Mediated Radical Addition

Photolytic radical generation with hexamethylditin has shown promise for addition 

We became interested in manganese carbonyl [Mn2(CO)io] [29], which requires no sensitizer ( Vrnax 340 nm, OMn-Mn o Mn-Mn) for homolytic metal metal bond cleavage. This process had apparently been scarcely recognized by synthetic organic chemists before a series of studies were published by Parsons [30]. 

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A new approach to piperidines via cyclization of dienes, such as 158, employs a phosphorus hydride mediated radical addition/cyclization reaction <06JOC3656>. This reaction proceeds with complete regioselectivity to create the 6-exo-trig product 159, although as an inseparable mixture of two of the four possible diastereomers. 

Iron(II) salts, usually in conjunction with catalytic amounts of copper(II) compounds, have also been used to mediate radical additions to dienes91,92. Radicals are initially generated in these cases by reductive cleavage of peroxyesters of hydroperoxides to yield, after rearrangement, alkyl radicals. Addition to dienes is then followed by oxidation of the allyl radical and trapping by solvent. Hydroperoxide 67, for example, is reduced by ferrous sulfate to acyclic radical 68, which adds to butadiene to form adduct radical 69. Oxidation of 69 by copper(H) and reaction of the resulting allyl cation 70 with methanol yield product 71 in 61% yield (equation 29). 

Scheme 20. Stannyl-mediated radical addition to the arene was low yielding possibly because of poor chain propagation...

CAN-mediated radical addition of acetylacetone to glycal (142) affords O-methyl glycoside (143) (eq. 4.50). 

The first test of the chiral /V-acylhydrazones was in tin-mediated radical addition [47,48]. Addition of isopropyl iodide to propionaldehyde hydrazone 3a was chosen for initial screening (Scheme 2). Using the tin hydride method with triethylborane initiation [51, 52] (Bu3SnH, Et3B/02), with InCl3 and ZnCU as Lewis acid additives, desired adduct 13a was obtained with high diastereoselectivity. In contrast, 13a was produced with poor selectivity (diastereomer ratio, dr 2 1) in the absence of Lewis acid. 

Table 3 Scope of tin-mediated radical addition to chiral IV-acylhydrazone 3a in the presence of ZnCl2...

Because disconnection of a-alkoxy-y-amino acid 28 calls for (3-alkoxyhydra-zone 30, the potential for (3-elimination of the alkoxy group from the hydrazone precursor 30 (Scheme 7) makes non-basic conditions critical. In fact, treatment of 30 with TBAF in THF led to just such a (3-elimination (Marie, University of Iowa, unpublished). However, the manganese-mediated radical addition of isopropyl iodide proceeded in 77% yield, without any evidence of (3-elimination, to afford 31 as a single diastereomer. Reductive removal of the chiral auxiliary and oxidation to the carboxylic acid gave 28 in good overall yield [103]. 

Phenylacetaldehyde /V-acylhydrazone 32 served as the radical acceptor for assembly of y-amino acid 29 (Scheme 8), employing difunctional iodide 33 in the manganese-mediated radical addition (56% yield, single diastereomer) [103]. As with 31 (shown above), this radical adduct 34 was converted through the same four-step sequence to y-amino acid 29. 

Although the aforementioned routes provided the desired y-amino acids, it was desirable to develop a synthesis which incorporates the carboxylic acid oxidation state prior to coupling. We hypothesized that manganese-mediated radical addition would accomplish this objective, and therefore initiated a study of manganese-mediated coupling of alkyl iodides with y-hydrazonoesters [104]. We had already shown that the manganese-mediated radical addition conditions offer excellent chemoselectivity, but it remained to be seen whether the stereocontrol model would be disrupted would an additional Lewis basic ester function in the hydra-zone interfere with the role of In(III) in two-point binding and rotamer control ... 

Rusling et al. performed electrochemically and light mediated radical additions of alkyl iodides to cyclohexenone in conductive microemulsions catalyzed by 20 mol% of 247 in 14—81% yield [303]. Radical allylations of alkyl bromides 249 with allyl sulfides, sulfones, or phosphates catalyzed by 5 mol% of cobalt (iminate) complex 250 in the presence of zinc as reducing agent proceeded in 52-85% yield [304],... 

