This article is licensed under CC-BY 4.0 pubs.acs.org/joc Article Difluoroalkylation of Anilines via Photoinduced Methods Albert Gallego-Gamo, Albert Granados, Roser Pleixats, Carolina Gimbert-Suriñach,* and Adelina Vallribera* Cite This: J. Org. Chem. 2023, 88, 12585−12596 Read Online ACCESS Metrics & More Article Recommendations * sı Supporting Information ABSTRACT: The development of sustainable and mild protocols See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. for the fluoroalkylation of organic backbones is of current interest in chemical organic synthesis. Herein, we present operationally simple and practical transition-metal-free methods for the preparation of difluoroalkyl anilines. First, a visible-light organo- Downloaded via 79.117.19.253 on October 11, 2023 at 07:06:30 (UTC). photocatalytic system working via oxidative quenching is described, providing access to a wide range of difluoroalkyl anilines under mild conditions. In addition, the formation of an unprecedented electron donor−acceptor (EDA) complex between anilines and ethyl difluoroiodoacetate is reported and exploited as an alternative, efficient, and straightforward strategy to prepare difluoroalkyl derivatives. ■ INTRODUCTION The presence of tethered fluorinated groups in bioactive Scheme 1. Precedents in Difluoroalkylation Protocols of Arenes and This Work (TM: Transition Metal; PC: Photocatalyst) molecules is a well-known strategy for altering their chemical properties, including conformational bias, reactivity, stability, and lipophilicity.1 Thus, in the last decades, synthetic organic chemists have done great efforts to develop efficient methods for the introduction of fluorinated motifs in organic architectures.2 Nowadays, around 20% of the marketed drugs are fluoropharmaceuticals, and in 2019, 13 new fluorinated compounds were approved by US Food and Drug Admin- istration (FDA) accounting for 41% of all small-molecule drugs.3 The trifluoromethyl group has been one of the most studied fluorinated groups in medicinal chemistry;4 therefore, its introduction to organic molecules has been widely explored.5 In addition, in recent years, the gem-difluoro group is emerging as an equally interesting motif because of its pharmacological properties as a carbonyl or sulfonyl groups bioisostere, modulator of lipophilicity, as well as its oxidative stability.6 The gem-difluoroalkylation of arenes can be provided by transition-metal,7 photoredox,8 or metallaphotoredox9 catalysis approaches (Scheme 1, top). All of these methods utilize common difluoroalkylating agents, such as FSO2CF2CO2Me, TMSCF2CO2R, or XCF2Z (X = Br, I; Z = CO2R or P(O)(OEt)2).10 Interestingly, the installation of these motifs can offer further opportunities for derivatization, but also they can yield the corresponding difluoromethyl- group,8c which can be used as a bioisostere of hydroxyl, Received: June 12, 2023 mercapto, or amino groups.11 Published: August 16, 2023 Herein, we present two methods for the photoinduced difluoroalkylation of anilines, the first based on a redox-neutral approach using an organic photocatalyst and the latest via electron donor−acceptor (EDA) complex formation. Many © 2023 The Authors. Published by American Chemical Society https://doi.org/10.1021/acs.joc.3c01298 12585 J. Org. Chem. 2023, 88, 12585−12596 The Journal of Organic Chemistry pubs.acs.org/joc Article Table 1. Optimization of Reaction Conditionsa entry radical precursor eosin Y loading yield of 3 (%)b 1 2a 10 25 2 2a 5 40 3 2a 2.5 48 4 2a 1 52 5 2b 1 79 (63)c 6 2b 1 70d 7 2b 1 33e 8 2b 0 38 9 2b 1 0f a Reaction conditions: aniline 1a (0.3 mmol), 2 (0.4 mmol), Eosin Y (1 mol %) in DMF (1.0 mL), 24 h irradiation with a 525 nm Kessil lamp. b Yields were determined by 1H NMR analysis. cIsolated yield. dNo TBAI as a phase transfer agent in the reaction. eNo base added. fReaction in the absence of light irradiation. arene difluoroalkylation reports utilize transition-metal (TM) both cases (Table 1, entries 7−8). Finally, the photochemical catalysts,7 such as Ni or Pd from both C−H or C−Y nature of this transformation was confirmed when control substitution (Scheme 1, top, Y = B(OH)2, I, Br). Also, experiments in the absence of light showed no conversion to photoinduced methods8,9 provide access to the difluoroalky- product 3 (Table 1, entry 9). lated arenes through simple photocatalysts or by synergistic With the suitable reaction conditions determined, we transition-metal and photocatalyst dual catalysis. For example, examined the scope of this difluoroalkylation of anilines Molander9b explored the installation of the gem-difluoro group (Table 2). using boronic acids via Ir/Cu combination. Organic photo- First, the scope using different N,N-dimethylanilines having catalysts can be extensively modified, and they are also cheaper substituents at the para position was evaluated. In general, this and more sustainable than transition-metal-based photo- transformation is amenable to a wide range of anilines catalysts.12 In this vein of sustainability, the development of containing electron-rich and moderate electron-withdrawing synthetic methods driven by photoactive EDA complexes is groups. The presence of halogens in this position allowed the also very attractive because they are able to trigger single- formation of the desired difluoroalkylated product in good electron process reactions without the presence of an yields (3-6). Interestingly, the para-iodo N,N-dimethylaniline exogenous photocatalyst.13 Last year, an efficient protocol for also proved to be a competent substrate for this trans- the difluoroalkylation of anilines was reported via an iridium- formation, providing 5, which could serve as an excellent based photoredox approach (Scheme 1, middle), although the feedstock for cross-coupling reactions in further trans- method uses large amounts of difluoroalkylating reagent and a formations. Next, the medicinally relevant trifluoromethyl fluorinated base.14 Assembling the gem-difluoro unit into ether and trifluoromethyl substituents were also competent anilines is an exciting area of research because these organic substrates for this transformation (7 and 8). However, this backbones are present in many synthetic routes for the methodology did not present high reactivity in the presence of elaboration of more sophisticated medicinal chemistry analogs, aldehyde (9) and nitrile (10), indicating low yields because the such as bioactive molecules and natural products.15 starting material was not fully consumed. In general, ■ RESULTS AND DISCUSSION First, to investigate the feasibility of the organophotoredox electronically rich substituents, such as aryl (11), alkyl (12), methylthio (13), alkoxy (14), and amino groups (15-17), can be accommodated as well in this transformation. In the cases of difluoroalkylation method, we selected Eosin Y (E (PC+/*PC) more activated anilines (14-17), we also detected the = −1.66 V vs Fc+/Fc)16 as a model photocatalyst, and 4- formation of the meta-N,N-dimethylaniline difluoroalkylated bromo-N,N-dimethylaniline (1a) and ethyl bromodifluoroace- product and the 2,5-bis(difluoroalkyl)-substituted compounds. tate (2a) as model substrates (Table 1). We observed that 1 Then, we further evaluated some disubstituted anilines using mol % of Eosin Y was the optimal loading to yield 3 (Table 1 our standard reaction conditions. Once again, deactivated entries 1−4) in DMF as a solvent and using K2CO3 as a base anilines provide the difluoroalkylated product in low yield (18 under green Kessil (λmax = 525 nm) lamp irradiation. and 19). On the other hand, the installation of the Subsequently, we observed a higher efficiency to form 3 difluoroalkylated ester was amenable to 2,6-disubstituted aryl when using the radical precursor 2b (Table 1, entry 5), which (20) and alkyl (21) anilines. Finally, the difluoroalkylation of has a higher reduction potential (Ered = −1.67 V vs Fc+/Fc)16 N,N-dimethylnaphthalen-1-amine provided 22 in 61% yield. than 2a (Ered = −1.94 V vs Fc+/Fc).16 The addition of [(n- Next, we sought to investigate the operative mechanism of Bu)4N]I (TBAI) contributed to better base solubility, this organophotoinduced transformation. To this end, we providing better efficacy (Table 1, entries 5−6), and the performed radical trapping studies under the standard reaction presence of base and organophotocatalyst is also crucial for this conditions (Scheme 2, see also the Supporting Information). transformation, although we observed moderate reactivity in The addition of the Galvinoxyl free radical totally inhibited the 12586 https://doi.org/10.1021/acs.joc.3c01298 J. Org. Chem. 2023, 88, 12585−12596 The Journal of Organic Chemistry pubs.acs.org/joc Article Table 2. Evaluation of Substrate Scopea Fc)16 affords the corresponding radical A. The generated oxidized EY+ undergoes a new SET with the corresponding aniline to recover the ground state of the photocatalyst (EY) and the radical cation B. This species collapses with radical A to generate the cationic C intermediate. The rearomatization of the phenyl ring in the presence of base provides the difluoroalkylated aniline. At this stage, we explored the feasibility of the synthesis of the described difluoroalkylated anilines without the use of an exogenous photocatalyst. We envisioned anilines can act as electron donor molecules and 2b as an electron-acceptor substrate. Thus, an electron donor−acceptor (EDA) complex can form if these two species efficiently interact, generating a new molecular aggregate in the ground state (Scheme 5). Further, this EDA complex can be activated by visible light to deliver a radical cationic species from aniline (B) and the reduced fluoroalkylated radical (A) pair. Control experiments in the absence of EY afforded product 3 in 38% yield, suggesting that the EDA pathway is indeed plausible (Table 1, entry 8). Thus, the next step was to study the potential of this route. Given the mild reaction conditions required to activate EDA complexes, their use has undoubtedly become a powerful strategy for the preparation of organic backbones in a sustainable manner.13,17 We started the study by exploring different solvents since the formation of EDA complexes is known to be directly related to solvent choice.18 We were delighted to observe a yield increase from 38% in DMF to 52% yield when DCM was used as a solvent in the formation of 3 (Table 3, entry 1). The examination of other solvents indicated that DMSO was the best option (Table 3, entry 2). Afterwards, we explored other bases, observing the highest yield using Na2CO3 (Table 3, entries 5−9). Finally, the use of 427 nm Kessil afforded the product in the highest yield (Table 1 entries 5, 10, and 11). Once we had the optimized conditions for this trans- a Reaction conditions: aniline 1 (0.3 mmol), 2b (0.4 mmol), Eosin Y formation via the generation of the EDA complex, we sought (1 mol %) in DMF (1.0 mL), 24 h irradiation with a 525 nm Kessil to explore different substituted anilines (Table 4). We were lamp. delighted to observe a more efficient reaction when using electron-deficient anilines compared to the reaction proceeding via Eosin Y. Thus, para-trifluoromethyl ether (7) and aldehyde product formation, and we detected by 19F NMR and HRMS the formation of the difluoroalkylated Galvinoxyl product (23). (9) derivatives were isolated in moderate yields, 49 and 30%, The reaction was also avoided in the presence of 1,1- respectively. Additionally, the presence of more electronically diphenylethene as radical scavenger. Specifically, the difluor- rich substituents in the aromatic ring of the anilines such as oalkylated compounds 24 and 25 were detected as major para-phenyl (11), -tertbutyl (12), methoxy (14), and methyl reaction products by 1H and 19F NMR. Additionally, the (21) proved to be the best electron donor substrates for this presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) transformation obtaining good to excellent yields. Particularly, also constrains the formation of aniline 12, and we could when using 4-methoxy-N,N-dimethylaniline as substrate, we detect difluoroalkylated-TEMPO adduct 26 in 33% yield. All observed the formation of the dialkylated product 14 along of these experiments support the generation of the with the bis(difluoroalkylated) aniline as a side product. In this difluoroalkyl radical during the reaction. In addition, the example, we detected that after 1 h of irradiation, the intended redox properties of all reaction components were analyzed by monodifluoralkylated product 14 was formed in an 85% yield. cyclic voltammetry experiments to assess the thermodynami- Of note, the preparation of 12 was done at 1.0 mmol scale in cally allowed single electron transfer (SET) processes (Tables high yield (80%), showcasing the efficiency of this trans- S2 and S3 in the Supporting Information). formation. Next, we examined ortho-, meta-substituted, and Based on the mechanistic findings described herein, the unbiased substrates (see products 23-26). In general, we substrate scope, the spectroscopic and electrochemical observed three regioisomers being the para-substituted the characterization of the reaction components,16 and reported most predominant, which during the purification process literature,14 a plausible mechanism for this transformation is underwent hydrolysis of the gem-difluoro moiety19 (see depicted in Scheme 3. compound 29 in the Supporting Information). Interestingly, After photoirradiation of Eosin Y (EY) photocatalyst (E when using p-tert-butylaniline as the organic backbone in this (PC+/*PC) = −1.66 V vs Fc+/Fc),16 a SET event from EY* to transformation, the difluorinated indolin-2-one 27 was isolated the fluorinated radical precursor 2b (Ered = −1.67 V vs Fc+/ in a good 55% yield. This experiment opens new molecular 12587 https://doi.org/10.1021/acs.joc.3c01298 J. Org. Chem. 2023, 88, 12585−12596 The Journal of Organic Chemistry pubs.acs.org/joc Article Scheme 2. Radical-Trapping Experiments Using Galvinoxyl, 1,1-Diphenylethene and TEMPO with the Optimized Standard (std) Reaction Conditions a Determined by 1H NMR. Scheme 3. Proposed Mechanism for the Photoinduced formation is not favored with such electron-poor nitrogenated Difluoroalkylation of Anilines Promoted by Eosin Y (EY) as substrates. Photocatalyst (SET: Single Electron Transfer) Then, we targeted the cyclization