Intramolecular reactions homolytic additions

Streamlined with the incorporation of the SH model into the commercially available MacroModcl modeling package [lO]. Both models have been used extensively to model a large cross-section of intramolecular homolytic addition reactions. Not only can regio- and stereochemical trends be modeled accurately, but the rate-altering effects of substitution are also well reproduced (Table 2). Some calculated transition structures are displayed in Fig, 1,... 

With this information in hand, it seemed reasonable to attempt to use force field methods to model the transition states of more complex, chiral systems. To that end, transition state.s for the delivery of hydrogen atom from stannanes 69 71 derived from cholic acid to the 2.2,.3-trimethy 1-3-pentyl radical 72 (which was chosen as the prototypical prochiral alkyl radical) were modeled in a similar manner to that published for intramolecular free-radical addition reactions (Beckwith-Schicsscr model) and that for intramolecular homolytic substitution at selenium [32]. The array of reacting centers in each transition state 73 75 was fixed at the geometry of the transition state determined by ah initio (MP2/DZP) molecular orbital calculations for the attack of methyl radical at trimethyltin hydride (viz. rsn-n = 1 Si A rc-H = i -69 A 6 sn-H-C = 180°) [33]. The remainder of each structure 73-75 was optimized using molecular mechanics (MM2) in the usual way. In all, three transition state conformations were considered for each mode of attack (re or ) in structures 73-75 (Scheme 14). In general, the force field method described overestimates experimentally determined enantioseleclivities (Scheme 15), and the development of a flexible model is now being considered [33]. 

It also appears that intramolecular thiyl radical addition is a very efficient process compared to other free radical cyclizations. But competitive reactions such as polymerization are sometimes very difficult to suppress. Furthermore, other easy cyclization pathways, such as ionic ones, may complicate the interpretation of the results. Dronov s work exemplifies this possibility. Under all the experimental conditions used, l-pentene-5-thiol led to a Cy5/Cy6 mixture of products, with the (Cy5) compound being favored in sulfuric-acid-promoted cyclization and the (Cy6) compound being favored in photolysis. Thus the claim to have observed a homolytic reaction in cyclizations of ethylenic thiols generated from fatty acids, under conditions which did not avoid acid treatment, must be considered with care. 

The same group recently disclosed a related free radical process, namely an efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Homer-Wadsworth-Emmons olefination, for the production of a small library of a,/3-unsaturated oxindoles (Scheme 6.164) [311]. Suitable TEMPO-derived alkoxy-amine precursors were exposed to microwave irradiation in N,N-dimethylformam-ide for 2 min to generate an oxindole intermediate via a radical reaction pathway (intramolecular homolytic aromatic substitution). After the addition of potassium tert-butoxide base (1.2 equivalents) and a suitable aromatic aldehyde (10-20 equivalents), the mixture was further exposed to microwave irradiation at 180 °C for 6 min to provide the a,jS-unsaturated oxindoles in moderate to high overall yields. A number of related oxindoles were also prepared via the same one-pot radical/ionic pathway (Scheme 6.164). 

An interesting method for the preparation of epoxides using radical methodology has been reported [95AJC233]. Addition of cyclohexyl iodide 1 under reductive or non reductive conditions to ethyl t-butylperoxymethylpropenoate 2 at refluxing temperatures furnished the epoxide 4 in moderate yield. The reaction proceeds through an intramolecular homolytic displacement. 

The distinction between those reactions which do involve the alkyne excited state and those which do not becomes blurred in the case of intramolecular processes of compounds where the alkyne is part of an extended conjugated system. For example, radical production as a result of homolytic cleavage of a P—C bond in the phosphine 16 leads ultimately to an intramolecular addition product involving one of the acetylenic C=C bonds (equation 40) . 

The most important methodology for the aliphatic C-C bond formation via radical reactions is the addition of the radical to an alkene double bond, both inter -and intramolecularly (with the 5-exo-ring cyclisation mode preferred in the latter case). This reaction leads to adduct radicals that must be converted to non-radical products before polymerisations can take place. For this reason, polymerisation is avoided either by intermolecular trapping of adduct radicals or by intramolecular, homolytic bond cleavage. Hydrogen atom donors X-H, heteroatom donors X-Z or electron donors M"+ are used as trapping agents (Scheme 7.1). 

BusSnH-mediated intramolecular arylations of various heteroarenes such as substituted pyrroles, indoles, pyridones and imidazoles have also been reported [51]. In addition, aryl bromides, chlorides and iodides have been used as substrates in electrochemically induced radical biaryl synthesis [52]. Curran introduced [4-1-1] annulations incorporating aromatic substitution reactions with vinyl radicals for the synthesis of the core structure of various camptothecin derivatives [53]. The vinyl radicals have been generated from alkynes by radical addition reactions [53, 54]. For example, aryl radical 27, generated from the corresponding iodide or bromide, was allowed to react with phenyl isonitrile to afford imidoyl radical 28, which further reacts in a 5-exo-dig process to vinyl radical 29 (Scheme 8) [53a,b]. The vinyl radical 29 then reacts in a 1,6-cyclization followed by oxidation to the tetracycle 30. There is some evidence [55] that the homolytic aromatic substitution can also occur via initial ipso attack to afford spiro radical 31, followed by opening of this cyclo-... 

S02-extrusion affords the electrophilic radical 49 (Scheme 10). Intramolecular homolytic substitution eventually gives tetrahydronaphthalene 50 (92%). Beckwith showed that the A-(o-bromophenyl)amide 51 can be transformed into the corresponding oxindole 54 (70%) at high temperatures using BusSnH via tandem radical translocation of the initially formed aryl radical 52 to form 53 with subsequent intramolecular homolytic substitution [77]. The nucleophilic a-aminomethyl radical 55 reacted in a tandem addition/homolytic aromatic substitution reaction via radical 56 to tetrahydroquinoline 57 [78]. Radical 55 can either be prepared by oxida-... 

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