The C–F bond cleavage and C–C bond formation (i.e., carbodefluorination) of readily accessible (per)fluoroalkyl groups constitutes an atom-economical and efficient route to partially fluorinated compounds. However, the selective mono-carbodefluorination of trifluoromethyl (CF3) groups remains a challenge, due to the notorious inertness of C–F bond and the risk of over-defluorination arising from C–F bond strength decrease as the defluorination proceeds. Herein, we report a carbene-initiated rearrangement strategy for the carbodefluorination of fluoroalkyl ketones with β,γ-unsaturated alcohols to provide skeletally and functionally diverse α-mono- and α,α-difluoro-γ,δ-unsaturated ketones. The reaction starts with the formation of silver carbenes from fluoroalkyl N-triftosylhydrazones, followed by nucleophilic attack of a β,γ-unsaturated alcohol to form key silver-coordinated oxonium ylide intermediates, which triggers selective C–F bond cleavage by HF elimination and C–C bond formation through Claisen rearrangement of in situ generated difluorovinyl ether. The origin of chemoselectivity and the reaction mechanism are determined by experimental and DFT calculations. Collectively, this strategy by an intramolecular cascade process offers significant advances over existing stepwise strategies in terms of selectivity, efficiency, functional group tolerance, etc.
The construction of C–C bonds is fundamental to the art of organic synthesis as it provides access to the backbone of organic molecules, including pharmaceuticals, agrochemicals, and functional materials1,2,3,4,5. The development of new methods, that are advantageous in terms of selectivity, availability and affordability of starting materials, functional group tolerance, and environmental sustainability is a constant focus of organic chemistry. Among numerous C–C bond-forming reactions, dehalogenative cross-coupling reactions have long been regarded as the most reliable and efficient tactics for assembling carbon scaffolds6,7,8,9. However, in contrast to other C–X bonds (X = Cl, Br, I), the cleavage of a C–F bond and formation of a new C–C bond (so-called carbodefluorination) remain a formidable challenge in modern organic chemistry, especially in readily accessible trifluoromethyl (CF3) groups10,11,12,13,14,15,16. The main challenge with this respect is the notorious inertness of C–F bonds, accompanied by a decrease in bond dissociation energy (BDE) as defluorination takes place17, which often results in undesired over-defluorination (Fig. 1a)10,18,19,20. In this context, great efforts have been invested in achieving selective mono-carbodefluorination of the CF3 group, especially in CF3-substituted arenes and alkenes through the generation of difluoro-substituted carbanion (by low-valent metal or electrochemical reduction)21,22,23,24,25, carbocation (using strong Lewis acids)26,27 or radical (using excited state photocatalysts) intermediates by either heterolytic or homolytic cleavage of a C–F bond28,29,30,31,32,33,34,35, where the in situ generated difluoromethylene reactive intermediates can be stabilized through p–π conjugation (Fig. 1b). While the acyl-CF3 compounds (CF3C=O) are most abundant and easily available, only two classes of selective mono-defluorinative C–C bond-forming reactions of acyl-CF3 derivatives have been disclosed, namely: (i) copper or low-valent magnesium promoted defluorinative coupling of trifluoromethyl ketones with aldehydes or ketones23,36,37,38; and (ii) radical defluorinative coupling of acyl-CF3 with alkenes by spin-center shift (SCS) or photocatalysis28,34,35, which can be ascribed to the incompatibility between the conditions required for the generation of reactive intermediates and high reactivity of the C=O bond. Nevertheless, these approaches to the carbodefluorination of CF3-arenes, -alkenes, and -acyl compounds generally require a stepwise mechanism via reactive difluoromethylene intermediates, such as carbanions, carbocations, or radicals, which can generally lower the extent of selectivity, efficiency, substrate scope, and functional group tolerance. Through the formation of N-sulfonylhydrazones, fluoroalkyl ketones have recently become versatile coupling partners, especially as a source of fluoroalkyl carbene in a range of C–C bond-forming reactions39,40,41,42,43,44,45,46,47. Moreover, the rearrangement reaction of fluorine-containing molecules can provide various fluorine-containing molecular frameworks48,49,50,51,52,53. Hence, the development of a strategy enabling the integration of successive C–F bond cleavage and C–C bond formation into an intramolecular cascade process would offer significant advantages over existing stepwise strategies.
Here, we report a carbene-initiated rearrangement strategy for the carbodefluorination of fluoroalkyl ketones (Fig. 1c, up). We envisage that an intramolecular rearrangement strategy could provide an advantageous route for the efficient carbodefluorination of trifluoromethyl ketones, i.e., the formation of a metal-coordinated ylide intermediate by nucleophilic attack of β,γ-unsaturated alcohols to a fluoroalkyl metal carbene might enable a sequential C–F bond cleavage / C–C bond formation through the Claisen rearrangement of an in situ generated difluorovinyl ether intermediate (Fig. 1c, bottom). We eventually implement this carbene-initiated rearrangement strategy for selective carbodefluorination of fluoroalkyl ketones through the reaction between their N-triftosylhydrazones and β,γ-unsaturated alcohols by silver catalysis. The scope of this transformation includes five-membered (benzo-fused)heteroaryl carbinols, allyl and propargyl alcohols, thus providing access to skeletally and functionally diverse α-mono- and α,α-difluoro-γ,δ-unsaturated (cyclo)alkyl ketones (Fig. 1c, middle).
