Cyclization, 5-hexenyl radical intermediate

As described in section 3.1, when a radical cyclization reaction involves the 5-hexenyl radical intermediate, the 6-endo-trig radical cyclization will prevail when the usually favoTed 5-exo-trig regioselectivity is suppressed by substitution at the 5-position. Such a tactic was... 

In contrast to the large body of data pertaining the 5-exo and 6-exo cyclization modes, the 6-endo-trig mode has limited applications. This is simply because the 5-exo-trig cyclization is kinetically favored for S-hexenyl radical intermediates. Nevertheless, when the usually favored 5-exo-trig regioselectivity is surpressed by a substituent (e.g. bromine or ethyl) at the 5-position, the 6-endo-trig cyclization mode prevails. 

Fig. 1.42. Cyclization of a 5-hexenyl radical intermediate from a Barton-McCombie defunctionalization as a method for cyclopentane annulation (cyclizing defunctionalization, in terms of Figure 1.2 this means a "substitution including a fragmentation and an addition ).

Fig. 1.35. Cyclization of a 5-hexenyl radical intermediate from a Barton-McCombie defunctionalization as a method for cyclopentane annulation.

The first example of a cyclization of fluorine-containing 5-hexenyl radicals was the study of the radical-iniOated cyclodimenzation reaction of 3,3,4,4-tetra-fluoro-4-iodo-1-butene. In this reaction, the intermediate free radical adds either to more of the butene or to an added unsaturated species [54, 55] (equation 56). Electron-deficient alkenes are not as effective trapping agents as electron-nch alkenes and alkynes [55]. 

One experimental test for the involvement of radical intermediates is to study 5-hexenyl systems and look for the characteristic cyclization to cyclopentane derivatives (see Part A, Section 11.2.3). When 5-hexenyl bromide or iodide reacts with LiAlH4, no cyclization products are observed. However, the more hindered 2,2-dimethyl-5-hexenyl iodide gives mainly cyclic product.164... 

One of the fundamental questions about the mechanism is whether the radical is really free in the sense of diffusing from the metal surface.7 For alkyl halides, there is considerable evidence that the radicals behave similarly to alkyl free radicals.8 One test for the involvement of radical intermediates is to determine whether cyclization occurs in the 6-hexenyl system, where radical cyclization is rapid (see Part A, Section 12.2.2). 

Small amounts of cyclized products are obtained after the preparation of Grignard reagents from 5-hexenyl bromide.9 This indicates that cyclization of the intermediate radical competes to a small extent with combination of the radical with the metal. Quantitative kinetic models that compare competing processes are consistent with diffusion of the radicals from the surface.10 Alkyl radicals can be trapped with high efficiency by the nitroxide radical TMPO.11 Nevertheless, there remains disagreement about the extent to which the radicals diffuse away from the metal surface.12... 

Photoinduced electron transfer promoted cyclization reactions of a-silyl-methyl amines have been described by two groups. The group of Pandey cyclized amines of type 135 obtaining pyrrolidines and piperidines 139 in high yields [148]. The cyclization of the a-silylated amine 140 leads to a 1 1 mixture of the isomers 141 and 142 [149]. The absence of diastereoselectivity in comparison to analogous 3-substituted-5-hexenyl radical carbocyclization stereochemistry [9] supports the notion that a reaction pathway via a free radical is unlikely in this photocyclization. The proposed mechanism involves delocalized a-silylmethyl amine radical cations as reactive intermediates. For stereochemical purposes, Pandey has investigated the cyclization reaction of 143, yielding... 

One experimental test for the involvement of radical intermediates is to study 5-hexenyl systems and look for the characteristic cyclization to cyclopentane derivatives (see Section... 