reaction from aniline 1j via N-Me bond scission in one-pot sequence (Scheme 4). After using our optimal conditions, we added NH4I and tert-butyl hydroperoxide (TBHP)20 and let the reaction to proceed for 4 h at 80 °C. To our delight, we isolate the corresponding compound 28 in a 65% yield. Given the efficiency of this EDA complex strategy, we investigated the use of other fluoroalkyl iodides as radical precursors. Of note, we could extend our optimized reaction conditions for the preparation of difluorophosphonate, difluoroamide, and perfluorohexyl derivatives in moderate yield (Table 5). Next, we sought to study the mechanism of this trans- formation. The UV−vis absorption spectra of each of the reaction components and mixtures in DMSO evidenced the formation of an EDA complex between aniline 1a and fluorinated 2b (Table 4, bottom). Aniline 1a (black line) presents an absorption band in the ultraviolet range and 2b in the visible-light area (light gray line), while the mixture of reaction components exhibits a significant bathochromic shift complexity in organofluorine chemical space without using any with a visible-light absorption tailing in the 450−500 nm range. exogenous photocatalyst. This bathochromic shift is in agreement with the visual The exploration of other more electronically deficient appearance of the individuals and all of the reaction anilines, including amides and N-Boc-protected anilines, components mixture. The solution of 1a is colorless and that resulted in only traces of product. These results support the of 1b is slightly yellow, while the solution of all of the reaction mechanistic pathway through the EDA complex, whose components remains intense yellow (see the inset in Table 4, 12588 https://doi.org/10.1021/acs.joc.3c01298 J. Org. Chem. 2023, 88, 12585−12596 The Journal of Organic Chemistry pubs.acs.org/joc Article Table 3. Optimization of Reaction Conditions via EDA Complex Strategya entry solvent base yield of 3 (%)b 1 DCM K2CO3 52 2 DMSO K2CO3 70 3 DMA K2CO3 60 4 MeCN K2CO3 0 5 DMSO Na2CO3 79 (70)c 6 DMSO Cs2CO3 65 7 DMSO K3PO4 46 8 DMSO NaHCO3 63 9 DMSO None 0 10 DMSO Na2CO3 74d 11 DMSO Na2CO3 0e a Reaction conditions: aniline 1a (0.3 mmol), 2b (0.4 mmol, 1.3 equiv), base (1.5 equiv) in the indicated solvent (3 mL), 16 h irradiation with a 427 nm Kessil lamp. bYields were determined by 1H NMR analysis. cIsolated yield. d456 nm Kessil lamp irradiation. eReaction in the dark. bottom). Additionally, the formation of this EDA complex is were recorded in a UV−vis spectrophotometer HP 8453 (Servei supported by 19F NMR titrations, which show a significant d’Anàlisi Quı ́mica, UAB), at room temperature, with the appropriate upfield shift of the fluorine resonance upon adding increasing solvent. The cyclic voltammetry experiments were performed with a amounts of aniline (Figure S3 in the Supporting Information). BioLogic SP-50 Single Channel Potentiostat, in a one-compartment three-electrode setup using a glassy carbon disk as the working Photochemical quantum yield (Φ) experiments provided key electrode (ø = 3 mm), platinum wire as the auxiliary electrode, and information about the mechanism of this reaction. We AgNO3/Ag (0.01 M AgNO3, 0.1 M [(Bu)4N]PF6 (TBAPF6), MeCN) measured Φ = 2.7, thus indicating that the radical chain as the reference electrode. Experiments were performed at room scenario is operating this transformation. Given this exper- temperature using the appropriate solvent, degassing with Ar, using imental value and previous reports,21 we propose a radical TBAPF6 as supporting electrolyte (0.1 M). All of the experiments chain mechanism initiated by a halogen bonding assisted EDA were referred to ferrocene as an internal standard. Polishing of the complex (Scheme 5). First, aniline 1a and fluorinated 2b meet working electrode has been done using an alumina polishing pad with in a new molecular aggregate in the ground state, which after a solution of 0.05 μm alumina in water (purchased from BAS INC.). photoirradiation undergoes SET. This event generates the For irradiation, commercially available Kessil PR160-purple LED fluorinated radical A and the cationic radical species B. lamp (30 W High Luminous DEX 2100 LED, λmax = 390 nm), Kessil A160WE Tuna Blue LED lamp (40 W, λmax = 456 nm), or a PR160- Subsequently, 1a reacts with A to yield radical species C. Then, green LED lamp (44 W High Luminous DEX 2100 LED, λmax = 525 this radical species reduces the fluorinated reagent 2b and nm) were placed 4 cm away from the reaction vials. The NMR oxidized D is obtained. Finally, the base abstracts a proton to experiments were performed in the Servei de Ressonància Magnètica obtain the desired difluoroalkylated aniline. With the Nuclear, UAB using the following Bruker Avance machines: DPX-250, mechanistic findings described above, the reaction of radical DPX-360, NEO 300, NEO 400, or III 400SB. Structural assignments pairs A and B to yield D is an unlikely process. were made with additional information from gCOSY, gHSQC, and ■ CONCLUSIONS In summary, we are presenting two complementary synthetic gHMBC experiments. The HRMS (ESI+) was done by the Servei d’Anàlisi Quı ́mica, UAB using a Bruker micrOTOF-QII mass spectrometer (fly time analyzer) through positive electrospray ionization. All reagents and solvents were purchased from Sigma- methods for the difluoroalkylation of anilines, avoiding the use Aldrich/Merck and BLDPharm except for 2,6-difluoroaniline, which of transition-metal photocatalysts. Our first protocol promotes was purchased from FluoroChem. All compounds were used as the difluoroalkylation using Eosin Y as an organic photo- received, except 2,6-dimethylaniline and 2,6-difluoroaniline, which catalyst under very mild conditions. The reaction works well were distilled under reduced pressure. when using electronically rich anilines. The mechanistic General Procedure 1 for the Difluoroalkylation of Anilines findings evidenced the generation of the ·CF2CO2Et radical via Eosin Y (GP1). In a 4 mL vial equipped with a magnetic stirring as an intermediate. Additionally, we describe the formation of a bar, Eosin Y (1.9 mg, 0.003 mmol, 0.01 equiv), the corresponding new EDA complex formed by the combination of anilines and aniline (0.3 mmol, 1 equiv), K2CO3 (62.2 mg, 0.45 mmol, 1.5 equiv), ethyl difluoroiodoacetate. The simple photoexcitation of this TBAI (55.4 mg, 0.15 mmol, 0.5 equiv), and ICF2COOEt (51 μL, 0.4 mmol, 1.3 equiv) were added. The vial was closed with a screw cap new molecular aggregate promotes the formation of difluor- provided with a rubber septum and degassed by alternating vacuum oalkylated arenes in an efficient manner with chemical yields evacuation and N2 backfill. Then, 1 mL of anhydrous DMF was up to 89%. added, and the mixture was degassed again by Ar bubbling. After 5 ■ EXPERIMENTAL SECTION General Information. All chemical transformations requiring an min of degassing, the vial was well sealed with Parafilm. The reaction mixture was stirred under Ar and irradiated by a 525 nm LED (PR160L Kessil) at room temperature. After 24 h, the mixture was inert atmosphere were done using Schlenk line techniques with a 4- or diluted with water and