Ex situ generation of stoichiometric HCN and its application in the Pd-catalysed cyanation of aryl bromides: evidence for a transmetallation step between two oxidative addition Pd-complexes

We demonstrate how hydrogen cyanide can be exploited for the cyanation of aryl bromides with Pd-catalysis.


General methods S3
Handling of hydrogen cyanide S3 Optimisation of the Ni-catalysed hydrocyanation of olefins S4 General procedure for Scheme 2: Ni-catalysed hydrocyanations of olefins S6 Optimisation of the Pd-catalysed cyanation of aryl bromides S9 General procedure for Scheme 3: Pd-catalysed cyanation of aryl bromides S13 Starting materials and procedures for Scheme 4 S20

Mechanistic Investigations S23
Isolation of 32 and 33 S23 Procedure for    At this point it was realized that DCE could diffuse to the "HCN Consuming Chamber", which potentially could hamper the reaction. Adding 250 μL DCE to the reaction as depicted in Table S3 entry IV resulted in 0% conversion to 1. Therefore, DCE was substituted for ethylene glycol, which gave a 87% conversion to product (see Table S4, entry VII). H NMR yield using mesitylene as an internal standard.

General procedure for Scheme 2: Ni-catalysed hydrocyanation of olefins
In an argon filled glovebox Ni(COD) 2 (13.8 mg, 0.05 mmol) and XantPhos (43.4 mg, 0.075 mmol) were premixed in CPME (1 mL) in a 4 mL dry vial for 20 min. HCN consuming chamber (A): To chamber A of the two-chamber system olefin (1.0 mmol) and the premixed Ni-complex were added. The total volume was increased to 2 mL of CPME. The chamber was sealed with a PTFE H-Cap and a screw cap. The HCN producing chamber (B, 1.5 equiv HCN): To chamber B of the two-chamber system KCN (97.7 mg, 1.5 mmol) and ethylene glycol (1 mL) were added. Lastly, AcOH (0.52 mL, 9 equiv) was carefully added on top of the ethylene glycol layer. The chamber was sealed with a PTFE H-Cap and a screw cap. Outside the glovebox the reaction was heated to 60 o C. After 18 hours the reaction was cooled to rt before the content of chamber A was filtered through a small Celite plug. The crude was concentrated onto Celite. Purification by flash column chromatography on silica gel using an appropriate eluent afforded the desired hydrocyanated product.
The organic phase was concentrated under reduced pressure, dried over MgSO 4 , filtered and evaporated    NaOAc was abandoned, since KOAc came as a fine powder, while NaOAc had to be grinded prior to use.    H NMR yield using mesitylene as an internal standard. S13 H NMR yield using mesitylene as an internal standard.

General procedure for Scheme 4: Pd-catalysed cyanation of aryl bromides
All reactions were set up in an argon filled glovebox. The HCN consuming chamber (A): To chamber A of the two-chamber system P(tBu) 3 -Pd-G3 (14.3 mg, 0.025 mmol), KOAc (0.295 g, 3.0 mmol), aryl bromide (1.0 mmol), dioxane (1 mL) and H 2 O (2 mL) were added. The chamber was sealed with a PTFE H-Cap and a screw cap. The HCN producing chamber (B, 1.5 equiv HCN): To chamber B of the two-chamber system KCN (97.7 mg, 1.5 mmol) or K 13 CN (99.2 mg, 1.5 mmol) and ethylene glycol (1 mL) were added. Lastly, AcOH (0.52 mL, 9 equiv) was added carefully on top of the ethylene glycol layer. The chamber was sealed with a PTFE H-Cap and a screw cap. Outside the glovebox chamber A was heated to 60 o C, while chamber B was kept at rt.
After 16 hours chamber A was cooled to rt before its content was filtered through a small Celite plug. The mixture was added H 2 O (5 mL) and the two phases were separated. The aqueous phase was extracted with CH 2 Cl 2 (3x5 mL), and the combined organic phases were dried over MgSO 4 , filtrated and concentrated onto Celite. Purification by flash column chromatography on silica gel using an appropriate eluent afforded the desired benzonitrile.
Product was purified by flash column chromatography using pentane/acetone (7:1) as eluent which afforded 28 as a colorless solid (Run 1: 118.9

Bis(4-bromophenyl)methanol
A 500 mL round-bottom flask was under argon charged with 1,4dibromobenzene (18.87 g, 80 mmol), a stirbar and anhydrous THF (200 mL). The mixture was cooled to -78 °C before n-BuLi (50 mL, 80 mmol, 1.6M in hexane) was added dropwise. The reaction was stirred for 20 minutes before a solution of 4-bromobenzaldehyde (14.80 g, 80 mmol) dissolved in anhydrous THF (50 mL) was added dropwise. The reaction was stirred for 30 minutes before cooling was removed. Once the reaction had reached room temperature H 2 O (100 mL) was added and the organic phase was separated, and the aqueous phase was extracted with EtOAc (3x 40 mL). The combined organic phases were dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude was triturated with heptane to obtain a white solid, which was washed with heptane to afford the desired product (23.22 g, 85%).

