Urea and oxamide derivatives are crucial in a diverse array of fields, including biological metabolism, medical therapeutics and small molecule catalysis^[1−2]. Traditionally, these compounds have been synthesized using methods involving phosgene and oxalyl chloride, which pose significant environmental and corrosive risks (Fig. 1(a))^[3]. In an effort to address these concerns and improve synthesis efficiency, the field has seen a shift towards the oxidative carbonylation^[4−8] of amines using carbon monoxide as a carbonyl source with various transition metal catalysts like Au^[9−11], Co^[12] and Pd^[13−19] (Fig. 1(b)). Despite this progress, achieving selectivity between mono- and double-carbonylation remains a substantial challenge. The literature indicates that precise control over this selectivity is complex, necessitating sophisticated catalyst design and meticulous condition optimization^[20−24]. Further-more, safety concerns persist due to the potential explosiveness of oxygen-CO mixtures during these reactions.

Our design presents a reactivity control strategy of palladium amide enabled by regulating the competitive reactivity of palladium amide intermediates in the palladium-catalyzed amine carbonylation reaction (Fig. 1(c)). In this reaction, the palladium amide may undergo oxidation and future reacting with the amine, yielding a mono-carbonyl product. At higher CO concentrations, a faster subsequent CO reaction prior to reaction of the Pd amide with the amine would favor the formation of the oxamide. Based on this mechanism, we utilize sodium percarbonate (SPC), which can act as both an oxidant and a base^[25]. In contrast to molecular oxygen (e.g. E_1/2(O₂) vs NHE (Normal Hydrogen Electrode) = −1.23 V), hydrogen peroxide tends to possess stronger oxidant activities (e.g. E_1/2(H₂O₂) vs NHE = −1.78 V)^[26]. Given the superior oxidizing strength of hydrogen peroxide, the use of SPC is anticipated to positively influence the reaction progress, enabling reaction to proceed under milder, safer and more practical conditions. Although palladium-catalyzed double-carbonylation is well-known, this catalytic system has not been applied to controllable mono-carbonyl reactions of secondary amines. Our experimental results show that using SPC as a dual reagent, urea can be obtained in the yield of 61%~89% with the selectivity of 91%~99% at room temperature and 0.1 MPa CO; when the CO pressure is increased to 3 MPa, the reaction selectivity of is reversed, and oxamide can be obtained in the yield of 66%~94% with selectivity of 95%~99% (Fig. 1(d)). Consequently, SPC emerges as an eco-friendly and versatile reagent, presenting a practical alternative to traditional oxidative carbonylation methods in laboratory settings. An in-depth understanding of the reaction mechanism allows for control over the formation of targeted carbonylated products, presenting an alternative approach for more selective and safer synthesis.

1 Experimental section 1.1 General procedure

All commercially available reagents were purchased in high purity and used without further purification. All air sensitive manipulations were carried out using a standard Schlenk techniques or nitrogen-filled glove box under N₂ atmosphere. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker Avance-400 (400 MHz) spectrometer. The chemical shifts (δ) were given in 10⁻⁶ related to internal tetramethyl silane (TMS, δ=0 for ^lH NMR), CDCl₃ (δ=77.16 for ¹³C NMR). All ¹H NMR spectra were reported in delta (δ) units, 10⁻⁶ downfield from the internal standard. Coupling constants are reported in Hertz (Hz). The multiplicities of signals are designated by the following abbreviations: s (singlet), d (doublet), t (triplet), q (quarter), m (multiplet), dd (doublet and doublet), dt (doublet and triplet), td (triplet and doublet). GC was performed on an Agilent 6890 instrument equipped with a HP-5 (30 m × 0.53 mm × 1.0 μm), biphenyl as an internal standard. Electron impact (EI) mass spectra were recorded on SHIMADZU GCMS-QP2010 SE mass spectrometer. High resolution mass spectra were recorded on an Agilent 1260-6530 Accurate-Mass Q-TOF LC/MS.

