P(III)-Mediated Formal Reductive N–H Bond Insertion Reaction of Hydrazones to α-Keto Esters

Abstract

A diazo-, metal-, and base-free multi-substituted hydrazone synthesis via a formal reductive N–H bond insertion reactions of hydrazones to α-keto esters has been developed. The protocol features a broad substrate scope and good functional group tolerance, providing N–H bond insertion products in moderate to excellent yields. Moreover, P(III)-mediated N–H functionalization of pharmaceutical containing hydrazone moiety was also successfully achieved.

Introduction

X–H bond insertion reactions (X = C, N, O, S, Si) are valuable transformations, wherein C1 units such as carbenes, carbenoids, and their surrogates can be incorporated into X–H bonds to form X–C–H bond.^1–3) Among these reactions, N–H bond insertion reactions have been well developed as enantioselective versions, facilitating direct access to the synthesis of chiral amines.^4–13) However, to achieve successful N–H bond insertion reactions, the use of diazo compounds¹⁴⁾ that are associated with potential explosion hazards is essential. Furthermore, efficient conversion necessitates the use of (i) transition metal catalysts,^4–13) (ii) thermal conditions (50–100 °C),^15,16) or (iii) blue LED irradiations.^17,18) Despite the existence of a few excellent methodologies for diazo-free N–H bond insertion reactions using sulfoxonium ylides,^19–21) there is an ongoing need for the continuous development of efficient, diazo- and transition-metal-free N–H bond insertion reactions, particularly concerning safety. In addition, various amines, including aromatic and aliphatic amines,^4–9) carbamates,^10,11) carbazole,¹²⁾ and imines¹³⁾ that can be used in N–H bond insertion reactions have been reported. However, there are limited reports on the N–H bond insertion reaction utilizing hydrazone and hydrazide as a nitrogen source.^22,23) Hydrazones and their derivatives bearing N–N bonds are common structural motifs in various medicines and biologically active compounds.^24–27) Therefore, several N–H functionalization methods for hydrazones have been developed, including alkylation/arylation in the presence of a base,^28–33) Michael addition,^34,35) and other transformations.^36–39) However, these reactions occasionally lead to the decomposition of substrates because of the requirement for basic or thermal conditions. Therefore, the development of practical N–H functionalization reactions under mild reaction conditions is highly desirable for the synthesis of multi-substituted hydrazones.

We aim to pioneer innovative approaches for the diazo-free N–H bond insertion reaction of N-acyl hydrazones, paving the way for diverse synthetic applications, including late-stage functionalization of pharmaceuticals and biologically active compounds. In our recent work, we successfully developed a procedure for the diazo-free O–H bond insertion reaction involving an oxime with a bench-stable α-keto ester utilizing Kukhtin–Ramirez adducts (KRAs)^40–43) which were generated in situ from 1,2-dicarbonyl compounds and a phosphine (III) reagent⁴⁴⁾ (Chart 1A). The use of N–H hydrazone 2 under these conditions would allow for the N–H bond insertion reaction of N–H hydrazone 2 to α-keto ester 1 to afford multi-substituted hydrazones 3 (Chart 1B). The reaction of 1 with P(NMe₂)₃ leads to the formation of KRAs A and B. Subsequently, the protonation of KRAs by hydrazone 2 generates alkoxyphosphonium intermediate C and D, which undergo an S_N2-type reaction to yield multi-substituted hydrazone 3. Although formal reductive N–H bond insertion reactions using several tosylated amines and two examples of an imidazole and a pyrazole have been reported,^45,46) to the best of our knowledge, the reaction of KRAs with hydrazones remains unexplored. This protocol facilitates the formal reductive N–H functionalization of hydrazones while avoiding the use of α-diazo compounds, metal-catalysis, base, and thermal conditions. Herein we present a detailed account of the diazo-free N–H bond insertion reaction of a hydrazone with a α-keto ester, elucidating substrate scope, exploring cyclic acyl hydrazones, and demonstrating a manipulation of pharmaceuticals.

Chart 1. Formal Reductive O–H/N–H Bond Insertion Reaction of Oxime/Hydrazone to α-Keto Ester

Results and Discussion

In accordance with our preceding communication,⁴⁴⁾ we initially examined the reaction of ethyl benzoylformate (1a) and benzyloxycarbonyl (Cbz)-hydrazone 2a with tris(dimethylamino)phosphine (P(NMe₂)₃) in CH₂Cl₂ at a temperature range from 0 °C to room temperature (Chart 2). As expected, the desired N–H insertion product 3aa was obtained in 82% yield. Encouraged by this result, the substituent effects of amino groups on the imine moiety were evaluated. In the case of protected hydrazones such as tert-butoxycarbonyl (Boc)-hydrazone 2b, EtO₂C-hydrazone 2c, Ac-hydrazone 2d, and Ms-hydrazone 2e, the reactions proceeded to afford the corresponding N–H insertion products 3ab–ae in moderate to good yields. In contrast, the use of the unprotected hydrazone 2f led to the formation of complex mixtures. Notably, the reaction was found to be scalable; thus, the reaction of 2a with 1a on a 3.0 mmol scale afforded 3aa in 94% yield. Considering both yield and scalability, Cbz-hydrazone 2a was selected as the model hydrazone.

