Ring-Restructuring of gem-Difluorocyclopropanes: Diverse Access to Four- to Nine-Membered Ring Skeletons

Abstract

Since their first synthesis by Atkinson in 1952, gem-difluorocyclopropanes (gem-DFCPs) have become indispensable building blocks in both organic synthesis and medicinal chemistry. These fluorinated three-membered carbocycles exhibit remarkable reactivity patterns due to their inherent ring strain and the electronic effects of fluorine substitution, which facilitate diverse ring-editing transformations. This comprehensive review systematically examines recent advancements in gem-DFCPs-mediated ring restructuring reactions, including their transformation into four-, five-, six-, and extended-membered ring systems. Particular emphasis is placed on elucidating the underlying reaction mechanisms, stereochemical control elements, and practical synthetic applications. Through this analysis, we aim to provide a structured framework that guides future research in the rapidly expanding field of fluorinated cycloaddition chemistry.

Keyword

gem-difluorocyclopropanes - fluorinated cycloaddition chemistry

Introduction

Fluorine, with its exceptional electronegativity (4.0) and atomic radius (1.47 Å) comparable to that of hydrogen (1.2 Å), imparts unique chemical properties to fluorinated compounds.[1] [2] The introduction of fluorine atoms into organic molecules changes the structure and electronic properties of the compounds, causing profound changes in physicochemical properties. Therefore, the fluorinated ring systems, including fluorobenzenes and their derivatives, gem-difluorocyclopentanones, and gem-difluorocyclobutanes, have become ubiquitous structural motifs in natural products and indispensable pharmacophores in medicinal chemistry ([Scheme 1]).[3] [4] [5] [6] [7] For instance[8] when a fluorine atom replaces the natural hydroxyl group at the 2'-position of the deoxycytidine sugar ring of gemcitabine, a pyrimidine-based drug used for cancer treatment, the therapeutic effect will be significantly enhanced. This fluorine substitution confers resistance to degradation by cytidine deaminase, thereby substantially prolonging the drug's half-life. Moreover, the fluorine atom enables a dual antitumor mechanism: it inhibits ribonucleotide reductase, disrupting the supply of DNA synthesis precursors, while its active metabolites are incorporated into DNA strands, leading to termination of DNA elongation. Such a synergistic action markedly enhances the antitumor activity of the drug.

Scheme 1 Representative examples of fluorine-containing drug molecules.

On the other hand, gem-DFCPs have emerged as particularly valuable synthetic intermediates due to their unique structural features: the presence of two fluorine atoms on the same carbon atom induces substantial ring strain compared with their nonfluorinated cyclopropane counterparts.[9] [10] [11] [12] [13] [14] This inherent strain not only enhances their reactivity but also facilitates selective C–C bond cleavage, allowing the construction of diverse fluorinated architectures. Consequently, the [3 + n]-cycloaddition chemistry of gem-DFCPs has attracted considerable attention in recent years, offering versatile strategies for the synthesis of complex fluorinated molecules.

The chemistry of gem-difluorocyclopropanes (gem-DFCPs) has evolved significantly since their first synthesis in 1953 by Tarrant et al, who successfully prepared gem-DFCP via the Zn-mediated reaction of 1,3-dibromo-1,1-difluoro-2-methylbutane.[15] Afterward, Taguchi et al developed the Michael-induced ring closure strategy, where activated alkenes containing BrCF₂ groups were utilized in reactions with nucleophiles, and provided a unique route for the highly enantioselective synthesis of gem-DFCPs ([Fig. 1]).[16] Entering the 21st century, the emergence of new reagents greatly propelled the field forward: Zhu et al introduced TFDA (FSO₂CF₂CO₂SiMe₃) in 2000 ([Fig. 1]),[17] which was later followed by the development of MFDA (FSO₂CF₂CO₂Me) in 2012.[18] These reagents enabled efficient transformations of electron-deficient substrates such as acrylates. In 2011, Wang et al systematically developed the Ruppert–Prakash reagent (TMSCF₃/NaI) system ([Fig. 1]),[19] which has since become the most widely used method due to its excellent functional group compatibility (e.g., tolerance to Boc-amines and esters) and scalability. That same year, Li et al also reported the more reactive Me₃SiCF₂Br/TBAB system ([Fig. 1]).[20] More recently, to tackle the challenges posed by electron-deficient alkenes, Goswami et al pioneered a new cobalt-catalyzed TMSCF₃ strategy in 2017 ([Fig. 1]).[21] Developed across different periods, these methods together constitute a versatile toolkit applicable to a broad spectrum of substrate types, strongly facilitating the exploration and application of such fluorinated structures in various cutting-edge research areas.

