Visible-Light-Promoted Tandem Difluoroalkylation–Amidation: Access

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Visible-Light-Promoted Tandem Difluoroalkylation−Amidation: Access to Difluorooxindoles from Free Anilines Ling-Chao Yu,† Ji-Wei Gu,‡ Shu Zhang,*,† and Xingang Zhang*,‡ †

School of Energy Science and Engineering, University of Electronic Science and Technology of China, 2006 Xiyuan Avenue, West High-Tech Zone, Chengdu, Sichuan 611731, China ‡ Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China S Supporting Information *

ABSTRACT: An efficient and synthetically convenient method for the synthesis of 3,3-difluoro-2-oxindole through a visible-light-induced photoredox difluoromethylation−amidation is described. The process can generate a broad range of difluorooxindoles using bromodifluoroacetate and broadly available free anilines. The wide range of substrate tolerance and mild reaction conditions make this transformation a highly valuable method in applications for drug discovery and development. raw materials in fine chemical, pharmaceutical, and agrochemical industries, would be the appealing starting molecules to construct such difluorooxindoles11 because the construction by direct intermolecular difluoroalkylation−amidation of free aniline via a photocatalysis process is more step-economic and synthetically convenient than the previous approaches. Although a one-pot synthesis of difluorooxindoles has been reported from free anilines and BrCF2CO2Et catalyzed by iron, the electron-deficient anilines provided low to moderate yields, and electron-rich anilines were not suitable substrates.11a Herein, we report a visible-light-promoted direct ortho-C−H difluoroacetylation of free anilines with bromodifluoroacetate and the consecutive intramolecular amidation to synthesize Nunprotected 3,3-difluoro-2-oxindoles by one-pot reaction in which both electron-rich and electron-deficient anilines are applicable to the reaction, provides moderate to good yields. We started our investigation by choosing 4-chloroaniline 1a and widely available bromodifluoroacetate (BrCF2CO2Et, 2a)12 as the model substrate under photochemical conditions toward synthesis of 3,3-difluoro-2-oxindole (Table 1; for details, see the Supporting Information). When the reaction was conducted in 1,2-dichloroethane (DCE) with fac-Ir(ppy)3 (0.5 mol %) as a photocatalyst and K2CO3 as a base, it was encouraging to find that the desired product 3a was obtained in 16% yield without observation of ortho- or meta-difluoroacetylated aniline product after irradiation by a blue light-emitting diode (LED) bulb (12 w) for 24 h at room temperature (for details, see the Supporting Information). Increasing the ratio of 1a/2a benefited the reaction efficiency, and the yield of desired product was increased to 48% when the ratio was 3/1 (entry 1). Encouraged by these results, a survey of the reaction factors

D

erivatives of isatin and oxindole are important pharmaceutical compounds that display antimicrobial, anticancer, antiviral, and anti-inflammatory activities.1 As a common strategy to optimize new medicinal agents, the incorporation of fluorine(s) into these compounds should modify their features in terms of metabolic stability, lipophilicity, and bioavailability based on the general properties of fluorinecontaining compounds.2 For instance, replacement of the keto carbonyl (CO) in isatins with the bioisoteric analogue moiety difluoromethylene (CF2) leads to 3,3-difluoro-2oxindoles, which should be of great biological significance in the development of potential medicinal agents.3 It has been well demonstrated that various complex molecules containing the 3,3-difluoro-2-oxindole ring moieties show biomedical activities.4 In contrast, a relatively limited number of synthesis approaches has been reported to access such a type of compound. Difluorooxindoles can be generally obtained by deoxyfluorination of isatins with thermally unstable diethylaminosulfur trifluoride (DAST)5 or by electrophilic fluorination of indoles with N-fluorobenzenesulfonimide (NFSI)6 (Scheme 1). However, the limited stability of the fluorinating reagents and modest functional-group tolerance restrict the utility and practicality of these fluorination procedures. Alternatively, synthesis of the difluorooxindole ring system can be furnished through transition-metal mediated7 or photoredox catalyzed8 intramolecular cyclization of halodifluoroacetamides (Scheme 1). However, these intramolecular cyclization reactions are limited to N-substituted halodifluoroacetamides, which require additional steps to prepare, thus restricting their widespread applications in organic synthesis. Recently, the intermolecular addition of difluoroalkyl radicals to electron-rich aromatic rings via a photoredox catalysis process has received great attention.9,10 We envisioned that readily available and various free anilines (ArNH2), important © 2017 American Chemical Society