Results and discussion
Transition-metal-catalyzed dearomative functionalization of (hetero)aromatics has recently emerged as a powerful method to access aliphatic cyclic compounds54,55,56,57,58,59,60. Dearomative functionalization of indoles to generate valuable indolines is particularly interesting due to the frequent occurrence of the latter substructures in natural products and other alkaloids55. Despite many advances, the formation of new carbon-carbon bonds via defluorinative dearomatization of indoles remains elusive54,56,57. The chemical inertness of the C–F bond, and the energetic barrier associated with the disruption of aromaticity are the main factors that prevent the success of the approach via indole defluorinative dearomatization. At the outset, we choose trifluoromethyl ketone-derived N-sulfonylhydrazones as diazo surrogates to verify the planned reaction hypothesis, with indole-3-carbinols serving as the nucleophile. A survey of various combinations of different fluoroalkyl N-sulfonylhydrazones, metal catalysts, solvents and temperature revealed that a mixture of phenyl trifluoromethyl ketone N-triftosylhydrazone (1a), indole-3-carbinol (2aa), K2CO3 (2.0 equiv) and TpBr3Ag (10 mol%) in toluene at 80 °C achieved the desired defluorinative [3,3]-rearrangement product (3) in 84% yield (Fig. 2). The driving force to destroy the aromaticity of the substrate comes from the flow of electrons during the opening of the six-membered ring transition state during the [3,3]-rearrangement61. With these optimized conditions in hand, we sought to examine the scope of this defluorinative dearomatization reaction with respect to various indole-3-carbinols. As shown in Fig. 2, all the primary indole-3-carbinols that were investigated afforded the desired rearrangement products 3–12 in high yield, regardless of the position and electronic effect of the substituents. A range of secondary indole-3-carbinols was also suitable for this reaction, forming 2-difluoroacylated indolines (13–18) in moderate to good yield with excellent stereoselectivity (E/Z up to >20:1). However, we observed that tertiary alcohols are not suitable for this transformation, possibly because the structures of tertiary alcohols are more sterically hindered during electrophilic attack. Again, the substitution patterns of the C2-substituted indoles did not affect significantly the reaction outcomes (19–22). This strategy thus provides an opportunity for the construction of non-aromatic N-heterocycles containing a quaternary carbon center, which is the key precursor for the synthesis of polycyclic complex molecules59,60,62. Variation of the N-protecting group on the indole-3-carbinol was also well tolerated, including aryl and alkyl N-sulfonyl (23–30), N-Boc (31), N-Cbz (32) and N-acetyl (33) groups. In addition to indole-3-carbinols, indole-2-carbinols could also be employed without difficulty in this transformation, affording the corresponding products featuring an enamine motif (34–38), which are difficult to access with conventional methods63,64. Regarding the scope of N-triftosylhydrazones, an array of substrates reacted smoothly with indole-3-carbinol, affording the corresponding products (39–56) in high yield. Functional groups such as methyl (39, 40), tert-butyl (41), methoxy (42, 53), trifluoromethoxy (43), phenyl (44), halogen (45–48, 51, 52), trifluoromethyl (49), and vinyl (50) were well tolerated. The use of indole-2-carbinol in the reaction with a p-Br-phenyl trifluoromethyl ketone N-triftosylhydrazone also gave a similar reaction outcome (57). It should be noted that N-triftosylhydrazones derived from alkyl trifluoromethyl ketone are not suitable substrates, as undergo competitive 1,2-hydrogen shifts to form alkenes.
We were pleased to find that a wide array of other heteroaryl carbinols are also suitable for this dearomatizing rearrangement. In addition to benzofurans and benzothiophenes, a variety of heterocyclic rings with a greater degree of aromaticity such as pyrrole, furan, and thiophene carbinols underwent the defluorinative dearomatization with phenyl trifluoromethyl N-triftosylhydrazone to generate the corresponding α,α-difluoro-γ,δ-unsaturated alkyl ketone products (58–85) in moderate to excellent yield, with good functional group tolerance. The formation of a quaternary center on a fused-ring furan (80) is particularly notable in view of the congested nature of this system. Collectively, these results demonstrate the dearomative carbodefluorination of C(sp3)–F bonds, which constitutes a powerful method for the synthesis of a wide range of α-heterocyclic fluoroalkyl ketones.
Having established a strategy for the highly selective defluorinative functionalization of C–F bonds in the acyl CF3 group with heteroaromatic carbinols, we speculated whether the scope of this transformation could be expanded to other β,γ-unsaturated alcohols. In the event, this chemistry indeed proved suitable for application with these other substrates, with optimization of the carbodefluorination reaction between 1a and allyl alcohol (2c) summarized in Supplementary Tables 2, 3. Under these optimized conditions (Fig. 3), a broad range of 1,1- and 1,2-disubstituted primary allyl alcohols bearing different (cyclo)alkyl and aryl substituents were found to give good to excellent yield of the desired products (86–100). Functionalities such as halogens (91, 92, 99), alkene (93) and alkyne (94) motifs remain intact, allowing for further derivatizations. Trisubstituted allyl alcohols possessing styryl (101), alkenyl chloride (102), alkenyl ester (103), and (hetero)cyclic alkene (104, 105) also performed well. Similar to primary allyl alcohols, secondary alcohols bearing functionalities such as cycloalkyl (106, 115), phenyl (107), ester (108), piperidine (109), alkenyl (110, 113), allyl ether (111), ketal (112) and methyl (114, 117) groups at the α-position were suitable for this transformation, affording a range of disubstituted homoallylic α,α-difluoroketones (106–117) in 53–94% yield. α,α-Difluoro-γ,δ-enones with a fluoroalkyl all-carbon quaternary center could be prepared (118–122) in moderate to excellent yield using 1,1-disubstituted allyl alcohols; such α-difluoroalkyl quaternary carbons, which cannot be easily prepared by conventional methods65,66. This protocol was also applicable for the late-stage modification of natural products, such as myrtenol (123), geraniol (124) and insect repellent cyclocitral (125) with high selectivity and high yield.
