to difunctionalize activated olefins, but the organometallic reagents required can be limiting. The reductive cross-electrophile coupling of unhindered primary alkyl bromides with enones and chlorosilanes to form silyl enol ether products is catalyzed by a nickel-complexed ortho-brominated terpyridine ligand. The conditions are compatible with a variety of cyclic/acyclic enones and functional groups.

A decarboxylative approach for regioselective hydroarylation of alkynes.

Regioselective activation of aromatic C-H bonds is a long-standing challenge for arene functionalization reactions such as the hydroarylation of alkynes. One possible solution is to employ a removable directing group that activates one of several aromatic C-H bonds. Here we report a new catalytic method for regioselective alkyne hydroarylation with benzoic acid derivatives during which the carboxylate functionality directs the alkyne to the ortho-C-H bond with elimination in situ to form a vinylarene product. The decarboxylation stage of this tandem sequence is envisioned to proceed with the assistance of an ortho-alkenyl moiety, which is formed by the initial alkyne coupling. This ruthenium-catalysed decarboxylative alkyne hydroarylation eliminates the common need for pre-existing ortho-substitution on benzoic acids for substrate activation, proceeds under redox-neutral and relatively mild conditions, and tolerates a broad range of synthetically useful aromatic functionality. Thus, it significantly increases the synthetic utility of benzoic acids as easily accessible aromatic building blocks.

Nickel-catalyzed reductive arylation of activated alkynes with aryl iodides.

The direct, regioselective, and stereoselective arylation of activated alkynes with aryl iodides using a nickel catalyst and manganese reductant is described. The reaction conditions are mild (40 °C in MeOH, no acid or base) and an intermediate organomanganese reagent is unlikely. Functional groups tolerated include halides and pseudohalides, free and protected anilines, and a benzyl alcohol. Other activated alkynes including an amide and a ketone also reacted to form arylated products in good yields.

Sterically controlled, palladium-catalyzed intermolecular amination of arenes.

We report the Pd-catalyzed amination of arenes to form N-aryl phthalimides with regioselectivity controlled predominantly by steric effects. Mono-, di-, and trisubstituted arenes lacking a directing group undergo amination reactions with moderate to high yields and high regioselectivities from sequential addition of PhI(OAc)2 as an oxidant in the presence of Pd(OAc)2 as catalyst. This sterically derived selectivity contrasts that for analogous arene acetoxylation.

Nickel-catalyzed reductive conjugate addition to enones via allylnickel intermediates.

An alternative method to copper-catalyzed conjugate addition followed by enolate silylation for the synthesis of ß-disubstituted silyl enol ether products (R(1)(R(2))HCCH═C(OSiR(4)(3))R(3)) is presented. This method uses haloarenes instead of nucleophilic aryl reagents. Nickel ligated to either neocuproine or bipyridine couples an α,ß-unsaturated ketone or aldehyde (R(2)HC═CHC(O)R(3)) with an organic halide (R(1)-X) in the presence of a trialkylchlorosilane reagent (Cl-SiR(4)(3)). Reactions are assembled on the benchtop and tolerate a variety of functional groups (aldehyde, ketone, nitrile, sulfone, pentafluorosulfur, and N-aryltrifluoroacetamide), electron-rich iodoarenes, and electron-poor haloarenes. Mechanistic studies have confirmed the first example of a catalytic reductive conjugate addition of organic halides that proceeds via an allylnickel intermediate. Selectivity is attributed to (1) rapid, selective reaction of LNi(0) with chlorotriethylsilane and enone in the presence of other organic electrophiles, and (2) minimization of enone dimerization by ligand steric effects.

[2,2'-Bis(diphenyl-phosphan-yl)-1,1'-binaphthyl-κP,P']chlorido(4-methyl-phenyl-sulfon-yl-κS)palladium(II) dichloro-methane tris-olvate monohydrate.