Received: January 17, 2017 Published: March 15, 2017 3943

DOI: 10.1021/acs.joc.7b00111 J. Org. Chem. 2017, 82, 3943−3949

Note

The Journal of Organic Chemistry Scheme 1. Different Protocols for Construction of 3,3-Difluoro-2-oxindoles

Table 1. Representative Results for Optimization of Difluoroalkylation−Amidation of Free Anilinea,

1 2 3 4 5 6 7 8 9 10 11 12c 13d 14e

base (equiv)

solvent

3a/4a yield (%)b

K2CO3 (2.0) K2CO3 (2.0) K2CO3 (2.0) K2CO3 (2.0) K2CO3 (2.0) K2CO3 (2.0) Cs2CO3 (2.0) K3PO4 (2.0) K2HPO4 (2.0) Na2HPO4 (2.0) KOAc (2.0) Na2CO3 (2.0) Na2CO3 (2.0) Na2CO3 (2.0)

DCE CH2Cl2 THF 1,4-dioxane DMF DMSO CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2

48/0 68/0 6/0 29/0 0/18 0/0 0/0 23/0 12/48 30/23 12/52 73/0 nr nr

a

Reaction conditions (unless otherwise specified): 1a (3.0 equiv), 2a (0.4 mmol, 1.0 equiv), base (2.0 equiv), solvent (4 mL). bDetermined by 19F NMR spectroscopy using fluorobenzene as an internal standard; the number within parentheses represents the isolated yield. cAfter being stirred for 24 h at room temperature, the reaction mixture was concentrated, and the residue was heated to 60 °C in EtOH for 6 h. dThe reaction was conducted in the absence of fac-Ir(ppy)3. eThe reaction was conducted in the absence of fac-Ir(ppy)3 and blue LED. nr = no reaction.

base, this two-step one-pot difluoroalkylation−amidation strategy gave the desired difluorooxindole in 73% yield upon isolation (entry 12) along with some uncertain byproducts. No reaction occurred in the absence of either photocatalyst or light source, thus indicating that the reaction was conducted via a visible-light-promoted photoredox process (entries 13 and 14). To demonstrate the substrate scope of this method, a variety of free anilines was examined (Scheme 2). The visible-lightpromoted tandem difluoroalkylation−amidation protocol has a very broad and impressive substrate scope. A series of free anilines with electron-rich, electron-neutral, and electron-

such as solvents and bases was investigated (entries 2−11). It was found that a dramatically improved yield (68%) of 3a was obtained when dichloromethane was used as a reaction media instead of 1,2-dichloroethane (entry 2). Different bases, including K2HPO4, Na2HPO4, and KOAc, were then tested (entries 7−11), but the yield of desired product 3a was decreased dramatically, accompanied by the formation of noncyclized ortho-difluoroacetylated aniline product 4a. To our delight, after the as-prepared mixture of 3a and 4a was treated with ethanol at 60 °C for 6 h, 4a was fully converted to desired difluorooxindole 3a. When Na2CO3 was employed as a 3944

DOI: 10.1021/acs.joc.7b00111 J. Org. Chem. 2017, 82, 3943−3949

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The Journal of Organic Chemistry Scheme 2. Visible-Light-Mediated Difluoroalkylation−Amidation of Free Anilinesa,b,c

a Reaction conditions: 1 (3.0 equiv), 2a (0.4 mmol, 1.0 equiv), CH2Cl2 (4 mL), 24 h; then, EtOH (4 mL), 60 °C, 6−14 h. All reported yields are isolated yields. b1 (3.0 equiv), 2a (0.4 mmol, 1.0 equiv), Na2CO3 (0.8 mmol, 2.0 equiv), Ru(bpy)3Cl2·6H2O (0.5 mol %), MeCN (4 mL), rt, 24 h. c Compounds 3e and 3e′ were not separated.

dimethylaniline was examined (3e and 3e′). Given the prevalence of heterocycles in medicinal chemistry, we also investigated the scope of heterocyclic substrates. The free aniline containing a heterocycle substitute in the aromatic ring (3p) and tetrahydroquinoline ring system (3s and 3t) were applicable to the reaction by using Ru(bpy)3Cl2·6H2O as a catalyst. The N-substituted anilines were also suitable substrates, thus highlighting the generality of the current process (3q and 3r). Additionally, mono-ortho-substituted aniline also furnished the corresponding product 3u in moderate yield (56%), although a para-difluoroacetylated aniline side product 3u′ was provided. However, when basic aniline was examined, only 30% yield of 3v was afforded due to

deficient substitutes on the aromatic ring were found to undergo the desired transformation, providing the corresponding N-unprotected difluorooxindoles in moderate to good yields. The aniline derivatives with a halogen substitute at paraposition afforded satisfying results (3a−c, 3i), and the resulting intact chloride, bromide, and iodine provided good opportunities for downstream transformation. This process exhibited high functional group tolerance. Many versatile functional groups such as alkoxycarbonyl, ketone, cyano, and mesyl were compatible with the reaction conditions (3k−n). It is noteworthy that arylboronic acid ester containing substrate (3o) could tolerate the visible-light-induced process as well. A mixture of regioisomers were provided when 3,43945