The propargylic Claisen rearrangement is a powerful method for the synthesis of allenes67,68,69. With this in mind, we next examined the carbodefluorination of trifluoromethyl ketones with propargyl alcohols, with a view to accessing difluoroalkyl-subsituted allenes, which are gaining importance in drug discovery. We were delighted to find that a variety of propargyl alcohols provided the desired α-CF2 allenyl products in good yield and selectivity (126–154). To our knowledge, this is the first example of selective C–F allenylation of CF3 groups10,11,12,13,14,15,16. This chemistry proved most effective using propargyl alcohol itself, which exhibited high reactivity and gave the desired product (126) in near quantitative yield. However, also both acylic (linear or branched) and cycloalkyl-substituted propargyl alcohols smoothly afforded the corresponding allenes in 78–97% yield (127–130). Pleasingly, propargyl alcohols bearing phenyl (131), naphthyl (132), thienyl (133), TMS (134) and halogen (135, 136) groups on the alkyne terminus proved suitable substrates, providing the corresponding products in good yield in almost all cases. TMS, Cl or Br functionalities could be retained in the products, which allows for further orthogonal functionalization of the thus obtained products. Alkyl propargyl alcohols containing various functionalities on the alkyl sidechain, such as phenyl (137), chloro (138), ether (139), ester (140), pyran (141), alkenyl (142), and alkynyl (143) groups, were all amenable in this reaction. Notably, the free alkenyl and alkynyl units in 142 and 143 were untouched, which demonstrates the high selectivity of the alcohol hydroxyl (-OH) group toward metal carbene trapping to form the proposed intermediate silver-coordinated oxonium ylides42. Polyfunctionalized allenes were found to be hard to prepare by existing methods69,70,71,72,73. Furthermore, a cyclohexene-conjugated difluoroalkyl allene (144), a useful synthon in cycloaddition reaction to access polycyclic fluorinated molecules, was also obtained in 80% yield from the corresponding enyne. Secondary propargyl alcohols proved to be similarly suitable substrates, providing diverse disubstituted and trisubstituted allenes (145–152). Notably, this strategy enables access to structures bearing pharmaceutically relevant sidechains, such as floramelon (153) and citronellal (154).
Finally, we turned our attention to fluoroalkyl ketone N-triftosylhydrazones. Both electron-withdrawing and -donating groups on the phenyl ring of the N-triftosylhydrazones showed little influence on the reaction outcome and in all instances the desired C–F allylated (155–162) and C–F allenylated (166–173) products were obtained in good to excellent yield. Piperonyl (163, 176), naphthyl (164, 174), furyl (165), and fluorenyl (175) N-triftosylhydrazones were also found to be suitable starting materials. We note that superior efficiency was observed using (Rh2(esp)2 as catalyst instead of TpBr3Ag in the reaction of N-triftosylhydrazones derived from alkyl trifluoromethyl ketones (177–182). Remarkably, the reaction was not restricted to α-trifluoromethyl N-triftosylhydrazones. In fact, hydrazones derived from α,α-difluoromethyl (183, 184, 188) and α,α-difluoropentyl (185) ketones, a α,α-difluoroketoester (186, 190) and a difluorocycloalkyl (191) ketone were also capable of undergoing this coupling/rearrangement reaction, providing unprecedented opportunities to access a broad array of chemical diversity under a single reactivity platform. In the case of pentafluoroethyl ketone-derived N-triftosylhydrazones, the α-C–F bond could be converted to the corresponding allylated (187) and allenylated products (189) in 92% and 71% yield, respectively, featuring α-fluoro-β-trifluoromethyl functionality.
Gram-scale reaction and further transformations
The above results demonstrate that readily available α-fluoroalkyl ketones can be converted into a wide variety of valuable α,α-difluoro-γ,δ-unsaturated (cyclo)alkyl ketones with diverse substitution patterns through a silver carbene-initiated defluorination and rearrangement cascade of the corresponding sulfonyl hydrazones. Most of these compounds are newly synthesized and inaccessible by other conventional methods74,75,76. To test the scalability and practicality of this protocol, the gram-scale synthesis of 3, 86, and 127 were carried out with the standard set of conditions that we have developed, providing the corresponding products with synthetic efficiency equivalent to the smaller-scale reactions (Fig. 4). Given the importance of α,α-difluoroketones as privileged substructures in medicinal chemistry and the versatile reactivity of carbonyl, heterocyclic, vinyl, and allenyl moieties, these products could be easily transformed into a broad range of fluorinated building blocks of medicinal relevance. For example, the terminal alkene unit of dearomatization product 3 could be readily cyclopropanated with formyl or trifluoromethyl diazomethanes, affording the corresponding spiroindolines (192, 193) in excellent yield. Furthermore, carbonyl reduction, alkene hydrogenation, alkene bromination, and carbonyl olefination of 3 were achieved with good efficiency (194–197), while combining olefination with aromatizing (3,3)-sigmatropic rearrangement offers an attractive entry to 1,1-difluoroalkene products (198). The selective nucleophilic gem-difluorination of the carbonyl group of 86 and 127 with DAST provided the corresponding tetrafluoro products (199, 204) in 77% and 97% yield, respectively. Compounds 86 and 127 were readily reduced to alcohols in the presence of NaBH4, which enabled monofluorination of products 200 and 205 with DAST to afford the trifluoroalkylated products 201 and 206 in high yield. These conversions enable the synthesis of products with tuneable multivicinal fluorination77,78,79. This platform is attractive for the site-specific introduction of fluorine in aliphatic chains. Notably, the secondary fluoroalkyl alcohol units in compounds 194, 200, and 215 are important motifs in bioactive molecules80. Carbonyl alkenylation of 86 and 127 gave the desired products 202 and 207 in 85% and 80% yield, respectively. Finally, the radical difunctionalization of olefins (86) and allenes (127) reliably provided products 203 (69% yield, dr = 5:4) and 208 (76%, stereoselectivity 2:1), respectively.
