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DOI: 10.1055/s-0043-1775391
Recent Advances in Fluoroalkylation Strategies: Exploring Novel Reactivities and Synthetic Applications of Sulfone- and Sulfinate-Based Reagents for Mono-, Di-, and Trifluoromethylations
This review is dedicated to Prof. H. Ila in honor of her 80th birthday
Abstract
Fluoroalkylation serves as a pivotal strategy for chemists to precisely alter the properties of small molecules. Among the established fluoroalkylation protocols, sulfone and sulfinate reagents stand out as versatile tools for these reactions, particularly in mono-, di-, and trifluoromethylations. Their versatility lies in offering multiple pathways, encompassing electrophilic, nucleophilic, as well as radical mechanisms, thus providing diverse routes for controlled molecular modifications through a variety of very exciting mechanistic paths.
1 Introduction
2 Monofluoromethylation Strategies
2.1 Fluorobis(phenylsulfonyl)methane (FBSM)
2.2 2-Fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide (FBDT)
2.3 Benzothiazole-SO2CH2F, NaSO2CH2F, and ClSO2CH2F
2.4 PhSO2CH2F
3 Difluoromethylation Strategies
3.1 PhSO2CF2H
3.2 Benzothiazole-SO2CF2H
3.3 2-PyrSO2CF2H
3.4 NaSO2CF2H
4 Trifluoromethylation Strategies
4.1 PhSO2CF3
4.2 2-PyrSO2CF3
4.3 Benzothiazole-SO2CF3
4.4 NaSO2CF3
4.4.1 Electrochemical Approaches
4.4.2 Photochemical Approaches
4.4.3 Other Noteworthy Approaches
5 Conclusion
#
Key words
fluoroalkylation - sulfone - sulfinate - monofluoromethylation - difluoromethylation - trifluoromethylationBiographical Sketches
Alexander Knieb received his B.Sc. in chemistry in 2018 from the University of Münster, Germany, under supervision of Prof. Dr. Fabian Dielmann. In fall of 2020, he joined the Loker Hydrocarbon Research Institute at the University of Southern California (USC) as a Ph.D. student under the supervision of Prof. G. K. Surya Prakash. His research is currently focused on the development of novel methodologies for metal-mediated and metal-free fluoroalkylation chemistry. His research is complemented by a strong background in both inorganic and organic synthetic methodology with expertise in designing complex metal catalysts for small molecule activation and synthesizing small organic molecules as potential drug candidates, focusing on strategic incorporation of relevant structural motifs and scaffolds aligned with current pharmaceutical interests.
G. K. Surya Prakash received his B.Sc. (Honors) in 1972 from Bangalore University, his M.Sc. in 1974 from the Indian Institute of Technology, Madras, and his Ph.D. in 1978 from USC under the tutelage of late Prof. G. A. Olah. He joined the USC faculty in 1981 and is currently a Distinguished Professor in the Department of Chemistry and Director of the Loker Hydrocarbon Research Institute, holding the Olah Nobel Laureate Chair in Hydrocarbon Chemistry. His research interests include fluorination and synthetic methods, mechanistic studies, superacid chemistry, electrochemistry, and the methanol economy. He is a prolific author with 850 publications, 120 issued patents, and 14 books. He has received three ACS national awards. He is a co-proponent of the Methanol Economy concept with the late Prof. Olah, for which he shared with Prof. Olah the 2013 Eric and Sheila Samson Prime Minister’s Prize for Alternative Fuels for Transportation from the State of Israel.
Introduction
The fluorination of small molecules has garnered significant attention due to the profound impact on their chemical, biological, as well as physiochemical properties.[1] This strategic modification has led to the discovery of properties with immense importance across diverse fields such as agrochemicals, pharmaceuticals, and material sciences. Particularly noteworthy is the incorporation of fluoroalkyl groups, including CH2F, CF2H, and CF3 groups, which have been identified as bioisosteres of commonly encountered functional groups in naturally occurring biologically active molecules. Such fluoroalkyl substituents mimic the properties of methyl, hydroxy(methyl), thio(methyl), amino(methyl), deuterium, or even nitro groups.[2] [3] [4] Among the various classes of reagents available for introducing fluoroalkyl groups, sulfone reagents stand out for their versatility, offering multiple activation methods to access nucleophilic, electrophilic, or radical pathways. In recent years, numerous activation protocols have been investigated, focusing on metal-free, metal-mediated, electrochemical, as well as photochemical approaches to harness the potential of these fluoroalkyl sulfone reagents for their respective fluoroalkyl-transfer potential. This review highlights the utilization of sulfone reagents for mono-, di-, and trifluoromethylation reactions during the last decade. While sulfone reagents have been widely used for decades and are well-documented in earlier reviews by Hu,[5–7] this review aims to highlight the significant advancements made in the period 2014 to early 2024.
# 2
Monofluoromethylation Strategies
Monofluoromethylation reactions are important in incorporating fluorine into small organic molecules, offering access to compounds with unique properties vital in pharmaceuticals, agrochemicals, and materials sciences.[2] [8] Monofluoromethyl groups serve as bioisosteres, mimicking other functional groups like CH2OH, CH2SH, and CH2NH2, while introducing distinct chemical and physical properties into small molecules (change of pK a, inducing of hydrogen-bonding properties, increased lipophilicity, and decreased metabolic liability).[2] [4] [9] Despite their significance, methods for their introduction are relatively scarce, prompting intense research efforts for the selective introduction of this group. This section is focused on examining sulfone reagents commonly encountered in monofluoromethylation reactions (Figure [1]). It will offer a thorough analysis of recent developments and achievements, providing an extensive overview of the current state of monofluoromethylation strategies. From foundational principles to the latest methodologies and their applications, this comprehensive exploration will offer valuable insights into the various approaches employed to incorporate fluorine atoms into organic molecules through monofluoromethylation reactions.
2.1Fluorobis(phenylsulfonyl)methane (FBSM)
Fluorobis(phenylsulfonyl)methane (FBSM) is a simple, symmetric monofluoromethylation reagent that exhibits remarkable Brønsted C–H acidity properties with a pK a of 14.3.[10] [11] Its facile deprotonation enables efficient nucleophilic transfer to various electrophiles due to the presence of the multiple electron-withdrawing groups. This reagent was first reported in 2006 independently by the Shibata group[12] and the Hu group,[13] and subsequently optimized by the Prakash group.[14] The Prakash group were the first to synthesize and fully characterize the stable, persistent α-fluoro carbanion and supported their findings by theoretical calculations and by X-ray crystallographic studies of the corresponding metal and ammonium salts.[15] This reagent represents a significant advancement in fluorine chemistry, offering a versatile and practical approach to introducing fluoromethyl groups (CH2F) into organic molecules. Its development underscores the ongoing efforts for the synthesis of fluorine-containing compounds, with applications found in drug discovery for active pharmaceutical ingredients (APIs), fluorinated agrochemicals, and in material science. Significant advancements have been made in the field of monofluoromethylation reactions, offering versatile synthetic strategies for example through Mitsunobu reaction, 1,4-addition to unsaturated compounds via Michael reaction, enantioselective substitution reactions, three-component Mannich-type reactions, addition to carbonyl compounds for the synthesis of α-fluoromethyl alcohols, and also epoxide ring-opening reactions.[10] , [16] [17] [18]
In 2014, Rios and Yang introduced the use of FBSM as a monofluoromethylation reagent by a cascade of ring-closure reactions with utilizing enals to synthesize fluoromethyl-substituted indane and chromanol derivatives (Scheme [1]).[19] Employing diphenylprolinol trimethylsilyl ether catalysis, they achieved remarkable yields of up to 75%, with excellent enantio- as well as diastereoselectivity, showcasing the potential of FBSM in complex molecule synthesis.
Further expanding the synthetic applications, Bischoff and co-workers reported a notable example of monofluoromethylated pyridine synthesis using pyridine N-oxide and phosphonium salt PyBrOP as a coupling reagent (Scheme [2]).[20] With quantitative conversion, this method offers an efficient route for the introduction of the fluoromethyl group into pyridine derivatives, underscoring the versatility of FBSM for the introduction of the valuable CH2F group in combination with PyBrOP as a coupling reagent for diverse fluorination reactions.
In 2016, the Shibata group achieved a significant breakthrough in the enantioselective allylic substitution reactions of allyl fluorides.[21] Leveraging the Ruppert–Prakash reagent TMSCF3, they showed a unique activation mechanism of the strong C–F bond through coordination with the silicon atom of TMSCF3, enabling enantioselective substitution with a fluorobis(phenylsulfonyl)methyl group (Scheme [3]). The fluoromethylated product was formed in 72% yield and 78% ee, thus their method represents a valuable advancement in asymmetric fluorine chemistry, showcasing the potential for diverse fluoromethylation reactions.
In the same year Prakash, Mayr, and co-workers contributed to the understanding of monofluoromethanide anions by demonstrating their persistence in synthetic reactions (Scheme [4]).[22] Their study focused on comparing reactivities of various α-substituted carbanions, including FBSM, FBDT, fluoromalonate ester, and ethyl 2-(phenylsulfonyl)acetate, regarding their ability to add to electrophiles like benzhydrylium tetrafluoroborate. Remarkably, they achieved 71% conversion to the fluoroalkylated framework, highlighting the enhanced reactivity of the carbanions due to α-fluorine substitution in small molecules. This work sheds light on the potential of fluorinated compounds in enhancing synthetic reactivity and opens avenues for further exploration in organic synthesis.
In a parallel effort to Shibata’s work (Scheme [3]), Moberg and co-workers explored the palladium-catalyzed allylic substitution of allyl acetates (Scheme [5]).[23] Their investigation revealed the versatility of allylic substitution for various nucleophiles, employing a valuable oxazoline and biaryl phosphite chiral catalyst. Notably, they achieved the synthesis of the fluorobis(phenylsulfonyl)methylated product in 76% yield with an exceptional 99% ee of the R-isomer. This study underscores the potential of allylic substitution reactions in asymmetric synthesis, offering efficient routes to fluorinated organic molecules with high stereochemical purity.
In 2018, Guo and co-workers[24a] and Ma and co-workers[24b] independently reported on the monofluoromethylation of allenes. Guo and co-workers demonstrated a silver-mediated fluoroalkylation reaction of purin-9-yl allenes in good 77–86% yields (Scheme [6]).[24a] This methodology provides a valuable approach for the synthesis of relevant bioactive nucleoside analogues with potential antiviral properties. Their work highlights the versatility of monofluoromethylation reactions in accessing biologically relevant compounds with enhanced pharmacological properties.
In 2022, Yu and co-workers introduced a highly selective method for regio- and enantioselective hydromonofluoroalkylation of 1,3-dienes mediated by Ni(COD)2 (Scheme [7]).[25] This nickel-mediated approach achieved yields of up to 99% with excellent enantiomeric excess with the addition of bisphosphine-based chiral ligands. Despite prolonged reaction times, the method offers the incorporation of valuable monofluoromethyl groups into small organic molecules with exceptional enantioselectivity. Further, reductive desulfonylation mediated by magnesium metal ensures the retention of excellent enantioselectivity, underscoring the potential of this methodology in the synthesis of complex fluorinated compounds.
In 2022, Chen and co-workers introduced an novel approach, utilizing FBSM not as a monofluoromethylating reagent but as a catalyst for an amine-co-catalyzed hydrogen–deuterium exchange (Scheme [8]).[26] They employed α,β-unsaturated aldehydes and observed hydrogen–deuterium exchange in the presence of catalytic FBSM and a proline derivative in deuterium oxide. This unconventional use of FBSM as a catalyst opens new avenues for hydrogen–deuterium exchange reactions, expanding the scope of fluorine chemistry in catalytic transformations.
In 2023, Yu and co-workers further advanced their hydrofluoromethylation reaction to synthesize chiral allenes under cost-effective nickel-mediated conditions from enynes. This expansion resulted in the formation of chiral monofluoromethylated allenes in up to 98% yields and 97:3 er (Scheme [9]).[27] Yu’s work not only broadens the scope of hydrofluoromethylation reactions but also offers a practical and efficient route to accessing chiral allenes, demonstrating the continued evolution of fluorine chemistry in organic synthesis.
In 2023, Knieb, Prakash, and co-workers reported the monofluoromethylation of both symmetric and unsymmetric aryliodonium salts, focusing on the fluoroalkylation of arenes (Scheme [10]).[28] Initially targeting symmetric aryliodonium salts (R = H; 84–93%), they later developed a more efficient method by introducing an inexpensive auxiliary group (R = OMe; trimethoxyphenyl, TMP; 40–97%) to form corresponding iodoarene as a stable byproduct, thereby utilizing the entire molecule effectively without losing a valuable part of the active drug molecule. The excellent regioselectivity observed offered further insight into the mechanism of the reaction. A mixture of regioisomers would be indicative of an aryne intermediate, whereas the observed single regioisomer suggests an SNAr-type mechanism (Scheme [10]).
Overcoming previous challenges of prolonged reaction times, their approach operated under mild conditions at elevated temperatures, yielding products in good to excellent yields of up to 97%. This advancement represents a significant step forward in optimizing monofluoromethylation reactions for efficient synthesis of fluorinated organic frameworks.
Also in 2023, Zeng, Cahard, and co-workers reported the ring-opening reaction of cyclic sulfamidates and sulfates (Scheme [11]).[29] This approach yielded 1,2-difunctionalized products, including α-hydroxy or α-amine-containing compounds, in excellent yields from cyclic sulfamidates (76–95%) and cyclic sulfates (82–94%), respectively. This work underscores the synthetic potential of ring-opening reactions with cyclic sulfamidates and sulfates, offering efficient routes to diverse functionalized scaffolds.
Subsequently, Yu and co-workers showcased the palladium-catalyzed hydroalkylation reaction of alkoxyallenes (Scheme [12]).[30] This methodology afforded fluorobis(phenylsulfonyl)methylated allyl alkoxides in excellent, up to 99%, yields. Yu’s work demonstrates the versatility of palladium catalysis in promoting hydrofluoroalkylation reactions, providing a robust strategy for accessing fluorinated allyl alkoxides with high efficiency.
# 2.2
2-Fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide (FBDT)
In 2010, the Shibata group reported the first synthesis of 2-fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide (FBDT), a cyclic analogue of FBSM, offering a distinct variation in monofluoromethylation chemistry.[31] While FBSM has been extensively studied, FBDT has garnered less attention despite its potential advantages. Both reagents are not commercially available and require synthesis, which may limit their utility. However, the unique structure of FBDT, characterized by its cyclic sulfonylphenyl framework, enables it to add in a nucleophilic fashion to aldehydes, a capability not exhibited by FBSM.[32] This distinction opens up new avenues for monofluoromethylating strategies. FBDT can be easily prepared from its non-fluorinated precursor, and its use is highly encouraged to expand the potential of monofluoromethylation protocols.
In 2021, Yan and co-workers developed a copper-mediated cross-dehydrogenative coupling of tetrahydroisoquinolines (Scheme [13]).[33] By employing 15 mol% of CuBr as a catalyst, excellent yields of 52–98% were obtained for the addition of FBDT to tetrahydroisoquinolines. This approach demonstrates the potential of this analogue for reactions commonly not performed with FBSM due its reduced steric demand.
# 2.3
Benzothiazole-SO2CH2F, NaSO2CH2F, and ClSO2CH2F
The novel reagent, 2-((fluoromethyl)sulfonyl)benzothiazole (benzothiazole-SO2CH2F, BT-SO2CH2F), alongside NaSO2CH2F, present a promising reagent for direct monofluoromethyl transfer. Unlike traditional methods involving FBSM and FBDT, which initially transfer the fluorobis(phenylsulfonyl) unit, these reagents bypass this step. The Hu group synthesized the sodium fluoromethanesulfinate salt from the corresponding benzothiazole derivative, facilitating its facile reduction with NaBH4 in anhydrous ethanol (Scheme [14]).[34]
Sulfinates represent a different class of reagents but are closely related sulfur-containing organic reagents that have been used in fluoroalkylation reactions, differing primarily in their oxidation states. Sulfinates are salts or esters of sulfinic acid (RSO2H), featuring the sulfinyl group, where the sulfur is bonded to two oxygen atoms, one of which is double-bonded. Sulfones, on the other hand, are fully oxidized forms (RSO2R′), containing the sulfonyl group, where sulfur is double-bonded to two oxygen atoms and single-bonded to two carbon atoms or one carbon atom and one hydrogen atom. The transformation of sulfinates to sulfones generally involves oxidation, highlighting their interconvertible nature through changes in oxidation state and therefore the utilization of both classes for fluoroalkylation reactions is noteworthy to mention in this review. The nearly quantitative reduction of BT-SO2CH2F with NaBH4 (Scheme [14]) yields NaSO2CH2F, which serves as the shelf stable and highly efficient monofluoromethylating reagent. This streamlined approach not only simplifies the synthesis process but also offers enhanced efficiency and control over monofluoromethyl transfer reactions. In addition to the utilization of NaSO2CH2F, the Dolbier group directed their efforts towards the effective generation of fluoroalkyl radicals through the use of ClSO2CH2F in 2014 and 2015 (Scheme [15]).[35] [36] [37] Their research showcased the efficient generation of CH2F radicals by this reagent, enabling applications such as photoredox-catalyzed tandem radical cyclization of N-arylacrylamides and visible-light-induced addition reactions to alkenes. These approaches signify a pivotal expansion in the repertoire of monofluoromethyl sulfone reagents.