Radical coupling of organic halides with alkenes or alkynes takes place intermolecularly (Equation (12)).54 Tin hydride-mediated radical additions to a series of a-methyleneglutarates furnish 2,4-dialkyl-substituted glutarates.55 Using MgBr2-OEt2 as an additive, exclusive yy/t-selectivities are achieved upon tert-butyl radical addition at —78 °C. 

The finely tuned reactivity of tri-n-butyltin hydride and of the resulting tin radical allows it to mediate radical additions to alkenes and alkynes in reductive carbon-carbon bond formation and for radical ring closures . It is a highly versatile and efficient reagent, but not a very green one delivering one useful atom (hydrogen, MW = 1) for every 40 atoms (MW = 290) lost as waste. 

Intermolecular alkyl radical addition to imine derivatives was studied in aqueous media using indium as a single electron transfer radical initiator. The one-pot reaction based on radical addition to glyoxylic hydrazone provided a convenient method for preparing the a-amino acids. Indium-mediated radical addition to an electron-deficient C=C bond also proceeded effectively to provide a new carbon-carbon bond-forming method in aqueous media (Scheme 7.11).15... 

The first test of the chiral N acylhydrazones was in tin mediated radical addition [24]. 

A variety of aldehyde hydrazones were screened [24b]. Branching at a saturated a carbon was detrimental in the tin mediated radical additions, but an aromatic benzaldehyde hydrazone 12 offered some success, with yields ranging from 30 to 83% (Table 2.3, entries 5 8). With the exception of 8a, which decomposed under the reaction conditions, the reactions were quite dean. Even in the examples with lower yields, the mass balance after recovery of the hydrazone precursor was generally 80 90%, demonstrating the excellent chemoselectivity of the reactions of radicals with N acylhydrazones. We were delighted to find that the radical additions had occurred with excellent stereocontrol in all secondary and tertiary radical additions to hydrazones 8 and 12 (Table 2.3), with diastereomer ratios ranging from 93 7 to 99 1 [24]. 

Table 2.6 Results of metal mediated radical addition to propionaldehyde hydrazone 8a. O. O-...

The Mn mediated radical additions offer an inherently flexible carbon carbon bond construction approach to amine synthesis. Because of the broad functional group compatibility in both the radical precursor and the aldehyde hydrazone acceptor, the roles of these precursors can be switched to result in the construction of either of two C C bonds at the chiral amine (Scheme 2.10) with excellent stereocontrol. The epimeric configuration can be selected by either (a) employing the enantiomeric auxiliary or (b) interchanging the roles of R and in the alkyl halide and aldehyde precursors [47]. By combining these two tactics, the optimal roles of R and with respect to yield and selectivity can be chosen. Such strategic flexibility contributes to the synthetic potential of these radical addition reactions. 

Later the same group reported that a-bromo carbonyl compounds could be added to terminal alkenes [108] or coupled with allylgallium [109] through intermolec-ular radical reactions still initiated with triethylborane. Another remarkable example was reported by Miyabe et al. They described the indium [110] or triethylborane [111]-mediated radical addition of alkyl iodide to electron deficient C=N bond and C=C bond in water (Eq. 10). 

Similarly, the use of CTAB and EPHP in presence of 4,4 -azobis(4-cyanovaleric acid) (ABCVA) promoted the indium-mediated radical addition to /(-substituted cconjugated alkenes in water. This method produced 1,4-addition products to afi-enones while the classical allylindium reagents lack generally of regioselectivity [113]. 

The tributyltin hydride-mediated carbon-carbon bond formation via radical addition and cyclization of alkyl halides with alkenes has often been a choice for construction of various organic molecules [1], However, the requirement for high-temperature initiators or photo initiation and the difficulties associated with purification of the products from tributyltin halides tend to limit the widespread use of these methods, despite the efforts to make the methods easier [Ic, 2], Recently, nickel-mediated radical additions and cyclizations have been introduced as promising alternatives to the tributyltin hydride methods. These are the nickel powder-acetic acid method for cyclization of haloamides to y-lactams, y -lactams and in-dolones, the borohydride exchange resin-nickel boride method for radical addition, nickel-catalyzed electroreductive cyclization and nickel-catalyzed Kharasch addition of polyhalo compounds. 

Scheme 2. CAN-mediated radical additions of CH-acidic compounds 1 to arenes 6...

Scheme 6. CAN-mediated radical addition by oxidation of thiocyanate le...

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