Photochemical thiocarbonyl difluoride generation enables azetidine synthesis

Domain: chemistry
Published: 2026-02-11
Editorial outcome: minor_revision

Abstract
The activation of amines into thiocarbamoyl fluorides (TCarbFs) provides access to valuable nitrogen-based functionalities. However, their broader use has been hindered by the reliance on harsh reagents and conditions. Here we report a photochemical method for in situ generation of thiocarbonyl difluoride (TCF) from N-trifluoromethylthiophthalimide (Phth–SCF₃) using visible light and organic reductants. This strategy allows the synthesis of structurally complex azetidines from strained azabicyclo[1.1.0]butanes (ABBs). TCF-mediated ring opening followed by semipinacol rearrangement or nucleophilic addition enables direct access to spiro- and fluorinated TCarbF-azetidines in a single step. Mechanistic studies support a single-electron reduction pathway and rationalize the impact of the photocatalyst on the observed selectivity. The discovery offers a general platform for amine activation and addresses a long-standing gap in azetidine functionalization.

Introduction
The facile activation of amines into synthetically versatile reactive intermediates is a key strategy for accessing or modifying nitrogen-containing functionalities1. This approach has fostered the popularity of several commodity reagents (Fig. 1A, left), such as thiophosgene, carbonyldiimidazole (CDI), as well as sulfonyl fluorides2,3, carbonyl difluoride, and thiocarbonyl difluoride (TCF)4. TCF activates amines into the corresponding thiocarbamoyl fluorides, powerful synthetic intermediates that can be swiftly transformed into thioureas and thiocarbamates, undergo cross-coupling, and, notably, can be directly converted into the N-CF₃ moieties, valuable yet elusive functionalities in medicinal chemistry5–10. Despite its synthetic potential, the chemistry of thiocarbamoyl fluorides (TCarbFs) is limited, as their synthesis historically entails the reaction of thiophosgene as a dimer with antimony trifluoride at temperatures above 400°C to generate TCF11,12. Renewed interest in accessing TCarbFs emerged in 2017, marked by the development of reagents and strategies that offer several advantages over the harsh pioneering synthetic methods13–21. The increasing focus on this area has led to the publication of diverse approaches for the synthesis of TCarbFs, with success resorting to the in situ generation of TCF through various means (gray box in Fig. 1A). However, several challenges remain, as the preparation of these TCF sources involves air sensitive reagents and high loadings of fluorinating reagents which unavoidably result in the generation of substantial fluorinated waste22–24. For instance, Me₄NSCF₃ is prepared from the highly hygroscopic Me₄NF in combination with CF₃SiMe₃; Ph₃P+CF₂CO₂- stems from triphenylphosphine and potassium bromodifluoroacetate; whereas the synthesis of N-tosyl, N-methyltrifluoromethylsulfenamide (BB23) requires (diethylamino)sulfur trifluoride (DAST) and iodomethane25.

Regardless of the strategy chosen, it is intriguing that the reactivity of azetidines with TCF remains virtually unexplored (red box in Fig. 1A). Therefore, the direct activation of azetidines into the corresponding TCarbFs would establish an ideal strategy for their functionalization, significantly expanding the chemical space related to this four-membered heterocycle26,27.

In a separate framework, N-trifluoromethylthiophthalimide (Phth-SCF₃)28, is a well-established reagent commonly employed for the introduction of the SCF₃ group into organic molecules (Fig. 1B, left). Its preparation employs N-bromophthalimide and AgSCF₃ without the need of inert atmosphere. Phth-SCF₃ has traditionally served as an electrophile, as a SOMOphile (SOMO = singly occupied molecular orbital), and as a precursor to (trifluoromethyl)thiyl radicals (•SCF₃)29–32. However, its high synthetic reliability and extensive application for these purposes might result in missed opportunities for the development of new applications. Our research motivation is to offer the scientific community an alternative solution to the safe and efficient generation of TCF for amine activation, by rejuvenating the chemistry of Phth-SCF₃. This study reports an unexpected and previously unrecognized photochemical reactivity of Phth–SCF₃ under the control of light-absorbing organic molecules, enabling the in-situ generation of TCF under mild and operationally friendly conditions (Fig. 1C). Successful implementation of the discovery allows the direct conversion of strained azabicyclo[1.1.0]butanes (ABBs) and other commercially available amines into structurally complex TCarbFs.