In 2017, Kananovich and co-workers reported two distinct ring-opening protocols employing commercially available sodium fluoromethanesulfinate (Scheme [16]).[38] [39] These approaches utilized cost-effective transition metal catalysts to yield γ-keto sulfones, via ring-opening oxidative sulfonylation, in 28–70% yield.
Interestingly, their attempts to synthesize γ-fluoro ketones using NaSO2CH2F resulted in low conversions, merely reaching 17–20% under similar reaction conditions, due to lower stability of the carbon-centered monofluoromethyl radical • CH2F, favoring the formation of the γ-keto sulfone, via sulfur-centered fluoromethyl sulfone radical • SO2CH2F (Schemes 16 and 17).
Also in 2017, Liu and co-workers presented a photochemical strategy employing NaSO2CH2F as a fluoroalkylsulfonyl radical source for accessing monofluoromethylated phenanthridines (Scheme [18]).[40] Under photochemical conditions, the sodium sulfinate salt undergoes oxidation by the photoexcited photocatalyst 9-mesityl-10-methylacridinium perchlorate (Mes-Acr+ClO4 –) generating the monofluoromethyl radical • CH2F. This radical subsequently adds to the isocyanide-containing substrate, forming an imidoyl radical, which cyclizes to yield the desired monofluoromethylated phenanthridines. The observed moderate 21–24% yields can be attributed, at least in part, to the decreased stability of the monofluoromethyl radical compared to the trifluoromethyl radical, leading to increased reactivity and potentially higher rates of side reactions or decomposition. Despite these challenges, this photochemical approach offers an efficient path for synthesizing fluorinated compounds using NaSO2CH2F as a convenient fluoroalkyl radical precursor.
In 2018, the Hu group explored fluoroalkylsulfonylation reactions, investigating the reaction of diazonium salts with NaSO2CH2F under copper-mediated conditions (Scheme [19]).[41] They obtained moderate to good yields (up to 73%) in the monofluoromethylsulfonylation of arenediazonium tetrafluoroborates, with activated substrates showing higher conversion rates than with electron-poor substrates. The reaction likely proceeds through a nucleophilic pathway, as arenediazonium tetrafluoroborates were unable to oxidize the sulfinates to fluoroalkyl radicals. These findings contribute to the understanding of fluoroalkylsulfonylation reactions and their synthetic potential.
In 2020, Li and co-workers presented a method for the silver-catalyzed monofluoromethylation of alkynoates to synthesize fluorinated coumarins (Scheme [20]).[42] Utilizing alkynoates as model substrates, their proposed mechanism involves the oxidation of NaSO2CH2F by Ag(II) to generate the CH2F radical.
Their proposed mechanism consists of the radical addition to the triple bond of the alkynoate, followed by a 5-exo cyclization and intramolecular ester migration, yielding monofluoromethylated coumarins in moderate to good yields. This method offers a valuable approach for accessing monofluoromethylated coumarin scaffolds, showcasing these fluorinated derivatives as potential drug candidates due to their modified chemical, biological, and physicochemical properties.
In 2021, the Hu group demonstrated a copper-mediated cross-coupling of diazo compounds with mono- and difluoromethanesulfinates, yielding the fluoromethylsulfonyl and difluoromethylsulfonyl products (see also Section 3.4) in good to excellent yields of up to 97% (Scheme [21]).[43] Their mechanistic investigations revealed that due to their stronger binding forces with the generated copper carbene, the monofluoromethanesulfinates showed better conversions.
Then Zhang, Wang, and co-workers reported the electrochemically promoted nickel-catalyzed oxidative fluoroalkylation of commercially available, inexpensive aryl iodides, introducing a novel protocol for electrochemically initiated radical cross-coupling reactions (Scheme [22]).[44] They achieved good conversions of up to 85% under electrochemical conditions utilizing graphite electrodes, highlighting the effectiveness of this approach for electrochemical cross-coupling of fluoroalkyl radicals. The compatibility of nickel catalysts and oxidative fluoroalkylating agents under this paired electrolysis protocol demonstrates its versatility and potential for broader application in synthetic chemistry.
In 2022, Tlili and co-workers reported a compelling photochemical synthesis method under visible light conditions, employing the commodity chemical styrene (Scheme [23]).[45] They introduced a solvent- and photocatalyst-dependent approach, influencing the outcome between dimerized and monofluoroalkylated products. Utilizing the fluoroalkyl reagent in MeCN with the photocatalyst 1 (PC1) led to the formation of fluoroalkylated dimerized products (up to 84%), while employing DMSO with the photocatalyst 2 (PC2; Cz = carbazole) resulted in linear fluoroalkylated products (up to 45%). This tunable strategy demonstrated the versatility of cyanoarenes as organophotocatalysts, providing mechanistic insights and expanding the scope of fluoroalkylation reactions.
Also in 2022, Xia, Zhang, and co-workers reported a novel method for the (fluoromethylsulfonyl)methylation of quinoxalinones using NaSO2CH2F, targeting C–F bond cleavage (Scheme [24]).[46] They proposed a unique reaction mechanism wherein the generated monofluoromethyl radical undergoes addition to the quinoxalinone (Scheme [25]). Subsequent 1,2-hydrogen shift, silver(I)-mediated reduction of the formed radical species to the corresponding carbanion, and β-fluoride elimination led to the formation of a methylene unit, which then reacts with another equivalent of the rapidly generated SO2CH2F radical. This mechanism elucidates the observed methylene spacer between the quinoxalinone and the SO2CH2F units.
In 2023, Wang and co-workers introduced a valuable three-component reaction system that converts styrenes into γ-fluoro ketones under ruthenium and NHC-mediated photocatalysis, achieving conversions of up to 73% (Scheme [26]).[47] Their novel approach relies on ruthenium-mediated CH2F radical generation, which adds to the styrene substrate. The formed transient radical is subsequently trapped by the NHC catalyst, facilitating the generation of the ketone moiety from the incorporated acyl fluoride.
The groups of Chen, Molander, and Liu all reported diverse photochemical approaches for the in situ generation of CH2F radicals in 2023 (Schemes 27–29).[48] [49] [50] The Chen group demonstrated the addition of CH2F radicals to 5-vinylisoxazoles to give 5-(3-fluoropropyl)isoxazoles in moderate yields of up to 53% (Scheme [27]).[48]
The Molander group showcased an iridium-mediated approach for the fluorofunctionalization of [1.1.1]propellanes to give 1-(fluoromethyl)-3-(aminomethyl)bicyclo[1.1.1]pentanes in up to 68% yield (Scheme [28]), highlighting a valuable approach for functionalization of this bicyclopentane scaffold, which shows enormous potential in drug discovery.[49]
The Liu group reported an iridium-mediated strategy for the fluoroalkylation of pyridinium-masked enols, accessing valuable α-monofluoromethyl ketones (up to 35%) and α-monofluoromethylsulfonyl ketones (up to 80%) (Scheme [29]).[50]
These reactions showed in this section highlight the importance of sulfinate salts as valuable precursors for radical fluoroalkyl groups.
# 2.4
PhSO2CH2F
PhSO2CH2F is a potent monofluoromethyl sulfone that has played a significant role in monofluoroalkylation chemistry for over two decades, since its first mention by Yagupolskii and co-workers in 1968 and a second report in 1973, and first synthetically utilized in nucleophilic substitution reactions by Makosza and co-workers in 1984 and as a fluoromethyl equivalent by Peet, McCarthy, and co-workers in 1985.[51] [52] [53] [54] In 2018, Wang and Liu published an intriguing application by showcasing the vinylation reaction of PhSO2CH2F using a vinyliodonium salt (Scheme [30]).[55] They demonstrated that PhSO2CH2F can withstand reductive zinc conditions without undergoing reductive desulfonylation. Instead, it forms an organozinc compound that undergoes Csp3–Csp2 coupling, mediated by copper, resulting in the α-vinylation of PhSO2CH2F in 85% yield. This study highlights the versatility and utility of PhSO2CH2F as a valuable reagent in synthetic transformations.
In 2019, the Hu group presented a highly diastereoselective and thermodynamically controlled nucleophilic addition of α-fluoro-α-phenylthio-α-phenylsulfonylmethane (FTSM) to aldehydes (Scheme [31]).[56] This reagent, derived from PhSO2CH2F, incorporates a thiophenol unit to address diastereoselectivity issues encountered in earlier studies within their group; PhSO2CH2F exhibited low diastereoselectivity when adding to aldehydes. The reaction of FTSM with the α,β-unsaturated carbonyl compound 3-phenylpropanal gave a highly diastereoselective outcome giving the product with a remarkable 99:1 dr (syn/anti).
In 2022, Veselý and co-workers introduced a simplistic, yet impactful, approach focusing on the addition of PhSO2CH2F onto ester scaffolds at low temperatures (Scheme [32]).[57] This straightforward nucleophile-electrophile coupling yielded fluoro(phenylsulfonyl)methyl ketones in excellent yields of up to 96%.
These approaches underscore the importance of the PhSO2CH2F reagent for the introduction of CH2F groups onto small molecules.
#
# 3
Difluoromethylation Strategies
Difluoromethylation stands as a prominent strategy in contemporary organic synthesis, garnering more attention and development compared to its monofluoromethylation counterpart.[9] [58] [59] While monofluoromethylation reactions have been relatively scarce, recent advancements have been made as demonstrated in Section 2. Conversely, difluoromethylation reactions have long captivated the interest of researchers owing to the remarkable biological activities exhibited by small molecules containing difluoromethyl groups. The CF2H moiety has emerged as a versatile functional group capable of engaging in weak hydrogen bonding and serving as a bioisostere for methyl, hydroxy, and thiol functional groups, rendering it an ideal substitution group in drug discovery research.[2] Over the years, numerous difluoromethylating reagents have been identified, offering diverse synthetic pathways (Figure [2]). In this report, we delve into the main achievements since 2014 in the area of sulfone-based difluoromethylating reagents, shedding light on their synthesis and applications in modern organic synthesis.
PhSO2CF2H
Difluoromethyl phenyl sulfone (PhSO2CF2H) is a notable aryl difluoromethyl sulfone employed for introducing the valuable difluoromethyl group into small molecules.[60] [61] Although initially reported in 1960 by Hine and Porter, it garnered increased attention in the 2000s.[62] Prakash and co-workers have explored the reactivity of this reagent in various reagents, like its role as a difluoromethylene dianion and its reactivity towards alkyl halides and carbonyl compounds, showcasing its enormous potential for difluoromethylation reactions.[63] [64] [65] [66] Research on this reagent has highlighted its role as a synthon of the CF2H anion and its utility in stereoselective difluoromethylenation and difluorocarbene generation, among other significant reactions. The work of Shibata has notably demonstrated the transformation of this reagent into a sulfonium salt, altering its reactivity from its known nucleophilic to now electrophilic character. The high acidity of PhSO2CF2H enables facile deprotonation, allowing it to function as a PhSO2CF2 – nucleophile in various transformations. The reductive desulfonylation of the phenylsulfonyl group requires magnesium or zinc treatment, vide infra.
In 2014, the Shibata group reported a protocol that introduced PhSO2CF2-sulfonium salt as a transfer reagent for electrophilic -CF2SO2Ph onto β-keto esters, β-diketones, and dicyanoalkylidenes, showcasing its versatility in organic synthesis, while changing the common reactivity this established reagent (Scheme [33]).[67] This reaction demonstrated an elegant method for electrophilically transferring the entire CF2SO2Ph scaffold yielding products in 27–98% yield.
Also in 2014, the Hu group introduced the synthesis of another reagent derived from PhSO2CF2H, from readily available esters, yielding shelf-stable valuable N-tert-butylsulfinyl imines. This reagent exhibits the characteristics of a 1,3-dipole, enabling cycloaddition with arynes to form sulfoximines in up to 91% yield (Scheme [34]).[68] They also demonstrated magnesium mediated reductive desulfonylation, yielding the corresponding difluoromethyl analogs up to 94% yield.
In 2016, the Hu group presented the preparation of a high-yielding cuprate reagent derived from PhSO2CF2H using CuCl and sodium tert-butoxide (Scheme [35]).[69] They demonstrated its potential in coupling reactions with arylboronic acids, highlighting ipso-difluoro(phenylsulfonyl)methylations under mild conditions, obtaining products in good yields (45–82%).
The Hu group elucidated the palladium-catalyzed reaction between aryl aldehydes and arylboronic acids to access a range of 1,1-diaryl-2,2-difluoroethene products (Scheme [36]).[70] The reaction proceeds through a palladium-mediated dehydrosulfonylative cross-coupling of in situ generated difluoro(phenylsulfonyl)methyl tosylates and arylboronic acids to afford 1,1-diaryl-2,2-difluoroethenes in good yields (up to 76%).
The Hu group presented a protocol for difluoro(phenylsulfonyl)methylated phenanthridines, serving as fluoroalkyl sulfone reagents for subsequent modifications through desulfonylation reactions (Scheme [37]).[71] While metal-mediated reductive desulfonylation represents a common strategy for accessing the difluoromethyl scaffold, the Hu group explored alternative methodologies. Their work demonstrated the potential for further post-functionalization of these scaffolds, yielding corresponding sulfides, ethers, and malonate derivatives in excellent yields.
In 2021, Xu and co-workers reported the synthesis of fluorinated sulfides from in situ generated organothiocyanates derived from alkyl and aryl halides (Scheme [38]).[72] This protocol yielded good to excellent yields, offering a versatile method for accessing fluorinated sulfides. This method involves utilizing commercially available thiocyanates or halides, which in situ generate the organothiocyanate species, facilitating the synthesis of fluorinated sulfides.
The exploration of sulfonium salts as common reagents for electrophilic transfer reactions has garnered significant attention. Such salts offer umpolung-type reactivity, initiated by the nucleophilic addition of the group of interest to a sulfide or disulfide, followed by oxidation to the corresponding sulfoxide. The sulfoxide can then undergo Friedel–Crafts-type reactions to yield the electrophilic reagent. The work of Besset and co-workers in 2021, similar to Shibata’s approach (Scheme [33]),[67] focused on synthesizing a cyclic sulfonium salt for electrophilic CF2SO2Ph transfer into C–H bonds of heterocyclic structures, achieving good yields (Scheme [39]).[73]
In 2022, the Gouverneur group made strides in the generation of 18F-labeled difluorocarbene, a breakthrough with significant implications for positron emission tomography (PET) applications (Scheme [40]).[74] Their research, focusing on novel radiotracer development for clinical diagnostics, underscores the importance of short-lived 18F as a radioactive fluorine isotope, renowned for its exceptional properties as a radiotracer commonly introduced via small bioactive molecules. Their utilization of 18F-labeled PhSO2CF2H as a difluorocarbene synthon enabled efficient difluoromethylation of alcohols, thiols, amines, as well as arylboronic acids via metal-mediated reactions. This approach achieved remarkable conversions of radiolabeled products within very short reaction times, demonstrating promising results for PET imaging advancements.
A recent advancement by Beier and co-workers include the synthesis of difluoro(phenylsulfonyl)methylated triazoles via PhSO2CF2N3 formation (Scheme [41]).[75] Given the pivotal role of organic azides in medicinal chemistry and life sciences, their research holds significant relevance.[76] Demonstrating a simplistic methodology for the generation of the azidodifluoromethyl phenyl sulfone, they employed the extensively studied azide-alkyne click reaction to achieve the formation of fluorinated azides with good efficacy up to quantitative conversion into the corresponding triazoles. This work represents an important contribution to the synthesis of fluorinated triazoles, thereby opening new avenues for the development of bioactive compounds of pharmaceutical interest.
