The catalytic transformation of carbon dioxide (CO₂) into valuable chemicals has attracted much attention as CO₂ is an abundant, inexpensive, and renewable C1 feedstock [1-7]. Compared to the industrial large-scale transformation of CO₂ into bulk chemicals, such as urea, salicylic acid, carbonate, and methanol, the preparation of fine chemicals using CO₂ as a synthetic unit remains scarce [8]. Therefore, the development of more efficient reactions to catalytically convert CO₂ into various valuable compounds is of high relevance [9, 10]. Among these strategies, cyclization reactions represent the most commonly used and powerful approach as heterocycles offer tremendous diversity and are widely present in biologically important molecules [11, 12]. Since CO₂ usually serves as an electrophile, it can be incorporated into heterocyclic compounds via the reaction with nitrogen [13-15], oxygen [16-20], or carbon nucleophiles [21-26].

1, 3, 4-Oxadiazin-2-ones are important structural subunits found in many pharmacologically potent and biologically active compounds. Those compounds can be used as selective Ca²⁺ sensitizers, anticonvulsants, anxiolytic, antiulcer agents [27, 28], and useful 1, 2-diaza-1, 3-butadiene precursors for the construction of other fine chemicals [29]. Typically, 1, 3, 4-oxadiazin-2-ones are prepared by the reaction of cyclic carbonate with hydrazine or by using carbazates through laborious multistep procedures [30, 31]. Therefore, the development of more efficient and atom-economical approaches using CO₂ as the carboxylative reagent is highly desirable. As a continuation of our interest in catalytic transformations of CO₂ into fine chemicals [32-34], herein we report a silver-catalyzed carboxylative cyclization of alkynic hydrazones with CO₂ to give 1, 3, 4-oxadiazin-2-ones in good yield under mild reaction conditions.

Unless otherwise stated, all manipulations were performed using standard Schlenk techniques under dry nitrogen or CO₂ atmosphere. DMF and DMSO were distilled under N₂ atmosphere with CaH₂. CH₃CN was distilled with P₂O₅. THF was distilled from sodium/benzophenone. All solvents were stored over 4Å molecular sieves before use. Column chromatography was performed on silica gel (200–300 mesh). Thin layer chromatography was performed on 0.20 mm GF254 plates, which were visualized under UV light (254 nm). Unless otherwise stated, CO₂ (99.999%), commercial silver, copper, and palladium salts, and various bases were used without further purification.

NMR spectra were recorded on a 400M or 500M (¹H NMR, 400 or 500 MHz; ¹³C NMR, 101 or 126 MHz) spectrometer in CDCl₃ at ambient temperature, and the chemical shifts are expressed in parts per million (δ, ppm). The proton chemical shifts have been referenced to 7.26 ppm (CHCl₃) or 2.50 ppm (DMSO) and carbon chemical shifts to 77.0 ppm (CHCl₃) or 39.5 ppm (DMSO). The data is reported using the following abbreviations: s, singlet; d, doublet; t, triplet; m, multiplet; hept, heptet; and J, coupling constant in Hz. High resolution mass spectra (HRMS) were recorded on a Q-TOF mass spectrometer equipped with a Z-spray ionization source. Infrared (IR) spectra were measured using a Nicolet NEXUS FT-IR spectrophotometer.

Substrates 1 and 4 were prepared according to reported procedures [35].

A 20 mL oven-dried autoclave containing a stir bar was charged with hydrazone (0.30 mmol), Cs₂CO₃ (4.9 mg, 5 mol%), AgOAc (2.5 mg, 5 mol%), and 3.0 mL DMSO in a glove box. After removal from the glove box, the autoclave was purged with CO₂ three times and then pressurized at 2.0 MPa CO₂. The reaction mixture was stirred at 25 ℃ for 2 h, after which the remaining gas was vented slowly in the hood. The reaction mixture was diluted with 10 mL water and extracted with diethyl ether (3 × 10 mL). The combined organic phase was washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using petroleum/ethyl acetate as the eluent to afford the following oxadiazinone products.