DOI: 10.1021/acs.joc.7b00111 J. Org. Chem. 2017, 82, 3943−3949

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The Journal of Organic Chemistry Scheme 3. Radical Trapping Experiment

Scheme 4. Proposed Reaction Mechanism

quartet, m = multiplet, br = broad. NMR yield was determined by 19F NMR using fluorobenzene as an internal standard before working up the reaction. Materials. Blue LEDs (460−470 nm) was bought on the net. All reagents were used as received from commercial sources unless specified otherwise or prepared as described in the literature. All reagents were weighed and handled in the air. Dichloromethane, 1,2dichloroethane (DCE), DMF, DMA, and DMSO were distilled from CaH2. 1,4-Dioxane, THF, and DME were distilled from sodium immediately and degassed before used. General Procedure for Visible-Light-Promoted Difluoroalkylation−Amidation of Free Aniline. A 25 mL Schlenk tube equipped with a magnetic stir bar was charged with photocatalyst fac-Ir(ppy)3 (0.5 mol %) and aniline (1.2 mmol, 3.0 equiv) under air, followed by addition of Na2CO3 (0.8 mmol, 2.0 equiv). The vessel was evacuated and backfilled with Ar (3 times); BrCF2CO2Et (81.2 mg, 0.4 mmol, 1.0 equiv) and anhydrous CH2Cl2 (4 mL) were then added. The tube was screw capped and stirred at room temperature under irradiation of blue LED (12 W) for 24 h. The reaction mixture was concentrated in vacuo, and the residue was redissolved in ethanol (4 mL). The resulting mixture was heated at 60 °C for 6 h. The reaction mixture was then cooled to room temperature and concentrated. The residue was subjected to column chromatography on silica gel to afford the pure product. 5-Chloro-3,3-difluoroindolin-2-one (3a). The product (59 mg, 73% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 5/1) as a light-yellow solid. This compound is known, and the data reported here are consistent with the literature.11a 1H NMR (400 MHz, acetone-d6) δ 10.13 (brs, 1H), 7.68 (dd, J = 3.7 Hz, 1.8 Hz, 1H), 7.55 (ddt, J = 8.4 Hz, 2.1 Hz, 1.1 Hz, 1H), 7.11 (dt, J = 8.4 Hz, 1.6 Hz, 1H). 13C NMR (101.0 MHz, acetone-d6) δ 166.4 (t, J = 29.3 Hz), 142.4 (t, J = 7.6 Hz), 134.9 (t, J = 1.5 Hz), 129.2, 126.0, 122.5 (t, J = 23.2 Hz), 114.4, 111.6 (t, J = 251.0 Hz). 19F NMR (376 MHz, acetone-d6) δ −112.5 (s, 2F). 5-Bromo-3,3-difluoroindolin-2-one (3b). The product (65 mg, 66% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 5/1) as a yellow oil. 1H NMR (300 MHz, acetone-d6) δ 10.15 (brs, 1H), 7.84 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H). 13C NMR (101.0 MHz, acetone-d6) δ 166.3 (t, J = 29.8 Hz), 142.9 (t, J = 7.4 Hz), 137.8 (t, J = 1.6 Hz), 128.8, 122.9 (t, J = 23.3 Hz), 116.2 (t, J = 2.5 Hz), 114.8, 111.5 (t, J = 251.0 Hz). 19F NMR

the formation of large amount of para-difluoroacetylated aniline, which is unstable upon purification with silica gel chromatography. To probe whether a difluoroacetyl radical is involved in the reaction, a radical trapping reaction with TMPO as a radical scavenger was conducted (Scheme 3). When the reaction of 1a and 2a was treated with TMPO under standard reaction conditions, a TEMPO trapped difluoroacetylated product 5 instead of compound 4a was obtained, thus demonstrating that a free difluoroalkyl radical is involved in the reaction. On the basis of previous reports9a and current results, we propose a plausible reaction mechanism for this two-step onepot transformation (Scheme 4). First, single electron transfer (SET) from the excited-state of the photocatalyst *[Ir(ppy)3] to BrCF2CO2Et (2a) generates a free difluoroacetyl radical and IrIV(ppy)3. Subsequently, the resulting radical reacts with free aniline to deliver the intermediate (A). A is oxidized by IrIV(ppy)3, followed by the abstraction of a proton with the base to produce difluoroalkylated product 4. Consecutively, intramolecular amidation of the amino group with the adjacent ethoxycarbonyldifluoromethyl affords the desired 3,3-difluoro2-oxindole 3 under the basic conditions. In conclusion, we disclosed an efficient and synthetically convenient method for the synthesis of N-unprotected 3,3difluoro-2-oxindoles directly from bromodifluoroacetate and broadly available free aniline through a visible-light-promoted photocatalytic process. The high functional group tolerance and mild reaction conditions make this transformation have implications in drug discovery and development.

