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DOI: 10.1055/s-0040-1719888
Indium-Mediated Reformatsky Reaction of Iododifluoro Ketones with Aldehydes: Preparation of α,α-Difluoro-β-hydroxyketone Derivatives in Water
Abstract
Indium can efficiently mediate the Reformatsky reaction of iododifluoroacetylketones with aldehydes to afford the corresponding α,α-difluoro-β-hydroxyketones in high yield in pure water This reaction has excellent substrate suitability and functional group selectivity and provides an efficient approach for the synthesis of bioactive molecules containing the α,α-difluoro-β-hydroxyketone pharmacophore.
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The traditional Reformatsky reaction utilizes zinc to mediate the addition of α-halogenated esters to carbonyl compounds and is an important method to prepare β-hydroxy esters.[1] [2] [3] [4] In addition to zinc, other metals (Sm, Cr, Cu, In, etc.) have also been developed to mediate the Reformatsky reaction.[5] [6] [7] [8] [9] [10] Among them, indium has attracted much more attention because of its similar properties to zinc and the mildness of the reaction conditions when using it, especially the ability to react in the aqueous phase. Since Rieke et al.[10] first applied indium in the Reformatsky reaction in 1975, research on indium-mediated organic synthesis reactions has made great progress.[12] [13] [14] [15]
In medicinal chemistry, the α,α-difluoro-β-hydroxyketone skeleton has received considerable attention due to the unique biological properties present in a variety of active pharmaceutical ingredients such as HMG-CoA inhibitors, analgesics, protease inhibitors, and GABA agonists (Figure [1]).[16] [17] [18] [19] In 2016, Ogoshi and co-workers reported the β-F elimination of trifluoroacetophenone to obtain α-metalated alkoxides and aldehydes to give the corresponding α,α-difluoro-β-hydroxyketones.[20]
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Usually, α,α-difluoro-β-hydroxyketones are constructed by zinc-mediated Reformatsky reaction between halodifluoroketones and aldehydes, although there are some disadvantages with this reaction, such as harsh reaction conditions, low yields, or substrate-scope limitations. The zinc-mediated Reformatsky reaction reported by Liu and co-workers in 2013[19] was applied to the synthesis of α,α-difluorinated β-hydroxy carbonyl compounds through reaction of bromodifluoromethyl ketones with aldehydes in the presence of Zn/CuCl to give the corresponding difluorinated compounds in good yields. However, they noted that reaction of bromodifluoromethyl ketones with a nitro substituent failed to promote any adduct resulting in full recovery of the starting material (Scheme [1a]). The indium-mediated Reformatsky reaction can provide an important method for the construction of α,α-difluoro-β-hydroxyketones using chloro-/bromodifluoroketones or esters as substrates.
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However, those reactions are also restricted due to the problems of using aqueous medium, resulting in poor reaction yields, serious side reactions, and limited substrate scope. For example, Welch's group used 2-chloro-2,2-difluoro-1-furan-2-yl ethylenedione (I) to perform the Reformatsky reaction with various aldehydes. When pure water was used as the solvent, side products (the reduction product II and a small amount of condensation product III), accounting for 53% product yield, are observed[21] (Scheme [1b]). Médebielle et al. reported the use of β-aminovinylchlorodifluoromethyl ketones and a series of heteroaryl aldehydes in H2O/THF (4:1) to obtain the corresponding α,α-difluoro-β-hydroxyketones. It is worth noting that the reaction failed when 4-pyridinecarboxaldehyde or trifluoromethylbenzaldehyde is applied, which may be due to intervention of the nitrogen atom in the indium intermediate and the formation of pinacol coupling products[22] (Scheme [1c]). Meanwhile, Poisson et al. prepared α,α-difluoro-β-hydroxyesters through indium-mediated Reformatsky reaction, but the reaction needs to be carried out in THF[23] (Scheme [1d]).
For many years, our group has been committed to investigating radical reactions of iododifluoroketone compounds.[24] [25] [26] [27] [28] [29] During an experiment to reduce the carbonyl group of 2-iodo-2,2-difluoroacetophenone with LiEt3BH, we unexpectedly obtained the aldol self-condensation product and the corresponding α,α-difluoro-β-hydroxyketone in the presence of an aldehyde[30] (Scheme [1e]). In this respect, it has been reported that alkyl iodides can react with alkenes through indium-mediated radical addition reactions.[31] [32] [33] [34] We envisaged that an indium-mediated Reformatsky reaction of iododifluoroketones would be advantageous compared with the previous use of α-Cl-/α-Br-α,α-difluoroketones or esters for the preparation of α,α-difluoro-β-hydroxyketones.[35–37] Herein, we wish to describe a more convenient and useful synthetic method for the preparation of α,α-difluoro-β-hydroxyketones using the indium-mediated Reformatsky reaction of iododifluoroketones and aldehydes in tap water (Scheme [2]).
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Firstly, we used iododifluoroacetophenone (1a) as substate to examine the Reformatsky reaction with benzaldehyde (2a) in various solvents at room temperature in the presence of 2.0 equiv of indium (entries 1–12, Table [1]). To our satisfaction, the reaction proceeded smoothly in water to afford 3a in 91% yield (entry 1, Table [1]). It is worth noting that the reduction product of 1a and its self-condensed product were not observed in this reaction. However, 3a was obtained in low yield together with several reduction byproducts and substantial quantities of self-condensation byproducts when the reaction was carried out in aprotic solvents such as DMF, NMP, and 1,4-dioxane (entries 2–4, Table [1]). The yield was moderate in MeCN and THF; whereas when H2O–THF (4:1) was used as a mixed solvent, the yield of 3a was significantly improved to 82% yield compared to the yield obtained pure THF (entries 5–7, Table [1]). Among alcohol solvents, MeOH and 50% MeOH–H2O (v/v) worked well, resulting in 89% and 90% yield, respectively. However, when the reaction was carried out in absolute ethanol, 95% EtOH–H2O (v/v) and n-BuOH as solvent, the yield of 3a was extremely low, and 1a was mainly converted into reduction byproducts (entries 8–12, Table [1]).
a Reaction conditions (unless otherwise specified): 1a (0.2 g, 1.0 equiv), 2a (1.2 equiv).
b Isolated yield.
c 1.2 equiv trifluoroacetophenone.
d 1.2 equiv chlorodifluoroacetophenone.
e 1.2 equiv bromodifluoroacetophenone.
Using water as reaction solvent, the influences of reaction temperature and the amount of indium were studied (entries 13–19, Table [1]). When the reaction was carried out at 40–50 °C, the yield of 3a was equal to that at room temperature, but the reaction time could be reduced to 2–5 h. Evaluating the reaction at 70–100 °C led to a decrease in yield due to the increase of reduction byproducts. Theoretically, 0.33 equiv of indium are required and we found that 0.50 equiv of indium were enough and gave the same yield of 3a as when using 1.0 and 2.0 equiv of indium (entries 1, 16, 17, Table [1]). Reducing the amount of indium further led to a dramatic drop in yield (entries 18 and 19, Table [1]). We also examined the reaction of other halodifluoroacetophenone substrates and found that trifluoroacetophenone did not react, and chloro- or bromodifluoroacetophenone only gave 3a in 24% and 36% yield, respectively, under the same conditions (entries 20–22, Table [1]).
Under the optimized reaction conditions (0.5 equiv indium, 50 °C in water), we examined the scope and limitations of substrates 1 and 2 (Scheme [3]). As shown in Scheme [3], this reaction is efficient with aromatic aldehydes, regardless whether the substituents are halogens (2b–d), electron-donating groups (2e–i), electron-withdrawing groups (2j,k), as well as with the heterocyclic aromatic aldehyde (2o). It should be emphasized that the yield of halogen-substituted aromatic aldehydes 2b–d is relatively high, and the presence of an unprotected phenolic hydroxyl group has no effect on the reaction (3n). Aliphatic aldehydes 2p,q and α,β-unsaturated aldehydes 2r,s also react to obtain the corresponding products 3p–s with a yield of 80–87%. It is worth noting that for α,β-unsaturated aldehydes products 3r and 3s are also obtained in good yields, and no Michael addition products are produced. Finally, under the same reaction conditions, reaction of various α-iodo-α,α-difluoroketones 1t–aa with aldehydes 2t–aa proceeded smoothly to afford the desired products 3t–aa in 81–91% yield.