Chart 2. Formal Reductive N–H Bond Insertion Reaction of Hydrazones 2 to α-Keto Ester 1a

Next, we investigated the substrate scope of α-keto esters and Cbz-hydrazones (Table 1). The reaction of α-keto esters 1b and 1c which have the aromatic ring carrying p-methoxy and p-bromo groups with 2a gave hydrazones 3ba and 3ca in good yields.⁴⁷⁾ However, in the case of 1d bearing an electron-withdrawing p-cyano group, N–H insertion product 3da could not be detected due to the formation of a complex mixture. Allyl, propargyl, and benzyl moieties at R² of ester were accommodated, producing the expected products 3ea–ga in moderate yields. Hydrazones 2g–n, containing electron-donating or electron-withdrawing groups at the para-position of the benzene ring, as well as nitrogen-containing aromatic rings such as pyridines and quinolines, underwent conversion to the corresponding N–H insertion products 3ag–an in moderate to high yields. The formal reductive N–H insertion reaction of hydrazone 2o, bearing a methoxy carbonyl group at the imino carbon of R³, afforded 3ao in 90% yield. The scope of hydrazones 2p–r derived from ketones such as acetophenone, nabumetone, and pentoxifylline was then investigated. Formal reductive N–H insertion products 3ap–ar were obtained in moderate to good yields.

Table 1. Substrate Scope^a)

a) 1 (0.25 mmol), 2 (0.26 mmol), P(NMe₂)₃ (0.26 mmol), CH₂Cl₂ (2.5 mL), 0 °C to room temperature (r.t.), 15 min.

To further explore the scope of this transformation, we examined the reaction of conjugated hydrazones with 1a (Chart 3). When the reaction was applied to conjugated hydrazones 2s and 2t, formal reductive N–H bond insertion proceeded smoothly to afford 3as and 3at in high yields. Product 3as was structurally characterized using X-ray crystallography (CCDC 2323149). This protocol was amplified to a 2.0 mmol scale, and the corresponding product 3as was formed in 90% yield.

Chart 3. Reactions of Conjugated Hydrazones 2s and 2t with 1a

Furthermore, cyclic acyl hydrazones are viable substrates for this transformation. For example, the reaction of 3(2H)-pyridazinone (4a) and phthalazone (4b) proceeded smoothly to provide the corresponding products 5aa and 5ab in excellent yields (Chart 4).

Chart 4. Reactions of Cyclic Acyl Hydrazones 4a and 4b with 1a

As an extension of the present method, late-stage functionalization of biologically active hydrazones was performed (Chart 5). The tuberculostatic drug fronazide (4c) was selected for the N–H bond insertion reaction. The introduction of fronazide (4c) into α-keto ester 1a was successfully achieved to obtain the corresponding N–H insertion product 5ac in high yield.

Chart 5. Reaction of Biologically Active Hydrazones with 1a

Conclusion

We have developed a formal reductive N–H bond insertion reaction of hydrazones with α-keto esters, presenting an efficient strategy for the synthesis of multi-substituted hydrazones. This method avoids the use of hazardous diazo compounds, transition metal catalysts, and thermal reaction conditions, while employing readily available, easy-to-handle, and bench-stable reagents. Moreover, this method demonstrated a broad substrate scope, excellent functional group tolerance, and the N–H functionalization of pharmaceuticals. This method holds significant promise for application in N–H bond insertion chemistry, and ongoing studies are exploring its applications.

General Information

NMR spectra were recorded at 400 MHz/100 MHz (¹H-NMR/¹³C-NMR) using 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, m = multiplet), coupling constants, and integration. IR spectra were recorded on a Perkin–Elmer SpectrumOne A spectrometer using NaCl plates or KBr pallets. The high-resolution mass spectra (HR-MS) 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 Silicycle silica gel (SiliaFlash^® F60, 40–63 µm) or Biotage Automated Liquid Chromatography System Isolera One using Biotage SNAP KP-Sil 10 or 25g silica gel cartridges. Unless otherwise stated, all of the reagents and solvents were used as received from the manufacturer.

Preparation of Hydrazones 2

General Procedure

To a solution of CbzNHNH₂ (5.0 mmol) in EtOH (10.0 mL) was added aldehyde or ketone (5.0 mmol) at room temperature. After being stirred at reflux for several hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography to give corresponding hydrazones 2 (Supplementary Materials).

