Arylation of active methylene compounds

Sonochemistry has been applied to acceleration of the Reformatsky reaction, Diels-Alder reactions, the arylation of active methylene compounds nucleophilic aromatic substitution of haloarenes, and to hydrostannation and tin hydride reduction. " Other sonochemical applications involve the reaction of benzyl chloride and nitrobenzene, a Sr I reaction in liquid ammonia at room temperature, and Knoevenagel condensation of aromatic aldehydes. lodination of aliphatic hydrocarbons can be accelerated, and oxyallyl cations have been prepared from ot,ot -diiodoketones using sonochemistry. Sonochemistry has been applied to the preparation of carbohydrate compounds.When sonochemistry is an important feature of a chemical reaction, this fact will be noted in the reactions presented in Chapters 10-19. 

The arylation of activated methylene compounds mediated by copper salts is a well-established process, dating back to the Hurtly reaction in 1929. In the following reports of this process, high yields were only obtained with aryl hahdes bearing electron-withdrawing groups or ortho-substituents that could be... 

Arylation of active methylene compounds has been carried out using Cu salts as promoters under severe conditions [2], Recently it was discovered that the reaction can be carried out much more smoothly using Pd catalysts. The first Pd-catalyzed intermolecular arylation of cyanoacetate and malononitrile with aryl iodides was carried out by Takahashi using PPhs as a ligand, and was applied to a simple synthesis of tetracyanoquinodimethane (2) by the reaction of p-diiodobenzene with malononitrile [3], The intramolecular arylation of malonates and -diketones with aryl iodides proceeds smoothly. Presence of a cyano group seemed to be important [4,5], The arylation has been successfully extended to halides of heterocycles, such as pyridine, quinoline and isoquinoline. The reaction of bromoxazole 3 with sulfone 4 is an example [6]. 

Classical Aldol. Aldol reaction is an important reaction for creating carbon-carbon bonds. The condensation reactions of active methylene compounds such as acetophenone or cyclohexanone with aryl aldehydes under basic or acidic conditions gave good yields of aldols along with the dehydration compounds in water.237 The presence of surfactants led mainly to the dehydration reactions. The most common solvents for aldol reactions are ethanol, aqueous ethanol, and water.238 The two-phase system, aqueous sodium hydroxide-ether, has been found to be excellent for the condensation reactions of reactive aliphatic aldehydes.239... 

Coupling of aryl bromides with diethyl sodiomalonate. CuBr is the most effective Cu(I) catalyst for effecting coupling of aryl iodides or bromides with the sodium salts of active methylene compounds such as diethyl sodiomalonate. Coupling is facilitated by ori/io-substituents in the halide, particularly nitro, carbomethoxy, and methoxy groups.1 This reaction has been adapted to synthesis of benzofurane-2-ones.2... 

Although arylation or alkenylation of active methylene compounds can be carried out using a Cu catalyst, the reaction is sluggish. However, the arylation of malononitrile (390) or cyanoacetate proceeds smoothly in the presence of a base and Pd catalysts [189], Tetracyanoquinodimethane (392) is prepared by the coupling of / -diiodoben-zene with malononitrile (390) to give 391, followed by oxidation [190], Presence of the cyano group seems to be essential for intermolecular reactions. However, the intramolecular arylation of malonates, / -keto esters and /i-diketones proceeds smoothly [191]. The bromoxazole 393 reacts with phenylsulphonylacetonitrile (394)... 

The use of C-H bonds is obviously one of the simplest and most straightforward methods in organic synthesis. From the synthetic point of view, the alkylation, alkenylation, arylation, and silylation of C-H bonds are regarded as practical tools since these reactions exhibit high selectivity, high efficiency, and are widely applicable, all of which are essential for practical organic synthesis. The hydroacylation of olefins provides unsymmetrical ketones, which are highly versatile synthetic intermediates. Transition-metal-catalyzed aldol and Michael addition reactions of active methylene compounds are now widely used for enantioselective and di-astereoselective C-C bond formation reactions under neutral conditions. 

Also reported is the reaction of a series of active methylene compounds with tetrachloropyrazine (83JHC365) and the arylation of chloropyrazines with acetanilides (83EUP96517). 

CuI/L-proUne (LI) was proved to be a quite efficient catalytic system for this coupling. The reaction proceeded smoothly in DMSO at 40-50°C in the presence of CS2CO3 (Table 9.14, entry 1) [67]. Both aryl iodides and bromides were suitable substrates. A wide range of activated methylene compounds, including ethyl ace-toacetate, ethyl benzoyl acetate, and diethyl malonate were compatible with these reaction conditions. This catalytic system could also be used for the arylation of aryl iodides with acetylacetone and ethyl cyanoacetate (entry 2) [68]. Recently, it was found that 2-picoUnic acid (L4) could lead to the arylation of aryl iodides and diethyl malonate worked at room temperature (entry 3) [69]. For hindered substrates or aryl bromides, higher reaction temperatures were still required. Additionally, Chxn-Py-Al (L16) was revealed to accelerate the Cul-catalyzed coupling of iodobenzene with diethyl malonate, ethyl cyanoacetate and malononitrile (entry 4) [26],... 

