Intermolecular radical addition

The hexabutyldistannane used in this reaction is not involved in the propagation sequence but may be involved in initiation or scavenging of potential chain-termination radicals. Intermolecular additions of alkyl radicals to alkynes have also been observed. 

Intramolecular eyclization is subject to the same factors as intermolecular addition (see 2.3). However, stereoelectronic factors achieve greater significance because the relative positions of the radical and double bond are constrained by being part of the one molecule (see 2.3.4) and can lead to head addition being the preferred pathway for the intramolecular step. 

As with carbocation-initiated polyene cyclizations, radical cyclizations can proceed through several successive steps if the steric and electronic properties of the reactant provide potential reaction sites. Cyclization may be followed by a second intramolecular step or by an intermolecular addition or alkylation. Intermediate radicals can be constructed so that hydrogen atom transfer can occur as part of the overall process. For example, 2-bromohexenes having radical stabilizing substituents at C(6) can undergo cyclization after a hydrogen atom transfer step.348... 

A rather new concept in the context of domino radical cydizations has been developed by Gansauer and coworkers utilizing titanocene-complexes for the radical opening of unsaturated epoxides. The titanocene-catalyzed reactions [61] of 3-145 primarily led to radical 3-146, which underwent a subsequent intermolecular addition to a present a,(3-unsaturated carbonyl compound to form bicyclic carbocy-cles of type 3-148 via the intermediate 3-147 after aqueous work-up (Scheme 3.38) [62]. From a kinetic point of view, the reaction is remarkable since the intermolecular addition of simple radicals to a,(3-unsaturated carbonyl compounds is not an easy task, as highlighted above. 

Recently, Narasaka and co-workers have found that 1-nitroalkyl radicals are generated by oxidation of aci-nitroanions with CAN, and they undergo the intermolecular addition to electron-rich olefins.61 For example, when oxidation is carried out in the presence of silylenol ethers, (3-nitroketones are formed in good yield. (3-Nitroketones are readily converted into enones on treatment with base (see Section 7.3), as shown in Eq. 5.43. 

Curran2 has reviewed recent applications of the tin hydride method for initiation of radical chain reactions in organic synthesis (191 references). The review covers intermolecular additions of radicals to alkenes (Giese reaction) as well as intramolecular radical cyclizations, including use of vinyl radical cyclization. 

All the examples presented under Sect. 4.1 used an iodine atom transfer to generate the desired radicals. Another approach involving abstraction of hydrogen atom is also reported. For instance, ethers and acetals undergo direct intermolecular addition to aldehydes under treatment with Et3B/air... 

The endo-mode of cyclization is found to be the preferred path also in the lower homologues. Reaction (6.2) shows the reactions of two silanes (8) with thermally generated t-BuO radicals to afford the five-membered ring in low yields via a 5-endo-trig cyclization [1], EPR spectra recorded from these two silanes with photogenerated t-BuO radicals are assigned to secondary alkyl radical intermediates formed by an intermolecular addition involving the expected silyl radical and the parent silane [2],... 

Investigations conducted by the same group using laser flash photolysis techniques elucidated details of the PET-reductive activation of selenosilanes and the application of this chemistry to a bimolecular group-transfer radical reaction and intermolecular radical chain-transfer addition [59], Based on this new concept, a catalytic procedure utilizing PhSeSiRs for radical reactions such as cycliza-tion, intermolecular addition and tandem anellation was designed (Scheme 39) [60],... 

Intermolecular addition of radicals, generated by photo-electrochemical catalysis, to activated alkenes can also be brought about. The reaction of 66 is used as a key step in one synthesis of the insect pheromone, brevicomin [219]. The reaction of a secondary radical from 67 occurs at low cathode potentials and without photochemical assistance [219]. This illustrates the equiibrium between a secondary al-kylcobalt(m) species and the radical - cobalt(ii) pair. The carbon radical is eventually captured by reaction with the alkene. Further steps in the synthesis lead to four isomers of the pheromone, multistriatin, each of which is a pure enantiomer since... 

C-Glycoside synthesis via the intermolecular addition of anomeric radicals to activated alkenes has been pioneered by Giese and co-workers [120]. A wide variety of acceptors have been used in this area and both simple [131,132] and more complex (a C-disaccharide 290) [133] examples are shown (Scheme 77). 

From our discussion of intermolecular additions, we would not expect these cyclizations of carbon radicals to occur in the elimination direction, and indeed cyclic radicals in five-membered or larger rings do not ordinarily open according to Equation 9.115. If the ring is small or highly strained, on the other hand,... 

