Cyclization, radicals with alkenes

Most of the recent synthetic developments in the field of radical cyclization have involved the reactions of carbon-centered radicals with alkenes and alkynes. Other useful acceptors include allenes,31 dienes30 and vinyl epoxides.32 The same methods are used for cyclizations to these acceptors as for radical additions, and the preceding chapter should be consulted for specific details on an individual method (the organization of this section parallels that of Section 4.1.6). Selection of a particular method to conduct a proposed cyclization is based on a variety of criteria, including the availability of the requisite pre-... 

It is important to note here that both of the 5-exo radical cyclizations (133—>132—>131, Scheme 27) must proceed in a cis fashion the transition state leading to a strained mms-fused bicy-clo[3.3.0]octane does not permit efficient overlap between the singly occupied molecular orbital (SOMO) of the radical and the lowest unoccupied molecular orbital (LUMO) of the alkene. The relative orientation of the two side chains in the monocyclic radical precursor 134 is thus very significant because it dictates the relationship between the two outer rings (i. e. syn or anti) in the tricyclic product. The cis-anti-cis ring fusion stereochemistry of hirsutene would arise naturally from a cyclization precursor with trans-disposed side chain appendages (see 134). 

The above-mentioned important and impressive applications of titanocene mediated and catalyzed epoxide opening have been achieved by using the already classical 5-exo, 6-exo and 6-endo cyclizations with alkenes or alkynes as radical acceptors. Besides these achievements, the high chemoselectiv-ity of radical generation and slow reduction of the intermediate radicals by Cp2TiCl has resulted in some remarkable novel methodology. 

The transformation of2-734 involves an initial generation of an organosamarium species 2-735 with subsequent nucleophilic addition to the lactone carbonyl. Presumably, a tetrahedral intermediate 2-736 is formed that collapses to yield the ketone 2-737. This reacts with Sml2 to give a ketyl radical 2-738, which undergoes an intramolecular S-exo radical cyclization reaction with the alkene moiety. The resultant... 

Similar to the intramolecular addition of neutral carbon-centered radicals to alkenes, the formation of radical cations starting from alkenes with subsequent cyclization offers a convenient method for constructing carbocyclic ring systems. In contrast to the regioselective 1,5-ring closure (5-cxo-trig cyclization) of the... 

The intramolecular cyclization of oximes with alkene substituents to dihydropyrroles in the presence of radical initiator or by heating was also describedThus, oxime 83 underwent a tandem 1,2-prototropy-cycloaddition sequence and gave an unstable cycloadduct 84, which on treatment with NaOH afforded indolizine 85 (equation 36). ... 

Another way to construct alkenes is by the addition of carbon radicals to nitrostyrenes such as 5. Ching-Fa Yao of National Taiwan Normal University in Taipei has reported (J. Org. Chem. 2004,69, 3961) an extension of this work, generating the acyl radical from the aldehyde 6, cyclizing it to generate a new radical, then trapping that radical with 5 to give 7. This article includes an overview of the several ways of adding radicals to 5. 

Even though radicals can be nucleophilic or electrophilic, the chemistry of radicals is not naturally intertwined with the carbonyl group and related functionalites in the same way that the chemistry of ionic reactions is. This notation does not now account for the frequent need for radicals and alkenes to be electronically paired for a successful reaction. This is in part because I could not envision a simple, unambiguous notation device and more importantly because such a device could be artificial and misleading in the realm of radical cyclizations where arrangement of the double bond and the radical site in the molecule is often much more important than any electronic pairing. 

The alcohol is oxidized to the corresponding aldehyde with 1 equivalent of IBX at room temperature. The use of 2.2 equivalents of IBX at a higher temperature causes the additional interaction with the amide moiety, leading to a radical cation that cyclizes on the alkene. Employing excess of IBX in the presence of /j-TsOH produces the introduction of an alkene conjugated with the initially formed aldehyde. 

The addition of thiyl radicals to alkenes or alkynes to initiate tandem sequences has also been explored. A highly stereo-controlled phenyl thiyl radical addition, 10-endo macrocyclization, termination process has been used to furnish the macrocycle (37) from the dimethylacrylic ester (36).48 In other work the vinyl radical (38) fonned from addition of a thiyl radical to an enyne gives a mixture of the three products (39)-(41) formed either by 6-exo cyclization (39), addition into the aromatic ring followed by trapping with AIBN (40), or rearomatization and fragmentation to give the sulfide (41) (Scheme 15).49... 

The cyclization of secondary alkyl radicals with a, fi-alkynyl esters 18 proceeded with high stereoselectivity to give predominantly (Z)-exocyclic alkenes at low temperature upon reaction with (TMS SiH (equation 54)79. On the other hand, the formation of (E)-exocyclic alkenes predominated with Bu3SnH, the E/Z ratio being 98 2 at 80 °C. It has been suggested that the main factor controlling the formation of these products is the ability of (TMS Si and Bu3Sn radicals to isomerize the product alkene. That is,... 

Intermolecular addition and addition-cyclization reactions of aminium cation radicals with electron-rich alkenes such as ethyl vinyl ether (EVE) allow an entry into products containing the N—C—C—O moiety of 13-amino ethers 70 or the equivalent of /3-amino aldehydes 71. The mild conditions under which aminium cation radicals are generated from PTOC carbamates makes the reactions described in Scheme 22 possible. In the absence of hydrogen atom donors, the /3-amino ethoxy(2-pyridylthio) acetal 71 was the major product. The mixed acetal can easily be converted... 

It was initially presumed that one would observe a polarity-driven kinetic advantage in 5-hexenyl radical cyclizations if one constructed such radicals with either a hydrocarbon radical site adding to a fluorinated alkene segment or, vice-versa, with a fluorinated radical site adding to a hydrocarbon alkene segment. As it turns out, only the latter combination led to a significant cycliza-tion rate enhancement. 

The overall reactivities of these radicals in their ummolecular 5-hexenyl cyclization processes reflects those same factors which affect the reactivity of partially-fluorinated radicals in their bimolecular addition reactions with alkenes, such as styrene. Table 17 indicates this clearly, and it also reflects the general leveling effect which would be expected for the more facile unimolecular cyclization processes which have log A s about 1-2 units larger than those for the bimolecular additions. 

Benzylpalladation.11 Benzyl halides do not undergo usual radical cyclizations effected with organic halides, but do undergo Pd-catalyzed cyclization with alkenes and alkynes. A typical reaction is formulated in equation (I). The leaving group can also be Br, I, or OMs, but not OCOOCH3 or OCOCH3. Attempts to cyclize 1 with... 

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