Conjugate addition of radicals

R,R)-4,6-Dibenzofiirandiyl-2,2 -bis(4-phenyloxazoline), DBFOX/Ph (5), is a novel tridentate bisoxazoline ligand developed by Kanemasa and coworkers that has been successfully used as a chiral Lewis acid in enantioselective Diels-Alder-reactions, nitrone cycloadditions and conjugate additions of radicals and thiols to 3-(2-alkenoyl)-2-oxazolidinones. Representative examples for cycloadditions using the Ni(C104)2-6H20 derived complex are shown below. 

Conjugate addition of radicals generated by decarboxylative fragmentation of (diacyloxyiodo)benzene 564 to dehydroamino acid derivatives 563 has been used in the synthesis of diaminopimelic acid analogues 565 (Scheme 3.223) [612]. 

Another example of resort to heteroatoms to obtain both oral potency and a split between androgenic and anabolic activities Ls tiomestrone (99). Trienone, 98, prepared in much the same way as 23, undergoes sequential 1,6 and 1,4 conjugate addition of thioacetic acid under either irradiation or free radical catalysis to afford the compound containing two sulfur atoms. 

The success of intramolecular conjugate additions of carbon-centered radicals in multifunctional contexts is noteworthy. Compound 57 (see Scheme 10), prepared by an interesting sequence starting from meto-toluic acid (54) (see 54 > 55 > 56 > 57), can be converted to the highly functionalized perhydroindane 58 through an intramolecular conjugate addition of a hindered secondary radical.21-22 This radical cyclization actually furnishes a 6 1 mixture of perhydroindane diastereoisomers, epimeric at C-7, in favor of 58 (96 % total yield). It should be noted that a substantially less strained cis-fused bicyclo[4.3.0] substructure is formed in this cyclization. 

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... 

This reaction is extended to the intramolecular ring closure of the intermediate radical 224 with olefinic or trimethylsilylacetylenic side chains [121]. Cu(BF4)2 is also effective as an oxidant (Scheme 89) [122]. Conjugate addition of Grignard reagents to 2-eyclopenten-l-one followed by cyclopropanation of the resulting silyl enol ethers gives the substituted cyclopropyl silyl ethers, which are oxidized to 4-substituted-2-cyclohexen-l-ones according to the above-mentioned method [123]. (Scheme 88 and 89)... 

Toru has investigated the stereoselectivity of the conjugate addition of trialkylboranes to 2-arylsulfinylcyclopentenones. Excellent stereocontrol is achieved with different alkyl radicals (Scheme 27) [73-76]. In the acyclic series, the lack of diastereoselectivity in the addition step and a competitive Pummerer rearrangement have limited the synthetic potential of this reaction [77]. 

Scheme 29 Diethylboranes mediated conjugate addition of secondary alkyl radicals...

Scheme 37 Radical chain mechanism for the conjugate addition of B-alkylcatecholboranes to activated olefins (R = alkyl group EWG = electron withdrawing group R O =Me0C(0)0, MeO )...

ESR and CIDNP studies intended to detect the radical intermediates failed [63], Conjugate addition of a vinylcuprate reagent to an enone takes place with retention of the vinyl geometry indicating that no vinyl radical intermediate is involved [64, 65], Kinetic isotope effects and substituent effects in cuprate addition to benzophenone indicate that C-C bond formation is rate-determining, which is not consistent with the involvement of a radical ion pair intermediate [66]. 

The same group2 now finds that a zinc/copper couple prepared by sonication of Zn and Cul in ethanol/H20 (9 1) permits conjugate addition of alkyl halides to enones and enals. The order of reactivity is RI > RBr and tert > sec primary. THF/H20 or Py/HzO or even pure water can be used as solvent. This reaction can hardly involve a classical organometallic reagent, but probably involves an alkyl radical. 

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