Carbamoyl Fluorides Research Articles

Pd-catalyzed Suzuki-type cross-coupling of 2-pyridyl carbamoyl fluorides.

We describe a palladium-catalyzed Suzuki-type cross-coupling reaction of 2-pyridyl carbamoyl fluorides with boronic acids, which provides entry to medicinally relevant pyridyl amides. Mechanistic studies, including the synthesis and reactivity of carbamoyl Pd-F complexes, reveal the importance of both the fluoride electrophile and nitrogen directing group for aiding reactivity.

EFluorination for the Rapid Synthesis of Carbamoyl Fluorides from Oxamic Acids.

In this letter, we disclose the anodic oxidation of oxamic acids in the presence of Et3N·3HF as a practical, scalable, and robust method to rapidly access carbamoyl fluorides from readily available and stable precursors. The simplicity of this method also led us to develop the first flow electrochemical preparation of carbamoyl fluorides, demonstrating scale-up feasibility as a proof of concept.

Catalytic Synthesis of Carbonyl Compounds Using Acyl Fluorides, Carbamoyl Fluorides, and Fluoroformates: An Overview

AbstractAcyl fluorides, carbamoyl fluorides and fluoroformates have been employed as efficient reagents in a number of organic syntheses. Their application in catalytic transformations, however, began to be explored in the early 2000s. Recently, these reagents have increasingly gained attention owing to their unique reactivity in diverse catalytic systems. This review aims to overview the advancements in the development of catalytic processes, including transition‐metal catalysis, organocatalysis, and cooperative NHC/photoredox catalysis, where these organofluorine compounds are employed as acyl, carbamoyl, and ester group donors.

Access to N-Difluoromethyl Amides, (Thio)Carbamates, Ureas, and Formamides.

The first efficient access to N-difluoromethyl amides, carbamates, thiocarbamates, ureas, formamides, and their derivatives is reported herein. The synthetic strategy relies on the initial synthesis and straightforward derivatization of N-CF2H carbamoyl fluorides, which were prepared through a desulfurization-fluorination of thioformamides (─NH─C(H)═S) coupled with carbonylation. The newly made N-CF2H carbonyl compounds proved to be highly robust and compatible with numerous chemical transformations and downstream derivatizations, underscoring the potential of this novel motif as a building block in complex functional molecules.

Visible-Light-Induced DDQ-Catalyzed Fluorocarbamoylation Using CF3SO2Na and Oxygen.

The synthesis of carbamoyl fluorides via visible-light induced DDQ catalysis of secondary amines is described. This protocol employs sodium trifluorosulfinate and molecular oxygen for the in situ generation of carbonyl difluoride, which is reacted with amines to afford the corresponding carbamoyl fluorides efficiently. Moreover, carbamoyl fluorides are easily transformed to synthetically useful carbonyl compounds under mild reaction conditions.

Fluoride-Catalyzed Cross-Coupling of Carbamoyl Fluorides and Alkynylsilanes.

We report the synthesis of alkynamides via the cross-coupling of carbamoyl fluorides and alkynylsilanes catalyzed by tetrabutylammonium fluoride (TBAF). In contrast to previously reported transformations of carbamoyl fluorides, C-F bond cleavage is achieved under exceptionally mild conditions (room temperature, low catalyst loadings, and short reaction times) without the need for strongly nucleophilic reagents and/or catalysts. This method offers distinct advantages over transition-metal-catalyzed approaches, such as tolerance to aryl halide moieties and complementary chemoselectivity.

Oxidation of Difluorocarbene by Pyridine N‐Oxide and Ensuing Access to Carbamoyl Fluorides†

Comprehensive SummaryA practical one‐pot preparation of carbamoyl fluorides from easily obtained pyridine N‐oxide, commercially available secondary amines and synthetically versatile difluorocarbene precursors (Ruppert‐Prakash reagent or Chen's reagent) was developed herein, which dexterously resorted to the oxidation of difluorocarbene by external pyridine N‐oxide to produce the toxic and gaseous fluorophosgene in situ. Notable features of this method include nice functionality tolerance, late‐stage modification of drug molecules and the recovery and recycle of quinoline.

