The Virtue of the Multifunctional Triazene Linkers in the Efficient Solid-Phase Synthesis of Heterocycle Libraries

Abstract

With the implementation of combinatorial chemistry into the modern drug discovery process, the approach to novel diverse heterocycle libraries is an indispensable requirement. Triazenes, which are concealed diazonium salts, can be used to link functionalized arenes and amines to generate various heterocyclic structures, namely, benzoannelated nitrogen heterocycles, upon cleavage from the resin. Since triazene anchors are stable toward various reagents and perform well under a range of reaction conditions, these multifunctional linkers are well suited for automated solid-phase syntheses and the syntheses of complex organic molecules, such as natural products, on solid supports.

The Structural Influence in the Stability of Polymer‐Bound Diazonium Salts

“…This means that, in this evaluation, the diazonium ion p-Cl-C 6 H 4 N 2 BF 4 is the most stable both in the free form and in the complexed state. According to the results in Table 1, p-Cl-C 6 H 4 N 2 BF 4 in the uncomplexed form is approximately 3500 times more stable than m-CH 3 O-C 6 H 4 N 2 BF 4 , which indicates that the T2 linker [24,25] is the most unstable diazonium salt. Furthermore, p-Cl-C 6 H 4 N 2 BF 4 is stabilized with [18]crown-6 by a factor of 10 and with [21]crown-7 by a factor of 60.…”

“…The complexation with [18]crown-6 shifts the NN stretching vibration clearly to higher wave numbers (shifts of 20-29 cm À1 are mentioned in literature [25] ), whereas the complexation with [21]crown-7 leads to small shifts only (about + 5 cm À1 relative to the uncomplexed diazonium ion). In spite of a high excess of crown ether the polymer-bound diazonium salt 4 could not be transformed into its [18]crown-6 complex 4·18 c6 quantitatively, because the rates of complexation are lower than in the case of the www.chemeurj.org corresponding [21]crown-7 complexes.…”

“…The stability of diazonium ions can be increased by complexation with crown ethers, [25] with [21]crown-7 showing the highest thermal stability. Therefore the polymer-bound diazonium ion 4 was shaken with [18]crown-6 or [21]crown-7 to give the new resins 4·18 c6, and 4·21 c7, respectively ( Figure 3).…”

Antagonistic Effect of Acetates in C–N Bond Formation with In Situ Generated Diazonium Salts: A Combined Theoretical and Experimental Study

“…The sensitivity of the triazene species towards acidic conditions (methanesulfonic acid in this case) was suspected to stop the catalytic cycle. Nevertheless, triazenes are not necessarily unreactive species and can be used as concealed diazonium salts or protected amines [29][30][31] regenerated by acidic treatment (usually 5 % trifluoroacetic acid, weaker than MeSO 3 H).…”

Trifluoromethylation of 1‐Aryl‐3,3‐diisopropyltriazenes

“…[9] Our group has been working on triazenes and their applications in solid-phase synthesis as well as "solution" chemistry for years. [10] Aromatic triazenes are easily accessible via a simple one-step procedure These are not the final page numbers! ÞÞ UPDATES starting from commercially available aniline derivatives.…”