A Formal Reductive N–H Bond Insertion Reaction of Hydrazones 2 with α-Keto Esters 1

General Procedure

To a solution of α-keto ester 1 (0.25 mmol) and hydrazone 2 (0.26 mmol) in CH₂Cl₂ (2.5 mL) was slowly added tris(dimethylamino)phosphine (47.3 µL, 0.26 mmol) at 0 °C under an argon atmosphere. After being stirred at the same temperature for 5 min, the reaction mixture was allowed to warm to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (Biotage Isolera One) or PTLC to afford corresponding N–H insertion products 3.

Benzyl (E)-2-Benzylidene-1-(2-ethoxy-2-oxo-1-phenylethyl)hydrazine-1-carboxylate (3aa)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2a (66.1 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3aa (86.6 mg, 82%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 1747, 1712 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.70 (br s, 1H), 7.59–7.56 (m, 2H), 7.43–7.28 (m, 13H), 6.16 (s, 1H), 5.27 (s, 2H), 4.26–4.17 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 169.1, 153.6, 151.4, 135.7, 134.8, 134.6, 130.0, 129.1, 128.5, 128.25, 128.16, 128.0, 127.4, 68.1, 65.4, 61.7, 14.1; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₂₅H₂₄O₄N₂Na 439.1628. Found 439.1624. Some carbon signals (Csp²) are overlapped.

Procedure for the Reaction of 1a with 2a on 3.0 mmol Scale

To a solution of 1a (477.3 µL, 3.0 mmol) and 2a (801.0 mg, 3.15 mmol) in CH₂Cl₂ (20 mL) was slowly added P(NMe₂)₃ (571.2 µL, 3.15 mmol) at 0 °C under an argon atmosphere. After being stirred at the same temperature for 5 min, the reaction mixture was allowed to warm to room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane/AcOEt = 10/1 to 3/1) to afford 3aa (1.18 g, 94% yield).

tert-Butyl (E)-2-Benzylidene-1-(2-ethoxy-2-oxo-1-phenylethyl)hydrazine-1-carboxylate (3ab)

Following to the general procedure using 1a (119.3 µL, 0.75 mmol), 2b (174.0 mg, 0.79 mmol), P(NMe₂)₃ (143.3 µL, 0.79 mmol), and CH₂Cl₂ (7.5 mL) for 30 min, 3ab (216.2 mg, 75%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 5/1 to 3/1); a colorless oil; IR (neat): 1748, 1709 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.67 (br s, 1H), 7.59–7.57 (m, 2H), 7.43–7.30 (m, 8H), 6.02 (s, 1H), 4.31–4.22 (m, 2H), 1.51 (s, 9H), 1.25 (t, J = 7.3 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 169.5, 152.8, 150.4, 135.2, 129.8, 129.0, 128.5, 128.2, 128.0, 127.6, 127.3, 82.6, 65.7, 61.6, 28.2, 14.2; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₂₂H₂₆O₄N₂Na 405.1785. Found 405.1780.

Ethyl (E)-2-Benzylidene-1-(2-ethoxy-2-oxo-1-phenylethyl)hydrazine-1-carboxylate (3ac)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2c (50.0 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 30 min, 3ac (63.8 mg, 84%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 1748, 1709 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.63 (br s, 1H), 7.61–7.57 (m, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.37–7.29 (m, 6H), 6.16 (s, 1H), 4.34–4.22 (m, 4H), 1.34 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 169.2, 153.9, 150.6, 134.9, 134.6, 130.0, 129.1, 128.5, 128.3, 128.1, 127.4, 65.1, 62.7, 61.7, 14.4, 14.2; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₂₀H₂₂O₄N₂Na 377.1472. Found 377.1468.

Ethyl (E)-2-(1-Acetyl-2-benzylidenehydrazineyl)-2-phenylacetate (3ad)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2d (42.2 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3ad (60.5 mg, 75%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 1743, 1688 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.55–7.52 (m, 3H), 7.37–7.25 (m, 8H), 6.70 (s, 1H), 4.32–4.22 (m, 2H), 2.61 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 173.2, 168.3, 141.3, 134.2, 132.3, 129.9, 128.6, 128.0, 127.7, 127.0, 61.9, 57.9, 22.0, 14.1; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₁₉H₂₀O₃N₂Na 347.1367. Found 347.1365. One of carbon signals (Csp²) is overlapped.

Ethyl (E)-2-[2-Benzylidene-1-(methylsulfonyl)hydrazineyl]-2-phenylacetate (3ae)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2e (51.5 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 60 min, 3ae (41.3 mg, 46%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 1744, 1350, 1160 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.11 (s, 1H), 7.62–7.59 (m, 2H), 7.48 (d, J = 7.3 Hz, 2H), 7.41–7.31 (m, 6H), 6.24 (s, 1H), 4.32–4.23 (m, 2H), 3.03 (s, 3H), 1.24 (t, J = 7.3 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 168.6, 151.8, 133.7, 133.2, 130.7, 128.9, 128.7, 128.5, 127.6, 64.8, 62.1, 37.9, 14.1; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₁₈H₂₀O₄N₂SNa 383.1036. Found 383.1033. Some carbon signals (Csp²) are overlapped.