BF3-Catalyzed Intramolecular Fluorocarbamoylation of Alkynes via Halide Recycling

A BF3-catalyzed atom-economical fluorocarbamoylation reaction of alkyne-tethered carbamoyl fluorides is reported. The catalyst acts as both a fluoride source and Lewis acid activator, thereby enabling the formal insertion of alkynes into strong C-F bonds through a halide recycling mechanism. The developed method provides access to 3-(fluoromethylene) oxindoles and γ-lactams with excellent stereoselectivity, including fluorinated derivatives of known protein kinase inhibitors. Experimental and computational studies support a stepwise mechanism for the fluorocarbamoylation reaction involving a turnover-limiting cyclization step, followed by internal fluoride transfer from a BF3-coordinated carbamoyl adduct. For methylene oxindoles, a thermodynamically driven Z-E isomerization is facilitated by a transition state with aromatic character. In contrast, this aromatic stabilization is not relevant for γ-lactams, which results in a higher barrier for isomerization and the exclusive formation of the Z-isomer.

Recent Advances in the Synthesis and Transformation of Carbamoyl Fluorides, Fluoroformates, and Their Analogues.

Carbamoyl fluorides, fluoroformates, and their analogues are a class of important compounds and have been evidenced as versatile building blocks for the preparation of useful molecules in organic chemistry. While major achievements were made in the synthesis of carbamoyl fluorides, fluoroformates, and their analogues in the last half of 20th century, an increasing number of reports have focused on using O/S/Se=CF2 species or their equivalents as the fluorocarbonylation reagents for the direct construction of these compounds from the parent heteroatom-nucleophiles in recent years. This review mainly summarizes the advances in the synthesis and typical application of carbamoyl fluorides, fluoroformates, and their analogues by the halide exchanges and fluorocarbonylation reactions since 1980.

Access to N-CF3 Formamides by Reduction of N-CF3 Carbamoyl Fluorides.

The departure into unknown chemical space is essential for the discovery of new properties and function. We herein report the first synthetic access to N-trifluoromethylated formamides. The method involves the reduction of bench-stable NCF3 carbamoyl fluorides and is characterized by operational simplicity and mildness, tolerating a broad range of functional groups as well as stereocenters. The newly made N-CF3 formamide motif proved to be highly robust and compatible with diverse chemical transformations, underscoring its potential as building block in complex functional molecules.

Access to N−CF3 Formamides by Reduction of N−CF3 Carbamoyl Fluorides

AbstractThe departure into unknown chemical space is essential for the discovery of new properties and function. We herein report the first synthetic access to N‐trifluoromethylated formamides. The method involves the reduction of bench‐stable NCF3 carbamoyl fluorides and is characterized by operational simplicity and mildness, tolerating a broad range of functional groups as well as stereocenters. The newly made N−CF3 formamide motif proved to be highly robust and compatible with diverse chemical transformations, underscoring its potential as building block in complex functional molecules.

Enantioselective Synthesis of α-Alkenylated γ-Lactam Enabled by Ni-Catalyzed 1,4-Arylcarbamoylation of 1,3-Dienes

Enantioselective Synthesis of α-Alkenylated γ-Lactam Enabled by Ni-Catalyzed 1,4-Arylcarbamoylation of 1,3-Dienes

Synthesis of Carbamoyl Fluorides Using a Difluorophosgene Surrogate Derived from Difluorocarbene and Pyridine N-Oxides.

We report a method for the synthesis of carbamoyl fluorides from secondary amines using bench-stable, inexpensive, and readily accessible starting materials that, when combined, yield a surrogate for toxic difluorophosgene (COF2) gas. In contrast to state-of-the-art methods for the synthesis of carbamoyl fluorides, our protocol does not require the use of pre-functionalized substrates, the preparation of light-, temperature-, and/or moisture-sensitive chemicals, or the application of explosive fluorinating reagents.