CAUTION: Carbon monoxide is an odorless, colorless, tasteless, poisonous gas. The permissible exposure limit (PEL) for CO set forth by OSHA is 50 mg∙L⁻¹ for eight hours. The immediately dangerous to life or health (IDLH) value set forth by the US National Institute for Occupational Safety and Health (NIOSH) is 1200 mg∙L⁻¹. CO handling requires a well-ventilated, operational fume hood. However, if any amount of CO is detected in the laboratory, steps must be taken to stop the leakage and potential exposure to CO.

1.2 Synthesis of Pd-Cl amide^[27]

A 25 mL thick-walled Schlenk tube with a Teflon vale was charged with a magnetic stir bar, Pd(PPh₃)₂Cl₂ (500.0 mg, 0.71 mmol, mole ratio 1), piperidine (604.5 mg, 7.1 mmol, mole ratio 10), and then CH₃CN (10 mL) was added under N₂ atmosphere. The mixture was sealed and degassed by three freeze-pump-thaw cycles and refilled with CO (0.1 MPa). The reaction was then placed under dark condition and stirred for 2 h at room temperature. The product was filtered, washed with ethanol and Et₂O to obtain white powder (532 mg, yield 96%).

Crystals of Pd-Cl amide were grown by slow diffusion of hexane into CH₂Cl₂, resulting in thin colorless crystals. The structure was further confirmed by X-ray crystallography (CCDC 2322811). A suitable crystal was selected and collected on a Bruker APEX-II CCD diffractometer. The crystal was kept at −123.15 °C during data collection. Using OLEX2^[28], the structure was solved with the SHELXT^[29] structure solution program using Intrinsic Phasing and refined with the SHELXL^[30] refinement package using Least Squares minimisation.

¹H NMR (400 MHz, CDCl₃) δ 7.78 – 7.34 (m, 30H), 3.69 – 3.62 (m, 2H), 2.46 – 2.21 (m, 2H), 1.11 – 0.84 (m, 4H), 0.50 (s, 2H).

³¹P NMR (162 MHz, CDCl₃) δ 23.30, 20.13.

1.3 Procedure A for mono-carbonylation of amines

In a nitrogen-filled glove box, the reactions were carried out in a 10 mL Schlenk tube with a magnetic stirrer. As a typical run, piperidine (85.1 mg, 1 mmol, mole ratio 1) and Na₂CO₃·1.5H₂O₂ (314.0 mg, 2 mmol, mole ratio 2) were introduced following adding Pd(acac)₂ (0.01 mmol, 3.0 mg) and tetra-n-hexylammonium iodide ⁿHex₄NI (0.1 mmol, 48.1 mg). The mixture was stirred for 1 min after adding THF (2 mL). After sealing with a rubber stopper, the tube was removed from the glove box and a balloon of CO was connected to the tube. Then the tube was stirred at room temperature until the piperidine had been completely consumed as judged by GC analysis. The reaction mixture was then washed with water and ethyl acetate and the organic layer was concentrated in vacuo. After removal of the solvent, the residues were purified by flash column chromatography on silica gel using hexane/ethyl acetate as eluent to afford corresponding product.

1.4 Procedure B for double-carbonylation of amines

The reactions were carried out in a 25 mL stainless steel autoclave with a magnetic stirrer. As a typical run, piperidine (85.1 mg, 1 mmol, mole ratio 1) and Na₂CO₃·1.5H₂O₂ (314.0 mg, 2 mmol, mole ratio 2) were introduced following adding Pd(acac)₂ (0.01 mmol, 3.0 mg), ⁿHex₄NI (0.1 mmol, 48.1 mg) and THF (2 mL). The autoclave is flushed with carbon monoxide for three times and then carbon monoxide was charged to desired pressure. Then the autoclave was stirred at room temperature for 5 h. After being cooled to room temperature, the reaction pressure was reduced to the atmosphere. After removal of the solvent, the residue was purified by flash column chromatography on silica gel using ethyl acetate as eluent to afford corresponding product.

