Metal-free, photoinduced remote C(sp)-H borylation.

Here, we describe a protocol for the metal-free, photo-induced borylation of unactivated C(sp)-H bonds distal to an -oxalate hydroxamic ester functionality. The methodology requires only substrate and bis(catecholato)diboron under light irradiation to effect the desired transformation. A range of linear and cyclic tertiary and secondary borylation products are obtained in good yields and high site-selectivity enabling the late-stage C(sp)-H borylation of natural product derivatives and drug-like compounds.

Fluorosulfonamide-Directed Heteroarylation of Aliphatic C(sp)-H Bonds.

Herein, we describe a formal dehydrogenative cross coupling of heterocycles with unactivated aliphatic amines. The resulting transformation enables the direct alkylation of common heterocycles by merging N-F-directed 1,5-HAT with Minisci chemistry, leading to predictable site selectivity. The reaction provides a direct route for the transformation of simple alkyl amines to value-added products under mild reaction conditions, making this an attractive option for C(sp)-H heteroarylation.

Iron-Catalyzed, Directed Benzylic Borylation.

Herein, we describe an iron-catalyzed benzylic C-H borylation reaction. The reaction targets primary and secondary C(sp)-H bonds to deliver high-value boronic esters under mild conditions with short (7-8 min) reaction times. Functional groups are well tolerated, and complete site selectivity is observed in the presence of multiple benzylic C-H bonds.

Directed Ni-Catalyzed Reductive Arylation of Aliphatic C-H Bonds.

Herein, we describe the nickel-catalyzed reductive arylation of remote C(sp)-H bonds with aryl electrophiles. The reaction targets secondary and tertiary C(sp)-H bonds to deliver all-carbon quaternary centers. The success of this method relies on a novel amidyl radical precursor that tolerates reducing conditions, namely -oxalate hydroxamic acid esters.

Csp-H Trifluoromethylation of Unactivated Aliphatic Systems.

A straightforward method for the undirected trifluoromethylation of unactivated methylene units was developed. The reaction proceeds in aqueous acetonitrile with Grushin's reagent, bpyCu(CF), under broad-spectrum white-light irradiation. The trifluoromethylation tolerates a wide range of functional groups including ketones, esters, nitriles, amides, alcohols, and carboxylic acids.

Interrupting the Barton-McCombie Reaction: Aqueous Deoxygenative Trifluoromethylation of -Alkyl Thiocarbonates.

The site-selective trifluoromethylation of aliphatic systems remains an important challenge. This work describes a light-driven, copper-mediated trifluoromethylation of -alkyl thiocarbonates. The reaction provides broad functional group tolerance (e.

Cu-Catalyzed C-N Coupling with Sterically Hindered Partners.

Copper, an earth-abundant metal, has reemerged as a viable alternative to the versatile Pd-catalyzed C-N coupling. Coupling sterically hindered reaction partners, however, remains challenging. Herein, we disclose the discovery and development of a pyrrole-ol ligand to facilitate the coupling of -substituted aryl iodides with sterically hindered amines.

N-Directed fluorination of unactivated Csp-H bonds.

Site-selective fluorination of aliphatic C-H bonds remains synthetically challenging. While directed C-H fluorination represents the most promising approach, the limited work conducted to date has enabled just a few functional groups as the arbiters of direction. Leveraging insights gained from both computations and experimentation, we enabled the use of the ubiquitous amine functional group as a handle for the directed C-H fluorination of Csp-H bonds.

Copper-Catalyzed, N-Directed Csp-H Trifluoromethylthiolation (-SCF) and Trifluoromethylselenation (-SeCF).

A direct and versatile copper-catalyzed trifluoromethylthiolation and trifluoromethylselenation of primary, secondary, and tertiary aliphatic C-H bonds was developed. The reaction provides direct access to molecules containing these emerging moieties in the presence of a wide range of common functional groups and in complex molecular environments.

Fenton-Inspired C-H Functionalization: Peroxide-Directed C-H Thioetherification.

Substoichiometric iron mediates the thioetherification of unactivated aliphatic C-H bonds directed by resident silylperoxides. Upon exposure to a catalytic amount of iron(II) triflate, TIPS-protected peroxides bearing primary, secondary, and tertiary C-H sites undergo chemoselective thioetherification of remote C-H bonds with diaryl disulfides. The reaction demonstrates a broad substrate scope and functional group tolerance without the use of any noble metal additives.

Synthesis of Tetrahydroisoquinolines Through an Iron-Catalyzed Cascade: Tandem Alcohol Substitution and Hydroamination.

Rapid assembly of saturated nitrogen heterocycles-the synthetically more challenging variants of their aromatic relatives-can expedite the synthesis of biologically relevant molecules. Starting from a benzylic alcohol tethered to an unactivated alkene, an iron-catalyzed tandem alcohol substitution and hydroamination provides access to tetrahydroisoquinolines in a single synthetic step. Using a mild iron-based catalyst, the combination of these operations forms two carbon-nitrogen bonds and provides a unique annulation strategy to access this valuable core.

1,2-(Bis)trifluoromethylation of Alkynes: A One-Step Reaction to Install an Underutilized Functional Group.

Modifying the electronic properties of olefins is the quintessential approach to tuning alkene reactivity. In this context, the exploration of trifluoromethyl groups as divergent electronic modifiers has not been considered. In this work, we describe a copper-mediated 1,2-(bis)trifluoromethylation of acetylenes to create E-hexafluorobutenes (E-HFBs) under blue light in a single step.

