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. Author manuscript; available in PMC: 2025 Sep 18.
Published in final edited form as: J Am Chem Soc. 2025 Sep 12;147(38):34218–34224. doi: 10.1021/jacs.5c10954

Modular Access to N-SF5 azetidines

Renzhe Li 1,‡, Chao Hu 1,‡, Chang Liu 1,‡, Thomas Lyness 1, Wenyuan Li 1, Chen-Yan Cai 1, Eric Crossley 1, Yuzuru Kanda 2, Rohan R Merchant 3, Bryan S Matsuura 3, Noelle S Williams 1, Tian Qin 1
PMCID: PMC12443333  NIHMSID: NIHMS2110711  PMID: 40939176

Abstract

A general and modular strategy has been developed for the synthesis of N–SF5 azetidines, a new class of scaffolds with potential utility in medicinal chemistry. This transformation leverages bench-stable and scalable SF5-transfer reagents to generate SF5 radical, which engages azabicyclo[1.1.0]butanes (ABBs) bearing ketone, ester, alkyl, or aryl substituents in strain-release difunctionalization reactions. The method proceeds under mild reaction conditions, features broad functional group tolerance, and offers operational simplicity. The resulting N–SF5 azetidines demonstrate high aqueous stability and increased lipophilicity, positioning them as a novel class of potential bioisosteres in medicinal chemistry.

Aliphatic amines have emerged as one of the most prevalent functional groups in small-molecule pharmaceuticals, owing to their ability to modulate drug-target affinity (DTA) through ionic interactions and hydrogen bonding.1 In pursuit of more desirable pharmacokinetic profiles, the pentafluorosulfanyl amine (N–SF5) group has been proposed as a bioisosteric replacement for N-tBu and N-CF32,3 groups (Figure 1A).4 In the past several decades, various alkyl C–SF5 compounds have been elegantly synthesized via radical-type SF5 transfer reactions to unsaturated bonds and strained bonds using SF5Cl and other reagents as pioneered by Dolbier5a,5b, Welch5c, Paquin5h,5o, Qing5g,5j, Pitts5i,5l,5n,5p, and many other groups5,6. Yet, the synthetic access to N–SF5 compounds is less explored, limiting reports on their physicochemical or biological property besides one recent study from Tantillo and Pitts.7 In a groundbreaking report, Clifford described the preparation of the simplest N–SF5 compound (H2N–SF5)8 via the reaction between thiazyl trifluoride (N≡SF3) and gaseous HF. Additionally, directly coupling the SF5 group onto a nitrogen center is also feasible, as illustrated in the reactions between SF5Cl and specialized nitriles or imines under irradiation reported between the 1960s to 1990s.9 While these methods to access N–SF5 compounds are insightful, they often require harsh reaction conditions, involve the usage of corrosive and toxic gases, and offer limited substrate scope in low isolated yields (Figure 1B).5a Given these constraints, the development of practical and efficient strategies for constructing the N–SF5 moiety, especially those utilizing user-friendly, bench-stable SF5-transfer reagents, remains a highly desirable goal in synthetic and medicinal chemistry.

Figure 1. Background and synthetic approaches towards N-SF5 compounds.

Figure 1.

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(A) (Bio)isosteric replacement of N-Me/N-tBu groups; (B) Literature synthetic access of N-SF5 compounds; (C) Strain release difunctionalization of azabicyclo[1.1.0]butanes (ABBs); (D) Our recently developed bench-stable SF5 transfer reagents and their applications; (E) Our design for modular installation of N-SF5 azetidine skeleton (This work).

Azetidine is an important core scaffold in medicinal chemistry and is incorporated in several FDA-approved drugs.10 Compared to traditional functionalizations on the azetidine backbone, utilizing the highly strained azabicyclo[1.1.0] butanes (ABBs) as precursors for substituted azetidines has recently experienced a resurgence (Figure 1C).11 As illustrated in the elegant reports from Baran,12 Aggarwal,13 and others,14 ABBs can readily undergo polar-type strain release difunctionalization to afford valuable azetidine building blocks. In addition to these two-electron processes, Dell’Amico recently reported a radical-initiated ring-opening difunctionalization of ABBs to access N–sulfonyl azetidines.15 Building upon these studies, we envisioned that our recently engineered, bench-stable, solid SF5 reagent16—previously demonstrated to successfully couple with olefins, alkynes, and [1.1.0]bicyclobutane (BCB) (Figure 1D)—could facilitate efficient transfer of the SF5 radical (F5S•) to functionalize a diverse range of ABBs. This would, in turn, pave the way for a modular and practical synthesis of N–SF5 azetidines (Figure 1E). During the preparation of our manuscript, Pitts and Tlili reported the strain-release syntheses focused on 3-aryl N–SF5 azetidines from ABBs using SF5Cl or Ph2C=NSF5, respectively.7,17 Herein, we report a general and operationally simple synthetic approach for accessing structurally diverse N–SF5 azetidines using our bench-stable SF5 and other persulfuranyl transfer reagents. Notably, the resulting N–SF5 azetidines exhibit exceptional chemical stability in various aqueous and buffered media.

