Rapid screening schemes

The glass plate was exposed to microwave irradiation, eluted, and viewed by standard TLC visualization procedures to assess the results of the reaction. In this particular example, the synthesis of an arylpiperazine library (Scheme 4.25) was described, but the simplicity and general utility of the approach for the rapid screening of solvent-free microwave reactions may make this a powerful screening and reaction optimization tool. The synthesized compounds were later screened for their antimicrobial activity without their removal from the TLC plate utilizing bioautogra-phical methods [84],... 

Chemistry as a subject has developed through the synthesis of individual compounds in a number of distinct steps. Recently it has benefited from the introduction of combinatorial/parallel chemistry techniques as well as microwave-enhanced technology but so far these studies have not been combined [80]. Lockley and coworkers [81-83] have shown very nicely how parallel chemistry techniques can be used for the rapid screening and ranking of catalysts using the hydrogenation of 3-methyl-3-butenylisonicotinate as the model reaction (Scheme 13.8). 

Of the methods developed for the identification of hydrocarbon mixtures, only coupled gas chromatography-mass spectrometry holds any real promise of certain identification and this only at a prohibitive cost in time spent characterising minor peaks. It would be far more efficient to develop rapid screening procedures which would eliminate all but a few possibilities, and then use gas chromatography-mass spectrometry to isolate and identify a few key peaks to confirm the characterisation. This is precisely the scheme adopted independently by a number of laboratories. 

TLC is also one of the analytical techniques that is commonly used to support evidence in courts of law. The chemistry concept for visualization is not unique since this reaction scheme, converting explosive to pink dyes, is decades old. TLC provide rapid screening capability for the presence of a broad range of explosive residues. TLC also provides a means for obtaining specificity, i.e., identifying numerous types of explosives, their concentrations, and also provides the capability to ratio the amounts of the explosives present. For example, Comp B has a mixture of RDX and TNT in its formulation, and if present in the sample the ratio would be 60 40, respectively. This ratio becomes visually apparent by the density of the spots with TLC technology (See Figure 2). 

Automated parallel experiments were carried out to rapidly screen and optimize the reaction conditions for ATRP of methyl methacrylate (MMA) [34]. A set of 108 different reactions was designed for this purpose. Different initiators and different metal salts have been used, namely ethyl-2-bromo-tTo-butyrate (EBIB), methyl bromo propionate (MBP), (1-bromo ethyl) benzene (BEB), and p-toluene sulfonyl chloride (TsCl), and CuBr, CuCl, CuSCN, FeBr2, and FeCl2, respectively. 2,2 -Bipyridine and its derivatives were used as ligands. The overall reaction scheme and the structure of the used reagents are shown in Scheme 2. 

The modular structure of peptides and the well-established methods for their assembly enable the rapid synthesis of many structurally diverse catalyst candidates. For rapid screening of these Miller et al. developed the indicator 28 which becomes fluorescent on protonation (Scheme 12.14). In other words, catalyst candidates are usually incubated with acetic anhydride, the proton sensor 28 [32], and the two individual substrate enantiomers in separate microtiter plates. A related assay based on pH color indicators was developed by Davis et al. [34b],... 

Douthwaite et al. have published two types of chiral bidentate NHC ligands [39]. The first of these contains an imidazolylidene and an imine linked by a frans-cyclohexanediamine core according to the synthetic strategy outlined in Scheme 14. The facile modular variation of the peripheral substituents in this class of ligands principally allows for the rapid screening of large ligand libraries. 

Scheme 1. Reactions Utilized for the Rapid Screening of Ligsinds for Ethylene Poljrmerization Catsdysts Ni(COD)2 + Ugand + HBAF 2Et20 Pda(dba)3 + 2 Ligand + 2 HBAF 2Et20...

Heteroaromatic aldehydes are excellent electrophiles in the MBH reaction because of their increased electrophilicity. The heteroatom also facilitates the proton transfers involved in the reaction (Scheme 1.53)/ In the presence of DABCO, pyridine-2-carboxaldehyde derivatives react rapidly with acrylates, methyl vinyl ketone and acrylonitrile to give excellent yields of the MBH adducts 112, which can be further transformed into indolizines 114 by thermal cyclization of their acetate derivatives 113 (Scheme 1.54)/ Notably, a small amount of indolizine 114 was formed along with normal MBH adduct 112 in the reaction of pyridine-2-carboxaldehyde with methyl vinyl ketone. Similarly, substituted 2-chloronicotin aldehydes 115 are reactive and efficient in the MBH reaction of methyl acrylates, acrylonitrile and cyclic enones catalyzed by various tertiary amine catalysts, such as DABCO, DBU, imidazole and 1-methylimidazole, to provide novel MBH adducts 116 and 117 for biological activity screening (Scheme 1.55). ... 

Microwave-assisted reactions allow rapid product generation in high yield under uniform conditions. Therefore, they should be ideally suited for parallel synthesis applications. The first example of parallel reactions carried out under microwave irradiation conditions involved the nucleophilic substitution of an alkyl iodide with 60 diverse piperidine or piperazine derivatives (Scheme 4.22) [76]. Reactions were carried out in a multimode microwave reactor in individual sealed polypropylene vials using acetonitrile as solvent. Screening of the resulting 2-aminothiazole library in a herpes simplex virus-1 (HSV-1) assay led to three confirmed hits, demonstrating the potential of this method for rapid lead optimization. 

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