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. 2024 Jan 5;146(2):1276–1281. doi: 10.1021/jacs.3c13711

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

Filip G Zivkovic 1, Gina Wycich 1, Linhao Liu 1, Franziska Schoenebeck 1,*
PMCID: PMC10913043  PMID: 38180777

Abstract

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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.

Amides and their close relatives are of exceptional importance in the physical and life sciences, medicine, and agrochemical, pharmaceutical, and materials research.1 For example, more than 25% of the top 100 (in retail) drugs contain an amide group.2 The closely related compound families, e.g., carbamates, ureas, or formamides, find uses as insecticides, in polymers, as preservatives, in cosmetics, and in medical treatment (e.g., in chemotherapy and as anti-inflammatory or HIV agents).3

As the R2N—C=O functionality is the key unit that dictates properties and function, its molecular editing to currently untapped chemical space is expected to unleash novel properties and/or function.4 With fluorination of organic molecules having become a well-established tool to alter physical properties (such as conformation, stability, pH, or lipophilicity),5 and N-methylation of peptides being known to enhance metabolic stabilities and cellular permeabilities,6 their combined N-CF3-carbamoyl motif has also recently gained significant traction.7 Access to a variety of N-CF3 compounds, such as amides,8,9 ureas,8,10 carbamates,8 formamides,11 hydrazines,12 amines,13 indoles,12a and derivatives,10,14 has recently been unlocked. While N-CF3 amines are of modest stability,15 the corresponding N-CF3 carbonyl compounds were found to be highly robust.8,10,14 Their further structural editing therefore has significant potential to unleash novel properties.

In this context, we envisioned that access to N-difluoromethylated amides (and their relatives) would be beneficial, as the difluoromethyl group likely displays different lipophilicity as compared to CF3, while also having H-bonding capabilities (Figure 1).16 The innate propensity of amides to engage in H-bonding, which controls binding, 3D structure, and function, would therefore to some extent be maintained via CF2H interactions (as compared to no H-bonding in N-CF3 amides), while potentially mirroring more closely the lipophilicity of N-Me amides but with greater electron deficiency and hence potentially even more enhanced metabolic stability.

Figure 1.

Figure 1

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Currently accessible N-CF2H compounds and this work.

However, due to a lack of general and efficient synthetic methodology to make N-difluoromethylated amides and their relatives, these compounds have remained essentially unexplored to date.17

Indeed, the single reported synthesis to acyclic N-difluoromethyl amides relies on the unselective functionalization of low-functionality N-aromatic amides with difluorocarbene under highly basic conditions (in ≤30% yield in a mixture with O-difluoromethylation).18 The current synthetic repertoire to N-CF2H compounds only provides efficient access to selected N-difluoromethylated heterocycles,19 such as triazoles,20 indoles,21 2-pyridones22a or (benz)imidazoles,22b tosyl-protected N-CF2H amines,23 tosyl-protected hydrazones,24 or ammonium salts.25 Any attempt to remove the tosyl group in Ts-protected N-CF2H amines to the corresponding free N-difluoromethyl amines [i.e., H-N(CF2H)R] has so far remained unsuccessful, however, owing to their instability.

Consequently, even if difluoromethylamines could be made in high yield, the corresponding amide bond formation will be challenging with the currently available synthetic methodology that is largely based on acidic or basic conditions.1b Indeed, the analogous amide bond formation with the corresponding secondary N-CF3 amines has so far also not been achieved. For N-CF3 amides, an indirect synthetic strategy proved successful, which focused on the derivatization of readily accessible and bench-stable N-CF3 carbamoyl fluorides.8 The latter compounds were readily prepared through the AgF-mediated desulfurization of isothiocyanates. An added benefit of this synthetic approach is that it provides access to the entire carbamoyl family through appropriate derivatizations.

We therefore set out to develop a methodology to synthesize N-difluoromethyl carbamoyl fluorides for the first time with the overarching goal to unlock access to the entire N-CF2H carbonyl family, which is currently uncharted territory in chemical space.

To this end, we had started our investigations by focusing on the N-thioformyl motif (i.e., R2N—C(H)=S). We questioned whether a desulfurization–fluorination sequence would similarly also be possible for this functionality, as this would, in principle, deliver the corresponding N-CF2H directly (Scheme 1A). N-cyclohexyl-N-thioformylbenzamide 1 was initially tested and subjected to 2 equiv of AgF in MeCN. While this indeed led to the desired N-CF2H amide 2 at room temperature within 10 min, and the feasibility of desulfurizative fluorination of HC=S—H was hence established, the yield of 2 was only 13%. The remainder of the mass balance resulted from competing fluoride attack at the formyl site (yielding benzoyl fluoride in 50% yield; see path b in Scheme 1A) as well as competing hydrolysis. To alter the relative preference of fluoride attack, additional reaction media were explored. It was ultimately identified that the same reaction in DCM/HFIP gives N-CF2H amide 2 as the main product in 66% yield in 4 h at room temperature (with only 5% of benzoyl fluoride byproduct and 5% hydrolysis). However, the subsequent exploration of the generality of these conditions revealed that while structurally very similar compounds could also be transformed to the corresponding N-CF2H amide in similar yield, any deviation toward, e.g., nonaromatic compounds or more electron-rich aromatics or replacing cyclohexyl with, e.g., butyl led to either only very low yields or no N-CF2H amide formation at all, as the competing side reactions were favored in these cases.

