Benzyl amide

Primary benzyl amides are not cleaved under these conditions. 

Li, catalytic naphthalene, -78°, THF, 97-99% yield. In addition, benzyl-amides and methanesulfonamides are efficiently cleaved. " ... 

The process is not limited to amines. Amides can also be dealkylated. N-Benzyl amides are debenzylated in the presence of NBS and AIBN. ... 

The templated syntheses of amide-based rotaxanes discussed until now have made use of the threading-followed-by-capping method. However there are also examples in which the clipping approach has been employed. Leigh, for example, has used a five-component clipping method to prepare [2]rotaxanes. Isophthalamide and peptide-based threads were shown to template the formation of benzylic amide macrocycles about them in non-polar solvents [69, 70]. When the peptide-based threads (49) contain bulky stoppers at their ends, the [2]rotaxanes (50) can be prepared in high yields (see Scheme 24) [71]. 

There are dozens of linkers available for synthesis, and nearly all of them, once acylated by a protected amino acid, provide a benzyl ester or a benzyl amide that has been sensitized to cleavage by acid by the presence of electron-donating moieties such as alkoxy, phenyl, or substituted phenyl. There are cases in which a peptide chain is bound to a support through two different linkers in series. This allows for versatility in synthesis. The distinction between designation of a moiety affixed to a support as a handle or linker is sometimes arbitrary. 

This polarimetric method was made even more general by utilizing chiral HPLC techniques. The L-UNCAwas dissolved in the solvent at a concentration of 0.33 M at 20 °C. The tertiary amine (1.5 equiv) was added at time zero. The solution was allowed to stand for an experimentally determined delay time, during which the only process that can occur was epimerization, since there is no nucleophile present. The delay time was determined after carrying out several experiments with different delay times and chosen so as to fall within or just after the first half-life for racemization. At the end of the delay period, benzylamine was added. Benzylamine is a very powerful nucleophile that reacts virtually instantly (regardless of the type of activation) with the resulting mixture of l- and d-UNCAs to form the benzyl amides and quench the epimerization process. Thus, a snapshot of the ratio of l/d activated intermediates at the instant of benzylamine addition was obtained by measurement of the l/d ratio of the benzyl amide products. 

The ratio of the enantiomeric benzyl amide products was determined by analyzing a diluted aliquot of the quenched reaction mixture by HPLC using a chiral stationary phase column (Chiralcel OD, Daicel Chemical Co.). Since racemization is a pseudo-first-order kinetic process, these data (along with the time zero value) are sufficient for determination of the intrinsic rate of racemization kR. The half-life for racemization lRU2 can be directly calculated from the l/d ratio (or % enantiomeric excess, %ee) where t was the time of benzylamine addition (the delay time) ... 

Figure 13.28 The electrochemically induced shuttling in the benzylic amide rotaxane 30.

Scheme 15.9 Reversible shuttling of the benzylic amide macrocycle in [2]rotaxane 53 by redox reactions.

Reaction of the dilithiated species 416 and 419 with alkyl halides, aliphatic and aromatic aldehydes, and TMSC1 leads to products 421 and 422 in modest yields (Scheme 129) [83TL4735 86JCR(S)20]. In cases of the N-benzyl amides corresponding to 415 and 418, small amounts of benzylic functionalization is observed (see also later). The methyl and carbinol derivatives corresponding to 421 and 422 were quantitively hydrolyzed into useful synthons 423 and 424, and 425 and 426, respectively. 

Alkoxy-2-hydroxybenzylamides (Entry 13, Table 3.9) can also be cleaved by treatment with TFA (see also Section 16.1.5). If the phenolic hydroxyl group is acy-lated, however, acidolysis proceeds more slowly. Hence, 4-alkoxy-2-(acyloxy)benzyl-amides can serve as linkers that are stable towards both acids and bases, but which can be activated towards acidolysis by saponification to the corresponding 4-alkoxy-2-hydroxybenzylamide [211],... 

