Nitriles radical acceptors

Oxime ethers and imines are viable intramolecular radical acceptors. Advanced precursors of (—)-tetrodotoxin were prepared via radical cyclization reactions using oxime ethers as radical acceptors [105]. In the synthesis of (+)-7-deoxypancratistatin (160) [106] (Scheme 55), the intermediate 159 was prepared via tandem radical cyc-lizations of the precursor 158 possessing an A -aziridinylimine and an 0-benzyloxime moiety. Direct formation of lactones is possible as shown in the reaction of the (2,2-diphenylhydrazono)acetate 161, which afforded the hydrazino lactone 162 along with the epimer 163. (-t-)-Furanomycin (164) was synthesized from 162 [107] (Scheme 56). Normally, use of nitrile radical acceptors is limited to cyclopentanone synthesis, but the rigidity of the 1,6-anhydro scaffolding in the bromide 166 enabled radical cyclization to give the tricyclic ketone 167, which comprises the entire skeletal framework of tetrodotoxin [108] (Scheme 57). 

For the route A, acyl radicals donors like iS are readily generated from acyl selenides (ISa) or acyl cobalt derivatives (iSb) and radicals acceptors 2S are usually multiple bonds as in methyl vinyl ketone (2Sa) -although some homolytic substitutions are possible. On the other hand, nitriles GSal are useful acceptors (3S) in radical cyclisations and 4Sa is an obvious synthon equivalent of radical donor 4S (See Table 7.2). 

While tin reagents have provided ample methods for the generation of anomeric radicals, the variety of structures useful as radical acceptors is extremely diverse. In addition to the conjugated nitriles and conjugated carbonyl compounds, oximes have also been used. As shown in Scheme 5.2.14, Hart, et al.,22 effected a C-glycosidation utilizing an O-benzyl oxime and a tin reagent. The reaction proceeded in 80% yield with a anomeric selectivity. 

The ideal substrates for these reactions are 1,6-dienes [37-38], for example (Scheme 7), dimethyl diallylmalonate is easily transformed into cyclopentane derivatives, as a mixture of cis and trans isomers. The methodology also applies to analogous enynes [39-40], diynes [41], or eneallenes [42]. The radical acceptor in the cyclization step can even be an imino group [43a-c], or a nitrile [43d]. 

Point 2 above is understandable (Eq. I) since in apolar solvents the energy for charge separation is large and makes electron transfer slow. In the case of aromatic nitriles as acceptors, with which we are particularly concerned, there is obviously also a strong n-interaction that can occur between donor and acceptor, and irradiation in aprotic solvents usually causes no reaction but only quenching of the nitrile monomolecular fluorescence and appearance of a new red-shifted emission attributable to the exciplex (see Section 2.2). Independent solvation of the radical ions is also important. For example, the bichro-mophoric molecules 5 and 6 show strong exciplex emission and... 

So-called lower order cyanocuprates RCu(CN)Li do not generally react with acceptor-substituted enynes. An exception is the cuprate t-BuCu(CN)Li which undergoes anti-Michael additions with 2-cn-4-ynoates and nitriles (equation 61)151. The mechanistic aspects of this very unusual reaction are unknown radical intermediates and electron transfer steps have not been found. 

This has been applied to the cyclization of dihalides [45, 46], nonconjugated, unsaturated ketones [47] and esters [48], oxoalkylpyridinium salts [49], aldehydes and unsaturated nitriles [50], halides, and unsaturated esters [51], The umpoled acceptors, mostly radical anions or carban-ions (see Scheme 1), can also be used in intermolecular reactions such as acylation, alkylation, or carboxylation (Eq. 5). 

