Copper-Catalyzed Cyclopropenation of Alkynes with Difluoromethyl Carbene

Copper-Catalyzed Cyclopropenation of Alkynes with Difluoromethyl Carbene | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Chinese Journal of Chemistry This is a preprint and has not been peer reviewed. Data may be preliminary. 6 February 2025 V1 Latest version Share on Copper-Catalyzed Cyclopropenation of Alkynes with Difluoromethyl Carbene Authors : Yong Yang , Paramasivam Sivaguru 0000-0003-2225-0054 , Qingmin Song , Zhaohong Liu , Yong Ji , Wei Song , Karunanidhi Murali , Jacek Mlynarski 0000-0002-1794-306X , and Xihe Bi 0000-0002-6694-6742 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.173880924.49257053/v1 Published Chinese Journal of Chemistry Version of record Peer review timeline 549 views 271 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract The [2+1] cycloaddition of alkynes with fluoroalkyl carbenes is the most straightforward approach for synthesizing fluoroalkylated cyclopropenes. However, until now, this strategy has not been applicable to difluoromethyl carbene, as its precursor, difluoromethyl diazomethane, tendeds to undergo [3+2] cycloaddition with alkynes to form pyrazoles. This study presents the first example of cyclopropenation of alkynes with difluoromethyl carbene under copper catalysis, utilizing difluoroacetaldehyde triftosylhydrazone as the carbene precursor. A wide range of internal and terminal alkynes, featuring diverse functional groups, were successfully converted into the corresponding difluoromethyl cyclopropenes in good to high yields. Mechanistic insight, supported by DFT calculations, revealed that the bulky Tp Br3 Cu(NCMe) catalyst was essential in facilitating the cyclopropenation of alkynes with difluoromethyl carbenes via a concerted pathway. Cite this paper: Chin. J. Chem. 2024 , 42 , XXX—XXX. DOI: 10.1002/cjoc.202400XXX Copper-Catalyzed Cyclopropenation of Alkynes with Difluoromethyl Carbene Yong Yang, a Paramasivam Sivaguru , a Qingmin Song, a Zhaohong Liu, * , a Yong Ji, a Wei Song, a Karunanidhi Murali, a Jacek Mlynarski, b and Xihe Bi * ,a,c a Department of Chemistry, Northeast Normal University Changchun 130024, China b Institute of Organic Chemistry, Polish Academy of Sciences,Kasprzaka 44/52, 01-224 Warsaw, Poland c State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China Cyclopropenation | Alkynes | Difluoromethyl carbenes | Difluoromethyl cyclopropenes |Copper catalysis| Triftosylhydrazone8 Comprehensive Summary The [2+1] cycloaddition of alkynes with fluoroalkyl carbenes is the most straightforward approach for synthesizing fluoroalkylated cyclopropenes. However, until now, this strategy has not been applicable to difluoromethyl carbene, as its precursor, difluoromethyl diazomethane, tendeds to undergo [3+2] cycloaddition with alkynes to form pyrazoles. This study presents the first example of cyclopropenation of alkynes with difluoromethyl carbene under copper catalysis, utilizing difluoroacetaldehyde triftosylhydrazone as the carbene precursor. A wide range of internal and terminal alkynes, featuring diverse functional groups, were successfully converted into the corresponding difluoromethyl cyclopropenes in good to high yields. Mechanistic insight, supported by DFT calculations, revealed that the bulky Tp Br3 Cu(NCMe) catalyst was essential in facilitating the cyclopropenation of alkynes with difluoromethyl carbenes via a concerted pathway. Background and Originality Content Fluorine atoms have been demonstrated to exert a significant influence on the physical and biological properties of connected small molecules. [1] As a consequence, fluoroalkyl-substituted molecules have found wide applications in pharmaceuticals, [2] agrochemicals [3] and materials sciences. [4] Over recent decades, considerable research efforts have focused on introducing fluoroalkyl groups into organic molecules, [5,6] leading to the discovery of over 90 marketed drugs that contain a trifluoromethyl (CF 3 ) group. In contrast, only 10 examples bearing a difluoromethyl (CF 2 H) group have been identified. [2c] Recently, the -CF 2 H group has attracted considerable attention from synthetic and medicinal chemists due to its unique properties and potential advantages in drug design. [7] Its incorporation into drug-like molecules can notably alter ADME (absorption, distribution, metabolism, and excretion) properties. [2,3,7] Moreover, the -CF 2 H group acts as a lipophilic hydrogen bond donor, mimicking polar functional groups such as alcohols, thiols, amines, and carbonyl moieties. [8] For instance, the replacement of the -CF 3 group with the -CF 2 H group in acylsulfonamide-based hepatitis C virus (HCV) protease inhibitors resulted in a 17-fold increase in potency due to the hydrogen-bonding interactions exerted by the -CF 2 H group (Figure 1A). [9] Analogous to the fluorine effect in pharmaceuticals, the strategic incorporation of a constrained cyclopropene ring often alters