Cyclization of Alkoxyl Radicals

Cyclic ethers were also obtained by cyclization of alkoxyl radicals, generated in a radical chain reaction by reacting the thione 42 with (TMSfsSiH under photochemical conditions at 20 °C (Reaction 46). Regioselectivities of cyclization have been investigated and a progressive increase of the 6-endo-trig selectivity along the series R2 = H[Pg.140]

Scheme 5 Generation and cyclization of alkoxyl radicals by Giacomelli [5]...

The Barton nitrite ester photolysis is undeniably one of the most popular and useful reactions in radical chemistry for the functionalization of remote and inactivated positions within steroids (Scheme 19). Photolysis of nitrite esters gives nitric oxide and an alkoxyl radical that abstracts an ideally positioned hydrogen atom (1,5-hydrogen atom abstraction). The resulting alkyl radical reacts with nitric oxide in a solvent cage to afford the nitroso-alcohol derivative that is finally isolated as an oxime [53]. Related cyclizations of alkoxyl radicals have been reported by Surzur photolysis of y,(5-alkenyl nitrite esters leads to alkoxyl radicals that undergo subsequent tandem 5-exo cyclization followed by NO-trapping [54, 55]. 

In contrast to aminyl radicals, alkoxyl (and acyloxy) radicals are highly reactive. As illustrated in equation (7), their cyclization reactions are extremely rapid and irreversible. However, the rapidity of such cyclizations does not guarantee success because alkoxyl radicals are also reactive in inter- and intramolecular hydrogen abstractions, and -fragmentations (see Section 4.2.S.2). This lack of selectivity may limit the use of alkoxyl radicals in cyclizations, but S-exo cyclizations are so rapid that they should succeed in many cases, and other types of cyclizations may also be possible. 

Alkoxyl radicals can be generated by a variety of methods including peroxide reduction, nitrite ester photolysis, hypohalite thermolysis, and fragmentation of epoxyalkyl radicals (for additional examples of alkoxyl radical generation, see Section 4.2.S.2). Hypohalites are excellent halogen atom donors to carbon-centered radicals, and a recent example of this type of cyclization from the work of Kraus is illustrated in Scheme 43.182 Oxidation of the hemiketal (57) presumably forms an intermediate hypoiodite, which spontaneously cyclizes to (58) by an atom transfer mechanism. Unfortunately, the direct application of the Barton method for the generation of alkoxyl radicals fails because the intermediate pyridine-thione carbonates are sensitive to hydrolytic reactions. However, in a very important recent development, Beckwith and Hay have shown that alkoxyl radicals are formed from N-alkoxypyridinethiones.183 Al-... 

Stereo- and regioselectivities of alkoxyl radical cyclizations may be improved by lowering the reaction temperature. Thus, the selectivity for the formation of trans-2-isopropyl-5-methyl tetrahydrofuran from A -(l-isopropyl-4-penten-l-oxy)pyridine-2(l//)-thione increases from cis/trans 40 60 to 25 75 if the reaction temperature is changed from 140 °C to 15 °C. Likewise, the ratio of 2-isopropyl-5-methyl tetrahydrofuran (5-exo-trig) to 2-isopropyl tetrahydropyran [6-endo-tng) increases from 94 6 to 98 2 in the same temperature range. 

Cyclizations of 5-alkyl-substituted 4-penten-l-oxyl radicals are faster and frequently more selective than those of terminal unsubstituted derivatives [48, 53]. This finding is in accord with the electrophilic nature of alkoxyl radicals in addition reaction to C-C double bonds. 5-Alkyl- or 5-phenyl-substituted 4-pentenoxyl radicals, such as intermediates 25 or 26, were generated from a number of different sources. For example, alkyl nitrites [39], A-alkoxypyridine-2(l//)-thiones [46], and A-alkoxy-(/ -chlorophenyl)thiazole-2(3/f)-thiones [54] in photochemically induced reactions, and A-alkoxyphthalimides [55] or type IV radical precursors [53] in thermally initiated reactions have been applied for this purpose (Scheme 6). 

These two examples exemplify the care which must be taken in assuming that cyclized products result from intramolecular addition of alkoxyl radicals. For instance, at the beginning of our studies we tried to prepare hypochlorites of ethylenic alcohols as precursors of pentenyloxyl radicals, but were unable to isolate the hypochlorites, cyclized products being obtained directly. We assumed that these products could arise from alkoxyl radicals, but further work fits the ionic pathway (Scheme 32 X = Cl) better. ... 