Mechanistic experiments and computational studies were conducted to explore the mechanism of this cascade carbodefluorination process. The progress of the reaction depicted in Fig. 5a was first examined by 1H NMR. This showed initial formation of intermediate 209, which reached maximum intensity within an hour. This was transformed to give product 3, the latter being the near sole reaction component by 16 h. This result suggests that rapid gem-difluoroalkenylation is a critical step for the success of this reaction, with this reactive intermediate 209 readily undergoing Claisen rearrangement to afford the final product. Indeed, the subjection of isolated 209 (62% yield (after 40 min), Fig. 5b, eq. 1) to the reaction conditions resulted in 91% yield of product 3, while the reaction of this intermediate in the absence of silver catalyst afforded 3 in 64% yield (Fig. 5b, eq. 2). These results suggest that the Ag catalyst plays a critical role in formation of the difluoroalkene intermediate, and also facilitates the rearrangement process. A control experiment showed that exposing pre-prepared ether 210 to the standard conditions failed to give the defluorinative rearrangement product 44 (Fig. 5b, eq. 3). This result excluded the possibility of forming an ether intermediate through O–H carbene insertion81. Overall, these results suggest that HF elimination to form a gem-difluorinated vinyl ether is more favorable than the 1,2-H transfer process of metal ylide to give an ether.
Density functional theory (DFT) calculations at the SMD(toluene)// B3LYP-D3/def2tzvp level of theory were carried out to rationalize the proposed pathway, with the reaction between 1a and indole-3-carbinol 2aa selected as a model. As summarized in Fig. 5c, this pathway involves nucleophilic attack, C–F bond cleavage, and [3,3] rearrangement. Compound 1a is known to undergoes easily a base-mediated decomposition to form a diazo species, which then reacts with TpBr3Ag catalyst to give a silver carbene44. The energy barrier for generation of a silver-coordinated oxonium ylide Int2 by reaction of indole-3-carbinol with this silver carbene is low (2.6 kcal mol−1). The NPA charge analysis of Int2 shows the F atoms carry more negative charge than the carbene carbon atom, which facilitates abstraction of the hydroxyl proton to form HF. This occurs via a 5-membered ring transition state TS2 to generate the gem-difluorovinyl ether intermediate Int4 by single bond rotation of initially formed silver-associated gem-difluorovinyl ether intermediate Int3. Notably, the energy barrier for the HF elimination is lower (ΔΔG‡ = 11.8 kcal mol−1) than proton transfer to form an O–H insertion product (ΔΔG‡ = 20.8 kcal mol–1) (see Supplementary Fig. 7 for details), which is in good agreement with the experimental observations above. Eventually, formation of product 3 takes place by silver-promoted [3,3] rearrangement from Int4 via TS3, which possesses an energy barrier of ΔG‡ = 15.5 kcal mol−1 and constitutes the rate-determining step. However, in the absence of silver catalysis, the energy barrier for this step is as high as 20.7 kcal mol−1. To explain this reactivity difference, the NPA charge analysis of Int4 and Int4’ were carried out. We found that the O–Ag weak coordination in Int4, which is absent in Int4’, enhances the C1–O bond polarity (NPA charge differences: 0.46 in Int4 vs 0.39 in Int4’), thus weakens this bond in Int4 and makes it easier to break (1.48 Å vs 1.45 Å). Furthermore, the color-filled reduced density gradient (RDG) isosurface analysis82,83 indicate the presence of a strong stabilizing interaction between Ag and O atoms, and also a weak Br···π interaction between the ligand and the benzene ring, both can stabilize the transition state TS3 (Fig. 5C) (for TS3’ RDG isosurface, see Supplementary Fig. 8). In a word, all of these factors facilitate the silver-catalyzed [3,3] rearrangement.
In summary, we have established a carbene-initiated rearrangement strategy for the carbodefluorination of fluoroalkyl ketones by the merger of silver catalysis and fluoroalkyl N-triftosylhydrazones. This method enables the integration of successive C–F bond cleavage and C–C bond formation on a single molecule entity through a silver carbene-triggered defluorination and rearrangement cascade, including sequential carbene generation, nucleophilic attack, C–F bond cleavage, and eventual C–C bond formation through Claisen rearrangement of resultant difluorovinyl ethers. A broad range of (hetero)aryl/alkyl fluoroalkyl ketones and β,γ-unsaturated alcohols (heteroaryl (indole, pyrrole, (benzo)furan, (benzo)thiophene) carbinols, allyl alcohols and propargyl alcohols) were all found to be amenable to this silver-catalyzed protocol, thereby allowing single-step access to skeletally and functionally diverse α-mono- and α,α-difluoro-γ,δ-unsaturated ketones. These highly functionalized fluorinated molecules will be of great interest as building blocks in drug discovery and materials science. Overall, we believe that this work has opened an avenue to exploit the carbodefluorination of C(sp3)–F bonds.
General procedure for the synthesis of TpBr3Ag44
Pre-sublimated 1H−3,4,5-tribromopyrazole (40 mmol, 4.0 equiv) and TlBH4 (10 mmol, 1.0 equiv) were added to a 250 mL Schlenk tube and mix well (no magnetic stir required). The tube was fitted with a reflux condenser and a nitrogen balloon (to balance the increased pressure of hydrogen production during the reaction), and three vacuum/nitrogen cycles were made. The reaction was heated at 180 °C for 2 h, then the temperature was raised to 200 °C and the reaction was continued for 2 h. After cooling to room temperature, unreacted pyrazole was removed by vacuum sublimation (150 °C, 2 mbar) to give TlTpBr3 as a white solid. AgOTf (10 mmol, 1.0 equiv) and TlTpBr3 (10 mmol, 1.0 equiv) were added to the acetone solution to dissolve. After stirring in the dark for 20 h, a white solid precipitated from the initially colorless solution. The solid was filtered off and dried under vacuum for 12 h to give the complex [TpBr3Ag]2·CH3COCH3. [TpBr3Ag]2·CH3COCH3 (10 mmol) was stirred in freshly distilled tetrahydrofuran (100 mL) for 30 min in the dark. The solvent was removed under reduced pressure, and white solid TpBr3Ag was quantitatively obtained after vacuum drying.
