A-Alkylated piperidines

Rearrangement alkylation of cycloalkylhydroxylamine carbonates.9 These hydroxy lamines, which can be prepared from cycloalkyl amines or cyclic ketones, on reaction with a trialkylaluminum rearrange to an a-alkylated nitrogen-containing heterocycle. The complete sequence is formulated for synthesis of an a-alkylated piperidine (equation I). 

Metalated piperidine amides and formamidines may be converted to a-alkylated piperidines, as illustrated in Scheme 9. Again, the two examples illustrate the superiority of the formamidine moiety in both yield and ease of removal. 

In the Hofmann-Loffler reaction an A-alkyl-A-haloamine is heated under acidic conditions to give the/V-alkyl-pyrrolidine or A-alkyl-piperidine product. A related process is the Barton reaction, in which a methyl group that is 5 to a hydroxyl group is oxidised into an aldehyde. 

These A -alkylations are potentially applicable to the preparation of nitrogen heterocy-cles. For examples, reactions of amines with 1,5-pentadiol [136], 1,4-pentadiol [137], or 2-butyne-1.4-diol [138] give A -alkyl piperidine, pyrrolidine, or pyrrole, respectively, in high yield (Scheme 10.16). 

The reaction of perfluorinated cyclic amines with strong Lewis acids, such as SbFs or aluminum chlorofluoride (ACF), at elevated temperature results in rapid cleavage of amine, leading to the formation of cyclic perfluorinated imidoyl fluorides (Fig. 9.23). In contrast to AICI3 reactions, this process is catalytic. The outcome of the reaction depends on the structure of amine. For example, the reaction of A-alkyl piperidines or morpholines leads to the elimination of perfluoroalkane... 

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. 

In essence, the synthesis of pimozide lies in the A(-alkylation of 4-(2-benzimidazolinon)piperidine (6.6.4), which is synthesized by the reduction of 1-(1,2,3,6-tetrahydro-4-piridyl)-2-benzimideazolone (6.3.10) using hydrogen over Raney nickel of pimozide (6.6.5), by the earlier synthesized 4,4-fc/x-(4-fluorophenyl)butylchloride (6.6.3). 

A new piperidine alkaloid Adalinine 352 was prepared in racemic form, using a rearrangement as a key step (equation 134). Enolate chemistry allowed double a-alkylation of cyclopentanone, producing 350 after oxime formation. Rearrangement provided a clear conversion into the lactam 351, easily converted to racemic Adalinine 352. 

A very elegant synthetic approach was reported a year later by Davies et al., leveraging asymmetric C-H activation chemistry to accomplish a one-pot synthesis of d-threo methyiphenidate (Scheme 17.10) (Davies et al., 1999). A-Boc piperidine (33) was selectively alkylated by the carbene formed by decomposition of diazoester 34 in a reaction mediated by 25 mol% of chiral Rh (II) catalyst 35, giving the A-Boc protected (2R,2 R) isomer in a single step. TFA was added to accomplish removal of the Boc group after the C-H insertion reaction was complete, affording (R,R)-methylphenidate (2) with an ee of 86% in 52% overall yield. 

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. 

The reduced basicity of phenothiazine nitrogen requires that even acylation proceed via the anion. The amide (34-2) from the methyl thioether (34-1) can be prepared, for example, by sequential reaction with sodium amide and acetic anhydride. Oxidation of that intermediate with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone this affords the phenothiazine (34-3) on hydrolysis of the amide. Complex side chains are most conveniently incorporated in a stepwise fashion. The first step in the present sequence involves reaction of (34-3) as its anion with l-bromo-3-chloropropane to give (34-4). The use of that halide with alkylate piperidine-4-carboxamide (34-5) affords the antipsychotic agent metopimazine (34-6) [35]. 

Enamines with a tertiary nitrogen atom may be more basic than tertiary amines or enamines with a primary or secondary nitrogen atom [5-9]. The presence of a-alkyl substituents increases basicity, whereas /3-alkyl substituents decrease basicity [10]. Stamhuis [11a] and co-workers found that the morpholine, piperidine, and pyrrolidine enamines of isobutyraldehyde in aqueous solutions are 200-1000 times weaker bases than the starting secondary amines and 30-200 times less basic than the corresponding saturated tertiary amines [11a]. For further discussion of enamine basicity see Stollenberger and Martin [lib]. 

