Radical cyclization, with alkynes

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. 

The synthesis of oxygen heterocycles in which cyclization onto a pendant alkyne is a key step has also been achieved. Reaction (7.36) shows an example of iodoacetal 29 cyclization at low temperature that afforded the expected furanic derivative in moderate Z selectivity [47]. A nice example of Lewis acid complexation which assists the radical cyclization is given by aluminium tris(2,6-diphenyl phenoxide) (ATPH) [48]. The (3-iodoether 30 can be com-plexed by 2 equiv of ATPH, which has a very important template effect, facilitating the subsequent radical intramolecular addition and orienting the (TMS)3SiH approach from one face. The result is the formation of cyclization products with Z selectivity and in quantitative yield (Reaction 7.37). 

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-... 

Each of the syntheses of seychellene summarized in Scheme 20 illustrates one of the two important methods for generating vinyl radicals. In the more common method, the cyclization of vinyl bromide (34) provides tricycle (35).93 Because of the strength of sjp- bonds to carbon, the only generally useful precursors of vinyl radicals in this standard tin hydride approach are bromides and iodides. Most vinyl radicals invert rapidly, and therefore the stereochemistry of the radical precursor is not important. The second method, illustrated by the conversion of (36) to (37),94 generates vinyl radicals by the addition of the tin radical to an alkyne.95-98 The overall transformation is a hydrostannylation, but a radical cyclization occurs between the addition of the stannyl radical and the hydrogen transfer. Concentration may be important in these reactions because direct hydrostannylation of die alkyne can compete with cyclization. Stork has demonstrated that the reversibility of the stannyl radical addition step confers great power on this method.93 For example, in the conversion of (38) to (39), the stannyl radical probably adds reversibly to all of the multiple bond sites. However, the radicals that are produced by additions to the alkene, or to the internal carbon of the alkyne, have no favorable cyclization pathways. Thus, all the product (39) derives from addition to the terminal alkyne carbon. Even when cyclic products might be derived from addition to the alkene, followed by cyclization to the alkyne, they often are not found because 0-stannyl alkyl radicals revert to alkenes so rapidly that they do not close. 

Benzylpalladation.11 Benzyl halides do not undergo usual radical cyclizations effected with organic halides, but do undergo Pd-catalyzed cyclization with alkenes and alkynes. A typical reaction is formulated in equation (I). The leaving group can also be Br, I, or OMs, but not OCOOCH3 or OCOCH3. Attempts to cyclize 1 with... 

Synthesis of 12- and 13-membered sulfur-containing lactones by homolytic macrocyclization of mercaptoacetic esters and alkynes has been investigated [95S307]. Reaction of the mercaptoester 245 with alkynes using triethyl borane radical initiation gave the macrolactones 247 and 248 in low yield [95TL2293], Remote asymmetric induction is observed during the cyclization. 

Evidence based on product mixtures now suggests, at least in the cases of a-halocarbonyl and perhaloalkyl starting marterials, that these reactions are in fact atom transfer radical cyclizations (equation 166)324,325. In them, the palladium catalyst is proposed to have roles both as the radical initiator and as a trap for iodine, similar to the more commonly used hexabutylditin. Intramolecular allyl halide-alkyne cyclizations proceed with trans-addition to the triple bond this is evidence that a still different mechanism may be operating in these cases (equation 167)1,326. 

There are also cases where addition of thiyi radicals to unsaturated carbon-carbon bonds is the crucial step for thiophene ring formation. Flash vacuum pyrolysis (FVP) of the phosphorus ylide 90 affords initially the alkyne 91, which produces thiyi radical with loss of methyl radical. Cyclization of the resulting radical affords thienothiophene 92 as the final product with loss of one more methyl radical (Scheme 20) <1995SL53>. FVP of ylide 93 results in a multistep cascade reaction leading to 7-(2-benzothienyl)benzofuran 94 (Scheme 21) <2001SL228>. 

Reaction of diazonium salt 654 with alkynes in the presence of FeS04 or TiCh gives 2-arylbenzothiophenes 655 in a single step. The reaction process involves aryl radical addition to the alkyne and cyclization followed by demethyla-tion <2000S970>. 

However, their intermolecular addition reactions with alkynes are mostly aimed at synthesizing substituted aLkenes, ° and only very few cascade reactions that are initiated by P radical addition to C = C triple bonds have been reported. Renaud and coworkers developed a simple one-pot procedure for the cyclization of terminal alkynes mediated by dialkyl phosphites (Scheme 2.35). In this radical chain procedure, dialkyl phosphite radicals, (R0)2P =0, undergo addition to the C = C triple bond in 190, which triggers a radical translocation (l,5-HAT)/5-eAO cyclization cascade. The sequence is terminated by hydrogen transfer from dialkyl phosphite to the intermediate 194 and regeneration of P-centered radicals. 