Our study commenced with a model reaction between SF5 transfer reagent 1 and 3-benzoyl-substituted ABB 2, furnishing the desired N–SF5 azetidine 3, a noncanonical α-amino ketone18. Through extensive optimizations, we identified an efficient protocol that proceeds under 395 nm at room temperature within 1 h, requiring only 3 mol% of 2,7-dibromo-9H-thioxanthen-9-one (2,7-Br2-TXT) as a photocatalyst, affording the desired product 3 in 86% NMR yield (Table 1, entry 1). Detailed optimization data are provided in the Supporting Information, with selected experiments summarized in Table 1. Solvent effects were found to be critical, with less polar solvents such as cyclohexane markedly enhancing reaction efficacy (entries 2–5). Further improvement was achieved by incorporating methyl tert-butyl ether (MTBE) as a co-solvent, which minimized the decomposition of ABB 2 while improving solubility of both substrate and catalyst in the mixed-solvent system (Supplementary Tables S2). Any deviation from the optimized condition, such as altering the photocatalyst (entries 6 and 7) or the light source (entries 8 and 9), led to lower yields. Decreasing the loading of reagent 1 also resulted in lower conversion of 2 and diminished yield (entry 10). Notably, the optimized condition exhibits partial tolerance to air (entry 11), as a 49% NMR yield was still obtained under ambient atmosphere. Given the varying reactivity profiles of ABBs with different types of 3-substitution, we performed separate optimization studies for alkyl- and aryl-type ABBs. These efforts culminated in the establishment of three protocols: Condition A for ketone-type ABBs, Condition B for ester-type ABBs and Condition C for aryl-type ABBs.

Table 1.

Optimization of the strain-release pentafluorosulfanylation on ABBsa

graphic file with name nihms-2110711-t0001.jpg
Entry Deviation from above Yield (%)b
1 none 86
2 c-hexane as solvent 80
3 MTBE as solvent 69
4 CH2Cl2 as solvent 9
5 MeCN as solvent 5
6 TXT instead of 2,7-Br2-TXT 78
7 2-Br-TXT instead of 2,7-Br2-TXT 83
8 365 nm instead of 395 nm 78
9 420 nm instead of 395 nm 80
10 1.1 equiv. of reagent 1 60
11 under air 49
graphic file with name nihms-2110711-t0002.jpg
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a

Reaction conditions: 1 (0.085 mmol), 2 (0.05 mmol), 2,7-Br2-TXT (3 mol%), solvent (1.0 mL), argon, 395 nm, 1 h.

b

Yield was determined by NMR analysis with CH2Br2 as an internal standard. MTBE, methyl tert-butyl ether. c-hexane, cyclohexane.

