New Pd-catalyzed selective reduction of carboxylic acids to aldehydes

View Online New Pd-catalyzed selective reduction of carboxylic acids to aldehydes Lukas J. Gooßen* and Keya Ghosh Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr, Germany. E-mail: goossen@mpi-muelheim.mpg.de; Fax: +49-208-306-2985; Tel: +49-208-306-2392 Received (in Cambridge, UK) 12th February 2002, Accepted 1st March 2002 First published as an Advance Article on the web 21st March 2002 DOI: 10.1039/b201577n Downloaded on 09 November 2010 Published on 21 March 2002 on http://pubs.rsc.org | doi:10.1039/B201577N A catalyst generated in situ from palladium acetate and tricyclohexylphosphine efficiently catalyzes the reduction of carboxylic acids with sodium hypophosphite in the presence of pivalic anhydride to give aldehydes with high selectivity. The low cost and convenient handling of the reagents makes this process a valuable alternative to hydrogenations and metal hydride reductions. 836 The synthesis of aldehydes from carboxylic acid derivatives is an important transformation often used in commercial and laboratory scale organic synthesis.1 Several suitable reducing agents have been reported for the selective reduction of acids, esters, and amides such as lithium tris-tert-butoxyaluminium hydride,2 aminoaluminium hydrides,3 DIBAL-H,4 and NaAlH4.5 Alternatively, the sensitive and highly reactive acid chlorides can be hydrogenated in a Rosenmund catalytic reduction6 and related reactions using metal hydrides.7,8 However, in all these methods, the acid derivatives have to be generated in an additional reaction step and the handling of the metal hydrides requires extreme caution and rigorous exclusion of air and moisture. Recently, Yamamoto et al. developed an elegant process for the direct hydrogenation of carboxylic acids to aldehydes by using pivalic anhydride to convert the acids in situ into mixed anhydrides, and reducing these at high hydrogen gas pressures.9,10 The mixed anhydrides are selectively hydrogenated at the sterically less demanding site, so that pivalic acid is always produced as the by-product along with the desired aldehyde.9 Pivalic anhydride itself is inert under these conditions. Although this reaction protocol is excellent for industrial scale applications, the need for high-pressure equipment makes it rather inconvenient for small-scale laboratory applications. We herein present a practical and simple process for the selective hydrogenation of carboxylic acids to aldehydes using cheap and easy-to-handle aqueous sodium hypophosphite solution as the reductant (Scheme 1). In some initial experiments, we observed that in contrast to other reducing agents such as silanes, boranes, metal hydrides, or formates, hypophosphorous acid salts could selectively reduce carboxylic anhydrides into aldehydes in the presence of Pd–phosphine complexes. This was surprising since hypophosphites had been used to reduce aldehydes to alcohols in the presence of Pd/C or Raney nickel.11 Intrigued by this observation, we studied the reduction of a mixture of benzoic acid 1a and pivalic anhydride 2 in some detail, screening several Pd– phosphine complexes under various conditions in order to identify an efficient catalyst system (Scheme 1). Selected results are shown in Table 1. In good accordance with the findings described above,11 the desired selectivity for the aldehyde 3a was achieved only with Pd–phosphine complexes as catalysts (Entries 1–3, 7). Whenever this catalyst decayed during the reaction and non-ligated palladium formed, the benzyl alcohol 5a was produced in Scheme 1 Reduction of benzoic acid with sodium hypophosphite. CHEM. COMMUN., 2002, 836–837 significant quantities (Entry 2). The addition of a mild base was found to stabilize the palladium complexes and ensure a high selectivity for the aldehyde versus the alcohol. In this respect, potassium phosphate and sodium carbonate were most effective (Entries 3–7). Besides sodium hypophosphite, other hypophosphite salts can be used (Entries 8 and 9) but did not appear advantageous. When hypophosphorous acid itself was used as the reducing agent in the absence of a base, no product was formed (Entry 10). Among all phosphines tested, the electron rich, sterically demanding cyclohexylphosphine gave the best results (Entries 11–16). Among the palladium precursors, palladium acetate was most effective (Entries 17–19). The reaction proceeds best in THF as the solvent (Entries 7, 20–22) and the presence of water is beneficial (Entries 7, 23, 24). In the absence of water, the reaction is extremely slow, probably due to the insolubility of the reducing agent. If too much water is added, the hydrolysis of the anhydrides becomes most prevalent, thus lowering the yield. The reaction is not particularly sensitive towards oxygen; however, it is beneficial Table 1 Optimization of the reaction conditions Entry Catalyst Base Solvent 3a (%) 1 2 3 4 5 6 7 8a 9b 10c 11 12 13 14 15 16 17 18 19 20 21 22 23d 24e 5a (%) Pd(OAc)2 — THF