Cyclizable radical probe

Three main sources of information are available for solving the ET versus 8 2 problem, namely, comparative kinetic studies, stereochemistry and cyclizable radical-probe experiments. 

The reaction of bornyl and isobornyl bromides with the nucleophile (Scheme 18) is another case where the amount of inversion is small and the rate constant close to that observed with an aromatic anion radical of the same standard potential (Daasbjerg et al., 1989) it can therefore be rationalized along the same lines. Cyclizable radical-probe experiments carried out with the same nucleophile and 6-bromo-6-methyl-1-heptene, a radical clock presumably slower than the preceding one, showed no cyclized coupling product. It should be noted, on the other hand, that, unlike the case... 

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... 

Furthermore, the reaction of a primary alkyl iodide having a cyclizable radical probe with MeySnNa did not occur exclusively by Sn2 and HME pathways, as previously... 

Figure 4.3. Design of a radical probe mechanistic study. Formation of the rearranged product implicates the intermediate 5-hexenyl radical that cyclized to cyclopentylmethyl.

In a more recent study Co(dppe)I2 was used as a catalyst for reductive additions of primary, secondary, and tertiary alkyl bromides or iodides 249 to alkyl acrylates, acrylonitrile, methyl vinyl ketone, or vinylsulfone 248 in an acetonitrile/water mixture using zinc as a stoichiometric reducing agent [305]. The yields of the resulting esters 252 were mostly good. The authors tested radical probes, such as cyclopropylmethyl bromide or 6-bromo-1-hexene (cf. Part 1, Fig. 8). However, the latter did not cyclize, but isomerized during addition, while the former afforded complicated mixtures. On this basis the authors proposed a traditional two-electron mechanism to be operative the results do not, however, exclude a radical-based Co(I) catalytic cycle convincingly (Fig. 61). 

Inspired by Nature, hydroxocobalamine 247 (X=OH) itself or modified vitamin B12 derivatives (review [331]) were probed as catalysts for radical cyclizations. This methodology is mediated by light and electrochemical or chemical reduction to close the catalytic cycle. It was applied to total syntheses of forskolin 280 by Pattenden [325] (Fig. 67, entry 13) as well as of jasmonate 284 and prostaglandin precursors 287 by Scheffold (entry 14) [326, 327], Starting materials were bromoacetaldehyde cyclohexenyl or cyclopentenyl acetals 278, 281, or 285, which cyclized in the presence of 247 to annulated butyrolactols 279, 283, or 287. In the forskolin synthesis the cyclized radical was reduced directly, while a radical addition ensued in the presence of acetoxyacrylonitrile 282 or ynone 286 in... 

Similar cyclizations of 234c bearing substituents at the alkene terminus catalyzed by 10 mol% of (CuOTf)2 C6H6 resulted in contrast in 30-95% yield of 2-alkenylpyrrolidines [327]. Ligand transfer is less favored under these conditions, so that SET oxidation of the cyclized radical by coformed Cu(II) and subsequent deprotonation prevailed. 6-exo Cyclizations were also probed. 

Not only radical scavengers, radical reduction and/or radical dimerization products but also radical probes were used in order to prove the presence of radicals as intermediates along the S l propagation cycle. Thus the formation of cyclized and uncyclized substitution products was taken as an indication of radical intermediates in the reaction of neopentyl-type halides containing a cyclizable probe of the 5-hexenyl type 2. These reactions were performed with PhS and Ph2P ions as nucleophiles (equation 13)52. 

In order to determine the degree of competition between both processes, the photo -stimulated reaction of the radical probe 3-bromo-2-tetrahydropyranyl allyl ether (83) with Ph2P ions in liquid ammonia was studied. In this reaction both the substitution 84 (20% yield) and the cyclized 85 (69% yield) substitution products were formed (equation 67)54,151. 

Radical probes 92a and 92b react with PhS and Ph2P ions in liquid ammonia or DMSO, to give uncyclized 93 and cyclized 94 substitution products (equation 71)52. 

The generation of amidyl radicals from N-allylsulfonamides and their subsequent cyclization was probed by Moutrille and Zard [130]. This strategy allowed the preparation of lactams such as 140 by treatment of acylsulfon-amide 138 with lauryl peroxide and a xanthate in DCE (Scheme 44). However, when the stability of the generated amidyl radical (as with 137) was not high enough, the extrusion of sulfur dioxide turned to be too slow, and premature cyclization of the N-amidosulfonyl radical intermediate took place, leading to 139. 

