Alkyl radicals, sources

Benzoxazinones 141 and 143 have been reacted in a reductive radical alkylation using triethylborane as the alkyl radical source <2004SL2597>. Triethylborane could also be used in catalytic amount with isopropyl, tert-h xVj, or cyclohexyl iodide as the alkylating agent. Zinc with copper iodide could also he used as initiator (Scheme 8). 

TEMPO can also be introduced by the use of alkoxyamines. These compounds are readily prepared by decomposing an alkyl radical source such as AIBN in the presence of a nitroxide ... 

In the case of alkyl radicals [e.g., methyl radical (197, 198) and cyclohexyl radical (198)], their nucleophilic behaviour enhances the reactivity of the 2-position. Here it is necessary to have full protonation of the nitrogen atom and to use specific solvents and radical sources. 

This ladical-geneiating reaction has been used in synthetic apphcations, eg, aioyloxylation of olefins and aromatics, oxidation of alcohols to aldehydes, etc (52,187). Only alkyl radicals, R-, are produced from aliphatic diacyl peroxides, since decarboxylation occurs during or very shortiy after oxygen—oxygen bond scission in the transition state (187,188,199). For example, diacetyl peroxide is well known as a source of methyl radicals (206). 

Diacyl peroxides are sources of alkyl radicals because the carboxyl radicals that are intitially formed lose CO2 very rapidly. In the case of aroyl peroxides, products may be derived from the carboxyl radical or the radical formed by decarboxylation. The decomposition of peroxides can also be accomplished by photochemical excitation. 

Alkyl hydroperoxides give alkoxy radicals and the hydroxyl radical. r-Butyl hydroperoxide is often used as a radical source. Detailed studies on the mechanism of the decomposition indicate that it is a more complicated process than simple unimolecular decomposition. The alkyl hydroperoxides are also sometimes used in conjunction with a transition-metal salt. Under these conditions, an alkoxy radical is produced, but the hydroxyl portion appears as hydroxide ion as the result of one-electron reduction by the metal ion. ... 

In more recent studies, the Barton group has shown that 0-acyl thiohydroxamates (thiohydroxamate esters) are convenient sources of alkyl radicals.490,51,52 Barton s thiohydroxamate ester chemistry is mild and easily executed, and the intermediate organic radicals are amenable to a wide variety of useful transformations. A thiohydroxamate ester of the type 125 (see Scheme 23) can be formed... 

Dialkyldiazenes (15, R—alkyl) are sources of alkyl radicals. While there is dear evidence for the transient existence of diazcnyl radicals (17 Scheme 3.18) during the decomposition of certain unsymmetrieal diazenes49 51 and of cis-diazenes,54 all isolable products formed in thermolysis or photolysis of dialkyldiazenes (15) are attributable to the reactions of alkyl radicals. 

Diacyl or diaroy] peroxides (36, R- alkyl or aryl respectively) are given specific coverage in reviews by Fujimori,141 Bouillion et c//.,14 and Hiatt.14j They are sources of acyloxy radicals which in turn are sources of aryl or alkyl radicals. Commercially available peroxides of this type include dibenzoyl peroxide (BPO), didodecanoyl or dilauroyl peroxide (LPO), didecanoyl peroxide (42) and succinic acid peroxide (43). 

In 1988 a paper by Zard and coworkers4(, reported that xanlhates were a convenient source of alkyl radicals by reversible addition-fragmentation and used the chemistry for the synthesis of a monoadduct to monomer (a maleimide). Many applications of the chemistry in organic synthesis have now been described in papers and reviews by the Zard group.406 407... 

A completely different method of synthesis of azo compounds from diazonium salts involving radical intermediates was found by Citterio et al. (1980, 1982 c), Cit-terio and Minisci (1982), and Fontana et al. (1988). It is a new general synthesis of arylazoalkanes based on the addition of an alkyl radical to an arenediazonium ion followed by reduction of the intermediate azo radical cation adduct by a metal salt (Scheme 12-80). The preferred source for the alkyl radical R in this reaction is an alkyl iodide, which gives rise to alkyl radicals cleanly in the presence of an arenediazonium salt and a Ti3+ or Fe2+ salt as in Scheme 12-81. The overall stoichiometric equation is therefore as given in Scheme 12-82. The yields vary between 36% and 79% (with respect to alkyl iodide). 

Allylic stannanes are an important class of compounds that undergo substitution reactions with alkyl radicals. The chain is propagated by elimination of the trialkyl -stannyl radical.315 The radical source must have some functional group that can be abstracted by trialkylstannyl radicals. In addition to halides, both thiono esters316 and selenides317 are reactive. 

