Perfluoroalkylation Reactions Research Articles

Perfluoroalkylation Reactions by Electron Donor‐Acceptor Complexes: Recent Advances

AbstractThis Perspective analyses the perfluoroalkylation reactions by electron donor‐acceptor (EDA) complexes since 2018, while summarizes, in Tables , the vast majority of representative perfluoroalkylation reactions of various classes of organic compounds by EDA complexes and halogen‐bonding interactions. Numerous intriguing reaction methodologies and valuable synthetic instances have emerged. We aim to delve into these new examples comprehensively, while also contemplating the future directions in the field. Subsequent sections will elaborate on the perfluoroalkylation of (hetero)aromatic compounds, carbon‐carbon multiple bonds, perfluoroalkylation of carbonyl compounds, and perfluoroalkylation of isocyanides, covering their synthetic scope and mechanistic insights. Perfluoroalkylation reactions of (hetero)aromatic compounds by EDA complexes. Entry Substrate Complex Reaction conditions Product Ref. 1 [13] 2 [46] 3 RFI (3 equiv.) KOH (1.5 equiv.) Blue LEDs H2O, Ar, 20 h [47] 4 TEEDA (3 equiv.) CFL (25 W) THF, r.t. RF−I (3 equiv.) [48] 5 ICF2CO2Et (1.3 equiv.) Na2CO3 (1.5 equiv.) DMSO (3 mL) Ar, rt. 427 nm LED, 16 h [49] 6 TMG (2.5 equiv.) RF−I (2.5 equiv.) 23 W CFL, MeCN/Hexf (5 : 1) [42,50] 7 TMG (2.5 equiv.) RF−I (2.5 equiv.) 23 W CFL, MeCN [51] 8 Umemoto's reagent (2 equiv.) N‐methylmorpholine (2.5 equiv.) DMF, r.t. [52] 9 Cs2CO3 (2 equiv.) RF−I (3 equiv.) white light H2O (3 equiv.) DMF, r.t., 2 h [53] 10 4.5 W 450 nm laser CaCl2, MeNO2, 0 °C [3] 11 RF−I (1.5 equiv.) t‐BuONa (2 equiv.) DMF Green LEDs [54] 12 or EDA complex I−Rf (2.1 equiv.) TMEDA (2 equiv.) or DBU (2 equiv.) Blue LEDs 24 W [55,56] 13 TFE/water (1 : 1) (0.2 M) CF3SO2Na Blue LEDs r.t., 12 h [84] Perfluoroalkylation reactions of carbon‐carbon multiple bonds and constrained cyclic compounds by EDA complexes. Entry Substrate Complex Reaction conditions Product Ref. 1 Bu4NCl, Hg lamp (6 W) RF−I (1.2 equiv.) CH3OH, 1.5 h r.t, Ar [39] 2 RFI (3 equiv.) KOH (1.5 equiv.) Blue LEDs H2O, Ar, 20 h [47] 3 [57] 4 DIPEA or TMEDA or DBU or TEEDA ……..CF3I CF3−I (3 equiv.) Base (2 equiv.) MeCN or DMF or THF CFL, 25 W with DIPEA, TMEDA or TEEDA; with DBU [48,58,59] 5 Bn2NH MeCN RF−I Blue LED, r.t. [60] 6 Base, Blue LEDs DMF or THF [61] 7 I−RF H2O/toluene=9 : 1 Blue LEDs, 65 °C, 12 h [41] 8 K3PO4 (3 equiv.) RF−I (3 equiv.) CuCl (10 mol%) TMSNCS (3 equiv.) CH3CN (2 mL) Violet LEDs (24 W) Ar, 4 h [37] 9 RF−I (3 equiv.) Diphenylacetaldehyde (10 mol%) Pyrrolidine (40 mol%) DIPEA (2 equiv.) DCE (2.5 mL); O2 (0.8 eq.); Ar White LEDs (2.5 W); 24 h [44,62] 10 DIPEA,DMA Ar (trace air) Blue LEDs, rt. 36–72 h [63] 11 TMEDA Blue LEDs n‐C4F9I DMSO air, 24 h RT [64] 12 K3PO4 (2 equiv.) DABCO (1.2 equiv.) hυ (400 Watt) 50 °C CnF2n+1I (1.8 equiv.) [65–67] 13 Blue LEDs DCE, r.t. [27] 14 2,4,6‐trimethylpyridine MeCN, 60 °C Togni's reagent [68] 15 PMDETA (2 equiv.) DMSO (2 mL) N2, Blue LEDs [69] 16 Blue LEDs [70,71] 17 MeCN (0.2 M) with less than 1 % water CF3SO2Na (1 mmol) Blue LEDs [84] Perfluoroalkylation of carbonyl compounds, isocyanides and hydrazones. Entry Substrate Complex Reaction conditions Product Ref. 1 [72,73] 2 RF−I (0.2 mmol) cis‐catalyst M (20 mol%) 2,6‐lutidine (1.2 equiv.) Blue LEDs, Et2O (0.7 M) ‐10 °C, 20 h [74] 3 white light RF−I [75] 4 phase transfer catalyst Cs2CO3, C6H5Cl/8F18 (2 : 1), 25 °C, RF−I [32] 5 ambient light C4F9−I NaOH (4.1 equiv.) MeCN, R.T. [76] 6 RFI (3 equiv.) KOH (1.5 equiv.) Blue LEDs THF, Ar, 36 h [47] 7 RF−I (2 equiv.) TMEDA (2 equiv.) THF (2 mL) Blue LEDs (25 W) 30 °C, N2 [77] 8 TEEDA (1.5 equiv.) CFL (25 W) THF I−C4F9 [48] 9 Bn2NH Blue LEDs MeCN, RT RF−I [78] 10 TMG (1.5 equiv.) ambient light MeCN, RT I−RF [79] 11 Imidazole (3 equiv.) MeCN, RF−I (2 equiv.) r.t. [80]