Scheme 1. Scope of N-CF2H Carbamoyl Fluorides.

Scheme 1

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Reaction conditions: thioformamide (1 equiv), AgOCF3 (5 equiv), AgF (3 equiv), MeCN, 50 °C, 2 h.

Given the observed substrate dependence as a consequence of competing processes, we reconsidered the conceptual approach. In light of fluoride attack on the carbonyl being the main side reaction in the thioformyl–amide strategy (Scheme 1A), and desulfurization–fluorination of H—C=S appearing to be feasible, it was next considered to start from monosubstituted thioformamide (i.e. HN—C(H)=S) directly and trigger a desulfurization–fluorination coupled with carbonylation (Scheme 1B). To this end, N-biphenyl thioformamide was synthesized.26 We previously showed that mixing of AgF with triphosgene leads to in situ formation of F2C=O.8,27 However, adopting the latter strategy by mixing N-biphenyl thioformamide with triphosgene and AgF led only to isocyanate (R—N=C=O) formation, indicating that the relative sequence of desulfurization–fluorination and reaction with F2C=O had to be controlled. We hence turned to AgOCF3, which although a stable reagent by itself in solution, upon interaction with a coordinating nucleophile liberates AgF and F2C=O in an equimolar and controlled manner in situ.27 Subjection of N-biphenyl thioformamide to 2.0 equiv of AgOCF3 in MeCN under slight heating (50 °C) for 15 h led to the desired N-difluoromethyl carbamoyl fluoride 3 in 25% isolated yield (Scheme 3). Further alteration of reaction parameters in terms of equivalents of used AgOCF3, additives (such as AgF) and reaction time revealed that using 5 equiv of AgOCF3 with 3 equiv of AgF led to the desired N-CF2H carbamoyl fluorides in moderate to high yields, regardless of electronic or steric variation in the thioformamides. Lower amounts of silver salts are feasible (i.e., 1 equiv. AgOCF3 and 1 equiv. AgF), however with slightly lower yields (42% of 3). See SI for additional information. (We speculate that addition of AgF facilitates initial desulfurization fluorination and thus additionally enhances fragmentation of AgOCF3.)

Scheme 3. Physical Properties and Derivatizations of N-CF2H Carbonyl Compounds.

Scheme 3

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Reaction conditions: (a) N-CF2H carbamate (1 equiv), Pd(PPh3)2Cl2 (5 mol %), PPh3 (10 mol %), CuI (1.5 equiv), Et3N (2.8 equiv), TMS-acetylene (1.3 equiv), DMF, 80 °C, 16 h; (b) N-CF2H urea (1 equiv), Pd(OAc)2 (20 mol %), PtBu3 (20 mol %), Cs2CO3 (1.5 equiv), 2-oxa-6-azaspiro[3.3]heptane (1.5 equiv), PhMe, 105 °C, 24 h; (c) N-CF2H alkynamide (1 equiv), PPh3 (0.4 equiv), AcOH (0.5 equiv), PhMe, 90 °C, 12 h; (d) N-CF2H alkynamide (1 equiv), [AuI(MeCN)(JohnPhos)][SbF6] (10 mol %), DCE, 75 °C, 40 h.

With these conditions in hand, a wider scope was subsequently explored (Scheme 1C). Pleasingly, both aromatic and aliphatic thioformamides exhibited the desired reactivity. While electron-donating groups (OMe, SMe) were tolerated (3–5), electron-withdrawing groups (NO2, CO2R, CF3) as well as halogens (F, Cl, Br, I) led to the corresponding carbamoyl fluorides (6–9) in the highest yields (80–90%). The latter functionalities are also highly valuable for further derivatizations.

Beyond aromatic rings, medicinally and agrochemically relevant heterocyclic cores such as thiophene or carbazole were also compatible with the employed methodology (10, 11). A benzylic site (12) was also tolerated. Compounds bearing alkyl chains on nitrogen (13) as well as terminal alkenes (14) were similarly effective, with the latter displaying a synthetic linchpin for further double-bond functionalizations. Moreover, the method also enabled access to the first N-CF2H amino-acid-based building block (15). Substrates bearing a secondary carbon bound to nitrogen (i.e., N-cyclohexyl, N-Boc/Bn piperidine) did not lead to product formation, however.

With these N-CF2H carbamoyl fluorides synthesized and isolated for the first time, their derivatizations to N-CF2H amides and their relatives were next investigated (Scheme 2).

Scheme 2. Derivatizations of N-CF2H Carbamoyl Fluorides.