(Z)-6-Benzylidene-3-(2-hydroxyethyl)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (2a). White solid (0.30 mmol scale, 59 mg, 85% yield). R_f = 0.4 (EtOAc/petroleum ether = 2:1). ¹H NMR (400 MHz, CDCl₃): δ 7.68 (d, J = 7.3 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.32–7.30 (m, 1H), 7.23 (s, 1H), 5.76 (s, 1H), 3.97–3.92 (m, 4H), 2.59 (s, 1H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 144.52, 141.09, 138.07, 132.29, 129.68, 128.73, 128.64, 113.05, 60.39, 53.01 ppm. HRMS (ESI, m/z) calculated for C₁₂H₁₃N₂O₃ [M+H]⁺: 233.0926, found: 233.0924. IR (neat): ν 3443, 2925, 1732, 1275 cm^–1.

(Z)-6-Benzylidene-3-(2-cyanoethyl)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (2b). White solid (0.30 mmol scale, 56 mg, 77% yield). R_f = 0.3 (EtOAc/petroleum ether = 1:1). ¹H NMR (400 MHz, CDCl₃): δ 7.68 (d, J = 7.6 Hz, 2H), 7.43–7.28 (m, 4H), 5.82 (s, 1H), 4.06 (t, J = 6.8 Hz, 2H), 2.79 (t, J = 6.8 Hz, 2H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 143.62, 140.74, 138.57, 132.03, 129.78, 128.98, 128.67, 116.89, 114.00, 46.59, 16.38 ppm. HRMS (ESI, m/z) calculated for C₁₃H₁₂N₃ [M+H]⁺: 242.0930, found: 242.0929. IR (neat): ν 2924, 2250, 1738, 1630 cm^–1.

(Z)-6-Benzylidene-3-isopropyl-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (2c). White solid (0.30 mmol scale, 48 mg, 69% yield. R_f = 0.5 (EtOAc/petroleum ether = 1:5). ¹H NMR (400 MHz, CDCl₃): δ 7.70 (d, J = 7.6 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.32–7.24 (m, 2H), 5.73 (s, 1H), 4.70 (p, J = 6.7 Hz, 1H), 1.30 (d, J = 6.7 Hz, 6H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 143.57, 141.21, 137.59, 132.67, 129.57, 128.64, 128.45, 111.85, 50.46, 19.96 ppm. HRMS (ESI, m/z) calculated for C₁₃H₁₄N₂NaO₂ [M+Na]⁺: 253.0953, found: 253.0953. IR (neat): ν 3443, 2921, 1732 cm^–1.

(Z)-3-Benzyl-6-benzylidene-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (2d). White solid (0.30 mmol scale, 75 mg, 90% yield). R_f = 0.4 (EtOAc/petroleum ether = 1:5). ¹H NMR (400 MHz, CDCl₃): δ 7.70 (d, J = 7.5 Hz, 2H), 7.45–7.31 (m, 8H), 7.23 (s, 1H), 5.76 (s, 1H), 4.94 (s, 2H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 144.03, 141.39, 138.09, 135.97, 132.43, 129.70, 128.70, 128.64, 128.55, 128.53, 128.08, 112.85, 54.55 ppm. HRMS (ESI, m/z) calculated for C₁₇H₁₅N₂O₂ [M+H]⁺: 279.1134, found: 279.1130. IR (neat): ν 3424, 2914, 1732 cm^–1.

(Z)-6-(4-Fluorobenzylidene)-3-(2-hydroxyethyl)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (2e). White solid (0.30 mmol scale, 52 mg, 69% yield). R_f = 0.3 (EtOAc/petroleum ether = 2:1). ¹H NMR (400 MHz, CDCl₃): δ 7.67–7.63 (m, 2H), 7.21 (s, 1H), 7.03 (t, J = 8.7 Hz, 2H), 5.71 (s, 1H), 3.95–3.90 (m, 4H), 2.63 (s, 1H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 162.54 (d, J = 251.49 Hz), 144.43, 140.77, 137.93, 131.54 (d, J = 8.1 Hz), 128.57 (d, J = 4.1 Hz), 115.75 (d, J = 22.2 Hz), 111.77, 60.29, 53.02 ppm. HRMS (ESI, m/z) calculated for C₁₂H₁₁FN₂NaO₃ [M+Na]⁺: 273.0651, found: 273.0652. IR (neat): ν 3430, 2921, 1720 cm^–1.

