Benzylamine linkers

4-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], 

Treatment of tertiary benzylamines with acylating agents can lead to debenzylation. If the benzyl group is linked to an insoluble polymer, acylation and debenzylation will lead to the release of an acylated amine into solution (Entry 6, Table 3.9). These cleavage reactions generally yield products that are contaminated with acylating agent and so require further purification. 

Entry Loaded resin Cleavage conditions Product, yield (purity) Ref. 

Photolabile linkers for amides are most often based on 2-nitrobenzyl derivatives (Table 3.10 for the preparation of these and similar linkers, see also [147,153,235]). The mechanism of photolysis is the same as for the related 2-nitrobenzyl alcohol linkers (Section 3.1.3). 

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The attachment of amides to supports as A-(diarylmethyl)amides can be achieved either by acylation of resin-bound (diarylmethyl)amines, or by acid-catalyzed N-alky-lation of amides with resin-bound benzhydryl alcohols [46]. The former strategy is by far the more general. For the preparation of secondary amides RNHCOR by backbone amide linking, benzylamine linkers (Table 3.9) are more appropriate than (diary lmethyl) amine linkers, because V-al ky I - N- (di ary 1 met hy 1) amines are often difficult to acylate because of steric hindrance [242,243]. A few examples of the preparation of secondary amides by backbone amide linking to (diarylmethyl)amine linkers have been reported (Table 3.11). 

As illustrated by the examples in Table 3.9, resin-bound 4-alkoxybenzylamides often require higher concentrations of TFA and longer reaction times than carboxylic acids esterified to Wang resin. For this reason, the more acid-sensitive di- or (trialkoxy-benzyl)amines [208] are generally preferred as backbone amide linkers. The required resin-bound, secondary benzylamines can readily be prepared by reductive amination of resin-bound benzaldehydes (Section 10.1.4 and Figure 3.17 [209]) or by A-alkyla-tion of primary amines with resin-bound benzyl halides or sulfonates (Section 10.1.1.1). Sufficiently acidic amides can also be A-alkylated by resin-bound benzyl alcohols under Mitsunobu conditions (see, e.g., [210] attachment to Sasrin of Fmoc cycloserine, an O-alkyl hydroxamic acid). 

Benzhydrylamines are better suited than benzylamines as acid-labile linkers for amines. The MBHA linker ( methylbenzhydrylamine ), which is usually used to prepare peptide amides (see Section 3.3), can also be used as a linker for amines (Entry 1, Table 3.21). Hydrogen fluoride is, however, required as the cleavage reagent. Easier to cleave are alkoxy-substituted benzhydrylamines (Entries 2-5, Table 3.21), which can be prepared from the corresponding benzhydryl chlorides [263] or by reductive alkylation [410] or solvolysis [411] of the Rink amide linker. In the case of benzhydrylamines linked to polystyrene as benzyl ethers, treatment with TFA can lead to the release of the linker into solution (acidolysis of the benzylic C-O bond, see Figure 3.18). 

Table 3.25. Benzylamine and benzhydrylamine linkers for aromatic amines.

The synthesis of monocyclic p-lactams via the ester-enolate imine condensation route has been reported to be carried out utilizing triazene esters (Scheme 54), [141], Esters were attached to benzylamine resin by a triazene linker employing the respective diazonium salts. Immobilized ester-enolates were reacted with various imines to give polymer-bound p-lactams in different substitution patterns. Traceless cleavage from the triazene linker yielded the desired p-lactams. 

The triazene linker can be used for the immobilization of aromatic diazonium salts, and therefore for aromatic amines, but not for aliphatic amines due to the instability of their diazonium salts. Cleavage of the linker can be achieved under mild acidic conditions to yield the benzylamine resin and the corresponding diazonium salt [136,145,146]. The main difference between the preparation of triazenes in solution and triazenes on solid support is the respective amine, namely bisben-zylamine and polymer-supported benzylamine 114. In solution, it was used in excess to quench unstable diazonium salts and force the reaction to completion. In the solid-phase approach it was immobilized and cannot be used in excess with respect to low loadings. A simple three-step procedure (Scheme 36) starting from benzylamine resin 114 via carboxylate 115 led to the successful preparation of ester resins 116 in essentially higher loadings. Treatment of resin 114 with 4-carboxy-benzene diazonium tetrafluoroborate yielded benzoic acid resin 115. 

Various imines and imine precursors reacted with immobilized ester-enolate-derived triazene esters 481 to give polymer-bounded azetidin-2-ones 482 (Scheme 68). The esters were bound to a benzylamine resin by a triazene linker employing diazonium salts. Traceless cleavage from the triazene linker yielded the desired azetidin-2-ones 483 <2002JOC8034>. 

A -Alkyl-A -(/3-keto)amides 1216 have been prepared using a traceless linker strategy starting from resin-bound benzylamines 1215. The ketoamides 1217 released from the resin react with an ammonium salt to afford 1,2,4-trisubstituted imidazoles 1218 in good yields and high purities (Scheme 297) <20000L323>. 

Elimination of the sulfone linker has also been used in the formation of aryl sulfonamides, dehydroalanine, and heterocyclic 2-substituted-4-piperidones." Pendant phosphonium sulfone intermediate 169 was subjected to Wittig reagent to form sulfone-bound vinyl ketones 170 (Scheme 12.35). Benzylamine as nucleophile and base was then... 

Overview Waldmann and his group recently reported the development of a penicillin G acylase sensitive safety catch linker for the attachment of alcohols and anilines to a polymeric support (Fig. 6) (20). The release of the synthesized target molecule from the support is initiated by the hydrolysis of the phenylacetamide moiety contained in the linker 28 under extremely mild conditions (pH 7.0, room temperature or 37°C). The liberated benzylamine 29 intermediate cyclizes instantaneously to release the desired target molecule with the tetrahydroisoquinolinone 30 formed in the course of this process remaining on the polymer. 

Fig. 6. An enzyme labile phenylacetamide linker. Penicillin acylase cleaves the acetamide group of polymer-supported linker 28. The benzylamine derivative 29 then cyclizes to release the target compound.

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