Cyclization 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]

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]. 

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-... 

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... 

Another common scenario in competition kinetics utilizes unimolecular radical reactions as a clock against which other reactions can be timed. Among the most commonly used free radical clocks are the cyclization of 1 -hexenyl and other radicals with double or triple bonds in the chain,33 ring opening,34 and p-elimination from alkoxyl radicals.35... 

Eq. 4.54 shows the reaction of n-heptanol (151) with Pb(OAc)4 under high-pressured carbon monoxide with an autoclave to generate the corresponding 8-lactone (152). This reaction proceeds through the formation of an oxygen-centered radical by the reaction of alcohol (151) with Pb(OAc)4,1,5-H shift, reaction with carbon monoxide to form an acyl radical, oxidation of the acyl radical with Pb(OAc)4, and finally, polar cyclization to provide 8-lactone [142-146]. This reaction can be used for primary and secondary alcohols, while (3-cleavage reaction of the formed alkoxyl radicals derived from tertiary alcohols occurs. 

Instead of alkyl nitrite, other alkoxyl radical precursors such as ROOH, ROOR, ROI, ROC1, etc. can also be used for the same type of reaction. The high reactivity of these compounds comes from the weak bond dissociation energies in O-O, 0-1, and O-Cl bonds. Another simple method is as follows. Photolytical treatment of alcohol (5) with NIS (AModosuccinimide) provides the tetrahydrofuran skeleton (6), through the formation of alkyl hypoiodite (ROI), homolytic cleavage of the 0-1 bond to form an alkoxyl radical, 1,5-H shift to form a carbon-centered radical, reaction with ROI to form 8-iodoalcohol, and finally ionic cyclization to form a tetrahydrofuran skeleton, together... 

TBS-Protected 7-lactol is obtained through the formation of hypoiodite, followed by the formation of an alkoxyl radical, 1,5-H shift, and then formation of 8-iodoalcohol, and finally polar cyclization. The Fenton system with ROOH and Fe2+ also generates alkoxyl radical, RO. These reactions indicate that the Barton (-type) reactions are remote functionalization of non-activated C-H bonds at the 8- or e-position. 

Carbonate and carbamate derivatives, prepared from the reaction of alcohols and amines with phosgene and /V-hydroxy-2-thiopyridone, provide the corresponding alkoxyl radicals and aminyl radicals respectively, via radical decarboxylation [71-81]. For example, photolytic treatment of carbamate (57) derived from 4-pentenylamine generates the corresponding 4-pentenylaminyl radical, as shown in eq. 8.24. Under neutral conditions in the presence of tert-BuSH, a direct reduction product (A) of 4-pentenylaminyl radical is formed, while, in acidic conditions, cyclized product (C), pyrrolidine, via 5-exo-trig manner from 4-pentenylaminyl radical is formed. Under the latter conditions, the real reactive species is an electrophilic 4-pentenylaminium radical which rapidly cyclized via 5-exo-trig manner. 

Mukaiyama et al. transformed the Co(II)-catalyzed hydrofunctionalizations (see Sect. 5.7) to intramolecular oxidative alkoxyl radical cyclizations by omission of the silane (Fig. 98). 4-Penten-l-ols 417 (R2=H) cyclized in the presence of 20 mol%... 

Fig. 98 Cobalt-catalyzed alkoxyl radical cyclization reactions...

Ni(0) catalyst. A radical 5-exo cyclization to the potentially zinc or nickel-complexed ketone provides an alkoxyl radical that combines with the co-produced Ni(I) species. A transmetalation to a zinc alkoxide regenerates the catalyst and forms the zinc cyclopentoxide, from which products 79 are liberated on hydrolysis. A bimetallic Cu(I)-Mn(II) system provided similar results (see Sect. 8.4). Analogous samarium diiodide-mediated reactions require in contrast stoichiometric amounts of the reducing agent and are less diastereoselective [26, 27],... 

Stereoselective syntheses of the tetrahydrofuran nucleus by alkoxyl radical cyclizations have been reviewed by Hartung <2001EJ0619>. Cyclizations of C-centered radicals are also freqently employed in the synthesis of tetrahydrofurans. In tandem radical cyclizations, high diastereoselectivities can be obtained. Hoffmann has shown that an a-silyl effect can be exploited to obtain enhanced diastereoselectivities in such reactions (Equation 94) <1997T8401>. A tra r-selective synthesis of 2,3-disubstituted tetrahydrofurans also makes use of a vinylsilane group <1994TL5837>. 

In contrast to intramolecular cyclizations, the intermolecular addition of O-centered radicals to ti systems as initiating step in complex radical cyclization cascades has only recently attracted considerable attention. The reason for the low number of papers published on O radical addition to alkenes and alkynes could originate from the perception that O-centered radicals, such as alkoxyl radicals, RO, or acyloxyl radicals, RC(0)0", may not react with 7t systems through addition at rates that are competitive to other pathways, for example, allylic hydrogen abstraction and p-fragmentation in the case of RO" or decarboxylation in the case of RC(0)0" (Scheme 2.9). 

A related reaction occurs on irradiation of a hypochlorite (Scheme 2). The alkoxyl radical can again abstract a hydrogen atom in a l,S-shift, and the final chloro alcohol can be cyclized to form a tetrahydro-furan. Some processes lead directly to the cyclic product For instance, an alcohol with an accessible 8-hydrogen can be directly converted to a tetrahydrofuran on refluxing with lead tetraacetate. In a related reaction, treatment of an alcohol with silver carbonate and bromine can lead to the cyclic ether by initial formation of a hypohalite. The cyclization occurs when the rearranged radical is converted to a cation, either by oxidation with Pb(OAc)4 or by silver-assisted loss of halide ion. Hypoiodites are also fiequent-ly used, generated in situ. ... 

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

Hartung, J. Stereoselective Contraction of the Tetrahydrofuran Nucleus by Alkoxyl Radical Cyclization, Eur. J. Org. Chem. 2001, 619-632. 

This presents an interesting analytical quandary. Epoxides are major products of lipid oxidation and derive from LO cyclization as well as LOO additions (see Section 3.2.2). Consequently, it may be difficult to determine the mechanism that is operative in a given reaction system, and indeed, both may contribute. For example, Hendry (283) reacted a series of ROO with their parent compounds at 60°C and found 40% of the products were epoxides. Rate constants of k = 20 to 1130 M sec were calculated assuming the reactions were aU additions, but at the elevated temperature of the study, hydrogen abstraction to form the hydroperoxides, followed by homolytic scission to alkoxyl radicals, could also have contributed to the yields. 

Propagation by Alkoxyl Radicals, LO Alkoxyl (LO ) radicals are responsible for propagation of the radical chain during the very rapid oxidation that ensues after the induction period ends. In the earliest stages of oxidation, LOO cyclization and addition reactions can proceed before LOOH formation via H abstraction, but LO can only be generated via LOOH decomposition, so their reactions become important as secondary events in oxidation. Nevertheless, because LO react faster than LOO by several orders of magnitude, LO becomes dominant almost as soon as LOOH breaks down. 

Cyclization of LO is stereospecific. The configuration of epoxides is fixed by the conformation of the fatty acid alkoxyl radical at the point of cyclization rather than postcyclization isomerization (319, 320). As with LOO, there is a stronger tendency for LO to cyclize from internal positions, probably due to the orientation of the -O relative to the bis-allylic hydrogens, and consequently, photosensitized oxidations yield high concentrations of cyclic products (321). The levels and positional distribution of these products are characteristic markers distinguishing auto-xidation from photosensitized oxidation. 

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