Mechanism, radical cyclization

This process, called Ruzicka cyclization, is good for the preparation of rings of six and seven members and, with lower yields, of Cg and Cio to C30 cyclic ketones. Not much work has been done on the mechanism of this reaction. However, a free-radical mechanism has been suggested on the basis of a thorough study of all the side products. ° ... 

A moderate diastereoselectivity was observed in these reactions where a mixture of diastereomers could be generated.58 The reactivity of the halides followed the order of tertiary > secondary primary and iodide> bromide (chlorides did not react). The preferred solvent system was aqueous ethanol. The process was suggested to proceed by a free radical mechanism occurring on the metal surface under sonochemical conditions. Efforts to trap the intermediate [A] intramolecularly gave only a very low yield of the cyclization product (Scheme 10.4).59... 

Cyclizable radical-probe experiments have been extensively used in ET versus Spj2 investigations (see Ashby, 1988, and references cited therein). Attention has, however, been recently drawn to causes of possible misinterpretation, particularly in the case of iodides, where an iodine-atom-transfer chain mechanism is able to convert most of the starting linear iodide into the cyclized iodide, even if only a minute amount of linear-chain radical is present in 7-8 2 reactions (Newcomb and Curran, 1988). Rather puzzling results were found in the reaction of (CH3)3Sn ions with secondary bromides, which should not be involved in atom-exchange chain reactions... 

The stepwise dehydrocyclization of hydrocarbons with quaternary carbon atoms over chromia was interpreted by Pines 94). Here a skeletal isomerization step prior to cyclization was assumed. This is not of a cationic type reaction, and the results were explained by a free radical mechanism accompanied by vinyl migration (Scheme IXA). Attention is drawn to the fact that... 

This section is devoted to cyclizations and cycloadditions of ion-radicals. It is common knowledge that cyclization is an intramolecular reaction in which one new bond is generated. Cycloaddition consists of the generation of two new bonds and can proceed either intra- or intermolecularly. For instance, the transformation of 1,5-hexadiene cation-radical into 1,4-cyclohexadienyl cation-radical (Guo et al. 1988) is a cyclization reaction, whereas Diels-Alder reaction is a cycloaddition reaction. In line with the consideration within this book, ring closure reactions are divided according to their cation- or anion-radical mechanisms. 

Another cyclization thought to proceed via a free radical mechanism was the aromatization of 174 to produce phenazine 175 along with varying amounts of ketones 176 <99JHC1057>. It was noted that each product could be selectively formed depending on the nitrogen substituents. 

A reaction by Clough et al. comes close to the direct synthesis shown in Scheme 1 (89TL7469). Here amides (62) react in a radical mechanism to 4-methylene compounds (63) that with 03/PPh3 are converted to tetramic acids (64). (See Fig. 29.) Several authors, however, prepared esters of 4-amino-3-oxo-butanoic acid, which served as precursors for intramolecular cyclization to tetramic acids (82JHC883). Koehler and Gerlach in an initial stage of a synthesis of dysidine, contained in marine sponge... 

The aliphatic alicyclic hydrocarbon precursor is not well recognized as the major aliphatic component in dissolved humic substances, although it was previously postulated to occur (II). This precursor might arise from terpenoid hydrocarbon lipids, but the data presented in this chapter favor polyunsaturated lipid precursors that are oxidatively coupled and cyclized by free-radical mechanisms (20). Degradative studies have not identified this aliphatic component in recognizable fragments. The quantitative, structural-model approach presented here combines the results of 13C NMR, NMR,... 

The highly strained double bond in methylenecyclopropane displays enhanced reactivity in cycloaddition reactions. In addition to normal [4+2] cycloaddition to 1,3-dienes (e.g. equation 13)32, methylenecyclopropane and its derivatives have a pronounced tendency to undergo thermal [2+2] cycloaddition reactions. For example, thermal dimerization of methylenecyclopropane in the gas phase results in formation of isomeric dispirooctanes 16 and 17 (equation 14)33. This unusual cyclization is considered to proceed via a stepwise radical mechanism involving the intermediacy of biradical 18 (equation 15)34. Equation 15 demonstrates that methylenecyclopropanes possessing substituents capable of stabilizing intermediate radicals undergo efficient [2+2] dimerization even... 

For H-acid catalysis stereospecifity is lowered and appears to be the same as in the reactions initiated with trifluroacetic acid instead of the ammoniumyl salt. For the cation-radical mechanism the sterically hindered base 2,6-bis(tert-butyl)pyridine does not inhibit the cyclization triarylamine retards this reaction photosensibilized one-electron oxidation of a diene leads to the same products, which are formed in the presence of the ammoniumyl salt. As shown, in the majority of cases only the cation radical chain mechanism of the diene-diene cyclization is feasible (Bauld, Bellville, Harirchian 1987). Meanwhile, cyclodimerizations of 2,4-dimethylpenta-1,3-diene (Gassman Singleton 1984) and 1,4-dimethylcyclohexa-1,3- or -1,4-diene (Davies et al. 1985) proceed through both mechanisms. 

The free-radical mechanism frequently leads to long primary chains. Extensive cyclization reactions in these primary chains lead to the appearance of a distribution of microgels, each one composed of one or more primary chains (Sun et al., 1997 see Chapter 8). This may lead to different concentrations of monomers and initiator molecules inside and outside the microgels. This partition effect implies that elementary steps may occur with a different rate in both regions. 

The Re(III) complex Re(PPh3)2(MeCN)Cl3 (2 mol%) catalyzes the ATRA of tetrachloromethane or bromotrichloromethane to terminal alkenes in 39-76% yield [303]. p-Pinene suffered a cyclobutylcarbinyl radical ring opening, thus supporting the free radical mechanism. With l, -dienes double addition was found, while 1,3-dienes gave the 1,4-addition product. Internal alkenes were almost inert under the reaction conditions. 1,6-Dienes 158 underwent a tandem radical addition/ cyclization reaction to cycles 159 in 64—87% yield with 3-6 1 c/s-diastereos-electivity (cf. Fig 43). This compares well to the results obtained with the most frequently used catalyst Ru(PPh3)3Cl2 (see Part 2, Sects. 3.3.1 and 3.3.2). 

Intramolecular cyclizations have been used to prepare a variety of ring sizes. Carbon-carbon bond formation resulting in oxindole formation has been done in this manner by intramolecular reaction of A-acyl-o-chloroanilines (equation 85)571,572. A similar process has been used to prepare isoquinolinones571,573,574. Cephalotaxinone, an intermediate in the synthesis of the anti-leukaemia agent cephalotoxin, has been prepared by reaction of a complex enone iodide with base (equation 86)575. This reaction may occur via a radical mechanism and it has been used to prepare larger rings in reasonable yields540. 

A mild and novel reaction route to 2,1-benzisoxazoles from 2-nitrobenzalde-hydes in the presence of allyl bromide and zinc dust has been established [449], The reductive cyclization of 2,6-dinitrobenzaldehyde was strongly retarded probably because of the inhibitory effect of the second nitro group [441, 449], The authors assume a radical mechanism of the reaction, as demonstrated in Scheme 2.69 [449],... 

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