Triazenes linkers

Cleavage reagents Benzyl- type linkers Ketal/ acetal linkers Esters/ amide linkers Silyl linkers Triazene linkers Selenium/ sulfur/ stannane linkers... 

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. 

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. 

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-... 

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

Examples for multifunctional cleavage are given by the use of sulfone-, silyl- or triazene-linkers [202]. Wagner et al. for example used a cleavage Suzuki reaction on a sulfonium-linker (105) (Scheme 3.8) [206]. 

Promoted Amidation on Solid phase A New Monitoring for the T1 Triazene Linker, September 1—30, 2000. 

The triazene linker featured above is a traceless one that efficiently yields an aryl iodide upon treatment with methyl iodide. It is perhaps not well known to the combinatorial chemistry community. 

A series of special linkers and cleavage strategies has been developed for the release of amines from insoluble supports (Table 3.23). These include the attachment of amines as triazenes, enamines, aminals, amidines, sulfonamides, sulfinamides, hydrazines, or amides. 

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. 

Schunk and Enders [134] disclosed the first solid-phase synthesis of (5-1 actants via ester enolate-imine condensation employing an immobilized ester enolate in a simple three-step procedure (Scheme 31). The protocol showed high purity, excellent diastereoselectivity, and good yields of the product. The substrates were attached to the polymer with a Tl-triazene linker, which was cleaved traceless. The... 

Tl-triazene linker resulted in decomposition of the sensitive p-lactams. The relative configuration of p-lactams, was determined by NOE experiments to be the trans-configuration as observed in solution-phase synthesis [137]. 

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. 

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

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... 

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... 

The triazene T2 linker14 and the improved T2 linker57 systems offer a unique approach to the formation of guanidines in which all three substituents can be varied to a wide extent. Starting from disubstituted triazene on the T2 linker, deprotonation using NaH/DMF and subsequently acylation by the addition of isothiocyanates (Scheme 12) yielded a library of resin-bound thioureas. For the reaction of the thioureas with amines, the use... 

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

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>. 

---