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EXPERIMENTAL SECTION

General Information. 1H NMR and 13C NMR spectra were recorded on an AM400 spectrometer. 19F NMR was recorded on an AM400 spectrometer (CFCl3 as outside standard and low field is positive). Chemical shifts (δ) are reported in ppm, and coupling constants (J) are in Hertz (Hz). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = 3946

DOI: 10.1021/acs.joc.7b00111 J. Org. Chem. 2017, 82, 3943−3949

Note

The Journal of Organic Chemistry (283 MHz, acetone-d6) δ −112.8 (s, 2F). MS (EI): m/z (%) 247 (M+). HRMS (EI-TOF): calcd for C8H4BrF2NO [M]+ 246.9444; found: 246.9447. 3,3-Difluoro-5-iodoindolin-2-one (3c). The product (83 mg, 70% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 5/1) as a brown solid. Mp 153−155 °C. 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 7.83 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H). 13C NMR (101.0 MHz, CDCl3) δ 166.4 (t, J = 30.3 Hz), 142.4, 140.6 (t, J = 7.1 Hz), 133.8, 122.2 (t, J = 23.2 Hz), 113.7, 110.1 (t, J = 253.5 Hz), 86.1 (t, J = 2.0 Hz). 19F NMR (376 MHz, CDCl3) δ −111.8 (s, 2F). MS (EI): m/z (%) 295 (M+). HRMS (EI-TOF): calcd for C8H4IF2NO [M]+ 294.9306; found: 294.9298. 3,3-Difluoro-5-methylindolin-2-one (3d). The product (53 mg, 72% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 5/1) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.91 (brs, 1H), 7.35 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 2.35 (s, 3H). 13C NMR (101.0 MHz, CDCl3) δ 167.5 (t, J = 30.8 Hz), 138.6 (t, J = 7.6 Hz), 134.0 (t, J = 2.0 Hz), 133.9 (t, J = 2.0 Hz), 125.5, 120.2 (t, J = 23.2 Hz), 111.6, 110.2 (t, J = 251.5 Hz), 20.9. 19 F NMR (376 MHz, CDCl3) δ −111.9 (s, 2F). MS (EI): m/z (%) 183 (M+). HRMS (EI-TOF): calcd for C9H7F2NO [M]+ 183.0496; found: 183.0493. 3,3-Difluoro-5,6-dimethylindolin-2-one (3e) and 3,3-Difluoro4,5-dimethylindolin-2-one (3e′). The reaction was carried out with Ru(bpy)3Cl2·6H2O (0.5 mol %) in anhydrous MeCN (4 mL). The mixture of 3e and 3e′ (3e/3e′ = 1.4/1.0, 62 mg, 79% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 5/1) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) 3e: δ 8.31 (s, 1H), 7.30 (s, 1H), 6.75 (s, 1H), 2.29 (s, 3H), 2.25 (s, 3H); 3e′: δ 8.31 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 2.36 (s, 3H), 2.24 (s, 3H). 