Piperidine amides alkylation

The C2-symmetrical chiral amine tran.v-(2/ ,6y )-2,6-bis(benzyloxymethyl)piperidine (1), prepared15 from commercially available (S)-2-(benzyloxymethyl)oxirane, has been used in diastereoselective amide alkylations. Thus, the chiral amine of 76% ee is acylated [anhydride or mixed trimethylacetic acid anhydride, 1.2 equivalents of triethylamine and 0.05 equivalents of 4-(dimethylamino)pyridine] and the resulting amide 2 treated with 2.1 equivalents of lithium diisopropylamide at —78 CC to give the enolate. This is then alkylated to give high diastereo-meric ratios (>94 6) of alkylation products 3 in 60-93% yield16. 

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. 

The NH group in the 3-position of 2-methylpyrido[2,3-fif pyrimidin-4(3//)-one has been used for Mannich condensations with formaldehyde and piperidine or alkylated by a variety of chloro compounds after conversion into the anion by sodium amide.82,328-330 Applying the Mitsunobu reaction with iodomethane to 6-bromo-2-(pivaloylamino)pyrido[2,3-t/]pyrimidin-4(3//)-one results in methylation of Nl.331... 

Meyers and co-workers have continued their studies to exploit the synthetic potential of a-lithio-formamidines and have now described an efficient synthesis of 2-aryl- or 2-heteroaryl-pyrrolidines and -piperidines (266 ). " Alkylation of formamidines (264) gives intermediates (265) which cyclize in situ after cleavage of the amidine unit. The aza-Wittig reaction has been utilized in a general synthesis of heterocyclic vinylogous ure-thanes and amides (268). Staudinger reaction of azides (267)... 

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. 

Aminonitrile formation on 125 with potassium cyanide and piperidine hydrochloride affords the derivative, 135. Hydrolysis as above gives the corresponding amide (136). Debenzylation is accomplished by catalytic reduction. Alkylation of the secondary amine with the side chain (96) used in the preparation of diphenoxylate affords pirintramide (138) This compound, interest-... 

The other method results directly from the piperidine-2-carboxylic acid chloride, which is reacted with 2,6-dimethylaniline. The resulting amide (2.2.8) is further alkylated with butyl bromide to bupivacaine [17-19]. 

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]. 

Urethanes analogous to the amides of the previous section undergo similar deprotonation followed by alkylation and condoisation reactions. For example, 2,4,6-tri-r-butylphenol may be converted into the corresponding urethane which can be further functionalized (equation 32). N-Carbomethoxy-3-pyrroline has been convoted into both the trail pheromone for the Pharaoh ant and gq)hyrotoxin 223 by using regiospecific alkylations (Scheme 3). ° Similar tqjproaches were used in the preparation of the natural product supinidine. Piperidines also have been alkylated via the r-BOC-protected amines. ... 

The amide (a) is the least basic (lone pair conjugated with the carbonyl group). The pyridine (c) nitrogen, with the lone pair in an sp- hybridized orbital, is less basic than the piperidine (d). The most basic is the quinuclidine (b), which is a tertiary amine in which the ring system ties the alkyl groups back, exposing the lone pair. 

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