In 2023, the Hu group presented a noteworthy study on the enantioselective difluoromethylation-alkynylation of alkenes (Scheme [42]).[77] Their research focused on employing blue light irradiation to activate terminal alkynes and alkenes in the presence of difluoromethyl phenyl sulfone. This protocol facilitated the synthesis of chiral difluoromethylated alkynes, achieving excellent enantiomeric excesses of up to 99%. These results underscore the potential of their method for accessing valuable chiral building blocks with high enantioselectivity.
The mechanistic investigations proposed the formation of a CF2H radical species, which undergoes addition to the alkene scaffold, producing a benzyl radical. Subsequently, this radical adds to the copper alkyne intermediate, leading to the desired product through reductive elimination. The reaction proceeded smoothly, yielding the desired products in moderate to high 50–88% yields. These experiments provide valuable insights into the reaction mechanism, further enhancing our understanding of this transformation.
The Hu group also studied the Sulfox-CF2SO2Ph reagent that has a novel divergent difluoroalkyl radical and difluorocarbene generation mechanism (Scheme [43]).[78] Sulfox-CF2SO2Ph is synthesized from Sulfox-Fluor and PhSO2CF2H under strong basic conditions at –78 °C in high 77% yield. Through iridium-mediated blue light photochemical conversion, the Hu group successfully demonstrated the generation of the PhSO2CF2 radical, subsequently transforming styrene derivatives into difluoromethylated alcohols in up to 91% yield. Expanding their investigation, they explored difluorocarbene generation under basic conditions using potassium hydroxide in aqueous media, resulting in the formation of difluoromethylated ethers and sulfides in up to 88% and up to 61% yields, respectively (Scheme [43]).
# 3.2
Benzothiazole-SO2CF2H
2-((Difluoromethyl)sulfonyl)benzothiazole (benzothiazol-2-yl difluoromethyl sulfone, BT-SO2CF2H) serves as the analogous counterpart to the previously discussed monofluoromethyl reagent, as outlined in Section 2.3. Its application spans various transformations, with recent protocols focusing on difluoromethylation reactions under photochemical or electrochemical conditions. Like its monofluoromethyl analog, this difluoromethylating reagent yields the corresponding sodium sulfinate salt under the conditions demonstrated by the Hu group (see Section 2.3, Scheme [14]) using reductive NaBH4 conditions.[34] The Wang group has also explored the reactivity of BT-SO2CF2H for the difluoromethylation of methacryloyl benzamides.[79] In section 4.3, the corresponding trifluoromethylation using the trifluoromethyl analog is also discussed.[79]
A notable study by Fun and co-workers in 2019 presented a detailed visible-light-induced iridium-mediated radical difluoromethylation of β,γ-unsaturated oximes (Scheme [44]).[80] This methodology facilitated the synthesis of 5-difluoromethylated isoxazolines under mild reaction conditions in up to 84% yield.
Also in 2019, Luxen, Genicot, and co-workers contributed to similar applications to the Gouverneur group (Scheme [40]),[74] particularly in their research concerning the 18F labeling of PhSO2CF2H. They presented the late-stage 18F-difluoromethyl labeling of N-heteroaromatic systems tailored for PET imaging applications (Scheme [45]).[81] They demonstrated the potential of the 18F analog of BT-SO2CF2H for radiolabeling purposes, showcasing good radiochemical conversions of heteroaromatic scaffolds derived from theophylline, acyclovir, and 1,3-dimethyluracil. These conversions exhibited good yields and fast reaction times under blue light irradiation, underscoring the versatility and efficiency of this labeling approach for PET imaging applications.
Zhu and co-workers (2019)[82] and Sheng and co-workers (2020)[83] introduced distinct methodologies for cyclization reactions of β,γ-unsaturated nitrogen-containing scaffolds (Scheme [46]). Their approaches focused on iridium- or ruthenium-mediated processes, both employing CF2H radical generation facilitated by the respective metal catalysts. This radical species selectively reacted with the unsaturated alkene scaffold, leading to subsequent cyclization to form the corresponding oxindoles (up to 85% yield) and oxazolidin-2-imines (up to 90% yield), respectively.
The introduction of fluoroalkyl groups into small molecules represents a unique strategy for fine-tuning molecular properties, such as lipophilicity and stability. Studies have demonstrated that fluorinated groups typically enhance lipophilicity (reducing hydrophilicity), thus holding significant potential for drug discovery applications.[84] [85] [86]
Fluorinated sulfides, in particular, have garnered considerable attention due to their ability to decrease metabolic liability while increasing lipophilic properties. In 2020, the Hu group presented a noteworthy contribution in this field with the electrophilic fluoromethylthiolation of indoles (Scheme [47]).[87] This reaction involves the formation of difluoromethanesulfenic acid as a key intermediate, generated after the activation of phosphite by BT-SO2CF2H, followed by the collapse of the intermediate. The sulfenic acid subsequently undergoes conversion into difluoromethanesulfenyl chloride, serving as the electrophilic CF2H species responsible for the fluoromethylthiolation of the indole substrate. This methodology offers a promising approach for the functionalization of indoles with fluorinated sulfide groups, contributing to the diversification of molecular structures for various applications in chemical synthesis and drug discovery.
In 2021, the Hu group showcased a significant advancement in the field of electrochemistry with the demonstration of the electrochemical reduction of BT-SO2CF2H and the subsequent generation of CF2H radicals through direct single electron transfer (SET) of the sulfone reagent and its addition to alkenes (Scheme [48]).[88] This method provided a valuable and operationally simple protocol for the introduction of CF2H groups under mild electrochemical conditions employing graphite electrodes. Notably, the work of the Hu group extended beyond mere methodology development, as they effectively translated this process into synthetic applications through late-stage functionalization of potential drug candidates.
The utilization of this electrochemical strategy facilitated the efficient incorporation of CF2H groups into various molecular scaffolds, resulting in good yields of the desired products. The research of the Hu group represents a pivotal step forward in the utilization of electrochemistry for the synthesis of fluorinated compounds, offering promising opportunities for the development of novel drug molecules and other functional materials of simple alkene scaffolds representing valuable commodity chemicals.
The groups of Wang and Fu have independently contributed to the advancement of synthetic fluoroalkylation methodologies through their demonstrations of iridium-catalyzed coupling reactions involving alkene scaffolds and in situ generated CF2H radicals.[89] [90] Wang and Zhang focused on the NHC-mediated photoredox reaction, where aryl aldehydes underwent coupling with styrene derivatives to afford difluoromethylated ketones (Scheme [49]).[89] The proposed mechanism involved the iridium-mediated generation of fluoroalkyl radicals, followed by the formation of a benzyl radical upon reaction with a styrene derivative. Subsequent coupling with the thiazolium salt activated aldehyde yielded the desired fluoroalkylated products in excellent yields of up to 89%. These studies underscore the utility of iridium catalysis in facilitating the construction of valuable fluoroalkylated compounds.
Fu and co-workers presented another iridium-catalyzed photochemical approach for the synthesis of difluoromethylated phenanthridines in up to 85% yield via cascade radical insertion-cyclization reaction (Scheme [50]).[90]
Both approaches showcase the stepwise reaction of the alkene scaffold with the in situ generated difluoromethyl radical and, in the case of Fu and co-workers, subsequent cyclization reaction with the nitrile moiety leading to the desired phenanthridines.
The deoxygenative difluoromethylation of alcohols represents a pivotal transformation in synthetic chemistry, offering a direct route to convert alcohols into their corresponding difluoromethyl analogs. This reaction holds immense significance in medicinal chemistry applications, as the CF2H group serves as the bioisostere of the hydroxy moiety, enabling the direct substitution of these functional groups. Such interconversion presents the opportunity to establish a database containing both functionalities, facilitating the discovery of highly efficient drug candidates.
The MacMillan group introduced a metallaphotoredox protocol as a robust method for this transformation, notable for its tolerance towards air and moisture, crucial attributes for pharmaceutical applications (Scheme [51]).[91] Their methodology demonstrates excellent conversion even with unactivated alkenes, traditionally challenging substrates for such reactions, yielding difluoromethylated products with efficiencies reaching up to 83%. Furthermore, they showcased late-stage functionalizations of various bioactive molecules, underscoring the versatility and potential of this approach for accessing diverse fluorinated compounds of geraniol, menthol, serine, myrtenol, and many more of pharmaceutical relevance (Figure [3]).
# 3.3
2-PyrSO2CF2H
Pyridin-2-yl difluoromethyl sulfone (2-PyrSO2CF2H), introduced in 2010, constitutes to a new class of stable difluoromethylating agents with diverse applications, including radical difluoromethylation and the nucleophilic transfer of the entire PyrSO2CF2 unit.[92] [93] [94] Notably, these reagents offer a significant improvement in desulfonylation properties compared to PhSO2CF2H, as desulfonylation can occur under mild conditions, which they have demonstrated by the synthesis of difluorinated sulfonates by Prakash, Hu, and co-workers.[93] As mentioned in Section 3.1, PhSO2CF2H typically necessitates magnesium or zinc for its reductive desulfonylation. In 2018, the Hu group introduced a novel methodology involving the cross-coupling reaction of 2-PyrSO2CF2H with diarylzinc reagents, expanding the repertoire of traditional functionalization reactions typically demonstrated with aryl halides (Scheme [52]).[95] This protocol presents an efficient means to incorporate CF2H groups into small organic molecules under cost-effective iron-catalyzed reaction conditions with short reaction times and impressive yields of up to 96%. The work of the Hu group not only advances the synthesis of fluorinated compounds but also underscores the versatility and practicality of pyridine-based difluoromethyl sulfone reagents in modern organic synthesis utilizing organometallic reagents.
In 2019, Liu and co-workers subsequent demonstrated the versatile application of pyridine-based difluoromethyl sulfone reagents in cyclization reactions catalyzed by iridium under photochemical conditions (Scheme [53]).[96] By leveraging these reagents, they successfully accessed difluoromethylated 2-oxindoles and quinoline derivatives with excellent yields of up to 80% and up to 75%, respectively.
Building upon this foundation, Gouverneur, Davis, and co-workers extended the functionality of these reagents by synthesizing the iodinated Pyr-SO2CF2I variant. This modification enabled the chemoselective functionalization of proteins with side chains of varying lengths under ruthenium- and iron-mediated photocatalytic conditions, accomplished within a remarkably short time frame of 15 minutes, making it a valuable approach for its demand for PET imaging. Leveraging this strategy, they synthesized a library of difluoromethylated tagged proteins, paving the way for potential post-translational modifications and opening new avenues for chemical biology research and drug discovery efforts (Scheme [54]).[97]
The contribution by Shi and co-workers to the field has involved the expansion of CF2H radical addition to unsaturated scaffolds, particularly focusing on vinyl-substituted quaternary centers under iridium-mediated photocatalytic conditions (Scheme [55]).[98] They observed an intriguing 1,2-aryl migration phenomenon when employing these substrates in difluoromethylation reactions. The studied reaction pathway highlights the complexity and versatility of CF2H radical chemistry, providing valuable insights into the mechanistic intricacies of these transformations via in situ formed spiro[2.5]octadienyl radical involvement.
In 2021 and 2023, the Hu group conducted intriguing investigations into a ligand-dependent cross-coupling phenomenon utilizing Pyr-SO2CF2H and aryl iodides (Scheme [56]).[99] [100] Building on their previous work, which focused on coupling aryl iodides with the sulfone reagent to access aryl-pyridine connected products under nickel-catalyzed conditions, in 2021 they employed a 1,3-bis(diphenylphosphino)propane (dppp) complex as the ligand. Remarkably, this ligand facilitated the formation of these products in excellent yields of up to 92%.
In their subsequent study in 2023, they delved deeper into assessing the influence of the ligand on the reaction outcome and made a fascinating observation: the reaction outcome was highly dependent on the chosen ligand and transitioning from dppp to terpyridine resulted in the formation of difluoromethylarenes instead of the previously presented pyridine addition products. This elegant approach underscores the critical role of ligand selection in cross-coupling reactions, as it profoundly influences not only the amount but also the identity of the product formed throughout the reaction. The different ligands investigated by the Hu group enabled the development of a selective protocol for further functionalizing 2-PyrSO2CF2H, either by activating the C–S bond between the pyridine ring and the sulfur atom, or selectively the C–S bond between the CF2H group and the sulfur atom under nickel-catalyzed conditions, exemplifying the versatility and strategic importance of ligand design in organic synthesis (Scheme [56]).
The Hu group also explored the application of 2-PyrSO2CF2H reagent in reactions involving arynes.[101] They developed a novel reagent derived from 2-PyrSO2CF2H by initially adding it to aryl aldehydes, followed by oxidation and ketimine formation, via reaction with enantiomerically pure tert-butanesulfinamide (Scheme [57]). This unique ketimine derivative was utilized for the synthesis of cyclic sulfoximines through reaction with fluoride initiated in situ aryne formation, achieving up to 91% yield and remarkable diastereoselectivity exceeding 99:1 dr (Scheme [58]).[101]
Additionally, the Hu group have demonstrated the iron-mediated difluoromethylation of arenes utilizing a pyrimidine analog, difluoromethyl 4,6-dimethylpyrimidin-2-yl sulfone, and difluoro(phenylsulfonyl)methylation of benzothiazoles using 2-PyrSO2CF2H, showcasing the feasibility of sulfone reagents for introducing the difluoromethyl scaffold via various reaction pathways (Scheme [59]).[102] [103] They highlighted the high-yielding hydroxide-mediated desulfonylation, which enabled the transformation into the desired 2-(difluoromethyl)benzothiazoles, further expanding the synthetic utility of CF2H-containing sulfone reagents in diverse chemical transformations.
Work in 2023 by the Qiu group represents an important achievement in transition-metal-free chemistry with the discovery of a method for the formation of acyl fluorides and benzoic acid derivatives from cyclohexadienones via the in situ generation of (difluoromethylene)cyclohexadiene (Scheme [60]).[104] This approach marks the first known instance of generating these two vital products directly from cyclohexadienones, bypassing the need for transition metal catalysts. By harnessing the reactivity of (difluoromethylene)cyclohexadiene, they has unveiled a novel synthetic pathway that offers exciting opportunities for the efficient synthesis of acyl fluorides and benzoic acid derivatives, enriching the toolkit of organic chemists and potentially facilitating the discovery of new compounds with diverse applications.
In 2023, Gouverneur, Davies, and co-workers introduced a novel approach utilizing this precursor for the synthesis of sulfur-functionalized reagents tailored for the fluoroalkyl-functionalization of proteins (Scheme [61]).[105] This strategy holds promise for applications in selective posttranslational editing of proteins, offering a valuable toolkit for biological probe development and further studies of medicinal relevance.
The resulting fluorinated proteins can be investigated using 19F NMR spectroscopy, providing insights into their structure and function. This pioneering work represents a significant advancement in the field of chemical biology, opening new avenues for the exploration of protein function and interaction through fluorine chemistry-based methodologies (Scheme [62]).
# 3.4
NaSO2CF2H
In 2018, the Hu group elucidated a significant advancement in organic synthesis by revealing the (2-thiophenecarboxylato)copper (CuTc) mediated reaction of arenediazonium salts and sodium difluoromethanesulfinate, leading to the formation of (difluoromethylsulfonyl)arenes in notable yields of up to 88% (Scheme [63]).[41]
Concurrently, Liu and co-workers introduced a redox-neutral difluoromethylation technique, employing unsaturated para-quinone systems, resulting in the production of difluoromethylated phenol derivatives with good 42–81% yields under photochemical conditions with Mes-Acr+ (Scheme [64]).[106]
Zhang and co-workers proposed an alternative copper-catalyzed method for incorporating azide groups into small molecules through the 1,2-functionalization of alkenes with NaSO2CF2H and azidotrimethylsilane at elevated temperatures (Scheme [65]).[107] This approach furnished 1,2-azidodifluoromethylated products in moderate to good yields. The resulting azide linkers hold promise for biological applications, serving as clickable linkers for the introduction of biomarkers via triazole formation reactions upon reacting with alkynes.
