2023 Volume 71 Issue 2 Pages 83-92
Direct oxidation of the C(sp3)–H bond of β-(alkoxy)imino carbonyl compounds using copper acetate and molecular oxygen has been established. The protocol features a broad substrate scope and generates 1-imino-2,3-dicarbonyls in good to excellent yields.
Vicinal tricarbonyls (VTCs) are versatile building blocks widely applied in organic synthesis owing to their highly electrophilic central carbon,1,2) and are ubiquitous in various biologically and pharmaceutically important compounds.3–5) In addition, imine derivatives of VTCs exist not only in biologically active compounds, such as fungicides6) and pesticides,7) but are also used as synthetic intermediates for antibiotics,8) anticancer agents,9,10) and CRF-1 antagonists11) as well as functionalized polymers.12) In contrast to the diversity of approaches published for the preparation of VTCs,1,2,13–23) the synthesis of VTC imine derivatives is scarcely reported. Direct C(sp3)–H oxidation of readily available β-imino carbonyl compounds, such as 3-iminobutanoates, represents the most convenient method for accessing 1-imino-2,3-dicarbonyl compounds. However, only a few examples of direct α-oxygenation have been reported, even in the case of simple imines. Ottenheijm and colleagues demonstrated a 2,3-dichloro-5,6-dicyano-1,4-benzoquinone-mediated C–H oxidation of α-indolyl imines; however, only two examples were reported.24) Gatti and colleagues achieved the C–H oxidation of cyclic imines employing a combination of stoichiometric SeO2 and tert-butyl hydroperoxide, but the yields were relatively low.25) The aerobic oxidation of acetimidates, developed by Kumar, produces α-ketoesters or α-ketoamides, whereas α-ketoimines could not be synthesized via this method.26,27) Although Du and Zhao and colleagues developed an efficient synthetic method for α-ketoimines entailing the oxidative decyanation of β-imino nitriles using molecular oxygen and a base, the direct oxidation of two C–H bonds to generate the carbonyl group would be a more attractive alternative in view of atom economy and synthetic aspects.28) In the past decade, much effort has been focused on the benzylic oxygenation of 2-benzylpyridine using molecular oxygen,29–34) and in some cases, tautomerization followed by oxidation of the resulting enamine has been proposed as the reaction mechanism.30,34) Inspired by the oxidation of enamines and our previous research on the hydroxylation of α-imino radicals,35,36) herein we report the direct synthesis of 1-imino-2,3-dicarbonyl compounds via the copper(II)-catalyzed C–H aerobic oxidation of β-(alkoxy)imino carbonyl compounds. Although the diverse reactivity of oximes has been investigated in depth,37–39) the chemistry of α-carbon in the oxime, or N-alkoxyenamines as a tautomer of oxime ethers, remains underdeveloped.
Initially, an E/Z mixture of methyl 3-((benzyloxy)imino)butanoate (1a) prepared via the condensation of methyl acetoacetate and O-benzylhydroxylamine, was utilized as a model substrate to examine the oxidation reaction conditions (Table 1). The reaction of 1a with Cu(OAc)2 (10 mol%) in MeCN under an air atmosphere at 100 °C for 1 h provided the target oxidized product 2a in 40% NMR yield along with 41% of unreacted 1a (entry 1). The survey of catalysts revealed that Cu(OAc)2 is a superior catalyst to the other catalysts such as CuCl2, CuCl, CuBr and CuI. Subsequent solvent screening revealed a substantial solvent effect on the product yield. N,N-Dimethylformamide (DMF) was found to be an efficient solvent, enabling the synthesis of 2a in 80% NMR yield, whereas a significant decrease in the reaction efficiency was observed in the cases of MeOH and AcOH (entries 2–4). Interstingly, a mixture of AcOH and MeCN (v/v = 5/1) was found to be the most effective solvent for the copper-catalyzed C–H oxidation, whereby 2a was formed in 90% NMR yield (entry 5). Moreover, the yield was improved further by utilizing O2 gas instead of air (entry 6). Reducing the amount of AcOH led to a decrease in the yield (entry 7). The reaction proceeded quantitatively in the presence of 5 mol% Cu(OAc)2, providing 2a in 99% NMR yield (92% isolated yield) (entry 8). Molecular oxygen was found to be essential because the desired product 2a was not obtained under an Ar atmosphere (entry 9).
 | ||||
|---|---|---|---|---|
| Entry | Cu(OAc)2 (mol%) | Solvent (v/v) | Oxidant | Yield (%)b) |
| 1 | 10 mol% | MeCN | air | 40c) |
| 2 | 10 mol% | DMF | air | 80 |
| 3 | 10 mol% | AcOH | air | 5%d) |
| 4 | 10 mol% | MeOH | air | trace |
| 5 | 10 mol% | AcOH/MeCN (5/1) | air | 90 |
| 6 | 10 mol% | AcOH/MeCN (5/1) | O2 | 99 (92)e) |
| 7 | 10 mol% | AcOH/MeCN (1/5) | O2 | 74 |
| 8 | 5 mol% | AcOH/MeCN (5/1) | O2 | 99 (92)e) |
| 9 | 5 mol% | AcOH/MeCN (5/1) | Ar | trace |
a) Reaction conditions: 1a (0.25 mmol), solvent (6.0 mL), room temperature, 1 h. b) Determined by 1H-NMR of the crude reaction mixture using dibromomethane as an internal standard. c) 41% of unreacted 1a was observed. d) 95% of unreacted 1a was observed. e) Isolated yields are in parentheses.
Having established the optimal reaction conditions, the substrate scope of the C–H oxidation reaction was evaluated. Initially, various β-(alkoxy)iminoesters were investigated (Chart 1). Variation of the alkoxy groups on the imine moiety afforded 2b and 2c. Although a relatively low yield (19%) was observed for phenoxyimine 2d because of the instability of substrate 1d under acidic conditions, the reaction using 10 mol% Cu(OAc)2 in DMF proceeded efficiently to give 2d in 63% yield. Ethyl, cyclopropyl, and acetate moieties substituted at the imino carbon of R2 were readily accommodated, producing the expected 3-(benzyloxy)imino-2-oxopropanoates 2e–g. Although the reactivity was reduced when aryls were introduced as R2, a longer reaction time or a higher catalyst loading resulted in acceptable product yields. 3-((Benzyloxy)imino)-3-arylpropanoates containing electron-donating or electron-withdrawing groups at the para, meta, or ortho positions of the benzene ring were converted to the corresponding imino ketoesters in moderate to high yields (2h–o). Notably, a large scale reaction was also feasible; thus, the reaction of 1i on a 2.5 mmol scale afforded 2i in 58% yield. Furthermore, ketones bearing naphthalene (2p) and heteroaryls (2q and 2r) were produced from the corresponding β-iminoesters using this method.
Next, the scope of β-(alkoxy)iminoamides was explored (Chart 2). The amide functional group did not affect the course of the reaction; thus, the copper-catalyzed C(sp3)–H oxidation reaction of β-imino-N,N-dimethylamide 3a formed the desired iminoketoamide 4a in good yield. Moreover, the reaction was also applicable to β-iminolactam 3b, affording oxidized lactam 4b in high yield.
The protocol was successfully applied to the oxygenation of β-iminoketones (Chart 3). β-Iminoketones 5a–d, prepared from symmetrical β-diketones, namely acetylacetone, dibenzoylmethane, 1,3-indandione, and asymmetrical benzoylacetone, respectively, were converted smoothly to the expected iminodiketones 6a–d in moderate to good yields.
Control experiments were conducted to elucidate the reaction pathway of the Cu-catalyzed C–H oxidation (Chart 4). The C–H oxidation of β-iminoester 1s bearing a tert-butyl group did not proceed under the optimized conditions even after 64 h, and 1s was completely recovered (Eq. 1). This result suggested that isomerization from the oxime to the enamine was a crucial step in the reaction, because the generation of enamine 1s’ is sterically inhibited. In addition, the reaction of β-ketoester 7 led to the formation of a complex mixture of compounds, suggesting that the present reaction system is not suitable for the oxidation of enols (Eq. 2). Finally, it was found that the carbonyl group was not essential for this reaction; thus, copper-catalyzed C–H oxidation of dioxime ether 8 provided the corresponding ketone 9 in good yield.