Halogen‐Bond‐Promoted Hydroxyperfluoroalkylation of Olefins with Molecular Oxygen under Visible‐Light Irradiation

AbstractFluorinated organic compounds are indispensable, and the development of perfluoroalkylation reaction is an important topic of concern. In this paper, we present the generation of an amine‐promoted visible‐light‐induced hydroxyperfluoroalkylation reaction of olefines using molecular oxygen as a hydroxy source. This reaction is caused by the formation of perfluoroalkyl radicals due to visible‐light irradiation to halogen‐bonded complex of a tertiary amine and a perfluoroalkyl iodide. This transformation is applicable for various types of electron‐deficient olefins and styrene, and various fluoroalkyl iodides are acceptable as well. This visible‐light induced, metal‐free reaction using inexpensive and readily available reagents is a sustainable method for the synthesis of fluorine‐containing compounds.

Visible light-mediated radical perfluoroalkylation reactions using heterogeneous graphitic carbon nitride

Photocatalytic radical fluoroalkylation has become an important approach to prepare valuable organofluorine compounds under mild conditions. Compared to the homogenous photocatalytic fluoroalkylation reactions based on the precious metal complexes or organic dyes, heterogeneous photocatalysis using metal-free carbon nitride catalyst shows cost-effective, easier separation and excellent recyclability. In this work, we report the visible-light-induced photocatalytic perfluoroalkylation of alkynes with perfluoroalkyl iodides (RfI) using heterogeneous cyano-modified graphitic carbon nitride (g-NCNCNx) as the photocatalyst. The mechanism proposed by the experimental and computational studies reveals that the long-lived triplet excited states in photoinduced g-NCNCNx are involved in the initial bimolecular electron transfer process, resulting in the effective activation of RfI and the improvement of sequential photocatalytic reactions. Moreover, the stronger interaction between the substate and surface of catalyst g-NCNCNx can further improve the photocatalytic activity, comparing to the pristine carbon nitride (g-CNx). Through simple variation of the reaction conditions, the photocatalytic addition or coupling reaction can be achieved effectively and selectively. Importantly, the heterogeneous g-NCNCNx photocatalyst can not only show high performance with a wide reaction scope, but also be readily recovered and reused for at least five catalytic cycles with high photocatalytic activity. This work provides a sustainable alternative to the conventional metal-based photocatalysts for organofluorine synthesis.

