Palladium-Catalyzed Hydrogenolysis

An unusual by-product was obtained in small yield in palladium-catalyzed reduction of 2-amino-4,5-dimethoxyindanone hydrochloride, The reduction was done in two stages first, a rapid absorption of 1 mol of hydrogen at 38 C to give the amino alcohol, and then a much slower reduction in the presence of HCIO4 at 70 "C. The rearranged by-product was shown to arise from attack of acid on the amino alcohol (50), Resistance to hydrogenolysis is characteristic of / -amino aromatic alcohols (56), a fact that makes reduction of aromatic oximino ketones to amino benzyl alcohols a useful synthetic reaction. 

Palladium-catalyzed aminations of aryl halides is now a well-documented process [86-88], Heo et al. showed that amino-substituted 2-pyridones 54 and 55 can be prepared in a two-step procedure via a microwave-assisted Buchwald-Hartwig amination reaction of 5- or 6-bromo-2-benzyloxypyri-dines 50 and 51 followed by a hydrogenolysis of the benzyl ether 52 and 53, as outlined in Fig. 9 [89]. The actual microwave-assisted Buchwald-Hartwig coupling was not performed directly at the 2-pyridone scaffold, but instead at the intermediate pyridine. Initially, the reaction was performed at 150 °C for 10 min with Pd2(dba)3 as the palladium source, which provided both the desired amino-pyridines (65% yield) as well as the debrominated pyridine. After improving the conditions, the best temperature and time to use proved... 

The palladium-catalyzed opening of an oxazolidine ring followed by the hydrogenolysis of a benzylic OH group was performed over 5% Pd/C in ethanol at 140 atm H2 in 45 hours (Scheme 4.17).35... 

Scheme 7.124 Hydrogenolysis reactions catalyzed by palladium on charcoal.

Benzyl alcohol linkers, such as those described in Section 3.1.1.1, can also be cleaved by palladium-catalyzed hydrogenolysis. Carboxylic acids have, for example, been obtained by hydrogenolysis of insoluble benzyl esters with Pd(OAc)2/DMF/H2 [89,161]. Resin-bound benzylic carbamates [162,163] and amides [164] can also be released by treatment with Pd(OAc)2 in DMF in the presence of a hydrogen source, such as 1,4-cyclohexadiene or ammonium formate. These reactions are quite surprising, because they require the formation of metallic palladium within the gelated beads. 

The benzyl group has been widely used for the protection of hydroxyl functions in carbohydrate and nucleotide chemistry (C.M. McCloskey, 1957 C.B. Reese, 1965 B.E. Griffin, 1966). A common benzylation procedure involves heating with neat benzyl chloride and strong bases. A milder procedure is the reaction in DMF solution at room temperature with the aid of silver oxide (E. Reinefeld, 1971). Benzyl ethers are not affected by hydroxides and are stable towards oxidants (e.g. periodate, lead tetraacetate), LiAlH, and weak acids. They are, however, readily cleaved in neutral solution at room temperature by palladium-catalyzed hydrogenolysis (S. Tejima, 1963) or by sodium in liquid ammonia or alcohols (E.J. Reist, 1964). 

The palladium catalyzed hydrogenolysis of 3-amino 4-aryl azetidin-2-ones, Fig. 11, constitutes an excellent and reliable strategy to access a-amino acid derived peptides. The discovery, development, and synthetic opportunities of this approach have been reviewed by Ojima [145-148], and will not be covered here. Only the... 

Palladium-Catalyzed Hydrogenolysis of Allylic and Propargylic Compounds with Various Hydrides. Tsuji, J. Mandai, T. Synthesis 1996,1. 

Naphthylmethyl and 2-naphthylmethyl esters have been proposed as protecting groups as they are selectively cleaved in the presence of a benzyl ester by homogeneous palladium-catalyzed hydrogenolysis using ammonium formate.P ... 

Since aliphatic aldehydes and ketones are not hydrogenated over palladium, this reaction provides a means of selectively removing an aromatic carbonyl group in the presence of an aliphatic aldehyde or ketone (Eqn. 18.10).32 The palladium catalyzed hydrogenolysis of aryl aldehydes and ketones is preferable to any of the chemical reduction procedures such as the Wolff-Kishner or Clemmenson reactions for the removal of an aryl carbonyl group. 

---