Radical cyclizations chain methods

Curran2 has reviewed recent applications of the tin hydride method for initiation of radical chain reactions in organic synthesis (191 references). The review covers intermolecular additions of radicals to alkenes (Giese reaction) as well as intramolecular radical cyclizations, including use of vinyl radical cyclization. 

This chapter begins with an introduction to the basic principles that are required to apply radical reactions in synthesis, with references to more detailed treatments. After a discussion of the effect of substituents on the rates of radical addition reactions, a new method to notate radical reactions in retrosynthetic analysis will be introduced. A summary of synthetically useful radical addition reactions will then follow. Emphasis will be placed on how the selection of an available method, either chain or non-chain, may affect the outcome of an addition reaction. The addition reactions of carbon radicals to multiple bonds and aromatic rings will be the major focus of the presentation, with a shorter section on the addition reactions of heteroatom-centered radicals. Intramolecular addition reactions, that is radical cyclizations, will be covered in the following chapter with a similar organizational pattern. This second chapter will also cover the use of sequential radical reactions. Reactions of diradicals (and related reactive intermediates) will not be discussed in either chapter. Photochemical [2 + 2] cycloadditions are covered in Volume 5, Chapter 3.1 and diyl cycloadditions are covered in Volume 5, Chapter 3.1. Related functional group transformations of radicals (that do not involve ir-bond additions) are treated in Volume 8, Chapter 4.2. 

Most radical cyclizations are conducted by one of the common chain methods. Kinetic analysis and synthetic planning are usually more straightforward than in addition reactions because the cyclizations are intramolecular. 

Fraser-Reid and co-workers have examined serial radical cyclization of pyranose-derivatives [95AJC333] in the stereocontrolled synthesis of Woodward s reserpine precursor [95JOC3859]. Treatment of the bromosilane 188 under reductive conditions resulted in a 5-exo followed by a 6-exo cyclization. The intermediate radical eliminates phenylsulfinyl radical to provide the alkene 189 as the product. The intermediate has been converted to the reserpine precursor 190. The temporary silicon method has been utilized for the synthesis of brassinolide side chain [95SL850]. 

Exploring different methods for the intramolecular radical cyclization of 78 (Scheme 15)95, Usui and Paquette observed that (TMS SiH under normal conditions affords the expected functionalized diquinane 79 in 80% yield and in a a fi ratio of 82 18. MM2 calculations suggest it is the result of a kinetic controlled process. It is worth mentioning that the endothermic reaction 42 is expected to be one of the propagation steps in this chain process (vide infra). By replacing the silane with tin hydride under similar experimental conditions, the unexpected product 80 was obtained in a 77% yield. 

In 1989 Curran and co-workers reported on a photocatalytically induced free-radical cyclization leading to various cyclic, bi-, or polycyclic carbocycles (fused and spiro) via isomerization of unsaturated iodides (alkenes, alkynes) [63]. This corresponds to the nonreductive variant of the tin hydride method. Under sunlight irradiation and in the presence of 10 mol% hexabutylditin, a-iodo esters, ketones, and malonates are efficiently transformed via an iodide atom transfer chain mechanism (eq. (4)). 

Radical reactions represent a well-established method for the formation of cyclic molecules. The sequencing of a radical addition followed by a radical cyclization provides the opportunity of increasing molecular complexity in a single reaction. In recent years, attention has focused on novel ways to initiate the radical chain reaction for the synthesis of heterocyclic ring systems. 

The alkylating-cyclization method may be extended to the enantioselective introduction of an alkyl chain, if a chiral alcohol is used as starting material. The tributyltin hydride mediated radical cyclization of the bromoacetal of 18,19-bisnor-9/i-podocarp-l 3-en-12-one gives a tetracyclic d-lactone, the characteristic structural feature of quassinoids, a complex family of degraded triterpenes82. The hydrogen abstraction in the last step of the reaction has to occur stereoselectively, because only two C-16 diastereomers are formed during the reaction. 

Azocino[3,2-6]indoles were obtained when seleno ester precursors bearing 3-butenylamino and allylaminomethyl chains on the C-3 position of the indole were subjected to the same reductive radical conditions used previously with indole 237. Inclusion of a bromine atom on the alkene acceptor gave the most rewarding result (shown below) at a hydride concentration of 0.02 M yielding 75% of the %-endo product 241, without the detection of any products, formed as a result of reductirm or the alternative 1-exo cyclization. This method proved to be a nice complement to the ring-closing metathesis protocol used in this laboratory to effect similar cyclizations and recently resulted in the total synthesis of apparicine [126, 127]. 

As illustrated in Scheme 6, there are two general methods which imply thiyl radicals in multistep radical reactions. In the first approach (thiol as a coreactant) the thiyl radicals add to the substrate to form an initial radical which undergoes a radical cyclization to give the final radical. Hydrogen abstraction from the thiol gives the desired product and thiyl radical, thus completing the cycle of this chain reaction. In the second approach (thiyl radical as a catalyst) the initial thiyl radical adduct proceeds through a multistep reaction and the final radical terminates via ejection of the thiyl radical. The prototype of this approach is the Z)-(E) interconversion of olefins mentioned above. 

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. 

It is the opinion of the present authors that isomerization of a tertiary alkyl radical to a primary radical as in the formation of II from I is improbable. The formation of IV is similarly unlikely. The cycliza-tion of V by intramolecular alkylation seems quite plausible however, equation 9 does not explain either the formation of V or its subsequent cyclization. The following mechanism has the advantages that, like the generally accepted free radical-initiated mechanisms, it postulates a chain reaction and that the intramolecular alkylation step is directly analogous to that proposed for thermal alkylation, namely addition of an alkyl radical to the double bond of the alkene (Frey and Hepp, 12). The method of formation of the chain initiator, R —, again is not critical since R —, merely starts the first cycle of the chain reaction it may be formed by decomposition of the isobutylene. 

A very large number of these systems with ring junction heteroatoms exists, and this number is constantly increasing. Only illustrative examples of the preparation of such systems can be given here. The synthetic methods for the formation of this type of heterocycle can be usefully classified as follows (i) various cyclocondensations between the corresponding heterocyclic derivatives and bifunctional units, (ii) intramolecular cyclizations of electrophilic, nucleophilic or (still rare) radical type, (iii) cycloadditions, (iv) intramolecular oxidative coupling, (v) intramolecular insertions, (vi) cyclization of open-chained predecessors, (vii) various reactions (quite often unusual) which are specific for each type of system. Examples given below illustrate all these cases. 

The recognition of the usefulness of radical reactions as a synthetic tool has prompted the exploration of this method for branched-chain sugars synthesis. Radical addition to an olefin is one of the most popular reactions yet investigated [10], Two approaches have been devised an intramolecular version, which is mostly a 5-exo cyclization and an inter-molecular version in which the radical is trapped by an activated olefin. 

Of all the radical reactions, the exo-l,5-cycIization of a hex-5-enyl radical to cyclopen-tylmethyl radical and its subsequent trapping by various reagents have attracted the most attention from synthetic chemists (Scheme 1) [4-7]. Starting materials that are most often used for the tin method (initiation of the chain by trialkyl tin radical) are halides, sulfides, selenides, or thionocarbonates. The generation and cyclization of the radical proceeds under exceptionally mild neutral conditions, and these conditions are compatible with a wide variety of common functional groups. A prototypical example of an application in carbohydrate chemistry is shown in Scheme 2 [8]. Readily available 2,3-di-O-isopropyl-ideneribonolactone 1 was converted into the bromoacrylate 2 in three steps. Radical... 

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