the conformation of attached molecules, thereby modulating their biological properties. [10] By combining the unique characteristics of the CF 2 H group with those of the cyclopropene ring, difluoromethyl cyclopropenes are widely recognized as privileged structures for modern drug design. [11] However, the commercialisation of pharmaceuticals or agrochemicals containing this motif has been precluded by the lack of efficient synthetic methods. [2,3] Thus, the development of a general and practical approach to access difluoromethyl or other fluoroalkyl-substituted cyclopropene for studing their structure–activity relationships (SAR) remains a high priority. In this context, fluorinated diazoalkanes have became powerful precursors for fluoroalkyl carbenes, enabling the introduction of fluoroalkyl groups into small molecules (Figure 1B). [12] While trifluorodiazoethane (CF 3 CHN 2 ) has been extensively studied, [12a-d] its difluoromethyl analogue (CF 2 HCHN 2 ) has received comparatively little attantion (Figure 1B). [12e] This is primarily due to the paucity of practical generation methods for the latter. The in situ or flow generation of CF 2 HCHN 2 from difluoroethylamine with tert -butyl nitrite, however, has been demonstrated by Mykhailiuk, [13] and the base-promoted decomposition of difluoroacetaldehyde triftosylhydrazone (DFHZ-Tfs) was described by our group, [14] both of which have led to a series of encouraging synthetic applications of CF 2 HCHN 2 . [12e,15,16] It is noteworthy that, despite the successful Figure 1 State-of-the-art in cyclopropenation of alkynes with fluoroalkyl carbenes. application of these fluorinated reagents in the catalytic cyclopropanation of alkenes to access difluoromethyl cyclopropanes with excellent chemo- and stereoselectivity, [14,16] the majority of transformations based on CF 2 HCHN 2 are focused on metal-free reactions, such as [3+2]-cycloadditions and esterifications. [15] This is largelly due to the highly polarized C−H bond in the CF 2 H group, which readily interacts with metal centres and impedes the formation of reactive difluoromethyl carbene species (Figure 1C). [12c-e] In recent years, we have endeavored to develop catalytic carbene transfer reactions for the construction of fluorinated molecules, utilising operationally safe fluoroalkyl triftosylhydrazones as carbene sources. [20,21] Our studies revealed that DFHZ-Tfs undergoes decomposition to form CF 2 HCHN 2 at a slow rate under mild conditions, which would effectively impede the occurrence of the undesired side reactions associated with unstable fluorinated diazo compounds. [14] Building on this observation, we envisioned that this strategy could suppress the undesired [3+2] cycloaddition of alkynes with CF 2 HCHN 2 and enable the in situ generation of reactive CF 2 H-only metal carbene, thereby opening the door to cyclopropenation of alkynes. In this study, we present the successful execution of copper-catalysed cyclopropenation of alkynes with difluoromethyl carbene, which is generated in situ from DFHZ-Tfs, to access valuable CF 2 H-substituted cyclopropenes (Figure 1D). This operationally convenient cyclopropenation reaction employs the more valuable alkynes as the limiting reagent and works for both internal and terminal alkynes bearing diverse functional groups, making it potentially useful for the late-stage modification of complex bioactive molecules. Furthermore, extending this chemistry to other fluoroalkyl triftosylhydrazones enables efficient access to diverse perfluoroalkyl-substituted cyclopropenes, which are challenging to access through currently existing methods. [11,19] Results and Discussion To establish a practical and late-stage cyclopropenation method, our study began by an examination of various carbene transfer catalysts in the model reaction. The reaction employed 1-phenyl-1-propyne 2a as the limiting reagent, DFHZ-Tfs 1a as the difluoromethyl carbene precursor, and K 2 CO 3 as the base in trifluorotoluene (PhCF 3 ) at 60 °C ( Table 1). Initially, Fe(TPP)Cl, an effective catalyst for cyclopropanation with DFHZ-Tfs, [14] was tested, but only a trace amount of the desired cyclopropene product 3a was yielded (Table 1, entry 1). However, the yield was improved to 25% using Rh 2 (esp) 2 (entry 2), the optimal catalyst for cyclopropanation with CF 2 HCHN 2 , generated from difluoroethylamine under a continuous-flow system. [16a] jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf We then proceeded to evaluate the catalytic activity of tris(pyrazolyl)borate (Tp X ) coinage metal complexes, [22] which have demonstrated exceptional catalytic activity in triftosylhydrazone-based carbene chemistry. [20] It was observed that Tp Br3 Cu(NCMe) significantly enhanced the yield of product 3a to 81%, whereas almost no desired product was observed with Tp Br3 Ag(thf) (entries 3 and 4). Simple copper salts (e.g., CuI) proved to be ineffective, highlighting the crucial role of bulky Tp X ligand (entry 5). Subsequent experimentation indicated that altering the base and solvent did not enhance the reaction yield (entries 6–9). The impact of carbene precursors on the reaction outcome was found to be dramatic. N -Nosylhydrazone 1b and N -tosylhydrazone 1c (entries 10 and 11) gave much lower product yields due to the faster generation of CF 2 HCHN 2 . [20,23] Table 1 Optimization of the reaction conditions. a 1 1a Fe(TPP)Cl K 2 CO 3 PhCF 3 trace 2 1a Rh 2 (esp) 2 c K 2 CO 3 PhCF 3 25 3 1a Tp Br3 Ag(thf) K 2 CO 3 PhCF 3 n.d. 4 1a Tp Br3 Cu(NCMe) K 2 CO 3 PhCF 3 81 5 1a CuI K 2 CO 3 PhCF 3 16 6 1a Tp Br3 Cu(NCMe) NaH PhCF 3 66 7 1a Tp Br3 Cu(NCMe) DiPEA PhCF 3 n.d. 8 1a Tp Br3 Cu(NCMe) K 2 CO 3 DCM 50 9 1a Tp Br3 Cu(NCMe) K 2 CO 3 Dioxane trace 10 1b Tp Br3 Cu(NCMe) K 2 CO 3 PhCF 3 21 11 1c Tp Br3 Cu(NCMe) K 2 CO 3 PhCF 3 <10 jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf a Conditions (unless otherwise specified): 2 (0.3 mmol), 1a (2.0 equiv.), base (4.0 equiv.), Cat. (10 mol%) in PhCF 3 (5 mL), under N 2 for 24 h. [a] Isolated yield. b Isolated yield. c 1 mol% of Rh 2 (esp) 2 . n.d. = not detected. With the optimised reaction conditions established, the scope and limitations of this cyclopropenation reaction were investigated (Scheme 1A). A variety of internal aryl alkynes bearing electron-withdrawing or electron-donating substituents on the para -, meta - or ortho -positions of the aromatic ring were well tolerated, delivering the desired difluoromethyl cyclopropenes (3b–3k ) in good to high yields. Similarly, 1- propynes with fused and heteroaromatic rings, such as naphthalene, benzofuran, and furan, were readily cyclopropenated with high yields (3l–3n). Notably, steric hindrance exerted a deleterious effect on the cyclopropenation process. For instance, internal alkynes bearing an ortho -substituted phenyl ring (3b) and longer alkyl chains (3o and 3p) were found to be suitable for this cyclopropenation, albeit with slightly lower yields (63–72%). In contrast, only a trace amount of product 3q was detected when using more sterically congested 1,2-diaryl alkyne. It was found that 1,2-dialkyl alkynes also proved to be competent substrates, with cycloadducts 3r and 3s being formed in 84% and 65% yields, respectively. In the standard condition, reactions with symmetrical dialkynes yield a mixture of mono- and bis-cyclopropenation products. Increasing the stoichiometry of DFHZ-Tfs to 4.0 equivalents exclusively affords the bis-cyclopropenation products 3t and 3u in excellent yields. Notably, we were able to isolate mono-cyclopropenation products 3v and 3w in synthesically useful yields by adjusting the ratio of dialkynes and DFHZ-Tfs to 3:1. The facile cyclopropenation of internal alkynes with DFHZ-Tfs encouraged further investigation into the reactivity of terminal alkynes, which were more susceptible to undergo [3+2] cycloaddition with CF 2 HCHN 2 . [13,15a,b] Delightfully, this Cu-catalysed protocol tolerates a wide range of linear, as well as phenyl, ether, ester, and amide-tethered aliphatic terminal alkynes, providing the corresponding CF 2 H-substituted cyclopropenes (3x–3z, 3aa, and 3ab) in decent to excellent yields, thus significantly expanding the scope of this transformation. Scheme 1 Cyclopropenation of alkynes with difluoromethyl carbene. Unless otherwise noted, reactions were performed at 0.3-mmol scale, using 2 equiv. of DFHZ-Tfs 1a, 4 equiv. of K 2 CO 3 and 10 mol% of Tp Br3 Cu(NCMe). a Diynes (0.3 mmol) and 1a (4 equiv.) b Diynes (3 equiv.) and 1a (0.3 mmol). jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf A notable adventage of using alkynes as the limiting reagent is its suitability to late-stage functionalization of complex bioactive molecules (Scheme 1B). The copper-catalysed cyclopropenation reaction demonstrated excellent performance when utilising internal alkynes derived from cholesterol and L-borneol, as well as estrone-derived terminal alkyne, yielding the difluoromethyl cyclopropene products (4a–4c) in substantial yields. This outcome substantiates the prospective utilisation of this methodology for the modification of complex bioactive molecules. To further demonstrate the practical applicability of our protocol, we carried out the cyclopropenation of 2-(prop-1-yn-1-yl)naphthalene with DFHZ-Tfs 1a on an 8 mmol scale, affording the desired product 3l in a slightly lower yield (1.3 g, 71% yield) (Scheme 1C). As mentioned above, cyclopropenes are highly reactive and useful building blocks in organic synthesis. [10] Hence, we performed various downstream reactions leveraging the olefin functionality of cyclopropene 3l. For example, the Pd-catalyzed selective reduction of 3l under hydrogen atmosphere provided the trisubstituted all- cis -cyclopropane 5a with 82% yield. Cyclopropene 3l underwent copper-catalyzed hydroboration with bis(pinacolato)diboron to afford difluoromethyl cyclopropylborate 5b in high yield and diastereoselectivity, providing a functional