1.5 Gram-scale experiment

In a nitrogen-filled glove box, the reactions were carried out in a 100 mL Schlenk tube with a magnetic stirrer. As a typical run, piperidine (1.70 g, 20 mmol, mole ratio 1) and Na₂CO₃·1.5H₂O₂ (6.28 g, 40 mmol, mole ratio 2, based on amount of Na₂CO₃) were introduced following adding Pd(acac)₂ (0.2 mmol, 60.9 mg) and ⁿHex₄NI (2.0 mmol, 963 mg). The mixture was stirred for 1 min after adding THF (20 mL). After sealing with a rubber stopper, the tube was removed from the glove box and a balloon of CO was connected to the tube. Then the tube was stirred at room temperature until the piperidine had been completely consumed as judged by GC analysis. The selectivity was detected by GC-MS. The reaction mixture was then washed with water and ethyl acetate and the organic layer was concentrated in vacuo. After removal of the solvent, the residue was purified by flash column chromato-graphy on silica gel using hexane/ethyl acetate as eluent to afford corresponding product as oil (1.73 g, 73%).

1.6 Characterization data of product

The title compound was prepared according to the general procedure A and purified by column chromatography using: Hexane∶ethyl acetate = 10∶1 as eluent to afford corresponding product as light-yellow oil (79.5 mg, 81%).

¹H NMR (400 MHz, CDCl₃) δ 3.23 – 3.12 (m, 8H), 1.62 – 1.47 (m, 12H).

¹³C NMR (101 MHz, CDCl₃) δ 164.85, 48.01, 25.85, 24.85.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₁H₂₁N₂O⁺) requires m/z 197.1648, Found m/z = 197.1650.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as light-yellow oil (55.5 mg, 66%).

¹H NMR (400 MHz, CDCl₃) δ 3.43 – 3.30 (m, 8H), 1.89 – 1.77 (m, 8H).

¹³C NMR (101 MHz, CDCl₃) δ 161.47, 47.96, 25.58.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₉H₁₇N₂O⁺) requires m/z 169.1335, Found m/z = 169.1331.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as light-yellow oil (83.0 mg, 74%).

¹H NMR (400 MHz, CDCl₃) δ 3.31 (t, 8H), 1.79 – 1.67 (m, 8H), 1.64 – 1.49 (m, 8H).

¹³C NMR (101 MHz, CDCl₃) δ 165.78, 49.46, 28.74, 27.53.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₃H₂₅N₂O⁺) requires m/z 225.1961, Found m/z = 225.196 3.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as white powder (68.1 mg, 68%).

¹H NMR (400 MHz, CDCl₃) δ 3.68 (t, 8H), 3.28 (t, 8H).

¹³C NMR (101 MHz, CDCl₃) δ 163.83, 66.64, 47.26.

HRMS (ESI-TOF) exact mass calculated for [M+Na]⁺ (C₉H₁₆N₂O₃Na⁺) requires m/z 223.1053, Found m/z = 223.1055.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as light-yellow oil (49.0 mg, 68%).

¹H NMR (400 MHz, CDCl₃) δ 3.18 (q, J = 7.1 Hz, 4H), 2.77 (s, 6H), 1.14 (t, J = 7.1 Hz, 6H).

¹³C NMR (101 MHz, CDCl₃) δ 165.52, 45.17, 35.74, 12.85.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₇H₁₇N₂O⁺) requires m/z 145.1335, Found m/z = 145.133 6.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as white powder (89.1 mg, 89%).

¹H NMR (400 MHz, CDCl₃) δ 5.67 (s, 2H), 3.13 (t, J = 6.7 Hz, 4H), 1.47 (m, 4H), 1.35 – 1.25 (m, 8H), 0.89 (t, J = 6.9 Hz, 6H).

¹³C NMR (101 MHz, CDCl₃) δ 159.47, 40.32, 30.21, 29.22, 22.52, 14.05.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₁H₂₅N₂O⁺) requires m/z 201.1961, Found m/z = 201.196 3.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as white powder (99.3 mg, 87%).

¹H NMR (400 MHz, CDCl₃) δ 5.53 (s, 2H), 3.12 (t, J = 7.1 Hz, 4H), 1.59 – 1.39 (m, 4H), 1.35 – 1.20 (m, 12H), 0.88 (t, J = 6.8 Hz, 6H).

