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

Abstract

A protocol for the Pd-catalysed cyanation of aryl bromides using near stoichiometric and gaseous hydrogen cyanide is reported for the first time. A two-chamber reactor was adopted for the safe liberation of ex situ generated HCN in a closed environment, which proved highly efficient in the Ni-catalysed hydrocyanation as the test reaction. Subsequently, this setup was exploited for converting a range of aryl and heteroaryl bromides (28 examples) directly into the corresponding benzonitriles in high yields, without the need for cyanide salts. Cyanation was achieved employing the Pd(0) precatalyst, P(tBu)₃-Pd-G3 and a weak base, potassium acetate, in a dioxane-water solvent mixture. The methodology was also suitable for the synthesis of ¹³C-labelled benzonitriles with ex situ generated ¹³C-hydrogen cyanide. Stoichiometric studies with the metal complexes were undertaken to delineate the mechanism for this catalytic transformation. Treatment of Pd(P(tBu)₃)₂ with H¹³CN in THF provided two Pd-hydride complexes, (P(tBu)₃)₂Pd(H)(¹³CN), and [(P(tBu)₃)Pd(H)]₂Pd(¹³CN)₄, both of which were isolated and characterised by NMR spectroscopy and X-ray crystal structure analysis. When the same reaction was performed in a THF : water mixture in the presence of KOAc, only (P(tBu)₃)₂Pd(H)(¹³CN) was formed. Subjection of this cyano hydride metal complex with the oxidative addition complex (P(tBu)₃)Pd(Ph)(Br) in a 1 : 1 ratio in THF led to a transmetallation step with the formation of (P(tBu)₃)₂Pd(H)(Br) and ¹³C-benzonitrile from a reductive elimination step. These experiments suggest the possibility of a catalytic cycle involving initially the formation of two Pd(ii)-species from the oxidative addition of L _n Pd(0) into HCN and an aryl bromide followed by a transmetallation step to L _n Pd(Ar)(CN) and L _n Pd(H)(Br), which both reductively eliminate, the latter in the presence of KOAc, to generate the benzonitrile and L _n Pd(0).

Scheme 1. Previous developments in Pd-catalysed cyanation protocols and our new approach applying gaseous HCN.

Scheme 2. Ni-catalysed hydrocyanation of styrenes employing a two-chamber system with ex situ generated HCN. ^aChamber A: styrene (1.0 mmol), Ni(COD)₂ (5.0 mol%), XantPhos (7.5 mol%) and CPME (2 mL). Chamber B: KCN (1.5 mmol), ethylene glycol (1 mL), AcOH (9.0 mmol). Isolated yields are given as an average of 2 runs.

Scheme 3. Pd-catalysed cyanation of aryl bromides. ^aChamber A: aryl bromide (1.0 mmol), P(tBu)₃-Pd-G3 (2.5 mol%) and KOAc (3.0 mmol) in dioxane (1 mL) and H₂O (2 mL). Chamber B: KCN (1.5 mmol) or K¹³CN (1.5 mmol) ethylene glycol (1 mL) and AcOH (9 mmol). Isolated yields are given as an average of 2 runs. ^b5.0 mol% catalyst used. ^c4.0 equiv. of KOAc used. ^dHCN consuming chamber only heated to 45 °C.

Scheme 4. Synthesis of pharmaceuticals by Pd-catalysed cyanation and scale up studies. ^aFor reactions on 1.0 mmol scale, yields are an average of two runs.

Scheme 5. Accepted mechanism for the cyanation of aryl halides with cyanide salts.

Fig. 1. ¹H NMR (J_H–C = 53.0 Hz, J_H–P = 4.7 Hz) and ³¹P NMR (J_P–C = 11.7 Hz) of compound 32 in THF-d₈.

Fig. 2. ORTEP representation of complex 32.

Fig. 3. ¹H NMR and ³¹P NMR of compound 33 in CDCl₃.

Fig. 4. ORTEP representation of complex 33.

Scheme 6. Reaction between Pd(PPh₃)₄ and H¹³CN. ^aReaction performed on a 0.1 mmol scale with a two-chamber system. The reaction was stopped after 3 h.

Scheme 7. Reactivity studies between complex 32 with 4-bromo-biphenyl. ^a0.02 mmol of both 32 and 4-bromobiphenyl were added to a NMR-tube. Mesitylene was used as an internal standard.

Fig. 5. ¹H NMR (J_H–P = 7.2 Hz) and ³¹P NMR (J = 1.9 Hz) of compound 35 in THF-d₈.

Fig. 6. ORTEP representation of complex 35.

Fig. 7. ³¹P NMR spectra of the reaction between complex 32 and p-bromobiphenyl.

Scheme 8. A proposed mechanism for the Pd-catalysed cyanation of aryl bromides with HCN.

Scheme 9. Transmetallation studies with complex 36. ^a0.02 mmol of either 32, 33 or K₂[Pd(CN)₄] with 36 were added to a NMR-tube. Mesitylene was used as an internal standard.

Scheme 10. Pd-Catalysed cyanation of aryl bromides using 32 instead of P(tBu₃)-Pd-G3. ^aChamber A: 4-bromobiphenyl (1.0 mmol), 33 (2.5 mol%) and KOAc (3.0 mmol) in dioxane (1.0 mL) and H₂O (2.0 mL). Chamber B: KCN (1.5 mmol), ethylene glycol (1.0 mL) and AcOH (9.0 mmol).

Scheme 11. Robustness screening on the formation of benzonitrile 9. ^aChamber A: 4-bromophenol (1.0 mmol), 2-acetyl-5-bromothiophene (1.0 mmol) P(tBu)₃-Pd-G3 (2.5 mol%) and KOAc (3.0 mmol) in dioxane (1.0 mL) and H₂O (2.0 mL). Chamber B: KCN (1.5 mmol), ethylene glycol (1.0 mL) and AcOH (9.0 mmol).

Scheme 12. Formation of Pd₂(μ-Br)₂(P(tBu)₃)₂ and 5,5′-diacetyl-2,2′-bithiophene from Pd(P(tBu)₃)₂. ^aReaction performed on a 0.1 mmol scale.