13C NMR (101.0 MHz, CDCl3) 3e and 3e′: δ 167.0 (t, J = 30.8 Hz), 166.2 (t, J = 27.8 Hz), 143.0, 138.8 (t, J = 7.1 Hz), 138.6 (t, J = 7.1 Hz), 137.7, 134.0, 133.1, 132.5, 125.9, 118.8 (t, J = 24.7 Hz), 117.6 (t, J = 23.2 Hz),112.7, 112.1 (t, J = 251.5 Hz), 111.1 (t, J = 251.5 Hz), 108.5, 20.6, 19.4, 18.8, 14.7. 19F NMR (376 MHz, CDCl3) 3e: δ −110.9 (s, 2F); 3e′: δ −112.9 (s, 2F). MS (EI): m/z (%) 197 (M+). HRMS (EI-TOF): calcd for C10H9F2NO [M]+ 197.0652; found: 197.0655. 3,3-Difluoro-5,7-dimethylindolin-2-one (3f). The reaction was carried out with Ru(bpy)3Cl2·6H2O (0.5 mol %) in anhydrous MeCN (4 mL). The product (53 mg, 67% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 5/1) as a lightyellow solid. Mp 165−167 °C. 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.19 (s, 1H), 7.07 (s, 1H), 2.32 (s, 3H), 2.24 (s, 3H). 13C NMR (101.0 MHz, CDCl3) δ 167.7 (t, J = 30.3 Hz), 137.1 (t, J = 7.1 Hz), 135.4, 133.8, 122.8, 120.8, 120.0 (t, J = 22.7 Hz), 110.6 (t, J = 251.0 Hz), 20.9, 15.8. 19F NMR (376 MHz, CDCl3) δ −111.5 (s, 2F). MS (EI): m/z (%) 197 (M+). HRMS (EI-TOF): calcd for C10H9F2NO [M]+ 197.0652; found: 197.0650. 3,3-Difluoro-5-isopropylindolin-2-one (3g). The product (66 mg, 78% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 5/1) as a brown solid. Mp 83−85 °C. 1H NMR (400 MHz, acetone-d 6) δ 9.85 (s, 1H), 7.50 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 2.93 (hept, J = 6.8 Hz, 1H), 1.23 (d, J = 6.8 Hz, 6H). 13C NMR (101.0 MHz, acetone-d6) δ 166.9 (t, J = 29.8 Hz), 145.5 (t, J = 2.0 Hz), 141.4 (t, J = 7.4 Hz), 132.9 (t, J = 2.0 Hz), 123.6, 121.0 (t, J = 23.2 Hz), 112.6, 112.4 (t, J = 249.5 Hz), 34.6, 24.4. 19F NMR (376 MHz, acetone-d6) δ −112.0 (s, 2F). MS (EI): m/z (%) 196(100), 211 (M+). HRMS (EI-TOF): calcd for C11H11F2NO [M]+ 211.0809; found: 211.0808. 5-Ethoxy-3,3-difluoroindolin-2-one (3h). The product (41 mg, 48% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 5/1) as a light-yellow solid. Mp 118−122 °C. 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.10 (d, J = 1.6 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.02 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). 13C NMR (101.0 MHz, CDCl3) δ 167.2 (t, J = 30.3 Hz), 156.0, 133.9 (t, J = 7.1 Hz), 121.2 (t, J = 22.7 Hz), 119.6, 112.4, 111.7, 111.1 (t, J = 252.0 Hz), 64.4, 14.7. 19F NMR (376 MHz, CDCl3) δ −111.7 (s, 2F). MS (EI): m/z (%) 157 (100), 213 (M+). HRMS (EITOF): calcd for C10H9F2NO2 [M]+ 213.0601; found: 213.0595.