Cover Feature: Study of Carbamoyl Fluoride: Synthesis, Properties and Applications (Chem. Eur. J. 43/2022)

Carbamoyl fluorides are among the emerging fluorinated motifs. but are still quite underexplored. So, an efficient, fast, inexpensive, metal-free and easy-to-perform method to access such compounds easily, even with sophisticated molecules, is described. The physicochemical properties of these compounds were measured to give an insight into the potential of carbamoyl fluorides—in particular, their stability under close-to-physiological conditions. Finally, a first application in radiochemistry to obtain fluorine-18 radiolabeled compounds easily is proposed. More information can be found in the Research Article by F. Toulgoat, T. Billard, and co-workers (DOI: 10.1002/chem.202201589).

Study of Carbamoyl Fluoride: Synthesis, Properties and Applications.

Carbamoyl fluoride is a fluorinated group that, to this date, remains underexplored, probably due to the lack of data concerning its properties. In this paper, a study of carbamoyl fluoride is presented. Stability studies, in particular under physiological conditions, and lipophilicity measurement were performed. A new easy, safe, inexpensive, and metal-free synthesis method is also described. Finally, a potential use in radiochemistry through a 18 F/19 F isotopic exchange is demonstrated.

P-051 - Carbamoyl fluoride as a potential new tag for 18F-labeling

P-051 - Carbamoyl fluoride as a potential new tag for 18F-labeling

Synthesis of N-CF3 Alkynamides and Derivatives Enabled by Ni-Catalyzed Alkynylation of N-CF3 Carbamoyl Fluorides.

The expansion of chemical space associated with ubiquitous motifs is key to unleash new properties and functions. In this context, alkynamides, prevalent in numerous drugs and materials, represent an untapped resource. We herein report the first synthetic access to N-trifluoromethyl alkynamides. Our strategy relies on a mild and operationally simple Ni-catalyzed coupling of N-CF3 carbamoyl fluorides with alkynyl silanes. The synthesized N-CF3 alkynamides proved to be highly robust and readily functioned as a platform to unlock access to valuable derivatives, such as N-CF3 decorated alkenyl amides, oxindoles, or quinolones, all of which were inaccessible to date.

Synthesis of Carbamoyl Fluorides via a Selective Fluorinative Beckmann Fragmentation.

A fluorinative Beckmann fragmentation of α-oximinoamides was devised to provide synthetically useful carbamoyl fluorides. High selectivity for fragmentation over a potentially competing Beckmann rearrangement was observed. This protocol has a distinct mechanism and thus a different substrate scope compared with other synthetic methods. α-Oximinoamides derived from the readily available secondary amines, lactams, or isatins were converted into structurally diverse carbamoyl fluorides.

Broad Scope and High-Yield Access to Unsymmetrical Acyclic [11 C]Ureas for Biomedical Imaging from [11 C]Carbonyl Difluoride.

Effective methods are needed for labelling acyclic ureas with carbon-11 (t1/2 =20.4 min) as potential radiotracers for biomedical imaging with positron emission tomography (PET). Herein, we describe the rapid and high-yield syntheses of unsymmetrical acyclic [11 C]ureas under mild conditions (room temperature and within 7 min) using no-carrier-added [11 C]carbonyl difluoride with aliphatic and aryl amines. This methodology is compatible with diverse functionality (e. g., hydroxy, carboxyl, amino, amido, or pyridyl) in the substrate amines. The labelling process proceeds through putative [11 C]carbamoyl fluorides and for primary amines through isolable [11 C]isocyanate intermediates. Unsymmetrical [11 C]ureas are produced with negligible amounts of unwanted symmetrical [11 C]urea byproducts. Moreover, the overall labelling method tolerates trace water and the generally moderate to excellent yields show good reproducibility. [11 C]Carbonyl difluoride shows exceptional promise for application to the synthesis of acyclic [11 C]ureas as new radiotracers for biomedical imaging with PET.

Enantioselective Ni-Catalyzed Synthesis of Chiral γ-Lactams from Carbamoyl Fluorides and Boronic Acids

Enantioselective Ni-Catalyzed Synthesis of Chiral γ-Lactams from Carbamoyl Fluorides and Boronic Acids