Reductive cyanation of organic chlorides using CO2 and NH3 via Triphos–Ni(I) species

Cyano-containing compounds constitute important pharmaceuticals, agrochemicals and organic materials. Traditional cyanation methods often rely on the use of toxic metal cyanides which have serious disposal, storage and transportation issues. Therefore, there is an increasing need to develop general and efficient catalytic methods for cyanide-free production of nitriles. Here we report the reductive cyanation of organic chlorides using CO2/NH3 as the electrophilic CN source. The use of tridentate phosphine ligand Triphos allows for the nickel-catalyzed cyanation of a broad array of aryl and aliphatic chlorides to produce the desired nitrile products in good yields, and with excellent functional group tolerance. Cheap and bench-stable urea was also shown as suitable CN source, suggesting promising application potential. Mechanistic studies imply that Triphos-Ni(I) species are responsible for the reductive C-C coupling approach involving isocyanate intermediates. This method expands the application potential of reductive cyanation in the synthesis of functionalized nitrile compounds under cyanide-free conditions, which is valuable for safe synthesis of (isotope-labeled) drugs.


Entry
Cat. (mol%) Yield (%) 1 PdCl2 (5)  heptane to yield a fine yellow powder. The crude product was collected and re-crystallized from a mixture of dichloromethane and heptane to yield (160 mg 41%) as a brown solid.
[Ni(CH3CN)6](BF4)2 (S1) was prepared following the literature procedure using Ni and NOBF4. 2 Ni(dppp)2 (S2) was prepared following the literature procedure using Ni(COD)2 and 1,3-Bis(diphenylphosphino)propane o-tolylNi(dppf)Cl (S5) was prepared following the literature procedure. [4][5] NiCl2 (4 mmol, 530 mg), EtOH (15 mL) and a magnetic stir bar were placed in a 50 mL two-neck round bottomed flask fitted with a refluxing condenser. The solution was stirred at room temperature in nitrogen for 15 min. Then dppf (4 mmol, 2310 mg) was added in one portion. The reaction mixture was heated to 80°C for 1 h and then cooled to room temperature. Once cool, the flask was chilled to 0°C for 10 min, after which the solid was collected by filtration, washed twice with ethanol (10 mL) and twice with ether (10 mL

1) Cyanation of aryl chlorides with trimethylsilyl cyanide (TMS-CN)
Upon exposure of TMS-CN to standard conditions (with or without PhSiH3), no product 2a was detected while substrate 1a was mostly recovered. Such result suggested that CNis not involved in the reaction mechanism.
2) Detection of cyanide anion by indicator paper [7][8][9] Upon exposure of cyanide indicator paper to reaction mixture (after the reaction was finished), the test paper didn't changed color. Such experiment indicated that no detectable CNwas produced in the reaction mechanism.
3) Cyanation of aryl chlorides using 13 CO2 13 CO2 instead of CO2 was used at standard conditions. After the reaction finished, dodecane was added. And were injected by syringe. The tube was then sealed and the mixture was stirred for 1 h at room temperature. After this, TMS-NCO (2.0 equiv., 0.2 mmol) was injected by syringe and the mixture was stirred for 20 h at 140 o C.
After the reaction finished, the tube was cooled to room temperature and the pressure was carefully released. The result was obtained by GC and GC-MS analysis.

X-Ray diffraction characterization
Single crystal of 2aa was obtained by recrystallization in EA. CCDC: 1974249 contains the supplementary crystallographic data which can be obtained free of charge from the Cambridge Crystallography Data Center via www.ccdc.cam.ac.uk/data_request/cif.

Supplementary Figure 5. Thermal Ellipsoid Depiction of Compound 2aa
Supplementary   Table 4 Crystal data and structure refinement for compound 13