Radical Perfluoroalkylation of Aliphatic Substrates

A selection of perfluoroalkylation reactions of aliphatic substrates that display methodological and synthetic amplitude will be studied, giving examples of their applications and mechanistic details. An array of synthetic approaches for fluoroalkylation reactions are documented; in particular, radical protocols are prominent among perfluoroalkylation methods. To that effect, addition reactions of perfluoroalkyl radicals RF (RF=CnF2n+1, n > 1) to unsaturated organic substrates serve as one of the most direct and efficacious ways to access fluoroalkylated scaffolds. The syntheses of perfluoroalkyl-substituted vinyl, alkynyl, and allylic compounds; the syntheses of perfluoroalkyl-substituted hydro-, iodo-, and oxy-perfluoroalkylated alkanes and olefins; the syntheses of perfluoroalkyl-substituted carbonyl compounds; the syntheses of perfluoroalkyl-substituted enamides, amides, thioamides, and hydrazones; and multicomponent perfluoroalkylation reactions will be studied. While there are a number of accomplished reports on organofluorination, we aim to provide an overview of radical-involved perfluoroalkylation reactions of aliphatic substrates, covering examples from 2018 to early 2023, as summarized in Tables 1–4.

Development of Electrophilic Radical Perfluoroalkylation of Electron-Deficient Olefins.

Fluorinated organic compounds have attracted significant attention over the past few decades owing to their unique properties and versatility. An established method for the synthesis of fluorinated organic compounds involves radical perfluoroalkylation reactions towards double bonds. In this radical pathway, electrophilic perfluoroalkyl radicals exhibit excellent reactivity towards electron-rich olefins. Therefore, several splendid perfluoroalkylation reactions of electron-rich olefins have been reported. However, there are only a few examples of reaction involving electron-deficient olefins because of their poor electronic compatibility with perfluoroalkyl radicals. This review focuses on the reports that challenge this long-standing issue. Radical perfluoroalkylation/bifunctionalization reactions of electron-deficient olefins are described according to the radical generation methods.

CuCF3 mediated deoxyfluorination of redox-active esters

Trifluoromethyl copper (CuCF3), as a diverse fluorination reagent, has been widely used in trifluoromethylation, perfluoroalkylation, and difluorocarbene reactions. However, it has rarely been reported as a single fluorine source involved in nucleophilic fluorination reactions. This work describes a general strategy involving copper-mediated deoxyfluorination of redox-active esters to rapidly access various aliphatic and aromatic acyl fluorides. The highly active CuF species could be generated from either copper fluoride salts or CuCF3. A plausible mechanism of CuCF3 forming an [F-CuCF2F5]- intermediate and NHBC ester forming acyl fluoride has been derived from DFT calculations.

Activation of perfluoroalkyl iodides by anions: extending the scope of halogen bond activation to C(sp3)-H amidation, C(sp2)-H iodination, and perfluoroalkylation reactions.

A simple, efficient, and convenient activation of perfluoroalkyl iodides by tBuONa or KOH, without expensive photo- or transition metal catalysts, allows the promotion of versatile α-sp3 C-H amidation reactions of alkyl ethers and benzylic hydrocarbons, C-H iodination of heteroaryl compounds, and perfluoroalkylations of electron-rich π bonds. Mechanistic studies show that these novel protocols are based on the halogen bond interaction between perfluoroalkyl iodides and tBuONa or KOH, which promote homolysis of perfluoroalkyl iodides under mild conditions.

Visible-Light-Induced Metal-Free Decarboxylative Perfluoroalkylation of Aryl Acrylic Acids.

Perfluoroalkylation is important for late-stage modification of biologically active molecules. Herein, we report a protocol for visible-light-induced perfluoroalkylation reactions of aryl acrylic acids. These reactions, which use perfluoroalkyl iodides as radical precursors and inexpensive eosin Y as a photocatalyst, proceed in a decarboxylative manner. The easy accessibility of perfluoroalkyl iodides and the broad substrate scope, mild conditions, and metal-free catalyst make this protocol applicable for the transformation of inexpensive raw materials to high-value chemicals.