Fig. 1 Synthesis of gem-difluorocyclopropanes.

Over the past seven decades, these unique fluorinated cyclopropanes have become the focus of extensive synthetic and mechanistic investigations.[17] [22] [23] [24] The field has witnessed remarkable progress, evolving from early studies of homocyclization and isomerization processes[25] to contemporary breakthroughs in transition metal-catalyzed ring-opening transformations.[17] [26] A pivotal moment in the field occurred in 2003 with Dolbier and Battiste's comprehensive review, which systematically cataloged the structural features, synthetic methods, reactivity patterns, and applications of gem-DFCPs up to 2002. The field continued to advance, as evidenced by Zhu and colleagues' review (2023), which focused specifically on transition metal-catalyzed cross-coupling reactions of gem-DFCPs.[17] More recently, in 2024, Li's group contributed another significant review that highlighted innovative transformations of gem-DFCPs via double C–F bond cleavage, accompanied by in-depth analyses of design principles, selectivity control, and mechanistic insights.[26]

Despite these comprehensive reviews, there remains a notable limitation in the systematic analysis of ring-restructuring reactions of gem-DFCPs. While transition metal-catalyzed ring-opening reactions have dominated recent research efforts, the emerging field of ring-editing transformations has gained considerable momentum and warrants dedicated attention. This review, therefore, aims to address this limitation by providing a comprehensive synthesis of recent advancements in the ring-restructuring chemistry of gem-DFCPs. Through detailed mechanistic analyses and systematic classification of reaction pathways, we aim to provide a solid foundation for future innovations in this rapidly evolving field of fluorinated cyclopropane chemistry.

Synthesis of Five-Membered Rings from gem-Difluorocyclopropanes

Five-membered ring architectures represent a privileged structural motif that is widely distributed in natural products,[27] [28] [29] biologically relevant molecules,[3] [30] [31] and functional materials.[32] [33] [34] Of particular importance, functionalized five-membered carbocyclic frameworks serve as essential core units in a diverse array of biologically relevant compounds.[35] [36] [37] [38] [39] [40] [41] Recent advances in synthetic methodologies have highlighted the remarkable utility of gem-DFCPs as versatile building blocks, enabling efficient construction of these five-membered ring systems through innovative ring-opening and ring-recombination strategies.

Synthesis of gem-Difluorocyclopentanes

Zeng and Xia developed an Rh-catalyzed [3 + 2] cycloaddition reaction between gem-DFCPs and internal olefins, enabling the efficient synthesis of gem-difluorinated cyclopentanes ([Scheme 2]).[42] The reaction mechanism starts with the conversion of the Rh precursor [Rh(C₂H₄)₂Cl]₂ into the tetra-coordinated cationic Rh species 4 in the presence of BINAP, AgBF₄, and an excess of olefinic substrate 2. Subsequent oxidative addition of gem-DFCPs 1 to the active Rh complex 5 generates the key gem-DFMCB intermediate 6. In the presence of excess olefinic substrate 2, the intermediate 6 coordinates to 2, and the coordinating alkene ligand migrates and inserts itself into the cross-cyclic ring from the less sterically hindered side of 7, followed by the formation of the six-membered cross-ring intermediate 8. Finally, the C(benzyl)-C(benzyl) bond undergoes reductive elimination, yielding the gem-difluorinated cyclopentane product 3 and regenerating the rhodium catalyst 5 for the subsequent catalytic cycle.

Scheme 2 Synthesis of gem-difluorocyclopentane via [3 + 2] ring-loading-addition reactions.

Archer et al reported a novel [3 + 2] radical cascade reaction, catalyzed by a newly discovered cationic sulfur-centered radical, promoting the transformation of 9 with olefins 10 to give gem-difluoro-2-vinylcyclopentanes 11 ([Scheme 3]).[43] The proposed reaction mechanism for this reaction involves several key steps: first, the single-electron oxidation of the thiol precursor 12 generates the reactive thiyl radical 13, which is rapidly captured by 9 to form intermediate 15 through a ring-opening/radical addition sequence. The reaction of intermediate 15 with 10 leads to the formation of intermediate 16. This is followed by a 5-exo-trig cyclization occurs, releasing the product 11 in a thermodynamically favored trans configuration and regenerating the thiyl radical 13. Finally, the catalytic cycle is completed through the reduction of the dicationic dimer 14 by Ir^II, regenerating both the active radical species 13 and the thiol precursor 12.

Scheme 3 Synthesis of gem-difluorovinyl cyclopentanes via [3 + 2] radical cascade reactions.