7-Bromo-3,3-difluoro-5-(trifluoromethoxy)indolin-2-one (3i). The product (55 mg, 41% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 5/1) as a light-yellow solid. Mp 120−122 °C. 1H NMR (400 MHz, acetone-d 6) δ 10.45 (brs, 1H), 7.80 (s, 1H), 7.77 (s, 1H). 13C NMR (101.0 MHz, acetone-d6) δ 166.3 (t, J = 29.8 Hz), 145.7 (t, J = 2.5 Hz), 142.8 (t, J = 7.1 Hz), 131.3, 123.2 (t, J = 24.2 Hz), 121.5 (q, J = 258.6 Hz), 119.1, 111.7 (t, J = 252.0 Hz), 105.4. 19F NMR (376 MHz, acetone-d6) δ-59.5 (s, 3F), −111.7 (s, 2F). MS (EI): m/z (%) 331 (M+). HRMS (EI-TOF): calcd for C9H3BrF5NO2 [M] + 330.9267; found: 330.9266. 3,3-Difluoro-5-(trifluoromethyl)indolin-2-one (3j). The product (52 mg, 55% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 5/1) as a brown solid. Mp 121−123 °C. 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 7.80 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H). 13C NMR (101.0 MHz, CDCl3) δ 166.7 (t, J = 30.3 Hz), 144.0 (t, J = 7.6 Hz), 131.3 (t, J = 2.0 Hz), 126.8 (q, J = 34.0 Hz), 123.4 (q, J = 272.7 Hz), 122.6 (q, J = 3.7 Hz), 120.8 (t, J = 23.2 Hz), 111.9, 109.9 (t, J = 253.0 Hz). 19F NMR (376 MHz, CDCl3) δ −62.3 (s, 3F), −112.3 (s, 2F). MS (EI-TOF): m/z (%) 209 (100), 237 (M+). HRMS (EI): calcd for C9H4F5NO [M]+ 237.0213; found: 237.0220. Ethyl 3,3-Difluoro-2-oxoindoline-5-carboxylate (3k). The product (64 mg, 66% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 5/1) as a light-yellow solid. This compound is known, and the data reported here are consistent with the literature.11a 1 H NMR (400 MHz, acetone-d6) δ 10.34 (brs, 1H), 8.20−8.18 (m, 2H), 7.21 (dt, J = 8.7 Hz, 1.3 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H). 13C NMR (101.0 MHz, acetone-d6) δ 166.8 (t, J = 30.3 Hz), 165.7, 147.7 (t, J = 7.1 Hz), 136.8 (t, J = 1.0 Hz), 127.0 (t, J = 1.5 Hz), 126.7, 121.1 (t, J = 23.2 Hz), 112.8, 111.6 (t, J = 250.0 Hz), 61.9, 14.7. 19F NMR (376 MHz, acetone-d6) δ −112.7 (s, 2F). 3,3-Difluoro-2-oxoindoline-5-carbonitrile (3l). The product (41 mg, 53% yield) was purified with silica gel chromatography (hexane/ ethyl acetate = 2/1) as a light-yellow solid. This compound is known, and the data reported here are consistent with the literature.11a 1H NMR (400 MHz, acetone-d6) δ 8.11 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H). 13C NMR (101.0 MHz, acetoned6) δ 166.4 (t, J = 29.8 Hz), 147.6 (t, J = 7.1 Hz), 139.7, 129.8, 121.9 (t, J = 23.7 Hz), 118.7, 113.9, 111.0 (t, J = 251.5 Hz), 107.9 (t, J = 2.0 Hz). 19F NMR (376 MHz, acetone-d6) δ −113.0 (s, 2F). 5-Acetyl-3,3-difluoroindolin-2-one (3m). The product (55 mg, 65% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 1/1) as a light-yellow solid. This compound is known, and the data reported here are consistent with the literature.11a 1H NMR (400 MHz, acetone-d6) δ 10.42 (brs, 1H), 8.23 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 2.61 (s, 3H). 13C NMR (101.0 MHz, acetone-d6) δ 196.2, 167.0 (t, J = 30.3 Hz), 147.6 (t, J = 7.6 Hz), 135.8 (t, J = 1.5 Hz), 134.1 (t, J = 1.5 Hz), 125.9, 121.1 (t, J = 23.2 Hz), 112.7, 111.7 (t, J = 250.0 Hz), 26.7. 19F NMR (376 MHz, acetone-d6) δ −112.7 (s, 2F). 3,3-Difluoro-5-(methylsulfonyl)indolin-2-one (3n). The product (76 mg, 77% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 1/2) as a light-yellow solid. Mp 210−212 °C. 1 H NMR (400 MHz, acetone-d 6) δ 8.18 (q, J = 1.7 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 3.19 (s, 3H). 13C NMR (101.0 MHz, acetone-d6) δ 166.6 (t, J = 29.8 Hz), 148.2 (t, J = 7.1 Hz), 137.6 (t, J = 2.0 Hz), 135.1 (t, J = 2.0 Hz), 125.4, 121.5 (t, J = 23.7 Hz), 113.4, 111.2 (t, J = 251.0 Hz), 44.5. 19F NMR (376 MHz, acetone-d6) δ −113.0 (s, 2F). MS (EI-TOF): m/z (%) 247 (M+). HRMS (EI): calcd for C9H7F2NO3S [M] + 247.0115; found: 247.0108. 3,3-Difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (3o). The product (80 mg, 68% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 5/1) as a brown solid. Mp 196−198 °C. 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.99 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 1.35 (s, 12H). 13C NMR (101.0 MHz, acetone-d6) δ 166.8 (t, J = 29.8 Hz), 146.2 (t, J = 7.6 Hz), 141.6 (t, J = 1.5 Hz), 131.4, 120.7 (t, J = 23.7 Hz), 112.3, 112.0 (t, J = 250.0 Hz), 85.0, 25.3. 19F NMR (376 MHz, CDCl3) δ −111.7 (s, 2F). MS (EI): m/z (%) 280 (100), 295 (M+). 3947

