Synthesis of arylacetic acid derivatives via reductive carbonylation of mandelic acid derivatives catalyzed by a highly active Pd-HCl system

The reduction of mandelic acid derivatives (ArCHOHCOOH) to phenylacetic acid derivatives by carbon monoxide catalyzed by a Pd-HCl system easily occurs when the aromatic ring is para-substituted with a hydroxy group. Other electron-releasing substituents such as a methoxy group have a much lower promoting effect. The reaction practically does not occur with mandelic acid. A compound of Pd(II), such as PdX2, [Pd(1,3-η-C3H5)Cl]2 or PdX2(PPh3)2 (X=Cl, AcO) can be used as catalyst precursor. The reaction occurs to an appreciable extent only in the presence of HCl. Under the reaction conditions tested (70–110 °C, 50–100 atm of carbon monoxide, benzene-ethanol as reaction medium, [Pd(II)] = 10−3-10−2 M, substrate/HCl/Pd = 100:50:1) decomposition to Pd metal occurs. Pd/C can also be used: it gives practically the same results as the precursors listed above. The key steps of the proposed catalytic cycle are: (i) the chloride ArCHClCOOR (R = H, Et), formed in situ by substitution of the α-hydroxy group of ArCHOHCOOR upon reaction with HCl, oxidatively adds to a Pd(0) species with formation of a catalytic intermediate having a Pd-[CH(Ar)COOR] moiety; (ii) the Pd-C σ-bond of this species inserts carbon monoxide, yielding an acyl intermediate of the type Pd-[COCH(Ar)COOR]; (iii) nucleophilic attack of ROH on the carbon atom of the carbonyl ligand yields a phenylmalonic acid derivative which splits off CO2 yielding the final product, ArCH2COOR. Alternatively, H+ may react with the intermediate formed in step (i), yielding directly the final product and a Pd(II) species, which is reduced by CO to Pd(0), which starts another catalytic cycle. The promoting effect of the hydroxy substituent in para position is discussed in terms of resonance structures. This reaction is compared with the carbonylation of aromatic aldehydes to ArCH2COOR, catalyzed by a Pd-PPh3-HCl system. Also in this case there is a marked promoting effect of a hydroxy substituent in the para position. However, the carbonylation of the aldehydes occurs only in the presence of both PPh3 and HCl, at variance with the reductive carbonylation described in this paper, where this ligand does not play any major role.