Carbon-centered radicals alkenes

Carbon-centered radicals generated by Barton s thiohydroxamate method can also participate in ring-forming reactions (see Scheme 26).52b,s3 For example, irradiation of 129 results in the formation of compound 130 (82% yield). The outcome of this transformation is reminiscent of Stork s elegant radical cyclization/trapping processes (see Schemes 7 and 8), in that/botn alkene carbon atoms have become functionalized. / I... 

The Arrhenius frequency factors [log(T/M V)] for addition of carbon centered radicals to the unsubstiUited terminus of monosubslituted or 1,1-disubstituted olefins cover a limited range (6.0-9.0), depend primarily on the steric demand of the attacking radical and are generally unaffected by remote alkene substituents. Typical values of log(T/M" V) are ca 6.5 for tertiary polymeric (e.g. PMMA ), ca 7.0 for secondary polymeric (PS, PMA, and ca 7.5, 8.0 and 8.5 for small tertiary (e.g. /-C4H9 ), secondary (i-CiH ) and primary (CHj, CbHs ) radicals respectively (Section 4.5.4).4 For 1,2,2-trisubstituted alkenes the frequency factors arc about an order of magnitude lower.4 The trend in values is consistent with expectation based on Iheoretical calculations. 

The carbon-centered radical R, resulting from the initial atom (or group) removal by a silyl radical or by addition of a silyl radical to an unsaturated bond, can be designed to undergo a number of consecutive reactions prior to H-atom transfer. The key step in these consecutive reactions generally involves the intra-or inter-molecular addition of R to a multiple-bonded carbon acceptor. As an example, the propagation steps for the reductive alkylation of alkenes by (TMSfsSiH are shown in Scheme 6. 

Numerous reports published in recent years have focused on carbon-centered radicals derived from compounds with selected substitution patterns such as alkanes [40,43,47], halogenated alkanes [43,48,49,51-57], alkenes [19], benzene derivatives [43,47], ethers [51,58], aldehydes [48], amines [10,59], amino acids [23,60-67] etc. Particularly significant advances have been made in the theoretical treatment of radicals occurring in polymer chemistry and biological chemistry. The stabilization of radicals in all of these compounds is due to the interaction of the molecular orbital carrying the unpaired electron with energetically and spatially adjacent molecular orbitals, and four typical scenarios appear to cover all known cases [20]. 

Similar to the intramolecular addition of neutral carbon-centered radicals to alkenes, the formation of radical cations starting from alkenes with subsequent cyclization offers a convenient method for constructing carbocyclic ring systems. In contrast to the regioselective 1,5-ring closure (5-cxo-trig cyclization) of the... 

Cyclization of nitro-stabilized radicals provides another method for the generation of cyclic nitronates (221). Oxidation of the aci-foim of nitroalkanes with ceric ammonium nitrate generates the ot-carbon centered radical, which in the presence of an alkene, leads to the homologation of the a-radical. In the case of a tethered alkene of appropriate length, radical addition leads to a cyclic nitronate (Scheme 2.20). 

Additions. Homolytic bimolecular addition reactions of carbon-centered radicals to unsaturated groups have been studied in detail because these are the reactions of synthesis and polymerization. Within this group, radical additions to substituted alkenes are by far the best understood. An excellent compilation of rate constants for carbon radical additions to alkenes is recommended for many specihc kinetic values. ... 

H. Eischer and L. Radom, Factors controlling the addition of carbon-centered radicals to alkenes—an experimental and theoritical perspective, Angew. Chem., Int. Ed. Engl. 2001, 40, 1340 (rate constants for radical additions to alkenes). 

ADDITIONS OF CARBON-CENTERED RADICALS TO ALKENES AND ALKYNES 735... 

One of the mildest general techniques to extend a carbon chain entails the addition of a carbon-centered radical to an alkene or alkyne. The method for conducting these addition reactions often determines the types of precursors and acceptors that can be used and the types of products that are formed. In the following section, synthetically useful radical additions are grouped into chain and non-chain reactions and then further subdivided by the method of reaction. Short, independent sections that follow treat the addition of carbon-centered radicals to other multiple bonds and aromatic rings and the additions of hete-roatom-centered radicals. 

Most of the recent synthetic developments in the field of radical cyclization have involved the reactions of carbon-centered radicals with alkenes and alkynes. Other useful acceptors include allenes,31 dienes30 and vinyl epoxides.32 The same methods are used for cyclizations to these acceptors as for radical additions, and the preceding chapter should be consulted for specific details on an individual method (the organization of this section parallels that of Section 4.1.6). Selection of a particular method to conduct a proposed cyclization is based on a variety of criteria, including the availability of the requisite pre-... 

There has been considerable effort directed towards obtaining a fundamental understanding of the factors that govern the reactivities of carbon-centered radicals in bimolecular reactions, particularly with respect to their addition to alkenes [84]. From early liquid and gas phase studies, reactivity in such addition reactions was concluded to derive from a complex interplay of polar, steric, and bond-strength terms [85], which is much influenced by the nature and position of substituents on both the radical and the alkene. 

Additions of carbon-centered radicals to alkenes are generally strongly exothermic since a cr-bond is formed at the expense of a rr-bond (e. g., addition of methyl radical to styrene has a AH°= -38.5 kcal/mol). Thus, according to the Hammond... 

Not only alkenes and arenes but also other types of electron-rich compound can be oxidized by oxygen. Most organometallic reagents react with air, whereby either alkanes are formed by dimerization of the metal-bound alkyl groups (cuprates often react this way [80]) or peroxides or alcohols are formed [81, 82]. The alcohols result from disproportionation or reduction of the peroxides. Similarly, enolates, metalated nitriles, phenolates, enamines, and related compounds with nucleophilic carbon can react with oxygen by intermediate formation of carbon-centered radicals to yield dimers (Section 5.4.6 [83, 84]), peroxides, or alcohols. The oxidation of many organic compounds by air will, therefore, often proceed faster in the presence of bases (Scheme 3.21). 

