Cation-Radical Ring Closure

SCHEME 14 Comparison between radical and radical cationic ring closure selectivity. 

Oxidation of methionine residues has been widely studied. Reaction of OH is fast (k= 10 mol I s l) and proceed via formation of an OH-adduct > S-OH, the hydroxy sulfuranyl radical (42). This radical eliminates water, yielding the monomeric radical cation >S + which then stabilizes through formation of >S-X radical species, X= N, O or S (56). In methionine amino-acid, the free radical undergoes ring closure with the amine function to give cyclic >SN radical (57) which then gets decarboxylated. Final compound seems to be methionine sulfoxide. When methionine is in a peptide, the fate of the hydroxy sulfuranyl radical is strongly dependent on the position of methionine in the peptide. 

Although reactivity depends upon the exact chemical reaction under study, there are clear trends related to ring size. The ease of intramolecular formation of a particular ring size generally follows the trend, 5>6>3>7>4> 8-10. This holds for intramolecular nucleophilic, as well as radical and cationic ring closures. 

In addition to nucleophilic reactions, Baldwin s rules also apply to homo-lytic and cationic processes. Table 21 lists rate constants for ring closure of lower -alkenyl radicals (71), in which intramolecular addition to the double bond occurs in the exo-mode (Beckwith, 1981). It is unfortunate that EM-... 

Examples of the coupling of enam-ines are rare [60]. In most cases, the enamines undergo methanolysis to form electroinactive aminoacetals prior to the coupling reaction. Enamino ketones or enamino esters, however, yield via dimerization of the radical cations and subsequent ring closure pyrrole derivatives... 

Similar to the intramolecular addition of neutral carbon-centered radicals to alkenes, the formation of radical cations starting from alkenes with subsequent cyclization offers a convenient method for constructing carbocyclic ring systems. In contrast to the regioselective 1,5-ring closure (5-cxo-trig cyclization) of the... 

In simple olefins of the stilbene type, cis —> trans isomerization in the cation-radical state is known to proceed readily because the exocyclic double bond is weakened. In the case of the 1,2-di(aryloxy)cylobutane cation-radical, cis —> trans isomerization also takes place (see Evans et al. 1975), but the reaction inevitably should include the open form of the distonic type, ArOCH CH2— CH2CH+OAr. Free rotation in this distonic cation-radical around CH2—CH2 bond permits ensuing ring closure with the formation of the more stable trans isomer. 

This section is devoted to cyclizations and cycloadditions of ion-radicals. It is common knowledge that cyclization is an intramolecular reaction in which one new bond is generated. Cycloaddition consists of the generation of two new bonds and can proceed either intra- or intermolecularly. For instance, the transformation of 1,5-hexadiene cation-radical into 1,4-cyclohexadienyl cation-radical (Guo et al. 1988) is a cyclization reaction, whereas Diels-Alder reaction is a cycloaddition reaction. In line with the consideration within this book, ring closure reactions are divided according to their cation- or anion-radical mechanisms. 

In the case of p-methoxystyrene (p-MeOCgH4CH=CH2), the cation-radical ring closure can lead to 1,2-dianisylcyclobntane or 4-anisyl-6-methoxy-3,4-dihydronaphthalene. Thermodynamic simulations show that the former should be favored in the absence of a solvent, whereas the latter product could be stabilized by a polar solvent (O Neil and Wiest 2006). Of course, such a solvent has to be fairly polar and not nncleophilic. 

Alkylimidazolinm tetraflnoroborates are, for example, ionic liquids at room-temperature that can provide an anion to stabilize an intermediate cation-radical with no possibility of nucleophilic attack on it. Ionic liquids have a huge memory effect, and their total friction is greater than that of conventional polar solvents. Thus, the total friction of l-ethyl-3-methylimidazolium hexafluoro-phosphate is about 50 times greater than that of AN (Shim et al. 2007). The solvent effects of ionic liquids on ion-radical ring closures deserve a special investigation. The ring closure reactions can be, in principal, controlled by solvent effects. 

Arylhydrazones of /3-aryl-a,/3-unsaturated ketones are converted into pyrazoles by 3 mol equivalents of T CIO4 (Scheme 2). The ring closure occurs via radical cation 45 and is not simply oxidation of a preclosed dihydropyrazole, as evidenced by dimerization (- 46) of such a possible intermediate upon treatment with the radical cation (Scheme 3) (88JOC1973). 

A recent development in the synthesis of 3//-3-benzazepin-2-ones has been the photocyc-lization of A-(chloroacetyl)phenethylamines (Scheme 25). Ring closure is by homolysis of the alkyl halide followed by intramolecular coupling of the alkyl radical with an aromatic radical cation. Yields are good, especially with a stabilizing electron-donating group (MeO, NMe2) at the position meta to the ethylamino function (i.e. ortho or para to the site of cyclization). Isomeric benzazepinones are normally obtained (Scheme 25) with meta-substituted phenethylamines (80H(14)ll). 

The fully aromatic diquaternary system 81 is prepared by acid ring closure of the salt (79) obtained by quaternization of 1,10-phen-anthroline with bromoacetaldehyde followed by dehydration of the resulting hydroxy diquaternary salt (80) with thionyl chloride.310,311 The salt 81 is unstable in aqueous solution above a pH of about 5.0. In the pH range 3.3-5.0 it is reduced by a one-electron transfer to the corresponding radical cation at a potential (E0) of —0.12 volt.311 Its reduction in dimethylformamide solution has also been studied.15,307 Substituted derivatives of 81 have been prepared.312... 

There are two main approaches to the corrin system. One of them completes the macrocycle by ring closure between C-l and C-19. This is the main route and quite versatile. The first example was reported for the octadehydrocorrin synthesis.239 Biladienes-a,c were cyclized in the presence of metal salts and air to 1,19-frms-ODC complexes, and radical Yin and cationic 16m conrotatory mechanisms have been suggested. The cyclization is also induced by light (Scheme 85). Similarly 1-ethoxy-2,3-dihydro-19-methyl-b-bilene is cyclized to l-ethoxy-19-methyl-7,8,12,13,17,18-HDC (M = Ni).239-249... 

Other olefinic substrates known to dimerize through photo-induced electron transfer sensitization include enamines (72), diarylethylenes (73-75), vinyl ethers (76), styrenes (77,78), and phenyl acetylenes (79). Alternate ring closures (besides cyclobutanes) are sometimes observed, probably via 1,4-radical cationic intermediates. For example, a tetrahydronaphthalene is formed from the radical cation of 1,1-diphenylethylene, eq. 

Photoinduced electron transfer from the amine to C6o to yield a radical ion pair is suggested to be the initial step for the formation of 54a-b. This is followed by deprotonation of the amine cation by the fullerene anion to give an a-aminoalkyl and HC6o radical pain [134], Subsequent combination of the radical pair leads to the final product. Formation of 55 is likely to be initiated by PET from 54b to C6o. This is then followed by successive intermolecular proton transfer, hydrogen abstraction, and ring closure to give l,2-H2C6o and 55 (Scheme 21). 

Further attention is given to the reaction of aryl- and heteryldiamines with S2CI2. In contrast with the complex reaction of 1,5-diaminonaphthalene, the condensation of 2,6-diaminonaphthalene with S2GI2 in the presence of pyridine proceeds via electrophilic ring closure at both pm-positions to afford naphtho[2,l-radical cation 154, which is reduced by PhjSb to neutral compound 24 (Scheme 29) <1998CC1939>. Chlorination of the remaining C-H positions does not occur. 

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