Radical annulation

Smith and co-workers have recently expanded the scope of the [4+1] radical annulation reaction between isonitriles and 1-iodoalkynes to include vinylisonitriles <00JCS(P1)641>. Thus, vinylisonitrile 17 and iodide 18 afford annulated pyridine 19. 

A novel [3 + 2] radical annulation of o-cyano-substituted aryl radicals with alkynes has been reported. The reactions occur by addition of the aryl radical to the alkynes... 

Feldman239,240 and Oshima and Utimoto241 have introduced a very sophisticated sequence of reactions that effects a radical annulation starting from a vinylcyclopropane. Scheme 59 provides two examples and a likely mechanism for this sequence, which involves fragmentation, addition and cyclization. The... 

The field of macrocyclization reactions was recently augmented by the same group69 with an n + 1 radical annulation which results in the incorporation of a CO molecule in the macrocycle. Thus, in the presence of highly diluted (0.005-0.01 M) (TMS)3SiH, -iodoacrylates underwent efficient three-step radical chain reaction to generate 10- to 17-membered macrocycles in 28-78% yields, respectively (equation 46). It has also been shown that (TMS SiFI mediates a 14-endo-trig macrocyclization in 55% yield as a key... 

Several reports appear in the more recent literature of syntheses using electrochemical or PIET oxidation of compounds containing >C=N— bonds. These fall into three categories based upon a mechanism or presumed mechanism Cycloadditions, nucleophilic attack on >C=N— + cation radicals and radical annulations. The latter will not be reviewed here179 as none of the annulations appears to involve >C=N— + cation radicals. It should be pointed out that it is by no means certain that the electronic structure of >C=N— + is that of a 7r-cation radical rather than of an iminium cation radical (Figure 5). As will be seen below, reactivity appears sometimes in one guise and sometimes in the other. 

The moderate yield may be due to the purification by reverse-phase chromatography, because 1 contains a tertiary amine. Preparation of other derivatives of 2 has shown that the radical annulation normally proceeds with 50-60 % yield and that many functional groups are tolerated (free alcohols, amines, esters, chlorides and terminal alkenes). Also (Me3Si)4Si may be a useful substitute for hexamethylditin, because tin residues are toxic and difficult to separate from the products. 

Srikrishna and co-workers have described cyclopentannulation of allyl alcohols by radical cyclizations as, protocols for the synthesis of sesquiterpenes. The total synthesis of 4-epibakkenolide-A 98 wherein two radical annulations were used for key carbon-carbon bond formations is illustrated [95CC469]. Radical cyclizations based on the 5-exo-dig pathway have been used as the key step in the total synthesis of sporothriolide and 4-epi-ethisolide [95TL2661] and in an approach to eriolanin skeleton [95TL2067],... 

Last and Hoffmann described 5-exo radical annulation reactions of cyclic p-bromo propargyl ethers or acetals 259 (X=CH2) and their benzo analogs catalyzed by 5 mol% 255 as an approach towards the total synthesis of aflatoxins and analogs (entry 3) [311]. The cyclizations gave the products 260 in 35-95% yield. 

Macrocyclization reactions resulting from an (n + l)-type radical annulation were further investigated105. An example of 13-membered ring formation is shown in equation 53. It is worth mentioning that these reactions need high dilution conditions. 

Three pyrido[3,2-e]-l,2,4-triazines (333a-c) were prepared from the imines (332a-c) via a free radical annulation reaction onto the nitrogen-nitrogen double bond of dead. For example, compound (333a) is obtained from imine (332a) in 47% yield. The mechanism by which this reaction takes place is shown in Scheme 21 <89CC7 57>. 

Further developments include for example identification and studies of the substance 109 as a cytotoxic agent <07BP610>, physical studies of, among other related compounds, the system 110 <07JPC(B)7488>, and investigations of 2,3-dihydrobenzo[Z>]selenophene-5-ol antioxidants <07JOC2583>. In addition, tetrahydroselenophenes have been isolated as products from radical annulation of alkyl pent-4-enyl selenides <07TL9077>. 

On the basis of preceding experience in the synthesis of methylenecyclopentanes, Curran discovered a cascade reaction proceeding via a 4 + 1 radical annulation mechanism that led to a new synthesis of cyclopenta-fused quinolines [60] (Scheme 16.15). 

Scheme 16.15 Curran radical annulation to cyclopenta [2,3-b]quinolines.

On the other hand, carbonylation via a one-electron reduction system by reducing metals can also lead to useful transformations [Scheme 4-33]. The first example in Scheme 4-34 shows that a zinc reduction system of pent-4-enyl iodide undergoes dual annulations, a [4-f1] radical annulation with CO and a [3-f2] anion annulation with alkenes, to give a bicyclo[3.3.0]octanol, in which four C-C bonds are produced [59]. An extension of the present strategy to the construction of bicyclo[3.2.1]octanol skeletons has also been successful with a system in which 6-endo cyclization is favored over 5-exo cyclization. In these two reactions three C-C bonds were created by radical reactions and one by anionic reaction. 

Addition of SO2 to the allenes 15 has been demonstrated to give the thiophene derivatives 16. The regio- and stereoselectivity of these reactions was corroborated by a computational study <05OL1565>. The formation of tetrahydrothiophene 1,1-dioxides has also been observed during radical annulations using SO2 as a radical acceptor/donor <05JOC10854>. 

A few radical annulation approaches to fused indoles have been reported. 2-Indolylacyl radicals generated from selenoesters provided ellipticine quinones <05JOC9077>. A radical cyclization of haloacetamide derivatives was applied to the preparation of indolo[2,l-rf][l,5]benzodiazocines <05T941> and indolo[3,2-d][l]benzazepin-6-ones <05T5489>. 3,3-... 

A similar iruns stereoselectivity is observed in the radical annulation of cyclic a-iodoanrides derived from norephedrine73 and the reductive cyclization of l-trichloroacctyl-2-vinylpyrro-lidine"4. 

Cyclopentyl radicals annulated to cyclohexyl rings yield somewhat lower selectivities28, ... 

Recently, Saicic and coworkers [16] extended this methodology in combination with a radical annulation sequence. Photolysis of the esters 49 in the presence of dimethyl acetylenedicarboxylate generated the bicyclo[3.1.0]hex-2-enes 50. Inter-molecular addition of the initial radical to the acetylenedicarboxylate followed by 5-exo trig cyclization of the resulting acyclic radical 51 led to the radical 52, which on... 

In conclusion, it is now possible to assemble highly functionalized linear triquinanes from acyclic precursors with high diastereocontrol. The sequence mixing intramolecular cyclizations and a [3-f2] radical annulation appears as the strategy of choice. To probe its versatility, this strategy will have to materialize into total syntheses of natural products. 

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