Deng and co-workers showcased an important strategy utilizing eosin Y photocatalysis for the C–H activation of coumarins (Scheme [66]).[108] Their work unveiled the efficient difluoromethylation of the α-hydrogen in coumarin derivatives under mild photochemical conditions to give difluoromethylated coumarins in good, up to 82%, yields within 24 hours at room temperature. Through mechanistic investigations, they uncovered the pivotal role of molecular oxygen as an oxidant in the reaction, facilitating the transformation of the in situ formed coumarin radical into the corresponding cationic species. This approach not only expands the synthetic toolbox for accessing valuable difluoromethylated motifs but also sheds light on the intricate mechanistic intricacies underlying C–H activation processes for the synthesis of these biologically relevant materials.
Many other protocols have been demonstrated for the addition of CF2H radicals to unsaturated systems, resulting in the synthesis of diverse difluoromethylated scaffolds such as lactones, cyclic amides, and difluoromethylated aliphatic ketones, or piperidine-dione type systems. Employing electrochemical conditions, their collective research showcased the important electro- or photochemical conversion of NaSO2CF2H into the fluoroalkyl radical species, resulting in the formation of these fluorinated compounds with good efficacy (Scheme [67]).[109] [110] [111] [112] [113]
In 2020, Xu, Hammond, and co-workers introduced a transition-metal-free protocol for the radical azodifluoromethylation of unactivated alkenes, leveraging diazonium tetrafluoroborates. This method exhibited good functional group tolerance, while also accommodating a wide array of mono-, di-, and trisubstituted alkenes, ultimately yielding difluoromethylated azo compounds in moderate yields up to 62% (Scheme [68]).[114]
Guo and co-workers unveiled a novel strategy for the difluoromethylthiolation of electron-rich indoles in 47–89% yield (Scheme [69]).[115] Despite its efficiency, this approach necessitates the use of highly toxic triphosgene as a reductant, marking a notable limitation.
In a significant advancement reported in 2020, Meng, Li, and co-workers introduced a transformative methodology for the difluoromethylation of nitrogen- and sulfur-containing heterocyclic compounds, employing Rose Bengal as an organic photocatalyst (Scheme [70]).[116] This new protocol demonstrated outstanding efficiency, delivering difluoromethylated analogs in up to 90% yield. Notably, they validated the synthetic utility of this method by synthesizing medicinally relevant difluoromethylated derivatives, with a particular focus on their potential as inhibitors of tumor cell growth. Impressively, the resulting analogs exhibited improved antitumor activity, underscoring the practicality of this difluoromethylation strategy and its promising implications for drug discovery endeavors aimed at developing active pharmaceutical agents.[116]
In 2021, Ackermann and co-workers presented a significant advancement in organic synthesis with the electrooxidative dearomatization of biaryls, facilitating the rapid construction of structurally diverse spiro molecules (Scheme [71]).[117] This methodology showcased the first electrooxidative 6-exo-trig radical dearomative spirocyclization process, resulting in the formation of attractive spirocyclic scaffolds in synthetically useful yields of up to 62%.
Understanding the lipophilicity properties of drugs is paramount in drug discovery and development. Lipophilicity refers to the affinity of a molecule for lipid or fatlike substances, which directly impacts its ability to cross biological barriers and interact with target proteins.[118] [119] Fine-tuning the lipophilicity of a drug is crucial for achieving optimal pharmacokinetic and pharmacodynamic properties. A delicate balance between lipophilicity and hydrophilicity must be struck to ensure site-selective activity and therapeutic efficacy.[2,120,121] Drugs with excessively high lipophilicity may exhibit poor solubility, leading to reduced bioavailability or non-specific interactions, while those with insufficient lipophilicity may fail to penetrate cellular membranes or reach their intended targets. Thus, a thorough understanding of lipophilicity properties enables the rational design of drugs with enhanced selectivity, potency, and safety profiles, ultimately facilitating the development of more effective therapeutic agents.
In 2021, the Shibata group directed their focus towards the underexplored difluoromethanesulfinyl group, recognizing its potential significance despite its limited attention in recent years (Scheme [72]).[122] Their research addressed this gap by introducing a novel system for the difluoromethanesulfinylation of alcohols, yielding previously undiscovered difluoromethanesulfinic esters. Remarkably, this method achieved good to excellent yields, with conversions approaching quantitative levels.
Central to their approach was the in situ generation of a highly reactive sulfinic acid anhydride species, enabling efficient transformation of alcohols into the desired difluoromethylsulfinylated products. The work of the Shibata group not only expands the synthetic repertoire for accessing difluoromethylsulfinylated compounds but also underscores the untapped potential of this functional group in small molecule synthesis.
In 2021, the Hu group presented a significant advancement in synthetic methodology with the copper-mediated cross-coupling of diazo compounds with sulfinates (Scheme [73]).[43] This approach facilitated the synthesis of fluoroalkylated sulfones, a class of compounds typically challenging to access. Central to this method was the migration insertion of copper carbene species, enabling the rapid construction of structurally diverse sulfones. By harnessing the reactivity of diazo compounds and sulfinates under copper mediation, the work of the Hu group provides a versatile and efficient route to fluoroalkylated sulfones, thereby expanding the synthetic toolbox for accessing this important class of molecules.
Also in 2021, Zhang, Wang, and co-workers presented a noteworthy contribution by demonstrating the difluoromethylation reaction of aryl iodides under electrochemical conditions (Scheme [74]).[44] Their approach enabled the transformation of aryl halides as readily available starting materials into difluoromethylated products in good, up to 89%, yields. Investigating electrochemical nickel-mediated cross-coupling reactions, this work offered a sustainable and efficient pathway for accessing difluoromethylated arenes in high yields.
Concurrently, Zhang and co-workers reported a transition-metal-free approach for the difluoromethylation of heterocycles, showcasing the efficacy of K2S2O8 as an oxidant, compared to previously employed silver salts (Scheme [74]).[123] Their methodology facilitated a direct Csp2–H difluoromethylation reaction with broad substrate scope and tolerance, delivering the desired products in good yields. Together, these studies highlight the versatility and potential of electrochemical and transition-metal-free methodologies in accessing valuable difluoromethylated materials.
In 2022, Alemán and co-workers unveiled a novel methodology for the difluoromethylation of α,β unsaturated carbonyl compounds via organocatalysis (Scheme [75]).[124] This remarkable protocol, driven by visible light, enabled enantioselective gem-difluoroalkylation of α,β-unsaturated aldehydes. Notably, the significance of their work was underscored by performing the reaction under sunlight in Madrid, Spain, yielding the corresponding difluoromethylated products in impressive yields of up to 71%. Furthermore, they showcased the versatility of their protocol by demonstrating its applicability under flow chemistry conditions, yielding fluoroalkylated materials in remarkable up to 88% yields.
The functionalization of N-heterocyclic systems emerges as a highly valuable strategy, particularly considering the significant bioactivity exhibited by many nitrogen-containing natural compounds. In 2022, Zhang, Fang, and co-workers presented a noteworthy advancement in this area with their N-ortho-selective difluoromethylation of quinoline and isoquinoline N-oxides under carbon-platinum electrochemical conditions, yielding the desired ortho-difluoromethylated heterocyclic systems in up to 87% yield (Scheme [76]).[125]
Also in 2022, Wu and co-workers contributed to the late-stage functionalization of nitrogen-containing compounds by reporting the electrochemical synthesis of fluoroalkylated spiroindolines in moderate yields (22–58%) (Scheme [77]).[126]
Wang and co-workers introduced a multicomponent approach in 2022, utilizing thiazolium salt mediation for the coupling of styrene derivatives with aryl aldehydes, enabling access to β-difluoromethyl ketones at elevated temperatures (Scheme [78]).[127] These methodologies collectively underscore the versatility and importance of functionalizing nitrogen-containing compounds in organic synthesis, offering new avenues for accessing diverse and biologically relevant drug candidates.
In 2023, Wu and co-workers made a significant contribution to synthetic methodology by reporting the photochemical difluoromethylation of alkynes, targeting the synthesis of dioxodibenzothiazepines (Scheme [79]).[128] This class of 7-membered nitrogen-containing cyclic systems holds notable therapeutic potential for treating neuropsychiatric disorders.[129] Leveraging Eosin Y photocatalyzed conditions, they successfully converted sulfonamide-substituted aryl alkynes into benzothiazepines, demonstrating synthetic utility with synthetic useful yields of up to 82%.
Chen and co-workers presented a complementary approach in 2023, reporting the photocatalytic generation of CF2H radicals coupled with 2-arylideneindane-1,3-diones (Scheme [80]).[130] Operating within a simple Mes-Acr+-mediated system, this methodology showcased the efficient synthesis of fluorinated products, offering a versatile strategy for accessing structurally diversified fluorinated molecules.
[1.1.1]Propellane and bicyclopentane (BCP) structures have emerged as valuable motifs in medicinal chemistry due to their unique properties and versatile applications.[131] [132] [1.1.1]Propellane, with its strained and rigid framework, offers opportunities for designing novel molecular architectures with enhanced stability and reactivity. In contrast, BCP structures serve as effective bioisosteric replacements for 1,4-substituted phenyl rings, imparting desirable pharmacokinetic properties to drug candidates.[133] Both motifs have garnered considerable attention for their ability to modulate molecular properties such as lipophilicity, conformational rigidity, and steric interactions, which are crucial for optimizing drug potency, selectivity, and metabolic stability. The incorporation of non-planar BCP structures into small molecules represents a promising strategy in medicinal chemistry, enabling the development of therapeutically relevant compounds with improved bioavailability, target affinity, and pharmacological profiles.
In 2023, the Molander group introduced an exciting protocol for the difunctionalization of [1.1.1]propellane, a versatile scaffold with promising applications in organic and medicinal chemistry (Scheme [81]).[49] Leveraging the emerging significance of bicyclopentanes as bioisosteric replacements for 1,4-substituted phenyl rings, their work addressed a critical need for strategies in drug design. Their multicomponent reaction incorporated a wide range of readily available nucleophilic radical precursors, facilitating the installation of diverse fluoroalkyl groups into small molecules. This transformative approach not only expands the synthetic toolbox for accessing functionalized propellane derivatives but also holds promise for enhancing pharmacokinetic properties and advancing drug discovery efforts. The protocol represents a significant contribution to the field, addressing the demand for novel linkers with potential applications in medicinal chemistry.
In 2023, Xiao and co-workers delved into the dehydroxylative sulfonylation of alcohols, focusing on the phosphine-mediated reaction of fluoroalkylated sulfinates with benzylic alcohols (Scheme [82]).[134] Through meticulous mechanistic investigations, they unveiled that this dehydroxylative substitution proceeds via an SN2 process. This conclusion was supported by the observation of inversion of configuration and partial racemization during the substitution of enantiomerically pure secondary alcohols, providing valuable insights into the reaction mechanism. Their research not only sheds light on the fundamental mechanistic pathways involved in alcohol functionalization but also paves the way for the development of efficient and selective methodologies for synthesizing valuable sulfonylated compounds.
In 2023, significant progress was made in investigations regarding the addition to unsaturated systems, with several notable contributions. Zhang and co-workers developed a three-component reaction involving quinoxalin-2(1H)-ones, vinylarenes, and NaSO2CF2H under Eosin Y photochemical conditions that yielded important difluorobenzyl analogs in up to 69% yield (Scheme [83]).[135]
The Chen group reported the Mes-Acr+-mediated photocatalytic conversion of 5-vinylisoxazoles into 5-(3,3-difluoropropyl)isoxazoles in excellent yields reaching up to 90% (Scheme [84]), showcasing potential as drug candidates due to their anticancer and antifungal properties.[48]
The Liu group presented an intriguing approach to further functionalize enol-type moieties via pyridinium masking (Scheme [85]).[50] Exploiting the efficacy of pyridinium as a leaving group, their work on the synthesis of α-difluoromethyl ketones revealed the versatility of this protocol, demonstrating that by simply changing the F– source from NaSO2CF3 to NaSO2CF2H, all corresponding products could be obtained. This highlights the versatility of their developed protocol and underscores the potential for further variation in the fluoroalkyl source to access a wide range of products, showcasing the continual innovation and diversity in modern synthetic methodologies.
The coupling of carbonyl-containing compounds with amines has been a subject of investigation for many decades in organic chemistry. Despite the potential utility of these reactions, their implementation has often been hindered by the moisture sensitivity of the resulting imine products, as water can mediate their conversion back into starting materials. However, recent research by Wu and co-workers has shed new light on this process. Through iridium photocatalytic conditions, they demonstrated the in situ formation of imines and their subsequent transformation via CF2H radical addition to the carbon of the imine bond (Scheme [86]).[136] This novel approach, reminiscent of previous reports on the addition of alkenes and alkynes, leads to the synthesis of α-difluoromethylated secondary amines in moderate to good yields ranging between 43–79%.
#
# 4
Trifluoromethylation Strategies
Trifluoromethylation stands as one of the most extensively studied and widely utilized strategies in modern synthetic chemistry.[137] [138] [139] This method allows chemists to introduce trifluoromethyl groups into organic molecules, imparting unique properties and enhancing their utility in various applications. Over the years, numerous reagents and methodologies have been developed for trifluoromethylation, including nucleophilic, electrophilic, and radical approaches. Among these, sulfone reagents have garnered considerable attention and have been extensively investigated for their efficacy in trifluoromethylation reactions, shown by our group for the synthesis of trifluoromethyl-containing silane reagents, and addition of nucleophilic trifluoromethyl anion to various electrophiles like carbonyls, or disulfides.[64,140] This introduction sets the stage for exploring the diverse strategies and applications of trifluoromethylation, with a particular focus on the role of sulfone reagents in this important field of synthetic chemistry (Figure [4]).
4.1PhSO2CF3
Trifluoromethyl phenyl sulfone (PhSO2CF3) stands as a widely utilized reagent in nucleophilic trifluoromethylation reactions, holding significant importance in synthetic chemistry. It was first synthesized by Creary in 1980, as a demonstration of the oxidative power of triflic anhydride in the presence of Grignard reagents.[141] Over the years, it has been an important reagent for nucleophilic fluoroalkylation methodologies, extensively explored by our group for the synthesis the Ruppert–Prakash reagent TMSCF3, and utilization for addition to carbonyl-containing compounds, and disulfides.[64] [140] The trifluoromethanide anion was observed for the first time in solution by our group in 2014, and further studied by low-temperature 13C and 19F NMR. The trifluoromethyl anion was previously believed to be a short-lived transient species but our investigations showed a significant stability and increased lifetime of this species at sub-ambient temperatures.[142] These results are crucial for future investigations of the previously postulated key intermediates in trifluoromethylation reactions, as they confirm the stability and long-lived nature of this anion. In 2015, the Hu group made a pivotal advancement in the synthesis of in situ generated organocopper species for fluoroalkylation chemistry. Their research compared the reactivity of trifluoromethyl phenyl sulfone (PhSO2CF3) with trifluoromethyl phenyl sulfoxide (PhS(O)CF3) in generating CuCF3 species (Scheme [87]).[143] Remarkably, they found that the sulfoxide precursor yielded CuCF3 in up to 93% yield, while the more sterically hindered sulfone resulted in only around 17% yield.
Further investigations unveiled the trifluoromethylation potential of these reagents in reactions with aryl halides, alkynes, and boronic acids, yielding trifluoromethylarenes and terminal trifluoromethyl-substituted alkynes in excellent and good yields, respectively (Scheme [88]).[143] This significant breakthrough highlights the potential of sulfone and sulfoxide reagents in generating more reactive organometallic species for fluoroalkylation purposes, surpassing the capabilities of sulfone alone.
In 2018, the Shibata group introduced a significant approach for the ortho-substitution of PhSO2CF3 derivatives, representing a departure from its traditional use in trifluoromethylation reactions (Scheme [89]).[144] Instead, these derivatives were employed as substrates for further postfunctionalization reactions. The research of the Shibata group revealed a novel role for SO2CF3 as an ortho-directing-metalation group (DMG), effectively guiding incoming electrophilic substituents to positions adjacent to it. Expanding upon this discovery, they explored ortho-substitution using various electrophiles, including alkyl iodide, elemental halides, boronic esters, benzyl halides, and acyl chlorides.
