Pyridines—continued nucleophilicity

The supported aqueous phase methodology was applied to the system Pd(OAc)2/5 TPPTS, a catalytic precursor for the Trost-Tsuji reaction. The characterization of the solid by 31P MAS NMR confirms the presence of Pd°(TPPTS)3 as the main surface species. The catalytic properties of the solid were tested for the allylic substitution of E-cinnamylethylcarbonate by different nucleophiles such as ethyl acetoacetate, dimethyl malonate, morpholine, phenol, and 2-mercapto-pyridine. The absence of palladium leaching was demonstrated, and having solved the problem of water leaching from the solid to the organic phase, the SAP-Pd catalyst was successfully recycled several times without loss in its activity. It was used in a continuous flow experiment which... 

The analgesic Flupirtine 23 is a simple pyridine with three substituents at the 2, 3, and 6 positions. Removal of the amide shows the core 24. The 4-fluorobenzylamine 25 could be added by nucleophilic substitution (easier in pyridines than in benzenes) and we shall delay the choice of the leaving group (X in 26) for the moment. The only amino group we could conceivably add by nitration is the one in the 3-position so we might continue by FGI (reduction) and C—N disconnection 27. 

The above-considered calculational data point to high effectiveness of the bifunctional catalysis in hydrolytic reactions and the reactions related to these, due to involvement of molecular chains of water and ammonia, as well as to the preferability in these reactions of a concerted mechanism. This conclusion is fairly general and is corroborated by calculations on other types of nucleophilic reactions, such as hydrolysis of methyl fluoride, tautomerization of pyridine in aqueous solution etc. [110]. An advisable piece of work would apparently, be an analysis, in the light of the conclusions discussed, of mechanisms of the catalytic act in enzymic hydrolysis reactions of the ester and peptide bonds. In the most advanced up-to-date models for, e.g., the reactions with participation of a-chymotrypsin (see Ref. [Ill]), the steps of the base and the acid catalysis are separated. The latter is commonly thought [84, 111] to be operative at the stage of enzymic decomposition of the tetrahedral intermediate. However, taking into account the possibility of realization of the conformationally excited states of the active enzymic center, it would not be hard to think of some realistic schemes of concerted mechanisms, the more so that the fast growing body of calculational material continuously supplies fresh evidence in favor of such mechanisms. 

Electron-withdrawing substituents facilitate nucleophilic additions. A substrate like 3-(trifluoroniethyl)pyridine can even drive researchers to despair. Whatever base selected, it will act as a nucleophile and dock at the 6-position. The immediately ensuing ejection of metal fluoride gives birth to the semiquinoid species 191 (Scheme 1-137) that partly tautomerizes to 2-butyl-5-(difluoromethyl)pyridine but mainly continues to combine with more organolithium and ultimately produces tars ("dark colored high molecular-weight materials"). ... 

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