Arylations Using Aryl Radicals

This synthesis is only one example of a wide range of reactions which involve aryl (or alkyl) radical addition to electron-deficient double bonds resulting in reduction.The corresponding oxidative reaction using aryl radicals is the well known Meerwein reaction, which uses copper(II) salts. 

Homolytic cleavage of dlazonlum salts to produce aryl radicals is induced by titan1um(III) salt, which is also effective in reducing the a-carbonylalkyl radical adduct to olefins, telotnerization of methyl vinyl ketone, and dimerization of the adduct radicals. The reaction can be used with other electron-deficient olefins, but telomerization or dimerization are important side reactions. 

A number of methods are available for generating aryl radicals. They have been reviewed recently as has the evidence that the processes result in the generation of free aryl radicals, Those methods which have been used for the arylation of heterocyclic compounds are described here, and their applications to the arylation of specific heterocycles are discussed and tabulated in Section II,C,D and E. 

Modifications of this method, such as the use of the more stable diazonium trifluoroacetates and the decomposition of benzenedia-zonium zincichloride with zinc dust, have been used as sources of aryl radicals, although not in the arylation of heterocyclic compounds. Pyridine, quinoline, and thiophene can be phenylated by treatment with benzenediazonium chloride and aluminum trichloride. ... 

Free-radical arylation of heterocyclic compounds is a relatively inefficient process in which yields of particular products greater than 50% are rare. This is the inevitable result of the high reactivity and low selectivity of aryl radicals not only is it usual for the heterocyclic compound to be attacked at each of its available positions, but, as shown in preceding sections, other by-products are numerous. Nevertheless, the method often presents the only short route to a given compound and it has been widely applied. Preparative uses are grouped in this section under the heading of the heterocyclic system concerned. 

Fewer methods are available for the generation of alkyl than of aryl radicals and a number of these can only be used to produce methyl radicals. Methylation has been, therefore, the most commonly studied alkylation. 

Scaiano and Kim-Thuan (1983) searched without success for the electronic spectrum of the phenyl cation using laser techniques. Ambroz et al. (1980) photolysed solutions of three arenediazonium salts in a glass matrix of 3 M LiCl in 1 1 (v/v) water/acetone at 77 K. With 2,4,5-trimethoxybenzenediazonium hexafluorophos-phate Ambroz et al. observed two relatively weak absorption bands at 415 and 442 nm (no e-values given) and a reduction in the intensity of the 370 nm band of the diazonium ion. The absence of any ESR signals indicates that these new bands are not due to aryl radicals, but to the aryl cation in its triplet ground state. 

Packer and Richardson (1975) and Packer et al. (1980) made use of the fact that electrons can be generated in water by y-radiation from a 60Co source (Scheme 8-29) to induce a free radical chain reaction between diazonium ions and alcohols, aldehydes, or formate ion. It has to be emphasized that the radiolytically formed solvated electron in Scheme 8-29 is only a part of the initiation steps (Scheme 8-30) by which an aryl radical is formed. The aryl radical initiates the propagation steps shown in Scheme 8-31. Here the alcohol, aldehyde, or formate ion (RH2) is the reducing agent (i.e., the electron donor) for the main reaction. The process is a hydro-de-diazoniation. 

Stronger reducing agents than Cu1 can be used for reactions that are related to the classical Meerwein reaction. Tim salts not only catalyze the formation of aryl radicals from diazonium ions but, as shown by Citterio and Vismara (1980) and Cit-terio et al. (1982 a), in stoichiometric proportions they also reduce the primary aryl-ethane radical to the arylethyl anion, which is finally protonated by the solvent SH (Scheme 10-61). This method is the subject of a contribution to Organic Syntheses (Citterio, 1990), in which 4-(4 -chlorophenyl)buten-2-one is obtained in 65-75% yield from 4-chlorobenzenediazonium chloride and but-3-en-2-one. 

The C-Se and C-Te bonds are formed by an internal homolytic substitution of vinyl or aryl radicals at selenium or tellurium with the preparation of selenophenes and tellurophenes, respectively. An example is shown below, where (TMSIsSiH was used in the cyclization of vinyl iodide 65 that affords... 

Sulfur dioxide (see above) as well as S02, SO , and SOj have been used as building blocks in three-component sulfone syntheses. It has long been known that aromatic sulfinic acids are easily available from diazonium salts and sulfur dioxide under copper catalysis . Mechanistically, aryl radicals as reactive intermediates add to sulfur dioxide generating arenesulfonyl radicals, which either take up an electron (or hydrogen) yielding a sulfinic acid or add to an olefinic double bond yielding final y -halogenated alkyl aryl sulfones (equation 78). 

Meerwein Arylation Reactions. Aryl diazonium ions can also be used to form certain types of carbon-carbon bonds. The copper-catalyzed reaction of diazonium ions with conjugated alkenes results in arylation of the alkene, known as the Meerwein arylation reaction.114 The reaction sequence is initiated by reduction of the diazonium ion by Cu(I). The aryl radical adds to the alkene to give a new (3-aryl radical. The final step is a ligand transfer that takes place in the copper coordination sphere. An alternative course is oxidation-deprotonation, which gives a styrene derivative. 

In the classical procedure, base is added to a two-phase mixture of the aqueous diazonium salt and an excess of the aromatic that is to be substituted. Improved yields can be obtained by using polyethers or phase transfer catalysts with solid aryl diazonium tetrafluoroborate salts in an excess of the aromatic reactant.177 Another source of aryl radicals is A-nitrosoacetanilides, which rearrange to diazonium acetates and give rise to aryl radicals via diazo oxides.178... 

The exo and the endo ring closures (the kc reactions) are in competition with the aryl radical-tributyltin hydride transfer (the ks or ku reaction). These workers162 used this competition to determine the primary hydrogen-deuterium kinetic isotope effect in the hydride transfer reaction between the aryl radical and tributyltin hydride and deuteride. 

Recently, Curran described a procedure using triethylborane for the synthesis of spirooxindoles and spirodihydroquinolones through intramolecular addition of aryl radicals at the ipso position 4-alkoxy-substituted aromatic rings [15]. The key step for a formal synthesis of the vasopressin inhibitor SR121463A is described in Scheme 5. The initiation was performed with Et3B in an open to air reaction vessel. 

Note The pictorial term scrambling is used in mass spectrometry to describe rapid processes of (intramolecular) positional interchange of atoms. Scrambling may occur with hydrogens or may involve the complete carbon skeleton of an ion. Aryl radical ions and protonated aryl compounds are well known for their numerous scrambling processes. [54,55]... 

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