Benzyl (E)-2-Benzylidene-1-[2-ethoxy-1-(4-methoxyphenyl)-2-oxoethyl]hydrazine-1-carboxylate (3ba)

Following to the general procedure using 1b (52.1 mg, 0.25 mmol), 2a (66.1 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3ba (83.7 mg, 75%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 1747, 1710 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.71 (br s, 1H), 7.60–7.57 (m, 2H), 7.37–7.30 (m, 10H), 6.87–6.84 (m, 2H), 6.10 (s, 1H), 5.27 (s, 2H), 4.23–4.18 (m, 2H), 3.77 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 169.4, 159.4, 153.6, 151.6, 135.7, 134.8, 130.5, 130.0, 128.5, 128.2, 128.0, 127.4, 126.7, 113.6, 68.0, 64.9, 61.6, 55.2, 14.1; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₂₆H₂₆O₅N₂Na 469.1734. Found 469.1731. One of carbon signals (Csp²) is overlapped.

Benzyl (E)-2-Benzylidene-1-[1-(4-bromophenyl)-2-ethoxy-2-oxoethyl]hydrazine-1-carboxylate (3ca)

Following to the general procedure using 1c (86.9 µL, 0.50 mmol), 2a (134.8 mg, 0.53 mmol), P(NMe₂)₃ (96.1 µL, 0.53 mmol), and CH₂Cl₂ (5.0 mL) for 15 min, 3ca (210.5 mg, 81%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 1748, 1712 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.74 (br s, 1H), 7.60–7.57 (m, 2H), 7.47–7.43 (m, 2H), 7.39–7.31 (m, 8H), 7.29–7.25 (m, 2H), 6.08 (s, 1H), 5.26 (s, 2H), 4.26–4.14 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 168.7, 153.5, 152.2, 135.5, 134.6, 133.8, 131.4, 130.9, 130.3, 128.6, 128.4, 128.1, 127.4, 122.4, 68.2, 65.0, 61.8, 14.1; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₂₅H₂₃O₄N₂⁷⁹BrNa 517.0733. Found 517.0730. One of carbon signals (Csp²) is overlapped.

Benzyl (E)-1-[2-(Allyloxy)-2-oxo-1-phenylethyl]-2-benzylidenehydrazine-1-carboxylate (3ea)

Following to the general procedure using 1e (47.5 mg, 0.25 mmol), 2a (66.1 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3ea (69.2 mg, 47%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 1749, 1710 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.72 (br s, 1H), 7.58–7.32 (m, 15H), 6.19 (s, 1H), 5.87–5.77 (m, 1H), 5.27–5.13 (m, 4H), 4.69–4.61 (m, 2H); ¹³C-NMR (101 MHz, CDCl₃) δ: 168.9, 153.6, 151.7, 135.6, 134.8, 134.5, 131.6, 130.1, 129.2, 128.54, 128.51, 128.3, 128.0, 127.5, 118.7, 68.1, 66.2, 65.5; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₂₆H₂₄O₄N₂Na 451.1628. Found 451.1628. Some carbon signals are overlapped.

Benzyl (E)-2-Benzylidene-1-[2-oxo-1-phenyl-2-(prop-2-yn-1-yloxy)ethyl]hydrazine-1-carboxylate (3fa)

Following to the general procedure using 1f (47.0 mg, 0.25 mmol), 2a (66.1 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3fa (58.4 mg, 55%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 2254, 1757, 1708 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.75 (br s, 1H), 7.59–7.58 (m, 2H), 7.40–7.32 (m, 13H), 6.19 (s, 1H), 5.27 (s, 2H), 4.77–4.68 (m, 2H), 2.37 (s, 1H); ¹³C-NMR (101 MHz, CDCl₃) δ: 168.5, 153.5, 151.9, 135.6, 134.7, 134.2, 130.1, 129.2, 128.6, 128.5, 128.4, 128.3, 128.0, 127.5, 77.3, 75.2, 68.2, 65.4, 52.8; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₂₆H₂₂O₄N₂Na 449.1472. Found 449.1472. One of carbon signals (Csp²) is overlapped.

Benzyl (E)-2-Benzylidene-1-[2-(benzyloxy)-2-oxo-1-phenylethyl]hydrazine-1-carboxylate (3ga)

Following to the general procedure using 1g (60.1 mg, 0.25 mmol), 2a (66.1 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3ga (78.8 mg, 66%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 1748, 1709 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.70 (br s, 1H), 7.53–7.23 (m, 20H), 6.21 (s, 1H), 5.25–5.14 (m, 4H); ¹³C-NMR (101 MHz, CDCl₃) δ: 169.1, 153.6, 151.8, 135.6, 135.4, 134.7, 134.5, 130.1, 129.2, 128.5, 128.49, 128.40, 128.3, 128.20, 128.15, 128.0, 127.5, 68.1, 67.3, 65.5; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₃₀H₂₆O₄N₂Na 501.1782. Found 501.1785. Some carbon signals are overlapped.