Through ortho-lithiation and subsequent substitution with diverse electrophiles, the Shibata group demonstrated a straightforward yet novel approach utilizing commercially available starting materials, yielding products with high efficiency, reaching up to 73% yield. Remarkably, this method displayed selectivity, as no observable reaction occurred with highly reactive carbonyl-containing electrophiles. The work of the Shibata group underscores the versatility of PhSO2CF3 derivatives as valuable substrates for ortho-substitution reactions, opening up new avenues for synthetic transformations with broad applicability in organic synthesis.
In 2022, the Hu group made a groundbreaking advancement with the visible-light-promoted sulfur trifluoromethylation of thiophenols using PhSO2CF3 (Scheme [90]).[145] Their investigation unveiled the formation of an electron-donor-acceptor complex (EDA complex) between the deprotonated thiophenol and the sulfone reagent. This EDA complex efficiently absorbed visible light, initiating the generation of a reactive thiophenol radical species. Subsequent a trifluoromethyl transfer reaction ensued, culminating in the synthesis of aryl trifluoromethyl sulfides in good to excellent yields. Notably, this metal-free and photocatalyst-free protocol represents a valuable addition to trifluoromethylation methodologies, underscoring the significance of donor-acceptor complexes capable of interacting with light in a manner akin to photocatalysts. This research not only expands the synthetic toolbox for accessing trifluoromethylated compounds but also highlights the potential of EDA complexes as versatile platforms for light-mediated transformations in organic synthesis.
Although outside of the scope of this review, another noteworthy approach was reported by Zhao, Hu, and co-workers in 2022, where they reported an approach to regioselectively access functionalized perfluoro-tert-butylated arenes via nucleophilic addition to arynes, utilizing perfluoro-tert-butyl phenyl sulfone.[146]
In 2023, the Hu group furthered their exploration into multicomponent, enantioselective trifluoromethylation reactions by incorporating the alkynylation of alkenes under mild copper-mediated photochemical conditions (Scheme [91]).[77] Their approach led to the synthesis of structurally diverse chiral fluoroalkylated propargylic compounds in good yields with exceptional enantioselectivity of up to 98% ee. Remarkably, this protocol was seamlessly extended to asymmetric fluoroalkylation-alkynylation reactions with various fluoroalkyl sulfones, facilitating the efficient installation of trifluoromethyl, difluoroalkyl, difluorobenzyl, difluoro(phenylsulfonyl)methyl, and monofluoromethyl groups into the products. This versatility underscores its potential significance in drug discovery endeavors, particularly for molecules of pharmaceutical interest. The development of this methodology represents a notable advancement in synthetic chemistry, offering a valuable tool for accessing chiral fluoroalkylated compounds with high efficiency and stereocontrol.
# 4.2
2-PyrSO2CF3
In recent years, pyridin-2-yl trifluoromethyl sulfone (2-PyrSO2CF3) has garnered limited exploration, primarily serving as a tool for introducing the pyridine scaffold into molecules rather than for trifluoromethyl transfer. Notably, there exists one particularly noteworthy report on its application in the selective C–H trifluoromethoxylation reaction, which introduced a novel concept of trifluoromethoxy radical generation mediated by molecular oxygen. This approach delved into the intricate interplay between oxygen and highly reactive radical species, a phenomenon typically hindered by their mutual intolerance, which often obstructs radical formation and product generation. The reaction mechanism involves the initial generation of CF3 radicals from 2-PyrSO2CF3. The CF3 radicals subsequently react with molecular oxygen, forming trifluoromethylperoxy radicals (CF3OO • ), which are then electrochemically reduced to form the active trifluoromethoxy radical species. Through electrocatalyzed trifluoromethoxylation of (hetero)aromatics, this protocol navigated the transformation of CF3 radicals into trifluoromethylperoxy (CF3OO) radicals, via reaction with molecular oxygen (Scheme [92]).[147]
The method represents a significant advancement in radical transfer processes, showcasing excellent functional group tolerance and delivering trifluoromethoxyarenes in outstanding yields of up to 90%. The exploration of this reagent is highly encouraged, as it represents a valuable but underexplored reagent for trifluoromethylation reactions.
# 4.3
Benzothiazole-SO2CF3
2-((Trifluoromethyl)sulfonyl)benzothiazole (benzothiazol-2-yl trifluoromethyl sulfone, BT-SO2CF3) has emerged as a valuable reagent for trifluoromethyl transfer through diverse pathways. Over recent years, extensive exploration of metal-mediated, electrochemical, and photochemical approaches has underscored the enormous potential of this reagent in facilitating fluoroalkyl group transfer reactions. These investigations have illuminated the versatility of benzothiazole as a scaffold for diverse synthetic transformations, offering valuable avenues for accessing trifluoromethylated compounds. The utilization of different methodologies highlights the adaptability of benzothiazole in various reaction environments, further emphasizing its significance in modern organic synthesis.
In 2016, the Hu group introduced an iridium-mediated photocatalytic approach for trifluoromethyl radical generation and transfer onto vinylarenes (Scheme [93]).[148] This transformative methodology harnessed visible light photoredox catalysis to achieve the synthesis of 1,2-functionalized trifluoroethyl benzyl alcohols.
By leveraging the unique properties of iridium as a photocatalyst, this protocol enabled the efficient and selective introduction of trifluoromethyl groups onto the vinylarene substrates, offering a versatile strategy for accessing valuable trifluoromethylated compounds in excellent yields between 60–92%. This research represents a significant advancement in the field of photoredox catalysis, showcasing its potential in facilitating complex synthetic transformations of fluoroalkyl sulfone reagents for metal-mediated fluoroalkylation reactions.
Isoquinolinediones represent another class of heterocyclic compounds that have garnered significant attention in organic synthesis and medicinal chemistry. These molecules are characterized by a fused isoquinoline and lactam ring system, imparting unique structural and physicochemical properties. Isoquinolinediones exhibit diverse biological activities and have found applications in the synthesis of natural products, pharmaceuticals, and agrochemicals.[149] Their versatile reactivity and ability to engage in various synthetic transformations make them valuable building blocks for the construction of complex molecular architectures. Furthermore, their presence in numerous bioactive compounds underscores their importance in drug discovery and development. This introduction highlights the significance of isoquinolinediones as versatile and biologically relevant scaffolds in organic chemistry. In 2017, Zou and Wang presented a significant advancement with the visible-light-induced trifluoromethylation of N-methacryloylbenzamides utilizing BT-SO2CF3, facilitating the synthesis of CF3-containing isoquinolinediones under mild reaction conditions (Scheme [94]).[79] This methodology offered operational simplicity and broad substrate scope, accommodating a diverse array of N-methacryloyl-N-methylbenzamides bearing both electron-donating and -withdrawing groups.
The transformation yielded moderate to good yields of the desired CF3-containing isoquinoline-1,3(2H,4H)-diones, showcasing the potential of this approach in accessing valuable trifluoromethylated heterocycles. This research not only underscores the significance of visible-light-induced reactions but also highlights the utility of trifluoromethyl groups in enhancing the structural diversity and pharmaceutical relevance of isoquinolinedione derivatives.
A 2019 report by the Hu group detailed the reductive fluoroalkanesulfinylation of electron-rich (hetero)arenes, highlighting the efficacy of diphenylphosphinic chloride as a potent reducing agent (Scheme [95]).[150] Unlike previously reported protocols, which predominantly involved nucleophilic or radical pathways, this approach represents a novel method to access the reductive pathway for transferring fluorosulfinyl groups.
This protocol demonstrated the conversion of both electron-donating and electron-withdrawing scaffolds into the corresponding trifluoromethyl sulfoxide products in good yields. Notably, the versatility of this methodology was showcased through its application in synthesizing complex heteroaromatic systems. Moreover, the practicality and scalability of the reaction was illustrated by successfully conducting it on a larger scale, up to 10 mmol. This research represents a significant advancement in the field, offering a valuable strategy for the synthesis of CF3S(O)-containing compounds.
The last relevant report by Fun and co-workers in 2019, pertains to the visible-light-induced radical trifluoromethylation of β,γ-unsaturated oximes for the synthesis of isoxazolines (Scheme [96]).[80] Isoxazolines exhibit a wide range of biological activities, including antimicrobial, anticonvulsant, anti-inflammatory, antitumor, and insecticidal properties.[151] Their structural diversity and ability to modulate specific biological targets make them promising candidates for drug development across various therapeutic areas. This approach not only showcases the need for diversifying isoxazolines core motifs but also demonstrates their potential as valuable scaffolds in medicinal chemistry, owing to their diverse biological activities and structural adaptability.
Fun and co-workers reported a smooth protocol for the photocatalytic tandem radical trifluoromethylation-cyclization reaction giving access to 5-trifluoromethylated isoxazolines in good 78–88% yield. This methodology not only provides an efficient synthetic route to isoxazolines but also underscores their potential as valuable building blocks in medicinal chemistry endeavors.
# 4.4
NaSO2CF3
The utilization of trifluoromethanesulfinate salts, notably sodium trifluoromethanesulfinate (NaSO2CF3), in trifluoromethylation reactions has garnered significant attention in organic synthesis. With over 10,000 reported documents to date, spanning various trifluoromethylation strategies, this reagent has emerged as a cornerstone in fluoroalkylation chemistry since its introduction in 1974 and utilization by Langlois in 1991.[152] The years 2023 and 2024 alone witnessed over 1500 reports detailing the diverse applications of this reagent. In this section, we aim to present the most common strategies for utilizing these reagents, highlighting their versatility and significance in modern organic synthesis.
Most reported protocols for trifluoromethanesulfinate salts, can be broadly classified into three main categories: electrochemical generation of CF3 radicals, photochemical generation of CF3 radicals, and metal-free or metal-mediated generation of CF3 radicals. These approaches capitalize on distinct methodologies to access CF3 radicals, which subsequently participate in trifluoromethylation reactions. The diversity within these categories underscores the versatility of trifluoromethanesulfinate salts as reagents for introducing trifluoromethyl groups into organic molecules.
4.4.1Electrochemical Approaches
The electrochemical generation of CF3 radicals utilizing sodium trifluoromethanesulfinate salt (NaSO2CF3) has been a subject of extensive investigation over the past few decades. As methods continue to advance, becoming increasingly efficient and selective, the exploration of these methodologies remains a vibrant area of research. In recent years, there have been numerous documented reports focusing on the electrochemical generation of CF3 radicals, particularly for cyclization reactions for accessing highly valuable core motifs like phenanthridines, benzoxazines, isoxazolines, indoles, or imidazoles (Scheme [97]).[153] [154] [155] [156] [157]
The reaction mechanism for all of the described protocols involves the anodic oxidation of NaSO2CF3, resulting in the formation of the corresponding CF3SO2 radical through single electron oxidation (Figure [5]).[154] [155]
Subsequently, this radical readily undergoes fragmentation, releasing SO2 and generating the desired fluoroalkyl radical. This key step serves as the initiation point for various transformations, including cyclization reactions and functional group manipulations, enabling the synthesis of diverse fluorinated organic compounds.
# 4.4.2
Photochemical Approaches
The realm of photochemical approaches for fluoroalkylation reactions has witnessed exponential growth, reflecting the increasing importance of this discipline in organic chemistry. These methods have emerged as powerful tools for synthesizing important motifs through fluoroalkylation reactions. It has been demonstrated that the trifluoromethyl radical can be readily generated via photoredox catalysis, enabling efficient and selective transformations. The use of light as a driving force for radical generation offers unique advantages, including mild reaction conditions, high selectivity, and broad substrate scope. As such, photochemical approaches hold immense potential for the rapid and streamlined synthesis of diverse fluorinated organic compounds. As evidenced in previous sections, many fluoroalkylation approaches rely on transition metals, such as ruthenium or iridium, for catalysis. However, an increasing number of protocols have been reported where these transition metals are circumvented in favor of organocatalysts (Scheme [98]).[49] [130] , [158] [159] [160] [161] This shift underscores a growing trend in organic synthesis towards the development of metal-free methodologies, driven by considerations such as cost, toxicity, and environmental impact. Organocatalysts offer distinct advantages, including milder reaction conditions, improved functional group compatibility, and enhanced atom economy.
A very interesting approach was reported by Liu, Yi, and co-workers in 2024, where they investigated the photocatalyzed ditrifluoromethylthiolation of alkenes using NaSO2CF3 (Scheme [99]).[160] Despite the previously demonstrated trifluoromethylation via radical generation from NaSO2CF3, they presented the unprecedented use of NaSO2CF3 as a radical trifluoromethylthiolation reagent. This novel method proceeds through deoxygenative reduction and photoredox radical processes, showcasing a unique PPh3-mediated activation of NaSO2CF3 in generating the electrophilic F3CS-SCF3 species (Scheme [99]).
By highlighting the role of organocatalysis in fluoroalkylation reactions, these emerging protocols contribute to the diversification and sustainability of synthetic methodologies in organic chemistry. In recent years, numerous reports have focused on the synthesis of structurally diverse motifs containing trifluoromethyl groups, leading to the formation of valuable structures across various chemical classes. These photochemical approaches, mediated by popular organocatalysts, such as Eosin Y, 4CzIPN, or Mes-Acr+, offer efficient and selective routes to fluoroalkylation reactions. Alternatively, transition metals, like iridium, copper with appropriate ligands, or as presented in previous sections, ruthenium, provide versatile catalytic platforms for photochemical transformations, enabling the synthesis of diverse trifluoromethyl-containing compounds. These include trifluoromethylated indenediones, piperidines, pyrrolidines, and indolequinoxalinones, among others. There has been a notable increase in research targeting the synthesis of fluoroalkylated bicyclo[1.1.1]pentanes, reflecting the growing interest of these scaffolds highlighted for applications in medicinal chemistry, materials science, agrochemistry (Scheme [98]).[49]
The reaction mechanism typically involves the initial excitation of the photocatalyst, whether it be a metal-based or organocatalyst, to an excited state upon absorption of light (Figure [6]).[130] [159] Subsequently, the trifluoromethyl precursor undergoes oxidation by the excited catalyst, leading to the formation of the unstable SO2CF3 radical; fragmentation releases SO2, serving as a driving force for the reaction, while concurrently generating the highly reactive CF3 radical. Meanwhile, the excited photocatalyst is reduced, forming a radical anion species. This reactive radical anion often participates in subsequent reduction steps within the reaction sequence, ultimately returning to the ground state and initiating another catalytic cycle. This intricate interplay of oxidation and reduction steps underpins the efficiency and selectivity of photochemical fluoroalkylation reactions highlighting the high yields obtained in the photocatalytic approaches yielding products up to 99%.[162] [163]
# 4.4.3
Other Noteworthy Approaches
In 2023, Chatterjee and Pattanayak demonstrated a regio- and stereoselective tandem trifluoromethylation of unsaturated carbonyl-containing systems to afford diverse isoxazoles with pharmaceutical potential in up to 85% yield (Scheme [100]).[164]
Similarly, Balalaie and co-workers showcased a manganese-mediated regioselective C–H trifluoromethylation of imidazopyridines and quinoxalines with high functional group tolerance and excellent yields of up to 90% (Scheme [101]).[165] These studies underscore the versatility and approaches in accessing valuable fluorinated compounds.
#
#
# 5
Conclusion
This review has shed light on the recent advancements in nucleophilic, electrophilic, and radical mono-, di-, and trifluoromethylation reactions. Sulfone reagents have emerged as a crucial class of substrates for these transformations, offering diverse reaction pathways for accessing fluoroalkylated compounds of interest. The extensive investigation has uncovered numerous valuable approaches for synthesizing structures with applications in pharmaceuticals, agrochemicals, material science, and beyond, prompting ongoing development in fluoroalkylating reagents. While this review primarily focused on key reagents such as PhSO2CFX2, pyridine-based SO2CFX2, benzothiazole-based SO2CFX2, and NaSO2CFX2, it also highlighted the relative underexploration of monofluoromethylation reactions compared to difluoro- and trifluoromethylation reactions. Encouraging research in monofluoromethylation via these pathways is warranted, given the versatile properties it offers, including tunable lipophilicity, metabolic stability, hydrogen-bonding ability, and bioisosteric potential. Fluoroalkyl sulfone reagents remain a crucial topic in organic synthesis, with ongoing utilization and development crucial to meet the increasing demand for fluoroalkylated materials in the face of evolving restrictions. Continued efforts towards developing novel and efficient protocols are essential to address these challenges and advance the field further.
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Conflict of Interest
The authors declare no conflict of interest.
