Directing-Group-Free Arene C(sp2)-H Amination Using Bulky Aminium Radicals and DFT Analysis of Regioselectivity.

A hydroxylamine-derived electrophilic aminating reagent produces a transient and bulky aminium radical intermediate upon in situ activation by either TMSOTf or TFA and a subsequent electron transfer from an iron(II) catalyst. Density functional theory calculations were used to examine the regioselectivity of arene C-H amination reactions on diversely substituted arenes. The calculations suggest a simple charge-controlled regioselectivity model that enables prediction of the major C(sp2)-H amination product.

Dual Photoredox/Nickel-Promoted Alkylation of Heteroaryl Halides with Redox-Active Esters.

Herein a method for the radical alkylation of heteroaryl halides that relies upon the combination of photoredox and nickel catalysis is described. The use of aliphatic N-(acyloxy)phthalimides as redox-active esters affords primary and secondary radicals for the decarboxylative dual cross-coupling with pyrimidine and pyridine heteroaryl chlorides, bromides, and iodides. The method provides an additional synthetic tool for the incorporation of medicinally relevant heterocyclic motifs.

Synthesis of Highly Substituted Cyclopropanes via the Quasi-Favorskii Rearrangement of α,α-Dichlorocyclobutanols.

A method for the synthesis of highly substituted cyclopropanes via a quasi-Favorskii rearrangement is described. The method includes the combination two chemical transformations starting from α,α-dichlorocyclobutanones prepared via the [2 + 2] Staudinger ketene cycloaddition between either terminal- or cis-olefins and dichloroketene. First, α,α-dichlorocyclobutanones are reacted with organocerium reagents to afford the corresponding tertiary alcohols in good to excellent yields through a nucleophilic addition reaction that provided exclusively anti-products. Second, upon irreversible deprotonation, the tertiary α,α-dichlorocyclobutanols underwent a ring-contraction reaction (i.e., quasi-Favorskii rearrangement) to form structurally diverse cyclopropanes in moderate to good yields. The syn-stereoselectivity during the quasi-Favorskii rearrangement was evaluated using DFT analysis.

Titanium-Mediated Synthesis of Spirocyclic NH-Azetidines from Oxime Ethers.

The TiIV -mediated synthesis of spirocyclic NH-azetidines from oxime ethers using either an alkyl Grignard reagent or terminal olefin ligand exchange coupling partner is described. Through a proposed Kulinkovich-type mechanism, a titanacyclopropane intermediate forms and serves as a 1,2-aliphatic dianion equivalent, inserting into the 1,2-dielectrophilc oxime ether to ultimately give rise to the desired N-heterocyclic four-membered ring. This transformation proceeds in moderate yield to furnish previously unreported and structurally diverse NH-azetidines in a single step.

Direct Primary Amination of Alkylmetals with NH-Oxaziridine.

A method for the primary electrophilic amination of primary, secondary, and tertiary organometallic substrates from a bench-stable NH-oxaziridine reagent is described. This facile and highly chemoselective transformation occurs at ambient temperature and without transition metal catalysts or purification by column chromatography to provide alkylamine products in a single step. Density functional theory (DFT) calculations revealed that, despite the basicity of alkylmetals, the direct NH-transfer pathway is favored over proton and O-transfer.

Copper-Catalyzed Synthesis of Hindered Ethers from α-Bromo Carbonyl Compounds.

A catalytic method for the synthesis of sterically hindered ethers and thioethers from α-bromo carbonyl compounds and the corresponding nucleophiles using an inexpensive Cu(I) catalytic system is reported. This facile transformation takes place at ambient temperature and does not require the exclusion of air or moisture; thus, it is well-suited for the functionalization and derivatization of complex organic molecules.

Rapid heteroatom transfer to arylmetals utilizing multifunctional reagent scaffolds.

Arylmetals are highly valuable carbon nucleophiles that are readily and inexpensively prepared from aryl halides or arenes and widely used on both laboratory and industrial scales to react directly with a wide range of electrophiles. Although C-C bond formation has been a staple of organic synthesis, the direct transfer of primary amino (-NH2) and hydroxyl (-OH) groups to arylmetals in a scalable and environmentally friendly fashion remains a formidable synthetic challenge because of the absence of suitable heteroatom-transfer reagents. Here, we demonstrate the use of bench-stable N-H and N-alkyl oxaziridines derived from readily available terpenoid scaffolds as efficient multifunctional reagents for the direct primary amination and hydroxylation of structurally diverse aryl- and heteroarylmetals. This practical and scalable method provides one-step synthetic access to primary anilines and phenols at low temperature and avoids the use of transition-metal catalysts, ligands and additives, nitrogen-protecting groups, excess reagents and harsh workup conditions.

Non-Deprotonative Primary and Secondary Amination of (Hetero)Arylmetals.

Herein we disclose a novel method for the facile transfer of primary (-NH2) and secondary amino groups (-NHR) to heteroaryl- as well as arylcuprates at low temperature without the need for precious metal catalysts, ligands, excess reagents, protecting and/or directing groups. This one-pot transformation allows unprecedented functional group tolerance and it is well-suited for the amination of electron-rich, electron-deficient as well as structurally complex (hetero)arylmetals. In some of the cases, only catalytic amounts of a copper(I) salt is required.