Library triazines

Birkert O., Tunnemann R., Jung G., Gauglitz G., Label-Free Parallel Screening of Combinatorial Triazine Libraries Using Reflectometric Interference Spectroscopy, Anal Chem 2002 74 834. 

Several functionalized membranes could be synthesized by conventional methods at room temperature. In contrast, microwave heating was employed for both the synthesis of the triazine membrane and the practical generation of an 8000-member library of triazines bound to an amino-functionalized cellulose membrane (Scheme 7.26). 

An 8000-member library of trisamino- and aminooxy-l,3,5-triazines has been prepared by use of highly effective, microwave-assisted nucleophilic substitution of polypropylene (PP) or cellulose membrane-bound monochlorotriazines. The key step relied on the microwave-promoted substitution of the chlorine atom in monochlorotriazines (Scheme 12.7) [35]. Whereas the conventional procedure required relatively harsh conditions such as 80 °C for 5 h or very long reaction times (4 days), all substitution reactions were found to proceed within 6 min, with both amines and solutions of cesium salts of phenols, and use of microwave irradiation in a domestic oven under atmospheric reaction conditions. The reactions were conducted by applying a SPOT-synthesis technique [36] on 18 x 26 cm cellulose membranes leading to a spatially addressed parallel assembly of the desired triazines after cleavage with TFA vapor. This concept was later also extended to other halogenated heterocycles, such as 2,4,6-trichloropyrimidine, 4,6-dichloro-5-nitropyrimidine, and 2,6,8-trichloro-7-methylpurine, and applied to the synthesis of macrocyclic peptidomimetics [37]. 

Figure 7.9 Structural representation of amines used in the triazines library generation.

Fig. 3. Solid-phase combinatorial synthesis of triazine-scaffolded library of ligands using a modified mix and split strategy.

The 1,2,4-triazine core is a synthetically important scaffold because it could be readily transformed into a range of different heterocyclic systems such as pyridines (Sect. 3.1) via intramolecular Diels-Alder reactions with acetylenes. 1,2,4-Triazines have been synthesized by the condensation of 1,2-diketones with acid hydrazides in the presence of NH4OH in acetic acid for up to 24 h at reflux temperature. Microwave dielectric heating in closed vessels allowed the reaction to be performed at 180 °C (60 °C above the boiling point of acetic acid). As a result, the reaction time was reduced to merely 5 minutes. Subsequently, a 48-membered library of 1,2,4-triazines was generated from diverse acyl hydrazides and a-diketones [139]. Two thirds of the desired heterocycles precipitated from the reaction mixture upon cooling with > 75% purity, while the remaining part of the library was purified by preparative LCMS (Scheme 56). 

The decoration of a central scaffold is illustrated by the triazine library Lll reported by Gustafson et al. (46) where trichlorotriazine was sequentially substituted with anilines (Ar), primary aliphatic amines (Ri), and secondary aliphatic amines (R2,3). The library, made up of 20 x 16 x 20 = 12,800 compounds, was prepared as discretes (Fig. 4.12) and used as a primary library to be screened on various assays. The introduction of sugars, dipeptides, and a-ketoamides among other amine substituents in Lll created diversity in the components even though each of them shares a common 2,4,6-triaminotriazine scaffold. Examples of individuals from LI 1 are provided in Fig. 4.12. Such a decoration library can be made when a suitable scaffold is available in large amounts, either commercially or through a simple synthetic route. Constrained... 

Figure 4.12 Structure of a solution-phase triazine library Lll.

Figure 7.6 SP synthesis of a 12,000-member triazine SP pool library LI.

Whitten et al. (77) reported the synthesis of a focused triazine library L3 (Fig. 8.13) of >350 members based on the known corticotrophin releasing factor 1 (CRF-1) antagonist, 8.24 (Fig. 8.13), to discover more potent triazine analogues. The two-step synthetic scheme leading to L3 from dichlorotriazines 8.25a,b using two amine monomer sets Mi and M2, is reported in Fig. 8.13. 

Figure 8.13 Synthesis of the solution-phase, discrete triazine library L3 inspired by the CRF-1 antagonist 8.24.

The same group (85) has also reported the synthesis of a > 40,000-member triazine library from multiple decoration of cyanuric chloride. Another group that developed its own automated instrumentation reported the synthesis of a 1920-member tetrahy-droquinoline library using a three-component cycloaddition between anilines, aldehydes, and aUcenes (86). 

A classic illustration of scaffold decoration is the trisubstituted 1,3,5-triazine. The starting material trichloro-l,3,5-triazine is inexpensive, and the halogens can be displaced by nucleophilic aromatic substitutions one by one. Such chemistry was well precedented in pre-combinatorial days, and used on a large scale for the synthesis of colour-fast reactive dyes. The overall reaction sequence has an appeal in its simplicity, and both academic and industrial practitioners have reported a steady trickle of such triazine-based libraries over the last 20 years. Novelty will come either from the particular set of nucleophiles employed or the assay targets. 

Todorovic et al. [21] gave the synthesis of a library of 3-aryl-pyrimido [5,4-e] [l,2,4]-triazine-5,7-(lH,6H)-dione (v) following microwave approach. The use of microwave irradiation allowed the rapid reaction times and good yields of products. It also avoids the use of metal salts. 

Todorovic N, Giacomelli A, Hassell JA et al (2010) Microwave-assisted synthesis of 3-aryl-pyrimido[5,4-e][l,2,4]triazine-5,7- (lH,6H)-dione libraries derivatives of toxoflavin. Tetrahedron Lett 51 6037-6040... 

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