Solid radical-mediated reactions

Continuing with the approach of this chapter from previous years metal-mediated reactions, cycloadditions, radical processes and asymmetric applications will be highlighted. Syntheses using traditional approaches will not be covered, unless improvements are reported. Due to the volume of publications concerning pyridines and associated heterocycles many subject areas could not be covered. Combinatorial or solid-phase synthesis will not represented since the area is rather specialized and many of the processes utilize existing methodology. The synthesis and reactions of polyaza-fused systems of the pyridine class will also not be included in this review. 

For the purpose of arriving at polymeric reagents the formation of a carbon-carbon bond via radical means was desired. Trapping radicals in this way has been well known to modern organic chemists25. However, our problem in modifying PCTFE by this method was the heterogeneity of the polymer. In the solid state, PCTFE may be excluded from a solution-mediated reaction, and recovered unreacted. 

Alkanes can be prepared by the addition of carbon radicals to C=C double bonds (Figure 5.4). The highest yields are usually obtained when electron-rich radicals (e.g. alkyl radicals or heteroatom-substituted radicals) add to acceptor-substituted alkenes, or when electron-poor radicals add to electron-rich double bonds. These reactions have also been performed on solid phase, and polystyrene-based supports seem to be particularly well suited for radical-mediated processes [39,40]. 

In an interesting development for combinatorial chemistry, Sm -promoted radical cyclizations have been adapted for use on solid support [27], The procedures developed have some inherent advantages over -Bu3SnH-mediated reactions and sometimes even to the corresponding solution phase SmE-promoted reactions. Unfortunately, they still appear to lack the consistency necessary for general use in the synthesis of chemical libraries. 

A series of aryl radical cyclizations were reported by a group at Novartis [10], and some of these processes were also compared with bond formation by Pd-mediated Heck cyclization of the same substrates. The tributyltin hydride-mediated reaction of iodo alkenes 7 (Scheme 3), immobilized on polystyrene resin through a linker, gave dihydrobenzofurans 8 [11]. It was also possible to perform a tandem cyclization using allyltributyltin to give the allylated product 9, although the yields were less satisfactory. The radical cyclization onto enol ethers was demonstrated [12] by the conversion of 10 to 11. For best results, the tributyltin hydride and AIBN were added portionwise every 5-8 h. The impressive 95% yield was in fact higher than that for the solid-phase Heck cyclization of 10. Similarly, cyclization of anilide 12 afforded the phenanthridine 13. 

Solid supported catalysts have been utihzed in ATRA and ATRC reactions in order to facilitate reaction work-up and enable catalyst recycling. In one example, V-alkyl-2-pyridylmethanimines were immobihzed on sihca and in conjunction with Cu Br or Cutl utilized in ATRC reactions of trichloro-, dichloro- and monobromo-substrates. Efficient 5-exo and 5-endo cyclizations could be mediated using this immobilized system, however, as coimnonly encountered, the solid supported catalyst was much less active than its homogeneous counterpart. The decrease in the catalytic activity was not induced by catalyst leaching, but rather accumulation of copper(II) deactivator. The accumulation of deactivator during ATRA or ATRC process was result of irreversible and often diffusion controlled radical-radical couphng reactions (A 1.0xl0 M- s- ). 

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... 

Routledge et al. [7] investigated the formation of dihydrobenzofuran 1 from an aryl halide precursor (Scheme 1). With polystyrene, more than 1 equivalent of AIBN was required, while the reaction was complete within 20 h using 6 mol% of AIBN on TentaGel resin (which has a polyethylene spacer between the polystyrene and the site of compound attachment). Addition of t-butanol helped prevent an alternative y -elimination pathway. An attempt to force the latter was made with thiyl linker 2, but only trace amounts of the )9-elimination product 3 were formed. Also investigated were the cyclizations of iodides 4, in which the cyclization of an alkyl radical to an acetylene is approximately 10 times slower than the aryl radical cyclization to a double bond. A direct comparison of the same reaction on solution phase was attempted, but yields could not be determined for the latter because of contamination by tin residues. This illustrates one advantage of solid-phase radical reactions mediated by tributyltin hydride, namely the ease of product purification. 

Solid-state radical reactions of in situ generated imines mediated by Mn(0Ac)3-2H20. 

Reproduced from Zhang Z, Wang G-W, Miao C-B, Dong Y-W. Shen Y-B. Solid-state radical reactions of 1,3-cyclohexanediones with in situ generated hihes mediated by manganese(lll) acetate under mechancal milling conditions. Chem Commun 2004 1832-3, with permission from the Royal Society of Chemistry. 

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