Results
A serendipitous discovery
In conjunction with our research program for developing novel light-mediated transformations on ABBs33–39, we faced an unforeseen reaction outcome while exploring 1 (Fig. 2A). The reported three-component reaction uses TBCzTrz as photocatalyst (PC) (Fig. S7) and proceeds through triplet sensitization of aldimine 2, delivering the C3-SCF₃ sulfonylazetidine340. Under these conditions, Phth-SCF₃ acts as a SOMOphile for the integration of the SCF₃ group (Figs. S3–S6). In an unexpected turn, performing the same reaction in non-anhydrous ethyl acetate resulted in the formation of compound 4. A retrosynthetic analysis of 4 (Fig. 2B) allowed us to identify three possible events: (1) formation of the TCarbF unit by opening the ABB 1 in polar fashion leveraged by TCF, (2) generation of a transient electrophilic site at C3 and (3) sulfonamide formation through hydrolysis of 2. Considering that Phth-SCF₃ is the only fluorine-containing entity in the media, the question thus became: How does one generate TCF from Phth-SCF₃? Exploratory experiments combining 1 with p-toluenesulfonamide and Phth-SCF₃ allowed the formation of 4 (Tables S3, S4). Attempted optimization revealed that light and a PC were required, but this transformation had a poor prognosis for improvement; also, similar scaffolds were already investigated in our previous report. The potential to generate a transient electrophilic site at the C3 position was considered a promising strategy for accessing structurally complex azetidines, particularly those in which the nitrogen atom is directly functionalized with a non-protecting group. The knowledge that azabicyclo[1.1.0]butylcarbinols can undergo strain-release reactions upon N-activation41–43, encouraged us to explore TCF as an activator (Fig. 2C). In line with previous reports, we anticipated that the activation of 5 with TCF would be well suited for the generation of an electrophilic C3, facilitating a semipinacol rearrangement, consequently furnishing synthetically flexible products.

Development of a light-mediated semipinacol rearrangement
Initial experimentation focused on clarifying if the targeted reactivity could be achieved by exclusively polar means. The reaction of 5 with tetramethylammonium trifluoromethanethiolate (Me₄NSCF₃) as a documented source of TCF44, did not afford the expected product 6; the use of additives or alternative solvents proved unsuccessful (Table S5). We thus proceeded to evaluate the photochemical domain, screening different parameters for the reaction between 5 and Phth-SCF₃ (Table S6). Mixing 5 (1 equiv) with Phth-SCF₃ (2.5 equiv) and TBCzTrz (2.5 mol %) under 427 nm irradiation, gave 21%, with no recovery of starting material and low selectivity with respect to the undesired spiroepoxyazetidine 7 (6% yield). Further tests of additives led to a refined protocol involving commercially available Hantzsch ester (HE, 2.5 equiv) and toluene as solvent (Fig. 3A and Table S6). These conditions afforded 6 in 69% yield, with improved selectivity (7=9% yield, 19F NMR yields). During this optimization phase (see Tables S3–S7), we realized that removing the PC while exploiting the photoactivity of HE, it is possible to access 6 although with a diminished selectivity (Fig. 3A). Interestingly, replacing Phth-SCF₃ with the N-SCF₃ derivatives of succinimide (Succ-SCF₃) and saccharin (Sacc-SCF₃), led to 6 in 52% (7=19%) and 0% yield (7=0%), respectively (Fig. 3A).