General procedure carbodefluorination reaction of indole-3-carbinols
To a dried sealed tube was charged with N-tfsylhydrazone (0.3 mmol, 1.0 equiv), indole-3-carbinol (0.6 mmol, 2.0 equiv), TpBr3Ag (10 mol%), K2CO3 (0.6 mmol, 2.0 equiv) in an argon-filled glovebox. Anhydrous toluene (4 mL) was added. The resulting mixture was stirred at 80 °C for 16 h. When the reaction was completed, the crude reaction mixture was allowed to reach room temperature, and filtered through a short pad of diatomite with ethyl acetate (EtOAc) as an eluent. The filtrate was concentrated in vacuo, and the resulting crude product was purified by column chromatography using ethyl acetate/petroleum ether (1: 25; v: v) to obtain the product.
General procedure carbodefluorination reaction of 2-substituted indole-3-carbinols
To a dried sealed tube was charged with N-tfsylhydrazone (0.3 mmol, 1.0 equiv), 2-substituted indole-3-carbinols (0.6 mmol, 2.0 equiv), TpBr3Ag (10 mol%), K2CO3 (0.6 mmol, 2.0 equiv) in an argon-filled glovebox. Anhydrous toluene (4 mL) was added. The resulting mixture was stirred at 80 °C for 8 h, then the temperature was increased to 120 °C and stirring was continued for 24 h. When the reaction was completed, the crude reaction mixture was allowed to reach room temperature, and filtered through a short pad of diatomite with ethyl acetate (EtOAc) as an eluent. The filtrate was concentrated in vacuo, and the resulting crude product was purified by column chromatography using ethyl acetate/petroleum ether (1: 25; v: v) to obtain the product.
General procedure carbodefluorination reaction of pyrrole and (benzo)furan carbinols
To a dried sealed tube was charged with N-tfsylhydrazone (0.3 mmol, 1.0 equiv), TpBr3Ag (10 mol%), K2CO3 (0.6 mmol, 2.0 equiv) in an argon-filled glovebox. Anhydrous dichloromethane (DCM) (3 mL) was added, then added pyrrole or (benzo)furan carbinols (0.9 mmol, 3.0 equiv) dissolved in DCM (1 mL). The resulting mixture was stirred at 80 °C for 12 h. When the reaction was completed, the crude reaction mixture was allowed to reach room temperature, and filtered through a short pad of diatomite with EtOAc as an eluent. The filtrate was concentrated in vacuo and then the resulting crude product was purified by column chromatography using petroleum ether as eluent to obtain the product. It needs to be treated in a neutral or alkaline medium, and it is easy to restore the aroma under acidic conditions.
General procedure carbodefluorination reaction of (benzo)thiophene carbinols
To a dried sealed tube was charged with N-tfsylhydrazone (0.3 mmol, 1.0 equiv), TpBr3Ag (10 mol%), Cs2CO3 (0.6 mmol, 2.0 equiv) in an argon-filled glovebox. Anhydrous toluene (3 mL) was added, then added (benzo)thiophene carbinols (0.9 mmol, 3.0 equiv) dissolved in toluene (1 mL). The resulting mixture was stirred at 100 °C for 16 h. When the reaction was completed, the crude reaction mixture was allowed to reach room temperature, and filtered through a short pad of diatomite with EtOAc as an eluent. The filtrate was concentrated in vacuo and then the resulting crude product was purified by column chromatography using petroleum ether as eluent to obtain the product. It needs to be treated in a neutral or alkaline medium, and it is easy to restore the aroma under acidic conditions.
General procedure carbodefluorination reaction of β,γ-unsaturated alcohols
To a dried sealed tube was charged with N-tfsylhydrazone (0.3 mmol, 1.0 equiv), TpBr3Ag (10 mol%), K2CO3 (0.6 mmol, 2.0 equiv) in an argon-filled glovebox. Anhydrous 1,2-dichloroethane (DCE) (3 mL) was added, then added allyl alcohols (or propargyl alcohols) (0.6 mmol, 2.0 equiv) dissolved in DCE (1 mL). The resulting mixture was stirred at 80 °C for 12 h. When the reaction was completed, the crude reaction mixture was allowed to reach room temperature, and filtered through a short pad of diatomite with EtOAc as an eluent. The filtrate was concentrated in vacuo and then the resulting crude product was purified by column chromatography using petroleum ether as eluent to obtain the product. (The reaction time for propargyl alcohols is 18 h.)
General procedure carbodefluorination reaction of alkyl-N-triftosylhydrazones with β,γ-unsaturated alcohols
To a dried sealed tube was charged with alkyl-N-tfsylhydrazone (0.3 mmol, 1.0 equiv), Rh2(esp)2 (2 mol%) in an argon-filled glovebox. Anhydrous 1,2-dichloroethane (DCE) (3 mL) was added, then added DIPEA (0.6 mmol, 2.0 equiv) and allyl alcohols (or propargyl alcohols) (0.6 mmol, 2.0 equiv) dissolved in DCE (1 mL). The resulting mixture was stirred at 80 °C for 12 h. When the reaction was completed, the crude reaction mixture was allowed to reach room temperature, and filtered through a short pad of diatomite with EtOAc as an eluent. The filtrate was concentrated in vacuo and then the resulting crude product was purified by column chromatography using petroleum ether as eluent to obtain the product.