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To investigate the reaction mechanism, the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and a trivalent indium reagent were used as controls compared with the standard conditions. The reaction was completely inhibited by TEMPO and we isolated the radical scavenger adduct in 85% yield; whereas the trivalent indium reagent was ineffective. (Scheme [4]) These results confirmed that this reaction proceeds by a radical process. With reference to relevant literature,[31] [32] [33] [34] , [38] we propose the following possible mechanism: single-electron transfer (SET) reaction between 1 and indium firstly produces a difluoromethyl radical, which is further reduced by indium or indium iodide to give the difluoromethyl-indium reagent i, that further isomerizes to generate α,α-difluoroenol structure ii. Then, addition to an aldehyde forms intermediate iii to afford the Reformatsky reaction product on H2O or D2O quench (Scheme [5]).
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To demonstrate the efficiency and viability of our developed methodology, GABAB agonist 7 was prepared on a gram-scale in 89% yield from 5 and 6, and no addition product to the ketone group of 6 was isolated. In addition, we also examined the reaction of two nature product substrates, citral (8) and retinaldehyde (10), and the corresponding Reformatsky products 9 and 11 were obtained in 70% and 63% yield, respectively (Scheme [6]).
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These examples emphasize that the indium-mediated Reformatsky reaction of iododifluoroketones has good selectivity for aldehydes.
In addition to showing good reactivity with aldehydes, applying this strategy to the reaction of iododifluoroacetophenone and isatin worked well in water, allowing efficient construction of the quaternary oxindoles 13 featuring a CF2 group at C3 (Scheme [7]). It should be noted that the synthesis of quaternary oxindoles is of current interest as they present privileged scaffolds in medicinal research.[39]
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In summary, we have demonstrated that indium is an efficient reagent for the Reformatsky reaction of iododifluoroketones with various aldehydes as well as isatin under mild conditions using water as the solvent. This reaction has extensive substrate scope and excellent selectivity. This environmentally friendly approach has been applied to the gram-scale preparation of GABAB receptor agonist 7 and other molecules with the α,α-difluoro-β-hydroxyketone pharmacophore.
Reactions were monitored by thin-layer chromatography using UV light to visualize the plates. Purification of reaction products was carried out by flash chromatography on silica gel. Chemical yields refer to pure isolated substances. NMR spectra were obtained at 500/400 MHz (1H NMR), 376 MHz (19F NMR), and 126/101 MHz (13C NMR) using CDCl3 or (CD3)2SO with the residual proton solvent resonance as the internal standard. Chemical shifts are reported in ppm relative to TMS. The following abbreviations are used to designate multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Coupling constants, J, are reported in hertz.
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General Procedure for the Reaction of α-Iodo-α,α-Difluoroketones with Aldehydes
To a 20 mL vial α-iodo-α,α-difluoroketones 1 (200 mg, 0.7 mmol, 1.0 equiv), indium powder (0.5 equiv), and aldehyde 2 (1.2 equiv) were added, followed by H2O (8 mL). The reaction mixture was stirred at 50 °C for 2 h (monitored by TLC). Then ethyl acetate (3 × 10 mL) was added to extract the aqueous layer, the organic phase was concentrated and purified by column chromatography to afford the products 3a–aa.
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2,2-Difluoro-3-hydroxy-1,3-diphenylpropan-1-one (3a)[40]
White solid, mp 62–63 °C, 0.169 g, 91% yield.
1H NMR (500 MHz, CDCl3): δ = 8.09 (d, J = 8.0 Hz, 2 H), 7.65 (t, J = 7.4 Hz, 1 H), 7.54 (d, J = 4.1 Hz, 2 H), 7.49 (t, J = 7.8 Hz, 2 H), 7.44–7.40 (m, 3 H), 5.40 (dt, J = 18.4, 4.7 Hz, 1 H), 3.12 (1 H).
13C NMR (126 MHz, CDCl3): δ = 191.11 (dd, J = 31.5, 28.7 Hz), 134.91, 134.59, 132.58, 130.29 (t, J = 2 Hz), 129.06, 128.69, 128.35, 128.19, 116.03 (dd, J = 264.3, 256.4 Hz), 73.37 (dd, J = 28.5, 23.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –104.4 (d, J = 79 Hz, 1 F), –116.8 (d, J = 79 Hz, 1 F).
HRMS (ESI): m/z calcd for C15H12O2F2Na [M + Na]+: 285.0698; found: 285.0699
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2,2-Difluoro-3-(3-fluorophenyl)-3-hydroxy-1-phenylpropan-1-one (3b)
White solid, mp 78–79 °C, 0.182 g, 92% yield.
1H NMR (500 MHz, CDCl3): δ = 8.08 (d, J = 7.9 Hz, 2 H), 7.65 (t, J = 7.4 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 2 H), 7.36 (dd, J = 13.9, 7.6 Hz, 1 H), 7.28 (d, J = 7.8 Hz, 2 H), 7.12–7.05 (m, 1 H), 5.40 (dt, J = 18.6, 4.5 Hz, 1 H), 3.63 (d, J = 4.5 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 190.86 (dd, J = 31.6, 28.8 Hz), 163.68, 161.73, 137.35 (d, J = 7.5 Hz), 134.76, 132.33, 130.29 (t, J = 2 Hz), 129.77 (d, J = 8.1 Hz), 128.73, 123.87, 115.92 (d, J = 21.1 Hz), 115.49 (t, J = 90 Hz), 115.23 (d, J = 22.7 Hz), 72.63 (t, J = 110 Hz).
19F NMR (376 MHz, CDCl3): δ = –104.1 (dd, J =15.0, 263 Hz, 1 F), –112.3 (m, 1 F), –116.7 (dd, J = 19, 338 Hz, 1 F).
HRMS (ESI): m/z calcd for C15H12O2F2Na [M + Na]+: 303.0603; found: 303.0603.
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2,2-Difluoro-3-(4-fluorophenyl)-3-hydroxy-1-phenylpropan-1-one (3c)[41]
White solid, mp 70–72 °C, 0.188 g, 95% yield.
1H NMR (500 MHz, CDCl3): δ = 8.07 (d, J = 7.9 Hz, 2 H), 7.65 (t, J = 7.4 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 4 H), 7.09 (t, J = 8.6 Hz, 2 H), 5.38 (dt, J = 18.6, 4.5 Hz, 1 H), 3.55 (d, J = 4.3 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 191.21–190.72 (dd, J = 115 Hz, 10 Hz), 163.16 (d, J = 247.5 Hz), 134.73, 132.37, 130.65, 130.28 (t, J = 6.4 Hz, 3.6 Hz), 129.98 (d, J = 8.3 Hz), 128.73, 117.82–113.68 (dd, J = 8.2 Hz), 115.28 (d, J = 21.6 Hz), 72.83–72.42 (dd, J = 162.83, 25 Hz).
19F NMR (376 MHz, CDCl3): δ = –104.1 (dd, J =15.0, 263 Hz, 1 F), –112.3 (m, 1 F), –116.7 (dd, J = 19, 338 Hz, 1 F).
HRMS (ESI): m/z calcd for C15H12O2F2Na [M + Na]+: 303.0603; found: 303.0603.
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3-(4-Bromophenyl)-2,2-difluoro-3-hydroxy-1-phenylpropan-1-one (3d)[40]
White solid, mp 79–81 °C, 0.212 g, 93% yield.
1H NMR (500 MHz, CDCl3): δ = 8.06 (d, J = 7.9 Hz, 2 H), 7.65 (t, J = 7.4 Hz, 1 H), 7.54–7.45 (m, 4 H), 7.38 (d, J = 8.2 Hz, 2 H), 5.35 (dd, J = 18.7, 5.0 Hz, 1 H), 3.70 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 190.84 (dd, J = 31.5, 28.8 Hz), 134.76, 133.94, 132.33, 131.45, 130.37–130.16 (m), 129.85, 128.75, 123.19, 115.67 (dd, J = 265.0, 256.7 Hz), 72.62 (dd, J = 28.7, 23.3 Hz).
19F NMR (376 MHz, CDCl3): δ = –104.6(d, J = 184 Hz, 1 F), –116.7 (d, J = 248 Hz, 1 F).
HRMS (ESI): m/z calcd for C15H11O2BrF2Na [M + Na]+: 362.9803; found: 362.9806.
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2,2-Difluoro-3-hydroxy-1-phenyl-3-(p-tolyl)propan-1-one (3e)[41]
White solid, mp 67–69 °C, 0.162 g, 83% yield.
