Dienes radical cyclization

Gomez, A.M., L6pez, J.C., Fraser-Reid, B. (1994) Serial Radical Cyclization ofPyranose-Derived Dienes in the StereocontroUed Synthesis of Densely Functionalized Cyclohexanes. A Route to Woodward s Reserpine Precursor. Journal of Organic Chemistry, 59, 4048M 050. 

Further variations of the general scenario described in Scheme 4 consist in trapping adduct radical 48 before oxidation occurs7. This can be achieved if intramolecular radical additions are possible, as is the case in radical 62. Oxidation of 62 to the corresponding allyl cation is slower than 6-ew-cyclization to the chlorobenzene ring to form radical 63, which subsequently is oxidized to yield tetrahydronaphthalene 64 as the main product (equation 27). This sequence does not work well for other dienes such as 2,3-dimethyl-1,3-butadiene, for which oxidation of the intermediate allyl radical is too rapid to allow radical cyclization onto the aromatic TT-system. 

A new entry to exocyclic dienes was reported by Sha who uncovered that a radical cyclization of the vinyl iodide 100 can lead to the formation of an exocyclic dienes fused with a tetrahydrofuran ring. The cyclization is proposed to proceed in a 5-(n-exo)-exo-dig fashion <00OL2011>. 3,4-Disubstituted tetrahydrofurans can also be constructed via the cyclization of O-stannyl ketyls and allylic 0-stannyI ketyls onto electron-rich or electron-poor alkenes <00TL8941>. 

The aryl radical cyclization has been successfully used for the preparation of substituted dihydrobenzo[Z)]indoline derivatives [59], An example is shown in Reaction (7.49). The diene 42 was preliminarly subjected to ring-closure metathesis using Grubbs catalyst and then treated with (TMS)3SiH and EtsB at -20 °C, in the presence of air, to provide the compound 43 with an excellent diastereoselectivity. 

Turning from the intramolecular process to the intermolecular ones, we now extend our comparison of the thermal and cation-radical cyclizations. It is also interesting to take sonication into account as a route to initiate cyclizations. The reaction between 2-butenal A,A-dimethylhydrazone (a diene) and 5-hydroxy-l,4-naphthoquinone (a dienophile) gives such an opportunity. In toluene, at 20°C, the reaction follows as depicted in Scheme 7.28 (Nebois et al. 1996). 

Among these are the factors controlling the regiochemistry of the reaction, the employed diene compounds, and the possible intramolecular cyclization of various alk-4-enol and ene-diene radical cations (Scheme 49) [70-72], Also, by changing the nucleophile from the generally used methanol to, for instance, acetonitrile can yield photo-NOCAS products in good yields [73,74],... 

The combination of allylic amination, ring-closing metathesis, and a free radical cyclization provides a convenient approach to the dihydrobenzo[b]indoline skeleton, as illustrated in Scheme 10.10. The rhodium-catalyzed aUylic amination of 43 with the lithium anion of 2-iodo-(N-4-methoxybenzenesulfonyl)arrihne furnished the corresponding N-(arylsulfonyl)aniline 44. The diene 44 was then subjected to ring-closing metathesis and subsequently treated with tris(trimethylsilyl)silane and triethylborane to afford the dihydrobenzojhjindole derivative 46a in 85% yield [14, 43]. 

Intramolecular radical addition to vinylsilane moiety has been used for the synthesis of statine 148 (equation 124)216 and the pyrrolizidine skeleton217. Tandem [2+1] radical cyclization of bromides 149 with BusSnH is extremely sensitive to the nature of the substituent on the diene moiety. Bicyclo[3.1.0] skeleton 150 is obtained in the presence of the silyl substituent (equation 125). When the silyl substituent in 149 is replaced by a t-butyl group, the six-membered ring product 151 is obtained exclusively218. 

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. 

It is very important to consider trienes of the general formula MeCH=CH— CH=CH—CH2—CH2—CH2—CH=CHR. Such trienes contain moieties of both the diene and dienophile types in the framework of the same molecule. Upon initiation by the Ar3N+ cation radical, cyclization takes place. Tetrahydroindanes are formed. The trienes of R = PhS, / -MeOC6H4CH2, and H have been studied. The third triene, R = H, contains the dienophile fragment of lowered oxidizability it is not cyclized at all. The diene synthesis proceeds in the cases of the first two trienes only (Harirchian Bauld 1987) (Scheme 6-19). 

Fraser-Reid s stereocontrolled synthesis of the Woodward reserpine precursor 195 relied upon a tandem 5-exol6-exo radical cyclization of pyranose-derived dienes [76-77]. As outlined in Scheme 36, a,P-unsaturated ester 188 was prepared by free radical coupling of iodide 187 with a tin acrylate. After hydrolysis of 188 (MeONa, MeOH, 100%) to give primary alcohol 189, the silicon tethered diene 190 was installed by silylation. Treatment of 190 with n-BujSnH led to the desired cage molecule 192 in high yield via a 5-exo-trig cyclization to intermediate 191 followed by a 6-exo cyclization. Tamao oxidation of tricycle 192 led to diol... 