(Z)-6-(4-Chlorobenzylidene)-3-(2-hydroxyethyl)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (2f). White solid (0.30 mmol scale, 61 mg, 76% yield). R_f = 0.3 (EtOAc/petroleum ether = 2:1). ¹H NMR (400 MHz, CDCl₃): δ 7.61 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.23 (s, J = 10.0 Hz, 1H), 5.72 (s, 1H), 3.96–3.94 (m, 4H), 2.37 (s, 1H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ 144.31, 141.47, 137.79, 134.60, 130.88, 130.85, 128.96, 111.76, 60.61, 53.16 ppm. HRMS (ESI, m/z) calculated for C₁₂H₁₂ClN₂O₃ [M+H]⁺: 267.0536, found: 267.0533. IR (neat): ν 3358, 2923, 1656 cm^–1.

(Z)-3-(2-Hydroxyethyl)-6-(4-methylbenzylidene)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (2g). White solid (0.30 mmol scale, 52 mg, 71% yield). R_f = 0.4 (EtOAc/petroleum ether = 2:1). ¹H NMR (400 MHz, CDCl₃): δ 7.58 (d, J = 8.1 Hz, 2H), 7.21 (s, 1H), 7.17 (d, J = 8.0 Hz, 2H), 5.74 (s, 1H), 3.96–3.93 (m, 4H), 2.53 (s, 1H), 2.35 (s, 3H) ppm. ¹³C NMR (101 MHz, CDCl₃) δ 144.71, 140.60, 139.06, 138.26, 129.69, 129.53, 129.41, 113.25, 60.51, 52.99, 21.37 ppm. HRMS (ESI, m/z) calculated for C₁₃H₁₅N₂O₃ [M+H]⁺: 247.1083, found: 247.1077. IR (neat): ν 3430, 3054, 1728, 1464 cm^–1.

(Z)-3-(2-Hydroxyethyl)-6-(4-methoxybenzylidene)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (2h). White solid (0.30 mmol scale, 63 mg, 80% yield). R_f = 0.4 (EtOAc/petroleum ether = 2:1). ¹H NMR (400 MHz, CDCl₃): δ 7.67 (d, J = 8.8 Hz, 2H), 7.22 (s, 1H), 6.91 (d, J = 8.8 Hz, 2H), 5.76 (s, 1H), 3.99–3.96 (m, 4H), 3.84 (s, 3H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 159.99, 144.84, 139.83, 138.42, 131.39, 125.14, 114.21, 113.11, 60.77, 55.29, 52.99 ppm. HRMS (ESI, m/z) calculated for C₁₃H₁₅N₂O₄ [M+H]⁺: 263.1032, found: 263.1028. IR (neat): ν 3437, 3065, 1719, 1594, 1275 cm^–1.

(Z)-3-(2-Hydroxyethyl)-6-pentylidene-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (2i). Colorless liquid (0.30 mmol scale, 50 mg, 78% yield). R_f = 0.4 (EtOAc/petroleum ether = 2:1). ¹H NMR (400 MHz, CDCl₃): δ 7.08 (s, 1H), 5.05–5.01 (m, 1H), 3.93–3.88 (m, 4H), 2.23–2.19 (m, 2H), 1.40–1.30 (m, 4H), 0.91–0.87 (m, 3H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 145.57, 141.77, 137.51, 116.17, 60.26, 52.68, 30.56, 23.75, 22.16, 13.66 ppm. HRMS (ESI, m/z) calculated for C₁₀H₁₇N₂O₃ [M+H]⁺: 213.1239, found: 213.1235. IR (neat): ν 3448, 2956, 1724, 1654 cm^–1.

(Z)-6-Hexylidene-3-(2-hydroxyethyl)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (2j). Colorless liquid (0.30 mmol scale, 53 mg, 78% yield). R_f = 0.4 (EtOAc/petroleum ether = 2:1). ¹H NMR (400 MHz, CDCl₃): δ 7.06 (s, 1H), 5.01 (t, J = 7.8 Hz, 1H), 3.85 (s, 4H), 2.73 (s, 1H), 2.20–2.14 (m, 2H), 1.39–1.24 (m, J = 44.2 Hz, 6H), 0.85 (t, J = 6.9 Hz, 3H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 145.58, 141.76, 137.53, 116.26, 60.33, 52.68, 31.26, 28.13, 24.02, 22.26, 13.82 ppm. HRMS (ESI, m/z) calculated for C₁₁H₁₉N₂O₃ [M+H]⁺: 227.1396, found: 227.1386. IR (neat): ν 3440, 2926, 1724, 1652 cm^–1.