Based on the results of the above control experiments and previous reports,30,34) a plausible reaction pathway is proposed in Chart 5. Initially, AcOH-promoted isomerization of 1a catalyzed by Cu(OAc)2 provides enamine A. Subsequent oxidation by molecular oxygen generates copper peroxide B. Finally, the heterolytic dissociation of B through deprotonation produces product 2a and Cu(OAc)OH, which then reacts with AcOH to regenerate Cu(OAc)2.
We have developed a copper(II)-catalyzed oxidation of the C(sp3)-H bond of β-(alkoxy)iminocarbonyl compounds, providing an efficient strategy for constructing 1-imino-2,3-dicarbonyl compounds. The present reaction is characterized by simple operability, atom economy, environmental benignity, and broad substrate scope. A variety of β-imino-α-ketoesters, β-imino-α-ketoamides, and β-imino-α-diketones can be accessed via the developed protocol. Efforts to define the reaction pathway in detail and broaden the synthetic utility of the methodology are currently underway in our laboratory.
NMR spectra were recorded at 300 MHz/75 MHz (1H-NMR/13C-NMR) or 400 MHz/100 MHz (1H-NMR/13C-NMR) using Varian MERCURY plus 300 (300 MHz) or JEOL ECZ400S spectrometers. Chemical shifts (δ) are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, ddt = doublet of doublets of triplets, m = multiplet), coupling constants, and integration. IR spectra were recorded on a Perkin-Elmer SpectrumOne A spectrometer. The high resolution mass spectra (HRMS) were obtained using Thermo Fischer Scientific Exactive Orbitrap mass spectrometer by electrospray ionization (ESI) technique. Melting points (uncorrected) were determined on BÜCHI M-565. Preparative TLC separations (PTLC) were carried out on precoated silica gel plates (E. Merck 60F254). Flash column chromatography was performed using Kanto Chemical Co., Inc. (Tokyo, Japan) silica gel 60 N (spherical, neutral 40–50 µm). Medium-pressure column chromatography (MCC) was performed using Yamazene ULTRAPACK SI-40A. Unless otherwise stated, all of the reagents and solvents were used as received from the manufacturer. An oil bath was used as the heat source in all heating reaction conditions.
Preparation for β-(Alkoxy)imino Carbonyl Compounds (1a–s, 3a–b, 5a–d and 8)General Procedure ATo a solution of β-keto carbonyl compounds in MeOH were added O-alkylhydroxylamine hydrochloride and sodium acetate at room temperature. After being stirred for 1 h, the reaction mixture was diluted with H2O and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification by flash column chromatography or MCC (hexane : AcOEt = 5/1-10/1) afforded the corresponding oxime ethers.
Methyl (E/Z)-3-((O-Phenylmethoxy)imino)butanoate (1a)Following to the general procedure A using methyl acetoacetate (5.0 g, 43 mmol), O-benzylhydroxylamine hydrochloride (8.3 g, 52 mmol), sodium acetate (4.2 g, 52 mmol) and MeOH (50 mL), 1a (9.5 g, 99%) was obtained after purification by flash column chromatography; 1 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 2953, 1742 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 7.36–7.26 (m, 5H), 5.11 (s, 2/2H), 5.08 (s, 2/2H), 3.71 (s, 3/2H), 3.66 (s, 3/2H), 3.38 (s, 2/2H), 3.23 (s, 2/2H), 1.97 (s, 3/2H), 1.96 (s, 3/2H); 13C-NMR (75 MHz, CDCl3) δ: 170.0, 169.2, 151.8, 150.7, 137.82, 137.78, 128.25, 128.22, 127.9, 127.7, 127.64, 127.61, 75.6, 75.5, 52.04, 51.96, 41.1, 35.3, 20.6, 14.7; HRMS (ESI) m/z: [M + H]+ Calcd for C12H16O3N 222.1125; Found 222.1126.
Methyl (E/Z)-3-((Allyloxy)imino)butanoate (1b)Following to the general procedure A using methyl acetoacetate (5.0 g, 43 mmol), O-allylhydroxylamine hydrochloride (5.7 g, 52 mmol), sodium acetate (4.3 g, 52 mmol) and MeOH (50 mL), 1b (5.8 g, 79%) was obtained after purification by flash column chromatography; 2 : 3 mixture of geometric isomers as a pale yellow oil; IR (neat): 1743 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 6.06–5.89 (m, 1H), 5.32–5.17 (m, 2H), 4.59–4.53 (m, 2H), 3.72 (s, 9/5H), 3.70 (s, 6/5H), 3.37 (s, 4/5H), 3.23 (s, 6/5H), 1.98 (s, 6/5H), 1.95 (s, 9/5H); 13C-NMR (75 MHz, CDCl3) δ: 170.0, 169.2, 151.5, 150.4, 134.22, 134.17, 117.1, 116.9, 74.5, 74.3, 51.99, 51.96, 41.0, 35.1, 20.5, 14.5; HRMS (ESI) m/z: [M + H]+ Calcd for C8H14O3N 172.0968; Found 172.0970.
Methyl (E/Z)-3-(Methoxyimino)butanoate (1c)Following to the general procedure A using methyl acetoacetate (1.0 g, 8.6 mmol), O-methylhydroxylamine hydrochloride (0.862 g, 10.3 mmol), sodium acetate (0.847 g, 10.3 mmol) and MeOH (17.2 mL), 1c (1.25 g, 67%) was obtained after purification by flash column chromatography; 1 : 2 mixture of geometric isomers as a colorless oil; IR (neat): 1739 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 3.86 (s, 6/3H), 3.84 (s, 3/3H), 3.72 (s, 3/3H), 3.71 (s, 6/3H), 3.35 (s, 2/3H), 3.22 (s, 4/3H), 1.97 (s, 3/3H), 1.92 (s, 6/3H); 13C-NMR (100 MHz, CDCl3) δ: 170.1, 169.3, 151.3, 150.2, 61.5, 61.4, 52.1, 41.1, 34.9, 20.5, 14.4; HRMS (ESI) m/z: [M + H]+ Calcd for C6H12O3N 146.0812; Found 146.0812.
Methyl (E/Z)-3-(Phenoxyimino)butanoate (1d)Following to the general procedure A using methyl acetoacetate (1.0 g, 8.6 mmol), O-phenylhydroxylamine hydrochloride (1.5 g, 10.3 mmol), sodium acetate (0.85 g, 10.3 mmol) and MeOH (17.2 mL), 1d (1.42 g, 80%) was obtained after purification by MCC; 4 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 1740 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.31–7.27 (m, 2H), 7.18–7.16 (m, 2H), 7.03–6.99 (m, 1H), 3.75 (s, 12/5H), 3.72 (s, 3/5H), 3.55 (s, 2/5H), 3.38 (s, 8/5H), 2.14 (s, 12/5H), 2.12 (s, 3/5H); 13C-NMR (100 MHz, CDCl3) δ: 169.7, 168.8, 159.1, 158.9, 155.1, 154.0, 129.2, 122.1, 114.71, 114.66, 52.2, 41.1, 35.7, 20.6, 15.2; HRMS (ESI) m/z: [M + H]+ Calcd for C11H14O3N 208.0968; Found 208.0970.
Methyl (E/Z)-3-((Benzyloxy)imino)pentanoate (1e)Following to the general procedure A using methyl 3-oxopentanoate (0.50 g, 3.8 mmol), O-benzylhydroxylamine hydrochloride (0.74 g, 4.6 mmol), sodium acetate (0.38 g, 4.6 mmol) and MeOH (7.7 mL), 1e (0.75 g, 83%) was obtained after purification by flash column chromatography; 7 : 3 mixture of geometric isomers as a colorless oil; IR (neat): 2953, 1744 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.35–7.27 (m, 5H), 5.09 (s, 14/10H), 5.08 (s, 6/10H), 3.68 (s, 9/10H), 3.61 (s, 21/10H), 3.32 (s, 14/10H), 3.22 (s, 6/10H), 2.45 (q, J = 7.6 Hz, 6/10H), 2.30 (q, J = 7.6 Hz, 14/10H), 1.10 (t, J = 7.6 Hz, 21/10H), 1.05 (t, J = 7.6 Hz, 9/10H); 13C-NMR (100 MHz, CDCl3) δ: 170.1, 169.3, 156.4, 154.7, 137.9, 137.8, 128.2, 128.1, 127.79, 127.75, 127.6, 127.5, 75.6, 75.5, 52.0, 51.9, 39.0, 34.0, 28.1, 21.2, 10.5, 9.8; HRMS (ESI) m/z: [M + H]+ Calcd for C13H18O3N 236.1281; Found 236.1282.
