Hexenyl radicals cyclizations

Effects of substituent on the regiochemistry of the 5-hexenyl radical cyclization... 

By using either one of these photosystems, one-electron (3-activation of a,(3-unsaturated carbonyl compounds produced carbon-centered radical precursors which cyclize efficiently and stereoselectively to tethered activated olefins or carbonyl groups. The 1,2-anti-stereochemistry observed contrasts with the general trend of syn-stereochemistry expected in 5-hexenyl radical cyclizations. Application of this methodology was successfully demonstrated by the stereoselective synthesis of optically pure C-furanoside, starting from L-tartaric acid (Scheme 38) [57,58]. 

The intramolecular C—C bond formation (or cyclization) mediated by (TMS SiH has been the subject of numerous publications. Scheme 5 presents the simplest and more popular type of 5-hexenyl radical cyclization. Thus, a 50 mmolar solution of 5-hexenyl bromide and silane (or tin hydride) lead to a 24 1 (or 6 1) ratio of cyclized versus uncyclized products61. Therefore, under the same conditions the silane gives higher yields of cyclization than the stannane. 

G. A. Russell and H. Tashtoush, J. Am. Chem. Soc. 105, 1398 (1983). Reported rates were corrected for the more accurate value for 5-hexenyl radical cyclization, 2.2 x 105 s l (81JA7739). 

A kinetic study of partially- uorinated 5-hexenyl radicals has demonstrated the kinetic importance of polarity factors while providing substantial insight into a number of factors which affect both the rate and the regiochemistry of 5-hexenyl radical cyclizations. 

It was initially presumed that one would observe a polarity-driven kinetic advantage in 5-hexenyl radical cyclizations if one constructed such radicals with either a hydrocarbon radical site adding to a fluorinated alkene segment or, vice-versa, with a fluorinated radical site adding to a hydrocarbon alkene segment. As it turns out, only the latter combination led to a significant cycliza-tion rate enhancement. 

Kinetic data for radicals 13-17, all of which involve 5-hexenyl radical cyclizations of a 1° hydrocarbon radical site onto a fluorinated alkene segment, given in Table 15, indicate that the degree of fluorination of the double bond has little impact upon the rate of cyclization of a 5-hexenyl radical [163,164]. 

Table 15. Absolute rates for 5-hexenyl radical cyclizations in involving hydrocarbon radical adding to fluorinated alkene, at 30 °C in C6D6 [161,162] ...

Although radicals are not nearly so prone to rearrangement as are, for example, carbocations, there are a few such rearrangements which have become identified as characteristic of carbon radicals. These include radical cyclizations, particularly the 5-hexenyl radical cyclization, and radical C-C bond cleavages, particularly the cyclopropylcarbinyl to allyl carbinyl radical rearrangement. In hydrocarbon systems, as organic synthetic chemists have learned how to control rapid chain processes, such rearrangements have become important synthetic tools [176-179]. 

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... 

Hexenyl radicals cyclize to cyclopentylmethyl radicals (see Volume 4, Chapter 4.2). Thus radical decarboxylation of 6-heptenoic acids, by whatever means, usually results in die formation of five-mem-v beied rings. Although this fact had been appreciated previously it is only recendy, widi the advent of the 0-acyl thiohydroxamates, that it has been exploited from a syndietic point of view. An example is provided by the synthesis of bicyclo[4.3.0]proline derivatives from aspartic acid carried out by the Barton group (equation 51). It will be noted that activation of die C—C double bond acting as a radical trap is not necessary in these intramolecular reactions. 

Enholm, E J, Cottone, J S, Allais, F, Highly diastereoselective 5-hexenyl radical cyclizations with Lewis acids and carbohydrate scaffolds, Org. Lett., 3, 145-147, 2001. 

Newcomb, M., Varick, T.R., Ha, C., Manek, M.B., and Yue, X., Picosecond radical kinetics. Rate constants for reaction of benzeneselenol with primary alkyl radicals and calibration of the 6-cyano-5-hexenyl radical cyclization, J. Am. Chem. Soc., 114, 8158, 1992. 

The second example in Table 5 shows the cyclization-carbonylation-allylation sequence, in which 5-hexenyl radical cyclization precedes CO trapping. Because of the nucleophilic nature of acyl radicals, in a mixed alkene system comprised of an electron deficient alkene and allyltin, they favor the electron deficient alkene first and the resulting product radical, which have an electrophilic character, and then smoothly add to allyltributyltin. This four-component coupling reaction provides a powerful radical cascade approach leading to y -functionalized, -unsaturated ketones, which are not readily accessible by other methods [52]. 

The 2-methyl-5-hexenyl radical (and the 4-methyl-5-hexenyl radical) cyclizes to give predominantly the trans-dimethyl product. 

Cyclization of the 6-hexenyl radical could conceivably be used to make cyclohexanes via (>-exo ring closure. However, this reaction is far less widely used in synthesis than the 5-hexenyl radical cyclization since ... 

All attempts to obtain cyclized products from the 4-pentenyl radical using the same conditions under which the 5-hexenyl radical cyclizes readily failed. This was early recognized and confirmed later. Only in special cases, as by the use of vibrationally excited radicals in the gas phase or carbene triplets has cyclization been observed. In these instances, only (Cy5) and no (Cy4) products were obtained. In solution, cyclized products have been observed only from 4-pentenyl radicals possessing special features, e.g., the radical (A ) which results from intermolecular free radical addition to cis cis-1,5-cyclooctadiene (Scheme 15). 

The first use of 5-hexenyl radical cyclization as a mechanistic tool was proposed in 1966 by Garst and Lamb for the study of alkyl halides reduction by naphthalene radical anion. Since then, Garst has extensively used this method in the study of the one-electron transfer reactions from aromatic radical anions to alkyl halides critical discussion of the use of the method may be... 

The 5-hexenyl radical cyclization rate and other intramolecular radical isomerization rates have been used as a kinetic standard by Garst since 1969540b 6y Kochi since 1970. According to Scheme 164, a linear relationship between the concentration of the transfer reagent [XY] and the relative yields of uncyclized products [AY] and methylcyclopentane derivatives [Cy5Y] must obtain according to the following equation ... 

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