Benzyl (E)-1-(2-Ethoxy-2-oxo-1-phenylethyl)-2-(4-methoxybenzylidene)hydrazine-1-carboxylate (3ag)

Following to the general procedure using 1a (79.5 µL, 0.50 mmol), 2g (150.7 mg, 0.53 mmol), P(NMe₂)₃ (96.1 µL, 0.53 mmol), and CH₂Cl₂ (5.0 mL) for 15 min, 3ga (151.4 mg, 68%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 1747, 1709 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.60 (br s, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.41–7.26 (m, 10H), 6.86 (d, J = 8.9 Hz, 2H), 6.13 (s, 1H), 5.25 (s, 2H), 4.26–4.15 (m, 2H), 3.79 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 169.2, 161.3, 153.7, 152.7, 135.8, 134.7, 129.2, 129.0, 128.4, 128.2, 128.1, 127.9, 127.3, 113.9, 67.9, 65.3, 61.6, 55.2, 14.1; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₂₆H₂₆O₅N₂Na 469.1734. Found 469.1732. One of carbon signals (Csp²) is overlapped.

Benzyl (E)-2-(4-Bromobenzylidene)-1-(2-ethoxy-2-oxo-1-phenylethyl)hydrazine-1-carboxylate (3ah)

Following to the general procedure using 1a (79.5 µL, 0.50 mmol), 2h (176.1 mg, 0.53 mmol), P(NMe₂)₃ (96.1 µL, 0.53 mmol), and CH₂Cl₂ (5.0 mL) for 15 min, 3ah (222.9 mg, 90%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 1748, 1713 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.70 (br s, 1H), 7.47–7.27 (m, 14H), 6.16 (s, 1H), 5.26 (s, 2H), 4.27–4.13 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 168.9, 153.4, 149.3, 135.4, 134.4, 133.7, 131.6, 129.0, 128.6, 128.4, 128.24, 128.17, 127.9, 127.4, 124.1, 68.1, 65.5, 61.6, 14.0; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₂₅H₂₃O₄N₂⁷⁹BrNa 517.0733. Found 517.0730.

Benzyl (E)-1-(2-Ethoxy-2-oxo-1-phenylethyl)-2-(4-nitrobenzylidene)hydrazine-1-carboxylate (3ai)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2i (77.8 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3ai (91.3 mg, 79%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); colorless crystals; mp 102–103 °C (hexane-AcOEt); IR (KBr): 1741, 1712, 1521 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.92 (br s, 1H), 8.17 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H), 7.38–7.34 (m, 10H), 6.20 (s, 1H), 5.29 (s, 2H), 4.27–4.18 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 168.9, 153.2, 148.2, 146.3, 141.2, 135.2, 134.1, 129.1, 128.6, 128.5, 128.42, 128.36, 128.1, 127.6, 123.8, 68.5, 65.9, 61.8, 14.1; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₂₅H₂₃O₆N₃Na 484.1479. Found 484.1478.

Benzyl (E)-1-(2-Ethoxy-2-oxo-1-phenylethyl)-2-(pyridin-4-ylmethylene)hydrazine-1-carboxylate (3aj)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2j (66.4 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3aj (104.0 mg, 93%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 5/1 to 1/1); an yellow oil; IR (neat): 1747, 1717 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (br s, 1H), 8.58 (d, J = 5.5 Hz, 2H), 7.39–7.26 (m, 12H), 6.18 (s, 1H), 5.29 (s, 2H), 4.27–4.17 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 168.9, 153.2, 150.2, 146.3, 142.4, 135.3, 134.1, 129.1, 128.6, 128.5, 128.40, 128.35, 128.1, 121.0, 68.4, 65.9, 61.8, 14.1; HR-MS (ESI) m/z: [M + H]⁺ Calcd for C₂₄H₂₄O₄N₃ 418.1761. Found 418.1761.

Benzyl (E)-1-(2-Ethoxy-2-oxo-1-phenylethyl)-2-(pyridin-3-ylmethylene)hydrazine-1-carboxylate (3ak)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2k (66.4 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3ak (96.4 mg, 92%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 5/1 to 1/1); a colorless oil; IR (neat): 1747, 1714 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (br s, 1H), 8.70 (d, J = 1.8 Hz, 1H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H), 7.88 (dt, J = 8.1, 1.9 Hz, 1H), 7.40–7.30 (m, 10H), 7.27–7.24 (m, 1H), 6.18 (s, 1H), 5.28 (s, 2H), 4.26–4.17 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 169.0, 153.4, 150.7, 149.2, 147.2, 135.4, 134.3, 133.5, 130.9, 129.2, 128.6, 128.4, 128.3, 128.0, 123.5, 68.3, 65.7, 61.7, 14.1; HR-MS (ESI) m/z: [M + H]⁺ Calcd for C₂₄H₂₄O₄N₃ 418.1761. Found 418.1762. One of carbon signals (Csp²) is overlapped.