¹³C NMR (101 MHz, CDCl₃) δ 159.38, 40.44, 31.74, 30.50, 26.79, 22.70, 14.11.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₃H₂₉N₂O⁺) requires m/z 229.227 4, Found m/z = 229.227 4.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as light-yellow powder (64.7 mg, 61%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 2H), 7.47 (d, J = 7.7 Hz, 4H), 7.28 (t, J = 7.9 Hz, 4H), 6.97 (t, J = 7.3 Hz, 2H).

¹³C NMR (101 MHz, DMSO-d₆) δ 152.56, 139.74, 128.81, 121.82, 118.19.

HRMS (ESI-TOF) exact mass calculated for [M+Na]⁺ (C₁₃H₁₂N₂ONa⁺) requires m/z 235.0842, Found m/z = 235.084 7.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as white powder (76.9 mg, 64%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.35 – 7.19 (m, 10H), 6.48 – 6.40 (m, 2H), 4.33 – 4.13 (m, 4H).

¹³C NMR (101 MHz, DMSO-d₆) δ 158.20, 140.96, 128.27, 127.03, 126.60, 43.04.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₅H₁₇N₂O⁺) requires m/z 241.1335, Found m/z = 241.133 8.

The title compound was prepared according to the general procedure B and purified by column chromatography using: Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as light-yellow powder (103.1 mg, 92%).

¹H NMR (400 MHz, CDCl₃) δ 3.58 (t, 4H), 3.34 (t, 4H), 1.72 – 1.56 (m, 12H).

¹³C NMR (101 MHz, CDCl₃) δ 163.55, 47.23, 41.75, 26.45, 25.34, 24.43.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₂H₂₁N₂O₂⁺) requires m/z 225.1598, Found m/z = 225.159 6.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as white solid (92.2 mg, 94%).

¹H NMR (400 MHz, CDCl₃) δ 3.63 – 3.31 (m, 8H), 2.00 – 1.88 (m, 8H).

¹³C NMR (101 MHz, CDCl₃) δ 163.09, 46.68, 44.84, 25.65, 23.93.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₀H₁₇N₂O₂⁺) requires m/z 197.1285, Found m/z = 197.129 1.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as colorless oil (90.8 mg, 72%).

¹H NMR (400 MHz, CDCl₃) δ 3.60 – 3.48 (m, 4H), 3.45 – 3.37 (m, 4H), 1.84 – 1.71 (m, 8H), 1.67 – 1.56 (m, 8H).

¹³C NMR (101 MHz, CDCl₃) δ 165.26, 47.99, 44.58, 28.93, 27.90, 27.00, 26.41.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₄H₂₅N₂O₂⁺) requires m/z 253.1911, Found m/z = 253.191 4.

Ethyl acetate as eluent to afford corresponding product as white powder (84.4 mg, 74%).

¹H NMR (400 MHz, CDCl₃) δ 3.75 – 3.69 (m, 8H), 3.66 (t, 4H), 3.45 (t, 4H).

¹³C NMR (101 MHz, CDCl₃) δ 162.81, 66.89, 66.59, 46.58, 41.51.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₀H₁₇N₂O₄⁺) requires m/z 229.1183, Found m/z = 229.118 8.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as light-yellow oil (76.6 mg, 89%).

¹H NMR (400 MHz, CDCl₃) δ 3.47 (q, J = 7.2 Hz, 2H), 3.31 (q, J = 7.1 Hz, 2H), 2.97 (d, J = 1.2 Hz, 3H), 2.96 (d, J = 1.7 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 165.05, 164.72, 44.86, 44.75, 40.95, 40.90, 34.52, 34.25, 30.79, 30.75, 13.46, 13.42, 11.87, 11.84.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₈H₁₇N₂O₂⁺) requires m/z 173.1285, Found m/z = 173.129 0.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as white solid (76.6 mg, 89%).