The data that support the findings of this study are available within the paper and its Supplementary Information and Supplementary Data files. Raw data are available from the corresponding author on request. Materials and methods, computational studies, experimental procedures, characterization data, 1H, 13C, 19F NMR spectra, and mass spectrometry data are available in the Supplementary Information. Supplementary Data File 1 contains the cartesian coordinates and energies for the computed structures.
Kumara, R. & Van der Eycken, E. V. Recent approaches for C–C bond formation via direct dehydrative coupling strategies. Chem. Soc. Rev. 42, 1121–1146 (2013).
Zetzsche, L. E. & Narayan, A. R. H. Broadening the scope of biocatalytic C–C bond formation. Nat. Rev. Chem. 4, 334–346 (2020).
Wang, C.-S., Dixneuf, P. H. & Soulé, J.-F. Photoredox catalysis for building C–C bonds from C(sp2)–H bonds. Chem. Rev. 118, 7532–7585 (2018).
Zhao, B. L., Rogge, T., Ackermann, L. & Shi, Z. Z. Metal-catalysed C–Het (F, O, S, N) and C–C bond arylation. Chem. Soc. Rev. 50, 8903–8953 (2021).
Balanta, A., Godard, C. & Claver, C. Pdnanoparticles for C–C coupling reactions. Chem. Soc. Rev. 40, 4973–4985 (2011).
Negishi, E. A. Handbook of Organopalladium Chemistry for Organic Synthesis (Wiley-Interscience: New York, 2002).
Miyaura, N. Cross-Coupling Reactions: A Practical Guide (Springer: New York, 2002).
Espinet, P. & Echavarren, A. M. The mechanisms of the Stille reaction. Angew. Chem. Int. Ed. 43, 4704–4734 (2004).
Beletskaya, I. P. & Cheprakov, A. V. The Heck reaction as a sharpening stone of palladium catalysis. Chem. Rev. 100, 3009–3066 (2000).
Amii, H. & Uneyama, K. C–F Bond activation in organic synthesis. Chem. Rev. 109, 2119–2183 (2009).
Ahrens, T., Kohlmann, J., Ahrens, M. & Braun, T. Functionalization of fluorinated molecules by transition-metal-mediated C–F bond activation to access fluorinated building blocks. Chem. Rev. 115, 931–972 (2015).
Ma, X. & Song, Q. Recent progress on selective deconstructive modes of halodifluoromethyl and trifluoromethyl-containing reagents. Chem. Soc. Rev. 49, 9197–9219 (2020).
Jaroschik, F. Picking one out of three: Selective single C−F activation in trifluoromethyl groups. Chem. Eur. J. 24, 14572–14582 (2018).
Uneyama, K. & Amii, H. A review of Mg metal-promoted C−F bond activation; a reliable synthetic approach to difluorinated organic compounds. J. Fluor. Chem. 114, 127–131 (2002).
Stahl, T., Klare, H. F. T. & Oestreich, M. Main-group Lewis acids for C–F bond activation. ACS Catal. 3, 1578–1587 (2013).
Pattison, G. Methods for the synthesis of α,α-difluoroketones. Eur. J. Org. Chem. 2018, 3520–3540 (2018).
O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C–F bond. Chem. Soc. Rev. 37, 308–319 (2008).
Shen, Q. et al. Review of recent advances in C–F bond activation of aliphatic fluorides. J. Fluor. Chem. 179, 14–22 (2015).
Wettergren, J., Ankner, T. & Hilmersson, G. Selective α-defluorination of polyfluorinated esters and amides using SmI2/Et3N/H2O. Chem. Commun. 46, 7596–7598 (2010).
Iwamoto, H., Imiya, H., Ohashi, M. & Ogoshi, S. Cleavage of C(sp3)–F bonds in trifluoromethylarenes using a bis(NHC)nickel(0) complex. J. Am. Chem. Soc. 142, 19360–19367 (2020).
Uneyama, K., Maeda, K., Kato, T. & Katagiri, T. Preparation of 2,2-difluoroenol silyl ethers by electroreductive defluorination of trifluoromethyl ketones. Tetrahedron Lett. 39, 3741–3744 (1998).
Yamauchi, Y., Fukuhara, T., Hara, S. & Senboku, H. Electrochemical carboxylation of α,α-difluorotoluene derivatives and its application to the synthesis of a-fluorinated nonsteroidal anti-inflammatory drugs. Synlett 3, 438–442 (2008).
Amii, H., Kobayashi, T., Hatamoto, Y. & Uneyama, K. Mg0-Promoted selective C–F bond cleavage of trifluoromethyl ketones: a convenient method for the synthesis of 2,2-difluoro enol silanes. Chem. Commun. 1999, 1323–1324 (1999).
Hata, H., Kobayashi, T., Amii, H., Uneyama, K. & Welch, J. T. A new sequential defluorination route to α-fluoro-α,β-unsaturated ketones from trifluoromethyl ketones. Tetrahedron Lett. 43, 6099–6102 (2002).
Amii, H., Hatamoto, Y., Seo, M. & Uneyama, K. A new C–F bond-cleavage route for the synthesis of octafluoro[2.2]paracyclophane. J. Org. Chem. 66, 7216–7218 (2001).
Mandal, D., Gupta, R., Jaiswal, A. K. & Young, R. D. Frustrated Lewis-pair-meditated selective single fluoride substitution in trifluoromethyl groups. J. Am. Chem. Soc. 142, 2572–2578 (2020).
Briceno-Strocchia, A. I., Johnstone, T. C. & Stephan, D. W. Using frustrated Lewis pairs to explore C–F bond activation. Dalton Trans. 49, 1319–1324 (2020).
Yu, Y. J. et al. Sequential C–F bond functionalizations of trifluoroacetamides and acetates via spin-center shifts. Science 371, 1232–1240 (2021).
