Library phenols

As in the case of benzimidazole, a parallel synthesis of benzoxazoles was described. The authors report that mixing directly differently substituted o-amino phenols 193 with acylating agents 194 and heating at 200 °C for 10-15 min under microwave irradiation, a collection of benzoxazoles 195 was obtained (Scheme 70). With this reaction, a 48-member library of benzoxazoles with different substituents on the aromatic rings was obtained [125]. 

Meyers HV, Dilley GJ, Durgin TL, Powers TS, Winssinger NA, Zhu H, Pavia MR. Multiple simultaneous synthesis of phenolic libraries. Mol Diversity 1995 1 13-20. 

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]. 

The effects of competition among the IR rules were explored by using the complete system, with the STIRS module disabled, to interpret the spectra of 1807 compounds from the library. For the test, we selected 500 of the 900 chemical substructures which both are chemically interesting and display at least one distinctive infrared band. Some of the selected substructures were subsets of others for example, alcohol, phenol, and primary alcohol were all in the test set. As expected, some functional groups displaying very distinctive infrared bands were detected much more reliably than others. Figure 6 shows the reliability, false positive and recall rates for a few selected functional groups. 

Two artificial compound libraries were chosen as compound mixtures, of which library 1 was composed only of dummy ligands (acetanilide, amitryptiline, benzoic acid, (+)-bicuculline, 4-chloraniline, 2,3-dichloraniline, methylbenzoate, phenol, tramadol see Fig. 7.11), whereas library 2 contained, in addition to these compounds, naloxone, a known //-opioid receptor ligand. 

ARO reaction with phenols and alcohols as nucleophiles is a logical extension of HKR of epoxides to synthesize libraries of stereochemically defined ring-opened products in high optical purity. To this effect Annis and Jacobsen [69] used their polymer-supported Co(salen) complex 36 as catalyst for kinetic resolution of epoxides with phenols to give l-aiyloxy-2-alcohols in high yield, purity and ee (Scheme 17). Conducting the same reaction in the presence of tris(trifluoromethyl)methanol, a volatile, nonnucleophilic protic acid additive accelerates KR reaction with no compromise with enantioselectivity and yield. Presumably the additive helped in maintaining the Co(III) oxidation state of the catalyst. 

The presence of lignin structural units was confirmed by retention time data and by comparisons of mass spectra to library spectra, to spectra of authentic standards, and to published mass spectra of lignin phenols Fill. 

A similar type of compounds, without the nitro group, was achieved by Wessjohann and coworkers (Scheme 15) [79]. Their approach also uses the Ugi reaction to build the linear peptoid intermediates, but a nucleophilic substitution is employed for the ring closure, which is a difficult task with a strained phenolate. A small library of macrocycles with general formula 15a was prepared, including also some 15-membered ansa-cycles (not shown). 

Nonoligomeric libraries. Peptide and peptoid libraries are examples of oligomeric (polymeric) libraries made up of repeating monomers (a-amino acids, A-substitutcd glycines). Random libraries composed of nonoligomeric compounds have been extensively explored. One illustration comes from the former laboratories at Organon (Fig. 1.6) (16). Thirteen different secondary amino-phenol inputs were attached to solid support by reaction with REM resin yielding resin-bound b-amino propionates. Two-site derivatization was then used to drive library diversity. The free phenolic OH was subjected to O-alkylation,... 

Phenol is present in plant and animal organic wastes as a result of decomposition. The level of phenol present in poultry manure, for example, has been shown to increase as degradation proceeds. Phenol is an important industrial chemical and enters the environment in air emissions and wastewater connected with its use as a chemical intermediate, disinfectant and antiseptic (United States National Library of Medicine, 1997). 

Trichlorophenol may enter the environment as emissions from combustion of fossil fuels and incineration of municipal wastes, as well as emissions from its manufacture and use as a pesticide, and in the use of 2,4-D, in which it is an impurity. Significant amounts may result from the chlorination of phenol-containing waters (United States National Library of Medicine, 1997). 

For the preparation of large compound libraries, the cost of reagents and resins is a further issue that must be considered. Some supports, e.g. resin-bound phenols or N-hydroxybenzotriazole, which enable the preparation of resin-bound, reactive esters (Section 3.3.3), can be reused many times without the need to dismantle the reactor, and are therefore much more cost-efficient than supports that can only be used once [136,137], Reactions such as the acylation of amines with resin-bound acylating agents have the additional advantage that only one equivalent of amine is needed, which again leads to a substantial reduction of costs. 

The directed sorting approach has been widely applied both in industry and in academia. Two examples are detailed in this chapter. Some other recently published examples include a benzopyran library synthesized using the Nanokan system,15 libraries derived from phenolic amino acid scaffolds prepared with the Accutag system,16 and libraries of l,5-benzodiazepine-2-one derivatives.17... 

To expand the diversity of their libraries Brill et al.16 also modified various heterocycles by alkylation, acylation, or metal-mediated coupling reaction prior to resin capture. A remaining chloro substituent was still available for nucleophilic displacement or a palladium-mediated coupling reaction with anilines, phenols, and boronic acids on solid phase [see Fig. 10 for the preparation of purine derivative (62)]. 

A number of other solid-phase chemistries have been described for the generation of combinatorial libraries. This includes the synthesis of urea-linked diamines [51], bisamide phenols [52,53], polyphenols [54], thiazolidinones [55,56], thiazolines [57], hydantoins [58], and diaminoalcohols [59,60], Readers interested in more details of these libraries are referred to the section on small molecule libraries. 

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