(Z)-6-(5-Chloropentylidene)-3-(2-hydroxyethyl)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (2k). White solid (0.30 mmol scale, 55 mg, 75% yield). R_f = 0.3 (EtOAc/petroleum ether = 2:1). ¹H NMR (400 MHz, CDCl₃): δ 7.09 (s, 1H), 5.01 (t, J = 7.8 Hz, 1H), 3.87 (s, 4H), 3.52 (t, J = 6.5 Hz, 2H), 2.58 (s, 1H), 2.26–2.21 (m, 2H), 1.81–1.52 (m, 4H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 145.43, 142.18, 137.31, 115.00, 60.41, 52.76, 44.54, 31.88, 25.73, 23.32 ppm. HRMS (ESI, m/z) calculated for C₁₀H₁₆ClN₂O₃ [M+H]⁺: 247.0849, found: 247.0845. IR (neat): ν 3450, 2935, 1727, 1654 cm^–1.

(Z)-3-(2-Hydroxyethyl)-6-(2-phenoxyethylidene)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (2l). White solid (0.30 mmol scale, 45 mg, 57% yield). R_f = 0.3 (EtOAc/petroleum ether = 2:1). ¹H NMR (400 MHz, CDCl₃): δ 7.32–7.27 (m, 2H), 7.18 (s, 1H), 6.99–6.89 (m, 3H), 5.30 (t, J = 6.4 Hz, 1H), 4.78 (d, J = 6.4 Hz, 2H), 3.95–3.91 (m, 4H), 2.02 (s, 1H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ 157.92, 144.58, 142.70, 136.26, 129.56, 121.28, 114.56, 109.90, 60.79, 60.40, 53.08 ppm. HRMS (ESI, m/z) calculated for C₁₃H₁₄N₂NaO₄ [M+Na]⁺: 285.0851, found: 285.0851. IR (neat): ν 3408, 2924, 1737, 1236 cm^–1.

(Z)-6-Benzylidene-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (5a). Pale white solid (0.30 mmol scale, 47 mg, 83% yield). R_f = 0.3 (EtOAc/petroleum ether = 1:2). ¹H NMR (400 MHz, CDCl₃): δ 8.17 (s, 1H), 7.71 (d, J = 7.6 Hz, 2H), 7.41–7.31 (m, 3H), 7.24 (s, 1H), 5.85 (s, 1H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ 154.38, 149.91, 143.79, 141.00, 138.09, 132.15, 129.88, 128.99, 128.75, 114.15 ppm. HRMS (ESI, m/z) calculated for C₁₀H₉N₂O₂ [M+H]⁺: 189.0664, found: 189.0654. IR (neat): ν 2921, 1727, 1630 cm^–1.

(Z)-6-(4-Fluorobenzylidene)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (5b). White solid (0.30 mmol scale, 54 mg, 87% yield). R_f = 0.3 (EtOAc/petroleum ether = 1:2). ¹H NMR (500 MHz, CDCl₃): δ 8.15 (s, 1H), 7.72–7.69 (m, 2H), 7.22 (s, 1H), 7.09–7.06 (m, 2H), 5.81 (s, 1H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ 162.77 (d, J = 252 Hz), 143.65, 140.67, 137.95, 131.77 (d, J = 7.6 Hz)), 128.44, (d, J = 3.8 Hz), 115.90 (d, J = 22.7 Hz), 112.75 ppm. HRMS (ESI, m/z) calculated for C₁₀H₆FN₂O₂ [M–H]^–: 205.0413, found: 205.0420. IR (neat): ν 2925, 1729, 1590 cm^–1.