Benzyl (E)-1-(2-Ethoxy-2-oxo-1-phenylethyl)-2-(pyridin-2-ylmethylene)hydrazine-1-carboxylate (3al)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2l (66.4 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3 aL (87.2 mg, 84%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 5/1 to 1/1); a colorless oil; IR (neat): 1747, 1716 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.54 (d, J = 4.6 Hz, 2H), 7.84 (d, J = 8.2 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.39–7.30 (m, 10H), 7.20 (dd, J = 6.6, 5.7 Hz, 1H), 6.19 (s, 1H), 5.32 (s, 2H), 4.24–4.18 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 168.6, 154.0, 153.6, 149.2, 148.0, 136.3, 135.5, 133.8, 128.8, 128.5, 128.4, 128.3, 128.2, 128.1, 123.8, 120.2, 68.4, 64.5, 61.8, 14.1; HR-MS (ESI) m/z: [M + H]⁺ Calcd for C₂₄H₂₄O₄N₃ 418.1761. Found 418.1758.

Benzyl (E)-1-(2-Ethoxy-2-oxo-1-phenylethyl)-2-(quinolin-2-ylmethylene)hydrazine-1-carboxylate (3am)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2m (78.9 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3am (109.2 mg, 93%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 1747, 1717 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.74 (br s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.68 (dd, J = 8.2, 6.9 Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.43–7.30 (m, 10H), 6.20 (s, 1H), 5.35 (s, 2H), 4.27–4.18 (m, 2H), 1.19 (t, J = 7.3 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 168.6, 154.4, 153.5, 147.8, 136.2, 135.5, 133.8, 129.6, 129.3, 128.8, 128.5, 128.4, 128.34, 128.30, 128.2, 128.1, 127.6, 127.0, 117.7, 68.5, 64.6, 61.8, 14.1; HR-MS (ESI) m/z: [M + H]⁺ Calcd for C₂₈H₂₆O₄N₃ 468.1918. Found 468.1918. One of carbon signals (Csp²) is overlapped.

Benzyl (E)-1-(2-Ethoxy-2-oxo-1-phenylethyl)-2-(quinolin-8-ylmethylene)hydrazine-1-carboxylate (3an)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2n (78.9 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3an (104.9 mg, 90%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 1747, 1710 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 9.95 (br s, 1H), 8.89–8.87 (m, 1H), 8.29 (dd, J = 7.3, 1.4 Hz, 1H), 8.10 (dd, J = 8.2, 1.8 Hz, 1H), 7.81 (dd, J = 8.0, 1.1 Hz, 1H), 7.55–7.47 (m, 3H), 7.43–7.26 (m, 9H), 6.26 (s, 1H), 5.34 (s, 2H), 4.30–4.17 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 169.1, 153.9, 149.9, 148.2, 146.2, 136.0, 135.8, 134.6, 131.9, 129.6, 129.2, 128.4, 128.2, 128.11, 128.08, 128.0, 126.3, 126.0, 121.2, 68.1, 64.8, 61.6, 14.1; HR-MS (ESI) m/z: [M + H]⁺ Calcd for C₂₈H₂₆O₄N₃ 468.1918. Found 468.1919. One of carbon signals (Csp²) is overlapped.

Benzyl (E)-1-(2-Ethoxy-2-oxo-1-phenylethyl)-2-(2-methoxy-2-oxoethylidene)hydrazine-1-carboxylate (3ao)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2o (61.4 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 60 min, 3ao (54.0 mg, 90%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/CHCl₃ = 1/10 to 1/3); a colorless oil; IR (neat): 1748, 1725 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.87 (br s, 1H), 7.35–7.25 (m, 10H), 6.17 (s, 1H), 5.30 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.78 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 167.8, 163.7, 153.1, 135.4, 134.9, 132.7, 128.6, 128.5, 128.4, 128.2, 69.0, 65.0, 62.0, 52.2, 13.9; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₂₁H₂₂O₆N₂Na 421.1370. Found 421.1369. Some carbon signals (Csp²) are overlapped.

Benzyl (E)-1-(2-Ethoxy-2-oxo-1-phenylethyl)-2-(1-phenylethylidene)hydrazine-1-carboxylate (3ap)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2p (66.1 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3ap (84.2 mg, 78%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); colorless crystals; mp 113–114 °C (hexane-AcOEt); IR (KBr): 1745, 1712 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.65 (d, J = 7.8 Hz, 2H), 7.41–7.25 (m, 13H), 6.10 (s, 1H), 5.20 (s, 2H), 4.25–4.17 (m, 2H), 2.12 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 172.9, 169.6, 153.1, 137.4, 136.0, 134.7, 130.4, 129.8, 128.4, 128.2, 128.1, 128.0, 127.0, 67.9, 65.8, 61.4, 17.3, 14.1; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₂₆H₂₆O₄N₂Na 453.1784. Found 453.1781. Some carbon signals (Csp²) are overlapped.