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References
- 1 Böhm H, Banner D, Bendels S, Kansy M, Kuhn B, Müller K, Obst-Sander U, Stahl M. ChemBioChem 2004; 5: 637
- 2 Meanwell NA. J. Med. Chem. 2018; 61: 5822
- 3 Tseng C.-C, Baillie G, Donvito G, Mustafa MA, Juola SE, Zanato C, Massarenti C, Dall’Angelo S, Harrison WT. A, Lichtman AH, Ross RA, Zanda M, Greig IR. J. Med. Chem. 2019; 62: 5049
- 4 Ogawa Y, Tokunaga E, Kobayashi O, Hirai K, Shibata N. iScience 2020; 23: 101467
- 5 Ni C, Hu M, Hu J. Chem. Rev. 2015; 115: 765
- 6 Xiao P, Ni C, Miao W, Zhou M, Hu J, Chen D, Hu J. J. Org. Chem. 2019; 84: 8345
- 7 Wang X, Hu J. Phosphorus, Sulfur Silicon Relat. Elem. 2024; 199: 10
- 8 Liang T, Neumann CN, Ritter T. Angew. Chem. Int. Ed. 2013; 52: 8214
- 9 Hu J, Zhang W, Wang F. Chem. Commun. 2009; 7465
- 10 Prakash GK. S, Chacko S, Alconcel S, Stewart T, Mathew T, Olah GA. Angew. Chem. Int. Ed. 2007; 46: 4933
- 11 Zheng H, Li Z, Jing J, Xue X, Cheng J. Angew. Chem. Int. Ed. 2021; 60: 9401
- 12 Fukuzumi T, Shibata N, Sugiura M, Yasui H, Nakamura S, Toru T. Angew. Chem. Int. Ed. 2006; 45: 4973
- 13 Ni C, Li Y, Hu J. J. Org. Chem. 2006; 71: 6829
- 14 Prakash GK. S, Shao N, Wang F, Ni C. Org. Synth. 2013; 90: 130
- 15 Prakash GK. S, Wang F, Shao N, Mathew T, Rasul G, Haiges R, Stewart T, Olah GA. Angew. Chem. Int. Ed. 2009; 48: 5358
- 16 Prakash GK. S, Zhao X, Chacko S, Wang F, Vaghoo H, Olah GA. Beilstein J. Org. Chem. 2008; 4: 17
- 17 Prakash GK. S, Ledneczki I, Chacko S, Ravi S, Olah GA. J. Fluorine Chem. 2008; 129: 1036
- 18 Ispizua-Rodriguez X, Krishnamurti V, Coe M, Prakash GK. S. Org. Synth 2019; 96: 474
- 19 Kim YS, Kim SM, Wang B, Companyó X, Li J, Moyano A, Im S, Tošner Z, Yang JW, Rios R. Adv. Synth. Catal. 2014; 356: 437
- 20 Lecointre B, Azzouz R, Bischoff L. Tetrahedron Lett. 2014; 55: 1913
- 21 Nishimine T, Taira H, Tokunaga E, Shiro M, Shibata N. Angew. Chem. Int. Ed. 2016; 55: 359
- 22 Zhang Z, Puente Á, Wang F, Rahm M, Mei Y, Mayr H, Prakash GK. S. Angew. Chem. Int. Ed. 2016; 55: 12845
- 23 Bellini R, Magre M, Biosca M, Norrby P.-O, Pàmies O, Diéguez M, Moberg C. ACS Catal. 2016; 6: 1701
- 24a Guo Z, Xie M, Han R, Qu G, Guo H. Chin. J. Org. Chem. 2018; 38: 112
- 24b Dai J, Duan X, Zhou J, Fu C, Ma S. Chin. J. Chem. 2018; 36: 387
- 25 Liao L, Zhang Y, Wu Z.-W, Ye Z.-T, Zhang X.-X, Chen G, Yu J.-S. Chem. Sci. 2022; 13: 12519
- 26 Qian P, Zhang S, Luo F, Wang J, Zhang X, Liu X, Chen X, Wang W, Chen X. Chem. Commun. 2022; 58: 11458
- 27 Zhang Y, Yang J, Ruan Y.-L, Liao L, Ma C, Xue X.-S, Yu J.-S. Chem. Sci. 2023; 14: 12676
- 28 Knieb A, Krishnamurti V, Zhu Z, Prakash GK. S. J. Fluorine Chem. 2023; 267: 110095
- 29 Zeng J, Niu L, Wang Z, Wei R, Cahard D. Eur. J. Org. Chem. 2023; 26: e202300651
- 30 Liao L, Zhao Z.-P, Gu B.-N, Yu J.-S, Zhou J. Synthesis 2023; 55: 3090
- 31 Furukawa T, Goto Y, Kawazoe J, Tokunaga E, Nakamura S, Yang Y, Du H, Kakehi A, Shiro M, Shibata N. Angew. Chem. Int. Ed. 2010; 49: 1642
- 32 Shen X, Zhang L, Zhao Y, Zhu L, Li G, Hu J. Angew. Chem. Int. Ed. 2011; 50: 2588
- 33 Huang B, Chen Y, Zhang X, Yan M. Eur. J. Org. Chem. 2021; 2021: 3015
- 34 He Z, Tan P, Ni C, Hu J. Org. Lett. 2015; 17: 1838
- 35 Tang X.-J, Thomoson CS, Dolbier WR. Org. Lett. 2014; 16: 4594
- 36 Tang X, Dolbier WR. Angew. Chem. Int. Ed. 2015; 54: 4246
- 37 Zhang Z, Tang X.-J, Dolbier WR. Org. Lett. 2016; 18: 1048
- 38 Konik YA, Elek GZ, Kaabel S, Järving I, Lopp M, Kananovich DG. Org. Biomol. Chem. 2017; 15: 8334
- 39 Konik YA, Kudrjashova M, Konrad N, Kaabel S, Järving I, Lopp M, Kananovich DG. Org. Biomol. Chem. 2017; 15: 4635
- 40 Fang J, Shen W.-G, Ao G.-Z, Liu F. Org. Chem. Front. 2017; 4: 2049
- 41 Xing B, Ni C, Hu J. Chin. J. Chem. 2018; 36: 206
- 42 Fu W, Sun Y, Li X. Synth. Commun. 2020; 50: 388
- 43 Wang Q, Liu A, Wang Y, Ni C, Hu J. Org. Lett. 2021; 23: 6919
- 44 Zou Z, Li H, Huang M, Zhang W, Zhi S, Wang Y, Pan Y. Org. Lett. 2021; 23: 8252
- 45 Louvel D, Souibgui A, Taponard A, Rouillon J, Ben Mosbah M, Moussaoui Y, Pilet G, Khrouz L, Monnereau C, Vantourout JC, Tlili A. Adv. Synth. Catal. 2022; 364: 139
- 46 Dai P, Li Y, Chen Y, Jiao J, Wang Q, Li C, Gu Y, Zhang Y, Xia Q, Zhang W.-H. Org. Lett. 2022; 24: 1357
- 47 Tian S, Chen M, Tang Y, Cheng K, Tsui GC, Wang Q. Org. Chem. Front. 2023; 10: 6124
- 48 Zheng J, Xu Y, Song S, Huang L, Cao D, Zhong A, Yang J, Chen D. J. Org. Chem. 2023; 88: 10206
- 49 Huang W, Zheng Y, Keess S, Molander GA. J. Am. Chem. Soc. 2023; 145: 5363
- 50 Xu J, Li Y, Zhu X, Lv S, Xu Y, Cheng T, Liu G, Liu R. Org. Lett. 2023; 25: 6211
- 51 Yagupolskii LM, Aleksandrov AM. Zh. Obshch. Khim. 1968; 38: 1503
- 52 Lutskii AE, Obukhova EM, Kolesnik MI, Pukhovetskii AYa, Yagupol’skii LM, Korin’ko VA. Teor. Eksp. Khim. 1973; 9: 126
- 53 Makosza M, Golinski J, Baran J. J. Org. Chem. 1984; 49: 1488
- 54 Inbasekaran M, Peet NP, McCarthy JR, Le Tourneau ME. J. Chem. Soc., Chem. Commun. 1985; 678
- 55 Liu C, Wang Q. Angew. Chem. Int. Ed. 2018; 57: 4727
- 56 Ye W, Zhu L, Luo Q, Ni C, Hu J. Tetrahedron 2020; 76: 130877
- 57 Bhosale VA, Císařová I, Kamlar M, Veselý J. Chem. Commun. 2022; 58: 9942
- 58 Yerien DE, Barata-Vallejo S, Postigo A. Chem. Eur. J. 2017; 23: 14676
- 59 Erickson JA, McLoughlin JI. J. Org. Chem. 1995; 60: 1626
- 60 Prakash GK. S, Hu J, Wang X. Difluoromethyl Phenyl Sulfone. In e-EROS Encyclopedia of Reagents for Organic Synthesis [Online]. Wiley & Sons; New York: 2023
- 61 Prakash GK. S, Hu J, Wang Y, Olah GA. Angew. Chem. Int. Ed. 2004; 43: 5203
- 62 Hine J, Porter JJ. J. Am. Chem. Soc. 1960; 82: 6178
- 63 Prakash GK. S, Hu J, Mathew T, Olah GA. Angew. Chem. Int. Ed. 2003; 42: 5216
- 64 Prakash GK. S, Hu J, Olah GA. J. Org. Chem. 2003; 68: 4457
- 65 Prakash GK. S, Hu J, Wang Y, Olah GA. Org. Lett. 2004; 6: 4315
- 66 Prakash GK. S, Hu J, Wang Y, Olah GA. Eur. J. Org. Chem. 2005; 2005: 2218
- 67 Wang X, Liu G, Xu X, Shibata N, Tokunaga E, Shibata N. Angew. Chem. Int. Ed. 2014; 53: 1827
- 68 Ye W, Zhang L, Ni C, Rong J, Hu J. Chem. Commun. 2014; 50: 10596
- 69 Li X, Zhao J, Hu M, Chen D, Ni C, Wang L, Hu J. Chem. Commun. 2016; 52: 3657
- 70 Zhang R, Ni C, Zhao Y, Hu J. Tetrahedron 2018; 74: 5295
- 71 Xiao P, Rong J, Ni C, Guo J, Li X, Chen D, Hu J. Org. Lett. 2016; 18: 5912
- 72 Wu C, Shen X, Dai J, Xu J, Xu H. Org. Biomol. Chem. 2021; 19: 7607
- 73 Nobile E, Castanheiro T, Besset T. Chem. Commun. 2021; 57: 12337
- 74 Sap JB. I, Meyer CF, Ford J, Straathof NJ. W, Dürr AB, Lelos MJ, Paisey SJ, Mollner TA, Hell SM, Trabanco AA, Genicot C, Am Ende CW, Paton RS, Tredwell M, Gouverneur V. Nature 2022; 606: 102
- 75 Ziabko M, Klepetářová B, Beier P. J. Org. Chem. 2023; 88: 6939
- 76 Bräse S, Gil C, Knepper K, Zimmermann V. Angew. Chem. Int. Ed. 2005; 44: 5188
- 77 Wei Z, Zheng W, Wan X, Hu J. Angew. Chem. Int. Ed. 2023; 62: e202308816
- 78 Li S, Wang X, Yang Y, Ni C, Hu J. Org. Lett. 2024; 26: 872
- 79 Zhou, G.; Wang, X. Org. Biomol. Chem. 2017, 15, 8748.
- 80 Zhu M, Fun W, Guo W, Tian Y, Wang Z, Xu C, Ji B. Eur. J. Org. Chem. 2019; 2019: 1614
- 81 Trump L, Lemos A, Lallemand B, Pasau P, Mercier J, Lemaire C, Luxen A, Genicot C. Angew. Chem. Int. Ed. 2019; 58: 13149
- 82 Zhu M, You Q, Li R. J. Fluorine Chem. 2019; 228: 109391
- 83 Bao K, Wei J, Yan H, Sheng R. RSC Adv. 2020; 10: 25947
- 84 Kuchar M, Mamat C. Molecules 2015; 20: 16186
- 85 Johnson BM, Shu Y.-Z, Zhuo X, Meanwell NA. J. Med. Chem. 2020; 63: 6315
- 86 Obach RS, Walker GS, Brodney MA. Drug Metab. Dispos. 2016; 44: 634
- 87 Wei J, Bao K, Wang Y, Sheng R, Hu J. Org. Biomol. Chem. 2020; 18: 4556
- 88 Zhou X, Ni C, Deng L, Hu J. Chem. Commun. 2021; 57: 8750
- 89 Zhang B, Wang J. Org. Lett. 2022; 24: 3721
- 90 Zhu M, Tian Y, Sha J, Fu W. ChemistrySelect 2022; 7: e202203986
- 91 Mao E, Prieto Kullmer CN, Sakai HA, MacMillan DW. C. J. Am. Chem. Soc. 2024; 146: 5067
- 92 Zhao Y, Huang W, Zhu L, Hu J. Org. Lett. 2010; 12: 1444
- 93 Prakash GK. S, Ni C, Wang F, Hu J, Olah GA. Angew. Chem. Int. Ed. 2011; 50: 2559
- 94 Prakash GK. S, Ni C, Wang F, Zhang Z, Haiges R, Olah GA. Angew. Chem. Int. Ed. 2013; 52: 10835
- 95 Miao W, Zhao Y, Ni C, Gao B, Zhang W, Hu J. J. Am. Chem. Soc. 2018; 140: 880
- 96 Sun H, Jiang Y, Yang Y.-S, Li Y.-Y, Li L, Wang W.-X, Feng T, Li Z.-H, Liu J.-K. Org. Biomol. Chem. 2019; 17: 6629
- 97 Josephson B, Fehl C, Isenegger PG, Nadal S, Wright TH, Poh AW. J, Bower BJ, Giltrap AM, Chen L, Batchelor-McAuley C, Roper G, Arisa O, Sap JB. I, Kawamura A, Baldwin AJ, Mohammed S, Compton RG, Gouverneur V, Davis BG. Nature 2020; 585: 530
- 98 Li Z, Wang M, Shi Z. Angew. Chem. Int. Ed. 2021; 60: 186
- 99 Miao W, Ni C, Xiao P, Jia R, Zhang W, Hu J. Org. Lett. 2021; 23: 711
- 100 Du W, Luo Q, Wei Z, Wang X, Ni C, Hu J. Sci. China: Chem. 2023; 66: 2785
- 101 Rong J, Ni C, Gu Y, Hu J. Helv. Chim. Acta 2021; 104: e2100019
- 102 Wei Z, Miao W, Ni C, Hu J. Angew. Chem. Int. Ed. 2021; 60: 13597
- 103 Wang X, Ye W, Kong T, Wang C, Ni C, Hu J. Org. Lett. 2021; 23: 8554
- 104 Yang M, Huang X, Miao W, Yi L, Cai J, Zhao Z, He J, Qiu D. Org. Chem. Front. 2023; 10: 1975
- 105 Isenegger PG, Josephson B, Gaunt B, Davy MJ, Gouverneur V, Baldwin AJ, Davis BG. Nat. Protoc. 2023; 18: 1543
- 106 Wu Q.-Y, Ao G.-Z, Liu F. Org. Chem. Front. 2018; 5: 2061
- 107 Xiong Y, Sun Y, Zhang G. Org. Lett. 2018; 20: 6250
- 108 Dai P, Yu X, Teng P, Zhang W.-H, Deng C. Org. Lett. 2018; 20: 6901
- 109 Zhang S, Li L, Zhang J, Zhang J, Xue M, Xu K. Chem. Sci. 2019; 10: 3181
- 110 Ruan Z, Huang Z, Xu Z, Mo G, Tian X, Yu X.-Y, Ackermann L. Org. Lett. 2019; 21: 1237
- 111 Zou Z, Zhang W, Wang Y, Kong L, Karotsis G, Wang Y, Pan Y. Org. Lett. 2019; 21: 1857
- 112 Shao J, Wang Y, Chen S, Wang S, Wu Y, Li X, Zhang W, Deng C. Tetrahedron 2021; 79: 131822
- 113 Yuan X, Cui Y, Zhang X, Qin L, Sun Q, Duan X, Chen L, Li G, Qiu J, Guo K. Chem. Eur. J. 2021; 27: 6522
- 114 Lu Z, Hennis O, Gentry J, Xu B, Hammond GB. Org. Lett. 2020; 22: 4383
- 115 Gao H, Gu Y, Wang Z, Yuan Y, Wang Y, Guo S. Synlett 2020; 31: 1838
- 116 Zhang W, Xiang X.-X, Chen J, Yang C, Pan Y.-L, Cheng J.-P, Meng Q, Li X. Nat. Commun. 2020; 11: 638
- 117 Zhang Y, Ma C, Struwe J, Feng J, Zhu G, Ackermann L. Chem. Sci. 2021; 12: 10092
- 118 Stephens C, Lucena MI, Andrade RJ. Idiosyncratic Drug-Induced Liver Injury: Mechanisms and Susceptibility Factors . In Comprehensive Toxicology, 3rd ed., Vol. 2. McQueen CA. Elsevier; Amsterdam: 2018: 625-650
- 119 Chandrasekaran B, Abed SN, Al-Attraqchi O, Kuche K, Tekade RK. Computer-Aided Prediction of Pharmacokinetic (ADMET) Properties . In Dosage Form Design Parameters, Vol. II. Tekade RA. Elsevier; Amsterdam: 2018: 731-755
- 120 Efremov RG, Chugunov AO, Pyrkov TV, Priestle JP, Arseniev AS, Jacoby E. Curr. Med. Chem. 2007; 14: 393
- 121 Ditzinger F, Price DJ, Ilie A.-R, Köhl NJ, Jankovic S, Tsakiridou G, Aleandri S, Kalantzi L, Holm R, Nair A, Saal C, Griffin B, Kuentz M. J. Pharm. Pharmacol. 2019; 71: 464
- 122 Sumii Y, Sasaki K, Matsubara O, Shibata N. Org. Lett. 2021; 23: 2777
- 123 Dai P, Jiao J, Wang Q, Yu X, Teng P, Zhu Y, Gu Y.-C, Zhang W.-H. Tetrahedron 2021; 100: 132466
