Synthetically Useful Hydrogenolysis Reactions

Halides are common components of organic molecules, and in many cases they must be removed. One way to do this is reduction to the corresponding hydrocarbon by hydrogenolysis. A nickel catalyst (usually 

Raney nickel) can be used, as in reduction of the iodomethyl furanose derivative 416 to the methoxy lactol, 417418 

Aromatic hydrocarbons and heterocycles are important in many natural products and reduction of the aromatic ring is very important from a synthetic viewpoint. Clearly, the most simple example is reduction of 

Rhodium and ruthenium are used if hydrogenolysis is to be avoided. The catalyst of choice changes somewhat with fused ring aromatic hydrocarbons. The relative order for reduction of naphthalene to tetralin (424) is  

This order is due, in part, to the slowness of palladium to further reduce the aromatic ring in 424. Rhodium initially reduces naphthalene to 424, but further reduction to decalin (425) is so rapid that 424 is a minor constituent of the final product mixture. 

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Although not directly related to this article, a brief summary of the hydrogenolysis of bicyclic acetals, a synthetically useful reaction, is given. 

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. 

Catalytic hydrogenolysis is the cleavage of a molecule into fragments by hydrogen in the presence of a catalyst It is a useful and frequent synthetic reaction. This chapter is organized around the type of bond being cleaved. 

As seen in the retro-synthetic Scheme 5.3, intermediate 15 is useful for both routes. The choice of benzyl protection group was made based on the robust stability of benzyl phenol ethers toward most reactions and several possible avenues to remove it, although it was reported from Medicinal Chemistry that benzyl group removal via hydrogenolysis posed challenges in this compound. The choice of iodide substitution was born out of the known high reactivity of iodides in the Ullmann-type coupling reaction with alcohols and the robust stability of aryl iodides in many other common reactions. 

Denmark and coworkers have found that methylaluminum bis (2,6-di-tert-butyl-4-methyl-phenoxide) (MAD) or methylaluminum bis(2,6-diphenylphenoxide) (MAPh) is effective as the Lewis acid promoter for cycloaddition of 2,2-disubstituted 1-nitroalkenes (Eq. 8.100).158 Other Lewis acids such as SnCl4, TiCl4, and TiCl2(Oi-Pr)2 fail to promote the cycloaddition of 2,2-disubstituted 1-nitroalkenes. The products are converted into 3,3-disubstituted pyrrolidines via hydrogenolysis.158 Reductive cleavage of N-0 bonds produces oxime hemiacetals, which are further reduced to amido aldehydes and finally to pyrrolidines. This reaction provides a useful synthetic method for pyrrolidines, which is discussed later. 

Deoxy- and dideoxy-aldonolactones have also been prepared via the bromo derivatives, which on hydrogenolysis yield the corresponding deoxyaldonolactones.293 3-Deoxyaldonolactones have been obtained via /1-elimination reactions on aldonolactones and catalytic hydrogenation of the intermediate 2-enonolactone derivatives.37 The synthetic potential of this reaction was used for the synthesis of 3-deoxyaldonolactones by combining the base-catalyzed elimination of peracylated lactones with the in situ reduction.294... 

N- and O-benzyl groups are among the most useful protective groups in synthetic organic chemistry and the method of choice for their removal is catalytic hydrogenolysis [37]. Recently the most important reaction conditions were identified [38] Usually 5-20% Pd/C the best solvents are alcoholic solvents or acetic acid acids promote debenzylation, whereas amines can both promote and hinder hydrogenolysis. Chemoselectivity can mainly be influenced by modifying the classical Pd/C catalysts. 

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