Synthesis of gem-Difluorocyclopentene

Cyclopentene frameworks are widely used in both synthetic and naturally occurring bioactive molecules. In 2014, Orr et al made a significant contribution to the field by reporting a novel thermal rearrangement of ethyl3-(2,2-difluoro-3-phenylcyclopropyl)acrylate 17 ([Scheme 4]).[44] The researchers elucidated the stereospecific nature of this transformation through meticulous ¹⁹F NMR spectroscopic analysis, and showed that the observed stereochemical results were determined by competitive stereoisomerization processes of the cyclopropane precursors prior to the vinyl cyclopropane rearrangement. Their systematic investigation revealed different mechanistic pathways for the geometric isomers: while trans-17 underwent direct rearrangement to yield 19, its cis counterpart 18 required initial isomerization to the trans configuration before proceeding to the final product.

Scheme 4 Synthesis of gem-difluorocyclopentenes by thermal rearrangement reaction.

Building upon their previous findings, the same group subsequently developed an atom-economical synthetic route to novel gem-difluorocyclopentenes 21 under practical reaction conditions (100°C), supported by advanced computational studies of the reaction mechanism ([Scheme 5]).[45] In this reaction, difluorovinylcyclopropane derivatives 20 served as key precursors, which were efficiently transformed to the target products 21 through a well-defined vinylcyclopropane rearrangement (VCPR) pathway. This methodology not only demonstrated excellent atomic efficiency but also provided a practical and scalable route to access these valuable fluorinated structures.

Scheme 5 Synthesis of gem-difluorocyclopentenes via the VCPR thermal rearrangement pathway. VCPR, vinyl cyclopropane rearrangement.

Zhang and Gevorgyan have reported a significant advancement in this field. They developed an innovative hydroalkenylation/diastereoselective rearrangement cascade for the construction of difluorocyclopentene scaffolds ([Scheme 6]).[46] Their systematic investigation revealed that gem-DFCPs 22 bearing phenyl and thioether substituents readily undergo hydroalkenylation with alkenes 23, followed by a facile ring-expansion cycloisomerization to afford gem-difluorocyclopentenes 24 in good yields. This methodology proved particularly effective for the synthesis of tricyclic systems, as demonstrated by the successful preparation of compounds 24c and 24e from indene derivatives. Notably, the rearrangement process exhibits remarkable diastereoselectivity, exclusively generating cis-substituted cyclopentenes, highlighting the synthetic utility of this transformation for the stereocontrolled construction of complex fluorinated architectures.

Scheme 6 Synthesis of gem-difluorocyclopentene via a hydroalkenylation/diastereoselective rearrangement cascade.

Furthermore, the domino reaction, involving the in situ generation and subsequent transformation of gem-DFCPs, was developed. Aono et al reported an efficient nickel-catalyzed reaction between silyl dienol ethers 25, derived from α,β-unsaturated ketones, and trimethylsilyl gem-difluoro-2-(fluorosulfonyl)acetate ([Scheme 7]).[47] This innovative reaction proceeds through a two-step sequence: it first enables the formation of siloxydifluorovinylcyclopropanes 27 at the electron-rich alkene moiety, which subsequently undergoes a smooth vinylcyclopropane–cyclopentene rearrangement to furnish the silyl gem-difluorocyclopent-1-en-1-yl ethers 26 in excellent yield. This cascade process not only demonstrates the synthetic versatility of gem-DFCPs but also provides a streamlined approach to accessing valuable fluorinated cyclopentene derivatives.

Scheme 7 Synthesis of silyl gem-difluorocyclopentenyl ethers via VCP rearrangement reaction. VCP, vinyl cyclopropane.

The same research group also developed an organocatalytic approach for the synthesis of 1-(tert-butyldimethylsilyloxy)-5,5-difluorocyclopent-1-en e 31 via the decomposition of diene 29 ([Scheme 8]).[48] This methodology employs naphthalene-1,8-diamine 32 as an organocatalyst for the generation of gem-difluorocarbene intermediates. The resulting carbene species are chemoselectively added to silyl dienol ethers to form intermediates 30, which subsequently undergo a vinylcyclopropane rearrangement to yield 31. This metal-free process shows remarkable versatility, accommodating a wide range of substrates 29 bearing either electron-donating or electron-withdrawing groups at both terminal (R¹) and internal (R²) positions, and yielding the corresponding products 31a–h in excellent yields. In particular, the methodology proved effective for more complex substrates, as demonstrated by the successful transformation of a cyclohexene-containing silyl dienol ether to the bicyclic product 31g in 66% yield.

