Free-radical additions and cyclizations

Snider BB (2009) Mechanisms of Mn(OAc)3-based oxidative free-radical additions and cyclizations. Tetrahedron 65 10738-10744... 

Mn(OAc)3-Based Oxidative Free-Radical Additions and Cyclizations... 

Mn(OAc)3-based oxidative free-radical additions and cyclizations proceed by at least two different mechanisms. The rate-determining step is the slow reaction of acetic acid or 3-keto ester with Mn(OAc)3 to give Mn(III) enolates. The rate of proton loss is proportional to the acidity of the... 

Guindon Y, Godin F, Mochirian PA, PrevostM. Selected diastereoselective reactions free radical additions and cyclizations. In Carreira EM, Yamamoto H, eds. Comprehensive Chirality. Amsterdam Elsevier 2012 472—503. 

A5-hexenyl substituent, extensive cyclization occurs to yield the cyclopentylcarbinyl product from the yields of uncyclized and cyclized products for A5-hexenylmercury chloride, the rate constants for equation 50 have been estimated (vide supra). The SH2 reaction 49 has also been invoked to be the key step in the alkylation of -substituted styrenes by a free-radical addition-elimination sequence, namely96... 

With good methods available for producing carbon-centered free radicals, the cyclization process can be examined in greater detail. Cyclization involves the intramolecular addition of a free-radical to a double bond. Of course, this requires that the two reacting parts of the molecule, the free-radical center and the n bond, come within bonding distance of one another. 

An intramolecular free radical addition was used to prepare the 1,2-thiazepine derivatives 30 and 31 from 29 (Equation 6). A further elegant intramolecular radical cyclization was then used to convert 30 to a new aza-bicyclic system with a bridgehead nitrogen <2001JOC3564>. 

An interesting aspect of fluorinated 4-pentenyl radicals that distinguishes them from their hydrocarbon counterparts is their ability to cyclize to form four-membered rings. As mentioned in Sect. 5.3.2, Piccardi and his coworkers reported in 1971 that C2F5I underwent free radical addition to 3,3,4,4-tetra-fluoro-l,5-hexadiene to form a four-membered ring product [173]. Subsequently they observed similar results in the addition of CC14 [323]. 

Using supported ditin compounds, it is possible to promote free radical addition of organic iodides to ttiple bonds and atom transfer cyclization of e-unsaturated iodoacetates or iodoamides using UV irradiation. In this latter case, tin contamination was found to be 5-34 ppm using 0.1 eq. of ditin reagent, and recycling of the tin reagent was also possible. 

A related route, leading to furan 73, involves free-radical addition of acetaldehyde to 64. Adduct 71 undergoes cyclization with base and then the... 

Cyclization and expansion of dichlorocyclobutanonesf Reaction of BujSnH/ AIBN with the adduct (1) of the reaction of enfree radical addition to the free double bond and reduction of the remaining chloride to provide 2. Reaction of 2 with lSi(CH3)3/Znl2 results in transformation to a seven-membered cyclic cr-iodo ketone, which is converted to cnone 3 by DBU. 

Manganese(III)-mediated radical reactions have become a valuable method for the formation of carbon-carbon bonds over the past thirty years since the oxidative addition of acetic acid (1) to alkenes to give y-butyrolactones 6 (Scheme 1) was first reported by Heiba and Dessau [1] and Bush and Finkbeiner [2] in 1968. This method differs from most radical reactions in that it is carried out under oxidative, rather than reductive, conditions leading to more highly functionalized products from simple precursors. Mn(III)-based oxidative free-radical cyclizations have been extensively developed since they were first reported in 1984-1985 [3-5] and extended to tandem, triple and quadruple cyclizations. Since these additions and cyclizations have been exhaustively reviewed recently [6-11], this chapter will present an overview with an emphasis on the recent literature. 

Tetrahydrofuran derivatives. With the EtMgBr-neopentyl iodide system in THF, the solvent becomes iodinated at C-2 (free radical process) and 2-aryltetrahydrofurans are obtained on addition of EtI and EtMgBr to arylmagnesium halides in THP. Radical cyclization of allyl P-iodoacetals is induced by EtMgBr in DME. ... 

Free radical addition to alkenes. Generation of the toluenesulfonyl radical in the presence of proper alkenes leads to sulfones, and cyclization occurs when a free radical can be created in a remote position. 

