Allyl radical, cyclization

Allyl radical cyclization.s Allylic radicals are less reactive than vinyl ones, but can undergo cyclization with Bu,SnH/AIBN. 

Scheme 52. Zearalenone synthesis via allylic radical cyclization...

A small library of highly functionalized pyrrolines 95 was synthesized by reaction of allylic and propargylic isocyanides 94 with thiols followed by radical cyclization (Scheme 33). The radical reaction was carried out using a radical initiator (AIBN) under flash heating microwave irradiation [67]. 

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic... 

Osmium tetroxide used in combination with sodium periodate can also effect alkene cleavage.191 Successful oxidative cleavage of double bonds using ruthenium tetroxide and sodium periodate has also been reported.192 In these procedures the osmium or ruthenium can be used in substoichiometric amounts because the periodate reoxidizes the metal to the tetroxide state. Entries 1 to 4 in Scheme 12.18 are examples of these procedures. Entries 5 and 6 show reactions carried out in the course of multistep syntheses. The reaction in Entry 5 followed a 5-exo radical cyclization and served to excise an extraneous carbon. The reaction in Entry 6 followed introduction of the allyl group by enolate alkylation. The aldehyde group in the product was used to introduce an amino group by reductive alkylation (see Section 5.3.1.2). 

Radical addition to alkenes has been used in cyclizations in aqueous media. Oshima and co-worker studied triethylborane-induced atom-transfer radical cyclization of iodoacetals and iodoacetates in water.121 Radical cyclization of the iodoacetal proceeded smoothly both in aqueous methanol and in water. Atom-transfer radical cyclization of allyl iodoacetate is much more efficient in water than in benzene or hexane. For instance, treatment of allyl iodoacetate with triethylborane in benzene or hexane at room temperature did not yield the desired lactone. In contrast, the compound cyclized much more smoothly in water and yielded the corresponding y-lactone in high yield (Eq. 3.31). 

An intramolecular radical cyclization gives the cxo-cyclic compounds, which has been extensively used in the synthesis of cyclic compounds. Michael additions of allyl alcohols or propargy 1 alcohols to nitroalkenes and the subsequent treatment with tin radicals provide a useful method for the preparation of substituted furans (Eqs. 7.83 and 7.84).126... 

As in the case of linear peroxidation products, the initiation step of the formation of isoprostanes is the abstraction of a hydrogen atom from unsaturated acids by a radical of initiator. Initiation is followed by the addition of oxygen to allylic radicals and the cyclization of peroxyl radicals into bicyclic endoperoxide radicals, which form hydroperoxides reacting with hydrogen donors. 

The reactivity of allyl radicals does, however, appear to be sufficient for intramolecular radical reactions. In a systematic study, Stork and Reynolds investigated the feasibility of allyl radical 5-exo cyclizations41. It was found that cyclization proceeds readily for a variety of systems, especially for those with geminal 3,3-diester substitution. Mixtures of c/s/fraws-cyclopentanes are formed as the major products, while 6-enclo cyclization is hardly observed42. Allyl radicals behave in this respect much like alkyl radicals43. Cyclization is not even hindered by the presence of substituents at the attacked carbon... 

Cyclization has also been observed for those cases in which allyl radicals are stabilized by additional substituents. Radicals 9, which carry an ester group at one allyl terminus, cyclize readily in a 5-exo fashion to furnish products 10 in good yield. No 6-exo product was found in this instance (equation 7)45. 

Finally, allyl radicals have successfully been employed in macrocyclization reactions, in which the slower rate of reaction of allyl radicals with hydrogen donors turned out to be advantageous46. Thus, radical 11 cyclizes in 1 A-endo mode to provide, after trapping with tin hydrogen, the product 12 as a fi -mixture of the C2/C3 double bond. No products derived from 6-exo or 10-exo cyclizations could be found (equation 8). This can be rationalized by assuming a faster rate of addition of the nucleophilic allyl radical to the electron-deficient terminal double bond than to the C6 or CIO double bonds. 