Scheme 8 Synthesis of 5,5-difluorocyclopent-1-en-1-ylsilyl ethers via VCP rearrangement reactions. VCP, vinyl cyclopropane.

Synthesis of Cyclopent-2-en-1-ones

Cyclopent-2-en-1-ones bearing various substituents on the ring are valuable building blocks in organic synthesis. A domino reaction was developed and proved to provide an efficient access to cyclopent-2-en-1-ones via the key gem-DFCP intermediates. In 2016, Song and co-workers reported a catalytic difluorocyclopropanation of enolizable ketones 33 by using TMSCF₂Br as a unique difluorocarbene source. The in situ generated siloxydifluorocyclopropanes 36 were used for the synthesis of gem-difluorocyclopentenone 35 ([Scheme 9]).[49] This process, facilitated by copper or silver, generated metal difluorohomoenolates, which then underwent intramolecular addition and elimination to efficiently yield 35.

Scheme 9 Synthesis of gem-difluorocyclopentenone by a ring-opening addition-elimination reaction.

A plausible reaction mechanism for the formation of α-ene-difluorocyclopentanone 35 can be proposed as follows: First, the reaction of 33 with Br-activated TMSCF₂Br produces intermediate 36 through catalytic enolization and difluorocyclopropanation. Treatment of 36 with CuCl, assisted by a halide anion, forms copper alkoxide 38, which is then converted to copper difluorohomoenolate 39 via β-carbon elimination. The coordination of the copper in 39 then shifts from oxygen to sulfur to give the intermediate 40. This intermediate underwent addition-elimination (via 41) to afford 35 as the final product ([Scheme 9]).

In addition, Fuchibe et al discovered that silyl dienol ethers 42, derived from α,β-unsaturated ketones, underwent proton-sponge-catalyzed cyclopropanation with trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate in a regioselective manner, leading to 1,1-difluoro-2-siloxy-2-vinylcyclopropanes 43 in good yields ([Scheme 10]).[50] These cyclopropanes 43 were subsequently subjected to fluoride-ion-catalyzed ring-opening to produce 1-fluorovinyl vinyl ketones 44 (i.e., Nazarov precursors). Treatment of these precursors with Me₃Si⁺B(OTf)₄ ⁻ regioselectively promoted the Nazarov cyclization to produce the intermediate 45. The rate and regioselectivity of this cyclization were significantly enhanced by the presence of the fluoro substituent, enabling the efficient synthesis of biologically promising α-fluorocyclopentenone derivatives 46.

Scheme 10 Synthesis of gem-difluorocyclopentenones via ring opening and Nazarov cyclisation reactions.

Synthesis of Pyrroles

Fluoropyrroles represent a crucial structural motif in numerous pharmacologically active compounds.[51] [52] [53] Yang et al developed a Brønsted acid-mediated regioselective ring-opening reaction of 47 with nitrile derivatives 48, leading to the synthesis of fluoropyrroles 49 ([Scheme 11]).[54] Their mechanistic investigation revealed that the reaction proceeds through the protonation of gem-difluorocyclopropyl ketone 50, followed by partial ring opening to generate intermediate 51. This protonation step facilitates the selective cleavage of the proximal C–C bond, as the resulting carbocation is stabilized by the adjacent fluorine atoms. Subsequent nucleophilic attack by acetonitrile and intramolecular cyclization forms the five-membered ring intermediate 52. The final product 49 is obtained through a dehydrofluorination process followed by the rearrangement of intermediate 52.

Scheme 11 Reaction of gem-difluorocyclopropyl ketones with nitriles to form 2-fluoropyrroles.

In a recent significant advancement, Wu et al reported a novel ligand-controlled regioselective ring-opening/defluorocyclization of gem-DFCPs with enaminones 53 ([Scheme 12]).[55] This palladium-catalyzed transformation demonstrates remarkable selectivity in synthesizing structurally diverse pyrroles 55 and 56 through the strategic use of different phosphine ligands. The methodology exhibits broad substrate scope, delivering various pyrrole derivatives in moderate to excellent yields.

Scheme 12 Synthesis of pyrroles via ring-opening/defluorocyclisation reactions.

Mechanistic studies revealed that the catalytic cycle initiates with the oxidative addition of strained gem-DFCPs to Pd⁽⁰⁾, generating palladium complex 57. Subsequent β-F elimination produces the key allyl-Pd^(II) intermediate 58. The reaction pathway then diverges based on the steric properties of the phosphine ligand: (1) when employing the sterically demanding QPhos ligand, N-coordination with enaminone 53 forms intermediate 59; (2) with the less hindered XPhos ligand, intermediate 60 is generated instead. Both pathways proceed through inner-sphere 3,3'-reductive elimination, regenerating the catalyst and yielding either branched fluoroalkene 61 or linear fluoroalkene 62. These intermediates then undergo annulation/tautomerization sequences to afford the final pyrrole products 55 and 56, respectively.