With the optimized pentafluorosulfanylation protocol, the substrate scope and limitations of the transformation were systematically investigated (Figure 2). Initially, a broad range of ketone-substituted ABBs were evaluated with Condition A. For example, the substituent at the ketone position could be aryls of different electronic properties (5, 8, 9) or bearing ortho-substitutions (11). Aryl halides (6, 7, 10) were accommodated. Various heterocycles, including furans (12), thiophenes (13), pyridines (14), and quinolines (15), were compatible with our conditions. Ketone-bearing ABBs with cyclic (19–25, 27) and acyclic (16–18, 26) aliphatic substituents participated in this reaction. Saturated heterocycles such as tetrahydro-2H-pyran rings (24) and piperidines (25) were also viable substrates for this transformation. Notably, successful pentafluorosulfanylations were achieved on sterically demanding ketones, such as those with tert-butyl (26) or 1-adamantyl groups (27). Next, other classes of ABB substrates bearing diverse substitutions patterns were examined to further evaluate the generality of the pentafluorosulfanylation strategy. C3 ester-substituted ABBs, which serve as useful precursors to amino acid derivatives, underwent smooth strain-release pentafluorosulfanylation to afford 28 and 29 in 46% and 52% yields under Condition B, respectively. The imine group in 29 can be hydrolyzed under mild conditions to provide the corresponding N-SF5-azetidine amino acid 30. Secondary alkyl-ABBs proved to be successful coupling partners for the synthesis of products 31 and 32 as amino alcohol precursors. A primary alkyl-ABB (33) was also allowed. Aryl-ABBs demonstrated higher reactivity than other ABB types in this transformation. As a result, CH2Cl2 was used instead of cyclohexane to accelerate the reaction and prevent the self-decomposition of phenyl-ABBs (Supplementary Tables S5, Condition C). Under these conditions, 3-phenyl ABB delivered 34, the structure of which was unambiguously confirmed by X-ray analysis. Aryl-ABBs containing nitrile (35) and nitro (36) functionalities or C2-substituents (37, 38) successfully delivered the corresponding products. Furthermore, this strategy was also effective in transferring trifluoromethyltetrafluoro-λ6-sulfanyl group (-SF4CF3) from the corresponding reagent to afford N–SF4CF3-azetidine 39 in a 70% yield. To further demonstrate the late-stage applicability of this strategy, ABBs derived from ibuprofen (42), febuxostat (43), and lithocholic acid (44) were shown to undergo iminylpentafluorosulfanylation, thus smoothly installing this innovative chemical moiety.

Figure 2. Substrate scope of ABBs coupling with bench-stable SF5 reagents.

Figure 2.

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Unless otherwise noted, reactions in this table were performed at 0.1 mmol scale. Isolated yields are reported. Diastereomeric ratios were determined by NMR analysis of the crude reaction mixture. Condition A: SF5 reagent 1 (1.7 equiv.), ABBs (1.0 equiv.), 2,7-Br2-TXT (3 mol%), c-hexane/MTBE (7:3, 0.05 M), 395 nm LEDs, Ar, 1 h. Condition B: SF5 reagent 1 (2.0 equiv.), ABBs (1.0 equiv.), 2,7-Br2-TXT (5 mol%), n-pentane (0.025 M), 365 nm LEDs, Ar, 1 h. Condition C: SF5 reagent 1 (1.1 equiv.), ABBs (1.0 equiv.), TXT (5 mol%), CH2Cl2/MTBE (1:1, 0.05 M), 395 nm LEDs, Ar, 1 h. a NMR yield. b Reagent 1 (2.0 equiv.) was used. c HCl (conc.), acetone (0.1 M), rt, 8 h. d MTBE (0.05 M) was used instead of c-hexane/MTBE (7:3, 0.05 M). See SI, section 2 and 5 for experimental details.

During the investigation of coupling with alkyl-ABBs 45, the unexpected spirocyclization product 46 was obtained (Figure 3A). This suggests that the tertiary alkyl radical formed after the attack of an F5S• may preferentially undergo intramolecular radical cyclization with the phenyl ring rather than being trapped by the iminyl radical. To gain further insights into the reaction mechanism, we conducted a radical trapping experiment (Figure 3B). The addition of TEMPO completely inhibited ABBs difunctionalization and led to the quantitative formation of 47 from reagent 1, which further substantiated the radical character of this reaction. Moreover, among the screening of solvents, the SF5–iminyl coupling product 49 was isolated when pentane was used19. Therefore, a self-coupling experiment of 1 in the absence of ABBs was performed and afforded both known coupling product 4816 and the new product 49 (Figure 3C). Meanwhile, the purified compound 48 failed to convert to 49 under the same conditions, indicating a direct radical recombination between F5S• and iminyl radical.

Figure 3. Mechanistic studies and stability tests.

Figure 3.

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(A) Unexpected spirocyclization via intramolecular radical trapping, Condition: SF5 reagent 1 (1.7 equiv.), ABBs (1.0 equiv.), 2,7-Br2-TXT (3 mol%), c-hexane/MTBE (1:1, 0.05 M), 395 nm LEDs, Ar, 1 h. (B) The radical trapping experiment by TEMPO; Condition: SF5 reagent 1 (1.7 equiv.), ABBs (1.0 equiv.), 2,7-Br2-TXT (3 mol%), c-hexane/MTBE (7:3, 0.05 M), 395 nm LEDs, Ar, 1 h. (C) Radical self-cross-coupling in the absence of additional ABBs; Condition: SF5 reagent 1 (2.0 equiv.), 2,7-Br2-TXT (5 mol%), n-pentane (0.025 M), 365 nm LEDs, Ar, 1 h. (D) Gram-scale synthesis of 34 and stability tests of 51. FBS, fetal bovine serum; PBS, phosphate-buffered saline. See SI, section 6 for experimental details.

