2024 Volume 72 Issue 8 Pages 772-774
We report chemoselective hydrogenation of α,β-unsaturated anilides catalyzed by the palladium-polymethylhydrosiloxane (hydrosilane) system. Under this condition, C–C double bonds are selectively reduced while other reducible groups such as acetyl groups, nitro groups, nitriles, benzyl ethers, and halogens are largely tolerated. This chemoselective hydrogenation is promising for the development of efficient synthetic routes for multi-functional compounds.
Palladium-catalyzed hydrogenation is a powerful and useful reaction in synthetic organic chemistry. However, the chemoselective hydrogenation1,2) of C–C double bonds remains challenging because of its high catalytic activity, which leads to the reduction of reducible functionalities in the same molecule. In 1986, Keinan and Greenspoon reported the chemoselective hydrogenation3) of C–C double bonds of activated alkene (α,β-unsaturated ketones) using Pd(OAc)2 and diphenylsilane as a reducing reagent (Chart 1a). In this study, only the activated C–C double bond was reduced in the presence of bromobenzene part or an unactivated alkene in the same molecule. Since this report, various reaction conditions4–7) applicable to the reduction of unactivated alkenes have been developed using the palladium-hydrosilane system. Although the chemoselective hydrogenation8) of alkenes and alkynes is an important and challenging theme in modern organic chemistry, there are no reported examples of the subsequent development of chemoselective reduction. In 2024, we reported a palladium-catalyzed reductive Heck hydroarylation9) of unactivated alkenes using Pd(OAc)2 and polymethylhydrosiloxane (PMHS) as reducing reagents (Chart 1b). Although this hydroarylation was carried out under reducing conditions, reducible functionalities such as halogen, benzyloxy, nitro, and carbonyl groups on the aromatic ring were not reduced. Inspired by this work, we expected that the chemoselective hydrogenation of alkenes could be achieved under conditions similar to those of the hydroarylation system. In this study, we report chemoselective hydrogenation of α,β-unsaturated anilides using the palladium-PMHS system (Chart 1c).
We designed the reaction system containing Pd(OAc)2, PMHS, and potassium fluoride (KF) as a fluoride ion source based on the conditions of the reported reductive Heck hydroarylation.9) We selected a series of α,β-unsaturated anilide with C–C double bond and reducible substituents at the para-position to evaluate the chemoselective reduction. First, we conducted a preliminary experiment using a model substrate 1a with an acetyl group (Chart 2). Consequently, product 2a, in which only the C–C double bond was reduced, was obtained in 72% yield. In this reaction, the generation of undesired products, in which the acetyl group was reduced,10,11) was not observed. Encouraged by this result, we examined the reactivity of substrate 1b–1f with reducible functional groups under reducing conditions such as nitro,12) nitrile,13) and benzyloxy,7) bromo,14) and chloro14) groups (Chart 2). While the C–C double bond was selectively reduced in all substrates, it should be noted that nitro, bromo, and chloro groups (in 2b, 2e, 2f) were also partially reduced under the present conditions. Among the reactions examined, the nitro group in 2b was most affected, and the yield of the aniline product generated by the reduction of the nitro group was estimated as 12% yield. In the case of substrates with bromo or chloro groups in 2c and 2d, an over-reduced product 2i through dehalogenation14) was generated in 11 and 2% yield, respectively. Conversely, when using substrate 1c with a nitrile group, no effect on the nitrile group was observed, and the reduced product 2c was obtained in 81% yield. The hydrogenation of substrates with electron-donating groups (1d, 1h, and 1j) and electron-withdrawing groups (1a–c, 1e–g, and 1k) was carried out, and selective reduction of the C–C double bond was observed for all substrates.
a Reaction conditions: 1 (0.25 mmol), Pd(OAc)2 (0.005 mmol), KF (0.75 mmol), PMHS (0.75 mmol), and AcOEt (1.0 mL). b DMF (0.5 mL) was added. c DMF (0.1 mL) was added. d Pd(OAc)2 (0.0125 mmol) was used. e Reaction time of 14 h. f Isolated yield. g Yield was evaluated by 1H-NMR.
Herein, we found that palladium catalyzed chemoselective hydrogenation of α,β-unsaturated anilides using PMHS as a reducing reagent. The C–C double bond was selectively reduced under this condition, and other reducible functionalities, such as acetyl, nitro, nitrile, benzyloxy, and halogen groups, were largely tolerated. This chemoselective hydrogenation is expected to be useful for establishing efficient synthetic routes for compounds with multi-functional groups. We believe that further optimization of the reaction conditions will improve the chemoselectivity. Further studies are underway to elucidate this reaction mechanism.
1H-NMR spectra were recorded on a Bruker NMR 500 MHz (AVANCE III HD500) spectrometer, and chemical shifts were recorded relative to Si(CH3)4 (0.0 ppm) or CHCl3 (7.26 ppm). The multiplicities were denoted as s (singlet), d (doublet), t (triplet), and m (multiplet). The number of protons (n) for a given resonance was denoted as nH. The coupling constants were reported as a J value in Hz. 13C-NMR spectra were recorded at 126 MHz, and chemical shifts were recorded relative to CDCl3 (77.16 ppm). 19F-NMR spectra were recorded at 471 MHz. As an external standard, fluorine chemical shifts were reported relative to hexafluorobenzene (C6F6: δ −164.9 ppm). All reagents were purchased from commercial sources and used without further purification. Normal phase column chromatography was performed with Yamazen Smart Flash (EPCLC Al-580S) and Biotage® Sfär Silica (High-Capacity Duo 20 µm). High-resolution mass spectra (HRMS) were measured on Thermo Fisher (LTQ OrbitrapXL, Thermo Fisher Scientific, Waltham, MA, U.S.A.).
SynthesisPd(OAc)2 (1.1 mg, 0.0049 mmol, 2.0 mol%) and KF (43.6 mg, 0.75 mmol, 3.0 equivalent (equiv.)) were dissolved in dried ethyl acetate in a test tube. Subsequently, alkene 1 (0.25 mmol, 1.0 equiv.) and PMHS (46 µL, 0.75 mmol, 3.0 equiv.) were added sequentially. The whole was stirred at room temperature (25 °C) for 24 h. The reaction mixture was filtered through a glass filter charged with Celite and washed with ethyl acetate (×5). The filtrate was concentrated on a rotary evaporator under reduced pressure, and the resulting residue was purified using silica gel column chromatography.
This work was supported in parts by JSPS KAKENHI Grant 21K15228 (Takahiro SHIRAI), as well as by the Natural Science Center for Basic Research and Development (NBARD-00066).
The authors declare no conflict of interest.
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