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 new entry to exocyclic dienes was reported by Sha who uncovered that a radical cyclization of the vinyl iodide 100 can lead to the formation of an exocyclic dienes fused with a tetrahydrofuran ring. The cyclization is proposed to proceed in a 5-(n-exo)-exo-dig fashion <00OL2011>. 3,4-Disubstituted tetrahydrofurans can also be constructed via the cyclization of O-stannyl ketyls and allylic 0-stannyI ketyls onto electron-rich or electron-poor alkenes <00TL8941>. 

FIGURE 6 Speculative mechanism of Crl hydrocarbon biosynthesis from fatty acid hydroperoxides in algae. Homolytic cleavage of the hydroperoxide is assumed to give an allyl radical, which cyclizes to the thermolabile (1S,2R)-cyclopropane. The sequence is terminated by transfer of a hydrogen radical from C(16) to the -X-0 function. The cyclopropane rearranges to (6S)-ectocarpene as shown in Figure 4. 

Radical cyclization of N-alkenylamino acid derivatives Proline derivatives can be obtained by cyclization of N-alkenyl amino acid derivatives. Thus the (3-iodo allylic amine 2, prepared in 54% yield from threonine, cyclizes in the presence... 

Stereocontrolled radical cyclization to furansRadical cyclization of allyl 2-haloethyl ethers such as 1 show only slight stereoselectivity. However similar cyclization, but involving a dichloromethyl radical, can be highly cis-selective, whereas cyclization involving a monochloromethyl radical is frans-selective. The... 

The electrocyclic reactions of n systems containing an impaired electron are difficult to interpret using the above simple theories. The symmetry of the HOMO of the radical system corresponds to that of the corresponding anion. Thus the allyl radical would be expected to cyclize in the same manner as the alkyl anion i.e., in a conrotatory manner. In fact the interconversion takes place in a disrotatory manner. Theoretical calculations based on Huckets theory also give ambiguous or incorrect predictions. And therefore more sophisticated calculations are required to obtain reliable results. 

In a rare example of the use of phenylselenides as radical precursors in the generation of alkene radical cations by the fragmentation approach, Giese and coworkers generated a thymidine C3/,C4/ radical cation by expulsion of diethyl phosphate. Trapping experiments were conducted with methanol and with allyl alcohol (Scheme 16), when nucleophilic attack was followed by radical cyclization [66]. 

A series of N-allyl sulfamates, phosphoramides, and phosphorimidates was prepared to explore the possibility of O- N rearrangements via the intermediacy of the contact alkene radical cation/anion pair, followed by 5-exo-trigonal radical cyclizations (Fig. 4) [142],... 

Concerning the structure, the cyclopropane derivatives 524—526 deviate from the generally observed cycloadducts of cyclic allenes with monoalkenes (see Scheme 6.97 and many examples in Section 6.3). The difference is caused by the different properties of the diradical intermediates that are most likely to result in the first reaction step. In most cases, the allene subunit is converted in that step into an allyl radical moiety that can cyclize only to give a methylenecyclobutane derivative. However, 5 is converted to a tropenyl-radical entity, which can collapse with the radical center of the side-chain to give a methylenecyclobutane or a cyclopropane derivative. Of these alternatives, the formation of the three-membered ring is kinetically favored and hence 524—526 are the products. The structural relationship between both possible product types is made clear in Scheme 6.107 by the example of the reaction between 5 and styrene. 

The 5-dig-mode of cyclization has been applied in the synthesis of N-heterocycles. For example, treatment of the /i-allenyl dithiosemicarbazide 37 with Bu3SnH and AIBN in hot benzene furnishes the substituted 3H-pyrrole 38 in 41% yield and the isomeric heterocycle 39 in 30% yield (Scheme 11.13) [68], Iminyl radical 40 is formed via Bu3Sn addition to the thiocarbonyl group of the radical precursor 37 and fragmentation of the adduct (not shown). Nitrogen-centered radical 40 adds 5-dig-selectively to provide substituted allyl radical 41. The latter intermediate is trapped by Bu3SnH to furnish preferentially product 38 with an endocydic double bond. 

