Cyclization iodine atom transfer

Cyclizations involving iodine-atom transfers have been developed. Among the most effective examples are reactions involving the cyclization of 6-iodohexene derivatives. The 6-hexenyl radical generated by iodine-atom abstraction rapidly cyclizes to a cyclo-pentylmethyl radical. The chain is propagated by iodine-atom transfer. 

Reaction conditions have been developed in which the cyclized radical can react in some manner other than hydrogen atom abstraction. One such reaction is an iodine atom transfer. The cyclization of 2-iodo-2-methyl-6-heptyne is a structurally simple example. 

The fact that the cyclization is directed toward an acetylenic group and leads to formation of an alkenyl radical is significant. Formation of a saturated iodide could lead to a more complex product mixture because the cyclized product could undergo iodine atom transfer and proceed to add to a second unsaturated center. Vinyl iodides are much less reactive and the reaction product is unreactive. Owing to the potential... 

These cyclizations can also be carried out without a hydrogen donor, in which case the chain is propagated by iodine atom transfer.331 If necessary, ethyl iodide can be added to facilitate iodine atom transfer. 

Examples of tandem intermolecular addition-cyclization under iodine atom-transfer conditions are depicted in Scheme 16 [38,41],... 

Scheme 15 Cyclizations through iodine atom transfer...

Cyclizable radical-probe experiments have been extensively used in ET versus Spj2 investigations (see Ashby, 1988, and references cited therein). Attention has, however, been recently drawn to causes of possible misinterpretation, particularly in the case of iodides, where an iodine-atom-transfer chain mechanism is able to convert most of the starting linear iodide into the cyclized iodide, even if only a minute amount of linear-chain radical is present in 7-8 2 reactions (Newcomb and Curran, 1988). Rather puzzling results were found in the reaction of (CH3)3Sn ions with secondary bromides, which should not be involved in atom-exchange chain reactions... 

By contrast, for iodide 18 having the triple bond activated by a phenyl group, conversion to the cyclic organozinc species 25 occurred effectively and the latter could be efficiently functionalized, provided that traces of moisture were excluded by pre-treatment of zinc powder with Mel. The substituted benzylidene cyclopentanes 26 and 27 were respectively obtained after iodinolysis and palladium-catalyzed cross-coupling reaction with benzoyl chloride (equation 10). However, it could not be assessed whether the formation of organozinc 25 was attributable to an anionic or a radical cyclization pathway (or both) as, had iodide 26 been produced by a radical iodine atom-transfer, it would have been converted to 25 by reaction with metallic zinc due to the presence of the activating phenyl group21. 

Iodine atom transfer reactions between alkyl radicals and iodocarbonyls are very rapid (107 M-1 s-1 to 109 M-1 s-1).130 This means that, even when these iodides are cyclized by the tin hydride method, iodine atom transfer may supersede hydrogen transfer, and the reductively cyclized product will ultimately be derived from the reduction of a cyclic iodide. Tin hydride cyclizations of halocarbonyls also often require very low concentration to avoid reduction of the initial radical prior to cyclization. For these reasons, reductively cyclized products are best formed by atom transfer cyclization at high concentration, followed by reduction of the product in situ. In a recent full paper, we have described in detail the preparative and mechanistic features of these cyclizations,19 and Jolly and Livinghouse have reported a modification of our reaction conditions that appears to be especially useful for substrates that cyclize very slowly.131 Cyclizations of a-iodocarbonyls can also be promoted by palladium.132... 

Radical cyclization with iodine atom transfer of a highly functionalized propiolic ester 103 using dibenzoyl peroxide as an initiator gave the a-methylene-y-butyrolactone 104 in good yield [95T11257]. The relative stereochemistry at carbon atoms 4 and 5 are established during the reaction. The intermediate 104 has been converted to the anti-tumor agent (-)-methylenolactocin 105. 

