Radical addition - intramolecular

Scheme 13. Intramolecular radical addition/fragmentation in Boger s synthesis of (+)-CC-1065.

The rate of radical addition is most dramatically affected by substituents either at the site of attack or at the radical center. Remote substituents generally have only a small influence on the stereochemistry and regiospecificity of addition unless these groups are very bulky or the geometry of the molecules is constrained (e.g. intramolecular addition - Section 1,2.4). 

A radical carboxyarylation approach was introduced as the key step in the total synthesis of several biologically important natural products (Scheme 27). Treatment of thiocarbonate derivatives 112 (R = Me or TBS) with 1.1 equiv of (TMS)3SiH in refluxing benzene and in the presence of AIBN (0.4 equiv added over 6h) as radical initiator, produced compound 113 in 44% yield. This remarkable transformation resulted from a radical cascade, involving (TMSlsSi radical addition to a thiocarbonyl function (112 114), 5-era cyclization (114->115) and intramolecular 1,5-ipso substitution (115 116) with the final ejection of (TMSlsSiS radical. 

In certain cases, Michael reactions can take place under acidic conditions. Michael-type addition of radicals to conjugated carbonyl compounds is also known.Radical addition can be catalyzed by Yb(OTf)3, but radicals add under standard conditions as well, even intramolecularly. Electrochemical-initiated Michael additions are known, and aryl halides add in the presence of NiBr2. Michael reactions are sometimes applied to substrates of the type C=C—Z, where the co-products are conjugated systems of the type C=C—Indeed, because of the greater susceptibility of triple bonds to nucleophilic attack, it is even possible for nonactivated alkynes (e.g., acetylene), to be substrates in this... 

Epoxides can also be reductively opened to form a radical. An example of an intramolecular cyclization of such a radical has recently been reported <06TL7755>. Treatment of 40 with Cp2TiCl generates an intermediate alkoxy radical, which then adds to the carbonyl of the formate ester. The product, 41, is formed as a 2 1 mixture of isomers at the anomeric carbon. This reaction is one of the first examples of a radical addition to an ester. The major byproduct of this reaction is the exo-methylene compound, 42, arising from a P-hydrogen elimination. 

The reactions of intramolecular isomerization occur and are important in the oxidation of natural and synthetic rubbers. The peroxyl radical addition to the double bond occurs very rapidly. For example, the peroxyl radical adds to the double bond of 2-methylpropene by 25 times more rapidly than abstraction of hydrogen atom from this hydrocarbon (see Chapter 4). Therefore, the oxidation of polymers having double bonds proceeds as a chain process with parallel reactions of P02 with double and C—H bonds including the intramolecular isomerization of the type [12] ... 

The mechanism of PIP degradation appeared to be principally different. PIP has double bonds and oxidizes through intramolecular peroxyl radical addition to the double bond with formation of peroxide bridges. 

The oxidation of PIB occurs mainly via intramolecular addition of dioxygen to double bonds of polymer. The reaction of peroxyl radical addition to the phenoxyl radical leads to the formation of quinolide peroxide (see Chapter 15). This peroxide is unstable, and its decomposition provokes the degradation of PIB. Another reaction predominates in case of aromatic diamine. 

Further variations of the general scenario described in Scheme 4 consist in trapping adduct radical 48 before oxidation occurs7. This can be achieved if intramolecular radical additions are possible, as is the case in radical 62. Oxidation of 62 to the corresponding allyl cation is slower than 6-ew-cyclization to the chlorobenzene ring to form radical 63, which subsequently is oxidized to yield tetrahydronaphthalene 64 as the main product (equation 27). This sequence does not work well for other dienes such as 2,3-dimethyl-1,3-butadiene, for which oxidation of the intermediate allyl radical is too rapid to allow radical cyclization onto the aromatic TT-system. 

A tandem radical addition/cyclization process has been described for the formation of benzindolizidine systems from l-(2-iodoethyl)indoles and methyl acrylate <00TL10181>. In this process, sun-lamp irradiation of a solution of the l-(2-iodoethyl)ethylindoles 149 in refluxing benzene containing hexamethylditin and methyl acrylate effects intermolecular radical addition to the activated double bond leading to the stabilized radical 150. Intramolecular cyclization to the C-2 position of the indole nucleus then affords the benzindolzidine derivatives 151 after rearomatization of the tricyclic radical. 

