Piperidine anodic oxidation

A convenient method to affect the oxidation p- to nitrogen in piperidines is based on the anodic oxidation of N-carboalkoxy piperidines (Scheme 35). The electrochemical oxidation of piperidine (152) in the presence of acetic acid and potassium acetate, for example, afforded a mixture of isomeric 2-hydroxy-3-acetoxypiperidines (153) in a combined yield of 93%, following an aqueous workup [61]. Reduction with sodium boro-hydride severed the C-OH bond. Treatment with acid and then base completed a synthesis of pseudoconhydrine (154). 

Imine intermediates can be trapped by an added nucleophile. However the only reactions of general preparative value are those in which a carbon-carbon bond is formed. In most other cases the product is unstable under the reaction conditions, reverting to the imine which reacts further. Reactions are best carried out in the flow through cell devised by Moinet and Raoult, illustrated in Figure 8.1 [87]. This cell permits total oxidation of tlie substrate in one pass through the porous anode, tlius exposing the product to further oxidation for only a short time, a-aminonitriles are obtained when cyanide ion is added to the electrolyte [88, 89]. In the case of piperidine ring oxidation, addition to the imine is from the less hindered... 

The electrolytic oxidation of N- methoxycarbonylpiperidines provides an interesting and potentially valuable method for the functionalization of piperidine derivatives (81JA1172). Anodic oxidation of piperidine (101) gave (102) which reacted, presumably through the acyl imine, with enol ethers to form a carbon-carbon bond a to the nitrogen atom (Scheme 9). The regiochemical control in this reaction is illustrated by the exclusive oxidation at the less substituted carbon atom (55JA439). 

The a-methoxylated derivatives are shown to be versatile synthons because of the reactivity of the methoxy group near the nitrogen atom, a-Methoxycarbamates, prepared by anodic oxidation, were used as key intermediates in the synthesis of a-amino acids,200 a new carbon-phosphorus bond-forming reaction,200 and in a new method of acylation of aliphatic amines at the -position.201 The application of this reaction to the synthesis of pyrrolidine, piperidine, and tropane alkaloids is also described.202... 

A key intermediate for the synthesis of the indole alkaloid, vineamine, has been prepared by the anodic oxidation of l-earbomethoxy-3-ethyl-3-(P-carboxyethyl)-piperidine 33 in methanol. The regioselective methoxylation at the 2-position was not possible, instead the 6-position was also methoxylated. Thus, the starting material has been methoxylated at both 2- and 6-positions to give 34 and the methoxy group on the 6-position is eliminated during the formation of lactone ring at the 2-position24). 

The anodic oxidation of carbamates of pyrrolidine and piperidine in a nucleophilic solvent such as acetic acid or methanol yields a,/ -disubstituted compounds in which the nature of the a- and -substituents depends on the reaction conditions employed (equation 9)10. This a,/ -disubstitution has been explained by the intermediary formation of the enecarbamate and its further anodic oxidation. 

The anodic oxidation of piperidine derivatives in acetic acid gives a,p-disubstituted products in good yields (equation 49). ... 

Anodic oxidation in the synthesis of piperidine alkaloids 90YGK814. Antitumor sesbanimides, total synthesis of 87YGK983. l-Azaspiro[5.5]undecane system of histrionicotoxines, syntheses of 89BSF370. 

Similar cyclizations using piperidines with leaving groups at C-2 are probably mediated by iminium ions. For example, a total synthesis of epilupinine <83H(20)40i > relies on the anodic oxidation of the lactam (223) to the methoxy derivative (224), which was subsequently converted into the quinolizidine (225) through a titanium tetrachloride-mediated cyclization, a reaction that has been... 

A silyl group a to the nitrogen atom in tetrahydroisoquinolines and piperidines governs the regiochemistry, leads to an exclusive cyanation at this position, and additionally lowers the oxidation potential compared to the nonsilylated analogs [47]. Anodic cyanation of A-2,2,2-trifluoroethyl... 

A-Formylated 1,4-oxazines, including morpholine, can be oxidized anodically in metha-nolic solution to 3-methoxy derivatives, which under acidic conditions lose methanol to N-acylenamines these are of potential synthetic interest [280]. Other acylated secondary amines, such as those from pyrrolidine, piperidine, and tetrahydroisoquinoline, behave similarly (Chapter 24) [281]. 

Essentially the same mechanism has been proposed for anodic or-amination of tetra-hydrofuran, which may be accomplished by oxidation of, for example, R2NH or R2NLi, in this solvent [188]. The best yields (70-80%) were observed when R2NH was piperidine. 

---