Vinylic radical, alkyne reduction

The key features of the catalytic cycle are trapping of the radical generated after cycliza-tion by an a,P-unsaturated carbonyl compound, reduction of the enol radical to give an enolate, and subsequent protonation of the titanocene alkoxide and enolate. The diaster-eoselectivity observed is essentially the same as that achieved in the simple cyclization reaction. An important point is that the tandem reactions can be carried out with alkynes as radical acceptors. The trapping of the formed vinyl radical with unsaturated carbonyl compounds occurs with very high stereoselectivity, as shown in Scheme 12.21. 

Vinyl radicals also add to carbon-carbon double bonds intramolecularly to give 2,6-cw-disubstituted cyclic ethers (Equation (5)).41 In the tin hydride-mediated cyclization of the substrates including alkynes, alkyl radicals attack to carbon-carbon triple bonds leading to uco-alkylidene allylic alcohols (Equation (6)).42 The coupling reaction between alkyl radicals may afford cyclization products. Thus, the reduction of 1,3-diiodopropane derivatives with a tin hydride provides substituted cyclopropanes.4... 

Bachi and Bosch used Sn radicals as mediator for the cyclization of the p-lactam-substimted alkynes 119 through a sequence consisting of radical addition and 1,5-HAT, followed by a 6-endo cyclization of the radical intermediate 122, to give the bicyclic p-lactam 120 after p-fragmentation and release of Bu3Sn radicals (Scheme 2.22). The moderately low yield of this cyclization is due to the competing fast reduction of the vinyl radical 121 to the corresponding alkene by the tin hydride (not shown). 

One of the earliest radical cyclization cascades initiated by addition of S-centered radicals to alkynes was reported in 1987 by Broka and Reichert (Scheme 2.25). Thiophenyl radicals, PhS, which were generated under radical chain conditions, undergo addition to the terminal end of the C = C triple bond in enyne 138. The resulting vinyl radical 141 can undergo cychzation in both 6-endo (preferred) and 5-exo fashion, and reduction of the radical intermediates 142 and 143 leads to the final observed products 139 and 140, respectively. 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

The stereochemistry of the vinyl sulfone does not matter because it is immediately reduced by an electron from sodium to give a vinyl radical. Much as you saw above, in the Birch reduction of alkynes, the vinyl radical collects a second electron and becomes a vinyl anion, which chooses to adopt the more stable configuration before being protonated to give the predominantly alkene. 

The preference of the tin radical for the olefin can be due to the low solubility of oxygen in organic solvents. The oxygen concentration is probably kept to a constant and sufficient level by the improved contact between the gas and the sonicated solution (nebulization effect). The carbon radical which reacts with oxygen gives a peroxyl radical. From alkynes, the vinyl radical formed by addition of the trialkyltin group is more reactive towards the tin hydride, and preferential reduction occurs without any hydroxystannylation. 

The two hydrogen atoms add to the opposite faces of the alkene (i.e. anti-addition) using sodium in liquid ammonia. This dissolving metal reduction produces a solvated electron, which adds to the alkyne to produce a radical anion (bearing a negative charge and an unpaired electron). The bulky R groups in the radical anion, vinyl radical and subsequently in the vinyl anion lie as far apart as possible to avoid steric strain. 

The mechanism for this reduction, shown in the preceding box, involves successive electron transfers from lithium (or sodium) atoms and proton transfers from amines (or ammonia). In the first step, a lithium atom transfers an electron to the alkyne to produce an intermediate that bears a negative charge and has an unpaired electron, called a radical anion. In the second step, an amine transfers a proton to produce a vinylic radical. Then, transfer of another electron gives a vinylic anion. It is this step that determines the stereochemistry of the reaction. The trawi-vinylic anion is formed preferentially because it is more stable the bulky alkyl groups are farther apart. Protonation of the trani-vinylic anion leads to the trans-alkene. 

After the dealkoxyhalogenation, the mechanism of the Sml2-mediated cyclization of the intermediate aldehyde is shown in Scheme 3.32. The process is probably initiated by a single electron reduction of the aldehyde to form a ketyl radical, followed by an exo-cyclization onto the double bond. The resulting primary radical undergoes cyclization onto the tethered alkyne and the highly reactive vinyl radical that results is quenched by abstraction of a hydrogen atom from the solvent [68]. 

Reductive termination of the reaction sequence by hydrogen abstraction is occasionally the desired reaction. This is particularly important in converting vinyl radicals (obtained from addition to alkynes) to alkenes because vinyl radicals are not oxidized to vinyl cations. The hydrogen can come from the solvent or from the R-hydrogen of another molecule of the 3-dicarbonyl compound. Ethanol is... 

In an effort to identify a more stereoselective route to dihydroagarofuran (15), trimethylsilylated alkyne 17 was utilized as a substrate for radical cyclization (Scheme 2). Treatment of 17 with a catalytic amount of AIBN and tri-n-butyltin hydride (1.25 equiv) furnishes a mixture of stereoisomeric vinyl silanes 18 (72% combined yield) along with an uncyclized reduction product (13% yield). The production of stereoisomeric vinyl silanes in this cyclization is inconsequential because both are converted to the same alkene 19 upon protodesiiyiation. Finally, a diastereoselective di-imide reduction of the double bond in 19 furnishes dihydroagaro-... 

Iron porphyrins containing vinyl ligands have also been prepared by hydromet-allation of alkynes with Fe(TPP)CI and NaBH4 in toluene/methanol. Reactions with hex-2-yne and hex-3-yne are shown in Scheme 4. with the former giving two isomers. Insertion of an alkyne into an Fe(III) hydride intermediate, Fe(TPP)H, formed from Fe(TPP)Cl with NaBH4, has been proposed for these reactions. " In superficially similar chemistry, Fe(TPP)CI (present in 10 mol%) catalyzes the reduction of alkenes and alkynes with 200 mol% NaBH4 in anaerobic benzene/ethanol. For example, styrene is reduced to 2,3-diphenylbutane and ethylbenzene. Addition of a radical trap decreases the yield of the coupled product, 2,3-diphenylbutane. Both Fe(lll) and Fe(II) alkyls, Fe(TPP)CH(Me)Ph and [Fe(TPP)CH(Me)Ph] , were propo.sed as intermediates, but were not observed directly. ... 

Clive and coworkers have developed a new domino radical cyclization, by making use of a silicon radical as an intermediate to prepare silicon-containing bicyclic or polycyclic compounds such as 3-271 and 3-272 (Scheme 3.69) [109], After formation of the first radical 3-267 from 3-266, a 5-exo-dig cyclization takes place followed by an intramolecular 1,5-transfer of hydrogen from silicon to carbon, providing a silicon-centered radical 3-269 via 3-268. Once formed, this has the option to undergo another cyclization to afford the radical 3-270, which can yield a stable product either by a reductive interception with the present organotin hydride species to obtain compounds of type 3-271. On the other hand, when the terminal alkyne carries a trimethylstannyl group, expulsion of a trimethylstannyl radical takes place to afford vinyl silanes such as 3-272. 

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