Formylation Reaction of Amines Using N-Formylcarbazole

Abstract

Formamides are useful starting materials for pharmaceutical syntheses. Although various synthetic methods have been documented in this regard, the use of N-formylcarbazole as a formylation reagent for amines has not yet been reported. We report here the first examples of the use of N-formylcarbazole for the formylation of amines. The characteristic reactivity of N-formylcarbazole enables the selective formylation of sterically less hindered aliphatic primary and secondary amines. In contrast, sterically bulkier amines and weakly nucleophilic amines such as anilines are less reactive under the reaction conditions.

Introduction

N-Formamide derivatives are important substrates for the preparation of bioactive molecules and pharmaceuticals.^1–3) In nature, various N-formamides have been isolated as biologically active natural products and drugs such as cyclotheonamide A,⁴⁾ N-formylmethionine,⁵⁾ hadacidin,⁶⁾ orlistat,⁷⁾ an unnamed terphenyl formamide,⁸⁾ and malonganenone K⁹⁾ (Fig. 1, see also Supplementary Materials, Charts S1 and S2).¹⁰⁾

Fig. 1. Representative N-Formyl Biologically Active Compounds and Natural Products

N-Formylation reactions have been extensively researched due to the biological interests of N-formamides and their synthetic utility.^1–14) Most of the formylation reagents reported to date are in liquid or gaseous form^11–14) (Chart 1). Some of the liquid reagents must be prepared in situ and could not be stored for a long time since they are sensitive to water. To overcome this practical inconvenience, stable solid N-formylation reagents such as 4-formyl-2-methyl-1,3,4-thiadiazoline-5-thione (3a), N-formylbenzotriazole (3b), N-(diethylcarbamoyl)-N-methoxyformamide (3c), and N-formylsaccharin (3d) have been developed^15–18) (Chart 2). In addition to their practical benefits, these solid reagents show interesting reactivity and selectivity in N-formylation. The selectivity profiles of 3a–3d in N-formylation are summarized in Chart 2((A)–(E)). All the primary and secondary amines underwent smooth N-formylation with the reagents at room temperature in short reaction periods to give the corresponding N-formamides in good-to-high yields (A and B). Sterically hindered primary amines were formylated with 3b and 3c at elevated temperatures and prolonged reaction periods (C). In contrast, N-formylsaccharin (3d) reacted with sterically hindered primary amines at room temperature, probably because of the better leaving group ability of the N-acylsulfonamide moiety than that in the others. N-Formylation of amino alcohols occurred at the amino group without O-formylation of the hydroxy group in a functional-group-selective manner (D). Amines with less nucleophilic amino groups, such as arylamines, were formylated with 3a, 3c, and 3d under mild conditions (E). The formylation using 3b required harsher conditions. These results indicate that the reactivity depends on the steric and electronic nature of the leaving groups in the reagents.

Chart 1. Representative N-Formylating Reagents

Chart 2. Reactivity of Solid Formylation Reagents 3a–3d

We recently developed N-acylcarbazoles (NACs) 4a and 4b as mild benchtop-stable solid N-acylation reagents¹⁹⁾ (Chart 3). It is worth noting that NACs 4a and 4b reacted slowly with sterically less hindered amines at 30 °C for 24 h in tetrahydrofuran (THF) (1 M) to give amides 2 in high yields. Amino alcohols underwent N-selective acylation with 4a and 4b to afford the corresponding amides 2. On the other hand, 4a and 4b were found to be inert toward sterically hindered primary and secondary amines as well as less nucleophilic aromatic amines, resulting in no reactions or poor conversion. In conjunction with the potential synthetic utility of NAC for the selective acylation of amines, we were interested in the reactivity and potency of N-formylcarbazole (NFC, 4c)^20,21) for N-formylation. NFC 4c was previously reported by Dixon and Lucas as a C-formylation reagent and could be easily prepared by the N-formylation of carbazole (5) using HCO₂H on a 50 g scale.²⁰⁾ However, the use of 4c in N-formylation has not been reported in the literatures. Herein, we would like to report the unique reactivity of 4c in N-formylation for the first time.

