4-pentenyl radicals, cyclization

A major focus of our research program has been the development of synthetically useful radical-mediated methodologies in recent years. Our interest in this area was partly initiated by asking how to generate five- and six-membered ring radicals from acyclic radical precursors. This problem has been unsolved in radical chemistry due to a disfavored 5-endo cyclization in pentenyl radical cyclizations. This simple but intriguing curiosity led us to study radical reactions of yV-aziridinylimines. The outcome of this research is the development of a novel consecutive carbon-carbon bond formation approach, which has tremendous synthetic potential. This review provides a full account of radical cyclizations of V-aziridinylimines and their applications to sesquiterpene natural products. 

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. 

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). 

Intramolecular enone-alkene cycloadditions are also possible. In the case of (3-(5-pentenyl) substituents, there is a general preference for exo-type cyclization to form a five-membered ring.195 This is consistent with the general pattern for radical cyclizations and implies initial bonding at the (3-carbon of the enone. 

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

Nevertheless, in spite of this observation, it was found that the parent system, the perfluoro-4-pentenyl radical, 24, failed to cyclize even when Et3SiH was employed as the hydrogen atom transfer agent [ 140]. Either the equilibrium between 24 and the cyclized radical must be very unfavorable or the rate constant for 24 s cyclization is less than lx 104 s 1 at 30°C. Thus the lack of cyclization of 24 could be due to either thermodynamic or kinetic factors. 

An interesting aspect of fluorinated 4-pentenyl radicals that distinguishes them from their hydrocarbon counterparts is their ability to cyclize to form four-membered rings. As mentioned in Sect. 5.3.2, Piccardi and his coworkers reported in 1971 that C2F5I underwent free radical addition to 3,3,4,4-tetra-fluoro-l,5-hexadiene to form a four-membered ring product [173]. Subsequently they observed similar results in the addition of CC14 [323]. 

Cekovic, Z. Saidc, R. Radical cyclization reactions. Cydopropane ring formation by 3-exo-cycbzation of 5-phenylfhio-3-pentenyl radicals. Tetrahedron Lett. 1990, 31, 6085—6088. 

Park, S.-U. Varick, T. R. Newcomb, M. Acceleration of the 4-exo radical cyclization to a synthetically useful rate. Cyclization of the 2,2-di-methyl-5-cyano-4-pentenyl radical. Tetrahedron Lett. 1990, 31, 2975-2978. 

On treatment with a radical generator, the 4-mercaptopentyl derivatives of vinylcyclopropanes 456 cyclize to a mixture of stereoisomers of tetrahydrothiopyran (Equation 146) <1993SL827> and a tetrahydrothiopyran 1,1-dioxide results from a 1,3-rearrangement prior to the radical cyclization of allylic pentenyl sulfones 457 (Equation 147) <1993TL2537>. 

A-(4-Pentenyl)iodoacetamides (i.e., 142 and 145) underwent atom transfer radical cyclization reactions in the presence of trifluoroborate etherate at room temperature, usually with an excellent 8-endo regioselectivity (Schemes 59 and 60 <2005JOC1539>). It was thus shown that 8-endo cyclization of iV-alkenyl a-carbamoyl radicals is an intrinsically favored process easily promoted by a Lewis acid, such as BF3-OEt2. 

Chatgialialoglu and coworkers applied carbonylative cyclization to a unique synthesis of polyketones from 1,4-c -polybutadiene and CO [30]. This polymer contains a unit each of cyclopentanone and cyclohexanone as well as an unreacted olefin unit. Carbonylative 6-endo cyclization which leads to a selective formation of cyclohexanones is also possible using 4-pentenyl radical precursors having a substituent at the 4-position [31]. Scheme 7 illustrates such an example. 

The 4-pentenyl radical can undergo 4-exo or 5-endo cyclization. UB3LYP/6-3IG calculations find a preference of 1.8 kcal/mol for the 5-endo TS. The angle to approach to the double bond is found to be about 89°... 

Next, the cyclization of a hot 4-pentenyl radical, i.e., reaction 33 was postulated. 

C=C, was excluded from the whole scheme by the following reasons. Firstly, no cyclopentane was detected experimentally. Secondly, the cyclopentyl radical may have released its energy in the course of cyclization reaction, reaction 33. A hot 4-pentenyl radical itself may partly be quenched by reaction 36. 

Figure 10 illustrates the heat contents of key radicals such as reported in the literature (23,26,28,33). Activation energies obtained in the present investigation for reactions starting from allyl radical plus ethylene to cyclopentene and 1-pentene formation fit the diagram consistently. This figure strongly supports the conclusions that it is impossible to produce any linear (cyclized) C5 radicals from stable cyclopentyl (4-pentenyl) radicals, and that, in the case of the reaction of an allyl radical with ethylene, it is possible to produce both cyclized and linear C5 compounds at the same time. 

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). 

Dimethyl iodo(4-pentenyl)malonate (926) undergoes a Pd-catalyzed intramolecular radical-type reaction to form the alkyl iodides 927 and 928. rather than a Heck-type reaction product(775]. The same products are also obtained by a radical reaction promoted by tin hydride(776]. Although yield was low, a similar cyclization of the n-chloro ester 929 to form the seven-membered ring 930 was ob,served(777(. 

Treatment of 329, the A-butyl-A-4-pentenyl analogue of 327, with trifluoroacetic acid and r-butylthiolate radicals (from r-butylthiol) under irradiation with visible light gives the aminyl radical 330, which cyclizes to the pyrrolidine 331 and a r-butylthiolate radical is regenerated (equation 115). It is believed that the process involves, at least partially,... 

The AM-pentenyl analogue 337 affords the radical cation 338, which cyclizes to 2-methylpyrrolidine, isolated as the 7V-benzoyl derivative 339 in high yield383. 

A series of bicyclo[3.3.0]octanols are accessible by electroreductive tandem cyclization of linear allyl pentenyl ketones 189, as shown by Kariv-Miller et al. [189]. The electrolyses are carried out with an Hg-pool cathode and a Pt-flag anode. As electrolyte, tetrabutylammonium tetrafluororborate is used. The reaction is stereoselective, yielding only two isomers 192 and 193. In a competing reaction, a small amount of the monocyclic alcohol is formed. Since all the monocycles have the 1-allyl and the 2-methyl group in trans geometry it is assumed that this terminates the reaction. The formation of a bicyclic product requires that the first cyclization provides the cis radical anion which leads to cis-ring juncture [190] (Scheme 37). 

Similarly, cyclizative tandem double-carbonylation reactions of 4-pentenyl iodide under irradiation conditions, is boosted by the addition of a catalytic amount of palladium complexes [72]. When performed in the presence of diethylamine, the carbonylation provided a triply carbonylated a,<5-diketo amide as the major product along with the doubly carbonylated y-keto amide (Scheme 6.48). Experimental evidence supports the interplay of two reactive species, radicals and organopalladium... 

Intramolecular cyclizations of alkenylaminyl radicals produced from tetrazenes have been reported. The regioselectivity of cyclizations of aminyl radicals derived from N-3-butenyltetrazene (1), A-4-pentenyl tetrazene (2), and JV-5-hexenyl tetrazene (3) have been studied (78MI1). The position of the alkene moiety is important because other reaction pathways can compete with cyclization. 

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