Continuing interest has been paid to the development of novel synthetic methods using gem-DFCPs. In this context, Liu et al have developed a Pd-IPent-catalyzed selective ring-opening deprotonation annulation reaction of gem-DFCPs with enamides 64 to efficiently construct multisubstituted N–H pyrrole derivatives 65 by selective cleavage of the C₁–C₃ bond, two C–F bonds, and the C–N bond ([Scheme 13]).[56] The reaction proceeds via oxidative addition of gem-DFCPs over a Pd⁽⁰⁾ catalyst to form the palladium cyclic intermediate 66, which is subsequently coordinated with deprotonated enamides 64 and substance 67 to form the bis(η ¹-allyl)palladium intermediate 71. Elimination by 3,3́-reduction generates the monofluorinated intermediate 72, which then undergoes intramolecular nucleophilic substitution and tautomerization to produce the N–Ac pyrrole 74. After the base-assisted deacetylation reaction, N–H pyrrole products 75 were obtained in good to excellent yields.

Scheme 13 Pd-IPent-catalyzed ring-opening defluorinative annulation reaction.

Synthesis of Furans

Furan derivatives represent a versatile class of heterocyclic compounds that possess diverse physicochemical properties, enabling their widespread applications across various fields, including medicinal chemistry, photochemistry, and electrochemistry.[58] [59] In a notable contribution to furan synthesis, Xu et al discovered that gem-difluorocyclopropyl aryl ketones 76 undergo a unique ring-opening/cyclization sequence in the presence of anhydrous MgI₂, leading to complete defluorination and subsequent formation of furan derivatives 77 ([Scheme 14]).[60] This transformation proceeds through a sophisticated mechanism involving multiple iodide-mediated steps. First, the nucleophilic attack of the iodide ion on intermediate 78 triggers the ring-opening to generate the enol intermediate 79. Subsequent elimination of a fluorine atom yields the enone intermediate 80, followed by β-elimination of a second fluoride ion to form the allenic intermediate 81. In the absence of imine, the reaction pathway diverges through an electrophilic activation by molecular iodine (I₂) of the enone intermediate 81 to give the intermediate 82. The 83 subsequently converts to intermediate 84, leading to the final iodofuran product 77 through a deprotonation process.

Scheme 14 MgI₂-mediated cycloaddition to access furans.

Moreover, Sugiishi et al demonstrated that the synthesis of 3-fluoro-2,5-disubstituted furans 85 from gem-difluorocyclopropyl ketones 84 could be efficiently achieved using trifluoro methanesulfonic acid (CF₃SO₃H) via a ring expansion process, facilitated by the activation of the carbonyl group in the starting material ([Scheme 15]).[61] [Scheme 15] illustrates a plausible mechanism for this transformation. Initially, CF₃SO₃H coordinates with the oxygen atom of the carbonyl group in compound 84, forming the activated intermediate 86. This is followed by a ring-opening reaction, which generates the benzylic carbocation intermediate 87. Subsequently, the oxygen atom of the enol then attacks the carbocation, leading to the formation of intermediate 88 through intramolecular cyclization. Finally, deprotonation and aromatization close the reaction, yielding the desired fluorofuran product 85.

Scheme 15 Synthesis of 3-fluoro-2,5-disubstituted furans by ring expansion of gem-difluorocyclopropyl ketones.

Lv et al developed an efficient catalytic system for the synthesis of diverse furan derivatives 90 from readily accessible gem-DFCPs and ketones 89, utilizing sterically unencumbered Pd catalysts ([Scheme 16]).[62] The mechanistic investigation revealed a well-defined reaction pathway. The catalytic cycle was initiated by the oxidative addition of gem-DFCPs to Pd⁽⁰⁾, accompanied by C–C bond activation and C–F bond cleavage, to generate the crucial allyl-Pd^(II) complex 91. This intermediate then underwent a transmetalation reaction with enol 97, which was generated in situ through base-mediated deprotonation of ketone 89, forming the key bis(η ¹-allyl) intermediate 93 along with its isomerization product 94. The sterically demanding NHC ligand facilitates the subsequent reductive elimination of 93, yielding the branched product 95 while regenerating the Pd⁽⁰⁾ catalyst. The final furan product 90 was formed through a base-mediated sequence involving enolization, nucleophilic substitution, and rearomatization, which was promoted by the less sterically hindered Pd catalyst system. This elegant methodology, enabled by precise control of the coordination environment and optimization of reaction parameters (including base selection and reaction time), allowed for the selective synthesis of both β-monofluorinated alkenes and their corresponding furan derivatives through controlled C–F bond cleavage.

