RuO4-mediated oxidation of N-benzylated tertiary amines. 3. Behavior of 1,4-dibenzylpiperazine and its oxygenated derivatives

Abstract

1,4-Dibenzylpiperazine (1), -2-piperazinone (7), -2,6-piperazinedione (9), and 1-benzoyl-4-benzylpiperazine (30) were oxidized by RuO 4 (generated in situ) by attack at their endocyclic and exocyclic (i.e., benzylic) aminic N -α-C-H bonds to afford various oxygenated derivatives, including acyclic diformamides, benzaldehyde, and benzoic acid. The reaction outcome was complicated by (i) the hydrolysis of diformamides, occurred during the work-up, and (ii) the reaction of benzaldehyde with the hydrolysis-derived amines giving imidazolidines and/or Schiff bases. Benzoic acid resulted from benzaldehyde only. Compounds 7, 30, and 1-benzylpiperazine, but not 9, were transiently formed during the oxidation of 1. In the same reaction conditions, 1,4-dibenzyl-2,3-(or 2,5)-piperazinedione, 1,4-dibenzyl-2,3,6-piperazinetrione, 4-benzoyl-1-benzyl-2-piperazinone, and 1,4-dibenzoylpiperazine were inert. The proposed oxidation mechanism involves the formation of endocyclic and exocyclic iminium cations, as well as of cyclic enamines. The latter intermediates probably result by base-induced deprotonation of the iminium cations, provided an N + −β-proton is available. In the case of 1, the cations were trapped with NaCN as the corresponding α-aminonitriles. The statistically corrected regioselectivity (endocyclic/exocyclic) of the RuO 4 -induced oxidation reaction of 1, 7, and 30 was 1.2-1.3.

Identification of a Unique Cationic Impurity in Preladenant™ Using Accurate MS and NMR

“…The cationic impurity formation could be attributed to piperazine ring contraction, which has been reported previously [15]. Scheme shows a plausible mechanism of the dihydroimidazolium impurity 2 formation through an oxidation pathway proposed based on the few precedents available [15–17]. Oxidation of piperazine possibly by oxygen (from solvent or air) under heated acidic conditions can generate diformamide 5 .…”

New efficient enantioselective synthesis of 2-oxopiperazines: a practical access to chiral 3-substituted 2-oxopiperazines

“…The next key step in our strategy involved a regioselective oxidation at the a-position to the nitrogen atom bearing the function methylester. Previous work was carried out by Petride et al 31 on a mechanistic study of the oxidation of 1,4-dibenzylpiperazine and 1-benzoyl-4-benzylpiperazine by ruthenium tetroxide. They proposed RuO 4 attack (generated in situ) at the endocyclic and exocyclic (benzylic) aminic N-a-C-H bonds resulting in endocyclic or exocyclic iminium cations.…”

RuO4-mediated oxidation of secondary amines 2. imines as main reaction intermediates

“…27 Consequently, this paper analyzes route a as the mechanistic choice. By analogy with the previously discussed case of tertiary amines, [11][12][13][14][15] the intermediacy of imines will be proved by cyano-trapping reactions.…”

“…Several mechanisms for the oxidation of alkanes, 1 arenes, 1 olefins, 2 alcohols 3 and amines [3][4][5][6] using various ruthenium-containing catalysts are known, but they refer to totally different substrates and/or oxidants than those used in the present study. Mechanisms for the oxidation of alkanes, 7,8 alkenes, 9 alcohols, 10 ethers 7 and tertiary amines [11][12][13][14][15] with RuO 4 as an oxidant 16 were previously proposed. For instance, it was advanced that N,N-dialkylanilines are oxidized by RuCl 3 /O 2 /NaCN (i.e., in situ generated RuO 4 ) via iminium cations, formed through single electron transfer (SET) steps.…”

“…11 Independently, iminium ions were also proposed as key intermediates for the RuO 4 -oxidation of tertiary aliphatic amines. [13][14][15] In all these cases, [11][12][13][14][15] the transient existence of iminium ions was proved by cyanide-trapping to give α-aminonitriles (Strecker reaction).…”