Thermal intramolecular [2 + 2]-cydoadditions of phenylsulfonyl-substituted allenes 33 gave 34 stereoselectively. An initial carbon-carbon bond formation occurred at the central allenic carbon and the proximal olefmic carbon. The resulting non-allylic radical 35 is unstable and cyclizes rapidly which may account for the high stereoselectivity [30]. 

Birch reduction-alkylation of 5 with 2-bromoethyl acetate was carried out with complete facial selectivity to give 57. This tetrafunctional intermediate was converted to the bicyclic iodolactone 58 ( > 99% ee) from which the radical cyclization substrate 59 was prepared. The key radical cyclization occurred with complete regio- and facial-selectivity and subsequent stereoselective reduction of the resulting tertiary radical gave 60 with the required trans BC ring fusion.The allylic alcohol rmit of (+)-lycorine was obtained by a photochemical radical decarboxylation, 62 63. 

Homolytic substitution reactions including homolytic allylation, radical [2,3]-migrations and stereochemical reactions been reviewed. The review also highlights the possible applications of homolytic substitution reactions. ni reactions at silicon (by carbon-centred radicals in the a-position of stannylated silyl ethers) are efficient UMCT reactions producing cyclized alkoxysilanes. Bimolecular reactions can also be facilitated in good yield (Schemes 32 and 33). ... 

Various transition metals have been used in redox processes. For example, tandem sequences of cyclization have been initiated from malonate enolates by electron-transfer-induced oxidation with ferricenium ion Cp2pe+ (51) followed by cyclization and either radical or cationic termination (Scheme 41). ° Titanium, in the form of Cp2TiPh, has been used to initiate reductive radical cyclizations to give y- and 5-cyano esters in a 5- or 6-exo manner, respectively (Scheme 42). The Ti(III) reagent coordinates both to the C=0 and CN groups and cyclization proceeds irreversibly without formation of iminyl radical intermediates.The oxidation of benzylic and allylic alcohols in a two-phase system in the presence of r-butyl hydroperoxide, a copper catalyst, and a phase-transfer catalyst has been examined. The reactions were shown to proceed via a heterolytic mechanism however, the oxidations of related active methylene compounds (without the alcohol functionality) were determined to be free-radical processes. 

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic 2-bromo-2-deoxysugars, in the presence of 1,1,2,2-tetraphenyldisilane as the radical mediator and AIBN in refluxing ethyl acetate. The corresponding cis-fused bicyclic sugars have been prepared in moderate to good yields (Reaction 7.28) [39]. 

The combination of allylic amination, ring-closing metathesis, and a free radical cyclization provides a convenient approach to the dihydrobenzo[b]indoline skeleton, as illustrated in Scheme 10.10. The rhodium-catalyzed aUylic amination of 43 with the lithium anion of 2-iodo-(N-4-methoxybenzenesulfonyl)arrihne furnished the corresponding N-(arylsulfonyl)aniline 44. The diene 44 was then subjected to ring-closing metathesis and subsequently treated with tris(trimethylsilyl)silane and triethylborane to afford the dihydrobenzojhjindole derivative 46a in 85% yield [14, 43]. 

Radical cyclization of oxime ethers having allylic substiffients to five-membered rings including furan and pyrrole derivatives was described in reviews A thiophenol-promoted radical cyclization of oxime ethers into tetrahydrofurans was recently described. For example, oxime derivative 36 in the presence of thiophenol and azobisisobuty-ronitrile (AIBN) afforded substimted tetrahydrofurans 37 and 38 in a ratio 1.2-3 1 (equation 17) . Radical cyclization of oxime ethers 39 to tetrahydrofurans 40 was successfully realized in the presence of alkyl iodides and EtsB in refluxing toluene (equation 18) . ... 

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