Piperidine nucleophilicity, -alkylation

Experimental evidence, obtained in protonation (3,6), acylation (1,4), and alkylation (1,4,7-9) reactions, always indicates a concurrence between electrophilic attack on the nitrogen atom and the -carbon atom in the enamine. Concerning the nucleophilic reactivity of the j3-carbon atom in enamines, Opitz and Griesinger (10) observed, in a study of salt formation, the following series of reactivities of the amine and carbonyl components pyrrolidine and hexamethylene imine s> piperidine > morpholine > cthyl-butylamine cyclopentanone s> cycloheptanone cyclooctanone > cyclohexanone monosubstituted acetaldehyde > disubstituted acetaldehyde. 

Alkylations of 6-methoxycarbonyl six-membered cyclic (V-acyliminium ions show a strong preference for the formation of m-products. This is explained by the A0-3 strain between the substituent and the (V-mcthoxycarbonyl group of the iminium ion, forcing the substituent into an axial position. Stereoelectronically preferred axial attack by the nucleophile then leads to the 2,6-d.v-disubstituted piperidine derivatives. 

Examples of the more frequent nucleophilic attack of a piperidine nitrogen atom onto an alkyl halide to yield quinolizidine derivatives are described below. Piperidinediol 142, after debenzylation and treatment with PBr5... 

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. 

Just as pyridine is a weaker base than piperidine, it is also a poorer nucleophile. Nevertheless, it reacts with electrophiles to form stable pyridinium salts. In the examples shown, primary alkyl halides form N-alkylpyridinium salts, whereas acyl halides and anhydrides react to give N-acylpyridinium salts. 

Alkylation of pyrrohdine and piperidine heterocycles was investigated extensively by Gawley and coworkers. The initial evaluation of 2-lithio-A-methylpiperidine and 2-lithio-A-methylpyrrolidine as nucleophiles was conducted on racemic material, but... 

In summary (Scheme 15), 2-lithiopiperidines and 2-lithiopyrrolidines appear to be very versatile nucleophiles for the elaboration of these heterocyclic systems, affording a variety of 2-substituted heterocycles in excellent yields. The stereoselectivity of the reaction is near 100% in the piperidine series with most carbonyl electrophiles (retention of configuration) and alkyl halides (inversion of configuration). In the pyrrolidine series, the selectivity is also near 100% with carbonyl electrophiles (retention), but less selective (inversion predominates) with alkyl halides (less problematic with Af-aUylpyrrolidines). 

Piperidine is a secondary amine pK 11.3 cf. diethylamine, pK 11.0) it is more basic than pyridine pK 5.2). It is also a good nucleophile, and it is A-alkylated by alkyl halides in the presence of potassium carbonate to form first A-alkylpiperidines and then quaternary salts. 

Similarly, the 2-cyano-6-oxazolopiperidine 75 (Scheme 16) can be used to provide a variety of substituted piperidines <99TL3731, 99H(51)2065>. Conversion to the enamide 76 provides a means to introduce C-3 alkyl groups by Michael reaction <99TL3699>. Electrochemical bis-bromination and dehydrohalogenation affords the vinyl bromide 77, which can imdergo substitution at the 4-position by the addition of nucleophiles as simple as water <99T8931>. 

The polymer-supported superbase 30 was developed and used for the deprotonation and alkylation of weakly acidic nitrogen heterocycles such as indoles, phthalazinones, and pyrazoles.46 The diagram below illustrates the use of superbase 30 to alkylate a weakly basic pyrazole NH after acylation or alkylation of the more nucleophilic piperidine NH. Ami-nomethyl resin 1 was added after each step to sequester excess alkyl and/or acyl halide from the solution phase. 

Dibenzothiophene 5-oxide can be 0-alkylated the alkoxy group in the product can be displaced by nucleophiles (Scheme 189) however, l-methoxy-2,3-dibromobenzo[6]thio-phenium perchlorate regenerates the sulfoxide on treatment with piperidine (72JCS(Pl)899>. 

Alkyl-l,4-bis(4-tolylsulfonyl)-l,2,3,4-tetrahydropyridines 196, which can be synthesized from chiral (V-tosylazir-idines 195, are versatile compounds that can be converted into numerous piperidine and tetrahydropyridine species (Scheme 51). Nucleophilic substitution of the 4-tosyl group of 195 requires addition of a Lewis acid. Bulky substituents at the 2-position give 2,-4-anti- 1,2,3,4-tetrahydropyridine 197 while with smaller substituents a mixture of syn- and anti-isomers is formed <2001TL8369>. 

A ruthenacyclopentane 48 has been proposed as an intermediate in this reaction, after coordination of the allene and enone. Exocyclic /1-hydride elimination led to the 1,3-dienes. This ruthenacycle possessed a o-bound ruthenium allyl, allowing nucleophilic additions by alcohols or amines. Alkylative cycloetherification [29] (Eq. 20) and synthesis of pyrrolidine and piperidine [30] were thus achieved. 

Based on the above argument, the order of increasing nucleophilicity for this group of amines is shown below. Regarding the first two amines, the piperidine is more nucleophilic because, unlike ferf-butyl isobutylamine, the alkyl groups are tied back into a ring and not able to move. This allows the nitrogen to more readily present its lone pair. 

Oxoalkyl- and 3-oxoalkyl-triphenylbismuthonium salts transfer the alkyl groups to various hetero nucleophiles such as piperidine, triphenylphosphane, arylsulfinates, alcohols, arylthiolates, dimethyl sulfide, and metal halides under mild conditions (Equation (132)).214 215 Methyl- and allyl-triphenylbismuthonium salts also alkylate some heteronucleophiles.216 The leaving ability of the triphenylbismuthonio group has been found to be higher than that of the triflate anion. 

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