Macrocyclization radical reactions

Free radical reactions have been used in organic synthesis not only for ring expansion, but also for formation of macrocyclic ketones [48] [51]. 

A second, and more chemical, verification is due to Finke et al.,21 who also invented the descriptive phrase persistent radical effect and gave a prototype example to the extreme. The thermal reversible 1,3-benzyl migration in a coenzyme B12 model complex leads to the equilibrium of Scheme 9. Earlier work had shown that the reaction involves freely diffusing benzyl and persistent cobalt macrocycle radicals, but the expected self-termination product bibenzyl of benzyl was missing. Extending the detection limits, the authors found traces of bibenzyl and deduced a selectivity for the formation of the cross-products to the self-termination products of 100 000 1 or 99.999%. Kinetic modeling further showed that over a time of 1000 years only 0.18% of bibenzyl would be formed, and this stresses the long-time duration of the phenomenon. 

Other attempts to promote radical DA reactions were pursued, notably to open an entry into steroidal structures. An interesting case is the radical cyclization of ynone 153 in order to prepare tetracyclic ketone 155 through a 13-e rfo-dig macrocyclization-radical tandem transannular DA cascade. The unique resulting tetracyclic compound 158, displays a completely different structure with two contiguous quaternary sp carbons and two conjugated enone moieties (Scheme 42),... 

Interestingly, placement of the (bromomethyl)dimethyl-silylether to the other propargylic position of the macrocycle (i.e., 121, Scheme 20.32) led to a transannular radical reaction cascade to give a single diastereomeric 4-6-5 tricyclic 126, which was converted to 127 by the Tamao oxidation in 47% yield over two steps. The high chemo-selectivity of the radical reaction of the primary radical 122 toward the 5-exo-dig versus 5-exo-trig cyclization was also notable for the mixed allylic and propargylic (bromo-methyl)dimethylsilyl ether 121 (Scheme 20.32). 

A tandem macrocyclization/transannular radical cyclization of iodopolyene 134 was employed by Pattenden and co-workers for synthesis of ( )-estrone. The radical reaction cascade involved the 5-endo-trig cyclization of 134 to form the cyclopropylmethyl radical 136 (Scheme 20.34), which underwent opening of the... 

Methylation of [Co(tmt)]2+ with Mel leads to the potent methyl carbanion donor trans-[Co(tmt)Me2]+ (186). Reaction of this complex with variety of methyl-lead(IV) compounds in MeCN is rapid, leading to the same monomethylcobalt(III) product, but resulting in different methylated Pb derivatives depending on the reaction stoichiometry and Pb compound.839 The same complex rapidly transfers Me groups to Zn2+ and Cd2+ in MeCN,840 or Pb2+ and Sn2+ in water.302,841 The kinetics of Co—C bond formation in the reactions with primary alkyl and substituted primary alkyl radicals has been found to be influenced more by the structure of the macrocycle than by the nature of the radicals.842... 

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. 

As will be discussed later, the novel pentacyclic antitumor alkaloid roseophilin continues to attract much synthetic effort and several approaches relied on the venerable Paal-Knorr condensation for construction of the pyrrole moiety. For instance, Trost utilized this reaction upon diketone 1 to afford the tricyclic core 2 of roseophilin in a strategy featuring an enyne metathesis as a key step <00JA3801>, while another formal synthesis of this alkaloid utilized a radical macrocyclization to produce the ketopyrrole core <00JCS(P1)3389>. 

Most of the kinetic models predict that the sulfite ion radical is easily oxidized by 02 and/or the oxidized form of the catalyst, but this species was rarely considered as a potential oxidant. In a recent pulse radiolysis study, the oxidation of Ni(II and I) and Cu(II and I) macrocyclic complexes by SO was studied under anaerobic conditions (117). In the reactions with Ni(I) and Cu(I) complexes intermediates could not be detected, and the electron transfer was interpreted in terms of a simple outer-sphere mechanism. In contrast, time resolved spectra confirmed the formation of intermediates with a ligand-radical nature in the reactions of the M(II) ions. The formation of a product with a sulfonated macrocycle and another with an additional double bond in the macrocycle were isolated in the reaction with [NiCR]2+. These results may require the refinement of the kinetic model proposed by Lepentsiotis for the [NiCR]2+ SO/ 02 system (116). 

Pletcher and associates [155, 159, 160] have studied the electrochemical reduction of alkyl bromides in the presence of a wide variety of macrocyclic Ni(II) complexes. Depending on the substrate, the mediator, and the reaction conditions, mixtures of the dimer and the disproportionation products of the alkyl radical intermediate were formed (cf. Section 18.4.1). The same group [161] reported that traces of metal ions (e.g., Cu2+) in the catholyte improved the current density and selectivity for several cathodic processes, and thus the conversion of trichloroacetic acid to chloroacetic acid. Electrochemical reductive coupling of organic halides was accompanied several times by hydrodehalogena-tion, especially when Ni complexes were used as mediators. In many of the reactions examined, dehalogenation of the substrate predominated over coupling [162-165]. 

The use of porphyrinic ligands in polymeric systems allows their unique physio-chemical features to be integrated into two (2D)- or three-dimensional (3D) structures. As such, porphyrin or pc macrocycles have been extensively used to prepare polymers, usually via a radical polymerization reaction (85,86) and more recently via iterative Diels-Alder reactions (87-89). The resulting polymers have interesting materials and biological applications. For example, certain pc-based polymers have higher intrinsic conductivities and better catalytic activity than their parent monomers (90-92). The first example of a /jz-based polymer was reported in 1999 by Montalban et al. (36). These polymers were prepared by a ROMP of a norbor-nadiene substituted pz (Scheme 7, 34). This pz was the first example of polymerization of a porphyrinic macrocycle by a ROMP reaction, and it represents a new general route for the synthesis of polymeric porphyrinic-type macrocycles. 

The field of alkyl radical macrocyclization reactions was further augmented with an n + 1) strategy, which incorporates a CO unit in the macrocycle [93], Thus, in the presence of highly diluted (0.005-0.01 M) (TMS)3SiH, co-iodoacrylates underwent an efficient three-step radical chain reaction to generate 10- to 17-membered macrocycles in 28-78% yields, respectively (Reaction 7.82). 

Steric constraints dictate that reactions of organohalides catalysed by square planar nickel complexes cannot involve a cw-dialkyl or diaryl Ni(iii) intermediate. The mechanistic aspects of these reactions have been studied using a macrocyclic tetraaza-ligand [209] while quantitative studies on primary alkyl halides used Ni(n)(salen) as catalyst source [210]. One-electron reduction affords Ni(l)(salen) which is involved in the catalytic cycle. Nickel(l) interacts with alkyl halides by an outer sphere single electron transfer process to give alkyl radicals and Ni(ii). The radicals take part in bimolecular reactions of dimerization and disproportionation, react with added species or react with Ni(t) to form the alkylnickel(n)(salen). Alkanes are also fonned by protolysis of the alkylNi(ii). 

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