Benzyl amines hydrogenolysis

Benzylic amines are resistant to hydrogenolysis under Birch reduction conditions, unless the amine is quaternary, as in the Emde reaction. A means of preserving an aryl carbonyl group is therefore to protect it as an aminal derivative. An illustration is provided by the preparation of aldehyde (213), an important flavor constituent of cumin, as outlined in Scheme 47." ... 

Benzylic halides have also been reduced to hydrocarbons by hydrogenolysis over Raney nickel (equation 31). Benzylic amines have been cleaved by hydrogenolysis over Raney nickel (equation 32) or by treatment of a methiodide salt with basic Raney nickel (equation 33). ... 

Benzylic amines are particularly susceptible to hydrogenolysis by catalytic hydrogenation or dissolving metal reduction. " Note that the Wolff-Kishner reduction in 19-61 involved formation of a hydrazone and deprotonation by base led to loss of nitrogen and reduction. Ceric ammonium nitrate in aqueous acetonitrile has also been shown to reductively cleave the V-benzyl group. Primary amines have been reduced to RH with hydroxylamine-O-sulfonic acid and... 

Aryl benzyl ethers are cleaved more easily than are alkyl benzyl ethers. The presence of an amine hinders the hydrogenolysis of alkyl benzyl ethers but has no effect on the cleavage of aryl benzyl ethers. - Because of this the benzyl ether is selectively hydrogenolyzed in compounds containing both a benzyl amine and an aryl benzyl ether (Eqn. 20.24)55 but the benzyl amine is selectively cleaved in compounds having both a benzyl amine and an alkyl benzyl ether (Eqn. 20.25).53,54,56... 

The ease of hydrogenolysis of benzyl amines depends on the nature of the substituents on the nitrogen atom. The debenzylation of tertiary benzyl amines takes place over palladium on charcoal at 25°-50°C and 2-4 atmospheres of hydrogen (Eqn. 20.43). 2 Platinum and rhodium catalysts generally promote... 

Benzyl amides are more resistant to hydrogenolysis than are secondary benzyl amines (Eqn. 20.47). Higher temperatures and pressures are required to debenzylate these amides. 

The stereochemical course of benzyl amine hydrogenolysis is such that inversion of configuration is observed with both palladium 3- 5 and nickel ... 

Both catalytic and chemical methods are effective for the hydrogenolysis of benzyl ethers. Catalytic methods have found much wider use than the chemical methods, presumably because of the milder conditions that prevail. A general survey of the hydrogenolysis of benzyl compounds (benzyl amines, sulfides, and esters are also subject to hydrogenolysis to varying degrees) has recently been made, and the reader is referred to this discussion for a complete treatment of the scope of the reaction. 

Reductive Methods. The following table shows that substituents have a significant effect on the rate of hydrogenolysis of benzyl amines. 

What happens to them is a hydrogenolysis—a reaction that is liable to occur under catalytic hydrogenation conditions whenever a heteroatom (in particular O or N) finds itself bonded to a carbon atom adjacent to a benzene ring, in other words with benzylic amines, alcohols or ethers. 

The most useful protecting group for this purpose is the carbobenzyloxy group. The utility of this group lies in the ease with which it can be removed. Because of the lability of the benzyl C-O bonds towards hydrogenolysis, the amine can be regenerated from a carbobenzyloxy derivative by hydrogenation, which is accompanied by spontaneous decarboxylation ... 

Partial and selective benzylic hydrogenolysis Tert. amines ... 

Amino Acids. Chloroformates play a most important role for the protection of the amino group of amino acids (qv) during peptide synthesis (32). The protective carbamate formed by the reaction of benzyl chloroformate and amino acid (33) can be cleaved by hydrogenolysis to free the amine after the carboxyl group has reacted further. The selectivity of the amino groups toward chloroformates results in amino-protected amino acids with the other reactive groups unprotected (34,35). Methods for the preparation of protected amino acids on an industrial scale have been developed (36,37). A wide variety of chloroformates have been used that give various carbamates that are stable or cleaved under different conditions. 

Aryl esters, prepared from the phenol and an acid chloride or anhydride in the presence of base, are readily cleaved by saponification. In general, they are more readily cleaved than the related esters of alcohols, thus allowing selective removal of phenolic esters. 9-Fluorenecarboxylates and 9-xanthenecarboxylates are also cleaved by photolysis. To permit selective removal, a number of carbonate esters have been investigated aryl benzyl carbonates can be cleaved by hydrogenolysis aryl 2,2,2-trichloroethyl carbonates by Zn/THF-H20. Esters of electron-deficient phenols are good acylating agents for alcohols and amines. 

Condensation of normeperidine (81) with 3-chloropropan-l-ol affords the compound possessing the alcohol side chain (88). The hydroxyl is then converted to chlorine by means of thionyl chloride (89) displacement of the halogen by aniline yields pimino-dine (90). ° Condensation of the secondary amine, 81, with styrene oxide affords the alcohol, 91 removal of the benzyllic hydroxyl group by hydrogenolysis leads to pheneridlne (92). ... 

The synthesis of a benzamide with a somewhat more complex side chain starts by condensation of acid 144 with racemic cis-aminopiperidine 152. Removal of the benzyl group of 153 by hydrogenolysis gives the secondary amine 154. Alkylation on nitrogen with the halide 155 gives finally the dopamine antagonist, cisapride (156) [38,39]. 

Nickel in the presence of ammonia is often used for reduction of nitriles to primary amines. The reaction is done at elevated temperatures and pressures ( 100 C, 1000 psig) unless massive amounts of nickel are used. Cobalt is used similarly but mainly under even more vigorous conditions. Nitriles containing a benzylamine can be reduced over Raney nickel to an amine without hydrogenolysis of the benzyl group (7). A solution of butoxycarbonyl)-3-aminopropyl]-N-<3-cyanopropyl)benzylamine (13.6 g) in 100 ml of ethanol containing 4 g. NaOH was reduced over 3.0 g Raney nickel at 40 psig for 28 h. The yield of A/ -benzyl-Air -(f-butoxycarbonyl)s >ermidine was 95% (7). 

Tertiary amines are effective promoters in hydrogenolysis of hindered benzyl esters that otherwise may undergo cleavage only with difficulty (187). 

Inhibition of O-benzyl hydrogenolysis was shown to be due to the presence of an amine, a finding with synthetic utility. 

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... 

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