Kariv-Miller and coworkers have developed indirect electroreductive cyclizations with the dimethyl-pyrrolidinium ion (DMP") as a mediator. Preparative electrolysis of 6-hepten-2-one (9) at a graphite cathode afforded cu-dimethylcyclopentanol (10) in 90% yield (equation 5). The reduction is believed to occur via the ketyl radical anion, which cyclizes onto the alkenic bond. In the absence of DMP simple reduction to 6-hepten-2-ol takes place.Very recently it was shown that instead of DMP several aromatic hydrocarbons can be used as mediators to initiate the cyclization reaction. The carbonyl group can also be cyclized onto an alkynic bond and even an aromatic ring. - ... 

There is an inherent competition between simple reduction of the ketone and the reductive cyclization process with unsaturated carbonyl substrates. Cyclization processes that are slower than that of the ketyl-alkene cyclization forming a five-membered ring, suffer frtxn lower yields owing to this competition. For example, ketyl-alkyne coupling can also be achieved when mediated by Smb, but yields are lower than those achieved with analogous keto-alkenes (equation 68). This might have been expected on the basis that radical additions to alkynes are slower than corresponding additions to alkenes. Similarly, the rate... 

In a related approach, Murakami synthesized clavicipitic acid and costaclavine [79], and later extended this chemistry to a synthesis of chanoclavine-1 featuring the intramolecular Heck vinylation 251 to 252 [265]. The corresponding enone failed to cyclize under these conditions. Noteworthy is that radical cyclizations, which often compete successfully with Heck reactions, were poor in this system. Martin developed a novel route to the ergot skeleton that features a Heck cyclization of bromo alkyne 253 [266]. 

Most of the useful iodine transfer radical reactions arise from the addition of alkyl iodides, which have been activated by one or more adjacent carbonyl or nitrile substituents, to unactivated olefins. This both labilizes the initial iodide, facilitating chain initiation, and helps ensure that the atom transfer step is exothermic. The requisite iodides are typically synthesized by deprotonation with EDA or NaH, followed by iodination with I2 or A-iodosuccinimide. Cyclization of an iodoester yields primarily lactone product, proceeding through the intermediacy of the I-transfer products as shown in Scheme 5 [19]. Reactions in which a-iodoesters cyclized with alkynes also proved efficient. Similar ketones yielded less synthetically useful mixtures of cyclopentyl and cyclohexyl (arising from 6-endo transition states) products. 

It is worth noting that, unlike the analogous reactions with alkynes, all of these annulations involving the cyano group always led to a unique quinoxaline derivative, since the final iminyl radical cyclizes onto the aromatic ring of the isonitrile in an exclusive 1,6-fashion. 

Radicals interact with cyano groups in much the same way as they interact with alkynes when both groups are in the same molecule, this leads to cyclization. The cyclic radical 118 formed is unstable, and undergoes ring opening to give the rearranged radical, 119. The... 

Feldman and coworkers have generated radicals from vinylcyclopropanes in the presence of thiyl radicals and studied their reaction with alkynes to give vinylcyclopentenes. A general [3+2] annulation strategy considers vinylcyclopropanes 39 as the three atom components and alkynes 40 as the two atom counterparts (Scheme 14). The vinylcyclopentene products have been obtained as mixtures of syn- and a /-substituted stereoisomers the authors considered that product stereochemistry is set during the cyclization of the 5-hexadienyl radical 41 and derives from the two conformations (chair- or boat-like) in the transition state. 

Reactions with alkynes may lead to the formation of cyclized products. The reaction of iodobenzenes with two equivalents of an alkyne has been shown to give naphthalene derivatives in the presence of cobalt catalyst with a manganese reduc-tant. The process, shown in Scheme 15, is thought to involve oxidative addition of the aryliodide to cobalt followed by double alkyne insertion. The cobalt-catalysed annulation step probably involves an pathway. The cyclopentadienyl-rhodium-catalysed annulation of benzoic acids with alkynes has been used to form isocoumarin derivatives, such as (126). The process is thought to involve cyclorhodation at the ortho-position of a rhodium benzoate intermediate, followed by alkyne insertion to form a seven-membered rhodacycle and reductive elimination The silver-catalysed annulations of diphenylphosphine oxides with alkynes proceed in the absence of rhodium. Benzophosphole oxides such as (127), formed with diphenylethyne, are produced. Here, the proposed mechanism involves homolytic cleavage of the phosphorus-hydrogen bond to give a radical which can add to the alkyne and subsequently cyclize. ... 

After the report on the visible-light-induced [4-f2] benzannulation of biaryl-diazonium salts and alkynes [31], Zhou and coworkers [32] also demonstrated the radical cyclization of trifluoroacetimidoyl chlorides with alkynes, yielding various 2-trifluoromethyl quinolones (Scheme 13.15). It is worth noting that this is the first example where the activation of sp C-Cl bonds by a photoredox catalyst... 

In the total synthesis of the hesitine-type aconite alkaloid nominine, the C-ring was constructed by radical cyclization to form 118 from the enyne precursor 117. ° In the first step, the tin radical reacted with alkyne 117 to form a radical that underwent a 6-exo-trig radical cyclization. The resulting radical was trapped by BuaSnH to give a vinyl stannane, which afforded 117 after destannylation with SiOi (Scheme 25.56). 

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-... 

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