Download PDF
Synthesis
DOI: 10.1055/a-2557-7635
short review
Bürgenstock Special Section 2024 – Future Stars in Organic Chemistry

Carbamoyl Fluorides: A Platform to Interrogate Fluoride-Enabled Reactivity

Maryam Jabbarpoor
,
Christine M. Le  ∗

This work was financially supported by the Natural Sciences and Engineering Council of Canada (NSERC) Discovery (RGPIN-2021-03630) and CREATE (575259-2023) Grant Programs.
› Further Information
 
 PDF Download Permissions and Reprints All articles of this category


Abstract

The strong and polar nature of C–F bonds impart organofluorine compounds with highly desirable properties, making them indispensable in pharmaceutical, agrochemical, and polymer research. While this bond strength makes the modification of organofluorine compounds challenging, it also creates opportunities for the development of innovative strategies for their functionalization. Carbamoyl fluorides represent an emerging class of fluorinated electrophiles, showcasing unique fluoride-enabled reactivity and serving as versatile building blocks for accessing valuable amides and heterocyclic compounds. This review highlights recent progress in the synthesis and reactivity of carbamoyl fluorides, including comparisons to their chlorinated counterparts where relevant.

1 Introduction

2 Synthesis and Simple Nucleophilic Substitution Reactions of Carbamoyl Fluorides

2.1 Direct Use of Difluorophosgene

2.2 Use of (Di)fluorophosgene Equivalents

2.2.1 From Isocyanates and Thioformamides

2.2.2 From Amines

2.3 Use of Difluorocarbene Sources

2.4 Use of CO2 and Deoxyfluorinating Reagents

2.5 Miscellaneous Methods

3 Reactivity of Carbamoyl Fluorides

3.1 Covalent Inhibition of Enzymes

3.2 Nucleophilic Substitution

3.3 Transition-Metal-Catalyzed C–F Bond Activation

3.4 Lewis Acid and Base Catalyzed Carbamoylation

4.0 Outlook and Conclusion


#

Key words

fluorine - carbamoyl fluoride - fluoride-enabled reactivity - carbamoylation - C–F bond functionalization - difluorocarbene - fluorophosgene
1

Introduction

Zoom Image
Maryam Jabbarpoor (left) obtained her B.Sc. from Shahid Beheshti University, Iran, where she developed a strong interest in organic and inorganic chemistry. She then pursued her M.Sc. under the supervision of Dr. Nasser Safari, working on the development of heterogeneous catalysts. Maryam began her Ph.D. in 2022 at York University in the Le Group, where her research centers on the development of alternative strategies for the synthesis of amide-containing compounds from fluorinated precursors. Christine Le (right) is an Assistant Professor at York University in Toronto (Canada). She received her B.Sc. from Western University (2011), and her M.Sc. (2012) and Ph.D. degrees (2016) from the University of Toronto in the labs of Professor Vy Dong and Professor Mark Lautens, respectively. In 2017, Christine moved to UC Berkeley as an NSERC Postdoctoral Fellow, working under the guidance of Professor F. Dean Toste. Her current research program focuses on the synthesis of fluorinated building blocks and their application in catalysis and fluoride-enabled transformations.

Organofluorine compounds are ubiquitous across numerous industrial sectors due to the unique chemical and physical properties conferred by fluorine substitution.[1] [2] [3] The exceptional strength of the C–F bond imparts characteristic stability to these compounds, a property that proves highly advantageous in applications spanning pharmaceuticals, agrochemicals, polymers, and functional materials.[4] [5] [6] At the same time, however, this stability poses significant challenges for C–F bond cleavage, necessitating the development of specialized reagents and catalysts for effective functionalization.[7] [8] [9] [10] Nevertheless, the synthetic versatility of organofluorine building blocks has been extensively demonstrated.[11] [12] [13] [14] [15] Among these, carbamoyl fluorides have recently emerged as a particularly promising class of electrophiles, combining enhanced stability, reactivity, and selectivity compared to related derivatives, such as acyl fluorides and carbamoyl chlorides.[16] [17] Notably, carbamoyl fluorides are important precursors for pharmaceutically relevant scaffolds, including amides, lactams, ureas, and carbamates (Figure [1]).[18] [19] [20] In biological contexts, carbamoyl fluorides serve as bioisosteres of the carbamate functionality, and can also behave as acetylcholinesterase (AChE) inhibitors themselves.[21] [22]

