Fragmentation alkoxyl radicals

A sequential alkoxyl radical fragmentation-transannular radical cyclisation has been used in a new approach to the bicyclo-[5.3.0]decanone ring system,irradiation of the 8-decanol (125) in the presence of iodosylbenzene diacetate and iodine, for example, gave the substituted hydroazulenone (126) via the mono-cyclic radical (127). 

Rate constants for some alkoxyl radical fragmentations are shown in Fig. 9. The tcrt-butoxyl radical (26) fragmentation to acetone and the methyl radical has been studied for years, but the rate constant shown below is from a very recent work that employed time-resolved ESR methods [2]. The cumyloxyl radical (27) fragmentation was studied directly by LFP methods, taking advantage of the IR and UV absorbances of this radical [57]. The rate constants for the reversible ring opening of the cyclopentyloxyl radical (28) were determined by competition kinetics [58], and one should note that the kinetic values are at 80 °C. 

Alkoxyl radical cleavages have log A terms of about 13 as expected for fragmentation reactions. Increasing alkyl substitution, such that the product alkyl radicals are increasingly more stable, results in considerable kinetic accelerations [59]. One should note that the kinetics of alkoxyl radical fragmentations arc sensitive to... 

Interestingly, a cascade alkoxyl radical fragmentation-peroxidation-hydrogen abstraction reaction occurs in some cases when a hemiacetal is treated with DIB/I2 under oxygen pressure. This reaction may have interesting applications in synthetic organic chemistry. We have used it in a one-step synthesis of A and A rings of the tetranortriterpene limonene and related compounds (Eq. 19, Scheme 6) [48]. 

Alonso-Cmz, C.R. Kennedy, A.R. Rodriguez, M.S. Suarez, E. Alkoxyl radical fragmentation of 3-azido-2,3-dideoxy-2-halo-hexopyranoses a new entry to chiral poly-hydroxylated 2-azido-l-halo-l-alkenes. Tetrahedron Lett. 2007, 48, 7207. 

Oxaziranes derived from isobutyraldehyde react with ferrous salts to give only substituted formamides fEq. (23)], The chain propagating radical 30 thus suffers fission with elimination of the isopropyl group. An H-transfer would lead to substituted butyramides, which are not found. Here is seen a parallel to the fragmentation of alkoxyl radicals, where the elimination of an alkyl group is also favored over hydrogen. The formulation of the oxazirane fission by a radical mechanism is thus supported. 

Scheme 27 Trimethyl phosphite as alkoxyl radical scavenger to characterize C-0 vs C-C fragmentation for oxyranylcarbinyl radicals. Reprinted with permission from [64]. Copyright 2003 American Chemical Society...

The fragmentation of alkoxyl radicals is especially favorable because the formation of a carbonyl bond makes such reactions exothermic. Rearrangements of radicals frequently occur by a series of addition-fragmentation steps. The following two reactions involve radical rearrangements that proceed through addition-elimination sequences. 

Among the most useful radical fragmentation reactions from a synthetic point of view are decarboxylations and fragmentations of alkoxyl radicals. The use of (V-hydroxy-2-thiopyridine esters for decarboxylation is quite general. Several procedures and reagents are available for preparation of the esters,353 and the reaction conditions are compatible with many functional groups.354 f-Butyl mercaptan and thiophenol can serve as hydrogen atom donors. 

Interestingly, homolytic substitution at boron does not proceed with carbon centered radicals [8]. However, many different types of heteroatom centered radicals, for example alkoxyl radicals, react efficiently with the organoboranes (Scheme 2). This difference in reactivity is caused by the Lewis base character of the heteroatom centered radicals. Indeed, the first step of the homolytic substitution is the formation of a Lewis acid-Lewis base complex between the borane and the radical. This complex can then undergo a -fragmentation leading to the alkyl radical. This process is of particular interest for the development of radical chain reactions. 

Brown and Suzuki have shown that treatment of trialkylboranes with ethenyl-(Scheme 42, Eq. 42a) and ethynyloxiranes (Scheme 42, Eq. 42b) in the presence of a catalytic amount of oxygen, affords the corresponding allylic or allenic alcohols. The mechanism may involve the addition of alkyl radicals to the unsaturated system leading to l-(oxiranyl)alkyl and l-(oxiranyl)alkenyl radicals followed by rapid fragmentation to give alkoxyl radicals that finally complete the chain process by reacting with the trialkylborane [104-106]. 