DOI: 10.1021/acs.joc.7b00111 J. Org. Chem. 2017, 82, 3943−3949

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The Journal of Organic Chemistry HRMS (EI): calcd for C14H16B10F2NO3 [M]+ 294.1228; found: 294.1230. 5-((1H-1,2,4-Triazol-1-yl)methyl)-3,3-difluoroindolin-2-one (3p). The product (74 mg, 74% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 1/1) as a brown solid. Mp 261−263 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.66 (s, 1H), 7.98 (s, 1H), 7.62 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 5.40 (s, 2H). 13C NMR (101.0 MHz, DMSO-d6) δ 166.3 (t, J = 29.3 Hz), 142.8 (t, J = 7.6 Hz), 134.7, 132.0, 125.2, 119.9 (t, J = 23.2 Hz), 112.6, 111.5 (t, J = 250.5 Hz), 51.9. 19F NMR (376 MHz, DMSO-d6) δ −111.0 (s, 2F). MS (EI): m/z (%) 250 (M+). HRMS (EI-TOF): calcd for C11H8F2N4O [M] + 250.0666; found: 250.0657. 3,3-Difluoro-1,5-dimethylindolin-2-one (3q). The reaction was carried out with Ru(bpy)3Cl2·6H2O (0.5 mol %) in anhydrous MeCN (4 mL). The product (67 mg, 85% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 6/1) as a brown solid. This compound is known, and the data reported here are consistent with the literature.11a 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 3.19 (s, 3H), 2.36 (s, 3H). 13 C NMR (101.0 MHz, CDCl3) δ 165.3 (t, J = 30.3 Hz), 141.5 (t, J = 7.6 Hz), 133.8, 133.7, 125.2, 122.0 (t, J = 23.2 Hz), 111.1 (t, J = 250.5 Hz), 109.2, 26.2, 20.9. 19F NMR (376 MHz, CDCl3) δ −112.2 (s, 2F). 3,3,5-Trifluoro-1-methylindolin-2-one (3r). The reaction was carried out with Ru(bpy)3Cl2·6H2O (0.5 mol %) in anhydrous MeCN (4 mL). The product (64 mg, 79% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 10/1) as a lightyellow solid. This compound is known, and the data reported here are consistent with the literature.8 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 6.4 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.86 (dd, J = 8.1 Hz, 3.0 Hz, 1H), 3.21 (s, 3H). 13C NMR (101.0 MHz, CDCl3) δ 164.9 (t, J = 30.3 Hz), 159.4 (dt, J = 245.4 Hz, 2.5 Hz), 139.8 (td, J = 7.0 Hz, 2.5 Hz), 121.2 (td, J = 23.1 Hz, 8.0 Hz), 120.0 (dt, J = 24.2 Hz, 1.0 Hz), 112.8 (d, J = 26.3 Hz), 110.5 (t, J = 8.1 Hz), 110.4 (t, J = 252.5 Hz), 26.4. 19 F NMR (376 MHz, CDCl3) δ −112.5 (s, 2F), −117.56 to −117.61 (m, 1F). 1,1-Difluoro-8-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin2(1H)-one (3s). The reaction was carried out with Ru(bpy)3Cl2·6H2O (0.5 mol %) in anhydrous MeCN (4 mL). The product (66 mg, 74% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 10/1) as a brown solid. Mp 84−86 °C. 1H NMR (400 MHz, CDCl3) δ 7.16 (s, 1H), 7.04 (s, 1H), 3.68 (t, J = 5.6 Hz, 2H), 2.72 (t, J = 5.6 Hz, 2H), 2.32 (s, 3H), 2.03−1.97 (m, 2H). 13C NMR (101.0 MHz, CDCl3) δ 164.0 (t, J = 31.3 Hz), 137.2 (t, J = 7.1 Hz), 133.2, 132.7, 122.8, 121.3, 118.5 (t, J = 23.2 Hz), 112.3(t, J = 253.5 Hz), 38.6, 23.9, 21.1, 20.6. 19F NMR (376 MHz, CDCl3) δ −112.0 (s, 2F). MS (EI-TOF): m/z (%) 223 (M+). HRMS (EI): calcd for C12H11F2NO [M]+ 223.0809; found: 223.0814. 1,1-Difluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (3t). The reaction was carried out with Ru(bpy)3Cl2·6H2O (0.5 mol %) in anhydrous MeCN (4 mL). The product (29 mg, 35% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 6/1) as a light-yellow solid. This compound is known, and the data reported here are consistent with the literature.8 1H NMR (300 MHz, CDCl3) δ 7.36 (d, J = 7.2 Hz, 1H), 7.27−7.23 (m, 1H), 7.05 (t, J = 7.5 Hz, 1H), 3.74−3.70 (m, 2H), 2.79 (t, J = 5.9 Hz, 2H), 2.08−2.00 (m, 2H). 13C NMR (101.0 MHz, CDCl3) δ 164.0 (t, J = 31.3 Hz), 139.7 (t, J = 7.1 Hz), 132.3 (t, J = 1.5 Hz), 123.3 (t, J = 1.5 Hz), 122.3, 121.6, 118.6 (t, J = 23.2 Hz), 112.0 (t, J = 253.5 Hz), 38.7, 24.1, 20.4. 19F NMR (283 MHz, CDCl3) δ −112.6 (s, 2F). Ethyl 3,3-Difluoro-2-oxoindoline-7-carboxylate (3u). The product (54 mg, 56% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 6/1) as a white solid. Mp 115−117 °C; 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 7.3 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ −112.43 (s, 2F). 13C NMR (126 MHz, CDCl3) δ 165.4 (t, J = 60.5 Hz), 165.1, 143.7 (t, J = 7.0 Hz), 133.9 (t, J = 1.3 Hz), 129.1, 123.1 (t, J = 1.6 Hz), 121.3 (t, J = 23.3 Hz), 113.2, 109.6 (t, J = 251.4 Hz), 61.9, 14.2. MS