Zoom Image
Figure 1 Advances in carbamoyl fluorides synthesis and reactivity

Although the carbamoyl fluoride functional group has been known for some time,[23] its reported reactivity has been largely considered esoteric, with few documented applications. This dearth of research is likely due to the generally poor electrophilicity of carbamoyl fluorides, combined with limited user-friendly methods available for their synthesis.[24] Traditionally, carbamoyl fluorides have been prepared from the corresponding chlorides via halogen exchange using excess fluoride salts,[24] [25] [26] [27] or via the fluorocarbonylation of amines using difluorophosgene (COF2) or chlorocarbonyl fluoride (COFCl).[28–31] However, these approaches present practical challenges, as the synthesis of moisture-sensitive carbamoyl chlorides requires toxic phosgene (COCl2) or related equivalents. Difluorophosgene is similarly toxic as well as difficult to handle and source commercially.[28] , [31] [32] [33] [34] [35] [36] [37] [38] Over the last decade, the chemistry of carbamoyl fluorides has seen remarkable progress, driven largely by advances in their efficient synthetic preparation.[16] This has facilitated a deeper exploration of the reactivity of carbamoyl fluorides, revealing their potential as a distinct class of electrophiles in various transformations, such as simple nucleophilic substitutions as well as catalytic reactions enabled by Lewis acids, Lewis bases, and late transition metals.[20] This work has been briefly highlighted in several insightful reviews that focus primarily on their synthetic preparation and/or general reactivity.[16] , [18] [19] [20] In addition to providing a concise overview of the synthetic methods for carbamoyl fluoride synthesis and reactivity to-date, this review will draw attention to the novel chemistry that they enable by virtue of fluorine substitution.


# 2

Synthesis and Simple Nucleophilic Substitution Reactions of Carbamoyl Fluorides

Since the 1940s, various reports have documented the formation of carbamoyl fluorides through the reaction of isocyanates with highly corrosive HF,[39] [40] or through the fluorocarbonylation of amines[28,31] and other N-nucleophiles[41] [42] [43] [44] with COF2 or COFCl.[29] [30] While these early studies have enriched our understanding of this underutilized functionality, practical methods for the synthesis of carbamoyl fluorides have only emerged recently.[18] Notably, these methods are generally marked by a more diverse substrate scope, with modern protocols providing safer alternatives to the direct use of COFX (X = F or Cl) gas.

2.1

Direct Use of Difluorophosgene

Few methods use difluorophosgene directly, as there are limited commercial suppliers of COF₂, requiring this toxic gas to be prepared in-house. In 2015, Quan and co-workers explored the synthesis of isocyanates from primary amines 1 using difluorophosgene, which proceeds via carbamoyl fluoride intermediate 2 (Scheme [1a]).[45] [46] Elevated temperatures (T2) were required for the elimination step to form isocyanates 3. While the yields for some examples were slightly lower compared to the phosgenation method using COCl2, the toxicity of COF2 is much lower than phosgene. Pike and co-workers also reported the intermediacy of carbamoyl fluorides 6 and 7 in the synthesis of acyclic symmetrical and unsymmetrical [11C]-labelled acyclic ureas 9, which are potential PET radiotracer candidates (Scheme [1b]).[47] Their method involves the use of amines 4 or ammonium salts 5 as starting materials in the presence of [11C]COF2. Methods that use COCl2 require specialized equipment, generate hazardous chlorine gas, and yield a mixture of desired unsymmetrical and undesired symmetrical ureas. In contrast, this mild approach tolerates trace amounts of water and offers a broad scope with good reproducibility.

Zoom Image
Scheme 1 Carbamoyl fluoride intermediates from COF2 and amines

# 2.2

Use of (Di)fluorophosgene Equivalents

A more practical approach for the fluorocarbonylation of amines involves the use of easier-to-handle reagents that liberate COF2 in situ. The following examples highlight the development of such difluorophosgene equivalents, and where appropriate, their subsequent reactivity in simple nucleophilic substitution reactions will be discussed.

2.2.1

From Isocyanates and Thioformamides

In 2019, the Schoenebeck group reported the synthesis of N-CF3 carbamoyl fluorides 11 starting from isothiocyanates 10, which employed excess AgF along with triphosgene as the carbonyl source (Scheme [2a]).[48] Further derivatization via nucleophilic substitution reactions provided entry to N-CF3 carboxamide derivatives 13 in good to excellent yields. Considering the synthetic inaccessibility and poor reactivity of N-CF3 amines towards acylation, this method provides a complementary approach to access valuable N-CF3 amides. The Schoenebeck group later discovered that a storable solution of AgOCF3 can be prepared and subjected directly to isothiocyanates to afford N-CF3 carbamoyl fluorides 12 in high yields.[49] Their result indicated that, following desulfurization, difluoromethyl imine 14 is generated, which, in the presence of excess AgF, leads to the formation of nucleophilic trifluoromethylamine 15. This intermediate can react with an in situ generated fluorocarbonyl source to yield compounds 11 or 12. They suggested that AgOCF3 is a stable source of COF2 which can be ‘activated’ upon coordination with isothiocyanates, liberating COF2 and AgF in a controlled manner.

Zoom Image
Scheme 2 N-Fluoromethyl-substituted carbamoyl fluorides from isothiocyanates and thioformamides

In 2024, the Schoenebeck group also applied this strategy in a desulfurization-fluorination sequence of thioformamides 16 combined with carbonylation to prepare N-CF2H carbamoyl fluorides 17 (Scheme [2b]).[50] They started with various monosubstituted thioformamides and further derivatized the N-CF2H carbamoyl fluorides to the corresponding N-CF2H amides, carbamates, thiocarbamates, ureas, and formamides. Also in 2024, Yi, Guo, Jiang, and co-workers reported a similar protocol to access N-CF2H carbamoyl fluorides 20 starting from thioformamides 16 via a one-pot desulfurization-fluorination and acylation process.[51] The carbamoyl fluoride products can serve as a starting point for reactions with strong nucleophiles to afford various N-CF2H carbonyl-containing compounds like amides, ureas, carbamates, thiocarbamates, selenocarbamates, and azides.


