Iodine-transfer cyclization

Iodine-transfer cyclization. Irradiation of unsaturated a-iodo carbonyl compounds in the presence of a hexaalkylditin (5-10%) can result in isomerization to cyclic y-iodo carbonyls.1 The reaction is very slow in the absence of an initiator. Thus under these conditions 1 isomerizes to a mixture of 2 and 3 in which 2 predominates. The reaction is particularly useful for formation of fused bicyclic systems (4 - 5). 

An equimolar mixture of DIBAL and THF efficiently promotes iodine transfer cyclization of hex-5-ynyl iodides to formfive mem-bered rings (eq 52). The reaction proceeds via a radical pathway to afford the E and Z isomers in a 1 1 ratio, with no trace of j8-fragmentation. 

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. 

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... 

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]. 

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

Most of the useful iodine transfer radical reactions arise from the addition of alkyl iodides, which have been activated by one or more adjacent carbonyl or nitrile substituents, to unactivated olefins. This both labilizes the initial iodide, facilitating chain initiation, and helps ensure that the atom transfer step is exothermic. The requisite iodides are typically synthesized by deprotonation with EDA or NaH, followed by iodination with I2 or A-iodosuccinimide. Cyclization of an iodoester yields primarily lactone product, proceeding through the intermediacy of the I-transfer products as shown in Scheme 5 [19]. Reactions in which a-iodoesters cyclized with alkynes also proved efficient. Similar ketones yielded less synthetically useful mixtures of cyclopentyl and cyclohexyl (arising from 6-endo transition states) products. 

The chain is propagated by abstraction of iodine by the cyclized vinyl radical intermediate. This sequence of reactions benefits from the high reactivity of the intermediate alkenyl reaction in the iodine transfer step. 

A synthetic method for the introduction of an ethynyl group in cyclic structures is based on an intramolecular silicon-tethered radical cyclization with iodine transfer (Scheme 25.8). For example, starting from alkyne 10, a triethyl borane-initiated process allows a radical formation and cyclization to give the alkenyl radical 11. An iodine atom is abstracted from the starting material to give the alkenyl iodide 12, thus, propagating the chain. Treatment of 12 with tetra-/j-butylammonium fluoride (TBAF) results in elimination to furnish 13 in good yields. 

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. 

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... 

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. 

Malonic acid allylic esters undergo intramolecular cyclization reaction under solid-liquid phase transfer catalytic conditions in the presence of Aliquat 336, potassium carbonate, and iodine (Eq. 60) [84]. Application of microwave irradiation to this procedure enabled 2-3-fold reduction in the reaction time compared with conventional conditions. It was found that use of microwaves affected the exo/endo diastereoi-somers ratio - a linear correlation between microwave power and exo isomer concentration was observed [85]. 

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. 

Enol lactones with a halogen at the vinylic position have been synthesized as potential mechanism-based inactivators of serine hydrolyases <81JA5459). 5-Hexynoic acids (181) can be cyclized with mercury(II) ion catalysis to y-methylenebutyrolactones (182) (Scheme 41). Cyclization of the 6-bromo and 6-chloro analogues leads stereospecifically to the (Z)-haloenol lactones (trans addition) but is quite slow. Cyclization of unsubstituted or 6-methyl or 6-trimethylsilyl substituted 5-hexynoic acids is more rapid but alkene isomerization occurs during the reaction. Direct halolactonization of the 5-hexynoic acids with bromine or iodine in a two-phase system with phase transfer catalysis was successful in the preparation of various 5-halomethylene- or 5-haloethylidene-2-phenylbutyrolactones and 6-bromo-and iodo-methylenevalerolactones (Scheme 42). 

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). 

Thus, while cyclization occurred to the tune of overall 45%, almost half of it proceeded with loss of C21-C22 stereochemistry. A radical process through homolytic cleavage of the carbon-iodine bond and subsequent isomerization of the vinyl radical could be responsible (vide supra), possibly initiated by electron transfer from Ni(I) in the mixture. 78 Nevertheless, a third approach to strychnine had been developed. Having accomplished such and one author s graduate career... 

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