Nucleophilic scavengers

The alternative selective cleavage of the allyl ester was achieved by Pd(0)-catalyzed allyl transfer. Because the Fmoc group is sensitive to morpholine, a very weak base must be used as the allyl-trapping nucleophile. IV-Methyl aniline was favorable, and its use as a scavenger nucleophile gave rise to the acid 29 in a high yield. 

Frechet and coworkers have reported the development of a functionalized polymer monolith for use in parallel solution phase synthesis in continuous flow applications [10]. In this report, the authors outline the preparation of an azalac-tone-functionalized monolith for scavenging nucleophiles. This method involves the preparation of a macroporous polyfchloromethylstyrene co-divinylbenzene) monolith via the polymerization of the relevant mixture of monomer, initiator and porogen. These are allowed to react with a free radical initiator (4-cyanovaleric acid), followed by reaction with the monomer of choice, to synthesize the functionalized monolith. The authors have thus prepared monoliths functionalized with VAZ to provide an azalactone-functionalized monolith. These monoliths were then demonstrated to completely remove amines after flowing a solution of amine in THF through the monolith for 30 min. They have also reported the reaction of these monoliths with alcohols as well. A small demonstration library of ureas was prepared and after 8 min of residence time up to 76% of the alkyl amines were found to be scavenged (Scheme 8.6). 

Recently, Pattarawarapan and coworker reported the synthesis of a Si-supported DCT for scavenging nucleophiles [27]. 3-Aminopropyltrimethoxysilane was allowed to react with commercial silica gel in toluene. TCT (trichloroazine) was then reacted with the Si-immobilized amine to provide the supported DCT reagent. This was found to sequester both amines (primary and secondary) as well as alcohols with remarkable facility and two libraries of sulfonamides and amides were prepared in parallel format. Filtration was the sole purification step (Scheme 8.18). 

Reaction of 1,3-propanediamine and a mixture of a and isomers of 5-bromo-5-deoxy-D-xylofuranose in H2O for 10 min gave 1 R-(la,8p,9a9aa)-7,8,9-trihydroxyperhydropyrido[l, 2-u]pyrimidine (112, R = H) in 27% yield (99T6759). Reaction of 5-bromo-5-deoxy-D-xylofuranose and A -methyl-1,3-propanediamine in H2O at room temperature afforded a 5 1 mixture of 1-methyl 117 and 5-methyl 118 derivatives of 7,8,9-trihydroxyperhydropyr-ido[l, 2-u]pyrimidine 112 (R = H). When this reaction was carried out in the presence of 3 moles of NEts the product ratio of 117 to 118 was 1 2. The influence of NEt3 on the product ratio may be a consequence of it scavenging HBr and freeing the more basic and more nucleophilic methylamino group for participation in the displacement reaction. 

Normally, the radical anion could be the starting point for a competitive process leading also to the same arylated nucleophile but the presence of radical scavengers, such as dinitrobenzene or ditertiobutylphenol would inhibit this secondary way of arylation, increasing the overall yield of arylation. 

A reverse cross-coupling reactions mediated by palladium was used to develop a colorimetric sensitive chemodosimeter for the detection of trace palladium (II) salts [93]. The decolorization of 4 is produced by a nucleophilic attack of ethanethiol in basic DMSO solutions. Palladium detection is done via thiol scavenging from the 4-ethanethiol complex leading to a color turn-on of the parent squaraine. Naked-eye detection of Pd(NC>3)2 is as sensitive as 0.5 ppm in solution, and the instrument-based detection can go as low as 0.1 ppm. 

However, it has since been found that the curvature observed in these excess acidity plots is an artifact, caused by insufficiently effective halogen scavenging in the original experiments,247 and that when corrected for this the excess acidity plots of log - log Ch+ against X for these reactions are linear, not curved. This is a very interesting result, as it means that the base, B in Scheme 6, does not appear in the rate law, unlike the nucleophile in equation (42), see Figs 10 and 11. Why this should be is, at present, not clear further work seems necessary. 

Analogously, 5-tributylstannylimidazole 29 was easily obtained from the regioselective deprotonation of 1,2-disubstituted imidazole 28 at C(5) followed by treatment with tributyltin chloride [24]. In the presence of 2.6 equivalents of LiCl, the Stille reaction of 29 with aryl triflate 30 afforded the desired 1,2,5-trisubstituted imidazole 31 with 2,6-di-tert-butyl-4-methylphenol (BHT) as a radical scavenger. Reversal of the nucleophile and electrophile of the Stille reaction also provided satisfactory results. For example, the coupling reaction of 5-bromoimidazole 33, derived from imidazole 32 via a regioselective bromination at C(5), and vinylstannane 34 produced adduct 35 [24],... 

Silverman has pointed out that several criteria must be met to demonstrate that a compound is a true suicide substrate 1101 (1) Loss of enzyme activity must be time-dependent, and it must be first-order in [inactivator] at low concentrations and zero-order at higher concentrations (saturation kinetics), (2) substrate must protect the enzyme from inactivation (by blocking the active site), (3) the enzyme must be irreversibly inactivated and be shown to have a 11 stoichiometry of suicide substrate active site (dialysis of enzyme previously treated with radiolabeled suicide substrate must not release radiolabel into the buffer), (4) the enzyme must unmask the suicide substrate s potent electrophile via a catalytic step,1121 and (5) the enzyme must not be covalently labeled with the activated form of the suicide substrate following its escape from the active site (the presence of bulky scavenging thiol nucleophiles in the buffer must not decrease the observed rate of inactivation). 

When reactive metabolites are formed by metabolic activation, some of them can escape from the active site and bind to external protein residues or be trapped by reduced glutathione (GSH) or other nucleophiles. The remaining molecules that are not released from the active site will cause the suicide inhibition [7]. The ratio of the number of reactive molecules remaining in the active site and those escaping is a measure of the reactivity of the intermediates formed. The addition of scavengers or GSH to the incubation mixture does not affect and cannot prevent the CYP mechanism-based inhibition. However, GSH can reduce the extent of the nonspecific covalent binding to proteins by those reactive molecules that escape from the active site. In contrast, addition of substrates or inhibitors that compete for the same catalytic center usually results in reduction of the extent of inhibition. 

The allenylsilanes are excellent nucleophiles and they can react with a variety of electrophilic species in annulation processes that provide access to diverse products. Allenylsilane 112 (Eq. 13.36) reacts with tropylium fluoroborate 111 to provide azu-lene 113 [35]. The reaction is slow and it is necessary to use an acid scavenger so as to inhibit protiodesilylation by the fluoroboric acid that is generated during the course of the annulation. The excess tropylium salt abstracts a hydride from the reaction intermediate leading to the azulene. There are relatively few direct methods for the synthesis of azulenes. 

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