Chart 3. Selective Acylations with N-Acylcarbazoles (NACs) 4a–4c

Results and Discussion

The potential synthetic utility of NFC 4c in N-formylation was preliminarily tested using amines 1a–1c (Chart 4). NFC 4c was prepared according to the literature.²⁰⁾ N-Formylation with 4c was performed under the same conditions as those for N-acylation with NFCs 4a and 4b.¹⁹⁾ Benzylamine 1a reacted with 4c (1.2 equivalent (equiv.)) at room temperature in THF (1 M) to give 2a in 88% yield (eq. 1). At lower concentrations (<1 M), the product yield decreased. Secondary amine 1b also underwent N-formylation, affording 2b in 75% yield (eq. 2). In contrast, 4-methylaniline 1c was inert to 4c even at an elevated temperature (eq. 3). These results reveal the characteristic reactivity of NFC 4c, which preferentially reacts with nucleophilic amines.

Chart 4. N-Formylation of Amines 1a–1c with 4c

Based on the above results, the substrate scope of amines 1d–1t was investigated (Chart 5). NFC 4c was allowed to react with the sterically less hindered amino group of diamines 1d, 1e, and 1f at room temperature (condition A) to give monoformylated products 2d (isolated as an N-tert-butoxycarbonyl (Boc) form), 2e, and 2f in 87, 89, and 100% yields, respectively. At an elevated temperature (condition B), 1d was converted to diformamide 2d′ in 91% yield. On the other hand, 1e and 1f did not undergo di-N-formylation under the condition B. Amino alcohol 1g was selectively transformed to the corresponding N-formamide 2g in 94% yield under the condition A. Amino alcohols 1h, 1i, and 1j were also selectively formylated under the condition A, followed by silyl protection, affording formamide derivatives 2h, 2i, and 2j in 94, 86, and 91% yields, respectively. The silyl protection was required for the isolation of the highly polar N-(3-hydroxypropyl)formamide, N-(5-hydroxypentyl)formamide, and N-(2-hydroxyethyl)-N-methylformamide from 1h, 1i, and 1j. Hydroxylamine 1k was formylated with 4c to give 2k in 74% yield under the condition A. Phenylhydrazine 1l underwent selective N-formylation at the more nucleophilic and sterically less hindered amino group to provide monoformamide 2l in 83% yield. In contrast, no formylation was observed when benzoylhydrazine 1m was employed, probably due to the electron-withdrawing effect of the N-benzoyl group. The synthetic value of NFC 4c is highlighted by the selective N-formylation of diamines 1n–1t. In these cases, the more nucleophilic amino groups of 1n–1t were selectively formylated, leaving the less nucleophilic anilide moieties intact, to provide 2n–2t in 84–100% yields.

Chart 5. N-Formylation of Amines 1d–1t with 4c

Conclusion

In conclusion, the unique selectivity and reactivity of NFC 4c were unveiled in the present study. The formylation using 4c occurred favorably at sterically less hindered primary and secondary amines. It is noteworthy that weakly nucleophilic amines such as aromatic amines and hydroxyl groups could not be formylated by NFC 4c. Solid NFC 4c can be easily handled in the laboratory. Indeed, no significant decomposition was observed when NFC 4a was kept on a benchtop (10–35 °C, more than one year). Further synthetic applications are underway in our laboratory.

Experimental

General Experimental Details

For reactions that required heating, an oil bath was used as the heat source. Column chromatography was performed on Kanto Kagaku Silica Gel 60 N (spherical, neutral), 100–210 µm. When column chromatography required methanol as the eluent, silica gel was washed with methanol prior to use in order to remove inorganic salt impurity. Reactions and chromatography fractions were analyzed by TLC on a Wako Silica gel 70 F254 TLC Plate-Wako, with visualization by UV irradiation at 254 nm, phosphomolybdic acid, anisaldehyde, ninhydrin, and/or potassium permanganate staining. ¹H-NMR spectra were recorded on a 400 MHz (100 MHz for ¹³C-NMR) JEOL JNM-ECZ-400S instrument. Chemical shifts and coupling constants are presented in ppm δ (relative to tetramethylsilane (0.00 ppm), CHCl₃ (7.26 ppm), or CD₂HOD (3.31 ppm)), and Hz, respectively. Chloroform-d₁ (δ 77.16 ppm) and methanol-d₄ (δ 49.00 ppm) were used as the internal standards for ¹³C-NMR spectroscopy. High-resolution MS (HR-MS) were obtained on a JEOL JMS-T100LP instrument for electrospray ionization (ESI). Fourier transform (FT)-IR spectra were recorded with a ThermoFisher Nicolet iS5 instrument with an iD5 attenuated total reflection (ATR) attachment and are reported in terms of frequency absorption (cm⁻¹). All reagents were purchased from chemical companies and were used as received. Dehydrated solvents were purchased for the reactions and used without further desiccation, unless otherwise mentioned.