Scheme 2

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Reaction conditions: (a) N-CF2H carbamoyl fluoride (1 equiv), Grignard reagent (1.2 equiv), PhMe, r.t., 10 min; (b) N-CF2H carbamoyl fluoride (1 equiv), NaBH4 (2 equiv), DCM/tAmOH, r.t., 1–2 h; (c) N-CF2H carbamoyl fluoride (1 equiv), alcohol (1.2 equiv) DMAP (10 mol %), DIPEA (1.2equiv), DCM, r.t., 16 h; (d) N-CF2H carbamoyl fluoride (1 equiv), sodium thiolate (1.2 equiv), THF, r.t., 16 h; (e) N-CF2H carbamoyl fluoride (1 equiv), Ni(cod)2 (10 mol %), dtbbpy (12 mol %), Zn (1.5 equiv), TMS-alkyne (1.5 equiv), DMF, 60 °C, 3 h; (f) N-CF2H carbamoyl fluoride (1 equiv), amine(•HCl) (1.2 equiv) DMAP (10 mol %), DIPEA (1.2-2.4 equiv), DCM, r.t., 16 h.

Subjection of the N-CF2H carbamoyl fluorides (3, 5, 8) with alkyl or aryl Grignard reagents8 at room temperature in toluene for 10 min led to the corresponding N-CF2H amides in high yields upon isolation (16–18, 33, see Scheme 2B, 3A). Moreover, drugs and biologically active molecules such as Ciprofloxacine (29), Tryptamine (30), Nortryptiline (31) and Mexiletine (32) were successfully linked to the N-CF2H carbonyl motif via C–N bond formation delivering corresponding hybrid-drug candidates containing the N-CF2H urea functionality in high yields.

Facile reduction of the carbamoyl fluorides with NaBH411 was also effective and allowed the first access to N-CF2H variants of biologically and medicinally important formamides (19, 20). Similarly, our recently developed method14b for Ni-catalyzed coupling of carbamoyl fluorides with TMS-alkynes was also applicable to the N-CF2H analogues, delivering another novel and biologically highly relevant motif, N-CF2H alkynamides (27, 28).

Having unlocked the synthetic access to N-difluoromethyl amides, ureas, (thio-)carbamates, and formamides, we next examined their physical properties and late-stage derivatizations which will ultimately dictate the wider enabling potential of these novel compound classes (Scheme 3). To this end, a comparative study was undertaken with the corresponding N-CF3 and N-Me amides of biphenyl N-CF2H amide 33. Variable temperature 19F-NMR spectroscopic investigations indicated that the N-CF2H derivative lies in-between the corresponding N-Me and N-CF3 analogues but shows overall closer resemblance to the N-Me amide in terms of measured coalescence point of amide rotamers as well as IR carbonyl stretching frequency (see Scheme 3A and SI). Our preliminary calculations of the logP values,28 which is an estimate of a compound’s lipophilicity (and hence membrane permeability), indicates a lower lipophilicity for N-CF2H amide 33 (4.55) than for the corresponding N-CF3 analogue (4.86) and overall enhanced lipophilicity relative to N-Me (3.80). However, in light of previous observations of pronounced substituent effects on relative lipophilicity trends of difluoromethyl-containing compounds,16 more comprehensive investigations will be needed.

The robustness toward typical synthetic derivatization under oxidative, reductive, or transition metal catalyzed cross-coupling conditions was next investigated. The building block was subjected to two-step transformations involving a variety of cross-coupling conditions (C–C, C–N) and highlighting the diversity of combinations for derivatization of both sides of the HF2C—N—C=O motif (34, 35, Scheme 3). Moreover, the N-CF2H alkynamides showed desired reactivity in redox isomerization in the presence of PPh3/AcOH to form conjugated dienes of N-CF2H amide (36), as well as in AuI catalyzed cyclization toward the N-CF2H decorated quinolone (37). The N-CF2H motif also proved compatible with oxidative (m-CPBA) and reductive conditions (H2, Pd/C) with its full recovery as an additive in the epoxidation and reduction of alkenes (see Supporting Information).

In conclusion, the first efficient access to N-CF2H amides, carbamates, thiocarbamates, ureas, formamides, and their derivatives was unlocked herein. The synthetic strategy relied on the initial synthesis and derivatization of N-CF2H carbamoyl fluorides, which were accessed through a desulfurization–fluorination sequence of thioformamides coupled with carbonylation. The N-CF2H motif was found to be highly robust toward numerous synthetic downstream derivatizations, while preliminary investigations of rotational and lipophilicity properties place the N-CF2H carbonyl compound class in-between N-Me and N-CF3 carbonyl compounds.

Acknowledgments

We thank the RWTH Aachen University and the European Research Council for funding. We thank Dr. Theresa Sperger (RWTH Aachen) for helpful discussions and assistance in calculations.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c13711.

  • Experimental procedures and characterization data of compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ja3c13711_si_001.pdf (12.2MB, pdf)

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