To assess the robustness of the reaction and obtain sufficient N–SF5-azetidine-containing compounds for stability tests, we synthesized the product 34 on a gram scale with a comparable isolated yield (Figure 3D). Compound 34 was then subjected to acid-mediated deprotection to produce the more water-soluble amine derivative 51. The stability of 51 was evaluated across seven different media (acetone-d6, methanol-d4, DMSOd6, FBS buffer, PBS buffer [pH = 7.5], 0.01 M HCl solution [pH = 2.0], and 0.01 M KOH solution [pH = 12.0]). These results indicated that compound 51 remained stable in six of the seven media, with only 3% decomposition observed in 0.01 M KOH after 24 hours through 19F-NMR monitoring. These findings highlight the remarkable aqueous stability of N–SF5 azetidines.

Furthermore, the rationale for targeting N–SF5 azetidines was supported by preliminary profiling of their physicochemical properties and ADME (absorption, distribution, metabolism, and excretion) characteristics in biologically relevant scaffolds. The bioisosteric switch of the N–tBu azetidine-containing compound 55, a GPR52 modulator potent in treating neurological disorders,20 was performed to generate its surrogate 54, which was synthesized from amino acid derivative 52 via photocatalytic decarboxylative reduction21 and amide coupling. Both compounds were profiled for ADME studies (Figure 4), and the data highlight that increase in LogD values by introducing the N–SF5 group also results in a substantial increase of lipophilicity and decrease in measured solubility, while retaining comparable stability. This case demonstrates N-SF5 azetidines as novel scaffolds of medicinal chemistry importance.

Figure 4. Synthesis and ADME study of GPR52 modulator 55 and its N–SF5 azetidine analogue 54.

Figure 4.

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LogD, distribution coefficient; Caco2, colorectal adenocarcinoma cells; Papp, apparent permeability; Solubility, 24 h solubility in 0.1% DMSO and buffer at indicated pH; Clint, intrinsic clearance. Reaction conditions: (a) (PhS)2 (10 mol%), 2,6-lutidine (20 mol%), 9-mesityl-10-methylacridinium perchlorate (1 mol%), DCE (0.05 M), 450 nm LEDs, Ar, 16 h; (b) (i) TFA/DCM (1:10, 0.02 M), rt, 0.5 h; (ii) 53 (1.1 equiv.), HATU (1.2 equiv.), DMF (0.05 M), rt, 16 h. See SI, section 7 for experimental details.

In conclusion, we have developed a general, operationally simple, and modular approach to access N–SF5 azetidines—novel scaffolds of medicinal significance. At the heart of this approach lies the use of our bench-stable SF5 transfer reagents to generate the ambiphilic F5S•, which undergoes selective addition to strained azabicyclobutanes to form the underexplored N–SF5 bond. This method features mild reaction conditions, broad functional group tolerance, and enables late-stage functionalization. Additionally, pharmacokinetic profiling revealed that N–SF5 azetidines are stable in aqueous and buffer conditions and exhibit enhanced lipophilicity compared to their parental N-alkyl analogs. Therefore, N–SF5 azetidines have the potential to be used as bioisosteres in medicinal chemistry applications and open access to underexplored chemical space. As such, we foresee that these findings will inspire the creation and exploration of diverse N-SF5-containing molecules, thereby facilitating advances across medicinal, materials, and broader chemical research fields.

Supplementary Material

SI

Detailed experimental procedures, and characterization data for all compounds. (PDF)

Crystallographic information for 34 (CIF).

ACKNOWLEDGMENT

We thank Feng Lin (UTSW) for assistance with NMR spectroscopy; Hamid Baniasadi (UTSW) for HRMS; Joseph H. Reibenspies (Texas A&M University) for X-ray crystallographic analysis. We acknowledge resources and expertise provided by the institutionally supported UTSW Preclinical Pharmacology Core for ADME profiling. We appreciate the Chen, Tambar, Ready, DeBrabander, Smith, and Falck groups (UTSW) for their generous access to equipment and helpful discussions.

Funding Sources

Financial support for this work was provided by the Welch Foundation (I-2155-20230405) and National Institutes of Health (R01GM141088).