- 124 Rodríguez RI, Sicignano M, Alemán J. Angew. Chem. Int. Ed. 2022; 61: e202112632
- 125 Zhang D, Cai J, Du J, Wang Q, Yang J, Geng R, Fang Z, Guo K. Org. Lett. 2022; 24: 1434
- 126 Mo K, Zhou X, Wu J, Zhao Y. Org. Lett. 2022; 24: 2788
- 127 She K, Liang F, Tian S, Wang H, Tsui GC, Wang Q. Org. Lett. 2022; 24: 4840
- 128 Chen X, Geng Y, Liu B, Zhu Y, Zou D, Wu Y, Wu Y. Org. Chem. Front. 2023; 10: 1968
- 129 Kok L, Slooter AJ, Hillegers MH, Van Dijk D, Veldhuijzen DS. Crit. Care Med. 2018; 46: 1673
- 130 Zheng J, Wu Y, Cao D, Song S, Yang Y, Huang L, Chen D. J. Fluorine Chem. 2023; 266: 110090
- 131 Shire BR, Anderson EA. JACS Au 2023; 3: 1539
- 132 Zhao J.-X, Chang Y.-X, He C, Burke BJ, Collins MR, Del Bel M, Elleraas J, Gallego GM, Montgomery TP, Mousseau JJ, Nair SK, Perry MA, Spangler JE, Vantourout JC, Baran PS. Proc. Natl. Acad. Sci. U.S.A. 2021; 118: e2108881118
- 133 Ratni H, Baumann K, Bellotti P, Cook XA, Green LG, Luebbers T, Reutlinger M, Stepan AF, Vifian W. RSC Med. Chem. 2021; 12: 758
- 134 Xiang Y.-J, Liu S, Zhou J, Lin J.-H, Yao X, Xiao J.-C. J. Org. Chem. 2023; 88: 4818
- 135 Shen L, Yuan J.-W, Zhang B, Song S.-Y, Yang L.-R, Xiao Y.-M, Zhang S.-R, Qu L.-B. Z. Naturforsch., B: J. Chem. Sci. 2023; 78: 245
- 136 Zhang S, Geng Y, Jiao J, Zou D, Wu Y, Wu Y. Adv. Synth. Catal. 2023; 365: 4132
- 137 Besset T, Schneider C, Cahard D. Angew. Chem. Int. Ed. 2012; 51: 5048
- 138 Tomashenko OA, Grushin VV. Chem. Rev. 2011; 111: 4475
- 139 Barata-Vallejo S, Lantaño B, Postigo A. Chem. Eur. J. 2014; 20: 16806
- 140 Prakash GK. S, Hu J, Olah GA. Org. Lett. 2003; 5: 3253
- 141 Creary X. J. Org. Chem. 1980; 45: 2727
- 142 Prakash GK. S, Wang F, Zhang Z, Haiges R, Rahm M, Christe KO, Mathew T, Olah GA. Angew. Chem. Int. Ed. 2014; 53: 11575
- 143 Li X, Zhao J, Zhang L, Hu M, Wang L, Hu J. Org. Lett. 2015; 17: 298
- 144 Sumii Y, Taniguchi M, Xu X.-H, Tokunaga E, Shibata N. Tetrahedron 2018; 74: 5635
- 145 Wei Z, Lou Z, Ni C, Zhang W, Hu J. Chem. Commun. 2022; 58: 10024
- 146 Wei Z, Wen L, Zhu K, Wang Q, Zhao Y, Hu J. J. Am. Chem. Soc. 2022; 144: 22281
- 147 Ouyang Y, Xu X, Qing F. Angew. Chem. Int. Ed. 2022; 61: e202114048
- 148 Rong J, Ni C, Wang Y, Kuang C, Gu Y, Hu J. Acta Chim. Sin. 2017; 75: 105
- 149 Karanja CW, Naganna N, Abutaleb NS, Dayal N, Onyedibe KI, Aryal U, Seleem MN, Sintim HO. Molecules 2022; 27: 5085
- 150 Wei J, Bao K, Qi C, Liu Y, Ni C, Sheng R, Hu J. Adv. Synth. Catal. 2019; 361: 5528
- 151 Shaik A, Bhandare RR, Palleapati K, Nissankararao S, Kancharlapalli V, Shaik S. Molecules 2020; 25: 1047
- 152 Langlois BR, Laurent E, Roidot N. Tetrahedron Lett. 1991; 32: 7525
- 153 La-ongthong K, Chantarojsiri T, Soorukram D, Leowanawat P, Reutrakul V, Kuhakarn C. Org. Biomol. Chem. 2023; 21: 4225
- 154 Mahanty K, Saha SK, Halder A, De Sarkar S. Chem. Commun. 2023; 59: 4467
- 155 Chen D, Yang X, Wang D, Li Y, Shi L, Liang D. Org. Chem. Front. 2023; 10: 2482
- 156 Chen X, Jiang J, Huang X.-J, He W.-M. Org. Chem. Front. 2023; 10: 3898
- 157 Yan Z.-H, Yan Y, Wei Z.-L, Liao W.-W. J. Org. Chem. 2024; 89: 2718
- 158 Zhou Q.-H, Dai J.-Y, Zhao W.-J, Zhong X.-Y, Liu C.-Y, Luo W.-W, Li Z.-W, Li J.-S, Liu W.-D. Org. Biomol. Chem. 2023; 21: 3317
- 159 Zhang L, Zheng K, Zhang P, Jiang M, Shen J, Chen C, Shen C. Green Synth. Catal. 2024; 5: 51
- 160 Chen F, Jiang L, Hu C, Liu J, Yi W. Sci. China: Chem. 2024; 67: 587
- 161 Li H, Zhang Y, Yang X, Deng Z, Zhu Z, Zhou P, Ouyang X, Yuan Y, Chen X, Yang L, Liu M, Shu C. Angew. Chem. Int. Ed. 2023; 62: e202300159
- 162 Chatterjee T, Iqbal N, You Y, Cho EJ. Acc. Chem. Res. 2016; 49: 2284
- 163 Lin D, Coe M, Krishnamurti V, Ispizua-Rodriguez X, Prakash GK. S. Chem. Rec. 2023; 23: e202300104
- 164 Pattanayak P, Chatterjee T. J. Org. Chem. 2023; 88: 5420
- 165 Firuz ME, Rajai-Daryasarei S, Rominger F, Biglari A, Balalaie S. J. Org. Chem. 2023; 88: 10599
Corresponding Author
Publication History
Received: 11 June 2024
Accepted after revision: 16 July 2024
Article published online:
05 September 2024
© 2024. Thieme. All rights reserved
Georg Thieme Verlag KG
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References
- 1 Böhm H, Banner D, Bendels S, Kansy M, Kuhn B, Müller K, Obst-Sander U, Stahl M. ChemBioChem 2004; 5: 637
- 2 Meanwell NA. J. Med. Chem. 2018; 61: 5822
- 3 Tseng C.-C, Baillie G, Donvito G, Mustafa MA, Juola SE, Zanato C, Massarenti C, Dall’Angelo S, Harrison WT. A, Lichtman AH, Ross RA, Zanda M, Greig IR. J. Med. Chem. 2019; 62: 5049
- 4 Ogawa Y, Tokunaga E, Kobayashi O, Hirai K, Shibata N. iScience 2020; 23: 101467
- 5 Ni C, Hu M, Hu J. Chem. Rev. 2015; 115: 765
- 6 Xiao P, Ni C, Miao W, Zhou M, Hu J, Chen D, Hu J. J. Org. Chem. 2019; 84: 8345
- 7 Wang X, Hu J. Phosphorus, Sulfur Silicon Relat. Elem. 2024; 199: 10
- 8 Liang T, Neumann CN, Ritter T. Angew. Chem. Int. Ed. 2013; 52: 8214
- 9 Hu J, Zhang W, Wang F. Chem. Commun. 2009; 7465
- 10 Prakash GK. S, Chacko S, Alconcel S, Stewart T, Mathew T, Olah GA. Angew. Chem. Int. Ed. 2007; 46: 4933
- 11 Zheng H, Li Z, Jing J, Xue X, Cheng J. Angew. Chem. Int. Ed. 2021; 60: 9401
- 12 Fukuzumi T, Shibata N, Sugiura M, Yasui H, Nakamura S, Toru T. Angew. Chem. Int. Ed. 2006; 45: 4973
- 13 Ni C, Li Y, Hu J. J. Org. Chem. 2006; 71: 6829
- 14 Prakash GK. S, Shao N, Wang F, Ni C. Org. Synth. 2013; 90: 130
- 15 Prakash GK. S, Wang F, Shao N, Mathew T, Rasul G, Haiges R, Stewart T, Olah GA. Angew. Chem. Int. Ed. 2009; 48: 5358
- 16 Prakash GK. S, Zhao X, Chacko S, Wang F, Vaghoo H, Olah GA. Beilstein J. Org. Chem. 2008; 4: 17
- 17 Prakash GK. S, Ledneczki I, Chacko S, Ravi S, Olah GA. J. Fluorine Chem. 2008; 129: 1036
- 18 Ispizua-Rodriguez X, Krishnamurti V, Coe M, Prakash GK. S. Org. Synth 2019; 96: 474
- 19 Kim YS, Kim SM, Wang B, Companyó X, Li J, Moyano A, Im S, Tošner Z, Yang JW, Rios R. Adv. Synth. Catal. 2014; 356: 437
- 20 Lecointre B, Azzouz R, Bischoff L. Tetrahedron Lett. 2014; 55: 1913
- 21 Nishimine T, Taira H, Tokunaga E, Shiro M, Shibata N. Angew. Chem. Int. Ed. 2016; 55: 359
- 22 Zhang Z, Puente Á, Wang F, Rahm M, Mei Y, Mayr H, Prakash GK. S. Angew. Chem. Int. Ed. 2016; 55: 12845
- 23 Bellini R, Magre M, Biosca M, Norrby P.-O, Pàmies O, Diéguez M, Moberg C. ACS Catal. 2016; 6: 1701
- 24a Guo Z, Xie M, Han R, Qu G, Guo H. Chin. J. Org. Chem. 2018; 38: 112
- 24b Dai J, Duan X, Zhou J, Fu C, Ma S. Chin. J. Chem. 2018; 36: 387
- 25 Liao L, Zhang Y, Wu Z.-W, Ye Z.-T, Zhang X.-X, Chen G, Yu J.-S. Chem. Sci. 2022; 13: 12519
- 26 Qian P, Zhang S, Luo F, Wang J, Zhang X, Liu X, Chen X, Wang W, Chen X. Chem. Commun. 2022; 58: 11458
- 27 Zhang Y, Yang J, Ruan Y.-L, Liao L, Ma C, Xue X.-S, Yu J.-S. Chem. Sci. 2023; 14: 12676
- 28 Knieb A, Krishnamurti V, Zhu Z, Prakash GK. S. J. Fluorine Chem. 2023; 267: 110095
- 29 Zeng J, Niu L, Wang Z, Wei R, Cahard D. Eur. J. Org. Chem. 2023; 26: e202300651
- 30 Liao L, Zhao Z.-P, Gu B.-N, Yu J.-S, Zhou J. Synthesis 2023; 55: 3090
- 31 Furukawa T, Goto Y, Kawazoe J, Tokunaga E, Nakamura S, Yang Y, Du H, Kakehi A, Shiro M, Shibata N. Angew. Chem. Int. Ed. 2010; 49: 1642
- 32 Shen X, Zhang L, Zhao Y, Zhu L, Li G, Hu J. Angew. Chem. Int. Ed. 2011; 50: 2588
- 33 Huang B, Chen Y, Zhang X, Yan M. Eur. J. Org. Chem. 2021; 2021: 3015
- 34 He Z, Tan P, Ni C, Hu J. Org. Lett. 2015; 17: 1838
- 35 Tang X.-J, Thomoson CS, Dolbier WR. Org. Lett. 2014; 16: 4594
- 36 Tang X, Dolbier WR. Angew. Chem. Int. Ed. 2015; 54: 4246
- 37 Zhang Z, Tang X.-J, Dolbier WR. Org. Lett. 2016; 18: 1048
- 38 Konik YA, Elek GZ, Kaabel S, Järving I, Lopp M, Kananovich DG. Org. Biomol. Chem. 2017; 15: 8334
- 39 Konik YA, Kudrjashova M, Konrad N, Kaabel S, Järving I, Lopp M, Kananovich DG. Org. Biomol. Chem. 2017; 15: 4635
- 40 Fang J, Shen W.-G, Ao G.-Z, Liu F. Org. Chem. Front. 2017; 4: 2049
- 41 Xing B, Ni C, Hu J. Chin. J. Chem. 2018; 36: 206
- 42 Fu W, Sun Y, Li X. Synth. Commun. 2020; 50: 388
- 43 Wang Q, Liu A, Wang Y, Ni C, Hu J. Org. Lett. 2021; 23: 6919
- 44 Zou Z, Li H, Huang M, Zhang W, Zhi S, Wang Y, Pan Y. Org. Lett. 2021; 23: 8252
- 45 Louvel D, Souibgui A, Taponard A, Rouillon J, Ben Mosbah M, Moussaoui Y, Pilet G, Khrouz L, Monnereau C, Vantourout JC, Tlili A. Adv. Synth. Catal. 2022; 364: 139
- 46 Dai P, Li Y, Chen Y, Jiao J, Wang Q, Li C, Gu Y, Zhang Y, Xia Q, Zhang W.-H. Org. Lett. 2022; 24: 1357
- 47 Tian S, Chen M, Tang Y, Cheng K, Tsui GC, Wang Q. Org. Chem. Front. 2023; 10: 6124
- 48 Zheng J, Xu Y, Song S, Huang L, Cao D, Zhong A, Yang J, Chen D. J. Org. Chem. 2023; 88: 10206
- 49 Huang W, Zheng Y, Keess S, Molander GA. J. Am. Chem. Soc. 2023; 145: 5363
- 50 Xu J, Li Y, Zhu X, Lv S, Xu Y, Cheng T, Liu G, Liu R. Org. Lett. 2023; 25: 6211
- 51 Yagupolskii LM, Aleksandrov AM. Zh. Obshch. Khim. 1968; 38: 1503
- 52 Lutskii AE, Obukhova EM, Kolesnik MI, Pukhovetskii AYa, Yagupol’skii LM, Korin’ko VA. Teor. Eksp. Khim. 1973; 9: 126
- 53 Makosza M, Golinski J, Baran J. J. Org. Chem. 1984; 49: 1488
- 54 Inbasekaran M, Peet NP, McCarthy JR, Le Tourneau ME. J. Chem. Soc., Chem. Commun. 1985; 678
- 55 Liu C, Wang Q. Angew. Chem. Int. Ed. 2018; 57: 4727
- 56 Ye W, Zhu L, Luo Q, Ni C, Hu J. Tetrahedron 2020; 76: 130877
- 57 Bhosale VA, Císařová I, Kamlar M, Veselý J. Chem. Commun. 2022; 58: 9942
- 58 Yerien DE, Barata-Vallejo S, Postigo A. Chem. Eur. J. 2017; 23: 14676
- 59 Erickson JA, McLoughlin JI. J. Org. Chem. 1995; 60: 1626
- 60 Prakash GK. S, Hu J, Wang X. Difluoromethyl Phenyl Sulfone. In e-EROS Encyclopedia of Reagents for Organic Synthesis [Online]. Wiley & Sons; New York: 2023
- 61 Prakash GK. S, Hu J, Wang Y, Olah GA. Angew. Chem. Int. Ed. 2004; 43: 5203
- 62 Hine J, Porter JJ. J. Am. Chem. Soc. 1960; 82: 6178
- 63 Prakash GK. S, Hu J, Mathew T, Olah GA. Angew. Chem. Int. Ed. 2003; 42: 5216
- 64 Prakash GK. S, Hu J, Olah GA. J. Org. Chem. 2003; 68: 4457
- 65 Prakash GK. S, Hu J, Wang Y, Olah GA. Org. Lett. 2004; 6: 4315
- 66 Prakash GK. S, Hu J, Wang Y, Olah GA. Eur. J. Org. Chem. 2005; 2005: 2218
- 67 Wang X, Liu G, Xu X, Shibata N, Tokunaga E, Shibata N. Angew. Chem. Int. Ed. 2014; 53: 1827
- 68 Ye W, Zhang L, Ni C, Rong J, Hu J. Chem. Commun. 2014; 50: 10596
- 69 Li X, Zhao J, Hu M, Chen D, Ni C, Wang L, Hu J. Chem. Commun. 2016; 52: 3657
- 70 Zhang R, Ni C, Zhao Y, Hu J. Tetrahedron 2018; 74: 5295
- 71 Xiao P, Rong J, Ni C, Guo J, Li X, Chen D, Hu J. Org. Lett. 2016; 18: 5912
- 72 Wu C, Shen X, Dai J, Xu J, Xu H. Org. Biomol. Chem. 2021; 19: 7607
- 73 Nobile E, Castanheiro T, Besset T. Chem. Commun. 2021; 57: 12337
- 74 Sap JB. I, Meyer CF, Ford J, Straathof NJ. W, Dürr AB, Lelos MJ, Paisey SJ, Mollner TA, Hell SM, Trabanco AA, Genicot C, Am Ende CW, Paton RS, Tredwell M, Gouverneur V. Nature 2022; 606: 102
- 75 Ziabko M, Klepetářová B, Beier P. J. Org. Chem. 2023; 88: 6939
- 76 Bräse S, Gil C, Knepper K, Zimmermann V. Angew. Chem. Int. Ed. 2005; 44: 5188
- 77 Wei Z, Zheng W, Wan X, Hu J. Angew. Chem. Int. Ed. 2023; 62: e202308816
- 78 Li S, Wang X, Yang Y, Ni C, Hu J. Org. Lett. 2024; 26: 872
- 79 Zhou, G.; Wang, X. Org. Biomol. Chem. 2017, 15, 8748.
