Cyclization of radicals

In this analysis, the activation barrier for both C1-C6 and C1-C5 cyclizations of enediyne radical-anions can be described as the avoided crossing between the out-of-plane and in-plane MOs (configurations). One-electron reduction populates the out-of-plane LUMO of the enediyne moiety. At the TS (the crossing), the electron is transferred between the orthogonal re-systems to the new (in-plane) LUMO. This effect leads to the accelerated cyclization of radical-anions of benzannelated enediynes, a large sensitivity of this reaction to re-conjugative effects of remote substituents and the fact that this selectivity is inverse compared to that of the Bergman cyclization. Similar electronic effects should apply to the other reductive cyclization reactions that were mentioned in the introduction. 

As a first step towards this goal, we managed to develop a titanocene-catalyzed 5 -exo cyclization of radicals derived from suitably unsaturated epoxides. The mechanism of the cyclization is depicted in Scheme 12.18 [31],... 

Models accounting for the observed selectivities can be obtained from simple analysis of transition structures, according to the work of Spellmeyer and Houk [37]. These authors have calculated the transition states for cyclizations of radicals to be those shown in Scheme 12.19, but with a hydrogen atom being replaced by the CH2OTiCp2Cl group. 

The Arrhenius expression for the reaction of the o(allyloxy)phenyl radical (9) with (Me3Si)3SiH relative to this unimolecular rearrangement [Eq. (4)] has been measured, v/z., og(kclku) (M) = 2.6 - 1.6/0.36 When the competition study was performed, however, reliable absolute rate constants for the cyclization of radical 9 to radical 10 were not available, although a... 

The competitive kinetics of Scheme 3.1 can also be applied to calibrate the unimolecular radical reactions provided that kn is a known rate constant. In particular the reaction of primary alkyl radicals with (Mc3Si)3SiH has been used to obtain kinetic data for some important unimolecular reactions such as the p-elimination of octanethiyl radical from 12 (Reaction 3.5) [12], the ring expansion of radical 13 (Reaction 3.6) [8] and the S-endo-trig cyclization of radical 14 (Reaction 3.7) [13]. The relative Arrhenius expressions shown below for the... 

Scheme 6.2) [2], Evidence for a five-membered ring product in 1 % yield has also been obtained. Furthermore, EPR studies of the same reaction allowed for the identification of the silacyclohexyl radical 6 with two unequivalent (S-hydrogen atoms in the temperature range between —73 and -25 °C, as the only observable intermediate. A kinetic investigation placed the rate constant for the cyclization of radical 5 between 10 < A < 10 s [2]. 

Radical intermediates are also trapped by intramolecular reaction with an alkene or alkyne bond. At a mercury cathode this process competes with formation of the dialkylmercury [51], At a reticulated vitreous carbon cathode, this intramolecular cyclization of radicals generated by reduction of iodo compounds is an important process. Reduction of l-iododec-5-yne 5 at vitreous carbon gives the cyclopentane... 

The slight enhancement observed for cyclization of radical 20 is consistent with the slight electrophilicity of such radicals which was demonstrated earlier in the studies of their bimolecular olefin addition reactivity [70], The similar reactivities of 20 and hydrocarbon parent are consistent with the similarity of the ESR parameters for these two types of radicals [169]. That is they are both effectively planar rr-radicals. 

The cyclization kinetics of a number of other partially-fluorinated systems as well as those for the cyclization of the parent perfluoro-5-hexenyl radical have been discussed earlier in Sect. 5.3.1 of this review [140,162]. Other than these examples, the only remaining reports of cyclizations of radicals with fluorine proximate to the radical center involve some examples of a,a-difluoro-> /J,/ -difluoro- and a-trifluoromethyl-5-hexenyl radical systems. 

Radical cyclizations catalyzed by 67a require the regeneration of the titanocene catalysts by a stoichiometric reductant, such as manganese. When 10 mol% of substituted cyclopentadienyltitanium complex 47e is applied instead truly catalytic cyclization sequences of epoxides 86 are possible (Fig. 25) [160]. Reductive radical generation from 86 promoted by titanocene chloride 67e and subsequent 5-exo cyclization of radical 86A generates a titanoxy cyclopentylalkyl radical 86B. Since the electron-poor titanocene chloride 67e reduces the tertiary radical 86B only sluggishly, its extended lifetime allows for a 1,5-SHi affording the bicyclic tetrahy-drofuran ring system 87. At the same time catalyst 67e is liberated. The reaction... 

C. S. Wilcox and L. M. Thomasco, New syntheses of carbocycles from carbohydrates. Cyclization of radicals derived from unsaturated halo sugars, J. Org. Chem. 50 546 (1985) see also S. Hanessian, D. S. Dhanoa, and P. L. Beaulieu, Synthesis of u>-substitoted a,p-unsaturated esters via radical-induced cyclizations. Can. J. Chem. 65 1859 (1987). 

The regioselectivity in diene addition reactions can also be influenced by ring strain effects in cyclization reactions. The regioselectivity is highly predictable in those cases, in which addition to the preferred diene center forms the preferred ring size. Thus, the cyclization of radical 15 proceeds readily to form the ct s-disubstituted cyclopentyhnethyl radical 16 with high selectivity. Similarly, cyclization of 17 affords exclusively bicyclic radical 18, in which the additional cyclopentane ring has been formed by addition to the terminal position of the butadiene subunit. This preference for 5-exo cyclizations onto dienes is not even dismpted by substiments at the C1 or C4 positions of the diene system, as seen for radical 19, which cyclizes to 20 (equation lO). This is in contrast to alkyl radical cyclizations to alkenes, in which major amounts of 6-endo cyclization is observed for 5-substituted systems. ... 

Cyclizations that form a single carbon-carbon bond can be accomplished by oxidative cyclization of unsaturated -diketones, y9-keto esters, or f3-keto amides 55 that lead to cycloalkanone radicals 56 and 57, unsaturated )ff-diketones, )ff-keto esters, or malonate esters 58 that lead to cycloalkanes 59 and 60, and unsaturated esters or amides 61 that lead to lactams or lactones 62 and 63 (Scheme 19) [10, 37], Cyclizations of radicals stabilized by two carbonyl groups will only occur with electron-rich aromatic rings as in the conversion of 64 to 65 (Scheme 20) [39] the initial cyclization product is acetoxylated under the reaction conditions. The addi-... 

Phenyl-substituted radical clocks (Fig. 6) display definite enthalpy effects that one expects for strong radical-stabilizing groups. The result is that unimolecular clock reactions are orders of magnitude less rapid than their non-substituted counterparts as evidenced in the rate constants at ambient temperatures for 5-exo cyclization of radical 9 [39] and ring openings of radicals 10 [4, 40], 11 [4], and 12 [41]. Note that... 

Beckwith and coworkers reported that the BS model accurately predicts the isomeric outcome during the tandem cascade cyclization of radical 24 (Scheme 2)... 

Scheme 41. Generation and cyclization of radicals at acetal centers...

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