handle for further boron-based transformations. [24] Furthermore, the Pauson-Khand reaction of 3l with hexacarbonyl-dicobalt complex under heating conditions produced the cyclopentenone-fused CF 2 H-cyclopropane 5c. [25] Finally, the Diels-Alder reaction with 2,3-dimethylbutadiene was successfully performed to obtain the highly complex polycycle 5d in high yield. [26] Notably, all modified products were obtained exclusively as a single diastereomer. Scheme 2 Cyclopropenation of alkynes with perfluoroalkyl triftosylhydrazones. Unless otherwise noted, reactions were performed at 0.3-mmol scale, using 2 equiv. of triftosylhydrazone, 4 equiv. of NaH and 10 mol% of Tp Br3 Cu(NCMe). Next, we sought to extend our developed protocol to the synthesis of perfluoroalkyl cyclopropenes, enabling rapid investigations of structure–activity relationships among multifarious fluorinated cyclopropenes. [2] The formation of the targeted trifluoromethyl cyclopropene 7a was observed through the reaction of trifluoroacetaldehyde-derived triftosylhydrazone (TFHZ-Tfs, 6a) with alkyne 2 under standard conditions; however, the yield was unsatisfactory. As such, we re-optimized the reaction conditions and found that NaH was the optimal base, producing cyclopropene 7a in 94% yield (for details, see Table S2 in Supporting Information). Under the slightly modified conditions, a wide range of electronically differentiated internal and terminal alkynes reacted smoothly with CF 3 - and CF 2 CF 3 -substituted triftosylhydrazones, furnishing corresponding fluoroalkyl cyclopropenes 7b–7p in 73–95% yields. The compatibility of this protocol with a range of functional groups, including alkyl, aryl, trifluoromethoxy, halogen, acetyl, ester, and ether groups, is a testament to its versatility. Furthermore, the length of the perfluoroalkyl chain of triftosylhydrazones had a negligible effect on the reaction outcome, producing heptafluoropropyl (7q), nonafluorobutyl (7r), undecafluoropentyl (7s), tridecafluorohexyl (7t), and heptadecafluorooctyl (7u) cyclopropenes in excellent yields, which are difficult to prepare using existing methods. [11,19] Figure 2. Mechanistic proposal and DFT studies. ΔG, Gibbs free energy change. All energies are in kcal/mol. Distances are in angstroms. Values in parentheses represent NPA charges and the unit is e. To gain insights into the reaction mechanism, density functional theory (DFT) calculations were performed at the SMD(Toluene)-M06/6-31G(d,p)/SDD(Cu, Br) level of theory (see Figure 2 and the Supporting Information for computational details). The calculations were started with difluoromethyl diazomethane IntI generated in situ from DFHZ-Tfs 1a under basic conditions. [14] The process of Tp Br3 Cu-catalysed extrusion of nitrogen from IntI results in the formation of the reactive copper carbene intermediate IntII via transition state TSI, with an activation energy of 14.0 kcal/mol, which is identified as the rate-determining step of the catalytic cycle. Subsequently, copper carbene IntII concertedly attacks alkyne 2a through an early transition state TSII to produce the cyclopropene product 3a, a process with a low energy barrier of 1.4 kcal/mol (Fig. 2A). For comparison, the stepwise cyclopropenation mechanism was also calculated. The computational studies suggest that the electrophilic copper carbene would preferentially attack the more nucleophilic C1 position of 2a (NPA charges: -0.038 e of C1 vs 0.021 e of C2) via a late transition state TSII’, which has 1.4 kcal/mol more energy than the concerted transition state TSII (see Fig. 2B). Consequently, stepwise cyclopropenation is less favorable than concerted cyclopropenation. Conversely, the energy barrier for the competitive concerted [3+2] cycloaddition of alkyne 2a with IntI via transition state TSI’ to give intermediate IntII’ is 25.4 kcal/mol, which is 11.4 kcal/mol higher than that for copper carbene formation via TSI (see Fig. 2B). This finding is in full agreement with the experimental observation that only trace amounts of pyrazole were detected in the reaction conditions employed. Conclusions In summary, a decade after Mykhailiuk’s successful synthesis of CF 2 HCHN 2 , we have achieved the first example of alkyne cyclopropenation with difluoromethyl carbene generated in situ from DFHZ-Tfs. This provides an efficient and direct route to synthetically and medicinally valuable difluoromethyl cyclopropenes. The operationally simple method is applicable to the late-stage modification of bioactive complex molecules and the synthesis of diverse trifluoromethyl and perfluoroalkyl cyclopropenes. DFT computations reveal that the bulky Tp Br3 Cu catalyst facilitates the preferential formation of reactive difluoromethyl copper carbene, enabling concerted cyclopropenation with a modest activation barrier. This finding opens new opportunities for exploring carbene transfer reactions involving unstable CF 2 HCHN 2 . Experimental General procedure for copper-catalyzed