1H NMR (500 MHz, CDCl3): δ = 8.10 (d, J = 8.0 Hz, 2 H), 7.67 (t, J = 7.1 Hz, 1 H), 7.51 (t, J = 7.7 Hz, 2 H), 7.43 (d, J = 7.8 Hz, 2 H), 7.25 (d, J = 7.9 Hz, 2 H), 5.45 – 5.30 (m, 1 H), 3.31 (d, J = 3.2 Hz, 1 H), 2.42 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 191.06 (t, J = 31.5 Hz), 138.92, 134.53, 131.88, 130.33–130.23 (m), 129.25, 129.08, 128.66, 128.06, 115.99 (dd, J = 264.1, 256.1 Hz), 73.28 (dd, J = 28.6, 23.2 Hz), 21.27.
19F NMR (376 MHz, CDCl3): δ = –104.5 (d, J = 188 Hz, 1 F), –116.5 (d, J = 316 Hz, 1 F).
HRMS (ESI): m/z calcd for C16H14F2O2Na [M + Na]+: 299.0854; found: 299.0851.
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2,2-Difluoro-3-hydroxy-3-(4-methoxyphenyl)-1-phenylpropan-1-one (3f)[40]
White solid, mp 67–68 °C, 0.174 g, 84% yield.
1H NMR (500 MHz, CDCl3): δ = 8.07 (d, J = 7.9 Hz, 2 H), 7.63 (t, J = 7.4 Hz, 1 H), 7.48 (t, J = 7.7 Hz, 2 H), 7.43 (d, J = 8.4 Hz, 2 H), 6.93 (d, J = 8.5 Hz, 2 H), 5.38–5.29 (m, 1 H), 3.81 (s, 3 H), 3.46 (d, J = 4.4 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 191.19 (t, J = 30.24 Hz), 160.11, 134.51, 132.68, 130.38–130.11 (m), 129.44, 128.66, 127.05, 116.15 (dd, J = 263.7, 255.8 Hz), 113.80, 73.04 (dd, J = 28.8, 23.1 Hz), 55.28.
19F NMR (376 MHz, CDCl3): δ = –104.5 (d, J = 252 Hz, 1 F), –116.5 (d, J = 263 Hz, 1 F).
HRMS (ESI): m/z calcd for C16H14F2O3Na [M + Na]+: 315.0809; found: 315.0801.
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2,2-Difluoro-3-hydroxy-3-(3-methoxyphenyl)-1-phenylpropan-1-one (3g)[42]
White solid, mp 59–62 °C, 0.166 g, 80% yield.
1H NMR (500 MHz, CDCl3): δ = 8.07 (d, J = 8.0 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), 7.48 (t, J = 7.7 Hz, 2 H), 7.31 (t, J = 8.1 Hz, 1 H), 7.08 (s, 2 H), 6.96–6.91 (m, 1 H), 5.36 (dt, J = 18.4, 5.0 Hz, 1 H), 3.81 (s, 3 H), 3.38 (d, J = 4.6 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 190.94 (dd, J = 31.4, 28.5 Hz), 160.61 (s), 137.15 (s), 134.52 (s), 132.63 (s), 130.21 (s), 128.65 (s), 115.99 (dd, J = 264.6, 256.5 Hz), 106.16 (s), 101.13 (s), 73.36 (dd, J = 28.0, 23.2 Hz), 55.38 (s).
19F NMR (376 MHz, CDCl3): δ = –104.5 (d, J = 252 Hz, 1 F), –116.0 (d, J = 34 Hz, 1 F).
HRMS (ESI): m/z calcd for C16H14F2O3 [M + Na]+: 315.0803; found: 315.0803.
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3-(3,5-Dimethoxyphenyl)-2,2-difluoro-3-hydroxy-1-phenylpropan-1-one (3h)
White solid, mp 63–65 °C, 0.196 g, 86% yield.
1H NMR (500 MHz, CDCl3): δ = 8.06 (d, J = 7.9 Hz, 2 H), 7.63 (t, J = 7.4 Hz, 1 H), 7.48 (t, J = 7.8 Hz, 2 H), 6.67 (d, J = 1.6 Hz, 2 H), 6.48 (t, J = 2.1 Hz, 1 H), 5.31 (dt, J = 18.3, 4.5 Hz, 1 H), 3.78 (s, 6 H), 3.44 (d, J = 4.2 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 190.93 (t, J = 34.02 Hz), 160.61, 137.15, 134.52, 132.63, 130.21, 128.65, 115.99 (dd, J = 264.6, 256.5 Hz), 106.16, 101.13, 73.32 (t, J = 42.84 Hz), 55.38.
19F NMR (376 MHz, CDCl3): δ = –103.9 (d, J = 45 Hz, 1 F), –116.25 (d, J = 297 Hz, 1 F).
HRMS (ESI): m/z calcd for C17H16F4O2Na [M + Na]+: 345.0909; found: 345.0911.
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2,2-Difluoro-3-hydroxy-1-phenyl-3-(3,4,5-trimethoxyphenyl)propan-1-one (3i)
White solid, mp 93–95 °C, 0.195 g, 78% yield.
1H NMR (500 MHz, CDCl3): δ = 8.04 (d, J = 7.9 Hz, 2 H), 7.62 (t, J = 7.4 Hz, 1 H), 7.47 (t, J = 7.8 Hz, 2 H), 6.68 (s, 2 H), 5.29 (dd, J = 17.9, 5.5 Hz, 1 H), 3.82 (s, 9 H), 3.54 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 191.06 (dd, J = 31.0, 28.3 Hz), 152.96, 138.19, 134.48, 132.74, 130.58, 130.17 (t, J = 18.9 Hz), 128.61, 116.11 (dd, J = 264.3, 256.0 Hz), 105.19, 73.44 (dd, J = 28.5, 23.4 Hz), 60.82, 56.08.
19F NMR (376 MHz, CDCl3): δ = –103.7 (d, J = 41 Hz, 1 F), –115.6 (d, J = 41 Hz, 1 F).
HRMS (ESI): m/z calcd for C18H18F2O5Na [M + Na]+: 375.1015; found: 375.1018.
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2,2-Difluoro-3-hydroxy-1-phenyl-3-[3-(trifluoromethyl)phenyl]propan-1-one (3j)
White solid, mp 77–79 °C, 0.192 g, 82% yield.
1H NMR (501 MHz, CDCl3): δ = 8.09 (d, J = 7.9 Hz, 2 H), 7.84 (s, 1 H), 7.72 (d, J = 7.7 Hz, 1 H), 7.66 (t, J = 7.5 Hz, 2 H), 7.51 (dt, J = 15.5, 7.8 Hz, 3 H), 5.48 (dt, J = 19.1, 4.4 Hz, 1 H), 3.69 (d, J = 4.5 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 190.75 (dd, J = 31.7, 29.1 Hz), 135.86, 134.89, 132.13, 131.58, 130.83 (t, J = 32.5 Hz), 130.29 (t, J = 11.34 Hz), 128.76, 128.73, 125.76 (q, J = 3.6 Hz), 125.04 (d, J = 3.8 Hz), 124.02 (dd, J = 189.0, 272.16 Hz), 115.51 (dd, J = 265.6, 257.0 Hz), 72.58 (dd, J = 28.7, 23.3 Hz).
19F NMR (376 MHz, CDCl3): δ = –62.64 (s, CF3), –103.8 (d, J = 297 Hz, 1 F), –115.8 (d, J = 301 Hz, 1 F).
HRMS (ESI): m/z calcd for C16H11 F5O2Na [M + Na]+: 353.0577; found: 353.0568.
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2,2-Difluoro-3-hydroxy-3-(4-nitrophenyl)-1-phenylpropan-1-one (3k)
Yellow liquid, 0.176 g, 81% yield.
1H NMR (500 MHz, CDCl3): δ = 8.26 (d, J = 8.5 Hz, 2 H), 8.10 (d, J = 8.0 Hz, 2 H), 7.72 (d, J = 8.5 Hz, 2 H), 7.69 (t, J = 7.5 Hz, 1 H), 7.52 (t, J = 7.7 Hz, 2 H), 5.55 (dt, J = 19.3, 3.9 Hz, 1 H), 3.49 (d, J = 4.3 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 190.31 (dd, J = 31.7, 29.3 Hz), 148.29, 141.76, 135.11, 131.82, 130.34 (t, J = 3.1 Hz), 129.18, 128.86, 123.30, 115.15 (dd, J = 266.5, 258.2 Hz), 72.25 (dd, J = 27.7, 23.6 Hz).
19F NMR (376 MHz, CDCl3): δ = –104.0 (d, J = 338 Hz, 1 F), –116.0 (d, J = 376 Hz, 1 F).
HRMS (ESI): m/z calcd for C15H11F2NO4Na [M + Na]+: 330.0548; found: 330.0546.
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2,2-Difluoro-3-hydroxy-3-(4-methoxy-3-nitrophenyl)-1-phenylpropan-1-one (3l)
Yellow liquid, 0.196 g, 82% yield.