Scheme 36. A tandem 5-exo/6-exo radical cyclization of a pyronose-derived diene...

Vitamin E is effective as an antioxidant in arachidonate autoxidation, trapping the kinetic peroxyl radical product before cyclization can occur. Adding vitamin E in arachidonate autoxidation results in reducing radical cyclization products and forming the kinetic product distribution, six simple trans, cis diene hydroperoxides. 

Free radical cyclization of 1,6-diene (120) using diethyl phosphite or diphenylpho-sphine oxide initiated by peroxide, produces an organophosphorus compound (121) via the addition of a phosphonyl radical to an olefinic group (eq. 4.42a). Radical addition of PH3 to limonene (122) results in the formation of 4,8-dimethyl-2-phosphabicyclo[3.3.1]-nonane (123) (eq. 4.42b) [121, 122]. 

Fig. 16 Oxygenative radical cyclizations of dienes catalyzed by (phthalocyanine)iron complex 71...

Allenic hydrocarbons, including cyclic ones, underwent chlorine addition under radical conditions only one double bond reacted [12], A number of conjugated dienes added chlorine in their reaction with (dichloroiodo)benzene under radical conditions. Both 1,2- and 1,4-addition occurred their ratios varied, depending on the substitution of the non-cyclic substrate and the size of the cyclic ones trans products were normally favoured [13]. 1,6-Dienes were cyclized to 1,2-bis chloromethyl cyclopentanes [14] ... 

Stereoselective radical cyclization of 1,5-cyclooctadienes. Winkler and Sridar14 have noted transannular effects on the stereochemistry of cyclization of these octadienes (equation I). Thus radical cyclization of cis-1 and of the corresponding ketone (3) is highly frans-selective and is more rrans-selective than that of the monosubstituted diene 5. Cyclization of a 3,8-disubstituted cyclooctene is... 

A radical diphosphanylation of alkynes using tetraorganodiphosphanes as precursors for phosphanyl radicals has been applied to the synthesis of a doubly phosphinated diene 200 (Scheme 2.37)7 Tetraphenyldiphosphane was generated in situ from diphenylphosphane with an excess of chlorodiphenylphosphane in the presence of triethylamine. Addition of the phosphanyl radical to one C = C triple bond in the dialkyne 199 leads to vinyl radical 201, which undergoes a 5-exo cyclization (out of a Z-configured vinyl radical to minimize sterical hindrance in the cyclization) to give vinyl radical intermediate 202. The latter is trapped by a second phosphine moiety in a radical substitution step. The radical cyclization product is ultimately isolated as bis-phosphane sulfide 200 after treatment of the intermediate phosphane 203 with sulfur. 

Harrowven [33] has reported two methods for carrying out the radical cyclization reactions of dienes attached to a Wang polystyrene support. Treatment of solid-supported diene 195 with either thiophenol or p-tolylbenzeneselenosulfonate, in the presence of AIBN, triggers 5-exo-trig... 

In addition to cationic cyclizations, other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol. For example, treatment of (259) and (260) with Mn(III) and Cu(II) afford the D-homo-5a-androstane-3-ones (261) and (262), respectively, in approximately 30% yield. In this cyclization, seven asymmetric centers are established in one chemical step (226,227). Another intramolecular cyclization reaction of iodo-ene poly-ynes was reported using a carbopaUadation cascade terminated by carbonylation. This carbometalation—carbonylation cascade using CO at 111 kPa (1.1 atm) at 70°C converted an acycHc iodo—tetra-yne (263) to a D-homo-steroid nucleus (264) [162878-44-6] in approximately 80% yield in one chemical step (228). Intramolecular aimulations between two alkynes and a chromium or tungsten carbene complex have been examined for the formation of a variety of different fiised-ring systems. A tandem Diels-Alder—two-alkyne annulation of a triynylcarbene complex demonstrated the feasibiHty of this strategy for the synthesis of steroid nuclei. Complex (265) was prepared in two steps from commercially available materials. Treatment of (265) with Danishefsky s diene in CH CN at room temperature under an atmosphere of carbon monoxide (101.3 kPa = 1 atm), followed by heating the reaction mixture to 110°C, provided (266) in 62% yield (TBS = tert — butyldimethylsilyl). In a second experiment, a sequential Diels-Alder—two-alkyne annulation of triynylcarbene complex (267) afforded a nonaromatic steroid nucleus (269) in approximately 50% overall yield from the acycHc precursors (229). 

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