cyclopropenation of alkynes with difluoromethyl carbenes: To an oven-dried screw-cap reaction tube equipped with a Teflon-coated magnetic stir bar were added difluoroacetaldehyde N -triftosylhydrazone (0.6 mmol, 2.0 equiv.), K 2 CO 3 (1.2 mmol, 4.0 equiv.), alkyne (0.3 mmol), Tp Br3 Cu(NCMe) (10.0 mol%) and dry PhCF 3 (5 mL) inside a glove box with nitrogen atmosphere. After transfer out of the glove box, the reaction was continued for an additional 24 h at 60 °C. After the reaction completed, the reaction mixture was filtered through a short pad of silica gel with CH 2 Cl 2 as an eluent. After removal of the solvent under vacuum, the residue was purified by flash chromatography on silica gel (using petroleum ether/EtOAc as eluent) to obtain the desired products 3a-3s, 3x-3ab and 4a-4c. Compound 3a : According to the general procedure using difluoroacetaldehyde N -triftosylhydrazone (181.2 mg, 0.6 mmol) and prop-1-yn-1-ylbenzene (34.8 mg, 0.3 mmol) afforded product 3a (43.8 mg, 81% yield) as a colorless liquid. 1 H NMR (500 MHz, CDCl 3 ) δ 7.53-7.51 (m, 2H), 7.43-7.39 (m, 2H), 7.35-7.32 (m, 1H), 5.43 (td, J = 57.0, 5.0 Hz, 1H), 2.34 (s, 3H), 2.10 (q, J = 5.0, 1H). 13 C NMR (151 MHz, CDCl 3 ) δ 129.2, 128.7, 128.6, 128.0, 120.6 (t, J = 240.1 Hz), 108.4 (dd, J = 9.1, 3.0 Hz), 108.0 (dd, J = 10.6, 3.0 Hz), 22.8 (t, J = 30.2 Hz), 11.3. 19 F NMR (565 MHz, CDCl 3 ) δ (-108.45)-(-110.38) (m, 2F). HRMS (ESI) m/z calcd. for C 11 H 10 F 2 Na [M+Na] + 203.0648, found 203.0642. Supporting Information The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.202400xxx. Acknowledgement The research reported in this publication was supported by the National Natural Science Foundation of China (22331004 and 22371035) and the Science and Technology Development Plan Project of Jilin Province, China (20240305092YY and 20230508054RC). References 1. (a) O’Hagana, D. Understanding organofluorine chemistry. An introduction to the C–F bond. Chem. Soc. Rev. 2008 , 37 , 308–319; (b) Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 2018 , 61 , 5822−5880; (b). Nia, C.; Hu, J. The unique fluorine effects in organic reactions: recent facts and insights into fluoroalkylations. Chem. Soc. Rev. 2016 , 45 , 5441–5454. 2. (a) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas. Chem. Rev. 2016 , 116 , 422−518; (b) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 2015 , 58 , 8315–8359; (c) Inoue, M.; Sumii, Y.; Shibata, N. Contribution of organofluorine compounds to pharmaceuticals. ACS Omega 2020 , 5 , 10633–10640. 3. Ogawa, Y.; Tokunaga, E.; Kobayashi, O.; Hirai, K.; Shibata, N. Current contributions of organofluorine compounds to the agrochemical industry. iScience 2020 , 23 , 101467. 4. (a) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J. Organic fluorine compounds: a great opportunity for enhanced materials properties. Chem. Soc. Rev. 2011 , 40 , 3496–3508; (b) Lemoine, K.; Hemon-Ribaud, A.; Leblanc, M.; Lhoste, J.; Tarascon, J.-M.; Maisonneuve, V. Fluorinated materials as positive electrodes for Li- and Na-Ion batteries. Chem. Rev. 2022 , 122 , 14405−14439. 5. For selected reviews, see: (a) Ma, J.-A.; Cahard, D. Asymmetric fluorination, trifluoromethylation, and perfluoroalkylation reactions. Chem. Rev. 2004 , 104 , 6119−6146; (b) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Asymmetric construction of stereogenic carbon centers featuring a trifluoromethyl group from prochiral trifluoromethylated substrates. Chem. Rev. 2011 , 111 , 455–529; (c) Merino, E.; Nevado, C. Addition of CF 3 across unsaturated moieties: a powerful functionalization tool. Chem. Soc. Rev. 2014 , 43 , 6598–6608; (d) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation teactions. Chem. Rev. 2015 , 115 , 826–870; (e) Feng, Z.; Xiao, Y.-L.; Zhang, X. Transition-metal (Cu, Pd, Ni)-catalyzed difluoroalkylation via cross-coupling with difluoroalkyl halides. Acc. Chem. Res . 2018 , 51 , 2264−2278; (f) Ma, X.; Song, Q. Recent progress on selective deconstructive modes of halodifluoromethyl and trifluoromethyl-containing reagents. Chem. Soc. Rev. 2020 , 49 , 9197−9219; (g) Ma, X.; Su, J.; Song, Q. Unconventional transformations of difluorocarbene with amines and ethers. Acc. Chem. Res. 2023 , 5 6 , 592−607. 6. For recent examples, see: (a) Li, M.; Yuan, Y.; Harrison, W.; Zhang, Z.; Zhao, H. Asymmetric photoenzymatic incorporation of fluorinated motifs into olefins. Science 2024 , 385 , 416–421; (b) Campbell, B. M.; Gordon, J. B.; Raguram, E. R.; Gonzalez, M. I.; Reynolds, K. G.; Nava, M.; Nocera, D. G. Electrophotocatalytic perfluoroalkylation by LMCT excitation of Ag(II) perfluoroalkyl carboxylates. Science 2024 , 383 , 279–284; (c) Luo, Y.-C.; Zhang, X. Transition-metal-mediated fluoroalkylation of carbon electrophiles through cross-electrophile couplings. Chin. J. Chem. 2024 , 42 , 3499–3517; (d) Zeng, X.; Li, Y.; Min, Q.-Q.; Xue, X.