Scheme 16 Synthesis of furans from gem-DFCPs and ketones. gem-DFCPs, gem-difluorocyclopropanes.

gem-DFCP diesters have emerged as novel donor–acceptor cyclopropanes, demonstrating remarkable reactivity in [3 + 2] cycloaddition reactions with a wide range of aldehydes and ketones.[63] [64] [65] [66] In this context, Liu et al pioneered the use of gem-difluoro substituents as an unconventional donor group for activating cyclopropane substrates 98 in catalytic cycloaddition reactions ([Scheme 17]).[67] This innovative approach enables the efficient assembly of various densely functionalized gem-difluorotetrahydrofuran skeletons 100 in high yields under mild reaction conditions. The proposed mechanism involves initial coordination with AlCl₃ to generate intermediate 101, followed by an S_N2 nucleophilic attack of aldehyde 99 on C₁ of 101 to produce intermediate 102. Subsequent rotation of the C₁–C₃ bond and intramolecular cyclization of 102, accompanied by the dissociation of AlCl₃, ultimately affords the final product 100 through the process of generation and transformation of intermediate 103.

Scheme 17 Synthesis of gem-difluorotetrahydrofuran by [3 + 2] cycloaddition.

Synthesis of Pyrazoles

Qian et al successfully developed a novel Pd/NHC-catalyzed reaction between hydrazones 104 and gem-DFCPs, enabling the synthesis of two distinct types of pyrazoles 105 and 106 through a defluorinated allylation/annulation cascade reaction ([Scheme 18]).[68] This innovative approach demonstrated remarkable regioselectivity, allowing for the specific incorporation of different carbon atoms from the gem-DFCPs into the pyrazole ring.

Scheme 18 Synthesis of pyrazoles via defluorinated chimeric allylation/chimeric cascade reactions.

The proposed mechanism involves the initial oxidative addition of the Pd⁽⁰⁾ catalyst into the gem-DFCP ring, facilitating C–C bond activation and subsequent C–F bond cleavage to generate the allyl-Pd^II complex 66. Subsequent N-coordination and deprotonation of the hydrazones lead to the formation of bis(η-allyl) intermediates 108 and 109. For aryl hydrazones, intermediate 108 undergoes a Pd/NHC-mediated inner-sphere 3,3'-reductive elimination, yielding the E-linear products 95. In contrast, aldehyde hydrazones (R² = H) follow a distinct pathway, where Pd-assisted intramolecular defluorination/annulation/tautomerization affords pyrazoles 105. Interestingly, alkyl hydrazones preferentially undergo 3,3'-reductive elimination through an alternative regioisomeric pathway, producing branched products 110. Similarly, for aldehyde hydrazones (R² = H), an analogous Pd-assisted intramolecular defluorination/annulation/tautomerization sequence leads to pyrazole product 106, with the C₂ and C₃ atoms of the gem-DFCPs being selectively incorporated into the pyrazole ring.

Synthesis of Six-Membered Rings from gem-difluorocyclopropanes

Six-membered rings represent a ubiquitous structural motif widely found in various bioactive natural products, pharmaceutical compounds, and functional materials.[69] [70] Recent advances in synthetic methodology have demonstrated that these crucial six-membered ring structures can be efficiently constructed through gem-DFCPs rearrangement and ring expansion reactions.

In 2020, Ahmed et al presented a novel palladium-catalyzed gem-difluorinated cyclopropane alkynylation reaction, which proceeds via C–C bond activation and C–F bond cleavage, followed by C–C coupling. This method operated under mild reaction conditions and demonstrated broad substrate compatibility, enabling both 1,1-disubstituted and complex-molecule-modified gem-difluorinated cyclopropanes to react smoothly with alkynes 114, yielding a diverse array of valuable aromatic compounds 115 ([Scheme 19]).[71] A plausible reaction mechanism, as illustrated in [Scheme 19], was proposed. The process begins with the activation of a C–C bond in the presence of a palladium catalyst and a fluorinated substrate, forming intermediate 57. Next, β-F elimination from intermediate 57 generates the π-allyl palladium complex 58, which then reacts with alkynes to produce intermediate 116. Through C–C bond elimination, monofluorinated enynes 117 are formed, releasing the palladium catalyst for further catalytic cycles. Isomerization of the skipped enyne 118 leads to the formation of the enallene intermediate 120. Finally, intramolecular C–H bond activation and 6π-electron electrocyclization afford the desired product 115.

