Cyclization, radicals compounds

An improved synthesis of 3,4-dihydro-2,l-benzothiazine 2,2-dioxide was reported by Togo and co-workers using photochemical conditions . Treatment of A-alkyl 2-(aryl)ethanesulfonamides 18 with (diacetoxyiodo)arenes under irradiation with a tungsten lamp at 20-30 °C afforded 2,1-benzothiazines 19 and 20. Chemical yields and selectivities were dependent upon the choice of solvents and the reactant s substituents 18 (Table 1). When THF and EtOH were used as solvents, the reactions failed to give the cyclized products, since their a-hydrogen was abstracted by the intermediate sulfonamidyl radical. Compound 20 was obtained as a major product when 1,2-dichloroethane was employed as a solvent. In contrast, in the case of EtOAc as solvent, compound 19 was obtained as the major product. 

Ames and Opalko have developed a palladium-catalysed cyclization of compound 24 to afford compound 25 in 56% yield (Scheme 5) <84T1919>. Glover and co-workers published a study involving the synthesis and photolysis of A-halogenobiphenyl-2-sulfonamides (26a or 26b) <86JCS(P2)645>. The photolysis of compound 26a or compound 26b in benzene formed an intermediate A-methylbiphenyl-2-sulfonamidyl radical, which resulted in compound 27a or 27b in 21% or 50% yield, respectively. In this procedure, the reaction only afforded the six-membered ring product 27(Scheme 6). 

An example of the influence of structure and geometry on radical cyclization is shown by the stereoselectivity of the 5-enJo-tng cyclization in compound 52 and 5-exo-trig cyclization in 53 using (TMS)3SiH as radical mediators [66]. In system52 a mixture of cA-fused and trans-imtd rings are obtained, whereas in system 53 the reaction proceeds in a stereoselective manner to give only the cw-fused product. 

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. 

Other methods for the preparation of selenium-containing molecules for radical reactions have been used as well. In Scheme 8 the radical cyclization of compound 44 to the tetrahydrofuran derivative 45 is shown as a crucial step in natural product syntheses. Mixed acetal can also be used for the generation of radicals. 1-Alkoxy and 1-aminoalkyl radicals can be generated from 0,Se- and N,Se-acetals in a direct way. The corresponding 0,Hal- or N,Hal-mixed acetals are instable and this approach is rarely used. But the selenium-containing mixed acetals can be isolated and purified and are excellent radical precursors.241 For example, acetals such as 139 can be converted into the mixed 0,Se-aeetals by reaction with diisobutylaluminum phenyl selenide. The mixed acetal 140 is then used under radical reaction conditions for the efficient formation of new carbon-carbon bonds (Scheme 36).242... 

A tandem carbonylation-cyclization radical process in heteroaromatic systems bearing electron-attracting substituents such as l-(2-iodoethyl)indoles and pyrroles 970 result in the formation of 2,3-dihydto-l//-pyrrolo[l,2- ]indol-1-ones and 2,3-dihydro-l//-pyrrolizin-l-ones 974 (Scheme 188). The AIBN-induced radical reaction of compounds 970 with Bu3SnH under pressure of CO suggests that the acyl radical 972, derived from radical 971 and CO, would undergo intramolecular addition to C-2 of heteroaromatic system, and the benzylic radical 973 so obtained, upon in situ oxidation would produce final product 974 <1999TL7153>. 

A frequently used indirect method involves cyclizable (cf. (7)) or other mechanistic probes which should provide evidence for free radical intermediates and thus for SET [19,37,59]. However, Newcomb and Curran have pointed out the pitfalls of such an approach especially if iodide precursors are used [17]. The supposedly radical-indicative reaction may come about albeit slower by a different, nonradical mechanism or the radical formation may occur via a secondary process which is not directly related to the first reaction step. A similar side-route can be made responsible for the appearance of stable radical compounds which may arise via a comproportionation reaction between non-reduced starting material and the doubly reduced species which can be formed from a hydro form (the normal product, Eq. (5)) and the usually strongly basic organometallic or hydridic reagents (Eq. (9)) [58]. The ability of strong bases to produce reduced radical species via complicated electron/proton transfer processes has been known for some time in the chemistry of quinones and quaternary salts [60,61]. 