Preparation of N-Formylcarbazole (4c)

N-Formylcarbazole 4c was prepared using a slightly modified version of the procedure described by Dixon and Lucas.²⁰⁾ A mixture of carbazole (50.0 g, 29.9 mmol) and formic acid (375 mL) was heated under reflux for 24 h. The reaction mixture was concentrated under reduced pressure. The resulting purple residue was dissolved in dichloromethane (200 mL). Activated charcoal (10.0 g) was then added to the mixture. The whole suspension was filtered through Celite, which was washed with dichloromethane (200 mL). The combined filtrate was concentrated under reduced pressure to give solids. Ether (200 mL) was then added, and the mixture was vigorously stirred for 1 h. The resulting suspension was filtered to give 4c as a white powder (43.8 g, 75%). The NMR data for 4c were identical with the reported values (see Supplementary materials for the spectrum).²²⁾

Typical Synthetic Procedure (Condition A)

To a solution of N-formylcarbazole 4c (0.300 mmol) in THF (0.125 mL) was added amine (0.250 mmol) at 25 °C. After stirring for 24 h at 25 °C, the reaction mixture was diluted with dichloromethane (2.0 mL). The mixture was directly subjected to silica gel column chromatography. Carbazole, the stoichiometric byproduct was typically recovered in the first fractions eluted with dichloromethane.

Typical Synthetic Procedure (Condition B)

To a solution of N-formylcarbazole 4c (0.600 mmol) in THF (0.125 mL) was added amine (0.250 mmol) at 25 °C. After refluxing for 24 h, the reaction mixture was cooled to room temperature and diluted with dichloromethane (2.0 mL). The mixture was directly subjected to silica gel column chromatography. Carbazole, the stoichiometric byproduct was typically recovered in the first fractions eluted with dichloromethane.

Typical Synthetic Procedure (Condition C)

To a solution of N-formylcarbazole 4c (0.300 mmol) in THF (0.250 mL) was added amine (0.250 mmol) at 25 °C. After stirring for 12 h at 25 °C, the reaction mixture was diluted with dichloromethane (2.0 mL). The mixture was directly subjected to silica gel column chromatography. Carbazole, the stoichiometric byproduct was typically recovered in the first fractions eluted with dichloromethane.

Synthesis and Characterization of Compounds

The yields of 2a²³⁾ and 2b²⁴⁾ were determined by crude ¹H-NMR spectroscopy using triphenylmethane as the internal standard. The NMR data for the synthetic formamides 2g,²⁵⁾2k,²⁶⁾2l,²⁷⁾2n,²⁸⁾2o,²⁹⁾ and 2p³⁰⁾ were identical to the literature values (see Supplementary materials for the spectra). The analytical data for the new compounds are as follows.

N¹-tert-Butoxycarbonyl-N¹-cyclohexyl-N³-formylpropane-1,3-diamine (2d)

Following the formylation of 1d under “Condition A,” Boc₂O (0.375 mmol) was added to the reaction mixture. After stirring for 1 h at 25 °C, the reaction mixture was diluted with dichloromethane (2.0 mL). The reaction mixture was directly subjected to silica gel column chromatography to obtain the title compound (62.0 mg, 87%) as colorless oil; ¹H-NMR (CDCl₃, 60 °C) δ: 8.16 (1H, s), 3.59 (1H, br s), 3.28–3.20 (4H, m), 1.79 (2H, d, J = 13.1 Hz), 1.71–1.62 (4H, m), 1.50–1.36 (9H + 3H, m), 1.33–1.24 (2H, m), 1.13–1.02 (1H, m); ¹³C-NMR (CDCl₃) δ: 164.7, 161.5, 79.9, 57.1, 40.3, 34.3, 31.5, 30.0, 28.6, 26.2, 25.6; IR (ATR) cm⁻¹: 3307, 3061, 2971, 2930, 2855, 1660, 1537, 1411, 1364, 1301, 1245; HR-MS m/z: 307.1998 (Calcd for C₁₅H₂₈N₂Na₂O₃⁺: 307.1992).