(Z)-6-(4-Chlorobenzylidene)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (5c). White solid (0.30 mmol scale, 53 mg, 79% yield). R_f = 0.3 (EtOAc/petroleum ether = 1:2). ¹H NMR (500 MHz, CDCl₃): δ 8.05 (s, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.23 (s, 1H), 5.80 (s, 1H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ 143.40, 141.28, 137.79, 134.83, 131.02, 130.67, 129.02, 112.63 ppm. HRMS (ESI, m/z) calculated for C₁₀H₆ClN₂O₂ [M–H]^–: 221.0118, found: 221.0131. IR (neat): ν 2933, 1737, 1599 cm^–1.

(Z)-6-(4-Methylbenzylidene)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (5d). White solid (0.30 mmol scale, 52 mg, 85% yield). R_f = 0.3 (EtOAc/petroleum ether = 1:2). ¹H NMR (500 MHz, CDCl₃): δ 8.19 (s, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.21–7.18 (m, 3H), 5.82 (s, 1H), 2.37 (s, 3H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ 144.03, 140.47, 139.32, 138.25, 129.86, 129.50, 129.40, 114.13, 21.44 ppm. HRMS (ESI, m/z) calculated for C₁₁H₉N₂O₂ [M–H]^–: 201.0664, found: 201.0679. IR (neat): ν 2924, 1763, 1616 cm^–1.

(Z)-6-(4-Methoxybenzylidene)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (5e). Pale white solid (0.30 mmol scale, 41 mg, 63% yield). R_f = 0.2 (EtOAc/petroleum ether = 1:2). ¹H NMR (400 MHz, CDCl₃): δ 8.02 (s, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.19 (s, 1H), 6.91 (d, J = 8.6 Hz, 2H), 5.80 (s, 1H), 3.84 (s, 3H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 160.12, 144.07, 139.68, 138.35, 131.53, 124.97, 114.24, 113.86, 55.32 ppm. HRMS (ESI, m/z) calculated for C₁₁H₉N₂O₃ [M–H]^–: 217.0613, found: 217.0625. IR (neat): ν 2930, 1755, 1611, 1147 cm^–1.

(Z)-6-(Biphenylmethylene)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (5f). White solid (0.30 mmol scale, 49 mg, 62% yield). R_f = 0.3 (EtOAc/petroleum ether = 1:2). ¹H NMR (400 MHz, CDCl₃): δ 8.05 (s, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.64–7.61 (m, 5H), 7.48–7.35 (m, 3H), 5.89 (s, 1H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 143.71, 141.59, 141.05, 140.19, 138.09, 131.19, 130.35, 128.88, 127.74, 127.34, 127.01, 113.66 ppm. HRMS (ESI, m/z) calculated for C₁₆H₁₁N₂O₂ [M–H]^–: 263.0821, found: 263.0834. IR (neat): ν 2922, 1738, 1635 cm^–1.

(Z)-6-(Cyclohexylmethylene)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (5g). White solid (0.30 mmol scale, 40 mg, 69% yield). R_f = 0.3 (EtOAc/petroleum ether = 1:2). ¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 1H), 7.03 (s, 1H), 4.94 (d, J = 9.6 Hz, 1H), 2.61–2.59 (m, 1H), 1.72–1.61 (m, 14.0 Hz, 5H), 1.34–1.28 (m, 2H), 1.20–1.09 (m, 3H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 145.10, 140.28, 137.75, 122.46, 33.39, 32.09, 25.77, 25.41 ppm. HRMS (ESI, m/z) calculated for C₁₀H₁₃N₂O₂ [M–H]^–: 193.0977, found: 193.0987. IR (neat): ν 2930, 1762, 1242 cm^–1.

(Z)-6-Hexylidene-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (5h). White solid (0.30 mmol scale, 39 mg, 71% yield). R_f = 0.3 (EtOAc/petroleum ether = 1:4). ¹H NMR (400 MHz, CDCl₃): δ 8.63 (s, 1H), 7.07 (s, 1H), 5.08 (t, J = 7.7 Hz, 1H), 2.21 (q, J = 7.4 Hz, 2H), 1.43–1.29 (m, 6H), 0.88 (t, J = 6.3 Hz, 3H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 145.37, 141.65, 137.52, 117.10, 31.32, 28.18, 24.02, 22.34, 13.91 ppm. HRMS (ESI, m/z) calculated for C₉H₁₃N₂O₂ [M–H]^–: 181.0977, found: 181.0988. IR (neat): ν 2924, 1747, 1659 cm^–1.