One approach to oligomer control in a free-radical polymerization utilizes bound monomers and relies on templated radical macrocyclization reactions. Successful execution of this strategy requires that cyclotelomerization effectively compete with intermo-lecular chain transfer. Scheme 8-2 in Section 8.1 depicts this chemistry schematically wherein radical addition (A), cyclization (C), and chain transfer (T) provide an =3 telomer. The key macrocyclizations (cyclotelomerizations) must precede chain transfer. These transformations are well precedented by systematic investigations of free-radical macrocyclizations that appeared in the 1980s [19-23] and by the seminal contributions of Kammerer, Scheme 8-4 [24-34]. 

The methodology of EtsB-mediated addition of RsSnH to an acetylenic bond has also been successfully applied in the cyclization of enynes . An example is given in equation 35. The use of triphenylgermanium hydride, thiophenol, diphenyl diselenide (equation 36), tris(phenylseleno)borane, Se-phenyl areneselenosulfonates (equation 37) and diphenylphoshine under free-radical conditions induces cyclization of enynes like tributyltin hydride. That is, if the chain-transfer step in Scheme 11 is much faster than the ring expansion, the methylenecyclopentane adduct should be the sole product. 

Although examples of intramolecular radical additions and radical cyclizations continue to dominate the literature, there are a few examples of intermolecular additions mainly to the C-2 or C-3 positions of the indole ring. Early examples utilized hydrogen peroxide and FeS04-7H20, oxidative free-radical reaction conditions (Mn(III), Fe(II) and Ce(IV)) [7], or photolysis [8], but required a large excess of reagents and suffered from low product yields. 

Academic research, role in benign by design chemistry, 11 2-Acylhydroquinones, synthesis, 78-79 Additions and cyclizations, Mn(OAc)3-based oxidative free-radical, 85-86 Adipic acid applications, 32... 

Additive-type chlorination of natural rubber can also be carried out with phenyl iododichloride or with sulfuryl chloride. Traces of peroxides must be present to initiate the reactions. This suggests a free-radical mechanism. Some cyclization accompanies this reaction as well. In (XU, for the first 25 chlorine atoms that add per each 100 isoprene units, 23 double bonds disappear and only a small quantity of HCl forms. The subsequent 105 chlorinations, however, cause a loss of only 53 double bonds. 

All attempts to obtain cyclized products from the 4-pentenyl radical using the same conditions under which the 5-hexenyl radical cyclizes readily failed. This was early recognized and confirmed later. Only in special cases, as by the use of vibrationally excited radicals in the gas phase or carbene triplets has cyclization been observed. In these instances, only (Cy5) and no (Cy4) products were obtained. In solution, cyclized products have been observed only from 4-pentenyl radicals possessing special features, e.g., the radical (A ) which results from intermolecular free radical addition to cis cis-1,5-cyclooctadiene (Scheme 15). 

A very particular example of free radical intramolecular addition to an allene has been described by Gompper. It involves the free radical addition of thiophenol to 164 with opening of the vinylcyclopropyl radical (A ) to A and cyclization of A (in a Cy5/Cy4 case) to the (Cy 4) radical, which gives finally 165 (Scheme 74). An analogous selectivity in the Cy5/Cy4 case has been proposed by Shellhamer but, here as well, the evidence is indirect. 

Often the cyclized radical opens in the other direction to give rearranged products. This possibility has been used to explain the results of the pyrolysis of cyclopropyl acetates, of the lead tetraacetate oxidation of a-acetoxy alcohols,and of the stannane reduction of a-acetoxy chlorides. In all these cases free radical addition followed by -scission has been proposed, e.g., as in the 1,2-rearrangement of )ff-acyloxyl radicals 205 to 207 (Scheme 90) discovered independently by Teissier and by Tanner,and whose mechanism, while not completely elucidated, is presumed to proceed through 206, which must be considered as a transition state rather than an intermediate. 

An analogous cyclization process is observed in the free radical addition of dithioacids to 1,2- and 1,3-dienes. ... 

In conclusion, intramolecular free radical addition may be a useful method of synthesizing bridged cyclic compounds. From the examples of the Cy5/Cy6 case noted in this section, it may be concluded that a large preference for the (Cy 5) radical formation again exists and that, in some cases, a very high stereoselectivity in the last transfer step may be observed. The same stereoselectivity is often observed in cationic-induced cyclizations. 

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