Benzyl (E/Z)-1-(2-Ethoxy-2-oxo-1-phenylethyl)-2-[4-(6-methoxynaphthalen-2-yl)butan-2-ylidene]hydrazine-1-carboxylate (3aq)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2q (97.9 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3aq (75.1 mg, 56%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 5/1 to 1/1); a colorless oil; IR (neat): 1745, 1709 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.66–7.62 (m, 2H), 7.48 (m, 1H), 7.37–7.21 (m, 10H), 7.12–7.08 (m, 2H), 5.96 (s, 1H), 5.21 and 5.16 (each s, 2H), 4.22–4.15 (m, 2H), 3.88 (s, 3H), 2.86–2.81 (m, 2H), 2.63–2.58 (m, 2H), 1.72 (s, 3H), 1.25–1.17 (m, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 178.6, 169.6, 157.2, 153.3, 136.3, 136.0, 134.6, 133.0, 129.9, 129.4, 129.0, 128.9, 128.5, 128.4, 128.2, 128.1, 128.0, 127.5, 126.7, 126.1, 118.7, 105.5, 68.1, 67.8, 65.2, 61.5, 61.4, 55.2, 40.1, 32.1, 19.1, 14.1; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₃₃H₃₄O₅N₂Na 561.2360. Found 561.2360. An inseparable mixture of E,Z-isomers. The geometries (E:Z or Z:E) of 3aq were not determined. Some carbon signals are overlapped.

Benzyl (E/Z)-2-[6-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)hexan-2-ylidene]-1-(2-ethoxy-2-oxo-1-phenylethyl)hydrazine-1-carboxylate (3ar)

Following to the general procedure using 1a (119.3 µL, 0.75 mmol), 2r (336.1 mg, 0.79 mmol), P(NMe₂)₃ (143.3 µL, 0.79 mmol), and CH₂Cl₂ (7.5 mL) for 30 min, 3ar (183.8 mg, 42%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 1/3 to 1/20); a colorless oil; IR (neat): 1746, 1705, 1661 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.50 (s, 1H), 7.33–7.24 (m, 11H), 5.93 (s, 1H), 5.16 (s, 2H), 4.19 (q, J = 7.0 Hz, 2H), 3.98–3.92 (m, 5H), 3.57 and 3.56 (each s, 3H), 2.27 (t, J = 7.5 Hz, 2H), 1.67–1.44 (m, 6H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 169.6, 155.1, 151.3, 148.6, 141.3, 136.1, 134.6, 130.3, 129.9, 128.3, 128.0, 127.9, 107.5, 67.6, 65.1, 61.3, 40.9, 38.0, 33.5, 29.6, 27.5, 23.5, 18.6, 14.0; HR-MS (ESI) m/z: [M + H]⁺ Calcd for C₃₁H₃₇O₆N₆ 589.2769. Found 589.2764. An inseparable mixture of E,Z-isomers. The geometries (E:Z or Z:E) of 3ar were not determined. Some carbon signals are overlapped.

Benzyl (E)-1-(2-Ethoxy-2-oxo-1-phenylethyl)-2-[(E)-4-ethoxy-4-oxobut-2-en-1-ylidene]hydrazine-1-carboxylate (3as)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2s (71.8 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3as (99.0 mg, 90%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); colorless crystals; mp 95–96 °C; IR (KBr): 1746, 1712 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.39 (br s, 1H), 7.39–7.23 (m, 11H), 6.17 (s, 1H), 6.07 (d, J = 16.0 Hz, 1H), 5.27 (s, 2H), 4.25–4.15 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 168.5, 166.0, 153.2, 147.4, 141.4, 135.2, 133.7, 128.8, 128.6, 128.5, 128.4, 128.3, 128.1, 127.2, 68.6, 65.1, 61.9, 60.7, 14.2, 14.1; HR-MS (ESI) m/z: [M +Na]⁺ Calcd for C₂₄H₂₆O₆N₂Na 461.1683. Found 461.1680. The ORTEP diagram is shown in Supplementary materials, and the crystal data and structure refinement are listed in Supplementary materials (CCDC 2323149).

Procedure for the Reaction of 1a with 2t on 2.0 mmol Scale

To a solution of 1a (318.0 µL, 2.0 mmol) and 2s (580.2 mg, 2.1 mmol) in CH₂Cl₂ (20 mL) was slowly added P(NMe₂)₃ (343.0 µL, 2.1 mmol) at 0 °C under an argon atmosphere. After being stirred at the same temperature for 5 min, the reaction mixture was allowed to warm to room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane/AcOEt = 10/1 to 3/1) to afford oxime ether 3as (930.6 mg, 94% yield).