In the title compound, [Pd(C(7)H(7)O(2)S)Cl(C(44)H(32)P(2))]·3CH(2)Cl(2)·H(2)O, the geometry around the metal atom is distorted square planar, with a twist angle between the P-Pd-P and S-Pd-Cl planes of 28.11 (2)°. The two Pd-P bond lengths differ by about 0.04 Šand the biphosphane bite angle is slightly obtuse [92.92 (2)°]. There are three dichloro-methane and one water mol-ecule co-crystallized with the palladium mol-ecule, all with atoms in general positions. Alternating water and palladium mol-ecules form four-membered cyclic units through O-H⋯Cl and O-H⋯O hydrogen bonding. One of the dichloromethane solvent molecules is disordered over two positions in a 0.55:0.45 ratio.

Reductive conjugate addition of haloalkanes to enones to form silyl enol ethers.

A new method is presented for tandem reductive conjugate addition and silyl enol ether formation from cyclic and acyclic enones and enals in the presence of a Mn reductant, a Ni(terpyridine) catalyst, and a trialkylchlorosilane. The addition of secondary, tertiary, and hindered primary haloalkanes is demonstrated. Preliminary studies on the mechanism show that the intermediacy of L1(Ni)(η(3)-1-triethylsilyloxyalkenyl)X or in-situ-formed RMnX is unlikely.

Nickel-catalyzed reductive cross-coupling of aryl halides with alkyl halides.

The direct reductive cross-coupling of alkyl halides with aryl halides is described. The transformation is efficient (equimolar amounts of the starting materials are used), generally high-yielding (all but one between 55 and 88% yield), highly functional-group-tolerant [OH, NHBoc, NHCbz, Bpin, C(O)Me, CO(2)Et, and CN are all tolerated], and easy to perform (uses only benchtop-stable reagents, tolerates small amounts of water and oxygen, changes color when complete, and uses filtration workup). The reaction appears to avoid the formation of intermediate organomanganese species, and a synergistic effect was found when a mixture of two ligands was employed.

alpha-Synuclein budding yeast model: toxicity enhanced by impaired proteasome and oxidative stress.

Parkinson's disease (PD) is a common neurodegenerative disorder that results from the selective loss of midbrain dopaminergic neurons. Misfolding and aggregation of the protein alpha-synuclein, oxidative damage, and proteasomal impairment are all hypotheses for the molecular cause of this selective neurotoxicity. Here, we describe a Saccharomyces cerevisiae model to evaluate the misfolding, aggregation, and toxicity-inducing ability of wild-type alpha-synuclein and three mutants (A30P, A53T, and A30P/A53T), and we compare regulation of these properties by dysfunctional proteasomes and by oxidative stress. We found prominent localization of wild-type and A53T alpha-synuclein near the plasma membrane, supporting known in vitro lipid-binding ability. In contrast, A30P was mostly cytoplasmic, whereas A30P/A53T displayed both types of fluorescence. Surprisingly, alpha-synuclein was not toxic to several yeast strains tested. When yeast mutants for the proteasomal barrel (doa3-1) were evaluated, delayed alpha-synuclein synthesis and membrane association were observed; yeast mutant for the proteasomal cap (sen3-1) exhibited increased accumulation and aggregation of alpha-synuclein. Both sen3-1and doa3-1 mutants exhibited synthetic lethality with alpha-synuclein. When yeasts were challenged with an oxidant (hydrogen peroxide), alpha-synuclein was extremely lethal to cells that lacked manganese superoxide dismutase Mn-SOD (sod2Delta) but not to cells that lacked copper, zinc superoxide dismutase Cu,Zn-SOD (sod1Delta). Despite the toxicity, sod2Delta cells never displayed intracellular aggregates of alpha-synuclein. We suggest that the toxic alpha-synuclein species in yeast are smaller than the visible aggregates, and toxicity might involve alpha-synuclein membrane association. Thus, yeasts have emerged effective organisms for characterizing factors and mechanisms that regulate alpha-synuclein toxicity.