Footnotes

The authors declare no competing financial interest.

REFERENCES

  • (1).(a) Marshall CM; Federice JG; Bell CN; Cox PB; Njardarson JT An update on the nitrogen heterocycle compositions and properties of US FDA-approved pharmaceuticals (2013–2023). J. Med. Chem 2024, 67, 11622–11655. [DOI] [PubMed] [Google Scholar]; (b) Kerru N; Gummidi L; Maddila S; Gangu KK; Jonnalagadda SB A review on recent advances in nitrogen-containing molecules and their biological applications. Molecules 2020, 25, 1909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (2).(a) Asahina Y; Araya I; Iwase K; Iinuma F; Hosaka M; Ishizaki T Synthesis and antibacterial activity of the 4-quinolone-3-carboxylic acid derivatives having a trifluoromethyl group as a novel N-1 substituent. J. Med. Chem 2005, 48, 3443–3446. [DOI] [PubMed] [Google Scholar]; (b) Scattolin T; Deckers K; Schoenebeck F Efficient synthesis of trifluoromethyl amines through a formal umpolung strategy from the bench-Stable Precursor (Me4N)SCF3. Angew. Chem. Int. Ed 2017, 129, 221–224. [Google Scholar]; (c) Scattolin T; Bouayad-Gervais S; Schoenebeck F Straightforward access to N-trifluoromethyl amides, carbamates, thiocarbamates and ureas. Nature 2019, 573, 102–107. [DOI] [PubMed] [Google Scholar]; (d) Bouayad-Gervais S; Scattolin T; Schoenebeck F N-Trifluoromethyl Hydrazines, Indoles and Their Derivatives. Angew. Chem. Int. Ed 2020, 132, 11908–11912. [Google Scholar]; (e) Wycich G; Ponce-de-León J; Liu L; Schoenebeck F Desulfurizative Fluorination of N-CF3 Thioformamides for the Efficient Synthesis of N(CF3)(CF2H) Amines with Enhanced Stability. Angew. Chem. Int. Ed 2025, e202506154. [Google Scholar]
  • (3).(a) Schiesser S; Chepliaka H; Kollback J; Quennesson T; Czechtizky W; Cox RJ N-Trifluoromethyl amines and azoles: An underexplored functional group in the medicinal chemist’s toolbox. J. Med. Chem 2020, 63, 13076–13089. [DOI] [PubMed] [Google Scholar]; (b) Crousse B Recent Advances in the Syntheses of N-CF3 Scaffolds up to Their Valorization. Chem. Rec 2023, 23, e202300011. [DOI] [PubMed] [Google Scholar]
  • (4).Sowaileh MF; Hazlitt RA; Colby DA Application of the Pentafluorosulfanyl Group as a Bioisosteric Replacement. ChemMedChem 2017, 12, 1481–1490. [DOI] [PubMed] [Google Scholar]
  • (5).For selected examples on radical-type pentafluorosulfanylation, see:; (a) Aït-Mohand S; Dolbier WR New and Convenient Method for Incorporation of Pentafluorosulfanyl (SF5) Substituents Into Aliphatic Organic Compounds. Org. Lett 2002, 4, 3013–3015. [DOI] [PubMed] [Google Scholar]; (b) Dolbier WR; Aït-Mohand S; Schertz TD; Sergeeva TA; Cradlebaugh JA; Mitani A; Gard GL; Winter RW; Thrasher JS A convenient and efficient method for incorporation of pentafluorosulfanyl (SF5) substituents into aliphatic compounds. J. Fluorine Chem 2006, 127, 1302–1310. [Google Scholar]; (c) Penger A; von Hahmann CN; Filatov AS; Welch JT Diastereoselectivity in the Staudinger reaction of pentafluorosulfanylaldimines and ketimines. Beilstein J. Org. Chem 2013, 9, 2675–2680. [DOI] [PMC free article] [PubMed] [Google Scholar]; (d) Rombach D; Wagenknecht H-A Photoredox Catalytic Activation of Sulfur Hexafluoride for Pentafluorosulfanylation of α-Methyl- and α-Phenyl Styrene. ChemCatChem 2018, 10, 2955–2961. [Google Scholar]; (e) Rombach D; Wagenknecht H-A