Access to Cyclic N-Trifluoromethyl Ureas through Photocatalytic Activation of Carbamoyl Azides.

We report the mild activation of carbamoyl azides to the corresponding nitrenes using a blue light/[Ir]-catalyzed strategy, which enables stereospecific access to N-trifluoromethyl imidazolidinones and benzimidazolones. These novel structural motifs proved to be highly robust, allowing their downstream diversification. On the basis of our combined computational and experimental studies, we propose that an electron rebound with the excited metal catalyst is undergone, involving a reduction-triggered nitrogen loss, followed by oxidation to the corresponding carbamoyl nitrene and subsequent C-H insertion.

Modular Generation of (Iodinated) Polyarenes Using Triethylgermane as Orthogonal Masking Group.

While the modular construction of molecules from suitable building blocks is a powerful means to more rapidly generate a diversity of molecules than through customized syntheses, the further evolution of the underlying coupling methodology is key to realize widespread applications. We herein disclose a complementary modular coupling approach to the widely employed Suzuki coupling strategy of boron containing precursors, which relies on organogermane containing building blocks as key orthogonal functionality and an electrophilic (rather than nucleophilic) unmasking event paired with air-stable PdI dimer based bond construction. This allows to significantly shorten the reaction times for the iterative coupling steps and/or to close gaps in the accessible compound space, enabling straightforward access also to iodinated compounds.

Orthogonal Stability and Reactivity of Aryl Germanes Enables Rapid and Selective (Multi)Halogenations.

While halogenation is of key importance in synthesis and radioimaging, the currently available repertoire is largely designed to introduce a single halogen per molecule. This report makes the selective introduction of several different halogens accessible. Showcased here is the privileged stability of nontoxic aryl germanes under harsh fluorination conditions (that allow selective fluorination in their presence), while displaying superior reactivity and functional-group tolerance in electrophilic iodinations and brominations, outcompeting silanes or boronic esters under rapid and additive-free conditions. Mechanistic experiments and computational studies suggest a concerted electrophilic aromatic substitution as the underlying mechanism.

Selective ortho-Functionalization of Adamantylarenes Enabled by Dispersion and an Air-Stable Palladium(I) Dimer.

Contrary to the general belief that Pd-catalyzed cross-coupling at sites of severe steric hindrance are disfavored, we herein show that the oxidative addition to C-Br ortho to an adamantyl group is as favored as the corresponding adamantyl-free system due to attractive dispersion forces. This enabled the development of a fully selective arylation and alkylation of C-Br ortho to an adamantyl group, even if challenged with competing non-hindered C-OTf or C-Cl sites. The method makes use of an air-stable PdI dimer and enables straightforward access to diversely substituted therapeutically important adamantylarenes in 5-30 min.

Efficient Synthesis of Trifluoromethyl Amines through a Formal Umpolung Strategy from the Bench-Stable Precursor (Me4 N)SCF3.

Reported herein is the one-pot synthesis of trifluoromethylated amines at room temperature using the bench-stable (Me4 N)SCF3 reagent and AgF. The method is rapid, operationally simple and highly selective. It proceeds via a formal umpolung reaction of the SCF3 with the amine, giving quantitative formation of thiocarbamoyl fluoride intermediates within minutes that can readily be transformed to N-CF3 . The mildness and high functional group tolerance render the method highly attractive for the late-stage introduction of trifluoromethyl groups on amines, as demonstrated herein for a range of pharmaceutically relevant drug molecules.

Squaramide-Catalyzed Asymmetric aza-Friedel-Crafts/N,O-Acetalization Domino Reactions Between 2-Naphthols and Pyrazolinone Ketimines.

N-Boc ketimines derived from pyrazolin-5-ones were explored to develop an unprecedented domino aza-Friedel-Crafts/N,O-acetalization reaction with 2-naphthols. The novel method requires a catalyst loading of only 0.5 mol % of a bifunctional squaramide catalyst, is scalable to gram amounts, and provides a new series of furanonaphthopyrazolidinone derivatives bearing two vicinal tetra-substituted stereogenic centers in excellent yields (95-98 %) and stereoselectivity (>99:1 d.r. and 97-98 % ee). A different reactivity was observed in the case of 1-naphthols and other electron-rich phenols, which led to the aza-Friedel-Crafts adducts in 70-98 % yield and 47-98 % ee.

Asymmetric Synthesis of Spiropyrazolones by Sequential Organo- and Silver Catalysis.