Redox and homolytic substitution reactions almost never directly form C—C, C—N and C—O bonds. Such bonds are generated in radical addition reactions (Scheme 14). Intermolecular addition reactions are presented in this chapter. Cyclization reactions have important similarities with, and differences from, bimolecular additions, and they are presented in Chapter 4.2 of this volume. Falling under the umbrella of addition reactions are radical eliminations (the reverse of addition) and radical migrations (which are usually, but not always, comprised of an addition and an elimination). 

The intermediate a-heterosubstituted carbon radicals generated by reaction of (TMS)3Si radical with 1,3-dithiane28, or A-(ethoxycarbonyl)- , 3-thiazolidinc76 derivatives, can participate in consecutive intramolecular C—C bond formation reactions in the presence of proximate 1,2-disubstituted double bonds (equation 51). In the presence of terminal double bonds or in an attempted intermolecular addition of the intermediate... 

Kinetics is used to investigate mechanisms of radical additions to alkenes. Outside the solvent cage, the initiator-derived radicals may undergo the desired bimolecular reaction with the substrate, or side reactions. When the substrate is an alkene, the exothermic intermolecular addition of the reactive radical (R ) to the double bond results in the formation of two new single carbon-carbon bonds in place of the double bond. This reaction represents conversion of an initiator into a propagating radical in radical polymerisations, and is becoming increasingly important in a number of synthetically useful intermolecular small molecule reactions. The addition of R to monosubstituted and 1,1-disubstituted alkenes is nearly always at the unsubstituted carbon atom (tail addition), and thus is normally not affected by the individual steric demand of the alkene substituents. Equation 10.4 is the expression for the rate of addition (R ) of R to an alkene where [M] is the monomeric alkene concentration ... 

The electronic nature of a nitrogen centered radical, dictated by reaction conditions and/or the radical precursor employed, is crucial to the mode of reaction, to the ability to undergo efficient intramolecular cyclizations or intermolecular additions, and to the products isolated from the radical reaction. The types of radicals discussed in this review include neutral aminyl radicals, protonated aminyl radicals (aminium cation radicals), metal complexed aminyl radicals, and amidyl radicals. Sulfonamidyl and urethanyl radicals are known (71S1 78T3241), but they are not within the scope of this chapter. 

Intermolecular addition and addition-cyclization reactions of aminium cation radicals with electron-rich alkenes such as ethyl vinyl ether (EVE) allow an entry into products containing the N—C—C—O moiety of 13-amino ethers 70 or the equivalent of /3-amino aldehydes 71. The mild conditions under which aminium cation radicals are generated from PTOC carbamates makes the reactions described in Scheme 22 possible. In the absence of hydrogen atom donors, the /3-amino ethoxy(2-pyridylthio) acetal 71 was the major product. The mixed acetal can easily be converted... 

The PTOC protocol for the preparation of nitrogen centered radicals is also compatible with a variety of Lewis acids that apparently complex with the aminyl radicals to give reactive, electrophilic species. Lewis acids offer potentially milder reaction conditions than protic acids for sensitive compounds. Efficient intermolecular addition reactions have... 

Analogous results obtain in intermolecular addition of alkyl radicals to unsaturated amides. Thus addition of n-hexyl radical to the unsaturated amide 4 derived from (S,S)-1 results in four products, two by addition a to the ketone and two by addition a to the amide enol. The former products are formed with slight selectivity, (60 40), but the latter products (5) are formed in ratio of 93 7.3... 

Intermolecular addition of C-, S-, or / -centered radicals to the exocyclic unsaturated C-C bond of 2,6-anhydro-hept-l-enitols leads to anomeric radicals that, after subsequent hydrogen quenching, can produce C-glycosyl compounds or... 

The intermolecular addition of an alkyl radical to an enaminoketone in a 6-exo-trig mode has been investigated [95TL417]. Reductive cyclization of 212 provides a diastereomeric mixture of 213 in excellent yield. Compound 213 has been transformed to the piperidine alkaloid dihydropinidine 214. 

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]. 

The benzyl anion generated from benzyl chloride gave a low yield of phenyl-acetic acid 305). The radical anion dimer of benzalacetone 75 reacts simultaneously by intramolecular addition to the carbonyl group and intermolecular addition to C02 to the cyclopentane derivative 76 306 (Eq. (135) ). 

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