1H NMR (500 MHz, CDCl3): δ = 8.09 (d, J = 7.8 Hz, 2 H), 8.03 (d, J = 1.3 Hz, 1 H), 7.68 (dd, J = 17.6, 8.4 Hz, 2 H), 7.51 (t, J = 7.8 Hz, 2 H), 7.12 (d, J = 8.7 Hz, 1 H), 5.41 (dd, J = 19.0, 4.3 Hz, 1 H), 3.99 (s, 3 H), 3.50 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 190.53 (dd, J = 31.9, 29.1 Hz), 153.30, 139.27, 134.93, 133.90, 132.07, 130.28 (t, J = 12.6 Hz), 128.80, 127.31, 125.56, 115.33 (d, J = 8.6 Hz), 113.33, 71.78 (dd, J = 29.5, 23.4 Hz), 56.65.
19F NMR (376 MHz, CDCl3): δ = –103.8 (d, J = 331 Hz, 1 F), –114.6 (d, J = 331 Hz, 1 F).
HRMS (ESI): m/z calcd for C16H13F2NO5Na [M + Na]+: 360.0659; found: 360.0662.
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2,2-Difluoro-3-hydroxy-3-(3-hydroxyphenyl)-1-phenylpropan-1-one (3m)
Yellow liquid, 0.173 g, 88% yield.
1H NMR (501 MHz, DMSO): δ = 9.49 (s, 1 H), 8.05 (d, J = 7.8 Hz, 2 H), 7.73 (t, J = 7.4 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 2 H), 7.19 (t, J = 7.8 Hz, 1 H), 6.97 (s, 1 H), 6.92 (d, J = 7.6 Hz, 1 H), 6.79 (dd, J = 8.0, 1.8 Hz, 1 H), 6.61 (s, 1 H), 5.18 (d, J = 3.0 Hz, 1 H).
13C NMR (126 MHz, DMSO): δ = 191.48 (dd, J = 30.0, 25.7 Hz), 157.59, 138.47, 134.75, 133.53, 130.16, 129.38, 129.28, 119.20, 117.76 (d, J = 9.7 Hz), 115.95, 115.36, 72.87 (dd, J = 28.8, 23.5 Hz).
19F NMR (376 MHz, CDCl3): δ = –103.4 (d, J = 353 Hz, 1 F), –116.7 (d, J = 353 Hz, 1 F).
HRMS (ESI): m/z calcd for C15H11O2BrF2Na [M + Na]+: 339.9910; found: 339.9912.
#
2,2-Difluoro-3-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-1-phenylpropan-1-one (3n)
Yellow liquid, 0.194 g, 89% yield.
1H NMR (500 MHz, CDCl3): δ = 8.09 (d, J = 8.0 Hz, 2 H), 7.65 (t, J = 7.4 Hz, 1 H), 7.54 (d, J = 4.1 Hz, 2 H), 7.49 (t, J = 7.8 Hz, 2 H), 7.44–7.40 (m, 3 H), 5.40 (dt, J = 18.4, 4.7 Hz, 1 H), 3.46 (d, J = 4.4 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 191.11 (dd, J = 31.5, 28.7 Hz), 134.91, 134.59, 132.58, 130.29 (t, J = 2 Hz), 129.06, 128.69, 128.35, 128.19, 116.03 (dd, J = 264.3, 256.4 Hz), 73.37 (dd, J = 28.5, 23.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –103.5 (d, J = 331 Hz, 1 F), –114.8 (d, J = 316 Hz, 1 F).
HRMS (ESI): m/z calcd for C16H14F2O4Na [M + Na]+: 331.0752; found: 331.0754.
#
2,2-Difluoro-3-hydroxy-1-phenyl-3-(pyridin-4-yl)propan-1-one (3o)
Yellow liquid, 0.143 g, 77% yield.
1H NMR (501 MHz, CDCl3): δ = 8.48 (d, J = 5.0 Hz, 2 H), 8.09 (d, J = 7.9 Hz, 2 H), 7.66 (t, J = 7.4 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 4 H), 5.42 (dd, J = 18.9, 5.1 Hz, 1 H).
13C NMR (126 MHz, DMSO): δ = 191.45 (dd, J = 31.9, 26.2 Hz), 154.68, 150.82, 137.79, 136.86, 129.57, 129.11, 128.49, 124.38, 117.64 (dd, J = 262.1, 253.0 Hz), 71.41 (t, J = 23.94, 3.78 Hz).
19F NMR (376 MHz, CDCl3): δ = –103.5 (d, J = 305 Hz, 1 F), –114.8 (d, J = 305 Hz, 1 F).
HRMS (ESI): m/z calcd for C14H11 F2NO2Na [M + Na]+: 286.0650; found: 286.0650.
#
2,2-Difluoro-3-hydroxy-1-phenylhexan-1-one (3p)
Colorless liquid, 0.133 g, 82% yield.
1H NMR (501 MHz, CDCl3): δ = 8.13 (d, J = 7.8 Hz, 2 H), 7.66 (t, J = 7.4 Hz, 1 H), 7.51 (t, J = 7.8 Hz, 2 H), 4.31–4.23 (m, 1 H), 2.67 (d, J = 5.9 Hz, 1 H), 1.75–1.63 (m, 3 H), 1.48 (dt, J = 14.4, 6.5 Hz, 1 H), 1.00 (t, J = 7.0 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 190.72 (t, J = 31.5), 134.51, 133.15, 132.56, 130.19 (t, J = 3.3 Hz), 128.68, 124.23, 116.22 (dd, J = 261.5, 257.0 Hz), 72.73 (dd, J = 28.0, 24.6 Hz), 17.97.
19F NMR (376 MHz, CDCl3): δ = –103.6 (d, J = 263 Hz, 1 F), –114.4 (d, J = 263 Hz, 1 F).
HRMS (ESI): m/z calcd for C12 H14F2O2 [M + Na]+: 228.0962; found: 228.0965.
#
2,2-Difluoro-3-hydroxy-1,5-diphenylpentan-1-one (3q)
Yellow liquid, 0.179 g, 87% yield.
1H NMR (501 MHz, CDCl3): δ = 8.15 (d, J = 7.8 Hz, 2 H), 7.68 (t, J = 7.4 Hz, 1 H), 7.53 (t, J = 7.8 Hz, 2 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.27 (dd, J = 17.5, 7.0 Hz, 3 H), 4.37–4.25 (m, 1 H), 3.04 (ddd, J = 14.1, 9.4, 5.1 Hz, 1 H), 2.86–2.77 (m, 2 H), 2.19–2.01 (m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 190.59 (t, J = 30.24 Hz), 141.13, 134.70, 132.25, 130.29 (t, J = 3.1 Hz), 128.77, 128.57, 126.18, 116.63 (t, J = 262.08 Hz), 70.55 (t, J = 26.46 Hz), 31.40, 30.41.
19F NMR (376 MHz, CDCl3): δ = –103.6 (d, J = 259 Hz, 1 F), –114.5 (d, J = 256 Hz, 1 F).
HRMS (ESI): m/z calcd for C17H16F2O2Na [M + Na]+: 313.1011; found: 313.1009.
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(E)-2,2-Difluoro-3-hydroxy-1-phenylhex-4-en-1-one (3r)
Transparent liquid, 0.128 g, 80% yield.
1H NMR (500 MHz, CDCl3): δ = 8.10 (d, J = 7.9 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 2 H), 5.95 (dq, J = 13.1, 6.5 Hz, 1 H), 5.65 (dd, J = 15.4, 7.1 Hz, 1 H), 4.77–4.66 (m, 1 H), 2.99 (s, 1 H), 1.76 (d, J = 6.5 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 190.62 (t, J = 28.92 Hz), 134.51, 133.15, 132.56, 130.19 (t, J = 3.3 Hz), 128.68, 124.23, 116.22 (dd, J = 261.5, 257.0 Hz), 72.73 (dd, J = 28.0, 24.6 Hz), 17.97.
19F NMR (376 MHz, CDCl3): δ = –106.0 (d, J = 368 Hz, 1 F), –115.6 (d, J = 368 Hz, 1 F).
HRMS (ESI): m/z calcd for C12H12F2O2Na [M + Na]+: 249.0698; found: 249.0700.
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(E)-2,2-Difluoro-3-hydroxy-1,5-diphenylpent-4-en-1-one (3s)
Yellow liquid, 0.204 g, 81% yield.
