Meerwein reactions

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. 

Replacement of the Diazonio Group by Alkenes and Alkynes The Meerwein Reaction... 

More recently, Beckwith demonstrated that intramolecular Meerwein reactions are also possible if one uses an arenediazonium salt with an aliphatic side-chain in the ortho position containing a double or triple CC bond in 8-position. We will discuss them in Section 10.11. 

The Meerwein reaction is a valuable method for the arylation of alkenes because of the easy availability of cheap aromatic amines and compounds containing double bonds. A disadvantage is that the yield is often low (normally 20-50%, in exceptional cases reaching 80%, see Table 10-3). The reaction can be carried out in water if the alkene derivative is sufficiently soluble otherwise an organic co-solvent is necessary. Meerwein et al. (1939) used acetone, which is still the most popular solvent used today. The mechanistic function of acetone will be discussed later in this section. 

As shown in Schemes 10-44 and 10-45, two products may be formed in a Meerwein reaction Scheme 10-44 shows a simple aryl-de-hydrogenation of cinnamic aldehyde, whereas Scheme 10-45 shows an aryl-de-hydrogenation combined with the addition of HC1 to the double bond of the methyl ester of cinnamic acid. No systematic studies have been made as to which of the two products will be formed in a given reaction, what experimental conditions will favor one or the other product, and what substituents or other structural characteristics of the alkene influence the ratio of the two types of product. The addition product can, in most cases, easily be converted... 

Table 10-3. Representative examples of products and yields in Meerwein reactions of ethene and some of its derivatives.

Butadienes are arylated in the 1-position and add the chlorine in the 4-position, thus yielding 2-butene derivatives. The double bond in 2-butene is much less reactive than those in 1,3-butadiene, and therefore the latter does not form diarylbutane derivatives when more than one equivalent of the diazonium salt is present. An extensive study of the effects of reaction conditions on Meerwein reactions with butadiene was made by Dombrovskii and Ganushchak (1961). 

Meerwein reactions can conveniently be used for syntheses of intermediates which can be cyclized to heterocyclic compounds, if an appropriate heteroatom substituent is present in the 2-position of the aniline derivative used for diazotization. For instance, Raucher and Koolpe (1983) described an elegant method for the synthesis of a variety of substituted indoles via the Meerwein arylation of vinyl acetate, vinyl bromide, or 2-acetoxy-l-alkenes with arenediazonium salts derived from 2-nitroani-line (Scheme 10-46). In the Meerwein reaction one obtains a mixture of the usual arylation/HCl-addition product (10.9) and the carbonyl compound 10.10, i. e., the product of hydrolysis of 10.9. For the subsequent reductive cyclization to the indole (10.11) the mixture of 10.9 and 10.10 can be treated with any of a variety of reducing agents, preferably Fe/HOAc. 

Alkynes can also be arylated by the Meerwein procedure, as shown by Muller in 1949. The reaction of buta-l-en-3-yne (Scheme 10-47) was studied by Kheruze and Petrov (1960). Arylation at an sp2-hybridized carbon is obviously considerably faster than the analogous reaction at an sp-hybridized carbon. A mechanistically interesting case of a Meerwein reaction with phenylacetylene will be discussed later in this section. 

Enolizable compounds can be used for Meerwein reactions provided that the keto-enol equilibrium is not too far on the side of the ketone for example, P-dicar-bonyl compounds such as acetylacetone are suitable (Citterio and Ferrario, 1983). The arylation of enol esters or ethers (10.12) affords a convenient route for arylating aldehydes and ketones at the a-carbon atom (Scheme 10-48). Silyl enol ethers [10.12, R = Si(CH3)3] can be used instead of enol ethers (Sakakura et al., 1985). The reaction is carried out in pyridine. 

Another arylation reaction which uses arenediazonium salts as reagents and is catalyzed by copper should be discussed in this section on Meerwein reactions. It is the Beech reaction (Scheme 10-49) in which ketoximes such as formaldoxime (10.13, R=H), acetaldoxime (10.13, R=CH3), and other ketoximes with aliphatic residues R are arylated (Beech, 1954). The primary products are arylated oximes (10.14) yielding a-arylated aldehydes (10.15, R=H) or ketones (10.15, R=alkyl). Obviously the C=N group of these oximes reacts like a C = C group in classical Meerwein reactions. It is interesting that the addition of some sodium sulfite is necessary for the Beech reaction (0.1 to 0.2 equivalent of CuS04 and 0.03 equivalent of Na2S03). 