Visible light-induced phosphine-catalyzed perfluoroalkylation of indoles

A photo-induced, catalytic PPh3-promoted perfluoroalkylation reaction of indole molecules is developed to give perfluoroalkylated products in moderate to excellent yields, of which 13 F-containing indoles exhibited good antibacterial activities.

Visible-light-induced Mn(0)-catalyzed direct C-3 mono-, di- and perfluoroalkylation reactions of 2H-indazoles.

A general and efficient method for visible-light-driven fluoroalkylation, such as difluoromethylphosphonation, difluoroacetamidation, monofluoromethylation, difluoromethylation, and perfluoroalkyalation, of 2H-indazoles using an inexpensive Mn2(CO)10 photocatalyst has been developed. The present methodology affords a new series of C-3 fluoroalkylated 2H-indazole derivatives with wide functional group tolerance in good to excellent yields. Difluoromethylenated indiazoles are also prepared from difluoroester derivatives. Our mechanistic investigations support a radical pathway for the reaction.

Radical Perfluoroalkylation Enabled by a Catalytically Generated Halogen Bonding Complex and Visible Light Irradiation.

Exploiting charge-transfer complexes in visible light-promoted single-electron redox reactions is a promising route for opening novel synthetic pathways, and catalytic approaches to complex formation are critical for facilitating this chemistry. This report describes the use of a substituted hydroquinone catalyst to promote radical perfluoroalkylation reactions. Mechanistic studies indicate that the reaction is initiated through formation of a visible light-absorbing halogen bonding complex between the hydroquinone catalyst and the perfluoroalkyl halide radical precursor.

Visible-light-mediated direct C-H perfluoroalkylation of imidazoheterocycles

A novel protocol for photochemical perfluoroalkylation reaction of imidazoheterocycles with readily available perfluoroalkyl iodide is reported. A library of perfluoroalkyl products can be afforded in moderate to good yields. Notable advantages of this method include wide substrates, mild conditions, and not using photoredox catalyst.

External Photocatalyst-Free Visible Light-Promoted 1,3-Addition of Perfluoroalkyl Iodides to Vinyldiazoacetates

External Photocatalyst-Free Visible Light-Promoted 1,3-Addition of Perfluoroalkyl Iodides to Vinyldiazoacetates

Visible-light induced photochemistry of Electron Donor-Acceptor Complexes in Perfluoroalkylation Reactions: Investigation of halogen bonding interactions through UV–Visible absorption and Raman spectroscopies combined with DFT calculations

Visible light promoted perfluoroalkylation reactions initiated via halogen bonding interactions between perfluoroalkyl iodides (Rf–I, Rf = CnF2n+1) and Lewis bases have been recognized as a powerful tool in the field of radical synthetic chemistry. In order to provide some insights into the nature, strength and role in the activation process of halogen bonding interactions, we have performed a combined UV–Visible/Raman/DFT study on a model Rf–I (C4F9I) and a series of Lewis bases (LB) frequently used for the activation of perfluoroalkylation reactions, including DBU, MTBD, TMG, TMEDA and Et3N. Raman studies conducted in acetonitrile solutions show that the band at 279 cm−1 associated with the CI stretching normal mode of C4F9I shifts about 20 cm−1 towards lower wavenumbers upon formation of the halogen-bonded complexes. Additionally, the Raman study revealed that at concentrations typically used for perfluoroalkylation reactions, the [C4F9I-LB] complexes are the main species present in solution. UV–Vis spectroscopy revealed that complex formation is characterized by a strong increase in absorption from 225 to 350 nm. The higher the basicity of the Lewis base, the higher the increase of the UV absorbance.

Silver-Mediated Perfluoroalkylation of Terminal Alkynes with Perfluoroalkyl Iodides.