# 2.2.2

From Amines

In 2019, Zhang and co-workers developed a highly efficient fluorocarbonylation of secondary aliphatic amines 22 using trifluoromethyl trifluoromethanesulfonate (CF3SO3CF3 or TFMT) as a COF2 reservoir (Scheme [3a]).[52] They proposed that the reaction can be initiated by nucleophilic substitution of TFMT with a sacrificial amine, resulting in the formation of –OCF3 24, followed by its rapid decomposition to COF2 and F–. In the case of primary amines, symmetrical ureas are formed via an intermediate isocyanate species. Although their method offers an alternative to directly using COF2, TFMT is a highly volatile liquid (bp 19 °C) that requires use at low temperatures and storage over P2O5. Commercially available TFMT is usually produced from trifluoromethanesulfonyl derivatives and fluorinating agents. However, these methods often lead to low yields, involve handling reactive reagents, and require specialized equipment, making TFMT costly to manufacture.[53] Also in 2019, Konig and co-workers observed the formation of carbamoyl fluoride intermediates 26 in an ex situ NMR study of a visible-light-induced method for COF2 generation to access carbonate, carbamates, and urea derivatives 27 (Scheme [3b]).[54] Upon irradiation by 400 nm LEDs, an excited state photocatalyst (PC*) forms a catalyst-charge transfer complex dimer with a ground state PC, which subsequently disproportionates to PC•– and PC•+ . SET reduction of 4-(trifluoromethoxy)benzonitrile by PC•– leads to the formation of the corresponding aryl radical and –OCF3, which can eventually fragment to COF2.

Zoom Image
Scheme 3 Carbamoyl fluorides from amines and –OCF3 sources

Similarly, Tang and co-workers suggested the formation of carbamoyl fluoride intermediate 29 in a silver-catalyzed ring-opening reaction of N-tosylaziridine 28 with trifluoromethyl arenesulfonate (TFMS) (Scheme [3c]).[55] Under the reaction conditions, the mixture of AgF, KF, and TFMS leads to the in situ formation of AgOCF3, a reported reservoir for COF2. However, the highly electrophilic carbamoyl fluoride formed in this step becomes hydrolyzed upon work-up. As mentioned in the previous section, the Schoenebeck group also used AgOCF3 as a stable source of –OCF3 anion for the direct formation of carbamoyl fluorides 32 from simple secondary amines 31, where R1,R2 = alkyl or aryl (Scheme [3d]).[49] Although a stable stock solution of AgOCF3 can be prepared and stored, the use of stoichiometric amounts of expensive silver salts is a limitation.

To remove the use of excess silver salts and triphosgene for reagent preparation, Toulgoat, Billard, and co-workers introduced a stable –OCF3 salt 35 derived from inexpensive 2,4-dinitro-1-(trifluoromethoxy)benzene (DNTFB; 34) (Scheme [3e]).[56] [57] Stability studies in this report indicate that carbamoyl fluorides are resistant to solvolysis in various environments, including a range of organic solvents, water, and physiological media. However, they tend to hydrolyze under highly basic aqueous conditions (pH >10). Their observed stability, coupled with PET radiochemistry studies via 18F/19F isotope exchange, highlights the potential of application of carbamoyl fluorides as radiotracers. In 2025, Gobec and co-workers reported a three-step, chromatography-free procedure to access carbamoyl fluorides via N-carbamoylimidazole activation.[58] The method works best with unhindered secondary amines without alkylation-prone functional groups.

Zoom Image
Scheme 4 Carbamoyl fluorides from difluorocarbene sources

#
# 2.3

Use of Difluorocarbene Sources

Over the past few decades, difluorocarbene (DFC) has emerged as a versatile reactive intermediate for incorporating fluorinated C1 units into organic molecules.[59] [60] DFC has been used in various transformations, such as trifluoromethylation, difluoromethylation, fluorocyclization, gem-difluoroolefination, and transition metal coordination.[61,62] In 2016, Bolm and co-workers discovered novel reactivity of BrCF2CO2Na, a readily available DFC source, with hydroxylamines 37 to prepare carbamoyl fluorides 41 (Scheme [4a]).[62] While various alkyl hydroxylamines were converted in moderate to excellent yields, carbonyl-substituted hydroxylamines reacted poorly due to their low nucleophilicity. The proposed mechanism involves formation of zwitterionic species 39 through a substrate-assisted decomposition pathway of BrCF2CO2Na via intermediate 38 or through the coordination of hydroxylamines to DFC. Both pathways are energetically feasible based on DFT calculations. Subsequent hydroxy migration to the difluoromethylide group yields alcohol 40, which can form carbamoyl fluorides 41 upon HF elimination.