Sultams can also be accessed by intramolecular cyclization of compounds containing preformed C-S-N-C-C fragments with a C-C bond formation as demonstrated in a one-pot synthesis of tricyclic sultam 236 <05SL577>. Tetrahydropyridine 235, obtained from 77,7/-bis(allyl)sulfonamide 234 by ring-closure-metathesis (RCM) followed by isomerization, undergoes radical cyclization in the presence of tris(trimethylsilyl)silane (TTMSS) to give tricycle sultam 236. 

Aromatic isonitriles, particularly orf/jo-alkenyl-substituted aryl isonitriles, were also successfully employed by Fukuyama in the synthesis of indole derivatives [19]. Cyclization of compounds 26 was accomplished with tin radicals, and 6-membered ring closure did not significantly compete except in one case (R = -Bu) where, on the other hand, this problem was interestingly alleviated by using the Z-alkene instead of the Z-analog (Scheme 11). 

For synthetic purposes cyclized radicals are preferentially trapped by chlorine [16], bromine [60], or iodine atom donors [54] to provide y9-functionalized tetrahy-drofurans, for instance halides 35-37 (Scheme 9), which serve as building blocks for subsequent ionic or free-radical reactions. This radical version of the classical halogen cyclization (Bartlett reaction [61]) is particularly useful if functionalized tetrahydrofurans can be obtained from terminal alkyl- or aryl-substituted alkenols. If these compounds are reacted for example with iodine or with A -bromosuccin-imide, tetrahydropyrans are formed from ionic cyclofunctionalizations [62], If, however, the corresponding alkenols are converted into a thiohydroxamic acid... 

The allene functionality is also useful in radical cyclizations. Radical precursor 867 (R=OH OAc SePh) is readily cyclized to a 5 1 mixture of 868 and 862 together with two other cyclic compounds. After separation of the desired product 868, the methyl group is oxidized to an alcohol and then acetylated. Finally, the carbonyl groups are reduced to give ( + )-heliotridine (850) [191]. 

The cyclization of an aryl radical is a useful process for the preparation of (hetero)cyclic compounds such as tetrahydrobenzofurans, chromanes, indanes, indolines and tetrahydroquinolines [147]. The synthetic strategy involves the generation of an aryl radical which subsequently adds to an unsaturated moiety, most usually in a 5-exo or a 6-exo trig process (Scheme 13.19). After ring closure, the intermediate cyclized radical 93 can either be reduced (pathway A) or it can react further with a nucleophile (SRNl-type process, pathway C) or with another radical acceptor to yield, after reduction, compounds of type 94 (pathway B). 

The photochemical behavior of o-allylanilines such as 88 has been studied. Such compounds cyclize to give the (Cy5) compounds, indolines (89) (Scheme 45). This result is clearly reminiscent of the photochemical behavior of o-allylphenols (Section VIII.3), and although the selectivity is the one expected from aminyl radical intramolecular addition, it also seems best explained by photochemical excitation of the n double bond. This is an interesting conclusion since metal-salt-induced cyclization of compounds such as 88 generally yields a mixture of (Cy5) and (Cy6) products. 

With nonstabilized carbon radicals, Dessy suggested in 1965 that when an organometallic and an acetylenic bond are put in rigid and close proximity to an aromatic substrate, ring closure to Cy5 (in the Cy5/Cy6 case) proceeds both by a carbanionic and a radical pathway. In a simpler case. Ward proposed that steric coercion is not a requirement and that, when treated with n-butyllithium, the acetylenic bromide corresponding to a CyS/Cy6 case 150 provided the cyclized (CyS) compound 151 (60%) as the major product, along with the coupling product 152 (20%) by a homolytic pathway (Scheme 68). ... 

Another polycyclization possibility has been described by Julia.In this case, an aromatic ring is attacked in the last step (Scheme 146). The radical 396 generated from the corresponding cyanoester by BP initiation in cyclohexane at 80°C gives the cyclized trans compound 398 (42% yield) in addition to the monocyclization product. Compound 399, when treated with BP in refluxing benzene, gives the trans compound 402 in 20% yield. ... 

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