Triazene anchors

Multifunctional Linkers as an Efficient Tool for the Synthesis of Diverse Small Molecule Libraries The Triazene Anchors... 

Benzylamine is immobilized on chloromethyl-PS/DVB. The treatment of the secondary amine with diazonium salts yields the triazen anchor. 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

A combination of the SNAr feature and the coordination ability of a copper complex has led to the development of a new O-arylation method that makes use of a triazene as an activating and directing group (Equation (2)).32,33 This protocol, though necessitating a three-step removal sequence of the triazene moiety, has been successfully applied to the total synthesis of vancomycin1 6 and extended to a solid-phase synthesis in which the triazene unit serves as an anchor to the resin.37... 

The T2 linker has recently been shown to be a versatile backbone amide anchor. Immobilized disubstituted triazenes were acylated with carboxylic acid anhydrides or chlorides to give amide derivatives. These amides were cleaved under very mild conditions using trimethyl chlorosilane. This sequence thus employs the T2 system as backbone amine linker and was demonstrated in the automated library synthesis of substituted amide derivatives.54... 

In summary, the triazene T2 linker system displays an original anchoring group with ample possibilities for variations (Scheme 14). 

Because of an increased demand for flexible anchoring of molecules, other new families of linkers such as the sulfur linkers and triazene linkers have emerged. The most abundant type of linkers developed so far are based on benzylic-type groups. 

The T1 linker system consists of 3,3-diaIkyl-l-aryl triazenes boimd to the support via the alkyl chain (either via a dibenzyl type or a piperazinyl type anchoring). The T2 Unker family is based on immobilized arene diazonium salts [228-231]. 

Coupling of the diazonium resins such as the T2 or T2 diazonium resins with various primary or secondary amines smoothly leads to the formation of a series of triazene resins 292 and 293 (Scheme 49), respectively [245, 246]. The Erase group demonstrated the use of this anchoring group in the... 

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