1H NMR (500 MHz, CDCl3): δ = 8.17 (d, J = 6.8 Hz, 1 H), 7.66 (s, 1 H), 7.52 (d, J = 6.7 Hz, 1 H), 7.45 (d, J = 6.3 Hz, 1 H), 7.34 (dd, J = 16.7, 6.4 Hz, 2 H), 6.88 (d, J = 15.9 Hz, 1 H), 6.40 (dd, J = 15.7, 6.0 Hz, 1 H), 5.02 (d, J = 7.9 Hz, 1 H), 3.30 (d, J = 2.4 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 191.11 (dd, J = 31.5, 28.7 Hz), 134.91, 134.59, 132.58, 130.29 (t, 2 Hz), 129.06, 128.69, 128.35, 128.19, 116.03 (dd, J = 264.3, 256.4 Hz), 73.37 (dd, J = 28.5, 23.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –106.0 (d, J = 368 Hz, 1 F), –115.4 (d, J = 368 Hz, 1 F).
HRMS (ESI): m/z calcd for C17H14F2O2Na [M + Na]+: 311.0854; found: 311.0859.
#
2,2-Difluoro-3-hydroxy-1-(pyridin-3-yl)-3-(p-tolyl)propan-1-one (3t)
Yellow liquid, 0.159 g, 81% yield.
1H NMR (500 MHz, DMSO): δ = 9.21 (s, 1 H), 8.88 (d, J = 3.9 Hz, 1 H), 8.42 (d, J = 7.9 Hz, 1 H), 7.63 (dd, J = 7.9, 4.9 Hz, 1 H), 7.44 (d, J = 7.8 Hz, 2 H), 7.22 (d, J = 7.9 Hz, 2 H), 6.80 (d, J = 5.2 Hz, 1 H), 5.27 (dt, J = 20.1, 5.5 Hz, 1 H), 2.32 (s, 3 H).
13C NMR (101 MHz, DMSO): δ = 191.57 (dd, J = 31.8, 26.4 Hz), 154.60, 150.85, 138.45, 137.77, 133.91, 129.66, 129.08, 128.43, 124.33, 116.48 (t, J = 112.14 Hz), 72.81 (dd, J = 29.4, 23.5 Hz), 21.21.
19F NMR (376 MHz, CDCl3): δ = –104.5 (d, J = 323 Hz, 1 F), –115.4 (d, J = 323 Hz, 1 F).
HRMS (ESI): m/z calcd for C15H13F2NO2Na [M + Na]+: 300.0807; found: 300.0810.
#
2,2-Difluoro-3-(4-fluorophenyl)-3-hydroxy-1-(pyridin-3-yl)propan-1-one (3u)
Yellow liquid, 0.169 g, 85% yield.
1H NMR (501 MHz, DMSO): δ = 9.21 (s, 1 H), 8.88 (d, J = 4.0 Hz, 1 H), 8.41 (t, J = 11.2 Hz, 1 H), 7.62 (td, J = 8.2, 5.6 Hz, 3 H), 7.25 (t, J = 8.8 Hz, 2 H), 6.90 (dd, J = 17.5, 5.2 Hz, 1 H), 5.36 (dt, J = 20.1, 5.4 Hz, 1 H).
13C NMR (101 MHz, DMSO): δ = 191.28 (dd, J = 31.6, 26.4 Hz), 164.06, 161.62, 154.65, 150.86, 137.78, 133.11, 130.60, 130.52, 129.58, 124.33, 177.68 (t, J = 232.96 Hz), 115.46, 115.25, 72.17 (dd, J = 29.5, 23.4 Hz).
19F NMR (376 MHz, CDCl3): δ = –105.4 (dd, J =15.0, 331 Hz, 1 F), –111.9 (m, 1 F), –113.6 (dd, J = 15.0, 331 Hz, 1 F).
HRMS (ESI): m/z calcd for C14H10F3NO2Na [M + Na]+: 304.0556; found: 304.0556.
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2,2-Difluoro-1-(4-fluorophenyl)-3-hydroxy-3-(4-methoxyphenyl)propan-1-one (3v)
White solid, mp 82–83 °C, 0.188 g, 91% yield.
1H NMR (501 MHz, CDCl3): δ = 8.09 (dd, J = 8.1, 5.6 Hz, 2 H), 7.41 (d, J = 8.5 Hz, 2 H), 7.13 (t, J = 8.6 Hz, 2 H), 6.91 (d, J = 8.7 Hz, 2 H), 5.29 (dd, J = 18.3, 6.1 Hz, 1 H), 3.80 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 189.68 (dd, J = 31.4, 28.9 Hz), 166.49 (d, J = 257.7 Hz), 160.17, 133.24 (dd, J = 6.1, 3.4 Hz), 132.34, 129.40, 129.13, 126.98, 115.93 (d, J = 22.0 Hz), 113.82, 73.00 (dd, J = 28.7, 23.3 Hz), 55.25.
19F NMR (376 MHz, CDCl3): δ = –105.7 (dd, J =15.0, 331 Hz, 1 F), –112.2 (m, 1 F), –116.3 (dd, J = 15.0, 331 Hz, 1 F).
HRMS (ESI): m/z calcd for C16H13F3O3Na [M + Na]+: 333.0709; found: 333.0711.
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(E)-1-(4-Chlorophenyl)-2,2-difluoro-3-hydroxyhex-4-en-1-one (3w)
Pale yellow liquid, 0.145 g, 88% yield.
1H NMR (501 MHz, CDCl3): δ = 8.05 (d, J = 8.0 Hz, 2 H), 7.49 (d, J = 7.2 Hz, 2 H), 5.97 (dd, J = 14.9, 6.9 Hz, 1 H), 5.64 (dd, J = 15.3, 7.0 Hz, 1 H), 4.77–4.57 (m, 1 H), 2.65 (d, J = 4.5 Hz, 1 H), 1.79 (d, J = 6.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 189.48 (t, J = 29.5 Hz), 141.32, 133.44, 131.63, 130.85, 129.12, 124.04, 116.04 (t, J = 257.85 Hz), 72.70 (t, J = 24.85 Hz), 18.01.
19F NMR (376 MHz, CDCl3): δ = –106.2 (d, J = 274 Hz, 1 F), –115.5 (d, J = 274 Hz, 1 F).
HRMS (ESI): m/z calcd for C12H11ClF2O2Na [M + Na]+: 283.0308; found: 283.0308.
#
1-[2-(Benzyloxy)-4-methoxyphenyl]-2,2-difluoro-3-hydroxy-3-(4-methoxy-3-nitrophenyl)propan-1-one (3x)
Yellow solid, mp 105–107 °C, 0.199 g, 88% yield.
1H NMR (501 MHz, CDCl3): δ = 7.85 (d, J = 1.4 Hz, 1 H), 7.68 (d, J = 8.6 Hz, 1 H), 7.51 (d, J = 8.6 Hz, 1 H), 7.43 (d, J = 7.4 Hz, 2 H), 7.35 (t, J = 7.4 Hz, 2 H), 7.30 (d, J = 7.3 Hz, 1 H), 6.95 (d, J = 8.8 Hz, 1 H), 6.52 (d, J = 1.8 Hz, 1 H), 6.48 (dd, J = 8.8, 1.9 Hz, 1 H), 5.34 (d, J = 18.1 Hz, 1 H), 5.08 (s, 2 H), 3.85 (s, 3 H), 3.78 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 190.52 (t, J = 30.24 Hz), 153.29, 139.26, 134.92, 133.89, 132.06, 128.78, 127.29, 125.54, 115.33 (t, J = 209.07 Hz), 71.77 (dd, J = 19.19, 5.05 Hz), 56.64.
19F NMR (376 MHz, CDCl3): δ = –103.8 (d, J = 297 Hz, 1 F), –114.2 (d, J = 297 Hz, 1 F).
HRMS (ESI): m/z calcd for C24H21F2NO7Na [M + Na]+: 496.1178; found: 496.1182.
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2,2-Difluoro-3-hydroxy-1-phenyl-3-(pyridin-2-yl)propan-1-one (3y)[43]
White solid, mp 70–72 °C, 0.152 g, 81% yield.
1H NMR (501 MHz, CDCl3): δ = 8.71 (d, J = 8 Hz, 1 H), 8.16–8.15 (m, 2 H), 7.90–7.87 (m, 1 H), 7.77–7.75 (m, 1 H), 7.69–7.63 (m, 3 H), 7.38–7.37 (m, 1 H), 5.55 (dt, J = 18.6, 4.5 Hz, 1 H), 3.50 (d, J = 4.5 Hz, 1 H).
HRMS (ESI): m/z calcd for C14H11F2NO2Na [M + Na]+: 286.0656; found: 286.0655.