N¹-Cyclohexyl-N¹-formyl-N³-formylpropane-1,3-diamine (2d′)

The reaction under “Condition B” gave the title compound (48.3 mg, 91%) as pale yellow oil; ¹H-NMR (CDCl₃) δ: 8.21 (1H, s), 8.18 (1H, d, J = 1.2 Hz), 7.06 (1H, br s), 3.36 (2H, t, J = 6.5 Hz), 3.30–3.18 (3H, m), 1.92–1.77 (4H, m), 1.70 (3H, dt, J = 12.5, 6.5 Hz), 1.52 (2H, qd, J = 12.5, 3.5 Hz), 1.33 (2H, qt, J = 12.5, 3.5 Hz), 1.13 (1H, qt, J = 12.5, 3.5 Hz); ¹³C-NMR (CDCl₃) δ: 163.5, 161.4, 58.9, 38.2, 34.2, 33.0, 29.9, 25.8, 25.1; IR (ATR) cm⁻¹: 3292, 3052, 3052, 2931, 2855, 1651, 1532, 1468, 1449, 1426, 1383, 1355, 1296, 1235; HR-MS m/z: 235.1412 (Calcd for C₁₁H₂₀N₂O₂Na⁺: 235.1423).

N-(4-(2,2,6,6-Tetramethyl)piperidyl)formamide (2e)

The reaction under “Condition A” with column chromatography (EtOAc then MeOH) gave the title compound (41.2 mg, 89%) as clear yellow oil; ¹H-NMR (CDCl₃) δ: 8.18 (0.2H, d, J = 12.0 Hz), 8.13 (0.8H, s), 5.39 (0.2NH, br s), 5.25 (0.8NH, br s), 4.41–4.31 (0.8H, m), 3.84–3.68 (0.2H, m), 1.92 (1.6H, dd, J = 12.8, 3.8 Hz), 1.85 (0.4H, dd, J = 12.8, 3.8 Hz), 1.26 (4.8H, s), 1.24 (1.2H, s), 1.15 (1.2H, s), 1.13 (4.8H, s), 1.04 (0.2H, t, J = 12.3 Hz), 0.95 (1.8H, t, J = 12.3 Hz); ¹³C-NMR (CDCl₃, major rotamer) δ: 160.5, 51.1, 45.2, 41.5, 35.0, 28.6; ¹³C-NMR (CDCl₃) δ: 163.7, 51.0, 46.9, 45.5, 34.9, 28.6; IR (ATR) cm⁻¹: 3266, 3251, 3174, 2966, 2918, 2856, 1663, 1548, 1460, 1399, 1387, 1381, 1369, 1309, 1254, 1224; HR-MS m/z: 185.1654 (Calcd for C₁₀H₂₁N₂O⁺ required 185.1648).

N⁴-Formyl-cis-2,6-dimethylpiperazine (2f)

The reaction under “Condition A” gave the title compound (39.2 mg, 100%) as clear yellow oil; ¹H-NMR (CDCl₃) δ: 8.03 (1H, s), 4.29 (1H, d, J = 12.5 Hz), 3.42 (1H, d, J = 12.5 Hz), 2.93–2.75 (2H, m), 2.72 (1H, t, J = 11.7 Hz), 2.26 (1H, t, J = 11.7 Hz), 1.10 (6H, d, J = 6.1 Hz); ¹³C-NMR (CDCl₃) δ: 160.8, 52.5, 51.9, 50.6, 46.68, 19.4, 19.3; IR (ATR) cm⁻¹: 3493, 3294, 2965, 2905, 2860, 1658, 1439, 1397, 1317, 1259, 1216; HR-MS m/z: 143.1184 (Calcd for C₇H₁₅N₂O⁺: 143.1179).

N-(3-tert-Butyldiphenylsiloxy)propylformamide

After 1h was formylated under “Condition C” without column chromatography, silylation of the primary alcohol was conducted via a one-pot operation. Imidazole (0.200 mmol) and tert-butyldiphenylsilyl chloride (TBDPSCl) (0.375 mmol) were then added to the reaction mixture. After stirring for 48 h at 25 °C, the reaction was quenched with H₂O. The mixture was extracted with EtOAc thrice, and the combined organic layers were washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (80.6 mg, 94%) as colorless oil; ¹H-NMR (CDCl₃) δ: 8.06 (0.9H, s), 8.02 (0.1H, s), 7.71–7.61 (4H, m), 7.50–7.35 (6H, m), 5.98 (0.9NH, s), 5.74 (0.1NH, s), 3.78 (1.8H, t, J = 5.6 Hz), 3.73 (0.2H, t, J = 5.7 Hz), 3.45 (1.8H, q, J = 6.0 Hz), 3.40 (0.2H, q, J = 6.4 Hz), 1.81–1.67 (2H, m), 1.07 (9H, s); ¹³C-NMR (CDCl₃, major rotamer) δ: 161.2, 135.7, 133.4, 130.2, 128.0, 62.8, 36.6, 31.4, 27.0, 19.3; ¹³C-NMR (CDCl₃, minor rotamer) δ: 164.8, 135.7, 133.4, 130.2, 128.0, 60.9, 39.1, 33.5, 27.0, 19.3; IR (ATR) cm⁻¹: 3287, 2930, 2857, 1669, 1111, 702; HR-MS m/z: 364.1696 (C₂₀H₂₇NO₂SiNa⁺: 364.1709).