A stereoselective one-pot synthesis of spiropyrazolones through an organocatalytic asymmetric Michael addition and a formal Conia-ene reaction has been developed. Depending on the nitroalkene, the 5-exo-dig-cyclization could be achieved by silver-catalyzed alkyne activation or by oxidation of the intermediate enolate. The mechanistic pathways have been investigated using computational chemistry and mechanistic experiments.

Direct Synthesis of Acyl Fluorides from Carboxylic Acids with the Bench-Stable Solid Reagent (Me4N)SCF3.

A convenient, highly efficient, and selective transformation of aliphatic and aromatic carboxylic acids to acyl fluorides is reported. In contrast to established approaches that require toxic or volatile additives and base and reaction control (i.e., cooling, slow addition), this protocol allows for a straightforward access to various R-COF entities upon direct reaction with the bench-stable, solid reagent (Me4N)SCF3 at room temperature. The method is base- and additive-free, compatible with late-stage synthetic applications, high functional group tolerance, and facile target compound purification via filtration.

Enantioselective synthesis of pyrazolone α-aminonitrile derivatives via an organocatalytic Strecker reaction.

A new organocatalytic enantioselective Strecker reaction of pyrazolone-derived ketimine electrophiles has been developed. Using pseudo-enantiomeric squaramide catalysts the nucleophilic 1,2-addition of trimethylsilyl cyanide to the ketimines efficiently provides a direct entry to both enantiomers of pyrazolone α-aminonitrile derivatives at will in good yields and high enantioselectivities for a wide variety of substrates.

Enantioselective synthesis of 4H-pyranonaphthoquinones via sequential squaramide and silver catalysis.

An enantioselective one-pot Michael addition/hydroalkoxylation reaction between 2-hydroxy-1,4-naphthoquinones and alkyne-tethered nitroalkenes catalyzed by a cinchona-derived squaramide and a silver(I) salt has been developed. The sequential protocol provides a direct access to 4H-pyranonaphthoquinones in moderate to very good yields and good to excellent enantioselectivities at a very low catalyst loading (0.5 mol%) of the squaramide.

Combining silver- and organocatalysis: an enantioselective sequential catalytic approach towards pyrano-annulated pyrazoles.

A one-pot asymmetric Michael addition/hydroalkoxylation sequence, catalyzed by a sequential catalytic system consisting of a squaramide and a silver salt, provides a new series of chiral pyrano-annulated pyrazole derivatives in excellent yields (up to 95%) and high enantioselectivities (up to 97% ee).

Organocatalytic Asymmetric Synthesis of Functionalized 1,3,5-Triarylpyrrolidin-2-ones via an Aza-Michael/Aldol Domino Reaction.

The organocatalytic asymmetric synthesis of functionalized 1,3,5-triarylpyrrolidin-2-ones bearing three contiguous stereocenters through an aza-Michael/aldol domino reaction of α-ketoamides with α,ß-unsaturated aldehydes is described. The domino products were further derivatized by aldehyde olefination under one-pot conditions. The reaction proceeds with excellent diastereoselectivities (>20:1) and good to excellent enantioselectivities (60-96% ee).

An Asymmetric Organocatalytic Quadruple Cascade to Tetraaryl-Substituted 2-Azabicyclo[3.3.0]octadienones.

A new asymmetric organocatalytic three-component quadruple cascade of α-ketoamides with α,ß-unsaturated aldehydes is described. The reaction is catalyzed by the (S)-diphenylprolinol TMS ether catalyst and proceeds via an aza-Michael/aldol condensation/vinylogous Michael/aldol condensation sequence to yield tetraaryl-substituted 2-azabicyclo[3.3.0]octadienone derivatives. The cascade products are obtained with good to very good yields (34-71%), virtually complete diastereoselectivities (>20:1), and very good enantioselectivities (84-97%).

Combining silver catalysis and organocatalysis: a sequential Michael addition/hydroalkoxylation one-pot approach to annulated coumarins.

A highly stereoselective one-pot procedure for the synthesis of five-membered annulated hydroxycoumarins has been developed. By merging primary amine catalysis with silver catalysis, a series of functionalized coumarin derivatives were obtained in good yields (up to 91%) and good to excellent enantioselectivities (up to 99% ee) via a Michael addition/hydroalkoxylation reaction. Depending on the substituents on the enynone, the synthesis of annulated six-membered rings is also feasible.