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2,2-Difluoro-3-(furan-2-yl)-3-hydroxy-1-phenylpropan-1-one (3z)[44]
Yellow oil, 0.155 g, 86% yield.
1H NMR (501 MHz, CDCl3): δ = 8.11 (d, J = 1 Hz, 2 H), 7.62 (t, J = 1.5 Hz, 1 H), 7.37 (t, J = 2.5 Hz, 2 H), 7.26 (d, J = 1 Hz, 1 H), 6.63 (d, J = 5 Hz, 1 H), 6.48 (d, J = 2.5 Hz, 1 H), 5.56 (dt, J = 18.4, 5 Hz, 1 H), 3.30 (d, J = 7 Hz, 1 H).
HRMS (ESI): m/z calcd for C13H10F2O3Na [M + Na]+: 275.0496; found: 275.0497.
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2,2-Difluoro-3-hydroxy-3-phenyl-1-(thiophen-2-yl)propan-1-one (3aa)[42]
White solid, mp 60–61 °C, 0.169 g, 90% yield.
1H NMR (500 MHz, CDCl3): δ = 7.76 (d, J = 3 Hz, 1 H), 7.64–7.59 (m, 2 H), 7.49–7.47 (m, 4 H), 6.59 (dd, J = 18.7, 5.0 Hz, 1 H). 5.39 (dd, J = 18.7, 5.0 Hz, 1 H), 3.70 (s, 1 H)
HRMS (ESI): m/z calcd for C13H10F2O2SNa [M + Na]+: 291.0267; found: 291.0270.
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Procedure for the Mechanistic Investigation
To a 20 mL vial, α-iodo-α,α-difluoroketone 1a (200 mg, 0.7 mmol, 1.0 equiv), indium powder (0.5 equiv), benzaldehyde 2a (1.2 equiv), and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 1.2 equiv) were added, followed H2O (8 mL). The reaction mixture was stirred at 50 °C for 2 h (monitored by TLC). Then ethyl acetate (3 × 10 mL) was added to extract the aqueous layer, the organic phase was concentrated and purified by column chromatography to afford the product 4, with no 3a being detected.
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2,2-Difluoro-1-phenyl-2-[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]ethan-1-one (4)[45]
Pale yellow liquid, 0.187 g, 85% yield.
1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 7.7 Hz, 2 H), 7.68–7.62 (m, 1 H), 7.52 (t, J = 7.8 Hz, 2 H), 1.59 (dt, J = 10.0, 5.7 Hz, 5 H), 1.39 (s, 1 H), 1.25 (s, 3 H), 1.13 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 184.11 (t, J = 37.3 Hz), 134.42, 131.47, 130.39, 128.64, 117.13 (t, J = 278.0 Hz), 61.20, 40.20, 33.75 (t, J = 4.4 Hz), 20.94, 16.93.
19F NMR (376 MHz, CDCl3): δ = –71.85.
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Procedure for the Preparation of (GABAB Agonist) 7
To a 20 mL vial, 1-[(3r,5r,7r)-adamantan-1-yl]-2,2-difluoro-2-iodoethan-1-one (5, 500 mg, 1.47 mmol), indium powder (85 mg, 0.74 mmol), and 4-acetylbenzaldehyde (6, 262 mg, 1.76 mmol) were added, followed by H2O (10 mL). The reaction mixture was stirred at 50 °C for 2 h (monitored by TLC). Then ethyl acetate (3 × 20 mL) was added to extract the aqueous layer, the organic phase was concentrated and purified by column chromatography to afford the product 7.
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3-(4-Acetylphenyl)-1-[(3r,5r,7r)-adamantan-1-yl]-2,2-difluoro-3-hydroxypropan-1-one (7)[17b]
Pale yellow solid, mp 45–47 °C,[5] 0.33 g, 89% yield.
1H NMR (500 MHz, CDCl3): δ = 7.99 (td, J = 8.5, 2.0 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 2 H), 5.35 (dt, J = 18.0, 5.5 Hz, 1 H), 3.01 (d, J = 5.0 Hz, 1 H), 2.65 (s, 3 H), 2.05 (br s, 3 H), 2.01 (br s, 6 H), 1.72 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 205.52 (dd, J = 29.3, 25.9 Hz), 197.82, 140.12, 137.34, 129.08, 128.57, 116.15 (dd, J = 267, 259 Hz), 72.6 (dd, J = 27.9, 23.47 Hz), 46.85 (t, J = 2.3 Hz), 36.51, 36.55, 27.25, 26.71.
19F NMR (376 MHz, CDCl3): δ = –106.0 (dd, J = 19, 173 Hz, 1 F), –118.2 (dd, J = 19, 173 Hz, 1 F).
HRMS (ESI): m/z calcd for C21H24F2O3Na [M + Na]+: 385.1591; found: 385.1593.
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Procedure for the Preparation of 9
To a 20 mL vial, α-iodo-α,α-difluoroketone 1a (500 mg, 1.77 mmol), indium powder (102 mg, 0.89 mmol), and citral (8, 324 mg, 2.13 mmol) were added, followed by H2O (10 mL). The reaction mixture was stirred at 50 °C for 2 h (monitored by TLC) Then ethyl acetate (3 × 20 mL) was added to extract the aqueous layer, the organic phase was concentrated and purified by column chromatography to afford the product 9.
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(E)-2,2-Difluoro-3-hydroxy-5,9-dimethyl-1-phenyldeca-4,8-dien-1-one (9)
Light yellow liquid, 0.382 g, 70% yield.
1H NMR (501 MHz, CDCl3): δ = 8.11 (d, J = 7.7 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), 7.50 (t, J = 7.7 Hz, 2 H), 5.39 (dd, J = 28.7, 9.0 Hz, 1 H), 2.65 (dd, J = 50.3, 5.3 Hz, 1 H), 2.19 – 2.04 (m, 4 H), 1.82 (s, 1 H), 1.72 (s, 2 H), 1.70 (s, 1 H), 1.68 (s, 2 H), 1.62 (s, 1 H), 1.60 (s, 2 H).
13C NMR (126 MHz, CDCl3): δ = 190.61 (t, J = 24.24 Hz), 145.54, 145.13, 134.41, 132.69, 132.50, 131.98, 130.15 (d, J = 3.3 Hz), 128.65, 123.54 (d, J = 5.3 Hz), 117.97, 116.75 (t, J = 199.48 Hz), 68.79 (t, J = 21.21 Hz), 39.72, 32.66, 26.45, 26.17, 25.63, 23.65, 17.66 (d, J = 2.9 Hz), 17.07.
19F NMR (376 MHz, CDCl3): δ = –106.7 (d, J = 274 Hz, 1 F), –116.2 (d, J = 274 Hz, 1 F).
HRMS (ESI): m/z calcd for C18H22F2O2Na [M + Na]+: 331.1480; found: 331.1480.
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Procedure for the Preparation of 11
To a 20 mL vial, α-iodo-α,α-difluoroketone 1a (200 mg, 0.71 mmol), indium powder (41 mg, 0.35 mmol), and retinaldehyde (10, 242 mg, 0.85 mmol) were added, followed by H2O (8 mL). The reaction mixture was stirred at 50 °C for 2 h (monitored by TLC). Then ethyl acetate (3 × 10 mL) was added to extract the aqueous layer, the organic phase was concentrated and purified by column chromatography to afford the product 11.
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(4E,6E,8E,10E)-2,2-Difluoro-3-hydroxy-5,9-dimethyl-1-phenyl-11-(2,6,6-trimethylcyclohex-1-en-1-yl)undeca-4,6,8,10-tetraen-1-one (11)
Yellow liquid, 0.196 g, 63% yield.
1H NMR (501 MHz, CDCl3): δ = 8.11 (d, J = 7.7 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), 7.50 (t, J = 7.7 Hz, 2 H), 6.71 (dd, J = 15.1, 11.4 Hz, 1 H), 6.32 (d, J = 15.1 Hz, 1 H), 6.22 (d, J = 16.1 Hz, 1 H), 6.16–6.09 (m, 2 H), 5.39 (dd, J = 28.7, 9.0 Hz, 1 H), 5.15–4.96 (m, 1 H), 2.70 (s, 1 H), 2.07–2.02 (m, 2 H), 1.98 (s, 3 H), 1.94 (s, 3 H), 1.74 (s, 3 H), 1.64 (dt, J = 8.8, 6.1 Hz, 2 H), 1.49 (dd, J = 7.7, 4.0 Hz, 2 H), 1.27 (t, J = 7.1 Hz, 1 H), 1.05 (s, 6 H).
