Captodative radical addition reactions

Some mechanistic aspects of the above cascade reaction deserve comment. Thus, after the intermolecular addition of the nucleophilic acyl radical to the alkene, the electrophilic radical adduct A, instead of undergoing reduction, reacts intramolecularly at the indole 3-position (formally a 5-endo cyclization) to give a new stabilized captodative radical B, which is oxidized to the fully aromatic system. (For a discussion of this oxidative step, see Section 1.5.)... 

In addition to the stabilization by suitable substituents and the absence of other termination reactions than recombination, it is the strength of the bond formed in the dimerization which is a necessary cofactor for the observation of free radicals by esr spectroscopy. The stability of nitroxides [4] or hydrazyls [5] (Forrester et al., 1968) derives not only from their merostabilized or captodative character but also from a weak N-N bond in the dimer. The same should be the case for captodative-substituted aminyls... 

Already, at an early stage of the studies on the captodative effect, Viehe s group (Lahousse et ai, 1984) measured relative rates for the addition of t-butoxyl radicals to 4,4 -disubstituted 1,1-diphenylethylenes and to substituted styrenes. This study did not reveal a special character of captodative-substituted olefins in such reactions. It might be that the stability of the radical to be formed does not influence the early transition state of the addition step. The rationalization of the kinetic studies mentioned above in terms of the FMO model indicates, indeed, an early transition state for these reactions, with the consequence that product properties should not influence the reactivity noticeably. 

Viehe and his collaborators investigated the addition of different radicals to various captodative olefins. They first studied the reaction of an equimolar amount of azo-bis-isobutyronitrile (AIBN) with captodative olefins in benzene at 80 °C [2]. The only isolated products were the bisadducts 1 of two isobutyronitrile radicals... 

The generalization of these reactions to other captodative olefins was often successful from a preparative point of view, as demonstrated by the reported results on the addition of fBuO, MeCO [55], RS [54], and MeCONMe—CH2 [54] radicals to various captodative olefins (Table 3). Additions of (iV-methyl-iV-... 

However, a careful HPLC analysis of the mixture arising from the photo-stimulated reaction between a-methoxydeoxybenzoin and methyl ot-methoxy-acrylate at room temperature demonstrated that a considerable number of products are formed during this reaction [62]. Besides the expected products, some were found to result from the addition of a captodative (methoxy)-(methoxycarb-onyl)alkyl radical to the captodative olefin itself, i.e. a propagation step. The HPLC analysis was not quantitative, but the presence of these products even at high olefin/initiator ratio (2/1) implies that a propagation step cannot be ruled out for all the above experiments only on the basis of the isolation of low-molecular weight products in good yields. As we will show the polymerizability of captodative olefins is confirmed by an analysis of the literature. 

Experimental conditions are also a very important factor to consider reaction of a-methylthioacrylonitrile with AIBN was found to give either 69% of isolated low-molecular weight products [2] or 92% of polymer [67], depending on the conditions. The nature and concentration of the initiator also influence the polymerization. The rate of addition of the primary radical (initiator radical) to the captodative olefin is dependent on the nature of the initiator as observed by ESR [85]. Moreover termination by recombination of the persistent propagating radical with a primary radical becomes very important, as expected from the small molecule chemistry. Therefore the initiator influences both the initiation and termination. 

Work in the group of Speckamp has shown that C-Cl bonds in a captodative position are weak enough to lead to radical chain cyclization reactions by chlorine atom transfer [28], Chlorine atom transfer from 34 to the catalyst, Cu Cl-bipyridine, leads to radical 35 which then undergoes 5-exo intramolecular addition to form the proline derivative 36 (Eq. 1). The captodative substitution is necessary for this radical process in the absence of an electron-withdrawing substituent, a cationic reaction leading to a piperidine occurs instead [29]. 

Captodative alkenes 67 can be dialkylated, for example, by addition of iso-butyronitrile radical derived from thermal decomposition of AIBN under the same conditions as those which lead to polymerization of other acrylic alkenes. For example, a-morpholino-acrylonitrile (67, c = CN, d = N(CH2CH2)20) leads to 69, in 71% yield (Scheme 12) [4a]. With a-/-butylthio-acrylonitrile (67, c = CN, d = SC(CHj)3), the same process leads to 70 in 88% yield [7]. The adduct radical 68 is highly stabilized, and is in equilibrium with dimer 70. The reaction is quite general, and has been applied to other captodative alkenes (c = CN, COR, CO2R and d = NR2, OR, SR) together with various sorts of radical partners, derived from alkanes, alcohols, thiols, thioethers, amines, amides, ketones, aldehydes, acetals and thioacetals [44, 45]. 

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