Triazene-Based Linkers

Triazenes are disguised diazonium ions which can be released under very mild acidic conditions. Inspired by the use of triazenes in natural product synthesis by Nicolaou et al. [127] and the pioneering work of Moore et al. [128, 129] and Tour et al. [130] in the synthesis of triazenes on a solid support and the final detachment to give iodoarenes, a whole set of triazene-based linkers has been developed (Tab. 3.10) [131]. The arene diazonium salts generated from the triazene linkers offer diverse opportunities for multifunctional cleavage. Two linkers based on tria- 

T1 resin traceless linker [131-134], synthesis of phenols [135], biaryls, alkyl arenes [136, 137], azides [138], aromatic hydrazines, halides [cf. 128, 129, 139], ester, azo compounds, cinno-lines [140], benzotriazoles [141] 

T2 resin synthesis of substituted amines [142], amides (peptides) [143], (thio)ureas [143, 

hydrazines, alcohols, esters [145, 146], guanidines [143], alkyl halides [145, 146], sulf- 

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I 3 Organic Synthesis on Polymeric Supports Tab. 3.10 Overview of triazene-based linker. 

Brase S, Kobberling J, Enders D, Lazny R, Wang M, Brandtner S. Nitrogen-based linker. 3. Triazenes as robust and simple linkers for amines in solid-phase organic synthesis. Tetrahedron Lett 1999 40 2105-2108. 

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. 

Two linkers based on the triazene chemistry have been developed. While the Tj linker system consists of 3,3-dialkyl-l-aryl triazene bound to... 

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. 

This linker system is based on the principle that triazenes can be efficiently generated by reactions of diazonium salts with amines. Under basic conditions, these triazenes are stable, but they can be cleaved under mildly acidic conditions to regenerate a diazonium salt and an amine. Based on this system, originally pubhshed by Moore and Tour [151, 152], two different hnkers have been developed. In the so-called T1 variant (Scheme 63), a secondary amine is created on the sohd support and reacted with a diazonium salt to yield the triazene 136. After the synthetic manipulations leading to 137, the triazene is cleaved, resulting in the formation of the initial support and the desired product [153]. Besides the traceless cleavage from the support, the diazonium salt formed as intermediate during the... 

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]. 

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