extracted with EtOAc (20 mL × 3). The 5-port dual-bank manifold. For the one-pot reaction that required organics were combined, washed with water (15 mL) and brine (15 heating, an oil bath was used as a heating source. The UV−vis spectra mL × 2), and finally dried over anhydrous Na2SO4. After solvent 12589 https://doi.org/10.1021/acs.joc.3c01298 J. Org. Chem. 2023, 88, 12585−12596 The Journal of Organic Chemistry pubs.acs.org/joc Article Table 4. Substrate Scope for Difluoroalkylation of Anilines stirring bar, the corresponding aniline (0.3 mmol, 1 equiv), Na2CO3 via EDA Complex Strategya and UV−Vis Studiesb (47.7 mg, 0.45 mmol, 1.5 equiv), and ICF2COOEt (51 μL, 0.4 mmol, 1.3 equiv) were added. The vial was closed with a screw cap provided with a rubber septum and degassed by alternating vacuum evacuation and N2 backfill. Then, 1 mL of anhydrous DMSO was added, and the mixture was degassed again by Ar bubbling. After 5 min of degassing, the vial was well sealed with Parafilm. The reaction mixture was stirred under Ar and irradiated by a 427 nm LED (PR160L Kessil) at room temperature. After 16 h, the mixture was diluted with water and extracted with EtOAc (20 mL × 3). The organics were combined, washed with water (15 mL) and brine (15 mL × 2), and finally dried over anhydrous Na2SO4. After solvent removal under high vacuum, the product was purified by flash column chromatography through silica gel. Procedure for the Difluoroalkylation via EDA Complex at 1.0 mmol Scale. In a 20 mL Schlenk equipped with a magnetic stirring bar, 4-(tert-butyl)-N,N-dimethylaniline (177 mg, 1.0 mmol, 1 equiv), Na2CO3 (157 mg, 1.5 mmol, 1.5 equiv), and ICF2COOEt (170 μL, 1.3 mmol, 1.3 equiv) were added. The Schlenk was closed with a septum and degassed by alternating vacuum evacuation and N2 backfill. Then, 10 mL of anhydrous DMSO was added, and the mixture was degassed again by Ar bubbling. Then, the vial was well sealed with Parafilm. The reaction mixture was stirred under Ar and irradiated by two 427 nm LEDs (PR160L Kessil) at room temperature. After 16 h, the mixture was diluted with water and extracted with EtOAc (25 mL). The organics were combined, washed with water (15 mL) and brine (15 mL × 3), and finally dried over anhydrous Na2SO4. After solvent removal under a high vacuum, the product was purified by flash column chromatography through silica gel, yielding 12 in 80% yield (239 mg, 0.08 mmol). Ethyl 2-(5-Bromo-2-(dimethylamino)phenyl)-2,2-difluoroacetate (3).22 Colorless oil (60.9 mg, 0.19 mmol, 63% yield from 60 mg of N,N-dimethyl-4-bromoaniline following GP1; 67.0 mg, 0.21 mmol, 70% yield from 60 mg of N,N-dimethyl-4-bromoaniline following GP2); Rf = 0.68 (hexane:ethyl acetate, 9.5:0.5). 1H NMR (400 MHz, CDCl3), δ (ppm): 7.81 (d, 4J = 4.0 Hz, 1H), 7.59 (dd, 3J = 16 Hz, 4J = 4.0 Hz, 1H), 7.20 (d, 3JH,H = 16 Hz, 1 H), 4.30 (q, 3JH,H = 12.0 Hz, 2H), 2.55 (s, 6 H), 1.30 (t 3JH,H = 12.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3), δ (ppm): 163.9 (t, 2JF,C = 34.0 Hz), 151.9 (t, 3JF,C = 5.0 Hz), 135.3, 133.3 (t, 2JF,C = 22.0 Hz), 129.8 (t, 3JF,C = 7.0 Hz), 124.8, 118.8, 112.1 (t, 1JF,C = 246.0 Hz), 62.7, 45.6 (2C), 14.4; 19F NMR (235 MHz, CDCl3), δ (ppm): −99.1; FT-IR (cm−1, neat, ATR), 2941, 1760, 1282, 1257, 1233, 1136; HRMS (ESI+) m/z: [M + H]+ Calcd for C12H15BrF2NO2 322.0249; found 322.0250. Ethyl 2-(5-Chloro-2-(dimethylamino)phenyl)-2,2-difluoroacetate (4). Yellow oil (42.9 mg, 0.15 mmol, 52% yield from 46.6 mg of 4- a Reaction conditions: aniline (0.3 mmol), 2b (0.4 mmol, 1.3 equiv), chloro-N,N-dimethylaniline following GP1); Rf = 0.38 (hexane:ethyl Na2CO3 (1.5 equiv) in DMSO (3 mL), 16 h irradiation with a 427 acetate, 9.5:0.5). 1H NMR (400 MHz, CDCl3), δ (ppm): 7.67 (d, 4 nm Kessil lamp. bUV−vis absorption spectra and picture of individual JH,H = 4.0 Hz 1H), 7.44 (dd, 3JH,H = 9.0 Hz, 4JH,H = 4.0 Hz, 1H), 7.26 reaction components and a combination thereof (see the Supporting (d, 3JH,H = 8.0 Hz, 1H), 4.30 (q, 3JH,H = 8.0 Hz, 2H), 2.54 (s, 6H), Information for details). cIsolated yield at 1.0 mmol scale. d1H NMR 1.30 (t, 3JH,H = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3), δ yield after 1 h of irradiation. eMixture of isomers (see the (ppm): 163.8 (t, 2JF,C = 32.0 Hz), 151.3, 133.0 (t, 2JF,C = 24.0 Hz), Experimental Section for details). 132.3, 131.2, 126.9 (t, 3JF,C = 7.0 Hz), 124.5, 112.1 (t, 1JF,C = 245.0 Hz), 62.7, 45.7 (2C), 14.4; 19F NMR (282 MHz, CDCl3), δ (ppm): −98.7; FT-IR (cm−1, neat, ATR), 2947, 1770, 1370, 1283, 1256, Scheme 4. One-Pot Formation of 3,3-Difluoroindolin-2-one 1234, 1164; HRMS (ESI+) m/z: [M + Na] + Calcd for 28 C12H14ClF2NO2Na 300.0573; found 300.0578. Ethyl 2-(2-(Dimethylamino)-5-iodophenyl)-2,2-difluoroacetate (5). Colorless to yellow oil (49.9 mg, 0.14 mmol, 45% yield from 74.1 mg of N,N-dimethyl-4-iodoaniline following GP1); Rf = 0.38 (hexane:ethyl acetate, 9.5:0.5). 1H NMR (300 MHz, CDCl3), δ (ppm): 8.00 (d, 4JH,H = 3.0 Hz, 1H), 7.79 (dd, 3JH,H = 9.0 Hz, 4JH,H = 3.0 Hz, 1H), 7.07 (d, 3JH,H = 9.0 Hz 1H), 4.30 (q, 3JH,H = 9.0 Hz, 2H), 2.54 (s, 6 H), 1.30 (t, 3JH,H = 9.0 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3), δ (ppm): 163.9 (t, 2JF,C = 32.3 Hz), 152.6 (t, 3JF,C = removal under high vacuum, the product was purified by flash column 5.3 Hz), 141.3 (t, 4JF,C = 1.5 Hz), 135.7 (t, 3JF,C = 7.5 Hz), 133.3 (t, 2 chromatography through silica gel. JF,C = 23.3 Hz), 125.1, 111.9 (t, 1JF,C = 246.0 Hz), 89.5, 62.7, 45.6 General Procedure for the Difluoroalkylation of Anilines via (2C), 14.5; 19F NMR (282 MHz, CDCl3), δ (ppm): −98.6; FT-IR EDA Complex (GP2). In a 4 mL vial equipped with a magnetic (cm−1, neat, ATR), 2947, 1769, 1313, 1280, 1260, 1233, 1168; 12590 https://doi.org/10.1021/acs.joc.3c01298 J. Org. Chem. 2023, 88, 12585−12596 The Journal of Organic Chemistry pubs.acs.org/joc Article Table 5. Substrate Scope for Difluoroalkylation of Aniline 1j via EDA Complex Strategy Using Different Fluoroalkyl Iodidesa a Reaction conditions: aniline (0.3 mmol), 2b−e (0.4 mmol, 1.3 equiv), Na2CO3 (1.5 equiv) in DMSO (3 mL), 16 h irradiation with a 427 nm Kessil lamp. Scheme 5. Proposed Mechanism for the Photoinduced Exogenous Photocatalyst Difluoroalkylation of Anilines HRMS (ESI+) m/z: [M + H]+ Calcd for C12H15IF2NO2 370.0110; 7.55 (d, 3JH,H = 4.0 Hz, 1H), 7.33 (m, 2H), 4.31 (q, 3JH,H = 8.0 Hz, found 370.0107. 2H), 2.56 (s, 6H), 1.31 (t, 3JH,H = 8.0 Hz, 3H); 13C{1H} NMR (100 Ethyl 2-(2-(Dimethylamino)-5-fluorophenyl)-2,2-difluoroacetate MHz, CDCl3), δ (ppm): 163.8 (t, 2JF,C = 33.0 Hz), 151.4 (t, 3JF,C = (6). Colorless oil (22.7 mg, 0.09 mmol, 29% yield from 41.8 mg of 5.0 Hz), 146.5 (q, 3JF,C = 2.0 Hz), 133.2 (t, 2JF,C = 24.0 Hz), 124.9, N,N-dimethyl-4-fluoroaniline following GP1); Rf = 0.38 (hexane:E- 124.6, 120.8 (q, 1JF,C = 259.0 Hz), 119.7 (t, 3JF,C = 7.0 Hz), 112.0 (t, tOAc, 9.5:0.5). 