Mechanistic investigations
Mechanistic studies gave insight into the evolution of Phth-SCF₃ and how it serves as an activator of the ABBs to access TCarbF azetidines (Fig. 3B). Time-resolved luminescence experiments on TBCzTrz were performed to provide evidence on the primary photochemical process. While negligible quenching of the prompt fluorescence (PF) of TBCzTrz is observed in the presence of all reactants (τ ∼ 19 ns as measured by time-correlated single photon counting, see Fig. S13), laser flash photolysis (LFP) experiments demonstrate that the delayed fluorescence (DF) component is efficiently quenched by the HE (bimolecular rate constant of k = 2.4 × 10⁹ M⁻¹s⁻¹, Fig. 3C), whereas quenching by 5 or by the Phth-SCF₃ is substantially less effective (bimolecular rate constants of k = 3.7 × 10⁶ and 5.0 × 10⁵ M⁻¹s⁻¹, respectively, Figs. S14–S19). Additionally, steady-state absorption studies of the reaction components showed no evidence of ground-state associations (Fig. S20). Altogether, these experiments indicate that the main photochemical event involves the interaction between the triplet excited state of TBCzTrz and HE. The progress of the reaction was monitored using 19F NMR, which showed a signal at −46.9 parts per million (ppm) (Fig. 3D). This signal was assigned to bis(trifluoromethyl)disulfide (F₃CSSCF₃). Additionally, analysis of both the headspace and the reaction bulk by gas chromatography-mass spectrometry (GC-MS) corroborated the presence of F₃CSSCF₃ (Figs. S53, S54). The formation of F₃CSSCF₃ under the given reaction conditions can be exclusively attributed to the homocoupling of the •SCF₃ radical, providing key mechanistic insight into the reaction pathway. In agreement with the literature32, electrochemical studies revealed that the one electron reduction of Phth-SCF₃ triggers its heterolytic scission, resulting in the formation of the phthalimide anion (Phth-N⁻) and •SCF₃. This knowledge allowed us to assume that reductive quenching of TBCzTrz by the HE (TBCzTrz* + HE → TBCzTrz•⁻ + HE•+), followed by single electron transfer (SET) with Phth-SCF₃ (E TBCzTrz•⁻/TBCzTrz = −1.58 V vs SCE (DCM), E Phth-SCF₃/Phth-SCF₃•⁻ = −1.44 V vs SCE (DCM)) generates (Phth-N⁻) together with •SCF₃, restoring the ground state of the PC. To further corroborate the generation of •SCF₃, while gathering more information about the overall mechanistic machinery, electronic paramagnetic resonance (EPR) studies were conducted. A reaction mixture of TBCzTrz and Phth-SCF₃, with or without 5, was incubated in the presence of PBN (N-tert-Butyl-α-phenylnitrone) as a spin trap. The samples were kept either in the dark or subjected to irradiation under conditions optimized for the reaction. While the solutions were EPR silent in the absence of irradiation, the spectra obtained after irradiation revealed the presence of a single, identical radical species in both solutions (Fig. 3E, Figs. S40, S41). This observation ruled out the possibility that the trapped radical originated from the heterocycle. The fact that azetidines 6 and 7 were formed in comparable overall yields regardless of the presence or absence of the photocatalyst, albeit with differences in selectivity (Figs. S50, S51), prompted us to perceive these synthetic transformations as two distinct mechanistic scenarios.

We propose that in the photocatalyzed scenario (Fig. 3B), both the (Phth-N⁻) and (•SCF₃) generated upon one electron reduction of Phth-SCF₃, enter a loop in which the •SCF₃ radical undergoes homocoupling, as its polarity mismatch renders it unreactive toward the substrates in solution. Subsequently, the nucleophilic addition of (Phth-N⁻) on the newly formed dimer regenerates Phth-SCF₃ and yields the trifluoromethanethiolate anion (−SCF₃). The feasibility of this step was independently corroborated by treating potassium phthalimide (PhthN-K) with freshly prepared F₃CSSCF₃ (Fig. 3F, S44–46). Once generated, the (-SCF₃) anion undergoes fluoride extrusion, forming TCF. We believe this step is aided by the nature of the involved counterions and driven by their reversible reaction between TCF and the ABB. Next, the so activated ABB 5 undergoes semipinacol rearrangement leading to 6. It is worth noting that under the proposed reaction platform, two photons are responsible for the generation of one molecule of TCF. In fact, as the loop is fueled with two molar equivalents of Phth-SCF₃ and HE to produce one molar equivalent of 6, we surmise it is profitable until depletion of 5.