Chen, K., Berg, N., Gschwind, R. & König, B. Selective single C(sp3)–F bond cleavage in trifluoromethylarenes: merging visible-light catalysis with Lewis acid activation. J. Am. Chem. Soc. 139, 18444–18447 (2017).
Vogt, D. B., Seath, C. P., Wang, H. & Jui, N. T. Catalytic defluoroalkylation of trifluoromethylaromatics with unactivated alkenes. J. Am. Chem. Soc. 141, 13203–13211 (2019).
Luo, C. S. & Bandar, J. S. Selective defluoroallylation of trifluoromethyl. J. Am. Chem. Soc. 141, 14120–14125 (2019).
Luo, Y.-C., Tong, F.-F., Zhang, Y., He, C.-Y. & Zhang, X. G. Visible-light-induced palladium-catalyzed selective defluoroarylation of trifluoromethylarenes with arylboronic acids. J. Am. Chem. Soc. 143, 13971–13979 (2021).
Yan, S.-S. et al. Visible-light photoredox-catalyzed selective carboxylation of C(sp3)–F bonds with CO2. Chem 7, 3099–3113 (2021).
Ghosh, S. et al. HFIP-assisted single C–F bond activation of trifluoromethyl ketones using visible-light photoredox catalysis. Angew. Chem. Int. Ed. https://doi.org/10.1002/anie.202115272 (2021).
Campbell, M. W. et al. Photochemical C–F activation enables defluorinative alkylation of trifluoroacetates and -acetamides. J. Am. Chem. Soc. 143, 19648–19654 (2021).
Amii, H., Kobayashi, T., Terasawa, H. & Uneyama, K. Difluorinated danishefsky’s diene: A versatile C4 building block for the fluorinated six-membered rings. Org. Lett. 3, 3103–3105 (2001).
Doi, R., Ohashi, M. & Ogoshi, S. Copper-catalyzed reaction of trifluoromethylketones with aldehydes via a copper difluoroenolate. Angew. Chem. Int. Ed. 55, 341–344 (2016).
Uneyama, K., Mizutani, G., Maeda, K. & Kato, T. Electroreductive defluorination of trifluoromethyl ketones and trifluoroacetic acid derivatives. J. Org. Chem. 64, 6717–6723 (1999).
Xia, Y., Qiu, D. & Wang, J. Transition-metal-catalyzed cross-couplings through carbene migratory insertion. Chem. Rev. 117, 13810–13889 (2017).
Xia, Y. & Wang, J. N-tosylhydrazones: versatile synthons in the construction of cyclic compounds. Chem. Soc. Rev. 46, 2306–2362 (2017).
Sivaguru, P. & Bi, X. Fluoroalkyl N-sulfonylhydrazones: an efficient reagent for the synthesis of fluoroalkylated compounds. Sci. China Chem. 64, 1614–1629 (2021).
Zhang, X. Y. et al. Fluoroalkyl N-triftosylhydrazones as easily decomposable diazo surrogates for asymmetric [2 + 1] cycloaddition: Synthesis of chiral fluoroalkyl cyclopropenes and cyclopropanes. ACS Catal. 11, 8527–8537 (2021).
Zhang, X. Y. et al. Use of trifluoroacetaldehyde N-tfsylhydrazone as a trifluorodiazoethane surrogate and its synthetic applications. Nat. Commun. 10, 284–292 (2019).
Liu, Z. et al. Site-selective C–H benzylation of alkanes with N-triftosylhydrazones leading to alkyl aromatics. Chem 6, 2110–2124 (2020).
Ning, Y. et al. Difluoroacetaldehyde N-triftosylhydrazone (DFHZ-Tfs) as a bench-stable crystalline diazo surrogate for diazoacetaldehyde and difluorodiazoethane. Angew. Chem. Int. Ed. 59, 6473–6481 (2020).
Wang, H., Ning, Y., Sun, Y., Sivaguru, P. & Bi, X. Cycloaddition of trifluoroacetaldehyde N-triftosylhydrazone (TFHZ-Tfs) with alkynes for synthesizing 3-trifluoromethylpyrazoles. Org. Lett. 22, 2012–2016 (2020).
Ma, Y., Reddy, B. R. P. & Bi, X. Coupling of trifluoroacetaldehyde N-triftosylhydrazone with organoboronic acids for the synthesis of gem-difluoroalkenes. Org. Lett. 21, 9860–9863 (2019).
Metcalf, B. W., Jarvi, E. T. & Burkhart, J. P. The synthesis of α,α-difluoroaldehydes and ketones via Claisen rearrangements. Tetrahedron Lett. 26, 28612–28864 (1985).
Percy, J. M. & Prime, M. E. Rearrangement routes to selectively fluorinated compounds. J. Fluor. Chem. 100, 147–156 (1999).
Tranel, F. & Haufe, G. Claisen rearrangements based on vinyl fluorides. J. Fluor. Chem. 125, 1593–1608 (2004).
Lam, Y.-H., Stanway, S. J. & Gouverneur, V. Recent progress in the use of fluoroorganic compounds in pericyclic reactions. Tetrahedron 65, 9905–9933 (2009).
Decostanzi, M., Campagne, J.-M. & Leclerc, E. Fluorinated enol ethers: their synthesis and reactivity. Org. Biomol. Chem. 13, 7351–7380 (2015).
Zhu, C., Sun, M.-M., Chen, K., Liu, H. & Feng, C. Selective C–F bond allylation of trifluoromethylalkenes. Angew. Chem. Int. Ed. 60, 20237–20242 (2021).
Pape, A. R., Kaliappan, K. P. & Kündig, E. P. Transition-metal-mediated dearomatization reactions. Chem. Rev. 100, 2917–2940 (2000).
