Radical substitution methods

Although a number of such radical reactions are known, few promise much synthetic potential, Examples include the 2-phenylation of imidazole and benzimidazole by benzoyl peroxide, but both products are more readily obtained by other routes. Homolytic alkylations of imidazole and benzimidazole also occur at C-2, but usually give indifferent yields [10]. A potentially useful reaction is the synthesis of 2- and 4-trifluoromethylimidazoles from imidazoles and photochemically generated trifluoromethyl radicals. 1-Substituted imidazoles are largely substituted at C-5 in these reactions benzimidazole reacts initially at the 4-position [11-14]. 

---

Above 170 °C the amidrazone ylide (36) decomposes with loss of triethylamine and concurrent cyclization to give an 85% yield of 2-phenylbenzimidazole (Scheme 19) (B-75M140800). Poorer yields ( 40%) are obtained when N-benzyl-o-nitroaniline is pyrolyzed in the presence of iron oxalate. No doubt this last reaction is similar in many respects to the reactions shown in Scheme 2. Both 2-phenyl-imidazoles and -benzimidazoles (as well as other 2-substituted analogues) can be obtained as a result of thermal rearrangement of the 1-substituted isomers (Section 4.07.1.2.2), by radical substitution methods (Section 4.07.1.7) or via the 2-lithio derivatives (Sections 4.07.1.6, 4.07.3.7). 

Qualitatively, the results shown in Tables IV and V indicate that the methyl radical, just as the phenyl radical, substitutes pyridine preferentially in the 2- and 4-positions. The absence of the 3-isomer in these reactions is probably a result of the method of analysis... 

Experimental data on the substitution reactions of free radicals with peroxides were analyzed by the IPM method [64]. The calculated parameters are collected in Table 6.27. The activation energies and the rate constants of radical substitution reactions calculated by the IPM method are presented in Table 6.28. 

The Baylis-Hillman reaction of TV-protected 3-substituted 4-formylazetidin-2-ones with methyl vinyl ketone has been used to prepare intermediates from which highly functionalised P-lactams fused to medium rings were obtained by radical, stereocontrolled methods <99CC1913>. 

Harrod-type catalytic dehydrocoupling method using early transition metal catalysts (see COMC II (1995), chapter Organopolysilanes, p 99, and earlier in this review, Section 3.11.4.1.3. (i)).69,75 Si-H bonds are susceptible to free radical attack, and use of this was made in the free radical substitution of 38 to prepare a number of oxy-functionalized polysilanes, as shown in Scheme 25.185,186... 

An attempt to combine electrochemical and micellar-catalytic methods is interesting from the point of view of the mechanism of anode nitration of 1,4-dimethoxybenzene with sodinm nitrite (Laurent et al. 1984). The reaction was performed in a mixture of water in the presence of 2% surface-active compounds of cationic, anionic, or neutral nature. It was established that 1,4-dimethoxy-2-nitrobenzene (the product) was formed only in the region of potentials corresponding to simultaneous electrooxidation of the substrate to the cation-radical and the nitrite ion to the nitrogen dioxide radical (1.5 V versus saturated calomel electrode). At potentials of oxidation of the sole nitrite ion (0.8 V), no nitration was observed. Consequently, radical substitution in the neutral substrate does not take place. Two feasible mechanisms remain for addition to the cation-radical form, as follows ... 

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

Aromatic substitution reactions are often complicated and multistep processes. A correlation, however, in many cases can be found between the charged attacking species and the electron density distribution in the molecule attacked during electrophilic and nucleoph c substitution. No such correlation is expected in radical substitution where the attacking particles are neutral, rather a correlation between the reactivities of separate bonds and a free valency index of the bond order. This allows the prediction of the most reactive bonds. Such an approach has been used by researchers who applied quantum calculations to estimate the reactivities of the isomeric thienothiophenes and to compare them with thiophene or naphthalene. " Until recently quantum methods for studying reactivities of aromatics and heteroaromatics were developed mainly in the r-electron approximation (see, for example, Streitwieser and Zahradnik ). The M orbitals of a sulfur atom were shown not to contribute substantially to calculations of dipole moments, polarographic reduction potentials, spin-density distribution, ... 

Chlorination of Alkanes. The most direct and economical method for the manufacture of chloromethanes is the thermal free-radical chlorination of methane.176 177 Whereas in the 1940s and 1950s photochlorination was practiced in some plants, thermal chlorination is the principal industrial process today. The product chloromethanes are important solvents and intermediates. Commercial operations perform thermal chlorination at about 400-450°C. Vapor-phase photochemical chlorination of methane may be accomplished at 50-60°C. Fast and effective removal of heat associated with thermally induced free-radical substitution is a crucial point. Inadequate heat control may lead to explosion attributed to the uncontrollable pyrolysis liberating free carbon and much heat ... 

Radical substitution plays a part in the thermal chemistry of aromatic compounds, but not in the photochemistry, except in so far as many radicals that attack aromatic compounds are generated by photochemical methods from other addends. The reason for this is that reactive radicals exist only in low concentrations, and electronically excited states similarly are formed only in low concentrations the rate of bimolecular reaction between two such reactive species is generally much lower than the rates of alternative processes such as attack of the radical on ground-state aromatic compounds. 