Another method consists in generating an electrophilic carbon-centered radical (e.g. the CH3COCH2- radical from acetone, peroxydisulfate and Ag(I)) which, instead of reacting with the protonated heteroarene, readily adds to simple alkenes forming a radical adduct that, owing to its nucleophilic character, selectively reacts with the heterocyclic ring (Scheme 4) [2]. 

Alcohols are not only source of ketyl radicals generated by hydrogen abstraction from the a-C-H position (Eq. (7), Table 1). Oxidation of alcohols with Pb(OAc)4, PhI(OAc)2, and S2082 with Ag(I) as catalyst produces alkoxy radicals (RO-) which may further undergo /3-scission (Eq. 13), intramolecular hydrogen abstraction, or intra- and intermolecular addition to alkenes, generating a nucleophilic carbon-centered radical useful for heteroaromatic substitution (Scheme 6) [2]. 

Treatment of arenesulfinate salts with Cu2+, Mn3+, or Ce4+ generates arenesulfonyl radicals, via single electron oxidation. Thus, reaction of alkene (50) with p-TsNa in the presence of Cu(OAc)2 in AcOH gives p-tolyl allyl sulfone (51) through the addition of a toluenesulfonyl radical onto alkene, oxidation of the formed carbon-centered radical with Cu2+, and then deprotonation (eq. 4.20a). This reaction requires acidic conditions for effective oxidation with Cu2+ or Mn3+ [53-58]. Eq. 4.20b is the same addition... 

Ce4+ can be also used for the same type of reaction, since it is a strong one-electron oxidant. Generation of sp2 carbon-centered radicals such as aryl radicals, is not so easy, except for the reactions of aryl halides with Bu3SnH or Ph4Si2H2. However, treatment of arylhydrazines with Cu2+ generates aryl radicals through the initial oxidation to the arenediazonium ion with Cu2+, and subsequent SET from Cu+. Aryl radicals are much more reactive than alkyl radicals, and rapidly react with alkenes or imines as shown below (eq. 4.22) [60-63]. 

Radical stabilization energies for a wide variety of carbon-centered radicals have been calculated at G3(MP2)-RAD or better level. While the interpretation of these values as the result of substituent effects on radical stability is not without problems, the use of these values in rationalizing radical reactions is straight forward. This is not only true for reactions involving hydrogen atom transfer steps but also for other reactions involving typical elementary reactions such as the addition to alkene double bonds and thiocarbonyl compounds. 

The cyclisation presumably proceeds via carbon-centered radicals. Nevertheless, the termination step of the process is subject to water-dependent control, which is unusual in free-radical chemistry. Thus the reaction can be controlled to afford either exocyclic alkenes or the corresponding reduction products, simply by... 

Most studies involve reactions of carbon-centered radicals with alkenes and alkynes as radical traps. Heteroatom radical traps such as carbonyl groups, imines, and nitriles have received much less attention. Since radical reactions involving carbon-centered radicals and C=C bonds lead to the loss of the two participating functional groups, one of the advantages in radical reactions using heteroatom radical traps is to retain synthetically useful functionality for further manipulations. 

O-Stannyl ketyls have been proposed as intermediates for almost 30 years. Much of the early work came from the laboratories of Davies [9a], Pereyre [3, 9b, 9c] and Beckwith [6a, 10] and provided a framework for a modern understanding of O-stannyl ketyls. These seminal studies were often focussed on mechanistic aspects of tin ketyls in a-cyclopropyl- and a-epoxy-ketone ring openings. In one of the first carbonyl-alkene cyclizations, it was determined that the tributyltin radical added to a ketone in a somewhat sluggish manner and that excess amounts of tin hydride were needed to drive the reaction to completion [6a]. It was also understood that a ketyl radical anion is more stable than a simple carbon-centered radical, likely attributed to more effective delocalization. Ketyl reactive intermediates are now being utilized in new strained-ring cleavage-recyclization sequences (see below) and are... 

Annulation reactions are possible when a precursor monocyclic substrate contains an activated alkene in a tether [4a]. As demonstrated in Scheme 5, an ester was employed to activate the olefin appended to cycloalkanone 17. Upon generation of the 0-stannyl ketyl with tributyltin hydride, the carbon-centered radical attacks the electron-poor /(-position on the activated alkene. The corresponding cyclized adduct 18 is a bicyclic skeleton with a bridgehead hydroxyl group. An example of this reaction shows cyclopentanone 19 undergoing cyclization to diquinane 20 and tricycle 21 (76 24) in 69% yield. The presence of reasonable amounts of the minor, yet readily isolable, jn-diastereomers in the reaction indicated that the reaction may not be reversible. 

Despite their overall electtical neutrality, carbon-centered radicals can show pronounced electrophilic or nucleophilic character, depending on the substituents present. " This electrophilic or nucleophilic character is reflected in rates of reaction with nonradical species, for example, in additions to substituted alkenes. Alkyl radicals and a-alkoxyalkyl radicals are distinctly nucleophilic in character and react most rapidly with alkenes having EWG substituents. Even methyl radicals with a single EWG, such as t-butoxycarbonyl or cyano are weakly nucleophilic. Radicals having two EWGs, such as those derived from malonate esters, react preferentially with double bonds having ERG substituents. Perfluoro radicals are electiophilic and are about 10 more reactive than alkyl radicals. ... 

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