N-(5-tert-Butyldiphenylsilyloxy)pentylformamide (2i)

After 1i was formylated under condition C,” the reaction mixture was diluted with dichloromethane (0.8 mL) and then, imidazole (0.200 mmol) and TBDPSCl (0.375 mmol) were added to the reaction mixture. After stirring for 24 h at 25 °C, the reaction was quenched with H₂O. The mixture was extracted with EtOAc thrice, and the combined organic layers were washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (63.9 mg, 86%) as colorless oil; ¹H-NMR (CDCl₃) δ: 8.14 (0.8H, s, 1H), 8.02 (0.2H, d, J = 12.0 Hz), 7.66 (4H, dd, J = 7.8, 1.5 Hz), 7.48–7.33 (6H, m), 5.45 (1NH, br s), 3.66 (2H, t, J = 6.3 Hz), 3.27 (1.6H, q, J = 6.6 Hz), 3.17 (0.4H, q, J = 6.7 Hz), 1.60–1.36 (6H, m), 1.05 (9H, s); ¹³C-NMR (CDCl₃, major rotamer) δ: 161.2, 135.7, 134.2, 129.7, 127.77, 63.8, 38.3, 32.2, 29.3, 27.0, 23.3, 19.4; ¹³C-NMR (CDCl₃, minor rotamer) δ: 164.6, 135.7, 134.1, 129.8, 127.78, 63.6, 41.8, 32.1, 31.1, 27.0, 22.9, 19.4; IR (ATR) cm⁻¹: 2931, 2855, 1670, 1541, 1109, 702; HR-MS m/z: 392.2019 (Calcd for C₂₂H₃₁NO₂SiNa⁺: 392.2022).

N-2-(tert-Butyldiphenylsiloxy)ethyl-N-methylformamide (2j)

After 1j was formylated under “Condition C” without column chromatography, silylation of the primary alcohol was conducted via a one-pot operation. Imidazole (0.200 mmol) and TBDPSCl (0.375 mmol) were then added to the reaction mixture. After stirring for 48 h at 25 °C, the reaction was quenched with H₂O. The mixture was extracted with EtOAc thrice, and the combined organic layers were washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (78.0 mg, 91%) as colorless oil; ¹H-NMR (CDCl₃) δ: 8.08 (0.7H, s), 8.03 (0.3H, s), 7.69–7.59 (4H, m), 7.49–7.36 (6H, m), 3.81 (0.6H, t, J = 5.4 Hz), 3.70 (1.4H, t, J = 5.2 Hz), 3.48 (0.6H, t, J = 5.4 Hz), 3.33 (1.4H, t, J = 5.2 Hz), 3.02 (0.9H, s), 2.79 (2.1H, s), 1.05 (2.7H, s), 1.05 (6.3H, s); ¹³C-NMR (CDCl₃, major rotamer) δ: 163.4, 135.62, 133.0, 130.0, 127.9, 60.7, 51.8, 30.1, 26.86, 19.15; ¹³C-NMR (CDCl₃, minor rotamer) δ: 162.8, 135.61, 133.3, 129.9, 127.8, 62.0, 46.9, 36.3, 26.91, 19.20; IR (ATR) cm⁻¹: 2930, 2857, 1672, 1428, 1111, 703; HR-MS m/z: 364.1692 (Calcd for C₂₀H₂₇NO₂SiNa⁺: 364.1709).

