Cychzation radical

Formalin [Formaldehyde], 55, 45 Formamide,AGV-dimethyl-, 55, 58 Free radical cychzation, 55, 57... 

With 6-alkenoic acids the intermediate radical partially cyclizes to a cyclopentyl-methyl radical in a 5-exo-trig cycHzation [139] (Eq. 6) [138 a, 140] (see also chap. 6). To prevent double bond migration with enoic acids the electrolyte has to be hindered to become alkaline by using a mercury cathode. Z-4-Enoic acids partially isomerize to -configurated products. Results from methyl and deuterium labelled carboxylic acids support an isomerization by way of a reversible ring closure to cyclopropyl-carbinyl radicals. The double bonds of Z-N-enoic acids with N > 5 fully retain their configuration [140]. 

Cobaloxime-mediated intramolecular radical cychzation of oxime ethers 41 to furan derivatives 42 occurred during electrolysis in yields up to 76% (equation 19) . ... 

HomoaUyhc peroxy-radicals, alkenyl hydroperoxide cychzation, 213-14 Homodesmic reactions, dioxetanes, 164 Homologous series acyl peroxides, 162... 

Two para-substituents, phenyl and cyano depress and retard the rate of cyclization significantly (Table 11.2)." p-Phenyl and p-cyano are both radical stabilizing substituents. These conjugative substituents reduce the spin density on the carbon ortho to the nitrene nitrogen. The reduced spin density at carbons ortho to the nitrogen lowers the rate at which the 1,3-biradical cychzes. The effect with p-cyano and p-biphenyl singlet phenylnitrene is quite dramatic. The lifetimes of these singlet nitrenes at ambient temperature are 8 and 15 ns, respectively, and the activation barriers to cychzation are 7.2 and 6.8 kcal/mol, respectively. 

In 1967, Heiba and Dessau reported perhaps one of the earliest examples of a radical cychzation cascade that is initiated by intermolecular addition of C-centered radicals to alkynes. Reaction of carbon tetrachloride with 1-heptynes 1 in the presence of benzoyl peroxide (BPO) as radical initiator resulted, among other products, in the formation of 1,1-dichlorovinylcyclopentane derivatives 2 in moderate yields (Scheme 2.1). °... 

One of the earliest radical cyclization cascades initiated by addition of S-centered radicals to alkynes was reported in 1987 by Broka and Reichert (Scheme 2.25). Thiophenyl radicals, PhS, which were generated under radical chain conditions, undergo addition to the terminal end of the C = C triple bond in enyne 138. The resulting vinyl radical 141 can undergo cychzation in both 6-endo (preferred) and 5-exo fashion, and reduction of the radical intermediates 142 and 143 leads to the final observed products 139 and 140, respectively. 

Cyclobutadiene iron tricarbonyl complexes also stabilized carbocations on an adjacent carbon. The cation reacts with silyl enol ethers to afford alkylated complexes such as (127) (Scheme 187). A samarimn diiodide -mediated intermolecular radical cychzation of iron tricarbonyl complex (128) is depicted in Scheme 188. An excellent stereocontrol at three contiguous centers is observed. 

Enchaining radical cyclizations steps to provide polycyclic compounds is the simplest approach. Because the 5-exo cychzation is the most straightforward mode of cychzation, polyquinanes have been the object of many studies [20]. Roimd-trip strategies as defined by Haney and Curran [21], from a vinyl radical such as 8 have been developed by Takasu et al. [22] and revisited by Tripp et al. (Scheme 3) [23]. Mixtures of diastereomers 9 are obtained from hnear precursor 7. The same group has examined the intramolecular addition of a vinyl radical onto a dienoate to produce [4 -l-1]- or [4 + 2]-annulated compounds [24]. Tandem 5-exo-trig cyclizations have also been shown to yield tricyclo[6.2.1.0 ]undecan-4-one and related polycyclic compounds, using a nickel-catalyzed electroreduction [25]. 

Haney and Curran also studied the radical cychzation of vinyl iodide 10 in the presence of the fluorous tin hydride 14 (Scheme 4) [21]. After fluorous... 

Harrington-Frost and Pattenden have reported a new synthesis of pental-ene, a natural angular triqiunane, using a novel tandem cychzation involving a ketene radical intermediate [26]. 