Methyl (E/Z)-3-((Benzyloxy)imino)-3-cyclopropylpropanoate (1f)Following to the general procedure A using methyl 3-cyclopropyl-3-oxopropanoate (1.0 g, 7.03 mmol), O-benzylhydroxylamine hydrochloride (1.3 g, 8.44 mmol), sodium acetate (0.69 g, 8.44 mmol) and MeOH (10 mL), 1f (0.66 g, 38%) was obtained after purification by flash column chromatography; 10 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 1742 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 7.39–7.29 (m, 5H), 5.14 (s, 2H), 3.69 (s 3H), 2.92 (s, 2H), 2.40–2.30 (m, 1H), 0.89–0.68 (m, 4H); 13C-NMR (75 MHz, CDCl3) δ: 170.0, 155.4, 139.3, 137.9, 128.2, 127.9, 127.5, 75.8, 52.2, 35.8, 33.5, 9.8, 5.2; HRMS (ESI) m/z: [M + H]+ Calcd for C14H18O3N 248.1281; Found 248.1281. Some carbon signals are overlapped.
Dimethyl 3-((Benzyloxy)imino)pentanedioate (1g)Following to the general procedure A using 1,5-dimethyl 3-oxopentanedioate (0.50 g, 2.9 mmol), O-benzylhydroxylamine hydrochloride (0.55 g, 3.4 mmol), sodium acetate (0.28 g, 3.4 mmol) and MeOH (5.7 mL), 1g (0.79 g, 99%) was obtained as a single isomer after purification by flash column chromatography. The E/Z geometry was not determined; an colorless oil; IR (neat): 2955, 1743 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.35–7.28 (m, 5H), 5.11 (s, 2H), 3.68 (s, 3H), 3.63 (s, 3H), 3.53 (s, 2H), 3.40 (s, 2H); 13C-NMR (100 MHz, CDCl3) δ: 169.8, 168.9, 147.8, 137.3, 128.2, 127.8, 127.7, 75.9, 52.0, 51.9, 39.4, 33.6; HRMS (ESI) m/z: [M + H]+ Calcd for C14H18O5N 280.1180; Found 280.1177.
Methyl 3-((Benzyloxy)imino)-3-phenylpropanoate (1h)Following to the general procedure A using methyl 3-oxo-3-phenylpropanoate (1.78 g, 10.0 mmol), O-benzylhydroxylamine hydrochloride (1.9 g, 12.0 mmol), sodium acetate (0.98 g, 12.0 mmol) and MeOH (20.0 mL), 1h (1.6 g, 56%) was obtained as a single isomer after purification by flash column chromatography. The E/Z geometry was not determined; an colorless oil; IR (neat): 1741 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 7.66–7.61 (m, 2H) 7.41–7.30 (m, 8H), 5.27 (s, 2H), 3.80 (s, 2H), 3.63 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ: 169.2, 151.4, 137.6, 135.1, 129.4, 128.5, 128.3, 128.0, 127.8, 126.1, 76.5, 52.1, 33.1; HRMS (ESI) m/z: [M + H]+ Calcd for C17H18O3N 284.1281; Found 284.1283.
Methyl 3-((Benzyloxy)imino)-3-(4-methylphenyl)propanoate (1i)Following to the general procedure A using methyl 3-oxo-3-(p-tolyl)propanoate (3.3 g, 17.2 mmol), O-benzylhydroxylamine hydrochloride (3.3 g, 20.6 mmol), sodium acetate (1.7 g, 20.6 mmol) and MeOH (34.4 mL), 1i (3.5 g, 68%) was obtained as a single isomer after purification by MCC. The E/Z geometry was not determined; an colorless oil; IR (neat): 2952, 1740 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.54–7.52 (m, 2H), 7.45–7.33 (m, 5H), 7.18–7.16 (m, 2H), 5.25 (s, 2H), 3.78 (s, 2H), 3.62 (s, 3H), 2.35 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 169.4, 151.4, 139.5, 137.7, 132.4, 129.2, 128.3, 128.0, 127.8, 126.1, 76.4, 52.1, 33.1, 21.3; HRMS (ESI) m/z: [M + H]+ Calcd for C18H20O3N 298.1438; Found 298.1438.
Methyl 3-((Benzyloxy)imino)-3-(4-methoxyphenyl)propanoate (1j)Following to the general procedure A using methyl 3-(4-methoxyphenyl)-3-oxopropanoate (0.40 g, 1.92 mmol), O-benzylhydroxylamine hydrochloride (0.369 g, 2.31 mmol), sodium acetate (0.189 g, 2.31 mmol) and MeOH (20 mL), 1j (0.468 g, 78%) was obtained as a single isomer after purification by flash column chromatography. The E/Z geometry was not determined; an colorless oil; IR (neat): 1738 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.64–7.57 (m, 2H), 7.41–7.28 (m, 5H), 6.90–6.88 (m, 2H), 5.24 (s, 2H), 3.81 (s, 3H), 3.77 (s, 2H), 3.62 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 169.4, 160.6, 151.0, 137.7, 128.3, 128.0, 127.72, 127.66, 127.5, 113.9, 76.3, 55.3, 52.1, 33.1; HRMS (ESI) m/z: [M + H]+ Calcd for C18H20O4N 314.1387; Found 314.1388.
Methyl 3-((Benzyloxy)imino)-3-(4-bromophenyl)propanoate (1k)Following to the general procedure A using methyl 3-(4-bromophenyl)-3-oxopropanoate (0.40 g, 1.56 mmol), O-benzylhydroxylamine hydrochloride (0.30 g, 1.87 mmol), sodium acetate (0.15 g, 1.87 mmol) and MeOH (20 mL), 1k (553 mg, 98%) was obtained as a single isomer after purification by flash column chromatography. The E/Z geometry was not determined; an colorless oil; IR (neat): 1740 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.53–7.48 (m, 4H), 7.37–7.29 (m, 5H), 5.26 (s, 2H), 3.77 (s, 2H), 3.63 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 169.0, 150.5 137.4, 134.1, 131.7, 128.4, 128.0, 127.9, 127.7, 123.8, 76.7, 52.3, 32.8; HRMS (ESI) m/z: [M + H]+ Calcd for C17H17O3N79Br 362.0386; Found 362.0390.
Methyl (E/Z)-3-((Benzyloxy)imino)-3-(4-fluorophenyl)propanoate (1l)Following to the general procedure A using methyl 3-(4-fluorophenyl)-3-oxopropanoate (0.50 g, 2.6 mmol), O-benzylhydroxylamine hydrochloride (0.49 g, 3.1 mmol), sodium acetate (0.25 g, 3.1 mmol) and MeOH (5.1 mL), 1l (0.71 g, 92%) was obtained after purification by MCC; 9 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 1742 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.63–7.59 (m, 2H), 7.36–7.29 (m, 5H), 7.06–7.01 (m, 2H), 5.25 (s, 18/10H), 5.14 (s, 2/10H), 3.76 (s, 18/10H), 3.61 (s, 3H), 3.57 (s, 2/10H); 13C-NMR (100 MHz, CDCl3) δ: 169.9, 169.0, 163.4 (d, J = 248.1 Hz), 162.7 (d, J = 248.2 Hz), 150.4, 149.8, 137.6, 137.5, 131.3 (d, J = 3.8 Hz), 130.3 (d, J = 8.6 Hz), 128.3, 128.1, 128.01, 127.95, 127.8, 127.7, 115.5 (d, J = 21.1 Hz), 115.2 (d, J = 21.0 Hz), 76.5, 76.3, 52.14, 52.08, 40.8, 33.3; HRMS (ESI) m/z: [M + Na]+ Calcd for C17H16O3NFNa 324.1006; Found 324.1004. Some carbon signals are overlapped.
