Cyclization substituted radicals

Rate constants for reactions of Bu3SnH with some a-substituted carbon-centered radicals have been determined. These values were obtained by initially calibrating a substituted radical clock on an absolute kinetic scale and then using the clock in competition kinetic studies with Bu3SnH. Radical clocks 24 and 25 were calibrated by kinetic ESR spectroscopy,88 whereas rate constants for clocks 26-31 were measured directly by LFP.19,89 90 For one case, reaction of Bu3SnH with radical 29, a rate constant was measured directly by LFP using the cyclization of 29 as the probe reaction.19... 

The tertiary a-ester (26) and a-cyano (27) radicals react about an order of magnitude less rapidly with Bu3SnH than do tertiary alkyl radicals. On the basis of the results with secondary radicals 28-31, the kinetic effect is unlikely to be due to electronics. The radical clocks 26 and 27 also cyclize considerably less rapidly than a secondary radical counterpart (26 with R = H) or their tertiary alkyl radical analogue (i.e., 26 with R = X = CH3), and the slow cyclization rates for 26 and 27 were ascribed to an enforced planarity in ester- and cyano-substituted radicals that, in the case of tertiary species, results in a steric interaction in the transition states for cyclization.89 It is possible that a steric effect due to an enforced planar tertiary radical center also is involved in the kinetic effect on the tin hydride reaction rate constants. 

The absolute rate constants for a variety of cyclizafions have been measured. In particular, the rates of decarbonylafion of a variety of alkoxycarbonyl radicals have been obtained by LFP studies on PTOC oxalates." From these data, rate constants for the reduction of alkoxycarbonyl radicals with BusSnH and their 5-exo cyclizafions were determined. Whereas cyclizations were slightly faster than the analogous alkyl radical 5-exo cyclizations, their reactions with BusSnH were 10 times slower, indicating that cyclization processes should be synthetically useful. The rate constants for the cyclization of a number of variously substituted a-amide radicals have been determined together with their relative reactivities towards reduction using BusSnH (Scheme 16). Cyclizations of secondary-based radicals were found to be similar to the corresponding alkyl-substituted radicals. In addition, the rate constants were subject to minor electronic... 

An explanation for the non-formation of aromatic products under entry 4 in Table 1 is that hydrogen atom abstraction from the corresponding dihydro derivative would lead to a /3-thio substituted radical, which would rapidly eliminate a thiyl radical, which in turn would readily polymerize. The last entry in the table is also surprising in that the cyclization takes place on the naphthalene /3-position when an a-position is free. The use of this photocyclization-oxidation sequence for the construction of heterohelicenes has been reviewed (71ACR65). 

Because of the centrality of the carbonyl group in synthesis, carbonyl-substituted radicals are especially useful. The above results indicate that, if planned addition or cyclization reaction of a carbonyl-substituted radical fails due to lack of reactivity of the acceptor, one should consider activation of the alkene not only with electron donors but also with electron acceptors. 

Because of the centrality of the carbonyl group in synthesis, the cyclizations of carbonyl-substituted radicals are of special importance. At present, there are no accurately known rate constants for the cyclizations of any carbonyl-substituted radicals, and quantitative statements are risky. Because carbonyl-substituted radicals add more rapidly to simple alkenes than alkyl radicals add, it might be suspected that they cyclize more rapidly as well. However, qualitative evidence does not support this analogy. 

Ah initio studies (UHF/6—31G ) have been used to investigate the 5-endo cyclization of various substituted radicals including the 5-oxapenta-2,4-dienoyl radical. The results show that the 5-endo cyclization is both kinetically and thermodynamically favoured.39... 

The observed 5-exo-trig cyclization in the above reaction is attributed to the formation of more stabilized malononitrile radical intermediate compared to the trialkyl-substituted radical. The stereochemical outcome of these transformations with regards to the malonodinitrile group is consistently P-sclcctivc this suggests least steric interactions between these substituents as compared to the alternative methyl-methyl interaction in the transition state. 

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... 

These results have been explained as follows [730] the cyclization of the intermediate 1,4-biradical, formed after y-H-abstraction, requires rotation of the phenyl-substituted radical centre away from its equilibrium position. That is, the phenyl group... 

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. ... 

Reductive cyclizations. Substituted pyrrolidines and piperidines are obtained by the Ti(Il)-mediated cyclization of enyne carbonates. 5-Ketoesters and ketonitriles undergo radical cyclization with CpjTiPh which is obtained as a dark green solution by sequential treatment of Cp TiClj with i-PrMgCl and PhMgBr. 

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