Building on the fact that the formation of TCF from (-SCF₃) is not a spontaneous event13–15, together with the described lack of reactivity of tertiary amines towards TCF and the recovery of unreacted substrates in the polar tests (Table S5), we cannot exclude the possibility of an alternative activation system for compound 5. Reductive quenching of the PC by HE generates [HE•+], which is sufficiently acidic (pKa ≈ 245–47) to protonate and generate the corresponding ammonium species of compound 548,49, stabilized by the (-SCF₃) anion. This interaction could facilitate the formation of TCF and concurrently promote the semipinacol rearrangement (Fig. S49). The feasibility of this hypothesis was assessed by dissecting the overall transformation into two individual steps: i) the acid-mediated opening of compound 5, followed by ii) the treatment with Me₄NSCF₃ to afford compound 6 (Fig. 3G, Figs. S47, S48). Although this pathway appears reasonable, the free NH azetidine 8 resulting from the semipinacol rearrangement was never detected in the photochemical reactions, thereby hindering us from presenting this mechanistic premise.

Alternatively, in the absence of PC, light irradiation promotes HE to its single excited state [HE]*. This species is anticipated to be responsible for the one electron reduction of Phth-SCF₃ entering the loop as described above (Fig. S56). Indeed, luminescence studies show that the fluorescence of HE is efficiently quenched upon the addition of increasing amounts of Phth-SCF₃ (Fig. S21) and Stern–Volmer analysis yields a bimolecular rate constant of k = 1.8 × 10¹⁰ M⁻¹s⁻¹. This process is thermodynamically allowed by ca 0.6 eV according to the estimated redox potentials (E ox HE*/HE•+ = −1.93 V vs SCE, E red Phth-SCF₃/Phth-SCF₃•⁻ = −1.29 V vs SCE in MeCN). Based on the experimental observations and gathered spectroscopical evidence, we posit that the relative rate of formation of the (-SCF₃) anion highly impacts on the final selectivity between 6 and 7. When TBCzTrz is included, the concentration of the reactive specimens is very low, because the loop is fed in catalytic fashion; contrary to the stoichiometric amounts of [HE]*. Spectro-electrochemistry (SEC) studies allowed us to follow the evolution of HE towards the pyridine analogue and confirm the formation of the (Phth-N⁻) anion (see Figs. S31–S38). These observations aided us in discarding the participation of the (Phth-N⁻) anion in any light-induced event50. Further EPR experiments involved mixtures of Phth-SCF₃ with and without HE incubated with a different spin trap (MNP, 2-methyl-2-nitrosopropane). These solutions were either kept in the dark or subjected to irradiation. Notably, significant radical formation was observed only in the irradiated mixture containing Phth-SCF₃, HE, and MNP (Figs. S42, S43). The EPR spectrum confirmed the generation of an SCF₃ radical, accompanied by a modest signal (∼10%) corresponding to a C–H-centered radical, attributed to the Hantzsch ester radical [HE•]. Importantly, regardless of the presence or absence of the photocatalyst, both HE and Phth-SCF₃ were fully converted into the corresponding pyridine derivative and phthalimide (Phth-NH), indicating that the same radical species are formed under all reaction conditions.

Generality of the method
This optimized protocol afforded various TCarbF (spiro)azetidines 9-25 containing a quaternary centre with yields up to 95% (Fig. 4, conditions A). The generality of the process includes multiple (hetero) aromatic rings as the migrating group, a variety of azaspiro[3.n]alkane ring systems (n=5, 6, 7), and azetidine-containing analogues of oxcarbaz of oxcarbazepine, naproxen and ibuprofen. Additionally, olefins proved successful as migrating group (26, 26’, 27, 27’), displaying an effect of the mechanistic platform on the final stereochemistry (E/Z) and pleasingly unreactive towards the possible •SCF₃ addition. We also showcased the possibility of conducting the reaction on a bigger scale as compounds 17, 18, and 21 were furnished in synthetically useful yields (69%, 83%, 81%, respectively performing in 1 mmol scale. 21 was obtained in 66% yield operating in 17 mmol scale).

