Poison to Promise: The Resurgence of Organophosphorus Fluoride Chemistry.

Organophosphorus(V) fluorides have a long and tumultuous history, with early applications as toxins and nerve agents reflecting their poisonous past. Behind these very real safety considerations, there is also growing potential in a wide range of fields, from chemical biology to drug development. The recent inclusion of organophosphorus(V) fluorides in click chemistry exemplifies the promise these compounds possess and brings these molecules to the brink of a resurgence. In this Perspective, we delve into the history of P(V)-F compounds, discuss the precautions needed to work with them safely, and explore recent advancements in their synthesis and application. We conclude by discussing how this field can continue on a path toward innovation.

Expanded Access to Fluoroformamidines via a Modular Synthetic Pathway.

Fluoroformamidines are an underutilized and understudied functional group despite combining two of the most highly prized elements in drug design: nitrogen and fluorine. We report a practical and modular synthesis of fluoroformamidines via the rearrangement of in situ-generated amidoximes. High yields in just 60 s at room temperature highlight the efficiency of this protocol. Furthermore, fluoroformamidines proved to be useful intermediates in the synthesis of diverse ureas and carbamimidates.

A modified Beckmann rearrangement for the facile synthesis of amidines and imidates via imidoyl fluoride intermediates.

Herein, we report a modified Beckmann rearrangement using sulfone iminium fluoride (SIF) reagents to rapidly synthesize imidoyl fluoride intermediates. Subsequently, amidine and imidate products can be formed following the introduction of amine and alcohol nucleophiles, respectively. Overall, approximately 50 amidine and imidate products have been isolated in high yields utilizing mild conditions.

Rapid Generation of P(V)-F Bonds Through the Use of Sulfone Iminium Fluoride Reagents.

Phosphorus-fluorine bonds have become increasingly relevant in the pharmaceutical industry. To continue their exploration, more efficient synthetic methods are needed. Here, we report the application of sulfone iminium fluoride (SIF) reagents to the synthesis of P(V)-F bonds. The SIF reagents promote the deoxyfluorination of phosphinic acids in just 60 s with excellent yields and scope. The same P(V)-F products can also be synthesized from secondary phosphine oxides using an SIF reagent.

Synthesis of Highly Reactive Sulfone Iminium Fluorides and Their Use in Deoxyfluorination and Sulfur Fluoride Exchange Chemistry.

We report the synthesis of sulfone iminium fluorides (SIFs), a reactive class of sulfur(VI) molecules. The synthesis is tolerant of a variety of substituents on the sulfur and nitrogen components. The SIF reagents were applied to the deoxyfluorination of alcohols and carboxylic acids, providing high yields of fluorinated products in 60 s at room temperature. The SIF reagents were then utilized in sulfur fluoride exchange (SuFEx), creating the first ionic SuFEx products to date.

Room Temperature Deoxyfluorination of Benzaldehydes and α-Ketoesters with Sulfuryl Fluoride and Tetramethylammonium Fluoride.

A method for the room temperature deoxyfluorination of benzaldehydes and α-ketoesters using sulfuryl fluoride and Me4NF is described. A large scope of aryl and heteroaryl substrates is demonstrated, and this method compares favorably to other common deoxyfluorination methods for many substrates.

Rapidly Activating Pd-Precatalyst for Suzuki-Miyaura and Buchwald-Hartwig Couplings of Aryl Esters.

Esters are valuable electrophiles for cross-coupling due to their ubiquity and ease of synthesis. However, harsh conditions are traditionally required for the effective cross-coupling of ester substrates. Utilizing a recently discovered precatalyst, Pd-catalyzed Suzuki-Miyaura and Buchwald-Hartwig reactions involving cleavage of the C(acyl)-O bond of aryl esters that proceed under mild conditions are reported. The Pd(II) precatalyst is highly active because it is reduced to the Pd(0) active species more rapidly than previous precatalysts.

Well-defined nickel and palladium precatalysts for cross-coupling.