As with any intermediate, a transient radical can be implicated from products formed in a reaction specific to the radical of interest. Experimentally, this is the basis of so-called mechanistic probe studies. An application of this method might employ, for example, 6-bromo-l-hexene as a probe for a radical intermediate as shown in Figure 4.3. If the 5-hexenyl radical is formed as a transient with an adequate lifetime, then cyclization of this radical to the cyclopentyhnethyl radical could eventually give the cyclic product, and detection of the cyclic product provides evidence that a radical was formed. The mechanistic probe approach is deceptively simple, however. To be useful, one must exclude other possibilities for formation of the rearranged product and demonstrate that the transient was formed in the reaction of interest and not in a side reaction. The latter is especially difficult to demonstrate, and, unfortunately, some mechanistic probe studies that seemingly provided proof of radical intermediates were later found to be complicated by radical-forming side reactions. 

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.

The behavior of the S-hexenyl radical merits special attention not only because it is one of the best understood reactive intermediates in organic chemistry, but also because it is a representative parent of a larger class of cyclizations. Because it is a cyclization of intermediate rate, it provides a convenient (if arbitrary) dividing point for synthetic planning cyclizations that are more rapid than that of the hexenyl radical are easily conducted, but those that are significantly slower may present experimental difficulties. 

The use of this chemistry in a reductive cyclization (eq. 4.7) also proved successful. The key step in this reaction is the cyclization of the intermediate A5-hexenyl radical 5 (eq. 4.8). 

A particularly stable ketyl radical is derived from benzophenone (cf. Figure 17.52). This is why additions of the Grignard reagents R2Mg2Hal2 to this substrate proceed more frequently via radicals as intermediates than others. An example in which the occurrence of such a radical intermediate is documented by the typical radical cyclization 5-hexenyl —> cyclopentyl-carbinyl (cf. Section 1.10.2) is the following ... 

Key-step in the mechanistic scenario is a primary electron transfer process involving a sacrificial electron donor as exemplary shown for the triphenylphosphine case in Sch. 28. The 9,10-dicyanoanthracene radical anion (DCA -) thus generated undergoes a secondary thermal electron transfer to the unsaturated ketone. The resulting carbon-centered radical or radical anionic intermediate, subsequently cyclizes stereoselectively with a proximate olefin. The observed 1,2- 77 -stereochemistry of the C-C bond formation step contrasts with the commonly observed -stereoselectivity of 5-hexenyl radical cyclizations. As sacrificial electron donors, the... 

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. 

Despite that the regioselective cyclization of 5-hexenyllithiums could be synthetically useful, in those years there was no real development of this methodology9, probably due to the lack of a convenient and efficient procedure for the preparation of unsaturated alkyllithiums and to the conventional belief that simple alkenes are not thought of as sites of nucleophilic attack. Moreover, this was a period when radical cyclizations and radical cascade reactions came to the fore10, and 5-hexenyl substrates were used as probes for radical intermediates in reactions suspected of proceeding via single-electron transfer (SET). 

Because of the rather fast cyclization 131 - 132 (kj = 1 10s s"1 at 25 °C)90) this reaction or the cyclization of the related l-methyl-5-hexenyl radical 134 91) and the o-(3-butenyl)phenyl radical 135 92> is often used as a radical clock in reactions possibly passing through radical intermediates 93... 

The data of Table 5 indicate that the conversion of the anion 145 into 146 is very much slower (by a factor of 108-1010) than the cyclization of the 5-hexenyl radical 131. However, nonnegligible quantities of product containing the cyclopentylmethyl group may still arise from cyclization of the anion 145 since the half-life for this process at temperatures above 0 °C (t1/2 = 23 min at 0 °C 5.5 min at 23 °C) is short relative to the time scale of many experiments that seek radical intermediates 103). A differentiation between radical and anion cyclization, as in the case of 134 and 138, is not available with 131 and 145. The cyclization of the anion 145 is, however, very slow at lower temperatures like —78 °C. 

Similar to the selectivities observed in five-ring annulations of carbocyclic systems (see previous section), cyclic 3-oxa-5-hexenyl radicals exhibit a distinct preference for the formation of l,5-c( s-configurated products. This is illustrated by the reaction of five- and six-membered /i-phenylselenocrotonates with triphenyltin hydride59. The intermediate cyclopentyl or cyclohexyl radicals cyclize exclusively in the 5-exo mode to yield the corresponding c -fused "/-lactones. 

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