-S.; Zhang, X. Copper-catalysed difluorocarbene transfer enables modular synthesis. Nat. Chem. 2023 , 15 , 1064–1073; (e) Han J., J Han, J.; Chen, S.; Zhong, T.; He, Y.; Yang, X.; Wang, G.; Zhu, C.; Xie, J. Photoinduced manganese-catalysed hydrofluorocarbofunctionalization of alkenes. Nat. Synth. 2022 , 1 , 475–486; (f) Gao, X.; Ren, X.; Deng, W.; Zhang, X. Copper-catalyzed highly stereoselective hydrodifluoroallylation of cyclopropenes and alkenyl boronates with 3,3-difluoroallyl sulfonium salts. Chin. J. Chem. 2023 , 41 , 3521–3527; (g) Zhang, X.; Nottingham, K. G.; Patel, C.; Alegre-Requena, J. V.; Levy, J. N.; Paton, R. S.; McNally, A. Phosphorus-mediated sp 2 –sp 3 couplings for C–H fluoroalkylation of azines. Nature 2021 , 594 , 217–222. 7. Sap, J. B. I.; Meyer, C. F.; Straathof, N. J. W.; Iwumene, N.; am Ende, C. W.; Trabanco, A. A.; Gouverneur, V. Late-stage difluoromethylation: concepts, developments and perspective. Chem. Soc. Rev. 2021 , 50 , 8214–8247. 8. (a) Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov, E.; Saphier, S. Difluoromethyl bioisostere: examining the “lipophilic hydrogen bond donor” concept. J. Med. Chem. 2017 , 60 , 797–804; (b) Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 2018 , 61 , 5822−5880. 9. Zheng, B.; D’Andrea, S. V.; Sun, L.-Q.; Wang, A. X.; Chen, Y.; Hrnciar, P.; Friborg, J.; Falk, P.; Hernandez, D.; Yu, F.; Sheaffer, A. K.; Knipe, J. O.; Mosure, K.; Rajamani, R.; Good, A. C.; Kish, K.; Tredup, J.; Klei, H. E.; Paruchuri, M.; Ng, A.; Gao, Q.; Rampulla, R. A.; Mathur, A.; Meanwell, N. A.; McPhee, F.; Scola, P. M. Potent inhibitors of hepatitis C virus NS 3 protease: employment of a difluoromethyl group as a hydrogen-bond donor. ACS Med. Chem. Lett. 2018 , 9 , 143–148. 10. (a) Cohen, Y.; Marek, I. Regio- and diastereoselective carbometalation reaction of cyclopropenes. Acc. Chem. Res. 2022 , 55 , 2848–2868; (b) Vicente, R. C–C Bond cleavages of cyclopropenes: operating for selective ring-opening reactions. Chem. Rev. 2021 , 121 , 162–226; (c) Zhu, Z.-B.; Wei, Y.; Shi, M. Recent developments of cyclopropene chemistry. Chem. Soc. Rev. 2011 , 40 , 5534−5563; (d) Rubin, M.; Rubina, M.; Gevorgyan, V. Transition metal chemistry of cyclopropenes and cyclopropanes. Chem. Rev. 2007 , 107 , 3117−3179. 11. (a) Pons, A.; Delion, L.; Poisson, T.; Charette, A. B.; Jubault, P. Asymmetric synthesis of fluoro, fluoromethyl, difluoromethyl, and trifluoromethylcyclopropanes. Acc. Chem. Res. 2021 , 54 , 2969–2990; (b) Decaens, J.; Couve-Bonnaire, S.; Charette, A. B.; Poisson, T.; Jubault, P. Synthesis of fluoro-, monofluoromethyl-, difluoromethyl-, and trifluoromethyl-substituted three-membered rings. Chem. Eur. J. 2021 , 27 , 2935–2962; (c) Dolbier, W. R.; Battiste, M, A. Structure, synthesis, and chemical reactions of fluorinated cyclopropanes and cyclopropenes. Chem. Rev. 2003 , 103 , 1071−1098. 12. (a) Mykhailiuk, P. K. 2,2,2-Trifluorodiazoethane (CF 3 CHN 2 ): a long journey since 1943. Chem. Rev . 2020 , 120 , 12718–12755; (b) Mertens, L.; Koenigs, R. M. Fluorinated diazoalkanes–a versatile class of reagents for the synthesis of fluorinated compounds. Org. Biomol. Chem . 2016 , 14 , 10547–10556; (c) Wang, Y.; Zhang, C.; Li, S.; Liu, L.; Feng, X.; Liu, Z. Transition-metal-catalyzed reactions involving trifluoro diazo compounds and their surrogates. Eur. J. Org. Chem . 2024 , 27 , e202400304; (d) Sivaguru, P.; Bi, X. Fluoroalkyl N -sulfonyl hydrazones: an efficient reagent for the synthesis of fluoroalkylated compounds. Sci. China Chem . 2021 , 64 , 1614–1629; (e) Mykhailiuk, P. K.; Koenigs, R. M. Difluorodiazoethane (CF 2 HCHN 2 ): a new reagent for the introduction of the difluoromethyl group. Chem. Eur. J . 2019 , 25 , 6053–6063. 13. Mykhailiuk, P. K. In situ generation of difluoromethyl diazomethane for [3+2] cycloadditions with alkynes. Angew. Chem. Int. Ed. 2015 , 5 , 6558-6561. 14. Ning, Y.; Zhang, X.; Gai, Y.; Dong, Y.; Sivaguru, P.; Wang, Y.; Bi, X. Difluoroacetaldehyde N -triftosylhydrazone (DFHZ-Tfs) as a bench-stable crystalline diazo ssurrogate for diazoacetaldehyde and difluorodiazoethane. Angew. Chem. Int. Ed . 2020 , 59 , 6473–6481. 15. (a) Mertens, L.; Hock, K. J; Koenigs, R. M.; Fluoroalkyl-substituted diazomethanes and their application in a general synthesis of pyrazoles and pyrazolines. Chem. Eur. J . 2016 , 22 , 9542–9545; (b) Britton, J.; Jamison, T. F. A unified continuous flow assembly-line synthesis of highly substituted pyrazoles and pyrazolines. Angew. Chem. Int. Ed . 2017 , 56 , 8823–8827; (c) Mykhailiuk, P. K.; Kishko, I.; Kubyshkin, V.; Budisa, N.; Cossy, J. Selective 19 F-labeling of functionalized carboxylic acids with difluoromethyl diazomethane (CF 2 HCHN 2 ). Chem. Eur. J. 2017 , 23 , 13279–13283; (d) Hock, K. J.; Mertens, L.; Metze, F. K.; Schmittmann, C.; Koenigs, R. M.; Difluoro-and trifluoro diazoalkanes-complementary approaches in batch and flow and their application in cycloaddition reactions. Green Chem . 