N-[(3-Aminophenyl)methyl]-N-methylformamide (2q)

The reaction under “Condition A” gave the title compound (41.0 mg, 100%) as clear pale brown oil; ¹H-NMR (CDCl₃) 8.23 (0.6H, s), 8.13 (0.4H, s), 7.14–7.07 (1H, m), 6.63–6.48 (3H, m), 4.41 (0.8H, s), 4.28 (1.2H, s), 3.78 (2NH, br s), 2.83 (1.2H, s), 2.77 (1.8H, s); ¹³C-NMR (CDCl₃, major rotamer) δ: 162.9, 147.2, 137.0, 129.8, 117.3, 114.7, 113.5, 53.5, 29.5; ¹³C-NMR (CDCl₃, minor rotamer) δ: 162.7, 147.0, 137.2, 129.5, 118.3, 114.6, 114.4, 47.6, 34.1; IR (ATR) cm⁻¹: 3430, 3349, 3231, 3037, 3014, 2923, 2863, 1652, 1604, 1492, 1463, 1393, 1314, 1295, 1259, 1210; HR-MS m/z: 165.1002 (Calcd for C₉H₁₃N₂O⁺: 165.1022).

N-Despropyl-N-formylprampexole (2r)

The reaction under “Condition A” gave the title compound (41.6 mg, 84%) as clear pale brown oil; ¹H-NMR (CD₃OD) δ: 8.02 (1H, s), 4.60 (1NH, br s), 4.32–4.20 (1H, m), 2.88 (1H, dd, J = 15.5, 4.8 Hz), 2.58 (2H, dd, J = 7.5, 5.9 Hz), 2.48 (1H, ddt, J = 15.5, 7.5, 2.0 Hz), 2.06–1.93 (1H, m), 1.92–1.78 (1H, m); ¹³C-NMR (CD₃OD) δ: 169.8, 163.3, 144.6, 114.5, 45.6, 29.8, 29.1, 24.9; IR (ATR) cm⁻¹: 3296, 3192, 2925, 2851, 1662, 1522, 1370, 1307, 1272, 1237; HR-MS m/z: 198.0711 (C₈H₁₂N₃OS⁺: 198.0696).

4-Aminophenethylformamide (2s)

The reaction under “Condition A” gave the title compound (36.2 mg, 88%) as clear pale brown oil; ¹H-NMR (CDCl₃) δ: 8.06 (0.8H, s), 7.88 (0.2H, d, J = 12.0 Hz), 6.97 (1.6H, d, J = 8.3 Hz), 6.93 (0.4H, d, J = 8.3 Hz), 6.63 (2H, d, J = 8.3 Hz), 5.83 (1NH, br s), 3.63 (2NH, br s), 3.49 (1.6H, q, J = 6.7 Hz), 3.38 (0.4H, q, J = 6.7 Hz), 2.76–2.62 (2H, m); ¹³C-NMR (CDCl₃, major rotamer) δ: 164.6, 145.3, 129.6, 128.3, 115.46, 39.5, 34.6; ¹³C-NMR (CDCl₃, minor rotamer) δ: 161.3, 145.1, 129.7, 128.3, 115.54, 43.5, 36.9; IR (ATR) cm⁻¹: 3337, 3234, 3050, 3033, 3018, 3004, 2934, 2860, 1660, 1516, 1453, 1385, 1275, 1237; HR-MS m/z: 187.0874 (Calcd for C₉H₁₂N₂NaO⁺: 187.0842).

N¹-Formyl-2-anilinomethylpyrrolidine (2t)

The reaction under “Condition A” gave the title compound (47.9 mg, 94%) as clear pale brown oil; ¹H-NMR (CDCl₃) δ: 8.26 (0.5H, s), 8.21 (0.5H, s), 7.19–7.13 (2H, m), 6.75–6.57 (3H, m), 4.37–4.31 (0.5H, m), 4.08–4.02 (0.5H, m), 3.65–3.53 (1H, m), 3.48–3.35 (1H, m), 3.30–3.04 (2H, m), 2.18–1.72 (4H, m); ¹³C-NMR (CDCl₃, major rotamer) δ: 162.5, 148.3, 129.2, 117.0, 112.5, 55.1, 48.6, 476.9, 29.4, 23.9; ¹³C-NMR (CDCl₃, minor rotamer) δ: 161.5, 147.1, 129.5, 118.0, 112.8, 56.1, 48.1, 43.5, 28.5, 22.5; IR (ATR) cm⁻¹: 3348, 3051, 3026, 2970, 2877, 1651, 1601, 1506, 1499, 1417, 1382, 1319, 1259; HR-MS m/z: 205.1343 (Calcd for C₁₂H₁₇N₂O⁺: 205.1335).

Acknowledgments

This work was financially supported by the Tenure Track Support Program of Kobe University (for Bubwoong Kang) and a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS KAKENHI, Grant No. JP21K14792 for Bubwoong Kang; No. JP20H02745 for Tetsuya Satoh and Tetsuro Shinada).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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