I managed to convince chemists at Merck Sharp and Dohme in Harlow that this new reaction was worth investigating further, and in collaboration with them I appointed my second PhD student, Anjum Ahmed, to work on this project. We quickly established that the cyclisation is a general reaction of /V-benzyl amides,29,30 along with some allyl-substituted amides.31 Naphthamides29 such as 11 were easier to... 

V-Benzylamides of acids from esters. Esters are converted into the N-benzyl-amides of the corresponding acids by heating with benzylamine in the presence of a little ammonium chloride as catalyst ... 

N-Benzylamides are recommended when the corresponding acid is liquid and/or water-soluble so that it cannot itself serve as a derivative. The benzyl-amides derived from the simple fatty acids or their esters are not altogether satisfactory since they are often low melting those derived from most hydroxy acids and from polybasic acids or their esters are formed in good yield and are easily purified. The esters of aromatic acids yield satisfactory derivatives but the method must compete with the equally simple process of hydrolysis and precipitation of the free acid, an obvious derivative when the acid is a solid. The procedure fails with esters of keto acids, sulphonic acids and inorganic acids and some halogenated aliphatic esters. 

Warren and coworkers have reported an interesting synthesis of nonracemic allenes by reaction of vinylphosphine oxides with aldehydes in the presence of chiral lithium [(R)-l-phenylethyl](benzyl)amide to give hydroxyvinylphosphine oxides in 33-87% yields (0-51% ee) [38]. These products underwent a Horner-Wittig elimination reaction to produce nonracemic allenes. A mechanism similar to the Baylis-Hillman reaction was suggested. 

The rotaxane is composed of a glycylglycine chain, a simple dipeptide, bearing two diphenylmethane blocking groups, which prevent the dethreading of the benzylic amide macrocycle. The synthesis of the rotaxane structure is based on... 

Scheme8 Translational isomerism in an amphibilic benzylic amide [2]catenane 16 [55]...

In a study of chiral dipeptide [2]rotaxanes it was found that the presence of an intrinsically achiral benzylic amide macrocycle near to the chiral center could induce an asymmetric response in the aromatic ring absorption bands [62], This induced circular dichroism (ICD) effect was stronger in apolar solvents (Fig. 9), where intercomponent interactions are maximized, showing a direct relationship to the tightness with which the macrocycle binds the chiral thread. Computer simulations showed that chirality is transmitted from the amino acid asymmetric center on the thread via the achiral macrocycle to the aromatic rings of the achiral C-terminal stopper. 

Fig. 12 Examples of the use of color in depictions of various types of MIMs. Note how the colors and positions of constituent parts in the three-dimensional structures reflect those in the structural drawings to enhance clarity between representations of (a) a donor-acceptor [2]catenane [75] and (b) an ammonium-binding [2]rotaxane [76] from our group, (c) a transition metal-templated Solomon Knot from the Sauvage and Fujita groups [77], and (d) a benzylic amide [2]catenane from the Leigh group [78]. Reproduced with permission from [75] (copyright 1991 Royal Society of Chemistry), [76] (copyright 2000 Wiley-VCH), [77] (copyright 1999 Royal Society of Chemistry), [78] (copyright 1995 Wiley-VCH)...

Fig. 27 Examples of thermodynamically controlled reactions employed in the near-quantitative synthesis of MIMs. (a) Disulfide-exchange reaction permits equilibration between a bis(ammo-nium) disulfide dumbbell and a crown ether macrocycle to yield a mixture of [2]- and [3]rotaxanes quantitatively [194], (b) Olefin metathesis at high concentration on a benzylic amide macrocycle greatly favors the catenated species [196]. (c) Self-correcting imine bonds allow for nearly quantitative selection of a [2]rotaxane from an appropriate dynamic combinatorial library [76], (d) A weak nucleophile (E) equilibrates the components of a donor-acceptor [2]catenane in a dynamic Sn2 reaction [205]...

During studies aimed at the synthesis of the marine alkaloid Sarain A, Weinreb and co-workers391 reductively cleaved an N-benzyl amide in the presence of an /V-benzylamine using sodium in liquid ammonia [Scheme 8.185]. 

Malonsaure Nitroso- -1-benzyl-amid-3-ethylester-1-imid E16a, 953 (CH - C-NO)... 

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