Jung Min Joo

C–H Bonds as Ubiquitous Functionality: A General Approach to Complex Arylated Imidazoles via Regioselective Sequential Arylation of All Three C–H Bonds and Regioselective N-Alkylation Enabled by SEM-Group Transposition

Imidazoles are an important group of the azole family of heterocycles frequently found in pharmaceuticals, drug candidates, ligands for transition metal catalysts, and other molecular functional materials. Owing to their wide application in academia and industry, new methods and strategies for the generation of functionalized imidazole derivatives are in demand. We here describe a general and comprehensive approach for the synthesis of complex aryl imidazoles, where all three C-H bonds of the imidazole core can be arylated in a regioselective and sequential manner. We report new catalytic methods for selective C5- and C2-arylation of SEM-imidazoles and provide a mechanistic hypothesis for the observed positional selectivity based on electronic properties of C-H bonds and the heterocyclic ring. Importantly, aryl bromides and low-cost aryl chlorides can be used as arene donors under practical laboratory conditions. To circumvent the low reactivity of the C-4 position, we developed the SEM-switch that transfers the SEM-group from N-1 to N-3 nitrogen and thus enables preparation of 4-arylimidazoles and sequential C4-C5-arylation of the imidazole core. Furthermore, selective N3-alkylation followed by the SEM-group deprotection (trans-N-alkylation) allows for regioselective N-alkylation of complex imidazoles. The sequential C-arylation enabled by the SEM-switch allowed us to produce a variety of mono-, di-, and triarylimidazoles using diverse bromo- and chloroarenes. Using our approach, the synthesis of individual compounds or libraries of analogues can begin from either the parent imidazole or a substituted imidazole, providing rapid access to complex imidazole structures.

C–H Arylation of Pyridines: High Regioselectivity as a Consequence of the Electronic Character of C–H Bonds and Heteroarene Ring

We report a new catalytic protocol for highly selective C-H arylation of pyridines containing common and synthetically versatile electron-withdrawing substituents (NO(2), CN, F and Cl). The new protocol expands the scope of catalytic azine functionalization as the excellent regioselectivity at the 3- and 4-positions well complements the existing methods for C-H arylation and Ir-catalyzed borylation, as well as classical functionalization of pyridines. Another important feature of the new method is its flexibility to adapt to challenging substrates by a simple modification of the carboxylic acid ligand or the use of silver salts. The regioselectivity can be rationalized on the basis of the key electronic effects (repulsion between the nitrogen lone pair and polarized C-Pd bond at C2-/C6-positions and acidity of the C-H bond) in combination with steric effects (sensitivity to bulky substituents).

Catalytic C-H allylation and benzylation of pyrazoles.

We describe a general approach for the synthesis of allylated and benzylated pyrazoles. An electron-withdrawing substituent, such as nitro, chloro, and ester groups, at C4 renders the Lewis basic nitrogen atom to be less basic and the C-H bond more acidic than the ones of the parent ring, enabling Pd-catalyzed C-H allylation and benzylation reactions of pyrazoles. The new method expanding the scope of the C-H functionalization of pyrazoles beyond arylation reactions provides a rapid access to complex pyrazole compounds.

Concise Synthesis of the Erythrina Alkaloid 3-Demethoxyerythratidinone via Combined Rhodium Catalysis

The total synthesis of the erythrina alkaloid 3-demethoxyerythratidinone has been achieved via a strategy based on combined rhodium catalysis. The catalytic tandem cyclization effected by the interplay of alkynyl and vinylidene rhodium species allows for efficient access to the A and B rings of the tetracyclic erythrinane skeleton in a single step. The synthesis also features rapid preparation of the requisite precursor for the double ring closure and thus has been completed in only 7 total steps in 41% overall yield.

Synthesis of (+)-Lasonolide A: (-)-lasonolide A is the biologically active enantiomer.

(+)-Lasonolide A was synthesized following the established procedure. (-)-Lasonolide A was found to be the biologically active enantiomer.

C-H bonds as ubiquitous functionality: preparation of multiple regioisomers of arylated 1,2,4-triazoles via C-H arylation.

We describe a general approach for the synthesis of complex aryl 1,2,4-triazoles. The electronic character of the C-H bonds and the triazole ring allows for the regioselective C-H arylation of 1-alkyl- and 4-alkyltriazoles under catalytic conditions. We have also developed the SEM and THP switch as well as trans-N-alkylation, which enable sequential arylation of the triazole ring to prepare 3,5-diaryltriazoles. This new strategy provides rapid access to a variety of arylated 1,2,4-triazoles and well complements existing cyclization methods.

Preparation of 2-Aminopyridoimidazoles and 2-Aminobenzimidazoles via Phosphorus Oxychloride-Mediated Cyclization of Aminoureas

The novel preparation of 2-aminopyridoimidazoles and 2-aminobenzimidazoles via the cyclization of (2-aminopyridin-3-yl)urea and (2-aminophenyl)urea substrates in the presence of phosphorus oxychloride is described. This methodology is demonstrated for a range of urea substrates with aminoimidazole products obtained in good yields and with excellent levels of purity.