The base-catalysed ring contraction of 1,3-dioxepanes offers an attractive route to 4-formyl tetrahydropyrans (Scheme 14) , whilst fused exo-cyclic dienes 27 result from the radical cyclisation of alkenyl iodides 26 (Scheme 15) <00OL2011>. Intramolecular radical addition to vinylogous sulfonates is highly stereoselective, leading to the ci s-2,6-disubstituted tetrahydropyran (Scheme 16) . 

Intramolecular addition of trialkylboranes to imines and related compounds have been reported and the main results are part of review articles [94, 95]. Addition of ethyl radicals generated from Et3B to aldimines affords the desired addition product in fair to good yield but low diaster control (Scheme 40, Eq. 40a) [96]. Similar reactions with aldoxime ethers [97], aldehyde hydrazones [97], and N-sulfonylaldimines [98] are reported. Radical addition to ketimines has been recently reported (Eq. 40b) [99]. Addition of triethylborane to 2H-azirine-3-carboxylate derivatives is reported [100]. Very recently, Somfai has extended this reaction to the addition of different alkyl radicals generated from trialkylboranes to a chiral ester of 2ff-azirine-3-carboxylate under Lewis acid activation with CuCl (Eq. 40c) [101]. 

Intramolecular Radical Additions to Cumulated Double Bonds 716... 

Table 6.23 presents calculated barriers for the cyclization of the but-3-enyl radical [i.e. the reverse of reaction (7.2)]. This reaction is an example of an intramolecular radical addition. A number of the features observed in the barriers for the intermolecular radical additions (e.g. methyl radical addition to ethylene, Table 6.14) are also seen here. 

The present volume contains 13 chapters written by experts from 11 countries, and treats topics that were not covered, or that are complementary to topics covered in Volume 1. They include chapters on mass spectra and NMR, two chapters on photochemistry complementing an earlier chapter on synthetic application of the photochemistry of dienes and polyenes. Two chapters deal with intermolecular cyclization and with cycloadditions, and complement a chapter in Volume 1 on intramolecular cyclization, while the chapter on reactions of dienes in water and hydrogen-bonding environments deals partially with cycloaddition in unusual media and complements the earlier chapter on reactions under pressure. The chapters on nucleophiliic and electrophilic additions complements the earlier chapter on radical addition. The chapter on reduction complements the earlier ones on oxidation. Chapters on organometallic complexes, synthetic applications and rearrangement of dienes and polyenes are additional topics discussed. 

A convenient route to triquinanes is based on a strategy of silyl radical addition to conjugated dienes to form allylic type radicals and their subsequent intramolecular addition to C=C double bonds. By exposure of 10 to (TMS)3SiH and AIBN at 80 °C (Reaction 7.16) the triquinane 11 is obtained with an unoptimized 51 %> yield [26]. 

The following scheme shows that (2-propargyloxyphenyl)acyltellurides and (2-propar-gyloxyalkyl)aryltellurides undergo an intramolecular version of the above radical addition, promoted respectively by photolysis (tungsten lamp) and irradiation in the presence of (Bu3Sn)2 or BujSnH/AlBN giving chromanone and furan vinyltelluro derivatives (see also Section 5.7). 

Free radical addition to oximes and oxime ethers emerged as a useful alternative to addition of organometallic reagents, particularly for intramolecular reactions. The most important advantage of free radical V5. organometallic addition is its tolerance for almost any functional group (with the exception of thiocarbonyl and iodoalkyl functions). 

On the other hand, since oxime ethers were electrochemically more inert than ketones under the electroreduction conditions, the electroreductive intra- and inter-molecular coupling of ketones with oxime ethers proceeded via anion radicals in good yields (equations 5 and 6) °4i. Moreover, cobaloxime-mediated intramolecular radical addition onto oxime functions in the electrolysis media proceeded to afford the cyclized aminoethers (equation 7). ... 

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