Ethyl (E/Z)-3-((Benzyloxy)imino)-3-(4-nitrophenyl)propanoate (1m)Following to the general procedure A using ethyl 3-(4-nitrophenyl)-3-oxopropanoate (0.70 g, 3.0 mmol), O-benzylhydroxylamine hydrochloride (0.56 g, 3.5 mmol), sodium acetate (0.29 g, 3.5 mmol) and EtOH (10 mL), 1m (1.0 g, 98%) was obtained after purification by flash column chromatography; 5 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 2983, 1737, 1520, 1347 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 8.24–8.22 (m, 2H), 7.82–7.80 (m, 10/6H), 7.64–7.62 (m, 2/6H), 7.42–7.38 (m, 5H), 5.31 (s, 10/6H), 5.15 (s, 2/6H), 4.11 (q, J = 7.2 Hz, 10/6H), 4.09 (q, J = 7.2 Hz, 2/6H), 3.82 (s, 10/6H), 3.61 (s, 2/6H), 1.172 (t, J = 7.2 Hz, 15/6H), 1.165 (t, J = 7.2 Hz, 3/6H),; 13C-NMR (100 MHz, CDCl3) δ: 169.0, 168.2, 149.8, 149.5, 148.1, 147.7, 141.3,139.2, 137.2, 137.0, 129.2, 128.4, 128.1, 127.9, 127.0, 123.7, 123.3, 77.2, 77.1, 61.4, 61.3, 40.7, 32.9, 14.0; HRMS (ESI) m/z: [M + H]+ Calcd for C18H19O5N2 343.1289; Found 343.1287. Some carbon signals are overlapped.
Methyl-3-((Benzyloxy)imino)-3-(2-methoxyphenyl)propanoate (1n)Following to the general procedure A using methyl 3-(2-methoxyphenyl)-3-oxopropanoate (2.7 g, 13 mmol), O-benzylhydroxylamine hydrochloride (2.5 g, 15.6 mmol), sodium acetate (1.3 g, 15.6 mmol) and MeOH (26 mL), 1n (2.88 g, 71%) was obtained as a single isomer after purification by flash column chromatography. The E/Z geometry was not determined; an colorless oil; IR (neat): 1737 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.45–7.30 (m, 7H), 6.96 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 5.24 (s, 2H), 3.79 (s, 3H), 3.78 (s, 2H), 3.59 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 169.5, 157.3, 152.7, 137.7, 130.7, 130.2, 128.2, 127.9, 127.7, 124.9, 120.8, 110.8, 76.2, 55.3, 51.8, 35.4; HRMS (ESI) m/z: [M + H]+ Calcd for C18H20O4N 314.1387; Found 314.1388.
Methyl (E/Z)-3-((Benzyloxy)imino)-3-(3-methoxyphenyl)propanoate (1o)Following to the general procedure A using methyl 3-(3-methoxyphenyl)-3-oxopropanoate (2.7 g, 13 mmol), O-benzylhydroxylamine hydrochloride (2.4 g, 15.6 mmol), sodium acetate (1.3 g, 15.6 mmol) and MeOH (26 mL), 1o (2.5 g, 63%) was obtained after purification by flash column chromatography; 9 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 1739 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.39–7.17 (m, 8H), 6.91–6.89 (m, 1H), 5.26 (s, 18/10H), 5.14 (s, 2/10H), 3.79 (s, 27/10H), 3.77 (s, 2H), 3.73 (s, 3/10H), 3.61 (s, 3/10H), 3.60 (s, 27/10H); 13C-NMR (100 MHz, CDCl3) δ: 169.9, 169.1, 159.6, 159.0, 151.2, 150.8, 137.7, 137.5, 136.5, 133.9, 129.4, 129.1, 128.2, 128.0, 127.9, 127.8, 127.7, 127.6, 120.1, 118.6, 115.2, 114.9, 113.7, 111.4, 76.5, 76.2, 55.2, 52.0, 40.9, 33.1; HRMS (ESI) m/z: [M + H]+ Calcd for C18H20O4N 314.1387; Found 314.1386.
Methyl 3-((Benzyloxy)imino)-3-(naphthalen-2-yl)propanoate (1p)Following to the general procedure A using methyl 3-(naphthalen-2-yl)-3-oxopropanoate (3.38 g, 14.8 mmol), O-benzylhydroxylamine hydrochloride (2.8 g, 17.8 mmol), sodium acetate (1.5 g, 17.8 mmol) and MeOH (30 mL), 1p (2.99 g, 61%) was obtained as a single isomer after purification by flash column chromatography. The E/Z geometry was not determined; an colorless oil; IR (neat): 1739 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.97 (m, 1H), 7.92–7.90 (m, 1H), 7.86–7.80 (m, 3H), 7.50–7.47 (m, 2H), 7.44–7.29 (m, 5H), 5.32 (s, 2H), 3.92 (s, 2H), 3.63 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 169.3, 151.3, 137.6, 133.7, 133.0, 132.6, 128.5, 128.3, 128.2, 128.0, 127.8, 127.6, 126.8, 126.4, 125.9, 123.5, 76.7, 52.2, 32.9; HRMS (ESI) m/z: [M + H]+ Calcd for C21H20O3N 334.1438; Found 334.1438.
Methyl (E/Z)-3-((Benzyloxy)imino)-3-(furan-2-yl)propanoate (1q)Following to the general procedure A using methyl 3-(furan-2-yl)-3-oxopropanoate (0.61 g, 3.65 mmol), O-benzylhydroxylamine hydrochloride (0.70 g, 4.38 mmol), sodium acetate (0.36 g, 4.38 mmol) and MeOH (7.3 mL), 1q (0.96 g, 96%) was obtained after purification by MCC; 5 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 2953, 1744 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.47–7.31 (m, 6H), 6.70–6.68 (m, 1H), 6.48 (dd, J = 3.6, 2.0 Hz, 1/6H), 6.45 (dd, J = 3.6, 2.0 Hz, 5/6H), 5.27 (s, 2/6H), 5.26 (s, 10/6H), 3.70 (s, 10/6H + 3/6H), 3.65 (s, 2/6H), 3.62 (s, 15/6H); 13C-NMR (100 MHz, CDCl3) δ: 170.3, 168.7, 149.0, 143.9, 142.6, 140.1, 137.3, 137.2, 128.4, 128.3, 128.0, 127.9, 118.3, 112.2, 111.6, 110.4, 76.8, 52.2, 37.3, 32.3; HRMS (ESI) m/z: [M + H]+ Calcd for C15H16O4N 274.1074; Found 274.1071. Some carbon signals are overlapped.
Methyl (E/Z)-3-((Benzyloxy)imino)-3-(thiophen-2-yl)propanoate (1r)Following to the general procedure A using methyl 3-oxo-3-(thiophen-2-yl)propanoate (1.84 g, 10 mmol), O-benzylhydroxylamine hydrochloride (1.9 g, 12 mmol), sodium acetate (0.98 g, 12 mmol) and MeOH (20 mL), 1r (2.42 g, 84%) was obtained after purification by MCC; 2 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 1742 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.49–7.48 (m, 1/3H), 7.45–7.42 (m, 2/3H), 7.40–7.24 (m, 5H + 1/3H), 7.19–7.17 (m, 2/3H), 7.04 (dd, J = 4.9, 4.2 Hz, 1/3H), 6.98 (dd, J = 5.1, 3.5 Hz, 2/3H), 5.33 (s, 2/3H), 5.21 (s, 4/3H), 3.75 (s, 4/3H), 3.69 (s, 2/3H), 3.66 (s, 3/3H), 3.60 (s, 6/3H); 13C-NMR (100 MHz, CDCl3) δ: 170.2, 168.7, 147.2, 144.1, 138.9, 137.3, 131.0, 129.3, 128.2, 128.1, 128.0, 127.8, 127.3, 127.0, 126.6, 125.6, 76.9, 76.6, 52.3, 52.2, 39.7, 33.3; HRMS (ESI) m/z: [M + H]+ Calcd for C15H16O3NS 290.0845; Found 290.0843. Some carbon signals are overlapped.
Methyl 3-((Benzyloxy)imino)-4,4-dimethylpentanoate (1s)Following to the general procedure A using methyl 4,4-dimethyl-3-oxopentanoate (0.50 g, 3.16 mmol), O-benzylhydroxylamine hydrochloride (0.60 g, 3.79 mmol), sodium acetate (0.31 g, 3.79 mmol) and MeOH (6.3 mL), 1s (0.83 g, 99%) was obtained as a single isomer after purification by MCC. The E/Z geometry was not determined; an colorless oil; IR (neat): 1745 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.33–7.25 (m, 5H), 5.07 (s, 2H), 3.55 (s, 3H), 3.24 (s, 2H), 1.14 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ: 169.8, 159.9, 137.9, 128.1, 127.9, 127.5, 75.6, 51.8, 36.9, 31.7, 27.3; HRMS (ESI) m/z: [M + H]+ Calcd for C15H22O3N 264.1594; Found 264.1592.