1H NMR (400 MHz, CDCl3), δ (ppm): 7.39 (dd, J = 1 JF,C = 246.0 Hz), 62.7, 45.8 (2C), 14.4; 19F NMR (376 MHz, 8.0 Hz, J = 4.0 Hz, 1H), 7.31 (dd, J = 4.0 Hz, J = 8.0 Hz, 1H), 7.18 CDCl3), δ (ppm): −58.1 (s, 3F), −98.7 (s, 2F); FT-IR (cm−1, neat, (dd, J = 8.0 Hz, J = 4.0 Hz, 1H), 4.31 (q, 3JH,H = 8.0 Hz, 2H), 2.53 (s, ATR), 2949, 1771, 1252, 1214, 1159; HRMS (ESI+) m/z: [M + H]+ 6H), 1.31 (t, 3JH,H = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3), Calcd for C13H15F5NO3 328.0967; found 328.0964. δ (ppm): 163.9 (t, 2JF,C = 32.0 Hz), 160.2 (d, 1JF,C = 244.0 Hz), 148.6 Ethyl 2-(2-(Dimethylamino)-5-(trifluoromethyl)phenyl)-2,2-di- (m), 133.4 (td, 2JF,C = 24.0 Hz, 3JF,C = 7.0 Hz), 124.7 (t, 3JF,C = 8.0 fluoroacetate (8). Colorless to yellow oil (33.9 mg, 0.11 mmol, Hz), 119.1 (d, 2JF,C = 22.0 Hz), 113.7 (dt, 2JF,C = 25.0 Hz, 3JF,C = 7.0 52% yield from 56.7 mg of N,N-dimethyl-4-(trifluoromethyl)aniline Hz), 112.1 (t, 1JF,C = 246.0 Hz), 62.7, 45.9 (2C), 14.5; 19F NMR (282 following GP1); Rf = 0.38 (hexane:ethyl acetate, 9.5:0.5). 1H NMR MHz, CDCl3), δ (ppm): −98.6 (s, 2F), −115.3 (m, 1F); FT-IR (400 MHz, CDCl3), δ (ppm): 7.98 (d, 3JH,H = 4.0 Hz, 1H), 7.74 (d, (cm−1, neat, ATR), 2945, 1769, 1291, 1268, 1236, 1186; HRMS (ESI 3 JH,H = 8.0 Hz, 1H), 7.42 (d, 3JH,H = 8.0 Hz, 1H), 4.31 (q, 3JH,H = 8.0 +) m/z: [M + Na]+ Calcd for C12H14F3NO2Na 284.0869; found 284.0863. Hz, 2H), 2.61 (s, 6H), 1.31 (t, 3JH,H = 8.0 Hz, 3H); 13C{1H} NMR Ethyl 2-(2-(Dimethylamino)-5-(trifluoromethoxy)phenyl)-2,2-di- (75 MHz, CDCl3), δ (ppm): 124.0 (q, 1JF,C = 270.0 Hz), 163.9 (t, 2 fluoroacetate (7). Colorless to orange oil (44.4 mg, 0.14 mmol, 45% JF,C = 32.0 Hz), 156.1 (t, 3JF,C = 3.8 Hz), 131.9 (t, 2JF,C = 24.0 Hz), yield from 61.6 mg of N,N-dimethyl-4-(trifluoromethoxy)aniline 129.3 (m), 127.8 (q, 2JF,C = 33.0 Hz), 124.3 (m), 124.0 (q, 1JF,C = following GP1; 48.3 mg, 0.15 mmol, 49% yield from 61.6 mg of 270.0 Hz), 123.7, 112.1 (t, 1JF,C = 267.0 Hz), 63.0, 45.6 (2C), 14.4; 19 N,N-dimethyl-4-(trifluoromethoxy)aniline following GP2); Rf = 0.43 F NMR (282 MHz, CDCl3), δ (ppm): −62.4 (s, 3F), −98.3 (s, 2F); (hexane:ethyl acetate, 9:1). 1H NMR (400 MHz, CDCl3), δ (ppm): FT-IR (cm−1, neat, ATR), 2840, 1768, 1336, 1261, 1229, 1163; 12591 https://doi.org/10.1021/acs.joc.3c01298 J. Org. Chem. 2023, 88, 12585−12596 The Journal of Organic Chemistry pubs.acs.org/joc Article HRMS (ESI+) m/z: [M + H]+ Calcd for C13H15F5NO2 312.1017; 7.25 (d, 3JH,H = 9.0 Hz, 1H), 4.30 (q, 3JH,H = 6.0 Hz, 2H), 2.54 (s, found 312.1017. 6H), 2.50 (s, 3H), 1.31 (t, 3JH,H = 6.0 Hz, 3H); 13C{1H} NMR (75 Ethyl 2-(2-(Dimethylamino)-5-formylphenyl)-2,2-difluoroacetate MHz, CDCl3), δ (ppm): 164.4 (t, 2JF,C = 33.0 Hz), 151.8 (t, 3JF,C = (9). Colorless to yellow oil (20.1 mg, 0.07 mmol, 25% yield from 44.8 4.5 Hz), 140.4, 138.9, 131.7 (t, 2JF,C = 23.3 Hz), 130.8, 129.2 (2C), mg of 4-(dimethylamino)benzaldehyde following GP1; 24.1 mg, 0.09 127.9, 127.4 (2C), 125.3 (t, 3JF,C = 6.8 Hz), 123.3, 112.9 (t, 1JF,C = mmol, 30% yield from 44.8 mg of 4-(dimethylamino)benzaldehyde 244.5 Hz), 63.1, 45.8 (2C), 16.5, 14.5; 19F NMR (235 MHz, CDCl3), following GP2); Rf = 0.30 (hexane:ethyl acetate, 8:2). 1H NMR (300 δ (ppm): −98.6; FT-IR (cm−1, neat, ATR), 2944, 1769, 1371, 1313, MHz, CDCl3), δ (ppm): 10.00 (s, 1H), 8.23 (d, 3JH,H = 3.0 Hz, 1H), 1286, 1264, 1236, 1189; HRMS (ESI+) m/z: [M + H]+ Calcd for 8.01 (dd, 3JH,H = 9.0 Hz, 4JH,H = 3.0 Hz, 1H), 7.43 (d, 3JH,H = 9.0 Hz, C13H18F2NO2S 290.1020; found 290.1011. 1H), 4.29 (q, 3JH,H = 6.0 Hz, 2H), 2.65 (s, 6H), 1.28 (t, 3JH,H = 6.0 Ethyl 2-(2-(Dimethylamino)-5-methoxyphenyl)-2,2-difluoroace- Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3), δ (ppm): 190.8, 163.9 tate (14). Yellow oil (38.3 mg, 0.14 mmol, 47% yield from 45.4 mg (t, 2JF,C = 33.0 Hz), 158.4 (t, 3JF,C = 5.0 Hz), 133.3, 132.9, 131.5 (t, of 4-methoxy-N,N-dimethylaniline following GP1; 54.5 mg, 0.22 2 JF,C = 24.0 Hz), 129.4 (t, 3JF,C = 7.0 Hz), 123.2, 112.3 (t, 1JF,C = 246.0 mmol, 73% yield from 45.4 mg of 4-methoxy-N,N-dimethylaniline Hz), 62.8, 45.5 (2C), 14.4; 19F NMR (282 MHz, CDCl3), δ (ppm): following GP2); Rf = 0.58 (hexane:ethyl acetate, 9:1). 1H NMR (300 −97.8; FT-IR (cm−1, neat, ATR), 2948, 1767, 1696, 1370, 1303, MHz, CDCl3), δ (ppm): 7.26 (d, 3JH,H = 9.0 Hz, 1H), 7.20 (d, 4JH,H = 1269, 1242, 1176; HRMS (ESI+) m/z: [M + Na]+ Calcd for 3.0 Hz, 1H), 7.01 (dd, 3JH,H = 9.0 Hz, 4JH,H = 3.0 Hz, 1H), 4.31 (q, 3 C13H15F2NO3Na 294.0912; found 294.0909. JH,H = 9.0 Hz, 2H), 3.81 (s, 3H), 2.51 (s, 6H), 1.31 (t, 3JH,H = 9.0 Hz, Ethyl 2-(5-Cyano-2-(dimethylamino)phenyl)-2,2-difluoroacetate 3H); 13C{1H} NMR (100 MHz, CDCl3), δ (ppm): 164.2 (t, 2JF,C = (10). Colorless to yellow oil (7.24 mg, 0.03 mmol, 9% yield from 43.9 33.0 Hz), 157.4, 145.4 (t, 3JF,C = 6.0 Hz), 132.4 (t, 2JF,C = 24.0 Hz), mg of 4-(dimethylamino)benzonitrile following GP1; traces from 43.9 124.1, 118.3, 112.7 (t, 1JF,C = 245.0 Hz), 110.9 (t, 3JF,C = 7.0 Hz), mg of 4-(dimethylamino)benzonitrile following GP2); Rf = 0.48 62.4, 55.9, 45.8 (2 C), 14.5; 19F NMR (282 MHz, CDCl3), δ (ppm): (hexane:ethyl acetate, 8:2). 1H NMR (400 MHz, CDCl3), δ (ppm): −98.7; FT-IR (cm−1, neat, ATR), 2941, 1767, 1279, 1215, 1178; 8.00 (d, 3JH,H = 4.0 Hz, 1H), 7.75 (dd, 3JH,H = 8.0 Hz, 4JH,H = 4.0 Hz, HRMS (ESI+) m/z: [M + H]+ Calcd for C13H18F2NO3 274.1249; 1H), 7.38 (d, 3JH,H = 8.0 Hz, 1H), 4.29 (q, 3JH,H = 8.0 Hz, 2H), 2.62 found 274.1251. (s, 6H), 1.29 (t, 3JH,H = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, Ethyl 2-(2,5-bis(Dimethylamino)phenyl)-2,2-difluoroacetate CDCl3), δ (ppm): 163.6 (t, 2JF,C = 33.0 Hz), 157.0 (t, 3JF,C = 4.0 Hz), (15). Colorless oil (35.4 mg, 0.12 mmol, 41% yield from 49.3 mg 135.9, 132.1 (t, 2JF,C = 24.0 Hz), 131.3 (t, 3JF,C = 7.0 Hz), 123.7, of N1,N1,N4,N4-tetramethylbenzene-1,4-diamine following GP1); Rf = 118.4, 111.7 (t, 1JF,C = 267.0 Hz), 109.1, 63.0, 45.5 (2C), 14.4;19F 0.20 (hexane:ethyl acetate, 9.5:0.5). 1H NMR (400 MHz, CDCl3), δ NMR (282 MHz, CDCl3), δ (ppm): −97.3; HRMS (ESI+) m/z: [M (ppm): 7.21 (d, 3JH,H = 8.0 Hz, 1H), 7.00 (d, 4JH,H = 4.0 Hz, 1H), + Na]+ Calcd for C13H14F2N2O2Na 291.0916; found 291.0917. 6.82 (dd, 3JH,H = 8.0 Hz, 4JH,H = 4.0 Hz, 1H), 4.31 (q, 3JH,H = 8.0 Hz, Ethyl 2-(4-(Dimethylamino)-[1,1′-biphenyl]-3-yl)-2,2-difluoroa- 2H), 2.96 (s, 6H), 2.51 (s, 6H), 1.32 (t, 3JH,H = 8.0 Hz, 3H); 13C{1H} cetate (11). Yellow to colorless oil (61.4 mg, 0.19 mmol, 64% yield NMR (100 MHz, CDCl3), δ (ppm): 164.4 (t, 2JF,C = 33.0 Hz), 148.7, from 59.2 mg of N,N-dimethyl-[1,1′-biphenyl]-4-amine following 141.5 (t, 3JF,C = 5.0 Hz), 131.8 (t, 2JF,C = 22.0 Hz), 123.5, 116.1, 113.2 GP1; 65.2 mg, 0.20 mmol, 68% yield from 59.2 mg of N,N-dimethyl- (t, 1JF,C = 245.0 Hz), 109.4 (t, 3JF,C = 7.0 Hz), 62.3, 45.9 (2C), 41.1 [1,1′-biphenyl]-4-amine following GP2); Rf = 0.28 (hexane:ethyl (2C), 14.5; 19F NMR (376 MHz, CDCl3), δ (ppm): −98.2; FT-IR acetate, 9.5:0.5). 1H NMR (300 MHz, CDCl3), δ (ppm): 7.93 (d, (cm−1, neat, ATR), 2939, 1765, 1309, 1265, 1223, 1177; HRMS (ESI 3 JH,H = 9.0 Hz, 1H), 7.71 (dd, 3JH,H = 9.0 Hz, 4JH,H = 3.0 Hz, 1H), +) m/z: [M + H]+ Calcd for C14H21F2N2O2 287.1566; found 7.58−7.62 (m, 2H), 7.36−7.48 (m, 4H), 4.33 (q, 3JH,H = 6.0 Hz, 2 287.1573. H), 2.62 (s, 6 H), 1.34 (t, 3JH,H = 6.0 Hz, 3H); 13C{1H} NMR (75 Ethyl 2-(2-(Dimethylamino)-5-morpholinophenyl)-2,2-difluoroa- MHz, CDCl3), δ (ppm): 164.4 (t, 2JF,C = 33.0 Hz), 151.8 (t, 3JF,C = cetate (16). Yellow oil (33.0 mg, 0.10 mmol, 34% yield from 62.0 mg 4.5 Hz), 140.4, 138.9, 131.7 (t, 2JF,C = 23.3 Hz), 130.8, 129.2 (2C), of N,N-dimethyl-4-morpholinoaniline following GP1); Rf = 0.45 127.9, 127.4 (2C), 125.3 (t, 3JF,C = 6.8 Hz), 123.3, 112.9 (t, 1JF,C = (hexane:ethyl acetate, 8:2). 