Protonated amino radicals addition

The reaction was most effective when X was an electron withdrawing substituent, but only because this suppressed the competing ionic chlorination of the double bond. In some cases, the ionic chlorination was the predominant reaction. Protonated amino radical addition to unsubstituted olefins, acetylenes and al-lenes, however, gave acceptable yields of products, particularily in the case of the sterically unhindered substrates. The products obtained from the acetylenes were the a-chloroketones or aldehydes. 

Complexed Amino Radicals. Since protonated amino radicals perform so well in addition reactions it Is not altogether surprising that metal complexed amino radicals also add well to unsaturated substrates. This area of amino radical chemistry has been studied by Minisci and his co-workers (18-21). 

The reductive couphng of imines can follow different pathways, depending on the nature of the one-electron reducing agent (cathode, metal, low-valent metal salt), the presence of a protic or electrophihc reagent, and the experimental conditions (Scheme 2). Starting from the imine 7, the one-electron reduction is facihtated by the preliminary formation of the iminiiim ion 8 by protonation or reaction with an electrophile, e.g., trimethylsilyl (TMS) chloride. Alternatively, the radical anion 9 is first formed by direct reduction of the imine 7, followed by protonation or reaction with the electrophile, so giving the same intermediate a-amino radical 10. The 1,2-diamine 11 can be formed from the radical 10 by dimerization (and subsequent removal of the electrophile) or addition to the iminium ion 8, followed by one-electron reduction of the so formed aminyl radical. In certain cases/conditions the radical 9 can be further reduced to the carbanion 12, which then attacks the... 

Nitramines are known to photodissociate from their jt,jt state to give aminyl and nitric oxide radicals in the presence of an acid the aminyl radicals are protonated to give aminium radicals, which can initiate addition to olefins. As a synthetic reaction, photolysis of nitramines in the presence of acids can be conveniently run under oxygen to give oxidative addition similar to those shown in equation 145 indeed TV-nitrodimethylamine is photolysed with triene 299 under such conditions to give a mixture of 301 and 302, similar to results observed in the oxidative nitrosamine photoaddition169. To simplify the isolation, the crude products are reduced with LAH to form the open-chain amino alcohol 303. Some other oxidative photoadditions of N-nitro dimethylamine to other olefins are reported. As the photoreaction has to use a Corex filter and product yields are no better than those shown by nitrosamines, further investigations were scarcely carried out. 

One of the main reactions of "OH is the abstraction of the hydrogen from the a-carbon of an amino acid residue to form a carbon-centered radical. Addition to this radical of the oxygen molecule produces a peroxyl radical. Its reduction to an anion by intramolecular electron transfer or by superoxide yields a hydroperoxide anion, which binds a proton to form an amino acid hydroperoxide. Hydroperoxides of some amino acids are semistable, and some decompose spontaneously to... 

Protonated Amino Radicals. The reac.tion of hydroxyl amine with TiCl, in aqueous, acidic methanol results in the formation of the simplest protonated amino radical, NH,T. This radical added readily to butadiene and to simple olefins to form products which were the result of coupling of the intermediate B-aminoalkyl radicals ( ). The addition reactions of protonated di-alkylamino radicals were described in a series of elegant papers by Neale and his co-workers (5-10). The radicals were generated from the appropriate N-chloroamines in presence of the unsaturated system. The most effective acid solvent combination was found to be 4M sulfuric acid in glacial acetic acid, but other acid/solvent combinations were also used. The reactions proceeded by chain mechanisms, which were initiated by light or by... 

Intramolecular addition of protonated amino radicals has been examined by several groups. The following reaction has been carried out using silver perchlorate in acetone, ferrous sulfate or acidic (4M H2SO4) conditions (11). The yields varied. 

Under these conditions, amine radical cation la is deprotonated to form a-amino radical Ilia, which reacts with the olefin to form radical adduct Ka. Since no external oxidant is present, the adduct radical presumably turns over Ru to Ru and is reduced to the anion. Protonation of the enolate forms the product. For intramolecular additions, dehydrogenation occurs rather than reduction to provide 5,6-dihydroindolo[2,l-a]-THIQs such as 18. 

SCHEME 31.34. Radical addition of fluoro alkyl chain followed by enantioselective proton transfer chiral fluoro amino acid derivative synthesis. 

Yajima T, Tonoi T, Nagano H, Tomita Y, Mikami K. Direct racemic mixture synthesis of fiuorinated amino acids by perfluoroalkyl radical addition to dehydroamino acids terminated by asymmetric protonation. Eur. J. Org. Chem. 2010 2461-2464. 

Some other interesting observations regarding free radicals in these systems are noteworthy. In many instances, multiple conformations of radicals are found at lower but not higher temperatures. This indicates that the radicals exist in shallow energy wells at low temperature this phenomenon was observed very early, in the 4 K ENDOR investigation of radical formation in amino acids.23 Unlike the process in DNA. In which it is well understood that the thymine anion radical protonates at C6 to form T(C6)H-, in the crystalline state there is a not clear link between pyrimidine electron adducts and H-addition radicals. We finally note that a deuterium isotope effect of protonation/deprotonation processes was found in cytosine.HCl and 2 -deoxycytidine.HCl, as evidenced by a lower propensity for these processes to occur in partially deuterated systems than in predated ones. 

Fig. 3. Nature of free radical associated with compound I in peroxidases/catalases. Structure of first intermediate, following peroxide addition to ferric peroxidases and catalases. Boxes denote porphyrin ring. The amino-acid free radicals are depicted as protonated (tryptophan) and deprotonated (tyrosine), although this is yet to be conclusively determined.

However, recently it has proved possible to positively identify tryptophan radicals in cytochromec peroxidase[147] and tyrosine radicals in ribonucleotide reductase, prostaglandin H synthase and photosystem II of chloroplasts [148], This has been achieved by a combination of the techniques discussed already, but with the powerful, additional non-invasive tool of isotopic substitution. As deuterons (5=1) give different splitting than protons (S = 1/2), substituting different labelled amino-acid residues into the enzyme should reveal the nature of the radical-containing residue. This is easily achieved in an auxotrophic mutant that requires this amino acid to be supplied in the medium. The specific residue can then be identified by site-directed mutagenesis of the evolutionary conserved amino-acid residues [108,149-151]. 

Benzophenones have been described as useful sensitisers for PET catalysed conjugate addition reactions of a-amino alkyl radicals to enones (Bertrand et al. 2000). We tried to modify this reaction and synthesised the pyrrolidinylethyl-substituted quinolone 35 from the known bromide (Bauer et al. 2005). Upon electron transfer from the pyrrolidine to a given acceptor, a radical cyclisation occurs (Scheme 15), which after electron and proton transfer generates a pyrrolizidine. We found 4,4/-dimethoxybenzophenone to be a suitable catalyst for this reaction. Remarkably, the reaction proceeded with excellent simple diastereos-electivity and a single diastereoisomeric product rac-36 was obtained. With 10 mol% of the catalyst, a chemical yield of 71% was achieved. 

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