A Supramolecular Model for the Co-Catalytic Role of Nitro Compounds in Brønsted Acid Catalyzed Reactions.

Nitro compounds are known to change reaction rates and kinetic concentration dependence of Brønsted-acid-catalyzed reactions. Yet, no mechanistic model exists to account for these observations. In this work, an atomistic model for the catalytically active form for an alcohol dehydroazidation reaction is presented, which is generated by DFT calculations and consists of an H-bonded aggregate of two molecules of Brønsted acid and two molecules of nitro compound. The computed O-H stretching frequencies for the aggregate indicate they are stronger acids than the individual acid molecules and serve as predictors for experimental reaction rates. By applying the model to a chemically diverse set of potential promoters, it was predicted and verified experimentally that sulfate esters induce a similar co-catalytic effect. The important implication is that Brønsted-acid catalysis must be viewed from a supramolecular perspective that accounts for not only the pKa of the acid and the bulk properties of a solvent, but also the weak interactions between all molecules in solution.

Catalytic Synthesis of Trifluoromethylated Allenes, Indenes, Chromenes, and Olefins from Propargylic Alcohols in HFIP.

A general method to access CF3-substituted allenes from propargylic alcohols under Lewis acid catalysis in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvent is described. By tuning the reaction time and temperature, the obtained allenes rearrange to 1,3-biaryl-1-trifluoromethyl-1H-indenes. By tuning the structure of the propargylic alcohol substrates, a range of trifluoromethylated 2H-chromenes were successfully synthesized with the use of catalytic quantities of strong Brønsted acid in HFIP. The present method is therefore highly potent for the synthesis of a number of potentially pharmaceutically interesting new trifluoromethylated compounds and produces water as the only stoichiometric byproduct.

Catalytic Friedel-Crafts Reactions of Highly Electronically Deactivated Benzylic Alcohols.

Highly electronically deactivated benzylic alcohols, including those with a CF3 group adjacent to the OH-bearing carbon, undergo dehydrative Friedel-Crafts reactions upon exposure to catalytic Brønsted acid in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) solvent. Titration and kinetic experiments support the involvement of higher order solvent/acid clusters in catalysis.

Enantioselective and Regiodivergent Functionalization of N-Allylcarbamates by Mechanistically Divergent Multicatalysis.

A pair of mechanistically divergent multicatalytic reaction sequences has been developed consisting of nickel-catalyzed isomerization of N-allylcarbamates and subsequent phosphoric-acid-catalyzed enantioselective functionalization of the resulting intermediates. By appropriate selection of reaction partners, in situ generated imines and ene-carbamates are mechanistically partitioned to yield opposing functionalized products. Formal α-functionalization to give protected α-arylamines is achieved upon enantioselective Friedel-Crafts reaction with arene nucleophiles, whereas formal ß-functionalization is achieved upon reaction with diarylimine electrophiles in an enantioselective Povarov-[4+2] cycloaddition.

Ligand Control of E/Z Selectivity in Nickel-Catalyzed Transfer Hydrogenative Alkyne Semireduction.

A nickel-catalyzed transfer hydrogenative alkyne semireduction protocol that can be applied to both internal and terminal alkynes using formic acid and Zn as the terminal reductants has been developed. In the case of internal alkynes, the (E)- or (Z)-olefin isomer can be accessed selectively under the same reaction conditions by judicious inclusion of a triphos ligand.

An asymmetric pericyclic cascade approach to 3-alkyl-3-aryloxindoles: generality, applications and mechanistic investigations.

The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3-alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology.

Nucleophilic Ring Opening of Donor-Acceptor Cyclopropanes Catalyzed by a Brønsted Acid in Hexafluoroisopropanol.

A general, Brønsted acid catalyzed method for the room temperature, nucleophilic ring opening of donor-acceptor cyclopropanes in fluorinated alcohol solvent, HFIP, is described. Salient features of this method include an expanded cyclopropane scope, including those bearing single keto-acceptor groups and those bearing electron-deficient aryl groups. Notably, the catalytic system proved amenable to a wide range of nucleophiles including arenes, indoles, azides, diketones, and alcohols.

Ring-opening hydroarylation of monosubstituted cyclopropanes enabled by hexafluoroisopropanol.

Ring-opening hydroarylation of cyclopropanes is typically limited to substrates bearing a donor-acceptor motif. Here, the transformation is achieved for monosubstituted cyclopropanes by using catalytic Brønsted acid in hexafluoroisopropanol (HFIP) solvent, constituting a rare example where such cyclopropanes engage in intermolecular C-C bond formation. Branched products are obtained when electron-rich arylcyclopropanes react with a broad scope of arene nucleophiles in accord with a simple SN1-type ring-opening mechanism. In contrast, linear products are obtained when cyclopropylketones react with electron-rich arene nucleophiles. In the latter case, mechanistic experiments and DFT-calculations support a homo-conjugate addition pathway.

Identifying lead hits in catalyst discovery by screening and deconvoluting complex mixtures of catalyst components.

A reaction-economic combinatorial strategy is described for lead hit identification in catalyst discovery efforts directed towards a specific transformation. Complex mixtures of rationally chosen precatalysts and ligands are screened against various reaction parameters to identify lead conditions in a small number of reactions. Iterative deconvolution of the resulting hits identifies which components contribute to the lead in situ generated catalyst. Application of this strategy rapidly uncovered a new mild in situ generated catalyst for the dehydrative Friedel-Crafts reaction as well as conditions for selective monoarylation in catalytic ortho-C-H arylation of unsubstituted N-(quinolin-8-yl)benzamide.

Asymmetric pericyclic cascade approach to spirocyclic oxindoles.

The reaction of chiral N-arylnitrones with carbocyclic alkylarylketenes generates spirocyclic oxindoles in good yields and with excellent levels of enantioselectivity (90-99% ee) via a pericyclic cascade process.