Scheme 19 Palladium-catalyzed alkynylation of gem-DFCPs. gem-DFCPs, gem-difluorocyclopropanes.

In the same year, Liu et al discovered that the defluorinated ring-opening indolylation of siloxydifluorocyclopropane 121 with indoles 122 could be catalyzed by AgBF₄, yielding α-fluoro-β-indolylacetone 123. Subsequent cyclization of 123 in the presence of trifluoroacetic anhydride (TFAA) in toluene at room temperature afforded carbazoles 124 ([Scheme 20]).[72] A plausible mechanism was proposed for this transformation. The process begins with Ag(I)-mediated defluorinated ring-opening indolylation of 121 and 122, involving the formation of an allyl cation intermediate 125, followed by a Friedel–Crafts reaction to produce α-fluoro-β-indolylacetone 123. Next, acylation at the C-3 position of the indole ring in 123 by TFAA generates the 3-trifluoroacetylindole iminium intermediate 126, which isomerizes into the enamine intermediate 127. Intramolecular nucleophilic addition of the enamine onto the TFAA-activated keto carbonyl in 127 then forms intermediate 129 via 128. Finally, driven by aromatization, intermediate 129 undergoes sequential hydrolysis and elimination of both CF₃CO₂H and HF to yield carbazole 124 as the final product. Very recently, Fuchibe et al reported the synthesis of 2-(1,1-difluoroethyl)-2H-1,3-benzoxazines 132 through the regioselective ring-opening of aryloxy-1,1-difluorocyclopropanes 130, followed by a Friedel–Crafts-type ring-closing reaction ([Scheme 21]).[73] The reaction begins with the treatment of 130 with trifluorocarboxylic acid, leading to the regioselective cleavage of the C–C bond at the distal end of the CF₂ group via protonation. This step generates the corresponding oxocarbonylium ion intermediate 131, which undergoes nucleophilic attack with nitriles, followed by Friedel − Crafts-type ring closure to afford 2-(1,1-difluoroethyl)benzoxazines 132. Under optimized conditions, this method was successfully applied to various 2-aryloxy-1,1-difluorocyclopropanes.

Scheme 20 Carbazole synthesis via defluorination ring opening, and cyclisation.

Scheme 21 Synthetic of 2-(1,1-difluoroethyl)-2H-1,3-benzoxazines via ring opening of gem-DFCPs. gem-DFCPs, gem-difluorocyclopropanes.

Other interesting work was reported by Hang et al, who explored the [3 + 2]-cycloaddition reactions of difluoro(methylidene)cyclopropanes (F₂MCPs) 133 with nitronitriles 134 to access cycloaddition products 136. The resulting cycloaddition products underwent further rearrangements to yield highly substituted 3,3-difluorinated tetrahydropyridinols 135 ([Scheme 22]).[74] The proposed mechanism for this rearrangement involves a diradical process. Initially, the reaction proceeds through the formation of difluorinated spirocyclopropane isoxazolidines 136. Upon heating, the N–O bond in intermediate 136 cleaves, generating a diradical intermediate 137. This intermediate undergoes ring opening to form a new diradical species 138, which subsequently cyclizes to produce the difluorinated tetrahydropyridinol 135.

Scheme 22 [3 + 2] Cycloaddition to access 3,3-difluoro-tetrahydropyridin-4-ols.

Synthesis of Other Rings from gem-difluorocyclopropanes

Medium-sized carbocycles and heterocycles have garnered significant attention in medicinal chemistry due to their diverse biological activities and pharmaceutical potential.[75] [76] Similarly, the synthesis of large-sized carbocycles and heterocycles has been achieved through innovative approaches involving gem-DFCPs rearrangement and ring expansion reactions, expanding the synthetic toolbox for complex ring systems.

Orr et al discovered that not only can the aforementioned gem-difluorovinylcyclopropane 139 undergo thermal rearrangement to form gem-difluorocyclopentene, but trans/cis-3-(2,2-difluoro-3-phenylcyclopropyl)acrylic acid ethyl ester also undergoes [3,3]-sigmatropic rearrangement at elevated temperatures (180°C). This process yields mixtures of compounds 142 and 143, which were monitored by ¹⁹F NMR spectroscopy, revealing an integration ratio of 9:1 in favor of 142 ([Scheme 23]).[44] The reaction is anticipated to involve HF elimination through rearomatization. Furthermore, heating isolated 142 at 180°C (in diphenyl ether for 17.5 hours) resulted in the formation of the more conjugated product 143, likely via a [1,5]-hydrogen shift.