Drawing from the success of the semipinacol rearrangement, we proceeded to investigate an alternative family of ABBs for TCF activation. Initial experiments with 1 revealed the mono-fluorination at the C3 position in the final azetidines (Table S4). This finding not only offered further evidence that the activation of ABBs via the developed method proceeds through polar ring opening but also facilitates access to complex molecular structures that are typically difficult to obtain51. During the exploratory stage of this synthetic variation, we observed an intriguing, yet useful effect on the reaction outcome when conducting the reaction with and without the photocatalyst. The use of 5 TBCzBN (Fig. 5, conditions B), diminished the yield of the mono-fluorinated azetidine, delivering as the major product the analogue with the SCF₃ functionality incorporated at C3 (compare 28 and 34, 77%/22% yield). Conversely, the removal of the PC (Fig. 5, condition C) reversed the outcome (compare 28 and 34, 27%/72% yield), preserving the reaction efficiency (Fig. S57). Diverse representative functionalities were evaluated, displaying good yields and a high impact on the anion trapping selectivity. The lack of an absolute chemodivergency on the method might be attributed to a variety of physicochemical factors, such as anion stability by solvation, as well as stereo- and electronic parameters. Beyond doubt, the incorporation of single fluorine atoms and the SCF₃ group is of significant interest for tuning active pharmaceutical ingredients52,53. However, and more important, these examples further substantiate the hypothesis that fluoride (-F) and (-SCF₃) anions are generated during the reaction.

The N-CF₃ fragment and other synthetic manipulations
Among the synthetic strategies that allow the preparation of N-CF₃ derivatives, the direct fluorination of thiocarbamoyl fluorides is one of the most straightforward approaches. As a proof of concept, we subjected some of the TCarbFs obtained in our study to standard fluorination conditions (Fig. 6A, left), displaying the corresponding N-CF₃ azetidine derivatives 40-46 in good yields (62%-91%). The lack of general methodologies for synthesizing these biorelevant functionalities represents an open challenge in organic synthesis. In this regard, it is noteworthy that the only available method to access N-CF₃ azetidine relies on the pyrolysis of perfluorooxazinane 5554, obtaining the corresponding perfluorinated azetidine 56 (Fig. 6B). We then set out to transform selected primary and secondary amines into the corresponding thioureas (Fig. 6A, right). (S)−2-Phenylglycinol showcased its selective N-functionalization leading to 47. Anisylamine produced 48 in 91% yield and served as a valuable precursor for the synthesis of aminotetrazole 49, the core structure of a LPA1 antagonist55.

Additionally, the acetal of 1-aminoglycerol, along with tryptamine and amoxapine, was employed to successfully functionalize various mono-fluoro- and thiotrifluoromethyl-containing azetidines 50-54. Subsequently, the generality of the developed photochemical method for the TFC-based activation of feedstock amines was investigated (Fig. 6C). A set of structurally diverse candidates was efficiently transformed into the corresponding TCarbFs 57-61 in good yields (46%-97%). The designed protocol profits from the photoactivity of HE as a reductant, circumventing the risk of unintended oxidation of the employed amines that photoredox catalysis represents. Having established the developed photochemical protocol as a general strategy for activating not only strained ABBs but also a broader range of amines, we turned our attention to the lack of a general process to access TCarbF azetidines. Since the direct treatment of 5 with Me₄NSCF₃ failed to yield 6, and considering the obtained results through the two-steps strategy, (Fig. 3G) we performed a comparative study using commercially available azetidine 62 as model substrate (Fig. 6D).

Under photochemical conditions, compound 63 was obtained in 25% yield, whereas thermal treatment with Me₄NSCF₃ yielded 63 in 14% yield, alongside 13% of the thiourea 64.

We speculatively attribute the diverse selectivity to differences in the kinetics of in-situ TCF generation, reinforcing the premise that this discovery represents a reliable synthetic solution.

Inspired by an initial serendipitous observation, we have revealed an unpredictable reactivity of Phth-SCF₃ under light-driven one-electron chemistry, expanding its use in organic synthesis. This discovery accesses azetidine frameworks that have remained challenging to synthesize using pre-existing strategies. The method differs critically from other in-situ TCF generation protocols in the markedly facile preparation and handling of the reagent. Mechanistic investigations revealed that Phth-SCF₃ undergoes a photoinduced single-electron reduction, ultimately generating TCF, and we hope this concept will find applications in other research fields. More broadly, we are confident that this work marks a significant advance in photochemical transformations, particularly those involving reagents whose reactivity diverges from traditional expectations, paving the way for new reaction design and mechanistic understanding.

