Baldwin rules, radical cyclization

According to Baldwin s rules [10], the 5-endo-trig mode of cyclization is disfavored stereoelectronically. As a result, most five-membered ring formations employing intramolecular radical cyclization proceed via the 5-exo-trig path. The few exceptions to Baldwin s rule occur when substrates possess structural moieties (e.g. an amide bond) that conformationally bias the substrates in favor of the 5-endo-trig mode. 

Generation of a radical in a molecule that contains a site of unsaturation presents an opportunity for (yclization. These types of radical cyclizations have been developed into very useful synthetic reactions. The synthetic utility of these cyclizations is enhanced by the abhity to predict the regiochemistry of cyclization by applying the Baldwin rules. The Baldwin rules cover the formation of three- to seven-membered rings by various reactions and are based on consideration of both kinetic and thermodynamic factors. (See Beckwith, A. L. J. Easton, D. J. Serelis, A. K. J. Chem. Soc., Chem. Commun. 1980, 482-483, and Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-736.)... 

It should be noted that the radical cyclization proceeds to yield a five-membered ring and not a six-membered one. This is predicted by the Baldwin rules for ring-closure and is classified as a 5-exo-trig closure ". LiAlH4 has also been used to generate the cyclopropyl radical which also underwent a 5-exo-trig ring-closure. ... 

These findings have been rationalized by the rule offive (Srinivasan and Carlough, 1967), according to which five-membered cyclic biradicals are preferentially formed, as shown in Scheme 15. (Cf. also the Baldwin rules for radical cyclizations, Baldwin, 1976.)... 

Cyclizations of pent-4-enyl radicals are very interesting, because neither the 4-exo trig nor the 5-endo trig cyclizations are considered favorable (Eq. 4). The 4-exo cyclizations are unfavorable because of the strain and rapid opening of the cyclo-butylmethyl radical to pent-4-enyl radical, whereas the 5-endo trig cyclization is disfavored based on Baldwin s rules of ring closures [18]. As in the case of 3-exo cyclizations, neither the 4-exo nor 5-endo radical cyclization reactions were reported in the literature prior to 1988. 

Alabugin, I. V., Timokhin, V. I., Abrams, 1. N., Manoharan, M., Ghiviriga, L, Abrams, R. (2008). In Search of Efficient 5-Endo-dig Cyclization of a Carbon-Centered Radical 40 Years from a Prediction to Another Success for the Baldwin Rules. Journal of the American Chemical Society, 130, 10984-10995. 

In this case, the information was taken from the study of the n-BusSnH-media-ted cyclization of substituted A -(phenylthio)amides 8, detailed in Scheme 39.6. The reaction is a radical process in which the nitrogen-eentered radical 11 formed in the first instance, cyclizes onto the C=C double bond to give carbon-centered radical species 13 which, after quenching, yields cyclized compound 9. The cyclization step follows the exo-mode in agreement with the Baldwin rules (5-exo-trig). 

The electroreductive cyclization reaction of 6-heptene-2-one 166, producing CIS-1,2-dimethylcyclopentanol 169, was discovered more than twenty years ago [166]. In agreement with Baldwin s rules, the 5-exo product is obtained in a good yield. Since that time, the mechanism of this remarkable regio- and stereoselective reaction has been elucidated by Kariv-Miller et al. [167-169]. Reversible cyclization of the initially formed ketyl radical anion 167 provides either the cis or the trans distonic radical anion. Subsequent electron transfer and protonation from the kinetically preferred 168 leads to the major cis product 169. The thermodynamically preferred 170 is considered as a source of the trace amounts of the trans by-product 171 (Scheme 32). 

Intramolecular cyclization can also be initiated from the radical-cation of a styrene residue [57], Oxidative cyclization of 31, n = 1 and 31, n = 2 give five and seven membered ring products respectively but in contrast 32 failed to yield a five membered ring product, giving only intractable mixtures. This difference in reactivities can be explained in terms of Baldwin s rules where the 5-endo-trig cyclization of the radical-cation from 32 is disfavoured [58]. 

One typical radical reaction is cyclization. This cyclization has been used as an indirect proof for radical reactions and a strategic method for the construction of 5- and 6-membered cyclic compounds. The experienced rule for the cyclization is Baldwin s rule [19]. There are two cyclization modes, i.e. exo and endo moreover, there are three types of hybridization in a carbon atom, sp3 (tetrahedral tet), sp2 (trigonal trig), and sp (digonal dig). Baldwin s rule is the cyclization rule based on the experimentally obtained cyclization results. The cyclization mode and kinds of hybridization in an intramolecular radical acceptor are shown in Figure 1.15. 

When stereogenic centers are introduced on the tether, a large asymmetric induction can also be observed, especially when the product results from an initial 1,5-ring closure. The relaxed excited state of the starting enone behaves as the 5-hexenyl radicals and prefers to cyclize in a 5-exotrig process [47] according to Baldwin s rules [48]. The model used to determine the selectivity of the intramolecular addition of 5-hexenyl radicals can be applied to 66 and 68. Then the stereochemistry of the major diastereoisomers 67 and 69 can be deduced from the transition states that place the largest substiment in equatorial position, as... 

Several examples of intramolecular addition of (5-unsaturated sulfonyl radicals have also been reported [36], In agreement with Baldwin s rule and notwithstanding the reversibility of the cyclization step, the 5-exo mode is preferred when the reaction is catalyzed by copper salts, since in this case the carbon-centered radical is trapped through a fast atom transfer reaction [36b],... 

Finally, it should be noted that Baldwin, in a brief communication, has proposed some empirical rules governing ring closure reactions and although he is mainly concerned with nucleophilic cyclizations processes " he has also considered free radical ones the origin of these rules appears similar to the one just discussed. 

In conclusion, except in very special cases, reasonable yields of cyclized products cannot be expected in the Cy4/Cy5 case since if they are formed the (Cy 4) radical will open readily (i.e., it is the opening and not the closing process which is favored). The absence of cyclization toward the (Cy 5) radical is an excellent example of the disfavored 5-endo-trigonal closure in accord with Baldwin s rules. 

Except for this last example which involves a Cy3/Cy4 case it is of interest to emphasize that the examples of intramolecular addition to carbethoxy groups so far reported deal exclusively with the formation of (Cy 5) radicals in Cy5/Cy4 cases. This cyclization was already observed with the carbonyl group (Section X.1), but other cyclization modes such as Cy6/Cy5 were also observed. What is particularly striking with the carbethoxy group is that a search for Cy5/Cy6 cyclizations, for example, with the next higher homolog of 205, failed. This is the opposite of the behavior of olefinic bonds and is in disagreement with Baldwin s rules. ... 

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