¹H NMR (400 MHz, CDCl₃) δ 3.45 (q, J = 7.2 Hz, 4H), 3.29 (q, J = 7.1 Hz, 4H), 1.25 – 1.16 (m, 12H).

¹³C NMR (101 MHz, CDCl₃) δ 164.70, 42.26, 38.25, 13.95, 12.54.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₀H₂₁N₂O₂⁺) requires m/z 201.1598, Found m/z = 201.160 1.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as light-yellow oil (85.9 mg, 67%).

¹H NMR (400 MHz, CDCl₃) δ 3.34 (t, 4H), 3.15 (t, 4H), 1.70 – 1.56 (m, 8H), 0.94 (t, J = 7.4 Hz, 6H), 0.88 (t, J = 7.4 Hz, 6H).

¹³C NMR (101 MHz, CDCl₃) δ 165.15, 49.65, 45.37, 21.66, 20.38, 11.33, 11.09.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₄H₂₉N₂O₂⁺) requires m/z 257.2224, Found m/z = 257.223 1.

Hexane∶ethyl acetate = 1∶1 as eluent to afford corresponding product as light-yellow oil (103.1 mg, 66%).

¹H NMR (400 MHz, CDCl₃) δ 3.37 (t, 4H), 3.17 (t, 4H), 1.64 – 1.50 (m, 8H), 1.38 – 1.24 (m, 8H), 0.96 – 0.88 (m, 12H).

¹³C NMR (101 MHz, CDCl₃) δ 165.14, 47.87, 43.60, 30.60, 29.34, 20.26, 20.09, 13.87, 13.76.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₈H₃₇N₂O₂⁺) requires m/z 313.2850, Found m/z = 313.285 4.

Hexane∶ethyl acetate = 3∶1 as eluent to afford corresponding product as light-yellow oil (80.5 mg, 82%).

¹H NMR (400 MHz, CDCl₃) δ 5.87 – 5.71 (m, 2H), 5.33 – 5.20 (m, 4H), 4.03 (t, J = 6.3 Hz, 2H), 3.88 (dd, J = 10.9, 6.0 Hz, 2H), 2.95 (t, J = 0.0 Hz, 6H).

¹³C NMR (101 MHz, CDCl₃) δ 164.93, 164.89, 164.64, 164.58, 132.34, 132.17, 131.44, 131.43, 118.91, 118.47, 118.38, 52.68, 52.46, 48.39, 48.30, 34.66, 34.31, 31.21, 31.14.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₀H₁₇N₂O₂⁺) requires m/z 197.1285, Found m/z = 197.128 7.

Ethyl acetate as eluent to afford corresponding product as white solid (112.3 mg, 82%).

¹H NMR (400 MHz, CDCl₃) δ 3.84 – 3.31 (m, 8H), 3.10 – 2.92 (m, 2H), 2.06 – 1.80 (m, 8H).

¹³C NMR (101 MHz, CDCl₃) δ 162.64, 120.39, 44.19, 44.07, 38.91, 38.78, 28.73, 28.68, 27.89, 27.84, 26.18, 26.12.

HRMS (ESI-TOF) exact mass calculated for [M+H]⁺ (C₁₄H₁₉N₄O₂⁺) requires m/z 275.1503, Found m/z = 275.148 9.

Ethyl acetate as eluent to afford corresponding product as white solid (111.4 mg, 79%).

¹H NMR (400 MHz, CDCl₃) δ 4.46 – 4.33 (m, 2H), 3.83 – 3.58 (m, 6H), 3.43 – 3.28 (m, 2H), 2.29 – 2.04 (m, 4H), 1.98 – 1.81 (m, 4H).

¹³C NMR (101 MHz, CDCl₃) δ 162.92, 162.89, 56.00, 55.91, 43.05, 42.93, 37.73, 37.61, 34.87, 34.79, 33.96, 33.90.

HRMS (ESI-TOF) exact mass calculated for [M+Na]⁺ (C₁₂H₁₈Cl₂N₂O₂Na⁺) requires m/z 315.0638, Found m/z = 315.064 3.

Ethyl acetate as eluent to afford corresponding product as colorless oil (88.1 mg, 62%).