1H NMR (300 MHz, CDCl3), δ (ppm): 244.5 Hz), 63.1, 45.8 (2C), 14.5; 19F NMR (235 MHz, CDCl3), δ 7.21 (m, 2H), 7.01 (m, 1H), 4.31 (q, 3JH,H = 6.0 Hz, 2H), 3.85 (m, (ppm): −98.2; FT-IR (cm−1, neat, ATR), 2940, 1766, 1299, 1222, 4H), 3.17 (m, 4H), 2.51 (s, 6H), 1.31 (t, 3JH,H = 6.0 Hz, 3H); 13 1137; HRMS (ESI+) m/z: [M + H]+ Calcd for C18H20F2NO2 C{1H} NMR (75 MHz, CDCl3), δ (ppm): 164.3 (t, 2JF,C = 33.0 320.1456; found 320.1444. Hz), 149.3, 144.7 (t, 3JF,C = 5.3 Hz), 132.0 (t, 2JF,C = 22.5 Hz), 119.3 Ethyl 2-(5-(tert-Butyl)-2-(dimethylamino)phenyl)-2,2-difluoroa- (t, 4JF,C = 1.5 Hz), 113.1 (t, 3JF,C = 7.5 Hz), 113.0 (t, 1JF,C = 245.3 cetate (12). Colorless to yellow oil (61.1 mg, 0.21 mmol, 68% Hz), 109.4 (t, 3JF,C = 7.5 Hz), 67.2 (2C), 62.4, 49.7 (2C), 45.8 (2C), yield from 53.2 mg of 4-(tert-butyl)-N,N-dimethylaniline following 14.5; 19F NMR (235 MHz, CDCl3), δ (ppm): −98.6; FT-IR (cm−1, GP1; 80.0 mg, 0.27 mmol, 89% yield from 53.2 mg of 4-(tert-butyl)- neat, ATR), 2920, 1743, 1318, 1303, 1274, 1244, 1117; HRMS (ESI N,N-dimethylaniline following GP2); Rf = 0.40 (hexane:ethyl acetate, +) m/z: [M + H]+ Calcd for C16H23F2N2O3 329.1671; found 9.5:0.5). 1H NMR (400 MHz, CDCl3), δ (ppm): 7.70 (d, 4JH,H = 4.0 329.1695. Hz, 1H), 7.50 (dd, 3JH,H = 12.0 Hz, 4JH,H = 4.0 Hz, 1H), 7.25 (d, 3JH,H Ethyl 2-(5-((tert-Butoxycarbonyl)amino)-2-(dimethylamino)- = 12.0 Hz, 1H), 4.31 (q, 3JH,H = 8.0 Hz, 2H), 2.54 (s, 6H), 1.34 (s, phenyl)-2,2-difluoroacetate (17). Yellowish oil (56.5 mg, 0.16 9H), 1.33 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3), δ (ppm): mmol, 53% yield from 70.9 mg of tert-butyl (4-(dimethylamino)- 164.6 (t, 2JF,C = 32.0 Hz), 149.9 (t, 3JF,C = 5.0 Hz), 148.8, 130.6 (t, phenyl)carbamate following GP1); Rf = 0.65 (hexane:ethyl acetate, 2 JF,C = 23.0 Hz), 129.3, 123.1 (t, 3JF,C = 6.0 Hz), 122.3, 113.2 (t, 1JF,C 8:2). 1H NMR (400 MHz, CDCl3), δ (ppm): 7.59 (m, 2H), 7.25 (d, 3 = 244.0 Hz), 109.3, 62.4, 45.7 (2C), 35.0, 31.7 (3C), 14.5; 19F NMR JH,H = 8.0 Hz, 1H), 6.59 (s, 1H), 4.29 (q, 3JH,H = 8.0 Hz, 2H), 2.52 (376 MHz, CDCl3), δ (ppm): −97.8; FT-IR (cm−1, neat, ATR), (s, 6H), 1.51 (s, 9H), 1.30 (t, 3JH,H = 8.0 Hz, 3H); 13C{1H} NMR 2955, 1768, 1366, 1231; HRMS (ESI+) m/z: [M + H]+ Calcd for (100 MHz, CDCl3), δ (ppm): 164.2 (t, 2JF,C = 32.0 Hz), 153.1, 147.6 C16H24F2NO2 300.1769; found 300.1764; Elem. Anal. Calcd for (t, 3JF,C = 5.0 Hz), 136.2, 132.0 (t, 2JF,C = 23 Hz), 123.6, 122.5, 116.7 C16H23F2NO2: C, 64.20; H, 7.74; N, 4.68. Found: C, 64.66; H, 8.09; (t, 3JF,C = 7.0 Hz), 112.6 (t, 1JF,C = 245.0 Hz), 81.2, 62.5, 45.8 (2C), N, 4.59. 28.6 (3C), 14.5; 19F NMR (376 MHz, CDCl3), δ (ppm): −98.7; FT- Ethyl 2-(2-(Dimethylamino)-5-(methylthio)phenyl)-2,2-difluor- IR (cm−1, neat, ATR), 3356, 2980, 1762, 1725, 1522, 1455, 1425, oacetate (13). Brown to orange oil (59.2 mg, 0.21 mmol, 68% 1393, 1368, 1298, 1234, 1152; HRMS (ESI+) m/z: [M + Na]+ Calcd yield from 50.2 mg of N,N-dimethyl-4-(methylthio)aniline following for C17H24F2N2O4Na 381.1596; found 381.1595. GP1; 59.2 mg, 0.21 mmol, 68% yield from 50.2 mg of N,N-dimethyl- Ethyl 2-(4-Amino-3,5-difluorophenyl)-2,2-difluoroacetate (18). 4-(methylthio)aniline following GP2); Rf = 0.33 (hexane:ethyl Brownish oil (12.8 mg, 0.05 mmol, 17% yield from 38.7 mg of 2,6- acetate, 9.5:0.5). 1H NMR (300 MHz, CDCl3), δ (ppm): 7.57 (d, difluoroaniline following GP1; 16.9 mg, 0.07 mmol, 23% yield from 4 JH,H = 3.0 Hz, 1H), 7.37 (dd, 3JH,H = 9.0 Hz, 4JH,H = 3.0 Hz, 1H), 38.7 mg of 2,6-difluoroaniline following GP2); Rf = 0.35 12592 https://doi.org/10.1021/acs.joc.3c01298 J. Org. Chem. 2023, 88, 12585−12596 The Journal of Organic Chemistry pubs.acs.org/joc Article (hexane:ethyl acetate, 8.5:1.5). 1H NMR (400 MHz, CDCl3), δ MHz, CD2Cl2), δ (ppm): −101.8; HRMS (ESI+) m/z: [M + H]+ (ppm): 7.10 (d, 3JH,H = 8.0 Hz, 2 H), 4.30 (q, 3JH,H = 6.0 Hz, 2H), Calcd for C12H15ClF2NO2 278.0754; found 278.0735. 3.98 (bs, 2H), 1.32 (t, 3JH,H = 6.0 Hz, 3H); 13C{1H} NMR (75 MHz, Ethyl 2-(4-Chloro-3-(dimethylamino)phenyl)-2,2-difluoroacetate CDCl3), δ (ppm): 163.8 (t, 2JF,C = 61.6 Hz), 151.5 (dd, 2C, 1JF,C = (23b). Colorless oil (12.5 mg, 0.05 mmol, 15% yield from 47.0 mg of 240.0 Hz, 3JF,C = 8.3 Hz), 127.1 (t, 2JF,C = 29.92 Hz), 121.2 (t, 3JF,C = 2-chloro-N,N-dimethylaniline following GP2); Rf = 0.43 (hexane:eth- 8.3 Hz), 112.8 (tt, 1JF,C = 251.0 Hz, 4JF,C = 2.3 Hz), 109.2 (m, 2C), yl acetate, 9.7:0.3). 1H NMR (300 MHz, CD2Cl2), δ (ppm): 7.42 (d, 3 63.6, 14.2; 19F NMR (282 MHz, CDCl3), δ (ppm): −102.6 (s, 2F), JH,H = 9.0 Hz, 1H), 7.25 (d, 3JH,H = 3.0 Hz, 1 H), 7.14 (dd, 3JH,H = −131.1 (d, 4JF,C = 3.5 Hz, 2F); HRMS (ESI+) m/z: [M + Na]+ Calcd 9.0 Hz, 4JH,H = 3.0 Hz, 1 H), 4.29 (q, 3JH,H = 6.0 Hz, 2 H), 2.82 (s, 6 for C10H9F4NO2Na 274.0462; found 274.0445. Elem. Anal. Calcd for H), 1.29 (t, 3JH,H = 6.0 Hz, 3 H); 13C{1H} NMR (125 MHz, C10H9F4NO2: C, 47.82; H, 3.61; N, 5.58. Found: C, 47.72; H, 3.64; CD2Cl2), δ (ppm): 164.2 (t, 2JF,C = 35.0 Hz), 151.3, 132.4 (t, 2JF,C = N, 5.35. 25.0 Hz), 131.4, 131.2, 120.0 (t, 3JF,C = 6.3 Hz), 117.3 (t, 3JF,C = 6.3 Ethyl 2-(4-Amino-3,5-dibromophenyl)-2,2-difluoroacetate (19). Hz), 113.6 (t, 1JF,C = 250.0 Hz), 63.8, 43.6 (2 C), 14.1; 19F NMR Yellow to orange powder (10.5 mg, 0.03 mmol, 9% yield from 75.3 (282 MHz, CD2Cl2), δ (ppm): −103.8; FT-IR (cm−1, neat, ATR), mg of 2,6-dibromoaniline following GP1; traces from 75.3 mg of 2,6- 2947, 1769, 1313, 1280, 1260, 1233, 1168; HRMS (ESI+) m/z: [M + dibromoaniline following GP2); Rf = 0.35 (hexane:ethyl acetate, H]+ Calcd for C12H15ClF2NO2 278.0754; found 278.0735. 9.5:0.5); mp: 57−59 °C. 1H NMR (300 MHz, CDCl3), δ (ppm): Ethyl 2-(3-Chloro-4-(dimethylamino)phenyl)-2,2-difluoroacetate 7.62 (s, 2H), 4.84 (bs, 2H), 4.31 (q, 3JH,H = 6.0 Hz, 2H), 1.33 (t, 3JH,H (23c). Colorless oil (22.5 mg, 0.08 mmol, 27% yield from 47.0 mg of = 6.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3), δ (ppm): 164.2 2-chloro-N,N-dimethylaniline following GP2); Rf = 0.35 (hexane:eth- (t, 2JF,C = 35 Hz), 144.6, 129.5 (t, 3JF,C = 7.0 Hz), 123.7 (t, 2JF,C = 27.9 yl acetate, 9.7:0.3). 1H NMR (300 MHz, CDCl3), δ (ppm): 7.58 (d, 3 Hz), 112.4 (t, 1JF,C = 252.0 Hz), 108.3, 63.7, 14.3; 19F NMR (282 JH,H = 3.0 Hz, 1H), 7.42 (dd, 3JH,H = 9.0 Hz, 4JH,H = 3.0 Hz, 1 H), MHz, CDCl3), δ (ppm): −102.6; FT-IR (cm−1, neat, ATR), 2924, 7.07 (d, 3JH,H = 9.0 Hz, 1 H), 4.30 (q, 3JH,H = 6.0 Hz, 2 H), 2.86 (s, 6 1770, 1244, 1098; HRMS (ESI+) m/z: [M + Na]+ Calcd for H), 1.32 (t, 3JH,H = 6.0 Hz, 3 H); 13C{1H} NMR (125 MHz, CDCl3), C10H9Br2F2NO2 393.8860; found 393.8856. δ (ppm): 164.2 (t, 2JF,C = 35.0 Hz), 152.8, 128.3 (t, 3JF,C = 6.3 Hz), Ethyl 2-(2′-Amino-[1,1′:3′,1″-terphenyl]-5′-yl)-2,2-difluoroace- 127.7, 126.8 (t, 2JF,C = 26.3 Hz), 124.9 (t, 3JF,C = 6.3 Hz), 119.7, 113.0 tate (20). Red oil (40.6 mg, 0.11 mmol, 37% yield from 73.6 mg of (t, 1JF,C = 250.0 Hz), 63.3, 43.5 (2 C), 14.1; 19F NMR (282 MHz, [1,1′:3′,1″-terphenyl]-2′-amine following GP1); Rf = 0.15 (hex- CDCl3), δ (ppm): −103.0; FT-IR (cm−1, neat, ATR), 2947, 1769, ane:ethyl acetate, 9.5:0.5). 