Photoredox Catalytic α-Alkoxypentafluorosulfanylation of α-Methyl- and α-Phenylstyrene Using SF6. Angew. Chem. Int. Ed 2019, 59, 300–303. [Google Scholar]; (f) Lefebvre G; Charron O; Cossy J; Meyer C Radical Addition of SF5Cl to Cyclopropenes: Synthesis of (Pentafluorosulfanyl)cyclopropanes. Org. Lett 2021, 23, 5491–5495. [DOI] [PubMed] [Google Scholar]; (g) Shou J-Y; Xu X-H; Qing F-L Chemoselective Hydro(Chloro)pentafluorosulfanylation of Diazo Compounds with Pentafluorosulfanyl Chloride. Angew. Chem. Int. Ed 2021, 60, 15271–15275. [Google Scholar]; (h) Birepinte M; Champagne PA; Paquin J-F Photoinitiated anti-Hydropentafluorosulfanylation of Terminal Alkynes. Angew. Chem. Int. Ed 2022, 61, e202112575. [Google Scholar]; (i) Kraemer Y; Ghiazza C; Ragan AN; Ni S; Lutz S; Neumann EK; Fettinger JC; Nöthling N; Goddard R; Cornella J; Pitts CR Strain-Release Pentafluorosulfanylation and Tetrafluoro(aryl)sulfanylation of [1.1.1] Propellane: Reactivity and Structural Insight. Angew. Chem. Int. Ed 2022, 61, e202211892. [Google Scholar]; (j) Zhao X; Shou J-Y; Qing F-L Iodopentafluorosulfanylation of [1.1.1] propellane and further functionalizations. Sci. China Chem 2023, 66, 2871–2877. [Google Scholar]; (k) Nguyen TM; Legault CY; Blanchard N; Bizet V; Cahard D Tracking SF5I in the Iodopentafluorosulfanylation of Alkynes. Chem. Eur. J 2023, 29, e202302914. [DOI] [PubMed] [Google Scholar]; (l) Kraemer Y; Buldt JA; Kong W-Y; Stephens AM; Ragan AN; Park S; Haidar ZC; Patel AH; Shey R; Dagan R; McLoughlin CP; Fettinger JC; Tantillo DJ; Pitts CR Overcoming a Radical Polarity Mismatch in Strain-Release Pentafluorosulfanylation of [1.1.0] Bicyclobutanes: An Entryway to Sulfone- and Carbonyl-Containing. SF5-cyclobutanes. Angew. Chem. Int. Ed 2024, 63, e202319930. [Google Scholar]; (m) Jiang Y; Meng X; Zhang J; Wu G; Lin X; Guo S Photo-induced hydroxypentafluorosulfanylation of alkenes with SF5Cl and oxygen gas and their further derivatization. Nat. Comm 2024, 15, 9705. [Google Scholar]; (n) Buldt JA; Kong W-Y; Kraemer Y; Belsuzarri MM; Patel AH; Fettinger JC; Tantillo DJ; Pitts CR Controlled oligomerization of [1.1.1] propellane through radical polarity matching: selective synthesis of SF5-and CF3SF4-containing [2] staffanes. Beilstein J. Org. Chem 2024, 20, 3134–3143. [DOI] [PMC free article] [PubMed] [Google Scholar]; (o) Verret L; Burchell-Reyes K; Morin J-F; Paquin J-F Exploration of 2-(pentafluoro-λ6-sulfanyl)ethane-1-sulfonyl chloride as a novel pentafluorosulfanylation reagent. J. Fluor. Chem 2025, 282, 110387. [Google Scholar]; (p) Kraemer Y; Stephens AM; Buldt JA; Young A; McLoughlin CP; Fettinger JC; Holder LM; Pitts CR Strain-release trifluoromethoxylation and pentafluorosulfanoxylation of [1.1.0] bicyclobutanes: expanded access to fluorinated cyclobutane hybrid bioisosteres. Chem. Commun 2025, 61, 3159–3162. [Google Scholar]; (q) Li J-Y; Liu Y; Sun D; Wu G; Yue S-S; Yang H-Y; Zhang H; Zhang W; Zheng M-M; Xue X-S; Guo S Radical 1,3-Difunctionalization of β, γ-Unsaturated Ketones via Concomitant 1,2-Carbonyl Migration: An Entrance to β-SF5-/β-CF3SF4 Ketones. J. Am. Chem. Soc 2025, 147, 26124–26132. [DOI] [PubMed] [Google Scholar]