A microdroplet-accelerated Biginelli reaction: mechanisms and separation of isomers using IMS-MS.

Electrospray ionization (ESI) combined with ion mobility spectrometry (IMS) and mass spectrometry (MS) techniques is used to examine the Biginelli reaction in an ensemble of ions generated from droplets. We find evidence for rapid dihydropyrimidinone formation from condensation of ethyl acetoacetate, benzaldehyde, and urea on the very short timescales associated with the electrospray process (∼10 μs to ∼1.0 ms).

Iron-Catalyzed Hydroamination and Hydroetherification of Unactivated Alkenes.

The hydrofunctionalization of alkenes, explored for over 100 years, offers the potential for a direct, atom-economical approach to value-added products. While thermodynamically favored, the kinetic barrier to such processes necessitates the use of catalysts to control selectivity and reactivity. Modern variants typically rely on noble metals that require different ligands for each class of hydrofunctionalization, thereby limiting generality.

Stereoinversion of Unactivated Alcohols by Tethered Sulfonamides.

The direct, catalytic substitution of unactivated alcohols remains an undeveloped area of organic synthesis. Moreover, catalytic activation of this difficult electrophile with predictable stereo-outcomes presents an even more formidable challenge. Described herein is a simple iron-based catalyst system which provides the mild, direct conversion of secondary and tertiary alcohols to sulfonamides.

Aqueous Benzylic C-H Trifluoromethylation for Late-Stage Functionalization.

The installation of trifluoromethyl groups has become an essential step across a number of industries such as agrochemicals, drug discovery, and materials. Consequently, the rapid introduction of this critical functional group in a predictable fashion would benefit current practitioners in those fields. This communication describes a mild trifluoromethylation of benzylic C-H bonds with high selectivity for the least hindered hydrogen atom.

Iron-Catalyzed, Fluoroamide-Directed C-H Fluorination.

This communication describes a mild, amide-directed fluorination of benzylic, allylic, and unactivated C-H bonds mediated by iron. Upon exposure to a catalytic amount of iron(II) triflate (Fe(OTf)), N-fluoro-2-methylbenzamides undergo chemoselective fluorine transfer to provide the corresponding fluorides in high yield. The reaction demonstrates broad substrate scope and functional group tolerance without the use of any noble metal additives.

Manganese-Catalyzed Borylation of Unactivated Alkyl Chlorides.

The use of low-cost manganese(II) bromide (MnBr2) and tetramethylethylenediamine (TMEDA) catalyzes the cross coupling of (bis)pinacolatodiboron with a wide range of alkyl halides, demonstrating the first manganese-catalyzed coupling with alkyl electrophiles. This method allows access to primary, secondary, and tertiary boronic esters from the parent chlorides, which were previously inaccessible as coupling partners. The reaction proceeds in high yield with as little as 1000 ppm catalyst loading, while 5 mol % can provide high yields in as little as 30 min.

Iron-catalyzed coupling of aryl sulfamates and aryl/vinyl tosylates with aryl Grignards.

The iron-catalyzed coupling of aryl sulfamates and tosylates with aryl Grignard reagents is reported for the first time. The methodology employs air-stable, low-cost FeF3·3H2O and the N-heterocyclic carbene ligand IPr·HCl as the preligand to form a long-lived catalyst upon treatment with aryl Grignards. The reaction provides a range of cross-coupled products in good-to-excellent yields.

A unified strategy for iron-catalyzed ortho-alkylation of carboxamides.

Using 8-aminoquinoline-based aryl carboxamides, the direct ortho-alkylation can be achieved in high yields in the presence of an iron source, 1,2-bis(diphenylphosphino)ethane (dppe) and phenylmagnesium bromide. The reactions proceed without overalkylation and provide high levels of regioselectivity. The benzylation reactions can be performed in air with reagent-grade THF, while the alkylation works well with unactivated secondary bromides and iodides in 2-methyltetrahydrofuran.

Iron-catalyzed borylation of alkyl electrophiles.

The use of low-cost iron(III) acetoacetate (Fe(acac)3) and tetramethylethylenediamine (TMEDA) enables the direct cross-coupling of alkyl halides with bis(pinacolato)diboron. This approach allows for the borylation of activated or unactivated primary, secondary, and tertiary bromides. Moreover, even the borylation of benzylic or allylic chlorides, tosylates, and mesylates are possible.

Iron-catalyzed arene alkylation reactions with unactivated secondary alcohols.

A simple, iron-based catalytic system allows for the inter- and intramolecular arylation of unactivated secondary alcohols. This transformation expands the substrate scope beyond the previously required activated alcohols and proceeds under mild reaction conditions, tolerating air and moisture. Furthermore, the use of an enantioenriched secondary alcohol provides an enantioenriched product for the intramolecular reaction, thereby offering a convenient approach to nonracemic products.

Palladium-catalyzed alkyne insertion/reduction route to trisubstituted olefins.

A new route to trisubstituted olefins through a palladium-catalyzed alkyne insertion/reduction reaction with unactivated alkyl iodides is reported. The reaction proceeds under mild conditions and tolerates a range of functional groups and substitution patterns. Preliminary mechanistic inquiry suggests that the transformation may proceed through a hybrid radical/organometallic pathway.