N-centered radicals such as iminyl radicals can also be generated from a radical cyclization step onto nitrile groups. The fate of the iminyl radical depends on the nature of the a-substituent. When this latter is an alkyl group, further cychzation can take place [45]. A combination of both processes has been achieved addition of a staimyl radical onto an azide moiety generated a N-stannylaminyl radical that cyclized onto a nitrile and underwent further cyclization, thus opening access to pyrrolopyrroles and pyrrolopyridines derivatives [46]. 

Tokuda and Senboku have studied the radical cychzation of aminyl radicals resulting from the reaction of tributyltin hydride with N-chloro pre-... 

We observed that vinyl radicals show exquisite reactivity for efficient and chemoselective H-abstraction [64]. The resulting translocated radical can then undergo various types of inter- or intramolecular transformations. Interestingly, we have also shown that the hydrogen transfer step can serve as a driving force for the unfavorable 4-exo-dig mode of cychzation [65]. 

The imique reactivity of methylenecyclopropanes prompted Zhou to test on this substrate the manganese (Ill)-mediated free radical cychzation of alkenes with 1,3-dicarbonyl compoimds [149]. It was found that benzyh-... 

Booker-Milburn et al. used the oxidative ring-expansion/cycHzation strategy they previously developed as an efficient way to stereoselectively build the bicyclo [5.3.0] framework of terpene-based natural products. For example, reaction of substrate 258 with iron (in) nitrate in DMF led to the formation of keto-alcohol 260 in fair yield as a single diastereomer (Scheme 76) [214]. Reduction of the final radical coming from the cyclization of 259 by 1,4-cyclohexadiene was smooth and the overall reaction proceeded without protection of the tertiary alcohol, opening the way to the total synthesis of pogostol and kessane. 

An elegant extension of this work has been contributed by Lee et al., who showed that aryl-cyclopropylamines easily obtained by a Kuhnkovich cy-clopropanation could also imdergo the oxidative fragmentation/cycHzation reaction (Scheme 76) [217]. Interestingly, the radical issued from the cycH-zation of 262 was trapped by molecular oxygen and afforded alcohol 263 after... 

To study the effects of water and other solvents on titanocene(III)-mediated processes we used the transannular cychzation of epoxygerma-crolides as a model reaction [47]. Thus, we found that in anhydrous, non-halogenated solvents such as THF the reaction led selectively to decalins with an exocyclic double bond (Scheme 5). In an aqueous medium (THF/H2O), however, the characteristic lime green color of Cp2TiCl turned deep blue and the main product was a reduced decalin (Scheme 5). Under these conditions, water (either H2O or D2O) proved to be more effective than the toxic and expensive hydrogen-atom donor 1,4-cyclohexadiene for the reduction of tertiary radicals [47]. This is an unusual phenomenon in free-radical chemistry [48-50], subsequently exploited by us for the selective reduction of aromatic ketones as we shall see later [51,52]. 

Some controversy remains concerning contemporary radical chemistry as to whether radical cascade cychzations take place in a concerted or stepwise fashion [48]. Within this context we have recently reported theoretical and... 

Enholm [26] has reported the first examples of asymmetric radical cy-clizations on soluble polymer supports. The stereocontrol element employed consists of a (+)-isosorbide group attached by a 4-carbon chain to each subunit of a soluble succinimide-derived ROMP backbone. Treatment of the radical cychzation substrate 162 with tributyltin hydride in the presence of zinc chloride followed by hydrolysis of the resulting polymer-supported ester 163 gave the desired product 164 in 80% yield and > 90% ee (Scheme 38). The use of alternative Lewis acids, such as magnesium bromide etherate and ytterbiiun (III) triflate, resulted in lower enantioselectivities, 84% and 72% respectively. No such decrease in selectivity was observed in analogous reactions carried out off-support [27], suggesting that the polymer backbone is somehow responsible for this phenomenon. 

Enholm s strategy [26] involves incorporation of all the structural features required for the 6-heptenyl radical cychzation reaction into the monomer subunit prior to metathesis polymerization, thus ensuring maximum possible loading. Although several steps are needed to prepare the monomer unit and recycling the support is not possible, this work does show the potential of using chiral linking imits to control the stereochemistry of radical cycliza-tions on polymer supports. 

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