In 2022, our group developed a direct method for synthesizing carbamoyl fluorides 47 using DFC sources in the presence of an external organic oxidant (Scheme [4b]).[63] This approach eliminates the need for pre-functionalized substrates and the use of toxic or sensitive fluorinating reagents. The method applies bench-stable (triphenylphosphonio)difluoroacetate (PDFA) 42 as a convenient DFC source and 4-methylpyridine N-oxide (44) as a mild oxidant. In accordance with previous reports,[64] [65] PDFA undergoes thermally induced decarboxylation to generate phosphonium ylide 45, which is in equilibrium with free DFC. Subsequent trapping of DFC by the nucleophilic pyridine N-oxide forms a zwitterionic species 46, which can fragment to form COF2 and an equivalent of 4-methylpyridine, a base that can neutralize the HF generated in the fluorocarbonylation step. The substrate scope of this method has proven to be quite broad, with >60 unique carbamoyl fluorides prepared in our lab to-date.

Subsequently, Wang, Feng, and co-workers developed a similar protocol to access carbamoyl fluorides using DFC precursors, such as TMSCF3 (Ruppert–Prakash reagent) or FSO2CF2CO2SiMe3 in the presence of quinoline N-oxides as the oxidant.[66]


# 2.4

Use of CO2 and Deoxyfluorinating Reagents

Zoom Image
Scheme 5 Carbamoyl fluorides with CO2 and deoxyfluorinating reagents

In 2019, Tlili and co-workers introduced an innovative approach where carbamoyl fluorides 49 could be synthesized from secondary amines using CO2 as a C1 source along with a deoxyfluorinating reagent (DAST) (Scheme [5]).[67] This transformation can be carried out efficiently under mild conditions with atmospheric CO2 and is amenable to isotopic labelling using [13C]CO2. The reaction conditions are exceptionally mild, enabling a broad substrate scope. Although this system avoids the use or in situ generation of COF2, the high cost and shock-sensitivity of DAST could present some limitations for industrial scale-up. Towards a more environmentally sustainable method for carbamoyl fluoride synthesis, Tlili and co-workers replaced DAST with a novel SF5-based deoxyfluorinating reagent 50. This reagent can be prepared from tetrakis(dimethylamino)ethylene (TDAE) via a two-electron reduction of SF6 under blue LED light irradiation.[19] [68] Given the potency of SF6 as an anthropogenic greenhouse gas, the development of methods for the valorization of SF6 is highly desirable.


# 2.5

Miscellaneous Methods

In 2021, Lim and Song reported the synthesis of carbamoyl fluorides 53 from α-oxyiminoamides, α-oxyiminolactams, and isatin-3-oximes 52 using DAST through a highly selective fluorinative Beckmann fragmentation (Scheme [6]).[69] They proposed that DAST functions both as an oxime activator and a fluoride source, yielding carbamoyl fluorides that subsequently can undergo further transformations, such as base-assisted intramolecular annulation, to form lactams and ureas.

In 2024, the Lam group explored an anodic oxidation of oxamic acids 54 with Et3N·3HF to prepare carbamoyl fluorides 55 (Scheme [6]).[70] The full synthetic procedure, starting from secondary amines, can often be completed without requiring chromatographic purification. This simple isolation technique, combined with the avoidance of silver salts or DAST, makes their method cost-effective. They demonstrated the scalability of the protocol, in both batch and flow electrochemistry, which offers an efficient way for carbamoyl fluoride preparation on larger scales.

Zoom Image
Scheme 6 Synthesis of carbamoyl fluorides with other methods. a R1R2NH (10 equiv).

Visible-light-induced carbamoylation reactions have recently gained attention due to their sustainability, high selectivity, and mild reaction conditions. Min and co-workers explored a visible-light-induced DDQ-catalyzed reaction of secondary amines 51 to access carbamoyl fluorides 56 (Scheme [6]).[38] The proposed mechanism is initiated by oxidation of CF3SO2Na (Langlois reagent) by an excited state DDQ* species to form a CF3SO2 radical. Loss of SO2 generates a CF3 radical, which is eventually transformed to COF2 in the presence of molecular oxygen and a proton source. Further derivatization of carbamoyl fluorides to ureas, carbamates, and amides was also demonstrated in this study.

In 2025, Shimakoshi and co-workers developed a photocatalytic approach to synthesize carbamoyl fluorides 57 from tribromofluoromethane (CBr3F), employing a hybrid B12Mg2+/TiO2 catalyst under visible light exposure.[71] CBr3F is converted into bromofluorophosgene (COBrF), which reacts with secondary amines to form carbamoyl fluorides. Based on their DFT calculations and spectroscopic data, they suggested that a B12Mg2+/TiO2 catalyst and atmospheric oxygen converts CX4 to COX2 via a combination of SN2 and SET mechanism, which subsequently provide a variety of carbonylation products with different nucleophiles. This innovative photoinduced method offers an alternative sustainable option to access carbamoyl fluorides.


#
# 3

Reactivity of Carbamoyl Fluorides

The recent development of efficient methods to access carbamoyl fluorides has permitted their further exploration in organic synthesis. Unlike carbamoyl chlorides, which are highly reactive and readily undergo carbon–halogen bond cleavage, carbamoyl fluorides typically require stronger nucleophiles to undergo substitution reactions. Although carbamoyl fluorides are less electrophilic, when they are paired with catalysts or reagents that specifically target the fluorine atom, a distinct reactivity and selectivity profile arises that cannot be observed in their halogenated counterparts. This section will describe modern reactions of carbamoyl fluorides to access medicinally important scaffolds, with comparisons to the reactivity of carbamoyl chlorides where appropriate.