¹H NMR (400 MHz, CDCl₃) δ 3.88 – 3.75 (m, 2H), 3.62 – 3.45 (m, 6H), 3.36 (s, 6H), 3.28 – 3.16 (m, 2H), 2.00 – 1.80 (m, 4H), 1.74 – 1.57 (m, 4H).

¹³C NMR (101 MHz, CDCl₃) δ 163.35, 163.32, 74.74, 55.90, 43.11, 37.73, 30.98, 30.95, 29.82, 29.78.

HRMS (ESI-TOF) exact mass calculated for [M+Na]⁺ (C₁₄H₂₄N₂O₄Na⁺) requires m/z 307.1628, Found m/z = 307.162 8.

Ethyl acetate as eluent to afford corresponding product as white solid (149.7 mg, 76%).

¹H NMR (400 MHz, CDCl₃) δ 7.15 (d, J = 30.0 Hz, 1H), 7.06 (d, J = 4.7 Hz, 1H), 4.71 (d, J = 11.7 Hz, 2H), 4.62 – 4.57 (m, 2H), 3.32 – 3.18 (m, 2H), 3.13 – 3.05 (m, 3H), 3.04 – 2.97 (m, 3H), 1.42 – 1.29 (m, 12H).

¹³C NMR (101 MHz, CDCl₃) δ 178.50, 178.41, 178.28, 178.26, 165.20, 165.10, 165.05, 164.94, 150.58, 150.54, 150.43, 115.68, 115.48, 114.75, 114.34, 50.01, 49.52, 46.02, 45.55, 35.74, 35.06, 33.17, 33.14, 31.81, 31.57, 23.10, 23.05.

HRMS (ESI-TOF) exact mass calculated for [M+Na]⁺ (C₁₈H₂₆N₄O₂S₂Na⁺) requires m/z 417.1389, Found m/z = 417.139 0.

2 Results and discussion

At the beginning, inspired by previous literature, we focused on the role of Pd-Cl amide in the carbonylation of amines (Fig. 2)^{[17, 27]}. The synthesis of Pd-Cl amide was achieved by reacting Pd(PPh₃)₂Cl₂ with carbon monoxide (CO) and piperidine (1a) under ambient conditions. High-resolution mass spectrometry (HR-MS) confirmed the formation of the Pd amide species with an m/z of 742.1614, corresponding to the Pd⁺ amide ion. Single crystal X-ray diffraction revealed a four-coordinate palladium complex (Fig. 2(a)). The bond angles between Pd―C and P1, Pd―C and P2 are 89.7° and 88.3°, respectively. The Pd―C bond length is 0.200 1 nm, and the C―O bond length is 0.122 7 nm. Infrared (IR) spectra further validated the formation of Pd-Cl amide, with characteristic absorption bands at 1585 cm⁻¹ and 1598 cm⁻¹, indicative of the CO stretch in the amide complex, absent in the spectrum of the starting Pd(PPh₃)₂Cl₂ (Fig. 2(b)).