(Z)-6-(4-Chlorobutylidene)-3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-one (5i). White solid (0.30 mmol scale, 33 mg, 54% yield). R_f = 0.3 (EtOAc/petroleum ether = 1:4). ¹H NMR (400 MHz, CDCl₃): δ 8.39 (s, 1H), 7.09 (s, 1H), 5.09 (t, J = 7.8 Hz, 1H), 3.55 (t, J = 6.6 Hz, 2H), 2.40 (q, J = 7.6 Hz, 2H), 1.91 (p, J = 6.9 Hz, 2H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 144.79, 142.45, 137.09, 114.50, 44.04, 31.28, 21.60 ppm. HRMS (ESI, m/z) calculated for C₇H₈ClN₂O₂ [M–H]^–: 187.0274, found: 187.0290. IR (neat): ν 2930, 1747, 1659, 1059 cm^–1.

Alkynic hydrazones were firstly synthesized by the reaction of alkynals with hydrazines according to reported procedures [35]. In an initial investigation, alkynic aryl hydrazone was found to react with CO₂ to give very low yields of the cyclization product under different reaction conditions due to the low nucleophilic reactivity of the nitrogen atom. As a consequence, phenylpropynal 2-hydroxyethylhydrazone (1a) was chosen as the model substrate for the reaction with CO₂ to identify the optimal conditions (Table 1).

Considering that silver(I) salts can function as an effective π-Lewis acid catalyst for alkyne activation in carboxylation and other reactions [36-41], various silver-based catalytic systems were screened. The reaction of 1a with 2 MPa CO₂ using 5 mol% AgOAc as the catalyst and 1.5 equivalent Cs₂CO₃ as the base in DMSO at 25 ℃ was found to readily afford the carboxylative cyclization product 3, 6-dihydro-2H-1, 3, 4-oxadiazin -2-one (2a) in 87% isolated yield (Table 1, entry 1). It should be noted that the geometry of the C=N bond in hydrazone substrates had no effect on the reactivity, probably due to the rapid conversion of the two isomers Z-1a and E-1a. The structural assignment of the isolated product was further confirmed by single-crystal X-ray analysis of 2a [42]. As shown in Fig. 1, the newly formed C=C bond in the product exhibits Z configuration, the typical structure obtained from Ag-catalyzed electrophilic cyclizations. Other silver(I) salts such as AgI, AgBF₄, Ag₂CO₃, and AgNO₃ displayed inferior catalytic performance than AgOAc (see SI). CuI showed lower catalytic activity than AgOAc (entry 2), while Pd(OAc)₂ afforded no carboxylated product and 1a was fully recovered (entry 3). The replacement of Cs₂CO₃ with K₂CO₃ or CsF resulted in a slight decrease in the yield of 2a (entries 4 and 5). Although DBU is frequently employed as an efficient base in many carboxylation reactions using CO₂, only 30% yield of 2a was obtained when applied as the base (entry 6). Switching the base to KO^tBu and NaH led to the exclusive formation of the non-carboxylative cyclization product pyrazole 3a (entries 7 and 8) [35, 43]. The CO₂ pressure had an obvious effect on the reaction. A lower yield of 2a was obtained when the reaction was conducted at low CO₂ pressure (entry 9). The reaction did not proceed in the absence of CO₂, indicating that the carbonyl moiety in the resulting product originates from CO₂ rather than from the carbonate base (entry 10). Interestingly, 2a in 75% yield was still obtained in the absence of a base (entry 11), implying that hydrazone 1a itself may serve as a base in this process. To maintain the high efficiency of the reaction, a catalytic amount of base was added. The presence of 5 mol% Cs₂CO₃ was enough to achieve 85% yield of 2a (entry 11), which is comparable to the result using stoichiometric bases (entries 1 and 4). No product was observed in the absence of the catalyst, confirming the catalytic role of the silver(I) salt (entry 12). Finally, further screening experiments revealed DMSO as the optimal solvent for this reaction (see SI).