Methods
Photocatalyzed semipinacol rearrangement
A 4 mL glass vial containing an oven dried Teflon coated stirring bar, was charged with the corresponding ABB (0.05 mmol, 1 equiv), Phth-SCF₃ (31 mg, 0.125 mmol, 2.5 equiv), Hantzsch ester (32 mg, 0.125 mmol, 2.5 equiv) and TBCzTrz (1.4 mg, 2.5 mol%). The vial was closed using a screw cap with hole (PTFE/silicone septum) and purged with argon for 1 min. Under argon flux, previously deoxygenated toluene (0.7 mL) was added using a syringe. The reaction was irradiated under stirring for 21 h using the photochemical setup presented in the supplementary information. After completion, the reaction mixture was filtered to remove the resulting insoluble phthalimide, the filtrate was evaporated under reduced pressure and purified by flash column chromatography.

Photocatalyzed anion trapping strategy
A 4 mL glass vial containing an oven dried Teflon coated stirring bar, was charged with the corresponding ABB (0.05 mmol, 1 equiv), Phth-SCF₃ (31 mg, 0.125 mmol, 2.5 equiv) and Hantzsch ester (32 mg, 0.125 mmol, 2.5 equiv). 5 TBCzBN (1.4 mg, 2.5 mol%) was added only if indicated. The vial was closed using a screw cap with hole (PTFE/silicone septum) and purged with argon for 1 min. Under argon flux, previously deoxygenated ethyl (0.7 mL) was added using a syringe. The reaction was irradiated under stirring for 21 h using the photochemical setup presented in the supplementary information. After completion, the reaction mixture was filtered to remove the resulting insoluble phthalimide, the filtrate was evaporated under reduced pressure and purified by flash column chromatography.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "The authors have addressed my previous comments.", "reviewer_3": "The authors have revised their manuscript, originally submitted to Nature Catalysis and subsequently transferred to Nature\nCommunications. I served as Reviewer #3 for the initial submission. While some of the comments were partially addressed\nin the revised version, several points were met primarily with explanations rather than substantive revisions.\nI remain unconvinced of the novelty of the methodology presented. The responses provided to Reviewer #1 clearly indicate\nthat the development of an additional reagent to generate thiocarbonyl fluorides (TCFs)—which the authors describe as the\nfoundation of the current manuscript—constitutes an incremental improvement over existing state-of-the-art methods\nrather than a conceptual advance. Although Scheme 6 includes a limited number of examples involving amines other than\nazetidines, these compounds could, in principle, be accessed using methodologies already cited in the introduction. As\nsuch, the only apparent advantage of the proposed strategy lies in the simultaneous activation of the substrate and formation\nof the corresponding thiocarbonyl fluorides. However, as presented, this dual functionality appears to be applicable only to a\nvery narrow class of substrates, namely ABBs. To date, the authors have not demonstrated that this dual activation concept\ncan be extended to other substrate classes.\nFurthermore, in their response to Reviewer #1, the authors state that “to the best of our knowledge, accessing these free NH\nazetidines through alternative methods requires the installation and subsequent removal of N-protecting groups, increasing\nthe number of synthetic steps.” This statement is inaccurate. While some reported methods indeed rely on electrophilic\npreactivation of ABBs, it has been demonstrated that nucleophilic reagents, such as amides or Grignard reagents, can be\nused to prepare NH azetidines without the need for installing and removing N-protecting groups (10.1021/jacs.6b13229 and\n10.1039/D1CC07053C).\nFinally, the authors justify the development of new conditions for TCF generation by arguing that it fills a synthetic gap\ntoward azetidine thiocarbonyl fluorides. I am not convinced that “filling a gap is sufficient to justify publication in Nature\nCommunications.\nAgain, if this article discloses the synthesis of azetidines as a complementary method, comparative references are missing\n(already mentioned in my previous review):\n- Science 2016, DOI: 10.1126/science.aad6252\n- JACS 2017, DOI: 10.1021/jacs.6b13229\n- Org. Lett. 2019, DOI: 10.1021/acs.orglett.9b00321\n- Chem. Commun. 