Benzyl (E)-1-(2-Ethoxy-2-oxo-1-phenylethyl)-2-[(E)-3-phenylallylidene]hydrazine-1-carboxylate (3at)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 2t (68.2 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 3at (101.3 mg, 91%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); a colorless oil; IR (neat): 1747, 1709 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.23 (br s, 1H), 7.43–7.24 (m, 15H), 6.88 (dd, J = 16.0, 9.1 Hz, 1H), 6.77 (d, J = 16.5 Hz, 1H), 6.17 (s, 1H), 5.28 (s, 2H), 4.26–4.17 (m, 2H), 1.22–1.19 (m, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 169.0, 153.9, 153.5, 140.0, 135.9, 135.7, 134.1, 128.9, 128.7, 128.5, 128.3, 128.2, 128.1, 128.0, 127.0, 125.8, 68.3, 64.5, 61.8, 14.1; HR-MS (ESI) m/z: [M + H]⁺ Calcd for C₂₇H₂₇O₄N₂ 443.1965. Found 443.1963. One of carbon signals (Csp²) is overlapped.

Ethyl 2-[6-Oxopyridazin-1(6H)-yl]-2-phenylacetate (5aa)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), 3(2H)-pyridazinone (4a) (25.0 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 5aa (62.5 mg, 97%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 3/1 to 1/1); a colorless oil; IR (neat): 1747, 1669, 1589 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.76–7.75 (m, 1H), 7.47–7.36 (m, 5H), 7.15 (dd, J = 9.4, 3.9 Hz, 1H), 6.94 (dd, J = 9.4, 1.6 Hz, 1H), 6.76 (s, 1H), 4.30–4.22 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 168.5, 160.2, 136.1, 133.6, 131.3, 130.0, 129.6, 128.8, 128.4, 64.1, 62.0, 14.0; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₁₄H₁₄O₃N₂Na 281.0897. Found 281.0897.

Ethyl 2-[1-Oxophthalazin-2(1H)-yl]-2-phenylacetate (5ab)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), phthalazone (4b) (38.0 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 5ab (75.6 mg, 98%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 10/1 to 3/1); colorless crystals; mp 63–64 °C (hexane-AcOEt); IR (KBr): 1747, 1667, 1590 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.43 (d, J = 7.3 Hz, 1H), 8.16 (s, 1H), 7.81–7.73 (m, 2H), 7.66 (d, J = 7.3 Hz, 1H), 7.58–7.46 (m, 2H), 7.44–7.30 (m, 3H), 6.91 (s, 1H), 4.34–4.23 (m, 2H), 1.25 (t, J = 7.3 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 169.1, 159.3, 138.0, 134.5, 133.4, 131.7, 129.9, 129.5, 128.6, 128.4, 127.5, 126.9, 126.1, 63.5, 61.8, 14.1; HR-MS (ESI) m/z: [M + Na]⁺ Calcd for C₁₈H₁₆O₃N₂Na 331.1053. Found 331.1052.

Ethyl (E)-2-[2-[1-(Furan-2-yl)ethylidene]-1-isonicotinoylhydrazineyl]-2-phenylacetate (5ac)

Following to the general procedure using 1a (39.8 µL, 0.25 mmol), fronazide (4c) (59.6 mg, 0.26 mmol), P(NMe₂)₃ (47.3 µL, 0.26 mmol), and CH₂Cl₂ (2.5 mL) for 15 min, 5ac (90.0 mg, 92%) was obtained after purification by flash column chromatography (Biotage Isolera One, hexane/AcOEt = 3/1 to 1/3) and preparative TLC (CHCl₃); a colorless oil; IR (neat): 1748, 1622, 1596 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 8.72 (d, J = 5.9 Hz, 2H), 7.87 (d, J = 5.9 Hz, 2H), 7.62–7.52 (m, 3H), 7.45–7.39 (m, 3H), 6.83 (d, J = 3.2 Hz, 1H), 6.49 (d, J = 1.4 Hz, 1H), 6.13 (s, 1H), 4.26–4.16 (m, 2H), 2.34 (s, 3H), 1.23 (t, J = 7.3 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ: 169.3, 157.6, 155.5, 152.5, 149.8, 144.4, 136.6, 134.4, 129.1, 128.7, 127.4, 124.2, 111.8, 111.7, 61.6, 61.4, 14.04, 13.97; HR-MS (ESI) m/z: [M + H]⁺ Calcd for C₂₂H₂₂O₄N₃ 392.1605. Found 392.1604.

Acknowledgments

This work was supported by JSPS KAKENHI (Grant Numbers: JP19K05467, N.T. and JP21K06465, M.U.). We also thank Rimi Konishi from the Division of Material Science, Advanced Research Support Center (ADRES), Ehime University for the technical assistance with the X-ray crystallographic analysis.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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