2017 , 19 , 905–909; (e) Li, J.; Yu, X. L.; Cossy, J.; Lv, S. Y.; Zhang, H. L.; Su, F.; Mykhailiuk, P. K.; Wu, Y. Synthesis of CF 2 H-Substituted Pyrazolines by [3+2] Cycloaddition between CF 2 HCHN 2 and electron-deficient Alkenes. Eur. J. Org. Chem. 2017 , 2017 , 266–270. 16. (a) Hock, K. J.; Mertens, L.; Koenigs, R. M.; Rhodium catalyzed synthesis of difluoromethyl cyclopropanes. Chem. Commun . 2016 , 52 , 13783-13786; (b) Zhang, X. W.; Hu, W. L.; Chen, S.; Hu, X. G. Cu-catalyzed synthesis of fluoroalkylated isoxazoles from commercially available amines and alkynes. Org. Lett . 2018 , 20 , 860−863. 17. (a) Zeng, J. L.; Chen, Z.; Zhang, F. G.; and Ma, J. A. Direct regioselective [3+2] cycloaddition reactions of masked difluorodiazoethane with electron-deficient alkynes and alkenes: synthesis of difluoromethyl-substituted pyrazoles. Org. Lett. 2018 , 20 , 4562−4565; (b) Zhang, Z. Q.; Zheng, M. M.; Xue, X. S.; Marek, I.; Zhang, F. G; Ma, J. A. Catalytic enantioselective cyclopropenation of internal alkynes: access to difluoromethylated three-membered carbocycles. Angew. Chem. Int. Ed . 2019 , 58 , 18191–18196; (c) Peng, X.; Zhang, F. G; Ma, J. A. Cu-catalysed three-component reaction of aryldiazonium salts with fluorinated diazo reagents and nitriles: access to difluoro- and trifluoromethylated N 1 -aryl-1,2,4-triazoles. Adv. Synth. Catal . 2020 , 362 , 4432–4437; (d) Zhao, C.; Besset, T.; Jubault, P. Ruthenium(II)-catalyzed enantioselective synthesis of 1,2-trans-disubstituted PhSO 2 CF 2 -containing cyclopropanes. Adv. Synth. Catal . 2024 , 366 , 3423–3429. 18. For selected examples of cyclopropanation with trifluoromethyl carbenes, see: (a) Lee, W. C. C.; Wang, D. S.; Zhu, Y.; Zhang, X. P. Iron(III)-based metalloradical catalysis for asymmetric cyclopropanation via a stepwise radical mechanism. Nat. Chem . 2023 , 15 , 1569–1580; (b) Schaus, L.; Das, A.; Knight, A. M.; Jimenez-Osés, G.; Houk, K. N.; Garcia-Borràs, M.; Arnold, F. H; Huang, X. Protoglobin-catalyzed formation of cis -trifluoromethyl-substituted cyclopropanes by carbene transfer. Angew. Chem. Int. Ed . 2023 , 62 , e202208936; (c) Altarejos, J.; Sucunza, D.; Vaquero, J. J.; Carreras, J. Enantioselective copper-catalyzed synthesis of trifluoromethyl-cyclopropylboronates. Org. Lett . 2021 , 23 , 6174–6178; (d) Kotozaki, M.; Chanthamath, S.; Fujii, T.; Shibatomi, K.; Iwasa, S. Highly enantioselective synthesis of trifluoromethyl cyclopropanes by using Ru(II)–Pheox catalysts. Chem. Commun . 2018 , 54 , 5110–5113; (e) Tinoco, A.; Steck, V.; Tyagi, V.; Fasan, R. Highly diastereo- and enantioselective synthesis of trifluoromethyl-substituted cyclopropanes via myoglobin-catalyzed transfer of trifluoromethylcarbene. J. Am. Chem. Soc . 2017 , 139 , 5293−5296; (f) Morandi, B.; Carreira, E. M. Iron-catalyzed cyclopropanation with trifluoroethylamine hydrochloride and olefins in aqueous media: in situ generation of trifluoromethyl diazomethane. Angew. Chem. Int. Ed . 2010 , 49 , 938–941. 19. For selected examples of cyclopropenation with fluoroalkyl carbenes, see: (a) Cui, X. Q.; Zheng, M. M.; Tang, X.; Zhang, Z. Q.; Xue, X. S.; Marek, I.; Zhang, F. G. Dirhodium(II)-catalyzed enantioselective cyclopropenation of internal alkynes with trifluoromethyl carbene. Chem Catal . 2023 , 3 , 100637; (b) Zhang, X.; Ning, Y.; Tian, C.; Zanoni, G.; Bi, X. Asymmetric [2+1] cycloaddition of difluoroalkyl-substituted carbenes with alkenes under rhodium catalysis: Synthesis of chiral difluoroalkyl-substituted cyclopropanes. iScience 2023 , 26 , 105896; (c) Zhou, G.; Shen, X. Synthesis of cyclopropenols enabled by visible-light-induced organocatalyzed [2+1] cyclization. Angew. Chem. Int. Ed . 2022 , 61 , e202115334; (d) Tran, U. P.; Hommelsheim, R.; Yang, Z.; Empel, C.; Hock, K. J.; Nguyen, T. V.; Koenigs, R. M. Catalytic synthesis of trifluoromethyl cyclopropenes and oligo-cyclopropenes. Chem. Eur J . 2020 , 26 , 1254–1257; (e) Morandi, B.; Carreira, E. M. Rhodium-catalyzed cyclopropenation of alkynes: synthesis of trifluoromethyl-substituted cyclopropenes. Angew. Chem. Int. Ed. 2010 , 49 , 4294–4296. 20. For reviews, see: (a) Liu, Z.; Zhang, X.; Sivaguru, P.; Bi, X. Triftosylhydrazone in single-atom skeletal editing. Acc. Chem. Res. 2025 , 58 , 130–149; (b) Liu, Z.; Sivaguru, P.; Zanoni, G.; Bi, X. N -Triftosylhydrazones: a new chapter for diazo-based carbene chemistry. Acc. Chem. Res. 2022 , 55 , 1763–1781; (c) Sivaguru, P.; Pan, Y.; Wang, N.; Bi, X. Who is who in the ccarbene chemistry of N -sulfonyl hydrazones. Chin. J. Chem. 2024 , 42 , 2071–2108. 21. For selected recent examples, see: (a) Zhang, X.; Liu, Z.; Yang, X.; Dong, Y.; Virelli, M.; Zanoni, G.; Anderson, E. A.; Bi, X. Use of trifluoroacetaldehyde N -tfsylhydrazone as a trifluorodiazoethane surrogate and its synthetic applications. Nat. Commun. 2019 , 10 , 284; (b) Li, L.; Ning, Y.; Chen, H.; Ning, Y.; Sivaguru, P.; Liao, P.; Zhu, Q.; Ji, Y.; de Ruiter, G.; Bi, X. Dearomative insertion of fluoroalkyl carbenes into azoles leading to fluoroalkyl heterocycles with a quaternary center. Angew. Chem. Int. Ed . 