Diazotization of amines for Meerwein reactions is almost always carried out using an aqueous solution of HC1. Meerwein et al. observed in their pioneering investigation of 1939 that the use of sulfuric or nitric acid for diazotization failed. 

Table 10-4. Yields of Meerwein reactions with 4-Y — C6H4NJX (Ganushchak et al., 1973).

Some observations are important for improvement of the yield and for the elucidation of the mechanism of the Meerwein reaction. Catalysts are necessary for the process. Cupric chloride is used in almost all cases. The best arylation yields are obtained with low CuCl2 concentrations (Dickerman et al., 1969). One effect of CuCl2 was detected by Meerwein et al. (1939) in their work in water-acetone systems. They found that in solutions of arenediazonium chloride and sodium acetate in aqueous acetone, but in the absence of an alkene, the amount of chloroacetone formed was only one-third of that obtained in the presence of CuCl2. They concluded that chloroacetone is formed according to Scheme 10-50. The formation of chloroacetone with CuCl2 in the absence of a diazonium salt (Scheme 10-51) was investigated by Kochi (1955 a, 1955 b). Some Cu11 ion is reduced by acetone to Cu1 ion, which provides the electron for the transfer to the diazonium ion (see below). 

In this context two observations reported by Rondestvedt (1960, p. 214) should be mentioned (i) Meerwein reactions proceed faster in the presence of small amounts of nitrite ion. Meerwein reactions in which N2 evolution ceased before completion of the reaction can be reinitiated by addition of some NaN02. (ii) Optimal acidity for Meerwein reactions is usually between pH 3 and 4, but lower (pH — 1) with very active diazonium compounds such as the 4-nitrobenzenediazonium ion or the diphenyl-4,4 -bisdiazonium ion. At higher acidities more chloro-de-diazoniation products are formed (Sandmeyer reaction) and in less acidic solutions (pH 6) more diazo tars are formed. 

Preparative aspects of the Meerwein reactions are treated in comprehensive reviews by Rondestvedt (1960, 1976) and by Engel (1990, Table 107). It is interesting to note in the 1976 review that about two-thirds of all papers published between 1955 and 1974 originated from the Soviet Union. Only two examples of Meerwein reactions were published in Organic Syntheses (Reynolds and VanAllen, 1963 a Ropp and Coyner, 1963). The Meerwein reaction was extensively reviewed by Dombrovskii (1984) and by Saunders and Allen (1985, p. 594). 

The reviews by Rondestvedt (1960, 1976) are outdated so far as the mechanism of the Meerwein reaction is concerned. This statement is substantiated by Rondestvedt s own comment in his 1976 review (p. 226) in which he states that the generally accepted mechanism involves the aryl radical. .., though the manner of its formation and its subsequent reaction are still controversial . Meerwein et al., in their original paper (1939), expressed the opinion that the reaction is ionic in nature. A radical mechanism was first proposed by Koelsch in 1943 (see also Koelsch and Bockelheide, 1944). He received immediate support from Bergmann et al. (1944) and Bergmann and Weizmann (1944), in spite of the fact that Koelsch s claim was based on rather uncertain and vague arguments. 

The chain process of the Meerwein reaction can be visualized as shown in Scheme 10-57. There are at least two likely termination reactions for the chain process, namely the addition of a chlorine atom from CuCl2 to the aryl radical (Scheme 10-58) or reaction of the aryl radical with a hydrogen atom of acetone, followed by the formation of chloroacetone (Scheme 10-59). 

Kochi (1956a, 1956b) and Dickerman et al. (1958, 1959) studied the kinetics of the Meerwein reaction of arenediazonium salts with acrylonitrile, styrene, and other alkenes, based on initial studies on the Sandmeyer reaction. The reactions were found to be first-order in diazonium ion and in cuprous ion. The relative rates of the addition to four alkenes (acrylonitrile, styrene, methyl acrylate, and methyl methacrylate) vary by a factor of only 1.55 (Dickerman et al., 1959). This result indicates that the aryl radical has a low selectivity. The kinetic data are consistent with the mechanism of Schemes 10-52 to 10-56, 10-58 and 10-59. This mechanism was strongly corroborated by Galli s work on the Sandmeyer reaction more than twenty years later (1981-89). 

Thus the Meerwein reaction is a homologation of the Sandmeyer reaction. The arylethane radical 10.17 is a homologue of the aryl radical in the Sandmeyer reaction. 