(E/Z)-3-((Benzyloxy)imino)-N,N-dimethylbutanamide (3a)Following to the general procedure A using N,N-dimethyl-3-oxobutanamide (1.0 g, 7.7 mmol), O-benzylhydroxylamine hydrochloride (1.5 g, 9.3 mmol), sodium acetate (0.76 g, 9.3 mmol) and MeOH (10 mL), 3a (1.8 g, 99%) was obtained after purification by flash column chromatography; 1 : 2 mixture of geometric isomers as a colorless oil; IR (neat): 1651 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.35–7.26 (m, 5H), 5.09 (s, 4/3H), 5.08 (s, 2/3H), 3.44 (s, 2/3H), 3.24 (s, 4/3H), 2.92 (s, 12/3H), 2.90 (s, 6/3H), 1.97 (s, 6/3H), 1.96 (s, 3/3H); 13C-NMR (100 MHz, CDCl3) δ: 168.6, 168.2, 153.3, 152.1, 138.1, 137.6, 128.20, 128.15, 128.0, 127.8, 127.7, 127.5, 75.5, 75.4, 41.3, 37.3, 35.4, 34.9, 20.1, 14.6; HRMS (ESI) m/z: [M + H]+ Calcd for C13H19O2N2 235.1441; Found 235.1441.
1-Benzyl-4-((benzyloxy)imino)piperidin-2-one (3b)Following to the general procedure A using 1-benzylpiperidine-2,4-dione (0.67 g, 3.22 mmol), O-benzylhydroxylamine hydrochloride (0.62 g, 3.86 mmol), sodium acetate (0.32 g, 3.86 mmol) and MeOH (6.4 mL), 3b (0.83 g, 83%) was obtained as a single isomer after purification by MCC. The E/Z geometry was not determined; an colorless oil; IR (neat): 1655 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.38–7.24 (m, 10H), 5.08 (s, 2H), 4.64 (s, 2H), 3.54 (s, 2H), 3.32 (t, J = 6.0 Hz, 2H), 2.53 (t, J = 6.0 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ: 166.6, 152.6, 137.6, 136.5, 128.7, 128.4, 128.1, 127.92, 127.86, 127.7, 75.8, 50.3, 44.5, 33.3, 29.0; HRMS (ESI) m/z: [M + H]+ Calcd for C19H21O2N2 309.1598; Found 309.1597.
Procedure for Preparation of 5a and 8Following to the general procedure A using pentane-2,4-dione (1.0 g, 10 mmol), O-benzylhydroxylamine hydrochloride (2.4 g, 1.5 mmol), sodium acetate (1.2 g, 1.5 mmol) and MeOH (10 mL), 5a (0.45 g, 22%) and 8 (2.07 g, 67%) were obtained after purification by flash column chromatography.
(E/Z)-4-((Benzyloxy)imino)pentan-2-one (5a)2 : 3 mixture of geometric isomers; an colorless oil; IR (neat): 1721 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 7.38–7.27 (m, 5H), 5.11 (s, 6/5H), 5.07 (s, 4/5H), 3.43 (s, 4/5H), 3.29 (s, 6/5H), 2.15 (s, 9/5H), 2.14 (s, 6/5H), 1.94 (s, 6/5H), 1.92 (s, 9/5H); 13C-NMR (75 MHz, CDCl3) δ: 204.7, 203.1, 152.7, 151.7, 137.9, 137.6, 128.29, 128.25, 128.0, 127.8, 127.7, 127.6, 75.6, 75.5, 50.4, 44.8, 30.0, 29.5, 21.1, 15.0; HRMS (ESI) m/z: [M + H]+ Calcd for C12H16O2N 206.1176; Found 206.1176.
Pentane-2,4-dione O,O-Dibenzyl Dioxime (8)1 : 2 : 3 mixture of geometric isomers as a colorless oil; IR (neat): 2941, 1455, 1368 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 7.36–7.28 (m, 10H), 5.10–5.05 (m, 2H), 3.38 (s, 2/6H), 3.28 (s, 4/6H), 3.00 (s, 6/6H), 1.83 (s, 6/6H + 12/6H), 1.79 (s, 18/6H); 13C-NMR (75 MHz, CDCl3) δ: 170.2, 168.7, 147.2, 144.1, 138.9, 137.3, 131.0, 129.3, 128.2, 128.1, 128.0, 127.8, 127.3, 127.0, 126.6, 125.6, 76.9, 76.6, 52.3, 52.2, 39.7, 33.3; HRMS (ESI) m/z: [M + H]+ Calcd for C19H23O2N2 311.1754; Found 311.1752. Some carbon signals are overlapped.
3-(Benzyloxy)imino-1,3-diphenylpropan-1-one (5b)Following to the general procedure A using 1,3-diphenylpropane-1,3-dione (1.0 g, 4.5 mmol), O-benzylhydroxylamine hydrochloride (1.1 g, 6.8 mmol), sodium acetate (0.56 g, 6.5 mmol) and MeOH (10 mL), 5b was obtained as a single isomer after purification by flash column chromatography. The E/Z geometry was not determined; an colorless oil; IR (neat): 1688 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 7.98–7.95 (m, 2H), 7.65–7.62 (m, 2H), 7.59–7.53 (m, 1H), 7.44–7.28 (m, 10H), 5.23 (s, 2H), 4.44 (s, 2H); 13C-NMR (75 MHz, CDCl3) δ: 194.8, 153.0, 137.5, 136.4, 135.5, 133.3, 129.3, 128.6, 128.5, 128.3, 128.1, 127.8, 126.4, 76.5, 38.0; HRMS (ESI) m/z: [M + H]+ Calcd for C22H20O2N 330.1489; Found 330.1488. Some carbon signals are overlapped.
((Benzyloxy)imino)-2,3-dihydro-1H-inden-1-one (5c)Following to the general procedure A using 1,3-indandione (1.0 g, 6.84 mmol), O-benzylhydroxylamine hydrochloride (1.09 g, 6.84 mmol), sodium acetate (0.56 g, 6.84 mmol) and MeOH (27.4 mL), 5c (0.197 g, 8%) was obtained as a single isomer after purification by MCC; The E/Z geometry was not determined; colorless crystals; mp 110–120 °C (hexane-AcOEt); IR (neat): 1726 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.93 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 7.1 Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.43–7.32 (m, 5H), 5.28 (s, 2H), 3.40 (s, 2H); 13C-NMR (100 MHz, CDCl3) δ: 198.9, 152.6, 144.8, 138.5, 137.4, 135.1, 130.9, 128.4, 128.2, 128.0, 123.5, 122.0, 76.9, 37.6; HRMS (ESI) m/z: [M + H]+ Calcd for C16H14O2N 252.1019; Found 252.1020.
3-((Benzyloxy)imino)-1-phenylbutan-1-one (5d)Following to the general procedure A using 1-phenylbutane-1,3-dione (1.0 g, 6.17 mmol), O-benzylhydroxylamine hydrochloride (0.98 g, 6.17 mmol), sodium acetate (0.51 g, 6.17 mmol) and MeOH (12.3 mL), 5d (0.53 g, 32%) was obtained as a single isomer after purification by MCC; The E/Z geometry was not determined; colorless crystals; mp 68–71 °C (hexane-AcOEt); IR (neat): 2253, 1685 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.98–7.96 (m, 2H), 7.59–7.55 (m, 1H), 7.46–7.42 (m, 2H), 7.36–7.29 (m, 5H), 5.12 (s, 2H), 3.86 (s, 2H), 1.97 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 196.0, 153.3, 138.1, 136.3, 133.4, 128.6, 128.4, 128.3, 127.9, 127.6, 75.6, 46.0, 15.0; HRMS (ESI) m/z: [M + H]+ Calcd for C17H18O2N 268.1332; Found 268.1331.
Copper-Catalyzed Aerobic Oxidation of β-(Alkoxy)imino Carbonyl CompoundsGeneral Procedure BTo a solution of β-(alkoxy)imino carbonyl compounds in acetic acid and MeCN was added Cu(OAc)2 at room temperature. After being stirred at 100 °C under O2, the reaction mixture was diluted with H2O and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification by flash column chromatography on SiO2 or PTLC (hexane : AcOEt = 5/1–10/1) afforded the corresponding 1-imino-2,3-dicarbonyls.
Methyl 3-((Benzyloxy)imino)-2-oxobutanoate (2a)Following to the general procedure B using 1a (55.3 mg, 0.25 mmol), Cu(OAc)2 (2.3 mg, 0.0125 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 1 h, 2a (54.0 mg, 92%) was obtained as a single isomer after purification by flash column chromatography; The E/Z geometry was not determined; an colorless oil; IR (neat): 1749, 1701 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 7.35–7.31 (m, 5H), 5.28 (s, 2H), 3.85 (s, 3H), 1.98 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ: 185.5, 164.6, 153.4, 135.7, 128.6, 128.4, 128.3, 78.4, 52.2, 8.2; HRMS (ESI) m/z: [M + H]+ Calcd for C12H14O4N 236.0917; Found 236.0919.
