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. 2017 Dec 1;8(12):8094-8105.
doi: 10.1039/c7sc03912c. Epub 2017 Oct 6.

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

Steffan K Kristensen  1 , Espen Z Eikeland  2 , Esben Taarning  3 , Anders T Lindhardt  4 , Troels Skrydstrup  1
Affiliations

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

Steffan K Kristensen et al. Chem Sci. .

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).

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Figures

Scheme 1
Scheme 1. Previous developments in Pd-catalysed cyanation protocols and our new approach applying gaseous HCN.
Scheme 2
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
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
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
Scheme 5. Accepted mechanism for the cyanation of aryl halides with cyanide salts.
Fig. 1
Fig. 1. 1H NMR (JH–C = 53.0 Hz, JH–P = 4.7 Hz) and 31P NMR (JP–C = 11.7 Hz) of compound 32 in THF-d8.
Fig. 2
Fig. 2. ORTEP representation of complex 32.
Fig. 3
Fig. 3. 1H NMR and 31P NMR of compound 33 in CDCl3.
Fig. 4
Fig. 4. ORTEP representation of complex 33.
Scheme 6
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
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
Fig. 5. 1H NMR (JH–P = 7.2 Hz) and 31P NMR (J = 1.9 Hz) of compound 35 in THF-d8.
Fig. 6
Fig. 6. ORTEP representation of complex 35.
Fig. 7
Fig. 7. 31P NMR spectra of the reaction between complex 32 and p-bromobiphenyl.
Scheme 8
Scheme 8. A proposed mechanism for the Pd-catalysed cyanation of aryl bromides with HCN.
Scheme 9
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
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
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
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.
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