A remarkable case of a Meerwein reaction of phenylacetylene was reported by Leardini et al. (1985) in a new synthetic route to benzothiophene derivatives. Aryldi-azonium salts with a thioether group in the 2-position add phenylacetylene and substituted phenylacetylenes in the presence of metallic copper or iodide ion in acetone, or of FeS04 in DMSO (Scheme 10-60). The radical 10.21 formed initially is attacked intramolecularly by the sulfur atom of the thioether group to give the benzothiophene 10.22 in high yields (55-95%) as shown in (Scheme 10-60). Lear-... 

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. 

With Pd(dba)2 in acetone/dichloromethane (1 1) and ethene (6-8 atm), styrene is formed from benzenediazonium tetrafluoroborate in 51% yield with seven substituted benzenediazonium salts the yields were 62-75%, but very small yields were obtained with the 2,4,6-trimethyl and the 2- and 4-nitro derivatives (Kikukawa et al., 1979). The two nitrodiazonium salts are good substrates in the Meerwein reaction... 

There are some reactions in which an aryl radical reacts with an sp2-carbon atom of an aliphatic side chain. In such reactions a carbo- or heteroalicyclic ring fused with a benzene ring is formed (Scheme 10-80). They may be called intramolecular Meerwein reactions. Techniques for these syntheses were developed by Beckwith s group in the 1980s. The majority of Beckwith s investigations were made with 2-(2 -propenyloxy)- and 2[(2 -methyl-2 -propenyl)oxy]benzenediazonium tetrafluoro-... 

Photochemical arylations of ethene derivatives by arenediazonium salts, i.e., photo-Meerwein reactions, were carried out by Becker and Israel (1975), but were not studied or applied later. 

Telomers, in Meerwein reactions 248 Tetrahydropyridazines 129 Tetraphenylborates, in phase transfer catalysis of azo coupling reactions 378 f. 

Meerwein reaction, preparation of p-acety1-a-bromohydro-cinnamic acid, 51, 1 Mercuric acetate, 54, 71 reaction with cyclooctatetra- / ene, 50, 24... 

By single electron transfer from an electron donor, e.g. a transition metal ion, a trivalent phosphorous derivative or a base, followed by dissociation of the intermediate diazenyl radical in an aryl radical and dinitrogen. The aryl radical reacts with the solvent or with added reagents in various ways, as shown by the relatively large number of classical named reactions (Sandmeyer, Pschorr, Gomberg-Bachmann, Meerwein reactions). 

In this section we include the intramolecular arylation of the Pschorr type, the inter-molecular arylation (Gomberg-Bachmann reaction), the arylation of alkenes and alkynes (Meerwein reaction) and related processes. 

The arylation of alkenes was discovered by Meerwein146 in 1939 using ,/)-unsaturated carbonyl compounds, namely coumarin and cinnamic derivatives. Diazotizations for Meerwein reactions are made in aqueous HC1. The substitution proper may be combined with addition of HC1 to the double bond. As catalyst, CuCl2 is used. Various observations (see elsewhere7k) demonstrate that in typical Meerwein systems, part of Cu11 is reduced to Cu1. 

Another new catalyst was described by Leardini and coworkers158, namely FeSC>4 in DMSO. It was applied to a Meerwein reaction of phenylethyne and substituted phenylethynes with arenediazonium salts containing a thioether group in the 2-position. 

Meerwein reaction consists of condensation of ethylenic compounds with aryldiazonium salts in the presence of cupric and cuprous salts ... 

Ganushchak et al. (1972, 1984) proposed to perform the Meerwein chloroarylation of ethylenic compounds using the preliminarily prepared aryldiazonium tetrachlorocuprates. They found that methyl, ethyl, butyl acrylate, methyl methacrylate, and acrylonitrile in the polar solvent reacted with tetrachlorocuprate. Chloroarylation products were obtained with better yields than when using the traditional Meerwein reaction conditions. 

There are reasons to explain the catalytic activity of copper(ll) in terms of cation-radical mechanism. This mechanism is confirmed by the unusual direction of Meerwein reaction in some cases, for example, when the replacement of halogen by an aryl radical occurs in the reaction of halo-styrenes with aryldiazonium salts (Obushak et al. 1991). A cation-radical in the system [olefin-Cu(II)] has been detected by UV spectroscopy (Obushak et al. 1991). In the cases of cis isomers of benzylidenacetone (Allard and Levisalles 1972) and maleic esters (Isaev et al. 1972), the unreacted... 

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