Methyl 3-((Allyloxy)imino)-2-oxobutanoate (2b)Following to the general procedure B using 1b (42.8 mg, 0.25 mmol), Cu(OAc)2 (2.3 mg, 0.0125 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 1 h, 2b (28.4 mg, 61%) was obtained as a single isomer after purification by PTLC; The E/Z geometry was not determined; an colorless oil; IR (neat): 1751, 1702 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 6.00 (ddt, J = 17.0, 10.0, 6.0 Hz, 1H), 5.37–5.27 (m, 2H), 4.79 (d, J = 6.0 Hz, 2H), 3.88 (s, 3H), 2.00 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ: 185.8, 164.8, 153.5, 132.5, 119.2, 77.4, 52.4, 8.4; HRMS (ESI) m/z: [M + H]+ Calcd for C8H12O4N 186.0761; Found 186.0763.
Methyl 3-(Methoxyimino)-2-oxobutanoate (2c)Following to the general procedure B using 1c (36.3 mg, 0.25 mmol), Cu(OAc)2 (2.3 mg, 0.0125 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 1 h, 2c (18.3 mg, 46%) was obtained as a single isomer after purification by flash column chromatography; The E/Z geometry was not determined; an colorless oil; IR (neat): 1750, 1700 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 4.11 (s, 3H), 3.90 (s, 3H), 1.98 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 185.7, 164.8, 153.3, 64.1, 52.5, 8.3; HRMS (ESI) m/z: [M + H]+ Calcd for C6H10O4N 160.0604; Found 160.0605.
Methyl 2-Oxo-3-(phenoxyimino)butanoate (2d)Following to the general procedure B using 1d (51.8 mg, 0.25 mmol), Cu(OAc)2 (4.5 mg, 0.025 mmol) and DMF (5.0 mL) for 3 h, 2d (35.0 mg, 63%) was obtained as a single isomer after purification by flash column chromatography; The E/Z geometry was not determined; an colorless oil; IR (neat): 1750, 1706 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.38–7.33 (m, 2H), 7.38–7.33 (m, 2H), 7.14 (t, J = 7.5 Hz, 1H), 3.94 (s, 3H), 2.22 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 185.4, 164.5, 158.6, 155.4, 129.5, 124.1, 115.0, 52.7, 9.1; HRMS (ESI) m/z: [M + H]+ Calcd for C11H12O4N 222.0761; Found 222.0761.
Methyl 3-((Benzyloxy)imino)-2-oxopentanoate (2e)Following to the general procedure B using 1e (58.8 mg, 0.25 mmol), Cu(OAc)2 (2.3 mg, 0.0125 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 1 h, 2e (38.9 mg, 63%) was obtained as a single isomer after purification by PTLC. The E/Z geometry was not determined; an colorless oil; IR (neat): 2943, 1748, 1698 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.40–7.31 (m, 5H), 5.29 (s, 2H), 3.86 (s, 3H), 2.52 (q, J = 7.6 Hz, 2H), 1.04 (t, J = 7.6 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ: 185.6, 164.9, 158.0, 135.9, 128.6, 128.5, 78.6, 52.4, 16.4, 10.0; HRMS (ESI) m/z: [M + H]+ Calcd for C13H16O4N 250.1074; Found 250.1074. Some carbon signals are overlapped.
Methyl (E/Z)-3-((Benzyloxy)imino)-3-cyclopropyl-2-oxopropanoate (2f)Following to the general procedure B using 1f (50.0 mg, 0.202 mmol), Cu(OAc)2 (1.8 mg, 0.0101 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 1 h, 2f (41.1 mg, 78%) was obtained after purification by PTLC; 2 : 3 mixture of geometric isomers as a colorless oil; IR (neat): 1751, 1703 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 7.41–7.27 (m, 5H), 5.24 (s, 4/5H), 5.02 (s, 6/5H), 3.81 (s, 6/5H), 3.63 (s, 9/5H), 2.12–2.05 (m, 2/5H), 1.77–1.70 (m, 3/5H), 1.46–1.41 (m, 1H), 0.92–0.86 (m, 3H); 13C-NMR (75 MHz, CDCl3) δ: 185.7, 164.7, 155.4, 135.9, 128.7, 128.48, 128.45, 78.6, 52.2, 7.7, 6.3; HRMS (ESI) m/z: [M + H]+ Calcd for C14H16O4N 262.1074; Found 262.1074.
Dimethyl 3-((Benzyloxy)imino)-2-oxopentanedioate (2g)Following to the general procedure B using 1g (69.8 mg, 0.25 mmol), Cu(OAc)2 (2.3 mg, 0.0125 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 1 h, 2g (39.2 mg, 54%) was obtained as a single isomer after purification by PTLC. The E/Z geometry was not determined; an colorless oil; IR (neat): 2956, 1749, 1702 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.40–7.32 (m, 5H), 5.34 (s, 2H), 3.89 (s, 3H), 3.61 (s, 3H), 3.57 (s, 2H); 13C-NMR (100 MHz, CDCl3) δ: 184.4, 167.5, 164.0, 149.9, 135.3, 128.7, 128.6, 128.5, 79.2, 52.6, 52.4, 28.6; HRMS (ESI) m/z: [M + H]+ Calcd for C14H16O6N 294.0972; Found 294.0972.
Methyl (E/Z)-3-((Benzyloxy)imino)-2-oxo-3-phenylpropanoate (2h)Following to the general procedure B using 1h (50.0 mg, 0.18 mmol), Cu(OAc)2 (1.6 mg, 0.0088 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 14 h, 2h (28.8 mg, 54%) was obtained after purification by PTLC; 4 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 1747, 1704 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 7.57–7.31 (m, 10H), 5.33 (s, 8/5H), 5.23 (s, 2/5H), 3.89 (s, 12/5H), 3.70 (s, 3/5H); 13C-NMR (75 MHz, CDCl3) δ: 185.4, 165.0, 152.1, 135.7, 136.1, 130.7, 130.2, 129.6, 129.4, 128.8, 128.7, 128.6, 128.5, 128.4, 128.34, 128.30, 128.0, 126.6, 126.1, 79.2, 77.9, 53.1, 52.4; HRMS (ESI) m/z: [M + H]+ Calcd for C17H16O4N 298.1074; Found 298.1075. Some carbon signals are overlapped.
Methyl (E/Z)-3-((Benzyloxy)imino)-2-oxo-3-(4-methylphenyl)propanoate (2i)Following to the general procedure B using 1i (74.3 mg, 0.25 mmol), Cu(OAc)2 (2.3 mg, 0.0125 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 48 h, 2i (42.9 mg, 55%) was obtained after purification by flash column chromatography; 6 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 2954, 1748, 1705 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.45–7.32 (m, 7H), 7.24–7.18 (m, 2H), 5.31 (s, 12/7H), 5.21 (s, 2/7H), 3.88 (s, 18/7H), 3.69 (s, 3/7H), 2.37 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 185.8, 185.6, 165.1, 160.3, 154.9, 152.2, 141.1, 140.6, 136.2, 135.8, 129.6, 129.4, 128.8, 128.7, 128.6, 128.5, 128.34, 128.27, 126.8, 126.6, 123.3, 79.1, 77.8, 53.1, 52 .4, 21.5, 21.4; HRMS (ESI) m/z: [M + H]+ Calcd for C18H18O4N 312.1230; Found 312.1229. Some carbon signals are overlapped.
Procedure for Large-Scale Reaction of 1iTo a solution of 1i in acetic acid (5.0 mL) and MeCN (1.0 mL) was added Cu(OAc)2 (22.7 mg, 0.125 mmol) at room temperature. After being stirred at 100 °C under O2 for 24 h, the reaction mixture was diluted with H2O and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification by MCC afforded 2i (454.1 mg, 58%).
