And Meerwein arylation

The reactant corresponding to retrosynthetic path b in Scheme 2.2 can be obtained by Meerwein arylation of vinyl acetate with o-nitrophcnyldiazonium ions[9], Retrosynthetic path c involves oxidation of a 2-(o-nitrophenyl)ethanol. This transformation has also been realized for 2-(o-aminophenyl)ethanols. For the latter reaction the best catalyst is Ru(PPhj)2Cl2. The reaction proceeds with evolution of hydrogen and has been shown to be applicable to a variety of ring-substituted 2-(o-aminophenyl)ethanols[10]. 

The arylation of alkenes by treatment with a diazonium chloride (or bromide) solution and cupric chloride (or bromide) is called the Meerwein arylation reaction, after its discoverer (Meerwein et al., 1939). Originally, it was discovered using a,P-unsaturated carbonyl compounds, namely coumarin (Scheme 10-43) and cinnamic derivatives (Schemes 10-44 and 10-45). As Scheme 10-45 shows, the Meerwein reac-... 

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. 

Doyle et al. (1977 c) and Oae et al. (1980) reported modified Meerwein arylations with significant improvements in the yield by the use of aryl amines and alkyl nitrites in place of arenediazonium salts. However, good yields are only achieved if alkenes activated by electron-withdrawing groups are present. 

Alkenes activated by an electron-withdrawing group (Z may be C=C, halogen, C=0, Ar, CN, etc.) can be arylated by treatment with a diazonium salt and a cupric chloride catalyst. This is called the Meerwein arylation reaction Addition of... 

The reaction gives better yield with dienes, styrenes, or alkenes substituted with EWGs than with simple alkenes. These groups increase the rate of capture of the aryl radical. The standard conditions for the Meerwein arylation employ aqueous solutions of diazonium ions. Conditions for in situ diazotization by f-butyl nitrite in the presence of CuCl2 and acrylonitrile or styrene are also effective.115... 

The Meerwein arylation is at least formally related to the atom transfer method because a net introduction of an aromatic ring and a chlorine across a double bond is accomplished (Scheme 62). Facile elimination of HC1 provides an efficient route to the kinds of substituted styrenes that are frequently prepared by Heck arylations. Standard protocol calls for the generation of an arene diazonium chloride in situ, followed by addition of an alkene (often electron deficient because aryl radicals are nucleophilic) and a catalytic quantity of copper(II) chloride. It is usually suggested that the copper salt operates in a catalytic redox cycle, reducing the diazonium salt to the aryl radical as Cu1 and trapping the adduct radical as Cu11. 

Mella, M., Coppo, P., Guizzardi, B., Fagnoni, M., Freccero, M. and Alhini, M. (2001) Photoinduced, ionic meerwein arylation of olefins. Journal of Organic Chemistry, 66, 6344—6352. 

In comparison to the cyclization reactions shown above, intermolecular Meerwein arylations are often more difficult to conduct. Since the aryl radical addition to the alkene is no longer favored by the close proximity of the reacting centers, the probability for a direct recombination of the aryl radical with scavengers Y is significantly increased (Scheme 17). To maintain the desired reaction course from 44 to 45 including steps (1) and (2) [89, 90], Meerwein arylations have for a long time mostly been conducted with activated alkenes, such as acrylates (R = COOR ), vinylketones (R = COR ), styrenes (R = Ph), or conjugated dienes [91,92]. These types of alkenes are known for fast addition of aryl radicals. 

Further new applications of the Meerwein arylation include the synthesis of benzothiophenes [94] and benzylmethyl ketones [95]. 

The ability of diazonium salts to act as radical scavengers for nucleophilic alkyl radicals was first discovered in mechanistic studies on the Meerwein arylation [96]. Shortly after, this concept was applied for the functionalization of a limited group of activated alkenes [97-99]. The much greater synthetic potential of this functionalization type, which arises from the successful use of non-activated alkenes as substrates, has recently been investigated. In a typical reaction, as illustrated in Scheme 19, the diazonium salt 48 acts as source for aryl radicals 49 and as radical scavenger [100]. 

In contrast to classical Meerwein arylations, non-activated alkenes are well suited for this reaction type for two reasons. First, due to the relatively slow formation of azo compounds by addition of aryl radical 49 to 48, this undesired pathway cannot compete successfully with the attack of 49 on the alkene to give radical adduct 50. Second, a nucleophilic alkyl radical 50 arises from the addition step, which is effectively trapped by electrophilic salt 48 to give azo compound 51. As a result of several improvements, the methodology is now applicable for a wide range of polar to non-polar alkenes with almost no restrictions on the substitution pattern of the diazonium salt [101, 102]. Moderate diastereoselectivities have been obtained in first attempts with chiral auxiliaries [103]. The azo compounds accessible, such as 51, can be converted to carboamination products 52 by hydrogenation and to various other heterocycles. 

