Amines aminium radical reactions

A similar pattern of reactivity has been observed by Burrows and coworkers for the reaction between A -acetyllysine methyl ester (Lys) and dG. This reaction was studied in order to gain an understanding of structural aspects of DNA-protein cross-links (DPCs). These cross-links are regarded as a common lesion of oxidative damage to cells, but remain, from a chemical point, a poorly understood DNA lesion. As pointed out by Burrows, oxidation of protein-DNA complexes should occur preferentially at the primary amines since these sites have a lower oxidation potential (1.1 V vs. NHE, pH 10) than G. While protonation of the primary amine inhibits the oxidative process, transient deprotonation of a lysine residue would give rise to a lysine aminyl radical (or aminium radical cation). Using... 

One of the best methods for the controlled generation of alkenaminyl radicals is via PTOC carbamates (Section II,E). These precursors react in efficient radical chain reactions with hydrogen atom donors to form amines and pyrrolidines. They are stable to anhydrous acids and, therefore, are suitable precursors for aminium radicals produced by protonation of the first-formed neutral aminyl radical. 

In summary, these results constitute strong evidence for the two-step reaction sequence. They require that the deprotonation of the aminium radical cation be competitive on the CIDNP timescale i.e. surprisingly fast since it involves a carbon acid. The results delineate the fate of the amine derived intermediates with particular clarity, since they are observed directly for amine derived products. The conclusions based on the above CIDNP results were confirmed by time resolved optical spectroscopy in a variety of systems [179-182]. However, in essentially all these systems the reaction progress is monitored by following the complementary spectra of the acceptor derived radical intermediates, such as ketyl, semiquinone, stilbene, or thioindigo radical anions. 

The photoreduction of 9,10-anthraquinone-1,5-disulfonate by 2,2,6,6-tetramethyl piperidine in aqueous media has been studied in the nanosecond and microsecond time domains by use of time-resolved optical and ESR measurements [171]. Electron transfer from the amine to the excited state of the anthraquinone derivative occurs with a rate constant of 5.7 x 10 m s . The aminyl radicals formed via deprotonation of the aminium radicals are long-lived (ca 0.5 ms), because the steric hindrance of these radicals slows down recombination reactions. The aminyl radicals formed in these systems have been characterized by ESR. 

Studies using isotopic labeling as well as mechanism based on inactivation such as 4-alkyldihydropyridines and cycloalkylamines have supported the view that the first step involves an electron-transfer process (path a. Scheme 23) [18, 184-186, 211]. Deprotonation of the resultant aminium radical would yield the a-aminoalkyl radical. The formation of the dealkylated amine and carbonyl derivative has been proposed to occur via a second electron transfer to the enzyme and a nonenzymatic hydrolysis of the imine formed. In the P-450 catalyzed reaction, however this process is proposed to occur via a radical recombination process to yield a carbinolamine (99) which then decomposes to the dealkylated amine and the corresponding carbonyl derivative. Evidence for this was obtained by the incorporation of label from 02, into the carbonyl derivative [212-214]. 

Because of the relative instability of amine radicals, their synthetic applications in thermal one-electron-catalyzed reactions are rare. In contrast free radicals generated in the oxidation of amides are more common [19-23, 228]. Aminium radicals gen-... 

Synthesis of oxazabicycloalkanes and related products was achieved by a one pot electron-proton-electron (EPE) transfer mediated reactions of the amine moiety [317]. Here the iminium cation is formed from the second electron oxidation of the a-aminoalkyl radical, generated via the a-deprotonation of the planar aminium radical owing to their low ionization potential. The iminium cation thus formed can... 

Tor a review of aminium radical ions, see Chow, Y.L. React. Intermed. (Plenum) 1980, 1, 151. The reaction has been extended to the formation of primary aromatic amines, but the scope is narrow Citterio, A. Gentile, A. Minisci, R Navarrini, V. Serravalle, M. Ventura, S. J. Org. Chem. 1984, 49, 4479. 

J.K. Cha et al. developed a stereocontrolled synthesis of bicyclo[5.3.0]decan-3-ones from readily available acyclic substrates. Acyclic olefin-tethered amides were first subjected to the intramolecular Kulinkovich reaction to prepare bicyclic aminocyclopropanes. This was followed by a tandem ring-expansion-cyclization sequence triggered by aerobic oxidation. The reactive intermediates in this tandem process were aminium radicals (radical cations). The p-anisidine group was chosen to lower the amine oxidation potential. This substituent was crucial for the generation of the aminium radical (if Ar = phenyl, the ring aerobic oxidation is not feasible). 

Amination refers to the reaction of the aminium radical (NH ) and its dialkyl derivatives (R2NH +) with organic substrates, particularly with olefins and aromatics. The aminium radical itself can be generated by the reduction of hydroxylamine O-sulfonic acid with ferrous ion (147) (Minisci and Galli, 1965). Dialkylaminium radicals are generated in several ways, the most common being the reduction of N-chlorodialkylamines by ferrous ion in acidic solution (148) and... 

The mechanism in Scheme 8 was proposed for the oxidation reaction. In the first step, the Cu(II) salt, which is formed in the autooxidation of cuprous chloride, forms a complex with the amine. This is followed by a rate-determining electron transfer from the amine to the Cu(II) species giving Cu(I) and an aminium radical. The subsequent steps were considered to be fast. The authors accounted for the secondary hydrogen-deuterium kinetic isotope effect by suggesting that there was hyperconjugative electron release to the aminium ion nitrogen that forms in the slow step of the reaction. 