The major focus in this chapter will be on synthesis, with emphasis placed on more recent applications, particularly those where regiochemistry and stereochemistry are precisely controlled. The reader is referred to the earlier reviews for full mechanistic information and details of historic interest. Electrophilic addition of X—Y to an alkene, where X is the electrophile, gives products with functionality Y (3 to the heteroatom X. Further transformations of X and/or Y provide the basis for diverse synthetic applications. These transformations include replacement of Y by hydrogen, elimination to form a ir-bond (either including the carbon bonded to X or (3 to that carbon so that X is now in an allylic position), and nucleophilic or radical substitution. Representative examples of these synthetic methods will be given below. This chapter will include examples of heterocycles formed in one-pot reactions where the the initial alkene-electrophile adduct contains an electrophilic group that can react further. Examples of heterocycles formed in several steps from alkene-electrophile adducts will also be considered. Cases in which activation by an external electrophile directly results in addition of an internal heteroatom nucleophile are treated in Chapter 1.9 of this volume. 

In contrast to the highly specific ionic reactions of diamonoid hydrocarbons discussed above, free radical substitutions are much less selective. Thus, free radical reactions provide a method for the preparation of a greater number of the possible isomers of a given hydrocarbon than might be available by ionic processes. The complex product mixtures which result, however, are generally difficult to separate. Consequently, there are few examples of the synthesis of specific derivatives of diamonoid hydrocarbons by this method. 

Quinoline derivatives have been substituted by nucleosides <94JCS(P1)2931> and by ert-butyl groups <95JOC(60)5390> via radical substitution reactions. Palladium-catalyzed cross coupling method has been used to couple quinoline triflates with acetylene <95T(51)3737>. 4-Quinolones, in contrast to 2-quinolones, react with peroxodisulfate anions in aqueous base to form 3-hydroxyquinolines via the 3-sulfate ester <95JCR(S)164>. 

The benzylselenoaldehyde could be reduced using samarium(ll) iodide to the corresponding carbon radical. This underwent an intramolecular radical substitution affording the two anomers of deoxyseleno-D-ribopyranose 121 in quite a reasonable yield (Scheme 10) <2000T3995>. Other selenopyranoses such as 122 and 123 could also be prepared using this method. 

These free valence numbers in the S method run parallel to the self-polarizability from the M.O. description which has still to be discussed. A larger free valence therefore also means a smaller activation energy for (electrophilic) substitution and probably for radical substitution (p. 284). A high bond order runs parallel to a low bond localization energy of a tu electron pair in this bond and thus with a low activation energy for molecular addition and ozonization. 

The most remarkable feature of this method is that even acyclic enamines undergo reductive alkylation with good diastereoselectivity. The reaction of propiophenone enamines 31-33 with primary carbon-centered radicals substituted by different electron-... 

Free Radical Processes. Homolytic alkylation and arylation of pyridines has been studied extensively and reviewed (U ). The products are almost invariably mixtures of several Isomers depending on the nature of the pyridine substrate, the free radical (audits method of generation) and the type of medium in which the reaction is carried out. Tho gh early reports suggested 2-, and -substitution exclusively, more sensitive analytical techniques have shown the earlier claims to be erroneous 6ind studies into the various factors affecting product formation have been reported (1 6-62). 

Solubility differences of fatty acid salts In 1828, Gusserow introduced a method that lead salts or soaps of fatty acids in ether can be separated depending on the solubility differences. Saturated and unsaturated fatty acids form salts with metallic ions (e.g., Li) whose solubihties in water and organic solvents vary with the nature of the metallic ion and the chain length, degree of unsaturation, and other characteristics of the acid radicals. Substitution of ethanol for diethyl ether (113) allows better separation. 

A disadvantage of traditional acrylamide polymerization reactions is the heterogeneity of the products that result. A radical polymerization method that produces polymers of similar structure but that are much more homogeneous is atom-transfer radical polymerization (ATRP) [155,156]. ATRP has been used to synthesize carbohydrate-substituted polymers with low polydispersities [157,158,159,160,161]. Materials that display sugar residues such as glu-cofuranose [160], glucopyranose [161], and A-acetyl-D-glucosamines [159]. 

A new and general method of substitution at aromatic carbon has been uncovered. Reactions involve electron transfer steps and the formation of radical anion and radical intermediates. Many of the transformations are unprecedented in aromatic chemistry they represent major, new sequences which will have considerable value in syntheses. The radical anion method of substitution at aromatic carbon was first reported by Kim and Bunnett in 1970.96,97) The method is related to radical-anion substitution at aliphatic carbon.98, ")... 

The phenylation of pyridazine and quinoxaline has been carried out using dibenzoyl peroxide, iV-nitrosoacetanilide, and benzenedia-zonium hydroxide as the sources of phenyl radical, the first two methods giving very much better yields than the third.63 The most reactive positions in these ring systems are the 4-position in pyridazine and the 2-position in quinoxaline. Phthalazine has been phenylated with iV-nitrosoacetanilide, giving a low yield of 5-phenylphthalazine, but the main product from cinnoline in this reaction was 4,4 -bicin-nolyl, although a small quantity of 4-phenylcinnoline was obtained.63 Pyrimidine has been arylated only with the 4-nitrophenyl radical, substitution occurring at the 2- and 4-positions.12... 

Many rDA reactions are carried out at temperatures of 150 °C or more in solution phase and often at temperatures of 400-600 °C using the flash vapor pyrolysis (FVP) method individual conditions are referenced throughout the text. However, an accelerating effect by anionic, cationic and radical substitution on either the dienophile or at the termini of the diene fragments has been predicted by Carpenter. Experimentally, this prediction has been substantiated only for anionic substitution. In 1%7, Hart reported what is likely the first example of an oxyanion-accelerated rDA reaction. Both oxyanionic " and car-banionic - substituents accelerate the cycloreversion reaction such that they proceed rapidly at room temperature (for example, equation 3). In addition, acid-catalyzed rDA reactions have been reported in which protonation effectively makes the dienophile fragment of the adduct more electron deficient. - Grieco has utilized a room temperature retro aza DA reaction useful for the V-methylation of dipeptides and amino acid derivatives (equation 4). "... 

---