Palladium-catalyzed carbonylation of benzyl alcohol derivatives to phenylacetic acid derivatives

Benzyl alcohols are carbonylated to phenylacetic acid derivatives in the presence of a palladium catalyst. Typical reaction conditions are: temperature 90–120°C;P(CO)=20–80 atm; benzyl alcohol/ROH/Pd=100–200/300–1000/1; [Pd]=0.5×10−2−1 × 10−2 M; solvent: dioxane, benzene, ethanol; reaction time 1–4 h. Under these experimental conditions high yields are obtained only when the aromatic ring contains a hydroxy substituent at the para position and when the palladium precursor is a chloride used in combination with 2–4 equivalents of PPh3. When the substituent is in a m- or o-position or is a methoxy group, or in the case of benzyl alcohol, only trace amounts of phenylacetic acid derivatives are obtained. The system PdY2(PPh3)2-PPh3 yields the same results as PdY2 with equivalent amounts of phosphine (Y=Cl, Br, I, CH3COO). When the precursor is employed in combination with a base, catalysis does not occur to an appreciable extent. On the contrary, when HCl is added in an amount comparable to that of the palladium precursor (HCl/Pd=2-15), slightly higher yields are obtained. These results suggest that the starting benzyl alcohol reacts with HCl to yield the corresponding chloride, which initiates the catalytic cycle. Moreover, it has been observed that the best results are obtained when the palladium(II) precursor decomposes to metallic palladium. Pd/C is also active, provided that it is employed in combination with HCl and PPh3. Thus, for example, the system Pd/C-HCl-PPh3 is catalytically equivalent to the system that originates from the initial precursor PdCl2(PPh3)-PPh3, eventually in the presence of added HCl. Low catalytic activity is observed in the absence of PPh3 or when this ligand is added in relatively small amounts. The highest yields are obtained when P/Pd=2–3. These facts suggest that the PPh3 ligand eases the oxidative addition step by enhancing the electron density on the metal. Under these conditions, the yield increases with increasing gas pressure. When the ligand is present in relatively large excess, the catalytic activity drops dramatically, probably because PPh3 competes with the coordination to the metal. The catalytic activity is strongly influenced by the nature of the solvent. The yield decreases in the order: dioxane » ethanol ≈ benzene, and depends also on the ROH/solvent ratio; the highest yields are achieved when the EtOH/dioxane ratio is ca. 1/5 (ml). At higher concentrations of EtOH the yield is significantly lower, probably because the equilibrium between benzyl alcohol and hydrochloric acid is less favorable to the formation to benzyl chloride and/or the acid competes with the chloride for the oxidative addition to the metal. A mechanism for the catalytic cycle is proposed: (i) oxidative addition of ArCH2Cl to ‘reduced palladium’, which may be palladium coordinated by other palladium atoms, and/or carbon monoxide, and/or phosphine ligands. (ii) Carbon monoxide ‘insertion’ into Pd-benzyl intermediate with formation of an acyl intermediate. (iii) Nucleophilic attack of EtOH on the carbon atom of the acyl intermediate to give the desired product and return the catalyst back to the catalytic cycle. The promoting effect of the hydroxy substituent in the para position is interpreted in terms of resonance structures, in which deprotonation of this substituent may play an important role in weakening the Cl-Cl bond, thus easing the initial step of the catalysis.