2022, DOI: 10.1039/d1cc07053c\n- JACS 2025, DOI: 10.1021/jacs.5c07227\nGiven the reservations detailed above, I do not recommend publication of this work in Nature Communications.", "reviewer_4": "The authors have addressed most of the comments. The main point, however, does not change; generation of thiocarbonyl\nfluoride has already been well-established, which also includes methods that are more practical to the procedures described\nin the manuscript. The semipinacol rearrangement has also been reported. Thus, it is difficult to justify acceptance in the\njournal. However, if the other reviewers recommend the manuscript after corrections, this reviewer will not oppose\npublication."}, "author_response": "Nature Catalysis Manuscript\nTitle:\" Photochemical Thiocarbonyl Difluoride Generation Enables Azetidine Synthesis\"\nPoint-by-point answer to the reviewers’ comments\nReviewer 3:\nThe authors have revised their manuscript, originally submitted to Nature Catalysis and\nsubsequently transferred to Nature Communications. I served as Reviewer #3 for the initial\nsubmission. While some of the comments were partially addressed in the revised version, several\npoints were met primarily with explanations rather than substantive revisions.\nI remain unconvinced of the novelty of the methodology presented. The responses provided to\nReviewer #1 clearly indicate that the development of an additional reagent to generate\nthiocarbonyl fluorides (TCFs)—which the authors describe as the foundation of the current\nmanuscript—constitutes an incremental improvement over existing state-of-the-art methods\nrather than a conceptual advance. Although Scheme 6 includes a limited number of examples\ninvolving amines other than azetidines, these compounds could, in principle, be accessed using\nmethodologies already cited in the introduction. As such, the only apparent advantage of the\nproposed strategy lies in the simultaneous activation of the substrate and formation of the\ncorresponding thiocarbonyl fluorides. However, as presented, this dual functionality appears to be\napplicable only to a very narrow class of substrates, namely ABBs. To date, the authors have not\ndemonstrated that this dual activation concept can be extended to other substrate classes.\nIn their response to Reviewer #1, the authors state that “to the best of our knowledge, accessing\nthese free NH azetidines through alternative methods requires the installation and subsequent\nremoval of N-protecting groups, increasing the number of synthetic steps.” This statement is\ninaccurate. While some reported methods indeed rely on electrophilic preactivation of ABBs, it has\nbeen demonstrated that nucleophilic reagents, such as amides or Grignard reagents, can be used\nto prepare NH azetidines without the need for installing and removing N-protecting groups\n(10.1021/jacs.6b13229 and 10.1039/D1CC07053C).\nAnswer by the authors: None of the cited references provide examples with quaternary centers at\nC3 or the architectures are reported in this manuscript, this is the reason of our original statement\nreads “accessing these free NH azetidines”. Extending the logic of organometallic addition to the\nABB substrates studied in this report may not be feasible due to functional groups incompatibility.\nFollowing this reviewer’s viewpoint, an acid-mediated semipinacol rearrangement could yield free\nNH azetidines, which in principle could then be subjected to any of the reported methods for\ngenerating thiocarbamoyl fluorides. We assessed the feasibility of this idea in Figure 5G; however,\nthe experimental results indicate that our approach is not only more practical but lead to improved\nperformances under very mild conditions.\nFinally, the authors justify the development of new conditions for TCF generation by arguing that it\nfills a synthetic gap toward azetidine thiocarbonyl fluorides. I am not convinced that “filling a gap\nis sufficient to justify publication in Nature Communications.\nAgain, if this article discloses the synthesis of azetidines as a complementary method, comparative\nreferences are missing (already mentioned in my previous review):\n- Science 2016, DOI: 10.1126/science.aad6252\n- JACS 2017, DOI: 10.1021/jacs.6b13229\n- Org. Lett. 2019, DOI: 10.1021/acs.orglett.9b00321\n- Chem. Commun. 2022, DOI: 10.1039/d1cc07053c\n- JACS 2025, DOI: 10.1021/jacs.5c07227\nAnswer by the authors: All the reviewer’s suggested references (33–39) have now been\nincorporated."}, {"round": 2, "reviewer_comments": {"reviewer_3": "Regardless of the modifications that were introduced in the manuscript, ans as I mentioned in my previous report, I do\nnot think the chemistry that the author describe fits the standards of Nature Communications in terms of novelty and\nurgency.\nFrom what I've read, Reviewer #4 also agreed regarding the novelty point.\nMy recommendation is to reject the manuscript."}, "author_response": ""}]

Decision letter