Scheme 10.17 illustrates allylation by reaction of radical intermediates with allyl stannanes. The first entry uses a carbohydrate-derived xanthate as the radical source. The addition in this case is highly stereoselective because the shape of the bicyclic ring system provides a steric bias. In Entry 2, a primary phenylthiocar-bonate ester is used as the radical source. In Entry 3, the allyl group is introduced at a rather congested carbon. The reaction is completely stereoselective, presumably because of steric features of the tricyclic system. In Entry 4, a primary selenide serves as the radical source. Entry 5 involves a tandem alkylation-allylation with triethylboron generating the ethyl radical that initiates the reaction. This reaction was done in the presence of a Lewis acid, but lanthanide salts also give good results. 

Because reductive cleavage of aliphatic nitro compounds with Bu3SnH proceeds via alkyl radicals, nitro compounds are also used as precursors to alkyl radicals. Reactions using nitro compounds may have some advantages over other ones, since aliphatic nitro compounds are available from various sources. For example, the sequence of the Michael additions of nitro compounds provides an excellent method for the construction of quaternary carbon compounds (Eq. 7.79).126 Newkome has used this strategy for the construction of dendritic polymers (Eq. 7.80).127... 

MnP is the most commonly widespread of the class II peroxidases [72, 73], It catalyzes a PLC -dependent oxidation of Mn2+ to Mn3+. The catalytic cycle is initiated by binding of H2O2 or an organic peroxide to the native ferric enzyme and formation of an iron-peroxide complex the Mn3+ ions finally produced after subsequent electron transfers are stabilized via chelation with organic acids like oxalate, malonate, malate, tartrate or lactate [74], The chelates of Mn3+ with carboxylic acids cause one-electron oxidation of various substrates thus, chelates and carboxylic acids can react with each other to form alkyl radicals, which after several reactions result in the production of other radicals. These final radicals are the source of autocataly tic ally produced peroxides and are used by MnP in the absence of H2O2. The versatile oxidative capacity of MnP is apparently due to the chelated Mn3+ ions, which act as diffusible redox-mediator and attacking, non-specifically, phenolic compounds such as biopolymers, milled wood, humic substances and several xenobiotics [72, 75, 76]. 

I. Addition of C-Radicals to Nitrones Recently (525), the addition of alkyl radicals to chiral nitrones as a new method of asymmetrical synthesis of a-amino acids has been described. Addition of ethyl radicals to glycosyl nitrone (286) using Et3B as a source of ethyl radicals appears to proceed with a high stereo-control rate. 

Lastly, we show in Scheme 18.2 what would be two logical reaction products of the alkyl radical which is produced. The hydrogen abstraction was already proposed [11, 25] by others on the basis of spectroscopic evidence for an aldehyde but it has not been confirmed that the species was an aliphatic aldehyde being produced as opposed to an aromatic one and so is ambiguous. Hydrolysis of the top product of this section of the scheme would produce formic acid, which has been reported [11], However, more reasonable sources of formic acid exist in Schemes 18.3 and 18.4 (see below). The other product that one would expect to see would result in trimellitic acid being observed in the hydrolysate of the degraded polyester. This has, to our knowledge, not been reported as yet. 

Homolytic alkylation of homocyclic aromatic substrates is of much less interest than homolytic arylation because, in addition to the low selectivity, which also characterizes arylation, yields are usually poor, due to side reactions which compete seriously with the simple substitution reaction. The behavior of nonprotonated heteroaromatic substrates is similar. The case is quite different with protonated heteroaromatic bases because side reactions are eliminated or minimized, yields are generally good, and, above all, the selectivity is very high. Moreover, very versatile and easily available sources of alkyl radicals can be used under simple experimental condition it follows that homolytic alkylation of protonated heteroaromatic bases can be considered one of the main reactions of this class of compounds. 

The oxidative decarboxylation of carboxylic acids is the most convenient source for the alkylation of protonated heteroaromatic bases owing to their easy availability and the high versatility of the reaction, which permits methyl, primary, secondary, and tertiary alkyl radicals to be obtained under very simple experimental conditions. The following methods have been utilized. 

Heterocyclic compound Alkyl radical Radical source Method (Section II, B) Position of substitution (%) Yield (%) Ref. ... 

Kinetics and Photochemical Processes The mechanism of alkylation is closely connected with the source of the alkyl radicals. The first two steps generally involve the formation of alkyl radicals [Eq. (13)] and their addition to the heteroaromatic ring [Eq. (14)]. 

The usual sources used for the homolytic aromatic arylation have been utilized also in the heterocyclic series. They are essentially azo- and diazocompounds, aroyl peroxides, and sometimes pyrolysis and photolysis of a variety of aryl derivatives. Most of these radical sources have been described in the previous review concerning this subject, and in other reviews concerning the general aspects of homolytic aromatic arylation. A new source of aryl radicals is the silver-catalyzed decarboxylation of carboxylic acids by peroxydisulfate, which allows to work in aqueous solution of protonated heteroaromatic bases, as for the alkyl radicals. 

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