Isolation of compounds 32 and 33
In an argon filled glovebox, a two-chamber system made from two glass vials (8 mL each) connected by a glass tube was utilized for the reaction. To the HCN consuming chamber (A) Pd(P(tBu) 3  consisted of a mixture of 32 and 33. To the solid was added THF (6 mL) and the mixture was heated to reflux. As the solution cooled down, 33 recrystallized from the solution as colorless needles. The crystals were filtered and washed with pentane which gave crystals of 33 that were suitable for X-ray analysis. The mother liquid was dissolved in CH 2 Cl 2 and layered with heptane. After two days colorless crystals had emerged. The solution was decanted and the crystals were gently washed with heptane. This afforded colorless crystals of 32 which were suitable for X-ray analysis.   Table 2 In an argon filled glovebox, a two-chamber system made from two glass vials (8 mL each) connected with a glass tube, the HCN consuming chamber (A) was charged with Pd(P(tBu) 3 ) 2 (102.2 mg, 0.2 mmol), solvent (2 mL), a stir bar and for entry 2-6 KOAc. The HCN producing chamber (B) was charged with K 13 CN, ethylene glycol (1 mL), octanoic acid (4 equiv compared to K 13 CN) and a stir bar. After 3 hours the content of chamber A was transferred to a 50 mL round bottom flask and evaporated dry. Crude NMR was used to deduce the distribution between the different Pd-species.

Procedure for Scheme 6:
In an argon filled glovebox, a two-chamber system made from two glass vials (8 mL each) connected with a glass tube, the HCN consuming chamber (A) was charged with Pd(PPh 3 ) 4 (115.6 mg, 0.1 mmol), THF (2 mL) and a stir bar. The HCN producing chamber (B) was charged with K 13 CN (19.8 mg, 0.3 mmol), ethylene glycol (0.5 mL), octanoic acid (0.19 mL, 2.4 mmol) and a stir bar. Stirring was initiated at room temperature.
After 3 hours the content of chamber A was transferred to a 8 mL vial, diluted with THF (3 mL) and heated to reflux. The solution was allowed to cool to rt. After 14 hours the solution was decanted and the crystals were washed with pentane. This gave both colorless and yellow crystals. The yellow crystals were determined to be Pd(PPh 3 ) 4 , while the colorless crystals were determined to be compound 34. The colorless crystals could easily be separated from the yellow Pd(PPh 3 ) 4 crystals by manual separation, thereby obtaining crystals of 34 which were suitable for X-ray analysis. In an argon filled glovebox, a 8 mL vial was charged with Pd(P(tBu) 3
The mixture was transferred to a NMR-tube with THF-d 8 (total volume 0.8 mL). Mesitylene (2.0 μL) was added as an internal standard. The NMR tube was sealed and removed from the glovebox, and NMR was used to follow the reaction progress.

Procedure for Scheme 9b:
In an argon filled glovebox, 33 (8.0 mg, 0.0065 mmol) and 36 (3.0 mg, 0.02 mmol) were added to a 4 mL vial. The mixture was transferred to a NMR-tube with CDCl 3 (total volume 0.8 mL). Mesitylene (20.0 μL) was added as an internal standard. The NMR tube was sealed and removed from the glovebox, and NMR was used to follow the reaction progress.

Procedure for Scheme 9c:
In an argon filled glovebox, 36 (9.3 mg, 0.02 mmol) and K 2 Pd(CN) 4 x(H 2 O) (6.1 mg, 0.02 mmol) were added to a NMR-tube along with THF-d 8 (0.7 mL) and D 2 O (0.1 mL). Mesitylene (2.0 μL) was added as an internal standard. The NMR tube was sealed and removed from the glovebox, and NMR was used to follow the reaction progress. Table S13. Crystallographic information for the four structures solved using single crystal X-ray diffraction. Four diffraction experiments (32 -35) were performed on a SuperNova diffractometer from Agilent Technologies, using #$ radiation ( = 0.71073 Å). The diffracted intensities were collected on a CCD detector and data were integrated and corrected for absorption using CrysAlisPro. [1] The last diffraction experiment (38) was conducted on a Apex2 diffractometer from Bruker, using A #$ radiation ( = 0.56086 Å). Data were collected on a CCD detector, integrated using SAINT+ [2] and absorption-corrected in SADABS. [3] The structure solution and refinement were carried out with SHELXT, using Olex2, for all compounds. [4] Sample