Roche, S. P. & Porco, J. A. Jr Dearomatization strategies in the synthesis of complex natural products. Angew. Chem. Int. Ed. 50, 4068–4093 (2011).
Zheng, C. & You, S.-L. Advances in catalytic asymmetric dearomatization. ACS Cent. Sci. 7, 432–444 (2021).
Liang, X.-W., Zheng, C. & You, S.-L. Dearomatization through halofunctionalization reactions. Chem. Eur. J. 22, 11918–11933 (2016).
Nair, V. N. et al. Catalyst-controlled regiodivergence in rearrangements of indole-based onium ylides. J. Am. Chem. Soc. 143, 9016–9025 (2021).
Boyarskikh, V., Nyong, A. & Rainier, J. D. Highly diastereoselective sulfonium ylide rearrangements to quaternary substituted indolines. Angew. Chem. Int. Ed. 47, 5374–5377 (2008).
Novikov, A. V., Kennedy, A. R. & Rainier, J. D. Sulfur ylide-initiated thio-Claisen rearrangements. The synthesis of highly substituted indolines. J. Org. Chem. 68, 993–996 (2003).
Castro, A. M. M. Claisen rearrangement over the past nine decades. Chem. Rev. 104, 2939–3002 (2004).
James, M. J., O’Brien, P., Taylor, R. J. K. & Unsworth, W. P. Synthesis of spirocyclic indolenines. Chem. Eur. J. 22, 2856–2881 (2016).
Kida, N. et al. Control of charge transfer phase transition and ferromagnetism by photoisomerization of spiropyran for an organic-inorganic hybrid system, (SP)[FeIIFeIII(dto)3] (SP = spiropyran, dto = C2O2S2). J. Am. Chem. Soc. 131, 212–220 (2009).
Hammarson, M., Nilsson, J. R., Li, S. M., Lincoln, P. & Andréasson, J. DNA-Binding properties of amidine-substituted spiropyran photoswitches. Chem. Eur. J. 20, 15855–15862 (2014).
Yu, J. et al. Highly efficient “On water” catalyst-free nucleophilic addition reactions using difluoroenoxysilanes: dramatic fluorine effects. Angew. Chem. Int. Ed. 53, 9512–9516 (2014).
Hu, X. et al. Regioselective markovnikov hydrodifluoroalkylation of alkenes using difluoroenoxysilanes. Nat. Commun. 11, 5500–5508 (2020).
Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).
Yu, S. & Ma, S. Allenes in catalytic asymmetric synthesis and natural product syntheses. Angew. Chem. Int. Ed. 51, 3074–3112 (2012).
Bäckvall, J.-E., Posevins, D. & Bermejo-López, A. Iron-catalyzed cross-coupling of propargyl ethers with grignard reagents for the synthesis of functionalized allenes and allenols. Angew. Chem. Int. Ed. 60, 22178–22183 (2021).
Song, T. et al. Kinetically controlled radical addition/elimination cascade: from alkynyl aziridine to fluorinated allenes. Org. Lett. 22, 2419–2424 (2020).
Jaye, J. A. & Sletten, E. M. Simple synthesis of fluorinated ene-ynes via in situ generation of allenes. Synthesis 53, 4297–4307 (2021).
Hoffmann-Röder, A. & Krause, N. Enantioselective synthesis of and with allenes. Angew. Chem. Int. Ed. 41, 2933–2935 (2002).
Brummond, K. M. & DeForest, J. E. Synthesizing allenes today (1982–2006). Synthesis 6, 795–818 (2007).
Furuya, T., Kamlet, A. & Ritter, T. Catalysis for fluorination and trifluoromethylation. Nature 473, 470–477 (2011).
Campbell, M. G. & Ritter, T. Modern carbon-fluorine bond forming reactions for aryl fluoride synthesis. Chem. Rev. 115, 612–633 (2015).
Yang, X., Wu, T., Phipps, R. J. & Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev. 115, 826–870 (2015).
Hunter, L. & O’Hagan, D. Multivicinal fluoroalkanes: a new class of organofluorine compounds. Org. Biomol. Chem. 6, 2843–2848 (2008).
O’Hagan, D. Organofluorine chemistry: synthesis and characterisation of vicinal fluoromethylene motifs. J. Org. Chem. 77, 3689–3699 (2012).
Meyer, S., Häfliger, J. & Gilmour, R. Expanding organofluorine chemical space: the design of chiral fluorinated isosteres enabled by I(I)/I(III) catalysis. Chem. Sci. 12, 10686–10695 (2021).
Wouters, J. et al. A reversible monoamine oxidase an inhibitor, befloxatone: structural approach of its mechanism of action. Bioorg. Med. Chem. 7, 1683–1693 (1999).
Ren, Y. Y., Zhu, S. F. & Zhou, Q. L. Chiral proton-transfer shuttle catalysts for carbene insertion reactions. Org. Biomol. Chem. 16, 3087–3094 (2018).
Johnson, E. R. et al. Revealing noncovalent interactions. J. Am. Chem. Soc. 132, 6498–6506 (2010).
Lu, T. & Chen, F. Multiwfn: a multifunctional wavefunction analyzer. J. Comput. Chem. 33, 580–592 (2012).
This work was supported by NSFC (21871043, 21961130376, 22101044), Postdoctoral Innovation Talent Support Program (BX20200079), Department of Science and Technology of Jilin Province (20190701012GH, 20200801065GH), Fundamental Research Funds for the Central Universities (2412020FZ006). X.B. and E.A. thank the Newton Trust for support (NAF\R1\191210).
The authors declare no competing interests.
Peer review information
Nature Communications thanks Chao Feng and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Li, L., Zhang, X., Ning, Y. et al. Carbodefluorination of fluoroalkyl ketones via a carbene-initiated rearrangement strategy. Nat Commun 13, 4280 (2022). https://doi.org/10.1038/s41467-022-31976-z