Alkynes radical cyclizations

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-... 

The (TMS)3Si radical addition to terminal alkenes or alkynes, followed by radical cyclization to oxime ethers, were also studied (Reaction 50). The radical reactions proceeded effectively by the use of triethylborane as a radical initiator to provide the functionalized pyrrolidines via a carbon-carbon bond-forming process. Yields of 79 and 63% are obtained for oxime ethers connected with an olefin or propargyl group, respectively. 

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. 

Methylenetetrahydrofurans can also be realized by an intramolecular radical cyclization of bromoalkynes utilizing indium(I) iodide as a radical initiator <06TL2859>. 3-Diiodomethylenetetrahydrofurans were also prepared from l,to-diiodo-l-alkynes in the presence of l-hexynyllithium<06CC638>. 

Skrydstrup, Beau and co-workers122 have adapted Stork s method to the SmI2-reduction of glycosyl pyridyl sulfones bearing a silicon-tethered unsaturated group at HO-C(2). An example is shown with the synthesis of methyl a-C-zso-maltoside 172 from alkyne 170 via the 5-exo-dig radical cyclization of 171 (Scheme 56).144... 

Allenyl ethers are useful key building blocks for the synthesis of a-methylene-y-butyrolactones [129, 130], The synthesis of the antileukemic botryodiplodin was accomplished with the crucial steps briefly presented in Scheme 8.56. Bromoallenyl ethers 225 were easily prepared by base-induced isomerization from the corresponding /3-bromoalkyl alkynyl ether compounds and then subjected to electrophilic bro-mination with NBS. The resulting acetals 226 were converted into 2-alkoxy-3-methy-lenetetrahydrofurans 227 by dehydrohalogenation of the alkenyl bromide unit to an alkyne and subsequent radical cyclization employing tributyltin hydride [130],... 

Chloropyridinecobaloxime(III) 279 also serves as a convenient source of nucleophilic cobalt, and as a means of promoting radical cyclizations [77]. For example, its reduction in the presence of a bromoalkyne such as 280 leads to the formation of a radical 281 which closes onto the alkyne, leading eventually to the ,Z-alkenes 283 and 284 in an 81% yield. Cyclizations of this type are obviously complementary to those effected using tributyltin hydride. 

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). 

A radical cyclization has been achieved from a 1,3-dioxolanyl-thiocarbonate containing an alkyne group in an appropriate position (Equation 49) <2003TA2961>. The stereocontrol between cis- and trans-ivscd tricycles was 1.5-4.2 1. The products were similar to those depicted in Equation (36). 

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. 

Radical cyclizations to carbon-nitrogen multiple bonds resemble additions to carbon-carbon multiple bonds in that they usually give products of irreversible exo cyclization. To date, the most useful acceptors have been oximes189 and nitriles,190 and one example of each type of cyclization is given in Scheme 45.191 Nitriles are useful because the intermediate imines are readily hydrolyzed by mild acid to ketones. Although this route to ketones is shorter than the two-step sequence of alkyne cyclization/ozo-nolysis, nitriles are slightly poorer acceptors than terminal alkynes, and much poorer acceptors than activated alkynes. Thus, when slow cyclizations are involved, the two-step protocol is preferable. 

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... 

Samarium(H) diiodide mediated ketyl radical addition to alkyne results in the formation of an alkene after radical cyclization [95SL277]. Compound 65, a product from one such reaction, has been converted to the carbohydrate portion of miharamycin A, a nucleoside antibiotic. 

An asymmetric synthesis of novel tin functionalized carbopenem system through radical cyclization of an enyne has been reported [95TA1055]. Treatment of the p-lactam 171 with tributyltin hydride resulted in the addition of tin radical to the alkyne followed by 5-exo cyclization to provide 172 in 80% yield. The product was obtained as a 88 12 mixture of... 

Intramolecular radical cyclization of an aryl bromide and an alkyne can be used to produce dihydroquinolines (Equation 57) <1998TL2965>. An analogous reaction setup utilizes a Lewis acid-catalyzed novel one-pot domino pathway using silver catalysis in high regioselectivity (Scheme 26) <2005OL2675>. Three mole equivalents of the alkyne are used with the final cyclization step arising from alkynic addition. 

Michael addition of pentM-yn-1-thiol to an activated alkyne produces co-yne vinylsulfides 424 as a separable mixture of the E and Z isomers. On treatment with -Uu (SnI I and a radical initiator, these substrates undergo a double radical cyclization accompanied by [(-fragmentation of the stannyl radical. The process is regio-, chemo-, and stereo-selective and produces the -isomer of the 5-substituted 3,4-dihydm-2//-thiopyran (Scheme 134) <1997JOC8630>. 

The major problem with using Wilkinson s catalyst is that it also constitutes an excellent hydrogenation catalyst [56]. Thus, alkynes and terminal alkenes are not tolerated under the conditions of the coupled catalytic cycles. This implies that radical cyclizations terminated by a CHAT cannot be carried out under these conditions. 

Triethylborane can also initiate radical cyclization of unsaturated alkynes to vinylstannanes. 

Recently, most radical cyclizations of halides have been performed using iodides with intramolecular alkene or alkyne functionality. As with chain elongation reactions, both chain and nonchain processes are possible, with the former being the most common. The nonchain processes are not covered here and the reader is referred to the excellent reviews in the literature for details. 

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. 

The radical intermediates from Cr(II) reduction of alkyl halides can in principle be used synthetically, but have only seen limited attention to this point. co-Haloalkynes (bromides, iodides), in the presence of excess Cr(C104)2, undergo cyclization reactions to form exo-alkylidene cycloalkanes (equation 176)347. These reactions proceed by the radical cyclization of intermediate 42 onto the alkyne unit, which undergoes subsequent reduction by Cr(II) to give a hydrolytically unstable vinylchromium(III). Rings of four, five and six members can be formed. Alternatively, a-iodo esters undergo intramolecular atom transfer radical cyclizations onto alkynes or alkenes with catalytic or stoichiometric amounts of... 

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>. 

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