The incorporation of a perfluoroalkyl group (RF) into drug candidates has become an increasingly important strategy in drug molecule design. In this study, the silver-mediated perfluoroalkylation reaction based on the addition-elimination process of terminal alkynes which was initiated by a perfluoroalkyl radical to form a C(sp)-RF bond has been developed. The reaction proceeds under mild conditions using readily available, low-cost perfluoroalkyl iodides as the sources of the RF group. This method allows access to a variety of perfluoroalkylated alkynes.

The role of photocatalysts in radical chains in homolytic aromatic substitution, radical addition to olefins, and nucleophilic radical substitution mechanisms

Initiation, propagation and chain termination steps in oxidative and reductive quenching cycles for the photoinitiated perfluoroalkylation reaction of an olefin.

Synthesis of perfluoroalkylene oligo(ethylene glycol) alternative polymer via photoinduced polyaddition

Fluoropolymers are one of the most versatile materials with widespread applications in daily life. However, the variety of available fluoropolymers is limited. Herein, new fluorinated polymers were synthesized via the polyaddition of diene and diiodoperfluoroalkane, through photo-irradiated radical perfluoroalkylation reaction. The reaction proceeded to afford the corresponding alkyl fluoroalkyl alternative polymer. The use of a diene, which had a poly(ethylene glycol) (PEG) unit, enabled the control of the extent of hydrophobicity in the synthesized polymer by varying the lengths of the fluoroalkyl and PEG units.

Photoinitiated Reactions of Haloperfluorocarbons with Gold(I) Organometallic Complexes: Perfluoroalkyl Gold(I) and Gold(III) Complexes.

The study of perfluoroalkyl metal complexes is key to understand and improve metal-promoted perfluoroalkylation reactions. Herein, we report the synthesis of the first gold complexes with primary or secondary perfluoroalkyl ligands by photoinitiated reactions between AuI organometallic complexes and iodoperfluoroalkanes. Complexes of the types LAuRF (L=PPh3 or N,N-bis(2,6-diisopropylphenyl)imidazol-2-ylidene; RF =n-C4 F9 , n-C6 F13 , i-C3 F7 , c-C6 F11 ) and [Au(RF )(Ar)I(PPh3 )] (Ar=2,4,6-trimethylphenyl) have been isolated and characterized. Alkynes RF C≡CR were formed by reaction of Ph3 PAuC≡CR (R=Ph, nHex) with IRF (RF =n-C4 F9 , i-C3 F7 ). According to the evidences obtained, this transformation undergoes through a photoinitiated radical mechanism. AuIII complexes [Au(n-C4 F9 )(X)(Y)L] (X=Y=Cl, Br, I, Me; X=Me, Y=I) have been prepared or in situ generated, and their thermal or photochemical decomposition reactions have been studied.

Radical fluoroalkylation reactions of (hetero)arenes and sulfides under red light photocatalysis.

Fluoroalkylation reactions of (hetero)aromatics have been accomplished through the low-power illumination from red LEDs (λmax = 635 nm) of commercially available perfluoroalkyl iodides RF-I and phthalocyanine zinc salt as photocatalyst in MeCN : DMF solvent mixture. This methodology has been extended to the perfluorobutylation of sulfides. As far as we are concerned, this is the first report on a perfluoroalkylation reaction of (hetero)aromatics and sulfides under red-light photocatalysis.

Radical Fluoroalkylation Reactions

Recent protocols and reactions for catalytic radical perfluoroalkylations will be described. The production of perfluoroalkyl radicals (RF = CnF2n+1, n ≥ 2), which effect both addition and substitution reactions on organic substrates, can be realized through a range of diverse methods such as the well-established visible-light transition-metal-mediated photocatalysis, organic-dye-photocatalyzed reactions, electron donor–acceptor complexes, and more recently frustrated Lewis pairs. Thus, perfluoroalkylation reactions of carbon–carbon multiple bonds, isocyanides, nitrones, hydrazones, β-keto esters, α-cyano arylacetates, sulfides, and (hetero)arenes will be described. Special emphasis will be placed on examples published after 2015, where higher fluorinated series of fluoroalkylating reagents are studied.