13C NMR (126 MHz, CDCl3): δ = 190.61 (t, J = 31.5 Hz), 145.13, 134.41, 132.69, 131.98, 130.15 (d, J = 3.3 Hz), 128.65, 123.52, 117.97, 116.68 (t, J = 250.11 Hz), 68.89 (dd, J = 23.94, 3.78 Hz), 39.72, 25.63, 17.07.
19F NMR (376 MHz, CDCl3): δ = –106.6 (d, J = 368 Hz, 1 F), –116.3 (d, J = 368 Hz, 1 F).
HRMS (ESI): m/z calcd for C28H34F2O2Na [M + Na]+: 463.2419; found: 463.2413.
#
General Procedure for the Preparation of 13
To a 20 mL vial, isatin derivative 12 (200 mg, 1.0 equiv), indium powder (0.5 equiv), and 2,2-difluoro-2-iodo-1-phenylethan-1-one (1, 1.2 equiv) were added, followed by H2O (10 mL). The reaction mixture was stirred at 50 °C for 2 h (monitored by TLC). Then the mixture was filtered and washed with petroleum ether to afford the product 13.
#
3-(1,1-Difluoro-2-oxo-2-phenylethyl)-3-hydroxyindolin-2-one (13a)[38]
Yellow solid, mp 117–118 °C, 0.392 g, 95% yield.
1H NMR (501 MHz, DMSO): δ = 8.07 (d, J = 7.6 Hz, 1 H), 7.74 (t, J = 7.0 Hz, 1 H), 7.58 (t, J = 7.1 Hz, 1 H), 7.47 (s, 1 H), 7.41 (dd, J = 18.9, 7.7 Hz, 1 H), 7.08 (d, J = 7.2 Hz, 1 H), 3.14 (s, 1 H).
13C NMR (126 MHz, DMSO): δ = 188.28 (t, J = 28.4 Hz), 172.14, 144.80, 135.14, 132.97, 131.31, 130.69, 129.62, 129.20, 126.06, 125.88, 117.34 (t, J = 262.4 Hz), 109.50, 76.01 (t, J = 25.4 Hz), 26.65.
#
3-(1,1-Difluoro-2-oxo-2-phenylethyl)-5-fluoro-3-hydroxyindolin-2-one (13b)[46]
Yellow solid, mp 135–137 °C, 0.373 g, 96% yield.
1H NMR (501 MHz, DMSO): δ = 8.10 (d, J = 7.7 Hz, 2 H), 7.74 (t, J = 7.2 Hz, 1 H), 7.58 (t, J = 7.6 Hz, 2 H), 7.17 (t, J = 8.2 Hz, 2 H), 6.90 (dd, J = 8.1, 4.1 Hz, 1 H).
13C NMR (126 MHz, DMSO): δ = 188.16 (t, J = 29.0 Hz), 173.70, 159.15, 157.26, 139.72, 135.17, 132.97, 130.75, 129.19, 128.29 (d, J = 7.6 Hz), 117.53 (d, J = 23.4 Hz), 119.49–114.82 (m), 113.89 (d, J = 25.1 Hz), 111.53 (d, J = 7.5 Hz), 78.07–74.46 (m).
#
5-Chloro-3-(1,1-difluoro-2-oxo-2-phenylethyl)-3-hydroxyindolin-2-one (13c)[41]
Yellow solid, mp 82–84 °C, 0.353 g, 95% yield.
1H NMR (501 MHz, DMSO): δ = 8.10 (d, J = 7.8 Hz, 1 H), 7.74 (t, J = 7.3 Hz, 1 H), 7.59 (t, J = 7.7 Hz, 1 H), 7.38 (dd, J = 8.3, 1.7 Hz, 1 H), 7.33 (s, 1 H), 6.92 (d, J = 8.3 Hz, 1 H).
13C NMR (126 MHz, DMSO): δ = 188.15 (t, J = 29.3 Hz), 173.58, 142.75, 135.20, 132.93, 130.98, 130.77, 129.21, 128.81, 126.11 (d, J = 4.0 Hz), 119.42–114.80 (m), 112.18 (s), 76.40 (t, J = 24.8 Hz).
#
5-Bromo-3-(1,1-difluoro-2-oxo-2-phenylethyl)-3-hydroxyindolin-2-one (13d)[46]
Yellow solid, mp 122–124 °C, 0.318 g, 94% yield.
1H NMR (501 MHz, DMSO): δ = 8.11 (d, J = 7.8 Hz, 1 H), 7.75 (t, J = 7.3 Hz, 1 H), 7.60 (t, J = 7.7 Hz, 1 H), 7.39 (dd, J = 8.3, 1.7 Hz, 1 H), 7.35 (s, 1 H), 6.93 (d, J = 8.3 Hz, 1 H).
13C NMR (126 MHz, DMSO): δ = 188.09 (t, J = 29.3 Hz), 173.52, 142.69, 135.14, 132.87, 130.92, 130.71, 129.14, 128.75, 126.05 (d, J = 4.0 Hz), 119.47–114.77 (m), 112.11 (s), 76.33 (t, J = 24.8 Hz).
#
3-(1,1-Difluoro-2-oxo-2-phenylethyl)-3-hydroxy-5-methylindolin-2-one (13e)[41]
Yellow solid, mp 101–103 °C, 0.362 g, 92% yield.
1H NMR (501 MHz, DMSO): δ = 8.10 (d, J = 7.7 Hz, 1 H), 7.73 (t, J = 7.2 Hz, 1 H), 7.58 (t, J = 7.6 Hz, 1 H), 7.17 (s, 1 H), 7.11 (d, J = 7.8 Hz, 1 H), 6.77 (d, J = 7.8 Hz, 1 H), 2.24 (s, 1 H).
13C NMR (126 MHz, DMSO): δ = 188.32 (t, J = 27.5 Hz), 173.80, 141.04, 134.97, 133.23, 131.30, 131.14, 130.77, 129.62, 129.10, 126.86, 117.44 (dd, J = 263.9, 259.7 Hz), 110.28 (s), 76.85–76.05 (m), 21.05.
#
3-(1,1-Difluoro-2-oxo-2-phenylethyl)-3-hydroxy-5-methoxyindolin-2-one (13f)[47]
Yellow solid, mp 131–132 °C, 0.346 g, 92% yield.
1H NMR (501 MHz, DMSO): δ = 8.10 (d, J = 7.6 Hz, 1 H), 7.73 (t, J = 7.2 Hz, 1 H), 7.58 (t, J = 7.3 Hz, 1 H), 6.93 (s, 1 H), 6.90 (d, J = 8.5 Hz, 1 H), 6.81 (d, J = 8.3 Hz, 1 H), 3.70 (s, 2 H).
13C NMR (126 MHz, DMSO): δ = 188.45 (t, J = 16.6 Hz), 155.19, 136.66, 135.02, 133.21, 130.79, 129.62, 129.12, 127.89, 115.76, 113.11, 111.02, 55.97.
#
3-(1,1-Difluoro-2-oxo-2-phenylethyl)-3-hydroxy-5,7-dimethylindolin-2-one (13g)[47]
Yellow solid, mp 105–107 °C, 0.34 g, 90% yield.
1H NMR (501 MHz, DMSO): δ = 10.59 (s, 1 H), 8.11 (d, J = 7.7 Hz, 2 H), 7.72 (t, J = 7.3 Hz, 1 H), 7.58 (t, J = 7.7 Hz, 2 H), 7.28 (s, 1 H), 7.01 (s, 1 H), 6.94 (s, 1 H), 2.21 (s, 3 H), 2.18 (s, 3 H).
13C NMR (126 MHz, DMSO): δ = 188.31 (t, J = 28.6 Hz), 174.25, 139.50, 134.93, 133.28, 132.70, 131.10, 130.79, 129.07, 126.56, 124.16, 119.56, 119.66–115.30 (m), 77.05–76.12 (m), 20.96, 16.66.
#
3-(1,1-Difluoro-2-oxo-2-phenylethyl)-3-hydroxy-1-methylindolin-2-one (13h)[41]
Yellow solid, mp 95–97 °C, 0.374 g, 95% yield.
1H NMR (501 MHz, DMSO): δ = 8.07 (d, J = 7.6 Hz, 1 H), 7.74 (t, J = 7.0 Hz, 1 H), 7.58 (t, J = 7.1 Hz, 1 H), 7.47 (s, 1 H), 7.41 (dd, J = 18.9, 7.7 Hz, 1 H), 7.08 (d, J = 7.2 Hz, 1 H), 3.14 (s, 1 H).
13C NMR (126 MHz, DMSO): δ = 188.28 (t, J = 28.4 Hz), 172.14, 144.80, 135.14, 132.97, 131.31, 130.69, 129.62, 129.20, 126.06, 125.88, 117.34 (t, J = 262.4 Hz), 109.50 (s), 76.01 (t, J = 25.4 Hz), 26.65.