Scheme 55, Eq. 55a) [119]. A plausible mechanism is depicted in Scheme 55 and involves radical addition of the 2-tetrahydrofuryl radical to the aldehyde followed by a rapid reaction of the alkoxyl radical with Et3B. Triethylborane has a crucial role since by reacting with the alkoxyl radical it favors the formation of the condensation product relative to the -fragmentation process (back reaction). A similar reaction with tertiary amines, amides and urea is also possible (Eq. 55b) [120]. 

For dissociative electron transfer, an analogous thermochemical cycle can be derived (Scheme 2). In this case the standard potential includes a contribution from the bond fragmentation. Using equations (40) and (41) one can derive another useful expression for BDFEab-, equation (42). While direct electrochemical measurements on solutions may provide b. b, for example, of phenoxides and thiophenoxides (Section 4), the corresponding values for alkoxyl radicals are not as easily determined. Consequently, these values must be determined from a more circuitous thermochemical cycle (Scheme 3), using equation (43). The values of E°h+/h io a number of common solvents are tabulated elsewhere. Values of pKa in organic solvents are available from different sources. " A comparison of some estimated E° values with those determined by convolution voltammetry can be found in Section 3. 

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-... 

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... 

Similarly, the p-fragmentation of tertiary alkoxyl radicals [reaction (2)] is a well-known process. Interestingly, this unimolecular decay is speeded up in a polar environment. For example, the decay of the ferf-butoxyl radical into acetone and a methyl radical proceeds in the gas phase at a rate of 103 s 1 (for kinetic details and quantum-mechanical calculations see Fittschen et al. 2000), increases with increasing solvent polarity (Walling and Wagner 1964), and in water it is faster than 106 s 1 (Gilbert et al. 1981 Table 7.2). 

Oxyl radicals are also formed upon the addition of-OH to sulfoxides. Like other tertiary alkoxyl radicals they undergo rapid fragmentation [reactions (9) and (10) Veltwisch et al. 1980]. 

In most peroxyl radical systems investigated so-far alkoxyl radicals play a certain, albeit often not dominating role [cf. reaction (49)]. As mentioned above and discussed in more detail in Chap. 7.2, primary and secondary alkoxyl radicals undergo in water rapid (k 106s ) 1,2-H-shift [reaction (51)]. In competition, P-fragmentation also occurs [reaction (60)]. 

The rate of this reaction (which is the main decay of tertiary alkoxyl radicals) is also strongly enhanced in water as compared to the gas phase and organic solvents. If different substituents can be cleaved off, it is the more highly-substituted one (weaker C-C bond) that is broken preferentially (Riichardt 1987). Thus in the case of secondary alkoxyl radicals, substitution in p-position also decides the ratio of 1,2-H-shift and -fragmentation (Schuchmann and von Sonntag 1982). Because of the fast 1,2-H-shift and p-fragmentation reactions in water, intermolecular H-abstraction reactions of alkoxyl radicals [reaction (61)] are usually inefficient, but intramolecular H-abstraction may occur quite readily if an H atom is in a favorable distance (e.g., six-membered transition state). 

When the alkoxyl radical and the hydrogen to be abstracted are not properly disposed for the Barton reaction, the reactions of the alkoxyl radical, for example -fragmentation, intramolecular addition to the double bond, disproportionation or a-hydrogen fission, and intermolecular hydrogen abstraction, compete with the Barton reaction or result in an exclusive reaction. Among these reactions, /l-frag-... 

Alkenes were cleaved to aldehydes by 5 mol% of a (salen VCl complex in the presence of air and thiophenols in 58-95% yield. Other V(III) and V(IV) catalysts are similarly effective. The reaction involves an initial thiyl radical addition to the olefin and trapping by oxygen. The resulting peroxyl radical is in turn most likely transformed to an alkoxyl radical by the catalyst and undergoes -fragmentation to form the most stable radical [198]. 

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