Oxidative reactions at carbon predominate in the biotransformation of cyclic amiiies, and an important consequence of this is often the cleavage of the carbon-nitrogen bond. For example, A-dealkylation of N- alkyl substituted pyrrolidine (or piperidine, morpholine, etc.) involves an initial oxidative attack at the a- alkyl carbon atom to yield an N hydroxyalkyl derivative (carbinolamine), which is then metabolized to a secondary amine and the corresponding aldehyde. The metabolic conversion of nicotine to nornicotine (30 see Scheme 3) probably involves this mechanism, although the iminium ion (31) has also been suggested as an intermediate in the biotransformation (76JMC1168). Carbinolamines are unstable intermediates and have been identified only in a few cases, e.g. A-hydroxymethylcarbazole... 

Over half of the compounds reported for lithistid sponges were isolated from Theonella (family Theonellidae). Theonella species have been reported to contain a wide variety of cyclic and linear peptides and polyketides, as well as 3-alkyl piperidine derivatives nearly identical to those reported from the order Haplosclerida.58 There is also a single report of cyano- and isothiocyano-sesquiter-penes similar to those isolated from Axinellidae (order Halichondrida).42 Bewley et al. performed a cellular localization study on Theonella swinhoei in which several types of microorganisms were separated from the sponge cells. Chemical analysis of the extracts from the separated cells indicated that the bicyclic peptide theopalauamide was found exclusively in filamentous bacteria while the polyketide swinholide A was localized to a mixed population of unicellular bacteria.59... 

No products of disproportionation have ever been observed in the studies of Katzer s and Satterfield s groups, probably because either these products would be too heavy to desorb and thus to be detected, or steric hindrance due to the second ring, absent in the pyridine-piperidine reactions, prevents the alkyl transfer. However Schultz et al.33 found alkyl addition products, but did not specify whether these were A-alkyl or C-alkyl molecules. The formation of C-alkyl products will be shown later with the low pressure reaction. 

Synthesis of 3-alkylated piperidine derivatives could of course be performed most directly by alkylation of 2-deoxyaldono- 1,5-lactams, as outlined in Scheme 8. After unsucessfull experiments due to solubility problems, we turned our interest to the alkylation at C-2 of unprotected 2-deoxy- -bromodeoxyaldonolactons. This strategy requires set-up of a dianion in the presence of a primary bromine, followed by stereoselective alkylation at C-2, two possible doubtful reactions (Scheme 9). Gratifyingly, both reactions could be performed satisfactory. 

Heating or photolytic treatment of A,A-dialkyl-A-haloamine in sulfuric acid or trifluoroacetic acid, followed by neutralization with a base, generates a pyrrolidine or piperidine skeleton. This is the Hofmann-Loffler-Frey tag reaction, and the reaction comprises of the formation of an electrophilic aminium radical, 1,5-H shift (6-membered transition state) or 1,6-H shift (7-membered transition state), formation of 4-haloalkyl ammonium or 5-haloalkyl ammonium, and its polar cyclization by neutralization with a base. Eq. 6.16 shows the formation of A-alkyl pyrrolidine (31) from A-chloro-A-alkyl-A-butylamine (30) in sulfuric acid [46, 47]. 

The synthetic value of these transformations was further demonstrated through the synthesis of optically active oc-alkyl piperidines or a-amino acid derivatives, respectively [37]. 

Gutman,50 in his process route, which did not report any yields, hydrogenated the pyridine ring first to access the piperidine moiety and constructed the indanone ring system via an intramolecular Friedel-Crafts acylation (Scheme 5). Hydrogenation of diester 31, obtained from condensation of 4-pyridine carboxaldehyde and dimethyl malonate, followed by benzylation of the piperidine intermediate afforded A-benzylated piperidine 32. Alkylation of 32 with 3,4-dimethoxybenzyl chloride (33) and subsequent hydrolysis gave dicarboxylic acid 34. Subjection of 34 to strong acid resulted in intramolecular Friedel-Crafts acylation and in situ decarboxylation to provide 3. 

Reaction with N-protected 2-hydroxypyrrolidines or -piperidines. The Wittig reaction with these substrates provides a-alkylated pyrrolidines or piperidines after base-catalyzed intramolecular Michael addition.1... 

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