3.1

Covalent Inhibition of Enzymes

In 1964, Wilson and Metzger noted that carbamoyl fluorides were effective reversible covalent inhibitors of chymotrypsin, trypsin, and acetylcholinesterase.[72] When compared to the analogous carbamoyl chlorides, the fluorides provided rate enhancement across all tested enzymes, despite their reduced reactivity in conventional organic reactions. These results led the authors to conclude that an electrophilic component is involved in the mechanism of action, wherein the smaller size and higher electronegativity of fluorine favour the formation of the anionic tetrahedral intermediate 60 (Scheme [7]). Moreover, in this canonical catalytic triad, the neighbouring histidine residue can facilitate fluoride expulsion through hydrogen bonding. Although fluoride is typically considered a ‘poor leaving group,’ its higher electronegativity, basicity, and ability to form strong hydrogen bonds make fluoride electrophiles more susceptible to acid catalysis.[73] Overall, these factors explain why carbamoyl fluorides are better inhibitors than the corresponding chlorides.

Zoom Image
Scheme 7 Carbamoyl fluorides as acid-transferring enzyme inhibitors
Zoom Image
Scheme 8 (a) Synthesis of N-CF3 hydrazines and their derivatives from carbamoyl fluorides and carbamoyl azides. (b) Further product derivatization: reagents and conditions: (A): ketone (2.0 equiv), H2SO4, MeOH, 80 °C, 4 h; (B): sulfonyl-Cl (1.5 equiv), pyridine (1.5 equiv), DCM, r.t., 16; (C): aldehyde (2.0 equiv), AcOH, MeOH, 80 °C, 4 h.

# 3.2

Nucleophilic Substitution

The synthetic application of carbamoyl fluorides for the industrial-scale production of carbamate-containing pesticides and insecticides has been documented in patent literature since the 1970s.[74] [75] [76] In 1978, Hatch described the preparation of N-sulfenylated carbamates, an effective class of insecticides that possess low mammalian toxicity, from carbamoyl fluorides under phase-transfer conditions, which allowed them to override certain patent restrictions.[39] To the best of our knowledge, these studies represent the earliest examples of carbamoyl fluorides being applied in synthesis. In Section 2, the reactivity of carbamoyl fluorides with simple heteroatom nucleophiles (e.g., amines, alcohols, thiols) and Grignard reagents, was shown briefly. In recent years, the reactions of carbamoyl fluorides with a wider range of nucleophiles have been examined, leading to the formation of key structural motifs that hold substantial promise for the synthesis of other biologically relevant functionalities. In this section, we describe the development of new reaction methods employing carbamoyl fluorides, with several studies exemplifying the synthetic advantages of using this emerging class of electrophiles.

In 2020, the Schoenebeck group described the reaction of N-CF3 carbamoyl fluorides 61 with azide nucleophiles to generate the corresponding carbamoyl azides 62, which can subsequently undergo a Curtius-type rearrangement to form N-CF3 hydrazines 63 (Scheme [8]).[77] Their approach provides simple and mild conditions to access stable carbamoyl azides, which can be isolated or used directly in following step without the need for additional purification (Scheme [8a]). Subsequent derivatization of the N-CF3 hydrazines provided entry to highly valuable indoles, hydrazones, and sulfonyl hydrazines (Scheme [8b]).

The Schoenebeck group also developed a straightforward and efficient route to access N-CF3 formamides 70 from carbamoyl fluorides 69 via NaBH4 reduction (Scheme [9a]).[78] N-CF3 Formamides provided via this method were shown to have high functional group tolerance under a variety of conditions, including hydrogenation with Pd/C and H2, transition-metal-catalyzed coupling reactions, as well as acidic or basic media (Scheme [9c]). Reduction with NaBD4 provides convenient entry to deuterium-labelled substrates.

Zoom Image
Scheme 9 (a) Reduction of N-CF3 carbamoyl fluorides and (b) reduction of other carbamoyl halides to access formamides. (c) Selected derivatization: reagents and conditions: (A) H2 (1 atm), Pd/C (10 mol%), MeOH, r.t., 24 h; (B): trimethylsilylacetylene (1.3 equiv), Pd(PPh3)2Cl2 (5 mol%), PPh3 (10 mol%), CuI (1.5 equiv) Et3N (2.8 equiv), DMF, 80 °C, 16 h; (C): Step 1: TFA, DCM, r.t., 16 h; step 2: HBTU, DIPEA, H-Val-O t Bu·HCl, DCM, r.t., 16 h (yield over 2 steps).
Zoom Image
Scheme 10 Enantioselective carbamoyl fluoride enabled intramolecular carbocarbamoylation of unactivated alkenes with Ni catalysts to access γ-lactams