(EI): m/z (%) 241 (M+). HRMS (EI-TOF): calcd for C11H9F2NO3 [M] + 241.0550; found: 241.0547. Ethyl 2-amino-5-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate (3u′). The product (14 mg, 12% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 6/1) as a white solid. Mp 80−82 °C. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.46 (dd, J = 8.6, 1.8 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 6.04 (s, 2H), 4.32 (dq, J = 14.4, 7.1 Hz, 4H), 1.39 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 167.5, 164.4 (t, J = 36.5 Hz), 152.2, 130.7 (t, J = 5.6 Hz), 129.1 (t, J = 6.5 Hz), 120.1 (t, J = 27.1 Hz), 116.7, 113.4 (t, J = 252.0 Hz), 110.3, 63.0, 60.7, 14.3, 13.9.19F NMR (376 MHz, CDCl3) δ −102.5 (s, 2F). MS (ESI): m/z (%) 288.1 ([M + H]+). HRMS (DART): calcd for C13H16F2NO4 [M + H] + 288.1042; found: 288.1041. 3,3-Difluoroindolin-2-one (3v). The product (21 mg, 30% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 6/ 1) as a white solid. This compound is known, and the data reported here are consistent with the literature.13 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 7.55 (d, J = 7.0 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 167.4 (t, J = 30.2 Hz), 141.0 (t, J = 7.4 Hz), 133.7 (t, J = 1.6 Hz), 125.0, 124.1 (t, J = 1.7 Hz), 120.3 (t, J = 23.3 Hz), 111.8, 110.9 (t, J = 250.7 Hz). 19F NMR (376 MHz, CDCl3) δ −111.9 (s, 2F). Ethyl 2,2-Difluoro-2-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)acetate (5). A 25 mL Schlenk tube equipped with a magnetic stir bar was charged with photocatalyst fac-Ir(ppy)3 (0.5 mol %), 4chloroaniline (1.2 mmol, 3.0 equiv), and TEMPO (0.4 mmol, 1.0 equiv) under air, followed by addition of Na2CO3 (0.8 mmol, 2.0 equiv). The vessel was evacuated and backfilled with Ar (3 times); BrCF2CO2Et (81.2 mg, 0.4 mmol, 1.0 equiv) and anhydrous CH2Cl2 (4 mL) were then added. The tube was screw capped and stirred at room temperature under irradiation of blue LED (12 W) for 24 h. The reaction mixture was then cooled to room temperature and concentrated. The product 5 (45 mg, 40% yield) was purified with silica gel chromatography (hexane/ethyl acetate = 20/1) as a white solid. This compound is known, and the data reported here are consistent with the literature.14 1H NMR (400 MHz, CDCl3) δ 4.35 (q, J = 7.2 Hz, 2H), 1.55 (m, 5H), 1.36 (t, J = 7.2 Hz, 4H), 1.19 (s, 6H), 1.16 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 160.7 (t, J = 42.8 Hz), 115.5 (t, J = 272.2 Hz), 62.9, 61.4, 40.2, 33.40 (t, J = 4.4 Hz), 20.7, 16.9, 13.9. 19F NMR (376 MHz, CDCl3) δ −73.5 (s, 2F).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00111. Detailed experimental procedures and characterization data for new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xingang Zhang: 0000-0002-4406-6533 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (Grants 21425208, 21672238, 21332010, and 2141002), the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant XDB20000000), and the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences. 3948

DOI: 10.1021/acs.joc.7b00111 J. Org. Chem. 2017, 82, 3943−3949

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The Journal of Organic Chemistry

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REFERENCES

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DOI: 10.1021/acs.joc.7b00111 J. Org. Chem. 2017, 82, 3943−3949