Meerwein arylation. Detailed directions are given for diazolization of p-amino-acelophcnone with 48 % hydrobromic acid and aqueous sodium nitrite in acetone and Meerwein reaction of the diazonium sail in the presence of coppcr(l) bromide (Fisher, reagent grade, washed with acetone until the washings are colorless and dried) with acrylic acid to produce p-acetyl-a-bromohydrocinnamic acid. The yield of white needles, m.p. 159-160°, is, 56-.59 / . 

In the laboratory of R. Bihovsky, a series of peptide mimetic aldehyde inhibitors of calpain I was prepared in which the P2 and P3 amino acids were replaced with substituted 3,4-dihydro-1,2-benzothiazine-3-carboxylate-1,1-dioxides. The synthesis began with the diazotization of the substituted aniline substrate using sodium nitrite and hydrochloric acid. The aqueous solution of the corresponding diazonium chloride product was added dropwise to the solution of acrylonitrile in a water-acetone mixture, which contained catalytic amounts of copper(ll) chloride. This Meerwein arylation step afforded the chloronitrile derivative, which was subjected to sulfonation with chlorosulfonic acid, and the resulting sulfonyl chloride was treated with the solution of ammonia in dioxane to give the desired 3,4-dihydro-1,2-benzothiazine-2-carboxamide. 

The synthesis of the aglycone of the antibiotic giivocarcin-M was accompiished by T.C. McKenzie et ai. by a sequentiai Meerwein arylation-Diels-Alder cycloaddition.The anthraniiic methyi ester substrate was first subjected to diazotization and then the resuiting diazonium chioride was coupied to 2,6-dichiorobenzoquinone in water to afford the quinone product in moderate yieid. it is important to mention that the Meerwein arylation was conducted in water at 80 C in the absence of a cataiyst. 

Weis, C. D. Meerwein arylation reactions of olefins with anthraquinone diazonium hydrogen sulfates formation of new carbon bonds at the carbon atoms C-1 and at C-1,5 of the anthraquinone system. Dyes Pigm. 1988, 9, 1-20. 

Doyle, M. P., Siegfried, B., Elliott, R. C., Dellaria, J. F., Jr. Alkyl nitrite-metal halide deamination reactions. 3. Arylation of olefinic compounds in the deamination of arylamines by alkyl nitrites and copper(ll) halides. A convenient and effective variation of the Meerwein arylation reaction. J. Org. Chem. 1977, 42, 2431-2436. 

Cristol, S. J., All, M. B., Sankar, I. V. Photochemical transformations. 48. The nonconcertedness of nucleofuge loss and anti-aryl migration in photochemical Wagner-Meerwein rearrangements. J. Am. Chem. Soc. 1989, 111, 8207-8211. 

The Pd )-catalyzed reaction of aryl diazonium salts with mono-substituted alkenes [1] was found to be an interesting alternative to the well-known Pd - catalyzed arylhalide alkene coupling (Heck type reaction) or the copper mediated reaction of aryl diazonium salts with alkenes (Meerwein arylation) [2], The reaction can be run without isolation of the diazonium salt in presence of only 0.5 to 1 mol% of the Palladium catalyst in a one pot procedure, in high yield and under nuld conditions. The resulting styrene is reduced in a subsequent hydrogenation step with an in situ generated heterogeneous Pd-catalyst. The combination of three reaction steps without isolation of intermediates and the virtually complete recovery of the Pd-metal at the end of the reaction sequence makes this process [4] extremely efficient. 

Carbon-carbon bonds can be formed in very varied ways in reactions of diazonium compounds. For example, l-chloro-4-(/ -nitrophenyl)-2-butene (88% yield) is formed from diazotized / -nitroaniline and butadiene in aqueous acetone containing copper chloride and sodium acetate,787 whereas in the same conditions 5-phenyl-2,4-pentadienoic acid gives l-(/ -nitrophenyl)-4-phenyl-1,3-butadiene.788 The latter reaction is a special case of Meerwein arylation, by which stilbenes are formed in good yields from diazonium salts and cinnamic acids 789... 

The original synthesis of dantrolene by Snyder and co-workers (shown below) employed a Meerwein arylation to produce the corresponding 5-aryl-2-fliraldehyde intermediate. Condensation of this intermediate with 1-aminohydantoin under acidic conditions produced the target compound dantrolene. 

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