Indeed, radical probe studies have very decisively excluded the radical cyclization mechanism in at least one typical case. This experiment relies upon the circumstance that the cyclization of a carbon-centered radical to an aldehyde carbon group is known to occur at approximately the same rate as the exo-trig cyclization of such a radical to a carbon-carbon double bond. In a probe molecule designed to provide an opportunity for a hypothetical radical intermediate to add to either or both of these functionalities, no addition to the vinyl double bond was observed (Scheme 75). 

Likewise, no isomerization (cyclization) was observed when 5-hexenylmagnesium bromide, a well-studied radical probe, was reacted with benzophenone. The authors concluded that this indicates that either the reaction is polar or, if SET, no free radical character is exhibited. ... 

Newer developments in the study of the reactions of benzophenone with Grignard reagents have been the use of radical probes. If the alkyl of the reagent has the ability to undergo isomerization as, for example, cyclization or cia-inms isomerization, while it exists as a free radical, it is possible to get information about the nitc of recombination of alkyl and kclyl in the formation of the various reaction products.. S-Hexenylmagnesium bromide has been used in the study of the free radical type mechanism by its reactions with oxygen and the rate of cyclization of the, S-hexenyi radical was known to he 10 s. ... 

These results provide the first detailed calibration for a series of intramolecular radical cation probes based on cycloaddition chemistry. The cyclization rate constants cover several orders of magnitude in timescale, an ideal case for using 1—3 as probes for radical cations of different lifetimes. However, the time-resolved experiments demonstrate that the application of radical cation probes, at least those based on aryl alkene cycloaddition chemistry, may be considerably less straightforward than similar experiments with free radical probes or clocks. Some of the problems that need to be addressed include the variation of products with the reaction conditions and method of radical cation generation, and the possibility of reversibility of the initial adduct formation. Furthermore, at least some radical cation reactions are quite sensitive to solvent and this may mean that calibrations for radical cation cycloadditions will have to be done in a variety of solvents. 

It must be emphasized that isomerization of a probe can be taken as positive evidence for a radical intermediate in a substitution reaction, but failure to observe cyclization with such a probe does not rule out a radical intermediate. For example, reaction of 6-bromo-l-hexene with NaSN(CH3)3 in THF was found not to produce cyclized product. CycHzed product was observed when the same reaction was carried out in 1 1 THF-pentane, however. ° These results suggested that cyclization of the radical probe occurs outside the solvent cage in which it is formed and that a lower viscosity solvent allows more radicals to diffuse from the radical cage so that cyclization can occur. 

The electron-transfer formulation in equation (23) was further substantiated by Ashby et al.49 by using cyclizable probes for the detection of alkyl radicals from the mesolytic scission of RMgX+ (Scheme 10). 

In an extensive investigation of the stereochemical memory effect, a series of six diastereomeric pairs of substrates was prepared to probe the effect of single, then multiple substituents on the 5-exo cyclization of amines onto alkene radical cations [144,145]. Overall, these cyclizations were highly dia-stereoselective and were accounted for by a transition-state model employing a chairlike transition state with attack of the nucleophilic amine on the opposite face of the alkene radical to the one shielded by the phosphate anion in the initial contact ion pair (Scheme 34), as exemplified in Schemes 35 and 36. 

Rate constants for reactions of Bu3SnH with some a-substituted carbon-centered radicals have been determined. These values were obtained by initially calibrating a substituted radical clock on an absolute kinetic scale and then using the clock in competition kinetic studies with Bu3SnH. Radical clocks 24 and 25 were calibrated by kinetic ESR spectroscopy,88 whereas rate constants for clocks 26-31 were measured directly by LFP.19,89 90 For one case, reaction of Bu3SnH with radical 29, a rate constant was measured directly by LFP using the cyclization of 29 as the probe reaction.19... 

Analogous transformations have been initiated using alternative methods. Tributyltin hydride and sodium naphthalenide [101], for example, were examined in an effort to probe the possible intermediacy of a radical or carbanion, respectively. The results were compared with those achieved electrochemically. As illustrated, the results were different for each set of reagents, though the sodium naphthalenide and electrochemical results are most similar. This information has b n used to suggest that a carbanion is formed electrochemically and participates in the cyclization event. 

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