Radical cyclizations to carbon-nitrogen multiple bonds resemble additions to carbon-carbon multiple bonds in that they usually give products of irreversible exo cyclization. To date, the most useful acceptors have been oximes189 and nitriles,190 and one example of each type of cyclization is given in Scheme 45.191 Nitriles are useful because the intermediate imines are readily hydrolyzed by mild acid to ketones. Although this route to ketones is shorter than the two-step sequence of alkyne cyclization/ozo-nolysis, nitriles are slightly poorer acceptors than terminal alkynes, and much poorer acceptors than activated alkynes. Thus, when slow cyclizations are involved, the two-step protocol is preferable. 

Even molecules with heteroatoms can be used as electron acceptors. The initiating anion radicals are formed from aromatic ketones [192] (e. g. benzophenone) or nitriles [193] (e. g. benzonitrile, naphthonitrile). It appears that both ketones and nitriles can react in several ways, and the evidence concerning the correctness of the proposed mechanisms does not at present seem to be conclusive [194]. 

MO calculations have been carried out on the isomerization of cyclopropane to propene, and the MNDO method has been used to study the reaction pathway and to optimize the structure of reactant, transition structure, and product of the ring opening reaction of bicyclo[1.1.0]butane. Various methods have been employed to estimate the rate constants for ring opening of the 2-cyclopropyl-2-propyl radical. 1-Acceptor-1-sulfenyl-substituted 2-vinylcyclopropanes of the type (430) have been found to afford 6-sulfenyl-a,jS y, -unsaturated carboxylic esters and nitriles (431) upon treatment with acid, by a process which involves C(l)—C(2) bond fission and a novel 1,5-sulfenyl rearrangement (see Scheme 110). It has been shown that the benzophenone-sensitized photolysis of vinyl norcaradiene derivatives, such as 5-(2-methylprop-l-enyl)-3-oxatricyclo[4.4.0.0 ]deca-7,9-dien-4-ones (432), results in the regioselective cleavage of only one of the cyclopropyl c-bonds to afford isochroman-3-one derivatives (433). It has been reported that the major product obtained from the reaction of structurally diverse a-diazo ketones with an electron-rich alkene in the... 

Quadricyclanes (160) also undergo a valence isomerization to norborna-dienes if irradiated in the presence of electron acceptors such as fumaro-nitrile (Jones and Becker, 1982). Two distinct radical cation structures are observed for the hydrocarbon, corresponding roughly to the bonding patterns of norbornadiene and quadricylane, respectively (Roth et al., 1981). 

Enaminoesters, -ketones, and -nitriles have also successfully been applied in electro-chemically induced radical cation cycloaddition reactions, especially with 2-vinylindoles or 2-vinylpyrroles. Some examples are given in Eq. (31). Depending on the structures, the reaction starts with the formation of either the vinylindole or vinylpyrrole radical cation or the radical cation of the enamidoester, -ketone, or -nitrile. In Eq. (32), a representative reaction pathway for the cycloaddition between a 2-vinylpyrrole and an acceptor-substituted enamine is formulated via the enamine radical cation [159]. 

The effects of the length of the polyene chain and acceptor substituents on the stability of carotenoid cation radicals have been studied [117]. For esters of conjugated carotenoid carboxylic acids, the stability of then-cation radicals decreased with increasing length of the polyene chain. For conjugated aldehydes or nitriles there was no profound effect. 

While Fe(SCys)4, [2Fe-2S], [3Fe-4S] and [4Fe-4S] clusters all function as one-electron donors or acceptors, the more complex double-cubane [8Fe-7S] cluster that is found only in nitrogenases (see Nitrogenase Catalysis Assembly) has the potential to mediate two-electron transfer processes.Three methods have been employed to functionalize Fe-S centers for substrate binding and activation. The first involves having an accessible Fe coordination site as in the mononuclear Fe centers of nitrile hydratase and SOR, and the [4Fe-4S] clusters at the active sites of hydratases/dehydratases and radical-5-adenosylmethionine (SAM) enzymes.Indeed the recent recognition of the importance of the superfamily of radical-SAM enzymes in initiating radical reactions, via cluster-mediated reductive cleavage of SAM to yield a... 

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