Scheme 23 Synthesis of cyclopentene via [3,3]-sigmatropic rearrangement.

Siloxydifluorocyclopropanes are recognized as highly versatile building blocks for synthesizing a wide range of difluoromethylene compounds. However, their inherent instability has posed significant challenges in the chemical exploration of fluorinated homoenolates for the preparation of α,α-difluorinated ketones. In 2015, the Amii research group addressed this issue by reporting the ring-opening reactions of silyloxydifluorocyclopropanes 145. These reactions yielded α,α-difluorocycloalkanones 146 when treated with Na₂CO₃ in methanol, and monofluorinated cycloalk-2-en-1-ones 147 when treated with tetrabutylammonium fluoride in THF ([Scheme 24]).[77] This approach enabled the selective generation of gem-difluorinated cycloalkanones and monofluorinated cycloalk-2-en-1-ones, providing a valuable strategy for accessing these fluorinated structures.

Scheme 24 Synthesis of difluorocycloalkanones and monofluoroalkenones via a ring-opening reaction.

In the study by Kobayashi et al, the transformation of gem-difluorosubstituted bicyclo[4.1.0]heptan-1-yl acetate 147 to 2-fluorocyclohept-2-en-1-one 149 and subsequently to the 3-methoxylated analogue 152 was demonstrated to proceed through a synergistic solubilization process involving the allylic cation intermediate 153 ([Scheme 25]).[78] In contrast, nucleophilic attack by MeLi on the ester carbonyl group led to the cleavage of the cyclopropane ring, yielding ring-opening products 149 via intermediate 148. However, upon further nucleophilic attack by MeLi on the carbonyl group, only fluoroallyl alcohol 150 was isolated, with a yield of 70%.

Scheme 25 Conversion of difluorocyclopropyl acetate to cycloheptenone, cycloheptanone, or fluoroalkenol.

Functionalized gem-(difluorocyclopropyl)amines exhibit significant synthetic potential. Although extensive research has been conducted on the transformations of gem-difluorocyclopropanol derivatives, studies on the reactivity of gem-(difluorocyclopropyl)amines remain limited. In 2004, Nowak et al developed a method for synthesizing the bridged gem-(difluorocyclopropyl)amines 155 from the enamines 154 and investigated their ring-opening decomposition.[79] Prolonged heating of 155 was observed to lead to their gradual disappearance, resulting in the formation of fluorinated diene amine 157 alongside the loss of a fluorine atom through the intermediate 156. Additionally, a small amount of the hydrolyzed ketone product 158 was generated as a byproduct ([Scheme 26]).

Scheme 26 Ring-opening decomposition of gem-(difluorocyclopropyl)amine to form fluoro-dienylamine and fluoro-dienone.

Conclusion

Over the past two decades, fluorinated cyclopropanes have emerged as a focal point of intense research interest across organic synthesis, pharmaceutical development, and materials science. Extensive investigations into gem-DFCPs have unveiled novel reactivity patterns and selective transformations, enabling efficient access to diverse fluorinated cyclic architectures. While significant progress has been made in understanding gem-DFCPs' chemistry, several key challenges and opportunities remain in the exploration of their ring-opening and ring-recombination reactions.

First, current methodologies are predominantly limited to monosubstituted gem-DFCPs, highlighting the need for innovative strategies to access sterically demanding disubstituted and multisubstituted derivatives. Second, the synthesis of other gem-difluorocarbocycles with varying ring sizes presents an exciting frontier, particularly through the incorporation of valuable unsaturated components such as alkynes, carbon monoxide, and carbenes. Finally, although transition metal-catalyzed cyclizations of gem-difluorinated carbocycles are proposed to proceed via gem-difluorinated metallocyclobutane intermediates, the precise mechanistic details of these transformations warrant further elucidation through combined experimental and computational studies.

Continued advancements in gem-DFCP chemistry are poised to make substantial contributions to the broader fields of organic synthesis and medicinal chemistry. This review aims to provide researchers with a comprehensive and accurate understanding of recent progress in this dynamic field, with the ultimate goal of inspiring innovative developments in gem-DFCPs ring-editing strategies. We anticipate that these efforts will yield transformative synthetic methodologies with significant implications for drug discovery and materials development in the near future.

Conflict of Interest

None declared.

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Publication History

Received: 31 March 2025

Accepted: 13 January 2026

Article published online:
16 February 2026