The relatively high yields of cyclic products, often even better than with carbon radicals, observed in the Cy5/Cy6 case is somewhat surprising when one recalls that the intermolecular addition of alkoxyl radicals to olefins is a very unfavorable process. One possible reason that this is so when the alkoxyl radicals are generated by nitrite ester photolysis is that scavenging of the cyclized (Cy 5) radical by NO (Scheme 33) is a very fast process, so that competitive reactions are minor ones. But it is also necessary to postulate that the cyclization process is very fast in the Cy5/Cy6 case. Actually, photolysis of... 

In the preceding sections it was concluded that the cyclization of alkoxyl and aminyl radicals parallels that of carbon radicals under kinetic control. It will be seen in this section that the situation is much less clear as regards the behavior of unsaturated thiyl radicals. 

This way of rationalization is substantiated by the photolytic behavior of, -unsaturated aldehydes (478) (Scheme 162). Only in one of the five cases studied was 479 observed this result is in accordance with the difficult intramolecular addition of alkoxyl radicals in the Cy6/Cy7 case. Since thiyl cyclizations appear efficient even in the Cy6/Cy7 case one might expect to observe easy photocyclizations of unsaturated thiones also in this case the easy photochemical synthesis of quinolines from A -(o-styryl)thioamides appears to be an excellent illustration of this view. Here, the sulfur analog of 479 would be an intermediate. To complete the analogy, one may expect the converse P-scission reaction to be efficient with radicals that readily open such as oxyranylalkyl ones (see Section VIII.2) in this way an interesting macrolide synthesis was described by Carlson. Photolysis of epoxycyclanone (480)... 

Insertion of Oxygen Atom of Alkoxyl Radical Generated from Fused Cyclic Alcohols by Tandem P-Fragmentation-Cyclization... 

Suginome and collaborators have found that heterocyclic compounds can be formed by insertion of the oxygen atom of alkoxyl radicals into alicyclic compounds the insertion takes place through a tandem P-fragmentation-cyclization sequence. 

In this context Fernandez-Mateos and his group reported efficient cyclizations with aldehydes and ketones as radical traps [115]. The authors propose a reduction of the intermediate alkoxyl radicals by a second equivalent of... 

In the case of the hematin-catalyzed reaction we have proposed that peroxyl radicals are the epoxidizing agents (40). The mechanism is illustrated in Figure 8. Hematin reduces the hydroperoxide to an alkoxyl radical that cyclizes to the adjacent double bond. 

It is worth mentioning that in a few cases the (3-elimination of the silyl radical from the a-silyl alkoxyl radical (47) with the formation of corresponding carbonyl derivative was observed [63,64]. Evidently the fate of a-silyl alkoxyl radical depends on the method of radical generation and/or the nature of the substrate. Two examples that delineate the potentialities of this rearrangements are reported in Reactions (5.33) and (5.34). In the former, the 5-exo cyclization of secondary alkyl radical on the carbonyl moiety followed by the radical Brook rearrangement afforded the cyclopentyl silyl ether [65], whereas Reaction (5.34) shows the treatment of an a-silyl alcohol with lead tetracetate to afford the mixed acetyl silyl acetal under mild conditions [63]. 

This is rather surprising because primary nitroalkanes (which would give more stable alkyl radicals) are not readily reduced by tin hydride. The third example in Scheme 43 illustrates a cyclization of an alkoxyl radical derived from a nitrate ester. 

When a cyclization reaction precedes a fragmentation, carbon-carbon bonds are exchanged rather than created. Nonetheless, such sequences are very useful for reorganizing the carbon skeleton of a molecule, especially when easily fragmentable alkoxyl radicals are formed in the cyclization step. Depending on... 

Cyclizations arising by intramolecular radical addition have been widely employed in the synthesis of oxygen and sulfur heterocycles. The tetra-hydrofuran derivatives (494) have been prepared in this way via alkoxyl radicals, generated in turn by photolysis of the unsaturated nitrites (495).431 Bridged oxabicyclic compounds have been similarly prepared,432 and the photodecomposition of a nitrite has been employed in the synthesis of the... 

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