Cyclization alkyl radical

Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good yields and diastereoselectivities. Two examples are shown in Reaction (80), where treatment of 100 with E3B, air, and (TMS)3SiH provided the tricycle 101 in excellent yields as a single diastereomer. Interestingly, the bulky silyl ether moiety is not required to achieve stereoselectivity in this process. 

Scheme 11.17 Diastereoselective formation of a tetrahydrofuran nucleus via 5-exo-trig alkyl radical cyclization on to an allene functionality in the course of a total synthesis of (+)-samin (56) [75], a)33 67 mixture of diastereomers.

An efficient way of introducing selenium in a radical precursor is the use of selenium containing building blocks. The selenides are particularly appropriate when the reaction sequence involves reaction steps that are incompatible with halides or when the corresponding halides are not stable. In Eq. (7), preparation of the selenenylated alkenyl sulfoxide 35 by alkylation of malonate 33 with the bromide 34 is described [18]. This procedure is not feasible with the corresponding halide due to cyclopropane formation via intramolecular alkylation. Radical cyclization of 35 in a 5-exo mode affords, after elimination of the phenylsulfinyl radical, the methylenecyclopentane 36 in good yield and excellent enantioselec-tivity. 

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 cyclizations. 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/frtms-cyclopentanes are formed as the major products, while 6-endo cyclization is hardly observed. Allyl radicals behave in this respect much like alkyl radicals. Cyclization is not even hindered by the presence of substituents at the attacked carbon... 

The regioselectivity in diene addition reactions can also be influenced by ring strain effects in cyclization reactions. The regioselectivity is highly predictable in those cases, in which addition to the preferred diene center forms the preferred ring size. Thus, the cyclization of radical 15 proceeds readily to form the ct s-disubstituted cyclopentyhnethyl radical 16 with high selectivity. Similarly, cyclization of 17 affords exclusively bicyclic radical 18, in which the additional cyclopentane ring has been formed by addition to the terminal position of the butadiene subunit. This preference for 5-exo cyclizations onto dienes is not even dismpted by substiments at the C1 or C4 positions of the diene system, as seen for radical 19, which cyclizes to 20 (equation lO). This is in contrast to alkyl radical cyclizations to alkenes, in which major amounts of 6-endo cyclization is observed for 5-substituted systems. ... 

The alkyl radical cyclization onto an N-C double bond proceeds in both nitrogen-philic and carbon-philic modes (Scheme 4-50) [86]. On the other hand, vinyl radical cyclizations favor the carbon atom of the N-C double bond (Scheme 4-50) [87]. An important issue, in this regard, is the preference for acyl radical cyclization. 

Most Sml2-promoted alkyl radical cyclizations onto unactivated alkenes occur with rates that are too slow to be synthetically useful [3, 4a]. One strategy to improve the cyclization event is to employ substrates with more persistent radicals,... 

Intramolecular alkyl and aryl radical additions onto the azo group were investigated by Beckwith and Warkentin [66]. Alkyl radicals cyclize preferentially in a... 

Analogues of 2-deoxy-o-eryr/iro-pentose 3-phosphate have been prepared by way of alkyl radical cyclization onto vinyl phosphonates. Thus compound 43... 

To shed light on the reaction pathway, a cyclization with methylhydrazine was carried out (70ZOR439 73ZOR832), since pyrazoles with nonequivalent positions 3 and 5 are obtained in this case. From l-methoxybut-l-en-3-yne and methylhydrazine sulfate a 4 5 mixture of 1,3- (110) and 1,5-dimethylpyrazoles (111) was formed (GLC) (70ZOR439). In the reaction of methoxybutenyne homologs (R = Ft, -Pr) with methylhydrazine (72°C, H", H2O, 2 h), lengthening of the alkyl radical leads to an increase in the content of 1,5-isomer (111), with yields of 50-60%. Thus, when R = Ft, the ratio is 2 3 (73ZOR832). 

Examples of the intermolecular C-P bond formation by means of radical phosphonation and phosphination have been achieved by reaction of aryl halides with trialkyl phosphites and chlorodiphenylphosphine, respectively, in the presence of (TMSlsSiH under standard radical conditions. The phosphonation reaction (Reaction 71) worked well either under UV irradiation at room temperature or in refluxing toluene. The radical phosphina-tion (Reaction 72) required pyridine in boiling benzene for 20 h. Phosphinated products were handled as phosphine sulfides. Scheme 15 shows the reaction mechanism for the phosphination procedure that involves in situ formation of tetraphenylbiphosphine. This approach has also been extended to the phosphination of alkyl halides and sequential radical cyclization/phosphination reaction. ... 