In 30 % aqueous alcoholic methanol, electron-withdrawing substituents reduce the ease of oxidation of tertiary alkylamines by [FeCCN) ] -. The closer the substituent to the reaction centre, the more effective is the retardation. Cyclic amines show evidence for through-space stabilization of the incipient aminium radical with an accompanying increase in rate. 

In contrast with the great wealth of information on both cationic and free-radical additions to alkenes and alkynes, not too much is known about analogous cation radical reactions. The most commonly known among these are additions of aminium radicals. The overall reaction is that of, say, an N-chloramine or N-nitros-amine in acid solution, brought about photochemically or by reaction with ferrous ion (eq. 23) ( ). A chain reaction occurs in... 

Information about the relative kinetic acidities of aminium radicals has also come from a number of studies probing product distributions of SET-promoted photochemical reactions. One of the earhest investigation in this area was conducted by Cohen and co-workers, in which product distributions of SET-induced photoreactions of unsymmetrically substituted tertiary amines were used to gain information about how alkyl substituents affect the rates of aminium radical a-CH deprotonation. Irradiation of solutions of 4-benzoylbenzoic acid containing a variety of tertiary amines leads to formation of dealkylation products (Scheme 9). In these processes, the initially formed aminium radical 10 transfer a proton to the 4-benzoylbenzoic acid anion radical to generate an a-amino radical, which then donates an electron to another 4-benzoylbenzoic acid molecule. Hydrolysis of iminium ions 11, formed in this manner, then gives carbonyl and secondary amine products. The results of these studies qualitatively indicate that dealkylation occurs preferentially at the less alkyl-substituted a-carbon. 

Detailed investigations of the SET photochemistry of tertiary amine-stilbene systems by Lewis and co-workers - have elucidated a number of factors that govern the relative rates of a-deprotonation reactions of aminium radicals. As shown in Scheme 10, photoreactions of stilbene with unsymmetricaUy substituted tertiary amines in acetonitrile proceed via pathways in which contact ion radical pairs (CIRP), generated by excited-state SET, undergo proton transfer to yield radical pair precursors of stilbene-amine photoadducts. By careful analysis of the product distributions, Lewis has determined the relative kinetic a-CH acidities of the intermediate aminium radicals (Table 101.4). 

As with arene-amine radical ion pairs, the ion pairs formed between ketones and amines can also suffer a-deprotona-tion. When triplet benzophenone is intercepted by amino acids, the aminium cation radical can be detected at acidic pH, but only the radical formed by aminium deprotonation is detectable in base (178). In the interaction of thioxanthone with trialky lamines, the triplet quenching rate constant correlates with amine oxidation potential, implicating rate determining radical ion pair formation which can also be observed spectroscopically. That the efficiency of electron exchange controls the overall reaction efficiency is consistent with the absence of an appreciable isotope effect when t-butylamine is used as an electron donor (179). 

The use of /V-chloramines, in principle, allows the facile generation of aminyl radicals upon UV photolysis in neutral media. A radical chain can be envisioned for the formation of 2-chIoromethylpyrrolidines (Scheme 7). In practice, however, there is a slow step in this sequence, step A and/or B, such that other reaction pathways, disproportionation or H-abstraction from the solvent, compete. Surzur has studied the reaction in Scheme 7 in the alcoholic solvents MeOH and /-PrOH, which serve as hydrogen atom sources, and achieved acceptable ratios of cyclic products 25 and 26 to acyclic amine 27 (70TL3107). Other /V-chloroalkenylamines gave similar results (71TL903 80TL287). /8-chloro-substituted amine products such as 25 were the sole products when the reactions were carried out in acetic acid-water mixtures these reactions involve aminium cation radicals and are discussed further in Section III,B. 

The Hofmann-Loffler-Freytag (HLF) reaction is the oldest known reaction that involves aminium cation radicals (Scheme 14) (50JA2118 60JA1657). This reaction is a remote functionalization reaction where an N-chloro- or N-bromo-amine 46 is converted to a 8-haloamine 49 via the intermediate aminium cation radical 47. Pyrrolidine products are obtained by cyclization of the 8-haloamines under basic conditions. A comprehensive survey of the synthetic utility of this reaction has been reported by Wolff (63CRV55). 

The one-electron oxidation of a secondary amine results in the formation of a secondary aminium ion which on deprotonation gives an aminyl radical (Scheme 1). The nature of the final products derived from these intermediates dqiends very much on the structure of the substrate and the reaction conditions. If the amine has a hydrogen atom on the a-carbon atom the major products usually result from deprotonation at this a-position. With aromatic secondary amines, products can result from coupling of the delocalized radicals at a ring carbon atom. The formal dimerization of aminyl radicals shown in Scheme 21 is therefore not often a useful method of preparation of hydrazines. Nickel peroxide has been used to oxidize diphenylamine to tetraphenylhydrazine in moderate yield, and other secondary arylamines also give... 

No other adducts are formed, and the endo/exo diastereomeric ratio is essentially the same for all of these methods. Further, the existence of an acid catalyzed mechanism for cycloaddition can be explicitly excluded by using an excess of a hindered amine base (2,6-di-tert-butylpyridine, DTBP) in the aminium salt induced reaction and by examining the results of an authentic acid catalyzed reaction (using, for example, triflic acid). In the former case, the same endo and exo adducts are formed in virtually the same relative amounts, but in the latter case neither of these adducts is formed. It is worth noting that acid catalyzed reactions have indeed sometimes been observed under typical aminium salt conditions [70], but these have never been observed, nor would they be expected, under PET conditions. Finally, in the instance where cation radicals are generated by the aminium salt method, the intervention of substrate cation radicals can usually be verified by the addition of the reduced form of the catalyst, i.e., the neutral triarylamine, to the reaction mixture. 

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