Further cyclic voltammetry (CV) studies were employed to dissect the redox characteristics of the Pd-Cl amide and other possible catalytic species, providing insights into the electron transfer processes that underpin the carbonylation reaction (Fig. 3). The CV analysis implies that iodide ions may be preferentially oxidized over Pd-Cl amide and Pd(0) species, which could affect the course of the catalytic reaction and the formation of products (Fig. 3(a)-(ⅰ)). Furthermore, the mixture of Pd-Cl amide and ⁿHex₄NI showed an obvious peak at 0.7 V, indicating that the oxidation was generated by the reduction of I₂ under 0.1 MPa CO pressure^[31]. Further studies found that when Pd-Cl amide was mixed directly with iodine, an increase in chemical shifts was clearly seen in the ³¹P NMR spectra^[32−33], indicating that the palladium was further oxidized and the electronegativity of the palladium increased. In catalytic oxidative carbonylation reactions, the preferential oxidation of iodide ions could lead to the formation of iodine species, which may further interact with other reactants, such as Pd amide and Pd(0) species thus influencing the efficiency and selectivity of the entire oxidative carbonylation cycle^{[14, 34−38]}. The CV analysis revealed discernible electrochemical signatures for various ammonium salts, with the voltammetric profiles suggesting that anion and alkyl chain length significantly influences their redox behavior (Fig. 3(a)-(ⅱ)). Different onset potentials for oxidation were observed, with ⁿHex₄NI exhibiting easier oxidation. Subsequent reactivity studies of the Pd-Cl amide complex in mono-carbonylation reactions revealed its capability to transform amine 1a into the corresponding 2a under various conditions. When sodium percarbonate and ⁿHex₄NI were used in a 2∶1 mole ratio, a modest 17% GC yield of 2a was observed (Entry 1). In the absence of ⁿHex₄NI, no desired product was detected (n.d.), highlighting the importance of this additive (Entry 2). Likewise, the use of ⁿHex₄NI alone did not lead to product formation, suggesting that both the oxidant and the additive are crucial for the reaction to proceed (Entry 3). Notably, the inclusion of iodine (I₂) as an oxidant led to a significantly enhanced yield of 53%, indicating that iodine may play a role in activating the Pd-Cl amide towards 2a (Entry 4). For double-carbonylation reactions, the Pd-Cl amide complex demonstrated exceptional selectivity in the presence of a higher CO pressure (3.0 MPa), converting amine 1a exclusively to the double-carbonylated product 3a with a yield of over 99% (Fig. 3(b)). This stark contrast in reactivity under different CO pressures suggests that the Pd-Cl amide complex can be finely tuned to favor either mono- or double-carbonylation based on the reaction conditions. This information is crucial for understanding the catalytic mechanism and for further optimization of the catalytic system.

After having confirmed the successful control of the palladium amide reactivity, our next objective was to apply it in the oxidative carbonylation of amines. To demonstrate the viability of the strategy, we evaluate the outcomes of various systems in the carbonylation of piperidine at room temperature using palladium catalyst (0.01 mmol) and ⁿHex₄NI (0.10 mmol) (Table 1). Notably, the use of sodium percarbonate (SPC) as an oxidant yielded moderate to high yields of the desired carbonylation product 2a, with the highest yield of 86% being achieved under 0.1 MPa CO for 12 h (Entry 1 to 3). Conversely, using sodium perborate (NaBO₃) alone resulted in significantly lower yields (Entry 4), but when combined with Na₂CO₃, the yield and selectivity towards mono-carbonylation improved within 5 h (Entry 5), underscoring the synergistic effect of the base in enhancing catalytic activity. Since sodium percarbonate is solid peroxygen compounds, it will slowly release the hydrogen peroxide and the basic sodium carbonate in solution.^[39] At the same time, the slow release of anhydrous hydrogen peroxide will be more favorable to the reaction as sodium percarbonate is not soluble under THF in the system. When the reaction was conducted with H₂O₂ (30%) and Na₂CO₃ as the oxidant and base, no desired product was detected (n.d.) (Entry 6). The use of potassium persulfate (K₂S₂O₈) and tert-butyl hydroperoxide (TBHP) resulted in significantly lower 21 and 12 yields of 2a (Entry 7 and 8). We tested the results using ⁿBu₄NBr and ⁿBu₄NCl in place of ⁿHex₄NI and no product formation was detected, which also demonstrates the importance of the iodide ion in the reaction (Entry 9 and 10). This is in line with the previously mentioned results of using cyclic voltammetry to test different quaternary ammonium salts, ⁿHex₄NI is more susceptible to oxidation. (Fig. 3 (a)-(ⅱ)), and consequently the system is the most reactive when ⁿHex₄NI is used as a redox promoter.