In addition to the radical ipso-substitution of indolyl sulfones producing stannanes described earlier <96T11329>, Caddick has also reported an approach to fused [l,2-a]indoles based on the intramolecular cyclization of alkyl radicals. Thus, treatment of 112 with BuaSnH leads to the fused ring derivatives 113 (n = 1-4) <96JCS(P1)675>. 

One of the fundamental questions about the mechanism is whether the radical is really free in the sense of diffusing from the metal surface.7 For alkyl halides, there is considerable evidence that the radicals behave similarly to alkyl free radicals.8 One test for the involvement of radical intermediates is to determine whether cyclization occurs in the 6-hexenyl system, where radical cyclization is rapid (see Part A, Section 12.2.2). 

Small amounts of cyclized products are obtained after the preparation of Grignard reagents from 5-hexenyl bromide.9 This indicates that cyclization of the intermediate radical competes to a small extent with combination of the radical with the metal. Quantitative kinetic models that compare competing processes are consistent with diffusion of the radicals from the surface.10 Alkyl radicals can be trapped with high efficiency by the nitroxide radical TMPO.11 Nevertheless, there remains disagreement about the extent to which the radicals diffuse away from the metal surface.12... 

From a synthetic point of view, the regioselectivity and stereoselectivity of the cyclization are of paramount importance. As discussed in Section 11.2.3.3 of Part A, the order of preference for cyclization of alkyl radicals is 5-exo > 6-endo 6-exo > 7-endo S-endo > 1-exo because of stereoelectronic preferences. For relatively rigid cyclic structures, proximity and alignment factors determined by the specific geometry of the ring system are of major importance. Theoretical analysis of radical addition indicates that the major interaction of the attacking radical is with the alkene LUMO.321 The preferred direction of attack is not perpendicular to the it system, but rather at an angle of about 110°. 

As with carbocation-initiated polyene cyclizations, radical cyclizations can proceed through several successive steps if the steric and electronic properties of the reactant provide potential reaction sites. Cyclization may be followed by a second intramolecular step or by an intermolecular addition or alkylation. Intermediate radicals can be constructed so that hydrogen atom transfer can occur as part of the overall process. For example, 2-bromohexenes having radical stabilizing substituents at C(6) can undergo cyclization after a hydrogen atom transfer step.348... 

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). 

Alkyl radicals generated efficiently from allylsulfones in 80% aqueous formic acid induced a cyclization reaction on aromatic and heteroaromatic compounds to provide polycyclic aromatic and heteroaromatic derivatives (Eq. 7.17).37... 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

Alkyl Co oxime complexes have been used as chain transfer catalysts in free radical polymerizations.866,867 Regioselective hydronitrosation of styrene (with NO in DMF) to PhCMe=NOH is catalyzed by Co(dmg)2(py)Cl in 83% yield.868,869 Catalytic amounts of the trivalent Co(dmg2tn)I2 (192) (X = I) generate alkyl radicals from their corresponding bromides under mild reaction conditions, allowing the selective preparation of either saturated or unsaturated radical cyclization products.870... 

Scheme 3.7. Samarium(ll)iodide-induced domino radical cyclization/alkylation procedure...

Cobaloxime(I) generated by the electrochemical reductions of cobaloxime(III), the most simple model of vitamin Bi2, has been shown to catalyze radical cyclization of bromoacetals.307 Cobalt(I) species electrogenerated from [ConTPP] also catalyze the reductive cleavage of alkyl halides. This catalyst is much less stable than vitamin Bi2 derivatives.296 It has, however, been applied in the carboxylation of benzyl chloride and butyl halides with C02.308 Heterogeneous catalysis of organohalides reduction has also been studied at cobalt porphyrin-film modified electrodes,275,3 9-311 which have potential application in the electrochemical sensing of pollutants. 

The electron-transfer formulation in equation (23) was further substantiated by Ashby et al.49 by using cyclizable probes for the detection of alkyl radicals from the mesolytic scission of RMgX+ (Scheme 10). 

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