2024 , 63 , e202313807; (c) Yang, Y.; Song, Q.; Sivaguru, P.; Liu, Z.; Shi, D.; Tian, T.; de Ruiter, G.; Bi, X. Controllable skeletal and peripheral editing of pyrroles with vinylcarbenes. Angew. Chem. Int. Ed . 2024 , 63 , e202401359; (d) He, C.; Song, W.; Wei, D.; Zhao, W.; Yu, Q.; Tang, J.; Ning, Y.; Murali, K.; Sivaguru, P.; de Ruiter, G.; Bi, X. Rhodium-catalyzed asymmetric cyclopropanation of indoles with N -triftosylhydrazones. Angew. Chem. Int. Ed . 2024 , 63 , e202408220; (e) Liu, S.; Yang, Y.; Song, Q.; Liu, Z.; Sivaguru, P.; Zhang, Y.; de Ruiter, G.; Anderson, E. A.; Bi, X. Halogencarbene-free Ciamician-Dennstedt single-atom skeletal editing. Nat. Commun . 2024 , 15 , 9998; (f) Liu, S.; Yang, Y.; Song, Q.; Liu, Z.; Lu, Y.; Wang, Z.; Sivaguru, P. Bi, X. Tunable molecular editing of indoles with fluoroalkyl carbenes. Nat. Chem . 2024 , 16 , 988–997; (g) Zhang, X.; Song, Q.; Liu, S.; Sivaguru, P.; Liu, Z.; Yang, Y.; Ning, Y.; Anderson, E. A.; de Ruiter, G.; Bi, X. Asymmetric dearomative single-atom skeletal editing of indoles and pyrroles. Nat. Chem . 2025 , 17 , doi.org/10.1038/s41557-024-01680-0. 22. Muñoz-Molina, J. M.; Belderrain, T. R.; Pérez, P. J. Trispyrazolylborate coinage metals complexes: structural features and catalytic transformations. Coord. Chem. Rev . 2019 , 390 , 171–189. 23. (a) Liu, Z.; Babu, K. R.; Wang, F.; Yang, Y.; Bi, X. Influence of sulfonyl substituents on the decomposition of N -sulfonylhydrazones at room temperature. Org. Chem. Front . 2019 , 6 , 121–124; (b) Liu, Z.; Li, Q.; Liao, P.; Bi, X. 2017. Silver-catalyzed [2+1] cyclopropenation of alkynes with unstable diazoalkanes: N -nosylhydrazones as room-temperature decomposable diazo surrogates. Chem. Eur. J. 2017 , 23 , 4756–4760. 24. Augustin, A.U.; Di Silvio, S.; Marek, I. Borylated cyclopropanes as spring-loaded entities: access to vicinal tertiary and quaternary carbon stereocenters in acyclic systems. J. Am. Chem. Soc . 2022 , 144 , 16298–16302. 25. Escorihuela, J.; Sedgwick, D. M.; Llobat, A.; Medio-Simón, M.; Barrio, P.; Fustero, S. Pauson–Khand reaction of fluorinated compounds. Beilstein J. Org. Chem . 2020 , 16 , 1662–1682. 26. Lou, Y.; Horikawa, M.; Kloster, R. A.; Hawryluk, N. A.; Corey, E. J. A new chiral Rh(II) catalyst for enantioselective [2+1]-cycloaddition. Mechanistic implications and applications. J. Am. Chem. Soc . 2004 , 126 , 8916–8918. Manuscript received: XXXX, 2024 Manuscript revised: XXXX, 2024 Manuscript accepted: XXXX, 2024 Version of record online: XXXX, 2024 jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf Left to Right: (TOP) Yong Yang, Paramasivam Sivaguru, Qingmin Song, Zhaohong Liu, (Bottom) Karunanidhi Murali, Yong Ji, Wei Song, Jacek Mlynarski, and Xihe Bi Entry for the Table of Contents Copper-Catalyzed Cyclopropenation of Alkynes with Difluoromethyl Carbene Yong Yang, a Paramasivam Sivaguru , a Karunanidhi Murali, a Qingmin Song, a Zhaohong Liu, * ,a Yong Ji, a Wei Song, a Jacek Mlynarski, b and Xihe Bi * ,a,c Chin. J. Chem. 2024 , 42 , XXX—XXX. DOI: 10.1002/cjoc.202400XXX An unprecedented cyclopropenation of alkynes with difluoromethyl carbene has been achieved through the combination of difluoroacetaldehyde triftosylhydrazones (DFHZ-Tfs) and copper catalysis, providing direct access to a variety of difluoromethyl cyclopropenes with high yields. This one-step protocol has also proven to be applicable to the late-stage modification of complex molecules and the synthesis of diverse perfluoroalkyl cyclopropenes. Information & Authors Information Version history V1 Version 1 06 February 2025 Peer review timeline Published Chinese Journal of Chemistry Version of Record 24 Apr 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Chinese Journal of Chemistry Keywords alkynes copper catalysis cyclopropenation difluoromethyl carbenes difluoromethyl cyclopropenes triftosylhydrazone Authors Affiliations Yong Yang Northeast Normal University School of Chemistry View all articles by this author Paramasivam Sivaguru 0000-0003-2225-0054 Northeast Normal University School of Chemistry View all articles by this author Qingmin Song Northeast Normal University School of Chemistry View all articles by this author Zhaohong Liu Northeast Normal University School of Chemistry View all articles by this author Yong Ji Northeast Normal University School of Chemistry View all articles by this author Wei Song Northeast Normal University School of Chemistry View all articles by this author Karunanidhi Murali Northeast Normal University School of Chemistry View all articles by this author Jacek Mlynarski 0000-0002-1794-306X Polish Academy of Sciences View all articles by this author Xihe Bi 0000-0002-6694-6742 [email protected] Northeast Normal University School of Chemistry View all articles by this author Metrics & Citations Metrics Article Usage 549 views 271 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Yong Yang, Paramasivam Sivaguru, Qingmin Song, et al. 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