Free-radical ring closure reactions

Free-radical ring-closure polymerization has been a common phenomenon in polymer chemistry for some time. Inter-intramolecular polymerization dates from the publication of Butler and Angelo in 1957, in which diallyldi-methylammonium bromide was polymerized by a free radical mechanism to produce a soluble polymer with the formation of five-membered rings. Apparently the reaction is kineti-cally controlled since the formation of the five-membered... 

The formation of alicyclics by electrocyclic and cycloaddition reactions (Section 9.4) proceeds by one-step cyclic transition states having little or no ionic or free-radical character. Such pericyclic (ring closure) reactions are interpreted by the Woodward-Hoffmann rules in the reactions, the new a bonds of the ring are formed from the head-to-head overlap of p orbitals of the unsaturated reactants. 

In their enantioselective total synthesis of (+)-triptocallol (3-79), a naturally occurring terpenoid, Yang and coworkers made use of a concise Mn(OAc)rmediated and chiral auxiliary-assisted oxidative free-radical cyclization [39]. Reaction of 3-77, bearing a (R)-pulegone-based chiral auxiliary, with Mn(OAc)3 and Yb(OTf)3 yielded tricyclic 3-78 in a twofold ring closure in 60% yield and a diastereomeric ratio of 9.2 1 (Scheme 3.20). A further two steps led to (-i-)-triptocallol (3-79). For the interpretation of the stereochemical outcome, the authors proposed the hypothetical transition state TS-3-80, in which chelation of the (3-keto ester moiety with Yb(OTf)3 locks the two carbonyl groups in a syn orientation. The attack of the Mn -oxidation-generated radical onto the proximate double bond is then restricted to the more accessible (si)-face, as the (re)-face is effectively shielded by the 8-naphthyl moiety. 

Tosyl iodide, which is easily prepared by the reaction of the sodium salt of p-toluenesulfinic acid with iodine, is a useful reagent for cleavage of vinylcyclopropanes, resulting in functionalized 5-iodopent-2-enyl sulfones (Table 6). ° Experimentally, a dichloromethane solution of the vinylcyclopropane was added to tosyl iodide and propylene oxide in dichloromethane at 40°C. The mechanism probably involved both free-radical and cationic intermediates, and was sensitive to solvent polarity. The resulting 5-iodopent-2-enyl sulfones were formed with Z configuration which enabled their use in subsequent base-catalyzed ring-closure reactions. 

One of the most fascinating transformations in the biosynthesis of /S-lactam antibiotics is the key step of oxidative cyclisation by isopenicillin-N-synthase. Despite intensive searches for intermediates in the ring-closure reaction, enzyme-free monocyclic intermediates have never been found. It has been concluded, that both cyclisations occur within the same enzyme-substrate complex. Structural variations in the aminoadipoyl and (D)-valine moieties are well tolerated by the enzyme. On the other hand, cysteine cannot be altered. If the isopropyl group in valine is exchanged for an allyl or cyclopropylmethyl group, rearrangement products are found, which are typical of radical reactions. This indicates that an isopropyl radical is involved in the formation of the thiazolidine ring. 

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. 

Although some of the oxidative ring closures described above, e.g. reactions with lead tetraacetate (Section 4.03.4.1.2), may actually involve radical intermediates, little use has been made of this reaction type in the synthesis of five-membered rings with two or more heteroatoms. Radical intermediates involved in photochemical transformations are described in Section 4.03.9. Free radical substitutions are described in the various monograph chapters. 

A variant of the free-radical addition method has been used for ring closure. For example, treatment of 75 with the free-radical initiator hexamethylditin gave a mixture of cis- and tmns-76, with a small amount of cis- and trans-11 (total yield 83%). The reaction has been performed with a-iodo esters, ketones, and malonates. 

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. 

More recently, Bachi and coworkers extended and adapted the TOCO reaction to the synthesis of 2,3-dioxabicyclo[3.3.1]nonane derivatives hke 228 (Scheme 52) ° ° . As detailed in Scheme 53a, the bridged bicyclic hydroperoxide-endoperoxides hke 229 are obtained, from (S )-limonene (227), in a 4-component one-operation free-radical domino reaction in which 5 new bonds are sequentially formed. Particular experimental conditions are required in order to reduce the formation of by-products 230 and (PhS)2, and to favor the critical 6-exo-ring closure of peroxy-radical 231 to carbon-centered radical 232206 chemoselective reduction of bridged bicyclic hydroperoxide-endoperoxides... 

Free radical reactions are used less frequently, to effect six- rather than five-membered ring closures, because carbohydrate-derived hept-6-enyl radicals are less available than are hex-5-enyl analogues, these being the species required for normal exo ring closure processes. Such reactions can, however, be used with good efficiency to produce cyclohexane ring systems bearing a carbon substituent (see Chap. 25). 

It has been suggested that the reaction involves a free-radical process,294 but it is hard to see how an aldehyde could escape unscathed. We prefer to invoke closure to a five-membered ring biradical, followed by disproportionation between the two tertiary radical sites. 

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