Radical cyclization, with

Radical cyclizations of tetrahydropyridine scaffolds have been used to access diverse skeletal frameworks.An example of tandem radical cyclizations with two C-C bond formation is shown in Reaction (82). Treatment... 

Radical cyclization is compatible with the presence of other functional groups. Treatment of XCH2CON(R)-C(R )=CH2 derivatives (X = Cl, Br, 1) with Ph3SnH and AIBN led to formation of a lactam via radical cyclization. " Cyclization of N-iodoethyl-5-vinyl-2-pyrrolidinone led to the corresponding bicyclic lactam, " and there are other examples of radical cyclization with molecules containing a lactam unit " or an amide unit. Radical cyclization occurs with enamines as well. Photochemical irradiation of A,A-dialIyl acrylamide leads to formation of a lactam ring, and in this case thiophenol was added to generate the phenylthio derivative. Phenylseleno N-allylamines lead to cyclic amines. co-Iodo acrylate esters cyclize to form lactones. " ... 

The rare [1,4] hydrogen transfer has been observed in radical cyclizations. With respect to [1,7] hydrogen shifts, the rules predict the thermal reaction to be antarafacial. Unlike the case of [1,3] shifts, the transition state is not too greatly strained, and such rearrangements have been reported, for example,... 

This strategy was later refined by Stork and co-workers142 who used silicon (e.g. 164) as the tethering atom [Scheme 55a)]. The latter strategy was adapted by Sinay and co-workers143 for the synthesis of C-disaccharides (e.g. 169) by employing 8- and 9-endo radical cyclizations with the readily prepared silaketal connectors [Scheme 55b)]. 

In the gluco case (Scheme 13) the radical cyclization, with its requirement for the formation of a czs-fused ring junction [129,130], takes place uneventfully on the opposite face of the alkene radical cation to the one shielded by the phosphate anion, whereas in the manno series cyclization is severely retarded by the presence of the phosphate group above the face of the radical cation on which cyclization must occur. This steric retardation of the cyclization step results in a breakdown of chain propagation and results in the longer reaction times observed. Furthermore, the retardation of the radical cyclization step in the manno case enables the alkene radical cation to take... 

The photolysis of donor-acceptor systems provides unique synthetic opportunities. Direct irradiation of the donor-acceptor systems, such as systems containing arene and amine components, leads to intramolecular electron transfer, that is, to amine cation-radical and arene anion-radical moieties. After generation, these moieties undergo cyclization reactions providing efficient synthetic routes to fV-heterocycles with a variety of ring sizes. Thus, direct irradiation of secondary amino-ethyl and aminopropyl stilbenes leads to benzazepines in improved yields (Hintz et al. 1996). As known, benzazepines are used in medicine as antidepressants. Scheme 7.44 illustrates ion-radical cyclization with the formation of benzazepine derivative (65% yield). 

A high degree of stereoselectivity was achieved in reductive radical cyclizations with Coordination of the oxime function (e.g. 108) with samarium cation seems to play an important role, since the identical reaction with a tributyltin hydride/radical initiator system produces poor stereoselectivity (equation 79). ... 

In practice, Jasperse has developed a synthesis of modhephene that is a variant of strategy A (Scheme 22).78 Modhephene can be prepared from the enone (6). In turn, enone (6) is prepared by two separate radical cyclizations with complete control of regio- and stereo-chemistry. The vinylstannane serves as the synthetic equivalent of a double radical acceptor site ( / ) The whole synthetic route can be conceptualized in one simple diagram as shown in Scheme 23. Below the diagram, each synthon is associated with the actual starting material that was used to accomplish the required transformation in the synthesis. 

The following introduction will briefly recount some of the key features of radical cyclizations with an emphasis on basic concepts that control regio- and stereo-selectivity. More details will be provided in the following sections, which describe specific types of reactions. The factors affecting the cyclization reactions to carbon-heteroatom multiple bonds are treated separately in Section 4.2.5, and the cyclizations of heteroatom-centered radicals are contained in Section 4.2.4. 

Polar cyclization of diene hydroperoxide 304 has been successfully effected by Hg(NC>3 )2 to produce a 2 1 mixture of 1,2-dioxolane 305 and 1,2-dioxane 306. In contrast, a radical cyclization with (Bu CX)(. ())2 and O2 or /V-iodosuccinirnidc, respectively, is more selective giving only one 1,2-dioxane425. 