# 3.3

Transition-Metal-Catalyzed C–F Bond Activation

In 2020, Luan, Ye, and co-workers reported an enantioselective synthesis of γ-lactams 80 via a Ni-catalyzed intramolecular carbocarbamoylation of unactivated alkenes, which was enabled by the use of a carbamoyl fluoride electrophile (Scheme [10a]).[27] Notably, this method represents the first application of carbamoyl fluorides in a transition-metal-catalyzed cross-coupling reaction. When compared to the reactivity of carbamoyl chlorides 82, the use of a fluorinated electrophile improved both the reactivity and enantioselectivity (Scheme [10b]). Despite the comparatively low electrophilicity of carbamoyl fluorides, this study highlights the unique role of fluoride in facilitating this transformation. Interestingly, no direct coupling of carbamoyl fluorides with boronic acids occurred when a substrate bearing a saturated alkyl chain 85 was subjected to standard conditions (Scheme [10c]). Their mechanistic studies showed that intermediate 81 can be formed and undergo transmetalation with boronic acids in the presence of the base. Therefore, the authors propose that migratory insertion of the alkene occurs before the transmetalation step. Overall, this work illustrates the potential of carbamoyl fluorides as an alternative class of electrophiles to be further explored in transition-metal-catalyzed carbamoylation reactions.

A similar phenomenon was reported by Chen and co-workers in 2022, which described a Ni-catalyzed enantioselective 1,4-arylcarbamoylation of 1,3-dienes with boronic acids, yielding α-alkenylated γ-lactams 88 (Scheme [11a]).[79] Control experiments underscore the distinctive advantage of carbamoyl fluorides over the analogous chlorides 89 in both the efficacy and enantioselectivity of the reaction (Scheme [11b]). When enantiomerically enriched carbamoyl fluoride 91 was used with either (S)- or (R)-BINAP, the corresponding lactams 92 and 93 were formed with excellent diastereoselectivity, implying high catalyst control (Scheme [11c]). The proposed mechanism involves oxidative addition of C–F bond to Ni(0), followed by migratory insertion to form a η3-π-allyl nickel intermediate. Transmetalation with the boronic acid and reductive elimination forms the 1,4-product selectively. These methods provide practical and easy access to enantioenriched α-functionalized γ-lactams, with valuable bioactive applications, directly from acyclic precursors and unactivated alkenes.

Zoom Image
Scheme 11 Enantioselective carbamoyl fluoride enabled intramolecular 1,4-arylcarbamoylation of 1,3-dienes with Ni catalysts

In recent decades, carbamoyl electrophiles have demonstrated to be a highly effective class of electrophiles in transition-metal-catalyzed transformations.[17] Despite significant advances, most reactions are limited to the synthesis of heterocycles via intramolecular cross-coupling. Early studies by the Schoenebeck group demonstrated that while N-CF3 carbamoyl fluorides underwent nucleophilic substitution with a number of alkyl and aryl Grignard reagents, alkynyl derivatives were unreactive under the tested conditions.[48] This led the authors to develop an alkynylation method under transition metal catalysis (Scheme [12a]).[80] The use of a Ni catalyst in combination with alkynylsilanes as the cross-coupling partner enabled the efficient synthesis of N-CF3 alkynamides 96, which could be further transformed to previously inaccessible derivatives like alkenyl amides, oxindoles, or 2-quinolones (Scheme [12b]). Computational and experimental studies showed that the active catalyst, derived from Ni(COD)2/dtbbpy, preferentially undergoes oxidative addition to the C–F bond over the carbamoyl C–N bond. Despite the broad functional group tolerance and compatibility with both aryl and alkyl N-CF3 carbamoyl fluorides, the method did not yield the expected amide products with other organometallic coupling partners, such as RB(OH)2 and R2Zn.

Zoom Image
Scheme 12 (a) Intermolecular Ni-catalyzed alkynylation of N-CF3 carbamoyl fluorides. (b) Selected derivatization: reagents and conditions: (A) [AuI(MeCN)(JohnPhos)][SbF6] (5 mol%), 2-bromopyridine N-oxide (1.1 equiv); (B) PPh3 (1.5 equiv), AcOH (2 equiv), H2O (220 equiv);(C) [AuI(MeCN)(JohnPhos)][SbF6] (5 mol%).

Recently, our group disclosed the first intermolecular Pd-catalyzed Suzuki-type cross-coupling of carbamoyl fluorides 101 enabled by a directing group strategy (Scheme [13a]).[81] The 2-pyridyl group enhances reactivity by aiding in C–F bond cleavage, while minimizing the formation of undesired secondary amines 103 via decarbonylation. Control experiments revealed that without the pyridyl group, only a trace amount of product 106 is observable (Scheme [13b]). Moreover, the moderate reactivity of corresponding carbamoyl chlorides 108, along with their increased susceptibility towards hydrolysis, indicates that carbamoyl fluorides are particularly well-suited for this transformation (Scheme [13c]). In accordance with traditional Suzuki-type reactions, we hypothesize that the reaction involves the oxidative addition of Pd(0) catalyst into the C–F bond of 101, which is facilitated by coordination of the 2-pyridyl group, to form a 5-membered palladacycle 104 that is reluctant to undergo decarbonylation. Pd–F complex 112 was synthesized independently and its reactivity was tested in catalytic and stoichiometric contexts, which support the intermediacy of this species in catalysis (Scheme [13d]). It is worth noting that 112 is the first isolated and fully characterized Pd(II) carbamoyl fluoride complex. The high efficiency and potential for further derivatization highlight the importance of carbamoyl fluorides as alternative electrophiles to access medicinally relevant 2-pyridyl amides and the tertiary aminopyridines via reduction.