Under the optimized reaction conditions, the scope of the silver-catalyzed carboxylative cyclization with regard to alkynic hydrazone substrates was investigated (Table 2). In addition to phenylpropynal 2-hydroxyethylhydrazone (1a), other N-alkyl substituted hydrazones such as 2-cyanoethylhydrazone (1b), isopropylhydrazone (1c), and benzylhydrazone (1d) were found to be suitable substrates for this reaction. Arylpropynal 2-hydroxyethylhydrazones bearing various functional groups including electron-withdrawing (fluoro, chloro) and electron-donating (methyl, methoxyl) substituents reacted smoothly to afford the corresponding 3, 6-dihydro-2H-1, 3, 4-oxadiazin-2-ones (2e–2h) in good yield. Alkyl-substituted propynal 2-hydroxyethylhydrazones 1i–1l participated efficiently in the carboxylative cyclization reaction furnishing the corresponding products in moderate to good yield.

Since nitrogen heterocycles in medicinal compounds frequently present NH moieties, many synthetic processes involve redundant nitrogen protection/deprotection steps. Therefore, carboxylative cyclization reactions of propynal hydrazone substrates 4 to give directly N-unsubstituted products 5 were then examined (Table 3). Using the same reaction conditions to those applied to N-substituted hydrazone substrates 1, substrates 4 containing electron-withdrawing or electron-donating aryl and alkyl substituents on the alkyne moiety furnished the desired products 5 in satisfactory yield. The geometry of the newly formed C=C bonds in oxadiazinones 5 was also identified as that of Z isomers based on NOE experiments for products 5a and 5g (see SI).

This catalytic reaction is readily scalable for both types of substrates, as exemplified by the synthesis of 2a (83% yield) and 5a (85% yield) at gram scale with longer reaction times (Scheme 1). It should be mentioned that the isolated yield of 5a at 0.8 mmol scale (Scheme 1) was slightly higher than the yield obtained at 0.3 mmol scale (Table 3).

In addition to the control experiments in Table 1 illustrating the catalytic role of silver(I) salts and the need for CO₂ in this reaction, the reaction of 4a with CO₂ in DMSO-d₆ was further examined to detect possible reactive intermediates by NMR spectroscopy.

As shown in Fig. 2, the ¹H NMR spectrum of 4a saturated with atmospheric CO₂ in DMSO-d₆ (Fig. 2(a)) was found to be identical to that of 4a without CO₂, implying that the formation of a carbazate intermediate in the absence of an external base is inefficient despite the hydrazone itself being able to act as a base. When a catalytic amount of Cs₂CO₃ was added to the reaction system, two obvious new signals appeared at 6.26 and 8.23 ppm, assigned to the carbazate intermediate (Fig. 2(b)). The amount of this species gradually increased to a 1:4 ratio relative to 4a (Fig. 2(c)). When 10 mol% of AgOAc was added to the reaction system, the signals for the carbazate intermediate and 4a began to disappear, while the signals of product 5a started to emerge (Fig. 2(d)). After 2 h, the hydrazone substrate was completely converted into the oxadiazinone product and no obvious signals for the carbazate intermediate were detected anymore (Fig. 2(e)).

On the basis of the above experiments, a plausible mechanism for this reaction is proposed in Scheme 2. The Z-isomer of the hydrazone substrate enters a productive catalytic cycle where it interacts with the base. The reaction of the NH moiety of the hydrazone with CO₂ affords the reactive carbazate intermediate B. Then, the carboxylate oxygen atom conducts a nucleophilic attack on the silver(I)-activated alkyne moiety affording vinylic silver intermediate C. The following protonation reaction finally furnishes the carboxylative cyclization product, with concomitant regeneration of the catalyst and release of the base.

We have developed a silver(I)-catalyzed carboxylative cyclization of alkynic hydrazones under mild reaction conditions. Silver(I) salts show high activity in this reaction as π-Lewis acid catalysts for alkyne activation, and the use of catalytic amounts of a base such as cesium carbonate is sufficient to guarantee the rapid formation of the reactive carbazate intermediate. This reaction provides a highly efficient and convenient approach to synthesize biologically important 1, 3, 4-oxadiazin-2-one compounds in good yield using CO₂ as the carboxylative reagent.