1H NMR (300 MHz, CDCl3), δ (ppm) 1313, 1280, 1260, 1233, 1168; HRMS (ESI+) m/z: [M + H]+ Calcd 7.38−7.50 (m, 10H), 7.37 (s, 2H), 4.34 (q, 3JH,H = 6.0 Hz, 2H), 4.11 for C12H15ClF2NO2 278.0754; found 278.0735. (s, 2H), 1.34 (t, 3JH,H = 6.0 Hz, 3H); 13C{1H} NMR (75 MHz, Ethyl 2-(2-(Dimethylamino)phenyl)-2,2-difluoroacetate (24a).23 CDCl3), δ (ppm): 165.0 (t, 2JF,C = 36.8 Hz), 143.7 (t, JF,C = 2 Hz), Yellowish oil (11.2 mg, 0.05 mmol, 15% yield from 36.0 mg of N,N- 139.0, 129.5 (4C), 129.4 (4C), 128.1 (2C), 127.8 (2C), 127.2 (t, 3JF,C dimethylaniline following GP2); Rf = 0.40 (hexane:ethyl acetate, = 6.0 Hz, 2C), 122.2 (t, 2JF,C = 26.3 Hz), 114.1 (t, 1JF,C = 249.8 Hz), 9.5:0.5). 1H NMR (300 MHz, CDCl3), δ (ppm): 7.71 (dd, 3JH,H = 6.0 63.2, 14.3; 19F NMR (235 MHz, CDCl3), δ (ppm) −101.7; FT-IR Hz, 4JH,H = 3.0 Hz, 1H), 7.49 (t, 3JH,H = 6.0 Hz, 1 H), 7.30 (m, 2 H), (cm−1, neat, ATR), 3488, 3383, 2926, 1760, 1370, 1342, 1295, 1218; 4.30 (q, 3JH,H = 6.0 Hz, 2 H), 2.57 (s, 6 H), 1.31 (t, 3JH,H = 6.0 Hz, 3 HRMS (ESI+) m/z: [M + Na]+ Calcd for C22H19F2NO2Na 390.1276; H); 13C{1H} NMR (125 MHz, CDCl3), δ (ppm): 164.2 (t, 2JF,C = found 390.1257. 33.8 Hz), 152.5, 132.0, 131.3 (t, 2JF,C = 23.8 Hz), 126.4 (t, 3JF,C = 6.3 Ethyl 2-(4-Amino-3,5-dimethylphenyl)-2,2-difluoroacetate (21). Hz), 125.6, 122.7, 112.7 (t, 1JF,C = 245.0 Hz), 62.3, 45.6 (2 C), 14.3; Brownish oil (42.3 mg, 0.17 mmol, 58% yield from 36.4 mg of 2,6- 19 F NMR (282 MHz, CDCl3), δ (ppm) −98.3; FT-IR (cm−1, neat, dimethylaniline following GP1; 58.3 mg, 0.24 mmol, 80% yield from ATR), 2924, 1768, 1456, 1305, 1270, 1242, 1127. HRMS (ESI+) m/ 36.4 mg of 2,6-dimethylaniline following GP2); Rf = 0.43 z: [M + H]+ Calcd for C12H16F2NO2 244.1144; found 244.1152. (hexane:ethyl acetate, 8:2). 1H NMR (400 MHz, CDCl3), δ (ppm): Ethyl 2-(4-(Dimethylamino)phenyl)-2,2-difluoroacetate (24b). 7.17 (s, 2H), 4.29 (q, 3JH,H = 4.0 Hz, 2H), 3.80 (s, 2H), 2.19 (s, 6H), Brownish oil (14.0 mg, 0.06 mmol, 20% yield from 36.0 mg of 1.30 (t, 3JH,H = 4.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3), δ N,N-dimethylaniline following GP2); Rf = 0.45 (hexane:ethyl acetate, (ppm): 165.3 (t, 2JF,C = 36.0 Hz), 145.6, 125.7 (t, 2C, 3JF,C = 6.0 Hz), 9.5:0.5). 1H NMR (500 MHz, CDCl3), δ (ppm): 7.45 (d, 3JH,H = 10.0 121.8 (t, 2C, 2JF,C = 26.0 Hz), 121.6 (2C), 114.3 (t, 1JF,C = 250.0 Hz), Hz, 2H), 6.70 (d, 3JH,H = 10.0 Hz, 2 H), 4.29 (q, 3JH,H = 10.0 Hz, 2 63.1, 17.9 (2C), 14.3; 19F NMR (282 MHz, CDCl3), δ (ppm): H), 3.00 (s, 6 H), 1.31 (t, 3JH,H = 10.0 Hz, 3 H); 13C{1H} NMR (125 −101.9; HRMS (EI) m/z: [M + H]+ Calcd for C12H16F2NO2 MHz, CDCl3), δ (ppm): 165.0 (t, 2JF,C = 36.3 Hz), 152.1 (2 C), 126.7 244.1143; found: 244.1138. (t, 3JF,C = 5.0 Hz), 119.7 (t, 2JF,C = 26.3 Hz), 114.3 (t, 1JF,C = 250.0 Ethyl 2-(4-(Dimethylamino)naphthalen-1-yl)-2,2-difluoroacetate Hz), 111.6 (2 C), 62.9, 40.3 (2 C), 14.1; 19F NMR (282 MHz, (22). Yellow oil (53.5 mg, 0.18 mmol, 61% yield from 51.4 mg of CDCl3), δ (ppm) −101.9; FT-IR (cm−1, neat, ATR), 2923, 1762, N,N-dimethylnaphthalen-1-amine following GP1; 53.5 mg, 0.18 1614, 1593, 1530, 1368, 1275, 1195; HRMS (ESI+) m/z: [M + H]+ mmol, 61% yield from 51.4 mg of N,N-dimethylnaphthalen-1-amine Calcd for C12H16F2NO2 244.1144; found 244.1152. following GP2); Rf = 0.48 (hexane:ethyl acetate, 9.5:0.5). 1H NMR Ethyl 2-(4-(Diethylamino)phenyl)-2,2-difluoroacetate (25a). (400 MHz, CDCl3), δ (ppm): 8.29 (dd, 3JH,H = 8.0 Hz, 4JH,H = 4.0 Green oil (11.3 mg, 0.04 mmol, 14% yield from 44.8 mg of N,N- Hz, 1H), 8.18 (d, 4JH,H = 4.0 Hz, 1H), 7.75 (d, 3JH,H = 8.0 Hz, 1H), diethylaniline following GP2); Rf = 0.33 (hexane:ethyl acetate, 7.54 (m, 2H), 7.05 (d, 3JH,H = 8.0 Hz, 1H), 4.29 (q, 3JH,H = 8.0 Hz, 9.5:0.5). 1H NMR (300 MHz, CDCl3), δ (ppm): 7.42 (d, 2 H, 3JH,H = 2H), 2.93 (s, 6H), 1.26 (t, 3JH,H = 8.0 Hz, 3H); 13C{1H} NMR (100 6.0 Hz), 6.65 (d, 2 H, 3JH,H = 6.0 Hz), 4.29 (q, 2 H, 3JH,H = 6.0 Hz), MHz, CDCl3), δ (ppm): 165.1 (t, 2JF,C = 35.0 Hz), 154.4, 131.2 (t, 3.37 (q, 4 H, 3JH,H = 6.0 Hz), 1.31 (t, 3 H, 3JH,H = 6.0 Hz), 1.17 (t, 6 3 JF,C = 2.0 Hz), 129.2, 127.3, 125.8, 125.7, 125.6, 125.5, 125.0 (t, 3JF,C H, 3JH,H = 6.0 Hz); 13C{1H} NMR (100 MHz, CDCl3), δ (ppm): = 3.0 Hz), 122.7 (t, 2JF,C = 23.0 Hz), 115.1 (t, 1JF,C = 249.0 Hz), 164.9 (t, 2JF,C = 37.0 Hz), 149.2, 126.7 (t, 2 C, 3JF,C = 6.0 Hz), 114.1 112.6, 63.4, 45.3 (2C), 14.2; 19F NMR (376 MHz, CDCl3), δ (ppm): (t, 1JF,C = 249.0 Hz), 110.9 (2 C), 110.5, 62.7, 44.5 (2 C), 13.9, 12.4 −99.1; FT-IR (cm−1, neat, ATR), 2943, 1761, 1335, 1264, 1248, (2 C); 19F NMR (282 MHz, CDCl3), δ (ppm): −101.5 (CF2); 1191; HRMS (ESI+) m/z: [M + Na]+ Calcd for C16H17F2NO2Na HRMS (ESI+) m/z: [M + H]+ Calcd for C14H20F2NO2 272.1456; 316.1120; found 316.1129. found 272.1451. See also compound 29 in the Supporting Ethyl 2-(3-Chloro-2-(dimethylamino)phenyl)-2,2-difluoroacetate Information. (23a). Colorless oil (4.0 mg, 0.01 mmol, 5% yield from 47.0 mg of 2- Ethyl 2-(2-(Diethylamino)phenyl)-2,2-difluoroacetate (25b). chloro-N,N-dimethylaniline following GP2); Rf = 0.28 (hexane:ethyl (traces from 44.8 mg of N,N-diethylaniline following GP2); 1H acetate, 9.7:0.3). 1H NMR (300 MHz, CD2Cl2), δ (ppm): 7.37 (bs, 2 NMR (400 MHz, CDCl3), δ (ppm): 7.74 (d, 1 H, 3JH,H = 8.0 Hz), H), 7.26 (dd, 3JH,H = 6.0 Hz, 4JH,H = 3.0 Hz, 1 H), 4.31 (q, 3JH,H = 6.0 7.46 (t, 1 H, 3JH,H = 8.0 Hz), 7.26 (t, 2 H, 3JH,H = 8.0 Hz), 4.32 (q, 2 Hz, 2 H), 2.79 (s, 6 H), 1.29 (t, 3JH,H = 6.0 Hz, 3 H); 19F NMR (282 H, 3JH,H = 8.0 Hz), 2.93 (q, 4 H, 3JH,H = 8.0 Hz), 1.31 (t, 3 H, 3JH,H = 12593 https://doi.org/10.1021/acs.joc.3c01298 J. Org. Chem. 2023, 88, 12585−12596 The Journal of Organic Chemistry pubs.acs.org/joc Article 8.0 Hz), 0.98 (t, 6 H, 3JH,H = 8.0 Hz); 19F NMR (282 MHz, CDCl3), H), 2.65 (s, 6 H), 1.32 (t, 6 H, 3JH,H = 8.0 Hz), 1.31 (s, 9 H); δ (ppm): −97.2 (CF2). HRMS (ESI+) m/z: [M + H]+ Calcd for 13 C{1H} NMR (100 MHz, CDCl3), δ (ppm): 151.8, 147.6, 128.9, C14H20F2NO2 272.1456; found 272.1451. 124.5 (td, 3JF,C = 12.0 Hz, 3JP,C = 5.0 Hz), 122.6, 64.3 (d, 2 C, JC,P = Diethyl 2,2′-(4-(Diethylamino)-1,3-phenylene)bis(2,2-difluoroa- 7.0 Hz), 46.6 (2 C), 34.7, 31.4 (3 C), 16.5 (d, 2 C, JP,C = 6.0 Hz), two cetate) (25c). (traces from 44.8 mg of N,N-diethylaniline following quaternary carbons (CF2, α-CF2) are not seen due to oversplitting GP2); 1H NMR (400 MHz, CDCl3), δ (ppm): 7.99 (s, 1 H), 7.71 (d, with nearby F and P; 19F NMR (376 MHz, CDCl3), δ (ppm): −98.90 1 H,3JH,H = 12.0 Hz), 7.33 (d, 1 H, 3JH,H = 12.0 Hz), 4.32 (q, 4 H, (d, 2JP,F = 154.2 Hz); 31P NMR (162 MHz, CDCl3), δ (ppm): 7.39 3 JH,H = 12.0 Hz), 2.96 (q, 4 H, 3JH,H = 12.0 Hz), 1.34 (t, 6 H, 3JH,H = (tquint, 2JF,P = 153.9 Hz, 3JH,P = 9.7 Hz); HRMS (ESI+) m/z: [M + 12.0 Hz), 0.98 (t, 6 H, 3JH,H = 12.0 Hz); 19F NMR (282 MHz, H]+ Calcd for C17H29F2NO3P 364.1848; found 364.1853. CDCl3), δ (ppm): −97.8 (CF2), −103.5 (CF2). HRMS (ESI+) m/z: 4-(tert-Butyl)-N,N-dimethyl-2-(perfluorohexyl)aniline (32). Col- [M + Na]+ Calcd for C18H23F4NO4Na 416.1455; found 416.1447. orless oil (59.4 mg, 0.12 mmol, 40% yield from 53.2 mg of 4-(tert- Ethyl 2-(4-Chloro-2-(dimethylamino)phenyl)-2,2-difluoroacetate butyl)-N,N-dimethylaniline following GP2); Rf = 0.64 (hexane). 1H (26). Colorless oil (16.6 mg, 0.06 mmol, 20% yield from 47.0 mg of 3- NMR (300 MHz, CDCl3), δ (ppm): 7.55 (m, 2 H), 7.37 (dd, 1 H, 3 chloro-N,N-dimethylaniline following GP2); Rf = 0.35 (hexane:ethyl JH,H = 9.0 Hz, 4JH,H = 3.0 Hz), 2.63 (s, 6 H), 1.33 (s, 9 H); 13C{1H} acetate, 9.5:0.5). 