A -Acylpiperidines

A nitrogen atom at X results in a variable downfield shift of the a carbons, depending in its extent on what else is attached to the nitrogen. In piperidine (45 X = NH) the a carbon signal is shifted by about 20 p.p.m., to ca. S 47.7, while in A-methylpiperidine (45 X = Me) it appears at S 56.7. Quaternization at nitrogen produces further effects similar to replacement of NH by A-alkyl, but simple protonation has only a small effect. A-Acylpiperidines show two distinct a carbon atoms, because of restricted rotation about the amide bond. The chemical shift separation is about 6 p.p.m., and the mean shift is close to that of the unsubstituted amine (45 X=NH). The nitroso compound (45 X = N—NO) is similar, but the shift separation of the two a carbons is somewhat greater (ca. 12 p.p.m.). The (3 and y carbon atoms of piperidines. A- acylpiperidines and piperidinium salts are all upfield of the cyclohexane resonance, by 0-7 p.p.m. 

Regioselectivity and stereochemistry have been studied in the case of the anodic methoxylation of A-acylpiperidines and A-acylmorpholines [234]. Because of steric constraints imposed by the intermediate formation of the planar A-acyhminium ions, substitution is directed to the secondary carbon rather than to the tertiary position. The same reason accounts for the axial methoxylation in this reaction. 

A synthesis of a partially reduced indolizine which allows the introduction of a substituent at any of the C-3 to C-6 atoms utilizes an A -acylpiperidine-2-carboxylic acid which is cyclized on heating with ethyl propynate. A lactone intermediate is proposed for this interesting reaction. 

The loss of the ester group and formation of 134 was also observed with A-acylpiperidine in hydrochloric acid environment [220],... 

Palasz, P.D. and Utley, J.H.P. (1984) Regioselectivity and the stereochemistry of anodic methoxylation of A-acylpiperidines and A-acylmorpholines. Journal of the Chemical Society, Perkin Transactions 2, 807-813. 

The presence of an oxygen atom in the linking chain lowers the yield of cyclization markedly, but cyclization is facilitated by a nitrogen atom in the chain. Thus this cyclization is a useful route to N-acylpiperidines (equation I).2... 

A novel synthesis of 2-acylpiperidines via inverse electron demand Diels-Alder reaction of 5-acyl-l,2,4-triazines has been reported <01OPP501>. 

Katritzky et al. (2008PNAS7359) successfully developed classification ANN QSAR for 200 compounds used as repellents against mosquitoes. Mosquito repellent activities from USDA archives of N-acylpiperidines were extracted and modeled using molecular descriptors calculated by CODESSA PRO software. The ANN model was used for the correlation of these archival repellent activities and used to predict the activities of novel compounds of similar structures. The outcome of this QSAR led to a selection of 34 promising mosquito N-acylpiperidine repellent candidates which were synthesized by reactions of acylbenzotriazoles with piperidines. These synthesized compounds were screened as topical mosquito repellents by... 

Acylpyrrolidines. A soln. of diethyl 4-azidobutylboronate in dichloromethane treated at —78 with BCI3 in the same solvent, the mixture allowed to reach room temp, overnight, treated with methanol, and the crude pyrrolidine benzoylated by routine procedure N-benzoylpyrrolidine. Y 89%. F.e. inch 1-acylpiperidines and preparation of the startg. m. s. J.M. Jego et al., J. Chem. Soc. Chem. Commun. 1989, 142-3. 

The main hot component of black pepper is piperine, piperic acid amide or (2E,4E)-piperoyl-l-piperidine or (2 ,4 )-5-(l,3-benzodioxol-5-yl)-N-piperidinylpenta-2,4-dienamide (10-9). Black pepper also contains a number of related compounds as minor components, such as piperanine (10-9) and N-(3,4-methylendioxyphenyl)acylpiperidines with C3, C5, Cy and C9 acyls and the corresponding pyrroHdines, such as piperettine, piperyline, piperoleine A, piperoleine B (10-9) and other compounds. 

N-Acyliminium ions are hot and will even add to unactivated olefins. For example, N, 0-acetal 20 reacts with formic acid to provide 23. The stereochemistry of the process is relatively clean and can be rationalized by an twft -periplanar addition of electrophilic carbon and nucleophilic oxygen across the carbon-carbon double bond with a transition state that resembles a chair N-acylpiperidine. In reality, this process is mechanistically more complex than this simple model (for example, possible carbocation intermediates and in some cases, some underlying sigmatropic rearrangements), but the model is simple, easy to remember, and has excellent predictive value. How was this chemistry used to prepare perhydrohistrionicotoxin ... 

Fortunately, ANNs can overcome these limitations and be used to develop models for these types of data. Some of the earliest work with neural networks was done by McCulloch and Pitts in 1943. ANNs can be used for the evaluation of nonlinear data for the development of a predictive model. Thus, a nonlinear data set, such as the class system of CPT data in the USDA archive, can be used to develop a model and predict compound activities based on the compound structures and associated repellent activities that were incorporated into the neural network. Three-layer neural networks with different architectures were applied to the data sets of acylpiperidines in this chapter. 

The initial repellent model for the acylpiperidine data set was developed using 150 out of 200 selected acylpiperidines as the training set for the ANN. A fuU listing of the compounds (coded by AI3- numbers), structural information, and notation of whether they were in the training or validation subsets can be found in the supporting information for the work by Katritzky and others. This set did not include A13-35765 or A13-37220 in the model, but it did contain some compounds similar to those in the structures (Table 4.3, e.g., 4a -4d and others). The archival data used for the initial models in this study were accumulated from compounds submitted as early as 1942 and as late as 1994. The compound structures with A13- numbers can be found in Table SI of the supplementary information provided by Katritzky and others. Some of the modeled compounds were from acylpiperidines patented as insect repellents in 1981. ... 

The models for the acylpiperidines were developed with an 8-7-1 architecture, comprising eight initial descriptors as neurons for the input layer, followed by seven neurons in a hidden layer, and... 

With a satisfactory ANN model, structures can be devised and tested in the model to predict their repellent classes. This was performed with just over 2000 acylpiperidine structures. Some of these compounds were tested previously, but many others were novel in that they were not evaluated previously as mosquito repellents. From 2000 predicted compounds, 34 were selected for synthesis of them, 23 were novel compounds and 11 were chosen from those in the USDA archive. Selection of compounds tested previously allowed for comparison and validation of the current repellent testing methodology with that used decades ago. The repellency data generated for this study were more precise and linear, that is, the repellency was measured in days of protection, rather than put... 

The repellency class data of a set of acylpiperidines from the USDA archive were used to develop suitable ANN models to predict new repellent structures. Predicted compounds that were not previously examined for repellency along with compounds tested as repellents during the past 70 years were bioassayed for CPT. The results were used to develop a successful QSAR model to predict repellency duration (i.e., CPT), giving excellent correlation with experimental data (Figure 4.5). Compounds such as 4j, 4k, 4o, and 4o had durations of repellency three times better than deet. 

The approach used to produce successful modeling and prediction of acylpiperidines was also applied to a subset of carboxamides. Because of the greater structural diversity or imprecision in the nonlinear class data, ANN models were not as successful in the prediction of repellents with high efficacy. However, despite the inability of ANN models to produce a QSAR model of carboxamides, about one-third of the carboxamides had a CPT comparable or superior to that of deet and another compound had a minimum effective dose equivalent to that of deet. 

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