- 80 Zhu M, Fun W, Guo W, Tian Y, Wang Z, Xu C, Ji B. Eur. J. Org. Chem. 2019; 2019: 1614
- 81 Trump L, Lemos A, Lallemand B, Pasau P, Mercier J, Lemaire C, Luxen A, Genicot C. Angew. Chem. Int. Ed. 2019; 58: 13149
- 82 Zhu M, You Q, Li R. J. Fluorine Chem. 2019; 228: 109391
- 83 Bao K, Wei J, Yan H, Sheng R. RSC Adv. 2020; 10: 25947
- 84 Kuchar M, Mamat C. Molecules 2015; 20: 16186
- 85 Johnson BM, Shu Y.-Z, Zhuo X, Meanwell NA. J. Med. Chem. 2020; 63: 6315
- 86 Obach RS, Walker GS, Brodney MA. Drug Metab. Dispos. 2016; 44: 634
- 87 Wei J, Bao K, Wang Y, Sheng R, Hu J. Org. Biomol. Chem. 2020; 18: 4556
- 88 Zhou X, Ni C, Deng L, Hu J. Chem. Commun. 2021; 57: 8750
- 89 Zhang B, Wang J. Org. Lett. 2022; 24: 3721
- 90 Zhu M, Tian Y, Sha J, Fu W. ChemistrySelect 2022; 7: e202203986
- 91 Mao E, Prieto Kullmer CN, Sakai HA, MacMillan DW. C. J. Am. Chem. Soc. 2024; 146: 5067
- 92 Zhao Y, Huang W, Zhu L, Hu J. Org. Lett. 2010; 12: 1444
- 93 Prakash GK. S, Ni C, Wang F, Hu J, Olah GA. Angew. Chem. Int. Ed. 2011; 50: 2559
- 94 Prakash GK. S, Ni C, Wang F, Zhang Z, Haiges R, Olah GA. Angew. Chem. Int. Ed. 2013; 52: 10835
- 95 Miao W, Zhao Y, Ni C, Gao B, Zhang W, Hu J. J. Am. Chem. Soc. 2018; 140: 880
- 96 Sun H, Jiang Y, Yang Y.-S, Li Y.-Y, Li L, Wang W.-X, Feng T, Li Z.-H, Liu J.-K. Org. Biomol. Chem. 2019; 17: 6629
- 97 Josephson B, Fehl C, Isenegger PG, Nadal S, Wright TH, Poh AW. J, Bower BJ, Giltrap AM, Chen L, Batchelor-McAuley C, Roper G, Arisa O, Sap JB. I, Kawamura A, Baldwin AJ, Mohammed S, Compton RG, Gouverneur V, Davis BG. Nature 2020; 585: 530
- 98 Li Z, Wang M, Shi Z. Angew. Chem. Int. Ed. 2021; 60: 186
- 99 Miao W, Ni C, Xiao P, Jia R, Zhang W, Hu J. Org. Lett. 2021; 23: 711
- 100 Du W, Luo Q, Wei Z, Wang X, Ni C, Hu J. Sci. China: Chem. 2023; 66: 2785
- 101 Rong J, Ni C, Gu Y, Hu J. Helv. Chim. Acta 2021; 104: e2100019
- 102 Wei Z, Miao W, Ni C, Hu J. Angew. Chem. Int. Ed. 2021; 60: 13597
- 103 Wang X, Ye W, Kong T, Wang C, Ni C, Hu J. Org. Lett. 2021; 23: 8554
- 104 Yang M, Huang X, Miao W, Yi L, Cai J, Zhao Z, He J, Qiu D. Org. Chem. Front. 2023; 10: 1975
- 105 Isenegger PG, Josephson B, Gaunt B, Davy MJ, Gouverneur V, Baldwin AJ, Davis BG. Nat. Protoc. 2023; 18: 1543
- 106 Wu Q.-Y, Ao G.-Z, Liu F. Org. Chem. Front. 2018; 5: 2061
- 107 Xiong Y, Sun Y, Zhang G. Org. Lett. 2018; 20: 6250
- 108 Dai P, Yu X, Teng P, Zhang W.-H, Deng C. Org. Lett. 2018; 20: 6901
- 109 Zhang S, Li L, Zhang J, Zhang J, Xue M, Xu K. Chem. Sci. 2019; 10: 3181
- 110 Ruan Z, Huang Z, Xu Z, Mo G, Tian X, Yu X.-Y, Ackermann L. Org. Lett. 2019; 21: 1237
- 111 Zou Z, Zhang W, Wang Y, Kong L, Karotsis G, Wang Y, Pan Y. Org. Lett. 2019; 21: 1857
- 112 Shao J, Wang Y, Chen S, Wang S, Wu Y, Li X, Zhang W, Deng C. Tetrahedron 2021; 79: 131822
- 113 Yuan X, Cui Y, Zhang X, Qin L, Sun Q, Duan X, Chen L, Li G, Qiu J, Guo K. Chem. Eur. J. 2021; 27: 6522
- 114 Lu Z, Hennis O, Gentry J, Xu B, Hammond GB. Org. Lett. 2020; 22: 4383
- 115 Gao H, Gu Y, Wang Z, Yuan Y, Wang Y, Guo S. Synlett 2020; 31: 1838
- 116 Zhang W, Xiang X.-X, Chen J, Yang C, Pan Y.-L, Cheng J.-P, Meng Q, Li X. Nat. Commun. 2020; 11: 638
- 117 Zhang Y, Ma C, Struwe J, Feng J, Zhu G, Ackermann L. Chem. Sci. 2021; 12: 10092
- 118 Stephens C, Lucena MI, Andrade RJ. Idiosyncratic Drug-Induced Liver Injury: Mechanisms and Susceptibility Factors . In Comprehensive Toxicology, 3rd ed., Vol. 2. McQueen CA. Elsevier; Amsterdam: 2018: 625-650
- 119 Chandrasekaran B, Abed SN, Al-Attraqchi O, Kuche K, Tekade RK. Computer-Aided Prediction of Pharmacokinetic (ADMET) Properties . In Dosage Form Design Parameters, Vol. II. Tekade RA. Elsevier; Amsterdam: 2018: 731-755
- 120 Efremov RG, Chugunov AO, Pyrkov TV, Priestle JP, Arseniev AS, Jacoby E. Curr. Med. Chem. 2007; 14: 393
- 121 Ditzinger F, Price DJ, Ilie A.-R, Köhl NJ, Jankovic S, Tsakiridou G, Aleandri S, Kalantzi L, Holm R, Nair A, Saal C, Griffin B, Kuentz M. J. Pharm. Pharmacol. 2019; 71: 464
- 122 Sumii Y, Sasaki K, Matsubara O, Shibata N. Org. Lett. 2021; 23: 2777
- 123 Dai P, Jiao J, Wang Q, Yu X, Teng P, Zhu Y, Gu Y.-C, Zhang W.-H. Tetrahedron 2021; 100: 132466
- 124 Rodríguez RI, Sicignano M, Alemán J. Angew. Chem. Int. Ed. 2022; 61: e202112632
- 125 Zhang D, Cai J, Du J, Wang Q, Yang J, Geng R, Fang Z, Guo K. Org. Lett. 2022; 24: 1434
- 126 Mo K, Zhou X, Wu J, Zhao Y. Org. Lett. 2022; 24: 2788
- 127 She K, Liang F, Tian S, Wang H, Tsui GC, Wang Q. Org. Lett. 2022; 24: 4840
- 128 Chen X, Geng Y, Liu B, Zhu Y, Zou D, Wu Y, Wu Y. Org. Chem. Front. 2023; 10: 1968
- 129 Kok L, Slooter AJ, Hillegers MH, Van Dijk D, Veldhuijzen DS. Crit. Care Med. 2018; 46: 1673
- 130 Zheng J, Wu Y, Cao D, Song S, Yang Y, Huang L, Chen D. J. Fluorine Chem. 2023; 266: 110090
- 131 Shire BR, Anderson EA. JACS Au 2023; 3: 1539
- 132 Zhao J.-X, Chang Y.-X, He C, Burke BJ, Collins MR, Del Bel M, Elleraas J, Gallego GM, Montgomery TP, Mousseau JJ, Nair SK, Perry MA, Spangler JE, Vantourout JC, Baran PS. Proc. Natl. Acad. Sci. U.S.A. 2021; 118: e2108881118
- 133 Ratni H, Baumann K, Bellotti P, Cook XA, Green LG, Luebbers T, Reutlinger M, Stepan AF, Vifian W. RSC Med. Chem. 2021; 12: 758
- 134 Xiang Y.-J, Liu S, Zhou J, Lin J.-H, Yao X, Xiao J.-C. J. Org. Chem. 2023; 88: 4818
- 135 Shen L, Yuan J.-W, Zhang B, Song S.-Y, Yang L.-R, Xiao Y.-M, Zhang S.-R, Qu L.-B. Z. Naturforsch., B: J. Chem. Sci. 2023; 78: 245
- 136 Zhang S, Geng Y, Jiao J, Zou D, Wu Y, Wu Y. Adv. Synth. Catal. 2023; 365: 4132
- 137 Besset T, Schneider C, Cahard D. Angew. Chem. Int. Ed. 2012; 51: 5048
- 138 Tomashenko OA, Grushin VV. Chem. Rev. 2011; 111: 4475
- 139 Barata-Vallejo S, Lantaño B, Postigo A. Chem. Eur. J. 2014; 20: 16806
- 140 Prakash GK. S, Hu J, Olah GA. Org. Lett. 2003; 5: 3253
- 141 Creary X. J. Org. Chem. 1980; 45: 2727
- 142 Prakash GK. S, Wang F, Zhang Z, Haiges R, Rahm M, Christe KO, Mathew T, Olah GA. Angew. Chem. Int. Ed. 2014; 53: 11575
- 143 Li X, Zhao J, Zhang L, Hu M, Wang L, Hu J. Org. Lett. 2015; 17: 298
- 144 Sumii Y, Taniguchi M, Xu X.-H, Tokunaga E, Shibata N. Tetrahedron 2018; 74: 5635
- 145 Wei Z, Lou Z, Ni C, Zhang W, Hu J. Chem. Commun. 2022; 58: 10024
- 146 Wei Z, Wen L, Zhu K, Wang Q, Zhao Y, Hu J. J. Am. Chem. Soc. 2022; 144: 22281
- 147 Ouyang Y, Xu X, Qing F. Angew. Chem. Int. Ed. 2022; 61: e202114048
- 148 Rong J, Ni C, Wang Y, Kuang C, Gu Y, Hu J. Acta Chim. Sin. 2017; 75: 105
- 149 Karanja CW, Naganna N, Abutaleb NS, Dayal N, Onyedibe KI, Aryal U, Seleem MN, Sintim HO. Molecules 2022; 27: 5085
- 150 Wei J, Bao K, Qi C, Liu Y, Ni C, Sheng R, Hu J. Adv. Synth. Catal. 2019; 361: 5528
- 151 Shaik A, Bhandare RR, Palleapati K, Nissankararao S, Kancharlapalli V, Shaik S. Molecules 2020; 25: 1047
- 152 Langlois BR, Laurent E, Roidot N. Tetrahedron Lett. 1991; 32: 7525
- 153 La-ongthong K, Chantarojsiri T, Soorukram D, Leowanawat P, Reutrakul V, Kuhakarn C. Org. Biomol. Chem. 2023; 21: 4225
- 154 Mahanty K, Saha SK, Halder A, De Sarkar S. Chem. Commun. 2023; 59: 4467
- 155 Chen D, Yang X, Wang D, Li Y, Shi L, Liang D. Org. Chem. Front. 2023; 10: 2482
- 156 Chen X, Jiang J, Huang X.-J, He W.-M. Org. Chem. Front. 2023; 10: 3898
- 157 Yan Z.-H, Yan Y, Wei Z.-L, Liao W.-W. J. Org. Chem. 2024; 89: 2718
- 158 Zhou Q.-H, Dai J.-Y, Zhao W.-J, Zhong X.-Y, Liu C.-Y, Luo W.-W, Li Z.-W, Li J.-S, Liu W.-D. Org. Biomol. Chem. 2023; 21: 3317
- 159 Zhang L, Zheng K, Zhang P, Jiang M, Shen J, Chen C, Shen C. Green Synth. Catal. 2024; 5: 51
- 160 Chen F, Jiang L, Hu C, Liu J, Yi W. Sci. China: Chem. 2024; 67: 587
- 161 Li H, Zhang Y, Yang X, Deng Z, Zhu Z, Zhou P, Ouyang X, Yuan Y, Chen X, Yang L, Liu M, Shu C. Angew. Chem. Int. Ed. 2023; 62: e202300159
- 162 Chatterjee T, Iqbal N, You Y, Cho EJ. Acc. Chem. Res. 2016; 49: 2284
- 163 Lin D, Coe M, Krishnamurti V, Ispizua-Rodriguez X, Prakash GK. S. Chem. Rec. 2023; 23: e202300104
- 164 Pattanayak P, Chatterjee T. J. Org. Chem. 2023; 88: 5420
- 165 Firuz ME, Rajai-Daryasarei S, Rominger F, Biglari A, Balalaie S. J. Org. Chem. 2023; 88: 10599