1H NMR (400 MHz, CDCl3), δ (ppm): 7.64 (d, NMR (100 MHz, CDCl3), δ (ppm): 153.5, 148.2, 126.1 (t, 3JF,C = 9.0 3 JH,H = 8.0 Hz, 1H), 7.28 (s, 1 H), 7.27 (dd, 3JH,H = 8.0 Hz, 4JH,H = 4.0 Hz), 125.3 (t, 2JF,C = 21.0 Hz), 124.1, 108.5−119.5 (br, 6 C), 46.9 (2 Hz, 1 H), 4.29 (q, 3JH,H = 8.0 Hz, 2 H), 2.56 (s, 6 H), 1.30 (t, 3JH,H = C), 34.9, 31.5 (3 C); 19F NMR (282 MHz, CDCl3), δ (ppm): −80.9 8.0 Hz, 3 H); 13C{1H} NMR (125 MHz, CDCl3), δ (ppm): 163.9 (t, (t, 3 F, 3JF,F = 5.6 Hz), −104.4 (t, 2 F, 3JF,F = 14.1 Hz), −120.32 (m, 2 2 JF,C = 33.8 Hz), 153.8 (t, 3JF,C = 5.0 Hz), 137.8, 129.7 (t, 2JF,C = 23.8 F), −121.8 (m, 2 F), −122.7 (m, 2 F), −126.2 (m, 2 F); HRMS (ESI Hz), 127.8 (t, 3JF,C = 6.3 Hz), 125.8, 123.4, 112.3 (t, 1JF,C = 245.0 +) m/z: [M + H]+ Calcd for C18H19F13N 496.1304; found 496.1297. Hz), 62.5, 45.5 (2 C), 14.3; 19F NMR (376 MHz, CDCl3), δ (ppm): −98.2; FT-IR (cm−1, neat, ATR), 2947, 1771, 1595, 1268, 1136, 1104; HRMS (ESI+) m/z: [M + H]+ Calcd for C12H15ClF2NO2 ■ ASSOCIATED CONTENT Data Availability Statement 278.0754; found 278.0735. The data underlying this study are available in the published 5-(tert-Butyl)-3,3-difluoroindolin-2-one (27).24 Orange solid article and its Supporting Information. (36.1 mg, 0.16 mmol, 55% yield from 44.7 mg of 4-(tert-butyl)aniline following GP2); Rf = 0.17 (hexane:ethyl acetate, 9:1); mp: 133−135 * sı Supporting Information °C. 1H NMR (400 MHz, CDCl3), δ (ppm): 8.43 (bs, 1 H), 7.58 (d, The Supporting Information is available free of charge at 4 JH,H = 4.0 Hz, 1H), 7.48 (dd, 3JH,H = 8.0 Hz, 4JH,H = 4.0 Hz, 1H), https://pubs.acs.org/doi/10.1021/acs.joc.3c01298. 6.89 (d, 3JH,H = 8.0 Hz, 1 H), 1.32 (s, 9 H); 13C{1H} NMR (100 The Supporting Information is available free of charge MHz, CDCl3), δ (ppm): 167.5 (t, 2JF,C = 30.0 Hz), 147.8 (t, 4JF,C = on the ACS Publications Web site. Mechanistic studies, 2.0 Hz), 138.6 (t, 3JF,C = 8.0 Hz), 130.7, 122.2, 120.2 (t, 2JF,C = 22.0 cyclic voltammetry experiments, UV−vis studies, and Hz), 111.4 (t, 1JF,C = 249.0 Hz), 111.3, 34.9, 31.5 (3C); 19F NMR (376 MHz, CDCl3), δ (ppm) −111.4; FT-IR (cm−1, neat, ATR), NMR spectra (PDF) 3342, 3279, 2960, 1729, 1631, 1489, 1249, 1151; HRMS (ESI+) m/z: [M + Na]+ Calcd for C12H13F2NONa 248.0857; found 248.0851. 5-(tert-Butyl)-3,3-difluoro-1-methylindolin-2-one (28). Orange ■ AUTHOR INFORMATION Corresponding Authors oil (46.7 mg, 0.2 mmol, 65% yield) from 44.7 mg of 4-(tert-butyl)- Carolina Gimbert-Suriñach − Department of Chemistry and N,N-dimethylaniline. The product was prepared following GP2 and subsequently the reported procedure;20 Rf = 0.65 (hexane:ethyl Centro de Innovación en Química Avanzada acetate, 8:2). 1H NMR (400 MHz, CDCl3), δ (ppm): 7.59 (d, 4JH,H = (ORFEO−CINQA), Universitat Autònoma de Barcelona, 4.0 Hz, 1H), 7.51 (dd, 3JH,H = 8.0 Hz, 4JH,H = 4.0 Hz, 1H), 6.83 (dd, Cerdanyola del Vallès 08193 Barcelona, Spain; orcid.org/ 3 JH,H = 8.0 Hz, 4JH,H = 4.0 Hz, 1 H), 3.20 (s, 3 H), 1.33 (s, 9 H); 0000-0002-4412-7607; Email: carolina.gimbert@uab.es 13 C{1H} NMR (100 MHz, CDCl3), δ (ppm): 165.8 (t, 2JF,C = 30.0 Adelina Vallribera − Department of Chemistry and Centro de Hz), 147.9, 141.8 (t, 3JF,C = 7.0 Hz), 130.6, 122.1, 120.2 (t, 2JF,C = Innovación en Química Avanzada (ORFEO−CINQA), 23.0 Hz), 111.6 (t, 1JF,C = 248.0 Hz), 109.1, 35.1, 31.7 (3C), 26.6; 19F Universitat Autònoma de Barcelona, Cerdanyola del Vallès NMR (376 MHz, CDCl3), δ (ppm): −112.0; FT-IR (cm−1, neat, 08193 Barcelona, Spain; orcid.org/0000-0002-6452- ATR), 2961, 1747, 1626, 1496, 1300, 1246, 1118; HRMS (ESI+) m/ 4589; Email: adelina.vallribera@uab.es z: [M + H]+ Calcd for C13H16F2NO 240.1200; found 240.1216. 2-(5-(tert-Butyl)-2-(dimethylamino)phenyl)-N,N-diethyl-2,2-di- Authors fluoroacetamide (30). Yellowish oil (39.1 mg, 0.12 mmol, 40% yield Albert Gallego-Gamo − Department of Chemistry and Centro from 53.2 mg of 4-(tert-butyl)-N,N-dimethylaniline following GP2); de Innovación en Química Avanzada (ORFEO−CINQA), Rf = 0.25 (hexane:ethyl acetate, 9:1). 1H NMR (400 MHz, CDCl3), δ Universitat Autònoma de Barcelona, Cerdanyola del Vallès (ppm): 7.69 (d, 1 H, 4JH,H = 4.0 Hz), 7.45 (dd, 1 H, 3JH,H = 8.0 Hz, 08193 Barcelona, Spain; orcid.org/0000-0003-1278- 4 JH,H = 4.0 Hz), 7.20 (dd, 1 H, 3JH,H = 8.0 Hz, 4JH,H = 4.0 Hz), 3.37 9339 (q, 2 H, 3JH,H = 8.0 Hz), 3.10 (q, 2 H, 3JH,H = 8.0 Hz), 2.55 (s, 6 H), Albert Granados − Department of Chemistry and Centro de 1.31 (s, 9 H), 1.16 (t, 3 H, 3JH,H = 8.0 Hz), 0.85 (t, 3 H, 3JH,H = 8.0 Hz); 13C{1H} NMR (100 MHz, CDCl3), δ (ppm): 163.1 (t, 2JF,C = Innovación en Química Avanzada (ORFEO−CINQA), 29.0 Hz), 150.3 (t, 3JF,C = 8.0 Hz), 148.0, 131.2 (t, 2JF,C = 29.0 Hz), Universitat Autònoma de Barcelona, Cerdanyola del Vallès 128.5, 122.7 (t, 3JF,C = 7.0 Hz), 122.0, 114.8 (t, 1JF,C = 246.0 Hz), 45.9 08193 Barcelona, Spain; orcid.org/0000-0002-5362- (2 C), 41.8 (t, J = 3.0 Hz), 41.4, 34.7, 31.4 (3 C), 13.5, 12.6; 19F 5966 NMR (376 MHz, CDCl3), δ (ppm): −91.93; HRMS (ESI+) m/z: [M Roser Pleixats − Department of Chemistry and Centro de + H]+ Calcd for C18H29F2N2O 327.2242; found 327.2228. Innovación en Química Avanzada (ORFEO−CINQA), Diethyl ((5-(tert-Butyl)-2-(dimethylamino)phenyl)- Universitat Autònoma de Barcelona, Cerdanyola del Vallès difluoromethyl)phosphonate (31). Yellow oil (29.1 mg, 0.08 08193 Barcelona, Spain; orcid.org/0000-0003-2544- mmol, 25% yield from 53.2 mg of 4-(tert-butyl)-N,N-dimethylaniline 732X following GP2); Rf = 0.28 (hexane:ethyl acetate, 8:2). 1H NMR (400 MHz, CDCl3), δ (ppm): 7.60 (t, 1 H, 4JH,H = 4.0 Hz), 7.45 (dt, 1 H, Complete contact information is available at: 3 JH,H = 12.0 Hz, J = 4.0 Hz), 7.28 (d, 1 H, 3JH,H = 12.0 Hz), 4.20 (b, 4 https://pubs.acs.org/10.1021/acs.joc.3c01298 12594 https://doi.org/10.1021/acs.joc.3c01298 J. Org. Chem. 2023, 88, 12585−12596 The Journal of Organic Chemistry pubs.acs.org/joc Article Author Contributions Organophotoredox Strategy to Difluoroalkyl Bicycloalkane (CF2- All authors have given approval to the final version of the BCA) Hybrid Bioisosteres. Angew. Chem., Int. Ed. 2023, 62, manuscript. No. e202303585. (7) Selected examples on transition-metal catalyzed difluoroalkyla- Notes tion of arenes: (a) Feng, Z.; Min, Q. Q.; Xiao, Y. L.; Zhang, B.; Zhang, The authors declare no competing financial interest. X. Palladium-catalyzed difluoroalkylation of aryl boronic acids: a new ■ ACKNOWLEDGMENTS Support for this work under grants RTI2018-097853-B-I00, method for the synthesis of aryldifluoromethylated phosphonates and carboxylic acid derivatives. Angew. Chem., Int. Ed. 2014, 53, 1669− 1673. (b) Shi, S. L.; Buchwald, S. L. Palladium-catalyzed intra- molecular C-H difluoroalkylation: synthesis of substituted 3,3- PID2021-124916NB-I00, RED2022-134287-T, RYC2019- difluoro-2-oxindoles. Angew. Chem. Int. Ed. 2015, 54, 1646. (c) Ge, 027423-I, and PID2021-128496OB-I00 from the MICINN S.; Arlow, S. I.; Mormino, M. G.; Hartwig, J. F. Pd-Catalyzed α- (Spain) and SGR2017-0465, 2021SGR00064 from AGAUR- Arylation of Trimethylsilyl Enolates of α,α-Difluoroacetamides. J. Am. 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