Halides, aryl, with active methylene compounds

The coupling of aryl halides with active methylene compounds, such as mal-onitriles and cyanoacetates, is of increasing interest due to its inherent difficulty and the interest of the resulting products as synthetic intermediates in the preparation of bio active [36,37], heterocyclic [38,39] or conducting compounds [40]. Bulky NHCs have been found to be excellent ligands in the coupling of aryl halides with malonitrile [41] in hot pyridine using NaH as base (Scheme 7). 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

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]. 

The first report on a palladium-catalyzed carbonylative C-H activation was published in 1986 by Kobayashi and Tanaka [1]. They reported that the carbonylation of organic halides with activated methylene compounds in the presence of NEta under 20 bar of CO produces various ketones in good yields (Scheme 6.1). Aryl iodides, bromobenzene and one example of a vinyl bromide were used as starting materials. But relatively high pressure and high pressure are needed, and tri-ethylamine was used both as a base and solvent. 

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. 

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... 

On the other hand, the direct arylation of carbanionic species generated from substrates having relatively acidic hydrogens such as active methylene compounds and ketones can occur (mechanism B) [5,6]. Aryl halides are also capable of coupling directly with appropriately functionalized aromatic substrates and five-membered heteroaromatic compounds as formal carbon nucleophiles via cleavage of their unactivated C-H bonds [5,7-9]. The Fujiwra-Moritani reaction, which is the arylation of alkenes with arenes, is also useful for preparing arylalkenes without employing any halides (mechanism D) [10,11]. 

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].

Abstract Although requiring the use of stoichiometric amounts of metal and harsh conditions, the copper-mediated coupling reactions of aryl halides with amines and phenols (Ullmann craidensatiOTis), amides and carbamates (Ullmann-Goldberg condensations), or activated methylene compounds (Ullmann-Hurtley condensations) have been for a long time useful methods for the formation of C(aryl)-N, C(aryl)-0, and C(aryl)-C bonds. In 2001, a renaissance of the Ullmann reaction has been initiated with the discovery of versatile new copper catalytic systems for C-C, C-N, or C-O coupling under mild temperature ccmditions. 

It is noted that the coupling of aryl halides, especially iodides, with a number of active methylene and methine compounds are promoted effectively by a stoichiometric amount of copper(I) halides [8, 37, 38]. The reaction using cy-anoacetate esters and 1,3-diketones can catalytically proceed [39-41]. 

As with malonate, the two strong electron-withdrawing functional groups of cyanoacetate significantly enhance the acidity of the methylene group. Accordingly, it can be readily deprotonated and the anion reacts with abroad spectrum of electrophiles, such as alkyl and activated aryl halides, carbonyl compounds, a,/3-unsaturated carbonyl or carboxyl derivatives, and nitrous acid. 

---