  • (6).For reviews on radical-type pentafluorosulfanylation, see:; (a) Savoie PR; Welch JT Preparation and utility of organic pentafluorosulfanyl-containing compounds. Chem. Rev 2015, 115, 1130–1190. [DOI] [PubMed] [Google Scholar]; (b) Kordnezhadian R; Li BY; Zogu A; Demaerel J; De Borggraeve WM; Ismalaj E Chemistry of Pentafluorosulfanyl Derivatives and Related Analogs: From Synthesis to Applications. Chem. Eur. J 2022, 28, e202201491. [DOI] [PubMed] [Google Scholar]; (c) Haufe G Synthesis and application of pentafluorosulfanylation reagents and derived aliphatic SF5-containing building blocks. Tetrahedron 2022, 109, 132656. [Google Scholar]
  • (7).Kraemer Y; Park S; Kong W-Y; Chen Y; Witt AJ; Buldt JA; Ragan AN; Holder LM; Tantillo DJ; Pitts CR Direct N–SF5 and N–SF4CF3 Bond Formation through Strain-Release Functionalization of 3-Substituted [1.1.0] Azabicyclobutanes. J. Am. Chem. Soc 2025, 147, 27892–27904. [DOI] [PubMed] [Google Scholar]
  • (8).Thrasher JS; Howell JL; Clifford AF Acylations of pentafluorosulfanylamine, SF5NH2. Inorg. Chem 1982, 21, 1616–1622. [Google Scholar]
  • (9).(a) Tullock CW; Coffman DD; Muetterties EL Synthesis and Chemistry of SF5Cl. J. Am. Chem. Soc 1964, 86, 357–361. [Google Scholar]; (b) John EO; Mack HG; Oberhammer H; Kirchmeier RL; Shreeve J. n. M. Perfluoroalkyl (N-pentafluorosulfanyl) azidoazomethines and perfluoroalkyl (N-pentafluorosulfanyl) carbodiimides. Inorg. Chem 1993, 32, 287–290. [Google Scholar]
  • (10).Parmar DR; Soni JY; Guduru R; Rayani RH; Kusurkar RV; Vala AG Azetidines of pharmacological interest. Arch. Pharm 2021, 354, 2100062. [Google Scholar]
  • (11).(a) Andresini M; Degennaro L; Luisi R The renaissance of strained 1-azabicyclo [1.1.0] butanes as useful reagents for the synthesis of functionalized azetidines. Org. Biomol. Chem 2020, 18, 5798–5810. [DOI] [PubMed] [Google Scholar]; (b) Tyler JL; Aggarwal VK Synthesis and Applications of Bicyclo [1.1.0] butyl and Azabicyclo [1.1.0] butyl Organometallics. Chem. Eur. J 2023, 29, e202300008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (12).(a) Gianatassio R; Lopchuk JM; Wang J; Pan C-M; Malins LR; Prieto L; Brandt TA; Collins MR; Gallego GM; Sach NW; Spangler JE; Zhu H; Zhu J; Baran PS Strain-release amination. Science 2016, 351, 241–246. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Bielecki M; Nassir M; Sharma HA; Truax NJ; Raheja N; Thompson TM; Ewing TE-H; Melillo B; Cravatt BF; Baran PS Simple, Enantiocontrolled Azetidine Library Synthesis via Strain Release Functionalization of 1-Azabicyclobutanes. J. Am. Chem. Soc 2025, 147, 22209–22218. [DOI] [PubMed] [Google Scholar]
  • (13).(a) Fawcett A; Murtaza A; Gregson CH; Aggarwal VK Strain-release-driven homologation of boronic esters: application to the modular synthesis of azetidines. J. Am. Chem. Soc 2019, 141, 4573–4578. [DOI] [PubMed] [Google Scholar]; (b) Gregson CH; Noble A; Aggarwal VK Divergent, Strain-Release Reactions of Azabicyclo [1.1.0] butyl Carbinols: Semipinacol or Spiroepoxy Azetidine Formation. Angew. Chem. Int. Ed 2021, 133, 7360–7365. [Google Scholar]; (c) Tyler JL; Noble A; Aggarwal VK Strain-Release Driven Spirocyclization of Azabicyclo [1.1.0] butyl Ketones. Angew. Chem. Int. Ed 2021, 133, 11824–11829. [Google Scholar]; (d) Tyler JL; Noble A; Aggarwal VK Strain-release-driven friedel–crafts spirocyclization of azabicyclo [1.1.0] butanes. Angew. Chem. Int. Ed 2022, 134, e202114235. [Google Scholar]; (e) Tyler JL; Noble A; Aggarwal VK Four-Component Strain-Release-Driven Synthesis of Functionalized Azetidines. Angew. Chem. Int. Ed 2022, 61, e202214049. [Google Scholar]
