Piperidine aminolysis

Aminolysis of 0-aryloximes shows a third-order term for both pyrrolidine and piperidine bases temperature effects on different routes are reported and explained. Hydrolysis of a-hydroxy-a-phenylbenzeneacetic acid salicylidenehydrazide (33) in aqueous ethanol proceeds via fast protonation, followed by rate-determining attack of water the results are compared with several related molecules. 

In non-polar solvents many aminolysis reactions show a third-order dependence on the amine, B. This may be explained by catalysis of leaving-group departure by hydrogen-bonded homoconjugates, BH+B. Evidence for this pathway has been adduced from studies of the reactions of some nitro-activated (9-aryl oximes (7) with pyrrolidine in benzene, chlorobenzene, and dioxane, and with piperidine and hexylamine in cyclohexane. The third-order dependence on amine of the reaction of 2,6-dinitroanisole with butylamine in toluene and toluene-octanol mixtures has been interpreted in terms of a mechanism involving attack by dimers of the nucleophile. ... 

A report of a more extensive Hammett smdy has included estimates of values of Pacyi for aminolysis of members of the sulfamate ester series (XC6H4NHSO2ONP) in chloroform and acetonitrile using piperidine and a set of five pyridines variation of the pyridines allowed the determination of Ppyr values for several esters. The Pacyi values become less negative with decrease in amine basicity, apparently as a consequence of diminished H cleavage and a progression from a partial carbanion-like transition state to a more central E2 type mechanism (10). 

Preparation of the thioacids and their esters via SPPS is mainly restricted to the Boc methodology. The popular Fmoc approach is limited by aminolysis of the thioester bond during removal of the Fmoc group by piperidine. However, a modified Fmoc-deprotecting mixture (1-methyl pyrrolidine/hexamethyleneimine/HOBt/DMSO/NMP 25 2 2 35.5 35.5) gave the final desired peptide ester with 24% yield J24 ... 

Three O-substituted benzophenone oximes (29 X = OMe, F, Cl) have been subjected to aminolysis by pyrrolidine and piperidine, in benzene solution.483 Kinetics were third order in amine, and involved two routes one accelerates with a rise in temperature, the other decelerates. Of the many mechanisms proposed for this reaction in non-polar media, the results support Hirst s mechanism of electrophilic catalysis48b in this instance. 

Kinetic evidence for the involvement of a-hydroxydialkylnitrosamines (142) in the pH-independent solvolysis of the a-(acyloxy)dialkylnitrosamines (141) has been obtained.120 The aminolysis in benzene of 0-(2,4-dinitrophenyl)-/7,/ -disubstituted benzophenone oximes (143) with pyrrolidine and piperidine are third order in amine.121 Hir st s mechanism involving electrophilic catalysis operates and can explain the various effects observed. The bis(pentamethylphenyl)-A-isopropylketenimine (144) undergoes pre-equilibrium /V-protonation in aqueous acetonitrile followed by water attack. An inverse solvent isotope effect and the observation of the diol (145) confirm this.122... 

The aminolysis of Y-phenyl X-benzoates by piperidine in 20 mol% DMS0-H20 at 25 °C proceeded, on the basis of a curved Brpnsted-type plot, via a zwitterionic tetrahedral intermediate with a change in the RDS the curvature centre of the plots was at p Ka = 6.4 regardless of the electronic nature of the substituent X in thebenzoyl moiety 27 The rates of aminolysis of a series of Y-phenyl benzoates by acylic secondary amines were compared with new results for similar reactions with Y-phenyl diphenylphosphi-nates (discussed further in the section Phosphates and Phosphinates). The results showed that the C=0 compounds were more reactive than the P=0 compounds 28... 

Two papers on the aminolysis and hydrolysis of isatin (149) have appeared. In the aminolysis study using piperidine, the reaction rate was much faster in water than in aqueous MeOH or aqueous MeCN. A multi-step mechanism was proposed. In the hydrolysis study the focus was again on the effect of solvent on rate in base hydrolysis, both ethanol and ethylene glycol being used. The reaction rate decreases with increasing ethanol content and it passes through a minimum at about 30% ethylene glycol. 

The aminolysis and methanolysis of ionized phenyl salicylate (189) have been examined under micellar conditions. The effect of CTABr on the rates of aminolysis of (189) by -butylamine, piperidine, and pyrrolidine is to bring about a rate decrease (up to 17-fold with pyrrolidine). The results are interpreted in terms of binding constants for the amines with CTABr and the pseudo-phase model.The effects of mixed surfactants SDS and CTABr on the methanolysis of (189) and the alkaline hydrolysis of phenyl benzoate suggest that micellar aggregates are involved in the processes.The effects of NaOH and KBr on the intramolecular general base-catalysed methanolysis of (189) in the presence of CTABr has been investigated. Pseudo-first-order rate constants were not affected by either additive but other changes were noted. The effect of mixed MeCN-water solvents on the same reaction has also been probed. 

The sensitivity of thioester groups to aminolysis by piperidine has prevented the use of thioester-based linkers for Fmoc SPPS. Two groups d have adapted a modified form of Kenner s acylsulfonamide safety-catch linkerf for the synthesis of C-terminal thioester peptides using Fmoc protocols (Scheme 8). This approach is promising and future studies will more fully analyze the limitations of the method. 

Comparative A -oxide activation was likewise observed when other amines such as hexylamine, aniline, benzylamine, piperidine, and dimethylamine were used. It was also noted, in every example studied, that amination of the chloropyrazine A -oxide or alkylchloropyrazine 7V-oxide at elevated temperatures in a sealed vessel gave mixtures containing greater or lesser amounts of deoxygenated halogeno-pyrazine or aminopyrazine (921). Similar enhanced activation by theTV-oxide group was observed when 3-chloro-2,5-dimethylpyrazine and its 1-oxide in reaction with various amines were compared, although dialkyl substitution further retarded overall aminolysis (793,921). 

Compound 104 was subjected to aminolysis with 1 mol equiv of piperidine, the most useful amine nucleophile in the preliminary test, in CH2CI2 at — 30°C. As the result, a pure major product 105 as yellow needles and a pure minor product 106 as a yellow oil were obtained in a ratio of 88 12 (Scheme 20). 

Bridgehead nitrogen hydantoins have been obtained from imidazole-, pyrrolidine-, and piperidine-2-carboxylates,19 as well as spirohydantoins, such as 15, derived from the aminolysis products of isatincarboxamides.20 Amino nitriles react in a similar manner.1,3,21,22... 

A short, convenient, stereoselective synthesis of pepper-derived alkaloids has been carried out by condensing piperonal with the ylide from methyl (E)-4-(diethylphosphono)-2-butenoate to give methyl (E,E)-5-(1,3-benzodioxol-5-yl)-2,4-pentadienoate, which on methoxide-catalysed aminolysis (piperidine, pyrrolidine, etc.) gave the required alkaloid. 

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