Zoom Image
Scheme 13 Intermolecular Pd-catalyzed Suzuki-type reaction of 2-pyridyl carbamoyl fluorides

# 3.4

Lewis Acid and Base Catalyzed Carbamoylation

In line with the ability of fluoride ions to catalyze carbodesilylation reactions,[82] [83] we recently disclosed an efficient method to access alkynamides 115 via the fluoride-catalyzed cross-coupling of carbamoyl fluorides 113 with aryl-substituted alkynylsilanes 114 (Scheme [14a]).[84] The exceptionally mild reaction conditions eliminate the need for strong nucleophilic reagents or transition metals that are typically required to cleave challenging C–F bonds. Moreover, competitive decarbonylation of carbamoyl fluorides is no longer an issue under transition-metal-free conditions. Complementary chemoselectivity was observed with polyhalogenated substrate 116 under Pd/Cu-catalyzed Sonogashira cross-coupling conditions, as evidenced by the selective functionalization of the aryl iodide without affecting the carbamoyl fluoride (Scheme [14b]). Control experiments demonstrate the necessity of using silyl nucleophiles, as phenylacetylene did not yield alkynamides 120 under the optimized conditions (Scheme [14c]). Moreover, carbamoyl chlorides 121 proved to be ineffective even with a higher amount of TBAF, leading to the formation of carbamoyl fluorides 119 via halide exchange instead of the desired product 120 (Scheme [14d]). The efficient conversion of 121 into 120 could not be achieved by increasing reaction temperature and/or time, due to the presence of stoichiometric chloride inhibiting the reaction. Overall, this method highlights the importance of using catalytic fluoride to enable a controlled release of the silyl nucleophile, as previously documented by Olofson.[82]

Zoom Image
Scheme 14 Fluoride-catalyzed cross-coupling of carbamoyl fluorides with silane nucleophiles

Recently, carbamoyl fluorides have gained attention in carbofluorination reactions which form a new C–C and C–F bond across an unsaturated functionality, while preserving the carbamoyl and fluorine groups in the final product.[8] In 2023, we reported the first atom-economical carbofluorination reaction of alkyne-tethered carbamoyl fluorides 122, which was achieved using a simple and inexpensive BF3 catalyst (Scheme [15a]).[85] This method enabled the efficient synthesis of 3-(fluoromethylene)oxindoles 123 and fluoromethylene-substituted γ-lactams 124, including fluorinated derivatives of kinase inhibitors, with high yields and excellent stereoselectivity. The analogous carbamoyl chloride 134 did not yield the desired product 133 in the presence of stoichiometric BF3·OEt2. Instead, a low yield of the 3-(chloromethylene)oxindole 135 was observed, thus illustrating the critical role of fluorine to drive the thermodynamics of the reaction (Scheme [15b]). In contrast to related reactions with more electrophilic acyl fluorides,[86] our data indicate that carbamoyl fluorides are reluctant to undergo fluoride abstraction to form an isocyanate cation 126 (Scheme [15a]). Kinetic and DFT studies support an alternative mechanism involving the formation of Lewis adduct 127, followed by a turnover-limiting cyclization step and facile internal fluoride transfer from 128 to forge the key C–F bond. Fluoride abstraction from 129 regenerates the BF3 catalyst. This step was determined to be highly exergonic and irreversible due to the strength of B–F bonds. Considering the smaller driving force for B–Cl bond formation, these calculations provide insight as to why carbamoyl chlorides are ineffective in the reaction. Computations also rationalize the divergent stereoselectivity observed for methylene-oxindoles 123 and γ-lactams 124. Under the reaction conditions, Lewis adduct 131 can undergo isomerization to form the thermodynamically favoured E-isomer. The aromaticity of this transition state lowers the barrier for isomerization. In contrast, this aromatic stabilization is not relevant for γ-lactams 124, leading to the exclusive formation of the Z-isomer. Overall, this reaction provides important precedent for fluoride recycling in the context of atom-economical C–F bond insertion reactions.

Zoom Image
Scheme 15 Stereoselective BF3-catalyzed intramolecular fluorocarbamoylation of alkynes

#
# 4

Outlook and Conclusion

We have reviewed recent progress in the chemistry of carbamoyl fluorides, highlighting their emergence as a novel class of electrophiles for constructing carbon–heteroatom and carbon–carbon bonds. Despite their limited investigation until recently, the reactivity of carbamoyl fluorides is a flourishing area of research due to the advances in synthetic methods to access these building blocks. Their bench stability facilitates handling and long-term storage, providing practical advantages over related carbamoyl chlorides. Recent strategies demonstrate their distinct reactivity in nucleophilic substitutions, transition-metal-catalyzed reactions, and acid/base-catalyzed carbamoylation. However, further catalyst development is needed to activate a broader range of substrates, including the use of more diverse coupling partners. We, and others, have just begun to scratch the surface in this area. Fluoride-enabled reactivity is not a new concept. In fact, many parallels can be drawn to the rich history of related sulfonyl fluorides, which are considerably more stable than the analogous chlorides yet have found increasingly useful applications in synthetic chemistry and biology, most notably, in sulfur(IV) fluoride exchange (SuFEx) reactions.[87] Given their balanced stability-reactivity profile, we foresee a similar renaissance for carbamoyl fluorides, enabling transformations that may be less efficient, less selective, or even unattainable with other carbamoyl electrophiles. Throughout this review, we have highlighted the subtle ability of fluoride to improve reactivity and/or selectivity, thus providing motivation to explore this phenomenon further. Overall, we are excited about what the future holds for this promising class of building blocks.