Transition metal-catalysed cross-coupling is one of the most powerful synthetic methods and has led to vast improvements in the synthesis of pharmaceuticals, agrochemicals and precursors for materials chemistry. A major advance in cross-coupling over the past 20 years is the utilization of well-defined, bench-stable Pd and Ni precatalysts that do not require the addition of free ancillary ligand, which can hinder catalysis by occupying open coordination sites on the metal. The development of precatalysts has resulted in new reactions and expanded substrate scopes, enabling transformations under milder conditions and with lower catalyst loadings. This Review highlights recent advances in the development of Pd and Ni precatalysts for cross-coupling, and provides a critical comparison between the state of the art in Pd- and Ni-based systems.

DFT Investigation of Suzuki-Miyaura Reactions with Aryl Sulfamates Using a Dialkylbiarylphosphine-Ligated Palladium Catalyst.

Aryl sulfamates are valuable electrophiles for cross-coupling reactions because they can easily be synthesized from phenols and can act as directing groups for C-H bond functionalization prior to cross-coupling. Recently, it was demonstrated that (1-tBu-Indenyl)Pd(XPhos)Cl (XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) is a highly active precatalyst for room-temperature Suzuki-Miyaura couplings of a variety of aryl sulfamates. Herein, we report an in-depth computational investigation into the mechanism of Suzuki-Miyaura reactions with aryl sulfamates using an XPhos-ligated palladium catalyst. Particular emphasis is placed on the turnover-limiting oxidative addition of the aryl sulfamate C-O bond, which has not been studied in detail previously. We show that bidentate coordination of the XPhos ligand via an additional interaction between the biaryl ring and palladium plays a key role in lowering the barrier to oxidative addition. This result is supported by NBO and NCI-Plot analysis on the transition states for oxidative addition. After oxidative addition, the catalytic cycle is completed by transmetalation and reductive elimination, which are both calculated to be facile processes. Our computational findings explain a number of experimental results, including why elevated temperatures are required for the coupling of phenyl sulfamates without electron-withdrawing groups and why aryl carbamate electrophiles are not reactive with this catalyst.

Pd-Catalyzed Suzuki-Miyaura and Hiyama-Denmark Couplings of Aryl Sulfamates.

Using a recently discovered precatalyst, the first Pd-catalyzed Suzuki-Miyaura reactions using aryl sulfamates that occur at room temperature are reported. In complementary work, it is demonstrated that a related precatalyst can facilitate the coupling of aryl silanolates, which are less toxic and reactive nucleophiles than boronic acids with aryl chlorides. By combining our results using modern electrophiles and nucleophiles, the first Hiyama-Denmark reactions using aryl sulfamates are reported.

Comparison of the catalytic activity for the Suzuki-Miyaura reaction of (η(5)-Cp)Pd(IPr)Cl with (η(3)-cinnamyl)Pd(IPr)(Cl) and (η(3)-1-t-Bu-indenyl)Pd(IPr)(Cl).

Complexes of the type (η(3)-allyl)Pd(L)(Cl) and (η(3)-indenyl)Pd(L)(Cl) are highly active precatalysts for the Suzuki-Miyaura reaction. Even though allyl and indenyl ligands are similar to cyclopentadienyl (Cp) ligands, there have been no detailed comparative studies exploring the activity of precatalysts of the type (η(5)-Cp)Pd(L)(Cl) for Suzuki-Miyaura reactions. Here, we compare the catalytic activity of (η(5)-Cp)Pd(IPr)(Cl) (IPr = 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene, Cp) with two commercially available catalysts (η(3)-cinnamyl)Pd(IPr)(Cl) (Cin) and (η(3)-1-t-Bu-indenyl)Pd(IPr)(Cl) ( (tBu) Ind). We show that Cp gives slightly better catalytic activity than Cin, but significantly inferior activity than (tBu) Ind. This order of activity is rationalized by comparing the rates at which the precatalysts are activated to the monoligated Pd(0) active species along with the tendency of the starting precatalysts to comproportionate with monoligated Pd(0) to form inactive Pd(I) dimers. As part of this work the Cp supported Pd(I) dimer (µ-Cp)(µ-Cl)Pd2(IPr)2 (Cp (Dim) ) was synthesized and crystallographically characterized. It does not readily disproportionate to form monoligated Pd(0) and consequently Cp (Dim) is a poor catalyst for the Suzuki-Miyaura reaction.