Figure 8.8 Types of ligands used for the Cul-catalyzed intermolecular and intramolecular a-arylation of activated methylene or methine compounds with aryl halides [114-116].

Just like the aryl azides 2, the vinyl azides 11 are more reactive in their cycloadditions with active methylene compounds than are alkyl azides. In 1970, Alfred Hassner et al. developed a general synthetic approach to 1-vinyl-1,2,3-triazoles 12 and 14, (Scheme 4.4) [6] by the cycloaddition of active methylene compounds 10 or 13 with vinyl azides 11 (or their precursors, the P-haloalkyl azides), in the presence of 1 equiv. of an alkoxide (NaOMe). Decarboxylation of the l- dnyl-5-substituted l,2,3-triazole-4-carboxylic acids 14 synthesized from the reaction of ethyl acetoacetate or ethyl benzoylacetate with vinyl and P-haloalkyl azides led to 1-vinyl-5-substituted 1,2,3-triazoles in almost quantitative yield [6]. 

Condensation of aryl halides with various active methylene compounds is readily promoted by catalytic action of palladium to give the corresponding arene derivatives containing a functionalized ethyl group [7]. Yamanaka et al. extended this chemistry to haloazoles including oxazoles, thiazoles and imidazoles [8]. Thus, in the presence of Pd(Ph3P)4,2-chlorooxazole was refluxed with phenylsulfonylacetonitrile and NaH to form 4,5-diphenyl-a-phenylsulfonyl-2-oxazoloacetonitrile, which existed predominantly as its enamine tautomer. In a similar fashion, 4-bromooxazole and 5-bromooxazole also were condensed with phenylsulfonylacetonitrile under the same conditions. 

The electrogenerated Mn(lll)-assisted coupling of various olefins with active methylene compounds proceeds by indirect electrooxidation with a small amount of Mn(OAc)2 in the presence or absence of Cu(OAc)2 [196]. The Mn(Ill)-assisted carboxymethylation of styrenes (142) affords y-aryl-y-lactones (143) in good current yields (Scheme 57) [194, 195, 206, 207], (Table 9). 

The base-catalyzed condensation of azides with activated methylene compounds is a well-established route to IJT-triazoles. In particular, it is the best route to triazoles bearing a 5-amino or hydroxy substituent and an aryl or carbonyl-containing function in the 4-position. The addition is regiospecific. The reaction is a stepwise one, since anomerism of glycosyl azides has been observed in their reaction with activated methylene compounds, indicating the presence of an intermediate. The mechanism can be envisaged as a nucleophilic attack by the car-banion on the terminal nitrogen of the azide, followed by cyclization to a... 

It is well established that metallic copper or copper salts efficiently catalyze N- and O-arylation reaction using pentavalent and trivalent organobismuth compounds [5-9, 24]. The C-arylation reaction of phenols and active methylene compounds using pentavalent organobismuth compounds are usually mediated by a base. However, in some cases, copper catalysts mediate C-arylation using pentavalent organobismuth compounds. 

Thermolysis of the thiadiazole (164) leads to elimination of isocyanate and sulfur giving the triazine derivative (167). If the thermolysis is carried out in the presence of phenols 2-aryl-benzimidazoles (168) are produced <85JCS(P1)1007>. The S—N bond of (157) is readily cleaved with both N- and C-nucleophiles. Thus, treatment of (157) with an excess of amine gives the sulfenamide (169) (Scheme 39) and reaction of (157) with active methylene compounds leads to derivatives of type (170) (Scheme 39) which on heating furnish (171). Cyanide ion inserts into the S—N bond of (164), probably via the intermediate (172) which immediately recyclizes to give the thiadiazinone (173) (Scheme 40) <85JCS(P1)1007>. 

Active methylene compounds have more than one activating group such as carbonyl, cyano, sulfonyl, or aryl bound to a methylene carbon. Bases such as hydroxide ion easily remove a proton to form a reactive carbanion. The most widely studied example is the alkylation of phenylacetonitrile (Scheme 1). The abstraction of the proton is generally the rate limiting step. 

The direct alkenylation of arylamines at the ortho position has been reported in reactions of o -chloroalkenylmagnesium chloride with N-lithioarylamines.22 Use of the CuI-L-proline catalyst system in DMSO has been found to be successful in promoting reactions of aryl iodides and bromides with activated methylene compounds, such as ethyl acetoacetate and diethyl malonate.23 The same catalyst in dioxane has been used in intramolecular cyclization of ene-carbamates leading to indoles or pyrrolo[2,3-cjpyridines.24... 

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