Furthermore, the reaction atmosphere was found to be a critical parameter. Under ambient air, the system favored double-carbonylation exclusively (Entry 11). The yield of 3a is further amplified to 95% with increased CO pressure (Entry 12). A noteworthy observation is that increasing the CO pressure to 3.0 MPa in the presence of SPC as an oxidant drastically increased the selectivity towards the doubly carbonylated product 3a with 97% selectivity (Entry 13). These results suggest that the choice of oxidant, the presence of a base, and the reaction atmosphere play pivotal roles in dictating the yield and selectivity of carbonylation reactions. The use of SPC under low CO pressure appears to be the most effective condition among those tested, providing a promising route for the selective synthesis of the mono-carbonylated product. When the reaction pressure increases, the reaction selectivity is reversed and the reaction becomes more likely to obtain oxamide products.

The scope of the optimized carbonylation conditions was extensively investigated, with various amines subjected to both mono- and double-carbonylation reactions (Fig. 4). For mono-carbonylation, the reaction exhibits considerable versatility. Piperidine (1a) underwent carbonylation with an excellent yield of 81%. Large-scale synthesis confirmed the reaction's robustness, producing 1.73 g of the product from a 20 mmol starting amount of 1a. Other cyclic amines, such as pyrrolidine (1b), azepane (1c) and morpholine (1d), also provided 66%~74% yields, respectively. The reaction was further tested on N-methyl-ethylamine (1e), which produced a 68% yield. Primary amines (2f−2i), including alkyl, aromatic and aromatic amines were also successfully carbonylated, with yields ranging from 64% to 89%, demonstrating the applicability of our method. Under the optimized conditions for dicarbonylation, we observed similarly encouraging results. Piperidine (1a) achieved an exceptional yield of 92%, while pyrrolidine (1b), azepane (1c) and morpholine (1d) resulted in a 72%~94% yield. Moreover, the reaction was tolerant of different alkyl substituents on the nitrogen atom, as evidenced by the yields of 66%~89% for 3e−3h, with selectivity exceeding 95%. These findings demonstrate that the developed catalytic system possesses a broad substrate scope and can facilitate both mono- and double-carbonylation reactions of secondary amines with high efficiency. The reaction has a wide functional group tolerance and can be applied to amines with vinyl, cyano, chloro, methoxy, and thiazole rings (3i−3m). However, aniline yielded only a mono-carbonyl product even under high CO pressure. This versatility is indicative of the potential applicability of this catalytic system in the synthesis of a diverse array of amide compounds, which could have significant implications in the pharmaceutical and materials science sectors.

Drawing on our experimental results and relevant literature, we propose a tentative concerted catalytic mechanism for both mono- and double-carbonylation reactions (Fig. 5)^{[25, 39−41]}. In the mono-carbonylation cycle, sodium percarbonate, along with I⁻, activates the Pd amide complex. This complex then interacts with the amine, facilitating urea formation. Here, sodium percarbonate also serves as a base, deprotonating intermediates to aid the carbonylation step. For double-carbonylation, under high CO pressure, the activated Pd amide complex undergoes a second CO insertion step, leading to oxamide production. Sodium percarbonate again fulfills a dual role, both re-oxidizing the palladium center and providing the base for deprotonation. The combined spectroscopic and reactivity data presented in this study provide compelling evidence for the active role of the Pd-Cl amide complex in the catalytic cycle of amine carbonylation. The ability to control the selectivity of the reaction by varying the CO pressure and the use of ⁿHex₄NI offers a valuable insight into the mechanistic aspects of amide bond formation using palladium catalysis.

3 Conclusions

In this work, we have established a novel approach for selective carbonylation using reactivity control strategy of palladium amides, effectively addressing the challenge of achieving specific mono- or dicarbonylation on single substrates. Our study provides an in-depth understanding of palladium amide reactivity, illustrated by controlled experiments and cyclic voltammetry studies. We demonstrate that, under varying CO pressures, the use of sodium percarbonate as an oxidant and base enables a switchable carbonylation system, yielding urea with up to 89% and oxamide with up to 94% yield, showcasing impressive selectivity (91%~99% for urea, 95%~99% for oxamide). This approach not only enhances the efficiency of the carbonylation process but also significantly reduces the risk of explosions, a notable concern in traditional methods. We anticipate that this work will inspire further exploration in the field of catalysis chemistry, potentially leading to more advanced and sustainable chemical synthesis processes.