Methyl (E/Z)-3-((Benzyloxy)imino)-3-(4-methoxyphenyl)-2-oxopropanoate (2j)Following to the general procedure B using 1j (50.0 mg, 0.16 mmol) and Cu(OAc)2 (1.4 mg, 0.0080 mmol) and acetic acid (5.0 mL) and MeCN (1.0 mL) for 14 h, 2j (42.6 mg, 81%) was obtained after purification by PTLC; 4 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 1745, 1706 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.55–7.48 (m, 2H), 7.40–7.29 (m, 5H), 6.98–6.88 (m, 2H), 5.32 (s, 8/5H), 5.19 (s, 2/5H), 3.88 (s, 12/5H), 3.82 (s, 3H), 3.69 (s, 3/5H); 13C-NMR (100 MHz, CDCl3) δ: 185.9, 165.2, 161.6, 160.9, 154.6, 151.4, 136.3, 135.9, 131.4, 128.7, 128.6, 128.5, 128.4, 128.33, 128.26, 122.1, 118.4, 114.3, 113.5, 79.1, 77.7, 55.4, 55.3, 53.1, 52.4; HRMS (ESI) m/z: [M + H]+ Calcd for C18H18O5N 328.1180; Found 328.1180. Some carbon signals are overlapped.
Methyl (E/Z)-3-((Benzyloxy)imino)-3-(4-bromophenyl)-2-oxopropanoate (2k)Following to the general procedure B using 1k (50.0 mg, 0.138 mmol), Cu(OAc)2 (1.3 mg, 0.0069 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 24 h, 2k (38.1 mg, 74%) was obtained after purification by PTLC; 2 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 1746, 1703 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.57–7.51 (m, 2H), 7.44–7.32 (m, 7H), 5.33 (s, 4/3H), 5.22 (s, 2/3H), 3.90 (s, 6/3H), 3.69 (s, 3/3H); 13C-NMR (100 MHz, CDCl3) δ: 185.2, 185.1, 164.7, 160.4, 153.8, 151.2, 135.9, 135.5, 132.1, 131.4, 131.2, 128.80, 128.77, 128.6, 128.5, 128.44, 128.41, 128.1, 125.3, 124.9, 79.5, 78.2, 53.2, 52.6; HRMS (ESI) m/z: [M + H]+ Calcd for C17H15O4N79Br 376.0179; Found 376.0178. Some carbon signals are overlapped.
Methyl (E/Z)-3-((Benzyloxy)imino)-3-(4-fluorophenyl)-2-oxopropanoate (2l)Following to the general procedure B using 1l (75.3 mg, 0.25 mmol), Cu(OAc)2 (4.5 mg, 0.025 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 48 h, 2l (46.8 mg, 59%) was obtained after purification by flash column chromatography; 3 :1 mixture of geometric isomers as a colorless oil; IR (neat): 1748, 1706 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.57–7.50 (m, 2H), 7.41–7.32 (m, 5H), 7.14–7.06 (m, 2H), 5.33 (s, 6/4H), 5.21 (s, 2/4H), 3.90 (s, 9/4H), 3.70 (s, 3/4H); 13C-NMR (100 MHz, CDCl3) δ: 185.4, 164.9, 164.2 (d, J = 255.0 Hz), 163.5 (d, J = 250.0 Hz), 160.4, 153.7, 151.1, 136.0, 135.6, 131.9 (d, J = 8.6 Hz), 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 125.8, 122.1, 116.1 (d, J = 22.0 Hz), 115.3 (d, J = 22.0 Hz), 79.4, 78.0, 53.1, 52.5; HRMS (ESI) m/z: [M + H]+ Calcd for C17H15O4NF 316.0980; Found 316.0978. Some carbon signals are overlapped.
Ethyl (E/Z)-3-((Benzyloxy)imino)-3-(4-nitrophenyl)-2-oxopropanoate (2m)Following to the general procedure B using 1m (85.6 mg, 0.25 mmol), Cu(OAc)2 (4.6 mg, 0.025 mmol) and acetic acid (5.0 mL) and MeCN (1.0 mL) for 48 h, 2m (52.0 mg, 58%) was obtained after purification by flash column chromatography; 4 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 1744, 1704, 1524, 1349 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 8.28–8.23 (m, 2H), 7.75 (dt, J = 9.1, 2.1 Hz, 2/5H), 7.66–7.62 (m, 8/5H), 7.41–7.31 (m, 5H), 5.36 (s, 8/5H), 5.29 (s, 2/5H), 4.40 (q, J = 7.2 Hz, 8/5H), 4.20 (q, 2/5H), 1.37 (t, J = 7.2 Hz, 12/5H), 1.20 (t, J = 7.2 Hz, 3/5H); 13C-NMR (100 MHz, CDCl3) δ: 184.9, 184.6, 164.0, 160.0, 152.7, 150.5, 148.8, 148.4, 135.7, 135.5, 135.1, 132.3, 130.8, 128.9, 128.8, 128.70, 128.65, 128.57, 128.50, 127.6, 124.0, 123.2, 79.9, 78.8, 63.1, 62.4, 14.0, 13.7; HRMS (ESI) m/z: [M + H]+ Calcd for C18H17O6N2 357.1081; Found 357.1080.
Methyl 3-((Benzyloxy)imino)-3-(2-methoxyphenyl)-2-oxopropanoate (2n)Following to the general procedure B using 1n (78.3 mg, 0.25 mmol), Cu(OAc)2 (4.6 mg, 0.025 mmol) and acetic acid (5.0 mL) and MeCN (1.0 mL) for 24 h, 2n (66.3 mg, 80%) was obtained as a single isomer after purification by flash column chromatography. The E/Z geometry was not determined; an colorless oil; IR (neat): 1748, 1706 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.41–7.31 (m, 6H), 7.20–7.18 (m, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.30 (s, 2H), 3.89 (s, 3H), 3.71 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 184.5, 164.7, 156.8, 151.9, 136.1, 131.6, 130.3, 128.5, 128.4, 128.3, 120.3, 116.3, 111.2, 78.8, 55.6, 52.5; HRMS (ESI) m/z: [M + H]+ Calcd for C18H18O5N 328.1180; Found 328.1177.
Methyl (E/Z)-3-((Benzyloxy)imino)-3-(3-methoxyphenyl)-2-oxopropanoate (2o)Following to the general procedure B using 1o (78.3 mg, 0.25 mmol), Cu(OAc)2 (4.6 mg, 0.025 mmol) and acetic acid (5.0 mL) and MeCN (1.0 mL) for 24 h, 2o (76 mg, 93%) was obtained after purification by flash column chromatography; 4 : 1 mixture of geometric isomers as a colorless oil; IR (neat): 1749, 1706 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.41–7.32 (m, 6H), 7.14–6.96 (m, 3H), 5.32 (s, 8/5H), 5.23 (s, 2/5H), 3.89 (s, 12/5H), 3.82 (s, 3/5H), 3.77 (s, 12/5H), 3.70 (s, 3/5H); 13C-NMR (100 MHz, CDCl3) δ: 185.5, 185.3, 165.0, 160.2, 159.8, 159.1, 154.7, 152.1, 136.1, 135.7, 130.8, 129.9, 129.2, 128.7, 128.6, 128.53, 128.47, 128.35, 128.33, 127.3, 121.8, 119.4, 117.0, 116.2, 114.7, 111.3, 79.2, 78.0, 55.4, 55.3, 53.1, 52.5; HRMS (ESI) m/z: [M + H]+ Calcd for C18H18O5N 328.1180; Found 328.1179.
Methyl (E/Z)-3-((Benzyloxy)imino)-3-(naphthalen-2-yl)-2-oxopropanoate (2p)Following to the general procedure B using 1p (83.3 mg, 0.25 mmol), Cu(OAc)2 (4.5 mg, 0.025 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 24 h, 2p (43.9 mg, 52%) was obtained after purification by flash column chromatography; 5 : 2 mixture of geometric isomers as a pale yellow oil; IR (neat): 1747, 1710 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 8.00 (s, 1H), 7.89–7.81 (m, 4H), 7.56–7.48 (m, 2H), 7.40–7.31 (m, 5H), 5.36 (s, 10/7H), 5.27 (s, 4/7H), 3.92 (s, 15/7H), 3.72 (s, 6/7H); 13C-NMR (100 MHz, CDCl3) δ: 185.8, 185.4, 165.1, 155.0, 152.3, 136.2, 135.8, 134.2, 133.8, 132.8, 132.5, 130.1, 128.9, 128.8, 128.7, 128.6, 128.55, 128.49, 128.38, 128.34, 127.74, 127.67, 127.63, 127.50, 127.46, 126.8, 126.4, 125.9, 123.6, 122.8, 79.3, 78.1, 53.1, 52.5; HRMS (ESI) m/z: [M + H]+ Calcd for C21H18O4N 348.1230; Found 348.1232. Some carbon signals are overlapped.