  • (14).(a) Mlostoń G; Woźnicka M; Drabowicz J; Linden A; Heimgartner H Addition Reactions of Sulfenyl and Sulfinyl Chlorides with 3-Phenyl-1-azabicyclo [1.1.0] butane. Helv. Chim. Acta 2008, 91, 1419–1429. [Google Scholar]; (b) Hayashi K; Kujime E; Katayama H; Sano S; Nagao Y Reaction of 1-azabicyclo [1.1.0] butane with activated amides. Heterocycles 2009, 78, 1777–1786. [Google Scholar]; (c) Gianatassio R; Kadish D Direct alkylation of 1-azabicyclo [1.1.0] butanes. Org. Lett 2019, 21, 2060–2063. [DOI] [PubMed] [Google Scholar]; (d) Trauner F; Reiners F; Apaloo-Messan K-E; Nißl B; Shahbaz M; Jiang D; Aicher J; Didier D Strain-release arylations for the bis-functionalization of azetidines. Chem. Commun 2022, 58, 2564–2567. [Google Scholar]; (e) Hsu C-M; Lin H-B; Hou X-Z; Tapales RVPP; Shih C-K; Miñoza S; Tsai Y-S; Tsai Z-N; Chan C-L; Liao H-H Azetidines with all-carbon quaternary centers: merging relay catalysis with strain release functionalization. J. Am. Chem. Soc 2023, 145, 19049–19059. [DOI] [PubMed] [Google Scholar]; (f) Jaiswal V; Mondal S; Singh B; Singh VP; Saha J Cation-Promoted Strain-Release-Driven Access to Functionalized Azetidines from Azabicyclo [1.1.0] butanes. Angew. Chem. Int. Ed 2023, 135, e202304471. [Google Scholar]; (g) Singh B; Sasmal P; Taites A; Hazra S; Saha J Aza-ortho-Quinone Methide Promoted Strain-Release-Driven Conversion of Azabicyclo [1.1.0] butanes into Functionalized Azetidines. Org. Lett 2024, 26, 9558–9563. [DOI] [PubMed] [Google Scholar]
  • (15).Rodríguez RI; Corti V; Rizzo L; Visentini S; Bortolus M; Amati A; Natali M; Pelosi G; Costa P; Dell’Amico L Radical strain-release photocatalysis for the synthesis of azetidines. Nat. Catal 2024, 7, 1223–1231. [Google Scholar]
  • (16).Li R; Liu C; Hu C; Tsien J; Hayes M; Chen S-J; Kanda Y; Merchant R; Matsuura B; Qin T Bench-stable reagents for modular access to persulfuranyl scaffolds. Nat. Comm 2025, DOI: 10.1038/s41467-025-63621-w. [DOI] [Google Scholar]
  • (17).Yang Y; Han L; Canavero L; Brettnacher L; Khrouz L; Monnereau C; Médebielle M; Tlili A Strain-Release-Driven Synthesis of Pentafluorosulfanylated Four-Membered Rings under Energy Transfer Photocatalysis. J. Am. Chem. Soc 2025, 147, 27905–27911. [DOI] [PubMed] [Google Scholar]
  • (18).Allen LA; Raclea R-C; Natho P; Parsons PJ Recent advances in the synthesis of α-amino ketones. Org. Biomol. Chem 2021, 19, 498–513. [DOI] [PubMed] [Google Scholar]
  • (19).The de novo synthesis of same structure 49 was reported by Tlili:; Yang Y; Lulu H; Taponard A; Khrouz L; Bucher C; Cyrille M; Medebielle M; Tlili A A Shelf-Stable Reagent for Photocatalytic Radical Pentafluorosulfanylation of Styrene Derivatives. Angew. Chem. Int. Ed 2025, e202505146. [Google Scholar]
  • (20).Ashweek NJ; Charaschanya M; Galasiti Kankanamalage AC; Gandhi DM; Cueva-Garcia JP; Regan C; Lee W-L; Branum S Compounds and Compositions as GPR52 Modulators. WO 2024/091541: 2024.
  • (21).Cassani C; Bergonzini G; Wallentin C-J Photocatalytic decarboxylative reduction of carboxylic acids and its application in asymmetric synthesis. Org. Lett 2014, 16, 4228–4231. [DOI] [PubMed] [Google Scholar]

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