6-Heptenyl radical cyclization

It was proposed that the transition state requires approach of the radical directly above the site of attack and perpendicular to the plane containing the carbon-carbon double bond. An examination of molecular models shows that for the 3-butenyl and 4-pentenyl radicals (16, =1,2) such a transition state can only be reasonably achieved in < Xf>-cyclization (i.e. 16—> 15). With the 5-hexcnyl and 6-heptenyl radicals (16, w=3,4), the transition state for exo-cyclization (16- 15) is more easily achieved than that for enc/o-cyclization (i.e. 16 — 17). 

Interesting intramolecular cyclization of 1-nitroalkyl radicals generated by one-electron oxidation of aci-nitro anions with CAN is reported. As shown in Eq. 5.44, stereoselective formation of 3,4-functionalized tetrahydrofurans is observed.62 l-Nitro-6-heptenyl radicals generated by one electron oxidation of aci-nitroanions with CAN afford 2,3,4-trisubstituted tetrahydropyrans.63 The requisite nitro compounds are prepared by the Michael addition of 3-buten-l-al to nitroalkenes. 

One of the few examples of a synthetically useful 6-exo-trig cyclization from 3-aza-6-heptenyl radicals is found in the total synthesis of ( )-melinonine-E (159, Scheme 31) by Bonjoch et al. [66]. The cyclization precursor, a,P-unsaturated nitrile 157 was prepared from 1,4-cyclohexanedione monoethylene acetal (156) and tryptamine in 5 steps with 41% overall yield. Initially, when 157 was treated with 1.1 equiv. of n-BujSnH and 0.1 equiv. of AIBN in toluene for 16 h, the expected cyclization to the 2-azabicyclo[3.3.1]nonane ring took place to give 158 only as a minor product, along with its C(14) chloro- and dichloro-substituted derivatives as major products. An additional treatment of the crude mixture with 2.2 equiv. of BujSnH brought about the reduction of the C-Cl bonds to provide nitrile 158 in 38% yield over... 

Scheme 31. A 6-exo-trig cyclization from a 3-aza-6-heptenyl radical in the total synthesis of ( )-melinonine-E...

The rate constant measured for 1-endo closure in the simple heptenyl radical is near the lower limit for synthetic utility (ki ndo l x 102 s 1) [73]. Nonetheless, 1-endo and %-endo cyclizations do occur when the (conformationally restrained) intermediate radicals possess... 

In addition to these two problems in heptenyl radical cycliza-tions, competitive 1,5-hydrogen transfer may occur if there are accessible allylic hydrogens. Furthermore, in pentenyl radical cyclizations the formation of cyclobutane rings is very slow and the reverse reaction is greatly favored, whereas the formation of cyclopentane rings by 5-endo cyclization is disfavored. Therefore, despite the synthetic usefulness of radical cyclization processes, the cyclization pathway is mainly limited to 5-exo cyclization along with the much less efficient 6-exo and 6-endo cyclizations. 

Free-radical cyclization reactions (i.e., the intramolecular addition of an alkyl radical to a C=C ir bond) have emerged as one of the most interesting and widespread applications of free-radical chemistry to organic synthesis. Free-radical cyclizations are useful because they are so fast. The cyclization of the 5-hexenyl radical to the cyclopentylmethyl radical is very fast, occurring at a rate of about 1.0 X 105 s-1. In fact, the rate of formation of the cyclopentylmethyl radical is much faster than the rate of cyclization to the lower energy cyclohexyl radical. This stereoelectronic effect is derived from the fact that the overlap between the p orbital of the radical and the rr MO of the double bond is much better when Cl attacks C5 than when it attacks C6. The relative rates of 5-exo and 6-endo ring closures are strongly dependent on the nature of the substrate and especially on the amount of substitution on the ir bond. Cyclization of the 6-heptenyl radical in the 6-exo mode is also very favorable. 

An example of the cyclization of 5-hexenyl radicals with a substituent at C-l is shown by the intramolecular attack of an alkyl radical on an allylic dithiocarbonate4. The 1,3,3,6-te-tramethyl-7-(methylthiocarbonylthio)-5-heptenyl radical, generated from a 1.5-diol, cyclizes to yield predominately the cA-isomcr of 4-isopropenyl-1.1.3-trimethylcyclopentane5. 

For the formation of six-membered rings, the chair-Uke transition state 28 (Figure 4.19) generally explains the stereoselectivity observed when hept-6-en-l-yl radicals undergo 6-exo-cyclization. Both the substituent(s) and alkene prefer to adopt pseudo-equatorial positions, therefore 1-, 3-, and 5-substitutedheptenyl radicals give predominantly trans-disubstituted cyclohexyl products, while 2- and 4-substituted heptenyl radicals give predominantly ds-disubstituted cyclohexyl products. 

Fig. 10.13. MM2 models of exo and endo cyclization transition structures for 5-hexenyl, 6-heptenyl, and 7-octenyl radicals. Reproduced from Tetrahedron, 41, 3925 (1985), by permission of Elsevier.

The surprising efficiency with which an aldehyde group acts as a radical acceptor [see Eq. (5)] was indeed first realized [27] in the context of a heptenyl analogue [Eq. (13)]. Note that the minor product arises as a result of two consecutive hex-5-enyl cyclizations [26,27]. 

Butenyl,Pentenyl,Heptenyl and Other Radical Cyclizations 785... 

Heptenyl-type radicals preferentially undergo 6-exo instead of 1-endo cyclizations <85T3925 01OL2217>. 6-Exo cyclizations nevertheless are generally slower than the related... 

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