#
3-(1,1-Difluoro-2-oxo-2-phenylethyl)-3-hydroxy-5-nitroindolin-2-one (13i)[47]
Yellow solid, mp 112–114 °C, 0.33 g, 91% yield.
1H NMR (501 MHz, DMSO): δ = 8.29 (d, J = 8.6 Hz, 1 H), 8.16–8.07 (m, 3 H), 7.76 (t, J = 7.0 Hz, 1 H), 7.60 (t, J = 7.5 Hz, 2 H), 7.12 (d, J = 8.4 Hz, 1 H).
13C NMR (126 MHz, DMSO): δ = 189.08–187.37 (m), 173.78, 143.45, 135.03, 133.14, 131.15, 130.76, 129.13, 126.76, 126.26, 122.27, 117.40 (dd, J = 263.4, 259.8 Hz), 110.52, 76.31 (t, J = 25.3 Hz).
#
#
Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1719888.
- Supporting Information
-
References
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- 39 Zhou FLiu Y.-L. Zhou J. Adv. Synth. Catal. 2010; 352: 1381
- 40 Yuan Z.-L, Wei Y, Shi M. Tetrahedron 2010; 66: 7361
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- 42 Sasaki S, Suzuki T, Uchiya T, Toyota S, Hirano A, Tanemura M, Teramoto H, Yamauchi T, Higashiyama K. J. Fluorine Chem. 2016; 192: 78
- 43 Atsushi T, Mayuna O, Susumu S, Kazuyuki S, Masaaki O. RSC Adv. 2018; 8: 20568
- 44 Yuan J.-W, Liu S.-N, Mai W.-P. Org. Biomol. Chem. 2017; 15: 7654
- 45 Wu P.-J, Zheng C, Wang X, Wu J.-J, Wu F.-H. Eur. J. Org. Chem. 2021; 1420
- 46 Liu Z, Gao Y, Huang D, Gao Y, Yang Z, Hu X. CN110156659A, 2019
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Corresponding Authors
Publication History
Received: 14 November 2021
Accepted after revision: 21 December 2021
Article published online:
31 January 2022
© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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-
References
- 1 Choppin SL, Medeiros F, Barbarotto M, Colobert F. Chem. Soc. Rev. 2013; 42: 937
- 2 Cozzi PG. Angew. Chem. Int. Ed. 2007; 46: 2568
- 3 Cozzi PG. Angew. Chem. 2007; 119: 2620
- 4 Sato I, Takizawa Y, Soai K. Bull. Chem. Soc. Jpn. 2000; 73: 2825
- 5 Moslin RM, Jamison TF. J. Am. Chem. Soc. 2006; 128: 15106
- 6 Wessjohann LA, Scheid GO, Eichelberger U, Umbreen S. J. Org. Chem. 2013; 78: 10588
- 7 Lambert TH, Danishefsky SJ. J. Am. Chem. Soc. 2006; 128: 426
- 8 Grellepois F. J. Org. Chem. 2013; 78: 1127
- 9 Chan T.-H, Li C.-J, Lee M.-C, Wei Z.-Y. Can. J. Chem. 1994; 72: 1181
- 10 Chao L.-C, Rieke RD. A. J. Org. Chem. 1975; 40: 2253
- 11 Araki S, Hirashita T. Comprehensive Organometallic Chemistry, Vol. 9 . Crabtree RH, Mingos DM. P. Elsevier; Oxford: 2007: 649-722
- 12 Roy UK, Roy S. Chem. Rev. 2010; 110: 2472
- 13 Shen ZL, Wang SY, Chok YK, Xu YH, Loh TP. Chem. Rev. 2012; 113: 271
- 14 Pardoe JA, Downs AJ. Chem. Rev. 2007; 107: 2
- 15 Dreyer GB, Metcalf BW. Tetrahedron Lett. 1988; 29: 6885
- 16 Hamer RL, Freed B, Allen RC. US5006563, 1991
- 17a Han C, Salyer AE, Kim EH, Jiang X, Jarrard RE, Powers MS, Kirchhoff AM, Salvador TK, Chester JA, Hockerman GH, Colby DA. J. Med. Chem. 2013; 56: 2456
- 17b Han C, Kim EH, Colby DA. J. Am. Chem. Soc. 2011; 133: 5802
- 18 Kaneko S, Yamazaki T, Kitazume T. J. Org. Chem. 1993; 58: 2302
- 19 Yao H, Cao C.-R, Jiang M, Liu J.-T. J. Fluorine Chem. 2013; 156: 45
- 20 Doi R, Ohashi M, Ogoshi S. Angew. Chem. 2016; 128: 349
- 21 Chung WJ, Higashiya S, Welch JT. J. Fluorine Chem. 2001; 112: 343
- 22 Médebielle M, Onomura O, Keirouz R, Okada E, Yano H, Terauchi T. Synthesis 2002; 2601
- 23 Poisson T, Belhomme M.-C, Pannecoucke X. J. Org. Chem. 2012; 77: 9277
- 24 Wang J.-X, Wu J.-J, Chen H, Zhang S.-W, Wu F.-H. Chin. Chem. Lett. 2015; 26: 1381
- 25 Wang D.-F, Wu J.-J, Huang J.-W, Liang J.-Q, Peng P, Chen H, Wu F.-H. Tetrahedron 2017; 73: 3478
- 26 Chen H, Wang J.-X, Wu J.-J, Kuang Y.-J, Wu F.-H. J. Fluorine Chem. 2017; 200: 41
- 27 Liang J.-Q, Huang G.-Z, Peng P, Zhang T.-Y, Wu J.-J, Wu F.-H. Adv. Synth. Catal. 2018; 360: 2221
- 28 Wang X, Hu J, Ren J, Wu T.-C, Wu J.-J, Wu F.-H. Tetrahedron 2019; 75: 130715
- 29 Zhang T.-Y, Pan J, Duan J, Wu J.-J, Zhang W, Wu F.-H. ChemCatChem 2019; 11: 5778
- 30 Peng P, Wu J.-j, Liang J.-Q, Zhang T.-Y, Huang J.-W, Wu F.-H. RSC Adv. 2017; 7: 56034
- 31 Miyabe H, Nishimura A, Ueda M, Naito T. Chem. Commun. 2002; 14: 1454
- 32 Miyabe H, Ueda M, Nishimura A, Naito T. Org. Lett. 2002; 4: 131
- 33 Ueda M, Miyabe H, Nishimura A, Miyata O, Takemoto Y, Naito T. Org. Lett. 2003; 21: 3835
- 34 Miyabe H, Ueda M, Nishimura A, Naito T. Tetrahedron 2004; 60: 4227
- 35 Poisson T, Belhomme M.-C, Pannecoucke X. J. Org. Chem. 2012; 77: 9277
- 36 Dewar MJ. S, Merz KM. Jr. J. Am. Chem. Soc. 1987; 109: 6553
- 37 Maiz J, Arrieta A, Lopez X, Ugalde JM, Cossio FP. Tetrahedron Lett. 1993; 34: 6111
- 38 Yu J.-S, Liu Y.-L, Tang J, Wang X, Zhou J. Angew. Chem. Int. Ed. 2014; 53: 9512
- 39 Zhou FLiu Y.-L. Zhou J. Adv. Synth. Catal. 2010; 352: 1381
- 40 Yuan Z.-L, Wei Y, Shi M. Tetrahedron 2010; 66: 7361
- 41 Yu J.-SLiu Y.-L, Tang J, Wang X, Zhou J. Angew. Chem. Int. Ed. 2014; 53: 9512
- 42 Sasaki S, Suzuki T, Uchiya T, Toyota S, Hirano A, Tanemura M, Teramoto H, Yamauchi T, Higashiyama K. J. Fluorine Chem. 2016; 192: 78
- 43 Atsushi T, Mayuna O, Susumu S, Kazuyuki S, Masaaki O. RSC Adv. 2018; 8: 20568
- 44 Yuan J.-W, Liu S.-N, Mai W.-P. Org. Biomol. Chem. 2017; 15: 7654
- 45 Wu P.-J, Zheng C, Wang X, Wu J.-J, Wu F.-H. Eur. J. Org. Chem. 2021; 1420
- 46 Liu Z, Gao Y, Huang D, Gao Y, Yang Z, Hu X. CN110156659A, 2019
- 47 Li Y.-L, Wang X.-L, Xiao D, Liu M.-Y, Du Y, Deng J. Adv. Synth. Catal. 2018; 360: 4147
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