Radical iodine atom transfer [3 + 2]-cycloaddition with alkene (118) using dimethyl 2-(iodomethyl)cyclopropane-l,l-dicarboxylate (117) forms cyclopentane derivative (119), through the formation of an electron-deficient homoallyl radical, followed by the addition to alkene, and cyclization via 5-exo-trig manner as shown in eq. 4.41. 

Fig. 39 Pd-catalyzed iodine atom transfer cyclization reactions...

Naito has also described analogous tandem radical addition-cyclization processes under iodine atom-transfer reaction conditions [16,32], Treatment of 186 with z-PrI (30 eq.) and triethylborane (3x3 eq.) in toluene at 100 °C gave, after cleavage from the resin, the desired lactam product 190 in 69% yield (Scheme 46). Similar reactions involving cyclohexyl iodide, cyclopentyl iodide, and butyl iodide were also reported as well as the reaction with ethyl radical from triethylborane [16,32], The relative stereochemistry of the products was not discussed. 

Following the pioneer work of Kharasch [60], methods involving radical transfer of halides have been developed. The atom transfer method has emerged in the 1980s as one of the best method for conducting intra- and intermolecular radical additions to olefins [61]. This approach is particularly appealing from an atom economy point of view since all atoms remains in the final product. The non-reductive nature of these reactions is also particularly important for the preparation of functionalized molecules. Halides transfers and more particularly iodine atom transfers have found nice applications for cyclizations, annula-tions and cascade reactions [62]. These reactions are based on exothermic radical steps, such as the addition of an alkyl radical to an olefin, followed by an... 

The iodine-atom-transfer %-endo cyclization of a-carbamoyl radicals (i.e., 14 15 16) leads to the... 

The key features of Curran s productive and elegant tandem radical cyclization strategy are illustrated in a retrosynthetic analysis for hirsutene (1) (see Scheme 27). The final synthetic event was projected to be an intermolecular transfer of a hydrogen atom from tri-rc-butyltin hydride to the transitory tricyclic vinyl radical 131. The latter can then be traced to bicyclic tertiary radical 132 and thence to monocyclic primary radical 133 through successive hex-5-enyl-like radical cyclizations. It was anticipated that the initial radical 133 could be generated through the abstraction of the iodine atom from... 

Iodocarbonyls are excellent substrates for atom transfer cyclization, as shown by examples from our recent work in Scheme 29.19-129 When two carbonyl (or cyano) groups are present, bromides can also serve as radical precursors. Photolysis with 10% ditin usually provides excellent yields of kinetic products at high concentration, and alkene substituents often dictate the regioselectivity. The y-iodo ester products are particularly versatile for subsequent transformations, which can often be conducted in situ. Although tertiary iodine products sometimes go on to give lactones or alkenes, primary and secondary iodides can often be isolated if desired. The last example is particularly noteworthy the kinetic product from the cyclization presented in Scheme 27 is trapped, because bromine atom transfer is much more rapid that reverse cyclization. 

A radical eyclization was conducted with 2,2 -a/obisisobutyronitnle AIBN (37) as the radical initiator. Tributyltin hydride serves as the chain transfer reagent. Radical 38 arises from halide 15 through abstraction of an iodine atom, and this in turn cyclizes to radical 39. Compound 39 then abstracts a proton from tributyltin hydride. The resulting tributyltin hydnde radical reinitiates the radical mecha msm, in that it abstracts an iodine atom from another halide molecule 15 (see Chapter 14). 

Fiirstner reported the first McMurry-type reactions working with 5-10 mol% of titanium trichloride and stoichiometric amounts of zinc powder in the presence of chlorotrimethylsilane. The amount of TiCl3 could be reduced to 2 mol% when (ClMe2SiCH2)2 was used as a reagent [125, 131]. At the same time, Burton and coworkers reported atom transfer radical additions of perfluoroalkyl iodides 39 to alkenes 40 catalyzed by 20 mol% of a low-valent titanium compound generated from TiCLt and zinc powder affording 41 in 10-85% yield (Fig. 13). A tandem radical addition/5-exo cyclization/iodine transfer reaction with diallyl ether proceeded in 66% yield [132]. 

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