#
#

Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Christine M. Le
Department of Chemistry, York University
4700 Keele St, Toronto, ON M3J 1P3
Canada   

Publication History

Received: 27 January 2025

Accepted after revision: 13 March 2025

Accepted Manuscript online:
13 March 2025

Article published online:
28 April 2025

© 2025. Thieme. All rights reserved

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany


   Permissions and Reprints All articles of this category
Zoom Image
Maryam Jabbarpoor (left) obtained her B.Sc. from Shahid Beheshti University, Iran, where she developed a strong interest in organic and inorganic chemistry. She then pursued her M.Sc. under the supervision of Dr. Nasser Safari, working on the development of heterogeneous catalysts. Maryam began her Ph.D. in 2022 at York University in the Le Group, where her research centers on the development of alternative strategies for the synthesis of amide-containing compounds from fluorinated precursors. Christine Le (right) is an Assistant Professor at York University in Toronto (Canada). She received her B.Sc. from Western University (2011), and her M.Sc. (2012) and Ph.D. degrees (2016) from the University of Toronto in the labs of Professor Vy Dong and Professor Mark Lautens, respectively. In 2017, Christine moved to UC Berkeley as an NSERC Postdoctoral Fellow, working under the guidance of Professor F. Dean Toste. Her current research program focuses on the synthesis of fluorinated building blocks and their application in catalysis and fluoride-enabled transformations.
Zoom Image
Figure 1 Advances in carbamoyl fluorides synthesis and reactivity
Zoom Image
Scheme 1 Carbamoyl fluoride intermediates from COF2 and amines
Zoom Image
Scheme 2 N-Fluoromethyl-substituted carbamoyl fluorides from isothiocyanates and thioformamides
Zoom Image
Scheme 3 Carbamoyl fluorides from amines and –OCF3 sources
Zoom Image
Scheme 4 Carbamoyl fluorides from difluorocarbene sources
Zoom Image
Scheme 5 Carbamoyl fluorides with CO2 and deoxyfluorinating reagents
Zoom Image
Scheme 6 Synthesis of carbamoyl fluorides with other methods. a R1R2NH (10 equiv).
Zoom Image
Scheme 7 Carbamoyl fluorides as acid-transferring enzyme inhibitors
Zoom Image
Scheme 8 (a) Synthesis of N-CF3 hydrazines and their derivatives from carbamoyl fluorides and carbamoyl azides. (b) Further product derivatization: reagents and conditions: (A): ketone (2.0 equiv), H2SO4, MeOH, 80 °C, 4 h; (B): sulfonyl-Cl (1.5 equiv), pyridine (1.5 equiv), DCM, r.t., 16; (C): aldehyde (2.0 equiv), AcOH, MeOH, 80 °C, 4 h.
Zoom Image
Scheme 9 (a) Reduction of N-CF3 carbamoyl fluorides and (b) reduction of other carbamoyl halides to access formamides. (c) Selected derivatization: reagents and conditions: (A) H2 (1 atm), Pd/C (10 mol%), MeOH, r.t., 24 h; (B): trimethylsilylacetylene (1.3 equiv), Pd(PPh3)2Cl2 (5 mol%), PPh3 (10 mol%), CuI (1.5 equiv) Et3N (2.8 equiv), DMF, 80 °C, 16 h; (C): Step 1: TFA, DCM, r.t., 16 h; step 2: HBTU, DIPEA, H-Val-O t Bu·HCl, DCM, r.t., 16 h (yield over 2 steps).
Zoom Image
Scheme 10 Enantioselective carbamoyl fluoride enabled intramolecular carbocarbamoylation of unactivated alkenes with Ni catalysts to access γ-lactams
Zoom Image
Scheme 11 Enantioselective carbamoyl fluoride enabled intramolecular 1,4-arylcarbamoylation of 1,3-dienes with Ni catalysts
Zoom Image
Scheme 12 (a) Intermolecular Ni-catalyzed alkynylation of N-CF3 carbamoyl fluorides. (b) Selected derivatization: reagents and conditions: (A) [AuI(MeCN)(JohnPhos)][SbF6] (5 mol%), 2-bromopyridine N-oxide (1.1 equiv); (B) PPh3 (1.5 equiv), AcOH (2 equiv), H2O (220 equiv);(C) [AuI(MeCN)(JohnPhos)][SbF6] (5 mol%).
Zoom Image
Scheme 13 Intermolecular Pd-catalyzed Suzuki-type reaction of 2-pyridyl carbamoyl fluorides
Zoom Image
Scheme 14 Fluoride-catalyzed cross-coupling of carbamoyl fluorides with silane nucleophiles
Zoom Image
Scheme 15 Stereoselective BF3-catalyzed intramolecular fluorocarbamoylation of alkynes