Methyl 3-((Benzyloxy)imino)-3-(furan-2-yl)-2-oxopropanoate (2q)Following to the general procedure B using 1q (68.3 mg, 0.25 mmol), Cu(OAc)2 (4.5 mg, 0.025 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 24 h, 2q (29.2 mg, 41%) was obtained as a single isomer after purification by flash column chromatography. The E/Z geometry was not determined; an colorless oil; IR (neat): 1747, 1710 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.62–7.58 (m, 1H), 7.43–7.33 (m, 6H), 6.53–6.51 (m, 1H), 5.41 (s, 2H), 3.87 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 183.2, 164.1, 144.7, 141.9, 141.8, 135.7, 128.7, 128.6, 119.6, 111.6, 79.7, 52.6; HRMS (ESI) m/z: [M + H]+ Calcd for C15H14O5N 288.0867; Found 288.0868. Some carbon signals are overlapped.
Methyl 3-((Benzyloxy)imino)-2-oxo-3-(thiophen-2-yl)propanoate (2r)Following to the general procedure B using 1r (72.3 mg, 0.25 mmol), Cu(OAc)2 (4.5 mg, 0.025 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 24 h, 2r (20.7 mg, 29%) was obtained as a single isomer after purification by flash column chromatography. The E/Z geometry was not determined; an colorless oil; IR (neat): 1748, 1707 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 8.26 (dd, J = 4.0, 1.3 Hz, 1H), 7.59 (dd, J = 5.3, 1.1 Hz, 1H), 7.44–7.34 (m, 5H), 7.15 (dd, J = 5.0, 4.1 Hz, 1H), 5.48 (s, 2H), 3.87 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 185.2, 164.6, 144.8, 135.5, 133.0, 131.5, 128.8, 128.7, 128.6, 126.8, 126.3, 79.7, 52.5; HRMS (ESI) m/z: [M + H]+ Calcd for C15H14O4NS 304.0638; Found 304.0638.
3-((Benzyloxy)imino)-N,N-dimethyl-2-oxobutanamide (4a)Following to the general procedure B using 3a (50 mg, 0.213 mmol), Cu(OAc)2 (1.9 mg, 0.0107 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 1 h, 4a (41.4 mg, 78%) was obtained as a single isomer after purification by flash column chromatography. The E/Z geometry was not determined; an colorless oil; IR (neat): 1693, 1652 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 7.37–7.33 (m, 5H), 5.27 (s, 2H), 2.99 (s, 3H), 2.65 (s, 3H), 2.01 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ: 190.1, 167.0, 154.2, 136.3, 128.8, 128.4, 78.1, 36.6, 33.6, 8.5; HRMS (ESI) m/z: [M + H]+ Calcd for C13H17O3N2 249.1234; Found 249.1233. Some carbon signals are overlapped.
1-Benzyl-4-((benzyloxy)imino)piperidine-2,3-dione (4b)Following to the general procedure B using 4a (77.1 mg, 0.25 mmol), Cu(OAc)2 (2.3 mg, 0.0125 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 2 h, 4b (67.5 mg, 84%) was obtained as a single isomer after purification by flash column chromatography. The E/Z geometry was not determined; an colorless oil; IR (neat): 1721, 1659 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.40–7.29 (m, 10H), 5.38 (s, 2H), 4.74 (s, 2H), 3.44 (t, J = 6.0 Hz, 2H), 3.00 (t, J = 6.0 Hz, 2H); 13C-NMR (75 MHz, CDCl3) δ: 178.1, 158.8, 150.3, 135.6, 135.2, 128.9, 128.7, 128.63, 128.57, 128.4, 128.2, 78.9, 51.1, 42.0, 24.5; HRMS (ESI) m/z: [M + H]+ Calcd for C19H19O3N2 323.1390; Found 323.1389.
((Benzyloxy)imino)pentane-2,3-dione (6a)Following to the general procedure B using 5a (50.0 mg, 0.244 mmol), Cu(OAc)2 (2.2 mg, 0.0122 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 1 h, 6a (39.7 mg, 74%) was obtained as a single isomer after purification by PTLC. The E/Z geometry was not determined; an colorless oil; IR (neat): 1722, 1691 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 7.38–7.36 (m, 5H), 5.28 (s, 2H), 2.32 (s, 3H), 1.99 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ: 202.0, 192.7, 153.8, 135.9, 128.6, 128.53, 128.51, 78.4, 27.1, 8.6; HRMS (ESI) m/z: [M + H]+ Calcd for C12H14O3N 220.0968; Found 220.0968.
3-((Benzyloxy)imino)-1,3-diphenylpropane-1,2-dione (6b)Following to the general procedure B using 5b (50.0 mg, 0.152 mmol), Cu(OAc)2 (1.4 mg, 0.0076 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 3 h, 6b (37.4 mg, 72%) was obtained as a single isomer after purification by PTLC. The E/Z geometry was not determined; an colorless oil; IR (neat): 1698, 1678 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 7.88–7.85 (m, 2H), 7.69–7.44 (m, 8H), 7.27–7.08 (m, 5H), 5.15 (s, 2H); 13C-NMR (75 MHz, CDCl3) δ: 194.7, 193.1, 153.7, 135.6, 134.3, 133.3, 130.3, 129.6, 129.3, 128.85, 128.78, 128.41, 128.36, 128.1, 79.1; HRMS (ESI) m/z: [M + H]+ Calcd for C22H18O3N 344.1281; Found 344.1282. Some carbon signals are overlapped.
3-((Benzyloxy)imino)-1H-indene-1,2(3H)-dione (6c)Following to the general procedure B using 5c (62.8 mg, 0.25 mmol), Cu(OAc)2 (2.3 mg, 0.0125 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 14 h, 6c (32.4 mg, 49%) was obtained as a single isomer after purification by PTLC. The E/Z geometry was not determined; an colorless oil; IR (neat): 1732, 1604 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 8.44 (d, J = 7.8 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.84–7.80 (m, 1H), 7.71–7.68 (m, 1H), 7.48–7.36 (m, 5H), 5.55 (s, 2H); 13C-NMR (100 MHz, CDCl3) δ: 186.7, 185.0, 143.9, 139.3, 137.5, 135.7, 134.3, 132.6, 129.4, 128.8, 128.75, 128.70, 125.1, 80.0; HRMS (ESI) m/z: [M + H]+ Calcd for C16H12O3N 266.0812; Found 266.0813.
3-((Benzyloxy)imino)-1-phenylbutane-1,2-dione (6d)Following to the general procedure B using 5d (66.8 mg, 0.25 mmol), Cu(OAc)2 (2.3 mg, 0.0125 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 1 h, 6d (36.8 mg, 52%) was obtained as a single isomer after purification by PTLC. The E/Z geometry was not determined; an colorless oil; IR (neat): 1692 (br) cm−1; 1H-NMR (400 MHz, CDCl3) δ: 7.83–7.79 (m, 2H), 7.66–7.60 (m, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.29–7.20 (m, 3H), 7.15 (d, J = 8.2 Hz, 2H), 5.15 (s, 2H), 2.09 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ: 194.9, 193.5, 155.2, 135.7, 134.3, 133.1, 129.4, 128.8, 128.4, 128.4, 78.5, 8.7; HRMS (ESI) m/z: [M + H]+ Calcd for C17H16O3N 282.1125; Found 282.1126. Some carbon signals are overlapped.
2,4-Bis((benzyloxy)imino)pentane-3-one (9)Following to the general procedure B using 8 (50.0 mg, 0.16 mmol), Cu(OAc)2 (1.5 mg, 0.0081 mmol), acetic acid (5.0 mL) and MeCN (1.0 mL) for 1 h, 9 (32.2 mg, 62%) was obtained as a single isomer after purification by PTLC. The E/Z geometry was not determined; an colorless oil; IR (neat): 1670 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 7.37–7.29 (m, 10H), 5.02 (s, 4H), 2.03 (s, 6H); 13C-NMR (75 MHz, CDCl3) δ: 188.7, 155.0, 136.9, 128.2, 128.0, 127.8, 127.2, 76.4, 11.1; HRMS (ESI) m/z: [M + H]+ Calcd for C19H21O3N2 325.1547; Found 325.1547. Some carbon signals are overlapped.
This work was supported by Grants-in-Aid for JSPS KAKENHI (JP21K06465, M.U.; JP19K23815, M.Y.; JP19K05467, N.T.).
The authors declare no conflict of interest.
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