Steven Bloom

A Polycomponent Metal‐Catalyzed Aliphatic, Allylic, and Benzylic Fluorination

A group effort: Reported is the title reaction using a polycomponent catalytic system involving commercially available Selectfluor, a putative radical precursor N-hydroxyphthalimide, an anionic phase-transfer catalyst (KB(C(6)F(5))(4)), and a copper(I) bis(imine). The catalyst system formed leads to monofluorinated compounds selectively (see example) without the necessity for an excess of the alkane substrate.

Iron(II)-Catalyzed Benzylic Fluorination

Direct C-F functionalization of benzylic sp(3) C-H bonds is a synthetic challenge that has yet to be propitiously overcome. A mild, one-pot synthesis of monofluorinated benzylic substrates is reported with commercially available iron(II) acetylacetonate and Selectfluor in good to excellent yields and selectivity. A convenient route to β-fluorinated products of 3-aryl ketones is also highlighted, providing a synthetic equivalent to the difficult to accomplish conjugate addition of fluoride to α,β-unsaturated ketones.

Direct, Catalytic Monofluorination of sp3 C–H Bonds: A Radical-Based Mechanism with Ionic Selectivity

Recently, our group unveiled a system in which an unusual interplay between copper(I) and Selectfluor effects mild, catalytic sp(3) C-H fluorination. Herein, we report a detailed reaction mechanism based on exhaustive EPR, (19)F NMR, UV-vis, electrochemical, kinetic, synthetic, and computational studies that, to our surprise, was revealed to be a radical chain mechanism in which copper acts as an initiator. Furthermore, we offer an explanation for the notable but curious preference for monofluorination by ascribing an ionic character to the transition state.

A photocatalyzed aliphatic fluorination

We disclose a new approach to the catalysis of alkane fluorination employing ultraviolet light and a photosensitizer, 1,2,4,5-tetracyanobenzene (TCB). The process is efficient, mild, and operationally straightforward. We demonstrate reaction utility on a variety of substrates, from simple hydrocarbons to complex natural products. In a showcase example, we establish that the well-known photochemical rearrangement of α-santonin can be supplanted by a highly selective catalyzed fluorination.

Photocatalyzed Benzylic Fluorination: Shedding "Light" on the Involvement of Electron Transfer

The photocatalyzed oxidation of benzylic compounds by 1,2,4,5-tetracyanobenzene (TCB) in the presence of Selectfluor provides a synthetically efficient route to electron deficient, less substituted, and otherwise inaccessible benzylic fluorides. The virtue of this system is multifold: it is metal-free and mild, and the reagents are inexpensive. Mechanistically, the data suggest the intimate formation of intermediate radical cations in the key radical forming step, as opposed to a concerted hydrogen atom transfer process.

Metal-Catalyzed Benzylic Fluorination as a Synthetic Equivalent to 1,4-Conjugate Addition of Fluoride

We explore in detail the iron-catalyzed benzylic fluorination of substrates containing aromatic rings and electron-withdrawing groups positioned β to one another, thus providing direct access to β-fluorinated adducts. This operationally convenient process can be thought of not only as a contribution to the timely problem of benzylic fluorination but also as a functional equivalent to a conjugate addition of fluoride, furnishing products in moderate to good yields and in excellent selectivity.

Tricomponent catalytic α,α-difluorination of acid chlorides.

The selective α,α-difluorination of carbonyl compounds remains a challenge in modern organic synthesis; current methods often incorporate stepwise processes and/or harsh conditions, providing unsatisfactory mixtures of mono- and difluorinated products. In this communication, a practical, mild, and one-pot method for the selective α,α-difluorination of readily available acid chlorides is reported in which three separate catalysts act synergistically to form products in outstanding selectivity and fair to excellent yields.

Characterization of Highly Unusual NH+–O Hydrogen Bonding to Ester Ether Oxygen Atoms through Spectroscopic and Computational Studies

We characterize a highly unusual, charged NH-O hydrogen bond formed within esters of 8-(dimethylamino)naphthalen-1-ol in which an ammonium ion serves as an intramolecular hydrogen bond donor to spatially proximate ester ether oxygen atoms. Infrared spectroscopic analysis of the ester carbonyl frequencies demonstrates significant blue-shifting when ether hydrogen bonding is possible, in stark contrast to the more commonly observed red shift that occurs upon hydrogen bonding to the ester carbonyl oxygen. The intrinsic behavior of the linkage (i.e., in which counterions and solvent effects are eliminated) is provided by vibrational predissociation spectroscopy of the isolated gas-phase cations complexed with weakly bound D(2) molecules.

Decarboxylative alkylation for site-selective bioconjugation of native proteins via oxidation potentials

The advent of antibody–drug conjugates as pharmaceuticals has fuelled a need for reliable methods of site-selective protein modification that furnish homogeneous adducts. Although bioorthogonal methods that use engineered amino acids often provide an elegant solution to the question of selective functionalization, achieving homogeneity using native amino acids remains a challenge. Here, we explore visible-light-mediated single-electron transfer as a mechanism towards enabling site- and chemoselective bioconjugation. Specifically, we demonstrate the use of photoredox catalysis as a platform to selectivity wherein the discrepancy in oxidation potentials between internal versus C-terminal carboxylates can be exploited towards obtaining C-terminal functionalization exclusively. This oxidation potential-gated technology is amenable to endogenous peptides and has been successfully demonstrated on the protein insulin. As a fundamentally new approach to bioconjugation this methodology provides a blueprint toward the development of photoredox catalysis as a generic platform to target other redox-active side chains for native conjugation. Selectively targeting native amino acids for late-stage protein modification is a significant challenge, but now it has been shown that photoredox catalysis can be used to specifically target protein C-termini toward decarboxylative-alkylation with Michael acceptors. This technology harnesses innate differences in side-chain oxidation potentials to select between the various functional groups typical among proteins in order to form a single modified product.

A Chelating Nucleophile Plays a Starring Role: 1,8-Naphthyridine-Catalyzed Polycomponent α,α-Difluorination of Acid Chlorides

A dually activated ketene enolate, generated from an acid chloride, the unusual chelating nucleophile (1,8-naphthyridine), and a Lewis acid, reacts to afford a host of α,α-difluorinated products in the presence of a benchtop-stable fluorinating agent (Selectfluor). The use of this method to synthesize otherwise difficult to make products is highlighted along with computational and spectroscopic support for the proposed chelate.