Benzylic C-N Bonds

W2 Raney Nil Li/NH3 and Raney Ni also cleave benzylic C—N bonds. 

W2 Raney Ni. L1/NH3 and Raney Ni also cleave benzylic C-N bonds. Af-f-Butyldimethylsilylamide (TBDMS-NRCO-) i-C4H,(CH3)2Si-NRCO-... 

The alkoxycarbonyl group activates the N — N bond, so that a racemization-free reductive cleavage by treatment with a large excess of lithium in liquid ammonia is possible (sec procedure below). This method is not suitable for hydrazines containing a benzylic C-N bond, because it is cleaved under the reducing conditions. 

The dissolving metal reduction is not suitable, because it effects a cleavage ol the benzylic C-N bond. b The cleavage of the N-N bond by hydrogenolysis is affected by some racemization. 

During the asymmetric synthesis of a-aminophosphonates (14 in Fig. 4.4), numerous attempts to cleave the benzylic C—N bond, involving catalytic or transfer hydrogenolysis, resulted in epimerization at the a-carbon.319... 

The benzyl C-N bond was hydrogenolyzed during a double O- and N-deprotection on Pd/C in mild acidic medium.352 The reaction flask was charged with a solution of the substrate in a mixture of EtOH-AcOH (2 1). After the addition of 10% Pd/C (0.085 mol Pd/mol compound) the apparatus was charged with hydrogen. The reaction was complete within 30 min to 1 hour under stirring and enantiomerically pure (S)-pipecolic acid (29) was produced (Scheme 4.105).353... 

Phenyl-2-butylhydrazine was hydrogenolyzed on Pt02.550 Because the benzyl C-N bond is hydrogenolyzed easily, the hydrazones of the aromatic ketones can be converted directly to hydrocarbons. 

Several different types of linker have been developed that yield amides upon cleavage. These linkers can often also be used to prepare sulfonamides, carbamates, or ureas. There are essentially three different strategies for the release of amides from insoluble supports (a) cleavage of the benzylic C-N bond of resin-bound N-alkyl-N-benzylamides (backbone amide linkers, BAL linkers), (b) nucleophilic cleavage of resin-bound acylating agents with amines, and (c) acylation/debenzylation of resin-bound /V-benzyl-/V,A -dialkylamines. 

Figure 3.19. Inhibition of the cleavage of benzylic C N bonds by basic functional groups in the support-bound amide.

One of the oldest linkers for amides is the (4-methylbenzhydryl)amine linker (MBHA Entry 1, Table 3.11). In contrast to the corresponding benzhydrol linker (which is cleavable by 5% TFA in DCM, 5 min [45]), acidolysis of the benzylic C-N bond of the MBHA linker requires treatment with hydrogen fluoride or a similar acid. As for A-benzylamides, the acid-lability of Al-(diarylmethyl)amides increases with the number of electron-donating substituents on the aryl groups. 

Hydrolysis of the diastereoisomerically pure Strecker product under racemization-free acidic conditions, followed by hydrogenolysis of the benzylic C-N bond, results in a 73% overall yield of (S)-tert-leucine (11). The amino acid 11 is an interesting, sterically constrained amino acid that is applied in various new antiviral and anti-HIV (human immunodeficiency virus) agents. 

Furthermore, trifluoroacetic acid anhydride treatment of allylic, propargylic, homopropargylic, and some benzylic tertiary 2,4-dimethoxybenzyl amines 7 leads to highly selective cleavage of their benzylic C —N bonds. The resultant trilluoroacetamides (e,g 8a) can then be readily converted into the corresponding secondary amines. ... 

Synthesis of Enantiomerically Pure C2-symmetric Vicinal Diamines via Chirality Transfer from DPEN. Several C2-sym-metric vicinal diamines and their derivatives are prepared in optically pure form by chirality transfer from DPEN. For example, condensation of (5, 5)-DPEN with butane-2,3-dione in benzene at the reflux temperature is followed by stereoselective reduction with NaBHsCN and PPTS at -20 °C to afford the (25,35,5R,6R)-piperazine 4 and its diastereomer in a 15 1 ratio (eq 12). The crude product is purified by silica gel column chromatography. Formation of the biscarbamate followed by reductive cleavage of benzylic C-N bonds with lithium in liquid ammonia, and then removal of isobutyloxycarbonyl with HBr in acetic acid results in (/ ,/ )-2,3-diaminobutane dihydrobromide 5 in 99% ee. 

Primary, secondary and tertiary benzylic halides are cleaved with zinc dust in acetic acid or under basic conditions (equations 80 and 81). Benzylic C—N bonds can also be cleaved (equation 82)," with particular ease when quaternary ammonium salts are reduced (equation 83).There has also been a recent report of cyclopropane cleavage with zinc metal and zinc chloride (equation 84). ... 

Reductive cleavage of imidazolidines 641 was implicated in the one-pot synthesis of N,N,N -trisubstituted ethylenediamines 643 from V,V -disubstituted ethylene diamines and an aldehyde R CHO. Presumably the intermediate iminium ion 642 is reduced by NaBH4 (Scheme 154) <2003SC3193>. Naphthalene-catalyzed lithiation of l,3-dimethyl-2-phenylimidazoline 644 leads to benzylic C-N bond cleavage. The intermediate dianion can be trapped with electrophiles (HjO, alkyl halides, ketones, and aldehydes) to afford diamines 645 <2005T3177>. 

Removing the chiral auxiliary is more tricky. One hydrogenation cleaves both benzylic C-0 bonds and releases 65. This is not isolated but hydrogenated under stronger catalysis in acidic solution to cleave the benzylic C-N bond and release aza-tyrosine 56 as its dihydrochloride. The chiral auxiliary is destroyed in this process. 

Resin-bound pyridinium betaine acted as an azomethine ylide that reacted with phenyl vinyl sulfone giving various tropane derivatives (Scheme 11.10). Cleavage of benzylic C—N bond was obtained with acyl chlorides in the presence of potassium iodide, and... 

Scheme 11.10. Cleavage of the benzylic C-N bond of tropane derivatives.

Cycloaddition of polymer-supported nitrones with alkenes gave polymer-supported isoxazolidines as intermediates (Scheme 11.31). A catalytic amount of ytterbium(lll) triflate activated the alkenes, and the cycloaddition proceeded smoothly at room temperature. Oxidative cleavage of the benzylic C N bond was achieved with DDQ, releasing 2-isoxazolines in a traceless manner. 

Davies has developed methodology for the preparation of )3-aminoesters. One application of this methodology was to the synthesis of 171, related to the Schultz and Overman intermediates, carried on to pumiliotoxin-C in the usual manner. Pulegone once again served as the source of chirality for the methyl-bearing carbon. This was converted to 168, which then reacted with chiral lithium amide 169 to provide 170 after protonation of the intermediate enolate with 2,6-di-f rf-butylphenol. Hydrogenolysis of the benzylic C-N bonds and the olefin, followed by formation of the sulfonamide, gave 171. 

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