Scheme 27.6-exo-trig Radical cyclization with excellent 1,2-asymmetric induction... 

Radical cyclization with iodine atom transfer of a highly functionalized propiolic ester 103 using dibenzoyl peroxide as an initiator gave the a-methylene-y-butyrolactone 104 in good yield [95T11257]. The relative stereochemistry at carbon atoms 4 and 5 are established during the reaction. The intermediate 104 has been converted to the anti-tumor agent (-)-methylenolactocin 105. 

Fused tetracyclic biaryl-2-azetidinones have been prepared by the radical cyclization of aryl /3-lactam-tethered haloarenes. Azetidin-2-one 504, having an extra radical acceptor on C-3, underwent radical cyclization with tributyltin hydride to give the biaryl-2-azetidinone 505 in a low yield, with debrominated 3-phcnoxyA-phcnyl-l -(/ -methoxy-phenyl)-2-azetidinone as the main product (60% yield) (Equation 82). But when the azetidinones 506 (Rz = R6 = H) bearing an extra link (O) on the radical precursor at C-3 or N-l of the /3-lactam ring were treated with tributyltin hydride, the expected cyclization products 507 were obtained. If azetidinones 506 (Rz = OMe, or Me R6 = H, OMe, or Me) were treated in the same way then the tetracyclic azetidinones 508 were produced (Equation 83) <2005T7894>. 

A radical cyclization controlled by sulfur yields the tetrahydroisoquinoline (Equation 49) <1997J(P1)2291>. In the absence of the sulfur groups, only the reduced product is isolated. Further reactions that utilize radical cyclizations with vinylsulfides show a cascade reaction eventually forming the benzo[ ]quinolizine system <1999TL1149> (Equation 50). 

Eq. 3.6 shows the direct preparation of furan derivative (19) by the successive treatment of vinyl ethers with propargyl alcohol/NBS, radical cyclization with Bu3SnH/AIBN, and lastly, aromatization with p-TsOH. 

Fig. 25 Titanium-catalyzed radical cyclization with catalyst regeneration by homolytic substitution (only major diastereomer shown)...

Acylation of isoquinolines. A mixture of an isoquinoline and Bu,SnH reacts at — 78° with a 3-halopropionyl chloride in CH,C12 to give N-acyl-l,2-dihydroiso-quinolines in 80-95% yield (cf., 13, 10). These can undergo radical cyclization with BujSnH/AIBN to furnish benzoindolizidin-3-ones. 

Methylating only one phenol on each ring of norreticuline leaves the other one free for radical coupling. Reticuline is oxidized in the plant to isoboldine by a radical cyclization with the formation of a new C-C bond. 

Transition state for radical cyclization with alkene. 

A tandem aldol condensation-radical cyclization sequence has been developed for the preparation of functionalized bicyclo[3.3.0]octane systems [116]. Conjugate addition of Me2AlSePh to dimethylcyclopentanone (118) followed by trapping of the resulting enolate with aldehyde gave predominantly the trans, erythro aldol 119 this then underwent radical cyclization with BusSnH and catalytic AIBN yielding the bicyclic ketol 120 stereospecifically (Sch. 80). 

Enholm, E J, Cottone, J S, Allais, F, Highly diastereoselective 5-hexenyl radical cyclizations with Lewis acids and carbohydrate scaffolds, Org. Lett., 3, 145-147, 2001. 

Reductive cyclizations. Substituted pyrrolidines and piperidines are obtained by the Ti(Il)-mediated cyclization of enyne carbonates. 5-Ketoesters and ketonitriles undergo radical cyclization with CpjTiPh which is obtained as a dark green solution by sequential treatment of Cp TiClj with i-PrMgCl and PhMgBr. 

Eliminations. Specially designed sulfones undergo elimination which is initiated by a remote radical. The alkyl moiety is converted to an alkene. The core of the squalene synthase inhibitor CP-225917 has been synthesized via a radical cyclization with ejection of an allylic phenylthio group. The radical precursor is an a-bromoacetic ester. 

Cobalt-catalyzed Aryl Radical Cyclizations with Grignard Reagent... 

---